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TW201730192A - Novel substituted spiro-[indoline heterocycloalkane] compounds as phosphodiesterase inhibitors - Google Patents

Novel substituted spiro-[indoline heterocycloalkane] compounds as phosphodiesterase inhibitors Download PDF

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TW201730192A
TW201730192A TW105142607A TW105142607A TW201730192A TW 201730192 A TW201730192 A TW 201730192A TW 105142607 A TW105142607 A TW 105142607A TW 105142607 A TW105142607 A TW 105142607A TW 201730192 A TW201730192 A TW 201730192A
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porphyrin
pyrimidin
spiro
alkyl
oxocyclobutane
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TW105142607A
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英葛 柯奈茲奇
芙羅利安 雅寇柏
馬庫斯 華格納
安德烈 瑋柏斯
克利斯提安 賀斯林格
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歌林達有限公司
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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Abstract

The invention relates to novel spiro-[indoline heterocycloalkane] compounds characterized in that the compound has general formula (I) in which the chemical groupings, substituents, variables and indices are as defined in the description, and to their use as medicaments, in particular as medicaments for the treatment of conditions and diseases that can be treated by inhibition of the PDE4 enzyme.

Description

作為磷酸二酯酶抑制劑之新穎經取代之螺-[吲哚啉雜環烷]化合物 Novel substituted spiro-[porphyrin heterocycloalkane] compounds as phosphodiesterase inhibitors

本發明係關於可用作藥劑之新穎經取代螺-吲哚啉雜環烷化合物。此發明也關於該化合物用以製造藥劑之用途及包括將該化合物施用至需要治療之人類之治療方法。此發明也關於該新穎之化合物之製備。此外此發明係關於包括該化合物之藥學組成物及套組。 This invention relates to novel substituted spiro-porphyrin heterocycloalkane compounds useful as pharmaceutical agents. This invention also relates to the use of the compound for the manufacture of a medicament and to the treatment of the compound to be administered to a human in need of treatment. This invention also relates to the preparation of the novel compounds. Further, the invention relates to pharmaceutical compositions and kits comprising the compound.

磷酸二酯酶(簡寫為PDEs)或更精確之3',5'-還核苷酸磷酸二酯酶，係催化第二傳信cAMP(環腺核苷酸單磷酸)及cGMP(環鳥糞核苷單磷酸)水解為5'-AMP(5'-單磷酸鹽腺苷酸)及5'-GMP(5'-單磷酸鳥苷)之酵素。磷酸二酯酶係涵蓋11個基因家族(PDE1-11)之一群酵素，其特別在對於cAMP及cGMP親和力上有不同。磷酸二酯酶之抑制性因此表現調節細胞代謝過程之機制且可以用於減輕或治療疾病之症狀。已知特定PDEs之抑制劑。 Phosphodiesterase (abbreviated as PDEs) or more precisely 3', 5'-fractional nucleotide phosphodiesterase, catalyzes the second signaling cAMP (cyclic adenosine monophosphate) and cGMP (circle guano) The nucleoside monophosphate is hydrolyzed to the enzyme of 5'-AMP (5'-monophosphate adenosine) and 5'-GMP (5'-monophosphate guanosine). The phosphodiesterase system covers one of the 11 gene families (PDE1-11), which differs in particular in affinity for cAMP and cGMP. The inhibition of phosphodiesterase thus manifests a mechanism that modulates cellular metabolic processes and can be used to alleviate or treat the symptoms of the disease. Inhibitors of specific PDEs are known.

發現第二傳信cAMP在許多發炎反應過程中扮演重要角色且PDE4在控制發炎反應過程之細胞中被大量表現(特別見Schudt,C.et al.(1995))。PDE同功異構酵素係以抗哮喘藥物之作為目標。European Respiratory Journal 8,1179-1183)導致具抗發炎效果之PDE4抑制劑之開發。該等具抗發炎效果之PDE4抑制劑之一例如為羅氟斯特(roflumilast)(商品名Daxas®)，其被核准用於治療COPD(慢性阻塞性肺臟疾病)之藥劑。另一PDE4 抑制劑係阿普斯特(apremilast)(Otezla®)，其最近被核准用於治療牛皮癬性關節炎及斑塊狀牛皮癬(plaque psoriasis)。除羅氟斯特及阿普斯特之期望抗發炎效果外，然而，觀察到會限制人類劑量之諸如噁心、腹瀉及頭痛之副作用。 The second signaling cAMP was found to play an important role in many inflammatory responses and PDE4 is abundantly expressed in cells that control the inflammatory response process (see especially Schudt, C. et al. (1995)). PDE isoforms are targeted at anti-asthmatic drugs. European Respiratory Journal 8 , 1179-1183) led to the development of PDE 4 inhibitors with anti-inflammatory effects. One of these with the anti-inflammatory effects of a PDE4 inhibitor Roflumilast, for example, Lancaster (roflumilast) (trade name Daxas ®), which is an agent approved for the treatment of COPD (chronic obstructive lung disease resistance) of. Another PDE4 inhibitor is apremilast (Otezla ® ), which has recently been approved for the treatment of psoriatic arthritis and plaque psoriasis. In addition to the expected anti-inflammatory effects of Roflux and Apster, however, side effects such as nausea, diarrhea and headaches which limit human doses have been observed.

不僅在羅氟斯特及阿普斯特而且在其他PDE4抑制劑觀察到人類之非期望副作用，以使得該等藥劑之治療範圍(治療區間(therapeutic window))相對較窄。因此希望能提供具較不嚴重或較少副作用及較佳治療區間之PDE4抑制劑。 The undesired side effects of humans were observed not only in Rofluster and Apster but also in other PDE4 inhibitors, so that the therapeutic range (therapeutic window) of these agents was relatively narrow. It is therefore desirable to provide a PDE4 inhibitor with less severe or less side effects and a preferred therapeutic interval.

磷酸二酯酶4(PDE4)係cAMP-特異性且涵括4個不同亞型(PDE4A、PDE4B、PDE4C及PDE4D)。如下所述，正在努力尋找具較不嚴重或沒有副作者之亞型選擇性PDE4抑制劑(尤其為PDE4B-選擇性抑制劑)，因此顯著增加該等化合物之治療範圍。 Phosphodiesterase 4 (PDE4) is cAMP-specific and encompasses four different subtypes (PDE4A, PDE4B, PDE4C and PDE4D). As described below, efforts are being made to find subtype selective PDE4 inhibitors (especially PDE4B-selective inhibitors) that are less severe or have no co-authors, thus significantly increasing the therapeutic range of such compounds.

該PDE4D之抑制性與非期望副作用之發生相關，諸如例如腹瀉、嘔吐及噁心(此方面見Mori,F.et al.(2010)：The human area postrema and other nuclei related to the emetic reflex express cAMP phosphodiesterases 4B and 4D,Journal of Chemical Neuroanatomy 40,36-42；Press,N.J.；Banner K.H(2009)：PDE4 inhibitors-A review of the current field,Progress in Medicinal Chemistry 47,37-74；Robichaud,A.et al.(2002)：Deletion of PDE4D in mice shortens α2-adrenoceptor-mediated anesthesia,a behavioral correlate of emesis,The Journal of Clinical Investigation 110,1045-52；Lee et al.,(2007)：Dynamic regulation of CFTR by competitive interactions of molecular adaptors,Journal of Biological Chemistry 282,10414-10422；Giembycz,M.A.(2002)：4D or not 4D-the emetogenic basis of PDE4 inhibitors uncovered？,Trebds in Pharmacological Sciences 23,548)。 The inhibition of this PDE4D is associated with the occurrence of undesired side effects such as, for example, diarrhea, vomiting, and nausea (see Mori, F. et al. (2010): The human area postrema and other nuclei related to the emetic reflex express cAMP phosphodiesterases 4B and 4D, Journal of Chemical Neuroanatomy 40 , 36-42; Press, NJ; Banner KH (2009): PDE4 inhibitors-A review of the current field, Progress in Medicinal Chemistry 47 , 37-74; Robichaud, A. et al (2002): Deletion of PDE4D in mice shortens α2-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis, The Journal of Clinical Investigation 110 , 1045-52; Lee et al., (2007): Dynamic regulation of CFTR by competitive Interactions of molecular adaptors, Journal of Biological Chemistry 282 , 10414-10422; Giembycz, MA (2002): 4D or not 4D-the emetogenic basis of PDE4 inhibitors uncovered?, Trebds in Pharmacological Sciences 23 , 548).

數種表現出PDE4B選擇性之化合物已被揭露(Naganuma et al.US2006/0293343；Naganuma et al.Bioorg.Med.Chem.Lett.19(2009)3174-3176；Goto et al.Bioorg.Med.Chem.Lett.24(2014)893-899；Hagen et al.Bioorg.Med.Chem.Lett.24(2014)4031-4034；Chappie et al.US 2014/0235612)。 Several compounds exhibiting PDE4B selectivity have been disclosed (Naganuma et al. US 2006/0293343; Naganuma et al. Bioorg. Med. Chem. Lett. 19 (2009) 3174-3176; Goto et al. Bioorg . Med. .Lett. 24 (2014) 893-899; Hagen et al. Bioorg. Med. Chem. Lett. 24 (2014) 4031-4034; Chappie et al. US 2014/0235612).

基於以上，需要較佳之PDE4B-選擇性(意指能以特定量活性成分抑制PDE4B但不會抑制或僅微弱抑制PDE4D亞型)之化合物(活性成分)。該PDE4B選擇性之優點在於各種副作用不會發生或僅發生程度很小，因此可以獲得更大藥物活性成分之治療範圍。該藥物活性成分之治療範圍描述其治療劑量及導致有毒或非期望效果之劑量間之差距。該治療範圍愈大，某些有毒或非期望副作用之發生愈少見或愈不可能，因此藥物活性成分或藥劑就更安全及更易被接受。該治療範圍通常被稱為治療區間或治療指數(therapeutic index)。在本申請書中此等名稱係以同義使用。 Based on the above, there is a need for a preferred PDE4B-selective (meaning a compound (active ingredient) capable of inhibiting PDE4B with a specific amount of active ingredient but not inhibiting or only weakly inhibiting the PDE4D subtype). The advantage of this PDE4B selectivity is that various side effects do not occur or occur only to a small extent, so that a therapeutic range of a larger pharmaceutically active ingredient can be obtained. The therapeutic range of the active ingredient of the drug describes the difference between its therapeutic dose and the dose that results in a toxic or undesired effect. The greater the therapeutic range, the less or the less likely the occurrence of certain toxic or undesired side effects, and thus the pharmaceutically active ingredient or agent is safer and more acceptable. This therapeutic range is often referred to as the treatment interval or the therapeutic index. These names are used synonymously in this application.

發明人目前發現新穎之經取代螺-吲哚啉雜環烷化合物，其具有期望之抑制及PDE4B-選擇性性質。此等螺-吲哚啉雜環烷化合物在於因此特別適合用於治療有利於PDE4酵素(特別為PDE4B)之抑制之疾病及症狀。 The inventors have now discovered novel substituted spiro-porphyrin heterocycloalkyl compounds having desirable inhibition and PDE4B-selective properties. These spiro-porphyrin heterocycloalkane compounds are therefore particularly suitable for the treatment of diseases and conditions which are beneficial for the inhibition of PDE4 enzymes, in particular PDE4B.

本發明之第一面向因此係關於一種化合物，其特徵為該化合物具有通式(I) 其中A、B及C獨立地代表CH或N；m為0、1、2或3且n為0、1、2或3，前提是(m+n)之和為2、3或4；L係選自於由C(=O)NR2、S(=O)、S(=O)2、S(=O)2NR2、P(=O)(R2)、O或鍵結所組成之群組；R1係選自於C1-6-烷基，其未經取代或經單或多取代；或C3-6-環烷基或3至7員雜環烷基，於每一種情況下其未經取代或經單或多取代；及R2係選自於H或C1-C6-烷基，其未經取代或經單或多取代；或R1及R2與其所連接之氮原子一起形成3至12員雜環烷基，其中該3至12員雜環烷基可含有選自於由O、S及N所組成之群組之一或二個另外之雜原子且可為單或雙環且其中該3至12員雜環烷基係未經取代或經單或多取代；及G代表苯基或5或6員雜芳基，其中該苯基或該5或6員雜芳基係未經取代或經以一、二、三或四個取代基Z取代；其中 Z每一次出現係獨立地選自於由以下所組成之群組：鹵素，OH，CN，SH，NO2，C1-C6-烷基，C2-C6-烯基，C2-C6-炔基，(C1-C6)-羥烷基，(C1-C6)-氰烷基，C1-C6-烷氧基，(C1-C6)-硫烷基，(C1-C6)-鹵烷基，(C1-C6-烷氧基)-(C1-C6-亞烷基)，(C1-C6-烷氧基)-C1-C6-烷氧基，(C1-C6)-thio鹵烷基，(C1-C6)-鹵烷氧基，(C1-C6-硫烷基)-(C1-C6-亞烷基)，C3-C6-環烷基，(C3-C6-環烷基)-(C1-C3-亞烷基)，3至7員雜環烷基，(3至7員雜環烷基)-(C1-C3-亞烷基)(該C3-6-環烷基及該3至7員雜環烷基於每一種情況下係未經取代或經單或多取代)，NH2，NH(C1-C6-烷基)，N(C1-C6-烷基)2，NHCO(C1-C6-烷基)，NHCO2(C1-C6-烷基)，NHC(O)NH2，NHCONH(C1-C6-烷基)，NHCON(C1-C6-烷基)2，(C1-C6-伸烷基)NH2，(C1-C6-伸烷基)NH(C1-C6-烷基)，(C1-C6-伸烷基)N(C1-C6-烷基)2，(C1-C6-伸烷基)NHCO(C1-C6-烷基)，(C1-C6-伸烷基)NHCO2(C1-C6-烷基)，(C1-C6-伸烷基)NHC(O)NH2，(C1-C6-伸烷基)NHCONH(C1-C6-烷基)，(C1-C6-伸烷基)NHCON(C1-C6-烷基)2，NH((C1-C6-伸烷基)-CO2(C1-C6-烷基)，NH(C1-C6-伸烷基)-CONH2，NH(C1-C6-伸烷基)-CONH(C1-C6-烷基)，NH(C1-C6-伸烷基)-CON(C1-C6-烷基)2，NHS(O)2OH，NHS(O)2(C1-C6-烷基)，NHS(O)2O(C1-C6-烷基)，NHS(O)2NH2，NHS(O)2NH(C1-C6-烷基)，NHS(O)2N(C1-C6-烷基)2，NH(C1-C6-伸烷基)-S(O)2OH，NH(C1-C6-伸烷基)-S(O)2(C1-C6-烷基)，NH(C1-C6-伸烷基)-S(O)2O(C1-C6-烷基)，NH(C1-C6-伸烷基)-S(O)2NH2，NH(C1-C6-伸烷基)-S(O)2NH(C1-C6-烷基)，CO2H，CO(C1-C6-烷基)，CO2(C1-C6-烷基)，O-CO(C1-C6-烷基)，O-CO2(C1-C6-烷基)，CONH2，CONH(C1-C6-烷基)，CON(C1-C6-烷基)2，OCONH(C1-C6-烷基)，OCON(C1-C6-烷基)2，OS(O)2(C1-C6-烷基)，OS(O)2OH，OS(O)2O(C1-C6-烷基)，OS(O)2NH2，OS(O)2NH(C1-C6-烷基)，OS(O)2N(C1-C6-烷基)2， S(O)(C1-C6-烷基)，S(O)2(C1-C6-烷基)，S(O)2OH，S(O)2O(C1-C6-烷基)，S(O)2NH2，S(O)2NH(C1-C6-烷基)及S(O)2N(C1-C6-烷基)2；其可擇地為單一立體異構物或立體異構物混合物之形式、游離化合物之形式及/或其生理上可接受之鹽類及/或生理上可接受之溶劑合物。 The first aspect of the invention is therefore directed to a compound characterized in that the compound has the general formula (I) Wherein A, B and C independently represent CH or N; m is 0, 1, 2 or 3 and n is 0, 1, 2 or 3, provided that the sum of (m + n) is 2, 3 or 4; Is selected from C(=O)NR 2 , S(=O), S(=O) 2 , S(=O) 2 NR 2 , P(=O)(R 2 ), O or bonding a group consisting of; R 1 is selected from C 1-6 -alkyl, which is unsubstituted or mono- or polysubstituted; or C 3-6 -cycloalkyl or 3 to 7-membered heterocycloalkyl, In each case it is unsubstituted or mono- or polysubstituted; and R 2 is selected from H or C 1 -C 6 -alkyl, unsubstituted or mono- or polysubstituted; or R 1 and R 2 Forming a 3 to 12 membered heterocycloalkyl group together with the nitrogen atom to which it is attached, wherein the 3 to 12 membered heterocycloalkyl group may contain one or two other groups selected from the group consisting of O, S, and N. a hetero atom and which may be mono- or bicyclic and wherein the 3 to 12 membered heterocycloalkyl group is unsubstituted or mono- or polysubstituted; and G represents a phenyl group or a 5 or 6 membered heteroaryl group, wherein the phenyl group or the The 5 or 6 membered heteroaryl is unsubstituted or substituted with one, two, three or four substituents Z; wherein each occurrence of Z is independently selected from the group consisting of: halogen, OH, CN, SH, NO 2 , C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, (C 1 -C 6 )-hydroxyalkyl, (C 1 -C 6 )-cyanide Alkyl, C 1 -C 6 -alkoxy, (C 1 -C 6 )-sulfanyl, (C 1 -C 6 )-haloalkyl, (C 1 -C 6 -alkoxy)-( C 1 -C 6 -alkylene), (C 1 -C 6 -alkoxy)-C 1 -C 6 -alkoxy, (C 1 -C 6 )-thiohaloalkyl, (C 1 - C 6 )-haloalkoxy, (C 1 -C 6 -sulfanyl)-(C 1 -C 6 -alkylene), C 3 -C 6 -cycloalkyl, (C 3 -C 6 - Cycloalkyl)-(C 1 -C 3 -alkylene), 3 to 7 membered heterocycloalkyl, (3 to 7 membered heterocycloalkyl)-(C 1 -C 3 -alkylene) (this C 3-6 -cycloalkyl and the 3 to 7 membered heterocycloalkyl are unsubstituted or mono- or polysubstituted in each case, NH 2 , NH(C 1 -C 6 -alkyl), N (C 1 -C 6 -alkyl) 2 ,NHCO(C 1 -C 6 -alkyl), NHCO 2 (C 1 -C 6 -alkyl), NHC(O)NH 2 ,NHCONH(C 1 -C 6 -alkyl), NHCON(C 1 -C 6 -alkyl) 2 , (C 1 -C 6 -alkylene)NH 2 ,(C 1 -C 6 -alkylene)NH(C 1 -C 6 -alkyl), (C 1 -C 6 -alkylene)N(C 1 -C 6 -alkyl) 2 ,(C 1 -C 6 -alkylene)NHCO(C 1 -C 6 -alkane Base), (C 1 -C 6 -alkylene)NHCO 2 (C 1 -C 6 -alkane) Base), (C 1 -C 6 -alkylene)NHC(O)NH 2 ,(C 1 -C 6 -alkylene)NHCONH(C 1 -C 6 -alkyl), (C 1 -C 6 -alkylene)NHCON(C 1 -C 6 -alkyl) 2 ,NH((C 1 -C 6 -alkylene)-CO 2 (C 1 -C 6 -alkyl), NH(C 1 - C 6 -alkylene)-CONH 2 ,NH(C 1 -C 6 -alkylene)-CONH(C 1 -C 6 -alkyl),NH(C 1 -C 6 -alkylene)-CON (C 1 -C 6 -alkyl) 2 ,NHS(O) 2 OH, NHS(O) 2 (C 1 -C 6 -alkyl), NHS(O) 2 O(C 1 -C 6 -alkyl ), NHS(O) 2 NH 2 , NHS(O) 2 NH(C 1 -C 6 -alkyl), NHS(O) 2 N(C 1 -C 6 -alkyl) 2 , NH(C 1 - C 6 -alkylene)-S(O) 2 OH, NH(C 1 -C 6 -alkylene)-S(O) 2 (C 1 -C 6 -alkyl), NH(C 1 -C 6 -alkylene)-S(O) 2 O(C 1 -C 6 -alkyl), NH(C 1 -C 6 -alkylene)-S(O) 2 NH 2 ,NH(C 1 - C 6 -alkylene)-S(O) 2 NH(C 1 -C 6 -alkyl), CO 2 H, CO(C 1 -C 6 -alkyl), CO 2 (C 1 -C 6 - Alkyl), O-CO(C 1 -C 6 -alkyl), O-CO 2 (C 1 -C 6 -alkyl), CONH 2 ,CONH(C 1 -C 6 -alkyl), CON( C 1 -C 6 -alkyl) 2 , OCONH(C 1 -C 6 -alkyl), OCON(C 1 -C 6 -alkyl) 2 ,OS(O) 2 (C 1 -C 6 -alkyl ), OS(O) 2 OH, OS(O) 2 O (C 1 -C 6 -alkyl), OS(O) 2 NH 2 , OS(O) 2 NH(C 1 -C 6 -alkyl), OS(O) 2 N(C 1 -C 6 -alkyl) 2 , S(O)(C 1 -C 6 -alkyl), S(O) 2 (C 1 -C 6 -alkyl), S(O) 2 OH,S(O) 2 O(C 1 -C 6 -alkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1 -C 6 -alkyl) and S(O) 2 N(C 1 -C 6 -alkyl) 2 ; Alternatively, it may be in the form of a single stereoisomer or a mixture of stereoisomers, in the form of a free compound and/or a physiologically acceptable salt thereof and/or a physiologically acceptable solvate.

該術語「單一立體異構物」於本發明意義中較佳地意指一單獨之鏡像異構物或非鏡像異構物。該術語「立體異構物之混合物」意指於此發明意義中之該消旋物及以任何比例混合之鏡像異構物及/或非鏡像異構物之混合物。 The term "single stereoisomer" in the sense of the present invention preferably means a single mirror image isomer or a non-image isomer. The term "mixture of stereoisomers" means the racemate in the sense of the invention and a mixture of mirror image isomers and/or non-image isomers mixed in any proportion.

該術語「生理上可接受之鹽類」於此發明意義中較佳地包括本發明至少一化合物之鹽類及至少一生理上可接受之酸類及鹼類。 The term "physiologically acceptable salts" in the sense of the invention preferably includes salts of at least one compound of the invention and at least one physiologically acceptable acid and base.

本發明至少一化合物之生理上可接受之鹽類及至少一生理上可接受之酸類或一生理上可接受之鹼類較佳地係指於此發明意義中本發明至少一化合物之鹽類與至少一無機或有機酸類或與至少一無機或有機之鹼類，其各自為生理上可接受者，特別為用於人類及/或其他哺乳動物中。 The physiologically acceptable salts of at least one compound of the invention and at least one physiologically acceptable acid or a physiologically acceptable base preferably refer to the salts of at least one compound of the invention in the sense of the invention At least one inorganic or organic acid or with at least one inorganic or organic base, each of which is physiologically acceptable, particularly for use in humans and/or other mammals.

該術語「生理上可接受之溶劑合物」於此發明意義中較佳地包括本發明一化合物之加合物及/或本發明至少一化合物之生理上可接受之鹽類與不同分子當量之一溶劑或多溶劑。 The term "physiologically acceptable solvate" preferably includes, in the sense of the invention, an adduct of a compound of the invention and/or a physiologically acceptable salt of at least one compound of the invention and a different molecular equivalent. A solvent or multiple solvents.

本發明之也包含本發明一化合物之同位素異構物及該化合物之同位素異構物之任何混合物，其中該化合物之至少一原子係被各該原子之同位素(其與天然優勢存在之同位素不同)取代。較佳之同位素係2H(氘)、3H(氚)、13C及14C。本發明一化合物之同位素異構物通常可藉由該領域技術人士已知之傳統製程製備。 The invention also includes any mixture of isotopic isomers of a compound of the invention and isotope isomers of the compound, wherein at least one atomic system of the compound is isotopically associated with the atom (which is different from the isotope in which the natural advantage exists) Replace. Preferred isotopes are 2 H (氘), 3 H (氚), 13 C and 14 C. Isotope isomers of a compound of the invention can generally be prepared by conventional procedures known to those skilled in the art.

在本發明範疇中，該術語「鹵素」代表F、Cl、Br及I之原子 團，較佳為F及Cl之原子團，特佳為F。 In the context of the present invention, the term "halogen" means an atom of F, Cl, Br and I. The group is preferably an atomic group of F and Cl, and particularly preferably F.

除非另有特定，該術語「C1-C6-烷基」係被理解為意指有分枝或無分枝之烷基基團，其含有1至6個碳原子。C1-C6-烷基原子團之例示為CH3、CH2CH3、(CH2)2CH3、CH(CH3)2、(CH2)3CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、n-戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、n-己基、1-甲基戊基、2-甲基戊基、3-甲基戊基、4-甲基戊基。較佳為C1-C4-烷基原子團，特別為CH3、CH2CH3、(CH2)2CH3或CH(CH3)2。 Unless otherwise specified, the term "C 1 -C 6 - alkyl" is understood to mean lines or no branching of the branched alkyl group containing from 1 to 6 carbon atoms. Examples of C 1 -C 6 -alkyl radicals are CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl. Preferred is a C 1 -C 4 -alkyl radical, especially CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 or CH(CH 3 ) 2 .

除非另有特定，該術語「C1-C6-烷氧基」係被理解為意指有分枝或無分枝之烷氧基基團，其含有1至6個碳原子。C1-C6-烷氧基原子團之例示為OCH3、OCH2CH3、O(CH2)2CH3、OCH(CH3)2、O(CH2)3CH3、OCH(CH3)CH2CH3、OCH2CH(CH3)2、OC(CH3)3、O(CH2)4CH3、O(CH2)2CH(CH3)2、OCH2CH(CH3)CH2CH3、OCH(CH3)(CH2)2CH3、OC(CH3)2CH2CH3、OCH2C(CH3)3、O(CH2)5CH3、O(CH2)3CH(CH3)2、O(CH2)2CH(CH3)CH2CH3、OCH2CH(CH3)(CH2)2CH3、OCH2C(CH3)2CH2CH3、OCH2CH(CH3)(CH2)2CH3、OCH(CH3)(CH2)3CH3、OC(CH3)2(CH2)2CH3、O(CH2)2C(CH3)3。較佳為C1-C4-烷氧基原子團，特別為OCH3、OCH2CH3、O(CH2)2CH3或OCH(CH3)2。 Unless otherwise specified, the term "C 1 -C 6 -alkoxy" is understood to mean a branched or unbranched alkoxy group containing from 1 to 6 carbon atoms. Examples of C 1 -C 6 -alkoxy radicals are OCH 3 , OCH 2 CH 3 , O(CH 2 ) 2 CH 3 , OCH(CH 3 ) 2 , O(CH 2 ) 3 CH 3 , OCH (CH 3 CH 2 CH 3 , OCH 2 CH(CH 3 ) 2 , OC(CH 3 ) 3 , O(CH 2 ) 4 CH 3 , O(CH 2 ) 2 CH(CH 3 ) 2 , OCH 2 CH(CH 3 CH 2 CH 3 , OCH(CH 3 )(CH 2 ) 2 CH 3 , OC(CH 3 ) 2 CH 2 CH 3 , OCH 2 C(CH 3 ) 3 , O(CH 2 ) 5 CH 3 , O ( CH 2 ) 3 CH(CH 3 ) 2 , O(CH 2 ) 2 CH(CH 3 )CH 2 CH 3 , OCH 2 CH(CH 3 )(CH 2 ) 2 CH 3 , OCH 2 C(CH 3 ) 2 CH 2 CH 3 , OCH 2 CH(CH 3 )(CH 2 ) 2 CH 3 , OCH(CH 3 )(CH 2 ) 3 CH 3 , OC(CH 3 ) 2 (CH 2 ) 2 CH 3 , O(CH 2 ) 2 C(CH 3 ) 3 . Preferred is a C 1 -C 4 -alkoxy radical, especially OCH 3 , OCH 2 CH 3 , O(CH 2 ) 2 CH 3 or OCH(CH 3 ) 2 .

除非另有特定，該術語「(C1-C6)-鹵烷基」係被理解為C1-C6-烷基，其中至少一氫係與一鹵素原子交換，較佳地為F或Cl，特佳為F。該鹵烷基可為有分枝或無分枝且可擇地經單或多取代。較佳之(C1-C6)-鹵烷基原子團為(C1-C3)-鹵烷基原子團，特別為CHF2、CH2F、CF3、CH2CH2F、CH2CHF2及CH2CF3。 Unless otherwise specified, the term "(C 1 -C 6 )-haloalkyl" is understood to be C 1 -C 6 -alkyl, wherein at least one hydrogen is exchanged with a halogen atom, preferably F or Cl, especially good for F. The haloalkyl group can be branched or unbranched and optionally mono- or polysubstituted. Preferably, the (C 1 -C 6 )-haloalkyl group is a (C 1 -C 3 )-haloalkyl group, particularly CHF 2 , CH 2 F, CF 3 , CH 2 CH 2 F, CH 2 CHF 2 And CH 2 CF 3 .

除非另有特定，該術語「(C1-C6)-鹵烷氧基」係被理解為一 C1-C6-烷氧基，其中至少一氫係與一鹵素原子交換，較佳為F或Cl，特佳為F。該鹵烷氧基原子團可為有分枝或無分枝且可擇地經單或多取代。較佳之(C1-C6)-鹵烷氧基原子團係(C1-C3)-鹵烷氧基原子團，特別為OCHF2、OCH2F、OCF3、OCF2CH3、OCH2CH2F、OCH2CHF2及OCH2CF3。 Unless otherwise specified, the term "(C 1 -C 6 )-haloalkoxy" is understood to be a C 1 -C 6 -alkoxy group, wherein at least one hydrogen is exchanged with a halogen atom, preferably F or Cl, especially good for F. The haloalkoxy radical may be branched or unbranched and optionally mono- or polysubstituted. Preferred (C 1 -C 6 )-haloalkoxy radicals are (C 1 -C 3 )-haloalkoxy radicals, especially OCHF 2 , OCH 2 F, OCF 3 , OCF 2 CH 3 , OCH 2 CH 2 F, OCH 2 CHF 2 and OCH 2 CF 3 .

除非另有特定，該術語「(C1-C6)-羥烷基」係被理解為一C1-C6-烷基，其中至少一氫係與一羥基基團交換。該羥烷基原子團可為有分枝或無分枝且可擇地經單或多取代。較佳之(C1-C6)-羥烷基原子團係(C1-C3)-羥烷基原子團，特別為CH2OH、CH2CH2OH、CH2CH2CH2OH及CH2CH(OH)CH2OH。 Unless otherwise specified, the term "(C 1 -C 6 )-hydroxyalkyl" is understood to mean a C 1 -C 6 -alkyl group in which at least one hydrogen is exchanged with a monohydroxy group. The hydroxyalkyl radical can be branched or unbranched and optionally mono- or polysubstituted. Preferred (C 1 -C 6 )-hydroxyalkyl radicals (C 1 -C 3 )-hydroxyalkyl radicals, in particular CH 2 OH, CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH and CH 2 CH(OH)CH 2 OH.

除非另有特定，該術語「(C1-C6)-氰烷基」係被理解為一C1-C6-烷基，其中至少一氫係與一氰基基團交換。該羥烷基原子團可為有分枝或無分枝且可擇地經單或多取代。較佳之(C1-C6)-氰烷基原子團係(C1-C3)-氰烷基原子團，特別為CH2CN、CH2CH2CN及CH2CH2CH2CN。 Unless otherwise specified, the term "(C 1 -C 6 )-cyanoalkyl" is understood to mean a C 1 -C 6 -alkyl group in which at least one hydrogen is exchanged with a cyano group. The hydroxyalkyl radical can be branched or unbranched and optionally mono- or polysubstituted. Preferred are (C 1 -C 6 )-cyanoalkyl radicals (C 1 -C 3 )-cyanoalkyl radicals, in particular CH 2 CN, CH 2 CH 2 CN and CH 2 CH 2 CH 2 CN.

除非另有特定，該術語「(C1-C6)-硫烷基」係被理解為意指有分枝或無分枝之硫烷基基團，其含有1至6個碳原子。(C1-C6)-硫烷基原子團之例示為SCH3、SCH2CH3、S(CH2)2CH3、SCH(CH3)2、S(CH2)3CH3、SCH(CH3)CH2CH3、SCH2CH(CH3)2、SC(CH3)3、S(CH2)4CH3、S(CH2)2CH(CH3)2、SCH2CH(CH3)CH2CH3、SCH(CH3)(CH2)2CH3、SC(CH3)2CH2CH3、SCH2C(CH3)3、S(CH2)5CH3、S(CH2)3CH(CH3)2、S(CH2)2CH(CH3)CH2CH3、SCH2CH(CH3)(CH2)2CH3、SCH2C(CH3)2CH2CH3、SCH2CH(CH3)(CH2)2CH3、SCH(CH3)(CH2)3CH3、SC(CH3)2(CH2)2CH3、S(CH2)2C(CH3)3。較佳為(C1-C4)-硫烷基原子團，特別為SCH3、SCH2CH3、SCH2CH2CH3或SCH(CH3)2。 Unless otherwise specified, the term "(C 1 -C 6) - sulfanyl" system is understood to mean a sulfur-free branching or branching alkyl group of which contains 1-6 carbon atoms. Examples of (C 1 -C 6 )-sulfanyl radicals are SCH 3 , SCH 2 CH 3 , S(CH 2 ) 2 CH 3 , SCH(CH 3 ) 2 , S(CH 2 ) 3 CH 3 , SCH ( CH 3 )CH 2 CH 3 , SCH 2 CH(CH 3 ) 2 , SC(CH 3 ) 3 , S(CH 2 ) 4 CH 3 , S(CH 2 ) 2 CH(CH 3 ) 2 , SCH 2 CH( CH 3 )CH 2 CH 3 , SCH(CH 3 )(CH 2 ) 2 CH 3 , SC(CH 3 ) 2 CH 2 CH 3 , SCH 2 C(CH 3 ) 3 , S(CH 2 ) 5 CH 3 , S(CH 2 ) 3 CH(CH 3 ) 2 , S(CH 2 ) 2 CH(CH 3 )CH 2 CH 3 , SCH 2 CH(CH 3 )(CH 2 ) 2 CH 3 , SCH 2 C(CH 3 2 CH 2 CH 3 , SCH 2 CH(CH 3 )(CH 2 ) 2 CH 3 , SCH(CH 3 )(CH 2 ) 3 CH 3 , SC(CH 3 ) 2 (CH 2 ) 2 CH 3 , S (CH 2 ) 2 C(CH 3 ) 3 . Preferred is a (C 1 -C 4 )-sulfanyl atom group, particularly SCH 3 , SCH 2 CH 3 , SCH 2 CH 2 CH 3 or SCH(CH 3 ) 2 .

除非另有特定，該術語「(C1-C6)-硫鹵烷基」係被理解為一(C1-C6)-硫烷基，其中至少一氫係與一鹵素原子交換，較佳為F或Cl，特佳為 F。該硫鹵烷基原子團可為有分枝或無分枝且可擇地經單或多取代。較佳之(C1-C6)-硫鹵烷基原子團為(C1-C3)-硫鹵烷基原子團，特別為SCHF2、SCH2F、SCF3、SCF2CH3、SCH2CH2F、SCH2CHF2及SCH2CF3。 Unless otherwise specified, the term "(C 1 -C 6 )-thiohaloalkyl" is understood to mean a (C 1 -C 6 )-sulfanyl group in which at least one hydrogen is exchanged with a halogen atom. Good for F or Cl, especially for F. The thiohaloalkyl group can be branched or unbranched and optionally mono- or polysubstituted. Preferably, the (C 1 -C 6 )-thiohaloalkyl group is a (C 1 -C 3 )-thiohaloalkyl group, in particular SCHF 2 , SCH 2 F, SCF 3 , SCF 2 CH 3 , SCH 2 CH 2 F, SCH 2 CHF 2 and SCH 2 CF 3 .

在本發明範疇中，該術語「C1-C3-伸烷基」及「C1-C6-伸烷基」係被理解為具有1、2或3碳原子或1、2、3、4、5或6個碳原子之非環狀飽和烴原子團，其可為有分枝或無分枝且為未經取代或經以相同或不同取代基取代一次或數次(例如2、3、4或5次)且其將一對應之部分(moiety)連接至主要結構。伸烷基基團較佳地可由CH2、CH2CH2、CH(CH3)、CH2CH2CH2、CH(CH3)CH2、C(CH3)2、CH(CH2CH3)所組成之群組選擇。該伸烷基基團特佳可由CH2、CH2CH2及CH2CH2CH2所組成之群組選擇。 In the scope of the invention, the term "C 1- C 3 - alkylene" and "C 1- C 6 - alkylene" is understood as a system having 2 or 3 carbon atoms or 2,3, a non-cyclic saturated hydrocarbon radical of 4, 5 or 6 carbon atoms which may be branched or unbranched and unsubstituted or substituted one or several times with the same or different substituents (eg 2, 3, 4 or 5 times) and it connects a corresponding moiety to the main structure. The alkylene group may preferably be CH 2 , CH 2 CH 2 , CH(CH 3 ), CH 2 CH 2 CH 2 , CH(CH 3 )CH 2 , C(CH 3 ) 2 , CH(CH 2 CH 3 ) The group selection consisting of. The alkylene group is particularly preferably selected from the group consisting of CH 2 , CH 2 CH 2 and CH 2 CH 2 CH 2 .

除非另有特定，該術語「C2-C6-烯基」係被理解為意指有分枝或無分枝之未飽和烷基基團，其含有2至6個碳原子且具有至少一雙鍵。C2-C6-烯基之例示為乙烯基(ethenyl)(也稱為乙烯基(vinyl))、丙-1-烯基、丙-2-烯基(也稱為丙烯基(allyl))、丁-1-烯基、丁-2-烯基、丁-3-烯基、戊-1-烯基及己-1-烯基。該名稱C2-C6-烯基包含所有可能之異構物，即結構異構物(constitutional isomers)及立體異構物((Z)及(E)異構物)。除非另有特定，該術語「C2-C6-炔基」係被理解為意指有分枝或無分枝之未飽和烷基基團，其含有2至6個碳原子且具有至少一三鍵。C2-C6-炔基之例示為乙炔基(ethinyl)。 Unless otherwise specified, the term "C 2 -C 6 - alkenyl" is understood to mean lines have no unsaturated branched or branched alkyl group of which contains 2-6 carbon atoms and having at least one Double key. An example of a C 2 -C 6 -alkenyl group is ethenyl (also known as vinyl), prop-1-enyl, prop-2-enyl (also known as allyl). , but-1-enyl, but-2-enyl, but-3-enyl, pent-1-enyl and hex-1-enyl. The name C 2 -C 6 -alkenyl contains all possible isomers, ie, structural isomers and stereoisomers ((Z) and (E) isomers). Unless otherwise specified, the term "C 2 -C 6 -alkynyl" is understood to mean a branched or unbranched unsaturated alkyl group containing from 2 to 6 carbon atoms and having at least one Three keys. An example of a C 2 -C 6 -alkynyl group is ethinyl.

除非另有特定，該術語「C3-6-環烷基」表示各具有3、4、5或6個碳原子之環狀飽和烴，其可為未經取代或經取代一次或數次，例如在一或多個環成員上以2、3、4或5個相同或不同原子團。C3-6-環烷基較佳可由環丙基、環丁基、環戊基及環己基所組成之群組中選擇。 Unless otherwise specified, the term "C 3-6 -cycloalkyl" means a cyclic saturated hydrocarbon each having 3, 4, 5 or 6 carbon atoms which may be unsubstituted or substituted one or several times, For example, 2, 3, 4 or 5 identical or different atomic groups on one or more ring members. The C 3-6 -cycloalkyl group is preferably selected from the group consisting of a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group.

除非另有特定，該術語「3至7員雜環烷基」及「3至12員雜環烷基」係被理解為意指具3至7個(即3、4、5、6或7個)或具有3至12個(即3、 4、5、6、7、8、9、10、11或12個)環成員之雜環脂族之飽和或未飽和(但非芳族)殘基，其中於每一種情況下至少一(如適當也可二或三)碳原子被一雜原子或一雜原子基團取代，各彼此獨立地選自於由O、S、S(=O)、S(=O)2、N、NH及N(C1-6-烷基)(諸如N(CH3))組成之群組，其中該環成員可為未經取代或經單或多取代。該雜環烷基殘基可為單或雙環狀。 Unless otherwise specified, the terms "3 to 7 membered heterocycloalkyl" and "3 to 12 membered heterocycloalkyl" are understood to mean 3 to 7 (ie 3, 4, 5, 6 or 7). Or a saturated or unsaturated (but non-aromatic) residue of a heterocyclic aliphatic group having 3 to 12 (ie, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) ring members a group wherein, in each case, at least one (if appropriate, two or three) carbon atoms are substituted by a hetero atom or a hetero atom group, each independently selected from O, S, S(=O) a group consisting of S(=O) 2 , N, NH, and N(C 1-6 -alkyl) (such as N(CH 3 )), wherein the ring member can be unsubstituted or mono- or polysubstituted . The heterocycloalkyl residue can be mono- or bicyclic.

除非另有特定，該術語「5或6員雜芳基」係被理解為代表含有至少1個(如適當也可為2、3、4或5個)雜原子之5或6員環狀芳族殘基，其中該雜原子各自較佳彼此獨立地選自於由S、N及O所組成之群組且該雜芳基殘基可為未經取代或經單或多取代，其包含N-氧化物之形成；例如，經以2、3、4或5個取代基取代，其中該取代基可為相同或不同且在該雜芳基之任何所欲及可能之位置。與該上級一般結構(superordinate general structure)之連接若無其他指示可經由該雜芳基殘基之任何所欲及可能之環成員進行。該雜芳基可與一4-、5-、6-或7-員環稠合，其為碳環族或雜環族，其中該雜環之雜原子較佳各自彼此獨立地選自於由S、N及O所組成之群組，且其中該稠合環可為飽和、部分未飽和或芳族且可為未經取代或經單或多取代；例如，經以2、3、4或5個取代基取代，其中該取代基可為相同或不同且在任何所欲及可能位置。該雜芳基部分(moieties)之例示為苯并呋喃基(benzofuranyl)、苯并咪唑基(benzoimidazolyl)、苯并噻吩基(benzo-thienyl)、苯并噻二唑基(benzothiadiazolyl)、苯并噻唑基(benzothiazolyl)、苯并三唑基(benzotriazolyl)、苯并噁唑基(benzooxazolyl)、苯并噁二唑基(benzooxadiazolyl)、喹唑啉基(quinazolinyl)、喹喔啉基(quinoxalinyl)、咔唑基(carbazolyl)、喹啉基(quinolinyl)、二苯并呋喃基(dibenzofuranyl)、二苯并噻吩基(dibenzothienyl)、呋喃基(furyl)(呋喃基(furanyl))、咪唑基(imidazolyl)、咪唑并噻唑基(imidazo-thiazolyl)、吲唑基(indazolyl)、吲嗪基(indolizinyl)、 吲哚啉基(indolyl)、異喹啉基(isoquinolinyl)、異噁唑基(isoxazoyl)、異噻唑基(isothiazolyl)、吲哚啉基(indolyl)、萘啶基(naphthyridinyl)、噁唑基(oxazolyl)、氧雜二唑基(oxadiazolyl)、吩嗪基(phenazinyl)、吩噻嗪基(phenothiazinyl)、酞嗪基(phthalazinyl)、吡唑基(pyrazolyl)、吡啶基(pyridyl)(2-吡啶基、3-吡啶基、4-吡啶基)、吡咯基(pyrrolyl)、噠嗪基(pyridazinyl)、嘧啶基(pyrimidinyl)、吡嗪基(pyrazinyl)、瞟呤基(purinyl)、吩嗪基(phenazinyl)、噻吩基(硫苯基)、三唑基(triazolyl)、四唑基(tetrazolyl)、噻唑基(thiazolyl)、噻二唑基(thiadiazolyl)及三嗪基(triazinyl)。 Unless otherwise specified, the term "5 or 6 membered heteroaryl" is understood to mean a 5 or 6 membered cyclic aryl containing at least one (as appropriate, 2, 3, 4 or 5) heteroatoms. a family residue, wherein the heteroatoms are each preferably selected independently of each other from the group consisting of S, N and O and the heteroaryl residue may be unsubstituted or mono- or polysubstituted, which comprises N - Formation of an oxide; for example, substituted with 2, 3, 4 or 5 substituents, wherein the substituents may be the same or different and at any desired and possible position of the heteroaryl. The linkage to the superordinate general structure can be carried out via any desired and possible ring member of the heteroaryl residue, unless otherwise indicated. The heteroaryl group may be fused to a 4-, 5-, 6- or 7-membered ring which is a carbocyclic or heterocyclic group, wherein the heteroatoms of the heterocyclic ring are preferably each independently selected from a group consisting of S, N and O, and wherein the fused ring may be saturated, partially unsaturated or aromatic and may be unsubstituted or mono- or polysubstituted; for example, by 2, 3, 4 or Substituted by five substituents, wherein the substituents may be the same or different and at any desired and possible position. Examples of the heteroaryl moieties are benzofuranyl, benzoimidazolyl, benzo-thienyl, benzothiadiazolyl, benzothiazole. Benzothiazolyl, benzotriazolyl, benzooxazolyl, benzooxadiazolyl, quinazolinyl, quinoxalinyl, anthraquinone Carbazolyl, quinolinyl, dibenzofuranyl, dibenzothienyl, furyl (furanyl), imidazolyl, Imidazo-thiazolyl, indazolyl, indolizinyl, Indolyl, isoquinolinyl, isoxazoyl, isothiazolyl, indolyl, naphthyridinyl, oxazolyl ( Oxazolyl), oxadiazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pyrazolyl, pyridyl (2-pyridine) , 3-pyridyl, 4-pyridyl), pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, purinyl, phenazinyl Phenazinyl), thienyl (thiophenyl), triazolyl, tetrazolyl, thiazolyl, thiadiazolyl and triazinyl.

除非另有特定，該術語「經取代」與非芳族部分「烷基」、「烯基」、「炔基」及「伸烷基」之關係於此發明之範疇係被理解為意指使以一取代基取代一氫原子團，其係選自於由以下所組成之群組：=O、OH、CN、鹵素、SH、NO2、C1-C6-烷氧基、(C1-C6)-羥烷氧基、(C1-C6)-硫烷基、(C1-C6-烷氧基)-C1-C6-烷氧基、(C1-C6)-硫鹵烷基、(C1-C6)-鹵烷氧基、C3-C6-環烷基、3至7員雜環烷基、NH2、NH(C1-C6-烷基)、N(C1-C6-烷基)2、NH(C1-C6-羥烷基)、N(C1-C6-烷基)(C1-C6-羥烷基)、N(C1-C6-羥烷基)2、=NH、=N(C1-C6-烷基)、=N(OH)、NHCO(C1-C6-烷基)、N(C1-C6-烷基)CO(C1-C6-烷基)、NHCO(C1-C6-羥烷基)、N(C1-C6-烷基)CO(C1-C6-羥烷基)、NHCOO(C1-C6-烷基)、NH-C(O)NH2、NHCONH(C1-C6-烷基)、NHCON(C1-C6-烷基)2、NH(C1-C6-伸烷基)-COO(C1-C6-烷基)、N(C1-C6-伸烷基)-CONH2、NH(C1-C6-伸烷基)-CONH(C1-C6-烷基)、NH(C1-C6-伸烷基)-CON(C1-C6-烷基)2、NHS(O)2OH、NHS(O)2(C1-C6-烷基)、NHS(O)2O(C1-C6-烷基)、NHS(O)2NH2、NHS(O)2NH(C1-C6-烷基)、NHS(O)2N(C1-C6-烷基)2、NH(C1-C6-伸烷基)-S(O)2OH、NH(C1-C6-伸烷基)-S(O)2(C1-C6-烷基)、NH(C1-C6-伸烷基)-S(O)2O(C1-C6-烷基)、NH(C1-C6-伸烷基)-S(O)2NH2、NH(C1-C6-伸烷 基)-S(O)2NH(C1-C6-烷基)、CO2H、CO(C1-C6-烷基)、COO(C1-C6-烷基)、OCO(C1-C6-烷基)、OCOO(C1-C6-烷基)、CONH2、CONH(C1-C6-烷基)、CON(C1-C6-烷基)2、OCONH(C1-C6-烷基)、OCON(C1-C6-烷基)2、OS(O)2(C1-C6-烷基)、OS(O)2OH、OS(O)2-(C1-C6-烷氧基)、OS(O)2NH2、OS(O)2NH(C1-C6-烷基)、O-S(O)2-N(C1-C6-烷基)2、S(O)(C1-C6-烷基)、S(O)2(C1-C6-烷基)、S(O)2OH、S(O)2O(C1-C6-烷基)、S(O)2NH2、S(O)2NH(C1-C6-烷基)及S(O)2N(C1-C6-烷基)2。若一部分(moiety)係經以多於1個取代基取代(經多取代)(例如以2、3、4或5個取代基)，此等取代基可在同或相同之原子上(例如在CF3或CH2CF3之情況)或在不同處(在CH(Cl)-CH=CH-CHCl2之情況)存在。以多於1個取代基之取代可包含相同或不同取代基，諸如例如CH(OH)-CH=CH-CHCl2之情況。 Unless otherwise specified, the term "substituted" and non-aromatic moieties "alkyl", "alkenyl", "alkynyl" and "alkylene" are used in the context of the invention to be understood to mean A substituent replaces a hydrogen atom selected from the group consisting of: =O, OH, CN, halogen, SH, NO 2 , C 1 -C 6 -alkoxy, (C 1 -C) 6 )-Hydroxyalkoxy, (C 1 -C 6 )-sulfanyl, (C 1 -C 6 -alkoxy)-C 1 -C 6 -alkoxy, (C 1 -C 6 )- Thiohaloalkyl, (C 1 -C 6 )-haloalkoxy, C 3 -C 6 -cycloalkyl, 3 to 7 membered heterocycloalkyl, NH 2 , NH(C 1 -C 6 -alkyl ), N(C 1 -C 6 -alkyl) 2 , NH(C 1 -C 6 -hydroxyalkyl), N(C 1 -C 6 -alkyl)(C 1 -C 6 -hydroxyalkyl) , N(C 1 -C 6 -hydroxyalkyl) 2 , =NH, =N(C 1 -C 6 -alkyl), =N(OH), NHCO(C 1 -C 6 -alkyl), N (C 1 -C 6 -alkyl)CO(C 1 -C 6 -alkyl), NHCO(C 1 -C 6 -hydroxyalkyl), N(C 1 -C 6 -alkyl)CO(C 1 -C 6 -hydroxyalkyl), NHCOO(C 1 -C 6 -alkyl), NH-C(O)NH 2 , NHCONH(C 1 -C 6 -alkyl), NHCON(C 1 -C 6 - Alkyl) 2 , NH(C 1 -C 6 -alkylene)-COO(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkylene)-CONH 2 , NH(C 1 -C 6 -alkylene)-CONH(C 1 -C 6 -alkyl), NH(C 1 -C 6 -alkylene)-CON(C 1 -C 6 -alkyl) 2 , NHS(O) 2 OH, NHS(O) 2 (C 1 -C 6 -alkyl), NHS(O) 2 O(C 1 -C 6 -alkyl), NHS(O) 2 NH 2 , NHS(O) 2 NH(C 1 -C 6 -alkyl), NHS(O) 2 N(C 1 -C 6 -alkyl) 2 , NH(C 1 -C 6 -alkylene)-S(O) 2 OH, NH(C 1 -C 6 -alkylene)-S(O) 2 (C 1 -C 6 -alkyl), NH(C 1 -C 6 - Alkyl)-S(O) 2 O(C 1 -C 6 -alkyl), NH(C 1 -C 6 -alkylene)-S(O) 2 NH 2 , NH(C 1 -C 6 -alkylene)-S(O) 2 NH(C 1 -C 6 -alkyl), CO 2 H, CO(C 1 -C 6 -alkyl), COO(C 1 -C 6 -alkyl) , OCO (C 1 -C 6 -alkyl), OCOO (C 1 -C 6 -alkyl), CONH 2 , CONH(C 1 -C 6 -alkyl), CON(C 1 -C 6 -alkyl 2 , OCONH(C 1 -C 6 -alkyl), OCON(C 1 -C 6 -alkyl) 2 , OS(O) 2 (C 1 -C 6 -alkyl), OS(O) 2 OH , OS(O) 2 -(C 1 -C 6 -alkoxy), OS(O) 2 NH 2 , OS(O) 2 NH(C 1 -C 6 -alkyl), OS(O) 2 - N(C 1 -C 6 -alkyl) 2 , S(O)(C 1 -C 6 -alkyl), S(O) 2 (C 1 -C 6 -alkyl), S(O) 2 OH , S (O) 2 O ( C 1 -C 6 - alkyl), S (O) 2 NH 2 S (O) 2 NH (C 1 -C 6 - alkyl) and S (O) 2 N (C 1 -C 6 - alkyl) 2. If a moiety is substituted with more than one substituent (multiple substitution) (eg, with 2, 3, 4 or 5 substituents), the substituents may be on the same or the same atom (eg, In the case of CF 3 or CH 2 CF 3 ) or at a different point (in the case of CH(Cl)-CH=CH-CHCl 2 ). In more than one substituent the substituents may comprise the same or different substituents, such as for example CH (OH) -CH = CH- CHCl 2 of the case.

較佳地，該取代基可選自於由以下所組成之群組：F、Cl、Br、CF3、CHF2、CH2F、OCF3、OH、CN、(C1-C6)-烷基，(C1-C6)-羥烷基、(C1-C6)-烷氧基、(C1-C6)-羥烷氧基、C3-C6-環烷基、NH2、NH(C1-C6-烷基)、N(C1-C6-烷基)CO(C1-C6-烷基)、NHCO(C1-C6-羥烷基)、N(C1-C6-烷基)-CO(C1-C6-羥烷基)、N(C1-C6-烷基)2、NH(C1-C6-羥烷基)、N(C1-C6-烷基)(C1-C6-羥烷基)、NHCO(C1-C6-烷基)、NH-CONH(C1-C6-烷基)、NHCON(C1-C6-烷基)2、NHS(O)2(C1-C6-烷基)、CONH2、CONH(C1-C6-烷基)、CON(C1-C6-烷基)2、S(O)(C1-C6-烷基)及S(O)2(C1-C6-烷基)。 Preferably, the substituent may be selected from the group consisting of F, Cl, Br, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, CN, (C 1 -C 6 )- Alkyl, (C 1 -C 6 )-hydroxyalkyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-hydroxyalkoxy, C 3 -C 6 -cycloalkyl, NH 2 , NH(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl)CO(C 1 -C 6 -alkyl), NHCO(C 1 -C 6 -hydroxyalkyl) , N(C 1 -C 6 -alkyl)-CO(C 1 -C 6 -hydroxyalkyl), N(C 1 -C 6 -alkyl) 2 , NH(C 1 -C 6 -hydroxyalkyl ), N(C 1 -C 6 -alkyl)(C 1 -C 6 -hydroxyalkyl), NHCO(C 1 -C 6 -alkyl), NH-CONH(C 1 -C 6 -alkyl) , NHCON(C 1 -C 6 -alkyl) 2 , NHS(O) 2 (C 1 -C 6 -alkyl), CONH 2 , CONH(C 1 -C 6 -alkyl), CON(C 1 - C 6 -alkyl) 2 , S(O)(C 1 -C 6 -alkyl) and S(O) 2 (C 1 -C 6 -alkyl).

除非另有特定，該術語「經取代」與該部分「環烷基」及「雜環烷基」之關係於此發明之範疇係被理解為意指以一取代基替換一氫原子團，其係選自於由以下所組成之群組：=O、OH、CN、鹵素、SH、NO2、C1-C6-烷基，C2-C6-烯基、C2-C6-炔基、(C1-C6)-羥烷基、(C1-C6)-氰烷基、C1-C6-烷氧基、(C1-C6)-硫烷基、(C1-C6)-鹵烷基、(C1-C6-烷氧基)-(C1-C6-亞烷基)、 (C1-C6-烷氧基)-C1-C6-烷氧基、(C1-C6)-thio鹵烷基、(C1-C6)-鹵烷氧基、(C1-C6-硫烷基)-(C1-C6-亞烷基)、C3-C6-環烷基、(C3-C6-環烷基)-(C1-C3-亞烷基)、3至7員雜環烷基、(3至7員雜環烷基)-(C1-C3-亞烷基)、NH2、NH(C1-C6-烷基)、N(C1-C6-烷基)2、NHCO(C1-C6-烷基)、NHCOO(C1-C6-烷基)、NH-C(O)NH2、NHCONH(C1-C6-烷基)、NHCON(C1-C6-烷基)2、(C1-C6-伸烷基)NH2、(C1-C6-伸烷基)NH(C1-C6-烷基)、(C1-C6-伸烷基)N(C1-C6-烷基)2、(C1-C6-伸烷基)NHCO(C1-C6-烷基)、(C1-C6-伸烷基)NHCO2(C1-C6-烷基)、(C1-C6-伸烷基)NHC(O)NH2、(C1-C6-伸烷基)NHCONH(C1-C6-烷基)、(C1-C6-伸烷基)NHCON(C1-C6-烷基)2、NH(C1-C6-伸烷基)-COO(C1-C6-烷基)、NH(C1-C6-伸烷基)-CONH2、NH(C1-C6-伸烷基)-CONH(C1-C6-烷基)、NH(C1-C6-伸烷基)-CON(C1-C6-烷基)2、NHS(O)2OH、NHS(O)2(C1-C6-烷基)、NHS(O)2O(C1-C6-烷基)、NHS(O)2NH2、NHS(O)2NH(C1-C6-烷基)、NHS(O)2N(C1-C6-烷基)2、NH(C1-C6-伸烷基)-S(O)2OH、NH(C1-C6-伸烷基)-S(O)2(C1-C6-烷基)、NH(C1-C6-伸烷基)-S(O)2O(C1-C6-烷基)、NH(C1-C6-伸烷基)-S(O)2NH2、NH(C1-C6-伸烷基)-S(O)2NH(C1-C6-烷基)、CO2H、CO(C1-C6-烷基)、COO(C1-C6-烷基)、OCO(C1-C6-烷基)、OCOO(C1-C6-烷基)、CONH2、CONH(C1-C6-烷基)、CON(C1-C6-烷基)2、OCONH(C1-C6-烷基)、OCON(C1-C6-烷基)2、OS(O)2(C1-C6-烷基)、OS(O)2OH、OS(O)2-(C1-C6-烷氧基)、OS(O)2NH2、OS(O)2NH(C1-C6-烷基)、O-S(O)2-N(C1-C6-烷基)2、S(O)(C1-C6-烷基)、S(O)2(C1-C6-烷基)、S(O)2OH、S(O)2O(C1-C6-烷基)、S(O)2NH2、S(O)2NH(C1-C6-烷基)及S(O)2N(C1-C6-烷基)2。若一部分為經以多於1個取代基取代(經多取代)(例如以2、3、4或5取代基)，此等取代基可在不同或相同原子或於不同處存在，且可包含相同或不同取代基。 Unless otherwise specified, the term "substituted" and the relationship between "cycloalkyl" and "heterocycloalkyl" in this section are understood to mean replacing a hydrogen radical with a substituent. Selected from the group consisting of: =O, OH, CN, halogen, SH, NO 2 , C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkyne , (C 1 -C 6 )-hydroxyalkyl, (C 1 -C 6 )-cyanoalkyl, C 1 -C 6 -alkoxy, (C 1 -C 6 )-sulfanyl, (C 1- C 6 )-haloalkyl, (C 1 -C 6 -alkoxy)-(C 1 -C 6 -alkylene), (C 1 -C 6 -alkoxy)-C 1 -C 6 - alkoxy, (C 1 -C 6) -thio haloalkyl, (C 1 -C 6) - haloalkoxy, (C 1 -C 6 - sulfanyl) - (C 1 -C 6 -alkylene), C 3 -C 6 -cycloalkyl, (C 3 -C 6 -cycloalkyl)-(C 1 -C 3 -alkylene), 3 to 7 membered heterocycloalkyl, 3 to 7 membered heterocycloalkyl)-(C 1 -C 3 -alkylene), NH 2 , NH(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl) 2 , NHCO(C 1 -C 6 -alkyl), NHCOO(C 1 -C 6 -alkyl), NH-C(O)NH 2 , NHCONH(C 1 -C 6 -alkyl), NHCON(C 1 - C 6 -alkyl) 2 , (C 1 -C 6 -alkylene)NH 2 , (C 1 -C 6 -alkylene)NH (C 1 -C 6 -alkyl), (C 1 -C 6 -alkylene)N(C 1 -C 6 -alkyl) 2 , (C 1 -C 6 -alkylene)NHCO (C 1 -C 6 -alkyl), (C 1 -C 6 -alkylene)NHCO 2 (C 1 -C 6 -alkyl), (C 1 -C 6 -alkylene)NHC(O)NH 2 , (C 1 -C 6 -alkylene)NHCONH(C 1 -C 6 -alkyl), (C 1 -C 6 -alkylene)NHCON(C 1 -C 6 -alkyl) 2 , NH(C 1 -C 6 -alkylene)-COO(C 1 -C 6 -alkyl), NH(C 1 -C 6 -alkylene)-CONH 2 , NH(C 1 -C 6 -alkylene) -CONH(C 1 -C 6 -alkyl), NH(C 1 -C 6 -alkylene)-CON(C 1 -C 6 -alkyl) 2 , NHS(O) 2 OH, NHS(O) 2 (C 1 -C 6 -alkyl), NHS(O) 2 O(C 1 -C 6 -alkyl), NHS(O) 2 NH 2 , NHS(O) 2 NH(C 1 -C 6 - Alkyl), NHS(O) 2 N(C 1 -C 6 -alkyl) 2 , NH(C 1 -C 6 -alkylene)-S(O) 2 OH, NH(C 1 -C 6 - Alkyl)-S(O) 2 (C 1 -C 6 -alkyl), NH(C 1 -C 6 -alkylene)-S(O) 2 O(C 1 -C 6 -alkyl) NH(C 1 -C 6 -alkylene)-S(O) 2 NH 2 , NH(C 1 -C 6 -alkylene)-S(O) 2 NH(C 1 -C 6 -alkyl ), CO 2 H, CO (C 1 -C 6 -alkyl), COO (C 1 -C 6 -alkyl), OCO (C 1 -C 6 -alkyl), OCOO (C 1 -C 6 - alkyl), CONH 2, CONH (C 1 -C 6 - Yl), CON (C 1 -C 6 - alkyl) 2, OCONH (C 1 -C 6 - alkyl), OCON (C 1 -C 6 - alkyl) 2, OS (O) 2 (C 1 - C 6 -alkyl), OS(O) 2 OH, OS(O) 2 -(C 1 -C 6 -alkoxy), OS(O) 2 NH 2 , OS(O) 2 NH(C 1 - C 6 -alkyl), OS(O) 2 -N(C 1 -C 6 -alkyl) 2 , S(O)(C 1 -C 6 -alkyl), S(O) 2 (C 1 - C 6 -alkyl), S(O) 2 OH, S(O) 2 O(C 1 -C 6 -alkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1 -C 6 -alkyl) and S(O) 2 N(C 1 -C 6 -alkyl) 2 . If a portion is substituted with more than one substituent (polysubstituted) (eg, with 2, 3, 4, or 5 substituents), such substituents may exist at different or identical atoms or at different points, and may include The same or different substituents.

較佳地，該取代基可選自於由以下所組成之群組：F、Cl、 Br、CF3、CHF2、CH2F、OCF3、OH、CN、(C1-C6)-烷基，(C1-C6)-經烷基、(C1-C6)-烷氧基、C3-C6-環烷基、NH2、NH(C1-C6-烷基)、N(C1-C6-烷基)2、NHCO(C1-C6-烷基)、NH-CONH(C1-C6-烷基)、NHCON(C1-C6-烷基)2、NHS(O)2(C1-C6-烷基)、CONH2、CONH(C1-C6-烷基)、CON(C1-C6-烷基)2、S(O)(C1-C6-烷基)及S(O)2(C1-C6-烷基)。 Preferably, the substituent may be selected from the group consisting of F, Cl, Br, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, CN, (C 1 -C 6 )- Alkyl, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, C 3 -C 6 -cycloalkyl, NH 2 , NH(C 1 -C 6 -alkyl ), N(C 1 -C 6 -alkyl) 2 , NHCO(C 1 -C 6 -alkyl), NH-CONH(C 1 -C 6 -alkyl), NHCON(C 1 -C 6 -alkane) 2 ), NHS(O) 2 (C 1 -C 6 -alkyl), CONH 2 , CONH(C 1 -C 6 -alkyl), CON(C 1 -C 6 -alkyl) 2 , S ( O) (C 1 -C 6 -alkyl) and S(O) 2 (C 1 -C 6 -alkyl).

除非另有特定，對於含有二或更多相同類型殘基之上級殘基，諸如N(C1-C6-烷基)2中之C1-C6-烷基，可理解該二或更多殘基係彼此為相同或不同。若該殘基係經取代，然後可理解各殘基係獨立地經取代。作為一例示，N(C1-C6-烷基)2，其中C1-C6-烷基係未經取代或經以OH取代，涵括例如特別為N(CH3)2、N(CH3)(CH2CH3)、N(CH2CH3)2、N(CH3)(CH2CH2OH)及N(CH2CH2OH)2。 Unless otherwise specified, to the residue containing two or more higher residues of the same type, such as N (C 1 -C 6 - alkyl) in the 2 C 1 -C 6 - alkyl, it is understood that two or more The multiple residues are identical or different from each other. If the residue is substituted, it will then be understood that each residue is independently substituted. As an example, N(C 1 -C 6 -alkyl) 2 , wherein the C 1 -C 6 -alkyl group is unsubstituted or substituted with OH, and includes, for example, especially N(CH 3 ) 2 , N ( CH 3 )(CH 2 CH 3 ), N(CH 2 CH 3 ) 2 , N(CH 3 )(CH 2 CH 2 OH) and N(CH 2 CH 2 OH) 2 .

在本發明之範圍內，在該式中使用之該符號 或-*表示對應殘基與該個別上級一般結構之連接。 Within the scope of the invention, the symbol is used in the formula Or -* indicates the connection of the corresponding residue to the individual superior structure.

在本發明第一態樣之一具體實施例，式(I)化合物之特徵在於每一A、B及C代表CH。 In a specific embodiment of the first aspect of the invention, the compound of formula (I) is characterized in that each of A, B and C represents CH.

在本發明第一態樣之另一具體實施例中，式(I)之化合物之特徵在於m為1及n為1(因此形成一3,3-氧環丁伸烷基)或m為1及n為2(因此形成一3,3-四氫亞呋喃基(furanylene))或m為2及n為2(因此形成一4,4-四氫亞吡喃基(pyranylen))或m為1及n為3(因此形成一3,3-四氫亞吡喃基(pyranylen)，較佳地m為1及n為1或m為1及n為2或m為2及n為2，較佳地m為1及n為1。 In another embodiment of the first aspect of the invention, the compound of formula (I) is characterized in that m is 1 and n is 1 (thus forming a 3,3-oxocyclobutanyl group) or m is 1 And n is 2 (thus forming a 3,3-tetrahydrofuranylene) or m is 2 and n is 2 (thus forming a 4,4-tetrahydropyranyl) or m is 1 and n are 3 (thus forming a 3,3-tetrahydropyranyl group, preferably m is 1 and n is 1 or m is 1 and n is 2 or m is 2 and n is 2, Preferably m is 1 and n is 1.

更佳地，式(I)之化合物之特徵在於m為1及n為1。 More preferably, the compound of formula (I) is characterized in that m is 1 and n is 1.

在本發明第一態樣另一具體實施例中，式(I)之化合物之特徵在於G為以下G1至G44群組之一 ，其中該以星號(*)標示處指出該連接處，其係與該嘧啶環連接；R12係選自於由H、CH3或CH2CH3所組成之群組；k於每次出現為0、1、2、3或4；及Z每次出現係獨立地選自於由以下所組成之群組：F、Cl、Br、CF3、CHF2、CH2F、OCF3、OCHF2、OH、CN、C1-C6-烷基，C1-C6-羥烷基、C1-C6-烷氧基、C3-C6-環烷基、3至7員雜環烷基、NH2、NH(C1-C6-烷基)、N(C1-C6-烷基)2、NHCO(C1-C6-烷基)、NHCONH(C1-C6-烷基)、NHCON(C1-C6-烷基)2、(C1-C6-伸烷基)NH2、(C1-C6-伸烷基)NH(C1-C6-烷基)、(C1-C6-伸烷基)N(C1-C6-烷基)2、NHS(O)2(C1-C6-烷基)、CONH2、CONH(C1-C6-烷基)、CON(C1-C6-烷基)2、S(O)2NH2、S(O)2NH(C1-C6-烷基)、S(O)2N(C1-C6-烷基)2、S(O)(C1-C6-烷基)及S(O)2(C1-C6-烷基)，其中該C1-C6-烷基、該C3-C6-環烷基及該3至7員雜環烷基係未經取代或經單或多取代。 In another embodiment of the first aspect of the invention, the compound of formula (I) is characterized in that G is one of the following G1 to G44 groups Wherein the linkage is indicated by an asterisk (*) indicating that the linkage is linked to the pyrimidine ring; R 12 is selected from the group consisting of H, CH 3 or CH 2 CH 3 ; 0, 1, 2, 3 or 4; and each occurrence of Z is independently selected from the group consisting of F, Cl, Br, CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF 2 , OH, CN, C 1 -C 6 -alkyl, C 1 -C 6 -hydroxyalkyl, C 1 -C 6 -alkoxy, C 3 -C 6 -cycloalkyl, 3 to 7 member Cycloalkyl, NH 2 , NH(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl) 2 , NHCO(C 1 -C 6 -alkyl), NHCONH (C 1 -C 6 -alkyl), NHCON(C 1 -C 6 -alkyl) 2 , (C 1 -C 6 -alkylene)NH 2 , (C 1 -C 6 -alkylene)NH(C 1 -C 6 -alkyl), (C 1 -C 6 -alkylene)N(C 1 -C 6 -alkyl) 2 , NHS(O) 2 (C 1 -C 6 -alkyl), CONH 2 , CONH (C 1 -C 6 -alkyl), CON(C 1 -C 6 -alkyl) 2 , S(O) 2 NH 2 , S(O) 2 NH(C 1 -C 6 -alkyl), S (O) 2 N(C 1 -C 6 -alkyl) 2 , S(O)(C 1 -C 6 -alkyl) and S(O) 2 (C 1 -C 6 -alkyl), wherein C 1 -C 6 - alkyl group, the C 3 -C 6 - cycloalkyl and the 3-7 heterocycloalkyl group unsubstituted or lines Mono- or polysubstituted.

在一較佳具體實施例中，式(I)之化合物之特徵在於G為G1至G44群組之一，其中R12係選自於由H、CH3或CH2CH3所組成之群組；k於每次出現為0、1、2、3或4；且Z於每次出現係獨立地選自於由F、Cl、CN、CF3、CHF2、CH2F、OCF3、OH、OCH3、OC2H5、OCOCH3、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、CH2CH2CH2CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、NHCOCH3、CH2OH、CH2CH2OH、C(CH3)2OH、CH(CH3)OH、CH2NH2、CH2CH2NH2、C(CH3)2NH2、CH(CH3)NH2、CH2NH(CH3)、CH2CH2NH(CH3)、 C(CH3)2NH(CH3)、CH(CH3)NH(CH3)、CH2N(CH3)2、CH2CH2N(CH3)2、C(CH3)2N(CH3)2、CH(CH3)N(CH3)2、CH2CN、SOCH3、SO2CH3、SOCH2CH3、SO2CH2CH3、SO2NH2、吡咯啶基、哌啶基、氮環丙烷基、環丙基、環丁基、環戊基及環己基所組成之群組，其中該吡咯啶基、哌啶基、氮環丙烷基、氧環丁烷基、嗎啉基、環丙基、環丁基、環戊基及環己基係未經取代或經以一或多個取代基單或多取代，其係選自於由F、Cl、CN、CF3、CHF2、CH2F、OCF3、OH、OCH3、OC2H5、OCOCH3、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、CH2CH2CH2CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2及NHCOCH3所組成之群組。 In a preferred embodiment, the compound of formula (I) is characterized in that G is one of the group of G1 to G44, wherein R 12 is selected from the group consisting of H, CH 3 or CH 2 CH 3 ;k is 0, 1, 2, 3 or 4 at each occurrence; and Z is independently selected from F, Cl, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH in each occurrence. , OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N (CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3 2 NH 2 , CH(CH 3 )NH 2 , CH 2 NH(CH 3 ), CH 2 CH 2 NH(CH 3 ), C(CH 3 ) 2 NH(CH 3 ), CH(CH 3 )NH( CH 3 ), CH 2 N(CH 3 ) 2 , CH 2 CH 2 N(CH 3 ) 2 , C(CH 3 ) 2 N(CH 3 ) 2 , CH(CH 3 )N(CH 3 ) 2 , CH 2 CN, SOCH 3 , SO 2 CH 3 , SOCH 2 CH 3 , SO 2 CH 2 CH 3 , SO 2 NH 2 , pyrrolidinyl, piperidinyl, nitrogen cyclopropane, cyclopropyl, cyclobutyl a group consisting of a cyclopentyl group and a cyclohexyl group, wherein the pyrrolidinyl group, piperidinyl group, nitrogen cyclopropyl group, oxycyclobutane group, morpholinyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group And the cyclohexyl group is unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F, Cl, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 2 ) The group consisting of 2 and NHCOCH 3 .

在一較佳具體實施例中，式(I)之化合物之特徵在於G為G1至G44群組之一，其中R12係選自於由H、CH3或CH2CH3所組成之群組；k於每次出現為0、1、2、3或4；且Z於每次出現係獨立地選自於由F、Cl、CN、CF3、CHF2、CH2F、OCF3、OCHF2、OH、OCH3、OC2H5、OCOCH3、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、CH2CH2CH2CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、NHCOCH3、CH2OH、CH2CH2OH、C(CH3)2OH、CH(CH3)OH、CH2CN、SOCH3、SO2CH3、SOCH2CH3、SO2CH2CH3、SO2NH2、環丙基、環丁基、環戊基、環己基、3-氧環丁烷基、1-吡咯啶基、1-哌啶基及1-嗎啉基所組成之群組。 In a preferred embodiment, the compound of formula (I) is characterized in that G is one of the group of G1 to G44, wherein R 12 is selected from the group consisting of H, CH 3 or CH 2 CH 3 ;k is 0, 1, 2, 3 or 4 at each occurrence; and Z is independently selected from F, Cl, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF in each occurrence. 2 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH(CH 3 CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 CN, SOCH 3 , SO 2 CH 3 , SOCH 2 CH 3 , SO 2 CH 2 CH 3 , SO 2 NH 2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-oxocyclobutane, 1-pyrrolidinyl, 1-piperidinyl And a group consisting of 1-morpholinyl groups.

較佳地Z於每次出現係獨立地選自於由F、Cl、CN、CF3、CHF2、CH2F、OCF3、OH、OCH3、OC2H5、OCOCH3、CH3、CH2CH3、CH2CH2CH3、 CH(CH3)2、CH2CH2CH2CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、NHCOCH3、CH2OH、CH2CH2OH、C(CH3)2OH、CH(CH3)OH、CH2NH2、CH2CH2NH2、C(CH3)2NH2、CH(CH3)NH2、CH2NH(CH3)、CH2CH2NH(CH3)、C(CH3)2NH(CH3)、CH(CH3)NH(CH3)、CH2N(CH3)2、CH2CH2N(CH3)2、C(CH3)2N(CH3)2、CH(CH3)N(CH3)2、CH2CN、SOCH3,SO2CH3、環丙基、環丁基、3-氧環丁烷基、2-氮環丙烷基、3-氮環丙烷基、1-吡咯啶基、1-哌啶基及1-嗎啉基所組成之群組，其中該環丙基、環丁基、3-氧環丁烷基、2-氮環丙烷基、3-氮環丙烷基、1-吡咯啶基、1-哌啶基及1-嗎啉基係未經取代或經以一或多個取代基單或多取代，其係選自於由F、Cl、CN、CF3、OCF3、OH、OCH3、CH3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、N(CH3)2及NHCOCH3所組成之群組。 Preferably, Z is independently selected from the group consisting of F, Cl, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3 ) 2 NH 2 , CH(CH 3 )NH 2 , CH 2 NH(CH 3 ), CH 2 CH 2 NH(CH 3 ), C(CH 3 ) 2 NH(CH 3 ), CH(CH 3 )NH(CH 3 ), CH 2 N(CH 3 ) 2 , CH 2 CH 2 N(CH 3 ) 2 , C(CH 3 ) 2 N(CH 3 ) 2 , CH(CH 3 )N(CH 3 ) 2 , CH 2 CN, SOCH 3 , SO 2 CH 3 , cyclopropyl, a group consisting of cyclobutyl, 3-oxocyclobutane, 2-nitrocyclopropane, 3-nitrocyclopropane, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl, wherein The cyclopropyl, cyclobutyl, 3-oxocyclobutane, 2-nitrocyclopropane, 3-nitrocyclopropane, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl groups are not Substituted or Mono- or polysubstituted with one or more substituents selected from the group consisting of F, Cl, CN, CF 3 , OCF 3 , OH, OCH 3 , CH 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 a group consisting of NH 2 , NH(CH 3 ), N(CH 3 ) 2 and NHCOCH 3 .

在一較佳具體實施例中，式(I)之化合物之特徵在於G為G1至G44群組之一，其中R12係選自於由H、CH3或CH2CH3所組成之群組；k於每次出現為0、1、2、3或4；且Z於每次出現係獨立地選自於由F、Cl、CN、CF3、CHF2、CH2F、OCF3、OCHF2、OH、OCH3、OC2H5、OCOCH3、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、CH2CH2CH2CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、NHCOCH3、CH2OH、CH2CH2OH、C(CH3)2OH、CH(CH3)OH、CH2NH2、CH2CH2NH2、C(CH3)2NH2、CH(CH3)NH2、CH2NH(CH3)、CH2CN、SOCH3、SO2CH3、SOCH2CH3、SO2CH2CH3、SO2NH2、環丙基、環丁基、環戊基、環己基、 3-氧環丁烷基、1-吡咯啶基、1-哌啶基及1-嗎啉基所組成之群組。 In a preferred embodiment, the compound of formula (I) is characterized in that G is one of the group of G1 to G44, wherein R 12 is selected from the group consisting of H, CH 3 or CH 2 CH 3 ;k is 0, 1, 2, 3 or 4 at each occurrence; and Z is independently selected from F, Cl, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF in each occurrence. 2 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH(CH 3 CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH 2 CH 2 NH 2 , C (CH 3 ) 2 NH 2 , CH(CH 3 )NH 2 , CH 2 NH(CH 3 ), CH 2 CN, SOCH 3 , SO 2 CH 3 , SOCH 2 CH 3 , SO 2 CH 2 CH 3 , SO 2 A group consisting of NH 2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-oxocyclobutane, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl.

在本發明第一態樣之較佳具體實施例中，式(I)之化合物之特徵在於G係選自於G1或G2，其中k於每次出現為0、1、2或3；且Z於每次出現係獨立地選自於由F、Cl、CF3、CHF2、CH2F、OCF3、OH、CN、C1-C6-烷基，(C1-C6)-羥烷基、C1-C6-烷氧基、C3-C6-環烷基、3至7員雜環烷基、NH2、NH(C1-C6-烷基)、N(C1-C6-烷基)2、NHCO(C1-C6-烷基)、CH2NH2、CH2CH2NH2、C(CH3)2NH2、CH(CH3)NH2、CH2NH(CH3)、NH-S(O)2(C1-C6-烷基)、CONH2、CONH(C1-C6-烷基)、CO-N(C1-C6-烷基)2、S(O)2NH2、S(O)2NH(C1-C6-烷基)、S(O)2N(C1-C6-烷基)2、S(O)(C1-C6-烷基)及S(O)2(C1-C6-烷基)所組成之群組，較佳地，Z於每次出現係獨立地選自於由F、Cl、CN、CF3、CHF2、CH2F、OCF3、OH、OCH3、OC2H5、OCOCH3、CH3、CH2CH3、(CH2)2CH3、CH(CH3)2、(CH2)3CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、NHCOCH3、CH2OH、CH2CH2OH、C(CH3)2OH、CH(CH3)OH、CH2NH2、CH2CH2NH2、C(CH3)2NH2、CH(CH3)NH2、CH2NH(CH3)、CH2CN、SOCH3、SO2CH3環丙基、環丁基、3-氧環丁烷基、1-吡咯啶基、1-哌啶基及1-嗎啉基所組成之群組。 In a preferred embodiment of the first aspect of the invention, the compound of formula (I) is characterized in that G is selected from G1 or G2, wherein k is 0, 1, 2 or 3 at each occurrence; Each occurrence is independently selected from the group consisting of F, Cl, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, CN, C 1 -C 6 -alkyl, (C 1 -C 6 )-hydroxyl Alkyl, C 1 -C 6 -alkoxy, C 3 -C 6 -cycloalkyl, 3 to 7 membered heterocycloalkyl, NH 2 , NH(C 1 -C 6 -alkyl), N (C) 1 -C 6 -alkyl) 2 , NHCO(C 1 -C 6 -alkyl), CH 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3 ) 2 NH 2 , CH(CH 3 )NH 2 , CH 2 NH(CH 3 ), NH-S(O) 2 (C 1 -C 6 -alkyl), CONH 2 , CONH(C 1 -C 6 -alkyl), CO-N (C 1 -C 6 -alkyl) 2 , S(O) 2 NH 2 , S(O) 2 NH(C 1 -C 6 -alkyl), S(O) 2 N(C 1 -C 6 -alkyl) 2 , a group consisting of S(O)(C 1 -C 6 -alkyl) and S(O) 2 (C 1 -C 6 -alkyl), preferably, Z is independently selected from each occurrence And by F, Cl, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3 ) 2 NH 2 , CH(CH 3 )NH 2 , CH 2 NH(CH 3 ), CH 2 CN, SOCH 3 , SO 2 CH 3 cyclopropyl, cyclobutyl, 3-oxocyclobutane, 1-pyrrolidinyl, A group consisting of 1-piperidinyl and 1-morpholinyl.

在本發明第一態樣之較佳具體實施例中，式(I)之化合物之特徵在於G係選自於G1或G2，其中k於每次出現為0、1、2或3；且Z於每次出現係獨立地選自於由F、Cl、CF3、CHF2、CH2F、OCF3、OH、CN、C1-C6-烷基，(C1-C6)-羥烷基、C1-C6-烷氧基、C3-C6-環烷基、3至7員雜環烷基、NH2、NH(C1-C6-烷基)、 N(C1-C6-烷基)2、NHCO(C1-C6-烷基)、CH2NH2、CH2CH2NH2、C(CH3)2NH2、CH(CH3)NH2、CH2NH(CH3)、NH-S(O)2(C1-C6-烷基)、CONH2、CONH(C1-C6-烷基)、CO-N(C1-C6-烷基)2、S(O)2NH2、S(O)2NH(C1-C6-烷基)、S(O)2N(C1-C6-烷基)2、S(O)(C1-C6-烷基)及S(O)2(C1-C6-烷基)所組成之群組，較佳地，Z於每次出現係獨立地選自於由F、Cl、CN、CF3、CHF2、CH2F、OCF3、OH、OCH3、OC2H5、OCOCH3、CH3、CH2CH3、(CH2)2CH3、CH(CH3)2、(CH2)3CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、NHCOCH3、CH2OH、CH2CH2OH、C(CH3)2OH、CH(CH3)OH、CH2NH2、CH2CH2NH2、C(CH3)2NH2、CH(CH3)NH2、CH2NH(CH3)、CH2CN、SOCH3、SO2CH3環丙基、環丁基、3-氧環丁烷基、1-吡咯啶基、1-哌啶基及1-嗎啉基所組成之群組。 In a preferred embodiment of the first aspect of the invention, the compound of formula (I) is characterized in that G is selected from G1 or G2, wherein k is 0, 1, 2 or 3 at each occurrence; Each occurrence is independently selected from the group consisting of F, Cl, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, CN, C 1 -C 6 -alkyl, (C 1 -C 6 )-hydroxyl Alkyl, C 1 -C 6 -alkoxy, C 3 -C 6 -cycloalkyl, 3 to 7 membered heterocycloalkyl, NH 2 , NH(C 1 -C 6 -alkyl), N (C) 1 -C 6 -alkyl) 2 , NHCO(C 1 -C 6 -alkyl), CH 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3 ) 2 NH 2 , CH(CH 3 )NH 2 , CH 2 NH(CH 3 ), NH-S(O) 2 (C 1 -C 6 -alkyl), CONH 2 , CONH(C 1 -C 6 -alkyl), CO-N (C 1 -C 6 -alkyl) 2 , S(O) 2 NH 2 , S(O) 2 NH(C 1 -C 6 -alkyl), S(O) 2 N(C 1 -C 6 -alkyl) 2 , a group consisting of S(O)(C 1 -C 6 -alkyl) and S(O) 2 (C 1 -C 6 -alkyl), preferably, Z is independently selected from each occurrence And by F, Cl, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3 ) 2 NH 2 , CH(CH 3 )NH 2 , CH 2 NH(CH 3 ), CH 2 CN, SOCH 3 , SO 2 CH 3 cyclopropyl, cyclobutyl, 3-oxocyclobutane, 1-pyrrolidinyl, A group consisting of 1-piperidinyl and 1-morpholinyl.

在更佳具體實施例中，式(I)之化合物之特徵在於G係以下G45或G2群組之一 ，其中該以星號(*)標示之位置指出該連接處，其係與該嘧啶環連接；k於每次出現為0、1或2；且ZA係H或F；Z於每次出現係獨立地選自於由F、Cl、CN、CF3、CHF2、CH2F、OCF3、OH、OCH3、OC2H5、OCOCH3、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、CH2CH2CH2CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、NHCOCH3、CH2OH、CH2CH2OH、C(CH3)2OH、CH(CH3)OH、CH2NH2、CH2CH2NH2、 C(CH3)2NH2、CH(CH3)NH5、CH2NH(CH3)、CH2CH2NH(CH3)、C(CH3)2NH(CH3)、CH(CH3)NH(CH3)、CH2N(CH3)2、CH2CH2N(CH3)2、C(CH3)2N(CH3)2、CH(CH3)N(CH3)2、CH5CN、SOCH3,SO2CH3、環丙基、環丁基、3-氧環丁烷基、2-氮環丙烷基、3-氮環丙烷基、1-吡咯啶基、1-哌啶基及1-嗎啉基所組成之群組，其中該環丙基、環丁基、3-氧環丁烷基、2-氮環丙烷基、3-氮環丙烷基、1-吡咯啶基、1-哌啶基及1-嗎啉基係未經取代或經以一或多個取代基單或多取代，其係選自於由F、Cl、CN、CF3、OCF3、OH、OCH3、CH3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、N(CH3)2及NHCOCH3所組成之群組。 In a more preferred embodiment, the compound of formula (I) is characterized by one of the G45 or G2 groups below G Where the position indicated by an asterisk (*) indicates the junction, which is linked to the pyrimidine ring; k is 0, 1 or 2 at each occurrence; and Z A is H or F; Z is present at each occurrence Independently selected from the group consisting of F, Cl, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3 ) 2 NH 2 , CH(CH 3 )NH 5 , CH 2 NH(CH 3 ), CH 2 CH 2 NH(CH 3 ), C(CH 3 ) 2 NH(CH 3 ), CH(CH 3 )NH(CH 3 ), CH 2 N(CH 3 ) 2 , CH 2 CH 2 N(CH 3 ) 2 , C(CH 3 ) 2 N(CH 3 ) 2 , CH(CH 3 )N(CH 3 ) 2 , CH 5 CN, SOCH 3 , SO 2 CH 3 , cyclopropyl, cyclobutyl, 3-oxocyclobutene a group consisting of an alkyl group, a 2-nitrocyclopropane group, a 3-nitrocyclopropane group, a 1-pyrrolidinyl group, a 1-piperidinyl group, and a 1-morpholinyl group, wherein the cyclopropyl group and the cyclobutyl group , 3-oxocyclobutane, 2-nitrocyclopropane, 3-nitrocyclopropane, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl are unsubstituted or have one or a plurality of substituents, single or multiple, selected from the group consisting of F, Cl, CN, CF 3 , OCF 3 , OH, OCH 3 , CH 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 a group consisting of NH(CH 3 ), N(CH 3 ) 2 and NHCOCH 3 .

在更佳具體實施例中，式(I)之化合物之特徵在於G為以下G45或G2群組之一 ，其中該以星號(*)標示之位置指出該連接處，其係與該嘧啶環連接；k於每次出現為0、1或2；且ZA係H或F；Z於每次出現係獨立地選自於由F、Cl、CN、CF3、CHF2、CH2F、OCF3、OH、OCH3、OC2H5、OCOCH3、CH3、CH2CH5、(CH2)2CH3、CH(CH3)2、(CH2)3CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、NHCOCH3、CH2OH、CH2CH2OH、C(CH3)2OH、CH(CH3)OH、CH2NH2、CH2CH2NH2、C(CH3)2NH2、CH(CH3)NH2、CH5NH(CH3)、CH2CN、SOCH3、SO2CH3、環丙基、環丁基、3-氧環丁烷基、1-吡咯啶基、1-哌啶基及1-嗎啉基所組成之群組。 In a more preferred embodiment, the compound of formula (I) is characterized in that G is one of the following G45 or G2 groups Where the position indicated by an asterisk (*) indicates the junction, which is linked to the pyrimidine ring; k is 0, 1 or 2 at each occurrence; and Z A is H or F; Z is present at each occurrence Independently selected from the group consisting of F, Cl, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 5 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3 ) 2 NH 2 , CH(CH 3 )NH 2 , CH 5 NH(CH 3 ), CH 2 CN a group consisting of SOCH 3 , SO 2 CH 3 , cyclopropyl, cyclobutyl, 3-oxocyclobutane, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl.

在本發明第一態樣之另一具體實施例中，式(I)之化合物之特徵在於L係選自於C(=O)NR2、S(=O)、S(=O)2、P(=O)(R2)、S(=O)2NR2或鍵結。 In another embodiment of the first aspect of the present invention, the compound of formula (I) is characterized in that L is selected from the group consisting of C(=O)NR 2 , S(=O), S(=O) 2 , P(=O)(R 2 ), S(=O) 2 NR 2 or bonded.

在本發明第一態樣之另一具體實施例中，式(I)之化合物之特徵在於L係選自於C(=O)NR2、S(=O)、S(=O)2、S(=O)2NR2或鍵結；且R1係選自於C1-C6-烷基、C3-C6-環烷基或3至7員雜環烷基，其中該C1-C6-烷基係未經取代或經以一、二、三或四個取代基取代，其係選自於由鹵素、CN、OH、=O、=NH、NH2、NH(C1-C6-烷基)、N(C1-C6-烷基)2、C1-C6-烷氧基、C3-C6-環烷基及3至7員雜環烷基所組成之群組；且其中該3至7員雜環烷基可含有一或二個雜原子，其係選自於由O、S及N所組成之群組且其中該C3-C6-環烷基及該3至7員雜環烷基係未經取代或經以一、二、三或四個取代基取代，其係選自於由鹵素、CN、OH、=O、NH2、NH(C1-C6-烷基)、N(C1-C6-烷基)2、C1-C6-烷基，(C1-C6)-羥烷基、(C1-C6)-鹵烷基及C1-C6-烷氧基所組成之群組；及R2係選自於H或C1-C6-烷基其中該C1-C6-烷基係未經取代或經以一、二、三或四個取代基取代，其係選自於由鹵素、OH、C1-C6-烷氧基及C3-C6-環烷基所組成之群組；或R1及R2與其所連接之氮原子一起形成一3至12員雜環烷基，其中該3至12員雜環烷基可含有一或二個另外之雜原子，其係選自於 由O、S及N所組成之群組且其中該3至12員雜環烷基係未經取代或經以一、二、三或四個取代基取代，其係選自於由鹵素、CN、OH、=O、NH2、NH(C1-C6-烷基)、N(C1-C6-烷基)2、C1-C6-烷基、(C1-C6)-羥烷基、(C1-C6)-鹵烷基及C1-C6-烷氧基所組成之群組。 In another embodiment of the first aspect of the present invention, the compound of formula (I) is characterized in that L is selected from the group consisting of C(=O)NR 2 , S(=O), S(=O) 2 , S(=O) 2 NR 2 or a bond; and R 1 is selected from C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl or 3 to 7 membered heterocycloalkyl, wherein the C 1- C 6 -alkyl is unsubstituted or substituted with one, two, three or four substituents selected from halogen, CN, OH, =O, =NH, NH 2 , NH(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl) 2 , C 1 -C 6 -alkoxy, C 3 -C 6 -cycloalkyl and 3 to 7 membered heterocycloalkyl a group consisting of; and wherein the 3 to 7 membered heterocycloalkyl group may contain one or two heteroatoms selected from the group consisting of O, S and N and wherein the C 3 -C 6 a cycloalkyl group and the 3 to 7 membered heterocycloalkyl group are unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH, =0, NH 2 , NH(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl) 2 , C 1 -C 6 -alkyl, (C 1 -C 6 )-hydroxyalkyl, (C 1 a group consisting of -C 6 )-haloalkyl and C 1 -C 6 -alkoxy; and R 2 is selected from H or C 1 -C 6 -alkyl The C 1 -C 6 -alkyl group is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, OH, C 1 -C 6 -alkoxy and C 3 a group consisting of -C 6 -cycloalkyl; or R 1 and R 2 together with the nitrogen atom to which they are attached form a 3 to 12 membered heterocycloalkyl group, wherein the 3 to 12 membered heterocycloalkyl group may contain one Or two additional heteroatoms selected from the group consisting of O, S and N and wherein the 3 to 12 membered heterocycloalkyl group is unsubstituted or passed through one, two, three or four a substituent substituted from halogen, CN, OH, =0, NH 2 , NH(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl) 2 , C 1 - A group consisting of C 6 -alkyl, (C 1 -C 6 )-hydroxyalkyl, (C 1 -C 6 )-haloalkyl and C 1 -C 6 -alkoxy.

較佳地，L係選自於C(=O)NR2、S(=O)或S(=O)2。 Preferably, L is selected from C(=O)NR 2 , S(=O) or S(=O) 2 .

在本發明第一態樣之一較佳具體實施例中，式(I)之化合物之特徵在於L為C(=O)NR2；R1係選自於C1-C6-烷基、C3-C6-環烷基或3至7員雜環烷基，其中該C1-C6-烷基係未經取代或經以一、二、三或四個取代基取代，其係選自於由鹵素、CN、OH、=O、NH2、NH(C1-C6-烷基)、N(C1-C6-烷基)2、C1-C6-烷氧基、C3-C6-環烷基或3至7員雜環烷基所組成之群組；且其中該3至7員雜環烷基可含有一或二個雜原子，其係選自於由O、S及N所組成之群組且其中該C3-C6-環烷基及該3至7員雜環烷基係未經取代或經以一、二、三或四個取代基取代，其係選自於由鹵素、CN、OH、=O、NH2、C1-C6-烷基、(C1-C6)-羥烷基、(C1-C6)-鹵烷基及C1-C6-烷氧基所組成之群組；及R2係選自於H或C1-C6-烷基其中該C1-C6-烷基係未經取代或經以一、二、三或四個取代基取代，其係選自於由鹵素、OH、C1-C6-烷氧基及C3-C6-環烷基所組成之群組；或 R1及R2與其所連接之氮原子一起形成一3至12員雜環烷基，其中該3至12員雜環烷基可含有一或二個另外之雜原子，其係選自於由O、S及N所組成之群組且其中該3至12員雜環烷基係未經取代或經以一、二、三或四個取代基取代，其係選自於由鹵素、CN、OH、=O、NH2、NH(C1-C6-烷基)、N(C1-C6-烷基)2、C1-C6-烷基、(C1-C6)-羥烷基、(C1-C6)-鹵烷基及C1-C6-烷氧基所組成之群組。 In a preferred embodiment of the first aspect of the invention, the compound of formula (I) is characterized in that L is C(=O)NR 2 ; R 1 is selected from C 1 -C 6 -alkyl, a C 3 -C 6 -cycloalkyl or a 3 to 7 membered heterocycloalkyl group, wherein the C 1 -C 6 -alkyl group is unsubstituted or substituted with one, two, three or four substituents, Selected from halogen, CN, OH, =O, NH 2 , NH(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl) 2 , C 1 -C 6 -alkoxy a group consisting of C 3 -C 6 -cycloalkyl or 3 to 7 membered heterocycloalkyl; and wherein the 3 to 7 membered heterocycloalkyl group may contain one or two heteroatoms selected from a group consisting of O, S and N and wherein the C 3 -C 6 -cycloalkyl group and the 3 to 7 membered heterocycloalkyl group are unsubstituted or substituted with one, two, three or four substituents Substituting, which is selected from the group consisting of halogen, CN, OH, =0, NH 2 , C 1 -C 6 -alkyl, (C 1 -C 6 )-hydroxyalkyl, (C 1 -C 6 )-halogen a group consisting of an alkyl group and a C 1 -C 6 -alkoxy group; and R 2 is selected from H or a C 1 -C 6 -alkyl group wherein the C 1 -C 6 -alkyl group is unsubstituted or Substituted by one, two, three or four substituents selected from halogen a group consisting of OH, C 1 -C 6 -alkoxy and C 3 -C 6 -cycloalkyl; or R 1 and R 2 together with the nitrogen atom to which they are attached form a 3 to 12 membered heterocyclic ring An alkyl group, wherein the 3 to 12 membered heterocycloalkyl group may contain one or two additional heteroatoms selected from the group consisting of O, S and N and wherein the 3 to 12 membered heterocycloalkane The base is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH, =0, NH 2 , NH(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl) 2 , C 1 -C 6 -alkyl, (C 1 -C 6 )-hydroxyalkyl, (C 1 -C 6 )-haloalkyl and C 1 -C A group consisting of 6 -alkoxy groups.

較佳地，L為C(=O)NR2；R1表示C1-6-烷基，其中該C1-C6-烷基係未經取代或經以一、二、三或四個取代基取代，其係選自於由鹵素、CN、=O、OH、C1-C6-烷氧基、(C1-C6-烷氧基)-C1-C6-烷氧基、(羥基)-C1-C6-烷氧基、NH2、NH(C1-C6-烷基)、N(C1-C6-烷基)2、NH(C1-C6-羥烷基)、N(C1-C6-烷基)(C1-C6-羥烷基)、N(C1-C6-羥烷基)2、NHCO(C1-C6-烷基)、N(C1-C6-烷基)CO(C1-C6-烷基)、NHCO(C1-C6-羥烷基)、N(C1-C6-烷基)CO(C1-C6-羥烷基)、CONH2、CONH(C1-C6-烷基)、CON(C1-C6-烷基)2、CONH(C1-C6-羥烷基)、CON(C1-C6-烷基)(C1-C6-羥烷基)、CON(C1-C6-羥烷基)2、C3-C6-環烷基及3至7員雜環烷基所組成之群組；或表示以下U1至U8群組之一 Preferably, L is C(=O)NR 2 ; R 1 represents C 1-6 -alkyl, wherein the C 1 -C 6 -alkyl group is unsubstituted or passed one, two, three or four a substituent substituted from halogen, CN, =0, OH, C 1 -C 6 -alkoxy, (C 1 -C 6 -alkoxy)-C 1 -C 6 -alkoxy , (hydroxy)-C 1 -C 6 -alkoxy, NH 2 , NH(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl) 2 , NH(C 1 -C 6 -hydroxyalkyl), N(C 1 -C 6 -alkyl)(C 1 -C 6 -hydroxyalkyl), N(C 1 -C 6 -hydroxyalkyl) 2 ,NHCO(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl)CO(C 1 -C 6 -alkyl), NHCO(C 1 -C 6 -hydroxyalkyl), N(C 1 -C 6 -alkane Base) CO(C 1 -C 6 -hydroxyalkyl), CONH 2 , CONH(C 1 -C 6 -alkyl), CON(C 1 -C 6 -alkyl) 2 , CONH(C 1 -C 6 -Hydroxyalkyl), CON(C 1 -C 6 -alkyl)(C 1 -C 6 -hydroxyalkyl), CON(C 1 -C 6 -hydroxyalkyl) 2 ,C 3 -C 6 -环a group consisting of an alkyl group and a 3 to 7 membered heterocycloalkyl group; or one of the following U1 to U8 groups

其中於每次出現n為0、1、2、3、4或5，且其中於每次出現X2係獨立地選自於由OH、=O、CN、F、Cl、Br、CF3、CHF2、CH2F、OCF3、C1-C6-烷基、C1-C6-烷氧基、NH2、NH(C1-C6-烷基)、N(C1-C6-烷基)2、NHCO(C1-C6-烷基)、CO2H、COO(C1-C6-烷基)、CONH2、CONH(C1-C6-烷基)及CON(C1-C6-烷基)2所組成之群組，且其中該U1至U8群組係經由C1-3-伸烷基與L相接，其係未經取代或經以1、2或3個取代基取代，其係獨立地選自於由F、Cl、CF3、=O、OCF3及OH所組成之群組，或表示以下V1至V33群組之一： Wherein each occurrence of n is 0, 1, 2, 3, 4 or 5, and wherein each occurrence of the X 2 system is independently selected from OH, =0, CN, F, Cl, Br, CF 3 , CHF 2 , CH 2 F, OCF 3 , C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, NH 2 , NH(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl) 2 , NHCO(C 1 -C 6 -alkyl), CO 2 H, COO(C 1 -C 6 -alkyl), CONH 2 , CONH(C 1 -C 6 -alkyl) and a group consisting of CON(C 1 -C 6 -alkyl) 2 , and wherein the U1 to U8 group is bonded to L via a C 1-3 -alkylene group, which is unsubstituted or subjected to 1 , 2 or 3 substituents, which are independently selected from the group consisting of F, Cl, CF 3 , =0, OCF 3 and OH, or one of the following V1 to V33 groups:

其中R6為H、(C1-C6-烷基)、(C1-C6)-羥烷基、(C1-C6)-氰烷基、C3-C6-環烷基、CO(C1-C6-烷基)或SO2(C1-C6-烷基)；m於每次出現為0、1、2、3、4或5，且 X3於每次出現係獨立地選自於由OH、=O、CN、F、Cl、Br、CF3、CHF2、CH2F、OCF3、C1-C6-烷基，C1-C6-烷氧基、NH2、N(C1-C6-烷基)、N(C1-C6-烷基)2、NHCO(C1-C6-烷基)、CO2H、COO(C1-C6-烷基)、CONH2、CONH(C1-C6-烷基)及CON(C1-C6-烷基)2所組成之群組，且其中該V1至V13群組係經由C1-3-伸烷基與L相接，其係未經取代或經以至少一取代基取代，其係獨立地選自於由F、Cl、CF3、=O、OCF3及OH所組成之群組，且R2係選自於H、C1-C6-烷基、(C1-C6)-羥烷基或(C1-C6-烷氧基)-C1-C6-烷基，較佳地R2係選自於H或CH3。 Wherein R 6 is H, (C 1 -C 6 -alkyl), (C 1 -C 6 )-hydroxyalkyl, (C 1 -C 6 )-cyanoalkyl, C 3 -C 6 -cycloalkyl , CO(C 1 -C 6 -alkyl) or SO 2 (C 1 -C 6 -alkyl); m is 0, 1, 2, 3 , 4 or 5 at each occurrence, and X 3 is each time The appearance lines are independently selected from OH, =0, CN, F, Cl, Br, CF 3 , CHF 2 , CH 2 F, OCF 3 , C 1 -C 6 -alkyl, C 1 -C 6 -alkane Oxyl, NH 2 , N(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl) 2 , NHCO(C 1 -C 6 -alkyl), CO 2 H, COO(C a group consisting of 1 -C 6 -alkyl), CONH 2 , CONH(C 1 -C 6 -alkyl) and CON(C 1 -C 6 -alkyl) 2 , and wherein the V1 to V13 group Is attached to L via a C 1-3 -alkylene group, which is unsubstituted or substituted with at least one substituent selected independently from F, Cl, CF 3 , =0, OCF 3 and a group consisting of OH, and R 2 is selected from H, C 1 -C 6 -alkyl, (C 1 -C 6 )-hydroxyalkyl or (C 1 -C 6 -alkoxy)-C 1 -C 6 -alkyl, preferably R 2 is selected from H or CH 3 .

更佳地，L為C(=O)NR2；R1係選自於以下M1至M76次結構之一： More preferably, L is C(=O)NR 2 ; R 1 is selected from one of the following M1 to M76 substructures:

及 R2係選自於H、C1-C6-烷基、(C1-C6)-羥烷基或(C1-C6-烷氧基)-C1-C6-烷基，較佳地R2係選自於H或CH3。 And R 2 is selected from H, C 1 -C 6 -alkyl, (C 1 -C 6 )-hydroxyalkyl or (C 1 -C 6 -alkoxy)-C 1 -C 6 -alkyl Preferably, R 2 is selected from H or CH 3 .

還較佳地，L為C(=O)NR2；且R1及R2與其所連接之氮原子一起形成一3至12員雜環烷基，其中該3至12員雜環烷基可含有一或二個另外之雜原子，其係選自於由O、S及N所組成之群組且其中該3至12員雜環烷基係未經取代或經以一、二、三或四個取代基取代，其係選自於由鹵素、CN、OH、=O、NH2、C1-C6-烷基、(C1-C6)-羥烷基、(C1-C6)-鹵烷基及C1-C6-烷氧基所組成之群組。 Further preferably, L is C(=O)NR 2 ; and R 1 and R 2 together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocycloalkyl group, wherein the 3 to 12 membered heterocycloalkyl group Containing one or two additional heteroatoms selected from the group consisting of O, S, and N and wherein the 3 to 12 membered heterocycloalkyl group is unsubstituted or substituted by one, two, three or Substituted by four substituents selected from halogen, CN, OH, =0, NH 2 , C 1 -C 6 -alkyl, (C 1 -C 6 )-hydroxyalkyl, (C 1 -C 6 ) A group consisting of a haloalkyl group and a C 1 -C 6 -alkoxy group.

還較佳地，L係C(=O)NR2；且R1及R2與其所連接之氮原子一起形成a3至12員雜環烷基，其中該3至12員雜環烷基表示以下Q1至Q34群組之一： Further preferably, L is C(=O)NR 2 ; and R 1 and R 2 together with the nitrogen atom to which they are attached form an a3 to 12 membered heterocycloalkyl group, wherein the 3 to 12 membered heterocycloalkyl group represents the following One of the Q1 to Q34 groups:

，其中該以星號(*)標示之位置指出該連接處，其係被連接至L之羰基基團；R5係選自於由H、C1-C6-烷基、(C1-C6)-羥烷基、(C1-C6)-氰烷基、C3-C6-環烷基、CO(C1-C6-烷基)及SO2-(C1-C6)-烷基所組成之群組；p於每次出現係0、1、2、3、4或5個；且X6於每次出現係獨立地選自於由OH、=O、CN、F、Cl、Br、CF3、CHF2、CH2F、OCF3、C1-C6-烷基、(C1-C6)-羥烷基、(C1-C6)-氰烷基、(C1-C6)-烷氧基、(C3-C6)-環烷基、NH2、NH(C1-C6-烷基)、N(C1-C6-烷基)2、NHCO(C1-C6-烷基)、CO2H、CO(C1-C6-烷基)、COO(C1-C6-烷基)、CONH2、CONH(C1-C6-烷基)及CON(C1-C6-烷基)2所組成之群組。 Wherein the position indicated by an asterisk (*) indicates the junction, which is linked to the carbonyl group of L; R 5 is selected from H, C 1 -C 6 -alkyl, (C 1 -C) 6 )-Hydroxyalkyl, (C 1 -C 6 )-cyanoalkyl, C 3 -C 6 -cycloalkyl, CO(C 1 -C 6 -alkyl) and SO 2 -(C 1 -C 6 a group of -alkyl groups; p is 0, 1, 2, 3, 4 or 5 in each occurrence; and X 6 is independently selected from OH, =O, CN, in each occurrence. F, Cl, Br, CF 3 , CHF 2 , CH 2 F, OCF 3 , C 1 -C 6 -alkyl, (C 1 -C 6 )-hydroxyalkyl, (C 1 -C 6 )-cyano , (C 1 -C 6 )-alkoxy, (C 3 -C 6 )-cycloalkyl, NH 2 , NH(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkane 2 ), NHCO (C 1 -C 6 -alkyl), CO 2 H, CO (C 1 -C 6 -alkyl), COO (C 1 -C 6 -alkyl), CONH 2 , CONH (C A group consisting of 1 -C 6 -alkyl) and CON(C 1 -C 6 -alkyl) 2 .

更佳地，L係C(=O)NR2；且R1及R2與其所連接之氮原子一起形成一3至12員雜環烷基，其中該3至12員雜環烷基表示以下Q’1至Q’65群組之一： More preferably, L is C(=O)NR 2 ; and R 1 and R 2 together with the nitrogen atom to which they are attached form a 3 to 12 membered heterocycloalkyl group, wherein the 3 to 12 membered heterocycloalkyl group represents the following One of the Q'1 to Q'65 groups:

較佳地，該3至12員雜環烷基係選自於由Q’8、Q’23、Q’32、Q’40及Q’44所組成之組群。 Preferably, the 3 to 12 membered heterocycloalkyl group is selected from the group consisting of Q'8, Q'23, Q'32, Q'40 and Q'44.

在本發明第一態樣另一較佳具體實施例中，式(I)之化合物之特徵在於L係S(=O)或S(=O)2及R1係選自於OH、CN、C1-C6-烷基、NH2、NH(C1-C6-烷基)、N(C1-C6-烷基)2、C3-C6-環烷基或3至7員雜環烷基，其中該C1-C6-烷基可為未經取代或經以一、二、三或四個取代基取代，其係選自於由鹵素、CN、OH、C1-C6-烷氧基、(C1-C6-烷氧基)-C1-C6-烷氧基、(羥基)-C1-C6-烷氧基、NH2、NH(C1-C6-烷基)、N(C1-C6-烷基)2、NH(C1-C6-羥烷基)、N(C1-C6-烷基)(C1-C6-羥烷基)、N(C1-C6-羥烷基)2、NHCO(C1-C6-烷基)、N(C1-C6-烷基)CO(C1-C6-烷基)、NHCO(C1-C6-羥烷基)、N(C1-C6-烷基)CO(C1-C6-羥烷基)；CONH2、CONH(C1-C6-烷基)、CON(C1-C6-烷基)2、CONH(C1-C6-羥烷基)、CON(C1-C6-烷基)(C1-C6-羥烷基)、CON(C1-C6-羥烷基)2、C3-C6-環烷基及3至7員雜環烷基所組成之群組；且 其中該3至7員雜環烷基可含有選自於由O、S及N所組成之群組之一或二個另外之雜原子且其中該C3-C6-環烷基及該3至7員雜環烷基係未經取代或經以一、二、三或四個取代基取代，其係選自於由鹵素、CN、OH、=O、NH2、C1-C6-烷基、(C1-C6)-羥烷基、(C1-C6)-鹵烷基及C1-C6-烷氧基所組成之群組。 In another preferred embodiment of the first aspect of the present invention, the compound of formula (I) is characterized in that L system S (= O) or S (= O) 2 and R 1 are selected from OH, CN, C 1 -C 6 -alkyl, NH 2 , NH(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl) 2 , C 3 -C 6 -cycloalkyl or 3 to 7 a heterocycloalkyl group, wherein the C 1 -C 6 -alkyl group may be unsubstituted or substituted with one, two, three or four substituents selected from halogen, CN, OH, C 1 -C 6 -alkoxy, (C 1 -C 6 -alkoxy)-C 1 -C 6 -alkoxy, (hydroxy)-C 1 -C 6 -alkoxy, NH 2 , NH(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl) 2 , NH(C 1 -C 6 -hydroxyalkyl), N(C 1 -C 6 -alkyl)(C 1 - C 6 -hydroxyalkyl), N(C 1 -C 6 -hydroxyalkyl) 2 , NHCO(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl)CO(C 1 - C 6 -alkyl), NHCO(C 1 -C 6 -hydroxyalkyl), N(C 1 -C 6 -alkyl)CO(C 1 -C 6 -hydroxyalkyl);CONH 2 ,CONH(C 1 -C 6 -alkyl), CON(C 1 -C 6 -alkyl) 2 , CONH(C 1 -C 6 -hydroxyalkyl), CON(C 1 -C 6 -alkyl)(C 1 - a group consisting of C 6 -hydroxyalkyl), CON(C 1 -C 6 -hydroxyalkyl) 2 , C 3 -C 6 -cycloalkyl and 3 to 7 membered heterocycloalkyl And wherein the 3 to 7 membered heterocycloalkyl group may contain one or two additional heteroatoms selected from the group consisting of O, S and N and wherein the C 3 -C 6 -cycloalkyl group And the 3 to 7 membered heterocycloalkyl group is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH, =0, NH 2 , C 1 - A group consisting of C 6 -alkyl, (C 1 -C 6 )-hydroxyalkyl, (C 1 -C 6 )-haloalkyl and C 1 -C 6 -alkoxy.

較佳地，式(I)之化合物之特徵在於L係S(=O)或S(=O)2且R1係選自於OH、CN、C1-C6-烷基、NH2、NH(C1-C6-烷基)、N(C1-C6-烷基)2、C3-C6-環烷基或3至7員雜環烷基，其中該C1-C6-烷基可為未經取代或經以一、二、三或四個取代基取代，其係選自於由鹵素、CN、OH、NH2、C1-C6-烷氧基、C3-C6-環烷基及3至7員雜環烷基所組成之群組；且其中該3至7員雜環烷基可含有選自於由O、S及N所組成之群組之一或二個另外之雜原子且其中該3至7員雜環烷基係未經取代或經以一、二、三或四個取代基取代，其係選自於由鹵素、CN、OH、=O、NH2、C1-C6-烷基、(C1-C6)-羥烷基、(C1-C6)-鹵烷基及C1-C6-烷氧基所組成之群組。 Preferably, the compound of formula (I) is characterized by L system S(=O) or S(=O) 2 and R 1 is selected from OH, CN, C 1 -C 6 -alkyl, NH 2 , NH(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl) 2 , C 3 -C 6 -cycloalkyl or 3 to 7 membered heterocycloalkyl, wherein the C 1 -C The 6 -alkyl group may be unsubstituted or substituted with one, two, three or four substituents selected from halogen, CN, OH, NH 2 , C 1 -C 6 -alkoxy, C a group consisting of a 3- C 6 -cycloalkyl group and a 3 to 7 membered heterocycloalkyl group; and wherein the 3 to 7 membered heterocycloalkyl group may have a group selected from the group consisting of O, S, and N One or two additional heteroatoms and wherein the 3 to 7 membered heterocycloalkyl group is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH , =O, NH 2 , C 1 -C 6 -alkyl, (C 1 -C 6 )-hydroxyalkyl, (C 1 -C 6 )-haloalkyl and C 1 -C 6 -alkoxy The group that makes up.

又較佳地，式(I)之化合物之特徵在於L係S(=O)或S(=O)2且R1係選自於C1-C6-烷基、C3-C6-環烷基或3至7員雜環烷基，其中該C1-C6-烷基可為未經取代或經以一、二、三或四個取代基取代，其係選自於由鹵素、CN、OH、C1-C6-烷氧基、(C1-C6-烷氧基)-C1-C6-烷氧基、(羥基)-C1-C6-烷氧基、NH2、NH(C1-C6-烷基)、N(C1-C6-烷基)2、NH(C1-C6-羥烷 基)、N(C1-C6-烷基)(C1-C6-羥烷基)、N(C1-C6-羥烷基)2、NHCO(C1-C6-烷基)、N(C1-C6-烷基)CO(C1-C6-烷基)、NHCO(C1-C6-羥烷基)、N(C1-C6-烷基)CO(C1-C6-羥烷基)；CONH2、CONH(C1-C6-烷基)、CON(C1-C6-烷基)2、CONH(C1-C6-羥烷基)、CON(C1-C6-烷基)(C1-C6-羥烷基)、CON(C1-C6-羥烷基)2、C3-C6-環烷基及3至7員雜環烷基所組成之群組；且其中該3至7員雜環烷基可含有選自於由O、S及N所組成之群組之一或二個另外之雜原子且其中該C3-C6-環烷基及該3至7員雜環烷基係未經取代或經以一、二、三或四個取代基取代，其係選自於由鹵素、CN、OH、=O、NH2、C1-C6-烷基、(C1-C6)-羥烷基、(C1-C6)-鹵烷基及C1-C6-烷氧基所組成之群組。 Still preferably, the compound of formula (I) is characterized by L-based S(=O) or S(=O) 2 and R 1 is selected from C 1 -C 6 -alkyl, C 3 -C 6 - a cycloalkyl or a 3 to 7 membered heterocycloalkyl group, wherein the C 1 -C 6 -alkyl group may be unsubstituted or substituted with one, two, three or four substituents selected from halogen , CN, OH, C 1 -C 6 -alkoxy, (C 1 -C 6 -alkoxy)-C 1 -C 6 -alkoxy, (hydroxy)-C 1 -C 6 -alkoxy , NH 2 , NH(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl) 2 , NH(C 1 -C 6 -hydroxyalkyl), N(C 1 -C 6 - Alkyl)(C 1 -C 6 -hydroxyalkyl), N(C 1 -C 6 -hydroxyalkyl) 2 , NHCO(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkane Base) CO(C 1 -C 6 -alkyl), NHCO(C 1 -C 6 -hydroxyalkyl), N(C 1 -C 6 -alkyl)CO(C 1 -C 6 -hydroxyalkyl) ;CONH 2 , CONH(C 1 -C 6 -alkyl), CON(C 1 -C 6 -alkyl) 2 , CONH(C 1 -C 6 -hydroxyalkyl), CON(C 1 -C 6 - Alkyl)(C 1 -C 6 -hydroxyalkyl), CON(C 1 -C 6 -hydroxyalkyl) 2 , C 3 -C 6 -cycloalkyl and 3 to 7 membered heterocycloalkyl a group; and wherein the 3 to 7 membered heterocycloalkyl group may have one or two additional groups selected from the group consisting of O, S, and N And wherein the hetero atom C 3 -C 6 - cycloalkyl and the 3-7-based heterocycloalkyl unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, which is based , CN, OH, =O, NH 2 , C 1 -C 6 -alkyl, (C 1 -C 6 )-hydroxyalkyl, (C 1 -C 6 )-haloalkyl and C 1 -C 6 - a group consisting of alkoxy groups.

較佳地，L係S(=O)或S(=O)2且R1係選自於以上M1至M76次結構之一。 Preferably, the L system is S(=O) or S(=O) 2 and R 1 is selected from one of the above M1 to M76 substructures.

更佳地，L係S(=O)且R1係選自於由CH3、CH2CH3、(CH2)2CH3、CH(CH3)2、(CH2)3CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CH2CONH2、CH2CON(CH3)2、CH2CH2OH、CH2CH2CH2OH、CH(CH3)CH2OH、CH2CH(CH3)OH、C(CH3)2CH2OH、CH(CH3)CH2CH2OH、環丙基、環丁基及3-氧環丁烷基所組成之群組。 More preferably, L is S (=O) and R 1 is selected from the group consisting of CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CH 2 CONH 2 , CH 2 CON(CH 3 ) 2 , CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH, CH(CH 3 )CH 2 OH, CH 2 CH(CH 3 )OH, C(CH 3 ) 2 CH 2 OH, CH(CH 3 )CH 2 CH 2 OH, cyclopropyl, cyclobutyl And a group consisting of 3-oxocyclobutane.

還更佳地，L係S(=O)2且R1係選自於由CH3、CH2CH3、(CH2)2CH3、CH(CH3)2、(CH2)3CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CH2CONH2、CH2CON(CH3)2、CH2CH2OH、CH2CH2CH2OH、CH(CH3)CH2OH、CH2CH(CH3)OH、C(CH3)2CH2OH、CH(CH3)CH2CH2OH、環丙基、環丁基及3-氧環丁烷基所 組成之群組。 Still more preferably, the L system is S(=O) 2 and R 1 is selected from the group consisting of CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CH 2 CONH 2 , CH 2 CON(CH 3 ) 2 , CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH, CH(CH 3 )CH 2 OH, CH 2 CH(CH 3 )OH, C(CH 3 ) 2 CH 2 OH, CH(CH 3 )CH 2 CH 2 OH, cyclopropyl, ring a group consisting of butyl and 3-oxocyclobutane.

在在本發明第一態樣又另一具體實施例中，式(I)之化合物之特徵在於該通式(I)化合物係選自於通式(Ia)、(Ib)、(Ic)、(Id)或(Ie)之一， 、或，其中R1、R2及G係如前文定義。 In still another embodiment of the first aspect of the invention, the compound of formula (I) is characterized in that the compound of formula (I) is selected from the group consisting of formula (Ia), (Ib), (Ic), One of (Id) or (Ie), ,or Wherein R 1 , R 2 and G are as defined above.

較佳地，式(I)之化合物係如式(Ia)之化合物，其中R1及R2與其所連接之氮原子一起形成以下Q19、Q23、Q25或Q26雜環之一， ，其中該以星號(*)標示之位置指出該連接處，其係與L之羰基基團連接；R5係H、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、環丙基、C(O)CH3、C(O)CH2CH3、C(O)CH2CH2CH3、C(O)CH(CH3)2、C(O)-環丙基、CH2CH2CN、CH2CH2OH或CH2CH2OCH3；於每次出現p係0、1、2或3：且 每一X6獨立地代表H、CH3、CH2CH3、OH、OCH3、CH2OH、CH2CH2OH或CH2CH2OCH3，或其中R1係CH3、CH2CH3、CH2CH2OH、CH2CH2CH2OH、CH2CH(CH3)OH、CH(CH3)CH2OH、CH2C(O)N(CH3)2、CH2C(O)NH(CH3)或CH2C(O)NH2及R2係H或CH3，較佳地R2係CH3；且G係選自於由如上定義之G1至G44所組成之群組，R12於每次出現係獨立地選自於由H、CH3及CH2CH3所組成之群組；k於每次出現0、1、2、3、4或5個；且Z每次出現係獨立地選自於由F、Cl、CN、CF3、CHF2、CH2F、OCF3、OH、OCH3、OC2H5、OCOCH3、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、CH2CH2CH2CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、NHCOCH3、CH2OH、CH2CH2OH、C(CH3)2OH、CH(CH3)OH、CH2NH2、CH2CH2NH2、C(CH3)2NH2、CH(CH3)NH2、CH2NH(CH3)、CH2CH2NH(CH3)、C(CH3)2NH(CH3)、CH(CH3)NH(CH3)、CH2N(CH3)2、CH2CH5N(CH3)2、C(CH3)2N(CH3)2、CH(CH3)N(CH3)2、CH2CN、SOCH3、SO2CH3、環丙基、環丁基、3-氧環丁烷基、2-氮環丙烷基、3-氮環丙烷基、1-吡咯啶基、1-哌啶基及1-嗎啉基所組成之群組，其中該環丙基、環丁基、3-氧環丁烷基、2-氮環丙烷基、3-氮環丙烷基、1-吡咯啶基、1-哌啶基及1-嗎啉基係未經取代或經以一或多個取代基單或多取代，其係選自於由F、Cl、CN、CF3、OCF3、OH、OCH3、CH3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、N(CH3)2及NHCOCH3所組成之群組， 較佳地Z於每次出現係獨立地選自於由F、Cl、CN、CF3、CHF2、CH2F、OCF3、OH、OCH3、OC2H5、OCOCH3、CH3、CH2CH3、(CH2)2CH3、CH(CH3)2、(CH2)3CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、NHCOCH3、CH2OH、CH2CH2OH、C(CH3)2OH、CH(CH3)OH、CH2NH2、CH2CH2NH2、C(CH3)2NH2、CH(CH3)NH2、CH2NH(CH3)、CH2CN、SOCH3、SO2CH3、環丙基、環丁基、3-氧環丁烷基、1-吡咯啶基、1-哌啶基及1-嗎啉基所組成之群組。 Preferably, the compound of formula (I) is a compound of formula (Ia) wherein R 1 and R 2 together with the nitrogen atom to which they are attached form one of the following Q19, Q23, Q25 or Q26 heterocycles, Wherein the position indicated by an asterisk (*) indicates the junction, which is linked to the carbonyl group of L; R 5 is H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH (CH 3 2 , cyclopropyl, C(O)CH 3 , C(O)CH 2 CH 3 , C(O)CH 2 CH 2 CH 3 , C(O)CH(CH 3 ) 2 , C(O)- Cyclopropyl, CH 2 CH 2 CN, CH 2 CH 2 OH or CH 2 CH 2 OCH 3 ; each occurrence of p-system 0, 1, 2 or 3: and each X 6 independently represents H, CH 3 , CH 2 CH 3 , OH, OCH 3 , CH 2 OH, CH 2 CH 2 OH or CH 2 CH 2 OCH 3 , or wherein R 1 is CH 3 , CH 2 CH 3 , CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH, CH 2 CH(CH 3 )OH, CH(CH 3 )CH 2 OH, CH 2 C(O)N(CH 3 ) 2 , CH 2 C(O)NH(CH 3 ) or CH 2 C (O) NH 2 and R 2 are H or CH 3 , preferably R 2 is CH 3 ; and G is selected from the group consisting of G1 to G44 as defined above, and R 12 is independent of each occurrence. Is selected from the group consisting of H, CH 3 and CH 2 CH 3 ; k is 0, 1, 2, 3, 4 or 5 each time; and each occurrence of Z is independently selected from F, Cl, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C ( CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3 ) 2 NH 2 , CH(CH 3 )NH 2 , CH 2 NH(CH 3 ), CH 2 CH 2 NH(CH 3 ), C(CH 3 ) 2 NH(CH 3 ), CH(CH 3 )NH(CH 3 ), CH 2 N(CH 3 ) 2 , CH 2 CH 5 N(CH 3 2 , C(CH 3 ) 2 N(CH 3 ) 2 , CH(CH 3 )N(CH 3 ) 2 , CH 2 CN, SOCH 3 , SO 2 CH 3 , cyclopropyl, cyclobutyl, 3- a group consisting of oxycyclobutane, 2-azacyclopropane, 3-nitrocyclopropane, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl, wherein the cyclopropyl group Butyl, 3-oxocyclobutane, 2-nitrocyclopropane, 3-nitrocyclopropane, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl are unsubstituted or substituted Or a plurality of substituents, single or multiple, selected from the group consisting of F, Cl, CN, CF 3 , OCF 3 , OH, OCH 3 , CH 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 Group NH (CH 3), N ( CH 3) 2 , and NHCOCH 3 composed of, preferably Z is independently in each occurrence selected from the Department of F, Cl, CN, CF 3 , CHF 2, CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH (CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3 ) 2 NH 2 , CH(CH 3 )NH 2 , CH 2 NH(CH 3 ), CH 2 CN, SOCH 3 , SO 2 CH 3 , cyclopropyl, cyclobutyl, 3-oxo A group consisting of cyclobutane, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl.

較佳地，式(I)之化合物係如式(Ib)之化合物，其中R1係選自於由CH3、CH2CH3、(CH2)2CH3、CH(CH3)2、(CH2)3CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CH2CONH2、CH2CON(CH3)2、CH2CH2OH、CH2CH2CH2OH、CH(CH3)CH2OH、CH2CH(CH3)OH、C(CH3)2CH2OH、CH(CH3)CH2CH2OH、環丙基、環丁基及3-氧環丁烷基所組成之群組；且G係選自於由如上定義之G1至G44所組成之群組，R12於每次出現係獨立地選自於由H、CH3及CH2CH3所組成之群組；k於每次出現0、1、2、3、4或5個；且Z於每次出現係獨立地選自於由F、Cl、CN、CF3、CHF2、CH2F、OCF3、OH、OCH3、OC2H5、OCOCH3、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、CH2CH2CH2CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、NHCOCH3、CH2OH、CH2CH2OH、C(CH3)2OH、CH(CH3)OH、CH2NH2、CH2CH2NH2、C(CH3)2NH2、CH(CH3)NH2、CH2NH(CH3)、CH2CH2NH(CH3)、C(CH3)2NH(CH3)、CH(CH3)NH(CH3)、CH2N(CH3)2、CH2CH2N(CH3)2、C(CH3)2N(CH3)2、CH(CH3)N(CH3)2、CH2CN、SOCH3、SO2CH3、環丙基、 環丁基、3-氧環丁烷基、2-氮環丙烷基、3-氮環丙烷基、1-吡咯啶基、1-哌啶基及1-嗎啉基所組成之群組，其中該環丙基、環丁基、3-氧環丁烷基、2-氮環丙烷基、3-氮環丙烷基、1-吡咯啶基、1-哌啶基及1-嗎啉基係未經取代或經以一或多個取代基單或多取代，其係選自於由F、Cl、CN、CF3、OCF3、OH、OCH3、CH3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、N(CH3)2及NHCOCH3所組成之群組，較佳地Z於每次出現係獨立地選自於由F、Cl、CN、CF3、CHF2、CH2F、OCF3、OH、OCH3、OC2H5、OCOCH3、CH3、CH2CH3、(CH2)2CH3、CH(CH3)2、(CH2)3CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、NHCOCH3、CH2OH、CH2CH2OH、C(CH3)2OH、CH(CH3)OH、CH2NH2、CH2CH2NH2、C(CH3)2NH2、CH(CH3)NH2、CH2NH(CH3)、CH2CN、SOCH3、SO2CH3、環丙基、環丁基、3-氧環丁烷基、1-吡咯啶基、1-哌啶基及1-嗎啉基所組成之群組。 Preferably, the compound of formula (I) is a compound of formula (Ib) wherein R 1 is selected from the group consisting of CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CH 2 CONH 2 , CH 2 CON(CH 3 ) 2 , CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH, CH(CH 3 )CH 2 OH, CH 2 CH(CH 3 )OH, C(CH 3 ) 2 CH 2 OH, CH(CH 3 )CH 2 CH 2 OH a group consisting of cyclopropyl, cyclobutyl, and 3-oxocyclobutane; and G is selected from the group consisting of G1 to G44 as defined above, and R 12 is independently present in each occurrence Selected from the group consisting of H, CH 3 and CH 2 CH 3 ; k appears 0, 1, 2, 3, 4 or 5 each time; and Z is independently selected from each occurrence line F, Cl, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 O H, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3 ) 2 NH 2 , CH(CH 3 )NH 2 , CH 2 NH( CH 3 ), CH 2 CH 2 NH(CH 3 ), C(CH 3 ) 2 NH(CH 3 ), CH(CH 3 )NH(CH 3 ), CH 2 N(CH 3 ) 2 , CH 2 CH 2 N(CH 3 ) 2 , C(CH 3 ) 2 N(CH 3 ) 2 , CH(CH 3 )N(CH 3 ) 2 , CH 2 CN, SOCH 3 , SO 2 CH 3 , cyclopropyl, cyclobutane a group consisting of a 3-oxocyclobutane group, a 2-nitrocyclopropane group, a 3-nitrocyclopropane group, a 1-pyrrolidinyl group, a 1-piperidinyl group, and a 1-morpholinyl group, wherein the ring Propyl, cyclobutyl, 3-oxocyclobutane, 2-azacyclopropanyl, 3-azacyclopropane, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl unsubstituted Or by mono- or poly-substitution with one or more substituents selected from F, Cl, CN, CF 3 , OCF 3 , OH, OCH 3 , CH 3 , CONH 2 , CONHCH 3 , CON(CH 3 2 , a group consisting of NH 2 , NH(CH 3 ), N(CH 3 ) 2 and NHCOCH 3 , preferably Z is independently selected from F, Cl, CN, CF 3 in each occurrence. , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , C H(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH (CH 3 )OH, CH 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3 ) 2 NH 2 , CH(CH 3 )NH 2 , CH 2 NH(CH 3 ), CH 2 CN, SOCH 3 , A group consisting of SO 2 CH 3 , cyclopropyl, cyclobutyl, 3-oxocyclobutane, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl.

較佳地，式(I)之化合物係如式(Ic)之化合物，其中R1係選自於由CH3、CH2CH3、(CH2)2CH3、CH(CH3)2、(CH2)3CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CH2CONH2、CH2CON(CH3)2、CH2CH2OH、CH2CH2CH2OH、CH(CH3)CH2OH、CH2CH(CH3)OH、C(CH3)2CH2OH、CH(CH3)CH2CH2OH、環丙基、環丁基及3-氧環丁烷基所組成之群組；且G係選自於由如上定義之G1至G44所組成之群組，R12於每次出現係獨立地選自於由H、CH3及CH2CH3所組成之群組；k於每次出現0、1、2、3、4或5個；且Z於每次出現係獨立地選自於由F、Cl、CN、CF3、CHF2、CH2F、OCF3、OH、OCH3、OC2H5、OCOCH3、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、 CH2CH2CH2CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、NHCOCH3、CH2OH、CH2CH2OH、C(CH3)2OH、CH(CH3)OH、CH2NH2、CH2CH2NH2、C(CH3)2NH2、CH(CH3)NH2、CH2NH(CH3)、CH2CH2NH(CH3)、C(CH3)2NH(CH3)、CH(CH3)NH(CH3)、CH2N(CH3)2、CH2CH2N(CH3)2、C(CH3)2N(CH3)2、CH(CH3)N(CH3)2、CH2CN、SOCH3,SO2CH3、環丙基、環丁基、3-氧環丁烷基、2-氮環丙烷基、3-氮環丙烷基、1-吡咯啶基、1-哌啶基及1-嗎啉基所組成之群組，其中該環丙基、環丁基、3-氧環丁烷基、2-氮環丙烷基、3-氮環丙烷基、1-吡咯啶基、1-哌啶基及1-嗎啉基係未經取代或經以一或多個取代基單或多取代，其係選自於由F、Cl、CN、CF3、OCF3、OH、OCH3、CH3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、N(CH3)2及NHCOCH3所組成之群組，較佳地Z於每次出現係獨立地選自於由F、Cl、CN、CF3、CHF2、CH2F、OCF3、OH、OCH3、OC2H5、OCOCH3、CH3、CH2CH3、(CH2)2CH3、CH(CH3)2、(CH2)3CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、NHCOCH3、CH2OH、CH2CH2OH、C(CH3)2OH、CH(CH3)OH、CH2NH2、CH2CH2NH2、C(CH3)2NH2、CH(CH3)NH2、CH2NH(CH3)、CH2CN、SOCH3、SO2CH3、環丙基、環丁基、3-氧環丁烷基、1-吡咯啶基、1-哌啶基及1-嗎啉基所組成之群組。 Preferably, the compound of formula (I) is a compound of formula (Ic) wherein R 1 is selected from the group consisting of CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CH 2 CONH 2 , CH 2 CON(CH 3 ) 2 , CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH, CH(CH 3 )CH 2 OH, CH 2 CH(CH 3 )OH, C(CH 3 ) 2 CH 2 OH, CH(CH 3 )CH 2 CH 2 OH a group consisting of cyclopropyl, cyclobutyl, and 3-oxocyclobutane; and G is selected from the group consisting of G1 to G44 as defined above, and R 12 is independently present in each occurrence Selected from the group consisting of H, CH 3 and CH 2 CH 3 ; k appears 0, 1, 2, 3, 4 or 5 each time; and Z is independently selected from each occurrence line F, Cl, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3 ) 2 NH 2 , CH(CH 3 )NH 2 , CH 2 NH( CH 3 ), CH 2 CH 2 NH(CH 3 ), C(CH 3 ) 2 NH(CH 3 ), CH(CH 3 )NH(CH 3 ), CH 2 N(CH 3 ) 2 , CH 2 CH 2 N(CH 3 ) 2 , C(CH 3 ) 2 N(CH 3 ) 2 , CH(CH 3 )N(CH 3 ) 2 , CH 2 CN, SOCH 3 , SO 2 CH 3 , cyclopropyl, cyclobutene a group consisting of a 3-oxocyclobutane group, a 2-nitrocyclopropane group, a 3-nitrocyclopropane group, a 1-pyrrolidinyl group, a 1-piperidinyl group, and a 1-morpholinyl group, wherein the ring Propyl, cyclobutyl, 3-oxocyclobutane, 2-azacyclopropanyl, 3-azacyclopropane, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl unsubstituted Or by mono- or poly-substitution with one or more substituents selected from F, Cl, CN, CF 3 , OCF 3 , OH, OCH 3 , CH 3 , CONH 2 , CONHCH 3 , CON(CH 3 2 , a group consisting of NH 2 , NH(CH 3 ), N(CH 3 ) 2 and NHCOCH 3 , preferably Z is independently selected from F, Cl, CN, CF 3 in each occurrence. , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH ( CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 ) OH, CH 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3 ) 2 NH 2 , CH(CH 3 )NH 2 , CH 2 NH(CH 3 ), CH 2 CN, SOCH 3 , SO 2 A group consisting of CH 3 , cyclopropyl, cyclobutyl, 3-oxocyclobutane, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl.

更佳地，該通式(I)之化合物係選自於通式(Ia)、(Ib)、(Ic)、(Id)或(Ie)之一，其中G係選自於G1或G2，其中k於每次出現係0、1、2或3； Z於每次出現係獨立地選自於由F、Cl、CN、CF3、CHF2、CH2F、OCF3、OH、OCH3、OC2H5、OCOCH3、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、CH2CH2CH2CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、NHCOCH3、CH2OH、CH2CH2OH、C(CH3)2OH、CH(CH3)OH、CH2NH2、CH2CH2NH2、C(CH3)2NH2、CH(CH3)NH2、CH2NH(CH3)、CH2CH2NH(CH3)、C(CH3)2NH(CH3)、CH(CH3)NH(CH3)、CH2N(CH3)2、CH2CH2N(CH3)2、C(CH3)2N(CH3)2、CH(CH3)N(CH3)2、CH2CN、SOCH3,SO2CH3、環丙基、環丁基、3-氧環丁烷基、2-氮環丙烷基、3-氮環丙烷基、1-吡咯啶基、1-哌啶基及1-嗎啉基所組成之群組，其中該環丙基、環丁基、3-氧環丁烷基、2-氮環丙烷基、3-氮環丙烷基、1-吡咯啶基、1-哌啶基及1-嗎啉基係未經取代或經以一或多個取代基單或多取代，其係選自於由F、Cl、CN、CF3、OCF3、OH、OCH3、CH3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、N(CH3)2及NHCOCH3所組成之群組，較佳地Z於每次出現係獨立地選自於由F、Cl、CN、CF3、CHF2、CH2F、OCF3、OH、OCH3、OC2H5、OCOCH3、CH3、CH2CH3、(CH2)2CH3、CH(CH3)2、(CH2)3CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、NHCOCH3、CH2OH、CH2CH2OH、C(CH3)2OH、CH(CH3)OH、CH2NH2、CH2CH2NH2、C(CH3)2NH2、CH(CH3)NH2、CH2NH(CH3)、CH2CN、SOCH3、SO2CH3、環丙基、環丁基、3-氧環丁烷基、1-吡咯啶基、1-哌啶基及1-嗎啉基所組成之群組。 More preferably, the compound of the formula (I) is selected from one of the formulae (Ia), (Ib), (Ic), (Id) or (Ie), wherein the G group is selected from G1 or G2, Wherein k is present at each occurrence of 0, 1, 2 or 3; Z is independently selected from the group consisting of F, Cl, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 2 ) NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3 ) 2 NH 2 , CH(CH 3 )NH 2 , CH 2 NH(CH 3 ), CH 2 CH 2 NH(CH 3 ), C(CH 3 ) 2 NH(CH 3 ), CH(CH 3 )NH(CH 3 ) , CH 2 N(CH 3 ) 2 , CH 2 CH 2 N(CH 3 ) 2 , C(CH 3 ) 2 N(CH 3 ) 2 , CH(CH 3 )N(CH 3 ) 2 , CH 2 CN, SOCH 3 , SO 2 CH 3 , cyclopropyl, cyclobutyl, 3-oxocyclobutane, 2-nitrocyclopropane, 3-azacyclopropane, 1-pyrrolidinyl, 1-piperidinyl and a group consisting of 1-morpholinyl groups, Wherein the cyclopropyl, cyclobutyl, 3-oxocyclobutane, 2-nitrocyclopropane, 3-nitrocyclopropane, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl systems Unsubstituted or mono- or polysubstituted with one or more substituents selected from F, Cl, CN, CF 3 , OCF 3 , OH, OCH 3 , CH 3 , CONH 2 , CONHCH 3 , CON a group consisting of (CH 3 ) 2 , NH 2 , NH(CH 3 ), N(CH 3 ) 2 and NHCOCH 3 , preferably Z is independently selected from F, Cl, CN in each occurrence. , CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3 ) 2 NH 2 , CH(CH 3 )NH 2 , CH 2 NH(CH 3 ), CH 2 CN, SOCH 3 , SO 2 CH 3 , cyclopropane Composition of cyclo, cyclobutyl, 3-oxocyclobutane, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl Group of.

更佳地，該通式(Ia)、(Ib)、(Ic)、(Id)或(Ie)之化合物之特徵在於G係選自於G1或G2，其中 k於每次出現為0、1、2或3；Z於每次出現係獨立地選自於由F、Cl、CN、CF3、CHF2、CH2F、OCF3、OH、OCH3、OC2H5、OCOCH3、CH3、CH2CH3、(CH2)2CH3、CH(CH3)2、(CH2)3CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、NHCOCH3、CH2OH、CH2CH2OH、C(CH3)2OH、CH(CH3)OH、CH2NH2、CH2CH2NH2、C(CH3)2NH2、CH(CH3)NH2、CH2NH(CH3)、CH2CN、SOCH3、SO2CH3、環丙基及環丁基所組成之群組。 More preferably, the compound of the formula (Ia), (Ib), (Ic), (Id) or (Ie) is characterized in that the G group is selected from G1 or G2, wherein k is 0, 1 per occurrence. , 2 or 3; Z is independently selected from the group consisting of F, Cl, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C (CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3 ) 2 NH 2 , CH(CH 3 )NH 2 , A group consisting of CH 2 NH(CH 3 ), CH 2 CN, SOCH 3 , SO 2 CH 3 , cyclopropyl and cyclobutyl.

甚至更佳地，通式(I)之化合物具有通式(Ia)、(Id)或(Ie)其中R1及R2與其所連接之氮原子一起形成一雜環，其中該雜環係選自於Q’1至Q’65之雜環或R1係CH3、CH2CH3、CH2CH2OH、CH2CH2CH2OH、CH2CH(CH3)OH、CH(CH3)CH2OH、CH2C(O)N(CH3)2或CH2C(O)NH2及R2係CH3；且G係選自於G1或G2，其中k於每次出現係0、1、2或3；Z於每次出現係獨立地選自於由F、Cl、CN、CF3、CHF2、CH2F、OCF3、OH、OCH3、OC2H5、OCOCH3、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、CH2CH2CH2CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、NHCOCH3、CH2OH、CH2CH2OH、C(CH3)2OH、CH(CH3)OH、CH2NH2、CH2CH2NH2、 C(CH3)2NH2、CH(CH3)NH2、CH2NH(CH3)、CH2CH2NH(CH3)、C(CH3)2NH(CH3)、CH(CH3)NH(CH3)、CH2N(CH3)2、CH2CH2N(CH3)2、C(CH3)2N(CH3)2、CH(CH3)N(CH3)2、CH2CN、SOCH3,SO2CH3、環丙基、環丁基、3-氧環丁烷基、2-氮環丙烷基、3-氮環丙烷基、1-吡咯啶基、1-哌啶基及1-嗎啉基所組成之群組，其中該環丙基、環丁基、3-氧環丁烷基、2-氮環丙烷基、3-氮環丙烷基、1-吡咯啶基、1-哌啶基及1-嗎啉基係未經取代或經以一或多個取代基進行單或多取代，該取代基係選自於由F、Cl、CN、CF3、OCF3、OH、OCH3、CH3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、N(CH3)2及NHCOCH3所組成之群組，較佳地Z於每次出現係獨立地選自於由F、Cl、CN、CF3、CHF2、CH2F、OCF3、OH、OCH3、OC2H5、OCOCH3、CH3、CH2CH3、(CH2)2CH3、CH(CH3)2、(CH2)3CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、NHCOCH3、CH2OH、CH2CH2OH、C(CH3)2OH、CH(CH3)OH、CH2NH2、CH2CH2NH2、C(CH3)2NH2、CH(CH3)NH2、CH2NH(CH3)、CH2CN、SOCH3、SO2CH3、環丙基、環丁基、3-氧環丁烷基、1-吡咯啶基、1-哌啶基及1-嗎啉基所組成之群組。 Even more preferably, the compound of the formula (I) has the formula (Ia), (Id) or (Ie) wherein R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein the heterocyclic ring is selected Heterocyclic ring from Q'1 to Q'65 or R 1 system CH 3 , CH 2 CH 3 , CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH, CH 2 CH(CH 3 )OH, CH(CH 3 ) CH 2 OH, CH 2 C(O)N(CH 3 ) 2 or CH 2 C(O)NH 2 and R 2 system CH 3 ; and G is selected from G1 or G2, wherein k is present at each occurrence 0, 1, 2 or 3; Z is independently selected from the group consisting of F, Cl, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3 ) 2 NH 2 , CH(CH 3 NH 2 , CH 2 NH(CH 3 ), CH 2 CH 2 NH(CH 3 ), C(CH 3 ) 2 NH(CH 3 ), CH(CH 3 )NH(CH 3 ), CH 2 N(CH 3 ) 2 , CH 2 CH 2 N ( CH 3 ) 2 , C(CH 3 ) 2 N(CH 3 ) 2 , CH(CH 3 )N(CH 3 ) 2 , CH 2 CN, SOCH 3 , SO 2 CH 3 , cyclopropyl, cyclobutyl, a group consisting of 3-oxocyclobutane, 2-azacyclopropane, 3-nitrocyclopropane, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl, wherein the cyclopropyl group , cyclobutyl, 3-oxocyclobutane, 2-nitrocyclopropane, 3-nitrocyclopropane, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl unsubstituted or via Mono- or poly-substitution with one or more substituents selected from the group consisting of F, Cl, CN, CF 3 , OCF 3 , OH, OCH 3 , CH 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) a group consisting of 2 , NH 2 , NH(CH 3 ), N(CH 3 ) 2 and NHCOCH 3 , preferably Z is independently selected from F, Cl, CN, CF in each occurrence. 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH ( CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3 ) 2 NH 2 , CH(CH 3 )NH 2 , CH 2 NH(CH 3 ), CH 2 CN, SOCH 3 , SO 2 CH 3 , cyclopropyl, cyclobutyl, 3-oxocyclobutane, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholine A group of bases.

甚至更佳地，該通式(I)之化合物係選自於通式(Ib)或(Ic)之一，其中其中R1係選自於由CH3、CH2CH3、(CH2)2CH3、CH(CH3)2、(CH2)3CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CH2CONH2、CH2CON(CH3)2、CH2CH2OH、CH2CH2CH2OH、CH(CH3)CH2OH、CH2CH(CH3)OH、C(CH3)2CH2OH、CH(CH3)CH2CH2OH、環丙基、環丁基及3-氧環丁烷基所組成之群組； 且G係選自於G1或G2，其中k於每次出現係0、1、2或3；Z於每次出現係獨立地選自於由F、Cl、CN、CF3、CHF2、CH2F、OCF3、OH、OCH3、OC2H5、OCOCH3、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、CH2CH2CH2CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、NHCOCH3、CH2OH、CH2CH2OH、C(CH3)2OH、CH(CH3)OH、CH2NH2、CH2CH2NH2、C(CH3)2NH2、CH(CH3)NH2、CH2NH(CH3)、CH2CH2NH(CH3)、C(CH3)2NH(CH3)、CH(CH3)NH(CH3)、CH2N(CH3)2、CH2CH2N(CH3)2、C(CH3)2N(CH3)2、CH(CH3)N(CH3)2、CH2CN、SOCH3,SO2CH3、環丙基、環丁基、3-氧環丁烷基、2-氮環丙烷基、3-氮環丙烷基、1-吡咯啶基、1-哌啶基及1-嗎啉基所組成之群組，其中該環丙基、環丁基、3-氧環丁烷基、2-氮環丙烷基、3-氮環丙烷基、1-吡咯啶基、1-哌啶基及1-嗎啉基係未經取代或經以一或多個取代基單或多取代，其係選自於由F、Cl、CN、CF3、OCF3、OH、OCH3、CH3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、N(CH3)2及NHCOCH3所組成之群組，較佳地Z於每次出現係獨立地選自於由F、Cl、CN、CF3、CHF2、CH2F、OCF3、OH、OCH3、OC2H5、OCOCH3、CH3、CH2CH3、(CH2)2CH3、CH(CH3)2、(CH2)3CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、NHCOCH3、CH2OH、CH2CH2OH、C(CH3)2OH、CH(CH3)OH、CH2NH2、CH2CH2NH2、C(CH3)2NH2、CH(CH3)NH2、CH2NH(CH3)、CH2CN、SOCH3、SO2CH3、環丙基、環丁基、3-氧環丁烷基、1-吡咯啶基、1-哌啶基及1-嗎啉基所組成之群組。 Even more preferably, the compound of the formula (I) is selected from one of the formula (Ib) or (Ic) wherein R 1 is selected from CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CH 2 CONH 2 , CH 2 CON(CH 3 ) 2 , CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH, CH(CH 3 )CH 2 OH, CH 2 CH(CH 3 )OH, C(CH 3 ) 2 CH 2 OH a group consisting of CH(CH 3 )CH 2 CH 2 OH, cyclopropyl, cyclobutyl and 3-oxocyclobutane; and G is selected from G1 or G2, wherein k is present in each occurrence 0, 1, 2 or 3; Z is independently selected from the group consisting of F, Cl, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3 ) 2 NH 2 , CH(CH 3 ) NH 2 , CH 2 NH(CH 3 ), CH 2 CH 2 NH(CH 3 ), C(CH 3 ) 2 NH(CH 3 ), CH(CH 3 )NH(CH 3 ), CH 2 N(CH 3 ) 2 , CH 2 CH 2 N(CH 3 ) 2 , C(CH 3 ) 2 N(CH 3 ) 2 , CH(CH 3 )N(CH 3 ) 2 , CH 2 CN, SOCH 3 , SO 2 CH 3 , ring a group consisting of propyl, cyclobutyl, 3-oxocyclobutane, 2-nitrocyclopropane, 3-nitrocyclopropane, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl a group wherein the cyclopropyl, cyclobutyl, 3-oxocyclobutane, 2-azacyclopropane, 3-azacyclopropane, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholine The base is unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F, Cl, CN, CF 3 , OCF 3 , OH, OCH 3 , CH 3 , CONH 2 , CONHCH 3 a group consisting of CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), N(CH 3 ) 2 and NHCOCH 3 , preferably Z is independently selected from F, Cl in each occurrence. , CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CO NHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3 ) 2 NH 2 , CH(CH 3 )NH 2 , CH 2 NH(CH 3 ), CH 2 Group consisting of CN, SOCH 3 , SO 2 CH 3 , cyclopropyl, cyclobutyl, 3-oxocyclobutane, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl.

在又另一較佳具體實施例中，本發明係關於選自於由以下所 組成之群組之化合物 In yet another preferred embodiment, the invention is selected from the following Group of compounds

1 1-(5-(2-氟苯基)嘧啶-2-基)-N,N-二甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 1 1-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N,N-dimethylspiro[porphyrin-3,3'-oxocyclobutane]-6-carboxamide

2 (1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 2 (1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)(morpholinyl)methanone

3 N-(2-胺-2-側氧乙基)-1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 3 N-(2-Amino-2-oxoethyl)-1-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)-N-methylspiro[porphyrin- 3,3'-oxycyclobutane]-6-formamide

4 嗎啉基(1-(5-苯基嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)甲酮 4-morpholinyl (1-(5-phenylpyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)methanone

5 N-(2-胺-2-側氧乙基)-1-(5-(2-氟-5-甲氧基苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 5 N-(2-Amino-2-oxoethyl)-1-(5-(2-fluoro-5-methoxyphenyl)pyrimidin-2-yl)-N-methylspiro[porphyrin -3,3'-oxocyclobutane]-6-carboxamide

6 N-(2-胺-2-側氧乙基)-N-甲基-1-(5-苯基嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 6 N-(2-Amino-2-oxoethyl)-N-methyl-1-(5-phenylpyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane] -6-formamide

7 N-(2-胺-2-側氧乙基)-1-(5-(5-乙基-2-氟苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 7 N-(2-Amino-2-oxoethyl)-1-(5-(5-ethyl-2-fluorophenyl)pyrimidin-2-yl)-N-methylspiro[porphyrin- 3,3'-oxycyclobutane]-6-formamide

8 嗎啉基(1-(5-(吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)甲酮 8 Morpholinyl (1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)methanone

9 (1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 9 (1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)(morpholinyl) Ketone

10 (1-(5-(4-甲氧基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 10 (1-(5-(4-Methoxypyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl) (morpholinyl) Ketone

11 N-(2-胺-2-側氧乙基)-1-(5-(2-氟苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 11 N-(2-Amino-2-oxoethyl)-1-(5-(2-fluorophenyl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3,3'- Oxycyclobutane]-6-formamide

12 -(2-胺-2-側氧乙基)-1-(5-(5-乙氧基-2-氟苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 12-(2-Amino-2-oxoethyl)-1-(5-(5-ethoxy-2-fluorophenyl)pyrimidin-2-yl)-N-methylspiro[porphyrin- 3,3'-oxycyclobutane]-6-formamide

13 N-(2-胺-2-側氧乙基)-N-甲基-1-(5-(吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'- 氧環丁烷]-6-甲醯胺 13 N-(2-Amino-2-oxoethyl)-N-methyl-1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'- Oxycyclobutane]-6-formamide

14 嗎啉基(1-(5-(3-(三氟甲基)苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)甲酮 14 morpholinyl (1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl) ketone

15 (1-(5-(2-氟-5-(三氟甲基)苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)-(嗎啉基)甲酮 15 (1-(5-(2-Fluoro-5-(trifluoromethyl)phenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl) -(morpholinyl)methanone

16 1-(5-(2-氟-5-(三氟甲基)苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 16 1-(5-(2-Fluoro-5-(trifluoromethyl)phenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3 , 3'-oxocyclobutane]-6-formamide

17 N-(2-羥乙基)-N-甲基-1-(5-(3-(三氟甲基)苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 17 N-(2-hydroxyethyl)-N-methyl-1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'- Oxycyclobutane]-6-formamide

18 (1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(吡咯啶-1-基)甲酮 18 (1-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)(pyrrolidin-1-yl)- ketone

19 (1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(哌嗪-1-基)甲酮 19(1-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)(piperazin-1-yl)- ketone

20 1-(5-(2-氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 20 1-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane] -6-formamide

21 (1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基(1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)甲酮 21 (1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl(1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[porphyrin- 3,3'-oxycyclobutane]-6-yl)methanone

22 (1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(哌嗪-1-基)甲酮 22 (1-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)(piperazine-1 Ketone

23 (1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(吡咯啶-1-基)甲酮 23(1-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)(pyrrolidin-1 Ketone

24 N-(2-羥乙基)-N-甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 24 N-(2-hydroxyethyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxygen Cyclobutane]-6-formamide

25 (1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基(1-(5-(4-甲基吡啶-2-基)嘧啶-2-基) 螺[吲哚啉-3,3'-氧環丁烷]-6-基)甲酮 25 (1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl(1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl) Spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)methanone

26 N-(2-胺-2-側氧乙基)-1-(5-(3-環丙基苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 26 N-(2-Amino-2-oxoethyl)-1-(5-(3-cyclopropylphenyl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3,3 '-oxycyclobutane]-6-formamide

27 N-(2-胺-2-側氧乙基)-N-甲基-1-(5-(m-甲苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 27 N-(2-Amino-2-oxoethyl)-N-methyl-1-(5-(m-methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxygen Cyclobutane]-6-formamide

28 (S)-N-(2-胺-2-側氧乙基)-1-(5-(2-氟-5-(1-羥乙基)苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 28 (S)-N-(2-Amino-2-oxoethyl)-1-(5-(2-fluoro-5-(1-hydroxyethyl)phenyl)pyrimidin-2-yl)-N -methyl spiro[porphyrin-3,3'-oxycyclobutane]-6-formamide

29 (R)-N-(2-胺-2-側氧乙基)-1-(5-(2-氟-5-(1-羥乙基)苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 29(R)-N-(2-Amino-2-oxoethyl)-1-(5-(2-fluoro-5-(1-hydroxyethyl)phenyl)pyrimidin-2-yl)-N -methyl spiro[porphyrin-3,3'-oxycyclobutane]-6-formamide

30 N-(2-胺-2-側氧乙基)-1-(5-(2-氟-5-(2-羥基丙-2-基)苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 30 N-(2-Amino-2-oxoethyl)-1-(5-(2-fluoro-5-(2-hydroxypropan-2-yl)phenyl)pyrimidin-2-yl)-N- Methyl spiro[porphyrin-3,3'-oxycyclobutane]-6-formamide

31 嗎啉基(1-(5-(m-甲苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)甲酮 31 morpholinyl (1-(5-(m-methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)methanone

32 (1-(5-(2-氟-5-甲氧基苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 32 (1-(5-(2-Fluoro-5-methoxyphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl) (morpholine) Ketone

33 (1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 33(1-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl) (morpholinyl) Ketone

34 (1-(5-(吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(吡咯啶-1-基)甲酮 34 (1-(5-(Pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)(pyrrolidin-1-yl)- ketone

35 (1-(5-(4-環丙基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(吡咯啶-1-基)甲酮 35 (1-(5-(4-cyclopropylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)(pyrrolidine- 1-yl)methanone

36 (1-(5-(4-甲氧基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(吡咯啶-1-基)甲酮 36(1-(5-(4-Methoxypyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)(pyrrolidine- 1-yl)methanone

37 (1-(5-(3-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 37 (1-(5-(3-Fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)(morpholinyl)methanone

38 (1-(5-(4-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 38 (1-(5-(4-Fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)(morpholinyl)methanone

39 (1-(5-(2,5-二氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 39 (1-(5-(2,5-Difluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)(morpholinyl) A ketone

40 (1-(5-(2,3-二氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 40 (1-(5-(2,3-Difluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)(morpholinyl)- ketone

41 (1-(5-(3,5-二氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 41 (1-(5-(3,5-Difluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)(morpholinyl)- ketone

42 1-(5-(3-氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 42 1-(5-(3-Fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane] -6-formamide

43 1-(5-(4-氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 43 1-(5-(4-Fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane] -6-formamide

44 1-(5-(2,5-二氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 44 1-(5-(2,5-Difluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxygen ring Butane]-6-formamide

45 1-(5-(2,3-二氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 45 1-(5-(2,3-Difluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxygen ring Butane]-6-formamide

46 1-(5-(3,5-二氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 46 1-(5-(3,5-Difluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxygen ring Butane]-6-formamide

47 N-(2-胺-2-側氧乙基)-1-(5-(3-氟苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 47 N-(2-Amino-2-oxoethyl)-1-(5-(3-fluorophenyl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3,3'- Oxycyclobutane]-6-formamide

48 N-(2-胺-2-側氧乙基)-1-(5-(4-氟苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 48 N-(2-Amine-2-oxoethyl)-1-(5-(4-fluorophenyl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3,3'- Oxycyclobutane]-6-formamide

49 N-(2-胺-2-側氧乙基)-1-(5-(2,5-二氟苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 49 N-(2-Amino-2-oxoethyl)-1-(5-(2,5-difluorophenyl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3, 3'-oxocyclobutane]-6-formamide

50 N-(2-胺-2-側氧乙基)-1-(5-(2,3-二氟苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 50 N-(2-Amino-2-oxoethyl)-1-(5-(2,3-difluorophenyl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3, 3'-oxocyclobutane]-6-formamide

51 N-(2-胺-2-側氧乙基)-1-(5-(3,5-二氟苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 51 N-(2-Amino-2-oxoethyl)-1-(5-(3,5-difluorophenyl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3, 3'-oxocyclobutane]-6-formamide

52 6-(乙亞磺醯基)-1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷] 52 6-(ethylsulfinyl)-1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]

53 6-(乙磺醯基)-1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷] 53 6-(ethanesulfonyl)-1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]

54 6-(乙亞磺醯基)-1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷] 54 6-(ethylsulfinyl)-1-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]

55 6-(乙磺醯基)-1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷] 55 6-(ethanesulfonyl)-1-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]

56 6-(乙亞磺醯基)-1-(5-(4-甲氧基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷] 56 6-(ethylsulfinyl)-1-(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]

57 6-(乙磺醯基)-1-(5-(4-甲氧基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷] 57 6-(ethanesulfonyl)-1-(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]

58 1-(5-(4-環丙基吡啶-2-基)嘧啶-2-基)-6-(乙亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷] 58 1-(5-(4-Cyclopropylpyridin-2-yl)pyrimidin-2-yl)-6-(ethylsulfinyl) spiro[porphyrin-3,3'-oxocyclobutane]

59 1-(5-(4-環丙基吡啶-2-基)嘧啶-2-基)-6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷] 59 1-(5-(4-Cyclopropylpyridin-2-yl)pyrimidin-2-yl)-6-(ethanesulfonyl)spiro[porphyrin-3,3'-oxocyclobutane]

60 1-(5-(4-乙基吡啶-2-基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 60 1-(5-(4-ethylpyridin-2-yl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxygen Cyclobutane]-6-formamide

61 1-(5-(4-環丙基吡啶-2-基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 61 1-(5-(4-Cyclopropylpyridin-2-yl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'- Oxycyclobutane]-6-formamide

62 N-(2-羥乙基)-1-(5-(4-甲氧基吡啶-2-基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 62 N-(2-hydroxyethyl)-1-(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3,3'- Oxycyclobutane]-6-formamide

63 1-(5-(4-乙氧基吡啶-2-基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 63 1-(5-(4-ethoxypyridin-2-yl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'- Oxycyclobutane]-6-formamide

64 N-(2-羥乙基)-N-甲基-1-(5-(吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁 烷]-6-甲醯胺 64 N-(2-hydroxyethyl)-N-methyl-1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane Alkane-6-carboxamide

65 N-(2-羥乙基)-N-甲基-1-(5-(4-(三氟甲基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 65 N-(2-hydroxyethyl)-N-methyl-1-(5-(4-(trifluoromethyl)pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3, 3'-oxocyclobutane]-6-formamide

66 N-(2-羥乙基)-1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 66 N-(2-hydroxyethyl)-1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[吲哚Porphyrin-3,3'-oxycyclobutane]-6-formamide

67 (1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(吡咯啶-1-基)甲酮 67 (1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6 -yl)(pyrrolidin-1-yl)methanone

68 (1-(5-(4-乙氧基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(吡咯啶-1-基)甲酮 68 (1-(5-(4-ethoxypyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)(pyrrolidine- 1-yl)methanone

69 吡咯啶-1-基(1-(5-(4-(三氟甲基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)甲酮 69 pyrrolidin-1-yl (1-(5-(4-(trifluoromethyl)pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane] -6-yl) ketone

70 (1-(5-(4-乙基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(吡咯啶-1-基)甲酮 70 (1-(5-(4-ethylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)(pyrrolidin-1 Ketone

71 (S)-或(R)-1-(3-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)-4-氟苯基)乙醇 71(S)- or (R)-1-(3-(2-(6-(ethylsulfonyl)) spiro[porphyrin-3,3'-oxocyclobutane]-1-yl)pyrimidine- 5-yl)-4-fluorophenyl)ethanol

72 (R)-或(S)-1-(3-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)-4-氟苯基)乙醇 72(R)- or (S)-1-(3-(2-(6-(ethylsulfonyl)) spiro[porphyrin-3,3'-oxocyclobutane]-1-yl)pyrimidine- 5-yl)-4-fluorophenyl)ethanol

73 2-(3-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)-4-氟苯基)丙-2-醇 73 2-(3-(2-(6-(ethylsulfonyl)) spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)-4-fluorobenzene Propan-2-ol

74 2-(3-(2-(6-(乙亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)-4-氟苯基)丙-2-醇 74 2-(3-(2-(6-(ethylsulfinyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)-4-fluoro Phenyl)propan-2-ol

75 2-(2-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-4-基)丙-2-醇 75 2-(2-(2-(6-(ethylsulfonyl)) spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)pyridin-4-yl Propan-2-ol

76 2-(2-(2-(6-(乙亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶 -4-基)丙-2-醇 76 2-(2-(2-(6-(ethylsulfinyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)pyridine -4-yl)propan-2-ol

77 (S)-或(R)-1-(2-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-4-基)乙醇 77 (S)- or (R)-1-(2-(2-(6-(ethylsulfonyl)) spiro[porphyrin-3,3'-oxocyclobutane]-1-yl)pyrimidine- 5-yl)pyridin-4-yl)ethanol

78 (R)-或(S)-1-(2-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-4-基)乙醇 78(R)- or (S)-1-(2-(2-(6-(ethylsulfonyl)) spiro[porphyrin-3,3'-oxocyclobutane]-1-yl)pyrimidine- 5-yl)pyridin-4-yl)ethanol

79 N-(2-羥乙基)-N-甲基-1-(5-苯基嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 79 N-(2-hydroxyethyl)-N-methyl-1-(5-phenylpyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-formamidine amine

80 N-(2-羥乙基)-N-甲基-1-(5-(m-甲苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 80 N-(2-hydroxyethyl)-N-methyl-1-(5-(m-methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]- 6-methylamine

81 1-(5-(3-環丙基苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 81 1-(5-(3-Cyclopropylphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane Alkane-6-carboxamide

82 N-(2-羥乙基)-1-(5-(3-甲氧基苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 82 N-(2-Hydroxyethyl)-1-(5-(3-methoxyphenyl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane Alkane-6-carboxamide

83 1-(5-(3-乙氧基苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 83 1-(5-(3-ethoxyphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane Alkane-6-carboxamide

84 1-(5-(3-氯苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 84 1-(5-(3-Chlorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane] -6-formamide

85 N-(2-羥乙基)-N-甲基-1-(5-(3-(三氟甲氧基)苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 85 N-(2-hydroxyethyl)-N-methyl-1-(5-(3-(trifluoromethoxy)phenyl)pyrimidin-2-yl)spiro[porphyrin-3,3' -oxycyclobutane]-6-formamide

86 1-(5-(3-胺苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 86 1-(5-(3-Aminophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane] -6-formamide

87 N-(2-羥乙基)-N-甲基-1-(5-(3-(吡咯啶-1-基)苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 87 N-(2-hydroxyethyl)-N-methyl-1-(5-(3-(pyrrolidin-1-yl)phenyl)pyrimidin-2-yl)spiro[porphyrin-3,3 '-oxycyclobutane]-6-formamide

88 N-(2-羥乙基)-1-(5-(3-(1-羥乙基)苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'- 氧環丁烷]-6-甲醯胺 88 N-(2-hydroxyethyl)-1-(5-(3-(1-hydroxyethyl)phenyl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3,3' - Oxycyclobutane]-6-formamide

89 1-(5-(3,4-二氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 89 1-(5-(3,4-Difluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxygen ring Butane]-6-formamide

90 1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 90 1-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'- Oxycyclobutane]-6-formamide

91 1-(5-(5-環丙基-2-氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 91 1-(5-(5-Cyclopropyl-2-fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3' -oxycyclobutane]-6-formamide

92 1-(5-(2-氟-5-甲氧基苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 92 1-(5-(2-Fluoro-5-methoxyphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3' -oxycyclobutane]-6-formamide

93 1-(5-(5-乙氧基-2-氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 93 1-(5-(5-Ethoxy-2-fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3' -oxycyclobutane]-6-formamide

94 1-(5-(2-氟-5-(三氟甲氧基)苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 94 1-(5-(2-Fluoro-5-(trifluoromethoxy)phenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin- 3,3'-oxycyclobutane]-6-formamide

95 1-(5-(5-胺-2-氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 95 1-(5-(5-Amino-2-fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxygen Cyclobutane]-6-formamide

96 1-(5-(5-(乙基胺)-2-氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 96 1-(5-(5-(ethylamine)-2-fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3, 3'-oxocyclobutane]-6-formamide

97 1-(5-(3-(乙基胺)苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 97 1-(5-(3-(ethylamine)phenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxygen Cyclobutane]-6-formamide

98 吡咯啶-1-基(1-(5-(4-(三氟甲基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)甲酮 98 pyrrolidin-1-yl (1-(5-(4-(trifluoromethyl)pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane] -6-yl) ketone

99 2-(2-(2-(6-(甲亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-4-基)丙-2-醇 99 2-(2-(2-(6-(methylsulfinyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)pyridine-4- Propan-2-ol

100 2-(2-(2-(6-(甲磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-4- 基)丙-2-醇 100 2-(2-(2-(6-(methylsulfonyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)pyridine-4- Propan-2-ol

101 1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)-N,N-二甲基螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺 101 1-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)-N,N-dimethylspiro[porphyrin-3,3'-oxocyclobutane]-6 -sulfonamide

102 1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺 102 1-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'- Oxycyclobutane]-6-sulfonamide

103 N,N-二甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺 103 N,N-Dimethyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6- Sulfonamide

104 N-(2-羥乙基)-N-甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺 104 N-(2-hydroxyethyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxygen Cyclobutane]-6-sulfonamide

105 N-甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)-N-(氧環丁烷-3-基甲基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 105 N-Methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-N-(oxocyclobutan-3-ylmethyl)spiro[porphyrin-3 , 3'-oxocyclobutane]-6-formamide

106 N-(環丙基甲基)-N-甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 106 N-(cyclopropylmethyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxygen Cyclobutane]-6-formamide

107 N-((3,3-二氟環丁基)甲基)-N-甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺-[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 107 N-((3,3-Difluorocyclobutyl)methyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl) snail-[吲Porphyrin-3,3'-oxycyclobutane]-6-carboxamide

108 6-(乙亞磺醯基)-1-(5-(噠嗪-3-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷] 108 6-(ethylsulfinyl)-1-(5-(pyridazin-3-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]

109 6-(乙磺醯基)-1-(5-(噠嗪-3-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷] 109 6-(ethanesulfonyl)-1-(5-(pyridazin-3-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]

110 2-(3-(2-(6-(乙亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)苯基)丙-2-醇 110 2-(3-(2-(6-(ethylsulfinyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)phenyl)propene -2-ol

111 2-(3-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)苯基)丙-2-醇 111 2-(3-(2-(6-(ethylsulfonyl)) spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)phenyl)propene- 2-alcohol

112 6-(乙亞磺醯基)-1-(5-(5-甲基噠嗪-3-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷] 112 6-(ethylsulfinyl)-1-(5-(5-methylpyridazin-3-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]

113 6-(乙磺醯基)-1-(5-(5-甲基噠嗪-3-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷] 113 6-(ethanesulfonyl)-1-(5-(5-methylpyridazin-3-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]

114 2-(6-(2-(6-(乙亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)噠嗪-4-基)丙-2-醇 114 2-(6-(2-(6-(ethylsulfinyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)pyridazine-4 -yl)propan-2-ol

115 2-(6-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)噠嗪-4-基)丙-2-醇 115 2-(6-(2-(6-(ethylsulfonyl)) spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)pyridazine-4- Propan-2-ol

116 2-((1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)亞磺醯基)乙醇 116 2-((1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)sulfin Mercapto)ethanol

117 2-((1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)磺醯基)乙醇 117 2-((1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)sulfonate Ethanol

118 2-(2-(2-(6-((2-羥乙基)亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-4-基)丙-2-醇 118 2-(2-(2-(6-((2-Hydroxyethyl)sulfinyl) spiro[porphyrin-3,3'-oxocyclobutane]-1-yl)pyrimidine-5- Pyridin-4-yl)propan-2-ol

119 2-(2-(2-(6-((2-羥乙基)磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-4-基)丙-2-醇 119 2-(2-(2-(6-((2-Hydroxyethyl))sulfonyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl Pyridin-4-yl)propan-2-ol

120 3-((1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)亞磺醯基)丙-1-醇 120 3-((1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)sulfin Mercapto-1-propanol

121 3-((1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)磺醯基)丙-1-醇 121 3-((1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)sulfonate Propan-1-ol

122 3-((1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)亞磺醯基)丙-1-醇 122 3-((1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane ]-6-yl) sulfinyl) propan-1-ol

124 3-((1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)磺醯基)丙-1-醇 124 3-((1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane ]-6-yl)sulfonyl)propan-1-ol

125 (1-(5-(6-羥基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 125 (1-(5-(6-Hydroxypyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)(morpholinyl)- ketone

126 (1-(5-(3-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 126 (1-(5-(3-Methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)(morpholinyl) Ketone

127 (1-(5-(2-氟-3-羥苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)-甲酮 127 (1-(5-(2-Fluoro-3-hydroxyphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)(morpholinyl) -ketone

128 (1-(5-(3-胺-2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)-甲酮 128 (1-(5-(3-Amino-2-fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)(morpholinyl) -ketone

129 (1-(6-甲基-[4,5'-聯嘧啶]-2'-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 129 (1-(6-Methyl-[4,5'-bipyrimidin]-2'-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl) (morpholinyl) Ketone

130 (1-(5-(2-氟-6-羥苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)-甲酮 130 (1-(5-(2-Fluoro-6-hydroxyphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)(morpholinyl) -ketone

131 (1-(5-(2-胺-6-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)-甲酮 131(1-(5-(2-Amine-6-fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)(morpholinyl) -ketone

132 (1-(5-(6-胺基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 132 (1-(5-(6-Aminopyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)(morpholinyl) Ketone

133 (1-(5-(2-氟-3-甲基苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 133 (1-(5-(2-Fluoro-3-methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl) (morpholinyl) Ketone

134 (1-(5-(2-氟-6-甲基苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 134 (1-(5-(2-Fluoro-6-methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl) (morpholinyl) Ketone

135 (1-(4-甲基-[2,5'-聯嘧啶]-2'-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 135 (1-(4-Methyl-[2,5'-bipyrimidin]-2'-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl) (morpholinyl) Ketone

136 (1-(4,6-二甲基-[2,5'-聯嘧啶]-2'-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 136 (1-(4,6-Dimethyl-[2,5'-bipyrimidin]-2'-yl) spiro[porphyrin-3,3'-oxocyclobutane]-6-yl) ( Morpholine) ketone

137 1-([2,5'-聯嘧啶]-2'-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 137 1-([2,5'-Bipyrimidinyl]-2'-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane] -6-formamide

138 N-(2-羥乙基)-N-甲基-1-(5-(吡嗪-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 138 N-(2-hydroxyethyl)-N-methyl-1-(5-(pyrazin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane ]-6-carbamamine

139 N-(2-羥乙基)-N-甲基-1-(5-(6-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 139 N-(2-hydroxyethyl)-N-methyl-1-(5-(6-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxygen Cyclobutane]-6-formamide

140 N-(2-羥乙基)-1-(5-(6-羥基吡啶-2-基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 140 N-(2-hydroxyethyl)-1-(5-(6-hydroxypyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3,3'-oxygen ring Butane]-6-formamide

141 N-(2-羥乙基)-1-(5-(6-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 141 N-(2-Hydroxyethyl)-1-(5-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[吲哚Porphyrin-3,3'-oxycyclobutane]-6-formamide

142 (1-(5-(6-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 142 (1-(5-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6 -yl)(morpholinyl)methanone

143 (1-(5-(6-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 143 (1-(5-(6-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)(morpholinyl) Ketone

144 N-((3-羥基氧環丁烷-3-基)甲基)-N-甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 144 N-((3-Hydroxyoxycyclobutane-3-yl)methyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl) snail [ Porphyrin-3,3'-oxycyclobutane]-6-carboxamide

145 N-((1-羥基環丙基)甲基)-N-甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 145 N-((1-Hydroxycyclopropyl)methyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3 , 3'-oxocyclobutane]-6-formamide

146 1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)-N,N-二甲基螺[吲哚啉-3,3'氧環丁烷]-6-甲醯胺 146 1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N,N-dimethylspiro[porphyrin-3,3' oxygen Cyclobutane]-6-formamide

147 1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 147 1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane Alkane-6-carboxamide

148 N-甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 148 N-Methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-carboxamide

149 N-(2-羥乙基)-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 149 N-(2-Hydroxyethyl)-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]- 6-methylamine

150 N-(2-羥乙基)-1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 150 N-(2-hydroxyethyl)-1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3 '-oxycyclobutane]-6-formamide

151 1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)-N-(2-羥乙基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 151 1-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)spiro[porphyrin-3,3'-oxocyclobutane] -6-formamide

152 (1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 152 (1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6 -yl)(morpholinyl)methanone

153 1-(5-(2-氟苯基)嘧啶-2-基)-N-(2-羥乙基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 153 1-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)spiro[porphyrin-3,3'-oxocyclobutane]-6-formamidine amine

154 N-(2-羥乙基)-1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺 154 N-(2-Hydroxyethyl)-1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[吲哚Porphyrin-3,3'-oxycyclobutane]-6-sulfonamide

155 N-(2-羥乙基)-1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺 155 N-(2-hydroxyethyl)-1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3 '-oxycyclobutane]-6-sulfonamide

156 N-(2-羥乙基)-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺 156 N-(2-hydroxyethyl)-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]- 6-sulfonamide

157 N-甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺 157 N-Methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-sulfonamide

158 1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺 158 1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane Alkane-6-sulfonamide

159 6-(乙亞磺醯基)-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷] 159 6-(ethylsulfinyl)-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]

161 6-(乙亞磺醯基)-1-(5-(吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷] 161 6-(ethylsulfinyl)-1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]

163 6-(乙磺醯基)-1-(5-(吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷] 163 6-(ethanesulfonyl)-1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]

164 2-(6-(2-(6-(乙亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-2-基)丙-2-醇 164 2-(6-(2-(6-(ethylsulfinyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)pyridine-2- Propan-2-ol

166 2-(6-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-2-基)丙-2-醇 166 2-(6-(2-(6-(ethylsulfonyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)pyridin-2-yl Propan-2-ol

167 2-((1-(5-(吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)亞磺醯基)乙醇 167 2-((1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)sulfinyl)ethanol

169 2-((1-(5-(吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)磺醯基)乙醇 169 2-((1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)sulfonyl)ethanol

170 2-(2-(2-(6-(乙亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-4-基)丙-2-胺 170 2-(2-(2-(6-(ethylsulfinyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)pyridine-4- Propyl-2-amine

171 2-(2-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-4-基)丙-2-胺 171 2-(2-(2-(6-(ethylsulfonyl)) spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)pyridin-4-yl Propyl-2-amine

172 2-(2-(6-(乙亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)異菸鹼醯胺 172 2-(2-(6-(ethylsulfinyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)isonicotinium amide

173 2-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)異菸鹼醯胺 173 2-(2-(6-(ethylsulfonyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)isonicotinamide

174 2-(2-(6-(嗎啉-4-羰基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)異菸鹼醯胺 174 2-(2-(6-(morpholine-4-carbonyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)isonicotinamide

175 1-(5-(4-胺甲醯基吡啶-2-基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 175 1-(5-(4-Aminomethylpyridin-2-yl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[Porphyrin-3,3' -oxycyclobutane]-6-formamide

176 2-(2-(6-(嗎啉-4-羰基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)異菸鹼甲腈 176 2-(2-(6-(morpholine-4-carbonyl)spiro[porphyrin-3,3'-oxocyclobutane]-1-yl)pyrimidin-5-yl)isonicotinonitrile

177 1-(5-(4-氰基吡啶-2-基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 177 1-(5-(4-Cyanopyridin-2-yl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxygen Cyclobutane]-6-formamide

178 N-(2-羥乙基)-N-甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)-2',3',5',6'-四氫螺[吲哚啉-3,4'-哌喃]-6-甲醯胺 178 N-(2-Hydroxyethyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-2',3',5',6' -tetrahydrospiro[porphyrin-3,4'-pyrano]-6-carboxamide

179 2-(4-氟-3-(2-(6-(1-(甲基胺)環丙基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)苯基)丙-2-醇 179 2-(4-Fluoro-3-(2-(6-(1-(methylamine))cyclopropyl)spiro[porphyrin-3,3'-oxocyclobutane]-1-yl)pyrimidine -5-yl)phenyl)propan-2-ol

180 1-(1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)-N-甲基環丙 胺 180 1-(1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)-N-methylcyclopropane amine

181 1-(1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)-N-甲基環丙胺 181 1-(1-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)-N -methylcyclopropylamine

182 1-(1-(5-(4-甲氧基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)-N-甲基環丙胺 182 1-(1-(5-(4-Methoxypyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)-N -methylcyclopropylamine

183 2-(2-(2-(6-(1-(甲基胺)環丙基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-4-基)丙-2-醇 183 2-(2-(2-(6-(1-(methylamine))cyclopropyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl Pyridin-4-yl)propan-2-ol

184 N-甲基-1-(1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)環丙胺 184 N-methyl-1-(1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6- Cyclopropylamine

185 N-乙基-1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺 185 N-Ethyl-1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane Alkane-6-sulfonamide

186 1-(5-(4-(2-胺基丙-2-基)吡啶-2-基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺 186 1-(5-(4-(2-Aminopropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3,3'-oxygen ring Butane]-6-sulfonamide

187 1-(5-(4-(2-胺基丙-2-基)吡啶-2-基)嘧啶-2-基)-N,N-二甲基螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺 187 1-(5-(4-(2-Aminopropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N,N-dimethylspiro[porphyrin-3,3' -oxycyclobutane]-6-sulfonamide

188 N-(2-羥乙基)-N-甲基-1'-(5-(4-甲基吡啶-2-基)嘧啶-2-基)-4,5-二氫-2H-螺-[呋喃-3,3'-吲哚啉]-6'-甲醯胺 188 N-(2-hydroxyethyl)-N-methyl-1'-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-4,5-dihydro-2H-spiro -[furan-3,3'-carboline]-6'-formamide

189 2-(2-(6-(乙亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)異菸鹼甲腈 189 2-(2-(6-(ethylsulfinyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)isonicotinonitrile

191 2-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)異菸鹼甲腈 191 2-(2-(6-(ethylsulfonyl)spiro[porphyrin-3,3'-oxocyclobutane]-1-yl)pyrimidin-5-yl)isonicotinonitrile

192 (1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)二甲基膦氧化物 192 (1-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)dimethylphosphine Oxide

193 (1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)二甲基膦氧化物 可擇地為單一立體異構物或立體異構物之混合物之形式、游離化合物之形式及/或其生理上可接受之鹽類及/或生理上可接受之溶劑合物。 193 (1-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)dimethylphosphine oxide Alternatively, it may be in the form of a single stereoisomer or a mixture of stereoisomers, in the form of a free compound and/or a physiologically acceptable salt thereof and/or a physiologically acceptable solvate.

由於其優異的藥理活性，本發明第一態樣之化合物(特別為式(I)、(Ia)、(Ib)、(Ic)或(Id)之通常結構)適於治療多種疾病或症狀，其中PDE4酵素之抑制性為其優點。 Due to its excellent pharmacological activity, the first aspect of the invention (particularly the general structure of formula (I), (Ia), (Ib), (Ic) or (Id)) is suitable for the treatment of various diseases or conditions, Among them, the inhibition of PDE4 enzyme is an advantage.

該等症狀及疾病特別為- 關節之發炎性疾病；- 皮膚之發炎性疾病；- 胃腸道疾病及病訴；- 內臟之發炎性疾病；- 增生性疾病；- 與黏液產生增多、發炎及/或呼吸道阻塞有關之呼吸道或肺部疾病；- 纖維化譜(fibrotic spectrum)之疾病；- 癌症；- 代謝疾病；- 心理疾患；及- 周圍或中樞神經系統疾病。 These symptoms and diseases are especially - inflammatory diseases of the joints; - inflammatory diseases of the skin; - gastrointestinal diseases and diseases; - inflammatory diseases of the internal organs; - proliferative diseases; - increased mucus production, inflammation and / Or respiratory or pulmonary diseases associated with airway obstruction; - diseases of fibrotic spectrum; - cancer; - metabolic diseases; - mental disorders; and - peripheral or central nervous system diseases.

本發明第一態樣化合物(特別為式(I)、(Ia)、(Ib)、(Ic)或(Id)之通常結構)之優點之一為其係選擇性PDE4B抑制劑。較佳地，PDE4D未被抑制或僅部分被抑制，因此使用這種選擇性PDE4B抑制劑不會產生副作用或顯著減輕之副作用，諸如嘔吐(emesis)及噁心(nausea)，特別為不適(indisposition)、嘔吐(vomiting)及生病(sickness)。本發明化合物之治療範圍因此為優勢。 One of the advantages of the first aspect of the present invention, particularly the general structure of formula (I), (Ia), (Ib), (Ic) or (Id), is that it is a selective PDE4B inhibitor. Preferably, PDE4D is not inhibited or only partially inhibited, so the use of such a selective PDE4B inhibitor does not produce side effects or significant side effects such as emesis and nausea, especially indisposition. , vomiting and sickness. The therapeutic range of the compounds of the invention is therefore an advantage.

本發明第二態樣係一藥學組成物(藥劑)，其含有本發明第一 態樣之至少一化合物，其特別為式(I)、(Ia)、(Ib)、(Ic)或(Id)之通常結構。 A second aspect of the present invention is a pharmaceutical composition (agent) comprising the first aspect of the present invention At least one compound of the aspect, which is in particular the general structure of formula (I), (Ia), (Ib), (Ic) or (Id).

本發明第三態樣化合物係本發明第一態樣之化合物(特別為式(I)、(Ia)、(Ib)、(Ic)或(Id)之通常結構)作為藥劑之用途，特別為用於治療可藉由抑制PDE4酵素(特別為PDE4B酵素)治療之症狀或疾病。 The third aspect of the present invention is a use of the compound of the first aspect of the present invention (particularly the general structure of the formula (I), (Ia), (Ib), (Ic) or (Id)) as a medicament, in particular It is used to treat symptoms or diseases that can be treated by inhibiting PDE4 enzymes, particularly PDE4B enzymes.

本發明第四態樣化合物係本發明第一態樣之化合物(特別為式(I)、(Ia)、(Ib)、(Ic)或(Id)之通常結構)作為治療以下之藥劑之用途：關節之發炎性疾病；及/或皮膚之發炎性疾病；及/或眼睛之發炎性疾病；胃腸道疾病及病訴；內臟之發炎性疾病；及/或增生性疾病；與黏液產生增多、發炎及/或呼吸道阻塞有關之呼吸道或肺部疾病；纖維化譜(fibrotic spectrum)之疾病；癌症；代謝疾病；心理疾患；及/或周圍或中樞神經系統疾病。 The fourth aspect of the present invention is the use of the compound of the first aspect of the present invention (particularly the general structure of the formula (I), (Ia), (Ib), (Ic) or (Id)) as a therapeutic agent for the following : an inflammatory disease of the joint; and/or an inflammatory disease of the skin; and/or an inflammatory disease of the eye; a gastrointestinal disease and a disease; an inflammatory disease of the internal organs; and/or a proliferative disease; Respiratory or pulmonary diseases associated with inflammation and/or airway obstruction; diseases of fibrotic spectrum; cancer; metabolic diseases; psychological disorders; and/or peripheral or central nervous system disorders.

本發明第四態樣之較佳具體實施例中，本發明因此也提供本發明第一態樣之化合物(特別為式(I)、(Ia)、(Ib)或(Ic)之通常結構)作為治療以下發炎性疾病之藥劑之用途：關節、皮膚、與黏液產生增多、發炎及/或呼吸道阻塞有關之呼吸道或肺部疾病、代謝疾病及/或心血管疾病。 In a preferred embodiment of the fourth aspect of the invention, the invention therefore also provides a compound of the first aspect of the invention (particularly the general structure of formula (I), (Ia), (Ib) or (Ic)) Use as a medicament for the treatment of inflammatory diseases such as joints, skin, respiratory or pulmonary diseases, metabolic diseases and/or cardiovascular diseases associated with increased mucus production, inflammation and/or airway obstruction.

本發明第五態樣係本發明第一態樣之化合物(特別為式(I)、(Ia)、(Ib)、(Ic)或(Id)之通常結構)用於製備治療本發明第四態樣之疾病及症狀之藥劑之用途。 A fifth aspect of the present invention is a compound of the first aspect of the present invention (particularly a general structure of the formula (I), (Ia), (Ib), (Ic) or (Id)) for use in the preparation of the fourth aspect of the present invention The use of the agent for the disease and symptoms of the state.

本發明第六態樣係用於治療本發明第四態樣之人類疾病及症狀之方法，其特徵在於施予一治療有效量之本發明第一態樣至少一化合物，特別為式(I)、(Ia)、(Ib)、(Ic)或(Id)之通常結構。 A sixth aspect of the invention is a method for treating a human disease and a symptom of a fourth aspect of the invention, characterized by administering a therapeutically effective amount of at least one compound of the first aspect of the invention, in particular, formula (I) The general structure of (Ia), (Ib), (Ic) or (Id).

欲對個人或病患施予該活性成分之量各異並取決於病患之體重、年齡及就醫歷史且與施予類型、適應症及病重程度。本發明第一態樣之至少一化合物(特別為式(I)、(Ia)、(Ib)、(Ic)或(Id)之通常結構)在傳統上會施予體重之0.1至5000mg/kg，特別為0.5至500mg/kg，較佳為1至250 mg/kg。 The amount of the active ingredient to be administered to an individual or a patient varies depending on the weight, age, and medical history of the patient and the type of administration, the indication, and the severity of the disease. At least one compound of the first aspect of the invention (particularly the general structure of formula (I), (Ia), (Ib), (Ic) or (Id)) is conventionally administered at a body weight of 0.1 to 5000 mg/kg. , especially from 0.5 to 500 mg/kg, preferably from 1 to 250 Mg/kg.

本發明第一態樣之所有具體實施例(特別為較佳之具體實施例)適用於本發明之所有其他態樣。 All of the specific embodiments (particularly preferred embodiments) of the first aspect of the invention are applicable to all other aspects of the invention.

本發明之藥劑、藥品及藥學組成物可為液體、半固體或固體劑型形式及例如注射溶液、滴劑、果汁(juices)、糖漿劑、噴霧劑、懸浮液、顆粒、片劑、錠劑、丸劑、透皮治療系統、膠囊、硬膏劑、栓劑、軟膏劑、霜劑(creams)、塗劑(lotions)、膠劑(gels)、乳劑(emulsions)或氣溶膠之形式並以該形式施予，且含有除了本發明第一態樣之至少一化合物(特別為式(I)、(Ia)、(Ib)、(Ic)或(Id)之通常結構)外根據藥學形式並取決於施予路徑之藥學輔助物質，諸如例如載體材料、填料、溶劑、稀釋劑、表面活性物質、染料、防腐劑、崩解劑(disintegrants)、助滑添加劑、潤滑劑、香味劑(flavourings)及/或黏合劑。 The medicament, medicament and pharmaceutical composition of the present invention may be in the form of a liquid, semi-solid or solid dosage form and, for example, injectable solutions, drops, juices, syrups, sprays, suspensions, granules, tablets, lozenges, Pills, transdermal therapeutic systems, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions or aerosols and administered in this form And containing at least one compound other than the first aspect of the invention (particularly the general structure of formula (I), (Ia), (Ib), (Ic) or (Id)) according to the pharmaceutical form and depending on the administration Pharmacological auxiliary substances of the route, such as, for example, carrier materials, fillers, solvents, diluents, surface active substances, dyes, preservatives, disintegrants, slip additives, lubricants, flavourings and/or bonds Agent.

輔助物質之選用及其數量取決於該藥劑是否藉由經口、皮下、非經腸胃、靜脈、陰道、肺、腹膜、透皮、肌內、鼻、頰或直腸方式或局部性(例如在皮膚、黏膜及眼睛上)施予，及該藥劑是否被設計為藉由立即(immediate)、持續(sustained)、延遲(delayed)或緩釋(extended release)方式遞送活性成分。製備本發明之藥劑及藥學組成物係使用先前技術(諸如「Remington's Pharmaceutical Sciences」,Ed.A.R.Gennaro,17th edition,Mack Publishing Company,Easton PD(1985)，特別在第8部分、第76至93章)已知之試劑、裝置、方法及製程進行。 The choice of auxiliary substance and its amount depends on whether the agent is administered orally, subcutaneously, parenterally, intravenously, vaginally, pulmonaryly, peritoneally, transdermally, intramuscularly, nasally, buccally or rectally or locally (for example, on the skin). , mucosal and ocular administration, and whether the agent is designed to deliver the active ingredient by immediate, sustained, delayed or extended release. Manufacture of a medicament and a pharmaceutically-based composition of the present invention using prior art (such as "Remington's Pharmaceutical Sciences", Ed.ARGennaro, 17 th edition, Mack Publishing Company, Easton PD (1985), especially in Part 8, Chapter 76 to 93 The known reagents, devices, methods and processes are carried out.

除非另有指示本發明之化合物可根據有機化學領域之一般知識及本文所述(cf.以下之反應架構)或類似方式合成。本文所述合成路徑之反應條件係為技術人士熟知且於對於某些情況在本文合成實施例中舉例說明。必要之原料可商購取得或者也可根據有機化學領域之一般知識獲得。 Unless otherwise indicated, the compounds of the present invention can be synthesized according to the general knowledge in the field of organic chemistry and as described herein (cf. Reaction Schemes below) or the like. The reaction conditions for the synthetic routes described herein are well known to those skilled in the art and are exemplified in the synthesis examples herein for some cases. The necessary raw materials are commercially available or can be obtained based on general knowledge in the field of organic chemistry.

若無另外說明，以下反應架構中所示化合物中之所有化學部分(moieties)、變量(variables)及指數(indices)係如式(I)化合物及其各種具體實施例之上下文中所定義。 Unless otherwise stated, all chemical moieties, variables, and indices in the compounds shown in the following reaction schemes are as defined in the context of the compounds of formula (I) and various specific embodiments thereof.

實施例：Example:

本發明之化合物係被具體化於下表中，但其並不限制本發明。 The compounds of the present invention are embodied in the following table, but they are not intended to limit the invention.

以下縮寫係用於實驗之描述中：(AtaPhos)2PdCl2=雙(二-三級-丁基(4-二甲基胺苯基)膦二氯鈀(II)；APCI=大氣壓力化學游離法；calc.=計算出；d=日；dba=二亞苄基-丙酮；DCM=二氯甲烷；DIPEA=二異丙基乙胺；DME=二甲氧基乙烷；DMF=N,N-二甲基甲醯胺；DMSO=二甲亞碸；dppp=1,3-雙(二苯基膦基)丙烷；EtOAc=乙酸乙酯；EtOH=乙醇；EDCxHCl=1-[3-(二甲基胺)丙基]-3-乙基碳化二亞胺鹽酸鹽；ES-MS=電灑質譜法(ES-MS)；eq.=當量；h=小時(s)；HOAt=1-羥-7-氮雜-1H-苯并三唑；KOt-Bu=叔丁醇鉀；LiHMDS=雙(三甲矽)胺化鋰；mCPBA=間氯過氧苯甲酸；min=分鐘(s)；MeOH=甲醇；MMPP=單過氧鄰苯二甲酸鎂；MTBE=甲基-叔丁基醚；PdCl2(dppf)=[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)DCM錯合物；Pd2(dba)3(0)=三(二亞苄基丙酮)二鈀(0)；PE=石油醚；rt=室溫；Rt=停留時間；SFC=超臨界流體層析法；TBDPS=叔丁基二苯基矽基；TBTU=2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基四氟硼酸鈾；TCCA=三氯異氰酸；tert=第三級；TEA=三乙胺；TFA=2,2,2-三氟乙酸；THF=四氫呋喃；TLC=薄層層析法；TOFMS=飛行時間質譜儀；Xantphos=4,5-雙(二苯基膦基)-9,9-二甲基二苯并哌喃。 The following abbreviations are used in the description of the experiment: (AtaPhos) 2 PdCl 2 = bis (di-tertiary-butyl (4-dimethylaminophenyl) phosphine dichloropalladium (II); APCI = atmospheric pressure chemical free Calc.=calculated; d=day; dba=dibenzylidene-acetone; DCM=dichloromethane; DIPEA=diisopropylethylamine; DME=dimethoxyethane; DMF=N,N - dimethylformamide; DMSO = dimethyl hydrazine; dppp = 1,3-bis(diphenylphosphino)propane; EtOAc = ethyl acetate; EtOH = ethanol; EDCxHCl = 1 - [3- (two Methylamine)propyl]-3-ethylcarbodiimide hydrochloride; ES-MS=electrospray mass spectrometry (ES-MS); eq.=equivalent; h=hour(s); HOAt=1- Hydroxy-7-aza-1H-benzotriazole; KO t -Bu = potassium t-butoxide; LiHMDS = lithium bis(trimethylammonium) amination; mCPBA = m-chloroperoxybenzoic acid; min = minute (s) MeOH = methanol; MMPP = magnesium monoperoxyphthalate; MTBE = methyl-tert-butyl ether; PdCl 2 (dppf) = [1,1'-bis(diphenylphosphino)ferrocene] Dichloropalladium(II) DCM complex; Pd 2 (dba) 3 (0) = tris(dibenzylideneacetone) dipalladium (0); PE = petroleum ether; rt = room temperature; R t = residence time ; SFC = supercritical fluid chromatography; TBDPS = tert-butyl diphenyl fluorenyl; TBTU = 2 - (1H -benzotriazol-1-yl)-1,1,3,3-tetramethyltetrafluoroborate uranium; TCCA = trichloroisocyanate; tert = third stage; TEA = triethylamine; TFA = 2 , 2,2-trifluoroacetic acid; THF = tetrahydrofuran; TLC = thin layer chromatography; TOFMS = time-of-flight mass spectrometer; Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethyl Dibenzopyran.

使用以下之分析HPLC法： The following analytical HPLC method was used:

方法1： method 1:

管柱：XBridge C18(150mm x 4.6mm,5.0μm)；管柱溫度：35℃；流速：1.2mL/min； Column: XBridge C18 (150mm x 4.6mm, 5.0μm); column temperature: 35 ° C; flow rate: 1.2mL / min;

注入體積：2μl；檢測：215nm Injection volume: 2 μl; detection: 215 nm

移動相A：10mM乙酸銨水溶液；B：乙腈；移動相 Mobile phase A: 10 mM aqueous solution of ammonium acetate; B: acetonitrile; mobile phase

梯度： gradient:

方法2： Method 2:

管柱：Resteck(30mm x 2.1mm,1.8μm)；管柱溫度：50℃；儀器：Waters ACQUITY UPLC；流速：1.5mL/min；注入體積：2μl；檢測：210至400nm(DAD) Column: Resteck (30mm x 2.1mm, 1.8μm); column temperature: 50°C; instrument: Waters ACQUITY UPLC; flow rate: 1.5mL/min; injection volume: 2μl; detection: 210 to 400nm (DAD)

移動相A：0.05%甲酸的水溶液；B：乙腈；移動相 Mobile phase A: aqueous solution of 0.05% formic acid; B: acetonitrile; mobile phase

梯度： gradient:

質譜條件： Mass spectrometry conditions:

儀器：Waters之ACQUITY SQD質譜儀(單段四極柱質譜儀)游離技術：ESI； Instrument: Waters ACQUITY SQD mass spectrometer (single-stage quadrupole mass spectrometer) free technique: ESI;

質量範圍：100至800Da；極性：+Ve Mass range: 100 to 800 Da; polarity: +Ve

方法3： Method 3:

管柱：Zorbax Extend C18(4.6 x 50mm,5μm)；管柱溫度：25℃；儀器：Shimadzu Prominence；流速：1.2mL/min；注入體積：2μL；檢測：220及260nm Column: Zorbax Extend C18 (4.6 x 50mm, 5μm); column temperature: 25°C; instrument: Shimadzu Prominence; flow rate: 1.2mL/min; injection volume: 2μL; detection: 220 and 260nm

移動相A：10mM乙酸銨水溶液；移動相B：乙腈 Mobile phase A: 10 mM aqueous ammonium acetate solution; mobile phase B: acetonitrile

梯度： gradient:

方法4： Method 4:

管柱：Zorbax Extend C18(4.6 x 50mm,5μm)；管柱溫度：25℃；儀器：Shimadzu Prominence；流速：1.2mL/min；注入體積：2μL；檢測：220及260nm Column: Zorbax Extend C18 (4.6 x 50mm, 5μm); column temperature: 25°C; instrument: Shimadzu Prominence; flow rate: 1.2mL/min; injection volume: 2μL; detection: 220 and 260nm

移動相A：10mM乙酸銨水溶液；移動相B：乙腈 Mobile phase A: 10 mM aqueous ammonium acetate solution; mobile phase B: acetonitrile

梯度： gradient:

方法5： Method 5:

管柱：Zorbax Extend C18(4.6 x 50mm,5μm)；儀器：Shimadzu Prominence； Column: Zorbax Extend C18 (4.6 x 50mm, 5μm); instrument: Shimadzu Prominence;

管柱溫度：25℃；注入體積：2μl；流速：1.0mL/min；檢測：220及260nm Column temperature: 25 ° C; injection volume: 2 μl; flow rate: 1.0 mL / min; detection: 220 and 260 nm

移動相A：10mM乙酸銨水溶液；移動相B：乙腈 Mobile phase A: 10 mM aqueous ammonium acetate solution; mobile phase B: acetonitrile

梯度： gradient:

質譜條件(用於方法3至5)： Mass spectrometry conditions (for methods 3 to 5):

儀器：Applied Biosystem之API 2000 LC/MS/MS；游離技術：使用API源之ESI；去簇電壓：10-70V，取決於化合物游離；質量範圍：100-800amu； Instrument: API 2000 LC/MS/MS of Applied Biosystem; free technique: ESI using API source; de-clustered voltage: 10-70 V, depending on compound free; mass range: 100-800 amu;

掃描類型：Q1；極性：+Ve；離子源：Turbo spray；離子噴灑電壓離子噴 Scan type: Q1; polarity: +Ve; ion source: Turbo spray; ion spray voltage ion spray

灑電壓：+Ve模式之+5500；質量源溫度：200℃ Sprinkling voltage: +5500 in +Ve mode; mass source temperature: 200 °C

方法6： Method 6:

管柱：Resteck(30mm x 2.1mm,1.8μm)；管柱溫度：50℃；儀器：Waters ACQUITY UPLC；流速：1mL/min；注入體積：2μl；檢測：210至400nm(DAD) Column: Resteck (30mm x 2.1mm, 1.8μm); column temperature: 50°C; instrument: Waters ACQUITY UPLC; flow rate: 1mL/min; injection volume: 2μl; detection: 210 to 400nm (DAD)

移動相A：0.05%甲酸水溶液；B：乙腈；移動相 Mobile phase A: 0.05% aqueous formic acid; B: acetonitrile; mobile phase

梯度： gradient:

質譜條件： Mass spectrometry conditions:

儀器：ACQUITY SQD質譜儀from Waters(單段四極柱質譜儀)游離技術： Instrument: ACQUITY SQD Mass Spectrometer from Waters (Single-Phase Quadrupole Mass Spectrometer) Free Technology:

ESI；質量範圍：100至800Da；極性：+Ve ESI; mass range: 100 to 800 Da; polarity: +Ve

方法7： Method 7:

管柱：Zorbax Extend C18(4.6 x 50mm,5μm)；管柱溫度：25℃；儀器：Shimadzu Prominence；流速：1.2mL/min；注入體積：2μL；檢測：220及260nm Column: Zorbax Extend C18 (4.6 x 50mm, 5μm); column temperature: 25°C; instrument: Shimadzu Prominence; flow rate: 1.2mL/min; injection volume: 2μL; detection: 220 and 260nm

移動相A：10mM乙酸銨水溶液；移動相B：乙腈 Mobile phase A: 10 mM aqueous ammonium acetate solution; mobile phase B: acetonitrile

梯度： gradient:

質譜條件： Mass spectrometry conditions:

儀器：Applied Biosystem之API 2000 LC/MS/MS；游離技術：使用API源之ESI；去簇電壓：10-70V，取決於化合物游離；質量範圍：100-800amu； Instrument: API 2000 LC/MS/MS of Applied Biosystem; free technique: ESI using API source; de-clustered voltage: 10-70 V, depending on compound free; mass range: 100-800 amu;

掃描類型：Q1；極性：+Ve；離子源：Turbo spray；離子噴灑電壓：+Ve Scan type: Q1; polarity: +Ve; ion source: Turbo spray; ion spray voltage: +Ve

模式之+5500；質量源溫度：200℃ Mode +5500; mass source temperature: 200 ° C

實施例化合物之合成 Synthesis of Example Compounds

式(I)化合物可依據一般反應架構01至07製備。 The compounds of formula (I) can be prepared according to the general reaction schemes 01 to 07.

反應架構03 Reaction Architecture 03

實施例1：1-(5-(2-氟苯基)嘧啶-2-基)-N,N-二甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 1: 1-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N,N-dimethylspiro[porphyrin-3,3'-oxocyclobutane]-6-A Guanamine

1a)叔丁基6-溴-2-側氧吲哚啉-1-羧酸酯 1a) tert-butyl 6-bromo-2-oxooxalin-1-carboxylate

NaHCO3(23g,283mmol,2.0eq)及二-叔丁基重碳酸鹽(46mL,212mmol,1.5eq)於rt被加入至THF(300mL)之6-溴吲哚啉-2-酮(30g,141.5mmol,1.0eq)攪拌溶液中。該混合物係經回流3h，然後冷卻至rt，以水(100mL)稀釋及以EtOAc(2x 100mL)萃取。該合併之有機層以鹽水(50mL)清洗、乾燥及在減壓下蒸發。該原產物以管柱層析法[矽膠100-200目，PE/EtOAc=9：1]純化。白色固體。產量：35g,(79%)。1H NMR(400MHz,CDCl3,δ ppm)：8.03(d,J=1.2Hz,1H),7.27(dd,J=8.0,1.6Hz,1H),7.12(d,J=8.0Hz,1H),3.58(s,2H),1.64(s,9H). NaHCO 3 (23 g, 283 mmol, 2.0 eq) and di-tert-butyl bicarbonate (46 mL, 212 mmol, 1.5 eq) was added to THF (300 mL) of 6-bromo porphyrin-2-one (30 g, 141.5 mmol, 1.0 eq) was stirred in the solution. The mixture was refluxed for 3 h then EtOAc (EtOAc) The combined organic layers were washed with brine (50 mL), dried and evaporated. The original product was purified by column chromatography [100-200 mesh, EtOAc = 9:1]. White solid. Yield: 35 g, (79%). 1H NMR (400MHz, CDCl 3 , δ ppm): 8.03 (d, J = 1.2 Hz, 1H), 7.27 (dd, J = 8.0, 1.6 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 3.58 (s, 2H), 1.64 (s, 9H).

1b)叔丁基6-溴-3,3-雙(羥甲基)-2-側氧吲哚啉-1-羧酸酯 1b) tert-butyl 6-bromo-3,3-bis(hydroxymethyl)-2-oxooxalin-1-carboxylate

於rt攪拌1hTHF(200mL)中之化合物1a)(35g,112.5mmol,1.0eq)、K2CO3(46g,337mmol,3.0eq)及多聚甲醛(paraformaldehyde)(81g,2700mmol,24eq)。該反應混合物係以水(100mL)稀釋及以EtOAc(2x 200mL)萃取。該合 併之有機層以鹽水(100mL)清洗、乾燥及在減壓下蒸發。該剩留物係以管柱層析法[矽膠100-200目，PE/EtOAc=1：1]純化。白色固體。產量：40g(95%).1H NMR(400MHz,DMSO-d6,δ ppm)：7.89(s,1H),7.39(d,J=7.2Hz,2H),4.96(t,J=5.2Hz,2H),3.73-3.64(m,4H),1.56(s,9H). Compound 1a) (35 g, 112.5 mmol, 1.0 eq), K 2 CO 3 (46 g, 337 mmol, 3.0 eq) and paraformaldehyde (81 g, 2700 mmol, 24 eq) were stirred at rt. The reaction mixture was diluted with water (100 mL) andEtOAcEtOAc. The combined organic layers were washed with brine (100 mL), dried and evaporated. The residue was purified by column chromatography [100-200 mesh, EtOAc/1:1]. White solid. Yield: 40 g (95%). 1H NMR (400 MHz, DMSO-d6, δ ppm): 7.89 (s, 1H), 7.39 (d, J = 7.2 Hz, 2H), 4.96 (t, J = 5.2 Hz, 2H) ), 3.73 - 3.64 (m, 4H), 1.56 (s, 9H).

1c)6-溴-3,3-雙(羥甲基)吲哚啉-2-酮 1c) 6-bromo-3,3-bis(hydroxymethyl) porphyrin-2-one

於0℃逐滴加入TFA(50mL)至DCM(200mL)中之化合物1b)(40g,107mmol,1.0eq)攪拌溶液。溫熱該反應混合物至rt及攪拌1h。然後以冷水(2x 25mL)清洗該混合物、經Na2SO4乾燥及在減壓下蒸發提供白色固體之目標化合物，其未經純化用於次一步驟。產量：23g(79%)。1H NMR(400MHz,DMSO-d6,δ ppm)：10.1(s,1H),7.22(d,J=8.0Hz,1H),7.10(dd,J=8.0,1.6Hz,1H),6.91(d,J=1.6Hz,1H),4.73(t,J=5.2Hz,2H),3.69(d,J=10.4Hz,2H),3.56(d,J=10.4Hz,2H). A solution of compound 1b) (40 g, 107 mmol, 1.0 eq) in TFA (50 mL) EtOAc. The reaction mixture was warmed to rt and stirred for 1 h. Then with cold water (2x 25mL) and the mixture was washed, dried over Na 2 SO 4 and evaporated under reduced pressure to provide the title compound as a white solid, which was used without purification in the next step. Yield: 23 g (79%). 1H NMR (400MHz, DMSO-d6, δ ppm): 10.1 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.10 (dd, J = 8.0, 1.6 Hz, 1H), 6.91 (d, J = 1.6 Hz, 1H), 4.73 (t, J = 5.2 Hz, 2H), 3.69 (d, J = 10.4 Hz, 2H), 3.56 (d, J = 10.4 Hz, 2H).

1d)(6-溴吲哚啉-3,3-二基)二MeOH 1d) (6-bromoporphyrin-3,3-diyl) di-MeOH

將THF(50mL)中之化合物1c)(10g,36.90mmol,1.0eq)於0℃加入至保持在N2下之THF(50mL)中之LiAlH4(2.8g,73.80mmol,2.0eq)攪拌溶液。使該混合物於60℃攪拌3h，然後於rt以飽和Na2SO4溶液(20mL)稀釋及過濾。該濾液係經以EtOAc(2x 50mL)萃取及以鹽水(2x 20mL)清洗該合併有機層、乾燥及在減壓下濃縮。該剩餘物係經以戊烷清洗而純化在乾燥後提供半流質液體之最終產物。產量：5.0g(53%).1H NMR(400MHz,DMSO-d6,δ ppm)：6.89(d,J=7.6Hz,1H),6.57(dd,J=7.8,1.8Hz,1H),6.52(d,J=1.6Hz,1H),5.69(s,1H),4.67(t,J=5.2Hz,2H),3.48-3.46(m,4H),3.28(s,2H). Compound (50mL) in the THF 1c) (10g, 36.90mmol, 1.0eq) was added at 0 ℃ to remain in under the N THF 2 (LiAlH 4 (2.8g, 73.80mmol, 2.0eq 50mL) in the) was . The mixture was stirred for 3h at 60 ℃, filtered and then diluted with a saturated solution of Na 2 SO 4 (20mL) at rt. The filtrate was extracted with EtOAc (2x EtOAc)EtOAc. The residue is purified by washing with pentane to provide the final product of the semi-liquid liquid after drying. Yield: 5.0 g (53%). 1H NMR (400 MHz, DMSO-d6, δ ppm): 6.89 (d, J = 7.6 Hz, 1H), 6.57 (dd, J = 7.8, 1.8 Hz, 1H), 6.52 ( d, J = 1.6 Hz, 1H), 5.69 (s, 1H), 4.67 (t, J = 5.2 Hz, 2H), 3.48-3.46 (m, 4H), 3.28 (s, 2H).

1e)(6-溴-1-(5-(2-氟苯基)嘧啶-2-基)吲哚啉-3,3-二基)二MeOH 1e) (6-Bromo-1-(5-(2-fluorophenyl)pyrimidin-2-yl)porphyrin-3,3-diyl)diMeOH

於rt將硫酸(0.5mL)加入至正丁醇(20mL)中之化合物1d)(5.0g,19.45mmol,1.0eq)及2-氯-5-(2-氟苯基)嘧啶(4.8g,23.34mmol,1.2eq)攪拌溶液。該混合物係經回流8h、冷卻至rt、以水(20mL)稀釋及以EtOAc(2x 20mL)萃取。該合併之有機層以鹽水(2x 20mL)清洗、乾燥及在減壓下濃縮。該剩留物以管柱層析法[矽膠100-200目，PE/EtOAc=3：7]純化。半流質液體。產量：3.4g(41%).1H NMR(400MHz,DMSO-d6,δ ppm)：8.86(d,J=1.2Hz,2H),8.54(d,J=1.6Hz,1H),7.67-6.64(m,1H),7.45-7.43(m,1H),7.39-7.34(m,2H),7.23(d,J=8.0Hz,1H),6.52(dd,J=7.8,1.8Hz,1H),4.92(t,J=5.2Hz,2H),4.13(s,2H),3.64-3.56(m,4H). To a solution of compound 1d) (5.0 g, 19.45 mmol, 1.0 eq) and 2-chloro-5-(2-fluorophenyl)pyrimidine (4.8 g, sulphuric acid (0.5 mL) in n-butanol (20 mL) 23.34 mmol, 1.2 eq) was stirred. The mixture was refluxed with EtOAc (2×20 mL). The combined organic layers were washed with brine (2×20 mL), dried and evaporated. The residue was purified by column chromatography [100-200 mesh, EtOAc = 3:7]. Semi-liquid liquid. Yield: 3.4 g (41%). 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.86 (d, J = 1.2 Hz, 2H), 8.54 (d, J = 1.6 Hz, 1H), 7.67-6.64 ( m,1H), 7.45-7.43 (m, 1H), 7.39-7.34 (m, 2H), 7.23 (d, J = 8.0 Hz, 1H), 6.52 (dd, J = 7.8, 1.8 Hz, 1H), 4.92 (t, J = 5.2 Hz, 2H), 4.13 (s, 2H), 3.64 - 3.56 (m, 4H).

1f)6-溴-1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷] 1f) 6-bromo-1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]

於rt將KOt-Bu(460mg,4.102mmol,1.1eq)經30min分批加入至吡啶(30mL)中之化合物1e)(1.6g,3.729mmol,1.0eq)攪拌溶液之後加入4-甲苯磺醯氯(853mg,4.474mmol,1.2eq)及另外之KOt-Bu(502mg,4.474mmol,1.2eq)。於100℃攪拌該混合物16h，然後降溫至rt，以水(10mL)稀釋及以EtOAc(2x 10mL)萃取。該合併之有機層以1N HCl(20mL)及鹽水(20mL)清洗、乾燥及在減壓下蒸發。該原產物以管柱層析法[矽膠100-200目，PE/EtOAc=4：1]純化。白色固體。產量：600mg(62%)。再回收1.0g之起始物質化合物1e)。1H NMR(400MHz,DMSO-d6,δ ppm)：8.86(dd,J=6.8,1.2Hz,2H),8.52(dd,J=21.6,2.0Hz,1H),7.71-7.64(m,2H),7.48-7.44(m,2H),7.23(dd,J=8.0,2.0Hz,1H),7.02-7.00(m,1H),4.76(dd,J=2.8,6.0Hz,2H),4.59(s,1H),4.27(s,2H),4.02(d,J=4.4Hz,1H). KO t -Bu (460 mg, 4.102 mmol, 1.1 eq) was added in portions over 30 min to compound 1e) (1.6 g, 3.729 mmol, 1.0 eq) in pyridine (30 mL). Chlorine (853 mg, 4.474 mmol, 1.2 eq) and further KO t- Bu (502 mg, 4.474 mmol, 1.2 eq). The mixture was stirred at EtOAc (3 mL). The combined organic layers were washed with 1N EtOAc (20 mL The original product was purified by column chromatography [100-200 mesh, EtOAc = 4:1]. White solid. Yield: 600 mg (62%). Further, 1.0 g of the starting material compound 1e) was recovered. 1H NMR (400MHz, DMSO-d6, δ ppm): 8.86 (dd, J = 6.8, 1.2 Hz, 2H), 8.52 (dd, J = 21.6, 2.0 Hz, 1H), 7.71-7.64 (m, 2H), 7.48-7.44 (m, 2H), 7.23 (dd, J = 8.0, 2.0 Hz, 1H), 7.02-7.00 (m, 1H), 4.76 (dd, J = 2.8, 6.0 Hz, 2H), 4.59 (s, 1H), 4.27 (s, 2H), 4.02 (d, J = 4.4 Hz, 1H).

1g)1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-羧酸甲酯 1g) methyl 1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-carboxylate

將TEA(0.4mL,3.20mmol,2.2eq)及PdCl2(dppf)(238mg,0.291mmol,0.1eq)加入DMF/MeOH(1：1,10mL)中之1f)(600mg,1.459mmol,1.0eq)溶液，其被保持在鈍氣氣氛下之高壓釜中。以600psi一氧化碳氣體加壓該混合物及於110℃攪拌48h。然後使該反應混合物降溫至rt，以水(10mL)稀釋及以EtOAc(2 x 10mL)萃取。該合併之有機層係以鹽水(20mL)清洗、乾燥及在減壓下濃縮。該剩留物以管柱層析法[矽膠100-200目，PE/EtOAc=7：3]純化。白色固體。產量：350mg(61%).1H NMR(400MHz,DMSO-d6,δ ppm)：8.91(d,J=1.6Hz,1H),8.88(d,J=1.2Hz,2H),7.89(d,J=8.0Hz,1H),7.75(dd,J=7.8,1.4Hz,1H),7.72-7.69(m,1H),7.48-7.44(m,1H),7.39-7.33(m,2H),4.76(d,J=6.4Hz,2H),4.78(d,J=6.4Hz,2H),4.63(s,2H),3.88(s,3H). TEA (0.4 mL, 3.20 mmol, 2.2 eq) and PdCl2 (dppf) (238 mg, 0.291 mmol, 0.1 eq) was added to 1F) (600 mg, 1.459 mmol, 1.0 eq) in DMF/MeOH (1:1, 10 mL) The solution, which was kept in an autoclave under an inert atmosphere. The mixture was pressurized with 600 psi of carbon monoxide gas and stirred at 110 ° C for 48 h. The reaction mixture was then cooled to EtOAc EtOAc (EtOAc) The combined organic layers were washed with brine (20 mL), dried and evaporated. The residue was purified by column chromatography [100-200 mesh, PE/EtOAc = 7:3]. White solid. Yield: 350 mg (61%). 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.91 (d, J = 1.6 Hz, 1H), 8.88 (d, J = 1.2 Hz, 2H), 7.89 (d, J) = 8.0 Hz, 1H), 7.75 (dd, J = 7.8, 1.4 Hz, 1H), 7.72-7.69 (m, 1H), 7.48-7.44 (m, 1H), 7.39-7.33 (m, 2H), 4.76 ( d, J = 6.4 Hz, 2H), 4.78 (d, J = 6.4 Hz, 2H), 4.63 (s, 2H), 3.88 (s, 3H).

1h)1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-羧酸 1h) 1-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-carboxylic acid

MeOH/水(1：1；10mL)中之化合物1g)(400mg,1.023mmol,1.0eq)及LiOH(171mg,4.092mmol,4.0eq)係於rt攪拌16h。於真空中移除該溶劑及以水(10mL)稀釋該剩餘物並以1N HCl溶液(pH~4)酸化。該沉澱固體係被過濾掉出乾燥。白色固體。產量：230mg(60%).1H NMR(400MHz,DMSO-d6,δ ppm)：12.9(s,1H),8.91(d,J=1.2Hz,1H),8.88(d,J=1.2Hz,2H),7.85(d,J=7.6Hz,1H),7.74-7.68(m,2H),7.49-7.44(m,1H),7.43-7.32(m,2H),4.89(d,J=6.4Hz,2H),4.78(d,J=6.0Hz,2H),4.62(s,2H). Compound 1g) (400 mg, 1.023 mmol, 1.0 eq) in MeOH / EtOAc (EtOAc:EtOAc) The solvent was removed in vacuo and the residue was diluted with water (10 mL) and acidified with 1N HCl solution (pH~4). The precipitated solid was filtered off and dried. White solid. Yield: 230 mg (60%). 1H NMR (400 MHz, DMSO-d6, δ ppm): 12.9 (s, 1H), 8.91 (d, J = 1.2 Hz, 1H), 8.88 (d, J = 1.2 Hz, 2H) ), 7.85 (d, J = 7.6 Hz, 1H), 7.74 - 7.68 (m, 2H), 7.49-7.44 (m, 1H), 7.43 - 7.32 (m, 2H), 4.89 (d, J = 6.4 Hz, 2H), 4.78 (d, J = 6.0 Hz, 2H), 4.62 (s, 2H).

1i)1-(5-(2-氟苯基)嘧啶-2-基)-N,N-二甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 1i) 1-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N,N-dimethylspiro[porphyrin-3,3'-oxocyclobutane]-6-carboxamide

於rt使TEA(0.096mL,0.688mmol,2.0eq)、HOAt(23mg,0.172mmol,0.5eq) 及EDCxHCl(72mg,0.378mmol,1.1eq)加入至在N2下攪拌之DMF(10mL)中之化合物1h)(130mg,0.344mmol,1.0eq)溶液。在15min後加入二甲胺(0.25mL,0.517mmol,1.5eq)並持續攪拌16h。該反應混合物係經以鹽水(10mL)稀釋及以EtOAc(2x 10mL)萃取。該有機層係經以鹽水(2x 10mL)清洗、乾燥及在減壓下蒸發。該剩留物係經以製備型TLC純化，其係使用3% MeOH之DCM作為洗滌液。白色固體。產量：80mg(58%).Melting range：174-177℃.HPLC(method 1)：Rt=6.48min.m/z：[M+H]+=405.0.1H NMR(400MHz,DMSO-d6,δ ppm)：8.62(d,J=1.6Hz,2H),8.34(d,J=1.2Hz,1H),7.85(d,J=7.6Hz,1H),7.68-7.63(m,1H),7.47-7.43(m,1H),7.39-7.32(m,2H),7.10(d,J=1.2Hz,1H),4.88(d,J=6.4Hz,2H),4.78(d,J=6.0Hz,2H),4.6(s,2H),2.98(d,J=26.0Hz,6H). So that at rt TEA (0.096mL, 0.688mmol, 2.0eq) , HOAt (23mg, 0.172mmol, 0.5eq) and EDCxHCl (72mg, 0.378mmol, 1.1eq) was added to a stirred of N 2 in the next DMF (10mL) in the Compound 1h) (130 mg, 0.344 mmol, 1.0 eq) solution. After 15 min dimethylamine (0.25 mL, 0.517 mmol, 1.5 eq) was added and stirring was continued for 16 h. The reaction mixture was diluted with brine (10 mL) andEtOAcEtOAc. The organic layer was washed with brine (2×10 mL), dried and evaporated. The residue was purified by preparative TLC using 3% MeOH in DCM. White solid. Yield: 80 mg (58%). Melting range: 174-177 ° C. HPLC (method 1): R t =6.48 min.m/z: [M+H] + =405.0.1H NMR (400 MHz, DMSO-d6, δ ppm): 8.62 (d, J = 1.6 Hz, 2H), 8.34 (d, J = 1.2 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.68-7.63 (m, 1H), 7.47 -7.43 (m, 1H), 7.39-7.32 (m, 2H), 7.10 (d, J = 1.2 Hz, 1H), 4.88 (d, J = 6.4 Hz, 2H), 4.78 (d, J = 6.0 Hz, 2H), 4.6 (s, 2H), 2.98 (d, J = 26.0 Hz, 6H).

實施例2：(1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 Example 2: (1-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)(morpholinyl)- ketone

依據合成規程(protocol)1i)由化合物1h)(100mg,0.265mmol,1.0eq)製備。白色固體。產量：70mg(59%).Melting range：240-243℃.HPLC(方法1)：Rt=6.33min.m/z：[M+H]+=447.0.1H NMR(300MHz,DMSO-d6,δ ppm)：8.86(s,2H),8.38(s,1H),7.80(d,J=7.8Hz,1H),7.69-7.63(m,1H),7.47-7.32(m,3H),7.10(d,J=7.8Hz,1H),4.88(d,J=6.3Hz,2H),4.78(d,J=5.7Hz,2H), 4.61(s,2H),3.61-3.38(m,8H). Prepared according to the protocol 1i) from compound 1h) (100 mg, 0.265 mmol, 1.0 eq). White solid. Yield: 70 mg (59%). Melting range: 240-243 ° C. HPLC (method 1): R t = 6.33 min. m/z: [M+H] + =447.0.1H NMR (300 MHz, DMSO-d6, δ ppm): 8.86 (s, 2H), 8.38 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.69-7.63 (m, 1H), 7.47-7.32 (m, 3H), 7.10 ( d, J = 7.8 Hz, 1H), 4.88 (d, J = 6.3 Hz, 2H), 4.78 (d, J = 5.7 Hz, 2H), 4.61 (s, 2H), 3.61-3.38 (m, 8H).

中間物1：甲基1-(5-溴嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-羧酸酯(Int-1) Intermediate 1: methyl 1-(5-bromopyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-carboxylate (Int-1)

Int-1a)6'-溴-2,2-二甲基螺[[1,3]二噁烷-5,3'-吲哚啉]-2'-酮 Int-1a) 6'-bromo-2,2-dimethylspiro[[1,3]dioxane-5,3'-carboline]-2'-one

無水DMF(1L)中之6-溴-3,3-雙(羥甲基)吲哚啉-2-酮(化合物1c,78g,287mmol)、2,2-二甲氧基-丙烷(106.6mL,860.3mmol)及4-甲苯磺醯氯單水合物(4.4g)溶液係於80℃經攪拌6h。該反應混合物係被降溫至rt、倒在冰水上及以MTBE(3 x 1L)萃取。該合併之有機層係經以飽和NaHCO3溶液清洗、經Na2SO4乾燥及濃縮。白色固體。產量：70g(78%).HPLC(方法3)：Rt=3.17min.,m/z：[M+H]+=314(MW calc.312.16). 6-Bromo-3,3-bis(hydroxymethyl)porphyrin-2-one (Compound 1c, 78 g, 287 mmol), 2,2-dimethoxy-propane (106.6 mL) in anhydrous DMF (1 L) , 860.3 mmol) and 4-toluenesulfonium chloride monohydrate (4.4 g) were stirred at 80 ° C for 6 h. The reaction mixture was cooled to rt, poured onto ice water and extracted with MTBE (3 x 1 L). The combined organic layers of the system was washed with saturated NaHCO 3 solution, dried over Na 2 SO 4 dried and concentrated. White solid. Yield: 70 g (78%). HPLC (Method 3): R t = 3.17 min., m/z: [M+H] + = 314 (MW calc. 312.16).

Int-1b)6'-溴-2,2-二甲基螺[[1,3]二噁烷-5,3'-吲哚啉] Int-1b) 6'-bromo-2,2-dimethylspiro[[1,3]dioxane-5,3'-carboline]

將Red-Al(66mL,224.3mmol)於rt逐滴加入無水甲苯(2.4L)中之Int-1a(35g,112.17mmol)溶液。然後使該反應混合物於80℃攪拌1.5h及以2N NaOH溶液於0℃淬滅。該水層係被分離及經以EtOAc(3 x 500mL)萃取。該合併之有機層係經以鹽水清洗、經Na2SO4乾燥及蒸發。淺褐色固體。產量：30g(94%).HPLC(方法3)：Rt=3.43min.,m/z：[M+H]+=300.1(MW calc.298.18). Red-Al (66 mL, 224.3 mmol) was added dropwise to a solution of <RTI ID=0.0>> The reaction mixture was then stirred at 80 <0>C for 1.5 h and quenched with EtOAc EtOAc. The aqueous layer was separated and extracted with EtOAc (3×500 mL). The combined organic layers of the system was washed with brine, dried over Na 2 SO 4 and evaporated. Light brown solid. Yield: 30 g (94%). HPLC (method 3): R t = 3.43 min., m/z: [M+H] + = 300.1 (MW calc. 298.18).

Int-1c)2,2-二甲基螺[[1,3]二噁烷-5,3'-吲哚啉]-6'-羧酸甲酯 Int-1c) Methyl 2,2-dimethylspiro[[1,3]dioxane-5,3'-carboline]-6'-carboxylate

於rt將PdCl2(dppf)加入至MeOH/DMF(5：1,480mL)中之Int-1b(32g,107.38mmol)及TEA(33mL,236.2mmol)溶液，其係被保持在Ar之Parr高壓釜中。然後使該反應混合物在CO氣氛下220psi壓力於110℃攪拌16h。使該高壓釜降溫至rt且使該混合物經矽藻土栓過濾。該過濾器係經以MeOH清洗及濃縮該濾液。該剩餘物係經以EtOAc稀釋、以水及鹽水清洗並乾燥。在減壓下移除該溶劑且使該剩留物以快速管柱層析法[矽石；己烷與6-15%丙酮]純化。白色固體。產量：21.5g(72%).HPLC(方法3)：Rt=3.12min.,m/z：[M+H]+=278.1(MW calc.277.32). PdCl 2 (dppf) was added to a solution of Int-1b (32 g, 107.38 mmol) and TEA (33 mL, 236.2 mmol) in MeOH/DMF (5:1, 480 mL) at rt. in. The reaction mixture was then stirred at 110 ° C for 16 h under a CO atmosphere at 220 psi. The autoclave was cooled to rt and the mixture was filtered through a pad of Celite. The filter was washed with MeOH and concentrated. The residue was diluted with EtOAc, washed with water and brine and dried. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography [EtOAc] White solid. Yield: 21.5 g (72%). HPLC (Method 3): R t = 3.12 min., m/z: [M+H] + =278.1 (MW calc.277.32).

Int-1d)3,3-雙(羥甲基)吲哚啉-6-羧酸甲酯 Int-1d) 3,3-bis(hydroxymethyl)porphyrin-6-carboxylic acid methyl ester

於rt將2N HCl溶液(349mL,698.5mmol)加入至THF(215mL)中之Int-1c(21.5g,77.61mmol)及於此溫度攪拌該混合物3h。該反應混合物係經濃縮、以飽和NaHCO3溶液中和及以EtOAc(10 x 250mL)萃取。該合併之有機層係經Na2SO4乾燥及蒸發。淺黃色固體。產量：13.5g(73%)。HPLC(方法3)：Rt=1.68min.,m/z：[M+H]+=238.1(MW calc.237.25). 2N HCl solution (349 mL, 698.5 mmol) was added to EtOAc (EtOAc (EtOAc) The reaction mixture was concentrated lines, and extracted with saturated NaHCO 3 solution to the neutralization and EtOAc (10 x 250mL). The combined organic layers were dried over Na 2 SO 4 and evaporated. Light yellow solid. Yield: 13.5 g (73%). HPLC (Method 3): R t = 1.68 min., m/z: [M+H] + = 238.1 (MW calc. 237.25).

Int-1e)1-(5-溴嘧啶-2-基)-3,3-雙(羥甲基)吲哚啉-6-羧酸甲酯 Int-1e) methyl 1-(5-bromopyrimidin-2-yl)-3,3-bis(hydroxymethyl)porphyrin-6-carboxylate

正丁醇(82mL)中之Int-1d(3.5g,14.76mmol)、5-溴-2-氯-嘧啶(4.28g,22.15mmol)及DIPEA(6.1mL,36.9mmol)係於130℃在密封管中攪拌36h。該反應混合物係被降溫至rt及該沉澱固體係被過濾出且以二乙醚及己烷之摻合物(blend)清洗。白色固體。產量：3.6g(61%).HPLC(方法3)：Rt=2.94min.,m/z：[M+H]+=396(MW calc.394.22). Int-1d (3.5 g, 14.76 mmol), 5-bromo-2-chloro-pyrimidine (4.28 g, 22.15 mmol) and DIPEA (6.1 mL, 36.9 mmol) in n-butanol (82 mL) were sealed at 130 ° C Stir in the tube for 36 h. The reaction mixture was cooled to rt and the precipitated solid was filtered and washed with a mixture of diethyl ether and hexane. White solid. Yield: 3.6 g (61%). HPLC (method 3): R t = 2.94 min., m/z: [M+H] + = 396 (MW calc. 394.22).

Int-1f)1-(5-溴嘧啶-2-基)-3-(羥甲基)-3-((甲苯磺醯氧基)甲基)吲哚啉-6-羧 酸甲酯 Int-1f) 1-(5-Bromopyrimidin-2-yl)-3-(hydroxymethyl)-3-((toluenesulfonyloxy)methyl)porphyrin-6-carboxylate Methyl ester

於-50℃經30min期間將LiHMDS(12.69mL,12.69mmol)逐滴加入至無水THF(500mL)中之Int-1e(5.0g,12.69mmol)溶液。於此溫度使該反應混合物攪拌30min之後緩慢加入THF(100mL)中之4-甲苯磺醯氯(2.41g,12.69mmol)。於rt使該反應混合物係經進一步攪拌1.5h然後以飽和NH4Cl溶液淬滅及以EtOAc(3 x 250mL)萃取。該合併之有機層係經Na2SO4乾燥且使該原產物以快速管柱層析法[矽石；己烷與10-20% EtOAc]純化。白色固體。產量：4g(57%).HPLC(方法3)：Rt=3.63min.,m/z：[M+H]+ 548.1(MW calc.548.41). LiHMDS (12.69 mL, 12.69 mmol) was added dropwise to a solution of Int-1e (5.0 g, 12.69 mmol) in anhydrous THF (500 mL) over 30 min. After stirring the reaction mixture for 30 min at this temperature, 4-toluenesulfonium chloride (2.41 g, 12.69 mmol) in THF (100 mL). At rt The reaction mixture was further stirred for 1.5h system then extracted with saturated NH 4 Cl solution and quenched in EtOAc (3 x 250mL). The combined organic layer system of 2 SO 4 dried, and that the original product was flash column chromatography over of Na [Silica; hexane with 10-20% EtOAc] purification. White solid. Yield: 4 g (57%). HPLC (Method 3): R t = 3.63 min., m/z: [M+H] + 548.1 (MW calc.548.41).

Int-1g)1-(5-溴嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-羧酸甲酯 Int-1g) 1-(5-bromopyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-carboxylic acid methyl ester

MeOH(288mL)中之Int-1e(8.0g,14.59mmol)及K2CO3(4.0g,29.19mmol)係於80℃經攪拌16h。該溶劑係經蒸發且使該剩餘物經以水(50mL)稀釋及以DCM(3x 300mL)萃取。該合併之有機層係經乾燥，在減壓下移除該溶劑且該原產物係經以乙醚研磨以提供白色固體之目標化合物。該反應混合物之水相係經以NaHSO4酸化並使出現之沉澱物被過濾出及乾燥藉此產出1.1g之1-(5-溴嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-羧酸。產量：3.7g甲酯(67%)。HPLC(方法3)：Rt=3.56min.,m/z：[M+H]+ 378.0(MW calc.376.20). MeOH Int-1e (8.0g, 14.59mmol ) (288mL) and in the K 2 CO 3 (4.0g, 29.19mmol ) based at 80 deg.] C stirred 16h. The solvent was evaporated and the residue was crystallised eluted with water (50 <RTIgt; The combined organic layers were dried and the solvent was removed <RTI ID=0.0>: </RTI><RTIgt; The aqueous-based phase of the reaction mixture was acidified with NaHSO 4 and appears to the precipitate was filtered off and dried thereby yield 1.1g of 1- (5-bromo-2-yl) spiro [indoline -3, 3'-oxocyclobutane]-6-carboxylic acid. Yield: 3.7 g of methyl ester (67%). HPLC (Method 3): R t =3.56 min., m/z: [M+H] + 378.0 (MW calc.376.20).

實施例3：N-(2-胺-2-側氧乙基)-1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 3: N-(2-Amine-2-oxoethyl)-1-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)-N-methylspiro[吲Porphyrin-3,3'-oxycyclobutane]-6-carboxamide

3a)1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-羧酸甲酯 3a) Methyl 1-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-carboxylate

K2CO3(0.33g,2.4mmol)及(AtaPhos)2PdCl2(56mg,0.08mmol)係保持在Ar中被加入至戊醇(8.0mL)及水(0.8mL)中之Int-1(0.30g,0.80mmol)及2-氟-5-甲基苯基硼酸(0.25g,1.60mmol)溶液中。該得到之混合物係於90℃攪拌5h然後降溫並經矽藻土栓過濾。該濾液係被濃縮且該剩餘物係經以快速管柱層析法[矽膠；DCM與3% MeOH]純化。淺黃色固體。產量：0.15g(46%)HPLC(方法3)：Rt=3.89min.,m/z：[M+H]+=406.1(MW calc.405.42) K 2 CO 3 (0.33 g, 2.4 mmol) and (AtaPhos) 2 PdCl 2 (56 mg, 0.08 mmol) were held in Ar to be added to pentanol (8.0 mL) and water (0.8 mL) of Int-1 ( 0.30 g, 0.80 mmol) and 2-fluoro-5-methylphenylboronic acid (0.25 g, 1.60 mmol). The resulting mixture was stirred at 90 ° C for 5 h and then cooled and filtered through a plug of diatomaceous earth. The filtrate was concentrated and the residue was purified by flash column chromatography [EtOAc EtOAc EtOAc Light yellow solid. Yield: 0.15 g (46%) HPLC (method 3): R t = 3.89 min., m/z: [M+H] + = 406.1 (MW calc. 405.42)

3b)1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-羧酸 3b) 1-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-carboxylic acid

於0℃將LiOH．H2O(62mg,1.48mmol)加入至THF、MeOH及水(1：1：1,6mL)摻合物中之化合物3a)(0.15g,0.37mmol)溶液中。該反應混合物係先於rt攪拌16h然後於60℃攪拌2h。該溶劑係被蒸發且該固體剩餘物係經以飽和KHSO4溶液酸化並經燒結漏斗(sintered funnel)過濾。剩餘之溶劑係藉由以甲苯重覆共蒸餾移除。白色固體。產量：0.14g(96%).HPLC(方法2)：Rt=2.77min,m/z：[M+H]+=392.36(MW calc.391.40) LiOH at 0 °C. H 2 O (62 mg, 1.48 mmol) was added to a solution of compound 3a) (0.15 g, 0.37 mmol) in THF, MeOH and water (1:1:1, 6 mL). The reaction mixture was stirred for 16 h before rt and then at 60 ° C for 2 h. The solvent was evaporated and the solid line is based residue was acidified with saturated KHSO 4 solution and filtered through a sintered funnel (sintered funnel). The remaining solvent was removed by repeated co-distillation with toluene. White solid. Yield: 0.14 g (96%). HPLC (Method 2): R t = 2.77 min, m/z: [M+H] + = 392.36 (MW calc.391.40)

3c)N-(2-胺-2-側氧乙基)-1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 3c) N-(2-Amino-2-oxoethyl)-1-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)-N-methylspiro[porphyrin -3,3'-oxocyclobutane]-6-carboxamide

TBTU(0.14g,0.423mmol)、N-甲基嗎啉(0.08mL,0.72mmol)及2-甲基胺- 乙醯胺鹽酸鹽(69mg,0.54mmol)係於0°C被加入至無水DMF(4mL)中之化合物3b)(0.14g,0.36mmol)溶液中且使該反應混合物係於rt攪拌16h。該混合物係經以冰水淬滅及使該沉澱固體濾出並以水清洗。該固以物質係被溶解在DCM中及以快速管柱層析法[矽膠；DCM與3% MeOH]純化之後在DCM/己烷(1：2)中研磨。白色固體。產量：75mg(45%).HPLC(方法2)：Rt=1.61min.,m/z：[M+H]+=462.1(MW calc.461.49).1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：8.80(s,2H),8.40(s,1H),7.78(d,1H,J=7.5Hz),7.44(d,1H,J=7.3Hz),7.23-7.14(m,3H),6.91(s,2H),4.89(d,2H,J=5.9Hz),4.82(d,2H,J=6.0Hz),4.61(s,2H),3.97(s,2H),2.99(s,3H),2.37(s,3H). TBTU (0.14g, 0.423mmol), N-methylmorpholine (0.08mL, 0.72mmol) and 2-methylamine-acetamide hydrochloride (69mg, 0.54mmol) were added to anhydrous at 0 ° C A solution of compound 3b) (0.14 g, 0.36 mmol) in DMF (4 mL). The mixture was quenched with ice water and the precipitated solid was filtered and washed with water. The solids were dissolved in DCM and purified by flash column chromatography [EtOAc, DCM & EtOAc] White solid. Yield: 75 mg (45%). HPLC (method 2): R t = 1.61 min., m/z: [M+H] + = 462.1 (MW calc.461.49).1H NMR (400MHz, DMSO-d6,100 °C, δ ppm): 8.80 (s, 2H), 8.40 (s, 1H), 7.78 (d, 1H, J = 7.5 Hz), 7.44 (d, 1H, J = 7.3 Hz), 7.23 - 7.14 (m, 3H), 6.91 (s, 2H), 4.89 (d, 2H, J = 5.9 Hz), 4.82 (d, 2H, J = 6.0 Hz), 4.61 (s, 2H), 3.97 (s, 2H), 2.99 ( s, 3H), 2.37 (s, 3H).

實施例4至7類似於合成實施例3由Int-1經三個步驟製備。 Examples 4 to 7 were prepared analogously to Synthesis Example 3 from Int-1 in three steps.

實施例4：嗎啉基(1-(5-苯基嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)甲酮 Example 4: Morpholinyl (1-(5-phenylpyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)methanone

白色固體。產量：55mg.HPLC(方法2)：Rt=1.68min.,m/z：[M+H]+=429.1(MW calc.428.48).1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：9.0(s,2H),8.39(s,1H),7.81-7.75(m,3H),7.52-7.48(m,2H),7.41-7.38(m,1H),7.14(d,1H,J=7.7Hz),4.89(d,2H,J=6.0Hz),4.80(d,2H,J=6.0Hz),4.61(s,2H),3.63-3.39(m,8H). White solid. Yield: 55 mg. HPLC (Method 2): R t = 1.68 min., m/z: [M+H] + = 429.1 (MW calc. 428.48). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm ): 9.0 (s, 2H), 8.39 (s, 1H), 7.81-7.75 (m, 3H), 7.52-7.48 (m, 2H), 7.41-7.38 (m, 1H), 7.14 (d, 1H, J) = 7.7 Hz), 4.89 (d, 2H, J = 6.0 Hz), 4.80 (d, 2H, J = 6.0 Hz), 4.61 (s, 2H), 3.63 - 3.39 (m, 8H).

實施例5：N-(2-胺-2-側氧乙基)-1-(5-(2-氟-5-甲氧基苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 5: N-(2-Amino-2-oxoethyl)-1-(5-(2-fluoro-5-methoxyphenyl)pyrimidin-2-yl)-N-methylspiro[ Porphyrin-3,3'-oxycyclobutane]-6-carboxamide

白色固體。產量：90mg.HPLC(方法2)：Rt=1.56min.,m/z：[M+H]+=478.1(MW calc.477.49).1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：8.83(s,2H),8.40(s,1H),7.79(d,1H,J=7.6Hz),7.26-7.21(m,1H),7.18-7.15(m,2H),7.0-6.92(m,3H),4.89(d,2H,J=6.0Hz),4.82(d,2H,J=6.0Hz),4.62(s,2H),3.97(s,2H),3.84(s,3H),2.99(s,3H). White solid. Yield: 90 mg. HPLC (Method 2): R t = 1.56 min., m/z: [M+H] + = 478.1 (MW calc. 477.49). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm ): 8.83 (s, 2H), 8.40 (s, 1H), 7.79 (d, 1H, J = 7.6 Hz), 7.26-7.21 (m, 1H), 7.18-7.15 (m, 2H), 7.0-6.92 ( m,3H), 4.89 (d, 2H, J = 6.0 Hz), 4.82 (d, 2H, J = 6.0 Hz), 4.62 (s, 2H), 3.97 (s, 2H), 3.84 (s, 3H), 2.99(s,3H).

實施例6：N-(2-胺-2-側氧乙基)-N-甲基-1-(5-苯基嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 6: N-(2-Amine-2-oxoethyl)-N-methyl-1-(5-phenylpyrimidin-2-yl)spiro[porphyrin-3,3'-oxygen ring Butane]-6-formamide

白色固體。產量：70mg.HPLC(方法2)：Rt=1.53min.,m/z：[M+H]+=430.1(MW calc.429.47).1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：8.93(s,2H),8.41(s,1H),7.78-7.71(m,3H),7.51-7.48(m,2H),7.41(d,1H,J=7.6Hz), 7.15(d,1H,J=7.1Hz),6.93(bs,2H),4.89(d,2H,J=5.8Hz),4.82(d,2H,J=5.9Hz),4.61(s,2H),3.98(s,2H),3.0(s,3H). White solid. Yield: 70 mg. HPLC (Method 2): R t = 1.53 min., m/z: [M+H] + = 430.1 (MW calc. 429.47). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm ): 8.93 (s, 2H), 8.41 (s, 1H), 7.78-7.71 (m, 3H), 7.51-7.48 (m, 2H), 7.41 (d, 1H, J = 7.6 Hz), 7.15 (d, 1H, J = 7.1 Hz), 6.93 (bs, 2H), 4.89 (d, 2H, J = 5.8 Hz), 4.82 (d, 2H, J = 5.9 Hz), 4.61 (s, 2H), 3.98 (s, 2H), 3.0 (s, 3H).

實施例7：N-(2-胺-2-側氧乙基)-1-(5-(5-乙基-2-氟苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 7: N-(2-Amine-2-oxoethyl)-1-(5-(5-ethyl-2-fluorophenyl)pyrimidin-2-yl)-N-methylspiro[吲Porphyrin-3,3'-oxycyclobutane]-6-carboxamide

白色固體。產量：90mg.HPLC(方法3)：Rt=3.11min.,m/z：[M+H]+=476.2(MW calc.475.51).1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：8.82(s,2H),8.41(s,1H),7.78(d,1H,J=7.5Hz),7.46(d,1H,J=7.5Hz),7.26-7.15(m,3H),6.89(s,2H),4.89(d,2H,J=5.7Hz),4.82(d,2H,J=5.7Hz),4.62(s,2H),3.98(s,2H),2.99(s,3H),2.72-2.67(m,2H),1.28-1.24(m,3H). White solid. Yield: 90 mg. HPLC (method 3): R t = 3.11 min., m/z: [M+H] + = 476.2 (MW calc. 475.51). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm ): 8.82 (s, 2H), 8.41 (s, 1H), 7.78 (d, 1H, J = 7.5 Hz), 7.46 (d, 1H, J = 7.5 Hz), 7.26-7.15 (m, 3H), 6.89 (s, 2H), 4.89 (d, 2H, J = 5.7 Hz), 4.82 (d, 2H, J = 5.7 Hz), 4.62 (s, 2H), 3.98 (s, 2H), 2.99 (s, 3H) , 2.72-2.67 (m, 2H), 1.28-1.24 (m, 3H).

實施例8：嗎啉基(1-(5-(吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)甲酮 Example 8: Morpholinyl (1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)methanone

8a)1-(5-溴嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-羧酸 8a) 1-(5-Bromopyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-carboxylic acid

LiOH．H2O(98mg,2.34mmol)係於0℃被加入至THF/水(1：1,10mL)混合物中之Int-1(0.22g,0.58mmol)溶液中及使該反應混合物於rt攪拌16h。該反應混合物係被濃縮且使該固體剩餘物以飽和KHSO4溶液酸化並經燒結漏斗過濾。剩餘溶劑係經以甲苯共蒸餾移除。白色固體。產量：0.20g(95%).HPLC(方法3)：Rt=2.18min.,m/z：[M+H]+=362.2/364.2(MW calc.362.18) LiOH. H 2 O (98 mg, 2.34 mmol) was added to a solution of EtOAc / EtOAc (EtOAc (EtOAc) . The reaction mixture was concentrated and the train is the solid residue was acidified with saturated KHSO 4 solution and filtered through a sintered funnel. The remaining solvent was removed by co-distillation with toluene. White solid. Yield: 0.20 g (95%). HPLC (Method 3): R t = 2.18 min., m/z: [M+H] + = 362.2/364.2 (MW calc. 362.18)

8b)(1-(5-溴嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 8b) (1-(5-Bromopyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)(morpholinyl)methanone

TBTU(0.21g,0.66mmol)、N-甲基嗎啉(0.12mL,1.10mmol)及嗎啉(0.063mL,0.72mmol)係於0℃被加入至無水DMF(3.5mL)中之化合物8a)(0.20g,0.55mmol)溶液中。該反應混合物係於rt攪拌16h然後以冰水淬滅。使沉澱物濾出且以水清洗。剩餘溶劑係經以甲苯共沸蒸餾移除。白色固體。產量：0.17g(72%).HPLC(方法3)：Rt=2.97min.,m/z：[M+H]+=431.2/433.2(MW calc.431.28) TBTU (0.21 g, 0.66 mmol), N-methylmorpholine (0.12 mL, 1.10 mmol) and morpholine (0.063 mL, 0.72 mmol) were added to compound 8a in anhydrous DMF (3.5 mL) at 0 ° C) (0.20 g, 0.55 mmol) in solution. The reaction mixture was stirred at rt for 16 h then quenched with ice water. The precipitate was filtered off and washed with water. The remaining solvent was removed by azeotropic distillation with toluene. White solid. Yield: 0.17 g (72%). HPLC (Method 3): R t = 2.97 min., m/z: [M+H] + =431.2/433.2 (MW calc.431.28)

8c)嗎啉基(1-(5-(吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)甲酮 8c) morpholinyl (1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)methanone

PdCl2(dppf)(24mg,0.029mmol)係被加入至無水二噁烷(10mL)中之化合物8b)(0.25g,0.58mmol)、雙(頻哪醇)二硼(0.24g,0.93mmol)及乙酸鉀(0.17g,1.74mmol)溶液，其係於rt在Ar中攪拌。在110℃下攪拌1.5h後，2-溴-吡啶(0.085mL,0.87mmol)、K2CO3水溶液(2M,0.9mL)及肆(三苯基膦)鈀(0)(33.5mg,0.029mmol)係被依次加入。使該反應混合物於100℃進一步攪拌4h，降溫至rt並經燒結漏斗過濾。該濾液係被濃縮且使該剩餘物經以快速管柱層析法[矽石；DCM與2% MeOH]純化之後以DCM/己烷(1：2)研磨。白色固體。產量：80mg(32%).HPLC(方法3)：Rt=2.88min.,m/z：[M+H]+ =430.3(MW calc.429.47).1H NMR(400MHz,DMSO-d6,δ ppm)：9.31(s,2H),8.68(d,1H,J=3.3Hz),8.42(s,1H),8.04(d,1H,J=8.0Hz),7.93-7.89(m,1H),7.82(d,1H,J=7.5Hz),7.38-7.36(m,1H),7.16(d,1H,J=7.5Hz),4.89(d,2H,J=5.9Hz),4.79(d,2H,J=5.9Hz),4.63(s,2H),3.63-3.42(m,8H). PdCl 2 (dppf) (24 mg, 0.029 mmol) was added as a compound 8b) (0.25 g, 0.58 mmol), bis (pinacol) diboron (0.24 g, 0.93 mmol) in anhydrous dioxane (10 mL) And a solution of potassium acetate (0.17 g, 1.74 mmol) which was stirred at rt in Ar. After stirring at 110 ° C for 1.5 h, 2-bromo-pyridine (0.085 mL, 0.87 mmol), aqueous K 2 CO 3 (2M, 0.9 mL) and bis(triphenylphosphine) palladium (0) (33.5 mg, 0.029) Methyl) are added sequentially. The reaction mixture was further stirred at 100 ° C for 4 h, cooled to rt and filtered th The filtrate was concentrated and the residue was purified by flash column chromatography eluting with EtOAc EtOAc (EtOAc) White solid. Yield: 80 mg (32%). HPLC (method 3): R t = 2.88 min., m/z: [M+H] + =430.3 (MW calc. 429.47).1H NMR (400 MHz, DMSO-d6, δ Ppm): 9.31 (s, 2H), 8.68 (d, 1H, J = 3.3 Hz), 8.42 (s, 1H), 8.04 (d, 1H, J = 8.0 Hz), 7.93 - 7.89 (m, 1H), 7.82 (d, 1H, J = 7.5 Hz), 7.38-7.36 (m, 1H), 7.16 (d, 1H, J = 7.5 Hz), 4.89 (d, 2H, J = 5.9 Hz), 4.79 (d, 2H) , J = 5.9 Hz), 4.63 (s, 2H), 3.63 - 3.42 (m, 8H).

實施例9及10係以類似於合成實施例8之方式製備。 Examples 9 and 10 were prepared in a manner similar to Synthesis Example 8. 實施例9：(1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 Example 9: (1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl) (? Phenyl) ketone

白色固體。產量：60mg.HPLC(方法3)：Rt=2.92min.,m/z：[M+H]+=444.1(MW calc.443.50).1H NMR(400MHz,DMSO-d6,δ ppm)：9.29(s,2H),8.53(d,1H,J=4.9Hz),8.41(s,1H)，7.88(s,1H),7.82(d,1H,J=7.5Hz),7.21(d,1H,J=4.4Hz),7.16(d,1H,J=7.7Hz),4.89(d,2H,J=6.0Hz),4.79(d,2H,J=6.1Hz),4.62(s,2H),3.64(s,8H),2.39(s,3H). White solid. Yield: 60 mg. HPLC (Method 3): R t = 2.92 min., m/z: [M+H] + = 444.1 (MW calc.443.50).1H NMR (400 MHz, DMSO-d6, δ ppm): 9.29 (s, 2H), 8.53 (d, 1H, J = 4.9 Hz), 8.41 (s, 1H), 7.88 (s, 1H), 7.82 (d, 1H, J = 7.5 Hz), 7.21 (d, 1H, J = 4.4 Hz), 7.16 (d, 1H, J = 7.7 Hz), 4.89 (d, 2H, J = 6.0 Hz), 4.79 (d, 2H, J = 6.1 Hz), 4.62 (s, 2H), 3.64 (s, 8H), 2.39 (s, 3H).

實施例10：(1-(5-(4-甲氧基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 Example 10: (1-(5-(4-Methoxypyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl) ( Morpholine) ketone

白色固體。產量：80mg.HPLC(方法2)：Rt=1.42min.,m/z：[M+H]+=460.1(MW calc.459.50).1H NMR(400MHz,DMSO-d6,δ ppm)：9.31(s,2H),8.49(d,1H,J=5.6Hz),8.42(s,1H),7.82(d,1H,J=7.6Hz),7.59(s,1H),7.16(d,1H,J=7.7Hz),6.97(d,1H,J=3.5Hz),4.89(d,2H,J=6.1Hz),4.79(d,2H,J=6.0Hz),4.63(s,2H),3.92(s,3H),3.63-3.40(m,8H). White solid. Yield: 80 mg. HPLC (Method 2): R t = 1.42 min., m/z: [M+H] + = 460.1 (MW calc.459.50).1H NMR (400 MHz, DMSO-d6, δ ppm): 9.31 (s, 2H), 8.49 (d, 1H, J = 5.6 Hz), 8.42 (s, 1H), 7.82 (d, 1H, J = 7.6 Hz), 7.59 (s, 1H), 7.16 (d, 1H, J = 7.7 Hz), 6.97 (d, 1H, J = 3.5 Hz), 4.89 (d, 2H, J = 6.1 Hz), 4.79 (d, 2H, J = 6.0 Hz), 4.63 (s, 2H), 3.92 (s, 3H), 3.63-3.40 (m, 8H).

中間物2：1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-羧酸(Int-2) Intermediate 2: 1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-carboxylic acid (Int-2)

Int-2a)(6-溴吲哚啉-3,3-二基)二甲醇 Int-2a)(6-bromoporphyrin-3,3-diyl)dimethanol

硼烷二甲硫醚複合物(Borane dimethyl sulfide complex)溶液(10.1M in THF,17.4mL,183.7mmol)係經20min期間於0℃加入至無水THF(110mL)中之6-溴-3,3-雙(羥甲基)吲哚啉-2-酮(化合物1c,10g,36.75mmol)懸浮液。該反應混合物係於rt攪拌隔夜，然後慢慢地加入碎冰淬滅之後加入濃縮之HCl(10.3mL)。該溶液係被溫熱至rt，攪拌15min然後在減壓下被濃縮。MeOH係被重覆地(4x)加入至該剩餘物中並在真空中移除。白色固體。產量：9g (95%).HPLC(方法2)：Rt=0.75min.,m/z：[M+H]+=260.0(MW calc.258.11) Borane dimethyl sulfide complex solution (10.1 M in THF, 17.4 mL, 183.7 mmol) was added to 6-bromo-3,3 in anhydrous THF (110 mL) at 0 ° C over 20 min. a suspension of bis(hydroxymethyl) porphyrin-2-one (compound 1c, 10 g, 36.75 mmol). The reaction mixture was stirred at rt overnight and then quenched slowly with iced ice and concentrated HCl (10.3 mL). The solution was warmed to rt, stirred for 15 min and then concentrated under reduced pressure. MeOH was added (4x) to the residue and removed in vacuo. White solid. Yield: 9 g (95%). HPLC (Method 2): R t = 0.75 min., m/z: [M+H] + = 260.0 (MW calc.258.11)

Int-2b)(6-溴-1-(5-(2-氟苯基)嘧啶-2-基)吲哚啉-3,3-二基)二MeOH Int-2b)(6-bromo-1-(5-(2-fluorophenyl)pyrimidin-2-yl)porphyrin-3,3-diyl)diMeOH

硫酸(0.65mL)及2-氯-5-(2-氟-苯基)-嘧啶(5.5g,26.5mmol)係於rt加入至正丁醇(52mL)中之Int-2a(6.5g,22.13mmol)懸浮液。該反應混合物係於120℃攪拌18h然後降溫至rt，以水稀釋並以EtOAc(3x 200mL)萃取。使該合併之有機層經Na2SO4乾燥及濃縮。使該剩留物經以快速管柱層析法[矽石，EtOAc/己烷=1：1]純化。白色固體。產量：2.3g(24%).HPLC(方法3)：Rt=3.55min.,m/z：[M+H]+=432.0(MW calc.430.27) Sulfuric acid (0.65 mL) and 2-chloro-5-(2-fluoro-phenyl)-pyrimidine (5.5 g, 26.5 mmol) were added to rt rt to n-butanol (52 mL). Mmmol) suspension. The reaction mixture was stirred at EtOAc (EtOAc) (EtOAc) The combined organic layers of dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography [EtOAc, EtOAc/hexane = 1:1]. White solid. Yield: 2.3 g (24%). HPLC (Method 3): R t = 3.55 min., m/z: [M+H] + =432.0 (MW calc.430.27)

Int-2c)6-溴-1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷] Int-2c) 6-bromo-1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]

KOt-Bu(0.574g,5.11mmol)係於rt被分批加入至吡啶(38mL)中之Int-2b(2g,4.64mmol,1.0eq)攪拌溶液，之後加入4-甲苯磺醯氯(1.06g,5.56mmol)及額外之KOt-Bu(0.63g,5.56mmol)。使該反應混合物於100℃攪拌16h，降溫至rt，以水(20mL)稀釋及以EtOAc(2x 50mL)萃取。使該合併之有機層以1N HCl溶液(20x 3mL)及鹽水(20mL)清洗、經Na2SO4乾燥並濃縮。該剩餘物以快速管柱層析法[矽石，EtOAc with 10-20%己烷]純化。白色固體。產量：0.96g(50%).HPLC(方法3)：Rt=2.46min.,m/z：[M+H]+=414.2(MW calc.412.26) KO t -Bu (0.574 g, 5.11 mmol) was added to a stirred solution of EtOAc EtOAc (EtOAc) g, 5.56 mmol) and additional KO t- Bu (0.63 g, 5.56 mmol). The reaction mixture was stirred at EtOAc (EtOAc) (EtOAc) The combined organic layers them with a 1N HCl solution (20x 3mL) and brine (20mL) washed, dried and concentrated over Na 2 SO 4. The residue was purified by flash column chromatography [EtOAc, EtOAc with 10-20% hexane]. White solid. Yield: 0.96 g (50%). HPLC (Method 3): R t = 2.46 min., m/z: [M+H] + = 414.2 (MW calc. 412.26)

Int-2d)1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-羧酸甲酯 Int-2d) 1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-carboxylic acid methyl ester

TEA(0.7mL,5.06mmol)及PdCl2(dppf)(0.17g,0.228mmol)係被加入DMF(15mL)及MeOH(25mL)中之Int-2c(0.94g,2.28mmol)攪拌溶液，其在高壓釜中被保持在Ar中。該混合物係於110℃在CO氣體250psi下經攪拌48h。 該反應混合物被降溫至rt，以水(25mL)稀釋及以EtOAc(2x 30mL)萃取。該合併之有機層係經以鹽水(20mL)清洗、乾燥及在減壓下濃縮。該原產物係經以快速管柱層析法[矽石；己烷與15-25% EtOAc]純化。白色固體。產量：0.46g(52%)。HPLC(方法3)：Rt=3.71min.,m/z：[M+H]+=392.2(MW calc.391.40) TEA (0.7 mL, 5.06 mmol) and PdCl 2 (dppf) (0.17 g, 0.228 mmol) were added to a stirred solution of int-2c (0.94 g, 2.28 mmol) in DMF (15 mL) and MeOH (25 mL) The autoclave was kept in Ar. The mixture was stirred at 110 ° C under a CO gas of 250 psi for 48 h. The reaction mixture was cooled to EtOAc (EtOAc)EtOAc. The combined organic layers were washed with brine (20 mL), dried and evaporated. The original product was purified by flash column chromatography [mistite; hexanes with 15-25% EtOAc]. White solid. Yield: 0.46 g (52%). HPLC (Method 3): R t =3.71 min., m/z: [M+H] + = 392.2 (MW calc.391.40)

Int-2e)1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-羧酸 Int-2e) 1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-carboxylic acid

在THF、MeOH及水(1：1：1,30mL)摻合物中之LiOH．H2O(0.2g,4.7mmol)及Int-2d(0.46g,1.17mmol)混合物先係於rt攪拌16h然後於60℃攪拌2h。使該反應混合物降溫至rt並濃縮。該固體剩餘物係經以飽和KHSO4溶液酸化並經燒結漏斗過濾。剩餘之溶劑係經以甲苯重複共沸蒸餾移除。白色固體。產量：0.4g(91%).HPLC(方法3)：Rt=2.64min.,m/z：[M+H]+=378.2(MW calc.377.37) LiOH in a blend of THF, MeOH and water (1:1:1, 30 mL). The mixture of H 2 O (0.2 g, 4.7 mmol) and EtOAc (0.46 g, 1.17 mmol) was stirred at rt for 16 h then at 60 ° C for 2 h. The reaction mixture was allowed to cool to rt and concentrated. The solid was filtered and the residue was acidified based solution saturated KHSO 4 sintered funnel. The remaining solvent was removed by repeated azeotropic distillation with toluene. White solid. Yield: 0.4 g (91%). HPLC (Method 3): R t = 2.64 min., m/z: [M+H] + =378.2 (MW calc.377.37)

實施例11：N-(2-胺-2-側氧乙基)-1-(5-(2-氟苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 11: N-(2-Amine-2-oxoethyl)-1-(5-(2-fluorophenyl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3, 3'-oxocyclobutane]-6-formamide

HOAt(48mg,0.349mmol)、EDCxHCl(67mg,0.349mmol)、TEA(0.122mL,0.873mmol)及2-甲基胺-乙醯胺鹽酸鹽(55mg,0.437mmol)係於0℃被加入至無水DMF(3mL)中之Int-2(0.11g,0.29mmol)溶液。該反應混合物係於 rt攪拌16h然後以碎冰淬滅。沉澱固體係被濾出並以水清洗。該固體係溶於DCM中並經以快速管柱層析法[矽石；DCM與3-4% MeOH]純化之後以DCM/己烷(1：5)研磨。白色固體。產量：60mg(46%).HPLC(方法3)：Rt=2.81min.,m/z：[M+H]+=448.3(MW calc.447.46).1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：8.82(s,2H),8.40(s,1H),7.77(d,J=8.0Hz,1H),7.65-7.61(m,1H),7.44(s,1H),7.34-7.29(m,2H),7.15(d,J=8.0Hz,1H),6.91(bs,2H),4.87(bs,2H),4.81(bs,2H),4.62(s,2H),3.97(bs,2H),2.99(s,3H). HOAt (48 mg, 0.349 mmol), EDCxHCl (67 mg, 0.349 mmol), TEA (0.122 mL, 0.873 mmol) and 2-methylamine-acetamide hydrochloride (55 mg, 0.437 mmol) were added at 0 °C A solution of Int-2 (0.11 g, 0.29 mmol) in dry DMF (3 mL). The reaction mixture was stirred at rt for 16 h then quenched with crushed ice. The precipitated solids were filtered off and washed with water. The solid was dissolved in DCM and purified by flash column chromatography eluting with EtOAc EtOAc EtOAc White solid. Yield: 60 mg (46%). HPLC (method 3): R t = 2.81 min., m/z: [M+H] + = 448.3 (MW calc.447.46).1H NMR (400 MHz, DMSO-d6, 100 °C, δ ppm): 8.82 (s, 2H), 8.40 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.65-7.61 (m, 1H), 7.44 (s, 1H), 7.34 7.29 (m, 2H), 7.15 (d, J = 8.0 Hz, 1H), 6.91 (bs, 2H), 4.87 (bs, 2H), 4.81 (bs, 2H), 4.62 (s, 2H), 3.97 (bs) , 2H), 2.99 (s, 3H).

實施例12：N-(2-胺-2-側氧乙基)-1-(5-(5-乙氧基-2-氟苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 12: N-(2-Amine-2-oxoethyl)-1-(5-(5-ethoxy-2-fluorophenyl)pyrimidin-2-yl)-N-methylspiro[ Porphyrin-3,3'-oxycyclobutane]-6-carboxamide

以類似於合成實施例3由化合物Int-1合成。白色固體。產量：80mg.HPLC(方法2)：Rt=1.61min.,m/z：[M+H]+=492.1(MW calc.491.51).1H NMR(300MHz,DMSO-d6,δ ppm)：8.84-8.86(m,2H),8.38(s,1H),7.81-7.76(m,1H),7.46-7.41(m,1H),7.29-7.24(m,1H),7.17-7.10(m,3H),6.97(bs,1H),4.87(bs,2H),4.79(bs,2H),4.60(bs,2H),4.09-4.03(m,3H),3.84(s,1H),2.95(s,3H),1.35-1.32(m,3H). Synthesis from Compound Int-1 was carried out in a similar manner to Synthesis Example 3. White solid. Yield: 80 mg. HPLC (Method 2): R t = 1.61 min., m/z: [M+H] + =492.1 (MW calc.491.51).1H NMR (300 MHz, DMSO-d6, δ ppm): 8.84 -8.86(m,2H),8.38(s,1H),7.81-7.76(m,1H),7.46-7.41(m,1H), 7.29-7.24(m,1H),7.17-7.10(m,3H) , 6.97 (bs, 1H), 4.87 (bs, 2H), 4.79 (bs, 2H), 4.60 (bs, 2H), 4.09-4.03 (m, 3H), 3.84 (s, 1H), 2.95 (s, 3H) ), 1.35-1.32 (m, 3H).

實施例13：N-(2-胺-2-側氧乙基)-N-甲基-1-(5-(吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 13: N-(2-Amine-2-oxoethyl)-N-methyl-1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3, 3'-oxocyclobutane]-6-formamide

以合成實施例3之類似方法由化合物Int-1製備。白色固體。產量：0.1g.HPLC(方法2)：Rt=1.40min.,m/z：[M+H]+=431.0(MW calc.430.46).1H NMR(300MHz,DMSO-d6,100℃,δ ppm)：9.25(s,2H),8.67(d,1H,J=4.5Hz,1H),8.43(s,1H),7.96(d,1H,J=8.0Hz),7.90-7.86(m,1H),7.78(d,1H,J=8.0Hz),7.36-7.33(m,1H),7.17(d,1H,J=7.5Hz),6.92(bs,2H),4.89(d,2H,J=5.7Hz),4.81(d,2H,J=6.0Hz),4.63(s,2H),3.98(s,2H),3.00(s,3H). Prepared from the compound Int-1 in a similar manner to the synthesis of Example 3. White solid. Yield: 0.1 g. HPLC (Method 2): R t = 1.40 min., m/z: [M+H] + =431.0 (MW calc.430.46).1H NMR (300 MHz, DMSO-d6, 100 ° C, δ Ppm): 9.25 (s, 2H), 8.67 (d, 1H, J = 4.5 Hz, 1H), 8.43 (s, 1H), 7.96 (d, 1H, J = 8.0 Hz), 7.90-7.86 (m, 1H) ), 7.78 (d, 1H, J = 8.0 Hz), 7.36-7.33 (m, 1H), 7.17 (d, 1H, J = 7.5 Hz), 6.92 (bs, 2H), 4.89 (d, 2H, J = 5.7 Hz), 4.81 (d, 2H, J = 6.0 Hz), 4.63 (s, 2H), 3.98 (s, 2H), 3.00 (s, 3H).

合成實施例14及15係由以下獲得：鈴木偶聯反應(Suzuki coupling)(1-(5-溴嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮(化合物8b)及各別之苯基硼酸，其係使用規程3a中所述之反應條件。 Synthesis Examples 14 and 15 were obtained by the following: Suzuki coupling (1-(5-bromopyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6 -yl)(morpholinyl)methanone (compound 8b) and the respective phenylboronic acid using the reaction conditions described in Scheme 3a.

實施例14：嗎啉基(1-(5-(3-(三氟甲基)苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)甲酮 Example 14: Morpholinyl (1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6- Ketone

白色固體。產量：0.1g.HPLC(方法2)：Rt=1.74min.,m/z：[M+H]+=497.1(MW calc.496.48).1H NMR(400MHz,DMSO-d6,δ ppm)：9.09(s,2H),8.40(s,1.0H),8.12-8.07(m,2H),7.82(d,1H,J=7.6Hz),7.74-7.7(m,2H),7.15-7.13(m,1H),4.89(d,2H,J=6.1Hz),4.8(d,2H,J=6Hz),4.61(s,2H),3.63-3.4(m,8H). White solid. Yield: 0.1 g. HPLC (Method 2): R t = 1.74 min., m/z: [M+H] + = 497.1 (MW calc.496.48).1H NMR (400 MHz, DMSO-d6, δ ppm): 9.09(s,2H), 8.40(s,1.0H),8.12-8.07(m,2H),7.82(d,1H,J=7.6Hz),7.74-7.7(m,2H),7.15-7.13(m , 1H), 4.89 (d, 2H, J = 6.1 Hz), 4.8 (d, 2H, J = 6 Hz), 4.61 (s, 2H), 3.63-3.4 (m, 8H).

實施例15：(1-(5-(2-氟-5-(三氟甲基)苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 Example 15: (1-(5-(2-Fluoro-5-(trifluoromethyl)phenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6 -yl)(morpholinyl)methanone

白色固體。產量：0.25g.HPLC(方法2)：Rt=1.74min.,m/z：[M+H]+=515.1(MW calc.514.47).1H NMR(400MHz,DMSO-d6,δ ppm)：8.93(s,2H),8.39(s,1H),8.07(d,1H,J=5.1Hz),7.82-7.8(m,2H),7.64-7.6(m,1H),7.16(d,1H,J=7.4Hz),4.87(d,2H,J=6.1Hz),4.78(d,2H,J=6Hz),4.61(s,2H),3.62-3.4(m,8H). White solid. Yield: 0.25 g. HPLC (method 2): R t = 1.74 min., m/z: [M+H] + = 515.1 (MW calc. 514.47). 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.93 (s, 2H), 8.39 (s, 1H), 8.07 (d, 1H, J = 5.1 Hz), 7.82-7.8 (m, 2H), 7.64-7.6 (m, 1H), 7.16 (d, 1H, J = 7.4 Hz), 4.87 (d, 2H, J = 6.1 Hz), 4.78 (d, 2H, J = 6 Hz), 4.61 (s, 2H), 3.62-3.4 (m, 8H).

合成實施例16及17係由1-(5-溴嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-羧酸(化合物8a)於二化學步驟製備，其包括使一醯胺與2-(甲基胺)乙醇偶聯、作為試劑之TBTU及鈴木偶聯反應(規程3a)。 Synthesis Examples 16 and 17 were prepared from 1-(5-bromopyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-carboxylic acid (Compound 8a) in two chemical steps. This includes coupling of monoamine to 2-(methylamine)ethanol, TBTU as a reagent, and Suzuki coupling reaction (Protocol 3a).

實施例16：1-(5-(2-氟-5-(三氟甲基)苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺-[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 16: 1-(5-(2-Fluoro-5-(trifluoromethyl)phenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro-[吲Porphyrin-3,3'-oxycyclobutane]-6-carboxamide

白色固體。產量：53mg.HPLC(方法2)：Rt=1.66min.,m/z：[M+H]+=503.1(MW calc.502.46).1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：8.81(s,2H),8.37(s,1H),8.01(d,1H,J=6.7Hz),7.79-7.77(m,2H),7.59-7.54(m,1H),7.15(d,1H,J=7.6Hz),4.88(d,2H,J=6.0Hz),4.81(d,2H,J=5.9Hz),4.63(s,2H),4.4(bs,1H),3.63-3.61(m,2H),3.45(bs,2H),3.02(s,3H). White solid. Yield: 53 mg. HPLC (Method 2): R t = 1.66 min., m/z: [M+H] + = 503.1 (MW calc. 502.46). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm ): 8.81 (s, 2H), 8.37 (s, 1H), 8.01 (d, 1H, J = 6.7 Hz), 7.79-7.77 (m, 2H), 7.59 - 7.54 (m, 1H), 7.15 (d, 1H, J = 7.6 Hz), 4.88 (d, 2H, J = 6.0 Hz), 4.81 (d, 2H, J = 5.9 Hz), 4.63 (s, 2H), 4.4 (bs, 1H), 3.63 - 3.61 ( m, 2H), 3.45 (bs, 2H), 3.02 (s, 3H).

實施例17：N-(2-羥乙基)-N-甲基-1-(5-(3-(三氟甲基)苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 17: N-(2-hydroxyethyl)-N-methyl-1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)spiro[porphyrin-3, 3'-oxocyclobutane]-6-formamide

白色固體。產量：0.11g.HPLC(方法2)：Rt=1.67min.,m/z：[M+H]+=485.1(MW calc.484.47).1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：9.01(s,2H),8.39(s,1H),8.03(bs,2H),7.86-7.71(m,3H),7.12(d,1H,J=7.3Hz),4.88(bs,2H),4.82(bs,2H),4.63(s,2H),4.41(bs,1H),3.62(bs,2H),3.45(bs,2H),3.02(s,3H). White solid. Yield: 0.11 g. HPLC (Method 2): R t = 1.67 min., m/z: [M+H] + =485.1 (MW calc.484.47).1H NMR (400 MHz, DMSO-d6, 100 ° C, δ Ppm): 9.01 (s, 2H), 8.39 (s, 1H), 8.03 (bs, 2H), 7.86-7.71 (m, 3H), 7.12 (d, 1H, J = 7.3 Hz), 4.88 (bs, 2H) ), 4.82 (bs, 2H), 4.63 (s, 2H), 4.41 (bs, 1H), 3.62 (bs, 2H), 3.45 (bs, 2H), 3.02 (s, 3H).

實施例18至21係由Int-2及各別之胺經由使胺與TBTU偶聯反應獲得(製程3c)。 Examples 18 to 21 were obtained by coupling an Int-2 and a respective amine via coupling of an amine with TBTU (Process 3c).

實施例18：(1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(吡咯啶-1-基)甲酮 Example 18: (1-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)(pyrrolidine-1- Ketone

白色固體。產量：60mg.HPLC(方法3)：Rt=3.38min.,m/z：[M+H]+=431.1(MW calc.430.47).1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：8.83(s,2H),8.46(s,1H),7.78(d,J=7.5Hz,1H),7.65-7.61(m,1H),7.45-7.44(m,1H), 7.34-7.29(m,2H),7.23(d,J=7.4Hz,1H),4.89(d,J=5.5Hz,2H),4.81(d,J=5.6Hz,2H),4.62(s,2H),3.48(bs,4H),1.88(bs,4H). White solid. Yield: 60 mg. HPLC (method 3): R t = 3.38 min., m/z: [M+H] + = 431.1 (MW calc. 430.47). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm ): 8.83 (s, 2H), 8.46 (s, 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.65-7.61 (m, 1H), 7.45-7.44 (m, 1H), 7.34-7.29 ( m, 2H), 7.23 (d, J = 7.4 Hz, 1H), 4.89 (d, J = 5.5 Hz, 2H), 4.81 (d, J = 5.6 Hz, 2H), 4.62 (s, 2H), 3.48 ( Bs, 4H), 1.88 (bs, 4H).

實施例19：(1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(哌嗪-1-基)甲酮 Example 19: (1-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)(piperazin-1- Ketone

白色固體。產量：50mg.HPLC(方法3)：Rt=2.71min.,m/z：[M+H]+=446.0(MW calc.445.49).1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：8.82(s,2H),8.36(s,1H),7.79(d,J=7.6Hz,1H),7.65-7.61(m,1H),7.45-7.44(m,1H),7.35-7.29(m,2H),7.11(d,J=8.0Hz,1H),4.89(d,J=5.7Hz,2H),4.81(d,J=6.0Hz,2H),4.62(s,2H),3.48(bs,4H),2.79(bs,4H). White solid. Yield: 50 mg. HPLC (method 3): R t = 2.71 min., m/z: [M+H] + = 446.0 (MW calc.445.49). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm ): 8.82 (s, 2H), 8.36 (s, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.65-7.61 (m, 1H), 7.45-7.44 (m, 1H), 7.35-7.29 ( m, 2H), 7.11 (d, J = 8.0 Hz, 1H), 4.89 (d, J = 5.7 Hz, 2H), 4.81 (d, J = 6.0 Hz, 2H), 4.62 (s, 2H), 3.48 ( Bs, 4H), 2.79 (bs, 4H).

實施例20：1-(5-(2-氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 20: 1-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxygen ring Butane]-6-formamide

白色固體。產量：60mg.HPLC(方法3)：Rt=3.02min.,m/z：[M+H]+=435.2 (MW calc.434.46).1H NMR(400MHz,DMSO-d6,δ ppm)：8.85(s,2H),8.35(s,1H),7.78(s,1H),7.66(t,J=8.3Hz,1H),7.46-7.45(m,1H),7.39-7.32(m,2H),7.13(d,J=7.0Hz,1H),4.88(d,J=5.6Hz,2H),4.81-4.79(m,3H),4.61(s,2H),3.64(bs,1H),3.52(bs,2H),3.32(1H,masked with DMSO/水peak),3.00-2.98(m,3H). White solid. Yield: 60 mg. HPLC (method 3): R t = 3.02 min., m/z: [M+H] + =435.2 (MW calc.434.46).1H NMR (400 MHz, DMSO-d6, δ ppm): 8.85 (s, 2H), 8.35 (s, 1H), 7.78 (s, 1H), 7.66 (t, J = 8.3 Hz, 1H), 7.46-7.45 (m, 1H), 7.39-7.32 (m, 2H), 7.13 (d, J = 7.0 Hz, 1H), 4.88 (d, J = 5.6 Hz, 2H), 4.81-4.79 (m, 3H), 4.61 (s, 2H), 3.64 (bs, 1H), 3.52 (bs) , 2H), 3.32 (1H, masked with DMSO/water peak), 3.00-2.98 (m, 3H).

實施例21：(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基(1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)甲酮 Example 21: (1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl(1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[吲Porphyrin-3,3'-oxycyclobutane]-6-yl)methanone

白色固體。產量：55mg.HPLC(方法2)：Rt=1.40min.,m/z：[M+H]+=458.1(MW calc.457.50).1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：8.82(s,2H),8.49(s,1H),7.80(d,J=7.2Hz,1H),7.63(bs,1H),7.45(bs,1H),7.33(bs,2H),7.24(d,J=7.3Hz,1H),4.89(d,J=5.3Hz,2H),4.81(s,2H),4.62(s,2H),4.44(bs,1H),3.75(bs,1H),3.56-3.53(m,1H),3.46-3.45(m,1H),3.10-2.97(m,3H),1.78(bs,1H),1.66(bs,1H). White solid. Yield: 55 mg. HPLC (Method 2): R t = 1.40 min., m/z: [M+H] + =458.1 (MW calc.457.50).1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm ): 8.82 (s, 2H), 8.49 (s, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.63 (bs, 1H), 7.45 (bs, 1H), 7.33 (bs, 2H), 7.24 (d, J = 7.3 Hz, 1H), 4.89 (d, J = 5.3 Hz, 2H), 4.81 (s, 2H), 4.62 (s, 2H), 4.44 (bs, 1H), 3.75 (bs, 1H) , 3.56-3.53 (m, 1H), 3.46-3.45 (m, 1H), 3.10-2.97 (m, 3H), 1.78 (bs, 1H), 1.66 (bs, 1H).

實施例22：(1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(哌嗪-1-基)甲酮 Example 22: (1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl) Pyrazin-1-yl)methanone

22a)1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-羧酸甲酯 22a) Methyl 1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-carboxylate

雙(頻哪醇)二硼(1.45g,5.74mmol)及乙酸鉀(1.05g,10.77mmol)係於rt被加入至在Ar下經攪拌之無水二噁烷(80mL)中之Int-1(1.35g,3.59mmol)溶液。PdCl2(dppf)(0.146g,0.179mmol)係被加入且使該混合物於100℃攪拌20min。其次，2-溴-4-甲基-吡啶(0.926g,5.38mmol)、2M之K2CO3水溶液(6.7mL)及肆(三苯基膦)鈀(0)(0.208g,0.179mmol)係被依序加入且使該反應混合物於100℃進一步攪拌5h。然後使該反應混合物降溫至rt並經燒結漏斗過濾。使該濾液被濃縮且使該剩留物經以快速管柱層析法[矽石；DCM與1.2% MeOH)純化。白色固體。產量：0.82g(59%)。HPLC(方法3)：Rt=3.46min.,m/z：[M+H]+=389.2(MW calc.388.42) Bis (pinacol) diboron (1.45 g, 5.74 mmol) and potassium acetate (1.05 g, 10.77 mmol) were added at rt to Int-1 (with stirring in anhydrous dioxane (80 mL) under ar. 1.35 g, 3.59 mmol) solution. PdCl 2 (dppf) (0.146 g, 0.179 mmol) was added and the mixture was stirred at 100 ° C for 20 min. Next, 2-bromo-4-methyl-pyridine (0.926 g, 5.38 mmol), 2M aqueous K 2 CO 3 (6.7 mL) and yttrium (triphenylphosphine) palladium (0) (0.208 g, 0.179 mmol) The reaction was added sequentially and the reaction mixture was further stirred at 100 ° C for 5 h. The reaction mixture was then cooled to rt and filtered through a fritted funnel. The filtrate was concentrated and the residue was purified by flash column chromatography [EtOAc] &lt White solid. Yield: 0.82 g (59%). HPLC (Method 3): R t = 3.46 min., m/z: [M+H] + = 389.2 (MW calc. 388.42)

22b)1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-羧酸 22b) 1-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-carboxylic acid

LiOH．H2O(0.355g,8.45mmol)係於0℃被加至在THF、水及MeOH(1：1：1,45mL)之摻合物中之化合物22a)(0.82g,2.11mmol)溶液。該反應混合物係於80℃經攪拌3h然後被濃縮。該固體餘留物係經以KHSO4溶液酸化並經燒結漏斗過濾。剩餘溶劑係經甲苯之重複共沸蒸餾移除。淺黃色固體。產量：0.72g(91%)。HPLC(方法4)：Rt=2.64min.,m/z：[M+H]+=373.0(MW calc.374.39) LiOH. H 2 O (0.355 g, 8.45 mmol) was added to a solution of compound 22a) (0.82 g, 2.11 mmol) in THF, water and MeOH (1:1:1, 45 mL). The reaction mixture was stirred at 80 ° C for 3 h and then concentrated. The remaining solid was acidified with KHSO 4 to over-based solution and filtered through a sintered funnel. The remaining solvent was removed by repeated azeotropic distillation of toluene. Light yellow solid. Yield: 0.72 g (91%). HPLC (Method 4): R t = 2.64 min., m/z: [M+H] + =373.0 (MW calc.374.39)

22c)(1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(哌嗪-1-基)甲酮 22c) (1-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl) (piperazine- 1-yl)methanone

TBTU(0.371g,1.15mmol)、N-甲基嗎啉(0.2mL,1.92mmol)及哌嗪(0.166g,1.92mmol)係於0℃被加入至無水DMF(10mL)中之化合物22b)(0.36g,0.962mmol)溶液。該反應混合物係於rt經攪拌16h然後以碎冰淬滅並以EtOAc(3 x 30mL)萃取。該合併之有機層係經Na2SO4乾燥且在減壓下濃縮。該剩餘物係經以快速管柱層析法[經氨平衡之矽石；DCM與5-8% MeOH]純化。白色固體。產量：60mg(14%)。HPLC(方法3)：Rt=2.63min.,m/z：[M+H]+=443.2(MW calc.442.51).1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：9.24(s,2H),8.52(d,J=4.9Hz,1H),8.39(s,1H),7.80-7.78(m,2H),7.18(d,J=4.1Hz,1H),7.12(d,J=7.6Hz,1H),4.89(d,J=5.7Hz,2H),4.81(d,J=5.8Hz,2H),4.62(s,2H),3.49(bs,4H),2.80(bs,4H),2.41(s,3H). TBTU (0.371 g, 1.15 mmol), N-methylmorpholine (0.2 mL, 1.92 mmol) and piperazine (0.166 g, 1.92 mmol) were added to compound 22b in anhydrous DMF (10 mL). 0.36 g, 0.962 mmol) solution. The reaction mixture was stirred with EtOAc EtOAc (EtOAc) The combined organic layer system of 2 SO 4 and dried over Na and concentrated under reduced pressure. The residue was purified by flash column chromatography [Ammonia-balanced vermiculite; DCM with 5-8% MeOH]. White solid. Yield: 60 mg (14%). HPLC (Method 3): R t = 2.63 min., m/z: [M+H] + = 443.2 (MW calc. 441.51). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 9.24 ( s, 2H), 8.52 (d, J = 4.9 Hz, 1H), 8.39 (s, 1H), 7.80-7.78 (m, 2H), 7.18 (d, J = 4.1 Hz, 1H), 7.12 (d, J) = 7.6 Hz, 1H), 4.89 (d, J = 5.7 Hz, 2H), 4.81 (d, J = 5.8 Hz, 2H), 4.62 (s, 2H), 3.49 (bs, 4H), 2.80 (bs, 4H) ), 2.41 (s, 3H).

實施例23及24係由1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-羧酸製備(類似製程3c之TBTU偶聯反應)。 Examples 23 and 24 are based on 1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-carboxylic acid Prepared (similar to the TBTU coupling reaction of Process 3c).

實施例23：(1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(吡咯啶-1-基)甲酮 Example 23: (1-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl) (pyrrole) Pyridin-1-yl)methanone

淺黃色固體。產量：65mg。HPLC(方法2)：Rt=1.65min.,m/z：[M+H]+=428.1(MW calc.427.50).1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：9.23(s,2H),8.51(d,J=4.9Hz,2H),7.79-7.77(m,2H),7.24(d,J=7.6Hz,1H),7.17(d,J=4.6Hz,1H),4.89(d,J=5.9Hz,2H),4.81(d,J=5.9Hz,2H),4.63(s,2H),3.49(bs,4H),2.32(s,3H),1.88(bs,4H). Light yellow solid. Yield: 65 mg. HPLC (Method 2): Rt = 1.65 min., m/z: [M+H] + = 428.1 (MW calc. 427.50). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 9.23 ( s, 2H), 8.51 (d, J = 4.9 Hz, 2H), 7.79-7.77 (m, 2H), 7.24 (d, J = 7.6 Hz, 1H), 7.17 (d, J = 4.6 Hz, 1H), 4.89 (d, J = 5.9 Hz, 2H), 4.81 (d, J = 5.9 Hz, 2H), 4.63 (s, 2H), 3.49 (bs, 4H), 2.32 (s, 3H), 1.88 (bs, 4H) ).

實施例24：N-(2-羥乙基)-N-甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 24: N-(2-hydroxyethyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3 '-oxycyclobutane]-6-formamide

白色固體。產量：100mg。HPLC(方法2)：Rt=1.43min.,m/z：[M+H]+=432.0(MW calc.431.49).1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：9.23(s,2H),8.51(d,J=4.8Hz,1H),8.39(s,1H),7.79-7.76(m,2H),7.18-7.12(m,2H),4.89(d,J=5.9Hz,2H),4.81(d,J=6.0Hz,2H),4.63(s,2H),4.41(bs,1H),3.64(bs,2H),3.46(bs,2H),3.03(s,3H),2.32(s,3H). White solid. Yield: 100 mg. HPLC (Method 2): rt = 1.43 min., m/z: [M+H] + = 432.0 (MW calc. 431.49). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 9.23 ( s, 2H), 8.51 (d, J = 4.8 Hz, 1H), 8.39 (s, 1H), 7.79-7.76 (m, 2H), 7.18-7.12 (m, 2H), 4.89 (d, J = 5.9 Hz) , 2H), 4.81 (d, J = 6.0 Hz, 2H), 4.63 (s, 2H), 4.41 (bs, 1H), 3.64 (bs, 2H), 3.46 (bs, 2H), 3.03 (s, 3H) , 2.32 (s, 3H).

實施例25：(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基(1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)甲酮 Example 25: (1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl(1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl) Spirulina [porphyrin-3,3'-oxycyclobutane]-6-yl)methanone

由1-(5-溴嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-羧酸及(1S,4S)-叔丁基2,5-二氮雜雙環[2.2.1]庚烷-2-羧酸酯以合成實施例8所述之類似方法製備。該保護基團係在最終步驟中以DCM中之TFA移除。淺黃色固體。產量：0.1g。HPLC(方法3)：Rt=2.56min.,m/z：[M+H]+=455.0(MW calc.454.52).1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：9.23(s,2H),8.52(s,2H),7.80(s,2H),7.25(d,J=7.5Hz,1H),7.17(s,1H),4.89(d,J=5.0Hz,2H),4.81(bs,2H),4.63(s,2H),4.45(bs,1H),3.69(s,1H),3.55-3.53(m,1H),3.29-3.27(m,1H),3.08-3.06(m,1H),2.41(s,3H),1.77-1.75(m,1H),1.64-1.62(m,1H). From 1-(5-bromopyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-carboxylic acid and (1S,4S)-tert-butyl 2,5-diaza Heterobicyclo[2.2.1]heptane-2-carboxylate was prepared in a similar manner as described in the synthesis of Example 8. This protecting group is removed in the final step with TFA in DCM. Light yellow solid. Yield: 0.1 g. HPLC (Method 3): Rt = 2.56 min., m/z: [M+H] + = 455.0 (MW calc.454.52).1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 9.23 ( s, 2H), 8.52 (s, 2H), 7.80 (s, 2H), 7.25 (d, J = 7.5 Hz, 1H), 7.17 (s, 1H), 4.89 (d, J = 5.0 Hz, 2H), 4.81 (bs, 2H), 4.63 (s, 2H), 4.45 (bs, 1H), 3.69 (s, 1H), 3.55-3.53 (m, 1H), 3.29-3.27 (m, 1H), 3.08-3.06 ( m, 1H), 2.41 (s, 3H), 1.77-1.75 (m, 1H), 1.64-1.62 (m, 1H).

實施例26：N-(2-胺-2-側氧乙基)-1-(5-(3-環丙基苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 26: N-(2-Amino-2-oxoethyl)-1-(5-(3-cyclopropylphenyl)pyrimidin-2-yl)-N-methylspiro[porphyrin- 3,3'-oxycyclobutane]-6-formamide

由Int-1及(3-環丙基苯基)硼酸以類似於合成實施例3之方式製備。白色固體。產量：70mg。HPLC(方法2)：Rt=1.63min.,m/z：[M+H]+=470.1(MW calc.469.54).1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：8.92(s,2H),8.41(s,1H),7.78(d,1H,J=7.3Hz),7.48-7.34(m,3H),7.15-7.11(m,2H),6.92(s,2H),4.89(d,2H,J=5.7Hz),4.82(d,2H,J=5.8Hz),4.61(s,2H),3.98(s,2H),3.00(s,3H),2.02(s,1H),0.99(d,2H,J=6.2Hz),0.79(d,2H,J=3.0Hz). It was prepared in a manner similar to Synthesis Example 3 from Int-1 and (3-cyclopropylphenyl)boronic acid. White solid. Yield: 70 mg. HPLC (Method 2): R t = 1.63 min., m/z: [M+H] + = 470.1 (MW calc. 469.54). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 8.92 ( s, 2H), 8.41 (s, 1H), 7.78 (d, 1H, J = 7.3 Hz), 7.48-7.34 (m, 3H), 7.15-7.11 (m, 2H), 6.92 (s, 2H), 4.89 (d, 2H, J = 5.7 Hz), 4.82 (d, 2H, J = 5.8 Hz), 4.61 (s, 2H), 3.98 (s, 2H), 3.00 (s, 3H), 2.02 (s, 1H) , 0.99 (d, 2H, J = 6.2 Hz), 0.79 (d, 2H, J = 3.0 Hz).

實施例27：N-(2-胺-2-側氧乙基)-N-甲基-1-(5-(m-甲苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 27: N-(2-Amino-2-oxoethyl)-N-methyl-1-(5-(m-methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3 '-oxycyclobutane]-6-formamide

由Int-1及m-甲苯基硼酸以類似合成實施例3之方式製備。白色固體。產量：0.14g。HPLC(方法2)：Rt=1.59min.,m/z：[M+H]+=444.1(MW calc.443.50).1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：8.91(s,2H),8.41(s,1H),7.78(d,1H,J=7.6Hz),7.53-7.49(m,2H),7.39-7.35(m,1H),7.22(d,1H,J=8.0Hz),7.15-7.13(m,1H),6.91(s,2H),4.89(d,2H,J=6.0Hz),4.82(d,2H,J=6.0Hz),4.61(s,2H),3.98(s,2H),3.0(s,3H),2.40(s,3H). It was prepared in the same manner as in Synthesis Example 3 from Int-1 and m-tolylboronic acid. White solid. Yield: 0.14 g. HPLC (Method 2): R t = 1.59 min., m/z: [M+H] + = 444.1 (MW calc.443.50).1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 8.91 ( s, 2H), 8.41 (s, 1H), 7.78 (d, 1H, J = 7.6 Hz), 7.53-7.49 (m, 2H), 7.39-7.35 (m, 1H), 7.22 (d, 1H, J = 8.0 Hz), 7.15-7.13 (m, 1H), 6.91 (s, 2H), 4.89 (d, 2H, J = 6.0 Hz), 4.82 (d, 2H, J = 6.0 Hz), 4.61 (s, 2H) , 3.98 (s, 2H), 3.0 (s, 3H), 2.40 (s, 3H).

實施例28：(S)-N-(2-胺-2-側氧乙基)-1-(5-(2-氟-5-(1-羥乙基)苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 28: (S)-N-(2-Amino-2-oxoethyl)-1-(5-(2-fluoro-5-(1-hydroxyethyl)phenyl)pyrimidin-2-yl )-N-methylspiro[porphyrin-3,3'-oxycyclobutane]-6-carboxamide

由Int-1及(S)-1-(3-溴-4-氟苯基)乙醇以類似於合成實施例22之方式製備。白色固體。產量：55mg。HPLC(方法2)：Rt=1.47min.,m/z：[M+H]+=492.2(MW calc.491.51).1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：8.81(s,2H),8.40(s,1H),7.78(d,1H,J=7.6Hz),7.57(d,1H,J=7.6Hz),7.42(s,1H),7.27-723(m,1H),7.16(d,1H,J=7.4Hz),6.92(s,2H),4.89-4.81(m,6 H),4.62(s,2H),3.97(s,2 H),2.97(s,3 H),1.35(d,3H,J=6.4Hz). Prepared from Int-1 and (S)-1-(3-bromo-4-fluorophenyl)ethanol in a similar manner to the synthesis of Example 22. White solid. Yield: 55 mg. HPLC (Method 2): Rt = 1.47 min., m/z: [M+H] + = 492.2 (MW calc.491.51).1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 8.81 ( s, 2H), 8.40 (s, 1H), 7.78 (d, 1H, J = 7.6 Hz), 7.57 (d, 1H, J = 7.6 Hz), 7.42 (s, 1H), 7.27-723 (m, 1H) ), 7.16 (d, 1H, J = 7.4 Hz), 6.92 (s, 2H), 4.89-4.81 (m, 6 H), 4.62 (s, 2H), 3.97 (s, 2 H), 2.97 (s, 3 H), 1.35 (d, 3H, J = 6.4 Hz).

實施例29：(R)-N-(2-胺-2-側氧乙基)-1-(5-(2-氟-5-(1-羥乙基)苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 29: (R)-N-(2-Amino-2-oxoethyl)-1-(5-(2-fluoro-5-(1-hydroxyethyl)phenyl)pyrimidin-2-yl )-N-methylspiro[porphyrin-3,3'-oxycyclobutane]-6-carboxamide

由Int-1及(R)-1-(3-溴-4-氟苯基)乙醇以類似於合成實施例22之方式製備。白色固體。產量：0.10g。HPLC(方法2)：Rt=1.47min.,m/z：[M+H]+=492.1(MW calc.491.51).1H NMR(400MHz,DMSO-d6,δ ppm)：8.85-8.83(m,2H),8.38(s,1H),7.80-7.76(m,1H),7.57(d,1H,J=7.2Hz),7.467.40(m,2H), 7.32-7.28(m,1H),7.13-7.09(m,2H),5.25(s,1H),4.88(d,2H,J=6.5Hz),4.80(d,3H,J=5.5Hz),4.60(s,2H),4.04(s,1H),3.84(s,1H),2.95(s,3H),1.37(d,3H,J=6.4Hz). Prepared from Int-1 and (R)-1-(3-bromo-4-fluorophenyl)ethanol in a similar manner to the synthesis of Example 22. White solid. Yield: 0.10 g. HPLC (Method 2): R t = 1.47 min., m/z: [M+H] + =492.1 (MW calc.491.51).1H NMR (400 MHz, DMSO-d6, δ ppm): 8.85-8.83 (m) , 2H), 8.38 (s, 1H), 7.80-7.76 (m, 1H), 7.57 (d, 1H, J = 7.2 Hz), 7.467.40 (m, 2H), 7.32-7.28 (m, 1H), 7.13-7.09(m,2H), 5.25(s,1H), 4.88(d,2H,J=6.5Hz), 4.80(d,3H,J=5.5Hz), 4.60(s,2H),4.04(s , 1H), 3.84 (s, 1H), 2.95 (s, 3H), 1.37 (d, 3H, J = 6.4 Hz).

實施例30：N-(2-胺-2-側氧乙基)-1-(5-(2-氟-5-(2-羥基丙-2-基)苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 30: N-(2-Amine-2-oxoethyl)-1-(5-(2-fluoro-5-(2-hydroxypropan-2-yl)phenyl)pyrimidin-2-yl) -N-methylspiro[porphyrin-3,3'-oxycyclobutane]-6-carboxamide

由Int-1及2-(3-溴-4-氟苯基)丙-2-醇以類似於合成實施例22之方式製備。白色固體。產量：0.10g。HPLC(方法3)：Rt=2.74min.,m/z：[M+H]+=506.2(MW calc.505.54).1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：8.82(s,2H),8.40(s,1H),7.78(d,1H,J=7.6Hz),7.68-7.66(m,1H),7.55-7.52(m,1H),7.25-7.14(m,2H),6.91(s,2H),4.89(d,2H,J=6.0Hz),4.82(d,2H,J=6.0Hz),4.76(s,1H),4.62(s,2H),3.97(s,2H),2.99(s,3H),1.51(s,6H). It was prepared in a similar manner to Synthesis Example 22 from Int-1 and 2-(3-bromo-4-fluorophenyl)propan-2-ol. White solid. Yield: 0.10 g. HPLC (Method 3): Rt = 2.74 min., m/z: [M+H] + = 506.2 (MW calc. 505.54). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 8.82 ( s, 2H), 8.40 (s, 1H), 7.78 (d, 1H, J = 7.6 Hz), 7.68-7.66 (m, 1H), 7.55-7.52 (m, 1H), 7.25-7.14 (m, 2H) , 6.91 (s, 2H), 4.89 (d, 2H, J = 6.0 Hz), 4.82 (d, 2H, J = 6.0 Hz), 4.76 (s, 1H), 4.62 (s, 2H), 3.97 (s, 2H), 2.99 (s, 3H), 1.51 (s, 6H).

合成實施例31及32係由鈴木偶聯反應(1-(5-溴嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮(化合物8b)及各別之苯基硼酸獲得，其係使用規程3a所述之反應條件。 Synthesis Examples 31 and 32 were carried out by Suzuki coupling reaction (1-(5-bromopyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl) (morpholinyl) The ketone (compound 8b) and the respective phenylboronic acid are obtained using the reaction conditions described in Scheme 3a.

實施例31：嗎啉基(1-(5-(m-甲苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6- 基)甲酮 Example 31: Morpholinyl (1-(5-(m-methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6- Ketone

白色固體。產量：65mg。HPLC(方法3)：Rt=3.42min.,m/z：[M+H]+=443.3(MW calc.442.51).1H NMR(400MHz,DMSO-d6,δ ppm)：8.98(s,2H),8.38(s,1H),7.80-7.79(d,1H),7.57-7.52(m,2H),7.37-7.35(t,1H),7.21-7.20(d,1H),7.13-7.11(d,1H),4.88-4.86(d,1H),4.79-4.78(d,1H),4.60(d,2H),3.63(bs,8H),2.38(s,3H). White solid. Yield: 65 mg. HPLC (Method 3): R t = 3.42 min., m/z: [M+H] + = 443.3 (MW calc. 441.51). 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.98 (s, 2H) ), 8.38 (s, 1H), 7.80-7.79 (d, 1H), 7.57-7.52 (m, 2H), 7.37-7.35 (t, 1H), 7.21-7.20 (d, 1H), 7.13-7.11 (d) , 1H), 4.88-4.86 (d, 1H), 4.79-4.78 (d, 1H), 4.60 (d, 2H), 3.63 (bs, 8H), 2.38 (s, 3H).

實施例32：(1-(5-(2-氟-5-甲氧基苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 Example 32: (1-(5-(2-Fluoro-5-methoxyphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl) (morpholinyl) ketone

白色固體。產量：75mg。HPLC(方法3)：Rt=3.20min.,m/z：[M+H]+=477(MW calc.476.50).1H NMR(400MHz,DMSO-d6,δ ppm)：8.87(s,2H),8.38(s,1H),7.81-7.79(d,1H),7.31-7.26(m,1H),7.20-7.19(d,1H),7.14-7.13(d,1H),6.99(m,1H),4.88-4.87(d,1H),4.80-4.78(d,1H),4.60(d,2H),3.81(s, 3H),3.63(bs,8H). White solid. Yield: 75 mg. HPLC (Method 3): R t = 3.20 min., m/z: [M+H] + = 477 (MW calc.476.50).1H NMR (400 MHz, DMSO-d6, δ ppm): 8.87 (s, 2H) ), 8.38(s,1H), 7.81-7.79(d,1H),7.31-7.26(m,1H), 7.20-7.19(d,1H),7.14-7.13(d,1H),6.99(m,1H) ), 4.88-4.87 (d, 1H), 4.80-4.78 (d, 1H), 4.60 (d, 2H), 3.81 (s, 3H), 3.63 (bs, 8H).

實施例33：(1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 Example 33: (1-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl) ( Morpholine) ketone

由Int-1以類似合成實施例3方式經三步驟製備。白色固體。產量：57mg。HPLC(方法3)：Rt=3.38min.,m/z：=461(MW calc.460.50).1H NMR(400MHz,DMSO-d6,δ ppm)：8.84(s,2H),8.38(s,1H),7.81-7.79(d,1H),7.47-7.45(d,1H),7.25-7.23(d,2H),7.14-7.13(d,1H),4.88-4.87(d,1H),4.79-4.78(d,1H),4.60(d,2H),3.62(bs,8H),2.38(s,3H). It was prepared from Int-1 in a similar manner to Synthesis Example 3 in three steps. White solid. Yield: 57 mg. HPLC (Method 3): R t = 3.38 min., m/z: 461 (MW calc. 460.50). 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.84 (s, 2H), 8.38 (s, 1H), 7.81-7.79(d,1H), 7.47-7.45(d,1H), 7.25-7.23(d,2H),7.14-7.13(d,1H),4.88-4.87(d,1H),4.79- 4.78(d,1H), 4.60(d,2H), 3.62(bs,8H), 2.38(s,3H).

實施例34至36係由1-(5-溴嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-羧酸(化合物8a)以類似合成實施例8方式製備。獲得之中間產物頻哪醇硼酸酯(pinacol boronates)係在鈴木偶聯反應中與2-溴吡啶(實施例34)、2-氯-4-環丙基吡啶(實施例35)及2-溴-4-甲氧基吡啶(實施例36)偶聯。 Examples 34 to 36 are based on 1-(5-bromopyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-carboxylic acid (Compound 8a) in a similar manner to Synthesis Example 8. Method of preparation. The intermediate product pinacol boronates obtained in the Suzuki coupling reaction with 2-bromopyridine (Example 34), 2-chloro-4-cyclopropylpyridine (Example 35) and 2- Bromo-4-methoxypyridine (Example 36) was coupled.

實施例34：(1-(5-(吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(吡咯啶-1-基)甲酮 Example 34: (1-(5-(Pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)(pyrrolidine-1- Ketone

白色固體。產量：65mg。m/z：=414.0(MW calc.413.47).1H NMR(400MHz,DMSO-d6,δ ppm)：9.30(s,2H),8.67-8.66(d,1H),8.51(s,1H),8.03-8.01(d,1H),7.92-7.90(m,1H),7.80-7.78(d,1H),7.38-7.35(m,1H),7.27-7.25(d,1H),4.89-4.88(d,1H),4.79-4.78(d,1H),4.63(d,2H),3.51-3.40(m,4H),1.91-1.80(m,4H). White solid. Yield: 65 mg. m/z: = 414.0 (MW calc. 413.47). 1H NMR (400MHz, DMSO-d6, δ ppm): 9.30 (s, 2H), 8.67-8.66 (d, 1H), 8.51 (s, 1H), 8.03 -8.01 (d, 1H), 7.92-7.90 (m, 1H), 7.80-7.78 (d, 1H), 7.38-7.35 (m, 1H), 7.27-7.25 (d, 1H), 4.89-4.88 (d, 1H), 4.79-4.78 (d, 1H), 4.63 (d, 2H), 3.51-3.40 (m, 4H), 1.91-1.80 (m, 4H).

實施例35：(1-(5-(4-環丙基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(吡咯啶-1-基)甲酮 Example 35: (1-(5-(4-cyclopropylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl) ( Pyrrolidin-1-yl)methanone

白色固體。產量：90mg。m/z：=453.8(MW calc.453.54).1H NMR(400MHz,DMSO-d6,δ ppm)：9.29(s,2H),8.51(s,1H),8.46-8.45(d,1H),7.80-7.78(d,1H),7.69(s,1H),7.26-7.24(d,1H),7.07(m,1H),4.89-4.88(d,1H),4.79-4.78(d,1H),4.62(s,2H),3.49-3.42(m,4H),1.99(m,1H),1.89-1.82(m,4H),1.10-1.08(d,2H),0.93(d,2H). White solid. Yield: 90 mg. m/z: = 453.8 (MW calc. 453.54). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.29 (s, 2H), 8.51 (s, 1H), 8.46-8.45 (d, 1H), 7.80 -7.78(d,1H), 7.69(s,1H), 7.26-7.24(d,1H),7.07(m,1H),4.89-4.88(d,1H),4.79-4.78(d,1H),4.62 (s, 2H), 3.49-3.42 (m, 4H), 1.99 (m, 1H), 1.89-1.82 (m, 4H), 1.10-1.08 (d, 2H), 0.93 (d, 2H).

實施例36：(1-(5-(4-甲氧基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(吡咯啶-1-基)甲酮 Example 36: (1-(5-(4-Methoxypyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl) ( Pyrrolidin-1-yl)methanone

白色固體。產量：110mg。m/z：=444.3(MW calc.443.50).1H NMR(400MHz,DMSO-d6,δ ppm)：9.30(s,2H),8.50(s,1H),8.48-8.46(d,1H),7.80-7.78(d,1H),7.58(s,1H),7.26-7.24(d,1H),6.95-6.94(d,1H),4.89-4.88(d,1H),4.79-4.77(d,1H),4.62(s,2H),3.91(s,3H),3.50-3.40(m,4H),1.99(m,1H),1.91-1.82(m,4H). White solid. Yield: 110 mg. m/z: = 444.3 (MW calc. 443.50). 1H NMR (400MHz, DMSO-d6, δ ppm): 9.30 (s, 2H), 8.50 (s, 1H), 8.48-8.46 (d, 1H), 7.80 -7.78(d,1H), 7.58(s,1H), 7.26-7.24(d,1H), 6.95-6.94(d,1H),4.89-4.88(d,1H),4.79-4.77(d,1H) , 4.62 (s, 2H), 3.91 (s, 3H), 3.50-3.40 (m, 4H), 1.99 (m, 1H), 1.91-1.82 (m, 4H).

實施例37：(1-(5-(3-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 Example 37: (1-(5-(3-Fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)(morpholinyl)- ketone

肆(三苯基膦)鈀(0)(80mg,0.07mmol)係於rt被加入至在Ar中經攪拌之DME/EtOH(1：1,12ml)中之化合物8b(150mg,0.35mmol)、3-氟苯基硼酸(98mg,0.7mmol)及2M Na2CO3溶液(0.34ml)溶液。該反應混合物於100℃攪拌6h，降溫至rt並經矽藻土墊(pad)過濾。該濾液係被蒸發且使該剩餘物 經以快速管柱層析法[DCM與5% MeOH]純化之後以DCM/己烷(1：2)研磨。淺黃色固體。產量：50mg(32%)。HPLC(方法3)：Rt=3.26min.,m/z：[M+H]+=447.1(MW calc.446.47).1H NMR(400MHz,DMSO-d6,δ ppm)：9.04(s,2H),8.39(s,1H),7.80(d,J=7.2Hz,1H),7.68-7.61(m,2H),7.54-7.52(m,1H),7.23-7.19(m,1H),7.13(d,J=7.6Hz,1H),4.87(d,J=6Hz,2H),4,78(d,J=6Hz,2H),4.60(s,2H),3.62(bs,8H). 肆(triphenylphosphine)palladium(0) (80 mg, 0.07 mmol) was added to compound 8b (150 mg, 0.35 mmol) in EtOAc EtOAc EtOAc A solution of 3-fluorophenylboronic acid (98 mg, 0.7 mmol) and 2M Na 2 CO 3 (0.34 mL). The reaction mixture was stirred at 100 ° C for 6 h, cooled to rt and filtered thru pad. The filtrate was evaporated and the residue was purified by flash chromatography eluting with EtOAc EtOAc EtOAc Light yellow solid. Yield: 50 mg (32%). HPLC (Method 3): R t = 3.26 min., m/z: [M+H] + = 447.1 (MW calc.446.47).1H NMR (400 MHz, DMSO-d6, δ ppm): 9.04 (s, 2H) ), 8.39 (s, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.68-7.61 (m, 2H), 7.54 - 7.52 (m, 1H), 7.23-7.19 (m, 1H), 7.13 ( d, J = 7.6 Hz, 1H), 4.87 (d, J = 6 Hz, 2H), 4, 78 (d, J = 6 Hz, 2H), 4.60 (s, 2H), 3.62 (bs, 8H).

實施例38至41係由化合物8b依據合成實施例37之製程獲得。 Examples 38 to 41 were obtained from the compound 8b according to the procedure of Synthesis Example 37.

實施例38：(1-(5-(4-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 Example 38: (1-(5-(4-Fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)(morpholinyl)- ketone

白色固體。產量：50mg。HPLC(方法3)：Rt=3.15min.,m/z：[M+H]+=447.0(MW calc.446.47).1H NMR(400MHz,DMSO-d6,δ ppm)：8.98(s,2H),8.38(s,1H),7.80-7.79(m,3H),7.36-7.31(m,2H),7.13-7.11(m,1H),4.87(d,J=6Hz,2H),4.79(d,J=5.6Hz,2H),4.60(s,2H),3.63(bs,8H). White solid. Yield: 50 mg. HPLC (Method 3): R t = 3.15 min., m/z: [M+H] + = 447.0 (MW calc.446.47).1H NMR (400 MHz, DMSO-d6, δ ppm): 8.98 (s, 2H) ), 8.38 (s, 1H), 7.80-7.79 (m, 3H), 7.36-7.31 (m, 2H), 7.13-7.11 (m, 1H), 4.87 (d, J = 6 Hz, 2H), 4.79 (d) , J = 5.6 Hz, 2H), 4.60 (s, 2H), 3.63 (bs, 8H).

實施例39：(1-(5-(2,5-二氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 Example 39: (1-(5-(2,5-Difluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl) (morpholine) Ketone

白色固體。產量：42mg。HPLC(方法3)：Rt=3.21min.,m/z：[M+H]+=464.8(MW calc.464.46).1H NMR(400MHz,DMSO-d6,δ ppm)：8.89(s,2H),8.38(s,1H),7.82-7.80(m,1H),7.61(m,1H),7.42(m,1H),7.29(m,1H),7.15(d,J=7.6Hz,1H),4.87(d,J=5.6Hz,2H),4.79(d,J=5.6Hz,2H),4.61(s,2H),3.63(bs,8H). White solid. Yield: 42 mg. HPLC (Method 3): R t = 3.21 min., m/z: [M+H] + = 464.8 (MW calc. 464.46).1H NMR (400 MHz, DMSO-d6, δ ppm): 8.89 (s, 2H) ), 8.38 (s, 1H), 7.82-7.80 (m, 1H), 7.61 (m, 1H), 7.42 (m, 1H), 7.29 (m, 1H), 7.15 (d, J = 7.6 Hz, 1H) , 4.87 (d, J = 5.6 Hz, 2H), 4.79 (d, J = 5.6 Hz, 2H), 4.61 (s, 2H), 3.63 (bs, 8H).

實施例40：(1-(5-(2,3-二氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 Example 40: (1-(5-(2,3-Difluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl) (morpholine) Ketone

產量：75mg。淺黃色固體。HPLC(方法3)：Rt=3.26min.,m/z：[M+H]+=465.3(MW calc.464.46).1H NMR(400MHz,DMSO-d6,δ ppm)：8.89(s,2H),8.38(s,1H),7.81(d,J=7.6Hz,1H),7.49-7.45(m,2H),7.35(m,1H),7.15(d,J=7.2Hz,1H),4.88(d,J=6Hz,2H),4.79(d,J=6Hz,2H),4.61(s,2H),3.62(bs,8H). Yield: 75 mg. Light yellow solid. HPLC (Method 3): R t = 3.26 min., m/z: [M+H] + = 465.3 (MW calc. 464.46). 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.89 (s, 2H) ), 8.38 (s, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.49-7.45 (m, 2H), 7.35 (m, 1H), 7.15 (d, J = 7.2 Hz, 1H), 4.88 (d, J = 6 Hz, 2H), 4.79 (d, J = 6 Hz, 2H), 4.61 (s, 2H), 3.62 (bs, 8H).

實施例41：(1-(5-(3,5-二氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 Example 41: (1-(5-(3,5-Difluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl) (morpholine) Ketone

白色固體。產量：65mg。HPLC(方法2)：Rt=1.72min.,m/z：[M+H]+=465.1(MW calc.464.46).1H NMR(400MHz,DMSO-d6,δ ppm)：9.08(s,2H),8.39(s,1H),7.81(d,J=7.6Hz,1H),7.60(d,J=7.6Hz,2H),7.27-7.24(m,1H),7.15(d,J=7.6Hz,1H),4.88(d,J=6Hz,2H),4.78(d,J=6Hz,2H),4.61(s,2H),3.63(bs,8H). White solid. Yield: 65 mg. HPLC (Method 2): R t = 1.72 min., m/z: [M+H] + = 465.1 (MW calc. 464.46). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.08 (s, 2H) ), 8.39 (s, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 7.6 Hz, 2H), 7.27-7.24 (m, 1H), 7.15 (d, J = 7.6 Hz) , 1H), 4.88 (d, J = 6 Hz, 2H), 4.78 (d, J = 6 Hz, 2H), 4.61 (s, 2H), 3.63 (bs, 8H).

實施例42至46係由1-(5-溴嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-羧酸(化合物8a)製備，其係經二步驟，其包括胺與2-(甲基胺)乙醇之偶聯反應之後類似於實施例37之鈴木偶聯反應。 Examples 42 to 46 were prepared from 1-(5-bromopyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-carboxylic acid (Compound 8a), which was A step comprising a Suzuki coupling reaction similar to that of Example 37 after a coupling reaction of an amine with 2-(methylamine)ethanol.

實施例42：1-(5-(3-氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 42: 1-(5-(3-Fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxo ring Butane]-6-formamide

白色固體。產量：60mg。HPLC(方法3)：Rt=2.89min.,m/z：[M+H]+=434.8(MW calc.434.46).1H NMR(400MHz,DMSO-d6,δ ppm)：9.03(s,2H),8.36(s,1H),7.78-7.77(m,1H),7.67-7.61(m,2H),7.53-7.52(m,1H),7.21(t,J=7.8Hz,1H),7.12(d,J=7.6Hz,1H),4.88(d,J=6Hz,2H),4.79-4.78(m,3H),4.61(s,2H),3.64(m,1H),3.52(bs,2H),3.0(m,3H). White solid. Yield: 60 mg. HPLC (Method 3): Rt = 2.89 min., m/z: [M+H] + =434.8 (MW calc.434.46).1H NMR (400 MHz, DMSO-d6, δ ppm): 9.03 (s, 2H) ), 8.36 (s, 1H), 7.78-7.77 (m, 1H), 7.67-7.61 (m, 2H), 7.53-7.52 (m, 1H), 7.21 (t, J = 7.8 Hz, 1H), 7.12 ( d, J = 7.6 Hz, 1H), 4.88 (d, J = 6 Hz, 2H), 4.79 - 4.78 (m, 3H), 4.61 (s, 2H), 3.64 (m, 1H), 3.52 (bs, 2H) , 3.0 (m, 3H).

實施例43：1-(5-(4-氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 43: 1-(5-(4-Fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxygen ring Butane]-6-formamide

褐色固體。產量：55mg。HPLC(方法3)：Rt=3.35min.,m/z：[M+H]+=435.4(MW calc.434.46).1H NMR(400MHz,DMSO-d6,δ ppm)：8.97(s,2H),8.35(s,1H),7.79-7.78(m,3H),7.33(t,J=8.4Hz,2H),7.11(d,J=7.2Hz,1H),4.87(d,J=5.6Hz,2H),4.80-4.78(m,3H),4.60(s,2H),3.64(m,3H),3.0(m,3H). Brown solid. Yield: 55 mg. HPLC (Method 3): R t = 3.35 min., m/z: [M+H] + =435.4 (MW calc.434.46).1H NMR (400 MHz, DMSO-d6, δ ppm): 8.97 (s, 2H) ), 8.35 (s, 1H), 7.79-7.78 (m, 3H), 7.33 (t, J = 8.4 Hz, 2H), 7.11 (d, J = 7.2 Hz, 1H), 4.87 (d, J = 5.6 Hz) , 2H), 4.80-4.78 (m, 3H), 4.60 (s, 2H), 3.64 (m, 3H), 3.0 (m, 3H).

實施例44：1-(5-(2,5-二氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 44: 1-(5-(2,5-Difluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3' -oxycyclobutane]-6-formamide

白色固體。產量：110mg。HPLC(方法2)：Rt=1.61min.,m/z：[M+H]+=453.0(MW calc.452.45).1H NMR(400MHz,DMSO-d6,δ ppm)：8.88(s,2H),8.35(s,1H),7.79-7.77(m,1H),7.62-7.58(m,1H),7.43-7.39(m,1H),7.31-7.28(m,1H),7.13(d,J=7.6Hz,1H),4.87(d,J=6Hz,2H),4.80-4.78(m,3H),4.61(s,2H),3.63-3.51(m,3H),3.0(m,3H). White solid. Yield: 110 mg. HPLC (Method 2): R t = 1.61 min., m/z: [M+H] + = 453.0 (MW calc.452.45).1H NMR (400 MHz, DMSO-d6, δ ppm): 8.88 (s, 2H) ), 8.35 (s, 1H), 7.79-7.77 (m, 1H), 7.62-7.58 (m, 1H), 7.43-7.39 (m, 1H), 7.31-7.28 (m, 1H), 7.13 (d, J) = 7.6 Hz, 1H), 4.87 (d, J = 6 Hz, 2H), 4.80 - 4.78 (m, 3H), 4.61 (s, 2H), 3.63 - 3.51 (m, 3H), 3.0 (m, 3H).

實施例45：1-(5-(2,3-二氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 45: 1-(5-(2,3-Difluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3' -oxycyclobutane]-6-formamide

白色固體。產量：90mg。HPLC(方法3)：Rt=2.91min.,m/z：[M+H]+=452.8(MW calc.452.45).1H NMR(400MHz,DMSO-d6,δ ppm)：8.88(s,2H),8.35(s,1H),7.79-7.77(m,1H),7.50-7.46(m,2H),7.35-7.33(m,1H),7.13(d,J=7.8Hz,1H),4.88(d,J=6.4Hz,2H),4.80-4.79(m,3H),4.61(s,2H),3.64(m,1H),3.52(bs,2H),3.0(m,3H). White solid. Yield: 90 mg. HPLC (Method 3): R t = 2.91 min., m/z: [M+H] + = 452.8 (MW calc.452.45).1H NMR (400 MHz, DMSO-d6, δ ppm): 8.88 (s, 2H) ), 8.35 (s, 1H), 7.79-7.77 (m, 1H), 7.50-7.46 (m, 2H), 7.35-7.33 (m, 1H), 7.13 (d, J = 7.8 Hz, 1H), 4.88 ( d, J = 6.4 Hz, 2H), 4.80-4.79 (m, 3H), 4.61 (s, 2H), 3.64 (m, 1H), 3.52 (bs, 2H), 3.0 (m, 3H).

實施例46：1-(5-(3,5-二氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 46: 1-(5-(3,5-Difluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3' -oxycyclobutane]-6-formamide

白色固體。產量：77mg。HPLC(方法3)：Rt=2.96min.,m/z：[M+H]+=452.8(MW calc.452.45).1H NMR(400MHz,DMSO-d6,δ ppm)：9.07(s,2H),8.36(s,1H),7.79-7.77(m,1H),7.59(d,J=7.6Hz,2H),7.24(t,J=9.6Hz,1H),7.13(d,J=7.2Hz,1H),4.88(d,J=6Hz,2H),4.80-4.78(m,3H),4.61(s,2H),3.64(m,1H),3.52(bs,2H),3.0(m,3H). White solid. Yield: 77 mg. HPLC (Method 3): R t = 2.96 min., m/z: [M+H] + = 452.8 (MW calc.452.45).1H NMR (400 MHz, DMSO-d6, δ ppm): 9.07 (s, 2H) ), 8.36 (s, 1H), 7.79-7.77 (m, 1H), 7.59 (d, J = 7.6 Hz, 2H), 7.24 (t, J = 9.6 Hz, 1H), 7.13 (d, J = 7.2 Hz) , 1H), 4.88 (d, J = 6 Hz, 2H), 4.80-4.78 (m, 3H), 4.61 (s, 2H), 3.64 (m, 1H), 3.52 (bs, 2H), 3.0 (m, 3H) ).

實施例47至51係由Int-1製備，其係經三步驟，其包括胺鈴木偶聯反應(類似於合成實施例37)、酯水解(規程3b)及與2-(甲基胺)乙醯胺之醯胺偶聯(規程3c)。 Examples 47 to 51 were prepared from Int-1 in three steps, including an amine Suzuki coupling reaction (similar to Synthesis Example 37), ester hydrolysis (Protocol 3b), and 2-(methylamine) B. Indoleamine coupling of indoleamine (Protocol 3c).

實施例47：N-(2-胺-2-側氧乙基)-1-(5-(3-氟苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 47: N-(2-Amine-2-oxoethyl)-1-(5-(3-fluorophenyl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3, 3'-oxocyclobutane]-6-formamide

白色固體。產量：55mg。HPLC(方法3)：Rt=2.75min.,m/z：[M+H]+=448.0(MW calc.447.49).1H NMR(400MHz,DMSO-d6,δ ppm)：9.05-9.02(m,2H),8.39(s,1H),7.89-7.76(m,1H),7.68-7.61(m,2H),7.54-7.42(m,2H),7.23-7.18(m,2H),7.10-7.08(m,1H),4.86(d,J=6.4Hz,2H),4.79(m,2H),4.61(s,2H),4.04(s,1H),3.84(s,1H),2.96(s,3H). White solid. Yield: 55 mg. HPLC (Method 3): R t = 2.75 min., m/z: [M+H] + = 448.0 (MW calc.447.49).1H NMR (400 MHz, DMSO-d6, δ ppm): 9.05-9.02 (m) , 2H), 8.39 (s, 1H), 7.89-7.76 (m, 1H), 7.68-7.61 (m, 2H), 7.54-7.42 (m, 2H), 7.23-7.18 (m, 2H), 7.10-7.08 (m, 1H), 4.86 (d, J = 6.4 Hz, 2H), 4.79 (m, 2H), 4.61 (s, 2H), 4.04 (s, 1H), 3.84 (s, 1H), 2.96 (s, 3H).

實施例48：N-(2-胺-2-側氧乙基)-1-(5-(4-氟苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 48: N-(2-Amine-2-oxoethyl)-1-(5-(4-fluorophenyl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3, 3'-oxocyclobutane]-6-formamide

白色固體。產量：125mg。HPLC(方法3)：Rt=3.23min.,m/z：[M+H]+=448.4(MW calc.447.49).1H NMR(400MHz,DMSO-d6,δ ppm)：8.98-8.96(m,2H),8.39(s,1H),7.80(m,3H),7.46-7.41(m,1H),7.33(m,2H),7.16-7.09(m,2H),4.87(m,2H),4.79(m,2H),4.59(s,2H),4.04(s,1H),3.84(s,1H),2.96(s,3H). White solid. Yield: 125 mg. HPLC (Method 3): R t = 3.23 min., m/z: [M+H] + = 448.4 (MW calc.447.49).1H NMR (400 MHz, DMSO-d6, δ ppm): 8.98-8.96 (m) , 2H), 8.39 (s, 1H), 7.80 (m, 3H), 7.46-7.41 (m, 1H), 7.33 (m, 2H), 7.16-7.09 (m, 2H), 4.87 (m, 2H), 4.79 (m, 2H), 4.59 (s, 2H), 4.04 (s, 1H), 3.84 (s, 1H), 2.96 (s, 3H).

實施例49：N-(2-胺-2-側氧乙基)-1-(5-(2,5-二氟苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 49: N-(2-Amine-2-oxoethyl)-1-(5-(2,5-difluorophenyl)pyrimidin-2-yl)-N-methylspiro[Porphyrin -3,3'-oxocyclobutane]-6-carboxamide

白色固體。產量：60mg。HPLC(方法3)：Rt=2.77min.,m/z：[M+H]+=465.8(MW calc.465.46).1H NMR(400MHz,DMSO-d6,δ ppm)：8.91-8.87(m,2H),8.38(s,1H),7.82-7.76(m,1H),7.61(m,1H),7.45-7.41(m,2H),7.29(m,1H),7.19-7.09(m,2H),4.87(m,2H),4.79(m,2H),4.60(s,2H),4.04(s,1H),3.84(s,1H),2.95(s,3H). White solid. Yield: 60 mg. HPLC (Method 3): R t = 2.77 min., m/z: [M+H] + = 465.8 (MW calc.465.46).1H NMR (400 MHz, DMSO-d6, δ ppm): 8.91-8.87 (m) , 2H), 8.38 (s, 1H), 7.82-7.76 (m, 1H), 7.61 (m, 1H), 7.45-7.41 (m, 2H), 7.29 (m, 1H), 7.19-7.09 (m, 2H) ), 4.87 (m, 2H), 4.79 (m, 2H), 4.60 (s, 2H), 4.04 (s, 1H), 3.84 (s, 1H), 2.95 (s, 3H).

實施例50：N-(2-胺-2-側氧乙基)-1-(5-(2,3-二氟苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 50: N-(2-Amino-2-oxoethyl)-1-(5-(2,3-difluorophenyl)pyrimidin-2-yl)-N-methylspiro[Porphyrin -3,3'-oxocyclobutane]-6-carboxamide

白色固體。產量：95mg。HPLC(方法3)：Rt=2.77min.,m/z：[M+H]+=466.3(MW calc.465.46).1H NMR(400MHz,DMSO-d6,δ ppm)：8.89-8.87(m,2H),8.38(s,1H),7.79-7.77(m,1H),7.61(m,1H),7.49-7.35(m,4H),7.19-7.09(m,2H),4.87-4.80(m,4H),4.60(s,2H),4.04(s,1H),3.84(s,1H),2.95(s,3H). White solid. Yield: 95 mg. HPLC (Method 3): Rt = 2.77 min., m/z: [M+H] + = 466.3 (MW calc.465.46).1H NMR (400 MHz, DMSO-d6, δ ppm): 8.89-8.87 (m) , 2H), 8.38 (s, 1H), 7.79-7.77 (m, 1H), 7.61 (m, 1H), 7.49-7.35 (m, 4H), 7.19-7.09 (m, 2H), 4.87-4.80 (m , 4H), 4.60 (s, 2H), 4.04 (s, 1H), 3.84 (s, 1H), 2.95 (s, 3H).

實施例51：N-(2-胺-2-側氧乙基)-1-(5-(3,5-二氟苯基)嘧啶-2-基)-N-甲基螺 [吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 51: N-(2-Amino-2-oxoethyl)-1-(5-(3,5-difluorophenyl)pyrimidin-2-yl)-N-methyl snail [Porphyrin-3,3'-oxycyclobutane]-6-carboxamide

白色固體。產量：120mg。HPLC(方法2)：Rt=1.58min.,m/z：[M+H]+=466.0(MW calc.465.46).1H NMR(400MHz,DMSO-d6,δ ppm)：9.09-9.05(m,2H),8.40(s,1H),7.78-7.76(m,1H),7.61-7.59(m,2H),7.46-7.42(m,1H),7.24-7.09(m,3H),4.87(m,2H),4.79(m,2H),4.60(s,2H),4.04(s,1H),3.84(s,1H),2.95(s,3H). White solid. Yield: 120 mg. HPLC (Method 2): R t = 1.58 min., m/z: [M+H] + = 466.0 (MW calc.465.46).1H NMR (400 MHz, DMSO-d6, δ ppm): 9.09-9.05 (m) , 2H), 8.40 (s, 1H), 7.78-7.76 (m, 1H), 7.61-7.59 (m, 2H), 7.46-7.42 (m, 1H), 7.24-7.09 (m, 3H), 4.87 (m) , 2H), 4.79 (m, 2H), 4.60 (s, 2H), 4.04 (s, 1H), 3.84 (s, 1H), 2.95 (s, 3H).

實施例52：6-(乙亞磺醯基)-1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷] Example 52: 6-(ethylsulfinyl)-1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]

52a)6-(乙硫基)吲哚啉-2-酮 52a) 6-(ethylthio) porphyrin-2-one

Pd2(dba)3(5.3g,5.8mmol,0.05eq)、Xanthphos(6.8g,11.7mmol,0.1eq)及乙硫醇(9.1ml,117mmol)係被加入至在N2中攪拌之1,4-二噁烷(750ml)中之6-溴吲哚啉-2-酮(25g,117mmol)及DIPEA(43.4ml,235mmol,2eq)之溶液。然後使該反應混合物回流16h，降溫至rt及經矽藻土墊過濾。該過濾器係 經以EtOAc淋洗且該濾液經以水(80ml)及鹽水(80ml)清洗、經Na2SO4乾燥及濃縮。使該剩餘物經以管柱層析法[100-200目矽膠；EtOAc/己烷=2：3]純化。褐色固體。產量：20g(88%)。 Pd 2 (dba) 3 (5.3 g, 5.8 mmol, 0.05 eq), Xanthphos (6.8 g, 11.7 mmol, 0.1 eq) and ethanethiol (9.1 ml, 117 mmol) were added to a stirred 1 in N 2 . A solution of 6-bromoporphyrin-2-one (25 g, 117 mmol) and DIPEA (43.4 mL, 235 mmol, 2 eq) in 4-dioxane (750 mL). The reaction mixture was then refluxed for 16 h, cooled to rt and filtered thru a pad. The filter system was rinsed with EtOAc and the filtrate was water (80ml) and brine (80ml) washed, dried over Na 2 SO 4 dried and concentrated. The residue was purified by column chromatography [100-200 EtOAc (EtOAc/hexane = 2:3). Brown solid. Yield: 20 g (88%).

52b)叔丁基6-(乙硫基)-2-側氧吲哚啉-1-羧酸酯 52b) tert-butyl 6-(ethylthio)-2-oxooxalin-1-carboxylate

於rt對THF(200ml)中之化合物52a(18g,93.26mmol,1eq)攪拌溶液加入NaHCO3(23.5g,280mmol,3eq)之後加入二-叔丁基重碳酸鹽(51ml,233mmol,2.5eq)。使該混合物經回流16h、過濾並在減壓下濃縮。該剩留物係經以管柱層析法[100-200目矽膠；EtOAc/己烷=1：9]純化。褐色膠質。產量：21g(77%).m/z：[M+H]+=294.1 After stirring the solution was added two of THF at rt Compound 52a (18g, 93.26mmol, 1eq) (200ml) was added in the NaHCO 3 (23.5g, 280mmol, 3eq ) - tert-butyl bicarbonate (51ml, 233mmol, 2.5eq) . The mixture was refluxed for 16 h, filtered and concentrated under reduced vacuum. The residue was purified by column chromatography [100-200 mesh EtOAc; EtOAc/hexane = 1:9]. Brown gum. Yield: 21g (77%).m/z: [M+H] + =294.1

52c)叔丁基6-(乙硫基)-3,3-雙(羥甲基)-2-側氧吲哚啉-1-羧酸酯 52c) tert-butyl 6-(ethylthio)-3,3-bis(hydroxymethyl)-2-oxooxalin-1-carboxylate

K2CO3(24g,174.06mmol,3.0eq)及多聚甲醛(42.19g,1392mmol,24eq)係於rt被加入至THF(200mL)中之化合物52b(17g,58.02mmol,1.0eq)攪拌溶液且使該混合物經攪拌1h。然後使該反應混合物經過濾且使該濾液經蒸發。該剩餘物以管柱層析法[矽膠100-200目，EtOAc/己烷=3：2]純化。白色固體。產量：17g(83%)。 K 2 CO 3 (24 g, 174.06 mmol, 3.0 eq) and paraformaldehyde (42.19 g, 1392 mmol, 24 eq) were added to a stirred solution of compound 52b (17 g, 58.02 mmol, 1.0 eq) in THF (200 mL). The mixture was allowed to stir for 1 h. The reaction mixture was then filtered and the filtrate was evaporated. The residue was purified by column chromatography [100-200 mesh, EtOAc/hexane = 3:2]. White solid. Yield: 17 g (83%).

52d)6-(乙硫基)-3,3-雙(羥甲基)吲哚啉-2-酮 52d) 6-(ethylthio)-3,3-bis(hydroxymethyl) porphyrin-2-one

TFA(4ml,49.47mmol,3.5eq)係於0℃被逐滴加入至DCM(50mL)中之化合物52c(5g,14.16mmol,1.0eq)攪拌溶液DCM(50mL)。使該混合物於rt經攪拌1h然後以冰淬滅。使該水層分離及以EtOAc(4 x 40ml)萃取。該合併之有機層係經以鹽水(20ml)清洗、經Na2SO4乾燥並濃縮。此物質未經任何進一步純化而被用於次一步驟。白色固體。產量：3g(84%).m/z：[M+H]+ =254.0. TFA (4 ml, 49.47 mmol, 3.5 eq) was taken from EtOAc (EtOAc) The mixture was stirred at rt for 1 h then quenched with ice. The aqueous layer was separated and extracted with EtOAc (EtOAc) The combined organic layers of the system was washed with brine (20ml) washed, dried over Na 2 SO 4 and concentrated. This material was used in the next step without any further purification. White solid. Yield: 3g (84%).m/z: [M+H] + =254.0.

52e)(6-(乙硫基)吲哚啉-3,3-二基)二甲醇 52e) (6-(ethylthio)porphyrin-3,3-diyl)dimethanol

硼烷二甲基硫化物複合物(Borane dimethyl sulfide complex)溶液(8.7ml,98.8mmol,5eq)係於0℃慢慢加入至THF(50ml)中之化合物52d(5g,19.76mmol,1eq)攪拌溶液。該反應混合物係於rt經攪拌16h、降溫至0℃、以濃縮之氯化氫(7ml)淬滅及攪拌15min。該溶劑係在減壓下被蒸發且剩餘之水係經與MeOH共沸蒸餾移除。該產生之白色固體未經任何進一步純化而用於次一步驟。產量：3.5g.m/z：[M+H]+=240.2. A solution of borane dimethyl sulfide complex (8.7 ml, 98.8 mmol, 5 eq) was added to compound 52d (5 g, 19.76 mmol, 1 eq) slowly added to THF (50 ml) at 0 ° C. Solution. The reaction mixture was stirred at rt for 16 h, cooled to EtOAc (EtOAc) The solvent was evaporated under reduced pressure and the remaining water was removed by azeotropic distillation with MeOH. The resulting white solid was used in the next step without any further purification. Yield: 3.5 gm/z: [M+H] + = 240.2.

52f)(1-(5-溴嘧啶-2-基)-6-(乙硫基)吲哚啉-3,3-二基)二甲醇 52f)(1-(5-Bromopyrimidin-2-yl)-6-(ethylthio)porphyrin-3,3-diyl)dimethanol

正丁醇(20ml)中之化合物52e(2.6g,9.45mmol,1eq)、5-溴-2-氯-嘧啶(2g,10.39mmol,1.1eq)、DIPEA(12ml,66.15mmol,7eq)係在密封管中於140℃經攪拌16h。該溶劑係在真空中被移除且該剩餘物係被溶於EtOAc。該有機相係經以水(40ml)及鹽水(40ml)清洗、經Na2SO4乾燥並濃縮。該原產物係經以管柱層析法[100-200目矽膠，EtOAc/己烷=1：1]純化白色固體。產量：2g(48%).m/z：[M+H]+=396.1. Compound 52e (2.6 g, 9.45 mmol, 1 eq), 5-bromo-2-chloro-pyrimidine (2 g, 10.39 mmol, 1.1 eq), DIPEA (12 ml, 66.15 mmol, 7 eq) in n-butanol (20 ml) The tube was stirred at 140 ° C for 16 h. The solvent was removed in vacuo and the residue was dissolved in EtOAc. The organic phase was based in water (40ml) and brine (40ml) washed, dried and concentrated over Na 2 SO 4. The original product was purified as a white solid by column chromatography [100-200 EtOAc, EtOAc/hexane = 1:1]. Yield: 2g (48%).m/z: [M+H] + =396.1.

52g)(1-(5-溴嘧啶-2-基)-6-(乙硫基)-3-(羥甲基)吲哚啉-3-基)甲基-4-甲基-苯磺酸酯 52g) (1-(5-Bromopyrimidin-2-yl)-6-(ethylthio)-3-(hydroxymethyl)porphyrin-3-yl)methyl-4-methyl-benzenesulfonic acid ester

LiHMDS(1M溶液in THF,3.28ml,3.28mmol,1eq)係於-78℃被緩慢加入至THF(150ml)中之化合物52f(1.3g,3.28mmol,1eq)攪拌溶液。該溶液係經攪拌20min.，經溶於THF中之甲苯磺醯基氯(0.62g,3.28mmol,1eq)加入並於-78℃持續攪拌2h。該反應混合物係經以飽和NH4Cl溶液淬滅及以 EtOAc(2x 50ml)萃取。該合併之有機層係經以鹽水(30ml)清洗、經Na2SO4乾燥並濃縮。該剩留物係經以純化管柱層析法[矽膠100-200目，EtOAc/己烷=2：3]純化。白色固體。產量：1.0g(55%). LiHMDS (1 M solution in THF, 3.28 mL, 3.28 mmol, 1 eq) was stirred in EtOAc (EtOAc) The solution was stirred for 20 min., toluenesulfonyl chloride (0.62 g, 3.28 mmol, 1 eq) in THF. The reaction mixture was extracted with saturated lines NH 4 Cl solution and quenched in EtOAc (2x 50ml). The combined organic layers of the system was washed with brine (30ml) washed, dried over Na 2 SO 4 and concentrated. The residue was purified by purification column chromatography [100-200 mesh, EtOAc/hexane = 2:3]. White solid. Yield: 1.0g (55%).

52h)1-(5-溴嘧啶-2-基)-6-(乙硫基)螺[吲哚啉-3,3'-氧環丁烷] 52h) 1-(5-Bromopyrimidin-2-yl)-6-(ethylthio)spiro[porphyrin-3,3'-oxocyclobutane]

叔丁醇(80ml)中之化合物52g(0.7g,1.27mmol,1eq)及KOH(0.213g,3.81mmol,3eq)係於50℃經攪拌30min。該溶劑係在減壓下經蒸發且該剩餘物係於EtOAc懸浮、以水(20ml)及鹽水(20ml)清洗、經Na2SO4乾燥及濃縮。該產生之白色固體未經任何進一步純化而用於次一步驟。產量：0.45g(94%).m/z：[M+H]+=380.2. Compound 52g (0.7 g, 1.27 mmol, 1 eq) and KOH (0.213 g, 3.81 mmol, 3 eq) in tert-butanol (80 ml) were stirred at 50 ° C for 30 min. The solvent-based and evaporated under reduced pressure and the residue was suspended in line with EtOAc, water (20ml) and brine (20ml) washed, dried over Na 2 SO 4 dried and concentrated. The resulting white solid was used in the next step without any further purification. Yield: 0.45 g (94%). m/z: [M+H] + = 380.2.

52i)6-(乙硫基)-1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷] 52i) 6-(ethylthio)-1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]

(AtaPhos)2PdCl2(0.05g,0.06mmol,0.1eq)係被加入至於rt在N2中攪拌之戊醇(10ml)中之化合物52h(0.26g,0.68mmol,1eq)、(2-氟苯基)硼酸(0.125g,0.89mmol,1.3eq)及10% K2CO3水溶液(0.8ml)溶液。然後該反應混合物係於80℃經攪拌16h並經矽藻土塞過濾。該過濾器係經以EtOAc淋洗且該濾液係經以水(10ml)及鹽水(10ml)清洗、經Na2SO4乾燥及濃縮。該剩留物係經以管柱層析法[EtOAc/己烷=3：7]純化。白色固體。產量：0.23g(85%).m/z：[M+H]+=394.3. (AtaPhos) 2 PdCl 2 (0.05g , 0.06mmol, 0.1eq) was added as to rt Department of stirring in N 2-pentanol Compound 52h (10ml) in the (0.26g, 0.68mmol, 1eq), (2- fluoro phenyl) boronic acid (0.125g, 0.89mmol, 1.3eq) and 10% K 2 CO 3 aqueous solution (0.8 ml of) solution. The reaction mixture was then stirred at 80 ° C for 16 h and filtered through a pad of Celite. The filter system was rinsed with EtOAc and the filtrate was based in water (10ml) and brine (10ml) washed, dried over Na 2 SO 4 dried and concentrated. The residue was purified by column chromatography [EtOAc /hexane = 3:7]. White solid. Yield: 0.23 g (85%). m/z: [M+H] + = 394.3.

52j)6-(乙亞磺醯基)-1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷] 52j) 6-(ethylsulfinyl)-1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]

mCPBA(68mg,0.3mmol,0.8eq)係於0℃.被緩慢加入至THF(10ml)中之化合物52i(150mg,0.38mmol,1eq)攪拌溶液。該混合物係於rt經攪拌2h然後以飽和NaHCO3溶液淬滅及以EtOAc(2x 15ml)萃取。該合併之有機 層係經以鹽水(10ml)清洗、經Na2SO4過濾及濃縮。該剩留物係經以管柱層析法[100-200目矽膠，己烷/EtOAc=1：4]純化。白色固體。產量：60mg(38%).m/z：[M+H]+=410.2.1H NMR(400MHz,CDCl3,δ ppm)：8.75(s,2H),8.64(s,1H),7.88(d,J=7.6Hz,1H),7.44(m,3H),7.27(m,1H),7.19(m,1H),4.94(s,4H),4.63(s,2H),2.98(m,1H),2.86(m,1H),1.27(t,J=14.2Hz,3H). mCPBA (68 mg, 0.3 mmol, 0.8 eq) was added to a stirred solution of compound 52i (150 mg, 0.38 mmol, 1 eq) which was slowly added to THF (10 ml). Based at rt 2h the mixture was then extracted with saturated NaHCO 3 solution and quenched in EtOAc (2x 15ml) was stirred. The combined organic layers of the system was washed with brine (10ml) washed, dried over Na 2 SO 4 filtered and concentrated. The residue was purified by column chromatography [100-200 mesh EtOAc, hexane / EtOAc = 1:4]. White solid. Yield: 60 mg (38%).m/z: [M+H] + = 410.2.1H NMR (400 MHz, CDCl3, δ ppm): 8.75 (s, 2H), 8.64 (s, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.44 (m, 3H), 7.27 (m, 1H), 7.19 (m, 1H), 4.94 (s, 4H), 4.63 (s, 2H), 2.98 (m, 1H), 2.86 (m, 1H), 1.27 (t, J = 14.2 Hz, 3H).

實施例53：6-(乙磺醯基)-1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷] Example 53: 6-(ethanesulfonyl)-1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]

mCPBA(114mg,0.5mmol,2eq)係於0℃被緩慢加入至THF(10ml)中之化合物52i(100mg,0.25mmol,1eq)攪拌溶液及該得到之混合物係於rt經攪拌2h。如規程52j所述方式操作。白色固體。產量：35mg(32%)。m/z：[M+H]+=426.4。1H NMR(400MHz,CDCl3,δ ppm)：8.95(s,1H),8.76(s,2H),7.90(d,J=7.8Hz,1H),7.67(d,J=7.72Hz,1H),7.44(m,2H),7.28(m,1H),7.2(m,1H),4.97(d,J=6.1Hz,2H),4.92(d,J=6.1Hz,2H),4.64(s,2H),3.21(m,2H),1.34(t,J=14.7Hz,3H). mCPBA (114 mg, 0.5 mmol, 2 eq) was stirred in EtOAc EtOAc (EtOAc) Operate as described in protocol 52j. White solid. Yield: 35 mg (32%). m/z: [M+H] + = 426.4. 1H NMR (400MHz, CDCl3, δ ppm): 8.95 (s, 1H), 8.76 (s, 2H), 7.90 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 7.72 Hz, 1H), 7.44 (m, 2H), 7.28 (m, 1H), 7.2 (m, 1H), 4.97 (d, J = 6.1 Hz, 2H), 4.92 (d, J) = 6.1 Hz, 2H), 4.64 (s, 2H), 3.21 (m, 2H), 1.34 (t, J = 14.7 Hz, 3H).

實施例54：6-(乙亞磺醯基)-1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷] Example 54: 6-(ethylsulfinyl)-1-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxygen ring Butane

白色固體。產量：70mg(34%).m/z：[M+H]+=424.1.1H NMR(400MHz,CDCl3,δ ppm)：8.73(s,2H),8.63(s,1H),7.88(d,J=7.7Hz,1H),7.41(dd,J=9.08Hz,1H),7.20(m,1H),7.14(m,1H),7.07(m,1H),4.94(m,4H),4.62(s,2H),2.98(m,1H),2.86(m,1H),2.38(s,3H),1.27(t,J=14.8Hz,3H). White solid. Yield: 70 mg (34%).m/z: [M+H] + = 424.1.1H NMR (400 MHz, CDCl3, δ ppm): 8.73 (s, 2H), 8.63 (s, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.41 (dd, J = 9.08 Hz, 1H), 7.20 (m, 1H), 7.14 (m, 1H), 7.07 (m, 1H), 4.94 (m, 4H), 4.62 ( s, 2H), 2.98 (m, 1H), 2.86 (m, 1H), 2.38 (s, 3H), 1.27 (t, J = 14.8 Hz, 3H).

實施例55：6-(乙磺醯基)-1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷] Example 55: 6-(ethylsulfonyl)-1-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane alkyl]

白色固體。產量：110mg(51%).m/z：[M+H]+=440.0.1H NMR(400MHz,CDCl3,δ ppm)：8.94(s,1H),8.75(s,2H),7.90(d,J=7.7Hz,1H),7.67(d,J=7.7Hz,1H),7.21(m,1H),7.15(m,1H),7.07(m,1H),4.97(m,4H),4.64(s,2H),3.21(m,2H),2.38(s,3H),1.34(t,J=14.6Hz,3H). White solid. Yield: 110 mg (51%).m/z: [M+H] + = 440.0.1H NMR (400 MHz, CDCl3, δ ppm): 8.94 (s, 1H), 8.75 (s, 2H), 7.90 (d, J = 7.7 Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.21 (m, 1H), 7.15 (m, 1H), 7.07 (m, 1H), 4.97 (m, 4H), 4.64 ( s, 2H), 3.21 (m, 2H), 2.38 (s, 3H), 1.34 (t, J = 14.6 Hz, 3H).

實施例56：6-(乙亞磺醯基)-1-(5-(4-甲氧基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷] Example 56: 6-(ethylsulfinyl)-1-(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxygen ring Butane

PdCl2(dppf)(0.065g,0.08mmol,0.05eq)係被加入至在Ar中於rt攪拌之二噁烷中之化合物52h(0.6g,1.58mmol,1eq)、乙酸鉀(0.31g,3.17mmol,2eq)及雙(頻哪醇)二硼(0.8g,3.17mmol,2eq)溶液。該反應混合物係經回流16h、降溫至rt及經矽藻土塞過濾。該過濾器係經以EtOAc淋洗且該濾液係經以水(20ml)及鹽水(20ml)清洗、經Na2SO4乾燥及濃縮。由此獲得之頻哪醇硼酸酯(0.7g)係被溶在二噁烷(25ml)中。2-溴-4-甲氧基吡啶(0.265g,1.41mmol)、10% K2CO3水溶液(3.5ml)及最後之肆(三苯基膦)鈀(0)(0.07g,0.06mmol)係被加入。該混合物係經回流16h、降溫至rt並經矽藻土塞過濾。該過濾器係經以EtOAc淋洗且該濾液係經以水(20ml)、鹽水(20ml)清洗)、經Na2SO4乾燥及濃縮。該剩留物係經以管柱層析法[EtOAc/己烷=1：1]純化。 PdCl 2 (dppf) (0.065 g, 0.08 mmol, 0.05 eq) was added to compound 52h (0.6 g, 1.58 mmol, 1 eq), potassium acetate (0.31 g, 3.17). A solution of mmol (2 eq) and bis(pinacol) diboron (0.8 g, 3.17 mmol, 2 eq). The reaction mixture was refluxed for 16 h, cooled to rt and filtered over EtOAc. The filter system was rinsed with EtOAc and the filtrate was based in water (20ml) and brine (20ml) washed, dried over Na 2 SO 4 dried and concentrated. The pinacol borate (0.7 g) thus obtained was dissolved in dioxane (25 ml). 2-Bromo-4-methoxypyridine (0.265 g, 1.41 mmol), 10% aqueous K 2 CO 3 (3.5 mL) and finally EtOAc (triphenylphosphine) palladium (0) (0.07 g, 0.06 mmol) The system was added. The mixture was refluxed for 16 h, cooled to rt and filtered thru a pad. The filter system was rinsed with EtOAc and the filtrate was based in water (20ml), brine (20ml) wash), dried over Na 2 SO 4 dried and concentrated. The residue was purified by column chromatography [EtOAc /hexane = 1:1].

白色固體。產量：0.27g.m/z：[M+H]+=406.8. White solid. Yield: 0.27 gm/z: [M+H] + = 406.8.

該鈴木偶聯反應之產物(200mg,0.49mmol)係經以mCPBA氧化成對應之亞碸，類似於52j製程。產量：60mg(30%).m/z：[M+H]+=423.0.1H NMR(400MHz,DMSO-d6,δ ppm)：9.33(s,2H),8.61(s,1H),8.48(d,J=5.6Hz,1H),7.94(d,J=7.8Hz,1H),7.62(s,1H),7.36(d,J=3.4Hz,1H),6.95(d,J=3.4Hz,1H),4.9(d,J=6.0Hz,2H),4.79(d,J=5.7Hz,1H),4.65(s,2H),3.03(m,1H),2.79(m,1H),1.1(t,J=13.5Hz,3H). The product of the Suzuki coupling reaction (200 mg, 0.49 mmol) was oxidized to the corresponding hydrazine by mCPBA, similar to the 52j process. Yield: 60 mg (30%). m/z: [M+H] + = 423.0.1H NMR (400 MHz, DMSO-d6, δ ppm): 9.33 (s, 2H), 8.61 (s, 1H), 8.48 ( d, J = 5.6 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.62 (s, 1H), 7.36 (d, J = 3.4 Hz, 1H), 6.95 (d, J = 3.4 Hz, 1H), 4.9 (d, J = 6.0 Hz, 2H), 4.79 (d, J = 5.7 Hz, 1H), 4.65 (s, 2H), 3.03 (m, 1H), 2.79 (m, 1H), 1.1 ( t, J = 13.5 Hz, 3H).

實施例57：6-(乙磺醯基)-1-(5-(4-甲氧基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'- 氧環丁烷] Example 57: 6-(ethylsulfonyl)-1-(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'- Oxycyclobutane

MMPP(973mg,1.97mmol,4eq)係於0℃被緩慢加入至根據實施例56在THF(20ml)中之6-(乙硫基)-1-(5-(4-甲氧基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷](200mg,0.49mmol,1eq)攪拌溶液。該反應混合物係於rt經攪拌2h，然後以飽和NaHCO3溶液淬滅及以EtOAc(2 x 15ml)萃取。該合併之有機層係經以鹽水(10ml)清洗、經Na2SO4乾燥及蒸發。該剩餘物係經以管柱層析法[100-200目矽膠，EtOAc/己烷=1：1]純化。白色固體。產量：100mg(47%)。m/z：[M+H]+=439.1. 1H NMR(400MHz,CDCl3,δ ppm)：9.36(s,2H),8.83(s,1H),8.48(d,J=5.6Hz,1H),8.03(d,J=7.8Hz,1H),7.66(m,2H),6.96(m,1H),4.91(d,J=5.9Hz,2H),4.79(d,J=6.1Hz,2H),4.67(s,2H),3.92(s,3H),3.32(m,2H),1.16(t,J=14.5Hz,3H). MMPP (973 mg, 1.97 mmol, 4 eq) was slowly added at 0 °C to 6-(ethylthio)-1-(5-(4-methoxypyridine-2) in THF (20 mL). -Based)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane] (200 mg, 0.49 mmol, 1 eq) was stirred. The reaction mixture was stirred at rt line 2h, then extracted with saturated NaHCO 3 solution and quenched in EtOAc (2 x 15ml). The combined organic layers of the system was washed with brine (10ml) washed, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography [100-200 EtOAc, EtOAc /hexane = 1:1]. White solid. Yield: 100 mg (47%). m/z: [M+H] + = 439.1. 1H NMR (400MHz, CDCl3, δ ppm): 9.36 (s, 2H), 8.83 (s, 1H), 8.48 (d, J = 5.6 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.66 (m, 2H), 6.96 (m, 1H), 4.91 (d, J = 5.9 Hz, 2H), 4.79 (d, J = 6.1 Hz, 2H), 4.67 (s, 2H), 3.92 (s, 3H), 3.32 (m, 2H), 1.16 (t, J = 14.5 Hz, 3H).

實施例58：1-(5-(4-環丙基吡啶-2-基)嘧啶-2-基)-6-(乙亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷] Example 58: 1-(5-(4-Cyclopropylpyridin-2-yl)pyrimidin-2-yl)-6-(ethylsulfinyl) spiro[porphyrin-3,3'-oxygen ring Butane

由化合物52h類似於實施例56方式製備。白色固體。產量：130mg。m/z：[M+H]+=433.1. 1H NMR(400MHz,DMSO-d6,δ ppm)：9.32(s,2H),8.61(s,1H),8.46(d,J=5.0Hz,1H),7.94(d,J=7.8Hz,1H),7.71(s,1H),7.35(d,J=7.1Hz,1H),7.09(d,J=4.4Hz,1H),4.9(d,J=6.1Hz,2H),4.79(d,J=5.9Hz,1H),4.65(s,2H),3.03(m,1H),2.79(m,1H),1.08(m,5H),0.95(m,2H). Prepared from compound 52h in a similar manner to Example 56. White solid. Yield: 130 mg. m/z: [M+H] + = 433.1. 1H NMR (400MHz, DMSO-d6, δ ppm): 9.32 (s, 2H), 8.61 (s, 1H), 8.46 (d, J = 5.0 Hz, 1H) ), 7.94 (d, J = 7.8 Hz, 1H), 7.71 (s, 1H), 7.35 (d, J = 7.1 Hz, 1H), 7.09 (d, J = 4.4 Hz, 1H), 4.9 (d, J) = 6.1 Hz, 2H), 4.79 (d, J = 5.9 Hz, 1H), 4.65 (s, 2H), 3.03 (m, 1H), 2.79 (m, 1H), 1.08 (m, 5H), 0.95 (m) , 2H).

實施例59：1-(5-(4-環丙基吡啶-2-基)嘧啶-2-基)-6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷] Example 59: 1-(5-(4-Cyclopropylpyridin-2-yl)pyrimidin-2-yl)-6-(ethanesulfonyl)spiro[porphyrin-3,3'-oxocyclobutane alkyl]

以類似實施例57方式製備。白色固體。產量：120mg。m/z：[M+H]+=449.0.1H NMR(400MHz,DMSO-d6,δ ppm)：9.34(s,2H),8.83(s,1H),8.47(d,J=5.0Hz,1H),8.02(d,J=7.8Hz,1H),7.73(s,1H),7.63(d,J=7.8Hz,1H),7.1(d,J=4.9Hz,1H),4.91(d,J=6.1Hz,2H),4.79(d,J=6.1Hz,2H),4.67(s,2H),3.28(s,2H),1.98(m,1H),1.16(m,5H),0.96(m,2H). Prepared in a similar manner to Example 57. White solid. Yield: 120 mg. m/z: [M+H] + = 449.0.1H NMR (400MHz, DMSO-d6, δ ppm): 9.34 (s, 2H), 8.83 (s, 1H), 8.47 (d, J = 5.0 Hz, 1H) ), 8.02 (d, J = 7.8 Hz, 1H), 7.73 (s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.1 (d, J = 4.9 Hz, 1H), 4.91 (d, J) = 6.1 Hz, 2H), 4.79 (d, J = 6.1 Hz, 2H), 4.67 (s, 2H), 3.28 (s, 2H), 1.98 (m, 1H), 1.16 (m, 5H), 0.96 (m) , 2H).

以類似合成實施例22方式製備實施例60至66。 Examples 60 to 66 were prepared in a similar manner to Synthesis Example 22.

實施例60：1-(5-(4-乙基吡啶-2-基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 60: 1-(5-(4-ethylpyridin-2-yl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3 '-oxycyclobutane]-6-formamide

白色固體。產量：48mg。HPLC(方法2)：Rt=1.44min.,m/z：[M+H]+=446.05(MW calc.445.51).1H NMR400MHz,DMSO-d6,100℃,δ ppm)：9.25(s,2H),8.53(d,1H,J=4.8Hz),8.4(s,1H),7.81-7.76(m,2H),7.2(s,1H),7.12(d,1H,J=7.4Hz),4.89-4.8(m,4H),4.63(s,2H),4.41(bs,1H),3.64(bs,2H),3.46(bs,2H),3.03(s,3H),2.75-2.66(m,2H),1.3-1.26(m,3H). White solid. Yield: 48 mg. HPLC (Method 2): R t = 1.44 min., m/z: [M+H] + =446.05 (MW calc.445.51).1H NMR 400 MHz, DMSO-d6, 100 ° C, δ ppm): 9.25 (s, 2H), 8.53 (d, 1H, J = 4.8 Hz), 8.4 (s, 1H), 7.81-7.76 (m, 2H), 7.2 (s, 1H), 7.12 (d, 1H, J = 7.4 Hz), 4.89-4.8 (m, 4H), 4.63 (s, 2H), 4.41 (bs, 1H), 3.64 (bs, 2H), 3.46 (bs, 2H), 3.03 (s, 3H), 2.75-2.66 (m, 2H), 1.3-1.26 (m, 3H).

實施例61：1-(5-(4-環丙基吡啶-2-基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 61:1-(5-(4-Cyclopropylpyridin-2-yl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3, 3'-oxocyclobutane]-6-formamide

白色固體。產量：105mg。HPLC(方法2)：Rt=1.41min.,m/z：[M+H]+=458.1(MW calc.457.52).1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：9.25(s,2H),8.45(d,1H,J=5.1Hz),8.4(s,1H),7.76(d,1H,J=7.6Hz),7.64(s,1H),7.12(d,1H,J=7.5Hz),7.04(d,1H,J=5.0Hz),4.88(d,2H,J=6Hz),4.8(d,2H,J=6Hz),4.63(s,2H),4.42(bs,1H),3.62(d,2H,J=5.4Hz),3.46(bs,2H),3.21(s,3H),2.05-1.99(m,1H),1.12-1.07(m,2H),0.94-0.9(m,2H). White solid. Yield: 105 mg. HPLC (Method 2): Rt = 1.41 min., m/z: [M+H] + = 458.1 (MW calc.457.52).1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 9.25 ( s, 2H), 8.45 (d, 1H, J = 5.1 Hz), 8.4 (s, 1H), 7.76 (d, 1H, J = 7.6 Hz), 7.64 (s, 1H), 7.12 (d, 1H, J) = 7.5 Hz), 7.04 (d, 1H, J = 5.0 Hz), 4.88 (d, 2H, J = 6 Hz), 4.8 (d, 2H, J = 6 Hz), 4.63 (s, 2H), 4.42 (bs, 1H), 3.62 (d, 2H, J = 5.4 Hz), 3.46 (bs, 2H), 3.21 (s, 3H), 2.05-1.99 (m, 1H), 1.12-1.07 (m, 2H), 0.94-0.9 (m, 2H).

實施例62：N-(2-羥乙基)-1-(5-(4-甲氧基吡啶-2-基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 62: N-(2-hydroxyethyl)-1-(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3, 3'-oxocyclobutane]-6-formamide

白色固體。產量：79mg。HPLC(方法2)：Rt=1.32min.,m/z：[M+H]+=448.1(MW calc.447.49).1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：9.25(s,2H),8.46(d,1H,J=5.6Hz),8.4(s,1H),7.76(d,1H,J=7.6Hz),7.51(s,1H),7.12(d,1H,J=7.4Hz),6.93-6.91(m,1H),4.88(d,2H,J=5.9Hz),4.81(d,2H,J=5.9Hz),4.63(s,2H),3.93(s,3H),3.63(bs,2H),3.46(bs,2H),3.02(merged with DMSO-水peak,4H). White solid. Yield: 79 mg. HPLC (Method 2): R t = 1.32 min., m/z: [M+H] + = 448.1 (MW calc.447.49). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 9.25 ( s, 2H), 8.46 (d, 1H, J = 5.6 Hz), 8.4 (s, 1H), 7.76 (d, 1H, J = 7.6 Hz), 7.51 (s, 1H), 7.12 (d, 1H, J) = 7.4 Hz), 6.93-6.91 (m, 1H), 4.88 (d, 2H, J = 5.9 Hz), 4.81 (d, 2H, J = 5.9 Hz), 4.63 (s, 2H), 3.93 (s, 3H) ), 3.63 (bs, 2H), 3.46 (bs, 2H), 3.02 (merged with DMSO-water peak, 4H).

實施例63：1-(5-(4-乙氧基吡啶-2-基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 63: 1-(5-(4-ethoxypyridin-2-yl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3, 3'-oxocyclobutane]-6-formamide

白色固體。產量：125mg。HPLC(方法2)：Rt=1.36min.,m/z：[M+H]+=462.1(MW calc.461.51).1H NMR(400MHz,DMSO-d6,δ ppm)：9.29(s,2H),8.45(d,1H,J=5.5Hz),8.33(s,1H),7.78(bs,1H),7.56(s,1H),7.12(d,1H,J=7.3Hz),6.92(bs,1H),4.88-4.78(m,5H),4.61(s,2H),4.24-4.2(m,2H),3.64(bs,1H),3.52(bs,2H),3-2.98(m,3H),1.39-1.35(m,3H). White solid. Yield: 125 mg. HPLC (Method 2): R t = 1.36 min., m/z: [M+H] + = 462.1 (MW calc.461.51).1H NMR (400 MHz, DMSO-d6, δ ppm): 9.29 (s, 2H) ), 8.45 (d, 1H, J = 5.5 Hz), 8.33 (s, 1H), 7.78 (bs, 1H), 7.56 (s, 1H), 7.12 (d, 1H, J = 7.3 Hz), 6.92 (bs) , 1H), 4.88-4.78 (m, 5H), 4.61 (s, 2H), 4.24 - 4.2 (m, 2H), 3.64 (bs, 1H), 3.52 (bs, 2H), 3-2.98 (m, 3H) ), 1.39-1.35 (m, 3H).

實施例64：N-(2-羥乙基)-N-甲基-1-(5-(吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 64: N-(2-hydroxyethyl)-N-methyl-1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxo ring Butane]-6-formamide

白色固體。產量：80mg。HPLC(方法2)：Rt=1.40min.,m/z：[M+H]+=418.1(MW calc.417.46).1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：9.25(s,2H),8.66(d,1H,J=4.4Hz),8.4(s,1H),7.96(d,1H,J=7.8Hz),7.89-7.85(m,1H),7.76(d,1H,J=7.6Hz),7.35-7.32(m,1H),7.12(d,1H,J=7.6Hz),4.88(d,2H,J=8.0Hz),4.8(d,2H,J=8.0Hz),4.63(s,2H),4.42(bs,1H),3.64-3.63(m,2H),3.46(bs,2H),3.03(s,3H). White solid. Yield: 80 mg. HPLC (Method 2): rt = 1.40 min., m/z: [M+H] + = 418.1 (MW calc. 417.46). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 9.25 ( s, 2H), 8.66 (d, 1H, J = 4.4 Hz), 8.4 (s, 1H), 7.96 (d, 1H, J = 7.8 Hz), 7.89-7.85 (m, 1H), 7.76 (d, 1H) , J = 7.6 Hz), 7.35-7.32 (m, 1H), 7.12 (d, 1H, J = 7.6 Hz), 4.88 (d, 2H, J = 8.0 Hz), 4.8 (d, 2H, J = 8.0 Hz) ), 4.63 (s, 2H), 4.42 (bs, 1H), 3.64 - 3.63 (m, 2H), 3.46 (bs, 2H), 3.03 (s, 3H).

實施例65：N-(2-羥乙基)-N-甲基-1-(5-(4-(三氟甲基)吡啶-2-基)嘧啶-2-基)螺-[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 65: N-(2-hydroxyethyl)-N-methyl-1-(5-(4-(trifluoromethyl)pyridin-2-yl)pyrimidin-2-yl)spiro-[吲哚Porphyrin-3,3'-oxycyclobutane]-6-formamide

白色固體。產量：150mg。HPLC(方法2)：Rt=1.57min.,m/z：[M+H]+=486.1(MW calc.485.46).1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：9.35(s,2H),8.92(bs,1H),8.42(s,1H),8.29(s,1H),7.78(d,1H,J=7.6Hz),7.65(d,1H,J=4.8Hz),7.14(d,1H,J=7.6Hz),4.9(d,2H,J=6.1Hz),4.8(d,2H,J=6Hz),4.65(s,2H),4.42(bs,1H),3.64-3.63(m,2H),3.46(bs,2H),3.03(s,3H). White solid. Yield: 150 mg. HPLC (Method 2): R t = 1.57 min., m/z: [M+H] + = 486.1 (MW calc. 485.46). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 9.35 ( s, 2H), 8.92 (bs, 1H), 8.42 (s, 1H), 8.29 (s, 1H), 7.78 (d, 1H, J = 7.6 Hz), 7.65 (d, 1H, J = 4.8 Hz), 7.14 (d, 1H, J = 7.6 Hz), 4.9 (d, 2H, J = 6.1 Hz), 4.8 (d, 2H, J = 6 Hz), 4.65 (s, 2H), 4.42 (bs, 1H), 3.64 -3.63 (m, 2H), 3.46 (bs, 2H), 3.03 (s, 3H).

實施例66：N-(2-羥乙基)-1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 66: N-(2-hydroxyethyl)-1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methyl snail [Porphyrin-3,3'-oxycyclobutane]-6-carboxamide

白色固體。產量：75mg。HPLC(方法2)：Rt=1.37min。m/z：[M+H]+=476.1 (MW calc.475.54).1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：9.25(s,2H),8.57(d,1H,J=4.9Hz),8.4(s,1H),7.97(s,1H),7.76(d,1H,J=7.4Hz),7.42(d,1H,J=4.8Hz),7.14-7.12(m,1H),4.94-4.8(m,5H),4.42(s,2H),4.42(bs,1H),3.6(bs,2H),3.46(bs,2H),3.03(s,3H),1.52(s,6H). White solid. Yield: 75 mg. HPLC (Method 2): R t = 1.37 min. m/z: [M+H] + = 476.1 (MW calc. 475.54). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 9.25 (s, 2H), 8.57 (d, 1H, J = 4.9 Hz), 8.4 (s, 1H), 7.97 (s, 1H), 7.76 (d, 1H, J = 7.4 Hz), 7.42 (d, 1H, J = 4.8 Hz), 7.14 - 7.12 (m, 1H) , 4.94-4.8 (m, 5H), 4.42 (s, 2H), 4.42 (bs, 1H), 3.6 (bs, 2H), 3.46 (bs, 2H), 3.03 (s, 3H), 1.52 (s, 6H) ).

以類似合成實施例8製備實施例67至73。 Examples 67 to 73 were prepared in a similar manner to Synthesis Example 8.

實施例67：(1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(吡咯啶-1-基)甲酮 Example 67: (1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane ]-6-yl)(pyrrolidin-1-yl)methanone

白色固體。產量：80mg。HPLC(方法2)：Rt=1.48min。m/z：[M+H]+=472.13(MW calc.471.55).1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：9.26(s,2H),8.57(d,1H,J=5.2Hz),8.51(s,1H),7.98(s,1H),7.77(d,1H,J=7.6Hz),7.43(d,1H,J=4.8Hz),7.23(d,1H,J=7.6Hz),4.95(s,1H),4.89(d,2H,J=6.0Hz),4.8(d,2H,J=6Hz),4.64(s,2H),3.49(bs,4H),1.89(bs,4H),1.52(s,6H). White solid. Yield: 80 mg. HPLC (Method 2): R t = 1.48 min. m/z: [M+H] + = 472.13 (MW calc. 471.55). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 9.26 (s, 2H), 8.57 (d, 1H, J = 5.2 Hz), 8.51 (s, 1H), 7.98 (s, 1H), 7.77 (d, 1H, J = 7.6 Hz), 7.43 (d, 1H, J = 4.8 Hz), 7.23 (d, 1H, J = 7.6 Hz), 4.95 (s, 1H), 4.89 (d, 2H, J = 6.0 Hz), 4.8 (d, 2H, J = 6 Hz), 4.64 (s, 2H), 3.49 (bs, 4H), 1.89 ( Bs, 4H), 1.52 (s, 6H).

實施例68：(1-(5-(4-乙氧基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(吡咯啶-1-基)甲酮 Example 68: (1-(5-(4-ethoxypyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl) ( Pyrrolidin-1-yl)methanone

白色固體。產量：0.09g。HPLC(方法2)：Rt=1.48min。m/z：[M+H]+=458.15(MW calc.457.52). 1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：9.25(s,2H),8.5-8.44(m,2H),7.7(d,1H,J=7.5Hz),7.48(s,1H),7.22(d,1H,J=7.7Hz),6.89(d,1H,J=3.3Hz),4.89(d,2H,J=5.8Hz),4.8(d,2H,J=5.9Hz),4.63(s,2H),4.28-4.23(m,2H),3.48(bs,4H),1.88(bs,4H),1.41-1.38(m,3H). White solid. Yield: 0.09 g. HPLC (Method 2): R t = 1.48 min. m/z: [M+H] + = 458.15 (MW calc. 457.52). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 9.25 (s, 2H), 8.5-8.44 (m, 2H) , 7.7 (d, 1H, J = 7.5 Hz), 7.48 (s, 1H), 7.22 (d, 1H, J = 7.7 Hz), 6.89 (d, 1H, J = 3.3 Hz), 4.89 (d, 2H, J = 5.8 Hz), 4.8 (d, 2H, J = 5.9 Hz), 4.63 (s, 2H), 4.28 - 4.23 (m, 2H), 3.48 (bs, 4H), 1.88 (bs, 4H), 1.41 1.38 (m, 3H).

實施例69：吡咯啶-1-基(1-(5-(4-(三氟甲基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)甲酮 Example 69: Pyrrolidin-1-yl (1-(5-(4-(trifluoromethyl)pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxygen ring Butane]-6-yl)methanone

白色固體。產量：0.085g。HPLC(方法2)：Rt=1.72min。m/z：[M+H]+=482.09(MW calc.481.47). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.4(s,2H),8.93(s,1H),8.52(s,1H),8.39(s,1H),7.79(d,1H,J=7.5Hz),7.72(d,1H,J=3.3Hz),7.27(d,1H,J=7.5Hz),4.8(d,2H,J=6.2Hz),4.78(d,2H,J=5.8Hz),4.6(bs,2H),3.49-3.43(m,4H),1.89-1.82(m,4H). White solid. Yield: 0.085 g. HPLC (Method 2): R t = 1.72 min. m/z: [M+H] + = 482.09 (MW calc. 481.47). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.4 (s, 2H), 8.93 (s, 1H), 8.52 (s, 1H), 8.39 (s, 1H), 7.79 (d, 1H, J = 7.5 Hz), 7.72 (d, 1H, J = 3.3 Hz), 7.27 (d, 1H, J = 7.5 Hz), 4.8 (d, 2H, J=6.2Hz), 4.78(d, 2H, J=5.8Hz), 4.6(bs, 2H), 3.49-3.43(m, 4H), 1.89-1.82(m, 4H).

實施例70：(1-(5-(4-乙基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(吡咯啶-1-基)甲酮 Example 70: (1-(5-(4-ethylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl) (pyrrole) Pyridin-1-yl)methanone

白色固體。產量：0.070g。HPLC(方法2)：Rt=1.61min。m/z：[M+H]+=442.1(MW calc.441.53). 1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：9.25(s,2H),8.54-8.5(m,2H),7.81-7.77(m,2H),7.24-7.19(m,2H),4.88(d,2H,J=5.5Hz),4.81(d,2H,J=5.8Hz),4.62(s,2H),3.49(bs,4H),2.74-2.69(m,2H),1.88(bs,4H),1.3-1.26(m,3H). White solid. Yield: 0.070 g. HPLC (Method 2): R t = 1.61 min. m/z: [M+H] + = 442.1 (MW calc. 441.53). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 9.25 (s, 2H), 8.54-8.5 (m, 2H) , 7.81-7.77 (m, 2H), 7.24-7.19 (m, 2H), 4.88 (d, 2H, J = 5.5 Hz), 4.81 (d, 2H, J = 5.8 Hz), 4.62 (s, 2H), 3.49 (bs, 4H), 2.74-2.69 (m, 2H), 1.88 (bs, 4H), 1.3-1.26 (m, 3H).

實施例71及72：1-(3-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)-4-氟苯基)乙醇(較快及較慢之洗析鏡像異構物) Examples 71 and 72: 1-(3-(2-(6-(ethylsulfonyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl) -4-fluorophenyl)ethanol (faster and slower elution of the mirror image isomer)

以類似合成實施例57方式經二步驟由化合物52h及1-(3-溴-4-氟苯基)乙醇製備消旋物(產量：330mg，白色固體)。該二鏡像異構物係由該消旋混合物 經掌性HPLC獲得，其使用掌性pack-IA管柱及己烷/EtOAc/EtOH/二乙胺(50/25/25/0.1)作為移動相。 The racemate was prepared from Compound 52h and 1-(3-bromo-4-fluorophenyl)ethanol in two steps (yield: 330 mg, white solid). The two-mirror isomer Obtained by palmar HPLC using a palmitic pack-IA column and hexane/EtOAc/EtOH/diethylamine (50/25/25/0.1) as mobile phase.

較快洗析之鏡像異構物(實施例71)：產量=77mg。白色固體。m/z：[M+H]+=470.3。特定旋光度：[α]589 25=-15.65°(c.0.4090,CHCl3). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.89(s,2H),8.79(s,1H),8.02(d,J=7.8Hz,1H),7.63(m,2H),7.44(m,1H),7.33(m,1H),5.25(d,J=4.4Hz,1H),4.91(d,J=6.2Hz,2H),4.80(t,J=11.2Hz,3H),4.66(s,2H),3.29(m,2H),1.38(d,J=6.4Hz,3H),1.16(t,J=14.6Hz,3H). The mirror image isomer was washed out faster (Example 71): Yield = 77 mg. White solid. m/z: [M+H] + = 470.3. Specific rotatory power: [α] 589 25 = -15.65° (c.0.4090, CHCl 3 ). 1H NMR (400MHz, DMSO-d6, δ ppm): 8.89 (s, 2H), 8.79 (s, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.63 (m, 2H), 7.44 (m, 1H), 7.33 (m, 1H), 5.25 (d, J = 4.4 Hz, 1H), 4.91 (d, J = 6.2 Hz, 2H), 4.80 (t, J = 11.2 Hz, 3H), 4.66 (s, 2H), 3.29 (m, 2H), 1.38 (d, J = 6.4 Hz, 3H), 1.16 (t, J = 14.6Hz, 3H).

較慢洗析之鏡像異構物(實施例72)：產量=65mg。白色固體。m/z：[M+H]+=470.3。特定旋光度：[α]589 25=+13.06°(c.0.4058,CHCl3). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.89(s,2H),8.79(s,1H),8.02(d,J=7.9Hz,1H),7.63(m,2H),7.44(m,1H),7.33(m,1H),5.25(d,J=4.3Hz,1H),4.91(d,J=6.2Hz,2H),4.80(t,J=11.2Hz,3H),4.66(s,2H),3.29(m,2H),1.38(d,J=6.4Hz,3H),1.16(t,J=14.6Hz,3H). The mirror image isomer of the slower elution (Example 72): Yield = 65 mg. White solid. m/z: [M+H] + = 470.3. Specific rotatory power: [α] 589 25 = +13.06° (c. 0.4058, CHCl 3 ). 1H NMR (400MHz, DMSO-d6, δ ppm): 8.89 (s, 2H), 8.79 (s, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.63 (m, 2H), 7.44 (m, 1H), 7.33 (m, 1H), 5.25 (d, J = 4.3 Hz, 1H), 4.91 (d, J = 6.2 Hz, 2H), 4.80 (t, J = 11.2 Hz, 3H), 4.66 (s, 2H), 3.29 (m, 2H), 1.38 (d, J = 6.4 Hz, 3H), 1.16 (t, J = 14.6Hz, 3H).

實施例73：2-(3-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)-4-氟-苯基)丙-2-醇 Example 73: 2-(3-(2-(6-(ethylsulfonyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)-4 -fluoro-phenyl)propan-2-ol

由化合物52h及2-(3-溴-4-氟苯基)丙-2-醇以類似合成實施例57經二步驟製 備。白色固體。產量：0.075g。m/z：[M+H]+=484.2. 1H NMR(400MHz,DMSO-d6,δ ppm)：8.9(s,2H),8.8(s,1H),8.0(d,J=7.8Hz,1H),8.06(m,2H),7.70(dd,J=9.7Hz,1H),7.63(dd,J=9.2Hz,1H),5.13(s,1H),4.91(d,J=6.2Hz,2H),4.80(d,J=6.2Hz,2H),4.66(s,2H),3.32(m,2H),1.47(s,6H),1.16(t,J=14.6Hz,3H). Compound 52h and 2-(3-bromo-4-fluorophenyl)propan-2-ol were prepared in a similar manner to the compound of Example 57. White solid. Yield: 0.075 g. m/z: [M+H] + = 484.2. 1H NMR (400MHz, DMSO-d6, δ ppm): 8.9 (s, 2H), 8.8 (s, 1H), 8.0 (d, J = 7.8 Hz, 1H) ), 8.06 (m, 2H), 7.70 (dd, J = 9.7 Hz, 1H), 7.63 (dd, J = 9.2 Hz, 1H), 5.13 (s, 1H), 4.91 (d, J = 6.2 Hz, 2H) ), 4.80 (d, J = 6.2 Hz, 2H), 4.66 (s, 2H), 3.32 (m, 2H), 1.47 (s, 6H), 1.16 (t, J = 14.6 Hz, 3H).

實施例74：2-(3-(2-(6-(乙亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)-4-氟-苯基)丙-2-醇 Example 74: 2-(3-(2-(6-(ethylsulfinyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)- 4-fluoro-phenyl)propan-2-ol

由化合物52h及2-(3-溴-4-氟苯基)丙-2-醇以類似合成實施例56方式經二步驟製備。白色固體。產量：0.075g。m/z：[M+H]+=468.0. 1H NMR(400MHz,DMSO-d6,δ ppm)：8.87(s,2H),8.58(s,1H),7.94(d,J=7.9Hz,1H),7.69(dd,J=10.0Hz,1H),7.55(m,1H),7.35(dd,J=9.1Hz,1H),7.30(m,1H),5.12(s,1H),4.89(d,J=6.2Hz,2H),4.8(d,J=5.8Hz,2H),4.64(s,2H),3.03(m,1H),2.79(m,1H),1.47(s,6H),1.1(t,J=14.7Hz,3H). Compound 52h and 2-(3-bromo-4-fluorophenyl)propan-2-ol were prepared in a two-step procedure analogous to the synthesis of Example 56. White solid. Yield: 0.075 g. m/z: [M+H] + = 468.0. 1H NMR (400MHz, DMSO-d6, δ ppm): 8.87 (s, 2H), 8.58 (s, 1H), 7.94 (d, J = 7.9 Hz, 1H) ), 7.69 (dd, J = 10.0 Hz, 1H), 7.55 (m, 1H), 7.35 (dd, J = 9.1 Hz, 1H), 7.30 (m, 1H), 5.12 (s, 1H), 4.89 (d) , J = 6.2 Hz, 2H), 4.8 (d, J = 5.8 Hz, 2H), 4.64 (s, 2H), 3.03 (m, 1H), 2.79 (m, 1H), 1.47 (s, 6H), 1.1 (t, J = 14.7 Hz, 3H).

實施例75：2-(2-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-4-基)丙-2-醇 Example 75: 2-(2-(2-(6-(ethylsulfonyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)pyridine- 4-yl)propan-2-ol

由化合物52h及2-(2-溴吡啶-4-基)丙-2-醇以類似合成實施例57方式經二步驟製備。白色固體。產量：100mg。m/z：[M+H]+=467.1. 1H NMR(400MHz,DMSO-d6,δ ppm)：9.36(s,2H),8.84(s,1H),8.6(d,J=5.0Hz,1H),8.06(m,2H),7.63(d,J=8.0Hz,1H),7.48(d,J=4.0Hz,1H),5.29(s,1H),4.92(d,J=6.2Hz,2H),4.79(d,J=6.2Hz,2H),4.67(s,2H),3.28(m,2H),1.49(s,6H),1.17(t,J=14.5Hz,3H). Compound 52h and 2-(2-bromopyridin-4-yl)propan-2-ol were prepared in a two-step procedure analogous to the compound. White solid. Yield: 100 mg. m/z: [M+H] + = 467.1. 1H NMR (400MHz, DMSO-d6, δ ppm): 9.36 (s, 2H), 8.84 (s, 1H), 8.6 (d, J = 5.0 Hz, 1H) ), 8.06 (m, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 4.0 Hz, 1H), 5.29 (s, 1H), 4.92 (d, J = 6.2 Hz, 2H) ), 4.79 (d, J = 6.2 Hz, 2H), 4.67 (s, 2H), 3.28 (m, 2H), 1.49 (s, 6H), 1.17 (t, J = 14.5 Hz, 3H).

實施例76：2-(2-(2-(6-(乙亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-4-基)丙-2-醇 Example 76: 2-(2-(2-(6-(ethylsulfinyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)pyridine -4-yl)propan-2-ol

由化合物52h及2-(2-溴吡啶-4-基)丙-2-醇以類似合成實施例56方式經二步驟製備。白色固體。產量：100mg。m/z：[M+H]+=451.2. 1H NMR(400MHz,DMSO-d6,δ ppm)：9.33(s,2H),8.62(m,2H),8.04(s,1H),7.94(d,J=7.7Hz1H),7.47(d,J=3.7Hz,1H),7.36(d,J=7.7Hz,1H),5.29(s,1H),4.9(d,J= 6.0Hz,2H),4.79(d,J=4.8Hz,2H),4.65(s,2H),3.04(m,1H),2.80(m.1H),1.48(s,6H),1.1(t,J=14.5Hz,3H). Compound 52h and 2-(2-bromopyridin-4-yl)propan-2-ol were prepared in a two-step procedure analogous to the synthesis of Example 56. White solid. Yield: 100 mg. m/z: [M+H] + = 451.2. 1H NMR (400MHz, DMSO-d6, δ ppm): 9.33 (s, 2H), 8.62 (m, 2H), 8.04 (s, 1H), 7.94 (d) , J = 7.7 Hz 1H), 7.47 (d, J = 3.7 Hz, 1H), 7.36 (d, J = 7.7 Hz, 1H), 5.29 (s, 1H), 4.9 (d, J = 6.0 Hz, 2H), 4.79 (d, J = 4.8 Hz, 2H), 4.65 (s, 2H), 3.04 (m, 1H), 2.80 (m.1H), 1.48 (s, 6H), 1.1 (t, J = 14.5 Hz, 3H) ).

實施例77及78：1-(2-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-4-基)乙醇(較快及較慢之洗析鏡像異構物) Examples 77 and 78: 1-(2-(2-(6-(ethylsulfonyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl) Pyridin-4-yl)ethanol (faster and slower elution of the mirror image isomer)

由化合物52h及1-(2-溴吡啶-4-基)乙醇以類似合成實施例57方式經二步驟製備該消旋碸(350mg)。該二鏡像異構物係由此消旋物經掌性HPLC衍生，其使用掌性pack-IE管柱及己烷/EtOAc/EtOH/二乙胺(50/25/25/0.1)作為移動相。 The racemic oxime (350 mg) was prepared from the compound 52h and 1-(2-bromopyridin-4-yl)ethanol in a similar manner to the compound. The two mirror image isomers were derived from the racemate by palmar HPLC using a palmitic pack-IE column and hexane/EtOAc/EtOH/diethylamine (50/25/25/0.1) as the mobile phase. .

較快洗析之鏡像異構物(實施例77)：產量=68mg。白色固體。m/z：[M+H]+=453.0。特定旋光度：[α]589 25=-14.84°(c.0.4042,CHCl3). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.31(s,2H),8.8(s,1H),8.58(d,J=5.2Hz,1H),8.0(m,2H),7.61(d,J=7.8Hz,1H),7.34(d,J=4.8Hz,1H),5.42(d,J=4.4Hz,1H),4.89(d,J=6.2Hz,2H),4.77(d,J=6.2Hz,3H),4.64(s,2H),3.25(m,2H),1.37(d,J=6.5Hz,3H),1.14(t,J=14.6Hz,3H). The mirror image isomer was eluted faster (Example 77): Yield = 68 mg. White solid. m/z: [M+H] + = 453.0. Specific rotatory power: [α] 589 25 = -14.84° (c.0.4042, CHCl 3 ). 1H NMR (400MHz, DMSO-d6, δ ppm): 9.31 (s, 2H), 8.8 (s, 1H), 8.58 (d, J = 5.2 Hz, 1H), 8.0 (m, 2H), 7.61 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 4.8 Hz, 1H), 5.42 (d, J = 4.4 Hz) , 1H), 4.89 (d, J = 6.2 Hz, 2H), 4.77 (d, J = 6.2 Hz, 3H), 4.64 (s, 2H), 3.25 (m, 2H), 1.37 (d, J = 6.5 Hz) , 3H), 1.14 (t, J = 14.6 Hz, 3H).

較慢洗析之鏡像異構物(實施例78)：產量=75mg。白色固體。質譜儀：m/z：[M+H]+=453.1。特定旋光度：[α]589 25=+15.23°(c.0.4072,CHCl3). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.34(s,2H),8.83(s,1H),8.61(d,J=4.5 Hz,1H),8.02(m,2H),7.63(d,J=7.5Hz,1H),7.37(d,J=3.4Hz,1H),5.46(d,J=4Hz,1H),4.92(d,J=5.7Hz,2H),4.79(d,J=5.8Hz,3H),4.67(s,2H),3.25(m,2H),1.40(d,J=6.2Hz,3H),1.17(t,J=14.2Hz,3H). The mirror image isomer of the slower elution (Example 78): Yield = 75 mg. White solid. Mass spectrometer: m/z: [M+H] + = 453.1. Specific rotatory power: [α] 589 25 = +15.23 ° (c. 0.4072, CHCl 3 ). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.34 (s, 2H), 8.83 (s, 1H), 8.61 (d, J = 4.5 Hz, 1H), 8.02 (m, 2H), 7.63 (d, J = 7.5 Hz, 1H), 7.37 (d, J = 3.4 Hz, 1H), 5.46 (d, J = 4 Hz, 1H), 4.92 (d, J = 5.7 Hz, 2H), 4.79 (d, J = 5.8 Hz, 3H), 4.67 (s, 2H), 3.25 (m, 2H), 1.40 (d, J = 6.2 Hz, 3H), 1.17 (t, J = 14.2 Hz, 3H).

合成實施例79及96係由1-(5-溴嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-羧酸(化合物8a)經二化學步驟獲得，其包括使一醯胺與2-(甲基胺)乙醇偶聯、TBTU作為試劑及鈴木偶聯反應(規程3a)。 Synthesis Examples 79 and 96 were obtained by two chemical steps from 1-(5-bromopyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-carboxylic acid (Compound 8a). This includes coupling monoamine with 2-(methylamine)ethanol, TBTU as reagent and Suzuki coupling reaction (Procedure 3a).

實施例79：N-(2-羥乙基)-N-甲基-1-(5-苯基嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 79: N-(2-hydroxyethyl)-N-methyl-1-(5-phenylpyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6 -Procarbamide

白色固體。產量：80mg。m/z：[M+H]+=416.8(MW calc.416.47). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.99(s,2H),8.36(s,1H),7.76-7.74(m,3H),7.51-7.47(m,2H),7.41-7.37(m,1H),7.12-7.10(m,1H),4.88-4.87(d,2H),4.80-4.75(m,3H),4.60(s,2H),3.64-3.52(m,4H),3.00-2.98(d,3H). White solid. Yield: 80 mg. m/z: [M+H] + = 416.8 (MW calc. 416.47). 1H NMR (400MHz, DMSO-d6, δ ppm): 8.99 (s, 2H), 8.36 (s, 1H), 7.76-7.74 ( m, 3H), 7.51-7.47 (m, 2H), 7.41-7.37 (m, 1H), 7.12-7.10 (m, 1H), 4.88-4.87 (d, 2H), 4.80-4.75 (m, 3H), 4.60 (s, 2H), 3.64 - 3.52 (m, 4H), 3.00-2.98 (d, 3H).

實施例80：N-(2-羥乙基)-N-甲基-1-(5-(m-甲苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 80: N-(2-hydroxyethyl)-N-methyl-1-(5-(m-methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane Alkane-6-carboxamide

白色固體。產量：90mg。m/z：[M+H]+=431.1(MW calc.430.50). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.96(s,2H),8.36(s,1H),7.78(m,1H),7.57-7.52(m,2H),7.39-7.35(t,1H),7.21-7.19(d,1H),7.12-7.10(m,1H),4.88-4.87(d,2H),4.80-4.78(m,3H),4.60(s,2H),3.64-3.37(m,4H),3.00-2.98(d,3H),2.38(s,3H). White solid. Yield: 90 mg. m/z: [M+H] + = 431.1 (MW calc. 430.50). 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.96 (s, 2H), 8.36 (s, 1H), 7.78 (m, 1H), 7.57-7.52 (m, 2H), 7.39-7.35 (t, 1H), 7.21-7.19 (d, 1H), 7.12-7.10 (m, 1H), 4.88-4.87 (d, 2H), 4.80- 4.78 (m, 3H), 4.60 (s, 2H), 3.64 - 3.37 (m, 4H), 3.00-2.98 (d, 3H), 2.38 (s, 3H).

實施例81：1-(5-(3-環丙基苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 81:1-(5-(3-Cyclopropylphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'- Oxycyclobutane]-6-formamide

白色固體。產量：80mg。m/z：[M+H]+=457.10(MW calc.456.54). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.97(s,2H),8.36(s,1H),7.78(m,1H),7.49-7.48(d,1H),7.41(s,1H),7.37-7.33(t,1H),7.11-7.08(m,2H),4.88-4.87(d,2H),4.80-4.75(m,3H),4.60(s,2H),3.65-3.52(m,4H),3.00-2.96(m,3H),1.99-1.95(m,1H),0.98-0.97(m,2H),0.79-0.78(m,2H). White solid. Yield: 80 mg. m/z: [M+H] + = 457.10 (MW calc. 456.54). 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.97 (s, 2H), 8.36 (s, 1H), 7.78 (m, 1H), 7.49-7.48 (d, 1H), 7.41 (s, 1H), 7.37-7.33 (t, 1H), 7.11-7.08 (m, 2H), 4.88-4.87 (d, 2H), 4.80-4.75 ( m,3H), 4.60 (s, 2H), 3.65-3.52 (m, 4H), 3.00-2.96 (m, 3H), 1.99-1.95 (m, 1H), 0.98-0.97 (m, 2H), 0.79- 0.78 (m, 2H).

實施例82：N-(2-羥乙基)-1-(5-(3-甲氧基苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 82: N-(2-hydroxyethyl)-1-(5-(3-methoxyphenyl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3,3'- Oxycyclobutane]-6-formamide

白色固體。產量：125mg。m/z：[M+H]+=447.3(MW calc.446.50). 1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：8.93(s,2H),8.37(s,1H),7.77-7.75(d,1H),7.42-7.38(t,1H),7.29-7.27(m,2H),7.12-7.10(d,1H),6.97-6.95(d,1H),4.89-4.87(d,2H),4.82-4.81(d,2H),4.61(s,2H),4.41-4.40(m,1H),3.86(s,3H),3.63-3.61(m,2H),3.45(m,2H),3.02(s,3H). White solid. Yield: 125 mg. m/z: [M+H] + = 447.3 (MW calc. 446.50). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 8.93 (s, 2H), 8.37 (s, 1H), 7.77 -7.75(d,1H), 7.42-7.38(t,1H), 7.29-7.27(m,2H), 7.12-7.10(d,1H), 6.97-6.95(d,1H),4.89-4.87(d, 2H), 4.82-4.81 (d, 2H), 4.61 (s, 2H), 4.41-4.40 (m, 1H), 3.86 (s, 3H), 3.63-3.61 (m, 2H), 3.45 (m, 2H) , 3.02 (s, 3H).

實施例83：1-(5-(3-乙氧基苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 83: 1-(5-(3-ethoxyphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'- Oxycyclobutane]-6-formamide

白色固體。產量：115mg。m/z：[M+H]+=461.3(MW calc.460.53). 1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：8.92(s,2H),8.37(s,1H),7.77-7.75(d, 1H),7.40-7.36(t,1H),7.27-7.25(m,2H),7.12-7.10(d,1H),6.95-6.93(d,1H),4.89-4.87(d,2H),4.82-4.80(d,2H),4.61(s,2H),4.41(m,1H),4.18-4.14(m,2H),3.62(m,2H),3.45(m,2H),3.02(s,3H),1.39-1.35(t,3H). White solid. Yield: 115 mg. m/z: [M+H] + = 461.3 (MW calc. 460.53). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 8.92 (s, 2H), 8.37 (s, 1H), 7.77 -7.75(d, 1H), 7.40-7.36(t,1H), 7.27-7.25(m,2H), 7.12-7.10(d,1H), 6.95-6.93(d,1H),4.89-4.87(d, 2H), 4.82-4.80 (d, 2H), 4.61 (s, 2H), 4.41 (m, 1H), 4.18-4.14 (m, 2H), 3.62 (m, 2H), 3.45 (m, 2H), 3.02 (s, 3H), 1.39-1.35 (t, 3H).

實施例84：1-(5-(3-氯苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 84: 1-(5-(3-Chlorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxo ring Butane]-6-formamide

白色固體。產量：62mg。m/z：[M+H]+=451.4(MW calc.450.92). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.02(s,2H),8.36(s,1H),7.86(m,1H),7.77(m,1H),7.74-7.72(m,1H),7.51-7.49(m,1H),7.45-7.43(m,1H),7.13-7.11(d,1H),4.88-4.87(d,2H),4.80-4.79(m,3H),4.61(s,2H),3.64-3.52(m,4H),3.00-2.98(d,3H). White solid. Yield: 62 mg. m/z: [M+H] + = 451.4 (MW calc. 450.92). 1H NMR (400MHz, DMSO-d6, δ ppm): 9.02 (s, 2H), 8.36 (s, 1H), 7.86 (m, 1H), 7.77 (m, 1H), 7.74-7.72 (m, 1H), 7.51-7.49 (m, 1H), 7.45-7.43 (m, 1H), 7.13-7.11 (d, 1H), 4.88-4.87 ( d, 2H), 4.80-4.79 (m, 3H), 4.61 (s, 2H), 3.64-3.52 (m, 4H), 3.00-2.98 (d, 3H).

實施例85：N-(2-羥乙基)-N-甲基-1-(5-(3-(三氟甲氧基)苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 85: N-(2-hydroxyethyl)-N-methyl-1-(5-(3-(trifluoromethoxy)phenyl)pyrimidin-2-yl)spiro[porphyrin-3 , 3'-oxocyclobutane]-6-formamide

白色固體。產量：85mg。m/z：[M+H]+=501(MW calc.500.48). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.05(s,2H),8.37(s,1H),7.82-7.79(m,3H),7.64-7.60(t,1H),7.39-7.37(d,1H),7.13-7.11(d,1H),4.89-4.87(d,2H),4.80-4.79(m,3H),4.61(s,2H),3.64-3.51(m,4H),3.00(d,3H). White solid. Yield: 85 mg. m/z: [M+H] + = 501 (MW calc. 500.48). 1H NMR (400MHz, DMSO-d6, δ ppm): 9.05 (s, 2H), 8.37 (s, 1H), 7.82-7.79 ( m,3H), 7.64-7.60(t,1H), 7.39-7.37(d,1H),7.13-7.11(d,1H),4.89-4.87(d,2H), 4.80-4.79(m,3H), 4.61 (s, 2H), 3.64 - 3.51 (m, 4H), 3.00 (d, 3H).

實施例86：1-(5-(3-胺苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 86: 1-(5-(3-Aminophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxo ring Butane]-6-formamide

白色固體。產量：80mg。m/z：[M+H]+=432.1(MW calc.431.50). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.83(s,2H),8.34(s,1H),7.77(m,1H),7.14-7.09(m,2H),6.84(m,2H),6.60-6.58(d,1H),5.22(s,2H),4.87-4.86(d,2H),4.79-4.78(m,3H),4.59(s,2H),3.64-3.52(m,4H),3.00(m,3H). White solid. Yield: 80 mg. m/z: [M+H] + = 432.1 (MW calc. 431.50). 1H NMR (400MHz, DMSO-d6, δ ppm): 8.83 (s, 2H), 8.34 (s, 1H), 7.77 (m, 1H), 7.14-7.09 (m, 2H), 6.84 (m, 2H), 6.60-6.58 (d, 1H), 5.22 (s, 2H), 4.87-4.86 (d, 2H), 4.79-4.78 (m, 3H), 4.59 (s, 2H), 3.64-3.52 (m, 4H), 3.00 (m, 3H).

實施例87：N-(2-羥乙基)-N-甲基-1-(5-(3-(吡咯啶-1-基)苯基)嘧啶-2-基)螺 [吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 87: N-(2-hydroxyethyl)-N-methyl-1-(5-(3-(pyrrolidin-1-yl)phenyl)pyrimidin-2-yl) snail [Porphyrin-3,3'-oxycyclobutane]-6-carboxamide

白色固體。產量：50mg。m/z：[M+H]+=485.8(MW calc.485.59). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.95(s,2H),8.34(s,1H),7.77(m,1H),7.27-7.23(m,2H),7.10-7.09(d,1H),6.92-6.90(d,1H),6.80(s,1H),6.56-6.54(d,1H),4.88-4.86(d,2H),4.80-4.79(m,3H),4.60(s,2H),3.64-3.51(m,4H),3.31(m,4H),3.00-2.97(m,3H),1.97(m,4H). White solid. Yield: 50 mg. m/z: [M+H] + = 485.8 (MW calc. 485.59). 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.95 (s, 2H), 8.34 (s, 1H), 7.77 (m, 1H), 7.27-7.23 (m, 2H), 7.10-7.09 (d, 1H), 6.92-6.90 (d, 1H), 6.80 (s, 1H), 6.56-6.54 (d, 1H), 4.88-4.86 ( d, 2H), 4.80-4.79 (m, 3H), 4.60 (s, 2H), 3.64-3.51 (m, 4H), 3.31 (m, 4H), 3.00-2.97 (m, 3H), 1.97 (m, 4H).

實施例88：N-(2-羥乙基)-1-(5-(3-(1-羥乙基)苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 88: N-(2-hydroxyethyl)-1-(5-(3-(1-hydroxyethyl)phenyl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3 , 3'-oxocyclobutane]-6-formamide

白色固體。產量：82mg。m/z：[M+H]+=460.8(MW calc.460.53). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.97(s,2H),8.36(s,1H),7.78(m,1H),7.67(s,1H),7.59-7.57(d,1H),7.45-7.41(m,1H),7.38-7.37(m,1H),7.12-7.10(d,1H), 5.21-5.20(d,1H),4.89-4.87(d,2H),4.80-4.79(m,4H),4.60(s,2H),3.64-3.52(m,4H),3.00(d,3H),1.38-1.37(d,3H). White solid. Yield: 82 mg. m/z: [M+H] + = 460.8 (MW calc. 460.53). 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.97 (s, 2H), 8.36 (s, 1H), 7.78 (m, 1H), 7.67 (s, 1H), 7.59-7.57 (d, 1H), 7.45-7.41 (m, 1H), 7.38-7.37 (m, 1H), 7.12-7.10 (d, 1H), 5.21-5.20 ( d, 1H), 4.89-4.87 (d, 2H), 4.80-4.79 (m, 4H), 4.60 (s, 2H), 3.64-3.52 (m, 4H), 3.00 (d, 3H), 1.38-1.37 ( d, 3H).

實施例89：1-(5-(3,4-二氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 89: 1-(5-(3,4-Difluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3' -oxycyclobutane]-6-formamide

白色固體。產量：82mg。m/z：[M+H]+=453(MW calc.452.46). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.98(s,2H),8.32(s,1H),7.90-7.86(m,1H),7.75(m,1H),7.59-7.56(m,1H),7.54-7.49(m,1H),7.10-7.08(d,1H),4.85-4.84(d,2H),4.77-4.72(m,3H),4.57(s,2H),3.61-3.49(m,3H),3.27(m,1H),2.97-2.93(m,3H). White solid. Yield: 82 mg. m/z: [M+H] + = 453 (MW calc. 452.46). 1H NMR (400MHz, DMSO-d6, δ ppm): 8.98 (s, 2H), 8.32 (s, 1H), 7.90-7.86 ( m, 1H), 7.75 (m, 1H), 7.59-7.56 (m, 1H), 7.54-7.49 (m, 1H), 7.10-7.08 (d, 1H), 4.85-4.84 (d, 2H), 4.77- 4.72 (m, 3H), 4.57 (s, 2H), 3.61-3.49 (m, 3H), 3.27 (m, 1H), 2.97-2.93 (m, 3H).

實施例90：1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 90: 1-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3, 3'-oxocyclobutane]-6-formamide

白色固體。產量：85mg。m/z：[M+H]+=449.1(MW calc.448.50). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.83(s,2H),8.34(s,1H),7.78(m,1H),7.46-7.45(d,1H),7.24-7.22(d,2H),7.13-7.11(m,1H),4.88-4.87(d,2H),4.80-4.78(m,3H),4.60(s,2H),3.64-3.51(m,4H),3.00(s,3H),2.35(s,3H). White solid. Yield: 85 mg. m/z: [M+H] + = 449.1 (MW calc. 448.50). 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.83 (s, 2H), 8.34 (s, 1H), 7.78 (m, 1H), 7.46-7.45 (d, 1H), 7.24-7.22 (d, 2H), 7.13-7.11 (m, 1H), 4.88-4.87 (d, 2H), 4.80-4.78 (m, 3H), 4.60 ( s, 2H), 3.64-3.51 (m, 4H), 3.00 (s, 3H), 2.35 (s, 3H).

實施例91：1-(5-(5-環丙基-2-氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 91:1-(5-(5-Cyclopropyl-2-fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3 , 3'-oxocyclobutane]-6-formamide

白色固體。產量：45mg。m/z：[M+H]+=474.8(MW calc.474.53). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.84(s,2H),8.35(s,1H),7.78(m,1H),7.31-7.30(m,1H),7.22-7.20(m,1H),7.13(m,1H),4.88-4.87(m,2H),4.80-4.79(m,3H),4.60(s,2H),3.64-3.51(m,4H),3.00(d,3H),1.97(m,1H),0.96-0.95(m,2H),0.75(m,2H). White solid. Yield: 45 mg. m/z: [M+H] + = 474.8 (MW calc. 474.53). 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.84 (s, 2H), 8.35 (s, 1H), 7.78 (m, 1H), 7.31-7.30 (m, 1H), 7.22-7.20 (m, 1H), 7.13 (m, 1H), 4.88-4.87 (m, 2H), 4.80-4.79 (m, 3H), 4.60 (s, 2H), 3.64-3.51 (m, 4H), 3.00 (d, 3H), 1.97 (m, 1H), 0.96-0.95 (m, 2H), 0.75 (m, 2H).

實施例92：1-(5-(2-氟-5-甲氧基苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 92: 1-(5-(2-Fluoro-5-methoxyphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3 , 3'-oxocyclobutane]-6-formamide

白色固體。產量：82mg。m/z：[M+H]+=464.8(MW calc.464.49). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.86(s,2H),8.35(s,1H),7.78(m,1H),7.30-7.26(m,1H),7.19(m,1H),7.13-7.11(m,1H),6.99-6.97(m,1H),4.88-4.87(d,2H),4.80-4.79(m,3H),4.60(s,2H),3.81(s,3H),3.63-3.52(m,4H),3.00(d,3H). White solid. Yield: 82 mg. m/z: [M+H] + = 464.8 (MW calc. 464.49). 1H NMR (400MHz, DMSO-d6, δ ppm): 8.86 (s, 2H), 8.35 (s, 1H), 7.78 (m, 1H), 7.30-7.26 (m, 1H), 7.19 (m, 1H), 7.13-7.11 (m, 1H), 6.99-6.97 (m, 1H), 4.88-4.87 (d, 2H), 4.80-4.79 ( m, 3H), 4.60 (s, 2H), 3.81 (s, 3H), 3.63-3.52 (m, 4H), 3.00 (d, 3H).

實施例93：1-(5-(5-乙氧基-2-氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 93: 1-(5-(5-Ethoxy-2-fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3 , 3'-oxocyclobutane]-6-formamide

白色固體。產量：85mg。m/z：[M+H]+=479(MW calc.478.52). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.85(s,2H),8.35(s,1H),7.78(m,1H),7.29-7.24(m,1H),7.17(m,1H),7.13-7.11(m,1H),6.97(m,1H),4.88-4.87(d,2H),4.80-4.79(m,3H),4.60(s,2H),4.09-4.07(m,2H),3.64-3.51(m,4H),3.00(d,3H),1.35-1.32(m,3H). White solid. Yield: 85 mg. m/z: [M+H] + = 479 (MW calc. 478.52). 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.85 (s, 2H), 8.35 (s, 1H), 7.78 (m, 1H), 7.29-7.24 (m, 1H), 7.17 (m, 1H), 7.13-7.11 (m, 1H), 6.97 (m, 1H), 4.88-4.87 (d, 2H), 4.80-4.79 (m, 3H), 4.60 (s, 2H), 4.09-4.07 (m, 2H), 3.64-3.51 (m, 4H), 3.00 (d, 3H), 1.35-1.32 (m, 3H).

實施例94：1-(5-(2-氟-5-(三氟甲氧基)苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基-螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 94: 1-(5-(2-Fluoro-5-(trifluoromethoxy)phenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methyl-spiro [ Porphyrin-3,3'-oxycyclobutane]-6-carboxamide

白色固體。產量：80mg。m/z：[M+H]+=518.8(MW calc.518.46). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.89(s,2H),8.35(s,1H),7.77(m,2H),7.53-7.50(m,2H),7.13-7.11(d,1H),4.89-4.87(d,2H),4.80-4.79(m,3H),4.61(s,2H),3.64-3.51(m,4H),3.00(d,3H). White solid. Yield: 80 mg. m/z: [M+H] + = 518.8 (MW calc. 518.46). 1H NMR (400MHz, DMSO-d6, δ ppm): 8.89 (s, 2H), 8.35 (s, 1H), 7.77 (m, 2H), 7.53-7.50 (m, 2H), 7.13-7.11 (d, 1H), 4.89-4.87 (d, 2H), 4.80-4.79 (m, 3H), 4.61 (s, 2H), 3.64-3.51 ( m, 4H), 3.00 (d, 3H).

實施例95：1-(5-(5-胺-2-氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 95: 1-(5-(5-Amino-2-fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3 '-oxycyclobutane]-6-formamide

白色固體。產量：80mg。m/z：[M+H]+=450.4(MW calc.449.48). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.74(s,2H),8.33(s,1H),7.78(m,1H),7.12-7.10(m,1H),7.02-6.97(d,1H),6.70-6.68(m,1H),6.60-6.57(m,1H), 5.08(s,2H),4.88-4.86(d,2H),4.79-4.78(m,3H),4.59(s,2H),3.64-3.52(m,4H),3.00-2.97(d,3H). White solid. Yield: 80 mg. m/z: [M+H] + = 450.4 (MW calc. 449.48). 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.74 (s, 2H), 8.33 (s, 1H), 7.78 (m, 1H), 7.12-7.10 (m, 1H), 7.02-6.97 (d, 1H), 6.70-6.68 (m, 1H), 6.60-6.57 (m, 1H), 5.08 (s, 2H), 4.88-4.86 ( d, 2H), 4.79-4.78 (m, 3H), 4.59 (s, 2H), 3.64-3.52 (m, 4H), 3.00-2.97 (d, 3H).

實施例96：1-(5-(5-(乙基胺)-2-氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 96: 1-(5-(5-(ethylamine)-2-fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin -3,3'-oxocyclobutane]-6-carboxamide

由Int-1及3-溴-N-乙基-4-茀苯胺經3步驟以類似合成實施例22方式製備。白色固體。產量：65mg。m/z：[M+H]+=478.2(MW calc.477.22). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.78(s,2H),8.34(s,1H),7.78(m,1H),7.12-7.10(m,1H),7.06(m,1H),6.66-6.65(m,2H),6.59-6.57(m,1H),5.56(m,1H),4.88-4.86(d,2H),4.80-4.79(m,3H),4.60(s,2H),3.63-3.51(m,4H),3.07-3.04(m,2H),3.00(m,3H),1.18-1.15(m,3H). From Int-1 and 3-bromo-N-ethyl-4-nonanilide were prepared in a similar manner to Synthesis Example 22 in three steps. White solid. Yield: 65 mg. m/z: [M+H] + = 478.2 (MW calc. 477.22). 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.78 (s, 2H), 8.34 (s, 1H), 7.78 (m, 1H), 7.12-7.10 (m, 1H), 7.06 (m, 1H), 6.66-6.65 (m, 2H), 6.59-6.57 (m, 1H), 5.56 (m, 1H), 4.88-4.86 (d, 2H), 4.80-4.79 (m, 3H), 4.60 (s, 2H), 3.63-3.51 (m, 4H), 3.07-3.04 (m, 2H), 3.00 (m, 3H), 1.18-1.15 (m, 3H).

實施例97：1-(5-(3-(乙基胺)苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 97: 1-(5-(3-(ethylamine)phenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3 '-oxycyclobutane]-6-formamide

由Int-1及3-溴-N-乙苯胺經3步驟以類似合成實施例22方式製備。白色固體。產量：75mg。m/z：[M+H]+=460.6(MW calc.459.55). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.88(s,2H),8.35(s,1H),7.77-7.76(m,1H),7.18-7.16(t,1H),7.10-7.09(d,1H),6.85-6.81(m,2H),6.59-6.57(d,1H),5.64(m,1H),4.88-4.86(d,2H),4.80-4.78(m,3H),4.59(s,2H),3.63-3.52(m,4H),3.12-3.09(m,2H),3.00(m,3H),1.20-1.16(m,3H). From Int-1 and 3-bromo-N-ethylaniline were prepared in a similar manner to Synthesis Example 22 in three steps. White solid. Yield: 75 mg. m/z: [M+H] + = 460.6 (MW calc. 459.55). 1H NMR (400MHz, DMSO-d6, δ ppm): 8.88 (s, 2H), 8.35 (s, 1H), 7.77-7.76 ( m,1H), 7.18-7.16(t,1H), 7.10-7.09(d,1H), 6.85-6.81(m,2H), 6.59-6.57(d,1H),5.64(m,1H),4.88- 4.86 (d, 2H), 4.80-4.78 (m, 3H), 4.59 (s, 2H), 3.63-3.52 (m, 4H), 3.12-3.09 (m, 2H), 3.00 (m, 3H), 1.20- 1.16 (m, 3H).

實施例98：1-(5-(2-氟-5-(吡咯啶-1-基)苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 98: 1-(5-(2-Fluoro-5-(pyrrolidin-1-yl)phenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[ Porphyrin-3,3'-oxycyclobutane]-6-carboxamide

98a)1-(5-(5-胺-2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-羧酸甲酯 98a) Methyl 1-(5-(5-amino-2-fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-carboxylate

由Int-1(400mg,1.063mmol)及3-溴-4-茀苯胺(403.98mg,2.126mmol)以類似於合成規程22a方式製備。淺褐色固體。產量：230mg(53%)。m/z：[M+H]+ =407.2(MW calc.406.41). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.90(s,1H),8.77(s,2H),7.89-7.87(d,1H),7.75-7.73(d,1H),7.03-6.98(m,1H),6.74-6.71(m,1H),6.61-6.57(m,1H),5.08(s,2H),4.89-4.88(d,2H),4.78-4.77(d,2H),4.61(s,2H),3.88(s,3H). Prepared by Int-1 (400 mg, 1.063 mmol) and 3-bromo-4-indolylamine (403.98 mg, 2.126 mmol) in a procedure similar to the procedure of procedure 22a. Light brown solid. Yield: 230 mg (53%). m/z: [M+H] + = 407.2 (MW calc. 406.41). 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.90 (s, 1H), 8.77 (s, 2H), 7.89-7. d,1H), 7.75-7.73(d,1H), 7.03-6.98(m,1H),6.74-6.71(m,1H),6.61-6.57(m,1H),5.08(s,2H),4.89- 4.88 (d, 2H), 4.78-4.77 (d, 2H), 4.61 (s, 2H), 3.88 (s, 3H).

98b)1-(5-(2-氟-5-(吡咯啶-1-基)苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-羧酸甲酯 98b) 1-(5-(2-Fluoro-5-(pyrrolidin-1-yl)phenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6- Methyl carboxylate

化合物98a(230mg,0.566mmol)、1,4-二溴丁烷(0.068ml,0.0566mmol)及DIPEA(0.327ml,1.981mmol)係在甲苯中於110℃經攪拌16h。該溶劑係在減壓中被移除且該剩餘物係經以快速管柱層析法[EtOAc/己烷=3：2]純化。黃色固體。產量：140mg(54%)。m/z：[M+H]+=461.1(MW calc.460.50). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.91(s,1H),8.87(s,2H),7.89-7.87(d,1H),7.75-7.73(d,1H),7.18-7.13(m,1H),6.69-6.67(m,1H),6.56-6.53(m,1H),4.90-4.88(d,2H),4.79-4.77(d,2H),4.62(s,2H),3.88(s,3H),3.26(m,4H),1.98-1.96(m,4H). Compound 98a (230 mg, 0.566 mmol), 1,4-dibromobutane (0.068 ml, 0.0566 mmol) and DIPEA (0.327 ml, 1.981 mmol) were stirred in toluene at 110 ° C for 16 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography [EtOAc/hexane = 3:2]. Yellow solid. Yield: 140 mg (54%). m/z: [M+H] + = 461.1 (MW calc. 460.50). 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.91 (s, 1H), 8.87 (s, 2H), 7.89-7. d, 1H), 7.75-7.73 (d, 1H), 7.18-7.13 (m, 1H), 6.69-6.67 (m, 1H), 6.56-6.53 (m, 1H), 4.90-4.88 (d, 2H), 4.79-4.77 (d, 2H), 4.62 (s, 2H), 3.88 (s, 3H), 3.26 (m, 4H), 1.98-1.96 (m, 4H).

98c)1-(5-(2-氟-5-(吡咯啶-1-基)苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 98c) 1-(5-(2-Fluoro-5-(pyrrolidin-1-yl)phenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[吲哚Porphyrin-3,3'-oxycyclobutane]-6-formamide

由化合物98b經二步驟(以LiOH水解酯，然後TBTU-介導與2-(甲基胺)乙醇之偶聯反應)獲得。白色固體。產量：110mg。m/z：[M+H]+=503.8(MW calc.503.57). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.84(s,2H),8.35(s,1H),7.78(m,1H),7.17-7.10(m,2H),6.64(m,1H),6.55(m,1H),4.88-4.87(d,2H),4.80-4.79(m,3H),4.60(s,2H),3.63-3.51(m,4H),3.25(m,4H),3.00(m,3H),1.96(m,4H). Obtained from compound 98b in two steps (hydrolysis of the ester with LiOH followed by TBTU-mediated coupling reaction with 2-(methylamine)ethanol). White solid. Yield: 110 mg. m/z: [M+H] + = 503.8 (MW calc. 503.57). 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.84 (s, 2H), 8.35 (s, 1H), 7.78 (m, 1H), 7.17-7.10 (m, 2H), 6.64 (m, 1H), 6.55 (m, 1H), 4.88-4.87 (d, 2H), 4.80-4.79 (m, 3H), 4.60 (s, 2H) , 3.63-3.51 (m, 4H), 3.25 (m, 4H), 3.00 (m, 3H), 1.96 (m, 4H).

實施例99：2-(2-(2-(6-(甲亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-4-基)丙-2-醇 Example 99: 2-(2-(2-(6-(methylsulfinyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)pyridine -4-yl)propan-2-ol

99a)6'-溴-2,2-二甲基螺[[1,3]二噁烷-5,3'-吲哚啉]-2'-酮 99a) 6'-Bromo-2,2-dimethylspiro[[1,3]dioxane-5,3'-carboline]-2'-one

無水THF(100mL)中之Int-1a(6.0g,19.22mmol)係於-30℃被逐滴加入至無水THF(120mL)中之KH(礦物油中30%,2.56g,19.22mmol)懸浮液。該反應混合物係於此溫度中經攪拌30min、叔BuLi(2M於戊烷，22.1mL,44.2mmol)係被加入且於-78℃經持續攪拌30min。無水THF(30mL)中之二甲基二硫化物(10.2mL,115.32mmol)溶液係於此溫度逐滴加入且該反應混合物係被緩慢回到RT並攪拌16h。該混合物係經以飽和NH4Cl溶液淬滅及以EtOAc(3x 100mL)萃取。該合併之有機層係經以鹽水清洗、經乾燥及濃縮。該剩餘物係經以快速管柱層析法[矽石；EtOAc/己烷=1：3]純化。白色固體。產量：1.3g(24%)。HPLC(方法3)：Rt=3.19min.,m/z：[M+H]+=280.4(MW calc.279.36). Int-1a (6.0 g, 19.22 mmol) in anhydrous THF (100 mL) was added dropwise at -30 ° C to a mixture of KH (30% in mineral oil, 2.56 g, 19.22 mmol) in anhydrous THF (120 mL) . The reaction mixture was stirred at this temperature for 30 min, tert-BuLi (2M in pentane, 22.1 mL, 44.2 <RTI ID=0.0> A solution of dimethyl disulfide (10.2 mL, 115.32 mmol) in dry THF (30 mL) was added dropwise at this temperature and the mixture was slowly returned to RT and stirred for 16 h. The mixture was extracted with saturated Department NH 4 Cl solution and quenched in EtOAc (3x 100mL). The combined organic layers were washed with brine, dried and concentrated. The residue was purified by flash column chromatography [EtOAc, EtOAc/hexane = 1:1]. White solid. Yield: 1.3 g (24%). HPLC (Method 3): R t = 3.19 min., m/z: [M+H] + = 280.4 (MW calc. 279.36).

99b)2,2-二甲基-6'-(甲硫基)螺[[1,3]二噁烷-5,3'-吲哚啉]-2'-酮 99b) 2,2-dimethyl-6'-(methylthio)spiro[[1,3]dioxane-5,3'-carboline]-2'-one

Red-Al(3.15mL,10.73mmol)係於rt逐滴加入至無水甲苯(40mL)中之化合物99a(1.5g,5.36mmol)溶液且該反應混合物係於80℃經加熱4h。該混 合物係被降溫至0℃及以2N NaOH溶液淬滅。該水相係被分離及以EtOAc(3x 50mL)萃取。該合併之有機層係經以鹽水清洗、經Na2SO4乾燥及濃縮。白色固體。產量：0.7g(50%)。HPLC(方法3)：Rt=3.23min.,m/z：[M+H]+=266.0(MW calc.265.37). Red-Al (3.15 mL, 10.73 mmol) was obtained from EtOAc EtOAc (EtOAc m. The mixture was cooled to 0 ° C and quenched with 2N NaOH solution. The aqueous phase was separated and extracted with EtOAc (3×50 mL). The combined organic layers of the system was washed with brine, dried over Na 2 SO 4 dried and concentrated. White solid. Yield: 0.7 g (50%). HPLC (Method 3): R t = 3.23 min., m/z: [M+H] + = 266.0 (MW calc. 265.37).

99c)2,2-二甲基-6'-(甲硫基)螺[[1,3]二噁烷-5,3'-吲哚啉] 99c) 2,2-dimethyl-6'-(methylthio)spiro[[1,3]dioxane-5,3'-carboline]

2N氯化氫溶液(35.6mL)係被加入至THF(21.2mL)中之99b(2.1g,7.91mmol)及該反應混合物係於rt經攪拌3h。該混合物係經濃縮、經以飽和NaHCO3溶液鹼化及以EtOAc(10x 25mL)萃取。該合併之有機層係經Na2SO4乾燥及濃縮。白色固體。產量：1.9g。HPLC(方法3)：Rt=1.94min.,m/z：[M+H]+=226.1(MW calc.225.31). 2N Hydrogen chloride solution (35.6 mL) was added to EtOAc (21.2 mL) &lt;RTI ID=0.0&gt; The mixture was concentrated Department, extracted with saturated NaHCO 3 solution and basified to EtOAc (10x 25mL). The combined organic layers were dried over Na 2 SO 4 and concentrated. White solid. Yield: 1.9 g. HPLC (Method 3): R t = 1.94 min., m/z: [M+H] + = 226.1 (MW calc. 225.31).

99d)(1-(5-溴嘧啶-2-基)-6-(甲硫基)吲哚啉-3,3-二基)二甲醇 99d) (1-(5-Bromopyrimidin-2-yl)-6-(methylthio)porphyrin-3,3-diyl)dimethanol

n-BuOH(10mL)中之99c(1.9g,8.43mmol)、DIPEA(6.9mL,42.15mmol)及5-溴-2-氯-嘧啶(3.2g,16.86mmol係在密封管中於130℃經攪拌16h。該反應混合物係被降溫至RT及該沉澱物係經以燒結漏斗濾出並以乙醚/己烷清洗。褐色固體。產量：1.5g(47%)。HPLC(方法3)：Rt=3.14min.,m/z：[M+H]+=382.0(MW calc.382.28). 99c (1.9g, 8.43mmol), DIPEA (6.9mL, 42.15mmol) and 5-bromo-2-chloro-pyrimidine (3.2g, 16.86mmol in n-BuOH (10mL) in a sealed tube at 130 ° C After stirring for 16 h, the reaction mixture was cooled to EtOAc EtOAc (EtOAc m .). =3.14 min., m/z: [M+H] + = 382.0 (MW calc.382.28).

99e)(1-(5-溴嘧啶-2-基)-3-(羥甲基)-6-(甲硫基)吲哚啉-3-基)甲基4-甲基-苯磺酸酯 99e) (1-(5-Bromopyrimidin-2-yl)-3-(hydroxymethyl)-6-(methylthio)porphyrin-3-yl)methyl 4-methyl-benzenesulfonate

LiHMDS(3mL,3.92mmol)係於-78℃經30min期間逐滴加入至無水THF(110mL)中之化合物99d(1.5g,3.92mmol)溶液。該反應混合物係於此溫度經攪拌30min，THF(40mL)中之甲苯磺醯基氯(0.75g,3.92mmol)係被緩慢 加入且於-78℃持續攪拌2h。該反應混合物係經以飽和NH4Cl溶液淬滅及以EtOAc(3x 250mL)萃取。該合併之有機層係經Na2SO4乾燥及濃縮。該剩留物係經以快速管柱層析法[矽石；EtOAc/己烷=3：7]純化。白色固體。產量：1.5g(71%)。HPLC(方法3)：Rt=3.78min,m/z：[M+H]+=538.2(MW calc.536.46). LiHMDS (3 mL, 3.92 mmol) was added dropwise to a solution of compound 99d (l. The reaction mixture was stirred at this temperature for 30 min. toluenesulfonyl chloride (0.75 g, 3.92 mmol) in THF (40 mL) was slowly added and stirring was continued at -78 °C for 2 h. The reaction mixture was extracted with saturated lines NH 4 Cl solution and quenched in EtOAc (3x 250mL). The combined organic layers were dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography [ vermiculite; EtOAc/hexane = 3:7]. White solid. Yield: 1.5 g (71%). HPLC (Method 3): R t = 3.78 min, m/z: [M+H] + = 538.2 (MW calc. 536.46).

99f)1-(5-溴嘧啶-2-基)-6-(甲硫基)螺[吲哚啉-3,3'-氧環丁烷] 99f) 1-(5-Bromopyrimidin-2-yl)-6-(methylthio)spiro[porphyrin-3,3'-oxocyclobutane]

化合物99e(1.5g,2.79mmol)及在t-BuOH(40mL)中研磨(pestled)之KOH(0.7g)係於70℃經攪拌30min。該反應混合物係被降溫至RT且該溶劑係被蒸發。該剩餘物係經以水(50mL)稀釋及以EtOAc(3x 30mL)萃取。該合併之有機層係被乾燥及濃縮。研磨該剩餘物得到該白色固體之目標化合物。產量：0.75g(75%)。HPLC(方法3)：Rt=3.85min.,m/z：[M+H]+=364.2(MW calc.364.26). Compound 99e (1.5 g, 2.79 mmol) and phos (0.7 g) which was crystallized from t-BuOH (40 mL) were stirred at 70 ° C for 30 min. The reaction mixture was cooled to RT and the solvent was evaporated. The residue was diluted with water (50 mL) andEtOAcEtOAc The combined organic layer is dried and concentrated. The residue was triturated to give the title compound as a white solid. Yield: 0.75 g (75%). HPLC (Method 3): R t = 3.85 min., m/z: [M+H] + = 364.2 (MW calc.364.26).

99g)2-(2-(2-(6-(甲亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-4-基)丙-2-醇 99g) 2-(2-(2-(6-(methylsulfinyl) spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)pyridine-4 -yl)propan-2-ol

由99f及2-(2-溴吡啶-4-基)丙-2-醇類似於實施例56方式製備。白色固體。產量：0.15g。HPLC(方法2)：Rt=1.45min,m/z：[M+H]+=437.1(MW calc.436.53). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.33(s,2H),8.67(s,1H),8.59(d,1H,J=4.9Hz),8.04(s,1H),7.94(d,1H,J=7.7Hz),7.47(d,1H,J=3.9Hz),7.40(d,1H,J=6.6Hz),5.29(bs,1H),4.90(d,2H,J=6Hz),4.79(d,2H,J=4Hz),4.65(s,2H),2.76(s,3H),1.48(s,6H). Prepared analogously to Example 56 from 99f and 2-(2-bromopyridin-4-yl)propan-2-ol. White solid. Yield: 0.15 g. HPLC (Method 2): R t = 1.45 min, m/z: [M+H] + = 437.1 (MW calc. 436.53). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.33 (s, 2H) ), 8.67 (s, 1H), 8.59 (d, 1H, J = 4.9 Hz), 8.04 (s, 1H), 7.94 (d, 1H, J = 7.7 Hz), 7.47 (d, 1H, J = 3.9 Hz) ), 7.40 (d, 1H, J = 6.6 Hz), 5.29 (bs, 1H), 4.90 (d, 2H, J = 6 Hz), 4.79 (d, 2H, J = 4 Hz), 4.65 (s, 2H), 2.76(s,3H), 1.48(s,6H).

實施例100：2-(2-(2-(6-(甲磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基) 吡啶-4-基)丙-2-醇 Example 100: 2-(2-(2-(6-(methylsulfonyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl) Pyridin-4-yl)propan-2-ol

由99f及2-(2-溴吡啶-4-基)丙-2-醇類似於實施例57方式製備。白色固體。產量：0.16g。HPLC(方法2)：Rt=1.47min,m/z：[M+H]+=453.1(MW calc.452.53). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.35(s,2H),8.87(s,1H),8.60(d,1H,J=4.9Hz),8.06(s,1H),8.02(d,1H,J=7.7Hz),7.69(d,1H,J=7.7Hz),7.48(d,1H,J=4.9Hz),5.29(bs,1H),4.92(d,2H,J=6Hz),4.79(d,2H,J=5.9Hz),4.67(s,2H),3.17(s,3H),1.49(s,6H). Prepared analogously to Example 57 from 99f and 2-(2-bromopyridin-4-yl)propan-2-ol. White solid. Yield: 0.16 g. HPLC (Method 2): R t = 1.47 min, m/z: [M+H] + = 453.1 (MW calc.452.53). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.35 (s, 2H) , 8.87 (s, 1H), 8.60 (d, 1H, J = 4.9 Hz), 8.06 (s, 1H), 8.02 (d, 1H, J = 7.7 Hz), 7.69 (d, 1H, J = 7.7 Hz) , 7.48 (d, 1H, J = 4.9 Hz), 5.29 (bs, 1H), 4.92 (d, 2H, J = 6 Hz), 4.79 (d, 2H, J = 5.9 Hz), 4.67 (s, 2H), 3.17(s,3H), 1.49(s,6H).

實施例101至104係由Int-5類似於合成實施例154合成。 Examples 101 to 104 were synthesized from Int-5 similarly to Synthesis Example 154.

實施例101：1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)-N,N-二甲基螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺 Example 101:1-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)-N,N-dimethylspiro[porphyrin-3,3'-oxycyclobutane ]-6-sulfonamide

白色固體。產量：0.09g。HPLC(方法3)：Rt=3.79min,m/z：[M+H]+=455.1 (MW calc.454.52). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.88(s,2H),8.69(s,1H),8.00(d,1H,J=7.8Hz),7.51-7.47(m,2H),7.25(d,2H,J=8.3),4.90(d,2H,J=6.2Hz),4.80(d,2H,J=6.2Hz),4.65(s,2H),2.66(s,6H),2.35(s,3H). White solid. Yield: 0.09 g. HPLC (Method 3): R t = 3.79 min, m/z: [M+H] + =455.1 (MW calc.454.52). 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.88 (s, 2H) , 8.69 (s, 1H), 8.00 (d, 1H, J = 7.8 Hz), 7.51 - 7.47 (m, 2H), 7.25 (d, 2H, J = 8.3), 4.90 (d, 2H, J = 6.2 Hz) ), 4.80 (d, 2H, J = 6.2 Hz), 4.65 (s, 2H), 2.66 (s, 6H), 2.35 (s, 3H).

實施例102：1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺 Example 102: 1-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3, 3'-oxocyclobutane]-6-sulfonamide

白色固體。產量：0.12g。HPLC(方法2)：Rt=1.69min,m/z：[M+H]+=485.1(MW calc.484.54). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.88(s,2H),8.71(s,1H),7.98(d,1H,J=7.8Hz),7.51(d,2H,J=7.5Hz),7.25(d,2H,J=8.2Hz),4.90(d,2H,J=5.9Hz),4.80-4.78(m,3H),4.65(s,2H),3.54-3.53(m,2H),3.06-3.03(m,2H),2.77(s,3H),2.35(s,3H). White solid. Yield: 0.12 g. HPLC (Method 2): Rt = 1.69 min, m/z: [M+H] + =485.1 (MW calc.484.54). 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.88 (s, 2H) , 8.71 (s, 1H), 7.98 (d, 1H, J = 7.8 Hz), 7.51 (d, 2H, J = 7.5 Hz), 7.25 (d, 2H, J = 8.2 Hz), 4.90 (d, 2H, J=5.9 Hz), 4.80-4.78 (m, 3H), 4.65 (s, 2H), 3.54-3.53 (m, 2H), 3.06-3.03 (m, 2H), 2.77 (s, 3H), 2.35 (s) , 3H).

實施例103：N,N-二甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺 Example 103: N,N-Dimethyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane] -6-sulfonamide

白色固體。產量：65mg。HPLC(方法2)：Rt=1.63min,m/z：[M+H]+=438.08(MW calc.437.52). 1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：9.28(s,2H),8.76(s,1H),8.52(s,1H),7.97(d,1H,J=7.8Hz),7.85(s,1H),7.51(d,1H,J=7.4Hz),7.19(s,1H),4.92(d,2H,J=6.1Hz),4.82(d,2H,J=6.0Hz),4.68(s,2H),2.74(s,6H),2.41(s,3H). White solid. Yield: 65 mg. HPLC (Method 2): R t = 1.63 min, m/z: [M+H] + = 438.08 (MW calc.437.52). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 9.28 (s) , 2H), 8.76 (s, 1H), 8.52 (s, 1H), 7.97 (d, 1H, J = 7.8 Hz), 7.85 (s, 1H), 7.51 (d, 1H, J = 7.4 Hz), 7.19 (s, 1H), 4.92 (d, 2H, J = 6.1 Hz), 4.82 (d, 2H, J = 6.0 Hz), 4.68 (s, 2H), 2.74 (s, 6H), 2.41 (s, 3H) .

實施例104：N-(2-羥乙基)-N-甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺 Example 104: N-(2-hydroxyethyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3 '-oxycyclobutane]-6-sulfonamide

白色固體。產量：75mg。HPLC(方法2)：Rt=1.51min,m/z：[M+H]+=468.08(MW calc.467.54). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.32(s,2H),8.75(s,1H),8.52(s,1H),7.98-7.94(m,2H),7.51(d,1H,J=7.6),7.21(d,1H,J=4.8Hz),4.90(d,2H,J=6.2Hz),4.82-4.77(m,3H),4.66(s,2H),3.54(bs,2H),3.06-3.03(m,2H),2.78(s,3H),2.39(s,3H). White solid. Yield: 75 mg. HPLC (Method 2): R t = 1.51 min, m/z: [M+H] + = 468.08 (MW calc. 467.54). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.32 (s, 2H) , 8.75 (s, 1H), 8.52 (s, 1H), 7.98-7.94 (m, 2H), 7.51 (d, 1H, J = 7.6), 7.21 (d, 1H, J = 4.8 Hz), 4.90 (d , 2H, J=6.2Hz), 4.82-4.77 (m, 3H), 4.66 (s, 2H), 3.54 (bs, 2H), 3.06-3.03 (m, 2H), 2.78 (s, 3H), 2.39 ( s, 3H).

實施例105：N-甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)-N-(氧環丁烷-3-基甲基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 105: N-Methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-N-(oxocyclobutan-3-ylmethyl)spiro[吲哚Porphyrin-3,3'-oxycyclobutane]-6-formamide

TBTU偶聯化合物22b與N-甲基-1-(氧環丁烷-3-基)甲胺(也參見製程22c)。白色固體。產量：0.1g。HPLC(方法3)：Rt=2.82min,m/z：[M+H]+=457.9(MW calc.457.52). 1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：9.24(s,2H),8.52(d,1H,J=4.8Hz),8.37(s,1H),7.83-7.8(m,2H),7.18(d,1H,J=4.7Hz),7.11(d,1H,J=7.6Hz),4.90(d,2H,J=6Hz),4.82(d,2H,J=6Hz),4.70-4.66(m,2H),4.63(s,2H),4.36(t,2H,J=6.0Hz),3.75(d,2H,J=7Hz),3.39-3.34(m,1H),2.95(s,3H),2.41(s,3H). TBTU coupled compound 22b with N-methyl-1-(oxocyclobutane-3-yl)methylamine (see also Process 22c). White solid. Yield: 0.1 g. HPLC (Method 3): R t = 2.82 min, m/z: [M+H] + = 457.9 (MW calc.457.52). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 9.24 (s) , 2H), 8.52 (d, 1H, J = 4.8 Hz), 8.37 (s, 1H), 7.83-7.8 (m, 2H), 7.18 (d, 1H, J = 4.7 Hz), 7.11 (d, 1H, J = 7.6 Hz), 4.90 (d, 2H, J = 6 Hz), 4.82 (d, 2H, J = 6 Hz), 4.70 - 4.66 (m, 2H), 4.63 (s, 2H), 4.36 (t, 2H, J=6.0 Hz), 3.75 (d, 2H, J=7 Hz), 3.39-3.34 (m, 1H), 2.95 (s, 3H), 2.41 (s, 3H).

實施例106：N-(環丙基甲基)-N-甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 106: N-(cyclopropylmethyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3 '-oxycyclobutane]-6-formamide

由化合物22b及1-環丙基-N-甲基甲胺以類似於製程22c方式製備。白色固體。產量：95mg。HPLC(方法3)：Rt=3.34min,m/z：[M+H]+=442.2(MW calc.441.53). 1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：9.23(s,2H),8.51(d,1H,J=4.8Hz),8.38(s,1H),7.79-7.77(m,2H),7.18(d,1H,J=4.6Hz),7.11(d,1H,J=7.5Hz),4.90(d,2H,J=6Hz),4.82(d,2H,J=5.9Hz),4.63(s,2H),3.29(d,2H,J=6.4Hz),3.05(s,3H),2.40(s,3H),1.05(bs,1H),0.54-0.50(m,2H),0.22(d,2H,J=4.1Hz). Prepared from compound 22b and 1-cyclopropyl-N-methylmethylamine in a similar manner to Process 22c. White solid. Yield: 95 mg. HPLC (Method 3): R t = 3.34 min, m/z: [M+H] + = 442.2 (MW calc.441.53). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 9.23 (s) , 2H), 8.51 (d, 1H, J = 4.8 Hz), 8.38 (s, 1H), 7.79-7.77 (m, 2H), 7.18 (d, 1H, J = 4.6 Hz), 7.11 (d, 1H, J = 7.5 Hz), 4.90 (d, 2H, J = 6 Hz), 4.82 (d, 2H, J = 5.9 Hz), 4.63 (s, 2H), 3.29 (d, 2H, J = 6.4 Hz), 3.05 ( s, 3H), 2.40 (s, 3H), 1.05 (bs, 1H), 0.54-0.50 (m, 2H), 0.22 (d, 2H, J = 4.1 Hz).

實施例107：N-((3,3-二氟環丁基)甲基)-N-甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 107: N-((3,3-Difluorocyclobutyl)methyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl) snail [Porphyrin-3,3'-oxycyclobutane]-6-carboxamide

醯胺偶聯化合物22b與1-(3,3-二氟環丁基)-N-甲基甲胺，類似於製程22c。淺黃色固體。產量：70mg。HPLC(方法2)：Rt=1.67min,m/z：[M+H]+=492.2(MW calc.491.53). 1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：9.23(s,2H),8.52(d,1H,J=4.9Hz),8.37(s,1H),7.79-7.78(m,2H),7.18(d,1H,J=4.8Hz),7.11(d,1H,J=7.6Hz),4.90(d,2H,J=5.7Hz),4.81(d,2H,J=5.9Hz),4.63(s,2H),3.60(d,2H,J=6.9Hz),2.97(s,3H),2.76(bs,2H),2.40(bs,5H). The indoleamine coupling compound 22b with 1-(3,3-difluorocyclobutyl)-N-methylmethylamine is similar to Process 22c. Light yellow solid. Yield: 70 mg. HPLC (Method 2): Rt = 1.67 min, m/z: [M+H] + = 492.2 (MW calc.491.53). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 9.23 (s) , 2H), 8.52 (d, 1H, J = 4.9 Hz), 8.37 (s, 1H), 7.79-7.78 (m, 2H), 7.18 (d, 1H, J = 4.8 Hz), 7.11 (d, 1H, J = 7.6 Hz), 4.90 (d, 2H, J = 5.7 Hz), 4.81 (d, 2H, J = 5.9 Hz), 4.63 (s, 2H), 3.60 (d, 2H, J = 6.9 Hz), 2.97 (s, 3H), 2.76 (bs, 2H), 2.40 (bs, 5H).

實施例108：6-(乙亞磺醯基)-1-(5-(噠嗪-3-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷] Example 108: 6-(ethylsulfinyl)-1-(5-(pyridazin-3-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]

由中間物52h及3-溴噠嗪以類似合成實施例56方式製備。白色固體。產量：0.15g。HPLC(方法2)：Rt=1.50min,m/z：[M+H]+=394.04(MW calc.393.46). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.40(s,2H),9.22(d,1H,J=3.6Hz),8.63(s,1H),8.34-8.31(m,1H),7.95(d,1H,J=7.8Hz),7.83-7.79(m,1H),7.38(d,1H,J=7.6Hz),4.91(d,2H,J=6.0Hz),4.80(d,2H,J=5.7Hz),4.67(s,2H),3.04-2.99(m,1H),2.80-2.75(m,1H),1.10-1.06(t,3H,J=7.2Hz). Prepared by intermediate 52h and 3-bromopyridazine in a similar manner as in Synthesis Example 56. White solid. Yield: 0.15 g. HPLC (Method 2): R t = 1.50 min, m/z: [M+H] + = 394.04 (MW calc. 393.46). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.40 (s, 2H) , 9.22 (d, 1H, J = 3.6 Hz), 8.63 (s, 1H), 8.34 - 8.31 (m, 1H), 7.95 (d, 1H, J = 7.8 Hz), 7.83 - 7.79 (m, 1H), 7.38 (d, 1H, J = 7.6 Hz), 4.91 (d, 2H, J = 6.0 Hz), 4.80 (d, 2H, J = 5.7 Hz), 4.67 (s, 2H), 3.04 - 2.99 (m, 1H) ), 2.80-2.75 (m, 1H), 1.10.10.06 (t, 3H, J = 7.2 Hz).

實施例109：6-(乙磺醯基)-1-(5-(噠嗪-3-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷] Example 109: 6-(ethanesulfonyl)-1-(5-(pyridazin-3-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]

由中間物52h及3-溴噠嗪以類似合成實施例56方式製備。白色固體。產量：90mg。HPLC(方法3)：Rt=2.60min,m/z：[M+H]+=410.0(MW calc.409.46). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.42(s,2H),9.23-9.21(m,1H),8.84(s,1H),8.35-8.33(m,1H),8.04-8.02(m,1H),7.83-7.79(m,1H),7.66-7.64(m,1H),4.92(d,2H,J=6.2),4.80(d,2H,J=6.2),4.69(s,2H),3.29-3.27(m,2H), 1.15(t,3H,J=7.3Hz). Prepared by intermediate 52h and 3-bromopyridazine in a similar manner as in Synthesis Example 56. White solid. Yield: 90 mg. HPLC (Method 3): R t = 2.60 min, m/z: [M+H] + = 410.0 (MW calc. 409.46). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.42 (s, 2H) , 9.23-9.21(m,1H), 8.84(s,1H), 8.35-8.33(m,1H),8.04-8.02(m,1H),7.83-7.79(m,1H),7.66-7.64(m, 1H), 4.92 (d, 2H, J = 6.2), 4.80 (d, 2H, J = 6.2), 4.69 (s, 2H), 3.29-3.27 (m, 2H), 1.15 (t, 3H, J = 7.3 Hz).

實施例110：2-(3-(2-(6-(乙亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)苯基)-丙-2-醇 Example 110: 2-(3-(2-(6-(ethylsulfinyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)benzene -propan-2-ol

由中間物52h及2-(3-溴苯基)丙-2-醇以類似合成實施例56方式製備。白色固體。產量：70mg。HPLC(方法3)：Rt=2.89min,m/z：[M+H]+=449.6(MW calc.449.57). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.00(s,2H),8.59(s,1H),7.93(d,1H,J=7.7Hz),7.80(s,1H),7.58(d,1H,J=7.4Hz),7.51(d,1H,J=7.7Hz),7.43-7.40(m,1H),7.34-7.32(m,1H),5.07(s,1H),4.89(d,2H,J=6.0Hz),4.80(d,2H,J=5.8Hz),4.63(s,2H),3.03-2.98(m,1H),2.79-2.74(m,1H),1.48(s,6H),1.08(t,3H,J=7.2Hz). Prepared by analogy Example 56 from intermediate 52h and 2-(3-bromophenyl)propan-2-ol. White solid. Yield: 70 mg. HPLC (Method 3): R t = 2.89 min, m/z: [M+H] + = 449.6 (MW calc. 449.57). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.00 (s, 2H) , 8.59 (s, 1H), 7.93 (d, 1H, J = 7.7 Hz), 7.80 (s, 1H), 7.58 (d, 1H, J = 7.4 Hz), 7.51 (d, 1H, J = 7.7 Hz) , 7.43-7.40 (m, 1H), 7.34-7.32 (m, 1H), 5.07 (s, 1H), 4.89 (d, 2H, J = 6.0 Hz), 4.80 (d, 2H, J = 5.8 Hz), 4.63 (s, 2H), 3.03-2.98 (m, 1H), 2.79-2.74 (m, 1H), 1.48 (s, 6H), 1.08 (t, 3H, J = 7.2 Hz).

實施例111：2-(3-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)苯基)-丙-2-醇 Example 111: 2-(3-(2-(6-(ethylsulfonyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)phenyl )-propan-2-ol

由中間物52h及2-(3-溴苯基)丙-2-醇以類似合成實施例56方式製備。白色固體。產量：70mg。HPLC(方法3)：Rt=3.05min,m/z：[M+H]+=465.8(MW calc.465.57). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.03(s,2H),8.80(s,1H),8.02(d,1H,J=7.8Hz),7.81(s,1H),7.61-7.58(m,2H),7.52(d,1H,J=7.7Hz),7.44-7.40(m,1H),5.07(s,1H),4.91(d,2H,J=6.4Hz),4.80(d,2H,J=6.1Hz),4.65(s,2H),3.29-3.25(m,2H),1.48(s,6H),1.15(t,3H,J=7.2Hz). Prepared by analogy Example 56 from intermediate 52h and 2-(3-bromophenyl)propan-2-ol. White solid. Yield: 70 mg. HPLC (Method 3): R t = 3.05 min, m/z: [M+H] + = 465.8 (MW calc.465.57). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.03 (s, 2H) , 8.80 (s, 1H), 8.02 (d, 1H, J = 7.8 Hz), 7.81 (s, 1H), 7.61 - 7.58 (m, 2H), 7.52 (d, 1H, J = 7.7 Hz), 7.44 7.40 (m, 1H), 5.07 (s, 1H), 4.91 (d, 2H, J = 6.4 Hz), 4.80 (d, 2H, J = 6.1 Hz), 4.65 (s, 2H), 3.29-3.25 (m) , 2H), 1.48 (s, 6H), 1.15 (t, 3H, J = 7.2 Hz).

實施例112：6-(乙亞磺醯基)-1-(5-(5-甲基噠嗪-3-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷] Example 112: 6-(ethylsulfinyl)-1-(5-(5-methylpyridazin-3-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxo ring Butane

由中間物52h及5-甲基噠嗪-3-基三氟甲磺酸酯以類似合成實施例56方式製備。白色固體。產量：70mg。HPLC(方法3)：Rt=2.56min,m/z：[M+H]+=408.0(MW calc.407.49). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.37(s,2H),9.09(s,1H),8.62(s,1H),8.18(s,1H),7.95(d,1H,J=7.7Hz),7.38(d,1H,J= 7.6Hz),4.91(d,2H,J=6.0Hz),4.80(d,2H,J=5.9Hz),4.63(s,2H),3.06-2.97(m,1H),2.82-2.75(m,1H),2.39(s,3H),1.08(t,3H,J=7.1Hz). Prepared by analogy Example 56 from intermediate 52h and 5-methylpyridazin-3-yl trifluoromethanesulfonate. White solid. Yield: 70 mg. HPLC (Method 3): R t = 2.56 min, m/z: [M+H] + = 408.0 (MW calc. 407.49). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.37 (s, 2H) , 9.09 (s, 1H), 8.62 (s, 1H), 8.18 (s, 1H), 7.95 (d, 1H, J = 7.7 Hz), 7.38 (d, 1H, J = 7.6 Hz), 4.91 (d, 2H, J=6.0 Hz), 4.80 (d, 2H, J=5.9 Hz), 4.63 (s, 2H), 3.06-2.97 (m, 1H), 2.82-2.75 (m, 1H), 2.39 (s, 3H) ), 1.08 (t, 3H, J = 7.1 Hz).

實施例113：6-(乙磺醯基)-1-(5-(5-甲基噠嗪-3-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷] Example 113: 6-(ethanesulfonyl)-1-(5-(5-methylpyridazin-3-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane alkyl]

由中間物52h及5-甲基噠嗪-3-基三氟甲磺酸酯以類似合成實施例56方式製備。白色固體。產量：60mg。HPLC(方法3)：Rt=2.71min,m/z：[M+H]+=424.0(MW calc.423.49). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.40(s,2H),9.10(s,1H),8.84(s,1H),8.21(s,1H),8.04(d,1H,J=7.8Hz),7.66-7.64(m,1H),4.92(d,2H,J=6.3Hz),4.80(d,2H,J=6.2Hz),4.69(s,2H),3.28-3.27(m,2H),2.39(s,3H),1.17-1.13(t,3H,J=7.3Hz). Prepared by analogy Example 56 from intermediate 52h and 5-methylpyridazin-3-yl trifluoromethanesulfonate. White solid. Yield: 60 mg. HPLC (Method 3): R t = 2.71 min, m/z: [M+H] + = 424.0 (MW calc. 423.49). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.40 (s, 2H) , 9.10 (s, 1H), 8.84 (s, 1H), 8.21 (s, 1H), 8.04 (d, 1H, J = 7.8 Hz), 7.66-7.64 (m, 1H), 4.92 (d, 2H, J = 6.3 Hz), 4.80 (d, 2H, J = 6.2 Hz), 4.69 (s, 2H), 3.28-3.27 (m, 2H), 2.39 (s, 3H), 1.17-1.13 (t, 3H, J = 7.3Hz).

實施例114：2-(6-(2-(6-(乙亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)噠嗪-4-基)丙-2-醇 Example 114: 2-(6-(2-(6-(ethylsulfinyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)indole Pyrazin-4-yl)propan-2-ol

114a)2-(6-(2-(6-(乙硫基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)噠嗪-4-基)丙-2-醇 114a) 2-(6-(2-(6-(ethylthio)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)pyridazine-4- Propan-2-ol

甲基溴化鎂(Methyl magnesium bromide)(3M in ether,2.02mL,6.06mmol係於-78℃逐滴加入至THF(150mL)中之1-(6-(2-(6-(乙硫基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)噠嗪-4-基)乙酮(0.85g,2.03mmol，由中間物52h及1-(6-氯噠嗪-4-基)乙酮以類似合成實施例56方式製備)溶液。該得到之混合物係於-78℃經攪拌1h，以NH4Cl溶液淬滅及以EtOAc(100mL)萃取。該有機相係經Na2SO4乾燥及蒸發且該剩餘物係經以快速管柱層析法[矽石；DCM與2-3.5% MeOH]純化。產量：0.4g(45%)。HPLC(方法3)：Rt=3.21min.,m/z：[M+H]+=436.1(MW calc.435.54). Methyl magnesium bromide (3M in ether, 2.02mL, 6.06mmol was added dropwise to -78 ° C to 1-(6-(2-(6-(ethylthio))) )Spirulinium [porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)pyridazin-4-yl)ethanone (0.85 g, 2.03 mmol, from intermediate 52h and 1) - (6-chloro-pyridazin-4-yl) ethanone was prepared in a manner similar to synthesis Example 56) to give a solution of the mixture was based at -78 deg.] C was stirred for 1h, NH 4 Cl solution to quench and in EtOAc (100mL The organic phase was dried over Na 2 SO 4 and evaporated, and the residue was purified by flash column chromatography eluted elute elute HPLC (method 3): R t = 3.21 min., m/z: [M+H] + = 436.1 (MW calc. 435.54).

114b)2-(6-(2-(6-(乙亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)噠嗪-4-基)丙-2-醇 114b) 2-(6-(2-(6-(ethylsulfinyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)pyridazine- 4-yl)propan-2-ol

THF(2mL)中之mCPBA(80mg,0.454mmol)溶液係被逐滴加入至THF(40mL)中之114a(0.2g,0.459mmol)。該得到之混合物係於rt經攪拌1h然後以EtOAc(30mL)稀釋。該有機相係依次經以飽和NaHCO3溶液(2x 15mL)及鹽水(15mL)清洗、經Na2SO4乾燥及蒸發。該剩留物係經以快速管柱層析法(矽石；DCM與5% MeOH)純化。白色固體。產量：75mg(36%)。HPLC(方 法3)：Rt=2.51min,m/z：[M+H]+=452.0(MW calc.451.54). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.41(s,2H),9.34(s,1H),8.64(s,1H),8.25(s,1H),7.95(d,1H,J=7.7Hz),7.38(d,1H,J=7.7),5.54(s,1H),4.91(d,2H,J=6.0Hz),4.80(d,2H,J=5.6Hz),4.67(s,2H),3.04-2.97(m,1H),2.80-2.75(m,1H),1.52(s,6H),1.08(t,3H,J=7.3Hz). A solution of mCPBA (80 mg, 0.454 mmol) in THF (2 mL). The resulting mixture was stirred at rt for 1 h then diluted with EtOAc (30 mL). The organic phase was sequentially based with saturated NaHCO 3 solution (2x 15mL) and brine (15mL) wash, dried over Na 2 SO 4 and evaporated. The residue was purified by flash column chromatography ( vermiculite; DCM with 5% MeOH). White solid. Yield: 75 mg (36%). HPLC (Method 3): R t = 2.51 min, m/z: [M+H] + = 452.0 (MW calc.451.54). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.41 (s, 2H) , 9.34 (s, 1H), 8.64 (s, 1H), 8.25 (s, 1H), 7.95 (d, 1H, J = 7.7 Hz), 7.38 (d, 1H, J = 7.7), 5.54 (s, 1H) ), 4.91 (d, 2H, J = 6.0 Hz), 4.80 (d, 2H, J = 5.6 Hz), 4.67 (s, 2H), 3.04 - 2.97 (m, 1H), 2.80 - 2.75 (m, 1H) , 1.52 (s, 6H), 1.08 (t, 3H, J = 7.3 Hz).

實施例115：2-(6-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)噠嗪-4-基)丙-2-醇 Example 115: 2-(6-(2-(6-(ethylsulfonyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)pyridazine -4-yl)propan-2-ol

以mCPBA氧化114a。白色固體。產量：70mg. 1H NMR(400MHz,DMSO-d6,δ ppm)：9.45(s,2H),9.35(s,1H),8.86(s,1H),8.27(s,1H),8.04(d,1H,J=7.8Hz),7.66(d,1H,J=7.7Hz),5.54(s,1H),4.93(d,2H,J=6.1Hz),4.80(d,2H,J=6.1Hz),4.70(s,2H),3.29-3.27(m,2H),1.52(s,6H),1.08(t,3H,J=7.3Hz). The 114a was oxidized with mCPBA. White solid. </ RTI> </ RTI> <RTIgt; , J = 7.8 Hz), 7.66 (d, 1H, J = 7.7 Hz), 5.54 (s, 1H), 4.93 (d, 2H, J = 6.1 Hz), 4.80 (d, 2H, J = 6.1 Hz), 4.70 (s, 2H), 3.29-3.27 (m, 2H), 1.52 (s, 6H), 1.08 (t, 3H, J = 7.3 Hz).

中間物3：1-(5-溴嘧啶-2-基)-6-((2-((叔丁基二苯基矽)氧基)乙基)硫)螺-[吲哚啉-3,3'-氧環丁烷](Int-3) Intermediate 3: 1-(5-bromopyrimidin-2-yl)-6-((2-((tert-butyldiphenyl)oxy)ethyl)sulfanyl)-[porphyrin-3, 3'-oxocyclobutane] (Int-3)

Int-3a)2-((2,2-二甲基螺[[1,3]二噁烷-5,3'-吲哚啉]-6'-基)硫)乙醇 Int-3a) 2-((2,2-Dimethylspiro[[1,3]dioxane-5,3'-carboline]-6'-yl)thio)ethanol

以Ar吹洗無水二氧雜環(dioaxane)(450mL)中之6'-溴-2,2-二甲基螺[[1,3]二噁烷-5,3'-吲哚啉](15g,50.3mmol)、2-巰-乙醇(3.5ml,50.3mmol)及DIPEA(17.5mL,100.6mmol)溶液。Xantphos(2.9g,5.03mmol)及Pd2(dba)3(2.3g,2.51mmol)係被加入且該得到之混合物係於120℃經加熱16h。該反應混合物係被降溫及經矽藻土墊過濾。該濾液係經蒸發且該剩餘物係經以快速管柱層析法[矽膠；DCM與1.5% MeOH]純化。褐色液體。產量：14.8g(100%)。HPLC(方法3)：Rt=2.73min,m/z：[M+H]+=296.0(MW calc.295.40). 6'-Bromo-2,2-dimethylspiro[[1,3]dioxane-5,3'-carboline] in anhydrous dioxane (450 mL) was purged with Ar ( 15 g, 50.3 mmol), 2-indole-ethanol (3.5 ml, 50.3 mmol) and DIPEA (17.5 mL, 100.6 mmol). Xantphos (2.9 g, 5.03 mmol) and Pd 2 (dba) 3 (2.3 g, 2.51 mmol) were added and the mixture obtained was heated at 120 ° C for 16 h. The reaction mixture was cooled and filtered through a pad of celite. The filtrate was evaporated and the residue was purified by flash column chromatography [EtOAc] Brown liquid. Yield: 14.8 g (100%). HPLC (Method 3): R t = 2.73 min, m/z: [M+H] + = 296.0 (MW calc.295.40).

Int-3b)6'-((2-((叔丁基二苯基矽)氧基)乙基)硫)-2,2-二甲基螺[[1,3]二噁烷-5,3'-吲哚啉] Int-3b) 6'-((2-((tert-Butyldiphenylphosphonium)oxy)ethyl)thio)-2,2-dimethylspiro[[1,3]dioxane-5, 3'-porphyrin]

對無水DMF(10mL)中之Int-3a(14.8g,50.17mmol)溶液於0℃加入咪唑(9.56g,140.47mmol)及TBDPS(19.7ml,75.25mmol)。該反應混合物係於rt經攪拌2h。冰水係被加入且該反應混合物係經以MTBE(100mL)萃取。該水相係被分離及以MTBE(2x 60mL)萃取。該合併之有機層係經以鹽水(60mL)清洗、經Na2SO4乾燥及濃縮。該剩餘物係經以管柱層析法[矽石；EtOAc/己烷=1：9]純化。褐色液體。產量：22g(82%)。HPLC(方法3)：Rt=3.13min,m/z：[M+H]+=534.2(MW calc.533.80). To a solution of Int-3a (14.8 g, 50.17 mmol) in dry DMF (10 mL). The reaction mixture was stirred at rt for 2 h. An ice water system was added and the reaction mixture was extracted with EtOAc (100 mL). The aqueous phase was separated and extracted with MTBE (2 x 60 mL). The combined organic layers of the system was washed with brine (60 mL) wash, dried over Na 2 SO 4 dried and concentrated. The residue was purified by column chromatography [EtOAc, EtOAc/hexanes: 1:1]. Brown liquid. Yield: 22 g (82%). HPLC (Method 3): R t =3.13 min, m/z: [M+H] + = 534.2 (MW calc. 533.80).

Int-3c)(6-((2-((叔丁基二苯基矽)氧基)乙基)硫)吲哚啉-3,3-二基)二甲醇 Int-3c)(6-((2-((tert-butyldiphenyl)oxy)ethyl)thio)porphyrin-3,3-diyl)dimethanol

THF(220mL)中之Int-3b(22g,41.27mmol)係於rt在有0.5N HCl(742mL)存在下經攪拌2h。該反應混合物係被濃縮、以sat.NaHCO3溶液鹼化及以EtOAc(10x 100mL)萃取。該合併之有機層係經Na2SO4乾燥及濃縮。淺褐色液體。產量：19g。HPLC(方法3)：Rt=2.10min,m/z：[M+H]+=494.3(MW calc.493.73). Int-3b (22 g, 41.27 mmol) from EtOAc (EtOAc) The reaction mixture was concentrated system, basified solution was extracted with sat.NaHCO 3 and in EtOAc (10x 100mL). The combined organic layers were dried over Na 2 SO 4 and concentrated. Light brown liquid. Yield: 19 g. HPLC (Method 3): R t = 2.10 min, m/z: [M+H] + =494.3 (MW calc.493.73).

Int-3d)(1-(5-溴嘧啶-2-基)-6-((2-((叔丁基二苯基矽)氧基)乙基)硫)吲哚啉-3,3-二基)二甲醇 Int-3d)(1-(5-bromopyrimidin-2-yl)-6-((2-((tert-butyldiphenyl)oxy)ethyl)thio)porphyrin-3,3- Dimethanol

n-BuOH(180mL)中之Int-3c(9.5g,19.27mmol)、5-溴-2-氯-嘧啶(7.4g,38.54mmol)及DIPEA(17.2mL,96.35mmol)係在密封管中於140℃經加熱16h。該反應混合物係被濃縮且該剩留物係經以快速管柱層析法[矽石；DCM與2% MeOH]純化。淺褐色固體。該反應分為每批9.5g之兩批進行，合併產量為15g(60%)。HPLC(方法3)：Rt=3.08min,m/z：[M+H]+=652.0(MW calc.650.70). Int-3c (9.5 g, 19.27 mmol), 5-bromo-2-chloro-pyrimidine (7.4 g, 38.54 mmol) and DIPEA (17.2 mL, 96.35 mmol) in n-BuOH (180 mL) were placed in a sealed tube. Heated at 140 ° C for 16 h. The reaction mixture was concentrated and the residue was purified by flash column chromatography [EtOAc, DCM with 2%MeOH]. Light brown solid. The reaction was carried out in two batches of 9.5 g per batch with a combined yield of 15 g (60%). HPLC (Method 3): R t = 3.08 min, m/z: [M+H] + = 652.0 (MW calc. 650.70).

Int-3e)(1-(5-溴嘧啶-2-基)-6-((2-((叔丁基二苯基矽)氧基)乙基)硫)-3-(羥甲基)吲哚啉-3-基)甲基4-甲基苯磺酸酯 Int-3e)(1-(5-bromopyrimidin-2-yl)-6-((2-((tert-butyldiphenyl))oxy)ethyl)thio)-3-(hydroxymethyl) Porphyrin-3-yl)methyl 4-methylbenzenesulfonate

LiHMDS(11.5mL,11.53mmol)係經30min逐滴加入至-78℃無水THF(750mL)中之Int-3d(7.5g,11.53mmol)溶液。該反應混合物於相同溫度經攪拌30min，無水THF(50mL)中之甲苯磺醯基氯(2.2g,11.53mmol)係被加入於-78℃持續攪拌2h。該反應混合物係經以sat.NH4Cl溶液淬滅及以EtOAc(3x 250mL)萃取。該合併之有機層係經Na2SO4乾燥及濃縮。該剩餘物係經以快速管柱層析法[矽石；EtOAc/己烷=3：7]純化。黃色半固體。該反應分為每批7.5g之兩批進行，合併產量為7g。HPLC(方法3)：Rt=3.65 min,m/z：[M+H]+=806.0(MW calc.804.89). LiHMDS (11.5 mL, 11.53 mmol) was added dropwise to a solution of &lt;RTI ID=0.0&gt;&gt; The reaction mixture was stirred at the same temperature for 30 min, and toluenesulfonyl chloride (2.2 g, 11.53 mmol) in anhydrous THF (50 mL) was added at -78 ° C for 2 h. The reaction mixture system was quenched with sat.NH 4 Cl solution and extracted with EtOAc (3x 250mL) to. The combined organic layers were dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography [EtOAc, EtOAc/hexane = 3:7]. Yellow semi-solid. The reaction was carried out in two batches of 7.5 g per batch with a combined yield of 7 g. HPLC (Method 3): R t =3.65 min, m/z: [M+H] + = 806.0 (MW calc. 804.89).

Int-3f)1-(5-溴嘧啶-2-基)-6-((2-((叔丁基二苯基矽)氧基)乙基)硫)螺-[吲哚啉-3,3'-氧環丁烷](Int-3) Int-3f) 1-(5-bromopyrimidin-2-yl)-6-((2-((tert-butyldiphenyl)oxy)ethyl)sulfide)-[porphyrin-3, 3'-oxocyclobutane] (Int-3)

KOH(0.95g,16.96mmol)係於RT加入t-BuOH(140mL)中之Int-3e(3.5g,4.35mmol)溶液。該反應混合物係經攪拌4h然後以水(50mL)稀釋及以EtOAc(3x100mL)萃取。該合併之有機層係經Na2SO4乾燥及濃縮。該原產物係經以乙醚研磨；白色固體。該反應分為每批3.5g之兩批進行，合併產量為6g。HPLC(方法3)：Rt=3.70min,m/z：[M+H]+=633.8(MW calc.632.69). KOH (0.95 g, 16.96 mmol) was added to a solution of &lt;RTI ID=0.0&gt;&gt; The reaction mixture was stirred for 4 h then diluted with EtOAc EtOAc (EtOAc) The combined organic layers were dried over Na 2 SO 4 and concentrated. The original product was triturated with diethyl ether; a white solid. The reaction was carried out in two batches of 3.5 g per batch with a combined yield of 6 g. HPLC (Method 3): R t = 3.70 min, m/z: [M+H] + = 633.8 (MW calc. 632.69).

中間物4：1-(5-溴嘧啶-2-基)-6-((3-((叔丁基二苯基矽)氧基)丙基)硫)螺[吲哚啉-3,3'-氧環丁烷](Int-4) Intermediate 4: 1-(5-bromopyrimidin-2-yl)-6-((3-((tert-butyldiphenylfluorenyl)oxy)propyl)sulfonyl) porphyrin-3,3 '-oxocyclobutane' (Int-4)

類似於Int-3方式製備。白色固體。HPLC(方法7)：Rt=5.62min.,m/z：[M+H]+=648.0(MW calc.646.71). Prepared similarly to the Int-3 method. White solid. HPLC (Method 7): R t = 5.62 min., m/z: [M+H] + = 648.0 (MW calc.646.71).

實施例116：2-((1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)亞磺醯基)乙醇 Example 116: 2-((1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl Sulfasulfonyl)ethanol

116a)6-((2-((叔丁基二苯基矽)氧基)乙基)亞磺醯基)-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷] 116a) 6-((2-((tert-Butyldiphenyl)oxy)ethyl)sulfinyl)-1-(5-(4-methylpyridin-2-yl)pyrimidin-2- Snail [porphyrin-3,3'-oxycyclobutane]

DCM(5mL)中之m-CPBA(0.15g,0.62mmol)係被緩慢加入冰冷之DCM(50mL)中之6-((2-((叔丁基二苯基矽)氧基)乙基)硫)-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷](0.5g,0.77mmol，由Int-3及2-溴-4-甲基吡啶類似於製程8c製得)溶液。該得到之混合物係於rt經攪拌1h然後以DCM(50mL)稀釋並依次以飽和NaHCO3溶液(2x 50mL)及鹽水(50mL)清洗。該有機層係經Na2SO4乾燥及蒸發。該剩留物係經以快速管柱層析法[矽石；DCM與3% MeOH]純化。白色固體。產量：0.43g(84%)。HPLC(方法3)：Rt=2.85min,m/z：[M+H]+=661.1(MW calc.660.90). m-CPBA (0.15 g, 0.62 mmol) in DCM (5 mL) was added 6-((2-((tert-butyldiphenyl)oxy)ethyl)). Sulfur)-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane] (0.5 g, 0.77 mmol, by Int -3 and 2-bromo-4-methylpyridine are similar to the solution prepared in Process 8c). The resultant mixture was stirred at rt for 1h lines and then washed sequentially with saturated NaHCO 3 solution (2x 50mL) and brine (50mL) to (50mL) diluted with DCM. The organic layer was dried over Na 2 SO 4 and evaporated. The residue was purified by flash column chromatography [ vermiculite; DCM with 3% MeOH]. White solid. Yield: 0.43 g (84%). HPLC (Method 3): R t = 2.85 min, m/z: [M+H] + = 661.1 (MW calc. 660.90).

116b)2-((1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)亞磺醯基)乙醇 116b) 2-((1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl) Sulfhydryl)ethanol

四丁基氟化銨溶液(1M in THF,2.3mL,2.28mmol)係於0℃被逐滴加入THF(20mL)中之116a(0.43g,0.65mmol)。該反應混合物係於rt經攪拌1h，然後經以sat.NH4Cl溶液淬滅及以EtOAc(3x 20mL)萃取。該合併之有機層係經以鹽水(30mL)清洗、經Na2SO4乾燥及濃縮。該剩留物係經以快速管柱層析法[矽石；DCM與5% MeOH]純化之後以DCM/戊烷(1：2)研磨。白色固體。產量：0.18g(66%)。HPLC(方法2)：Rt=1.41min,m/z：[M+H]+= 423.0(MW calc.422.50). 1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：9.3(s,2H),8.63(s,1H),8.52(d,1H,J=4.9Hz),7.94-7.9(m,2H),7.36(dd,1H,J=1.3,7.6Hz),7.19(d,1H,J=4.8Hz),5.11-5.08(m,1H),4.88(d,2H,J=6.2Hz),4.77(d,2H,J=5.9Hz),4.64(s,2H),3.88-3.8(m,1H),3.71-3.65(m,1H),3.02-2.95(m,1H),2.91-2.85(m,1H),2.38(s,3H). A solution of tetrabutylammonium fluoride (1 M in THF, 2.3 mL, 2.28 mmol) was added dropwise EtOAc (EtOAc) The reaction mixture was stirred at rt lines 1h, then was extracted with sat.NH 4 Cl solution and quenched in EtOAc (3x 20mL). The combined organic layers of the system was washed with brine (30mL) wash, dried over Na 2 SO 4 dried and concentrated. The residue was purified by flash column chromatography [M.sub.2; DCM with 5% MeOH] eluting with DCM/pentane (1:2). White solid. Yield: 0.18 g (66%). HPLC (Method 2): R t = 1.41 min, m/z: [M+H] + = 423.0 (MW calc.422.50). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 9.3 (s , 2H), 8.63 (s, 1H), 8.52 (d, 1H, J = 4.9 Hz), 7.94 - 7.9 (m, 2H), 7.36 (dd, 1H, J = 1.3, 7.6 Hz), 7.19 (d, 1H, J = 4.8 Hz), 5.11-5.08 (m, 1H), 4.88 (d, 2H, J = 6.2 Hz), 4.77 (d, 2H, J = 5.9 Hz), 4.64 (s, 2H), 3.88- 3.8 (m, 1H), 3.71-3.65 (m, 1H), 3.02-2.95 (m, 1H), 2.91-2.85 (m, 1H), 2.38 (s, 3H).

合成實施例117至119係由Int-3類似於實施例116獲得。 Synthesis Examples 117 to 119 were obtained from Int-3 similarly to Example 116.

實施例117：2-((1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)磺醯基)乙醇 Example 117: 2-((1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl Sulfhydryl)ethanol

白色固體。產量：0.16g。HPLC(方法3)：Rt=2.86min,m/z：[M+H]+=439.2(MW calc.438.50). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.32(s,2H),8.82(s,1H),8.51(d,1H,J=4.9Hz),8.01(d,1H,J=7.8Hz),7.93(s,1H),7.65(dd,1H,J=1.3 & 7.8Hz),7.2(d,1H,J=4.8Hz),4.91-4.89(m,3H),4.77(d,2H,J=6.2Hz),4.66(s,2H),3.74-3.69(m,2H),3.47-3.43(m,2H),2.38(s,3H). White solid. Yield: 0.16 g. HPLC (Method 3): R t = 2.86 min, m/z: [M+H] + = 439.2 (MW calc. 438.50). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.32 (s, 2H) , 8.82 (s, 1H), 8.51 (d, 1H, J = 4.9 Hz), 8.01 (d, 1H, J = 7.8 Hz), 7.93 (s, 1H), 7.65 (dd, 1H, J = 1.3 & 7.8) Hz), 7.2 (d, 1H, J = 4.8 Hz), 4.91-4.89 (m, 3H), 4.77 (d, 2H, J = 6.2 Hz), 4.66 (s, 2H), 3.74 - 3.69 (m, 2H) ), 3.47-3.43 (m, 2H), 2.38 (s, 3H).

實施例118：2-(2-(2-(6-((2-羥乙基)亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-4-基)丙-2-醇 Example 118: 2-(2-(2-(6-(2-hydroxyethyl)sulfinyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidine -5-yl)pyridin-4-yl)propan-2-ol

白色固體。產量：90mg。HPLC(方法2)：Rt=1.39min,m/z：[M+H]+=467.1(MW calc.466.55). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.33(s,2H),8.65(s,1H),8.59(d,1H,J=5.1Hz),8.04(s,1H),7.94(d,1H,J=7.7Hz),7.47(d,1H,J=4.1Hz),7.37(dd,1H,J=0.9,7.8Hz),5.3(s,1H),5.11(t,1H,J=4.96Hz),4.9(d,2H,J=6.2Hz),4.79(d,2H,J=6.1Hz),4.65(s,2H),3.86-3.81(m,1H),3.71-3.66(m,1H),3.02-2.95(m,1H),2.91-2.87(m,1H),1.48(s,6H). White solid. Yield: 90 mg. HPLC (Method 2): Rt = 1.39 min, m/z: [M+H] + = 467.1 (MW calc. 466.55). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.33 (s, 2H) , 8.65 (s, 1H), 8.59 (d, 1H, J = 5.1 Hz), 8.04 (s, 1H), 7.94 (d, 1H, J = 7.7 Hz), 7.47 (d, 1H, J = 4.1 Hz) , 7.37 (dd, 1H, J = 0.9, 7.8 Hz), 5.3 (s, 1H), 5.11 (t, 1H, J = 4.96 Hz), 4.9 (d, 2H, J = 6.2 Hz), 4.79 (d, 2H, J=6.1 Hz), 4.65 (s, 2H), 3.86-3.81 (m, 1H), 3.71-3.66 (m, 1H), 3.02-2.95 (m, 1H), 2.91-2.87 (m, 1H) , 1.48 (s, 6H).

實施例119：2-(2-(2-(6-((2-羥乙基)磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-4-基)丙-2-醇 Example 119: 2-(2-(2-(6-((2-hydroxyethyl))sulfonyl) spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidine- 5-yl)pyridin-4-yl)propan-2-ol

白色固體。產量：0.2g。HPLC(方法3)：Rt=2.71min,m/z：[M+H]+=483.2(MW calc.482.55). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.35(s,2H),8.84(s,1H),8.59(d,1H,J=4.9Hz),8.06(s,1H),7.99(d,1H,J=7.7Hz),7.63(d,1H,J=7.2Hz),7.47(d,1H,J=4.4Hz),5.29(s,1H),4.92-4.88(m,3H), 4.79-4.78(m,2H),4.67(s,2H),3.74-3.69(m,2H),3.46-3.31(m,2H),1.49(s,6H). White solid. Yield: 0.2 g. HPLC (Method 3): R t = 2.71 min, m/z: [M+H] + = 483.2 (MW calc.482.55). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.35 (s, 2H) , 8.84 (s, 1H), 8.59 (d, 1H, J = 4.9 Hz), 8.06 (s, 1H), 7.99 (d, 1H, J = 7.7 Hz), 7.63 (d, 1H, J = 7.2 Hz) , 7.47 (d, 1H, J = 4.4 Hz), 5.29 (s, 1H), 4.92-4.88 (m, 3H), 4.79-4.78 (m, 2H), 4.67 (s, 2H), 3.74 - 3.69 (m , 2H), 3.46-3.31 (m, 2H), 1.49 (s, 6H).

合成實施例120至124係由Int-4類似於實施例116獲得。 Synthesis Examples 120 to 124 were obtained from Int-4 similarly to Example 116.

實施例120：3-((1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)亞磺醯基)丙-1-醇 Example 120: 3-((1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl Sulfasulfonyl)-1-propanol

白色固體。產量：0.15g。HPLC(方法2)：Rt=1.43min,m/z：[M+H]+=437.1(MW calc.436.53). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.3(s,2H),8.61(s,1H),8.52(d,1H,J=4.9Hz),7.94-7.91(m,2H),7.35(d,1H,J=7.3Hz),7.19(d,1H,J=4.7Hz),4.9(d,2H,J=6.1Hz),4.79-4.78(m,2H),4.65(s,2H),4.62-4.59(m,1H),3.49-3.44(m,2H),3.01-2.94(m,1H),2.85-2.78(m,1H),2.38(s,3H),1.82-1.75(m,1H),1.64-1.6(m,1H). White solid. Yield: 0.15 g. HPLC (Method 2): R t = 1.43 min, m/z: [M+H] + = 437.1 (MW calc. 436.53). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.3 (s, 2H) , 8.61 (s, 1H), 8.52 (d, 1H, J = 4.9 Hz), 7.94 - 7.91 (m, 2H), 7.35 (d, 1H, J = 7.3 Hz), 7.19 (d, 1H, J = 4.7) Hz), 4.9 (d, 2H, J = 6.1 Hz), 4.79-4.78 (m, 2H), 4.65 (s, 2H), 4.62-4.59 (m, 1H), 3.49-3.44 (m, 2H), 3.01 -2.94 (m, 1H), 2.85-2.78 (m, 1H), 2.38 (s, 3H), 1.82-1.75 (m, 1H), 1.64-1.6 (m, 1H).

實施例121：3-((1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)磺醯基)丙-1-醇 Example 121: 3-((1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl Sulfhydryl)propan-1-ol

白色固體。產量：0.10g。HPLC(方法2)：Rt=1.46min,m/z：[M+H]+=453.1(MW calc.452.53). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.33(s,2H),8.82(s,1H),8.52(d,1H,J=4.9Hz),8.03(d,1H,J=7.8Hz),7.94(s,1H),7.62(d,1H,J=6.9Hz),7.2(d,1H,J=4.5Hz),4.91-4.9(m,2H),4.79-4.78(m,2H),4.67-4.62(m,3H),3.43(bs,2H),3.31(2H,merged with DMSO-水peak),2.39(s,3H),1.71(bs,2H). White solid. Yield: 0.10 g. HPLC (Method 2): R t = 1.46 min, m/z: [M+H] + = 453.1 (MW calc.452.53). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.33 (s, 2H) , 8.82 (s, 1H), 8.52 (d, 1H, J = 4.9 Hz), 8.03 (d, 1H, J = 7.8 Hz), 7.94 (s, 1H), 7.62 (d, 1H, J = 6.9 Hz) , 7.2 (d, 1H, J = 4.5 Hz), 4.91 - 4.9 (m, 2H), 4.79 - 4.78 (m, 2H), 4.67 - 4.62 (m, 3H), 3.43 (bs, 2H), 3.31 (2H) , merged with DMSO-water peak), 2.39 (s, 3H), 1.71 (bs, 2H).

實施例122及123：3-((1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)亞磺醯基)丙-1-醇(較快及較慢之洗析鏡像異構物) Examples 122 and 123: 3-((1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3' -oxycyclobutane]-6-yl)sulfinyl)propan-1-ol (faster and slower eluted mirroromers)

該消旋亞碸(200mg)係被分離成單一鏡像異構物，其係經由掌性製備型HPLC。(管柱：Chiralpak 21 x 250mm，粒徑5μm；移動相：己烷/EtOAc/乙醇/二乙胺=50/25/25/0.1；流速：21.0ml/min；檢測：UV(326nM)；運行時間：25min). The racemic hydrazine (200 mg) was isolated as a single mirror image isomer via a preparative HPLC. (column: Chiralpak 21 x 250 mm, particle size 5 μm; mobile phase: hexane/EtOAc/ethanol/diethylamine = 50/25/25/0.1; flow rate: 21.0 ml/min; detection: UV (326 nM); Time: 25min).

較快洗析之鏡像異構物(實施例122)：產量：80mg。鏡像異構物過量：100%(掌性HPLC). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.33(s,2H),8.64(s,1H),8.59(d,1H,J=5.0Hz),8.04(s,1H),7.94(d,1H,J=7.7Hz),7.46(d,1H,J=4.5Hz),7.37(d,1H,J=7.9Hz),5.29(s,1H),4.91-4.89(m,2H),4.8-4.78(m,2H),4.66-4.6(m,3H),3.49-3.44(m,2H),3.02-2.94(m,1H),2.85-2.78(m,1H),1.79-1.77(m,1H),1.66-1.58(m,1H),1.49(s,6H)。特定旋光度：[α]D 25=-184.64°(c.0.358%,CHCl3) The mirror image isomer was washed out faster (Example 122): Yield: 80 mg. Mirror image isomer excess: 100% (palm HPLC). 1H NMR (400MHz, DMSO-d6, δ ppm): 9.33 (s, 2H), 8.64 (s, 1H), 8.59 (d, 1H, J = 5.0) Hz), 8.04 (s, 1H), 7.94 (d, 1H, J = 7.7 Hz), 7.46 (d, 1H, J = 4.5 Hz), 7.37 (d, 1H, J = 7.9 Hz), 5.29 (s, 1H), 4.91-4.89 (m, 2H), 4.8-4.78 (m, 2H), 4.66-4.6 (m, 3H), 3.49-3.44 (m, 2H), 3.02-2.94 (m, 1H), 2.85- 2.78 (m, 1H), 1.79-1.77 (m, 1H), 1.66-1.58 (m, 1H), 1.49 (s, 6H). Specific optical rotation: [α] D 25 =-184.64° (c.0.358%, CHCl 3 )

較慢洗析之鏡像異構物(實施例123)：產量：90mg。鏡像異構物過量：100%(掌性HPLC). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.33(s,2H),8.64(s,1H),8.59(d,1H,J=5.0Hz),8.04(s,1H),7.94(d,1H,J=7.7Hz),7.46(d,1H,J=4.5Hz),7.37(d,1H,J=7.9Hz),5.29(s,1H),4.91-4.89(m,2H),4.8-4.78(m,2H),4.66-4.6(m,3H),3.49-3.44(m,2H),3.02-2.94(m,1H),2.85-2.78(m,1H),1.79-1.77(m,1H),1.66-1.58(m,1H),1.49(s,6H)。特定旋光度：[α]D 25=+169.29°(c.0.56%,CHCl3) Slow-washed Mirror Image Isomer (Example 123): Yield: 90 mg. Mirror image isomer excess: 100% (palm HPLC). 1H NMR (400MHz, DMSO-d6, δ ppm): 9.33 (s, 2H), 8.64 (s, 1H), 8.59 (d, 1H, J = 5.0) Hz), 8.04 (s, 1H), 7.94 (d, 1H, J = 7.7 Hz), 7.46 (d, 1H, J = 4.5 Hz), 7.37 (d, 1H, J = 7.9 Hz), 5.29 (s, 1H), 4.91-4.89 (m, 2H), 4.8-4.78 (m, 2H), 4.66-4.6 (m, 3H), 3.49-3.44 (m, 2H), 3.02-2.94 (m, 1H), 2.85- 2.78 (m, 1H), 1.79-1.77 (m, 1H), 1.66-1.58 (m, 1H), 1.49 (s, 6H). Specific optical rotation: [α] D 25 = +169.29° (c. 0.56%, CHCl 3 )

實施例124：3-((1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)磺醯基)丙-1-醇 Example 124: 3-((1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxygen Cyclobutane]-6-yl)sulfonyl)propan-1-ol

白色固體。產量：0.17g。HPLC(方法2)：Rt=1.43min,m/z：[M+H]+=496.1 (MW calc.496.58). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.35(s,2H),8.84(s,1H),8.59(d,1H,J=5.0Hz),8.06(s,1H),8.03(d,1H,J=7.8Hz),7.64-7.62(m,1H),7.47(d,1H,J=5.0Hz),5.28(s,1H),4.92-4.9(m,2H),4.79-4.78(m,2H),4.67(s,2H),4.62(t,1H,J=5.2Hz),3.45-3.4(m,2H),3.28(2H,merged with DMSO-水signals),1.75-1.68(m,2H),1.49(s,6H). White solid. Yield: 0.17 g. HPLC (Method 2): R t = 1.43 min, m/z: [M+H] + = 496.1 (MW calc. 496.58). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.35 (s, 2H) , 8.84 (s, 1H), 8.59 (d, 1H, J = 5.0 Hz), 8.06 (s, 1H), 8.03 (d, 1H, J = 7.8 Hz), 7.64 - 7.62 (m, 1H), 7.47 ( d,1H,J=5.0Hz), 5.28(s,1H),4.92-4.9(m,2H),4.79-4.78(m,2H),4.67(s,2H),4.62(t,1H,J= 5.2 Hz), 3.45-3.4 (m, 2H), 3.28 (2H, merged with DMSO-water signals), 1.75-1.68 (m, 2H), 1.49 (s, 6H).

實施例125至132係以類似於實施例8方式製備。 Examples 125 to 132 were prepared in a manner similar to that of Example 8.

實施例125：(1-(5-(6-羥基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 Example 125: (1-(5-(6-Hydroxypyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl) (morpholine) Ketone

黃色固體。產量：0.11g。HPLC(方法3)：Rt=2.41min,m/z：[M+H]+=445.9(MW calc.444.47). 1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：11.03(bs,1H),9.04(s,2H),8.39(s,1H),7.81(d,1H,J=7.6Hz),7.56(t,1H,J=7.7Hz),7.17(d,1H,J=7.5Hz),6.88(d,1H,J=5.7Hz),6.45(d,1H,J=8.7Hz),4.89(d,2H,J=6Hz),4.81(d,2H,J=6Hz),4.62(s,2H),3.65(t,4H,J=4.2Hz),3.55(d,4H,J=4.5Hz). Yellow solid. Yield: 0.11 g. HPLC (Method 3): R t = 2.41 min, m/z: [M+H] + = 445.9 (MW calc. 444.47). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 11.03 (bs , 1H), 9.04 (s, 2H), 8.39 (s, 1H), 7.81 (d, 1H, J = 7.6 Hz), 7.56 (t, 1H, J = 7.7 Hz), 7.17 (d, 1H, J = 7.5 Hz), 6.88 (d, 1H, J = 5.7 Hz), 6.45 (d, 1H, J = 8.7 Hz), 4.89 (d, 2H, J = 6 Hz), 4.81 (d, 2H, J = 6 Hz), 4.62 (s, 2H), 3.65 (t, 4H, J = 4.2 Hz), 3.55 (d, 4H, J = 4.5 Hz).

實施例126：(1-(5-(3-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 Example 126: (1-(5-(3-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl) Phenyl) ketone

白色固體。產量：75mg。HPLC(方法3)：Rt=2.80min,m/z：[M+H]+=443.8(MW calc.443.50). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.89(s,2H),8.53(d,1H,J=3.9Hz),8.40(d,1H,J=0.7Hz),7.81(d,1H,J=7.6Hz),7.77(d,1H,J=7.6Hz),7.34-7.31(m,1H),7.14-7.12(m,1H),4.89(d,2H,J=6.1Hz),4.80(d,2H,J=6.1Hz),4.62(s,2H),3.63-3.37(m,8H),2.43(s,3H). White solid. Yield: 75 mg. HPLC (Method 3): R t = 2.80 min, m/z: [M+H] + = 443.8 (MW calc.443.50). 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.89 (s, 2H) , 8.53 (d, 1H, J = 3.9 Hz), 8.40 (d, 1H, J = 0.7 Hz), 7.81 (d, 1H, J = 7.6 Hz), 7.77 (d, 1H, J = 7.6 Hz), 7.34 -7.31(m,1H),7.14-7.12(m,1H),4.89(d,2H,J=6.1Hz), 4.80(d,2H,J=6.1Hz),4.62(s,2H),3.63- 3.37 (m, 8H), 2.43 (s, 3H).

實施例127：(1-(5-(2-氟-3-羥苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 Example 127: (1-(5-(2-Fluoro-3-hydroxyphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl) Phenyl) ketone

白色固體。產量：0.07g。HPLC(方法3)：Rt=2.89min,m/z：[M+H]+=463.1(MW calc.462.47). 1H NMR(400MHz,DMSO-d6,δ ppm)：10.04(bs,1H),8.82(s,2H),8.37(s,1H),7.81(d,1H,J=7.6Hz),7.14-7.07(m,2H),7.01-6.97(m,2H),4.88(d,2H,J=6Hz),4.79(d,2H,J=6Hz),4.60(s,2H),3.63-3.40(m,8H). White solid. Yield: 0.07 g. HPLC (Method 3): R t = 2.89 min, m/z: [M+H] + = 463.1 (MW calc.462.47). 1H NMR (400 MHz, DMSO-d6, δ ppm): 10.04 (bs, 1H) , 8.82 (s, 2H), 8.37 (s, 1H), 7.81 (d, 1H, J = 7.6 Hz), 7.14 - 7.07 (m, 2H), 7.01-6.97 (m, 2H), 4.88 (d, 2H) , J = 6 Hz), 4.79 (d, 2H, J = 6 Hz), 4.60 (s, 2H), 3.63-3.40 (m, 8H).

實施例128：(1-(5-(3-胺-2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基) (嗎啉基)甲酮 Example 128: (1-(5-(3-Amine-2-fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl) (morpholinyl) ketone

白色固體。產量：61mg。HPLC(方法2)：Rt=1.56min,m/z：[M+H]+=462.2(MW calc.461.49). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.80(s,2H),8.37(s,1H),7.81(d,1H,J=7.5Hz),7.14(d,1H,J=7.4Hz),6.97(t,1H,J=7.8Hz),6.80(t,1H,J=7.8Hz),6.70(t,1H,J=6.6Hz),5.29(s,2H),4.88(d,2H,J=5.8Hz),4.79(d,2H,J=5.8Hz),4.60(s,2H),3.62-3.40(m,8H). White solid. Yield: 61 mg. HPLC (Method 2): R t = 1.56 min, m/z: [M+H] + = 462.2 (MW calc.461.49). 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.80 (s, 2H) , 8.37 (s, 1H), 7.81 (d, 1H, J = 7.5 Hz), 7.14 (d, 1H, J = 7.4 Hz), 6.97 (t, 1H, J = 7.8 Hz), 6.80 (t, 1H, J = 7.8 Hz), 6.70 (t, 1H, J = 6.6 Hz), 5.29 (s, 2H), 4.88 (d, 2H, J = 5.8 Hz), 4.79 (d, 2H, J = 5.8 Hz), 4.60 (s, 2H), 3.62-3.40 (m, 8H).

實施例129：(1-(6-甲基-[4,5'-聯嘧啶]-2'-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 Example 129: (1-(6-Methyl-[4,5'-bipyrimidin]-2'-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl) ( Morpholine) ketone

白色固體。產量：0.05g。HPLC(方法3)：Rt=2.64min,m/z：[M+H]+=445.3(MW calc.444.49). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.38(s,2H),9.07(s,1H),8.42(s,1H),8.04(s,1H),7.84(d,1H,J=7.5Hz),7.19(d,1H,J=7.5Hz),4.89(d,2H,J=6.1Hz),4.79(d,2H,J=6.1Hz),4.64(s,2H),3.63(bs,8H),2.52(s,3H). White solid. Yield: 0.05 g. HPLC (Method 3): R t = 2.64 min, m/z: [M+H] + = 445.3 (MW calc. 444.49). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.38 (s, 2H) , 9.07 (s, 1H), 8.42 (s, 1H), 8.04 (s, 1H), 7.84 (d, 1H, J = 7.5 Hz), 7.19 (d, 1H, J = 7.5 Hz), 4.89 (d, 2H, J = 6.1 Hz), 4.79 (d, 2H, J = 6.1 Hz), 4.64 (s, 2H), 3.63 (bs, 8H), 2.52 (s, 3H).

實施例130：(1-(5-(2-氟-6-羥苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)-(嗎啉基)甲酮 Example 130: (1-(5-(2-Fluoro-6-hydroxyphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)-( Morpholine) ketone

白色固體。產量：0.07g。HPLC(方法3)：Rt=2.93min,m/z：[M+H]+=463.0(MW calc.462.47). 1H NMR(400MHz,DMSO-d6,δ ppm)：10.23(bs,1H),8.67(s,2H),8.36(s,1H),7.80(d,1H,J=7.5Hz),7.22(t,1H,J=7.4Hz),7.13(d,1H,J=6.7Hz),6.84-6.76(m,2H),4.88(d,2H,J=5.9Hz),4.80(d,2H,J=5.8Hz),4.59(s,2H),3.62-3.38(m,8H). White solid. Yield: 0.07 g. HPLC (Method 3): R t = 2.93 min, m/z: [M+H] + = 463.0 (MW calc.462.47). 1H NMR (400 MHz, DMSO-d6, δ ppm): 10.23 (bs, 1H) , 8.67 (s, 2H), 8.36 (s, 1H), 7.80 (d, 1H, J = 7.5 Hz), 7.22 (t, 1H, J = 7.4 Hz), 7.13 (d, 1H, J = 6.7 Hz) , 6.84-6.76 (m, 2H), 4.88 (d, 2H, J = 5.9 Hz), 4.80 (d, 2H, J = 5.8 Hz), 4.59 (s, 2H), 3.62-3.38 (m, 8H).

實施例131：(1-(5-(2-胺-6-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 Example 131: (1-(5-(2-Amine-6-fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl) Phenyl) ketone

白色固體。產量：45mg。HPLC(方法2)：Rt=1.57min,m/z：[M+H]+=462.2(MW calc.461.49). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.56(s,2H),8.37(s,1H),7.81(d,1H,J=7.6Hz),7.13-7.04(m,2H),6.58(d,1H,J=8.1Hz), 6.42(t,1H,J=8.8Hz),5.26(s,2H),4.88(d,2H,J=6.1Hz),4.80(d,2H,J=6Hz),4.59(s,2H),3.62-3.35(m,8H). White solid. Yield: 45 mg. HPLC (Method 2): R t = 1.57 min, m/z: [M+H] + = 462.2 (MW calc.461.49). 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.56 (s, 2H) , 8.37 (s, 1H), 7.81 (d, 1H, J = 7.6 Hz), 7.13 - 7.04 (m, 2H), 6.58 (d, 1H, J = 8.1 Hz), 6.42 (t, 1H, J = 8.8 Hz), 5.26 (s, 2H), 4.88 (d, 2H, J = 6.1 Hz), 4.80 (d, 2H, J = 6 Hz), 4.59 (s, 2H), 3.62-3.35 (m, 8H).

實施例132：(1-(5-(6-氨吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 Example 132: (1-(5-(6-Aminopyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl) (morpholine) Ketone

白色固體。產量：0.1g。HPLC(方法2)：Rt=1.33min,m/z：[M+H]+=445.2(MW calc.444.49). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.17(s,2H),8.39(s,1H),7.81(d,1H,J=7.6Hz),7.46(t,1H,J=7.8Hz),7.14-7.09(m,2H),6.43(d,1H,J=8.2Hz),6.06(s,2H),4.88(d,2H,J=6.1Hz),4.78(d,2H,J=6Hz),4.60(s,2H),3.62-3.41(m,8H). White solid. Yield: 0.1 g. HPLC (Method 2): Rt = 1.33 min, m/z: [M+H] + = 445.2 (MW calc. 444.49). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.17 (s, 2H) , 8.39 (s, 1H), 7.81 (d, 1H, J = 7.6 Hz), 7.46 (t, 1H, J = 7.8 Hz), 7.14 - 7.09 (m, 2H), 6.43 (d, 1H, J = 8.2 Hz), 6.06 (s, 2H), 4.88 (d, 2H, J = 6.1 Hz), 4.78 (d, 2H, J = 6 Hz), 4.60 (s, 2H), 3.62-3.41 (m, 8H).

實施例133及134係由(1-(5-溴嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮8b製備，實施如3a所述之鈴木偶聯反應條件。 Examples 133 and 134 were prepared from (1-(5-bromopyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)(morpholinyl)methanone 8b. The Suzuki coupling reaction conditions as described in 3a were carried out.

實施例133：(1-(5-(2-氟-3-甲基苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 Example 133: (1-(5-(2-Fluoro-3-methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl) ( Morpholine) ketone

白色固體。產量：59mg。HPLC(方法2)：Rt=1.73min,m/z：[M+H]+=461.2(MW calc.460.50). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.84(s,2H),8.38(s,1H),7.81(d,1H,J=7.6Hz),7.45(t,1H,J=6.8Hz),7.33(t,1H,J=7.2Hz),7.24-7.20(m,1H),7.14(d,1H,J=7.6Hz),4.88(d,2H,J=6.1Hz),4.79(d,2H,J=6Hz),4.60(s,2H),3.63-3.39(m,8H),2.31(s,3H). White solid. Yield: 59 mg. HPLC (Method 2): R t = 1.73 min, m/z: [M+H] + = 461.2 (MW calc. 460.50). 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.84 (s, 2H) , 8.38 (s, 1H), 7.81 (d, 1H, J = 7.6 Hz), 7.45 (t, 1H, J = 6.8 Hz), 7.33 (t, 1H, J = 7.2 Hz), 7.24-7.20 (m, 1H), 7.14 (d, 1H, J = 7.6 Hz), 4.88 (d, 2H, J = 6.1 Hz), 4.79 (d, 2H, J = 6 Hz), 4.60 (s, 2H), 3.63 - 3.39 (m) , 8H), 2.31 (s, 3H).

實施例134：(1-(5-(2-氟-6-甲基苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 Example 134: (1-(5-(2-Fluoro-6-methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl) ( Morpholine) ketone

白色固體。產量：0.11g。HPLC(方法3)：Rt=3.20min,m/z：[M+H]+=461.4(MW calc.460.50). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.65(s,2H),8.37(s,1H),7.81(d,1H,J=7.6Hz),7.36(t,1H,J=6.2Hz),7.22-7.12(m,3H),4.88(d,2H,J=6Hz),4.80(d,2H,J=5.8Hz),4.61(s,2H),3.62-3.39(m,8H),2.23(s,3H). White solid. Yield: 0.11 g. HPLC (Method 3): Rt = 3.20 min, m/z: [M+H] + = 461.4 (MW calc. 460.50). 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.65 (s, 2H) , 8.37 (s, 1H), 7.81 (d, 1H, J = 7.6 Hz), 7.36 (t, 1H, J = 6.2 Hz), 7.22 - 7.12 (m, 3H), 4.88 (d, 2H, J = 6 Hz) ), 4.80 (d, 2H, J = 5.8 Hz), 4.61 (s, 2H), 3.62-3.39 (m, 8H), 2.23 (s, 3H).

實施例135及141係由Int-1以類似合成實施例22方式製備。 Examples 135 and 141 were prepared from Int-1 in a similar manner to Synthesis Example 22.

實施例135：(1-(4-甲基(Mthyl)-[2,5'-聯嘧啶]-2'-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 Example 135: (1-(4-Methyl(Mthyl)-[2,5'-bipyrimidinyl]-2'-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6- (morpholino) ketone

白色固體。產量：0.09g。HPLC(方法3)：Rt=2.80min,m/z：[M+H]+=445.1(MW calc.444.49). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.43(s,2H),8.74(d,1H,J=5.1Hz),8.42(s,1H),7.83(d,1H,J=7.6Hz),7.34(d,1H,J=5Hz),7.16(t,1H,J=7.6Hz),4.89(d,2H,J=6.2Hz),4.78(d,2H,J=6.1Hz),4.63(s,2H),3.64(bs,8H),2.54(s,3H). White solid. Yield: 0.09 g. HPLC (Method 3): R t = 2.80 min, m/z: [M+H] + = 445.1 (MW calc. 444.49). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.43 (s, 2H) , 8.74 (d, 1H, J = 5.1 Hz), 8.42 (s, 1H), 7.83 (d, 1H, J = 7.6 Hz), 7.34 (d, 1H, J = 5 Hz), 7.16 (t, 1H, J) =7.6 Hz), 4.89 (d, 2H, J = 6.2 Hz), 4.78 (d, 2H, J = 6.1 Hz), 4.63 (s, 2H), 3.64 (bs, 8H), 2.54 (s, 3H).

實施例136：(1-(4,6-二甲基-[2,5'-聯嘧啶]-2'-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 Example 136: (1-(4,6-Dimethyl-[2,5'-bipyrimidinyl]-2'-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6- (morpholino) ketone

白色固體。產量：76mg。HPLC(方法2)：Rt=1.71min,m/z：[M+H]+=459.3(MW calc.458.51). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.52-9.48(m,2H), 8.56(s,1H),7.78(d,1H,J=7.4Hz),7.20(d,1H,J=7.4Hz),6.92(s,1H),4.95-4.90(m,4H),4.63(s,2H),3.81-3.69(m,6H),3.53(s,2H),2.51(s,6H). White solid. Yield: 76 mg. HPLC (Method 2): R t = 1.71 min, m/z: [M+H] + = 459.3 (MW calc. 458.51). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.52-9.48 (m, 2H), 8.56(s,1H), 7.78(d,1H,J=7.4Hz), 7.20(d,1H,J=7.4Hz), 6.92(s,1H),4.95-4.90(m,4H), 4.63 (s, 2H), 3.81-3.69 (m, 6H), 3.53 (s, 2H), 2.51 (s, 6H).

實施例137：1-([2,5'-聯嘧啶]-2'-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 137: 1-([2,5'-Bipyrimidinyl]-2'-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxygen ring Butane]-6-formamide

白色固體。產量：0.11g。HPLC(方法3)：Rt=2.52min,m/z：[M+H]+=419.4(MW calc.418.45). 1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：9.43(s,2H),8.87(d,2H,J=4.5Hz),8.41(s,1H),7.80(d,1H,J=7.5Hz),7.40(d,1H,J=4.8Hz),7.17(d,1H,J=7.5Hz),4.90(d,2H,J=5.8Hz),4.81(d,3H,J=5.9Hz),4.65(s,2H),3.64-3.62(m,2H),3.46(bs,2H),2.97(bs,3H). White solid. Yield: 0.11 g. HPLC (Method 3): R t = 2.52 min, m/z: [M+H] + = 419.4 (MW calc. 418.45). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 9.43 (s) , 2H), 8.87 (d, 2H, J = 4.5 Hz), 8.41 (s, 1H), 7.80 (d, 1H, J = 7.5 Hz), 7.40 (d, 1H, J = 4.8 Hz), 7.17 (d , 1H, J = 7.5 Hz), 4.90 (d, 2H, J = 5.8 Hz), 4.81 (d, 3H, J = 5.9 Hz), 4.65 (s, 2H), 3.64 - 3.62 (m, 2H), 3.46 (bs, 2H), 2.97 (bs, 3H).

實施例138：N-(2-羥乙基)-N-甲基-1-(5-(吡嗪-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 138: N-(2-hydroxyethyl)-N-methyl-1-(5-(pyrazin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxygen Cyclobutane]-6-formamide

白色固體。產量：0.07g。HPLC(方法2)：Rt=1.43min,m/z：[M+H]+=419.2 (MW calc.418.45). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.34(s,2H),9.30(s,1H),8.71(s,1H),8.62(d,1H,J=2.3Hz),8.39(s,1H),7.80-7.78(m,1H),7.16(d,1H,J=7.6Hz),4.89(d,2H,J=6.1Hz),4.80(d,2H,J=6Hz),4.63(s,2H),3.64-6.53(m,3H),3.32(s,1H),3.01-2.98(m,3H). White solid. Yield: 0.07 g. HPLC (Method 2): R t = 1.43 min, m/z: [M+H] + = 419.2 (MW calc. 418.45). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.34 (s, 2H) , 9.30 (s, 1H), 8.71 (s, 1H), 8.62 (d, 1H, J = 2.3 Hz), 8.39 (s, 1H), 7.80-7.78 (m, 1H), 7.16 (d, 1H, J) = 7.6 Hz), 4.89 (d, 2H, J = 6.1 Hz), 4.80 (d, 2H, J = 6 Hz), 4.63 (s, 2H), 3.64 - 6.53 (m, 3H), 3.32 (s, 1H) , 3.01-2.98 (m, 3H).

實施例139：N-(2-羥乙基)-N-甲基-1-(5-(6-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 139: N-(2-hydroxyethyl)-N-methyl-1-(5-(6-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3 '-oxycyclobutane]-6-formamide

白色固體。產量：0.07g。HPLC(方法3)：Rt=3.95min,m/z：[M+H]+=432.4(MW calc.431.49). 1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：9.23(s,2H),8.39(s,1H),7.78-7.72(m,3H),7.21(d,1H,J=6.2Hz),7.14(d,1H,J=7.6Hz),4.89(d,2H,J=6Hz),4.82(d,2H,J=6Hz),4.63(s,2H),4.42(s,1H),3.62(t,2H,J=5.3Hz),3.46(bs,2H),3.03(s,3H),2.56(s,3H). White solid. Yield: 0.07 g. HPLC (Method 3): R t = 3.95 min, m/z: [M+H] + =432.4 (MW calc.431.49). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 9.23 (s) , 2H), 8.39 (s, 1H), 7.78-7.72 (m, 3H), 7.21 (d, 1H, J = 6.2 Hz), 7.14 (d, 1H, J = 7.6 Hz), 4.89 (d, 2H, J = 6 Hz), 4.82 (d, 2H, J = 6 Hz), 4.63 (s, 2H), 4.42 (s, 1H), 3.62 (t, 2H, J = 5.3 Hz), 3.46 (bs, 2H), 3.03 (s, 3H), 2.56 (s, 3H).

實施例140：N-(2-羥乙基)-1-(5-(6-羥基吡啶-2-基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 140: N-(2-hydroxyethyl)-1-(5-(6-hydroxypyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3,3' -oxycyclobutane]-6-formamide

淺黃色固體. 產量：60mg。HPLC(方法2)：Rt=1.37min,m/z：[M+H]+=434.3(MW calc.433.46). 1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：11.01(bs,1H),9.03(s,2H),8.37(s,1H),7.79(d,1H,J=7.6Hz),7.56(t,1H,J=7.3Hz),7.15(d,1H,J=7.6Hz),6.86(s,1H),6.45(d,1H,J=8.6Hz),4.89(d,2H,J=5.9Hz),4.81(d,2H,J=6Hz),4.62(s,2H),4.41(s,1H),3.63-3.62(m,2H),3.46(bs,2H),3.02(s,3H). Light yellow solid. Yield: 60 mg. HPLC (Method 2): R t = 1.37 min, m/z: [M+H] + =434.3 (MW calc. 433.46). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 11.01 (bs , 1H), 9.03 (s, 2H), 8.37 (s, 1H), 7.79 (d, 1H, J = 7.6 Hz), 7.56 (t, 1H, J = 7.3 Hz), 7.15 (d, 1H, J = 7.6 Hz), 6.86 (s, 1H), 6.45 (d, 1H, J = 8.6 Hz), 4.89 (d, 2H, J = 5.9 Hz), 4.81 (d, 2H, J = 6 Hz), 4.62 (s, 2H), 4.41 (s, 1H), 3.63-3.62 (m, 2H), 3.46 (bs, 2H), 3.02 (s, 3H).

實施例141：N-(2-羥乙基)-1-(5-(6-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 141: N-(2-hydroxyethyl)-1-(5-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methyl snail [Porphyrin-3,3'-oxycyclobutane]-6-carboxamide

白色固體。產量：0.15g。HPLC(方法2)：Rt=1.50min,m/z：[M+H]+=476.3(MW calc.475.54). 1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：9.28(s,2H),8.40(s,1H),7.85(t,1H,J=8.2Hz),7.78(t,2H,J=4.9Hz),7.61(d,1H,J=7.7Hz),7.13(d,1H,J=7.5Hz),4.89(t,3H,J=4.7Hz),4.82(d,2H,J=5.9Hz),4.63(s,2H),4.41(t,1H,J=4.4Hz),3.63(d,2H,J=5.4Hz),3.46(s,2H), 3.03(s,3H),1.55(s,6H). White solid. Yield: 0.15 g. HPLC (Method 2): R t = 1.50 min, m/z: [M+H] + = 476.3 (MW calc. 475.54). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 9.28 (s) , 2H), 8.40 (s, 1H), 7.85 (t, 1H, J = 8.2 Hz), 7.78 (t, 2H, J = 4.9 Hz), 7.61 (d, 1H, J = 7.7 Hz), 7.13 (d ,1H,J=7.5Hz),4.89(t,3H,J=4.7Hz),4.82(d,2H,J=5.9Hz),4.63(s,2H),4.41(t,1H,J=4.4Hz ), 3.63 (d, 2H, J = 5.4 Hz), 3.46 (s, 2H), 3.03 (s, 3H), 1.55 (s, 6H).

實施例142至143係類似於實施例8方式製備。 Examples 142 to 143 were prepared in a manner similar to that of Example 8.

實施例142：(1-(5-(6-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 Example 142: (1-(5-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane ]-6-yl)(morpholinyl)methanone

白色固體。產量：0.14g。HPLC(方法2)：Rt=1.58min,m/z：[M+H]+=488.2(MW calc.487.55). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.33(s,2H),8.41(s,1H),7.87-7.80(m,3H),7.61(d,1H,J=6Hz),7.15(d,1H,J=7.4Hz),5.26(s,1H),4.89(d,2H,J=5.8Hz),4.79(d,2H,J=6Hz),4.62(s,2H),3.92(bs,8H),1.51(s,6H). White solid. Yield: 0.14 g. HPLC (Method 2): R t = 1.58 min, m/z: [M+H] + = 488.2 (MW calc. 487.55). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.33 (s, 2H) , 8.41(s,1H), 7.87-7.80(m,3H), 7.61(d,1H,J=6Hz), 7.15(d,1H,J=7.4Hz), 5.26(s,1H),4.89(d , 2H, J = 5.8 Hz), 4.79 (d, 2H, J = 6 Hz), 4.62 (s, 2H), 3.92 (bs, 8H), 1.51 (s, 6H).

實施例143：(1-(5-(6-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 Example 143: (1-(5-(6-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl) Phenyl) ketone

白色固體。產量：187mg。HPLC(方法2)：Rt=1.51min.,m/z：[M+H]+=444.2(MW calc.443.50). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.27(s,2H),8.41(s,1H),7.80(bs,3H),7.23(d,1H,J=6.4Hz),7.15(d,1H,J=6.9Hz),4.89(d,2H,J=5.6Hz),4.79(d,2H,J=5.5Hz),4.61(s,2H),3.64(bs,8H),2.54(s,3H). White solid. Yield: 187 mg. HPLC (Method 2): R t = 1.51 min., m/z: [M+H] + = 444.2 (MW calc.443.50). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.27 (s, 2H) ), 8.41 (s, 1H), 7.80 (bs, 3H), 7.23 (d, 1H, J = 6.4 Hz), 7.15 (d, 1H, J = 6.9 Hz), 4.89 (d, 2H, J = 5.6 Hz) ), 4.79 (d, 2H, J = 5.5 Hz), 4.61 (s, 2H), 3.64 (bs, 8H), 2.54 (s, 3H).

實施例144：N-((3-羥氧環丁烷-3-基)甲基)-N-甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 144: N-((3-Hydroxyoxycyclobutan-3-yl)methyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl Spirulina [porphyrin-3,3'-oxycyclobutane]-6-carboxamide

由化合物22b製備。白色固體。產量：60mg。HPLC(方法2)：Rt=1.43min,m/z：[M+H]+=474.2(MW calc.473.52). 1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：9.23(s,2H),8.52(d,1H,J=4.7Hz),8.41(s,1H),7.80-7.77(m,2H),7.18-7.12(m,2H),5.69-5.66(m,1H),4.90(d,2H,J=5.9Hz),4.81(d,2H,J=6Hz),4.63(s,2H),4.53(d,2H,J=6.1Hz),4.47(d,2H,J=6.4Hz),3.83(s,2H),3.03(s,3H),2.41(s,3H). Prepared from compound 22b. White solid. Yield: 60 mg. HPLC (Method 2): R t = 1.43 min, m/z: [M+H] + = 474.2 (MW calc. 473.52). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 9.23 (s) , 2H), 8.52 (d, 1H, J = 4.7 Hz), 8.41 (s, 1H), 7.80-7.77 (m, 2H), 7.18-7.12 (m, 2H), 5.69-5.66 (m, 1H), 4.90 (d, 2H, J = 5.9 Hz), 4.81 (d, 2H, J = 6 Hz), 4.63 (s, 2H), 4.53 (d, 2H, J = 6.1 Hz), 4.47 (d, 2H, J = 6.4 Hz), 3.83 (s, 2H), 3.03 (s, 3H), 2.41 (s, 3H).

實施例145：N-((1-羥環丙基)甲基)-N-甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 145: N-((1-hydroxycyclopropyl)methyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl) snail [吲哚Porphyrin-3,3'-oxycyclobutane]-6-formamide

由化合物22b及1-((甲基胺)甲基)環丙醇類似於製程22c)。白色固體。產量：50mg。HPLC(方法3)：Rt=2.84min,m/z：[M+H]+=458.3(MW calc.457.52). 1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：9.23(s,2H),8.52(d,1H,J=5Hz),8.40(s,1H),7.78(t,2H,J=6Hz),7.16(t,2H,J=6.1Hz),5.05(s,1H),4.90(d,2H,J=6Hz),4.82(d,2H,J=6Hz),4.63(s,2H),3.53(s,2H),3.10(s,3H),2.96(s,1H),2.40(s,3H),0.66(s,2H),0.52(s,2H). Compound 22b and 1-((methylamine)methyl)cyclopropanol are similar to Process 22c). White solid. Yield: 50 mg. HPLC (Method 3): R t = 2.84 min, m/z: [M+H] + = 458.3 (MW calc.457.52). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 9.23 (s) , 2H), 8.52 (d, 1H, J = 5 Hz), 8.40 (s, 1H), 7.78 (t, 2H, J = 6 Hz), 7.16 (t, 2H, J = 6.1 Hz), 5.05 (s, 1H) ), 4.90 (d, 2H, J = 6 Hz), 4.82 (d, 2H, J = 6 Hz), 4.63 (s, 2H), 3.53 (s, 2H), 3.10 (s, 3H), 2.96 (s, 1H) ), 2.40 (s, 3H), 0.66 (s, 2H), 0.52 (s, 2H).

實施例146及147係由1-(5-溴嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-羧酸8a以類似於合成實施例8方式獲得。 Examples 146 and 147 were obtained from 1-(5-bromopyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-carboxylic acid 8a in a similar manner to that of Synthesis Example 8. .

實施例146：1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)-N,N-二甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 146: 1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N,N-dimethylspiro[porphyrin-3, 3'-oxocyclobutane]-6-formamide

白色固體。產量：62mg。HPLC(方法3)：Rt=2.67min,m/z：[M+H]+=446.1 (MW calc.445.51). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.30(s,2H),8.58(s,1H),8.40(s,1H),8.00(s,1H),7.80(d,1H,J=6.2Hz),7.45(s,1H),7.13(d,1H,J=6.6Hz),5.31(s,1H),4.88(s,2H),4.79(s,2H),4.61(s,2H),2.95(s,6H),1.48(s,6H). White solid. Yield: 62 mg. HPLC (Method 3): R t = 2.67 min, m/z: [M+H] + = 446.1 (MW calc.445.51). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.30 (s, 2H) , 8.58 (s, 1H), 8.40 (s, 1H), 8.00 (s, 1H), 7.80 (d, 1H, J = 6.2 Hz), 7.45 (s, 1H), 7.13 (d, 1H, J = 6.6 Hz), 5.31 (s, 1H), 4.88 (s, 2H), 4.79 (s, 2H), 4.61 (s, 2H), 2.95 (s, 6H), 1.48 (s, 6H).

實施例147：1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 147: 1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3,3'- Oxycyclobutane]-6-formamide

白色固體。產量：75mg。HPLC(方法3)：Rt=2.57min,m/z：[M+H]+=432.2(MW calc.431.49). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.31(s,2H),8.80(s,1H),8.59(d,1H,J=4.7Hz),8.41(s,1H),7.03(s,1H),7.82(d,1H,J=7.8Hz),7.57(d,1H,J=7.5Hz),7.46(d,1H,J=3.7Hz),5.32(s,1H),4.90(d,2H,J=5.8Hz),4.79(d,2H,J=5.7Hz),4.62(s,2H),2.80(d,3H,J=3.2Hz),1.48(s,6H). White solid. Yield: 75 mg. HPLC (Method 3): R t = 2.57 min, m/z: [M+H] + = 432.2 (MW calc.431.49). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.31 (s, 2H) , 8.80 (s, 1H), 8.59 (d, 1H, J = 4.7 Hz), 8.41 (s, 1H), 7.03 (s, 1H), 7.82 (d, 1H, J = 7.8 Hz), 7.57 (d, 1H, J = 7.5 Hz), 7.46 (d, 1H, J = 3.7 Hz), 5.32 (s, 1H), 4.90 (d, 2H, J = 5.8 Hz), 4.79 (d, 2H, J = 5.7 Hz) , 4.62 (s, 2H), 2.80 (d, 3H, J = 3.2 Hz), 1.48 (s, 6H).

以下二個實施例係由化合物22b獲得，其係經由分別與甲胺(2M in THF)及2-氨基乙醇進行TBTU偶聯反應。 The following two examples were obtained from compound 22b via a TBTU coupling reaction with methylamine (2M in THF) and 2-aminoethanol, respectively.

實施例148：N-甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁 烷]-6-甲醯胺 Example 148: N-Methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane Alkane-6-carboxamide

白色固體。產量：80mg。HPLC(方法2)：Rt=1.48min,m/z：[M+H]+=388.1(MW calc.387.43). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.29(s,2H),8.79(s,1H),8.53(d,1H,J=4.8Hz),8.39(s,1H),7.90(s,1H),7.81(d,1H,J=7.7Hz),7.56(d,1H,J=7.6Hz),7.20(d,1H,J=4.4Hz),4.89(d,2H,J=5.8Hz),4.79(d,2H,J=5.9Hz),4.62(s,2H),2.80(d,3H,J=4.0Hz),2.32(s,3H). White solid. Yield: 80 mg. HPLC (Method 2): R t = 1.48 min, m/z: [M+H] + = 388.1 (MW calc. 387.43). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.29 (s, 2H) , 8.79 (s, 1H), 8.53 (d, 1H, J = 4.8 Hz), 8.39 (s, 1H), 7.90 (s, 1H), 7.81 (d, 1H, J = 7.7 Hz), 7.56 (d, 1H, J=7.6Hz), 7.20(d,1H,J=4.4Hz), 4.89(d,2H,J=5.8Hz), 4.79(d,2H,J=5.9Hz),4.62(s,2H) , 2.80 (d, 3H, J = 4.0 Hz), 2.32 (s, 3H).

實施例149：N-(2-羥乙基)-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 149: N-(2-hydroxyethyl)-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane Alkane-6-carboxamide

白色固體。產量：70mg。HPLC(方法2)：Rt=1.40min,m/z：[M+H]+=418.1(MW calc.417.46). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.29(s,2H),8.79(s,1H),8.53(d,1H,J=4.6Hz),8.38(s,1H),7.90(s,1H),7.82(d,1H,J=7.7Hz),7.60(d,1H,J=7.6Hz),7.21(d,1H,J=4.2Hz),4.90(d,2H,J=5.9Hz),4.79(d,2H,J=5.8Hz),4.74-4.72(m,1H),4.62(s,2H),3.54-3.51(m,2H), 3.35-3.34(m,2H),2.32(s,3H). White solid. Yield: 70 mg. HPLC (Method 2): R t = 1.40 min, m/z: [M+H] + = 418.1 (MW calc. 417.46). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.29 (s, 2H) , 8.79 (s, 1H), 8.53 (d, 1H, J = 4.6 Hz), 8.38 (s, 1H), 7.90 (s, 1H), 7.82 (d, 1H, J = 7.7 Hz), 7.60 (d, 1H, J = 7.6 Hz), 7.21 (d, 1H, J = 4.2 Hz), 4.90 (d, 2H, J = 5.9 Hz), 4.79 (d, 2H, J = 5.8 Hz), 4.74 - 4.72 (m, 1H), 4.62 (s, 2H), 3.54-3.51 (m, 2H), 3.35-3.34 (m, 2H), 2.32 (s, 3H).

實施例150：N-(2-羥乙基)-1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 150: N-(2-hydroxyethyl)-1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin- 3,3'-oxycyclobutane]-6-formamide

由INT-1以類似於合成實施例22製程製備。白色固體。產量：0.1g。HPLC(方法3)：Rt=2.45min,m/z：[M+H]+=462.3(MW calc.461.51). 1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：9.27(s,2H),8.80(s,1H),8.59(d,1H,J=5.1Hz),7.99(s,1H),7.94(s,1H),7.80(d,1H,J=7.6Hz),7.59(d,1H,J=7.7Hz),7.44(d,1H,J=4.9Hz),4.94-4.89(m,3H),4.81(d,2H,J=6Hz),4.64(s,2H),4.36(s,1H),3.60(d,2H,J=5.1Hz),3.43-3.40(m,2H),1.52(s,6H). Prepared by INT-1 in a manner similar to the synthesis example 22. White solid. Yield: 0.1 g. HPLC (Method 3): R t = 2.45 min, m/z: [M+H] + = 462.3 (MW calc.461.51). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 9.27 (s) , 2H), 8.80 (s, 1H), 8.59 (d, 1H, J = 5.1 Hz), 7.99 (s, 1H), 7.94 (s, 1H), 7.80 (d, 1H, J = 7.6 Hz), 7.59 (d, 1H, J = 7.7 Hz), 7.44 (d, 1H, J = 4.9 Hz), 4.94 - 4.89 (m, 3H), 4.81 (d, 2H, J = 6 Hz), 4.64 (s, 2H), 4.36 (s, 1H), 3.60 (d, 2H, J = 5.1 Hz), 3.43-3.40 (m, 2H), 1.52 (s, 6H).

實施例151：1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)-N-(2-羥乙基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 151:1-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)spiro[porphyrin-3,3'-oxygen ring Butane]-6-formamide

TBTU偶聯反應中間物3b與2-氨基乙醇。白色固體。產量：80mg。HPLC(方法2)：Rt=1.64min,m/z：[M+H]+=435.08(MW calc.434.46). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.84(s,2H),8.76(s,1H),8.40-8.39(m,1H),7.81(d,1H,J=8Hz),7.59(d,1H,J=7.6Hz),7.48(d,1H,J=7.6Hz),7.25(d,2H,J=8.4Hz),4.89(d,2H,J=6.4Hz),4.79-4.72(m,3H),4.60(s,2H),3.54-3.50(m,2H),3.36-3.34(m,2H),2.35(s,3H). TBTU coupling reaction intermediate 3b with 2-aminoethanol. White solid. Yield: 80 mg. HPLC (Method 2): Rt = 1.64 min, m/z: [M+H] + = 435.08 (MW calc. 434.46). 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.84 (s, 2H) , 8.76 (s, 1H), 8.40-8.39 (m, 1H), 7.81 (d, 1H, J = 8 Hz), 7.59 (d, 1H, J = 7.6 Hz), 7.48 (d, 1H, J = 7.6 Hz) ), 7.25 (d, 2H, J = 8.4 Hz), 4.89 (d, 2H, J = 6.4 Hz), 4.79 - 4.72 (m, 3H), 4.60 (s, 2H), 3.54-3.50 (m, 2H) , 3.36-3.34 (m, 2H), 2.35 (s, 3H).

實施例152：(1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 Example 152: (1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane ]-6-yl)(morpholinyl)methanone

由(1-(5-溴嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮8b以類似於實施例8方式製備。白色固體。產量：80mg。HPLC(方法3)：Rt=2.80min,m/z：[M+H]+=488.0(MW calc.487.55). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.30(s,2H),8.59-8.58(m,1H),8.42(s,1H),8.01(s,1H),7.82(d,1H,J=7.6Hz),7.46-7.45(m,1H),7.15-7.13(m,1H),5.31(s,1H),4.89(d,2H,J=6.1Hz),4.79(d,2H,J=6.0Hz),4.62(s,2H),3.67-3.42(m,8H),1.48(s,6H). From (1-(5-bromopyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)(morpholinyl)methanone 8b in a manner similar to Example 8 preparation. White solid. Yield: 80 mg. HPLC (Method 3): R t = 2.80 min, m/z: [M+H] + = 488.0 (MW calc. 487.55). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.30 (s, 2H) , 8.59-8.58 (m, 1H), 8.42 (s, 1H), 8.01 (s, 1H), 7.82 (d, 1H, J = 7.6 Hz), 7.46-7.45 (m, 1H), 7.15-7.13 (m , 1H), 5.31 (s, 1H), 4.89 (d, 2H, J = 6.1 Hz), 4.79 (d, 2H, J = 6.0 Hz), 4.62 (s, 2H), 3.67-3.42 (m, 8H) , 1.48 (s, 6H).

實施例153：1-(5-(2-氟苯基)嘧啶-2-基)-N-(2-羥乙基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 153: 1-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)spiro[porphyrin-3,3'-oxocyclobutane]-6 -Procarbamide

TBTU偶聯反應Int-2及2-氨基乙醇。白色固體。產量：75mg。HPLC(方法3)：Rt=2.85min,m/z：[M+H]+=420.9(MW calc.420.44). 1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：8.86(s,2H),8.76(s,1H),8.38(t,1H,J=5.1Hz),7.81(d,1H,J=7.7Hz),7.67(t,1H,J=8Hz),7.59(d,1H,J=7.8Hz),7.48-7.43(m,1H),7.39-7.32(m,2H),4.89(d,2H,J=6Hz),4.79(d,2H,J=6Hz)4.72(t,1H,J=5.5Hz),4.60(s,2H),3.55-3.50(m,2H),3.35(t,2H,J=5.8Hz). TBTU coupling reaction Int-2 and 2-aminoethanol. White solid. Yield: 75 mg. HPLC (Method 3): R t = 2.85 min, m/z: [M+H] + = 420.9 (MW calc. 420.44). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 8.86 (s) , 2H), 8.76 (s, 1H), 8.38 (t, 1H, J = 5.1 Hz), 7.81 (d, 1H, J = 7.7 Hz), 7.67 (t, 1H, J = 8 Hz), 7.59 (d, 1H, J = 7.8 Hz), 7.48-7.43 (m, 1H), 7.39-7.32 (m, 2H), 4.89 (d, 2H, J = 6 Hz), 4.79 (d, 2H, J = 6 Hz) 4.72 (t , 1H, J = 5.5 Hz), 4.60 (s, 2H), 3.55-3.50 (m, 2H), 3.35 (t, 2H, J = 5.8 Hz).

中間物5：1-(5-溴嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯氯(Int-5) Intermediate 5: 1-(5-bromopyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-sulfonyl chloride (Int-5)

Int-5a)6'-(苄硫基)-2,2-二甲基螺[[1,3]二噁烷-5,3'-吲哚啉] Int-5a) 6'-(Benzylthio)-2,2-dimethylspiro[[1,3]dioxane-5,3'-carboline]

Xantphos(3.46g,6.04mmol)及Pd2(dba)3(2.75g,3.02mmol)係被加入保持在Ar中之無水二噁烷(800mL)中之6'-溴-2,2-二甲基螺[[1,3]二噁烷-5,3'-吲哚啉](Int-1b,18g,60.4mmol)、苯基-甲硫醇(7.0mL,60.4mmol)及DIPEA(21mL,120.8mmol)攪拌溶液。該得到之混合物係於120℃經加熱16h，然後降溫並經矽藻土栓過濾。該濾液係經蒸發且該剩留物係經以快速管柱層 析法[矽膠；己烷與10-15% EtOAc]純化。白色固體。產量：18g(87%)。HPLC(方法3)：Rt=3.73min,m/z：[M+H]+=341.9(MW calc.341.47). Xantphos (3.46 g, 6.04 mmol) and Pd 2 (dba) 3 (2.75 g, 3.02 mmol) were added to 6'-bromo-2,2-dimethyl in anhydrous dioxane (800 mL) maintained in Ar. Base snail [[1,3]dioxane-5,3'-carboline] (Int-1b, 18g, 60.4mmol), phenyl-methyl mercaptan (7.0mL, 60.4mmol) and DIPEA (21mL, 120.8 mmol) was stirred. The resulting mixture was heated at 120 ° C for 16 h, then cooled and filtered through a plug of diatomaceous earth. The filtrate was evaporated and the residue was purified by flash column chromatography [EtOAc] White solid. Yield: 18 g (87%). HPLC (Method 3): R t =3.73 min, m/z: [M+H] + = 341.9 (MW calc.341.47).

Int-5b)(6-(苄硫基)吲哚啉-3,3-二基)二甲醇 Int-5b)(6-(benzylthio)porphyrin-3,3-diyl)dimethanol

2N氯化氫溶液(304mL)係於rt加入THF(200mL)中之Int-5a(18.0g,52.7mmol)。該反應混合物係於此溫度經攪拌3h、濃縮、以sat.NaHCO3溶液鹼化及以EtOAc(10x 250mL)萃取。該合併之有機層係經Na2SO4乾燥及蒸發。白色固體。產量：16g。HPLC(方法3)：Rt=2.97min,m/z：[M+H]+=302.0(MW calc.301.40). 2N Hydrogen chloride solution (304 mL) was added to EtOAc (18.0 g, 52.7 mmol The reaction mixture was stirred at this temperature based 3h, concentrated to sat.NaHCO 3 solution and basified to EtOAc (10x 250mL) and extracted. The combined organic layers were dried over Na 2 SO 4 and evaporated. White solid. Yield: 16g. HPLC (Method 3): R t = 2.97 min, m/z: [M+H] + = 302.0 (MW calc.301.40).

Int-5c)(6-(苄硫基)-1-(5-溴嘧啶-2-基)吲哚啉-3,3-二基)二甲醇 Int-5c)(6-(benzylthio)-1-(5-bromopyrimidin-2-yl)porphyrin-3,3-diyl)dimethanol

正丁醇(80mL)中之Int-5b(5.2g,17.27mmol)、DIPEA(7.6mL,43.18mmol)及5-溴-2-氯-嘧啶(4.99g,25.9mmol)係在密封管中於130℃經加熱16h。該溶劑係在真空中被移除且該原產物係經以快速管柱層析法[矽石；DCM與1.5% MeOH]純化。白色固體。5.2g Int-5b之三批合併產量：18g(74%)。HPLC(方法3)：Rt=3.50min,m/z：[M+H]+=460.0(MW calc.458.37). Int-5b (5.2 g, 17.27 mmol), DIPEA (7.6 mL, 43.18 mmol) and 5-bromo-2-chloro-pyrimidine (4.99 g, 25.9 mmol) in n-butanol (80 mL) were placed in a sealed tube. Heating at 130 ° C for 16 h. The solvent was removed in vacuo and the crude product was purified by flash column chromatography [EtOAc, DCM with 1.5% MeOH]. White solid. The combined yield of 5.2g of three batches of Int-5b: 18g (74%). HPLC (Method 3): R t = 3.50 min, m/z: [M+H] + = 460.0 (MW calc. 458.37).

Int-5d)(6-(苄硫基)-1-(5-溴嘧啶-2-基)-3-(羥甲基)吲哚啉-3-基)甲基4-甲基-苯磺酸酯 Int-5d)(6-(Benzylthio)-1-(5-bromopyrimidin-2-yl)-3-(hydroxymethyl)porphyrin-3-yl)methyl 4-methyl-benzenesulfonate Acid ester

LiHMDS(39.3mL,39.30mmol)係經30min逐滴加入至於-78℃攪拌之無水THF(2L)中之Int-5c(18g,39.30mmol)溶液。該混合物係於此溫度經攪拌30min之後於-78℃緩慢加入無水THF(100mL)中之甲苯磺醯基氯(7.7g,39.30mmol)。該反應混合物係於此溫度經進一步攪拌2h，然後以sat.NH4Cl溶液淬滅及以EtOAc(3x 250mL)萃取。該合併之有機層係經Na2SO4乾燥 及濃縮。該剩餘物係經以快速管柱層析法[矽石；己烷與20-25% EtOAc]純化。白色固體。產量：15g(62%)。HPLC(方法3)：Rt=2.29min,m/z：[M+H]+=614.2(MW calc.612.56). LiHMDS (39.3 mL, 39.30 mmol) was added dropwise to a solution of &lt;RTI ID=0.0&gt;&gt; The mixture was slowly added to toluenesulfonyl chloride (7.7 g, 39.30 mmol) in dry THF (100 mL) at -78. The reaction mixture was further stirred at this temperature based 2h, and then extracted with sat.NH 4 Cl solution to quench and to EtOAc (3x 250mL). The combined organic layers were dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography [mistite; hexanes with 20-25%EtOAc]. White solid. Yield: 15 g (62%). HPLC (Method 3): R t = 2.29 min, m/z: [M+H] + = 614.2 (MW calc. 612.56).

Int-5e)6-(苄硫基)-1-(5-溴嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷] Int-5e) 6-(benzylthio)-1-(5-bromopyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]

t-BuOH(620mL)中之Int-5d(15g,24.5mmol)及KOH(5.2g,95.5mmol)係於50℃經加熱30min。該反應混合物係被降溫至RT且該溶劑係經蒸發。該剩餘物係經以水(100mL)稀釋及以EtOAc(3x 300mL)萃取。該合併之有機層係經Na2SO4乾燥及濃縮。白色固體。產量：8g(75%)。HPLC(方法3)：Rt=4.25min,m/z：[M+H]+=442.2(MW calc.440.36). Int-5d (15 g, 24.5 mmol) and KOH (5.2 g, 95.5 mmol) in t-BuOH (620 mL) were heated at 50 ° C for 30 min. The reaction mixture was cooled to RT and the solvent was evaporated. The residue was diluted with water (100 mL) andEtOAcEtOAc The combined organic layers were dried over Na 2 SO 4 and concentrated. White solid. Yield: 8 g (75%). HPLC (Method 3): R t = 4.25 min, m/z: [M+H] + = 442.2 (MW calc. 440.36).

Int-5g)1-(5-溴嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯氯(Int-5) Int-5g) 1-(5-bromopyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-sulfonyl chloride (Int-5)

1,3-二氯-5,5-二甲基咪唑啶-2,4-二酮(3.94g,20.45mmol)係於-5℃分批加入乙腈(120mL)、乙酸(5.5mL)及水(3.6mL)中之Int-5e(6g,13.63mmol)溶液。該反應混合物係於此溫度經攪拌20min，然後在減壓於低於<25℃濃縮，以DCM(250mL)稀釋及以水(200mL)清洗。該有機層係經Na2SO4乾燥及濃縮(溫度<25℃)以產出淺褐色固體之目標化合物，其未經進一步純化而被使用。產量：5g(92%). 1,3-Dichloro-5,5-dimethylimidazolidin-2,4-dione (3.94 g, 20.45 mmol) was added in portions at -5 °C acetonitrile (120 mL), acetic acid (5.5 mL) and water A solution of Int-5e (6 g, 13.63 mmol) in (3.6 mL). The reaction mixture was stirred at rt for 20 min then concentrated under reduced pressure <<RTIID=0.0></RTI><RTIgt; The organic-based layer over Na 2 SO 4 dried and concentrated (temperature <25 ℃) to yield the title compound as a light brown solid which was used without further purification. Yield: 5g (92%).

實施例154：N-(2-羥乙基)-1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺 Example 154: N-(2-hydroxyethyl)-1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methyl snail [Porphyrin-3,3'-oxycyclobutane]-6-sulfonamide

154a)1-(5-溴嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺 154a) 1-(5-Bromopyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane]-6-sulfonate amine

TEA(0.5mL,3.6mmol)及2-甲基胺-乙醇(136mg,1.8mmol)係於0℃加入至DCM(10mL)中之磺醯氯Int-5(0.5g,1.2mmol)溶液且該得到之混合物係於rt經攪拌2h。該反應混合物係經以DCM(20mL)稀釋且以sat.NH4Cl溶液(15mL)及鹽水(15mL)清洗。該有機層係經Na2SO4乾燥及濃縮。該剩留物係經以快速管柱層析法[矽石；DCM與0-0.5% MeOH]純化。白色固體。產量：0.3g(54%)。HPLC(方法3)：Rt=3.10min,m/z：[M+H]+=456.5(MW calc.455.33). TEA (0.5 mL, 3.6 mmol) and 2-methylamine-ethanol (136 mg, 1.8 mmol) were added to a solution of sulfonium chloride Int-5 (0.5 g, 1.2 mmol) in DCM (10 mL) at 0 ° C and The resulting mixture was stirred at rt for 2 h. The reaction mixture was diluted with lines in DCM (20mL) and with sat.NH 4 Cl solution (15mL) and brine (15mL) wash. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography [ vermiculite; DCM with 0-0.5% MeOH]. White solid. Yield: 0.3 g (54%). HPLC (Method 3): R t = 3.10 min, m/z: [M+H] + =456.5 (MW calc.455.33).

154b)N-(2-羥乙基)-1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺 154b) N-(2-hydroxyethyl)-1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[吲Porphyrin-3,3'-oxocyclobutane]-6-sulfonamide

PdCl2(dppf)(26mg,0.032mmol)係於rt加入至於rt在Ar中攪拌之無水二噁烷(15mL)中之154a)(0.30g,0.65mmol)、雙(頻哪醇)二硼(0.334g,1.3mmol)及KOAc(0.223g,2.27mmol)溶液。該反應混合物係於90℃經加熱30min。2-(2-溴吡啶-4-基)丙-2-醇(0.210g,0.97mmol)、2M K2CO3溶液(1.5mL)及肆(三苯基膦)鈀(0)(38mg,0.032mmol)係被依次加入且該反應混合物係於90℃經加熱另外16h。在被降至RT後，該混合物係經燒結漏斗過濾，該 濾液係被濃縮且該剩餘物係經以快速管柱層析法[矽石；DCM與1.5% MeOH]純化。白色固體。產量：90mg(27%)。HPLC(方法3)：Rt=2.72min,m/z：[M+H]+=512.1(MW calc.511.59). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.35(s,2H),8.76(s,1H),8.59(d,1H,J=4.7Hz),8.06(s,1H),7.98(d,1H,J=7.7Hz),7.51-7.46(m,2H),5.30(s,1H),4.91(d,2H,J=6Hz),4.79(d,3H,J=5.8Hz),4.67(s,2H),3.55(d,2H,J=5.2Hz),3.05(s,2H),2.78(s,3H),1.49(s,6H). PdCl 2 (dppf) (26 mg, 0.032 mmol) was added 154a) (0.30 g, 0.65 mmol), bis (pinacol) diboron in rt (15 mL) stirred in EtOAc. A solution of 0.334 g, 1.3 mmol) and KOAc (0.223 g, 2.27 mmol). The reaction mixture was heated at 90 ° C for 30 min. 2-(2-Bromopyridin-4-yl)propan-2-ol (0.210 g, 0.97 mmol), 2M K 2 CO 3 solution (1.5 mL) and bis(triphenylphosphine)palladium(0) (38 mg, 0.032 mmol) was added sequentially and the reaction mixture was heated at 90 ° C for an additional 16 h. After being reduced to RT, the mixture was filtered through a fritted funnel, the filtrate was concentrated and the residue was purified by flash column chromatography [Mer. White solid. Yield: 90 mg (27%). HPLC (Method 3): R t = 2.72 min, m/z: [M+H] + = 512.1 (MW calc. 51.59). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.35 (s, 2H) , 8.76 (s, 1H), 8.59 (d, 1H, J = 4.7 Hz), 8.06 (s, 1H), 7.98 (d, 1H, J = 7.7 Hz), 7.51-7.46 (m, 2H), 5.30 ( s, 1H), 4.91 (d, 2H, J = 6 Hz), 4.79 (d, 3H, J = 5.8 Hz), 4.67 (s, 2H), 3.55 (d, 2H, J = 5.2 Hz), 3.05 (s , 2H), 2.78 (s, 3H), 1.49 (s, 6H).

實施例155至158係經以類似合成實施例154製備。 Examples 155 to 158 were prepared in a similar manner to Synthesis Example 154.

實施例155：N-(2-羥乙基)-1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺 Example 155: N-(2-hydroxyethyl)-1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin- 3,3'-oxycyclobutane]-6-sulfonamide

白色固體。產量：70mg。HPLC(方法3)：Rt=2.56min,m/z：[M+H]+=498.2(MW calc.497.57). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.33(s,2H),8.82(s,1H),8.60(d,1H,J=4.9Hz),8.05(s,1H),7.96(d,1H,J=7.8Hz),7.65(d,1H,J=5.9Hz),7.56(d,1H,J=6.6Hz),7.47(s,1H,J=4.3Hz),5.30(s,1H),4.91(d,2H,J=5.9Hz),4.79(d,2H,J=6Hz),4.68(d,3H,J=7.6Hz),3.40-3.37(m,2H),2.84-2.81(m,2H),1.49(s,6H). White solid. Yield: 70 mg. HPLC (Method 3): R t = 2.56 min, m/z: [M+H] + = 498.2 (MW calc. 497.57). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.33 (s, 2H) , 8.82 (s, 1H), 8.60 (d, 1H, J = 4.9 Hz), 8.05 (s, 1H), 7.96 (d, 1H, J = 7.8 Hz), 7.65 (d, 1H, J = 5.9 Hz) , 7.56 (d, 1H, J = 6.6 Hz), 7.47 (s, 1H, J = 4.3 Hz), 5.30 (s, 1H), 4.91 (d, 2H, J = 5.9 Hz), 4.79 (d, 2H, J = 6 Hz), 4.68 (d, 3H, J = 7.6 Hz), 3.40-3.37 (m, 2H), 2.84 - 2.81 (m, 2H), 1.49 (s, 6H).

實施例156：N-(2-羥乙基)-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺 Example 156: N-(2-hydroxyethyl)-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane Alkane-6-sulfonamide

白色固體。產量：50mg。HPLC(方法3)：Rt=2.81min,m/z：[M+H]+=454.1(MW calc.453.52). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.31(s,2H),8.80(s,1H),8.53(s,1H,J=4.6Hz),7.95(d,2H,J=10.4Hz),7.66-7.63(m,1H),7.56(d,1H,J=7.5Hz),7.21(d,1H,J=4.3Hz),4.90(d,2H,J=6Hz),4.79(d,2H,J=6Hz),4.69-4.64(m,3H),3.42-3.38(m,2H,),2.86-2.83(m,2H),2.39(s,3H). White solid. Yield: 50 mg. HPLC (Method 3): R t = 2.81 min, m/z: [M+H] + = 454.1 (MW calc.453.52). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.31 (s, 2H) , 8.80 (s, 1H), 8.53 (s, 1H, J = 4.6 Hz), 7.95 (d, 2H, J = 10.4 Hz), 7.66-7.63 (m, 1H), 7.56 (d, 1H, J = 7.5) Hz), 7.21 (d, 1H, J = 4.3 Hz), 4.90 (d, 2H, J = 6 Hz), 4.79 (d, 2H, J = 6 Hz), 4.69 - 4.64 (m, 3H), 3.42-3.38 ( m, 2H,), 2.86-2.83 (m, 2H), 2.39 (s, 3H).

實施例157：N-甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺 Example 157: N-Methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6- Sulfonamide

白色固體。產量：0.1g。HPLC(方法3)：Rt=3.15min,m/z：[M+H]+=423.8(MW calc.423.49). 1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：9.27(s, 2H),8.81(s,1H),8.53(d,1H,J=4.9Hz),7.93(d,1H,J=7.6Hz),7.84(s,1H),7.56(d,1H,J=7.8Hz),7.19(d,1H,J=4.7Hz),7.13(s,1H),4.91(d,2H,J=6Hz),4.81(d,2H,J=6Hz),4.67(s,2H),2.54(s,3H),2.41(s,3H). White solid. Yield: 0.1 g. HPLC (Method 3): R t = 3.15 min, m/z: [M+H] + =423.8 (MW calc. 423.49). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 9.27 (s) , 2H), 8.81 (s, 1H), 8.53 (d, 1H, J = 4.9 Hz), 7.93 (d, 1H, J = 7.6 Hz), 7.84 (s, 1H), 7.56 (d, 1H, J = 7.8 Hz), 7.19 (d, 1H, J = 4.7 Hz), 7.13 (s, 1H), 4.91 (d, 2H, J = 6 Hz), 4.81 (d, 2H, J = 6 Hz), 4.67 (s, 2H) ), 2.54 (s, 3H), 2.41 (s, 3H).

實施例158：1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺 Example 158: 1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3,3'- Oxycyclobutane]-6-sulfonamide

白色固體。產量：80mg。HPLC(方法2)：Rt=1.60min,m/z：[M+H]+=468.2(MW calc.467.54). 1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：9.33(s,2H),8.81(s,1H),8.60(d,1H,J=4.5Hz),8.05(s,1H),7.97(d,1H,J=7.6Hz),7.54-7.47(m,3H),5.30(s,1H),4.91(d,2H,J=5.7Hz),4.79(d,2H,J=5.6Hz),4.66(s,2H),2.46(d,3H,J=4.4Hz),1.49(s,6H). White solid. Yield: 80 mg. HPLC (Method 2): R t = 1.60 min, m/z: [M+H] + = 468.2 (MW calc. 467.54). 1H NMR (400 MHz, DMSO-d6, 100 ° C, δ ppm): 9.33 (s) , 2H), 8.81 (s, 1H), 8.60 (d, 1H, J = 4.5 Hz), 8.05 (s, 1H), 7.97 (d, 1H, J = 7.6 Hz), 7.54 - 7.47 (m, 3H) , 5.30 (s, 1H), 4.91 (d, 2H, J = 5.7 Hz), 4.79 (d, 2H, J = 5.6 Hz), 4.66 (s, 2H), 2.46 (d, 3H, J = 4.4 Hz) , 1.49 (s, 6H).

實施例159及160：6-(乙亞磺醯基)-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷](較快及較慢之洗析之鏡像異構物) Examples 159 and 160: 6-(ethylsulfinyl)-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxygen Cyclobutane] (faster and slower crystallization of the image isomer)

該消旋之亞碸係由中間物52h以類似於合成實施例56方式製備。該二鏡像異構物係由此消旋物經製備型掌性HPLC獲得。 The racemic subunit was prepared by intermediate 52h in a manner similar to that of Synthesis Example 56. The diastereoisomer is obtained from the racemate HPLC by preparative palmitic HPLC.

較快洗析之鏡像異構物(實施例159)：產量=110mg。白色固體。MS：m/z：[M+H]+=470.3。特定旋光度：[α]589 25=-157.34°(c.0.2860,CHCl3)。1H NMR(400MHz,DMSO-d6,δ ppm)：9.30(s,2H),8.60(s,1H),8.52(d,1H,J=4.8Hz),7.93(d,2H,J=7.5Hz),7.35(d,1H,J=7.6Hz),7.21(d,1H,J=4.4Hz),4.89(d,2H,J=6.0Hz),4.78(d,2H,J=5.8Hz),4.65(s,2H),3.04-2.98(m,1H),2.80-2.74(m,1H),2.39(s,3H),1.08(t,3H,J=7.2Hz)。掌性HPLC：Rt=5.68min(掌性pak IA管柱(250mm x 4.6mm,5μm)及己烷/DCM/EtOH/二乙胺(50/25/25/0.1)作為移動相；流速=1.0ml/min). The mirror image isomer was washed out faster (Example 159): Yield = 110 mg. White solid. MS: m/z: [M+H] + = 470.3. Specific optical rotation: [α] 589 25 = -157.34 ° (c. 0.2860, CHCl 3 ). 1H NMR (400MHz, DMSO-d6, δ ppm): 9.30 (s, 2H), 8.60 (s, 1H), 8.52 (d, 1H, J = 4.8 Hz), 7.93 (d, 2H, J = 7.5 Hz) , 7.35 (d, 1H, J = 7.6 Hz), 7.21 (d, 1H, J = 4.4 Hz), 4.89 (d, 2H, J = 6.0 Hz), 4.78 (d, 2H, J = 5.8 Hz), 4.65 (s, 2H), 3.04-2.98 (m, 1H), 2.80-2.74 (m, 1H), 2.39 (s, 3H), 1.08 (t, 3H, J = 7.2 Hz). Palm HPLC: R t = 5.68 min (palm pak IA column (250 mm x 4.6 mm, 5 μm) and hexane/DCM/EtOH/diethylamine (50/25/25/0.1) as mobile phase; flow rate = 1.0ml/min).

較慢洗析之鏡像異構物(實施例160)：產量=122mg。白色固體。MS：m/z：[M+H]+=470.2。特定旋光度：[α]589 25=+140.81°(c.0.2784,CHCl3)。1H NMR(400MHz,DMSO-d6,δ ppm)：9.30(s,2H),8.60(s,1H),8.52(d,1H,J=4.8Hz),7.93(d,2H,J=6.8Hz),7.35(d,1H,J=7.5Hz),7.21(d,1H,J=4.6Hz),4.89(d,2H,J=6.1Hz),4.78(d,2H,J=5.5Hz),4.65(s,2H),3.04-2.98(m,1H),2.80-2.75(m,1H),2.39(s,3H),1.08(t,3H,J=7.2Hz)。掌性HPLC：Rt=8.11min(與峰值1相同條件)。 The mirror image isomer of the slower elution (Example 160): Yield = 122 mg. White solid. MS: m/z: [M+H] + = 470.2. Specific optical rotation: [α] 589 25 = +140.81 ° (c. 0.2784, CHCl 3 ). 1H NMR (400MHz, DMSO-d6, δ ppm): 9.30 (s, 2H), 8.60 (s, 1H), 8.52 (d, 1H, J = 4.8 Hz), 7.93 (d, 2H, J = 6.8 Hz) , 7.35 (d, 1H, J = 7.5 Hz), 7.21 (d, 1H, J = 4.6 Hz), 4.89 (d, 2H, J = 6.1 Hz), 4.78 (d, 2H, J = 5.5 Hz), 4.65 (s, 2H), 3.04 - 2.98 (m, 1H), 2.80 - 2.75 (m, 1H), 2.39 (s, 3H), 1.08 (t, 3H, J = 7.2 Hz). Palm HPLC: R t =8.11 min (same conditions as peak 1).

實施例161及162：6-(乙亞磺醯基)-1-(5-(吡啶-2-基)嘧啶-2-基)螺[吲哚啉 -3,3'-氧環丁烷](較快及較慢之洗析之鏡像異構物) Examples 161 and 162: 6-(ethylsulfinyl)-1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin -3,3'-oxocyclobutane] (faster and slower elution of the image isomer)

該消旋之亞碸係由中間物52h以類似於合成實施例56方式製備。該二鏡像異構物係由此消旋物經製備型掌性HPLC獲得。 The racemic subunit was prepared by intermediate 52h in a manner similar to that of Synthesis Example 56. The diastereoisomer is obtained from the racemate HPLC by preparative palmitic HPLC.

較快洗析之鏡像異構物(實施例161)：產量=80mg。白色固體。MS：m/z：[M+H]+=393.0。1H NMR(400MHz,DMSO-d6,δ ppm)：9.32(s,2H),8.68(s,1H),8.60(s,1H),8.06(d,1H,J=7.6Hz),7.94-7.88(m,2H),7.36-7.36(m,2H),4.90(d,2H,J=5.8Hz),4.79(d,2H,J=4.8Hz),4.65(s,2H),3.04-2.98(q,1H),2.80-2.75(q,1H),1.08(t,3H,J=7.2Hz)。掌性HPLC：Rt=5.85min(管柱：Chiralpak IA(250mm x 4.6mm,5μm)；移動相：己烷/DCM/EtOH/二乙胺=50/25/25/0.1；流速=1.0ml/min)。 The mirror image isomer was washed out faster (Example 161): Yield = 80 mg. White solid. MS: m/z: [M+H] + = 393.0. 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.32 (s, 2H), 8.68 (s, 1H), 8.60 (s, 1H), 8.06 (d, 1H, J = 7.6 Hz), 7.94 - 7.88 (m, 2H), 7.36-7.36 (m, 2H), 4.90 (d, 2H, J = 5.8 Hz), 4.79 (d, 2H, J = 4.8) Hz), 4.65 (s, 2H), 3.04-2.98 (q, 1H), 2.80-2.75 (q, 1H), 1.08 (t, 3H, J = 7.2 Hz). Palm HPLC: R t = 5.85 min (column: Chiralpak IA (250 mm x 4.6 mm, 5 μm); mobile phase: hexane/DCM/EtOH/diethylamine = 50/25/25/0.1; flow rate = 1.0 ml /min).

較慢洗析之鏡像異構物(實施例162)：產量=80mg。白色固體。MS：m/z：[M+H]+=392.9。1H NMR(400MHz,DMSO-d6,δ ppm)：9.32(s,2H),8.68(d,1H,J=4Hz),8.60(s,1H),8.06(d,1H,J=8Hz),7.94-7.88(m,2H),7.36(t,2H,J=7.7Hz),4.90(d,2H,J=6Hz),4.79(d,2H,J=5.4Hz),4.65(s,2H),3.00(t,1H,J=6.6Hz),2.78(t,1H,J=7.2Hz),1.08(t,3H,J=7.1Hz)。掌性HPLC：Rt=8.95min(與其他鏡像異構物相同分析方法)。 The mirror image isomer of the slower elution (Example 162): Yield = 80 mg. White solid. MS: m/z: [M+H] + = 392.9. 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.32 (s, 2H), 8.68 (d, 1H, J = 4 Hz), 8.60 (s, 1H), 8.06 (d, 1H, J = 8 Hz), 7.94 - 7.88 (m, 2H), 7.36 (t, 2H, J = 7.7 Hz), 4.90 (d, 2H, J = 6 Hz), 4.79 (d, 2H, J = 5.4 Hz), 4.65 (s, 2H), 3.00 (t, 1H, J = 6.6 Hz), 2.78 (t, 1H, J = 7.2 Hz), 1.08 (t, 3H, J = 7.1 Hz) . Palm HPLC: R t = 8.95 min (identical analysis with other smectomers).

實施例163：6-(乙磺醯基)-1-(5-(吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷] Example 163: 6-(ethanesulfonyl)-1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]

該消旋之亞碸係由中間物52h以類似於合成實施例56方式製備然後以MMPP氧化(參見實施例57)。白色固體。產量：0.08g。HPLC(方法3)：Rt=3.07min.,m/z：[M+H]+=409.1(MW calc.408.47)。1H NMR(400MHz,DMSO-d6,δ ppm)：9.32(s,2H),8.82(s,1H),8.68(d,1H,J=4.3Hz),8.09(d,1H,J=7.8Hz),8.03(d,1H,J=7.7Hz),7.91(t,1H,J=7.5Hz),7.64(d,1H,J=7.2Hz),7.38(t,1H,J=5.3Hz),4.91(d,2H,J=6.2Hz),4.79(d,2H,J=6.1Hz),4.67(s,2H),3.32-3.26(m,2H),1.15(t,3H,J=7.2Hz)。 The racemic subunit was prepared by intermediate 52h in a manner similar to that of Synthesis Example 56 and then oxidized with MMPP (see Example 57). White solid. Yield: 0.08 g. HPLC (Method 3): rt = 3.07 min., m/z: [M+H] + = 409.1 (MW calc. 408.47). 1H NMR (400MHz, DMSO-d6, δ ppm): 9.32 (s, 2H), 8.82 (s, 1H), 8.68 (d, 1H, J = 4.3 Hz), 8.09 (d, 1H, J = 7.8 Hz) , 8.03 (d, 1H, J = 7.7 Hz), 7.91 (t, 1H, J = 7.5 Hz), 7.64 (d, 1H, J = 7.2 Hz), 7.38 (t, 1H, J = 5.3 Hz), 4.91 (d, 2H, J = 6.2 Hz), 4.79 (d, 2H, J = 6.1 Hz), 4.67 (s, 2H), 3.32-3.26 (m, 2H), 1.15 (t, 3H, J = 7.2 Hz) .

實施例164及165：2-(6-(2-(6-(乙亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-2-基)丙-2-醇(較快及較慢之洗析鏡像異構物) Examples 164 and 165: 2-(6-(2-(6-(ethylsulfinyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl Pyridin-2-yl)propan-2-ol (faster and slower elution of the mirror image isomer)

該消旋之亞碸係由中間物52h以類似於合成實施例56方式製備。該二鏡像異構物係由此消旋物經製備型掌性HPLC獲得。 The racemic subunit was prepared by intermediate 52h in a manner similar to that of Synthesis Example 56. The diastereoisomer is obtained from the racemate HPLC by preparative palmitic HPLC.

較快洗析之鏡像異構物(實施例164)：產量=115mg。白色固體。HPLC(方法3)：Rt=1.62min,m/z：[M+H]+=451.02(MW calc.450.55). 1H NMR(400 MHz,DMSO-d6,δ ppm)：9.36(s,2H),8.62(s,1H),7.93(d,1H,J=7.2Hz),7.88(s,2H),7.61(bs,1H),7.35(d,1H,J=8.1Hz),5.27(s,1H),4.89(d,2H,J=6.0Hz),4.80(bs,2H),4.65(s,2H),3.02-3.00(m,1H),2.78(bs,1H),1.51(s,6H),1.08(t,3H,J=7.2Hz).Chiral HPLC：Rt=6.34min(管柱：Chiralpak IA 250mm x 4.6mm,5μm；移動相：己烷/DCM/EtOH/二乙胺=50/25/25/0.1；流速=1.0ml/min)。特定旋光度：[α]589 25=-130.6°(c.0.2588,CHCl3). The mirror image isomer was eluted faster (Example 164): Yield = 115 mg. White solid. HPLC (Method 3): R t = 1.62 min, m/z: [M+H] + =451.02 (MW calc. 450.55). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.36 (s, 2H) ), 8.62 (s, 1H), 7.93 (d, 1H, J = 7.2 Hz), 7.88 (s, 2H), 7.61 (bs, 1H), 7.35 (d, 1H, J = 8.1 Hz), 5.27 (s) , 1H), 4.89 (d, 2H, J = 6.0 Hz), 4.80 (bs, 2H), 4.65 (s, 2H), 3.02-3.00 (m, 1H), 2.78 (bs, 1H), 1.51 (s, 6H), 1.08 (t, 3H, J = 7.2 Hz). Chiral HPLC: R t = 6.34 min (column: Chiralpak IA 250 mm x 4.6 mm, 5 μm; mobile phase: hexane/DCM/EtOH/diethylamine = 50/25/25/0.1; flow rate = 1.0 ml/min). Specific optical rotation: [α] 589 25 =-130.6° (c.0.2588, CHCl 3 ).

較慢洗析之鏡像異構物(實施例165)：產量=110mg。白色固體。HPLC(方法3)：Rt=1.62min,m/z：[M+H]+=451.02(MW calc.450.55). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.36(s,2H),8.62(s,1H),7.93(d,1H,J=7.2Hz),7.88(s,2H),7.61(bs,1H),7.35(d,1H,J=8.1Hz),7.43-7.40(m,1H),5.28(s,1H),4.89(d,2H,J=6.0Hz),4.80(d,2H,J=4.8Hz),4.65(s,2H),3.02-2.99(m,1H),2.80-2.75(m,1H),1.51(s,6H),1.08(t,3H,J=7.2Hz).Chiral HPLC：Rt=8.63min(管柱：Chiralpak IA 250mm x 4.6mm,5μm；移動相：己烷/DCM/EtOH/二乙胺=50/25/25/0.1；流速=1.0ml/min)。特定旋光度：[α]589 25=+129.9°(c.0.2832,CHCl3). The mirror image isomer of the slower elution (Example 165): Yield = 110 mg. White solid. HPLC (Method 3): R t = 1.62 min, m/z: [M+H] + =451.02 (MW calc. 450.55). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.36 (s, 2H) , 8.62 (s, 1H), 7.93 (d, 1H, J = 7.2 Hz), 7.88 (s, 2H), 7.61 (bs, 1H), 7.35 (d, 1H, J = 8.1 Hz), 7.43-7.40 ( m, 1H), 5.28 (s, 1H), 4.89 (d, 2H, J = 6.0 Hz), 4.80 (d, 2H, J = 4.8 Hz), 4.65 (s, 2H), 3.02 - 2.99 (m, 1H) ), 2.80-2.75 (m, 1H), 1.51 (s, 6H), 1.08 (t, 3H, J = 7.2 Hz). Chiral HPLC: R t = 8.63 min (column: Chiralpak IA 250 mm x 4.6 mm, 5 μm Mobile phase: hexane/DCM/EtOH/diethylamine = 50/25/25/0.1; flow rate = 1.0 ml/min). Specific optical rotation: [α] 589 25 = +129.9° (c.0.2832, CHCl 3 ).

實施例166：2-(6-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-2-基)丙-2-醇 Example 166: 2-(6-(2-(6-(ethylsulfonyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)pyridine- 2-yl)propan-2-ol

類似於實施例56製備。白色固體。產量：400mg。HPLC(方法3)：Rt=3.15min,m/z：[M+H]+=467.1(MW calc.466.55). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.39(s,2H),8.83(s,1H),8.02(d,1H,J=7.7Hz),7.89-7.85(m,2H),7.62(t,2H,J=6.3Hz),5.28(s,1H),4.91(d,2H,J=5.9Hz),4.80(d,2H,J=6.0Hz),4.67(s,2H),3.32-3.28(m,2H),1.51(s,6H),1.15(t,3H,J=7.0Hz). Prepared analogously to Example 56. White solid. Yield: 400 mg. HPLC (Method 3): R t = 3.15 min, m/z: [M+H] + = 467.1 (MW calc. 466.55). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.39 (s, 2H) , 8.83 (s, 1H), 8.02 (d, 1H, J = 7.7 Hz), 7.89-7.85 (m, 2H), 7.62 (t, 2H, J = 6.3 Hz), 5.28 (s, 1H), 4.91 ( d, 2H, J = 5.9 Hz), 4.80 (d, 2H, J = 6.0 Hz), 4.67 (s, 2H), 3.32-3.28 (m, 2H), 1.51 (s, 6H), 1.15 (t, 3H) , J = 7.0Hz).

實施例167及168：2-((1-(5-(吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)亞磺醯基)乙醇(較快及較慢之洗析鏡像異構物) Examples 167 and 168: 2-((1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl) Sulfosyl) Ethanol (faster and slower elution of the mirror image isomer)

該消旋之亞碸係由Int-3類似於實施例116製備。隨後製備型掌性HPLC提供該單一鏡像異構物。 The racemic subunit was prepared from Int-3 analogous to Example 116. Subsequent preparative palm HPLC provides the single mirror image isomer.

較快洗析鏡像異構物(實施例167)：產量=80mg。白色固體。質譜儀：m/z：[M+H]+=409.4. 1H NMR(400MHz,DMSO-d6,δ ppm)：9.32(s,2 H),8.68(d,1H,J=4.5Hz),8.63(d,1H,J=0.7Hz),8.06(d,1H,J=8Hz),7.95-7.88(m,2H),7.39-7.35(m,2H),5.09(t,1H,J=4.8Hz),4.90(d,2H,J=6.2Hz),4.79(d,2H,J=5.9Hz),4.65(s,2H),3.85-3.81(m,1H),3.70-3.66(m,1H),3.01-2.95(m,1H),2.91-2.87(m,1H).掌性HPLC：Rt=7.24min(管柱：Chiralpak IA(250mm x 4.6mm,5μm)；移動相：己烷/DCM/EtOH/二乙胺=50/25/25/0.1；流速=1.0ml/min)。 The mirror image isomer was eluted faster (Example 167): Yield = 80 mg. White solid. Mass spectrometer: m/z: [M+H] + = 409.4. 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.32 (s, 2 H), 8.68 (d, 1H, J = 4.5 Hz), 8.63 (d, 1H, J = 0.7 Hz), 8.06 (d, 1H, J = 8 Hz), 7.95-7.88 (m, 2H), 7.39-7.35 (m, 2H), 5.09 (t, 1H, J = 4.8 Hz) ), 4.90 (d, 2H, J = 6.2 Hz), 4.79 (d, 2H, J = 5.9 Hz), 4.65 (s, 2H), 3.85-3.81 (m, 1H), 3.70-3.66 (m, 1H) , 3.01-2.95 (m, 1H), 2.91-2.87 (m, 1H). Palm HPLC: R t = 7.24 min (column: Chiralpak IA (250 mm x 4.6 mm, 5 μm); mobile phase: hexane/DCM /EtOH/diethylamine = 50/25/25/0.1; flow rate = 1.0 ml/min).

較慢洗析鏡像異構物(實施例168)：產量=81mg。白色固體。質譜儀： m/z：[M+H]+=409.2. 1H NMR(400MHz,DMSO-d6,δ ppm)：9.32(s,2 H),8.68(d,1H,J=4.3Hz),8.63(s,1H),8.06(d,1H,J=7.9Hz),7.95-7.88(m,2H),7.39-7.35(m,2H),5.09(t,1H,J=4.8Hz),4.90(d,2H,J=6.2Hz),4.79(d,2H,J=6.2Hz),4.65(s,2H),3.86-3.81(m,1H),3.70-3.66(m,1H),3.01-2.95(m,1H),2.90-2.86(m,1H)。掌性HPLC：Rt=19.18min(與其他鏡像異構物相同分析方法)。 The mirror image isomer was washed slowly (Example 168): Yield = 81 mg. White solid. Mass spectrometer: m/z: [M+H] + = 409.2. 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.32 (s, 2 H), 8.68 (d, 1H, J = 4.3 Hz), 8.63 (s, 1H), 8.06 (d, 1H, J = 7.9 Hz), 7.95-7.88 (m, 2H), 7.39-7.35 (m, 2H), 5.09 (t, 1H, J = 4.8 Hz), 4.90 ( d, 2H, J = 6.2 Hz), 4.79 (d, 2H, J = 6.2 Hz), 4.65 (s, 2H), 3.86-3.81 (m, 1H), 3.70-3.66 (m, 1H), 3.01-2.95 (m, 1H), 2.90-2.86 (m, 1H). Palm HPLC: R t = 19.18 min (identical analysis with other smectomers).

實施例169：2-((1-(5-(吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)磺醯基)乙醇 Example 169: 2-((1-(5-(Pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)sulfonyl Ethanol

由6-((2-((叔丁基二苯基矽)氧基)乙基)硫)-1-(5-(吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]經二步驟獲得，其包括以MMPP氧化(實施例57)及去掉一保護基(製程116b)。產量：0.09g。HPLC(方法3)：Rt=2.63min,m/z：[M+H]+=425.1(MW calc.424.47)。1H NMR(400MHz,DMSO-d6,δ ppm)：9.35(s,2 H),8.83(d,1H,J=1.3Hz),8.68(d,1H,J=4.4Hz),8.09(d,1H,J=8Hz),8.01(d,1H,J=7.8Hz),7.91(t,1H,J=7.7Hz),7.66-7.63(m,1H),7.39-7.36(m,1H),4.90(t,3H,J=5.5Hz),4.79(d,2H,J=6.2Hz),4.67(s,2H),3.74-3.69(m,2H),3.45(t,2H,J=6.4Hz)。 From 6-((2-((tert-butyldiphenyl)oxy)ethyl)sulfan)-1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin- 3,3'-oxocyclobutane] was obtained in two steps, including oxidation with MMPP (Example 57) and removal of a protecting group (Process 116b). Yield: 0.09 g. HPLC (Method 3): rt = 2.63 min, m/z: [M+H] + = 425.1 (MW calc. 424.47). 1H NMR (400MHz, DMSO-d6, δ ppm): 9.35 (s, 2 H), 8.83 (d, 1H, J = 1.3 Hz), 8.68 (d, 1H, J = 4.4 Hz), 8.09 (d, 1H) , J = 8 Hz), 8.01 (d, 1H, J = 7.8 Hz), 7.91 (t, 1H, J = 7.7 Hz), 7.66 - 7.63 (m, 1H), 7.39 - 7.36 (m, 1H), 4.90 ( t, 3H, J = 5.5 Hz), 4.79 (d, 2H, J = 6.2 Hz), 4.67 (s, 2H), 3.74 - 3.69 (m, 2H), 3.45 (t, 2H, J = 6.4 Hz).

實施例170：2-(2-(2-(6-(乙亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5- 基)吡啶-4-基)丙-2-胺 Example 170: 2-(2-(2-(6-(ethylsulfinyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidine-5- Pyridin-4-yl)propan-2-amine

經二步驟由化合物52h及2-(2-溴吡啶-4-基)丙-2-胺以類似合成實施例56方式製備。褐色固體。產量：40mg。HPLC(方法2)：Rt=1.33min,m/z：[M+H]+=450.1(MW calc.449.57)。1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：9.31(s,2H),8.64(s,1H),8.57(d,1H,J=3.9Hz),8.10(s,1H),7.93(d,1H,J=7.4Hz),7.47(s,1H),7.37(d,1H,J=8Hz),4.91-4.80(m,4H),4.67(s,2H),2.82-2.77(m,1H),2.82(m,1H，與DMSO-水訊號合併),1.47(s,6H),1.16(t,3H,J=7.3Hz)。 Prepared in a similar manner from compound 52h and 2-(2-bromopyridin-4-yl)propan-2-amine in a similar manner. Brown solid. Yield: 40 mg. HPLC (Method 2): rt = 1.33 min, m/z: [M+H] + = 450.1 (MW calc. 449.57). 1H NMR (400MHz, DMSO-d6, 100°C, δ ppm): 9.31 (s, 2H), 8.64 (s, 1H), 8.57 (d, 1H, J = 3.9 Hz), 8.10 (s, 1H), 7.93 (d, 1H, J = 7.4 Hz), 7.47 (s, 1H), 7.37 (d, 1H, J = 8 Hz), 4.91-4.80 (m, 4H), 4.67 (s, 2H), 2.82 - 2.77 (m , 1H), 2.82 (m, 1H, combined with DMSO-water signal), 1.47 (s, 6H), 1.16 (t, 3H, J = 7.3 Hz).

實施例171：2-(2-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-4-基)丙-2-胺 Example 171: 2-(2-(2-(6-(ethylsulfonyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)pyridine- 4-yl)propan-2-amine

MMPP氧化對應之硫醚(實施例170)。白色固體。產量：60mg。HPLC(方法3)：Rt=2.55min,m/z：[M+H]+=466.1(MW calc.465.57)。1H NMR(400 MHz,DMSO-d6,δ ppm)：9.38(s,2H),8.84(d,1H,J=1.4Hz),8.57(d,1H,J=5.2Hz),8.18(s,1H),8.03(d,1H,J=7.8Hz),7.64-7.61(m,1H),7.50-7.48(m,1H),4.92(d,2H,J=6.2Hz),4.80(d,2H,J=6.2Hz),4.67(s,2H),3.31-3.26(m,2H),2.27(bs,2H),1.41(s,6H),1.17(t,3H,J=7.3Hz)。 MMPP oxidizes the corresponding thioether (Example 170). White solid. Yield: 60 mg. HPLC (Method 3): rt = 2.55 min, m/z: [M+H] + = 466.1 (MW calc.465.57). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.38 (s, 2H), 8.84 (d, 1H, J = 1.4 Hz), 8.57 (d, 1H, J = 5.2 Hz), 8.18 (s, 1H) ), 8.03 (d, 1H, J = 7.8 Hz), 7.64 - 7.61 (m, 1H), 7.50 - 7.48 (m, 1H), 4.92 (d, 2H, J = 6.2 Hz), 4.80 (d, 2H, J = 6.2 Hz), 4.67 (s, 2H), 3.31-3.26 (m, 2H), 2.27 (bs, 2H), 1.41 (s, 6H), 1.17 (t, 3H, J = 7.3 Hz).

實施例172：2-(2-(6-(乙亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)異菸鹼醯胺 Example 172: 2-(2-(6-(ethylsulfinyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)isonicotinine hydrazine amine

由化合物52h及2-溴異菸鹼醯胺以類似合成實施例56方式製備。白色固體。產量：0.10g。HPLC(方法2)：Rt=1.46min,m/z：[M+H]+=436.2(MW calc.435.50)。1H NMR(400MHz,DMSO-d6,δ ppm)：9.35(s,2H),8.80(d,1H,J=5Hz),8.63(s,1H),8.40(s,1H),8.27(s,1H),7.94(d,1H,J=7.7Hz),7.81(s,1H),7.73(d,1H,J=4.9Hz),7.37(t,1H,J=7.7Hz),4.90(d,2H,J=6.1Hz),4.80(d,2H,J=6Hz),4.66(s,2H),3.06-2.97(m,1H),2.82-2.73(m,1H),1.10(t,3H,J=7.2Hz)。 Compound 52h and 2-bromoisonicotinamine were prepared in a similar manner as in Synthesis Example 56. White solid. Yield: 0.10 g. HPLC (Method 2): rt = 1.46 min, m/z: [M+H] + = 436.2 (MW calc. 435.50). 1H NMR (400MHz, DMSO-d6, δ ppm): 9.35 (s, 2H), 8.80 (d, 1H, J = 5Hz), 8.63 (s, 1H), 8.40 (s, 1H), 8.27 (s, 1H) ), 7.94 (d, 1H, J = 7.7 Hz), 7.81 (s, 1H), 7.73 (d, 1H, J = 4.9 Hz), 7.37 (t, 1H, J = 7.7 Hz), 4.90 (d, 2H) , J = 6.1 Hz), 4.80 (d, 2H, J = 6 Hz), 4.66 (s, 2H), 3.06 - 2.97 (m, 1H), 2.82 - 2.73 (m, 1H), 1.10 (t, 3H, J =7.2Hz).

實施例173：2-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)異 菸鹼醯胺 Example 173: 2-(2-(6-(ethylsulfonyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl) Nicotinamide

mCPBA氧化對應之硫醚。白色固體。產量：0.15g。HPLC(方法2)：Rt=1.47min,m/z：[M+H]+=452.2(MW calc.451.50)。1H NMR(400MHz,DMSO-d6,δ ppm)：9.38(s,2H),8.84-8.79(m,2H),8.43(s,1H),8.27(s,1H),8.03(d,1H,J=7.8Hz),7.81(s,1H),7.73(t,1H,J=0.7Hz),7.65-7.62(m,1H),4.92(d,2H,J=6.2Hz),4.80(d,2H,J=6.2Hz),4.68(s,2H),3.31-3.26(m,2H),1.17(t,3H,J=7.2Hz)。 mCPBA oxidizes the corresponding thioether. White solid. Yield: 0.15 g. HPLC (Method 2): rt = 1.47 min, m/z: [M+H] + = 452.2 (MW calc. 451.50). 1H NMR (400MHz, DMSO-d6, δ ppm): 9.38 (s, 2H), 8.84 - 8.79 (m, 2H), 8.43 (s, 1H), 8.27 (s, 1H), 8.03 (d, 1H, J) = 7.8 Hz), 7.81 (s, 1H), 7.73 (t, 1H, J = 0.7 Hz), 7.65 - 7.62 (m, 1H), 4.92 (d, 2H, J = 6.2 Hz), 4.80 (d, 2H) , J = 6.2 Hz), 4.68 (s, 2H), 3.31-3.26 (m, 2H), 1.17 (t, 3H, J = 7.2 Hz).

實施例174及175係由1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-羧酸甲酯以類似於合成實施例22方式製備。 Examples 174 and 175 are based on 1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-carboxylic acid The methyl ester was prepared in a similar manner to the synthesis of Example 22.

實施例174：2-(2-(6-(嗎啉-4-羰基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)異菸鹼醯胺 Example 174: 2-(2-(6-(morpholine-4-carbonyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)isonicotin Guanamine

白色固體。產量：40mg。HPLC(方法3)：Rt=2.38min,m/z：[M+H]+=473.2(MW calc.472.50)。1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：9.33(s,2H),8.80(d,1H,J=5Hz),8.42(s,1H),8.37(s,1H),8.28(s,1H),7.83(t,2H,J=3.5Hz),7.73(t,1H,J=0.8Hz),7.17(t,1H,J=7.6Hz),4.90(d,2H,J=6.1Hz),4.79(d,2H,J=6.1Hz),4.63(s,2H),3.63-3.41(m,8H)。 White solid. Yield: 40 mg. HPLC (Method 3): rt = 2.38 min, m/z: [M+H] + = 473.2 (MW calc. 472.50). 1H NMR (400MHz, DMSO-d6, 100 ° C, δ ppm): 9.33 (s, 2H), 8.80 (d, 1H, J = 5 Hz), 8.42 (s, 1H), 8.37 (s, 1H), 8.28 ( s, 1H), 7.83 (t, 2H, J = 3.5 Hz), 7.73 (t, 1H, J = 0.8 Hz), 7.17 (t, 1H, J = 7.6 Hz), 4.90 (d, 2H, J = 6.1) Hz), 4.79 (d, 2H, J = 6.1 Hz), 4.63 (s, 2H), 3.63 - 3.41 (m, 8H).

實施例175：1-(5-(4-胺甲醯基吡啶-2-基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 175: 1-(5-(4-Aminomethylpyridin-2-yl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3 , 3'-oxocyclobutane]-6-formamide

白色固體。產量：30mg。HPLC(方法2)：Rt=1.40min,m/z：[M+H]+=461.1(MW calc.460.49)。1H NMR(400MHz,DMSO-d6,δ ppm)：9.32(s,2H),8.80(d,1H,J=4.9Hz),8.40-8.36(m,2H),8.27(s,1H),7.80(bs,2H),7.72(d,1H,J=4.6Hz),7.15(d,1H,J=7.6Hz),4.90(d,2HJ=6Hz),4.80(d,3H,J=6Hz),4.64(s,2H),3.64-3.31(m,4H),3.01(s,3H)。 White solid. Yield: 30 mg. HPLC (Method 2): rt = 1.40 min, m/z: [M+H] + = 461.1 (MW calc. 460.49). 1H NMR (400MHz, DMSO-d6, δ ppm): 9.32 (s, 2H), 8.80 (d, 1H, J = 4.9 Hz), 8.40-8.36 (m, 2H), 8.27 (s, 1H), 7.80 ( Bs, 2H), 7.72 (d, 1H, J = 4.6 Hz), 7.15 (d, 1H, J = 7.6 Hz), 4.90 (d, 2HJ = 6 Hz), 4.80 (d, 3H, J = 6 Hz), 4.64 (s, 2H), 3.64 - 3.31 (m, 4H), 3.01 (s, 3H).

實施例176：2-(2-(6-(嗎啉-4-羰基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)異菸鹼甲腈 Example 176: 2-(2-(6-(morpholine-4-carbonyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)isonicotin Nitrile

由中間物8b以類似於製程8c方式合成。白色固體。產量：40mg。HPLC(方法2)：Rt=1.62min,m/z：[M+H]+=455.3(MW calc.454.48)。1H NMR(400MHz,DMSO-d6,δ ppm)：9.35(s,2H),8.91(d,1H,J=4.7Hz),8.54(s,1H),8.41(s,1H),7.83-7.81(m,2H),7.18(d,1H,J=7.3Hz),4.89(d,2H,J=5.7Hz),4.79(d,2H,J=5.8Hz),4.63(s,2H),3.63-3.38(m,8H)。 It is synthesized by the intermediate 8b in a manner similar to the process 8c. White solid. Yield: 40 mg. HPLC (Method 2): rt = 1.62 min, m/z: [M+H] + = 455.3 (MW calc.454.48). 1H NMR (400MHz, DMSO-d6, δ ppm): 9.35 (s, 2H), 8.91 (d, 1H, J = 4.7 Hz), 8.54 (s, 1H), 8.41 (s, 1H), 7.83-7.81 ( m, 2H), 7.18 (d, 1H, J = 7.3 Hz), 4.89 (d, 2H, J = 5.7 Hz), 4.79 (d, 2H, J = 5.8 Hz), 4.63 (s, 2H), 3.63 3.38 (m, 8H).

實施例177：1-(5-(4-氰基吡啶-2-基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 Example 177: 1-(5-(4-Cyanopyridin-2-yl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3 '-oxycyclobutane]-6-formamide

由1-(5-溴嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺以類似於製程8c製備。白色固體。產量：45mg。HPLC(方法3)：Rt=2.66min,m/z：[M+H]+=443.2(MW calc.442.47)。1H NMR(400MHz,DMSO-d6,δ ppm)：9.33(s,2H),8.90(d,1H,J=4.8Hz),8.51(s,1H),8.38(s,1H),7.81-7.80(m,2H),7.16(d,1H,J=7.5Hz),4.89(d,2H,J=6Hz),4.79(d,2H, J=6Hz),4.63(s,2H),3.65-3.53(m,4H，一部分與DMSO-水訊號合併),3.01(s,3H)。 From 1-(5-bromopyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane]-6-carboxamide Prepared in a manner similar to Process 8c. White solid. Yield: 45 mg. HPLC (Method 3): rt = 2.66 min, m/z: [M+H] + = 443.2 (MW calc. 442.47). 1H NMR (400MHz, DMSO-d6, δ ppm): 9.33 (s, 2H), 8.90 (d, 1H, J = 4.8 Hz), 8.51 (s, 1H), 8.38 (s, 1H), 7.81-7.80 ( m, 2H), 7.16 (d, 1H, J = 7.5 Hz), 4.89 (d, 2H, J = 6 Hz), 4.79 (d, 2H, J = 6 Hz), 4.63 (s, 2H), 3.65-3.53 ( m, 4H, part combined with DMSO-water signal), 3.01 (s, 3H).

實施例178：N-(2-羥乙基)-N-甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)-2',3',5',6'-四氫螺[吲哚啉-3,4'-哌喃]-6-甲醯胺 Example 178: N-(2-hydroxyethyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-2',3',5' ,6'-tetrahydrospiro[porphyrin-3,4'-pyrano]-6-carboxamide

178a)6-溴-2',3',5',6'-四氫螺[吲哚啉-3,4'-哌喃]-2-酮 178a) 6-Bromo-2',3',5',6'-tetrahydrospiro[porphyrin-3,4'-pyranyl]-2-one

n-BuLi(2M己烷溶液，22.6mL,45.27mmol)係於-40℃逐滴加入至THF(60mL)中之6-溴吲哚啉-2-酮(3g,14.14mmol)及二異丙基胺(6.3mL,45.27mmol)溶液。該混合物係於-40℃經攪拌45min，1-溴-2-(2-溴乙氧基)乙烷係於此溫度被逐滴加入且於rt持續攪拌16h。該反應混合物係經以4N氯化氫溶液(40mL)淬滅且該水相係被分離及以EtOAc(3x 60mL)萃取。該合併之有機層係經以鹽水(50mL)清洗、經Na2SO4乾燥及濃縮。該原產物係經以己烷(20mL)研磨及過濾。該過濾器係經以己烷/EtOAc=4：1(100mL)清洗以提供淺褐色固體之目標化合物。產量：1.2g(31%)。HPLC(方法1)：Rt=2.94min,m/z[M+H]+=282.1(MW calc.282.13)。 n-BuLi (2M in hexanes, 22.6 mL, 45.27 mmol) was added dropwise to - 6-bromoindolin-2-one (3 g, 14.14 mmol) and diisopropyl in THF (60 mL) at -40 °C. A solution of the base amine (6.3 mL, 45.27 mmol). The mixture was stirred at -40 ° C for 45 min, 1-bromo-2-(2-bromoethoxy)ethane was added dropwise at this temperature and stirring was continued at rt for 16 h. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. The combined organic layers of the system was washed with brine (50mL) wash, dried over Na 2 SO 4 dried and concentrated. The original product was triturated with hexane (20 mL) and filtered. The filter was washed with hexane / EtOAc = 4:1 (100 mL) to afford title compound. Yield: 1.2 g (31%). HPLC (Method 1): rt = 2.94 min, m/z [M+H] + = 282.1 (MW calc. 282.13).

178b)6-溴-2',3',5',6'-四氫螺[吲哚啉-3,4'-哌喃] 178b) 6-Bromo-2',3',5',6'-tetrahydrospiro[porphyrin-3,4'-pyran]

LiAlH4(0.54g,14.18mmol)係於0℃分批加入至THF(500mL)中之178a (1.6g,5.67mmol)溶液。該反應混合物係於80℃經加熱4h、降溫然後隨後依序以水(0.54mL)、20% NaOH溶液(0.54mL)及水(1.08mL)淬滅及於RT攪拌1h。該混合物係經矽藻土栓過濾且該過濾器係經以DCM/MeOH=4：1(3x 50mL)淋洗。該濾液係經蒸發且該剩餘物係經以快速管柱層析法[矽膠；己烷/EtOAc 4：1]純化。淺黃色固體. 產量：1.1g(73%)。HPLC(方法1)：Rt=3.27min,m/z[M+H]+=270.2(MW calc.268.15)。 LiAlH 4 (0.54g, 14.18mmol) at 0 ℃ based portionwise added to a THF (500mL) in the 178a (1.6g, 5.67mmol) was added. The reaction mixture was heated at 80 ° C for 4 h, cooled and then quenched sequentially with water (0.54 mL), 20% NaOH solution (0.54 mL) and water (1.08 mL) and stirred at RT for 1 h. The mixture was filtered through a pad of Celite and the filter was rinsed with DCM / MeOH = 4:1 (3 x 50 mL). The filtrate was evaporated and the residue was purified by flash column chromatography [EtOAc] Light yellow solid. Yield: 1.1 g (73%). HPLC (Method 1): rt = 3.27 min, m/z [M+H] + = 270.2 (MW calc. 268.15).

178c)2',3',5',6'-四氫螺[吲哚啉-3,4'-哌喃]-6-羧酸甲酯 178c) 2',3',5',6'-tetrahydrospiro[porphyrin-3,4'-piperane-6-carboxylic acid methyl ester

MeOH(25mL)及DMF(15mL)中之化合物178b(0.82g,3.06mmol)及TEA(0.93mL,6.73mmol)係在鈍氣氣氛下被置於高壓釜中。PdCl2(dppf)(0.22g,0.305mmol)係被加入且該高壓釜係以一氧化碳氣體被加壓至250psi。該混合物係於100℃經攪拌16h、降溫且經矽藻土栓過濾。該過濾器係經以MeOH淋洗且該濾液係被濃縮然後以EtOAc稀釋。該有機相係經以水及鹽水清洗、乾燥及蒸發。快速管柱層析法(矽石；己烷/EtOAc=7：3]該剩餘物提供淺黃色固體之產物。產量：0.5g(66%)。HPLC(方法5)：Rt=1.44min,m/z[M+H]+=248.08(MW calc.247.29)。 Compound 178b (0.82 g, 3.06 mmol) and TEA (0.93 mL, 6.73 mmol) in MeOH (25 mL) and DMF (15 mL) were placed in an autoclave under a dry atmosphere. PdCl 2 (dppf) (0.22 g, 0.305 mmol) was added and the autoclave was pressurized to 250 psi with carbon monoxide gas. The mixture was stirred at 100 ° C for 16 h, cooled and filtered through a plug of diatomaceous earth. The filter was rinsed with MeOH and the filtrate was concentrated then diluted with EtOAc. The organic phase is washed, dried and evaporated with water and brine. Flash column chromatography (Silica; Hexane / EtOAc = 7: 3] of the residue provides the product as a pale yellow solid Yield: 0.5g (66%) HPLC (method 5): R t = 1.44min, .. m/z [M+H] + = 248.08 (MW calc. 247.29).

178d)1-(5-溴嘧啶-2-基)-2',3',5',6'-四氫螺[吲哚啉-3,4'-哌喃]-6-羧酸甲酯 178d) methyl 1-(5-bromopyrimidin-2-yl)-2',3',5',6'-tetrahydrospiro[porphyrin-3,4'-pyrano]-6-carboxylate

正丁醇(10mL)中之化合物178c(0.4g,1.62mmol)、5-溴-2-氯-嘧啶(0.62g,3.24mmol)及DIPEA(1.4mL,8.09mmol)係於140℃經攪拌20h。該反應混合物係被降溫且以冰稀釋。該沉澱物係被濾出、以二乙基醚(50mL)清洗然後以快速管柱層析法[矽膠；己烷/EtOAc=4：1]純化。淺黃色固體。產量：0.44g(67%)。HPLC(方法1)：Rt=3.74min,m/z[M+H]+=404.0(MW calc.404.26)。 Compound 178c (0.4 g, 1.62 mmol), 5-bromo-2-chloro-pyrimidine (0.62 g, 3.24 mmol) and DIPEA (1.4 mL, 8.09 mmol) in n-butanol (10 mL) were stirred at 140 ° C for 20 h . The reaction mixture was cooled and diluted with ice. The precipitate was filtered, washed with diethyl ether (50 mL) and then purified with EtOAc EtOAc. Light yellow solid. Yield: 0.44 g (67%). HPLC (Method 1): rt = 3.74 min, m/z [M+H] + = 404.0 (MW calc. 404.26).

中間物178d係與2-溴-4-甲基吡啶反應然後進一步被轉換成合成實施例178，其係以類似於實施例2之規程。淺黃色固體。產量：85mg。HPLC(方法1)：Rt=2.81min,m/z：[M+H]+=460.2(MW calc.459.54)。1H NMR(400MHz,DMSO-d6,100℃,δ ppm)：9.23(s,2H),8.52(d,1H,J=4.8Hz),8.43(s,1H),7.78(s,1H),7.36(d,1H,J=7.4Hz),7.17(d,1H,J=4.5Hz),7.04(d,1H,J=7.6Hz),4.41(bs,1H),4.31(s,2H),3.94-3.92(m,2H),3.65-3.59(m,4H),3.46(bs,2H),3.02(s,3H),2.40(s,3H),2.03-1.97(m,2H),1.67-1.63(m,2H)。 Intermediate 178d was reacted with 2-bromo-4-methylpyridine and then further converted to Synthesis Example 178 in a similar manner to the procedure of Example 2. Light yellow solid. Yield: 85 mg. HPLC (Method 1): rt = 2. <RTI ID=0.0></RTI></RTI><RTIgt; 1H NMR (400MHz, DMSO-d6, 100°C, δ ppm): 9.23 (s, 2H), 8.52 (d, 1H, J = 4.8 Hz), 8.43 (s, 1H), 7.78 (s, 1H), 7.36 (d, 1H, J = 7.4 Hz), 7.17 (d, 1H, J = 4.5 Hz), 7.04 (d, 1H, J = 7.6 Hz), 4.41 (bs, 1H), 4.31 (s, 2H), 3.94 -3.92 (m, 2H), 3.65-3.59 (m, 4H), 3.46 (bs, 2H), 3.02 (s, 3H), 2.40 (s, 3H), 2.03-1.97 (m, 2H), 1.67-1.63 (m, 2H).

實施例179：2-(4-氟-3-(2-(6-(1-(甲基胺)環丙基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)苯基)丙-2-醇 Example 179: 2-(4-Fluoro-3-(2-(6-(1-(methylamine))cyclopropyl)spiro[porphyrin-3,3'-oxocyclobutane]-1- Pyrimidin-5-yl)phenyl)propan-2-ol

179a)1'-叔丁基6'-甲基2,2-二甲基螺[[1,3]二噁烷-5,3'-吲哚啉]-1',6'-二羧酸酯 179a) 1'-tert-Butyl 6'-methyl 2,2-dimethylspiro[[1,3]dioxane-5,3'-carboline]-1',6'-dicarboxylic acid ester

無水THF(10ml)中之Int-1c(500mg,1.81mmol)、二-叔丁基重碳酸鹽(669mg,3.07mmol)及TEA(0.8ml,5.42mmol)溶液係於rt經攪拌16h。該反應混合物係被濃縮且該剩餘物係經以快速管柱層析法[矽石，EtOAc/己烷=1：9]純化之後以己烷研磨。白色固體。產量：500mg(73%)。HPLC(方法1)：Rt=3.42min,m/z：[M+H]+=378.4(MW calc.377.43)。 A solution of Int-1c (500 mg, 1.81 mmol), di-tert-butyl bicarbonate (669 mg, 3.07 mmol) and TEA (0.8 mL, 5.42 mmol) in dry THF (10 mL) was stirred at rt for 16 h. The reaction mixture was concentrated and the residue was purified by flash column chromatography [EtOAc, EtOAc/hexane = 1:1]. White solid. Yield: 500 mg (73%). HPLC (Method 1): rt = 3.42 min, m/z: [M+H] + = 378.4 (MW calc.377.43).

179b)叔丁基6'-(1-羥環丙基)-2,2-二甲基螺[[1,3]二噁烷-5,3'-吲哚啉]-1'-羧酸酯 179b) tert-butyl 6'-(1-hydroxycyclopropyl)-2,2-dimethylspiro[[1,3]dioxane-5,3'-carboline]-1'-carboxylic acid ester

乙基溴化鎂(Ethyl magnesium bromide)(1.06ml,3.183mmol)係於-78℃被緩慢加至二乙基醚(10ml)中之Ti(Oi-Pr)4(0.5ml,1.59mmol)攪拌溶液且於此溫度持續攪拌1h。溶於二乙基醚(5ml)之179a(300mg,0.795mmol)係被緩慢加入且該反應混合物係被溫熱至RT及攪拌1h。該混合物係被降溫至0℃、以飽和NH4Cl溶液淬滅、攪拌10min及以EtOAc(3x 50ml)萃取。該合併之有機層係經以鹽水(40ml)清洗、經Na2SO4乾燥及濃縮。該剩留物係經以管柱層析法[230-400目矽膠，EtOAc/己烷=1：4]純化。白色固體。產量：173mg(58%)。 Ethyl magnesium bromide (1.06 ml, 3.183 mmol) was slowly added to a solution of Ti(Oi-Pr) 4 (0.5 ml, 1.59 mmol) in diethyl ether (10 ml) at -78 °C. The solution was stirred at this temperature for 1 h. 179a (300 mg, 0.795 mmol) dissolved in diethyl ether (5 ml) was slowly added and the reaction mixture was warmed to RT and stirred for 1 h. The mixture was cooled to 0 deg.] C is based, with saturated NH 4 Cl solution was quenched and stirred for 10min to EtOAc (3x 50ml) and extracted. The combined organic layers of the system was washed with brine (40ml) washed, dried over Na 2 SO 4 dried and concentrated. The residue was purified by column chromatography [230-400 mesh EtOAc, EtOAc/hexanes 1:1]. White solid. Yield: 173 mg (58%).

179c)叔丁基6'-(1-(1,3-二側氧異吲哚啉-2-基)環丙基)-2,2-二甲基螺[[1,3]二噁烷-5,3'-吲哚啉]-1'-羧酸酯 179c) tert-butyl 6'-(1-(1,3-dioxaisoxiloxalin-2-yl)cyclopropyl)-2,2-dimethylspiro[[1,3]dioxane -5,3'-porphyrin]-1'-carboxylate

THF中之化合物179b(22g,58.67mmol)、三苯基膦(16.9g,64.53mmol)、鄰苯二甲醯亞胺(9.48g,64.53mmol)及二乙基偶氮二羧酸酯(11.3g64.53mmol)係於80℃在鈍氣氣氛下經攪拌16h。該反應混合物係經以EtOAc(1000ml)稀釋、以水(500ml)及鹽水(500ml)清洗、經Na2SO4乾燥及濃縮。該剩餘物係經以管柱層析法[240-400目矽膠，EtOAc/己烷=15：85]純化。白色固體。產量：17.1g(58%)。HPLC(方法1)：Rt=3.92min,m/z：[M+H]+=378.4(MW calc.377.43)。 Compound 179b (22 g, 58.67 mmol), triphenylphosphine (16.9 g, 64.53 mmol), phthalimide (9.48 g, 64.53 mmol) and diethyl azodicarboxylate (11.3) in THF G64.53 mmol) was stirred at 80 ° C for 16 h under a dry atmosphere. The reaction mixture was diluted with lines in EtOAc (1000ml), water (500ml) and brine (500ml) washed, dried over Na 2 SO 4 dried and concentrated. The residue was purified by column chromatography [240-400 EtOAc, EtOAc/hexane = 15:85]. White solid. Yield: 17.1 g (58%). HPLC (Method 1): rt = 3.92 min, m/z: [M+H] + = 378.4 (MW calc.377.43).

179d)叔丁基6'-(1-氨基環丙基)-2,2-二甲基螺[[1,3]二噁烷-5,3'-吲哚啉]-1'-羧酸酯 179d) tert-butyl 6'-(1-aminocyclopropyl)-2,2-dimethylspiro[[1,3]dioxane-5,3'-carboline]-1'-carboxylic acid ester

乙醇(20ml)中之化合物179c(1g,1.984mmol)及水合肼(1ml)係於60℃ 經攪拌2h。該反應混合物係被濃縮且該剩留物係經以管柱層析法[240-400目矽膠，DCM與2% MeOH]純化。產量：500mg(67%)。HPLC(方法1)：Rt=3.20min,m/z：[M+H]+=375.0(MW calc.374.47)。 Compound 179c (1 g, 1.984 mmol) and hydrazine hydrate (1 ml) in ethanol (20 ml) were stirred at 60 ° C for 2 h. The reaction mixture was concentrated and the residue was purified by column chromatography [240-400 EtOAc, DCM with 2% MeOH]. Yield: 500 mg (67%). HPLC (Method 1): rt = 3.20 min, m/z: [M+H] + = 375.0 (MW calc. 374.47).

179e)叔丁基6'-(1-(((苄氧基)羰基)氨基)環丙基)-2,2-二甲基螺[[1,3]二噁烷-5,3'-吲哚啉]-1'-羧酸酯 179e) tert-butyl 6'-(1-(((benzyloxy)carbonyl)amino)cyclopropyl)-2,2-dimethylspiro[[1,3]dioxane-5,3'- Porphyrin]-1'-carboxylate

THF(110ml)中之化合物179d(10g,33.3mmol)係被降溫至0℃，DIPEA(18ml,99.9mmol)及氯甲酸苯酯(7.1ml,49.99mmol)係被加入且該混合物係於RT經攪拌16h。該反應混合物係經以EtOAc(500ml)稀釋，以飽和NaHCO3溶液(200ml)、水(200ml)及鹽水(200ml)清洗，經Na2SO4乾燥及濃縮。該原產物係經以管柱層析法[100-200目矽膠，EtOAc/己烷=1：3]純化。白色固體。產量：5.3g(31%)。HPLC(方法1)：Rt=3.72min,m/z：[M+H]+=509.4(MW calc.508.61)。 The compound 179d (10 g, 33.3 mmol) in THF (110 ml) was cooled to 0 ° C, DIPEA (18 ml, 99.9 mmol) and phenyl chloroformate (7.1 ml, 49.99 mmol) were added and the mixture was applied to RT Stir for 16 h. The reaction mixture line (500ml) was diluted with EtOAc, saturated NaHCO 3 solution (200ml), water (200ml) and brine (200ml) washed, dried over Na 2 SO 4 dried and concentrated. The original product was purified by column chromatography [100-200 EtOAc, EtOAc/hexanes: 1:1]. White solid. Yield: 5.3 g (31%). HPLC (Method 1): rt = 3.72 min, m/z: [M+H] + = 509.4 (MW calc. 508.61).

179f)叔丁基6'-(1-(((苄氧基)羰基)氨基)環丙基)-2,2-二甲基螺[[1,3]二噁烷-5,3'-吲哚啉]-1'-羧酸酯 179f) tert-butyl 6'-(1-(((benzyloxy)carbonyl)amino)cyclopropyl)-2,2-dimethylspiro[[1,3]dioxane-5,3'- Porphyrin]-1'-carboxylate

NaHe(50%,751mg,15.64mmol)係於0℃被分批加入DMF(50ml)中之化合物179e(5.3g,10.43mmol)攪拌溶液。持續攪拌20min，甲基碘(2.0ml,31.28mmol)係被加入且該混合物係經進一步攪拌2h。該反應混合物係經以冰淬滅及以EtOAc(3x 200ml)萃取。該合併之有機層係經以水(3x 200ml)及鹽水(250ml)清洗、經Na2SO4乾燥及濃縮。該原產物係經以管柱層析法[100-200目矽膠，EtOAc/己烷=1：4]純化。白色固體。產量：5.31g(97%)。HPLC(方法1)：Rt=4.55min.,m/z：[M+H]+=523.6(MW calc.522.63)。 NaHe (50%, 751 mg, 15.64 mmol) was added to a stirred solution of compound 179e (5.3 g, 10.43 mmol) in DMF (50 ml). Stirring was continued for 20 min, methyl iodide (2.0 ml, 31.28 mmol) was added and the mixture was further stirred for 2 h. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. The combined organic layers of the system was water (3x 200ml) and brine (250ml) washed, dried over Na 2 SO 4 dried and concentrated. The original product was purified by column chromatography [100-200 mesh EtOAc, EtOAc/hexanes: 1:1]. White solid. Yield: 5.31 g (97%). HPLC (Method 1): rt = 4.55 min., m/z: [M+H] + = 523.6 (MW calc. 522.63).

179g)叔丁基6-(1-(((苄氧基)羰基)(甲基)氨基)環丙基)-3,3-雙(羥甲基)吲哚啉-1-羧酸酯 179 g) tert-butyl 6-(1-(((benzyl))carbonyl)(methyl)amino)cyclopropyl)-3,3-bis(hydroxymethyl)porphyrin-1-carboxylate

THF(50ml)中之化合物179f(5.9g,11.302mmol)係於rt在有2N氯化氫溶液(12ml)存在下經攪拌2h。該反應混合物係被濃縮、經以飽和NaHCO3溶液鹼化及以EtOAc(10x 50ml)萃取。該合併之有機層係經Na2SO4乾燥及蒸發。淺褐色固體。產量：5.1g(94%)。HPLC(方法1)：Rt=3.26min,m/z：[M+H]+=483.2(MW calc.482.57)。 Compound 179f (5.9 g, 11.302 mmol) in EtOAc (EtOAc m. The reaction mixture system was concentrated, extracted with saturated NaHCO 3 solution and basified to EtOAc (10x 50ml). The combined organic layers were dried over Na 2 SO 4 and evaporated. Light brown solid. Yield: 5.1 g (94%). HPLC (Method 1): rt = 3.26 min, m/z: [M+H] + = 483.2 (MW calc.482.57).

179h)叔丁基6-(1-(((苄氧基)羰基)(甲基)氨基)環丙基)-3-(羥甲基)-3-((甲苯磺醯氧基)甲基)吲哚啉-1-羧酸酯 179h) tert-Butyl 6-(1-(((benzyl))carbonyl))(methyl)amino)cyclopropyl)-3-(hydroxymethyl)-3-((toluenesulfonyloxy)methyl Porphyrin-1-carboxylate

LiHMDS(10.3mL,10.37mmol)係於-78℃經30min期間逐滴加入無水THF(100ml)中之化合物179i(5.0g,10.37mmol)溶液。該反應混合物係於此溫度經攪拌30min之後加入無水THF(50ml)中之甲苯磺醯基氯(1.98g,10.37mmol)。於-78℃攪拌另外2h後，該反應混合物係經以飽和NH4Cl溶液(100ml)淬滅及以EtOAc(3x 100ml)萃取。該合併之有機層係經Na2SO4乾燥及濃縮。該剩留物係經以快速管柱層析法[230-400目矽石，己烷與15-40% EtOAc]純化。白色固體。產量：3.6g(55%)。HPLC(方法1)：Rt=2.17min,m/z：[M+18]+=654.3(MW calc.636.76)。 LiHMDS (10.3 mL, 10.37 mmol) was added dropwise a solution of compound 179i (5.0 g, 10.37 mmol) in anhydrous THF (100 mL) over 30 min. The reaction mixture was added to toluenesulfonyl chloride (1.98 g, 10.37 mmol) in dry THF (50 mL). After an additional stirring for 2h, the reaction mixture was based with saturated NH 4 Cl solution (100ml) and quenched in a EtOAc (3x 100ml) and extracted at -78 ℃. The combined organic layers were dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography [230-400 methane, hexanes and 15-40% EtOAc]. White solid. Yield: 3.6 g (55%). HPLC (Method 1): R t = 2.17 min, m/z: [M+18] + = 654.3 (MW calc. 636.76).

179i)叔丁基6-(1-(((苄氧基)羰基)(甲基)氨基)環丙基)螺[吲哚啉-3,3'-氧環丁烷]-1-羧酸酯 179i) tert-butyl 6-(1-(((benzyl))carbonyl)(methyl)amino)cyclopropyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-carboxylic acid ester

叔丁醇(150ml)中之化合物179h(3.6g,5.65mmol)及KOH(950mg,16.96mmol)係於80℃經攪拌30min。該反應混合物係被降溫至RT且該溶劑係在減壓中被蒸餾除去。該剩餘物係經以水(50ml)稀釋及以EtOAc(3x 50ml) 萃取。該合併之有機層係經Na2SO4乾燥及濃縮。由此獲得之該原產物係經以乙醚研磨以提供白色固體之目標化合物。產量：2.2g(83%)。HPLC(方法2)：Rt=1.79min,m/z：[M+18]+=465.21(MW calc.464.55)。 Compound 179h (3.6 g, 5.65 mmol) and KOH (950 mg, 16.96 mmol) in tert-butanol (150 ml) were stirred at 80 ° C for 30 min. The reaction mixture was cooled to RT and the solvent was removed by distillation under reduced pressure. The residue was diluted with water (50 mL) andEtOAcEtOAc The combined organic layers were dried over Na 2 SO 4 and concentrated. The original product thus obtained was triturated with diethyl ether to give the title compound as a white solid. Yield: 2.2 g (83%). HPLC (Method 2): rt = 1.79 min, m/z: [M+18] + = 465.21. (MW calc. 464.55).

179j)芐基甲基(1-(螺[吲哚啉-3,3'-氧環丁烷]-6-基)環丙基)胺基甲酸酯 179j) Benzylmethyl (1-(spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)cyclopropyl)carbamate

TFA(5ml)係於0℃被加入至DCM(25ml)中之化合物179i(2.2g,4.739mmol)且該得到之混合物係於rt經攪拌3h。該揮發物係在減壓下被去除且該剩餘物係經以二乙基醚清洗。白色固體。產量：1.6g(93%)。HPLC(方法1)：Rt=3.24min,m/z：[M+H]+=365.1(MW calc.364.44)。 TFA (5 ml) was added to compound 179i (2.2 g, 4.. The volatiles were removed under reduced pressure and the residue was washed with diethyl ether. White solid. Yield: 1.6 g (93%). HPLC (Method 1): rt = 3.24 min, m/z: [M+H] + = 365.1 (MW calc. 364.44).

179k)芐基(1-(1-(5-溴嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)環丙基)(甲基)胺基甲酸酯 179k) benzyl (1-(1-(5-bromopyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)cyclopropyl)(methyl)amine Carbamate

正丁醇(20ml)中之化合物179j(1.6g,4.39mmol)、5-溴-2-氯嘧啶(1.25g,6.59mmol)及DIPEA(5.4ml,30.73mmol)係在密封管中於140℃經攪拌20h。該反應混合物係被降溫至RT且該沉澱物係經濾出及以己烷(2x 100ml)及水(100ml)清洗。淺黃色固體。產量：1.2g(52%)。HPLC(方法1)：Rt=3.91min,m/z：[M+H]+=521(MW calc.521.41)。 Compound 179j (1.6 g, 4.39 mmol), 5-bromo-2-chloropyrimidine (1.25 g, 6.59 mmol) and DIPEA (5.4 ml, 30.73 mmol) in n-butanol (20 ml) were placed in a sealed tube at 140 ° C. Stirred for 20 h. The reaction mixture was cooled to RT and the precipitate was filtered and washed with hexane (2.times.100ml) and water (100ml). Light yellow solid. Yield: 1.2 g (52%). HPLC (Method 1): rt = 3.91 min, m/z: [M+H] + = 521 (MW calc. 521.

179l)芐基甲基(1-(1-(5-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)環丙基)胺基甲酸酯 179l) benzylmethyl (1-(1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl) Spirulina [porphyrin-3,3'-oxycyclobutane]-6-yl)cyclopropyl)carbamate

乙酸鉀(56.4mg,0.575mmol)及雙(頻哪醇)二硼(97.2mg,0.384mmol)係被加入至二噁烷(10ml)中之化合物179k(100mg,0.192mmol)。PdCl2(dppf)(7.8mg,0.010mmol)係在Ar中被加入且該反應混合物係經回流16h。該揮發性部分係在減壓下被移除且該剩餘物係未經進一步純化而用於次一步驟。 產量：109mg。HPLC(方法1)：Rt=4.75min,m/z：[M+H]+=569.4(MW calc.568.47)。 Potassium acetate (56.4 mg, 0.575 mmol) and bis(pinacol) diboron (97.2 mg, 0.384 mmol) were added to compound 179k (100 mg, 0.192 mmol) in dioxane (10 ml). PdCl 2 (dppf) (7.8 mg, 0.010 mmol) was added in Ar and the reaction mixture was refluxed for 16 h. The volatile portion was removed under reduced pressure and the residue was used in the next step without further purification. Yield: 109 mg. HPLC (Method 1): rt = 4.75 min, m/z: [M+H] + = 569.4 (MW calc. 568.47).

179m)芐基(1-(1-(5-(2-氟-5-(2-羥基丙-2-基)苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)環丙基)(甲基)胺基甲酸酯 179m) benzyl (1-(1-(5-(2-fluoro-5-(2-hydroxypropan-2-yl)phenyl)pyrimidin-2-yl) snail [porphyrin-3,3'- Oxycyclobutane]-6-yl)cyclopropyl)(methyl)urethane

肆(三苯基膦)鈀(0)(11.1mg,0.010mmol)係被加入至1,4-二噁烷(20ml)中之化合物179l(109mg,0.192mmol)、2-(3-溴-4-氟苯基)丙-2-醇(66.7mg,0.288mmol)及20% K2CO3溶液(2ml)懸浮液，其被保持在鈍氣氣氛中。該反應混合物係100℃經攪拌16h，然後降溫至RT且經矽藻土栓過濾。該濾液係在減壓下被濃縮且該剩餘物係被溶於EtOAc(50ml)中及以水(2x 20ml)及鹽水(20ml)清洗。該有機相無水Na2SO4乾燥及蒸發。該原產物係經以管柱層析法[230-400目矽膠；DCM與5% MeOH]純化。白色固體。產量：109mg(95%)。HPLC(方法1)：Rt=3.71min.,m/z：[M+H]+=595.2(MW calc.594.68)。 肆(triphenylphosphine)palladium(0) (11.1 mg, 0.010 mmol) is a compound 179l (109 mg, 0.192 mmol), 2-(3-bromo-) added to 1,4-dioxane (20 ml) A suspension of 4-fluorophenyl)propan-2-ol (66.7 mg, 0.288 mmol) and 20% K 2 CO 3 solution (2 ml) was maintained in a dry atmosphere. The reaction mixture was stirred at 100 ° C for 16 h, then cooled to RT and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and the residue was taken eluted with EtOAc (EtOAc) The organic phase was dried over anhydrous Na 2 SO 4 and evaporated. The original product was purified by column chromatography [230-400 mesh gel; DCM with 5% MeOH]. White solid. Yield: 109 mg (95%). HPLC (Method 1): rt = 3.71 min., m/z: [M+H] + = 595.2 (MW calc. 594.68).

179n)2-(4-氟-3-(2-(6-(1-(甲基胺)環丙基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)苯基)丙-2-醇 179n) 2-(4-Fluoro-3-(2-(6-(1-(methylamine))cyclopropyl)spiro[porphyrin-3,3'-oxocyclobutane]-1-yl) Pyrimidin-5-yl)phenyl)propan-2-ol

乙醇中之化合物179m(200mg,0.337mmol)溶液係於rt且在有Pearlman’s催化劑(100mg)存在下在H2氣氛下經攪拌1h。該催化劑係經以過濾去除且該過濾器係經以EtOH淋洗。該濾液係被濃縮且該原產物係經以管柱層析法[230-400目矽石，DCM與2% MeOH]純化。白色固體。產量：22mg。HPLC(方法1)：Rt=2.95min,m/z：[M+H]+=461(MW calc.460.54).1H NMR(400MHz,DMSO-d6,δ ppm)：8.83(s,2H),8.33(s,2H),7.66(t,J=8.1Hz,1H),7.51(bs,1H),7.26(t,J=9.0Hz,1H),7.12(d,J=7.7Hz,1H), 4.30(s,2H),5.13(s,1H),4.85(d,J=5.2Hz,1H),4.77(d,J=5.2Hz,1H),4.56(s,1H),2.17(s,3H),1.47(s,5H),0.90-0.85(m,4H)。 Ethanol The compound 179m (200mg, 0.337mmol) and the solution was stirred at rt for 1h system has at Pearlman's catalyst (100mg) under an atmosphere via the presence of H 2. The catalyst was removed by filtration and the filter was rinsed with EtOH. The filtrate was concentrated and the original product was purified by column chromatography [230-400 m.s., DCM with 2% MeOH]. White solid. Yield: 22 mg. HPLC (Method 1): R t = 2.95 min, m/z: [M+H] + = 461 (MW calc. 460.54).1H NMR (400 MHz, DMSO-d6, δ ppm): 8.83 (s, 2H) , 8.33 (s, 2H), 7.66 (t, J = 8.1 Hz, 1H), 7.51 (bs, 1H), 7.26 (t, J = 9.0 Hz, 1H), 7.12 (d, J = 7.7 Hz, 1H) , 4.30 (s, 2H), 5.13 (s, 1H), 4.85 (d, J = 5.2 Hz, 1H), 4.77 (d, J = 5.2 Hz, 1H), 4.56 (s, 1H), 2.17 (s, 3H), 1.47 (s, 5H), 0.90-0.85 (m, 4H).

實施例180及181係類似於合成實施例179方式製備，不同之處在於規程3a係被用於鈴木反應(Suzuki reaction)。 Examples 180 and 181 were prepared analogously to Synthesis Example 179, except that Procedure 3a was used for the Suzuki reaction.

實施例180：1-(1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)-N-甲基環丙胺 Example 180: 1-(1-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)-N-A Cyclic propylamine

白色固體。產量：12mg。HPLC(方法1)：Rt=3.33min,m/z：[M+H]+=403.4(MW calc.402.46). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.84(s,2H),8.34(s,2H),7.67(d,J=7.6Hz,1H),7.50(bs,1H),7.35(d,J=8.0Hz,1H),7.15(d,J=7.7Hz,1H),4.85(d,J=6.0Hz,1H),4.77(d,J=5.7Hz,1H),4.57(s,2H),2.20(s,3H),0.95-0.88(m,4H). White solid. Yield: 12 mg. HPLC (Method 1): R t = 3.33 min, m/z: [M+H] + = 403.4 (MW calc. 402.46). 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.84 (s, 2H) , 8.34 (s, 2H), 7.67 (d, J = 7.6 Hz, 1H), 7.50 (bs, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 7.7 Hz, 1H) , 4.85 (d, J = 6.0 Hz, 1H), 4.77 (d, J = 5.7 Hz, 1H), 4.57 (s, 2H), 2.20 (s, 3H), 0.95 - 0.88 (m, 4H).

實施例181：1-(1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)-N-甲基環丙胺 Example 181:1-(1-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl )-N-methylcyclopropylamine

白色固體。產量：22mg。HPLC(方法1)：Rt=3.59min.,m/z：[M+H]+=417.6(MW calc.416.49). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.82(s,2H),8.35(s,2H),7.68(bs,1H),7.48(d,J=7.7Hz,1H),7.24(d,J=7.6Hz,1H),7.16(bs,1H),4.85(d,J=5.2Hz,2H),4.77(d,J=5.2Hz,2H),4.57(s,2H),0.98-0.91(m,4H). White solid. Yield: 22 mg. HPLC (Method 1): R t = 3.59 min., m/z: [M+H] + = 417.6 (MW calc. 416.49). 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.82 (s, 2H) ), 8.35 (s, 2H), 7.68 (bs, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 7.16 (bs, 1H), 4.85 (d) , J = 5.2 Hz, 2H), 4.77 (d, J = 5.2 Hz, 2H), 4.57 (s, 2H), 0.98 - 0.91 (m, 4H).

實施例182至184係類似於合成實施例179合成。 Examples 182 to 184 were synthesized analogously to Synthesis Example 179.

實施例182：1-(1-(5-(4-甲氧基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)-N-甲基環丙胺 Example 182: 1-(1-(5-(4-Methoxypyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl )-N-methylcyclopropylamine

白色固體。產量：30mg。HPLC(方法1)：Rt=3.01min,m/z：[M+H]+=416.2(MW calc.415.49). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.32(s,2H),8.50(s,1H),8.47(d,J=5.7Hz,2H),7.79(d,J=7.7Hz,1H),7.62(d,J=2.2Hz,1H),7.30(d,J=7.3Hz,1H),6.96-6.94(m,1H),4.87(d,J=6.2Hz,2H),4.77 (d,J=6.1Hz,2H),4.61(s,2H),3.92(s,3H),2.40(s,3H),1.39(bs,2H),1.11-1.08(m,2H) White solid. Yield: 30 mg. HPLC (Method 1): R t = 3.01 min, m/z: [M+H] + = 416.2 (MW calc. 415.49). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.32 (s, 2H) , 8.50 (s, 1H), 8.47 (d, J = 5.7 Hz, 2H), 7.79 (d, J = 7.7 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.30 (d, J = 7.3 Hz, 1H), 6.96-6.94 (m, 1H), 4.87 (d, J = 6.2 Hz, 2H), 4.77 (d, J = 6.1 Hz, 2H), 4.61 (s, 2H), 3.92 (s, 3H), 2.40 (s, 3H), 1.39 (bs, 2H), 1.11-1.08 (m, 2H)

實施例183：2-(2-(2-(6-(1-(甲基胺)環丙基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-4-基)丙-2-醇 Example 183: 2-(2-(2-(6-(1-(methylamine))cyclopropyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidine- 5-yl)pyridin-4-yl)propan-2-ol

白色固體。產量：25mg。HPLC(方法1)：Rt=2.56min,m/z：[M+H]+=444.2(MW calc.443.54). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.30(s,2H),8.58(d,J=5.2Hz,1H),8.40(s,1H),8.03(s,1H),7.70(m,1H),7.45(d,J=3.6Hz,1H),7.20(m,1H),5.29(s,2H),4.86(d,J=6Hz,2H),4.76(d,J=6.0Hz,2H),4.59(s,2H),1.48(s,6H),2.40(s,3H),1.23(s,3H),0.91-0.83(m,4H). White solid. Yield: 25 mg. HPLC (Method 1): R t = 2.56 min, m/z: [M+H] + = 444.2 (MW calc.443.54). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.30 (s, 2H) , 8.58 (d, J = 5.2 Hz, 1H), 8.40 (s, 1H), 8.03 (s, 1H), 7.70 (m, 1H), 7.45 (d, J = 3.6 Hz, 1H), 7.20 (m, 1H), 5.29 (s, 2H), 4.86 (d, J = 6 Hz, 2H), 4.76 (d, J = 6.0 Hz, 2H), 4.59 (s, 2H), 1.48 (s, 6H), 2.40 (s) , 3H), 1.23 (s, 3H), 0.91-0.83 (m, 4H).

實施例184：N-甲基-1-(1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)環丙胺 Example 184: N-Methyl-1-(1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane] -6-yl)cyclopropylamine

白色固體。產量：16mg。HPLC(方法1)：Rt=2.94min,m/z：[M+H]+=400.4(MW calc.399.49). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.27(s,2H),8.51(d,J=5Hz,1H),8.36(s,1H),7.91(s,1H),7.65(d,J=7.8Hz,1H),7.19(d,J=4.8Hz,1H),7.12(d,J=7.8Hz,1H),4.85(d,J=5.2Hz,2H),4.76(d,J=5.2Hz,2H),4.58(s,2H),2.38(s,3H),2.18(s,3H),0.91-0.86(m,4H). White solid. Yield: 16 mg. HPLC (Method 1): R t = 2.94 min, m/z: [M+H] + = 400.4 (MW calc. 399.49). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.27 (s, 2H) , 8.51 (d, J = 5 Hz, 1H), 8.36 (s, 1H), 7.91 (s, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 4.8 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 4.85 (d, J = 5.2 Hz, 2H), 4.76 (d, J = 5.2 Hz, 2H), 4.58 (s, 2H), 2.38 (s, 3H), 2.18(s,3H), 0.91-0.86(m,4H).

實施例185：N-乙基-1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺 Example 185: N-Ethyl-1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[Porphyrin-3,3'- Oxycyclobutane]-6-sulfonamide

白色固體。產量：80mg。HPLC(方法2)：Rt=1.53min,m/z：[M+H]+=482.1(MW calc.481.57).1H NMR(400MHz,DMSO-d6,δ ppm)：9.33(s,2H),8.82(s,1H),8.60(d,1H,J=5.1Hz),8.05(s,1H),7.95-7.93(d,1H,J=7.8Hz),7.59(t,1H,J=5.6Hz),7.55(d,1H,J=7.7Hz),7.46(d,1H,J=4.9Hz),5.29(s,1H),4.91(d,2H,J=6.2Hz),4.79(d,2H,J=6.1Hz),4.66(s,2H),2.86-2.79(m,2H),1.49(s,6H),1.03(t,3H,J=7.2Hz). White solid. Yield: 80 mg. HPLC (Method 2): R t = 1.53 min, m/z: [M+H] + = 482.1 (MW calc. 481.57). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.33 (s, 2H) , 8.82 (s, 1H), 8.60 (d, 1H, J = 5.1 Hz), 8.05 (s, 1H), 7.95-7.93 (d, 1H, J = 7.8 Hz), 7.59 (t, 1H, J = 5.6 Hz), 7.55 (d, 1H, J = 7.7 Hz), 7.46 (d, 1H, J = 4.9 Hz), 5.29 (s, 1H), 4.91 (d, 2H, J = 6.2 Hz), 4.79 (d, 2H, J = 6.1 Hz), 4.66 (s, 2H), 2.86-2.79 (m, 2H), 1.49 (s, 6H), 1.03 (t, 3H, J = 7.2 Hz).

實施例185至187係類似於實施例154製備。 Examples 185 to 187 were prepared analogously to Example 154.

實施例186：1-(5-(4-(2-氨基丙-2-基)吡啶-2-基)嘧啶-2-基)-N-甲基螺[吲哚啉 -3,3'-氧環丁烷]-6-磺醯胺 Example 186: 1-(5-(4-(2-Aminopropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[Porphyrin -3,3'-oxycyclobutane]-6-sulfonamide

白色固體。產量：0.12g。HPLC(方法2)：Rt=1.30min,m/z：[M+H]+=467.1(MW calc.466.56). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.35(s,2H),8.81(s,1H),8.57-8.56(m,1H),8.17(s,1H),7.96(d,1H,J=7.5Hz),7.54-7.48(m,3H),4.91(d,2H,J=5.5Hz),4.79(d,2H,J=5.5Hz),4.66(s,2H),2.46(s,3H),1.41(s,6H). White solid. Yield: 0.12 g. HPLC (Method 2): R t = 1.30 min, m/z: [M+H] + = 467.1 (MW calc. 466.56). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.35 (s, 2H) , 8.81 (s, 1H), 8.57-8.56 (m, 1H), 8.17 (s, 1H), 7.96 (d, 1H, J = 7.5 Hz), 7.54 - 7.48 (m, 3H), 4.91 (d, 2H) , J = 5.5 Hz), 4.79 (d, 2H, J = 5.5 Hz), 4.66 (s, 2H), 2.46 (s, 3H), 1.41 (s, 6H).

實施例187：1-(5-(4-(2-氨基丙-2-基)吡啶-2-基)嘧啶-2-基)-N,N-二甲基螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺 Example 187: 1-(5-(4-(2-Aminopropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N,N-dimethylspiro[porphyrin-3, 3'-oxocyclobutane]-6-sulfonamide

白色固體。產量：45mg。HPLC(方法2)：Rt=1.36min,m/z：[M+H]+=481.0(MW calc.480.58). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.37(s,2H),8.75(d,1H,J=1.3Hz),8.55(d,1H,J=5.2Hz),8.18(s,1H),7.99(d,1H,J=7.8Hz),7.50-7.47(m,2H),4.92(d,2H,J=6.2Hz),4.80(d,2H,J=6.2Hz),4.67 (s,2H),2.67(s,6H),2.12(bs,2H),1.41(s,6H). White solid. Yield: 45 mg. HPLC (Method 2): R t = 1.36 min, m/z: [M+H] + = 481.0 (MW calc. 480.58). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.37 (s, 2H) , 8.75 (d, 1H, J = 1.3 Hz), 8.55 (d, 1H, J = 5.2 Hz), 8.18 (s, 1H), 7.99 (d, 1H, J = 7.8 Hz), 7.50-7.47 (m, 2H), 4.92 (d, 2H, J = 6.2 Hz), 4.80 (d, 2H, J = 6.2 Hz), 4.67 (s, 2H), 2.67 (s, 6H), 2.12 (bs, 2H), 1.41 ( s, 6H).

實施例188：N-(2-羥乙基)-N-甲基-1'-(5-(4-甲基吡啶-2-基)嘧啶-2-基)-4,5-二氫-2H-螺[呋喃-3,3'-吲哚啉]-6'-甲醯胺 Example 188: N-(2-hydroxyethyl)-N-methyl-1'-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-4,5-dihydro- 2H-spiro[furan-3,3'-carboline]-6'-formamide

188a)N-(5-(苄氧基)-2-溴苯基)四氫呋喃-3-甲醯胺 188a) N-(5-(Benzyloxy)-2-bromophenyl)tetrahydrofuran-3-carboxamide

吡啶(75mL)中之四氫呋喃-3-羧酸(1.58mL,16.5mmol)及5-(苄氧基)-2-溴苯胺(4.59g,16.5mmol)溶液係被降溫至-15℃。POCl3(1.69mL,18.2mmol)係被逐滴加入且於-15℃持續攪拌45min。冰水(~300mL)係被加入且該混合物係被溫熱至RT。該懸浮液係經過濾且該過濾器係經乾燥。產量：4.08g(66%).MS：m/z：=376.1/378.1(MW calc.376.05/378.05)。 A solution of tetrahydrofuran-3-carboxylic acid (1.58 mL, 16.5 mmol) and 5-(benzyloxy)-2-bromoaniline (4.59 g, 16.5 mmol) in pyridine (75 mL) was cooled to -15. POCl 3 (1.69 mL, 18.2 mmol) was added dropwise and stirring was continued at -15 ° C for 45 min. Ice water (~300 mL) was added and the mixture was warmed to RT. The suspension is filtered and the filter is dried. Yield: 4.08 g (66%). MS: m/z: =376.1/378.1 (MW calc.376.05/378.05).

188b)N-(5-(苄氧基)-2-溴苯基)-N-(4-甲氧基芐基)四氫呋喃-3-甲醯胺 188b) N-(5-(Benzyloxy)-2-bromophenyl)-N-(4-methoxybenzyl)tetrahydrofuran-3-carboxamide

無水乙腈(100mL)中之188a(4.37g,11.6mmol),4-甲氧基芐基氯(1.73mL,12.8mmol)及Cs2CO3(10.60g,32.5mmol)之混合物係經回流1.5h。該混合物係被將溫至RT及經矽藻土過濾。該過濾塊係經以乙腈及EtOAc淋洗、該濾液係被濃縮且該剩留物係經以快速層析法[矽石，庚烷/EtOAc=4：1至1：1]純化。產量：5.77g(100%)。MS：m/z：=496.1/498.1(MW calc.496.10/498.10)。 In anhydrous acetonitrile (100 mL) in the 188a (4.37g, 11.6mmol), 4- methoxybenzyl chloride (1.73mL, 12.8mmol), and Cs 2 CO 3 (10.60g, 32.5mmol ) the mixture was refluxed for 1.5h based . The mixture was warmed to RT and filtered through celite. The filter cake was rinsed with acetonitrile and EtOAc. The filtrate was concentrated and purified eluting with EtOAc EtOAc EtOAc. Yield: 5.77 g (100%). MS: m/z: =496.1/498.1 (MW calc. 496.10/498.10).

188c)6'-(苄氧基)-1'-(4-甲氧基芐基)-4,5-二氫-2H-螺[呋喃-3,3'-吲哚啉]-2'-酮 188c) 6'-(Benzyloxy)-1'-(4-methoxybenzyl)-4,5-dihydro-2H-spiro[furan-3,3'-carboline]-2'- ketone

無水1,4-二噁烷(115mL)中之188b(5.98g,12.1mmol)、Pd(OAc)2(270mg,1.21mmol)及NaOtBu(1.74g,18.1mmol)溶液係在手套箱中被製備。三環己基膦(338mg,1.21mmol)係被加入且獲得之褐色溶液係由該手套箱移除並於75℃攪拌隔夜。該混合物係被降溫至RT且被倒入飽和NH4Cl水溶液(700mL)中。該水層係經以EtOAc(2x 500mL)萃取且該合併之有機層以鹽水(200mL)清洗、乾燥(Na2SO4)及濃縮。該剩餘物係經以快速層析法[矽石，庚烷/EtOAc=3：1至1：1]純化。產量：2.75g(55%).MS：m/z：=416.2(MW calc.416.18)。 A solution of 188b (5.98 g, 12.1 mmol), Pd(OAc) 2 (270 mg, 1.21 mmol) and NaOtBu (1.74 g, 18.1 mmol) in anhydrous 1,4-dioxane (115 mL) was prepared in a glove box. . Tricyclohexylphosphine (338 mg, 1.21 mmol) was added and the brown solution obtained was removed from the glove box and stirred overnight at 75 °C. The mixture was cooled to RT and the train is being poured into saturated aqueous NH 4 Cl (700 mL of) the. The aqueous layer system (2x 500mL) and extracted with EtOAc and the organic layer was combined them with the brine (200mL) washed, dried (Na 2 SO 4) and concentrated. The residue was purified by flash chromatography [EtOAc, heptane /EtOAc = 3:1 to 1:1]. Yield: 2.75 g (55%). MS: m/z: = 416.2 (MW calc. 416.18).

188d)6'-(苄氧基)-1'-(4-甲氧基芐基)-4,5-二氫-2H-螺[呋喃-3,3'-吲哚啉] 188d) 6'-(Benzyloxy)-1'-(4-methoxybenzyl)-4,5-dihydro-2H-spiro[furan-3,3'-carboline]

甲苯(10.7mL,37.5mmol)中之3.5M Red-Al溶液係被逐滴加入至無水甲苯(70mL)中之化合物188c(2.6g,6.26mmol)係於80℃在Ar中攪拌。該得到之混合物係於此溫度經攪拌2h，然後以冰浴降溫且小心地以冰冷之2M NaOH水溶液淬滅。該混合物係經進一步以2M NaOH水溶液(~400mL總數)稀釋及以EtOAc(3x 150mL)萃取。該合併之有機層係經乾燥(Na2SO4)及濃縮。以快速層析法[矽石，庚烷/EtOAc=7：1至1：1]純化。產量：2.32g(92%).MS：m/z：=402.2(MW calc.402.20)。 The 3.5 M Red-Al solution in toluene (10.7 mL, 37.5 mmol) was added dropwise to dry toluene (70 mL). Compound 188c (2.6 g, 6.26 mmol) was stirred at 80 ° C in Ar. The resulting mixture was stirred at rt for 2 h then cooled in an ice bath and carefully quenched with ice cold 2M EtOAc. The mixture was further diluted with 2M aqueous NaOH (~~~~~~~~ The combined The organic layer was dried over lines (Na 2 SO 4) and concentrated. Purification by flash chromatography [oxime, heptane / EtOAc = 7:1 to 1:1]. Yield: 2.32 g (92%). MS: m/z: = 402.2 (MW calc. 402.20).

188e)4,5-二氫-2H-螺[呋喃-3,3'-吲哚啉]-6'-醇 188e) 4,5-dihydro-2H-spiro[furan-3,3'-carboline]-6'-ol

在氯化氫(37%,4.72mL,57.5mmol)、EtOH(40mL)及MeOH(60mL)水溶液中之化合物188d(2.31g,5.75mmol)係被氫化隔夜，其係使用鈀碳(10%,612mg,0.58mmol)作為催化劑。該混合物係經矽藻土墊過濾，該過濾器係 經以MeOH淋洗且該濾液係經濃縮。產量：1.72g(hydrochloride salt).MS：m/z：=192.1(MW calc.192.09)。 Compound 188d (2.31 g, 5.75 mmol) in hydrogen chloride (37%, 4.72 mL, 57.5 mmol), EtOH (40 mL) and MeOH (60 mL) was hydrogenated overnight using palladium carbon (10%, 612 mg, 0.58 mmol) was used as a catalyst. The mixture is filtered through a diatomaceous earth pad, the filter system It was rinsed with MeOH and the filtrate was concentrated. Yield: 1.72 g (hydrochloride salt). MS: m/z: = 192.1 (MW calc. 192.09).

188f)1'-(5-(4-甲基吡啶-2-基)嘧啶-2-基)-4,5-二氫-2H-螺[呋喃-3,3'-吲哚啉]-6'-醇 188f) 1'-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)-4,5-dihydro-2H-spiro[furan-3,3'-carboline]-6 '-alcohol

Pd(OAc)2(129mg,0.57mmol)及Xantphos(666mg,1.15mmol)係被加入至在Ar中攪拌之無水1,4-二噁烷(90mL)及三氟甲苯(10mL)中之化合物188e(1.72g,max.5.75mmol)、2-氯-5-(4-甲基吡啶-2-基)嘧啶(1.30g,6.33mmol)及Cs2CO3(5.25g,16.1mmol)之混合物中。該封閉之燒瓶係於110℃經加熱2h。安裝一冷卻器且該混合物係於120℃經攪拌隔夜。該混合物係經以水(400mL)及EtOAc(400mL)稀釋及過濾。該有機層係被分離，以水(100mL)清洗，乾燥(Na2SO4)及濃縮。該剩餘物係經以快速層析法[矽石，庚烷/EtOAc=3：2至0：1]純化且該分離物質係在熱MeOH/乙腈(~1：1,100mL)中經進一步研磨。產量：930mg(最後步驟45%)。MS：m/z：=361.2(MW calc.361.16)。 Pd(OAc) 2 (129 mg, 0.57 mmol) and Xantphos (666 mg, 1.15 mmol) were added to anhydrous 1,4-dioxane (90 mL) and trifluorotoluene (10 mL). (1.72 g, max. 5.75 mmol), a mixture of 2-chloro-5-(4-methylpyridin-2-yl)pyrimidine (1.30 g, 6.33 mmol) and Cs 2 CO 3 (5.25 g, 16.1 mmol) . The closed flask was heated at 110 ° C for 2 h. A cooler was installed and the mixture was stirred overnight at 120 °C. The mixture was diluted with water (400 mL) and EtOAc (400 mL) and filtered. The organic layer system was separated, water (100 mL) washed, dried (Na 2 SO 4) and concentrated. The residue was purified by flash chromatography [EtOAc, EtOAc/EtOAc = EtOAc (EtOAc) Yield: 930 mg (final step 45%). MS: m/z: = 361.2 (MW calc. 361.16).

188g)1'-(5-(4-甲基吡啶-2-基)嘧啶-2-基)-4,5-二氫-2H-螺[呋喃-3,3'-吲哚啉]-6'-基三氟甲磺酸酯 188g) 1'-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)-4,5-dihydro-2H-spiro[furan-3,3'-carboline]-6 '-yl triflate

三氟甲磺酸酐(trifluoro methanesulfonic acid anhydride)(419μL,2.48mmol)係於-15℃被逐滴加入至DCM(25mL)及乙腈(10mL)中之188f(447mg,1.24mmol)及TEA(864μL,6.20mmol)懸浮液。在攪拌15min後，該混合物係被溫熱至RT且在30min後逐滴加入另外之三氟甲磺酸酐(210μL,1.24mmol)。該混合物係於rt經攪拌1h，然後以DCM(100mL)稀釋及以飽和NaHCO3水溶液(200mL)清洗。該水層係經以DCM(100mL)萃取且該合 併之有機層係經乾燥(Na2SO4)及濃縮。以快速層析法[矽石，庚烷/EtOAc=3：2至1：4]純化。產量：340mg(56%).MS：m/z：=493.1(MW calc.493.11)。 Trifluoro methanesulfonic acid anhydride (419 μL, 2.48 mmol) was added dropwise to 188f (447 mg, 1.24 mmol) and TEA (864 μL) in DCM (25 mL) and acetonitrile (10 mL) at -15 °C. 6.20 mmol) suspension. After stirring for 15 min, the mixture was warmed to RT and after 30 min additional trifluoromethanesulfonic anhydride (210 [mu]L, 1.24 <RTIgt; The mixture was stirred at rt over lines 1h, then DCM (100mL) was diluted and washed with a saturated aqueous NaHCO 3 (200mL). The aqueous layer system (100 mL) and extracted with with DCM and the combined organic layers of the system was dried (Na 2 SO 4) and concentrated. Purification by flash chromatography [oxime, heptane / EtOAc = 3:2 to 1:4]. Yield: 340 mg (56%). MS: m/z: = 493.1 (MW calc. 493.11).

188h)1'-(5-(4-甲基吡啶-2-基)嘧啶-2-基)-4,5-二氫-2H-螺[呋喃-3,3'-吲哚啉]-6'-羧酸甲酯 188h) 1'-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)-4,5-dihydro-2H-spiro[furan-3,3'-carboline]-6 '-carboxylic acid methyl ester

MeOH(4.35mL,108mmol)及無水DMF(30mL)中之化合物188g(530mg,1.08mmol)及TEA(600μL,4.30mmol)溶液係被置於高壓釜中且以氬氣沖洗15min。Pd(OAc)2(24.2mg,108μmol)及dppp(44.4mg,108μmol)係被加入且該高壓釜係在一氧化碳氣氛(5bar)下於70℃經攪拌1h及於90℃經攪拌隔夜。該反應混合物係被降溫至0℃，以EtOAc(100mL)稀釋及以水(2x 200mL)清洗。該有機相係經乾燥(Na2SO4)且在減壓下濃縮。以快速層析法[矽石，庚烷/EtOAc=4：1至0：1]純化以提供甲基醚。產量：360mg(83%).MS：m/z：=403.2(MW calc.403.17)。 A solution of 188 g (530 mg, 1.08 mmol) and TEA (600 μL, 4.30 mmol) in MeOH (4.35 mL, 108 mmol) and dry DMF (30 mL) was placed in an autoclave and rinsed with argon for 15 min. Pd(OAc) 2 (24.2 mg, 108 μmol) and dppp (44.4 mg, 108 μmol) were added and the autoclave was stirred at 70 ° C for 1 h under a carbon monoxide atmosphere (5 bar) and stirred at 90 ° C overnight. The reaction mixture was cooled to 0.degree. C., diluted with EtOAc (EtOAc) The organic phase was dried and concentrated lines (Na 2 SO 4) under reduced pressure. Purification by flash chromatography [mite, heptane / EtOAc = 4:1 to 0:1] affords methyl ether. Yield: 360 mg (83%). MS: m/z: = 403.2 (MW calc. 403.17).

188i)1'-(5-(4-甲基吡啶-2-基)嘧啶-2-基)-4,5-二氫-2H-螺[映喃-3,3'-吲哚啉]-6'-羧酸 188i) 1'-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)-4,5-dihydro-2H-spiro[inopyran-3,3'-carboline]- 6'-carboxylic acid

對THF(20mL)、MeOH(10mL)及水(10mL)中之甲基醚188h(350mg,0.87mmol)溶液係被加入LiOH．H2O(182mg,4.35mmol)且該混合物係於RT經攪拌。該混合物係經濃縮、以水(50mL)稀釋且以二乙基醚(2 x 50mL)清洗。該水層係經以1M氯化氫溶液(~8mL)酸化。該出現之沉澱物係被濾出，經以水淋洗及以二乙基醚/戊烷(50mL,1：1)研磨。產量：308mg(91%).MS：m/z：=389.2(MW calc.389.15)。 A solution of methyl ether 188h (350mg, 0.87mmol) in THF (20mL), MeOH (10mL) and water (10mL) was added to LiOH. H 2 O (182 mg, 4.35 mmol) and the mixture was stirred at RT. The mixture was concentrated, diluted with water (50 mL) and washed with diethyl ether (2 x 50 mL). The aqueous layer was acidified with 1M aqueous hydrogen chloride (~8 mL). The precipitate which appeared was filtered off, rinsed with water and triethyl ether / pentane (50 mL, 1:1). Yield: 308 mg (91%). MS: m/z: = 389.2 (MW calc. 389.15).

188j)N-(2-羥乙基)-N-甲基-1'-(5-(4-甲基吡啶-2-基)嘧啶-2-基)-4,5-二氫 -2H-螺[呋喃-3,3'-吲哚啉]-6'-甲醯胺 188j) N-(2-hydroxyethyl)-N-methyl-1'-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-4,5-dihydro -2H-spiro[furan-3,3'-carboline]-6'-formamide

N-甲基嗎啉(164μL,1.49mmol)、2-(甲基胺)乙醇(180μL,2.23mmol)及TBTU(287mg,893μmol)係被加入至無水DMF(10mL)中之羧酸188i(289mg,744μmol)溶液且該混合物係於rt經攪拌45min。該混合物係被逐滴加入冰水(~100mL)及以EtOAc(100mL及50mL)萃取。該合併之有機層係經以鹽水(2x 200mL)清洗、乾燥(Na2SO4)及濃縮至乾。該剩餘物係經以快速層析法[矽石，EtOAc]純化。產量：205mg(62%)。MS：m/z：[M+H]+=446.2(MW calc.446.21). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.28(s,2H),8.52(d,J=5.0Hz,1H),8.42(s,1H),7.88(s,1H),7.39(d,J=7.6Hz,1H),7.21(d,J=4.9Hz,1H),7.04(d,J=7.4Hz,1H),4.81(br s,1H),4.31(d,J=11.8Hz,1H),4.24(d,J=11.8Hz,1H),4.08(td,J=8.5,4.7Hz,1H),3.97(q,J=7.9Hz,1H),3.89(d,J=8.3Hz,1H),3.74(d,J=8.4Hz,1H),3.59(br m,4H),3.00(d,J=7.5Hz,3H),2.39(s,3H),2.29(ddt,J=16.2,12.7,7.9Hz,2H)。 N-methylmorpholine (164 μL, 1.49 mmol), 2-(methylamine)ethanol (180 μL, 2.23 mmol) and TBTU (287 mg, 893 μmol) were added to carboxylic acid 188i (289 mg) in anhydrous DMF (10 mL). , 744 μmol) solution and the mixture was stirred at rt for 45 min. The mixture was added dropwise to ice water (~100 mL) and extracted with EtOAc (100 mL and 50 mL). The combined organic layers of the system was washed with brine (2x 200mL) washed, dried (Na 2 SO 4) and concentrated to dryness. The residue was purified by flash chromatography [EtOAc, EtOAc]. Yield: 205 mg (62%). MS: m/z: [M+H] + = 446.2 (MW calc. 446.21). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.28 (s, 2H), 8.52 (d, J = 5.0 Hz, 1H), 8.42 (s, 1H), 7.88 (s, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.21 (d, J = 4.9 Hz, 1H), 7.04 (d, J = 7.4 Hz, 1H), 4.81 (br s, 1H), 4.31 (d, J = 11.8 Hz, 1H), 4.24 (d, J = 11.8 Hz, 1H), 4.08 (td, J = 8.5, 4.7 Hz, 1H), 3.97 (q, J = 7.9 Hz, 1H), 3.89 (d, J = 8.3 Hz, 1H), 3.74 (d, J = 8.4 Hz, 1H), 3.59 (br m, 4H), 3.00 (d, J = 7.5) Hz, 3H), 2.39 (s, 3H), 2.29 (ddt, J = 16.2, 12.7, 7.9 Hz, 2H).

實施例189及190：2-(2-(6-(乙亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)異菸鹼甲腈(較快及較慢之洗析鏡像異構物) Examples 189 and 190: 2-(2-(6-(ethylsulfinyl) spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl) Alkaline carbonitrile (faster and slower elution of the mirror image isomer)

該消旋之亞碸係由52h類似於實施例56製備然後被分離成單一鏡像異構物，其係經由掌性製備型HPLC(管柱：Chiralpak IA 21 x 250mm，粒徑5μm； 移動相：己烷/乙醇/DCM/二乙胺=50/25/25/0.1；流速：21.0ml/min；檢測：UV,344nm；運行時間：20min)。 The racemic subunit was prepared from 52h analogous to Example 56 and then separated into a single mirror image isomer via a preparative HPLC (column: Chiralpak IA 21 x 250 mm, particle size 5 μm; Mobile phase: hexane/ethanol/DCM/diethylamine = 50/25/25/0.1; flow rate: 21.0 ml/min; detection: UV, 344 nm; run time: 20 min).

較快洗析之鏡像異構物(實施例189)：白色固體。產量：90mg。鏡像異構物過量：100%(掌性HPLC)。HPLC(方法2)：Rt=1.63min,m/z：[M+H]+=418.0(MW calc.417.48). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.35(s,2H),8.90(d,1H,J=5.0Hz),8.60(s,1H),8.55(s,1H),7.94(d,1H,J=7.8Hz),7.81-7.80(m,1H),7.38-7.35(m,1H),4.90(d,2H,J=6.2Hz),4.79(d,2H,J=6.12Hz),4.65(s,2H),3.04-2.97(m,1H),2.82-2.75(m,1H),1.08(t,3H,J=7.3Hz). The mirror image isomer was eluted faster (Example 189): white solid. Yield: 90 mg. Excess of mirror image isomer: 100% (palm HPLC). HPLC (Method 2): R t = 1.63 min, m/z: [M+H] + = 418.0 (MW calc. 417.48). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.35 (s, 2H) , 8.90 (d, 1H, J = 5.0 Hz), 8.60 (s, 1H), 8.55 (s, 1H), 7.94 (d, 1H, J = 7.8 Hz), 7.81-7.80 (m, 1H), 7.38- 7.35 (m, 1H), 4.90 (d, 2H, J = 6.2 Hz), 4.79 (d, 2H, J = 6.12 Hz), 4.65 (s, 2H), 3.04 - 2.97 (m, 1H), 2.82 - 2.75 (m, 1H), 1.08 (t, 3H, J = 7.3 Hz).

較慢洗析之鏡像異構物(實施例190)：白色固體。產量：90mg。鏡像異構物過量：100%(掌性HPLC)。HPLC(方法2)：Rt=1.63min,m/z：[M+H]+=418.1(MW calc.417.48). 1H NMR(400MHz,DMSO-d6,δ ppm)：9.35(s,2H),8.90(d,1H,J=5.0Hz),8.60(s,1H),8.55(s,1H),7.94(d,1H,J=7.8Hz),7.81-7.80(m,1H),7.37-7.35(m,1H),4.90(d,2H,J=6.2Hz),4.79(d,2H,J=6.12Hz),4.65(s,2H),3.06-2.97(m,1H),2.82-2.73(m,1H),1.08(t,3H,J=7.3Hz). Slower elution of the mirror image isomer (Example 190): white solid. Yield: 90 mg. Excess of mirror image isomer: 100% (palm HPLC). HPLC (Method 2): R t = 1.63 min, m/z: [M+H] + = 418.1 (MW calc. 417.48). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.35 (s, 2H) , 8.90 (d, 1H, J = 5.0 Hz), 8.60 (s, 1H), 8.55 (s, 1H), 7.94 (d, 1H, J = 7.8 Hz), 7.81-7.80 (m, 1H), 7.37- 7.35 (m, 1H), 4.90 (d, 2H, J = 6.2 Hz), 4.79 (d, 2H, J = 6.12 Hz), 4.65 (s, 2H), 3.06-2.97 (m, 1H), 2.82-2.73 (m, 1H), 1.08 (t, 3H, J = 7.3 Hz).

實施例191：2-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)異菸鹼甲腈 Example 191: 2-(2-(6-(ethylsulfonyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)isonicotinonitrile

由52h類似於實施例56製備。淡黃色固體。產量：120mg。HPLC(方法2)：Rt=1.63min,m/z：[M+H]+=434.1(MW calc.433.48)。1H NMR(400MHz,DMSO-d6,δ ppm)：9.38(s,2H),8.91(d,1H,J=4.9Hz),8.82(s,1H),8.57(s,1H),8.03(d,1H,J=7.8Hz),7.82(d,1H,J=4.8Hz),7.66(d,1H,J=7.8Hz),4.92(d,2H,J=6.2Hz),4.79(d,2H,J=6.12Hz),4.67(s,2H),3.28-3.27(m,2H),1.15(t,3H,J=7.3Hz)。 Prepared analogously to Example 56 from 52h. Light yellow solid. Yield: 120 mg. HPLC (Method 2): rt = 1.63 min, m/z: [M+H] + = 434.1 (MW calc. 433.48). 1H NMR (400MHz, DMSO-d6, δ ppm): 9.38 (s, 2H), 8.91 (d, 1H, J = 4.9 Hz), 8.82 (s, 1H), 8.57 (s, 1H), 8.03 (d, 1H, J = 7.8 Hz), 7.82 (d, 1H, J = 4.8 Hz), 7.66 (d, 1H, J = 7.8 Hz), 4.92 (d, 2H, J = 6.2 Hz), 4.79 (d, 2H, J = 6.12 Hz), 4.67 (s, 2H), 3.28-3.27 (m, 2H), 1.15 (t, 3H, J = 7.3 Hz).

中間物6：(1-(5-溴嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)二甲基膦氧化物(Int-6) Intermediate 6: (1-(5-bromopyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)dimethylphosphine oxide (Int-6)

Int-6a)(2,2-二甲基螺[[1,3]二噁烷-5,3'-吲哚啉]-6'-基)二甲基膦氧化物 Int-6a) (2,2-dimethylspiro[[1,3]dioxane-5,3'-carboline]-6'-yl)dimethylphosphine oxide

Xantphos(0.49g,0.838mmol)及Pd2(dba)3(0.77g,0.838mmol)係被加入至在Ar中攪拌之無水二噁烷(100mL)中之Int-1b(5g,16.76mmol)、二甲基膦氧化物(1.9g,25.15mmol)及三乙胺(7.06mL,50.28mmol)溶液。該得到之混合物係於110℃經加熱16h，然後降溫及經矽藻土栓過濾。該濾液係 經蒸發且該剩餘物係經以管柱層析法[矽膠；DCM與0-10% MeOH]純化。該分離出之白色固體係未經進一步純化而用於次一步驟。產量：定量(~5g)。HPLC(方法3)：Rt=2.17min.,m/z：[M+H]+=296.2(MW calc.295.31)。 Xantphos (0.49 g, 0.838 mmol) and Pd 2 (dba) 3 (0.77 g, 0.838 mmol) were added to Int-1b (5 g, 16.76 mmol) in anhydrous dioxane (100 mL) stirred in Ar. A solution of dimethylphosphine oxide (1.9 g, 25.15 mmol) and triethylamine (7.06 mL, 50.28 mmol). The resulting mixture was heated at 110 ° C for 16 h, then cooled and filtered through a plug of diatomaceous earth. The filtrate was evaporated and the residue was purified by column chromatography [EtOAc EtOAc. The isolated white solid was used in the next step without further purification. Yield: Quantitative (~5g). HPLC (Method 3): rt = 2.17 min., m/z: [M+H] + = 296.2 (MW calc.295.31).

中間物6係由Int-6a經4化學步驟製備，其係類似於前述製程(1d、1e、1f及1g)。白色固體。產量：0.32g(77% of theory)。HPLC(方法4)：Rt=3.21min,m/z：[M+H]+=394.0(MW calc.394.2)。 Intermediate 6 was prepared from Int-6a by 4 chemical steps similar to the previously described procedures (1d, 1e, 1f, and 1g). White solid. Yield: 0.32 g (77% of theory). HPLC (Method 4): rt = 3.21. min, m/z: [M+H] + = 394.0 (MW calc. 394.2).

實施例192：(1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)二甲基膦氧化物 Example 192: (1-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl) Methyl phosphine oxide

由Int-6及(2-氟-5-甲基苯基)硼酸類似於製程3a製備。白色固體。產量：0.09g。HPLC(方法3)：Rt=3.05min,m/z：[M+H]+=423.9(MW calc.423.42). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.85(s,2H),8.74(d,1H,J=12.4Hz),7.89-7.87(m,1H),7.50-7.46(m,2H),7.25-7.23(m,2H),4.89(d,2H,J=6.1Hz),4.79(d,2H,J=6.0Hz),4.60(s,2H),2.35(s,3H),1.68(s,3H),1.65(s,3H)。 Prepared from Int-6 and (2-fluoro-5-methylphenyl)boronic acid similar to Process 3a. White solid. Yield: 0.09 g. HPLC (Method 3): Rt = 3.05 min, m/z: [M+H] + = 423.9 (MW calc. 423.42). 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.85 (s, 2H) , 8.74 (d, 1H, J = 12.4 Hz), 7.89-7.87 (m, 1H), 7.50-7.46 (m, 2H), 7.25-7.23 (m, 2H), 4.89 (d, 2H, J = 6.1 Hz) ), 4.79 (d, 2H, J = 6.0 Hz), 4.60 (s, 2H), 2.35 (s, 3H), 1.68 (s, 3H), 1.65 (s, 3H).

實施例193：(1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)二甲基膦氧化物 Example 193: (1-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)dimethylphosphine oxide

油Int-6及(2-氟苯基)硼酸類似於製程3a製備。白色固體。產量：0.1g。HPLC(方法2)：Rt=1.72min,m/z：[M+H]+=410.1(MW calc.409.39). 1H NMR(400MHz,DMSO-d6,δ ppm)：8.87(s,2H),8.74(d,1H,J=12.5Hz),7.89-7.87(m,1H),7.70-7.66(m,1H),7.51-7.43(m,2H),7.39-7.32(m,2H),4.89(d,2H,J=6.2Hz),4.79(d,2H,J=6.1Hz),4.60(s,2H),1.68(s,3H),1.65(s,3H)。 Oils Int-6 and (2-fluorophenyl)boronic acid were prepared analogously to Process 3a. White solid. Yield: 0.1 g. HPLC (Method 2): R t = 1.72 min, m/z: [M+H] + = 410.1 (MW calc. 409.39). 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.87 (s, 2H) , 8.74 (d, 1H, J = 12.5 Hz), 7.89-7.87 (m, 1H), 7.70-7.66 (m, 1H), 7.51-7.43 (m, 2H), 7.39-7.32 (m, 2H), 4.89 (d, 2H, J = 6.2 Hz), 4.79 (d, 2H, J = 6.1 Hz), 4.60 (s, 2H), 1.68 (s, 3H), 1.65 (s, 3H).

生物測試Biological test 使用LANCE® Ultra cAMP套組以決定hPDE4B1活性之TR-FRET試驗 TR-FRET test using the LANCE® Ultra cAMP kit to determine hPDE4B1 activity

該化合物對人類PDE4B1活性之效果係藉由測定由cAMP產生5’AMP來定量，其係使用在Sf9細胞中表線之人類重組酵素及LANCE® Ultra cAMP套組(一種PerkinElmer之TR-FRET偵測方法)。該人類PDE4B1酵素係由SignalChem Lifesciences(Catalog# P92-31BG,Lot# H296-2)購買。 The effect of this compound on human PDE4B1 activity was quantified by measuring 5'AMP produced by cAMP, which uses human recombinant enzyme and LANCE® Ultra cAMP kit in the surface of Sf9 cells (a PerkinElmer TR-FRET assay) method). The human PDE4B1 enzyme was purchased from SignalChem Lifesciences (Catalog # P92-31BG, Lot # H296-2).

該測試化合物、參考化合物或水(對照組)與酵素(0.96U)在含有50mM Tris-HCl、50mM MgCl2及5mM DTT(pH 8.5)之反應緩充液中混合。之後，該反應係藉由加入500nM cAMP(基質)引發且該混合物係被保持在rt中30min。對於對照之基礎測量，該酵素從該反應混合物中被除去。30min後，該反應係被停止且以添加500μM IBMX之該反應緩充液稀釋100倍。然後該螢光供體(donor)(銪螯合物標記cAMP)及該螢光受體(以ULightTM染料標記之抗-cAMP抗體)及500μM IBMX一起被加入10μl等分試樣 (aliquot)中。在60min後，對應於剩留cAMP量之螢光轉移係於λex=337nm、λem=620nm及λem=665nm經測定，其係使用量盤分析儀(microplate reader)(PHERAstar,BMG)。該酵素活性係藉由將665nm測定信號除以在620nm測定信號(比)乘以10000來決定。結果係以該對照組酵素活性之抑制百分比表示。IC50值(IC50=引起半該對照組特定活性最大抑制性一半之濃度)係衍生自具10種不同濃度之劑量反應測定(n=3；N=1-3)。 The test compound, reference compound or water (control) was mixed with the enzyme (0.96 U) in a reaction buffer containing 50 mM Tris-HCl, 50 mM MgCl 2 and 5 mM DTT (pH 8.5). Thereafter, the reaction was initiated by the addition of 500 nM cAMP (matrix) and the mixture was maintained at rt for 30 min. The enzyme was removed from the reaction mixture for the base measurement of the control. After 30 min, the reaction was stopped and diluted 100-fold with 500 μM of IBMX in this reaction buffer. Then the fluorescence donor (Donor) (europium chelate labeled cAMP) and fluorescence of the receptor (anti ULight TM -cAMP of dye labeled antibody) is added and 500μM IBMX with 10μl aliquot (aliquot of) the . After 60 min, the fluorescence shift corresponding to the amount of residual cAMP was measured at λex = 337 nm, λem = 620 nm, and λem = 665 nm using a microplate reader (PHERAstar, BMG). This enzyme activity was determined by dividing the 665 nm measurement signal by the measured signal (ratio) at 620 nm and multiplied by 10,000. The results are expressed as a percentage inhibition of the enzyme activity of the control group. IC 50 values (IC 50 = concentration causing half of the control of the half maximum inhibition of the activity of a particular group) derived from lines having different concentrations of 10 kinds of dose response assays (n = 3; N = 1-3 ).

本發明之數化合物係經以上述試驗(assay)測試。結果示於下表中(實施例Nos.之PDE4B之IC50抑制性)： The compounds of the present invention were tested by the above assay. The results are shown in the following table (IC 50 inhibition of PDE4B of Example Nos.):

Claims (16)

一種式(I)化合物 其中A、B及C獨立地代表CH或N；m為0、1、2或3且n為0、1、2或3，前提是(m+n)之和為2、3或4；L係選自於由C(=O)NR2、S(=O)、S(=O)2、S(=O)2NR2、P(=O)(R2)、O或鍵結所組成之群組；R1係選自於C1-6-烷基，其未經取代或經單或多取代；或C3-6-環烷基或3至7員雜環烷基，於每一種情況下其未經取代或經單或多取代；R2係選自於H或C1-C6-烷基，其未經取代或經單或多取代；或R1及R2與其所連接之氮原子一起形成3至12員雜環烷基，其中該3至12員雜環烷基可含有選自於由O、S及N所組成之群組之一或二個另外之雜原子且可為單或雙環且其中該3至12員雜環烷基係未經取代或經單或多取代；G代表苯基或5或6員雜芳基，其中該苯基或該5或6員雜芳基係未經取代或經以一、二、三或四個取代基Z取代； 其中Z每一次出現係獨立地選自於由以下所組成之群組：鹵素，OH，CN，SH，NO2，C1-C6-烷基，C2-C6-烯基，C2-C6-炔基，(C1-C6)-羥烷基，(C1-C6)-氰烷基，C1-C6-烷氧基，(C1-C6)-硫烷基，(C1-C6)-鹵烷基，(C1-C6-烷氧基)-(C1-C6-亞烷基)，(C1-C6-烷氧基)-C1-C6-烷氧基，(C1-C6)-thio鹵烷基，(C1-C6)-鹵烷氧基，(C1-C6-硫烷基)-(C1-C6-亞烷基)，C3-C6-環烷基，(C3-C6-環烷基)-(C1-C3-亞烷基)，3至7員雜環烷基，(3至7員雜環烷基)-(C1-C3-亞烷基)(該C3-6-環烷基及該3至7員雜環烷基於每一種情況下係未經取代或經單或多取代)，NH2，NH(C1-C6-烷基)，N(C1-C6-烷基)2，NHCO(C1-C6-烷基)，NHCO2(C1-C6-烷基)，NHC(O)NH2，NHCONH(C1-C6-烷基)，NHCON(C1-C6-烷基)2，(C1-C6-伸烷基)NH2，(C1-C6-伸烷基)NH(C1-C6-烷基)，(C1-C6-伸烷基)N(C1-C6-烷基)2，(C1-C6-伸烷基)NHCO(C1-C6-烷基)，(C1-C6-伸烷基)NHCO2(C1-C6-烷基)，(C1-C6-伸烷基)NHC(O)NH2，(C1-C6-伸烷基)NHCONH(C1-C6-烷基)，(C1-C6-伸烷基)NHCON(C1-C6-烷基)2，NH((C1-C6-伸烷基)-CO2(C1-C6-烷基)，NH(C1-C6-伸烷基)-CONH2，NH(C1-C6-伸烷基)-CONH(C1-C6-烷基)，NH(C1-C6-伸烷基)-CON(C1-C6-烷基)2，NHS(O)2OH，NHS(O)2(C1-C6-烷基)，NHS(O)2O(C1-C6-烷基)，NHS(O)2NH2，NHS(O)2NH(C1-C6-烷基)，NHS(O)2N(C1-C6-烷基)2，NH(C1-C6-伸烷基)-S(O)2OH，NH(C1-C6-伸烷基)-S(O)2(C1-C6-烷基)，NH(C1-C6-伸烷基)-S(O)2O(C1-C6-烷基)，NH(C1-C6-伸烷基)-S(O)2NH2，NH(C1-C6-伸烷基)-S(O)2NH(C1-C6-烷基)，CO2H，CO(C1-C6-烷基)，CO2(C1-C6-烷基)，O-CO(C1-C6-烷基)，O-CO2(C1-C6-烷基)，CONH2，CONH(C1-C6-烷基)，CON(C1-C6-烷基)2，OCONH(C1-C6-烷基)，OCON(C1-C6-烷基)2，OS(O)2(C1-C6-烷基)，OS(O)2OH，OS(O)2O(C1-C6- 烷基)，OS(O)2NH2，OS(O)2NH(C1-C6-烷基)，OS(O)2N(C1-C6-烷基)2，S(O)(C1-C6-烷基)，S(O)2(C1-C6-烷基)，S(O)2OH，S(O)2O(C1-C6-烷基)，S(O)2NH2，S(O)2NH(C1-C6-烷基)及S(O)2N(C1-C6-烷基)2；其可擇地為單一立體異構物或立體異構物混合物之形式、游離化合物之形式及/或其生理上可接受之鹽類及/或生理上可接受之溶劑合物。 a compound of formula (I) Wherein A, B and C independently represent CH or N; m is 0, 1, 2 or 3 and n is 0, 1, 2 or 3, provided that the sum of (m + n) is 2, 3 or 4; Is selected from C(=O)NR 2 , S(=O), S(=O) 2 , S(=O) 2 NR 2 , P(=O)(R 2 ), O or bonding a group consisting of; R 1 is selected from C 1-6 -alkyl, which is unsubstituted or mono- or polysubstituted; or C 3-6 -cycloalkyl or 3 to 7-membered heterocycloalkyl, In each case it is unsubstituted or mono- or polysubstituted; R 2 is selected from H or C 1 -C 6 -alkyl, unsubstituted or mono- or polysubstituted; or R 1 and R 2 The nitrogen atom to be bonded together forms a 3 to 12 membered heterocycloalkyl group, wherein the 3 to 12 membered heterocycloalkyl group may contain one or two additional groups selected from the group consisting of O, S and N. An atom and may be mono- or bicyclic and wherein the 3 to 12 membered heterocycloalkyl group is unsubstituted or mono- or polysubstituted; G represents a phenyl group or a 5 or 6 membered heteroaryl group, wherein the phenyl group or the 5 or The 6-membered heteroaryl is unsubstituted or substituted with one, two, three or four substituents Z; wherein each occurrence of Z is independently selected from the group consisting of halogen, OH, CN, SH, NO 2 C 1 -C 6 - alkyl, C 2 -C 6 - alkenyl, C 2 -C 6 - alkynyl, (C 1 -C 6) - hydroxyalkyl, (C 1 -C 6) - cyanoalkyl , C 1 -C 6 -alkoxy, (C 1 -C 6 )-sulfanyl, (C 1 -C 6 )-haloalkyl, (C 1 -C 6 -alkoxy)-(C 1 -C 6 -alkylene), (C 1 -C 6 -alkoxy)-C 1 -C 6 -alkoxy, (C 1 -C 6 )-thiohaloalkyl, (C 1 -C 6 )-haloalkoxy, (C 1 -C 6 -sulfanyl)-(C 1 -C 6 -alkylene), C 3 -C 6 -cycloalkyl, (C 3 -C 6 -cycloalkane) Base)-(C 1 -C 3 -alkylene), 3 to 7 membered heterocycloalkyl, (3 to 7 membered heterocycloalkyl)-(C 1 -C 3 -alkylene) (C 3 -6 -cycloalkyl and the 3 to 7 membered heterocycloalkyl are unsubstituted or mono- or polysubstituted in each case, NH 2 , NH(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl) 2 ,NHCO(C 1 -C 6 -alkyl), NHCO 2 (C 1 -C 6 -alkyl), NHC(O)NH 2 ,NHCONH(C 1 -C 6 - Alkyl), NHCON(C 1 -C 6 -alkyl) 2 , (C 1 -C 6 -alkylene)NH 2 ,(C 1 -C 6 -alkylene)NH(C 1 -C 6 - Alkyl), (C 1 -C 6 -alkylene)N(C 1 -C 6 -alkyl) 2 ,(C 1 -C 6 -alkylene)NHCO(C 1 -C 6 -alkyl) , (C 1 -C 6 - alkylene) NHCO 2 (C 1 -C 6 - alkyl) (C 1 -C 6 - alkylene) NHC (O) NH 2, (C 1 -C 6 - alkylene) NHCONH (C 1 -C 6 - alkyl), (C 1 -C 6 - alkoxy extending NHCON(C 1 -C 6 -alkyl) 2 , NH((C 1 -C 6 -alkylene)-CO 2 (C 1 -C 6 -alkyl), NH(C 1 -C 6 - Alkyl)-CONH 2 ,NH(C 1 -C 6 -alkylene)-CONH(C 1 -C 6 -alkyl),NH(C 1 -C 6 -alkylene)-CON(C 1 -C 6 -alkyl) 2 , NHS(O) 2 OH, NHS(O) 2 (C 1 -C 6 -alkyl), NHS(O) 2 O(C 1 -C 6 -alkyl), NHS (O) 2 NH 2 , NHS(O) 2 NH(C 1 -C 6 -alkyl), NHS(O) 2 N(C 1 -C 6 -alkyl) 2 , NH(C 1 -C 6 - Alkyl)-S(O) 2 OH, NH(C 1 -C 6 -alkylene)-S(O) 2 (C 1 -C 6 -alkyl), NH(C 1 -C 6 -extended Alkyl)-S(O) 2 O(C 1 -C 6 -alkyl), NH(C 1 -C 6 -alkylene)-S(O) 2 NH 2 ,NH(C 1 -C 6 - Alkyl)-S(O) 2 NH(C 1 -C 6 -alkyl), CO 2 H, CO(C 1 -C 6 -alkyl), CO 2 (C 1 -C 6 -alkyl) , O-CO(C 1 -C 6 -alkyl), O-CO 2 (C 1 -C 6 -alkyl), CONH 2 ,CONH(C 1 -C 6 -alkyl), CON(C 1 - C 6 -alkyl) 2 , OCONH(C 1 -C 6 -alkyl), OCON(C 1 -C 6 -alkyl) 2 ,OS(O) 2 (C 1 -C 6 -alkyl), OS (O) 2 OH,OS(O) 2 O(C 1 -C 6 - alkyl), OS(O) 2 NH 2 , OS(O) 2 NH(C 1 -C 6 -alkyl), OS(O) 2 N(C 1 -C 6 -alkyl) 2 ,S( O) (C 1 -C 6 -alkyl), S(O) 2 (C 1 -C 6 -alkyl), S(O) 2 OH, S(O) 2 O(C 1 -C 6 -alkane Base), S(O) 2 NH 2 , S(O) 2 NH(C 1 -C 6 -alkyl) and S(O) 2 N(C 1 -C 6 -alkyl) 2 ; It is in the form of a single stereoisomer or a mixture of stereoisomers, in the form of a free compound and/or a physiologically acceptable salt thereof and/or a physiologically acceptable solvate. 如請求項1之化合物，其特徵在於各A、B及C代表CH。 The compound of claim 1, wherein each of A, B and C represents CH. 如請求項1中或2之一或多項之化合物，其特徵在於m為1及n為1或m為1及n為2或m為2及n為2，較佳m為1及n為1。 A compound according to one or more of claims 1 or 2, wherein m is 1 and n is 1 or m is 1 and n is 2 or m is 2 and n is 2, preferably m is 1 and n is 1. . 如請求項1至3中之一或多項之化合物，其中G為以下G1至G44之群組之一 其中該以星號(*)標記之位置指出該連接處，其係被連接至該嘧啶環；R12係選自於H、CH3或CH2CH3；每次出現之k為0、1、2、3或4；及每次出現之Z係獨立地選自於由以下所組成之群組：F、Cl、CN、CF3、CHF2、CH2F、OCF3、OH、OCH3、OC2H5、OCOCH3、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、CH2CH2CH2CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、NHCOCH3、CH2OH、CH2CH2OH、C(CH3)2OH、CH(CH3)OH、CH2NH2、CH2CH2NH2、C(CH3)2NH2、CH(CH3)NH2、CH2NH(CH3)、CH2CH2NH(CH3)、C(CH3)2NH(CH3)、CH(CH3)NH(CH3)、CH2N(CH3)2、CH2CH2N(CH3)2、C(CH3)2N(CH3)2、CH(CH3)N(CH3)2、CH2CN、SOCH3、SO2CH3、SOCH2CH3、SO2CH2CH3、SO2NH2、吡咯啶基、哌啶基、氮丙啶基(aziridinyl)、環丙基、環丁基、環戊基及環己基， 其中該吡咯啶基、哌啶基、氮丙啶基、氧環丁烷基、嗎啉基、環丙基、環丁基、環戊基及環己基係未經取代或經以一或多取代基單或多取代，該取代基係選自於由以下所組成之群組：F、Cl、CN、CF3、CHF2、CH2F、OCF3、OH、OCH3、OC2H5、OCOCH3、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、CH2CH2CH2CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2及NHCOCH3。 A compound according to one or more of claims 1 to 3, wherein G is one of the following groups of G1 to G44 Wherein the position marked with an asterisk (*) indicates the junction, which is attached to the pyrimidine ring; R 12 is selected from H, CH 3 or CH 2 CH 3 ; each occurrence of k is 0, 1. 2, 3 or 4; and each occurrence of the Z series is independently selected from the group consisting of F, Cl, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3 ) 2 NH 2 , CH(CH 3 )NH 2 , CH 2 NH(CH 3 ), CH 2 CH 2 NH(CH 3 ), C(CH 3 ) 2 NH(CH 3 ), CH(CH 3 )NH(CH 3 ), CH 2 N(CH 3 ) 2 , CH 2 CH 2 N(CH 3 ) 2 , C(CH 3 ) 2 N(CH 3 ) 2 , CH(CH 3 )N(CH 3 ) 2 , CH 2 CN, SOCH 3 , SO 2 CH 3 , SOCH 2 CH 3 , SO 2 CH 2 CH 3 , SO 2 NH 2 , pyrrolidinyl, piperidinyl, aziridinyl, cyclopropyl, Cyclobutyl, cyclopentyl and cyclohexyl, wherein the pyrrolidinyl, piperidinyl, aziridine, oxacyclobutane, morpholinyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl Unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F, Cl, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH(CH 3 ) CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ) , N(CH 3 ) 2 and NHCOCH 3 . 如請求項1至4中之一或多項之化合物，其中G為以下G45或G2之群組之一 其中該以星號(*)標記之位置指出該連接處，其係被連接至該嘧啶環；每次出現之k為0、1或2；且ZA為H或F；每次出現之Z係獨立地選自於由F、Cl、CN、CF3、CHF2、CH2F、OCF3、OH、OCH3、OC2H5、OCOCH3、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、CH2CH2CH2CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、NHCOCH3、CH2OH、CH2CH2OH、C(CH3)2OH、CH(CH3)OH、CH2NH2、CH2CH2NH2、C(CH3)2NH2、CH(CH3)NH2、CH2NH(CH3)、CH2CH2NH(CH3)、C(CH3)2NH(CH3)、CH(CH3)NH(CH3)、CH2N(CH3)2、CH2CH2N(CH3)2、C(CH3)2N(CH3)2、CH(CH3)N(CH3)2、CH2CN、SOCH3,SO2CH3、環丙基、環丁基、3-氧環丁烷基、2-氮丙啶基、3-氮丙啶基、1-吡咯啶基、1-哌啶 基及1-嗎啉基所組成之群組，其中該環丙基、環丁基、3-氧環丁烷基、2-氮丙啶基、3-氮丙啶基、1-吡咯啶基、1-哌啶基及1-嗎啉基係未經取代或經以一或多取代基單或多取代，該取代基係選自於由F、Cl、CN、CF3、OCF3、OH、OCH3、CH3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、N(CH3)2及NHCOCH3所組成之群組。 A compound according to one or more of claims 1 to 4, wherein G is one of the following groups of G45 or G2 Wherein the position marked with an asterisk (*) indicates the junction, which is attached to the pyrimidine ring; each occurrence of k is 0, 1 or 2; and Z A is H or F; each occurrence of the Z system Independently selected from the group consisting of F, Cl, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3 ) 2 NH 2 , CH(CH 3 )NH 2 , CH 2 NH(CH 3 ), CH 2 CH 2 NH(CH 3 ), C(CH 3 ) 2 NH(CH 3 ), CH(CH 3 )NH(CH 3 ), CH 2 N(CH 3 ) 2 , CH 2 CH 2 N(CH 3 ) 2 , C(CH 3 ) 2 N(CH 3 ) 2 , CH(CH 3 )N(CH 3 ) 2 , CH 2 CN, SOCH 3 , SO 2 CH 3 , cyclopropyl, cyclobutyl, 3-oxocyclobutene a group consisting of an alkyl group, a 2-aziridine group, a 3-aziridine group, a 1-pyrrolidinyl group, a 1-piperidinyl group, and a 1-morpholinyl group, wherein the cyclopropyl group, cyclobutyl group, 3 -oxycyclobutane, 2-aziridine, 3-aziridine, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl are unsubstituted or have one or more substituents Mono- or polysubstituted, the substituent is selected from the group consisting of F, Cl, CN, CF 3 , OCF 3 , OH, OCH 3 , CH 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH A group consisting of (CH 3 ), N(CH 3 ) 2 and NHCOCH 3 . 如請求項1至5中之任一項之化合物，其特徵在於L係選自於C(=O)NR2、S(=O)、S(=O)2、P(=O)(R2)、S(=O)2NR2或鍵結。 The compound according to any one of claims 1 to 5, wherein L is selected from the group consisting of C(=O)NR 2 , S(=O), S(=O) 2 , P(=O)(R) 2 ), S(=O) 2 NR 2 or bonding. 如請求項1至6中之任一項之化合物，其特徵在於L係選自於C(=O)NR2、S(=O)、S(=O)2、S(=O)2NR2或鍵結；及R1係選自於C1-C6-烷基、C3-C6-環烷基或3至7員雜環烷基，其中該C1-C6-烷基可為未經取代或經以一、二、三或四取代基取代，該取代基係選自於由鹵素、CN、OH、=O、=NH、NH2、NH(C1-C6-烷基)、N(C1-C6-烷基)2、C1-C6-烷氧基、C3-C6-環烷基及3至7員雜環烷基所組成之群組；且其中該3至7員雜環烷基可含有一或二個另外之雜原子，其係選自於由O、S及N所組成之群組且其中該C3-C6-環烷基及該3至7員雜環烷基係未經取代或經以一、二、三或四取代基取代，該取代基係選自於由鹵素、CN、OH、=O、NH2、NH(C1-C6-烷基)、N(C1-C6-烷基)2、C1-C6-烷基，(C1-C6)-羥烷基、(C1-C6)-鹵烷基及C1-C6-烷氧基所組成之群組；且R2係選自於H或C1-C6-烷基其中該C1-C6-烷基可為未經取代或經以一、二、三或四取代基取代，該 取代基係選自於由鹵素、OH、C1-C6-烷氧基及C3-C6-環烷基所組成之群組；或R1及R2與其所連接之氮原子一起形成3至12員雜環烷基，其中該3至12員雜環烷基可含有選自於由O、S及N所組成之群組之一或二個另外之雜原子，且其中該3至12員雜環烷基係未經取代或經以一、二、三或四取代基取代，該取代基係選自於由鹵素、CN、OH、=O、NH2、NH(C1-C6-烷基)、N(C1-C6-烷基)2、C1-C6-烷基、(C1-C6)-羥烷基、(C1-C6)-鹵烷基及C1-C6-烷氧基所組成之群組。 The compound according to any one of claims 1 to 6, wherein L is selected from the group consisting of C(=O)NR 2 , S(=O), S(=O) 2 , S(=O) 2 NR 2 or a bond; and R 1 is selected from C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl or 3 to 7 membered heterocycloalkyl, wherein the C 1 -C 6 -alkyl It may be unsubstituted or substituted with a mono-, di-, tri- or tetra-substituent selected from halogen, CN, OH, =O, =NH, NH 2 , NH(C 1 -C 6 - a group consisting of an alkyl group, N(C 1 -C 6 -alkyl) 2 , a C 1 -C 6 -alkoxy group, a C 3 -C 6 -cycloalkyl group and a 3 to 7 membered heterocycloalkyl group And wherein the 3 to 7 membered heterocycloalkyl group may contain one or two additional heteroatoms selected from the group consisting of O, S and N and wherein the C 3 -C 6 -cycloalkane And the 3 to 7 membered heterocycloalkyl group is unsubstituted or substituted with a mono-, di-, tri- or tetra-substituent selected from halogen, CN, OH, =0, NH 2 , NH (C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl) 2 , C 1 -C 6 -alkyl, (C 1 -C 6 )-hydroxyalkyl, (C 1 -C 6) - haloalkyl and C 1 -C 6 - the group consisting of alkoxy; and R 2 is selected from H or to a C 1 -C 6 - alkyl wherein C 1 -C 6 - alkyl group may be unsubstituted or substituted with one, two, three or four substituents selected from the substituent group consisting of halogen, OH, C 1 -C 6 - alkoxy and C a group consisting of 3 -C 6 -cycloalkyl; or R 1 and R 2 together with the nitrogen atom to which they are attached form a 3 to 12 membered heterocycloalkyl group, wherein the 3 to 12 membered heterocycloalkyl group may contain From one or two additional heteroatoms consisting of O, S and N, and wherein the 3 to 12 membered heterocycloalkyl group is unsubstituted or substituted with one, two, three or four substituents Substituting, the substituent is selected from the group consisting of halogen, CN, OH, =0, NH 2 , NH(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl) 2 , C 1 - A group consisting of C 6 -alkyl, (C 1 -C 6 )-hydroxyalkyl, (C 1 -C 6 )-haloalkyl and C 1 -C 6 -alkoxy. 如請求項1至7中之任一項之化合物，其特徵在於L為C(=O)NR2及R1係選自於以下M1至M76次結構之一： 且R2係選自於H或CH3。 The compound according to any one of claims 1 to 7, wherein L is C(=O)NR 2 and R 1 is selected from one of the following M1 to M76 substructures: And R 2 is selected from H or CH 3 . 如請求項1至7中之任一項之化合物，其特徵在於L為C(=O)NR2及R1及R2與其所連接之氮原子一起形成3至12員雜環烷基，其中該3至12員雜環烷基表示以下Q1至Q34基團之一： 其中該以星號(*)標記之位置指出該連接處，其係被連接至L之羰基基團；R5係選自於由H、C1-C6-烷基、(C1-C6)-羥烷基、(C1-C6)-氰烷基、C3-C6-環烷基、CO(C1-C6-烷基)及SO2-(C1-C6)-烷基所組成之群組；每次出現之p為0、1、2、3、4或5；且每次出現之X6係獨立地選自於由OH、=O、CN、F、Cl、Br、CF3、CHF2、CH2F、OCF3、C1-C6-烷基、(C1-C6)-羥烷基、(C1-C6)-氰烷基、(C1-C6)-烷氧基、(C3-C6)-環烷基、NH2、NH(C1-C6-烷基)、N(C1-C6-烷基)2、NHCO(C1-C6-烷基)、CO2H、CO(C1-C6-烷基)、COO(C1-C6-烷基)、CONH2、CONH(C1-C6-烷基)及CON(C1-C6-烷基)2所組成之群組。 The compound according to any one of claims 1 to 7, wherein L is C(=O)NR 2 and R 1 and R 2 together with the nitrogen atom to which they are attached form a 3 to 12 membered heterocycloalkyl group, wherein The 3 to 12 membered heterocycloalkyl group represents one of the following Q1 to Q34 groups: Wherein the position marked with an asterisk (*) indicates the junction, which is linked to the carbonyl group of L; R 5 is selected from H, C 1 -C 6 -alkyl, (C 1 -C 6 )-hydroxyalkyl, (C 1 -C 6 )-cyanoalkyl, C 3 -C 6 -cycloalkyl, CO(C 1 -C 6 -alkyl) and SO 2 -(C 1 -C 6 ) a group consisting of -alkyl groups; each occurrence of p is 0, 1, 2, 3, 4 or 5; and each occurrence of the X 6 system is independently selected from OH, =O, CN, F, Cl, Br, CF 3 , CHF 2 , CH 2 F, OCF 3 , C 1 -C 6 -alkyl, (C 1 -C 6 )-hydroxyalkyl, (C 1 -C 6 )-cyanoalkyl, (C 1 -C 6 )-alkoxy, (C 3 -C 6 )-cycloalkyl, NH 2 , NH(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl) 2 , NHCO (C 1 -C 6 -alkyl), CO 2 H, CO (C 1 -C 6 -alkyl), COO (C 1 -C 6 -alkyl), CONH 2 , CONH (C 1 - A group consisting of C 6 -alkyl) and CON(C 1 -C 6 -alkyl) 2 . 如請求項1至7中之任一項之化合物，其特徵在於L為S(=O)或S(=O)2及R1係選自於OH、CN、C1-C6-烷基、NH2、NH(C1-C6-烷基)、N(C1-C6-烷基)2、C3-C6-環烷基或3至7員雜環烷基，其中該C1-C6-烷基可為未經取代或經以一、二、三或四取代基取代，該取代基係選自於由鹵素、CN、OH、NH2、C1-C6-烷氧基、C3-C6-環烷基及3至7員雜環烷基所組成之群組；且其中該3至7員雜環烷基可含有選自於由O、S及N所組成之群組之一或二個另外之雜原子，且其中該3至7員雜環烷基係未經取代或經以一、二、三或四取代基取代， 該取代基係選自於由鹵素、CN、OH、=O、NH2、C1-C6-烷基、(C1-C6)-羥烷基、(C1-C6)-鹵烷基及C1-C6-烷氧基所組成之群組。 The compound according to any one of claims 1 to 7, wherein L is S(=O) or S(=O) 2 and R 1 is selected from OH, CN, C 1 -C 6 -alkyl , NH 2 , NH(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl) 2 , C 3 -C 6 -cycloalkyl or 3 to 7 membered heterocycloalkyl, wherein The C 1 -C 6 -alkyl group may be unsubstituted or substituted with a mono-, di-, tri- or tetra-substituent selected from halogen, CN, OH, NH 2 , C 1 -C 6 - a group consisting of an alkoxy group, a C 3 -C 6 -cycloalkyl group, and a 3 to 7 membered heterocycloalkyl group; and wherein the 3 to 7 membered heterocycloalkyl group may be selected from O, S, and N One or two additional heteroatoms of the group, and wherein the 3 to 7 membered heterocycloalkyl group is unsubstituted or substituted with a mono-, di-, tri- or tetra-substituent, the substituent is selected from From halogen, CN, OH, =O, NH 2 , C 1 -C 6 -alkyl, (C 1 -C 6 )-hydroxyalkyl, (C 1 -C 6 )-haloalkyl and C 1 - A group consisting of C 6 -alkoxy groups. 如請求項1至7中之任一項之化合物，其特徵在於L為S(=O)或S(=O)2及R1係選自於如請求項8之M1至M76次結構之一。 The compound according to any one of claims 1 to 7, wherein L is S(=O) or S(=O) 2 and R 1 is selected from one of M1 to M76 substructures as claimed in claim 8. . 如請求項1之化合物，其中該通式(I)之化合物係選自於通式(Ia)、(Ib)、(Ic)或(Id)之一， or其中R1、R2及G係如先前請求項之任一者所定義。 The compound of claim 1, wherein the compound of the formula (I) is selected from the group consisting of one of the formula (Ia), (Ib), (Ic) or (Id), Or where R 1 , R 2 and G are as defined in any of the prior claims. 如請求項12之化合物，其中該通式(Ia)、(Ib)、(Ic)、(Id)或(Ie)之化合物之特徵在於G係選自於G1或G2，其中每次出現之k為0、1、2或3；每次出現之Z係獨立地選自於由F、Cl、CN、CF3、CHF2、CH2F、OCF3、OH、OCH3、OC2H5、OCOCH3、CH3、CH2CH3、(CH2)2CH3、CH(CH3)2、 (CH2)3CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CONH2、CONHCH3、CON(CH3)2、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、NHCOCH3、CH2OH、CH2CH2OH、C(CH3)2OH、CH(CH3)OH、CH2NH2、CH2CH2NH2、C(CH3)2NH2、CH(CH3)NH2、CH2NH(CH3)、CH2CN、SOCH3、SO2CH3、環丙基及環丁基所組成之群組；且其中R1及R2係如先前請求項之任一者中所定義。 The compound of claim 12, wherein the compound of the formula (Ia), (Ib), (Ic), (Id) or (Ie) is characterized in that the G group is selected from G1 or G2, wherein each occurrence of k Is 0, 1, 2 or 3; each occurrence of the Z series is independently selected from the group consisting of F, Cl, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3 ) 2 NH 2 , CH(CH 3 a group consisting of NH 2 , CH 2 NH(CH 3 ), CH 2 CN, SOCH 3 , SO 2 CH 3 , cyclopropyl and cyclobutyl; and wherein R 1 and R 2 are as previously claimed As defined in either. 如一或多項前述請求項之化合物，其係選自於由以下所組成之群組1 1-(5-(2-氟苯基)嘧啶-2-基)-N,N-二甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺2 (1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮3 N-(2-胺-2-側氧乙基)-1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺4 嗎啉基(1-(5-苯基嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)甲酮5 N-(2-胺-2-側氧乙基)-1-(5-(2-氟-5-甲氧基苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺6 N-(2-胺-2-側氧乙基)-N-甲基-1-(5-苯基嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺7 N-(2-胺-2-側氧乙基)-1-(5-(5-乙基-2-氟苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺8 嗎啉基(1-(5-(吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)甲酮9 (1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮10 (1-(5-(4-甲氧基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮 11 N-(2-胺-2-側氧乙基)-1-(5-(2-氟苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺12 N-(2-胺-2-側氧乙基)-1-(5-(5-乙氧基-2-氟苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺13 N-(2-胺-2-側氧乙基)-N-甲基-1-(5-(吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺14 嗎啉基(1-(5-(3-(三氟甲基)苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)甲酮15 (1-(5-(2-氟-5-(三氟甲基)苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)-(嗎啉基)甲酮16 1-(5-(2-氟-5-(三氟甲基)苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺17 N-(2-羥乙基)-N-甲基-1-(5-(3-(三氟甲基)苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺18 (1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(吡咯啶-1-基)甲酮19 (1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(哌嗪-1-基)甲酮20 1-(5-(2-氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺21 (1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基(1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)甲酮22 (1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(哌嗪-1-基)甲酮 23 (1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(吡咯啶-1-基)甲酮24 N-(2-羥乙基)-N-甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺25 (1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基(1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)甲酮26 N-(2-胺-2-側氧乙基)-1-(5-(3-環丙基苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺27 N-(2-胺-2-側氧乙基)-N-甲基-1-(5-(m-甲苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺28 (S)-N-(2-胺-2-側氧乙基)-1-(5-(2-氟-5-(1-羥乙基)苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺29 (R)-N-(2-胺-2-側氧乙基)-1-(5-(2-氟-5-(1-羥乙基)苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺30 N-(2-胺-2-側氧乙基)-1-(5-(2-氟-5-(2-羥基丙-2-基)苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺31 嗎啉基(1-(5-(m-甲苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)甲酮32 (1-(5-(2-氟-5-甲氧基苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮33 (1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮34 (1-(5-(吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(吡咯啶-1-基)甲酮35 (1-(5-(4-環丙基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(吡 咯啶-1-基)甲酮36 (1-(5-(4-甲氧基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(吡咯啶-1-基)甲酮37 (1-(5-(3-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮38 (1-(5-(4-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮39 (1-(5-(2,5-二氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮40 (1-(5-(2,3-二氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮41 (1-(5-(3,5-二氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮42 1-(5-(3-氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺43 1-(5-(4-氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺44 1-(5-(2,5-二氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺45 1-(5-(2,3-二氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺46 1-(5-(3,5-二氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺47 N-(2-胺-2-側氧乙基)-1-(5-(3-氟苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺48 N-(2-胺-2-側氧乙基)-1-(5-(4-氟苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'- 氧環丁烷]-6-甲醯胺49 N-(2-胺-2-側氧乙基)-1-(5-(2,5-二氟苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺50 N-(2-胺-2-側氧乙基)-1-(5-(2,3-二氟苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺51 N-(2-胺-2-側氧乙基)-1-(5-(3,5-二氟苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺52 6-(乙亞磺醯基)-1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]53 6-(乙磺醯基)-1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]54 6-(乙亞磺醯基)-1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]55 6-(乙磺醯基)-1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]56 6-(乙亞磺醯基)-1-(5-(4-甲氧基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]57 6-(乙磺醯基)-1-(5-(4-甲氧基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]58 1-(5-(4-環丙基吡啶-2-基)嘧啶-2-基)-6-(乙亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]59 1-(5-(4-環丙基吡啶-2-基)嘧啶-2-基)-6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]60 1-(5-(4-乙基吡啶-2-基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺61 1-(5-(4-環丙基吡啶-2-基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 62 N-(2-羥乙基)-1-(5-(4-甲氧基吡啶-2-基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺63 1-(5-(4-乙氧基吡啶-2-基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺64 N-(2-羥乙基)-N-甲基-1-(5-(吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺65 N-(2-羥乙基)-N-甲基-1-(5-(4-(三氟甲基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺66 N-(2-羥乙基)-1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺67 (1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(吡咯啶-1-基)甲酮68 (1-(5-(4-乙氧基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(吡咯啶-1-基)甲酮69 吡咯啶-1-基(1-(5-(4-(三氟甲基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)甲酮70 (1-(5-(4-乙基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(吡咯啶-1-基)甲酮71 (S)-或(R)-1-(3-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)-4-氟苯基)乙醇72 (R)-或(S)-1-(3-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)-4-氟苯基)乙醇73 2-(3-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)-4-氟苯基)丙-2-醇 74 2-(3-(2-(6-(乙亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)-4-氟苯基)丙-2-醇75 2-(2-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-4-基)丙-2-醇76 2-(2-(2-(6-(乙亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-4-基)丙-2-醇77 (S)-或(R)-1-(2-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-4-基)乙醇78 (R)-或(S)-1-(2-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-4-基)乙醇79 N-(2-羥乙基)-N-甲基-1-(5-苯基嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺80 N-(2-羥乙基)-N-甲基-1-(5-(m-甲苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺81 1-(5-(3-環丙基苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺82 N-(2-羥乙基)-1-(5-(3-甲氧基苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺83 1-(5-(3-乙氧基苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺84 1-(5-(3-氯苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺85 N-(2-羥乙基)-N-甲基-1-(5-(3-(三氟甲氧基)苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 86 1-(5-(3-胺苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺87 N-(2-羥乙基)-N-甲基-1-(5-(3-(吡咯啶-1-基)苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺88 N-(2-羥乙基)-1-(5-(3-(1-羥乙基)苯基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺89 1-(5-(3,4-二氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺90 1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺91 1-(5-(5-環丙基-2-氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺92 1-(5-(2-氟-5-甲氧基苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺93 1-(5-(5-乙氧基-2-氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺94 1-(5-(2-氟-5-(三氟甲氧基)苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺95 1-(5-(5-胺-2-氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺96 1-(5-(5-(乙基胺)-2-氟苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺97 1-(5-(3-(乙基胺)苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 98 吡咯啶-1-基(1-(5-(4-(三氟甲基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)甲酮99 2-(2-(2-(6-(甲亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-4-基)丙-2-醇100 2-(2-(2-(6-(甲磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-4-基)丙-2-醇101 1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)-N,N-二甲基螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺102 1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺103 N,N-二甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺104 N-(2-羥乙基)-N-甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺105 N-甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)-N-(氧環丁烷-3-基甲基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺106 N-(環丙基甲基)-N-甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺107 N-((3,3-二氟環丁基)甲基)-N-甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺-[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺108 6-(乙亞磺醯基)-1-(5-(噠嗪-3-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]109 6-(乙磺醯基)-1-(5-(噠嗪-3-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]110 2-(3-(2-(6-(乙亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)苯基)丙-2-醇 111 2-(3-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)苯基)丙-2-醇112 6-(乙亞磺醯基)-1-(5-(5-甲基噠嗪-3-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]113 6-(乙磺醯基)-1-(5-(5-甲基噠嗪-3-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]114 2-(6-(2-(6-(乙亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)噠嗪-4-基)丙-2-醇115 2-(6-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)噠嗪-4-基)丙-2-醇116 2-((1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)亞磺醯基)乙醇117 2-((1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)磺醯基)乙醇118 2-(2-(2-(6-((2-羥乙基)亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-4-基)丙-2-醇119 2-(2-(2-(6-((2-羥乙基)磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-4-基)丙-2-醇120 3-((1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)亞磺醯基)丙-1-醇121 3-((1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)磺醯基)丙-1-醇122 3-((1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)亞磺醯基)丙-1-醇124 3-((1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁 烷]-6-基)磺醯基)丙-1-醇125 (1-(5-(6-羥基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮126 (1-(5-(3-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮127 (1-(5-(2-氟-3-羥苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)-甲酮128 (1-(5-(3-胺-2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)-甲酮129 (1-(6-甲基-[4,5'-聯嘧啶]-2'-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮130 (1-(5-(2-氟-6-羥苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)-甲酮131 (1-(5-(2-胺-6-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)-甲酮132 (1-(5-(6-胺基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮133 (1-(5-(2-氟-3-甲基苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮134 (1-(5-(2-氟-6-甲基苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮135 (1-(4-甲基-[2,5'-聯嘧啶]-2'-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮136 (1-(4,6-二甲基-[2,5'-聯嘧啶]-2'-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉 基)甲酮137 1-([2,5'-聯嘧啶]-2'-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺138 N-(2-羥乙基)-N-甲基-1-(5-(吡嗪-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺139 N-(2-羥乙基)-N-甲基-1-(5-(6-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺140 N-(2-羥乙基)-1-(5-(6-羥基吡啶-2-基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺141 N-(2-羥乙基)-1-(5-(6-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺142 (1-(5-(6-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮143 (1-(5-(6-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮144 N-((3-羥基氧環丁烷-3-基)甲基)-N-甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺145 N-((1-羥基環丙基)甲基)-N-甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺146 1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)-N,N-二甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺147 1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺148 N-甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲 醯胺149 N-(2-羥乙基)-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺150 N-(2-羥乙基)-1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺151 1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)-N-(2-羥乙基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺152 (1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)(嗎啉基)甲酮153 1-(5-(2-氟苯基)嘧啶-2-基)-N-(2-羥乙基)螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺154 N-(2-羥乙基)-1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺155 N-(2-羥乙基)-1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺156 N-(2-羥乙基)-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺157 N-甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺158 1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺159 6-(乙亞磺醯基)-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]161 6-(乙亞磺醯基)-1-(5-(吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷] 163 6-(乙磺醯基)-1-(5-(吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]164 2-(6-(2-(6-(乙亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-2-基)丙-2-醇166 2-(6-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-2-基)丙-2-醇167 2-((1-(5-(吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)亞磺醯基)乙醇169 2-((1-(5-(吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)磺醯基)乙醇170 2-(2-(2-(6-(乙亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-4-基)丙-2-胺171 2-(2-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-4-基)丙-2-胺172 2-(2-(6-(乙亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)異菸鹼醯胺173 2-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)異菸鹼醯胺174 2-(2-(6-(嗎啉-4-羰基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)異菸鹼醯胺175 1-(5-(4-胺甲醯基吡啶-2-基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺176 2-(2-(6-(嗎啉-4-羰基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)異菸鹼甲腈177 1-(5-(4-氰基吡啶-2-基)嘧啶-2-基)-N-(2-羥乙基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-甲醯胺 178 N-(2-羥乙基)-N-甲基-1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)-2',3',5',6'-四氫螺[吲哚啉-3,4'-哌喃]-6-甲醯胺179 2-(4-氟-3-(2-(6-(1-(甲基胺)環丙基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)苯基)丙-2-醇180 1-(1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)-N-甲基環丙胺181 1-(1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)-N-甲基環丙胺182 1-(1-(5-(4-甲氧基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)-N-甲基環丙胺183 2-(2-(2-(6-(1-(甲基胺)環丙基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)吡啶-4-基)丙-2-醇184 N-甲基-1-(1-(5-(4-甲基吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)環丙胺185 N-乙基-1-(5-(4-(2-羥基丙-2-基)吡啶-2-基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺186 1-(5-(4-(2-胺基丙-2-基)吡啶-2-基)嘧啶-2-基)-N-甲基螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺187 1-(5-(4-(2-胺基丙-2-基)吡啶-2-基)嘧啶-2-基)-N,N-二甲基螺[吲哚啉-3,3'-氧環丁烷]-6-磺醯胺188 N-(2-羥乙基)-N-甲基-1'-(5-(4-甲基吡啶-2-基)嘧啶-2-基)-4,5-二氫-2H-螺-[呋喃-3,3'-吲哚啉]-6'-甲醯胺189 2-(2-(6-(乙亞磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)異菸鹼甲腈 191 2-(2-(6-(乙磺醯基)螺[吲哚啉-3,3'-氧環丁烷]-1-基)嘧啶-5-基)異菸鹼甲腈192 (1-(5-(2-氟-5-甲基苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)二甲基膦氧化物193 (1-(5-(2-氟苯基)嘧啶-2-基)螺[吲哚啉-3,3'-氧環丁烷]-6-基)二甲基膦氧化物其可擇地為單一立體異構物或立體異構物混合物之形式、游離化合物之形式及/或其生理上可接受之鹽類及/或生理上可接受之溶劑。 A compound according to one or more of the preceding claims, which is selected from the group consisting of 1-(5-(2-fluorophenyl)pyrimidin-2-yl)-N,N-dimethylspiro[ Porphyrin-3,3'-oxycyclobutane]-6-carbamimidamine 2 (1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3' -oxycyclobutane]-6-yl)(morpholinyl)methanone 3 N-(2-amine-2-oxoethyl)-1-(5-(2-fluoro-5-methylphenyl) Pyrimidine-2-yl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane]-6-carbamidamine 4 morpholinyl (1-(5-phenylpyrimidin-2-) Spiral [porphyrin-3,3'-oxycyclobutane]-6-yl)methanone 5 N-(2-amine-2-oxoethyl)-1-(5-(2-fluoro -5-methoxyphenyl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane]-6-carboxamide 6 N-(2-amine- 2-sided oxyethyl)-N-methyl-1-(5-phenylpyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-carboxamide 7 N -(2-Amino-2-oxoethyl)-1-(5-(5-ethyl-2-fluorophenyl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3, 3'-oxocyclobutane]-6-carbamidamine 8 morpholinyl (1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxygen ring Butane]-6-yl)methanone 9 (1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane] -6-yl) (morpholinyl) Ketone 10 (1-(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl) (morpholine) Ketone 11 N-(2-Amino-2-oxoethyl)-1-(5-(2-fluorophenyl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3,3'- Oxycyclobutane]-6-formamide 12 N-(2-amine-2-oxoethyl)-1-(5-(5-ethoxy-2-fluorophenyl)pyrimidin-2-yl )-N-methylspiro[porphyrin-3,3'-oxycyclobutane]-6-formamide 13 N-(2-amine-2-oxoethyl)-N-methyl-1 -(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-formamide 14 morpholinyl (1-(5-(( 3-(Trifluoromethyl)phenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)methanone 15 (1-(5-(2- Fluoro-5-(trifluoromethyl)phenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)-(morpholinyl)methanone 16 1 -(5-(2-fluoro-5-(trifluoromethyl)phenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3 '-Oxycyclobutane]-6-formamide 17 N-(2-hydroxyethyl)-N-methyl-1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2- Spirulina [porphyrin-3,3'-oxycyclobutane]-6-formamide 18 (1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[porphyrin- 3,3'-oxocyclobutane]-6-yl)(pyrrolidin-1-yl)methanone 19 (1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[porphyrin -3,3'-oxocyclobutane]-6-yl)(piperazin-1-yl)methanone 20 1-(5-(2-fluorobenzene) Pyrimidine-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane]-6-carbamimidamide 21 (1S, 4S -2,5-diazabicyclo[2.2.1]heptan-2-yl(1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'- Oxycyclobutane]-6-yl)methanone 22 (1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane Alkyl]-6-yl)(piperazin-1-yl)methanone 23(1-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)(pyrrolidin-1 -yl)methanone 24 N-(2-hydroxyethyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3 , 3'-oxocyclobutane]-6-formamide 25 (1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl (1-(5-(4-A) Pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)methanone 26 N-(2-amine-2-side oxyethyl )-1-(5-(3-cyclopropylphenyl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane]-6-carboxamide 27 N-(2-Amine-2-oxoethyl)-N-methyl-1-(5-(m-methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxygen ring Butane]-6-carbamamine 28 (S)-N-(2-Amino-2-oxoethyl)-1-(5-(2-fluoro-5-(1-hydroxyethyl)phenyl) Pyrimidine-2-yl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane]-6-formamide 29 (R)-N-(2-amine-2-side oxygen Ethyl)-1-(5-(2-fluoro-5-(1-hydroxyethyl)phenyl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3,3'-oxygen ring Butane]-6-carbamamine 30 N-(2-Amino-2-oxoethyl)-1-(5-(2-fluoro-5-(2-hydroxypropan-2-yl)phenyl) Pyrimidin-2-yl)-N-methylspiro[porphyrin-3,3'-oxycyclobutane]-6-carbamimidyl 31 morpholinyl (1-(5-(m-) Phenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)methanone 32 (1-(5-(2-fluoro-5-methoxybenzene) Pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)(morpholinyl)methanone 33 (1-(5-(2-fluoro-5-) Methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)(morpholinyl)methanone 34 (1-(5-(pyridine-2) -yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl)(pyrrolidin-1-yl)methanone 35 (1-(5-(4- Cyclopropylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl) (pyridyl) "rrolidin-1-yl)methanone 36 (1-(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane] -6-yl)(pyrrolidin-1-yl)methanone 37 (1-(5-(3-fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane ]-6-yl)(morpholinyl)methanone 38 (1-(5-(4-fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]- 6-yl)(morpholinyl)methanone 39 (1-(5-(2,5-difluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane] -6-yl)(morpholinyl)methanone 40 (1-(5-(2,3-difluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane ]-6-yl)(morpholinyl)methanone 41 (1-(5-(3,5-difluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane Alkyl]-6-yl)(morpholinyl)methanone 42 1-(5-(3-fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[ Porphyrin-3,3'-oxocyclobutane]-6-carbamimid 43 1-(5-(4-fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)- N-methylspiro[porphyrin-3,3'-oxycyclobutane]-6-formamide 44 1-(5-(2,5-difluorophenyl)pyrimidin-2-yl)-N -(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane]-6-formamide 45 1-(5-(2,3-difluorophenyl) Pyrimidine-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxygen Butane]-6-formamide 46 1-(5-(3,5-difluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[吲哚Benzyl-3,3'-oxocyclobutane]-6-formamide 47 N-(2-amine-2-oxoethyl)-1-(5-(3-fluorophenyl)pyrimidin-2- ))-N-methylspiro[porphyrin-3,3'-oxocyclobutane]-6-formamide 48 N-(2-amine-2-oxoethyl)-1-(5- (4-fluorophenyl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3,3'- Oxycyclobutane]-6-formamide 49 N-(2-amine-2-oxoethyl)-1-(5-(2,5-difluorophenyl)pyrimidin-2-yl)-N -methylspiro[porphyrin-3,3'-oxocyclobutane]-6-formamide 50 N-(2-amine-2-oxoethyl)-1-(5-(2,3) -difluorophenyl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane]-6-formamide 51 N-(2-amine-2-side Oxyethyl)-1-(5-(3,5-difluorophenyl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane]-6- Methionamine 52 6-(ethylsulfinyl)-1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]53 6 -(ethanesulfonyl)-1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]54 6-(ethenesulfonate) -1(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]55 6-(ethanesulfonyl) -1(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]56 6-(ethylsulfinyl) -1(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]57 6-(ethionyl) 1-(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]58 1-(5-(4-ring) Propylpyridin-2-yl)pyrimidin-2-yl)-6-(ethylsulfinyl) snail [吲Porphyrin-3,3'-oxocyclobutane]59 1-(5-(4-cyclopropylpyridin-2-yl)pyrimidin-2-yl)-6-(ethanesulfonyl)spiro[porphyrin -3,3'-oxocyclobutane]60 1-(5-(4-ethylpyridin-2-yl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methyl snail [Porphyrin-3,3'-oxocyclobutane]-6-formamide 61 1-(5-(4-cyclopropylpyridin-2-yl)pyrimidin-2-yl)-N-(2 -hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxycyclobutane]-6-carboxamide 62 N-(2-hydroxyethyl)-1-(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3,3'- Oxycyclobutane]-6-formamide 63 1-(5-(4-ethoxypyridin-2-yl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methyl Spiro[porphyrin-3,3'-oxycyclobutane]-6-formamide 64 N-(2-hydroxyethyl)-N-methyl-1-(5-(pyridin-2-yl) Pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-carboxamide 65 N-(2-hydroxyethyl)-N-methyl-1-(5-( 4-(Trifluoromethyl)pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-carboxamide 66 N-(2-hydroxyethyl -1(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3,3'-oxygen Cyclobutane]-6-formamide 67 (1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3, 3'-oxocyclobutane]-6-yl)(pyrrolidin-1-yl)methanone 68 (1-(5-(4-ethoxypyridin-2-yl)pyrimidin-2-yl) snail [ Porphyrin-3,3'-oxocyclobutane]-6-yl)(pyrrolidin-1-yl)methanone 69 pyrrolidin-1-yl (1-(5-(4-(trifluoromethyl)) Pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)methanone 70 (1-(5-(4-ethylpyridine)- 2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6- (pyrrolidin-1-yl)methanone 71 (S)- or (R)-1-(3-(2-(6-(ethanesulfonyl)) spiro[porphyrin-3,3'-oxygen Cyclobutane]-1-yl)pyrimidin-5-yl)-4-fluorophenyl)ethanol 72 (R)- or (S)-1-(3-(2-(6-(ethanesulfonyl)) Spirulina [porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)-4-fluorophenyl)ethanol 73 2-(3-(2-(6-(ethanesulfonate) Sulforyl) porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)-4-fluorophenyl)propan-2-ol 74 2-(3-(2-(6-(ethylsulfinyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)-4-fluoro Phenyl)propan-2-ol 75 2-(2-(2-(6-(ethylsulfonyl)) spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidine-5 -yl)pyridin-4-yl)propan-2-ol 76 2-(2-(2-(6-(ethylsulfinyl)spiro[porphyrin-3,3'-oxocyclobutane]- 1-yl)pyrimidin-5-yl)pyridin-4-yl)propan-2-ol 77 (S)- or (R)-1-(2-(2-(6-(ethylsulfonyl)) snail [ Porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)pyridin-4-yl)ethanol 78 (R)- or (S)-1-(2-(2- (6-(ethanesulfonyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)pyridin-4-yl)ethanol 79 N-(2-hydroxyl Ethyl)-N-methyl-1-(5-phenylpyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-formamide 80 N-(2- Hydroxyethyl)-N-methyl-1-(5-(m-methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-carboxamide 81 1-(5-(3-cyclopropylphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxycyclobutane -6-Protonamine 82 N-(2-hydroxyethyl)-1-(5-(3-methoxyphenyl)pyrimidin-2-yl)-N-methylspiro[Porphyrin-3 , 3'-oxocyclobutane]-6-formamide 83 1-(5-(3-ethoxyphenyl)pyrimidin-2-yl)-N-(2-hydroxyl -N-methylspiro[porphyrin-3,3'-oxycyclobutane]-6-formamide 84 1-(5-(3-chlorophenyl)pyrimidin-2-yl)-N -(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxycyclobutane]-6-carboxamide 85 N-(2-hydroxyethyl)-N-methyl 1-(5-(3-(trifluoromethoxy)phenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-carboxamide 86 1-(5-(3-Aminophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane] -6-carbamamine 87 N-(2-hydroxyethyl)-N-methyl-1-(5-(3-(pyrrolidin-1-yl)phenyl)pyrimidin-2-yl) snail [吲Porphyrin-3,3'-oxycyclobutane]-6-formamide 88 N-(2-hydroxyethyl)-1-(5-(3-(1-hydroxyethyl)phenyl)pyrimidine- 2-yl)-N-methylspiro[porphyrin-3,3'-oxycyclobutane]-6-formamide 89 1-(5-(3,4-difluorophenyl)pyrimidine-2 -yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane]-6-formamide 90 1-(5-(2-fluoro -5-methylphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane]-6-formamidine Amine 91 1-(5-(5-cyclopropyl-2-fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3 '-Oxycyclobutane]-6-formamide 92 1-(5-(2-fluoro-5-methoxyphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N -methyl spiro[porphyrin-3,3'-oxocyclobutane]-6-carbamidamine 93 1-(5-(5-ethoxy-2-fluorophenyl)pyrimidin-2-yl) -N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxycyclobutane]-6-formamide 94 1-(5-(2-fluoro-5- (trifluoromethoxy)phenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxygen Butane]-6-formamide 95 1-(5-(5-Amino-2-fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[吲Porphyrin-3,3'-oxocyclobutane]-6-formamide 96 1-(5-(5-(ethylamine)-2-fluorophenyl)pyrimidin-2-yl)-N-( 2-Hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxycyclobutane]-6-formamide 97 1-(5-(3-(ethylamine)phenyl) Pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane]-6-carboxamide 98 pyrrolidin-1-yl (1-(5-(4-(trifluoromethyl)pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane] -6-yl)methanone 99 2-(2-(2-(6-(methylsulfinyl)) spiro[porphyrin-3,3'-oxocyclobutane]-1-yl)pyrimidine-5 -yl)pyridin-4-yl)propan-2-ol 100 2-(2-(2-(6-(methylsulfonyl)spiro[porphyrin-3,3'-oxycyclobutane]-1 -yl)pyrimidin-5-yl)pyridin-4-yl)propan-2-ol 101 1-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)-N,N-di Methyl spiro[porphyrin-3,3'-oxycyclobutane]-6-sulfonamide 102 1-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)-N -(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxycyclobutane]-6-sulfonamide 103 N,N-dimethyl-1-(5-( 4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-sulfonamide 104 N-(2-hydroxyethyl)-N -methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-sulfonamide 105 N -methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-N-(oxocyclobutan-3-ylmethyl)spiro[porphyrin-3,3 '-Oxycyclobutane]-6-formamide 106 N-(cyclopropylmethyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl ) snail [porphyrin-3,3'-oxycyclobutane]-6-formamide 107 N-( (3,3-Difluorocyclobutyl)methyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro-[porphyrin-3 ,3'-oxocyclobutane]-6-formamide 108 6-(ethylsulfinyl)-1-(5-(pyridazin-3-yl)pyrimidin-2-yl)spiro[porphyrin -3,3'-oxocyclobutane]109 6-(ethanesulfonyl)-1-(5-(pyridazin-3-yl)pyrimidin-2-yl)spiro[porphyrin-3,3' -oxocyclobutane]110 2-(3-(2-(6-(ethylsulfinyl)spiro[porphyrin-3,3'-oxocyclobutane]-1-yl)pyrimidine-5- Phenyl)propan-2-ol 111 2-(3-(2-(6-(ethylsulfonyl)) spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)phenyl)propene- 2-Alcohol 112 6-(ethylsulfinyl)-1-(5-(5-methylpyridazin-3-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxygen ring Butane]113 6-(ethanesulfonyl)-1-(5-(5-methylpyridazin-3-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane Alkyl]114 2-(6-(2-(6-(ethylsulfinyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)pyridazine 4-yl)propan-2-ol 115 2-(6-(2-(6-(ethylsulfonyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidine -5-yl)pyridazin-4-yl)propan-2-ol 116 2-((1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin- 3,3'-oxycyclobutane]-6-yl)sulfinyl)ethanol 117 2-((1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl) snail [ Porphyrin-3,3'-oxycyclobutane]-6-ylsulfonyl)ethanol 118 2-(2-(2-(6-((2-hydroxyethyl))sulfinyl)) snail [Porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)pyridin-4-yl)propan-2-ol 119 2-(2-(2-(6-( (2-Hydroxyethyl)sulfonyl) spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)pyridin-4-yl)propan-2-ol 120 3-((1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'- Oxycyclobutane]-6-yl)sulfinyl)propan-1-ol 121 3-((1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[吲Porphyrin-3,3'-oxycyclobutane]-6-yl)sulfonyl)-1-propanol 122 3-((1-(5-(4-(2-hydroxypropan-2-yl))) Pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)sulfinyl)propan-1-ol 124 3-((1- (5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane Alkyl]-6-yl)sulfonyl)propan-1-ol 125 (1-(5-(6-hydroxypyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'- Oxycyclobutane]-6-yl)(morpholinyl)methanone 126 (1-(5-(3-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3 '-Oxocyclobutane]-6-yl)(morpholinyl)methanone 127 (1-(5-(2-fluoro-3-hydroxyphenyl)pyrimidin-2-yl)spiro[porphyrin-3 ,3'-oxycyclobutane]-6-yl)(morpholinyl)-methanone 128 (1-(5-(3-amine-2-fluorophenyl)pyrimidin-2-yl) snail [吲哚Porphyrin-3,3'-oxycyclobutane]-6-yl)(morpholinyl)-methanone 129 (1-(6-methyl-[4,5'-bipyrimidine]-2'-yl) Spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)(morpholinyl)methanone 130 (1-(5-(2-fluoro-6-hydroxyphenyl)pyrimidin-2-) Spiral [porphyrin-3,3'-oxycyclobutane]-6-yl)(morpholinyl)-methanone 131 (1-(5-(2-amine-6-fluorophenyl)pyrimidine) -2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)(morpholinyl)-methanone 132 (1-(5-(6-aminopyridine)-2- Pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)(morpholinyl)methanone 133 (1-(5-(2-fluoro-3-) Methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)(morpholinyl)methanone 134 (1-(5-(2-fluoro) -6-methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane Alkyl]-6-yl)(morpholinyl)methanone 135 (1-(4-methyl-[2,5'-bipyrimidine]-2'-yl) snail [porphyrin-3,3'- Oxycyclobutane]-6-yl)(morpholinyl)methanone 136 (1-(4,6-dimethyl-[2,5'-bipyrimidine]-2'-yl) spiro[porphyrin -3,3'-oxocyclobutane]-6-yl) (morpholine) Methionone 137 1-([2,5'-bipyrimidin]-2'-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxygen Cyclobutane]-6-formamide 138 N-(2-hydroxyethyl)-N-methyl-1-(5-(pyrazin-2-yl)pyrimidin-2-yl)spiro[porphyrin -3,3'-oxocyclobutane]-6-formamide 139 N-(2-hydroxyethyl)-N-methyl-1-(5-(6-methylpyridin-2-yl)pyrimidine -2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-formamide 140 N-(2-hydroxyethyl)-1-(5-(6-hydroxypyridine-2 -yl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane]-6-formamide 141 N-(2-hydroxyethyl)-1-( 5-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane]-6 -Proline 142 (1-(5-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane Alkyl]-6-yl)(morpholinyl)methanone 143 (1-(5-(6-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxygen Cyclobutane]-6-yl)(morpholinyl)methanone 144 N-((3-hydroxyoxycyclobutane-3-yl)methyl)-N-methyl-1-(5-(4- Methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-formamide 145 N-((1-hydroxycyclopropyl)methyl )-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl Spirulina [porphyrin-3,3'-oxycyclobutane]-6-formamide 146 1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidine- 2-yl)-N,N-dimethylspiro[porphyrin-3,3'-oxocyclobutane]-6-formamide 147 1-(5-(4-(2-hydroxypropan-2) -yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane]-6-formamide 148 N-methyl-1- (5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-A Guanidine 149 N-(2-hydroxyethyl)-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane - 6-carbamamine 150 N-(2-hydroxyethyl)-1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl) snail [ Porphyrin-3,3'-oxycyclobutane]-6-formamide 151 1-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)-N-(2- Hydroxyethyl)spiro[porphyrin-3,3'-oxocyclobutane]-6-carbamimid 152 (1-(5-(4-(2-hydroxypropan-2-yl)pyridine-2-) Pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)(morpholinyl)methanone 153 1-(5-(2-fluorophenyl)pyrimidine -2-yl)-N-(2-hydroxyethyl)spiro[porphyrin-3,3'-oxycyclobutane]-6-formamide 154 N-(2-hydroxyethyl)-1- (5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane]- 6-sulfonamide 155 N-(2-hydroxyethyl)-1-(5-(4-(2-hydroxyprop-2-yl)pyridin-2-yl)pyrimidin-2-yl) snail Phenyl-3,3'-oxycyclobutane]-6-sulfonamide 156 N-(2-hydroxyethyl)-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl Spirulina [porphyrin-3,3'-oxycyclobutane]-6-sulfonamide 157 N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl ) spiro[porphyrin-3,3'-oxycyclobutane]-6-sulfonamide 158 1-(5-(4-(2- Propion-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane]-6-sulfonamide 159 6-( Ethylenesulfonyl)-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]161 6-(B Sulfosyl)-1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane] 163 6-(ethanesulfonyl)-1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]164 2-(6- (2-(6-(ethylsulfinyl) spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)pyridin-2-yl)propan-2- Alcohol 166 2-(6-(2-(6-(ethanesulfonyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)pyridine-2- Propan-2-ol 167 2-((1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl Sulfosyl)ethanol 169 2-((1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxocyclobutane]-6-yl Sulfhydryl)ethanol 170 2-(2-(2-(6-(ethylsulfinyl)) spiro[porphyrin-3,3'-oxocyclobutane]-1-yl)pyrimidine-5- Pyridin-4-yl)propan-2-amine 171 2-(2-(2-(6-(ethylsulfonyl)) spiro[porphyrin-3,3'-oxocyclobutane]-1- Benzylpyrimidin-5-yl)pyridin-4-yl)propan-2-amine 172 2-(2-(6-(ethylsulfinyl)spiro[porphyrin-3,3'-oxycyclobutane ]-1-yl)pyrimidin-5-yl)isonicotinium guanamine 173 2-(2-(6-(ethylsulfonyl)spiro[porphyrin-3,3'-oxocyclobutane]-1 -yl)pyrimidin-5-yl)isonicotininamide 174 2-(2-(6-(morpholine-4-carbonyl)spiro[porphyrin-3,3'-oxocyclobutane]-1- Aminopyrimidine-5-yl)isonicotinium guanamine 175 1-(5-(4-amine A) Pyridin-2-yl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxocyclobutane]-6-carboxamide 176 2-(2-(6-(morpholine-4-carbonyl)spiro[porphyrin-3,3'-oxocyclobutane]-1-yl)pyrimidin-5-yl)isonicotinonitrile 177 1-(5-(4-cyanopyridin-2-yl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[porphyrin-3,3'-oxygen ring Butane]-6-formamide 178 N-(2-Hydroxyethyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-2',3',5',6' - tetrahydrospiro[porphyrin-3,4'-piperan]-6-formamide 179 2-(4-fluoro-3-(2-(6-(1-(methylamine)))cyclopropyl) Spirulina [porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)phenyl)propan-2-ol 180 1-(1-(5-(2-fluorobenzene) Pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)-N-methylcyclopropylamine 181 1-(1-(5-(2-fluoro-) 5-methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)-N-methylcyclopropylamine 182 1-(1-(5- (4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)-N-methylcyclopropylamine 183 2-( 2-(2-(6-(1-(methylamine)cyclopropyl)spiro[porphyrin-3,3'-oxycyclobutane]-1-yl)pyrimidin-5-yl)pyridine-4 -yl)propan-2-ol 184 N-methyl-1-(1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[porphyrin-3,3'- Oxycyclobutane]-6-yl)cyclopropylamine 185 N-ethyl-1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl) snail [ Porphyrin-3,3'-oxocyclobutane]-6-sulfonamide 186 1-(5-(4-(2-Aminopropan-2-yl)pyridin-2-yl)pyrimidin-2- -N-methylspiro[porphyrin-3,3'-oxycyclobutane]-6-sulfonamide 187 1-(5-(4-(2-amine) Propion-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N,N-dimethylspiro[porphyrin-3,3'-oxocyclobutane]-6-sulfonamide 188 N-(2-hydroxyethyl)-N-methyl-1'-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-4,5-dihydro-2H-spiro- [furan-3,3'-carboline]-6'-formamide 189 2-(2-(6-(ethylsulfinyl) spiro[porphyrin-3,3'-oxycyclobutane ]-1-yl)pyrimidin-5-yl)isonicotinonitrile 191 2-(2-(6-(ethylsulfonyl)spiro[porphyrin-3,3'-oxocyclobutane]-1-yl)pyrimidin-5-yl)isonicotinonitrile 192 (1 -(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)dimethylphosphine oxide 193 (1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[porphyrin-3,3'-oxycyclobutane]-6-yl)dimethylphosphine oxide It is in the form of a single stereoisomer or a mixture of stereoisomers, in the form of a free compound and/or a physiologically acceptable salt thereof and/or a physiologically acceptable solvent. 一種包括如請求項1至14中之一項定義之至少一化合物之藥學組成物。 A pharmaceutical composition comprising at least one compound as defined in one of claims 1 to 14. 一種如請求項1至14中之一項定義之呈現形式或為單一立體異構物或立體異構物混合物之形式、游離化合物之形式及/或其生理上可接受之鹽類或溶劑合物之化合物用作治療可藉由抑制PDE4酵素治療之症狀或疾病之藥劑之用途，其中該可藉由抑制PDE4酵素治療之症狀或疾病係選自於以下群組：關節、皮膚及眼睛之發炎性疾病，胃腸道疾病及病訴，內臟之發炎性疾病；增生性疾病，與黏液產生增多、發炎及/或呼吸道阻塞有關之呼吸道或肺部疾病，纖維化譜(fibrotic spectrum)之疾病，癌症，代謝疾病，心理疾患，及周圍或中樞神經系統疾病。 A presentation form as defined in one of claims 1 to 14 or in the form of a single stereoisomer or mixture of stereoisomers, in the form of a free compound and/or a physiologically acceptable salt or solvate thereof The compound is used for the treatment of a medicament for inhibiting the symptoms or diseases of PDE4 enzyme treatment, wherein the symptoms or diseases which can be treated by inhibiting PDE4 enzyme are selected from the group consisting of inflammation of joints, skin and eyes. Diseases, gastrointestinal diseases and diseases, visceral inflammatory diseases; proliferative diseases, respiratory or pulmonary diseases associated with increased mucus production, inflammation and/or airway obstruction, diseases of fibrotic spectrum, cancer, Metabolic diseases, mental disorders, and peripheral or central nervous system diseases.
TW105142607A 2015-12-22 2016-12-22 Novel substituted spiro-[indoline heterocycloalkane] compounds as phosphodiesterase inhibitors TW201730192A (en)

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CN117924304B (en) * 2023-12-19 2025-09-16 成都大学 Chiral indolinone quinazolinone polycyclic compound containing dihydronaphthofuran structure, preparation method and application thereof

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