TW202542116A - Further substituted imidazoles as inhibitors of nav1.8 - Google Patents
Further substituted imidazoles as inhibitors of nav1.8Info
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本發明係關於根據通式(I)之化合物，其用作NaV1.8抑制劑且可用於治療疼痛。This invention relates to compounds according to general formula (I), It is used as a NaV 1.8 inhibitor and can be used to treat pain.
正常的痛覺(傷痛覺)主要用作一種生存機制，係身體之自我保護方式，從而警惕有害刺激造成的(進一步)組織損傷及疾病。例如，當外部環境(溫度、壓力、化學物質)激活皮膚內之模態特異性受體(傷痛覺受器)及離子通道時，可出現急性疼痛。疼痛信號傳導神經元之周圍末端(其細胞體存在於背根神經節[DRG]及三叉神經節[TG]中)將外部刺激轉化為電化學產生器電位。特定的電壓閘控鈉通道 (NaV)整合且放大此等產生器信號，直至達到動作電位[AP]之閾值。因此，在周圍開始的有害刺激最終會導致動作電位放電，並向中樞神經系統行進，首先在脊髓中之神經元上形成突觸且接著向大腦行進。NaV亦用於支持動作電位向脊髓內之中樞末端傳播。在沿著體感路徑行進結束時，動作電位信號被腦部解釋為疼痛(Lumpkin及Caterina, Nature (2007), 第445卷 第858-865頁；以及Crawford及Caterina Toxicologic Pathology (2020) 48(1)-174；Goodwin G及McMahon S.B. Nature Reviews Neuroscience (2021) 第22卷 第263-274頁；Bennett D.L.等人 Physiol Rev 99 (2019) 第99卷 第1079-1151頁)。Normal pain sensation (or pain sensation) primarily functions as a survival mechanism, a self-protective measure of the body, alerting it to further tissue damage and disease caused by harmful stimuli. For example, acute pain can occur when external environmental factors (temperature, pressure, chemicals) activate modality-specific receptors (pain receptors) and ion channels in the skin. The peripheral terminals of pain signaling neurons (whose cell bodies are located in the dorsal root ganglia [DRG] and trigeminal ganglia [TG]) convert external stimuli into electrochemical generator potentials. Specific voltage-gated sodium channels ( NaV ) integrate and amplify these generator signals until the action potential [AP] threshold is reached. Therefore, harmful stimuli that begin in the surrounding environment eventually lead to the discharge of action potentials, which travel to the central nervous system, first forming synapses on neurons in the spinal cord and then proceeding to the brain. NaV also plays a role in supporting the propagation of action potentials to the central terminals within the spinal cord. At the end of the journey along the somatosensory pathway, the action potential signal is interpreted by the brain as pain (Lumpkin and Caterina, Nature (2007), Vol. 445, pp. 858-865; and Crawford and Caterina Toxicologic Pathology (2020) 48(1)-174; Goodwin G and McMahon SB Nature Reviews Neuroscience (2021) Vol. 22, pp. 263-274; Bennett DL et al. Physiol Rev 99 (2019) Vol. 99, pp. 1079-1151).
異常的持續性神經病變疼痛係由於此體感路徑之病變或疾病而引起的。因應於神經損傷或發炎，離子通道表現之異常變化可引起疼痛信號傳導神經元及其神經/軸突之過度興奮，因此導致病理性疼痛。Abnormal persistent neuropathic pain is caused by lesions or diseases of this somatosensory pathway. In response to nerve damage or inflammation, abnormal changes in the manifestation of ion channels can cause overexcitation of pain signaling neurons and their nerves/axons, thus leading to pathological pain.
電壓閘控NaV1.8鈉通道為止痛之治療靶標，因為其表現譜受限(幾乎僅限於周圍感覺組織)，其位置沿著疼痛路徑(游離神經末梢、坐骨神經及DRG)，在疼痛信號傳導中具有突出的生理作用(支持AP之上衝且促進重複AP放電)，且支持遺傳/藥理學表型證據(人類/動物研究顯示NaV1.8功能之變化會引起疼痛敏感性的平行變化)。Voltage-gated sodium V 1.8 channels are therapeutic targets for pain relief because their spectrum of expression is limited (almost exclusively to peripheral sensory tissues), their location is along the pain pathway (free nerve endings, sciatic nerve, and DRG), and they play a prominent physiological role in pain signal transduction (supporting uprush of acute pain and promoting recurrent acute pain discharge). This supports genetic/pharmacological phenotypic evidence (human/animal studies show that changes in sodium V 1.8 function lead to parallel changes in pain sensitivity).
關於其沿疼痛路徑之表現譜，因為NaV1.8首先主要存在於背根神經節(DRG)及三叉神經節(TG)之周圍感覺神經元中，故其最初被稱為SNS (感覺神經元特異性)(Akopian A.N.等人 Nature (1996) 第379卷 第257-261頁)或PN3 (周圍神經3) (Sangameswaran L.等人 J. Biol. Chem. (1996) 第271卷 第5953-5956頁)。又，NaV1.8定位於游離神經末梢，此處疼痛信號傳導在皮膚中啟動(Persson A.K.等人 Mol. Pain. (2010) 6:84)且沿著坐骨神經之非髓鞘化軸突的整個長度廣泛定位(Rush A.M.等人 Eur.J.Neurosci (2005) 第22卷 第39-49頁)。Regarding its presentation spectrum along the pain pathway, since NaV 1.8 is primarily found in the peripheral sensory neurons of the dorsal root ganglion (DRG) and trigeminal ganglion (TG), it was initially referred to as SNS (sensory neuron specificity) (Akopian AN et al. Nature (1996) Vol. 379, pp. 257-261) or PN3 (peripheral nerve 3) (Sangameswaran L. et al. J. Biol. Chem. (1996) Vol. 271, pp. 5953-5956). Furthermore, Na V 1.8 is located at free nerve endings where pain signals are initiated in the skin (Persson AK et al. Mol. Pain. (2010) 6:84) and is widely located along the entire length of the unmyelinated axon of the sciatic nerve (Rush AM et al. Eur. J. Neurosci (2005) Vol. 22, pp. 39-49).
相較之下，NaV1.8在非神經元組織(諸如心臟及骨骼肌)及CNS (包括腦及脊髓)中具有最低表現(9、10、338、406) (Akopian A.N. op. cit.；Akopian A.N.等人 Nat. Neurosci (1999) 第2卷 第541-548頁；Novakovic S.D.等人 J. Neurosci. (1998) 第18卷, 第2174-2187頁；以及Sagameswaran L. op. cit.)。In comparison, NaV 1.8 showed the lowest expression in nonneuronal tissues (such as the heart and skeletal muscle) and CNS (including the brain and spinal cord) (9, 10, 338, 406) (Akopian AN op. cit.; Akopian AN et al. Nat. Neurosci (1999) Vol. 2, pp. 541-548; Novkovic SD et al. J. Neurosci. (1998) Vol. 18, pp. 2174-2187; and Sagameswaran L. op. cit.).
關於其生理作用，NaV1.8在傷痛性感覺神經元之全有或全無動作電位的上升階段貢獻大部分內向電流(Blair N.T.等人 J. Neurosci. (2003) 第23卷 第10338-10350頁及Renganathan M等人 J. Neurophysiol (2001) 第86卷 第629-640頁)，且亦在DRG神經元之重複放電期間的後續尖峰中貢獻大部分電流(Choi J.S. J. Neurophysiol (2011) 第106卷 第3173-3184頁；以及Tan Z.Y.等人 J. Neurosci. (2014) 第34卷第7190-7197頁)。Regarding its physiological function, NaV 1.8 contributes most of the inward current during the rising phase of the all-or-no-action potential of nociceptive neurons in pain receptors (Blair NT et al. J. Neurosci. (2003) Vol. 23, pp. 10338-10350 and Renganathan M et al. J. Neurophysiol (2001) Vol. 86, pp. 629-640), and also contributes most of the current during the subsequent spikes of repetitive discharges in DRG neurons (Choi JSJ Neurophysiol (2011) Vol. 106, pp. 3173-3184; and Tan ZY et al. J. Neurosci. (2014) Vol. 34, pp. 7190-7197).
關於遺傳及藥理學研究，在患有慢性神經病變疼痛(諸如小纖維神經病變)之患者中發現了NaV1.8之功能獲得型突變(Faber C.G.等人 (2012) Ann. Neurol 第71卷 第26-39頁；Han C等人 J. Neurol Neurosurg Psychiatry (2014) 第85卷 第499-505頁；以及Kist A.M.等人 PLoS One (2016) 第11卷 e0161789；Eijkenboom I.等人 J. Neurol Neurosurg Psychiatry (2019) 90 (3) 第342-352頁)；小鼠之功能喪失(基因剔除)研究降低了疼痛敏感性，尤其是在傷痛覺中(Laird J.M.等人 J. Neurosci (2002) J. Neurosci 第22卷 第8352-8356頁；Jarvis M.F.等人 Proc Natl Acad Sci USA (2007) 第104卷 第8520-8525頁；Joshi S.K.等人 Pain (2006) 第123卷 第75-82頁)及在神經病變模型中(Roza C.等人 J Physiol (2003) 第550卷 第921-926頁)；NaV1.8選擇性小分子抑制劑減輕了囓齒動物之疼痛，特別是在發炎及神經病變模型中(Jarvis等人 op. cit.；Kort M.E.等人 Bioorg Med Chem Lett (2010) 第20卷 第6812-6815頁；Scanio M.J.等人 Bioorg Med Chem (2010) 第18卷 第7816-7825頁；Payne C.E.等人 Br J Pharmacol (2015) 第172卷 第2654-2670頁)。Regarding genetic and pharmacological studies, a gain-of-function mutation of NaV 1.8 has been found in patients with chronic neuropathic pain (such as microfibroneuropathy) (Faber CG et al. (2012) Ann. Neurol Vol. 71 pp. 26-39; Han C et al. J. Neurol Neurosurg Psychiatry (2014) Vol. 85 pp. 499-505; and Kist AM et al. PLoS One (2016) Vol. 11 e0161789; Eijkenboom I. et al. J. Neurol Neurosurg Psychiatry (2019) 90 (3) pp. 342-352); loss-of-function (gene knockout) studies in mice have reduced pain sensitivity, especially in pain perception (Laird JM et al. J. Neurosci (2002) J. Neurosci). Volume 22, pp. 8352-8356; Jarvis MF et al., Proc Natl Acad Sci USA (2007), Volume 104, pp. 8520-8525; Joshi SK et al., Pain (2006), Volume 123, pp. 75-82) and in neuropathic models (Roza C. et al., J Physiol (2003), Volume 550, pp. 921-926); NaV 1.8 selective small molecule inhibitors alleviated pain in rodents, particularly in inflammatory and neuropathic models (Jarvis et al., op. cit.; Kort ME et al., Bioorg Med Chem Lett (2010), Volume 20, pp. 6812-6815; Scanio MJ et al., Bioorg Med Chem (2010)). Volume 18, pp. 7816-7825; Payne CE et al., Br J Pharmacol (2015), Volume 172, pp. 2654-2670.
目前，非選擇性NaV通道抑制劑用於治療癲癇、心律不整及慢性疼痛(Hille, B. J. Gen. Physiol. (1977) 第69卷 第497-515頁；Hille. B, Ion Channels of Excitable Membranes (1992) 第391-421頁；Sunderland, Mass., Sinauer Associates, Inc. 第3版；Hondeghem L.M.及Katzung B.G. Annu. Rev. Pharmacol. Toxicol. (1984) 第24卷. 第387-423頁；Catterall W.A. Trends Pharmacol. Sci. (1987) 第8卷 第57-65頁)，然而，由於與抑制NaV1.1/NaV1.2/1.6 (癲癇發作傾向)、抑制NaV1.4 (肌肉無力/麻痹)、抑制NaV1.5 (心律不整風險)相關之劑量限制性不良副作用，所有此等止痛劑之功效均有限。Currently, non-selective NaV channel inhibitors are used to treat epilepsy, arrhythmia, and chronic pain (Hille, BJ Gen. Physiol. (1977) Vol. 69, pp. 497-515; Hille. B, Ion Channels of Excitable Membranes (1992) pp. 391-421; Sunderland, Mass., Sinauer Associates, Inc. 3rd ed.; Hondeghem LM and Katzung BG Annu. Rev. Pharmacol. Toxicol. (1984) Vol. 24, pp. 387-423; Catterall WA Trends Pharmacol. Sci. (1987) Vol. 8, pp. 57-65). However, due to inhibition of NaV 1.1/ NaV 1.2/1.6 (epilepsy seizure tendency) and inhibition of NaV 1.4... The efficacy of these analgesics is limited due to dose-limiting adverse side effects such as muscle weakness/paralysis and inhibition of NaV 1.5 (risk of arrhythmia).
需要開發一種NaV1.8選擇性小分子抑制劑作為有效且安全的止痛劑。There is a need to develop a NaV 1.8 selective small molecule inhibitor as an effective and safe analgesic.
本發明之目標係提供新穎化合物，其為NaV1.8抑制劑，較佳為選擇性抑制劑，且較佳具有優於先前技術之化合物的優勢。該等新穎化合物應特別適用於治療疼痛。The objective of this invention is to provide novel compounds that are NaV 1.8 inhibitors, preferably selective inhibitors, and preferably compounds that have advantages over prior art compounds. These novel compounds should be particularly suitable for the treatment of pain.
此目標已藉由本專利申請專利範圍之標的物達成。This objective has been achieved by the subject matter of this patent application.
出人意料地發現，根據本發明之化合物為NaV1.8通道之高度有效且選擇性的抑制劑。此外，出人意料地發現，與先前技術之NaV1.8抑制劑相比，根據本發明之化合物具有有利的特性。Surprisingly, the compound according to the invention was found to be a highly effective and selective inhibitor of the NaV 1.8 channel. Furthermore, it was unexpectedly found that the compound according to the invention possesses advantageous properties compared to prior art NaV 1.8 inhibitors.
本發明係關於一種根據通式(I)之化合物，其中L1表示O、C(R7)2-O、O-C(R7)2、N(R7)、C(R7)2-N(R7)、N(R7)-C(R7)2、S、C(R7)2-S、S-C(R7)2、C(R7)2或C(R7)2C(R7)2；A及B彼此獨立地表示苯基、5員至10員雜芳基、C1-6烷基、C3-10環烷基或4員至10員雜環烷基；R2及R3彼此獨立地表示F、Cl、Br、CN、C1-6烷基、C3-6環烷基、NH2、N(H)C1-4烷基、N(C1-4烷基)2、OH、O-C1-4烷基、O-C3-6環烷基、SF5、苯基或C3-6環烷基；x及y彼此獨立地表示0、1、2、3或4；R4表示H、Cl、CN、C1-6烷基或C3-6環烷基；L2表示鍵、C1-3伸烷基或C1-2伸烷基-N(H)；且R5表示S(=O)R6、S(=O)(=NH)R6、S(=O)2R6或S(=O)2NH2；R6表示C1-6烷基；R7表示H或C1-4烷基；其中C1-6烷基、C1-4烷基、C1-4伸烷基、C1-3伸烷基及C1-2伸烷基在各情況下彼此獨立地為直鏈或分支鏈、飽和或不飽和的；其中C1-6烷基、C1-4烷基、C1-4伸烷基、C1-3伸烷基、C1-2伸烷基、C3-10環烷基、C3-7環烷基、C3-6環烷基、C5-7環烷基、4員至10員雜環烷基及4員至7員雜環烷基在各情況下彼此獨立地未經取代或經一或多個選自以下之取代基單取代或多取代：F；Cl；CN；C1-6烷基；CF3；CF2H；CFH2；OH；=O；OCF3；OCF2H；OCFH2；O-C1-6烷基；NH2；N(H)(C1-6烷基)；N(C1-6烷基)2；SCF3；SCF2H；SCFH2；及S-C1-6烷基；其中苯基、5員至10員雜芳基及5或6員雜芳基在各情況下彼此獨立地未經取代或經一或多個選自以下之取代基單取代或多取代：F；Cl；CN；C1-6烷基；CF3；CF2H；CFH2；OH；OCF3；OCF2H；OCFH2；O-C1-6烷基；NH2；N(H)(C1-6烷基)；及N(C1-6烷基)2；呈游離化合物或其生理學上可接受之鹽形式。This invention relates to a compound according to general formula (I), Where L1 represents O, C( R7 ) 2 -O, OC( R7 ) 2 , N( R7 ), C( R7 ) 2 -N(R7), N( R7 )-C( R7 ) 2 , S, C( R7 ) 2 -S, SC( R7 ) 2 , C( R7 ) 2 , or C( R7 ) 2C ( R7 ) 2 ; A and B independently represent phenyl, 5-10-membered heteroaryl, C1-6 alkyl, C3-10 cycloalkyl, or 4-10-membered heterocycloalkyl; R2 and R3 independently represent F, Cl, Br, CN, C1-6 alkyl, C3-6 cycloalkyl, NH2 , N(H) C1-4 alkyl, N( C1-4 alkyl) 2 , OH, OC 1-4 alkyl, OC 3-6 cycloalkyl, SF 5 , phenyl or C 3-6 cycloalkyl; x and y independently represent 0, 1, 2, 3 or 4; R 4 represents H, Cl, CN, C 1-6 alkyl or C 3-6 cycloalkyl; L 2 represents lignin, C 1-3 alkyl or C 1-2 alkyl-N(H); and R 5 represents S(=O)R 6 , S(=O)(=NH)R 6 , S(=O) 2R 6 or S(=O) 2NH 2 ; R 6 represents C 1-6 alkyl; R 7 represents H or C 1-4 alkyl; wherein C 1-6 alkyl, C 1-4 alkyl, C 1-4 alkyl, C 1-3 alkyl and C The 1-2 alkyl groups are, in each case, independently straight-chain or branched-chain, saturated or unsaturated; wherein the C1-6 alkyl, C1-4 alkyl, C1-4 alkylene, C1-3 alkylene, C1-2 alkylene, C3-10 cycloalkyl, C3-7 cycloalkyl, C3-6 cycloalkyl, C5-7 cycloalkyl, 4-10 heterocycloalkyl, and 4-7 heterocycloalkyl groups are, in each case, independently unsubstituted or monosubstituted or polysubstituted with one or more substituents selected from the following: F; Cl; CN; C1-6 alkyl; CF3 ; CF2H ; CFH2 ; OH; =O; OCF3 ; OCF2H ; OCFH2 ; OC1-6 alkyl; NH2 ; N(H)(C 1-6 alkyl); N(C 1-6 alkyl) 2 ; SCF 3 ; SCF 2 H; SCFH 2 ; and SC 1-6 alkyl; wherein the phenyl, 5- to 10-membered heteroaryl and 5 or 6-membered heteroaryl are, in each case, independently unsubstituted or monosubstituted or polysubstituted by one or more substituents selected from the following: F; Cl; CN; C 1-6 alkyl; CF 3 ; CF 2 H; CFH 2 ; OH; OCF 3 ; OCF 2 H; OCFH 2 ; OC 1-6 alkyl; NH 2 ; N(H)(C 1-6 alkyl); and N(C 1-6 alkyl) 2 ; are in the form of a free compound or a physiologically acceptable salt thereof.
在一較佳實施例中，根據本發明之化合物係以游離化合物之形式存在。出於說明書之目的，「游離化合物」較佳意謂根據本發明之化合物不以鹽形式存在。確定一種化學物質作為游離化合物抑或作為鹽存在之方法係熟練技術人員已知的，諸如14N或15N固態NMR、x射線繞射、x射線粉末繞射、IR、拉曼(Raman)、XPS。亦可使用在溶液中記錄之1H-NMR來考慮質子化之存在。In a preferred embodiment, the compound according to the invention exists in the form of a free compound. For the purposes of this specification, "free compound" preferably means that the compound according to the invention does not exist in the form of a salt. Methods for determining whether a chemical substance exists as a free compound or as a salt are known to those skilled in the art, such as 14 N or 15 N solid-state NMR, X-ray diffraction, X-ray powder diffraction, IR, Raman, and XPS. The presence of protonation can also be considered using 1 H-NMR recorded in solution.
在另一較佳實施例中，根據本發明之化合物係以生理學上可接受之鹽形式存在。出於本說明書之目的，術語「生理學上可接受之鹽」較佳係指自根據本發明之化合物及生理學上可接受之酸或鹼獲得的鹽。In another preferred embodiment, the compound according to the invention is present in the form of a physiologically acceptable salt. For the purposes of this specification, the term "physiologically acceptable salt" preferably means a salt obtained from the compound according to the invention and a physiologically acceptable acid or base.
根據本發明，根據本發明之化合物可以包括溶劑合物、共晶體及多晶型物在內的任何可能之形式存在。出於本說明書之目的，術語「溶劑合物」較佳係指(i)根據本發明之化合物及/或其生理學上可接受之鹽與(ii)不同分子當量之一或多種溶劑的加合物。According to the present invention, the compounds of the present invention may exist in any possible form, including solvent compounds, eutectics and polymorphs. For the purposes of this specification, the term "solvent compound" preferably means (i) an adduct of the compounds of the present invention and/or a physiologically acceptable salt thereof with (ii) one or more solvents of different molecular equivalents.
此外，根據本發明之化合物可以外消旋物、鏡像異構物、非鏡像異構物、互變異構物或其任何混合物之形式存在。熟習此項技術者知曉咪唑顯示環狀互變異構。Furthermore, the compounds according to the present invention may exist in the form of racemic derivatives, mirror isomers, non-mirror isomers, tautomers, or any mixture thereof. Those skilled in the art will know that imidazole exhibits cyclic tautomerism.
根據本發明之化合物可具有一或多個立構中心。熟習此項技術者藉由觀察化學結構知曉所描繪之化合物是否具有一或多個立構中心。The compounds according to this invention may have one or more stereocenters. Those skilled in this art can determine whether a described compound has one or more stereocenters by observing its chemical structure.
對於具有一或多個立構中心且在本申請案之實例中揭示化學結構的一些根據本發明之化合物，化學結構包括粗體鍵(bold bond)及/或散列鍵(hashed bond)以指示藉由粗體鍵及/或散列鍵連接至上層結構的彼等取代基之相對結構取向。若粗體鍵及/或散列鍵以楔形形式描繪，則化合物之絕對立體化學組態為已知的並由此進行指示。若粗體鍵及/或散列鍵以直鍵(亦即，無楔形)描繪，則化合物之絕對立體化學組態尚未確定。在彼情況下，粗體鍵及/或散列鍵僅用於指示此特定化合物作為一種鏡像異構物或一種非鏡像異構物(例如順式非鏡像異構物(亦即，兩種順式鏡像異構物之混合物)或反式非鏡像異構物(亦即，兩種反式鏡像異構物之混合物))存在。具有一或多個立構中心但在本申請案之實例中揭示之化學結構不包括粗體鍵及/或散列鍵的所有根據本發明之化合物均作為各別立體異構物之混合物存在。For compounds according to the invention that have one or more stereocenters and whose chemical structures are disclosed in examples of this application, the chemical structures include bold bonds and/or hash bonds to indicate the relative structural orientations of the substituents linked to the upper structure by the bold bonds and/or hash bonds. If the bold bonds and/or hash bonds are depicted in a wedge shape, the absolute stereochemical configuration of the compound is known and thus indicated. If the bold bonds and/or hash bonds are depicted in straight lines (i.e., without wedges), the absolute stereochemical configuration of the compound has not yet been determined. In that case, the bold key and/or hash key are used only to indicate that the particular compound exists as a mirror isomer or a non-mirror isomer (e.g., a cis-non-mirror isomer (i.e., a mixture of two cis-mirror isomers) or a trans-non-mirror isomer (i.e., a mixture of two trans-mirror isomers)). All compounds according to the invention that have one or more stereocenters but whose chemical structures disclosed in the examples of this application do not include bold keys and/or hash keys exist as mixtures of their respective stereoisomers.
本發明亦包括本發明化合物之同位素異構物，其中該化合物之至少一個原子經各別原子之同位素置換，該同位素不同於主要的天然存在之同位素；以及此類化合物之同位素異構物之任何混合物。較佳同位素為2H (氘)、3H (氚)、13C及14C。本發明化合物之同位素異構物通常可藉由熟習此項技術者已知之習知程序來製備。This invention also includes isotopic isomers of the compounds of the invention, wherein at least one atom of the compound is replaced by isotopic substitution of the other atoms, the isotopes being different from the main naturally occurring isotopes; and any mixtures of isotopic isomers of such compounds. Preferred isotopes are 2H (deuterium), 3H (tritium), 13C , and 14C . Isotopic isomers of the compounds of the invention can generally be prepared by means of known procedures known to those skilled in the art.
根據本發明，術語「C1-4烷基」及「C1-6烷基」較佳意謂無環且較佳飽和的烴基，其可為直鏈(亦即，無分支鏈)或分支鏈的且可未經取代或經單取代或多取代(例如，二取代或三取代)，且分別含有1至4個(亦即，1、2、3或4個)或1至6個(亦即，1、2、3、4、5或6個)碳原子。較佳地，C1-4烷基及C1-6烷基為飽和的。在另一較佳實施例中，C1-4烷基及C1-6烷基為不飽和的且選自C2-4烯基、C2-6烯基、C2-4炔基及C2-6炔基。較佳C1-4烷基選自由以下組成之群：甲基、乙基、正丙基、2-丙基、正丁基、異丁基、二級丁基及三級丁基。較佳C1-6烷基選自由以下組成之群：甲基、乙基、正丙基、2-丙基、正丁基、異丁基、二級丁基、三級丁基、正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、3-甲基丁-2-基、2-甲基丁-2-基、2,2-二甲基丙基及正己基。較佳C2-4烯基選自由以下組成之群：乙烯基、丙烯基及丁烯基。較佳C2-6烯基選自C2-4烯基。較佳C2-4炔基選自由以下組成之群：乙炔基、丙炔基及丁炔基，更佳地丙炔基，最佳地丙-1炔基。較佳C2-6炔基選自C2-4炔基。According to the present invention, the terms " C1-4 alkyl" and " C1-6 alkyl" preferably mean an acyclic and preferably saturated hydrocarbon, which may be straight-chain (i.e., unbranched) or branched and may be unsubstituted or monosubstituted or polysubstituted (e.g., disubstituted or trisubstituted), and respectively contain 1 to 4 (i.e., 1, 2, 3 or 4) or 1 to 6 (i.e., 1, 2, 3, 4, 5 or 6) carbon atoms. Preferably, the C1-4 alkyl and C1-6 alkyl are saturated. In another preferred embodiment, the C1-4 alkyl and C1-6 alkyl are unsaturated and selected from C2-4 alkenyl, C2-6 alkenyl, C2-4 ynyl, and C2-6 ynyl. Preferred C1-4 alkyl groups are selected from the group consisting of: methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, dibutyl, and tertiary butyl. Preferred C1-6 alkyl groups are selected from the group consisting of: methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, dibutyl, tertiary butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl-2-yl, 2-methylbutyl-2-yl, 2,2-dimethylpropyl, and n-hexyl. Preferred C2-4 alkenyl groups are selected from the group consisting of: vinyl, propenyl, and butenyl. Preferred C2-6 alkenyl groups are selected from C2-4 alkenyl groups. The preferred C2-4 ynyl group is selected from the group consisting of ethynyl, propynyl, and butynyl, more preferably propynyl, and most preferably propynyl-1. The preferred C2-6 ynyl group is selected from the C2-4 ynyl group.
更進一步根據本發明，術語「C3-7環烷基」、「C3-6環烷基」、「C5-7環烷基」及「C3-10環烷基」較佳意謂含有3至7個(亦即，3、4、5、6或7個)、3至6個(亦即，3、4、5或6個)、5至7個(亦即，5、6或7個)或3至10個(亦即，3、4、5、6、7、8、9或10個)碳原子之單環或多環、較佳地單環或雙環脂族烴，其中該等烴在各情況下可為飽和或不飽和的(但非芳族的)、未經取代或單取代或多取代的。Furthermore, according to the present invention, the terms " C3-7 cycloalkyl", " C3-6 cycloalkyl", " C5-7 cycloalkyl" and " C3-10 cycloalkyl" preferably mean a monocyclic or polycyclic, preferably monocyclic or bicyclic aliphatic hydrocarbon containing 3 to 7 (i.e., 3, 4, 5, 6 or 7), 3 to 6 (i.e., 3, 4, 5 or 6), 5 to 7 (i.e., 5, 6 or 7), or 3 to 10 (i.e., 3, 4, 5, 6, 7, 8, 9 or 10) carbon atoms, wherein such hydrocarbons may in each case be saturated or unsaturated (but not aromatic), unsubstituted or monosubstituted or polysubstituted.
出於本說明書之目的，「多環」及「雙環」應較佳意謂稠合、橋連或螺環系統。For the purposes of this manual, "multi-ring" and "double-ring" should preferably mean fused, bridged, or spiral systems.
較佳地，C3-7環烷基、C3-6環烷基、C5-7環烷基及C3-10環烷基為飽和的。C3-7環烷基、C3-6環烷基、C5-7環烷基及C3-10環烷基可經由環烷基之任何所需及可能的環成員與各別上位一般結構結合。C3-7環烷基、C3-6環烷基、C5-7環烷基及C3-10環烷基亦可與其他飽和或(部分)不飽和雜環烷基、芳族或雜芳族環系統(較佳地，芳族環系統)稠合，後者又可為未經取代或單取代或多取代的，從而成為具有至多14個環成員之雙環或多環系統之一部分。因此，術語「C3-7環烷基」、「C3-6環烷基」、「C5-7環烷基」及「C3-10環烷基」較佳包括含有3至7個、3至6個、5至7個或3至10個碳原子之單環或多環、較佳地單環或雙環脂族烴；該等烴與苯基部分稠合。較佳C3-7環烷基選自由以下組成之群：環丙基、環丁基、環戊基、環己基、環庚基、螺[2.2]戊基、螺[2.3]己基、螺[3.3]庚基、雙環[1.1.0]丁基、雙環[2.1.0]戊基、雙環[2.1.1]己基、雙環[3.1.1]庚基、雙環[2.2.1]庚基、雙環[3.1.0]己基、雙環[3.2.0]庚基、雙環[4.1.0]庚基及2,3-二氫-1H-茚基。Preferably, the C3-7 cycloalkyl, C3-6 cycloalkyl, C5-7 cycloalkyl, and C3-10 cycloalkyl groups are saturated. The C3-7 cycloalkyl, C3-6 cycloalkyl, C5-7 cycloalkyl, and C3-10 cycloalkyl groups can be combined with each other via any desired and possible ring members of the cycloalkyl group and the respective superordinate general structure. C3-7 cycloalkyl, C3-6 cycloalkyl, C5-7 cycloalkyl and C3-10 cycloalkyl may also be fused with other saturated or (partially) unsaturated heterocycloalkyl, aromatic or heteroaromatic ring systems (preferably aromatic ring systems), which may be unsubstituted or monosubstituted or polysubstituted, thereby becoming part of a bicyclic or polycyclic system having up to 14 ring members. Therefore, the terms " C3-7 cycloalkyl", " C3-6 cycloalkyl", " C5-7 cycloalkyl" and " C3-10 cycloalkyl" preferably include monocyclic or polycyclic, more preferably monocyclic or bicyclic aliphatic hydrocarbons containing 3 to 7, 3 to 6, 5 to 7 or 3 to 10 carbon atoms; such hydrocarbons are fused with the phenyl moiety. The preferred C3-7 cycloalkyl group is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[3.3]heptyl, bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.1.0]heptyl and 2,3-dihydro-1H-indenyl.
較佳C3-6環烷基選自由以下組成之群：環丙基、環丁基、環戊基、環己基、螺[2.2]戊基、螺[2.3]己基、雙環[1.1.0]丁基、雙環[2.1.0]戊基、雙環[2.1.1]己基、雙環[3.1.0]己基及2,3-二氫-1H-茚基。The preferred C3-6 cycloalkyl group is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2.2]pentyl, spiro[2.3]hexyl, bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.0]hexyl and 2,3-dihydro-1H-indenyl.
較佳C5-7環烷基選自由以下組成之群：環戊基、環己基、環庚基、螺[2.2]戊基、螺[2.3]己基、螺[3.3]庚基、雙環[2.1.0]戊基、雙環[2.1.1]己基、雙環[3.1.1]庚基、雙環[2.2.1]庚基、雙環[3.1.0]己基、雙環[3.2.0]庚基、雙環[4.1.0]庚基及2,3-二氫-1H-茚基。The preferred C5-7 cycloalkyl group is selected from the group consisting of: cyclopentyl, cyclohexyl, cycloheptyl, spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[3.3]heptyl, bicyclo[2.1.0]pentyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.1.0]heptyl and 2,3-dihydro-1H-indenyl.
較佳C3-10環烷基選自由以下組成之群：環丙基、環丁基、環戊基、環己基、環己烯基、環庚基、螺[2.5]辛基、螺[2.2]戊基、螺[2.3]己基、螺[3.3]庚基、雙環[1.1.0]丁基、雙環[2.1.0]戊基、雙環[2.1.1]己基、雙環[3.1.1]庚基、雙環[2.2.1]庚基、雙環[3.1.0]己基、雙環[3.2.0]庚基、雙環[2.2.2]辛基、雙環[4.1.0]庚基、2,3-二氫-1H-茚基、5,6,7,8-四氫異喹啉基、雙環[1.1.0]丁基、雙環[1.1.1]戊基、雙環[2.1.0]戊基、雙環[3.1.0]己基、雙環[2.2.0]己基、雙環[2.1.1]己基、5-氧雜螺[2.4]庚基、2-氧雜螺[3.4]辛基、雙環[4.1.0]庚基、雙環[2.2.1]庚基、雙環[3.3.0]辛基、螺[2.2]戊基、螺[2.3]己基、螺[3.3]庚基及二螺[2.0.2.1]庚基；更佳地，環丙基、環丁基、環戊基、環己基、環己烯基、螺[2.5]辛基、螺[2.3]己基、螺[3.3]庚基、雙環[3.1.1]庚基、雙環[2.2.1]庚基、雙環[3.2.0]庚基、雙環[2.2.2]辛基、雙環[4.1.0]庚基、2,3-二氫-1H-茚基、雙環[1.1.1]戊基、雙環[2.1.1]己基、5,6,7,8-四氫異喹啉基、5-氧雜螺[2.4]庚基及2-氧雜螺[3.4]辛基。The preferred C3-10 cycloalkyl group is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, spiro[2.5]octyl, spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[3.3]heptyl, bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.1] .0] Hexyl, Bicyclo[3.2.0] Heptyl, Bicyclo[2.2.2] Octyl, Bicyclo[4.1.0] Heptyl, 2,3-Dihydro-1H-Indene, 5,6,7,8-Tetrahydroisoquinolinyl, Bicyclo[1.1.0] Butyl, Bicyclo[1.1.1] Pentyl, Bicyclo[2.1.0] Pentyl, Bicyclo[3.1.0] Hexyl, Bicyclo[2.2.0] Hexyl, Bicyclo[2.1.1] Hexyl, 5-O Spirospiro[2.4]heptyl, 2-oxospiro[3.4]octyl, bicyclic[4.1.0]heptyl, bicyclic[2.2.1]heptyl, bicyclic[3.3.0]octyl, spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[3.3]heptyl and dispiro[2.0.2.1]heptyl; more preferably, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, spiro[2.5]octyl, spiro[2.3]hexyl, spiro[ 3.3] Heptyl, bicyclic [3.1.1] heptyl, bicyclic [2.2.1] heptyl, bicyclic [3.2.0] heptyl, bicyclic [2.2.2] octyl, bicyclic [4.1.0] heptyl, 2,3-dihydro-1H-indene, bicyclic [1.1.1] pentyl, bicyclic [2.1.1] hexyl, 5,6,7,8-tetrahydroisoquinolinyl, 5-oxozyrospiro [2.4] heptyl and 2-oxozyrospiro [3.4] octyl.
進一步根據本發明，術語「C1-4伸烷基」、「C1-3伸烷基」及「C1-2伸烷基」係指直鏈或分支鏈(較佳地，直鏈)且較佳地飽和脂族殘基，該等殘基較佳地選自由以下組成之群：亞甲基(-CH2-)、伸乙基(-CH2CH2-)、伸丙基(-CH2CH2CH2-或-C(CH3)2-)及伸丁基(-CH2CH2CH2CH2-、-CH2C(CH3)2-或-C(CH3)2CH2-)；更佳地，亞甲基(-CH2-)及伸乙基(-CH2CH2)。Further according to the present invention, the terms " C1-4 alkylene", " C1-3 alkylene" and " C1-2 alkylene" refer to straight-chain or branched-chain (preferably, straight-chain) and preferably saturated with aliphatic residues, which are preferably selected from the group consisting of: methylene ( -CH2- ), ethylene ( -CH2CH2- ) , propylene ( -CH2CH2CH2- or -C ( CH3 ) 2- ) and butylene ( -CH2CH2CH2CH2- , -CH2C ( CH3 ) 2- or -C ( CH3 ) 2CH2- ) ; more preferably, methylene ( -CH2- ) and ethylene ( -CH2CH2 ).
根據本發明，C1-6烷基、C1-4烷基、C1-4伸烷基、C1-3伸烷基及C1-2伸烷基在各情況下彼此獨立地為直鏈或分支鏈、飽和或不飽和的。在一較佳實施例中，C1-6烷基、C1-4烷基、C1-4伸烷基、C1-3伸烷基及C1-2伸烷基在各情況下彼此獨立地為直鏈或分支鏈的，且為飽和的。According to the present invention, the C1-6 alkyl, C1-4 alkyl, C1-4 proalkyl, C1-3 proalkyl, and C1-2 proalkyl groups are each independently linear or branched, saturated or unsaturated. In a preferred embodiment, the C1-6 alkyl, C1-4 alkyl, C1-4 proalkyl, C1-3 proalkyl, and C1-2 proalkyl groups are each independently linear or branched, and saturated.
根據本發明，術語「4至7員雜環烷基」、「5至7員雜環烷基」及「4至10員雜環烷基」較佳意謂具有4至7個(亦即，4、5、6或7個)、5至7個(亦即，5、6或7個)或4至10個(亦即，4、5、6、7、8、9或10個)環成員之單環或多環(較佳地，單環或雙環)雜環脂族飽和或不飽和(但非芳族)殘基，其中在各情況下，至少一個(若適宜，亦為兩個或三個)碳原子經各自彼此獨立地選自由以下組成之群的雜原子或雜原子基團置換：O、S、S(=O)、S(=O)2、N、NH及N(C1-4烷基) (諸如N(CH3))，其中環之碳原子可為未經取代或單取代或多取代的。較佳地，4至7員雜環烷基、5至7員雜環烷基及4至10員雜環烷基為飽和的。4至7員雜環烷基、5至7員雜環烷基及4至10員雜環烷基亦可與其他飽和或(部分)不飽和環烷基、芳族或雜芳族環系統(較佳地，芳族環系統)稠合，後者又可為未經取代或單取代或多取代的(若無另外指示)，從而成為具有至多14個環成員之雙環或多環系統之一部分。在一較佳實施例中，4至7員雜環烷基、5至7員雜環烷基及4至10員雜環烷基不與其他環系統稠合。更佳地，4至7員雜環烷基、5至7員雜環烷基及4至10員雜環烷基不與其他環系統稠合且為飽和的。在另一較佳實施例中，4至7員雜環烷基、5至7員雜環烷基及4至10員雜環烷基與其他環系統(較佳地，苯基、5至6員雜芳基或C3-6環烷基)縮合。若無另外指示，則4至7員雜環烷基、5至7員雜環烷基及4至10員雜環烷基可經由雜環脂族殘基之任何所需及可能的環成員與上位一般結構結合。在一較佳實施例中，4至7員雜環烷基、5至7員雜環烷基及4至10員雜環烷基經由碳原子與上位一般結構結合。在另一較佳實施例中，4至7員雜環烷基、5至7員雜環烷基及4至10員雜環烷基經由雜原子(特別地，N)與上位一般結構結合。According to the present invention, the terms "4 to 7-membered heterocycloalkyl", "5 to 7-membered heterocycloalkyl" and "4 to 10-membered heterocycloalkyl" preferably mean having 4 to 7 (i.e., 4, 5, 6 or 7), 5 to 7 (i.e., 5, 6 or 7), or 4 to 10 (i.e., 4, 5, 6, 7, 8, 9 or 10) ring members. The residue is a monocyclic or polycyclic (preferably monocyclic or bicyclic) heterocyclic aliphatic saturated or unsaturated (but not aromatic) residue, wherein in each case, at least one (or two or three, if appropriate) carbon atom is replaced by heteroatoms or heteroatom groups, each independently selected from the group consisting of: O, S, S(=O), S(=O) ₂ , N, NH and N (C₁ -4 alkyl) (such as N( CH₃ )), wherein the carbon atoms of the ring may be unsubstituted, monosubstituted or polysubstituted. Preferably, the 4- to 7-membered heterocyclic alkyl, 5- to 7-membered heterocyclic alkyl and 4- to 10-membered heterocyclic alkyl are saturated. The 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkyl, and 4- to 10-membered heterocycloalkyl may also be fused with other saturated or (partially) unsaturated cycloalkyl, aromatic, or heteroaromatic ring systems (preferably aromatic ring systems), which may be unsubstituted, monosubstituted, or polysubstituted (unless otherwise indicated), thus becoming part of a bicyclic or polycyclic system having up to 14 ring members. In a preferred embodiment, the 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkyl, and 4- to 10-membered heterocycloalkyl are not fused with other ring systems. More preferably, the 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkyl, and 4- to 10-membered heterocycloalkyl groups are not fused with other ring systems and are saturated. In another preferred embodiment, the 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkyl, and 4- to 10-membered heterocycloalkyl groups are condensed with other ring systems (preferably phenyl, 5- to 6-membered heteroaryl, or C3-6 cycloalkyl). Unless otherwise indicated, the 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkyl, and 4- to 10-membered heterocycloalkyl groups may be linked to the superposition general structure via any desired and possible ring member of the heterocyclic aliphatic residue. In one preferred embodiment, the 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkyl, and 4- to 10-membered heterocycloalkyl are bonded to the general structure via carbon atoms. In another preferred embodiment, the 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkyl, and 4- to 10-membered heterocycloalkyl are bonded to the general structure via heteroatoms (specifically, N).
較佳4至7員雜環烷基選自由以下組成之群：1,1-二側氧基四氫噻吩基、1-側氧基硫代嗎啉基、四氫哌喃基、氧雜環丁基、四氫呋喃基、嗎啉基、吡咯啶基、吡咯啶酮基、氮杂环丁基、哌嗪基、哌嗪酮基、哌啶基、硫雜環丁基、1,1-二侧氧基硫雜環丁基、2,6-二氮雜螺[3.3]庚基、2,5-二氮雜雙環[2.2.1]庚基、氮雜環庚基、二氧雜環庚基、氧氮雜環庚基、二氮雜環庚基、噻唑啶基、四氫噻吩基、四氫吡啶基、硫代嗎啉基、4-甲基哌嗪基、嗎啉酮基、二硫戊環基、二氫吡咯基、二噁烷基、二氧戊環基、二氫吡啶基、二氫呋喃基、二氫異噁唑基、二氫噁唑基、咪唑啶基、異噁唑啶基、噁唑啶基、吡唑啶基及克羅滿基(cromanyl)。Preferably, the 4 to 7 heterocyclic alkyl groups are selected from the group consisting of: 1,1-di-dioxytetrahydrothiopheneyl, 1-di-dioxythiomorpholinyl, tetrahydropiperanyl, oxo-heterocyclic butyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, pyrrolidoneyl, azacyclobutyl, piperazinyl, piperazinoneyl, piperidinyl, thio-heterocyclic butyl, 1,1-di-di-dioxythio-heterocyclic butyl, 2,6-diazaspiro[3.3]heptyl, 2,5-diazabicyclic[2.2.1]. Heptyl, azirmonoheptyl, dioxoheptyl, oxonitroheptyl, diazamonoheptyl, thiazolidinyl, tetrahydrothiopheneyl, tetrahydropyridyl, thiomorpholinyl, 4-methylpiperazinyl, morpholinoneyl, dithiopentaneyl, dihydropyrroleyl, dioxalkyl, dioxopentaneyl, dioxopentaneyl, dihydropyridyl, dihydrofuranyl, dihydroisooxazolyl, dihydrooxazolyl, imidazolidinyl, isoxazolyl, oxazolyl, pyrazolyl, and cromanyl.
尤其較佳之4至7員雜環烷基選自5至7員雜環烷基。較佳5至7員雜環烷基選自由以下組成之群：1,1-二側氧基四氫噻吩基、1-側氧基硫代嗎啉基、四氫哌喃基、四氫呋喃基、嗎啉基、吡咯啶基、吡咯啶酮基、哌嗪基、哌嗪酮基、哌啶基、2,6-二氮雜螺[3.3]庚基、2,5-二氮雜雙環[2.2.1]庚基、氮雜環庚基、二氧雜環庚基、氧氮雜環庚基、二氮雜環庚基、噻唑啶基、四氫噻吩基、四氫吡啶基、硫代嗎啉基、4-甲基哌嗪基、嗎啉酮基、二硫戊環基、二氫吡咯基、二噁烷基、二氧戊環基、二氫吡啶基、二氫呋喃基、二氫異噁唑基、二氫噁唑基、咪唑啶基、異噁唑啶基、噁唑啶基、吡唑啶基及克羅滿基。Particularly preferred are the 4 to 7-membered heterocycloalkyl groups selected from the 5 to 7-membered heterocycloalkyl groups. Preferably, the 5 to 7-membered heterocycloalkyl groups are selected from the group consisting of: 1,1-di-side-oxytetrahydrothiopheneyl, 1-side-oxythiomorphinyl, tetrahydropiperanyl, tetrahydrofuranyl, morphinyl, pyrrolidinyl, pyrrolidoneyl, piperazinyl, piperazinoneyl, piperidinyl, 2,6-diazaspiro[3.3]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, azirmonocycloheptyl, dioxane Heterocyclic heptyl, oxonitrocyclic heptyl, diazacyclic heptyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydropyridyl, thiomorpholinyl, 4-methylpiperazinyl, morpholinone, dithiopentaneyl, dihydropyrroleyl, dioxalkyl, dioxopentaneyl, dihydropyridyl, dihydrofuranyl, dihydroisooxazolyl, dihydrooxazolyl, imidazolidinyl, isoxazolyl, oxazolyl, pyrazolyl, and cromonyl.
較佳4至10員雜環烷基選自由以下組成之群：1,1-二側氧基四氫噻吩基、1-側氧基硫代嗎啉基、四氫哌喃基、氧雜環丁基、四氫呋喃基、嗎啉基、吡咯啶基、吡咯啶酮基、氮杂环丁基、哌嗪基、哌嗪酮基、哌啶基、硫雜環丁基、1,1-二侧氧基硫雜環丁基、2-氧雜螺[3.4]辛基、5-氧雜螺[2.4]庚基、2-氧雜雙環[2.1.1]己基、1,1-二侧氧基硫雜環丁基、2,3-二氫-[1,4]戴奧辛并[2,3-b]吡啶基、四氫-1,8-萘啶基、2,6-二氮雜螺[3.3]庚基、2,5-二氮雜雙環[2.2.1]庚基、氮雜環庚基、二氧雜環庚基、氧氮雜環庚基、二氮雜環庚基、噻唑啶基、四氫噻吩基、四氫吡啶基、硫代嗎啉基、4-甲基哌嗪基、嗎啉酮基、二硫戊環基、二氫吡咯基、二噁烷基、二氧戊環基、二氫吡啶基、二氫呋喃基、二氫異噁唑基、二氫噁唑基、咪唑啶基、異噁唑啶基、噁唑啶基、吡唑啶基、克羅滿基、5,7-二氫呋喃并[3,4-b]吡啶基及5,7-二氫呋喃并[3,4-d]嘧啶基；更佳地，四氫哌喃基、四氫呋喃基、2-氧雜螺[3.4]辛基、5-氧雜螺[2.4]庚基、2-氧雜雙環[2.1.1]己基、1,1-二侧氧基硫雜環丁基、2,3-二氫-[1,4]戴奧辛并[2,3-b]吡啶基、四氫-1,8-萘啶基、5,7-二氫呋喃并[3,4-b]吡啶基及5,7-二氫呋喃并[3,4-d]嘧啶基。Preferably, the 4 to 10 heterocyclic alkyl groups are selected from the group consisting of: 1,1-di-dioxytetrahydrothiophene, 1-di-dioxythiomorpholino, tetrahydropiperanyl, oxocyclobutyl, tetrahydrofuranyl, morpholino, pyrrolidinyl, pyrrolidone, aziridine, piperazinyl, piperazinone, piperidinyl, thiocyclobutyl, 1,1-di-di-dioxythiocyclobutyl, 2-oxozyro[3.4]octyl, 5-oxozyro[2.4]heptyl. 2-Oxadiazonium[2.1.1]hexyl, 1,1-di-side-oxythio-cyclobutyl, 2,3-dihydro-[1,4]dioxin[2,3-b]pyridyl, tetrahydro-1,8-naphthidyl, 2,6-diazaspiro[3.3]heptyl, 2,5-diazabiazonium[2.2.1]heptyl, azirmono-heptyl, dioxa-azirmono-heptyl, oxonitrile-azirmono-heptyl, diazirmono-heptyl, thiazolidinyl, tetrahydrothiophene, tetrahydro Pyridyl, thiomorpholinyl, 4-methylpiperazinyl, morpholinone, dithiopentaneyl, dihydropyrrolyl, dioxalkyl, dioxopentaneyl, dihydropyridinyl, dihydrofuranyl, dihydroisooxazolyl, dihydrooxazolyl, imidazodinyl, isoxazolidine, oxazolidine, pyrazolidine, cromonyl, 5,7-dihydrofurano[3,4-b]pyridinyl and 5,7-dihydrofurano[3,4-d]pyrimidinyl; more preferably, tetrahydrofurano[3,4-d]pyrimidinyl Piperanyl, tetrahydrofuranyl, 2-oxozyro[3.4]octyl, 5-oxozyro[2.4]heptyl, 2-oxozyrobicyclo[2.1.1]hexyl, 1,1-di-side-oxythiocyclobutyl, 2,3-dihydro-[1,4]diaoxin[2,3-b]pyridyl, tetrahydro-1,8-naphthidyl, 5,7-dihydrofuran[3,4-b]pyridyl and 5,7-dihydrofuran[3,4-d]pyrimidinyl.
根據本發明，術語「5至10員雜芳基」及「5員至6員雜芳基」較佳地分別意謂5、6、7、8、9或10員及5或6員單環或雙環芳族殘基，該殘基含有至少1個(若適宜，亦為2、3、4或5個)雜原子，其中該等雜原子各自彼此獨立地選自S、N及O之群，且該雜芳基殘基可為未經取代或單取代或多取代的(若無另外指示)。在雜芳基經取代之情況下，取代基可為相同或不同的且可在雜芳基之任何所需及可能的位置處。若無另外指示，則與上位一般結構之結合可經由雜芳基殘基之任何所需及可能的環成員來進行。較佳地，5至10員雜芳基及5員至6員雜芳基經由雜環之碳原子與上位一般結構結合。雜芳基亦可與其他飽和或(部分)不飽和環烷基或雜環烷基環系統稠合，後者又可為未經取代或單取代或多取代的，從而成為具有至多14個環成員之雙環或多環系統之一部分。在一較佳實施例中，5至10員雜芳基及5員至6員雜芳基不與其他飽和或(部分)不飽和環烷基或雜環烷基環系統稠合。在另一較佳實施例中，5至10員雜芳基及5員至6員雜芳基與其他飽和或(部分)不飽和環烷基或雜環烷基環系統稠合。較佳地，5至10員雜芳基選自5員至6員雜芳基。較佳地，5員至6員雜芳基選自由以下組成之群：吡啶基(亦即，2-吡啶基、3-吡啶基、4-吡啶基)、嘧啶基、嗒嗪基、吡嗪基、吡咯基、咪唑基、吡唑基、噁唑基、異噁唑基、噻唑基、異噻唑基、呋喃基、噻吩基(thienyl/thiophenyl)、三唑基、噻二唑基、4,5,6,7-四氫-2H-吲唑基、2,4,5,6-四氫環戊二烯并[c]吡唑基、苯并呋喃基、苯并咪唑基、苯并噻吩基、苯并噻二唑基、苯并噻唑基、苯并三唑基、苯并噁唑基、苯并噁二唑基、喹唑啉基、喹噁啉基、咔唑基、喹啉基、二苯并呋喃基、二苯并噻吩基、咪唑并噻唑基、吲唑基、吲嗪基、吲哚基、異喹啉基、萘啶基、噁唑基、噁二唑基、啡嗪基、啡噻嗪基、呔嗪基、嘌呤基、啡嗪基、四唑基及三嗪基。尤其較佳之5員至6員雜芳基選自由吡啶基(亦即，2-吡啶基、3-吡啶基、4-吡啶基)組成之群。According to the present invention, the terms "5 to 10 member heteroaryl" and "5 to 6 member heteroaryl" preferably mean 5, 6, 7, 8, 9 or 10 members and 5 or 6 members of a monocyclic or bicyclic aromatic residue, respectively, containing at least one (and, where appropriate, 2, 3, 4 or 5) heteroatoms, wherein each heteroatom is independently selected from the group of S, N and O, and the heteroaryl residue may be unsubstituted, monosubstituted or polysubstituted (unless otherwise indicated). In the case of substitution of the heteroaryl, the substituents may be the same or different and may be at any desired and possible position on the heteroaryl. Unless otherwise indicated, the combination with the general structure in the superposition may be carried out by any desired and possible ring member of the heteroaryl residue. Preferably, the 5- to 10-membered heteroaryl and the 5- to 6-membered heteroaryl are bonded to the general structure above the carbon atom of the heterocycle. The heteroaryl may also be fused with other saturated or (partially) unsaturated cycloalkyl or heterocycloalkyl ring systems, which may be unsubstituted, monosubstituted, or polysubstituted, thus becoming part of a bicyclic or polycyclic system having up to 14 ring members. In a preferred embodiment, the 5- to 10-membered heteroaryl and the 5- to 6-membered heteroaryl are not fused with other saturated or (partially) unsaturated cycloalkyl or heterocycloalkyl ring systems. In another preferred embodiment, the 5- to 10-membered heteroaryl group and the 5- to 6-membered heteroaryl group are fused with other saturated or (partially) unsaturated cycloalkyl or heterocycloalkyl ring systems. Preferably, the 5- to 10-membered heteroaryl group is selected from the 5- to 6-membered heteroaryl group. Preferably, the 5 to 6 heteroaryl groups are selected from the group consisting of: pyridinyl (i.e., 2-pyridinyl, 3-pyridinyl, 4-pyridinyl), pyrimidinyl, pyrazinyl, pyrazinyl, pyrroleyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, thienyl/thiophenyl, triazolyl, thiadiazolyl, 4,5,6,7-tetrahydro-2H-indazolyl, 2,4,5,6-tetrahydrocyclopentane. Dienzo[c]pyrazolyl, benzofuranyl, benzoimidazoyl, benzothiophenyl, benzothiadiazolyl, benzothiazoyl, benzotriazolyl, benzooxazolyl, benzooxiadiazolyl, quinazolinyl, quinoxolinyl, carbazole, quinolinyl, dibenzofuranyl, dibenzothiaphenyl, imidazothiazoyl, indazole, indazinyl, indolyl, isoquinolinyl, naphridinyl, oxazolyl, oxiadiazolyl, benazinoyl, benazinoyl, terazinyl, purinyl, benazinoyl, tetrazolyl, and triazinyl. Particularly preferred are the 5- to 6-membered heteroaryl groups selected from the group consisting of pyridinyl (i.e., 2-pyridinyl, 3-pyridinyl, 4-pyridinyl).
較佳地，5員至10員雜芳基選自由以下組成之群：吡啶基(亦即，2-吡啶基、3-吡啶基、4-吡啶基)、嘧啶基、嗒嗪基、吡嗪基、吡咯基、咪唑基、吡唑基、噁唑基、異噁唑基、噻唑基、異噻唑基、呋喃基、噻吩基(thienyl/thiophenyl)、三唑基、噻二唑基、4,5,6,7-四氫-2H-吲唑基、2,4,5,6-四氫環戊二烯并[c]吡唑基、苯并呋喃基、苯并咪唑基、苯并噻吩基、苯并噻二唑基、苯并噻唑基、苯并三唑基、苯并噁唑基、苯并噁二唑基、喹唑啉基、喹噁啉基、咔唑基、喹啉基、2,3-二氫-[1,4]戴奧辛并[2,3-b]吡啶基、四氫-1,8-萘啶基、噻吩并[3,2-b]吡啶基、5,6,7,8-四氫異喹啉基、5,7-二氫呋喃并[3,4-d]嘧啶基、5,7-二氫呋喃并[3,4-b]吡啶基、二苯并呋喃基、二苯并噻吩基、咪唑并噻唑基、吲唑基、吲嗪基、吲哚基、異喹啉基、萘啶基、噁唑基、噁二唑基、啡嗪基、啡噻嗪基、呔嗪基、嘌呤基、啡嗪基、四唑基及三嗪基；更佳地，吡啶基、嘧啶基、嗒嗪基、吡嗪基、吡唑基、噁唑基、噻唑基、噻二唑基、苯并噻唑基、喹啉基、2,3-二氫-[1,4]戴奧辛并[2,3-b]吡啶基、四氫-1,8-萘啶基、噻吩并[3,2-b]吡啶基、5,6,7,8-四氫異喹啉基、5,7-二氫呋喃并[3,4-d]嘧啶基及5,7-二氫呋喃并[3,4-b]吡啶基。Preferably, the 5 to 10 heteroaryl groups are selected from the group consisting of: pyridinyl (i.e., 2-pyridinyl, 3-pyridinyl, 4-pyridinyl), pyrimidinyl, pyrazinyl, pyrazinyl, pyrroleyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, thienyl/thiophenyl, triazolyl, thiadiazolyl, 4,5,6,7-tetrahydro-2H-indazole 2,4,5,6-Tetrahydrocyclopentadien[c]pyrazolyl, benzofuranyl, benzimidazolyl, benzothiophenyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, benzooxazolyl, benzooxadiazolyl, quinazolinyl, quinoxolinyl, carbazole, quinolinyl, 2,3-dihydro-[1,4]dioxin[2,3-b]pyridyl, tetrahydro-1,8-naphthidyl, thien[3,2-b]pyridyl, 5,6,7,8-Tetrahydroisoquinolinyl, 5,7-dihydrofurano[3,4-d]pyrimidinyl, 5,7-dihydrofurano[3,4-b]pyridinyl, dibenzofuranyl, dibenzothiophenyl, imidazothiazolyl, indazole, indazinyl, indolyl, isoquinolinyl, naphridinyl, oxazolyl, oxadiazolyl, benazinoyl, benazinoylthiazolyl, terazinyl, purine, benazinoyl, tetrazolyl, and triazinyl; more preferably, pyridinyl, pyrimidinyl... The following are listed: pyridyl, pyrazinyl, pyrazolyl, oxazolyl, thiazolyl, thiadiazolyl, benzothiazolyl, quinolinyl, 2,3-dihydro-[1,4]diaoxin[2,3-b]pyridyl, tetrahydro-1,8-naphthidyl, thieno[3,2-b]pyridyl, 5,6,7,8-tetrahydroisoquinolinyl, 5,7-dihydrofuran[3,4-d]pyrimidinyl, and 5,7-dihydrofuran[3,4-b]pyridyl.
結合術語「C1-6烷基」、「C1-4烷基」、「C1-4伸烷基」、「C1-3伸烷基」、「C1-2伸烷基」、「C3-10環烷基」、「C3-7環烷基」、「C3-6環烷基」、「C5-7環烷基」、「4員至10員雜環烷基」及「4員至7員雜環烷基」，在本發明之意義上與相應殘基或基團相關之術語「經取代」係指一或多個氫原子各自彼此獨立地經至少一個取代基單一取代(單取代)或多重取代(多取代)，例如二取代、三取代或四取代；更佳地，單取代、二取代或三取代。在多重取代之情況下，亦即在多取代殘基(諸如二取代或三取代殘基)之情況下，此等殘基可在不同或相同原子上經多取代，例如在同一碳原子上經三取代(如在CF3、CH2CF3之情況下)或經二取代(如在1,1-二氟環丙基之情況下)或在多個點處經多取代(如在1-氯-3-氟環丙基之情況下)。多重取代可使用相同取代基或使用不同取代基來進行。In conjunction with the terms " C1-6 alkyl", " C1-4 alkyl", " C1-4 cycloalkyl", " C1-3 cycloalkyl", " C1-2 cycloalkyl", " C3-10 cycloalkyl", " C3-7 cycloalkyl", " C3-6 cycloalkyl", " C5-7 cycloalkyl", "4-10-membered heterocycloalkyl", and "4-7-membered heterocycloalkyl", the term "substituted" in the sense of the present invention, in relation to the corresponding residual group or group, means that one or more hydrogen atoms are each independently substituted by at least one substituent in a single substitution (monosubstituted) or multiple substitution (polysubstituted), such as disubstituted, trisubstituted, or tetrasubstituted; more preferably, monosubstituted, disubstituted, or trisubstituted. In the case of multiple substitution, that is, in the case of multiple substituted residues (such as disubstituted or trisubstituted residues), these residues can be multiple substituted on different or the same atoms. For example, they can be trisubstituted on the same carbon atom (as in the case of CF3 , CH2CF3 ) or disubstituted (as in the case of 1,1-difluorocyclopropyl) or multiple substituted at multiple sites (as in the case of 1-chloro- 3 -fluorocyclopropyl). Multiple substitution can be carried out using the same substituents or using different substituents.
若殘基在分子內出現多次，則此殘基可針對多個取代基具有分別不同之含義：例如，若R4及R6均表示C1-6烷基，則C1-6烷基對於R4可表示例如甲基且對於R6可表示2-丙基。If a residual group appears multiple times within a molecule, then this residual group can have different meanings for multiple substituents: for example, if both R4 and R6 represent C1-6 alkyl, then C1-6 alkyl can represent, for example, methyl for R4 and 2-propyl for R6 .
根據本發明，C1-6烷基、C1-4烷基、C1-4伸烷基、C1-3伸烷基、C1-2伸烷基、C3-10環烷基、C3-7環烷基、C3-6環烷基、C5-7環烷基、4員至10員雜環烷基、4員至7員雜環烷基及5員至7員雜環烷基在各情況下彼此獨立地未經取代或經一或多個選自以下之取代基單取代或多取代：F；Cl；CN；C1-6烷基；CF3；CF2H；CFH2；OH；=O；OCF3；OCF2H；OCFH2；O-C1-6烷基；NH2；N(H)(C1-6烷基)；N(C1-6烷基)2；SCF3；SCF2H；SCFH2；及S-C1-6烷基；更佳地，F；OH；=O；O-C1-6烷基；N(C1-6烷基)2；及S-C1-6烷基。According to the present invention, C1-6 alkyl, C1-4 alkyl, C1-4 cycloalkyl, C1-3 cycloalkyl, C1-2 cycloalkyl, C3-10 cycloalkyl, C3-7 cycloalkyl, C3-6 cycloalkyl, C5-7 cycloalkyl, 4-10 heterocycloalkyl, 4-7 heterocycloalkyl, and 5-7 heterocycloalkyl are, in each case, independently unsubstituted or monosubstituted or polysubstituted with one or more substituents selected from the following: F; Cl; CN; C1-6 alkyl; CF3 ; CF2H ; CFH2 ; OH; =O; OCF3 ; OCF2H ; OCFH2 ; OCF1-6 alkyl; NH2 ; N(H)( C1-6 alkyl); N( C1-6 alkyl) 2 ;SCF 3 ;SCF 2 H ;SCFH 2 ; and SC 1-6 alkyl ; more preferably, F ;OH ;=O ;OC 1-6 alkyl ;N(C 1-6 alkyl) 2 ; and SC 1-6 alkyl .
進一步根據本發明，苯基、5員至10員雜芳基及5或6員雜芳基在各情況下彼此獨立地未經取代或經一或多個選自以下之取代基單取代或多取代：F；Cl；CN；C1-6烷基；CF3；CF2H；CFH2；OH；OCF3；OCF2H；OCFH2；O-C1-6烷基；NH2；N(H)(C1-6烷基)；及N(C1-6烷基)2；較佳地，F；Cl；C1-6烷基；CF3；OH；OCF3；及O-C1-6烷基；最佳地，F。Further according to the present invention, the phenyl, 5- to 10-membered heteroaryl and 5 or 6-membered heteroaryl are, in each case, independently unsubstituted or monosubstituted or polysubstituted by one or more substituents selected from the following: F ; Cl; CN; C1-6 alkyl; CF3 ; CF2H ; CFH2 ; OH; OCF3 ; OCF2H; OCFH2 ; OC1-6 alkyl; NH2 ; N(H)( C1-6 alkyl); and N( C1-6 alkyl) 2 ; preferably, F; Cl; C1-6 alkyl; CF3 ; OH; OCF3 ; and OC1-6 alkyl; most preferably, F.
根據本發明，A及B彼此獨立地表示苯基、5至10員雜芳基、C1-6烷基、C3-10環烷基或4員至10員雜環烷基；較佳地，苯基、5至10員雜芳基、C3-10環烷基或4員至10員雜環烷基。According to the present invention, A and B independently represent phenyl, 5 to 10-membered heteroaryl, C1-6 alkyl, C3-10 cycloalkyl or 4 to 10-membered heterocycloalkyl; preferably, phenyl, 5 to 10-membered heteroaryl, C3-10 cycloalkyl or 4 to 10-membered heterocycloalkyl.
在一較佳實施例中，A及B中之至少一者表示苯基或5員或6員雜芳基。In a preferred embodiment, at least one of A and B represents a phenyl or a 5- or 6-membered heteroaryl group.
在另一較佳實施例中，A表示苯基、5員或6員雜芳基或C3-7環烷基；更佳地，苯基或5員或6員雜芳基。In another preferred embodiment, A represents phenyl, 5- or 6-membered heteroaryl or C3-7 cycloalkyl; more preferably, phenyl or 5- or 6-membered heteroaryl.
在另一較佳實施例中，A表示苯基、噻吩基、吡啶基、環己基或環丁基；更佳地，苯基或噻吩基。In another preferred embodiment, A represents phenyl, thiophene, pyridyl, cyclohexyl, or cyclobutyl; more preferably, phenyl or thiophene.
在另一較佳實施例中，B表示苯基、5員至10員雜芳基、C1-6烷基、C3-10環烷基或4員至10員雜環烷基。In another preferred embodiment, B represents phenyl, 5- to 10-membered heteroaryl, C1-6 alkyl, C3- to 10 -cycloalkyl, or 4- to 10-membered heterocycloalkyl.
在又一較佳實施例中，B表示環丙基、環丁基、環戊基、環己基、環己烯基、螺[2.5]辛基、螺[2.3]己基、螺[3.3]庚基、雙環[3.1.1]庚基、雙環[2.2.1]庚基、雙環[3.2.0]庚基、雙環[2.2.2]辛基、雙環[4.1.0]庚基、2,3-二氫-1H-茚基、雙環[1.1.1]戊基、雙環[2.1.1]己基、5,6,7,8-四氫異喹啉基、5-氧雜螺[2.4]庚基、2-氧雜螺[3.4]辛基、四氫哌喃基、四氫呋喃基、2-氧雜雙環[2.1.1]己基、1,1-二側氧基硫雜環丁基、2,3-二氫-[1,4]戴奧辛并[2,3-b]吡啶基、四氫-1,8-萘啶基、5,7-二氫呋喃并[3,4-b]吡啶基、5,7-二氫呋喃并[3,4-d]嘧啶基、苯基、吡啶基、嘧啶基、嗒嗪基、吡嗪基、吡唑基、噁唑基、噻唑基、噻二唑基、苯并噻唑基、喹啉基、噻吩并[3,2-b]吡啶基、甲基、2-丙基或異戊烯基。In yet another preferred embodiment, B represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, spiro[2.5]octyl, spiro[2.3]hexyl, spiro[3.3]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.0]heptyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]heptyl, bicyclo[3.2.2]heptyl, bicyclo[3.2.2]heptyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.2]heptyl, bicyclo[3.1 ... Cyclo[2.2.2]octyl, bicyclo[4.1.0]heptyl, 2,3-dihydro-1H-indenyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, 5,6,7,8-tetrahydroisoquinolinyl, 5-oxozyro[2.4]heptyl, 2-oxozyro[3.4] Octyl, tetrahydropiperanyl, tetrahydrofuranyl, 2-oxobis(2.1.1)hexyl, 1,1-dioxythiobis(2,3-b)-pyridyl, tetrahydro-1,8-naphthidyl, 5,7-dihydrofuran(3,4-b)-pyridyl, 5,7-dihydrofuran(3,4-d)-pyrimidinyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazinyl, pyrazolyl, oxazolyl, thiazolyl, thiadiazolyl, benzothiazolyl, quinolinyl, thieno[3,2-b]pyridyl, methyl, 2-propyl or isopentenyl.
根據本發明，L1表示O、C(R7)2-O、O-C(R7)2、N(R7)、C(R7)2-N(R7)、N(R7)-C(R7)2、S、C(R7)2-S、S-C(R7)2、C(R7)2或C(R7)2C(R7)2。According to the present invention, L1 represents O, C( R7 ) 2 -O, OC( R7 ) 2 , N( R7 ), C( R7 ) 2 -N( R7 ), N( R7 )-C( R7 ) 2 , S, C( R7 ) 2 -S, SC( R7 ) 2 , C( R7 ) 2 or C( R7 ) 2C ( R7 ) 2 .
在一較佳實施例中，L1表示O、O-C(R7)2、N(R7)、S或C(R7)2。更佳地，L1表示O、O-CH(CH3)、O-CH2、NH或N(CH3)。In a preferred embodiment, L1 represents O, OC( R7 ) 2 , N( R7 ), S, or C( R7 ) 2 . More preferably, L1 represents O, O-CH( CH3 ), O- CH2 , NH, or N( CH3 ).
在一較佳實施例中，當L1表示NH時，B較佳表示5至10員雜芳基，更佳地5或6員雜芳基，其中該雜芳基較佳含有至少一個氮。In a preferred embodiment, when L1 represents NH, B preferably represents a 5 to 10-membered heteroaryl group, more preferably a 5 or 6-membered heteroaryl group, wherein the heteroaryl group preferably contains at least one nitrogen atom.
在另一較佳實施例中，當L1表示O或O-C(R7)2時，B較佳表示C3-10環烷基或苯基。In another preferred embodiment, when L1 represents O or OC( R7 ) 2 , B preferably represents C3-10 cycloalkyl or phenyl.
根據本發明，R7表示H或C1-4烷基。在一較佳實施例中，R7表示H或甲基。According to the present invention, R 7 represents H or C1-4 alkyl. In a preferred embodiment, R 7 represents H or methyl.
根據本發明，R2及R3彼此獨立地表示F、Cl、Br、CN、C1-6烷基、C3-6環烷基、NH2、N(H)C1-4烷基、N(C1-4烷基)2、OH、O-C1-4烷基、O-C3-6環烷基、SF5、苯基或C3-6環烷基。According to the present invention, R2 and R3 independently represent F, Cl, Br, CN, C1-6 alkyl, C3-6 cycloalkyl, NH2 , N(H) C1-4 alkyl, N( C1-4 alkyl) 2 , OH, OC1-4 alkyl, OC3-6 cycloalkyl, SF5 , phenyl or C3-6 cycloalkyl.
在一較佳實施例中，R2表示F、Cl、CN、C1-6烷基或O-C1-4烷基；較佳地，其中C1-6烷基及C1-4烷基在各情況下可獨立地未經取代、經F單取代、二取代或三取代。In a preferred embodiment, R2 represents F, Cl, CN, C1-6 alkyl or C1-4 alkyl; preferably, the C1-6 alkyl and C1-4 alkyl may, in each case, be independently unsubstituted, monosubstituted with F, disubstituted or trisubstituted.
在另一較佳實施例中，R3表示F、Cl、Br、OH、CN、C1-6烷基、O-C1-4烷基、O-C3-6環烷基、SF5、苯基或C3-6環烷基；較佳地，其中C1-6烷基及C1-4烷基在各情況下可獨立地未經取代、經以下單取代、二取代或三取代：F；OH；=O；O-C1-6烷基；N(C1-6烷基)2；或S-C1-6烷基。In another preferred embodiment, R3 represents F, Cl, Br, OH, CN, C1-6 alkyl, OC1-4 alkyl, OC3-6 cycloalkyl, SF5 , phenyl, or C3-6 cycloalkyl; preferably, the C1-6 alkyl and C1-4 alkyl may, in each case, be independently unsubstituted, monosubstituted, disubstituted, or trisubstituted: F; OH; =O; OC1-6 alkyl; N( C1-6 alkyl) 2 ; or SC1-6 alkyl.
在一較佳實施例中，當x及y為2、3或4時；R2之2、3或4個實體與R3之2、3或4個實體不相同。在一尤其較佳實施例中，當x表示2時，一個R2將表示F且一個R2將表示Cl，或兩個R2均將表示F，或兩個R2均將表示Cl。在一尤其較佳實施例中，當y表示2時，一個R3將表示F且一個R3將表示Cl。In a preferred embodiment, when x and y are 2, 3, or 4, the 2 , 3, or 4 entities of R 2 are not the same as the 2, 3, or 4 entities of R 3. In a particularly preferred embodiment, when x represents 2, one R 2 will represent F and one R 2 will represent Cl, or both R 2 will represent F, or both R 2 will represent Cl. In a particularly preferred embodiment, when y represents 2, one R 3 will represent F and one R 3 will represent Cl.
根據本發明，x及y彼此獨立地表示0、1、2、3或4。在一較佳實施例中，x及y彼此獨立地表示0、1、2或3；更佳地，0、1或2；最佳地，1或2。在一尤其較佳實施例中，x表示2。According to the present invention, x and y independently represent 0, 1, 2, 3, or 4. In a preferred embodiment, x and y independently represent 0, 1, 2, or 3; more preferably, 0, 1, or 2; most preferably, 1 or 2. In a particularly preferred embodiment, x represents 2.
根據本發明，R4表示H、Cl、CN、C1-6烷基或C3-6環烷基；較佳地，H或C1-6烷基；更佳地，H、CH3、CH2OH、CH2OCH3、CH2N(CH3)2或丙炔基。在一尤其較佳實施例中，R4表示H或CH3。According to the present invention, R4 represents H, Cl, CN, C1-6 alkyl or C3-6 cycloalkyl; preferably, H or C1-6 alkyl; more preferably, H, CH3 , CH2OH , CH2OCH3 , CH2N ( CH3 ) 2 or propynyl. In a particularly preferred embodiment, R4 represents H or CH3 .
根據本發明，L2表示表示鍵、C1-3伸烷基或C1-2伸烷基-N(H)。According to the present invention, L2 represents a bond, a C1-3 alkyl group or a C1-2 alkyl group -N(H).
在一較佳實施例中，L2表示鍵或C1-3伸烷基；更佳地，鍵、亞甲基或伸乙基。在一尤其較佳實施例中，L2表示鍵。In a preferred embodiment, L2 represents a bond or a C1-3 alkyl group; more preferably, a bond, a methylene group, or an ethyl group. In a particularly preferred embodiment, L2 represents a bond.
根據本發明，R5表示表示S(=O)R6、S(=O)(=NH)R6、S(=O)2R6或S(=O)2NH2。According to the present invention, R5 represents S (=O) R6 , S(=O)( = NH) R6 , S(=O) 2R6 or S(=O) 2NH2 .
在一較佳實施例中，R5表示S(=O)(=NH)R6、S(=O)R6、S(=O)2NH2或S(=O)2R6；其中R6表示甲基或2-丙基。In a preferred embodiment, R5 represents S(=O)(=NH) R6 , S(=O) R6 , S(=O) 2NH2 or S(=O) 2R6 ; wherein R6 represents methyl or 2- propyl .
根據本發明，R6表示C1-6烷基；更佳地，甲基或2-丙基；最佳地，甲基。According to the present invention, R 6 represents C 1-6 alkyl; more preferably, methyl or 2-propyl; most preferably, methyl.
根據本發明，根據本發明之化合物較佳選自由以下組成之群：
在一較佳實施例中，根據本發明之化合物為NaV1.8抑制劑。在本發明之意義上，術語「NaV1.8抑制劑」較佳意謂各別化合物在膜片鉗分析中展現以下對NaV1.8之IC50值：至多10 µM (10∙10-6mol/L)；更佳地，至多1 µM；更佳地，至多500 nM (10-9mol/L)；甚至更佳地，至多100 nM；且最佳地，至多10 nM。In a preferred embodiment, the compound according to the invention is a Na V 1.8 inhibitor. For the purposes of this invention, the term "Na V 1.8 inhibitor" preferably means that the individual compound exhibits the following IC50 values for Na V 1.8 in patch clamp analysis: up to 10 µM (10∙ 10⁻⁶ mol/L); more preferably, up to 1 µM; more preferably, up to 500 nM ( 10⁻⁹ mol/L); even more preferably, up to 100 nM; and most preferably, up to 10 nM.
以下實驗部分描述了用於測試化合物之效力的較佳分析以及用於確定對NaV1.8之IC50的方法。The experimental section below describes the preferred analysis used to test the potency of the compound and the method used to determine the IC50 for Na V 1.8.
在一較佳實施例中，根據本發明之化合物為NaV1.8之選擇性抑制劑。在本發明之意義上，術語「NaV1.8之選擇性抑制劑」較佳意謂各別化合物較佳地不對NaV1.1、NaV1.2、NaV1.4、NaV1.5及NaV1.6展現任何抑制活性。熟練技術人員知曉確定化合物是否對NaV1.1、NaV1.2、NaV1.4、NaV1.5及NaV1.6中之任一者展現抑制作用之適宜方式。In a preferred embodiment, the compound according to the invention is a selective inhibitor of Na V 1.8. For the purposes of this invention, the term "selective inhibitor of Na V 1.8" preferably means that the individual compound preferably does not exhibit any inhibitory activity against Na V 1.1, Na V 1.2, Na V 1.4, Na V 1.5, and Na V 1.6. Those skilled in the art know an appropriate manner for determining whether a compound exhibits inhibitory activity against any of Na V 1.1, Na V 1.2, Na V 1.4, Na V 1.5, and Na V 1.6.
因此，本發明係關於用於抑制NaV1.8之根據本發明之化合物。Therefore, this invention relates to a compound according to this invention for inhibiting Na V 1.8.
因此，本發明之另一態樣係關於用於治療疼痛的根據本發明之化合物。本發明之又一態樣係關於一種治療疼痛之方法；該方法包括向有需要之個體(較佳地，人類)投與治療有效量的根據本發明之化合物。Therefore, another aspect of the invention relates to the compound according to the invention for the treatment of pain. Yet another aspect of the invention relates to a method for treating pain, the method comprising administering a therapeutically effective amount of the compound according to the invention to an individual in need (preferably, a human).
本發明之另一態樣係關於作為藥劑的根據本發明之化合物。Another aspect of the invention relates to the compounds according to the invention as pharmaceutical preparations.
本發明之另一態樣係關於一種醫藥劑型，其包含根據本發明之化合物。較佳地，該醫藥劑型包含根據本發明之化合物及一或多種醫藥賦形劑，諸如生理學上可接受之載劑、添加劑及/或輔助物質；及視情況選用的一或多種其他藥理學活性成分。適宜生理學上可接受之載劑、添加劑及/或輔助物質之實例為填充劑、溶劑、稀釋劑、著色劑及/或黏合劑。此等物質為熟習此項技術者已知的(參見H. P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete, Editio Cantor Aulendoff)。Another aspect of the invention relates to a pharmaceutical dosage form comprising the compound according to the invention. Preferably, the pharmaceutical dosage form comprises the compound according to the invention and one or more pharmaceutical excipients, such as physiologically acceptable carriers, additives and/or excipients; and, where appropriate, one or more other pharmacologically active ingredients. Examples of suitable physiologically acceptable carriers, additives and/or excipients are fillers, solvents, diluents, colorants and/or binders. Such substances are known to those skilled in the art (see H. P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete, Editio Cantor Aulendoff).
根據本發明之醫藥劑型較佳用於全身、表面或局部投與，較佳用於經口投與。因此，該醫藥劑型可呈液體、半固體或固體形式，例如呈注射溶液、滴劑、汁液、糖漿、噴霧劑、懸浮液、錠劑、貼片、膜、膠囊、硬膏劑、栓劑、軟膏、乳膏、洗劑、凝膠、乳液、氣溶膠形式；或呈多微粒形式，例如呈集結粒或顆粒形式，在適當之情況下壓縮成錠劑、傾析至膠囊中或懸浮於液體中，且由此亦可進行投與。The pharmaceutical dosage form according to the present invention is preferably used for systemic, topical, or local administration, and is preferably used for oral administration. Therefore, the pharmaceutical dosage form can be in liquid, semi-solid, or solid form, such as injectable solutions, drops, juices, syrups, sprays, suspensions, tablets, patches, films, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions, or aerosols; or in multi-particle form, such as aggregates or particles, which, when appropriate, can be compressed into tablets, deposited into capsules, or suspended in a liquid, and can thus also be administered.
根據本發明之醫藥劑型較佳藉助於此項技術中已知之習知構件、裝置、方法及製程製備。欲投與至患者之根據本發明之化合物的量可發生變化且例如取決於患者之體重或年齡以及投與類型、適應症及病症之嚴重程度。較佳地，投與0.001至100 mg/kg、更佳地0.05至75 mg/kg、最佳地0.05至50 mg根據本發明之化合物/kg患者之體重。The pharmaceutical dosage form according to the invention is preferably prepared using conventional components, devices, methods, and processes known in the art. The amount of the compound according to the invention to be administered to a patient may vary and, for example, depend on the patient's weight or age, as well as the type of administration, indication, and severity of the condition. Preferably, 0.001 to 100 mg/kg, more preferably 0.05 to 75 mg/kg, and most preferably 0.05 to 50 mg of the compound according to the invention per kg of patient weight is administered.
因此，本發明之另一態樣係關於用於治療疼痛的根據本發明之醫藥劑型。本發明之另一態樣係關於一種治療疼痛之方法；該方法包括向有需要之個體(較佳地，人類)投與根據本發明之醫藥劑型。Therefore, another aspect of the invention relates to a pharmaceutical formulation according to the invention for the treatment of pain. Another aspect of the invention relates to a method for treating pain, the method comprising administering a pharmaceutical formulation according to the invention to an individual in need (preferably, a human).
本發明之實例可優先根據以下一般合成流程或使用熟習此項技術者已知之化學來合成。Examples of this invention can be synthesized preferably according to the following general synthetic procedure or using chemistry known to those skilled in the art.
一般合成流程所需L2-R5部分(如技術方案1中所定義)亦可但不排他地藉由熟習此項技術者已知之官能基相互轉化(FGI)來獲得。此類轉化之實例包括但不限於使用亞磺酸鹽(Synthesis,2016,48, 1939-1973)或多步驟程序將碘化或溴化中間物轉化為例如碸，以在過渡金屬催化下產生中間物硫醚，隨後氧化以產生亞碸(Chem. Rev. 2022,122, 16110-16293)或亞砜亞胺(Chem. Eur. J. 2021,27, 17293-17321)。此等轉化包括但不限於將中間物硫醚轉化為磺醯氯且進一步轉化為磺醯胺。可使用適宜保護基、保護及去保護方案來實現此類官能基相互轉化(FGI)。適宜保護基及相對反應性係文獻中已知的且包括例如SEM、苄基、Boc、酯基及TMS等(T. W. Green, P. G. M. Wuts,Protective Groups in Organic Synthesis, Wiley-Interscience,2007, 第4版, 872-893)。The L2 - R5 portion required in a typical synthetic procedure (as defined in Technical Scheme 1) can also be obtained, but not exclusively, by functional group interconversion (FGI) known to those skilled in the art. Examples of such conversions include, but are not limited to, using sulfinates ( Synthesis , 2016 , 48 , 1939-1973) or a multi-step procedure to convert iodide or bromide intermediates to, for example, sulfonates to produce intermediate sulfides under transition metal catalysis, followed by oxidation to produce sulfoxides ( Chem. Rev. 2022 , 122 , 16110-16293) or sulfoxides ( Chem. Eur. J. 2021 , 27 , 17293-17321). These transformations include, but are not limited to, the conversion of intermediate thioethers to sulfonyl chlorides and further to sulfonamides. Such functional group interconversions (FGIs) can be achieved using suitable protecting groups, protecting and deprotecting schemes. Suitable protecting groups and their relative reactivity are known in the literature and include, for example, SEM, benzyl, Boc, ester, and TMS (TW Green, PGM Wuts, Protective Groups in Organic Synthesis , Wiley-Interscience, 2007 , 4th ed., 872-893).
咪唑之保護可產生兩種不同的區域異構物。兩種區域異構物通常可在一組類似條件下經歷類似轉化。在以下流程中，為清楚起見，僅指示一種區域異構物。兩種區域異構物之去保護將產生相同的最終化合物。Protection of imidazole can yield two distinct regiomeric isomers. These two isomers typically undergo similar transformations under a set of similar conditions. In the following procedures, only one regiomeric isomer is indicated for clarity. Deprotection of both regiomeric isomers will produce the same final compound.
如流程1所示，可將去質子化之後的通式(A)或(B)之化合物(較佳鹼包括LDA)添加至通式(C)之醛中以產生通式(D)之醇。當使用通式(A)之化合物(其中H替代與R4相鄰的碳原子上之Hal)時，在金屬-有機加成步驟之後進行鹵化。較佳試劑包括NIS。As shown in Procedure 1, a deprotonated compound of general formula (A) or (B) (preferably including LDA) can be added to an aldehyde of general formula (C) to produce an alcohol of general formula (D). When using a compound of general formula (A) (where H replaces Hal on the carbon atom adjacent to R4 ), halogenation is performed after the metal-organic addition step. Preferred reagents include NIS.
通式(E)之化合物可由通式(D)之化合物藉由熟習此項技術者已知之官能基相互轉化(FGI)來製備。可將通式(E)之化合物去保護以產生通式(H)之化合物。通式(F)之化合物可藉由使用氧化劑(諸如MnO2)氧化通式(D)之化合物來製備。通式(G)之化合物可由通式(F)之化合物藉由熟習此項技術者已知之官能基相互轉化(FGI)來製備。 Compounds of general formula (E) can be prepared from compounds of general formula (D) by functional group interconversion (FGI) known to those skilled in the art. Compounds of general formula (E) can be deprotected to produce compounds of general formula (H). Compounds of general formula (F) can be prepared by oxidizing compounds of general formula (D) with an oxidizing agent (such as MnO₂ ). Compounds of general formula (G) can be prepared from compounds of general formula (F) by functional group interconversion (FGI) known to those skilled in the art.
流程 1 ：A、R2、R4、R5、L2及x係如技術方案1中所定義。PG =保護基，Hal = I、Br。 Process 1 : A, R2 , R4 , R5 , L2 , and x are as defined in Technical Solution 1. PG = Protective base, Hal = I, Br.
如流程2所示，通式(I-a)之化合物可由通式(H)之化合物在酸催化下使用通式(J)之胺來製備。適宜酸包括例如pTSA。通式(I-b)之化合物可藉由在酸催化下用醇(K)處理通式(H)之化合物來製備。適宜酸包括例如pTSA。 As shown in process 2, compounds of formula (Ia) can be prepared from compounds of formula (H) using amines of formula (J) under acid catalysis. Suitable acids include, for example, pTSA. Compounds of formula (Ib) can be prepared by treating compounds of formula (H) with alcohols (K) under acid catalysis. Suitable acids include, for example, pTSA.
流程 2 ：A、B、R2、R3、R4、R5、R7、L2、n= 0或1、x及y係如技術方案1中所定義。 Process 2 : A, B, R2 , R3 , R4 , R5 , R7 , L2 , n = 0 or 1, x and y are as defined in technical solution 1.
如流程3所示，通式(I-b)之化合物可替代地藉由用相應的烷基鹵化物(L)處理通式(E)之化合物、隨後去保護來獲得。通式(I-c)之化合物可替代地由(E)及(K)使用Mitsonobu條件、隨後去保護來獲得。適用於Mitsonubu反應之試劑包括DIAD及PPh3。 As shown in process 3, compounds of general formula (Ib) can alternatively be obtained by treating compounds of general formula (E) with the corresponding alkyl halogen (L) followed by deprotection. Compounds of general formula (Ic) can alternatively be obtained by using (E) and (K) under Mitsonobu conditions followed by deprotection. Reagents suitable for the Mitsonobu reaction include DIAD and PPh 3 .
流程 3 ：A、B、R2、R3、R4、R5、R7、L2、n= 0或1、L2、x及y係如技術方案1中所定義。PG =保護基。Hal = I、Br、Cl。 Process 3 : A, B, R2 , R3 , R4 , R5 , R7 , L2 , n = 0 or 1, L2 , x and y are as defined in technical solution 1. PG = protection base. Hal = I, Br, Cl.
如流程4所示，通式(I-d)之化合物可藉由使通式(M)之金屬-有機化合物與通式(G)之化合物反應，接著使用酸性條件(例如在諸如pTSA之酸及加熱存在下)消除中間物醇且同時進行去保護，隨後對中間物雙鍵進行氫化來製備。通式(I-a)之化合物可使用用通式(J)之胺進行還原胺化、隨後去保護之次序，由通式(G)之化合物製備。還原胺化採用熟習此項技術者已知之試劑及條件。 As shown in process 4, compounds of general formula (Id) can be prepared by reacting a metal-organic compound of general formula (M) with a compound of general formula (G), followed by elimination of the intermediate alcohol and deprotection under acidic conditions (e.g., in the presence of an acid such as pTSA and heating), and then hydrogenation of the intermediate double bonds. Compounds of general formula (Ia) can be prepared from compounds of general formula (G) by reductive amination with an amine of general formula (J) followed by deprotection. The reductive amination uses reagents and conditions known to those skilled in the art.
流程 4 ：A、B、R2、R3、R4、R5、R7、L2、n= 0或1、x及y係如技術方案1中所定義。PG =保護基。 Process 4 : A, B, R2 , R3 , R4 , R5 , R7 , L2 , n = 0 or 1, x and y are as defined in technical solution 1. PG = protection base.
如流程5所示，通式(B)之化合物可在採用Pd2(dba)3、Xanthphos及密封管中加熱之條件下使用通式(O)之試劑轉化為通式(P)之中間物。通式(P)之中間物可在諸如二乙醯氧基碘苯及碳酸銨之試劑存在下轉化為亞碸亞胺衍生物，其中L2-R5為S(=O)(=NH)R6)。 As shown in process 5, compounds of general formula (B) can be converted to intermediates of general formula (P) using reagents of general formula (O) under conditions of heating in a sealed tube with Pd₂ (dba) ₃ , Xanthphos, and a sealed tube. Intermediates of general formula (P) can be converted to monoxide derivatives in the presence of reagents such as diacetoxyiodobenzene and ammonium carbonate, wherein L₂ - R₅ is S(=O)(=NH) R₆ .
流程 5 ：R4、R5、L2係如技術方案1中所定義。Hal = I、Br。R12=如技術方案1中所定義之R6或保護基。 Process 5 : R4 , R5 , and L2 are as defined in technical solution 1. Hal = I, Br. R12 = R6 or the protection base as defined in technical solution 1.
如流程6所示，通式(R-1)、(R-2)、(R-3)及(R-4)之化合物可在通式(Q)之試劑及通式(C)之醛存在下，在諸如碳酸鈉之鹼存在下，由通式(A)、(B)、(P)或(N)之相應化合物獲得。通式(S-1)、(S-2)、(S-3)及(S-4)之化合物可藉由在諸如TFA之酸及/或BF3存在下，在溶劑(如二氯甲烷)中，在室溫下或在加熱下使通式(J)或(K)之試劑烷基化而由通式(R-1)、(R-2)、(R-3)及(R-4)之化合物製備，-OC=ON(R13)2將充當脫離基。轉化為(T-1)、(T-2)、(T-3)及(I)可能在相同反應條件下發生，或其可能需要額外去保護步驟。 As shown in process 6, compounds of general formulas (R-1), (R-2), (R-3), and (R-4) can be obtained from the corresponding compounds of general formulas (A), (B), (P), or (N) in the presence of a reagent of general formula (Q) and an aldehyde of general formula (C), in the presence of an alkali such as sodium carbonate. Compounds of general formulas (S-1), (S-2), (S-3), and (S-4) can be prepared from compounds of general formulas (R-1), (R-2), (R-3), and (R- 4 ) by alkylation of a reagent of general formula (J) or (K) in the presence of an acid such as TFA and/or BF3 in a solvent (such as dichloromethane) at room temperature or under heating, where -OC=ON(R 13 ) 2 will act as the desaturating group. The transformations to (T-1), (T-2), (T-3), and (I) may occur under the same reaction conditions, or may require additional protection steps.
流程 6 ：A、B、R2、R3、R4、R5、R7 ；L1、n= 0或1、x及y係如技術方案1中所定義，R12=如技術方案1中所定義之R6或保護基，R13=烷基。 Process 6 : A, B, R2 , R3 , R4 , R5 , R7 ; L1 , n = 0 or 1, x and y are as defined in technical solution 1, R12 = R6 or protecting group as defined in technical solution 1, R13 = alkyl group.
如流程7所示，通式(R-3-a)之化合物可在諸如存在Pd2(dba)3、Xanthphos及密封管中加熱之條件下使用通式(O-1)之試劑由通式(R-2)之化合物獲得。通式(R-3-a)之化合物可在諸如二乙醯氧基碘苯及碳酸銨之試劑存在下轉化為通式(R-4-a)之化合物。通式(R-3-a)之化合物可藉由在諸如含間氯過氧苯甲酸之二氯甲烷之試劑存在下氧化而轉化為通式(R-4-b)之化合物。(R-4-a)及(R-4-b)屬於(R-4)之一般定義。 As shown in process 7, compounds of general formula (R-3-a) can be obtained from compounds of general formula (R-2) using reagents of general formula (O-1) under conditions such as the presence of Pd₂ (dba) ₃ , Xanthphos, and heating in a sealed tube. Compounds of general formula (R-3-a) can be converted to compounds of general formula (R-4-a) in the presence of reagents such as acetylatedoiodobenzene and ammonium carbonate. Compounds of general formula (R-3-a) can be converted to compounds of general formula (R-4-b) by oxidation in the presence of reagents such as dichloromethane containing m-chloroperoxybenzoic acid. (R-4-a) and (R-4-b) are general definitions of (R-4).
流程 7 ：A、R2、R4、R6及x係如技術方案1中所定義。R13為烷基。 Process 7 : A, R2 , R4 , R6 and x are as defined in technical solution 1. R13 is an alkyl group.
如流程8所示，通式(U)之中間物可由通式(C)之醛及通式(J-1)之一級胺製備。可使用酸催化劑(如pTSA)、乾燥劑(諸如MgSO4)及加熱來進行此類轉化。在諸如LDA之鹼存在下使通式(A)、(B)、(P)或(N)之化合物去質子化，隨後添加通式(U)之中間物，產生通式(V-1)、(V-2)、(V-3)及(V-4)之化合物。此等化合物之去保護產生通式(W-1)、(W-2)、(W-3)及(I-e)之化合物。 As shown in process 8, intermediates of general formula (U) can be prepared from aldehydes of general formula (C) and primary amines of general formula (J-1). This type of conversion can be carried out using acid catalysts (such as pTSA), desiccants (such as MgSO₄ ), and heating. Deprotonation of compounds of general formulas (A), (B), (P), or (N) in the presence of an alkali such as LDA, followed by the addition of an intermediate of general formula (U), yields compounds of general formulas (V-1), (V-2), (V-3), and (V-4). Deprotection of these compounds yields compounds of general formulas (W-1), (W-2), (W-3), and (Ie).
流程 8 ：A、B、R2、R3、R4、R5、L2、x及y係如技術方案1中所定義且R12=如技術方案1中所定義之R6或保護基。 Process 8 : A, B, R2 , R3 , R4 , R5 , L2 , x and y are as defined in technical solution 1 and R12 = R6 or the protection base as defined in technical solution 1.
如流程9所示，通式(S-1)之化合物可轉化為通式(S-2)之化合物。較佳試劑包括NIS。通式(S-3)之化合物可由通式(S-2)之化合物藉由在諸如存在Pd2(dba)3、Xantphos及密封管中加熱之條件下與通式(O)之試劑反應而獲得。 As shown in process 9, the compound of general formula (S-1) can be converted into the compound of general formula (S-2). Preferred reagents include NIS. The compound of general formula (S-3) can be obtained from the compound of general formula (S-2) by reacting it with the reagent of general formula (O) under conditions such as the presence of Pd2 (dba) 3 , Xantphos, and heating in a sealed tube.
流程 9 ：A、R2、R3、R4、L1、x及y係如技術方案1中所定義。Hal = I、Br。R12=如技術方案1中所定義之R6或保護基。 Process 9 : A, R2 , R3 , R4 , L1 , x, and y are as defined in technical solution 1. Hal = I, Br. R12 = R6 or the protection base as defined in technical solution 1.
如流程10所示，通式(S-4-a)之化合物可在諸如二乙醯氧基碘苯及碳酸銨之試劑存在下由通式(S-3)之化合物獲得。通式(S-3)之化合物(其中R12為保護基，諸如PMB或Bn)可使用例如NCS及乙酸之試劑轉化為通式(X)之化合物。將氨添加至通式(X)之化合物中導致形成通式(S-4-c)之化合物。通式(S-4)之化合物包括通式(S-4-a)及(S-4-c)之化合物。 As shown in process 10, compounds of general formula (S-4-a) can be obtained from compounds of general formula (S-3) in the presence of reagents such as acetylatedoiodobenzene and ammonium carbonate. Compounds of general formula (S-3) (where R 12 is a protecting group, such as PMB or Bn) can be converted to compounds of general formula (X) using reagents such as NCS and acetic acid. Adding ammonia to a compound of general formula (X) results in the formation of a compound of general formula (S-4-c). Compounds of general formula (S-4) include compounds of general formulas (S-4-a) and (S-4-c).
流程 10 ：A、B、R2、R3、R4、L1、x及y係如技術方案1中所定義。R12=如技術方案1中所定義之R6或保護基。 Process 10 : A, B, R2 , R3 , R4 , L1 , x, and y are as defined in technical solution 1. R12 = R6 or the protection base as defined in technical solution 1.
如流程11所示，通式(S-4)之化合物可藉由去保護轉化為通式(I)之化合物。在咪唑上之SEM保護基的情況下，去保護可能在酸性條件下完成。通式(S-4-a)及(S-4-c)之化合物屬於通式(S-4)之化合物的一般定義。 As shown in process 11, compounds of general formula (S-4) can be transformed into compounds of general formula (I) by deprotection. In the case of a SEM protecting group on an imidazole, deprotection may be carried out under acidic conditions. Compounds of general formula (S-4-a) and (S-4-c) belong to the general definition of compounds of general formula (S-4).
流程 11 ：A、B、R2、R3、R4、R5、L1、L2、x及y係如技術方案1中所定義。 Process 11 : A, B, R2 , R3 , R4 , R5 , L1 , L2 , x and y are as defined in technical solution 1.
縮寫清單ABPR=自動背壓調節，ACN=乙腈，BINAP= 2,2'-雙(二苯基膦基)-1,1'-聯萘，Boc2O=二碳酸二-三級丁酯，DAST=二乙基胺基三氟化硫，dba=二亞苄基丙酮，DCE= 1,2-二氯乙烷，DCM=二氯甲烷；DIAD=偶氮二甲酸二異丙酯，DIBAL-H=二異丁基氫化鋁，DIPEA=N,N-二異丙基乙胺，DMF=二甲基甲醯胺，DMAP= 4-二甲基胺基吡啶；DMSO=二甲亞碸，dppf= 1,1'-雙(二苯基膦基)二茂鐵，EA=乙酸乙酯，FGI=官能基相互轉化，Hex=己烷，HPLC=高效液相層析，IPA=異丙醇，LCMS=液相層析-質譜法，LDA=二異丙基胺基鋰，mCPBA=間氯過氧苯甲酸，MW=微波，NCS= N-氯琥珀醯亞胺，NIS= N-碘琥珀醯亞胺，NMR=核磁共振，pet醚=石油醚，PG=保護基團，pTSA=對甲苯磺酸，RP=逆相，Rt=滯留時間，rt或RT=室溫，SEM= 2-(三甲基矽烷基)乙氧基甲基，SFC=超臨界流體層析，TBAF=四-正丁基氟化銨，TBDPS=四-丁基二苯基矽烷基，TEA=三乙胺，TFA=三氟乙酸，THF=四氫呋喃，TLC=薄層層析，Xantphos= (9,9-二甲基-9H-呫噸-4,5-二基)雙(二苯基磷烷)。 The abbreviations are: ABPR = Automatic Back Pressure Adjustment, ACN = Acetonitrile, BINAP = 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, Boc₂O = di-tert-butyl dicarbonate, DAST = diethylaminosulfur trifluoride, dba = dibenzylacetone, DCE = 1,2-dichloroethane, DCM = dichloromethane; DIAD = diisopropyl azodicarbonate, DIBAL-H = diisobutylaluminum hydrogenide, DIPEA = N , N -diisopropylethylamine, DMF = dimethylformamide, DMAP = 4-dimethylaminopyridine; DMSO = dimethyl sulfoxide, dppf = 1,1'-Bis(diphenylphosphino)ferrocene, EA = ethyl acetate, FGI = functional group interconversion, Hex = hexane, HPLC = high performance liquid chromatography, IPA = isopropanol, LCMS = liquid chromatography-mass spectrometry, LDA = diisopropylaminolithium, mCPBA = m-chloroperoxybenzoic acid, MW = microwave, NCS = N-chlorosuccinimide, NIS = N-iodosuccinimide, NMR = nuclear magnetic resonance, petroleum ether = petroleum ether, PG = protecting group, pTSA = p- toluenesulfonic acid, RP = reverse phase, Rt = retention time, rt or RT = room temperature, SEM = 2-(trimethylsilyl)ethoxymethyl, SFC = supercritical fluid chromatography, TBAF = tetra-n-butylammonium fluoride, TBDPS = tetra-butyldiphenylsilyl, TEA = triethylamine, TFA = trifluoroacetic acid, THF = tetrahydrofuran, TLC = thin-layer chromatography, Xantphos = (9,9-dimethyl-9H-xanton-4,5-diyl)bis(diphenylphosphine).
中間物 14-碘-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑及5-碘-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑之區域異構物混合物及 在0℃下將氫化鈉(礦物油中之60%分散液，0.297 g，12.372 mmol)添加至4-碘-1H-咪唑(2.0 g，10.310 mmol)於二甲基甲醯胺(20 mL)中之溶液中。將混合物在0℃下攪拌1 h，隨後在0℃下添加2-(三甲基矽烷基)乙氧基甲基氯(1.8 mL，10.3 mmol)。將反應物在rt下攪拌18 h。用冰水(10 mL)稀釋反應混合物且用乙酸乙酯(20 mL × 2)萃取。經無水Na2SO4乾燥合併之有機層，過濾且在減壓下濃縮，得到粗材料，藉由急驟層析純化，得到標題化合物之區域異構物混合物(1.7 g，51%)。 Intermediate 1 is a mixture of regiomeric isomers of 4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole and 5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole. and Sodium hydroxide (60% dispersion in mineral oil, 0.297 g, 12.372 mmol) was added to a solution of 4-iodo- 1H -imidazole (2.0 g, 10.310 mmol) in dimethylformamide (20 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h, followed by the addition of 2-(trimethylsilyl)ethoxymethyl chloride (1.8 mL, 10.3 mmol) at 0 °C. The reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with ice water (10 mL) and extracted with ethyl acetate (20 mL × 2). The organic layer was dried and combined with anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a crude material. The crude material was purified by rapid chromatography to obtain a mixture of regional isomers of the title compound (1.7 g, 51%).
中間物 24-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑及5-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑之區域異構物混合物及使用與針對中間物1所述類似之方法，由4-甲基-1H-咪唑製備標題化合物。產率：5.5 g，70%。LCMS: m/z [M+H]+= 213。 Intermediate 2 is a mixture of regiomeric isomers of 4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole and 5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole. and The title compound was prepared from 4-methyl-1H-imidazole using a method similar to that described for intermediate 1. Yield: 5.5 g, 70%. LCMS: m/z [M+H] + = 213.
中間物 3(3-氯-4-氟苯基)(4-碘-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲醇及(3-氯-4-氟苯基)(5-碘-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲醇之區域異構物混合物及在-78℃下將LDA (THF/正庚烷/乙苯中之2M溶液，12.4 mL，24.77 mmol)添加至4-碘-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑(中間物1，7.3 g，22.51 mmol)於THF中之溶液中。將反應物在-78℃下攪拌1 h，隨後添加3-氯-4-氟苯甲醛(3.570 g，22.51 mmol)。將反應混合物在-78℃下攪拌1 h。用飽和NH4Cl溶液(50 mL)淬滅反應物且用乙酸乙酯(100 mL × 2)萃取。經無水Na2SO4乾燥合併之有機層，過濾且蒸發，得到粗化合物，藉由急驟層析純化，得到標題化合物之區域異構物混合物(7.0 g，64%)。 Intermediate 3: A mixture of regiomeric isomers of (3-chloro-4-fluorophenyl)(4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol and (3-chloro-4-fluorophenyl)(5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol and LDA (12.4 mL, 24.77 mmol) in a 2M solution of THF/n-heptane/ethylbenzene was added to a solution of 4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl) -1H -imidazolium (intermediate 1, 7.3 g, 22.51 mmol) in THF at -78 °C. The reaction mixture was stirred at -78 °C for 1 h, followed by the addition of 3-chloro-4-fluorobenzaldehyde (3.570 g, 22.51 mmol). The reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched with saturated NH₄Cl solution (50 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were dried over anhydrous Na₂SO₄ , filtered, and evaporated to obtain a crude compound. The crude compound was purified by rapid chromatography to obtain a mixture of regional isomers of the title compound (7.0 g, 64%).
中間物 4(3-氯-4-氟苯基)(4-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲醇及(3-氯-4-氟苯基)(5-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲醇之區域異構物混合物及使用與針對中間物3所述類似之方法，由中間物2製備標題化合物。產率：2.5 g，29%。LCMS: m/z [M+H]+= 371。 Intermediate 4: A mixture of regiomeric isomers of (3-chloro-4-fluorophenyl)(4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol and (3-chloro-4-fluorophenyl)(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol and The title compound was prepared from intermediate 2 using a method similar to that described for intermediate 3. Yield: 2.5 g, 29%. LCMS: m/z [M+H] + = 371.
中間物 5(3-氯-4-氟苯基)(4-(甲基磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲醇及(3-氯-4-氟苯基)(5-(甲基磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲醇之區域異構物混合物及將L-脯胺酸(262.3 mg，2.278 mmol)添加至氫氧化鈉(91 mg，2.28 mmol)於DMSO (30 mL)中之氬氣吹掃溶液中。將混合物在rt下攪拌30 min，隨後在rt下添加中間物3之區域異構物混合物(1.1 g，2.28 mmol)、碘化銅(I) (434 mg，2.28 mmol)及甲烷亞磺酸鈉(930 mg，9.14 mmol)。將反應物加熱至120℃持續18 h。用水(30 mL)稀釋反應混合物且用乙酸乙酯(50 mL x 2)萃取。在減壓下蒸發有機層，產生標題化合物之區域異構物混合物(0.65 g，粗物質)，其未經進一步純化即用於下一步驟。 A mixture of intermediates of 5- (3-chloro-4-fluorophenyl)(4-(methylsulfonylurea)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol and (3-chloro-4-fluorophenyl)(5-(methylsulfonylurea)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol regiomeric isomers. and L-proline (262.3 mg, 2.278 mmol) was added to sodium hydroxide (91 mg, 2.28 mmol) in DMSO (30 mL) purged with argon. The mixture was stirred at rt for 30 min, followed by the addition of a mixture of regiomeric isomers of intermediate 3 (1.1 g, 2.28 mmol), copper(I) iodide (434 mg, 2.28 mmol), and sodium methanesulfinate (930 mg, 9.14 mmol) at rt. The reaction mixture was heated to 120 °C for 18 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL x 2). The organic layer was evaporated under reduced pressure, producing a mixture of regional isomers of the title compound (0.65 g, crude material), which was used in the next step without further purification.
中間物 6(3-氯-4-氟苯基)(4-(甲基磺醯基)-1H-咪唑-2-基)甲醇在rt下將中間物5 (500 mg，1.14 mmol)溶解於含4 M HCl之1,4-二噁烷(5 mL)中且將混合物攪拌18 h。在減壓下濃縮混合物，得到粗產物，藉由製備型HPLC純化，得到標題化合物(0.32 g)。LCMS m/z = 305 [M+H]+。 Intermediate 6- (3-chloro-4-fluorophenyl)(4-(methylsulfonylurea)-1H-imidazol-2-yl)methanol Intermediate 5 (500 mg, 1.14 mmol) was dissolved in 1,4-dioxane (5 mL) containing 4 M HCl under rt and the mixture was stirred for 18 h. The mixture was concentrated under reduced pressure to give a crude product, which was purified by preparative HPLC to give the title compound (0.32 g). LCMS m/z = 305 [M+H] + .
中間物 7(3-氯-4-氟苯基)(4-碘-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酮及(3-氯-4-氟苯基)(5-碘-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲醇之區域異構物混合物及在rt下向含中間物3之區域異構物混合物(5.0 g，10.373 mmol)之THF (100.0 mL)中添加MnO2(3.7 g，41.494 mmol)。將反應物加熱至60℃持續16 h。經由矽藻土床過濾反應混合物且在減壓下蒸發濾液，得到粗產物，藉由管柱層析純化，得到標題之區域異構物混合物(4.0 g，80%)。LCMS m/z = 481 [M+H]+。 Intermediate 7 is a mixture of regiomeric isomers of (3-chloro-4-fluorophenyl)(4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl) methyl ketone and (3-chloro-4-fluorophenyl)(5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl) methanol. and MnO₂ (3.7 g, 41.494 mmol) was added to THF (100.0 mL) containing a mixture of regional isomers (5.0 g, 10.373 mmol) of intermediate 3 at rt. The reaction mixture was heated to 60 °C for 16 h. The reaction mixture was filtered through a diatomaceous earth bed and the filtrate was evaporated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain the title regional isomer mixture (4.0 g, 80%). LCMS m/z = 481 [M+H] ⁺ .
中間物 8(3-氯-4-氟苯基)(4-(甲硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酮及(3-氯-4-氟苯基)(5-(甲硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酮之區域異構物混合物及用氬氣使含中間物7之區域異構物混合物(4.0 g，8.333 mmol)之1,4-二噁烷(100.0 mL)脫氣10 min。接著，在rt下添加NaSMe (0.875 g，12.5 mmol)、Xantphos (0.723 g，12.5 mmol)及Pd2(dba)3(0.763 g，0.833 mmol)。將反應混合物在密封管中加熱至110℃持續16 h。將反應混合物冷卻至rt且用冰水稀釋。用乙酸乙酯(2 x 100 mL)萃取水性部分。用鹽水洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮，得到粗產物，藉由管柱層析純化，產生標題化合物之區域異構物混合物(標題化合物(2.5 g，74%)。LCMS m/z = 401 [M+H]+。 Intermediate 8 is a mixture of regiomeric isomers of (3-chloro-4-fluorophenyl)(4-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ketone and (3-chloro-4-fluorophenyl)(5-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ketone. and The mixture of regiomeric isomers containing intermediate 7 (4.0 g, 8.333 mmol) and 1,4-dioxane (100.0 mL) was degassed with argon for 10 min. Then, NaSMe (0.875 g, 12.5 mmol), Xantphos (0.723 g, 12.5 mmol), and Pd₂ (dba) ₃ (0.763 g, 0.833 mmol) were added at rest. The reaction mixture was heated to 110 °C in a sealed tube for 16 h. The reaction mixture was cooled to rest and diluted with ice water. The aqueous fraction was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine, dried with Na₂SO₄ , and concentrated under reduced pressure to obtain a crude product. Purification by column chromatography yielded a mixture of regiomeric isomers of the title compound (title compound (2.5 g, 74%). LCMS m/z = 401 [M+H] ⁺) .
中間物 9(3-氯-4-氟苯基)(4-(甲基磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酮及(3-氯-4-氟苯基)(5-(甲基磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酮之區域異構物混合物及在0℃下向含中間物8之區域異構物混合物(1.5 g，3.732 mmol)之DCM (30.0 mL)中添加mCPBA (70%於水中；2.08 g，9.329 mmol)。將反應混合物在0℃下攪拌2 h。在0℃下用亞硫酸鈉及碳酸氫鈉溶液之(1:1)溶液淬滅反應混合物。用乙酸乙酯(3 × 60 mL)萃取水性部分。用鹽水洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮，得到粗產物，藉由CombiFlash管柱層析純化，產生經分離之區域異構物。 Intermediate 9 is a mixture of regiomeric isomers of (3-chloro-4-fluorophenyl)(4-(methylsulfonylurea)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl) methyl ketone and (3-chloro-4-fluorophenyl)(5-(methylsulfonylurea)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl) methyl ketone. and mCPBA (70% in water; 2.08 g, 9.329 mmol) was added to DCM (30.0 mL) containing a mixture of regiomeric isomers (1.5 g, 3.732 mmol) of intermediate 8 at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched at 0 °C with a (1:1) solution of sodium sulfite and sodium bicarbonate. The aqueous fraction was extracted with ethyl acetate (3 × 60 mL). The combined organic layers were washed with brine, dried over Na₂SO₄ , and concentrated under reduced pressure to give a crude product, which was purified by CombiFlash column chromatography to produce the separated regiomeric isomers.
中間物 9a：主要的區域異構物(0.9 g，55%)。LCMS m/z = 433 [M+H]+，Rt= 3.88 min，LCMS方法A Intermediate 9a : The main regional isomer (0.9 g, 55%). LCMS m/z = 433 [M+H] + , Rt = 3.88 min, LCMS method A
中間物 9b：次要的區域異構物(0.45 g，27%)。LCMS m/z = 433 [M+H]+，Rt= 3.66 min，LCMS方法A Intermediate 9b : minor regional isomer (0.45 g, 27%). LCMS m/z = 433 [M+H] + , Rt = 3.66 min, LCMS method A.
中間物 10(3-氯-4-氟苯基)(5-碘-4-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲醇及(3-氯-4-氟苯基)(4-碘-5-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲醇之區域異構物混合物及在0℃下向中間物4之區域異構物混合物(8.0 g，21.56 mmol)於MeCN (150 mL)中之攪拌溶液中添加NIS (5.83 g，25.88 mmol)。將反應混合物在rt下攪拌16 h。用飽和硫代硫酸鈉溶液淬滅反應混合物且用乙酸乙酯(3 x 500 mL)萃取。用鹽水(100 mL)洗滌合併之有機層，經無水Na2SO4乾燥且在減壓下濃縮，得到粗產物。藉由combi-flash管柱純化所得粗物質，產生產生經分離之區域異構物。 Intermediate 10 is a mixture of regiomeric isomers of (3-chloro-4-fluorophenyl)(5-iodo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol and (3-chloro-4-fluorophenyl)(4-iodo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol. and NIS (5.83 g, 25.88 mmol) was added to a stirred solution of intermediate 4 (8.0 g, 21.56 mmol) in MeCN (150 mL) at 0 °C. The reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched with saturated sodium thiosulfate solution and extracted with ethyl acetate (3 x 500 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na₂SO₄ , and concentrated under reduced pressure to give the crude product. The crude product was purified by combi-flash column chromatography to produce the separated regional isomers.
中間物 10a：主要的區域異構物(4.5 g，41%)。LCMS m/z = 497 [M+H]+，Rt= 2.14 min，LCMS方法B Intermediate 10a : the main regional isomer (4.5 g, 41%). LCMS m/z = 497 [M+H] + , Rt = 2.14 min, LCMS method B.
中間物 10b：次要的區域異構物(2.5 g，23%)。LCMS m/z = 497 [M+H]+，Rt= 2.20 min，LCMS方法B Intermediate 10b : minor regional isomer (2.5 g, 23%). LCMS m/z = 497 [M+H] + , Rt = 2.20 min, LCMS method B.
中間物 11(3-氯-4-氟苯基)(5-碘-4-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酮或(3-氯-4-氟苯基)(4-碘-5-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酮或在rt下向中間物10b (次要的區域異構物，3.5 g，7.04 mmol)於THF (50 mL)中之溶液中添加MnO2(2.45 g，28.18 mmol)。將反應物加熱至80℃持續16 h。將反應混合物冷卻至rt且經由燒結漏斗過濾。在減壓下蒸發濾液，得到粗產物，藉由combi-flash管柱層析純化，得到標題化合物(2.2 g，63%)。LCMS m/z = 495 [M+H]+。 Intermediate 11 (3-chloro-4-fluorophenyl)(5-iodo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl) methyl ketone or (3-chloro-4-fluorophenyl)(4-iodo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl) methyl ketone or MnO₂ (2.45 g, 28.18 mmol) was added to a solution of intermediate 10b (minor regional isomer, 3.5 g, 7.04 mmol) in THF (50 mL) at rt. The reaction mixture was heated to 80 °C for 16 h. The reaction mixture was cooled to rt and filtered through a sintered funnel. The filtrate was evaporated under reduced pressure to give a crude product, which was purified by combi-flash column chromatography to give the title compound (2.2 g, 63%). LCMS m/z = 495 [M+H] ⁺ .
中間物 12(3-氯-4-氟苯基)(4-甲基-5-(甲硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酮或(3-氯-4-氟苯基)(5-甲基-4-(甲硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酮或用氬氣使中間物11 (2.2 g，4.583 mmol)於1,4-二噁烷(70 mL)中之溶液脫氣10 min，隨後在rt下添加NaSMe (0.482 g，6.875 mmol)、Xantphos (0.4 g，0.687 mmol)及Pd2(dba)3(0.42 g，0.458 mmol)。將反應混合物在密封管中加熱至110℃持續16 h。將反應混合物冷卻至rt且用冰水稀釋。用乙酸乙酯(3 x 300 mL)萃取水性部分。用鹽水洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮。藉由CombiFlash管柱層析純化所得粗產物，產生標題化合物(1.1 g，58%)。LCMS m/z = 415 [M+H]+。 Intermediate 12 (3-chloro-4-fluorophenyl)(4-methyl-5-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl) methyl ketone or (3-chloro-4-fluorophenyl)(5-methyl-4-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl) methyl ketone or The intermediate 11 (2.2 g, 4.583 mmol) solution in 1,4-dioxane (70 mL) was degassed with argon for 10 min, followed by the addition of NaSMe (0.482 g, 6.875 mmol), Xantphos (0.4 g, 0.687 mmol), and Pd₂ (dba) ₃ (0.42 g, 0.458 mmol) at rest. The reaction mixture was heated to 110 °C in a sealed tube for 16 h. The reaction mixture was cooled to rest and diluted with ice water. The aqueous fraction was extracted with ethyl acetate (3 x 300 mL). The combined organic layer was washed with brine, dried over Na₂SO₄ , and concentrated under reduced pressure. The crude product was purified by CombiFlash column chromatography to yield the title compound (1.1 g, 58%). LCMS m/z = 415 [M+H] + .
中間物 13(3-氯-4-氟苯基)(4-甲基-5-(甲基磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酮或(3-氯-4-氟苯基)(5-甲基-4-(甲基磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酮或在0℃下向中間物12 (1.1 g，2.644 mmol)於DCM (30 mL)中之攪拌溶液中添加mCPBA (77%，1.8 g，7.9 mmol)。將反應物在rt下攪拌5 h。用飽和Na2SO3:NaHCO3(1:1)溶液淬滅反應混合物且用乙酸乙酯(2 x 300 mL)萃取。經Na2SO4乾燥合併之有機層且在減壓下蒸發，得到粗產物，藉由combi-flash管柱層析純化，產生標題化合物(1.0 g，84%)。LCMS m/z = 447 [M+H]+。 Intermediate 13 (3-chloro-4-fluorophenyl)(4-methyl-5-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl) methyl ketone or (3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl) methyl ketone or mCPBA (77%, 1.8 g, 7.9 mmol) was added to a stirred solution of intermediate 12 (1.1 g, 2.644 mmol) in DCM (30 mL) at 0 °C. The reaction mixture was stirred at rt for 5 h. The reaction mixture was quenched with a saturated Na₂SO₃ : NaHCO₃ (1:1) solution and extracted with ethyl acetate ( 2 x 300 mL). The combined organic layers were dried over Na₂SO₄ and evaporated under reduced pressure to give the crude product, which was purified by combi-flash column chromatography to give the title compound (1.0 g, 84%). LCMS m/z = 447 [M+H] ⁺ .
中間物 144-碘-5-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑及5-碘-4-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑之區域異構物混合物及在0℃下向4-碘-5-甲基-1H-咪唑(50 g，240.39 mmol)於二甲基甲醯胺(250 mL)中之溶液中逐份添加氫化鈉(9.2 g，384.62 mmol)且將混合物攪拌30 min。在0℃下向反應混合物中添加SEM-Cl (51 mL，288.46 mmol)且接著將混合物在環境溫度下攪拌1 h。用冷NH4Cl水溶液(400 mL)淬滅反應混合物且用乙酸乙酯(2 × 600 mL)萃取。用冷水(2 × 300 mL)、鹽水(300 mL)洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮，得到粗產物，藉由急驟管柱層析(SiO2，40% EtOAc/己烷)純化，得到標題化合物(60 g，74%)。LCMS m/z = 339 [M+H]+。 Intermediate 14 is a mixture of regiomeric isomers of 4-iodo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole and 5-iodo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole. and Sodium hydroxide (9.2 g, 384.62 mmol) was added fractionally to a solution of 4-iodo-5-methyl-1H-imidazole (50 g, 240.39 mmol) in dimethylformamide (250 mL) at 0 °C, and the mixture was stirred for 30 min. SEM-Cl (51 mL, 288.46 mmol) was added to the reaction mixture at 0 °C, and the mixture was then stirred at ambient temperature for 1 h. The reaction mixture was quenched with a cold aqueous solution of NH₄Cl (400 mL) and extracted with ethyl acetate (2 × 600 mL). The combined organic layers were washed with cold water (2 × 300 mL) and brine (300 mL), dried with Na₂SO₄ and concentrated under reduced pressure to obtain a crude product. Purification was then performed by rapid column chromatography ( SiO₂ , 40% EtOAc/hexane) to give the title compound (60 g, 74%). LCMS m/z = 339 [M+H] ⁺ .
中間物 154-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑及5-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑之區域異構物混合物及在-78℃下向中間物14 (6 g，17.738 mmol，1 equiv.)於THF (100 mL)中之攪拌溶液中添加LDA (1M於THF中，26 mL，26.6 mmol，1.5 equiv.)且攪拌1 h，接著在-78℃下添加含5-氯噻吩-2-甲醛(3.120 g，21.285 mmol，1.2 equiv.)之THF (10 mL)且攪拌1 h。用飽和氯化銨(150 mL)淬滅反應混合物，用乙酸乙酯(2 × 200 mL)萃取。用鹽水(300 mL)洗滌合併之有機層，經硫酸鈉乾燥，且在減壓下濃縮，得到粗產物。藉由網狀矽膠管柱層析純化粗產物，得到(5-氯噻吩-2-基)(4-碘-5-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲醇(2 g，58%)。 Intermediate 15 is a mixture of regiomeric isomers of 4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium and 5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium. and LDA (1M in THF, 26 mL, 26.6 mmol, 1.5 equiv.) was added to a stirred solution of intermediate 14 (6 g, 17.738 mmol, 1 equiv.) in 100 mL of THF at -78 °C and stirred for 1 h. Then, THF containing 3.120 g, 21.285 mmol, 1.2 equiv. (5-chlorothiophene-2-carboxaldehyde) was added at -78 °C and stirred for 1 h. The reaction mixture was quenched with saturated ammonium chloride (150 mL) and extracted with ethyl acetate (2 × 200 mL). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography to obtain (5-chlorothiophene-2-yl)(4-iodo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol (2 g, 58%).
中間物 16(5-氯噻吩-2-基)(5-甲基-4-(甲基磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲醇及(5-氯噻吩-2-基)(4-甲基-5-(甲基磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲醇之區域異構物混合物及在rt下，在氬氣脫氣下向中間物15 (4.0 g，8.250 mmol，1 equiv.)及甲烷亞磺酸鈉鹽(3.3 g，33.0 mmol，4 equiv.)於DMSO (40 mL)中之攪拌溶液中添加氫氧化鈉粉末(0.330 g，8.25 mmol，1 equiv.)及碘化銅(I) (0.943 g，4.950 mmol，0.6 equiv.)，隨後添加L-脯胺酸(0.950 g，8.250 mmol，1 equiv.)。將所得反應混合物在120℃下攪拌16 h。藉由TLC及LCMS監測反應進展。藉由冰冷水(100 mL)淬滅反應混合物，用乙酸乙酯(3 × 50 mL)萃取。經無水Na2SO4乾燥合併之有機層且在減壓下蒸發溶劑且藉由層析純化，得到標題化合物(0.5 g，14%)。 Intermediate 16 is a mixture of regiomeric isomers of (5-chlorothiophen-2-yl)(5-methyl-4-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol and (5-chlorothiophen-2-yl)(4-methyl-5-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol. and Under argon degassing, sodium hydroxide powder (0.330 g, 8.250 mmol, 1 equiv.) and copper(I) iodide (0.943 g, 4.950 mmol, 0.6 equiv.) were added to a stirred solution of intermediate 15 (4.0 g, 8.250 mmol, 1 equiv.) and sodium methanesulfinate (3.3 g, 33.0 mmol, 4 equiv.) in DMSO (40 mL). L-proline (0.950 g, 8.250 mmol, 1 equiv.) was then added. The resulting reaction mixture was stirred at 120 °C for 16 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was quenched with ice-cold water (100 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over anhydrous Na₂SO₄ , the solvent was evaporated under reduced pressure, and the mixture was purified by chromatography to give the title compound (0.5 g, 14%).
中間物 17(5-氯噻吩-2-基)(5-甲基-4-(甲基磺醯基)-1H-咪唑-2-基)甲醇在0℃下向中間物16 (0.5 g，1.144 mmol，1.0 equiv.)於DCM (5.0 mL)中之攪拌溶液中添加含HCl (4N)之1,4-二噁烷(10 mL)。將所得溶液在rt下攪拌16 h。藉由TLC及LCMS監測反應進展。在減壓下濃縮反應物質，得到粗物質。用乙酸乙酯(30 mL)稀釋所得粗物質，用飽和NaHCO3溶液(10 mL)洗滌，經硫酸鈉乾燥且在減壓下移除溶劑，得到0.4 g粗物質。LCMS m/z = 307 [M+H]+。 Intermediate 17 (5-chlorothiophen-2-yl)(5-methyl-4-(methylsulfonylurea)-1H-imidazol-2-yl)methanol 1,4-Dioxane (10 mL) containing HCl (4N) was added to a stirred solution of intermediate 16 (0.5 g, 1.144 mmol, 1.0 equiv.) in DCM (5.0 mL) at 0 °C. The resulting solution was stirred at rt for 16 h. The reaction progress was monitored by TLC and LCMS. The reactants were concentrated under reduced pressure to obtain a crude product. The crude product was diluted with ethyl acetate (30 mL), washed with saturated NaHCO3 solution (10 mL), dried over sodium sulfate, and the solvent was removed under reduced pressure to obtain 0.4 g of crude product. LCMS m/z = 307 [M+H] + .
中間物 185-甲基-4-(甲硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑及4-甲基-5-(甲硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑之區域異構物混合物及用氬氣使中間物14 (區域異構物之混合物，20 g，59.13 mmol)於1,4-二噁烷中之攪拌溶液脫氣10分鐘，隨後添加NaSMe (8.3 g，118.25 mmol)、Xantphos (2.05 g，3.55 mmol)及Pd2(dba)3(2.17 g，2.37 mmol)。將混合物在密封管中加熱至90℃持續16 h。過濾反應混合物。在減壓下濃縮濾液，獲得殘餘物，用水(160 mL)稀釋且用乙酸乙酯(2 × 200 mL)萃取。用鹽水(100 mL)洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮，得到粗產物，藉由急驟層析純化，得到標題化合物(10 g，65%)。LCMS m/z = 259 [M+H]+。 Intermediate 18 is a mixture of regiomeric isomers of 5-methyl-4-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium and 4-methyl-5-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium. and The stirred solution of intermediate 14 (a mixture of regiomeric isomers, 20 g, 59.13 mmol) in 1,4-dioxane was degassed with argon for 10 min, followed by the addition of NaSMe (8.3 g, 118.25 mmol), Xantphos (2.05 g, 3.55 mmol), and Pd₂ (dba) ₃ (2.17 g, 2.37 mmol). The mixture was heated to 90 °C in a sealed tube for 16 h. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was diluted with water (160 mL) and extracted with ethyl acetate (2 × 200 mL). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄ , and concentrated under reduced pressure to give a crude product. Purification by rapid chromatography yielded the title compound (10 g, 65%). LCMS m/z = 259 [M+H] ⁺ .
中間物 19二異丙基胺基甲酸(3-氯-4-氟苯基)(5-甲基-4-(甲硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯及二異丙基胺基甲酸(3-氯-4-氟苯基)(4-甲基-5-(甲硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯之區域異構物混合物及向中間物18 (區域異構物之混合物，39 g，150 mmol)於乙腈(200 mL)中之攪拌溶液中添加3-氯-4-氟苯甲醛(19.7 mL，165 mmol)、二異丙基胺基甲醯氯(37 g，225 mmol)及DIPEA (80 mL，451 mmol，3 equiv.)。將混合物在80℃下攪拌16 h。在減壓下濃縮反應混合物，獲得殘餘物，用乙酸乙酯(900 mL)稀釋且用水(400 mL)、鹽水(35 mL)洗滌，且接著經無水Na2SO4乾燥。在減壓下蒸發溶劑，得到粗產物，藉由急驟層析純化，得到標題化合物(45 g，55%)。LCMS m/z = 544 [M+H]+。 Intermediate 19: A mixture of regiomeric isomers of diisopropylaminocarboxylic acid (3-chloro-4-fluorophenyl)(5-methyl-4-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester and diisopropylaminocarboxylic acid (3-chloro-4-fluorophenyl)(4-methyl-5-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester. and To an intermediate 18 (a mixture of regiomeric isomers, 39 g, 150 mmol) in acetonitrile (200 mL) with stirred solution, 3-chloro-4-fluorobenzaldehyde (19.7 mL, 165 mmol), diisopropylaminomethylchlorodichlorodimethyl chloride (37 g, 225 mmol), and DIPEA (80 mL, 451 mmol, 3 equiv.) were added. The mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was diluted with ethyl acetate (900 mL) and washed with water (400 mL) and brine (35 mL), and then dried over anhydrous Na₂SO₄ . The solvent was evaporated under reduced pressure to obtain a crude product, which was purified by rapid chromatography to give the title compound (45 g, 55%). LCMS m/z = 544 [M+H] + .
中間物 20二異丙基胺基甲酸(3-氯-4-氟苯基)(5-甲基-4-(S-甲基亞磺醯亞胺基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯及二異丙基胺基甲酸(3-氯-4-氟苯基)(4-甲基-5-(S-甲基亞磺醯亞胺基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯之區域異構物混合物及在0℃下向中間物19 (區域異構物之混合物，30 g，55.13 mmol)於MeOH (360 mL)中之攪拌溶液中添加二乙醯氧基碘苯(89 g，275.6 mmol)及碳酸銨(17.2 g，220 mmol)。接著將混合物在環境溫度下攪拌16 h。用乙酸乙酯(600 mL)稀釋反應混合物，用水(300 mL)及鹽水(200 mL)洗滌。用鹽水(100 mL)洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮，得到粗產物，藉由急驟層析純化，得到標題化合物(14.2 g，45%)。LCMS m/z = 575 [M+H]+。 A mixture of intermediates 20 -diisopropylaminocarboxylic acid (3-chloro-4-fluorophenyl)(5-methyl-4-(S-methylsulfinimino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester and regiomeric isomers of diisopropylaminocarboxylic acid (3-chloro-4-fluorophenyl)(4-methyl-5-(S-methylsulfinimino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester. and Diethoxyiodobenzene (89 g, 275.6 mmol) and ammonium carbonate (17.2 g, 220 mmol) were added to a stirred solution of intermediate 19 (a mixture of regiomeric isomers, 30 g, 55.13 mmol) in MeOH (360 mL) at 0 °C. The mixture was then stirred at ambient temperature for 16 h. The reaction mixture was diluted with ethyl acetate (600 mL) and washed with water (300 mL) and brine (200 mL). The combined organic layer was washed with brine (100 mL ) , dried over Na₂SO₄ and concentrated under reduced pressure to give a crude product, which was purified by rapid chromatography to give the title compound (14.2 g, 45%). LCMS m/z = 575 [M+H] + .
中間物 21二異丙基胺基甲酸(3-氯-4-氟苯基)(4-碘-5-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯及二異丙基胺基甲酸(3-氯-4-氟苯基)(5-碘-4-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯之區域異構物混合物及在環境溫度下向中間物14 (12 g，35.475 mmol)於乙腈(50 mL)中之溶液中添加二異丙基胺基甲醯氯(6.38 g，39.0 mmol)、3-氯-4-氟苯甲醛(8.4 g，53.2 mmol)及N,N-二異丙基乙胺(19.6 mL，106.4 mmol)。將所得混合物加熱至80℃持續16 h。用水(150 mL)稀釋反應混合物且用乙酸乙酯(2×150 mL)萃取。經無水Na2SO4乾燥合併之有機層，過濾且在減壓下濃縮，得到粗產物，在藉由急驟層析純化後得到15 g (68%)標題化合物。LCMS m/z = 624 [M+H]+。 Intermediate 21: A mixture of regiomeric isomers of diisopropylaminocarboxylic acid (3-chloro-4-fluorophenyl)(4-iodo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester and diisopropylaminocarboxylic acid (3-chloro-4-fluorophenyl)(5-iodo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester. and Diisopropylaminomethylchlorodichlorodimethyl chloride (6.38 g, 39.0 mmol), 3-chloro-4-fluorobenzaldehyde (8.4 g, 53.2 mmol), and N,N-diisopropylethylamine (19.6 mL, 106.4 mmol) were added to a solution of intermediate 14 (12 g, 35.475 mmol) in acetonitrile (50 mL) at ambient temperature. The resulting mixture was heated to 80 °C for 16 h. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (2 × 150 mL). The combined organic layers were dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure to give a crude product, which was purified by rapid chromatography to give 15 g (68%) of the title compound. LCMS m/z = 624 [M+H] + .
中間物 22二異丙基胺基甲酸(4-氯-3-氟苯基)(4-碘-5-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯及二異丙基胺基甲酸(4-氯-3-氟苯基)(5-碘-4-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯之區域異構物混合物及使用與針對中間物21所述類似之方法，由適當的前驅體(4-氯-3-氟苯甲醛)製備標題化合物。LCMS m/z = 624 [M+H]+。 Intermediate 22: A mixture of regiomeric isomers of diisopropylaminocarboxylic acid (4-chloro-3-fluorophenyl)(4-iodo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester and diisopropylaminocarboxylic acid (4-chloro-3-fluorophenyl)(5-iodo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester. and The title compound was prepared from a suitable precursor (4-chloro-3-fluorobenzaldehyde) using a method similar to that described for intermediate 21. LCMS m/z = 624 [M+H] + .
中間物 23二異丙基胺基甲酸(3-氯-2,4-二氟苯基)(4-碘-5-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯及二異丙基胺基甲酸(3-氯-2,4-二氟苯基)(5-碘-4-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯之區域異構物混合物或使用與針對中間物21所述類似之方法，由適當的前驅體3-氯-2,4-二氟苯甲醛製備標題化合物。 Intermediate 23 is a mixture of regiomeric isomers of diisopropylaminocarboxylic acid (3-chloro-2,4-difluorophenyl)(4-iodo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester and diisopropylaminocarboxylic acid (3-chloro-2,4-difluorophenyl)(5-iodo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester. or The title compound was prepared from the appropriate precursor 3-chloro-2,4-difluorobenzaldehyde using a method similar to that described for intermediate 21.
中間物 24二異丙基胺基甲酸(3-氯-2,4-二氟苯基)(4-碘-5-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯及二異丙基胺基甲酸(3-氯-2,4-二氟苯基)(5-碘-4-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯之區域異構物混合物或使用與針對中間物21所述類似之方法，由適當的前驅體3-氯-2,4-二氟苯甲醛製備標題化合物。A mixture of regiomeric isomers of intermediate 24 -diisopropylaminocarboxylic acid (3-chloro-2,4-difluorophenyl)(4-iodo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester and diisopropylaminocarboxylic acid (3-chloro-2,4-difluorophenyl)(5-iodo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester. or The title compound was prepared from the appropriate precursor 3-chloro-2,4-difluorobenzaldehyde using a method similar to that described for intermediate 21.
中間物 25二異丙基胺基甲酸(3-氟-4-(三氟甲氧基)苯基)(4-碘-5-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯及二異丙基胺基甲酸(3-氟-4-(三氟甲氧基)苯基)(5-碘-4-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯之區域異構物混合物或使用與針對中間物21所述類似之方法，由適當的前驅體3-氟-4-(三氟甲氧基)苯甲醛製備標題化合物。LCMS m/z = 674.1 [M+H]+。 Intermediate 25 : A mixture of regiomeric isomers of diisopropylaminocarboxylic acid (3-fluoro-4-(trifluoromethoxy)phenyl)(4-iodo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester and diisopropylaminocarboxylic acid (3-fluoro-4-(trifluoromethoxy)phenyl)(5-iodo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester. or The title compound was prepared from a suitable precursor, 3-fluoro-4-(trifluoromethoxy)benzaldehyde, using a method similar to that described for intermediate 21. LCMS m/z = 674.1 [M+H] + .
中間物 26二異丙基胺基甲酸((3,4-二氯-2-氟苯基)(4-碘-5-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯及二異丙基胺基甲酸(3,4-二氯-2-氟苯基)(5-碘-4-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯之區域異構物混合物及使用與針對中間物21所述類似之方法，由適當的前驅體3,4-二氯-2-氟苯甲醛製備標題化合物。 Intermediate 26 is a mixture of regiomeric isomers of diisopropylaminocarboxylic acid ((3,4-dichloro-2-fluorophenyl)(4-iodo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester and diisopropylaminocarboxylic acid (3,4-dichloro-2-fluorophenyl)(5-iodo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester. and The title compound was prepared from the appropriate precursor 3,4-dichloro-2-fluorobenzaldehyde using a method similar to that described for intermediate 21.
中間物 27二異丙基胺基甲酸(3-氯-4-氟苯基)(5-甲基-4-(甲基磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯及二異丙基胺基甲酸(3-氯-4-氟苯基)(4-甲基-5-(甲基磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯之區域異構物混合物及將中間物21 (7 g，11.2 mmol)、甲烷磺酸鈉(5.3 g，44.8 mmol)、碳酸銫(3.6 g，11.2 mmol)、L-脯胺酸(1.3 g，11.2 mmol)及碘化銅(I) (1.7 g，9.0 mmol)於DMSO (80 mL)中之混合物在密封管中在120℃下攪拌16 h。將反應混合物冷卻至環境溫度，用水(100 mL)稀釋且用乙酸乙酯(3×100 mL)萃取。用鹽水(2×80 mL)洗滌合併之有機層，經無水Na2SO4乾燥，過濾，在減壓下濃縮，藉由層析純化，提供3.0 g標題化合物。LCMS m/z = 576 [M+H]+。 Intermediate 27 is a mixture of regiomeric isomers of diisopropylaminocarboxylic acid (3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester and diisopropylaminocarboxylic acid (3-chloro-4-fluorophenyl)(4-methyl-5-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester. and A mixture of intermediate 21 (7 g, 11.2 mmol), sodium methanesulfonate (5.3 g, 44.8 mmol), cesium carbonate (3.6 g, 11.2 mmol), L-proline (1.3 g, 11.2 mmol), and copper iodide (I) (1.7 g, 9.0 mmol) in DMSO (80 mL) was stirred in a sealed tube at 120 °C for 16 h. The reaction mixture was cooled to ambient temperature, diluted with water (100 mL), and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (2 × 80 mL), dried over anhydrous Na₂SO₄ , filtered, concentrated under reduced pressure, and purified by chromatography to provide 3.0 g of the title compound. LCMS m/z = 576 [M+H]+.
中間物 28(3-氯-4-氟苯基)(4-甲基-5-(甲基磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲醇及(3-氯-4-氟苯基)(5-甲基-4-(甲基磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲醇之區域異構物混合物及向中間物10 (700 mg，1.4 mmol)於DMSO (20 mL)中之攪拌溶液中添加甲烷亞磺酸鈉(575.3 mg，5.6 mmol)、Cs2CO3(459 mg，1.4 mmol)、碘化銅(161 mg，0.845 mmol)且用氬氣脫氣5分鐘，之後添加L-脯胺酸(162 mg，1.4 mmol)且將反應混合物在120℃下攪拌16 h。用水(50 mL)稀釋反應混合物且用乙酸乙酯(2×50 mL)萃取。經無水Na2SO4乾燥合併之有機層，過濾且在減壓下濃縮，獲得粗化合物，在藉由急驟管柱層析(C18，12 g濾筒，用0.1%甲酸及乙腈溶析)純化後得到300 mg (47%)標題化合物。LCMS m/z = 449.5 [M+H]+。 Intermediate 28 is a mixture of regiomeric isomers of (3-chloro-4-fluorophenyl)(4-methyl-5-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol and (3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol. and Sodium methanesulfinate (575.3 mg, 5.6 mmol), Cs₂CO₃ (459 mg, 1.4 mmol), and copper iodide (161 mg, 0.845 mmol) were added to a stirred solution of intermediate 10 (700 mg, 1.4 mmol) in DMSO (20 mL), and the mixture was degassed with argon for 5 min. L-proline (162 mg, 1.4 mmol) was then added, and the reaction mixture was stirred at 120 °C for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a crude compound. Purification by rapid column chromatography (C18, 12 g filter cartridge, precipitated with 0.1% formic acid and acetonitrile) yielded 300 mg (47%) of the title compound. LCMS m/z = 449.5 [M+H]⁺.
中間物 295-氯-N-((5-氯噻吩-2-基)(5-甲基-4-(甲硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲基)吡啶-2-胺及5-氯-N-((5-氯噻吩-2-基)(4-甲基-5-(甲硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲基)吡啶-2-胺之區域異構物混合物及在RT下向中間物16 (1 g，1.680 mmol，1 equiv.)、95%純甲硫醇鈉(141.4 mg，2.0 mmol，1.2 equiv.)於1,4-二噁烷(20 mL)中之攪拌溶液中添加用於分析之99.5%碳酸銫(820 mg，2.5 mmol，1.5 equiv.)且用氬氣脫氣15 min。在RT下向反應混合物中添加Pd2(dba)3(153.8 mg，0.168 mmol，0.1 equiv.)及Xantphos (145.6 mg，0.25 mmol，0.15 equiv.)。將所得反應混合物加熱至90℃且在相同溫度下在氮氣氛圍下攪拌2 h。藉由TLC監測反應進展。將反應混合物冷卻至RT，用水(50 mL)稀釋，且用乙酸乙酯(3 × 50 mL)萃取。用水(100 mL)、鹽水(100 mL)洗滌合併之有機層，經硫酸鈉乾燥且在減壓下濃縮，得到粗產物。藉由管柱層析純化粗產物，得到標題化合物(650 mg，75%)。 Intermediate 29 is a mixture of regiomeric isomers of 5-chloro-N-((5-chlorothiophen-2-yl)(5-methyl-4-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl)pyridine-2-amine and 5-chloro-N-((5-chlorothiophen-2-yl)(4-methyl-5-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl)pyridine-2-amine. and The analytically prepared 99.5% cesium carbonate (820 mg, 2.5 mmol, 1.5 equiv.) was added to a stirred solution of intermediate 16 (1 g, 1.680 mmol, 1 equiv.) and 95% sodium methanethiol (141.4 mg, 2.0 mmol, 1.2 equiv.) in 1,4-dioxane (20 mL) under RT, and the mixture was degassed with argon for 15 min. Pd₂ (dba) ₃ (153.8 mg, 0.168 mmol, 0.1 equiv.) and Xantphos (145.6 mg, 0.25 mmol, 0.15 equiv.) were added to the reaction mixture under RT. The resulting reaction mixture was heated to 90 °C and stirred at the same temperature under nitrogen atmosphere for 2 h. The reaction progress was monitored by TLC. The reaction mixture was cooled to RT, diluted with water (50 mL), and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography to give the title compound (650 mg, 75%).
中間物 30二異丙基胺基甲酸(3-氯-4-氟苯基)(5-甲基-4-(甲基磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯及二異丙基胺基甲酸(3-氯-4-氟苯基)(4-甲基-5-(甲基磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯之區域異構物混合物及在室溫下向中間物21 (40 mg，0.18 mmol，1 equiv.)於DMSO (4.0 mL)中之攪拌溶液中添加MeSO2Na (42 mg，0.27 mmol，1.5 equiv.)。使反應混合物在氬氣氛圍下脫氣，隨後添加CuI及L-脯胺酸且在氬氣氛圍下進一步脫氣。將反應混合物在120℃下攪拌36小時。藉由LCMS監測反應混合物。用冰冷水淬滅成功的反應混合物且用乙酸乙酯(20 mL)萃取。用水(4 mL)、鹽水(10 mL)洗滌有機層且經Na2SO4乾燥。在減壓下濃縮溶劑，得到粗產物，藉由矽膠上之急驟管柱層析純化，以46%產率得到最終產物。 Intermediate 30: A mixture of regiomeric isomers of diisopropylaminocarboxylic acid (3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester and diisopropylaminocarboxylic acid (3-chloro-4-fluorophenyl)(4-methyl-5-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester. and MeSO₂Na (42 mg, 0.27 mmol, 1.5 equiv.) was added to a stirred solution of intermediate 21 (40 mg, 0.18 mmol, 1 equiv.) in DMSO (4.0 mL) at room temperature. The reaction mixture was degassed under argon, followed by the addition of CuI and L-proline, and further degassed under argon. The reaction mixture was stirred at 120 °C for 36 hours. The reaction mixture was monitored by LCMS. The successfully reacted mixture was quenched with ice-cold water and extracted with ethyl acetate (20 mL). The organic layer was washed with water (4 mL) and brine (10 mL) and dried over Na₂SO₄ . The solvent was concentrated under reduced pressure to obtain a crude product, which was then purified by rapid column chromatography on silicone to obtain the final product in 46% yield.
中間物 312-((3-氯-4-氟苯基)(4-甲基-5-(甲基磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲氧基)吡啶及2-((3-氯-4-氟苯基)(5-甲基-4-(甲基磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲氧基)吡啶之區域異構物混合物及在0℃下向中間物28 (100 mg，0.22 mmol，1.0 equiv.)於1,4二噁烷(4 mL)中之攪拌溶液中添加KOtBu (50 mg，0.44 mmol，2 equiv.)且攪拌15 min，隨後添加2-氟吡啶(32 mg，0.33 mmol ,1.5 equiv.)且在100℃下攪拌16 h。用水淬滅反應混合物且用乙酸乙酯(50 mL)萃取。用水(10 mL)、鹽水(10 mL)洗滌有機層且經Na2SO4乾燥。在減壓下濃縮溶劑，得到粗產物，藉由急驟管柱層析純化，得到68%所需化合物。 Intermediate 31 is a mixture of regiomeric isomers of 2-((3-chloro-4-fluorophenyl)(4-methyl-5-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methoxy)pyridine and 2-((3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methoxy)pyridine. and KO t Bu (50 mg, 0.44 mmol, 2 equiv.) was added to a stirred solution of intermediate 28 (100 mg, 0.22 mmol, 1.0 equiv.) in 1,4-dioxane (4 mL) at 0 °C and stirred for 15 min. Then, 2-fluoropyridine (32 mg, 0.33 mmol, 1.5 equiv.) was added and stirred at 100 °C for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate (50 mL). The organic layer was washed with water (10 mL) and brine (10 mL) and dried over Na₂SO₄ . The solvent was concentrated under reduced pressure to give the crude product, which was purified by rapid column chromatography to give 68% of the desired compound.
中間物 322-((3-氯-4-氟苯基)(4-氟苯氧基)甲基)-4-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑及相應SEM區域異構物。步驟-1：在室溫下向中間物4 (4.7 g，12.67 mmol，1.0 equiv.)於THF (100 mL)中之攪拌溶液中添加4-氟苯酚(1.4 g，12.67 mmol，1.0 equiv.)、PPh3(4.0 g，15.2 mmol，1.2 equiv.)及偶氮二甲酸二異丙酯(3.0 mL，15.2 mmol，1.2 equiv.)。將反應混合物在室溫下攪拌16 h。在減壓下濃縮反應混合物。藉由combi flash管柱層析純化所得粗物質，產生標題化合物。產率：25.4% (1.5 g，3.23 mmol)。LCMS: m/z [M+H]+= 465.2。 Intermediate 32: 2-((3-chloro-4-fluorophenyl)(4-fluorophenoxy)methyl)-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium and its corresponding SEM region isomers. Step 1: 4-Fluorophenol (1.4 g, 12.67 mmol, 1.0 equiv.), PPh 3 (4.0 g, 15.2 mmol, 1.2 equiv.), and diisopropyl azodicarbonate (3.0 mL, 15.2 mmol, 1.2 equiv.) were added to a stirred solution of intermediate 4 (4.7 g, 12.67 mmol, 1.0 equiv.) in 100 mL of THF at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then concentrated under reduced pressure. The crude product was purified by combi flash column chromatography to yield the title compound. Yield: 25.4% (1.5 g, 3.23 mmol). LCMS: m/z [M+H]+= 465.2.
中間物 332-((3-氯-4-氟苯基)(4-氟苯氧基)甲基)-5-碘-4-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑及相應SEM區域異構物步驟-2：在0℃下向步驟-1之產物(7.6 g，16.34 mmol，1.0 equiv.)於二甲基甲醯胺(75 mL)中之攪拌溶液中添加NIS (4.4 g，19.61 mmol，1.2 equiv.)。將反應混合物在室溫下攪拌16 h。用Na2SO3溶液稀釋反應混合物且用乙酸乙酯(3 × 800 mL)萃取。用鹽水洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮。藉由管柱層析純化所得粗物質，產生所需化合物。產率：79% (6 g，12.90 mmol)。LCMS: m/z [M+H]+= 465.2。 Intermediate 33: 2-((3-chloro-4-fluorophenyl)(4-fluorophenoxy)methyl)-5-iodo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium and corresponding SEM region isomers Step 2: NIS (4.4 g, 19.61 mmol, 1.2 equiv.) was added to a stirred solution of the product of Step 1 (7.6 g, 16.34 mmol, 1.0 equiv.) in dimethylformamide (75 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with Na₂SO₃ solution and extracted with ethyl acetate (3 × 800 mL). The combined organic layer was washed with brine, dried over Na₂SO₄ , and concentrated under reduced pressure. The crude product was purified by column chromatography to yield the desired compound. Yield: 79% (6 g, 12.90 mmol). LCMS: m/z [M+H] ⁺ = 465.2.
中間物 34a 及 34b2-((3-氯-4-氟苯基)(4-氟苯氧基)甲基)-4-甲基-5-(甲硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑及相應SEM區域異構物及步驟-3：用氬氣使步驟-2之產物(4.3 g，7.28 mmol，1.0 equiv.)於二噁烷(50 mL)中之攪拌溶液脫氣10 min，隨後在室溫下添加NaSMe (0.8 g，10.91 mmol，1.5 equiv.)、Xantphos (0.6 g，1.09 mmol，0.15 equiv.)及Pd2(dba)3(0.7 g，0.73 mmol，0.1 equiv.)。將反應混合物在110℃下在密封管中加熱16 h。將反應混合物冷卻至室溫且用冰水稀釋。用乙酸乙酯(3 × 800 mL)萃取所得混合物。用鹽水洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮。首先藉由combi flash管柱層析，隨後藉由SFC對掌性分離來純化所得粗物質。中間物34a (第一種溶析之鏡像異構物)：(1 g，27%)。中間物34b：(第二種溶析之鏡像異構物)：(1 g，27%)。製備型對掌性SFC：管柱：(R, R)-Whelk-O-1 (21.1 x 250 mm) 5 μm；共溶劑：0.3% iPrNH2/正己烷/MeOH/iPrOH (60:30:10)，流量：70 mL/min；共溶劑%：10%；ABPR：100 br；T：35℃。 Intermediates 34a and 34b : 2-((3-chloro-4-fluorophenyl)(4-fluorophenoxy)methyl)-4-methyl-5-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium and corresponding SEM region isomers and Step 3: Degas the product of Step 2 (4.3 g, 7.28 mmol, 1.0 equiv.) in a stirred solution of dioxane (50 mL) with argon for 10 min. Then, add NaSMe (0.8 g, 10.91 mmol, 1.5 equiv.), Xantphos (0.6 g, 1.09 mmol, 0.15 equiv.), and Pd₂(dba) ₃ (0.7 g, 0.73 mmol, 0.1 equiv.) at room temperature. Heat the reaction mixture in a sealed tube at 110 °C for 16 h. Cool the reaction mixture to room temperature and dilute with ice water. Extract the resulting mixture with ethyl acetate ( 3 × 800 mL). The combined organic layers were washed with brine, dried with Na₂SO₄ , and concentrated under reduced pressure. The crude material was first purified by combi flash column chromatography, followed by SFC separation. Intermediate 34a (first precipitated mirror isomer): (1 g, 27%). Intermediate 34b (second precipitated mirror isomer): (1 g, 27%). Preparation of palm-shaped SFC: Column: (R, R)-Whelk-O-1 (21.1 x 250 mm) 5 μm; Cosolvent: 0.3% iPrNH2/ n -hexane/MeOH/iPrOH (60:30:10), Flow rate: 70 mL/min; Cosolvent %: 10%; ABPR: 100 br; T: 35℃.
中間物 354-碘-5-(甲氧基甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑及5-碘-4-(甲氧基甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑之區域異構物混合物及 Intermediate 35 is a mixture of regiomeric isomers of 4-iodo-5-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole and 5-iodo-4-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole. and
步驟-1：將1H-咪唑-4-基甲醇鹽酸鹽(5 g，37.15 mmol，1.0 equiv.)於二甲基甲醯胺(50 mL)中之攪拌溶液冷卻至0℃，添加DIPEA (17 mL，94.0 mmol，2.53 equiv.)，隨後添加SEM-Cl (7.3 mL，40.87 mmol，1.1 equiv.)且將反應混合物在rt下攪拌16 h。用水淬滅反應混合物且用乙酸乙酯(2x50 mL)萃取。用鹽水(50 mL)洗滌合併之有機物，經無水Na2SO4乾燥，過濾且濃縮，得到粗產物，藉由管柱層析(矽膠100-200目，含3-4%甲醇之DCM作為溶析劑)純化，得到(1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-4-基)甲醇(區域異構物混合物)。產率：82% (7 g，30.5 mmol)。LC-MS: m/z [M+H]+= 229。Step 1: Cool a stirred solution of 1H-imidazol-4-ylmethanol hydrochloride (5 g, 37.15 mmol, 1.0 equiv.) in dimethylformamide (50 mL) to 0 °C, add DIPEA (17 mL, 94.0 mmol, 2.53 equiv.), followed by SEM-Cl (7.3 mL, 40.87 mmol, 1.1 equiv.), and stir the reaction mixture at rt for 16 h. Quench the reaction mixture with water and extract with ethyl acetate (2 x 50 mL). The combined organic matter was washed with brine (50 mL), dried over anhydrous Na₂SO₄ , filtered, and concentrated to obtain a crude product. Purification was performed by column chromatography (using 100-200 mesh silica gel and DCM containing 3-4% methanol as the solvent) to give (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methanol (a mixture of regiomeric isomers). Yield: 82% (7 g, 30.5 mmol). LC-MS: m/z [M+H] ⁺ = 229.
步驟-2：在0℃下向步驟-1之產物(7 g，30.5 mmol，1.0 equiv.)於THF (100 mL)中之攪拌溶液中逐份添加NaH (60%於油中) (2.5 g，61.04 mmol，2.0 equiv.)且在相同溫度下攪拌30 min。將MeI (2.85 mL，45.78 mmol，1.5 equiv.)添加至反應物質中且在rt下攪拌16 h。用飽和NH4Cl溶液(50 mL)淬滅反應混合物且用乙酸乙酯(2 x 50 mL)萃取。用鹽水(50 mL)洗滌合併之有機物，經Na2SO4乾燥且在減壓下濃縮，得到標題化合物，其由此用於下一步驟。產量：6.2 g (粗物質)。LC-MS: m/z [M+H]+= 243。Step 2: NaH (60% in oil) (2.5 g, 61.04 mmol, 2.0 equiv.) was added fractionally to a stirred solution of the product of Step 1 (7 g, 30.5 mmol, 1.0 equiv.) in THF (100 mL) at 0 °C, and the mixture was stirred for 30 min at the same temperature. MeI (2.85 mL, 45.78 mmol, 1.5 equiv.) was added to the reaction mixture and stirred at rt for 16 h. The reaction mixture was quenched with saturated NH₄Cl solution (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic matter was washed with brine (50 mL), dried over Na₂SO₄ , and concentrated under reduced pressure to obtain the title compound, which was then used in the next step. Yield: 6.2 g (crude matter). LC -MS: m/z [M+H] ⁺ = 243.
中間物 364-(甲硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑或5-(甲硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑或用與中間物18之製備類似之方法由中間物1製備該中間物。產率：54% (4.1 g，16.77 mmol)。LC-MS: m/z [M+H]+= 245。 Intermediate 36 : 4-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium or 5-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium or The intermediate was prepared from intermediate 1 using a method similar to that used for intermediate 18. Yield: 54% (4.1 g, 16.77 mmol). LC-MS: m/z [M+H] + = 245.
中間物 37二異丙基胺基甲酸(3-氯-4-氟苯基)(5-(甲氧基甲基)-4-(甲硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯及二異丙基胺基甲酸(3-氯-4-氟苯基)(4-(甲氧基甲基)-5-(甲硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯之區域異構物混合物及使用與針對中間物21所述類似之方法，由適當的中間物及3,4-二氯-2-氟苯甲醛製備標題化合物。 Intermediate 37 is a mixture of regiomeric isomers of diisopropylaminocarboxylic acid (3-chloro-4-fluorophenyl)(5-(methoxymethyl)-4-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester and diisopropylaminocarboxylic acid (3-chloro-4-fluorophenyl)(4-(methoxymethyl)-5-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester. and The title compound is prepared from a suitable intermediate and 3,4-dichloro-2-fluorobenzaldehyde using a method similar to that described for intermediate 21.
中間物 385-氯-4-氟-2-甲氧基苯甲醛 Intermediate 38 : 5-Chloro-4-fluoro-2-methoxybenzaldehyde
步驟-1：在0℃下向4-氯-3-氟苯酚(10.0 g，68.23 mmol，1.0 equiv.)之攪拌溶液中添加TFA (65.0 mL)且分成小份添加1,3,5,7-四氮雜金剛烷(11.5 g，81.88 mmol，1.2 equiv.)。接著將混合物在80℃下回流隔夜，接著使其在0℃下冷卻，隨後添加濃H2SO4(0.433 mL)及水(65.0 mL)，將反應物在室溫下攪拌1 h。藉由TLC監測反應完成。用DCM萃取混合物，用水及鹽水洗滌合併之萃取物，經Na2SO4乾燥，濃縮且藉由急驟層析純化，得到5-氯-4-氟-2-羥基苯甲醛(2.47 g，21%)。1HNMR (CDCl3, 400 MHz, 25℃): δ 11.21 (s, 1H), 9.79 (s, 1H), 7.60 (d, J= 7.9 Hz, 1H), 6.78 (d, J= 7.9 Hz, 1H)。Step 1: TFA (65.0 mL) was added to a stirred solution of 4-chloro-3-fluorophenol (10.0 g, 68.23 mmol, 1.0 equiv.) at 0 °C, and 1,3,5,7-tetraaza-dragonane (11.5 g, 81.88 mmol, 1.2 equiv.) was added in fractions. The mixture was then refluxed at 80 °C overnight, followed by cooling at 0 °C. Concentrated H₂SO₄ (0.433 mL) and water (65.0 mL) were then added, and the reaction mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC until completion. The mixture was extracted with DCM, and the combined extracts were washed with water and brine . The extracts were dried over Na₂SO₄ , concentrated, and purified by rapid chromatography to give 5-chloro-4-fluoro-2-hydroxybenzaldehyde (2.47 g, 21%). ¹H NMR ( CDCl₃ , 400 MHz, 25 °C): δ 11.21 (s, 1H), 9.79 (s, 1H), 7.60 (d, J = 7.9 Hz, 1H), 6.78 (d, J = 7.9 Hz, 1H).
步驟-2：在0℃下向5-氯-4-氟-2-羥基苯甲醛(2.43 g，13.921 mmol，1.0 equiv.)於二甲基甲醯胺(20.0 mL)中之攪拌溶液中添加碳酸鉀(3.848 g，27.842 mmol，2.0 equiv.)及碘甲烷(1.7 mL，27.8 mmol，2.0 equiv.)且將反應物在RT下攪拌16 h。藉由LCMS及TLC監測反應完成{20% EtOAc-己烷；Rf 0.4}。使用乙酸乙酯(3 × 25 mL)及水(5 × 15 mL)萃取反應混合物，用鹽水(4 × 10 mL)洗滌有機層，經無水Na2SO4乾燥，且在低溫下在減壓下濃縮，獲得5-氯-4-氟-2-甲氧基苯甲醛(2.47 g，94%)。1HNMR (CDCl3, 400 MHz, 25℃): δ 10.31 (s, 1H), 7.87 (d, J= 8.6 Hz, 1H), 6.78 (d, J= 10 Hz, 1H), 3.92 (s, 3H)。Step 2: Potassium carbonate (3.848 g, 27.842 mmol, 2.0 equiv.) and methyl iodoform (1.7 mL, 27.8 mmol, 2.0 equiv.) were added to a stirred solution of 5-chloro-4-fluoro-2-hydroxybenzaldehyde (2.43 g, 13.921 mmol, 1.0 equiv.) in dimethylformamide (20.0 mL) at 0 °C, and the reaction mixture was stirred at RT for 16 h. The reaction was monitored by LCMS and TLC to determine the reaction completion {20% EtOAc-hexane; Rf 0.4}. The reaction mixture was extracted with ethyl acetate (3 × 25 mL) and water (5 × 15 mL), the organic layer was washed with brine (4 × 10 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure at low temperature to give 5-chloro-4-fluoro-2-methoxybenzaldehyde (2.47 g, 94%). ¹H NMR ( CDCl₃ , 400 MHz, 25 °C): δ 10.31 (s, 1H), 7.87 (d, J = 8.6 Hz, 1H), 6.78 (d, J = 10 Hz, 1H), 3.92 (s, 3H).
中間物 39-60以與中間物19之製備類似之方法由相應的醛製備該等中間物。
中間物 61二異丙基胺基甲酸(3-氯-4-氟苯基)(5-碘-4-(甲硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯及二異丙基胺基甲酸(3-氯-4-氟苯基)(4-碘-5-(甲硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯之區域異構物混合物及在RT下向化合物二異丙基胺基甲酸(3-氯-4-氟苯基)(4-(甲硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯中間物50 (3.5 gm，6.59 mmol，1.0 equiv.)於乙腈(30 mL)中之攪拌溶液中添加NIS (4.45 gm，19.77 mmol，3.0 equiv.)且在80℃下攪拌2 h。用乙酸乙酯(2 × 100 mL)萃取反應混合物。用鹽水(100 mL)洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮，得到粗產物，藉由急驟管柱層析純化，得到二異丙基胺基甲酸(3-氯-4-氟苯基)(5-碘-4-(甲硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯(區域異構物之混合物)。產率：69% (3 g，4.57 mmol)。LC-MS: m/z [M+H]+ = 656.0。 Intermediate 61 is a mixture of regiomeric isomers of diisopropylaminocarboxylic acid (3-chloro-4-fluorophenyl)(5-iodo-4-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester and diisopropylaminocarboxylic acid (3-chloro-4-fluorophenyl)(4-iodo-5-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester. and NIS (4.45 gm, 19.77 mmol, 3.0 equiv.) was added to a stirred solution of diisopropylaminocarboxylic acid (3-chloro-4-fluorophenyl)(4-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester intermediate 50 (3.5 gm, 6.59 mmol, 1.0 equiv.) in acetonitrile (30 mL) under RT and stirred at 80 °C for 2 h. The reaction mixture was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄ , and concentrated under reduced pressure to give a crude product. Purification by rapid column chromatography yielded diisopropylaminocarboxylic acid (3-chloro-4-fluorophenyl)(5-iodo-4-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester (a mixture of regiomeric isomers). Yield: 69% (3 g, 4.57 mmol). LC-MS: m/z [M+H]⁺ = 656.0.
中間物 622-((3-氯-4-氟苯基)((二異丙基胺甲醯基)氧基)甲基)-4-(甲硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-5-甲酸甲酯及2-((3-氯-4-氟苯基)((二異丙基胺甲醯基)氧基)甲基)-5-(甲硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-4-甲酸甲酯之區域異構物混合物及向二異丙基胺基甲酸(3-氯-4-氟苯基)(5-碘-4-(甲硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯(中間物61) (3 g，4.566 mmol，1.0 equiv.)於MeOH (80 mL)中之溶液中添加三乙胺(13 mL，91.314 mmol，20.0 equiv.)且用氬氣脫氣10分鐘，隨後添加Pd(OAc)2(0.103 g，0.457 mmol，0.1 equiv.)且在CO氛圍下在高壓釜中在70℃及120 psi下攪拌16 h。經矽藻土床過濾反應混合物，用乙酸乙酯洗滌且在減壓下濃縮濾液，得到粗產物，藉由急驟管柱層析純化，產生2-((3-氯-4-氟苯基)((二異丙基胺甲醯基)氧基)甲基)-4-(甲硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-5-甲酸甲酯(區域異構物之混合物)。產率：67% (1.8 g，3.06 mmol)。LC-MS: m/z [M+H]+ = 588.2。 Intermediate 62 is a mixture of regiomeric isomers of methyl 2-((3-chloro-4-fluorophenyl)((diisopropylaminomethoxy)methyl)-4-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-carboxylate and methyl 2-((3-chloro-4-fluorophenyl)((diisopropylaminomethoxy)methyl)-5-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-carboxylate. and Triethylamine (13 mL, 91.314 mmol, 20.0 equiv.) was added to a solution of diisopropylaminocarboxylic acid (3-chloro-4-fluorophenyl)(5-iodo-4-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester (intermediate 61) (3 g, 4.566 mmol, 1.0 equiv.) in MeOH (80 mL), and the mixture was degassed with argon for 10 min. Subsequently, Pd(OAc) ₂ (0.103 g, 0.457 mmol, 0.1 equiv.) was added, and the mixture was stirred for 16 h in a high-pressure autoclave at 70 °C and 120 psi under a CO atmosphere. The reaction mixture was filtered through a diatomaceous earth bed, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to give a crude product. Purification by rapid column chromatography yielded methyl 2-((3-chloro-4-fluorophenyl)((diisopropylaminomethoxy)oxy)methyl)-4-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-carboxylate (a mixture of regiomeric isomers). Yield: 67% (1.8 g, 3.06 mmol). LC-MS: m/z [M+H]+ = 588.2.
中間物 63-86以與中間物20之製備類似之方法由相應的醛製備該等中間物。
中間物 87二異丙基胺基甲酸(3-氯-4-氟苯基)(5-甲基-4-(甲基亞磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯及二異丙基胺基甲酸(3-氯-4-氟苯基)(4-甲基-5-(甲基亞磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯之區域異構物混合物及在0℃下向二異丙基胺基甲酸(3-氯-4-氟苯基)(5-甲基-4-(甲硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯中間物19 (1.85 g，3.4 mmol，1.0 equiv.)於DCM (100 mL)中之溶液中添加mCPBA (920 mg，3.74 mmol，1.1 equiv.)且在RT下攪拌2 h。將Ca(OH)2(2000 mg)添加至反應混合物中且在RT下攪拌30 min。過濾反應混合物，用乙酸乙酯(200 mL)洗滌。在減壓下濃縮濾液，用乙酸乙酯(250 mL)稀釋，用水(100 mL)及飽和NaHCO3溶液(100 mL)洗滌。經硫酸鈉乾燥有機層且在減壓下濃縮，得到粗產物，藉由管柱層析純化，得到所需中間物。產率：89% (1.7 g，3.04 mmol)。LC-MS: m/z [M+H]+= 560.2。 Intermediate 87 is a mixture of regiomeric isomers of diisopropylaminocarboxylic acid (3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester and diisopropylaminocarboxylic acid (3-chloro-4-fluorophenyl)(4-methyl-5-(methylsulfinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester. and mCPBA (920 mg, 3.74 mmol, 1.1 equiv.) was added to a solution of diisopropylaminocarbamate (3-chloro-4-fluorophenyl)(5-methyl-4-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester intermediate 19 (1.85 g, 3.4 mmol, 1.0 equiv.) in DCM (100 mL) at 0 °C and stirred at RT for 2 h. Ca(OH) ₂ (2000 mg) was added to the reaction mixture and stirred at RT for 30 min. The reaction mixture was filtered and washed with ethyl acetate (200 mL). The filtrate was concentrated under reduced pressure, diluted with ethyl acetate (250 mL), and washed with water (100 mL) and saturated NaHCO3 solution (100 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain the desired intermediate. Yield: 89% (1.7 g, 3.04 mmol). LC-MS: m/z [M+H] + = 560.2.
中間物 887,7-二氟螺[2.5]辛-4-醇 Intermediate 88 7,7-difluorospiro[2,5]octyl-4-ol
步驟-1：在RT下向1-氯烷基-2-甲基氫硫基-乙烷(5.0 g，36.16 mmol，1.0 equiv.)之攪拌溶液中添加MeI (11.3 mL，180.82 mmol，5.0 equiv.)且在RT下攪拌36 h。在減壓下濃縮反應混合物，得到粗產物，在乙醚(50 mL)中攪拌30 min。過濾沈澱之固體，用乙醚(20 mL)、丙酮(20 mL)洗滌且在減壓下乾燥，得到2-氯乙基-二(甲基)碘化鋶。Step 1: MeI (11.3 mL, 180.82 mmol, 5.0 equiv.) was added to a stirred solution of 1-chloroalkyl-2-methylhydrothioethane (5.0 g, 36.16 mmol, 1.0 equiv.) under RT and stirred for 36 h at RT. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was stirred in diethyl ether (50 mL) for 30 min. The precipitated solid was filtered, washed with diethyl ether (20 mL) and acetone (20 mL), and dried under reduced pressure to give 2-chloroethyl-di(methyl)silane iodide.
步驟-2：向三級丁醇鉀(1.9 g，17.15 mmol，2.0 equiv.)於tBuOH (100 mL)中之攪拌溶液中添加4,4-二氟環己-1-酮(1.0 g，7.45 mmol，1.0 equiv.)且在RT下攪拌30 min。向反應混合物中逐份添加(2-氯乙基)二甲基碘化鋶(1.5 g，5.96 mmol，0.8 equiv.)且在RT下攪拌16 h。過濾反應混合物，用水(200 mL)稀釋濾液且用乙酸乙酯(2 × 200 mL)萃取。用水(200 mL)、鹽水溶液(200 mL)洗滌合併之有機層，經硫酸鈉乾燥且在減壓下濃縮，得到粗產物，其未經進一步純化即用於下一步驟。Step 2: Add 4,4-difluorocyclohexane-1-one (1.0 g, 7.45 mmol, 1.0 equiv.) to a stirred solution of potassium terebutoxide (1.9 g, 17.15 mmol, 2.0 equiv.) in tBuOH (100 mL) and stir at RT for 30 min. Add (2-chloroethyl)dimethylsilyl iodide (1.5 g, 5.96 mmol, 0.8 equiv.) partically to the reaction mixture and stir at RT for 16 h. Filter the reaction mixture, dilute the filtrate with water (200 mL), and extract with ethyl acetate (2 × 200 mL). The combined organic layer was washed with water (200 mL) and brine solution (200 mL), dried with sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was used in the next step without further purification.
步驟-3：在0℃下向7,7-二氟螺[2.5]辛-4-酮(500 mg，3.12 mmol，1.0 equiv.)於MeOH (10 mL)中之溶液中添加NaBH4(237 mg，6.24 mmol，2.0 equiv.)且在RT下攪拌1 h。用水(50 mL)淬滅反應混合物且用DCM (100 mL)萃取。用鹽水(50 mL)洗滌有機層，經Na2SO4乾燥且在減壓下濃縮，得到粗產物，其未經進一步純化即使用。Step 3: NaBH₄ (237 mg, 6.24 mmol, 2.0 equiv.) was added to a solution of 7,7-difluorospiro[2.5]oct-4-one (500 mg, 3.12 mmol, 1.0 equiv.) in MeOH (10 mL) at 0 °C and stirred for 1 h at RT. The reaction mixture was quenched with water (50 mL) and extracted with DCM (100 mL). The organic layer was washed with brine (50 mL), dried over Na₂SO₄ , and concentrated under reduced pressure to obtain the crude product, which was used without further purification.
中間物 895-氯-6-(二氟甲基)吡啶-2-胺 Intermediate 89: 5-Chloro-6-(difluoromethyl)pyridine-2-amine
步驟1：在-78℃下向6溴-3-氟吡啶甲酸(1 g，4.229 mmol)於THF (15 mL)中之攪拌溶液中添加二異丁基氫化鋁(甲苯中之1M溶液10.5 mL)且將混合物在-78℃下攪拌3 h。用飽和NH4Cl溶液(50 mL)淬滅反應混合物且用乙酸乙酯(2×200 mL)萃取。用鹽水(50 mL)洗滌合併之有機層，經無水Na2SO4乾燥，過濾且在減壓下濃縮，得到粗化合物，在藉由急驟層析純化後得到500 mg (53%) 6-溴-3-氯吡啶甲醛。Step 1: Diisobutylaluminum hydroxide (10.5 mL of 1M toluene) was added to a stirred solution of 6-bromo-3-fluoropyridinecarboxylic acid (1 g, 4.229 mmol) in THF (15 mL) at -78 °C, and the mixture was stirred at -78 °C for 3 h. The reaction mixture was quenched with saturated NH₄Cl solution (50 mL) and extracted with ethyl acetate (2 × 200 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure to give a crude compound, which was purified by rapid chromatography to give 500 mg (53%) of 6-bromo-3-chloropyridinecarboxaldehyde.
步驟2：在-78℃下向6-溴-3-氯吡啶甲醛(500 mg，2.268 mmol)於DCM (10 mL)中之攪拌溶液中添加二乙基胺基三氟化硫(1.65 mL)且接著將反應混合物在環境溫度下攪拌3 h。用飽和NaHCO3溶液(20 mL)淬滅反應混合物且用乙酸乙酯(2×100 mL)萃取。用鹽水(30 mL)洗滌合併之有機層，經無水Na2SO4乾燥，過濾且在減壓下濃縮，獲得粗化合物，在藉由急驟層析純化後得到200 mg (36%) 6-溴-3-氯-2-(二氟甲基)吡啶。Step 2: Diethylaminosulfur trifluoride (1.65 mL) was added to a stirred solution of 6-bromo-3-chloropyridinecarboxaldehyde (500 mg, 2.268 mmol) in DCM (10 mL) at -78 °C, and the reaction mixture was then stirred at ambient temperature for 3 h. The reaction mixture was quenched with saturated NaHCO3 solution (20 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4 , filtered, and concentrated under reduced pressure to obtain a crude compound, which was purified by rapid chromatography to give 200 mg (36%) of 6 -bromo-3-chloro-2-(difluoromethyl)pyridine.
步驟3：在環境溫度下向6-溴-3-氯-2-(二氟甲基)吡啶(200 mg，0.825 mmol)於1,4-二噁烷(5 mL)中之攪拌溶液中添加胺基甲酸三級丁酯(386.5 mg)及碳酸銫(806 mg)。用氬氣使混合物脫氣5 min，之後添加xantphos (47 mg)及Pd2(dba)3(37 mg)。將混合物加熱至100℃持續16 h。經由矽藻土墊過濾反應混合物且用水(10 mL)稀釋濾液且用乙酸乙酯(2×50 mL)萃取。用鹽水(20 mL)洗滌合併之有機層，經無水Na2SO4乾燥且過濾。在減壓下濃縮濾液，獲得粗化合物，在藉由急驟層析(C18，12 g濾筒，用0.1%甲酸及乙腈溶析)純化後得到180 mg (78%)(5-氯-6-(二氟甲基)吡啶-2-基)胺基甲酸三級丁酯。LCMS m/z = 279 [M+H]+。Step 3: At ambient temperature, tributyl carbamate (386.5 mg) and cesium carbonate (806 mg) were added to a stirred solution of 6-bromo-3-chloro-2-(difluoromethyl)pyridine (200 mg, 0.825 mmol) in 1,4-dioxane (5 mL). The mixture was degassed with argon for 5 min, followed by the addition of xantphos (47 mg) and Pd₂ (dba) ₃ (37 mg). The mixture was heated to 100 °C for 16 h. The reaction mixture was filtered through a diatomaceous earth mat, the filtrate was diluted with water (10 mL), and extracted with ethyl acetate (2 × 50 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄ , and filtered. The crude compound was obtained by concentrated filtrate under reduced pressure, and purified by rapid chromatography (C18, 12 g filter cartridge, precipitate with 0.1% formic acid and acetonitrile) to give 180 mg (78%) (5-chloro-6-(difluoromethyl)pyridin-2-yl)aminoformate tributyl ester. LCMS m/z = 279 [M+H] + .
步驟4：在0℃下向(5-氯-6-(二氟甲基)吡啶-2-基)胺基甲酸三級丁酯(180 mg)於1,4二噁烷(2 mL)中之攪拌溶液中添加含4 M HCl之1,4-二噁烷(2 mL)且使反應混合物在環境溫度下攪拌2 h。在減壓下濃縮反應混合物，獲得殘餘物，用乙醚(2×20 mL)濕磨該殘餘物，傾析且乾燥，獲得120 mg呈HCl鹽形式之標題化合物。Step 4: At 0°C, 1,4-dioxane (2 mL) containing 4 M HCl was added to a stirred solution of (5-chloro-6-(difluoromethyl)pyridin-2-yl)aminocarbamate tributyl ester (180 mg) in 1,4-dioxane (2 mL), and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was wet-milled with diethyl ether (2 × 20 mL), decanted, and dried to obtain 120 mg of the title compound in the form of an HCl salt.
中間物 903,5-二氟-6-甲基吡啶-2-胺 Intermediate 90: 3,5-Difluoro-6-methylpyridine-2-amine
步驟-1：向3,5-二氟吡啶-2,6-二胺(10 g，68.91 mmol，1.0 equiv.)於乙酸(100 mL)中之溶液中添加異苯并呋喃-1,3-二酮(11.3 g，75.81 mmol，1.0 equiv.)且在100℃下攪拌3 h。用水(200 mL)淬滅反應混合物，過濾沈澱之固體，用水(100 mL)洗滌且在減壓下乾燥，得到2-(6-胺基-3,5-二氟吡啶-2-基)-2,3-二氫-1H-異吲哚-1,3-二酮。產率：84% (16 g，58.18 mmol)。Step 1: Isobenzofuran-1,3-dione (11.3 g, 75.81 mmol, 1.0 equiv.) was added to a solution of 3,5-difluoropyridin-2,6-diamine (10 g, 68.91 mmol, 1.0 equiv.) in acetic acid (100 mL) and stirred at 100 °C for 3 h. The reaction mixture was quenched with water (200 mL), the precipitated solid was filtered, washed with water (100 mL), and dried under reduced pressure to give 2-(6-amino-3,5-difluoropyridin-2-yl)-2,3-dihydro-1H-isoindole-1,3-dione. Yield: 84% (16 g, 58.18 mmol).
步驟-2：在0℃下向2-(6-胺基-3,5-二氟吡啶-2-基)-2,3-二氫-1H-異吲哚-1,3-二酮(16 g，58.14 mmol，1.0 equiv.)於乙腈(100 mL)中之攪拌溶液中添加CuBr (16.68 g，2.0 equiv.)及亞硝酸三級丁酯(14 mL，2.0 equiv.)且在80℃下攪拌6 h。濃縮反應混合物，用乙酸乙酯(500 mL)稀釋，用水(150 mL)及鹽水(150 mL)洗滌。經硫酸鈉乾燥有機層且在減壓下濃縮，得到粗產物，藉由管柱層析純化，得到2-(6-溴-3,5-二氟吡啶-2-基)-2,3-二氫-1H-異吲哚-1,3-二酮。產率：51% (10 g，29.49 mmol)。Step 2: CuBr (16.68 g, 2.0 equiv.) and tributyl nitrite (14 mL, 2.0 equiv.) were added to a stirred solution of 2-(6-amino-3,5-difluoropyridin-2-yl)-2,3-dihydro-1H-isoindole-1,3-dione (16 g, 58.14 mmol, 1.0 equiv.) in acetonitrile (100 mL) at 0 °C, and the mixture was stirred at 80 °C for 6 h. The reaction mixture was concentrated, diluted with ethyl acetate (500 mL), and washed with water (150 mL) and brine (150 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give 2-(6-bromo-3,5-difluoropyridin-2-yl)-2,3-dihydro-1H-isoindole-1,3-dione. Yield: 51% (10 g, 29.49 mmol).
步驟-3：將2-(6-溴-3,5-二氟吡啶-2-基)-2,3-二氫-1H-異吲哚-1,3-二酮(15 g，44.23 mmol，1.0 equiv.)及7 M NH3於MeOH (50 mL)中之混合物在RT下攪拌2 h。在減壓下濃縮反應混合物，得到粗產物，藉由管柱層析純化，得到6-溴-3,5-二氟吡啶-2-胺。產率：86% (8.0 g，38.46 mmol)。Step 3: A mixture of 2-(6-bromo-3,5-difluoropyridin-2-yl)-2,3-dihydro-1H-isoindole-1,3-dione (15 g, 44.23 mmol, 1.0 equiv.) and 7 M NH3 in MeOH (50 mL) was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give 6-bromo-3,5-difluoropyridin-2-amine. Yield: 86% (8.0 g, 38.46 mmol).
步驟-4：用氬氣使6-溴-3,5-二氟吡啶-2-胺(4.0 g，1.0 equiv.)、甲基硼酸(5.8 g，5.0 equiv.)及K2CO3(8.0 g，3.0 equiv.)於1,4-二噁烷(30 mL)中之混合物脫氣5 min，隨後添加Pd(PPh3)4(1.10 g，0.05 equiv.)，且在100℃下攪拌16 h。在減壓下濃縮反應混合物，用乙酸乙酯(150 mL)稀釋，用水(100 mL)及鹽水(100 mL)洗滌。經硫酸鈉乾燥有機層且在減壓下濃縮，得到粗產物，藉由管柱層析純化，得到3,5-二氟-6-甲基吡啶-2-胺。產率：47% (1.3 g，9.02 mmol)。Step 4: Degas a mixture of 6-bromo-3,5-difluoropyridine-2-amine (4.0 g, 1.0 equiv.), methylboronic acid (5.8 g, 5.0 equiv.), and K₂CO₃ (8.0 g, 3.0 equiv.) in 1,4-dioxane (30 mL) for 5 min with argon. Then add Pd( PPh₃ ) ₄ (1.10 g, 0.05 equiv.) and stir at 100 °C for 16 h. Concentrate the reaction mixture under reduced pressure, dilute with ethyl acetate (150 mL), and wash with water (100 mL) and brine (100 mL). The organic layer was dried with sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to give 3,5-difluoro-6-methylpyridin-2-amine. Yield: 47% (1.3 g, 9.02 mmol).
HCl鹽。HCl salt.
中間物 915-氟-6-(甲基-d3)吡啶-2-胺 Intermediate 91: 5-Fluoro-6-(methyl-d3)pyridine-2-amine
步驟-1：在0℃下向6-溴-5-氟吡啶-2-胺(1.7 g，8.9 mmol，1.0 equiv.)於DCM (30.0 mL)中之攪拌溶液中添加三乙胺(1.86 mL，13.35 mmol，1.5 equiv.)、4-二甲基胺基吡啶(0.109 g，0.89 mmol，0.1 equiv.)及Boc2O (2.5 equiv.)且將反應混合物在RT下攪拌16 h。在反應完成後，用乙酸乙酯(10 mL)稀釋反應混合物且用H2O (2 × 10 mL)及鹽水(2 × 10 mL)洗滌。經無水Na2SO4乾燥有機萃取物，過濾且在減壓下濃縮，得到粗產物，藉由急驟層析純化，得到(6-溴-5-氟吡啶-2-基)[三級丁基(甲醯基)-{3}-氧烷基]胺基甲酸三級丁酯(1.7 g，48%)。LC-MS: m/z [M+H]+= 391.1Step 1: Triethylamine (1.86 mL, 13.35 mmol, 1.5 equiv.), 4-dimethylaminopyridine (0.109 g, 0.89 mmol, 0.1 equiv.), and Boc₂O (2.5 equiv.) were added to a stirred solution of 6-bromo-5-fluoropyridine-2-amine (1.7 g, 8.9 mmol, 1.0 equiv.) in DCM (30.0 mL) at 0 °C, and the reaction mixture was stirred at RT for 16 h. After the reaction was complete, the reaction mixture was diluted with ethyl acetate (10 mL) and washed with H₂O (2 × 10 mL) and brine (2 × 10 mL). The organic extract was dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure to give a crude product. Purification by rapid chromatography yielded tributyl (6-bromo-5-fluoropyridin-2-yl)[tert-butyl(methacryl)-{3}-oxoalkyl]aminoformate (1.7 g, 48%). LC-MS: m/z [M+H] ⁺ = 391.1
步驟-2：用氬氣使甲酸{2-[(6-溴-5-氟吡啶-2-基)[2-(甲醯氧基)-2-甲基丙-2-基]胺基]-2-甲基丙-2-基}酯(2.0 g，5.08 mmol，1.0 equiv.)於二噁烷(4.0 mL)及水(1.0 mL)中之混合物脫氣10 min。在室溫下添加(甲基-d3)硼酸(1.59 g，25.4 mmol，5.0 equiv.)、K3PO4(2.15 g，10.17 mmol，2.0 equiv.)及Pd(dppf)Cl2.DCM (0.415 g，0.509 mmol，0.1 equiv.)。將反應混合物在110℃下在密封管中加熱16 h。用水(10 mL)稀釋反應混合物且用乙酸乙酯(2 x 10 mL)萃取。用鹽水(10 mL)洗滌合併之有機層，經硫酸鈉乾燥，且在減壓下蒸發，得到粗產物。藉由急驟層析純化粗產物，得到甲酸{2-[(5-氟-6-甲基吡啶-2-基)[2-(甲醯氧基)-2-甲基丙-2-基]胺基]-2-甲基丙-2-基}酯(0.6 g，36%)。LC-MS: m/z [M+H]+= 330.1Step 2: Degas a mixture of formic acid {2-[(6-bromo-5-fluoropyridin-2-yl)[2-(methoxy)-2-methylpropyl-2-yl]amino]-2-methylpropyl-2-yl} ester (2.0 g, 5.08 mmol, 1.0 equiv.) in dioxane (4.0 mL) and water (1.0 mL) for 10 min using argon. Add (methyl-d3)boronic acid (1.59 g, 25.4 mmol, 5.0 equiv.), K₃PO₄ (2.15 g, 10.17 mmol, 2.0 equiv.), and Pd(dppf) Cl₂ ·DCM (0.415 g, 0.509 mmol, 0.1 equiv.) at room temperature. Heat the reaction mixture at 110 °C in a sealed tube for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and evaporated under reduced pressure to give the crude product. The crude product was purified by rapid chromatography to give formate {2-[(5-fluoro-6-methylpyridin-2-yl)[2-(methoxy)-2-methylpropyl-2-yl]amino]-2-methylpropyl-2-yl} ester (0.6 g, 36%). LC-MS: m/z [M+H] + = 330.1
步驟-3：在0℃下向[三級丁基(甲醯基)-{3}-氧烷基](5-氟-6-甲基吡啶-2-基)胺基甲酸三級丁酯(0.75 g，2.26 mmol，1.0 equiv.)於DCM (10.0 mL)中之攪拌溶液中添加TFA (2.0 mL )且將反應混合物在RT下攪拌4 h。反應後，在減壓下蒸發反應混合物且藉由使用NaHCO3溶液(10.0 mL)淬滅，用乙酸乙酯(20 mL)稀釋且用H2O (2 × 10 mL)及鹽水(2 × 10 mL)洗滌。經無水Na2SO4乾燥有機萃取物，過濾且在減壓下濃縮，得到粗產物。藉由急驟層析純化粗產物，得到5-氟-6-甲基吡啶-2-胺(0.25 g，85%)。LC-MS: m/z [M+H]+= 130.1。Step 3: TFA (2.0 mL) was added to a stirred solution of [tert-butyl(methoxyalkyl)-{3}oxoalkyl](5-fluoro-6-methylpyridin-2-yl)aminocarbamate (0.75 g, 2.26 mmol, 1.0 equiv.) in DCM (10.0 mL) at 0 °C, and the reaction mixture was stirred at RT for 4 h. After the reaction, the reaction mixture was evaporated under reduced pressure and quenched with NaHCO3 solution (10.0 mL), diluted with ethyl acetate (20 mL), and washed with H2O (2 × 10 mL) and brine (2 × 10 mL). The organic extract was dried over anhydrous Na2SO4 , filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by rapid chromatography to give 5-fluoro-6-methylpyridin-2-amine (0.25 g, 85%). LC-MS: m/z [M+H] + = 130.1.
中間物 926-(1,1-二氟乙基)-5-氟吡啶-2-胺 Intermediate 92 6-(1,1-difluoroethyl)-5-fluoropyridine-2-amine
步驟-1：在0℃下向1-(6-溴-3-氟吡啶-2-基)乙-1-酮(2.5 g，11.47 mmol，1.0 equiv.)於DCM (30 mL)中之攪拌溶液中逐滴添加二乙基胺基三氟化硫(15 mL，114.67 mmol，10.0 equiv.)且在RT下攪拌16 h。在0℃下用NaHCO3溶液淬滅反應混合物且用DCM (50 mL)稀釋。分離有機層，用水 (20 mL)及鹽水(20 mL)洗滌。經硫酸鈉乾燥溶劑且在減壓下濃縮，得到粗產物，藉由急驟管柱層析純化，得到6-溴-2-(1,1-二氟乙基)-3-氟吡啶。產率：29% (800 mg，3.33 mmol)。LC-MS: m/z [M+H]+= 340.9。Step 1: Diethylaminosulfur trifluoride (15 mL, 114.67 mmol, 10.0 equiv.) was added dropwise to a stirred solution of 1-(6-bromo-3-fluoropyridin-2-yl)ethyl-1-one (2.5 g, 11.47 mmol, 1.0 equiv.) in DCM (30 mL) at 0 °C, and the mixture was stirred at RT for 16 h. The reaction mixture was quenched with NaHCO3 solution at 0 °C and diluted with DCM (50 mL). The organic layer was separated and washed with water (20 mL) and brine (20 mL). The solvent was dried over sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by rapid column chromatography to give 6-bromo-2-(1,1-difluoroethyl)-3-fluoropyridine. Yield: 29% (800 mg, 3.33 mmol). LC-MS: m/z [M+H] + = 340.9.
步驟-2：用氬氣使6-溴-2-(1,1-二氟乙基)-3-氟吡啶(400 mg，1.67 mmol，1.0 equiv.)於二噁烷(10 mL)中之溶液脫氣10 min，隨後添加二苯甲酮亞胺(604 mg，3.53 mmol，2.0 equiv.)、Cs2CO3(1.1 g，3.33 mmol，2.0 equiv.)、BINAP (104 mg，0.17 mmol，0.1 equiv.)、Pd(OAc)2(37 mg，0.17 mmol，0.1 equiv.)且在密封管中在100℃下攪拌16 h。用水(50 mL)稀釋反應混合物且用[M+H]+ (2 × 100 mL)萃取。用鹽水(50 mL)洗滌合併之有機層，經Na2SO4乾燥，且在減壓下濃縮，得到粗產物，藉由急驟管柱層析純化，得到N-(6-(1,1-二氟乙基)-5-氟吡啶-2-基)-1,1-二苯甲酮亞胺。LC-MS: m/z [M+H]+= 340.9。Step 2: Degas the solution of 6-bromo-2-(1,1-difluoroethyl)-3-fluoropyridine (400 mg, 1.67 mmol, 1.0 equiv.) in dioxane (10 mL) for 10 min with argon. Then add benzophenone imine (604 mg, 3.53 mmol, 2.0 equiv.), Cs₂CO₃ ( 1.1 g, 3.33 mmol, 2.0 equiv.), BINAP (104 mg, 0.17 mmol, 0.1 equiv.), and Pd(OAc) ₂ (37 mg, 0.17 mmol, 0.1 equiv.) and stir in a sealed tube at 100 °C for 16 h. Dilute the reaction mixture with water (50 mL) and extract with [M+H]⁺ (2 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄ , and concentrated under reduced pressure to obtain the crude product. Purification by rapid column chromatography yielded N-(6-(1,1-difluoroethyl)-5-fluoropyridin-2-yl)-1,1-benzophenone imine. LC-MS: m/z [M+H] ⁺ = 340.9.
步驟-3：在0℃下向N-(6-(1,1-二氟乙基)-5-氟吡啶-2-基)-1,1-二苯甲酮亞胺(800 mg，2.35 mmol，1.0 equiv.)於THF (10 mL)中之溶液中添加1(N) HCl (10 mL)且在RT下攪拌3 h。用水(25 mL)稀釋反應混合物，用飽和NaHCO3溶液中和至pH~7且用[M+H]+ (2× 200 mL)萃取。用鹽水(50 mL)洗滌合併之有機層，經硫酸鈉乾燥，且在減壓下濃縮，得到粗產物，藉由急驟管柱層析純化，獲得6-(1,1-二氟乙基)-5-氟吡啶-2-胺。產率：84% (350 mg，1.98 mmol)。LC-MS: m/z [M+H]+= 176.8。Step 3: Add 1 (N) HCl (10 mL) to a solution of N-(6-(1,1-difluoroethyl)-5-fluoropyridin-2-yl)-1,1-benzophenone imine (800 mg, 2.35 mmol, 1.0 equiv.) in THF (10 mL) at 0 °C and stir for 3 h at RT. Dilute the reaction mixture with water (25 mL), neutralize to pH ~7 with saturated NaHCO3 solution, and extract with [M+H]+ (2 × 200 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the crude product. Purification by rapid column chromatography yielded 6-(1,1-difluoroethyl)-5-fluoropyridine-2-amine. Yield: 84% (350 mg, 1.98 mmol). LC-MS: m/z [M+H] + = 176.8.
中間物 935-氟-4-甲基嘧啶-2-胺將2-氯-5-氟-4-甲基嘧啶(1.0 g，6.82 mmol，1.0 equiv.)於含7 M NH3之MeOH (20 mL)中之溶液在密封管中在80℃下攪拌24 h。在減壓下濃縮反應混合物，得到粗產物，藉由急驟管柱層析純化，得到5-氟-4-甲基嘧啶-2-胺。產率：57.7 % (500 mg，3.93 mmol)。LC-MS: m/z [M+H] + = 128.1。 Intermediate 93 5-Fluoro-4-methylpyrimidin-2-amine A solution of 2-chloro-5-fluoro-4-methylpyrimidine (1.0 g, 6.82 mmol, 1.0 equiv.) in MeOH (20 mL) containing 7 M NH₃ was stirred in a sealed tube at 80 °C for 24 h. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by rapid column chromatography to give 5-fluoro-4-methylpyrimidine-2-amine. Yield: 57.7% (500 mg, 3.93 mmol). LC-MS: m/z [M+H]⁺ = 128.1.
中間物 946-(二氟甲基)-5-氟吡啶-2-胺 Intermediate 94 : 6-(difluoromethyl)-5-fluoropyridine-2-amine
步驟-1：在-30℃下向6-氯-3-氟吡啶-2-甲醛(3 g，18.8 mmol，1.0 equiv.)於DCM (50 mL)中之溶液中逐滴添加二乙基胺基三氟化硫(4.47 mL，33.84 mmol，1.8 equiv.)且經4 h逐漸加溫至RT。在0℃下用NaHCO3溶液(100 mL)淬滅反應混合物，用DCM (200 mL)稀釋，分離各層，且用水(100 mL)及鹽水(100 mL)洗滌有機層。經Na2SO4乾燥有機層且在減壓下濃縮，得到粗產物，藉由急驟管柱層析純化，得到6-氯-2-(二氟甲基)-3-氟吡啶。產率：73% (2.5 g，13.8 mmol)。Step 1: Diethylaminosulfur trifluoride (4.47 mL, 33.84 mmol, 1.8 equiv.) was added dropwise to a solution of 6-chloro-3-fluoropyridine-2-carboxaldehyde (3 g, 18.8 mmol, 1.0 equiv.) in DCM (50 mL) at -30 °C, and the mixture was gradually heated to RT over 4 h. The reaction mixture was quenched with NaHCO3 solution (100 mL) at 0 °C, diluted with DCM (200 mL), and the layers were separated. The organic layer was washed with water (100 mL) and brine (100 mL). The organic layer was dried with Na₂SO₄ and concentrated under reduced pressure to obtain a crude product, which was purified by rapid column chromatography to give 6-chloro-2-(difluoromethyl)-3-fluoropyridine. Yield: 73% (2.5 g, 13.8 mmol).
步驟-2：用氬氣使6-氯-2-(二氟甲基)-3-氟吡啶(3 g，16.52 mmol，1.0 equiv.)、二苯甲酮亞胺(5.5 mL，33.05 mmol，2.0 equiv.)及Cs2CO3(10.8 g，33.05 mmol，2.0 equiv.)於1,4-二噁烷(60 mL)中之混合物脫氣15 min，隨後添加BINAP (1029 mg，1.65 mmol，0.1 equiv.)、Pd(OAc)2(371 mg，1.65 mmol，0.1 equiv.)且在100℃下攪拌16 h。過濾反應混合物，用乙酸乙酯(100 mL)洗滌，在減壓下濃縮濾液，用水(100 mL)稀釋且用乙酸乙酯(2 × 100 mL)萃取。用鹽水(100 mL)洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮，得到粗產物，藉由急驟管柱層析純化，得到6-(二氟甲基)-N-(二苯基亞甲基)-5-氟吡啶-2-胺。產率：78% (4.2 g，12.88 mmol)。LC-MS: m/z [M+H]+ = 327.2。Step 2: Degas a mixture of 6-chloro-2-(difluoromethyl)-3-fluoropyridine (3 g, 16.52 mmol, 1.0 equiv.), benzophenone imine (5.5 mL, 33.05 mmol, 2.0 equiv.), and Cs₂CO₃ ( 10.8 g, 33.05 mmol, 2.0 equiv.) in 1,4-dioxane (60 mL) for 15 min with argon. Then add BINAP (1029 mg, 1.65 mmol, 0.1 equiv.) and Pd(OAc) ₂ (371 mg, 1.65 mmol, 0.1 equiv.) and stir at 100 °C for 16 h. The reaction mixture was filtered, washed with ethyl acetate (100 mL), concentrated under reduced pressure, diluted with water (100 mL), and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (100 mL ) , dried over Na₂SO₄ , and concentrated under reduced pressure to give the crude product, which was purified by rapid column chromatography to give 6-(difluoromethyl)-N-(diphenylmethylene)-5-fluoropyridin-2-amine. Yield: 78% (4.2 g, 12.88 mmol). LC-MS: m/z [M+H]⁺ = 327.2.
步驟-3：在0℃下向6-(二氟甲基)-N-(二苯基亞甲基)-5-氟吡啶-2-胺(4.2 g，12.87 mmol，1.0 equiv.)於THF (60 mL)中之溶液中添加1N HCl (60 mL)且在RT下攪拌16 h。在減壓下濃縮反應混合物，得到殘餘物，用飽和NaHCO3溶液鹼化至pH~8且用乙酸乙酯(2 × 100 mL)萃取。用鹽水(100 mL)洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮，得到粗產物，藉由急驟管柱層析純化，得到6-(二氟甲基)-5-氟吡啶-2-胺。產率：76% (1.6 g，9.87 mmol)。LC-MS: m/z [M+H]+= 163.1。Step 3: 1N HCl (60 mL) was added to a solution of 6-(difluoromethyl)-N-(diphenylmethylene)-5-fluoropyridine-2-amine (4.2 g, 12.87 mmol, 1.0 equiv.) in THF (60 mL) at 0 °C, and the mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was alkalized to pH ~8 with saturated NaHCO3 solution and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 , and concentrated under reduced pressure to obtain a crude product, which was purified by rapid column chromatography to give 6-(difluoromethyl)-5-fluoropyridine-2-amine. Yield: 76% (1.6 g, 9.87 mmol). LC-MS: m/z [M+H] + = 163.1.
中間物 956-環丙基-5-氟吡啶-2-胺 Intermediate 95: 6-Cyclopropyl-5-Fluoropyridine-2-amine
步驟-1：向6-溴-5-氟吡啶-2-胺(1 g，5.236 mmol，1 equiv.)於1,4-二噁烷:水(15 ml)中之攪拌溶液中添加Cs2CO3(5.12 g，15.707 mmol，3 equiv.)且用氬氣脫氣5 min。添加環丙基硼酸(2.25 g，26.178 mmol，5 equiv.)及Pd(dppf)Cl2(0.383 g，0.524 mmol，0.1 equiv.)且將反應混合物在100℃下攪拌16 h。完成後(藉由LCMS監測)，經由矽藻土床過濾反應混合物，在減壓下濃縮濾液，得到粗產物，藉由combiflash層析純化，得到6-乙基-5-氟吡啶-2-胺(0.6 g，75%)。LC-MS: m/z [M+H] + = 153.1。Step 1: Cs₂CO₃ (5.12 g, 15.707 mmol, 3 equiv.) was added to a stirred solution of 6-bromo-5- fluoropyridine -2-amine (1 g, 5.236 mmol, 1 equiv.) in 1,4-dioxane:water (15 ml), and the mixture was degassed with argon for 5 min. Cyclopropylboronic acid (2.25 g, 26.178 mmol, 5 equiv.) and Pd(dppf) Cl₂ (0.383 g, 0.524 mmol, 0.1 equiv.) were added, and the reaction mixture was stirred at 100 °C for 16 h. After completion (monitored by LCMS), the reaction mixture was filtered through a diatomaceous earth bed, and the filtrate was concentrated under reduced pressure to obtain a crude product. Purification by combiflash chromatography yielded 6-ethyl-5-fluoropyridine-2-amine (0.6 g, 75%). LC-MS: m/z [M+H]+ = 153.1.
中間物 966-環丙基-5-氟吡啶-2-胺 Intermediate 96: 6-Cyclopropyl-5-Fluoropyridine-2-amine
步驟-1：向6-溴-5-氟吡啶-2-胺(1 g，5.236 mmol，1 equiv.)於1,4-二噁烷:水(15 ml)中之攪拌溶液中添加K3PO4(3.33 g，15.707 mmol，3 equiv.)且用氬氣脫氣5 min。添加乙基硼酸(1.93 g，26.178 mmol，5 equiv.)及Pd(dppf)Cl2.DCM(0.428 g，0.524 mmol，0.1 equiv.)且將反應混合物在100℃下攪拌16 h。完成後(藉由LCMS監測)，經由矽藻土床過濾反應混合物，在減壓下濃縮濾液，得到粗產物，藉由combiflash層析純化，得到6-乙基-5-氟吡啶-2-胺(0.5 g，68%)。LC-MS: m/z [M+H] + = 140.06。Step 1: K₃PO₄ (3.33 g, 15.707 mmol, 3 equiv.) was added to a stirred solution of 6-bromo- 5 -fluoropyridine-2-amine (1 g, 5.236 mmol, 1 equiv.) in 1,4-dioxane:water (15 ml), and the mixture was degassed with argon for 5 min. Ethylboronic acid (1.93 g, 26.178 mmol, 5 equiv.) and Pd(dppf) Cl₂ ·DCM (0.428 g, 0.524 mmol, 0.1 equiv.) were added, and the reaction mixture was stirred at 100 °C for 16 h. After completion (monitored by LCMS), the reaction mixture was filtered through a diatomaceous earth bed, and the filtrate was concentrated under reduced pressure to obtain a crude product. Purification by combiflash chromatography yielded 6-ethyl-5-fluoropyridine-2-amine (0.5 g, 68%). LC-MS: m/z [M+H]+ = 140.06.
中間物 974-甲氧基-5-甲基嘧啶-2-胺 Intermediate 97 4-Methoxy-5-methylpyrimidine-2-amine
步驟-1：用氬氣使2-氯-4-甲氧基-5-甲基嘧啶(600 mg，3.78 mmol，1 equiv.)於二噁烷(8 mL)中之溶液脫氣10 min，隨後添加二苯甲酮亞胺(1.4 g，7.57 mmol，2.0 equiv.)、Cs2CO3(2.4 g，7.57 mmol，2.0 equiv.)、BINAP (0.23 g，0.38 mmol，0.1 equiv.)及Pd(OAc)2(0.085 g，0.38 mmol，0.1 equiv.)且在100℃下攪拌16 h。用水(100 mL)稀釋反應混合物且用乙酸乙酯(2 × 200 mL)萃取。用鹽水(100 mL)洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮，得到粗產物，藉由急驟層析純化，得到N-(二苯基亞甲基)-4-甲氧基-5-甲基嘧啶-2-胺。產率：31% (360 mg，1.18 mmol)。LC-MS: m/z [M+H]+= 303.7Step 1: Degas a solution of 2-chloro-4-methoxy-5-methylpyrimidine (600 mg, 3.78 mmol, 1 equiv.) in dioxane (8 mL) for 10 min with argon. Then add benzophenone imine (1.4 g, 7.57 mmol, 2.0 equiv.), Cs₂CO₃ (2.4 g, 7.57 mmol, 2.0 equiv.), BINAP (0.23 g, 0.38 mmol, 0.1 equiv.), and Pd(OAc) ₂ (0.085 g, 0.38 mmol, 0.1 equiv.) and stir at 100 °C for 16 h. Dilute the reaction mixture with water (100 mL) and extract with ethyl acetate (2 × 200 mL). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄ , and concentrated under reduced pressure to give the crude product. Purification by rapid chromatography yielded N-(diphenylmethylene)-4-methoxy-5-methylpyrimidine-2-amine. Yield: 31% (360 mg, 1.18 mmol). LC-MS: m/z [M+H] ⁺ = 303.7
步驟-2：在0℃下向N-(二苯基亞甲基)-4-甲氧基-5-甲基嘧啶-2-胺(2 g，6.59 mmol，1.0 equiv.)於THF (10 mL)中之溶液中添加1(N) HCl (10 mL)且在RT下攪拌2 h。用飽和NaHCO3溶液中和反應混合物且用乙酸乙酯(2 × 200 mL)萃取。用鹽水(50 mL)洗滌合併之有機層，經硫酸鈉乾燥且在減壓下濃縮，得到4-甲氧基-5-甲基嘧啶-2-胺。產率：66% (610 mg，4.38 mmol)。LC-MS (方法S): m/z [M+H]+= 139.9。Step 2: 1 (N) HCl (10 mL) was added to a solution of N-(diphenylmethylene)-4-methoxy-5-methylpyrimidine-2-amine (2 g, 6.59 mmol, 1.0 equiv.) in THF (10 mL) at 0 °C, and the mixture was stirred at RT for 2 h. The reaction mixture was neutralized with saturated NaHCO3 solution and extracted with ethyl acetate (2 × 200 mL). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give 4-methoxy-5-methylpyrimidine-2-amine. Yield: 66% (610 mg, 4.38 mmol). LC-MS (Method S): m/z [M+H] + = 139.9.
中間物 98(3-(三氟甲基)雙環[1.1.1]戊-1-基)甲醇在0℃下向含2.4 (M) LiAlH4之THF (4.6 mL，11.103 mmol，2 equiv.)於THF (40 mL)中之溶液中添加含3-(三氟甲基)雙環[1.1.1]戊烷-1-甲酸(1 gm，5.55 mmol，1 equiv.)之THF (1 mL)且在RT下攪拌4 h。用10% NaOH水溶液(2.5 mL)淬滅反應混合物且過濾沈澱之固體且經Na2SO4乾燥濾液，濃縮至乾，得到標題化合物，其直接用於以下步驟。產率：70% (650 mg，3.91 mmol)。 Intermediate 98 (3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methanol At 0 °C, a solution containing 4.6 mL (11.103 mmol, 2 equiv.) of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid ( 1 gm, 5.55 mmol, 1 equiv.) in 40 mL of THF containing 2.4 (M) LiAlH4 was added to THF, and the mixture was stirred at RT for 4 h. The reaction mixture was quenched with 2.5 mL of 10% NaOH aqueous solution, and the precipitate was filtered and dried over Na2SO4 . The filtrate was concentrated to dryness to give the title compound, which was used directly in the following steps. Yield: 70% (650 mg, 3.91 mmol).
中間物 994-(苄基硫基)-5-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑及相應SEM區域異構物用氬氣使4-碘-5-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑(區域異構物之混合物，5 g，14.78 mmol)於1,4-二噁烷(100 mL)中之溶液脫氣10 min，隨後在室溫下添加苄基硫醇(3.5 mL，29.65 mmol)、DIPEA (7.7 mL，44.34 mmol)、Xantphos (1.3 g，2.22 mmol)及Pd2(dba)3(1.4 g，1.48 mmol)。將反應混合物在密封管中加熱至110℃持續16 h。過濾反應混合物且濃縮濾液。用水(90 mL)稀釋所獲得之殘餘物且用乙酸乙酯(2 × 90 mL)萃取。用鹽水(70 mL)洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮，得到粗產物，藉由管柱層析(SiO2，50% EtOAc/Hex)純化，得到標題化合物。產率：61% (3 g)。LCMS m/z = 335 [M+H]+。 Intermediate 99 : 4-(benzylthio)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium and corresponding SEM region isomers The solution of 4-iodo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (a mixture of regiomeric isomers, 5 g, 14.78 mmol) in 1,4-dioxane (100 mL) was degassed with argon for 10 min. Then, benzyl mercaptan (3.5 mL, 29.65 mmol), DIPEA (7.7 mL, 44.34 mmol), Xantphos (1.3 g, 2.22 mmol), and Pd₂ (dba) ₃ (1.4 g, 1.48 mmol) were added at room temperature. The reaction mixture was heated to 110 °C in a sealed tube for 16 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was diluted with water (90 mL) and extracted with ethyl acetate (2 × 90 mL). The combined organic layers were washed with brine (70 mL), dried over Na₂SO₄ , and concentrated under reduced pressure to give the crude product, which was purified by column chromatography ( SiO₂ , 50% EtOAc/Hex) to give the title compound. Yield: 61% (3 g). LCMS m/z = 335 [M+H] ⁺ .
中間物 100-101使用與中間物99之製備類似之方法由相應的起始材料製備該等中間物。
中間物 1025-(((三級丁基二苯基矽烷基)氧基)甲基)-4-((4-甲氧基苄基)硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑及相應SEM區域異構物 Intermediate 102: 5-(((trimethylbutyldiphenylsilyl)oxy)methyl)-4-((4-methoxybenzyl)thio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium and corresponding SEM region isomers
步驟1：使4-碘-1H-咪唑(20 g，103.11 mmol)、乙酸鈉(14.4 g，176.31 mmol)、乙酸(8.8 mL，154.66 mmol)及37% HCHO (72 mL)之混合物回流30 h。冷卻反應混合物且用乙酸乙酯(3 × 150 mL)萃取。用鹽水(50 mL)洗滌合併之有機層，經Na2SO4乾燥，過濾且在減壓下濃縮，得到粗產物，藉由管柱層析(SiO2，10% MeOH/DCM)純化，產生(4-碘-1H-咪唑-5-基)甲醇。產率：35% (8.0 g)。LCMS m/z = 225[M+H]+。Step 1: A mixture of 4-iodo-1H-imidazole (20 g, 103.11 mmol), sodium acetate (14.4 g, 176.31 mmol), acetic acid (8.8 mL, 154.66 mmol), and 37% HCHO (72 mL) was refluxed for 30 h. The reaction mixture was cooled and extracted with ethyl acetate (3 × 150 mL). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄ , filtered , and concentrated under reduced pressure to obtain the crude product. Purification was performed by column chromatography ( SiO₂ , 10% MeOH/DCM) to produce (4-iodo-1H-imidazole-5-yl)methanol. Yield: 35% (8.0 g). LCMS m/z = 225[M+H] + .
步驟2：在0℃下向(4-碘-1H-咪唑-5-基)甲醇(8 g，35.71 mmol)於二甲基甲醯胺(70 mL)中之溶液中添加氫化鈉(60%於礦物油中，1.4 g，35.71 mmol)且將混合物攪拌30 min，隨後添加SEM-Cl (6.3 mL，35.71 mmol)。將反應混合物在室溫下攪拌16 h且接著用冷NH4Cl溶液(50 mL)淬滅且用EtOAc (2 × 150 mL)萃取。用冷水(3 × 50 mL)、鹽水(50 mL)洗滌合併之有機層，經硫酸鈉乾燥，過濾且在減壓下濃縮，得到粗(4-碘-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-5-基)甲醇及相應N-SEM區域異構物。產率：定量(9 g)。LCMS m/z = 355 [M+H]+。Step 2: Sodium hydroxide (60% in mineral oil, 1.4 g, 35.71 mmol) was added to a solution of (4-iodo-1H-imidazol-5-yl)methanol (8 g, 35.71 mmol) in dimethylformamide (70 mL) at 0 °C, and the mixture was stirred for 30 min, followed by the addition of SEM-Cl (6.3 mL, 35.71 mmol). The reaction mixture was stirred at room temperature for 16 h, then quenched with cold NH4Cl solution (50 mL) and extracted with EtOAc (2 × 150 mL). The combined organic layer was washed with cold water (3 × 50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude (4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)methanol and the corresponding N-SEM isomers. Yield: quantitative (9 g). LCMS m/z = 355 [M+H] + .
步驟3：在0℃下向(4-碘-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-5-基)甲醇及相應N-SEM區域異構物(5.5 g，15.48 mmol)於二甲基甲醯胺(60 mL)中之溶液中添加咪唑(4.2 g，61.92 mmol)及4-二甲基胺基吡啶(0.38 g，3.1 mmol)，隨後添加三級丁基(氯)二苯基矽烷(16.1 mL，61.92 mmol)且將混合物在室溫下攪拌16 h。用水(50 mL)淬滅反應混合物且用乙酸乙酯(2 × 100 mL)萃取。用鹽水(50 mL)洗滌合併之有機層，經Na2SO4乾燥，過濾且在減壓下濃縮，得到粗產物，藉由管柱層析(SiO2，20% EtOAc/hex)純化，產生5-(((三級丁基二苯基矽烷基)氧基)甲基)-4-碘-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑及相應SEM區域異構物。產率：43% (4 g)。LCMS m/z = 593 [M+H]+。Step 3: Imidazole (4.2 g, 61.92 mmol) and 4-dimethylaminopyridine (0.38 g, 3.1 mmol) were added to a solution of (4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)methanol and the corresponding N-SEM region isomer (5.5 g, 15.48 mmol) in dimethylformamide (60 mL) at 0 °C, followed by the addition of tributyl(chloro)diphenylsilane (16.1 mL, 61.92 mmol), and the mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a crude product. Purification was performed by column chromatography ( SiO₂ , 20% EtOAc/hex) to produce 5-(((trimethylbutyldiphenylsilyl)oxy)methyl)-4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium and corresponding SEM isomers. Yield: 43% (4 g). LCMS m/z = 593 [M+H] ⁺ .
步驟4：向5-(((三級丁基二苯基矽烷基)氧基)甲基)-4-碘-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑及相應SEM區域異構物(3.5 g，5.9 mmol)及(4-甲氧基苯基)甲硫醇(0.9 mL，6.49 mmol)於1,4-二噁烷(40 mL)中之溶液中添加Xantphos (0.51 g，0.88 mmol)及DIPEA (2.3 mL，12.97 mmol)，隨後用氬氣吹掃15 min。添加Pd2dba3(0.54 g，0.59 mmol)且將混合物加熱至100℃持續16 h。經由矽藻土墊過濾反應混合物，用乙酸乙酯(20 mL)洗滌該墊且在減壓下濃縮濾液，得到粗產物(區域異構物之混合物)，藉由管柱層析(SiO2，50% EtOAc/hex)純化，產生標題化合物。產率：82% (3 g)。LCMS m/z = 619 [M+H]+。Step 4: Xantphos (0.51 g, 0.88 mmol) and DIPEA (2.3 mL, 12.97 mmol) were added to a solution of 5-(((trimethylsilyl)ethoxy)methyl)-4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium and its corresponding SEM region isomer (3.5 g, 5.9 mmol) and (4-methoxyphenyl)methanethiol (0.9 mL, 6.49 mmol) in 1,4-dioxane (40 mL), followed by purging with argon for 15 min. Pd 2 dba 3 (0.54 g, 0.59 mmol) was added and the mixture was heated to 100 °C for 16 h. The reaction mixture was filtered through a diatomaceous earth mat, which was then washed with ethyl acetate (20 mL) and the filtrate was concentrated under reduced pressure to give a crude product (a mixture of regional isomers). Purification by column chromatography ( SiO₂ , 50% EtOAc/hex) yielded the title compound. Yield: 82% (3 g). LCMS m/z = 619 [M+H] ⁺ .
中間物 1031-(3-氯-4-氟苯基)-N-(5-氟-6-甲基吡啶-2-基)甲酮亞胺 Intermediate 103 1-(3-chloro-4-fluorophenyl)-N-(5-fluoro-6-methylpyridin-2-yl)methyl ketone imine
步驟1：在室溫下向3-氯-4-氟苯甲醛(5 g，31.53 mmol)於甲苯(50 mL)中之溶液中添加5-氟-6-甲基吡啶-2-胺(4 g，31.53 mmol)且使混合物回流16 h，並使用Dean-stark裝置共沸移除水。冷卻反應混合物且在減壓下濃縮，產生標題化合物，其未經進一步純化即用於下一步驟。產率：定量(7.0 g)。LCMS m/z = 267 [M+H]+。Step 1: 5-Fluoro-6-methylpyridin-2-amine (4 g, 31.53 mmol) was added to a solution of 3-chloro-4-fluorobenzaldehyde (5 g, 31.53 mmol) in toluene (50 mL) at room temperature, and the mixture was refluxed for 16 h. Water was removed by azeotropic extraction using a Dean-Stark apparatus. The reaction mixture was cooled and concentrated under reduced pressure to produce the title compound, which was used in the next step without further purification. Yield: Quantitative (7.0 g). LCMS m/z = 267 [M+H] + .
中間物 104二異丙基胺基甲酸(4-(苄基硫基)-5-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)(3-氯-4-氟苯基)甲酯及相應SEM區域異構物在室溫下向4-(苄基硫基)-5-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑(中間物99，區域異構物之混合物，2.5 g，7.47 mmol)於乙腈(15 mL)中之攪拌溶液中添加3-氯-4-氟苯甲醛(1 mL，8.22 mmol)、二異丙基胺基甲醯氯(1.8 g，11.21 mmol)及DIPEA (4 mL，22.42 mmol)。將所得溶液在80℃下攪拌16 h。接著濃縮反應混合物。用乙酸乙酯(200 mL)稀釋所獲得之殘餘物，相繼用水(80 mL)、鹽水(80 mL)洗滌，經無水Na2SO4乾燥且在減壓下濃縮，得到粗產物，藉由管柱層析(SiO2，10% EtOAc/Hex)純化，得到標題化合物。產率：76% (3.5 g，5.64 mmol)。LCMS m/z = 620 [M+H]+。 Intermediate 104 diisopropylaminocarboxylic acid (4-(benzylthio)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)(3-chloro-4-fluorophenyl) methyl ester and corresponding SEM region isomers At room temperature, 3-chloro-4-fluorobenzaldehyde (1 mL, 8.22 mmol), diisopropylaminomethylchlorodimethyl chloride (1.8 g, 11.21 mmol), and DIPEA (4 mL, 22.42 mmol) were added to a stirred solution of 4-(benzylthio)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (intermediate 99, a mixture of regiomeric isomers, 2.5 g, 7.47 mmol) in acetonitrile (15 mL). The resulting solution was stirred at 80 °C for 16 h. The reaction mixture was then concentrated. The residue was diluted with ethyl acetate (200 mL), washed successively with water (80 mL) and brine (80 mL ) , dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give a crude product. Purification by column chromatography ( SiO₂ , 10% EtOAc/Hex) yielded the title compound. Yield: 76% (3.5 g, 5.64 mmol). LCMS m/z = 620 [M+H] ⁺ .
中間物 105-107以與中間物104之製備類似之方法由相應的醛製備該等中間物。
中間物 108二異丙基胺基甲酸(4-(苄基硫基)-5-(甲氧基甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)(3-氯-4-氟苯基)甲酯及相應SEM區域異構物 Intermediate 108 diisopropylaminocarboxylic acid (4-(benzylthio)-5-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)(3-chloro-4-fluorophenyl) methyl ester and corresponding SEM region isomers
步驟1：在0℃下向1H-咪唑-4-基甲醇鹽酸鹽(5 g，37.15 mmol)於二甲基甲醯胺(50 mL)中之攪拌溶液中添加DIPEA (17 mL，94.0 mmol)，隨後添加SEM-Cl (7.3 mL，40.87 mmol)且將反應混合物在室溫下攪拌16 h。用水淬滅反應混合物且用乙酸乙酯(2 x 50 mL)萃取。用鹽水(50 mL)洗滌合併之有機層，經無水Na2SO4乾燥，過濾且濃縮，得到粗產物，藉由管柱層析(SiO2，3-4%甲醇/DCM)純化，得到(1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-4-基)甲醇及相應N-SEM區域異構物。產率：82% (7 g)。LCMS m/z = 229 [M+H]+。Step 1: DIPEA (17 mL, 94.0 mmol) was added to a stirred solution of 1H-imidazol-4-ylmethanol hydrochloride (5 g, 37.15 mmol) in dimethylformamide (50 mL) at 0 °C, followed by the addition of SEM-Cl (7.3 mL, 40.87 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄ , filtered, and concentrated to give a crude product. Purification was performed by column chromatography ( SiO₂ , 3-4% methanol/DCM) to give (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methanol and the corresponding N-SEM isomers. Yield: 82% (7 g). LCMS m/z = 229 [M+H] ⁺ .
步驟2：在0℃下向(1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-4-基)甲醇及相應N-SEM區域異構物(7 g，30.5 mmol)於THF (100 mL)中之攪拌溶液中逐份添加NaH (60%於礦物油中，2.5 g，61.04 mmol)。接著將混合物在0℃下攪拌30分鐘。添加MeI (2.85 mL，45.78 mmol)，在室溫下繼續攪拌16 h。用飽和NH4Cl溶液(50 mL)淬滅反應混合物且用乙酸乙酯(2x50 mL)萃取。用鹽水(50 mL)洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮，得到4-(甲氧基甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑及相應SEM區域異構物。產量：6.2 g (粗物質)。LCMS m/z = 243 [M+H]+。Step 2: NaH (60% in mineral oil, 2.5 g, 61.04 mmol) was added fractionally to a stirred solution of (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methanol and the corresponding N-SEM region isomer (7 g, 30.5 mmol) in THF (100 mL) at 0 °C. The mixture was then stirred at 0 °C for 30 min. MeI (2.85 mL, 45.78 mmol) was added, and stirring was continued at room temperature for 16 h. The reaction mixture was quenched with saturated NH4Cl solution (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over Na₂SO₄ , and concentrated under reduced pressure to give 4-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium and the corresponding SEM region isomers. Yield: 6.2 g (crude material). LCMS m/z = 243 [M+H] ⁺ .
步驟3：在室溫下向4-(甲氧基甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑及相應SEM區域異構物(3 g，12.38 mmol)於乙腈(35 mL)中之溶液中添加3-氯-4-氟苯甲醛(2 g，12.38 mmol)及二異丙基胺基甲醯氯(2 g，12.38 mmol)，隨後添加DIPEA (6.5 mL，37.13 mmol)且將所得反應混合物加熱至80℃持續16 h。濃縮反應混合物。用乙酸乙酯(50 mL)稀釋所獲得之殘餘物，相繼用水(50 mL)、鹽水(40 mL)洗滌。經無水Na2SO4乾燥有機層且在減壓下濃縮，得到粗產物，藉由管柱層析(SiO2，15-20% EtOAc/hex)純化，得到二異丙基胺基甲酸(3-氯-4-氟苯基)(4-(甲氧基甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯及相應SEM區域異構物。產率：49% (3.2 g)。LCMS m/z = 528 [M+H]+。Step 3: At room temperature, 3-chloro-4-fluorobenzaldehyde (2 g, 12.38 mmol) and diisopropylaminomethylchlorodimethyl chloride (2 g, 12.38 mmol) were added to a solution of 4-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium in acetonitrile (35 mL). Then, DIPEA (6.5 mL, 37.13 mmol) was added, and the resulting reaction mixture was heated to 80 °C for 16 h. The reaction mixture was then concentrated. The residue was diluted with ethyl acetate (50 mL) and washed successively with water (50 mL) and brine (40 mL). The organic layer was dried in anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain a crude product. Purification by column chromatography ( SiO₂ , 15-20% EtOAc/hex) yielded diisopropylaminocarboxylic acid (3-chloro-4-fluorophenyl)(4-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester and corresponding SEM isomers. Yield: 49% (3.2 g). LCMS m/z = 528 [M+H] ⁺ .
步驟4：在室溫下向二異丙基胺基甲酸(3-氯-4-氟苯基)(4-(甲氧基甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯及相應SEM區域異構物(3 g，5.67 mmol)於ACN (50 mL)中之攪拌溶液中添加NIS (5.1 g，22.68 mmol)。將反應混合物在80℃下攪拌6 h，隨後在室溫下攪拌16 h。濃縮反應混合物，用硫代硫酸鈉溶液(50 mL)淬滅所獲得之殘餘物且用DCM (2 x 30 mL)萃取。用鹽水(30 mL)洗滌合併之有機層，經無水Na2SO4乾燥，過濾且濃縮，得到粗產物，藉由管柱層析(SiO2，15-20% EtOAc/hex)純化，得到二異丙基胺基甲酸(3-氯-4-氟苯基)(5-碘-4-(甲氧基甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯及相應SEM區域異構物。產率：43% (1.6 g)。LCMS m/z = 654 [M+H]+。Step 4: NIS (5.1 g, 22.68 mmol) was added to a stirred solution of diisopropylaminocarboxylic acid (3-chloro-4-fluorophenyl)(4-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester and the corresponding SEM region isomer (3 g, 5.67 mmol) in ACN (50 mL) at room temperature. The reaction mixture was stirred at 80 °C for 6 h, followed by stirring at room temperature for 16 h. The reaction mixture was concentrated, and the residues were quenched with sodium thiosulfate solution (50 mL) and extracted with DCM (2 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄ , filtered, and concentrated to obtain the crude product. Purification by column chromatography ( SiO₂ , 15-20% EtOAc/hex) yielded diisopropylaminocarbamate (3-chloro-4-fluorophenyl)(5-iodo-4-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester and corresponding SEM isomers. Yield: 43% (1.6 g). LCMS m/z = 654 [M+H] ⁺ .
步驟5：用氬氣使二異丙基胺基甲酸(3-氯-4-氟苯基)(5-碘-4-(甲氧基甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯及相應SEM區域異構物(5 g，7.633 mmol)於1,4-二噁烷(75 mL)中之攪拌溶液脫氣10分鐘，隨後在室溫下添加苄基硫醇(1.8 mL，15.266 mmol)、DIPEA (4.0 mL，22.90 mmol)、Xantphos (0.670 g，1.145 mmol)及Pd2(dba)3(0.7 g，0.763 mmol)。將反應混合物在密封管中加熱至110℃持續16 h。過濾反應混合物且濃縮濾液。用水(90 mL)稀釋所獲得之殘餘物且用乙酸乙酯(2 × 200 mL)萃取。用鹽水(100 mL)洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮，得到粗產物，藉由急驟管柱層析(SiO2，50% EtOAc/hex)純化，產生標題化合物。產率：71% (3.5 g)。LCMS m/z =650 [M+H]+。Step 5: Degas the stirred solution of diisopropylaminocarboxylic acid (3-chloro-4-fluorophenyl)(5-iodo-4-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester and the corresponding SEM region isomer (5 g, 7.633 mmol) in 1,4-dioxane (75 mL) for 10 min with argon. Then, add benzyl mercaptan (1.8 mL, 15.266 mmol), DIPEA (4.0 mL, 22.90 mmol), Xantphos (0.670 g, 1.145 mmol) and Pd₂ (dba) ₃ (0.7 g, 0.763 mmol) at room temperature. Heat the reaction mixture to 110 °C in a sealed tube for 16 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was diluted with water (90 mL) and extracted with ethyl acetate (2 × 200 mL). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄ , and concentrated under reduced pressure to give the crude product, which was purified by rapid column chromatography ( SiO₂ , 50% EtOAc/hex) to give the title compound. Yield: 71% (3.5 g). LCMS m/z = 650 [M+H] ⁺ .
中間物 1095-甲基-4-((甲硫基)甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑及相應SEM區域異構物 Intermediate 109: 5-Methyl-4-((methylthio)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium and corresponding SEM region isomers
步驟-1：在0℃下向(5-甲基-1H-咪唑-4-基)甲醇(10 g，89.18 mmol，1.0 equiv.)於二甲基甲醯胺(50 mL)中之溶液中添加DIPEA (46.6 mL，267.55 mmol，3.0 equiv.)及SEM-Cl (17.7 mL，133.77 mmol，1.5 equiv.)且在RT下攪拌6 h。濃縮反應混合物，用水(150 mL)稀釋，用乙酸乙酯(300 mL)萃取。用鹽水(100 mL)洗滌有機層，經硫酸鈉乾燥且在減壓下濃縮，得到粗產物，藉由管柱層析純化，得到(5-甲基-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-咪唑-4-基)甲醇。產率：30% (6.5 g，26.85 mmol)。LC-MS: m/z [M+H]+= 243.24。Step 1: DIPEA (46.6 mL, 267.55 mmol, 3.0 equiv.) and SEM-Cl (17.7 mL, 133.77 mmol, 1.5 equiv.) were added to a solution of (5-methyl-1H-imidazol-4-yl)methanol (10 g, 89.18 mmol, 1.0 equiv.) in dimethylformamide (50 mL) at 0 °C and stirred at RT for 6 h. The reaction mixture was concentrated, diluted with water (150 mL), and extracted with ethyl acetate (300 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a crude product. Purification by column chromatography yielded (5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-4-yl)methanol. Yield: 30% (6.5 g, 26.85 mmol). LC-MS: m/z [M+H] + = 243.24.
步驟-2：在0℃下向(5-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-4-基)甲醇(3 g，12.38 mmol，1.0 equiv.)於DCM (50 mL)中之溶液中添加SOCl2(4.5 mL，61.88 mmol，5.0 equiv.)且在RT下攪拌2 h。用水(100 mL)淬滅反應混合物且用乙酸乙酯(200 mL)萃取。用鹽水(100 mL)洗滌有機層，經硫酸鈉乾燥且在減壓下濃縮，得到4-(氯甲基)-5-甲基-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-咪唑，其直接用於下一步驟。產量：2.5 g (粗物質)。Step 2: SOCl₂ (4.5 mL, 61.88 mmol, 5.0 equiv.) was added to a solution of (5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methanol (3 g, 12.38 mmol, 1.0 equiv.) in DCM (50 mL) at 0 °C and stirred at RT for 2 h. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to give 4-(chloromethyl)-5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazolium, which was used directly in the next step. Yield: 2.5 g (crude material).
步驟-3：向步驟1之產物於THF (50 mL)中之溶液中添加三乙胺(4.1 mL)、NaSMe (3.4 g，47.92 mmol，5.0 equiv.)且在RT下攪拌16 h。用水(100 mL)淬滅反應混合物且用乙酸乙酯(150 mL)萃取。用鹽水(100 mL)洗滌有機層，經硫酸鈉乾燥且在減壓下濃縮，得到粗產物，藉由急驟管柱層析純化，得到5-甲基-4-[(甲基氫硫基)甲基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-咪唑。產量：500 mg，1.83 mmol。LC-MS: m/z [M+H]+= 273.3。Step 3: Triethylamine (4.1 mL) and NaSMe (3.4 g, 47.92 mmol, 5.0 equiv.) were added to a solution of the product from Step 1 in THF (50 mL), and the mixture was stirred at RT for 16 h. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (150 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the crude product, which was purified by rapid column chromatography to give 5-methyl-4-[(methylhydrothio)methyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazolium. Yield: 500 mg, 1.83 mmol. LC-MS: m/z [M+H] + = 273.3.
中間物 110二異丙基胺基甲酸(3-氯-4-氟苯基)(5-甲基-4-((甲基磺醯基)甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯及相應SEM區域異構物 Intermediate 110 : Diisopropylaminocarboxylic acid (3-chloro-4-fluorophenyl)(5-methyl-4-((methylsulfonyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester and corresponding SEM region isomers
步驟-1：在RT下向5-甲基-4-[(甲基氫硫基)甲基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-咪唑(中間物109，500 mg，1.84 mmol，1.0 equiv.)及3-氯-4-氟苯甲醛(436 mg，2.75 mmol，1.5 equiv.)於THF (20 mL)中之混合物中添加N,N-雙(丙-2-基)胺甲醯氯(900 mg，5.51 mmol，3.0 equiv.)及K2CO3(703 mg，3.67 mmol，2.0 equiv.)且在80℃下攪拌16 h。在減壓下濃縮反應混合物且用乙酸乙酯(100 mL)稀釋殘餘物。用水(100 mL)、鹽水(75 mL洗滌有機部分，經無水Na2SO4乾燥且在減壓下濃縮，得到粗產物，藉由管柱層析純化，得到N,N-雙(丙-2-基)胺基甲酸(3-氯-4-氟苯基)({5-甲基-4-[(甲基氫硫基)甲基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-咪唑-2-基})甲酯。產率：34% (350 mg，0.627 mmol)。LC-MS: m/z [M+H]+= 273.3。Step 1: N,N-bis(propyl-2-yl)aminomethylchloro(2-chloro-4-[(methylhydrothio)methyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazolium (intermediate 109, 500 mg, 1.84 mmol, 1.0 equiv.) and 3-chloro- 4 -fluorobenzaldehyde (436 mg, 2.75 mmol, 1.5 equiv.) in THF (20 mL) were added to a mixture at RT and stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (100 mL). The organic fraction was washed with water (100 mL) and brine (75 mL), dried over anhydrous Na₂SO₄ , and concentrated under reduced pressure to give a crude product. Purification by column chromatography yielded N,N-bis(propane-2-yl)aminocarboxylic acid (3-chloro-4-fluorophenyl)({5-methyl-4-[(methylhydrothio)methyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl}) methyl ester. Yield: 34% (350 mg, 0.627 mmol). LC-MS: m/z [M+H] ⁺ = 273.3.
步驟-2：向二異丙基胺基甲酸(3-氯-4-氟苯基)(5-甲基-4-((甲基磺醯基)甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯(375 mg，0.67 mmol，1.0 equiv.)於DCM (10 mL)中之溶液中添加mCPBA ( 120 mg，0.67 mmol，1.0 equiv.，77%)且在RT下攪拌16 h。用飽和NaHCO3溶液淬滅反應混合物且用DCM (100 mL)萃取。經硫酸鎂乾燥有機層且在減壓下濃縮，得到(3-氯-4-氟苯基)(5-甲基-4-((甲基磺醯基)甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲基，其用於下一步驟。產量：300 mg (粗物質)。LC-MS: m/z [M+H]+= 590.3。Step 2: Add mCPBA (120 mg, 0.67 mmol, 1.0 equiv., 77%) to a solution of diisopropylaminocarboxylic acid (3-chloro-4-fluorophenyl)(5-methyl-4-((methanesulfonyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl ester (375 mg, 0.67 mmol, 1.0 equiv.) in DCM (10 mL) and stir at RT for 16 h. Quench the reaction mixture with saturated NaHCO3 solution and extract with DCM (100 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give (3-chloro-4-fluorophenyl)(5-methyl-4-((methylsulfonylurea)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl, which was used in the next step. Yield: 300 mg (crude material). LC-MS: m/z [M+H] + = 590.3.
實例 12-((3-氯-4-氟苯基)(甲氧基)甲基)-4-(甲基磺醯基)-1H-咪唑 Example 1: 2-((3-chloro-4-fluorophenyl)(methoxy)methyl)-4-(methylsulfonyl)-1H-imidazolium
步驟1：在0℃下將氫化鈉(礦物油中之60%分散液，41 mg，1.035 mmol)添加至中間物5 (300 mg，0.690 mmol)於二甲基甲醯胺(10 mL)中之攪拌溶液中且將混合物攪拌30 min。30分鐘後，添加碘甲烷(0.13 mL，2.069 mmol)且將反應混合物在0℃下攪拌1 h。用水(10 mL)稀釋混合物且用乙酸乙酯(20 mL × 2)萃取。經Na2SO4乾燥合併之有機層且在減壓下濃縮，得到粗產物，其未經任何進一步純化即用於下一步驟。Step 1: Sodium hydroxide (60% dispersion in mineral oil, 41 mg, 1.035 mmol) was added to intermediate 5 (300 mg, 0.690 mmol) in a stirred solution of dimethylformamide (10 mL) at 0 °C, and the mixture was stirred for 30 min. After 30 min, methyl iodoformide (0.13 mL, 2.069 mmol) was added, and the reaction mixture was stirred at 0 °C for 1 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure to obtain the crude product, which was used in the next step without any further purification.
步驟2：在rt下將步驟1之粗產物(330 mg，粗物質)溶解於含4M HCl之1,4-二噁烷(15 mL)中且將混合物攪拌18 h。在減壓下濃縮混合物，得到粗化合物，藉由製備型HPLC純化，得到標題化合物(36 mg，15%，經兩個步驟)。1H-NMR (400 MHz, DMSO-d6): 13.10 (s, 1H), 7.81 (s, 1H), 7.66 (dd, 1H), 7.44-7.40 (m, 2H), 5.50 (s, 1H), 3.31 (s, 3H), 3.07 (s, 3H)。LCMS m/z = 319 [M+H]+。Step 2: The crude product from Step 1 (330 mg, crude material) was dissolved in 1,4-dioxane (15 mL) containing 4 M HCl under rt and the mixture was stirred for 18 h. The mixture was concentrated under reduced pressure to obtain a crude compound, which was purified by preparative HPLC to give the title compound (36 mg, 15%, after two steps). ¹H -NMR (400 MHz, DMSO- d⁶ ): 13.10 (s, ¹H), 7.81 (s, ¹H), 7.66 (dd, ¹H), 7.44–7.40 (m, 2H), 5.50 (s, ¹H), 3.31 (s, 3H), 3.07 (s, 3H). LCMS m/z = 319 [M+H] ⁺ .
實例 22-((3-氯-4-氟苯基)(異丙氧基)甲基)-4-(甲基磺醯基)-1H-咪唑在rt下將對甲苯磺酸單水合物(187.3 mg，0.985 mmol)添加至(3-氯-4-氟苯基)(4-(甲基磺醯基)-1H-咪唑-2-基)甲醇(中間物6，100 mg，0.328 mmol)及Na2SO4(50 mg)於丙-2-醇(10 mL)中之攪拌溶液中。接著將混合物加熱至120℃持續18 h。冷卻至rt之後，在減壓下濃縮混合物，得到粗產物，藉由製備型HPLC純化，得到標題化合物(40 mg，35%)。1H-NMR (400 MHz, DMSO-d6): 12.97 (s, 1H), 7.80 (s, 1H), 7.64 (d, 1H), 7.42 (dd, 1H), 5.70 (s, 1H), 3.61-3.56 (m, 1H), 3.07 (s, 3H), 1.12 (d, 6H)。LCMS m/z = 347 [M+H]+。 Example 2 : 2-((3-chloro-4-fluorophenyl)(isopropoxy)methyl)-4-(methylsulfonylurea)-1H-imidazolium p-Toluenesulfonic acid monohydrate (187.3 mg, 0.985 mmol) was added to a stirred solution of (3-chloro-4-fluorophenyl)(4-(methylsulfonylurea)-1H-imidazol-2-yl)methanol (intermediate 6, 100 mg, 0.328 mmol) and Na₂SO₄ ( 50 mg) in propan-2-ol (10 mL) at rt. The mixture was then heated to 120 °C for 18 h. After cooling to rt, the mixture was concentrated under reduced pressure to give a crude product, which was purified by preparative HPLC to give the title compound (40 mg, 35%). 1 H-NMR (400 MHz, DMSO-d 6 ): 12.97 (s, 1H), 7.80 (s, 1H), 7.64 (d, 1H), 7.42 (dd, 1H), 5.70 (s, 1H), 3.61-3.56 (m, 1H), 3.07 (s, 3H), 1.12 (d, 6H). LCMS m/z = 347 [M+H] + .
實例 32-((3-氯-4-氟苯基)(環己氧基)甲基)-4-(甲基磺醯基)-1H-咪唑在rt下將對甲苯磺酸單水合物(280.9 mg，1.477 mmol)添加至(3-氯-4-氟苯基)(4-(甲基磺醯基)-1H-咪唑-2-基)甲醇(中間物6，150 mg，0.492 mmol)、環己醇(0.26 mL，2.461 mmol)及硫酸鈉(50 mg)於甲苯(10 mL)中之攪拌溶液中。接著將混合物加熱至120℃持續4 h。接著在減壓下濃縮混合物，得到粗化合物，藉由製備型HPLC純化，得到標題化合物(30 mg，15%)。1H-NMR (400 MHz, DMSO-d6): 12.95 (s, 1H), 7.80 (s, 1H), 7.66 (d, 1H), 7.42 (d, 2H), 5.75 (s, 1H), 1.85-1.82 (m, 2H), 1.66-1.64 (m, 2H), 1.45-1.44 (m, 1H), 1.33-1.30 (m, 6H), 1.20-1.16 (m, 3H)。LCMS m/z = 387 [M+H]+。 Example 3: 2-((3-chloro-4-fluorophenyl)(cyclohexyloxy)methyl)-4-(methylsulfonylurea)-1H-imidazolium p-Toluenesulfonic acid monohydrate (280.9 mg, 1.477 mmol) was added to a stirred solution of (3-chloro-4-fluorophenyl)(4-(methylsulfonylurea)-1H-imidazol-2-yl)methanol (intermediate 6, 150 mg, 0.492 mmol), cyclohexanol (0.26 mL, 2.461 mmol), and sodium sulfate (50 mg) in toluene (10 mL). The mixture was then heated to 120 °C for 4 h. The mixture was then concentrated under reduced pressure to give a crude compound, which was purified by preparative HPLC to give the title compound (30 mg, 15%). 1 H-NMR (400 MHz, DMSO-d 6 ): 12.95 (s, 1H), 7.80 (s, 1H), 7.66 (d, 1H), 7.42 (d, 2H), 5.75 (s, 1H), 1.85-1.82 (m, 2H), 1.66-1.64 (m, 2H), 1.45-1.44 (m, 1H), 1.33-1.30 (m, 6H), 1.20-1.16 (m, 3H). LCMS m/z = 387 [M+H] + .
實例 4-6 。使用與針對實例3所述類似之方法，由適當的醇製備標題化合物。可在合成後使用對掌性SFC或對掌性HPLC分離對掌性化合物。
實例 72-((3-氯-4-氟苯基)(苯氧基)甲基)-4-(甲基磺醯基)-1H-咪唑 Example 7: 2-((3-chloro-4-fluorophenyl)(phenoxy)methyl)-4-(methylsulfonyl)-1H-imidazolium
步驟1：在0℃下向中間物5 (0.200 g，0.460 mmol)及苯酚(0.064 g，0.690 mmol)於THF (10 mL)中之攪拌溶液中添加偶氮二甲酸二乙酯(0.108 mL，0.690 mmol)及三苯膦(0.180 g，0.690 mmol)。將反應混合物在rt下攪拌3 h。用水(50 mL)稀釋反應混合物且用乙酸乙酯(2 × 50 mL)萃取。經無水Na2SO4乾燥合併之有機層且在減壓下濃縮，產生粗產物，藉由急驟層析(SiO2，20-30% EtOAc/PE)純化，產生產物(0.140 g，60%)。Step 1: Diethyl azodicarbonate (0.108 mL, 0.690 mmol) and triphenylphosphine (0.180 g, 0.690 mmol) were added to a stirred solution of intermediate 5 (0.200 g, 0.460 mmol) and phenol (0.064 g, 0.690 mmol) in THF (10 mL) at 0 °C. The reaction mixture was stirred at rt for 3 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The organic layers were dried and combined with anhydrous Na₂SO₄ and concentrated under reduced pressure to produce a crude product. The crude product was purified by rapid chromatography ( SiO₂ , 20-30% EtOAc/PE) to produce a product (0.140 g, 60%).
步驟2：在rt下將步驟1之產物(0.120 g，0.235 mmol)溶解於含HCl (4N)之1,4-二噁烷(2.0 mL)中且將混合物攪拌4 h。接著用NaHCO3水溶液鹼化反應混合物且乙酸乙酯(2 × 30 mL)萃取。經無水Na2SO4乾燥合併之有機層且在減壓下濃縮。藉由急驟層析(SiO2，50% EtOAc/PE)純化殘餘物，得到標題化合物(0.030 g，34%)。1H-NMR (400 MHz, DMSO-d6): 13.29 (s, 1H), 7.89 (s, 1H), 7.81 (dd, 1H), 7.59 -7.55 (m, 1H), 7.46 (t, 1H), 7.30 - 7.26 (m, 2H), 7.05 (d, 2H), 6.98 (t, 1H), 6.67 (s, 1H), 3.09 (s, 3H)。LCMS m/z = 381 [M+H]+。Step 2: The product of Step 1 (0.120 g, 0.235 mmol) was dissolved in 1,4-dioxane (2.0 mL) containing HCl (4N) under rt and the mixture was stirred for 4 h. The reaction mixture was then alkalized with an aqueous solution of NaHCO3 and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid chromatography ( SiO2 , 50% EtOAc/PE) to give the title compound (0.030 g, 34%). 1 H-NMR (400 MHz, DMSO-d 6 ): 13.29 (s, 1H), 7.89 (s, 1H), 7.81 (dd, 1H), 7.59 -7.55 (m, 1H), 7.46 (t, 1H), 7.30 - 7.26 (m, 2H), 7.05 (d, 2H), 6.98 (t, 1H), 6.67 (s, 1H), 3.09 (s, 3H). LCMS m/z = 381 [M+H] + .
實例 82-((3-氯-4-氟苯基)(4-氟苯氧基)甲基)-4-(甲基磺醯基)-1H-咪唑使用與針對實例7所述類似之方法，由適當的中間物及試劑製備標題化合物。產率：11 mg，17%，1H-NMR (400 MHz, DMSO-d6, 25℃): δ: 13.29 (s, 1H), 7.90 (s, 1H), 7.80 (dd, J = 7.2 Hz, J = 2.0 Hz, 1H), 7.55-7.53 (m, 1H), 7.45 (t, J = 8.8 Hz), 7.14-7.05 (m, 4H), 6.63 (s, 1H), 5.77 (s, 1H), 3.08 (s, 3H)。LCMS m/z = 399 [M+H]+。 Example 8: 2-((3-chloro-4-fluorophenyl)(4-fluorophenoxy)methyl)-4-(methylsulfonyl)-1H-imidazolium The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Example 7. Yield: 11 mg, 17%, ¹H -NMR (400 MHz, DMSO-d6, 25 °C): δ: 13.29 (s, 1H), 7.90 (s, 1H), 7.80 (dd, J = 7.2 Hz, J = 2.0 Hz, 1H), 7.55–7.53 (m, 1H), 7.45 (t, J = 8.8 Hz), 7.14–7.05 (m, 4H), 6.63 (s, 1H), 5.77 (s, 1H), 3.08 (s, 3H). LCMS m/z = 399 [M+H] + .
實例 9-102-((3-氯-4-氟苯基)(4-氟-2-甲氧基苯氧基)甲基)-5-(甲基磺醯基)-1H-咪唑及 Examples 9-10: 2-((3-chloro-4-fluorophenyl)(4-fluoro-2-methoxyphenoxy)methyl)-5-(methylsulfonylurea)-1H-imidazolium and
步驟1：在氬氣下，在0℃下向中間物5 (300 mg，0.690 mmol，1.0 equiv.)及4-氟-2-甲氧基苯酚(0.12 mL，1.5 equiv.)於甲苯(10 mL)中之攪拌溶液中依序添加1,1'-(偶氮二羰基)二哌啶97% (522 mg，2.1 mmol.)及三丁基膦(0.5 mL)。將所得反應混合物在rt下攪拌16 h。藉由LC-MS監測反應進展。用水(30 mL)稀釋反應混合物且用乙酸乙酯(3×30 mL)萃取。用鹽水(20 mL)洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮。藉由正相管柱層析純化粗產物。Step 1: Under argon atmosphere and at 0°C, 1,1'-(azodicarbonyl)dipiperidine 97% (522 mg, 2.1 mmol.) and tributylphosphine (0.5 mL) were sequentially added to a stirred solution of intermediate 5 (300 mg, 0.690 mmol, 1.0 equiv.) and 4-fluoro-2-methoxyphenol (0.12 mL, 1.5 equiv.) in toluene (10 mL). The resulting reaction mixture was stirred at rt for 16 h. The reaction progress was monitored by LC-MS. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layer was washed with brine (20 mL), dried over Na₂SO₄ , and concentrated under reduced pressure. The crude product was purified by normal phase column chromatography.
步驟2：在0℃下將步驟1之產物溶解於含HCl (4N)之1,4-二噁烷(10 mL)中。將所得反應混合物在rt下攪拌4 h。在真空下濃縮反應混合物，在0℃下用NaHCO3溶液(pH~9)鹼化且用乙酸乙酯(3×15 mL)萃取。經無水Na2SO4乾燥合併之有機層且在減壓下濃縮。藉由製備型HPLC純化粗產物，得到外消旋化合物(0.030 g，34%)，隨後進行對掌性SFC，產生作為個別鏡像異構物之標題化合物。Step 2: The product of Step 1 was dissolved in 1,4-dioxane (10 mL) containing HCl (4N) at 0 °C. The resulting reaction mixture was stirred at rt for 4 h. The reaction mixture was concentrated under vacuum, alkalized with NaHCO3 solution (pH ~9) at 0 °C, and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give a racemic compound (0.030 g, 34%), which was then subjected to palmar SFC to produce the title compound as a separate mirror isomer.
400 MHz, DMSO-d6, 25℃): δ: 13.24 (s, 1H), 7.88 (s, 1H), 7.76 (dd, J = 7.2 Hz, 2.0 Hz, 1H), 7.52-7.48 (m, 1H), 7.46-7.42 (m, 1H), 6.97-6.92 (m, 2H), 6.62 (td, J = 8.8 Hz, 3.2 Hz, 1H), 6.44 (s, 1H), 3.80 (s, 3H), 3.08 (m, 3H)。LCMS m/z = 429.16 [M+H]+。對掌性SFC：管柱：(R,R)Whelk -01 (250 x 4.6) 5µ；共溶劑：MeOH，流量：3 g/min；共溶劑%：20%；P = 150巴，T：30℃；9：Rt = 2.11 min (第一次溶析)；10：Rt = 2.38 min (第二次溶析)。400 MHz, DMSO-d6, 25℃): δ: 13.24 (s, 1H), 7.88 (s, 1H), 7.76 (dd, J = 7.2 Hz, 2.0 Hz, 1H), 7.52-7.48 (m, 1H), 7.46-7.42 (m, 1H), 6.97-6.92 (m, 2H), 6.62 (td, J = 8.8 Hz, 3.2 Hz, 1H), 6.44 (s, 1H), 3.80 (s, 3H), 3.08 (m, 3H). LCMS m/z = 429.16 [M+H] + . For palm-shaped SFC: Column: (R,R)Whelk-01 (250 x 4.6) 5µm; Cosolvent: MeOH, Flow rate: 3 g/min; Cosolvent %: 20%; P = 150 bar, T: 30℃; 9 : Rt = 2.11 min (first precipitation); 10 : Rt = 2.38 min (second precipitation).
實例 112-((3-氯-4-氟苯基)(3-甲氧基苯氧基)甲基)-4-甲基-5-(甲基磺醯基)-1H-咪唑 Example 11 2-((3-chloro-4-fluorophenyl)(3-methoxyphenoxy)methyl)-4-methyl-5-(methylsulfonyl)-1H-imidazolium
步驟-1：在0℃下向中間物28 (100 mg，0.23 mmol，1.0 equiv.)於甲苯(4 mL)中之攪拌溶液中添加三苯膦(91 mg，0.35 mmol，1.5 equiv.)且攪拌15 min，隨後添加3-甲氧基苯酚(2 equiv.)及偶氮二甲酸二異丙酯(0.06 ml，0.35 mmol，1.5 equiv.)且在100℃下攪拌16 h。藉由LCMS監測反應混合物。用水淬滅成功的反應混合物且用乙酸乙酯(50 mL)萃取。用水(10 mL)、鹽水(10 mL)洗滌有機層且經Na2SO4乾燥。在減壓下濃縮溶劑，得到粗產物，藉由矽膠上之急驟管柱層析純化。Step 1: Triphenylphosphine (91 mg, 0.35 mmol, 1.5 equiv.) was added to a stirred solution of intermediate 28 (100 mg, 0.23 mmol, 1.0 equiv.) in toluene (4 mL) at 0 °C and stirred for 15 min. Subsequently, 3-methoxyphenol (2 equiv.) and diisopropyl azodicarbonate (0.06 mL, 0.35 mmol, 1.5 equiv.) were added and stirred at 100 °C for 16 h. The reaction mixture was monitored by LCMS. The successfully reacted mixture was quenched with water and extracted with ethyl acetate (50 mL). The organic layer was washed with water (10 mL) and brine (10 mL) and dried over Na₂SO₄ . The solvent was concentrated under reduced pressure to obtain a crude product, which was then purified by rapid column chromatography on silicone.
步驟-2：在0℃下向步驟1之產物(1 equiv.)於二噁烷(5 mL)中之攪拌溶液中添加二噁烷-HCl (0.5 mL)且將反應混合物在相同溫度下攪拌1.5小時。藉由製備型HPLC純化反應物。LCMS m/z = 425.2 [M+H]+。Step 2: Add 0.5 mL of dioxane-HCl to the stirred solution of the product (1 equiv.) from Step 1 in dioxane (5 mL) at 0 °C and stir the reaction mixture at the same temperature for 1.5 hours. Purify the reactants by preparative HPLC. LCMS m/z = 425.2 [M+H] + .
實例 12-13使用與針對實例11所述類似之方法，由適當的中間物及試劑製備標題化合物。
實例 142-((3-氯-4-氟苯基)(4-氟-2-甲基苯氧基)甲基)-4-甲基-5-(甲基磺醯基)-1H-咪唑在0℃下向中間物30 (1.0 equiv.)於DCM (4 mL)中之攪拌溶液中添加醇4-氟-2-甲基苯酚(5.0 equiv.)且攪拌15 min，隨後在0℃下添加TFA (6.0 equiv.)、BF3-Et2O (1.5 equiv.)且將反應混合物在80℃下攪拌1小時。藉由製備型HPLC純化反應物且分離出所需化合物。LCMS m/z = 427.1 [M+H]+。 Example 14 2-((3-chloro-4-fluorophenyl)(4-fluoro-2-methylphenoxy)methyl)-4-methyl-5-(methylsulfonyl)-1H-imidazolium Alcohol 4-fluoro-2-methylphenol (5.0 equiv.) was added to a stirred solution of intermediate 30 (1.0 equiv.) in DCM (4 mL) at 0 °C and stirred for 15 min. Subsequently, TFA (6.0 equiv.) and BF3 - Et2O (1.5 equiv.) were added at 0 °C, and the reaction mixture was stirred at 80 °C for 1 hour. The reactants were purified by preparative HPLC, and the desired compounds were separated. LCMS m/z = 427.1 [M+H] + .
實例 15-162-((3-氯-4-氟苯基)(((順式)-4-甲基環己基)氧基)甲基)-5-甲基-4-(甲基磺醯基)-1H-咪唑及在0℃下向中間物27 (0.3 g，0.521 mmol)及(順式)-4-甲基環己-1-醇(0.297 g，2.60 mmol，5.0 equiv.)於THF (3.0 mL)中之混合物中添加三氟化硼乙醚(0.1 mL，0.8 mmol)，隨後添加三氟乙酸(0.179 mL，2.343 mmol)。將所得反應混合物加熱至90℃且在密封管中攪拌90 min。在減壓下濃縮反應混合物，獲得殘餘物，用冰水(100 mL)稀釋且用碳酸氫鈉溶液調節至pH 7.0，隨後用乙酸乙酯(2×100 mL)萃取。用鹽水(100 mL)洗滌合併之有機層，經無水Na2SO4乾燥，過濾且在減壓下濃縮，得到粗產物，在藉由GRACE急驟層析[C18，12 g，RP管柱]使用乙腈及水作為溶析劑純化後，得到100 mg標題化合物。接著使用對掌性SFC將標題化合物分離成個別鏡像異構物。 Examples 15-16: 2-((3-chloro-4-fluorophenyl)(((cis)-4-methylcyclohexyl)oxy)methyl)-5-methyl-4-(methylsulfonylurea)-1H-imidazolium and At 0 °C, boron trifluoride diethyl ether (0.1 mL, 0.8 mmol) was added to a mixture of intermediate 27 (0.3 g, 0.521 mmol) and (cis)-4-methylcyclohexane-1-ol (0.297 g, 2.60 mmol, 5.0 equiv.) in THF (3.0 mL), followed by the addition of trifluoroacetic acid (0.179 mL, 2.343 mmol). The resulting reaction mixture was heated to 90 °C and stirred in a sealed tube for 90 min. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was diluted with ice water (100 mL) and adjusted to pH 7.0 with sodium bicarbonate solution, followed by extraction with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a crude product. Purification was then performed by GRACE rapid chromatography [C18, 12 g, RP column] using acetonitrile and water as solvents to yield 100 mg of the title compound. The title compound was then separated into individual mirror isomers using a palmar spectral fractionation (SFC).
LCMS m/z = 415 [M+H]+；1H-NMR (400 MHz, DMSO-d6): δ: 12.61 (s, 1H), 7.64 (dd, 1H), 7.45-7.39 (m, 2H), 5.61 (s, 1H), 3.53-3.51 (m, 1H), 3.04 (s, 3H), 2.37 (s, 3H), 1.82-1.75 (m, 2H), 1.44-137 (m, 5H), 1.31-122 (m, 2H), 0.86 (d, 1H)。對掌性SFC：管柱：Chiralpak IC (4.6 x 150 mm) 5 μm；共溶劑：含0.5% iPrNH2之iPrOH，流量：3 mL/min；共溶劑%：20%；ABPR：1500 psi T：30℃；15：Rt = 4.62 min (第一次溶析)；16：Rt = 8.06 min (第二次溶析)。LCMS m/z = 415 [M+H] + ; 1 H-NMR (400 MHz, DMSO-d 6 ): δ: 12.61 (s, 1H), 7.64 (dd, 1H), 7.45-7.39 (m, 2H), 5.61 (s, 1H), 3.53-3.51 (m, 1H), 3.04 (s, 3H), 2.37 (s, 3H), 1.82-1.75 (m, 2H), 1.44-137 (m, 5H), 1.31-122 (m, 2H), 0.86 (d, 1H). Palmarized SFC: Column: Chiralpak IC (4.6 x 150 mm) 5 μm; Cosolvent: iPrOH containing 0.5% iPrNH2 , flow rate: 3 mL/min; Cosolvent %: 20%; ABPR: 1500 psi; T: 30℃; 15 : Rt = 4.62 min (first precipitation); 16 : Rt = 8.06 min (second precipitation).
實例 17-182-((3-氯-4-氟苯基)(((反式)-4-甲基環己基)氧基)甲基)-5-甲基-4-(甲基磺醯基)-1H-咪唑及使用與針對實例15-16所述類似之方法，由適當的中間物及試劑製備標題化合物。LCMS m/z = 415.3 [M+H]+；1H-NMR (400 MHz, DMSO-d6): δ: 12.61 (s, 1H), 7.64 (dd, 1H), 7.43-7.38 (m, 2H), 5.68 (s, 1H), 3.27-3.21 (m, 1H), 3.03 (s, 3H), 2.37 (s, 3H), 1.99-193 (m, 2H), 1.65-1.62 (m, 2H), 1.34-1.18 (m, 3H), 0.91- 0.86 (m, 5H)。對掌性SFC：管柱：(R,R) WHELK-01 (4.6 x 150 mm) 3.5 μm；共溶劑：MeOH，流量：3 mL/min；共溶劑%：10%；ABPR：1500 psi T：30℃；17：Rt = 4.91 min (第一次溶析)；18：Rt = 6.23 min (第二次溶析)。 Examples 17-18: 2-((3-chloro-4-fluorophenyl)(((trans)-4-methylcyclohexyl)oxy)methyl)-5-methyl-4-(methylsulfonylurea)-1H-imidazolium and The title compound was prepared using a method similar to that described for Examples 15-16, from suitable intermediates and reagents. LCMS m/z = 415.3 [M+H] + ; 1H -NMR (400 MHz, DMSO- d6 ): δ: 12.61 (s, 1H), 7.64 (dd, 1H), 7.43-7.38 (m, 2H), 5.68 (s, 1H), 3.27-3.21 (m, 1H), 3.03 (s, 3H), 2.37 (s, 3H), 1.99-193 (m, 2H), 1.65-1.62 (m, 2H), 1.34-1.18 (m, 3H), 0.91-0.86 (m, 5H). Palmar SFC: Column: (R,R) WHELK-01 (4.6 x 150 mm) 3.5 μm; Cosolvent: MeOH, Flow rate: 3 mL/min; Cosolvent %: 10%; ABPR: 1500 psi; T: 30℃; 17 : Rt = 4.91 min (first precipitation); 18 : Rt = 6.23 min (second precipitation).
實例 19-202-((3-氯-4-氟苯基)((1-甲基環己基)氧基)甲基)-5-甲基-4-(甲基磺醯基)-1H-咪唑及 Examples 19-20: 2-((3-chloro-4-fluorophenyl)((1-methylcyclohexyl)oxy)methyl)-5-methyl-4-(methylsulfonylurea)-1H-imidazolium and
步驟1：在rt下在N2氣體下向中間物27 (0.2 g，0.347 mmol，1.0 equiv.)及1-甲基環己-1-醇(10.0 equiv.)於THF (2.0 mL)中之溶液中添加三氟化硼乙醚(0.5 mmol，1.5 equiv.)且隨後添加三氟乙酸(0.12 mL，1.562 mmol，4.5 equiv.)。將所得反應混合物在攪拌下在90℃下維持30 min。藉由LC-MS監測反應。用冰水(25 mL)稀釋反應混合物且用NaHCO3溶液調節pH-8.0且用二氯甲烷(2×50 mL)萃取。用鹽水(25 mL)洗滌合併之萃取物，經無水Na2SO4乾燥且過濾，在減壓下濃縮濾液，得到0.28 g粗產物。Step 1: Under nitrogen atmosphere at rest, add boron trifluoride diethyl ether (0.5 mmol, 1.5 equiv.) to a solution of intermediate 27 (0.2 g, 0.347 mmol, 1.0 equiv.) and 1-methylcyclohexane-1-ol (10.0 equiv.) in THF (2.0 mL), followed by the addition of trifluoroacetic acid (0.12 mL, 1.562 mmol, 4.5 equiv.). Maintain the resulting reaction mixture at 90 °C for 30 min with stirring. Monitor the reaction by LC-MS. Dilute the reaction mixture with ice water (25 mL), adjust the pH to 8.0 with NaHCO3 solution, and extract with dichloromethane (2 × 50 mL). The combined extract was washed with brine (25 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to give 0.28 g of crude product.
步驟2：將含(0.19 g，0.349 mmol，1.0 equiv.)及四-正丁基氟化銨於THF (1.75 mL)中之1M溶液之THF (1.9 mL)在90℃下攪拌1 h。用冰水(50 mL)稀釋反應混合物且用二氯甲烷(2×50 mL)萃取。用鹽水(25 mL)洗滌合併之萃取物，經無水Na2SO4乾燥且過濾。在減壓下濃縮濾液，得到粗產物。藉由製備型HPLC純化粗產物，得到85 mg (58%)且隨後進行對掌性SFC，產生作為個別鏡像異構物之標題化合物。Step 2: A 1M solution of THF (1.9 mL) containing (0.19 g, 0.349 mmol, 1.0 equiv.) and tetra-n-butylammonium fluoride in THF (1.75 mL) was stirred at 90 °C for 1 h. The reaction mixture was diluted with ice water (50 mL) and extracted with dichloromethane (2 × 50 mL). The combined extract was washed with brine (25 mL), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC to give 85 mg (58%), and subsequent palmar SFC was performed to generate the title compound as a separate mirror isomer.
LCMS m/z = 413.15 [M+H]+。對掌性SFC：管柱：(R,R)Whelk -01 (250 x 4.6) 5µ；共溶劑：異丙醇，流量：3 mL/min；共溶劑%：15%；P = 150巴，T：30℃；19：Rt = 9.15 min (第一次溶析)；20：Rt = 11.39 min (第二次溶析)。LCMS m/z = 413.15 [M+H] + . Hand-type SFC: Column: (R,R)Whelk-01 (250 x 4.6) 5µ; Cosolvent: Isopropanol, Flow rate: 3 mL/min; Cosolvent %: 15%; P = 150 bar, T: 30℃; 19 : Rt = 9.15 min (first precipitation); 20 : Rt = 11.39 min (second precipitation).
實例 212-((苄氧基)(3-氯-4-氟苯基)甲基)-5-甲基-4-(甲基磺醯基)-1H-咪唑在0℃下向中間物31 (80 mg，0.15 mmol，1.0 equiv.)於DCE (4 mL)中之溶液中添加FeCl3(1 mg)及苯甲醇(5 equiv.)且在85℃下攪拌17 h。藉由製備型HPLC純化反應物，產生所需化合物。LCMS m/z = 409.1 [M+H]+。 Example 21: 2-((benzyloxy)(3-chloro-4-fluorophenyl)methyl)-5-methyl-4-(methylsulfonyl)-1H-imidazolium FeCl₃ (1 mg) and benzyl alcohol (5 equiv.) were added to a solution of intermediate 31 (80 mg, 0.15 mmol, 1.0 equiv.) in DCE (4 mL) at 0 °C, and the mixture was stirred at 85 °C for 17 h. The desired compound was obtained by preparative HPLC purification of the reactants. LCMS m/z = 409.1 [M+H] ⁺ .
實例 22-23使用與針對實例21所述類似之方法，由適當的醇製備標題化合物。
實例 242-((3-氯-4-氟苯基)(((2S,3S)-2,6,6-三甲基雙環[3.1.1]庚-3-基)氧基)甲基)-5-甲基-4-(甲基磺醯基)-1H-咪唑在0℃下向中間物31 (80 mg，0.15 mmol，1.0 equiv.)於DCM (4 mL)中之溶液中添加2,6,6-三甲基雙環[3.1.1]庚-3-醇(5.0 equiv.)且攪拌15 min，隨後在0℃下添加TFA (6 equiv.)、BF3-Et2O (1.5 equiv.)且將反應混合物在70℃下攪拌1小時。藉由製備型HPLC純化反應物，產生所需化合物。LCMS m/z = 455.2 [M+H]+。 Example 24 2-((3-chloro-4-fluorophenyl)(((2S,3S)-2,6,6-trimethylbis(3.1.1)hept-3-yl)oxy)methyl)-5-methyl-4-(methylsulfonylurea)-1H-imidazolium 2,6,6-trimethylbis(3.1.1)hepta-3-ol (5.0 equiv.) was added to a solution of intermediate 31 (80 mg, 0.15 mmol, 1.0 equiv.) in DCM (4 mL) at 0 °C and stirred for 15 min. Then, TFA (6 equiv.) and BF3 - Et2O (1.5 equiv.) were added at 0 °C, and the reaction mixture was stirred at 70 °C for 1 hour. The reactants were purified by preparative HPLC to produce the desired compound. LCMS m/z = 455.2 [M+H] + .
實例 25-28使用與針對實例24所述類似之方法，由適當的醇製備標題化合物。
實例 292-((3-氯-4-氟苯基)(環丁基甲氧基)甲基)-5-甲基-4-(甲基磺醯基)-1H-咪唑在0℃下向中間物27 (1.0 equiv.)於DCM (4 mL)中之攪拌溶液中添加環丁基甲醇(5.0 equiv.)且攪拌15 min，隨後在0℃下添加TFA (6.0 equiv.)、BF3-Et2O (1.5 equiv.)且將反應混合物在80℃下攪拌1小時。藉由製備型HPLC純化反應物，產生所需化合物。LCMS m/z = 387.1 [M+H]+。 Example 29 2-((3-chloro-4-fluorophenyl)(cyclobutylmethoxy)methyl)-5-methyl-4-(methylsulfonyl)-1H-imidazolium Cyclobutylmethanol (5.0 equiv.) was added to a stirred solution of intermediate 27 (1.0 equiv.) in DCM (4 mL) at 0 °C and stirred for 15 min. Subsequently, TFA (6.0 equiv.) and BF3 - Et2O (1.5 equiv.) were added at 0 °C, and the reaction mixture was stirred at 80 °C for 1 hour. The reactants were purified by preparative HPLC to produce the desired compound. LCMS m/z = 387.1 [M+H] + .
實例 30-34使用與針對實例29所述類似之方法，由適當的醇製備標題化合物。
實例 352-((雙環[3.1.0]己-3-基氧基)(3-氯-4-氟苯基)甲基)-5-甲基-4-(甲基磺醯基)-1H-咪唑 Example 35 2-((bicyclo[3.1.0]hex-3-yloxy)(3-chloro-4-fluorophenyl)methyl)-5-methyl-4-(methylsulfonylurea)-1H-imidazolium
步驟-1：在0℃下向中間物27 (1.0 equiv.)於DCM (4.0 mL)中之攪拌溶液中添加雙環[3.1.0]己-3-醇(5.0 equiv.)且攪拌15 min，隨後在0℃下添加TFA (6.0 equiv.)且將反應混合物在80℃下攪拌1小時。用水淬滅反應混合物且用DCM (20 mL)萃取。用水(4 mL)、鹽水(10 mL)洗滌有機層且經Na2SO4乾燥。在減壓下濃縮溶劑，得到粗產物，藉由矽膠上之急驟管柱層析純化，得到所需化合物。Step 1: Bicyclo[3.1.0]hexane-3-ol (5.0 equiv.) was added to the stirred solution of intermediate 27 (1.0 equiv.) in DCM (4.0 mL) at 0 °C and stirred for 15 min. Then, TFA (6.0 equiv.) was added at 0 °C and the reaction mixture was stirred at 80 °C for 1 hour. The reaction mixture was quenched with water and extracted with DCM (20 mL). The organic layer was washed with water (4 mL) and brine ( 10 mL) and dried over Na₂SO₄ . The solvent was concentrated under reduced pressure to obtain the crude product, which was purified by rapid column chromatography on silicone to obtain the desired compound.
步驟-5：在0℃下向步驟-1之產物(1.0 equiv.)於THF (4 mL)中之攪拌溶液中添加TBAF (3.0 equiv.)且將反應混合物在70℃下攪拌2小時。藉由製備型HPLC純化反應物，產生所需化合物。LCMS m/z = 397.0 [M-H]+。Step-5: Add TBAF (3.0 equiv.) to a stirred solution of the product of Step-1 (1.0 equiv.) in THF (4 mL) at 0°C and stir the reaction mixture at 70°C for 2 hours. Purify the reaction mixture by preparative HPLC to obtain the desired compound. LCMS m/z = 397.0 [MH] + .
實例 36-39使用與針對實例35所述類似之方法，由適當的醇製備標題化合物。
實例 40 、 412-((3-氯-4-氟苯基)(1-甲基環丁氧基)甲基)-5-甲基-4-(甲基磺醯基)-1H-咪唑及 Examples 40 and 41 : 2-((3-chloro-4-fluorophenyl)(1-methylcyclobutoxy)methyl)-5-methyl-4-(methylsulfonylurea)-1H-imidazolium and
步驟-1：向中間物27 (300 mg，0.521 mmol，1.0 equiv.)、1-甲基環丁-1-醇(180 mg，2.083 mmol，4 equiv.)於THF (10 mL)中之溶液中添加三氟化硼乙醚(0.1 mL，0.781 mmol，1.5 equiv.)，隨後添加三氟乙酸(0.18 mL，2.343 mmol，4.5 equiv.)且在密封管中在60℃下(預加熱之油浴)攪拌2 h。用乙酸乙酯(50 mL)稀釋反應混合物，用飽和NaHCO3水溶液(50 mL)、水(50 mL)、鹽水(50 mL)洗滌且經Na2SO4乾燥。在減壓下濃縮溶劑，得到粗2-((3-氯-4-氟苯基)(1-甲基環丁氧基)甲基)-5-甲基-4-(甲基磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑，其未經進一步純化即用於下一步驟。LC-MS m/z [M+H] + = 517.2。Step 1: Add boron trifluoride diethyl ether (0.1 mL, 0.781 mmol, 1.5 equiv.) to a solution of intermediate 27 (300 mg, 0.521 mmol, 1.0 equiv.) and 1-methylcyclobut-1-ol (180 mg, 2.083 mmol, 4 equiv.) in THF (10 mL), followed by the addition of trifluoroacetic acid (0.18 mL, 2.343 mmol, 4.5 equiv.), and stir in a sealed tube at 60 °C (preheated oil bath) for 2 h. Dilute the reaction mixture with ethyl acetate (50 mL), wash with saturated NaHCO3 aqueous solution (50 mL), water (50 mL), and brine (50 mL), and dry with Na2SO4 . The solvent was concentrated under reduced pressure to give crude 2-((3-chloro-4-fluorophenyl)(1-methylcyclobutoxy)methyl)-5-methyl-4-(methylsulfonylurea)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium, which was used in the next step without further purification. LC-MS m/z [M+H]+ = 517.2.
步驟-2：向步驟-1之產物於THF (10 mL)中之溶液中添加含1 M TBAF之THF (6 mL，5.80 mmol，10 equiv.)且在80℃下攪拌16 h。用飽和NH4Cl溶液(30 mL)淬滅反應混合物且用乙酸乙酯(2 × 100 mL)萃取。用鹽水(50 mL)洗滌合併之有機層，經無水Na2SO4乾燥且在減壓下濃縮，得到粗產物，藉由逆相製備型HPLC純化，得到外消旋2-((3-氯-4-氟苯基) (1-甲基環丁氧基)甲基)-5-甲基-4-(甲基磺醯基)-1H-咪唑，隨後進行對掌性SFC，產生作為個別鏡像異構物之標題化合物。Step 2: Add 6 mL of THF (5.80 mmol, 10 equiv.) containing 1 M TBAF to the solution of the product from Step 1 in THF (10 mL) and stir at 80 °C for 16 h. Quench the reaction mixture with saturated NH4Cl solution (30 mL) and extract with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse-phase preparative HPLC to give racemic 2 -((3-chloro-4-fluorophenyl)(1-methylcyclobutoxy)methyl)-5-methyl-4-(methylsulfonylurea)-1H-imidazolium. Subsequently, palmar SFC was performed to produce the title compound, which serves as the individual mirror isomer.
LCMS m/z = 387.1 [M+H]+。1H-NMR (400 MHz, DMSO-d6, 25℃): δ: 12.58 (bs, 1H), 7.63 (d, J = 7.08 Hz, 1H), 7.40 (d, J = 6.96 Hz, 2H), 5.66 (s, 1H), 3.03 (s, 1H), 2.36 (s, 3H), 2.14-2.03 (m, 2H), 1.81-1.74 (m, 2H), 1.66-1.58 (m, 1H), 1.55-1.48 (m, 1H), 1.27-1.23 (m, 3H)。製備型對掌性SFC：管柱：(R,R) Whelk -01 (21.1 mm × 250 mm )，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，共溶劑%：20%；流量：100 mL/min；P = 100巴，T：35℃；40：第一次溶析之鏡像異構物；41：第二次溶析之鏡像異構物。LCMS m/z = 387.1 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6, 25℃): δ: 12.58 (bs, 1H), 7.63 (d, J = 7.08 Hz, 1H), 7.40 (d, J = 6.96 Hz, 2H), 5.66 (s, 1H), 3.03 (s, 1H), 2.36 (s, 3H), 2.14-2.03 (m, 2H), 1.81-1.74 (m, 2H), 1.66-1.58 (m, 1H), 1.55-1.48 (m, 1H), 1.27-1.23 (m, 3H). Preparative palmar SFC: Column: (R,R) Whelk-01 (21.1 mm × 250 mm), 5µm; Cosolvent: isopropanol containing 0.2% (methanol containing 7N ammonia), cosolvent %: 20%; Flow rate: 100 mL/min; P = 100 bar, T: 35℃; 40 : mirror image isomer of the first dissolution; 41 : mirror image isomer of the second dissolution.
實例 42 、 432-((3-氯-4-氟苯基)(環己基氧基)甲基)-5-甲基-4-(甲基磺醯基)-1H-咪唑及 Examples 42 and 43 : 2-((3-chloro-4-fluorophenyl)(cyclohexyloxy)methyl)-5-methyl-4-(methylsulfonyl)-1H-imidazolium and
步驟-1：在室溫下向(中間物27 (500 mg，0.87 mmol，1 equiv.)及環己醇(0.45 mL，4.34 mmol，5 equiv.)於THF (10 mL)中之攪拌溶液中添加三氟化硼乙醚(48%) (0.32 mL，1.30 mmol，1.5 equiv.)，隨後添加TFA (0.3 mL，3.91 mmol，4.5 equiv.)。將所得溶液在密封管中在60℃下攪拌30 min。在起始材料完成(藉由LCMS監測)後，用碳酸氫鈉溶液(10 mL)淬滅反應混合物且用乙酸乙酯(2 × 20 mL)萃取。相繼用水、鹽水(20 mL)洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮。產量：(380 mg，粗物質)。LC-MS m/z [M+H]+= 531.2。Step 1: At room temperature, add boron trifluoride diethyl ether (48%) (0.32 mL, 1.30 mmol, 1.5 equiv.) to a stirred solution of intermediate 27 (500 mg, 0.87 mmol, 1 equiv.) and cyclohexanol (0.45 mL, 4.34 mmol, 5 equiv.) in THF (10 mL), followed by TFA (0.3 mL, 3.91 mmol, 4.5 equiv.). Stir the resulting solution in a sealed tube at 60 °C for 30 min. After the starting material is complete (monitored by LCMS), quench the reaction mixture with sodium bicarbonate solution (10 mL) and extract with ethyl acetate (2 × 20 mL). Wash the combined organic layer successively with water and brine (20 mL), then pass through Na₂SO₄ . 4. Dry and concentrated under reduced pressure. Yield: (380 mg, crude matter). LC-MS m/z [M+H] + = 531.2.
步驟-2：在0C下向步驟-1之產物(380 mg，0.72 mmol，1 equiv.)於DCM (1 mL)中之攪拌溶液中添加TFA (6 mL)。將所得溶液在80℃下攪拌6 h。在起始材料完成(藉由LCMS監測)後，濃縮反應混合物。藉由碳酸氫鈉溶液(20 mL)淬滅所獲得之殘餘物且用乙酸乙酯(2 × 20 mL)萃取。相繼用水、鹽水(20 mL)洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮，得到粗產物。藉由combi flash管柱層析(矽膠100-200目，使用60%乙酸乙酯/己烷作為溶析劑)純化所獲得之粗產物，得到外消旋的所需產物。產率：52%，經2個步驟(180 mg，0.45 mmol)，隨後進行對掌性SFC，產生兩種鏡像異構物。Step 2: TFA (6 mL) was added to a stirred solution of the product of Step 1 (380 mg, 0.72 mmol, 1 equiv.) in DCM (1 mL) at 0°C. The resulting solution was stirred at 80°C for 6 h. After the starting material was completely dissolved (monitored by LCMS), the reaction mixture was concentrated. The residues were quenched with sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed successively with water and brine (20 mL), dried over Na₂SO₄ , and concentrated under reduced pressure to obtain the crude product. The crude product was purified by Combi Flash column chromatography (silicone 100-200 mesh, using 60% ethyl acetate/hexane as the solvent) to obtain the racemic desired product. Yield: 52%, obtained by two steps (180 mg, 0.45 mmol), followed by palmar SFC, yielding two mirror isomers.
LCMS m/z = 401.2 [M+H]+。1H-NMR (400 MHz, DMSO-d6, 25℃): δ: 12.62 (s, 1H), 7.65-7.63 (d, J = 6.92 Hz, 1H), 7.44-7.40 (m, 2H), 5.67 (s, 1H), 3.32 (m, 1H), 3.04 (s, 3H), 2.37 (s, 3H), 1.83 (m, 2H), 1.65 (m, 2H), 1.45 (m, 1H), 1.31 (m, 2H), 1.20-1.18 (m, 3H)。製備型對掌性SFC：管柱：(R,R) Whelk -01 (21.1 mm × 250 mm )，5µ；共溶劑：異丙醇，共溶劑%：30%；流量：100 mL/min；P = 100巴，T：35℃；42(產量：91 mg)：第一次溶析之鏡像異構物；43(產量：77 mg)：第二次溶析之鏡像異構物。LCMS m/z = 401.2 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6, 25℃): δ: 12.62 (s, 1H), 7.65-7.63 (d, J = 6.92 Hz, 1H), 7.44-7.40 (m, 2H), 5.67 (s, 1H), 3.32 (m, 1H), 3.04 (s, 3H), 2.37 (s, 3H), 1.83 (m, 2H), 1.65 (m, 2H), 1.45 (m, 1H), 1.31 (m, 2H), 1.20-1.18 (m, 3H). Preparation of palmar SFC: Column: (R,R) Whelk-01 (21.1 mm × 250 mm), 5µm; Cosolvent: isopropanol, cosolvent %: 30%; Flow rate: 100 mL/min; P = 100 bar, T: 35℃; 42 (yield: 91 mg): mirror image isomer of the first dissolution; 43 (yield: 77 mg): mirror image isomer of the second dissolution.
實例 44 、 452-((3-氯-4-氟苯基)((3-氟苄基)氧基)甲基)-5-甲基-4-(甲基磺醯基)-1H-咪唑及 Examples 44 and 45 : 2-((3-chloro-4-fluorophenyl)((3-fluorobenzyl)oxy)methyl)-5-methyl-4-(methylsulfonylurea)-1H-imidazolium and
步驟-1：在0℃下向中間物27 (250 mg，0.43 mmol，1.0 equiv.)及2-氟苯基)甲醇(0.1 mL，0.86 mmol，2.0 equiv.)於THF (15 mL)中之溶液中添加三氟化硼乙醚(0.08 mL，0.65 mmol，1.5 equiv.)及TFA (0.15 mL，1.95 mmol，4.5 equiv.)。將反應混合物在密封管中在60℃下攪拌1 h。在減壓下濃縮反應混合物，用冰冷水(20 mL)稀釋且用飽和NaHCO3溶液中和。用乙酸乙酯(2 × 60 mL)萃取水性部分。用鹽水(20 mL)洗滌合併之有機層，經硫酸鈉乾燥且在減壓下濃縮，得到粗2-((3-氯-4-氟苯基)((2-氟苄基)氧基)甲基)-5-甲基-4-(甲基磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑，其未經進一步純化即用於下一步驟。Step 1: Add boron trifluoride diethyl ether (0.08 mL, 0.65 mmol, 1.0 equiv.) and TFA (0.15 mL, 1.95 mmol, 4.5 equiv.) to a solution of intermediate 27 (250 mg, 0.43 mmol, 1.0 equiv.) and 2-fluorophenyl)methanol (0.1 mL, 0.86 mmol, 2.0 equiv.) in THF (15 mL) at 0 °C. Stir the reaction mixture in a sealed tube at 60 °C for 1 h. Concentrate the reaction mixture under reduced pressure, dilute with ice-cold water (20 mL), and neutralize with saturated NaHCO3 solution. Extract the aqueous fraction with ethyl acetate (2 × 60 mL). The combined organic layer was washed with brine (20 mL), dried with sodium sulfate, and concentrated under reduced pressure to obtain crude 2-((3-chloro-4-fluorophenyl)((2-fluorobenzyl)oxy)methyl)-5-methyl-4-(methylsulfonylurea)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium, which was used in the next step without further purification.
步驟-2：將步驟-1之粗產物及TFA (4 mL)之混合物在80℃下攪拌1 h。在減壓下濃縮反應混合物，用MeOH (15 mL)稀釋，添加Amberlyst A21樹脂(100 mg)且在RT下攪拌2 h。過濾後，在減壓下濃縮濾液，得到粗產物，藉由RP-製備型HPLC純化，得到外消旋的最終產物(80 mg，0.187 mmol)，隨後進行對掌性SFC，產生作為個別鏡像異構物之標題化合物。Step 2: The crude product from Step 1 and the mixture of TFA (4 mL) were stirred at 80 °C for 1 h. The reaction mixture was concentrated under reduced pressure, diluted with MeOH (15 mL), and Amberlyst A21 resin (100 mg) was added and stirred at RT for 2 h. After filtration, the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by RP-preparative HPLC to obtain the racemic final product (80 mg, 0.187 mmol). Subsequently, palmar SFC was performed to generate the title compound as an individual mirror isomer.
LCMS m/z = 427.2 [M+H]+。1H-NMR (400 MHz, DMSO-d6, 25℃): δ: 12.75 (bs, 1H), 7.69-7.67 (m, 1H), 7.51-7.36 (m, 4H), 7.23-7.17 (m, 2H), 5.76 (s, 1H), 4.56 (s, 2H), 3.05 (s, 3H), 2.36 (s, 3H)。製備型對掌性SFC：管柱：(R,R) Whelk -01 (21.1 mm × 250 mm )，5µ；共溶劑：異丙醇，共溶劑%：40%；流量：100 mL/min；P = 100巴，T：35℃；44(產量：35 mg)：第一次溶析之鏡像異構物；45(產量：34 mg)：第二次溶析之鏡像異構物。LCMS m/z = 427.2 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6, 25℃): δ: 12.75 (bs, 1H), 7.69-7.67 (m, 1H), 7.51-7.36 (m, 4H), 7.23-7.17 (m, 2H), 5.76 (s, 1H), 4.56 (s, 2H), 3.05 (s, 3H), 2.36 (s, 3H). Preparation of palmar SFC: Column: (R,R) Whelk-01 (21.1 mm × 250 mm), 5µm; Cosolvent: isopropanol, cosolvent %: 40%; Flow rate: 100 mL/min; P = 100 bar, T: 35℃; 44 (yield: 35 mg): mirror image isomer of the first dissolution; 45 (yield: 34 mg): mirror image isomer of the second dissolution.
實例 46-50使用與針對實例44所述類似之方法，由中間物27及適當的試劑製備標題化合物。可在合成後使用對掌性SFC或對掌性HPLC分離對掌性化合物。
實例 512-(((3-氯-4-氟苯基)(5-甲基-4-(甲基磺醯基)-1H-咪唑-2-基)甲氧基)甲基)吡啶 Example 51 2-(((3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfonyl)-1H-imidazol-2-yl)methoxy)methyl)pyridine
步驟-1：向中間物27 (200 mg，0.346 mmol，1.0 equiv.)、吡啶-2-基甲醇(0.34 mL，3.465 mmol，10.0 equiv.)於DCM (4.0 mL)中之溶液中添加三氟化硼乙醚(0.17 mL，1.386 mmol，4 equiv.)，隨後添加三氟乙酸(0.26 mL，3.465 mmol，10.0 equiv.)且在預加熱之油浴中在60℃下攪拌3 h。用NaHCO3水溶液淬滅反應混合物且用乙酸乙酯(2 × 50 mL)萃取。用鹽水(50 mL)洗滌合併之有機萃取物，經無水Na2SO4乾燥，且在減壓下濃縮，得到粗2-(((3-氯-4-氟苯基)(5-甲基-4-(甲基磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲氧基)甲基)吡啶，其未經進一步純化即用於下一步驟。LC-MS: m/z [M+H] + = 539.7Step 1: Add boron trifluoride diethyl ether (0.17 mL, 1.386 mmol, 4 equiv.) to a solution of intermediate 27 (200 mg, 0.346 mmol, 1.0 equiv.) in DCM (4.0 mL), followed by the addition of trifluoroacetic acid (0.26 mL, 3.465 mmol, 10.0 equiv.) and stirring in a preheated oil bath at 60 °C for 3 h. Quench the reaction mixture with an aqueous solution of NaHCO3 and extract with ethyl acetate (2 × 50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na₂SO₄ , and concentrated under reduced pressure to give crude 2-(((3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methoxy)methyl)pyridine, which was used in the next step without further purification. LC-MS: m/z [M+H]⁺ = 539.7
步驟-2：將步驟-1之粗產物及TFA (1.0 mL)之混合物在60℃下攪拌20 min。在減壓下濃縮反應混合物，得到殘餘物，將其溶解於MeOH (10 mL)中，添加Amberlyst-A21離子交換樹脂(500 mg)且攪拌2 h。過濾反應混合物且在減壓下濃縮濾液，得到粗產物，藉由RP-製備型HPLC純化，產生外消旋2-(((3-氯-4-氟苯基)(5-甲基-4-(甲基磺醯基)-1H-咪唑-2-基)甲氧基)甲基)吡啶。Step 2: The crude product from Step 1 and the mixture of TFA (1.0 mL) were stirred at 60 °C for 20 min. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was dissolved in MeOH (10 mL), and Amberlyst-A21 ion exchange resin (500 mg) was added and stirred for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by RP-preparative HPLC to produce racemic 2-(((3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfonyl)-1H-imidazol-2-yl)methoxy)methyl)pyridine.
產率：11 mg，6%。LCMS m/z = 410.1 [M+H]+。1H-NMR (400 MHz, DMSO-d6, 25℃): δ: 11.60 (brs, 1H), 8.52 (d, J = 4.4 Hz, 1H), 7.82 (t, J = 7.64 Hz, 1H), 7.72 (d, J = 7.0 Hz, 1H), 7.53 (d, J = 7.76 Hz, 1H), 7.46-7.44 (m, 2H), 7.33-7.30 (m, 1H), 5.73 (s, 1H), 4.58 (s, 2H), 3.05 (s, 3H), 2.37 (s, 3H)。Yield: 11 mg, 6%. LCMS m/z = 410.1 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6, 25℃): δ: 11.60 (brs, 1H), 8.52 (d, J = 4.4 Hz, 1H), 7.82 (t, J = 7.64 Hz, 1H), 7.72 (d, J = 7.0 Hz, 1H), 7.53 (d, J = 7.76 Hz, 1H), 7.46-7.44 (m, 2H), 7.33-7.30 (m, 1H), 5.73 (s, 1H), 4.58 (s, 2H), 3.05 (s, 3H), 2.37 (s, 3H).
實例 52 、 53使用與針對實例44所述類似之方法，由中間物27及適當的試劑製備標題化合物。可在合成後使用對掌性SFC或對掌性HPLC分離對掌性化合物。
實例 54 、 552-(((3-氯-4-氟苯基)(5-甲基-4-(甲基磺醯基)-1H-咪唑-2-基)甲氧基)甲基)-5-甲基噻唑及 Examples 54 and 55 : 2-(((3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfonyl)-1H-imidazol-2-yl)methoxy)methyl)-5-methylthiazole and
步驟-1：向中間物27 250 mg，0.43 mmol，1.0 equiv.)、(5-甲基-1,3-噻唑-2-基)甲醇(280 mg，2.16 mmol，5.0 equiv.)於THF (6 mL)中之溶液中添加三氟化硼乙醚(0.1 mL，0.78 mmol，1.5 equiv.)，隨後添加三氟乙酸(0.18 mL，2.34 mmol，4.5 equiv.)且在密封管中在60℃下加熱90 min。用NaHCO3水溶液淬滅反應混合物且用乙酸乙酯(2 × 50 mL)萃取。用鹽水(50 mL)洗滌合併之有機萃取物，經無水Na2SO4乾燥，且在減壓下濃縮，得到粗2-(((3-氯-4-氟苯基)(5-甲基-4-(甲基磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲氧基)甲基)-5-甲基噻唑，其未經進一步純化即用於下一步驟。LC-MS: m/z [M+H] + = 559.9。Step 1: Add boron trifluoride diethyl ether (0.1 mL, 0.78 mmol, 1.5 equiv.) to a solution of intermediate 27 250 mg, 0.43 mmol, 1.0 equiv. and (5-methyl-1,3-thiazolyl-2-yl)methanol (280 mg, 2.16 mmol, 5.0 equiv.) in THF (6 mL), followed by the addition of trifluoroacetic acid (0.18 mL, 2.34 mmol, 4.5 equiv.) and heat in a sealed tube at 60 °C for 90 min. Quench the reaction mixture with an aqueous solution of NaHCO3 and extract with ethyl acetate (2 × 50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na₂SO₄ , and concentrated under reduced pressure to give crude 2-(((3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfonylurea)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methoxy)methyl)-5-methylthiazole, which was used in the next step without further purification. LC-MS: m/z [M+H]⁺ = 559.9.
步驟-2：將步驟-之粗產物於TFA (3 mL)中之混合物在預加熱之油浴中在80℃下攪拌15 min。在減壓下濃縮反應混合物，用MeOH (10 mL)稀釋，添加Amberlyst-A21離子交換樹脂(500 mg)且攪拌2 h。過濾後，在減壓下濃縮濾液，得到粗產物，藉由RP-製備型HPLC純化，得到外消旋化合物，隨後進行對掌性SFC，產生作為個別鏡像異構物之標題化合物。Step 2: The crude product from Step 2 was mixed with TFA (3 mL) and stirred in a preheated oil bath at 80 °C for 15 min. The reaction mixture was concentrated under reduced pressure, diluted with MeOH (10 mL), and Amberlyst-A21 ion exchange resin (500 mg) was added and stirred for 2 h. After filtration, the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by RP-preparative HPLC to obtain the racemic compound. Subsequently, palmar SFC was performed to generate the title compound as the individual mirror isomer.
1H-NMR (400 MHz, DMSO-d6, 25℃): δ: 12.75 (bs, 1H), 7.69-7.67 (m, 1H), 7.51-7.36 (m, 4H), 7.23-7.17 (m, 2H), 5.76 (s, 1H), 4.56 (s, 2H), 3.05 (s, 3H), 2.36 (s, 3H)。LCMS m/z = 445.2 [M+H]+。製備型對掌性SFC：管柱：(R,R) Whelk -01 (21.1 mm × 250 mm )，5µ；共溶劑：異丙醇，共溶劑%：40%；流量：70 mL/min；P = 100巴，T：35℃；54(產量：35 mg)：第一次溶析之鏡像異構物；55(產量：34 mg)：第二次溶析之鏡像異構物。 1 H-NMR (400 MHz, DMSO-d6, 25℃): δ: 12.75 (bs, 1H), 7.69-7.67 (m, 1H), 7.51-7.36 (m, 4H), 7.23-7.17 (m, 2H), 5.76 (s, 1H), 4.56 (s, 2H), 3.05 (s, 3H), 2.36 (s, 3H). LCMS m/z = 445.2 [M+H]+. Preparation of palmar SFC: Column: (R,R) Whelk-01 (21.1 mm × 250 mm), 5µm; Cosolvent: isopropanol, cosolvent %: 40%; Flow rate: 70 mL/min; P = 100 bar, T: 35℃; 54 (yield: 35 mg): mirror image isomer of the first dissolution; 55 (yield: 34 mg): mirror image isomer of the second dissolution.
實例 56 、 572-((3-氯-4-氟苯基)((3,5-二氟苄基)氧基)甲基)-5-甲基-4-(甲基磺醯基)-1H-咪唑及在0℃下向中間物27 (250 mg，0.43 mmol，1.0 equiv.)及(2,6-二氟苯基)甲醇(313 mg，2.17 mmol，5.0 equiv.)於DCM (20 mL)中之溶液中添加BF3.Et2O (0.08 mL，0.65 mmol，1.5 equiv.)及TFA (0.17 mL，2.17 mmmol，5.0 equiv.)且在RT下攪拌16 h。濃縮反應混合物，用冰冷卻之水(20 mL)稀釋，用飽和NaHCO3溶液(50 mL)中和且用乙酸乙酯(150 mL)萃取。經硫酸鈉乾燥有機層且在減壓下濃縮，得到粗產物，藉由逆相製備型HPLC純化，得到外消旋2-((3-氯-4-氟苯基)((3,5-二氟苄基)氧基)甲基)-5-甲基-4-(甲基磺醯基)-1H-咪唑，隨後進行對掌性SFC，產生作為個別鏡像異構物之標題化合物。 Examples 56 and 57 : 2-((3-chloro-4-fluorophenyl)((3,5-difluorobenzyl)oxy)methyl)-5-methyl-4-(methylsulfonylurea)-1H-imidazolium and BF3·Et2O (0.08 mL, 0.65 mmol, 1.5 equiv.) and TFA (0.17 mL, 2.17 mmol, 5.0 equiv.) were added to a solution of intermediate 27 (250 mg, 0.43 mmol, 1.0 equiv.) and ( 2,6 -difluorophenyl)methanol (313 mg, 2.17 mmol, 5.0 equiv.) in DCM (20 mL) at 0 °C, and the mixture was stirred at RT for 16 h. The reaction mixture was concentrated, diluted with ice-cold water (20 mL), neutralized with saturated NaHCO3 solution (50 mL), and extracted with ethyl acetate (150 mL). The organic layer was dried with sodium sulfate and concentrated under reduced pressure to obtain a crude product. Purification by reverse-phase preparative HPLC yielded racemic 2-((3-chloro-4-fluorophenyl)((3,5-difluorobenzyl)oxy)methyl)-5-methyl-4-(methylsulfonylurea)-1H-imidazolium. Subsequently, palmar SFC was performed to produce the title compound, which serves as the individual mirror isomer.
1H-NMR (400 MHz, DMSO-d6, 25℃): δ: 12.75 (bs, 1H), 7.69-7.67 (m, 1H), 7.51-7.36 (m, 4H), 7.23-7.17 (m, 2H), 5.76 (s, 1H), 4.56 (s, 2H), 3.05 (s, 3H), 2.36 (s, 3H)。LCMS m/z = 445.2 [M+H]+。製備型對掌性SFC：管柱：(R,R) Whelk -01 (21.1 mm × 250 mm )，5µ；共溶劑：異丙醇，共溶劑%：40%；流量：70 mL/min；P = 100巴，T：35℃；56(產量：35 mg)：第一次溶析之鏡像異構物；57(產量：34 mg)：第二次溶析之鏡像異構物。 1 H-NMR (400 MHz, DMSO-d6, 25℃): δ: 12.75 (bs, 1H), 7.69-7.67 (m, 1H), 7.51-7.36 (m, 4H), 7.23-7.17 (m, 2H), 5.76 (s, 1H), 4.56 (s, 2H), 3.05 (s, 3H), 2.36 (s, 3H). LCMS m/z = 445.2 [M+H] + . Preparation of palmar SFC: Column: (R,R) Whelk-01 (21.1 mm × 250 mm), 5µm; Cosolvent: isopropanol, cosolvent %: 40%; Flow rate: 70 mL/min; P = 100 bar, T: 35℃; 56 (yield: 35 mg): mirror image isomer of the first dissolution; 57 (yield: 34 mg): mirror image isomer of the second dissolution.
實例 58-101使用與針對實例56/57所述類似之方法，由中間物27及適當的試劑製備標題化合物。可在合成後使用對掌性SFC或對掌性HPLC分離對掌性化合物。
實例 104 、 105使用與針對實例102/103所述類似之方法，由中間物27及適當的試劑製備標題化合物。可在合成後使用對掌性SFC或對掌性HPLC分離對掌性化合物。
實例 106 、 1072-((3-氯-4-氟苯基)((4-甲基苄基)氧基)甲基)-5-甲基-4-(甲基磺醯基)-1H-咪唑及 Examples 106 and 107 : 2-((3-chloro-4-fluorophenyl)((4-methylbenzyl)oxy)methyl)-5-methyl-4-(methylsulfonyl)-1H-imidazolium and
步驟-1：在0℃下向中間物27 (250 mg，0.43 mmol，1.0 equiv.)及對甲苯基甲醇(265 mg，2.17 mmol，5.0 equiv.)於DCM (20 mL)中之混合物中添加BF3.Et2O (0.08 mL，0.65 mmol，1.5 equiv.)及TFA (0.17 mL，2.17 mmmol，5.0 equiv.)且在RT下攪拌16 h。在減壓下濃縮反應混合物，用冰冷卻之水(20 mL)稀釋，用飽和NaHCO3溶液(50 mL)中和且用乙酸乙酯(150 mL)萃取。經硫酸鈉乾燥有機層且在減壓下濃縮，得到粗2-((3-氯-4-氟苯基)((4-甲基苄基)氧基)甲基)-5-甲基-4-(甲基磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑，其直接用於下一步驟。LC-MS: m/z [M+H]+= 553.21Step 1: Add BF3·Et2O (0.08 mL, 0.65 mmol, 1.0 equiv.) and TFA (0.17 mL, 2.17 mmol, 5.0 equiv.) to a mixture of intermediate 27 (250 mg, 0.43 mmol, 1.0 equiv.) and p- tolylethanol (265 mg, 2.17 mmol, 5.0 equiv.) in DCM (20 mL) at 0 °C and stir for 16 h at RT. Concentrate the reaction mixture under reduced pressure, dilute with ice-cold water (20 mL), neutralize with saturated NaHCO3 solution (50 mL), and extract with ethyl acetate (150 mL). The organic layer was dried with sodium sulfate and concentrated under reduced pressure to give crude 2-((3-chloro-4-fluorophenyl)((4-methylbenzyl)oxy)methyl)-5-methyl-4-(methylsulfonylurea)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium, which was used directly in the next step. LC-MS: m/z [M+H] + = 553.21
步驟-2：在RT下向步驟-1之粗產物於THF (50 mL)中之溶液中添加TBAF溶液(5.4 mL，5.4 mmol，5.0 equiv.，1M於THF中)且在65℃下攪拌1 h。用飽和NH4Cl溶液(50 mL)淬滅反應物且用乙酸乙酯(150 mL)萃取。經硫酸鈉乾燥有機層且在減壓下濃縮，得到粗產物，藉由逆相製備型HPLC純化，得到外消旋的最終產物(120 mg)，隨後進行對掌性SFC，產生作為個別鏡像異構物之標題化合物。Step 2: TBAF solution (5.4 mL, 5.4 mmol, 5.0 equiv., 1 M in THF) was added to the crude product of Step 1 in THF (50 mL) under RT and stirred at 65 °C for 1 h. The reaction mixture was quenched with saturated NH₄Cl solution (50 mL) and extracted with ethyl acetate (150 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product, which was purified by reverse-phase preparative HPLC to give the racemic final product (120 mg). This was then subjected to palmar SFC to generate the title compounds as individual mirror isomers.
1H-NMR (400 MHz, DMSO-d6, 25℃): δ: 12.75 (bs, 1H), 7.67-7.65 (m, 1H), 7.44-7.41 (m, 2H), 7.24-7.23 (m, 2H), 7.17-7.15 (m, 2H), 5.6 (s, 1H), 4.45 (s, 2H), 3.05 (s, 3H), 2.37 (s, 3H), 2.29 (s, 3H)。LCMS m/z = 423.2 [M+H]+。製備型對掌性SFC：管柱：(R,R) Whelk -01 (21.1 mm × 250 mm)，5µ；共溶劑：異丙醇，共溶劑%：40%；流量：70 mL/min；P = 100巴，T：35℃。106(產量：41 mg)：第一次溶析之鏡像異構物；107(產量：41 mg)：第二次溶析之鏡像異構物。 1 H-NMR (400 MHz, DMSO-d6, 25℃): δ: 12.75 (bs, 1H), 7.67-7.65 (m, 1H), 7.44-7.41 (m, 2H), 7.24-7.23 (m, 2H), 7.17-7.15 (m, 2H), 5.6 (s, 1H), 4.45 (s, 2H), 3.05 (s, 3H), 2.37 (s, 3H), 2.29 (s, 3H). LCMS m/z = 423.2 [M+H]+. Preparation of palmar SFC: Column: (R,R) Whelk-01 (21.1 mm × 250 mm), 5 µm; Cosolvent: isopropanol, cosolvent %: 40%; Flow rate: 70 mL/min; P = 100 bar, T: 35 °C. 106 (yield: 41 mg): mirror image isomer of the first dissolution; 107 (yield: 41 mg): mirror image isomer of the second dissolution.
實例 108. 109使用與針對實例106/107所述類似之方法，由中間物27及適當的試劑製備標題化合物。可在合成後使用對掌性SFC或對掌性HPLC分離對掌性化合物。
實例 110-195使用以下一般合成方法來製備標題化合物。 Examples 110-195 use the following general synthetic methods to prepare the title compound.
合成方法(B) ：向中間物27 (50.0 mg，92.57 µmol)及適當試劑/親核劑(5當量)於THF (1 ml)中之溶液中添加三氟硼烷乙醚複合物(131.52 mg，925.68 µmol，120.0 µl，10.0 equiv)。將所得混合物在攪拌下在80℃下維持4 h。藉由LCMS監測反應進展。反應完成後，在減壓下蒸發反應混合物。使殘餘物經受製備型HPLC。Synthetic Method (B) : A trifluoroborane diethyl ether complex (131.52 mg, 925.68 µmol, 120.0 µl, 10.0 equiv) was added to a solution of intermediate 27 (50.0 mg, 92.57 µmol) and a suitable reagent/nucleophile (5 equivalents) in THF (1 ml). The resulting mixture was maintained at 80 °C for 4 h with stirring. The reaction progress was monitored by LCMS. After the reaction was complete, the reaction mixture was evaporated under reduced pressure. The residue was subjected to preparative HPLC.
合成方法(B1) ：向中間物27 (50.0 mg，86.78 µmol)及適當試劑/親核劑(5當量)於THF (1 mL)中之溶液中添加三氟硼烷乙醚複合物(61.61 mg，433.66 µmol，50.0 µl，5.0 equiv)。將所得混合物在攪拌下在80℃下維持1 h。藉由LCMS監測反應進展。反應完成後，在減壓下蒸發反應混合物。使殘餘物經受製備型HPLC。Synthetic Method (B1) : A trifluoroborane diethyl ether complex (61.61 mg, 433.66 µmol, 50.0 µl, 5.0 equiv) was added to a solution of intermediate 27 (50.0 mg, 86.78 µmol) and a suitable reagent/nucleophile (5 equivalents) in THF (1 mL). The resulting mixture was maintained at 80 °C for 1 h with stirring. The reaction progress was monitored by LCMS. After the reaction was complete, the reaction mixture was evaporated under reduced pressure. The residue was subjected to preparative HPLC.
實例 196N-((3-氯-4-氟苯基)(4-(甲基磺醯基)-1H-咪唑-2-基)甲基)-4-氟苯胺在rt下將對甲苯磺酸單水合物(0.280 g，1.477 mmol)添加至中間物6 0.150 g，0.492 mmol)及4-氟苯胺(0.164 g，1.477 mmol)於甲苯(10 mL)中之攪拌溶液中且接著將混合物加熱至120℃持續4 h。冷卻至rt之後，在減壓下濃縮反應混合物，得到粗產物，藉由製備型HPLC純化，得到標題化合物(0.020 g，10%)。1H-NMR (400 MHz, DMSO-d6): δ: 11.98 (s, 1H), 7.80 (s, 1H), 7.73 (dd, 1H), 7.51 - 7.47 (m, 1H), 7.40 (t, 1H), 6.94 - 6.89 (m, 2H), 6.68 - 6.64 (m, 2H), 6.54 (d, 1H), 5.78 (d, 1H), 3.07 (s, 3H)。LCMS m/z = 398 [M+H]+。 Example 196 N-((3-chloro-4-fluorophenyl)(4-(methylsulfonyl)-1H-imidazol-2-yl)methyl)-4-fluoroaniline p-Toluenesulfonic acid monohydrate (0.280 g, 1.477 mmol) was added to intermediate 6 (0.150 g, 0.492 mmol) and 4-fluoroaniline (0.164 g, 1.477 mmol) in toluene (10 mL) under rt, and the mixture was then heated to 120 °C for 4 h. After cooling to rt, the reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by preparative HPLC to give the title compound (0.020 g, 10%). 1 H-NMR (400 MHz, DMSO-d 6 ): δ: 11.98 (s, 1H), 7.80 (s, 1H), 7.73 (dd, 1H), 7.51 - 7.47 (m, 1H), 7.40 (t, 1H), 6.94 - 6.89 (m, 2H), 6.68 - 6.64 (m, 2H), 6.54 (d, 1H), 5.78 (d, 1H), 3.07 (s, 3H). LCMS m/z = 398 [M+H] + .
實例 197-212使用與針對實例196所述類似之方法，由適當的中間物及試劑製備標題化合物。可在合成後使用對掌性SFC或對掌性HPLC分離對掌性化合物。
實例 213 、 214N-((3-氯-4-氟苯基)(4-(甲基磺醯基)-1H-咪唑-2-基)甲基)-4,4-二氟環己-1-胺及 Examples 213 and 214 : N-((3-chloro-4-fluorophenyl)(4-(methylsulfonyl)-1H-imidazol-2-yl)methyl)-4,4-difluorocyclohexane-1-amine and
步驟1：在0℃下向中間物9 (0.5 g，1.157 mmol)於DCM (20.0 mL)中之溶液中添加4,4-二氟環己-1-胺鹽酸鹽(0.3 g，1.736 mmol)、三乙胺(0.3 mL，1.736 mmol)及TiCl4(1M於DCM中；1.75 mL，0.173 mmol)。將反應混合物在0℃下攪拌3 h。接著在0℃下向此混合物中添加MeOH (10.0 mL)及NaCNBH3(0.15 g，2.315 mmol)。將反應混合物在rt下攪拌16 h。用NaHCO3溶液中和反應混合物且用乙酸乙酯(2 x 80 mL)萃取。用鹽水洗滌合併之有機層，經硫酸鈉乾燥且在減壓下濃縮，得到粗產物，其未經進一步純化即用於下一步驟(0.48 g，75%)。LCMS m/z = 552 [M+H]+。Step 1: Add 4,4-difluorocyclohexane-1-amine hydrochloride (0.3 g, 1.736 mmol), triethylamine (0.3 mL, 1.736 mmol), and TiCl₄ (1 M in DCM; 1.75 mL, 0.173 mmol) to a solution of intermediate 9 (0.5 g, 1.157 mmol) in DCM (20.0 mL) at 0 °C. Stir the reaction mixture at 0 °C for 3 h. Then add MeOH (10.0 mL) and NaCNBH₃ (0.15 g, 2.315 mmol) to this mixture at 0 °C. Stir the reaction mixture at rt for 16 h. Neutralize the reaction mixture with NaHCO₃ solution and extract with ethyl acetate (2 x 80 mL). The combined organic layers were washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was used in the next step (0.48 g, 75%) without further purification. LCMS m/z = 552 [M+H] + .
步驟2：在0℃下向步驟1之粗產物(0.5 g，0.906 mmol，1.0 eq.)於DCM (5.0 mL)中之攪拌溶液中添加含4(M) HCl之二噁烷(15.0 mL)。將反應物在rt下攪拌4 h。在減壓下濃縮反應混合物，獲得殘餘物，用NaHCO3溶液中和且用乙酸乙酯(2×100 mL)萃取。用鹽水洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮。相繼藉由CombiFlash管柱層析、對掌性SFC純化所得粗產物，產生作為個別鏡像異構物之標題化合物。Step 2: Dioxane (15.0 mL) containing 4 (M) HCl was added to a stirred solution of the crude product from Step 1 (0.5 g, 0.906 mmol, 1.0 eq.) in DCM (5.0 mL) at 0 °C. The reaction mixture was stirred at rt for 4 h. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was neutralized with NaHCO3 solution and extracted with ethyl acetate (2 × 100 mL). The combined organic layer was washed with brine, dried over Na2SO4 , and concentrated under reduced pressure. The crude product was then purified by CombiFlash column chromatography and palmar SFC to produce the title compounds as individual mirror isomers.
LCMS m/z = 422 [M+H]+。1H NMR (DMSO-d6, 400 MHz, 25℃): 12.76 (s, 1H), 7.78 (s, 1H), 7.70 (d, 1H), 7.43-7.36 (m, 2H), 5.07 (s, 1H), 3.05 (s, 3H), 2.91-2.81 (m, 1H), 2.49-2.81 (m, 1H), 2.07-1.85 (m, 2H), 1.81-1.62 (m, 4H), 1.51-1.41 (m, 2H)。對掌性SFC：管柱：Chiralpak IC (4.6 x 250 mm) 5 μm；共溶劑：含0.5%異丙胺之異丙醇，流量：4 mL/min；共溶劑%：40%；ABPR：100巴，T：35℃；213(產率：85 mg，22%)：第一次溶析之鏡像異構物。Rt = 2.18 min；214(產率：80 mg，20%)：第二次溶析之鏡像異構物Rt = 2.71 min。LCMS m/z = 422 [M+H] + . 1 H NMR (DMSO-d6, 400 MHz, 25℃): 12.76 (s, 1H), 7.78 (s, 1H), 7.70 (d, 1H), 7.43-7.36 (m, 2H), 5.07 (s, 1H), 3.05 (s, 3H), 2.91-2.81 (m, 1H), 2.49-2.81 (m, 1H), 2.07-1.85 (m, 2H), 1.81-1.62 (m, 4H), 1.51-1.41 (m, 2H). Palmar SFC: Column: Chiralpak IC (4.6 x 250 mm) 5 μm; Cosolvent: Isopropanol containing 0.5% isopropylamine, flow rate: 4 mL/min; Cosolvent %: 40%; ABPR: 100 bar, T: 35℃; 213 (Yield: 85 mg, 22%): Mirror isomer of the first dissolution. Rt = 2.18 min; 214 (Yield: 80 mg, 20%): Mirror isomer of the second dissolution. Rt = 2.71 min.
實例 215 、 2163-氯-N-((3-氯-4-氟苯基)(4-(甲基磺醯基)-1H-咪唑-2-基)甲基)苯胺及在0℃下向中間物9a (第一次溶析之區域異構物，0.25 g，0.577 mmol)及3-氯苯胺(0.074 g，0.577 mmol)於DCM (10.0 mL)中之溶液中相繼逐滴添加三乙胺(0.25 mL，1.73 mmol)及TiCl4(1M於DCM中，0.9 mL，0.86 mmol)。將反應混合物在0℃下攪拌3 h，隨後在0℃下添加MeOH (10 mL)及NaCNBH3(0.73 g，1.15 mmol)。將反應混合物在rt下攪拌16 h。用NaHCO3溶液中和反應混合物且用乙酸乙酯(2 × 50 mL)萃取。用鹽水洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮。相繼藉由CombiFlash管柱層析(SiO2，0-60% EtOAc/Hex)、SFC純化殘餘物，產生作為個別鏡像異構物之標題化合物。 Examples 215 and 216 : 3-Chloro-N-((3-chloro-4-fluorophenyl)(4-(methylsulfonyl)-1H-imidazol-2-yl)methyl)aniline and Triethylamine (0.25 mL, 1.73 mmol) and TiCl₄ (1 M in DCM, 0.9 mL, 0.86 mmol) were added dropwise to a solution of intermediate 9a (the regional isomer precipitated in the first dissolution, 0.25 g, 0.577 mmol) and 3-chloroaniline (0.074 g, 0.577 mmol) in DCM (10.0 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 3 h, followed by the addition of MeOH (10 mL) and NaCNBH₃ (0.73 g, 1.15 mmol) at 0 °C. The reaction mixture was stirred at rt for 16 h. The reaction mixture was neutralized with NaHCO₃ solution and extracted with ethyl acetate (2 × 50 mL). The combined organic layer was washed with brine, dried with Na₂SO₄ , and concentrated under reduced pressure. The residue was then purified by CombiFlash column chromatography ( SiO₂ , 0-60% EtOAc/Hex) and SFC to produce the title compounds, which serve as individual mirror isomers.
LCMS m/z = 413 [M+H]+。1H NMR (DMSO-d6, 400 MHz, 25℃): 12.72 (s, 1H), 7.74 (s, 1H), 7.54 (d, 1H), 7.37-7.30 (m, 2H), 7.18-7.14 (m, 2H), 7.04-6.99 (m, 2H), 4.44-4.40 (m, 1 H), 3.48-3.42 (m, 1H), 3.24-3.18 (m, 1H), 3.09 (s, 3H)。對掌性SFC：管柱：Chiralpak IC (4.6 x 250 mm) 5 μm；共溶劑：含0.5%異丙胺之異丙醇，流量：4 mL/min；共溶劑%：40%；ABPR：100巴，T：35℃；215(產率：27 mg，11%)：第一次溶析之鏡像異構物。Rt = 2.33 min；216(產率：30 mg，12%)：第二次溶析之鏡像異構物Rt = 2.87 min。LCMS m/z = 413 [M+H] + . 1 H NMR (DMSO-d6, 400 MHz, 25℃): 12.72 (s, 1H), 7.74 (s, 1H), 7.54 (d, 1H), 7.37-7.30 (m, 2H), 7.18-7.14 (m, 2H), 7.04-6.99 (m, 2H), 4.44-4.40 (m, 1H), 3.48-3.42 (m, 1H), 3.24-3.18 (m, 1H), 3.09 (s, 3H). Palmar SFC: Column: Chiralpak IC (4.6 x 250 mm) 5 μm; Cosolvent: Isopropanol containing 0.5% isopropylamine, flow rate: 4 mL/min; Cosolvent %: 40%; ABPR: 100 bar, T: 35℃; 215 (yield: 27 mg, 11%): Mirror isomer of the first dissolution. Rt = 2.33 min; 216 (yield: 30 mg, 12%): Mirror isomer of the second dissolution. Rt = 2.87 min.
實例 217-220使用與針對實例215/216所述類似之方法，由適當的中間物(9及13)及試劑製備標題化合物。可在合成後使用對掌性SFC或對掌性HPLC分離對掌性化合物。
實例 221N-((3-氯-4-氟苯基)(4-(甲基磺醯基)-1H-咪唑-2-基)甲基)-4-氟-N-甲基苯胺 Example 221 N-((3-chloro-4-fluorophenyl)(4-(methylsulfonyl)-1H-imidazol-2-yl)methyl)-4-fluoro-N-methylaniline
步驟-1：在0℃下向中間物9 (0.6 g，1.386 mmol，1.0 equiv.)於DCM (20.0 mL)中之溶液中逐滴添加4-氟苯胺4-氟苯胺(0.231 g，2.079 mmol，1.0 equiv.)、三乙胺 (0.3 mL，2.079 mmol，1.5 equiv.)及TiCl4(1M於DCM中；2.1 mL 2.079 mmol，1.5 equiv.)。將反應混合物在0℃下攪拌3 h。在0℃下向此等混合物中添加MeOH (10 mL)及NaCNBH3(0.175 g，2.772 mmol，2.0 equiv.)。將反應混合物在室溫下攪拌16 h。用NaHCO3溶液中和反應混合物且用乙酸乙酯(2 x 100 mL)萃取。用鹽水洗滌合併之有機層，經硫酸鈉乾燥且在減壓下濃縮，得到粗產物。藉由combiflash管柱層析純化所得粗物質，產生N-((3-氯-4-氟苯基)(5-(甲基甲磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲基)-4-氟苯胺。產率：68% (0.5 g，0.948 mmol)。LCMS: m/z [M+H]+= 528.19。Step 1: Add 4-fluoroaniline (0.231 g, 2.079 mmol, 1.0 equiv.), triethylamine (0.3 mL, 2.079 mmol, 1.5 equiv.), and TiCl₄ (1 M in DCM; 2.1 mL, 2.079 mmol, 1.5 equiv.) dropwise to a solution of intermediate 9 (0.6 g, 1.386 mmol, 1.0 equiv.) in DCM (20.0 mL) at 0 °C. Stir the reaction mixture at 0 °C for 3 h. Add MeOH (10 mL) and NaCNBH₃ (0.175 g, 2.772 mmol, 2.0 equiv.) to this mixture at 0 °C. Stir the reaction mixture at room temperature for 16 h. The reaction mixture was neutralized with NaHCO3 solution and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by combiflash column chromatography to give N-((3-chloro-4-fluorophenyl)(5-(methylmethanesulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl)-4-fluoroaniline. Yield: 68% (0.5 g, 0.948 mmol). LCMS: m/z [M+H] + = 528.19.
步驟-2：在0℃下向含步驟-1之產物(0.25 g，0.473 mmol，1.0 equiv.)之甲醇(12.0 mL)中添加乙酸(1.5 mL)、甲醛(37%，5.0 mL)及氰基硼氫化鈉(0.12 g，1.894 mmol，3.0 equiv.)。將反應混合物在室溫下攪拌2 h。用冰水稀釋反應物且用NaHCO3溶液中和。用乙酸乙酯(2 x 100 mL)萃取水層。用鹽水洗滌合併之有機層且經Na2SO4乾燥且在減壓下濃縮，得到N-((3-氯-4-氟苯基)(5-(甲基甲磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲基)-4-氟-N-甲基苯胺，其未經進一步純化即用於下一步驟。LCMS: m/z [M+H]+= 542.2。Step 2: At 0°C, add acetic acid (1.5 mL), formaldehyde (37%, 5.0 mL), and sodium cyanoboronide (0.12 g, 1.894 mmol, 3.0 equiv.) to methanol (12.0 mL) containing the product of Step 1 (0.25 g, 0.473 mmol, 1.0 equiv.). Stir the reaction mixture at room temperature for 2 h. Dilute the reaction mixture with ice water and neutralize with NaHCO3 solution. Extract the aqueous layer with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine, dried with Na₂SO₄ , and concentrated under reduced pressure to give N-((3-chloro-4-fluorophenyl)(5-(methylmethanesulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl)-4-fluoro-N-methylaniline, which was used in the next step without further purification. LCMS: m/z [M+H] ⁺ = 542.2.
步驟-3：在0℃下向步驟-2之粗產物於DCM (5.0 mL)中之攪拌溶液中添加含4(M) HCl之二噁烷(15.0 mL)。將反應物在室溫下攪拌4 h。在減壓下濃縮反應混合物，得到殘餘物，用NaHCO3溶液中和且用乙酸乙酯(2×100 mL)萃取。用鹽水洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮，得到粗產物。藉由combiflash管柱層析純化所得粗物質，產生標題化合物。產率(經2個步驟)：57% (0.11 g，0.267 mmol)。LCMS m/z = 410.2 [M+H]+。1H NMR (400 MHz, DMSO-d6, 25℃) δ (ppm): 12.99 (s, 1H), 7.87 (s, 1H), 7.47 (d, J= 5.52 Hz, 1H), 7.40 (t, J= 9 Hz, 1H), 7.27-6.24 (m, 1H), 7.04 (t, J= 8.68 Hz, 2H), 6.92-6.89 (m, 2H), 6.27 (s, 1H), 3.08 (s, 3H), 2.69 (s, 3H)。Step 3: Dioxane (15.0 mL) containing 4 (M) HCl was added to a stirred solution of the crude product from Step 2 in DCM (5.0 mL) at 0 °C. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was neutralized with NaHCO3 solution and extracted with ethyl acetate (2 × 100 mL). The combined organic layer was washed with brine, dried over Na2SO4 , and concentrated under reduced pressure to obtain the crude product. The crude product was purified by combiflash column chromatography to give the title compound. Yield (after 2 steps): 57% (0.11 g, 0.267 mmol). LCMS m/z = 410.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, 25℃) δ (ppm): 12.99 (s, 1H), 7.87 (s, 1H), 7.47 (d, J= 5.52 Hz, 1H), 7.40 (t, J= 9 Hz, 1H), 7.27-6.24 (m, 1H), 7.04 (t, J= 8.68 Hz, 2H), 6.92-6.89 (m, 2H), 6.27 (s, 1H), 3.08 (s, 3H), 2.69 (s, 3H).
實例 2223-氯-N-((3-氯-4-氟苯基)(4-(甲基磺醯基)-1H-咪唑-2-基)甲基)-N-甲基苯胺使用與針對實例221之步驟1及步驟2所述類似之方法，由適當的中間物及試劑製備標題化合物，但步驟3如下：在室溫下向步驟2之產物(0.6 g，1 equiv.)於二甲基甲醯胺(15.0 mL)中之攪拌溶液中添加CsF (0.66 g，4.0 equiv.)。將反應物在80℃下攪拌16 h。用冰水稀釋反應混合物且用乙酸乙酯(2 x 100 mL)萃取。用鹽水洗滌合併之有機層，經硫酸鈉乾燥，且在減壓下濃縮，得到粗產物。藉由RP製備型HPLC純化所得粗物質，產生標題化合物。 Example 222: 3-Chloro-N-((3-chloro-4-fluorophenyl)(4-(methylsulfonyl)-1H-imidazol-2-yl)methyl)-N-methylaniline The title compound was prepared using a method similar to steps 1 and 2 described for Example 221, from suitable intermediates and reagents, but step 3 was as follows: CsF (0.66 g, 4.0 equiv.) was added to a stirred solution of the product of step 2 (0.6 g, 1 equiv.) in dimethylformamide (15.0 mL) at room temperature. The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with ice water and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC using RP to produce the title compound.
LCMS: m/z [M-H]-= 426.09；1H NMR (400 MHz, DMSO-d6, 25℃) δ (ppm): 13.01 (s, 1H), 7.90 (s, 1H), 7.46-7.40 (m, 2H), 7.25-7.24 (m, 1H), 7.20 (t, J= 8.16 Hz, 1H), 6.90 (s, 1H), 6.85-6.82 (m, 1H), 6.74 (d, J= 7.76 Hz, 1H), 6.44, (s, 1H), 3.09 (s, 3H), 2.75 (s, 3H)。LCMS: m/z [MH] - = 426.09; 1 H NMR (400 MHz, DMSO-d6, 25℃) δ (ppm): 13.01 (s, 1H), 7.90 (s, 1H), 7.46-7.40 (m, 2H), 7.25-7.24 (m, 1H), 7.20 (t, J= 8.16 Hz, 1H), 6.90 (s, 1H), 6.85-6.82 (m, 1H), 6.74 (d, J= 7.76 Hz, 1H), 6.44, (s, 1H), 3.09 (s, 3H), 2.75 (s, 3H).
實例 223 、 2245-氯-N-((3-氯-4-氟苯基)(5-甲基-4-(甲基磺醯基)-1H-咪唑-2-基)甲基)-3-甲氧基吡啶-2-胺及 Examples 223 and 224 : 5-chloro-N-((3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfonyl)-1H-imidazol-2-yl)methyl)-3-methoxypyridine-2-amine and
步驟1：在環境溫度下向中間物27 (0.300 g，0.521 mmol)於THF (15 mL)中之溶液中添加5-氯-3-甲氧基吡啶-2-胺(0.413 g，2.603 mmol)，隨後添加三氟化硼乙醚(0.111 g，0.781 mmol)及三氟乙酸(0.267 g，2.343 mmol)。將所得混合物加熱至80℃持續1 h。在減壓下濃縮混合物，得到粗殘餘物，用飽和NaHCO3溶液(20 mL)稀釋且用乙酸乙酯(2×20 mL)萃取。用水(20 mL)洗滌合併之有機層，經無水Na2SO4乾燥，過濾，在減壓下濃縮且藉由急驟層析純化。Step 1: At ambient temperature, 5-chloro-3-methoxypyridine-2-amine (0.413 g, 2.603 mmol) was added to a solution of intermediate 27 (0.300 g, 0.521 mmol) in THF (15 mL), followed by the addition of boron trifluoride ether (0.111 g, 0.781 mmol) and trifluoroacetic acid (0.267 g, 2.343 mmol). The resulting mixture was heated to 80 °C for 1 h. The mixture was concentrated under reduced pressure to obtain a crude residue, which was diluted with saturated NaHCO3 solution (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layer was washed with water (20 mL), dried with anhydrous Na₂SO₄ , filtered, concentrated under reduced pressure, and purified by rapid chromatography.
步驟2：在環境溫度下向含步驟1之產物(0.230 g，0.390 mmol)之THF (11.5 mL)中添加四丁基氟化銨(THF中之1M溶液，1.951 mL，1.951 mmol)。將所得混合物加熱至90℃持續1 h。在減壓下濃縮混合物，獲得殘餘物，用飽和NaHCO3溶液(20 mL)稀釋且用乙酸乙酯(2×20 mL)萃取。用水(20 mL)洗滌合併之有機層，經無水Na2SO4乾燥，過濾且在減壓下濃縮，獲得粗化合物，在藉由急驟層析(C18，12 g管柱，使用乙腈及水作為溶析劑)純化後，得到55 mg (36%)標題化合物。接著使用對掌性SFC將標題化合物分離成個別鏡像異構物。Step 2: Tetrabutylammonium fluoride (1M solution in THF, 1.951 mL, 1.951 mmol) was added to 11.5 mL of THF containing the product of Step 1 (0.230 g, 0.390 mmol) at ambient temperature. The resulting mixture was heated to 90 °C for 1 h. The mixture was concentrated under reduced pressure to obtain a residue, which was diluted with saturated NaHCO3 solution (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with water (20 mL), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a crude compound. Purification by rapid chromatography (C18, 12 g column, using acetonitrile and water as solvents) yielded 55 mg (36%) of the title compound. The title compound was then separated into individual mirror isomers using a palmar spectral fractionation (SFC).
1H-NMR (400 MHz, DMSO-d6): δ: 12.62 (s, 1H), 7.62-7.59 (m, 2H), 7.39-7.33 (m, 2H), 7.21 (d, 1H), 6.89 (d, 1H), 6.34 (d, 1H), 3.88 (s, 3H), 3.05 (s, 3H), 2.37 (s, 3H)。LCMS m/z = 459 [M+H]+。對掌性SFC：管柱：Chiralpak IG (4.6 x 150 mm) 5 μm；共溶劑：含0.5% DEA之MeOH，流量：3 mL/min；共溶劑%：30%；ABPR：1500 psi T：30℃；223：第一次溶析之鏡像異構物。Rt = 1.44 min；224：第二次溶析之鏡像異構物Rt = 1.87 min。 1 H-NMR (400 MHz, DMSO-d 6 ): δ: 12.62 (s, 1H), 7.62-7.59 (m, 2H), 7.39-7.33 (m, 2H), 7.21 (d, 1H), 6.89 (d, 1H), 6.34 (d, 1H), 3.88 (s, 3H), 3.05 (s, 3H), 2.37 (s, 3H). LCMS m/z = 459 [M+H] + . Palmar SFC: Column: Chiralpak IG (4.6 x 150 mm) 5 μm; Cosolvent: MeOH containing 0.5% DEA, flow rate: 3 mL/min; Cosolvent %: 30%; ABPR: 1500 psi; T: 30℃; 223 : Mirror isomer of the first dissolution. Rt = 1.44 min; 224 : Mirror isomer of the second dissolution. Rt = 1.87 min.
實例 225-230使用與針對實例223-224所述類似之方法，由適當的中間物及試劑製備標題化合物。可在合成後使用對掌性SFC或對掌性HPLC分離對掌性化合物。
實例 231. 232N-((3-氯-4-氟苯基)(5-甲基-4-(甲基磺醯基)-1H-咪唑-2-基)甲基)吡啶-2-胺及 Example 231. 232 N-((3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfonyl)-1H-imidazol-2-yl)methyl)pyridine-2-amine and
步驟1：向中間物27 (300 mg，0.521 mmol)於THF (10 mL)中之攪拌溶液中添加吡啶-2-胺(245.013 mg，2.603 mmol)，隨後添加三氟化硼乙醚(0.097 mL，0.781 mmol)及三氟乙酸(0.191 mL，2.343 mmol)，將反應混合物加熱至100℃持續2 h。在減壓下濃縮反應混合物且用飽和NaHCO3溶液(10 mL)中和殘餘物且用乙酸乙酯(2×50 mL)萃取。經無水Na2SO4乾燥合併之有機層，過濾且在減壓下濃縮，獲得粗化合物，在藉由急驟層析(C18，24 g濾筒，用0.1%甲酸及乙腈溶析)純化後得到150 mg (55%)所需中間物。Step 1: Add pyridine-2-amine (245.013 mg, 2.603 mmol) to a stirred solution of intermediate 27 (300 mg, 0.521 mmol) in THF (10 mL), followed by the addition of boron trifluoride diethyl ether (0.097 mL, 0.781 mmol) and trifluoroacetic acid (0.191 mL, 2.343 mmol). Heat the reaction mixture to 100 °C for 2 h. Concentrate the reaction mixture under reduced pressure, neutralize the residue with saturated NaHCO3 solution (10 mL), and extract with ethyl acetate (2 × 50 mL). The combined organic layers were dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a crude compound. After purification by rapid chromatography (C18, 24 g filter cartridge, dissolved in 0.1% formic acid and acetonitrile), 150 mg (55%) of the required intermediate was obtained.
步驟2：在0℃下向經分離之中間物於1,4-二噁烷(5 mL)中之攪拌溶液中添加含4M HCl之1,4-二噁烷(2 mL)且將混合物在環境溫度下攪拌16 h。在減壓下濃縮混合物且用乙醚(20 mL)濕磨殘餘物，傾析且乾燥。藉由製備型HPLC純化所獲得之材料，產生60 mg (53%)標題化合物。接著使用對掌性SFC將標題化合物分離成個別鏡像異構物。Step 2: 1,4-Dioxane (2 mL) containing 4M HCl was added to a stirred solution of the separated intermediate in 1,4-dioxane (5 mL) at 0°C, and the mixture was stirred at ambient temperature for 16 h. The mixture was concentrated under reduced pressure, and the residue was wet-milled with ether (20 mL), decanted, and dried. The obtained material was purified by preparative HPLC to produce 60 mg (53%) of the title compound. The title compound was then separated into individual mirror isomers using a palmar SFC.
LCMS m/z = 395 [M+H]+；1H-NMR (400 MHz, DMSO-d6): δ: 12.68 (s, 1H), 7.95 (dd, 1H), 7.63 (dd, 1H), 7.51 (d, 1H), 7.44-7.35 (m, 3H), 6.70 (d, 1H), 6.56-6.53 (m, 1H), 6.34 (d, 1H), 3.03 (s, 3H), 2.37 (s, 3H)。對掌性SFC：管柱：Chiralpak AS-3 (4.6 x 150 mm) 3 μm；共溶劑：含0.5% DEA之MeOH，流量：3 mL/min；共溶劑%：10%；ABPR：1500 psi T：30℃；231：第一次溶析之鏡像異構物。Rt = 2.12 min；232：第二次溶析之鏡像異構物Rt = 2.75 min。LCMS m/z = 395 [M+H] + ; 1 H-NMR (400 MHz, DMSO-d 6 ): δ: 12.68 (s, 1H), 7.95 (dd, 1H), 7.63 (dd, 1H), 7.51 (d, 1H), 7.44-7.35 (m, 3H), 6.70 (d, 1H), 6.56-6.53 (m, 1H), 6.34 (d, 1H), 3.03 (s, 3H), 2.37 (s, 3H). Palmar SFC: Column: Chiralpak AS-3 (4.6 x 150 mm) 3 μm; Cosolvent: MeOH containing 0.5% DEA, flow rate: 3 mL/min; Cosolvent %: 10%; ABPR: 1500 psi; T: 30℃; 231 : Mirror image isomer of the first dissolution. Rt = 2.12 min; 232 : Mirror image isomer of the second dissolution. Rt = 2.75 min.
實例 233-239使用與針對實例231-232所述類似之方法，由適當的中間物及試劑製備標題化合物。可在合成後使用對掌性SFC或對掌性HPLC分離對掌性化合物。
實例 240-2415-氯-N-((3-氯-4-氟苯基)(5-甲基-4-(甲基磺醯基)-1H-咪唑-2-基)甲基)嘧啶-2-胺及 Examples 240-241: 5-Chloro-N-((3-Chloro-4-fluorophenyl)(5-methyl-4-(methylsulfonyl)-1H-imidazol-2-yl)methyl)pyrimidin-2-amine and
步驟1：向中間物27(250 mg，0.434 mmol，1.0 equiv.)及5-氯嘧啶-2-胺(281 mg，2.17 mmol，5.0 equiv.)於DCM (20.0 mL)中之攪拌溶液中添加三氟化硼乙醚(0.08 mL，0.65 mmol，1.5 equiv.)及TFA (0.149 mL，1.952 mmol，4.5 equiv.)且在rt下攪拌1 h min。用冰冷水(50 mL)稀釋反應混合物且用DCM (2 × 50 mL)萃取。用飽和NaHCO3溶液(50 mL)及鹽水(50 mL)洗滌合併之有機層。經無水硫酸鈉乾燥有機層且在減壓下濃縮，得到粗產物，其未經進一步純化即用於下一步驟。LC-MS: m/z [M+H]+= 560.0Step 1: Add boron trifluoride diethyl ether (0.08 mL, 0.65 mmol, 1.5 equiv.) and TFA (0.149 mL, 1.952 mmol, 4.5 equiv.) to a stirred solution of intermediate 27 (250 mg, 0.434 mmol, 1.0 equiv.) in DCM (20.0 mL) and stir at rt for 1 h min. Dilute the reaction mixture with ice-cold water (50 mL) and extract with DCM (2 × 50 mL). Wash the combined organic layer with saturated NaHCO3 solution (50 mL) and brine (50 mL). The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was used in the next step without further purification. LC-MS: m/z [M+H] + = 560.0
步驟2：將步驟1之產物於TFA (4.5 mL)中之攪拌溶液在60℃下加熱20 min。在減壓下濃縮反應混合物，得到粗產物，用MeOH (15.0 mL)稀釋，添加Amberlyst A21 (500 mg)樹脂且在RT下攪拌2 h。過濾反應混合物，用MeOH (10.0 mL)洗滌且在減壓下濃縮濾液，得到粗產物，藉由逆相製備型HPLC純化，得到外消旋標題化合物。接著使用對掌性SFC將標題化合物分離成個別鏡像異構物。Step 2: The product of Step 1 was heated in a stirred solution of TFA (4.5 mL) at 60 °C for 20 min. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was diluted with MeOH (15.0 mL), and Amberlyst A21 resin (500 mg) was added and stirred at RT for 2 h. The reaction mixture was filtered, washed with MeOH (10.0 mL), and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by reverse-phase preparative HPLC to obtain the racemic title compound. The title compound was then separated into individual mirror isomers using a palmar SFC.
LCMS m/z = 430.1 [M+H]+；1H-NMR (400 MHz, DMSO-d6): δ: 12.62 (br s, 1H), 8.40 (s, 2H), 8.35-8.33 (m, 1H), 7.67-7.65 (m, 1H), 7.45-7.36 (m, 2H), 6.25-6.23 (m, 1H), 3.02 (s, 3H), 2.36 (s, 3H)。製備型對掌性SFC：管柱：I Cellulose C (21.1 mm×250 mm)，5µ；共溶劑：MeOH，流量：70 mL/min；共溶劑%：35%；ABPR：100巴；T：35℃；240(產量：17 mg)：第一次溶析之鏡像異構物。241(產量：17 mg)：第二次溶析之鏡像異構物。LCMS m/z = 430.1 [M+H] + ; 1 H-NMR (400 MHz, DMSO-d 6 ): δ: 12.62 (br s, 1H), 8.40 (s, 2H), 8.35-8.33 (m, 1H), 7.67-7.65 (m, 1H), 7.45-7.36 (m, 2H), 6.25-6.23 (m, 1H), 3.02 (s, 3H), 2.36 (s, 3H). Preparation of palmar SFC: Column: I Cellulose C (21.1 mm × 250 mm), 5 µm; Cosolvent: MeOH, flow rate: 70 mL/min; Cosolvent %: 35%; ABPR: 100 bar; T: 35 °C; 240 (yield: 17 mg): Mirror isomer of the first precipitate. 241 (yield: 17 mg): Mirror isomer of the second precipitate.
實例 242-249使用與針對實例240-241所述類似之方法，由適當的中間物及試劑製備標題化合物。可在合成後使用對掌性SFC或對掌性HPLC分離對掌性化合物。
實例 250 、 251N-((3-氯-4-氟苯基)(5-甲基-4-(甲基磺醯基)-1H-咪唑-2-基)甲基)苯并[d]噻唑-2-胺及在RT下向中間物27 (0.300 g，0.521 mmol，1 equiv.)於THF (15 mL)中之溶液中添加苯并[d]噻唑-2-胺(0.391 g，2.603 mmol，5 equiv.)，隨後添加三氟化硼乙醚(0.111 g，0.781 mmol，1.5 equiv.)、三氟乙酸(0.267 g，2.343 mmol，4.5 equiv.)。接著將反應混合物在100℃下攪拌1 h。如藉由LC-MS判斷反應完成後，在減壓下濃縮反應混合物，得到殘餘物，用飽和NaHCO3溶液(20 mL)稀釋且用乙酸乙酯(2×20 mL)萃取。用水(20 mL)洗滌合併之有機層，經Na2SO4乾燥，過濾且在減壓下濃縮，獲得粗化合物，在相繼藉由急驟層析(C18，12 g管柱，使用乙腈及水作為溶析劑)、製備型HPLC純化後提供100 mg外消旋材料。藉由SFC進行進一步分離。 Examples 250 and 251 : N-((3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfonyl)-1H-imidazol-2-yl)methyl)benzo[d]thiazol-2-amine and Benzo[d]thiazol-2-amine (0.391 g, 2.603 mmol, 5 equiv.) was added to a solution of intermediate 27 (0.300 g, 0.521 mmol, 1 equiv.) in THF (15 mL) under RT, followed by the addition of boron trifluoride diethyl ether (0.111 g, 0.781 mmol, 1.5 equiv.) and trifluoroacetic acid (0.267 g, 2.343 mmol, 4.5 equiv.). The reaction mixture was then stirred at 100 °C for 1 h. After the reaction was determined to be complete by LC-MS, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was diluted with saturated NaHCO3 solution (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with water (20 mL), dried over Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a crude compound. This crude compound was then purified by rapid chromatography (C18, 12 g column, using acetonitrile and water as solvents) and preparative HPLC to provide 100 mg of racemic material. Further separation was performed using SFC.
LCMS m/z = 451.2 [M+H]+。對掌性SFC：管柱：Chiralcel OJ-H (4.6 x 250 mm) 5 μm；共溶劑：MeOH；流量：3 mL/min；共溶劑%：35%；P = 100巴，T：30℃；250(產量：25 mg)：第一次溶析之鏡像異構物。Rt = 2.48 min；251(產量：25 mg)：第二次溶析之鏡像異構物Rt = 4.31 min。LCMS m/z = 451.2 [M+H]+. Palmar SFC: Column: Chiralcel OJ-H (4.6 x 250 mm) 5 μm; Cosolvent: MeOH; Flow rate: 3 mL/min; Cosolvent %: 35%; P = 100 bar, T: 30℃; 250 (yield: 25 mg): Mirror image isomer of the first dissolution. Rt = 2.48 min; 251 (yield: 25 mg): Mirror image isomer of the second dissolution. Rt = 4.31 min.
實例 252-258使用與針對實例250-251所述類似之方法，由適當的中間物及試劑製備標題化合物。可在合成後使用對掌性SFC或對掌性HPLC分離對掌性化合物。
實例 259 、 2604,5-二氯-N-((3-氯-4-氟苯基)(5-甲基-4-(甲基磺醯基)-1H-咪唑-2-基)甲基)吡啶-2-胺及在環境溫度下向中間物27 (300 mg，0.521 mmol)於THF (10 mL)中之溶液中添加4,5-二氯吡啶-2-胺(169.7 mg，1.04 mmol)，隨後添加三氟化硼乙醚(0.8 mmol)及三氟乙酸(0.2 mL，2.3 mmol，4.5 equiv.)。將混合物加熱至80℃持續4 h。在減壓下濃縮混合物，得到粗化合物，在藉由急驟層析(C18，12 g管柱，使用含0.1%甲酸之水及乙腈作為溶析劑)純化後提供120 mg (50%)標題化合物。接著使用對掌性SFC將標題化合物分離成個別立體異構物。 Examples 259 and 260 : 4,5-Dichloro-N-((3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfonyl)-1H-imidazol-2-yl)methyl)pyridine-2-amine and At ambient temperature, 4,5-dichloropyridin-2-amine (169.7 mg, 1.04 mmol) was added to a solution of intermediate 27 (300 mg, 0.521 mmol) in THF (10 mL), followed by the addition of boron trifluoride diethyl ether (0.8 mmol) and trifluoroacetic acid (0.2 mL, 2.3 mmol, 4.5 equiv.). The mixture was heated to 80 °C for 4 h. The mixture was concentrated under reduced pressure to give a crude compound, which, after purification by rapid chromatography (C18, 12 g column, using water containing 0.1% formic acid and acetonitrile as solvent), yielded 120 mg (50%) of the title compound. The title compound was then separated into individual stereoisomers using a palmar SFC.
LCMS m/z = 463 [M+H]+；1H-NMR (400 MHz, DMSO-d6): δ: 12.72 (br s, 1H), 8.12 (s, 1H), 8.01 (d, 1H), 7.61 (d,J= 1H), 7.43-7.38 (m, 2H), 6.98 (s, 1H), 6.27 (d, 1H), 3.03 (s, 3H), 2.36 (s, 3H)。對掌性SFC：管柱：Chiracel OJ-H (4.6 x 250 mm) 5 μm；共溶劑：MeOH，流量：3 mL/min；共溶劑%：15%；ABPR：1500 psi T：30℃；259：第一次溶析之鏡像異構物。Rt = 7.16 min；260：第二次溶析之鏡像異構物Rt = 10.79 min。LCMS m/z = 463 [M+H] + ; 1 H-NMR (400 MHz, DMSO-d 6 ): δ: 12.72 (br s, 1H), 8.12 (s, 1H), 8.01 (d, 1H), 7.61 (d, J = 1H), 7.43-7.38 (m, 2H), 6.98 (s, 1H), 6.27 (d, 1H), 3.03 (s, 3H), 2.36 (s, 3H). Hand-type SFC: Column: Chiracel OJ-H (4.6 x 250 mm) 5 μm; Cosolvent: MeOH, flow rate: 3 mL/min; Cosolvent %: 15%; ABPR: 1500 psi; T: 30℃; 259 : Mirror image isomer of the first dissolution. Rt = 7.16 min; 260 : Mirror image isomer of the second dissolution. Rt = 10.79 min.
實例 261-292使用與針對259-260所述類似之方法，由適當的中間物及試劑製備標題化合物。可在合成後使用對掌性SFC或對掌性HPLC分離對掌性化合物。
實例 292 、 293N-((3-氯-4-氟苯基)(5-甲基-4-(甲基磺醯基)-1H-咪唑-2-基)甲基)-5-氟-6-甲基吡啶-2-胺及在0℃下向中間物27 (300 mg，0.521 mmol)及5-氟-6-甲基吡啶-2-胺(0.32 g，2.599 mmol，5 equiv.)於DCM (10 mL)中之溶液中添加BF3∙Et2O (0.2 mL，0.78 mmol，3 equiv.)及TFA (0.4 mL，2.33 mmol，9 equiv.)且在RT下攪拌16 h。在減壓下濃縮反應混合物，用冰冷卻之水(20 mL)稀釋，用飽和NaHCO3溶液(50 mL)中和且用乙酸乙酯(150 mL)萃取。經硫酸鈉乾燥有機層且在減壓下濃縮，得到粗產物，藉由逆相製備型HPLC純化，得到外消旋標題化合物。產率：40.5% (90 mg，0.21 mmol)。接著使用對掌性SFC將標題化合物分離成個別立體異構物。 Examples 292 and 293 : N-((3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfonyl)-1H-imidazol-2-yl)methyl)-5-fluoro-6-methylpyridin-2-amine and BF₃ ∙ Et₂O (0.2 mL, 0.78 mmol, 3 equiv.) and TFA (0.4 mL, 2.33 mmol, 9 equiv.) were added to a solution of intermediate 27 (300 mg, 0.521 mmol) and 5-fluoro-6-methylpyridin- 2 -amine (0.32 g, 2.599 mmol, 5 equiv.) in DCM (10 mL) at 0 °C and stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure, diluted with ice-cold water (20 mL), neutralized with saturated NaHCO₃ solution (50 mL), and extracted with ethyl acetate (150 mL). The organic layer was dried with sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was purified by reverse-phase preparative HPLC to give the racemic title compound. Yield: 40.5% (90 mg, 0.21 mmol). The title compound was then isolated into individual stereoisomers using an antipallet-based spherical fractional ...
LCMS m/z = 427.2 [M+H]+；1H-NMR (400 MHz, DMSO-d6): 12.65 (s, 1H), 7.65-7.63 (s, 1H), 7.44-7.28 (m, 4H), 6.54-6.51 (d, J=2.8 Hz, 1H), 6.25-6.23 (d, J=8.4 Hz, 1H), 3.04 (s, 3H), 2.36 (s, 3H), 2.20 (s, 3H)。製備型對掌性SFC：管柱：((21.1 mm x 250mm )，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：60 mL/min；共溶劑%：20%；ABPR：120巴，T：35℃；292(產量：31 mg)，第一次溶析之鏡像異構物。293(產量：27 mg)：第二次溶析之鏡像異構物。LCMS m/z = 427.2 [M+H] + ; 1 H-NMR (400 MHz, DMSO-d 6 ): 12.65 (s, 1H), 7.65-7.63 (s, 1H), 7.44-7.28 (m, 4H), 6.54-6.51 (d, J=2.8 Hz, 1H), 6.25-6.23 (d, J=8.4 Hz, 1H), 3.04 (s, 3H), 2.36 (s, 3H), 2.20 (s, 3H). Preparation of palmar SFC: Column: ((21.1 mm x 250 mm), 5 µm; Cosolvent: isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 60 mL/min; Cosolvent %: 20%; ABPR: 120 bar, T: 35 °C; 292 (yield: 31 mg), mirror isomer of the first precipitate. 293 (yield: 27 mg): mirror isomer of the second precipitate.
實例 294-297使用與針對292-293所述類似之方法，由適當的中間物及試劑製備標題化合物。可在合成後使用對掌性SFC或對掌性HPLC分離對掌性化合物。
實例 2985-溴-N-((3-氯-4-氟苯基)(5-甲基-4-(甲基磺醯基)-1H-咪唑-2-基)甲基)噻唑-2-胺 Example 298: 5-Bromo-N-((3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfonylurea)-1H-imidazol-2-yl)methyl)thiazol-2-amine
步驟1：向中間物27 (1 g，1.736 mmol)於THF (10 mL)中之攪拌溶液中添加噻唑-2-胺(868.99 mg，8.678 mmol)、BF3·Et2O (367.06 mg，2.603 mmol)及三氟乙酸(890.47 mg，7.810 mmol)且將反應混合物加熱至100℃持續1 h。在減壓下濃縮混合物且用飽和NaHCO3溶液(50 mL)中和殘餘物，接著用乙酸乙酯(2×200 mL)萃取。用鹽水(100 mL)洗滌合併之有機層，經無水Na2SO4乾燥，過濾且在減壓下濃縮，獲得粗化合物，在藉由急驟層析(C18，40 g濾筒，用0.1%甲酸及乙腈溶析)純化後得到200 mg (21%)經取代之中間物。LCMS m/z = 529 [M-H]- Step 1: Thiazol-2-amine (868.99 mg, 8.678 mmol), BF3 · Et2O (367.06 mg, 2.603 mmol), and trifluoroacetic acid (890.47 mg, 7.810 mmol) were added to a stirred solution of intermediate 27 (1 g, 1.736 mmol) in THF (10 mL), and the reaction mixture was heated to 100 °C for 1 h. The mixture was concentrated under reduced pressure, and the residue was neutralized with saturated NaHCO3 solution (50 mL), followed by extraction with ethyl acetate (2 × 200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a crude compound. Purification by rapid chromatography (C18, 40 g filter cartridge, precipitation with 0.1% formic acid and acetonitrile) yielded 200 mg (21%) of the substituted intermediate. LCMS m/z = 529 [MH] -
步驟2：在環境溫度下向N-((3-氯-4-氟苯基)(5-甲基-4-(甲基磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲基)噻唑-2-胺(150 mg，0.282 mmol)於二甲基甲醯胺(3 mL)中之攪拌溶液中添加N-溴琥珀醯亞胺(50.2 mg，0.28 mmol)且將混合物攪拌2 h。用水(20 mL)稀釋混合物且用乙酸乙酯(2×100 mL)萃取。用鹽水(30 mL)洗滌合併之有機層，經無水Na2SO4乾燥，過濾且在減壓下濃縮，獲得粗化合物，在藉由急驟層析(C18，12 g濾筒，用0.1%甲酸及乙腈溶析)純化後產生100 mg (58%) 5-溴-N-((3-氯-4-氟苯基)(5-甲基-4-(甲基磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲基)噻唑-2-胺。LCMS m/z = 609 [M+H]+ Step 2: At ambient temperature, N-bromosuccinimide (50.2 mg, 0.28 mmol) was added to a stirred solution of N-((3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfonylurea)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl)thiazol-2-amine (150 mg, 0.282 mmol) in dimethylformamide (3 mL) and the mixture was stirred for 2 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a crude compound. Purification by rapid chromatography (C18, 12 g filter cartridge, precipitated with 0.1% formic acid and acetonitrile) yielded 100 mg (58%) of 5-bromo-N-((3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfonylurea)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl)thiazolyl-2-amine. LCMS m/z = 609 [M+H] ⁺
步驟3：在0℃下向5-溴-N-((3-氯-4-氟苯基)(5-甲基-4-(甲基磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲基)噻唑-2-胺(100 mg，0.164 mmol)於1,4-二噁烷(2 mL)中之攪拌溶液中添加含4 M HCl之1,4-二噁烷(2 mL)且將反應混合物在環境溫度下攪拌16 h。在減壓下濃縮混合物且用乙醚(30 mL)濕磨所得殘餘物，傾析且乾燥。接著藉由製備型HPLC純化固體，產生12 mg (15%)標題化合物。LCMS m/z = 479 [M+H]+；1H-NMR (400 MHz, DMSO-d6): δ: 12.67 (bs, 1H), 8.84 (d, 1H), 7.63 (d, 1H), 7.44-7.39 (m, 2H), 7.06 (s, 1H), 6.08 (d, 1H), 3.04 (s, 3H), 2.37 (s, 3H)。Step 3: 1,4-Dioxane (2 mL) containing 4 M HCl was added to a stirred solution of 5-bromo-N-((3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl)thiazolyl-2-amine (100 mg, 0.164 mmol) in 1,4-dioxane (2 mL) at 0 °C, and the reaction mixture was stirred at ambient temperature for 16 h. The mixture was concentrated under reduced pressure, and the residue obtained by wet milling with diethyl ether (30 mL) was precipitated and dried. The solid was then purified by preparative HPLC to yield 12 mg (15%) of the title compound. LCMS m/z = 479 [M+H] + ; 1 H-NMR (400 MHz, DMSO-d 6 ): δ: 12.67 (bs, 1H), 8.84 (d, 1H), 7.63 (d, 1H), 7.44-7.39 (m, 2H), 7.06 (s, 1H), 6.08 (d, 1H), 3.04 (s, 3H), 2.37 (s, 3H).
實例 299N-((3-氯-4-氟苯基)(5-甲基-4-(甲基磺醯基)-1H-咪唑-2-基)甲基)-3-環丙基-5-氟吡啶-2-胺 Example 299 N-((3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfonyl)-1H-imidazol-2-yl)methyl)-3-cyclopropyl-5-fluoropyridine-2-amine
步驟1：在0℃下向中間物27 (0.3 g，0.521 mmol)及3-氯-5-氟吡啶-2-胺(0.153 g，1.04 mmol)於THF (6.0 mL)中之混合物中添加三氟化硼乙醚(0.1 mL，0.8 mmol)，隨後添加三氟乙酸(0.18 mL，2.3 mmol)。將所得混合物在密封管中加熱至90℃持續2 h。在減壓下濃縮混合物，得到殘餘物。用冰水(50 mL)稀釋殘餘物且用碳酸氫鈉溶液將pH調節至7.0且用乙酸乙酯(2×100 mL)萃取。用鹽水(20 mL)洗滌合併之有機層，經無水Na2SO4乾燥，過濾且在減壓下濃縮，得到粗產物，在藉由GRACE急驟層析[C18，12 g，RP管柱]使用乙腈及含0.1% FA之水作為溶析劑純化後得到150 mg 3-氯-N-((3-氯-4-氟苯基)(5-甲基-4-(甲基磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲基)-5-氟吡啶-2-胺。LCMS m/z = 577 [M+H]+ Step 1: Boron trifluoride diethyl ether (0.1 mL, 0.8 mmol) was added to a mixture of intermediate 27 (0.3 g, 0.521 mmol) and 3-chloro-5-fluoropyridin-2-amine (0.153 g, 1.04 mmol) in THF (6.0 mL) at 0 °C, followed by the addition of trifluoroacetic acid (0.18 mL, 2.3 mmol). The resulting mixture was heated to 90 °C in a sealed tube for 2 h. The mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with ice water (50 mL), the pH was adjusted to 7.0 with sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a crude product. Purification by GRACE rapid chromatography [C18, 12 g, RP column] using acetonitrile and water containing 0.1% FA as the solvent yielded 150 mg of 3-chloro-N-((3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl)-5-fluoropyridine-2-amine. LCMS m/z = 577 [M+H] +
步驟2：在環境溫度下向3-氯-N-((3-氯-4-氟苯基)(5-甲基-4-(甲基磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲基)-5-氟吡啶-2-胺(0.05 g，0.087 mmol)於甲苯:水(9:1)之混合物(2 mL)中之攪拌溶液中添加磷酸鉀(0.055 g，0.260 mmol)。用氬氣使混合物脫氣5分鐘，之後添加環丙基硼酸(0.007 g，0.087 mmol)、乙酸鈀(II) (0.002 g，0.009 mmol)及2-二環己基膦基-2',6'-二甲氧基聯苯(0.007 g，0.017 mmol)。將反應混合物加熱至100℃持續6 h。經由矽藻土墊過濾混合物，用水(20 mL)稀釋所得溶液且用乙酸乙酯(2 × 30 mL)萃取。用鹽水(2 × 10 mL)洗滌合併之有機層，經無水Na2SO4乾燥，過濾且在減壓下濃縮，得到粗化合物，在藉由GRACE急驟層析[C18，12 g，RP管柱]純化後得到0.008 g (16%) N-((3-氯-4-氟苯基)(5-甲基-4-(甲基磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲基)-3-環丙基-5-氟吡啶-2-胺。LCMS m/z = 583 [M+H]+ Step 2: Add potassium phosphate (0.055 g, 0.260 mmol) to a stirred solution of 3-chloro-N-((3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfonylurea)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl)-5-fluoropyridine-2-amine (0.05 g, 0.087 mmol) in a mixture of toluene and water (9:1) (2 mL) at ambient temperature. The mixture was degassed with argon for 5 minutes, followed by the addition of cyclopropylboronic acid (0.007 g, 0.087 mmol), palladium(II) acetate (0.002 g, 0.009 mmol), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.007 g, 0.017 mmol). The reaction mixture was heated to 100 °C for 6 h. The mixture was filtered through a diatomaceous earth mat, the resulting solution was diluted with water (20 mL), and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a crude compound. Purification by GRACE rapid chromatography [C18, 12 g, RP column] yielded 0.008 g (16%) N-((3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfonylurea)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl)-3-cyclopropyl-5-fluoropyridine-2-amine. LCMS m/z = 583 [M+H] ⁺
步驟3：在0℃下向N-((3-氯-4-氟苯基)(5-甲基-4-(甲基磺醯基)-1H-咪唑-2-基)甲基)-3-環丙基-5-氟吡啶-2-胺(0.1 g，0.17 mmol)於THF (2.0 mL)中之溶液中添加四丁基氟化銨(THF中之1M溶液，0.662 mL，0.662 mmol)。將所得反應混合物加熱至80℃持續2 h。在減壓下濃縮混合物，得到粗殘餘物。用冰水(20 mL)稀釋殘餘物且用碳酸氫鈉溶液將pH調節至7.0且用含10% MeOH之DCM (2×25 mL)萃取。用鹽水(2 x 10 mL)洗滌合併之萃取物，經無水Na2SO4乾燥，過濾且在減壓下濃縮，得到粗產物，在藉由製備型HPLC純化後得到25 mg標題化合物。LCMS m/z = 453 [M+H]+；1H-NMR (400 MHz, DMSO-d6): δ: 7.81 (d, 1H), 7.66 (dd, 1H), 7.46-7.42 (m, 1H), 7.37 (t, 1H), 7.2 (dd, 1H), 6.82 (d, 1H), 6.40 (d, 1H), 3.06 (s, 3H), 2.38 (s, 3H), 194-1.88 (m, 1H), 1.01-0.91 (m, 2H), 0.69-0.64 (m, 2H)。Step 3: Tetrabutylammonium fluoride (0.662 mL, 0.662 mmol, 1 M solution in THF) was added to a solution of N-((3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfonylurea)-1H-imidazol-2-yl)methyl)-3-cyclopropyl-5-fluoropyridine-2-amine (0.1 g, 0.17 mmol) in THF (2.0 mL) at 0 °C. The resulting reaction mixture was heated to 80 °C for 2 h. The mixture was concentrated under reduced pressure to obtain a crude residue. The residue was diluted with ice water (20 mL), the pH was adjusted to 7.0 with sodium bicarbonate solution, and the mixture was extracted with DCM (2 × 25 mL) containing 10% MeOH. The combined extracts were washed with brine (2 x 10 mL), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a crude product, which was then purified by preparative HPLC to obtain 25 mg of the title compound. LCMS m/z = 453 [M+H] + ; 1 H-NMR (400 MHz, DMSO-d 6 ): δ: 7.81 (d, 1H), 7.66 (dd, 1H), 7.46-7.42 (m, 1H), 7.37 (t, 1H), 7.2 (dd, 1H), 6.82 (d, 1H), 6.40 (d, 1H), 3.06 (s, 3H), 2.38 (s, 3H), 194-1.88 (m, 1H), 1.01-0.91 (m, 2H), 0.69-0.64 (m, 2H).
實例 300-348使用以下一般合成方法來製備標題化合物：向中間物27 (50.0 mg，86.78 µmol)及適當試劑(5當量)於THF (1 mL)中之溶液中添加三氟硼烷乙醚複合物(123.25 mg，867.45 µmol)。將所得混合物在攪拌下在80℃下維持2 h。藉由LCMS監測反應進展。反應完成後，在減壓下蒸發反應混合物且藉由製備型HPLC純化。
實例 349 、 3502-(1-(3-氯-4-氟苯基)-2-(4-氟苯基)乙基)-4-(甲基磺醯基)-1H-咪唑及 Examples 349 and 350 : 2-(1-(3-chloro-4-fluorophenyl)-2-(4-fluorophenyl)ethyl)-4-(methylsulfonylurea)-1H-imidazolium and
步驟1：將Mg (0.12 g，5.07 mmol)溶解於配備有回流冷凝器之雙頸燒瓶中且在氬氣氛圍下乾燥。添加Et2O (8.0 mL)，隨後添加催化量之I2。接著，在rt下將1-(溴甲基)-4-氟苯(0.8 g，4.23 mmol)於Et2O (3 mL)中之溶液逐滴添加至混合物中。將反應混合物在rt下攪拌1 h。接著在rt下向新近製備之格林納試劑中添加中間物9a (0.3 g，0.6 mmol)於Et2O (3 mL)中之溶液。將混合物在rt下攪拌16 h。用氯化銨溶液淬滅反應混合物。經由矽藻土床過濾水層且用乙酸乙酯(3 × 80 mL)萃取。用鹽水洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮，得到粗產物，藉由管柱層析純化，產生1-(3-氯-4-氟苯基)-2-(4-氟苯基)-1-(5-甲烷磺醯基-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-咪唑-2-基)乙-1-醇(0.33 g，90%)。Step 1: Dissolve Mg (0.12 g, 5.07 mmol) in a double-necked flask equipped with a reflux condenser and dry under argon atmosphere. Add Et₂O (8.0 mL), followed by a catalytic amount of I₂ . Then, add a solution of 1-(bromomethyl)-4-fluorobenzene (0.8 g, 4.23 mmol) in Et₂O (3 mL) dropwise to the mixture under reflux. Stir the reaction mixture under reflux for 1 h. Then, add a solution of intermediate 9a (0.3 g, 0.6 mmol) in Et₂O (3 mL) to freshly prepared Grindner reagent under reflux. Stir the mixture under reflux for 16 h. Quench the reaction mixture with ammonium chloride solution. The aqueous layer was filtered through a diatomaceous earth bed and extracted with ethyl acetate (3 × 80 mL). The combined organic layer was washed with brine, dried over Na₂SO₄ , and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to produce 1-(3-chloro-4-fluorophenyl)-2-(4-fluorophenyl)-1-(5-methanesulfonyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)ethanol (0.33 g, 90%).
步驟2：在rt下向1-(3-氯-4-氟苯基)-2-(4-氟苯基)-1-(5-甲烷磺醯基-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-咪唑-2-基)乙-1-醇(0.2 g，0.37 mmol)之溶液中添加甲苯(100.0 mL)及pTSA (0.06 g，0.37 mmol)。將反應混合物加熱至100℃持續16 h。將反應混合物冷卻至rt且在減壓下濃縮。用飽和NaHCO3溶液中和殘餘物且用乙酸乙酯(3 × 60 mL)萃取。用鹽水洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮，得到粗產物，藉由管柱層析純化，獲得2-[(E)-1-(3-氯-4-氟苯基)-2-(4-氟苯基)乙烯基]-5-甲烷磺醯基-1H-咪唑(0.13 g，89%)。LCMS m/z = 395 [M+H]+ Step 2: Toluene (100.0 mL) and pTSA (0.06 g, 0.37 mmol) were added to a solution of 1-(3-chloro-4-fluorophenyl)-2-(4-fluorophenyl)-1-(5-methanesulfonyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)ethanol-1-ol (0.2 g, 0.37 mmol) at rt. The reaction mixture was heated to 100 °C and held for 16 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was neutralized with saturated NaHCO3 solution and extracted with ethyl acetate (3 × 60 mL). The combined organic layers were washed with brine, dried with Na₂SO₄ , and concentrated under reduced pressure to obtain a crude product. Purification by column chromatography yielded 2-[(E)-1-(3-chloro-4-fluorophenyl)-2-(4-fluorophenyl)vinyl]-5-methanesulfonyl-1H-imidazolium (0.13 g, 89%). LCMS m/z = 395 [M+H] ⁺
步驟3：用N2使2-[(E)-1-(3-氯-4-氟苯基)-2-(4-氟苯基)乙烯基]-5-甲烷磺醯基-1H-咪唑(0.23 g，0.57 mmol)於MeOH (20.0 mL)中之溶液脫氣15分鐘，隨後在rt下添加PtO2(0.15 g)。將反應混合物在80℃下在高壓釜容器中在10.3巴H2氣壓下攪拌16 h。將反應混合物冷卻至rt且經由矽藻土過濾。在減壓下濃縮濾液，得到粗產物，藉由逆相製備型HPLC及對掌性HPLC純化，得到作為個別鏡像異構物之標題化合物。Step 3: Degas a solution of 2 -[(E)-1-(3-chloro-4-fluorophenyl)-2-(4-fluorophenyl)vinyl]-5-methanesulfonyl-1H-imidazolium (0.23 g, 0.57 mmol) in MeOH (20.0 mL) for 15 min with N₂, then add PtO₂ (0.15 g) at rt. Stir the reaction mixture in a high-pressure vessel at 80 °C and 10.3 bar H₂ for 16 h. Cool the reaction mixture to rt and filter through diatomaceous earth. Concentrate the filtrate under reduced pressure to obtain the crude product, which is purified by reverse-phase preparative HPLC and palmar HPLC to obtain the title compounds as individual mirror isomers.
峰 1，實例 349 ：產率：31% (0.115 g，0.289 mmol)。LCMS m/z = 397 [M+H]+；1H-NMR (400 MHz, DMSO-d6): 12.72 (s, 1H), 7.74 (s, 1H), 7.54 (d, 1H), 7.37-7.30 (m, 2H), 7.18-7.14 (m, 2H), 7.04-6.99 (m, 2H), 4.44-4.40 (m, 1 H), 3.48-3.42 (m, 1H), 3.24-3.18 (m, 1H), 3.09 (s, 3H)。對掌性HPLC：管柱：Chiralpak IC (4.6 x 250 mm) 5 μm；移動相：己烷/DCM/EtOH/iPrNH260/20/20/0.1；流動速率：1.0 mL/min；Rt = 4.83 min (第一次溶析)。 Peak 1 , Example 349 : Yield: 31% (0.115 g, 0.289 mmol). LCMS m/z = 397 [M+H] + ; 1H -NMR (400 MHz, DMSO- d6 ): 12.72 (s, 1H), 7.74 (s, 1H), 7.54 (d, 1H), 7.37–7.30 (m, 2H), 7.18–7.14 (m, 2H), 7.04–6.99 (m, 2H), 4.44–4.40 (m, 1H), 3.48–3.42 (m, 1H), 3.24–3.18 (m, 1H), 3.09 (s, 3H). HPLC with palmar spectroscopy: Column: Chiralpak IC (4.6 x 250 mm) 5 μm; Mobile phase: Hexane/DCM/EtOH/iPrNH 2 60/20/20/0.1; Flow rate: 1.0 mL/min; Rt = 4.83 min (first precipitation).
峰 2，實例 350 ：產率：30% (0.11 g，0.277 mmol)。LCMS m/z = 397 [M+H]+；1H-NMR (400 MHz, DMSO-d6): 12.72 (s, 1H), 7.74 (s, 1H), 7.54 (d, 1H), 7.37-7.30 (m, 2H), 7.18-7.14 (m, 2H), 7.04-6.99 (m, 2H), 4.44-4.40 (m, 1H), 3.48-3.42 (m, 1H), 3.24-3.18 (m, 1H), 3.09 (s, 3H)。對掌性HPLC：管柱：Chiralpak IC (4.6 x 250 mm) 5 μm；移動相：己烷/DCM/EtOH/iPrNH260/20/20/0.1；流動速率：1.0 mL/min；Rt = 5.38 min (第二次溶析)。 Peak 2 , Example 350 : Yield: 30% (0.11 g, 0.277 mmol). LCMS m/z = 397 [M+H] + ; 1H -NMR (400 MHz, DMSO- d6 ): 12.72 (s, 1H), 7.74 (s, 1H), 7.54 (d, 1H), 7.37–7.30 (m, 2H), 7.18–7.14 (m, 2H), 7.04–6.99 (m, 2H), 4.44–4.40 (m, 1H), 3.48–3.42 (m, 1H), 3.24–3.18 (m, 1H), 3.09 (s, 3H). HPLC with palmar spectroscopy: Column: Chiralpak IC (4.6 x 250 mm) 5 μm; Mobile phase: Hexane/DCM/EtOH/iPrNH 2 60/20/20/0.1; Flow rate: 1.0 mL/min; Rt = 5.38 min (second precipitation).
實例 351 、 352(2-((3-氯-4-氟苯基)(4-氟苯氧基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及 Examples 351 and 352 : (2-((3-chloro-4-fluorophenyl)(4-fluorophenoxy)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and
步驟-1：在室溫下向中間物34a (1.8 g，3.52 mmol，1.0 equiv.)於MeOH (80 mL)中之攪拌溶液中添加二乙醯氧基碘苯(211.3 g，35.22 mmol，10.0 equiv.)及碳酸銨(3.4 g，35.22 mmol，10.0 equiv.)。將反應混合物在室溫下攪拌2 h。用水洗滌反應混合物且用乙酸乙酯(3 × 200 mL)萃取。用冷鹽水洗滌合併之有機部分且經Na2SO4乾燥。在減壓下濃縮有機層，得到粗物質。藉由combi flash管柱層析(矽膠，含0-100%乙酸乙酯之己烷作為溶析劑)純化所得粗物質，得到(2-((3-氯-4-氟苯基)(4-氟苯氧基)甲基)-4-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-5-基)(亞胺基)(甲基)-l6-硫酮。產率：63% (1.2 g，2.2 mmol)。LCMS: m/z [M+H]+= 542.2，Step 1: Diacetyloxyiodobenzene (211.3 g, 35.22 mmol, 10.0 equiv.) and ammonium carbonate (3.4 g, 35.22 mmol, 10.0 equiv.) were added to a stirred solution of intermediate 34a (1.8 g, 35.22 mmol, 10.0 equiv.) in MeOH (80 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was washed with water and extracted with ethyl acetate (3 × 200 mL). The combined organic fraction was washed with cold brine and dried over Na₂SO₄ . The organic layer was concentrated under reduced pressure to obtain the crude material. The crude product was purified by Combi Flash column chromatography (silicone with hexane containing 0-100% ethyl acetate as the solvent) to give (2-((3-chloro-4-fluorophenyl)(4-fluorophenoxy)methyl)-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)(imino)(methyl)-16-thione. Yield: 63% (1.2 g, 2.2 mmol). LCMS: m/z [M+H]+ = 542.2.
步驟-2：將步驟-1之產物(0.2 g，0.37 mmol，1.0 equiv.)於AcOH (10 mL)及H2O (2 mL)中之攪拌溶液在70℃下加熱2 h。將反應混合物冷卻至室溫且在減壓下蒸發，得到粗物質。用飽和NaHCO3鹼化粗物質。用乙酸乙酯(3 × 80 mL)萃取水性部分且用鹽水洗滌。經Na2SO4乾燥合併之有機層，過濾且在減壓下蒸發，得到粗產物。經由combi flash管柱層析(含0-20% MeOH之EtOAc作為溶析劑)純化粗物質，獲得外消旋標題化合物，隨後進行正相對掌性分離。Step 2: The product of Step 1 (0.2 g, 0.37 mmol, 1.0 equiv.) was heated at 70 °C for 2 h in a stirred solution of AcOH (10 mL) and H₂O (2 mL). The reaction mixture was cooled to room temperature and evaporated under reduced pressure to obtain a crude product. The crude product was alkalized with saturated NaHCO₃ . The aqueous fraction was extracted with ethyl acetate (3 × 80 mL) and washed with brine. The combined organic layer was dried over Na₂SO₄ , filtered, and evaporated under reduced pressure to obtain the crude product. The crude material was purified by Combi flash column chromatography (using EtOAc containing 0-20% MeOH as a solvent) to obtain the racemic title compound, which was then subjected to normal-phase relative separation.
LCMS: 412.2 m/z [M+H]+。1H NMR (400 MHz, DMSO-d6, 25℃) δ (ppm): 12.75 (s, 1H), 7.79-7.77 (m, 1H), 7.56-7.52 (m, 1H), 7.47-7.43 (m, 1H), 7.14-7.05 (m, 4H), 6.54 (s, 1H), 3.92 (s, 1 H), 2.96 (s, 3H), 2.39 (s, 3H)。分析型對掌性HPLC：Chiralpak IC (4.6 x 250 mm) 5 µm，移動相：含0.5%異丙胺之iPrOH；流量：4 mL/min；共溶劑%：40%；ABPR：97巴；T：35℃；351(產量：20 mg)，第一次溶析之鏡像異構物，Rt = 2.49 min。352(產量：23 mg)：第二次溶析之鏡像異構物，Rt = 3.22 min。LCMS: 412.2 m/z [M+H] + . 1 H NMR (400 MHz, DMSO-d6, 25℃) δ (ppm): 12.75 (s, 1H), 7.79-7.77 (m, 1H), 7.56-7.52 (m, 1H), 7.47-7.43 (m, 1H), 7.14-7.05 (m, 4H), 6.54 (s, 1H), 3.92 (s, 1H), 2.96 (s, 3H), 2.39 (s, 3H). Analytical HPLC: Chiralpak IC (4.6 x 250 mm) 5 µm, mobile phase: iPrOH containing 0.5% isopropylamine; flow rate: 4 mL/min; cosolvent %: 40%; ABPR: 97 bar; T: 35 °C; 351 (yield: 20 mg), mirror image isomer after first precipitate, Rt = 2.49 min. 352 (yield: 23 mg): mirror image isomer after second precipitate, Rt = 3.22 min.
實例 353 、 354(2-((4-氯-3-氟苯基)((5-氯吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及使用與針對實例351/352所述類似之方法，由中間物34b製備標題化合物。LCMS: 412.2 m/z [M+H]+。1H NMR (400 MHz, DMSO-d6, 25℃) δ (ppm): 12.75 (s, 1H), 7.79-7.77 (m, 1H), 7.55-7.52 (m, 1H), 7.48-7.43 (m, 1H), 7.14-7.05 (m, 4H), 6.54 (s, 1H), 3.93 (s, 1 H), 2.96 (s, 3H), 2.39 (s, 3H)。分析型對掌性HPLC：Chiralpak IC (4.6 x 250 mm) 5 µm，移動相：含0.5%異丙胺之iPrOH；流量：4 mL/min；共溶劑%：40%；ABPR：97巴；T：35℃；353(產量：35 mg)，第一次溶析之鏡像異構物，Rt = 1.87 min。354(產量：40 mg)：第二次溶析之鏡像異構物，Rt = 2.71 min。 Examples 353 and 354 : (2-((4-chloro-3-fluorophenyl)((5-chloropyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and The title compound was prepared from intermediate 34b using a method similar to that described for Examples 351/352. LCMS: 412.2 m/z [M+H] + . 1H NMR (400 MHz, DMSO-d6, 25℃) δ (ppm): 12.75 (s, 1H), 7.79–7.77 (m, 1H), 7.55–7.52 (m, 1H), 7.48–7.43 (m, 1H), 7.14–7.05 (m, 4H), 6.54 (s, 1H), 3.93 (s, 1H), 2.96 (s, 3H), 2.39 (s, 3H). Analytical HPLC: Chiralpak IC (4.6 x 250 mm) 5 µm, mobile phase: iPrOH containing 0.5% isopropylamine; flow rate: 4 mL/min; cosolvent %: 40%; ABPR: 97 bar; T: 35 °C; 353 (yield: 35 mg), mirror image isomer after first precipitate, Rt = 1.87 min. 354 (yield: 40 mg): mirror image isomer after second precipitate, Rt = 2.71 min.
實例 355-358(2-((3-氯-4-氟苯基)(((反式)-4-(三氟甲基)環己基)氧基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮、、、向中間物20 (500 mg，0.86 mmol，1.0 equiv.)於DCM (20 mL)中之溶液中添加反式-4-(三氟甲基)環己-1-醇(365 mg，2.17 mmol，2.5 equiv.)、BF3-OEt2(0.2 mL，1.3 mmol，1.5 equiv.)及TFA (0.4 mL，4.36 mL，5.0 equiv.)且在RT下攪拌2 h。向反應混合物中添加TFA (2 mL) (用於完全SEM去保護)且在RT下攪拌16 h。在減壓下濃縮反應混合物，得到殘餘物，用乙酸乙酯(100 mL)稀釋。用NaHCO3溶液(50 mL)、鹽水(50 mL)洗滌有機部分且經無水硫酸鈉乾燥。在減壓下濃縮溶劑，得到粗產物，藉由RP製備型HPLC純化，得到4種標題化合物之立體異構物混合物。藉由對掌性SFC分離立體異構物。 Examples 355-358 (2-((3-chloro-4-fluorophenyl)(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione , , , Intermediate 20 (500 mg, 0.86 mmol, 1.0 equiv.) in DCM (20 mL) was mixed with trans-4-(trifluoromethyl)cyclohexane-1-ol (365 mg, 2.17 mmol, 2.5 equiv.), BF3 - OEt2 (0.2 mL, 1.3 mmol, 1.5 equiv.), and TFA (0.4 mL, 4.36 mL, 5.0 equiv.) and stirred at RT for 2 h. TFA (2 mL) (for complete SEM deprotection) was added to the reaction mixture and stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was diluted with ethyl acetate (100 mL). The organic fraction was washed with 50 mL of NaHCO3 solution and 50 mL of brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to obtain the crude product, which was purified by preparative HPLC using an RP method to yield a mixture of stereoisomers of the four title compounds. The stereoisomers were then separated by palmar SFC.
製備型第一對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：異丙醇，流量：70 mL/min；共溶劑%：35%；ABPR：100巴；T：35℃。第一次溶析：355及356之混合物，第二次溶析：357，第三次溶析：358。Preparation of the first pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: isopropanol, flow rate: 70 mL/min; Cosolvent %: 35%; ABPR: 100 bar; T: 35 °C. First dissolution: mixture of 355 and 356 , second dissolution: 357 , third dissolution: 358 .
製備型第二對掌性SFC：管柱：I Cellulose Z (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之乙腈-異丙醇(1:1)，流量：100 mL/min；共溶劑%：20%；ABPR：100巴；T：35℃。第一次溶析：355，第二次溶析：356。Preparation of the second pair of palmar SFCs: Column: I Cellulose Z (30 mm x 250 mm), 5 µm; Cosolvent: Acetonitrile-isopropanol (1:1) containing 0.2% (methanol containing 7N ammonia), flow rate: 100 mL/min; Cosolvent %: 20%; ABPR: 100 bar; T: 35 °C. First precipitation: 355 °C , Second precipitation: 356 ° C.
355：產率：8% (33 mg，0.07 mmol)。LC-MS: m/z [M+H]+= 468.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.43 (s, 1H), 7.65-7.63 (m, 1H), 7.44-7.39 (m, 2H), 5.69 (s, 1 H), 3.88 (bs, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.24-2.20 (m, 1H), 2.07-2.06 (m, 2H), 1.90-1.83 (m, 2H), 1.34-1.17 (m, 4H)。356：產率：8% (33 mg，0.07 mmol)。LC-MS: m/z [M+H]+= 468.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.43 (s, 1H), 7.64-7.62 (m, 1H), 7.44-7.39 (m, 2H), 5.69 (s, 1 H), 3.84 (bs, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.24-2.20 (m, 1H), 2.07-2.03 (m, 2H), 1.87-1.84 (m, 2H), 1.35-1.17 (m, 4H)。357：產率：8% (33 mg，0.07 mmol)。LC-MS: m/z [M+H]+= 468.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.43 (s, 1H), 7.64-7.62 (m, 1H), 7.44-7.39 (m, 2H), 5.69 (s, 1 H), 3.93 (bs, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.24-2.20 (m, 1H), 2.07-2.03 (m, 2H), 1.90-1.84 (m, 2H), 1.35-1.15 (m, 4H)。358：產率：8% (33 mg，0.07 mmol)。LC-MS: m/z [M+H]+= 468.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.44 (s, 1H), 7.65-7.63 (m, 1H), 7.44-7.39 (m, 2H), 5.69 (s, 1 H), 3.93 (bs, 1H), 2.96 (s, 3H), 2.37 (s, 3H), 2.24-2.20 (m, 1H), 2.06-2.03 (m, 2H), 1.90-1.83 (m, 2H), 1.35-1.15 (m, 4H)。 355 : Yield: 8% (33 mg, 0.07 mmol). LC-MS: m/z [M+H] + = 468.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.43 (s, 1H), 7.65-7.63 (m, 1H), 7.44-7.39 (m, 2H), 5.69 (s, 1 H), 3.88 (bs, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.24-2.20 (m, 1H), 2.07-2.06 (m, 2H), 1.90-1.83 (m, 2H), 1.34-1.17 (m, 4H). 356 : Yield: 8% (33 mg, 0.07 mmol). LC-MS: m/z [M+H] + = 468.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.43 (s, 1H), 7.64-7.62 (m, 1H), 7.44-7.39 (m, 2H), 5.69 (s, 1 H), 3.84 (bs, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.24-2.20 (m, 1H), 2.07-2.03 (m, 2H), 1.87-1.84 (m, 2H), 1.35-1.17 (m, 4H). 357 : Yield: 8% (33 mg, 0.07 mmol). LC-MS: m/z [M+H] + = 468.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.43 (s, 1H), 7.64-7.62 (m, 1H), 7.44-7.39 (m, 2H), 5.69 (s, 1 H), 3.93 (bs, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.24-2.20 (m, 1H), 2.07-2.03 (m, 2H), 1.90-1.84 (m, 2H), 1.35-1.15 (m, 4H). 358 : Yield: 8% (33 mg, 0.07 mmol). LC-MS: m/z [M+H] + = 468.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.44 (s, 1H), 7.65-7.63 (m, 1H), 7.44-7.39 (m, 2H), 5.69 (s, 1 H), 3.93 (bs, 1H), 2.96 (s, 3H), 2.37 (s, 3H), 2.24-2.20 (m, 1H), 2.06-2.03 (m, 2H), 1.90-1.83 (m, 2H), 1.35-1.15 (m, 4H).
實例 359-362(2-((3-氯-4-氟苯基)((3,3-二氟環丁基)甲氧基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮、、、使用與針對實例實例355-358所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 359-362 (2-((3-chloro-4-fluorophenyl)((3,3-difluorocyclobutyl)methoxy)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione , , , The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 355-358. Stereomeric derivatives were separated by palmar SFC.
製備型第一對掌性SFC：管柱：Chiralpak IG (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：100 mL/min；共溶劑%：35%；ABPR：100巴；T：35℃。第一次溶析：359及360之混合物，第二次溶析：361及362之混合物。Preparation of the first pair of palmar SFCs: Column: Chiralpak IG (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 100 mL/min; Cosolvent %: 35%; ABPR: 100 bar; T: 35 °C. First dissolution: mixture of 359 and 360 ; Second dissolution: mixture of 361 and 362 .
製備型第二對掌性SFC：管柱：I Cellulose Z (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之乙腈-異丙醇(1:1)，流量：100 mL/min；共溶劑%：35%；ABPR：100巴；T：35℃。第一次溶析：359，第二次溶析：360。Preparation of the second pair of palmar SFCs: Column: I Cellulose Z (30 mm x 250 mm), 5 µm; Cosolvent: Acetonitrile-isopropanol (1:1) containing 0.2% (methanol containing 7N ammonia), flow rate: 100 mL/min; Cosolvent %: 35%; ABPR: 100 bar; T: 35 °C. First precipitation: 359 °C , Second precipitation: 360 ° C.
製備型第三對掌性SFC：管柱：I Cellulose Z (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之乙腈-異丙醇(1:1)，流量：100 mL/min；共溶劑%：35%；ABPR：100巴；T：35℃。第一次溶析：361，第二次溶析：362。Preparation of the third palmar SFC: Column: I Cellulose Z (30 mm x 250 mm), 5 µm; Cosolvent: Acetonitrile-isopropanol (1:1) containing 0.2% (methanol containing 7N ammonia), flow rate: 100 mL/min; Cosolvent %: 35%; ABPR: 100 bar; T: 35 °C. First precipitation: 361 , Second precipitation: 362 .
359：產量：19 mg。LC-MS: m/z [M+H]+= 422.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.48 (br, 1H), 7.65 (d, J = 7.2 Hz, 1H), 7.45-7.38 (m, 2H), 5.54 (s, 1H), 3.85 (br, 1H), 3.46-3.45 (m, 2H), 2.96 (s, 3H), 2.66-2.59 (m, 2H), 2.43-2.32 (m, 6H)。360：產量：12 mg。LC-MS: m/z [M+H]+= 422.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.47 (br, 1H), 7.64 (d, J = 7.12 Hz, 1H), 7.45-7.39 (m, 2H), 5.54 (s, 1H), 3.85 (br, 1H), 3.47-3.45 (m, 2H), 2.95 (s, 3H), 2.66-2.59 (m, 2H), 2.45-2.32 (m, 6H)。361：產量：13 mg。LC-MS: m/z [M+H]+= 422.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.48 (br, 1H), 7.65-7.63 (m, 1H), 7.45-7.37 (m, 2H), 5.54 (s, 1H), 3.85 (br, 1H), 3.46 (d, J=8 Hz, 2H), 2.95 (s, 3H), 2.66-2.59 (m, 2H), 2.43-2.32 (m, 6H)。362：產量：20 mg。LC-MS: m/z [M+H]+= 422.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.48 (br, 1H), 7.65 (d, J = 7.2 Hz, 1H), 7.45-7.40 (m, 2H), 5.54 (s, 1H), 3.85 (br, 1H), 3.46-3.45 (m, 2H), 2.96 (s, 3H), 2.66-2.59 (m, 2H), 2.43-2.32 (m, 6H)。 359 : Yield: 19 mg. LC-MS: m/z [M+H] + = 422.1. 1H -NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) = 12.48 (br, 1H), 7.65 (d, J = 7.2 Hz, 1H), 7.45-7.38 (m, 2H), 5.54 (s, 1H), 3.85 (br, 1H), 3.46-3.45 (m, 2H), 2.96 (s, 3H), 2.66-2.59 (m, 2H), 2.43-2.32 (m, 6H). 360 : Yield: 12 mg. LC-MS: m/z [M+H] + = 422.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.47 (br, 1H), 7.64 (d, J = 7.12 Hz, 1H), 7.45-7.39 (m, 2H), 5.54 (s, 1H), 3.85 (br, 1H), 3.47-3.45 (m, 2H), 2.95 (s, 3H), 2.66-2.59 (m, 2H), 2.45-2.32 (m, 6H). 361 : Yield: 13 mg. LC-MS: m/z [M+H] + = 422.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.48 (br, 1H), 7.65-7.63 (m, 1H), 7.45-7.37 (m, 2H), 5.54 (s, 1H), 3.85 (br, 1H), 3.46 (d, J=8 Hz, 2H), 2.95 (s, 3H), 2.66-2.59 (m, 2H), 2.43-2.32 (m, 6H). 362 : Yield: 20 mg. LC-MS: m/z [M+H] + = 422.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.48 (br, 1H), 7.65 (d, J = 7.2 Hz, 1H), 7.45-7.40 (m, 2H), 5.54 (s, 1H), 3.85 (br, 1H), 3.46-3.45 (m, 2H), 2.96 (s, 3H), 2.66-2.59 (m, 2H), 2.43-2.32 (m, 6H).
實例 363-366(2-((3-氯-4-氟苯基)((4-氟苄基)氧基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮、、、使用與針對實例355-358所述類似之方法，但在密封小瓶中在80℃下加熱16 h，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 363-366 (2-((3-chloro-4-fluorophenyl)((4-fluorobenzyl)oxy)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione , , , The title compound was prepared using a method similar to that described for Examples 355-358, but heated at 80°C for 16 h in a sealed vial, from suitable intermediates and reagents. Stereomers were separated by palmar SFC.
製備型第一對掌性SFC：管柱：I Cellulose Z (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之乙腈-異丙醇(1:1)，流量：100 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：363，第二次溶析：364及365之混合物，第三次溶析：366。Preparation of the first pair of palmar SFCs: Column: I Cellulose Z (30 mm x 250 mm), 5 µm; Cosolvent: Acetonitrile-isopropanol (1:1) containing 0.2% (methanol containing 7N ammonia), flow rate: 100 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First precipitation: 363 , Second precipitation: a mixture of 364 and 365 , Third precipitation: 366 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：異丙醇，流量：100 mL/min；共溶劑%：40%；ABPR：100巴；T：35℃。第一次溶析：364，第二次溶析：365。Preparation of second-pair palmar SFC: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: isopropanol, flow rate: 100 mL/min; Cosolvent %: 40%; ABPR: 100 bar; T: 35 °C. First dissolution: 364 °C , Second dissolution: 365 ° C.
363：產量：23 mg。LC-MS: m/z [M+H]+= 426.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.56 (s, 1H), 7.67 (d, J = 7.44 Hz, 1H), 7.44-7.38 (m, 4H), 7.18 (t, J = 8.72 Hz, 2H) 5.60 (s, 1 H), 4.47 (s, 2H), 3.86 (s, 1H), 2.96 (s, 3H), 2.37(s, 3H)。364：產量：23 mg。LC-MS: m/z [M+H]+= 426.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.56 (s, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.44-7.38 (m, 4H), 7.18 (t, J = 8.72 Hz, 2H) 5.60 (s, 1 H), 4.48 (s, 2H), 3.86 (s, 1H), 2.95 (s, 3H), 2.37(s, 3H)。365：產量：23 mg。LC-MS: m/z [M+H]+= 426.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.56 (s, 1H), 7.67 (d, J = 6.64 Hz, 1H), 7.44-7.38 (m, 4H), 7.18 (t, J = 8.84 Hz, 2H) 5.60 (s, 1 H), 4.48 (s, 2H), 3.86 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H)。366：產量：23 mg。LC-MS: m/z [M+H]+= 426.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.56 (s, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.44-7.38 (m, 4H), 7.18 (t, J = 8.76 Hz, 2H) 5.60 (s, 1 H), 4.47 (s, 2H), 3.86 (s, 1H), 2.96 (s, 3H), 2.37(s, 3H)。 363 : Yield: 23 mg. LC-MS: m/z [M+H] + = 426.3. 1H -NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) = 12.56 (s, 1H), 7.67 (d, J = 7.44 Hz, 1H), 7.44–7.38 (m, 4H), 7.18 (t, J = 8.72 Hz, 2H), 5.60 (s, 1H), 4.47 (s, 2H), 3.86 (s, 1H), 2.96 (s, 3H), 2.37 (s, 3H). 364 : Yield: 23 mg. LC-MS: m/z [M+H] + = 426.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.56 (s, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.44-7.38 (m, 4H), 7.18 (t, J = 8.72 Hz, 2H) 5.60 (s, 1 H), 4.48 (s, 2H), 3.86 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H). 365 : Yield: 23 mg. LC-MS: m/z [M+H] + = 426.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.56 (s, 1H), 7.67 (d, J = 6.64 Hz, 1H), 7.44-7.38 (m, 4H), 7.18 (t, J = 8.84 Hz, 2H) 5.60 (s, 1 H), 4.48 (s, 2H), 3.86 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H). 366 : Yield: 23 mg. LC-MS: m/z [M+H] + = 426.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.56 (s, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.44-7.38 (m, 4H), 7.18 (t, J = 8.76 Hz, 2H) 5.60 (s, 1 H), 4.47 (s, 2H), 3.86 (s, 1H), 2.96 (s, 3H), 2.37 (s, 3H).
實例 367-370(2-((3-氯-4-氟苯基)((4,4-二氟環己基)氧基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮、、、使用與針對實例355-358所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 367-370 (2-((3-chloro-4-fluorophenyl)((4,4-difluorocyclohexyl)oxy)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione , , , The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 355-358. Stereomeric derivatives were separated by palmar SFC.
製備型第一對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之乙腈-異丙醇(1:1)，流量：90 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：367及368之混合物，第二次溶析：369，第三次溶析：370。Preparation of the first pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Acetonitrile-isopropanol (1:1) containing 0.2% (methanol containing 7N ammonia), flow rate: 90 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First dissolution: mixture of 367 and 368 , second dissolution: 369 , third dissolution: 370 .
製備型第二對掌性SFC：管柱：I Cellulose Z (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之乙腈-異丙醇(1:1)，流量：70 mL/min；共溶劑%：35%；ABPR：100巴；T：35℃。第一次溶析：367，第二次溶析：368。Preparation of the second pair of palmar SFCs: Column: I Cellulose Z (30 mm x 250 mm), 5 µm; Cosolvent: Acetonitrile-isopropanol (1:1) containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 35%; ABPR: 100 bar; T: 35 °C. First precipitation: 367 , Second precipitation: 368 .
367：產率：6%。LC-MS: m/z [M+H]+= 436.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.43 (bs, 1H), 7.65-7.64 (m, 1H) 7.43-7.41 (m, 2H), 5.68 (s, 1H), 3.85 (s, 1H), 3.58 (bs, 1H), 2.95 (s, 3H), 2.39 (s, 3H), 2.03-1.99 (m, 2H), 1.89-1.80 (m, 2H), 1.81-1.75 (m, 4H)。368：產率：3%。LC-MS: m/z [M+H]+= 436.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.43 (bs, 1H), 7.65-7.64 (m, 1H) 7.43-7.41 (m, 2H), 5.68 (s, 1H), 3.85 (s, 1H), 3.58 (bs, 1H), 2.95 (s, 3H), 2.39 (s, 3H), 2.01-1.96 (m, 2H), 1.89-1.82 (m, 2H), 1.81-1.75 (m, 4H)。369：產率：3%。LC-MS: m/z [M+H]+= 436.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.44 (bs, 1H), 7.65-7.63 (m, 1H) 7.43-7.41 (m, 2H), 5.68 (s, 1H), 3.86 (s, 1H), 3.58 (bs, 1H), 2.94 (s, 3H), 2.38 (s, 3H), 2.02-1.95 (m, 2H), 1.88-1.80 (m, 2H), 1.80-1.74 (m, 4H)。370：產率：7%。LC-MS: m/z [M+H]+= 436.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.44 (bs, 1H), 7.65-7.64 (m, 1H) 7.43-7.41 (m, 2H), 5.68 (s, 1H), 3.86 (s, 1H), 3.57 (bs, 1H), 2.95 (s, 3H), 2.38 (s, 3H), 2.0-1.95 (m, 2H), 1.88-1.80 (m, 2H), 1.79-1.71 (m, 4H)。 367 : Yield: 6%. LC-MS: m/z [M+H] + = 436.2. 1H -NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) = 12.43 (bs, 1H), 7.65-7.64 (m, 1H), 7.43-7.41 (m, 2H), 5.68 (s, 1H), 3.85 (s, 1H), 3.58 (bs, 1H), 2.95 (s, 3H), 2.39 (s, 3H), 2.03-1.99 (m, 2H), 1.89-1.80 (m, 2H), 1.81-1.75 (m, 4H). 368 : Yield: 3%. LC-MS: m/z [M+H] + = 436.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.43 (bs, 1H), 7.65-7.64 (m, 1H) 7.43-7.41 (m, 2H), 5.68 (s, 1H), 3.85 (s, 1H), 3.58 (bs, 1H), 2.95 (s, 3H), 2.39 (s, 3H), 2.01-1.96 (m, 2H), 1.89-1.82 (m, 2H), 1.81-1.75 (m, 4H). 369 : Yield: 3%. LC-MS: m/z [M+H] + = 436.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.44 (bs, 1H), 7.65-7.63 (m, 1H) 7.43-7.41 (m, 2H), 5.68 (s, 1H), 3.86 (s, 1H), 3.58 (bs, 1H), 2.94 (s, 3H), 2.38 (s, 3H), 2.02-1.95 (m, 2H), 1.88-1.80 (m, 2H), 1.80-1.74 (m, 4H). 370 : Yield: 7%. LC-MS: m/z [M+H] + = 436.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.44 (bs, 1H), 7.65-7.64 (m, 1H) 7.43-7.41 (m, 2H), 5.68 (s, 1H), 3.86 (s, 1H), 3.57 (bs, 1H), 2.95 (s, 3H), 2.38 (s, 3H), 2.0-1.95 (m, 2H), 1.88-1.80 (m, 2H), 1.79-1.71 (m, 4H).
實例 371-374(2-((3-氯苯基)(((反式)-4-(三氟甲基)環己基)氧基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮、、、使用與針對實例355-358所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 371-374 (2-((3-chlorophenyl)(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione , , , The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 355-358. Stereomeric derivatives were separated by palmar SFC.
製備型第一對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：異丙醇，流量：100 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：371及372之混合物，第二次溶析：373，第三次溶析：374。Preparation of the first pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: isopropanol, flow rate: 100 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First dissolution: mixture of 371 and 372 ; Second dissolution: 373 ; Third dissolution: 374 .
製備型第二對掌性SFC：管柱：Chiralpak IC (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之乙腈-異丙醇(1:1)，流量：70 mL/min；共溶劑%：35%；ABPR：100巴；T：35℃。第一次溶析：371，第二次溶析：372。Preparation of the second palmar SFC: Column: Chiralpak IC (30 mm x 250 mm), 5 µm; Cosolvent: Acetonitrile-isopropanol (1:1) containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 35%; ABPR: 100 bar; T: 35 °C. First precipitation: 371 , Second precipitation: 372 .
371：分析型對掌性HPLC條件：對掌性SFC：管柱：I-CELLULOSE C (4.6 x 150 mm)，5.0 μm，移動相含0.5%異丙胺之異丙醇；流量：4 mL/min；共溶劑%：40%；ABPR：1450 psi；T：35℃；Rt = 1.97 min。LC-MS: m/z [M+H]+= 450.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.41 (s, 1H), 7.50 (s, 1H), 7.39-7.33 (m, 3H), 5.67 (s, 1H), 3.83 (s, 1H), 3.31 (s, 1H, 用水峰遮蔽), 2.95 (s, 3H), 2.36 ( s, 3H), 2.32-2.21 (m, 1H), 2.08-2.05 (m, 2H), 1.86-1.83 (m, 2H), 1.31-1.20 (m, 4H)。372：分析型對掌性HPLC條件：對掌性SFC：管柱：I-CELLULOSE C (4.6 x 150 mm)，5.0 μm，移動相含0.5%異丙胺之異丙醇；流量：4 mL/min；共溶劑%：40%；ABPR：1450 psi；T：35℃；Rt = 2.42 min。LC-MS: m/z [M+H]+= 450.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.43 (s, 1H), 7.49 (s, 1H), 7.38-7.35 (m, 3H), 5.68 (s, 1H), 3.85 (s, 1H), 3.31 (s, 1H, 用水峰遮蔽), 2.95 (s, 3H), 2.37 ( s, 3H), 2.32-2.21 (m, 1H), 2.08-2.06 (m, 2H), 1.87-1.84 (m, 2H), 1.32-1.20 (m, 4H)。373：分析型對掌性HPLC條件：對掌性SFC：管柱：(R, R) WHELK-O1 (4.6 x 150 mm)，3.5 μm，移動相含0.5%異丙胺之異丙醇；流量：3 mL/min；共溶劑%：35%；ABPR：1595 psi；T：35℃；Rt = 3.67 min。LC-MS: m/z [M+H]+= 450.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.42 (s, 1H), 7.49 (s, 1H), 7.39-7.33 (m, 3H), 5.68 (s, 1H), 3.83 (s, 1H), 3.31 (s, 1H), 2.95 (s, 3H), 2.37 ( s, 3H), 2.32-2.21 (m, 1H), 2.08-2.06 (m, 2H), 1.87-1.84 (m, 2H), 1.32-1.20 (m, 4H)。374：分析型對掌性HPLC條件：對掌性SFC：管柱：(R, R) WHELK-O1 (4.6 x 150 mm)，3.5 μm，移動相含0.5%異丙胺之異丙醇；流量：3 mL/min；共溶劑%：35%；ABPR：1595 psi；T：35℃；Rt = 4.51 min。LC-MS: m/z [M+H]+= 450.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm12.42 (s, 1H), 7.50 (s, 1H), 7.41-7.33 (m, 3H), 5.67 (s, 1H), 3.86 (s, 1H), 3.30 (s, 1H), 2.96 (s, 3H), 2.37 ( s, 3H), 2.25-2.23 (m, 1H), 2.08-2.05 (m, 2H), 1.87-1.84 (m, 2H), 1.35-1.18 (m, 4H)。 371 : Analytical SFC conditions: SFC: Column: I-CELLULOSE C (4.6 x 150 mm), 5.0 μm; mobile phase: isopropanol containing 0.5% isopropylamine; flow rate: 4 mL/min; cosolvent %: 40%; ABPR: 1450 psi; T: 35℃; Rt = 1.97 min. LC-MS: m/z [M+H] + = 450.3. ¹H -NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) = 12.41 (s, 1H), 7.50 (s, 1H), 7.39-7.33 (m, 3H), 5.67 (s, 1H), 3.83 (s, 1H), 3.31 (s, 1H, with water peak masking), 2.95 (s, 3H), 2.36 (s, 3H), 2.32-2.21 (m, 1H), 2.08-2.05 (m, 2H), 1.86-1.83 (m, 2H), 1.31-1.20 (m, 4H). 372 : Analytical palmar HPLC conditions: Palmar SFC: Column: I-CELLULOSE C (4.6 x 150 mm), 5.0 μm; mobile phase: isopropanol containing 0.5% isopropylamine; flow rate: 4 mL/min; cosolvent %: 40%; ABPR: 1450 psi; T: 35℃; Rt = 2.42 min. LC-MS: m/z [M+H] + = 450.3. ¹H -NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) = 12.43 (s, 1H), 7.49 (s, 1H), 7.38-7.35 (m, 3H), 5.68 (s, 1H), 3.85 (s, 1H), 3.31 (s, 1H, with water peak masking), 2.95 (s, 3H), 2.37 (s, 3H), 2.32-2.21 (m, 1H), 2.08-2.06 (m, 2H), 1.87-1.84 (m, 2H), 1.32-1.20 (m, 4H). 373 : Analytical palmar HPLC conditions: Palmar SFC: Column: (R, R) WHELK-O1 (4.6 x 150 mm), 3.5 μm; mobile phase: isopropanol containing 0.5% isopropylamine; flow rate: 3 mL/min; cosolvent %: 35%; ABPR: 1595 psi; T: 35℃; Rt = 3.67 min. LC-MS: m/z [M+H] + = 450.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.42 (s, 1H), 7.49 (s, 1H), 7.39-7.33 (m, 3H), 5.68 (s, 1H), 3.83 (s, 1H), 3.31 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.32-2.21 (m, 1H), 2.08-2.06 (m, 2H), 1.87-1.84 (m, 2H), 1.32-1.20 (m, 4H). 374 : Analytical palmar HPLC conditions: Palmar SFC: Column: (R, R) WHELK-O1 (4.6 x 150 mm), 3.5 μm; mobile phase: isopropanol containing 0.5% isopropylamine; flow rate: 3 mL/min; cosolvent %: 35%; ABPR: 1595 psi; T: 35℃; Rt = 4.51 min. LC-MS: m/z [M+H] + = 450.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm12.42 (s, 1H), 7.50 (s, 1H), 7.41-7.33 (m, 3H), 5.67 (s, 1H), 3.86 (s, 1H), 3.30 (s, 1H), 2.96 (s, 3H), 2.37 (s, 3H), 2.25-2.23 (m, 1H), 2.08-2.05 (m, 2H), 1.87-1.84 (m, 2H), 1.35-1.18 (m, 4H).
實例 375-378亞胺基(甲基)(5-甲基-2-((((反式)-4-(三氟甲基)環己基)氧基)(3-(三氟甲基)苯基)甲基)-1H-咪唑-4-基)-l6-硫酮、、、使用與針對實例355-358所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 375-378: imino(methyl)(5-methyl-2-((((trans)-4-(trifluoromethyl)cyclohexyl)oxy)(3-(trifluoromethyl)phenyl)methyl)-1H-imidazol-4-yl)-16-thione , , , The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 355-358. Stereomeric derivatives were separated by palmar SFC.
製備型第一對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：100 mL/min；共溶劑%：20%；ABPR：100巴；T：35℃。第一次溶析：375及376之混合物，第二次溶析：377，第三次溶析：378。Preparation of the first pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 100 mL/min; Cosolvent %: 20%; ABPR: 100 bar; T: 35℃. First dissolution: mixture of 375 and 376 , second dissolution: 377 , third dissolution: 378 .
製備型第二對掌性SFC：管柱：I Cellulose C (21.1 mm×250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：60 mL/min；共溶劑%：20%；ABPR：100巴；T：35℃。第一次溶析：375，第二次溶析：376。Preparation of the second pair of palmar SFCs: Column: I Cellulose C (21.1 mm × 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 60 mL/min; Cosolvent %: 20%; ABPR: 100 bar; T: 35 °C. First precipitation: 375 °C , Second precipitation: 376 ° C.
375：分析型對掌性HPLC條件：對掌性SFC：管柱：CHIRALPAK IC (4.6 x 250 mm)，5 μm，移動相含0 .5%異丙胺之異丙醇；流量：3 mL/min；共溶劑%：30%；ABPR：1450 psi；T：35℃；Rt = 2.37 min。LC-MS: m/z [M+H]+= 484.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.48 (s, 1H), 7.81 (s, 1H), 7.69-7.66 (m, 2H), 7.62-7.60 (m, 1H), 5.79 (s, 1H), 3.85 (s, 1H), 3.35-3.33 (m, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.26-2.21 (m, 1H), 2.08 (d, J= 9.76 Hz, 2H), 1.85 (d, J= 12.12 Hz, 2H), 1.34-1.21 (m, 4H)。376：分析型對掌性HPLC條件：對掌性SFC：管柱CHIRALPAK IC (4.6 x 250 mm)，5 μm，移動相含0 .5%異丙胺之異丙醇；流量：3 mL/min；共溶劑%：30%；ABPR：1450 psi；T：35℃；Rt = 2.87 min。LC-MS: m/z [M+H]+= 484.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.48 (s, 1H), 7.80 (s, 1H), 7.66-7.62 (m, 2H), 7.62-7.60 (m, 1H), 5.79 (s, 1H), 3.85 (s, 1H), 3.35-3.33 (m, 1H), 2.95 ( s, 3H), 2.37 (s, 3H), 2.26-2.21 ( m, 1H), 2.08 (brs, 2H), 1.85 (d, J= 12.12 Hz, 2H), 1.34-1.21 (m, 4H)。377：分析型對掌性HPLC條件：對掌性SFC：管柱：((R, R) WHELK-O1 (4.6 x 150 mm)，3.5 μm，移動相含0.5%異丙胺之異丙醇；流量：3 mL/min；共溶劑%：30%；ABPR：1000 psi；T：35℃；Rt =2.72 min。LC-MS: m/z [M+H]+= 484.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.50 (s, 1H), 7.80 (s, 1H), 7.66-7.62 (m, 2H), 7.62-7.60 (m, 1H), 5.79 (s, 1H), 3.35-3.33 (m, 1H), 2.97 (s, 3H), 2.37 (s, 3H), 2.26-2.21 (m, 1H), 2.07 (brs, 2H), 1.85 (d, J= 12.12 Hz, 2H), 1.31-1.21 (m, 4H)。378：分析型對掌性HPLC條件：對掌性SFC：管柱(R, R) WHELK-O1 (4.6 x 150 mm)，3.5 μm，移動相含0 .5%異丙胺之異丙醇；流量：3 mL/min；共溶劑%：30%; ABPR：1000 psi；T：35℃；Rt =3.40 min。LC-MS: m/z [M+H]+= 484.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ 12.50 (s, 1H), 7.81 (s, 1H), 7.69-7.66 (m, 2H), 7.62-7.60 (m, 1H), 5.79 (s, 1H), 3.85 (s, 1H), 3.35-3.33 (m, 1H), 2.98 ( s, 3H), 2.37 (s, 3H), 2.26-2.21 ( m, 1H), 2.08 (d, J= 9.76 Hz, 2H), 1.85 (d, J= 12.12 Hz, 2H), 1.34-1.21 (m, 4H)。 375 : Analytical SFC conditions: SFC: Column: CHIRALPAK IC (4.6 x 250 mm), 5 μm; mobile phase: isopropanol containing 0.5% isopropylamine; flow rate: 3 mL/min; cosolvent %: 30%; ABPR: 1450 psi; T: 35℃; Rt = 2.37 min. LC-MS: m/z [M+H] + = 484.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.48 (s, 1H), 7.81 (s, 1H), 7.69-7.66 (m, 2H), 7.62-7.60 (m, 1H), 5.79 (s, 1H), 3.85 (s, 1H), 3.35-3.33 (m, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.26-2.21 (m, 1H), 2.08 (d, J= 9.76 Hz, 2H), 1.85 (d, J= 12.12 Hz, 2H), 1.34-1.21 (m, 4H). 376 : Analytical palmar HPLC conditions: Palmar SFC: CHIRALPAK IC column (4.6 x 250 mm), 5 μm; mobile phase containing 0.5% isopropylamine in isopropanol; flow rate: 3 mL/min; cosolvent %: 30%; ABPR: 1450 psi; T: 35℃; Rt = 2.87 min. LC-MS: m/z [M+H] + = 484.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.48 (s, 1H), 7.80 (s, 1H), 7.66-7.62 (m, 2H), 7.62-7.60 (m, 1H), 5.79 (s, 1H), 3.85 (s, 1H), 3.35-3.33 (m, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.26-2.21 (m, 1H), 2.08 (brs, 2H), 1.85 (d, J= 12.12 Hz, 2H), 1.34-1.21 (m, 4H). 377 : Analytical palmar HPLC conditions: Palmar SFC: Column: ((R, R) WHELK-O1 (4.6 x 150 mm), 3.5 μm, mobile phase containing 0.5% isopropylamine in isopropanol; flow rate: 3 mL/min; cosolvent %: 30%; ABPR: 1000 psi; T: 35℃; Rt = 2.72 min. LC-MS: m/z [M+H] + = 484.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) = 12.50 (s, 1H), 7.80 (s, 1H), 7.66-7.62 (m, 2H), 7.62-7.60 (m, 1H), 5.79 (s, 1H). 3.35–3.33 (m, 1H), 2.97 (s, 3H), 2.37 (s, 3H), 2.26–2.21 (m, 1H), 2.07 (brs, 2H), 1.85 (d, J = 12.12 Hz, 2H), 1.31–1.21 (m, 4H). 378 : Analytical palmar HPLC conditions: Palmar SFC: Column (R, R) WHELK-O1 (4.6 x 150 mm), 3.5 μm, mobile phase containing 0.5% isopropylamine in isopropanol; flow rate: 3 mL/min; cosolvent %: 30%; ABPR: 1000 psi; T: 35℃; Rt = 3.40 min. LC-MS: m/z [M+H] + = 484.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ 12.50 (s, 1H), 7.81 (s, 1H), 7.69-7.66 (m, 2H), 7.62-7.60 (m, 1H), 5.79 (s, 1H), 3.85 (s, 1H), 3.35-3.33 (m, 1H), 2.98 (s, 3H), 2.37 (s, 3H), 2.26-2.21 (m, 1H), 2.08 (d, J= 9.76 Hz, 2H), 1.85 (d, J= 12.12 Hz, 2H), 1.34-1.21 (m, 4H).
實例 379-382亞胺基(甲基)(5-甲基-2-((((反式)-4-(三氟甲基)環己基)氧基)(4-(三氟甲基)苯基)甲基)-1H-咪唑-4-基)-l6-硫酮、、、使用與針對實例355-358所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 379-382: imino(methyl)(5-methyl-2-((((trans)-4-(trifluoromethyl)cyclohexyl)oxy)(4-(trifluoromethyl)phenyl)methyl)-1H-imidazol-4-yl)-16-thione , , , The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 355-358. Stereomeric derivatives were separated by palmar SFC.
製備型對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之MeOH)之異丙醇，流量：100 mL/min；共溶劑%：20%；ABPR：100巴；T：35℃。分析型對掌性HPLC條件：對掌性SFC：管柱：(R, R) WHELK-O1 (4.6 x 150 mm)，3.5 μm，移動相含0.3 % iPrNH2之異丙醇；流量：3 mL/min；共溶劑%：20%；ABPR：1000 psi；T：35℃。第一次溶析：379，第二次溶析：380，第三次溶析：381，第四次溶析：382。Preparative palmar SFC: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (MeOH containing 7N ammonia), flow rate: 100 mL/min; Cosolvent %: 20%; ABPR: 100 bar; T: 35 °C. Analytical palmar HPLC conditions: Palmar SFC: Column: (R, R) WHELK-O1 (4.6 x 150 mm), 3.5 μm; Mobile phase: Isopropanol containing 0.3 % iPrNH₂; Flow rate: 3 mL/min; Cosolvent %: 20%; ABPR: 1000 psi; T: 35 °C. First dissolution: 379 , Second dissolution: 380 , Third dissolution: 381 , Fourth dissolution: 382 .
379：6%，Rt = 3.68 min (第一次溶析)。LC-MS: m/z [M+H]+= 484.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.43 (s, 1H), 7.75-7.73 (m, 2H), 7.64-7.62 (m, 2H), 5.77 (s, 1H), 3.83 (s, 1H), 3.36-3.35 (m, 1H), 2.95 ( s, 3H), 2.37 (s, 3H), 2.23 ( brs, 1H), 2.10-2.07 (m, 2H), 1.85 (d, J= 11.64 Hz, 2H), 1.33-1.21 (m, 4H)。380：6%，Rt = 3.82 min (第二次溶析)。LC-MS: m/z [M+H]+= 484.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.43 (s, 1H), 7.75-7.73 (m, 2H), 7.64-7.62 (m, 2H), 5.77 (s, 1H), 3.83 (s, 1H), 3.36-3.35 (m, 1H), 2.95 ( s, 3H), 2.37 (s, 3H), 2.23( brs, 1H), 2.10-2.07 (d, J= 11.48 Hz, 2H), 1.85 (d, J= 11.64 Hz, 2H), 1.33-1.21 (m, 4H)。381：3%，Rt = 5.28 min (第三次溶析)。LC-MS: m/z [M+H]+= 484.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.43 (s, 1H), 7.75-7.73 (m, 2H), 7.64-7.62 (m, 2H), 5.77 (s, 1H), 3.83 (s, 1H), 3.36-3.35 (m, 1H), 2.95 ( s, 3H), 2.37 (s, 3H), 2.23( brs, 1H), 2.10-2.07 (d, J= 11.48 Hz, 2H), 1.85 (d, J= 11.64 Hz, 2H), 1.33-1.21 (m, 4H)。382：3%，Rt = 6.20 min (第四次溶析)。LC-MS: m/z [M+H]+= 484.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.43 (s, 1H), 7.75-7.73 (m, 2H), 7.64-7.62 (m, 2H), 5.77 (s, 1H), 3.83 (s, 1H), 3.36-3.35 (m, 1H), 2.95 ( s, 3H), 2.37 (s, 3H), 2.24-2.23 ( m, 1H), 2.10-2.07 (d, J= 11.48 Hz, 2H), 1.85 (d, J= 11.64 Hz, 2H), 1.33-1.21 (m, 4H)。 379 :6%, Rt = 3.68 min (first precipitation). LC-MS: m/z [M+H] + = 484.3. ¹H -NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) = 12.43 (s, 1H), 7.75–7.73 (m, 2H), 7.64–7.62 (m, 2H), 5.77 (s, 1H), 3.83 (s, 1H), 3.36–3.35 (m, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.23 (brs, 1H), 2.10–2.07 (m, 2H), 1.85 (d, J = 11.64 Hz, 2H), 1.33–1.21 (m, 4H). 380 :6%, Rt = 3.82 min (second precipitation). LC-MS: m/z [M+H] + = 484.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.43 (s, 1H), 7.75-7.73 (m, 2H), 7.64-7.62 (m, 2H), 5.77 (s, 1H), 3.83 (s, 1H), 3.36-3.35 (m, 1H), 2.95 ( s, 3H), 2.37 (s, 3H), 2.23( brs, 1H), 2.10-2.07 (d, J= 11.48 Hz, 2H), 1.85 (d, J= 11.64 Hz, 2H), 1.33-1.21 (m, 4H). 381 :3%, Rt = 5.28 min (third precipitation). LC-MS: m/z [M+H] + = 484.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.43 (s, 1H), 7.75-7.73 (m, 2H), 7.64-7.62 (m, 2H), 5.77 (s, 1H), 3.83 (s, 1H), 3.36-3.35 (m, 1H), 2.95 ( s, 3H), 2.37 (s, 3H), 2.23( brs, 1H), 2.10-2.07 (d, J= 11.48 Hz, 2H), 1.85 (d, J= 11.64 Hz, 2H), 1.33-1.21 (m, 4H). 382 :3%, Rt = 6.20 min (fourth precipitation). LC-MS: m/z [M+H] + = 484.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.43 (s, 1H), 7.75-7.73 (m, 2H), 7.64-7.62 (m, 2H), 5.77 (s, 1H), 3.83 (s, 1H), 3.36-3.35 (m, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.24-2.23 (m, 1H), 2.10-2.07 (d, J= 11.48 Hz, 2H), 1.85 (d, J= 11.64 Hz, 2H), 1.33-1.21 (m, 4H).
實例 383-386(2-((3-(二氟甲基)苯基)(((反式)-4-(三氟甲基)環己基)氧基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮、、、使用與針對實例355-358所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 383-386 (2-((3-(difluoromethyl)phenyl)(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione , , , The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 355-358. Stereomeric derivatives were separated by palmar SFC.
製備型第一對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：70 mL/min；共溶劑%：35%；ABPR：100巴；T：35℃。第一次溶析：383及384之混合物，第二次溶析：385，第三次溶析：386。Preparation of the first pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 35%; ABPR: 100 bar; T: 35 °C. First dissolution: mixture of 383 and 384 ; Second dissolution: 385 ; Third dissolution: 386 .
製備型第二對掌性SFC：管柱CHIRALPAK IC (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：70 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：383，第二次溶析：384。Preparation of the second palmar SFC: Chiralpak IC column (30 mm x 250 mm), 5 µm; cosolvent: isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First precipitation: 383 , second precipitation: 384 .
383：分析型對掌性HPLC條件：對掌性SFC：管柱：CHIRALPAK IC (4.6 x 250 mm)，5 μm，移動相含0 .5%異丙胺之異丙醇；流量：3 mL/min；共溶劑%：30%；ABPR：1450 psi；T：35℃；Rt = 1.67 min。LC-MS: m/z [M+H]+= 465.9。384：分析型對掌性HPLC條件：對掌性SFC：管柱：CHIRALPAK IC (4.6 x 250 mm)，5 μm，移動相含0 .5%異丙胺之異丙醇；流量：3 mL/min；共溶劑%：30%；ABPR：1450 psi；T：35℃；Rt = 2.03 min。LC-MS: m/z [M+H]+= 465.9。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) 12.45 (s, 1H), 7.63 (s,1H), 7.56-7.53 (m, 1H), 7.51-7.48 (m, 2H), 7.05 (t, J= 55.7 Hz, 1H), 5.73 (s, 1H), 3.85 (s, 1H), 2.95 ( s, 3H), 2.37 (s, 3H), 2.25-2.21 (m,1H), 2.08 (d, J= 11.6 Hz, 2H), 1.85 (d, J= 13.0 Hz, 2H), 1.33-1.20 (m, 4H)。385：分析型對掌性HPLC條件：對掌性SFC：管柱：(R, R) WHELK-O1 (4.6 mm x 150 mm)，3.5 μm，移動相含0 .5%異丙胺之異丙醇；流量：3 mL/min；共溶劑%：40%；ABPR：1595 psi；T：35℃；Rt = 1.67 min。LC-MS: m/z [M+H]+= 465.9。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) 12.43 (s, 1H), 7.63 (s, 1H), 7.54-7.49 (m, 3H) , 7.04 (t, J= 55.7 Hz, 1H), 5.73 (s, 1H), 3.83 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.25-2.21 (m, 1H), 2.08 (d, J= 11.6 Hz, 2H), 1.85 (d, J= 13.0 Hz, 2H), 1.36-1.17 (m, 4H)。386：分析型對掌性HPLC條件：對掌性SFC：管柱：(R, R) WHELK-O1 (4.6 mm x 150 mm)，3.5 μm，移動相含0 .5%異丙胺之異丙醇；流量：3 mL/min；共溶劑%：40%；ABPR：1595 psi；T：35℃；Rt = 2.08 min。LC-MS: m/z [M+H]+= 465.9。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)12.45 (s, 1H), 7.64 (s, 1H), 7.55-7.50 (m, 3H) , 7.04 (t, J= 55.7 Hz, 1H), 5.73 (s, 1H), 3.85 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.25-2.23 (m, 1H), 2.08 (d, J= 11.6 Hz, 2H), 1.85 (d, J= 12.4 Hz, 2H), 1.36-1.17 (m, 4H)。 383 : Analytical palmar HPLC conditions: Palmar SFC: Column: CHIRALPAK IC (4.6 x 250 mm), 5 μm; mobile phase: isopropanol containing 0.5% isopropylamine; flow rate: 3 mL/min; cosolvent %: 30%; ABPR: 1450 psi; T: 35℃; Rt = 1.67 min. LC-MS: m/z [M+H] + = 465.9. 384 : Analytical palmar HPLC conditions: Palmar SFC: Column: CHIRALPAK IC (4.6 x 250 mm), 5 μm; mobile phase: isopropanol containing 0.5% isopropylamine; flow rate: 3 mL/min; cosolvent %: 30%; ABPR: 1450 psi; T: 35℃; Rt = 2.03 min. LC-MS: m/z [M+H] + = 465.9. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) 12.45 (s, 1H), 7.63 (s,1H), 7.56-7.53 (m, 1H), 7.51-7.48 (m, 2H), 7.05 (t, J= 55.7 Hz, 1H), 5.73 (s, 1H), 3.85 (s, 1H), 2.95 ( s, 3H), 2.37 (s, 3H), 2.25-2.21 (m,1H), 2.08 (d, J= 11.6 Hz, 2H), 1.85 (d, J= 13.0 Hz, 2H), 1.33-1.20 (m, 4H). 385 : Analytical palmar HPLC conditions: Palmar SFC: Column: (R, R) WHELK-O1 (4.6 mm x 150 mm), 3.5 μm; mobile phase: isopropanol containing 0.5% isopropylamine; flow rate: 3 mL/min; cosolvent %: 40%; ABPR: 1595 psi; T: 35℃; Rt = 1.67 min. LC-MS: m/z [M+H] + = 465.9. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) 12.43 (s, 1H), 7.63 (s, 1H), 7.54-7.49 (m, 3H), 7.04 (t, J= 55.7 Hz, 1H), 5.73 (s, 1H), 3.83 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.25-2.21 (m, 1H), 2.08 (d, J= 11.6 Hz, 2H), 1.85 (d, J= 13.0 Hz, 2H), 1.36-1.17 (m, 4H). 386 : Analytical palmar HPLC conditions: Palmar SFC: Column: (R, R) WHELK-O1 (4.6 mm x 150 mm), 3.5 μm; mobile phase: isopropanol containing 0.5% isopropylamine; flow rate: 3 mL/min; cosolvent %: 40%; ABPR: 1595 psi; T: 35℃; Rt = 2.08 min. LC-MS: m/z [M+H] + = 465.9. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)12.45 (s, 1H), 7.64 (s, 1H), 7.55-7.50 (m, 3H), 7.04 (t, J= 55.7 Hz, 1H), 5.73 (s, 1H), 3.85 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.25-2.23 (m, 1H), 2.08 (d, J= 11.6 Hz, 2H), 1.85 (d, J= 12.4 Hz, 2H), 1.36-1.17 (m, 4H).
實例 387-390(2-((3,5-二氟苯基)(((反式)-4-(三氟甲基)環己基)氧基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮、、、使用與針對實例355-358所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 387-390 (2-((3,5-difluorophenyl)(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione , , , The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 355-358. Stereomeric derivatives were separated by palmar SFC.
製備型第一對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：120 mL/min；共溶劑%：20%；ABPR：100巴；T：35℃。第一次溶析：387及388之混合物，第二次溶析：389，第三次溶析：390。Preparation of the first pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 120 mL/min; Cosolvent %: 20%; ABPR: 100 bar; T: 35℃. First dissolution: mixture of 387 and 388 , second dissolution: 389 , third dissolution: 390 .
製備型第二對掌性SFC：管柱I Cellulose C (21.1 mm×250 mm )，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：70 mL/min；共溶劑%：25%；ABPR：100巴；T：35℃。第一次溶析：387，第二次溶析：388。Preparation of the second pair of palmar SFCs: Column I Cellulose C (21.1 mm × 250 mm), 5 µm; Cosolvent: isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 25%; ABPR: 100 bar; T: 35 °C. First precipitation: 387 , Second precipitation: 388 .
387：分析型對掌性HPLC條件：對掌性SFC：管柱：CHIRALPAK IC (4.6 x 250 mm)，5 μm，移動相含0 .5%異丙胺之異丙醇；流量：3 mL/min；共溶劑%：30%；ABPR：1450 psi；T：35℃；Rt = 2.56 min。LC-MS: m/z [M+H]+= 452.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) 12.44 (s, 1H), 7.20-7.13 (m, 3H), 5.71 (s, 1H), 3.87 (s, 1H), 3.36-3.35 (m, 1H), 2.96 ( s, 3H), 2.37 (s, 3H), 2.25-2.23 ( m, 1H), 2.10-2.07 (m, 2H), 1.85 (d, J= 13.12 Hz, 2H), 1.32-1.21 (m, 4H)。388：分析型對掌性HPLC條件：對掌性SFC：管柱：CHIRALPAK IC (4.6 x 250 mm)，5 μm，移動相含0 .5%異丙胺之異丙醇；流量：3 mL/min；共溶劑%：30%；ABPR：1450 psi；T：35℃；Rt = 2.95 min。LC-MS: m/z [M+H]+= 452.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) 12.44 (s, 1H), 7.20-7.13 (m, 3H), 5.71 (s, 1H), 4.19 (brs, 1H), 3.36-3.35 (m, 1H), 2.98 ( s, 3H), 2.38 (s, 3H), 2.25-2.23 ( m, 1H), 2.10-2.05 (m, 2H), 1.85 (d, J= 13.12 Hz, 2H), 1.32-1.17 (m, 4H)。389：分析型對掌性HPLC條件：對掌性SFC：管柱：(R, R) WHELK-O1 (4.6 mm x 150 mm)，3.5 μm，移動相含0 .5%異丙胺之異丙醇；流量：3 mL/min；共溶劑%：20%；ABPR：1595 psi；T：35℃；Rt = 6.55 min。LC-MS: m/z [M+H]+= 452.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) 12.43 (s, 1H), 7.20-7.12 (m, 3H), 5.71 (s, 1H), 3.86 (s, 1H), 2.95 ( s, 3H), 2.37 (s, 3H), 2.25-2.23 ( m, 1H), 2.10-2.05 (m, 2H), 1.85 (d, J= 13.12 Hz, 2H), 1.35-1.18 (m, 4H)。390：分析型對掌性HPLC條件：對掌性SFC：管柱：(R, R) WHELK-O1 (4.6 mm x 150 mm)，3.5 μm，移動相含0 .5%異丙胺之異丙醇；流量：3 mL/min；共溶劑%：20%；ABPR：1595 psi；T：35℃；Rt = 7.10 min。LC-MS: m/z [M+H]+= 452.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) 12.43 (s, 1H), 7.20-7.13 (m, 3H), 5.71 (s, 1H), 3.85 (s, 1H), 3.36-3.35 (m, 1H), 2.96 ( s, 3H), 2.37 (s, 3H), 2.25-2.23 ( m, 1H), 2.10-2.07 (m, 2H), 1.85 (d, J= 13.12 Hz, 2H), 1.32-1.21 (m, 4H)。 387 : Analytical palmar HPLC conditions: Palmar SFC: Column: CHIRALPAK IC (4.6 x 250 mm), 5 μm; mobile phase: isopropanol containing 0.5% isopropylamine; flow rate: 3 mL/min; cosolvent %: 30%; ABPR: 1450 psi; T: 35℃; Rt = 2.56 min. LC-MS: m/z [M+H] + = 452.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) 12.44 (s, 1H), 7.20-7.13 (m, 3H), 5.71 (s, 1H), 3.87 (s, 1H), 3.36-3.35 (m, 1H), 2.96 ( s, 3H), 2.37 (s, 3H), 2.25-2.23 (m, 1H), 2.10-2.07 (m, 2H), 1.85 (d, J= 13.12 Hz, 2H), 1.32-1.21 (m, 4H). 388 : Analytical SFC conditions: SFC: Column: CHIRALPAK IC (4.6 x 250 mm), 5 μm; mobile phase: isopropanol containing 0.5% isopropylamine; flow rate: 3 mL/min; cosolvent %: 30%; ABPR: 1450 psi; T: 35℃; Rt = 2.95 min. LC-MS: m/z [M+H] + = 452.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) 12.44 (s, 1H), 7.20-7.13 (m, 3H), 5.71 (s, 1H), 4.19 (brs, 1H), 3.36-3.35 (m, 1H), 2.98 ( s, 3H), 2.38 (s, 3H), 2.25-2.23 (m, 1H), 2.10-2.05 (m, 2H), 1.85 (d, J= 13.12 Hz, 2H), 1.32-1.17 (m, 4H). 389 : Analytical palmar HPLC conditions: Palmar SFC: Column: (R, R) WHELK-O1 (4.6 mm x 150 mm), 3.5 μm; mobile phase: isopropanol containing 0.5% isopropylamine; flow rate: 3 mL/min; cosolvent %: 20%; ABPR: 1595 psi; T: 35℃; Rt = 6.55 min. LC-MS: m/z [M+H] + = 452.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) 12.43 (s, 1H), 7.20-7.12 (m, 3H), 5.71 (s, 1H), 3.86 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.25-2.23 (m, 1H), 2.10-2.05 (m, 2H), 1.85 (d, J= 13.12 Hz, 2H), 1.35-1.18 (m, 4H). 390 : Analytical palmar HPLC conditions: Palmar SFC: Column: (R, R) WHELK-O1 (4.6 mm x 150 mm), 3.5 μm; mobile phase: isopropanol containing 0.5% isopropylamine; flow rate: 3 mL/min; cosolvent %: 20%; ABPR: 1595 psi; T: 35℃; Rt = 7.10 min. LC-MS: m/z [M+H] + = 452.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) 12.43 (s, 1H), 7.20-7.13 (m, 3H), 5.71 (s, 1H), 3.85 (s, 1H), 3.36-3.35 (m, 1H), 2.96 ( s, 3H), 2.37 (s, 3H), 2.25-2.23 (m, 1H), 2.10-2.07 (m, 2H), 1.85 (d, J= 13.12 Hz, 2H), 1.32-1.21 (m, 4H).
實例 391-394(2-((4-(二氟甲基)苯基)(((反式)-4-(三氟甲基)環己基)氧基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮、、、使用與針對實例355-358所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 391-394 (2-((4-(difluoromethyl)phenyl)(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione , , , The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 355-358. Stereomeric derivatives were separated by palmar SFC.
製備型第一對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：70 mL/min；共溶劑%：35%；ABPR：100巴；T：35℃。第一次溶析：391及392之混合物，第二次溶析：393，第三次溶析：394。Preparation of the first pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 35%; ABPR: 100 bar; T: 35℃. First dissolution: mixture of 391 and 392 ; Second dissolution: 393 ; Third dissolution: 394 .
製備型第二對掌性SFC：管柱：Chiralpak IC (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之乙腈-異丙醇(1:1)，流量：60 mL/min；共溶劑%：25%；ABPR：120巴；T：35℃。第一次溶析：391，第二次溶析：392。Preparation of the second palmar SFC: Column: Chiralpak IC (30 mm x 250 mm), 5 µm; Cosolvent: Acetonitrile-isopropanol (1:1) containing 0.2% (methanol containing 7N ammonia), flow rate: 60 mL/min; Cosolvent %: 25%; ABPR: 120 bar; T: 35 °C. First precipitation: 391 , Second precipitation: 392 .
391：分析型對掌性HPLC條件：對掌性SFC：管柱：CHIRALPAK IC (4.6 x 250 mm)，5 μm，移動相含0 .5%異丙胺之異丙醇；流量：4 mL/min；共溶劑%：40%；ABPR：1000 psi；T：35℃；Rt = 1.62 min。LC-MS: m/z [M-H]-= 464.11H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) 12.42 (s, 1H), 7.56-7.53 (m, 4H), 7.15-6.87 (m, 1H), 5.72 (s, 1H), 3.84 (s, 1H), 2.95 (s, 3H), 2.37 ( s, 3H), 2.28-2.21 (m, 1H), 2.10-2.07 (m, 2H), 1.87-1.84 (m, 2H), 1.33-1.20 (m, 4H)。392：分析型對掌性HPLC條件：對掌性SFC：管柱：CHIRALPAK IC (4.6 x 250 mm)，5 μm，移動相含0 .5%異丙胺之異丙醇；流量：4 mL/min；共溶劑%：40%；ABPR：1000 psi；T：35℃；Rt = 2.93 min。LC-MS: m/z [M+H]+= 466.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) 12.49 (s, 1H), 7.56 (s, 4H), 7.15-6.87 (m, 1H), 5.72 (s, 1H), 4.70 (s, 1H), 3.01 (s, 3H), 2.37 ( s, 3H), 2.32-2.23 (m, 1H), 2.10-2.07 (m, 2H), 1.87-1.84 (m, 2H), 1.33-1.17 (m, 4H)。393：分析型對掌性HPLC條件：對掌性SFC：管柱：(R, R) WHELK-O1 (4.6 mm x 150 mm)，3.5 μm，移動相含0 .5%異丙胺之異丙醇；流量：4 mL/min；共溶劑%：40%；ABPR：1450 psi；T：35℃；Rt = 1.67 min。LC-MS: m/z [M+H]+= 466.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) 12.42 (s, 1H), 7.57-7.55 (m, 4H), 7.15-6.87 (m, 1H), 5.71 (s, 1H), 3.83 (s, 1H), 2.95 (s, 3H), 2.36 ( s, 3H), 2.36-2.32 (m, 1H), 2.09-2.07 (m, 2H), 1.86-1.84 (m, 2H), 1.32-1.20 (m, 4H)。394：分析型對掌性HPLC條件：對掌性SFC：管柱：(R, R) WHELK-O1 (4.6 mm x 150 mm)，3.5 μm，移動相含0 .5%異丙胺之異丙醇；流量：4 mL/min；共溶劑%：40%；ABPR：1450 psi；T：35℃；Rt = 2.08 min。LC-MS: m/z [M+H]+= 466.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) 12.41 (s, 1H), 7.55 (s, 4H), 7.15-6.87 (m, 1H), 5.71 (s, 1H), 3.83 (s, 1H), 2.95 (s, 3H), 2.37 ( s, 3H), 2.36-2.32 (m, 1H), 2.09-2.07 (m, 2H), 1.86-1.84 (m, 2H), 1.32-1.20 (m, 4H)。 391 : Analytical palmar HPLC conditions: Palmar SFC: Column: CHIRALPAK IC (4.6 x 250 mm), 5 μm, mobile phase containing 0.5% isopropylamine in isopropanol; flow rate: 4 mL/min; cosolvent %: 40%; ABPR: 1000 psi; T: 35℃; Rt = 1.62 min. LC-MS: m/z [MH] - = 464.1 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) 12.42 (s, 1H), 7.56-7.53 (m, 4H), 7.15-6.87 (m, 1H), 5.72 (s, 1H), 3.84 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.28-2.21 (m, 1H), 2.10-2.07 (m, 2H), 1.87-1.84 (m, 2H), 1.33-1.20 (m, 4H). 392 : Analytical palmar HPLC conditions: Palmar SFC: Column: CHIRALPAK IC (4.6 x 250 mm), 5 μm; mobile phase: isopropanol containing 0.5% isopropylamine; flow rate: 4 mL/min; cosolvent %: 40%; ABPR: 1000 psi; T: 35℃; Rt = 2.93 min. LC-MS: m/z [M+H] + = 466.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) 12.49 (s, 1H), 7.56 (s, 4H), 7.15-6.87 (m, 1H), 5.72 (s, 1H), 4.70 (s, 1H), 3.01 (s, 3H), 2.37 (s, 3H), 2.32-2.23 (m, 1H), 2.10-2.07 (m, 2H), 1.87-1.84 (m, 2H), 1.33-1.17 (m, 4H). 393 : Analytical palmar HPLC conditions: Palmar SFC: Column: (R, R) WHELK-O1 (4.6 mm x 150 mm), 3.5 μm; mobile phase: isopropanol containing 0.5% isopropylamine; flow rate: 4 mL/min; cosolvent %: 40%; ABPR: 1450 psi; T: 35℃; Rt = 1.67 min. LC-MS: m/z [M+H] + = 466.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) 12.42 (s, 1H), 7.57-7.55 (m, 4H), 7.15-6.87 (m, 1H), 5.71 (s, 1H), 3.83 (s, 1H), 2.95 (s, 3H), 2.36 (s, 3H), 2.36-2.32 (m, 1H), 2.09-2.07 (m, 2H), 1.86-1.84 (m, 2H), 1.32-1.20 (m, 4H). 394 : Analytical palmar HPLC conditions: Palmar SFC: Column: (R, R) WHELK-O1 (4.6 mm x 150 mm), 3.5 μm; mobile phase: isopropanol containing 0.5% isopropylamine; flow rate: 4 mL/min; cosolvent %: 40%; ABPR: 1450 psi; T: 35℃; Rt = 2.08 min. LC-MS: m/z [M+H] + = 466.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) 12.41 (s, 1H), 7.55 (s, 4H), 7.15-6.87 (m, 1H), 5.71 (s, 1H), 3.83 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.36-2.32 (m, 1H), 2.09-2.07 (m, 2H), 1.86-1.84 (m, 2H), 1.32-1.20 (m, 4H).
實例 395-398(2-((3-氯-4-氟苯基)((3-(三氟甲基)雙環[1.1.1]戊-1-基)甲氧基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮、、、使用與針對實例355-358所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 395-398 (2-((3-chloro-4-fluorophenyl)((3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methoxy)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione , , , The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 355-358. Stereomeric derivatives were separated by palmar SFC.
製備型第一對掌性SFC：管柱：Chiralpak IC (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：110 mL/min；共溶劑%：35%；ABPR：120巴；T：35℃。第一次溶析：395及396之混合物，第二次溶析：397及398之混合物。Preparation of the first pair of palmar SFCs: Column: Chiralpak IC (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 110 mL/min; Cosolvent %: 35%; ABPR: 120 bar; T: 35 °C. First dissolution: mixture of 395 and 396 ; Second dissolution: mixture of 397 and 398 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：70 mL/min；共溶劑%：35%；ABPR：100巴；T：35℃。第一次溶析：395 ，第二次溶析：396。Preparation of the second pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 35%; ABPR: 100 bar; T: 35 °C. First precipitation: 395 , Second precipitation: 396 .
製備型第三對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之甲醇，流量：100 mL/min；共溶劑%：25%；ABPR：100巴；T：35℃。第一次溶析：397 ，第二次溶析：398。Preparation of a third-phase palmar SFC: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Methanol containing 0.2% (7N ammonia), flow rate: 100 mL/min; Cosolvent %: 25%; ABPR: 100 bar; T: 35 °C. First precipitation: 397 , Second precipitation: 398 .
395：LC-MS: m/z [M-H+= 466.21H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) 12.44 (bs, 1H), 7.63 (d, J = 3.77 Hz, 1H), 7.41 (t, J = 8.88 Hz, 2H), 5.52 (s, 1H), 3.86 (s, 1H), 3.49-3.48 (m, 2H), 2.95 (s, 3H), 2.38 (s, 3H), 1.92 (s, 6H)。396：LC-MS: m/z [M-H]+= 466.21H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) 12.44 (bs, 1H), 7.64-7.62 (m, 1H), 7.43-7.39 (m, 2H), 5.52 (s, 1H), 3.86 (s, 1H), 3.52-3.45 (m, 2H), 2.95 (s, 3H), 2.38 (s, 3H), 1.92 (s, 6H)。397：LC-MS: m/z [M-H]+= 466.21H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) 12.44 (bs, 1H), 7.64 (d, J = 6.84 Hz, 1H), 7.46-7.42 (m, 2H), 5.52 (s, 1H), 3.86 (s, 1H), 3.49-3.47 (m, 2H), 2.95 (s, 3H), 2.38 (s, 3H), 1.93 (s, 6H)。398：LC-MS: m/z [M-H]+= 466.21H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) 12.44 (bs, 1H), 7.63 (d, J = 7.16 Hz, 1H), 7.44-7.40 (m, 2H), 5.52 (s, 1H), 3.88 (s, 1H), 3.52-3.45 (m, 2H), 2.96 (s, 3H), 2.38 (s, 3H), 1.92 (s, 6H)。 395 : LC-MS: m/z [MH + = 466.2 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) 12.44 (bs, 1H), 7.63 (d, J = 3.77 Hz, 1H), 7.41 (t, J = 8.88 Hz, 2H), 5.52 (s, 1H), 3.86 (s, 1H), 3.49-3.48 (m, 2H), 2.95 (s, 3H), 2.38 (s, 3H), 1.92 (s, 6H). 396 : LC-MS: m/z [MH] + = 466.2 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) 12.44 (bs, 1H), 7.64-7.62 (m, 1H), 7.43-7.39 (m, 2H), 5.52 (s, 1H), 3.86 (s, 1H), 3.52-3.45 (m, 2H), 2.95 (s, 3H), 2.38 (s, 3H), 1.92 (s, 6H). 397 : LC-MS: m/z [MH] + = 466.2 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) 12.44 (bs, 1H), 7.64 (d, J = 6.84 Hz, 1H), 7.46-7.42 (m, 2H), 5.52 (s, 1H), 3.86 (s, 1H), 3.49-3.47 (m, 2H), 2.95 (s, 3H), 2.38 (s, 3H), 1.93 (s, 6H). 398 : LC-MS: m/z [MH] + = 466.2 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) 12.44 (bs, 1H), 7.63 (d, J = 7.16 Hz, 1H), 7.44-7.40 (m, 2H), 5.52 (s, 1H), 3.88 (s, 1H), 3.52-3.45 (m, 2H), 2.96 (s, 3H), 2.38 (s, 3H), 1.92 (s, 6H).
實例 399-402使用與針對實例395所述類似之方法，由適當的中間物及試劑製備標題化合物。
實例 403-406(2-((4-氯-3-氟苯基)((5-氯吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及 Examples 403-406 (2-((4-chloro-3-fluorophenyl)((5-chloropyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and
步驟1：在環境溫度下向二異丙基胺基甲酸(4-氯-3-氟苯基)(4-碘-5-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯中間物22 (1.5 g，2.404 mmol)及5-氯吡啶-2-胺(0.464 g，3.606 mmol)於THF (30 mL)中之攪拌溶液中添加三氟化硼乙醚(0.45mL, 1.5 mmol)及三氟乙酸(0.8 mL，10 mmol)。將所得反應混合物加熱至80℃持續1 h。用乙酸乙酯(100 mL)稀釋反應混合物且用NaHCO3水溶液(2×100 mL)洗滌。經無水硫酸鈉乾燥合併之有機層且在減壓下濃縮。藉由管柱層析(SiO2，15% EtOAc/PE)純化殘餘物，得到5-氯-N-((4-氯-3-氟苯基)(4-碘-5-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲基)吡啶-2-胺(1.0 g，68%)。Step 1: At ambient temperature, add boron trifluoride diethyl ether (0.45 mL, 1.5 mmol) and trifluoroacetic acid (0.8 mL, 10 mmol) to a stirred solution of diisopropylaminocarboxylic acid (4-chloro-3-fluorophenyl)(4-iodo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl) methyl ester intermediate 22 (1.5 g, 2.404 mmol) and 5-chloropyridin-2-amine (0.464 g, 3.606 mmol) in THF (30 mL). Heat the resulting reaction mixture to 80 °C for 1 h. Dilute the reaction mixture with ethyl acetate (100 mL) and wash with NaHCO3 aqueous solution (2 × 100 mL). The combined organic layers were dried in anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography ( SiO2 , 15% EtOAc/PE) to give 5-chloro-N-((4-chloro-3-fluorophenyl)(4-iodo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl)pyridine-2-amine (1.0 g, 68%).
步驟2：在環境溫度下向5-氯-N-((4-氯-3-氟苯基)(5-碘-4-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲基)吡啶-2-胺(1.5 g，2.470 mmol)於1,4-二噁烷(30 mL)中之連續氬氣吹掃溶液中添加碳酸銫(2.4 g，7.4 mmol)、甲硫醇鈉(0.260 g，3.705 mmol)、Xantphos (0.214 g，0.370 mmol)及Pd2(dba)3(0.226 g，0.247 mmol)。將所得反應混合物在120℃下攪拌18 h。經由矽藻土墊過濾反應混合物且在減壓下濃縮。藉由急驟管柱層析純化所得粗產物，得到5-氯-N-((4-氯-3-氟苯基)(4-甲基-5-(甲硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲基)吡啶-2-胺(0.65 g，50%)。Step 2: At ambient temperature, cesium carbonate (2.4 g, 7.4 mmol), sodium methanethiol (0.260 g, 3.705 mmol), Xantphos (0.214 g, 0.370 mmol), and Pd₂(dba)₃ (0.226 g, 0.247 mmol) were added to a continuously purged argon solution of 5-chloro-N-((4-chloro-3-fluorophenyl)(5-iodo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl)pyridin- 2 - amine (1.5 g, 2.470 mmol) in 1,4-dioxane (30 mL). The resulting reaction mixture was stirred at 120 °C for 18 h. The reaction mixture was filtered through a diatomaceous earth mat and concentrated under reduced pressure. The crude product was purified by rapid column chromatography to give 5-chloro-N-((4-chloro-3-fluorophenyl)(4-methyl-5-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl)pyridine-2-amine (0.65 g, 50%).
步驟3 ： 在環境溫度下向5-氯-N-((4-氯-3-氟苯基)(4-甲基-5-(甲硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲基)吡啶-2-胺(0.6 g，1.137 mmol)於MeOH (15 mL)中之攪拌溶液中添加(二乙醯氧基碘)苯(1.1 g，3.4 mmol)及碳酸銨(0.536 g，3.4 mmol)。將反應混合物在環境溫度下攪拌2 h。在減壓下濃縮反應混合物，得到(2-((4-氯-3-氟苯基)((5-氯吡啶-2-基)胺基)甲基)-4-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-5-基)(亞胺基)(甲基)-l6-硫酮(0.8 g，粗物質)。Step 3 : Add (diethoxyiodide)benzene (1.1 g, 3.4 mmol) and ammonium carbonate (0.536 g, 3.4 mmol) to a stirred solution of 5-chloro-N-((4-chloro-3-fluorophenyl)(4-methyl-5-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl)pyridin-2-amine (0.6 g, 1.137 mmol) in MeOH (15 mL) at ambient temperature. Stir the reaction mixture at ambient temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give (2-((4-chloro-3-fluorophenyl)((5-chloropyridin-2-yl)amino)methyl)-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)(imino)(methyl)-16-thione (0.8 g, crude material).
步驟4：在環境溫度下將(2-((4-氯-3-氟苯基)((5-氯吡啶-2-基)胺基)甲基)-4-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-5-基)(亞胺基)(甲基)-l6-硫酮(0.8 g，1.432 mmol)溶解於鹽酸(1,4-二噁烷中之4N溶液，10 mL)中且將混合物攪拌18 h。在減壓下濃縮反應混合物，獲得粗產物，相繼藉由製備型HPLC及對掌性SFC純化，得到標題化合物。Step 4: (2-((4-chloro-3-fluorophenyl)((5-chloropyridin-2-yl)amino)methyl)-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)(imino)(methyl)-16-thione (0.8 g, 1.432 mmol) was dissolved in hydrochloric acid (10 mL of 4N solution in 1,4-dioxane) at ambient temperature, and the mixture was stirred for 18 h. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was subsequently purified by preparative HPLC and palmar SFC to obtain the title compound.
分析型對掌性SFC：管柱：Chiralpak AD-H (4.6 x 250 mm) 5 μm；共溶劑：含0.5% (含7N NH3之甲醇)之iPrOH，流量：3 mL/min；共溶劑%：25%；ABPR：1500 psi T：30℃；403：Rt = 3.47 min (第一次溶析)；404：Rt = 3.66 min (第二次溶析)；405：Rt = 5.07 min (第三次溶析)；406：Rt = 7.80 min (第四次溶析)。Analytical diaphragmatic SFC: Column: Chiralpak AD-H (4.6 x 250 mm) 5 μm; Cosolvent: iPrOH containing 0.5% (methanol containing 7N NH3), flow rate: 3 mL/min; Cosolvent %: 25%; ABPR: 1500 psi; T: 30℃; 403 : Rt = 3.47 min (first precipitation); 404 : Rt = 3.66 min (second precipitation); 405 : Rt = 5.07 min (third precipitation); 406 : Rt = 7.80 min (fourth precipitation).
403：產率：29 mg，5%；LCMS m/z = 427 [M+H]+；1H-NMR (400 MHz, DMSO-d6): 12.50 (s, 1H), 7.95 (d, 1H), 7.78 (d, 1H), 7.57-7.48 (m, 2H), 7.43 (dd, 1H), 7.26 (dd, 1H), 6.77 (d, 1H), 6.27 (d, 1H), 3.82 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H)。404：產量：26 mg；LCMS m/z = 427 [M+H]+；1H-NMR (400 MHz, DMSO-d6): 12.51 (s, 1H), 7.95 (d, 1H), 7.78 (d, 1H), 7.57-7.48 (m, 2H), 7.43 (dd, 1H), 7.26 (dd, 1H),), 6.77 (d, 1H), 6.27 (d, 1H), 3.83 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H)。405：產量：31 mg；LCMS m/z = 427 [M+H]+；1H-NMR (400 MHz, DMSO-d6): 12.51 (s, 1H), 7.95 (d, 1H), 7.78 (d, 1H), 7.57-7.48 (m, 2H), 7.43 (dd, 1H), 7.26 (dd, 1H), 6.77 (d, 1H), 6.27 (d, 1H), 3.82 (s, 1H), 2.95 (s, 3H), 2.36 (s, 3H)。406：產量：31 mg；LCMS m/z = 427 [M+H]+；1H-NMR (400 MHz, DMSO-d6): 12.50 (s, 1H), 7.95 (d, 1H), 7.78 (d, 1H), 7.57-7.49 (m, 2H), 7.43 (dd, 1H), 7.26 (dd, 1H), 6.77 (d, 1H), 6.27 (d, 1H), 3.84 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H) 403 : Yield: 29 mg, 5%; LCMS m/z = 427 [M+H] + ; 1 H-NMR (400 MHz, DMSO-d 6 ): 12.50 (s, 1H), 7.95 (d, 1H), 7.78 (d, 1H), 7.57-7.48 (m, 2H), 7.43 (dd, 1H), 7.26 (dd, 1H), 6.77 (d, 1H), 6.27 (d, 1H), 3.82 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H). 404 : Yield: 26 mg; LCMS m/z = 427 [M+H] + ; 1 H-NMR (400 MHz, DMSO-d 6 ): 12.51 (s, 1H), 7.95 (d, 1H), 7.78 (d, 1H), 7.57-7.48 (m, 2H), 7.43 (dd, 1H), 7.26 (dd, 1H),), 6.77 (d, 1H), 6.27 (d, 1H), 3.83 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H). 405 : Yield: 31 mg; LCMS m/z = 427 [M+H] + ; 1 H-NMR (400 MHz, DMSO-d 6 ): 12.51 (s, 1H), 7.95 (d, 1H), 7.78 (d, 1H), 7.57-7.48 (m, 2H), 7.43 (dd, 1H), 7.26 (dd, 1H), 6.77 (d, 1H), 6.27 (d, 1H), 3.82 (s, 1H), 2.95 (s, 3H), 2.36 (s, 3H). 406 : Yield: 31 mg; LCMS m/z = 427 [M+H] + ; 1 H-NMR (400 MHz, DMSO-d 6 ): 12.50 (s, 1H), 7.95 (d, 1H), 7.78 (d, 1H), 7.57-7.49 (m, 2H), 7.43 (dd, 1H), 7.26 (dd, 1H), 6.77 (d, 1H), 6.27 (d, 1H), 3.84 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H)
實例 407-466使用與針對實例403-406所述類似之方法，由適當的中間物及試劑製備標題化合物。
實例 467-470(2-((3-氯-4-氟苯基)((5-氯-6-甲基吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及向中間物20 (350 mg，0.6 mmol，1.0 equiv.)於DCM (5 mL)中之溶液中添加5-氯-6-甲基吡啶-2-胺(173 mg，1.21 mmol，2 equiv.)、BF3-OEt2(0.15 mL，1.21 mmol，2 equiv.)及TFA (0.28 mL，3.64 mmol，6 equiv.)且在RT下攪拌2 h。用冰冷水(50 mL)稀釋反應混合物且用二氯甲 烷(2 × 50 mL)萃取。用碳酸氫鈉溶液(100 ml)、鹽水(100 mL)洗滌合併之有機層，經無水Na2SO4乾燥，過濾且在減壓下濃縮，得到粗產物，藉由逆相製備型HPLC純化，得到粗產物，藉由RP製備型HPLC純化。藉由對掌性SFC分離立體異構物。 Examples 467-470 (2-((3-chloro-4-fluorophenyl)((5-chloro-6-methylpyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and Add 5-chloro-6-methylpyridin-2-amine (173 mg, 1.21 mmol, 2 equiv.), BF3 -OEt2 (0.15 mL, 1.21 mmol, 2 equiv.), and TFA (0.28 mL, 3.64 mmol, 6 equiv.) to a solution of intermediate 20 (350 mg, 0.6 mmol, 1.0 equiv.) in DCM (5 mL) and stir at RT for 2 h. Dilute the reaction mixture with ice-cold water (50 mL) and extract with dichloromethane (2 × 50 mL). The combined organic layer was washed with sodium bicarbonate solution (100 mL) and brine (100 mL), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a crude product. This crude product was purified by reverse-phase preparative HPLC, followed by RP preparative HPLC purification. Stereomers were then separated by palmar SFC.
製備型第一對掌性SFC：管柱：Chiralpak IC (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：100 mL/min；共溶劑%：35%；ABPR：100巴；T：35℃。第一次溶析：467及468之混合物，第二次溶析：469，第三次溶析：470。Preparation of the first pair of palmar SFCs: Column: Chiralpak IC (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 100 mL/min; Cosolvent %: 35%; ABPR: 100 bar; T: 35 °C. First dissolution: a mixture of 467 and 468 , second dissolution: 469 , third dissolution: 470 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm )，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：90 mL/min；共溶劑%：40%；ABPR：100巴；T：35℃。第一次溶析：467 ，第二次溶析：468。Preparation of the second pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 90 mL/min; Cosolvent %: 40%; ABPR: 100 bar; T: 35 °C. First precipitation: 467 , Second precipitation: 468 .
467：產率：2%。LC-MS: m/z [M+H]+= 442.11H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (s, 1H), 7.64-7.61 (m, 2H), 7.42-7.35 (m, 3H), 6.57 (d, J = 8.72 Hz, 1H), 6.27 (d, J = 8.0 Hz, 1H), 3.84 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.29 (s, 3H)。468：產率：2%。LC-MS: m/z [M+H]+= 442.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.34 (br s, 1H), 7.64-7.61 (m, 2H), 7.42-7.35 (m, 3H), 6.57 (d, J = 8.8 Hz, 1H), 6.27 (d, J = 9.0 Hz, 1H), 3.84 (s, 1H), 2.92 (s, 3H), 2.36 (s, 3H), 2.29 (s, 3H)。469：產率：5%。LC-MS: m/z [M+H]+= 442.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm12.47 (s, 1H), 7.65-7.61 (m, 2H), 7.42-7.35 (m, 3H), 6.57 (d, J = 8.72 Hz, 1H), 6.27 (d, J = 7.76 Hz, 1H), 3.84 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.30 (s, 3H)。470：產率：5%。LC-MS: m/z [M+H]+= 442.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (s, 1H), 7.64-7.61 (m, 2H), 7.42-7.35 (m, 3H), 6.57 (d, J = 8.76 Hz, 1H), 6.27 (d, J = 8.04 Hz, 1H), 3.84 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.30 (s, 3H)。 467 : Yield: 2%. LC-MS: m/z [M+H] + = 442.1 1H -NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) = 12.46 (s, 1H), 7.64-7.61 (m, 2H), 7.42-7.35 (m, 3H), 6.57 (d, J = 8.72 Hz, 1H), 6.27 (d, J = 8.0 Hz, 1H), 3.84 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.29 (s, 3H). 468 : Yield: 2%. LC-MS: m/z [M+H] + = 442.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.34 (br s, 1H), 7.64-7.61 (m, 2H), 7.42-7.35 (m, 3H), 6.57 (d, J = 8.8 Hz, 1H), 6.27 (d, J = 9.0 Hz, 1H), 3.84 (s, 1H), 2.92 (s, 3H), 2.36 (s, 3H), 2.29 (s, 3H). 469 : Yield: 5%. LC-MS: m/z [M+H] + = 442.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm12.47 (s, 1H), 7.65-7.61 (m, 2H), 7.42-7.35 (m, 3H), 6.57 (d, J = 8.72 Hz, 1H), 6.27 (d, J = 7.76 Hz, 1H), 3.84 (s, 1H), 2.37 (s, 3H), 2.30 (s, 3H). 470 : Yield: 5%. LC -MS: m/z [M+H] + = 442.1. δ (ppm)= 12.46 (s, 1H), 7.64-7.61 (m, 2H), 7.42-7.35 (m, 3H), 6.57 (d, J = 8.76 Hz, 1H), 6.27 (d, J = 8.04 Hz, 1H), 3.84 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.30 (s, 3H).
實例 417-474(2-((3-氯-4-氟苯基)((4-(三氟甲基)噻唑-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 417-474 (2-((3-chloro-4-fluorophenyl)((4-(trifluoromethyl)thiazolyl-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Stereomeric derivatives were separated by palmar SFC.
製備型對掌性SFC：管柱：CHIRALPAK IC (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之MeOH)之異丙醇，流量：100 mL/min；共溶劑%：15%；ABPR：100巴；T：35℃。Preparation of palmar SFC: Column: CHIRALPAK IC (30 mm x 250 mm), 5µm; Cosolvent: Isopropanol containing 0.2% (MeOH containing 7N ammonia), flow rate: 100 mL/min; Cosolvent %: 15%; ABPR: 100 bar; T: 35℃.
471：5% (第一次溶析)。LC-MS: m/z [M+H]+= 468.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.57 (s, 1H), 9.13 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.43-7.41 (m, 3H), 6.11 (d, J = 7.2 Hz, 1H) 3.87 (s, 1 H), 2.96 (s, 3H), 2.37 (s, 3H)。472：4% (第二次溶析)。LC-MS: m/z [M+H]+= 468.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.59 (s, 1H), 9.11(s, 1H), 7.66-7.64 (m, 3H), 7.43-7.39(m, 3H), 6.10 (bs, 1 H), 3.89 (s, 1 H), 2.96 (s, 3 H), 2.37 (s, 3H)。473：4% (第三次溶析)。LC-MS: m/z [M+H]+= 468.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.60 (s, 1H), 9.13 (d, J = 6.4 Hz, 1H), 7.66-7.64 (m, 1H), 7.43-7.41 (m, 3H), 6.11 (bs, 1H) 3.88 (s, 1 H), 2.96 (s, 3H), 2.37 (s, 3H)。474：7% (第四次溶析)。LC-MS: m/z [M+H]+= 468.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.57 (s, 1H), 9.12 (s, 1H), 7.65 (d, J = 7.2 Hz, 1H), 7.43-7.41 (m, 3H), 6.10 (bs, 1H) 3.88 (s, 1 H), 2.96 (s, 3H), 2.37 (s, 3H)。 471 : 5% (first precipitation). LC-MS: m/z [M+H] + = 468.2. 1H -NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) = 12.57 (s, 1H), 9.13 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.43-7.41 (m, 3H), 6.11 (d, J = 7.2 Hz, 1H), 3.87 (s, 1H), 2.96 (s, 3H), 2.37 (s, 3H). 472 : 4% (second precipitation). LC-MS: m/z [M+H] + = 468.2. ¹H -NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) = 12.59 (s, 1H), 9.11 (s, 1H), 7.66–7.64 (m, 3H), 7.43–7.39 (m, 3H), 6.10 (bs, 1H), 3.89 (s, 1H), 2.96 (s, 3H), 2.37 (s, 3H). 473 : 4% (third precipitation). LC-MS: m/z [M+H] + = 468.2. ¹H -NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) = 12.60 (s, 1H), 9.13 (d, J = 6.4 Hz, 1H), 7.66–7.64 (m, 1H), 7.43–7.41 (m, 3H), 6.11 (bs, 1H), 3.88 (s, 1H), 2.96 (s, 3H), 2.37 (s, 3H). 474 : 7% (fourth precipitation). LC-MS: m/z [M+H] + = 468.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.57 (s, 1H), 9.12 (s, 1H), 7.65 (d, J = 7.2 Hz, 1H), 7.43-7.41 (m, 3H), 6.10 (bs, 1H) 3.88 (s, 1 H), 2.96 (s, 3H), 2.37 (s, 3H).
實例 475-478(2-((3-氯-4-氟苯基)((5-(二氟甲氧基)-6-甲基吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮、、、使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 475-478 (2-((3-chloro-4-fluorophenyl)((5-(difluoromethoxy)-6-methylpyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione , , , The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Stereomeric derivatives were separated by palmar SFC.
製備型第一對掌性SFC：管柱：管柱：Chiralpak IC (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：120 mL/min；共溶劑%：30%；ABPR：120巴；T：35℃。第一次溶析：475及476之混合物，第二次溶析：477，第三次溶析：478。Preparation of the first pair of palmar SFCs: Column: Chiralpak IC (30 mm x 250 mm), 5µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 120 mL/min; Cosolvent %: 30%; ABPR: 120 bar; T: 35℃. First dissolution: a mixture of 475 and 476 , second dissolution: 477 , third dissolution: 478 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之甲醇，流量：120 mL/min；共溶劑%：25%；ABPR：120巴；T：35℃。第一次溶析：475 ，第二次溶析：476。Preparation of the second pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Methanol containing 0.2% (7N ammonia), flow rate: 120 mL/min; Cosolvent %: 25%; ABPR: 120 bar; T: 35 °C. First precipitation: 475 ° C , Second precipitation: 476 ° C.
475：4%。LC-MS: m/z [M+H]+= 474.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (s, 1H), 7.65-7.63 (m, 1H), 7.52 (d, J = 8.16 Hz, 1H), 7.42-7.35 (m, 2H), 7.26 (d, J = 8.8 Hz, 1H), 7.11-6.74 (m, 1H), 6.55 (d, J = 8.8 Hz, 1H), 6.27 (d, J = 8.04 Hz, 1H), 3.83 (s, 1 H), 2.95 (s, 3H), 2.36 (s, 3H), 2.20 (s, 3H)。476：4%。LC-MS: m/z [M+H]+= 474.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (s, 1H), 7.65-7.63 (m, 1H), 7.52 (d, J = 8.16 Hz, 1H), 7.42-7.35 (m, 2H), 7.26 (d, J = 8.8 Hz, 1H), 7.11-6.74 (m, 1H), 6.55 (d, J = 8.8 Hz, 1H), 6.27 (d, J = 8.04 Hz, 1H), 3.83 (s, 1 H), 2.95 (s, 3H), 2.36 (s, 3H), 2.20 (s, 3H)。477：4%。LC-MS: m/z [M+H]+= 474.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (s, 1H), 7.65 (d, J = 6.76 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.42-7.35 (m, 2H), 7.26 (d, J = 8.72 Hz, 1H), 7.12-6.74 (m, 1H), 6.55 (d, J = 8.8 Hz, 1H), 6.27 (d, J = 8.04 Hz, 1H), 3.83 (s, 1 H), 2.95 (s, 3H), 2.36 (s, 3H), 2.21 (s, 3H)。488：5%。LC-MS: m/z [M+H]+= 474.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (s, 1H), 7.65 (d, J = 6.88 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.42-7.37 (m, 2H), 7.26 (d, J = 8.72 Hz, 1H), 7.12-6.74 (m, 1H), 6.55 (d, J = 8.8 Hz, 1H), 6.27 (d, J = 8.04 Hz, 1H), 3.83 (s, 1 H), 2.95 (s, 3H), 2.36 (s, 3H), 2.21 (s, 3H)。 475 : 4%. LC-MS: m/z [M+H] + = 474.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (s, 1H), 7.65-7.63 (m, 1H), 7.52 (d, J = 8.16 Hz, 1H), 7.42-7.35 (m, 2H), 7.26 (d, J = 8.8 Hz, 1H), 7.11-6.74 (m, 1H), 6.55 (d, J = 8.8 Hz, 1H), 6.27 (d, J = 8.04 Hz, 1H), 3.83 (s, 1 H), 2.95 (s, 3H), 2.36 (s, 3H), 2.20 (s, 3H). 476 : 4%. LC-MS: m/z [M+H] + = 474.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (s, 1H), 7.65-7.63 (m, 1H), 7.52 (d, J = 8.16 Hz, 1H), 7.42-7.35 (m, 2H), 7.26 (d, J = 8.8 Hz, 1H), 7.11-6.74 (m, 1H), 6.55 (d, J = 8.8 Hz, 1H), 6.27 (d, J = 8.04 Hz, 1H), 3.83 (s, 1 H), 2.95 (s, 3H), 2.36 (s, 3H), 2.20 (s, 3H). 477 : 4%. LC-MS: m/z [M+H] + = 474.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (s, 1H), 7.65 (d, J = 6.76 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.42-7.35 (m, 2H), 7.26 (d, J = 8.72 Hz, 1H), 7.12-6.74 (m, 1H), 6.55 (d, J = 8.8 Hz, 1H), 6.27 (d, J = 8.04 Hz, 1H), 3.83 (s, 1 H), 2.95 (s, 3H), 2.36 (s, 3H), 2.21 (s, 3H). 488 : 5%. LC-MS: m/z [M+H] + = 474.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (s, 1H), 7.65 (d, J = 6.88 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.42-7.37 (m, 2H), 7.26 (d, J = 8.72 Hz, 1H), 7.12-6.74 (m, 1H), 6.55 (d, J = 8.8 Hz, 1H), 6.27 (d, J = 8.04 Hz, 1H), 3.83 (s, 1 H), 2.95 (s, 3H), 2.36 (s, 3H), 2.21 (s, 3H).
實例 479-482(2-((3-氯-4-氟苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 479-482 (2-((3-chloro-4-fluorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Stereomeric derivatives were separated by palmar SFC.
製備型第一對掌性SFC：管柱：管柱：Chiralpak IC (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：100 mL/min；共溶劑%：35%；ABPR：120巴；T：35℃。第一次溶析：479及480之混合物，第二次溶析：481，第三次溶析：482。Preparation of the first pair of palmar SFCs: Column: Chiralpak IC (30 mm x 250 mm), 5µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 100 mL/min; Cosolvent %: 35%; ABPR: 120 bar; T: 35℃. First dissolution: a mixture of 479 and 480 , second dissolution: 481 , third dissolution: 482 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：異丙醇，流量：90 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：479 ，第二次溶析：480。Preparation of second-pair palmar SFC: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: isopropanol, flow rate: 90 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First precipitation: 479 , Second precipitation: 480 .
479：8%。LC-MS: m/z [M+H]+= 426.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.45 (s, 1H), 7.65-7.63 (m, 1H), 7.42-7.34 (m, 3H), 7.32-7.27 (m, 1H), 6.55-6.52 (m, 1H), 6.24-6.22 (m, 1H), 3.82 (s, 1 H), 2.95 (s, 3H), 2.36 (s, 3H), 2.21-2.20 (m, 3H)。480：6%。LC-MS: m/z [M+H]+= 426.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.45 (s, 1H), 7.65-7.63 (m, 1H), 7.42-7.27 (m, 4H), 6.55-6.52 (m, 1H), 6.23-6.21 (m, 1H), 3.82 (s, 1 H), 2.95 (s, 3H), 2.36 (s, 3H), 2.21-2.20 (m, 3H)。481：5%。LC-MS: m/z [M+H]+= 426.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.45 (s, 1H), 7.65-7.63 (m, 1H), 7.42-7.27 (m, 4H), 6.55-6.52 (m, 1H), 6.23-6.21 (m, 1H), 3.84 (s, 1 H), 2.95 (s, 3H), 2.36 (s, 3H), 2.21-2.20 (m, 3H)。482：8%。LC-MS: m/z [M+H]+= 426.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.45 (s, 1H), 7.65-7.63 (m, 1H), 7.42-7.27 (m, 4H), 6.55-6.52 (m, 1H), 6.23-6.21 (m, 1H), 3.83 (s, 1 H), 2.95 (s, 3H), 2.36 (s, 3H), 2.21-2.20 (m, 3H)。 479 : 8%. LC-MS: m/z [M+H] + = 426.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.45 (s, 1H), 7.65-7.63 (m, 1H), 7.42-7.34 (m, 3H), 7.32-7.27 (m, 1H), 6.55-6.52 (m, 1H), 6.24-6.22 (m, 1H), 3.82 (s, 1H), 2.95 (s, 3H), 2.36 (s, 3H), 2.21-2.20 (m, 3H). 480 : 6%. LC-MS: m/z [M+H] + = 426.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.45 (s, 1H), 7.65-7.63 (m, 1H), 7.42-7.27 (m, 4H), 6.55-6.52 (m, 1H), 6.23-6.21 (m, 1H), 3.82 (s, 1H), 2.95 (s, 3H), 2.36 (s, 3H), 2.21-2.20 (m, 3H). 481 : 5%. LC-MS: m/z [M+H] + = 426.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.45 (s, 1H), 7.65-7.63 (m, 1H), 7.42-7.27 (m, 4H), 6.55-6.52 (m, 1H), 6.23-6.21 (m, 1H), 3.84 (s, 1H), 2.95 (s, 3H), 2.36 (s, 3H), 2.21-2.20 (m, 3H). 482 : 8%. LC-MS: m/z [M+H] + = 426.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.45 (s, 1H), 7.65-7.63 (m, 1H), 7.42-7.27 (m, 4H), 6.55-6.52 (m, 1H), 6.23-6.21 (m, 1H), 3.83 (s, 1H), 2.95 (s, 3H), 2.36 (s, 3H), 2.21-2.20 (m, 3H).
實例 483-4865-氯-N-[(3-氯-4-氟苯基)-[5-甲基-4-(甲基亞磺醯亞胺基)-1H-咪唑-2-基]甲基]-6-(二氟甲基)吡啶-2-胺及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 483-486: 5-Chloro-N-[(3-Chloro-4-fluorophenyl)-[5-methyl-4-(methylsulfinimino)-1H-imidazol-2-yl]methyl]-6-(difluoromethyl)pyridine-2-amine and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Stereomeric derivatives were separated by palmar SFC.
製備型第一對掌性SFC：管柱：管柱：Chiralpak IC (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：120 mL/min；共溶劑%：30%；ABPR：120巴；T：35℃。第一次溶析：483及484之混合物，第二次溶析：485及486之混合物。Preparation of the first pair of palmar SFCs: Column: Chiralpak IC (30 mm x 250 mm), 5µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 120 mL/min; Cosolvent %: 30%; ABPR: 120 bar; T: 35℃. First dissolution: a mixture of 483 and 484 ; Second dissolution: a mixture of 485 and 486 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：異丙醇，流量：120 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：483 ，第二次溶析：484。Preparation of second palmar SFC: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: isopropanol, flow rate: 120 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First dissolution: 483 , Second dissolution: 484 .
製備型第三對掌性SFC：管柱：I-Cellulose-Z (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之乙腈-異丙醇(1:1)，流量：110 mL/min；共溶劑%：25%；ABPR：100巴；T：35℃。第一次溶析：485 ，第二次溶析：486。Preparation of the third palmar SFC: Column: I-Cellulose-Z (30 mm x 250 mm), 5 µm; Cosolvent: Acetonitrile-isopropanol (1:1) containing 0.2% (methanol containing 7N ammonia), flow rate: 110 mL/min; Cosolvent %: 25%; ABPR: 100 bar; T: 35 °C. First precipitation: 485 , Second precipitation: 486 .
483：LC-MS: m/z [M+H]+= 478.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.51 (s, 1H), 8.12-8.10 (d, j= 8.0 Hz, 1H), 7.67-7.61 (m, 2H), 7.43-7.36 (m, 2H), 7.04-6.78 (m, 2H), 6.27-6.22 (m, 2H), 3.86 (s, 1H), 2.96 (s, 3H), 2.32 (s, 3H)。484：LC-MS: m/z [M+H]+= 478.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.51 (s, 1H), 8.12-8.10 (d, j= 8.0 Hz, 1H), 7.67-7.61 (m, 2H), 7.43-7.36 (m, 2H), 7.04-6.78 (m, 2H), 6.27-6.22 (m, 2H), 3.86 (s, 1H), 2.96 (s, 3H), 2.32 (s, 3H)。485：LC-MS: m/z [M+H]+= 478.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.51 (s, 1H), 8.12-8.10 (d, j= 8.0 Hz, 1H), 7.67-7.61 (m, 2H), 7.43-7.36 (m, 2H), 7.04-6.78 (m, 2H), 6.27-6.22 (m, 2H), 3.86 (s, 1H), 2.96 (s, 3H), 2.32 (s, 3H)。486：LC-MS: m/z [M+H]+= 478.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.51 (s, 1H), 8.12-8.10 (d, j= 8.0 Hz, 1H), 7.67-7.61 (m, 2H), 7.43-7.36 (m, 2H), 7.04-6.78 (m, 2H), 6.27-6.22 (m, 2H), 3.86 (s, 1H), 2.96 (s, 3H), 2.32 (s, 3H)。 483 : LC-MS: m/z [M+H] + = 478.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.51 (s, 1H), 8.12-8.10 (d, j= 8.0 Hz, 1H), 7.67-7.61 (m, 2H), 7.43-7.36 (m, 2H), 7.04-6.78 (m, 2H), 6.27-6.22 (m, 2H), 3.86 (s, 1H), 2.96 (s, 3H), 2.32 (s, 3H). 484 : LC-MS: m/z [M+H] + = 478.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.51 (s, 1H), 8.12-8.10 (d, j= 8.0 Hz, 1H), 7.67-7.61 (m, 2H), 7.43-7.36 (m, 2H), 7.04-6.78 (m, 2H), 6.27-6.22 (m, 2H), 3.86 (s, 1H), 2.96 (s, 3H), 2.32 (s, 3H). 485 : LC-MS: m/z [M+H] + = 478.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.51 (s, 1H), 8.12-8.10 (d, j= 8.0 Hz, 1H), 7.67-7.61 (m, 2H), 7.43-7.36 (m, 2H), 7.04-6.78 (m, 2H), 6.27-6.22 (m, 2H), 3.86 (s, 1H), 2.96 (s, 3H), 2.32 (s, 3H). 486 : LC-MS: m/z [M+H] + = 478.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.51 (s, 1H), 8.12-8.10 (d, j= 8.0 Hz, 1H), 7.67-7.61 (m, 2H), 7.43-7.36 (m, 2H), 7.04-6.78 (m, 2H), 6.27-6.22 (m, 2H), 3.86 (s, 1H), 2.96 (s, 3H), 2.32 (s, 3H).
實例 487-490(2-((3-氯苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 487-490 (2-((3-chlorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Stereomeric derivatives were separated by palmar SFC.
製備型第一對掌性SFC：管柱：管柱：Chiralpak IC (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：100 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：487及488之混合物，第二次溶析：489，第三次溶析：490。Preparation of the first pair of palmar SFCs: Column: Chiralpak IC (30 mm x 250 mm), 5µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 100 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35℃. First dissolution: a mixture of 487 and 488 , second dissolution: 489 , third dissolution: 490 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm )，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：100 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：487 ，第二次溶析：488。Preparation of the second pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 100 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First precipitation: 487 , Second precipitation: 488 .
487：分析型對掌性HPLC條件：對掌性SFC：管柱：(R,R)-Whelk-O-1 (4.6 x 150 mm)，3.5 μm，移動相含0.5%異丙胺之異丙醇；流量：3 mL/min；共溶劑%：30%；ABPR：1450 psi；T：35℃；Rt = 4.97 min (第一次溶析)。LC-MS: m/z [M+H]+= 408.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (s, 1H), 7.49 (s, 1H), 7.36-7.33 (m, 3H), 7.31-7.27 (m, 2H), 6.56-6.54 (m, 1H), 6.25 (d, J=7.96 Hz, 1H), 3.83 (s, 1H), 2.95 (s, 3H), 2.36 ( s, 3H), 2.21-2.20 (s, 3H)。488：分析型對掌性HPLC條件：對掌性SFC：管柱：(R,R)-Whelk-O-1 (4.6 x 150 mm)，3.5 μm，移動相含0.5%異丙胺之異丙醇；流量：3 mL/min；共溶劑%：30%；ABPR：1450 psi；T：35℃；Rt 5.80 min (第二次溶析)。LC-MS: m/z [M+H]+= 408.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (s, 1H), 7.49 (s, 1H), 7.38-7.27 (m, 5H), 6.56-6.54 (m, 1H), 6.25 (d, J=8.16 Hz, 1H), 3.84 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.21-2.20 (s, 3H)。489：分析型對掌性HPLC條件：對掌性SFC：管柱：Chiralpak IC (4.6 x 150 mm)，3.5 μm，移動相含0.5%異丙胺之異丙醇；流量：4 mL/min；共溶劑%：40%；T：35℃；Rt = 3.72 min (第一次溶析)。LC-MS: m/z [M+H]+= 408.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.44 (s, 1H), 7.47 (s, 1H), 7.35-7.25 (m, 5H), 6.54-6.52 (m, 1H), 6.23 (d, J=8.12 Hz, 1H), 3.81 (s, 1H), 2.93 (s, 3H), 2.35 ( s, 3H), 2.19-2.18 (m, 3H)。490：分析型對掌性HPLC條件：對掌性SFC：管柱Chiralpak IC (4.6 x 150 mm)，3.5 μm，移動相含0.5%異丙胺之異丙醇；流量：4 mL/min；共溶劑%：40%；T：35℃；Rt = 4.37 min (第一次溶析)。LC-MS: m/z [M+H]+= 408.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (s, 1H), 7.48 (s, 1H), 7.35-7.25 (m, 5H), 6.54-6.52 (m, 1H), 6.23 (d, J=7.92 Hz, 1H), 3.81 (s, 1H), 2.93 (s, 3H), 2.35 ( s, 3H), 2.19-2.18 (m, 3H)。 487 : Analytical palmar HPLC conditions: Palmar SFC: Column: (R,R)-Whelk-O-1 (4.6 x 150 mm), 3.5 μm; mobile phase: isopropanol containing 0.5% isopropylamine; flow rate: 3 mL/min; cosolvent %: 30%; ABPR: 1450 psi; T: 35℃; Rt = 4.97 min (first precipitation). LC-MS: m/z [M+H] + = 408.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (s, 1H), 7.49 (s, 1H), 7.36-7.33 (m, 3H), 7.31-7.27 (m, 2H), 6.56-6.54 (m, 1H), 6.25 (d, J=7.96 Hz, 1H), 3.83 (s, 1H), 2.95 (s, 3H), 2.36 (s, 3H), 2.21-2.20 (s, 3H). 488 : Analytical palmar HPLC conditions: Palmar SFC: Column: (R,R)-Whelk-O-1 (4.6 x 150 mm), 3.5 μm; mobile phase: isopropanol containing 0.5% isopropylamine; flow rate: 3 mL/min; cosolvent %: 30%; ABPR: 1450 psi; T: 35℃; Rt 5.80 min (second precipitation). LC-MS: m/z [M+H] + = 408.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (s, 1H), 7.49 (s, 1H), 7.38-7.27 (m, 5H), 6.56-6.54 (m, 1H), 6.25 (d, J=8.16 Hz, 1H), 3.84 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.21-2.20 (s, 3H). 489 : Analytical palmar HPLC conditions: Palmar SFC: Column: Chiralpak IC (4.6 x 150 mm), 3.5 μm; mobile phase: isopropanol containing 0.5% isopropylamine; flow rate: 4 mL/min; cosolvent %: 40%; T: 35℃; Rt = 3.72 min (first precipitation). LC-MS: m/z [M+H] + = 408.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.44 (s, 1H), 7.47 (s, 1H), 7.35-7.25 (m, 5H), 6.54-6.52 (m, 1H), 6.23 (d, J=8.12 Hz, 1H), 3.81 (s, 1H), 2.93 (s, 3H), 2.35 (s, 3H), 2.19-2.18 (m, 3H). 490 : Analytical palmar HPLC conditions: Palmar SFC: Chiralpak IC column (4.6 x 150 mm), 3.5 μm; mobile phase containing 0.5% isopropylamine in isopropanol; flow rate: 4 mL/min; cosolvent %: 40%; T: 35℃; Rt = 4.37 min (first precipitation). LC-MS: m/z [M+H] + = 408.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (s, 1H), 7.48 (s, 1H), 7.35-7.25 (m, 5H), 6.54-6.52 (m, 1H), 6.23 (d, J=7.92 Hz, 1H), 3.81 (s, 1H), 2.93 (s, 3H), 2.35 (s, 3H), 2.19-2.18 (m, 3H).
實例 491-494(2-((3-氯-4-氟苯基)((5-氯-4-甲基吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 491-494 (2-((3-chloro-4-fluorophenyl)((5-chloro-4-methylpyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Stereomeric derivatives were separated by palmar SFC.
對掌性SFC管柱：CHIRALPAK IH (4.6 × 250 mm)，5 μm，移動相：90% CO2 + 10%含0.3% DEA之MeOH；流量：3 mL/min；共溶劑%：10%；ABPR：1500 psi；T：35℃；第一次溶析：491，第二次溶析：492，第三次溶析：493，第四次溶析494。Palmarized SFC column: CHIRALPAK IH (4.6 × 250 mm), 5 μm, mobile phase: 90% CO2 + 10% MeOH containing 0.3% DEA; flow rate: 3 mL/min; cosolvent %: 10%; ABPR: 1500 psi; T: 35℃; first dissolution: 491 , second dissolution: 492 , third dissolution: 493 , fourth dissolution: 494 .
491：LC-MS: m/z [M+H]+= 442.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.42 (bs, 1H), 7.87 (s, 1H), 7.62-7.56 (m, 2H), 7.36-7.31 (m, 2H), 6.66 (s, 1H), 6.23 (d, J = 8.04 Hz, 1H), 3.79 (bs, 1H), 2.92 (s, 3H), 2.34 (s, 3H), 2.16 (s, 3H)。492：LC-MS: m/z [M+H]+= 442.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.48 (bs, 1H), 7.90 (s, 1H), 7.68-7.56 (m, 2H), 7.38-7.36 (m, 2H), 6.68 (s, 1H), 6.25 (d, J = 8.12 Hz, 1H), 3.83 (bs, 1H), 2.95 (s, 3H), 2.36 (s, 3H), 2.19 (s, 3H)。493：LC-MS: m/z [M+H]+= 442.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (br, 1H), 7.90 (s, 1H), 7.64-7.56 (m, 2H), 7.39-7.36 (m, 2H), 6.68 (s, 1H), 6.26 (d, J = 7.96 Hz, 1H), 3.83 (s, 1H), 2.94 (s, 3H), 2.37 (s, 3H), 2.19 (s, 3H)。494：LC-MS: m/z [M+H]+= 442.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.47 (br, 1H), 7.89 (s, 1H), 7.64-7.59 (m, 2H), 7.38-7.36 (m, 2H), 6.68 (s, 1H), 6.25 (d, J = 8.04 Hz, 1H), 2.96 (s, 3H), 2.37 (s, 3H), 2.19 (s, 3H)。 491 : LC-MS: m/z [M+H] + = 442.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.42 (bs, 1H), 7.87 (s, 1H), 7.62-7.56 (m, 2H), 7.36-7.31 (m, 2H), 6.66 (s, 1H), 6.23 (d, J = 8.04 Hz, 1H), 3.79 (bs, 1H), 2.92 (s, 3H), 2.34 (s, 3H), 2.16 (s, 3H). 492 : LC-MS: m/z [M+H] + = 442.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.48 (bs, 1H), 7.90 (s, 1H), 7.68-7.56 (m, 2H), 7.38-7.36 (m, 2H), 6.68 (s, 1H), 6.25 (d, J = 8.12 Hz, 1H), 3.83 (bs, 1H), 2.95 (s, 3H), 2.36 (s, 3H), 2.19 (s, 3H). 493 : LC-MS: m/z [M+H] + = 442.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (br, 1H), 7.90 (s, 1H), 7.64-7.56 (m, 2H), 7.39-7.36 (m, 2H), 6.68 (s, 1H), 6.26 (d, J = 7.96 Hz, 1H), 3.83 (s, 1H), 2.94 (s, 3H), 2.37 (s, 3H), 2.19 (s, 3H). 494 : LC-MS: m/z [M+H] + = 442.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.47 (br, 1H), 7.89 (s, 1H), 7.64-7.59 (m, 2H), 7.38-7.36 (m, 2H), 6.68 (s, 1H), 6.25 (d, J = 8.04 Hz, 1H), 2.96 (s, 3H), 2.37 (s, 3H), 2.19 (s, 3H).
實例 495-498(2-((3-氯-4-氟苯基)((5-氯-6-環丙基吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 495-498 (2-((3-chloro-4-fluorophenyl)((5-chloro-6-cyclopropylpyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Stereomeric derivatives were separated by palmar SFC.
製備型第一對掌性SFC：管柱：管柱I-Cellulose-C (21 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：60 mL/min；共溶劑%：35%；ABPR：100巴；T：35℃。第一次溶析：495及496之混合物，第二次溶析：497，第三次溶析：498。Preparation of the first pair of palmar SFCs: Column: I-Cellulose-C (21 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 60 mL/min; Cosolvent %: 35%; ABPR: 100 bar; T: 35 °C. First dissolution: mixture of 495 and 496 , second dissolution: 497 , third dissolution: 498 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm )，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：100 mL/min；共溶劑%：35%；ABPR：100巴；T：35℃。第一次溶析：495 ，第二次溶析：496。Preparation of the second pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 100 mL/min; Cosolvent %: 35%; ABPR: 100 bar; T: 35 °C. First precipitation: 495 , Second precipitation: 496 .
495：LC-MS: m/z [M+H]+= 468.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.41 (s, 1H), 7.63-7.56 (m, 2H), 7.40-7.36 (m, 3H), 6.52-6.49 (m, 1H), 5.99 (d, J = 6.36 Hz, 1H), 3.83 (bs, 1H), 2.95 (s, 3H), 2.53 (s, 1H), 2.36 (s, 3H), 2.21-2.17 (m, 1H), 0.84-0.75 (m, 4H), 0.64-0.61 (m, 1H)。496：LC-MS: m/z [M+H]+= 468.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.42 (s, 1H), 7.62 (d, J = 7.6 Hz, 1H ), 7.57 (d, J = 6.4 Hz, 1H), 7.40-7.36 (m, 3H), 6.52-6.48 (m, 1H), 5.99 (d, J = 6.40 Hz, 1H), 3.80 (s, 1H), 2.95 (s, 3H), 2.53 (s, 1H), 2.36 (s, 3H), 2.20-2.19 (m, 1H), 1.03 (d, J = 6.08 Hz, 1H), 0.84-0.75 (m, 3H), 0.62-0.60 (m, 1H)。497：LC-MS: m/z [M+H]+= 468.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.41 (s, 1H), 7.62 (d, J = 7.08 Hz, 1H ), 7.56 (d, J = 6.4 Hz, 1H), 7.40-7.36 (m, 3H), 6.50 (d, J = 8.88 Hz, 1H), 6.00 (d, J = 6.40 Hz, 1H), 3.79 (s, 1H), 2.95 (s, 3H), 2.32 (s, 3H), 2.20-2.19 (m, 1H), 1.03 (d, J = 6.08 Hz, 1H), 0.84-0.76 (m, 4H), 0.62-0.61 (m, 1H)。498：LC-MS: m/z [M+H]+= 468.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.41 (s, 1H), 7.62 (d, J = 7.48 Hz, 1H ), 7.56 (d, J = 6.36 Hz, 1H), 7.40-7.36 (m, 3H), 6.50 (d, J = 8.80 Hz, 1H), 6.00 (d, J = 6.36 Hz, 1H), 3.81 (s, 1H), 2.96 (s, 3H), 2.32 (s, 3H), 2.21-2.16 (m, 1H), 1.03 (d, J = 6.12 Hz, 1H), 0.84-0.76 (m, 3H), 0.64-0.61 (m, 1H)。 495 : LC-MS: m/z [M+H] + = 468.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.41 (s, 1H), 7.63-7.56 (m, 2H), 7.40-7.36 (m, 3H), 6.52-6.49 (m, 1H), 5.99 (d, J = 6.36 Hz, 1H), 3.83 (bs, 1H), 2.95 (s, 3H), 2.53 (s, 1H), 2.36 (s, 3H), 2.21-2.17 (m, 1H), 0.84-0.75 (m, 4H), 0.64-0.61 (m, 1H). 496 : LC-MS: m/z [M+H] + = 468.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.42 (s, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 6.4 Hz, 1H), 7.40-7.36 (m, 3H), 6.52-6.48 (m, 1H), 5.99 (d, J = 6.40 Hz, 1H), 3.80 (s, 1H), 2.95 (s, 3H), 2.53 (s, 1H), 2.36 (s, 3H), 2.20-2.19 (m, 1H), 1.03 (d, J = 6.08 Hz, 1H), 0.84-0.75 (m, 3H), 0.62-0.60 (m, 1H). 497 : LC-MS: m/z [M+H] + = 468.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.41 (s, 1H), 7.62 (d, J = 7.08 Hz, 1H), 7.56 (d, J = 6.4 Hz, 1H), 7.40-7.36 (m, 3H), 6.50 (d, J = 8.88 Hz, 1H), 6.00 (d, J = 6.40 Hz, 1H), 3.79 (s, 1H), 2.95 (s, 3H), 2.32 (s, 3H), 2.20-2.19 (m, 1H), 1.03 (d, J = 6.08 Hz, 1H), 0.84-0.76 (m, 4H), 0.62-0.61 (m, 1H). 498 : LC-MS: m/z [M+H] + = 468.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.41 (s, 1H), 7.62 (d, J = 7.48 Hz, 1H), 7.56 (d, J = 6.36 Hz, 1H), 7.40-7.36 (m, 3H), 6.50 (d, J = 8.80 Hz, 1H), 6.00 (d, J = 6.36 Hz, 1H), 3.81 (s, 1H), 2.96 (s, 3H), 2.32 (s, 3H), 2.21-2.16 (m, 1H), 1.03 (d, J = 6.12 Hz, 1H), 0.84-0.76 (m, 3H), 0.64-0.61 (m, 1H).
實例 499-502(2-((3-氯-4-氟苯基)((3,5-二氟-6-甲基吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 499-502 (2-((3-chloro-4-fluorophenyl)((3,5-difluoro-6-methylpyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Stereomeric derivatives were separated by palmar SFC.
製備型第一對掌性SFC：管柱：管柱Chiralpak IC (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：110 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：499，第二次溶析：500及501之混合物，第三次溶析：502。Preparation of the first pair of palmar SFCs: Column: Chiralpak IC column (30 mm x 250 mm), 5µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 110 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35℃. First dissolution: 499 , Second dissolution: Mixture of 500 and 501 , Third dissolution: 502 .
製備型第二對掌性SFC：管柱：I-Cellulose-Z (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之乙腈-異丙醇(1:1)，流量：100 mL/min；共溶劑%：20%；ABPR：100巴；T：35℃。第一次溶析：500 ，第二次溶析：501。Preparation of the second pair of palmar SFCs: Column: I-Cellulose-Z (30 mm x 250 mm), 5 µm; Cosolvent: Acetonitrile-isopropanol (1:1) containing 0.2% (methanol containing 7N ammonia), flow rate: 100 mL/min; Cosolvent %: 20%; ABPR: 100 bar; T: 35 °C. First dissolution: 500 mL , Second dissolution: 501 mL .
499 ：LC-MS: m/z [M+H]+= 444.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.37 (bs, 1H), 7.67 (d, J = 6.8 Hz, 1H), 7.6 (t, J = 9.66 Hz, 1H), 7.44-7.43 (m, 1H), 7.39-7.34 (m, 1H), 7.25 (d, J = 7.88 Hz, 1H), 6.37 (d, J = 7.84 Hz, 1H), 3.84 (bs, 1 H), 2.96 (s, 3H), 2.38 (s, 3H), 2.21 (s, 3H)。500：LC-MS: m/z [M+H]+= 444.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.37 (bs, 1H), 7.68-7.66 (m, 1H), 7.63-7.58 (m, 1H), 7.45-7.43 (m, 1H), 7.39-7.34 (m, 1H), 7.25 (d, J = 7.88 Hz, 1H), 6.38 (d, J = 8.16 Hz, 1H), 3.84 (bs, 1 H), 2.96 (s, 3H), 2.38 (s, 3H), 2.21 (s, 3H)。501：LC-MS: m/z [M+H]+= 444.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.37 (bs, 1H), 7.68-7.58 (m, 2H), 7.44-7.43 (m, 1H), 7.39-7.35 (m, 1H), 7.26-7.24 (m, 1H), 6.38 (d, J = 8.16 Hz, 1H), 3.85 (bs, 1 H), 2.96 (s, 3H), 2.38 (s, 3H), 2.21 (s, 3H)。502：LC-MS: m/z [M+H]+= 444.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.37 (bs, 1H), 7.68-7.58 (m, 2H), 7.44-7.43 (m, 1H), 7.39-7.35 (m, 1H), 7.26-7.24 (m, 1H), 6.38 (d, J = 8.16 Hz, 1H), 3.84 (bs, 1 H), 2.96 (s, 3H), 2.38 (s, 3H), 2.21 (s, 3H)。 499 : LC-MS: m/z [M+H] + = 444.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.37 (bs, 1H), 7.67 (d, J = 6.8 Hz, 1H), 7.6 (t, J = 9.66 Hz, 1H), 7.44-7.43 (m, 1H), 7.39-7.34 (m, 1H), 7.25 (d, J = 7.88 Hz, 1H), 6.37 (d, J = 7.84 Hz, 1H), 3.84 (bs, 1H), 2.96 (s, 3H), 2.38 (s, 3H), 2.21 (s, 3H). 500 : LC-MS: m/z [M+H] + = 444.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.37 (bs, 1H), 7.68-7.66 (m, 1H), 7.63-7.58 (m, 1H), 7.45-7.43 (m, 1H), 7.39-7.34 (m, 1H), 7.25 (d, J = 7.88 Hz, 1H), 6.38 (d, J = 8.16 Hz, 1H), 3.84 (bs, 1 H), 2.96 (s, 3H), 2.38 (s, 3H), 2.21 (s, 3H). 501 : LC-MS: m/z [M+H] + = 444.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.37 (bs, 1H), 7.68-7.58 (m, 2H), 7.44-7.43 (m, 1H), 7.39-7.35 (m, 1H), 7.26-7.24 (m, 1H), 6.38 (d, J = 8.16 Hz, 1H), 3.85 (bs, 1H), 2.96 (s, 3H), 2.38 (s, 3H), 2.21 (s, 3H). 502 : LC-MS: m/z [M+H] + = 444.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.37 (bs, 1H), 7.68-7.58 (m, 2H), 7.44-7.43 (m, 1H), 7.39-7.35 (m, 1H), 7.26-7.24 (m, 1H), 6.38 (d, J = 8.16 Hz, 1H), 3.84 (bs, 1H), 2.96 (s, 3H), 2.38 (s, 3H), 2.21 (s, 3H).
實例 503-505(2-((3-氯-4-氟苯基)((5-氟-6-(甲基-d3)吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 503-505 (2-((3-chloro-4-fluorophenyl)((5-fluoro-6-(methyl-d3)pyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Stereomeric derivatives were separated by palmar SFC.
製備型第一對掌性SFC：管柱：管柱：Chiralpak IC (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：100 mL/min；共溶劑%：35%；ABPR：100巴；T：35℃。第一次溶析：503(2種立體異構物之混合物)，第二次溶析：504，第三次溶析：505。Preparation of the first pair of palmar SFCs: Column: Chiralpak IC (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 100 mL/min; Cosolvent %: 35%; ABPR: 100 bar; T: 35 °C. First dissolution: 503 (mixture of two stereoisomers), second dissolution: 504 , third dissolution: 505 .
503(2種立體異構物之混合物)：LC-MS: m/z [M+H]+= 429.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.44 (s, 1H), 7.65-7.63 (m, 1H), 7.41-7.34 (m, 3H), 7.30 (t, J = 9.04 Hz, 1H), 6.55-6.52 (m, 1H), 6.23 (d, J = 8.12 Hz, 1H), 3.83 (s, 1H), 2.88 (s, 3H), 2.37 (s, 3H), 2.22 (s, 3H)。504：LC-MS: m/z [M+H]+ = 429.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.45 (s, 1H), 7.64-7.63 (m, 1H), 7.41-7.35 (m, 3H), 7.30 (t, J = 9.04 Hz, 1H), 6.55-6.52 (m, 1H), 6.23 (d, J = 8.12 Hz, 1H), 3.85 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.22 (s, 3H)。505：LC-MS: m/z [M+H]+ = 429.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.44 (s, 1H), 7.64-7.63 (m, 1H), 7.41-7.35 (m, 3H), 7.30 (t, J = 9.04 Hz, 1H), 6.55-6.52 (m, 1H), 6.23 (d, J = 8.12 Hz, 1H), 3.83 (s, 1H), 2.95 (s, 3H), 2.32 (s, 3H), 2.22 (s, 3H)。 503 (a mixture of two stereoisomers): LC-MS: m/z [M+H] + = 429.2. 1H -NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) = 12.44 (s, 1H), 7.65-7.63 (m, 1H), 7.41-7.34 (m, 3H), 7.30 (t, J = 9.04 Hz, 1H), 6.55-6.52 (m, 1H), 6.23 (d, J = 8.12 Hz, 1H), 3.83 (s, 1H), 2.88 (s, 3H), 2.37 (s, 3H), 2.22 (s, 3H). 504 : LC-MS: m/z [M+H]+ = 429.2. 1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.45 (s, 1H), 7.64-7.63 (m, 1H), 7.41-7.35 (m, 3H), 7.30 (t, J = 9.04 Hz, 1H), 6.55-6.52 (m, 1H), 6.23 (d, J = 8.12 Hz, 1H), 3.85 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.22 (s, 3H). 505 : LC-MS: m/z [M+H]+ = 429.2. 1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.44 (s, 1H), 7.64-7.63 (m, 1H), 7.41-7.35 (m, 3H), 7.30 (t, J = 9.04 Hz, 1H), 6.55-6.52 (m, 1H), 6.23 (d, J = 8.12 Hz, 1H), 3.83 (s, 1H), 2.95 (s, 3H), 2.32 (s, 3H), 2.22 (s, 3H).
實例 506-509N-[(3-氯-4-氟苯基)-[5-甲基-4-(甲基亞磺醯亞胺基)-1H-咪唑-2-基]甲基]-5-甲基-4-(三氟甲基)-1,3-噻唑-2-胺及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 506-509 N-[(3-chloro-4-fluorophenyl)-[5-methyl-4-(methylsulfinimino)-1H-imidazol-2-yl]methyl]-5-methyl-4-(trifluoromethyl)-1,3-thiazolyl-2-amine and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Stereomeric derivatives were separated by palmar SFC.
製備型對掌性SFC：管柱：CHIRALPAK IC (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之MeOH)之異丙醇，流量：90 mL/min；共溶劑%：25%；ABPR：100巴；T：35℃。第一次溶析：506，第二次溶析：507，第三次溶析：508，第四次溶析509。Preparation of palmar SFC: Column: CHIRALPAK IC (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (MeOH containing 7N ammonia), flow rate: 90 mL/min; Cosolvent %: 25%; ABPR: 100 bar; T: 35 °C. First dissolution: 506 , Second dissolution: 507 , Third dissolution: 508 , Fourth dissolution : 509 .
506：13%。LC-MS: m/z [M+H]+= 482.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.55 (s, 1H), 8.85 (d, J = 7.96 Hz, 1H), 7.63 (d, J= 7.68 Hz, 1H), 7.40-7.42 (m, 2H), 6.03 (d, J = 7.96 Hz, 1H), 3.89 (s, 1H), 2.95 (s, 3H), 2.37(s, 3H), 2.30 (單峰, 3H)。507：4%。LC-MS: m/z [M+H]+= 482.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.55 (s, 1H), 8.84 (d, J = 8 Hz, 1H), 7.63 (d, J= 6.92 Hz, 1H), 7.40-7.42 (m, 2H), 6.03 (d, J = 8 Hz, 1H), 2.95 (s, 3H), 2.37(s, 3H), 2.30 (單峰, 3H)。508：4%。LC-MS: m/z [M+H]+= 488.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.55 (s, 1H), 8.85 (d, J = 7.96 Hz, 1H), 7.63 (d, J= 7.68 Hz, 1H), 7.40-7.42 (m, 2H), 6.03 (d, J = 7.96 Hz, 1H), 3.89 (s, 1H), 2.95 (s, 3H), 2.37(s, 3H), 2.30 (單峰, 3H)。509：7%。LC-MS: m/z [M+H]+= 488.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.55 (s, 1H), 8.85 (d, J = 7.96 Hz, 1H), 7.63 (d, J= 7.68 Hz, 1H), 7.40-7.42 (m, 2H), 6.03 (d, J = 7.96 Hz, 1H), 3.89 (s, 1H), 2.95 (s, 3H), 2.37(s, 3H), 2.30 (單峰, 3H)。 506 : 13%. LC-MS: m/z [M+H] + = 482.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.55 (s, 1H), 8.85 (d, J = 7.96 Hz, 1H), 7.63 (d, J= 7.68 Hz, 1H), 7.40-7.42 (m, 2H), 6.03 (d, J = 7.96 Hz, 1H), 3.89 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.30 (single peak, 3H). 507 : 4%. LC-MS: m/z [M+H] + = 482.2. ¹H -NMR (400 MHz, DMSO-d⁶, 25℃) δ (ppm) = 12.55 (s, 1H), 8.84 (d, J = 8 Hz, 1H), 7.63 (d, J = 6.92 Hz, 1H), 7.40–7.42 (m, 2H), 6.03 (d, J = 8 Hz, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.30 (single peak, 3H). 508 : 4%. LC-MS: m/z [M+H] ⁺ = 488.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.55 (s, 1H), 8.85 (d, J = 7.96 Hz, 1H), 7.63 (d, J= 7.68 Hz, 1H), 7.40-7.42 (m, 2H), 6.03 (d, J = 7.96 Hz, 1H), 3.89 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.30 (single peak, 3H). 509 : 7%. LC-MS: m/z [M+H] + = 488.2. ¹H -NMR (400 MHz, DMSO-d6, 25℃) δ (ppm) = 12.55 (s, 1H), 8.85 (d, J = 7.96 Hz, 1H), 7.63 (d, J = 7.68 Hz, 1H), 7.40–7.42 (m, 2H), 6.03 (d, J = 7.96 Hz, 1H), 3.89 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.30 (single peak, 3H).
實例 510-513(2-((3-氯-4-氟苯基)((6-(1,1-二氟乙基)-5-氟吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 510-513 (2-((3-chloro-4-fluorophenyl)((6-(1,1-difluoroethyl)-5-fluoropyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Stereomeric derivatives were separated by palmar SFC.
製備型第一對掌性SFC：管柱：管柱：I-Cellulose-C (21 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：70 mL/min；共溶劑%：40%；ABPR：100巴；T：35℃。第一次溶析：510及511之混合物，第二次溶析：512及513之混合物。Preparation of the first pair of palmar SFCs: Column: I-Cellulose-C (21 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 40%; ABPR: 100 bar; T: 35 °C. First dissolution: Mixture of 510 and 511 ; Second dissolution: Mixture of 512 and 513 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：90 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：510 ，第二次溶析：511。Preparation of the second pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 90 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First dissolution: 510 , Second dissolution: 511 .
製備型第三對掌性SFC：管柱：ChiralPak IG (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之己烷-異丙醇(1:1)，流量：90 mL/min；共溶劑%：25%；ABPR：100巴；T：35℃。第一次溶析：512 ，第二次溶析：513。Preparation of the third palmar SFC: Column: ChiralPak IG (30 mm x 250 mm), 5 µm; Cosolvent: Hexane-isopropanol (1:1) containing 0.2% (methanol containing 7N ammonia), flow rate: 90 mL/min; Cosolvent %: 25%; ABPR: 100 bar; T: 35 °C. First precipitation: 512 , Second precipitation: 513 .
510：LC-MS: m/z [M+H]+= 476.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.51 (s, 1H), 7.8 (d, J = 6.72 Hz, 1H), 7.68 (d, J = 7.12 Hz, 1H), 7.53 (t, J = 9.68 Hz, 1H), 7.44-7.37 (m, 2H), 6.90 (d, J = 8.0 Hz, 1H), 6.09 (d, J = 6.76 Hz, 1H), 3.82 (bs, 1 H), 2.94 (s, 3H), 2.37-2.32 (m, 3H), 1.88-1.78 (m, 3H)。511：LC-MS: m/z [M+H]+= 476.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.45 (s, 1H), 7.79 (d, J = 6.52 Hz, 1H), 7.68 (d, J = 6.92 Hz, 1H), 7.53 (t, J = 9.68 Hz, 1H), 7.44-7.38 (m, 2H), 6.90 (d, J = 8.68 Hz, 1H), 6.09 (d, J = 6.56 Hz, 1H), 3.81 (bs, 1 H), 2.94 (s, 3H), 2.37-2.32 (m, 3H), 1.88-1.78 (m, 3H)。512：LC-MS: m/z [M+H]+= 476.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.45 (s, 1H), 7.8 (d, J = 6.68 Hz, 1H), 7.68 (d, J = 6.76 Hz, 1H), 7.53 (t, J = 9.68 Hz, 1H), 7.44-7.37 (m, 2H), 6.90 (d, J = 8.76 Hz, 1H), 6.09 (d, J = 6.68 Hz, 1H), 3.87 (bs, 1 H), 2.95 (s, 3H), 2.37-2.29 (m, 3H), 1.88-1.78 (m, 3H)。513：LC-MS: m/z [M+H]+= 476.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.47 (s, 1H), 7.8 (d, J = 6.64 Hz, 1H), 7.68 (d, J = 6.6 Hz, 1H), 7.53 (t, J = 9.68 Hz, 1H), 7.44-7.37 (m, 2H), 6.90 (d, J = 8.8 Hz, 1H), 6.09 (d, J = 6.64 Hz, 1H), 3.87 (bs, 1 H), 2.95 (s, 3H), 2.37-2.32 (m, 3H), 1.88-1.78 (m, 3H)。 510 : LC-MS: m/z [M+H] + = 476.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.51 (s, 1H), 7.8 (d, J = 6.72 Hz, 1H), 7.68 (d, J = 7.12 Hz, 1H), 7.53 (t, J = 9.68 Hz, 1H), 7.44-7.37 (m, 2H), 6.90 (d, J = 8.0 Hz, 1H), 6.09 (d, J = 6.76 Hz, 1H), 3.82 (bs, 1 H), 2.94 (s, 3H), 2.37-2.32 (m, 3H), 1.88-1.78 (m, 3H). 511 : LC-MS: m/z [M+H] + = 476.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.45 (s, 1H), 7.79 (d, J = 6.52 Hz, 1H), 7.68 (d, J = 6.92 Hz, 1H), 7.53 (t, J = 9.68 Hz, 1H), 7.44-7.38 (m, 2H), 6.90 (d, J = 8.68 Hz, 1H), 6.09 (d, J = 6.56 Hz, 1H), 3.81 (bs, 1 H), 2.94 (s, 3H), 2.37-2.32 (m, 3H), 1.88-1.78 (m, 3H). 512 : LC-MS: m/z [M+H] + = 476.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.45 (s, 1H), 7.8 (d, J = 6.68 Hz, 1H), 7.68 (d, J = 6.76 Hz, 1H), 7.53 (t, J = 9.68 Hz, 1H), 7.44-7.37 (m, 2H), 6.90 (d, J = 8.76 Hz, 1H), 6.09 (d, J = 6.68 Hz, 1H), 3.87 (bs, 1 H), 2.95 (s, 3H), 2.37-2.29 (m, 3H), 1.88-1.78 (m, 3H). 513 : LC-MS: m/z [M+H] + = 476.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.47 (s, 1H), 7.8 (d, J = 6.64 Hz, 1H), 7.68 (d, J = 6.6 Hz, 1H), 7.53 (t, J = 9.68 Hz, 1H), 7.44-7.37 (m, 2H), 6.90 (d, J = 8.8 Hz, 1H), 6.09 (d, J = 6.64 Hz, 1H), 3.87 (bs, 1 H), 2.95 (s, 3H), 2.37-2.32 (m, 3H), 1.88-1.78 (m, 3H).
實例 514-517(2-((3-氯-4-氟苯基)((6-甲基吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 514-517 (2-((3-chloro-4-fluorophenyl)((6-methylpyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Stereomeric derivatives were separated by palmar SFC.
製備型對掌性SFC：管柱：管柱：Chiralpak IC (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：120 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：514及515之混合物，第二次溶析：516，第三次溶析：517。Preparation of palmar SFC: Column: Chiralpak IC (30 mm x 250 mm), 5µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 120 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35℃. First dissolution: mixture of 514 and 515 ; Second dissolution: 516 ; Third dissolution: 517 .
製備型第二對掌性SFC：管柱：I Cellulose Z (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之乙腈-異丙醇(1:1)，流量：90 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：514 ，第二次溶析：515。Preparation of the second pair of palmar SFCs: Column: I Cellulose Z (30 mm x 250 mm), 5 µm; Cosolvent: Acetonitrile-isopropanol (1:1) containing 0.2% (methanol containing 7N ammonia), flow rate: 90 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First precipitation: 514 , Second precipitation: 515 .
514：13%，LC-MS: m/z [M+H]+= 408.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.55 (s, 1H), 8.85 (d, J = 7.96 Hz, 1H), 7.63 (d, J= 7.68 Hz, 1H), 7.40-7.42 (m, 2H), 6.03 (d, J = 7.96 Hz, 1H), 3.89 (s, 1H), 2.95 (s, 3H), 2.37(s, 3H), 2.30 (單峰, 3H)。515：4%，LC-MS: m/z [M+H]+= 408.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.55 (s, 1H), 8.84 (d, J = 8 Hz, 1H), 7.63 (d, J= 6.92 Hz, 1H), 7.40-7.42 (m, 2H), 6.03 (d, J = 8 Hz, 1H), 2.95 (s, 3H), 2.37(s, 3H), 2.30 (單峰, 3H)。516：4%，LC-MS: m/z [M+H]+= 408.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.45 (s, 1H), 7.64 (d, J = 7.12 Hz, 1H), 7.42-7.28 (m, 4H), 6.47 (d, J = 8.04 Hz, 1H), 6.41 (d, J = 6.76 Hz, 1H), 6.34 (d, J = 7.76 Hz, 1H), 3.91-3.86 (m, 1H), 2.96 (s, 3H), 2.32 (s, 3H), 2.22 (s, 3H)。517：7%，LC-MS: m/z [M+H]+= 408.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.45 (s, 1H), 7.64 (d, J = 7.12 Hz, 1H), 7.42-7.27 (m, 4H), 6.47 (d, J = 8.04 Hz, 1H), 6.41 (d, J = 6.76 Hz, 1H), 6.34 (d, J = 7.76 Hz, 1H), 3.93-3.87 (m, 1H), 2.96 (s, 3H), 2.32 (s, 3H), 2.22 (s, 3H)。 514 : 13%, LC-MS: m/z [M+H] + = 408.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.55 (s, 1H), 8.85 (d, J = 7.96 Hz, 1H), 7.63 (d, J= 7.68 Hz, 1H), 7.40-7.42 (m, 2H), 6.03 (d, J = 7.96 Hz, 1H), 3.89 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.30 (single peak, 3H). 515 : 4%, LC-MS: m/z [M+H] + = 408.2. ¹H -NMR (400 MHz, DMSO-d⁶, 25℃) δ (ppm) = 12.55 (s, 1H), 8.84 (d, J = 8 Hz, 1H), 7.63 (d, J = 6.92 Hz, 1H), 7.40–7.42 (m, 2H), 6.03 (d, J = 8 Hz, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.30 (single peak, 3H). 516 : 4%, LC-MS: m/z [M+H] ⁺ = 408.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.45 (s, 1H), 7.64 (d, J = 7.12 Hz, 1H), 7.42-7.28 (m, 4H), 6.47 (d, J = 8.04 Hz, 1H), 6.41 (d, J = 6.76 Hz, 1H), 6.34 (d, J = 7.76 Hz, 1H), 3.91-3.86 (m, 1H), 2.96 (s, 3H), 2.32 (s, 3H), 2.22 (s, 3H). 517 : 7%, LC-MS: m/z [M+H] + = 408.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.45 (s, 1H), 7.64 (d, J = 7.12 Hz, 1H), 7.42-7.27 (m, 4H), 6.47 (d, J = 8.04 Hz, 1H), 6.41 (d, J = 6.76 Hz, 1H), 6.34 (d, J = 7.76 Hz, 1H), 3.93-3.87 (m, 1H), 2.96 (s, 3H), 2.32 (s, 3H), 2.22 (s, 3H).
實例 518-521(2-(((5-氟-6-甲基吡啶-2-基)胺基)(4-(三氟甲基)苯基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 518-521 (2-(((5-fluoro-6-methylpyridin-2-yl)amino)(4-(trifluoromethyl)phenyl)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Stereomeric derivatives were separated by palmar SFC.
製備型第一對掌性SFC：管柱：管柱：I Cellulose C (21.1 mm×250 mm)，5µ；共溶劑：異丙醇，流量：60 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：518及519之混合物，第二次溶析：520及521之混合物。Preparation of the first pair of palmar SFCs: Column: I Cellulose C (21.1 mm × 250 mm), 5 µm; Cosolvent: Isopropanol, Flow rate: 60 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First dissolution: Mixture of 518 and 519 ; Second dissolution: Mixture of 520 and 521 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：110 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：519 ，第二次溶析：520。Preparation of the second palmar SFC: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 110 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First precipitation: 519 , Second precipitation: 520 .
製備型第三對掌性SFC：管柱：管柱：I Cellulose C (21 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之乙腈-異丙醇(7:3)，流量：70 mL/min；共溶劑%：25%；ABPR：100巴；T：35℃。第一次溶析：521 ，第二次溶析：522。Preparation of the third palmar SFC: Column: I Cellulose C (21 mm x 250 mm), 5 µm; Cosolvent: Acetonitrile-isopropanol (7:3) containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 25%; ABPR: 100 bar; T: 35 °C. First precipitation: 521 , Second precipitation: 522 .
520：LC-MS: m/z [M+H]+= 442.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.5 (s, 1H), 7.70 (d, J=8.2 Hz, 2H), 7.62 (d, J=8.12Hz, 2H), 7.42 (d, J=8.08 Hz, 1H), 7.29 (t, J=9.08 Hz, 1H), 6.57-6.54 (m,1H), 6.33 (d, J=8.16 Hz, 1H), 3.82 (s, 1H), 2.95 ( s, 3H), 2.37 (s, 3H), 2.20-2.19 (m, 3H)。520：LC-MS: m/z [M+H]+= 442.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.5 (s, 1H), 7.70 (d, J=8.2 Hz, 2H), 7.62 (d, J=8.12Hz, 2H), 7.42 (d, J=8.08 Hz, 1H), 7.29 (t, J=9.08 Hz, 1H), 6.57-6.54 (m,1H), 6.33 (d, J=8.16 Hz, 1H), 3.82 (s, 1H), 2.95 ( s, 3H), 2.37 (s, 3H), 2.20-2.19 (m, 3H)。520：LC-MS: m/z [M+H]+= 442.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.5 (s, 1H), 7.70 (d, J=8.2 Hz, 2H), 7.62 (d, J=8.12Hz, 2H), 7.42 (d, J=8.08 Hz, 1H), 7.29 (t, J=9.08 Hz, 1H), 6.57-6.54 (m,1H), 6.33 (d, J=8.16 Hz, 1H), 3.82 (s, 1H), 2.95 ( s, 3H), 2.37 (s, 3H), 2.20-2.19 (m, 3H)。520：LC-MS: m/z [M+H]+= 442.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.5 (s, 1H), 7.70 (d, J=8.2 Hz, 2H), 7.62 (d, J=8.12Hz, 2H), 7.42 (d, J=8.08 Hz, 1H), 7.29 (t, J=9.08 Hz, 1H), 6.57-6.54 (m,1H), 6.33 (d, J=8.16 Hz, 1H), 3.82 (s, 1H), 2.95 ( s, 3H), 2.37 (s, 3H), 2.20-2.19 (m, 3H)。 520 : LC-MS: m/z [M+H] + = 442.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.5 (s, 1H), 7.70 (d, J=8.2 Hz, 2H), 7.62 (d, J=8.12Hz, 2H), 7.42 (d, J=8.08 Hz, 1H), 7.29 (t, J=9.08 Hz, 1H), 6.57-6.54 (m,1H), 6.33 (d, J=8.16 Hz, 1H), 3.82 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.20-2.19 (m, 3H). 520 : LC-MS: m/z [M+H] + = 442.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.5 (s, 1H), 7.70 (d, J=8.2 Hz, 2H), 7.62 (d, J=8.12Hz, 2H), 7.42 (d, J=8.08 Hz, 1H), 7.29 (t, J=9.08 Hz, 1H), 6.57-6.54 (m,1H), 6.33 (d, J=8.16 Hz, 1H), 3.82 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.20-2.19 (m, 3H). 520 : LC-MS: m/z [M+H] + = 442.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.5 (s, 1H), 7.70 (d, J=8.2 Hz, 2H), 7.62 (d, J=8.12Hz, 2H), 7.42 (d, J=8.08 Hz, 1H), 7.29 (t, J=9.08 Hz, 1H), 6.57-6.54 (m,1H), 6.33 (d, J=8.16 Hz, 1H), 3.82 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.20-2.19 (m, 3H). 520 : LC-MS: m/z [M+H] + = 442.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.5 (s, 1H), 7.70 (d, J=8.2 Hz, 2H), 7.62 (d, J=8.12Hz, 2H), 7.42 (d, J=8.08 Hz, 1H), 7.29 (t, J=9.08 Hz, 1H), 6.57-6.54 (m,1H), 6.33 (d, J=8.16 Hz, 1H), 3.82 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.20-2.19 (m, 3H).
實例 522-525(2-((3,4-二氯苯基)((5-氟-4-甲基嘧啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 522-525 (2-((3,4-dichlorophenyl)((5-fluoro-4-methylpyrimidin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Stereomeric derivatives were separated by palmar SFC.
製備型第一對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之乙腈-異丙醇(1:1)，流量：100 mL/min；共溶劑%：20%；ABPR：100巴；T：35℃。第一次溶析：522 ，第二次溶析：523，第三次溶析：524及525之混合物。Preparation of the first pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: acetonitrile-isopropanol (1:1) containing 0.2% (methanol containing 7N ammonia), flow rate: 100 mL/min; Cosolvent %: 20%; ABPR: 100 bar; T: 35 °C. First dissolution: 522 , second dissolution: 523 , third dissolution: a mixture of 524 and 525 .
製備型第二對掌性SFC：管柱：ChiralPak IC (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之乙腈-異丙醇(1:1)，流量：120 mL/min；共溶劑%：45%；ABPR：100巴；T：35℃。第一次溶析：524 ，第二次溶析：525。Preparation of the second pair of palmar SFCs: Column: ChiralPak IC (30 mm x 250 mm), 5 µm; Cosolvent: Acetonitrile-isopropanol (1:1) containing 0.2% (methanol containing 7N ammonia), flow rate: 120 mL/min; Cosolvent %: 45%; ABPR: 100 bar; T: 35 °C. First precipitation: 524 °C , Second precipitation: 525 ° C.
522：LC-MS: m/z [M+H]+= 443.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.38 (s, 1H), 8.24 (d, J = 1.28 Hz, 1H), 7.95 (d, J = 8.44 Hz, 1H), 7.7-7.69 (m, 1H), 7.6 (d, J = 8.24 Hz, 1H), 7.41-7.39 (m, 1H), 6.22 (d, J = 8.48 Hz, 1H), 3.84 (bs, 1 H), 2.95 (s, 3H), 2.37 (s, 3H), 2.29-2.28 (m, 3H)。523：LC-MS: m/z [M+H]+= 443.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.36 (s, 1H), 8.22 (s, 1H), 7.93 (d, J = 8.44 Hz, 1H), 7.67 (bs, 1H), 7.58 (d, J = 8.32 Hz, 1H), 7.39-7.37 (m, 1H), 6.20 (d, J = 8.4 Hz, 1H), 3.82 (bs, 1 H), 2.92 (s, 3H), 2.35 (s, 3H), 2.26 (s, 3H)。524：LC-MS: m/z [M+H]+= 443.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.39 (s, 1H), 8.24 (s, 1H), 7.95 (d, J = 8.44 Hz, 1H), 7.70-7.69 (m, 1H), 7.60 (d, J = 8.32 Hz, 1H), 7.41-7.39 (m, 1H), 6.22 (d, J = 8.4 Hz, 1H), 3.84 (bs, 1 H), 2.95 (s, 3H), 2.37 (s, 3H), 2.29-2.28 (m, 3H)。525：LC-MS: m/z [M+H]+= 443.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.38 (s, 1H), 8.24 (s, 1H), 7.95 (d, J = 8.44 Hz, 1H), 7.70 (bs, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.41-7.39 (m, 1H), 6.22 (d, J = 8.24 Hz, 1H), 3.91 (bs, 1 H), 2.95 (s, 3H), 2.37 (s, 3H), 2.32-2.28 (m, 3H)。 522 : LC-MS: m/z [M+H] + = 443.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.38 (s, 1H), 8.24 (d, J = 1.28 Hz, 1H), 7.95 (d, J = 8.44 Hz, 1H), 7.7-7.69 (m, 1H), 7.6 (d, J = 8.24 Hz, 1H), 7.41-7.39 (m, 1H), 6.22 (d, J = 8.48 Hz, 1H), 3.84 (bs, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.29-2.28 (m, 3H). 523 : LC-MS: m/z [M+H] + = 443.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.36 (s, 1H), 8.22 (s, 1H), 7.93 (d, J = 8.44 Hz, 1H), 7.67 (bs, 1H), 7.58 (d, J = 8.32 Hz, 1H), 7.39-7.37 (m, 1H), 6.20 (d, J = 8.4 Hz, 1H), 3.82 (bs, 1 H), 2.92 (s, 3H), 2.35 (s, 3H), 2.26 (s, 3H). 524 : LC-MS: m/z [M+H] + = 443.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.39 (s, 1H), 8.24 (s, 1H), 7.95 (d, J = 8.44 Hz, 1H), 7.70-7.69 (m, 1H), 7.60 (d, J = 8.32 Hz, 1H), 7.41-7.39 (m, 1H), 6.22 (d, J = 8.4 Hz, 1H), 3.84 (bs, 1 H), 2.95 (s, 3H), 2.37 (s, 3H), 2.29-2.28 (m, 3H). 525 : LC-MS: m/z [M+H] + = 443.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.38 (s, 1H), 8.24 (s, 1H), 7.95 (d, J = 8.44 Hz, 1H), 7.70 (bs, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.41-7.39 (m, 1H), 6.22 (d, J = 8.24 Hz, 1H), 3.91 (bs, 1 H), 2.95 (s, 3H), 2.37 (s, 3H), 2.32-2.28 (m, 3H).
實例 526-5296-(((3,4-二氯苯基)(5-甲基-4-(S-甲基亞磺醯亞胺基)-1H-咪唑-2-基)甲基)胺基)-2-甲基菸鹼甲腈及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 526-529: 6-(((3,4-dichlorophenyl)(5-methyl-4-(S-methylsulfinimino)-1H-imidazol-2-yl)methyl)amino)-2-methylnicotinamide and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Stereomeric derivatives were separated by palmar SFC.
製備型第一對掌性SFC：管柱：ChiralPak IC (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之乙腈-異丙醇(1:1)，流量：70 mL/min；共溶劑%：50%；ABPR：120巴；T：35℃。第一次溶析：526及527之混合物，第二次溶析：528及529之混合物。Preparation of the first pair of palmar SFCs: Column: ChiralPak IC (30 mm x 250 mm), 5 µm; Cosolvent: Acetonitrile-isopropanol (1:1) containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 50%; ABPR: 120 bar; T: 35 °C. First dissolution: mixture of 526 and 527 ; Second dissolution: mixture of 528 and 529 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：70 mL/min；共溶劑%：45%；ABPR：100巴；T：35℃。第一次溶析：526 ，第二次溶析：527。Preparation of the second pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 45%; ABPR: 100 bar; T: 35 °C. First precipitation: 526 , Second precipitation: 527 .
製備型第三對掌性SFC：管柱：ChiralPak IG (30 mm x 250 mm)，5µ；共溶劑：含0.4% (含7N氨之甲醇)之乙腈-甲醇(7:3)，流量：110 mL/min；共溶劑%：20%；ABPR：120巴；T：35℃。第一次溶析：528 ，第二次溶析：529。Preparation of the third palmar SFC: Column: ChiralPak IG (30 mm x 250 mm), 5 µm; Cosolvent: Acetonitrile-methanol (7:3) containing 0.4% (7N ammonia), flow rate: 110 mL/min; Cosolvent %: 20%; ABPR: 120 bar; T: 35 °C. First precipitation: 528 , Second precipitation: 529 .
526：LC-MS: m/z [M+H]+= 449.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.52 (bs, 1H), 8.48 (d, J = 7.64 Hz, 1H), 7.69-7.67 (m, 2H), 7.63-7.61 (m, 1H), 7.41-7.39 (m, 1H), 6.64 (d, J = 8.72 Hz, 1H), 6.45-6.44 (m, 1H), 3.85 (bs, 1H), 2.95 (s, 3H), 2.41-2.37 (m, 6H)。527：LC-MS: m/z [M+H]+= 449.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.52 (bs, 1H), 8.48 (d, J = 7.8 Hz, 1H), 7.69-7.67 (m, 2H), 7.63-7.61 (m, 1H), 7.42-7.39 (m, 1H), 6.63 (d, J = 8.72 Hz, 1H), 6.45-6.43 (m, 1H), 3.88 (bs, 1H), 2.96 (s, 3H), 2.41-2.38 (m, 6H)。528：LC-MS: m/z [M+H]+= 449.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.54 (bs, 1H), 8.49 (d, J = 7.08 Hz, 1H), 7.69-7.67 (m, 2H), 7.63-7.61 (m, 1H), 7.41-7.39 (m, 1H), 6.64 (d, J = 8.76 Hz, 1H), 6.45-6.44 (m, 1H), 3.87 (bs, 1H), 2.95 (s, 3H), 2.41-2.37 (m, 6H)。529：LC-MS: m/z [M+H]+= 449.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.53 (bs, 1H), 8.50 (d, J = 7.64 Hz, 1H), 7.69-7.67 (m, 2H), 7.63-7.61 (m, 1H), 7.41-7.39 (m, 1H), 6.64 (d, J = 8.68 Hz, 1H), 6.46-6.44 (m, 1H), 3.88 (bs, 1H), 2.96 (s, 3H), 2.41-2.37 (m, 6H)。 526 : LC-MS: m/z [M+H] + = 449.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.52 (bs, 1H), 8.48 (d, J = 7.64 Hz, 1H), 7.69-7.67 (m, 2H), 7.63-7.61 (m, 1H), 7.41-7.39 (m, 1H), 6.64 (d, J = 8.72 Hz, 1H), 6.45-6.44 (m, 1H), 3.85 (bs, 1H), 2.95 (s, 3H), 2.41-2.37 (m, 6H). 527 : LC-MS: m/z [M+H] + = 449.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.52 (bs, 1H), 8.48 (d, J = 7.8 Hz, 1H), 7.69-7.67 (m, 2H), 7.63-7.61 (m, 1H), 7.42-7.39 (m, 1H), 6.63 (d, J = 8.72 Hz, 1H), 6.45-6.43 (m, 1H), 3.88 (bs, 1H), 2.96 (s, 3H), 2.41-2.38 (m, 6H). 528 : LC-MS: m/z [M+H] + = 449.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.54 (bs, 1H), 8.49 (d, J = 7.08 Hz, 1H), 7.69-7.67 (m, 2H), 7.63-7.61 (m, 1H), 7.41-7.39 (m, 1H), 6.64 (d, J = 8.76 Hz, 1H), 6.45-6.44 (m, 1H), 3.87 (bs, 1H), 2.95 (s, 3H), 2.41-2.37 (m, 6H). 529 : LC-MS: m/z [M+H] + = 449.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.53 (bs, 1H), 8.50 (d, J = 7.64 Hz, 1H), 7.69-7.67 (m, 2H), 7.63-7.61 (m, 1H), 7.41-7.39 (m, 1H), 6.64 (d, J = 8.68 Hz, 1H), 6.46-6.44 (m, 1H), 3.88 (bs, 1H), 2.96 (s, 3H), 2.41-2.37 (m, 6H).
實例 530-533(2-((3,4-二氯苯基)((5-氟吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 530-533 (2-((3,4-dichlorophenyl)((5-fluoropyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Stereomeric derivatives were separated by palmar SFC.
製備型第一對掌性SFC：管柱：ChiralPak IC (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：120 mL/min；共溶劑%：35%；ABPR：100巴；T：35℃。第一次溶析：530及531之混合物，第二次溶析：532，第三次溶析：533。Preparation of the first pair of palmar SFCs: Column: ChiralPak IC (30 mm x 250 mm), 5µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 120 mL/min; Cosolvent %: 35%; ABPR: 100 bar; T: 35℃. First dissolution: mixture of 530 and 531 ; Second dissolution: 532 ; Third dissolution: 533 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：90 mL/min；共溶劑%：45%；ABPR：100巴；T：35℃。第一次溶析：530 ，第二次溶析：531。Preparation of the second pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 90 mL/min; Cosolvent %: 45%; ABPR: 100 bar; T: 35 °C. First dissolution: 530 °C , Second dissolution: 531 °C .
530：LC-MS: m/z [M+H]+= 428.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.49 (bs, 1H), 7.92-7.91 (m, 1H), 7.67 (s, 1H), 7.60-7.56 (m, 2H), 7.44-7.37 (m, 2H), 6.77-6.74 (m, 1H), 6.22 (d, J = 7.84 Hz, 1H), 3.82 (bs, 1H), 2.94 (s, 3H), 2.37 (s, 3H)。531：LC-MS: m/z [M+H]+= 428.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.52 (bs, 1H), 7.92-7.91 (m, 1H), 7.67 (s, 1H), 7.60-7.56 (m, 2H), 7.44-7.38 (m, 2H), 6.77-6.74 (m, 1H), 6.22 (d, J = 7.64 Hz, 1H), 4.09 (bs, 1H), 2.96 (s, 3H), 2.37 (s, 3H)。532：LC-MS: m/z [M+H]+= 428.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.49 (bs, 1H), 7.92-7.91 (m, 1H), 7.67 (s, 1H), 7.60-7.56 (m, 2H), 7.44-7.38 (m, 2H), 6.77-6.74 (m, 1H), 6.22 (d, J = 7.88 Hz, 1H), 3.83 (bs, 1H), 2.94 (s, 3H), 2.37 (s, 3H)。533：LC-MS: m/z [M+H]+= 428.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.50 (bs, 1H), 7.92-7.91 (m, 1H), 7.67 (s, 1H), 7.61-7.58 (m, 2H), 7.42-7.37 (m, 2H), 6.77-6.74 (m, 1H), 6.22 (d, J = 7.92 Hz, 1H), 3.83 (bs, 1H), 2.94 (s, 3H), 2.37 (s, 3H)。 530 : LC-MS: m/z [M+H] + = 428.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.49 (bs, 1H), 7.92-7.91 (m, 1H), 7.67 (s, 1H), 7.60-7.56 (m, 2H), 7.44-7.37 (m, 2H), 6.77-6.74 (m, 1H), 6.22 (d, J = 7.84 Hz, 1H), 3.82 (bs, 1H), 2.94 (s, 3H), 2.37 (s, 3H). 531 : LC-MS: m/z [M+H] + = 428.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.52 (bs, 1H), 7.92-7.91 (m, 1H), 7.67 (s, 1H), 7.60-7.56 (m, 2H), 7.44-7.38 (m, 2H), 6.77-6.74 (m, 1H), 6.22 (d, J = 7.64 Hz, 1H), 4.09 (bs, 1H), 2.96 (s, 3H), 2.37 (s, 3H). 532 : LC-MS: m/z [M+H] + = 428.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.49 (bs, 1H), 7.92-7.91 (m, 1H), 7.67 (s, 1H), 7.60-7.56 (m, 2H), 7.44-7.38 (m, 2H), 6.77-6.74 (m, 1H), 6.22 (d, J = 7.88 Hz, 1H), 3.83 (bs, 1H), 2.94 (s, 3H), 2.37 (s, 3H). 533 : LC-MS: m/z [M+H] + = 428.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.50 (bs, 1H), 7.92-7.91 (m, 1H), 7.67 (s, 1H), 7.61-7.58 (m, 2H), 7.42-7.37 (m, 2H), 6.77-6.74 (m, 1H), 6.22 (d, J = 7.92 Hz, 1H), 3.83 (bs, 1H), 2.94 (s, 3H), 2.37 (s, 3H).
實例 534-537(2-((3-氯苯基)((5-(二氟甲氧基)-6-甲基吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮、、、使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 534-537 (2-((3-chlorophenyl)((5-(difluoromethoxy)-6-methylpyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione , , , The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Stereomeric derivatives were separated by palmar SFC.
製備型第一對掌性SFC：管柱：Cellulose-SC (20 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇(1:1)，流量：70 mL/min；共溶劑%：25%；ABPR：100巴；T：35℃。第一次溶析：534及535之混合物，第二次溶析：536，第三次溶析：537。Preparation of the first pair of palmar SFCs: Column: Cellulose-SC (20 mm x 250 mm), 5 µm; Cosolvent: Isopropanol (1:1) containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 25%; ABPR: 100 bar; T: 35 °C. First dissolution: mixture of 534 and 535 ; Second dissolution: 536 ; Third dissolution: 537 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：100 mL/min；共溶劑%：35%；ABPR：100巴；T：35℃。第一次溶析：534 ，第二次溶析：535。Preparation of the second pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 100 mL/min; Cosolvent %: 35%; ABPR: 100 bar; T: 35 °C. First precipitation: 534 , Second precipitation: 535 .
534：LC-MS: m/z [M+H]+= 454.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.92 (bs, 1H), 7.55-7.52 (m, 2H), 7.39-7.26 (m, 4H), 7.13-6.75 (m, 1H), 6.58 (d, J = 8.8 Hz, 1H), 6.30 (d, J = 7.56 Hz, 1H), 2.39 (s, 3H), 2.20 (s, 3H)。535：LC-MS: m/z [M+H]+= 454.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.73 (bs, 1H), 7.53-7.51 (m, 2H), 7.38-7.26 (m, 4H), 7.12-6.75 (m, 1H), 6.57 (d, J = 8.84 Hz, 1H), 6.31 (d, J = 8.04 Hz, 1H), 3.16 (s, 1H), 2.39 (s, 3H), 2.21 (s, 3H)。536：LC-MS: m/z [M+H]+= 454.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.8 (bs, 1H), 7.53-7.51 (m, 2H), 7.38-7.26 (m, 4H), 7.12-6.75 (m, 1H), 6.58 (d, J = 8.8 Hz, 1H), 6.31 (d, J = 7.96 Hz, 1H), 3.20 (s, 1H), 2.39 (s, 3H), 2.21 (s, 3H)。537：LC-MS: m/z [M+H]+= 454.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.87 (bs, 1H), 7.55-7.52 (m, 2H), 7.39-7.32 (m, 3H), 7.28 (d, J = 8.8 Hz, 1H), 7.13-6.75 (m, 1H), 6.58 (d, J = 8.84 Hz, 1H), 6.30 (d, J = 7.72 Hz, 1H), 3.27 (s, 1H), 2.39 (s, 3H), 2.20 (s, 3H)。 534 : LC-MS: m/z [M+H] + = 454.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.92 (bs, 1H), 7.55-7.52 (m, 2H), 7.39-7.26 (m, 4H), 7.13-6.75 (m, 1H), 6.58 (d, J = 8.8 Hz, 1H), 6.30 (d, J = 7.56 Hz, 1H), 2.39 (s, 3H), 2.20 (s, 3H). 535 : LC-MS: m/z [M+H] + = 454.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.73 (bs, 1H), 7.53-7.51 (m, 2H), 7.38-7.26 (m, 4H), 7.12-6.75 (m, 1H), 6.57 (d, J = 8.84 Hz, 1H), 6.31 (d, J = 8.04 Hz, 1H), 3.16 (s, 1H), 2.39 (s, 3H), 2.21 (s, 3H). 536 : LC-MS: m/z [M+H] + = 454.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.8 (bs, 1H), 7.53-7.51 (m, 2H), 7.38-7.26 (m, 4H), 7.12-6.75 (m, 1H), 6.58 (d, J = 8.8 Hz, 1H), 6.31 (d, J = 7.96 Hz, 1H), 3.20 (s, 1H), 2.39 (s, 3H), 2.21 (s, 3H). 537 : LC-MS: m/z [M+H] + = 454.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.87 (bs, 1H), 7.55-7.52 (m, 2H), 7.39-7.32 (m, 3H), 7.28 (d, J = 8.8 Hz, 1H), 7.13-6.75 (m, 1H), 6.58 (d, J = 8.84 Hz, 1H), 6.30 (d, J = 7.72 Hz, 1H), 3.27 (s, 1H), 2.39 (s, 3H), 2.20 (s, 3H).
實例 538-5416-(((3-氯-4-氟苯基)(5-甲基-4-(S-甲基亞磺醯亞胺基)-1H-咪唑-2-基)甲基)胺基)-2-甲基菸鹼甲腈及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 538-541: 6-(((3-chloro-4-fluorophenyl)(5-methyl-4-(S-methylsulfinimino)-1H-imidazol-2-yl)methyl)amino)-2-methylnicotinamide and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Stereomeric derivatives were separated by palmar SFC.
製備型第一對掌性SFC：管柱：I-Cellulose-C (21 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：70 mL/min；共溶劑%：40%；ABPR：100巴；T：35℃。第一次溶析：538及539之混合物，第二次溶析：540及541之混合物。Preparation of the first pair of palmar SFCs: Column: I-Cellulose-C (21 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 40%; ABPR: 100 bar; T: 35 °C. First dissolution: mixture of 538 and 539 ; Second dissolution: mixture of 540 and 541 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：70 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：538 ，第二次溶析：539。Preparation of the second palmar SFC: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First precipitation: 538 , Second precipitation: 539 .
製備型第三對掌性SFC：管柱：ChiralPak IG (30 mm x 250 mm)，5µ；共溶劑：含0.4% (含7N氨之甲醇)之乙腈-甲醇(1:1)；流量：110 mL/min；共溶劑%：15%；ABPR：100巴；T：35℃。第一次溶析：540 ，第二次溶析：541。Preparation of the third palmar SFC: Column: ChiralPak IG (30 mm x 250 mm), 5 µm; Cosolvent: Acetonitrile-methanol (1:1) containing 0.4% (7N ammonia); Flow rate: 110 mL/min; Cosolvent %: 15%; ABPR: 100 bar; T: 35 °C. First precipitation: 540 , Second precipitation: 541 .
538：LC-MS: m/z [M+H]+= 433.31H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.51 (s, 1H), 8.47 (d, J = 7.16 Hz, 1H), 7.69-7.63 (m, 2H), 7.42-7.38 (m, 2H), 6.63 (d, J = 8.72 Hz, 1H), 6.45-6.43 (m, 1H), 3.87 (s, 1 H), 2.96 (s, 3H), 2.37 (s, 3H), 2.32 (s, 3H)。539：LC-MS: m/z [M+H]+= 433.31H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.51 (s, 1H), 8.45 (d, J = 7.48 Hz, 1H), 7.69-7.63 (m, 2H), 7.42-7.40 (m, 2H), 6.63 (d, J = 8.72 Hz, 1H), 6.44-6.43 (m, 1H), 3.87 (s, 1 H), 2.96 (s, 3H), 2.38-2.32 (m, 6H)。540：LC-MS: m/z [M+H]+= 433.31H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 8.60 (bs, 1H), 7.69-7.62 (m, 2H), 7.42-7.37 (m, 2H), 6.63 (d, J = 8.64 Hz, 1H), 6.42 (bs, 1H), 3.87 (s, 1 H), 2.95 (s, 3H), 2.41-2.35 (m, 6H)。541：LC-MS: m/z [M+H]+= 433.31H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.56 (bs, 1H), 8.58 (bs, 1H), 7.69-7.62 (m, 2H), 7.42-7.38 (m, 2H), 6.63 (d, J = 8.6 Hz, 1H), 6.42 (bs, 1H), 3.79 (s, 1 H), 2.95 (s, 3H), 2.41-2.37 (m, 6H)。 538 : LC-MS: m/z [M+H] + = 433.3 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.51 (s, 1H), 8.47 (d, J = 7.16 Hz, 1H), 7.69-7.63 (m, 2H), 7.42-7.38 (m, 2H), 6.63 (d, J = 8.72 Hz, 1H), 6.45-6.43 (m, 1H), 3.87 (s, 1H), 2.96 (s, 3H), 2.37 (s, 3H), 2.32 (s, 3H). 539 : LC-MS: m/z [M+H] + = 433.3 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.51 (s, 1H), 8.45 (d, J = 7.48 Hz, 1H), 7.69-7.63 (m, 2H), 7.42-7.40 (m, 2H), 6.63 (d, J = 8.72 Hz, 1H), 6.44-6.43 (m, 1H), 3.87 (s, 1H), 2.96 (s, 3H), 2.38-2.32 (m, 6H). 540 : LC-MS: m/z [M+H] + = 433.3 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 8.60 (bs, 1H), 7.69-7.62 (m, 2H), 7.42-7.37 (m, 2H), 6.63 (d, J = 8.64 Hz, 1H), 6.42 (bs, 1H), 3.87 (s, 1H), 2.95 (s, 3H), 2.41-2.35 (m, 6H). 541 : LC-MS: m/z [M+H] + = 433.3 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.56 (bs, 1H), 8.58 (bs, 1H), 7.69-7.62 (m, 2H), 7.42-7.38 (m, 2H), 6.63 (d, J = 8.6 Hz, 1H), 6.42 (bs, 1H), 3.79 (s, 1H), 2.95 (s, 3H), 2.41-2.37 (m, 6H).
實例 542-545(2-((3-氯-4-氟苯基)((6-(二氟甲基)-5-氟吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 542-545 (2-((3-chloro-4-fluorophenyl)((6-(difluoromethyl)-5-fluoropyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Stereomeric derivatives were separated by palmar SFC.
製備型第一對掌性SFC：管柱：I-Cellulose-C (21 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：70 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：542及543之混合物，第二次溶析：544，第三次溶析：545。Preparation of the first pair of palmar SFCs: Column: I-Cellulose-C (21 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First dissolution: mixture of 542 and 543 ; Second dissolution: 544 ; Third dissolution: 545 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：110 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：542 ，第二次溶析：543。Preparation of the second palmar SFC: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 110 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First precipitation: 542 , Second precipitation: 543 .
542：8%。LC-MS: m/z [M+H]+= 462.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.50 (bs, 1H), 7.89 (d, J = 7.96 Hz, 1H) 7.67-7.65 (m, 1H), 7.59-7.54 (m, 1H), 7.45-7.36 (m, 2H), 6.99-6.72 (m, 2H), 6.22 (d, J = 7.96 Hz, 1H), 3.85 (bs, 1H), 2.96 (s, 3H), 2.37 (s, 3H)。543：8%。LC-MS: m/z [M+H]+= 462.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.49 (bs, 1H), 7.86 (d, J = 7.96 Hz, 1H) 7.67-7.65 (m, 1H), 7.59-7.54 (m, 1H), 7.44-7.35 (m, 2H), 6.99-6.72 (m, 2H), 6.21 (d, J = 7.96 Hz, 1H), 3.85 (bs, 1H), 2.95 (s, 3H), 2.37 (s, 3H)。544：7%。LC-MS: m/z [M+H]+= 462.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.48 (bs, 1H), 7.86 (d, J = 7.84 Hz, 1H) 7.67-7.65 (m, 1H), 7.59-7.54 (m, 1H), 7.43-7.35 (m, 2H), 6.98-6.72 (m, 2H), 6.21 (d, J = 7.84 Hz, 1H), 3.84 (bs, 1H), 2.95 (s, 3H), 2.37 (s, 3H)。545：7%。LC-MS: m/z [M+H]+= 462.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.48 (bs, 1H), 7.87 (d, J = 7.88 Hz, 1H) 7.67-7.65 (m, 1H), 7.59-7.54 (m, 1H), 7.43-7.37 (m, 2H), 6.99-6.72 (m, 2H), 6.22 (d, J = 7.88 Hz, 1H), 3.83 (bs, 1H), 2.96 (s, 3H), 2.37 (s, 3H)。 542 : 8%. LC-MS: m/z [M+H] + = 462.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.50 (bs, 1H), 7.89 (d, J = 7.96 Hz, 1H) 7.67-7.65 (m, 1H), 7.59-7.54 (m, 1H), 7.45-7.36 (m, 2H), 6.99-6.72 (m, 2H), 6.22 (d, J = 7.96 Hz, 1H), 3.85 (bs, 1H), 2.96 (s, 3H), 2.37 (s, 3H). 543 : 8%. LC-MS: m/z [M+H] + = 462.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.49 (bs, 1H), 7.86 (d, J = 7.96 Hz, 1H) 7.67-7.65 (m, 1H), 7.59-7.54 (m, 1H), 7.44-7.35 (m, 2H), 6.99-6.72 (m, 2H), 6.21 (d, J = 7.96 Hz, 1H), 3.85 (bs, 1H), 2.95 (s, 3H), 2.37 (s, 3H). 544 : 7%. LC-MS: m/z [M+H] + = 462.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.48 (bs, 1H), 7.86 (d, J = 7.84 Hz, 1H) 7.67-7.65 (m, 1H), 7.59-7.54 (m, 1H), 7.43-7.35 (m, 2H), 6.98-6.72 (m, 2H), 6.21 (d, J = 7.84 Hz, 1H), 3.84 (bs, 1H), 2.95 (s, 3H), 2.37 (s, 3H). 545 : 7%. LC-MS: m/z [M+H] + = 462.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.48 (bs, 1H), 7.87 (d, J = 7.88 Hz, 1H) 7.67-7.65 (m, 1H), 7.59-7.54 (m, 1H), 7.43-7.37 (m, 2H), 6.99-6.72 (m, 2H), 6.22 (d, J = 7.88 Hz, 1H), 3.83 (bs, 1H), 2.96 (s, 3H), 2.37 (s, 3H).
實例 546-549(2-((3-氯-4-氟苯基)((6-(二氟甲基)-5-氟吡啶-2-基)胺基)甲基)-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 546-549 (2-((3-chloro-4-fluorophenyl)((6-(difluoromethyl)-5-fluoropyridin-2-yl)amino)methyl)-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Stereomeric derivatives were separated by palmar SFC.
製備型第一對掌性SFC：管柱：ChiralPak IC (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之甲醇；流量：90 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：546及547之混合物，第二次溶析：548，第三次溶析：549。Preparation of the first pair of palmar SFCs: Column: ChiralPak IC (30 mm x 250 mm), 5µm; Cosolvent: Methanol containing 0.2% (7N ammonia); Flow rate: 90 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35℃. First dissolution: mixture of 546 and 547 ; Second dissolution: 548 ; Third dissolution: 549 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：70 mL/min；共溶劑%：25%；ABPR：100巴；T：35℃。第一次溶析：546 ，第二次溶析：547。Preparation of the second palmar SFC: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 25%; ABPR: 100 bar; T: 35 °C. First precipitation: 546 , Second precipitation: 547 .
546：15%。LC-MS: m/z [M+H]+= 448.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.73 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 7.24 Hz, 1H), 7.61-7.55 (m, 2H), 7.44-7.38 (m, 2H), 6.94 (d, J = 8.56 Hz, 1H), 6.85 (t, J = 53.6 Hz, 1H), 6.30 (d, J = 8.0 Hz, 1H), 3.93 (s, 1H), 2.99 (s, 3H)。547：15%。LC-MS: m/z [M+H]+= 448.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.73 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 7.24 Hz, 1H), 7.61-7.55 (m, 2H), 7.44-7.38 (m, 2H), 6.94 (d, J = 8.56 Hz, 1H), 6.85 (t, J = 53.6 Hz, 1H), 6.30 (d, J = 8.0 Hz, 1H), 3.93 (s, 1H), 2.99 (s, 3H)。548：13%。LC-MS: m/z [M+H]+= 448.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.73 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 7.0 Hz, 1H), 7.62-7.55 (m, 2H), 7.44-7.38 (m, 2H), 6.94 (d, J = 9.08 Hz, 1H), 6.85 (t, J = 53.6 Hz, 1H), 6.30 (d, J = 8.0 Hz, 1H), 3.93 (s, 1H), 2.99 (s, 3H)。549：13%。LC-MS: m/z [M+H]+= 448.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.72 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.68 (dd, J = 7.0, 1.6 Hz, 1H), 7.62-7.55 (m, 2H), 7.46-7.36 (m, 2H), 6.94-6.71 (m, 2H), 6.29 (d, J = 8.0 Hz, 1H), 3.93 (s, 1H), 2.99 (s, 3H)。 546 : 15%. LC-MS: m/z [M+H] + = 448.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.73 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 7.24 Hz, 1H), 7.61-7.55 (m, 2H), 7.44-7.38 (m, 2H), 6.94 (d, J = 8.56 Hz, 1H), 6.85 (t, J = 53.6 Hz, 1H), 6.30 (d, J = 8.0 Hz, 1H), 3.93 (s, 1H), 2.99 (s, 3H). 547 : 15%. LC-MS: m/z [M+H] + = 448.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.73 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 7.24 Hz, 1H), 7.61-7.55 (m, 2H), 7.44-7.38 (m, 2H), 6.94 (d, J = 8.56 Hz, 1H), 6.85 (t, J = 53.6 Hz, 1H), 6.30 (d, J = 8.0 Hz, 1H), 3.93 (s, 1H), 2.99 (s, 3H). 548 : 13%. LC-MS: m/z [M+H] + = 448.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.73 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 7.0 Hz, 1H), 7.62-7.55 (m, 2H), 7.44-7.38 (m, 2H), 6.94 (d, J = 9.08 Hz, 1H), 6.85 (t, J = 53.6 Hz, 1H), 6.30 (d, J = 8.0 Hz, 1H), 3.93 (s, 1H), 2.99 (s, 3H). 549 : 13%. LC-MS: m/z [M+H] + = 448.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.72 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.68 (dd, J = 7.0, 1.6 Hz, 1H), 7.62-7.55 (m, 2H), 7.46-7.36 (m, 2H), 6.94-6.71 (m, 2H), 6.29 (d, J = 8.0 Hz, 1H), 3.93 (s, 1H), 2.99 (s, 3H).
實例 550-553(2-((3-氯-4-氟苯基)((6-乙基-5-氟吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 550-553 (2-((3-chloro-4-fluorophenyl)((6-ethyl-5-fluoropyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Stereomeric derivatives were separated by palmar SFC.
製備型對掌性HPLC：管柱：ChiralPak IC (20 mm x 250 mm)；溶劑：己烷-乙醇(9:1)，流量：18 mL/min；T：rt。第一次溶析：550及551之混合物，第二次溶析：552，第三次溶析：553。Preparative palmar HPLC: Column: ChiralPak IC (20 mm x 250 mm); Solvent: Hexane-ethanol (9:1); Flow rate: 18 mL/min; T: rt. First precipitation: mixture of 550 and 551 ; Second precipitation: 552 ; Third precipitation: 553 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：100 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：550 ，第二次溶析：551。Preparation of the second pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 100 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First precipitation: 550 °C , Second precipitation: 551 °C .
550：12%。LC-MS: m/z [M+H]+= 440.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= )= 12.48 (s, 1H), 7.65 (d, J = 6.76 Hz, 1H), 7.43-7.41 (m, 1H), 7.39-7.34 (m, 2H), 7.28 (t, J = 9.2 Hz, 1H) 6.55-6.53 (m, 1 H), 6.17 (d, J = 7.36 Hz, 1H), 4.34 (bs, 1H), 2.98 (s, 3H), 2.56-2.53(m, 2H), 2.36 (s, 3H), 1.06 (t, J = 7.44 Hz, 3H)。551：11%。LC-MS: m/z [M+H]+= 440.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= )= 12.43 (s, 1H), 7.65 (d, J = 6.48 Hz, 1H), 7.42-7.41 (m, 1H), 7.38-7.34 (m, 2H), 7.28 (t, J = 9.16 Hz, 1H), 6.55-6.53 (m, 1 H), 6.17 (d, J = 7.32 Hz, 1H), 3.81 (s, 1H), 2.94 (s, 3H), 2.56-2.53(m, 2H), 2.36 (s, 3H), 1.06 (t, J = 7.44 Hz, 3H)。552：17%。LC-MS: m/z [M+H]+= 440.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= )= 12.44 (s, 1H), 7.66-7.64 (m 1H), 7.42-7.41 (m, 1H), 7.39-7.34 (m, 2H), 7.28 (t, J = 9.16 Hz, 1H), 6.55-6.52 (m, 1 H), 6.17 (d, J = 7.6 Hz, 1H), 3.82 (s, 1H), 2.94 (s, 3H), 2.56-2.52 (m, 2H), 2.37 (s, 3H), 1.05 (t, J = 7.44 Hz, 3H)。553：15%。LC-MS: m/z [M+H]+= 440.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= )= 12.44 (s, 1H), 7.66-7.64 (m 1H), 7.42-7.40 (m, 1H), 7.39-7.36 (m, 2H), 7.28 (t, J = 9.16 Hz, 1H), 6.55-6.52 (m, 1H), 6.17 (d, J = 7.6 Hz, 1H), 3.82 (s, 1H), 2.94 (s, 3H), 2.55-2.52 (m, 2H), 2.36 (s, 3H), 1.05 (t, J = 7.44 Hz, 3H)。 550 : 12%. LC-MS: m/z [M+H] + = 440.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= )= 12.48 (s, 1H), 7.65 (d, J = 6.76 Hz, 1H), 7.43-7.41 (m, 1H), 7.39-7.34 (m, 2H), 7.28 (t, J = 9.2 Hz, 1H) 6.55-6.53 (m, 1 H), 6.17 (d, J = 7.36 Hz, 1H), 4.34 (bs, 1H), 2.98 (s, 3H), 2.56-2.53(m, 2H), 2.36 (s, 3H), 1.06 (t, J = 7.44 Hz, 3H). 551 :11%. LC-MS: m/z [M+H] + = 440.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= )= 12.43 (s, 1H), 7.65 (d, J = 6.48 Hz, 1H), 7.42-7.41 (m, 1H), 7.38-7.34 (m, 2H), 7.28 (t, J = 9.16 Hz, 1H), 6.55-6.53 (m, 1 H), 6.17 (d, J = 7.32 Hz, 1H), 3.81 (s, 1H), 2.94 (s, 3H), 2.56-2.53(m, 2H), 2.36 (s, 3H), 1.06 (t, J = 7.44 Hz, 3H). 552 : 17%. LC-MS: m/z [M+H] + = 440.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= )= 12.44 (s, 1H), 7.66-7.64 (m 1H), 7.42-7.41 (m, 1H), 7.39-7.34 (m, 2H), 7.28 (t, J = 9.16 Hz, 1H), 6.55-6.52 (m, 1 H), 6.17 (d, J = 7.6 Hz, 1H), 3.82 (s, 1H), 2.94 (s, 3H), 2.56-2.52 (m, 2H), 2.37 (s, 3H), 1.05 (t, J = 7.44 Hz, 3H). 553 : 15%. LC-MS: m/z [M+H] + = 440.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= )= 12.44 (s, 1H), 7.66-7.64 (m 1H), 7.42-7.40 (m, 1H), 7.39-7.36 (m, 2H), 7.28 (t, J = 9.16 Hz, 1H), 6.55-6.52 (m, 1H), 6.17 (d, J = 7.6 Hz, 1H), 3.82 (s, 1H), 2.94 (s, 3H), 2.55-2.52 (m, 2H), 2.36 (s, 3H), 1.05 (t, J = 7.44 Hz, 3H).
實例 554-557(2-((3-氯-4-氟苯基)((6-環丙基-5-氟吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 554-557 (2-((3-chloro-4-fluorophenyl)((6-cyclopropyl-5-fluoropyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Stereomeric derivatives were separated by palmar SFC.
製備型第一對掌性SFC：管柱：管柱：I-Cellulose-C (21 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：70 mL/min；共溶劑%：35%；ABPR：100巴；T：35℃。第一次溶析：554及555之混合物，第二次溶析：556及557之混合物。Preparation of the first pair of palmar SFCs: Column: I-Cellulose-C (21 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 35%; ABPR: 100 bar; T: 35 °C. First dissolution: a mixture of 554 and 555 ; Second dissolution: a mixture of 556 and 557 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：100 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：554 ，第二次溶析：555。Preparation of the second pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 100 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First precipitation: 554 , Second precipitation: 555 .
製備型第三對掌性HPLC：管柱：ChiralPak IG (30 mm x 250 mm)；溶劑：己烷-乙醇(9:1)，流量：27 mL/min；T：rt。第一次溶析：556 ，第二次溶析：557。Preparation of the third pair of palmar HPLC: Column: ChiralPak IG (30 mm x 250 mm); Solvent: hexane-ethanol (9:1); Flow rate: 27 mL/min; T: rt. First precipitation: 556 , Second precipitation: 557 .
554：21%。LC-MS: m/z [M+H]+= 452.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.39 (s, 1H), 7.62 (d, J = 6 Hz, 1H), 7.42-7.37 (m, 2H), 7.33 (d, J = 6.44 Hz, 1H), 7.26 (t, J = 9.2 Hz, 1H), 6.47-6.44 (m, 1 H), 5.95 (d, J = 6.4 Hz, 1H), 3.81 (s, 1H), 2.95 (s, 3H), 2.35 (s, 3H), 2.04-2.01 (m, 1H), 0.84-0.76 (m, 3H), 0.64-0.60 (m, 1H)。555：21%。LC-MS: m/z [M+H]+= 452.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.40 (s, 1H), 7.63-7.61 (m, 1H), 7.42-7.37 (m, 2H), 7.34 (d, J = 6.6 Hz, 1H), 7.26 (t, J = 9.2 Hz, 1H), 6.47-6.44 (m, 1 H), 5.95 (d, J = 6.4 Hz, 1H), 3.79 (s, 1H), 2.94 (s, 3H), 2.36 (s, 3H), 2.04-2.01 (m, 1H), 0.83-0.76 (m, 3H), 0.64-0.61 (m, 1H)。556：9%。LC-MS: m/z [M+H]+= 452.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.53 (s, 1H), 7.63 (d, J = 6.84 Hz, 1H), 7.40-7.38 (m, 2H), 7.35-7.33 (m, 2H), 7.26 (t, J = 9.16 Hz, 1H), 6.48-6.45 (m, 1 H), 5.97 (m, 1H), 3.07 (s, 3H), 2.36 (s, 3H), 2.03 (m, 1H), 0.81-0.74 (m, 3H), 0.66-0.64(m, 1H)。557：8%。LC-MS: m/z [M+H]+= 452.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.41 (s, 1H), 7.63-7.62 (m,1H), 7.40-7.34 (m, 3H), 7.26 (t,J= 9.2 Hz, 1H), 6.47-6.45 (m, 1 H), 5.96 (d,J= 6.4 Hz, 1H), 3.80 (s, 1H), 2.95 (s, 3H), 2.32 (s, 3H), 2.04-2.02 (m, 1H), 0.83-0.77 (m, 3H), 0.65-0.62 (m, 1H)。 554 : 21%. LC-MS: m/z [M+H] + = 452.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.39 (s, 1H), 7.62 (d, J = 6 Hz, 1H), 7.42-7.37 (m, 2H), 7.33 (d, J = 6.44 Hz, 1H), 7.26 (t, J = 9.2 Hz, 1H), 6.47-6.44 (m, 1 H), 5.95 (d, J = 6.4 Hz, 1H), 3.81 (s, 1H), 2.95 (s, 3H), 2.35 (s, 3H), 2.04-2.01 (m, 1H), 0.84-0.76 (m, 3H), 0.64-0.60 (m, 1H). 555 : 21%. LC-MS: m/z [M+H] + = 452.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.40 (s, 1H), 7.63-7.61 (m, 1H), 7.42-7.37 (m, 2H), 7.34 (d, J = 6.6 Hz, 1H), 7.26 (t, J = 9.2 Hz, 1H), 6.47-6.44 (m, 1H), 5.95 (d, J = 6.4 Hz, 1H), 3.79 (s, 1H), 2.94 (s, 3H), 2.36 (s, 3H), 2.04-2.01 (m, 1H), 0.83-0.76 (m, 3H), 0.64-0.61 (m, 1H). 556 : 9%. LC-MS: m/z [M+H] + = 452.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.53 (s, 1H), 7.63 (d, J = 6.84 Hz, 1H), 7.40-7.38 (m, 2H), 7.35-7.33 (m, 2H), 7.26 (t, J = 9.16 Hz, 1H), 6.48-6.45 (m, 1H), 5.97 (m, 1H), 3.07 (s, 3H), 2.36 (s, 3H), 2.03 (m, 1H), 0.81-0.74 (m, 3H), 0.66-0.64(m, 1H). 557 : 8%. LC-MS: m/z [M+H] + = 452.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.41 (s, 1H), 7.63-7.62 (m,1H), 7.40-7.34 (m, 3H), 7.26 (t, J = 9.2 Hz, 1H), 6.47-6.45 (m, 1 H), 5.96 (d, J = 6.4 Hz, 1H), 3.80 (s, 1H), 2.95 (s, 3H), 2.32 (s, 3H), 2.04-2.02 (m, 1H), 0.83-0.77 (m, 3H), 0.65-0.62 (m, 1H).
實例 558-561(2-((3-(二氟甲基)苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 558-561 (2-((3-(difluoromethyl)phenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Stereomeric derivatives were separated by palmar SFC.
製備型第一對掌性SFC：管柱：管柱：I Cellulose C (21.1 mm×250 mm )，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：70 mL/min；共溶劑%：35%；ABPR：100巴；T：35℃。第一次溶析：558及559之混合物，第二次溶析：560，第三次溶析：561。Preparation of the first pair of palmar SFCs: Column: I Cellulose C (21.1 mm × 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 35%; ABPR: 100 bar; T: 35 °C. First dissolution: mixture of 558 and 559 , second dissolution: 560 , third dissolution: 561 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：70 mL/min；共溶劑%：25%；ABPR：100巴；T：35℃。第一次溶析：558 ，第二次溶析：559。Preparation of the second pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 25%; ABPR: 100 bar; T: 35 °C. First precipitation: 558 , Second precipitation: 559 .
558：分析型對掌性HPLC條件：對掌性SFC：管柱：(R,R)-Whelk-O-1 (4.6 x 150 mm)，3.5 μm，移動相含0.5%異丙胺之異丙醇；流量：3 mL/min；共溶劑%：35%；ABPR：1595 psi；T：35℃；Rt = 2.57 min (第一次溶析)。LC-MS: m/z [M+H]+= 424.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (s, 1H), 7.64 (s,1H), 7.58 (d, J=7.2 Hz, 1H), 7.49-7.42 (m, 2H) , 7.34-7.26 (m, 2H), 7.01 (t, J= 55.8 Hz, 1H), 6.56-6.55 (m,1H), 6.30 (, J=8.0 Hz, 1H), 3.81 (s, 1H), 2.96 ( s, 3H), 2.37 (s, 3H), 2.21 (s, 3H)。559：分析型對掌性HPLC條件：對掌性SFC：管柱：(R,R)-Whelk-O-1 (4.6 x 150 mm)，3.5 μm，移動相含0.5%異丙胺之異丙醇；流量：3 mL/min；共溶劑%：35%；ABPR：1595 psi；T：35℃；Rt = 2.98 min (第二次溶析)。LC-MS: m/z [M+H]+= 424.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (s, 1H), 7.64 (s,1H), 7.58 (d, J=7.2 Hz, 1H), 7.47-7.43 (m, 2H) , 7.34-7.26 (m, 2H), 7.01 (t, J= 55.8 Hz, 1H), 6.56-6.55 (m,1H), 6.30 (, J=8.0 Hz, 1H), 3.81 (s, 1H), 2.96 ( s, 3H), 2.37 (s, 3H), 2.21 (s, 3H)。560：分析型對掌性HPLC條件：對掌性SFC：管柱：CHIRALPAK IC (4.6 x 250 mm)，5 μm，移動相含0 .3 %異丙胺之異丙醇；流量：3 mL/min；共溶劑%：25%；ABPR：1450 psi；T：35℃；Rt = 7.20 min。(第一次溶析)。LC-MS: m/z [M+H]+= 424.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (s, 1H), 7.64 (s,1H), 7.58 (d, J=7.2 Hz, 1H), 7.49-7.742 (m, 2H) , 7.34-7.26 (m, 2H), 7.01 (t, J= 55.8 Hz, 1H), 6.56-6.55 (m,1H), 6.30 (, J=8.0 Hz, 1H), 3.81 (s, 1H), 2.96 ( s, 3H), 2.37 (s, 3H), 2.21 (s, 3H)。561：分析型對掌性HPLC條件：對掌性SFC：管柱：CHIRALPAK IC (4.6 x 250 mm)，5 μm，移動相含0 .3 %異丙胺之異丙醇；流量：3 mL/min；共溶劑%：25%；ABPR：1450 psi；T：35℃；Rt = 7.81 min。(第二次溶析)。LC-MS: m/z [M+H]+= 424.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (s, 1H), 7.64 (s,1H), 7.58 (d, J=7.2 Hz, 1H), 7.47-7.43 (m, 2H) , 7.34-7.26 (m, 2H), 7.01 (t, J= 55.8 Hz, 1H), 6.56-6.55 (m,1H), 6.30 (, J=8.0 Hz, 1H), 3.81 (s, 1H), 2.96 ( s, 3H), 2.37 (s, 3H), 2.21 (s, 3H)。 558 : Analytical palmar HPLC conditions: Palmar SFC: Column: (R,R)-Whelk-O-1 (4.6 x 150 mm), 3.5 μm; mobile phase: isopropanol containing 0.5% isopropylamine; flow rate: 3 mL/min; cosolvent %: 35%; ABPR: 1595 psi; T: 35℃; Rt = 2.57 min (first precipitation). LC-MS: m/z [M+H] + = 424.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (s, 1H), 7.64 (s, 1H), 7.58 (d, J=7.2 Hz, 1H), 7.49-7.42 (m, 2H), 7.34-7.26 (m, 2H), 7.01 (t, J= 55.8 Hz, 1H), 6.56-6.55 (m,1H), 6.30 (, J=8.0 Hz, 1H), 3.81 (s, 1H), 2.96 (s, 3H), 2.37 (s, 3H), 2.21 (s, 3H). 559 : Analytical palmar HPLC conditions: Palmar SFC: Column: (R,R)-Whelk-O-1 (4.6 x 150 mm), 3.5 μm; mobile phase: isopropanol containing 0.5% isopropylamine; flow rate: 3 mL/min; cosolvent %: 35%; ABPR: 1595 psi; T: 35℃; Rt = 2.98 min (second precipitation). LC-MS: m/z [M+H] + = 424.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (s, 1H), 7.64 (s, 1H), 7.58 (d, J=7.2 Hz, 1H), 7.47-7.43 (m, 2H), 7.34-7.26 (m, 2H), 7.01 (t, J= 55.8 Hz, 1H), 6.56-6.55 (m,1H), 6.30 (, J=8.0 Hz, 1H), 3.81 (s, 1H), 2.96 (s, 3H), 2.37 (s, 3H), 2.21 (s, 3H). 560 : Analytical SFC conditions: SFC: Column: CHIRALPAK IC (4.6 x 250 mm), 5 μm; mobile phase: isopropanol containing 0.3% isopropylamine; flow rate: 3 mL/min; cosolvent %: 25%; ABPR: 1450 psi; T: 35℃; Rt = 7.20 min (first precipitation). LC-MS: m/z [M+H] + = 424.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (s, 1H), 7.64 (s, 1H), 7.58 (d, J=7.2 Hz, 1H), 7.49-7.742 (m, 2H), 7.34-7.26 (m, 2H), 7.01 (t, J= 55.8 Hz, 1H), 6.56-6.55 (m,1H), 6.30 (, J=8.0 Hz, 1H), 3.81 (s, 1H), 2.96 (s, 3H), 2.37 (s, 3H), 2.21 (s, 3H). 561 : Analytical palmar HPLC conditions: Palmar SFC: Column: CHIRALPAK IC (4.6 x 250 mm), 5 μm; mobile phase: isopropanol containing 0.3% isopropylamine; flow rate: 3 mL/min; cosolvent %: 25%; ABPR: 1450 psi; T: 35℃; Rt = 7.81 min (second precipitation). LC-MS: m/z [M+H] + = 424.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (s, 1H), 7.64 (s, 1H), 7.58 (d, J=7.2 Hz, 1H), 7.47-7.43 (m, 2H), 7.34-7.26 (m, 2H), 7.01 (t, J= 55.8 Hz, 1H), 6.56-6.55 (m,1H), 6.30 (, J=8.0 Hz, 1H), 3.81 (s, 1H), 2.96 (s, 3H), 2.37 (s, 3H), 2.21 (s, 3H).
實例 562-565(2-(((5-氟-6-甲基吡啶-2-基)胺基)(3-(三氟甲氧基)苯基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 562-565 (2-(((5-fluoro-6-methylpyridin-2-yl)amino)(3-(trifluoromethoxy)phenyl)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Stereomeric derivatives were separated by palmar SFC.
製備型第一對掌性SFC：管柱：CHIRALPAK IC (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之乙腈-異丙醇，流量：120 mL/min；共溶劑%：25%；ABPR：100巴；T：35℃。第一次溶析：562及563之混合物，第二次溶析：564，第三次溶析：565。Preparation of the first pair of palmar SFCs: Column: CHIRALPAK IC (30 mm x 250 mm), 5 µm; Cosolvent: Acetonitrile-isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 120 mL/min; Cosolvent %: 25%; ABPR: 100 bar; T: 35 °C. First dissolution: mixture of 562 and 563 ; Second dissolution: 564 ; Third dissolution: 565 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：100 mL/min；共溶劑%：35%；ABPR：100巴；T：35℃。第一次溶析：562 ，第二次溶析：563。Preparation of the second pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 100 mL/min; Cosolvent %: 35%; ABPR: 100 bar; T: 35 °C. First precipitation: 562 , Second precipitation: 563 .
562：LC-MS: m/z [M+H]+= 458.31H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.49 (bs, 1H), 7.46-7.38 (m, 4H), 7.31-7.27 (m, 1H), 7.24-7.22 (m, 1H), 6.57-6.55 (m, 1H), 6.28 (d, J = 8.12 Hz, 1H), 3.83 (bs, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.21-2.20 (m, 3H)。563: LC-MS: m/z [M+H]+= 458.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.49 (bs, 1H), 7.46-7.43 (m, 3H), 7.38-7.36 (m, 1H), 7.31-7.27 (m, 1H), 7.23-7.22 (m, 1H), 6.57-6.55 (m, 1H), 6.28 (d, J = 8.08 Hz, 1H), 3.82 (bs, 1H), 2.95 (s, 3H), 2.38 (s, 3H), 2.21-2.20 (m, 3H)。564：LC-MS: m/z [M+H]+= 458.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.50 (bs, 1H), 7.45-7.43 (m, 3H), 7.40-7.38 (m, 1H), 7.32-7.24 (m, 2H), 6.57-6.55 (m, 1H), 6.28 (d, J = 8.20 Hz, 1H), 3.84 (bs, 1H), 2.95 (s, 3H), 2.38 (s, 3H), 2.21-2.20 (m, 3H)。565：LC-MS: m/z [M+H]+= 458.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.50 (bs, 1H), 7.46-7.43 (m, 3H), 7.41-7.39 (m, 1H), 7.32-7.24 (m, 2H), 6.57-6.55 (m, 1H), 6.29 (d, J = 8.16 Hz, 1H), 3.84 (bs, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.21-2.20 (m, 3H)。 562 : LC-MS: m/z [M+H] + = 458.3 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.49 (bs, 1H), 7.46-7.38 (m, 4H), 7.31-7.27 (m, 1H), 7.24-7.22 (m, 1H), 6.57-6.55 (m, 1H), 6.28 (d, J = 8.12 Hz, 1H), 3.83 (bs, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.21-2.20 (m, 3H). 563 : LC-MS: m/z [M+H] + = 458.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.49 (bs, 1H), 7.46-7.43 (m, 3H), 7.38-7.36 (m, 1H), 7.31-7.27 (m, 1H), 7.23-7.22 (m, 1H), 6.57-6.55 (m, 1H), 6.28 (d, J = 8.08 Hz, 1H), 3.82 (bs, 1H), 2.95 (s, 3H), 2.38 (s, 3H), 2.21-2.20 (m, 3H). 564 : LC-MS: m/z [M+H] + = 458.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.50 (bs, 1H), 7.45-7.43 (m, 3H), 7.40-7.38 (m, 1H), 7.32-7.24 (m, 2H), 6.57-6.55 (m, 1H), 6.28 (d, J = 8.20 Hz, 1H), 3.84 (bs, 1H), 2.95 (s, 3H), 2.38 (s, 3H), 2.21-2.20 (m, 3H). 565 : LC-MS: m/z [M+H] + = 458.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.50 (bs, 1H), 7.46-7.43 (m, 3H), 7.41-7.39 (m, 1H), 7.32-7.24 (m, 2H), 6.57-6.55 (m, 1H), 6.29 (d, J = 8.16 Hz, 1H), 3.84 (bs, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.21-2.20 (m, 3H).
實例 566-569(2-((3-(二氟甲氧基)苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 566-569 (2-((3-(difluoromethoxy)phenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Stereomeric derivatives were separated by palmar SFC.
製備型第一對掌性SFC：管柱：CHIRALPAK IC (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之乙腈-異丙醇，流量：120 mL/min；共溶劑%：25%；ABPR：120巴；T：35℃。第一次溶析：566及567之混合物，第二次溶析：568，第三次溶析：569。Preparation of the first pair of palmar SFCs: Column: CHIRALPAK IC (30 mm x 250 mm), 5µm; Cosolvent: Acetonitrile-isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 120 mL/min; Cosolvent %: 25%; ABPR: 120 bar; T: 35℃. First dissolution: mixture of 566 and 567 , second dissolution: 568 , third dissolution: 569 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：70 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：566 ，第二次溶析：567。Preparation of the second pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First precipitation: 566 , Second precipitation: 567 .
566：LC-MS: m/z [M+H]+= 440.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.44 (bs, 1H), 7.39-7.00 (m, 7H), 6.56-6.54 (m, 1H), 6.26-6.24 (m, 1H), 3.81 (bs, 1H), 2.96 (s, 3H), 2.37 (s, 3H), 2.21-2.20 (m, 3H)。567：LC-MS: m/z [M+H]+= 440.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.44 (bs, 1H), 7.39-7.00 (m, 7H), 6.56-6.54 (m, 1H), 6.26-6.24 (m, 1H), 3.81 (bs, 1H), 2.96 (s, 3H), 2.37 (s, 3H), 2.21-2.20 (m, 3H)。568：LC-MS: m/z [M+H]+= 440.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (bs, 1H), 7.39-7.01 (m, 7H), 6.56-6.54 (m, 1H), 6.26-6.24 (m, 1H), 3.89 (bs, 1H), 2.96 (s, 3H), 2.37 (s, 3H), 2.21-2.20 (m, 3H)。569：LC-MS: m/z [M+H]+= 440.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (bs, 1H), 7.39-7.04 (m, 7H), 6.57-6.56 (m, 1H), 6.26-6.24 (m, 1H), 3.83 (bs, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.21-2.20 (m, 3H)。 566 : LC-MS: m/z [M+H] + = 440.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.44 (bs, 1H), 7.39-7.00 (m, 7H), 6.56-6.54 (m, 1H), 6.26-6.24 (m, 1H), 3.81 (bs, 1H), 2.96 (s, 3H), 2.37 (s, 3H), 2.21-2.20 (m, 3H). 567 : LC-MS: m/z [M+H] + = 440.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.44 (bs, 1H), 7.39-7.00 (m, 7H), 6.56-6.54 (m, 1H), 6.26-6.24 (m, 1H), 3.81 (bs, 1H), 2.96 (s, 3H), 2.37 (s, 3H), 2.21-2.20 (m, 3H). 568 : LC-MS: m/z [M+H] + = 440.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (bs, 1H), 7.39-7.01 (m, 7H), 6.56-6.54 (m, 1H), 6.26-6.24 (m, 1H), 3.89 (bs, 1H), 2.96 (s, 3H), 2.37 (s, 3H), 2.21-2.20 (m, 3H). 569 : LC-MS: m/z [M+H] + = 440.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (bs, 1H), 7.39-7.04 (m, 7H), 6.57-6.56 (m, 1H), 6.26-6.24 (m, 1H), 3.83 (bs, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.21-2.20 (m, 3H).
實例 570-573(2-((3-氯-4-氟苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-5-(甲氧基甲基)-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮、、、使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。產率：33%。藉由對掌性SFC分離立體異構物。 Examples 570-573 (2-((3-chloro-4-fluorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-5-(methoxymethyl)-1H-imidazol-4-yl)(imino)(methyl)-16-thione , , , The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Yield: 33%. Stereomers were separated by palmar SFC.
製備型第一對掌性製備型HPLC：管柱：CELLULOSE SC (20 mm x 250 mm)；5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：70 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：570及571之混合物，第二次溶析：572，第三次溶析：573。Preparative HPLC (first pair of plates): Column: CELLULOSE SC (20 mm x 250 mm); 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia); Flow rate: 70 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First precipitation: mixture of 570 and 571 ; Second precipitation: 572 ; Third precipitation: 573 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：70 mL/min；共溶劑%：25%；ABPR：100巴；T：35℃。第一次溶析：570 ，第二次溶析：571。Preparation of the second palmar SFC: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 25%; ABPR: 100 bar; T: 35 °C. First precipitation: 570 ° C , Second precipitation: 571 °C .
570：LC-MS: m/z [M+H]+= 456.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.79 (brs, 1H), 7.66-7.64 (m, 1H), 7.43-7.27 (m, 4H), 6.57-6.54 (m, 1H), 6.32-6.3 (d, J=8.4 Hz, 1H), 4.68-4.6 (m, 2H), 3.97 (s, 1H), 3.26 (s, 3H), 2.99 (s, 3H), 2.21-2.2 (d, J=2.4 Hz, 3H)。571：LC-MS: m/z [M+H]+= 456.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.79 (brs, 1H), 7.67-7.64 (m, 1H), 7.45-7.27 (m, 4H), 6.57-6.54 (m, 1H), 6.32-6.3 (d, J=8.4 Hz, 1H), 4.64 (m, 2H), 3.97 (s, 1H), 3.26 (s, 3H), 2.99 (s, 3H), 2.21-2.2 (d, J=2.4 Hz, 3H)。572：LC-MS: m/z [M+H]+= 456.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.81 (brs, 1H), 7.67-7.65 (m, 1H), 7.43-7.28 (m, 4H), 6.57-6.55 (m, 1H), 6.32-6.3 (d, J=8.4 Hz, 1H), 4.64 (s, 2H), 3.98 (s, 1H), 3.27 (s, 3H), 2.99 (s, 3H), 2.21-2.2 (d, J=2.4 Hz, 3H)。573：LC-MS: m/z [M+H]+= 456.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.81 (brs, 1H), 7.66-7.64 (m, 1H), 7.43-7.27 (m, 4H), 6.56-6.54 (m, 1H), 6.29-6.27 (d, J=8.4 Hz, 1H), 4.65-4.57 (m, 2H), 3.95 (s, 1H), 3.26 (s, 3H), 2.99 (s, 3H), 2.21-2.2 (d, J=2.4 Hz, 3H)。 570 : LC-MS: m/z [M+H] + = 456.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.79 (brs, 1H), 7.66-7.64 (m, 1H), 7.43-7.27 (m, 4H), 6.57-6.54 (m, 1H), 6.32-6.3 (d, J=8.4 Hz, 1H), 4.68-4.6 (m, 2H), 3.97 (s, 1H), 3.26 (s, 3H), 2.99 (s, 3H), 2.21-2.2 (d, J=2.4 Hz, 3H). 571 : LC-MS: m/z [M+H] + = 456.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.79 (brs, 1H), 7.67-7.64 (m, 1H), 7.45-7.27 (m, 4H), 6.57-6.54 (m, 1H), 6.32-6.3 (d, J=8.4 Hz, 1H), 4.64 (m, 2H), 3.97 (s, 1H), 3.26 (s, 3H), 2.99 (s, 3H), 2.21-2.2 (d, J=2.4 Hz, 3H). 572 : LC-MS: m/z [M+H] + = 456.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.81 (brs, 1H), 7.67-7.65 (m, 1H), 7.43-7.28 (m, 4H), 6.57-6.55 (m, 1H), 6.32-6.3 (d, J=8.4 Hz, 1H), 4.64 (s, 2H), 3.98 (s, 1H), 3.27 (s, 3H), 2.99 (s, 3H), 2.21-2.2 (d, J=2.4 Hz, 3H). 573 : LC-MS: m/z [M+H] + = 456.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.81 (brs, 1H), 7.66-7.64 (m, 1H), 7.43-7.27 (m, 4H), 6.56-6.54 (m, 1H), 6.29-6.27 (d, J=8.4 Hz, 1H), 4.65-4.57 (m, 2H), 3.95 (s, 1H), 3.26 (s, 3H), 2.99 (s, 3H), 2.21-2.2 (d, J=2.4 Hz, 3H).
實例 574-577(2-((3-氯-4-氟苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-5-(羥基甲基)-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮、、、 Examples 574-577 (2-((3-chloro-4-fluorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-5-(hydroxymethyl)-1H-imidazol-4-yl)(imino)(methyl)-16-thione , , ,
步驟-1：向2-((3-氯-4-氟苯基)((二異丙基胺甲醯基)氧基)甲基)-4-(S-甲基亞磺醯亞胺基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-5-甲酸甲酯中間物75 (250 mg，0.396 mmol)、5-氟-6-甲基吡啶-2-胺(255 mg，2.019 mmol，5 equiv.)於DCM (8 mL)中之溶液中添加三氟化硼乙醚(0.5 mL，3.96 mmol，10 equiv.)、TFA (0.6 mL，7.921 mmol，20 equiv.)且在RT下攪拌2 h。用冰冷水(50 mL)稀釋反應混合物且用乙酸乙酯(2 × 50 mL)萃取。用飽和NaHCO3溶液(50 mL)、鹽水(50 mL)洗滌合併之有機層且經無水Na2SO4乾燥。在減壓下濃縮溶劑，得到粗產物，藉由急驟管柱層析純化，得到2-((3-氯-4-氟苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-4-(S-甲基亞磺醯亞胺基)-1H-咪唑-5-甲酸甲酯。產率：80.6% (150 mg，0.31 mmol)。LC-MS: m/z [M+H]+ = 470.10。Step 1: Add boron trifluoride diethyl ether (0.5 mL, 3.96 mmol, 10 equiv.) and TFA (0.6 mL, 7.921 mmol, 20 equiv.) to a solution of 2-((3-chloro-4-fluorophenyl)((diisopropylaminomethoxy)oxy)methyl)-4-(S-methylsulfinimino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium-5-carboxylate intermediate 75 (250 mg, 0.396 mmol), 5-fluoro-6-methylpyridin-2-amine (255 mg, 2.019 mmol, 5 equiv.) in DCM (8 mL) and stir at RT for 2 h. Dilute the reaction mixture with ice-cold water (50 mL) and extract with ethyl acetate (2 × 50 mL). The combined organic layers were washed with saturated NaHCO3 solution (50 mL) and brine (50 mL) and dried over anhydrous Na2SO4 . The solvent was concentrated under reduced pressure to give the crude product, which was purified by rapid column chromatography to give methyl 2-((3-chloro-4-fluorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-4-(S-methylsulfinimino)-1H-imidazol-5-carboxylate. Yield: 80.6% (150 mg, 0.31 mmol). LC-MS: m/z [M+H]+ = 470.10.
步驟-2：在0℃下在氮氣氛圍下向步驟-1之產物(300 mg，0.64 mmol，1 equiv.)於THF (6 mL)中之攪拌溶液中添加LiBH4(1M於THF中) (1.2 mL，1.28 mmol，2 equiv.)。將混合物在室溫下攪拌16 h。用NH4Cl水溶液淬滅反應物且用乙酸乙酯(2 × 100 ml)萃取水性部分。用鹽水(100 ml)洗滌合併之有機層，經無水Na2SO4乾燥且在減壓下濃縮，得到粗產物，藉由急驟管柱層析純化，得到(2-((3-氯-4-氟苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-5-(羥基甲基)-1H-咪唑-4-基)(亞胺基)(甲基)- λ6-硫酮。產率：33.9% (96 mg，0.21 mmol)。藉由對掌性SFC分離立體異構物。Step 2: LiBH₄ (1M in THF) (1.2 mL, 1.28 mmol, 2 equiv.) was added to a stirred solution of the product of Step 1 (300 mg, 0.64 mmol, 1 equiv.) in THF (6 mL) at 0 °C under a nitrogen atmosphere. The mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with aqueous NH₄Cl solution and the aqueous fraction was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (100 ml), dried over anhydrous Na₂SO₄ , and concentrated under reduced pressure to give a crude product. Purification by rapid column chromatography yielded (2-((3-chloro-4-fluorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-5-(hydroxymethyl)-1H-imidazol-4-yl)(imino)(methyl) -λ6 -thione. Yield: 33.9% (96 mg, 0.21 mmol). Stereomers were separated by palmar SFC.
製備型第一對掌性SFC：管柱：I-Cellulose-Z (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之乙腈-異丙醇，流量：70 mL/min；共溶劑%：25%；ABPR：100巴；T：35℃。第一次溶析：574及575之混合物，第二次溶析：576，第三次溶析：577。Preparation of the first pair of palmar SFCs: Column: I-Cellulose-Z (30 mm x 250 mm), 5 µm; Cosolvent: Acetonitrile-isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 25%; ABPR: 100 bar; T: 35 °C. First dissolution: mixture of 574 and 575 ; Second dissolution: 576 ; Third dissolution: 577 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：70 mL/min；共溶劑%：20%；ABPR：120巴；T：35℃。第一次溶析：574 ，第二次溶析：575。Preparation of the second pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 20%; ABPR: 120 bar; T: 35 °C. First precipitation: 574 , Second precipitation: 575 .
574：LC-MS: m/z [M+H]+= 442.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.65 (s, 1H), 7.67-7.64 (m, 1H), 7.45-7.42 (m, 1H), 7.39-7.28 (m, 3H), 6.57-6.54 (m, 1H), 6.52 (s, 1H), 6.34 (d, J= 8.68 Hz, 1H), 5.44-5.43 (m, 1H), 4.68 (s, 2H), 4.00 (s, 1H), 2.99 (s, 3H), 2.22-2.21 (m, 3H)。575：LC-MS: m/z [M+H]+= 442.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.64 (s, 1H), 7.66-7.65 (m, 1H), 7.45-7.43 (m, 1H), 7.39-7.28 (m, 3H), 6.57-6.54 (m, 1H), 6.50 (s, 1H), 6.33 (d, J= 8.6 Hz, 1H), 5.45-5.42 (m, 1H), 4.73-4.62 (m, 2H), 4.00 (s, 1H), 3.00 (s, 3H), 2.22-2.21 (m, 3H)。576：LC-MS: m/z [M+H]+= 442.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.60 (s, 1H), 7.66-7.65 (m, 1H), 7.39-7.30 (m, 4H), 6.57-6.54 (m, 1H), 6.33 (d, J= 8.56 Hz, 1H), 5.42 (s, 1H), 4.69-4.66 (m, 2H), 4.98 (s, 1H), 3.00 (s, 3H), 2.22-2.21 (m, 3H)。577：LC-MS: m/z [M+H]+= 442.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.62 (s, 1H), 7.66-7.64 (m, 1H), 7.43-7.27 (m, 4H), 6.57-6.54 (m, 1H), 6.33 (d, J= 8.64 Hz, 1H), 5.41-5.39 (m, 1H), 4.69-4.67 (m, 2H), 3.98 (s, 1H), 3.00 (s, 3H), 2.22-2.21 (m, 3H)。 574 : LC-MS: m/z [M+H] + = 442.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.65 (s, 1H), 7.67-7.64 (m, 1H), 7.45-7.42 (m, 1H), 7.39-7.28 (m, 3H), 6.57-6.54 (m, 1H), 6.52 (s, 1H), 6.34 (d, J= 8.68 Hz, 1H), 5.44-5.43 (m, 1H), 4.68 (s, 2H), 4.00 (s, 1H), 2.99 (s, 3H), 2.22-2.21 (m, 3H). 575 : LC-MS: m/z [M+H] + = 442.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.64 (s, 1H), 7.66-7.65 (m, 1H), 7.45-7.43 (m, 1H), 7.39-7.28 (m, 3H), 6.57-6.54 (m, 1H), 6.50 (s, 1H), 6.33 (d, J= 8.6 Hz, 1H), 5.45-5.42 (m, 1H), 4.73-4.62 (m, 2H), 4.00 (s, 1H), 3.00 (s, 3H), 2.22-2.21 (m, 3H). 576 : LC-MS: m/z [M+H] + = 442.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.60 (s, 1H), 7.66-7.65 (m, 1H), 7.39-7.30 (m, 4H), 6.57-6.54 (m, 1H), 6.33 (d, J= 8.56 Hz, 1H), 5.42 (s, 1H), 4.69-4.66 (m, 2H), 4.98 (s, 1H), 3.00 (s, 3H), 2.22-2.21 (m, 3H). 577 : LC-MS: m/z [M+H] + = 442.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.62 (s, 1H), 7.66-7.64 (m, 1H), 7.43-7.27 (m, 4H), 6.57-6.54 (m, 1H), 6.33 (d, J= 8.64 Hz, 1H), 5.41-5.39 (m, 1H), 4.69-4.67 (m, 2H), 3.98 (s, 1H), 3.00 (s, 3H), 2.22-2.21 (m, 3H).
實例 578-581(2-((3,4-二氟苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 578-581 (2-((3,4-difluorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Stereomeric derivatives were separated by palmar SFC.
製備型第一對掌性SFC：管柱：I Cellulose C (21.1 mm × 250 mm)，5µ；共溶劑：異丙醇，流量：70 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：578及579之混合物，第二次溶析：580，第三次溶析：581。Preparation of the first pair of palmar SFCs: Column: I Cellulose C (21.1 mm × 250 mm), 5 µm; Cosolvent: Isopropanol, flow rate: 70 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First dissolution: mixture of 578 and 579 ; Second dissolution: 580 ; Third dissolution: 581 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm )，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：100 mL/min；共溶劑%：35%；ABPR：100巴；T：35℃。第一次溶析：578 ，第二次溶析：579。Preparation of the second pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 100 mL/min; Cosolvent %: 35%; ABPR: 100 bar; T: 35 °C. First precipitation: 578 , Second precipitation: 579 .
578：LC-MS: m/z [M+H]+= 410.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.43 (s, 1H), 7.49-7.44 (m, 1H), 7.40-7.28 (m,4H), 6.55-6.55-6.52 (m, 1 H), 6.23 (d, J = 8.16 Hz, 1H), 3.82 (bs, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.21-2.20 (m, 3H)。579：LC-MS: m/z [M+H]+= 410.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.45 (s, 1H), 7.49-7.45 (m, 1H), 7.40-7.27 (m,4H), 6.55-6.52 (m, 1 H), 6.23 (d, J = 8.04 Hz, 1H), 3.82 (bs, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.21-2.20 (m, 3H)。580：LC-MS: m/z [M+H]+= 410.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.48 (s, 1H), 7.47-7.43 (m, 1H), 7.40-7.28 (m,4H), 6.55-6.55-6.52 (m, 1 H), 6.23 (d, J = 7.72 Hz, 1H), 3.82 (bs, 1H), 2.99 (s, 3H), 2.37 (s, 3H), 2.21-2.20 (m, 3H)。581：LC-MS: m/z [M+H]+= 410.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.43 (s, 1H), 7.49-7.44 (m, 1H), 7.40-7.28 (m,4H), 6.55-6.55-6.52 (m, 1 H), 6.23 (d, J = 8.16 Hz, 1H), 3.82 (bs, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.21-2.20 (m, 3H)。 578 : LC-MS: m/z [M+H] + = 410.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.43 (s, 1H), 7.49-7.44 (m, 1H), 7.40-7.28 (m,4H), 6.55-6.55-6.52 (m, 1 H), 6.23 (d, J = 8.16 Hz, 1H), 3.82 (bs, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.21-2.20 (m, 3H). 579 : LC-MS: m/z [M+H] + = 410.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.45 (s, 1H), 7.49-7.45 (m, 1H), 7.40-7.27 (m,4H), 6.55-6.52 (m, 1 H), 6.23 (d, J = 8.04 Hz, 1H), 3.82 (bs, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.21-2.20 (m, 3H). 580 : LC-MS: m/z [M+H] + = 410.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.48 (s, 1H), 7.47-7.43 (m, 1H), 7.40-7.28 (m,4H), 6.55-6.55-6.52 (m, 1 H), 6.23 (d, J = 7.72 Hz, 1H), 3.82 (bs, 1H), 2.99 (s, 3H), 2.37 (s, 3H), 2.21-2.20 (m, 3H). 581 : LC-MS: m/z [M+H] + = 410.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.43 (s, 1H), 7.49-7.44 (m, 1H), 7.40-7.28 (m,4H), 6.55-6.55-6.52 (m, 1 H), 6.23 (d, J = 8.16 Hz, 1H), 3.82 (bs, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.21-2.20 (m, 3H).
實例 582-585(2-((3,5-二氟苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物。 Examples 582-585 (2-((3,5-difluorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Stereomeric derivatives were separated by palmar SFC.
製備型第一對掌性SFC：管柱：I Cellulose C (21.1 mm × 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：70 mL/min；共溶劑%：35%；ABPR：100巴；T：35℃。第一次溶析：582及583之混合物，第二次溶析：584，第三次溶析：585。Preparation of the first pair of palmar SFCs: Column: I Cellulose C (21.1 mm × 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 35%; ABPR: 100 bar; T: 35 °C. First dissolution: mixture of 582 and 583 ; Second dissolution: 584 ; Third dissolution: 585 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm )，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：100 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：582 ，第二次溶析：583。Preparation of the second palmar SFC: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 100 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First precipitation: 582 , Second precipitation: 583 .
582：LC-MS: m/z [M+H]+= 410.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (s, 1H), 7.39 (d, J=8.28 Hz, 1H), 7.30 (t, J=9.08 Hz, 1H), 7.15-7.08 (m, 3H), 6.57-6.54 (m,1H), 6.26 (d, J=8.08 Hz, 1H), 3.84 (s, 1H), 2.95 ( s, 3H), 2.37 (s, 3H), 2.20-2.19 (m, 3H)。分析型對掌性HPLC條件：對掌性SFC：管柱：(R, R) WHELK-O1 (4.6 mm x 150 mm)，3.5 μm，移動相含0 .3%異丙胺之異丙醇；流量：3 mL/min；共溶劑%：30%；ABPR：1000 psi；T：35℃；Rt = 2.28 min。583：LC-MS: m/z [M+H]+= 410.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (s, 1H), 7.39 (d, J=8.28 Hz, 1H), 7.31 (t, J=9.08 Hz, 1H), 7.15-7.08 (m, 3H), 6.57-6.54 (m,1H), 6.26 (d, J=8.08 Hz, 1H), 3.84 (s, 1H), 2.95 ( s, 3H), 2.37 (s, 3H), 2.20-2.19 (m, 3H)。分析型對掌性HPLC條件：對掌性SFC：管柱：(R, R) WHELK-O1 (4.6 mm x 150 mm)，3.5 μm，移動相含0 .3%異丙胺之異丙醇；流量：3 mL/min；共溶劑%：30%；ABPR：1000 psi；T：35℃；Rt = 2.65 min。584：LC-MS: m/z [M+H]+= 410.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.50 (s, 1H), 7.38 (d, J=8.28 Hz, 1H), 7.30 (t, J=9.08 Hz, 1H), 7.15-7.08 (m, 3H), 6.57-6.54 (m,1H), 6.26 (d, J=8.08 Hz, 1H), 3.83 (s, 1H), 2.96 ( s, 3H), 2.37 (s, 3H), 2.21 (m, 3H)。分析型對掌性HPLC條件：對掌性SFC：管柱：CHIRALPAK IC (4.6 x 250 mm)，5 μm，移動相含0 .5%異丙胺之異丙醇；流量：3 mL/min；共溶劑%：40%；ABPR：1000 psi；T：35℃；Rt = 2.55 min。585：LC-MS: m/z [M+H]+= 410.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (s, 1H), 7.39 (d, J=8.28 Hz, 1H), 7.31 (t, J=9.08 Hz, 1H), 7.15-7.08 (m, 3H), 6.55-6.55 (m,1H), 6.26 (d, J=8.08 Hz, 1H), 3.84 (s, 1H), 2.95 ( s, 3H), 2.37 (s, 3H), 2.20-2.19 (m, 3H)。分析型對掌性HPLC條件：對掌性SFC：管柱：CHIRALPAK IC (4.6 x 250 mm)，5 μm，移動相含0 .5%異丙胺之異丙醇；流量：3 mL/min；共溶劑%：40%；ABPR：1000 psi；T：35℃；Rt = 2.85 min。 582 : LC-MS: m/z [M+H] + = 410.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (s, 1H), 7.39 (d, J=8.28 Hz, 1H), 7.30 (t, J=9.08 Hz, 1H), 7.15-7.08 (m, 3H), 6.57-6.54 (m,1H), 6.26 (d, J=8.08 Hz, 1H), 3.84 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.20-2.19 (m, 3H). Analytical HPLC conditions: SFC: Column: (R, R) WHELK-O1 (4.6 mm x 150 mm), 3.5 μm; mobile phase: isopropanol containing 0.3% isopropylamine; flow rate: 3 mL/min; cosolvent %: 30%; ABPR: 1000 psi; T: 35℃; Rt = 2.28 min. LC-MS: m/z [M+H] + = 410.3 . 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (s, 1H), 7.39 (d, J=8.28 Hz, 1H), 7.31 (t, J=9.08 Hz, 1H), 7.15-7.08 (m, 3H), 6.57-6.54 (m,1H), 6.26 (d, J=8.08 Hz, 1H), 3.84 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.20-2.19 (m, 3H). Analytical HPLC conditions: SFC: Column: (R, R) WHELK-O1 (4.6 mm x 150 mm), 3.5 μm; mobile phase: isopropanol containing 0.3% isopropylamine; flow rate: 3 mL/min; cosolvent %: 30%; ABPR: 1000 psi; T: 35℃; Rt = 2.65 min. LC-MS: m/z [M+H] + = 410.3 . 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.50 (s, 1H), 7.38 (d, J=8.28 Hz, 1H), 7.30 (t, J=9.08 Hz, 1H), 7.15-7.08 (m, 3H), 6.57-6.54 (m,1H), 6.26 (d, J=8.08 Hz, 1H), 3.83 (s, 1H), 2.96 (s, 3H), 2.37 (s, 3H), 2.21 (m, 3H). Analytical HPLC conditions: SFC: Column: CHIRALPAK IC (4.6 x 250 mm), 5 μm; mobile phase: isopropanol containing 0.5% isopropylamine; flow rate: 3 mL/min; cosolvent %: 40%; ABPR: 1000 psi; T: 35℃; Rt = 2.55 min. LC-MS: m/z [M+H] + = 410.3 . 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.46 (s, 1H), 7.39 (d, J=8.28 Hz, 1H), 7.31 (t, J=9.08 Hz, 1H), 7.15-7.08 (m, 3H), 6.55-6.55 (m,1H), 6.26 (d, J=8.08 Hz, 1H), 3.84 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.20-2.19 (m, 3H). Analytical palmar HPLC conditions: Palmar SFC: Column: CHIRALPAK IC (4.6 x 250 mm), 5 μm, mobile phase containing 0.5% isopropylamine in isopropanol; flow rate: 3 mL/min; cosolvent %: 40%; ABPR: 1000 psi; T: 35℃; Rt = 2.85 min.
實例 586-589(2-((3-氯-2,4-二氟苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。產率：40%。藉由對掌性SFC分離立體異構物。 Examples 586-589 (2-((3-chloro-2,4-difluorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Yield: 40%. Stereomers were separated by palmar SFC.
製備型第一對掌性SFC：管柱：I Cellulose C (21.1 mm × 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：70 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：586及587之混合物，第二次溶析：588，第三次溶析：589。Preparation of the first pair of palmar SFCs: Column: I Cellulose C (21.1 mm × 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First dissolution: mixture of 586 and 587 ; Second dissolution: 588 ; Third dissolution: 589 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm )，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：70 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：586 ，第二次溶析：587。Preparation of the second pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First precipitation: 586 , Second precipitation: 587 .
586：LC-MS: m/z [M+H]+= 444.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.57 (s, 1H), 7.52-7.49 (m, 2H), 7.33-7.29 (m, 2H), 6.55-6.47 (m, 2H), 3.82 (bs, 1H), 2.93 (s, 3H), 2.38 (s, 3H), 2.19-2.18 (m, 3H)。587：LC-MS: m/z [M+H]+= 444.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.56 (s, 1H), 7.51-7.47 (m, 2H), 7.33-7.29 (m, 2H), 6.55-6.48 (m, 2H), 3.82 (bs, 1H), 2.94 (s, 3H), 2.38 (s, 3H), 2.20-2.19 (m, 3H)。588：LC-MS: m/z [M+H]+= 444.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.58 (s, 1H), 7.50-7.48 (m, 2H), 7.33-7.28 (m, 2H), 6.54-6.47 (m, 2H), 3.83 (bs, 1H), 2.93 (s, 3H), 2.37 (s, 3H), 2.20-2.19 (m, 3H)。589：LC-MS: m/z [M+H]+= 444.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.58 (s, 1H), 7.51-7.50 (m, 2H), 7.33-7.28 (m, 2H), 6.55-6.48 (m, 2H), 4.01 (bs, 1H), 2.95 (s, 3H), 2.38 (s, 3H), 2.19-2.18 (m, 3H)。 586 : LC-MS: m/z [M+H] + = 444.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.57 (s, 1H), 7.52-7.49 (m, 2H), 7.33-7.29 (m, 2H), 6.55-6.47 (m, 2H), 3.82 (bs, 1H), 2.93 (s, 3H), 2.38 (s, 3H), 2.19-2.18 (m, 3H). 587 : LC-MS: m/z [M+H] + = 444.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.56 (s, 1H), 7.51-7.47 (m, 2H), 7.33-7.29 (m, 2H), 6.55-6.48 (m, 2H), 3.82 (bs, 1H), 2.94 (s, 3H), 2.38 (s, 3H), 2.20-2.19 (m, 3H). 588 : LC-MS: m/z [M+H] + = 444.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.58 (s, 1H), 7.50-7.48 (m, 2H), 7.33-7.28 (m, 2H), 6.54-6.47 (m, 2H), 3.83 (bs, 1H), 2.93 (s, 3H), 2.37 (s, 3H), 2.20-2.19 (m, 3H). 589 : LC-MS: m/z [M+H] + = 444.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.58 (s, 1H), 7.51-7.50 (m, 2H), 7.33-7.28 (m, 2H), 6.55-6.48 (m, 2H), 4.01 (bs, 1H), 2.95 (s, 3H), 2.38 (s, 3H), 2.19-2.18 (m, 3H).
實例 590-593(2-((3-氯-4-氟苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。產率：68%。藉由對掌性SFC分離立體異構物。 Examples 590-593 (2-((3-chloro-4-fluorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Yield: 68%. Stereomers were separated by palmar SFC.
製備型第一對掌性SFC：管柱：Chiralpak IC (30.0 mm x 250 mm )，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：120 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：590及591之混合物，第二次溶析：592，第三次溶析：593。Preparation of the first pair of palmar SFCs: Column: Chiralpak IC (30.0 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 120 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First dissolution: mixture of 590 and 591 , second dissolution: 592 , third dissolution: 593 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm )，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：70 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：590 ，第二次溶析：591。Preparation of the second pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First precipitation: 590 , Second precipitation: 591 .
590：LC-MS: m/z [M+H]+= 412.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.66 (s, 1H), 7.66-7.64 (m, 1H), 7.59 (bs, 1H), 7.44-7.28 (m, 4H), 6.57-6.54 (m, 1H), 6.32 (d, J = 8.24 Hz, 1H), 3.91 (s, 1H), 2.98 (s, 3H), 2.20 (s, 3H)。591：LC-MS: m/z [M+H]+= 412.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.67 (s, 1H), 7.66-7.60 (m, 2H), 7.44-7.28 (m, 4H), 6.56-6.54 (m, 1H), 6.31 (d, J = 8.24 Hz, 1H), 3.92 (s, 1H), 2.98 (s, 3H), 2.20 (s, 3H)。592：LC-MS: m/z [M+H]+= 412.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.67 (s, 1H), 7.65 (d, J = 6.92 Hz, 1H), 7.60 (bs, 1H), 7.44-7.35 (m, 3H), 7.32-7.28 (m, 1H), 6.55 (d, J = 8.68 Hz, 1H), 6.32 (d, J = 8.2 Hz, 1H), 3.91 (s, 1H), 2.98 (s, 3H), 2.20 (s, 3H)。593：LC-MS: m/z [M+H]+= 412.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.67 (s, 1H), 7.66 (d, J = 6.92 Hz, 1H), 7.60 (bs, 1H), 7.44-7.37 (m, 3H), 7.32-7.28 (m, 1H), 6.55 (d, J = 8.72 Hz, 1H), 6.31 (d, J = 8.16 Hz, 1H), 3.92 (s, 1H), 2.98 (s, 3H), 2.20 (s, 3H)。 590 : LC-MS: m/z [M+H] + = 412.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.66 (s, 1H), 7.66-7.64 (m, 1H), 7.59 (bs, 1H), 7.44-7.28 (m, 4H), 6.57-6.54 (m, 1H), 6.32 (d, J = 8.24 Hz, 1H), 3.91 (s, 1H), 2.98 (s, 3H), 2.20 (s, 3H). 591 : LC-MS: m/z [M+H] + = 412.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.67 (s, 1H), 7.66-7.60 (m, 2H), 7.44-7.28 (m, 4H), 6.56-6.54 (m, 1H), 6.31 (d, J = 8.24 Hz, 1H), 3.92 (s, 1H), 2.98 (s, 3H), 2.20 (s, 3H). 592 : LC-MS: m/z [M+H] + = 412.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.67 (s, 1H), 7.65 (d, J = 6.92 Hz, 1H), 7.60 (bs, 1H), 7.44-7.35 (m, 3H), 7.32-7.28 (m, 1H), 6.55 (d, J = 8.68 Hz, 1H), 6.32 (d, J = 8.2 Hz, 1H), 3.91 (s, 1H), 2.98 (s, 3H), 2.20 (s, 3H). 593 : LC-MS: m/z [M+H] + = 412.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.67 (s, 1H), 7.66 (d, J = 6.92 Hz, 1H), 7.60 (bs, 1H), 7.44-7.37 (m, 3H), 7.32-7.28 (m, 1H), 6.55 (d, J = 8.72 Hz, 1H), 6.31 (d, J = 8.16 Hz, 1H), 3.92 (s, 1H), 2.98 (s, 3H), 2.20 (s, 3H).
實例 594-597(2-((3-氯-2-甲氧基苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。產率：68%。藉由對掌性SFC分離立體異構物。 Examples 594-597 (2-((3-chloro-2-methoxyphenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Yield: 68%. Stereomers were separated by palmar SFC.
製備型第一對掌性SFC：管柱：管柱：I-Cellulose-C (21.1 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：70 mL/min；共溶劑%：40%；ABPR：100巴；T：35℃。第一次溶析：594及595之混合物，第二次溶析：596及597之混合物。Preparation of the first pair of palmar SFCs: Column: I-Cellulose-C (21.1 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 40%; ABPR: 100 bar; T: 35 °C. First dissolution: a mixture of 594 and 595 ; Second dissolution: a mixture of 596 and 597 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：120 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：594 ，第二次溶析：595。Preparation of the second pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 120 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First precipitation: 594 , Second precipitation: 595 .
製備型第三對掌性製備型HPLC：管柱：Chiralpak IB (21 mm x 250mm )，5µ；共溶劑：含0.2% (含7N氨之甲醇)之乙腈-異丙醇(7:3)，流量：70 mL/min；共溶劑%：15%；ABPR：100巴；T：35℃。第一次溶析：596 ，第二次溶析：597。Preparation-type third-pair palmar preparation-type HPLC: Column: Chiralpak IB (21 mm x 250 mm), 5 µm; Cosolvent: Acetonitrile-isopropanol (7:3) containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 15%; ABPR: 100 bar; T: 35 °C. First precipitation: 596 , Second precipitation: 597 .
594：LC-MS: m/z [M+H]+= 438.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.47 (bs, 1H), 7.43 (d, J = 7.68 Hz, 1H), 7.38-7.36 (m, 2H), 7.29 (t, J = 9.04 Hz, 1H), 7.12 (t, J = 7.88 Hz, 1H), 6.59-6.52 (m, 2H), 3.79-3.71 (m, 4H), 2.92 (s, 3H), 2.36 (s, 3H), 2.18 (s, 3H)。595：LC-MS: m/z [M+H]+= 438.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.44 (s, 1H), 7.42 (d, J = 7.48 Hz, 1H), 7.36 (t, J = 7.96 Hz, 2H), 7.28 (t, J = 9.00 Hz, 1H), 7.12 (t, J = 7.68 Hz, 1H), 6.59-6.52 (m, 2H), 3.79-3.71 (m, 4H), 2.91 (s, 3H), 2.37 (s, 3H), 2.18 (s, 3H)。596：LC-MS: m/z [M+H]+= 438.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.44 (bs, 1H), 7.42 (d, J = 7.32 Hz, 1H), 7.36-7.37 (m, 2H), 7.29 (t, J = 8.92 Hz, 1H), 7.13 (t, J = 7.52 Hz, 1H), 6.59-6.52 (m, 2H), 3.79-3.71 (m, 4H), 2.92 (s, 3H), 2.37 (s, 3H), 2.18 (s, 3H)。597：LC-MS: m/z [M+H]+= 438.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.39 (bs, 1H), 7.43 (d, J = 7.56 Hz, 1H), 7.38-7.36 (m, 2H), 7.28 (t, J = 8.96 Hz, 1H), 7.12 (t, J = 7.76 Hz, 1H), 6.59-6.52 (m, 2H), 3.79-3.71 (m, 4H), 2.92 (s, 3H), 2.37 (s, 3H), 2.18 (s, 3H)。 594 : LC-MS: m/z [M+H] + = 438.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.47 (bs, 1H), 7.43 (d, J = 7.68 Hz, 1H), 7.38-7.36 (m, 2H), 7.29 (t, J = 9.04 Hz, 1H), 7.12 (t, J = 7.88 Hz, 1H), 6.59-6.52 (m, 2H), 3.79-3.71 (m, 4H), 2.92 (s, 3H), 2.36 (s, 3H), 2.18 (s, 3H). 595 : LC-MS: m/z [M+H] + = 438.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.44 (s, 1H), 7.42 (d, J = 7.48 Hz, 1H), 7.36 (t, J = 7.96 Hz, 2H), 7.28 (t, J = 9.00 Hz, 1H), 7.12 (t, J = 7.68 Hz, 1H), 6.59-6.52 (m, 2H), 3.79-3.71 (m, 4H), 2.91 (s, 3H), 2.37 (s, 3H), 2.18 (s, 3H). 596 : LC-MS: m/z [M+H] + = 438.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.44 (bs, 1H), 7.42 (d, J = 7.32 Hz, 1H), 7.36-7.37 (m, 2H), 7.29 (t, J = 8.92 Hz, 1H), 7.13 (t, J = 7.52 Hz, 1H), 6.59-6.52 (m, 2H), 3.79-3.71 (m, 4H), 2.92 (s, 3H), 2.37 (s, 3H), 2.18 (s, 3H). 597 : LC-MS: m/z [M+H] + = 438.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.39 (bs, 1H), 7.43 (d, J = 7.56 Hz, 1H), 7.38-7.36 (m, 2H), 7.28 (t, J = 8.96 Hz, 1H), 7.12 (t, J = 7.76 Hz, 1H), 6.59-6.52 (m, 2H), 3.79-3.71 (m, 4H), 2.92 (s, 3H), 2.37 (s, 3H), 2.18 (s, 3H).
實例 598-601(2-((5-氯-4-氟-2-甲氧基苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。產率：36%。藉由對掌性SFC分離立體異構物。 Examples 598-601 (2-((5-chloro-4-fluoro-2-methoxyphenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Yield: 36%. Stereomers were separated by palmar SFC.
製備型第一對掌性SFC：管柱：Chiralpak IC (30.0 mm x 250 mm )，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：70 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：598及599之混合物，第二次溶析：600，第三次溶析：601。Preparation of the first pair of palmar SFCs: Column: Chiralpak IC (30.0 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First dissolution: a mixture of 598 and 599 , second dissolution: 600 , third dissolution: 601 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm )，5µ；共溶劑：異丙醇，流量：70 mL/min；共溶劑%：35%；ABPR：100巴；T：35℃。第一次溶析：598 ，第二次溶析：599。Preparation of second palmar SFC: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: isopropanol, flow rate: 70 mL/min; Cosolvent %: 35%; ABPR: 100 bar; T: 35 °C. First precipitation: 598 , Second precipitation: 599 .
598：LC-MS: m/z [M+H]+= 456.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.37 (s, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.31-7.27 (m, 2H), 7.17 (d, J= 11.4, 1H), 6.50-6.46 (m, 2H), 3.80 (s, 3H), 2.92 (s, 3H), 2.36 (s, 3H), 2.18 (s, 3H)。599：LC-MS: m/z [M+H]+= 456.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.37 (s, 1H), 7.55 (d, J=8.6 Hz, 1H), 7.31-7.26 (m, 2H), 7.17 (d, J= 11.4, 1H), 6.50-6.46 (m, 2H), 3.80 (s, 3H), 2.92 (s, 3H), 2.36 (s, 3H), 2.19 (s, 3H)。600：LC-MS: m/z [M+H]+= 456.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.34 (s, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.28-7.23 (m, 2H), 7.14 (d, J= 11.4, 1H), 6.47-6.43 (m, 2H), 3.77 (m, 3H), 2.89 (s, 3H), 2.33 (s, 3H), 2.16 (s, 3H)。601：LC-MS: m/z [M+H]+= 456.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.36 (s, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.31-7.26 (m, 2H), 7.16 (d, J= 11.4, 1H), 6.50-6.46 (m, 2H), 3.80-3.77 (m, 4H), 2.92 (s, 3H), 2.36 (s, 3H), 2.19 (s, 3H)。 598 : LC-MS: m/z [M+H] + = 456.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.37 (s, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.31-7.27 (m, 2H), 7.17 (d, J= 11.4, 1H), 6.50-6.46 (m, 2H), 3.80 (s, 3H), 2.92 (s, 3H), 2.36 (s, 3H), 2.18 (s, 3H). 599 : LC-MS: m/z [M+H] + = 456.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.37 (s, 1H), 7.55 (d, J=8.6 Hz, 1H), 7.31-7.26 (m, 2H), 7.17 (d, J= 11.4, 1H), 6.50-6.46 (m, 2H), 3.80 (s, 3H), 2.92 (s, 3H), 2.36 (s, 3H), 2.19 (s, 3H). 600 : LC-MS: m/z [M+H] + = 456.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.34 (s, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.28-7.23 (m, 2H), 7.14 (d, J= 11.4, 1H), 6.47-6.43 (m, 2H), 3.77 (m, 3H), 2.89 (s, 3H), 2.33 (s, 3H), 2.16 (s, 3H). 601 : LC-MS: m/z [M+H] + = 456.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.36 (s, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.31-7.26 (m, 2H), 7.16 (d, J= 11.4, 1H), 6.50-6.46 (m, 2H), 3.80-3.77 (m, 4H), 2.92 (s, 3H), 2.36 (s, 3H), 2.19 (s, 3H).
實例 602-605(2-((5-氯-2-甲氧基苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。產率：81%。藉由對掌性SFC分離立體異構物。 Examples 602-605 (2-((5-chloro-2-methoxyphenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Yield: 81%. Stereomers were separated by palmar SFC.
製備型第一對掌性SFC：管柱：Chiralpak IC (30.0 mm x 250 mm )，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：70 mL/min；共溶劑%：40%；ABPR：100巴；T：35℃。第一次溶析：602及603之混合物，第二次溶析：604，第三次溶析：605。Preparation of the first pair of palmar SFCs: Column: Chiralpak IC (30.0 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 40%; ABPR: 100 bar; T: 35 °C. First dissolution: a mixture of 602 and 603 ; Second dissolution: 604 ; Third dissolution: 605 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm )，5µ；共溶劑：異丙醇，流量：70 mL/min；共溶劑%：35%；ABPR：100巴；T：35℃。第一次溶析：602 ，第二次溶析：603。Preparation of the second pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: isopropanol, flow rate: 70 mL/min; Cosolvent %: 35%; ABPR: 100 bar; T: 35 °C. First dissolution: 602 °C , Second dissolution: 603 ° C.
602：LC-MS: m/z [M+H]+= 456.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.36 (bs, 1H), 7.44 (s, 1H), 7.30-7.22 (m, 3H), 7.02 (d, J = 8.72 Hz, 1H), 6.51 (d, J = 8.52 Hz, 2H), 3.77-3.75 (m, 4H), 2.92 (s, 3H), 2.36-2.32 (m, 3H), 2.19 (m, 3H)。603：LC-MS: m/z [M+H]+= 456.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.38 (bs, 1H), 7.44 (s, 1H), 7.30-7.22 (m, 3H), 7.01 (d, J = 8.72 Hz, 1H), 6.50 (d, J = 8.52 Hz, 2H), 3.78 (s, 4H), 2.92 (s, 3H), 2.36-2.33 (m, 3H), 2.19 (s, 3H)。604：LC-MS: m/z [M+H]+= 456.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.36 (bs, 1H), 7.44 (s, 1H), 7.28-7.23 (m, 3H), 7.02 (d, J = 8.76 Hz, 1H), 6.51 (d, J = 8.6 Hz, 2H), 3.78 (s, 4H), 2.92 (s, 3H), 2.36 (s, 3H), 2.19-2.18 (m, 3H)。605：LC-MS: m/z [M+H]+= 456.3。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.37 (bs, 1H), 7.44 (s, 1H), 7.30-7.24 (m, 3H) 7.02 (d, J = 8.68 Hz, 1H), 6.51 (d, J = 8.56 Hz, 2H), 3.77 (s, 4H), 2.92 (s, 3H), 2.36-2.32 (m, 3H), 2.19-2.18 (m, 3H)。 602 : LC-MS: m/z [M+H] + = 456.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.36 (bs, 1H), 7.44 (s, 1H), 7.30-7.22 (m, 3H), 7.02 (d, J = 8.72 Hz, 1H), 6.51 (d, J = 8.52 Hz, 2H), 3.77-3.75 (m, 4H), 2.92 (s, 3H), 2.36-2.32 (m, 3H), 2.19 (m, 3H). 603 : LC-MS: m/z [M+H] + = 456.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.38 (bs, 1H), 7.44 (s, 1H), 7.30-7.22 (m, 3H), 7.01 (d, J = 8.72 Hz, 1H), 6.50 (d, J = 8.52 Hz, 2H), 3.78 (s, 4H), 2.92 (s, 3H), 2.36-2.33 (m, 3H), 2.19 (s, 3H). 604 : LC-MS: m/z [M+H] + = 456.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.36 (bs, 1H), 7.44 (s, 1H), 7.28-7.23 (m, 3H), 7.02 (d, J = 8.76 Hz, 1H), 6.51 (d, J = 8.6 Hz, 2H), 3.78 (s, 4H), 2.92 (s, 3H), 2.36 (s, 3H), 2.19-2.18 (m, 3H). 605 : LC-MS: m/z [M+H] + = 456.3. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.37 (bs, 1H), 7.44 (s, 1H), 7.30-7.24 (m, 3H) 7.02 (d, J = 8.68 Hz, 1H), 6.51 (d, J = 8.56 Hz, 2H), 3.77 (s, 4H), 2.92 (s, 3H), 2.36-2.32 (m, 3H), 2.19-2.18 (m, 3H).
實例 606-609(2-((3,4-二氟-2-甲氧基苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。產率：68%。 Examples 606-609 (2-((3,4-difluoro-2-methoxyphenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared using a method similar to that described for Examples 467-470, from suitable intermediates and reagents. Yield: 68%.
製備型對掌性SFC：管柱：Chiralpak IC (30.0 mm x 250 mm )，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：70 mL/min；共溶劑%：35%；ABPR：100巴；T：35℃。第一次溶析：606 ，第二次溶析：607。第三次溶析：608。第四溶析：609。Preparation of a palmar SFC: Column: Chiralpak IC (30.0 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 35%; ABPR: 100 bar; T: 35 °C. First dissolution: 606 , Second dissolution: 607 , Third dissolution: 608 , Fourth dissolution: 609 .
606：LC-MS: m/z [M+H]+= 440.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.42 (s, 1H), 7.37-7.35 (d, J = 8.56 Hz, 1H), 7.29-7.27 (m, 1H ), 7.25-7.22 (m, 1H), 7.18-7.14 (m, 1H), 6.52-6.50 (m, 2H), 3.83 (s, 3H), 3.77 (m, 1H), 2.92 (s, 3H), 2.37 (s, 3H), 2.18 (s, 3H)。607：LC-MS: m/z [M+H]+= 440.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.43 (s, 1H), 7.37-7.35 (d, J = 8.56 Hz, 1H), 7.29-7.27 (m, 1H ), 7.24-7.21 (m, 1H), 7.18-7.14 (m, 1H), 6.52-6.50 (m, 2H), 3.84 (s, 3H), 3.79 (m, 1H), 2.91 (s, 3H), 2.37 (s, 3H), 2.18 (s, 3H)。608：LC-MS: m/z [M+H]+= 440.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.43 (bs, 1H), 7.37-7.35 (d, J = 8.56 Hz, 1H), 7.29-7.27 (m, 1H ), 7.25-7.22 (m, 1H), 7.18-7.14 (m, 1H), 6.52-6.50 (m, 2H), 3.83 (s, 3H), 3.79 (m, 1H), 2.91 (s, 3H), 2.37 (s, 3H), 2.18 (s, 3H)。609：LC-MS: m/z [M+H]+= 440.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.43 (s, 1H), 7.38-7.35 (d, J = 8.64 Hz, 1H), 7.29-7.27 (m, 1H ), 7.25-7.22 (m, 1H), 7.18-7.14 (m, 1H), 6.52-6.50 (m, 2H), 3.83 (s, 3H), 3.77 (m, 1H), 2.92 (s, 3H), 2.37 (s, 3H), 2.18 (s, 3H)。 606 : LC-MS: m/z [M+H] + = 440.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.42 (s, 1H), 7.37-7.35 (d, J = 8.56 Hz, 1H), 7.29-7.27 (m, 1H ), 7.25-7.22 (m, 1H), 7.18-7.14 (m, 1H), 6.52-6.50 (m, 2H), 3.83 (s, 3H), 3.77 (m, 1H), 2.92 (s, 3H), 2.37 (s, 3H), 2.18 (s, 3H). 607 : LC-MS: m/z [M+H] + = 440.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.43 (s, 1H), 7.37-7.35 (d, J = 8.56 Hz, 1H), 7.29-7.27 (m, 1H ), 7.24-7.21 (m, 1H), 7.18-7.14 (m, 1H), 6.52-6.50 (m, 2H), 3.84 (s, 3H), 3.79 (m, 1H), 2.91 (s, 3H), 2.37 (s, 3H), 2.18 (s, 3H). 608 : LC-MS: m/z [M+H] + = 440.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.43 (bs, 1H), 7.37-7.35 (d, J = 8.56 Hz, 1H), 7.29-7.27 (m, 1H ), 7.25-7.22 (m, 1H), 7.18-7.14 (m, 1H), 6.52-6.50 (m, 2H), 3.83 (s, 3H), 3.79 (m, 1H), 2.91 (s, 3H), 2.37 (s, 3H), 2.18 (s, 3H). 609 : LC-MS: m/z [M+H] + = 440.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.43 (s, 1H), 7.38-7.35 (d, J = 8.64 Hz, 1H), 7.29-7.27 (m, 1H ), 7.25-7.22 (m, 1H), 7.18-7.14 (m, 1H), 6.52-6.50 (m, 2H), 3.83 (s, 3H), 3.77 (m, 1H), 2.92 (s, 3H), 2.37 (s, 3H), 2.18 (s, 3H).
實例 610-613(2-((3-氯-4-氟苯基)((1-甲基-3-(三氟甲基)-1H-吡唑-5-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。產率：29%。藉由對掌性SFC分離立體異構物 Examples 610-613 (2-((3-chloro-4-fluorophenyl)((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Yield: 29%. Stereomers were separated by palmar SFC.
製備型第一對掌性SFC：管柱：管柱：I-Cellulose-Z (30 mm x 250 mm)，5µ；共溶劑：含0.1% (含7N氨之甲醇)之異丙醇，流量：90 mL/min；共溶劑%：25%；ABPR：100巴；T：35℃。第一次溶析：610及611之混合物，第二次溶析：612及613之混合物。Preparation of the first pair of palmar SFCs: Column: I-Cellulose-Z (30 mm x 250 mm), 5µm; Cosolvent: Isopropanol containing 0.1% (methanol containing 7N ammonia), flow rate: 90 mL/min; Cosolvent %: 25%; ABPR: 100 bar; T: 35℃. First dissolution: a mixture of 610 and 611 ; Second dissolution: a mixture of 612 and 613 .
製備型第二對掌性SFC：管柱：Chiralpak IC (30.0 mm x 250 mm )，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：120 mL/min；共溶劑%：25%；ABPR：120巴；T：35℃。第一次溶析：610 ，第二次溶析：611。Preparation of the second palmar SFC: Column: Chiralpak IC (30.0 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 120 mL/min; Cosolvent %: 25%; ABPR: 120 bar; T: 35 °C. First dissolution: 610 , Second dissolution: 611 .
製備型第三對掌性FC：管柱：Chiralpak IC (30.0 mm x 250 mm )，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：120 mL/min；共溶劑%：25%；ABPR：120巴；T：35℃。第一次溶析：612 ，第二次溶析：613。Preparation of the third palmar FC: Column: Chiralpak IC (30.0 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 120 mL/min; Cosolvent %: 25%; ABPR: 120 bar; T: 35 °C. First precipitation: 612 , Second precipitation: 613 .
610：LC-MS: m/z [M+H]+= 463.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.51 (bs, 1H), 7.81-7.78 (m, 1H), 7.58-7.56 (m, 1H), 7.44-7.41 (m, 1H), 6.84 (d, J = 6.8 Hz, 1H), 5.73 (s, 1H), 5.60 (d, J = 6.72 Hz, 1H), 3.85 (bs, 1H), 3.71 (s, 3H), 2.93 (s, 3H), 2.38 (s, 3H)。611：LC-MS: m/z [M+H]+= 463.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.52 (bs, 1H), 7.80-7.78 (m, 1H), 7.53-7.52 (m, 1H), 7.43-7.39 (m, 1H), 6.84 (d, J = 7.04 Hz, 1H), 5.73 (s, 1H), 5.60 (d, J = 6.88 Hz, 1H), 3.85 (bs, 1H), 3.70 (s, 3H). 2.96-2.93 (m, 3H), 2.38 (s, 3H)。612：LC-MS: m/z [M+H]+= 463.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.50 (bs, 1H), 7.80-7.78 (m, 1H), 7.52-7.48 (m, 1H), 7.43-7.41 (m, 1H), 6.83 (d, J = 6.96 Hz, 1H), 5.74 (s, 1H), 5.60 (d, J = 6.72 Hz, 1H), 3.85 (bs, 1H), 3.70 (s, 3H), 2.93 (s, 3H), 2.39 (s, 3H)。613：LC-MS: m/z [M+H]+= 463.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.52 (bs, 1H), 7.81-7.78 (m, 1H), 7.55-7.53 (m, 1H), 7.44-7.39 (m, 1H), 6.83 (d, J = 6.84 Hz, 1H), 5.73 (s, 1H), 5.60 (d, J = 6.72 Hz, 1H), 3.85 (bs, 1H), 3.71 (s, 3H). 2.96-2.93 (m, 3H), 2.38 (s, 3H)。 610 : LC-MS: m/z [M+H] + = 463.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.51 (bs, 1H), 7.81-7.78 (m, 1H), 7.58-7.56 (m, 1H), 7.44-7.41 (m, 1H), 6.84 (d, J = 6.8 Hz, 1H), 5.73 (s, 1H), 5.60 (d, J = 6.72 Hz, 1H), 3.85 (bs, 1H), 3.71 (s, 3H), 2.93 (s, 3H), 2.38 (s, 3H). 611 : LC-MS: m/z [M+H] + = 463.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.52 (bs, 1H), 7.80-7.78 (m, 1H), 7.53-7.52 (m, 1H), 7.43-7.39 (m, 1H), 6.84 (d, J = 7.04 Hz, 1H), 5.73 (s, 1H), 5.60 (d, J = 6.88 Hz, 1H), 3.85 (bs, 1H), 3.70 (s, 3H). 2.96-2.93 (m, 3H), 2.38 (s, 3H). 612 : LC-MS: m/z [M+H] + = 463.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.50 (bs, 1H), 7.80-7.78 (m, 1H), 7.52-7.48 (m, 1H), 7.43-7.41 (m, 1H), 6.83 (d, J = 6.96 Hz, 1H), 5.74 (s, 1H), 5.60 (d, J = 6.72 Hz, 1H), 3.85 (bs, 1H), 3.70 (s, 3H), 2.93 (s, 3H), 2.39 (s, 3H). 613 : LC-MS: m/z [M+H] + = 463.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.52 (bs, 1H), 7.81-7.78 (m, 1H), 7.55-7.53 (m, 1H), 7.44-7.39 (m, 1H), 6.83 (d, J = 6.84 Hz, 1H), 5.73 (s, 1H), 5.60 (d, J = 6.72 Hz, 1H), 3.85 (bs, 1H), 3.71 (s, 3H). 2.96-2.93 (m, 3H), 2.38 (s, 3H).
實例 614-617(2-((4-氯-3-氟苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。產率：45%。藉由對掌性SFC分離立體異構物 Examples 614-617 (2-((4-chloro-3-fluorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Yield: 45%. Stereomers were separated by palmar SFC.
製備型第一對掌性SFC：管柱：Chiralpak IC (30.0 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：100 mL/min；共溶劑%：35%；ABPR：100巴；T：35℃。第一次溶析：614及615之混合物，第二次溶析：616及617之混合物。Preparation of the first pair of palmar SFCs: Column: Chiralpak IC (30.0 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 100 mL/min; Cosolvent %: 35%; ABPR: 100 bar; T: 35 °C. First dissolution: a mixture of 614 and 615 ; Second dissolution: a mixture of 616 and 617 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm )，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：100 mL/min；共溶劑%：35%；ABPR：100巴；T：35℃。第一次溶析：614 ，第二次溶析：615。Preparation of the second pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 100 mL/min; Cosolvent %: 35%; ABPR: 100 bar; T: 35 °C. First precipitation: 614 , Second precipitation: 615 .
製備型第三對掌性FC：管柱：Chiralpak IC (30.0 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：100 mL/min；共溶劑%：35%；ABPR：110巴；T：35℃。第一次溶析：616 ，第二次溶析：617。Preparation of the third palmar FC: Column: Chiralpak IC (30.0 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 100 mL/min; Cosolvent %: 35%; ABPR: 110 bar; T: 35 °C. First precipitation: 616 , Second precipitation: 617 .
614：LC-MS: m/z [M+H]+= 426.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.49 (bs, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.45 (d, J = 10.24 Hz, 1H), 7.39 (d, J = 8.24 Hz, 1H), 7.33-7.27 (m, 2H), 6.54 (d, J = 7.56 Hz, 1H), 6.25 (d, J = 8 Hz, 1H), 4.20 (bs, 1H), 2.98 (s, 1H), 2.37 (s, 3H), 2.20 (s, 3H)。615：LC-MS: m/z [M+H]+= 426.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.45 (bs, 1H), 7.54 (t, J = 7.92 Hz, 1H), 7.45 (d, J = 10.44 Hz, 1H), 7.37 (d, J = 8.20 Hz, 1H), 7.32-7.27 (m, 2H), 6.54 (d, J = 8.88 Hz, 1H), 6.25 (d, J = 8.08 Hz, 1H), 4.20 (bs, 1H), 3.83 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.20 (s, 3H)。616：LC-MS: m/z [M+H]+= 426.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.47 (bs, 1H), 7.54 (t, J = 8.12 Hz, 1H), 7.45 (d, J = 10.60 Hz, 1H), 7.40 (d, J = 8.24 Hz, 1H), 7.32-7.27 (m, 2H), 6.54 (d, J = 7.24 Hz, 1H), 6.25 (d, J = 7.72 Hz, 1H), 3.84 (s, 1H), 2.95 (s, 3H), 2.95 (s, 3H), 2.37 (s, 3H), 2.20 (s, 3H)。617：LC-MS: m/z [M+H]+= 426.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.58 (bs, 1H), 7.54 (t, J = 8.04 Hz, 1H), 7.45 (d, J = 10.48 Hz, 1H), 7.40 (d, J = 8.12 Hz, 1H), 7.32-7.27 (m, 2H), 6.54 (d, J = 6.64 Hz, 1H), 6.25 (d, J = 7.92 Hz, 1H), 3.83 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.20 (s, 3H)。 614 : LC-MS: m/z [M+H] + = 426.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.49 (bs, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.45 (d, J = 10.24 Hz, 1H), 7.39 (d, J = 8.24 Hz, 1H), 7.33-7.27 (m, 2H), 6.54 (d, J = 7.56 Hz, 1H), 6.25 (d, J = 8 Hz, 1H), 4.20 (bs, 1H), 2.98 (s, 1H), 2.37 (s, 3H), 2.20 (s, 3H). 615 : LC-MS: m/z [M+H] + = 426.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.45 (bs, 1H), 7.54 (t, J = 7.92 Hz, 1H), 7.45 (d, J = 10.44 Hz, 1H), 7.37 (d, J = 8.20 Hz, 1H), 7.32-7.27 (m, 2H), 6.54 (d, J = 8.88 Hz, 1H), 6.25 (d, J = 8.08 Hz, 1H), 4.20 (bs, 1H), 3.83 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.20 (s, 3H). 616 : LC-MS: m/z [M+H] + = 426.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.47 (bs, 1H), 7.54 (t, J = 8.12 Hz, 1H), 7.45 (d, J = 10.60 Hz, 1H), 7.40 (d, J = 8.24 Hz, 1H), 7.32-7.27 (m, 2H), 6.54 (d, J = 7.24 Hz, 1H), 6.25 (d, J = 7.72 Hz, 1H), 3.84 (s, 1H), 2.95 (s, 3H), 2.95 (s, 3H), 2.37 (s, 3H), 2.20 (s, 3H). 617 : LC-MS: m/z [M+H] + = 426.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.58 (bs, 1H), 7.54 (t, J = 8.04 Hz, 1H), 7.45 (d, J = 10.48 Hz, 1H), 7.40 (d, J = 8.12 Hz, 1H), 7.32-7.27 (m, 2H), 6.54 (d, J = 6.64 Hz, 1H), 6.25 (d, J = 7.92 Hz, 1H), 3.83 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.20 (s, 3H).
實例 618-621(2-((3-氯-2-氟苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。產率：41%。藉由對掌性SFC分離立體異構物 Examples 618-621 (2-((3-chloro-2-fluorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Yield: 41%. Stereomers were separated by palmar SFC.
製備型第一對掌性SFC：管柱：Cellulose-SC (20.0 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之乙腈-異丙醇(1:1)，流量：70 mL/min；共溶劑%：20%；ABPR：100巴；T：35℃。第一次溶析：618及619之混合物，第二次溶析：620及621之混合物。Preparation of the first pair of palmar SFCs: Column: Cellulose-SC (20.0 mm x 250 mm), 5 µm; Cosolvent: Acetonitrile-isopropanol (1:1) containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 20%; ABPR: 100 bar; T: 35 °C. First dissolution: mixture of 618 and 619 ; Second dissolution: mixture of 620 and 621 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm )，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：90 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：618 ，第二次溶析：619。Preparation of the second palmar SFC: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 90 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First precipitation: 618 , Second precipitation: 619 .
製備型第三對掌性SFC：管柱：Unichiral CND (21.2 × 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之乙腈-異丙醇(1:1)；60 mL/min；共溶劑%：15%；ABPR：100巴；T：35℃。第一次溶析：620 ，第二次溶析：621。Preparation of the third palmar SFC: Column: Unichiral CND (21.2 × 250 mm), 5 µm; Cosolvent: Acetonitrile-isopropanol (1:1) containing 0.2% (methanol containing 7N ammonia); 60 mL/min; Cosolvent %: 15%; ABPR: 100 bar; T: 35 °C. First precipitation: 620 °C , Second precipitation: 621 ° C.
618：LC-MS: m/z [M+H]+= 426.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.58 (bs, 1H), 7.49-7.43 (m, 3H), 7.30 (t, J = 9.04 Hz, 1H), 7.20 (t, J = 7.84 Hz, 1H), 6.56-6.52 (m, 2H), 3.81 (s, 1H), 2.94 (s, 3H), 2.32 (s, 3H), 2.18 (s, 3H)。619：LC-MS: m/z [M+H]+= 426.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.58 (bs, 1H), 7.49-7.43 (m, 3H), 7.30 (t, J = 9.04 Hz, 1H), 7.20 (t, J = 7.96 Hz, 1H), 6.55-6.52 (m, 2H), 3.83 (s, 1H), 2.93 (s, 3H), 2.31 (s, 3H), 2.18 (s, 3H)。620：LC-MS: m/z [M+H]+= 426.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 7.47-7.45 (m, 3H), 7.30 (t, J = 9.04 Hz, 1H), 7.20-7.18 (m, 1H), 6.55-6.52 (m, 2H), 3.83 (s, 1H), 2.13 (s, 3H), 2.37 (s, 3H), 2.19 (s, 3H)。621：LC-MS: m/z [M+H]+= 426.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 7.54-7.43 (m, 3H), 7.30 (t, J = 9.04 Hz, 1H), 7.19 (t, J = 7.84 Hz, 1H), 6.54-6.52 (m, 2H), 3.82 (s, 1H), 2.94 (s, 3H), 2.32 (s, 3H), 2.18 (s, 3H)。 618 : LC-MS: m/z [M+H] + = 426.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.58 (bs, 1H), 7.49-7.43 (m, 3H), 7.30 (t, J = 9.04 Hz, 1H), 7.20 (t, J = 7.84 Hz, 1H), 6.56-6.52 (m, 2H), 3.81 (s, 1H), 2.94 (s, 3H), 2.32 (s, 3H), 2.18 (s, 3H). 619 : LC-MS: m/z [M+H] + = 426.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.58 (bs, 1H), 7.49-7.43 (m, 3H), 7.30 (t, J = 9.04 Hz, 1H), 7.20 (t, J = 7.96 Hz, 1H), 6.55-6.52 (m, 2H), 3.83 (s, 1H), 2.93 (s, 3H), 2.31 (s, 3H), 2.18 (s, 3H). 620 : LC-MS: m/z [M+H] + = 426.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 7.47-7.45 (m, 3H), 7.30 (t, J = 9.04 Hz, 1H), 7.20-7.18 (m, 1H), 6.55-6.52 (m, 2H), 3.83 (s, 1H), 2.13 (s, 3H), 2.37 (s, 3H), 2.19 (s, 3H). 621 : LC-MS: m/z [M+H] + = 426.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 7.54-7.43 (m, 3H), 7.30 (t, J = 9.04 Hz, 1H), 7.19 (t, J = 7.84 Hz, 1H), 6.54-6.52 (m, 2H), 3.82 (s, 1H), 2.94 (s, 3H), 2.32 (s, 3H), 2.18 (s, 3H).
實例 622-625(2-((5-氯-2-氟苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。產率：81%。藉由對掌性SFC分離立體異構物 Examples 622-625 (2-((5-chloro-2-fluorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Yield: 81%. Stereomers were separated by palmar SFC.
製備型第一對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm )，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：70 mL/min；共溶劑%：35%；ABPR：100巴；T：35℃。第一次溶析：622及623之混合物，第二次溶析：624，第三次溶析：625。Preparation of the first pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 35%; ABPR: 100 bar; T: 35 °C. First dissolution: a mixture of 622 and 623 ; Second dissolution: 624 ; Third dissolution: 625 .
製備型第二對掌性SFC：Chiralpak IC (30.0 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：90 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：622 ，第二次溶析：623。Preparation of the second palmar SFC: Chiralpak IC (30.0 mm x 250 mm), 5 µm; cosolvent: isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 90 mL/min; cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First precipitation: 622 , second precipitation: 623 .
622：LC-MS: m/z [M+H]+= 426.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.58 (bs, 1H), 7.57-7.55 (m, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.39-7.34 (m,1H), 7.32 (t, J = 9.02 Hz, 1H), 7.23 (t, J = 9.16 Hz, 1H), 6.55-6.50 (m, 2H), 3.82 (s, 1H), 2.93 (s, 3H), 2.37 (s, 3H), 2.20-2.19 (m, 3H)。623：LC-MS: m/z [M+H]+= 426.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.58 (bs, 1H), 7.57-7.55 (m, 1H), 7.47 (d, J = 8.24 Hz, 1H), 7.38-7.34 (m,1H), 7.32 (t, J = 9.02 Hz, 1H), 7.23 (t, J = 9.12 Hz, 1H), 6.55-6.50 (m, 2H), 3.84 (bs, 1H), 2.93 (s, 3H), 2.37 (s, 3H), 2.20-2.19 (m, 3H)。624：LC-MS: m/z [M+H]+= 426.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.57 (bs, 1H), 7.57-7.55 (m, 1H), 7.47 (d, J = 8.24 Hz, 1H), 7.38-7.34 (m,1H), 7.32 (t, J = 9.02 Hz, 1H), 7.23 (t, J = 9.12 Hz, 1H), 6.55-6.50 (m, 2H), 3.84 (bs, 1H), 2.93 (s, 3H), 2.37 (s, 3H), 2.20-2.19 (m, 3H)。625：LC-MS: m/z [M+H]+= 426.1。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.57 (bs, 1H), 7.57-7.55 (m, 1H), 7.49 (d, J = 8.36 Hz, 1H), 7.38-7.34 (m,1H), 7.32 (t, J = 9.02 Hz, 1H), 7.24 (t, J = 9.12 Hz, 1H), 6.55-6.50 (m, 2H), 3.82 (bs, 1H), 2.93 (s, 3H), 2.38 (s, 3H), 2.20-2.19 (m, 3H)。 622 : LC-MS: m/z [M+H] + = 426.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.58 (bs, 1H), 7.57-7.55 (m, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.39-7.34 (m,1H), 7.32 (t, J = 9.02 Hz, 1H), 7.23 (t, J = 9.16 Hz, 1H), 6.55-6.50 (m, 2H), 3.82 (s, 1H), 2.93 (s, 3H), 2.37 (s, 3H), 2.20-2.19 (m, 3H). 623 : LC-MS: m/z [M+H] + = 426.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.58 (bs, 1H), 7.57-7.55 (m, 1H), 7.47 (d, J = 8.24 Hz, 1H), 7.38-7.34 (m,1H), 7.32 (t, J = 9.02 Hz, 1H), 7.23 (t, J = 9.12 Hz, 1H), 6.55-6.50 (m, 2H), 3.84 (bs, 1H), 2.93 (s, 3H), 2.37 (s, 3H), 2.20-2.19 (m, 3H). 624 : LC-MS: m/z [M+H] + = 426.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.57 (bs, 1H), 7.57-7.55 (m, 1H), 7.47 (d, J = 8.24 Hz, 1H), 7.38-7.34 (m,1H), 7.32 (t, J = 9.02 Hz, 1H), 7.23 (t, J = 9.12 Hz, 1H), 6.55-6.50 (m, 2H), 3.84 (bs, 1H), 2.93 (s, 3H), 2.37 (s, 3H), 2.20-2.19 (m, 3H). 625 : LC-MS: m/z [M+H] + = 426.1. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.57 (bs, 1H), 7.57-7.55 (m, 1H), 7.49 (d, J = 8.36 Hz, 1H), 7.38-7.34 (m,1H), 7.32 (t, J = 9.02 Hz, 1H), 7.24 (t, J = 9.12 Hz, 1H), 6.55-6.50 (m, 2H), 3.82 (bs, 1H), 2.93 (s, 3H), 2.38 (s, 3H), 2.20-2.19 (m, 3H).
實例 626-629(2-((3-氯-5-氟苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。產率：40%。藉由對掌性SFC分離立體異構物 Examples 626-629 (2-((3-chloro-5-fluorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Yield: 40%. Stereomers were separated by palmar SFC.
製備型第一對掌性SFC：管柱：Chiralpak IC (30.0 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之乙腈-異丙醇(1:1)；120 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：626及627之混合物，第二次溶析：628，第三次溶析：629。Preparation of the first pair of palmar SFCs: Column: Chiralpak IC (30.0 mm x 250 mm), 5 µm; Cosolvent: Acetonitrile-isopropanol (1:1) containing 0.2% (methanol containing 7N ammonia); 120 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First dissolution: mixture of 626 and 627 ; Second dissolution: 628 ; Third dissolution: 629 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm )，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇；流量：70 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：626 ，第二次溶析：627。Preparation of the second pair of palmar SFCs: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia); Flow rate: 70 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First precipitation: 626 , Second precipitation: 627 .
626：LC-MS: m/z [M+H]+= 426.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.49 (bs, 1H), 7.43 (d, J = 8.32 Hz, 1H), 7.37 (bs, 1H), 7.33-7.25 (m, 3H), 6.57-6.54 (m, 1H), 6.25 (d, J = 8.32 Hz, 1H), 3.85 (bs, 1H), 2.95 (s, 3H), 2.4 (s, 3H), 2.21-2.20 (m, 3H)。627：LC-MS: m/z [M+H]+= 426.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.49 (bs, 1H), 7.43 (d, J = 8.28 Hz, 1H), 7.38 (bs, 1H), 7.33-7.26 (m, 3H), 6.57-6.54 (m, 1H), 6.26 (d, J = 8.0 Hz, 1H), 3.85 (bs, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.21-2.20 (m, 3H)。628：LC-MS: m/z [M+H]+= 426.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.48 (bs, 1H), 7.43-7.26 (m, 5H), 6.57-6.55 (m, 1H), 6.26 (d, J = 8.2 Hz, 1H), 3.85 (bs, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.21-2.20 (m, 3H)。629：LC-MS: m/z [M+H]+= 426.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.48 (bs, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.37 (bs, 1H), 7.33-7.26 (m, 5H), 6.56 (d, J = 8.8 Hz, 1H), 6.26 (d, J = 8.12 Hz, 1H), 3.84 (bs, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.21-2.20 (m, 3H)。 626 : LC-MS: m/z [M+H] + = 426.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.49 (bs, 1H), 7.43 (d, J = 8.32 Hz, 1H), 7.37 (bs, 1H), 7.33-7.25 (m, 3H), 6.57-6.54 (m, 1H), 6.25 (d, J = 8.32 Hz, 1H), 3.85 (bs, 1H), 2.95 (s, 3H), 2.4 (s, 3H), 2.21-2.20 (m, 3H). 627 : LC-MS: m/z [M+H] + = 426.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.49 (bs, 1H), 7.43 (d, J = 8.28 Hz, 1H), 7.38 (bs, 1H), 7.33-7.26 (m, 3H), 6.57-6.54 (m, 1H), 6.26 (d, J = 8.0 Hz, 1H), 3.85 (bs, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.21-2.20 (m, 3H). 628 : LC-MS: m/z [M+H] + = 426.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.48 (bs, 1H), 7.43-7.26 (m, 5H), 6.57-6.55 (m, 1H), 6.26 (d, J = 8.2 Hz, 1H), 3.85 (bs, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.21-2.20 (m, 3H). 629 : LC-MS: m/z [M+H] + = 426.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.48 (bs, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.37 (bs, 1H), 7.33-7.26 (m, 5H), 6.56 (d, J = 8.8 Hz, 1H), 6.26 (d, J = 8.12 Hz, 1H), 3.84 (bs, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.21-2.20 (m, 3H).
實例 630-633(2-((4-(二氟甲基)苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-基)(亞胺基)(甲基)-l6-硫酮及及及使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。藉由對掌性SFC分離立體異構物 Examples 630-633 (2-((4-(difluoromethyl)phenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-yl)(imino)(methyl)-16-thione and and and The title compound was prepared from suitable intermediates and reagents using a method similar to that described for Examples 467-470. Stereomers were separated by palmar SFC.
製備型第一對掌性SFC：管柱：Chiralpak IC (30.0 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇；100 mL/min；共溶劑%：40%；ABPR：100巴；T：35℃。第一次溶析：630及631之混合物，第二次溶析：632及633之混合物。Preparation of the first pair of palmar SFCs: Column: Chiralpak IC (30.0 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia); 100 mL/min; Cosolvent %: 40%; ABPR: 100 bar; T: 35 °C. First dissolution: a mixture of 630 and 631 ; Second dissolution: a mixture of 632 and 633 .
製備型第二對掌性SFC：管柱：(R,R)-Whelk-O-1 (30 mm x 250 mm )，5µ；共溶劑：含0.2% (含7N氨之甲醇)之異丙醇，流量：70 mL/min；共溶劑%：35%；ABPR：100巴；T：35℃。第一次溶析：630 ，第二次溶析：631。Preparation of the second palmar SFC: Column: (R,R)-Whelk-O-1 (30 mm x 250 mm), 5 µm; Cosolvent: Isopropanol containing 0.2% (methanol containing 7N ammonia), flow rate: 70 mL/min; Cosolvent %: 35%; ABPR: 100 bar; T: 35 °C. First precipitation: 630 ° C , Second precipitation: 631 °C .
製備型第一對掌性SFC：管柱：Chiralpak IC (30.0 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之乙腈-異丙醇(1:1)；90 mL/min；共溶劑%：40%；ABPR：100巴；T：35℃。第一次溶析：632 ，第二次溶析：633。Preparation of the first pair of palmar SFCs: Column: Chiralpak IC (30.0 mm x 250 mm), 5 µm; Cosolvent: Acetonitrile-isopropanol (1:1) containing 0.2% (methanol containing 7N ammonia); 90 mL/min; Cosolvent %: 40%; ABPR: 100 bar; T: 35 °C. First precipitation: 632 , Second precipitation: 633 .
630：LC-MS: m/z [M+H]+= 424.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.48 (s, 1H), 7.56-7.51 (m, 4H), 7.35-7.27 (m, 2H), 7.12-6.84 (m, 1H), 6.54 (d, J=8.12 Hz, 1H), 6.28 (d, J=7.72 Hz, 1H), 3.82 (s, 1H), 2.95 (s, 3H), 2.37 ( s, 3H), 2.21-2.20 (s, 3H)。631：LC-MS: m/z [M+H]+= 424.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.48 (s, 1H), 7.56-7.51 (m, 4H), 7.35-7.27 (m, 2H), 7.13-6.85 (m, 1H), 6.54 (d, J=8.48 Hz, 1H), 6.28 (d, J=7.88 Hz, 1H), 3.83 (s, 1H), 2.95 (s, 3H), 2.37 ( s, 3H), 2.21-2.20 (s, 3H)。632：LC-MS: m/z [M+H]+= 424.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.58 (s, 1H), 7.56-7.51 (m, 4H), 7.34-7.27 (m, 2H), 7.13-6.85 (m, 1H), 6.54 (d, J=8.16 Hz, 1H), 6.28 (d, J=7.84 Hz, 1H), 3.82 (s, 1 H), 2.95 (s, 3H), 2.37 ( s, 3H), 2.20 (s, 3H)。633：LC-MS: m/z [M+H]+= 424.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.58 (s, 1H), 7.58-7.51 (m, 4H), 7.32-7.27 (m, 2H), 7.13-6.85 (m, 1H), 6.57-6.55 (m, 1H), 6.30 (s, 1H), 3.04 (s, 3H), 2.38 ( s, 3H), 2.20 (s, 3H)。 630 : LC-MS: m/z [M+H] + = 424.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.48 (s, 1H), 7.56-7.51 (m, 4H), 7.35-7.27 (m, 2H), 7.12-6.84 (m, 1H), 6.54 (d, J=8.12 Hz, 1H), 6.28 (d, J=7.72 Hz, 1H), 3.82 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.21-2.20 (s, 3H). 631 : LC-MS: m/z [M+H] + = 424.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.48 (s, 1H), 7.56-7.51 (m, 4H), 7.35-7.27 (m, 2H), 7.13-6.85 (m, 1H), 6.54 (d, J=8.48 Hz, 1H), 6.28 (d, J=7.88 Hz, 1H), 3.83 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.21-2.20 (s, 3H). 632 : LC-MS: m/z [M+H] + = 424.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.58 (s, 1H), 7.56-7.51 (m, 4H), 7.34-7.27 (m, 2H), 7.13-6.85 (m, 1H), 6.54 (d, J=8.16 Hz, 1H), 6.28 (d, J=7.84 Hz, 1H), 3.82 (s, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 2.20 (s, 3H). 633 : LC-MS: m/z [M+H] + = 424.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.58 (s, 1H), 7.58-7.51 (m, 4H), 7.32-7.27 (m, 2H), 7.13-6.85 (m, 1H), 6.57-6.55 (m, 1H), 6.30 (s, 1H), 3.04 (s, 3H), 2.38 (s, 3H), 2.20 (s, 3H).
實例 634-637N-((3-氯-4-氟苯基)(5-甲基-4-(甲基亞磺醯基)-1H-咪唑-2-基)甲基)-5-氟-6-甲基吡啶-2-胺及及及在0℃下向二異丙基胺基甲酸(3-氯-4-氟苯基)(5-甲基-4-(甲基亞磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯中間物87 (1 g，1.78 mmol，1.0 equiv.)及5-氟-6-甲基吡啶-2-胺(338 mg，2.68 mmol，1.5 equiv.)於DCM (50 mL)中之混合物中添加BF3·Et2O (2.2 mL，17.85 mmol，10.0 equiv.)及TFA (2.73 mL，35.7 mmol，20.0 equiv.)且在RT下攪拌16 h。濃縮反應混合物，用冰冷卻之水(20 mL)稀釋，用飽和NaHCO3溶液(50 mL)中和且用乙酸乙酯(350 mL)萃取。經硫酸鈉乾燥有機層且在減壓下濃縮，得到粗產物，藉由逆相製備型HPLC純化。產率：36%。藉由對掌性SFC分離立體異構物。 Examples 634-637 N-((3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfinyl)-1H-imidazol-2-yl)methyl)-5-fluoro-6-methylpyridin-2-amine and and and At 0 °C, BF3·Et2O (2.2 mL, 17.85 mmol, 10.0 equiv.) and TFA (2.73 mL, 35.7 mmol, 20.0 equiv.) were added to a mixture of diisopropylaminocarboxylic acid (3-chloro-4-fluorophenyl)(5-methyl-4-(methylsulfinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl) methyl ester intermediate 87 (1 g, 1.78 mmol, 1.0 equiv.) and 5-fluoro-6-methylpyridin -2 -amine (338 mg, 2.68 mmol, 1.5 equiv.) in DCM (50 mL), and the mixture was stirred at RT for 16 h. The reaction mixture was concentrated, diluted with ice-cold water (20 mL), neutralized with saturated NaHCO3 solution (50 mL), and extracted with ethyl acetate (350 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by reverse-phase preparative HPLC. Yield: 36%. Stereomers were separated by palmar SFC.
製備型第一對掌性SFC：管柱：Chiralpak IC (30.0 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之乙腈-異丙醇(1:1)；100 mL/min；共溶劑%：20%；ABPR：100巴；T：35℃。第一次溶析：634，第二次溶析：635及636之混合物，第三次溶析637 。 Preparation of the first pair of palmar SFCs: Column: Chiralpak IC (30.0 mm x 250 mm), 5 µm; Cosolvent: Acetonitrile-isopropanol (1:1) containing 0.2% (methanol containing 7N ammonia); 100 mL/min; Cosolvent %: 20%; ABPR: 100 bar; T: 35 °C. First precipitation: 634 , Second precipitation: a mixture of 635 and 636 , Third precipitation: 637 .
製備型第一對掌性SFC：管柱：Chiralpak IC (30.0 mm x 250 mm)，5µ；共溶劑：含0.2% (含7N氨之甲醇)之乙腈-異丙醇(7:3)；100 mL/min；共溶劑%：30%；ABPR：100巴；T：35℃。第一次溶析：635 ，第二次溶析：636。Preparation of the first pair of palmar SFCs: Column: Chiralpak IC (30.0 mm x 250 mm), 5 µm; Cosolvent: Acetonitrile-isopropanol (7:3) containing 0.2% (methanol containing 7N ammonia); 100 mL/min; Cosolvent %: 30%; ABPR: 100 bar; T: 35 °C. First precipitation: 635 °C , Second precipitation: 636 °C .
634：LC-MS: m/z [M+H]+= 411.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.45-12.44 (m, 1H), 7.66-7.64 (m, 1H), 7.43-7.28 (m, 4H), 6.55-6.52 (m, 1H), 6.23 (d, J = 8.0 Hz, 1H), 2.75 (s, 3H), 2.28 (s, 3H), 2.21-2.20 (m, 3H)。635：LC-MS: m/z [M+H]+= 411.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.42-12.41 (m, 1H), 7.66-7.64 (m, 1H), 7.43-7.28 (m, 4H), 6.56-6.53 (m, 1H), 6.26 (d, J = 8.16 Hz, 1H), 2.76 (s, 3H), 2.29 (s, 3H), 2.21-2.20 (m, 3H)。636：LC-MS: m/z [M+H]+= 411.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.42-12.41 (m, 1H), 7.66-7.64 (m, 1H), 7.44-7.28 (m, 4H), 6.56-6.53 (m, 1H), 6.26 (d, J = 8.12 Hz, 1H), 2.76 (s, 3H), 2.29 (s, 3H), 2.21-2.20 (m, 3H)。637：LC-MS: m/z [M+H]+= 411.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.45-12.44 (m, 1H), 7.66-7.64 (m, 1H), 7.45-7.28 (m, 4H), 6.55-6.52 (m, 1H), 6.23 (d, J = 8.04 Hz, 1H), 2.75 (s, 3H), 2.28 (s, 3H), 2.20-2.19 (m, 3H)。 634 : LC-MS: m/z [M+H] + = 411.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.45-12.44 (m, 1H), 7.66-7.64 (m, 1H), 7.43-7.28 (m, 4H), 6.55-6.52 (m, 1H), 6.23 (d, J = 8.0 Hz, 1H), 2.75 (s, 3H), 2.28 (s, 3H), 2.21-2.20 (m, 3H). 635 : LC-MS: m/z [M+H] + = 411.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.42-12.41 (m, 1H), 7.66-7.64 (m, 1H), 7.43-7.28 (m, 4H), 6.56-6.53 (m, 1H), 6.26 (d, J = 8.16 Hz, 1H), 2.76 (s, 3H), 2.29 (s, 3H), 2.21-2.20 (m, 3H). 636 : LC-MS: m/z [M+H] + = 411.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.42-12.41 (m, 1H), 7.66-7.64 (m, 1H), 7.44-7.28 (m, 4H), 6.56-6.53 (m, 1H), 6.26 (d, J = 8.12 Hz, 1H), 2.76 (s, 3H), 2.29 (s, 3H), 2.21-2.20 (m, 3H). 637 : LC-MS: m/z [M+H] + = 411.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.45-12.44 (m, 1H), 7.66-7.64 (m, 1H), 7.45-7.28 (m, 4H), 6.55-6.52 (m, 1H), 6.23 (d, J = 8.04 Hz, 1H), 2.75 (s, 3H), 2.28 (s, 3H), 2.20-2.19 (m, 3H).
實例 634-637使用與針對實例467-470所述類似之方法，由適當的中間物及試劑製備標題化合物。
實例 6492-((3-氯-4-氟苯基)((6,6-二氟雙環[3.1.0]己-3-基)氧基)甲基)-5-甲基-4-(甲基磺醯基)-1H-咪唑使用與針對實例15-16所述類似之方法，由適當的醇製備標題化合物。LCMS m/z = 435.1 [M+H]+。 Example 649 2-((3-chloro-4-fluorophenyl)((6,6-difluorobis[3.1.0]hex-3-yl)oxy)methyl)-5-methyl-4-(methylsulfonylurea)-1H-imidazolium The title compound was prepared from a suitable alcohol using a method similar to that described for Examples 15-16. LCMS m/z = 435.1 [M+H] + .
實例 650-6512-((3-氯-4-氟苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-磺醯胺及 Examples 650-651: 2-((3-chloro-4-fluorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-sulfonamide and
步驟1：在0℃下向二異丙基胺基甲酸(4-(苄基硫基)-5-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)(3-氯-4-氟苯基)甲酯及相應SEM區域異構物(中間物104，2.4 g，3.87 mmol)於DCM (50 mL)中之攪拌溶液中添加5-氟-6-甲基吡啶-2-胺(2.4 g，19.35 mmol)，隨後添加BF3∙Et2O (0.9 mL，6.96 mmol)及TFA (1.8 mL，23.22 mmol)。將所得反應混合物在60℃下攪拌3 h。使用冷飽和NaHCO3溶液(50 mL)淬滅反應混合物且用DCM (2 × 80 mL)萃取。相繼用水(50 mL)、鹽水(50 mL)洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮，得到粗產物，藉由管柱層析(SiO2，20% EtOAc/Hex)純化，得到N-((4-(苄基硫基)-5-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)(3-氯-4-氟苯基)甲基)-5-氟-6-甲基吡啶-2-胺及相應SEM區域異構物。產率：77% (1.8 g)。LCMS m/z = 602 [M+H]+。Step 1: At 0°C, 5-fluoro-6-methylpyridin-2-amine (2.4 g, 19.35 mmol) was added to a stirred solution of diisopropylaminocarboxylic acid (4-(benzylthio)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)(3-chloro-4-fluorophenyl) methyl ester and its corresponding SEM region isomer (intermediate 104, 2.4 g, 3.87 mmol) in DCM (50 mL), followed by the addition of BF3 ∙ Et2O (0.9 mL, 6.96 mmol) and TFA (1.8 mL, 23.22 mmol). The resulting reaction mixture was stirred at 60°C for 3 h. The reaction mixture was quenched with cold saturated NaHCO3 solution (50 mL) and extracted with DCM (2 × 80 mL). The combined organic layers were washed successively with water (50 mL) and brine (50 mL), dried over Na2SO4 , and concentrated under reduced pressure to give the crude product. Purification by column chromatography ( SiO2 , 20% EtOAc/Hex) yielded N-((4-(benzylthio)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)(3-chloro-4-fluorophenyl)methyl)-5-fluoro-6-methylpyridin-2-amine and the corresponding SEM isomers. Yield: 77% (1.8 g). LCMS m/z = 602 [M+H] + .
步驟2：在0℃下向N-((4-(苄基硫基)-5-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)(3-氯-4-氟苯基)甲基)-5-氟-6-甲基吡啶-2-胺及相應SEM區域異構物(1 g，1.66 mmol)於乙酸(10 mL)中之攪拌溶液中添加NCS (0.67 g，4.99 mmol)。將反應混合物在室溫下攪拌16 h。用乙酸乙酯(2 × 100 mL)萃取反應混合物。用鹽水(100 mL)洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮，得到2-[(3-氯-4-氟苯基)[(5-氟-6-甲基吡啶-2-基)胺基]甲基]-5-甲基-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-咪唑-4-磺醯氯及相應SEM區域異構物，其未經純化即用於下一步驟。產量：(800 mg，粗物質)。Step 2: NCS (0.67 g, 4.99 mmol) was added to a stirred solution of N-((4-(benzylthio)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)(3-chloro-4-fluorophenyl)methyl)-5-fluoro-6-methylpyridin-2-amine and the corresponding SEM region isomer (1 g, 1.66 mmol) in acetic acid (10 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄ , and concentrated under reduced pressure to give 2 -[(3-chloro-4-fluorophenyl)[(5-fluoro-6-methylpyridin-2-yl)amino]methyl]-5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-4-sulfonyl chloride and the corresponding SEM region isomers, which were used in the next step without purification. Yield: (800 mg, crude material).
步驟3：在密封管中在-78℃下向2-[(3-氯-4-氟苯基)[(5-氟-6-甲基吡啶-2-基)胺基]甲基]-5-甲基-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-咪唑-4-磺醯氯及相應SEM區域異構物(200 mg，0.35 mmol)於THF (3 mL)中之攪拌溶液中添加含飽和NH3之THF (3 mL)。將反應混合物在室溫下攪拌16 h。用乙酸乙酯(2 × 50 mL)萃取反應混合物。相繼用水(20 mL)、鹽水(20 mL)洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮，得到2-((3-氯-4-氟苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-5-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-4-磺醯胺及相應SEM區域異構物，其未經純化即用於下一步驟。產量：(150 mg，粗物質)。LCMS m/z = 558 [M+H]+。Step 3: In a sealed tube, add 3 mL of saturated NH3 to a stirred solution of 2-[(3-chloro-4-fluorophenyl)[(5-fluoro-6-methylpyridin-2-yl)amino]methyl]-5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-4-sulfonyl chloride and its corresponding SEM region isomer (200 mg, 0.35 mmol) in 3 mL of THF. Stir the reaction mixture at room temperature for 16 h. Extract the reaction mixture with ethyl acetate (2 × 50 mL). The combined organic layer was washed successively with water (20 mL) and brine (20 mL ) , dried over Na₂SO₄ and concentrated under reduced pressure to give 2-((3-chloro-4-fluorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-sulfonamide and the corresponding SEM region isomers, which were used in the next step without purification. Yield: (150 mg, crude). LCMS m/z = 558 [M+H] ⁺ .
步驟4：在0℃下向2-((3-氯-4-氟苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-5-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-4-磺醯胺及相應SEM區域異構物(900 mg，粗物質)於DCM (10 mL)中之攪拌溶液中添加含4M HCl之二噁烷(6 mL)。將所得溶液在室溫下攪拌16 h。濃縮反應混合物。用水(50 mL)稀釋所獲得之殘餘物，使用NaHCO3水溶液鹼化且用乙酸乙酯(2 × 50 mL)萃取。用鹽水(20 mL)洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮，得到粗化合物，藉由逆相製備型HPLC純化，得到標題化合物。產率：經三個步驟14% (150 mg)。LCMS m/z = 428 [M+H]+。Step 4: Dioxane (6 mL) containing 4 M HCl was added to a stirred solution of 2-((3-chloro-4-fluorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-sulfonamide and the corresponding SEM region isomer (900 mg, crude material) in DCM (10 mL) at 0 °C. The resulting solution was stirred at room temperature for 16 h. The reaction mixture was concentrated. The residue obtained was diluted with water (50 mL), alkalized with NaHCO3 aqueous solution, and extracted with ethyl acetate (2 × 50 mL). The combined organic layer was washed with brine (20 mL), dried over Na₂SO₄ , and concentrated under reduced pressure to obtain the crude compound. Purification by reverse-phase preparative HPLC yielded the title compound. Yield: 14% (150 mg) after three steps. LCMS m/z = 428 [M+H] ⁺ .
1H-NMR (400 MHz, DMSO-d6): δ: 12.35 (s, 1H), 7.63-7.62 (m, 1H), 7.41-7.28 (m, 4H), 6.98 (s, 2H), 6.52-6.50 (m, 1H), 6.23-6.21 (d, 1H), 2.32 (s, 3H), 2.21 (s, 3H)。對掌性SFC：管柱：(R,R) WHELK O-1 (4.6 x 150 mm) 3.5 μm；共溶劑：含0.3% iPrNH2之iPrOH，流量：3 mL/min；共溶劑%：20%；ABPR：1500 psi T：35℃；鏡像異構物1 (650)：Rt = 3.37 min (第一次溶析)；鏡像異構物2 (651)：Rt = 3.59 min (第二次溶析)。 1 H-NMR (400 MHz, DMSO-d 6 ): δ: 12.35 (s, 1H), 7.63-7.62 (m, 1H), 7.41-7.28 (m, 4H), 6.98 (s, 2H), 6.52-6.50 (m, 1H), 6.23-6.21 (d, 1H), 2.32 (s, 3H), 2.21 (s, 3H). Palmar SFC: Column: (R,R) WHELK O-1 (4.6 x 150 mm) 3.5 μm; Cosolvent: iPrOH containing 0.3% iPrNH2, flow rate: 3 mL/min; Cosolvent %: 20%; ABPR: 1500 psi; T: 35℃; Mirror isomer 1 ( 650 ): Rt = 3.37 min (first precipitation); Mirror isomer 2 ( 651 ): Rt = 3.59 min (second precipitation).
實例 652-653使用與針對實例650-651所述類似之方法，由適當的中間物及試劑製備標題化合物。
實例 654-6552-((3,4-二氟苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-磺醯胺及 Examples 654-655: 2-((3,4-difluorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-sulfonamide and
步驟1：在0℃下向二異丙基胺基甲酸(4-(苄基硫基)-5-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)(3,4-二氟苯基)甲酯及相應SEM區域異構物(中間物105，3 g，4.968 mmol)於THF (40 mL)中之攪拌溶液中添加5-氟-6-甲基吡啶-2-胺(1.6 g，12.42 mmol)，隨後添加BF3∙Et2O (1.84 mL，14.905 mmol)及TFA (2.3 mL，29.81 mmol)。將所得反應混合物在60℃下攪拌3 h。使用冷飽和NaHCO3溶液(50 mL)淬滅反應混合物且用DCM (2 × 80 mL)萃取。相繼用水(50 mL)、鹽水(50 mL)洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮，得到粗產物，藉由管柱層析(SiO2，20% EtOAc/Hex)純化，獲得N-((4-(苄基硫基)-5-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)(3,4-二氟苯基)甲基)-5-氟-6-甲基吡啶-2-胺及相應SEM區域異構物。產率：67% (2 g)。Step 1: At 0°C, 5-fluoro-6-methylpyridine-2-amine (1.6 g, 12.42 mmol) was added to a stirred solution of diisopropylaminocarboxylic acid (4-(benzylthio)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)(3,4-difluorophenyl) methyl ester and its corresponding SEM region isomer (intermediate 105, 3 g, 4.968 mmol) in THF (40 mL), followed by the addition of BF3 ∙ Et2O (1.84 mL, 14.905 mmol) and TFA (2.3 mL, 29.81 mmol). The resulting reaction mixture was stirred at 60°C for 3 h. The reaction mixture was quenched with cold saturated NaHCO3 solution (50 mL) and extracted with DCM (2 × 80 mL). The combined organic layers were washed successively with water (50 mL) and brine (50 mL), dried over Na2SO4 , and concentrated under reduced pressure to give the crude product. Purification by column chromatography ( SiO2 , 20% EtOAc/Hex) yielded N-((4-(benzylthio)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)(3,4-difluorophenyl)methyl)-5-fluoro-6-methylpyridin-2-amine and the corresponding SEM isomers. Yield: 67% (2 g).
步驟2：在0℃下向N-((4-(苄基硫基)-5-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)(3,4-二氟苯基)甲基)-5-氟-6-甲基吡啶-2-胺及相應SEM區域異構物(1 g，1.707 mmol)於乙酸(15 mL)中之攪拌溶液中添加NCS (0.68 g，5.121 mmol)。將反應混合物在室溫下攪拌16 h。用乙酸乙酯(100 mL)稀釋反應混合物且用冷水(2 × 50 mL)洗滌。用鹽水(100 mL)洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮，得到2-((3,4-二氟苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-磺醯氯，其未經純化即用於下一步驟。產量：(800 mg，粗物質)Step 2: NCS (0.68 g, 5.121 mmol) was added to a stirred solution of N-((4-(benzylthio)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)(3,4-difluorophenyl)methyl)-5-fluoro-6-methylpyridin-2-amine and the corresponding SEM region isomer (1 g, 1.707 mmol) in acetic acid (15 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with cold water (2 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄ , and concentrated under reduced pressure to give 2-((3,4-difluorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol-4-sulfonyl chloride, which was used in the next step without purification. Yield: (800 mg, crude material)
步驟3：在密封管中在-78℃下向2-((3,4-二氟苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-5-甲基-1H-咪唑-4-磺醯氯(800 mg，1.21 mmol)於THF (4 mL)中之攪拌溶液中添加含飽和NH3之THF (5 mL)。將反應混合物在室溫下攪拌16 h。用乙酸乙酯(2 × 50 mL)萃取反應混合物。相繼用水(20 mL)、鹽水(20 mL)洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮，得到粗產物，藉由逆相製備型HPLC純化，得到標題化合物。產率：經兩個步驟16% (110 mg)。LCMS m/z = 412 [M+H]+。Step 3: In a sealed tube at -78°C, add 5 mL of saturated NH3-containing THF to a stirred solution of 2-((3,4-difluorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-5-methyl-1H-imidazol- 4 -sulfonyl chloride (800 mg, 1.21 mmol) in 4 mL of THF. Stir the reaction mixture at room temperature for 16 h. Extract the reaction mixture with ethyl acetate (2 × 50 mL). Wash the combined organic layers successively with water (20 mL) and brine (20 mL), dry with Na2SO4 and concentrate under reduced pressure to give the crude product, which is purified by reverse-phase preparative HPLC to give the title compound. Yield: 16% (110 mg) after two steps. LCMS m/z = 412 [M+H] + .
使用對掌性SFC將外消旋混合物分離成相應鏡像異構物。The racemic mixture was separated into corresponding mirror isomers using a palmar SFC.
1H-NMR (400 MHz, DMSO-d6): δ: 12.34 (s, 1H), 7.49-7.26 (m, 5H), 6.98 (s, 2H), 6.53-6.50 (m, 1H), 6.23-6.21 (d, 1H), 2.32 (s, 3H), 2.21 (s, 3H)。分析型對掌性SFC：管柱：Chiralpak IC (4.6 x 250 mm) 5 μm；共溶劑：含0.3% iPrNH2之hex/異丙醇(60/40)，流量：3 mL/min；共溶劑%：40%；ABPR：1500 psi；T：35℃；鏡像異構物1 (654)：Rt = 6.48 min (第一次溶析)；鏡像異構物2 (655)：Rt = 7.39 min (第二次溶析)。 1 H-NMR (400 MHz, DMSO-d 6 ): δ: 12.34 (s, 1H), 7.49-7.26 (m, 5H), 6.98 (s, 2H), 6.53-6.50 (m, 1H), 6.23-6.21 (d, 1H), 2.32 (s, 3H), 2.21 (s, 3H). Analytical palmar SFC: Column: Chiralpak IC (4.6 x 250 mm) 5 μm; Cosolvent: hex/isopropanol (60/40) containing 0.3 % iPrNH2, flow rate: 3 mL/min; Cosolvent %: 40%; ABPR: 1500 psi; T: 35℃; Mirror isomer 1 ( 654 ): Rt = 6.48 min (first precipitation); Mirror isomer 2 ( 655 ): Rt = 7.39 min (second precipitation).
實例 656-661使用與針對實例654-655所述類似之方法，由適當的中間物及試劑製備標題化合物。
實例 662-6632-((3-氯-4-氟苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-1H-咪唑-4-磺醯胺及 Examples 662-663: 2-((3-chloro-4-fluorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-1H-imidazol-4-sulfonamide and
步驟1：在0℃下向二異丙基胺基甲酸(4-(苄基硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)(3-氯-4-氟苯基)甲酯(中間物106，區域異構物之混合物，1.5 g，2.47 mmol)於THF (30 mL)中之溶液中添加5-氟-6-甲基吡啶-2-胺(0.62 g，4.95 mmol)及三氟化硼乙醚(0.92 mL，7.42 mmol)，隨後添加TFA (1.14 mL，14.85 mmol)。將所得反應混合物在密封管中加熱至80℃持續90 min。在減壓下濃縮反應混合物。用飽和NaHCO3淬滅所獲得之殘餘物且用DCM (2x20 mL)萃取。用鹽水(15 mL)洗滌合併之有機物，經無水Na2SO4乾燥且在減壓下濃縮，得到N-((4-(苄基硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基) (3-氯-4-氟苯基)甲基)-5-氟-6-甲基吡啶-2-胺及相應SEM區域異構物。產量：1.45 g (粗物質)。LCMS m/z = 587 [M+H]+。Step 1: Add 5-fluoro-6-methylpyridin-2-amine (0.62 g, 4.95 mmol) and boron trifluoride diethyl ether (0.92 mL, 7.42 mmol) to a solution of diisopropylaminocarboxylic acid (4-(benzylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)(3-chloro-4-fluorophenyl) methyl ester (intermediate 106, a mixture of regiomeric isomers, 1.5 g, 2.47 mmol) in THF (30 mL) at 0 °C, followed by the addition of TFA (1.14 mL, 14.85 mmol). Heat the resulting reaction mixture to 80 °C in a sealed tube for 90 min. Concentrate the reaction mixture under reduced pressure. The residue was quenched with saturated NaHCO3 and extracted with DCM (2 x 20 mL). The combined organic matter was washed with brine (15 mL), dried over anhydrous Na2SO4 , and concentrated under reduced pressure to give N-((4-(benzylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)(3-chloro-4-fluorophenyl)methyl)-5-fluoro-6-methylpyridin-2-amine and the corresponding SEM isomers. Yield: 1.45 g (crude). LCMS m/z = 587 [M+H] + .
步驟2：在0℃下向N-((4-(苄基硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基) (3-氯-4-氟苯基)甲基)-5-氟-6-甲基吡啶-2-胺(區域異構物之混合物，1.6 g，2.73 mmol)於乙酸(24 mL)中之攪拌溶液中添加NCS (1.09 g，8.17 mmol，3.0 equiv.)。將所得反應混合物在室溫下攪拌16 h。用水(30 mL)淬滅反應混合物且用乙酸乙酯(2 x 30 mL)萃取。用鹽水(30 mL)洗滌合併之有機物，經無水Na2SO4乾燥且在減壓下濃縮，得到2-((3-氯-4-氟苯基) ((5-氟-6-甲基吡啶-2-基)胺基)甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-4-磺醯氯及相應SEM區域異構物。產量：1.5 g (粗物質)。Step 2: NCS (1.09 g, 8.17 mmol, 3.0 equiv.) was added to a stirred solution of N-((4-(benzylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)(3-chloro-4-fluorophenyl)methyl)-5-fluoro-6-methylpyridin-2-amine (a mixture of regiomeric isomers, 1.6 g, 2.73 mmol) in acetic acid (24 mL) at 0 °C. The resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic matter was washed with brine (30 mL), dried over anhydrous Na₂SO₄ , and concentrated under reduced pressure to give 2-((3-chloro-4-fluorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-sulfonyl chloride and the corresponding SEM region isomers. Yield: 1.5 g (crude matter).
步驟3：在密封管中在-78℃下向2-((3-氯-4-氟苯基) ((5-氟-6-甲基吡啶-2-基)胺基)甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-4-磺醯氯(區域異構物之混合物，1.5 g，2.66 mmol)於THF (1 mL)中之溶液中添加含飽和NH3之THF (20 mL)。將所得反應混合物在室溫下攪拌16 h。在減壓下濃縮反應混合物，得到2-((3-氯-4-氟苯基) ((5-氟-6-甲基吡啶-2-基)胺基)甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-4-磺醯胺及相應SEM區域異構物。產量：1.4 g (粗物質)。LCMS m/z = 544 [M+H]+。Step 3: In a sealed tube at -78°C, add 20 mL of saturated NH3-containing THF to a solution of 2-((3-chloro-4-fluorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-sulfonyl chloride (a mixture of regiomeric isomers, 1.5 g, 2.66 mmol) in 1 mL of THF. Stir the resulting reaction mixture at room temperature for 16 h. Concentration of the reaction mixture under reduced pressure yielded 2-((3-chloro-4-fluorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-sulfonamide and its corresponding SEM region isomers. Yield: 1.4 g (crude material). LCMS m/z = 544 [M+H] + .
步驟4：向2-((3-氯-4-氟苯基) ((5-氟-6-甲基吡啶-2-基)胺基)甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-4-磺醯胺(區域異構物之混合物，1.3 g，2.39 mmol)於THF (3 mL)中之攪拌溶液中添加TFA (7 mL)且將所得反應混合物加熱至70℃持續1 h。濃縮反應混合物，用飽和NaHCO3鹼化殘餘物且用乙酸乙酯(2x20 mL)萃取。用鹽水(20 mL)洗滌合併之有機物，經無水Na2SO4乾燥，過濾且濃縮，得到粗產物，藉由製備型HPLC (逆相)純化，得到標題化合物。產率：16% (160 mg)。LCMS m/z = 414 [M+H]+。Step 4: Add TFA (7 mL) to a stirred solution of 2-((3-chloro-4-fluorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-sulfonamide (a mixture of regiomeric isomers, 1.3 g, 2.39 mmol) in THF (3 mL) and heat the resulting reaction mixture to 70 °C for 1 h. Concentrate the reaction mixture, alkalize the residue with saturated NaHCO3 , and extract with ethyl acetate (2 x 20 mL). The combined organic compounds were washed with brine (20 mL), dried over anhydrous Na₂SO₄ , filtered, and concentrated to obtain a crude product. Purification was performed by preparative HPLC (reverse phase) to obtain the title compound. Yield: 16% (160 mg). LCMS m/z = 414 [M+H] ⁺ .
使用對掌性SFC將外消旋混合物分離成相應鏡像異構物。The racemic mixture was separated into corresponding mirror isomers using a palmar SFC.
1H-NMR (400 MHz, DMSO-d6): δ: 12.57 (brs, 1H), 7.65-7.63 (d, 1H), 7.50 (s, 1H), 7.41-7.36 (m, 3H), 7.33-7.28 (t, 1H), 7.10 (s, 2H), 6.54-6.52 (m, 1H), 6.32-6.30 (d, 1H), 2.21 (s, 3H)。對掌性SFC：管柱：：(R,R) Whelk-O-1 (4.6 x 150 mm) 3.5 μm；共溶劑：含0.3% iPrNH2之異丙醇，流量：3 mL/min；共溶劑%：20%；ABPR：1500 psi；T：35℃；鏡像異構物1 (662)：Rt = 3.08 min (第一次溶析)；鏡像異構物2 (663)：Rt = 3.33 min (第二次溶析)。 1 H-NMR (400 MHz, DMSO-d 6 ): δ: 12.57 (brs, 1H), 7.65-7.63 (d, 1H), 7.50 (s, 1H), 7.41-7.36 (m, 3H), 7.33-7.28 (t, 1H), 7.10 (s, 2H), 6.54-6.52 (m, 1H), 6.32-6.30 (d, 1H), 2.21 (s, 3H). Palmarized SFC: Column: (R,R) Whelk-O-1 (4.6 x 150 mm) 3.5 μm; Cosolvent: Isopropanol containing 0.3% iPrNH2 , Flow rate: 3 mL/min; Cosolvent %: 20%; ABPR: 1500 psi; T: 35℃; Mirror isomer 1 ( 662 ): Rt = 3.08 min (first precipitation); Mirror isomer 2 ( 663 ): Rt = 3.33 min (second precipitation).
實例 664-665使用與針對實例662-663所述類似之方法，由適當的中間物及試劑製備標題化合物。
實例 6662-((3-氯苯基)((6-(二氟甲基)-5-氟吡啶-2-基)胺基)甲基)-1H-咪唑-4-磺醯胺 Example 666: 2-((3-chlorophenyl)((6-(difluoromethyl)-5-fluoropyridin-2-yl)amino)methyl)-1H-imidazol-4-sulfonamide
步驟1：在室溫下向N,N-雙(丙-2-基)胺基甲酸(3-氯苯基)(4-{[(4-甲氧基苯基)甲基]氫硫基}-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-咪唑-2-基)甲酯及相應SEM區域異構物(中間物107，500 mg，0.81 mmol)於THF (20 mL)中之溶液中添加6-(二氟甲基)-5-氟吡啶-2-胺(170 mg，1.05 mmol)、三氟化硼乙醚(0.15 mL，1.21 mmol)及TFA (0.31 mL，4.04 mmol)且接著將混合物在密封管中加熱至120℃持續30 min。用EtOAc (150 mL)稀釋反應混合物，用水(25 mL)及飽和NaHCO3溶液(50 mL)洗滌。經硫酸鈉乾燥有機層且在減壓下濃縮，得到N-((3-氯苯基)(4-((4-甲氧基苄基)硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲基)-6-(二氟甲基)-5-氟吡啶-2-胺及相應SEM區域異構物，其直接用於下一步驟。產量：500 mg (粗物質)。LCMS m/z = 635 [M+H]+。Step 1: At room temperature, add 6-(difluoromethyl)-5-fluoropyridine-2-amine (170 mg, 1.05 mmol), boron trifluoride ether (0.15 mL, 1.21 mmol), and TFA (0.31 mL, 4.04 mmol) to a solution of N,N-bis(prop-2-yl)aminocarboxylic acid (3-chlorophenyl)(4-{[(4-methoxyphenyl)methyl]hydrothioyl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl) methyl ester and the corresponding SEM region isomer (intermediate 107, 500 mg, 0.81 mmol) in THF (20 mL) and then heat the mixture in a sealed tube to 120 °C for 30 min. The reaction mixture was diluted with EtOAc (150 mL) and washed with water (25 mL) and saturated NaHCO3 solution (50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give N-((3-chlorophenyl)(4-((4-methoxybenzyl)thio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl)-6-(difluoromethyl)-5-fluoropyridine-2-amine and the corresponding SEM region isomers, which were used directly in the next step. Yield: 500 mg (crude material). LCMS m/z = 635 [M+H] + .
步驟2：在0℃下向N-((3-氯苯基)(4-((4-甲氧基苄基)硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲基)-6-(二氟甲基)-5-氟吡啶-2-胺及相應SEM區域異構物(500 mg，0.79 mmol)於AcOH (20 mL)中之溶液中添加NCS (315 mg，2.36 mmol)且接著將混合物在室溫下攪拌16 h。在減壓下濃縮反應混合物，獲得粗2-[(3-氯苯基)({[6-(二氟甲基)-5-氟吡啶-2-基]胺基})甲基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-咪唑-4-磺醯氯及相應SEM區域異構物，其直接用於下一步驟。產量：500 mg (粗物質)。Step 2: NCS (315 mg, 2.36 mmol) was added to a solution of N-((3-chlorophenyl)(4-((4-methoxybenzyl)thio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl)-6-(difluoromethyl)-5-fluoropyridine-2-amine and the corresponding SEM region isomer (500 mg, 0.79 mmol) in AcOH (20 mL) at 0 °C, and the mixture was then stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to obtain crude 2-[(3-chlorophenyl)({[6-(difluoromethyl)-5-fluoropyridin-2-yl]amino})methyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-4-sulfonyl chloride and the corresponding SEM region isomers, which were used directly in the next step. Yield: 500 mg (crude material).
步驟3：在0℃下向2-[(3-氯苯基)({[6-(二氟甲基)-5-氟吡啶-2-基]胺基})甲基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-咪唑-4-磺醯氯及相應SEM區域異構物(500 mg，0.86 mmol)中添加含7 (M) NH3之MeOH (20 mL)且將混合物在室溫下攪拌2 h。在減壓下濃縮反應混合物，獲得粗2-[(3-氯苯基)({[6-(二氟甲基)-5-氟吡啶-2-基]胺基})甲基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-咪唑-4-磺醯胺及相應SEM區域異構物，其直接用於下一步驟。產量：500 mg (粗物質)。LCMS m/z = 562 [M+H]+。Step 3: Add 20 mL of MeOH containing 7 (M) NH3 to 2-[(3-chlorophenyl)({[6-(difluoromethyl)-5-fluoropyridin-2-yl]amino})methyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-4-sulfonyl chloride and the corresponding SEM region isomer (500 mg, 0.86 mmol) at 0 °C and stir the mixture at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to obtain crude 2-[(3-chlorophenyl)({[6-(difluoromethyl)-5-fluoropyridin-2-yl]amino})methyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-4-sulfonamide and the corresponding SEM region isomers, which were used directly in the next step. Yield: 500 mg (crude material). LCMS m/z = 562 [M+H] + .
步驟4：在室溫下向2-[(3-氯苯基)({[6-(二氟甲基)-5-氟吡啶-2-基]胺基})甲基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-咪唑-4-磺醯胺及相應SEM區域異構物(500 mg，0.89 mmol)於THF (25 mL)中之溶液中添加TBAF (1 M於THF中，4.5 mL)且將反應混合物加熱至60℃持續2 h。用EtOAc (50 mL)稀釋反應混合物，用水(20 mL)及鹽水(20 mL)洗滌。經硫酸鈉乾燥有機層且在減壓下濃縮，得到粗產物，藉由逆相製備型HPLC純化，得到標題化合物。產率：2% (9 mg，0.02 mmol)。Step 4: At room temperature, TBAF (1 M in THF, 4.5 mL) was added to a solution of 2-[(3-chlorophenyl)({[6-(difluoromethyl)-5-fluoropyridin-2-yl]amino})methyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-4-sulfonamide and its corresponding SEM region isomer (500 mg, 0.89 mmol) in 25 mL of THF, and the reaction mixture was heated to 60 °C for 2 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (20 mL) and brine (20 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product, which was purified by reverse-phase preparative HPLC to obtain the title compound. Yield: 2% (9 mg, 0.02 mmol).
LCMS m/z = 432 [M+H]+。1H-NMR (400 MHz, DMSO-d6): δ: 12.70 (bs, 2H), 7.88 (d, 1H), 7.57 (d, 1H), 7.51 (s, 2H), 7.40-7.31 (m, 3H), 7.08 (s, 2H), 6.96-6.69 (m, 2H), 6.31 (d, 1H)。LCMS m/z = 432 [M+H] + . 1 H-NMR (400 MHz, DMSO-d 6 ): δ: 12.70 (bs, 2H), 7.88 (d, 1H), 7.57 (d, 1H), 7.51 (s, 2H), 7.40-7.31 (m, 3H), 7.08 (s, 2H), 6.96-6.69 (m, 2H), 6.31 (d, 1H).
實例 6672-((3-氯-4-氟苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-5-(羥基甲基)-1H-咪唑-4-磺醯胺 Example 667 2-((3-chloro-4-fluorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-5-(hydroxymethyl)-1H-imidazol-4-sulfonamide
步驟1：在-78℃下向5-(((三級丁基二苯基矽烷基)氧基)甲基)-4-((4-甲氧基苄基)硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑或4-(((三級丁基二苯基矽烷基)氧基)甲基)-5-((4-甲氧基苄基)硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑(中間物102，1.7 g，2.74 mmol)於無水THF (10 mL)中之溶液中添加2.5 (M) n-BuLi (1.7 mL，4.11 mmol)且使混合物經45 min加溫至室溫。在0℃下向反應混合物中添加1-(3-氯-4-氟苯基)-N-(5-氟-6-甲基吡啶-2-基)甲酮亞胺(中間物103，0.73 g，2.74 mmol)於無水THF (10 mL)中之溶液且將混合物在室溫下攪拌5 h。用NH4Cl水溶液(20 mL)淬滅反應混合物且用乙酸乙酯(100 ml)萃取。用鹽水(20 mL)洗滌有機層，經Na2SO4乾燥，過濾且在減壓下濃縮濾液，得到粗產物，藉由管柱層析(SiO2，10% EtOAc/Hex)純化，產生N-((5-(((三級丁基二苯基矽烷基)氧基)甲基)-4-((4-甲氧基苄基)硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)(3-氯-4-氟苯基)甲基)-5-氟-6-甲基吡啶-2-胺或相應SEM區域異構物。產率：20% (500 mg)。LCMS m/z = 885 [M+H]+。Step 1: Add 2.5 (M) n-BuLi (1.7 mL, 4.11 mmol) to a solution of 5-(((tri-butyldiphenylsilyl)oxy)methyl)-4-((4-methoxybenzyl)thio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (intermediate 102, 1.7 g, 2.74 mmol) in anhydrous THF (10 mL) at -78 °C and allow the mixture to warm to room temperature for 45 min. A solution of 1-(3-chloro-4-fluorophenyl)-N-(5-fluoro-6-methylpyridin-2-yl)methyl ketone imine (intermediate 103, 0.73 g, 2.74 mmol) in anhydrous THF (10 mL) was added to the reaction mixture at 0 °C, and the mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with an aqueous solution of NH4Cl (20 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (20 mL), dried over Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Purification was performed by column chromatography ( SiO₂ , 10% EtOAc/Hex) to produce N-((5-(((trimethylbutyldiphenylsilyl)oxy)methyl)-4-((4-methoxybenzyl)thio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)(3-chloro-4-fluorophenyl)methyl)-5-fluoro-6-methylpyridin-2-amine or the corresponding SEM region isomer. Yield: 20% (500 mg). LCMS m/z = 885 [M+H] ⁺ .
步驟2：在0℃下向N-((5-(((三級丁基二苯基矽烷基)氧基)甲基)-4-((4-甲氧基苄基)硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)(3-氯-4-氟苯基)甲基)-5-氟-6-甲基吡啶-2-胺或相應SEM區域異構物(800 mg，0.9 mmol)於AcOH (15 mL)中之溶液中添加NCS (361 mg，2.71 mmol)且將混合物在室溫下攪拌16 h。在減壓下濃縮反應混合物，得到粗5-(((三級丁基二苯基矽烷基)氧基)甲基)-2-((3-氯-4-氟苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-4-磺醯氯或相應SEM區域異構物，其未經進一步純化即用於下一步驟。產量：定量(800 mg)。LCMS m/z = 831 [M+H]+。Step 2: Add NCS (361 mg, 2.71 mmol) to a solution of N-((5-(((trimethylbutyldiphenylsilyl)oxy)methyl)-4-((4-methoxybenzyl)thio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)(3-chloro-4-fluorophenyl)methyl)-5-fluoro-6-methylpyridin-2-amine or the corresponding SEM region isomer (800 mg, 0.9 mmol) in AcOH (15 mL) at 0 °C and stir the mixture at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to give crude 5-(((trimethylbutyldiphenylsilyl)oxy)methyl)-2-((3-chloro-4-fluorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-sulfonyl chloride or the corresponding SEM region isomer, which was used in the next step without further purification. Yield: quantified (800 mg). LCMS m/z = 831 [M+H] + .
步驟3：在0℃下向5-(((三級丁基二苯基矽烷基)氧基)甲基)-2-((3-氯-4-氟苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-4-磺醯氯或相應SEM區域異構物(800 mg，0.96 mmol)中添加含7 M NH3之MeOH (6 mL)且接著將混合物在室溫下攪拌3 h。在減壓下濃縮反應混合物，得到粗產物，用水(10 mL)稀釋且用乙酸乙酯(2 × 50 mL)萃取。經Na2SO4乾燥合併之有機層，過濾且在減壓下濃縮濾液，得到粗產物，藉由急驟管柱層析(SiO2，20% EtOAc/Hex)純化，產生5-(((三級丁基二苯基矽烷基)氧基)甲基)-2-((3-氯-4-氟苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-4-磺醯胺或相應SEM區域異構物。產率：25% (200 mg)。LCMS m/z = 812 [M+H]+。Step 3: At 0°C, MeOH (6 mL) containing 7 M NH₃ was added to 5-(((trimethylbutyldiphenylsilyl)oxy)methyl)-2-((3-chloro-4-fluorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol- 4 -sulfonyl chloride or the corresponding SEM region isomer (800 mg, 0.96 mmol), and the mixture was then stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was diluted with water (10 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Purification was performed by rapid column chromatography ( SiO₂ , 20% EtOAc/Hex) to produce 5-(((trimethylbutyldiphenylsilyl)oxy)methyl)-2-((3-chloro-4-fluorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-sulfenamide or the corresponding SEM region isomer. Yield: 25% (200 mg). LCMS m/z = 812 [M+H] ⁺ .
步驟4：向5-(((三級丁基二苯基矽烷基)氧基)甲基)-2-((3-氯-4-氟苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-4-磺醯胺或相應SEM區域異構物(500 mg，0.73 mmol)中添加TFA (0.6 mL)且將混合物在60℃下攪拌30 min。在減壓下濃縮反應混合物，獲得殘餘物，將其溶解於MeOH (10 mL)中。接著添加Amberlyst樹脂(500 mg)且將混合物在室溫下攪拌1 h。過濾混合物且在減壓下濃縮濾液，得到粗產物，藉由逆相製備型HPLC純化，得到標題化合物。產率：8% (25 mg)Step 4: Add TFA (0.6 mL) to 5-(((trimethylbutyldiphenylsilyl)oxy)methyl)-2-((3-chloro-4-fluorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-sulfonamide or the corresponding SEM region isomer (500 mg, 0.73 mmol) and stir the mixture at 60 °C for 30 min. Concentrate the reaction mixture under reduced pressure to obtain a residue, which is dissolved in MeOH (10 mL). Then add Amberlyst resin (500 mg) and stir the mixture at room temperature for 1 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by reverse-phase preparative HPLC to obtain the title compound. Yield: 8% (25 mg)
LCMS m/z = 444 [M+H]+。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.58 (br s, 1H), 7.64-7.63 (m, 1H), 7.42-7.28 (m, 4H), 7.01 (s, 2H), 6.53 (d, 1H), 6.32 (d, 1H), 5.34 (br s, 1H), 4.64 (s, 2H), 2.22-2.21 (m, 3H)。LCMS m/z = 444 [M+H] + . 1 H-NMR (400 MHz, DMSO-d 6 , 25℃) δ (ppm)= 12.58 (br s, 1H), 7.64-7.63 (m, 1H), 7.42-7.28 (m, 4H), 7.01 (s, 2H), 6.53 (d, 1H), 6.32 (d, 1H), 5.34 (br s, 1H), 4.64 (s, 2H), 2.22-2.21 (m, 3H).
實例 668-6692-((3-氯-4-氟苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-5-(甲氧基甲基)-1H-咪唑-4-磺醯胺及 Examples 668-669: 2-((3-chloro-4-fluorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-5-(methoxymethyl)-1H-imidazol-4-sulfonamide and
步驟1：在0℃下向二異丙基胺基甲酸(4-(苄基硫基)-5-(甲氧基甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)(3-氯-4-氟苯基)甲酯及相應SEM區域異構物(中間物108，2 g，3.071 mmol)於THF (30 mL)中之攪拌溶液中添加5-氟-6-甲基吡啶-2-胺(0.780 g，6.14 mmol)，隨後添加BF3∙Et2O (1.2 mL，9.21 mmol)及TFA (1.4 mL，8.424 mmol)。將所得反應混合物在80℃下攪拌2 h。使用冷飽和NaHCO3溶液(100 mL)淬滅反應混合物且用乙酸乙酯(2 × 100 mL)萃取。相繼用水(100 mL)、鹽水(100 mL)洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮，得到粗產物，藉由管柱層析(SiO2，20% EtOAc/Hex)純化，得到N-((5-(苄基硫基)-4-(甲氧基甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)(3-氯-4-氟苯基)甲基)-5-氟-6-甲基吡啶-2-胺及相應SEM區域異構物。產率：78% (1.5 g)。LCMS m/z = 631 [M+H]+。Step 1: At 0°C, 5-fluoro-6-methylpyridin-2-amine (0.780 g, 6.14 mmol) was added to a stirred solution of diisopropylaminocarboxylic acid (4-(benzylthio)-5-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)(3-chloro-4-fluorophenyl) methyl ester and its corresponding SEM region isomer (intermediate 108, 2 g, 3.071 mmol) in THF (30 mL), followed by the addition of BF3 ∙ Et2O (1.2 mL, 9.21 mmol) and TFA (1.4 mL, 8.424 mmol). The resulting reaction mixture was stirred at 80°C for 2 h. The reaction mixture was quenched with cold saturated NaHCO3 solution (100 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed successively with water (100 mL) and brine (100 mL), dried over Na2SO4 , and concentrated under reduced pressure to give the crude product. Purification by column chromatography ( SiO2 , 20% EtOAc/Hex) yielded N-((5-(benzylthio)-4-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)(3-chloro-4-fluorophenyl)methyl)-5-fluoro-6-methylpyridin-2-amine and the corresponding SEM isomers. Yield: 78% (1.5 g). LCMS m/z = 631 [M+H] + .
步驟2：在0℃下向N-((5-(苄基硫基)-4-(甲氧基甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)(3-氯-4-氟苯基)甲基)-5-氟-6-甲基吡啶-2-胺及相應SEM區域異構物(1.5 g，2.994 mmol)於乙酸(15 mL)中之攪拌溶液中添加NCS (1.2 g，8.98 mmol)。將反應混合物在室溫下攪拌16 h。用乙酸乙酯(100 mL)稀釋反應混合物且用冷水(2 × 50 mL)洗滌。用鹽水(100 mL)洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮，得到2-[(3-氯-4-氟苯基)[(5-氟-6-甲基吡啶-2-基)胺基]甲基]-4-(甲氧基甲基)-1H-咪唑-5-磺醯氯，其未經純化即用於下一步驟。產量：(600 mg，粗物質)Step 2: NCS (1.2 g, 8.98 mmol) was added to a stirred solution of N-((5-(benzylthio)-4-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)(3-chloro-4-fluorophenyl)methyl)-5-fluoro-6-methylpyridin-2-amine and the corresponding SEM region isomer (1.5 g, 2.994 mmol) in acetic acid (15 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with cold water (2 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄ , and concentrated under reduced pressure to give 2 -[(3-chloro-4-fluorophenyl)[(5-fluoro-6-methylpyridin-2-yl)amino]methyl]-4-(methoxymethyl)-1H-imidazol-5-sulfonyl chloride, which was used in the next step without purification. Yield: (600 mg, crude material)
步驟3：在密封管中在-78℃下向2-[(3-氯-4-氟苯基)[(5-氟-6-甲基吡啶-2-基)胺基]甲基]-4-(甲氧基甲基)-1H-咪唑-5-磺醯氯(300 mg，0.629 mmol)於THF (5 mL)中之攪拌溶液中添加含飽和NH3之THF (5 mL)。將反應混合物在室溫下攪拌16 h。用乙酸乙酯(2 × 50 mL)萃取反應混合物。相繼用水(20 mL)、鹽水(20 mL)洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮，得到粗產物。反應分兩個單獨批次進行。藉由逆相製備型HPLC純化合併之所獲得之粗化合物，得到標題化合物。產率：經兩個步驟5% (60 mg)。LCMS m/z = 458 [M+H]+。Step 3: In a sealed tube at -78°C, add 5 mL of saturated NH3-containing THF to a stirred solution of 2 -[(3-chloro-4-fluorophenyl)[(5-fluoro-6-methylpyridin-2-yl)amino]methyl]-4-(methoxymethyl)-1H-imidazol-5-sulfonyl chloride (300 mg, 0.629 mmol) in 5 mL of THF. Stir the reaction mixture at room temperature for 16 h. Extract the reaction mixture with ethyl acetate (2 × 50 mL). Wash the combined organic layers successively with water (20 mL) and brine ( 20 mL), dry with Na2SO4 , and concentrate under reduced pressure to obtain the crude product. The reaction was carried out in two separate batches. The crude compound obtained by reverse-phase preparative HPLC purification and merging yielded the title compound. Yield: 5% (60 mg) after two steps. LCMS m/z = 458 [M+H] + .
使用對掌性SFC將外消旋混合物分離成相應鏡像異構物。The racemic mixture was separated into corresponding mirror isomers using a palmar SFC.
1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.70 (s, 1H), 7.63-7.64 (m, 1H), 7.42-7.29 (m, 4H), 7.13 (s, 2H), 6.53-6.52 (d, 1H), 6.30-6.28 (d, 1H), 4.57 (s, 2H), 3.26 (s, 3H), 2.21 (s, 3H)。對掌性SFC：管柱：Chiralpak IC (4.6 x 250 mm) 5 μm；共溶劑：含0.3% iPrNH2之異丙醇，流量：3 mL/min；共溶劑%：30%；ABPR：1500 psi；T：35℃；鏡像異構物1 (668)：Rt = 3.42 min (第一次溶析)；鏡像異構物2 (669)：Rt = 3.97 min (第二次溶析)。 1 H-NMR (400 MHz, DMSO-d 6 , 25℃) δ (ppm)= 12.70 (s, 1H), 7.63-7.64 (m, 1H), 7.42-7.29 (m, 4H), 7.13 (s, 2H), 6.53-6.52 (d, 1H), 6.30-6.28 (d, 1H), 4.57 (s, 2H), 3.26 (s, 3H), 2.21 (s, 3H). Palmarized SFC: Column: Chiralpak IC (4.6 x 250 mm) 5 μm; Cosolvent: Isopropanol containing 0.3 % iPrNH2, Flow rate: 3 mL/min; Cosolvent %: 30%; ABPR: 1500 psi; T: 35℃; Mirror isomer 1 ( 668 ): Rt = 3.42 min (first precipitation); Mirror isomer 2 ( 669 ): Rt = 3.97 min (second precipitation).
實例 670-6712-((3-氯苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-1H-咪唑-4-磺醯胺及 Examples 670-671: 2-((3-chlorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-1H-imidazol-4-sulfonamide and
步驟1：在0℃下向二異丙基胺基甲酸(3-氯苯基)(4-((4-甲氧基苄基)硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯(中間物107，區域異構物之混合物，3 g，4.85 mmol)及5-氟-6-甲基吡啶-2-胺(3.1 g，24.26 mmol)於DCM (80 mL)中之溶液中添加BF3·Et2O (1.8 mL，14.56 mmol)及TFA (2.6 mL，33.96 mmol)且接著將混合物在室溫下攪拌16 h。用冰冷水(100 mL)稀釋反應混合物且用DCM (2 × 100 mL)萃取。用NaHCO3溶液(100 mL)及鹽水(100 mL)洗滌合併之有機層。經無水Na2SO4乾燥有機層且在減壓下濃縮，得到粗產物，藉由管柱層析(SiO2，20% EtOAc/Hex)純化，得到N-((3-氯苯基)(4-((4-甲氧基苄基)硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲基)-5-氟-6-甲基吡啶-2-胺及相應SEM區域異構物。產率：45% (1.3 g)。LCMS m/z = 599 [M+H]+。Step 1: At 0°C, add BF3·Et2O (1.8 mL, 14.56 mmol) and TFA (2.6 mL, 33.96 mmol) to a solution of diisopropylaminocarboxylic acid (3-chlorophenyl)(4-((4-methoxybenzyl)thio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol- 2 - yl ) in DCM (80 mL) and then stir the mixture at room temperature for 16 h. Dilute the reaction mixture with ice-cold water (100 mL) and extract with DCM (2 × 100 mL). The combined organic layers were washed with 100 mL of NaHCO3 solution and 100 mL of brine. The organic layers were dried with anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. Purification by column chromatography ( SiO2 , 20% EtOAc/Hex) yielded N-((3-chlorophenyl)(4-((4-methoxybenzyl)thio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl)-5-fluoro-6-methylpyridin-2-amine and corresponding SEM isomers. Yield: 45% (1.3 g). LCMS m/z = 599 [M+H] + .
步驟2：在0℃下向N-((3-氯苯基)(4-((4-甲氧基苄基)硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲基)-5-氟-6-甲基吡啶-2-胺(區域異構物之混合物，700 mg，1.17 mmol)於AcOH (7 mL)中之溶液中添加NCS (467.95 mg，3.5 mmol)且將混合物在室溫下攪拌1 h。在減壓下濃縮反應混合物，得到2-((3-氯苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-4-磺醯氯及相應SEM區域異構物，其直接用於下一步驟。產量：750 mg (粗物質)。LCMS m/z = 545 [M+H]+。Step 2: Add NCS (467.95 mg, 3.5 mmol) to a solution of N-((3-chlorophenyl)(4-((4-methoxybenzyl)thio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methyl)-5-fluoro-6-methylpyridin-2-amine (a mixture of regiomeric isomers, 700 mg, 1.17 mmol) in AcOH (7 mL) at 0 °C and stir the mixture at room temperature for 1 h. Concentration of the reaction mixture under reduced pressure yielded 2-((3-chlorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-sulfonyl chloride and the corresponding SEM region isomers, which were used directly in the next step. Yield: 750 mg (crude material). LCMS m/z = 545 [M+H] + .
步驟3：將2-((3-氯苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-4-磺醯氯及相應SEM區域異構物(750 mg，1.38 mmol)於含7 (M) NH3之MeOH (25 mL)中之溶液在室溫下攪拌16 h。在減壓下濃縮反應混合物，得到2-((3-氯苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-4-磺醯胺及相應SEM區域異構物，其直接用於下一步驟。產量：700 mg (粗物質)。LCMS m/z = 526 [M+H]+。Step 3: A solution of 2-((3-chlorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-sulfonyl chloride and its corresponding SEM region isomer (750 mg, 1.38 mmol) in MeOH ( 25 mL) containing 7 (M) NH3 was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to give 2-((3-chlorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-sulfonamide and its corresponding SEM region isomer, which was used directly in the next step. Yield: 700 mg (crude material). LCMS m/z = 526 [M+H] + .
步驟4：在0℃下向2-((3-氯苯基)((5-氟-6-甲基吡啶-2-基)胺基)甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-4-磺醯胺及相應SEM區域異構物(700 mg，1.33 mmol)於DCM (20 mL)中之溶液中添加含4M HCl之二噁烷(10 mL)且將混合物在室溫下攪拌16 h。在減壓下濃縮反應混合物且用MeOH (15 mL)稀釋。添加Amberlyst A21游離鹼樹脂(500 mg)且將混合物在室溫下攪拌2 h。過濾反應混合物，用MeOH (10 mL)洗滌且在減壓下濃縮濾液，得到粗產物，藉由逆相製備型HPLC純化，得到標題化合物。產率：15% (80 mg)。LCMS m/z = 396 [M+H]+。Step 4: At 0°C, dioxane (10 mL) containing 4 M HCl was added to a solution of 2-((3-chlorophenyl)((5-fluoro-6-methylpyridin-2-yl)amino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-sulfonamide and its corresponding SEM region isomer (700 mg, 1.33 mmol) in DCM (20 mL), and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and diluted with MeOH (15 mL). Amberlyst A21 free alkali resin (500 mg) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was filtered, washed with MeOH (10 mL), and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by reverse-phase preparative HPLC to give the title compound. Yield: 15% (80 mg). LCMS m/z = 396 [M+H] + .
使用對掌性SFC將外消旋混合物分離成相應鏡像異構物。The racemic mixture was separated into corresponding mirror isomers using a palmar SFC.
1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.57 (bs, 1H), 7.49 (bs, 2H), 7.37-7.36 (m, 3H), 7.32-7.30 (m, 2H), 7.09 (bs, 2H), 6.56-6.53 (m, 1H), 6.32-6.30 (m, 1H), 2.20 (s, 3H)。對掌性SFC：管柱：(R,R) Whelk O-1 (4.6 x 150 mm) 5 μm；共溶劑：含0.5% iPrNH2之異丙醇，流量：3 g/min；共溶劑%：25%；ABPR：100巴；T：35℃；鏡像異構物1 (670)：Rt = 3.02 min (第一次溶析)；鏡像異構物2 (671)：Rt = 3.45 min (第二次溶析)。 1 H-NMR (400 MHz, DMSO-d 6 , 25℃) δ (ppm)= 12.57 (bs, 1H), 7.49 (bs, 2H), 7.37-7.36 (m, 3H), 7.32-7.30 (m, 2H), 7.09 (bs, 2H), 6.56-6.53 (m, 1H), 6.32-6.30 (m, 1H), 2.20 (s, 3H). Palmar SFC: Column: (R,R) Whelk O-1 (4.6 x 150 mm) 5 μm; Cosolvent: Isopropanol containing 0.5% iPrNH2 , Flow rate: 3 g/min; Cosolvent %: 25%; ABPR: 100 bar; T: 35℃; Mirror isomer 1 ( 670 ): Rt = 3.02 min (first precipitation); Mirror isomer 2 ( 671 ): Rt = 3.45 min (second precipitation).
實例 672-6732-((3-氯-4-氟苯基)((3,3-二氟環丁基)甲氧基)甲基)-5-甲基-1H-咪唑-4-磺醯胺及 Examples 672-673: 2-((3-chloro-4-fluorophenyl)((3,3-difluorocyclobutyl)methoxy)methyl)-5-methyl-1H-imidazol-4-sulfonamide and
步驟1：在0℃下向二異丙基胺基甲酸(4-(苄基硫基)-5-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)(3-氯-4-氟苯基)甲酯(中間物104，區域異構物之混合物，1.3 g，2.092 mmol)於THF (15 mL)中之攪拌溶液中添加(3,3-二氟環丁基)甲醇(0.9 g，7.323 mmol)，隨後添加BF3∙Et2O (0.8 mL，6.28 mmol)及TFA (1.0 mL，12.55 mmol)。將所得反應混合物在60℃下攪拌3 h。使用冷飽和NaHCO3溶液(50 mL)淬滅反應混合物且用DCM (2 × 80 mL)萃取。相繼用水(50 mL)、鹽水(50 mL)洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮，得到粗產物，藉由管柱層析(SiO2，20% EtOAc/Hex)純化，得到4-(苄基氫硫基)-2-[(3-氯-4-氟苯基)[(3,3-二氟環丁基)甲氧基]甲基]-5-甲基-1H-咪唑。產率：77% (1.8 g)。Step 1: At 0°C, methyl diisopropylaminocarbamate (4-(benzylthio)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)(3-chloro-4-fluorophenyl)methyl ester (intermediate 104, a mixture of regiomeric isomers, 1.3 g, 2.092 mmol) in a stirred solution of diisopropylaminocarbamate (4-(benzylthio)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)(3-chloro-4-fluorophenyl)methyl ester (intermediate 104, a mixture of regiomeric isomers, 1.3 g, 2.092 mmol) in 15 mL of THF was added to a stirred solution of diisopropylaminocarbamate (4-(benzylthio)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol- 2- yl)(3-chloro-4-fluorophenyl)methyl ester (intermediate 104, a mixture of regiomeric isomers, 1.3 g, 2.092 mmol) in 15 mL of THF, followed by the addition of BF3 ∙ Et2O (0.8 mL, 6.28 mmol) and TFA (1.0 mL, 12.55 mmol). The resulting reaction mixture was stirred at 60°C for 3 h. The reaction mixture was quenched with cold saturated NaHCO3 solution (50 mL) and extracted with DCM (2 × 80 mL). The combined organic layers were washed successively with water (50 mL) and brine (50 mL), dried over Na2SO4 , and concentrated under reduced pressure to give a crude product. Purification by column chromatography ( SiO2 , 20% EtOAc/Hex) yielded 4-(benzylhydrothio)-2-[(3-chloro-4-fluorophenyl)[(3,3-difluorocyclobutyl)methoxy]methyl]-5-methyl-1H-imidazolium. Yield: 77% (1.8 g).
步驟2：在0℃下向4-(苄基氫硫基)-2-[(3-氯-4-氟苯基)[(3,3-二氟環丁基)甲氧基]甲基]-5-甲基-1H-咪唑(500 mg，1.071 mmol)於乙酸(15 mL)中之攪拌溶液中添加NCS (0.43 g，3.21 mmol)。將反應混合物在室溫下攪拌16 h。用乙酸乙酯(100 mL)稀釋反應混合物且用冷水(2 × 50 mL)洗滌。用鹽水(100 mL)洗滌有機層，經Na2SO4乾燥且在減壓下濃縮，得到2-((3-氯-4-氟苯基)((3,3-二氟環丁基)甲氧基)甲基)-5-甲基-1H-咪唑-4-磺醯氯。反應以相同大小進行兩次，合併粗物質。產量：(800 mg，粗物質)Step 2: Add NCS (0.43 g, 3.21 mmol) to a stirred solution of 4-(benzylhydrothio)-2-[(3-chloro-4-fluorophenyl)[(3,3-difluorocyclobutyl)methoxy]methyl]-5-methyl-1H-imidazolium (500 mg, 1.071 mmol) in acetic acid (15 mL) at 0 °C. Stir the reaction mixture at room temperature for 16 h. Dilute the reaction mixture with ethyl acetate (100 mL) and wash with cold water (2 × 50 mL). The organic layer was washed with brine (100 mL), dried over Na₂SO₄ , and concentrated under reduced pressure to give 2-((3-chloro-4-fluorophenyl)((3,3-difluorocyclobutyl)methoxy)methyl)-5-methyl-1H-imidazol-4-sulfochloro. The reaction was carried out twice with equal magnitudes, and the crude products were combined. Yield: (800 mg, crude product)
步驟3：在密封管中在-78℃下向2-((3-氯-4-氟苯基)((3,3-二氟環丁基)甲氧基)甲基)-5-甲基-1H-咪唑-4-磺醯氯(700 mg，1.21 mmol)於THF (4 mL)中之攪拌溶液中添加含飽和NH3之THF (5 mL)。將反應混合物在室溫下攪拌16 h。用乙酸乙酯(2 × 50 mL)萃取反應混合物。相繼用水(20 mL)、鹽水(20 mL)洗滌合併之有機層，經Na2SO4乾燥且在減壓下濃縮，得到粗產物，藉由逆相製備型-HPLC純化，得到標題化合物。產率：22% (200 mg)。LCMS m/z = 424 [M+H]+。Step 3: In a sealed tube at -78°C, add 5 mL of saturated NH3-containing THF to a stirred solution of 2-((3-chloro-4-fluorophenyl)((3,3-difluorocyclobutyl)methoxy)methyl)-5-methyl-1H-imidazol- 4 -sulfonyl chloride (700 mg, 1.21 mmol) in 4 mL of THF. Stir the reaction mixture at room temperature for 16 h. Extract the reaction mixture with ethyl acetate (2 × 50 mL). Wash the combined organic layers successively with water (20 mL) and brine (20 mL), dry with Na2SO4 and concentrate under reduced pressure to give the crude product, which is purified by reverse-phase preparative-HPLC to give the title compound. Yield: 22% (200 mg). LCMS m/z = 424 [M+H] + .
使用對掌性SFC將外消旋混合物分離成相應鏡像異構物。The racemic mixture was separated into corresponding mirror isomers using a palmar SFC.
1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.42 (s, 1H), 7.64-7.62 (m, 1H), 7.46-7.37 (m, 2H), 7.02 (s, 2H), 5.52 (s, 1H), 3.46-3.45 (m, 2H), 2.63-2.33 (m, 5H), 1.98 (s, 3H)。對掌性SFC：管柱：(R,R) Whelk O-1 (4.6 x 250 mm) 5 μm；共溶劑：含0.5% iPrNH2之異丙醇，流量：3 g/min；共溶劑%：25%；ABPR：110巴；T：35℃；鏡像異構物1 (672)：Rt = 2.86 min (第一次溶析)；鏡像異構物2 (673)：Rt = 4.01 min (第二次溶析)。 1 H-NMR (400 MHz, DMSO-d 6 , 25℃) δ (ppm)= 12.42 (s, 1H), 7.64-7.62 (m, 1H), 7.46-7.37 (m, 2H), 7.02 (s, 2H), 5.52 (s, 1H), 3.46-3.45 (m, 2H), 2.63-2.33 (m, 5H), 1.98 (s, 3H). Palmarized SFC: Column: (R,R) Whelk O-1 (4.6 x 250 mm) 5 μm; Cosolvent: Isopropanol containing 0.5% iPrNH2 , Flow rate: 3 g/min; Cosolvent %: 25%; ABPR: 110 bar; T: 35℃; Mirror isomer 1 ( 672 ): Rt = 2.86 min (first precipitation); Mirror isomer 2 ( 673 ): Rt = 4.01 min (second precipitation).
實例 6742-((3-氯苯基)((4,4-二氟環己基)氧基)甲基)-1H-咪唑-4-磺醯胺 Example 674 2-((3-chlorophenyl)((4,4-difluorocyclohexyl)oxy)methyl)-1H-imidazol-4-sulfonamide
步驟1：在0℃下向二異丙基胺基甲酸(3-氯苯基)(4-((4-甲氧基苄基)硫基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯(中間物107，500 mg，0.807 mmol)及4,4-二氟環己-1-醇(1.1 g，8.074 mmol)於THF (6 mL)中之溶液中添加三氟化硼乙醚(0.2 mL，1.61 mmol)及TFA (0.31 mL，4.04 mmol)。接著在微波照射下將混合物加熱至120℃持續20 min。用NaHCO3水溶液(30 mL)稀釋反應混合物且用EtOAc (2 × 30 mL)萃取。用鹽水(50 mL)洗滌合併之有機層且經無水Na2SO4乾燥。在減壓下移除溶劑，得到粗產物，藉由急驟管柱層析(SiO2，0-100% EtOAc/Hex)純化，得到2-((3-氯苯基)((4,4-二氟環己基)氧基)甲基)-4-((4-甲氧基苄基)硫基)-1H-咪唑。產率：98% (380 mg)。LCMS m/z = 479 [M+H]+。Step 1: At 0°C, add boron trifluoride diethyl ether (0.2 mL, 1.61 mmol) and TFA (0.31 mL, 4.04 mmol) to a solution of diisopropylaminocarboxylic acid (3-chlorophenyl)(4-((4-methoxybenzyl)thio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl) in THF (6 mL). Then, heat the mixture to 120°C for 20 min under microwave irradiation. Dilute the reaction mixture with an aqueous solution of NaHCO3 (30 mL) and extract with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na₂SO₄ . The solvent was removed under reduced pressure to give the crude product, which was purified by rapid column chromatography ( SiO₂ , 0-100% EtOAc/Hex) to give 2-((3-chlorophenyl)((4,4-difluorocyclohexyl)oxy)methyl)-4-((4-methoxybenzyl)thio)-1H-imidazolium. Yield: 98% (380 mg). LCMS m/z = 479 [M+H] ⁺ .
步驟2：在20℃下向2-((3-氯苯基)((4,4-二氟環己基)氧基)甲基)-4-((4-甲氧基苄基)硫基)-1H-咪唑(800 mg，1.67 mmol)於AcOH (20 mL)中之攪拌溶液中添加NCS (666 mg，5.01 mmol)且將混合物在20℃下攪拌1 h。用冰水(30 mL)淬滅混合物且用DCM (2 × 30 mL)萃取。經Na2SO4乾燥合併之有機層，過濾且在減壓下濃縮，得到粗2-((3-氯苯基)((4,4-二氟環己基)氧基)甲基)-1H-咪唑-4-磺醯氯，其未經進一步純化即用於下一步驟。產量：定量(700 mg)。Step 2: Add NCS (666 mg, 5.01 mmol) to a stirred solution of 2-((3-chlorophenyl)((4,4-difluorocyclohexyl)oxy)methyl)-4-((4-methoxybenzyl)thio)-1H-imidazolium (800 mg, 1.67 mmol) in AcOH (20 mL) at 20 °C and stir the mixture at 20 °C for 1 h. Quench the mixture with ice water (30 mL) and extract with DCM (2 × 30 mL). The combined organic layer was dried over Na₂SO₄ , filtered, and concentrated under reduced pressure to give crude 2-((3-chlorophenyl)((4,4-difluorocyclohexyl)oxy)methyl)-1H-imidazol-4-sulfochloro, which was used in the next step without further purification. Yield: Quantitative (700 mg).
步驟3：向2-((3-氯苯基)((4,4-二氟環己基)氧基)甲基)-1H-咪唑-4-磺醯氯(800 mg，1.64 mmol)中添加含7 (M) NH3之MeOH (10 mL)且將混合物在密封管中在室溫下攪拌16 h。在減壓下濃縮反應混合物，得到粗產物，藉由逆相製備型HPLC純化，獲得標題化合物。產率：3% (22 mg)。Step 3: 10 mL of MeOH containing 7 (M) NH₃ was added to 2-((3-chlorophenyl)((4,4-difluorocyclohexyl)oxy)methyl)-1H-imidazol-4-sulfonyl chloride (800 mg, 1.64 mmol), and the mixture was stirred in a sealed tube at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by reverse-phase preparative HPLC to obtain the title compound. Yield: 3% (22 mg).
LCMS m/z = 406 [M+H]+。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 12.67 (br s, 1H), 7.56 (s, 1H), 7.49 (s, 1H), 7.42 - 7.39 (m, 3H), 7.11 (s, 2H), 5.72 (s, 1H), 3.59 (br s, 1H), 2.07 - 1.97 (m, 2H), 1.88 - 1.82 (m, 2H), 1.77 - 1.75 (m, 4H)。LCMS m/z = 406 [M+H] + . 1 H-NMR (400 MHz, DMSO-d 6 , 25℃) δ (ppm)= 12.67 (br s, 1H), 7.56 (s, 1H), 7.49 (s, 1H), 7.42 - 7.39 (m, 3H), 7.11 (s, 2H), 5.72 (s, 1H), 3.59 (br s, 1H), 2.07 - 1.97 (m, 2H), 1.88 - 1.82 (m, 2H), 1.77 - 1.75 (m, 4H).
實例 675N-[(3-氯-4-氟苯基)-[4-甲基-5-(甲基磺醯基甲基)-1H-咪唑-2-基]甲基]-5-氟-6-甲基吡啶-2-胺向二異丙基胺基甲酸(3-氯-4-氟苯基)(5-甲基-4-((甲基磺醯基)甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)甲酯(中間物110，300 mg，0.52 mmol，1.0 equiv.)於THF (10 mL)中之溶液中添加5-氟-6-甲基吡啶-2-胺(99 mg，0.78 mmol，1.5 equiv.)、BF3·OEt2(0.2 mL，1.56 mmol，3.0 equiv.)及TFA (0.2 mL，1.56 mmol，5.0 equiv.)且在MW中在120℃下加熱30 min。在減壓下濃縮反應混合物，用乙酸乙酯(100 mL)稀釋且用NaHCO3溶液(50 mL)、鹽水(50 mL)洗滌。經無水硫酸鈉乾燥有機層且在減壓下濃縮，得到粗產物，藉由逆相製備型HPLC純化，得到標題化合物。 Example 675 N-[(3-chloro-4-fluorophenyl)-[4-methyl-5-(methylsulfonylmethane)-1H-imidazol-2-yl]methyl]-5-fluoro-6-methylpyridin-2-amine Add 5-fluoro-6-methylpyridin-2-amine (99 mg, 0.78 mmol, 1.5 equiv.), BF3·OEt2 (0.2 mL, 1.56 mmol, 3.0 equiv.), and TFA (0.2 mL, 1.56 mmol, 5.0 equiv.) to a solution of diisopropylaminocarboxylic acid (3-chloro-4-fluorophenyl)(5-methyl-4-((methanesulfonyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl) -1H -imidazol- 2 -yl) methyl ester (intermediate 110, 300 mg, 0.52 mmol, 1.0 equiv.) in THF (10 mL), and heat in MW at 120 °C for 30 min. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (100 mL), and washed with NaHCO3 solution (50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product, which was purified by reverse-phase preparative HPLC to obtain the title compound.
產量：18 mg，0.040 mmol。LC-MS: m/z [M+H]+ = 441.2。1H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 11.95 (bs, 1H), 7.63 (s, 1H), 7.40-7.28 (m, 4H), 6.53 (d, J= 8.64 Hz, 1H), 6.17 (d, J = 6.72 Hz, 1H), 4.22 (s, 2H), 2.86 (s, 3H), 1.19-2.09 (m, 6H)。Yield: 18 mg, 0.040 mmol. LC-MS: m/z [M+H]+ = 441.2. 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ (ppm)= 11.95 (bs, 1H), 7.63 (s, 1H), 7.40-7.28 (m, 4H), 6.53 (d, J= 8.64 Hz, 1H), 6.17 (d, J = 6.72 Hz, 1H), 4.22 (s, 2H), 2.86 (s, 3H), 1.19-2.09 (m, 6H).
可根據一般流程且藉由與上述合成程序類比來合成以下預示性實例：
LCMS 方法 LCMS 方法 A ：附接有Waters SQD 2質譜儀之Water Acquity H類UPLC，所用管柱：Waters Acquity UPLC BEH C8 (2.1 × 50 mm，1.7 µm)，管柱溫度：50℃，溶劑A：含0.05%甲酸之水及溶劑B：含0.05% HCOOH之MeCN:水(90:10)，流動速率：0.8 mL/min，(移動相：5% [含0.05% HCOOH之水]及95% [含0.05% HCOOH之MeCN:水(90:10)]，保持0.75 min，接著在1.5 min內達到75% [含0.05% HCOOH之水]及25% [含0.05% HCOOH之MeCN:水(90:10)]，進一步在3.00 min內達到5% [含0.05% HCOOH之水]及95% [含0.05% HCOOH之MeCN:水(90:10)]，將此移動相組合物保持至4.00 min且最終在4.50 min內回到初始條件且將此組合物保持至5.10 min)。 LCMS Method A : Water Acquity Class H UPLC with a Waters SQD 2 mass spectrometer. Column used: Waters Acquity UPLC BEH C8 (2.1 × 50 mm, 1.7 µm). Column temperature: 50 °C. Solvent A: water containing 0.05% formic acid and solvent B: MeCN:water (90:10) containing 0.05% HCOOH. Flow rate: 0.8 mL/min (mobile phase: 5% [water containing 0.05% HCOOH] and 95% [MeCN:water (90:10) containing 0.05% HCOOH]). Hold for 0.75 min, then reach 75% [water containing 0.05% HCOOH] and 25% [MeCN:water (90:10)] within 1.5 min. [HCOOH in MeCN:water (90:10)], further reaching 5% [water containing 0.05% HCOOH] and 95% [MeCN:water (90:10) containing 0.05% HCOOH] within 3.00 min, this mobile phase composition was maintained to 4.00 min and finally returned to the initial conditions within 4.50 min and this composition was maintained to 5.10 min).
電離方法：電噴霧，毛細管(kV) 3.50，錐孔(V) 25.00，源溫度(℃) 150，去溶劑化溫度(℃) 400，錐孔氣體流量(L/H) -50，去溶劑化氣體流量(L /H) -750，質量範圍：160至900 Da。DAD波長范圍(nm)：210至400。Ionization method: Electrospray, capillary (kV) 3.50, orifice (V) 25.00, source temperature (°C) 150, desolvation temperature (°C) 400, orifice gas flow rate (L/H) -50, desolvation gas flow rate (L/H) -750, mass range: 160 to 900 Da. DAD wavelength range (nm): 210 to 400.
LCMS 方法 B ：儀器名稱：LCMS/MS API 2000，儀器製造商：Applied Biosystem，HPLC：Shimadzu Prominence，管柱(名稱、大小、類型)：Xbridge( C18 4.6 × 50 mm，5 µm)；溶析劑(溶劑)：A通道：含10 mM NH4OAc之水。B通道：MeCN (有機相)，雙波長：在220及260 nm下，偵測器：UV；梯度條件：A：緩衝液含10 mM NH4OAc之水，B：MeCN，流動速率：1.2 mL/min，管柱溫度：25℃，注射體積：2 µL，LC-MS梯度：移動相：在1.5 min內自90% [緩衝液]及10% [MeCN]至70% [緩衝液]及30% [MeCN]，在3.0 min內進一步達到10% [緩衝液]及90% [MeCN]，將此移動相組合物保持至4 min且最終在5 min內回到初始條件)。 LCMS Method B : Instrument Name: LCMS/MS API 2000, Instrument Manufacturer: Applied Biosystem, HPLC: Shimadzu Prominence, Column (Name, Size, Type): Xbridge (C18 4.6 × 50 mm, 5 µm); Solvent: Channel A: Water containing 10 mM NH4OAc . Channel B: MeCN (organic phase), dual wavelengths: 220 and 260 nm, detector: UV; gradient conditions: A: buffer water containing 10 mM NH4OAc , B: MeCN, flow rate: 1.2 mL/min, column temperature: 25℃, injection volume: 2 µL, LC-MS gradient: mobile phase: from 90% [buffer] and 10% [MeCN] to 70% [buffer] and 30% [MeCN] within 1.5 min, further reaching 10% [buffer] and 90% [MeCN] within 3.0 min, holding this mobile phase combination for 4 min and finally returning to the initial conditions within 5 min).
質量條件：電離技術：使用API (大氣壓電離)源之ESI (電子噴霧電離)，去簇電位：10-70 V，取決於化合物之電離，質量範圍：100-800 amu，掃描類型：Q1，極性：+ Ve，離子源：Turbo spray，離子噴霧電壓：對於+ve模式為+5500，質量源溫度：200℃Quality Conditions: Ionization Technology: ESI (Electron Spray Ionization) using an API (Atmospheric Pressure Ionization) source; Decluster Potential: 10-70 V, depending on the compound's ionization; Mass Range: 100-800 amu; Scan Type: Q1; Polarity: +Ve; Ion Source: Turbo spray; Ion Spray Voltage: +5500 for +Ve mode; Mass Source Temperature: 200℃
電生理學：電壓 - 鉗記錄使用以下NaV1.8重組細胞株進行記錄：HEK-NaV1.8 (NM_006514.1)與b3 (NM_018400.3)。 Electrophysiology: Voltage - clamp recording was performed using the following Na V 1.8 recombinant cell lines: HEK-Na V 1.8 (NM_006514.1) and b3 (NM_018400.3).
使用Qube384 (Sophion A/S, Copenhagen, Denmark)自動電壓鉗平台在全細胞組態中使用膜片鉗技術來量測鈉電流。「多孔」板用於表現NaV1.8之細胞株，而「單孔或多孔」板用於表現其他亞型之重組細胞株。應用適當的濾波器(用於最小密封電阻及最小電流大小)及串聯電阻補償(用於高品質鈉通道記錄)。資料在環境室溫或19℃下收集。Sodium current was measured in whole-cell configuration using patch clamp technology on a Qube384 (Sophion A/S, Copenhagen, Denmark) automated voltage clamp platform. "Multi-well" plates were used to represent NaV 1.8 cell lines, while "single-well or multi-well" plates were used to represent other subtypes of recombinant cell lines. Appropriate filters (for minimum seal resistance and minimum current magnitude) and series resistance compensation (for high-quality sodium channel recording) were applied. Data were collected at ambient temperature or 19°C.
細胞外記錄溶液含有(以mM計)：NaCl 145 mM、KCl 4 mM、CaCl22 mM、MgCl21 mM、HEPES 10 mM、葡萄糖10 mM，pH 7.4 (NaOH)。細胞內記錄溶液含有(以mM計)：CsF 120 mM、CsCl 20 mM、NaCl 10 mM、EGTA 10 mM、HEPES 10 mM，pH 7.2 (CsOH)。以25 kHz取樣頻率記錄電流且以5 kHz進行濾波。串聯電阻補償以65%應用。The extracellular recording solution contained (in mM): NaCl 145 mM, KCl 4 mM, CaCl₂ 2 mM, MgCl₂ 1 mM, HEPES 10 mM, glucose 10 mM, pH 7.4 (NaOH). The intracellular recording solution contained (in mM): CsF 120 mM, CsCl 20 mM, NaCl 10 mM, EGTA 10 mM, HEPES 10 mM, pH 7.2 (CsOH). Current was recorded at a sampling frequency of 25 kHz and filtered at 5 kHz. Series resistance compensation was applied at 65%.
媒劑(VEH)為細胞暴露於不含化合物之0.3% DMSO的對照條件。所有運行均包括VEH對照，該等對照暴露於相同的電壓方案，以評估非化合物相關現象(諸如衰減(run down))，接著用於隔離對電流之化合物依賴性影響。The mediator (VEH) was a control condition in which cells were exposed to 0.3% DMSO without the compound. All runs included a VEH control, which was exposed to the same voltage scheme to evaluate non-compound-related phenomena (such as run-down) and subsequently to isolate the compound-dependent effects on current.
為了檢查狀態依賴性抑制，每隔20秒施加以下電壓序列：自-120 mV之靜止膜電位開始，施加第一測試脈衝(P1；20 ms至-10 mV)以檢查靜止狀態下之通道，隨後短暫恢復(100 ms至-120 mV)，接著將膜電壓保持在V1/2(在電壓下4秒以獲得一半處於靜止狀態且一半處於失活狀態之通道)，施加後續第二測試脈衝(P2；20 ms至-10 mV)以檢查處於失活狀態之通道，隨後為另一短暫恢復(20 ms至-120 mV)及最終第三測試脈衝(P3；20 ms至-10 mV)以檢查恢復的通道。To examine state-dependent inhibition , the following voltage sequence was applied every 20 seconds: starting with a resting membrane potential of -120 mV, a first test pulse (P1; 20 ms to -10 mV) was applied to examine the channels in the resting state, followed by a brief recovery (100 ms to -120 mV), then the membrane voltage was maintained at V 1/2 (for 4 seconds to obtain channels that are half resting and half inactive), followed by a second test pulse (P2; 20 ms to -10 mV) to examine the channels in the inactive state, followed by another brief recovery (20 ms to -120 mV) and finally a third test pulse (P3; 20 ms to -120 mV). (ms to -10 mV) to check the recovered channel.
為了檢查頻率依賴性抑制，應用10 Hz方案及20 Hz方案；亦即自-120 mV之靜止膜電位開始，在10 Hz (脈衝之間間隔100 ms)下，接著在20 Hz (脈衝之間間隔50 ms)下施加40個脈衝(10 ms至-10 mV)。To examine frequency-dependent inhibition , a 10 Hz scheme and a 20 Hz scheme were applied; that is, starting from a resting membrane potential of -120 mV, 40 pulses (10 ms to -10 mV) were applied at 10 Hz (100 ms interval between pulses) and then at 20 Hz (50 ms interval between pulses).
在建立基線之對照期(持續約5分鐘)及應用測試化合物(或媒劑)之化合物期(持續約12分鐘)之過程中記錄各參數(P1、P2、P3、在10 Hz下之P40及在20 Hz下之P40)。對於各參數，將化合物期結束時之值正規化為媒劑基線；如下 During the baseline establishment control period (approximately 5 minutes) and the compounding period (approximately 12 minutes) of the test compound (or mediator), various parameters (P1, P2, P3, P40 at 10 Hz, and P40 at 20 Hz) were recorded. For each parameter, the values at the end of the compounding period were normalized to the mediator baseline; as follows.
為了調節化合物期之過程中Na+電流訊號之任何變化(由於與化合物無關之累積失活或生物物理隨時間之轉變)，每個384板中的記錄孔之專用區段專門用於僅進行媒劑暴露。此等僅媒劑之記錄用於校正實驗中之任何明顯的「升高(run-up)」或「衰減」。 To account for any changes in the Na + current signal during compounding (due to compound-independent cumulative inactivation or biophysical changes over time), a dedicated section of each well in the 384 plate is specifically designated for media-only exposure. This media-only recording is used to calibrate any apparent "run-up" or "decay" in experiments.
經調節之抑制計算如下： The regulated inhibition is calculated as follows:
確定抑制百分比且使用XLFit軟體(IDBS, Boston MA)內之4參數邏輯模型計算IC50值：其中A及B分別為最大及最小抑制，C為IC50濃度且D為(希爾)斜率。Determine the inhibition percentage and calculate the IC50 value using the 4-parameter logic model within XLFit software (IDBS, Boston MA): Where A and B are the maximum and minimum inhibition, respectively, C is the IC50 concentration, and D is the (Hill) slope.
實例化合物之效力資料概述於下表中(A類：人類NaV1.8 IC50≤ 0.1 μM；B類：0.1 μM ＜人類NaV1.8 IC50≤ 1 μM；C類：1 μM ＜人類NaV1.8 IC50≤ 10 μM；「n.d.」：未確定)：
無without
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