TW202136195A - Novel compounds - Google Patents

Novel compounds Download PDF

Info

Publication number
TW202136195A
TW202136195A TW109137209A TW109137209A TW202136195A TW 202136195 A TW202136195 A TW 202136195A TW 109137209 A TW109137209 A TW 109137209A TW 109137209 A TW109137209 A TW 109137209A TW 202136195 A TW202136195 A TW 202136195A
Authority
TW
Taiwan
Prior art keywords
oxy
methylene
syx
compound
disease
Prior art date
Application number
TW109137209A
Other languages
Chinese (zh)
Inventor
麥可 寇克
大衛 克森
馬修 菲
巴瑞 堤爾伯
史蒂芬 湯姆
Original Assignee
英商喜翠克斯治療有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/GB2020/051059 external-priority patent/WO2020222010A1/en
Application filed by 英商喜翠克斯治療有限公司 filed Critical 英商喜翠克斯治療有限公司
Publication of TW202136195A publication Critical patent/TW202136195A/en

Links

Landscapes

  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention relates to compounds of formula (I) and to their use in treating or preventing an inflammatory disease or a disease associated with an undesirable immune response:
Figure 109137209-A0202-11-0001-2
wherein RA, RB, RC and RD are as defined herein

Description

新穎之化合物 Novel compounds

本發明關於化合物及彼等於治療或預防發炎性疾病或與不良免疫反應有關的疾病之用途,及關於組成物、方法和中間化合物。 The present invention relates to compounds and their use in the treatment or prevention of inflammatory diseases or diseases related to adverse immune reactions, and to compositions, methods and intermediate compounds.

慢性發炎性疾病諸如類風濕性關節炎、全身性紅斑狼瘡(SLE)、多發性硬化症、牛皮癬、克隆氏症、潰瘍性結腸炎(ulcerative colitis)、葡萄膜炎及慢性阻塞性肺病(COPD)代表因為終生使人衰弱的疾病、增加的死亡率和高治療和護理費用而成為社會的重大負擔(Straub R.H.及Schradin C.,2016)。非類固醇抗發炎藥(NSAIDs)是用於治發炎性病症之最廣泛的藥物,但這些藥劑不能防止發炎的發展且只能治療伴隨的症狀。糖皮質素是有效的抗發炎劑,使其成為急性發炎發紅的緊急治療方法,但長期服用後,這些藥物會引起過多的不良副作用,且也可能會對個體產生抗性(Straub R.H.and Cutolo M.,2016)。因此,對於發炎性疾病的治療仍然存在相當大的醫療需求,並且正在努力尋找減輕這些疾病負擔的新藥(Hanke T.et al.,2016)。 Chronic inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE), multiple sclerosis, psoriasis, Crohn's disease, ulcerative colitis, uveitis, and chronic obstructive pulmonary disease (COPD) It represents a major burden to society due to life-long debilitating diseases, increased mortality, and high treatment and care costs (Straub RH and Schradin C., 2016). Non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely used drugs for the treatment of inflammatory disorders, but these drugs cannot prevent the development of inflammation and can only treat the accompanying symptoms. Glucocorticoids are effective anti-inflammatory agents, making them an emergency treatment for acute inflammation and redness, but after long-term use, these drugs can cause too many adverse side effects and may also develop resistance to individuals (Straub RHand Cutolo M., 2016). Therefore, there is still considerable medical demand for the treatment of inflammatory diseases, and efforts are being made to find new drugs that reduce the burden of these diseases (Hanke T. et al., 2016).

延胡索酸二甲酯(DMF),檸檬酸循環(CAC)中間延胡索酸之二酯,係用作為治療牛皮癬(Brück J.et al.,2018)和多發性硬化症(Mills E.A.et al.,2018)的口服療法。重要的是,口服投予後,血漿中均未檢測到此藥劑(Dibbert S.et al.,2013),觀察到的唯一與藥物相關的化合物為親體(DMF)和代謝物(MMF)二者之水解產物延胡索酸單甲酯(MMF)和麩胱甘肽(GSH)結合物。DMF的作用機制複雜且有爭議。此化合物的效用歸因於多種不同現象,包括蛋白質的共價修飾和“前驅藥”DMF轉化為MMF。特別地,強調以下路徑為與DMF的抗炎作用有關:1)活 化抗氧化劑,抗發炎類核因子(類胡蘿蔔素衍生的2)2(NRF2)路徑,為親電性α,β-不飽和酯部分與Kelch樣ECH相關蛋白1(KEAP1)上之親核性半胱胺酸殘基反應的結果(Brennan M.S.et al.,2015);2)誘導活化轉錄因子3(ATF3),導致抑制促發炎細胞介素介白素(IL)-6及IL-8(Müller S.et al.,2017);3)透過催化半胱胺酸殘基與Michael接受的不飽和酯之琥珀酸化而使糖類分解酶甘油醛3-磷酸鹽去氫酶(GAPDH)失活(Kornberg M.D.et al.,2018;Angiari S.及O’Neill L.A.,2018);4)抑制核因子-κB(NF-κB)驅動的細胞介素產生(Gillard G.O.et al.,2015);5)預防PKCθ與共刺激受體CD28之締合以減少IL-2的產生並阻斷T細胞活化(Blewett M.M.et al.,2016);6)親電性的α,β-不飽和酯與抗氧化劑GSH的親核性硫醇的反應,影響細胞對氧化壓力(oxidative stress)的反應(Lehmann J.C.U.et al.,2007);7)藉由透過DMF水解體內產生的MMF之羥基羧酸受體2(HCA2)的促效作用(von Glehn F.et al.,2018);8)p90核醣體S6激酶的異位共價抑制(Andersen J.L.et al.,2018);9)缺氧誘導因子-1α(HIF-1α)及其靶基因諸如IL-8的表現和功能之抑制(Zhao G.et al.,2014);及10)類鐸受體受體(TLR誘導的M1和K63泛素鏈形成之抑制(McGuire V.A.et al.,2016)。通常,除HCA2促效作用外(Tang H.et al.,2008),與其單酯對應物MMF比較,膜可滲透性二酯DMF在細胞中傾向於呈現更重大的生物效應。然而,體內缺乏DMF的全身暴露導致一些研究人員斷言:MMF實際上是口服DMF投予後的主要活性成分(Mrowietz U.et al.,2018)。因此,很明顯,由於DMF在體內水解為MMF,因此喪失DMF在細胞中所發揮的一些重大的生物效應。 Dimethyl fumarate (DMF), the diester of fumarate in the middle of the citric acid cycle (CAC), is used as a treatment for psoriasis (Brück J. et al., 2018) and multiple sclerosis (Mills EA et al., 2018) Oral therapy. Importantly, after oral administration, the drug was not detected in plasma (Dibbert S. et al., 2013), and the only drug-related compounds observed were both the parent (DMF) and the metabolite (MMF) The hydrolyzate is a combination of monomethyl fumarate (MMF) and glutathione (GSH). The mechanism of DMF is complex and controversial. The utility of this compound is attributed to a variety of different phenomena, including the covalent modification of proteins and the conversion of "prodrug" DMF to MMF. In particular, it is emphasized that the following pathways are related to the anti-inflammatory effect of DMF: 1) Live Antioxidant, anti-inflammatory nuclear factor (carotenoid-derived 2)2 (NRF2) pathway, which is the nucleophilicity between the electrophilic α,β-unsaturated ester moiety and Kelch-like ECH-related protein 1 (KEAP1) The result of cysteine residue reaction (Brennan MSet al., 2015); 2) Induces activation of transcription factor 3 (ATF3), leading to inhibition of pro-inflammatory cytokines interleukin (IL)-6 and IL-8 ( Müller S.et al., 2017); 3) by catalyzing the succinic acidification of cysteine residues with the unsaturated ester accepted by Michael to inactivate the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) ( Kornberg MDet al., 2018; Angiari S. and O'Neill LA, 2018); 4) Inhibition of nuclear factor-κB (NF-κB)-driven cytokine production (Gillard GOet al., 2015); 5) Prevent the association of PKCθ with the costimulatory receptor CD28 to reduce IL-2 production and block T cell activation (Blewett MM et al., 2016); 6) Electrophilic α, β-unsaturated esters and antioxidants The nucleophilic thiol reaction of GSH affects the response of cells to oxidative stress (Lehmann JCU et al., 2007); 7) Hydrolyze the hydroxycarboxylic acid receptor 2 ( HCA2) agonist effect (von Glehn F. et al., 2018); 8) ectopic covalent inhibition of p90 ribosomal S6 kinase (Andersen JLet al., 2018); 9) hypoxia-inducible factor-1α ( HIF-1α) and its target genes such as IL-8 performance and function inhibition (Zhao G. et al., 2014); and 10) Duo receptor receptor (TLR-induced M1 and K63 ubiquitin chain formation) Inhibition (McGuire VA et al., 2016). Generally, in addition to HCA2 agonist effects (Tang H. et al., 2008), compared with its monoester counterpart MMF, membrane permeable diester DMF tends to be in cells Presents a more significant biological effect. However, the lack of systemic exposure to DMF in the body has led some researchers to assert that MMF is actually the main active ingredient after oral DMF administration (Mrowietz U. et al., 2018). Therefore, it is obvious that due to DMF is hydrolyzed into MMF in the body, thus losing some of the major biological effects of DMF in cells.

最近,已經發現,在發炎巨噬細胞活化期間,CAC變得回補(anaplerotic)並轉移,使得產生不飽和二酸衣康酸,“伊康酸酯”(Murphy M.P.和O’Neill L.A.J.,2018;O’Neill L.A.J.和Artyomov M.N.,2019;Yu X.-H。et al.,2019)。以烏頭酸酯水合酶代替水合成異檸檬酸酯,CAC中間烏頭酸酯以免疫應答基因1(IRG1)(促發炎條件下巨噬細胞中最高上調基因之一,隨後被稱為烏頭酸酯脫羧基酶1)之蛋白質產物進行脫羧基以生產伊康酸(Michelucci A.et al., 2013)。此不飽和二酸為細菌酶異檸檬酸酯解離酶的抑制劑,且因此,其發揮抗菌活性。此外,伊康酸已顯示抑制CAC琥珀酸酯去氫酶(SDH)(Ackermann et al.,1949),因此導致琥珀酸酯積累(Cordes T.et al.,2016)。藉由抑制SDH(一種對發炎反應至關重要的酶)(E.L.Mills et al.,2016),伊康酸酯可在巨噬細胞活化和缺血再灌注損傷期間改善體內和體外的發炎(E.L.Mills et al.,2016)。 Recently, it has been found that during the activation of inflamed macrophages, CAC becomes anaplerotic and metastasizes, resulting in the production of unsaturated diacid itaconic acid, "itaconate" (Murphy MP and O'Neill LAJ, 2018 ; O'Neill LAJ and Artyomov MN, 2019; Yu X.-H. et al., 2019). Aconitate hydratase is used instead of hydration to synthesize isocitrate. CAC intermediate aconitate uses immune response gene 1 (IRG1) (one of the highest up-regulated genes in macrophages under pro-inflammatory conditions, which is later called aconitate decapitation). The protein product of carboxylase 1) undergoes decarboxylation to produce itaconic acid (Michelucci A. et al., 2013). This unsaturated diacid is an inhibitor of the bacterial enzyme isocitrate dissociation enzyme, and therefore, it exerts antibacterial activity. In addition, itaconic acid has been shown to inhibit CAC succinate dehydrogenase (SDH) (Ackermann et al., 1949), thus causing succinate accumulation (Cordes T. et al., 2016). By inhibiting SDH, an enzyme essential for inflammation (ELMills et al., 2016), itconate can improve inflammation in vivo and in vitro (ELMills et al., 2016) during macrophage activation and ischemia-reperfusion injury. Mills et al., 2016).

像延胡索酸一樣,伊康酸為α,β-不飽和羧酸。因此,其為Michael接受體,其誘導整體的親電性壓力反應。在此方面,伊康酸二酯伊康酸二甲酯(DMI)(像DMI)產生抗發炎反應,降低脂多醣(LPS)-刺激的骨髓巨噬細胞中發炎細胞介素IL-1β、IL-6、IL-12及IL-18的表現程度(WO2017/142855A1,以引用方式納入本文中)。此反應似乎部分是由NRF2活化媒介,藉由親電性α,β-不飽和酯部分經由KEAP1半胱胺酸殘基之烷基化(Mills E.L.et al.,2018),其增強具有抗氧化劑和抗發炎能力的下游基因之表現。然而,並非由DMI產生之所有明顯的免疫調節效應都可歸因於NRF2活化。特別地,DMI對IκBζ的調節與NRF2無關,且經由ATF3(免疫活化的總體負調節劑,其下調各種細胞介素諸如IL-6)的上調來媒介(Bambouskova M.et al.,2018)。而且,藉由抑制IκBζ蛋白產生,DMI改善IL-17媒介的病理,突顯此調節路徑的治療可能性(WO2019/036509A1,以引用方式納入本文中)。進一步突顯其藥理可能性,DMI最近已報導1)證明對腦缺血/再灌注損傷具有保護作用,從而為治療缺血性中風提供可能性(Zhang D.et al.,2019);2)提供防止阿黴素(doxorubicin)的心臟毒性作用(Shan Q.et al.,2019);及3)在小鼠中藉由活化MAPKs及NRFrf2同時抑制NF-κB信號路徑來防止脂多醣引起的乳腺炎(Zhao C.et al.,2019)。此外,據說DMI在預防和治療潰瘍性結腸炎(ulcerative colitis)和其癌化中具有效用(CN110731955,Sun Yat-sen University Cancer Center);且據報導可藉由活化NRF2/HO-1信號路徑來防止真菌性角膜炎(Gu L.et al.,2020)。儘管如此,應該注意的是DMI不會在細胞內代謝為伊康酸(ElAzzouny M.et al.,2017)。其他α,β-不飽和酯在巨噬細胞中藉由抑制NLRP3發炎體(inflammasome)而呈現IL-1β-降低效應(Cocco M.et al.,2017和2014),並已被證明 抑制TLR4途徑,最終導致抑制LPS-引起的NF-κB、腫瘤壞死因子(TNF)-α、IL-1β刺激及一氧化氮釋放(Zhang S.et al.,2012)。 Like fumaric acid, itaconic acid is an α,β-unsaturated carboxylic acid. Therefore, it is a Michael acceptor, which induces an overall electrophilic stress response. In this regard, the diester of itaconic acid, dimethyl Iconate (DMI) (like DMI), produces an anti-inflammatory response and reduces lipopolysaccharide (LPS)-stimulated inflammatory cytokines IL-1β, IL in bone marrow macrophages. -6. The degree of expression of IL-12 and IL-18 (WO2017/142855A1, incorporated herein by reference). This reaction seems to be partly mediated by NRF2 activation, by the alkylation of the electrophilic α,β-unsaturated ester moiety through the alkylation of KEAP1 cysteine residues (Mills EL et al., 2018), which enhances the presence of antioxidants And the performance of downstream genes of anti-inflammatory ability. However, not all the obvious immunomodulatory effects produced by DMI can be attributed to NRF2 activation. In particular, the regulation of IκBζ by DMI has nothing to do with NRF2, and is mediated by the up-regulation of ATF3, an overall negative regulator of immune activation, which down-regulates various cytokines such as IL-6 (Bambouskova M. et al., 2018). Moreover, by inhibiting the production of IκBζ protein, DMI improves IL-17-mediated pathology, highlighting the therapeutic possibilities of this regulatory pathway (WO2019/036509A1, incorporated herein by reference). To further highlight its pharmacological possibilities, DMI has recently reported 1) to prove that it has a protective effect on cerebral ischemia/reperfusion injury, thereby providing the possibility of treating ischemic stroke (Zhang D. et al., 2019); 2) providing Prevent the cardiotoxic effects of doxorubicin (Shan Q.et al., 2019); and 3) Prevent mastitis caused by lipopolysaccharide by activating MAPKs and NRFrf2 while inhibiting the NF-κB signaling pathway in mice (Zhao C.et al., 2019). In addition, DMI is said to be effective in the prevention and treatment of ulcerative colitis (ulcerative colitis) and its carcinogenesis (CN110731955, Sun Yat-sen University Cancer Center); and it is reported to be effective by activating the NRF2/HO-1 signal pathway Prevent fungal keratitis (Gu L. et al., 2020). Nevertheless, it should be noted that DMI will not be metabolized to itaconic acid in the cell (ElAzzouny M. et al., 2017). Other α,β-unsaturated esters exhibit IL-1β-lowering effects in macrophages by inhibiting the NLRP3 inflammasome (Cocco M. et al., 2017 and 2014), and have been proven Inhibition of the TLR4 pathway ultimately leads to the inhibition of LPS-induced NF-κB, tumor necrosis factor (TNF)-α, IL-1β stimulation and nitric oxide release (Zhang S. et al., 2012).

其他伊康酸衍生物已證明具有抗發炎作用(Bagavant G.et al.,1994)。值得注意的實例為伊康4-辛酸(4OI),一種具有改良細胞攝取之伊康酸酯衍生物。因為α,β-不飽和羧酸在4OI中沒有被酯化,所以此親電子劑顯示與生物硫醇的低反應性(Schmidt T.J.et al.,2007),就像伊康酸本身遇到的情況一樣。由於其低反應性/親電性,4OI的NRF2-活化作用不會被GSH減弱,此與以更高反應性的DMI之發現相反。在後一種情況下,α,β-不飽和羧酸酸被酯化,結果,DMI的IL-6降低和NRF2活化作用分別被巰基N-乙酰半胱胺酸和GSH逆轉。透過與KEAP1的反應及所得NRF2活化,以及GAPDH抑制(Liao S.-T.et al.,2019),已證明4OI產生範圍廣泛的有趣生物學效應,包括:1)防止神經細胞之過氧化氫(Liu H.et al.,2018);2)抑制SLE患者之末稍血液單個核細胞中促炎細胞介素的產生(Tang C.et al.,2018);及3)防止人臍靜脈內皮細胞之高血糖(Tang C.et al.,2019);4)藉由抑制E3泛蛋白連接酶Hrd1及活化NRF2信號來抑制破骨細胞生成(Sun X.et al.,2019);5)在來自患有STING依賴性干擾素病的患者之細胞中誘導NRF2抑制STING和I型IFN產生(Olagnier D.et al.,2018);6)經由抑制TGF-β/Smad路徑、自噬和減少活性氧的產生來防止腎臟纖維化(Tian F.et al.,2020);7)降低Zika病毒顱內注射小鼠的腦病毒負荷(Daniels B.P.et al.2019);及8)防止肝臟缺血再灌注損傷(Yi F.et al.2020)。此外,據報導伊康酸酯調節三羧酸和氧化還原代謝以減輕再灌注損傷(Cordes T.et al.,2020)。另外,血漿伊康酸酯含量升高証證明與用習知疾病修飾抗風濕藥(cDMARD)治療的開始後之類風濕關節炎疾病活性評分的降低明顯相關(Daly R.et al.2019)。 Other derivatives of itaconic acid have been shown to have anti-inflammatory effects (Bagavant G. et al., 1994). A notable example is Iconate 4-octanoic acid (4OI), a derivative of itaconic acid ester with improved cellular uptake. Because α,β-unsaturated carboxylic acid is not esterified in 4OI, this electrophile shows low reactivity with biological thiols (Schmidt TJet al., 2007), just like itaconic acid itself encounters The situation is the same. Due to its low reactivity/electrophilicity, the NRF2-activation effect of 4OI will not be weakened by GSH, which is contrary to the discovery of higher reactivity DMI. In the latter case, the α,β-unsaturated carboxylic acid is esterified, and as a result, the IL-6 reduction of DMI and the activation of NRF2 are reversed by mercapto N-acetylcysteine and GSH, respectively. Through the reaction with KEAP1 and the resulting activation of NRF2, as well as GAPDH inhibition (Liao S.-T. et al., 2019), 4OI has been shown to produce a wide range of interesting biological effects, including: 1) Prevention of hydrogen peroxide in nerve cells (Liu H. et al., 2018); 2) Inhibit the production of pro-inflammatory cytokines in the peripheral blood mononuclear cells of SLE patients (Tang C. et al., 2018); and 3) Prevent human umbilical vein endothelium Cellular hyperglycemia (Tang C. et al., 2019); 4) Inhibition of osteoclastogenesis by inhibiting E3 ubiquitin ligase Hrd1 and activating NRF2 signal (Sun X. et al., 2019); 5) In Induced NRF2 in cells from patients suffering from STING-dependent interferon disease to inhibit STING and type I IFN production (Olagnier D. et al., 2018); 6) Through inhibition of TGF-β/Smad pathway, autophagy and reduced activity Oxygen production to prevent renal fibrosis (Tian F. et al., 2020); 7) Reduce brain viral load in mice injected with Zika virus intracranially (Daniels BP et al. 2019); and 8) Prevent liver ischemia and recurrence Perfusion injury (Yi F. et al. 2020). In addition, it has been reported that itconate modulates tricarboxylic acid and redox metabolism to reduce reperfusion injury (Cordes T. et al., 2020). In addition, the syndrome of elevated plasma levels of iticonate proved to be significantly related to the decrease in the disease activity score of rheumatoid arthritis after the start of treatment with conventional disease-modified anti-rheumatic drugs (cDMARD) (Daly R. et al. 2019).

Artyomov等人(WO2017/142855;WO2019/036509)揭示伊康酸酯、丙二酸酯或其衍生物作為免疫調節劑之用途。 Artyomov et al. (WO2017/142855; WO2019/036509) disclosed the use of iticonate, malonate or their derivatives as immunomodulators.

儘管有上述發現,但仍需要鑑定和開發相較於目前市場上出售的抗發炎劑(諸如DMF)具有增強性質的新伊康酸酯衍生物。本發明人現己驚奇地發 現:某些伊康酸酯二酯在減少細胞中細胞介素的釋放及/或活化NRF2驅動的作用方面是高度有效的。這些性質以及其他性質使其可能比DMI及/或延胡索酸二甲酯更有效。因此,該等化合物具有優異的抗發炎性質。 Despite the above findings, there is still a need to identify and develop new iconate derivatives that have enhanced properties compared to anti-inflammatory agents currently on the market (such as DMF). The inventor has now surprisingly found Present: Certain Iconate diesters are highly effective in reducing the release of cytokines in cells and/or activating NRF2-driven effects. These and other properties make it possible to be more effective than DMI and/or dimethyl fumarate. Therefore, these compounds have excellent anti-inflammatory properties.

本發明提供一種式(I)化合物: The present invention provides a compound of formula (I):

Figure 109137209-A0202-12-0005-4
Figure 109137209-A0202-12-0005-4

其中, in,

RA係選自由下列所組成之群組:C1-10烷基、C3-10環烷基和C5-10螺環烷基;其中RA未經取代或經一或多個選自由下列所組成群組之取代基取代:側氧基、R1A、OR2A、NR2AR3A、SR2A、SOR9A、SO2R9A、SO2NR2AR3A、C(O)R2A和CONR2AR3AR A group consisting of the following selected from the group consisting of: C 1-10 alkyl, C 3-10 cycloalkyl and C 5-10 spiro cycloalkyl; wherein R A is unsubstituted or substituted with one or more selected from the group consisting of Substituent substitutions of the following groups: pendant oxy, R 1A , OR 2A , NR 2A R 3A , SR 2A , SOR 9A , SO 2 R 9A , SO 2 NR 2A R 3A , C(O)R 2A and CONR 2A R 3A ;

R1A係選自由下列所組成之群組:氟基、甲基、氰基、SiR4AR5AR6A、C3-8環烷基和苯基;其中甲基、C3-8環烷基和苯基係未經取代或經R7A及/或R8A取代; R 1A is selected from the group consisting of fluoro, methyl, cyano, SiR 4A R 5A R 6A , C 3-8 cycloalkyl and phenyl; among them, methyl, C 3-8 cycloalkyl And phenyl is unsubstituted or substituted with R 7A and/or R 8A ;

R4A、R5A和R6A係獨立地選自由下列所組成之群組:C1-4烷基和苯基; R 4A , R 5A and R 6A are independently selected from the group consisting of: C 1-4 alkyl and phenyl;

R7A和R8A係獨立地選自由下列所組成之群組:側氧基、C1-4烷基、C1-4烷氧基、C1-4鹵烷基、C1-4鹵烷氧基、羥基、CO2H、氰基、甲磺醯基和鹵基; R 7A and R 8A are independently selected from the group consisting of: pendant oxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkyl Oxy, hydroxy, CO 2 H, cyano, methanesulfonyl and halo;

或,R7A和R8A一起形成C3-8環烷基或4-7員雜環; Or, R 7A and R 8A together form a C 3-8 cycloalkyl group or a 4-7 membered heterocyclic ring;

R2A和R3A獨立地為H、C1-8烷基、C3-8環烷基或苯基; R 2A and R 3A are independently H, C 1-8 alkyl, C 3-8 cycloalkyl or phenyl;

或,R2A和R3A一起形成4-7員雜環; Or, R 2A and R 3A together form a 4-7 membered heterocyclic ring;

R9A為C1-8烷基、C3-8環烷基或苯基;及 R 9A is C 1-8 alkyl, C 3-8 cycloalkyl or phenyl; and

RB為經CO2H取代之C1-2烷基和係視需要地進一步經三氟甲基或甲基取代; R B is C 1-2 alkyl substituted with CO 2 H and optionally further substituted with trifluoromethyl or methyl;

RC和RD係獨立地選自由下列所組成之群組:H、C1-2烷基、羥基、甲氧基和氟 基; R C and R D are independently selected from the group consisting of H, C 1-2 alkyl, hydroxy, methoxy and fluoro;

或其醫藥上可接受的鹽及/或溶劑合物。 Or a pharmaceutically acceptable salt and/or solvate thereof.

本發明提供一種醫藥組成物,其包含一種式(I)化合物或其醫藥上可接受的鹽及/或溶劑合物。 The present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof.

本發明提供一種用作為藥劑的式(I)化合物或其醫藥上可接受的鹽及/或溶劑合物。 The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof for use as a medicament.

本發明提供一種用於治療或預防發炎性疾病或與不良免疫反應有關的疾病之式(I)化合物或其醫藥上可接受的鹽及/或溶劑合物。 The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof for the treatment or prevention of inflammatory diseases or diseases related to adverse immune reactions.

本發明提供一種式(I)化合物或其醫藥上可接受的鹽及/或溶劑合物之用途,係用於製造用於治療或預防發炎性疾病或與不良免疫反應有關的疾病之藥物。 The present invention provides a use of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof for the manufacture of drugs for the treatment or prevention of inflammatory diseases or diseases related to adverse immune reactions.

本發明提供一種治療或預防發炎性疾病或與不良免疫反應有關的疾病之方法,其包括投予式(I)化合物或其醫藥上可接受的鹽及/或溶劑合物。 The present invention provides a method for treating or preventing inflammatory diseases or diseases related to adverse immune reactions, which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof.

亦提供用於製備式(I)化合物之中間化合物。 Intermediate compounds used in the preparation of compounds of formula (I) are also provided.

發明之詳細說明 Detailed description of the invention

式(I)化合物 Compound of formula (I)

本文關於式(I)化合物所述之實施態樣及優先選擇同樣適用於本發明之醫藥組成物、使用之化合物、用途及方法態樣。 The embodiments and preferences described herein for the compound of formula (I) are also applicable to the pharmaceutical composition, the used compound, the use and the method of the present invention.

術語“C1-10烷基”係指具有1至10個碳原子之直鏈或支鏈完全飽和烴基團。術語包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、二級丁基、三級丁基、正戊基、正庚基、正己基和正辛基。也包括其他支鏈變體諸如庚基-CH(CH3)-及己基-CH(CH3)-。另外的支鏈變體包括正戊基-CH(CH2CH3)-及(n-Bu)2CH-。其他支鏈變體包括正戊基-C(CH3)2-或正己基-C(CH3)2-。另一支鏈變體為-CH(t-Bu)2。其他烷基,例如C1-9烷基、C1-8烷基、C1-7烷基、C1-6烷基、C1-5烷基、C1-4烷基、C1-3烷基、C1-2烷基、C2-10烷基、C2-9烷基、C2-8烷基、C2-7烷基、 C2-6烷基、C2-5烷基、C2-4烷基、C2-3烷基、C3-10烷基、C3-9烷基、C3-8烷基、C3-7烷基、C3-6烷基、C3-5烷基、C3-4烷基、C4-10烷基、C4-9烷基、C4-8烷基、C4-7烷基、C4-6烷基、C4-5烷基、C5-10烷基、C5-9烷基、C5-8烷基、C5-7烷基、C5-6烷基、C6-10烷基、C6-9烷基、C6-8烷基、C7-10烷基、C7-9烷基、C7-8烷基、C8-10烷基、C8-9烷基和C9-10烷基係如上述所定義但含不同數目的碳原子。術語“C1-10烷基”亦包括“C1-10伸烷基”,其為具有從1至10個碳原子的雙官能直鏈或支鏈完全飽和烴基團。實例“C1-10伸烷基”基團包括亞甲基、伸乙基、伸正丙基、伸正丁基、伸正戊基、伸正庚基、伸正己基及伸正辛基。 The term "C 1-10 alkyl" refers to a straight or branched chain fully saturated hydrocarbon group having 1 to 10 carbon atoms. The terms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, n-pentyl, n-heptyl, n-hexyl, and n-octyl. Other branched variants such as heptyl-CH(CH 3 )- and hexyl-CH(CH 3 )- are also included. Additional branched chain variants include n-pentyl-CH(CH 2 CH 3 )- and (n-Bu) 2 CH-. Other branched variants include n-pentyl-C(CH 3 ) 2 -or n-hexyl-C(CH 3 ) 2 -. Another branched variant is -CH(t-Bu) 2 . Other alkyl, e.g. C 1-9 alkyl, C 1-8 alkyl, C 1-7 alkyl, C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1- 3 alkyl, C 1-2 alkyl, C 2-10 alkyl, C 2-9 alkyl, C 2-8 alkyl, C 2-7 alkyl, C 2-6 alkyl, C 2-5 alkyl group, C 2-4 alkyl, C 2-3 alkyl, C 3-10 alkyl, C 3-9 alkyl, C 3-8 alkyl, C 3-7 alkyl, C 3-6 alkoxy group, C 3-5 alkyl, C 3-4 alkyl, C 4-10 alkyl, C 4-9 alkyl, C 4-8 alkyl, C 4-7 alkyl, C 4-6 alkyl , C 4-5 alkyl, C 5-10 alkyl, C 5-9 alkyl, C 5-8 alkyl, C 5-7 alkyl, C 5-6 alkyl, C 6-10 alkyl, C 6-9 alkyl, C 6-8 alkyl, C 7-10 alkyl, C 7-9 alkyl, C 7-8 alkyl, C 8-10 alkyl, C 8-9 alkyl and C The 9-10 alkyl group is as defined above but contains a different number of carbon atoms. The term "C 1-10 alkyl" also includes "C 1-10 alkylene", which is a bifunctional linear or branched fully saturated hydrocarbon group having from 1 to 10 carbon atoms. Examples of "C 1-10 alkylene" groups include methylene, ethylene, n-propyl, n-butyl, n-pentyl, n-heptyl, n-hexyl, and n-octyl.

術語“C1-4烷氧基”係指單獨鍵結至氧的如上述所定義之C1-4烷基(例如C1-3烷基、C1-2烷基或C1烷基)。術語包括甲氧基、乙氧基、1-丙氧基和2-丙氧基,及適當地為甲氧基。 The term "C 1-4 alkoxy" refers to a C 1-4 alkyl group as defined above (for example, C 1-3 alkyl, C 1-2 alkyl, or C 1 alkyl) independently bonded to oxygen . The term includes methoxy, ethoxy, 1-propoxy and 2-propoxy, and suitably methoxy.

術語“C1-4鹵烷基”(例如C1-3鹵烷基、C1-2鹵烷基或C1鹵烷基)如本文所用係指含有指定數目的碳原子及至少一個鹵素原子(諸如氟基或氯基,尤其是氟基)之直鏈或支鏈完全飽和烴鏈。鹵烷基之實例為CF3。鹵烷基之其他實例為CHF2和CH2CF3The term "C 1-4 haloalkyl" (e.g., C 1-3 haloalkyl, C 1-2 haloalkyl, or C 1 haloalkyl) as used herein refers to containing the specified number of carbon atoms and at least one halogen atom (Such as fluorine or chlorine, especially fluorine) straight or branched fully saturated hydrocarbon chain. An example of haloalkyl is CF 3 . Other examples of haloalkyl groups are CHF 2 and CH 2 CF 3 .

術語“C1-4鹵烷氧基”係指單獨鍵結至氧的如上述所定義之C1-4鹵烷基(例如C1-3鹵烷基、C1-2鹵烷基或C1鹵烷基)。C1-4鹵烷氧基之實例包括OCF3、OCHF2及OCH2CF3The term "C 1-4 haloalkoxy" refers to a C 1-4 haloalkyl as defined above (e.g. C 1-3 haloalkyl, C 1-2 haloalkyl or C 1 haloalkyl). Examples of C 1-4 haloalkoxy groups include OCF 3 , OCHF 2 and OCH 2 CF 3 .

術語“C3-10環烷基”係指具有從3至10個碳原子之完全飽和環狀烴基團。術語包含環丙基、環丁基、環戊基、環己基、環庚基、環辛基、環壬基及環癸基以及橋聯系統諸如雙環[1.1.1]戊基、雙環[2.2.1]庚基、雙環[2.2.2]辛基和金剛烷基。其他環烷基,例如C3-9環烷基、C3-8環烷基、C3-7環烷基、C3-6環烷基、C3-5環烷基、C3-4環烷基、C4-10環烷基、C4-9環烷基、C4-8環烷基、C4-7環烷基、C4-6環烷基、C4-5環烷基、C5-10環烷基、C5-9環烷基、C5-8環烷基、C5-7環烷基、C5-6環烷基、C6-10環烷基、C6-9環烷基、C6-8環烷基、C6-7環烷基、C7-10環烷基、C7-9環烷 基、C7-8環烷基、C8-10環烷基、C8-9環烷基和C9-10環烷基係如上述所定義但含有不同數目的碳原子。 The term "C 3-10 cycloalkyl" refers to a fully saturated cyclic hydrocarbon group having from 3 to 10 carbon atoms. The term includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl and bridged systems such as bicyclo[1.1.1]pentyl, bicyclo[2.2. 1] Heptyl, bicyclo[2.2.2]octyl and adamantyl. Other cycloalkyl groups, such as C 3-9 cycloalkyl, C 3-8 cycloalkyl, C 3-7 cycloalkyl, C 3-6 cycloalkyl, C 3-5 cycloalkyl, C 3-4 Cycloalkyl , C 4-10 cycloalkyl, C 4-9 cycloalkyl, C 4-8 cycloalkyl, C 4-7 cycloalkyl, C 4-6 cycloalkyl, C 4-5 cycloalkane Group, C 5-10 cycloalkyl, C 5-9 cycloalkyl, C 5-8 cycloalkyl, C 5-7 cycloalkyl, C 5-6 cycloalkyl, C 6-10 cycloalkyl, C 6-9 cycloalkyl, C 6-8 cycloalkyl, C 6-7 cycloalkyl, C 7-10 cycloalkyl, C 7-9 cycloalkyl, C 7-8 cycloalkyl, C 8 -10 cycloalkyl, C 8-9 cycloalkyl and C 9-10 cycloalkyl are as defined above but contain different numbers of carbon atoms.

術語“C5-10螺環烷基”係指其中兩個環僅通過一個原子連接之雙環環烷基。該等環可為不同或相同。術語包含螺[3.3]庚基。其他螺環烷基,例如C5-9螺環烷基、C5-8螺環烷基和C5-7螺環烷基係如上述所定義但含有不同數目的碳原子。 The term "C 5-10 spirocycloalkyl" refers to a bicyclic cycloalkyl in which two rings are connected by only one atom. The rings can be different or the same. The term includes spiro[3.3]heptyl. Other spirocycloalkyls, such as C 5-9 spirocycloalkyl, C 5-8 spirocycloalkyl, and C 5-7 spirocycloalkyl are as defined above but contain different numbers of carbon atoms.

術語“4-7員雜環基”係指具有4至7個環原子及至少一個選自N、O、S和B的雜原子之非芳族環狀基團。術語“雜環基”可與“雜環”可互換。術語包括氧呾基(oxetanyl)、硫雜環丁烷基(thietanyl)、氮呾基(azetidinyl)、吡咯啶基、四氫呋喃基、四氫噻吩基、四氫哌喃基、哌啶基、哌

Figure 109137209-A0202-12-0008-154
基、嗎啉基、硫嗎啉基(thiomorpholinyl)和高嗎啉基(homomorpholinyl)。其他雜環基,例如,4-6員雜環基及4-5員雜環基係如上述所定義但含有不同數目的環原子。4-7員雜環基通常可經一或多個側氧基取代。適當地,硫雜環丁烷基(thietanyl)係經一或多二個側氧基取代。亦包含雙環雜環化合物,諸如下列: The term "4-7 membered heterocyclic group" refers to a non-aromatic cyclic group having 4 to 7 ring atoms and at least one heteroatom selected from N, O, S, and B. The term "heterocyclyl" can be interchanged with "heterocycle". The term includes oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropiperanyl, piperidinyl, piperidine
Figure 109137209-A0202-12-0008-154
Group, morpholinyl, thiomorpholinyl and homomorpholinyl. Other heterocyclic groups, for example, 4-6 membered heterocyclic groups and 4-5 membered heterocyclic groups are as defined above but contain different numbers of ring atoms. The 4-7 membered heterocyclic group can generally be substituted with one or more pendant oxy groups. Suitably, the thietanyl group is substituted with one or more pendant oxy groups. It also includes bicyclic heterocyclic compounds, such as the following:

Figure 109137209-A0202-12-0008-5
Figure 109137209-A0202-12-0008-5

術語“羥基”(其亦可稱為“羥基(hydroxyl)”)係指-OH基。 The term "hydroxyl" (which may also be referred to as "hydroxyl") refers to the -OH group.

術語“側氧基”係指=O取代基,藉以氧原子與碳雙鍵(例如C=O)或另一元素(例如S=O、S(=O)2)鍵結。碳或其他元素適當地為烷基、環烷基、螺環烷基或雜環基的原子。 The term "pendant oxy group" refers to an =0 substituent, whereby an oxygen atom is bonded to a carbon double bond (for example, C=O) or another element (for example, S=O, S(=O) 2 ). The carbon or other element is suitably an atom of an alkyl group, a cycloalkyl group, a spirocycloalkyl group or a heterocyclic group.

術語“鹵基”如本文所用係指氟、氯、溴或碘。鹵基之特定實例為氟及氯,尤其是氟。 The term "halo" as used herein refers to fluorine, chlorine, bromine or iodine. Specific examples of halo are fluorine and chlorine, especially fluorine.

在取代基被表示為視需要地經取代例如在下述的實施態樣及優先選擇中在式(I)中視需要地進一步經取代之情形下,除非另有說明,否則如給定式中所指定,該等取代基視需要地經取代,例如視需要地進一步經取代,即使可能的取代未在實施態樣中明確列出。 In the case where a substituent is represented as optionally substituted, for example, in the following embodiments and preferences, where it is optionally further substituted in formula (I), unless otherwise specified, as specified in a given formula, These substituents are optionally substituted, for example, if necessary, further substituted, even if possible substitutions are not explicitly listed in the embodiments.

在一個實施態樣中,RA係選自由下列所組成之群組:C1-10烷基和C3-10環烷基。 In one embodiment aspect, R A group consisting of the following selected from the group consisting of: C 1-10 alkyl and C 3-10 cycloalkyl.

在一個實施態樣中,RA為C1-10烷基,特別是C1-8烷基。 In one aspect of the embodiment, R A is C 1-10 alkyl, especially C 1-8 alkyl.

適當地,RA係選自由下列所組成之群組:甲基、乙基、正丙基、異丙基、正丁基、正戊基、正己基、正庚基和正辛基,及特別是係選自由下列所組成之群組:甲基、乙基、正丙基、異丙基、正丁基、正己基和正辛基。 Suitably, R A group consisting of the following selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl group, and especially It is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, n-hexyl and n-octyl.

適當地,RA為C6-10烷基,特別是正庚基、正辛基、庚基-CH(CH3)-及己基-CH(CH3)-,諸如己基-CH(CH3)-。 Suitably, R A is C 6-10 alkyl, especially n-heptyl, n-octyl, heptyl group -CH (CH 3) - and hexyl groups -CH (CH 3) -, such as a hexyl group -CH (CH 3) - .

適當地,RA為正戊基-C(CH3)2-或正己基-C(CH3)2-。 Suitably, R A is a n-pentyl group -C (CH 3) 2 - or n-hexyl group -C (CH 3) 2 -.

適當地,RA為正己基-CH(CH3)-、正戊基-C(CH3)2-或正己基-C(CH3)2-。 Suitably, R A is a n-hexyl group -CH (CH 3) -, n-pentyl, -C (CH 3) 2 - or n-hexyl group -C (CH 3) 2 -.

最適當地,RA為己基-CH(CH3)-及具有下列結構: Most suitably, R A is a hexyl group -CH (CH 3) - and has the following structure:

Figure 109137209-A0202-12-0009-6
Figure 109137209-A0202-12-0009-6

在一個實施態樣中,RA為C3-10環烷基,特別是C3-8環烷基。適當地,RA為C6-10環烷基,特別是C8環烷基。 In one aspect of the embodiment, R A is a C 3-10 cycloalkyl, particularly C 3-8 cycloalkyl. Suitably, R A is a C 6-10 cycloalkyl, in particular is a C 8 cycloalkyl group.

適當地,RA係選自由下列所組成之群組:環丙基、環丁基、環戊基、環己基、環庚基、環辛基和雙環[2.2.1]庚基;及特別是環丁基、環戊基、環己基、環辛基或雙環[2.2.1]庚基。適當地,RA係選自由下列所組成之群組:環丙基、環丁基、環戊基、環己基、環庚基和環辛基,及特別是環丁基或環辛基。適當地,RA為環辛基。或者RA為環丁基。 Suitably, the group consisting of selected from the group consisting of R A following: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and bicyclo [2.2.1] heptyl; and especially Cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, or bicyclo[2.2.1]heptyl. Suitably, R A system selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, and, especially, cyclobutyl or cyclooctyl. Suitably, R A is cyclooctyl. Or R A is cyclobutyl.

適當地,RA為1-金剛烷基: Suitably, R A is 1-adamantyl:

Figure 109137209-A0202-12-0009-7
Figure 109137209-A0202-12-0009-7

在一個實施態樣中,RA為C5-10螺環烷基,諸如C5-8螺環烷基,且特別為螺[3.3]庚基。 In one aspect of the embodiment, R A is a C 5-10 spiro cycloalkyl group, such as a C 5-8 spiro cycloalkyl group, and in particular spiro [3.3] heptyl.

在一個實施態樣中,RA例如如上述所定義,係未經取代。適當地,RA為己基-CH(CH3)-且末經取代。 In one aspect of the embodiment, R A is as defined above, e.g., based unsubstituted. Suitably, R A is a hexyl group -CH (CH 3) - Qiemo substituted.

在另一實施態樣中,RA例如如上述所定義,係經取代。 In another aspect of the embodiment, R A is as defined above, e.g., based substituted.

在一個實施態樣中,RA係經一或多個選自由下列所組成群組之取代基取代:側氧基、R1A、NR2AR3A、SR2A、SOR9A、SO2R9A、SO2NR2AR3A、C(O)R2A和CONR2AR3A。適當地,一或多個取代基為R1A。適當地,RA係經一個R1A取代。或者,RA係經二個R1A取代。或者,RA係經三個R1A取代。在上述實施態樣任一者中,R1A可為相同或不同例如相同。 In one embodiment, R A system with one or more selected from the group consisting of substituents aspects: oxo, R 1A, NR 2A R 3A , SR 2A, SOR 9A, SO 2 R 9A, SO 2 NR 2A R 3A , C(O)R 2A and CONR 2A R 3A . Suitably, one or more substituents are R 1A . Suitably, R A is substituted with one R 1A. Alternatively, R A is replaced by two R 1A. Alternatively, R A is replaced by three R 1A. In any of the above embodiments, R 1A may be the same or different, such as the same.

當RA係經至少一個R1A基團取代時,該取代基可取代RA中存在的任何C-H鍵。當RA係經至少兩個R1A基團取代時,R1A基團可在相同碳原子或不同碳原子上。當時RA為C3-10環烷基或C5-10螺環烷基,該基團可在RA連接到氧原子之處被取代,使得下列結構形成: When R A system with at least one R 1A substituent group, the substituent may be any substituent R A CH bonds present. When R A system with at least two substituent groups R 1A, R 1A groups may be on the same carbon atom or different carbon atoms. When R A is a C 3-10 cycloalkyl or a C 5-10 spiro cycloalkyl group, the group R A may be attached to the oxygen atoms are substituted, such that the following structure is formed:

Figure 109137209-A0202-12-0010-8
Figure 109137209-A0202-12-0010-8

在一個實施態樣中,R1A係選自由下列所組成之群組:氟基、甲基、氰基、SiR4AR5AR6A和苯基。 In one embodiment, R 1A is selected from the group consisting of fluoro, methyl, cyano, SiR 4A R 5A R 6A and phenyl.

適當地,R1A為氟基。或者,R1A為甲基。或者,R1A為氰基。或者,R1A為SiR4AR5AR6A。或者,R1A為C3-8環烷基。或者,R1A為苯基。 Suitably, R 1A is a fluoro group. Alternatively, R 1A is methyl. Alternatively, R 1A is cyano. Alternatively, R 1A is SiR 4A R 5A R 6A . Alternatively, R 1A is a C 3-8 cycloalkyl group. Alternatively, R 1A is phenyl.

最適當地,R1A係選自氟基、甲基、C3-8環烷基和苯基,諸如氟基和苯基,尤其是氟基。 Most suitably, R 1A is selected from fluoro, methyl, C 3-8 cycloalkyl and phenyl, such as fluoro and phenyl, especially fluoro.

在另一實施態樣中,RA係經一個苯基取代。在另一實施態樣中,RA係經三個氟基取代。適當地該三個氟基團連接同一末端之碳原子形成CF3基。 In another aspect of the embodiment, R A phenyl group substituted with one system. In another aspect of the embodiment, R A system substituted with three fluoro groups. Suitably the three fluoro groups are connected to the same terminal carbon atom to form a CF 3 group.

在一個實施態樣中,R4A、R5A和R6A係獨立地選自由下列所組成之群組:C1-4烷基和苯基。適當地,R4A、R5A和R6A係獨立地選自由下列所組成之群組:甲基、乙基、異丙基、三級丁基和苯基。 In one embodiment, R 4A , R 5A and R 6A are independently selected from the group consisting of C 1-4 alkyl and phenyl. Suitably, R 4A , R 5A and R 6A are independently selected from the group consisting of methyl, ethyl, isopropyl, tertiary butyl and phenyl.

在一個實施態樣中,當R1A為甲基、C3-8環烷基和苯基時,R1A係經R7A及/或R8A取代。適當地,R1A係經R7A和R8A取代。或者,R1A係經R7A或R8A取代。在一個實施態樣中,當R1A為甲基、C3-8環烷基和苯基時,R1A不經R7A及/或R8A取代。在一個實施態樣中R1A係經R7A取代且R8A不存在。 In one aspect, when R 1A is methyl, C 3-8 cycloalkyl and phenyl, R 1A is substituted with R 7A and/or R 8A. Suitably, R 1A is substituted with R 7A and R 8A. Alternatively, R 1A is substituted with R 7A or R 8A. In one aspect, when R 1A is methyl, C 3-8 cycloalkyl and phenyl, R 1A is not substituted with R 7A and/or R 8A. In one embodiment, R 1A is substituted with R 7A and R 8A is not present.

在一個實施態樣中,R7A和R8A係獨立地選自由下列所組成之群組:側氧基、C1-4烷基、C1-4烷氧基、羥基、CO2H、氰基、甲磺醯基和鹵基;或,R7A和R8A一起形成C3-8環烷基或4-7員雜環。 In one embodiment, R 7A and R 8A are independently selected from the group consisting of: pendant oxy, C 1-4 alkyl, C 1-4 alkoxy, hydroxyl, CO 2 H, cyanide Or, R 7A and R 8A together form a C 3-8 cycloalkyl group or a 4-7 membered heterocyclic ring.

適當地,R7A和R8A係獨立地選自由下列所組成之群組:側氧基、甲基、乙基、甲氧基、羥基、CO2H、氰基、甲磺醯基和鹵基(例如氟基)諸如側氧基、甲基、乙基、甲氧基、羥基、氰基、甲磺醯基和鹵基(例如氟基);或,R7A和R8A一起形成C3-8環烷基或4-7員雜環。在一個實施態樣中,R7A和R8A為氟基。在一個實施態樣中,R7A和R8A為氯基。在一個實施態樣中,R7A和R8A係獨立地選自由下列所組成之群組:側氧基、C1-4烷基、C1-4烷氧基、羥基、氰基、甲磺醯基和鹵基。 Suitably, R 7A and R 8A are independently selected from the group consisting of pendant oxy, methyl, ethyl, methoxy, hydroxy, CO 2 H, cyano, methanesulfonyl and halo (E.g. fluoro group) such as pendant oxy, methyl, ethyl, methoxy, hydroxyl, cyano, methanesulfonyl and halo (e.g. fluoro); or, R 7A and R 8A together form C 3- 8 -cycloalkyl or 4-7 membered heterocyclic ring. In one embodiment, R 7A and R 8A are fluoro groups. In one embodiment, R 7A and R 8A are chloro groups. In one embodiment, R 7A and R 8A are independently selected from the group consisting of: pendant oxy, C 1-4 alkyl, C 1-4 alkoxy, hydroxyl, cyano, methanesulfonate Aceto and halo.

適當地,R7A為側氧基。或者,R7A為C1-4烷基,諸如甲基。或者,R7A為C1-4烷氧基諸如甲氧基。或者,R7A為C1-4鹵烷基諸如CF3。或者,R7A為C1-4鹵烷氧基諸如OCF3。或者,R7A為羥基。或者,R7A為CO2H。或者,R7A為氰基。或者,R7A為甲磺醯基。或者,R7A為鹵基諸如氯基或氟基,例如,氯基。在上述實施態樣中的任一者中,適當地R8A不存在。最適當地,R7A為鹵基諸如氯基或氟基,例如,氯基、或C1-4鹵烷基諸如CF3和R8A不存在。 Suitably, R 7A is a pendant oxy group. Alternatively, R 7A is C 1-4 alkyl, such as methyl. Alternatively, R 7A is C 1-4 alkoxy such as methoxy. Alternatively, R 7A is C 1-4 haloalkyl such as CF 3 . Alternatively, R 7A is C 1-4 haloalkoxy such as OCF 3 . Alternatively, R 7A is a hydroxyl group. Alternatively, R 7A is CO 2 H. Alternatively, R 7A is cyano. Alternatively, R 7A is methanesulfonyl. Alternatively, R 7A is a halo group such as a chloro group or a fluoro group, for example, a chloro group. In any of the above-mentioned embodiments, R 8A is appropriately absent. Most suitably, R 7A is a halo group such as a chloro group or a fluoro group, for example, a chloro group, or a C 1-4 haloalkyl group such as CF 3 and R 8A are not present.

適當地,R8A為側氧基。或者,R8A為C1-4烷基,諸如甲基。或者,R8A為C1-4烷氧基諸如甲氧基。或者,R8A為C1-4鹵烷基諸如CF3。或者,R8A為C1-4鹵烷氧基諸如OCF3。或者,R8A為羥基。或者,R8A為CO2H。或者,R8A為氰基。 或者,R8A為甲磺醯基。或者,R8A為鹵基諸如氯基或氟基,例如,氯基。在上述實施態樣中的任一者中,適當地R7A不存在。 Suitably, R 8A is a pendant oxy group. Alternatively, R 8A is C 1-4 alkyl, such as methyl. Alternatively, R 8A is C 1-4 alkoxy such as methoxy. Alternatively, R 8A is C 1-4 haloalkyl such as CF 3 . Alternatively, R 8A is C 1-4 haloalkoxy such as OCF 3 . Alternatively, R 8A is a hydroxyl group. Alternatively, R 8A is CO 2 H. Alternatively, R 8A is cyano. Alternatively, R 8A is methylsulfonyl. Alternatively, R 8A is a halo group such as a chloro group or a fluoro group, for example, a chloro group. In any of the above-mentioned embodiments, R 7A is appropriately absent.

在另一實施態樣中,R7A和R8A一起形成C3-8環烷基或4-7員雜環。適當地,R7A和R8A形成C3-8環烷基環諸如C3-6環烷基環。適當地,R7A和R8A形成4-7員雜環諸如4-6員雜環。 In another embodiment, R 7A and R 8A together form a C 3-8 cycloalkyl group or a 4-7 membered heterocyclic ring. Suitably, R 7A and R 8A form a C 3-8 cycloalkyl ring such as a C 3-6 cycloalkyl ring. Suitably, R 7A and R 8A form a 4-7 membered heterocyclic ring such as a 4-6 membered heterocyclic ring.

在一個實施態樣中,R2A和R3A獨立地為H、C1-8烷基、C3-8環烷基或苯基。適當地,R2A和R3A獨立地為H、C1-4烷基、C3-8環烷基或苯基。 In one embodiment, R 2A and R 3A are independently H, C 1-8 alkyl, C 3-8 cycloalkyl, or phenyl. Suitably, R 2A and R 3A are independently H, C 1-4 alkyl, C 3-8 cycloalkyl or phenyl.

適當地,R2A為H。或者,R2A為C1-8烷基,諸如C1-4烷基例如甲基。或者,R2A為C3-8環烷基諸如C3-6環烷基。或者,R2A為苯基。 Suitably, R 2A is H. Alternatively, R 2A is C 1-8 alkyl, such as C 1-4 alkyl such as methyl. Alternatively, R 2A is C 3-8 cycloalkyl such as C 3-6 cycloalkyl. Alternatively, R 2A is phenyl.

在一個實施態樣中,R2A為甲基或苯基,特別是苯基。 In one embodiment, R 2A is methyl or phenyl, especially phenyl.

適當地,R3A為H。或者,R3A為C1-8烷基,諸如C1-4烷基例如甲基。或者,R3A為C3-8環烷基,諸如C3-6環烷基。或者,R3A為苯基。 Suitably, R 3A is H. Alternatively, R 3A is C 1-8 alkyl, such as C 1-4 alkyl such as methyl. Alternatively, R 3A is C 3-8 cycloalkyl, such as C 3-6 cycloalkyl. Alternatively, R 3A is phenyl.

在一個實施態樣中,R3A為甲基。 In one embodiment, R 3A is methyl.

在一個實施態樣中,R2A和R3A形成4-7員雜環。 In one embodiment, R 2A and R 3A form a 4-7 membered heterocyclic ring.

在一個實施態樣中,R9A為C1-8烷基、C3-8環烷基或苯基。適當地,R9A為C1-4烷基、C3-8環烷基或苯基。適當地,R9A為C1-4烷基諸如甲基。或者,R9A為C3-8環烷基諸如C3-5環烷基。或者,R9A為苯基。 In one embodiment, R 9A is C 1-8 alkyl, C 3-8 cycloalkyl or phenyl. Suitably, R 9A is C 1-4 alkyl, C 3-8 cycloalkyl or phenyl. Suitably, R 9A is C 1-4 alkyl such as methyl. Alternatively, R 9A is C 3-8 cycloalkyl such as C 3-5 cycloalkyl. Alternatively, R 9A is phenyl.

在一個實施態樣中,R9A為甲基或苯基,特別是苯基。 In one embodiment, R 9A is methyl or phenyl, especially phenyl.

在一個實施態樣中,RA含有6更多個碳原子,諸如6、7、8、9或10個碳原子,諸如8、9或10個碳原子。適當地,RA含有6碳原子。或者,RA含有7個碳原子。或者,RA含有8個碳原子。或者,RA含有9個碳原子。或者,RA含有10個碳原子。 In one aspect of the embodiment, R A contains 6 carbon atoms and more, such as 8, 9 or 10 carbon atoms, such as 8, 9 or 10 carbon atoms. Suitably, R A contains 6 carbon atoms. Alternatively, R A contain 7 carbon atoms. Alternatively, R A contains 8 carbon atoms. Alternatively, R A contains 9 carbon atoms. Alternatively, R A contains 10 carbon atoms.

在一個實施態樣中,RB為經CO2H取代之C1烷基。適當地,RB為經CO2H取代之C1烷基及與酯氧原子相鄰的RB之C1烷基碳亦連接至至少一個(諸如一個)氫原子。在另一實施態樣中,RB為經CO2H取代之C2烷基。適當地,RB為經CO2H取代之C2烷基及與酯氧原子相鄰的RB的碳原子亦連接至至少一個(諸如 一個)氫原子。在此等施態樣中的任一者中,適當地RB不進一步經三氟甲基或甲基取代。 In one embodiment, R B is a C 1 alkyl group substituted with CO 2 H. Suitably, R B is a C 1 alkyl group substituted with CO 2 H and the C 1 alkyl carbon of R B adjacent to the ester oxygen atom is also connected to at least one (such as one) hydrogen atom. In another embodiment, R B is a C 2 alkyl substituted with CO 2 H. Suitably, R B is a C 2 alkyl group substituted with CO 2 H and the carbon atom of R B adjacent to the ester oxygen atom is also connected to at least one (such as one) hydrogen atom. In applying these aspects in any one of the appropriately R B is not further substituted by trifluoromethyl or methyl.

當RB係經CO2H取代及係視需要地進一步經三氟甲基或甲基取代時,取代基可取代RB中存在的任何C-H鍵。當RB係經CO2H和三氟甲基取代時,該等取代基可在相同碳原子或不同碳原子上。當RB係經CO2H和甲基取代時,該等取代基可在相同碳原子或不同碳原子上。 When substituted, and R B-based system optionally further substituted with methyl or trifluoromethyl by CO 2 H, can be substituted with any substituent group R B CH bonds present. When R B system substituted with CO 2 H, and trifluoromethyl, these groups may be substituted on the same carbon atom or different carbon atoms. When R B system substituted with CO 2 H and methyl, these groups may be substituted on the same carbon atom or different carbon atoms.

適當地該CO2H基係連接至末端碳,即使得下列部分形成: Suitably the CO 2 H group is connected to the terminal carbon, i.e. so that the following moieties are formed:

Figure 109137209-A0202-12-0013-9
Figure 109137209-A0202-12-0013-9

其中p為1或2(例如2)。 Where p is 1 or 2 (for example, 2).

當RB係經CO2H取代及係視需要地進一步經三氟甲基或甲基取代時,適當地與酯氧原子相鄰的RB之碳原子亦連接至至少一個(諸如一個)氫原子,即使得下列部分形成: When R B is substituted with CO 2 H and optionally further substituted with trifluoromethyl or methyl, the carbon atom of R B that is appropriately adjacent to the ester oxygen atom is also connected to at least one (such as one) hydrogen Atom, that is, the following parts are formed:

Figure 109137209-A0202-12-0013-162
Figure 109137209-A0202-12-0013-162

在一個實施態樣中,RB係未經進一步取代。 In one aspect of the embodiment, R B system without further substituted.

在另一實施態樣中,RB係進一步經三氟甲基取代。適當地,該三氟甲基係與酯氧原子相鄰的RB之碳原子連接,即使得下列部分形成: In another aspect of the embodiment, R B train further substituted with trifluoromethyl. Suitably, the trifluoromethyl group is connected to the carbon atom of R B adjacent to the oxygen atom of the ester, so that the following parts are formed:

Figure 109137209-A0202-12-0013-12
Figure 109137209-A0202-12-0013-12

在另一實施態樣中,RB係進一步經甲基取代。適當地,甲基係與酯氧原子相鄰的RB之碳原子連接,即使得列部分形式: In another aspect of the embodiment, R B train further substituted with methyl. Suitably, the methyl group is connected to the carbon atom of R B adjacent to the oxygen atom of the ester, that is, the column part is in the form of:

Figure 109137209-A0202-12-0013-11
Figure 109137209-A0202-12-0013-11

在一個實施態樣中,RC和RD係獨立地選自由下列所組成之群組:H、C1-2烷基、羥基、甲氧基和氟基。適當地,RC和RD係獨立地選自由下列所組成之 群組:H、C1-2烷基、羥基和氟基。在一個實施態樣中,RC和RD係獨立地選自由下列所組成之群組:H、甲氧基和氟基。 In one embodiment, R C and R D are independently selected from the group consisting of H, C 1-2 alkyl, hydroxy, methoxy and fluoro. Suitably, R C and R D are independently selected from the group consisting of H, C 1-2 alkyl, hydroxyl and fluoro. In one embodiment, R C and R D are independently selected from the group consisting of H, methoxy and fluoro.

在一個實施態樣中,RC為H。在一個實施態樣中,RC為C1-2烷基,特別是甲基。在一個實施態樣中,RC為羥基。在一個實施態樣中,RC為氟基。在一個實施態樣中,RC為甲氧基。 In one embodiment, R C is H. In one aspect, R C is C 1-2 alkyl, especially methyl. In one embodiment, R C is a hydroxyl group. In one embodiment, R C is a fluoro group. In one embodiment, R C is methoxy.

在一個實施態樣中,RD為H。在一個實施態樣中,RD為C1-2烷基,特別是甲基。在一個實施態樣中,RD為羥基。在一個實施態樣中,RD為氟基。在一個實施態樣中,RD為甲氧基。 In one embodiment, R D is H. In one aspect, R D is C 1-2 alkyl, especially methyl. In one embodiment, R D is a hydroxyl group. In one embodiment, R D is a fluoro group. In one embodiment, R D is methoxy.

在一個實施態樣中,RC為H、C1-2烷基(特別是甲基)、羥基或氟基;和RD為H、C1-2烷基(特別是甲基)、或氟基。在一個實施態樣中,RC為H、C1-2烷基(特別是甲基)、羥基或氟基;和RD為H、C1-2烷基(特別是甲基)或氟基。在一個實施態樣中,RC為H、C1-2烷基(特別是甲基)、羥基或氟基;和RD為H或C1-2烷基(特別是甲基)。在一個實施態樣中,RC為H、C1-2烷基(特別是甲基)、羥基或氟基;和RD為H或氟基。在一個實施態樣中,RC為H、C1-2烷基(特別是甲基)、羥基或氟基;和RD為H。在一個實施態樣中,RC為H和RD為H或C1-2烷基(特別是甲基)。在一個實施態樣中,RC為H和RD為H或氟基。在一個實施態樣中,RC為H或C1-2烷基(特別是甲基);和RD為H、C1-2烷基(特別是甲基),或氟基。在一個實施態樣中,RC為H或C1-2烷基(特別是甲基);和RD為H或C1-2烷基(特別是甲基)。在一個實施態樣中,RC為H或C1-2烷基(特別是甲基);和RD為H。在一個實施態樣中,RC為H和RD為H。在一個實施態樣中,RC和RD之二者不為羥基。在一個實施態樣中,RC為甲氧基和RD為H。 In one embodiment, R C is H, C 1-2 alkyl (especially methyl), hydroxyl or fluoro; and R D is H, C 1-2 alkyl (especially methyl), or Fluorine-based. In one embodiment, R C is H, C 1-2 alkyl (especially methyl), hydroxyl or fluoro; and R D is H, C 1-2 alkyl (especially methyl) or fluoro base. In one embodiment, R C is H, C 1-2 alkyl (especially methyl), hydroxyl or fluoro; and R D is H or C 1-2 alkyl (especially methyl). In one embodiment, R C is H, C 1-2 alkyl (especially methyl), hydroxyl or fluoro; and R D is H or fluoro. In one aspect, R C is H, C 1-2 alkyl (especially methyl), hydroxyl or fluoro; and R D is H. In one aspect, R C is H and R D is H or C 1-2 alkyl (especially methyl). In one aspect, R C is H and R D is H or a fluoro group. In one embodiment, R C is H or C 1-2 alkyl (especially methyl); and R D is H, C 1-2 alkyl (especially methyl), or fluoro. In one aspect, R C is H or C 1-2 alkyl (especially methyl); and R D is H or C 1-2 alkyl (especially methyl). In one aspect, R C is H or C 1-2 alkyl (especially methyl); and R D is H. In one embodiment, R C is H and R D is H. In one embodiment, both of R C and R D are not hydroxyl groups. In one embodiment, R C is methoxy and R D is H.

在一個實施態樣中,當RB含有2更多個碳原子及4或更多個雜原子時,則RA必須含有6更多個碳原子,和RA中的碳原子數必須超過RA中的雜原子數至少3個原子。 In one embodiment aspect, when R B contains 2 more carbon atoms and 4 or more heteroatoms, the R A 6 must contain more carbon atoms, and R A number of carbon atoms in R must exceed The number of heteroatoms in A is at least 3 atoms.

在一個實施態樣中,式(I)化合物的分子量為150Da-450Da。 In one aspect, the molecular weight of the compound of formula (I) is 150 Da-450 Da.

在上述實施態樣中的任一者中,適當地當RA

Figure 109137209-A0202-12-0015-13
時,RA 係未經取代。 In any of the above embodiments, when R A is
Figure 109137209-A0202-12-0015-13
At the time, R A is not substituted.

在一個實施態樣中提供一種式(I)化合物,其係選自由下列所組成之群組: In one embodiment, a compound of formula (I) is provided, which is selected from the group consisting of:

2-((2-亞甲基-4-(辛氧基)-4-側氧基丁醯基)氧基)乙酸[SYX-00205]; 2-((2-methylene-4-(octyloxy)-4- pendant oxybutyryl)oxy)acetic acid [SYX-00205];

2-((2-亞甲基-4-(辛氧基)-4-側氧基丁醯基)氧基)丙酸[SYX-00223]; 2-((2-methylene-4-(octyloxy)-4- pendant oxybutyryl)oxy)propionic acid [SYX-00223];

3-((2-亞甲基-4-(辛氧基)-4-側氧基丁醯基)氧基)丙酸[SYX-00230]; 3-((2-methylene-4-(octyloxy)-4- pendant oxybutyryl)oxy)propionic acid [SYX-00230];

3-((4-((4-氟苯甲基)氧基)-2-亞甲基-4-側氧基丁醯基)氧基)丙酸[SYX-00331]; 3-((4-((4-fluorobenzyl)oxy)-2-methylene-4-oxobutanoyl)oxy)propionic acid [SYX-00331];

3-((4-(環辛氧基)-2-亞甲基-4-側氧基丁醯基)氧基)丙酸[SYX-00332]; 3-((4-(cyclooctyloxy)-2-methylene-4- pendant oxybutyryl)oxy)propionic acid [SYX-00332];

3-((2-亞甲基-4-(新戊氧基)-4-側氧基丁醯基)氧基)丙酸[SYX-00333]; 3-((2-methylene-4-(neopentyloxy)-4- pendant oxybutyryl)oxy)propionic acid [SYX-00333];

(S)-3-((2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁醯基)氧基)丙酸[SYX-00338]; (S)-3-((2-methylene-4-(oct-2-yloxy)-4- pendant oxybutyryl)oxy)propionic acid [SYX-00338];

3-((4-(己氧基)-2-亞甲基-4-側氧基丁醯基)氧基)丙酸[SYX-00339]; 3-((4-(hexyloxy)-2-methylene-4- pendant oxybutyryl)oxy)propionic acid [SYX-00339];

3-((2-亞甲基-4-側氧基-4-(3-苯氧基丙氧基)丁醯基)氧基)丙酸[SYX-00340]; 3-((2-methylene-4- pendant oxy-4-(3-phenoxypropoxy)butyryl)oxy)propionic acid [SYX-00340];

3-((4-(環己氧基)-2-亞甲基-4-側氧基丁醯基)氧基)丙酸[SYX-00345]; 3-((4-(cyclohexyloxy)-2-methylene-4-oxobutyryl)oxy)propionic acid [SYX-00345];

(R)-3-((2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁醯基)氧基)丙酸[SYX-00347]; (R)-3-((2-methylene-4-(oct-2-yloxy)-4- pendant oxybutyryl)oxy)propionic acid [SYX-00347];

(S)-2-((2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁醯基)氧基)乙酸[SYX-00245]; (S)-2-((2-methylene-4-(oct-2-yloxy)-4-oxobutanoyl)oxy)acetic acid [SYX-00245];

2-((4-(環辛氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00255]; 2-((4-(cyclooctyloxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00255];

2-((4-(環己氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00259]; 2-((4-(cyclohexyloxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00259];

2-((2-亞甲基-4-(新戊氧基)-4-側氧基丁醯基)氧基)乙酸[SYX-00310]; 2-((2-methylene-4-(neopentyloxy)-4- pendant oxybutyryl)oxy)acetic acid [SYX-00310];

2-((4-((4-氟苯甲基)氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00330]; 2-((4-((4-fluorobenzyl)oxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00330];

2-((4-(己氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00350]; 2-((4-(hexyloxy)-2-methylene-4- pendant oxybutyryl)oxy)acetic acid [SYX-00350];

2-((2-亞甲基-4-側氧基-4-(3-苯氧基丙氧基)丁醯基)氧基)乙酸[SYX-00351]; 2-((2-methylene-4- pendant oxy-4-(3-phenoxypropoxy)butanoyl)oxy)acetic acid [SYX-00351];

2-((2-亞甲基-4-側氧基-4-(螺[3.3]庚-2-基氧基)丁醯基)氧基)乙酸[SYX-00358]; 2-((2-methylene-4- pendant oxy-4-(spiro[3.3]heptan-2-yloxy)butanoyl)oxy)acetic acid [SYX-00358];

2-((4-(環己氧基)-2-亞甲基-4-側氧基丁醯基)氧基)丙酸[SYX-00393]; 2-((4-(cyclohexyloxy)-2-methylene-4-oxobutyryl)oxy)propionic acid [SYX-00393];

(R)-2-((2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁醯基)氧基)乙酸[SYX-00748]; (R)-2-((2-methylene-4-(oct-2-yloxy)-4-oxobutanoyl)oxy)acetic acid [SYX-00748];

2-((4-((4,4-二氟環己基)甲氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00392]; 2-((4-((4,4-Difluorocyclohexyl)methoxy)-2-methylene-4-oxobutyryl)oxy)acetic acid [SYX-00392];

2-((4-(3-乙氧基丙氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00388]; 2-((4-(3-ethoxypropoxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00388];

2-((4-(雙環[2.2.1]庚-2-基氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00413]; 2-((4-(Bicyclo[2.2.1]heptan-2-yloxy)-2-methylene-4-oxobutyryl)oxy)acetic acid [SYX-00413];

2-((4-環丁氧基-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00414]; 2-((4-Cyclobutoxy-2-methylene-4- pendant oxybutyryl)oxy)acetic acid [SYX-00414];

2-((4-(環己氧基)-2-亞甲基-4-側氧基丁醯基)氧基)-3,3,3-三氟丙酸[SYX-00430]; 2-((4-(cyclohexyloxy)-2-methylene-4- pendant oxybutyryl)oxy)-3,3,3-trifluoropropionic acid [SYX-00430];

2-((4-(環辛氧基)-2-亞甲基-4-側氧基丁醯基)氧基)-3,3,3-三氟丙酸[SYX-00713]; 2-((4-(cyclooctyloxy)-2-methylene-4- pendant oxybutyryl)oxy)-3,3,3-trifluoropropionic acid [SYX-00713];

3-((4-(環辛氧基)-2-亞甲基-4-側氧基丁醯基)氧基)-4,4,4-三氟丁酸[SYX-00761]; 3-((4-(cyclooctyloxy)-2-methylene-4- pendant oxybutyryl)oxy)-4,4,4-trifluorobutanoic acid [SYX-00761];

2-(4-(環庚氧基)-2-亞甲基-4-側氧基丁醯氧基)乙酸[SYX-00820]; 2-(4-(cycloheptyloxy)-2-methylene-4-oxobutanoyloxy)acetic acid [SYX-00820];

2-(2-亞甲基-4-(辛-3-基氧基)-4-側氧基丁醯氧基)乙酸[SYX-00826]; 2-(2-methylene-4-(oct-3-yloxy)-4-oxobutanoyloxy)acetic acid [SYX-00826];

2-(2-亞甲基-4-(辛-4-基氧基)-4-側氧基丁醯氧基)乙酸[SYX-00827]; 2-(2-methylene-4-(oct-4-yloxy)-4-oxobutanoyloxy)acetic acid [SYX-00827];

2-((4-(庚-4-基氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00828]; 2-((4-(hept-4-yloxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00828];

2-((4-((金剛烷-2-基)氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00830]; 2-((4-((adamantan-2-yl)oxy)-2-methylene-4-oxobutyryl)oxy)acetic acid [SYX-00830];

2-((4-(1-環己基乙氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00831]; 2-((4-(1-cyclohexylethoxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00831];

2-((4-(1-環庚基乙氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00833]; 2-((4-(1-cycloheptylethoxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00833];

2-(2-亞甲基-4-側氧基-4-(螺[3.4]辛-2-基氧基)丁醯氧基)乙酸[SYX-00834]; 2-(2-methylene-4- pendant oxy-4-(spiro[3.4]oct-2-yloxy)butanoyloxy)acetic acid [SYX-00834];

2-(2-亞甲基-4-側氧基-4-(螺[3.5]壬-2-基氧基)丁醯氧基)乙酸[SYX-00835]; 2-(2-methylene-4- pendant oxy-4-(spiro[3.5]non-2-yloxy)butanoyloxy)acetic acid [SYX-00835];

2-(2-亞甲基-4-側氧基-4-(螺[3.5]壬-7-基氧基)丁醯氧基)乙酸[SYX-00836]; 2-(2-methylene-4- pendant oxy-4-(spiro[3.5]non-7-yloxy)butanoyloxy)acetic acid [SYX-00836];

2-((4-((2,2-二甲基環己基)氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00844]; 2-((4-((2,2-dimethylcyclohexyl)oxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00844];

2-((4-(環辛氧基)-3-甲基-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00843]; 2-((4-(cyclooctyloxy)-3-methyl-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00843];

2-((2-亞甲基-4-側氧基-4-(2,2,4,4-四甲基環丁氧基)丁醯基)氧基)乙酸[SYX-00878]; 2-((2-methylene-4- pendant oxy-4-(2,2,4,4-tetramethylcyclobutoxy)butyryl)oxy)acetic acid [SYX-00878];

(S)-2-(2-亞甲基-4-(辛-3-基氧基)-4-側氧基丁醯氧基)乙酸[SYX-00879]; (S)-2-(2-methylene-4-(oct-3-yloxy)-4-oxobutanoyloxy)acetic acid [SYX-00879];

2-((4-(環辛氧基)-3-甲氧基-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00880]; 2-((4-(cyclooctyloxy)-3-methoxy-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00880];

2-((4-((-金剛烷-1-基)氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00881]; 2-((4-((-adamantan-1-yl)oxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00881];

(R)-2-((4-(庚-2-基氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00890]; (R)-2-((4-(hept-2-yloxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00890];

2-((2-亞甲基-4-(壬-2-基氧基)-4-側氧基丁醯基)氧基)乙酸[SYX-00891]; 2-((2-methylene-4-(non-2-yloxy)-4- pendant oxybutyryl)oxy)acetic acid [SYX-00891];

2-((2-亞甲基-4-(壬-5-基氧基)-4-側氧基丁醯基)氧基)乙酸[SYX-00892]; 2-((2-methylene-4-(non-5-yloxy)-4- pendant oxybutyryl)oxy)acetic acid [SYX-00892];

2-((4-(1-(3,5-二氯苯基)乙氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00894]; 2-((4-(1-(3,5-Dichlorophenyl)ethoxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00894];

2-((4-((1-(3,5-二氯苯基)丙-2-基)氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00901]; 2-((4-((1-(3,5-Dichlorophenyl)prop-2-yl)oxy)-2-methylene-4-oxobutyryl)oxy)acetic acid (SYX- 00901];

(R)-2-(2-亞甲基-4-(辛-3-基氧基)-4-側氧基丁醯氧基)乙酸[SYX-00902]; (R)-2-(2-methylene-4-(oct-3-yloxy)-4-oxobutanoyloxy)acetic acid [SYX-00902];

2-((2-亞甲基-4-側氧基-4-(((1R,2S,4R)-1,7,7-三甲基雙環[2.2.1]庚-2-基)氧基)丁醯基)氧基)乙酸[SYX-00904]; 2-((2-methylene-4- pendant oxy-4-(((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)oxy (Yl)butyryl)oxy)acetic acid [SYX-00904];

2-((4-(1-環己基-2,2,2-三氟乙氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00905]; 2-((4-(1-cyclohexyl-2,2,2-trifluoroethoxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00905];

2-((4-(雙環[3.3.1]壬-9-基氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00908]; 2-((4-(Bicyclo[3.3.1]non-9-yloxy)-2-methylene-4-oxobutyryl)oxy)acetic acid [SYX-00908];

(S)-2-((2-亞甲基-4-側氧基-4-((1,1,1-三氟辛-2-基)氧基)丁醯基)氧基)乙酸[SYX-00909]; (S)-2-((2-methylene-4- pendant oxy-4-((1,1,1-trifluorooct-2-yl)oxy)butyryl)oxy)acetic acid (SYX- 00909];

(R)-2-((2-亞甲基-4-(壬-2-基氧基)-4-側氧基丁醯基)氧基)乙酸[SYX-00928]; (R)-2-((2-methylene-4-(non-2-yloxy)-4-oxobutanoyl)oxy)acetic acid [SYX-00928];

(R)-2-((4-(1-環己基乙氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00929]; (R)-2-((4-(1-cyclohexylethoxy)-2-methylene-4- pendant oxybutyryl)oxy)acetic acid [SYX-00929];

(R)-4,4,4-三氟-3-((2-亞甲基-4-(((R)-辛-2-基)氧基)-4-側氧基丁醯基)氧基)丁酸[SYX-00930]; (R)-4,4,4-Trifluoro-3-((2-methylene-4-(((R)-oct-2-yl)oxy)-4-oxobutanoyl)oxy ) Butyric acid [SYX-00930];

2-((4-(環辛氧基)-3-羥基-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00873]; 2-((4-(cyclooctyloxy)-3-hydroxy-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00873];

2-(3-亞甲基-5-(4-甲基庚-4-基氧基)-5-側氧基戊基-1-烯-2-基氧基)乙酸[SYX-00900]; 2-(3-methylene-5-(4-methylhept-4-yloxy)-5-oxopentyl-1-en-2-yloxy)acetic acid [SYX-00900];

2-((4-(1-環己基環丁氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00906]; 2-((4-(1-cyclohexylcyclobutoxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00906];

2-((2-亞甲基-4-((2-甲基辛-2-基)氧基)-4-側氧基丁醯基)氧基)乙酸[SYX-00907]; 2-((2-methylene-4-((2-methyloct-2-yl)oxy)-4-oxobutanoyl)oxy)acetic acid [SYX-00907];

2-((2-亞甲基-4-((2-甲基庚-2-基)氧基)-4-側氧基丁醯基)氧基)乙酸[SYX-00911]; 2-((2-methylene-4-((2-methylhept-2-yl)oxy)-4-oxobutanoyl)oxy)acetic acid [SYX-00911];

2-((2-亞甲基-4-側氧基-4-(1-戊基環丁氧基)丁醯基)氧基)乙酸[SYX-00922]; 2-((2-methylene-4- pendant oxy-4-(1-pentylcyclobutoxy)butyryl)oxy)acetic acid [SYX-00922];

2-((2-亞甲基-4-((2-甲基螺[3.5]壬-2-基)氧基)-4-側氧基丁醯基)氧基)乙酸[SYX-00923]; 2-((2-methylene-4-((2-methylspiro[3.5]non-2-yl)oxy)-4-oxobutyryl)oxy)acetic acid [SYX-00923];

2-((2-亞甲基-4-側氧基-4-(((外)-1,7,7-三甲基雙環[2.2.1]庚-2-基)氧基)丁醯基)氧基)乙酸[SYX-00933]; 2-((2-methylene-4- pendant oxy-4-(((ex)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy)butanyl) (Oxy)acetic acid [SYX-00933];

2-((2-亞甲基-4-側氧基-4-((2,2,6,6-四甲基環己基)氧基)丁醯基)氧基)乙酸[SYX-00938]; 2-((2-methylene-4- pendant oxy-4-((2,2,6,6-tetramethylcyclohexyl)oxy)butyryl)oxy)acetic acid [SYX-00938];

2-((4-(1-(3,5-二氯苯基)乙氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸(異構物1)[SYX-00939]; 2-((4-(1-(3,5-Dichlorophenyl)ethoxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid (isomer 1) (SYX- 00939];

2-((4-(1-(3,5-二氯苯基)乙氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸(異構物2)[SYX-00940]; 2-((4-(1-(3,5-Dichlorophenyl)ethoxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid (isomer 2) (SYX- 00940];

(R)-2-((2-亞甲基-4-側氧基-4-(1-(4-(三氟甲基)苯基)乙氧基)丁醯基)氧基)乙酸)[SYX-00941]; (R)-2-((2-Methylene-4-oxo-4-(1-(4-(trifluoromethyl)phenyl)ethoxy)butyryl)oxy)acetic acid)(SYX -00941];

(S)-2-((2-亞甲基-4-側氧基-4-(1-(4-(三氟甲基)苯基)乙氧基)丁醯基)氧基)乙酸)[SYX-00942]; (S)-2-((2-Methylene-4-oxo-4-(1-(4-(trifluoromethyl)phenyl)ethoxy)butyryl)oxy)acetic acid)(SYX -00942];

2-((4-(1-環己基環丙氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00944]; 2-((4-(1-cyclohexylcyclopropoxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00944];

(S)-2-((4-(1-環己基乙氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00945]; (S)-2-((4-(1-cyclohexylethoxy)-2-methylene-4- pendant oxybutyryl)oxy)acetic acid [SYX-00945];

2-((2-亞甲基-4-側氧基-4-((2,2,4,4-四甲基戊-3-基)氧基)丁醯基)氧基)乙酸[SYX-00946]; 2-((2-Methylene-4- pendant oxy-4-((2,2,4,4-tetramethylpent-3-yl)oxy)butyryl)oxy)acetic acid (SYX-00946 ];

(S)-4,4,4-三氟-3-((2-亞甲基-4-(((R)-辛-2-基)氧基)-4-側氧基丁醯基)氧基)丁酸[SYX-00947]; (S)-4,4,4-trifluoro-3-((2-methylene-4-(((R)-oct-2-yl)oxy)-4-oxobutanoyl)oxy ) Butyric acid [SYX-00947];

2-((2-亞甲基-4-側氧基-4-(1-戊基環丙氧基)丁醯基)氧基)乙酸[SYX-00949];及 2-((2-methylene-4- pendant oxy-4-(1-pentylcyclopropoxy)butyryl)oxy)acetic acid [SYX-00949]; and

3-((2-亞甲基-4-側氧基-4-(2,2,4,4-四甲基環丁氧基)丁醯基)氧基)丙酸[SYX-00948]; 3-((2-methylene-4- pendant oxy-4-(2,2,4,4-tetramethylcyclobutoxy)butyryl)oxy)propionic acid [SYX-00948];

或其醫藥上可接受的鹽及/或溶劑合物中任一者。 Or any of its pharmaceutically acceptable salts and/or solvates.

適當地,化合物係選自由下列所組成之群組: Suitably, the compound is selected from the group consisting of:

(R)-2-((2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁醯基)氧基)乙酸[SYX-00748]; (R)-2-((2-methylene-4-(oct-2-yloxy)-4-oxobutanoyl)oxy)acetic acid [SYX-00748];

(R)-3-((2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁醯基)氧基)丙酸[SYX-00347]; (R)-3-((2-methylene-4-(oct-2-yloxy)-4- pendant oxybutyryl)oxy)propionic acid [SYX-00347];

(S)-2-((2-亞甲基-4-側氧基-4-((1,1,1-三氟辛-2-基)氧基)丁醯基)氧基)乙酸[SYX-00909];及 (S)-2-((2-methylene-4- pendant oxy-4-((1,1,1-trifluorooct-2-yl)oxy)butyryl)oxy)acetic acid (SYX- 00909]; and

2-((2-亞甲基-4-((2-甲基辛-2-基)氧基)-4-側氧基丁醯基)氧基)乙酸[SYX-00907]; 2-((2-methylene-4-((2-methyloct-2-yl)oxy)-4-oxobutanoyl)oxy)acetic acid [SYX-00907];

或其醫藥上可接受的鹽及/或溶劑合物中任一者。 Or any of its pharmaceutically acceptable salts and/or solvates.

適當地,化合物係選自由下列所組成之群組: Suitably, the compound is selected from the group consisting of:

(R)-4,4,4-三氟-3-((2-亞甲基-4-(((R)-辛-2-基)氧基)-4-側氧基丁醯基)氧基)丁酸;及 (R)-4,4,4-Trifluoro-3-((2-methylene-4-(((R)-oct-2-yl)oxy)-4-oxobutanoyl)oxy ) Butyric acid; and

(S)-4,4,4-三氟-3-((2-亞甲基-4-(((R)-辛-2-基)氧基)-4-側氧基丁醯基)氧基)丁酸; (S)-4,4,4-trifluoro-3-((2-methylene-4-(((R)-oct-2-yl)oxy)-4-oxobutanoyl)oxy ) Butyric acid;

或其醫藥上可接受的鹽及/或溶劑合物中任一者。 Or any of its pharmaceutically acceptable salts and/or solvates.

式(I)化合物可如實施例中所述製備,例如如一般程序1-4中所述。 Compounds of formula (I) can be prepared as described in the examples, for example as described in general procedures 1-4.

例如,式(I)化合物可使用下列路徑製備: For example, the compound of formula (I) can be prepared using the following route:

Figure 109137209-A0202-12-0019-14
Figure 109137209-A0202-12-0019-14

RA、RB、RC和RD係如本文別處所定義。 R A , R B , R C and R D are as defined elsewhere herein.

步驟(i):在觸媒例如對-TsOH.H2O存在下、在溶劑(諸如甲苯)中,伊康酸酐(V)可與醇(VI)反應,其中RA'表示RA或其經保護的衍生物,以產生單酯(III)。 Step (i): In the example, the catalyst -TsOH.H 2 O in a solvent (such as toluene), itaconic anhydride (V) may be reacted with an alcohol (Vl), wherein RA 'represents R A, or by Protected derivatives to produce monoester (III).

步驟(ii):單酯(III)和醇(II),其中RB'表示RB或其經保護的衍生物,可如一般程序2及3中所示在標準偶合條件下縮合以在任何所需的去保護步驟之後產生式(I)化合物。或者,單酯(III)可在鹼諸如碳酸鉀存在下與化合物(II')反應, 其中RB'表示RB或其經保護的衍生物及X表示脫離基諸如氯基、溴基、碘基、烷磺酸根或芳烴磺酸根,以在任何必要的保護步驟後產生式(I)化合物。 Step (ii): monoesters (III) and the alcohol (II), wherein R B 'represents R B or a protected derivative thereof, may be as shown in General Procedure 2 and 3 condensed under standard coupling conditions to any After the required deprotection step, the compound of formula (I) is produced. Alternatively, the monoester (III) may be a base such as potassium carbonate in the presence of iodine with a compound (II ') the reaction, wherein R B' represents R B or a protected derivative thereof and X represents a leaving group such as chloro, bromo, Group, alkane sulfonate or arene sulfonate to produce a compound of formula (I) after any necessary protection steps.

式(I)化合物亦可藉由下列路徑製備: The compound of formula (I) can also be prepared by the following route:

Figure 109137209-A0202-12-0020-163
Figure 109137209-A0202-12-0020-163

RA、RB、RC和RD係如本文別處所定義。 R A , R B , R C and R D are as defined elsewhere herein.

步驟(i):在觸媒例如對-TsOH.H2O存在下、在溶劑(如甲苯)中,伊康酸酐(V)可與醇(VI)反應,其中PG表示與RB'中存在的任何保護基正交的保護基,以產生單酯(VII)。 Step (i): Iconic anhydride (V) can react with alcohol (VI) in the presence of a catalyst such as p-TsOH.H 2 O in a solvent (such as toluene), where PG represents the presence in R B' Any of the protecting groups are orthogonal to the protecting groups to produce the monoester (VII).

步驟(ii):單酯(VII)和醇(II),其中RB'表示RB或其經保護的衍生物,可在標準偶合條件下縮合以產生式(VIII)之二酯。 Step (ii): mono ester (VII) and alcohol (II), wherein R B 'represents R B or a protected derivative thereof, may be condensed to produce formula (VIII) bis ester under standard coupling conditions.

步驟(iii):使用熟習該項技術者已知的條件,除去正交保護基PG,以產生在4-位置上具有游離羧基的伊康酸酯(IX)。 Step (iii): Use conditions known to those skilled in the art to remove the orthogonal protecting group PG to produce itconate (IX) with a free carboxyl group at the 4-position.

步驟(iv):使伊康酸酯(IX)與醇(IV)在標準偶合條件下偶合,其中RA'表示RA或其經保護的衍生物,以在任何所需的去保護步驟之後產生單酯(I)。 Step (iv): that the itaconic acid ester (IX) with an alcohol (IV) coupling under standard coupling conditions, wherein R A 'represents R A or a protected derivative thereof, in any desired order after step deprotection The monoester (I) is produced.

式(I)化合物另外可藉由下列路徑製造: The compound of formula (I) can additionally be produced by the following route:

Figure 109137209-A0202-12-0021-16
Figure 109137209-A0202-12-0021-16

RA、RB、RC和RD係如本文別處所定義。 R A , R B , R C and R D are as defined elsewhere herein.

步驟(i):使醇(IV)與化合物(X)進行縮合,其中X1及X2表示脫離基,諸如鹵基例如,氯基、溴基或碘基,和RA'表示RA或其經保護的衍生物,以產生單酯(XI)。 Step (i): The alcohol (IV) is condensed with compound (X-), wherein X 1 and X 2 represents a leaving group such as halo e.g., chloro, bromo or iodo, and R A 'represents R A or Its protected derivatives to produce monoesters (XI).

步驟(ii):使單酯(XI)與式(XII)之三烷基膦基乙酸酯反應,其中R11和R12獨立地表示視需要經鹵基取代之C1-4烷基和RB'表示RB或其經保護的衍生物,以提供一種式(XIII)化合物。 Step (ii): reacting the monoester (XI) with the trialkylphosphinoacetate of formula (XII), wherein R 11 and R 12 independently represent a C 1-4 alkyl group substituted by a halogen group and R B 'or R B represents a protected derivative to provide a compound (XIII) of the formula.

步驟(iii):式(XIII)化合物與甲醛或其甲醛等同物(例如,聚甲醛)的縮合,及在任何視需要去保護步驟後,提供式(I)化合物。 Step (iii): the condensation of the compound of formula (XIII) with formaldehyde or its formaldehyde equivalent (for example, polyoxymethylene), and after any optional deprotection step, the compound of formula (I) is provided.

技術人員將理解保護基可在本文所述的整個合成流程中使用,以產生任何上述化合物或通式的保護衍生物。保護基和彼等去除的方法係描述於“Protective Groups in Organic Synthesis”,by Theodora W.Greene及Peter G.M.Wuts,published by John Wiley & Sons Inc;4th Rev Ed.,2006,ISBN-10:0471697540中。氮保護基的實例包括三苯甲基(Tr)、三級丁氧羰基(BOC)、9-茀基甲氧羰基(Fmoc)、乙醯基(Ac)、苯甲基(Bn)和對-甲氧基苯甲基(PMB)。氧保護基的實例包括乙醯基(Ac)、甲氧基甲基(MOM)、對甲氧基苯甲基(PMB)、苯甲基、三級丁基、甲基、乙基、四氫哌喃基(THP)、及矽基醚和酯(諸如三甲矽基(TMS)、三級丁基二甲矽基(TBDMS)、三-異丙矽基氧基甲基(TOM)和三異丙矽基(TIPS)醚和酯))。羧酸保護基之特定實例包括烷基酯(諸如C1-6烷基例如C1-4烷基酯)、苯甲基酯及矽基酯。 The skilled person will understand that protecting groups can be used throughout the synthetic schemes described herein to produce any of the above-mentioned compounds or protected derivatives of the general formula. The methods of protecting groups and their removal are described in "Protective Groups in Organic Synthesis", by Theodora W. Greene and Peter GMWuts, published by John Wiley & Sons Inc; 4th Rev Ed., 2006, ISBN-10:0471697540. Examples of nitrogen protecting groups include trityl (Tr), tertiary butoxycarbonyl (BOC), 9-phenoxycarbonyl (Fmoc), acetyl (Ac), benzyl (Bn) and p- Methoxybenzyl (PMB). Examples of oxygen protecting groups include acetyl (Ac), methoxymethyl (MOM), p-methoxybenzyl (PMB), benzyl, tertiary butyl, methyl, ethyl, tetrahydro Piperanyl (THP), and silyl ethers and esters (such as trimethylsilyl (TMS), tertiary butyldimethylsilyl (TBDMS), tri-isopropylsilyloxymethyl (TOM) and triisopropyl Propylsilyl (TIPS) ethers and esters)). Specific examples of carboxylic acid protecting groups include alkyl esters (such as C 1-6 alkyl such as C 1-4 alkyl esters), benzyl esters, and silyl esters.

因此,在一個實施態樣中提供一種製備式(I)化合物或其鹽諸如醫藥上可接受的鹽之方法,其包含使一種式(III)化合物: Therefore, in one aspect, there is provided a method of preparing a compound of formula (I) or a salt thereof, such as a pharmaceutically acceptable salt, which comprises making a compound of formula (III):

Figure 109137209-A0202-12-0022-164
Figure 109137209-A0202-12-0022-164

其中RA'、RC和RD係在本文別處定義, Where R A' , R C and R D are defined elsewhere in this article,

或其鹽; Or its salt;

與一種式(II)化合物: With a compound of formula (II):

RB'-OH(II) R B'- OH(II)

其中RB'係在本文別處定義, Wherein R B 'line defined elsewhere herein,

或其鹽反應。 Or its salt reaction.

在一個實施態樣中提供一種製備式(I)化合物或其鹽諸如醫藥上可接受的鹽之方法,其包含使一種式(III)化合物: In one aspect, there is provided a method for preparing a compound of formula (I) or a salt thereof, such as a pharmaceutically acceptable salt, which comprises making a compound of formula (III):

Figure 109137209-A0202-12-0022-17
Figure 109137209-A0202-12-0022-17

其中RA'、RC和RD係在本文別處定義, Where R A' , R C and R D are defined elsewhere in this article,

或其鹽; Or its salt;

與一種式(II’)化合物: With a compound of formula (II’):

RB'-X(II') R B'- X(II')

其中RB'及X係在本文別處定義, Where R B'and X are defined elsewhere in this article,

或其鹽反應。 Or its salt reaction.

亦提供一種製備式(III)化合物或其鹽之方法,其包含使一種式(V)之化合物: A method for preparing a compound of formula (III) or a salt thereof is also provided, which comprises making a compound of formula (V):

Figure 109137209-A0202-12-0023-19
Figure 109137209-A0202-12-0023-19

或其鹽; Or its salt;

與一種式(IV)化合物: With a compound of formula (IV):

RA'-OH(IV) R A '-OH (IV)

其中RA'係在本文別處定義, Wherein R A 'line defined elsewhere herein,

或其鹽反應。 Or its salt reaction.

亦提供一種製備式(I)化合物或其鹽之方法,其包含使一種式(IX)化合物: A method for preparing a compound of formula (I) or a salt thereof is also provided, which comprises making a compound of formula (IX):

Figure 109137209-A0202-12-0023-165
Figure 109137209-A0202-12-0023-165

其中RB'、RC和RD係在本文別處定義, Where R B' , R C and R D are defined elsewhere in this article,

或其鹽; Or its salt;

與一種式(IV)化合物: With a compound of formula (IV):

RA'-OH(IV) R A '-OH (IV)

其中RA'係在本文別處定義, Wherein R A 'line defined elsewhere herein,

或其鹽反應。 Or its salt reaction.

在一個實施態樣中提供一種製備式(VIII)化合物或其鹽之方法,其包含使一種式(VII)化合物:: In one aspect, a method for preparing a compound of formula (VIII) or a salt thereof is provided, which comprises making a compound of formula (VII):

Figure 109137209-A0202-12-0023-166
Figure 109137209-A0202-12-0023-166

其中PG、RC和RD係在本文別處定義, Where PG, R C and R D are defined elsewhere in this article,

或其鹽; Or its salt;

與一種式(II)化合物: With a compound of formula (II):

RB'-OH(II) R B'- OH(II)

其中RB'係在本文別處定義, Wherein R B 'line defined elsewhere herein,

或其鹽反應。 Or its salt reaction.

在一個實施態樣中提供一種製備式(I)化合物或其鹽諸如醫藥上可接受的鹽之方法,其包含使一種式(XIII)化合物: In one aspect, there is provided a method for preparing a compound of formula (I) or a salt thereof, such as a pharmaceutically acceptable salt, which comprises making a compound of formula (XIII):

Figure 109137209-A0202-12-0024-167
Figure 109137209-A0202-12-0024-167

或其鹽, Or its salt,

與甲醛或其等同物反應; React with formaldehyde or its equivalent;

其中RA'、RB'、RC、RD、R11和R12係在本文別處定義。 Wherein R A' , R B' , R C , R D , R 11 and R 12 are defined elsewhere in this document.

在一個實施態樣中提供一種製備式(XIII)化合物或其鹽之方法,其包含使一種式(XI)化合物: In one embodiment, a method for preparing a compound of formula (XIII) or a salt thereof is provided, which comprises making a compound of formula (XI):

Figure 109137209-A0202-12-0024-168
Figure 109137209-A0202-12-0024-168

其中RA'、RC、RD及X2係在本文別處定義, Where R A ', R C , R D and X 2 are defined elsewhere in this article,

或其鹽; Or its salt;

與一種式(XII)化合物: With a compound of formula (XII):

Figure 109137209-A0202-12-0024-170
Figure 109137209-A0202-12-0024-170

其中RB'、R11和R12係在本文別處定義, Where R B' , R 11 and R 12 are defined elsewhere in this article,

或其鹽反應。 Or its salt reaction.

在一個實施態樣中,提供一種式(III)化合物: In one embodiment, a compound of formula (III) is provided:

Figure 109137209-A0202-12-0025-26
Figure 109137209-A0202-12-0025-26

或其鹽,其中RA'、RC和RD係在本文別處定義。 Or a salt thereof, wherein RA ' , R C and R D are defined elsewhere herein.

在一個實施態樣中,提供一種式(IX)化合物: In one embodiment, a compound of formula (IX) is provided:

Figure 109137209-A0202-12-0025-29
Figure 109137209-A0202-12-0025-29

或其鹽,其中RB'、RC和RD係在本文別處定義。適當地,RB'表示經CO2H取代及進一步經三氟甲基或甲基取代之C1-2烷基及例如表示基團CH(CF3)CH2CO2H或CH(CH3)CH2CO2H、或其中羧酸被保護之對應基團。 Or a salt thereof, wherein R B' , R C and R D are defined elsewhere herein. Suitably, R B'represents C 1-2 alkyl substituted with CO 2 H and further substituted with trifluoromethyl or methyl and for example represents the group CH(CF 3 )CH 2 CO 2 H or CH(CH 3 ) CH 2 CO 2 H, or the corresponding group in which the carboxylic acid is protected.

在一個實施態樣中,提供一種式(VIII)化合物: In one embodiment, a compound of formula (VIII) is provided:

Figure 109137209-A0202-12-0025-28
Figure 109137209-A0202-12-0025-28

或其鹽,其中PG、RB'、RC和RD係在本文別處定義。適當地,RB’表示經CO2H取代及進一步經三氟甲基或甲基取代之C1-2烷基及例如表示基團CH(CF3)CH2CO2H或CH(CH3)CH2CO2H、或對應基團,其中羧酸被保護。 Or a salt thereof, wherein PG, R B' , R C and R D are defined elsewhere herein. Suitably, R B'represents C 1-2 alkyl substituted with CO 2 H and further substituted with trifluoromethyl or methyl and for example represents the group CH(CF 3 )CH 2 CO 2 H or CH(CH 3 ) CH 2 CO 2 H, or the corresponding group, where the carboxylic acid is protected.

在一個實施態樣中,提供一種式(XIII)化合物: In one embodiment, a compound of formula (XIII) is provided:

Figure 109137209-A0202-12-0025-32
Figure 109137209-A0202-12-0025-32

或其鹽,其中RA'、RB'、RC、RD、R11和R12係在本文別處定義。、 Or a salt thereof, wherein RA ' , R B' , R C , R D , R 11 and R 12 are defined elsewhere herein. ,

在一個實施態樣中,提供一種式(XI)化合物: In one embodiment, a compound of formula (XI) is provided:

Figure 109137209-A0202-12-0026-33
Figure 109137209-A0202-12-0026-33

或其鹽,其中RA'、RC、RD及X2係在本文別處定義。 Or a salt thereof, wherein RA ' , R C , R D and X 2 are defined elsewhere herein.

某些中間物是新穎的且主張作為本發明的一態樣: Certain intermediates are novel and claimed as aspects of the invention:

4-(環辛氧基)-2-亞甲基-4-側氧基丁酸[SYX-00026]; 4-(cyclooctyloxy)-2-methylene-4-oxobutyric acid [SYX-00026];

2-亞甲基-4-側氧基-4-(3-苯氧基丙氧基)丁酸[SYX-000134]; 2-methylene-4-oxo-4-(3-phenoxypropoxy)butanoic acid [SYX-000134];

4-((4-氟苯甲基)氧基)-2-亞甲基-4-側氧基丁酸[SYX-00181]; 4-((4-fluorobenzyl)oxy)-2-methylene-4-oxobutanoic acid [SYX-00181];

(R)-2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁酸[SYX-00229]; (R)-2-methylene-4-(oct-2-yloxy)-4-oxobutanoic acid [SYX-00229];

(S)-2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁酸[SYX-00510]; (S)-2-methylene-4-(oct-2-yloxy)-4-oxobutanoic acid [SYX-00510];

2-亞甲基-4-(新戊氧基)-4-側氧基丁酸;及 2-methylene-4-(neopentoxy)-4-oxobutyric acid; and

3-((2-(三級丁氧基)-2-側氧基乙氧基)羰基)丁-3-烯酸[SYX-00395]; 3-((2-(tertiary butoxy)-2-oxoethoxy)carbonyl)but-3-enoic acid [SYX-00395];

或其鹽。 Or its salt.

應理解為了用於治療,式(I)化合物之鹽應為醫藥上可接受的。適當醫藥上可接受的鹽對於熟習該項技術者將顯而易見的。醫藥上可接受的鹽包括酸加成鹽,適當地包含鹼基諸如胺基的本發明化合物之鹽,其係與無機酸例如鹽酸、氫溴酸、硫酸、硝酸、或磷酸形成。亦包括與有機酸例如琥珀酸、馬來酸、乙酸、延胡索酸、檸檬酸、酒石酸、苯甲酸、對甲苯磺酸、甲磺酸、萘磺酸及1,5-萘二磺酸形成之鹽。其他鹽例如草酸鹽或甲酸鹽可使用於例如式(I)化合物的分離中且包括在本發明的範圍內,作為鹼加成鹽諸如鈉、鉀、鈣、鋁、鋅、鎂及其他金屬鹽。 It should be understood that for use in therapy, the salt of the compound of formula (I) should be pharmaceutically acceptable. Appropriate pharmaceutically acceptable salts will be obvious to those familiar with the art. Pharmaceutically acceptable salts include acid addition salts, and salts of the compounds of the present invention suitably containing a base such as an amine group, which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid. It also includes salts with organic acids such as succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, and 1,5-naphthalenedisulfonic acid. Other salts such as oxalate or formate can be used, for example, in the separation of compounds of formula (I) and are included within the scope of the present invention, as base addition salts such as sodium, potassium, calcium, aluminum, zinc, magnesium and others Metal salt.

醫藥上可接受的鹽亦可與有機鹼諸如鹼性胺形成例如與氨、葡甲胺(meglumine)、緩血酸胺(tromethamine)、哌

Figure 109137209-A0202-12-0026-156
、精胺酸、膽鹼、二乙胺、苄乙二胺或離胺酸形成。因此,在一個實施態樣中提供一種呈醫藥上可接受的鹽之形式的式(I)化合物。或者,提供一種呈游離酸之形式的式(I)化合物。當化合物含有鹼性基團和游離酸時,其可為兩性離子。 Pharmaceutically acceptable salts can also be formed with organic bases such as basic amines, for example with ammonia, meglumine, tromethamine, piperidine
Figure 109137209-A0202-12-0026-156
, Arginine, choline, diethylamine, benzylethylenediamine or lysine. Therefore, in one embodiment, there is provided a compound of formula (I) in the form of a pharmaceutically acceptable salt. Alternatively, a compound of formula (I) in free acid form is provided. When the compound contains a basic group and a free acid, it may be a zwitterion.

適當地,式(I)化合物不為鹽例如不為醫藥上可接受的鹽。 Suitably, the compound of formula (I) is not a salt, such as a pharmaceutically acceptable salt.

適當地,其中式(I)化合物係呈鹽之形式,醫藥上可接受的鹽為一種鹼加成鹽的形式,諸如與第1族金屬(例如鈉或鉀鹽)、第2族金屬(例如鎂或鈣鹽)或鹼性胺的銨鹽(例如NH4 +鹽),諸如鈉鹽形成之羧酸鹽。 Suitably, where the compound of formula (I) is in the form of a salt, the pharmaceutically acceptable salt is in the form of a base addition salt, such as a group 1 metal (such as sodium or potassium salt), a group 2 metal (such as Magnesium or calcium salts) or ammonium salts of basic amines (e.g. NH 4 + salts), such as carboxylates formed from sodium salts.

式(I)化合物可以結晶或非結晶形式製備,且若結晶,則可視需要地溶劑合,例如呈水合物。本發明在其範圍內包括化學計量的溶劑合物(例如水合物)以及含有可變量的溶劑(例如水)的化合物。適當地,式(I)化合物不為溶劑合物。 The compound of formula (I) can be prepared in crystalline or non-crystalline form, and if crystallized, it may optionally be solvated, for example as a hydrate. The present invention includes within its scope stoichiometric solvates (such as hydrates) and compounds containing variable amounts of solvents (such as water). Suitably, the compound of formula (I) is not a solvate.

本發明擴展到其醫藥上可接受的衍生物,諸如式(I)化合物之醫藥上可接受的前驅藥。包含羧酸的式(I)化合物之典型前驅藥包括其酯(例如C1-6烷基例如C1-4烷基酯)衍生物。因此,在一個實施態樣中,式(I)化合物係以醫藥上可接受的前驅藥提供。在另一實施態樣中,式(I)化合物係不以醫藥上可接受的前驅藥提供。 The present invention extends to its pharmaceutically acceptable derivatives, such as pharmaceutically acceptable prodrugs of the compound of formula (I). Typical prodrugs of compounds of formula (I) containing carboxylic acids include their ester (e.g. C 1-6 alkyl such as C 1-4 alkyl ester) derivatives. Therefore, in one embodiment, the compound of formula (I) is provided as a pharmaceutically acceptable prodrug. In another embodiment, the compound of formula (I) is not provided as a pharmaceutically acceptable prodrug.

某些式(I)化合物可在某些條件下代謝,諸如藉由RB酯基團的水解。如生物例6中所述,某些式(I)化合物的代謝物具有活性。不希望被理論所束縛,式(I)化合物的活性代謝物的形成(諸如體內)可藉由促成式(I)化合物之觀察到的生物活性而有利。因此,在一個實施態樣中,提供式(I)化合物的活性代謝物及其在例如用於治療或預防本文所述疾病的藥物之用途。 Certain compounds of formula (I) can be metabolized under certain conditions, such as by hydrolysis of the ester group R B. As described in Biological Example 6, certain metabolites of the compound of formula (I) are active. Without wishing to be bound by theory, the formation (such as in vivo) of the active metabolite of the compound of formula (I) may be beneficial by contributing to the observed biological activity of the compound of formula (I). Therefore, in one aspect, there are provided active metabolites of the compound of formula (I) and their use in, for example, drugs for the treatment or prevention of the diseases described herein.

應理解本發明包括式(I)化合物的所有異構物,包括所有幾何、互變異構和光學形式,及其混合物(例如外消旋混合物)。在式(I)化合物中存在另外的手性中心的情況下,本發明在其範圍內包括所有可能的非鏡像異構物,包括其混合物。可藉由習知方法將不同的異構形式彼此分離或解析,或者可藉由習知的合成方法或藉由立體特異性或不對稱合成來獲得任何給定的異構物。 It should be understood that the present invention includes all isomers of the compound of formula (I), including all geometric, tautomeric and optical forms, and mixtures thereof (e.g., racemic mixtures). Where there are additional chiral centers in the compound of formula (I), the present invention includes all possible diastereomers, including mixtures thereof, within its scope. Different isomeric forms can be separated or resolved from each other by conventional methods, or any given isomer can be obtained by conventional synthetic methods or by stereospecific or asymmetric synthesis.

本發明亦包括本文提供的化合物之所有同位素形式,無論呈形式(i),其中給定原子序的所有原子具有自然界中占優勢的質量數(或質量數的混合)(在本文中稱為“天然同位素形式”),或(ii),其中一個或多個原子被具有相同 原子序,但質量數不同於自然界中佔優勢的原子之質量數的原子置換(在本文中稱為“非天然變體同位素形式”)。應理解,原子可以質量數的混合天然地存在。“非天然變體同位素形式”亦包括其中具有在自然界中較少發現的質量數之給定原子序的原子(在此稱為“罕見同位素”)之比例相對於其天然存在的比例已增加至例如原子序的原子數目之>20%、>50%、>75%、>90%、>95%或>99%的程度之實施態樣(後一個實施態樣稱為"同位素富集的變體形式")。術語“非天然變體同位素形式”亦包括其中罕見同位素的比例相對於其天然存在的比例已降低的實施態樣。同位素形式可包括放射性形式(即彼等併入放射性同位素)和非放射性形式。放射性形式通常將為同位素富集的變體形式。 The present invention also includes all isotopic forms of the compounds provided herein, regardless of form (i), in which all atoms of a given atomic order have a mass number (or a mixture of mass numbers) predominantly in nature (referred to herein as " Natural isotopic form"), or (ii), in which one or more atoms have the same Atomic order, but the mass number is different from the atomic mass number of the dominant atom in nature (referred to herein as "unnatural variant isotopic form"). It should be understood that atoms can naturally exist in a mixture of mass numbers. "Non-natural variant isotopic form" also includes the proportion of atoms with a given atomic order (herein referred to as "rare isotopes") having a mass number that is rarely found in nature has increased to For example, the number of atoms in the atomic order is >20%, >50%, >75%, >90%, >95%, or >99%. Body form"). The term "non-natural variant isotopic form" also includes embodiments in which the ratio of rare isotopes has been reduced relative to the ratio of naturally occurring isotopes. Isotopic forms can include radioactive forms (ie, they are incorporated into radioactive isotopes) and non-radioactive forms. The radioactive form will usually be a variant form enriched with isotopes.

化合物的非天然變體同位素形式因此可一個或多個原子中含有一種或多種人造或罕見的同位素諸如氘(2H或D)、碳-11(11C)、碳-13(13C)、碳-14(14C)、氮-13(13N)、氮-15(15N)、氧-15(15O)、氧-17(17O)、氧-18(18O)、磷-32(32P)、硫-35(35S)、氯-36(36Cl)、氯-37(37Cl),氟-18(18F)碘-123(123I)、碘-125(125I),或與自然界中占優勢地位的比例比較,一或多個原子中可含有增加比例的該等同位素。 The non-natural variant isotopic form of the compound can therefore contain one or more artificial or rare isotopes such as deuterium ( 2 H or D), carbon-11 ( 11 C), carbon-13 ( 13 C), Carbon-14 ( 14 C), Nitrogen-13 ( 13 N), Nitrogen-15 ( 15 N), Oxygen-15 ( 15 O), Oxygen-17 ( 17 O), Oxygen-18 ( 18 O), Phosphorus- 32 ( 32 P), sulfur-35 ( 35 S), chlorine-36 ( 36 Cl), chlorine-37 ( 37 Cl), fluorine-18 ( 18 F) iodine-123 ( 123 I), iodine-125 ( 125 I), or compared with the predominant proportion in nature, one or more atoms may contain an increased proportion of the isotopes.

包含放射性同位素的非天然變體同位素形式可以例如用於藥物及/或受質組織分佈研究。放射性同位素氚(即3H)和碳-14(即14C)鑒於其容易的併入性和現成的檢測方法而對此目的特別有用。併入氘(即2H或D)的非天然變體同位素形式可因更高的代謝穩定性(例如,體內半衰期增加或劑量要求降低)而提供某些治療優點,且因此在一些情況下可為較佳的。另外,可製備摻入正電子發射同位素(諸如11C、18F、15O及13N)的非天然變體同位素形式,且將用於正電子發射斷層攝影術(PET)研究以檢查受質受體佔有率。 Non-natural variant isotopic forms containing radioisotopes can be used, for example, in drug and/or substrate tissue distribution studies. The radioisotopes tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose due to their easy incorporation and readily available detection methods. Unnatural variant isotopic forms incorporating deuterium (ie 2 H or D) may provide certain therapeutic advantages due to higher metabolic stability (e.g., increased in vivo half-life or decreased dosage requirements), and therefore may be possible in some cases For better. In addition, unnatural variant isotopic forms incorporating positron emission isotopes (such as 11 C, 18 F, 15 O, and 13 N) can be prepared, and will be used in positron emission tomography (PET) research to examine the substrate Receptor occupancy rate.

在一個實施態樣中,式(I)化合物係以天然同位素形式提供。在一個實施態樣中,式(I)化合物係以非天然變體同位素形式提供。在一特定實施態樣中,非天然變體同位素形式為其中指定式(I)化合物之一或多個原子的化學結構中之氫併入氘(即2H或D)的形式。在一個實施態樣中,式(I)化合物之原子係呈不是放射性的同位素形式。在一個實施態樣中,式(I)化合物之一或多個原子係呈 放射性的同位素形式。適當地,放射性同位素為穩定同位素。適當地非天然變體同位素形式為醫藥上可接受的形式。 In one embodiment, the compound of formula (I) is provided in the form of natural isotopes. In one embodiment, the compound of formula (I) is provided as an isotopic form of a non-natural variant. In a specific embodiment, the non-natural variant isotopic form is a form in which hydrogen in the chemical structure of one or more atoms of the compound of formula (I) is incorporated into deuterium (ie, 2 H or D). In one embodiment, the atoms of the compound of formula (I) are in the form of isotopes that are not radioactive. In one embodiment, one or more atoms of the compound of formula (I) are in the form of radioactive isotopes. Suitably, the radioisotope is a stable isotope. Suitably the non-natural variant isotopic form is a pharmaceutically acceptable form.

在一個實施態樣中,提供一種式(I)化合物,藉以化合物之單一原子以非天然變體同位素形式存在。在另一實施態樣中,提供一種式(I)化合物,藉以二或更多個原子以非天然變體同位素形式存在。 In one embodiment, a compound of formula (I) is provided, whereby a single atom of the compound exists in the form of a non-natural variant isotope. In another aspect, there is provided a compound of formula (I), whereby two or more atoms exist as non-natural variant isotopes.

非天然同位素變體形式通常可藉由熟悉該項技術者已知的習知技術或藉由本文所述之方法(例如與彼等在所附用於製備天然同位素形式的實例中所述者類似的方法)來製備。因此,可藉由使用適當同位素變體(或標記的)試劑替代該等實例中使用的正常試劑來製備非天然同位素變體形式。由於式(I)化合物旨在用於醫藥組成物中,所以應容易理解彼等各自較佳地以實質上純的形式提供,例如至少60%純,更適當地至少75%純且較佳至少85%純,尤其是至少98%純(%係以重量為基準之重量)。化合物的不純製劑可用於製備醫藥組成物中所使用的更純形式。 Unnatural isotopic variant forms can generally be obtained by known techniques known to those skilled in the art or by the methods described herein (e.g., similar to those described in the accompanying examples for the preparation of natural isotopic forms.的方法) To prepare. Therefore, non-natural isotope variant forms can be prepared by replacing the normal reagents used in these examples with appropriate isotope variant (or labeled) reagents. Since the compounds of formula (I) are intended to be used in pharmaceutical compositions, it should be readily understood that each of them is preferably provided in a substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85% pure, especially at least 98% pure (% is based on weight). Impure formulations of compounds can be used to prepare more pure forms for use in pharmaceutical compositions.

治療適應症 Treatment indications

式(I)化合物可用於治療,特別是用於治療或預防發炎性疾病或與不良免疫反應有關的疾病。如下述生物例1所示,式(I)化合物的實施例化合物比伊康酸二甲酯更有效地減少細胞介素釋放,如以較低的IC50值所證實。細胞介素為發炎和免疫媒介疾病的重要介質,如以靶向彼等的抗體所產生的治療益處所證明。 The compound of formula (I) can be used for therapy, especially for the treatment or prevention of inflammatory diseases or diseases related to adverse immune response. As Bi Yikang dimethyl compound of Example 1 compound represented by the following biological examples of formula (I) is more effective in reducing cytokine release, such as a lower IC 50 values confirmed. Cytokines are important mediators of inflammation and immune-mediated diseases, as evidenced by the therapeutic benefits of antibodies that target them.

因此,在第一態樣中,本發明提供一種用作為藥劑的如本文所定義之式(I)化合物或其醫藥上可接受的鹽及/或溶劑合物。亦提供一種醫藥組成物,其包含一種如本文所定義之式(I)化合物或其醫藥上可接受的鹽及/或溶劑合物。該類醫藥組成物含有式(I)化合物及醫藥上可接受的載體或賦形劑。 Therefore, in the first aspect, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt and/or solvate thereof for use as a medicament. A pharmaceutical composition is also provided, which comprises a compound of formula (I) as defined herein or a pharmaceutically acceptable salt and/or solvate thereof. This type of pharmaceutical composition contains a compound of formula (I) and a pharmaceutically acceptable carrier or excipient.

在一另外態樣中,本發明提供一種用於治療或預防發炎性疾病或與不良免疫反應有關的疾病之如本文所定義之式(I)化合物或其醫藥上可接受的鹽 及/或溶劑合物。在一另外態樣中,本發明提供一種如本文所定義之式(I)化合物或其醫藥上可接受的鹽及/或溶劑合物之用途,其係用於製造用於治療或預防發炎性疾病或與不良免疫反應有關的疾病之藥劑。在一另外態樣中,本發明提供一種治療或預防發炎性疾病或與不良免疫反應有關的疾病之方法,其包括投予一種如本文所定義之式(I)化合物或其醫藥上可接受的鹽及/或溶劑合物。 In another aspect, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof for the treatment or prevention of inflammatory diseases or diseases associated with adverse immune responses And/or solvates. In another aspect, the present invention provides a use of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein, which is used in the manufacture for the treatment or prevention of inflammatory Drugs for diseases or diseases related to adverse immune reactions. In another aspect, the present invention provides a method for treating or preventing inflammatory diseases or diseases associated with adverse immune responses, which comprises administering a compound of formula (I) as defined herein or a pharmaceutically acceptable compound thereof Salts and/or solvates.

就本發明的所有態樣而言,適當地將該化合物投予至有需要的個體,其中該個體當地為人類個體。 For all aspects of the present invention, the compound is appropriately administered to an individual in need, wherein the individual is a human individual locally.

在一個實施態樣中提供一種用於治療發炎性疾病或與不良免疫反應有關的疾病之如本文所定義之式(I)化合物或其醫藥上可接受的鹽及/或溶劑合物。在本發明之一個實施態樣中提供一種如本文所定義式(I)化合物或其醫藥上可接受的鹽及/或溶劑合物用於製造用於治療發炎性疾病或與不良免疫反應有關的疾病之藥劑之用途。在本發明之一個實施態樣中提供一種治療發炎性疾病或與不良免疫反應有關的疾病之方法,其包括投予一種如本文所定義之式(I)化合物或其醫藥上可接受的鹽及/或溶劑合物。 In one aspect, there is provided a compound of formula (I) as defined herein or a pharmaceutically acceptable salt and/or solvate thereof for the treatment of inflammatory diseases or diseases related to adverse immune reactions. In one embodiment of the present invention, a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein is provided for use in the manufacture of a compound for the treatment of inflammatory diseases or related to adverse immune reactions Use of medicines for diseases. In one embodiment of the present invention, a method for treating inflammatory diseases or diseases related to adverse immune reactions is provided, which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein, and / Or solvate.

在一個實施態樣中提供一種如用於預防發炎性疾病或與不良免疫反應有關的疾病之如本文所定義之式(I)化合物或其醫藥上可接受的鹽及/或溶劑合物。在本發明之一個實施態樣中提供一種如本文所定義之式(I)化合物或其醫藥上可接受的鹽及/或溶劑合物於製造用於預防發炎性疾病或與不良免疫反應有關的疾病之藥劑之用途。在本發明之一個實施態樣中提供一種用於預防發炎性疾病或與不良免疫反應有關的疾病之方法,其包括投予一種如本文所定義之式(I)化合物或其醫藥上可接受的鹽及/或溶劑合物。 In one aspect, there is provided a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt and/or solvate thereof, for use in the prevention of inflammatory diseases or diseases related to adverse immune reactions. In one aspect of the present invention, there is provided a compound of formula (I) as defined herein or a pharmaceutically acceptable salt and/or solvate thereof for use in the manufacture of a compound for preventing inflammatory diseases or related to adverse immune reactions Use of medicines for diseases. In one embodiment of the present invention, there is provided a method for preventing inflammatory diseases or diseases related to adverse immune response, which comprises administering a compound of formula (I) as defined herein or a pharmaceutically acceptable compound thereof Salts and/or solvates.

在一個實施態樣中提供一種用於治療或預防發炎性疾病的如本文所定義之式(I)化合物或其醫藥上可接受的鹽及/或溶劑合物。在本發明之一個實施態樣中提供一種如本文所定義之式(I)化合物或其醫藥上可接受的鹽及/或溶劑合物於製造用於治療或預防發炎性疾病的藥劑之用途。在本發明之一個實施態樣 中提供一種治療或預防發炎性疾病之方法,其包括投予一種如本文所定義之式(I)化合物或其醫藥上可接受的鹽及/或溶劑合物。 In one aspect, there is provided a compound of formula (I) as defined herein or a pharmaceutically acceptable salt and/or solvate thereof for use in the treatment or prevention of inflammatory diseases. In one aspect of the present invention, there is provided a use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt and/or solvate thereof in the manufacture of a medicament for the treatment or prevention of inflammatory diseases. In an embodiment of the present invention There is provided a method for treating or preventing inflammatory diseases, which comprises administering a compound of formula (I) as defined herein or a pharmaceutically acceptable salt and/or solvate thereof.

在一個實施態樣中提供一種用於治療或預防與不良免疫反應有關的疾病之如本文所定義之式(I)化合物或其醫藥上可接受的鹽及/或溶劑合物。在本發明之一個實施態樣中提供一種如本文所定義之式(I)化合物或其醫藥上可接受的鹽及/或溶劑合物於製造用於治療或預防與不良免疫反應有關的疾病之藥劑之用途。在本發明之一個實施態樣提供一種治療或預防與不良免疫反應有關的疾病之方法,其包括投予一種如本文所定義之式(I)化合物或其醫藥上可接受的鹽及/或溶劑合物。 In one aspect, there is provided a compound of formula (I) as defined herein or a pharmaceutically acceptable salt and/or solvate thereof for the treatment or prevention of diseases related to adverse immune reactions. In one embodiment of the present invention, there is provided a compound of formula (I) as defined herein or a pharmaceutically acceptable salt and/or solvate thereof for use in the treatment or prevention of diseases related to adverse immune reactions. The purpose of the medicine. In one embodiment of the present invention, a method for treating or preventing diseases related to adverse immune response is provided, which comprises administering a compound of formula (I) as defined herein or a pharmaceutically acceptable salt and/or solvent thereof Compound.

不良免疫反應通常為引起病理的免疫反應,即病理性免疫反應或反應。 An adverse immune response is usually an immune response that causes pathology, that is, a pathological immune response or reaction.

在一個實施態樣中,發炎性疾病或與不良免疫反應有關的疾病為自體免疫疾病。 In one aspect, the inflammatory disease or disease associated with an adverse immune response is an autoimmune disease.

在一個實施態樣中,發炎性疾病或與不良免疫反應有關的疾病為選自由下列所組成群組之疾病,或與之相關:牛皮癬(包括慢性斑塊性、紅皮性、膿皰、滴狀、逆及指甲(nail)變異型)、氣喘、慢性阻塞性肺病(COPD,包括慢性支氣管炎及肺氣腫)、心臟衰竭(包括左心室衰竭)、心肌梗塞、狹心症、其他動脈粥狀硬化及/或動脈粥狀硬化相關疾病(包括末梢血管疾病及缺血性中風)、粒線體及神經退化性疾病(諸如帕金森氏症、阿茲海默症、杭丁頓氏舞蹈症、肌肉萎縮性脊髓側索硬化症、色素性視網膜炎或粒線體腦肌病(mitochondrial encephalomyopathy))、自體免疫伴腫瘤性視網膜病變(autoimmune paraneoplastic retinopathy)、移植排斥(包括抗體媒介和T細胞媒介的形式)、多發性硬化症、橫貫性脊髓炎(transverse myelitis)、缺血再灌注損傷(例如非急需手術期間諸如用於冠狀動脈繞道手術(coronary artery bypass grafting)之心肺分流或其他心臟手術、經皮冠狀動脈介入治療(percutaneous coronary intervention)後、急性ST上升型心肌梗塞的治療(ST-elevation myocardial infarction)或缺血性中風後、器官移植、或 急性間隔症候群(compartment syndrome))、AGE-誘導之基因組損傷、發炎性腸道疾病(例如克隆氏症或潰瘍性結腸炎(ulcerative colitis))、原發性硬化性膽管炎(PSC)、PSC-自體免疫性肝炎重疊症候群、非酒精性脂肪肝(非酒精性脂肪肝炎)、風濕性多關節炎、環狀肉芽腫瘤、紅斑性狼瘡(CLE)、全身性紅斑狼瘡(SLE)、狼瘡性腎炎、藥物導致之狼瘡、自體免疫心肌炎或心肌心包炎(myopericarditis)、Dressler氏症候群、巨細胞心肌炎、心包膜切開後症候群、藥物導致之過敏性症候群(包括過敏性心肌炎)、濕疹、類肉瘤病、結節性紅斑、急性瀰漫性腦脊髓炎(ADEM)、視神經脊髓炎譜系疾病(neuromyelitis optica spectrum disorders)、MOG(髓鞘寡樹突神經膠質細胞糖蛋白質(myelin oligodendrocyte glycoprotein))抗體相關疾病(包括MOG-EM)、視神經炎(optic neuritis)、CLIPPERS(類固醇激素反應性慢性淋巴球性炎症伴橋腦血管周圍強化症(chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids))、彌漫性脫髓鞘硬化症(diffuse myelinoclastic sclerosis)、Addison氏病、斑禿、關節黏連性脊椎炎、其他脊椎關節炎(spondyloarthritis)(包括周圍型脊椎關節炎(其與牛皮癬有關、發炎性腸道疾病、反應性關節或青少年發病形式))、抗磷脂質抗體症候群、自體免疫溶血性貧血(autoimmune hemolytic anemia)、自體免疫性肝炎、自體免疫性內耳病、類天疱瘡(包括大疱性類天疱瘡、黏膜類天疱瘡、瘢痕性類天疱瘡(cicatricial pemphigoid)、妊娠疱疹或妊娠期類天疱瘡、眼部瘢痕性類天疱瘡(ocular cicatricial pemphigoid))、線狀IgA病(linear IgA disease)、貝賽特氏病(Behçet’s disease)、乳糜瀉、Chagas氏病、皮肌炎、糖尿病I型、子宮內膜異位症、Goodpasture氏症候群、Graves氏病、格巴二氏症候群(Guillain-Barre syndrome)及其亞型(包括急性發炎去髓鞘型多發性神經病變、AIDP、急性運動軸索神經病變(acute motor axonal neuropathy)(AMAN)、急性運動及感覺軸索型神經病變(acute motor and sensory axonal neuropathy)(AMSAN)、咽-頸-臂變異型、Miller-Fisher變體及畢氏腦幹腦炎(Bickerstaff’s brainstem encephalitis))、進行性發炎神經性病變(progressive inflammatory neuropathy)、橋本氏病、化膿性汗腺炎(hidradenitis suppurativa)、包 涵體肌炎、壞死性肌病、Kawasaki氏病、IgA腎病變(IgA nephropathy)、Henoch-Schonlein二氏紫瘢病、自發性血小板減少紫瘢、栓塞性血小板減少性紫癜病(TTP)、Evans氏症候群、間質性膀胱炎(interstitial cystitis)、混合型結締組織疾病、未分化型結締組織病(undifferentiated connective tissue disease)、侷限性硬皮病、重症肌無力症(包括MuSK抗體陽性和血清反應陰性變體)、嗜睡症、神經性肌強直(neuromyotonia)、尋常型天疱瘡、惡性貧血(pernicious anaemia)、牛皮癬性關節炎、多發性肌炎、原發性膽汁性膽管炎(primary biliary cholangitis)(也稱為原發性膽汁性肝硬化)、類風濕性關節炎、復發性風濕症(palindromic rheumatism)、思覺失調症、自體免疫性(腦膜)腦炎症候群、硬皮症、休格倫氏症候群、僵體症候群、風濕性多肌痛(polymylagia rheumatica)、巨大細胞動脈炎(顳動脈炎(temporal arteritis))、高安氏關節炎(Takayasu arteritis)、結節性多動脈炎、Kawasaki氏病、肉芽腫病伴多發性血管炎(granulomatosis with polyangitis)(GPA;以前稱為華格納肉芽腫病(Wegener’s granulomatosis))、嗜伊紅性肉芽腫病伴多血管炎(EGPA;以前稱為Churg-Strauss二氏症候群)、顯微多發性動脈炎/多血管炎、低補體型蕁麻疹性血管炎(hypocomplementaemic urticarial vasculitis)、過敏性血管炎(hypersensitivity vasculitis)、冷凝球蛋白血症、血栓閉塞性脈管炎(Buerger氏病)、血管炎、白血球破碎性血管炎、白斑病、急性瀰漫性腦脊髓炎、腎上腺腦白質病、亞歷山大氏(Alexander’s)病、阿爾珀氏(Alper’s)病、巴洛同心性硬化或馬堡病毒症(balo concentric sclerosis or Marburg disease)、隱源性組織化肺炎(以前稱為阻塞性細支氣管炎組織化肺炎)、Canavan病、中樞神經系統血管炎症候群、夏馬杜三氏病(Charcot-Marie-Tooth disease)、兒童共濟失調伴中樞神經系統髓鞘化不良(childhood ataxia with central nervous system hypomyelination)、慢性發炎去髓鞘型多發性神經病變(CIDP)、糖尿病性視網膜病、球狀細胞白血質障礙(克拉培氏病(Krabbe disease))、移植物抗宿主疾病(GVHD)(包括急性及慢性形式,以及腸GVHD)、C型肝炎(HCV)感染或併發症、單純皰疹病毒感染或併發症、人類免疫不全病毒(HIV)感染或併發症、扁平苔蘚、單肢肌萎縮症、囊腫纖維化、肺 動脈高壓(PAH、包括特發性PAH)、肺類肉瘤病、特發性肺纖維化、小兒氣喘、異位性皮膚炎、過敏性皮膚炎、接觸性皮膚炎、過敏性鼻炎、鼻炎、鼻竇炎、結膜炎、過敏性結膜炎、乾性角膜結膜炎、乾眼症、乾眼症(xerophthalmia)、青光眼、黃斑水腫、糖尿病黃斑水腫、中心性視網膜靜脈阻塞(CRVO)、黃斑點退化(包括乾性及/或濕性年齡相關的黃斑點退化、AMD)、術後白內障發炎、葡萄膜炎(包括後、前、中間及全葡萄膜炎)、虹膜睫狀體炎、鞏膜炎、角膜移植物及角膜緣細胞移植排斥、麩質過敏性腸病(乳糜瀉)、疱疹性皮膚炎、嗜伊紅性食道炎、弛緩不能、自體免疫性自主神經機能障礙、自體免疫性腦脊髓炎、自體免疫性卵巢炎、自體免疫性睪丸炎、自體免疫性胰臟炎、主動脈炎及主動脈周圍炎(periaortitis)、自體免疫性視網膜病變、自體免疫性蕁痲疹、Behcet氏症、(特發性)Castleman氏病、Cogan氏症候群、IgG4相關疾病、腹膜後纖維變性、幼年型特發性關節炎包括系統性幼年型特發性關節炎(Still氏病)、成年發病型Still氏病、木樣結膜炎、Mooren氏潰瘍、急性痘瘡樣苔蘚樣糠疹(pityriasis lichenoides et varioliformis acuta)(PLEVA、也稱為Mucha-Habermann二氏病)、多灶性運動神經病變(MMN)、小兒急性發作神經精神病症候群(PANS)(包括與鏈球菌感染相關的兒童自體免疫神經精神異常(PANDAS))、伴腫瘤症候群(包括伴腫瘤性小腦變性、Eaton-Lambert二氏肌無力症候群、邊緣性腦炎、腦幹腦炎、眼陣攣肌陣攣共濟失調症候群、抗NMDA受體腦炎、胸腺瘤相關的多器官自體免疫)、靜脈周性腦脊髓炎、反射性交感神經失養症、復發性多發性軟骨炎、精子和睾丸自體免疫、Susac氏症候群、Tolosa-Hunt症候群、Vogt-Koyanagi-Harada病、抗合成酶症候群、自體免疫性腸病變、X-性聯免疫失調多內分泌病變腸病變(IPEX)、顯微鏡結腸炎、自體免疫性淋巴球增生症候群(ALPS)、自體免疫性多發性內分泌病-念珠菌病-外胚層器官失養症候群(APEX)、痛風、假性痛風類澱粉(包括AA或繼發性類澱粉變性)、嗜伊紅球性筋膜炎(Shulman症候群)黃體酮過敏(包括黃體酮皮膚炎)、家族性地中海熱(FMF)、腫瘤壞死因子(TNF)受體-相關的周期性發熱症候群(TRAPS)、高免疫球蛋白血症D伴有周期性發熱症候群(HIDS)、PAPA(化膿 性關節炎、壞疽性膿皮症(pyoderma gangrenosum)、嚴重囊性痤瘡)症候群、介白素-1受體拮抗劑缺乏(DIRA)、介白素-36-受體拮抗劑缺乏(DITRA)、隱熱蛋白相關週期症候群(cryopyrin-associated periodic syndromes)(CAPS)(包括家族性寒冷型自體發炎症候群[FCAS]、穆-韋二氏症候群(Muckle-Wells syndrome)、新生兒發病多系統發炎性疾病[NOMID])、NLRP12-相關的自體發炎病症(NLRP12AD)、週期性發熱口瘡口炎(PFAPA)、慢性非典型嗜中性球性皮膚病伴脂質失養症及體溫升高(CANDLE)、Majeed症候群、Blau症候群(也稱為青少年全身性肉芽腫病)、巨噬細胞活化症候群、慢性復發性多灶性骨髓炎(CRMO)、家族性寒冷型自體發炎症候群、突變體腺苷去胺酶2及單基因干擾素病(包括Aicardi-Goutières症候群、視網膜血管病變伴有大腦白質腦病、脊椎動脈硬化發育不良、STING[干擾素基因的刺激物]-相關的嬰兒期發病的血管病變、蛋白酶體相關的自體發炎症候群、家族性凍瘡狀狼瘡、遺傳性對稱性色素沉著異常)、Schnitzler症候群;家族性毛髮上皮瘤、先天性B淋巴球增多症、OTULIN-相關的自體發炎症候群、第2型糖尿病、胰島素抗性及代謝症候群(包括肥胖相關發炎)、動脈粥樣硬化病症(例如心肌梗塞、絞痛症、缺血性心臟衰竭、缺血性腎病、缺血性中風、末梢血管疾病、主動脈瘤)、腎臟發炎病症(例如糖尿病腎病變、膜性腎病變、微小改變疾病、新月形腎絲球腎炎、急性急性腎損傷、腎臟移植)。 In one embodiment, the inflammatory disease or disease related to adverse immune response is a disease selected from the group consisting of or related to: psoriasis (including chronic plaque, erythroderma, pustule, drip Symptoms, inverse and nail (nail) variants), asthma, chronic obstructive pulmonary disease (COPD, including chronic bronchitis and emphysema), heart failure (including left ventricular failure), myocardial infarction, stenosis, other atherosclerosis Atherosclerosis and/or atherosclerosis-related diseases (including peripheral vascular disease and ischemic stroke), mitochondrial and neurodegenerative diseases (such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease) , Amyotrophic lateral sclerosis, retinitis pigmentosa or mitochondrial encephalomyopathy (mitochondrial encephalomyopathy), autoimmune paraneoplastic retinopathy (autoimmune paraneoplastic retinopathy), transplant rejection (including antibody mediators and T cells) Media), multiple sclerosis, transverse myelitis, ischemia-reperfusion injury (e.g. during non-urgent surgery such as cardiopulmonary bypass for coronary artery bypass grafting or other cardiac surgery , After percutaneous coronary intervention, treatment of acute ST-elevation myocardial infarction (ST-elevation myocardial infarction) or after ischemic stroke, organ transplantation, or Acute compartment syndrome (compartment syndrome), AGE-induced genome damage, inflammatory bowel disease (such as Crohn's disease or ulcerative colitis), primary sclerosing cholangitis (PSC), PSC- Autoimmune hepatitis overlap syndrome, non-alcoholic fatty liver (non-alcoholic steatohepatitis), rheumatoid polyarthritis, annular granuloma, lupus erythematosus (CLE), systemic lupus erythematosus (SLE), lupus nephritis , Drug-induced lupus, autoimmune myocarditis or myopericarditis, Dressler’s syndrome, giant cell myocarditis, postpericardiotomy syndrome, drug-induced allergic syndrome (including allergic myocarditis), eczema, class Sarcoidosis, erythema nodosum, acute diffuse encephalomyelitis (ADEM), neuromyelitis optica spectrum disorders, MOG (myelin oligodendrocyte glycoprotein) antibody-related diseases (Including MOG-EM, optic neuritis, CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids), diffuse demyelination Diffuse myelinoclastic sclerosis, Addison's disease, alopecia areata, adhesive spondylitis, other spondyloarthritis (including peripheral spondyloarthritis (which is related to psoriasis, inflammatory bowel disease, reactive Joint or juvenile onset form)), antiphospholipid antibody syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, pemphigoid (including bullous pemphigoid , Mucosal pemphigoid, cicatricial pemphigoid, herpes pregnancy or pemphigoid during pregnancy, ocular cicatricial pemphigoid), linear IgA disease (linear IgA disease), shellfish Behçet's disease, celiac disease, Chagas' disease, dermatomyositis, diabetes type I, endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome and its subtypes (including acute inflamed and demyelinating polyneuropathy, AIDP, acute motor axonal neuropathy (AMAN), acute motor and sensory Acute motor and sensory axonal neuropathy (AMSAN), pharynx-neck-arm variant, Miller-Fisher variant and Bickerstaff's brainstem encephalitis), progressive inflammatory neuropathy (progressive inflammatory neuropathy), Hashimoto’s disease, hidradenitis suppurativa, package Inclusion body myositis, necrotizing myopathy, Kawasaki's disease, IgA nephropathy, Henoch-Schonlein purpura disease, spontaneous thrombocytopenic purpura, embolic thrombocytopenic purpura (TTP), Evans Syndrome, interstitial cystitis (interstitial cystitis), mixed connective tissue disease, undifferentiated connective tissue disease (undifferentiated connective tissue disease), localized scleroderma, myasthenia gravis (including MuSK antibody positive and serum reaction) Negative variants), narcolepsy, neuromyotonia, pemphigus vulgaris, pernicious anaemia, psoriatic arthritis, polymyositis, primary biliary cholangitis (Also known as primary biliary cirrhosis), rheumatoid arthritis, recurrent rheumatism (palindromic rheumatism), schizophrenia, autoimmune (meningeal) cerebral inflammation syndrome, scleroderma, Hugue Ren's syndrome, rigid body syndrome, polymylagia rheumatica, giant cell arteritis (temporal arteritis), Takayasu arteritis, polyarteritis nodosa, Kawasaki's disease , Granulomatosis with polyangitis (granulomatosis with polyangitis) (GPA; formerly known as Wegener's granulomatosis), eosinophilic granulomatosis with polyangitis (EGPA; formerly known as Churg- Strauss syndrome), microscopic polyarteritis/polyangiitis, hypocomplementaemic urticarial vasculitis, hypersensitivity vasculitis, cryoglobulinemia, thrombo-occlusive vein Vasculitis (Buerger's disease), vasculitis, leukocytosis vasculitis, leukoplakia, acute diffuse encephalomyelitis, adrenal leukoencephalopathy, Alexander's disease, Alper's disease, Barlow concentric Sclerosis or Marburg disease (balo concentric sclerosis or Marburg disease), cryptogenic organized pneumonia (formerly known as obstructive bronchiolitis organized pneumonia), Canavan disease, central nervous system vascular inflammation syndrome, Shamadzu Shi Charcot-Marie-Tooth disease, childhood ataxia with central nervous system hypomyelination, chronic inflammatory demyelinating polyneuropathy (CIDP), diabetic retinopathy , Globular cell leukemia (Krabbe disease), graft versus host disease (GVHD) (including acute and chronic forms, and intestinal GVHD), hepatitis C (HCV) infection or complications, simple Herpes virus infection or complication, human immunodeficiency virus (HIV) infection or complication, lichen planus, monolimb muscular atrophy, cystic fibrosis, lung Arterial hypertension (PAH, including idiopathic PAH), pulmonary sarcoidosis, idiopathic pulmonary fibrosis, pediatric asthma, atopic dermatitis, allergic dermatitis, contact dermatitis, allergic rhinitis, rhinitis, sinuses Inflammation, conjunctivitis, allergic conjunctivitis, dry keratoconjunctivitis, dry eye, xerophthalmia, glaucoma, macular edema, diabetic macular edema, central retinal vein occlusion (CRVO), macular degeneration (including dry and/or Wet age-related macular degeneration, AMD), postoperative cataract inflammation, uveitis (including posterior, anterior, intermediate and pan uveitis), iridocyclitis, scleritis, corneal grafts and limbal cells Transplant rejection, celiac disease (celiac disease), herpetic dermatitis, eosinophilic esophagitis, achalasia, autoimmune autonomic dysfunction, autoimmune encephalomyelitis, autoimmunity Ovarianitis, autoimmune testicularitis, autoimmune pancreatitis, aortitis and periaortitis (periaortitis), autoimmune retinopathy, autoimmune urticaria, Behcet's disease, (special (Main) Castleman's disease, Cogan's syndrome, IgG4-related diseases, retroperitoneal fibrosis, juvenile idiopathic arthritis, including systemic juvenile idiopathic arthritis (Still's disease), adult-onset Still's disease, Woody conjunctivitis, Mooren's ulcer, pityriasis lichenoides et varioliformis acuta (PLEVA, also known as Mucha-Habermann disease), multifocal motor neuropathy (MMN), acute onset nerves in children Psychiatric syndrome (PANS) (including childhood autoimmune neuropsychiatric disorders (PANDAS) associated with streptococcal infection), tumor-associated syndrome (including tumor-associated cerebellar degeneration, Eaton-Lambert myasthenia syndrome, limbic encephalitis, Brainstem encephalitis, ocular clonus myoclonus ataxia syndrome, anti-NMDA receptor encephalitis, thymoma-related multi-organ autoimmunity), perivenous encephalomyelitis, reflex sympathetic dystrophy, relapse Polychondrotis, sperm and testicular autoimmunity, Susac syndrome, Tolosa-Hunt syndrome, Vogt-Koyanagi-Harada disease, anti-synthetic enzyme syndrome, autoimmune bowel disease, X-linked immune disorders, polyendocrine disease Intestinal disease (IPEX), microscopic colitis, autoimmune lymphocytosis syndrome (ALPS), autoimmune multiple endocrine disease-candidiasis-ectodermal organ dystrophy syndrome (APEX), gout, pseudogout Amyloid (including AA or secondary amyloidosis), eosinophilic fasciitis (Shulman syndrome), progesterone allergy (including progesterone dermatitis), familial Mediterranean fever (FMF), tumor necrosis factor (TN) F) Receptor-related periodic fever syndrome (TRAPS), hyperimmune globulinemia D with periodic fever syndrome (HIDS), PAPA (suppurative Arthritis, pyoderma gangrenosum (pyoderma gangrenosum), severe cystic acne) syndrome, interleukin-1 receptor antagonist deficiency (DIRA), interleukin-36-receptor antagonist deficiency (DITRA), Cryopyrin-associated periodic syndromes (CAPS) (including familial cold-type autoinflammation syndrome [FCAS], Muckle-Wells syndrome (Muckle-Wells syndrome), neonatal-onset multi-system inflammatory Disease [NOMID]), NLRP12-related autoinflammatory disorder (NLRP12AD), periodic fever aphthous stomatitis (PFAPA), chronic atypical neutrophil globular skin disease with lipid dystrophy and elevated body temperature (CANDLE) , Majeed syndrome, Blau syndrome (also known as juvenile systemic granulomatosis), macrophage activation syndrome, chronic relapsing multifocal osteomyelitis (CRMO), familial cold type autologous inflammation syndrome, mutant adenosine Aminase 2 and single gene interferon disease (including Aicardi-Goutières syndrome, retinal vascular disease with leucoencephalopathy, dysplasia of spinal arteriosclerosis, STING [stimulus of interferon gene]-related infantile-onset vascular disease, Proteasome-related autoinflammation syndrome, familial frostbite-like lupus, hereditary symmetrical pigmentation abnormalities), Schnitzler syndrome; familial trichoepithelioma, congenital B lymphocytosis, OTULIN-related autoinflammation syndrome, Type 2 diabetes, insulin resistance and metabolic syndrome (including obesity-related inflammation), atherosclerotic disorders (e.g. myocardial infarction, colic, ischemic heart failure, ischemic nephropathy, ischemic stroke, peripheral blood vessels Diseases, aortic aneurysms), kidney inflammatory disorders (e.g. diabetic nephropathy, membranous nephropathy, minimal change diseases, crescent glomerulonephritis, acute acute kidney injury, kidney transplantation).

在一個實施態樣中,發炎性疾病或與不良免疫反應有關的疾病為選自下列自體發炎疾病之疾病,或與之相關:家族性地中海熱(FMF)、腫瘤壞死因子(TNF)受體-相關的周期性發熱症候群(TRAPS)、高免疫球蛋白血症D伴有周期性發熱症候群(HIDS)、PAPA(化膿性關節炎、壞疽性膿皮症(pyoderma gangrenosum)、及嚴重囊性痤瘡)症候群、介白素-1受體拮抗劑缺乏(DIRA)、介白素-36-受體拮抗劑缺乏(DITRA)、隱熱蛋白相關週期症候群(cryopyrin-associated periodic syndromes)(CAPS)(包括家族性寒冷型自體發炎症候群[FCAS]、穆-韋二氏症候群(Muckle-Wells syndrome)、及新生兒發病多系統發炎性疾病[NOMID])、NLRP12-相關的自體發炎病症(NLRP12AD)、週期性發 熱口瘡口炎(PFAPA)、慢性非典型嗜中性球性皮膚病伴脂質失養症及體溫升高(CANDLE)、Majeed症候群、Blau症候群(也稱為青少年全身性肉芽腫病)、巨噬細胞活化症候群、慢性復發性多灶性骨髓炎(CRMO)、家族性寒冷型自體發炎症候群、突變體腺苷去胺酶2及單基因干擾素病(包括Aicardi-Goutières症候群、視網膜血管病變伴有大腦白質腦病、脊椎動脈硬化發育不良、STING[干擾素基因的刺激物]-相關的嬰兒期發病的血管病變、蛋白酶體相關的自體發炎症候群、家族性凍瘡狀狼瘡、遺傳性對稱性色素沉著異常)和Schnitzler症候群。 In one aspect, the inflammatory disease or the disease associated with an adverse immune response is a disease selected from or related to the following auto-inflammatory diseases: Familial Mediterranean Fever (FMF), Tumor Necrosis Factor (TNF) Receptor -Related periodic fever syndrome (TRAPS), hyperimmune globulinemia D with periodic fever syndrome (HIDS), PAPA (suppurative arthritis, pyoderma gangrenosum), and severe cystic acne ) Syndrome, interleukin-1 receptor antagonist deficiency (DIRA), interleukin-36-receptor antagonist deficiency (DITRA), cryopyrin-associated periodic syndromes (CAPS) (including Familial cold autologous inflammation syndrome [FCAS], Muckle-Wells syndrome (Muckle-Wells syndrome), and neonatal-onset multisystem inflammatory disease [NOMID]), NLRP12-related autoinflammatory disorder (NLRP12AD) , Periodically issued Heat aphthous stomatitis (PFAPA), chronic atypical neutrophil globular skin disease with lipid dystrophy and elevated body temperature (CANDLE), Majeed syndrome, Blau syndrome (also known as juvenile systemic granulomatosis), macrophages Cell activation syndrome, chronic recurrent multifocal osteomyelitis (CRMO), familial cold autologous inflammation syndrome, mutant adenosine deaminase 2 and single gene interferon disease (including Aicardi-Goutières syndrome, retinal vascular disease with There are leukoencephalopathy, dysplasia of vertebral arteriosclerosis, STING [stimulus of interferon gene]-related infantile-onset vascular disease, proteasome-related autoinflammation syndrome, familial chilblain lupus, hereditary symmetry pigment Abnormal composure) and Schnitzler syndrome.

在一個實施態樣中,發炎性疾病或與不良免疫反應有關的疾病為選自下列由過量的NF-Kb媒介或NF-κB信號通路中的功能之獲得或在其中由其促成異常發病機制(包括非正則NF-κB信號)的疾病之疾病,或與之相關:家族性毛髮上皮瘤、先天性B淋巴球增多症、OTULIN-相關的自體發炎症候群、第2型糖尿病、胰島素抗性及代謝症候群(包括肥胖相關發炎)、動脈粥樣硬化病症(例如心肌梗塞、絞痛症、缺血性心臟衰竭、缺血性腎病、缺血性中風、末梢血管疾病、主動脈瘤)、腎臟發炎病症(例如糖尿病腎病變、膜性腎病變、微小改變疾病、新月形腎絲球腎炎、急性腎損傷、腎臟移植)、氣喘、COPD、第1型糖尿病、類風濕性關節炎、多發性硬化症、發炎性腸道疾病(包括潰瘍性結腸炎(ulcerative colitis)和克隆氏症)、及SLE。 In one embodiment, an inflammatory disease or a disease associated with an adverse immune response is selected from the following: excessive NF-Kb mediators or NF-κB signaling pathways are acquired by or contribute to abnormal pathogenesis ( Including non-canonical NF-κB signaling) diseases, or related to: familial trichoepithelioma, congenital B lymphocytosis, OTULIN-related autoinflammation syndrome, type 2 diabetes, insulin resistance and Metabolic syndrome (including obesity-related inflammation), atherosclerotic disorders (e.g. myocardial infarction, colic, ischemic heart failure, ischemic nephropathy, ischemic stroke, peripheral vascular disease, aortic aneurysm), kidney inflammation Conditions (e.g. diabetic nephropathy, membranous nephropathy, minimal change disease, crescent glomerulonephritis, acute kidney injury, kidney transplantation), asthma, COPD, type 1 diabetes, rheumatoid arthritis, multiple sclerosis Disease, inflammatory bowel disease (including ulcerative colitis and Crohn’s disease), and SLE.

在一個實施態樣中,疾病係選自由下列所組成之群組:類風濕性關節炎、牛皮癬性關節炎、關節黏連性脊椎炎、全身性紅斑性狼瘡症、多發性硬化症、牛皮癬、克隆氏症、潰瘍性結腸炎(ulcerative colitis)、葡萄膜炎、隱熱蛋白相關週期症候群(cryopyrin-associated periodic syndromes)、穆-韋二氏症候群(Muckle-Wells syndrome)、幼年型特發性關節炎及慢性阻塞性肺病。在一個實施態樣中,疾病為多發性硬化症。 In one embodiment, the disease is selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, joint adhesive spondylitis, systemic lupus erythematosus, multiple sclerosis, psoriasis, Crohn's disease, ulcerative colitis, uveitis, cryopyrin-associated periodic syndromes, Muckle-Wells syndrome, juvenile idiopathic joints Inflammation and chronic obstructive pulmonary disease. In one embodiment, the disease is multiple sclerosis.

在一個實施態樣中,疾病為牛皮癬。 In one embodiment, the disease is psoriasis.

在一個實施態樣中,(例如)如生物例1中所述,當在細胞介素分析測試中時,與伊康酸二甲酯比較,式(I)化合物呈現較低IC50。在一個實施態樣中, (例如)如生物例1中所述,當在細胞介素分析測試中時,與延胡索酸二甲酯比較,式(I)化合物呈現較低IC50In one embodiment aspect, (e.g.) as described in biological Example 1, when analyzed in a cytokine test in comparison with itaconic acid dimethyl ester, the compound of formula (I) exhibit lower IC 50. In one embodiment aspect, (e.g.) as described in biological Example 1, when analyzed in a cytokine test, compared with dimethyl fumarate, the compound of formula (I) exhibit lower IC 50.

在一個實施態樣中,(例如)如生物例3中所述,當在NRF2分析測試中時,與伊康酸二甲酯比較,式(I)化合物呈現較低EC50。在一個實施態樣中,(例如)如生物例3中所述,當在NRF2分析測試中時,與伊康酸二甲酯比較,式(I)化合物呈現較高Emax。在一個實施態樣中,(例如)如生物例3中所述,當在NRF2分析測試中時,與伊康酸二甲酯比較,式(I)化合物呈現較低EC50及/或較高Emax。在一個實施態樣中,(例如)如生物例3中所述,當在NRF2分析測試中時,與伊康酸二甲酯比較,式(I)化合物呈現較低EC50及較高EmaxIn one embodiment aspect, (e.g.) as described in biological Example 3, when NRF2 analysis and testing, compared with itaconic acid dimethyl ester, the compound of formula (I) exhibit a lower EC 50. In one embodiment, as described in Biological Example 3, for example, when in the NRF2 analysis test, the compound of formula (I) exhibits a higher Emax compared to dimethyl iconate. In one embodiment aspect, (e.g.) as described in biological Example 3, when NRF2 analysis and testing, compared with itaconic acid dimethyl ester, the compound of formula (I) exhibits a low EC 50 and / or high E max . In one embodiment, (for example) as described in Biological Example 3, when compared with dimethyl iconate in the NRF2 analysis test, the compound of formula (I) exhibits a lower EC 50 and a higher E max .

在一個實施態樣中,(例如)如生物例4中所述,與伊康酸二甲酯比較,式(I)化合物呈現改良的口服全身生體可用率。在一個實施態樣中,(例如)如生物例4中所述,與伊康酸二甲酯比較,式(I)化合物在靜脈內給藥後呈現血漿清除率降低。 In one aspect, for example, as described in Biological Example 4, the compound of formula (I) exhibits an improved oral systemic bioavailability compared to dimethyl iconate. In one aspect, for example, as described in Biological Example 4, the compound of formula (I) exhibits reduced plasma clearance after intravenous administration compared with dimethyl iconate.

在一個實施態樣中,(例如)如生物例5中所述,當在肝細胞穩定性分析測試中時,與伊康酸4-辛酯比較,式(I)化合物呈現較低的內生性清除率(intrinsic clearance)(CIint)。在一個實施態樣中,(例如)如生物例5中所述,當在肝細胞穩定性分析測試中時,與伊康酸4-辛酯比較,式(I)化合物呈現較長半衰期(T1/2)。 In one embodiment, (for example) as described in Biological Example 5, the compound of formula (I) exhibits lower endogeneity when compared with 4-octyl itaconic acid in the liver cell stability analysis test. Intrinsic clearance (CI int ). In one embodiment, (for example) as described in Biological Example 5, when in the liver cell stability analysis test, compared with 4-octyl Iconate, the compound of formula (I) exhibits a longer half-life (T1 /2).

投予 Vote for

式(I)化合物通常以醫藥組成物予。因此,在一個實施態樣中,提供一種醫藥組成物,其包含式(I)化合物及一或多種醫藥上可接受的稀釋劑或載體。 The compound of formula (I) is usually administered as a pharmaceutical composition. Therefore, in one aspect, a pharmaceutical composition is provided, which comprises a compound of formula (I) and one or more pharmaceutically acceptable diluents or carriers.

式(I)化合物可以任何方便的方法投予,例如以口服、腸胃外、口頰、舌下、經鼻、直腸、鞘內或透皮投予,及醫藥組成物相應地修改。 The compound of formula (I) can be administered by any convenient method, such as oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration, and the pharmaceutical composition can be modified accordingly.

式(I)化合物可局部投予至目標器官,例如局部投予至眼睛、肺、鼻或皮膚。因此,本發明提供一種醫藥組成物,其包含式(I)化合物組合一或多種局部可接受的稀釋劑或載體。 The compound of formula (I) can be administered locally to the target organ, for example, to the eyes, lungs, nose or skin. Therefore, the present invention provides a pharmaceutical composition comprising a compound of formula (I) in combination with one or more topically acceptable diluents or carriers.

當活性式(I)化合物口服投予時,可配製成液體或固體,例如調配成糖漿、懸浮劑、乳劑、錠劑、膠囊或口含錠。 When the active compound of formula (I) is administered orally, it can be formulated as a liquid or solid, for example, as a syrup, suspension, emulsion, lozenge, capsule or lozenge.

液體調配物通常將由式(I)化合物於適當液態載劑中之懸浮液或溶液組成。適當地,載體為非水性例如聚乙二醇或油。該調配物亦可包含懸浮劑、防腐劑、調味劑及/或著色劑。 Liquid formulations will generally consist of a suspension or solution of the compound of formula (I) in a suitable liquid carrier. Suitably, the carrier is non-aqueous such as polyethylene glycol or oil. The formulation may also contain suspending agents, preservatives, flavoring agents and/or coloring agents.

呈錠劑形式之組成物可使用例行用於製備固態調配物之任何適當醫藥載體(諸如硬脂酸鎂、澱粉、乳糖、蔗糖與纖維素)製備。 The composition in the form of a lozenge can be prepared using any suitable pharmaceutical carrier (such as magnesium stearate, starch, lactose, sucrose, and cellulose) routinely used for preparing solid formulations.

呈膠囊形式之組成物可使用例行之囊封程序製備,例如含有活性成份之丸劑可使用標準載體製備及接著填入硬明膠囊中;或者,分散液或懸浮液可使用任何合適醫藥載體製備,例如水性膠、纖維素、矽酸鹽或油類,及接著由分散液或懸浮液填入軟明膠囊中。 The composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, a pill containing the active ingredient can be prepared using a standard carrier and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier , Such as water-based glue, cellulose, silicate or oils, and then filled into soft gelatin capsules from dispersions or suspensions.

典型腸胃外組成物係由式(I)化合物於無菌水性載體或腸胃外可接受之油(例如聚乙二醇、聚乙烯基吡咯啶酮、卵磷脂、花生油或芝麻油)中之溶液或懸浮液組成。或者,溶液可凍乾及接著在即將投予前才使用合適溶劑復原。 A typical parenteral composition is a solution or suspension of a compound of formula (I) in a sterile aqueous carrier or a parenterally acceptable oil (e.g. polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or sesame oil) composition. Alternatively, the solution can be lyophilized and then reconstituted with a suitable solvent just before administration.

供經鼻投予之組成物合宜地調配成氣霧劑、滴劑、凝膠與粉劑。氣霧劑調配物通常包含式(I)化合物在醫藥上可接受之水性或非水性溶劑中之溶液或細懸浮液,且通常呈無菌型之單一或多重劑量存在於可呈以霧化裝置使用的匣或填充物形式之密閉容器中。或者,密封容器可為拋棄式配送裝置諸如單劑量鼻用吸入器或裝配計量閥之氣霧劑配送器。其中該劑型包含氣霧劑配送器,其將包含推進劑,其可為壓縮氣體(例如空氣)或有機推進劑(諸如氟氯碳化物(CFC)或氫氟碳化物(HFC))。氣霧劑劑型亦可呈泵壓霧化器型式。 The composition for nasal administration is suitably formulated into aerosols, drops, gels and powders. Aerosol formulations usually contain a solution or fine suspension of the compound of formula (I) in a pharmaceutically acceptable aqueous or non-aqueous solvent, and are usually in a sterile form in single or multiple doses that can be used as an atomizing device. In a closed container in the form of a box or filling. Alternatively, the sealed container may be a disposable dispensing device such as a single-dose nasal inhaler or an aerosol dispenser equipped with a metering valve. Where the dosage form contains an aerosol dispenser, it will contain a propellant, which can be a compressed gas (e.g. air) or an organic propellant (such as chlorofluorocarbons (CFC) or hydrofluorocarbons (HFC)). The aerosol dosage form can also be in the form of a pump atomizer.

藉由使用氣霧劑調配物可局部投予至肺部。氣霧劑調配物通常包含懸浮或溶解於適當氣霧劑推進劑(諸如氟氯碳化物(CFC)或氫氟碳化物(HFC))中之活性成份。 The aerosol formulation can be administered locally to the lungs. Aerosol formulations usually contain active ingredients suspended or dissolved in a suitable aerosol propellant, such as chlorofluorocarbons (CFC) or hydrofluorocarbons (HFC).

亦可使用非加壓式調配物諸如水溶液或懸浮液達到局部投予至肺部。此等可利用噴霧器之裝置投予,例如其可為手持式及可攜帶式或可家庭用或醫院用(亦非可攜帶式)。調配物可包含賦形劑諸如水、緩衝劑、張力調整劑、pH調整劑、界面活性劑與共溶劑。 Non-pressurized formulations such as aqueous solutions or suspensions can also be used for local administration to the lungs. These sprayers can be used for administration, for example, they can be hand-held and portable, or can be used in homes or hospitals (not portable). The formulation may contain excipients such as water, buffers, tonicity modifiers, pH modifiers, surfactants, and co-solvents.

可藉由使用乾粉調配物達成局部投予至肺。該調配物通常含有局部可接受的稀釋劑諸如乳糖、葡萄糖或甘露醇(較佳為乳糖)。 Local administration to the lungs can be achieved by using dry powder formulations. The formulation usually contains a topically acceptable diluent such as lactose, glucose or mannitol (preferably lactose).

本發明化合物亦可經直腸投予,例如呈栓劑或灌腸劑之型式,其包括水性或油性溶液及懸浮液與乳液及泡沫體。該等組成物係依照熟習該項技術者所熟知之標準程序製備。例如栓劑可藉由混合活性成份與習知栓劑基質(諸如可可脂或其他甘油酯)而製備。在此情況中,藥物與適當無刺激性賦形劑混合,該等賦形劑在常溫下呈固體,但在直腸溫度下則呈液體並因此將於直腸中融化而釋出藥物。該等物質為可可脂油與聚乙二醇。 The compounds of the present invention can also be administered rectally, for example in the form of suppositories or enemas, which include aqueous or oily solutions and suspensions and emulsions and foams. The compositions are prepared according to standard procedures well known to those skilled in the art. For example, suppositories can be prepared by mixing the active ingredient with a conventional suppository base (such as cocoa butter or other glycerides). In this case, the drug is mixed with appropriate non-irritating excipients, which are solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. These substances are cocoa butter oil and polyethylene glycol.

通常,欲用於局部投予至眼睛之組成物係呈眼滴劑或眼藥膏型式,通式(I)化合物之總量將為約0.0001至低於4.0%(w/w)。 Generally, the composition to be used for topical administration to the eye is in the form of eye drops or ophthalmic ointment, and the total amount of the compound of general formula (I) will be about 0.0001 to less than 4.0% (w/w).

較佳地,用於局部眼睛投予,根據本發明投予之組成物將調配成溶液、懸浮液、乳液與其他劑型。 Preferably, for topical ocular administration, the composition administered according to the present invention will be formulated into solutions, suspensions, emulsions and other dosage forms.

根據本發明投予之組成物亦可包括各種不同其他成分,包括但不限於張力劑、緩衝劑、界面活性劑、安定聚合物、防腐劑、共溶劑與黏度建造劑(viscosity building agents)。本發明適當醫藥組成物包括以張力劑與緩衝劑調配之本發明化合物。本發明醫藥組成物可進一步視需要地包括界面活性劑及/或緩和劑及/或安定聚合物。 The composition administered according to the present invention may also include various other ingredients, including but not limited to tonicity agents, buffers, surfactants, stabilizers, preservatives, co-solvents and viscosity building agents. Appropriate pharmaceutical compositions of the present invention include the compounds of the present invention formulated with tonicity agents and buffering agents. The pharmaceutical composition of the present invention may further include a surfactant and/or a demulcent and/or a stabilizer polymer as necessary.

可使用各種不同張力劑來調整組成物之張力,較佳係將眼用組成物調成天然淚液之張力。例如氯化鈉、氯化鉀、氯化鎂、氯化鈣、簡單糖類諸如 右旋糖、果糖、半乳糖、及/或簡單多元醇諸如糖醇類甘露糖醇、山梨糖醇、木糖醇、乳糖醇、異麥芽糖醇、麥芽糖醇、及氫化澱粉水解物可加至組成物中至接近生理張力。該等張力劑之量將將取決於所添加之特定藥劑而改變。然而,通常組成物將具有張力劑,其量足以使最終組成物具有眼科可接受之滲透壓(通常約150-450mOsm,較佳為250-350mOsm,且最佳為約290mOsm)。一般而言,本發明張力劑將以2至4%w/w的範圍存在。本發明較佳之張力劑包括簡單糖類或糖醇類,諸如D-甘露糖醇。 Various tonicity agents can be used to adjust the tension of the composition, preferably the ophthalmic composition is adjusted to the tension of natural tears. For example, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, simple sugars such as Dextrose, fructose, galactose, and/or simple polyols such as sugar alcohols mannitol, sorbitol, xylitol, lactitol, isomalt, maltitol, and hydrogenated starch hydrolysates can be added to the composition Medium to close to physiological tension. The amount of these tonicity agents will vary depending on the particular agent added. However, usually the composition will have a tonicity agent in an amount sufficient to give the final composition an ophthalmically acceptable osmotic pressure (usually about 150-450 mOsm, preferably 250-350 mOsm, and most preferably about 290 mOsm). Generally speaking, the tonicity agent of the present invention will be present in the range of 2 to 4% w/w. The preferred tonicity agents of the present invention include simple sugars or sugar alcohols, such as D-mannitol.

適當緩衝劑系統(例如磷酸鈉、乙酸鈉、檸檬酸鈉、硼酸鈉或硼酸)可加至組成物中,以防止在儲存條件下pH偏移。特定濃度將取決於所採用之藥劑而改變。然而較佳地,將選擇緩衝劑以使目標pH維持在pH 5至8範圍內,更佳為pH 5至7之目標pH。 An appropriate buffer system (such as sodium phosphate, sodium acetate, sodium citrate, sodium borate, or boric acid) can be added to the composition to prevent pH drift under storage conditions. The specific concentration will vary depending on the agent used. However, preferably, the buffering agent will be selected to maintain the target pH in the range of pH 5 to 8, more preferably the target pH of pH 5 to 7.

可視需要使用界面活性劑以遞送較高濃度之本發明化合物。界面活性劑作用為溶解化合物及安定膠體分散液,諸如微胞溶液、微乳液、乳液與懸浮液。可選擇性使用之界面活性劑的實例包括聚山梨酸酯、泊洛沙姆(poloxamer)、polyosyl 40硬脂酸酯、聚氧基蓖麻油、四丁酚醇(tyloxapol)、Triton及單月桂酸山梨糖醇酐酯。本發明中所使用之較佳界面活性劑具有範圍在12.4至13.2之親水性/親脂性/平衡"HLB",且就眼用而言是可接受的,諸如TritonX114和四丁酚醇。 Optionally, surfactants can be used to deliver higher concentrations of the compounds of the invention. Surfactants function to dissolve compounds and stabilize colloidal dispersions, such as microcellular solutions, microemulsions, emulsions and suspensions. Examples of optional surfactants include polysorbate, poloxamer, polyosyl 40 stearate, polyoxyl castor oil, tyloxapol, Triton, and monolauric acid Sorbitan esters. The preferred surfactants used in the present invention have a hydrophilicity/lipophilicity/balance "HLB" ranging from 12.4 to 13.2 and are acceptable for ophthalmic use, such as Triton X114 and tetrabutyl alcohol.

可加至本發明化合物之眼用組成物中的添加劑為緩和劑,其用作為安定聚合物。安定聚合物應為離子性/帶電荷的實例,優先用於局部眼部使用,更具體地說,在其表面上帶有負電荷之聚合物,其可呈現ζ電位(-)10-50mV之物理安定性,及能夠製造在水中之分散液(即水溶性)。本發明之較佳安定聚合物為來自交聯聚丙烯酸酯家族之聚電解質或聚電解質類(若超過一種時),諸如卡波姆(carbomer)與Pemulen(R),具體而言,為0.1-0.5% w/w之Carbomer 974p(聚丙烯酸)。 The additive that can be added to the ophthalmic composition of the compound of the present invention is a demulcent, which is used as a stabilizer polymer. Stabilizing polymer should be an ionic/charged example, and is preferentially used for local eye use. More specifically, a polymer with a negative charge on its surface can exhibit a zeta potential (-) of 10-50mV. Physical stability, and the ability to produce dispersion in water (ie, water-soluble). The preferred stable polymer of the present invention is a polyelectrolyte or polyelectrolyte (if more than one type) from the cross-linked polyacrylate family, such as carbomer and Pemulen(R), specifically, 0.1- 0.5% w/w Carbomer 974p (polyacrylic acid).

其他化合物亦可加至本發明化合物之眼用組成物中以增加載體之黏度,增黏劑之實例包括但不限於:多醣類,諸如玻尿酸與其鹽類、硫酸軟骨素與其鹽類、葡聚醣、纖維素家族之各種不同聚合物;乙烯基聚合物;及丙烯酸聚合物。 Other compounds can also be added to the ophthalmic composition of the compound of the present invention to increase the viscosity of the carrier. Examples of viscosity-increasing agents include, but are not limited to: polysaccharides, such as hyaluronic acid and its salts, chondroitin sulfate and its salts, dextran Various polymers of sugar and cellulose families; vinyl polymers; and acrylic polymers.

局部眼用產品通常以多劑量形式包裝。因此需要防腐劑來預防使用期間之微生物汙染。適當防腐劑包括:苯扎氯銨(benzalkonium chloride)、氯丁醇、苯扎溴銨(benzododecinium bromide)、對羥基苯甲酸甲酯、對羥基苯甲酸丙酯、苯基乙醇、乙二胺四乙酸二鈉、山梨酸、聚季銨鹽-1(polyquatemium-1)或熟習該項技術者己知的其他試劑。該等防腐劑通常以從0.001至1.0% w/v之含量使用。本發明之單位劑量組成物為無菌,但通常不防腐。因此,該等組成物通常將不含防腐劑。 Topical ophthalmic products are usually packaged in multi-dose form. Therefore, preservatives are needed to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, chlorobutanol, benzododecinium bromide, methylparaben, propylparaben, phenylethanol, ethylenediaminetetraacetic acid Disodium, sorbic acid, polyquatemium-1 (polyquatemium-1) or other reagents known to those skilled in the art. These preservatives are usually used in a content ranging from 0.001 to 1.0% w/v. The unit dose composition of the present invention is sterile, but usually not preserved. Therefore, these compositions will generally contain no preservatives.

適合於經頰或舌下投予之組成物包括錠劑、口含錠和丸粒,其中式(I)化合物與載體諸如糖和阿拉伯膠、黃蓍膠、或明膠和甘油的一起調配。 Compositions suitable for buccal or sublingual administration include lozenges, lozenges and pellets, wherein the compound of formula (I) is formulated with a carrier such as sugar and gum arabic, tragacanth, or gelatin and glycerin.

適合於透皮投予之組成物包括軟膏、凝膠和貼片。 Compositions suitable for transdermal administration include ointments, gels and patches.

組成物可含有從0.1重量%至100重量%,例如10至60重量%,的式(I)化合物,取決於投予之方法。組成物可含有從0重量%至99重量%,例如40重量%至90重量%,的載體,取決於投予之方法。組成物可含有從0.05mg至1000mg,例如從1.0mg至500mg,諸如從1.0mg至50mg,例如約10mg的式(I)化合物,取決於投予之方法。組成物可含有從50mg至1000mg,例如從100mg至400mg的載體,取決於投予之方法。用於治療上述疾病之化合物的劑量將以通常的方式隨疾病的嚴重程度、患者的體重以及其他類似因素而變化。然而,作為一般指南,適當的單位劑量可為0.05至1000mg,更多適當地為1.0至500mg,諸如從1.0mg至50mg,例如約10mg及該等單位劑量可每天投予超過一次,例如一天兩次或三次。該療法可持續數週或數月。 The composition may contain from 0.1% to 100% by weight, for example from 10 to 60% by weight, of the compound of formula (I), depending on the method of administration. The composition may contain from 0% to 99% by weight, for example, 40% to 90% by weight, of the carrier, depending on the method of administration. The composition may contain from 0.05 mg to 1000 mg, for example from 1.0 mg to 500 mg, such as from 1.0 mg to 50 mg, for example about 10 mg of the compound of formula (I), depending on the method of administration. The composition may contain from 50 mg to 1000 mg, for example from 100 mg to 400 mg of the carrier, depending on the method of administration. The dosage of the compound used to treat the aforementioned diseases will vary in the usual manner with the severity of the disease, the weight of the patient, and other similar factors. However, as a general guideline, a suitable unit dose may be 0.05 to 1000 mg, more suitably 1.0 to 500 mg, such as from 1.0 mg to 50 mg, for example about 10 mg, and such unit doses may be administered more than once a day, for example twice a day. Times or three times. The therapy can last for several weeks or months.

在本發明之一個實施態樣中,式(I)化合物與其他治療劑或劑等結合使用。當式(I)化合物與其他治療劑結合使用時,可藉由任何習知途徑依次或同時投予這些化合物。或者,該等化合物可分開投予。 In one embodiment of the present invention, the compound of formula (I) is used in combination with other therapeutic agents or agents. When the compound of formula (I) is used in combination with other therapeutic agents, these compounds can be administered sequentially or simultaneously by any conventional route. Alternatively, the compounds can be administered separately.

可與本發明結合使用之治療劑包括:皮質類固醇(醣皮質素)、類視色素(例如阿維A(acitretin)、異維A酸(isotretinoin)、他扎羅汀(tazarotene))、葸酚(anthralin)、維生素D類似物(例如骨化三醇(cacitriol)、鈣泊三醇(calcipotriol))、鈣調磷酸酶(calcineurin)抑制劑(例如他克莫司(tacrolimus)、吡美莫司(pimecrolimus)、光療法或光化學療法(例如補骨脂素紫外線照射、PUVA)或紫外光照射療法之其他形式、環孢靈(ciclosporine)、硫嘌呤(thiopurines)(例如硫唑嘌呤(azathioprine)、6-巰嘌呤)、甲氨蝶呤(methotrexate)、抗TNFα劑(例如英夫利昔單抗(infliximab)、依那西普(etanercept)、阿達木單抗(adalimumab)、賽妥珠單抗(certolizumab)、戈利木單抗(golimumab)和生物相似藥(biosimilars))、磷酸二酯酶-4(PDE4)抑制作用(例如阿普司特(apremilast)、克里博羅(crisaborole))、抗IL-17劑(例如布羅達單抗(brodalumab)、伊克珠單抗(ixekizumab)、蘇金單抗(secukinumab))、抗IL12/IL-23劑(例如烏斯替單抗(ustekinumab)、貝伐珠單抗(briakinumab))、抗IL-23劑(例如鼓賽庫單抗(guselkumab)、替拉珠單抗(tildrakizumab))、JAK(Janus激酶)抑制劑(例如托法替尼(tofacitinib)、魯索利替尼(ruxolitinib)、巴瑞替尼(baricitinib)、非戈替尼(filgotinib)、優帕替尼(upadacitinib))、血漿交換、靜脈免疫球蛋白(IVIG)、環磷醯胺、抗CD20 B細胞耗竭劑(例如利妥昔單抗(rituximab)、奧珠單抗(ocrelizumab)、奧法木單抗(ofatumumab)、奧比妥珠單抗(obinutuzumab))、蒽環類似物(例如米托蒽醌(mitoxantrone))、克拉屈濱(cladribine)、神經胺醇1-磷酸鹽受體調節物或神經胺醇類似物(例如芬戈莫德(fingolimod)、西波莫德(siponimod)、奧扎尼莫德(ozanimod)、依曲西莫德(ozanimod))、干擾素β製劑(包括干擾素β1b/1a)、格拉替雷(glatiramer)、抗CD3療法(例如OKT3)、抗CD52靶向劑(例如阿崙單抗(alemtuzumab))、來氟米特(leflunomide),特立氟胺(teriflunomide)、金化合物、 拉喹莫德(laquinimod)、鉀通道阻滯劑(例如達伐吡啶(dalfampridine)/4-胺基吡啶)、黴酚酸、黴酚酸嗎啉乙酯(mycophenolate mofetil)、嘌呤類似物(例如噴司他汀(pentostatin))、mTOR(雷帕黴素機制靶(mechanistic target of rapamycin))路徑抑制劑(例如西羅莫司(sirolimus)、依維莫司(everolimus))、抗胸腺細胞球蛋白(ATG)、IL-2受體(CD25)抑制劑(例如巴利昔單抗(basiliximab)、達克珠單抗(daclizumab))、抗IL-6受體或抗IL-6劑(例如托珠單抗(tocilizumab)、西妥昔單抗(siltuximab))、Bruton氏酪胺酸激酶(BTK)抑制劑(例如依魯替尼(ibrutinib))、酪胺酸激酶抑制劑(例如伊馬替尼(imatinib))、熊去氧膽酸、羥氯喹(hydroxychloroquine)、氯喹(chloroquine)、B細胞活化因子(BAFF、也稱為BLyS、B淋巴球刺激物)抑制劑(例如貝利木單抗(belimumab)、布利斯比莫德(blisibimod))、其他B細胞靶向療法包括靶向APRIL(A增殖誘導配體)和BLyS的融合蛋白(例如阿塞西普(atacicept))、PI3K抑制劑包括泛抑制劑或彼等靶向含同功型之p110δ及/或p110γ者(例如依達利昔布(idelalisib)、庫潘利昔布(copanlisib)、杜韋利昔布(duvelisib))、干擾素α受體抑制劑(例如阿尼洛單抗(anifrolumab)、西法木單抗(sifalimumab))、T細胞共刺激阻斷劑(例如阿巴西普(abatacept)、貝拉西普(belatacept))、沙利度胺(thalidomide)及其衍生物(例如來那度胺(lenalidomide))、達普松(dapsone)、氯法齊明(clofazimine)、白三烯素(leukotriene)拮抗劑(例如孟魯司特(montelukast))、茶鹼、抗IgE療法(例如奧馬佐單抗(omalizumab))、抗IL-5劑(例如美泊珠單抗(mepolizumab)、瑞利珠單抗(reslizumab))、長效毒蕈鹼劑(例如噻托溴銨(tiotropium)、阿地銨(aclidinium)、蕪地溴銨(umeclidinium))、PDE4抑制劑(例如rotlumilast)、利魯唑(riluzole)、自由基清除劑(例如依達拉奉(edaravone))、蛋白酶體抑制劑(例如硼替佐米(bortezomib))、補體級聯抑制劑包括彼等針對C5者(例如依庫珠單抗(eculizumab))、免疫吸附劑(immunoadsorbor),抗胸腺細胞球蛋白、5-胺水楊酸鹽及彼等之衍生物(例如柳氮磺胺吡啶(sulfasalazine)、巴柳氮(balsalazide)、美沙拉明(mesalamine))、抗整合素劑包括彼等靶向α4β1及/或α4β7整合素者(例如那他珠單抗(natalizumab)、維多珠單抗(vedolizumab))、抗CD11-α 劑(例如依法珠單抗(efalizumab))、非類固醇抗發炎藥(NSAIDs)包括水楊酸酯類(例如阿司匹靈)、丙酸類(例如伊布洛芬(ibuprofen)、萘普生(naproxen))、乙酸類(例如吲哚美洒辛(indomethacin)、雙氯芬酸(diclofenac)、依託度酸(etodolac))、昔康類(oxicams)(例如美洛昔康(meloxicam))和芬那酸鹽(fenamates)(例如甲芬那酸(mefenamic acid))、選擇性或相對選擇性COX-2抑制劑(例如塞來昔布(celecoxib)、依托昔布(etroxicoxib)、伐地昔布(valdecoxib)和依託度酸(etodolac)、美洛昔康(meloxicam)、萘丁美酮(nabumetone))、秋水仙素、IL-4受體抑制劑(例如杜比單抗(dupilumab))、局部/接觸式免疫療法(例如二苯基環丙烯酮、方酸二丁酯)、抗IL-1受體療法(例如阿那白滯素(anakinra))、IL-1β抑制劑(例如卡那單抗(canakinumab))、IL-1中和療法(例如利納西普(rilonacept))、苯丁酸氮芥(chlorambucil)、具有免疫調節性質及/或調節NRF2能力的特定抗生素(例如四環素包括米諾四環素(minocycline)、克林達黴素(clindamycin)、巨環內酯抗生素)、抗雄激素療法(例如環丙孕酮(cyproterone)、螺內酯(spironolactone)、非那雄安(finasteride))、己酮可可鹼(pentoxifylline)、熊去氧膽酸、奧貝膽酸(obeticholic acid)、貝特類(fibrate)、囊性纖維化跨膜電導調節劑(CFTR)調節物、VEGF(血管內皮生長因子)抑制劑(例如貝伐單抗(bevacizumab)、蘭尼單抗(ranibizumab)、哌加他尼(pegaptanib)、阿柏西普(aflibercept))、吡非尼酮(pirfenidone)、及咪唑立賓(mizoribine)。 Therapeutic agents that can be used in combination with the present invention include: corticosteroids (glucocorticoids), retinoids (such as acitretin, isotretinoin, tazarotene), anthropol (anthralin), vitamin D analogs (e.g., calcitriol, calcipotriol), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus) (pimecrolimus), phototherapy or photochemotherapy (such as psoralen ultraviolet radiation, PUVA) or other forms of ultraviolet radiation therapy, cyclosporine (ciclosporine), thiopurines (such as azathioprine) , 6-mercaptopurine), methotrexate (methotrexate), anti-TNFα agents (e.g. infliximab, etanercept, adalimumab, certuzumab (certolizumab, golimumab and biosimilars), phosphodiesterase-4 (PDE4) inhibition (e.g., apremilast, crisaborole) , Anti-IL-17 agents (e.g., brodalumab, ixekizumab, secukinumab), anti-IL12/IL-23 agents (e.g., ustizumab ( ustekinumab), bevacizumab (briakinumab), anti-IL-23 agents (e.g. guselkumab, tildrakizumab), JAK (Janus kinase) inhibitors (e.g. Tofa Tofacitinib, ruxolitinib, baricitinib, filgotinib, upadacitinib), plasma exchange, intravenous immunoglobulin (IVIG) , Cyclophosphamide, anti-CD20 B cell depleting agents (e.g. rituximab, ocrelizumab, ofatumumab, obinutuzumab) , Anthracycline analogs (e.g. mitoxantrone (mitoxantrone)), cladribine (cladribine), neramine 1-phosphate receptor modulator or neramine analogues (e.g. fingolimod (fingolimod), Siponimod ), ozanimod, ezanimod), interferon β preparations (including interferon β1b/1a), glatiramer, anti-CD3 therapy (e.g. OKT3), anti-CD3 CD52 targeting agents (such as alemtuzumab), leflunomide, teriflunomide, gold compounds, Laquinimod, potassium channel blockers (e.g. dalfampridine/4-aminopyridine), mycophenolic acid, mycophenolate mofetil, purine analogs (e.g. Penstatin (pentostatin), mTOR (mechanistic target of rapamycin) pathway inhibitors (e.g. sirolimus, everolimus), antithymocyte globulin (ATG), IL-2 receptor (CD25) inhibitors (e.g. basiliximab (basiliximab), daclizumab (daclizumab)), anti-IL-6 receptors or anti-IL-6 agents (e.g. Tocilizumab (tocilizumab, cetuximab (siltuximab)), Bruton's tyrosine kinase (BTK) inhibitors (such as ibrutinib), tyrosine kinase inhibitors (such as imatinib) (imatinib)), ursodeoxycholic acid, hydroxychloroquine, chloroquine, B cell activating factor (BAFF, also known as BLyS, B lymphocyte stimulant) inhibitors (such as belimumab ( belimumab), blisibimod), other B cell targeted therapies, including fusion proteins targeting APRIL (A proliferation-inducing ligand) and BLyS (such as atacicept), PI3K inhibitors Including pan-inhibitors or those targeting isoforms of p110δ and/or p110γ (e.g. idelalisib, copanlisib, duvelisib), interference Alpha receptor inhibitors (e.g., anifrolumab, sifalimumab), T cell costimulatory blockers (e.g., abatacept, belabacept) , Thalidomide and its derivatives (e.g. lenalidomide), dapsone, clofazimine, leukotriene antagonists (e.g. Meng Montelukast), theophylline, anti-IgE therapy (e.g. omalizumab), anti-IL-5 agents (e.g. mepolizumab, reslizumab) , Long-acting muscarinic agents (e.g. tiotropium, aclidinium) Umeclidinium), PDE4 inhibitors (e.g. rotlumilast), riluzole, free radical scavengers (e.g. edaravone), proteasome inhibitors (e.g. bortezomib) ), Complement cascade inhibitors include those that target C5 (such as eculizumab), immunoadsorbor, antithymocyte globulin, 5-amine salicylate and their derivatives (E.g. sulfasalazine, balsalazide, mesalamine), anti-integrin agents including those targeting α4β1 and/or α4β7 integrins (e.g. natalizumab (natalizumab), vedolizumab), anti-CD11-α Agents (e.g. efalizumab (efalizumab)), non-steroidal anti-inflammatory drugs (NSAIDs) include salicylates (e.g. aspirin), propionic acids (e.g. ibuprofen (ibuprofen), naproxen ( naproxen), acetic acids (e.g. indomethacin, diclofenac, etodolac), oxicams (e.g. meloxicam) and fenamic acid Salts (fenamates) (e.g. mefenamic acid), selective or relatively selective COX-2 inhibitors (e.g. celecoxib, etroxicoxib, valdecoxib) ) And etodolac, meloxicam, nabumetone), colchicine, IL-4 receptor inhibitors (such as dupilumab), topical/ Contact immunotherapy (e.g. diphenylcyclopropenone, dibutyl squarate), anti-IL-1 receptor therapy (e.g. anakinra), IL-1β inhibitors (e.g. Kanazumab) (canakinumab)), IL-1 neutralization therapy (e.g., rilonacept), chlorambucil, specific antibiotics with immunomodulatory properties and/or the ability to regulate NRF2 (e.g., tetracyclines include minocycline (minocycline, clindamycin, macrolide antibiotics), anti-androgen therapy (e.g. cyproterone, spironolactone, finasteride), hexanone Theobromine (pentoxifylline), ursodeoxycholic acid, obeticholic acid, fibrate, cystic fibrosis transmembrane conductance regulator (CFTR) regulator, VEGF (vascular endothelial growth factor) Inhibitors (such as bevacizumab, ranibizumab, pegaptanib, aflibercept), pirfenidone, and mizoribine ( mizoribine).

式(I)化合物可顯示下列所需性質中之一或多者: The compound of formula (I) may exhibit one or more of the following desired properties:

●抑制細胞介素例如IL-1β及/或IL-6從細胞釋放的低IC50值; ●Inhibit the low IC 50 value of cytokines such as IL-1β and/or IL-6 released from cells;

●活化NRF2路徑之低EC50及/或高Emax值; ●Low EC 50 and/or high E max value for activating NRF2 pathway;

●透過改良羧酸酯的水解穩定性及/或增強的最大反應之增強功效; ●Enhanced effect by improving the hydrolytic stability of carboxylic acid esters and/or enhancing the maximum response;

●透過改良之藥物動力學來降低劑量和給藥頻率; ●Reducing dosage and frequency of administration through improved pharmacokinetics;

●改良的口服全身生體可用率; ●Improved oral systemic bioavailability;

●靜脈內給藥後血漿清除率降低; ●The plasma clearance rate decreases after intravenous administration;

●改良的代謝穩定性,例如,如以改良的血漿和/或肝細胞的穩定性證實; ●Improved metabolic stability, for example, as confirmed by improved plasma and/or hepatocyte stability;

●細胞滲透性增強; ●Enhanced cell permeability;

●水溶性提高; ●Improved water solubility;

●良好的耐受性,例如,藉由限制口服DMF引起的潮紅及/或胃腸副作用(Hunt T.et al.,2015;WO2014/152494A1,以引用方式併入本文),可能藉由減少或消除HCA2活性; ●Good tolerability, for example, by limiting the flushing and/or gastrointestinal side effects caused by oral DMF (Hunt T. et al., 2015; WO2014/152494A1, incorporated herein by reference), it may be reduced or eliminated HCA2 activity;

●在相關治療劑量下的低毒性; ●Low toxicity at relevant therapeutic doses;

●不同的親電性導致不同的抗發炎特性,導致胱胺酸蛋白體的不同靶向(van der Reest J.et al.,2018),並因此,對基因活化的改良效應; ●Different electrophilicity leads to different anti-inflammatory properties, leading to different targeting of cystine proteasomes (van der Reest J. et al., 2018), and therefore, an improved effect on gene activation;

●麩胱甘肽-防護作用; ●Glutathione-protective effect;

●避免癌代謝物(oncometabolite)延胡索酸(Kulkarni R.A.et al.,2019)。 ●Avoid cancer metabolite (oncometabolite) fumaric acid (Kulkarni R.A. et al., 2019).

縮寫 abbreviation

Figure 109137209-A0202-12-0045-34
Figure 109137209-A0202-12-0045-34

Figure 109137209-A0202-12-0046-35
Figure 109137209-A0202-12-0046-35

Figure 109137209-A0202-12-0047-36
Figure 109137209-A0202-12-0047-36

Figure 109137209-A0202-12-0048-37
Figure 109137209-A0202-12-0048-37

Figure 109137209-A0202-12-0049-38
Figure 109137209-A0202-12-0049-38

Figure 109137209-A0202-12-0050-39
Figure 109137209-A0202-12-0050-39

實施例 Example

分析設備 Analysis equipment

使用配備Bruker 5mm探針的Bruker 400MHz Avance III光譜儀或配備Bruker 5mm SmartProbeTM的Bruker 500MHz Avance III HD光譜儀記錄NMR光譜。除非另有說明,否則光譜係在298K下測量,及參考相對於溶劑共振。化學位移以百萬分點報告。使用Bruker TopSpin軟體獲取數據。 Use Bruker 400MHz Avance III spectrometer equipped with Bruker 5mm probe or Bruker 500MHz Avance III HD spectrometer equipped with Bruker 5mm SmartProbeTM to record NMR spectra. Unless otherwise stated, the spectra were measured at 298K, and the reference was resonance with respect to the solvent. Chemical shifts are reported in parts per million. Use Bruker TopSpin software to obtain data.

在Waters Acquity UPLC系統上進行UPLC/MS分析,其係使用維持在40℃之溫度的Waters Acquity CSH C18或BEH C18管柱(2.1 x 30mm)並使用適合於化合物親脂性的線性乙腈梯度在3或10分鐘內以0.77mL/min的恆定流速溶析。流動相的水部分為0.1%甲酸(CSH C18管柱)或10mM碳酸氫銨(BEH C18管柱)。使用Waters Acquity PDA偵檢器在210至400nm之間記錄LC-UV層析圖。使用在正和負離子模式之間切換的電噴霧電離之Waters Acquity Qda偵檢器記錄質譜。調節樣品濃度以產生足夠的紫外線反應。 UPLC/MS analysis was performed on the Waters Acquity UPLC system using Waters Acquity CSH C18 or BEH C18 column (2.1 x 30mm) maintained at a temperature of 40°C and a linear acetonitrile gradient suitable for the lipophilicity of the compound at 3 or Dissolve at a constant flow rate of 0.77 mL/min within 10 minutes. The water part of the mobile phase is 0.1% formic acid (CSH C18 column) or 10 mM ammonium bicarbonate (BEH C18 column). A Waters Acquity PDA detector was used to record LC-UV chromatograms between 210 and 400 nm. The mass spectrum was recorded using an electrospray ionized Waters Acquity Qda detector that switched between positive and negative ion modes. Adjust the sample concentration to generate sufficient UV response.

在Waters Acquity UPLC系統上進行LCMS分析,其係使用維持在40℃之溫度的Waters Acquity CSH C18或BEH C18管柱(4.6 x 30mm)並使用適合 於化合物親脂性的線性乙腈梯度在4或15分鐘內以2.5mL/min的恆定流速溶析。流動相的水部分為0.1%甲酸(CSH C18管柱)或10mM碳酸氫銨(BEH C18管柱)。使用Agilent VWD或DAD偵檢器在254nm處記錄LC-UV層析圖。使用在正和負離子模式之間切換的電噴霧電離之Agilent MSD偵檢器記錄質譜。調節樣品濃度以產生足夠的紫外線反應。 The LCMS analysis was performed on the Waters Acquity UPLC system using Waters Acquity CSH C18 or BEH C18 column (4.6 x 30mm) maintained at a temperature of 40°C and suitable The lipophilic linear acetonitrile gradient of the compound elutes at a constant flow rate of 2.5 mL/min within 4 or 15 minutes. The water part of the mobile phase is 0.1% formic acid (CSH C18 column) or 10 mM ammonium bicarbonate (BEH C18 column). Use Agilent VWD or DAD detector to record LC-UV chromatogram at 254nm. The mass spectrum was recorded using an Agilent MSD detector with electrospray ionization that switched between positive and negative ion modes. Adjust the sample concentration to generate sufficient UV response.

或者,亦使用下列分析型LCMS設備和方法: Or, also use the following analytical LCMS equipment and methods:

Figure 109137209-A0202-12-0051-40
Figure 109137209-A0202-12-0051-40

商業材料 Commercial materials

伊康酸二甲酯[SYX-00002]係購自Sigma-Aldrich(產品編號:109533);伊康酸4-辛酯[SYX-00011]係購自BOC biosciences(產品編號:B0001-007866);伊康酸4-甲酯[SYX-00018]係購自Apollo Scientific(產品編號:OR10969);伊康酸4-丁酯[SYX-00119]係購自Combi-Blocks(產品編號:QV-5962)。 Dimethyl Iconate [SYX-00002] was purchased from Sigma-Aldrich (product number: 109533); 4-octyl Iconate [SYX-00011] was purchased from BOC biosciences (product number: B0001-007866); 4-Methyl Iconate [SYX-00018] was purchased from Apollo Scientific (product number: OR10969); 4-Butyl Iconate [SYX-00119] was purchased from Combi-Blocks (product number: QV-5962) .

一般方法 General method

除非另有說明,否則攪拌所有反應。例行地用無水硫酸鎂乾燥有機溶液。在Thales H-立方體流動反應器中在所述條件下或在氣體高壓釜(高壓罐(bomb))中在壓力下進行氫化反應。 Unless otherwise stated, all reactions are stirred. The organic solution is routinely dried with anhydrous magnesium sulfate. The hydrogenation reaction is carried out in a Thales H-cube flow reactor under the stated conditions or in a gas autoclave (bomb) under pressure.

一般程序1-單酯的合成 General Procedure 1-Synthesis of Monoester

Figure 109137209-A0202-12-0052-43
Figure 109137209-A0202-12-0052-43

將伊康酸酐(1eq.)在甲苯中之懸浮液用p-TsOH.H2O(10mol%)接著適當醇(R-OH,1eq.)(其在下述相關處定義)處理。將所得黃色溶液在80-110℃下攪拌。將反應混合物在矽膠上濃縮及將粗製產物藉由層析法(0-5% MeOH/DCM)在矽膠上純化以提供所需的單酯。 A suspension of itaconic anhydride (1 eq.) in toluene was treated with p-TsOH.H 2 O (10 mol%) followed by an appropriate alcohol (R-OH, 1 eq.) (which is defined in the relevant places below). The resulting yellow solution was stirred at 80-110°C. The reaction mixture was concentrated on silica gel and the crude product was purified on silica gel by chromatography (0-5% MeOH/DCM) to provide the desired monoester.

一般程序2-二酯的合成 General procedure 2-Synthesis of diesters

Figure 109137209-A0202-12-0052-41
Figure 109137209-A0202-12-0052-41

將適當伊康酸單酯(1eq.)(其在下述相關處定義)、EDC.HCl(1.5eq.)和DMAP(5-200mol%)在DCM中之溶液用DIPEA(3eq.)和適當醇(R2-OH,1.1eq.)(其在下述相關處定義)處理。將所得溶液在RT下攪拌20h。將反應混合物在二氧化 矽上濃縮並將粗製產物藉由層析法(0-5% MeOH/DCM)在矽膠上純化以提供所需的二酯。 The appropriate itaconic acid monoester (1eq.) (which is defined in the following relevant places), EDC.HCl (1.5eq.) and DMAP (5-200mol%) in DCM solution with DIPEA (3eq.) and appropriate alcohol (R 2 -OH, 1.1 eq.) (which is defined in the following relevant places) processing. The resulting solution was stirred at RT for 20h. The reaction mixture was concentrated on silica and the crude product was purified by chromatography (0-5% MeOH/DCM) on silica to provide the desired diester.

一般程序3-二酯的合成 General procedure 3-Synthesis of diesters

Figure 109137209-A0202-12-0053-45
Figure 109137209-A0202-12-0053-45

將適當醇(R2-OH,1eq.)(其在下述相關處定義)、HOBt.H2O水合物(2eq.)和EDC.HCl(2eq.)在DCM中之溶液用適當伊康酸單酯(1eq.)(其在下述相關處定義)處理,接著在RT下滴加DIPEA(3eq.)。將所得混合物在RT下攪拌16h。將反應混合物在真空中濃縮及藉由管柱層析法在矽膠上純化(DCM/EtOAc1:1)以提供所需的二酯。 The solution of the appropriate alcohol (R 2 -OH, 1eq.) (which is defined in the relevant places below), HOBt.H 2 O hydrate (2eq.) and EDC.HCl (2eq.) in DCM with the appropriate itaconic acid Monoester (1 eq.) (which is defined in the relevant places below) was treated, and then DIPEA (3 eq.) was added dropwise at RT. The resulting mixture was stirred at RT for 16 h. The reaction mixture was concentrated in vacuo and purified on silica gel by column chromatography (DCM/EtOAc 1:1) to provide the desired diester.

一般程序4-二酯的合成 General procedure 4-Diester synthesis

Figure 109137209-A0202-12-0053-47
Figure 109137209-A0202-12-0053-47

將適當伊康酸單酯(1eq.)(其在下述相關處定義)、碳酸鉀(1.2eq.)和碘甲烷(1.2eq.)在丙酮中的混合物在RT下攪拌18h。過濾混合物並在矽膠上濃縮濾液。將粗製產物藉由層析法在矽膠上(0-20% EtOAc/異己烷)純化以提供所需的二酯。 A mixture of appropriate monoester of itaconic acid (1 eq.) (which is defined in the relevant places below), potassium carbonate (1.2 eq.) and methyl iodide (1.2 eq.) in acetone was stirred at RT for 18 h. The mixture was filtered and the filtrate was concentrated on silica gel. The crude product was purified by chromatography on silica gel (0-20% EtOAc/isohexane) to provide the desired diester.

在上述一般程序之任一者中,適當地R1為RA',其係在本文別處定義。 In any one of the above-described general procedure, the appropriately R 1 is R A ', which system is defined elsewhere herein.

中間物1-4-(環辛氧基)-2-亞甲基-4-側氧基丁酸 Intermediate 1-4-(cyclooctyloxy)-2-methylene-4-oxobutanoic acid

Figure 109137209-A0202-12-0053-48
Figure 109137209-A0202-12-0053-48

根據一般程序1,使用環辛醇作為R-OH製備中間物1。1H NMR(500MHz,DMSO-d6)δ 12.59(br.s,1H),6.13(d,J=1.6Hz,1H),5.75-5.72(m,1H), 4.82(tt,J=8.2,3.9Hz,1H),3.25(s,2H),1.76-1.40(m,14H)。LCMS m/z 263.2(M+Na)+(ES+);239.2(M-H)-(ES-)。 According to general procedure 1, intermediate 1 was prepared using cyclooctanol as R-OH. 1 H NMR(500MHz,DMSO-d6)δ 12.59(br.s,1H), 6.13(d,J=1.6Hz,1H), 5.75-5.72(m,1H), 4.82(tt,J=8.2,3.9 Hz, 1H), 3.25 (s, 2H), 1.76-1.40 (m, 14H). LCMS m / z 263.2 (M + Na) + (ES +); 239.2 (MH) - (ES -).

中間物2-2-亞甲基-4-側氧基-4-(3-苯氧基丙氧基)丁酸 Intermediate 2-2-methylene-4-oxo-4-(3-phenoxypropoxy)butanoic acid

Figure 109137209-A0202-12-0054-51
Figure 109137209-A0202-12-0054-51

根據一般程序1,使用3-苯氧基丙-1-醇作為R-OH製備中間物2。1H NMR(500MHz,DMSO-d6)δ 12.65(br.s,1H),7.32-7.26(m,2H),6.95-6.91(m,3H),6.15(d,J=1.6Hz,1H),5.76(br.s,2H),4.18(t,J=6.4Hz,2H),4.02(t,J=6.3Hz,2H),3.33(br.s,4H),2.01(qu,J=6.3Hz,2H)。LCMS m/z 287.1(M+Na)+(ES+);263.1(M-H)-(ES-)。 According to general procedure 1, intermediate 2 was prepared using 3-phenoxyprop-1-ol as R-OH. 1 H NMR (500MHz, DMSO-d6) δ 12.65 (br.s, 1H), 7.32-7.26 (m, 2H), 6.95-6.91 (m, 3H), 6.15 (d, J=1.6Hz, 1H), 5.76(br.s,2H),4.18(t,J=6.4Hz,2H),4.02(t,J=6.3Hz,2H),3.33(br.s,4H),2.01(qu,J=6.3Hz ,2H). LCMS m / z 287.1 (M + Na) + (ES +); 263.1 (MH) - (ES -).

中間物3-4-(己氧基)-2-亞甲基-4-側氧基丁酸 Intermediate 3-4-(hexyloxy)-2-methylene-4-oxobutyric acid

Figure 109137209-A0202-12-0054-171
Figure 109137209-A0202-12-0054-171

根據一般程序1,使用己-1-醇作為R-OH製備中間物3。1H NMR(500MHz,DMSO-d6)δ 12.57(br.s,1H),6.15(d,J=1.6Hz,1H),5.78-5.74(m,1H),4.01(t,J=6.6Hz,2H),3.30(s,2H),1.58-1.51(m,2H),1.35-1.21(m,6H),0.87(t,J=6.8Hz,3H)。LCMS m/z 237.2(M+H)+(ES+);213.2(M-H)-(ES-)。 According to general procedure 1, intermediate 3 was prepared using hexan-1-ol as R-OH. 1 H NMR(500MHz,DMSO-d6)δ 12.57(br.s,1H), 6.15(d,J=1.6Hz,1H), 5.78-5.74(m,1H), 4.01(t,J=6.6Hz, 2H), 3.30 (s, 2H), 1.58-1.51 (m, 2H), 1.35-1.21 (m, 6H), 0.87 (t, J=6.8 Hz, 3H). LCMS m / z 237.2 (M + H) + (ES +); 213.2 (MH) - (ES -).

中間物4-4-(環己氧基)-2-亞甲基-4-側氧基丁酸 Intermediate 4-4-(cyclohexyloxy)-2-methylene-4-oxobutanoic acid

Figure 109137209-A0202-12-0054-50
Figure 109137209-A0202-12-0054-50

根據一般程序1,使用環己醇作為R-OH製備中間物4。1H NMR(500MHz,CDCl3)δ 6.44(d,J=0.9Hz,1H),5.81(d,J=1.2Hz,1H),4.90-4.69(m,1H)、3.32(s,2H),1.83-1.64(m,4H),1.55-1.16(m,6H)。1H NMR(500MHz,DMSO-d6)δ 12.62(s,1H),6.17(d,J=1.6Hz,1H),5.78(q,J=1.3Hz,1H),4.15-4.11(m,2H), 3.61-3.58(m,2H),3.54-3.51(m,2H),3.49-3.46(m,2H),3.43(q,J=7.0Hz,2H),3.33(s,2H),1.10(t,J=7.0Hz,3H)。LCMS m/z 210.7(M-H)-(ES-)。 According to general procedure 1, intermediate 4 was prepared using cyclohexanol as R-OH. 1 H NMR(500MHz, CDCl 3 )δ 6.44(d,J=0.9Hz,1H), 5.81(d,J=1.2Hz,1H), 4.90-4.69(m,1H), 3.32(s,2H), 1.83-1.64 (m, 4H), 1.55-1.16 (m, 6H). 1 H NMR(500MHz,DMSO-d6)δ 12.62(s,1H), 6.17(d,J=1.6Hz,1H), 5.78(q,J=1.3Hz,1H), 4.15-4.11(m,2H) , 3.61-3.58(m,2H),3.54-3.51(m,2H),3.49-3.46(m,2H),3.43(q,J=7.0Hz,2H),3.33(s,2H),1.10(t ,J=7.0Hz,3H). LCMS m / z 210.7 (MH) - (ES -).

中間物5-4-((4-氟苯甲基)氧基)-2-亞甲基-4-側氧基丁酸 Intermediate 5-4-((4-fluorobenzyl)oxy)-2-methylene-4-oxobutanoic acid

Figure 109137209-A0202-12-0055-52
Figure 109137209-A0202-12-0055-52

根據一般程序1,使用(4-氟苯基)甲醇作為R-OH製備中間物5。1H NMR(500MHz,DMSO-d6)δ 12.67(s,1H),7.44-7.38(m,2H),7.23-7.16(m,2H),6.17(d,J=1.6Hz,1H),5.81-5.77(m,1H),5.09(s,2H),3.38(s,2H)。LCMS m/z 237.3(M-H)-(ES-)。 According to general procedure 1, intermediate 5 was prepared using (4-fluorophenyl)methanol as R-OH. 1 H NMR(500MHz,DMSO-d6)δ 12.67(s,1H),7.44-7.38(m,2H),7.23-7.16(m,2H),6.17(d,J=1.6Hz,1H),5.81- 5.77 (m, 1H), 5.09 (s, 2H), 3.38 (s, 2H). LCMS m / z 237.3 (MH) - (ES -).

中間物6-(R)-2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁酸 Intermediate 6-(R)-2-methylene-4-(oct-2-yloxy)-4-oxobutyric acid

Figure 109137209-A0202-12-0055-53
Figure 109137209-A0202-12-0055-53

根據一般程序1,使用(R)-辛-2-醇作為R-OH製備中間物6。1H NMR(500MHz,CDCl3)δ 12.58(s,1H),6.13(d,J=1.6Hz,1H),5.74(d,J=1.6Hz,1H),4.88-4.58(m,1H),3.26(s,2H),1.54-1.38(m,2H),1.30-1.20(m,8H),1.13(d,J=6.2Hz,3H),0.85(t,J=6.7Hz,3H)。LCMS m/z 241.2(M-H)-(ES-)。 According to general procedure 1, intermediate 6 was prepared using (R)-octan-2-ol as R-OH. 1 H NMR(500MHz, CDCl 3 )δ 12.58(s,1H), 6.13(d,J=1.6Hz,1H), 5.74(d,J=1.6Hz,1H), 4.88-4.58(m,1H), 3.26 (s, 2H), 1.54-1.38 (m, 2H), 1.30-1.20 (m, 8H), 1.13 (d, J = 6.2 Hz, 3H), 0.85 (t, J = 6.7 Hz, 3H). LCMS m / z 241.2 (MH) - (ES -).

中間物7-(S)-2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁酸[SYX-00510] Intermediate 7-(S)-2-methylene-4-(oct-2-yloxy)-4-oxobutyric acid [SYX-00510]

Figure 109137209-A0202-12-0055-54
Figure 109137209-A0202-12-0055-54

根據一般程序1,使用(S)-辛-2-醇作為R-OH製備中間物7。1H NMR(500MHz,DMSO-d6)δ 12.58(s,1H),6.14(d,J=1.6Hz,1H),5.75(d,J=1.6Hz,1H),4.84-4.74(m,1H),3.26(s,2H),1.56-1.40(m,2H),1.33-1.20(m,8H),1.14(d,J=6.2Hz,3H),0.86(t,J=6.8Hz,3H)。LCMS m/z 241.0(M-H)-(ES-)。 According to general procedure 1, intermediate 7 was prepared using (S)-octan-2-ol as R-OH. 1 H NMR(500MHz,DMSO-d6)δ 12.58(s,1H), 6.14(d,J=1.6Hz,1H), 5.75(d,J=1.6Hz,1H), 4.84-4.74(m,1H) , 3.26 (s, 2H), 1.56-1.40 (m, 2H), 1.33-1.20 (m, 8H), 1.14 (d, J = 6.2 Hz, 3H), 0.86 (t, J = 6.8 Hz, 3H). LCMS m / z 241.0 (MH) - (ES -).

中間物8-2-亞甲基-4-(新戊氧基)-4-側氧基丁酸 Intermediate 8-2-methylene-4-(neopentoxy)-4-oxobutanoic acid

Figure 109137209-A0202-12-0056-172
Figure 109137209-A0202-12-0056-172

根據一般程序1,使用2,2-二甲基丙-1-醇作為R-OH製備中間物8。1H NMR(500MHz,DMSO-d6)δ 12.63(s,1H),6.16(d,J=1.6Hz,1H),5.77(d,J=1.4Hz,1H),3.72(s,2H),3.34(s,2H),0.88(s,9H)。LCMS m/z 198.9(M-H)-(ES-)。 According to general procedure 1, intermediate 8 was prepared using 2,2-dimethylpropan-1-ol as R-OH. 1 H NMR(500MHz,DMSO-d6)δ 12.63(s,1H), 6.16(d,J=1.6Hz,1H), 5.77(d,J=1.4Hz,1H), 3.72(s,2H), 3.34 (s, 2H), 0.88 (s, 9H). LCMS m / z 198.9 (MH) - (ES -).

中間物9-3-((2-(三級丁氧基)-2-側氧基乙氧基)羰基)丁-3-烯酸 Intermediate 9-3-((2-(tertiary butoxy)-2-oxoethoxy)carbonyl)but-3-enoic acid

Figure 109137209-A0202-12-0056-55
Figure 109137209-A0202-12-0056-55

步驟1 step 1

在氮氣下於RT將三氟化硼乙醇合物(1.43mL,11.6mmol)加至伊康酸酐(10g,89mmol)和2,2,2-三氯乙醇(15.4mL,161mmol)之混合物。將反應混合物加熱至95℃經30mins,接著冷卻至RT。將殘餘物用NaHCO3飽和水溶液(400mL)處理及用EtOAc(3 x 100mL)洗滌。將水相用濃HCl酸化至pH=2並用EtOAc(3 x 120mL)萃取。將合併的有機層乾燥(MgSO4)和濃縮。將殘餘物從甲苯和異己烷(1:1)的混合物(300mL)再結晶。將所得固體過濾,用異己烷洗滌及在真空中乾燥以提供呈白色結晶固體之2-亞甲基-4-側氧基-4-(2,2,2-三氯乙氧基)丁酸(13.7g,51.3mmol)。1H NMR(400MHz,DMSO-d6)δ 12.70(s,1H),6.21(d,J=1.5Hz,1H),5.86(d,J=1.3Hz,1H),4.88(s,2H),3.49(s,2H)。 Boron trifluoride ethanolate (1.43 mL, 11.6 mmol) was added to a mixture of itaconic anhydride (10 g, 89 mmol) and 2,2,2-trichloroethanol (15.4 mL, 161 mmol) at RT under nitrogen. The reaction mixture was heated to 95°C for 30 mins and then cooled to RT. The residue was treated with saturated aqueous NaHCO 3 (400 mL) and washed with EtOAc (3 x 100 mL). The aqueous phase was acidified with concentrated HCl to pH=2 and extracted with EtOAc (3 x 120 mL). The combined organic layer was dried (MgSO 4 ) and concentrated. The residue was recrystallized from a mixture (300 mL) of toluene and isohexane (1:1). The resulting solid was filtered, washed with isohexane and dried in vacuum to provide 2-methylene-4-oxo-4-(2,2,2-trichloroethoxy)butanoic acid as a white crystalline solid (13.7 g, 51.3 mmol). 1 H NMR(400MHz,DMSO-d6)δ 12.70(s,1H), 6.21(d,J=1.5Hz,1H), 5.86(d,J=1.3Hz,1H), 4.88(s,2H), 3.49 (s, 2H).

步驟2 Step 2

在RT下將碳酸鉀(4.16g,30.1mmol)分批加至2-亞甲基-4-側氧基-4-(2,2,2-三氯乙氧基)丁酸(7.50g,28.7mmol)在丙酮(140mL)中之溶液。5min之 後滴加溴乙酸三級丁酯(4.45mL,30.1mmol)。將反應混合物在RT下攪拌16h,接著用EtOAc(150mL)稀釋及過濾。將濾液濃縮以提供呈白色固體之2-亞甲基琥珀酸1-(2-(三級丁氧基)-2-側氧基乙基)酯4-(2,2,2-三氯乙基)酯(10.7g,28.5mmol)。1H NMR(400MHz,DMSO-d6)δ 6.36(d,J=1.2Hz,1H),6.03(q,J=1.1Hz,1H),4.89(s,2H),4.62(s,2H),3.58(d,J=1.0Hz,2H),1.42(s,9H)。 Potassium carbonate (4.16g, 30.1mmol) was added to 2-methylene-4-oxo-4-(2,2,2-trichloroethoxy)butanoic acid (7.50g, 28.7 mmol) in acetone (140 mL). After 5 min, tertiary butyl bromoacetate (4.45 mL, 30.1 mmol) was added dropwise. The reaction mixture was stirred at RT for 16 h, then diluted with EtOAc (150 mL) and filtered. The filtrate was concentrated to provide 2-methylenesuccinate 1-(2-(tertiary butoxy)-2-oxoethyl) ester 4-(2,2,2-trichloroethyl) as a white solid Yl) ester (10.7 g, 28.5 mmol). 1 H NMR(400MHz,DMSO-d6)δ 6.36(d,J=1.2Hz,1H), 6.03(q,J=1.1Hz,1H), 4.89(s,2H), 4.62(s,2H), 3.58 (d,J=1.0Hz,2H),1.42(s,9H).

步驟3 Step 3

經5min將鋅(11.2g,171mmol)分批加至2-亞甲基琥珀酸1-(2-(三級丁氧基)-2-側氧基乙基)酯4-(2,2,2-三氯乙基)酯(10.7g,28.5mmol)在乙酸(160mL)中之溶液。將反應混合物在RT下攪拌18h,接著用水(100mL)和EtOAc(300mL)稀釋。小心傾析混合物,並分離各相。用EtOAc(3 x 200mL)萃取水相。將合併的有機萃取物用鹽水(3 x 150mL)洗滌,乾燥(Na2SO4)及濃縮以提供呈無色固體之標題化合物(6.07g)。藉由少量樣品(300mg)從甲苯和異己烷(1:1)的再結晶獲得分析上純的樣品。1H NMR(400MHz,DMSO-d6)δ 12.35(s,1H),6.26(d,J=1.3Hz,1H),5.91-5.85(m,1H),4.62(s,2H),3.32(s,2H),1.42(s,9H)。LCMS m/z 267.1(M+Na)+(ES+)。 Zinc (11.2g, 171mmol) was added to 2-methylenesuccinate 1-(2-(tertiary butoxy)-2-oxoethyl) ester 4-(2,2, A solution of 2-trichloroethyl) ester (10.7 g, 28.5 mmol) in acetic acid (160 mL). The reaction mixture was stirred at RT for 18 h, then diluted with water (100 mL) and EtOAc (300 mL). Decant the mixture carefully and separate the phases. The aqueous phase was extracted with EtOAc (3 x 200 mL). The combined organic extracts were washed with brine (3 x 150 mL), dried (Na 2 SO 4 ), and concentrated to provide the title compound (6.07 g) as a colorless solid. An analytically pure sample was obtained by recrystallization of a small amount of sample (300 mg) from toluene and isohexane (1:1). 1 H NMR(400MHz,DMSO-d6)δ 12.35(s,1H), 6.26(d,J=1.3Hz,1H), 5.91-5.85(m,1H), 4.62(s,2H), 3.32(s, 2H), 1.42(s, 9H). LCMS m/z 267.1 (M+Na) + (ES + ).

實施例1-2-((2-亞甲基-4-(辛氧基)-4-側氧基丁醯基)氧基)乙酸 Example 1-2-((2-methylene-4-(octyloxy)-4-oxobutanoyl)oxy)acetic acid

Figure 109137209-A0202-12-0057-173
Figure 109137209-A0202-12-0057-173

步驟1 step 1

將溴乙酸三級丁酯(0.37mL,2.5mmol)加至伊康酸4-辛酯(0.50g,2.1mmol)和碳酸鉀(0.35g,2.5mmol)在丙酮(10mL)中之混合物。將反應混合物在RT下攪拌16h。將混合物用EtOAc(20mL)稀釋,過濾及在矽膠上濃縮。將粗製產物藉由層析法在矽膠上純化(0-30% EtOAc/異己烷)以提供呈無色油之2-亞甲基琥 珀酸1-(2-(三級丁氧基)-2-側氧基乙基)酯4-辛基酯。1H NMR(500MHz,DMSO-d6)δ 6.29(d,J=1.3Hz,1H),5.95-5.92(m,1H),4.61(s,2H),4.01(t,J=6.6Hz,2H),3.38(s,2H),1.60-1.50(m,2H),1.42(s,9H),1.34-1.21(m,10H),0.90-0.83(m,3H)。LCMS m/z 379.3(M+Na)+(ES+)。 Tertiary butyl bromoacetate (0.37 mL, 2.5 mmol) was added to a mixture of 4-octyl itaconic acid (0.50 g, 2.1 mmol) and potassium carbonate (0.35 g, 2.5 mmol) in acetone (10 mL). The reaction mixture was stirred at RT for 16 h. The mixture was diluted with EtOAc (20 mL), filtered and concentrated on silica gel. The crude product was purified by chromatography on silica gel (0-30% EtOAc/isohexane) to provide 2-methylenesuccinic acid 1-(2-(tertiary butoxy)-2- as a colorless oil Pendant oxyethyl) ester 4-octyl ester. 1 H NMR(500MHz,DMSO-d6)δ 6.29(d,J=1.3Hz,1H),5.95-5.92(m,1H),4.61(s,2H),4.01(t,J=6.6Hz,2H) , 3.38 (s, 2H), 1.60-1.50 (m, 2H), 1.42 (s, 9H), 1.34-1.21 (m, 10H), 0.90-0.83 (m, 3H). LCMS m/z 379.3 (M+Na) + (ES + ).

步驟2 Step 2

將TFA(5mL,65mmol)加至2-亞甲基琥珀酸1-(2-(三級丁氧基)-2-側氧基乙基)酯4-辛基酯(0.65g,1.82mmol)在DCM(5mL)中之溶液。將反應混合物攪拌30分鐘,用甲苯(10mL)稀釋及濃縮。將粗製產物藉由層析法在矽膠上純化(0-4% MeOH/DCM)以提供呈無色油之標題化合物。1H NMR(500MHz,DMSO-d6)δ 13.08(s,1H),6.29(d,J=1.2Hz,1H),5.93(q,J=1.2Hz,1H),4.64(s,2H),4.01(t,J=6.6Hz,2H),3.38(s,2H),1.60-1.48(m,2H),1.32-1.20(m,10H),0.92-0.82(m,3H)。LCMS m/z 323.2(M+Na)+(ES+)。 Add TFA (5mL, 65mmol) to 2-methylenesuccinate 1-(2-(tertiary butoxy)-2-oxoethyl) ester 4-octyl ester (0.65g, 1.82mmol) Solution in DCM (5 mL). The reaction mixture was stirred for 30 minutes, diluted with toluene (10 mL) and concentrated. The crude product was purified by chromatography on silica gel (0-4% MeOH/DCM) to provide the title compound as a colorless oil. 1 H NMR(500MHz,DMSO-d6)δ 13.08(s,1H), 6.29(d,J=1.2Hz,1H), 5.93(q,J=1.2Hz,1H), 4.64(s,2H), 4.01 (t, J=6.6 Hz, 2H), 3.38 (s, 2H), 1.60-1.48 (m, 2H), 1.32-1.20 (m, 10H), 0.92-0.82 (m, 3H). LCMS m/z 323.2 (M+Na) + (ES + ).

實施例2-2-((2-亞甲基-4-(辛氧基)-4-側氧基丁醯基)氧基)丙酸 Example 2-2-((2-methylene-4-(octyloxy)-4- pendant oxybutyryl)oxy)propionic acid

Figure 109137209-A0202-12-0058-59
Figure 109137209-A0202-12-0058-59

步驟1 step 1

將2-溴丙酸三級丁酯(1.03g,4.95mmol)加至伊康酸4-辛酯(1.00g,4.13mmol)和碳酸鉀(0.696g,5.03mmol)在丙酮(20mL)中之懸浮液。將反應混合物在RT下攪拌18h,接著加熱至50℃並攪拌另外5h。將反應混合物用乙酸乙酯(40mL)稀釋,過濾及濃縮以提供2-亞甲基琥珀酸1-(1-(三級丁氧基)-1-側氧基丙-2-基)酯4-辛基酯(1.7g,3.07mmol)。1H NMR(500MHz,DMSO-d6)δ 6.27(d,J=1.3 Hz,1H),5.95-5.88(m,1H),4.88(q,J=7.0Hz,1H),4.00(t,J=6.6Hz,2H),3.41-3.32(m,2H),1.59-1.51(m,2H),1.43-1.35(m,12H),1.32-1.18(m,10H),0.89-0.84(m,3H)。LCMS m/z 393.2(M+Na)+(ES+)。 Add tertiary butyl 2-bromopropionate (1.03 g, 4.95 mmol) to 4-octyl itaconic acid (1.00 g, 4.13 mmol) and potassium carbonate (0.696 g, 5.03 mmol) in acetone (20 mL). suspension. The reaction mixture was stirred at RT for 18 h, then heated to 50 °C and stirred for another 5 h. The reaction mixture was diluted with ethyl acetate (40 mL), filtered and concentrated to provide 2-methylenesuccinate 1-(1-(tertiary butoxy)-1-oxoprop-2-yl) ester 4 -Octyl ester (1.7 g, 3.07 mmol). 1 H NMR(500MHz,DMSO-d6)δ 6.27(d,J=1.3 Hz,1H),5.95-5.88(m,1H), 4.88(q,J=7.0Hz,1H), 4.00(t,J= 6.6Hz, 2H), 3.41-3.32 (m, 2H), 1.59-1.51 (m, 2H), 1.43-1.35 (m, 12H), 1.32-1.18 (m, 10H), 0.89-0.84 (m, 3H) . LCMS m/z 393.2 (M+Na) + (ES + ).

步驟2 Step 2

將TFA(11mL)加至2-亞甲基琥珀酸1-(1-(三級丁氧基)-1-側氧基丙-2-基)酯4-辛基酯(1.53g,4.13mmol)在DCM(11mL)中之溶液並將混合物在RT下攪拌30min。將反應用甲苯(20mL)稀釋及濃縮。將殘餘物溶解在乙酸乙酯(40mL)中並用水(10 x 25mL)洗滌。將有機相乾燥(MgSO4)及濃縮以提供呈無色油之標題化合物(1.00g,3.15mmol)。1H NMR(500MHz,DMSO-d6)δ 13.06(s,1H),6.27(d,J=1.3Hz,1H),5.90(d,J=1.3Hz,1H),4.96(q,J=7.1Hz,1H),4.00(t,J=6.6Hz,2H),3.36(s,2H),1.59-1.50(m,2H),1.42(d,J=7.0Hz,3H),1.31-1.22(m,10H),0.86(t,J=6.8Hz,3H)。LCMS m/z 337.2(M+Na)+(ES+)。 TFA (11mL) was added to 2-methylenesuccinic acid 1-(1-(tertiary butoxy)-1-oxoprop-2-yl) ester 4-octyl ester (1.53g, 4.13mmol ) Solution in DCM (11 mL) and the mixture was stirred at RT for 30 min. The reaction was diluted with toluene (20 mL) and concentrated. The residue was dissolved in ethyl acetate (40 mL) and washed with water (10 x 25 mL). The organic phase was dried (MgSO 4 ) and concentrated to provide the title compound (1.00 g, 3.15 mmol) as a colorless oil. 1 H NMR(500MHz,DMSO-d6)δ 13.06(s,1H), 6.27(d,J=1.3Hz,1H), 5.90(d,J=1.3Hz,1H), 4.96(q,J=7.1Hz ,1H),4.00(t,J=6.6Hz,2H),3.36(s,2H),1.59-1.50(m,2H),1.42(d,J=7.0Hz,3H),1.31-1.22(m, 10H), 0.86 (t, J=6.8Hz, 3H). LCMS m/z 337.2 (M+Na) + (ES + ).

實施例3-3-((2-亞甲基-4-(辛氧基)-4-側氧基丁醯基)氧基)丙酸 Example 3-3-((2-methylene-4-(octyloxy)-4- pendant oxybutyryl)oxy)propionic acid

Figure 109137209-A0202-12-0059-60
Figure 109137209-A0202-12-0059-60

步驟1 step 1

將伊康酸4-辛酯(2.00g,8.25mmol)、3-羥基丙酸三級丁酯(1.49mL,9.90mmol)、N-(3-二甲胺基丙基)-N'-乙基碳二亞胺鹽酸鹽(3.16g,16.5mmol)和DMAP(0.101g,0.83mmol)在DCM(60mL)中之溶液用DIPEA(2.88mL,16.5mmol)處理。將所得溶液在RT下攪拌20h。將反應混合物在矽膠上濃縮並將粗製產物藉由層析法在矽膠上純化(0-20% EtOAc/DCM或0-20% EtOAc/DCM)以提供呈透明 無色油之2-亞甲基琥珀酸1-(3-(三級丁氧基)-3-側氧基丙基)酯4-辛基酯(1.56g,4.13mmol)。1H NMR(500MHz,DMSO-d6)δ 6.30(d,J=1.0Hz,1H),5.70(d,J=1.2Hz,1H),4.39(t,J=6.5Hz,2H),4.08(t,J=6.8Hz,2H),3.32(s,2H),2.59(t,J=6.5Hz,2H),1.63-1.51(m,2H),1.45(s,9H),1.32-1.13(m,10H),0.88(t,J=6.9Hz,3H)。LCMS m/z 392.9(M+Na)+(ES+)。 The itaconic acid 4-octyl (2.00g, 8.25mmol), three 3-hydroxypropionic acid ester (1.49mL, 9.90mmol), N- ( 3- dimethylaminopropyl) -N '- B A solution of carbodiimide hydrochloride (3.16 g, 16.5 mmol) and DMAP (0.101 g, 0.83 mmol) in DCM (60 mL) was treated with DIPEA (2.88 mL, 16.5 mmol). The resulting solution was stirred at RT for 20h. The reaction mixture was concentrated on silica gel and the crude product was purified on silica gel by chromatography (0-20% EtOAc/DCM or 0-20% EtOAc/DCM) to provide 2-methylene amber as a clear colorless oil 4-octyl acid 1-(3-(tertiary butoxy)-3-oxopropyl) ester (1.56 g, 4.13 mmol). 1 H NMR(500MHz,DMSO-d6)δ 6.30(d,J=1.0Hz,1H), 5.70(d,J=1.2Hz,1H), 4.39(t,J=6.5Hz,2H), 4.08(t ,J=6.8Hz,2H),3.32(s,2H),2.59(t,J=6.5Hz,2H),1.63-1.51(m,2H),1.45(s,9H),1.32-1.13(m, 10H), 0.88 (t, J=6.9 Hz, 3H). LCMS m/z 392.9 (M+Na) + (ES + ).

步驟2 Step 2

將TFA(15mL)加至2-亞甲基琥珀酸1-(3-(三級丁氧基)-3-側氧基丙基)酯4-辛基酯(1.56g,4.21mmol)在DCM(15mL)中之溶液並將混合物在RT下攪拌2h。將反應用甲苯(50mL)稀釋及濃縮。將殘俆物與苯(2 x 20mL)共蒸發及在真空中乾燥以提供呈無色固體之標題化合物(1.546g,4.87mmol)。1H NMR(500MHz,DMSO-d6)δ 12.37(s,1H),6.16(d,J=1.3Hz,1H),5.82(d,J=1.4Hz,1H),4.25(t,J=6.2Hz,2H),4.00(t,J=6.6Hz,2H),3.32(s,2H),2.59(t,J=6.2Hz,2H),1.58-1.47(m,2H),1.36-1.16(m,10H),0.86(t,J=6.8Hz,3H)。LCMS m/z 337.2(M+Na)+(ES+)。 TFA (15mL) was added to 2-methylenesuccinic acid 1-(3-(tertiary butoxy)-3-oxopropyl) ester 4-octyl ester (1.56g, 4.21mmol) in DCM (15 mL) and the mixture was stirred at RT for 2 h. The reaction was diluted with toluene (50 mL) and concentrated. The residue was co-evaporated with benzene (2 x 20 mL) and dried in vacuo to provide the title compound (1.546 g, 4.87 mmol) as a colorless solid. 1 H NMR(500MHz,DMSO-d6)δ 12.37(s,1H), 6.16(d,J=1.3Hz,1H), 5.82(d,J=1.4Hz,1H), 4.25(t,J=6.2Hz ,2H),4.00(t,J=6.6Hz,2H),3.32(s,2H),2.59(t,J=6.2Hz,2H),1.58-1.47(m,2H),1.36-1.16(m, 10H), 0.86 (t, J=6.8Hz, 3H). LCMS m/z 337.2 (M+Na) + (ES + ).

實施例4-3-((4-((4-氟苯甲基)氧基)-2-亞甲基-4-側氧基丁醯基)氧基)丙酸 Example 4-3-((4-((4-fluorobenzyl)oxy)-2-methylene-4-oxobutyryl)oxy)propionic acid

Figure 109137209-A0202-12-0060-174
Figure 109137209-A0202-12-0060-174

根據實施例3之程序製備實施例4,但使用4-((4-氟苯甲基)氧基)-2-亞甲基-4-側氧基丁酸(中間物5)代替伊康酸4-辛酯。1H NMR(500MHz,DMSO-d6)δ 12.39(br s,1H),7.44-7.38(m,2H),7.25-7.17(m,2H),6.18(d,J=1.3Hz,1H),5.85(d,J=1.3Hz,1H),5.08(s,2H),4.24(t,J=6.2Hz,2H),3.41(s,2H),2.57(t,J=6.2Hz,2H)。LCMS m/z 333.3(M+Na)+(ES+)。 Example 4 was prepared according to the procedure of Example 3, but using 4-((4-fluorobenzyl)oxy)-2-methylene-4-oxobutyric acid (Intermediate 5) instead of itaconic acid 4-octyl ester. 1 H NMR(500MHz,DMSO-d6)δ 12.39(br s,1H),7.44-7.38(m,2H),7.25-7.17(m,2H),6.18(d,J=1.3Hz,1H),5.85 (d,J=1.3Hz,1H),5.08(s,2H), 4.24(t,J=6.2Hz,2H),3.41(s,2H), 2.57(t,J=6.2Hz,2H). LCMS m/z 333.3 (M+Na) + (ES + ).

實施例5-3-((4-(環辛氧基)-2-亞甲基-4-側氧基丁醯基)氧基)丙酸 Example 5-3-((4-(cyclooctyloxy)-2-methylene-4-oxobutanoyl)oxy)propionic acid

Figure 109137209-A0202-12-0061-63
Figure 109137209-A0202-12-0061-63

根據實施例3之程序製備實施例5,但使用4-(環辛氧基)-2-亞甲基-4-側氧基丁酸(中間物1)代替伊康酸4-辛酯。1H NMR(500MHz,DMSO-d6)δ 12.39(s,1H),6.15(d,J=1.4Hz,1H),5.85-5.74(m,1H),4.83(tt,J=8.1,3.9Hz,1H),4.26(t,J=6.2Hz,2H),3.30(s,2H),2.60(t,J=6.2Hz,2H),1.77-1.41(m,14H)。LCMS m/z 335.3(M+Na)+(ES+)。 Example 5 was prepared according to the procedure of Example 3, but using 4-(cyclooctyloxy)-2-methylene-4-oxobutanoic acid (Intermediate 1) instead of 4-octyl itaconic acid. 1 H NMR(500MHz,DMSO-d6)δ 12.39(s,1H), 6.15(d,J=1.4Hz,1H),5.85-5.74(m,1H), 4.83(tt,J=8.1,3.9Hz, 1H), 4.26(t,J=6.2Hz,2H), 3.30(s,2H), 2.60(t,J=6.2Hz,2H), 1.77-1.41(m,14H). LCMS m/z 335.3 (M+Na) + (ES + ).

實施例6-3-((2-亞甲基-4-(新戊氧基)-4-側氧基丁醯基)氧基)丙酸 Example 6-3-((2-methylene-4-(neopentyloxy)-4- pendant oxybutyryl)oxy)propionic acid

Figure 109137209-A0202-12-0061-64
Figure 109137209-A0202-12-0061-64

根據實施例3之程序製備實施例6,但使用2-亞甲基-4-(新戊氧基)-4-側氧基丁酸(中間物8)代替伊康酸4-辛酯。1H NMR(400MHz,DMSO-d6)δ 12.38(s,1H),6.18(d,J=1.4Hz,1H),5.88-5.82(m,1H),4.26(t,J=6.2Hz,2H),3.72(s,2H),3.38(s,2H),2.59(t,J=6.2Hz,2H),0.88(s,9H)。LCMS m/z 295.7(M+Na)+(ES+)。 Example 6 was prepared according to the procedure of Example 3, but using 2-methylene-4-(neopentoxy)-4-oxobutanoic acid (Intermediate 8) instead of 4-octyl itaconic acid. 1 H NMR(400MHz,DMSO-d6)δ 12.38(s,1H), 6.18(d,J=1.4Hz,1H), 5.88-5.82(m,1H), 4.26(t,J=6.2Hz,2H) , 3.72 (s, 2H), 3.38 (s, 2H), 2.59 (t, J = 6.2 Hz, 2H), 0.88 (s, 9H). LCMS m/z 295.7 (M+Na) + (ES + ).

實施例7-(S)-3-((2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁醯基)氧基)丙酸 Example 7-(S)-3-((2-methylene-4-(oct-2-yloxy)-4- pendant oxybutyryl)oxy)propionic acid

Figure 109137209-A0202-12-0061-175
Figure 109137209-A0202-12-0061-175

根據實施例3之程序製備實施例7,但使用S)-2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁酸(中間物7)代替伊康酸4-辛酯。1H NMR(400MHz,DMSO-d6)δ 12.39(s,1H),6.15(d,J=1.3Hz,1H),5.81(d,J=1.3Hz,1H),4.84-4.70(m,1H),4.25(t,J=6.2Hz,2H),3.30(s,2H),2.59(t,J=6.2Hz,2H),1.54-1.37(m,2H),1.25 (dd,J=10.7,5.2Hz,8H),1.13(d,J=6.2Hz,3H),0.85(t,J=6.4Hz,3H)。LCMS m/z 336.9(M+Na)+(ES+)。 Example 7 was prepared according to the procedure of Example 3, but using S)-2-methylene-4-(oct-2-yloxy)-4-oxobutanoic acid (Intermediate 7) instead of itaconic acid 4-octyl ester. 1 H NMR(400MHz,DMSO-d6)δ 12.39(s,1H), 6.15(d,J=1.3Hz,1H), 5.81(d,J=1.3Hz,1H), 4.84-4.70(m,1H) ,4.25(t,J=6.2Hz,2H),3.30(s,2H),2.59(t,J=6.2Hz,2H),1.54-1.37(m,2H),1.25 (dd,J=10.7,5.2 Hz, 8H), 1.13 (d, J = 6.2 Hz, 3H), 0.85 (t, J = 6.4 Hz, 3H). LCMS m/z 336.9 (M+Na) + (ES + ).

實施例8-3-((4-(己氧基)-2-亞甲基-4-側氧基丁醯基)氧基)丙酸 Example 8-3-((4-(hexyloxy)-2-methylene-4-oxobutanoyl)oxy)propionic acid

Figure 109137209-A0202-12-0062-176
Figure 109137209-A0202-12-0062-176

根據實施例3之程序製備實施例8,但使用4-(己氧基)-2-亞甲基-4-側氧基丁酸(中間物3)代替伊康酸4-辛酯。1H NMR(400MHz,DMSO-d6)δ 12.39(s,1H),6.16(d,J=1.4Hz,1H),5.82(d,J=1.3Hz,1H),4.25(t,J=6.2Hz,2H),4.00(t,J=6.6Hz,2H),3.33(s,2H),2.59(t,J=6.2Hz,2H),1.61-1.47(m,2H),1.32-1.19(m,6H),0.93-0.78(m,3H)。LCMS m/z 309.7(M+Na)+(ES+)。 Example 8 was prepared according to the procedure of Example 3, but using 4-(hexyloxy)-2-methylene-4-oxobutanoic acid (Intermediate 3) instead of 4-octyl itaconic acid. 1 H NMR(400MHz,DMSO-d6)δ 12.39(s,1H), 6.16(d,J=1.4Hz,1H), 5.82(d,J=1.3Hz,1H), 4.25(t,J=6.2Hz ,2H),4.00(t,J=6.6Hz,2H),3.33(s,2H),2.59(t,J=6.2Hz,2H),1.61-1.47(m,2H),1.32-1.19(m, 6H), 0.93-0.78 (m, 3H). LCMS m/z 309.7 (M+Na) + (ES + ).

實施例9-3-((2-亞甲基-4-側氧基-4-(3-苯氧基丙氧基)丁醯基)氧基)丙酸 Example 9-3-((2-methylene-4- pendant oxy-4-(3-phenoxypropoxy)butyryl)oxy)propionic acid

Figure 109137209-A0202-12-0062-177
Figure 109137209-A0202-12-0062-177

根據實施例3之程序製備實施例9,但使用2-亞甲基-4-側氧基-4-(3-苯氧基丙氧基)丁酸(中間物2)代替伊康酸4-辛酯。1H NMR(400MHz,DMSO-d6)δ 12.41(s,1H),7.35-7.24(m,2H),6.99-6.88(m,3H),6.17(d,J=1.3Hz,1H),5.83(q,J=1.2Hz,1H),4.24(t,J=6.2Hz,2H),4.19(t,J=6.4Hz,2H),4.01(t,J=6.3Hz,2H),3.37(s,2H),2.58(t,J=6.2Hz,2H),2.06-1.97(m,2H)。LCMS m/z 359.3(M+Na)+(ES+)。 Example 9 was prepared according to the procedure of Example 3, but using 2-methylene-4- pendant oxy-4-(3-phenoxypropoxy)butyric acid (Intermediate 2) instead of itaconic acid 4- Octyl ester. 1 H NMR (400MHz, DMSO-d6) δ 12.41 (s, 1H), 7.35-7.24 (m, 2H), 6.99-6.88 (m, 3H), 6.17 (d, J=1.3Hz, 1H), 5.83 ( q,J=1.2Hz,1H), 4.24(t,J=6.2Hz,2H), 4.19(t,J=6.4Hz,2H),4.01(t,J=6.3Hz,2H), 3.37(s, 2H), 2.58 (t, J=6.2 Hz, 2H), 2.06-1.97 (m, 2H). LCMS m/z 359.3 (M+Na) + (ES + ).

實施例10-3-((4-(環己氧基)-2-亞甲基-4-側氧基丁醯基)氧基)丙酸 Example 10-3-((4-(cyclohexyloxy)-2-methylene-4-oxobutanoyl)oxy)propionic acid

Figure 109137209-A0202-12-0062-67
Figure 109137209-A0202-12-0062-67

根據實施例3之程序製備實施例10,但使用4-(環己氧基)-2-亞甲基-4-側氧基丁酸(中間物4)代替伊康酸4-辛酯。1H NMR(400MHz,DMSO-d6)δ 12.40(s,1H),6.15(d,J=1.4Hz,1H),5.81(d,J=1.3Hz,1H),4.70-4.59(m,1H),4.25(t,J=6.2Hz,2H),3.31(s,2H),2.59(t,J=6.2Hz,2H),1.77-1.70(m,2H),1.65-1.55(m,2H),1.49-1.16(m,6H)。LCMS m/z 307.4(M+Na)+(ES+)。 Example 10 was prepared according to the procedure of Example 3, but using 4-(cyclohexyloxy)-2-methylene-4-oxobutanoic acid (Intermediate 4) instead of 4-octyl itaconic acid. 1 H NMR(400MHz,DMSO-d6)δ 12.40(s,1H), 6.15(d,J=1.4Hz,1H), 5.81(d,J=1.3Hz,1H), 4.70-4.59(m,1H) ,4.25(t,J=6.2Hz,2H),3.31(s,2H),2.59(t,J=6.2Hz,2H),1.77-1.70(m,2H),1.65-1.55(m,2H), 1.49-1.16 (m, 6H). LCMS m/z 307.4 (M+Na) + (ES + ).

實施例11-(R)-3-((2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁醯基)氧基)丙酸 Example 11-(R)-3-((2-methylene-4-(oct-2-yloxy)-4-oxobutyryl)oxy)propionic acid

Figure 109137209-A0202-12-0063-178
Figure 109137209-A0202-12-0063-178

根據實施例3之程序製備實施例11,但使用(R)-2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁酸(中間物6)代替伊康酸4-辛酯。1H NMR(400MHz,DMSO-d6)δ 12.38(s,1H),6.15(d,J=1.4Hz,1H),5.81(d,J=1.4Hz,1H),4.83-4.72(m,1H),4.25(t,J=6.2Hz,2H),3.30(s,2H),2.59(t,J=6.3Hz,2H),1.54-1.39(m,2H),1.29-1.16(m,8H),1.13(d,J=6.3Hz,3H),0.85(t,J=6.4Hz,3H)。LCMS m/z 337.4(M+Na)+(ES+)。 Example 11 was prepared according to the procedure of Example 3, but using (R)-2-methylene-4-(oct-2-yloxy)-4-oxobutanoic acid (Intermediate 6) instead of Ikon 4-octyl acid. 1 H NMR(400MHz,DMSO-d6)δ 12.38(s,1H), 6.15(d,J=1.4Hz,1H), 5.81(d,J=1.4Hz,1H), 4.83-4.72(m,1H) ,4.25(t,J=6.2Hz,2H),3.30(s,2H),2.59(t,J=6.3Hz,2H),1.54-1.39(m,2H),1.29-1.16(m,8H), 1.13(d,J=6.3Hz,3H), 0.85(t,J=6.4Hz,3H). LCMS m/z 337.4 (M+Na) + (ES + ).

實施例12-(S)-2-((2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁醯基)氧基)乙酸 Example 12-(S)-2-((2-methylene-4-(oct-2-yloxy)-4-oxobutyryl)oxy)acetic acid

Figure 109137209-A0202-12-0063-71
Figure 109137209-A0202-12-0063-71

步驟1 step 1

將(S)-2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁酸(中間物7,1g,4.13mmol)、溴乙酸三級丁酯(0.64mL,4.3mmol)和碳酸鉀(0.684g,4.95mmol)在丙酮(20mL)中的混合物在RT下攪拌過夜。將反應混合物濃縮並將殘餘物分溶在水(20mL)和EtOAc(10mL)之間。分離該等相並將水相用EtOAc(10mL)萃取。將合併的有機相用鹽水(10mL)洗滌,乾燥(MgSO4)及濃縮以提供呈無色油之2-亞甲基琥珀酸(S)-1-(2-(三級丁氧基)-2-側氧基乙基)酯4-辛-2-基酯(1.56g,4.07mmol)。1H NMR(500MHz,DMSO-d6)δ 6.28(s,1H),5.92(s,1H),4.82-4.75(m,1H),4.60(s,2H),3.35(s,2H),1.42(s,9H),1.31-1.20(m,10H),1.14(d,J=6.3Hz,3H),0.88-0.84(m,3H)。 Combine (S)-2-methylene-4-(oct-2-yloxy)-4-oxobutyric acid (intermediate 7,1g, 4.13mmol), tertiary butyl bromoacetate (0.64mL , 4.3 mmol) and potassium carbonate (0.684 g, 4.95 mmol) in acetone (20 mL) were stirred overnight at RT. The reaction mixture was concentrated and the residue was partitioned between water (20 mL) and EtOAc (10 mL). The phases were separated and the aqueous phase was extracted with EtOAc (10 mL). The combined organic phase was washed with brine (10 mL), dried (MgSO 4 ) and concentrated to provide 2-methylenesuccinic acid (S)-1-(2-(tertiary butoxy)-2 as a colorless oil -Pendant oxyethyl) ester 4-oct-2-yl ester (1.56 g, 4.07 mmol). 1 H NMR (500MHz, DMSO-d6) δ 6.28 (s, 1H), 5.92 (s, 1H), 4.82-4.75 (m, 1H), 4.60 (s, 2H), 3.35 (s, 2H), 1.42 ( s, 9H), 1.31-1.20 (m, 10H), 1.14 (d, J=6.3 Hz, 3H), 0.88-0.84 (m, 3H).

步驟2 Step 2

將TFA(7.5mL)加至2-亞甲基琥珀酸(S)-1-(2-(三級丁氧基)-2-側氧基乙基)酯4-辛-2-基酯(1.5g,3.79mmol)在DCM(7.5mL)中之溶液。將反應混合物攪拌2h,分溶在EtOAc(50mL)和水(50mL)之間及各相分離。將有機相用水(2 x 20mL)、鹽水(20mL)洗滌,乾燥(MgSO4)及濃縮。將殘餘物再溶解在DCM(10mL)中,用水洗滌(2 x 10mL),乾燥(MgSO4)及濃縮以提供呈無色油之標題化合物(0.922g,3.04mmol)。1H NMR(500MHz,DMSO-d6)δ 13.08(br.s,1H),6.28(d,J=1.2Hz,1H),5.92(d,J=1.3Hz,1H),4.83-4.74(m,1H),4.64(s,2H),3.35(s,2H),1.55-1.40(m,2H),1.31-1.18(m,8H),1.14(d,J=6.2Hz,3H),0.86(t,J=6.9Hz,3H)。LCMS m/z 323.2(M+H)+(ES+)。 Add TFA (7.5 mL) to 2-methylenesuccinic acid (S)-1-(2-(tertiary butoxy)-2-oxoethyl) ester 4-oct-2-yl ester ( 1.5 g, 3.79 mmol) in DCM (7.5 mL). The reaction mixture was stirred for 2 h, partitioned between EtOAc (50 mL) and water (50 mL) and the phases were separated. The organic phase was washed with water (2 x 20 mL), brine (20 mL), dried (MgSO 4 ) and concentrated. The residue was redissolved in DCM (10 mL), washed with water (2 x 10 mL), dried (MgSO 4 ), and concentrated to provide the title compound (0.922 g, 3.04 mmol) as a colorless oil. 1 H NMR(500MHz,DMSO-d6)δ 13.08(br.s,1H), 6.28(d,J=1.2Hz,1H), 5.92(d,J=1.3Hz,1H), 4.83-4.74(m, 1H), 4.64 (s, 2H), 3.35 (s, 2H), 1.55-1.40 (m, 2H), 1.31-1.18 (m, 8H), 1.14 (d, J=6.2Hz, 3H), 0.86 (t ,J=6.9Hz,3H). LCMS m/z 323.2 (M+H) + (ES + ).

實施例13-2-((4-(環辛氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸 Example 13-2-((4-(cyclooctyloxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid

Figure 109137209-A0202-12-0064-72
Figure 109137209-A0202-12-0064-72

根據實施例12之程序製備實施例13,但使用4-(環辛氧基)-2-亞甲基-4-側氧基丁酸(中間物1)代替(S)-2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁酸。1H NMR(500MHz,DMSO-d6)δ 13.11(s,1H),6.27(d,J=1.2Hz,1H),5.91(d,J=1.4Hz,1H),4.82(tt,J=8.1,3.9Hz,1H),4.63(s,2H),3.33(s,2H),1.75-1.42(m,14H)。LCMS m/z 321.3(M+Na)+(ES+)。 Example 13 was prepared according to the procedure of Example 12, but using 4-(cyclooctyloxy)-2-methylene-4-oxobutanoic acid (Intermediate 1) instead of (S)-2-methylene -4-(oct-2-yloxy)-4-oxobutanoic acid. 1 H NMR(500MHz,DMSO-d6)δ 13.11(s,1H), 6.27(d,J=1.2Hz,1H), 5.91(d,J=1.4Hz,1H), 4.82(tt,J=8.1, 3.9Hz, 1H), 4.63 (s, 2H), 3.33 (s, 2H), 1.75-1.42 (m, 14H). LCMS m/z 321.3 (M+Na) + (ES + ).

實施例14-2-((4-(環己氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸 Example 14-2-((4-(cyclohexyloxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid

Figure 109137209-A0202-12-0065-179
Figure 109137209-A0202-12-0065-179

根據實施例12之程序製備實施例14,但使用4-(環己氧基)-2-亞甲基-4-側氧基丁酸(中間物4)代替(S)-2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁酸。1H NMR(500MHz,DMSO-d6)δ 13.09(s,1H),6.27(d,J=1.3Hz,1H),5.91(d,J=1.3Hz,1H),4.68-4.59(m,3H),3.35(s,2H),1.77-1.70(m,2H),1.65-1.58(m,2H),1.50-1.17(m,6H)。LCMS m/z 293.6(M+Na)+(ES+)。 Example 14 was prepared according to the procedure of Example 12, but using 4-(cyclohexyloxy)-2-methylene-4-oxobutanoic acid (Intermediate 4) instead of (S)-2-methylene -4-(oct-2-yloxy)-4-oxobutanoic acid. 1 H NMR(500MHz,DMSO-d6)δ 13.09(s,1H), 6.27(d,J=1.3Hz,1H), 5.91(d,J=1.3Hz,1H), 4.68-4.59(m,3H) , 3.35 (s, 2H), 1.77-1.70 (m, 2H), 1.65-1.58 (m, 2H), 1.50-1.17 (m, 6H). LCMS m/z 293.6 (M+Na) + (ES + ).

實施例15-2-((2-亞甲基-4-(新戊氧基)-4-側氧基丁醯基)氧基)乙酸 Example 15-2-((2-Methylene-4-(neopentyloxy)-4-oxobutanoyl)oxy)acetic acid

Figure 109137209-A0202-12-0065-74
Figure 109137209-A0202-12-0065-74

根據實施例12之程序製備實施例15,但使用2-亞甲基-4-(新戊氧基)-4-側氧基丁酸(中間物8)代替(S)-2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁酸。1H NMR(500MHz,DMSO-d6)δ 13.08(s,1H),6.30(d,J=1.2Hz,1H),5.95(d,J=1.2Hz,1H),4.64(s,2H),3.73(s,2H),3.42(s,2H),0.88(s,9H)。LCMS m/z 280.7(M+Na)+(ES+)。 Example 15 was prepared according to the procedure of Example 12, but using 2-methylene-4-(neopentyloxy)-4-oxobutanoic acid (Intermediate 8) instead of (S)-2-methylene -4-(oct-2-yloxy)-4-oxobutanoic acid. 1 H NMR(500MHz,DMSO-d6)δ 13.08(s,1H), 6.30(d,J=1.2Hz,1H), 5.95(d,J=1.2Hz,1H), 4.64(s,2H), 3.73 (s, 2H), 3.42 (s, 2H), 0.88 (s, 9H). LCMS m/z 280.7 (M+Na) + (ES + ).

實施例16-2-((4-((4-氟苯甲基)氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸 Example 16-2-((4-((4-fluorobenzyl)oxy)-2-methylene-4-oxobutyryl)oxy)acetic acid

Figure 109137209-A0202-12-0065-180
Figure 109137209-A0202-12-0065-180

根據實施例12之程序製備實施例16,但使用4-((4-氟苯甲基)氧基)-2-亞甲基-4-側氧基丁酸(中間物5)代替(S)-2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁酸。1H NMR(400MHz,DMSO-d6)δ 13.10(br.s,1H),7.44-7.37(m,2H),7.25-7.17(m,2H),6.30(d,J=1.2Hz,1H),5.95(d,J=1.2Hz,1H),5.09(s,2H),4.63(s,2H),3.45(s,2H)。LCMS m/z 297.3(M+H)+(ES+)。 Example 16 was prepared according to the procedure of Example 12, but using 4-((4-fluorobenzyl)oxy)-2-methylene-4-oxobutanoic acid (Intermediate 5) instead of (S) -2-methylene-4-(oct-2-yloxy)-4-oxobutanoic acid. 1 H NMR(400MHz,DMSO-d6)δ 13.10(br.s,1H),7.44-7.37(m,2H),7.25-7.17(m,2H),6.30(d,J=1.2Hz,1H), 5.95 (d, J=1.2 Hz, 1H), 5.09 (s, 2H), 4.63 (s, 2H), 3.45 (s, 2H). LCMS m/z 297.3 (M+H) + (ES + ).

實施例17-2-((4-(己氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸 Example 17-2-((4-(hexyloxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid

Figure 109137209-A0202-12-0066-181
Figure 109137209-A0202-12-0066-181

根據實施例12之程序製備實施例17,但使用4-(己氧基)-2-亞甲基-4-側氧基丁酸(中間物3)代替(S)-2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁酸。1H NMR(400MHz,DMSO-d6)δ 13.10(s,1H),6.28(d,J=1.2Hz,1H),5.92(d,J=1.2Hz,1H),4.63(s,2H),4.00(t,J=6.6Hz,2H),3.37(s,2H),1.58-1.42(m,2H),1.31-1.11(m,6H),0.86(t,J=6.8Hz,3H)。LCMS m/z 295.3(M+Na)+(ES+)。 Example 17 was prepared according to the procedure of Example 12, but using 4-(hexyloxy)-2-methylene-4-oxobutanoic acid (Intermediate 3) instead of (S)-2-methylene- 4-(oct-2-yloxy)-4-oxobutanoic acid. 1 H NMR(400MHz,DMSO-d6)δ 13.10(s,1H), 6.28(d,J=1.2Hz,1H), 5.92(d,J=1.2Hz,1H), 4.63(s,2H), 4.00 (t, J=6.6 Hz, 2H), 3.37 (s, 2H), 1.58-1.42 (m, 2H), 1.31-1.11 (m, 6H), 0.86 (t, J=6.8 Hz, 3H). LCMS m/z 295.3 (M+Na) + (ES + ).

實施例18-2-((2-亞甲基-4-側氧基-4-(3-苯氧基丙氧基)丁醯基)氧基)乙酸 Example 18-2-((2-Methylene-4- pendant oxy-4-(3-phenoxypropoxy)butyryl)oxy)acetic acid

Figure 109137209-A0202-12-0066-182
Figure 109137209-A0202-12-0066-182

根據實施例12之程序製備實施例18,但使用2-亞甲基-4-側氧基-4-(3-苯氧基丙氧基)丁酸(中間物2)代替(S)-2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁酸。1H NMR(400MHz,DMSO-d6)δ 13.09(s,1H),7.33-7.25(m,2H),6.98-6.90(m,3H),6.29(d,J=1.2Hz,1H),5.97-5.90(m,1H),4.62(s,2H),4.19(t,J=6.4Hz,2H),4.01(t,J=6.3Hz,2H),3.41(s,2H),2.07-1.97(m,2H)。LCMS m/z 345.3(M+Na)+(ES+)。 Example 18 was prepared according to the procedure of Example 12, but using 2-methylene-4-oxo-4-(3-phenoxypropoxy)butanoic acid (Intermediate 2) instead of (S)-2 -Methylene-4-(oct-2-yloxy)-4-oxobutanoic acid. 1 H NMR (400MHz, DMSO-d6) δ 13.09 (s, 1H), 7.33-7.25 (m, 2H), 6.98-6.90 (m, 3H), 6.29 (d, J=1.2Hz, 1H), 5.97- 5.90(m,1H),4.62(s,2H),4.19(t,J=6.4Hz,2H),4.01(t,J=6.3Hz,2H),3.41(s,2H),2.07-1.97(m ,2H). LCMS m/z 345.3 (M+Na) + (ES + ).

實施例19-2-((2-亞甲基-4-側氧基-4-(螺[3.3]庚-2-基氧基)丁醯基)氧基)乙酸 Example 19-2-((2-Methylene-4-oxo-4-(spiro[3.3]hept-2-yloxy)butyryl)oxy)acetic acid

Figure 109137209-A0202-12-0067-183
Figure 109137209-A0202-12-0067-183

步驟1 step 1

將N-(3-二甲胺基丙基)-N'-乙基碳二亞胺鹽酸鹽(0.471g,2.46mmol)加至3-((2-(三級丁氧基)-2-側氧基乙氧基)羰基)丁-3-烯酸(中間物9,0.400g,1.64mmol)、螺[3.3]庚-2-醇(0.220g,1.97mmol)和DMAP(0.300g,2.46mmol)在DCM(10mL)中之溶液。將反應混合物在RT下攪拌18h。將反應混合物濃縮並將粗製產物藉由層析法(0-10% EtOAc/DCM)在矽膠上純化以提供不純的產物。將粗製產物藉由層析法在矽膠上純化(0-10% EtOAc/異己烷)以提供呈淺黃色油之2-亞甲基琥珀酸1-(2-(三級丁氧基)-2-側氧基乙基)酯4-螺[3.3]庚-2-基酯(146mg,0.41mmol)。 The N- (3- dimethylaminopropyl) -N '- ethylcarbodiimide hydrochloride (0.471g, 2.46mmol) was added to 3 - ((2- (three-butoxy) -2 -Pendant oxyethoxy)carbonyl)but-3-enoic acid (intermediate 9, 0.400g, 1.64mmol), spiro[3.3]heptan-2-ol (0.220g, 1.97mmol) and DMAP (0.300g, 2.46 mmol) in DCM (10 mL). The reaction mixture was stirred at RT for 18 h. The reaction mixture was concentrated and the crude product was purified by chromatography (0-10% EtOAc/DCM) on silica gel to provide impure product. The crude product was purified by chromatography on silica gel (0-10% EtOAc/isohexane) to provide 2-methylenesuccinic acid 1-(2-(tertiary butoxy)-2 as a light yellow oil Pendant oxyethyl) ester 4-spiro[3.3]heptan-2-yl ester (146 mg, 0.41 mmol).

步驟2 Step 2

將TFA(1mL)加至2-亞甲基琥珀酸1-(2-(三級丁氧基)-2-側氧基乙基)酯4-螺[3.3]庚-2-基酯(146mg,0.41mmol)在DCM(1mL)中之溶液。將反應混合物攪拌1h,用甲苯(5mL)稀釋及濃縮。將殘餘物溶解在EtOAc(10mL)中,用鹽水(10mL)洗滌,乾燥(MgSO4)及濃縮以提供呈無色油之標題化合物(90mg,0.316mmol)。1H NMR(400MHz,DMSO-d6)δ 13.08(br.s,1H),6.28(d,J=1.2Hz,1H),5.91(d,J=1.2Hz,1H),4.82-4.73(m,1H),4.64(s,2H),3.34(s,2H),2.43-2.34(m,2H),2.02-1.90(m,6H),1.85-1.74(m,2H)。LCMS m/z 305.3(M+Na)+(ES+)。 TFA (1mL) was added to 2-methylenesuccinic acid 1-(2-(tertiary butoxy)-2-oxoethyl) ester 4-spiro[3.3]heptan-2-yl ester (146mg , 0.41 mmol) in DCM (1 mL). The reaction mixture was stirred for 1 h, diluted with toluene (5 mL) and concentrated. The residue was dissolved in EtOAc (10 mL), washed with brine (10 mL), dried (MgSO4) and concentrated to provide the title compound (90 mg, 0.316 mmol) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ 13.08(br.s,1H), 6.28(d,J=1.2Hz,1H), 5.91(d,J=1.2Hz,1H), 4.82-4.73(m, 1H), 4.64 (s, 2H), 3.34 (s, 2H), 2.43-2.34 (m, 2H), 2.02-1.90 (m, 6H), 1.85-1.74 (m, 2H). LCMS m/z 305.3 (M+Na) + (ES + ).

實施例20-2-((4-(環己氧基)-2-亞甲基-4-側氧基丁醯基)氧基)丙酸 Example 20-2-((4-(cyclohexyloxy)-2-methylene-4-oxobutanoyl)oxy)propionic acid

Figure 109137209-A0202-12-0068-82
Figure 109137209-A0202-12-0068-82

使用與實施例2所述相同的程序製備實施例20,但使用4-(環己氧基)-2-亞甲基-4-側氧基丁酸(中間物4)代替伊康酸4-辛酯。1H NMR(400MHz,DMSO-d6)δ 13.03(s,1H),6.26(d,J=1.3Hz,1H),5.89(d,J=1.3Hz,1H),4.96(q,J=7.0Hz,1H),4.65(dq,J=8.6,4.0Hz,1H),3.40-3.29(m,2H),1.80-1.70(m,2H),1.64(ddd,J=13.0,6.9,3.9Hz,2H),1.42(d,J=7.1Hz,3H),1.52-1.19(m,6H)。LCMS m/z 307.6(M+Na)+(ES+)。 Example 20 was prepared using the same procedure as described in Example 2, but using 4-(cyclohexyloxy)-2-methylene-4-oxobutanoic acid (Intermediate 4) instead of itaconic acid 4- Octyl ester. 1 H NMR(400MHz,DMSO-d6)δ 13.03(s,1H), 6.26(d,J=1.3Hz,1H), 5.89(d,J=1.3Hz,1H), 4.96(q,J=7.0Hz ,1H),4.65(dq,J=8.6,4.0Hz,1H),3.40-3.29(m,2H),1.80-1.70(m,2H),1.64(ddd,J=13.0,6.9,3.9Hz,2H ), 1.42 (d, J=7.1 Hz, 3H), 1.52-1.19 (m, 6H). LCMS m/z 307.6 (M+Na) + (ES + ).

實施例21-(R)-2-((2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁醯基)氧基)乙酸 Example 21-(R)-2-((2-methylene-4-(oct-2-yloxy)-4-oxobutyryl)oxy)acetic acid

Figure 109137209-A0202-12-0068-184
Figure 109137209-A0202-12-0068-184

根據實施例12之程序製備實施例21,但使用(R)-2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁酸(中間物6)代替(S)-2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁酸。1H NMR(400MHz,DMSO-d6)δ 13.09(s,1H),6.28(d,J=1.2Hz,1H),5.92(d,J=1.2Hz,1H),4.84-4.74(m,1H),4.64(s,2H),3.35(s,2H),1.58-1.39(m,2H),1.31-1.18(m,8H),1.14(d,J=6.3Hz,3H),0.91-0.82(m,3H)。LCMS m/z 323.0(M+Na)+(ES+)。 Example 21 was prepared according to the procedure of Example 12, but using (R)-2-methylene-4-(oct-2-yloxy)-4-oxobutanoic acid (Intermediate 6) instead of (S )-2-methylene-4-(oct-2-yloxy)-4-oxobutanoic acid. 1 H NMR(400MHz,DMSO-d6)δ 13.09(s,1H), 6.28(d,J=1.2Hz,1H), 5.92(d,J=1.2Hz,1H), 4.84-4.74(m,1H) ,4.64(s,2H),3.35(s,2H),1.58-1.39(m,2H),1.31-1.18(m,8H),1.14(d,J=6.3Hz,3H),0.91-0.82(m ,3H). LCMS m/z 323.0 (M+Na) + (ES + ).

如下製備實施例21的鈉鹽: The sodium salt of Example 21 was prepared as follows:

實施例21a:(R)-2-((2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁醯基)氧基)乙酸鈉鹽[SYX-00748鈉鹽] Example 21a: (R)-2-((2-methylene-4-(oct-2-yloxy)-4-oxobutyryl)oxy)acetic acid sodium salt [SYX-00748 sodium salt]

Figure 109137209-A0202-12-0068-185
Figure 109137209-A0202-12-0068-185

將NaHCO3在水中之溶液(0.5M,6.27mL,3.14mmol)加至(R)-2-((2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁醯基)氧基)乙酸(1.0g,3.3mmol)在MeCN(10mL)中之溶液,並將混合物在室溫下攪拌10min。接著將混合物在減壓下於30℃濃縮以移除MeCN,及剩餘的水溶液用MTBE洗滌。接著將水溶液在減壓下於30℃濃縮以移除殘留的溶解MTBE,及最後凍乾以產生呈白色固體之(R)-2-((2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁醯基)氧基)乙酸鈉鹽(1.0g,3.1mmol,94%產率)。LCMS(系統2,方法B)m/z323.2(M+H)+(ES+)。1H NMR(400MHz,DMSO-d6)δ:6.18(d,J=0.8Hz,1H),5.75(d,J=0.8Hz,1H),4.82-4.74(m,1H),4.14(d,J=1.2Hz,2H),3.25(s,2H),1.52-1.38(m,2H),1.27-1.23(m,8H),1.13(d,J=6.4Hz,3H),0.85(t,J=6.4Hz,3H)。 Add a solution of NaHCO 3 in water (0.5M, 6.27mL, 3.14mmol) to (R)-2-((2-methylene-4-(oct-2-yloxy)-4- pendant oxy A solution of butanoyl)oxy)acetic acid (1.0 g, 3.3 mmol) in MeCN (10 mL), and the mixture was stirred at room temperature for 10 min. Then the mixture was concentrated under reduced pressure at 30°C to remove MeCN, and the remaining aqueous solution was washed with MTBE. Then the aqueous solution was concentrated under reduced pressure at 30°C to remove the remaining dissolved MTBE, and finally lyophilized to produce (R)-2-((2-methylene-4-(oct-2- Oxy)-4-oxobutanoyl)oxy)acetic acid sodium salt (1.0 g, 3.1 mmol, 94% yield). LCMS (System 2, Method B) m/z 323.2 (M+H) + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ: 6.18(d,J=0.8Hz,1H), 5.75(d,J=0.8Hz,1H), 4.82-4.74(m,1H), 4.14(d,J =1.2Hz,2H),3.25(s,2H),1.52-1.38(m,2H),1.27-1.23(m,8H),1.13(d,J=6.4Hz,3H),0.85(t,J= 6.4Hz, 3H).

實施例22-2-((4-((4,4-二氟環己基)甲氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸 Example 22-2-((4-((4,4-Difluorocyclohexyl)methoxy)-2-methylene-4-oxobutyryl)oxy)acetic acid

Figure 109137209-A0202-12-0069-186
Figure 109137209-A0202-12-0069-186

根據實施例19之程序製備實施例22,但使用4,4-二氟環己醇代替螺[3.3]庚-2-醇。1H NMR(400MHz,DMSO-d6)δ 13.08(s,1H),6.30(d,J=1.2Hz,1H),5.94(d,J=1.3Hz,1H),4.65(s,2H),3.92(d,J=6.1Hz,2H),3.41(s,2H),2.07-1.93(m,2H),1.89-1.68(m,5H),1.28-1.14(m,2H)。LCMS m/z 319.1(M-H)-(ES-)。 Example 22 was prepared according to the procedure of Example 19, but using 4,4-difluorocyclohexanol instead of spiro[3.3]heptan-2-ol. 1 H NMR(400MHz,DMSO-d6)δ 13.08(s,1H), 6.30(d,J=1.2Hz,1H), 5.94(d,J=1.3Hz,1H), 4.65(s,2H), 3.92 (d, J=6.1Hz, 2H), 3.41 (s, 2H), 2.07-1.93 (m, 2H), 1.89-1.68 (m, 5H), 1.28-1.14 (m, 2H). LCMS m / z 319.1 (MH) - (ES -).

實施例23-2-((4-(3-乙氧基丙氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸 Example 23-2-((4-(3-ethoxypropoxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid

Figure 109137209-A0202-12-0069-187
Figure 109137209-A0202-12-0069-187

步驟1 step 1

將EDC.HCl(0.371g,1.935mmol)加至3-((2-(三級丁氧基)-2-側氧基乙氧基)羰基)丁-3-烯酸(中間物9,0.35g,1.29mmol)、3-乙氧基丙-1-醇(0.18mL,1.56mmol)、DMAP(0.016g,0.13mmol)和DIPEA(0.34mL,1.95mmol)在DCM(10mL)中之溶液。將反應混合物在RT下攪拌18h。將反應混合物用水(50mL)稀釋並用DCM(3 x 20mL)萃取。將有機層合併及通過相分離器並在真空中濃縮。將粗製產物藉由層析法(0-10% EtOAc/DCM)以在矽膠上純化提供不純的產物。將粗製產物藉由層析法在矽膠上純化(0-20% EtOAc/DCM)以提供呈無色油之2-亞甲基琥珀酸1-(2-(三級丁氧基)-2-側氧基乙基)酯4-(3-乙氧基丙基)酯(260mg,0.71mmol)。1H NMR(400MHz,DMSO-d6)δ 6.30(d,J=1.2Hz,1H),5.95-5.92(m,1H),4.62(s,2H),4.07(t,J=6.5Hz,2H),3.43-3.35(m,6H),1.82-1.71(m,2H),1.42(s,9H),1.10(t,J=7.0Hz,3H)。LCMS m/z 353.3(M+Na)+(ES+)。 EDC.HCl (0.371g, 1.935mmol) was added to 3-((2-(tertiary butoxy)-2-oxoethoxy)carbonyl)but-3-enoic acid (intermediate 9, 0.35 g, 1.29 mmol), 3-ethoxypropan-1-ol (0.18 mL, 1.56 mmol), DMAP (0.016 g, 0.13 mmol) and DIPEA (0.34 mL, 1.95 mmol) in DCM (10 mL). The reaction mixture was stirred at RT for 18 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3 x 20 mL). The organic layers were combined and passed through a phase separator and concentrated in vacuo. The crude product was purified on silica gel by chromatography (0-10% EtOAc/DCM) to provide an impure product. The crude product was purified by chromatography on silica gel (0-20% EtOAc/DCM) to provide 2-methylenesuccinic acid 1-(2-(tertiary butoxy)-2-side as a colorless oil Oxyethyl) ester 4-(3-ethoxypropyl) ester (260 mg, 0.71 mmol). 1 H NMR(400MHz,DMSO-d6)δ 6.30(d,J=1.2Hz,1H),5.95-5.92(m,1H),4.62(s,2H),4.07(t,J=6.5Hz,2H) ,3.43-3.35(m,6H),1.82-1.71(m,2H),1.42(s,9H),1.10(t,J=7.0Hz,3H). LCMS m/z 353.3 (M+Na) + (ES + ).

步驟2 Step 2

將TFA(2.5mL)加至2-亞甲基琥珀酸1-(2-(三級丁氧基)-2-側氧基乙基)酯4-(3-乙氧基丙基)酯(260mg,0.71mmol)在DCM(2.5mL)中之溶液。將反應混合物攪拌2h,接著濃縮。將粗製產物藉由層析法(5-75% MeCN/水0.1%甲酸)在RP急速C18上接著藉由層析法在矽膠上純化(0-10% MeOH/DCM)以提供呈透明且無色膠之標題化合物(0.015g,0.052mmol)1H NMR(400MHz,DMSO-d6)δ 6.21(d,J=1.5Hz,1H),5.82-5.77(m,1H),4.20(s,2H),4.06(t,J=6.5Hz,2H),3.45-3.36(m,4H),3.34(s,2H),1.82-1.71(m,2H),1.10(t,J=7.0Hz,3H)。LCMS m/z 275.3(M+H)+(ES+)。 TFA (2.5 mL) was added to 2-methylene succinate 1-(2-(tertiary butoxy)-2-oxoethyl) ester 4-(3-ethoxypropyl) ester ( 260 mg, 0.71 mmol) in DCM (2.5 mL). The reaction mixture was stirred for 2 h, then concentrated. The crude product was purified by chromatography (5-75% MeCN/water 0.1% formic acid) on RP rapid C18 followed by chromatography on silica gel (0-10% MeOH/DCM) to provide a transparent and colorless The title compound of the gum (0.015g, 0.052mmol) 1 H NMR (400MHz, DMSO-d6) δ 6.21 (d, J=1.5Hz, 1H), 5.82-5.77 (m, 1H), 4.20 (s, 2H), 4.06(t,J=6.5Hz,2H),3.45-3.36(m,4H), 3.34(s,2H),1.82-1.71(m,2H), 1.10(t,J=7.0Hz,3H). LCMS m/z 275.3 (M+H) + (ES + ).

實施例24-2-((4-(雙環[2.2.1]庚-2-基氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸 Example 24-2-((4-(Bicyclo[2.2.1]heptan-2-yloxy)-2-methylene-4-oxobutyryl)oxy)acetic acid

Figure 109137209-A0202-12-0071-153
Figure 109137209-A0202-12-0071-153

根據實施例23之程序製備實施例24,但使用雙環[2.2.1]庚-2-醇代替3-乙氧基丙-1-醇。1H NMR(400MHz,DMSO-d6)δ 13.10(s,1H),6.27(d,J=1.2Hz,1H),5.96-5.86(m,1H),4.64(s,2H),4.55-4.47(m,1H),3.33(s,2H),2.29-2.17(m,2H),1.69-1.61(m,1H),1.52-1.29(m,4H),1.16-1.03(m,3H)。LCMS m/z 305.2(M+Na)+(ES+)。 Example 24 was prepared according to the procedure of Example 23, but using bicyclo[2.2.1]heptan-2-ol instead of 3-ethoxyprop-1-ol. 1 H NMR (400MHz, DMSO-d6) δ 13.10 (s, 1H), 6.27 (d, J=1.2Hz, 1H), 5.96-5.86 (m, 1H), 4.64 (s, 2H), 4.55-4.47 ( m, 1H), 3.33 (s, 2H), 2.29-2.17 (m, 2H), 1.69-1.61 (m, 1H), 1.52-1.29 (m, 4H), 1.16-1.03 (m, 3H). LCMS m/z 305.2 (M+Na) + (ES + ).

實施例25-2-((4-環丁氧基-2-亞甲基-4-側氧基丁醯基)氧基)乙酸 Example 25-2-((4-Cyclobutoxy-2-methylene-4-oxobutanoyl)oxy)acetic acid

Figure 109137209-A0202-12-0071-91
Figure 109137209-A0202-12-0071-91

根據實施例23之程序製備實施例25,但使用環丁醇代替3-乙氧基丙-1-醇。1H NMR(400MHz,DMSO-d6)δ 13.08(s,1H),6.29(s,1H),5.92(d,J=1.5Hz,1H),4.89(p,J=7.4Hz,1H),4.65(s,2H),3.36(s,2H),2.30-2.19(m,2H),2.06-1.92(m,2H),1.79-1.68(m,1H),1.65-1.50(m,1H)。LCMS m/z 265.1(M+Na)+(ES+)。 Example 25 was prepared according to the procedure of Example 23, but using cyclobutanol instead of 3-ethoxyprop-1-ol. 1 H NMR(400MHz,DMSO-d6)δ 13.08(s,1H), 6.29(s,1H), 5.92(d,J=1.5Hz,1H), 4.89(p,J=7.4Hz,1H), 4.65 (s, 2H), 3.36 (s, 2H), 2.30-2.19 (m, 2H), 2.06-1.92 (m, 2H), 1.79-1.68 (m, 1H), 1.65-1.50 (m, 1H). LCMS m/z 265.1 (M+Na) + (ES + ).

實施例26-2-((4-(環己氧基)-2-亞甲基-4-側氧基丁醯基)氧基)-3,3,3-三氟丙酸 Example 26-2-((4-(cyclohexyloxy)-2-methylene-4-oxobutanoyl)oxy)-3,3,3-trifluoropropionic acid

Figure 109137209-A0202-12-0071-90
Figure 109137209-A0202-12-0071-90

步驟1 step 1

將1-(氯甲基)-4-甲氧基苯(0.90mL,6.64mmol)加至3,3,3-三氟-2-羥基丙酸(1.00g,6.94mmol)和碳酸銫(2.26g,6.94mmol)在二甲基甲醯胺(30mL)中之 混合物。將混合物在RT下攪拌3h,接著加熱至70℃經2h,接著冷卻至RT並攪拌18h。將混合物倒入水(50mL)並用EtOAc(3 x 50mL)萃取。將合併的有機相用鹽水洗滌(100mL),乾燥(MgSO4)及濃縮。將粗製產物藉由層析法在矽膠上純化(0-50% EtOAc/異己烷)以提供呈無色油之3,3,3-三氟-2-羥基丙酸4-甲氧基苯甲基酯(640mg,2.30mmol)。1H NMR(400MHz,DMSO-d6)δ 7.36-7.30(m,2H),7.14(d,J=7.4Hz,1H),7.00-6.91(m,2H),5.22-5.14(m,2H),4.92-4.83(m,1H),3.76(s,3H)。 Add 1-(chloromethyl)-4-methoxybenzene (0.90mL, 6.64mmol) to 3,3,3-trifluoro-2-hydroxypropionic acid (1.00g, 6.94mmol) and cesium carbonate (2.26 g, 6.94 mmol) in dimethylformamide (30 mL). The mixture was stirred at RT for 3h, then heated to 70°C for 2h, then cooled to RT and stirred for 18h. The mixture was poured into water (50 mL) and extracted with EtOAc (3 x 50 mL). The organic phase was washed with brine (100mL), dried (MgSO 4) and concentrated. The crude product was purified by chromatography on silica gel (0-50% EtOAc/isohexane) to provide 3,3,3-trifluoro-2-hydroxypropionic acid 4-methoxybenzyl as a colorless oil Esters (640 mg, 2.30 mmol). 1 H NMR (400MHz, DMSO-d6) δ 7.36-7.30 (m, 2H), 7.14 (d, J=7.4Hz, 1H), 7.00-6.91 (m, 2H), 5.22-5.14 (m, 2H), 4.92-4.83 (m, 1H), 3.76 (s, 3H).

步驟2 Step 2

在0℃下將EDC.HCl(0.348g,1.81mmol)加至4-(環己氧基)-2-亞甲基-4-側氧基丁酸(中間物4,0.35g,1.65mmol)、3,3,3-三氟-2-羥基丙酸4-甲氧基苯甲基酯(0.523g,1.98mmol)、DMAP(0.020g,0.17mmol)和DIPEA(0.43mL,2.47mmol)在DCM(8mL)中之溶液。使反應混合物加熱至RT並攪拌72h。將反應混合物用1MHCl(30mL)稀釋。分離該等相並將水相用DCM(10mL)萃取。將合併的有機相用鹽水洗滌(30mL),乾燥(MgSO4)及濃縮。將粗製產物藉由層析法在矽膠上純化(0-20% EtOAc/異己烷)以提供呈無色油之2-亞甲基琥珀酸4-環己基酯1-(1,1,1-三氟-3-((4-甲氧基苯甲基)氧基)-3-側氧基丙-2-基酯(302mg,0.593mmol)。1H NMR(400MHz,DMSO-d6)δ 7.34-7.29(m,2H),6.98-6.92(m,2H),6.36(d,J=0.9Hz,1H),6.15(q,J=7.3Hz,1H),6.06(d,J=1.1Hz,1H),5.23(s,2H),4.70-4.61(m,1H),3.76(s,3H),3.41(s,2H),1.79-1.71(m,2H),1.68-1.59(m,2H),1.54-1.42(m,1H),1.41-1.21(m,5H)。LCMS m/z 481.3(M+Na)+(ES+)。 Add EDC.HCl (0.348g, 1.81mmol) to 4-(cyclohexyloxy)-2-methylene-4-oxobutyric acid (intermediate 4, 0.35g, 1.65mmol) at 0°C , 3,3,3-trifluoro-2-hydroxypropionic acid 4-methoxybenzyl ester (0.523g, 1.98mmol), DMAP (0.020g, 0.17mmol) and DIPEA (0.43mL, 2.47mmol) in Solution in DCM (8 mL). The reaction mixture was heated to RT and stirred for 72 h. The reaction mixture was diluted with 1M HCl (30 mL). The phases were separated and the aqueous phase was extracted with DCM (10 mL). The organic phase was washed with brine (30mL), dried (MgSO 4) and concentrated. The crude product was purified by chromatography on silica gel (0-20% EtOAc/isohexane) to provide 2-methylenesuccinate 4-cyclohexyl ester 1-(1,1,1-tris) as a colorless oil Fluoro-3-((4-methoxybenzyl)oxy)-3 -oxoprop-2-yl ester (302mg, 0.593mmol). 1 H NMR (400MHz, DMSO-d6) δ 7.34- 7.29(m,2H),6.98-6.92(m,2H),6.36(d,J=0.9Hz,1H),6.15(q,J=7.3Hz,1H),6.06(d,J=1.1Hz,1H ), 5.23 (s, 2H), 4.70-4.61 (m, 1H), 3.76 (s, 3H), 3.41 (s, 2H), 1.79-1.71 (m, 2H), 1.68-1.59 (m, 2H), 1.54-1.42 (m, 1H), 1.41-1.21 (m, 5H). LCMS m/z 481.3 (M+Na) + (ES + ).

步驟3 Step 3

將TFA(1mL)加至2-亞甲基琥珀酸4-環己基酯1-(1,1,1-三氟-3-((4-甲氧基苯甲基)氧基)-3-側氧基丙-2-基酯(302mg,0.659mmol)在DCM(2mL)中之溶液。將反應混合物攪拌1h,用甲苯(5mL)稀釋及濃縮。將粗製產物藉由層析法在矽膠 上純化(0-60% EtOAc/異己烷)以提供呈無色油之標題化合物(38mg,0.107mmol,16.20%產率)。1H NMR(400MHz,DMSO-d6)δ 14.49(br.s,1H),6.35(d,J=0.9Hz,1H),6.04(d,J=1.1Hz,1H),5.87(q,J=7.6Hz,1H),4.70-4.60(m,1H),3.47-3.35(m,2H),1.80-1.71(m,2H),1.69-1.58(m,2H),1.52-1.43(m,1H),1.42-1.18(m,5H)。LCMS m/z 337.2(M-H)-(ES-)。 Add TFA (1mL) to 4-cyclohexyl 2-methylenesuccinate 1-(1,1,1-trifluoro-3-((4-methoxybenzyl)oxy)-3- A solution of pendant oxyprop-2-yl ester (302 mg, 0.659 mmol) in DCM (2 mL). The reaction mixture was stirred for 1 h, diluted with toluene (5 mL) and concentrated. The crude product was chromatographed on silica gel Purification (0-60% EtOAc/isohexane) to provide the title compound (38 mg, 0.107 mmol, 16.20% yield) as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ 14.49 (br.s, 1H) ,6.35(d,J=0.9Hz,1H),6.04(d,J=1.1Hz,1H),5.87(q,J=7.6Hz,1H),4.70-4.60(m,1H),3.47-3.35( m,2H),1.80-1.71(m,2H),1.69-1.58(m,2H),1.52-1.43(m,1H),1.42-1.18(m,5H).LCMS m/z 337.2(MH) - (ES -).

實施例27-2-((4-(環辛氧基)-2-亞甲基-4-側氧基丁醯基)氧基)-3,3,3-三氟丙酸 Example 27-2-((4-(cyclooctyloxy)-2-methylene-4-oxobutanoyl)oxy)-3,3,3-trifluoropropionic acid

Figure 109137209-A0202-12-0073-189
Figure 109137209-A0202-12-0073-189

根據實施例26之程序製備實施例27,但使用4-(環辛氧基)-2-亞甲基-4-側氧基丁酸(中間物1)代替4-(環己氧基)-2-亞甲基-4-側氧基丁酸。1H NMR(400MHz,DMSO-d6)δ 14.47(s,1H),6.34(s,1H),6.03(s,1H),5.86(q,J=7.6Hz,1H),4.82(tt,J=8.2,4.0Hz,1H),3.37(d,J=2.1Hz,2H),1.80-1.32(m,12H)。LCMS m/z 390.0(M+H)+(ES+)。 Example 27 was prepared according to the procedure of Example 26, but using 4-(cyclooctyloxy)-2-methylene-4-oxobutanoic acid (Intermediate 1) instead of 4-(cyclohexyloxy)- 2-methylene-4-oxobutanoic acid. 1 H NMR(400MHz,DMSO-d6)δ 14.47(s,1H), 6.34(s,1H), 6.03(s,1H), 5.86(q,J=7.6Hz,1H), 4.82(tt,J= 8.2, 4.0 Hz, 1H), 3.37 (d, J = 2.1 Hz, 2H), 1.80-1.32 (m, 12H). LCMS m/z 390.0 (M+H) + (ES + ).

實施例28-3-((4-(環辛氧基)-2-亞甲基-4-側氧基丁醯基)氧基)-4,4,4-三氟丁酸 Example 28-3-((4-(cyclooctyloxy)-2-methylene-4-oxobutanoyl)oxy)-4,4,4-trifluorobutyric acid

Figure 109137209-A0202-12-0073-190
Figure 109137209-A0202-12-0073-190

步驟1 step 1

將1-(氯甲基)-4-甲氧基苯(0.86mL,6.3mmol)加至4,4,4-三氟-3-羥基丁酸(1.00g,6.33mmol)和碳酸銫(2.06g,6.33mmol)在DMF(27mL)中之混合物。將混合物在RT下攪拌1h,接著加熱至70℃經2h。將混合物冷卻至RT並攪拌18h。將混合物倒入水(50mL)中並用EtOAc(3 x 50mL)萃取。將合併的有機相用鹽水(100mL)洗滌,乾燥(MgSO4)及濃縮。將粗製產物藉由層析在矽膠上純化法(0-100% EtOAc/異己烷)以提供呈無色油之4,4,4-三氟-3-羥基丁酸4-甲氧基苯甲基酯(0.283g,0.97mmol)。1H NMR(400MHz,DMSO-d6)δ 7.37-7.26(m,2H),6.98-6.87(m,2H),6.58(d,J=6.7Hz,1H),5.08(d,J=13.5Hz,1H),5.05(d,J=13.6Hz,1H),4.35(dtt,J=17.3,7.2,3.3Hz,1H),3.75(s,3H),2.77(dd,J=15.8,3.3Hz,1H),2.57-2.52(m,1H)。 Add 1-(chloromethyl)-4-methoxybenzene (0.86mL, 6.3mmol) to 4,4,4-trifluoro-3-hydroxybutyric acid (1.00g, 6.33mmol) and cesium carbonate (2.06 g, 6.33 mmol) in DMF (27 mL). The mixture was stirred at RT for 1 h, and then heated to 70 °C for 2 h. The mixture was cooled to RT and stirred for 18h. The mixture was poured into water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phase was washed with brine (100 mL), dried (MgSO4) and concentrated. The crude product was purified by chromatography on silica gel (0-100% EtOAc/isohexane) to provide 4,4,4-trifluoro-3-hydroxybutyric acid 4-methoxybenzyl as a colorless oil Esters (0.283 g, 0.97 mmol). 1H NMR(400MHz,DMSO-d6)δ 7.37-7.26(m,2H), 6.98-6.87(m,2H), 6.58(d,J=6.7Hz,1H), 5.08(d,J=13.5Hz,1H ),5.05(d,J=13.6Hz,1H), 4.35(dtt,J=17.3,7.2,3.3Hz,1H), 3.75(s,3H),2.77(dd,J=15.8,3.3Hz,1H) , 2.57-2.52 (m, 1H).

步驟2 Step 2

在0℃下將N-(3-二甲胺基丙基)-N'-乙基碳二亞胺鹽酸鹽(0.28g,1.5mmol)在DCM(1.6mL)中之漿料慢慢地加至4-(環辛氧基)-2-亞甲基-4-側氧基丁酸(0.233g,0.97mmol)、4,4,4-三氟-3-羥基丁酸4-甲氧基苯甲基酯(0.283g,0.97mmol)、DIPEA(0.25mL,1.5mmol)和DMAP(0.012g,0.097mmol)在DCM(1.6mL)中之溶液。使混合物慢慢地加熱至RT並攪拌18h。將混合物用1MHCl(10mL)稀釋並用EtOAc(3 x 10mL)萃取。將合併的有機相用鹽水洗滌(15mL),乾燥(Na2SO4)及濃縮。將粗製產物藉由層析法在矽膠上純化(0-50% EtOAc/異己烷)以提供呈無色油之2-亞甲基琥珀酸4-環辛基酯1-(1,1,1-三氟-4-((4-甲氧基苯甲基)氧基)-4-側氧基丁-2-基)酯(0.304g,0.56mmol)。LCMS m/z 523.2(M+Na)+(ES+)。1H NMR(400MHz,DMSO-d6)δ 7.34-7.22(m,2H),6.96-6.85(m,2H),6.23(d,J=1.0Hz,1H),5.93(d,J=1.1Hz,1H),5.81(dqd,J=10.3,6.7,3.6Hz,1H),5.04(s,2H),4.80(tt,J=8.2,4.0Hz,1H),3.75(s,3H),3.31(s,2H),3.10(dd,J=16.8,3.6Hz,1H),2.87(dd,J=16.8,9.5Hz,1H),1.78-1.33(m,14H)。 The at 0 ℃ N- (3- dimethylaminopropyl) -N '- in the ethylcarbodiimide hydrochloride (0.28g, 1.5mmol) in DCM (1.6mL) slowly slurry Add to 4-(cyclooctyloxy)-2-methylene-4-oxobutyric acid (0.233g, 0.97mmol), 4,4,4-trifluoro-3-hydroxybutyric acid 4-methoxy A solution of benzyl ester (0.283 g, 0.97 mmol), DIPEA (0.25 mL, 1.5 mmol) and DMAP (0.012 g, 0.097 mmol) in DCM (1.6 mL). The mixture was slowly heated to RT and stirred for 18h. The mixture was diluted with 1M HCl (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phase was washed with brine (15 mL), dried (Na2SO4) and concentrated. The crude product was purified by chromatography on silica gel (0-50% EtOAc/isohexane) to provide 2-methylenesuccinate 4-cyclooctyl ester 1-(1,1,1- Trifluoro-4-((4-methoxybenzyl)oxy)-4-oxobut-2-yl) ester (0.304 g, 0.56 mmol). LCMS m/z 523.2 (M+Na)+ (ES+). 1H NMR(400MHz,DMSO-d6)δ 7.34-7.22(m,2H), 6.96-6.85(m,2H), 6.23(d,J=1.0Hz,1H), 5.93(d,J=1.1Hz,1H ), 5.81(dqd,J=10.3,6.7,3.6Hz,1H),5.04(s,2H),4.80(tt,J=8.2,4.0Hz,1H),3.75(s,3H),3.31(s, 2H), 3.10 (dd, J=16.8, 3.6 Hz, 1H), 2.87 (dd, J=16.8, 9.5 Hz, 1H), 1.78-1.33 (m, 14H).

步驟3 Step 3

在0℃下將三氟乙酸(1.4mL)加至2-亞甲基琥珀酸4-環辛基酯1-(1,1,1-三氟-4-((4-甲氧基苯甲基)氧基)-4-側氧基丁-2-基)酯(0.304g,0.56mmol)在DCM(5mL)中之溶液。將反應混合物加熱至RT,攪拌30min及濃縮。將殘餘物與甲苯(2 x 10mL)一起共蒸發。將粗製產物藉由層析法在矽膠上純化(0-50% EtOAc/DCM)以提供呈無色油之3-((4-(環辛氧基)-2-亞甲基-4-側氧基丁醯基)氧基)-4,4,4-三氟丁酸(0.127g,0.32mmol)。LCMS m/z 403.3(M+Na)+(ES+)。1H NMR(400MHz,DMSO-d6)δ 12.84(s,1H),6.29(d,J=1.1Hz,1H),5.96(d,J=1.2Hz,1H),5.83-5.71(m,1H),4.82(tt,J=8.1,3.9Hz,1H),3.35(s,2H),2.96(dd,J=16.9,3.8Hz,1H),2.74(dd,J=16.9,9.2Hz,1H),1.79-1.34(m,14H)。 Add trifluoroacetic acid (1.4 mL) to 4-cyclooctyl 2-methylenesuccinate 1-(1,1,1-trifluoro-4-((4-methoxybenzyl) at 0°C A solution of oxy)-4-oxobut-2-yl) ester (0.304 g, 0.56 mmol) in DCM (5 mL). The reaction mixture was heated to RT, stirred for 30 min and concentrated. The residue was co-evaporated with toluene (2 x 10 mL). The crude product was purified by chromatography on silica gel (0-50% EtOAc/DCM) to provide 3-((4-(cyclooctyloxy)-2-methylene-4- pendant oxygen as a colorless oil (Butyryl)oxy)-4,4,4-trifluorobutyric acid (0.127 g, 0.32 mmol). LCMS m/z 403.3 (M+Na)+ (ES+). 1H NMR(400MHz,DMSO-d6)δ 12.84(s,1H), 6.29(d,J=1.1Hz,1H), 5.96(d,J=1.2Hz,1H),5.83-5.71(m,1H), 4.82(tt,J=8.1,3.9Hz,1H), 3.35(s,2H), 2.96(dd,J=16.9,3.8Hz,1H), 2.74(dd,J=16.9,9.2Hz,1H), 1.79 -1.34(m,14H).

實施例29-2-(4-(環庚氧基)-2-亞甲基-4-側氧基丁醯氧基)乙酸 Example 29-2-(4-(cycloheptyloxy)-2-methylene-4-oxobutanoyloxy)acetic acid

Figure 109137209-A0202-12-0075-191
Figure 109137209-A0202-12-0075-191

步驟1 step 1

在0℃下將EDC.HCl(276mg,1.44mmol)加至3-((2-三級丁氧基-2-側氧基乙氧基)羰基)丁-3-烯酸(234mg,0.96mmol)、環庚醇(110mg,0.96mmol)和DMAP(117mg,0.96mmol)在DCM(4mL)中之溶液,並將所得混合物在室溫下攪拌1h。將混合物用NH4Cl(2mL)水溶液淬滅,分離該等相,將水相用DCM(2 x 3mL)萃取。將合併的有機相用鹽水洗滌,用Na2SO4乾燥及過濾。將濾液在減壓下於40℃濃縮,及藉由急速管柱層析法純化(25g二氧化矽,0-10% MTBE/石油醚)將殘餘物以產生呈淺黃色油之2-亞甲基琥珀酸1-(2-三級丁氧基-2-側氧基乙基酯4- 環庚基酯(130mg,0.38mmol,40%)。LCMS(系統2,方法B)m/z 363.3(M+Na)+(ES+)。 Add EDC.HCl (276mg, 1.44mmol) to 3-((2-tertiary butoxy-2-oxoethoxy)carbonyl)but-3-enoic acid (234mg, 0.96mmol) at 0°C ), a solution of cycloheptanol (110 mg, 0.96 mmol) and DMAP (117 mg, 0.96 mmol) in DCM (4 mL), and the resulting mixture was stirred at room temperature for 1 h. The mixture was quenched with aqueous NH 4 Cl (2 mL), the phases were separated, and the aqueous phase was extracted with DCM (2 x 3 mL). The combined organic phase was washed with brine, dried over Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure at 40°C, and purified by flash column chromatography (25g silica, 0-10% MTBE/petroleum ether) to produce 2-methylene as a pale yellow oil 1-(2-tertiary butoxy-2-oxoethyl ester 4-cycloheptyl succinate (130 mg, 0.38 mmol, 40%). LCMS (System 2, Method B) m/z 363.3 (M+Na) + (ES + ).

步驟2 Step 2

將2-亞甲基琥珀酸1-(2-三級丁氧基-2-側氧基乙基酯4-環庚基酯(130mg,0.38mmol)和在1,4-二

Figure 109137209-A0202-12-0076-157
烷之HCl溶液(4M,3mL,12mmol)在DCM(2mL)中的混合物在室溫下攪拌4h。將混合物在減壓下於40℃濃縮,並將殘餘物藉由製備型HPLC純化(管柱:Waters X-Bridge C18 OBD10μm 19 x 250mm;流速:20mL/min;溶劑系統:MeCN/(0.05% TFA/水);梯度:15-95% MeCN;收集波長:214nm)。將收集的部分在減壓下於40℃濃縮以移除MeCN,並將殘餘物凍乾以產生呈淺黃色油之2-(4-(環庚氧基)-2-亞甲基-4-側氧基丁醯氧基)乙酸(76mg,0.27mmol,70%)。LCMS(系統2,方法B)m/z 307.1(M+Na)+(ES+)。1H NMR(400MHz,DMSO-d6)δ:13.06(br,1H),6.27(d,J=0.8Hz,1H),5.91(d,J=0.8Hz,1H),4.83-4.78(m,1H),4.63(s,2H),3.33(s,2H),1.83-1.76(m,2H),1.62-1.51(m,4H),1.50-1.48(m,4H),1.42-1.37(m,2H)。 Combine 2-methylenesuccinic acid 1-(2-tertiary butoxy-2-oxoethyl ester 4-cycloheptyl ester (130mg, 0.38mmol) and in 1,4-di
Figure 109137209-A0202-12-0076-157
A mixture of alkane HCl solution (4M, 3 mL, 12 mmol) in DCM (2 mL) was stirred at room temperature for 4 h. The mixture was concentrated under reduced pressure at 40°C, and the residue was purified by preparative HPLC (column: Waters X-Bridge C18 OBD 10μm 19 x 250mm; flow rate: 20 mL/min; solvent system: MeCN/(0.05% TFA) /Water); gradient: 15-95% MeCN; collection wavelength: 214nm). The collected fractions were concentrated under reduced pressure at 40°C to remove MeCN, and the residue was lyophilized to give 2-(4-(cycloheptyloxy)-2-methylene-4- Pendant oxybutyroxy) acetic acid (76 mg, 0.27 mmol, 70%). LCMS (System 2, Method B) m/z 307.1 (M+Na) + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ: 13.06(br,1H), 6.27(d,J=0.8Hz,1H), 5.91(d,J=0.8Hz,1H),4.83-4.78(m,1H ), 4.63 (s, 2H), 3.33 (s, 2H), 1.83-1.76 (m, 2H), 1.62-1.51 (m, 4H), 1.50-1.48 (m, 4H), 1.42-1.37 (m, 2H) ).

使用類似的程序製造下列化合物: Use similar procedures to make the following compounds:

Figure 109137209-A0202-12-0076-96
Figure 109137209-A0202-12-0076-96

Figure 109137209-A0202-12-0077-97
Figure 109137209-A0202-12-0077-97

Figure 109137209-A0202-12-0078-98
Figure 109137209-A0202-12-0078-98

Figure 109137209-A0202-12-0079-99
Figure 109137209-A0202-12-0079-99

Figure 109137209-A0202-12-0080-100
Figure 109137209-A0202-12-0080-100

Figure 109137209-A0202-12-0081-101
Figure 109137209-A0202-12-0081-101

實施例40-2-((4-(環辛氧基)-3-甲基-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00843] Example 40-2-((4-(cyclooctyloxy)-3-methyl-2-methylene-4-oxobutyryl)oxy)acetic acid [SYX-00843]

Figure 109137209-A0202-12-0081-192
Figure 109137209-A0202-12-0081-192

步驟1 step 1

將LDA在THF/正庚/乙基苯之溶液(2M,2.38mL,4.76mmol)加至4-(環辛氧基)-2-亞甲基-4-側氧基丁酸(570mg,2.38mmol)在THF(10mL)中在-78℃下之溶液,並將反應混合物在-78℃下攪拌1h。接著在-78℃下添加碘甲烷(338mg,2.38mmol),並將反應混合物在-78℃下攪拌2h。將反應混合物用稀HCl水溶液(0.5M,20mL)淬滅並用EtOAc(2 x 20mL)萃取。將合併的有機相用Na2SO4乾燥,過濾及將濾液在減壓下於35℃濃縮以產生呈無色油之粗製4-(環辛氧基)-3-甲基-2-亞甲基-4-側氧基丁酸(550mg,2.16mmol,91%),將其使用在下一步驟中而無需純化。LCMS(系統2,方法C)m/z 277.4(M+Na)+(ES+)。 A solution of LDA in THF/n-heptane/ethylbenzene (2M, 2.38mL, 4.76mmol) was added to 4-(cyclooctyloxy)-2-methylene-4-oxobutanoic acid (570mg, 2.38 mmol) in THF (10 mL) at -78°C, and the reaction mixture was stirred at -78°C for 1 h. Then iodomethane (338 mg, 2.38 mmol) was added at -78°C, and the reaction mixture was stirred at -78°C for 2 h. The reaction mixture was quenched with dilute aqueous HCl (0.5M, 20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phase was dried with Na 2 SO 4 , filtered and the filtrate was concentrated under reduced pressure at 35°C to give crude 4-(cyclooctyloxy)-3-methyl-2-methylene as a colorless oil -4-oxobutyric acid (550 mg, 2.16 mmol, 91%), which was used in the next step without purification. LCMS (System 2, Method C) m/z 277.4 (M+Na) + (ES + ).

步驟2 Step 2

將碳酸鉀(329mg,2.39mmol)加至4-(環辛氧基)-3-甲基-2-亞甲基-4-側氧基丁酸(550mg,2.16mmol)在丙酮(10mL)中之溶液,並將反應混合物在室溫下攪拌30min。接著添加2-溴乙酸三級丁酯(464mg,2.39mmol)並將所得混合物在室溫下攪拌過夜。將反應混合物過濾並在減壓下於40℃濃縮濾液。將殘餘物藉由急速管柱層析法純化(25g二氧化矽,0-10%MTBE/石油醚)以產生呈黃色油之3-甲基-2-亞甲基琥珀酸1-(2-(三級丁氧基)-2-側氧基乙基)酯4-環辛基酯(380mg,1.0mmol,48%)。LCMS(系統2,方法B)m/z 391.3(M+Na)+(ES+)。 Potassium carbonate (329mg, 2.39mmol) was added to 4-(cyclooctyloxy)-3-methyl-2-methylene-4-oxobutanoic acid (550mg, 2.16mmol) in acetone (10mL) , And the reaction mixture was stirred at room temperature for 30 min. Then tert-butyl 2-bromoacetate (464 mg, 2.39 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated at 40°C under reduced pressure. The residue was purified by flash column chromatography (25g silica, 0-10% MTBE/petroleum ether) to produce 3-methyl-2-methylenesuccinic acid 1-(2- (Tertiary butoxy)-2-oxoethyl) ester 4-cyclooctyl ester (380 mg, 1.0 mmol, 48%). LCMS (System 2, Method B) m/z 391.3 (M+Na) + (ES + ).

步驟3 Step 3

將3-甲基-2-亞甲基琥珀酸1-(2-(三級丁氧基)-2-側氧基乙基)酯4-環辛基酯(180mg,0.49mmol)和在1,4-二

Figure 109137209-A0202-12-0082-158
烷中之HCl溶液(4M,2mL,8.0mmol)在DCM(2mL)中的混合物在室溫下攪拌4h,接著在減壓下於40℃濃縮。將殘餘物藉由製備型HPLC純化(管柱:Waters X-Bridge C18 OBD 10μm 19 x 250mm;流速:20mL/min;溶劑系統:MeCN/(0.05% TFA/水)梯度:30-95% MeCN;收集波長:214nm)。將該等部分在減壓下於40℃濃縮以移除MeCN,並將殘餘物凍乾以產生呈淺黃色油之2-((4-(環辛氧基)-3-甲基-2-亞甲基-4-側氧基丁醯基)氧基)乙酸(117mg,0.37mmol,77%)。 Combine 3-methyl-2-methylene succinic acid 1-(2-(tertiary butoxy)-2-oxoethyl) ester 4-cyclooctyl ester (180mg, 0.49mmol) in 1 ,4-two
Figure 109137209-A0202-12-0082-158
A mixture of HCl solution in alkane (4M, 2 mL, 8.0 mmol) in DCM (2 mL) was stirred at room temperature for 4 h, and then concentrated under reduced pressure at 40°C. The residue was purified by preparative HPLC (column: Waters X-Bridge C18 OBD 10μm 19 x 250mm; flow rate: 20mL/min; solvent system: MeCN/(0.05% TFA/water) gradient: 30-95% MeCN; Collection wavelength: 214nm). The fractions were concentrated under reduced pressure at 40°C to remove MeCN, and the residue was lyophilized to give 2-((4-(cyclooctyloxy)-3-methyl-2- Methylene-4-oxobutanoyl)oxy)acetic acid (117 mg, 0.37 mmol, 77%).

LCMS(系統2,方法B)m/z 335.2(M+Na)+(ES+)。1H NMR(400MHz,DMSO-d6)δ:13.10(br,1H),6.28(s,1H),5.85(s,1H),4.82-4.76(m,1H),4.64(d,J=1.6Hz,2H),3.51(q,J=6.8Hz,1H),1.70-1.62(m,6H),1.55-1.41(m,8H),1.27(d,J=7.2Hz,3H)。 LCMS (System 2, Method B) m/z 335.2 (M+Na) + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ: 13.10(br,1H), 6.28(s,1H), 5.85(s,1H), 4.82-4.76(m,1H), 4.64(d,J=1.6Hz ,2H),3.51(q,J=6.8Hz,1H),1.70-1.62(m,6H),1.55-1.41(m,8H),1.27(d,J=7.2Hz,3H).

實施例43-2-((4-(環辛氧基)-3-甲氧基-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00880] Example 43-2-((4-(Cyclooctyloxy)-3-methoxy-2-methylene-4-oxobutyryl)oxy)acetic acid [SYX-00880]

Figure 109137209-A0202-12-0083-103
Figure 109137209-A0202-12-0083-103

步驟1 step 1

將(2R,3R)-2,3-二羥基琥珀酸(3g,20mmol)、環辛醇(7.7g,60mmol)、無水對甲苯磺酸(344mg,2mmol)和無水Na2SO4(6g,42.2mmol)在甲苯(40mL)中的混合物在80℃下攪拌16h。將反應混合物冷卻至室溫及過濾。將濾液在減壓下於45℃濃縮並將殘餘物藉由逆相管柱層析法純化(120g C18二氧化矽;流速:40mL/min;50-70% MeCN/(10mM HCl/水);收集波長:214nm)。將收集的部分在減壓下於40℃濃縮以移除MeCN,並將殘餘物凍乾以產生呈白色固體之(2R,3R)-2,3-二羥基琥珀酸二環辛基酯(3.5g,9.4mmol,47%)。LCMS(系統2,方法B)m/z 393.3(M+Na)+(ES+)。1H NMR(400MHz,DMSO-d6)δ:5.38(d,J=8.0Hz,2H),4.90-4.86(m,2H),4.32(d,J=7.6Hz,2H),1.77-1.65(m,12H),1.58-1.49(m,16H)。 (2R,3R)-2,3-dihydroxysuccinic acid (3g, 20mmol), cyclooctanol (7.7g, 60mmol), anhydrous p-toluenesulfonic acid (344mg, 2mmol) and anhydrous Na 2 SO 4 (6g, A mixture of 42.2 mmol) in toluene (40 mL) was stirred at 80°C for 16 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure at 45°C and the residue was purified by reverse phase column chromatography (120g C18 silica; flow rate: 40mL/min; 50-70% MeCN/(10mM HCl/water); Collection wavelength: 214nm). The collected fraction was concentrated under reduced pressure at 40°C to remove MeCN, and the residue was lyophilized to give (2R,3R)-2,3-dihydroxysuccinic acid dicyclooctyl ester (3.5 g, 9.4 mmol, 47%). LCMS (System 2, Method B) m/z 393.3 (M+Na) + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ: 5.38(d,J=8.0Hz,2H), 4.90-4.86(m,2H), 4.32(d,J=7.6Hz,2H),1.77-1.65(m ,12H),1.58-1.49(m,16H).

步驟2 Step 2

在室溫下將NaIO4(2.3g,18.8mmol)加至(2R,3R)-2,3-二羥基琥珀酸二環辛基酯(3.5g,9.4mmol)在THF:H2O(2:1,40mL)中之溶液,並將反應混合物在室溫下攪拌2h。將反應混合物過濾,將濾液用EtOAc(30mL)稀釋,用Na2S2O3飽和水溶液淬滅,及分離。將有機層用NaHCO3飽和水溶液洗滌,用Na2SO4乾燥, 過濾及在減壓下於30℃濃縮。將殘餘物藉由急速管柱層析法純化(40g二氧化矽,0-20% EtOAc/石油醚)以之產生呈淺黃色油粗製2-側氧基乙酸環辛基酯(3g,16.3mmol,87%),將其直接使用於下一步驟。1H NMR(400MHz,CDCl3)δ:9.39(s,1H),5.08-5.03(m,1H),1.91-1.68(m,6H),1.60-1.58(m,8H)。 NaIO 4 (2.3g, 18.8mmol) was added to (2R,3R)-2,3-dihydroxysuccinic acid dicyclooctyl ester (3.5g, 9.4mmol) at room temperature in THF: H 2 O (2 :1, 40 mL), and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was filtered, the filtrate was diluted with EtOAc (30 mL), quenched with saturated aqueous Na 2 S 2 O 3, and separated. The organic layer was washed with saturated aqueous NaHCO 3 solution, dried with Na 2 SO 4 , filtered and concentrated at 30° C. under reduced pressure. The residue was purified by flash column chromatography (40g silica, 0-20% EtOAc/petroleum ether) to produce crude 2-oxoacetate cyclooctyl ester (3g, 16.3mmol) as a pale yellow oil , 87%), use it directly in the next step. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.39 (s, 1H), 5.08-5.03 (m, 1H), 1.91-1.68 (m, 6H), 1.60-1.58 (m, 8H).

步驟3 Step 3

將2-側氧基乙酸環辛基酯(3g,16.3mmol)、丙烯酸三級丁酯(3.1g,24.4mmol)和DABCO(914mg,8.1mmol)在1,4-二

Figure 109137209-A0202-12-0084-159
烷/DMSO/H2O的溶劑混合物(20mL,8/2/1)中的混合物在室溫下攪拌48h。將反應混合物過濾並將濾液在減壓下於50℃濃縮。將殘餘物藉由逆相管柱層析法純化(120g C18二氧化矽;流速:40mL/min;50-70% MeCN/H2O;收集波長:214nm)。將收集的部分在減壓下於40℃濃縮以移除MeCN,並將殘餘物凍乾以產生呈黃色油之3-羥基-2-亞甲基琥珀酸1-(三級丁基)酯4-環辛基酯(2.3g,7.4mmol,45%)。LCMS(系統2,方法B)m/z 335.2(M+Na)+(ES+)。 The cyclooctyl 2-oxoacetate (3g, 16.3mmol), tertiary butyl acrylate (3.1g, 24.4mmol) and DABCO (914mg, 8.1mmol) in 1,4-two
Figure 109137209-A0202-12-0084-159
The mixture in a solvent mixture of alkane/DMSO/H 2 O (20 mL, 8/2/1) was stirred at room temperature for 48 h. The reaction mixture was filtered and the filtrate was concentrated at 50°C under reduced pressure. The residue was purified by reverse phase column chromatography (120 g C18 silica; flow rate: 40 mL/min; 50-70% MeCN/H 2 O; collection wavelength: 214 nm). The collected fraction was concentrated under reduced pressure at 40°C to remove MeCN, and the residue was lyophilized to give 3-hydroxy-2-methylenesuccinate 1-(tertiarybutyl) ester 4 as a yellow oil -Cyclooctyl ester (2.3 g, 7.4 mmol, 45%). LCMS (System 2, Method B) m/z 335.2 (M+Na) + (ES + ).

步驟4 Step 4

將碘甲烷(818mg,5.76mmol)加至3-羥基-2-亞甲基琥珀酸1-(三級丁基)酯4-環辛基酯(300mg,0.96mmol)和Ag2O(445mg,1.92mmol)在DCM(1mL)中之混合物,並將反應混合物在40℃下攪拌16h。將混合物過濾及將濾液在減壓下於30℃濃縮以分別產生粗製產物呈3-甲氧基-2-亞甲基琥珀酸1-(三級丁基)酯4-環辛基酯及3-甲氧基-2-甲基延胡索酸1-(三級丁基酯)4-環辛基酯的5:1混合物。將粗製產物藉由急速管柱層析法純化(25g二氧化矽,0-10% MTBE/石油醚)以產生呈淺黃色油之純3-甲氧基-2-亞甲基琥珀酸1-(三級丁基)酯4-環辛基酯(250mg,0.77mmol,79%)。LCMS(系統2,方法B)m/z 349.3(M+Na)+(ES+)。1H NMR(400MHz,CDCl3)δ:6.31(d,J=0.8Hz,1H),5.88(s,1H),5.02-4.98(m,1H),4.58(s,1H),3.44(s,3H),1.86-1.64(m,6H),1.63-1.52(m,8H),1.48(s,9H)。 Iodomethane (818mg, 5.76mmol) was added to 3-hydroxy-2-methylenesuccinate 1-(tertiarybutyl) 4-cyclooctyl ester (300mg, 0.96mmol) and Ag 2 O (445mg, 1.92 mmol) in DCM (1 mL), and the reaction mixture was stirred at 40°C for 16 h. The mixture was filtered and the filtrate was concentrated under reduced pressure at 30°C to produce crude products as 3-methoxy-2-methylenesuccinate 1-(tributyl) ester 4-cyclooctyl ester and 3 -A 5:1 mixture of methoxy-2-methylfumarate 1-(tertiarybutyl) 4-cyclooctyl ester. The crude product was purified by flash column chromatography (25g silica, 0-10% MTBE/petroleum ether) to produce pure 3-methoxy-2-methylenesuccinic acid 1- (Tertiary butyl) ester 4-cyclooctyl ester (250 mg, 0.77 mmol, 79%). LCMS (System 2, Method B) m/z 349.3 (M+Na) + (ES + ). 1 H NMR(400MHz,CDCl 3 )δ: 6.31(d,J=0.8Hz,1H),5.88(s,1H),5.02-4.98(m,1H),4.58(s,1H),3.44(s, 3H), 1.86-1.64 (m, 6H), 1.63-1.52 (m, 8H), 1.48 (s, 9H).

步驟5 Step 5

將3-甲氧基-2-亞甲基琥珀酸1-(三級丁基)酯4-環辛基酯(230mg,0.71mmol)和TFA(2mL)在DCM(2mL)中的混合物在室溫下攪拌過夜。將混合物在減壓下於40℃濃縮。以產生粗製呈淺黃色油之4-(環辛氧基)-3-甲氧基-2-亞甲基-4-側氧基丁酸(200mg,0.71mmol,>100%),將其直接使用於下一步驟。LCMS(系統2,方法C)m/z 293.4(M+Na)+(ES+)。 A mixture of 3-methoxy-2-methylenesuccinate 1-(tertiary butyl) ester 4-cyclooctyl ester (230 mg, 0.71 mmol) and TFA (2 mL) in DCM (2 mL) was placed in the chamber Stir at warm overnight. The mixture was concentrated at 40°C under reduced pressure. To produce crude 4-(cyclooctyloxy)-3-methoxy-2-methylene-4-oxobutanoic acid (200mg, 0.71mmol, >100%) as a light yellow oil, it was directly Used in the next step. LCMS (System 2, Method C) m/z 293.4 (M+Na) + (ES + ).

步驟6 Step 6

將碳酸鉀(110mg,0.74mmol)加至製4-(環辛氧基)-3-甲氧基-2-亞甲基-4-側氧基丁酸(200mg,0.71mmol)在丙酮(5mL)中之溶液粗,並將反應混合物在室溫下攪拌30min。添加2-溴乙酸三級丁酯(171mg,0.89mmol)並將所得混合物在室溫下攪拌過夜。將反應混合物過濾,並在減壓下於40℃濃縮濾液。將殘餘物藉由急速管柱層析法純化(25g二氧化矽,0-10% MTBE/石油醚)以產生呈黃色油之3-甲氧基-2-亞甲基琥珀酸1-(2-(三級丁氧基)-2-側氧基乙基)酯4-環辛基酯(200mg,0.52mmol,73%)。LCMS(系統2,方法B)m/z 407.3(M+Na)+(ES+)。 Potassium carbonate (110mg, 0.74mmol) was added to 4-(cyclooctyloxy)-3-methoxy-2-methylene-4-oxobutyric acid (200mg, 0.71mmol) in acetone (5mL The solution in) was crude, and the reaction mixture was stirred at room temperature for 30 min. Tertiary butyl 2-bromoacetate (171 mg, 0.89 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated at 40°C under reduced pressure. The residue was purified by flash column chromatography (25g silica, 0-10% MTBE/petroleum ether) to produce 3-methoxy-2-methylenesuccinic acid 1-(2 -(Tertiary butoxy)-2-oxoethyl) ester 4-cyclooctyl ester (200 mg, 0.52 mmol, 73%). LCMS (System 2, Method B) m/z 407.3 (M+Na) + (ES + ).

步驟7 Step 7

將3-甲氧基-2-亞甲基琥珀酸1-(2-(三級丁氧基)-2-側氧基乙基)酯4-環辛基酯(200mg,0.52mmol)和TFA(2mL)在DCM(2mL)中的混合物在室溫下攪拌3h。將混合物在減壓下於40℃濃縮並將殘餘物藉由製備型HPLC純化(管柱:Waters X-Bridge C18 OBD 10μm 19 x 250mm;流速:20mL/min;溶劑系統:MeCN/(0.1% TFA/水)梯度:45-95% MeCN;收集波長:214nm)。將該等部分在減壓下於40℃濃縮以移除MeCN,並將殘餘物凍乾以產生呈白色固體之2-((4-(環辛氧基)-3-甲氧基-2-亞甲基-4-側氧基丁醯基)氧基)乙酸(144mg,0.44mmol,84%)。LCMS(系統2,方法B)m/z 351.2(M+Na)+(ES+)。1H NMR(400MHz, DMSO-d6)δ:12.97(br,1H),6.40(s,1H),6.03(s,1H),4.90-4.84(m,1H),4.65(s,2H),4.60(s,1H),3.33(s,3H),1.77-1.54(m,6H),1.49-1.38(m,8H)。 Combine 3-methoxy-2-methylenesuccinic acid 1-(2-(tertiary butoxy)-2-oxoethyl) ester 4-cyclooctyl ester (200mg, 0.52mmol) and TFA (2mL) A mixture in DCM (2mL) was stirred at room temperature for 3h. The mixture was concentrated under reduced pressure at 40°C and the residue was purified by preparative HPLC (column: Waters X-Bridge C18 OBD 10μm 19 x 250mm; flow rate: 20mL/min; solvent system: MeCN/(0.1% TFA /Water) gradient: 45-95% MeCN; collection wavelength: 214nm). The fractions were concentrated under reduced pressure at 40°C to remove MeCN, and the residue was lyophilized to give 2-((4-(cyclooctyloxy)-3-methoxy-2- Methylene-4-oxobutanoyl)oxy)acetic acid (144 mg, 0.44 mmol, 84%). LCMS (System 2, Method B) m/z 351.2 (M+Na) + (ES + ). 1 H NMR(400MHz, DMSO-d6)δ: 12.97(br,1H), 6.40(s,1H), 6.03(s,1H), 4.90-4.84(m,1H), 4.65(s,2H), 4.60 (s, 1H), 3.33 (s, 3H), 1.77-1.54 (m, 6H), 1.49-1.38 (m, 8H).

實施例44-2-((4-((-金剛烷-1-基)氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00881] Example 44-2-((4-((-adamantan-1-yl)oxy)-2-methylene-4- pendant oxybutyryl)oxy)acetic acid [SYX-00881]

Figure 109137209-A0202-12-0086-104
Figure 109137209-A0202-12-0086-104

步驟1 step 1

將金剛烷-1-醇(3.1g,20mmol)、溴乙酸(5.5g,40mmol)和無水對甲苯磺酸(172mg,1mmol)在甲苯(100mL)中的混合物在回流下加熱過夜。將反應混合物冷卻至室溫,用NaHCO3飽和水溶液稀釋,分離並用EtOAc(2 x 30mL)萃取水層。將合併的有機層用鹽水洗滌,用Na2SO4乾燥,過濾及在減壓下於40℃濃縮。將殘餘物藉由急速管柱層析法純化(80g二氧化矽,0-5% EtOAc/石油醚)以產生呈白色固體之2-溴乙酸金剛烷-1-基酯(4.5g,16.5mmol,83%)。1H NMR(400MHz,DMSO-d6)δ:4.02(s,2H),2.50(m,3H),2.05(d,J=3.2Hz,6H),1.62(t,J=2.8Hz,6H)。 A mixture of adamantane-1-ol (3.1 g, 20 mmol), bromoacetic acid (5.5 g, 40 mmol) and anhydrous p-toluenesulfonic acid (172 mg, 1 mmol) in toluene (100 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, diluted with saturated aqueous NaHCO 3 solution, separated and the aqueous layer was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4, filtered at 40 ℃ and concentrated under reduced pressure. The residue was purified by flash column chromatography (80 g silica, 0-5% EtOAc/petroleum ether) to give adamantane-1-yl 2-bromoacetate (4.5 g, 16.5 mmol) as a white solid , 83%). 1 H NMR (400MHz, DMSO-d6) δ: 4.02 (s, 2H), 2.50 (m, 3H), 2.05 (d, J=3.2 Hz, 6H), 1.62 (t, J=2.8 Hz, 6H).

步驟2 Step 2

在0℃下將在礦物油中的NaH懸浮液(60wt.%,236mg,5.9mmol)加至2-(二乙氧基磷醯基)乙酸乙基酯(1.2g,5.4mmol)在THF(10mL)中之溶液,將反應 混合物在0℃下攪拌0.5h,接著添加2-溴乙酸金剛烷-1-基酯(1.61g,5.9mmol)。將反應混合物在室溫下攪拌4h,接著添加稀HCl水溶液(0.5M,10mL)將其淬滅,調節至pH=5,並用EtOAc(2 x 10mL)萃取。將合併的有機層用鹽水洗滌,用Na2SO4乾燥,過濾及在減壓下於40℃濃縮。將殘餘物藉由急速管柱層析法純化(40g二氧化矽,0-30% EtOAc/石油醚)以產生呈黃色油之粗製2-(二乙氧基磷醯基)琥珀酸4-(金剛烷-1-基)酯1-乙基酯(2g,4.8mmol,90%)。LCMS(系統2,方法B)m/z 417.3(M+H)+(ES+)。1H NMR(400MHz,DMSO-d6)δ:4.13-4.00(m,6H),3.37-3.32(m,1H),2.75-2.72(m,1H),2.63-2.60(m,1H),2.11(m,3H),2.01(s,6H),1.60(m,6H),1.26-1.17(m,9H)。 A suspension of NaH in mineral oil (60wt.%, 236mg, 5.9mmol) was added to ethyl 2-(diethoxyphosphinyl) acetate (1.2g, 5.4mmol) in THF( 10mL), the reaction mixture was stirred at 0°C for 0.5h, and then 2-bromoacetic acid adamantane-1-yl ester (1.61g, 5.9mmol) was added. The reaction mixture was stirred at room temperature for 4 h, then it was quenched by the addition of dilute aqueous HCl (0.5M, 10 mL), adjusted to pH=5, and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4, filtered at 40 ℃ and concentrated under reduced pressure. The residue was purified by flash column chromatography (40 g silica, 0-30% EtOAc/petroleum ether) to produce crude 2-(diethoxyphosphoryl)succinic acid 4-( Adamantan-1-yl) ester 1-ethyl ester (2 g, 4.8 mmol, 90%). LCMS (System 2, Method B) m/z 417.3 (M+H) + (ES + ). 1 H NMR (400MHz, DMSO-d6) δ: 4.13-4.00 (m, 6H), 3.37-3.32 (m, 1H), 2.75-2.72 (m, 1H), 2.63-2.60 (m, 1H), 2.11 ( m, 3H), 2.01 (s, 6H), 1.60 (m, 6H), 1.26-1.17 (m, 9H).

步驟3 Step 3

在室溫下將在水中之甲醛溶液(37wt.%,7.8mL,96mmol)加至2-(二乙氧基磷醯基)琥珀酸4-(金剛烷-1-基)酯1-乙基酯(2g,4.8mmol)和碳酸鉀(1.3g,9.6mmol)在DMF(20mL)中之溶液,並將反應混合物在室溫下攪拌4h。將反應混合物用H2O(60mL)稀釋並用MTBE(2 x 30mL)萃取。將合併的有機層用H2O和鹽水洗滌,用Na2SO4乾燥,過濾及在減壓下於30℃濃縮。將殘餘物藉由急速管柱層析法純化(40g二氧化矽,0-10% MTBE/石油醚)以產生呈黃色油之2-亞甲基琥珀酸4-(金剛烷-1-基)酯1-乙基酯(800mg,3.0mmol,57%)。LCMS(系統2,方法B)m/z 315.3(M+Na)+(ES+)。1H NMR(400MHz,DMSO-d6)δ:6.14(d,J=1.2Hz,1H),5.75(d,J=1.2Hz,1H),4.13(q,J=7.2Hz,2H),3.26(s,2H),2.11(m,3H),2.01(d,J=2.8Hz,6H),1.60(s,6H),1.21(t,J=7.8Hz,3H)。 Add a formaldehyde solution (37wt.%, 7.8mL, 96mmol) in water to 2-(diethoxyphosphoryl)succinate 4-(adamantan-1-yl) ester 1-ethyl at room temperature A solution of ester (2g, 4.8mmol) and potassium carbonate (1.3g, 9.6mmol) in DMF (20mL), and the reaction mixture was stirred at room temperature for 4h. The reaction mixture was diluted with H 2 O (60 mL) and extracted with MTBE (2 x 30 mL). The combined organic layers were washed with H 2 O and brine, dried over Na 2 SO 4, filtered and concentrated under reduced pressure at 30 deg.] C. The residue was purified by flash column chromatography (40g silica, 0-10% MTBE/petroleum ether) to produce 2-methylenesuccinic acid 4-(adamantan-1-yl) as a yellow oil Ester 1-ethyl ester (800 mg, 3.0 mmol, 57%). LCMS (System 2, Method B) m/z 315.3 (M+Na) + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ: 6.14(d,J=1.2Hz,1H), 5.75(d,J=1.2Hz,1H), 4.13(q,J=7.2Hz,2H), 3.26( s, 2H), 2.11 (m, 3H), 2.01 (d, J = 2.8 Hz, 6H), 1.60 (s, 6H), 1.21 (t, J = 7.8 Hz, 3H).

步驟4 Step 4

將在水中之LiOH溶液(2M,4.5mL,9mmol)加至2-亞甲基琥珀酸4-(金剛烷-1-基)酯1-乙基酯(800mg,3.0mmol)在THF(10mL)中之溶液,並將反應混合物在室溫下攪拌過夜。將反應混合物在減壓下於30℃濃縮以移除THF。將殘餘 物用H2O(20mL)稀釋及用MTBE(2 x 10mL)洗滌。使用稀HCl水溶液(0.5M)將水層調整至pH=3並用EtOAc(2 x 10mL)萃取。將合併之EtOAc層用鹽水洗滌,用Na2SO4乾燥,過濾及在減壓下於40℃濃縮以產生呈淺黃色油之4-((金剛烷-1-基)氧基)-2-亞甲基-4-側氧基丁酸和4-((金剛烷-1-基)氧基)-2-甲基-4-側氧基丁-2-烯酸的1:1混合物(300mg,1.1mmol,38%),將其直接使用於下一步驟。LCMS(系統2,方法C)m/z 287.2(M+Na)+(ES+)。 The LiOH solution in water (2M, 4.5mL, 9mmol) was added to 2-methylenesuccinic acid 4-(adamantan-1-yl) ester 1-ethyl ester (800mg, 3.0mmol) in THF (10mL) And the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure at 30°C to remove THF. The residue was diluted with H 2 O (20 mL) and washed with MTBE (2 x 10 mL). The aqueous layer was adjusted to pH=3 using dilute aqueous HCl (0.5M) and extracted with EtOAc (2 x 10 mL). The combined the EtOAc layer was washed with brine and dried with Na 2 SO 4, filtered at reduced pressure and at 40 ℃ concentrated to give a pale yellow oil of 4 - ((adamantan-1-yl) oxy) -2- 1:1 mixture of methylene-4-oxobutyric acid and 4-((adamantan-1-yl)oxy)-2-methyl-4-oxobut-2-enoic acid (300mg , 1.1mmol, 38%), use it directly in the next step. LCMS (System 2, Method C) m/z 287.2 (M+Na) + (ES + ).

步驟5 Step 5

在室溫下將2-溴乙酸2,2,2-三氯乙基酯(354mg,1.3mmol)加至4-((金剛烷-1-基)氧基)-2-亞甲基-4-側氧基丁酸和4-((金剛烷-1-基)氧基)-2-甲基-4-側氧基丁-2-烯酸的1:1混合物(300mg,1.1mmol)和碳酸鉀(157mg,1.1mmol)在丙酮(10mL)中之溶液,並將反應混合物在室溫下攪拌過夜。接著將反應混合物過濾,及將濾液在減壓下於30℃濃縮。將殘餘物藉由急速管柱層析法純化(40g二氧化矽,0-10% MTBE/石油醚)以產生呈黃色油之2-亞甲基琥珀酸4-(金剛烷-1-基)酯1-(2-側氧基-2-(2,2,2-三氯乙氧基)乙基)酯(270mg,0.60mmol,54%)。LCMS(系統2,方法B)m/z 475.3(M+Na)+(ES+)。 Add 2,2,2-trichloroethyl 2-bromoacetic acid (354mg, 1.3mmol) to 4-((adamantan-1-yl)oxy)-2-methylene-4 at room temperature -1:1 mixture (300mg, 1.1mmol) of pendant oxybutyric acid and 4-((adamantan-1-yl)oxy)-2-methyl-4- pendant oxybut-2-enoic acid and A solution of potassium carbonate (157 mg, 1.1 mmol) in acetone (10 mL), and the reaction mixture was stirred at room temperature overnight. Then the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure at 30°C. The residue was purified by flash column chromatography (40g silica, 0-10% MTBE/petroleum ether) to produce 2-methylenesuccinic acid 4-(adamantan-1-yl) as a yellow oil Ester 1-(2-oxo-2-(2,2,2-trichloroethoxy)ethyl) ester (270 mg, 0.60 mmol, 54%). LCMS (System 2, Method B) m/z 475.3 (M+Na) + (ES + ).

步驟6 Step 6

將鋅粉(195mg,3mmol)加至2-亞甲基琥珀酸4-(金剛烷-1-基)酯1-(2-側氧基-2-(2,2,2-三氯乙氧基)乙基)酯(270mg,0.60mmol)在AcOH(5mL)中之溶液,並將反應混合物在室溫下攪拌過夜。將反應混合物過濾,及將濾液在減壓下於45℃濃縮。將殘餘物藉由製備型HPLC(管柱:Waters X-Bridge C18 OBD 10μm 19 x 250mm;流速:20mL/min;溶劑系統:MeCN/(0.05% TFA/水)梯度:50-95% MeCN;收集波長:214nm純化)。將該等部分在減壓下於40℃濃縮以移除MeCN,並將殘餘物凍乾以產生呈無色油之2-((4-((-金剛烷-1-基)氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸(72mg,37%)。LCMS(系統2,方法B)m/z 345.3 (M+Na)+(ES+)。1H NMR(400MHz,DMSO-d6)δ:13.07(br,1H),6.23(s,1H),5.86(s,1H),4.64(s,2H),3.27(s,2H),2.10(s,3H),2.01(d,J=2.4Hz,6H),1.60(m,6H)。 Add zinc powder (195mg, 3mmol) to 2-methylenesuccinate 4-(adamantan-1-yl) ester 1-(2-oxo-2-(2,2,2-trichloroethoxy) A solution of yl)ethyl)ester (270 mg, 0.60 mmol) in AcOH (5 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated at 45°C under reduced pressure. The residue was subjected to preparative HPLC (column: Waters X-Bridge C18 OBD 10μm 19 x 250mm; flow rate: 20 mL/min; solvent system: MeCN/(0.05% TFA/water) gradient: 50-95% MeCN; collection Wavelength: 214nm purification). The fractions were concentrated under reduced pressure at 40°C to remove MeCN, and the residue was lyophilized to give 2-((4-((-adamantan-1-yl)oxy)-2 as a colorless oil -Methylene-4-oxobutanoyl)oxy)acetic acid (72 mg, 37%). LCMS (System 2, Method B) m/z 345.3 (M+Na) + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ: 13.07(br,1H), 6.23(s,1H), 5.86(s,1H), 4.64(s,2H), 3.27(s,2H), 2.10(s ,3H),2.01(d,J=2.4Hz,6H),1.60(m,6H).

實施例57-(R)-4,4,4-三氟-3-((2-亞甲基-4-(((R)-辛-2-基)氧基)-4-側氧基丁醯基)氧基)丁酸[SYX-00930] Example 57-(R)-4,4,4-Trifluoro-3-((2-methylene-4-(((R)-oct-2-yl)oxy)-4- pendant oxy Butyryl)oxy)butyric acid [SYX-00930]

Figure 109137209-A0202-12-0089-105
Figure 109137209-A0202-12-0089-105

步驟1 step 1

在0℃下將PMBCl(327mg,2.09mmol)加至(R)-4,4,4-三氟-3-羥基丁酸(300mg,1.90mmol)和K2CO3(315mg,2.28mmol)在DMF(10mL)中之混合物,並將反應混合物在室溫下攪拌過夜。將反應混合物用水淬滅並用EtOAc萃取。將有機層用水和鹽水洗滌,用Na2SO4乾燥及過濾。將濾液在減壓下於40℃濃縮,並將殘餘物藉由急速管柱層析法純化(80g二氧化矽,0-20%MTBE/石油醚)以產生呈黃色油之(R)-4,4,4-三氟-3-羥基丁酸4-甲氧基苯甲基酯(320mg,1.15mmol,61%)。LCMS(系統2,方法B)m/z 301.1(M+Na)+(ES+)。 PMBCl (327mg, 2.09mmol) was added to (R)-4,4,4-trifluoro-3-hydroxybutyric acid (300mg, 1.90mmol) and K 2 CO 3 (315mg, 2.28mmol) at 0°C. DMF (10 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure at 40°C, and the residue was purified by flash column chromatography (80g silica, 0-20% MTBE/petroleum ether) to produce (R)-4 as a yellow oil , 4,4-Trifluoro-3-hydroxybutyric acid 4-methoxybenzyl ester (320 mg, 1.15 mmol, 61%). LCMS (System 2, Method B) m/z 301.1 (M+Na) + (ES + ).

步驟2 Step 2

在0℃下將EDC.HCl(331mg,1.725mmol)加至(R)-2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁酸(228mg,1.15mmol)、(R)-4,4,4-三氟-3-羥基丁酸4-甲氧基苯甲基酯(320mg,1.15mmol)和DMAP(140mg,1.15mmol)在DCM(3mL)中之溶液,及將所得淡黃色混合物在室溫下攪拌2h。將混合物用飽和水溶液NH4Cl溶液(1mL)淬滅,分離並將有機相用DCM(2 x 2mL)萃取。將分離之有機相用鹽水洗 滌,用Na2SO4乾燥及過濾。將濾液在減壓下於40℃濃縮,並將殘餘物藉由急速管柱層析法純化(25g二氧化矽,0-15%MTBE/石油醚)以產生呈黃色油之2-亞甲基琥珀酸4-((R)-辛-2-基)酯1-((R)-1,1,1-三氟-4-((4-甲氧基苯甲基)氧基)-4-側氧基丁-2-基)酯(300mg,0.60mmol,52%)。LCMS(系統2,方法C)m/z 525.3(M+Na)+(ES+)。 EDC.HCl (331mg, 1.725mmol) was added to (R)-2-methylene-4-(oct-2-yloxy)-4-oxobutanoic acid (228mg, 1.15mmol) at 0°C ), (R)-4,4,4-trifluoro-3-hydroxybutyric acid 4-methoxybenzyl ester (320mg, 1.15mmol) and DMAP (140mg, 1.15mmol) in DCM (3mL) Solution, and the resulting pale yellow mixture was stirred at room temperature for 2h. The mixture was quenched with saturated aqueous NH 4 Cl solution (1 mL), separated and the organic phase was extracted with DCM (2 x 2 mL). The separated organic phase was washed with brine, dried over Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure at 40°C, and the residue was purified by flash column chromatography (25g silica, 0-15% MTBE/petroleum ether) to produce 2-methylene as a yellow oil Succinic acid 4-((R)-oct-2-yl) ester 1-((R)-1,1,1-trifluoro-4-((4-methoxybenzyl)oxy)-4 -Pendant oxybut-2-yl) ester (300 mg, 0.60 mmol, 52%). LCMS (System 2, Method C) m/z 525.3 (M+Na) + (ES + ).

步驟3 Step 3

將2-亞甲基琥珀酸4-((R)-辛-2-基)酯1-((R)-1,1,1-三氟-4-((4-甲氧基苯甲基)氧基)-4-側氧基丁-2-基)酯(300mg,0.60mmol)在1,4-二

Figure 109137209-A0202-12-0090-160
烷中之HCl溶液(4M,3mL)中之溶液在室溫下攪拌4h。將混合物在減壓下於30℃濃縮並將殘餘物藉由製備型HPLC純化(管柱:Waters X-Bridge C18 OBD 10μm 19 x 250mm;流速:20mL/min;溶劑系統:MeCN/(0.05% TFA/水)梯度:60-95% MeCN;收集波長:214nm)。將該等部分在減壓下於40℃濃縮以移除MeCN,並將殘餘物凍乾以產生呈無色油之(R)-4,4,4-三氟-3-((2-亞甲基-4-(((R)-辛-2-基)氧基)-4-側氧基丁醯基)氧基)丁酸(134mg,0.35mmol 59%)。LCMS(系統2,方法B)m/z 405.3(M+Na)+(ES+)。1H NMR(400MHz,DMSO-d6)δ:12.85(br,1H),6.28(s,1H),5.96(d,J=0.8Hz,1H),5.79-5.73(m,1H),4.80-4.75(m,1H),3.40(s,2H),2.95(dd,J=22.8,4.0Hz,1H),2.74(dd,J=16.8,9.2Hz,1H),1.48-1.33(m,2H),1.29-1.23(m,8H),1.12(d,J=6.4Hz,3H),0.85(t,J=6.4Hz,3H)。 The 2-methylenesuccinic acid 4-((R)-oct-2-yl) ester 1-((R)-1,1,1-trifluoro-4-((4-methoxybenzyl) )Oxy)-4-oxobut-2-yl)ester (300mg, 0.60mmol) in 1,4-di
Figure 109137209-A0202-12-0090-160
The solution in HCl solution (4M, 3 mL) in alkane was stirred at room temperature for 4 h. The mixture was concentrated under reduced pressure at 30°C and the residue was purified by preparative HPLC (column: Waters X-Bridge C18 OBD 10 μm 19 x 250mm; flow rate: 20 mL/min; solvent system: MeCN/(0.05% TFA) /Water) gradient: 60-95% MeCN; collection wavelength: 214nm). The fractions were concentrated under reduced pressure at 40°C to remove MeCN, and the residue was lyophilized to produce (R)-4,4,4-trifluoro-3-((2-methylene 4-(((R)-oct-2-yl)oxy)-4-oxobutanoyl)oxy)butanoic acid (134 mg, 0.35 mmol 59%). LCMS (System 2, Method B) m/z 405.3 (M+Na) + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ: 12.85(br,1H), 6.28(s,1H), 5.96(d,J=0.8Hz,1H), 5.79-5.73(m,1H), 4.80-4.75 (m, 1H), 3.40 (s, 2H), 2.95 (dd, J = 22.8, 4.0 Hz, 1H), 2.74 (dd, J = 16.8, 9.2 Hz, 1H), 1.48-1.33 (m, 2H), 1.29-1.23(m,8H), 1.12(d,J=6.4Hz,3H), 0.85(t,J=6.4Hz,3H).

使用類似的程序合成下列化合物,但從(S)-4,4,4-三氟-3-羥基丁酸開始: The following compounds were synthesized using a similar procedure, but starting with (S)-4,4,4-trifluoro-3-hydroxybutyric acid:

Figure 109137209-A0202-12-0090-107
Figure 109137209-A0202-12-0090-107

Figure 109137209-A0202-12-0091-108
Figure 109137209-A0202-12-0091-108

實施例58-2-((4-(環辛氧基)-3-羥基-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00873] Example 58-2-((4-(Cyclooctyloxy)-3-hydroxy-2-methylene-4-oxobutyryl)oxy)acetic acid [SYX-00873]

Figure 109137209-A0202-12-0091-109
Figure 109137209-A0202-12-0091-109

步驟1 step 1

將3-羥基-2-亞甲基琥珀酸1-(三級丁基)酯4-環辛基酯(200mg,0.64mmol)和在1,4-二

Figure 109137209-A0202-12-0091-161
烷之HCl溶液(4M,2mL)在DCM(2mL)中的混合物在室溫下攪拌4h。將混合物在減壓下於40℃濃縮。以產生呈淺黃色油之粗製2-(氯甲基)-4-(環辛氧基)-3-羥基-4-側氧基丁酸(200mg,0.68mmol,>100%),將其直接使用於下一步驟。LCMS(系統2,方法C)m/z 315.2(M+Na)+(ES+)。 Combine 3-hydroxy-2-methylene succinate 1-(tertiary butyl) ester 4-cyclooctyl ester (200mg, 0.64mmol) and in 1,4-di
Figure 109137209-A0202-12-0091-161
A mixture of alkane HCl solution (4M, 2 mL) in DCM (2 mL) was stirred at room temperature for 4 h. The mixture was concentrated at 40°C under reduced pressure. To produce crude 2-(chloromethyl)-4-(cyclooctyloxy)-3-hydroxy-4-oxobutanoic acid (200mg, 0.68mmol, >100%) as a light yellow oil, it was directly Used in the next step. LCMS (System 2, Method C) m/z 315.2 (M+Na) + (ES + ).

步驟2 Step 2

將碳酸鉀(94mg,0.68mmol)加至粗製2-(氯甲基)-4-(環辛氧基)-3-羥基-4-側氧基丁酸(200mg,0.68mmol)在丙酮(5mL)中之溶液並將反應混合物在室溫下攪拌30min,接著添加2-溴乙酸三級丁酯(158mg,0.82mmol),並將所得混合物在室溫下攪拌過夜。將反應混合物過濾,將濾液在減壓下於40℃濃縮,及將殘餘物藉由急速管柱層析法純化(25g二氧化矽,0-20%MTBE/石油醚)以產生呈黃色 油之3-羥基-2-亞甲基琥珀酸1-(2-(三級丁氧基)-2-側氧基乙基酯4-環辛基酯(200mg,0.54mmol,79%)。LCMS(系統2,方法B)m/z 393.3(M+Na)+(ES+)。1H NMR(400MHz,CDCl3)δ:6.47(s,1H),6.00(s,1H),5.30(m,1H),4.85(d,J=6.0Hz,1H),4.66(d,J=16.0Hz,1H),4.52(d,J=16.0Hz,1H),3.56(d,J=6.0Hz,1H),1.86-1.65(m,6H),1.63-1.52(m,8H),1.42(s,9H)。 Potassium carbonate (94mg, 0.68mmol) was added to the crude 2-(chloromethyl)-4-(cyclooctyloxy)-3-hydroxy-4-oxobutanoic acid (200mg, 0.68mmol) in acetone (5mL ) And the reaction mixture was stirred at room temperature for 30 min, then 2-bromoacetic acid tertiary butyl ester (158 mg, 0.82 mmol) was added, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure at 40°C, and the residue was purified by flash column chromatography (25 g silica, 0-20% MTBE/petroleum ether) to produce a yellow oil 3-hydroxy-2-methylenesuccinic acid 1-(2-(tertiary butoxy)-2-oxoethyl ester 4-cyclooctyl ester (200mg, 0.54mmol, 79%). LCMS( System 2, Method B) m/z 393.3(M+Na) + (ES + ). 1 H NMR(400MHz, CDCl 3 )δ: 6.47(s,1H),6.00(s,1H),5.30(m, 1H), 4.85(d,J=6.0Hz,1H), 4.66(d,J=16.0Hz,1H), 4.52(d,J=16.0Hz,1H), 3.56(d,J=6.0Hz,1H) ,1.86-1.65(m,6H),1.63-1.52(m,8H),1.42(s,9H).

步驟3 Step 3

將3-羥基-2-亞甲基琥珀酸1-(2-(三級丁氧基)-2-側氧基乙基酯4-環辛基酯(200mg,0.54mmol)和TFA(2mL)在DCM(2mL)中的混合物在室溫下攪拌過夜。將混合物在減壓下於40℃濃縮。及將殘餘物藉由製備型HPLC純化(管柱:Waters X-Bridge C18 OBD 10μm 19 x 250mm;流速:20mL/min;溶劑系統:MeCN/(0.1%TFA/水)梯度:35-95%MeCN;收集波長:214nm)。將該等部分在減壓下於40℃濃縮以移除MeCN,並將殘餘物凍乾以產生呈無色油之2-((4-(環辛氧基)-3-羥基-2-亞甲基-4-側氧基丁醯基)氧基)乙酸(99mg,58%)。LCMS(系統2,方法B)m/z 337.3(M+Na)+(ES+)。1H NMR(400MHz,DMSO-d6)δ:13.10(br,1H),6.30(s,1H),6.07(m,1H),6.03(s,1H),4.85-4.79(m,1H),4.83(s,1H),4.64(s,2H),1.71-1.53(m,6H),1.49-1.36(m,8H)。 Combine 3-hydroxy-2-methylenesuccinic acid 1-(2-(tertiary butoxy)-2-oxoethyl ester 4-cyclooctyl ester (200mg, 0.54mmol) and TFA (2mL) The mixture in DCM (2mL) was stirred overnight at room temperature. The mixture was concentrated under reduced pressure at 40°C. And the residue was purified by preparative HPLC (column: Waters X-Bridge C18 OBD 10μm 19 x 250mm Flow rate: 20mL/min; Solvent system: MeCN/(0.1%TFA/water) gradient: 35-95% MeCN; Collection wavelength: 214nm). These fractions were concentrated under reduced pressure at 40°C to remove MeCN, And the residue was lyophilized to produce 2-((4-(cyclooctyloxy)-3-hydroxy-2-methylene-4-oxobutanoyl)oxy)acetic acid (99mg, 58 %). LCMS (System 2, Method B) m/z 337.3 (M+Na) + (ES + ). 1 H NMR (400MHz, DMSO-d6) δ: 13.10 (br, 1H), 6.30 (s, 1H) ), 6.07 (m, 1H), 6.03 (s, 1H), 4.85-4.79 (m, 1H), 4.83 (s, 1H), 4.64 (s, 2H), 1.71-1.53 (m, 6H), 1.49- 1.36 (m, 8H).

實施例59-2-(3-亞甲基-5-(4-甲基庚-4-基氧基)-5-側氧基戊基-1-烯-2-基氧基)乙酸[SYX-00900] Example 59-2-(3-methylene-5-(4-methylhept-4-yloxy)-5-oxopentyl-1-en-2-yloxy)acetic acid (SYX -00900]

Figure 109137209-A0202-12-0093-110
Figure 109137209-A0202-12-0093-110

步驟1 step 1

在0℃下將2-溴乙醯溴(3.49g,17.28mmol)慢慢地滴加至4-甲基庚-4-醇(1.50g,11.52mmol)和DBU(2.62g,17.28mmol)在1-甲基-2-吡咯啶酮(25mL)中之溶液,並將混合物在室溫下攪拌1h。將反應混合物用水(20mL)和MTBE(20mL)稀釋,分離各層並用MTBE(2 x 10mL)萃取水層。將合併的有機層用鹽水洗滌,用Na2SO4乾燥,過濾及在減壓下於40℃濃縮。將殘餘物藉由急速管柱層析法純化(25g二氧化矽,0-3%MTBE/石油醚)以產生呈無色油之2-溴乙酸4-甲基庚-4-基酯(2.00g,7.96mmol,69%)。1H NMR(400MHz,CDCl3)δ:3.75(s,2H),1.86-1.78(m,2H),1.74-1.67(m,2H),1.42(s,3H),1.36-1.26(m,4H),0.91(t,J=7.6Hz,6H)。 Slowly add 2-bromoacetyl bromide (3.49g, 17.28mmol) dropwise to 4-methylheptan-4-ol (1.50g, 11.52mmol) and DBU (2.62g, 17.28mmol) at 0°C. A solution in 1-methyl-2-pyrrolidone (25 mL), and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water (20 mL) and MTBE (20 mL), the layers were separated and the aqueous layer was extracted with MTBE (2 x 10 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4, filtered at 40 ℃ and concentrated under reduced pressure. The residue was purified by flash column chromatography (25g silica, 0-3% MTBE/petroleum ether) to produce 2-bromoacetic acid 4-methylhept-4-yl ester (2.00g , 7.96mmol, 69%). 1 H NMR (400MHz, CDCl 3 ) δ: 3.75 (s, 2H), 1.86-1.78 (m, 2H), 1.74-1.67 (m, 2H), 1.42 (s, 3H), 1.36-1.26 (m, 4H) ),0.91(t,J=7.6Hz,6H).

步驟2 Step 2

在0℃下將在礦物油中的NaH懸浮液(60wt.%,290mg,7.96mmol)加至2-(二乙氧基磷醯基)乙酸甲酯(1.52g,7.24mmol)在THF(30mL)中之溶液,並將反應混合物在0℃下攪拌0.5h。添加2-溴乙酸4-甲基庚-4-基酯(2.00g,7.96mmol)並將反應混合物在室溫下攪拌過夜。接著將反應混合物用稀HCl水溶液(0.5M,10mL)淬滅至pH=5,並用EtOAc(2 x 10mL)萃取。將合併的有機層用鹽水洗滌,用Na2SO4乾燥,過濾及在減壓下於40℃濃縮。將殘餘物藉由矽膠管柱層析法(25g 二氧化矽,1:4-1:2EtOAc/石油醚)純化以產生呈淺黃色油之2-(二乙氧基磷醯基)琥珀酸1-甲基酯4-(4-甲基庚-4-基)酯(2.30g,6.0mmol,83%)。LCMS(系統2,方法C)m/z 403.3(M+Na)+(ES+)。 A suspension of NaH in mineral oil (60wt.%, 290mg, 7.96mmol) was added to methyl 2-(diethoxyphosphoryl)acetate (1.52g, 7.24mmol) in THF (30mL at 0°C). ), and the reaction mixture was stirred at 0°C for 0.5h. 2-Bromoacetic acid 4-methylheptan-4-yl ester (2.00 g, 7.96 mmol) was added and the reaction mixture was stirred at room temperature overnight. Then the reaction mixture was quenched with dilute aqueous HCl (0.5M, 10 mL) to pH=5, and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4, filtered at 40 ℃ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25g silica, 1:4-1:2 EtOAc/petroleum ether) to produce 2-(diethoxyphosphoryl)succinic acid 1 as a pale yellow oil -Methyl ester 4-(4-methylheptan-4-yl) ester (2.30 g, 6.0 mmol, 83%). LCMS (System 2, Method C) m/z 403.3 (M+Na) + (ES + ).

步驟3 Step 3

在室溫下將在水中之甲醛溶液(37wt.%,5.5mL,68.40mmol)加至2-(二乙氧基磷醯基)琥珀酸1-甲基酯4-(4-甲基庚-4-基)酯(1.30g,3.42mmmol)和碳酸鉀(945mg,6.84mmol)在DMF(15mL)中之溶液,並將反應混合物在室溫下攪拌4h。將反應混合物用H2O(30mL)稀釋並用MTBE(2 x 20mL)萃取。將合併的有機層用H2O(2 x 15mL)和鹽水洗滌,用Na2SO4乾燥,過濾及在減壓下於30℃濃縮。將殘餘物藉由急速管柱層析法純化(25g二氧化矽,0-10%MTBE/石油醚)以產生呈無色油之2-亞甲基琥珀酸1-甲基酯4-(4-甲基庚-4-基)酯(600mg,2.34mmol,68%)。LCMS(系統2,方法C)m/z 279.4(M+Na)+(ES+)。 At room temperature, a formaldehyde solution (37wt.%, 5.5mL, 68.40mmol) in water was added to 2-(diethoxyphosphoryl)succinate 1-methyl 4-(4-methylhepta- A solution of 4-yl) ester (1.30 g, 3.42 mmmol) and potassium carbonate (945 mg, 6.84 mmol) in DMF (15 mL), and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with H 2 O (30 mL) and extracted with MTBE (2 x 20 mL). The combined organic layer was washed with H 2 O (2 x 15 mL) and brine, dried over Na 2 SO 4 , filtered and concentrated at 30° C. under reduced pressure. The residue was purified by flash column chromatography (25 g silica, 0-10% MTBE/petroleum ether) to produce 2-methylene succinate 1-methyl ester 4-(4- Methylheptan-4-yl) ester (600 mg, 2.34 mmol, 68%). LCMS (System 2, Method C) m/z 279.4 (M+Na) + (ES + ).

步驟4 Step 4

將在水中之LiOH(2M,4.7mL,9.36mmol)加至2-亞甲基琥珀酸1-甲基酯4-(4-甲基庚-4-基)酯(600mg,2.34mmol)在THF(10mL)中之溶液,並將反應混合物在室溫下攪拌過夜。將反應混合物用稀HCl水溶液(0.5M)酸化至pH=3,並用EtOAc(2 x 10mL)萃取。將EtOAc層用鹽水洗滌,用Na2SO4乾燥,過濾及在減壓下於40℃濃縮以產生呈淺黃色油之2-亞甲基-4-(4-甲基庚-4-基氧基)-4-側氧基丁酸和2-甲基-4-(4-甲基庚-4-基氧基)-4-側氧基丁-2-烯酸的5:1混合物(500mg,2.06mmol,88%),將其直接使用於下一步驟。LCMS(系統2,方法B)m/z 265.3(M+Na)+(ES+)。 LiOH (2M, 4.7mL, 9.36mmol) in water was added to 2-methylenesuccinic acid 1-methyl ester 4-(4-methylhept-4-yl) ester (600mg, 2.34mmol) in THF (10 mL) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was acidified with dilute aqueous HCl (0.5M) to pH=3, and extracted with EtOAc (2 x 10 mL). The EtOAc layer was washed with brine, dried over 2 SO 4 Na, and filtered at 40 ℃ concentrated under reduced pressure to yield a pale yellow oil of 2-methyl-4- (4-methyl-4-oxo-heptyl 5:1 mixture (500mg , 2.06mmol, 88%), use it directly in the next step. LCMS (System 2, Method B) m/z 265.3 (M+Na) + (ES + ).

步驟5 Step 5

將2-溴乙酸2,2,2-三氯乙基酯(558mg,2.06mmol)加至2-亞甲基-4-(4-甲基庚-4-基氧基)-4-側氧基丁酸和2-甲基-4-(4-甲基庚-4-基氧基)-4-側氧基丁-2-烯酸的5:1混合物(500mg,2.06mmol)、和碳酸鉀(313mg,2.26mmol)在丙酮(10mL)中之溶液,並將反應混合物在室溫下攪拌過夜。將反應混合物過濾並將濾液在減壓下於30℃濃縮。將殘餘物藉由急速管柱層析法純化(25g二氧化矽,0-10%MTBE/石油醚)以產生呈淺黃色油之2-亞甲基琥珀酸4-(4-甲基庚-4-基)酯1-(2-側氧基-2-(2,2,2-三氯乙氧基)乙基)酯(430mg,1.00mmol,48%)。LCMS(系統2,方法B)m/z 455.0(M+Na)+(ES+)。 Add 2,2,2-trichloroethyl 2-bromoacetic acid (558mg, 2.06mmol) to 2-methylene-4-(4-methylhept-4-yloxy)-4-oxo 5:1 mixture (500mg, 2.06mmol) of methylbutyric acid and 2-methyl-4-(4-methylhept-4-yloxy)-4-oxobut-2-enoic acid, and carbonic acid A solution of potassium (313 mg, 2.26 mmol) in acetone (10 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated at 30°C under reduced pressure. The residue was purified by flash column chromatography (25g silica, 0-10% MTBE/petroleum ether) to produce 2-methylenesuccinic acid 4-(4-methylhepta- 4-yl) ester 1-(2-oxo-2-(2,2,2-trichloroethoxy)ethyl) ester (430 mg, 1.00 mmol, 48%). LCMS (System 2, Method B) m/z 455.0 (M+Na) + (ES + ).

步驟6 Step 6

將鋅粉(325mg,4.98mmol)加至2-亞甲基琥珀酸4-(4-甲基庚-4-基)酯1-(2-側氧基-2-(2,2,2-三氯乙氧基)乙基)酯(430mg,1.00mmol)在AcOH(5mL)中之溶液,並將反應混合物在室溫下攪拌過夜。將反應混合物過濾並將濾液在減壓下於30℃濃縮。將殘餘物藉由製備型HPLC純化(管柱:Waters X-Bridge C18 OBD 10μm 19 x 250mm;流速:20mL/min;溶劑系統:MeCN/(0.1%TFA/水)梯度:50-95%MeCN;收集波長:214nm)。將該等部分在減壓下於30℃濃縮以移除MeCN,並將殘餘物凍乾以產生呈無色油之2-(3-亞甲基-5-(4-甲基庚-4-基氧基)-5-側氧基戊基-1-烯-2-基氧基)乙酸(72mg,0.24mmol,24%)。LCMS(系統2,方法B)m/z 323.2(M+Na)+(ES+)。1H NMR(400MHz,DMSO-d6)δ:13.09(br,1H),6.23(d,J=1.2Hz,1H),5.86(d,J=0.4Hz,1H),4.61(s,2H),3.28(s,2H),1.76-1.68(m,2H),1.64-1.56(m,2H),1.30(s,3H),1.28-1.18(m,4H),0.85(d,J=7.2Hz,6H)。 Add zinc powder (325mg, 4.98mmol) to 2-methylenesuccinate 4-(4-methylhept-4-yl) ester 1-(2-oxo-2-(2,2,2- A solution of trichloroethoxy)ethyl) ester (430 mg, 1.00 mmol) in AcOH (5 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated at 30°C under reduced pressure. The residue was purified by preparative HPLC (column: Waters X-Bridge C18 OBD 10μm 19 x 250mm; flow rate: 20mL/min; solvent system: MeCN/(0.1%TFA/water) gradient: 50-95%MeCN; Collection wavelength: 214nm). The fractions were concentrated under reduced pressure at 30°C to remove MeCN, and the residue was lyophilized to give 2-(3-methylene-5-(4-methylhept-4-yl) as a colorless oil (Oxy)-5-oxopentyl-1-en-2-yloxy)acetic acid (72 mg, 0.24 mmol, 24%). LCMS (System 2, Method B) m/z 323.2 (M+Na) + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ: 13.09(br,1H), 6.23(d,J=1.2Hz,1H), 5.86(d,J=0.4Hz,1H), 4.61(s,2H), 3.28(s,2H),1.76-1.68(m,2H),1.64-1.56(m,2H),1.30(s,3H),1.28-1.18(m,4H),0.85(d,J=7.2Hz, 6H).

使用類似的程序製造下列化合物: Use similar procedures to make the following compounds:

Figure 109137209-A0202-12-0095-111
Figure 109137209-A0202-12-0095-111

Figure 109137209-A0202-12-0096-112
Figure 109137209-A0202-12-0096-112

Figure 109137209-A0202-12-0097-113
Figure 109137209-A0202-12-0097-113

藉由將MeMgBr加至在THF中之對應市售酮製造2-甲基螺[3.5]壬-2-醇。1H NMR(400MHz,CDCl3)δ:1.92(d,J=14.6Hz,2H),1.89(d,J=14.4Hz,2H),1.71(m,1H),1.53-1.50(m,2H),1.43-1.34(m,8H),1.39(s,3H)。 2-Methylspiro[3.5]nonan-2-ol was produced by adding MeMgBr to the corresponding commercially available ketone in THF. 1 H NMR(400MHz,CDCl 3 )δ: 1.92(d,J=14.6Hz,2H), 1.89(d,J=14.4Hz,2H), 1.71(m,1H), 1.53-1.50(m,2H) ,1.43-1.34(m,8H),1.39(s,3H).

實施例65-2-((2-亞甲基-4-側氧基-4-(((外)-1,7,7-三甲基雙環[2.2.1]庚-2-基)氧基)丁醯基)氧基)乙酸[SYX-00933] Example 65-2-((2-Methylene-4- pendant oxy-4-(((ex)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)oxy (Yl)butyryl)oxy)acetic acid [SYX-00933]

Figure 109137209-A0202-12-0097-114
Figure 109137209-A0202-12-0097-114

步驟1 step 1

在0℃下將2-溴乙醯溴(1.97g,9.74mmol)慢慢地滴加至(外)-1,7,7-三甲基雙環[2.2.1]庚-2-醇(CAS號124-76-5)(1.00g,6.49mmol)和DBU(1.48g,9.74mmol)在1-甲基-2-吡咯啶酮(20mL)中之溶液,並將混合物在室溫下攪拌3h。將反應混合物用水(20mL)和MTBE(20mL)稀釋,分離並用MTBE(2 x 10mL)萃取水層。將合併的有機層用鹽水洗滌,用Na2SO4乾燥,過濾及在減壓下於40℃濃縮。將殘 餘物藉由急速管柱層析法純化(40g二氧化矽,0-3%MTBE/石油醚)以產生呈無色油之2-溴乙酸(外)-1,7,7-三甲基雙環[2.2.1]庚-2-基酯(1.5g,5.11mmol,79%)。1H NMR(400MHz,CDCl3)δ:4.74-4.71(m,1H),3.80(s,2H),1.86-1.68(m,4H),1.61-1.54(m,1H),1.18-1.08(m,2H),1.00(s,3H),0.80(s,3H),0.77(s,3H)。 Slowly add 2-bromoacetyl bromide (1.97g, 9.74mmol) to (external)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (CAS No. 124-76-5) (1.00g, 6.49mmol) and DBU (1.48g, 9.74mmol) in 1-methyl-2-pyrrolidone (20mL), and the mixture was stirred at room temperature for 3h . The reaction mixture was diluted with water (20 mL) and MTBE (20 mL), separated and the aqueous layer was extracted with MTBE (2 x 10 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4, filtered at 40 ℃ and concentrated under reduced pressure. The residue was purified by flash column chromatography (40g silica, 0-3% MTBE/petroleum ether) to produce 2-bromoacetic acid (exo)-1,7,7-trimethyl as a colorless oil Bicyclo[2.2.1]heptan-2-yl ester (1.5 g, 5.11 mmol, 79%). 1 H NMR (400MHz, CDCl 3 ) δ: 4.74-4.71 (m, 1H), 3.80 (s, 2H), 1.86-1.68 (m, 4H), 1.61-1.54 (m, 1H), 1.18-1.08 (m ,2H),1.00(s,3H),0.80(s,3H),0.77(s,3H).

步驟2 Step 2

在0℃下將在礦物油中的NaH懸浮液(60wt.%,225mg,5.62mmol)加至2-(二乙氧基磷醯基)乙酸三級丁基酯(1.29g,5.11mmol)在THF(20mL)中之溶液,並將反應混合物在0℃下攪拌0.5h,接著添加2-溴乙(外)-1,7,7-三甲基雙環[2.2.1]庚-2-基酸酯(1.50g,5.11mmol)。將反應混合物在室溫下攪拌過夜,接著用稀HCl水溶液(0.5M)淬滅至pH=5並用EtOAc(2 x 10mL)萃取。將合併的有機層用鹽水洗滌,用Na2SO4乾燥,過濾及在減壓下於40℃濃縮。將殘餘物藉由急速管柱層析法純化(40g二氧化矽,1:4-1:2EtOAc/石油醚)以產生呈無色油之2-(二乙氧基磷醯基)琥珀酸1-(三級丁基)酯4-((外)-1,7,7-三甲基雙環[2.2.1]庚-2-基)酯(1.60g,3.59mmol,70%)。LCMS(系統2,方法C)m/z 469.4(M+Na)+(ES+)。 A suspension of NaH in mineral oil (60wt.%, 225mg, 5.62mmol) was added to tributyl 2-(diethoxyphosphoryl)acetate (1.29g, 5.11mmol) at 0°C. THF (20mL), and the reaction mixture was stirred at 0°C for 0.5h, then 2-bromoethyl (exo)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl was added Esters (1.50 g, 5.11 mmol). The reaction mixture was stirred at room temperature overnight, then quenched with dilute aqueous HCl (0.5M) to pH=5 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4, filtered at 40 ℃ and concentrated under reduced pressure. The residue was purified by flash column chromatography (40 g silica, 1:4-1:2 EtOAc/petroleum ether) to produce 2-(diethoxyphosphoryl)succinic acid 1- (Tributyl) ester 4-((exo)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl) ester (1.60 g, 3.59 mmol, 70%). LCMS (System 2, Method C) m/z 469.4 (M+Na) + (ES + ).

步驟3 Step 3

在室溫下將在水中之甲醛溶液(37wt.%,2.9mL,35.9mmol)加至2-(二乙氧基磷醯基)琥珀酸1-(三級丁基)酯4-((外)-1,7,7-三甲基雙環[2.2.1]庚-2-基)酯(1.60g,3.59mmol)和碳酸鉀(990mg,7.17mmol)在DMF(10mL)中之混合物,並將反應混合物在室溫下攪拌4h。將反應混合物用H2O(15mL)稀釋並用MTBE(2 x 20mL)萃取。將合併的有機層用H2O(2 x 10mL)和鹽水洗滌,用Na2SO4乾燥,過濾及在減壓下於30℃濃縮。將殘餘物藉由急速管柱層析法純化(25g二氧化矽,0-10%MTBE/石油醚)以產生呈無色油之2-亞甲基琥珀酸1-(三級丁基)酯4-((外)-1,7,7-三甲基雙環[2.2.1]庚-2-基)酯(850mg,2.64mmol,73%)。LCMS(系統2,方法C)m/z 345.4(M+Na)+(ES+)。 Add formaldehyde solution (37wt.%, 2.9mL, 35.9mmol) in water to 2-(diethoxyphosphinyl) succinate 1-(tertiary butyl) ester 4-((external )-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)ester (1.60g, 3.59mmol) and potassium carbonate (990mg, 7.17mmol) in DMF (10mL), and The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with H 2 O (15 mL) and extracted with MTBE (2 x 20 mL). The combined organic layer was washed with H 2 O (2 x 10 mL) and brine, dried over Na 2 SO 4 , filtered and concentrated at 30° C. under reduced pressure. The residue was purified by flash column chromatography (25 g silica, 0-10% MTBE/petroleum ether) to produce 2-methylene succinate 1-(tertiary butyl) ester 4 as a colorless oil -((Ex)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl) ester (850 mg, 2.64 mmol, 73%). LCMS (System 2, Method C) m/z 345.4 (M+Na) + (ES + ).

步驟4 Step 4

將在1,4-二噁烷中的HCl溶液(4M,4.0mL)加至2-亞甲基琥珀酸1-(三級丁基)酯4-((外)-1,7,7-三甲基雙環[2.2.1]庚-2-基)酯(400mg,1.24mmol)在DCM(8mL)中之溶液,並將反應混合物在室溫下攪拌過夜。將反應混合物在減壓下於40℃濃縮以產生呈淺黃色油之粗製2-亞甲基-4-側氧基-4-(((外)-1,7,7-三甲基雙環[2.2.1]庚-2-基)氧基)丁酸(LCMS(系統2,方法C)m/z 289.4(M+Na)+(ES+))、2-甲基-4-側氧基-4-(((外)-1,7,7-三甲基雙環[2.2.1]庚-2-基)氧基)丁-2-烯酸(LCMS(系統2,方法C)m/z 289.4(M+Na)+(ES+))和2-(氯甲基)-4-側氧基-4-(((外)-1,7,7-三甲基雙環[2.2.1]庚-2-基)氧基)丁酸(LCMS(系統2,方法C)m/z 325.2(M+Na)+(ES+))(400mg)的33:20:47混合物,將其直接使用於下一步驟。 The HCl solution (4M, 4.0 mL) in 1,4-dioxane was added to 2-methylenesuccinate 1-(tertiarybutyl) ester 4-((ex)-1,7,7- A solution of trimethylbicyclo[2.2.1]heptan-2-yl) ester (400 mg, 1.24 mmol) in DCM (8 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure at 40°C to produce crude 2-methylene-4-oxo-4-(((外)-1,7,7-trimethylbicyclo[ 2.2.1]Hept-2-yl)oxy)butanoic acid (LCMS (System 2, Method C) m/z 289.4(M+Na) + (ES + )), 2-methyl-4- pendant oxy -4-(((外)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy)but-2-enoic acid (LCMS (System 2, Method C) m/ z 289.4(M+Na) + (ES + )) and 2-(chloromethyl)-4- pendant oxy-4-(((外)-1,7,7-trimethylbicyclo[2.2.1 ]Hept-2-yl)oxy)butanoic acid (LCMS (System 2, Method C) m/z 325.2 (M+Na) + (ES + )) (400mg) 33:20:47 mixture, directly Used in the next step.

步驟5 Step 5

將2-溴乙酸三級丁酯(331mg,1.24mmol)加至在丙酮(10mL)中之2-亞甲基-4-側氧基-4-(((外)-1,7,7-三甲基雙環[2.2.1]庚-2-基)氧基)丁酸、(2-甲基-4-側氧基-4-(((外)-1,7,7-三甲基雙環[2.2.1]庚-2-基)氧基)丁-2-烯酸和2-(氯甲基)-4-側氧基-4-(((外)-1,7,7-三甲基雙環[2.2.1]庚-2-基)氧基)丁酸(400mg)的粗製33:20:47混合物和碳酸鉀(342mg,2.48mmol),並將反應混合物在室溫下攪拌過夜。接著將混合物過濾,並將濾液在減壓下於30℃濃縮。將殘餘物藉由急速管柱層析法純化(25g二氧化矽,0-10%MTBE/石油醚)以產生呈淺黃色油之2-亞甲基琥珀酸1-(2-側氧基-2-(2,2,2-三氯乙氧基)乙基)酯4-((外)-1,7,7-三甲基雙環[2.2.1]庚-2-基)酯(450mg,0.99mmol,80%經過兩個步驟)。LCMS(系統2,方法C)m/z 477.0(M+Na)+(ES+)。 Tertiary butyl 2-bromoacetate (331 mg, 1.24 mmol) was added to 2-methylene-4-oxo-4-(((外)-1,7,7- Trimethylbicyclo[2.2.1]hept-2-yl)oxy)butanoic acid, (2-methyl-4- pendant oxy-4-(((外)-1,7,7-trimethyl) Bicyclo[2.2.1]hept-2-yl)oxy)but-2-enoic acid and 2-(chloromethyl)-4- pendant oxy-4-(((外)-1,7,7- A crude 33:20:47 mixture of trimethylbicyclo[2.2.1]hept-2-yl)oxy)butanoic acid (400mg) and potassium carbonate (342mg, 2.48mmol), and the reaction mixture was stirred at room temperature Overnight. Then the mixture was filtered, and the filtrate was concentrated under reduced pressure at 30°C. The residue was purified by flash column chromatography (25g silica, 0-10% MTBE/petroleum ether) to produce a light 2-methylene succinic acid 1-(2-oxo-2-(2,2,2-trichloroethoxy)ethyl) ester 4-((out)-1,7,7 in yellow oil -Trimethylbicyclo[2.2.1]heptan-2-yl)ester (450mg, 0.99mmol, 80% in two steps). LCMS (System 2, Method C) m/z 477.0(M+Na) + ( ES + ).

步驟6 Step 6

將鋅粉(322mg,4.96mmol)加至2-亞甲基琥珀酸1-(2-側氧基-2-(2,2,2-三氯乙氧基)乙基)酯4-((外)-1,7,7-三甲基雙環[2.2.1]庚-2-基)酯(450mg,0.99mmol)在AcOH(5mL)中之溶液,並將反應混合物在室溫下攪拌過夜。將反應混合物過濾並將濾液在減壓下於30℃濃縮。將殘餘物藉由製備型HPLC純化(管柱:Waters X-Bridge C18 OBD 10μm 19 x 250mm;流速:20mL/min;溶劑系統:MeCN/(0.05%TFA/水)梯度:40-95%MeCN;收集波長:214nm)。將該等部分在減壓下於30℃濃縮以移除MeCN,並將殘餘物凍乾以產生呈無色油之2-((2-亞甲基-4-側氧基-4-(((外)-1,7,7-三甲基雙環[2.2.1]庚-2-基)氧基)丁醯基)氧基)乙酸(77mg,0.23mmol,24%)。LCMS(系統2,方法B)m/z 347.2(M+Na)+(ES+)。1H NMR(400MHz,DMSO-d6)δ:13.06(br,1H),6.27(d,J=0.8Hz,1H),5.92(d,J=0.8Hz,1H),4.61(s,2H),4.54(dd,J=8.0,3.6Hz,1H),3.35(s,2H),1.74-1.60(m,4H),1.53-1.47(m,1H),1.13-1.01(m,2H),0.88(s,3H),0.79(s,3H),0.75(s,3H)。 Zinc powder (322mg, 4.96mmol) was added to 2-methylenesuccinic acid 1-(2-oxo-2-(2,2,2-trichloroethoxy)ethyl) ester 4-(( (Exo)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)ester (450mg, 0.99mmol) in AcOH (5mL), and the reaction mixture was stirred at room temperature overnight . The reaction mixture was filtered and the filtrate was concentrated at 30°C under reduced pressure. The residue was purified by preparative HPLC (column: Waters X-Bridge C18 OBD 10μm 19 x 250mm; flow rate: 20mL/min; solvent system: MeCN/(0.05%TFA/water) gradient: 40-95%MeCN; Collection wavelength: 214nm). The fractions were concentrated under reduced pressure at 30°C to remove MeCN, and the residue was lyophilized to give 2-((2-methylene-4- pendant oxy-4-(((( (Ex)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy)butyryl)oxy)acetic acid (77 mg, 0.23 mmol, 24%). LCMS (System 2, Method B) m/z 347.2 (M+Na) + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ: 13.06(br,1H), 6.27(d,J=0.8Hz,1H), 5.92(d,J=0.8Hz,1H), 4.61(s,2H), 4.54(dd,J=8.0,3.6Hz,1H),3.35(s,2H),1.74-1.60(m,4H),1.53-1.47(m,1H),1.13-1.01(m,2H),0.88( s, 3H), 0.79 (s, 3H), 0.75 (s, 3H).

使用類似的程序製備下列化合物: A similar procedure was used to prepare the following compounds:

Figure 109137209-A0202-12-0100-115
Figure 109137209-A0202-12-0100-115

藉由以在MeOH中的NaBH4將對應的市售酮還原製造2,2,6,6-四甲基環己-1-醇。1H NMR(400MHz,DMSO-d6)δ:4.40(br,1H),2.83(s,1H),1.56-1.48(1H、m),1.47-1.38(m,2H),1.36-1.28(m,1H),1.22-1.11(m,2H),0.93(s,6H),0.88(s,6H)。 2,2,6,6-Tetramethylcyclohexan-1-ol was produced by reducing the corresponding commercially available ketone with NaBH 4 in MeOH. 1 H NMR (400MHz, DMSO-d6) δ: 4.40 (br, 1H), 2.83 (s, 1H), 1.56-1.48 (1H, m), 1.47-1.38 (m, 2H), 1.36-1.28 (m, 1H), 1.22-1.11 (m, 2H), 0.93 (s, 6H), 0.88 (s, 6H).

根據實施例23之程序製備下列實施例,但使用下述醇代替3-乙氧基丙-1-醇: The following examples were prepared according to the procedure of Example 23, but using the following alcohol instead of 3-ethoxyprop-1-ol:

Figure 109137209-A0202-12-0101-116
Figure 109137209-A0202-12-0101-116

Figure 109137209-A0202-12-0102-117
Figure 109137209-A0202-12-0102-117

藉由下列方法製備1-(3,5-二氯苯基)乙-1-醇(異構物1):使用手性SFC(管柱:CHIRALPAK AY-3 4.6 x 100mm;流速:2mL/min;溶劑系統:10%IPA/CO2;收集波長:214nm)解析外消旋1-(3,5-二氯苯基)乙-1-醇。異構物1為於1.34min的第一溶析峰。 Prepare 1-(3,5-dichlorophenyl)ethan-1-ol (isomer 1) by the following method: use chiral SFC (column: CHIRALPAK AY-3 4.6 x 100mm; flow rate: 2mL/min ; Solvent system: 10% IPA/CO 2 ; Collection wavelength: 214 nm) Resolve racemic 1-(3,5-dichlorophenyl) ethane-1-ol. Isomer 1 is the first elution peak at 1.34 min.

藉由下列方法製備1-(3,5-二氯苯基)乙-1-醇(異構物2):使用手性SFC(管柱:CHIRALPAK AY-3 4.6 x 100mm;流速:2mL/min;溶劑系統:10%IPA/CO2;收集波長:214nm)解析外消旋1-(3,5-二氯苯基)乙-1-醇。異構物2為於1.53min的第二溶析峰。 Prepare 1-(3,5-dichlorophenyl)ethan-1-ol (isomer 2) by the following method: use chiral SFC (column: CHIRALPAK AY-3 4.6 x 100mm; flow rate: 2mL/min ; Solvent system: 10% IPA/CO 2 ; Collection wavelength: 214 nm) Resolve racemic 1-(3,5-dichlorophenyl) ethane-1-ol. Isomer 2 is the second elution peak at 1.53 min.

實施例71-2-((4-(1-環己基環丙氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00944] Example 71-2-((4-(1-cyclohexylcyclopropoxy)-2-methylene-4-oxobutyryl)oxy)acetic acid [SYX-00944]

Figure 109137209-A0202-12-0102-118
Figure 109137209-A0202-12-0102-118

步驟1 step 1

在0℃下將溴化乙基鎂在乙醚中之溶液(3M,30mL,90mmol)慢慢地加至環己烷甲酸甲酯(4.26g,30mmol)和四異丙醇鈦(11.93g,42mmol)在THF(60mL)中之溶液,並將混合物在室溫下攪拌16h。將反應混合物用水(60mL)淬滅,並攪拌1小時,直到形成灰色沉澱,及接著過濾。用MTBE(3 x 40mL)萃取濾液,並將合併的有機層用鹽水洗滌,用Na2SO4乾燥,過濾及在減壓下於40℃濃縮。將殘餘物藉由急速管柱層析法純化(0-3%EtOAc/石油醚)以產生呈無色油之1-環己基環丙-1-醇(2.50g,17.8mmol,60%)。1H NMR(400MHz,CDCl3)δ:1.80-1.75(m,4H),1.69-1.66(m,1H),1.26-1.17(m,5H),0.94-0.92(m,1H),0.70-0.67(m,2H),0.45-0.42(m,2H)。未觀察到一個可交換質子。 Slowly add a solution of ethylmagnesium bromide in ether (3M, 30mL, 90mmol) at 0°C to methyl cyclohexanecarboxylate (4.26g, 30mmol) and titanium tetraisopropoxide (11.93g, 42mmol) ) In THF (60 mL), and the mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water (60 mL) and stirred for 1 hour until a gray precipitate formed, and then filtered. With MTBE (3 x 40mL) The organic layer was extracted filtrate were combined and washed with brine, dried over Na 2 SO 4, filtered at 40 ℃ and concentrated under reduced pressure. The residue was purified by flash column chromatography (0-3% EtOAc/petroleum ether) to give 1-cyclohexylcyclopropan-1-ol (2.50 g, 17.8 mmol, 60%) as a colorless oil. 1 H NMR (400MHz, CDCl 3 ) δ: 1.80-1.75 (m, 4H), 1.69-1.66 (m, 1H), 1.26-1.17 (m, 5H), 0.94-0.92 (m, 1H), 0.70-0.67 (m, 2H), 0.45-0.42 (m, 2H). No exchangeable proton was observed.

步驟2 Step 2

在0℃下將2-溴乙醯溴(3.24g,16.05mmol)慢慢地滴加至1-環己基環丙-1-醇(1.50g,10.7mmol)和DBU(2.43g,16.05mmol)在1-甲基-2-吡咯啶酮(20mL)中之溶液,並將所得混合物在室溫下攪拌1h。將反應混合物用水(20mL)和MTBE(20mL)稀釋,分離並用MTBE(2 x 10mL)萃取水層。將合併的有機層用鹽水洗滌,用Na2SO4乾燥,過濾及在減壓下於40℃濃縮。將殘餘物藉由急速管柱層析法(25g二氧化矽,0-3%MTBE/石油醚)純化以產生呈無色油之2-溴乙酸1-環己基環丙基酯(1.70g,6.51mmol,61%)。1H NMR(400MHz,CDCl3)δ:3.74(s,2H),1.80-1.73(m,5H),1.67-1.64(m,1H),1.24-1.08(m,3H),0.95-0.79(m,2H),0.70-0.67(m,4H)。 Slowly add 2-bromoacetyl bromide (3.24g, 16.05mmol) dropwise to 1-cyclohexylcycloprop-1-ol (1.50g, 10.7mmol) and DBU (2.43g, 16.05mmol) at 0°C A solution in 1-methyl-2-pyrrolidone (20 mL), and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water (20 mL) and MTBE (20 mL), separated and the aqueous layer was extracted with MTBE (2 x 10 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4, filtered at 40 ℃ and concentrated under reduced pressure. The residue was purified by flash column chromatography (25g silica, 0-3% MTBE/petroleum ether) to produce 2-bromoacetic acid 1-cyclohexylcyclopropyl ester (1.70g, 6.51) as a colorless oil mmol, 61%). 1 H NMR (400MHz, CDCl 3 ) δ: 3.74 (s, 2H), 1.80-1.73 (m, 5H), 1.67-1.64 (m, 1H), 1.24-1.08 (m, 3H), 0.95-0.79 (m , 2H), 0.70-0.67 (m, 4H).

步驟3 Step 3

在0℃下將在礦物油中的NaH懸浮液(60wt.%,261mg,6.51mmol)加至2-(二乙氧基磷醯基)乙酸甲酯(1.36g,6.51mmol)在THF(30mL)中之溶液,並將反應混合物在0℃下攪拌0.5h。接著添加2-溴乙酸1-環己基環丙基酯(1.70g,6.51mmol),並將反應混合物在室溫下攪拌過夜。將反應混合物用稀HCl水溶液 (0.5M)淬滅至pH=5,並用EtOAc(2 x 10mL)萃取。將合併的有機層用鹽水洗滌,用Na2SO4乾燥,過濾及在減壓下於40℃濃縮以產生呈無色油之2-(二乙氧基磷醯基)琥珀酸4-(1-環己基環丙基)酯1-甲基酯(2.70g,6.92mmol,>100%)。將粗製產物直接使用於下一步驟。LCMS(系統2,方法B)m/z 413.2(M+Na)+(ES+)。 A suspension of NaH (60wt.%, 261mg, 6.51mmol) in mineral oil was added to methyl 2-(diethoxyphosphoryl)acetate (1.36g, 6.51mmol) in THF (30mL at 0°C). ), and the reaction mixture was stirred at 0°C for 0.5h. Then 1-cyclohexylcyclopropyl 2-bromoacetic acid (1.70 g, 6.51 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with dilute aqueous HCl (0.5M) to pH=5, and extracted with EtOAc (2 x 10 mL). The combined organic layer was washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure at 40°C to give 2-(diethoxyphosphoryl)succinic acid 4-(1- Cyclohexyl cyclopropyl) ester 1-methyl ester (2.70 g, 6.92 mmol, >100%). The crude product was used directly in the next step. LCMS (System 2, Method B) m/z 413.2 (M+Na) + (ES + ).

步驟4 Step 4

在室溫下將在水中之甲醛溶液(37wt.%,11.2mL,138mmol)加至2-(二乙氧基磷醯基)琥珀酸4-(1-環己基環丙基)酯1-甲基酯(2.70g,6.92mmmol)和碳酸鉀(1.83g,13.8mmol)在THF(20mL)中之混合物,並將反應混合物在室溫下攪拌4h。將反應混合物用H2O(20mL)稀釋並用MTBE(2 x 20mL)萃取。將合併的有機層用H2O(2 x 15mL)和鹽水洗滌,用Na2SO4乾燥,過濾及在減壓下於30℃濃縮。將殘餘物藉由急速管柱層析法純化(25g二氧化矽,0-10%MTBE/石油醚)以產生呈無色油之2-亞甲基琥珀酸4-(1-環己基環丙基)酯1-甲基酯(1.20g,4.51mmol,65%)。LCMS(系統2,方法B)m/z 267.3(M+H)+(ES+)。 Add formaldehyde solution (37wt.%, 11.2mL, 138mmol) in water to 2-(diethoxyphosphoryl)succinic acid 4-(1-cyclohexylcyclopropyl)ester 1-methyl at room temperature A mixture of methyl ester (2.70 g, 6.92 mmmol) and potassium carbonate (1.83 g, 13.8 mmol) in THF (20 mL), and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with H 2 O (20 mL) and extracted with MTBE (2 x 20 mL). The combined organic layer was washed with H 2 O (2 x 15 mL) and brine, dried over Na 2 SO 4 , filtered and concentrated at 30° C. under reduced pressure. The residue was purified by flash column chromatography (25g silica, 0-10% MTBE/petroleum ether) to produce 2-methylenesuccinic acid 4-(1-cyclohexylcyclopropyl) as a colorless oil ) Ester 1-methyl ester (1.20 g, 4.51 mmol, 65%). LCMS (System 2, Method B) m/z 267.3 (M+H) + (ES + ).

步驟5 Step 5

將在水中之LiOH溶液(2M,3.4mL,6.75mmol)加至2-亞甲基琥珀酸4-(1-環己基環丙基)酯1-甲基酯(600mg,2.25mmol)在THF(8mL)中之溶液,並將反應混合物在室溫下攪拌7h(約24%的起始材料殘留)。將反應混合物用稀HCl水溶液(0.5M)酸至pH=3並用EtOAc(2 x 10mL)萃取。將EtOAc層用鹽水洗滌,用Na2SO4乾燥,過濾及在減壓下於40℃濃縮以產生呈淺黃色油之4-(1-環己基環丙氧基)-2-亞甲基-4-側氧基丁酸和4-(1-環己基環丙氧基)-2-甲基-4-側氧基丁-2-烯酸的2:1混合物(500mg,1.98mmol,88%),將其直接使用於下一步驟。LCMS(系統2,方法C)m/z 253.4(M+H)+(ES+)。 The LiOH solution in water (2M, 3.4mL, 6.75mmol) was added to 2-methylenesuccinic acid 4-(1-cyclohexylcyclopropyl) ester 1-methyl ester (600mg, 2.25mmol) in THF ( 8mL), and the reaction mixture was stirred at room temperature for 7h (about 24% of the starting material remained). The reaction mixture was acidified with dilute aqueous HCl (0.5M) to pH=3 and extracted with EtOAc (2 x 10 mL). The EtOAc layer was washed with brine and dried with Na 2 SO 4, filtered at reduced pressure and at 40 ℃ concentrated to give a pale yellow oil of 4- (1-cyclohexyl-cyclopropyloxy) -2-methyl - A 2:1 mixture of 4-oxobutyric acid and 4-(1-cyclohexylcyclopropoxy)-2-methyl-4-oxobut-2-enoic acid (500mg, 1.98mmol, 88% ), use it directly in the next step. LCMS (System 2, Method C) m/z 253.4 (M+H) + (ES + ).

步驟6 Step 6

將2-溴乙酸2,2,2-三氯乙基酯(530mg,1.98mmol)加至4-(1-環己基環丙氧基)-2-亞甲基-4-側氧基丁酸和4-(1-環己基環丙氧基)-2-甲基-4-側氧基丁-2-烯酸的2:1混合物(500mg,1.98mmol)、及碳酸鉀(328mg,2.38mmol)在丙酮(10mL)中之溶液,並將反應混合物在室溫下攪拌過夜。將反應混合物過濾並將濾液在減壓下於30℃濃縮。將殘餘物藉由急速管柱層析法純化(25g二氧化矽,0-10%MTBE/石油醚)以產生呈淺黃色油之2-亞甲基琥珀酸4-(1-環己基環丙基)酯1-(2-側氧基-2-(2,2,2-三氯乙氧基)乙基)酯(300mg,0.68mmol,34%)。LCMS(系統2,方法B)m/z 463.1(M+Na)+(ES+)。 Add 2,2,2-trichloroethyl 2-bromoacetic acid (530mg, 1.98mmol) to 4-(1-cyclohexylcyclopropoxy)-2-methylene-4-oxobutanoic acid And 4-(1-cyclohexylcyclopropoxy)-2-methyl-4-oxobut-2-enoic acid 2:1 mixture (500mg, 1.98mmol), and potassium carbonate (328mg, 2.38mmol ) In acetone (10 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated at 30°C under reduced pressure. The residue was purified by flash column chromatography (25g silica, 0-10% MTBE/petroleum ether) to produce 2-methylenesuccinic acid 4-(1-cyclohexylcyclopropyl) as a pale yellow oil Yl) ester 1-(2-oxo-2-(2,2,2-trichloroethoxy)ethyl) ester (300 mg, 0.68 mmol, 34%). LCMS (System 2, Method B) m/z 463.1 (M+Na) + (ES + ).

步驟7 Step 7

將鋅粉(71mg,1.10mmol)和乙酸鈉(90mg,1.10mmol)加至2-亞甲基琥珀酸4-(1-環己基環丙基)酯1-(2-側氧基-2-(2,2,2-三氯乙氧基)乙基酯(100mg,0.22mmol)在THF(2mL)和水(0.5mL)中之溶液,並將反應混合物在室溫下攪拌過夜。將反應混合物過濾並將濾液在減壓下於30℃濃縮。將殘餘物藉由製備型HPLC純化(管柱:Waters X-Bridge C18 OBD 10μm 19 x 250mm;流速:20mL/min;溶劑系統:MeCN/(0.05%TFA/水)梯度:30-95%MeCN;收集波長:214nm)。將該等部分在減壓下於30℃濃縮以移除MeCN,並將殘餘物凍乾以產生呈無色油之2-((4-(1-環己基環丙氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸(6mg,0.019mmol,9%)。LCMS(系統2,方法B)m/z 311.2(M+H)+(ES+)。1H NMR(400MHz,CDCl3)δ:6.43(s,1H),5.80(s,1H),4.74(s,2H),3.31(s,2H),1.79-1.71(m,5H),1.66-1.63(m,1H),1.25-1.15(m,2H),1.11-1.05(m,1H),0.92-0.83(m,2H),0.74(d,J=2.0Hz,4H)。未觀察到一個可交換質子。 Add zinc powder (71mg, 1.10mmol) and sodium acetate (90mg, 1.10mmol) to 2-methylenesuccinic acid 4-(1-cyclohexylcyclopropyl) ester 1-(2-oxo-2- A solution of (2,2,2-trichloroethoxy) ethyl ester (100 mg, 0.22 mmol) in THF (2 mL) and water (0.5 mL), and the reaction mixture was stirred at room temperature overnight. The reaction The mixture was filtered and the filtrate was concentrated under reduced pressure at 30°C. The residue was purified by preparative HPLC (column: Waters X-Bridge C18 OBD 10 μm 19 x 250mm; flow rate: 20 mL/min; solvent system: MeCN/( 0.05%TFA/water) gradient: 30-95% MeCN; collection wavelength: 214nm). The fractions were concentrated under reduced pressure at 30°C to remove MeCN, and the residue was lyophilized to produce 2 as a colorless oil -((4-(1-cyclohexylcyclopropoxy)-2-methylene-4- pendant oxybutyryl)oxy)acetic acid (6mg, 0.019mmol, 9%). LCMS (System 2, Method B )m/z 311.2(M+H) + (ES + ). 1 H NMR(400MHz, CDCl 3 )δ: 6.43(s, 1H), 5.80(s, 1H), 4.74(s, 2H), 3.31( s, 2H), 1.79-1.71 (m, 5H), 1.66-1.63 (m, 1H), 1.25-1.15 (m, 2H), 1.11-1.05 (m, 1H), 0.92-0.83 (m, 2H), 0.74(d,J=2.0Hz,4H). No exchangeable proton was observed.

實施例73-2-((2-亞甲基-4-側氧基-4-((2,2,4,4-四甲基戊-3-基)氧基)丁醯基)氧基)乙酸(SYX-00946) Example 73-2-((2-Methylene-4- pendant oxy-4-((2,2,4,4-tetramethylpent-3-yl)oxy)butyryl)oxy)acetic acid (SYX-00946)

Figure 109137209-A0202-12-0106-119
Figure 109137209-A0202-12-0106-119

步驟1 step 1

在0℃下將LiAlH4(802mg,21.1mmol)加至2,2,4,4-四甲基戊-3-酮(1.5g,10.6mmol)在乾燥THF(40mL)中之溶液,並將所得混合物在室溫下攪拌1h。將反應混合物依次添加水(1mL)、NaOH水溶液(15wt%,1mL)、水(2.5mL)和Na2SO4(20g),將混合物在室溫下攪拌20min,過濾,及在減壓下於35℃濃縮以產生呈無色晶體之2,2,4,4-四甲基戊-3-醇(1.4g,9.70mmol,90%)。1H NMR(400MHz,CDCl3)δ:3.12(d,J=2.4Hz,1H),1.23(s,18H)。未觀察到一個可交換質子。 LiAlH 4 (802mg, 21.1mmol) was added to a solution of 2,2,4,4-tetramethylpentan-3-one (1.5g, 10.6mmol) in dry THF (40mL) at 0°C, and The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was sequentially added with water (1mL), aqueous NaOH (15wt%, 1mL), water (2.5mL) and Na 2 SO 4 (20g), and the mixture was stirred at room temperature for 20 min, filtered, and heated under reduced pressure. Concentrated at 35°C to produce 2,2,4,4-tetramethylpentan-3-ol (1.4 g, 9.70 mmol, 90%) as colorless crystals. 1 H NMR (400 MHz, CDCl 3 ) δ: 3.12 (d, J=2.4 Hz, 1H), 1.23 (s, 18H). No exchangeable proton was observed.

步驟2 Step 2

在0℃下將2-溴乙醯溴(3.64g,18.0mmol)慢慢地滴加至2,2,4,4-四甲基戊-3-醇(1.3g,9.02mmol)和DBU(2.74g,18.0mmol)在1-甲基-2-吡咯啶酮(45mL)中之溶液並將混合物在室溫下攪拌1h。將反應混合物用水(10mL)和MTBE(20mL)稀釋,分離並用MTBE(2 x 20mL)萃取水層。將合併的有機層用鹽水洗滌,用Na2SO4乾燥,過濾及在減壓下於40℃濃縮。將殘餘物藉由急速管柱層析法純化(50g二氧化矽,0-10%EtOAc/石油醚)以產生呈無色油之2-溴乙酸2,2,4,4-四甲基戊-3-基酯(1.50g,5.68mmol,62%)。1H NMR(400MHz,CDCl3)δ:4.63(s,1H),3.87(s,2H),1.04(s,18H)。 Slowly add 2-bromoacetyl bromide (3.64g, 18.0mmol) to 2,2,4,4-tetramethylpentan-3-ol (1.3g, 9.02mmol) and DBU( A solution of 2.74 g, 18.0 mmol) in 1-methyl-2-pyrrolidone (45 mL) and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water (10 mL) and MTBE (20 mL), separated and the aqueous layer was extracted with MTBE (2 x 20 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4, filtered at 40 ℃ and concentrated under reduced pressure. The residue was purified by flash column chromatography (50 g silica, 0-10% EtOAc/petroleum ether) to produce 2-bromoacetic acid 2,2,4,4-tetramethylpentan- 3-yl ester (1.50 g, 5.68 mmol, 62%). 1 H NMR (400MHz, CDCl 3 ) δ: 4.63 (s, 1H), 3.87 (s, 2H), 1.04 (s, 18H).

步驟3 Step 3

在0℃下將在礦物油中的NaH懸浮液(60wt.%,227mg,5.68mmol)加至2-(二乙氧基磷醯基)乙酸三級丁酯(1.43g,5.68mmol)在THF(15mL)中之溶液,並將反應混合物在0℃下攪拌0.5h。接著添加2-溴乙酸2,2,4,4-四甲基戊-3-基酯(1.5g,5.68mmol)並將反應混合物在室溫下攪拌過夜。將反應混合物用稀HCl水溶液(0.5M)淬滅至pH=5,並用EtOAc(3 x 20mL)萃取。將合併的有機層用鹽水洗滌,用Na2SO4乾燥,過濾及在減壓下於40℃濃縮以產生呈無色油之粗製2-(二乙氧基磷醯基)琥珀酸1-(三級丁基)酯4-(2,2,4,4-四甲基戊-3-基)酯(3.00g,6.87mmol,>100%)。將粗製產物直接使用於下一步驟。LCMS(系統2,方法B)m/z 459.3(M+Na)+(ES+)。 A suspension of NaH in mineral oil (60wt.%, 227mg, 5.68mmol) was added to tertiary butyl 2-(diethoxyphosphinyl) acetate (1.43g, 5.68mmol) in THF at 0°C (15mL), and the reaction mixture was stirred at 0°C for 0.5h. Then 2,2,4,4-tetramethylpent-3-yl 2-bromoacetic acid (1.5 g, 5.68 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with dilute aqueous HCl (0.5M) to pH=5, and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure at 40°C to give crude 2-(diethoxyphosphoryl)succinic acid 1-(tris) as a colorless oil 4-(2,2,4,4-tetramethylpent-3-yl) ester (3.00 g, 6.87 mmol, >100%). The crude product was used directly in the next step. LCMS (System 2, Method B) m/z 459.3 (M+Na) + (ES + ).

步驟4 Step 4

在室溫下將在水中之甲醛溶液(37wt.%,11.15mL,138mmol)加至2-(二乙氧基磷醯基)琥珀酸1-(三級丁基)酯4-(2,2,4,4-四甲基戊-3-基)酯(3.00g,~6.87mmol,粗製)和碳酸鉀(1.90g,13.8mmol)在THF(24mL)和H2O(6mL)中之溶液,並將反應混合物在室溫下攪拌4h。將反應混合物用H2O(15mL)稀釋並用MTBE(3 x 30mL)萃取。將合併的有機層用H2O(2 x 10mL)和鹽水洗滌,用Na2SO4乾燥,過濾及在減壓下於40℃濃縮。將殘餘物藉由急速管柱層析法純化(25g二氧化矽,0-20%MTBE/石油醚)以呈無色油之產生2-亞甲基琥珀酸1-(三級丁基)酯4-(2,2,4,4-四甲基戊-3-基)酯(1.45g,4.64mmol,68%)。LCMS(系統2,方法B)m/z 335.4(M+Na)+(ES+)。1H NMR(400MHz,CDCl3)δ:6.24(d,J=1.2Hz,1H),5.63(d,J=1.2Hz,1H),4.57(s,1H),3.35(d,J=0.8Hz,2H),1.48(s,9H),0.98(s,18H)。 Add formaldehyde solution (37wt.%, 11.15mL, 138mmol) in water to 2-(diethoxyphosphoryl) succinate 1-(tertiary butyl) ester 4-(2,2) at room temperature ,4,4-Tetramethylpent-3-yl) ester (3.00g, ~6.87mmol, crude) and potassium carbonate (1.90g, 13.8mmol) in THF (24mL) and H 2 O (6mL) , And the reaction mixture was stirred at room temperature for 4h. The reaction mixture was diluted with H 2 O (15 mL) and extracted with MTBE (3 x 30 mL). The combined organic layer was washed with H 2 O (2 x 10 mL) and brine, dried over Na 2 SO 4 , filtered and concentrated at 40° C. under reduced pressure. The residue was purified by flash column chromatography (25g silica, 0-20% MTBE/petroleum ether) to produce 2-methylene succinate 1-(tertiary butyl) ester 4 as a colorless oil -(2,2,4,4-tetramethylpent-3-yl) ester (1.45 g, 4.64 mmol, 68%). LCMS (System 2, Method B) m/z 335.4 (M+Na) + (ES + ). 1 H NMR(400MHz,CDCl 3 )δ: 6.24(d,J=1.2Hz,1H), 5.63(d,J=1.2Hz,1H), 4.57(s,1H), 3.35(d,J=0.8Hz , 2H), 1.48 (s, 9H), 0.98 (s, 18H).

步驟5 Step 5

將2-亞甲基琥珀酸1-(三級丁基)酯4-(2,2,4,4-四甲基戊-3-基)酯(450mg,1.44mmol)在TFA/DCM(2:1,7mL)中之溶液在室溫下攪拌4h。將混合 物在減壓下於40℃濃縮以產生呈無色油之2-亞甲基-4-側氧基-4-((2,2,4,4-四甲基戊-3-基)氧基)丁酸(400mg,1.56mmol,>100%),將其直接使用於下一步驟。LCMS(系統2,方法C)m/z 279.4(M+Na)+(ES+)。 The 2-methylene succinate 1-(tertiary butyl) ester 4-(2,2,4,4-tetramethylpent-3-yl) ester (450mg, 1.44mmol) in TFA/DCM (2 :1,7mL) was stirred at room temperature for 4h. The mixture was concentrated under reduced pressure at 40°C to produce 2-methylene-4- pendant oxy-4-((2,2,4,4-tetramethylpent-3-yl)oxygen as a colorless oil Yl)butyric acid (400mg, 1.56mmol, >100%), which was used directly in the next step. LCMS (System 2, Method C) m/z 279.4 (M+Na) + (ES + ).

步驟6 Step 6

將2-溴乙酸三級丁酯(608mg,3.12mmol)加至2-亞甲基-4-側氧基-4-((2,2,4,4-四甲基戊-3-基)氧基)丁酸(400mg,1.56mmol)和碳酸鉀(645mg,4.68mmol)在丙酮(10mL)中之溶液,並將反應混合物在室溫下攪拌2天。將反應混合物過濾,並在減壓下於40℃濃縮濾液。將殘餘物藉由急速管柱層析法純化(25g二氧化矽,0-20%MTBE/石油醚)以產生呈無色油之2-亞甲基琥珀酸1-(2-(三級丁氧基)-2-側氧基乙基)酯4-(2,2,4,4-四甲基戊-3-基)酯(430mg,1.16mmol,81%)。LCMS(系統2,方法C)m/z 393.4(M+Na)+(ES+)。 Add 2-bromoacetic acid tertiary butyl ester (608mg, 3.12mmol) to 2-methylene-4- pendant oxy-4-((2,2,4,4-tetramethylpent-3-yl) A solution of oxy)butyric acid (400 mg, 1.56 mmol) and potassium carbonate (645 mg, 4.68 mmol) in acetone (10 mL), and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was filtered, and the filtrate was concentrated at 40°C under reduced pressure. The residue was purified by flash column chromatography (25 g silica, 0-20% MTBE/petroleum ether) to produce 2-methylene succinic acid 1-(2-(tertiary butoxy) as a colorless oil Yl)-2-oxoethyl) ester 4-(2,2,4,4-tetramethylpent-3-yl) ester (430 mg, 1.16 mmol, 81%). LCMS (System 2, Method C) m/z 393.4 (M+Na) + (ES + ).

步驟7 Step 7

將2-亞甲基琥珀酸1-(2-(三級丁氧基)-2-側氧基乙基)酯4-(2,2,4,4-四甲基戊-3-基)酯(430mg,1.16mmol)在TFA/DCM(2:1,6mL)中之溶液在室溫下攪拌1h。將反應混合物過濾並在減壓下於40℃濃縮濾液。將殘餘物藉由製備型HPLC純化(管柱:Waters X-Bridge C18 OBD 10μm 19 x 250mm;流速:20mL/min;溶劑系統:MeCN/(0.05% TFA/水)梯度:50-95% MeCN;收集波長:214nm)。將該等部分在減壓下於40℃濃縮以移除MeCN,並將殘餘物凍乾以產生呈白色固體之2-((2-亞甲基-4-側氧基-4-((2,2,4,4-四甲基戊-3-基)氧基)丁醯基)氧基)乙酸(302mg,0.96mmol,83%)。LCMS(系統2,方法B)m/z 337.3(M+Na)+(ES+)。1H NMR(400MHz,CDCl3)δ:13.01(br,1H),6.30(d,J=1.2Hz,1H),5.97(s,J=1.2Hz,1H),4.62(s,2H),4.45(s,1H),3.45(s,2H),0.93(s,18H)。 The 2-methylene succinic acid 1-(2-(tertiary butoxy)-2-oxoethyl) ester 4-(2,2,4,4-tetramethylpent-3-yl) A solution of the ester (430 mg, 1.16 mmol) in TFA/DCM (2:1, 6 mL) was stirred at room temperature for 1 h. The reaction mixture was filtered and the filtrate was concentrated at 40°C under reduced pressure. The residue was purified by preparative HPLC (column: Waters X-Bridge C18 OBD 10μm 19 x 250mm; flow rate: 20mL/min; solvent system: MeCN/(0.05% TFA/water) gradient: 50-95% MeCN; Collection wavelength: 214nm). The fractions were concentrated under reduced pressure at 40°C to remove MeCN, and the residue was lyophilized to give 2-((2-methylene-4-oxo-4-((2 ,2,4,4-Tetramethylpent-3-yl)oxy)butyryl)oxy)acetic acid (302 mg, 0.96 mmol, 83%). LCMS (System 2, Method B) m/z 337.3 (M+Na) + (ES + ). 1 H NMR(400MHz,CDCl 3 )δ: 13.01(br,1H), 6.30(d,J=1.2Hz,1H), 5.97(s,J=1.2Hz,1H), 4.62(s,2H), 4.45 (s, 1H), 3.45 (s, 2H), 0.93 (s, 18H).

實施例77-3-((2-亞甲基-4-側氧基-4-(2,2,4,4-四甲基環丁氧基)丁醯基)氧基)丙酸[SYX-00948] Example 77-3-((2-Methylene-4- pendant oxy-4-(2,2,4,4-tetramethylcyclobutoxy)butyryl)oxy)propionic acid (SYX-00948 ]

Figure 109137209-A0202-12-0109-193
Figure 109137209-A0202-12-0109-193

實施例77根據實施例3之程序製備,但使用2,2,4,4-四甲基環丁-1-醇代替伊康酸4-辛酯。LCMS(系統2,方法B)m/z 335.2(M+Na)+(ES+)。1H NMR(400MHz,DMSO-d6)δ 12.41(br,1H),6.17(d,J=1.2Hz,1H),5.85(d,J=0.8Hz,1H),4.36(s,1H),4.25(t,J=2.0Hz,2H),3.39(s,2H),2.59(t,J=2.0Hz,2H),1.51(d,J=11.6Hz,1H),1.41(d,J=11.6Hz,1H),1.10(s,6H),1.00(s,6H)。 Example 77 was prepared according to the procedure of Example 3, but using 2,2,4,4-tetramethylcyclobutan-1-ol instead of 4-octyl itaconic acid. LCMS (System 2, Method B) m/z 335.2 (M+Na) + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 12.41(br,1H), 6.17(d,J=1.2Hz,1H), 5.85(d,J=0.8Hz,1H), 4.36(s,1H), 4.25 (t,J=2.0Hz,2H),3.39(s,2H),2.59(t,J=2.0Hz,2H),1.51(d,J=11.6Hz,1H),1.41(d,J=11.6Hz ,1H),1.10(s,6H),1.00(s,6H).

生物例1-THP-1 AlphaLISA IL-1β和IL-6細胞介素分析 Biological example 1-THP-1 AlphaLISA IL-1β and IL-6 cytokines analysis

測量對從THP-1s輸出之IL-1β和IL-6細胞介素的抑制效應 Measure the inhibitory effect on IL-1β and IL-6 cytokines exported from THP-1s

在分化THP-1細胞分析中測定式(I)化合物的細胞介素抑制輪廓。除非另有說明,否則所有分析均在補充有10%胎牛血清(FBS;Gibco)、1%青黴素-鏈黴素及1%丙酮酸鈉的RPMI-1640生長培養基(Gibco)中進行。如下所述,分別在分化THP-1細胞的背景下進行各IL-1β和IL-6細胞介素抑制分析。除非另有說明,否則所述的試劑全部均來自Sigma-Aldrich。將化合物製備為100mM DMSO儲備液。 The cytokine inhibition profile of the compound of formula (I) was determined in the analysis of differentiated THP-1 cells. Unless otherwise stated, all analyses were performed in RPMI-1640 growth medium (Gibco) supplemented with 10% fetal bovine serum (FBS; Gibco), 1% penicillin-streptomycin, and 1% sodium pyruvate. As described below, each IL-1β and IL-6 cytokine inhibition analysis was performed on the background of differentiated THP-1 cells. Unless otherwise stated, all the reagents described are from Sigma-Aldrich. The compound was prepared as a 100 mM DMSO stock solution.

分析程序 Analysis procedure

在適當生長培養基中,THP-1細胞以懸浮液形式擴展至80%的匯合。將細胞收穫,懸浮並用適當濃度的巴豆醇-12-十四烷酸酯-13-乙酸酯(phorbol-12-myristate-13-acetate)(PMA)處理經72hr。 In an appropriate growth medium, THP-1 cells expand to 80% confluence in suspension. The cells were harvested, suspended and treated with appropriate concentration of phorbol-12-myristate-13-acetate (PMA) for 72 hours.

在THP-1細胞培養72hr後,將細胞培養基移出並換成含有1%FBS的新鮮生長培養基。在10%FBS處理之生長培養基中分別製備工作濃度的化合物,並以細胞預培養30分鐘(37℃/5%CO2)。化合物預培養30分鐘後,將THP-1s用適當 濃度的LPS處理,隨後培養24hr(37℃/5% CO2)。接著將適當最終濃度的尼日利亞菌素(Nigericin)分配至THP-1板中,並培養1小時(37℃/5% CO2),之後收集THP-1上清液並單獨地收集在聚丙烯96孔固定板中,然後開始進行AlphaLISA細胞介素分析。 After the THP-1 cells were cultured for 72 hours, the cell culture medium was removed and replaced with fresh growth medium containing 1% FBS. Compounds of working concentration were prepared in the growth medium treated with 10% FBS, and the cells were pre-cultured for 30 minutes (37°C/5% CO 2 ). After the compound was pre-incubated for 30 minutes, THP-1s was treated with an appropriate concentration of LPS, and then incubated for 24 hr (37°C/5% CO 2 ). Then distribute the appropriate final concentration of nigericin to the THP-1 plate and incubate for 1 hour (37°C/5% CO 2 ), then collect the THP-1 supernatant and separately collect it in polypropylene 96 Fix the plate in the well, and then start the AlphaLISA cytokine analysis.

按照製造廠說明書製備並操作來自各IL-1β和IL-6商業套組(Perkin Elmer)之試劑。隨後,在微板讀數器(EnVision® Multilabel Reader,Perkin Elmer)中測量螢光信號檢測。 The reagents from each IL-1β and IL-6 commercial kit (Perkin Elmer) were prepared and operated according to the manufacturer's instructions. Subsequently, fluorescence signal detection was measured in a microplate reader (EnVision ® Multilabel Reader, Perkin Elmer).

藉由將樣品數據標準化為各板中使用的高和低對照組(分別為+/-LPS)來計算每細胞介素的抑制百分比。接著將百分比抑制對化合物濃度作圖及從所得濃度-反應曲線測定50%抑制濃度(IC50)。 The percent inhibition per cytokine was calculated by normalizing the sample data to the high and low control groups used in each plate (+/-LPS, respectively). Next, the percent inhibition was plotted against compound concentration and resulting from the concentration - response curves measured 50% inhibition concentration (IC 50).

測試許多實施例式(I)化合物,結果係顯示於下表1中。使用伊康酸二甲酯及延胡索酸二甲酯作為比較劑化合物。相較於伊康酸二甲酯及/或延胡索酸二甲酯,表1中所示之所有式(I)化合物呈現IL-1β及/或IL-6之可比較或改良的細胞介素-降低效力。相較於伊康酸二甲酯及/或延胡索酸二甲酯,某些化合物呈現IL-1β及/或IL-6之改良的細胞介素-降低效力。 Many example compounds of formula (I) were tested, and the results are shown in Table 1 below. Dimethyl iticonate and dimethyl fumarate were used as comparator compounds. Compared with dimethyl iconate and/or dimethyl fumarate, all compounds of formula (I) shown in Table 1 exhibit comparable or improved cytokine-decrease of IL-1β and/or IL-6 Effectiveness. Compared to dimethyl iconate and/or dimethyl fumarate, certain compounds exhibit improved cytokine-reducing efficacy of IL-1β and/or IL-6.

表1-THP-1細胞IL-1β和IL-6IC50值(μM)

Figure 109137209-A0202-12-0110-121
Table 1-THP-1 cells IL-1β and IL-6 IC 50 values (μM)
Figure 109137209-A0202-12-0110-121

Figure 109137209-A0202-12-0111-122
Figure 109137209-A0202-12-0111-122

Figure 109137209-A0202-12-0112-123
Figure 109137209-A0202-12-0112-123

NT*=未經測試 NT*=Untested

生物例2-人初單核細胞AlphaLISAIL-1β和IL-6細胞介素分析 Biological example 2-Analysis of human primary monocytes AlphaLISAIL-1β and IL-6 cytokines

測量對從分離的初人單核細胞輸出之IL-1β和IL-6細胞介素的抑制效應 Measure the inhibitory effect on IL-1β and IL-6 cytokines exported from isolated primary human monocytes

在CD14+分離的初人單核細胞分析中測定式(I)化合物的細胞介素抑制輪廓。除非另有說明,否則所有分析均在補充有熱滅活胎牛血清(FBS)和1%青 黴素-鏈黴素的RPMI-1640生長培養基(Gibco)中進行。如下所述,分別在分離的初人單核細胞的背景下進行各IL-1β和IL-6細胞介素抑制分析。除非另有說明,否則所述的試劑全部均來自Sigma-Aldrich。將化合物製備為100mM DMSO儲備液。 The cytokine inhibition profile of the compound of formula (I) was determined in the analysis of CD14 + isolated naive human monocytes. Unless otherwise stated, all analyses were performed in RPMI-1640 growth medium (Gibco) supplemented with heat-inactivated fetal bovine serum (FBS) and 1% penicillin-streptomycin. As described below, each IL-1β and IL-6 cytokine inhibition analysis was performed on the background of isolated primary human monocytes. Unless otherwise stated, all the reagents described are from Sigma-Aldrich. The compound was prepared as a 100 mM DMSO stock solution.

分析程序 Analysis procedure

從人全血中分離初末梢血液單核細胞(PBMCs)。PBMC分離後,進行CD14+單核細胞分離步驟,藉以將CD14+磁珠(Miltenyi Biotec)以預先用冰冷的T細胞分離緩衝液(PBS,0.5%BSA,2mM EDTA)處理之PBMC懸浮液培養15分鐘。磁珠培養後,將經處理的細胞懸液通過設計用於正選擇磁性標記細胞的磁分離管柱。隨後,在鋪平當天進行化合物處理之前,將分離的CD14+單核細胞以適當細胞密度鋪平進行分析。在僅RPMI-1640生長培養基中分別製備工作濃度的化合物,並以細胞預培養30分鐘(37℃/5% CO2)。化合物預培養30分鐘後,將初單核細胞用適當濃度的LPS處理,隨後培養24hr(37℃/5% CO2)。接著將適當最終濃度的尼日利亞菌素(Nigericin)分配至初單核細胞板中,並培養1小時(37℃/5% CO2),之後收獲並收集單核細胞上清液在個別聚丙烯96孔固定板中,然後開始進行AlphaLISA細胞介素分析。 Isolate primary peripheral blood mononuclear cells (PBMCs) from human whole blood. After PBMC is separated, perform the CD14 + monocyte separation step, whereby CD14 + magnetic beads (Miltenyi Biotec) are incubated with PBMC suspension that has been pre-treated with ice-cold T cell separation buffer (PBS, 0.5% BSA, 2mM EDTA) 15 minute. After the magnetic beads are cultured, the processed cell suspension is passed through a magnetic separation column designed for positive selection of magnetically labeled cells. Subsequently, the isolated CD14 + monocytes were flattened at an appropriate cell density for analysis before compound treatment on the day of flattening. Compounds of working concentration were prepared in RPMI-1640 growth medium only, and cells were pre-cultured for 30 minutes (37°C/5% CO 2 ). After the compound was pre-incubated for 30 minutes, the primary monocytes were treated with an appropriate concentration of LPS, and then cultured for 24 hours (37°C/5% CO 2 ). Then distribute the appropriate final concentration of nigericin to the primary mononuclear cell plate, and incubate for 1 hour (37℃/5% CO 2 ), then harvest and collect the monocyte supernatant in the individual polypropylene 96 Fix the plate in the well, and then start the AlphaLISA cytokine analysis.

按照製造廠說明書製備來自各IL-1β和IL-6商業套組(Perkin Elmer)之試劑,並進行操作。隨後,在微板讀數器(EnVision® Multilabel Reader,Perkin Elmer)中測量螢光信號。 Prepare reagents from each IL-1β and IL-6 commercial kit (Perkin Elmer) according to the manufacturer's instructions, and proceed. Subsequently, the fluorescence signal was measured in a microplate reader (EnVision ® Multilabel Reader, Perkin Elmer).

藉由將樣品數據標準化為各板中使用的高和低對照組(分別為+/-LPS)來計算每細胞介素的抑制百分比。接著將百分比抑制對化合物濃度作圖及從所得濃度-反應曲線測定50%抑制濃度(IC50)。 The percent inhibition per cytokine was calculated by normalizing the sample data to the high and low control groups used in each plate (+/-LPS, respectively). Next, the percent inhibition was plotted against compound concentration and resulting from the concentration - response curves measured 50% inhibition concentration (IC 50).

測試許多實施例式(I)化合物,結果係顯示於下表2中。使用延胡索酸二甲酯及伊康酸4-辛酯作為比較劑化合物。所有測試的化合物均呈現比伊康酸4-辛酯低的IC50Many example compounds of formula (I) were tested, and the results are shown in Table 2 below. Dimethyl fumarate and 4-octyl itaconic acid were used as comparator compounds. All tested compounds exhibited lower IC50 than 4-octyl Iconate.

表2-初單核細胞IL-1β和IL-6IC50值(μM)

Figure 109137209-A0202-12-0114-124
Table 2-Primary monocyte IL-1β and IL-6 IC 50 values (μM)
Figure 109137209-A0202-12-0114-124

NT*=未經測試 NT*=Untested

生物例3-NRF2+/-GSH活化分析 Biological example 3-NRF2+/-GSH activation analysis

在DiscoverX PathHunter NRF2易位套組中測量對抗發炎轉錄因子NRF2的化合物活化效應 Measure the compound activation effect of the anti-inflammatory transcription factor NRF2 in the DiscoverX PathHunter NRF2 translocation kit

使用PathHunter NRF2易位套組(DiscoverX)測定式(I)化合物針對感興趣的靶標活化NRF2(核因子紅血球2相關因子2(nuclear factor erythroid 2-related factor 2))的效力和功效。使用工程改造的重組細胞系,利用酶片段互補來確定Keap1-NRF2蛋白複合物的活化以及隨後將NRF2易位到核中進行NRF2易位分析。使用在PK靶定的NRF2易位到細胞核中形成功能性酶後消耗之化學發光受質來定量酶活性。 The PathHunter NRF2 translocation kit (DiscoverX) was used to determine the potency and efficacy of the compound of formula (I) to activate NRF2 (nuclear factor erythroid 2-related factor 2) against the target of interest. Using an engineered recombinant cell line, enzyme fragment complementation was used to determine the activation of the Keap1-NRF2 protein complex and subsequently translocate NRF2 into the nucleus for NRF2 translocation analysis. The chemiluminescent substrate consumed after the PK-targeted NRF2 translocates into the nucleus to form a functional enzyme is used to quantify the enzyme activity.

該分析在+/-GSH(麩胱甘肽)條件下運行,以測定GSH對目標化合物的衰減活性。 The analysis was run under +/-GSH (glutathione) conditions to determine the attenuating activity of GSH on target compounds.

另外,將定義濃度的延胡索酸二甲酯用作為‘高’對照組,以標準化測試化合物的活化反應。 In addition, a defined concentration of dimethyl fumarate was used as a'high' control group to standardize the activation response of the test compound.

分析程序 Analysis procedure

在鋪平之前,將U2OS PathHunter eXpress細胞從冷凍解凍。鋪平後,將U2OS細胞在提供細胞培養基的市售套組中培養24小時(37℃/5%CO2)。 Before paving, U2OS PathHunter eXpress cells were thawed from freezing. After paving, the U2OS cells were cultured for 24 hours (37°C/5% CO 2 ) in a commercially available kit provided with cell culture media.

在U2OS培養24小時後,對於-GSH條件,用適當最終濃度的化合物直接處理細胞,或+GSH條件,以6mM工作濃度的GSH溶液(溶於無菌PBS)中製備含有6x工作濃度之化合物儲備液的中間板。將化合物-GSH預培養30分鐘(37℃/5%CO2)用於+GSH處理後,將鋪平的U2OS細胞以適當終濃度的化合物和GSH培養。 After 24 hours of culture in U2OS, for -GSH conditions, directly treat the cells with the appropriate final concentration of the compound, or +GSH conditions, prepare a 6x working concentration compound stock solution in a 6mM working concentration GSH solution (dissolved in sterile PBS) Middle plate. After pre-incubating compound-GSH for 30 minutes (37°C/5%CO 2 ) for +GSH treatment, the flattened U2OS cells were cultured with appropriate final concentrations of compound and GSH.

化合物(+/-GSH)處理後,按照製造廠說明書在製備來自PathHunter NRF2商業套組的檢測試劑之前,將U2OS平板再培養6小時(37℃/5%CO2),及將其添加到測試板中。隨後,在微板讀數器中測量發光信號檢測(PHERAstar®,BMG Labtech)。 After compound (+/-GSH) treatment, incubate the U2OS plate for another 6 hours (37°C/5%CO 2 ) and add it to the test according to the manufacturer’s instructions before preparing the detection reagents from the PathHunter NRF2 commercial kit In the board. Subsequently, the luminescence signal detection was measured in a microplate reader (PHERAstar®, BMG Labtech).

藉由將樣品數據標準化為各板中使用的高/低對照組(+/-DMF)來計算百分比活化。接著對化合物濃度繪製百分比活化/反應,並從作圖之濃度-反應曲線中確定50%活化濃度(EC50)。 The percent activation was calculated by normalizing the sample data to the high/low control (+/-DMF) used in each plate. Next, the percentage activation/reaction is plotted against the compound concentration, and the 50% activation concentration (EC 50 ) is determined from the plotted concentration-response curve.

測試許多式(I)化合物,結果係顯示於下表3中。包括伊康酸二甲酯及延胡索酸二甲酯作為比較劑化合物。與伊康酸二甲酯及/或延胡索酸二甲酯比較,表3所示的某些式(I)化合物呈現較低或相當的EC50及/或較高EmaxMany compounds of formula (I) were tested and the results are shown in Table 3 below. Including dimethyl iconate and dimethyl fumarate as comparator compounds. Compared with dimethyl iconate and/or dimethyl fumarate, some of the compounds of formula (I) shown in Table 3 exhibit lower or comparable EC 50 and/or higher E max .

表3-NRF2活化

Figure 109137209-A0202-12-0115-194
Table 3-NRF2 activation
Figure 109137209-A0202-12-0115-194

Figure 109137209-A0202-12-0116-126
Figure 109137209-A0202-12-0116-126

生物例4-老鼠藥物動力學研究 Biological example 4-rat pharmacokinetic study

以可自由進食和飲水的6-8週齡雄性C57BL/6雄性小鼠進行藥物動力學研究。經由尾靜脈注射以10mg/kg(5mL/kg;媒液:10%DMSO-90%(在水中之25%HP-β-CD))進行靜脈給藥,並在3min、8min、15min、30min、1、2、4、6和8小時(即總共9個時間點)(N=3/時間點)使用半串行血漿出血(semi-serial bleeding for plasma)取樣。經由胃管灌食法以100mg/kg(10mL/kg;媒液:5%DMSO-95%(在水中之0.5%HPMC+0.1%Tween 80))進行口服化合物投予,分別在5min、15min、30min、1、2、4、6、8及24小時(即總共9個時間點)(N=3/時間點)使用半串行血漿出血(semi-serial bleeding for plasma)取樣。 The pharmacokinetic study was carried out with 6-8 week old male C57BL/6 male mice with free eating and drinking. 10mg/kg (5mL/kg; vehicle: 10% DMSO-90% (25% HP-β-CD in water)) via tail vein injection for intravenous administration, and at 3min, 8min, 15min, 30min, 1, 2, 4, 6 and 8 hours (ie 9 time points in total) (N=3/time point) were sampled using semi-serial bleeding for plasma. The compound was administered orally at 100 mg/kg (10 mL/kg; vehicle: 5% DMSO-95% (0.5% HPMC + 0.1% Tween 80 in water)) via gastric gavage, at 5 min, 15 min, 30min, 1, 2, 4, 6, 8 and 24 hours (ie 9 time points in total) (N=3/time point) were sampled using semi-serial bleeding for plasma.

對於靜脈內和口服途徑,在指定的時間點將小鼠人工約束,經由面靜脈將約110μL血液吸入K2EDTA管中。將血液樣品放在冰上並離心以獲得血漿樣品,藉由LC-MS/MS測量在各時間點之血漿樣品的濃度。 For the intravenous and oral routes, the mice were artificially restrained at the designated time point, and approximately 110 μL of blood was drawn into the K2EDTA tube via the facial vein. The blood sample was placed on ice and centrifuged to obtain a plasma sample, and the concentration of the plasma sample at each time point was measured by LC-MS/MS.

測試許多式(I)化合物,結果係顯示於下表4和表5中。包括伊康酸二甲酯作為比較劑化合物。所有式(I)化合物呈現比伊康酸二甲酯高的全身性暴 露,其只在靜脈內給藥後的一個時間點可定量,且在口服投予後的所有時間點均低於定量限制。 Many compounds of formula (I) were tested and the results are shown in Table 4 and Table 5 below. Include dimethyl iconate as a comparator compound. All compounds of formula (I) exhibit a higher systemic violence than dimethyl iconate It can only be quantified at one time point after intravenous administration, and it is below the quantitative limit at all time points after oral administration.

表4-靜脈投予後親體化合物濃度(ng/mL)

Figure 109137209-A0202-12-0117-195
Table 4-Concentration of parent compound after intravenous administration (ng/mL)
Figure 109137209-A0202-12-0117-195

Figure 109137209-A0202-12-0118-128
Figure 109137209-A0202-12-0118-128

*未取樣的時間點用破折號表示,“─“。 *The time points that are not sampled are indicated by dashes, "─".

表5-口服投予後之親體化合物濃度(ng/mL)

Figure 109137209-A0202-12-0118-129
Table 5-Parent compound concentration after oral administration (ng/mL)
Figure 109137209-A0202-12-0118-129

Figure 109137209-A0202-12-0119-130
Figure 109137209-A0202-12-0119-130

*未取樣的時間點用破折號表示,“─“。 *The time points that are not sampled are indicated by dashes, "─".

這些結果表明本發明化合物顯示改良的全身性暴露,如在此分析中某些式(I)化合物的血漿濃度所示。當靜脈投予時,與衣康酸二甲酯比較,表4中所示的所有式(I)化合物呈現較高的全身暴露,及當口服投予時,表5中所示的所有式(I)化合物均表現出較高的全身暴露。 These results indicate that the compounds of the present invention show improved systemic exposure, as shown by the plasma concentrations of certain compounds of formula (I) in this analysis. When administered intravenously, all the compounds of formula (I) shown in Table 4 exhibited higher systemic exposure compared with dimethyl itaconate, and when administered orally, all the compounds of formula (I) shown in Table 5 ( I) The compounds all showed higher systemic exposure.

生物例5-肝細胞穩定性分析 Biological Example 5-Analysis of Hepatocyte Stability

解凍之冷凍保存的肝細胞(生存力>70%)用於經由計算生性清除率(intrinsic clearance)(Clint;在沒有血流和細胞結合的情況下從肝臟中清除化合物的測量)來測定化合物的代謝穩定性。清除率數據對於體外操作特別重要,因為彼等可與體內數據結合使用,以預測藥物的半衰期和口服生體可用率。 Thawed and cryopreserved liver cells (viability> 70%) are used to determine the compound by calculating the intrinsic clearance (Cl int ; the measurement of the clearance of the compound from the liver without blood flow and cell binding) Metabolic stability. Clearance data is particularly important for in vitro operations because they can be used in conjunction with in vivo data to predict the half-life of drugs and oral bioavailability.

肝細胞分析中的代謝穩定性涉及使用陽性和陰性對照組的時間依賴性反應。細胞必須在37℃下預培養,接著摻入測試化合物(及陽性對照組);分析於預定時間間隔採集的樣品,以監測60分鐘內初始藥物化合物濃度的變化。緩衝液培養反應(不存在肝細胞)用作陰性對照組,及兩種含有已知高和低清除率值的化合物(維拉帕米(verapamil)/7-羥基香豆素和普萘洛爾(propranolol)/地爾硫卓(diltiazem))之雞尾酒溶(cocktail)液則用作陽性對照組。 Metabolic stability in hepatocyte analysis involves time-dependent reactions using positive and negative controls. The cells must be pre-cultured at 37°C, and then the test compound (and positive control group) is incorporated; samples collected at predetermined time intervals are analyzed to monitor changes in the initial drug compound concentration within 60 minutes. Buffer culture reaction (without hepatocytes) was used as a negative control group, and two compounds containing known high and low clearance values (verapamil/7-hydroxycoumarin and propranolol) The cocktail of propranolol/diltiazem was used as a positive control group.

1.在Leibovitz緩衝液中以0.5 x 106細胞/mL的細胞濃度進行分析。 1. Analysis of cell concentration of 0.5 x 10 6 cells / mL in Leibovitz buffer.

2.所有化合物和對照組均一式兩份操作。 2. All compounds and the control group were operated in duplicate.

3.化合物濃度為10μM。 3. The compound concentration is 10 μM.

4.將所有化合物和對照組以兩種細胞和緩衝液培養,以顯示更換(turnover)是由於肝代謝。 4. All the compounds and the control group were cultured with two kinds of cells and buffer to show that the turnover is due to liver metabolism.

5.培養板上的所有孔都將添加326.7μL細胞或緩衝液。 5. All wells on the culture plate will be added with 326.7μL of cells or buffer.

6.在分析之前,將僅含細胞和緩衝液的培養板在37℃下預培養10分鐘。 6. Before analysis, pre-incubate the culture plate containing only cells and buffer at 37°C for 10 minutes.

7.藉由加3.3μL的在10%DMSO-90%緩衝液中之1mM的化合物開始分析;最終DMSO濃度為0.1%。 7. Start the analysis by adding 3.3 μL of 1 mM compound in 10% DMSO-90% buffer; the final DMSO concentration is 0.1%.

8.在定期時間點(0、5、10、20、40、60分鐘)取樣,直到60分鐘。 8. Take samples at regular time points (0, 5, 10, 20, 40, 60 minutes) until 60 minutes.

9.樣品體積為40μL,並將其加至160μL衝擊溶液(crash solvent)(具有內標物之乙腈)中,並儲存在冰上。 9. The sample volume is 40 μL, and it is added to 160 μL crash solvent (acetonitrile with internal standard) and stored on ice.

10.分析結束時,將衝擊(crash)板在4℃下以3500rpm離心20分鐘。 10. At the end of the analysis, the crash plate was centrifuged at 3500 rpm for 20 minutes at 4°C.

11.移除80μL的澄清上清液,及與80μL的去離子水混合,接著以LC-MS/MS分析。 11. Remove 80 μL of clear supernatant, and mix with 80 μL of deionized water, and then analyze by LC-MS/MS.

將原始LC-MS/MS數據輸出至Microsoft Excel並在其中進行分析,以測定內生性清除率(intrinsic clearance)。使用初始濃度的峰面積作為100%監測化合物的剩餘百分比。使用剩餘百分數之自然對數對反應時間(分鐘)的圖計算內生性清除率和半衰期。使用圖的斜率(排除速率常數,k)和方程式1和2計算半衰期(min)和內生性清除率(Clint,μL min-1 10-6細胞中)值。 The raw LC-MS/MS data was exported to Microsoft Excel and analyzed there to determine the intrinsic clearance. Use the peak area of the initial concentration as the remaining percentage of the 100% monitoring compound. A plot of the natural logarithm of the remaining percentage versus reaction time (minutes) was used to calculate the endogenous clearance and half-life. Use the slope of the graph (excluding rate constant, k) and equations 1 and 2 to calculate the half-life (min) and endogenous clearance (Cl int , μL min -1 10 -6 cells) values.

Figure 109137209-A0202-12-0121-132
Figure 109137209-A0202-12-0121-132

Figure 109137209-A0202-12-0121-133
Figure 109137209-A0202-12-0121-133

在此分析中測試許多在生物例4中測試過的式(I)化合物,其結果顯示在下表6中。包括伊康酸4-辛酯作為比較劑化合物。 Many of the compounds of formula (I) tested in Biological Example 4 were tested in this analysis, and the results are shown in Table 6 below. Include 4-octyl itaconic acid as a comparator compound.

表6-肝細胞穩定性

Figure 109137209-A0202-12-0121-134
Table 6-Hepatocyte Stability
Figure 109137209-A0202-12-0121-134

Figure 109137209-A0202-12-0122-135
Figure 109137209-A0202-12-0122-135

*NT表示未在其分析中測試 *NT means not tested in its analysis

這些結果表明預期本發明化合物(至少表6中的化合物)具有可接受的或改良的代謝穩定性,如在此分析中以彼等之內生性清除率(intrinsic clearance)(CIint)和半衰期(T1/2)值顯示。與伊康酸4-辛酯比較,表6中所示的所有式(I)化合物都較穩定,即,至少在人類或小鼠物種中彼等呈現較低內生性清除率(CIint)和較長半衰期(T1/2)值。與伊康酸4-辛酯比較,在人類及小鼠物種中,較佳化合物皆呈現較低內生性清除率(CIint)和較長半衰期(T1/2)值。 These results indicate that the compounds of the present invention (at least the compounds in Table 6) are expected to have acceptable or improved metabolic stability, such as their intrinsic clearance (CI int ) and half-life ( T 1/2 ) value display. Compared with 4-octyl itaconic acid, all the compounds of formula (I) shown in Table 6 are relatively stable, that is, at least in human or mouse species, they exhibit a lower endogenous clearance rate (CI int ) and Longer half-life (T 1/2 ) value. Compared with 4-octyl itaconic acid, in human and mouse species, the better compounds show lower endogenous clearance (CI int ) and longer half-life (T 1/2 ) values.

生物例6-式(I)化合物的代謝物 Biological Example 6-Metabolites of the compound of formula (I)

Figure 109137209-A0202-12-0123-136
Figure 109137209-A0202-12-0123-136

實施例21[SYX-00748]進行體內水解以形成中間物6[SYX-00229],如以小鼠藥物動力學研究所證實-根據生物例4中概述的方案進行-其數據顯示於表7中。在生物例1和3所述之分析中測試中間物6[SYX-00229],結果列於表8中。實施例21[SYX-00748]也顯示為延胡索酸二甲酯[SYX-00023]及伊康酸二甲酯[SYX-00002],彼等作為比較劑化合物。 Example 21 [SYX-00748] was hydrolyzed in vivo to form Intermediate 6 [SYX-00229], as confirmed by the mouse pharmacokinetic study-according to the protocol outlined in Biological Example 4-the data is shown in Table 7 . Intermediate 6 [SYX-00229] was tested in the analysis described in Biological Examples 1 and 3, and the results are listed in Table 8. Example 21 [SYX-00748] is also shown as dimethyl fumarate [SYX-00023] and dimethyl iconate [SYX-00002], which are used as comparator compounds.

表7-對小鼠以100mg/kg口服投予後之實施例21[SYX-00748]及中間物6[SYX-00229]濃度(ng/mL)

Figure 109137209-A0202-12-0123-196
Table 7-Concentrations of Example 21 [SYX-00748] and Intermediate 6 [SYX-00229] after oral administration of 100 mg/kg to mice (ng/mL)
Figure 109137209-A0202-12-0123-196

*BQL表示低於可量化的限制 *BQL means below the quantifiable limit

如表7所示,這些結果表明中間物6(其為實施例21[SYX-00748])的代謝物)顯示改良的全身性暴露,如以此分析中之化合物的血漿濃度所示。當口服投予時,與伊康酸二甲酯比較,中間物6呈現更高的全身性暴露。 As shown in Table 7, these results indicate that Intermediate 6 (which is a metabolite of Example 21 [SYX-00748]) shows improved systemic exposure, as shown by the plasma concentration of the compound in this analysis. When administered orally, Intermediate 6 exhibited higher systemic exposure than dimethyl iconate.

表8:中間物6[SYX-00229]之生物分析數據

Figure 109137209-A0202-12-0124-138
Table 8: Bioanalysis data of Intermediate 6 [SYX-00229]
Figure 109137209-A0202-12-0124-138

如表8中所示,與伊康酸二甲酯比較,中間物6(其為實施例21[SYX-00748]的代謝物))呈現IL-1β及IL-6之改良的細胞介素-降低效力,及較低EC50及較高Emax。與延胡索酸二甲酯比較,中間物6亦顯示較高EmaxAs shown in Table 8, compared with dimethyl iconate, Intermediate 6 (which is a metabolite of Example 21 [SYX-00748]) exhibits improved cytokines for IL-1β and IL-6- Decrease effectiveness, and lower EC 50 and higher E max . Compared with dimethyl fumarate, Intermediate 6 also showed a higher E max .

參考文獻 references

本說明書中引用的下列出版物以彼等之全文以引用方式併入本文。 The following publications cited in this specification are incorporated herein by reference in their entirety.

Ackermann et al. Proc. Soc. Exp. Bio. Med. 1949, 72(1), 1-9. Ackermann et al. Proc. Soc. Exp. Bio. Med. 1949, 72(1), 1-9.

Andersen J. L. et al. Nat. Commun. 2018, 9, 4344. Andersen J. L. et al. Nat. Commun. 2018, 9, 4344.

Angiari S. and O’Neill L. A. Cell Res. 2018, 28, 613-615. Angiari S. and O’Neill L. A. Cell Res. 2018, 28, 613-615.

Bagavant G. et al. Indian J. Pharm. Sci. 1994, 56, 80-85. Bagavant G. et al. Indian J. Pharm. Sci. 1994, 56, 80-85.

Bambouskova M. et al. Nature 2018, 556, 501-504. Bambouskova M. et al. Nature 2018, 556, 501-504.

Blewett M. M. et al. Sci. Sign. 2016, 9 (445), rs10; 6. Blewett M. M. et al. Sci. Sign. 2016, 9 (445), rs10; 6.

Brennan M. S. et al. PLoS One 2015, 10, e0120254. Brennan M. S. et al. PLoS One 2015, 10, e0120254.

Brück J. et al. Exp. Dermatol. 2018, 27, 611-624. Brück J. et al. Exp. Dermatol. 2018, 27, 611-624.

Cocco M. et al. J. Med. Chem. 2014, 57, 10366-10382. Cocco M. et al. J. Med. Chem. 2014, 57, 10366-10382.

Cocco M. et al. J. Med. Chem. 2017, 60, 3656-3671. Cocco M. et al. J. Med. Chem. 2017, 60, 3656-3671.

Cordes T. et al. J. Biol. Chem. 2016, 291, 14274-14284. Cordes T. et al. J. Biol. Chem. 2016, 291, 14274-14284.

Cordes T. et al. Mol. Metab. 2020, 32, 122-135. Cordes T. et al. Mol. Metab. 2020, 32, 122-135.

Daly R. et al. medRxiv 2019, 19001594; doi: https://doi.org/10.1101/19001594. Daly R. et al. medRxiv 2019, 19001594; doi: https://doi.org/10.1101/19001594.

Daniels B. P. et al. Immunity 2019, 50(1), 64-76.e4. Daniels B. P. et al. Immunity 2019, 50(1), 64-76.e4.

Dibbert S. et al. Arch. Dermatol. Res. 2013, 305, 447-451. Dibbert S. et al. Arch. Dermatol. Res. 2013, 305, 447-451.

ElAzzouny M. et al. J. Biol. Chem. 2017, 292, 4766-4769. ElAzzouny M. et al. J. Biol. Chem. 2017, 292, 4766-4769.

Gillard G. O. et al. J. Neuroimmunol. 2015, 283, 74-85. Gillard G. O. et al. J. Neuroimmunol. 2015, 283, 74-85.

Gu L. et al. Immunol. Cell Biol. 2020 doi:10.1111/imcb.12316. Gu L. et al. Immunol. Cell Biol. 2020 doi:10.1111/imcb.12316.

Hanke T. et al. Pharmacol. Therapeut. 2016, 157, 163-187. Hanke T. et al. Pharmacol. Therapeut. 2016, 157, 163-187.

Hunt T. et al. Consortium of Multiple Sclerosis Centers 2015 Annual Meeting, 27-30 May 2015, Indianapolis, IN, USA: Poster DX37. Hunt T. et al. Consortium of Multiple Sclerosis Centers 2015 Annual Meeting, 27-30 May 2015, Indianapolis, IN, USA: Poster DX37.

Kornberg M. D. et al. Science 2018, 360, 449-453. Kornberg M. D. et al. Science 2018, 360, 449-453.

Kulkarni R. A. et al. Nat. Chem. Biol. 2019 10.1038/s41589-018-0217-y. Kulkarni R. A. et al. Nat. Chem. Biol. 2019 10.1038/s41589-018-0217-y.

Lampropoulou V. et al. Cell Metab. 2016, 24, 158-166. Lampropoulou V. et al. Cell Metab. 2016, 24, 158-166.

Lehmann J. C. U. et al. J. Invest. Dermatol. 2007, 127, 835-845. Lehmann J. C. U. et al. J. Invest. Dermatol. 2007, 127, 835-845.

Liao S.-T. et al. Nat. Commun. 2019, 10(1), 5091. Liao S.-T. et al. Nat. Commun. 2019, 10(1), 5091.

Liu H. et al. Cell Commun. Signal. 2018, 16, 81. Liu H. et al. Cell Commun. Signal. 2018, 16, 81.

McGuire V. A. et al. Sci. Rep. 2016, 6, 31159. McGuire V. A. et al. Sci. Rep. 2016, 6, 31159.

Michelucci A. et al. Proc. Natl. Acad. Sci. USA 2013, 110, 7820-7825. Michelucci A. et al. Proc. Natl. Acad. Sci. USA 2013, 110, 7820-7825.

Mills E. A. et al. Front. Neurol. 2018, 9, 5. Mills E. A. et al. Front. Neurol. 2018, 9, 5.

Mills E. L. et al. Cell 2016, 167, 457-470. Mills E. L. et al. Cell 2016, 167, 457-470.

Mills E. L. et al. Nature 2018, 556, 113-117. Mills E. L. et al. Nature 2018, 556, 113-117.

Mrowietz U. et al. Trends Pharmacol. Sci. 2018, 39, 1-12. Mrowietz U. et al. Trends Pharmacol. Sci. 2018, 39, 1-12.

Müller S. et al. J. Dermatol. Sci. 2017, 87, 246-251. Müller S. et al. J. Dermatol. Sci. 2017, 87, 246-251.

Murphy M. P. and O’Neill L. A. J. Cell 2018, 174, 780-784. Murphy M. P. and O’Neill L. A. J. Cell 2018, 174, 780-784.

O’Neill L. A. J. and Artyomov M. N. Nat. Rev. Immunol. 2019273-281. O’Neill L. A. J. and Artyomov M. N. Nat. Rev. Immunol. 2019273-281.

Olagnier D. et al. Nat. Commun. 2018, 9, 3506. Olagnier D. et al. Nat. Commun. 2018, 9, 3506.

Schmidt T. J. et al. Bioorg. Med. Chem. 2007, 15, 333-342. Schmidt T. J. et al. Bioorg. Med. Chem. 2007, 15, 333-342.

Shan Q. et al. Biochem. Biophys. Res. Commun. 2019, 517, 538-544. Shan Q. et al. Biochem. Biophys. Res. Commun. 2019, 517, 538-544.

Straub R. H. and Schradin C. Evol. Med. Public Health 2016, 1, 37-51S. Straub R. H. and Schradin C. Evol. Med. Public Health 2016, 1, 37-51S.

Straub R. H. and Cutolo M. Rheumatology 2016, 55 (Suppl. 2), ii6-ii14. Straub R. H. and Cutolo M. Rheumatology 2016, 55 (Suppl. 2), ii6-ii14.

Sun X. et al., FASEB J. 2019, 33, 12929-12940. Sun X. et al., FASEB J. 2019, 33, 12929-12940.

Tang C. et al. Cell Physiol. Biochem. 2018, 51, 979-990. Tang C. et al. Cell Physiol. Biochem. 2018, 51, 979-990.

Tang C. et al. Biochem. Biophys. Res. Commun. 2019, 508, 921-927. Tang C. et al. Biochem. Biophys. Res. Commun. 2019, 508, 921-927.

Tang H. et al. Biochem. Biophys. Res. Commun. 2008, 375, 562-565. Tang H. et al. Biochem. Biophys. Res. Commun. 2008, 375, 562-565.

Tian et al. Eur. J. Pharmacol. 2020, 873, 172989. Tian et al. Eur. J. Pharmacol. 2020, 873, 172989.

van der Reest J. et al. Nat. Commun. 2018, 9, 1581. van der Reest J. et al. Nat. Commun. 2018, 9, 1581.

von Glehn F. et al. Mult. Scler. Relat. Disord. 2018, 23, 46-50. von Glehn F. et al. Mult. Scler. Relat. Disord. 2018, 23, 46-50.

Yi F. et al. Hepatology 2020, 873, 172989. Yi F. et al. Hepatology 2020, 873, 172989.

Yu X.-H. et al. Immunol. Cell Biol. 2019, 97, 134-141. Yu X.-H. et al. Immunol. Cell Biol. 2019, 97, 134-141.

Zhang S. et al. Bioorg. Med. Chem. 2012, 20, 6073-6079. Zhang S. et al. Bioorg. Med. Chem. 2012, 20, 6073-6079.

Zhang D. et al. Int. Immunopharmacol. 2019, 77, 105924. Zhang D. et al. Int. Immunopharmacol. 2019, 77, 105924.

Zhao C. et al. Microb. Pathogen. 2019, 133, 103541. Zhao C. et al. Microb. Pathogen. 2019, 133, 103541.

Zhao G. et al. Biochem. Biophys. Res. Commun. 2014, 448, 303-307. Zhao G. et al. Biochem. Biophys. Res. Commun. 2014, 448, 303-307.

雜項 Miscellaneous

本申請案中所引用的所有參考文獻(包括專利和專利申請案)以最大可能程度的引用方式併入本文。 All references (including patents and patent applications) cited in this application are incorporated herein by reference to the greatest possible extent.

在整個說明書以及所附申請專利範圍中,除非上下文另有要求,否則詞語‘包含’,及變體諸如‘包含(comprises和comprising)’應理解為暗示包括所述整數、步驟、整數組或步驟組,但不排除任何其他整數、步驟、整數組或步驟組。 Throughout the specification and the scope of the appended application, unless the context requires otherwise, the word “comprises” and variants such as “comprises (comprises and comprising)” should be understood to imply including the integers, steps, groups of integers, or steps. Group, but does not exclude any other integers, steps, groups of integers, or groups of steps.

本說明書和申請專利範圍形成其一部分的申請案可用作關於任何後續申請案的優先權的基礎。該後續申請案的申請專利範圍可關於本文所述的任 何特徵或特徵的組合。彼等可採取產物、組成物、方法、或用途申請專利範圍的形式,並且可包括(舉例來說)但不限於下列申請專利範圍。 This specification and the application of which the scope of patent application forms a part can be used as the basis for the priority of any subsequent application. The scope of patent application for this subsequent application may be related to any of the What feature or combination of features. They can take the form of product, composition, method, or use patented scope, and can include, for example, but not limited to the following patented scope.

Figure 109137209-A0202-11-0002-3
Figure 109137209-A0202-11-0002-3

Claims (68)

一種式(I)化合物: A compound of formula (I):
Figure 109137209-A0202-13-0001-140
Figure 109137209-A0202-13-0001-140
其中, in, RA係選自由下列所組成之群組:C1-10烷基、C3-10環烷基和C5-10螺環烷基;其中RA未經取代或經一或多個選自由下列所組成群組之取代基取代:側氧基、R1A、OR2A、NR2AR3A、SR2A、SOR9A、SO2R9A、SO2NR2AR3A、C(O)R2A和CONR2AR3AR A group consisting of the following selected from the group consisting of: C 1-10 alkyl, C 3-10 cycloalkyl and C 5-10 spiro cycloalkyl; wherein R A is unsubstituted or substituted with one or more selected from the group consisting of Substituent substitutions of the following groups: pendant oxy, R 1A , OR 2A , NR 2A R 3A , SR2 A , SOR 9A , SO 2 R 9A , SO 2 NR 2A R 3A , C(O)R 2A and CONR 2A R 3A ; R1A係選自由下列所組成之群組:氟基、甲基、氰基、SiR4AR5AR6A、C3-8環烷基和苯基;其中甲基、C3-8環烷基和苯基係未經取代或經R7A及/或R8A取代; R 1A is selected from the group consisting of fluoro, methyl, cyano, SiR 4A R 5A R 6A , C 3-8 cycloalkyl and phenyl; among them, methyl, C 3-8 cycloalkyl And phenyl is unsubstituted or substituted with R 7A and/or R 8A ; R4A、R5A和R6A係獨立地選自由下列所組成之群組:C1-4烷基和苯基; R 4A , R 5A and R 6A are independently selected from the group consisting of: C 1-4 alkyl and phenyl; R7A和R8A係獨立地選自由下列所組成之群組:側氧基、C1-4烷基、C1-4烷氧基、C1-4鹵烷基、C1-4鹵烷氧基、羥基、CO2H、氰基、甲磺醯基和鹵基; R 7A and R 8A are independently selected from the group consisting of: pendant oxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkyl Oxy, hydroxy, CO 2 H, cyano, methanesulfonyl and halo; 或,R7A和R8A一起形成C3-8環烷基或4-7員雜環; Or, R 7A and R 8A together form a C 3-8 cycloalkyl group or a 4-7 membered heterocyclic ring; R2A和R3A獨立地為H、C1-8烷基、C3-8環烷基或苯基; R 2A and R 3A are independently H, C 1-8 alkyl, C 3-8 cycloalkyl or phenyl; 或,R2A和R3A一起形成4-7員雜環; Or, R 2A and R 3A together form a 4-7 membered heterocyclic ring; R9A為C1-8烷基、C3-8環烷基或苯基;及 R 9A is C 1-8 alkyl, C 3-8 cycloalkyl or phenyl; and RB為經CO2H取代之C1-2烷基及係視需要地進一步經三氟甲基或甲基取代; R B is C 1-2 alkyl substituted with CO 2 H and optionally further substituted with trifluoromethyl or methyl; RC和RD係獨立地選自由下列所組成之群組:H、C1-2烷基、羥基、甲氧基和氟基; R C and R D are independently selected from the group consisting of H, C 1-2 alkyl, hydroxy, methoxy and fluoro; 或其醫藥上可接受的鹽及/或溶劑合物。 Or a pharmaceutically acceptable salt and/or solvate thereof.
根據請求項1之化合物,其中RA為C1-10烷基。 The requested item of Compound 1, wherein R A is C 1-10 alkyl. 根據請求項2之化合物,其中RA為C1-8烷基。 The compound of the requested item 2, wherein R A is C 1-8 alkyl. 根據請求項3之化合物,其中RA為庚基-CH(CH3)-或己基-CH(CH3)-。 The compound of the requested item 3, wherein R A is a heptyl group -CH (CH 3) - or hexyl group -CH (CH 3) -. 根據請求項4之化合物,其中RA為己基-CH(CH3)-。 The compound of the requested item 4, wherein R A is a hexyl group -CH (CH 3) -. 根據請求項5之化合物,其中RA具有下列結構: The compound of the requested item 5, wherein R A has the following structure:
Figure 109137209-A0202-13-0002-141
Figure 109137209-A0202-13-0002-141
根據請求項2之化合物,其中RA係選自由下列所組成之群組:正戊基-C(CH3)2-和正己基-C(CH3)2-。 The compound of the requested item 2, wherein R A system selected from the group consisting of: n-pentyl group -C (CH 3) 2 - and n-hexyl -C (CH 3) 2 -. 根據請求項2之化合物,其中RA係選自由下列所組成之群組:正己基-CH(CH3)-、正戊基-C(CH3)2-和正己基-C(CH3)2-。 The compound of the requested item 2, wherein R A group consisting of the following selected from the group consisting of: n-hexyl group -CH (CH 3) -, n-pentyl, -C (CH 3) 2 - and n-hexyl -C (CH 3) 2 -. 根據請求項1之化合物,其中RA為C3-10環烷基。 The requested item of Compound 1, wherein R A is C 3-10 cycloalkyl. 根據請求項9之化合物,其中RA為C3-8環烷基。 The compound of the requested item 9, wherein R A is a C 3-8 cycloalkyl group. 根據請求項1之化合物,其中RA為C5-10螺環烷基。 The requested item of Compound 1, wherein R A is a C 5-10 spiro cycloalkyl. 根據請求項1至11中任一項之化合物,其中RA係未經取代。 A compound of the requested item 1 to 11, wherein R A is unsubstituted system. 根據請求項1至11中任一項之化合物,其中RA係經取代。 A compound of the requested item 1 to 11, wherein R A system substituted. 根據請求項12之化合物,其中RA係經單一基團取代。 The compound according to item 12 of the request, wherein R A system via a single substituent group. 根據請求項13或14之化合物,其中RA係經R1A取代。 Compound of the requested item 13 or 14, wherein R A system substituted by R 1A. 根據請求項15之化合物,其中RA係經一個R1A取代。 The compound according to claim 15, wherein R A is substituted with one R 1A. 根據請求項15之化合物,其中RA係經兩個R1A取代。 The compound of the requested item 15, wherein R A system substituted with two R 1A. 根據請求項15之化合物,其中RA係經三個R1A取代。 The compound of the requested item 15, wherein R A system substituted with three R 1A. 根據請求項1至18中任一項之化合物,其中各R1A為相同。 The compound according to any one of claims 1 to 18, wherein each R 1A is the same. 根據請求項1至18中任一項之化合物,其中各R1A為不相同。 The compound according to any one of claims 1 to 18, wherein each R 1A is different. 根據請求項1至20中任一項之化合物,其中R1A係選自由下列所組成之群組:氟基、甲基、氰基、SiR4AR5AR6A和苯基。 The compound according to any one of claims 1 to 20, wherein R 1A is selected from the group consisting of fluoro, methyl, cyano, SiR 4A R 5A R 6A and phenyl. 根據請求項之化合物,其中R1A為氟基。 The compound according to claim, wherein R 1A is a fluoro group. 根據請求項1至13中任一項之化合物,其中RA為經三個氟基團取代之C1-10烷基,其中該三個氟基團連接至相同末端碳原子以形成CF3基團。 The requested item of a compound according to 13, wherein R A is a fluorine-substituted groups of three C 1-10 alkyl, wherein the three fluoro groups attached to the same carbon atom to form a terminal CF 3 group group. 根據請求項21之化合物,其中R1A為苯基。 The compound according to claim 21, wherein R 1A is phenyl. 根據請求項1至24中任一項之化合物,其中當R1A係選自甲基、C3-8環烷基和苯基時,該甲基、C3-8環烷基或苯基係未經取代。 The compound according to any one of claims 1 to 24, wherein when R 1A is selected from methyl, C 3-8 cycloalkyl and phenyl, the methyl, C 3-8 cycloalkyl or phenyl is Not replaced. 根據請求項1至24中任一項之化合物,其中當R1A係選自甲基、C3-8環烷基和苯基時,該甲基、C3-8環烷基或苯基係經取代。 The compound according to any one of claims 1 to 24, wherein when R 1A is selected from methyl, C 3-8 cycloalkyl and phenyl, the methyl, C 3-8 cycloalkyl or phenyl is Replaced. 根據請求項26之化合物,其中該甲基、C3-8環烷基或苯基係經R7A或R8A取代。 The compound according to claim 26, wherein the methyl, C 3-8 cycloalkyl or phenyl group is substituted with R 7A or R 8A. 根據請求項26之化合物,其中該甲基、C3-8環烷基或苯基係經R7A和R8A取代。 The compound according to claim 26, wherein the methyl, C 3-8 cycloalkyl or phenyl group is substituted with R 7A and R 8A. 根據請求項27或28任一項之化合物,其中R7A和R8A係獨立地選自由下列所組成之群組:側氧基、C1-4烷基、C1-4烷氧基、羥基、CO2H、氰基、甲磺醯基和鹵基。 The compound according to any one of claim 27 or 28, wherein R 7A and R 8A are independently selected from the group consisting of pendant oxy, C 1-4 alkyl, C 1-4 alkoxy, hydroxyl , CO 2 H, cyano, methanesulfonyl and halo. 根據請求項29之化合物,其中R7A和R8A係獨立地選自由下列所組成之群組:側氧基、甲基、乙基、甲氧基、羥基、CO2H、氰基、甲磺醯基和鹵基。 The compound according to claim 29, wherein R 7A and R 8A are independently selected from the group consisting of pendant oxy, methyl, ethyl, methoxy, hydroxyl, CO 2 H, cyano, methanesulfonate Aceto and halo. 根據請求項30之化合物,其中R7A和R8A為氟基。 The compound according to claim 30, wherein R 7A and R 8A are fluoro groups. 根據請求項1至31中任一項之化合物,其中RB為經CO2H取代之C1烷基。 The compound according to any one of claims 1 to 31, wherein R B is a C 1 alkyl substituted with CO 2 H. 根據請求項1至31中任一項之化合物,其中RB為經CO2H取代之C2烷基。 The compound according to any one of claims 1 to 31, wherein R B is a C 2 alkyl substituted with CO 2 H. 根據請求項32或33中任一項之化合物,其中與酯氧原子相鄰的RB之碳原子亦連接至至少一個(諸如一個)氫原子。 A compound according to any one of the requested item 32 or 33, wherein the carbon adjacent to the ester oxygen atom of R B is also connected to at least one (such as one) hydrogen atoms. 根據請求項33之化合物,其中RB為經CO2H取代之C2烷基,其中CO2H連接至末端之碳。 The compound of the requested item 33, wherein R B is substituted by the CO 2 H C 2 alkyl, CO 2 H wherein the carbon is connected to the end of. 根據請求項1至35中任一項之化合物,其中RB為未進一步經取代。 Compound a requested item of any of 1 to 35, wherein R B is not further substituted. 根據請求項1至35中任一項之化合物,其中RB係進一步經三氟甲基取代。 Compound a requested item of any of 1 to 35, wherein R B system further substituted with trifluoromethyl. 根據請求項1至35中任一項之化合物,其中RB係進一步經甲基取代。 Compound a requested item of any of 1 to 35, wherein R B system further substituted with methyl. 根據請求項37或38之化合物,其中該三氟甲基或甲基基團係與酯氧原子相鄰的RB之碳原子連接。 The compound of items 37 or 38 requests, wherein the trifluoromethyl group or a methyl group and an ester-based carbon atom adjacent to the oxygen atom of R B is connected. 根據請求項1至39中任一項之化合物,其中RC為H。 A compound according to any one of claims 1 to 39, wherein R C is H. 根據請求項1至39中任一項之化合物,其中RC為C1-2烷基,特別是甲基。 A compound according to any one of claims 1 to 39, wherein R C is C 1-2 alkyl, especially methyl. 根據請求項1至39中任一項之化合物,其中RC為羥基。 The compound according to any one of claims 1 to 39, wherein R C is a hydroxyl group. 根據請求項1至39中任一項之化合物,其中RC為氟基。 The compound according to any one of claims 1 to 39, wherein R C is a fluoro group. 根據請求項1至39中任一項之化合物,其中RC為甲氧基。 The compound according to any one of claims 1 to 39, wherein R C is methoxy. 根據請求項1至44中任一項之化合物,其中RD為H。 A compound according to any one of claims 1 to 44, wherein R D is H. 根據請求項1之化合物,其係選自由下列組成的名單: The compound according to claim 1, which is selected from the list consisting of: 2-((2-亞甲基-4-(辛氧基)-4-側氧基丁醯基)氧基)乙酸[SYX-00205]; 2-((2-methylene-4-(octyloxy)-4- pendant oxybutyryl)oxy)acetic acid [SYX-00205]; 2-((2-亞甲基-4-(辛氧基)-4-側氧基丁醯基)氧基)丙酸[SYX-00223]; 2-((2-methylene-4-(octyloxy)-4- pendant oxybutyryl)oxy)propionic acid [SYX-00223]; 3-((2-亞甲基-4-(辛氧基)-4-側氧基丁醯基)氧基)丙酸[SYX-00230]; 3-((2-methylene-4-(octyloxy)-4- pendant oxybutyryl)oxy)propionic acid [SYX-00230]; 3-((4-((4-氟苯甲基)氧基)-2-亞甲基-4-側氧基丁醯基)氧基)丙酸[SYX-00331]; 3-((4-((4-fluorobenzyl)oxy)-2-methylene-4-oxobutanoyl)oxy)propionic acid [SYX-00331]; 3-((4-(環辛氧基)-2-亞甲基-4-側氧基丁醯基)氧基)丙酸[SYX-00332]; 3-((4-(cyclooctyloxy)-2-methylene-4- pendant oxybutyryl)oxy)propionic acid [SYX-00332]; 3-((2-亞甲基-4-(新戊氧基)-4-側氧基丁醯基)氧基)丙酸[SYX-00333]; 3-((2-methylene-4-(neopentyloxy)-4- pendant oxybutyryl)oxy)propionic acid [SYX-00333]; (S)-3-((2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁醯基)氧基)丙酸[SYX-00338]; (S)-3-((2-methylene-4-(oct-2-yloxy)-4- pendant oxybutyryl)oxy)propionic acid [SYX-00338]; 3-((4-(己氧基)-2-亞甲基-4-側氧基丁醯基)氧基)丙酸[SYX-00339]; 3-((4-(hexyloxy)-2-methylene-4- pendant oxybutyryl)oxy)propionic acid [SYX-00339]; 3-((2-亞甲基-4-側氧基-4-(3-苯氧基丙氧基)丁醯基)氧基)丙酸[SYX-00340]; 3-((2-methylene-4- pendant oxy-4-(3-phenoxypropoxy)butyryl)oxy)propionic acid [SYX-00340]; 3-((4-(環己氧基)-2-亞甲基-4-側氧基丁醯基)氧基)丙酸[SYX-00345]; 3-((4-(cyclohexyloxy)-2-methylene-4-oxobutyryl)oxy)propionic acid [SYX-00345]; (R)-3-((2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁醯基)氧基)丙酸[SYX-00347]; (R)-3-((2-methylene-4-(oct-2-yloxy)-4- pendant oxybutyryl)oxy)propionic acid [SYX-00347]; (S)-2-((2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁醯基)氧基)乙酸[SYX-00245]; (S)-2-((2-methylene-4-(oct-2-yloxy)-4-oxobutanoyl)oxy)acetic acid [SYX-00245]; 2-((4-(環辛氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00255]; 2-((4-(cyclooctyloxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00255]; 2-((4-(環己氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00259]; 2-((4-(cyclohexyloxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00259]; 2-((2-亞甲基-4-(新戊氧基)-4-側氧基丁醯基)氧基)乙酸[SYX-00310]; 2-((2-methylene-4-(neopentyloxy)-4- pendant oxybutyryl)oxy)acetic acid [SYX-00310]; 2-((4-((4-氟苯甲基)氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00330]; 2-((4-((4-fluorobenzyl)oxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00330]; 2-((4-(己氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00350]; 2-((4-(hexyloxy)-2-methylene-4- pendant oxybutyryl)oxy)acetic acid [SYX-00350]; 2-((2-亞甲基-4-側氧基-4-(3-苯氧基丙氧基)丁醯基)氧基)乙酸[SYX-00351]; 2-((2-methylene-4- pendant oxy-4-(3-phenoxypropoxy)butanoyl)oxy)acetic acid [SYX-00351]; 2-((2-亞甲基-4-側氧基-4-(螺[3.3]庚-2-基氧基)丁醯基)氧基)乙酸[SYX-00358]; 2-((2-methylene-4- pendant oxy-4-(spiro[3.3]heptan-2-yloxy)butanoyl)oxy)acetic acid [SYX-00358]; 2-((4-(環己氧基)-2-亞甲基-4-側氧基丁醯基)氧基)丙酸[SYX-00393]; 2-((4-(cyclohexyloxy)-2-methylene-4-oxobutyryl)oxy)propionic acid [SYX-00393]; (R)-2-((2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁醯基)氧基)乙酸[SYX-00748]; (R)-2-((2-methylene-4-(oct-2-yloxy)-4-oxobutanoyl)oxy)acetic acid [SYX-00748]; 2-((4-((4,4-二氟環己基)甲氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00392]; 2-((4-((4,4-Difluorocyclohexyl)methoxy)-2-methylene-4-oxobutyryl)oxy)acetic acid [SYX-00392]; 2-((4-(3-乙氧基丙氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00388]; 2-((4-(3-ethoxypropoxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00388]; 2-((4-(雙環[2.2.1]庚-2-基氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00413]; 2-((4-(Bicyclo[2.2.1]heptan-2-yloxy)-2-methylene-4-oxobutyryl)oxy)acetic acid [SYX-00413]; 2-((4-環丁氧基-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00414]; 2-((4-Cyclobutoxy-2-methylene-4- pendant oxybutyryl)oxy)acetic acid [SYX-00414]; 2-((4-(環己氧基)-2-亞甲基-4-側氧基丁醯基)氧基)-3,3,3-三氟丙酸[SYX-00430]; 2-((4-(cyclohexyloxy)-2-methylene-4- pendant oxybutyryl)oxy)-3,3,3-trifluoropropionic acid [SYX-00430]; 2-((4-(環辛氧基)-2-亞甲基-4-側氧基丁醯基)氧基)-3,3,3-三氟丙酸[SYX-00713]; 2-((4-(cyclooctyloxy)-2-methylene-4- pendant oxybutyryl)oxy)-3,3,3-trifluoropropionic acid [SYX-00713]; 3-((4-(環辛氧基)-2-亞甲基-4-側氧基丁醯基)氧基)-4,4,4-三氟丁酸[SYX-00761]; 3-((4-(cyclooctyloxy)-2-methylene-4- pendant oxybutyryl)oxy)-4,4,4-trifluorobutanoic acid [SYX-00761]; 2-(4-(環庚氧基)-2-亞甲基-4-側氧基丁醯氧基)乙酸[SYX-00820]; 2-(4-(cycloheptyloxy)-2-methylene-4-oxobutanoyloxy)acetic acid [SYX-00820]; 2-(2-亞甲基-4-(辛-3-基氧基)-4-側氧基丁醯氧基)乙酸[SYX-00826]; 2-(2-methylene-4-(oct-3-yloxy)-4-oxobutanoyloxy)acetic acid [SYX-00826]; 2-(2-亞甲基-4-(辛-4-基氧基)-4-側氧基丁醯氧基)乙酸[SYX-00827]; 2-(2-methylene-4-(oct-4-yloxy)-4-oxobutanoyloxy)acetic acid [SYX-00827]; 2-((4-(庚-4-基氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00828]; 2-((4-(hept-4-yloxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00828]; 2-((4-((金剛烷-2-基)氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00830]; 2-((4-((adamantan-2-yl)oxy)-2-methylene-4-oxobutyryl)oxy)acetic acid [SYX-00830]; 2-((4-(1-環己基乙氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00831]; 2-((4-(1-cyclohexylethoxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00831]; 2-((4-(1-環庚基乙氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00833]; 2-((4-(1-cycloheptylethoxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00833]; 2-(2-亞甲基-4-側氧基-4-(螺[3.4]辛-2-基氧基)丁醯氧基)乙酸[SYX-00834]; 2-(2-methylene-4- pendant oxy-4-(spiro[3.4]oct-2-yloxy)butanoyloxy)acetic acid [SYX-00834]; 2-(2-亞甲基-4-側氧基-4-(螺[3.5]壬-2-基氧基)丁醯氧基)乙酸[SYX-00835]; 2-(2-methylene-4- pendant oxy-4-(spiro[3.5]non-2-yloxy)butanoyloxy)acetic acid [SYX-00835]; 2-(2-亞甲基-4-側氧基-4-(螺[3.5]壬-7-基氧基)丁醯氧基)乙酸[SYX-00836]; 2-(2-methylene-4- pendant oxy-4-(spiro[3.5]non-7-yloxy)butanoyloxy)acetic acid [SYX-00836]; 2-((4-((2,2-二甲基環己基)氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00844]; 2-((4-((2,2-dimethylcyclohexyl)oxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00844]; 2-((4-(環辛氧基)-3-甲基-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00843]; 2-((4-(cyclooctyloxy)-3-methyl-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00843]; 2-((2-亞甲基-4-側氧基-4-(2,2,4,4-四甲基環丁氧基)丁醯基)氧基)乙酸[SYX-00878]; 2-((2-methylene-4- pendant oxy-4-(2,2,4,4-tetramethylcyclobutoxy)butyryl)oxy)acetic acid [SYX-00878]; (S)-2-(2-亞甲基-4-(辛-3-基氧基)-4-側氧基丁醯氧基)乙酸[SYX-00879]; (S)-2-(2-methylene-4-(oct-3-yloxy)-4-oxobutanoyloxy)acetic acid [SYX-00879]; 2-((4-(環辛氧基)-3-甲氧基-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00880]; 2-((4-(cyclooctyloxy)-3-methoxy-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00880]; 2-((4-((-金剛烷-1-基)氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00881]; 2-((4-((-adamantan-1-yl)oxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00881]; (R)-2-((4-(庚-2-基氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00890]; (R)-2-((4-(hept-2-yloxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00890]; 2-((2-亞甲基-4-(壬-2-基氧基)-4-側氧基丁醯基)氧基)乙酸[SYX-00891]; 2-((2-methylene-4-(non-2-yloxy)-4- pendant oxybutyryl)oxy)acetic acid [SYX-00891]; 2-((2-亞甲基-4-(壬-5-基氧基)-4-側氧基丁醯基)氧基)乙酸[SYX-00892]; 2-((2-methylene-4-(non-5-yloxy)-4- pendant oxybutyryl)oxy)acetic acid [SYX-00892]; 2-((4-(1-(3,5-二氯苯基)乙氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00894]; 2-((4-(1-(3,5-Dichlorophenyl)ethoxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00894]; 2-((4-((1-(3,5-二氯苯基)丙-2-基)氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00901]; 2-((4-((1-(3,5-Dichlorophenyl)prop-2-yl)oxy)-2-methylene-4-oxobutyryl)oxy)acetic acid (SYX- 00901]; (R)-2-(2-亞甲基-4-(辛-3-基氧基)-4-側氧基丁醯氧基)乙酸[SYX-00902]; (R)-2-(2-methylene-4-(oct-3-yloxy)-4-oxobutanoyloxy)acetic acid [SYX-00902]; 2-((2-亞甲基-4-側氧基-4-(((1R,2S,4R)-1,7,7-三甲基雙環[2.2.1]庚-2-基)氧基)丁醯基)氧基)乙酸[SYX-00904]; 2-((2-methylene-4- pendant oxy-4-(((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)oxy (Yl)butyryl)oxy)acetic acid [SYX-00904]; 2-((4-(1-環己基-2,2,2-三氟乙氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00905]; 2-((4-(1-cyclohexyl-2,2,2-trifluoroethoxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00905]; 2-((4-(雙環[3.3.1]壬-9-基氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00908]; 2-((4-(Bicyclo[3.3.1]non-9-yloxy)-2-methylene-4-oxobutyryl)oxy)acetic acid [SYX-00908]; (S)-2-((2-亞甲基-4-側氧基-4-((1,1,1-三氟辛-2-基)氧基)丁醯基)氧基)乙酸[SYX-00909]; (S)-2-((2-methylene-4- pendant oxy-4-((1,1,1-trifluorooct-2-yl)oxy)butyryl)oxy)acetic acid (SYX- 00909]; (R)-2-((2-亞甲基-4-(壬-2-基氧基)-4-側氧基丁醯基)氧基)乙酸[SYX-00928]; (R)-2-((2-methylene-4-(non-2-yloxy)-4-oxobutanoyl)oxy)acetic acid [SYX-00928]; (R)-2-((4-(1-環己基乙氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00929]; (R)-2-((4-(1-cyclohexylethoxy)-2-methylene-4- pendant oxybutyryl)oxy)acetic acid [SYX-00929]; (R)-4,4,4-三氟-3-((2-亞甲基-4-(((R)-辛-2-基)氧基)-4-側氧基丁醯基)氧基)丁酸[SYX-00930]; (R)-4,4,4-Trifluoro-3-((2-methylene-4-(((R)-oct-2-yl)oxy)-4-oxobutanoyl)oxy ) Butyric acid [SYX-00930]; 2-((4-(環辛氧基)-3-羥基-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00873]; 2-((4-(cyclooctyloxy)-3-hydroxy-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00873]; 2-(3-亞甲基-5-(4-甲基庚-4-基氧基)-5-側氧基戊基-1-烯-2-基氧基)乙酸[SYX-00900]; 2-(3-methylene-5-(4-methylhept-4-yloxy)-5-oxopentyl-1-en-2-yloxy)acetic acid [SYX-00900]; 2-((4-(1-環己基環丁氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00906]; 2-((4-(1-cyclohexylcyclobutoxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00906]; 2-((2-亞甲基-4-((2-甲基辛-2-基)氧基)-4-側氧基丁醯基)氧基)乙酸[SYX-00907]; 2-((2-methylene-4-((2-methyloct-2-yl)oxy)-4-oxobutanoyl)oxy)acetic acid [SYX-00907]; 2-((2-亞甲基-4-((2-甲基庚-2-基)氧基)-4-側氧基丁醯基)氧基)乙酸[SYX-00911]; 2-((2-methylene-4-((2-methylhept-2-yl)oxy)-4-oxobutanoyl)oxy)acetic acid [SYX-00911]; 2-((2-亞甲基-4-側氧基-4-(1-戊基環丁氧基)丁醯基)氧基)乙酸[SYX-00922]; 2-((2-methylene-4- pendant oxy-4-(1-pentylcyclobutoxy)butyryl)oxy)acetic acid [SYX-00922]; 2-((2-亞甲基-4-((2-甲基螺[3.5]壬-2-基)氧基)-4-側氧基丁醯基)氧基)乙酸[SYX-00923]; 2-((2-methylene-4-((2-methylspiro[3.5]non-2-yl)oxy)-4-oxobutyryl)oxy)acetic acid [SYX-00923]; 2-((2-亞甲基-4-側氧基-4-(((外)-1,7,7-三甲基雙環[2.2.1]庚-2-基)氧基)丁醯基)氧基)乙酸[SYX-00933]; 2-((2-methylene-4- pendant oxy-4-(((ex)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy)butanyl) (Oxy)acetic acid [SYX-00933]; 2-((2-亞甲基-4-側氧基-4-((2,2,6,6-四甲基環己基)氧基)丁醯基)氧基)乙酸[SYX-00938]; 2-((2-methylene-4- pendant oxy-4-((2,2,6,6-tetramethylcyclohexyl)oxy)butyryl)oxy)acetic acid [SYX-00938]; 2-((4-(1-(3,5-二氯苯基)乙氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸(異構物1)[SYX-00939]; 2-((4-(1-(3,5-Dichlorophenyl)ethoxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid (isomer 1) (SYX- 00939]; 2-((4-(1-(3,5-二氯苯基)乙氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸(異構物2)[SYX-00940]; 2-((4-(1-(3,5-Dichlorophenyl)ethoxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid (isomer 2) (SYX- 00940]; (R)-2-((2-亞甲基-4-側氧基-4-(1-(4-(三氟甲基)苯基)乙氧基)丁醯基)氧基)乙酸)[SYX-00941]; (R)-2-((2-Methylene-4-oxo-4-(1-(4-(trifluoromethyl)phenyl)ethoxy)butyryl)oxy)acetic acid)(SYX -00941]; (S)-2-((2-亞甲基-4-側氧基-4-(1-(4-(三氟甲基)苯基)乙氧基)丁醯基)氧基)乙酸)[SYX-00942]; (S)-2-((2-Methylene-4-oxo-4-(1-(4-(trifluoromethyl)phenyl)ethoxy)butyryl)oxy)acetic acid)(SYX -00942]; 2-((4-(1-環己基環丙氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00944]; 2-((4-(1-cyclohexylcyclopropoxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid [SYX-00944]; (S)-2-((4-(1-環己基乙氧基)-2-亞甲基-4-側氧基丁醯基)氧基)乙酸[SYX-00945]; (S)-2-((4-(1-cyclohexylethoxy)-2-methylene-4- pendant oxybutyryl)oxy)acetic acid [SYX-00945]; 2-((2-亞甲基-4-側氧基-4-((2,2,4,4-四甲基戊-3-基)氧基)丁醯基)氧基)乙酸[SYX-00946]; 2-((2-Methylene-4- pendant oxy-4-((2,2,4,4-tetramethylpent-3-yl)oxy)butyryl)oxy)acetic acid (SYX-00946 ]; (S)-4,4,4-三氟-3-((2-亞甲基-4-(((R)-辛-2-基)氧基)-4-側氧基丁醯基)氧基)丁酸[SYX-00947]; (S)-4,4,4-trifluoro-3-((2-methylene-4-(((R)-oct-2-yl)oxy)-4-oxobutanoyl)oxy ) Butyric acid [SYX-00947]; 2-((2-亞甲基-4-側氧基-4-(1-戊基環丙氧基)丁醯基)氧基)乙酸[SYX-00949];及 2-((2-methylene-4- pendant oxy-4-(1-pentylcyclopropoxy)butyryl)oxy)acetic acid [SYX-00949]; and 3-((2-亞甲基-4-側氧基-4-(2,2,4,4-四甲基環丁氧基)丁醯基)氧基)丙酸[SYX-00948]; 3-((2-methylene-4- pendant oxy-4-(2,2,4,4-tetramethylcyclobutoxy)butyryl)oxy)propionic acid [SYX-00948]; 或其任一者之醫藥上可接受的鹽及/或溶劑合物。 Or a pharmaceutically acceptable salt and/or solvate of any of them. 根據請求項1之化合物,其為: The compound according to claim 1, which is:
Figure 109137209-A0202-13-0008-143
Figure 109137209-A0202-13-0008-143
或其任一者之醫藥上可接受的鹽及/或溶劑合物[SYX-748]。 Or a pharmaceutically acceptable salt and/or solvate of any of them [SYX-748].
根據請求項1之化合物,其為: The compound according to claim 1, which is:
Figure 109137209-A0202-13-0008-144
Figure 109137209-A0202-13-0008-144
或其任一者之醫藥上可接受的鹽及/或溶劑合物[SYX-347]。 Or a pharmaceutically acceptable salt and/or solvate of any of them [SYX-347].
根據請求項1之化合物,其為: The compound according to claim 1, which is:
Figure 109137209-A0202-13-0009-145
Figure 109137209-A0202-13-0009-145
或其任一者之醫藥上可接受的鹽及/或溶劑合物[SYX-909]。 Or a pharmaceutically acceptable salt and/or solvate of any of them [SYX-909].
根據請求項1之化合物,其為: The compound according to claim 1, which is:
Figure 109137209-A0202-13-0009-146
Figure 109137209-A0202-13-0009-146
其任一者之醫藥上可接受的鹽及/或溶劑合物。[SYX-907] A pharmaceutically acceptable salt and/or solvate of any of them. [SYX-907]
一種醫藥組成物,其包含根據請求項1至50中任一項之化合物。 A pharmaceutical composition comprising a compound according to any one of claims 1 to 50. 一種根據請求項1至50中任一項之化合物或根據請求項51之醫藥組成物,其係用作為藥劑。 A compound according to any one of claims 1 to 50 or a pharmaceutical composition according to claim 51, which is used as a medicament. 一種根據請求項1至50中任一項之化合物或根據請求項51之醫藥組成物,其係用於治療或預防發炎性疾病或與不良免疫反應有關的疾病。 A compound according to any one of claims 1 to 50 or a pharmaceutical composition according to claim 51, which is used for the treatment or prevention of inflammatory diseases or diseases related to adverse immune reactions. 一種根據請求項1至50中任一項之化合物或根據請求項51之醫藥組成物於製造用以治療或預防發炎性疾病或與不良免疫反應有關的疾病之藥物的用途。 A use of a compound according to any one of claims 1 to 50 or a pharmaceutical composition according to claim 51 in the manufacture of a medicine for the treatment or prevention of inflammatory diseases or diseases related to adverse immune reactions. 一種治療或預防發炎性疾病或與不良免疫反應有關的疾病之方法,其包括投予根據請求項1至50中任一項之化合物或根據請求項51之醫藥組成物。 A method for treating or preventing inflammatory diseases or diseases related to adverse immune reactions, which comprises administering a compound according to any one of claims 1 to 50 or a pharmaceutical composition according to claim 51. 根據請求項1至55中任一項之化合物、醫藥組成物、使用之化合物、用途或方法,其係用於治療發炎性疾病或與不良免疫反應有關的疾病。 The compound, medical composition, used compound, use or method according to any one of claims 1 to 55, which is used to treat inflammatory diseases or diseases related to adverse immune reactions. 根據請求項1至55中任一項之化合物、醫藥組成物、使用之化合物、用途或方法,其係用於預防發炎性疾病或與不良免疫反應有關的疾病。 The compound, pharmaceutical composition, used compound, use or method according to any one of claims 1 to 55, which is used to prevent inflammatory diseases or diseases related to adverse immune reactions. 根據請求項1至55中任一項之化合物、醫藥組成物、使用之化合物、用途或方法,其係用於治療或預防發炎性疾病。 The compound, pharmaceutical composition, used compound, use or method according to any one of claims 1 to 55, which is used for the treatment or prevention of inflammatory diseases. 根據請求項1至55中任一項之化合物、醫藥組成物、使用之化合物、用途或方法,其係用於治療或預防與不良免疫反應有關的疾病。 The compound, pharmaceutical composition, used compound, use or method according to any one of claims 1 to 55, which is used to treat or prevent diseases related to adverse immune reactions. 根據請求項1至55中任一項之化合物、醫藥組成物、使用之化 合物、用途或方法,其中該發炎性疾病或與不良免疫反應有關的疾病為選自由下列所組成群組之疾病,或與之相關:牛皮癬(包括慢性斑塊性、紅皮性、膿皰、滴狀(guttate)、逆及指甲(nail)變異型)、氣喘、慢性阻塞性肺病(COPD,包括慢性支氣管炎及肺氣腫)、心臟衰竭(包括左心室衰竭)、心肌梗塞、狹心症、其他動脈粥狀硬化及/或動脈粥狀硬化相關疾病(包括末梢血管疾病及缺血性中風)、粒線體及神經退化性疾病(諸如帕金森氏症、阿茲海默症、杭丁頓氏舞蹈症、肌肉萎縮性脊髓側索硬化症、色素性視網膜炎或粒線體腦肌病(mitochondrial encephalomyopathy))、自體免疫伴腫瘤性視網膜病變(autoimmune paraneoplastic retinopathy)、移植排斥(包括抗體媒介和T細胞媒介的形式)、多發性硬化症、橫貫性脊髓炎(transverse myelitis)、缺血再灌注損傷(例如非急需手術期間諸如用於冠狀動脈繞道手術(coronary artery bypass grafting)之心肺分流或其他心臟手術、經皮冠狀動脈介入治療(percutaneous coronary intervention)後、急性ST上升型心肌梗塞的治療(ST-elevation myocardial infarction)或缺血性中風後、器官移植、或急性間隔症候群(compartment syndrome))、AGE-誘導之基因組損傷、發炎性腸道疾病(例如克隆氏症或潰瘍性結腸炎(ulcerative colitis))、原發性硬化性膽管炎(PSC)、PSC-自體免疫性肝炎重疊症候群、非酒精性脂肪肝(非酒精性脂肪肝炎)、風濕性多關節炎、環狀肉芽腫瘤、紅斑性狼瘡(CLE)、全身性紅斑狼瘡(SLE)、狼瘡性腎炎、藥物導致之狼瘡、自體免疫心肌炎或心肌心包炎(myopericarditis)、Dressler氏症候群、巨細胞心肌炎、心包膜切開後症候群、藥物導致之過敏性症候群(包括過敏性心肌炎)、濕疹、類肉瘤病、結節性紅斑、急性瀰漫性腦脊髓炎(ADEM)、視神經脊髓炎譜系疾病(neuromyelitis optica spectrum disorders)、MOG(髓鞘寡樹突神經膠質細胞糖蛋白質(myelin oligodendrocyte glycoprotein))抗體相關疾病(包括MOG-EM)、視神經炎(optic neuritis)、CLIPPERS(類固醇激素反應性慢性淋巴球性炎症伴橋腦血管周圍強化症(chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids))、彌漫性脫髓鞘硬化症(diffuse myelinoclastic sclerosis)、Addison氏病、斑禿、關節黏連性脊椎炎、其 他脊椎關節炎(spondyloarthritis)(包括周圍型脊椎關節炎(其與牛皮癬有關、發炎性腸道疾病、反應性關節或青少年發病形式))、抗磷脂質抗體症候群、自體免疫溶血性貧血(autoimmune hemolytic anemia)、自體免疫性肝炎、自體免疫性內耳病、類天疱瘡(包括大疱性類天疱瘡、黏膜類天疱瘡、瘢痕性類天疱瘡(cicatricial pemphigoid)、妊娠疱疹或妊娠期類天疱瘡、眼部瘢痕性類天疱瘡(ocular cicatricial pemphigoid))、線狀IgA病(linear IgA disease)、貝賽特氏病(Behçet’s disease)、乳糜瀉、Chagas氏病、皮肌炎、糖尿病I型、子宮內膜異位症、Goodpasture氏症候群、Graves氏病、格巴二氏症候群(Guillain-Barre syndrome)和其亞型(包括急性發炎去髓鞘型多發性神經病變、AIDP、急性運動軸索神經病變(acute motor axonal neuropathy)(AMAN)、急性運動及感覺軸索型神經病變(acute motor and sensory axonal neuropathy)(AMSAN)、咽-頸-臂變異型、Miller-Fisher變異型及畢氏腦幹腦炎(Bickerstaff’s brainstem encephalitis))、進行性發炎神經性病變(progressive inflammatory neuropathy)、橋本氏病、化膿性汗腺炎(hidradenitis suppurativa)、包涵體肌炎、壞死性肌病、Kawasaki氏病、IgA腎病變(IgA nephropathy)、Henoch-Schonlein二氏紫瘢病、自發性血小板減少紫瘢、栓塞性血小板減少性紫癜病(TTP)、Evans氏症候群、間質性膀胱炎(interstitial cystitis)、混合型結締組織疾病、未分化型結締組織病(undifferentiated connective tissue disease)、侷限性硬皮病、重症肌無力症(包括MuSK抗體陽性和血清反應陰性變異型)、嗜睡症、神經性肌強直(neuromyotonia)、尋常型天疱瘡、惡性貧血(pernicious anaemia)、牛皮癬性關節炎、多發性肌炎、原發性膽汁性膽管炎(primary biliary cholangitis)(也稱為原發性膽汁性肝硬化)、類風濕性關節炎、復發性風濕症(palindromic rheumatism)、思覺失調症、自體免疫性(腦膜)腦炎症候群、硬皮症、休格倫氏症候群、僵體症候群、風濕性多肌痛(polymylagia rheumatica)、巨大細胞動脈炎(顳動脈炎(temporal arteritis))、高安氏關節炎(Takayasu arteritis)、結節性多動脈炎、Kawasaki氏病、肉芽腫病伴多發性血管炎(granulomatosis with polyangitis)(GPA;以前稱為華格納肉芽腫病(Wegener’s granulomatosis))、嗜伊紅 性肉芽腫病伴多血管炎(eosinophilic granulomatosis with polyangiitis)(EGPA;以前稱為Churg-Strauss二氏症候群)、顯微多發性動脈炎/多血管炎、低補體型蕁麻疹性血管炎(hypocomplementaemic urticarial vasculitis)、過敏性血管炎(hypersensitivity vasculitis)、冷凝球蛋白血症、血栓閉塞性脈管炎(Buerger氏病)、血管炎、白血球破碎性血管炎、白斑病、急性瀰漫性腦脊髓炎、腎上腺腦白質病、亞歷山大氏(Alexander’s)病、阿爾珀氏(Alper’s)病、巴洛同心性硬化或馬堡病毒症(balo concentric sclerosis or Marburg disease)、隱源性組織化肺炎(以前稱為阻塞性細支氣管炎組織化肺炎)、Canavan病、中樞神經系統血管炎症候群、夏馬杜三氏病(Charcot-Marie-Tooth disease)、兒童共濟失調伴中樞神經系統髓鞘化不良(childhood ataxia with central nervous system hypomyelination)、慢性發炎去髓鞘型多發性神經病變(CIDP)、糖尿病性視網膜病、球狀細胞白血質障礙(克拉培氏病(Krabbe disease))、移植物抗宿主疾病(GVHD)(包括急性及慢性形式,以及腸GVHD)、C型肝炎(HCV)感染或併發症、單純皰疹病毒感染或併發症、人類免疫不全病毒(HIV)感染或併發症、扁平苔蘚、單肢肌萎縮症、囊腫纖維化、肺動脈高壓(PAH、包括特發性PAH)、肺類肉瘤病、特發性肺纖維化、小兒氣喘、異位性皮膚炎、過敏性皮膚炎、接觸性皮膚炎、過敏性鼻炎、鼻炎、鼻竇炎、結膜炎、過敏性結膜炎、乾性角膜結膜炎、乾眼症(dry eye)、乾眼症(xerophthalmia)、青光眼、黃斑水腫、糖尿病黃斑水腫、中心性視網膜靜脈阻塞(CRVO)、黃斑點退化(包括乾性及/或濕性年齡相關的黃斑點退化、AMD)、術後白內障發炎、葡萄膜炎(包括後、前、中間及全葡萄膜炎)、虹膜睫狀體炎、鞏膜炎、角膜移植物及角膜緣細胞移植排斥、麩質過敏性腸病(乳糜瀉)、疱疹性皮膚炎、嗜伊紅性食道炎、弛緩不能、自體免疫性自主神經機能障礙、自體免疫性腦脊髓炎、自體免疫性卵巢炎、自體免疫性睪丸炎、自體免疫性胰臟炎、主動脈炎及主動脈周圍炎(periaortitis)、自體免疫性視網膜病變、自體免疫性蕁痲疹、Behcet氏症、(特發性)Castleman氏病、Cogan氏症候群、IgG4相關疾病、腹膜後纖維變性、幼年型特發性關節炎包括系統性幼年型特發性關節炎(Still氏病)、成年發病型Still氏 病、木樣結膜炎、Mooren氏潰瘍、急性痘瘡樣苔蘚樣糠疹(pityriasis lichenoides et varioliformis acuta)(PLEVA,也稱為Mucha-Habermann二氏病)、多灶性運動神經病變(MMN)、小兒急性發作神經精神病症候群(PANS)(包括與鏈球菌感染相關的兒童自體免疫神經精神異常(PANDAS))、伴腫瘤症候群(包括伴腫瘤性小腦變性、Lambert-Eaton二氏肌無力症候群、邊緣性腦炎、腦幹腦炎、眼陣攣肌陣攣共濟失調症候群、抗NMDA受體腦炎、胸腺瘤相關的多器官自體免疫)、靜脈周性腦脊髓炎、反射性交感神經失養症、復發性多發性軟骨炎、精子和睾丸自體免疫、Susac氏症候群、Tolosa-Hunt症候群、Vogt-Koyanagi-Harada病、抗合成酶症候群、自體免疫性腸病變、X-性聯免疫失調多內分泌病變腸病變(IPEX)、顯微鏡結腸炎、自體免疫性淋巴球增生症候群(ALPS)、自體免疫性多發性內分泌病-念珠菌病-外胚層器官失養症候群(APEX)、痛風、假性痛風、類澱粉變性(包括AA或繼發性類澱粉變性)、嗜伊紅球性筋膜炎(Shulman症候群)黃體酮過敏(包括黃體酮皮膚炎)、家族性地中海熱(FMF)、腫瘤壞死因子(TNF)受體-相關的周期性發熱症候群(TRAPS)、高免疫球蛋白血症D伴有周期性發熱症候群(HIDS)、PAPA(化膿性關節炎、壞疽性膿皮症(pyoderma gangrenosum)、嚴重囊性痤瘡)症候群、介白素-1受體拮抗劑缺乏(DIRA)、介白素-36-受體拮抗劑缺乏(DITRA)、隱熱蛋白相關週期症候群(cryopyrin-associated periodic syndromes)(CAPS)(包括家族性寒冷型自體發炎症候群[FCAS]、穆-韋二氏症候群(Muckle-Wells syndrome)、新生兒發病多系統發炎性疾病[NOMID])、NLRP12-相關的自體發炎病症(NLRP12AD)、週期性發熱口瘡口炎(PFAPA)、慢性非典型嗜中性球性皮膚病伴脂質失養症及體溫升高(CANDLE)、Majeed症候群、Blau症候群(也稱為青少年全身性肉芽腫病)、巨噬細胞活化症候群、慢性復發性多灶性骨髓炎(CRMO)、家族性寒冷型自體發炎症候群、突變體腺苷去胺酶2及單基因干擾素病(包括Aicardi-Goutières症候群、視網膜血管病變伴有大腦白質腦病、脊椎動脈硬化發育不良、STING[干擾素基因的刺激物]-相關的嬰兒期發病的血管病變、蛋白酶體相關的自體發炎症候群、家族性凍瘡狀狼瘡、遺傳性對稱性色素沉著異常)、 Schnitzler症候群;家族性毛髮上皮瘤、先天性B淋巴球增多症、OTULIN-相關的自體發炎症候群、第2型糖尿病、胰島素抗性及代謝症候群(包括肥胖相關發炎)、動脈粥樣硬化病症(例如心肌梗塞、絞痛症、缺血性心臟衰竭、缺血性腎病、缺血性中風、末梢血管疾病、主動脈瘤)、腎臟發炎病症(例如糖尿病腎病變、膜性腎病變、微小改變疾病、新月形腎絲球腎炎、急性急性腎損傷、腎臟移植)。 According to any one of claims 1 to 55, the chemical compound, pharmaceutical composition, use Compound, use or method, wherein the inflammatory disease or disease related to adverse immune response is a disease selected from the group consisting of or is related to: psoriasis (including chronic plaque, erythroderma, pustular , Guttate, reverse and nail variants), asthma, chronic obstructive pulmonary disease (COPD, including chronic bronchitis and emphysema), heart failure (including left ventricular failure), myocardial infarction, stenosis Disease, other atherosclerosis and/or atherosclerosis-related diseases (including peripheral vascular disease and ischemic stroke), mitochondrial and neurodegenerative diseases (such as Parkinson’s disease, Alzheimer’s disease, Hangzhou Tinton's disease, amyotrophic lateral sclerosis, retinitis pigmentosa or mitochondrial encephalomyopathy (mitochondrial encephalomyopathy), autoimmune paraneoplastic retinopathy, transplant rejection (including Antibody vector and T cell vector), multiple sclerosis, transverse myelitis (transverse myelitis), ischemia-reperfusion injury (e.g. during non-urgent surgery such as heart and lung used for coronary artery bypass grafting) Shunt or other cardiac surgery, percutaneous coronary intervention, treatment of acute ST-elevation myocardial infarction (ST-elevation myocardial infarction) or after ischemic stroke, organ transplantation, or acute compartment syndrome (compartment) syndrome)), AGE-induced genome damage, inflammatory bowel disease (such as Crohn’s disease or ulcerative colitis), primary sclerosing cholangitis (PSC), PSC-autoimmune hepatitis Overlapping syndrome, non-alcoholic fatty liver (non-alcoholic steatohepatitis), rheumatoid polyarthritis, circular granuloma, lupus erythematosus (CLE), systemic lupus erythematosus (SLE), lupus nephritis, drug-induced lupus , Autoimmune myocarditis or myocardial pericarditis (myopericarditis), Dressler's syndrome, giant cell myocarditis, postpericardiotomy syndrome, drug-induced allergic syndrome (including allergic myocarditis), eczema, sarcoidosis, nodular Erythema, acute diffuse encephalomyelitis (ADEM), neuromyelitis optica spectrum disorders, MOG (myelin oligodendrocyte glycoprotein) antibody-related diseases ( Including MOG-EM), optic neuritis (optic neuritis), CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids), diffuse demyelination Sclerosis (diffuse myelinoclastic sclerosis), Addison's disease, alopecia areata, joint adhesive spondylitis, other Other spondyloarthritis (including peripheral spondyloarthritis (which is related to psoriasis, inflammatory bowel disease, reactive joint or juvenile onset forms)), antiphospholipid antibody syndrome, autoimmune hemolytic anemia (autoimmune hemolytic anemia), autoimmune hepatitis, autoimmune inner ear disease, pemphigoid (including bullous pemphigoid, mucosal pemphigoid, cicatricial pemphigoid), herpes pregnancy or pregnancy Pemphigus, ocular cicatricial pemphigoid), linear IgA disease, Behçet's disease, celiac disease, Chagas' disease, dermatomyositis, diabetes I Type, endometriosis, Goodpasture’s syndrome, Graves’ disease, Guillain-Barre syndrome and its subtypes (including acute inflamed demyelinating polyneuropathy, AIDP, acute motor axis Acute motor axonal neuropathy (AMAN), acute motor and sensory axonal neuropathy (AMSAN), pharynx-neck-arm variant, Miller-Fisher variant, and Pythagorean Brainstem encephalitis (Bickerstaff's brainstem encephalitis), progressive inflammatory neuropathy, Hashimoto's disease, hidradenitis suppurativa, inclusion body myositis, necrotizing myopathy, Kawasaki's disease, IgA nephropathy, Henoch-Schonlein purpura, spontaneous thrombocytopenic purpura, embolic thrombocytopenic purpura (TTP), Evans syndrome, interstitial cystitis, mixed Type connective tissue disease, undifferentiated connective tissue disease (undifferentiated connective tissue disease), localized scleroderma, myasthenia gravis (including MuSK antibody positive and seronegative variants), narcolepsy, neuromyotonia ), pemphigus vulgaris, pernicious anaemia, psoriatic arthritis, polymyositis, primary biliary bile ducts Inflammation (primary biliary cholangitis) (also called primary biliary cirrhosis), rheumatoid arthritis, recurrent rheumatism (palindromic rheumatism), schizophrenia, autoimmune (meningeal) cerebral inflammation syndrome, Scleroderma, Hughlen's syndrome, rigid body syndrome, polymylagia rheumatica (polymylagia rheumatica), giant cell arteritis (temporal arteritis), Takayasu arteritis (Takayasu arteritis), nodular polymyalgia Arteritis, Kawasaki's disease, granulomatosis with polyangitis (GPA; formerly known as Wegener's granulomatosis), eosinophilia Eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as Churg-Strauss syndrome), microscopic polyarteritis/polyangiitis, hypocomplementaemic urticarial vasculitis, hypersensitivity vasculitis, cryoglobulinemia, thromboangiitis obliterans (Buerger's disease), vasculitis, leukocyte crushing vasculitis, leukoplakia, acute diffuse encephalomyelitis, adrenal glands Leukemia, Alexander's disease, Alper's disease, Balo concentric sclerosis or Marburg disease, cryptogenic organized pneumonia (formerly known as obstructive Bronchiolitis tissue pneumonia), Canavan disease, central nervous system vascular inflammation syndrome, Charcot-Marie-Tooth disease, childhood ataxia with central nervous system nervous system hypomyelination), chronic inflammatory demyelinating polyneuropathy (CIDP), diabetic retinopathy, globular cell leukemia (Krabbe disease), graft versus host disease (GVHD) ( Including acute and chronic forms, as well as intestinal GVHD), hepatitis C (HCV) infection or complications, herpes simplex virus infection or complications, human immunodeficiency virus (HIV) infection or complications, lichen planus, single limb muscle atrophy Symptoms, cystic fibrosis, pulmonary hypertension (PAH, including idiopathic PAH), pulmonary sarcomatosis, idiopathic pulmonary fibrosis, infantile asthma, atopic dermatitis, allergic dermatitis, contact dermatitis, allergies Rhinitis, rhinitis, sinusitis, conjunctivitis, allergic conjunctivitis, dry keratoconjunctivitis, dry eye, xerophthalmia, glaucoma, macular edema, diabetic macular edema, central retinal vein occlusion (CRVO) , Macular degeneration (including dry and/or wet age-related macular degeneration, AMD), postoperative cataract inflammation, uveitis (including posterior, anterior, intermediate and pan uveitis), iridocyclitis, Scleritis, corneal graft and limbal cell transplant rejection, celiac disease (celiac disease), herpetic dermatitis, eosinophilic esophagitis, achalasia, autoimmune autonomic dysfunction, autologous Immune encephalomyelitis, autoimmune oophoritis, autoimmune testes Pill inflammation, autoimmune pancreatitis, aortitis and periaortitis (periaortitis), autoimmune retinopathy, autoimmune urticaria, Behcet's disease, (idiopathic) Castleman's disease, Cogan's syndrome, IgG4-related diseases, retroperitoneal fibrosis, juvenile idiopathic arthritis, including systemic juvenile idiopathic arthritis (Still's disease), adult-onset Still's Disease, woody conjunctivitis, Mooren’s ulcer, acute pityriasis lichenoides et varioliformis acuta (PLEVA, also known as Mucha-Habermann disease), multifocal motor neuropathy (MMN), acute pediatric Onset neuropsychiatric disorder syndrome (PANS) (including childhood autoimmune neuropsychiatric disorders (PANDAS) associated with streptococcal infection), tumor-associated syndrome (including tumor-associated cerebellar degeneration, Lambert-Eaton myasthenia syndrome, limbic brain Inflammation, brainstem encephalitis, ocular clonus myoclonus ataxia syndrome, anti-NMDA receptor encephalitis, thymoma-related multi-organ autoimmunity), perivenous encephalomyelitis, reflex sympathetic dystrophy , Recurrent polychondrotis, sperm and testicular autoimmunity, Susac syndrome, Tolosa-Hunt syndrome, Vogt-Koyanagi-Harada disease, anti-synthetic enzyme syndrome, autoimmune bowel disease, X-sex immune disorder Endocrine disease bowel disease (IPEX), microscopic colitis, autoimmune lymphoproliferative syndrome (ALPS), autoimmune multiple endocrine disease-candidiasis-ectodermal organ dystrophy syndrome (APEX), gout, false Gout, amyloidosis (including AA or secondary amyloidosis), eosinophilic fasciitis (Shulman syndrome), progesterone allergy (including progesterone dermatitis), familial Mediterranean fever (FMF), tumor Necrosis factor (TNF) receptor-related periodic fever syndrome (TRAPS), hyperimmune globulinemia D with periodic fever syndrome (HIDS), PAPA (suppurative arthritis, pyoderma gangrenosum (pyoderma gangrenosum) ), severe cystic acne) syndrome, interleukin-1 receptor antagonist deficiency (DIRA), interleukin-36-receptor antagonist deficiency (DITRA), cryopyrin-associated periodic syndromes ) (CAPS) (including familial cold-type autologous inflammation syndrome [FCAS], Muckle-Wells syndrome (Muckle-Wells syndrome), neonatal-onset multi-system inflammatory disease [NOMID]), NLRP12-related autologous Inflammatory disease (NLRP12AD), periodic fever aphthous stomatitis (PFAPA), chronic atypical neutrophil globular skin disease with lipid dystrophy and elevated body temperature (CANDLE), Majeed syndrome, Blau syndrome (also known as adolescent systemic Granulomatosis), macrophage activation syndrome, chronic relapsing multifocal osteomyelitis (CRMO), familial cold type autologous inflammation syndrome, mutant adenosine deaminase 2 and single gene interferon disease (including Aicardi -G Outières syndrome, retinal vascular disease with leukoencephalopathy, dysplasia of spinal arteriosclerosis, STING [stimulus of interferon gene]-related infantile-onset vascular disease, proteasome-related autoinflammation syndrome, familial chilblain Lupus, hereditary symmetrical hyperpigmentation), Schnitzler syndrome; familial hair epithelioma, congenital B lymphocytosis, OTULIN-related autoinflammation syndrome, type 2 diabetes, insulin resistance and metabolic syndrome (including obesity-related inflammation), atherosclerotic disorders ( For example, myocardial infarction, angina, ischemic heart failure, ischemic nephropathy, ischemic stroke, peripheral vascular disease, aortic aneurysm), kidney inflammation (e.g. diabetic nephropathy, membranous nephropathy, minimal change disease , Crescent glomerulonephritis, acute acute kidney injury, kidney transplantation). 根據請求項60之化合物、醫藥組成物、使用之化合物、用途或方法,其中該發炎性疾病或與不良免疫反應有關的疾病係選自由下列所組成之群組:類風濕性關節炎、牛皮癬性關節炎、關節黏連性脊椎炎、全身性紅斑狼瘡、多發性硬化症、牛皮癬、克隆氏症、潰瘍性結腸炎(ulcerative colitis)、葡萄膜炎、隱熱蛋白相關週期症候群(cryopyrin-associated periodic syndromes)、穆-韋二氏症候群(Muckle-Wells syndrome)、幼年型特發性關節炎及慢性阻塞性肺病。 The compound, pharmaceutical composition, compound used, use or method according to claim 60, wherein the inflammatory disease or disease associated with an adverse immune response is selected from the group consisting of rheumatoid arthritis, psoriasis Arthritis, joint adhesive spondylitis, systemic lupus erythematosus, multiple sclerosis, psoriasis, Crohn's disease, ulcerative colitis, uveitis, cryopyrin-associated periodic syndrome syndromes), Muckle-Wells syndrome, juvenile idiopathic arthritis and chronic obstructive pulmonary disease. 根據請求項61之化合物、醫藥組成物、使用之化合物、用途或方法,其中該發炎性疾病或與不良免疫反應有關的疾病為多發性硬化症。 The compound, pharmaceutical composition, compound used, use or method according to claim 61, wherein the inflammatory disease or disease related to an adverse immune response is multiple sclerosis. 根據請求項61之化合物、醫藥組成物、使用之化合物、用途或方法,其中該發炎性疾病或與不良免疫反應有關的疾病為牛皮癬。 The compound, pharmaceutical composition, compound used, use or method according to claim 61, wherein the inflammatory disease or disease related to an adverse immune response is psoriasis. 根據請求項1至61中任一項之化合物、醫藥組成物、使用之化合物、用途或方法,其中該化合物係用於投予至人類個體。 The compound, pharmaceutical composition, compound used, use or method according to any one of claims 1 to 61, wherein the compound is for administration to a human subject. 根據請求項1至64中任一項之化合物、醫藥組成物、使用之化合物、用途或方法,其係用於與另外的治療劑諸如下列組合使用:皮質類固醇(醣皮質素)、類視色素(例如阿維A(acitretin)、異維A酸(isotretinoin)、他扎羅汀(tazarotene))、葸酚(anthralin)、維生素D類似物(例如骨化三醇(cacitriol)、鈣泊三醇(calcipotriol))、鈣調磷酸酶(calcineurin)抑制劑(例如他克莫司(tacrolimus)、吡美莫司(pimecrolimus)、光療法或光化學療法(例如補骨脂素紫外線照射、PUVA)或紫外光照射療法之其他形式、環孢靈(ciclosporine)、硫嘌呤(thiopurine)(例如硫唑嘌呤(azathioprine)、6-巰嘌呤)、甲氨蝶呤(methotrexate)、抗TNFα劑(例如英夫利昔單抗(infliximab)、依那西普(etanercept)、阿達木單抗(adalimumab)、賽妥珠單 抗(certolizumab)、戈利木單抗(golimumab)或生物相似藥(biosimilar))、磷酸二酯酶-4(PDE4)抑制作用(例如阿普司特(apremilast)、克里博羅(crisaborole))、抗IL-17劑(例如布羅達單抗(brodalumab)、伊克珠單抗(ixekizumab)、蘇金單抗(secukinumab))、抗IL12/IL-23劑(例如烏斯替單抗(ustekinumab)、貝伐珠單抗(briakinumab))、抗IL-23劑(例如鼓賽庫單抗(guselkumab)、替拉珠單抗(tildrakizumab))、JAK(Janus激酶)抑制劑(例如托法替尼(tofacitinib)、魯索利替尼(ruxolitinib)、巴瑞替尼(baricitinib)、非戈替尼(filgotinib)、優帕替尼(upadacitinib))、血漿交換、靜脈免疫球蛋白(IVIG)、環磷醯胺、抗CD20 B細胞耗竭劑(例如利妥昔單抗(rituximab)、奧珠單抗(ocrelizumab)、奧法木單抗(ofatumumab)、奧比妥珠單抗(obinutuzumab))、蒽環類似物(例如米托蒽醌(mitoxantrone))、克拉屈濱(cladribine)、神經胺醇1-磷酸鹽受體調節物或神經胺醇類似物(例如芬戈莫德(fingolimod)、西波莫德(siponimod)、奧扎尼莫德(ozanimod)、依曲西莫德(ozanimod))、干擾素β製劑(包括干擾素β1b/1a)、格拉替雷(glatiramer)、抗CD3療法(例如OKT3)、抗CD52靶向劑(例如阿崙單抗(alemtuzumab))、來氟米特(leflunomide),特立氟胺(teriflunomide)、金化合物、拉喹莫德(laquinimod)、鉀通道阻滯劑(例如達伐吡啶(dalfampridine)/4-胺基吡啶)、黴酚酸、黴酚酸嗎啉乙酯(mycophenolate mofetil)、嘌呤類似物(例如噴司他汀(pentostatin))、mTOR(雷帕黴素機制靶(mechanistic target of rapamycin))路徑抑制劑(例如西羅莫司(sirolimus)、依維莫司(everolimus))、抗胸腺細胞球蛋白(ATG)、IL-2受體(CD25)抑制劑(例如巴利昔單抗(basiliximab)、達克珠單抗(daclizumab))、抗IL-6受體或抗IL-6劑(例如托珠單抗(tocilizumab)、西妥昔單抗(siltuximab))、Bruton氏酪胺酸激酶(BTK)抑制劑(例如依魯替尼(ibrutinib))、酪胺酸激酶抑制劑(例如伊馬替尼(imatinib))、熊去氧膽酸、羥氯喹(hydroxychloroquine)、氯喹(chloroquine)、B細胞活化因子(BAFF、也稱為BLyS、B淋巴球刺激物)抑制劑(例如貝利木單抗(belimumab)、布利斯比莫德(blisibimod))、其他B細胞靶向療法包括靶向APRIL(A增殖誘導配體)和BLyS兩者的融合蛋白(例如阿塞西普(atacicept))、PI3K抑制劑 包括泛抑制劑或彼等靶向含同功型之p110δ及/或p110γ者(例如依達利昔布(idelalisib)、庫潘利昔布(copanlisib)、杜韋利昔布(duvelisib))、干擾素α受體抑制劑(例如阿尼洛單抗(anifrolumab)、西法木單抗(sifalimumab))、T細胞共刺激阻斷劑(例如阿巴西普(abatacept)、貝拉西普(belatacept))、沙利度胺(thalidomide)和其衍生物(例如來那度胺(lenalidomide))、達普松(dapsone)、氯法齊明(clofazimine)、白三烯素(leukotriene)拮抗劑(例如孟魯司特(montelukast))、茶鹼、抗IgE療法(例如奧馬佐單抗(omalizumab))、抗IL-5劑(例如美泊珠單抗(mepolizumab)、瑞利珠單抗(reslizumab))、長效毒蕈鹼劑(例如噻托溴銨(tiotropium)、阿地銨(aclidinium)、蕪地溴銨(umeclidinium))、PDE4抑制劑(例如roflumilast)、利魯唑(riluzole)、自由基清除劑(例如依達拉奉(edaravone))、蛋白酶體抑制劑(例如硼替佐米(bortezomib))、補體級聯抑制劑包括彼等針對C5者(例如依庫珠單抗(eculizumab))、免疫吸附劑(immunoadsorbor),抗胸腺細胞球蛋白、5-胺水楊酸鹽及彼等之衍生物(例如柳氮磺胺吡啶(sulfasalazine)、巴柳氮(balsalazide)、美沙拉明(mesalamine))、抗整合素劑包括彼等靶向α4β1及/或α4β7整合素者(例如那他珠單抗(natalizumab)、維多珠單抗(vedolizumab))、抗CD11-α劑(例如依法珠單抗(efalizumab))、非類固醇抗發炎藥(NSAIDs)包括水楊酸酯類(例如阿司匹靈)、丙酸類(例如伊布洛芬(ibuprofen)、萘普生(naproxen))、乙酸類(例如吲哚美洒辛(indomethacin)、雙氯芬酸(diclofenac)、依託度酸(etodolac))、昔康類(oxicams)(例如美洛昔康(meloxicam))、芬那酸鹽(fenamate)(例如甲芬那酸(mefenamic acid))、選擇性或相對選擇性COX-2抑制劑(例如塞來昔布(celecoxib)、依托昔布(etroxicoxib)、伐地昔布(valdecoxib)和依託度酸(etodolac)、美洛昔康(meloxicam)、萘丁美酮(nabumetone))、秋水仙素、IL-4受體抑制劑(例如杜比單抗(dupilumab))、局部/接觸式免疫療法(例如二苯基環丙烯酮、方酸二丁酯)、抗IL-1受體療法(例如阿那白滯素(anakinra))、IL-1β抑制劑(例如卡那單抗(canakinumab))、IL-1中和療法(例如利納西普(rilonacept))、苯丁酸氮芥(chlorambucil)、具有免疫調節性質及/或調節NRF2能力的特定抗生素(例如四環素包括米諾四環素(minocycline)、 克林達黴素(clindamycin)、巨環內酯抗生素)、抗雄激素療法(例如環丙孕酮(cyproterone)、螺內酯(spironolactone)、非那雄安(finasteride))、己酮可可鹼(pentoxifylline)、熊去氧膽酸、奧貝膽酸(obeticholic acid)、貝特類(fibrate)、囊性纖維化跨膜電導調節劑(CFTR)調節物、VEGF(血管內皮生長因子)抑制劑(例如貝伐單抗(bevacizumab)、蘭尼單抗(ranibizumab)、哌加他尼(pegaptanib)、阿柏西普(aflibercept))、吡非尼酮(pirfenidone)或咪唑立賓(mizoribine)。 The compound, pharmaceutical composition, compound used, use or method according to any one of claims 1 to 64, which is used in combination with another therapeutic agent such as the following: corticosteroid (glucocorticoid), retinoid (E.g. acitretin, isotretinoin, tazarotene), anthralin, vitamin D analogs (e.g. calcitriol, calcipotriol) (calcipotriol)), calcineurin inhibitors (e.g. tacrolimus, pimecrolimus, phototherapy or photochemotherapy (e.g. psoralen ultraviolet radiation, PUVA) or Other forms of ultraviolet radiation therapy, ciclosporine, thiopurine (e.g. azathioprine, 6-mercaptopurine), methotrexate, anti-TNFα agents (e.g. Inflix) Infliximab (infliximab), etanercept (etanercept), adalimumab (adalimumab), certuzumab Anti (certolizumab), golimumab (golimumab) or biosimilar (biosimilar)), phosphodiesterase-4 (PDE4) inhibition (e.g. apremilast, crisaborole) ), anti-IL-17 agents (e.g., brodalumab, ixekizumab, secukinumab), anti-IL12/IL-23 agents (e.g., Ustrizumab (ustekinumab, bevacizumab (briakinumab)), anti-IL-23 agents (e.g. guselkumab, tildrakizumab), JAK (Janus kinase) inhibitors (e.g. Tofacitinib, ruxolitinib, baricitinib, filgotinib, upadacitinib), plasma exchange, intravenous immunoglobulin (IVIG) ), cyclophosphamide, anti-CD20 B cell depleting agents (e.g. rituximab, ocrelizumab, ofatumumab, obinutuzumab) ), anthracycline analogues (e.g. mitoxantrone (mitoxantrone)), cladribine (cladribine), neramine 1-phosphate receptor modulator or neramine alcohol analogues (e.g. fingolimod) , Siponimod, ozanimod, ezanimod, interferon β preparations (including interferon β1b/1a), glatiramer, anti-CD3 Therapies (such as OKT3), anti-CD52 targeting agents (such as alemtuzumab), leflunomide, teriflunomide, gold compounds, laquinimod, potassium Channel blockers (e.g. dalfampridine/4-aminopyridine), mycophenolic acid, mycophenolate mofetil, purine analogs (e.g. pentostatin), mTOR (Mechanistic target of rapamycin) pathway inhibitors (e.g. sirolimus, everolimus), antithymocyte globulin (ATG), IL-2 receptor (CD25) inhibitors (e.g. Barre Basiliximab, daclizumab), anti-IL-6 receptor or anti-IL-6 agents (e.g. tocilizumab, cetuximab), Bruton Tyrosine kinase (BTK) inhibitors (e.g., ibrutinib), tyrosine kinase inhibitors (e.g., imatinib), ursodeoxycholic acid, hydroxychloroquine, chloroquine (chloroquine), B cell activating factor (BAFF, also known as BLyS, B lymphocyte stimulator) inhibitors (e.g. belimumab, blisibimod), other B cell targets Therapies include fusion proteins targeting both APRIL (A proliferation-inducing ligand) and BLyS (e.g. atacicept), PI3K inhibitors Including pan-inhibitors or those targeting isoforms of p110δ and/or p110γ (e.g. idelalisib, copanlisib, duvelisib), interference Alpha receptor inhibitors (e.g., anifrolumab, sifalimumab), T cell costimulatory blockers (e.g., abatacept, belabacept) , Thalidomide and its derivatives (e.g. lenalidomide), dapsone, clofazimine, leukotriene antagonists (e.g. meng Montelukast), theophylline, anti-IgE therapy (e.g. omalizumab), anti-IL-5 agents (e.g. mepolizumab, reslizumab) , Long-acting muscarinic agents (e.g. tiotropium, aclidinium, umeclidinium), PDE4 inhibitors (e.g. roflumilast), riluzole, free radicals Scavengers (e.g. edaravone (edaravone)), proteasome inhibitors (e.g. bortezomib (bortezomib)), complement cascade inhibitors include those targeting C5 (e.g. eculizumab (eculizumab)), Immunoadsorbor, antithymocyte globulin, 5-amine salicylate and their derivatives (such as sulfasalazine, balsalazide, mesalamine) , Anti-integrin agents include those targeting α4β1 and/or α4β7 integrins (e.g. natalizumab, vedolizumab), anti-CD11-α agents (e.g. efalizumab) (efalizumab)), non-steroidal anti-inflammatory drugs (NSAIDs), including salicylate (e.g., aspirin), propionic acid (e.g., ibuprofen, naproxen), acetic acid ( Such as indomethacin (indomethacin), diclofenac (diclofenac), etodolac), oxicams (such as meloxicam), fenamate (such as methyl Fenamic acid (mefenamic acid), selective or relatively selective COX-2 inhibitors (e.g. celecoxib (ce lecoxib), etroxicoxib, valdecoxib and etodolac, meloxicam, nabumetone), colchicine, IL-4 receptor Body inhibitors (e.g. dupilumab), topical/contact immunotherapy (e.g. diphenylcyclopropenone, dibutyl squarate), anti-IL-1 receptor therapy (e.g. anakinra (anakinra)), IL-1β inhibitors (e.g. canakinumab), IL-1 neutralization therapy (e.g. rilonacept), chlorambucil, with immunomodulatory properties And/or specific antibiotics that regulate the ability of NRF2 (e.g. tetracyclines include minocycline, Clindamycin (clindamycin, macrolide antibiotics), anti-androgen therapy (e.g. cyproterone, spironolactone, finasteride), pentoxifylline ), ursodeoxycholic acid, obeticholic acid, fibrate, cystic fibrosis transmembrane conductance regulator (CFTR) regulator, VEGF (vascular endothelial growth factor) inhibitor (e.g. Bevacizumab, ranibizumab, pegaptanib, aflibercept, pirfenidone, or mizoribine. 一種化合物,其係選自由下列所組成之群組: A compound selected from the group consisting of:
Figure 109137209-A0202-13-0017-197
Figure 109137209-A0202-13-0017-197
Figure 109137209-A0202-13-0017-198
Figure 109137209-A0202-13-0017-198
Figure 109137209-A0202-13-0017-199
Figure 109137209-A0202-13-0017-199
Figure 109137209-A0202-13-0017-200
Figure 109137209-A0202-13-0017-200
Figure 109137209-A0202-13-0017-201
Figure 109137209-A0202-13-0017-201
其中: in: RA'為RA或其經保護的衍生物; R A'is R A or a protected derivative thereof; 其中RA係如請求項1至50中任一項所定義; Wherein R A is as defined in any one of claims 1 to 50; RB'為RB或其經保護的衍生物; R B 'is R B or a protected derivative thereof; 其中RB係如請求項1至50中任一項所定義; Where R B is as defined in any one of claims 1 to 50; RC和RD係如請求項1至50中任一項所定義;及 R C and R D are as defined in any one of claims 1 to 50; and PG為氧保護基; PG is an oxygen protecting group; R11為視需要地經鹵基取代之C1-4烷基; R 11 is a C 1-4 alkyl group optionally substituted with a halogen group; R12為視需要地經鹵基取代之C1-4烷基;及 R 12 is a C 1-4 alkyl group optionally substituted with a halogen group; and X2為脫離基諸如鹵基,例如氯基、溴基或碘基; X 2 is a leaving group such as a halo group, such as a chloro group, a bromo group or an iodo group; 或其鹽。 Or its salt.
根據請求項66之化合物,其係選自由下列所組成之群組: The compound according to claim 66, which is selected from the group consisting of: 4-(環辛氧基)-2-亞甲基-4-側氧基丁酸[SYX-00026]; 4-(cyclooctyloxy)-2-methylene-4-oxobutyric acid [SYX-00026]; 2-亞甲基-4-側氧基-4-(3-苯氧基丙氧基)丁酸[SYX-000134]; 2-methylene-4-oxo-4-(3-phenoxypropoxy)butanoic acid [SYX-000134]; 4-((4-氟苯甲基)氧基)-2-亞甲基-4-側氧基丁酸[SYX-00181]; 4-((4-fluorobenzyl)oxy)-2-methylene-4-oxobutanoic acid [SYX-00181]; (R)-2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁酸[SYX-00229]; (R)-2-methylene-4-(oct-2-yloxy)-4-oxobutanoic acid [SYX-00229]; (S)-2-亞甲基-4-(辛-2-基氧基)-4-側氧基丁酸[SYX-00510]; (S)-2-methylene-4-(oct-2-yloxy)-4-oxobutanoic acid [SYX-00510]; 2-亞甲基-4-(新戊氧基)-4-側氧基丁酸;及 2-methylene-4-(neopentoxy)-4-oxobutyric acid; and 3-((2-(三級丁氧基)-2-側氧基乙氧基)羰基)丁-3-烯酸[SYX-00395]; 3-((2-(tertiary butoxy)-2-oxoethoxy)carbonyl)but-3-enoic acid [SYX-00395]; 或其鹽。 Or its salt. 一種製備根據請求項1至50中任一項之化合物或其鹽諸如醫藥上可接受的鹽之方法,其包含: A method for preparing a compound according to any one of claims 1 to 50 or a salt thereof such as a pharmaceutically acceptable salt, which comprises: (a)使式(III)化合物: (a) Let the compound of formula (III):
Figure 109137209-A0202-13-0018-149
Figure 109137209-A0202-13-0018-149
或其鹽; Or its salt; 與式(II)化合物: With the compound of formula (II): RB'-OH(II) R B'- OH(II) 或其鹽反應; Or its salt reaction; (b)使式(III)化合物: (b) Let the compound of formula (III):
Figure 109137209-A0202-13-0019-152
Figure 109137209-A0202-13-0019-152
或其鹽; Or its salt; 與式(II’)化合物: With the compound of formula (II’): RB'-X(II') R B'- X(II') 或其鹽反應; Or its salt reaction; (c)使式(IX)化合物: (c) Let the compound of formula (IX):
Figure 109137209-A0202-13-0019-151
Figure 109137209-A0202-13-0019-151
或其鹽; Or its salt; 與式(IV)化合物: With the compound of formula (IV): RA'-OH(IV) R A '-OH (IV) 或其鹽反應;或 Or its salt reaction; or (d)使式(XIII)化合物: (d) Let the compound of formula (XIII):
Figure 109137209-A0202-13-0019-150
Figure 109137209-A0202-13-0019-150
或其鹽, Or its salt, 與甲醛或其同等物反應; React with formaldehyde or its equivalent; 其中: in: RA'為RA或其經保護的衍生物; R A'is R A or a protected derivative thereof; 其中RA係如請求項1至50中任一項所定義; Wherein R A is as defined in any one of claims 1 to 50; RB'為RB或其經保護的衍生物; R B 'is R B or a protected derivative thereof; 其中RB係如請求項1至50中任一項所定義; Where R B is as defined in any one of claims 1 to 50; RC和RD係如請求項1至50中任一項所定義; R C and R D are as defined in any one of claims 1 to 50; X為脫離基; X is the break-away base; R11為視需要地經鹵基取代之C1-4烷基;及 R 11 is a C 1-4 alkyl group optionally substituted with a halogen group; and R12為視需要地經鹵基取代之C1-4烷基。 R 12 is a C 1-4 alkyl group optionally substituted with a halogen group.
TW109137209A 2019-12-19 2020-10-27 Novel compounds TW202136195A (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
EP19217846 2019-12-19
EP19217846.5 2019-12-19
EP20162494.7 2020-03-11
EP20162494 2020-03-11
WOPCT/GB2020/051059 2020-04-30
PCT/GB2020/051059 WO2020222010A1 (en) 2019-04-30 2020-04-30 Itaconic acid derivatives and uses thereof in treating an inflammatory disease or a disease associated with an undesirable immune response

Publications (1)

Publication Number Publication Date
TW202136195A true TW202136195A (en) 2021-10-01

Family

ID=79601003

Family Applications (1)

Application Number Title Priority Date Filing Date
TW109137209A TW202136195A (en) 2019-12-19 2020-10-27 Novel compounds

Country Status (1)

Country Link
TW (1) TW202136195A (en)

Similar Documents

Publication Publication Date Title
EP3962602A1 (en) Itaconic acid derivatives and uses thereof in treating an inflammatory disease or a disease associated with an undesirable immune response
CN109415387B (en) Arginase inhibitors and therapeutic uses thereof
EP4200275A2 (en) Fumarate derivatives and their medical use
US20230219907A1 (en) Carboxy derivatives with antiinflamatory properties
US20240018111A1 (en) Alpha, beta unsaturated methacrylic esters with anti-inflammatory properties
WO2022090723A1 (en) Itaconic acid derivatives
EP4237402A1 (en) Novel compounds
TW202136275A (en) Pyridazinyl-thiazolecarboxamide compound
US20230399287A1 (en) Novel compounds
EP4384271A1 (en) Derivatives of itaconic acid and their use as anti-inflammatory agents
EP4359390A1 (en) Acrylamide derivatives useful as anti-inflammatory agents
EP4330231A1 (en) 2-methylene-4-oxo-butanoic acid drivatives for the treatment of inflammation
CA3238806A1 (en) Phthalazine derivatives as pyruvate kinase modulators
TW202136195A (en) Novel compounds
WO2024127030A1 (en) Substituted pyridines for use in treating or preventing inflammatory diseases or diseases associated with an undesirable immune response
WO2024089421A1 (en) Tetrazole derivatives
WO2023247958A1 (en) Oxadiazole derivatives, preparation process thereof and their use in treating inflammatory diseases