TW202241890A - Epidermal growth factor receptor inhibitors - Google Patents

Epidermal growth factor receptor inhibitors Download PDF

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TW202241890A
TW202241890A TW110149610A TW110149610A TW202241890A TW 202241890 A TW202241890 A TW 202241890A TW 110149610 A TW110149610 A TW 110149610A TW 110149610 A TW110149610 A TW 110149610A TW 202241890 A TW202241890 A TW 202241890A
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吉利爾 扎維亞拉夫
格奧爾基 雅各布森
沙米爾 卡德羅夫
阿德爾 海達羅夫
達里婭 貝科托娃
丹尼爾 波利安奇克
伊莉婭 斯米塔寧
拉米利亞 斯塔杜采娃
波琳娜 桑佐娃
狄密崔 哈拉布丁
阿爾西姆 什卡烏蘇
狄密崔 摩羅佐
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俄羅斯聯邦商拜奧卡德聯合股份公司
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/71—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators

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Abstract

The present invention relates to novel compounds of formula I: or pharmaceutically acceptable salt, solvate or stereoisomer thereof, which have EGFR inhibitor properties, to pharmaceutical compositions containing said compounds, to methods of treating diseases or disorders and the use of said compounds as pharmaceutical products for treating diseases or disorders.

Description

表皮生長因子受體之抑制劑Inhibitors of Epidermal Growth Factor Receptor

本發明涉及新的表皮生長因子受體(EGFR)抑制劑，還涉及其藥學上可接受的鹽、溶劑化物或立體異構體，涉及包含本發明化合物的藥物組合物，涉及治療疾病或病症的方法和本發明化合物作為藥物產品用於治療疾病或病症的用途。The present invention relates to a novel epidermal growth factor receptor (EGFR) inhibitor, also to its pharmaceutically acceptable salt, solvate or stereoisomer, to a pharmaceutical composition comprising the compound of the present invention, to a method for treating a disease or a disease Methods and uses of compounds of the invention as pharmaceutical products for the treatment of diseases or conditions.

表皮生長因子受體(EGFR)是跨膜糖蛋白-酪氨酸激酶，其是erbB受體家族的成員。EGFR由糖基化的外部配體結合結構域(621殘基)和胞質結構域(542殘基)組成，二者通過短的23個胺基酸的跨膜接頭結合。EGFR的細胞外部分含有25個二硫鍵和12個N-連接的糖基化位點，並且通常被認為由四個亞結構域組成。EGFR的X射線晶體結構提示受體可採用不能結合表皮生長因子(EGF)的自身抑制的束縛構象(Ferguson等，Mol Cell，2003，vol 11:507-517)和可能介導EGF配體結合和受體二聚化的活性構象(Garrett 等人, Cell 2002, vol 110:763-773; Ogiso 等人, Cell, 2002, vol 110:775-787)兩者。在生長因子配體如表皮生長因子(EGF)結合後，受體可與另一EGFR分子同源二聚化或與另一家族成員如erbB2 (FIER2)、erbB3 (HER3)或erbB4 (HER4)異源二聚化。erbB受體的同源和/或異源二聚化導致胞內結構域中關鍵酪氨酸殘基的磷酸化，並導致刺激參與細胞增殖和存活的許多細胞內信號轉導途徑Ciardiello F. N. Engl J Med 2008; 358:1160-1174和Robert Roskoski Jr. Biochemical and Biophysical Research Communications 319 (2004)1-11中提供了erbB受體信號傳導及其在腫瘤發生中的參與的詳細綜述。 當發現禽成紅細胞性白血病病毒的轉化v-ErbB癌基因是人EGFR的突變同源物時，EGFR與腫瘤疾病的聯繫被首次認識到(Downward J. Nature. 1984; 307:521-527)。發現v-erbB癌基因含有EGFR跨膜和胞質結構域的重組Olofsson B. Eur. J. Biochem. 1986; 160:261–266)，導致EGFR的癌症反常現象。除了突變外，還確定EGFR的過表達促進許多惡性腫瘤的進展(Gusterson B. Cell Biol. Int. Rep. 1984; 8:649-658)，包括肉瘤(Gusterson B. Int. J. Cancer. 1985; 36:689-693)、非小細胞肺癌 (NSCLC) (Veale D. Br. J. Cancer. 1987; 55:513-516)和惡性膠質瘤(Wong A.J. Proc. Natl. Acad. Sci. USA. 1987; 84:6899-6903)。 目前已知EGFR通過酪氨酸激酶介導的信號轉導途徑調節許多細胞過程，包括但不限於控制細胞增殖、分化、細胞存活、凋亡、腫瘤血管生成、有絲分裂發生和轉移(Atalay 等人, Ann. Oncology 14: 1346-1363 [2003]; Herbst R.S. Cancer. 2002; 94: 1593-1611; Modjtahedi 等人, Br. J. Cancer. 1996; 73: 228-235)。EGFR的過表達已經在許多人類惡性腫瘤中得到證實，包括膀胱癌、腦癌、頭頸癌、胰腺癌、肺癌、乳腺癌、卵巢癌、結腸癌、前列腺癌和腎癌(Atalay 等人, Ann. Oncology 14: 1346-1363 [2003]; Herbst R.S. Cancer. 2002; 94: 1593-1611; Modjtahedi 等人, Br. J. Cancer. 1996; 73: 228-235)。EGFR也在正常組織的細胞中表達，特別是在皮膚、肝臟和胃腸道的上皮組織中表達，儘管通常以比在惡性細胞中更低的水準表達(Herbst R. S. Cancer. 2002; 94: 1593-1611)。 已知低分子量EGFR酪氨酸激酶抑制劑用於治療腫瘤疾病，例如，用於治療非小細胞肺癌、胰腺癌；抗EGFR抗體用於治療結腸直腸癌和頭頸癌(Ping Wee. Cancers (Basel). 2017 May; 9(5): 52)。 在許多腫瘤疾病中觀察到頻繁的突變和EGFR高表達(Lu X. Med Res Rev. 2018 Sep; 38(5):1550-1581)，因此，仍然需要有新的有效和安全的藥物來抑制EGFR的活性。 Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein-tyrosine kinase that is a member of the erbB receptor family. EGFR consists of a glycosylated external ligand-binding domain (621 residues) and a cytoplasmic domain (542 residues), joined by a short 23 amino acid transmembrane linker. The extracellular portion of EGFR contains 25 disulfide bridges and 12 N-linked glycosylation sites and is generally considered to consist of four subdomains. The X-ray crystal structure of EGFR suggests that the receptor can adopt an autoinhibited tethered conformation that cannot bind epidermal growth factor (EGF) (Ferguson et al., Mol Cell, 2003, vol 11:507-517) and may mediate EGF ligand binding and Both active conformations of receptor dimerization (Garrett et al., Cell 2002, vol 110:763-773; Ogiso et al., Cell, 2002, vol 110:775-787). Upon binding of a growth factor ligand such as epidermal growth factor (EGF), the receptor can homodimerize with another EGFR molecule or heterologously with another family member such as erbB2 (FIER2), erbB3 (HER3) or erbB4 (HER4) Source dimerization. Homo and/or heterodimerization of the erbB receptor leads to phosphorylation of key tyrosine residues in the intracellular domain and leads to stimulation of many intracellular signal transduction pathways involved in cell proliferation and survival Ciardiello F. N. Engl J Med 2008; 358:1160-1174 and Robert Roskoski Jr. Biochemical and Biophysical Research Communications 319 (2004) 1-11 provide a detailed review of erbB receptor signaling and its involvement in tumorigenesis. The link between EGFR and neoplastic disease was first recognized when the transforming v-ErbB oncogene of avian erythroblastic leukemia virus was found to be a mutant homologue of human EGFR (Downward J. Nature. 1984; 307:521-527). Discovery of the v-erbB oncogene containing recombinant Olofsson B. Eur. J. Biochem. 1986; 160:261–266) containing EGFR transmembrane and cytoplasmic domains, leading to cancerous abnormalities of EGFR. In addition to mutations, it has been established that overexpression of EGFR promotes the progression of many malignancies (Gusterson B. Cell Biol. Int. Rep. 1984; 8:649-658), including sarcomas (Gusterson B. Int. J. Cancer. 1985; 36:689-693), non-small cell lung cancer (NSCLC) (Veale D. Br. J. Cancer. 1987; 55:513-516) and malignant glioma (Wong A.J. Proc. Natl. Acad. Sci. USA. 1987 ; 84:6899-6903). EGFR is currently known to regulate many cellular processes through tyrosine kinase-mediated signal transduction pathways, including but not limited to the control of cell proliferation, differentiation, cell survival, apoptosis, tumor angiogenesis, mitogenesis, and metastasis (Atalay et al., Ann. Oncology 14: 1346-1363 [2003]; Herbst R.S. Cancer. 2002; 94: 1593-1611; Modjtahedi et al., Br. J. Cancer. 1996; 73: 228-235). Overexpression of EGFR has been demonstrated in many human malignancies, including bladder, brain, head and neck, pancreas, lung, breast, ovary, colon, prostate, and kidney cancers (Atalay et al., Ann. Oncology 14: 1346-1363 [2003]; Herbst R.S. Cancer. 2002; 94: 1593-1611; Modjtahedi et al., Br. J. Cancer. 1996; 73: 228-235). EGFR is also expressed in cells of normal tissues, especially in epithelial tissues of the skin, liver and gastrointestinal tract, although usually at lower levels than in malignant cells (Herbst R. S. Cancer. 2002; 94: 1593-1611 ). Known low molecular weight EGFR tyrosine kinase inhibitors are used in the treatment of neoplastic diseases, for example, for the treatment of non-small cell lung cancer, pancreatic cancer; anti-EGFR antibodies are used for the treatment of colorectal cancer and head and neck cancer (Ping Wee. Cancers (Basel) . 2017 May; 9(5): 52). Frequent mutations and high expression of EGFR are observed in many tumor diseases (Lu X. Med Res Rev. 2018 Sep; 38(5):1550-1581), therefore, there is still a need for new effective and safe drugs to inhibit EGFR activity.

本發明說明書中使用的術語出現如下。 任選在一個、兩個、三個、四個或幾個位置上取代是指指定基團可以在一個、兩個、三個、四個或一至六個位置上被基團或基團的任意組合取代。 “稠合(annelated)化合物”或“稠合(condensed)化合物”是具有兩個共同的相鄰原子的多環化合物。稠合化合物的實例包括但不限於萘、喹啉、異喹啉、喹喔啉、吲哚、1H-吡咯並[2,3-b]吡啶、7H-吡咯並[2,3-d]嘧啶。 “烷基”是指具有1至12個碳原子，更優選1至6個碳原子的脂族直鏈或支鏈烴基。支鏈是指具有一個或多個“低級烷基”取代基的烷基鏈。烷基的實例包括但不限於甲基、乙基、正丙基、異丙基、正丁基、異丁基、仲丁基、叔丁基、正戊基、2-戊基、3-戊基、新戊基、正己基。烷基可以具有相同或不同結構的取代基。 “環烷基”是指含有3至10個碳環原子的完全飽和的碳環。環烷基可以具有相同或不同結構的取代基。環烷基可以與芳基、雜芳基、雜環基稠合。環烷基的實例包括但不限於單環基團，如環丙基、環丁基、環戊基、環己基、環庚基、環辛基、環壬基或環癸基，雙環基團，如雙環庚基或雙環辛基。 “烯基”是指含有一個或多個碳-碳雙鍵的具有2至12個碳原子，更優選2至6個碳原子的直鏈或支鏈烴基。烯基可以具有相同或不同結構的取代基。 “炔基”是指含有一個或多個碳-碳三鍵的具有2至12個碳原子，更優選2至6個碳原子的直鏈或支鏈烴基。炔基可具有相同或不同結構的取代基。 “芳基”是指具有6至14個碳原子，更優選6至10個碳原子的芳族單環或多環體系。芳基的實例包括但不限於苯基、亞苯基、苯三基、茚滿基、萘基、亞萘基、萘三基和亞蒽基。芳基可以具有相同或不同結構的取代基。芳基可以與雜環、環烷基或雜芳基稠合。 “烷氧基(Alkyloxy)”、“烷氧基(Alkoxy)”或“烷基氧基基團”是指烷基-О-基團，其中烷基在該部分中定義。烷氧基的實例包括但不限於甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、叔丁氧基、異丁氧基。 “芳氧基”或“芳氧基基團”是指芳基-O-基團，其中芳基在本部分中定義。芳氧基的實例為，但不限於苯氧基。 “環烷基氧基”或“環烷基氧基”是指環烷基-O-基團，其中環烷基在本部分中定義。環烷氧基的實例包括但不限於環己氧基、環戊氧基、環丁氧基或環丙氧基。 “胺基”是指R'R"N-基團。 “胺基羰基”是指-C(=O)NR"'R""基。 R',R",R"',R""的實例包括但不限於選自氫、烷基、烯基、炔基、環烷基、芳基、雜環基、雜芳基、雜烷基的取代基，或者R'和R"與它們所連接的碳原子一起可形成4-7元雜環基或雜芳基。 “烷基磺醯基”(-S(O) 2-(C1-C6)烷基)或 (-S(O) 2-(C3-C10)環烷基)是指如上定義的“烷基”或“環烷基”，通過磺醯基-SO 2-與分子的相應片段相連。烷基磺醯基的實例包括但不限於甲基磺醯基、乙基磺醯基、丙基磺醯基、環丙基磺醯基等。 “烷基磺醯胺”(-NH-S(O) 2-(С 1-С 6)烷基)或 (-NH-S(O) 2-(С 3-С 10)環烷基)是指通過磺醯胺基-NH-SO 2-與分子的相應片段連接的如上定義的“烷基”或“環烷基”。烷基磺醯胺的實例包括但不限於甲基磺醯胺、乙基磺醯胺、丙基磺醯胺、環丙基磺醯胺等。 “二烷基氧化膦”或“二烷基磷醯基” (-P(O)((C1-C6)烷基) 2)或(-P(O)((C3-C10)環烷基) 2)是指如上定義的“烷基”或“環烷基”，通過磷醯基

Figure 02_image001
與分子的相應片段連接。二烷基氧化膦的實例包括但不限於二甲基氧化膦、二乙基氧化膦、甲基乙基氧化膦、二丙基氧化膦、二環丙基氧化膦等。 本文所用的術語“氧代”涉及基團=O。 “低級烷基”是指具有1至4個碳原子的直鏈或支鏈烷基。 “鹵代”或“鹵素”(Hal)是指氟、氯、溴和碘。 “雜環”、“雜環基”、“雜環的環”是指具有3至11個碳原子的單環或多環體系，其中一個或多個碳原子被雜原子如氮、氧、硫取代。雜環可以具有一個或多個取代基，所述取代基可以是相同或不同的結構。雜環的氮和硫原子可以被氧化成N-氧化物、S-氧化物或S-二氧化物。雜環可以是飽和的、部分飽和的或不飽和的。雜環可以與環烷基、芳基或雜芳基稠合。雜環的實例包括但不限於氮雜環丁烷、吡咯烷、呱啶、2,8-二氮雜螺[4.5]癸烷、呱嗪、嗎啉、二氮雜環庚烷、氮雜環庚烷、氮雜雙環庚烷等。 “雜芳基”、“雜芳基環”是指具有5至11個碳原子，優選5至10個碳原子的芳族單環或多環體系，其中一個或多個碳原子被一個或多個雜原子如氮、硫或氧取代。雜芳基的氮原子可以被氧化為N-氧化物。雜芳基可以具有一個或多個取代基，所述取代基可以是相同或不同的結構。雜芳基的實例包括但不限於1H-吡咯並[2,3-b]吡啶、7H-吡咯並[2,3-d]嘧啶、吡咯、呋喃、吡啶、吡嗪、嘧啶、噠嗪、異噁唑、異噻唑、四唑、噁唑、噻唑、吡唑、呋咱、1,2,4-三唑、1,2,3-三唑、1,2,4-噻二唑、喹喔啉、咪唑並[1,2-a]吡啶、吲哚、苯並咪唑、喹啉、咪唑、吡唑、噻吩並吡啶、喹唑啉、萘啶、噻吩並嘧啶、咪唑並吡啶、異喹啉等。 “雜烷基”是指具有1-12個碳原子，更優選1-6個碳原子的直鏈或支鏈脂族烴基，其中一個或多個碳原子被雜原子如氮、硫或氧取代。支鏈是指具有一個或多個“低級烷基”取代基的雜烷基鏈。雜烷基可以具有一個或多個相同或不同結構的取代基。雜烷基的氮和硫原子可被氧化為N-氧化物、S-氧化物或S-二氧化物。雜烷基的實例包括但不限於甲氧基甲基、(2-(二甲基胺基)乙基)胺基、(2-(硫代甲基)乙基)胺基、(2-甲氧基乙基)胺基。 “取代基”是指與骨架(片段)連接的化學基團。 “溶劑化物”是由本發明化合物，包括其藥學上可接受的鹽，與一個或多個溶劑分子組成的分子聚集體。溶劑分子是已知對受體安全的普通藥物溶劑分子，例如水、乙醇、乙二醇等。其它溶劑，如MeOH、甲基叔丁基醚、乙酸乙酯、乙酸甲酯、(S)-丙二醇、(R)-丙二醇、1,4-丁二醇等，可以用作中間溶劑化物以獲得更理想的溶劑化物。 術語“水合物”是指複合物，其中溶劑分子是水。 溶劑化物和/或水合物優選以結晶形式存在。 術語“鍵”、“化學鍵”或“單鍵”是指當通過鍵連接的原子被認為是較大子結構的一部分時，兩個原子或兩個部分(即基團、片段)的化學鍵。 術語“立體異構體”是指具有相同化學組成和相同結構，但原子或其基團的空間排列不同的化合物。立體異構體可包括幾何異構體、對映異構體、非對映異構體。 術語“保護基”是指用於阻斷官能團如胺基、羧基或羥基的反應性的基團。保護基的實例包括但不限於叔丁氧基羰基(Boc)、苄氧基羰基(Cbz)、2-(三甲基甲矽烷基)乙氧基)甲基縮醛(SEM)、三烷基甲矽烷基、烷基(二芳基)甲矽烷基或烷基。 術語“賦形劑”在本文中用於描述除本發明化合物之外的任何成分。 “藥物組合物”是指包含本發明化合物和至少一種賦形劑的組合物。賦形劑可以選自藥學上可接受的和藥理學上相容的填充劑、溶劑、稀釋劑、載體、助劑、分散劑和感應劑、遞送劑，例如防腐劑、穩定劑、填充劑、崩解劑、濕潤劑、乳化劑、懸浮劑、增稠劑、甜味劑、調味劑、芳香劑、抗菌劑、殺真菌劑、潤滑劑和延長遞送控制劑，其選擇和比例取決於施用的性質和途徑以及劑量。懸浮劑的實例是乙氧基化異硬脂醇、聚氧乙烯、山梨醇和山梨醇醚、微晶纖維素、偏氫氧化鋁、膨潤土、瓊脂和黃芪膠以及它們的混合物。可以通過各種抗細菌劑和抗真菌劑，例如對羥基苯甲酸酯、氯丁醇、山梨酸和類似化合物，提供針對微生物作用的保護。組合物還可以含有等滲劑，例如糖、氯化鈉和類似化合物。組合物的延長作用可以通過減緩活性成分吸收的試劑來實現，例如單硬脂酸鋁和明膠。合適的載體、溶劑、稀釋劑和遞送劑的實例是水、乙醇、多元醇及其混合物、天然油(例如橄欖油)和用於注射的有機酯(例如油酸乙酯)。填充劑的實例是乳糖(lactose)、乳糖(milk sugar)、檸檬酸鈉、碳酸鈣、磷酸鈣等。崩解劑和分配劑的實例是澱粉、海藻酸及其鹽、矽酸鹽等。潤滑劑的實例是硬脂酸鎂、月桂基硫酸鈉、滑石以及高分子量的聚乙二醇。用於經口、舌下、經皮、肌內、靜脈內、皮下、局部或直腸施用活性成分的藥物組合物，單獨或與另一種活性成分組合，可以以標準施用形式，以與傳統藥物載體的混合物形式施用於動物和人。合適的標準給藥形式包括口服形式，例如片劑、明膠膠囊、丸劑、粉劑、顆粒劑、口香糖和口服溶液或懸浮液；舌下和經頰給藥形式；氣溶膠；植入物；局部、經皮、皮下、肌內、靜脈內、鼻內或眼內給藥形式和直腸給藥形式。 “藥學上可接受的鹽”是指本發明中公開的酸和鹼的相對無毒的有機和無機鹽。這些鹽可以在化合物的合成、分離或純化過程中原位製備，或者它們可以專門製備。特別地，鹼的鹽可以特別地由所公開的化合物的純化鹼和合適的有機或無機酸製備。以這種方式製備的鹽的實例是鹽酸鹽、氫溴酸鹽、硫酸鹽、硫酸氫鹽、磷酸鹽、硝酸鹽、乙酸鹽、草酸鹽、戊酸鹽、油酸鹽、棕櫚酸鹽、硬脂酸鹽、月桂酸鹽、硼酸鹽、苯甲酸鹽、乳酸鹽、對甲苯磺酸鹽、檸檬酸鹽、馬來酸鹽、富馬酸鹽、琥珀酸鹽、酒石酸鹽、甲磺酸鹽、丙二酸鹽、水楊酸鹽、丙酸鹽、乙烷磺酸鹽、苯磺酸鹽、胺基磺酸鹽等(這些鹽性質的詳細描述在Berge S.M., 等人, “Pharmaceutical Salts” J. Pharm. Sci. 1977, 66: 1-19中給出)。所公開的酸的鹽可以通過使純化的酸與合適的鹼反應來製備；此外，也可以合成金屬鹽和胺鹽。金屬鹽是鈉、鉀、鈣、鋇、鋅、鎂、鋰和鋁的鹽；最優選鈉鹽和鉀鹽。可由其製備金屬鹽的合適的無機鹼是：氫氧化鈉、碳酸鈉、碳酸氫鈉和氫氧化鈉；氫氧化鉀和碳酸氫鉀、氫氧化鋰、氫氧化鈣、氫氧化鎂、氫氧化鋅。可用於製備所公開的酸的鹽的有機鹼是胺和胺基酸，其鹼性足以產生穩定的鹽，並且其適用於醫療目的(特別是，它們必須具有低毒性)。這樣的胺包括氨、甲胺、二甲胺、三甲胺、乙胺、二乙胺、三乙胺、苄胺、二苄胺、二環己胺、呱嗪、乙基呱啶、三(羥甲基)胺基甲烷等。此外，可使用四烷基氫氧化銨，例如膽鹼、四甲基銨、四乙基銨等製備鹽。鹼性胺基酸，即賴氨酸、鳥氨酸和精氨酸，可以用作胺基酸。 “藥物(藥品、藥物產品)”-是片劑、顆粒劑、膠囊劑、注射劑、軟膏劑和其它用於恢復、改善或改變人和動物的生理功能以及用於治療和預防疾病，用於診斷、麻醉、避孕、美容等的現成形式的化合物(或作為藥物組合物的化合物的混合物)。 “治療”是指減輕或消除生物病症和/或其伴隨症狀中的至少一種的方法。術語“減輕”疾病、病症或病狀是指降低疾病、病症或病狀的症狀的嚴重性和/或發生頻率。此外，本文中提到的“治療”包括提及治癒性、姑息性治療。 “預防”、“預防性治療”是指一組旨在防止疾病或病症的發作、消除風險因素或早期檢測疾病或病症、其惡化、復發、併發症或其它後果的措施。 在一個方面，所述患者或治療或預防的受試者是哺乳動物。患者的實例包括但不限於人類受試者。所述受試者可以是任何年齡的男性或女性。 術語“病症”是指將受益於根據本發明的治療的任何病況。該術語的定義包括使哺乳動物易於發生所述疾病的慢性和急性病症或病理狀況。待治療疾病的非限制性實例包括良性和惡性腫瘤，或非特定性質的腫瘤，包括源自血細胞和淋巴樣細胞的腫瘤。該示例可以是：膀胱癌、卵巢癌、宮頸癌、結腸直腸癌、乳腺癌、胰腺癌、頭頸癌、膠質瘤、成膠質細胞瘤、黑素瘤、前列腺癌、白血病、淋巴瘤、非霍奇金淋巴瘤、霍奇金淋巴瘤、肺癌、肝細胞癌、食道癌、胃癌、胃腸道間質瘤、甲狀腺癌、膽管癌、子宮內膜癌、腎癌、肝癌、間變性大細胞淋巴瘤、急性髓性白血病、多發性骨髓瘤、黑素瘤、間皮瘤、血液惡性腫瘤。 “治療有效量”是指在治療過程中施用的治療劑的量，其將減輕所治療疾病的嚴重性或消除所治療疾病的症狀。 如本說明書和所附申請專利範圍中所用，除非上下文另有規定，否則詞語“具有”、“包含”和“包括”或其變型，例如“具有”、“包括”、“含有”或“含有”，將被理解為暗示包括所述之整體或整體的組，但不排除任何其它整體或整體的組。 Terms used in the description of the present invention appear as follows. Optionally substituted at one, two, three, four or several positions means that the specified group can be replaced by any group or group at one, two, three, four or one to six positions Combo replaces. "Annelated compounds" or "condensed compounds" are polycyclic compounds that have two adjacent atoms in common. Examples of fused compounds include, but are not limited to, naphthalene, quinoline, isoquinoline, quinoxaline, indole, 1H-pyrrolo[2,3-b]pyridine, 7H-pyrrolo[2,3-d]pyrimidine . "Alkyl" means an aliphatic straight or branched chain hydrocarbon group having 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms. Branched refers to an alkyl chain having one or more "lower alkyl" substituents. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl base, neopentyl, n-hexyl. The alkyl groups may have substituents of the same or different structures. "Cycloalkyl" means a fully saturated carbocyclic ring containing from 3 to 10 carbon ring atoms. Cycloalkyl groups may have substituents of the same or different structures. Cycloalkyl can be fused with aryl, heteroaryl, heterocyclyl. Examples of cycloalkyl groups include, but are not limited to, monocyclic groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, bicyclic groups, Such as bicycloheptyl or bicyclooctyl. "Alkenyl" means a straight or branched chain hydrocarbon group having 2 to 12 carbon atoms, more preferably 2 to 6 carbon atoms, containing one or more carbon-carbon double bonds. Alkenyl groups may have substituents of the same or different structures. "Alkynyl" means a straight or branched chain hydrocarbon group having 2 to 12 carbon atoms, more preferably 2 to 6 carbon atoms, containing one or more carbon-carbon triple bonds. Alkynyl groups may have substituents of the same or different structures. "Aryl" means an aromatic monocyclic or polycyclic ring system having 6 to 14 carbon atoms, more preferably 6 to 10 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, phenylene, benzenetriyl, indanyl, naphthyl, naphthylene, naphthalenetriyl, and anthracenyl. Aryl groups may have substituents of the same or different structures. Aryl groups can be fused with heterocycles, cycloalkyls or heteroaryls. "Alkyloxy", "Alkoxy" or "alkyloxy group" means an alkyl-O- group, where alkyl is defined in this section. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, isobutoxy. "Aryloxy" or "aryloxy group" means an aryl-O- group, where aryl is defined in this section. An example of, but not limited to, aryloxy is phenoxy. "Cycloalkyloxy" or "cycloalkyloxy" means a cycloalkyl-O- group, where cycloalkyl is defined in this section. Examples of cycloalkoxy include, but are not limited to, cyclohexyloxy, cyclopentyloxy, cyclobutoxy, or cyclopropoxy. "Amino" refers to a R'R"N- group. "Aminocarbonyl" refers to a -C(=O)NR"'R"" group. Examples of R', R", R"', R"" include, but are not limited to, those selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, heteroalkyl Substituents, or R' and R" together with the carbon atoms they are attached to form a 4-7 membered heterocyclic or heteroaryl group. "Alkylsulfonyl" (-S(O) 2 -(C1- C6) alkyl) or (-S(O) 2 -(C3-C10) cycloalkyl) refers to "alkyl" or "cycloalkyl" as defined above, through sulfonyl -SO 2 - and molecular The corresponding fragments are connected. Examples of alkylsulfonyl groups include but are not limited to methylsulfonyl, ethylsulfonyl, propylsulfonyl, cyclopropylsulfonyl, etc. "Alkylsulfonamide" (- NH-S(O) 2 -(С 1 -С 6 )alkyl) or (-NH-S(O) 2 -(С 3 -С 10 )cycloalkyl) refers to the sulfonamido-NH- SO2 - an "alkyl" or "cycloalkyl" as defined above attached to the corresponding segment of the molecule. Examples of alkylsulfonamides include, but are not limited to, methylsulfonamide, ethylsulfonamide, propylsulfonamide Amide, cyclopropylsulfonamide, etc. "Dialkylphosphine oxide" or "dialkylphosphoryl" (-P(O)((C1-C6)alkyl) 2 ) or (-P(O )((C3-C10)cycloalkyl) 2 ) means "alkyl" or "cycloalkyl" as defined above, by phosphoryl
Figure 02_image001
Ligate with the corresponding fragment of the molecule. Examples of dialkylphosphine oxides include, but are not limited to, dimethylphosphine oxide, diethylphosphine oxide, methylethylphosphine oxide, dipropylphosphine oxide, dicyclopropylphosphine oxide, and the like. The term "oxo" as used herein refers to the group =0. "Lower alkyl" means straight or branched chain alkyl having 1 to 4 carbon atoms. "Halo" or "Hal" refers to fluoro, chloro, bromo and iodo. "Heterocycle", "heterocyclyl", "heterocyclic ring" means a monocyclic or polycyclic ring system having 3 to 11 carbon atoms, wherein one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen, sulfur replace. A heterocyclic ring may have one or more substituents, which may be of the same or different structures. The nitrogen and sulfur atoms of the heterocycle can be oxidized to N-oxides, S-oxides or S-dioxides. Heterocycles can be saturated, partially saturated or unsaturated. A heterocycle can be fused with a cycloalkyl, aryl, or heteroaryl. Examples of heterocycles include, but are not limited to, azetidine, pyrrolidine, piperidine, 2,8-diazaspiro[4.5]decane, piperazine, morpholine, diazepane, azacyclo Heptane, azabicycloheptane, etc. "Heteroaryl", "heteroaryl ring" means an aromatic monocyclic or polycyclic ring system having 5 to 11 carbon atoms, preferably 5 to 10 carbon atoms, wherein one or more carbon atoms are replaced by one or more A heteroatom such as nitrogen, sulfur or oxygen is substituted. A nitrogen atom of a heteroaryl can be oxidized to an N-oxide. A heteroaryl group may have one or more substituents, which may be of the same or different structures. Examples of heteroaryl groups include, but are not limited to, 1H-pyrrolo[2,3-b]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, pyrrole, furan, pyridine, pyrazine, pyrimidine, pyridazine, iso Oxazole, isothiazole, tetrazole, oxazole, thiazole, pyrazole, furazan, 1,2,4-triazole, 1,2,3-triazole, 1,2,4-thiadiazole, quinoxa Line, imidazo[1,2-a]pyridine, indole, benzimidazole, quinoline, imidazole, pyrazole, thienopyridine, quinazoline, naphthyridine, thienopyrimidine, imidazopyridine, isoquinoline Wait. "Heteroalkyl" means a straight or branched chain aliphatic hydrocarbon group having 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, wherein one or more of the carbon atoms is replaced by a heteroatom such as nitrogen, sulfur or oxygen . Branched refers to a heteroalkyl chain having one or more "lower alkyl" substituents. A heteroalkyl group may have one or more substituents of the same or different structures. The nitrogen and sulfur atoms of the heteroalkyl group can be oxidized to N-oxide, S-oxide or S-dioxide. Examples of heteroalkyl include, but are not limited to, methoxymethyl, (2-(dimethylamino)ethyl)amino, (2-(thiomethyl)ethyl)amino, (2-methoxymethyl) Oxyethyl) amino group. "Substituent" refers to a chemical group attached to a backbone (fragment). A "solvate" is an aggregate of molecules consisting of a compound of the present invention, including pharmaceutically acceptable salts thereof, and one or more solvent molecules. Solvent molecules are common pharmaceutical solvent molecules known to be safe for the recipient, such as water, ethanol, ethylene glycol, etc. Other solvents, such as MeOH, methyl tert-butyl ether, ethyl acetate, methyl acetate, (S)-propylene glycol, (R)-propylene glycol, 1,4-butanediol, etc., can be used as intermediate solvates to obtain more desirable solvates. The term "hydrate" refers to complexes in which the solvent molecule is water. The solvates and/or hydrates are preferably present in crystalline form. The terms "bond", "chemical bond" or "single bond" refer to a chemical bond between two atoms or two parts (ie, groups, fragments) when the atoms joined by the bond are considered to be part of a larger substructure. The term "stereoisomer" refers to compounds that have the same chemical composition and the same structure, but differ in the arrangement of the atoms or groups thereof in space. Stereoisomers may include geometric isomers, enantiomers, diastereomers. The term "protecting group" refers to a group used to block the reactivity of a functional group such as an amine group, a carboxyl group or a hydroxyl group. Examples of protecting groups include, but are not limited to, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 2-(trimethylsilyl)ethoxy)methyl acetal (SEM), trialkyl Silyl, alkyl(diaryl)silyl or alkyl. The term "excipient" is used herein to describe any ingredient other than a compound of the invention. "Pharmaceutical composition" means a composition comprising a compound of the invention and at least one excipient. Excipients may be selected from pharmaceutically acceptable and pharmacologically compatible fillers, solvents, diluents, carriers, adjuvants, dispersing and sensing agents, delivery agents such as preservatives, stabilizers, fillers, Disintegrants, wetting agents, emulsifiers, suspending agents, thickeners, sweeteners, flavoring agents, fragrances, antibacterial agents, fungicides, lubricants and prolonged delivery control agents, the selection and ratio of which depends on the administered Nature and route and dosage. Examples of suspending agents are ethoxylated isostearyl alcohols, polyoxyethylenes, sorbitol and sorbitol ethers, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. Protection against the action of microorganisms can be afforded by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, sorbic acid, and similar compounds. The compositions may also contain isotonic agents, such as sugars, sodium chloride, and similar compounds. Prolonged action of the compositions can be brought about by agents which slow the absorption of the active ingredient, for example aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery agents are water, ethanol, polyols and mixtures thereof, natural oils such as olive oil and organic esters for injection such as ethyl oleate. Examples of fillers are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate, and the like. Examples of disintegrating and distributing agents are starch, alginic acid and its salts, silicates, and the like. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc and high molecular weight polyethylene glycols. Pharmaceutical compositions for the oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, topical or rectal administration of an active ingredient, alone or in combination with another active ingredient, in standard administration forms, in combination with conventional pharmaceutical carriers administered to animals and humans in mixtures. Suitable standard administration forms include oral forms such as tablets, gelatin capsules, pills, powders, granules, chewing gum and oral solutions or suspensions; sublingual and buccal forms; aerosols; implants; topical, Transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms. "Pharmaceutically acceptable salts" refers to the relatively non-toxic organic and inorganic salts of the acids and bases disclosed herein. These salts can be prepared in situ during the synthesis, isolation or purification of the compounds, or they can be prepared ad hoc. In particular, salts of bases can be prepared especially from purified bases of the disclosed compounds and suitable organic or inorganic acids. Examples of salts prepared in this way are hydrochloride, hydrobromide, sulfate, hydrogensulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate , stearate, laurate, borate, benzoate, lactate, p-toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, methanesulfonate salts, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates, etc. (a detailed description of the properties of these salts is given in Berge SM, et al., “Pharmaceutical Salts" J. Pharm. Sci. 1977, 66: 1-19). Salts of the disclosed acids can be prepared by reacting a purified acid with an appropriate base; in addition, metal and amine salts can also be synthesized. Metal salts are sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts; sodium and potassium salts are most preferred. Suitable inorganic bases from which metal salts can be prepared are: sodium hydroxide, sodium carbonate, sodium bicarbonate and sodium hydroxide; potassium hydroxide and potassium bicarbonate, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide . Organic bases useful in the preparation of salts of the disclosed acids are amines and amino acids which are basic enough to yield stable salts and which are suitable for medical purposes (in particular, they must have low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris(hydroxy Methyl)aminomethane, etc. In addition, tetraalkylammonium hydroxides, such as choline, tetramethylammonium, tetraethylammonium, and the like, can be used to prepare salts. Basic amino acids, ie, lysine, ornithine, and arginine, can be used as the amino acid. "Drugs (drugs, pharmaceutical products)" - are tablets, granules, capsules, injections, ointments and other preparations used to restore, improve or alter the physiological functions of humans and animals and for the treatment and prevention of diseases, for diagnosis , anesthetic, contraceptive, cosmetic, etc. in ready-to-form form (or as a mixture of compounds as a pharmaceutical composition). "Treatment" refers to methods of alleviating or eliminating at least one of a biological condition and/or its accompanying symptoms. The term "alleviate" a disease, disorder or condition refers to reducing the severity and/or frequency of symptoms of the disease, disorder or condition. Furthermore, references herein to "treatment" include references to curative, palliative treatment. "Prevention", "prophylactic treatment" refers to a group of measures aimed at preventing the onset of a disease or condition, eliminating risk factors or early detection of a disease or condition, its exacerbation, recurrence, complications or other consequences. In one aspect, the patient or subject of treatment or prevention is a mammal. Examples of patients include, but are not limited to, human subjects. The subject can be male or female of any age. The term "disorder" refers to any condition that would benefit from treatment according to the present invention. The definition of the term includes both chronic and acute disorders or pathological conditions that predispose the mammal to the disease. Non-limiting examples of diseases to be treated include benign and malignant tumors, or tumors of an unspecified nature, including those derived from blood cells and lymphoid cells. Examples of this could be: bladder cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodge Gold lymphoma, Hodgkin lymphoma, lung cancer, hepatocellular carcinoma, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, endometrial cancer, kidney cancer, liver cancer, anaplastic large cell lymphoma, Acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma, hematologic malignancies. A "therapeutically effective amount" refers to that amount of therapeutic agent administered during treatment that will lessen the severity of or eliminate the symptoms of the disease being treated. As used in this specification and the appended claims, unless the context requires otherwise, the words "have", "comprises" and "including" or variations thereof, such as "has", "comprises", "comprises" or "contains ”, will be understood to imply the inclusion of said integer or group of integers, but not the exclusion of any other integer or group of integers.

在一個實施方案中，本發明涉及式I的化合物：

Figure 02_image003
或其藥學上可接受的鹽、溶劑化物或立體異構體， 其中L 1為化學鍵或-NH-； X 1為-CH-、-N-或-C(R 6)-； 每個n、m獨立地為0、1、2、3或4； 每個R 1獨立地為-H；-Hal；-C(Hal) 3；-CN；-NR 7R 8；-C(O)NR 9R 10；-C(O)OR 11；-C(O)R 12；-OR 13；-(C 1-C 6)烷基，未取代或被一個或多個基團R 14取代；-(C 3-C 6)環烷基，未取代或被一個或多個基團R 14a取代； R 2為-P(O)((C 1-C 6)烷基) 2，未取代或被一個或多個基團R 15取代；-P(O)((C 3-C 6)環烷基) 2，未取代或被一個或多個基團R 15a取代；-P(O)((C 1-C 6)烷基))((C 3-C 6)環烷基)，未取代或被一個或多個基團R 15b取代；-P(O)(О(C 1-C 6)烷基) 2，未取代或被一個或多個基團R 15c取代；-P(O)(О(C 3-C 6)環烷基) 2，未取代或被一個或多個基團R 15d取代； -P(O)(О(C 1-C 6)烷基)(О(C 3-C 6)環烷基)，未取代或被一個或多個基團R 15e取代；P(O)(О(C 1-C 6)烷基)((C 3-C 6)環烷基)，未取代或被一個或多個基團R 15取代；-P(O)(О(C 1-C 6)烷基)((C 1-C 6)烷基)，未取代或被一個或多個基團R 15取代； -P(O)(О(C 3-C 6)環烷基)((C 1-C 6)烷基)，未取代或被一個或多個基團R 15取代；-P(O)(О(C 3-C 6)環烷基)((C 3-C 6)環烷基)，未取代或被一個或多個基團R 15取代；-SO 2(C 1-C 6)烷基，未取代或被一個或多個基團R 15f取代；或-SO 2(C 3-C 6)環烷基，未取代或被一個或多個基團R 15g取代； R 3為-H；-Hal；-CN；-C(Hal) 3；-NR 7aR 8a； -C(O)NR 9aR 10a；-C(O)OR 11a；-C(O)R 12a；-OR 13a；-(C 1-C 6)烷基，未取代或被一個或多個基團R 16a取代；-(C 3-C 6)環烷基，未取代或被一個或多個基團R 16b取代；-(C 6-C 12)芳基，未取代或被一個或多個基團R 16C取代；具有1或2個選自N、S或O的雜原子的4-10元雜芳基，未取代或被一個或多個基團R 16d取代； 每個R 4獨立地為-H；-Hal；-CN；-NR 7bR 8b；-C(Hal) 3；-C(O)NR 9bR 10b；-C(O)OR 11b；-C(O)R 12b；-OR 13b； -(C 1-C 6)烷基，未取代或被一個或多個基團R 17a取代； -(C 3-C 6)環烷基，未取代或被一個或多個基團R 17b取代；具有1或2個選自N、S或О的雜原子的4-10元雜環基，未取代或被一個或多個基團R 17c取代；或-(C 6-C 12)芳基，未取代或被一個或多個基團R 17d取代； R 5為： -NR 7сR 18；-NR 7dR 19；-W 1；-OW 2；-NR aW 3； -C(O)W 4；或-(CH 2)W 5； 其中每個W 1、W 2、W 3、W 4或W 5獨立地為-(C 3-C 6)環烷基，未取代或被一個或多個基團R 20取代；具有1或2個選自N、S或O的雜原子的4-7元雜環基，未取代或被一個或多個基團R 20取代， R 6為-Hal、-CN、-C(Hal) 3、CH (Hal) 2、CH 2Hal、 -NR 7eR 8C；-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R 7、R 7a、R 7b、R 7e、R 8、R 8a、R 8b、R 8C、R 9、R 9a、R 9b、R 10、R 10a、R 10b獨立地為-H、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代；-(C 3-C 6)環烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R 7c、R 7d、R a獨立地為-H、-(С 1-С 6)烷基； R 18為-(С 1-С 10)烷基，其未被取代或被一個或多個選自-Hal、-OH、-NO 2、-NR 23R 24、(=O)的取代基取代； R 19為具有1或2個選自N、S或O的雜原子的2-10元雜烷基，其未被取代或被一個或多個選自-Hal、-OH、-NO 2、 -NR 23R 24、(=O)的取代基取代； 每個R 11、R 12、R 13、R 11a、R 12a、R 13a、R 11b、R 12b、R 13b獨立地為-H；-(C 1-C 6)烷基，未取代或被一個或多個基團R 21取代；-(C 3-C 6)環烷基，未取代或被一個或多個基團R 21a取代；-(C 6-C 12)芳基，未取代或被一個或多個基團R 21b取代，具有1或2個選自N、S或О的雜原子的4-10元雜環基，未取代或被一個或多個基團R 21c取代； 每個R 14、R 14a、R 15、R 15a、R 15、R 15a、R 15b、R 15c、R 15d、R 15e、R 15f、R 15g、R 16、R 16a、R 16b、R 16C、R 16d、R 17、R 17a、R 17b、R 17c、R 17d獨立地為-Hal、-H、-OH、 -NO 2、-NR 23R 24、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R 20獨立地為(=O)、-NR 7fR 8d、-(C 1-C 6)烷基，未取代或被一個或多個基團R 22取代，-具有1或2個選自N、O或S的雜原子的2-8元雜烷基，未取代或被一個或多個基團R 22a取代，-(C 3-C 6)環烷基，未取代或被一個或多個基團R 22b取代，具有1或2個選自N、S或О的雜原子的4-10元雜環基，未取代或被一個或多個基團R 22с取代； 每個R 7f、R 8d獨立地為-H、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代；-(C 3-C 6)環烷基，其未被取代或被一個或多個選自 -Hal、-NH 2、-OH、(=O)的基團取代； 每個R 21、R 21a、R 21b、R 21с、R 22、R 22a、R 22b、R 22с獨立地為-Hal、-H、-OH、-NO 2、-NR 23R 24、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-O(C 1-C 6)烷基、-ОH、(=O)的基團取代； 每個R 23、R 24獨立地為-H；-(C 1-C 6)烷基，其未被取代或被一個或多個選自(=О)、-ОH、-NR 25R 26的基團取代；-(C 2-C 6)烯基，其未被取代或被一個或多個選自(=О)、-NR 25aR 26a的基團取代； 每個R 25、R 26、R 25a、R 26a獨立地為-H、-(C 1-C 6)烷基； Hal是氟、溴、氯或碘原子。 在另一個實施方案中，本發明涉及式I化合物，其中 L 1為化學鍵，R 2為-P(O)((C 1-C 6)烷基) 2，未取代或被一個或多個基團R 15取代；-P(O)((C 3-C 6)環烷基) 2，未取代或被一個或多個基團R 15a取代；-P(O)((C 1-C 6)烷基))((C 3-C 6)環烷基)，未取代或被一個或多個基團R 15b取代； -P(O)(О(C 1-C 6)烷基) 2，未取代或被一個或多個基團R 15c取代；-P(O)(О(C 3-C 6)環烷基) 2，未取代或被一個或多個基團R 15d取代；-P(O)(О(C 1-C 6)烷基)(О(C 3-C 6)環烷基)，未取代或被一個或多個基團R 15e取代；P(O)(О(C 1-C 6)烷基)((C 3-C 6)環烷基)，未取代或被一個或多個基團R 15取代； -P(O)(О(C 1-C 6)烷基)((C 1-C 6)烷基)，未取代或被一個或多個基團R 15取代；-P(O)(О(C 3-C 6)環烷基) ((C 1-C 6)烷基)，未取代或被一個或多個基團R 15取代；-P(O)(О(C 3-C 6)環烷基)((C 3-C 6)環烷基)，未取代或被一個或多個基團R 15取代；P(O)(О(C 1-C 6)烷基)((C 3-C 6)環烷基)，未取代或被一個或多個基團R 15取代；-P(O)(О(C 1-C 6)烷基)((C 1-C 6)烷基)，未取代或被一個或多個基團R 15取代；-P(O)(О(C 3-C 6)環烷基)((C 1-C 6)烷基)，未取代或被一個或多個基團R 15取代；-P(O)(О(C 3-C 6)環烷基)((C 3-C 6)環烷基)，未取代或被一個或多個基團R 15取代；或 L 1為-NH-，R 2為-SO 2(C 1-C 6)烷基，未取代或被一個或多個基團R 15f取代；或-SO 2(C 3-C 6)環烷基，未取代或被一個或多個基團R 15g取代，其中 每個R 15、R 15a、R 15、R 15a、R 15b、R 15c、R 15d、R 15e、R 15f、R 15g獨立地為-Hal、-H、-OH、-NO 2、-NR 23R 24、 -(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、 -NH 2、-OH、(=O)的基團取代； 每個R 23、R 24獨立地為-H；-(C 1-C 6)烷基，其未被取代或被一個或多個選自(=О)、-ОH、-NR 25R 26的基團取代；-(C 2-C 6)烯基，其未被取代或被一個或多個選自(=О)、-NR 25aR 26a的基團取代； 每個R 25、R 26、R 25a、R 26a獨立地為-H、-(C 1-C 6)烷基， Hal是氟、溴、氯或碘原子。 在另一個實施方案中，本發明涉及式I的化合物：
Figure 02_image005
或其藥學上可接受的鹽、溶劑化物或立體異構體， 其中L 1為化學鍵或-NH-； X 1為-CH-、-N-或-C(R 6)-； 每個n、m獨立地為0、1、2、3或4； 每個R 1獨立地為-H；-Hal；-C(Hal) 3；-CN；-NR 7R 8；-C(O)NR 9R 10；-C(O)OR 11；-C(O)R 12；-OR 13；-(C 1-C 6)烷基，未取代或被一個或多個基團R 14取代；-(C 3-C 6)環烷基，未取代或被一個或多個基團R 14a取代； R 2為-P(O)((C 1-C 6)烷基) 2，未取代或被一個或多個基團R 15取代；-P(O)((C 3-C 6)環烷基) 2，未取代或被一個或多個基團R 15a取代；-P(O)((C 1-C 6)烷基))((C 3-C 6)環烷基)，未取代或被一個或多個基團R 15b取代； -P(O)(О(C 1-C 6)烷基) 2，未取代或被一個或多個基團R 15c取代；-P(O)(О(C 3-C 6)環烷基) 2，未取代或被一個或多個基團R 15d取代；-P(O)(О(C 1-C 6)烷基)(О(C 3-C 6)環烷基)，未取代或被一個或多個基團R 15e取代；-SO 2(C 1-C 6)烷基，未取代或被一個或多個基團R 15f取代；P(O)(О(C 1-C 6)烷基)((C 3-C 6)環烷基)，未取代或被一個或多個基團R 15取代； -P(O)(О(C 1-C 6)烷基)((C 1-C 6)烷基)，未取代或被一個或多個基團R 15取代；-P(O)(О(C 3-C 6)環烷基)((C 1-C 6)烷基)，未取代或被一個或多個基團R 15取代；-P(O)(О(C 3-C 6)環烷基)((C 3-C 6)環烷基)，未取代或被一個或多個基團R 15取代；或-SO 2(C 3-C 6)環烷基，未取代或被一個或多個基團R 15g取代； R 3為-H；-Hal；-CN；-C(Hal) 3；-NR 7aR 8a； -C(O)NR 9aR 10a；-C(O)OR 11a；-C(O)R 12a；-OR 13a；-(C 1-C 6)烷基，未取代或被一個或多個基團R 16a取代；-(C 3-C 6)環烷基，未取代或被一個或多個基團R 16b取代；-(C 6-C 12)芳基，未取代或被一個或多個基團R 16C取代；具有1或2個選自N、S或O的雜原子的4-10元雜芳基，未取代或被一個或多個基團R 16d取代； 每個R 4獨立地為-H；-Hal；-CN；-NR 7bR 8b；-C(Hal) 3；-C(O)NR 9bR 10b；-C(O)OR 11b；-C(O)R 12b；-OR 13b； -(C 1-C 6)烷基，未取代或被一個或多個基團R 17a取代； -(C 3-C 6)環烷基，未取代或被一個或多個基團R 17b取代；具有1或2個選自N、S或О的雜原子的4-10元雜環基，未取代或被一個或多個基團R 17c取代；或-(C 6-C 12)芳基，未取代或被一個或多個基團R 17d取代； R 5為： -NR 7сR 18；-NR 7dR 19；-W 1；-OW 2；-NR aW 3； -C(O)W 4；或-(CH 2)W 5； 其中每個W 1、W 2、W 3、W 4或W 5獨立地為-(C 3-C 6)環烷基，未取代或被一個或多個基團R 20取代；具有1或2個選自N、S或O的雜原子的4-7元雜環基，未取代或被一個或多個基團R 20取代； R 6為-Hal、-CN、-C(Hal) 3、CH(Hal) 2、CH 2Hal、 -NR 7eR 8C；-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R 7、R 7a、R 7b、R 7e、R 8、R 8a、R 8b、R 8C、R 9、R 9a、R 9b、R 10、R 10a、R 10b獨立地為-H、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代；-(C 3-C 6)環烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R 7c、R 7d、R a獨立地為-H、-(С 1-С 6)烷基； R 18為-(С 1-С 10)烷基，其未被取代或被一個或多個選自-Hal、-OH、-NO 2、-NR 23R 24、(=O)的取代基取代； R 19為具有1或2個選自N、S或O的雜原子的2-10元雜烷基，其未被取代或被一個或多個選自-Hal、-OH、-NO 2、 -NR 23R 24、(=O)的取代基取代； 每個R 11、R 12、R 13、R 11a、R 12a、R 13a、R 11b、R 12b、R 13b獨立地為-H；-(C 1-C 6)烷基，未取代或被一個或多個基團R 21取代；-(C 3-C 6)環烷基，未取代或被一個或多個基團R 21a取代；-(C 6-C 12)芳基，未取代或被一個或多個基團R 21b取代，具有1或2個選自N、S或О的雜原子的4-10元雜環基，未取代或被一個或多個基團R 21c取代； 每個R 14、R 14a、R 15、R 15a、R 15、R 15a、R 15b、R 15c、R 15d、R 15e、R 15f、R 15g、R 16、R 16a、R 16b、R 16C、R 16d、R 17、R 17a、R 17b、R 17c、R 17d獨立地為-Hal、-H、-OH、 -NO 2、-NR 23R 24、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R 20獨立地為(=O)、-NR 7fR 8d、-(C 1-C 6)烷基，未取代或被一個或多個基團R 22取代，-具有1或2個選自N、O或S的雜原子的2-8元雜烷基，未取代或被一個或多個基團R 22a取代，-(C 3-C 6)環烷基，未取代或被一個或多個基團R 22b取代，具有1或2個選自N、S或О的雜原子的4-10元雜環基，未取代或被一個或多個基團R 22с取代； 每個R 7f、R 8d獨立地為-H、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代；-(C 3-C 6)環烷基，其未被取代或被一個或多個選自 -Hal、-NH 2、-OH、(=O)的基團取代； 每個R 21、R 21a、R 21b、R 21с、R 22、R 22a、R 22b、R 22с獨立地為-Hal、-H、-OH、-NO 2、-NR 23R 24、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-O(C 1-C 6)烷基、(=O)、-ОH的基團取代； 每個R 23、R 24獨立地為-H；-(C 1-C 6)烷基，其未被取代或被一個或多個選自(=О)、-ОH、-NR 25R 26的基團取代；-(C 2-C 6)烯基，其未被取代或被一個或多個選自(=О)、-NR 25aR 26a的基團取代； 每個R 25、R 26、R 25a、R 26a獨立地為-H、-(C 1-C 6)烷基； Hal是氟、溴、氯或碘原子。 在另一個實施方案中，本發明涉及式I化合物，其中 L 1為化學鍵，R 2為-P(O)((C 1-C 6)烷基) 2，未取代或被一個或多個基團R 15取代；-P(O)((C 3-C 6)環烷基) 2，未取代或被一個或多個基團R 15a取代；-P(O)((C 1-C 6)烷基))((C 3-C 6)環烷基)，未取代或被一個或多個基團R 15b取代； -P(O)(О(C 1-C 6)烷基) 2，未取代或被一個或多個基團R 15c取代；-P(O)(О(C 3-C 6)環烷基) 2，未取代或被一個或多個基團R 15d取代；-P(O)(О(C 1-C 6)烷基)(О(C 3-C 6)環烷基)，未取代或被一個或多個基團R 15e取代；P(O)(О(C 1-C 6)烷基)((C 3-C 6)環烷基)，未取代或被一個或多個基團R 15取代； -P(O)(О(C 1-C 6)烷基) ((C 1-C 6)烷基)，未取代或被一個或多個基團R 15取代；-P(O)(О(C 3-C 6)環烷基)((C 1-C 6)烷基)，未取代或被一個或多個基團R 15取代；-P(O)(О(C 3-C 6)環烷基)((C 3-C 6)環烷基)，未取代或被一個或多個基團R 15取代；或 L 1為-NH-，R 2為-SO 2(C 1-C 6)烷基，未取代或被一個或多個基團R 15f取代；或-SO 2(C 3-C 6)環烷基，未取代或被一個或多個基團R 15g取代，其中 每個R 15、R 15a、R 15、R 15a、R 15b、R 15c、R 15d、R 15e、R 15f、R 15g獨立地為-Hal、-H、-OH、-NO 2、-NR 23R 24、 -(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、 -NH 2、-OH、(=O)的基團取代； 每個R 23、R 24獨立地為-H；-(C 1-C 6)烷基，其未被取代或被一個或多個選自(=О)、-ОH、-NR 25R 26的基團取代；-(C 2-C 6)烯基，其未被取代或被一個或多個選自(=О)、-NR 25aR 26a的基團取代； 每個R 25、R 26、R 25a、R 26a獨立地為-H、-(C 1-C 6)烷基。 在另一個實施方案中，本發明涉及式I.1的化合物
Figure 02_image007
或其藥學上可接受的鹽、溶劑化物或立體異構體， 其中L 1為化學鍵或-NH-； X 1為-CH-、-N-或-C(R 6)-； m是0、1、2、3或4； 每個R 1a、R 1b、R 1c、R 1d獨立地為-H；-Hal； -C(Hal) 3；-CN；-NR 7R 8；-C(O)NR 9R 10；-C(O)OR 11； -C(O)R 12；-OR 13；-(C 1-C 6)烷基，未取代或被一個或多個基團R 14取代；-(C 3-C 6)環烷基，未取代或被一個或多個基團R 14a取代； R 2為-P(O)((C 1-C 6)烷基) 2，未取代或被一個或多個基團R 15取代；-P(O)((C 3-C 6)環烷基) 2，未取代或被一個或多個基團R 15a取代；-P(O)((C 1-C 6)烷基))((C 3-C 6)環烷基)，未取代或被一個或多個基團R 15b取代；-P(O)(О(C 1-C 6)烷基) 2，未取代或被一個或多個基團R 15c取代； -P(O)(О(C 3-C 6)環烷基) 2，未取代或被一個或多個基團R 15d取代；-P(O)(О(C 1-C 6)烷基)(О(C 3-C 6)環烷基)，未取代或被一個或多個基團R 15e取代；-SO 2(C 1-C 6)烷基，未取代或被一個或多個基團R 15f取代；P(O)(О(C 1-C 6)烷基)((C 3-C 6)環烷基)，未取代或被一個或多個基團R 15取代； -P(O)(О(C 1-C 6)烷基)((C 1-C 6)烷基)，未取代或被一個或多個基團R 15取代；-P(O)(О(C 3-C 6)環烷基)((C 1-C 6)烷基)，未取代或被一個或多個基團R 15取代；-P(O)(О(C 3-C 6)環烷基)((C 3-C 6)環烷基)，未取代或被一個或多個基團R 15取代；或-SO 2(C 3-C 6)環烷基，未取代或被一個或多個基團R 15g取代； R 3為-H；-Hal；-CN；-C(Hal) 3；-NR 7aR 8a； -C(O)NR 9aR 10a；-C(O)OR 11a；-C(O)R 12a；-OR 13a；-(C 1-C 6)烷基，未取代或被一個或多個基團R 16a取代；-(C 3-C 6)環烷基，未取代或被一個或多個基團R 16b取代；-(C 6-C 12)芳基，未取代或被一個或多個基團R 16C取代；具有1或2個選自N、S或O的雜原子的4-10元雜芳基，未取代或被一個或多個基團R 16d取代； 每個R 4獨立地為-H；-Hal；-CN；-NR 7bR 8b；-C(Hal) 3；-C(O)NR 9bR 10b；-C(O)OR 11b；-C(O)R 12b；-OR 13b；-(C 1-C 6)烷基，未取代或被一個或多個基團R 17a取代；-(C 3-C 6)環烷基，未取代或被一個或多個基團R 17b取代；具有1或2個選自N、S或О的雜原子的4-10元雜環基，未取代或被一個或多個基團R 17c取代；或-(C 6-C 12)芳基，未取代或被一個或多個基團R 17d取代； R 5為： -NR 7сR 18；-NR 7dR 19；-W 1；-OW 2；-NR aW 3； -C(O)W 4；或-(CH 2)W 5； 其中每個W 1、W 2、W 3、W 4或W 5獨立地為-(C 3-C 6)環烷基，未取代或被一個或多個基團R 20取代；具有1或2個選自N、S或O的雜原子的4-7元雜環基，未取代或被一個或多個基團R 20取代； R 6為-Hal、-CN、-C(Hal) 3、CH(Hal) 2、CH 2Hal、 -NR 7eR 8C；-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R 7、R 7a、R 7b、R 7e、R 8、R 8a、R 8b、R 8C、R 9、R 9a、R 9b、R 10、R 10a、R 10b獨立地為-H、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代；-(C 3-C 6)環烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R 7c、R 7d獨立地為-H、-(С 1-С 6)烷基； R18為-(С 1-С 10)烷基，其未被取代或被一個或多個選自-Hal、-OH、-NO2、-NR23R24、(=O)的取代基取代； R19為具有1或2個選自N、S或O的雜原子的2-10元雜烷基，其未被取代或被一個或多個選自-Hal、-OH、-NO2、-NR23R24、(=O)的取代基取代； 每個R11、R12、R13、R11a、R12a、R13a、R11 b、R12 b、R13 b獨立地為-H、-(C1-C6)烷基，未取代或被一個或多個基團R21取代，-(C 3-C6)環烷基，未取代或被一個或多個基團R21a取代，-(C 6-C 12)芳基，未取代或被一個或多個基團R 21b取代，具有1或2個選自N、S或О的雜原子的4-10元雜環基，未取代或被一個或多個基團R 21c取代； 每個R14、R14a、R15、R15a、R15、R15a、R15b、R15C、R15d、R15e、R15f、R15g、R16、R16a、R16 b、R16 C、R16 d、R17、R17 a、R17 b、R 17c、R17 d獨立地為 -Hal、-H、-OH、-NO2、-NR23R24、-(C1-C6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R20獨立地為(=O)、-NR 7fR 8d、-(C1-C6)烷基，其未被取代或被一個或多個基團R22取代，-具有1或2個選自N、O或S的雜原子的2-8元雜烷基，其未被取代或被一個或多個基團R 22a取代，(C 3-C6)環烷基，未取代或被一個或多個基團R 22b取代，具有1或2個選自N、S或О的雜原子的4-10元雜環基，其未被取代或被一個或多個基團R 22с取代； 每個R 7f、R 8d獨立地為-H、-(C1-C6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代；-(C 3-C6)環烷基，其未被取代或被一個或多個選自 -Hal、-NH 2、-OH、(=O)的基團取代； 每個R21、R21a、R 21b、R21с、R22、R 22a、R 22b、R 22с獨立地為-Hal、-H、-OH、-NO2、-NR23R24、-(C1-C6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、 -O(C1-C6)烷基、-ОH、(=O)的基團取代； 每個R23、R24獨立地為-H；-(C1-C6)烷基，其未被取代或被一個或多個選自(=О)、-ОH、-NR25R26的基團取代；-(C 2-C 6)烯基，其未被取代或被一個或多個選自(=О)、-NR 25aR 26a的基團取代； 每個R25、R26、R 25a、R 26a獨立地為-H、-(C1-C6)烷基； Hal是氟、溴、氯或碘原子。 在另一個實施方案中，本發明涉及式I.2的化合物
Figure 02_image009
或其藥學上可接受的鹽、溶劑化物或立體異構體， 其中L1為化學鍵或-NH-； X1為-CH-、-N-或-C(R6)-； n是0、1、2、3或4； 每個R1獨立地為-H；-Hal；-C(Hal)3；-CN； -NR7R8；-C(O)NR9R10；-C(O)OR11；-C(O)R12； -OR13；-(C1-C6)烷基，未取代或被一個或多個基團R14取代；-(C 3-C6)環烷基，未取代或被一個或多個基團R14a取代； R2為-P(O)((C1-C6)烷基) 2，未取代或被一個或多個基團R15取代；-P(O)((C 3-C6)環烷基) 2，未取代或被一個或多個基團R15a取代；-P(O)((C1-C6)烷基))((C 3-C6)環烷基)，未取代或被一個或多個基團R 15b取代； -P(O)(О(C1-C6)烷基) 2，未取代或被一個或多個基團R15C取代；-P(O)(О(C 3-C6)環烷基) 2，未取代或被一個或多個基團R15d取代；-P(O)(О(C1-C6)烷基)(О(C 3-C6)環烷基)，其未被取代或被一個或多個基團R15e取代；-SO 2(C1-C6)烷基，其未被取代或被一個或多個基團R15f取代； -P(O)(О(C1-C6)烷基)((C 3-C6)環烷基)，未取代或被一個或多個基團R15取代；-P(O)(О(C1-C6)烷基)((C1-C6)烷基)，未取代或被一個或多個基團R15取代；-P(O)(О(C 3-C6)環烷基)((C1-C6)烷基)，未取代或被一個或多個基團R15取代；-P(O)(О(C 3-C6)環烷基)((C 3-C6)環烷基)，未取代或被一個或多個基團R15取代；或-SO 2(C 3-C6)環烷基，未取代或被一個或多個基團R15g取代； R3為-H；-Hal；-CN；-C(Hal)3；-NR7 aR8 a； -C(O)NR 9aR10 a；-C(O)OR11 a；-C(O)R12 a；-OR13 a；-(C1-C6)烷基，未取代或被一個或多個基團R16a取代；-(C 3-C6)環烷基，未取代或被一個或多個基團R16 b取代；-(C 6-C 12)芳基，未取代或被一個或多個基團R16 C取代；具有1或2個選自N、S或O的雜原子的4-10元雜芳基，其未被取代或被一個或多個基團R16 d取代； 每個R 4a、R 4b、R 4c、R 4d獨立地為-H；-Hal；-CN； -NR7 bR8 b；-C(Hal)3；-C(O) NR9 bR10 b；-C(O)OR11 b； -C(O)R12 b；-OR13 b；-(C1-C6)烷基，未取代或被一個或多個基團R17 a取代；-(C 3-C6)環烷基，未取代或被一個或多個基團R17 b取代；具有1或2個選自N、S或О的雜原子的4-10元雜環基，其未被取代或被一個或多個基團R 17c取代；或-(C 6-C 12)芳基，其未被取代或被一個或多個基團R17 d取代； R 5為： -NR7сR18；-NR7 dR19；-W1；-OW2；-NR aW3； -C(O)W4；或-(CH 2)W5； 其中每個W1、W2、W3、W4或W5獨立地為-(C 3-C6)環烷基，其未被取代或被一個或多個基團R20取代；具有1或2個選自N、S或O的雜原子的4-7元雜環基，其未被取代或被一個或多個基團R20取代； R6為-Hal、-CN、-C(Hal)3、CH(Hal)2、CH 2Hal、 -NR7 eR8 C；-(C1-C6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R7、R7 a、R7 b、R7 e、R8、R8 a、R8 b、R8 C、R9、R 9a、R9 b、R10、R10 a、R10 b獨立地為-H、-(C1-C6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、 -OH、(=O)的基團取代；-(C 3-C6)環烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R7 c、R7 d獨立地為-H、-(С 1-С 6)烷基； R18為-(С 1-С 10)烷基，其未被取代或被一個或多個選自-Hal、-OH、-NO2、-NR23R24、(=O)的取代基取代； R19為具有1或2個選自N、S或O的雜原子的2-10元雜烷基，其未被取代或被一個或多個選自-Hal、-OH、-NO2、-NR23R24、(=O)、-(С 1-С 6)烷基的取代基取代； 每個R11、R12、R13、R11a、R12a、R13a、R11 b、R12 b、R13 b獨立地為-H、-(C1-C6)烷基，未取代或被一個或多個基團R21取代，-(C 3-C6)環烷基，未取代或被一個或多個基團R21a取代，-(C 6-C 12)芳基，未取代或被一個或多個基團R 21b取代，具有1或2個選自N、S或О的雜原子的4-10元雜環基，未取代或被一個或多個基團R 21c取代； 每個R14、R14a、R15、R15a、R15、R15a、R15b、R15C、R15d、R15e、R15f、R15g、R16、R16a、R16 b、R16 C、R16 d、R17、R17 a、R17 b、R 17c、R17 d獨立地為 -Hal、-H、-OH、-NO2、-NR23R24、- (C1-C6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R 20獨立地為(=O)、-NR 7fR 8d、-(C 1-C 6)烷基，未取代或被一個或多個基團R 22取代，-具有1或2個選自N、O或S的雜原子的2-8元雜烷基，未取代或被一個或多個基團R 22a取代，-(C 3-C 6)環烷基，未取代或被一個或多個基團R 22b取代，具有1或2個選自N、S或О的雜原子的4-10元雜環基，未取代或被一個或多個基團R 22с取代； 每個R 7f、R 8d獨立地為-H、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代；-(C 3-C 6)環烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R 21、R 21a、R 21b、R 21с、R 22、R 22a、R 22b、R 22с獨立地為-Hal、-H、-OH、-NO 2、-NR 23R 24、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、 -O(C 1-C 6)烷基、(=O)的基團取代； 每個R 23、R 24獨立地為-H；-(C 1-C 6)烷基，其未被取代或被一個或多個選自(=О)、-ОH、-NR 25R 26的基團取代；-(C 2-C 6)烯基，其未被取代或被一個或多個選自(=О)、-NR 25aR 26a的基團取代； 每個R 25、R 26、R 25a、R 26a獨立地為-H、-(C 1-C 6)烷基； Hal是氟、溴、氯或碘原子。 在另一個實施方案中，本發明涉及式I.3的化合物
Figure 02_image011
或其藥學上可接受的鹽、溶劑化物或立體異構體， 其中L 1為化學鍵-NH-； X 1為-СH-、-N-、-C(R 6)-； 每個R 1a、R 1b、R 1c、R 1d獨立地為-H；-Hal； -C(Hal) 3；-CN；-NR 7R 8；-C(O)NR 9R 10；-C(O)OR 11； -C(O)R 12；-OR 13；-(C 1-C 6)烷基，未取代或被一個或多個基團R 14取代；-(C 3-C 6)環烷基，未取代或被一個或多個基團R 14a取代； R 2為-P(O)((C 1-C 6)烷基) 2，未取代或被一個或多個基團R 15取代；-P(O)((C 3-C 6)環烷基) 2，未取代或被一個或多個基團R 15a取代；-P(O)((C 1-C 6)烷基))((C 3-C 6)環烷基)，未取代或被一個或多個基團R 15b取代； -P(O)(О(C 1-C 6)烷基) 2，未取代或被一個或多個基團R 15c取代；-P(O)(О(C 3-C 6)環烷基) 2，未取代或被一個或多個基團R 15d取代；-P(O)(О(C 1-C 6)烷基)(О(C 3-C 6)環烷基)，未取代或被一個或多個基團R 15e取代；-SO 2(C 1-C 6)烷基，未取代或被一個或多個基團R 15f取代；P(O)(О(C 1-C 6)烷基)((C 3-C 6)環烷基)，未取代或被一個或多個基團R 15取代； -P(O)(О(C 1-C 6)烷基)((C 1-C 6)烷基)，未取代或被一個或多個基團R 15取代；-P(O)(О(C 3-C 6)環烷基)((C 1-C 6)烷基)，未取代或被一個或多個基團R 15取代；-P(O)(О(C 3-C 6)環烷基)((C 3-C 6)環烷基)，未取代或被一個或多個基團R 15取代；或-SO 2(C 3-C 6)環烷基，未取代或被一個或多個基團R 15g取代； R 3為-H；-Hal；-CN；-C(Hal) 3；-NR 7aR 8a； -C(O)NR 9aR 10a；-C(O)OR 11a；-C(O)R 12a；-OR 13a；-(C 1-C 6)烷基，未取代或被一個或多個基團R 16a取代；-(C 3-C 6)環烷基，未取代或被一個或多個基團R 16b取代；-(C 6-C 12)芳基，未取代或被一個或多個基團R 16C取代；具有1或2個選自N、S或O的雜原子的4-10元雜芳基，未取代或被一個或多個基團R 16d取代； 每個R 4a、R 4b、R 4c、R 4d獨立地為-H；-Hal；-CN； -NR 7bR 8b；-C(Hal) 3；-C(O)NR 9bR 10b；-C(O)OR 11b； -C(O)R 12b；-OR 13b；-(C 1-C 6)烷基，未取代或被一個或多個基團R 17a取代；-(C 3-C 6)環烷基，未取代或被一個或多個基團R 17b取代；具有1或2個選自N、S或О的雜原子的4-10元雜環基，未取代或被一個或多個基團R 17c取代；或-(C 6-C 12)芳基，未取代或被一個或多個基團R 17d取代； R 5為： -NR 7сR 18；-NR 7dR 19；-W 1；-OW 2；-NR aW 3； -C(O)W 4；或-(CH 2)W 5； 其中每個W 1、W 2、W 3、W 4或W 5獨立地為-(C 3-C 6)環烷基，未取代或被一個或多個基團R 20取代；具有1或2個選自N、S或O的雜原子的4-7元雜環基，未取代或被一個或多個基團R 20取代； R 6為-Hal、-CN、-C(Hal) 3、CH (Hal) 2、CH 2Hal、 -NR 7eR 8C；-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R 7、R 7a、R 7b、R 7e、R 8、R 8a、R 8b、R 8C、R 9、R 9a、R 9b、R 10、R 10a、R 10b獨立地為-H、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代；-(C 3-C 6)環烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R 7c、R 7d獨立地為-H、-(С 1-С 6)烷基； R 18為-(С 1-С 10)烷基，其未被取代或被一個或多個選自-Hal、-OH、-NO 2、-NR 23R 24、(=O)的取代基取代； R 19為具有1或2個選自N、S或O的雜原子的2-10元雜烷基，其未被取代或被一個或多個選自-Hal、-OH、-NO 2、 -NR 23R 24、(=O)、-(С 1-С 6)烷基的取代基取代； 每個R 11、R 12、R 13、R 11a、R 12a、R 13a、R 11b、R 12b、R 13b獨立地為-H；-(C 1-C 6)烷基，未取代或被一個或多個基團R 21取代；-(C 3-C 6)環烷基，未取代或被一個或多個基團R 21a取代；-(C 6-C 12)芳基，未取代或被一個或多個基團R 21b取代，具有1或2個選自N、S或О的雜原子的4-10元雜環基，未取代或被一個或多個基團R 21c取代； 每個R 14、R 14a、R 15、R 15a、R 15、R 15a、R 15b、R 15c、R 15d、R 15e、R 15f、R 15g、R 16、R 16a、R 16b、R 16C、R 16d、R 17、R 17a、R 17b、R 17c、R 17d獨立地為-Hal、-H、-OH、 -NO 2、-NR 23R 24、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R 20獨立地為(=O)、-NR 7fR 8d、-(C 1-C 6)烷基，未取代或被一個或多個基團R 22取代，-具有1或2個選自N、O或S的雜原子的2-8元雜烷基，未取代或被一個或多個基團R 22a取代，-(C 3-C 6)環烷基，未取代或被一個或多個基團R 22b取代，具有1或2個選自N、S或О的雜原子的4-10元雜環基，未取代或被一個或多個基團R 22с取代； 每個R 7f、R 8d獨立地為-H、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代；-(C 3-C 6)環烷基，其未被取代或被一個或多個選自 -Hal、-NH 2、-OH、(=O)的基團取代； 每個R 21、R 21a、R 21b、R 21с、R 22、R 22a、R 22b、R 22с獨立地為-Hal、-H、-OH、-NO 2、-NR 23R 24、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、 -O(C 1-C 6)烷基、(=O)的基團取代； 每個R 23、R 24獨立地為-H；-(C 1-C 6)烷基，其未被取代或被一個或多個選自(=О)、-ОH、-NR 25R 26的基團取代；-(C 2-C 6)烯基，其未被取代或被一個或多個選自(=О)、-NR 25aR 26a的基團取代； 每個R 25、R 26、R 25a、R 26a獨立地為-H、-(C 1-C 6)烷基； Hal是氟、溴、氯或碘原子。 在一個實施方案中，本發明涉及式I化合物，其中R 6為-Hal、-CN、-C(Hal) 3、CH(Hal) 2、CH 2Hal。 在一個實施方案中，本發明涉及式I化合物，其中R 6為-Hal、-CN、-CF 3、CHF2、CHCl2、CHBr 2、CH 2F。 在另一個實施方案中，本發明涉及式I化合物，其中每個R 1獨立地為Hal；-C(Hal) 3，-O(CHal3)；-CN； -O(С 1-С 6)烷基，-O(CH 2) 2O-(С 1-С 6)烷基。 在另一個實施方案中，本發明涉及式I化合物，其中每個R 1獨立地為-F、-Cl、-Br、-CF 3、-CCl 3、-O(CF 3)、 -O(CCl 3)、-OCH 3、-OCH 2CH 3、-O(CH 2) 2O-СH3、 -O(CH 2) 2O-СH2-СH3。 在另一實施方案中，本發明涉及式I化合物，其中R 2為-P(O)((C 1-C 6)烷基) 2，-P(O)((C 3-C 6)環烷基) 2， -P(O)((C 1-C 6)烷基))((C 3-C 6)環烷基))， -P(O)(O(C 1-C 6)烷基) 2，-P(O)(O(C 3-C 6)環烷基) 2， -P(O)(O(C 1-C 6)烷基)((C 3-C 6)環烷基)，P(O)(O(C 1-C 6)烷基)((C 1-C 6)烷基)，P(O)(O(C 3-C 6)環烷基)((C 1-C 6)烷基)，P(O)(O(C 3-C 6)環烷基)((C 3-C 6)環烷基)、-SO 2(C 1-C 6)烷基。 在本發明的一個實施方案中，R 2是-P(O)(CH 3) 2、P(O)(CH 2CH 3) 2、-P(O)(CH 3)(CH 2CH 3)、-P(O)(環丙基) 2、 -P(O)(CH 3)(環丙基)、-P(O)(CH 2CH 3)(環丙基)、 -P(O)(OCH 3) 2、-P(O)(OCH 2CH 3) 2、 -P(O)(OCH 3)(OCH 2CH 3)、-P(O)(OCH 3)(CH 3)、 -P(O)(OCH 3)(CH 2CH 3)、-P(O)(OCH 2CH 3)(CH 3)、 -P(O)(OCH 2CH 3)(CH 2CH 3)、-P(O)(OCH 3)(環丙基)、 -P(O)(OСH2CH 3)(環丙基)、-SO 2CH 3、SO 2CH 2CH 3。 在另一個實施方案中，本發明涉及式I化合物，其中R 3為-H；-Hal；-С(Hal)3，-CN；-NR 7aR 8a；-C(O)NR 9aR 10a；-CO(O)R 11a；-C(O)R 12a；-OR 13a；-(C 1-C 6)烷基，未取代或被一個或多個基團R 16a取代；-(C 3-C 6)環烷基，未取代或被一個或多個基團R 16b取代；苯基，未取代或被一個或多個基團R 16C取代， 其中每個R 7a、R 8a、R 9a、R 10a獨立地為-H、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R 11a、R 12a、R 13a獨立地為-H；-(C 1-C 6)烷基，未取代或被一個或多個基團R 21取代；-(C 3-C 6)環烷基，未取代或被一個或多個基團R 21a取代；-(C6-C12)芳基，未取代或被一個或多個基團R21b取代；-(C 4-C 8)雜環基，其具有1或2個選自N、S或О的雜原子，未取代或被一個或多個基團R 21c取代； 每個R 16a、R 16b、R 16C、R 21、R 21a、R 21b、R 21с獨立地為-H、-OH、-NO 2、-NR 23R 24、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)、-O(C 1-C 6)烷基的基團取代； 每個R 23、R 24獨立地為-H；-(C 1-C 6)烷基，其未被取代或被一個或多個選自(=О)、-ОH、-NR 25R 26的基團取代；-(C 2-C 6)烯基，其未被取代或被一個或多個選自(=О)、-NR 25aR 26a的基團取代； 每個R 25、R 26、R 25a、R 26a獨立地為-H、-(C 1-C 6)烷基； Hal是氟、溴、氯或碘原子。 在另一個實施方案中，本發明涉及式I化合物，其中R 3為-H；-Hal；-С(Hal)3，-CN；-NR 7aR 8a；-C(O)NR 9aR 10a；-CO(O)R 11a；-C(O)R 12a；-OR 13a；-(C 1-C 6)烷基，未取代或被一個或多個基團R 16a取代；-(C 3-C 6)環烷基，未取代或被一個或多個基團R 16b取代；苯基，未取代或被一個或多個基團R 16C取代， 其中每個R 7a、R 8a、R 9a、R 10a獨立地為-H、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R 11a、R 12a、R 13a獨立地為-H；-(C 1-C 6)烷基，未取代或被一個或多個基團R 21取代；-(C 3-C 6)環烷基，未取代或被一個或多個基團R 21a取代；-(C6-C12)芳基，未取代或被一個或多個基團R21b取代；-(C 4-C 8)雜環基，其具有1或2個選自N、S或О的雜原子，未取代或被一個或多個基團R 21c取代； 每個R 16a、R 16b、R 16C、R 21、R 21a、R 21b、R 21с獨立地為-H、-OH、-NO 2、-NR 23R 24、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)、-O(C 1-C 6)烷基的基團取代； 每個R 23、R 24獨立地為-H；-(C 1-C 6)烷基，其未被取代或被一個或多個選自(=О)、-ОH、-NR 25R 26的基團取代；-(C 2-C 6)烯基，其未被取代或被一個或多個選自(=О)、-NR 25aR 26a的基團取代； 每個R 25、R 26、R 25a、R 26a獨立地為-H、-(C 1-C 6)烷基； Hal是氟、溴、氯或碘原子。 在本發明的一個實施方案中，R 3是-CN；苯基，其未被取代或被一個基團R 16C取代，選自丙-2-烯胺基]、3-羥基丙醯胺基、3-(二甲基胺基)丙醯胺基，其中R 16C是-Hal、-H、-OH、-NO 2、-NR 23R 24、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代。 在另一個實施方案中，本發明涉及式I化合物，每個R 4獨立地為-H；-Hal；-C(Hal) 3；-CN；-NR 7bR 8b； -C(O)NR 9bR 10b；-C(O)R 11b；-C(O)OR 12b；-OR 13b； -(C 1-C 6)烷基，未取代或被一個或多個基團R 17a取代，其中 每個R 7b、R 8b、R 9b、R 10b獨立地為-H、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R 11b、R 12b、R 13b獨立地為-H；-(C 1-C 6)烷基，未取代或被一個或多個基團R 21取代；-(C 3-C 6)環烷基，未取代或被一個或多個基團R 21a取代；-(C6-C12)芳基，未取代或被一個或多個基團R21b取代；-(C 4-C 8)雜環基，其具有1或2個選自N、S或О的雜原子，未取代或被一個或多個基團R 21c取代； 每個R 17a，R 21，R 21a，R 21b，R 21с獨立地為-H，-OH，-NO 2，-Hal，-NR 23R 24，-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal，-NH 2，-OH，(=O)，-O(C 1-C 6)烷基的基團取代； 每個R 23、R 24獨立地為-H；-(C 1-C 6)烷基，其未被取代或被一個或多個選自(=О)、-ОH、-NR 25R 26的基團取代；-(C 2-C 6)烯基，其未被取代或被一個或多個選自(=О)、-NR 25aR 26a的基團取代； 每個R 25、R 26、R 25a、R 26a獨立地為-H、-(C 1-C 6)烷基； Hal是氟、溴、氯或碘原子。 在另一個實施方案中，本發明涉及式I化合物，每個R 4獨立地為-H；-Hal；-C(Hal) 3；-CN；-NR 7bR 8b； -C(O)NR 9bR 10b；-C(O)R 11b；-C(O)OR 12b；-OR 13b； -(C 1-C 6)烷基，未取代或被一個或多個基團R 17a取代，其中 每個R 7b、R 8b、R 9b、R 10b獨立地為-H、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R 11b、R 12b、R 13b獨立地為-H；-(C 1-C 6)烷基，未取代或被一個或多個基團R 21取代；-(C 3-C 6)環烷基，未取代或被一個或多個基團R 21a取代；-(C6-C12)芳基，未取代或被一個或多個基團R21b取代；-(C 4-C 8)雜環基，其具有1或2個選自N、S或О的雜原子，未取代或被一個或多個基團R 21c取代； 每個R 17a、R 21、R 21a、R 21b、R 21с獨立地為-H、-OH、-NO 2、-NR 23R 24、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、-O(C 1-C 6)烷基、(=O)的基團取代； 每個R23、R24獨立地為-H；-(C1-C6)烷基，其未被取代或被一個或多個選自(=О)、-ОH、-NR25R26的基團取代；-(C 2-C 6)烯基，其未被取代或被一個或多個選自(=О)、-NR 25aR 26a的基團取代； 每個R25、R26、R 25a、R 26a獨立地為-H、-(C1-C6)烷基。 在本發明的一個實施方案中，每個R 4獨立地為-H； -(C1-C6)烷基、-O(C1-C6)烷基，其未被取代或被一個或多個選自-Hal、-OH、-NO2、-NH 2的基團取代。 在另一個實施方案中，本發明涉及式I化合物，其中R 5為： -NR7сR18；-NR7 dR19；-W1；-OW2；-NR aW3； -C(O)W4；或-(CH 2)W5； 其中每個W1、W2、W3、W4或W5獨立地為 未取代的或被一個或多個基團R20取代的- (C 3-C6)環烷基，選自
Figure 02_image013
具有1或2個選自N、S或О的雜原子的5-7元雜環基，其未被取代或被一個或多個基團R20取代，選自
Figure 02_image015
Figure 02_image017
Figure 02_image019
Figure 02_image021
其中р是0、1、2或3； 每個Y 1、Y 2獨立地為CH 2、СHR20、C(R20)2、NH、NR20、S或O； 每個R7 c、R7 dR a獨立地為-H、-(С 1-С 6)烷基； R18為-(С 1-С 10)烷基，其未被取代或被一個或多個選自-Hal、-OH、-NO2、-NR23R24、(=O)的取代基取代； R19為具有1或2個選自N、S或O的雜原子的2-10元雜烷基，其未被取代或被一個或多個選自-Hal、-OH、 -NO2、-NR23R24、(=O)的取代基取代； 每個R20獨立地為(=O)、-NR 7fR 8d、-(C1-C6)烷基，其未被取代或被一個或多個基團R22取代，具有1或2個選自N、O或S的雜原子的-(C 2-C 6)雜烷基，其未被取代或被一個或多個基團R 22a取代，-(C 3-C6)環烷基，其未被取代或被一個或多個基團R 22b取代，-(C 4-C 8)雜環基，其具有1或2個選自N、S或О的雜原子，其未被取代或被一個或多個基團R 22с取代； 每個R 7f、R 8d獨立地為H、- (C1-C6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R22、R 22a、R 22b、R 22с獨立地為-H、-OH、-NO2、-NR23R24、-(C1-C6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R23、R24獨立地為-H；-(C1-C6)烷基，其未被取代或被一個或多個選自(=О)、-ОH、-NR25R26的基團取代；-(C 2-C 6)烯基，其未被取代或被一個或多個選自(=О)、-NR 25aR 26a的基團取代； 每個R25、R26、R 25a、R 26a獨立地為-H、-(C1-C6)烷基； Hal是氟、溴、氯或碘原子。 在另一個實施方案中，本發明涉及式I化合物，其中R 5為： -NR7сR18；-NR7 dR19；-W1；-OW2；-NR aW3； -C(O)W4；或-(CH 2)W5； 其中每個W1、W2、W3、W4或W5獨立地為 未取代的或被一個或多個基團R20取代的-(C 3-C6)環烷基，選自
Figure 02_image023
Figure 02_image025
具有1或2個選自N、S或О的雜原子的5-7元雜環基，其未被取代或被一個或多個基團R20取代，選自
Figure 02_image027
Figure 02_image029
Figure 02_image031
Figure 02_image033
Figure 02_image035
Figure 02_image037
Figure 02_image039
其中q選自0、1或2，環狀體系取代基的總數選自0、1、2或3； 每個Y 1、Y 2獨立地為CH 2、СHR20、C(R20)2、NH、NR20、S或O； 每個R7 c、R7 d獨立地為-H、-(С 1-С 6)烷基； R18為-(С 1-С 10)烷基，其未被取代或被一個或多個選自-Hal、-OH、-NO2、-NR23R24、(=O)的取代基取代； R19為具有1或2個選自N、S或O的雜原子的2-10元雜烷基，其未被取代或被一個或多個選自-Hal、-OH、 -NO2、-NR23R24、(=O)的取代基取代； 每個R20獨立地為(=O)、-NR 7fR 8d、-(C1-C6)烷基，其未被取代或被一個或多個基團R22取代，具有1或2個選自N、O或S的雜原子的-(C 2-C 6)雜烷基，其未被取代或被一個或多個基團R 22a取代，-(C 3-C6)環烷基，其未被取代或被一個或多個基團R 22b取代，-(C 4-C 8)雜環基，其具有1或2個選自N、S或О的雜原子，其未被取代或被一個或多個基團R 22с取代； 每個R 7f、R 8d獨立地為H、-(C1-C6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R22、R 22a、R 22b、R 22с獨立地為-H、-OH、-NO2、-NR23R24、-(C1-C6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R23、R24獨立地為-H；-(C1-C6)烷基，其未被取代或被一個或多個選自(=О)、-ОH、-NR25R26的基團取代；-(C 2-C 6)烯基，其未被取代或被一個或多個選自(=О)、-NR 25aR 26a的基團取代； 每個R25、R26、R 25a、R 26a獨立地為-H、- (C1-C6)烷基。 在另一個實施方案中，本發明涉及式I化合物，其中R 5為： -NR7сR18；-NR7 dR19；-W1；-OW2；-NR aW3； -C(O)W4；或-(CH 2)W5； 其中每個W1、W2、W3、W4或W5獨立地為
Figure 02_image041
Figure 02_image043
Figure 02_image045
Figure 02_image047
Figure 02_image049
其中 p是0、1、2或3； 每個R7 c、R7 d獨立地為-H、-(С 1-С 6)烷基； R18為-(С 1-С 10)烷基，其未被取代或被一個或多個選自-Hal、-OH、-NO2、-NR23R24、(=O)的取代基取代； R19為具有1或2個選自N、S或O的雜原子的2-10元雜烷基，其未被取代或被一個或多個選自-Hal、-OH、-NO2、-NR23R24、(=O)的取代基取代； 每個R20獨立地為(=O)、-NR 7fR 8d、-(C1-C6)烷基，其未被取代或被一個或多個基團R22取代，具有1或2個選自N、O或S的雜原子的-(C 2-C 6)雜烷基，其未被取代或被一個或多個基團R 22a取代，-(C 3-C6)環烷基，其未被取代或被一個或多個基團R 22b取代，-(C 4-C 8)雜環基，其具有1或2個選自N、S或О的雜原子，其未被取代或被一個或多個基團R 22с取代； 每個R 7f、R 8d、R a獨立地為H、-(C1-C6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R22、R 22a、R 22b、R 22с獨立地為-H、-OH、-NO2、-NR23R24、-(C1-C6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R23、R24獨立地為-H；-(C1-C6)烷基，其未被取代或被一個或多個選自(=О)、-ОH、-NR25R26的基團取代；-(C 2-C 6)烯基，其未被取代或被一個或多個選自(=О)、-NR 25aR 26a的基團取代； 每個R25、R26、R 25a、R 26a獨立地為-H、-(C1-C6)烷基； Hal是氟、溴、氯或碘原子。 在另一個實施方案中，本發明涉及式I化合物，其中R 5為： -NR7сR18；-NR7 dR19；-W1；-OW2；-NR aW3； -C(O)W4；或-(CH 2)W5； 其中每個W1、W2、W3、W4或W5獨立地為
Figure 02_image051
Figure 02_image053
Figure 02_image055
Figure 02_image057
其中q選自0、1或2，環狀體系取代基的總數選自0、1、2或3； 每個R7 c、R7 d獨立地為-H、-(С 1-С 6)烷基； R18為-(С 1-С 10)烷基，其未被取代或被一個或多個選自-Hal、-OH、-NO2、-NR23R24、(=O)的取代基取代； R19為具有1或2個選自N、S或O的雜原子的2-10元雜烷基，其未被取代或被一個或多個選自-Hal、-OH、 -NO2、-NR23R24、(=O)、-(С 1-С 6)烷基的取代基取代； 每個R20獨立地為(=O)、-NR 7fR 8d、-(C1-C6)烷基，其未被取代或被一個或多個基團R22取代，具有1或2個選自N、O或S的雜原子的-(C 2-C 6)雜烷基，其未被取代或被一個或多個基團R 22a取代，-(C 3-C6)環烷基，其未被取代或被一個或多個基團R 22b取代，-(C 4-C 8)雜環基，其具有1或2個選自N、S或О的雜原子，其未被取代或被一個或多個基團R 22с取代； 每個R 7f、R 8d獨立地為H、-(C1-C6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R22、R 22a、R 22b、R 22с獨立地為-H、-OH、-NO2、-NR23R24、-(C1-C6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R23、R24獨立地為-H；-(C1-C6)烷基，其未被取代或被一個或多個選自(=О)、-ОH、-NR25R26的基團取代；-(C 2-C 6)烯基，其未被取代或被一個或多個選自(=О)、-NR 25aR 26a的基團取代； 每個R25、R26、R 25a、R 26a獨立地為-H、-(C1-C6)烷基。 在本發明的一個實施方案中，R 5是 [2-(二甲基胺基)乙基](甲基)胺基，4-(4-甲基呱嗪-1-基)呱啶-1-基，4-甲基呱嗪-1-基，4-(二甲基胺基)呱啶-1-基，4-嗎啉-1-基，4-甲基-1,4-二氮雜環庚烷-1-基，1-異丙基呱啶-4-基，(1-甲基呱啶-4-基)氧基，(1-甲基呱啶-3-基)胺基，(1-甲基呱啶-4-基)胺基，甲基(1-甲基呱啶-4-基)胺基，(4-甲基呱嗪-1-基)甲酮，(4-甲基呱嗪-1-基)甲基，(2-甲基-2-氮雜雙環[2.2.1]庚烷-5-基)氧基，(1-甲基吡咯烷-3-基)氧基，(1-甲基呱啶-4-基)氧基，1-乙醯基呱啶-1-基，呱啶-1-基，1-(2-(二甲基胺基)-2-氧代乙基)呱啶。 本發明所述之化合物可以作為和/或用作藥學上可接受的鹽。藥學上可接受的鹽的類型包括但不限於：酸加成鹽，通過使遊離鹼形式的化合物與藥學上可接受的無機酸如鹽酸、氫溴酸、硫酸、硝酸、磷酸、偏磷酸等反應而形成；或與有機酸如甲酸、乙酸、丙酸、己酸、環戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、蘋果酸、馬來酸、富馬酸、三氟乙酸、酒石酸、檸檬酸、苯甲酸、3-(4-羥基苯甲醯基)苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羥基乙二磺酸、苯磺酸、甲苯磺酸、2-萘磺酸、4-甲基雙環-[2.2.2]辛-2-烯-1-甲酸、葡庚糖酸、4,4'-亞甲基雙-3-羥基-2-烯-1-甲酸、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、月桂基硫酸、葡糖酸、谷氨酸、羥基萘甲酸、水楊酸、硬脂酸、黏康酸等反應。 可以使用各種方法分析和鑒定藥學上可接受的鹽的相應抗衡離子，所述方法包括但不限於離子交換色譜法、離子色譜法、毛細管電泳、電感耦合等離子體、原子吸收光譜法、質譜法或其任意組合。 通過使用至少一種以下技術回收所述鹽：過濾，用非溶劑沉澱，然後過濾，蒸發溶劑，或在水溶液的情況下，凍幹。應當理解，提及藥學上可接受的鹽包括其溶劑加成形式或晶體形式，特別是溶劑化物或多晶型物。溶劑化物包含化學計量或非化學計量的溶劑，並且可以在用藥學上可接受的溶劑如水、乙醇等結晶的過程中形成。當溶劑是水時形成水合物，或者當溶劑是醇時形成醇化物。本專利中所述化合物的溶劑化物可在本發明所述方法中方便地製備或形成。此外，本發明提供的化合物可以以非溶劑化以及溶劑化形式存在。通常，對於本發明提供的化合物和方法來說，溶劑化形式被認為與非溶劑化形式等價。 本發明所述之化合物可以以各種形式提供，包括但不限於無定形形式、研磨形式和納米顆粒形式。此外，本發明中描述的化合物包括結晶形式，也稱為多晶型物。多晶型物包括化合物的相同元素組成的不同晶體堆積排列。多晶型物通常具有不同的X-射線衍射圖、紅外光譜、熔點、不同的密度、硬度、晶體形狀、光學和電學性質、穩定性和溶解性。諸如重結晶溶劑、結晶速率和儲存溫度的各種因素可導致一種晶形佔優勢。 藥學上可接受的鹽、多晶型物和/或溶劑化物的篩選和表徵可以使用多種技術完成，包括但不限於熱分析、X射線衍射、光譜、蒸氣吸附和顯微鏡檢查。熱分析方法致力於分析熱化學降解或熱物理過程，包括但不限於多晶型轉變，並且此類方法用於分析多晶型形式之間的關係，以確定重量損失，以找到玻璃化轉變溫度，或用於賦形劑相容性研究。這些方法包括但不限於差示掃描量熱法(DSC)、調製差示掃描量熱法(MDCS)、熱重分析(TGA)、熱重和紅外分析(TG/IR)。結晶方法包括但不限於單晶和粉末衍射儀和同步加速器源。所用的各種光譜技術包括但不限於拉曼(組合散射)、FTIR、UVIS和NMR (液態和固態)。各種顯微鏡技術包括，但不限於，偏振光顯微鏡、具有能量色散X射線分析(EDX)的掃描電子顯微鏡(SEM)、具有EDX(在氣體或水蒸氣氣氛中)的環境掃描電子顯微鏡、IR顯微鏡和拉曼顯微鏡。 在本發明的另一個實施方案中涉及選自以下的化合物： 編碼 結構 名稱 EGFR_48
Figure 02_image059
 (2-((2-(4-((2-(二甲基胺基)乙基)(甲基)胺基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)二甲基氧化膦甲酸鹽 EGFR_58
Figure 02_image061
 (2-((2-(4-((2-(二甲基胺基)乙基)(甲基)胺基)苯基-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)-4-氟苯基)二甲基氧化膦甲酸鹽 EGFR_59
Figure 02_image063
 (2-((2-(4-((2-(二甲基胺基)乙基)(甲基)胺基)-2-甲氧基苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)二甲基氧化膦乙酸鹽 EGFR_60
Figure 02_image065
 (2-((2-(4-((2-(二甲基胺基)乙基)(甲基)胺基)-3-甲氧基苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)二甲基氧化膦乙酸鹽 EGFR_65
Figure 02_image067
 (2-((2-(4-((2-(二甲基胺基)乙基)(甲基)胺基)苯基-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)-5-氟苯基)二甲基氧化膦乙酸鹽 EGFR_66
Figure 02_image069
 (2-((2-(4-((2-(二甲基胺基)乙基)(甲基)胺基)苯基-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)-6-氟苯基)二甲基氧化膦甲酸鹽 EGFR_68
Figure 02_image071
 (2-((2-(4-((2-(二甲基胺基)乙基)(甲基)胺基)苯基-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)-4-(三氟甲基)苯基)二甲基氧化膦 EGFR_69
Figure 02_image073
 (2-((6-(4-((2-(二甲基胺基)乙基)(甲基)胺基)苯基-7 H-吡咯並[2,3- d]嘧啶-4-基)胺基)苯基)二甲基氧化膦 EGFR_70
Figure 02_image075
 2-((5-氯-2-(4-((2-(二甲基胺基)乙基)(甲基)胺基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)二甲基氧化膦甲酸鹽 EGFR_74
Figure 02_image077
 (2-((2-(4-((2-(二甲基胺基)乙基)(甲基)胺基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)二乙基氧化膦 EGFR_76
Figure 02_image079
 (2-((2-(4-((2-(二甲基胺基)乙基) (甲基)胺基)苯基) -1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)膦酸二甲酯 EGFR_79
Figure 02_image081
 N-(2-((2-(4-((2-(二甲基胺基)乙基)(甲基)胺基)苯基)-1 H-吡咯並[2,3- b]嘧啶-4-基)胺基)苯基)甲磺醯胺甲酸鹽 EGFR_338
Figure 02_image083
 2-(4-((2-(二甲基胺基)乙基)(甲基)胺基)苯基-4-((2-二甲基磷醯基)苯基)胺基)-1 H-吡咯並[2,3- b]吡啶-5-甲腈 EGFR_348
Figure 02_image085
 (4-氟-2-((2-(4-(4-(4-甲基呱嗪-1-基)呱啶-1-基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)二甲基氧化膦甲酸鹽 EGFR_437
Figure 02_image087
 (2-((6-(4-((2-(二甲基胺基)乙基)(甲基)胺基)苯基)-7 H-吡咯並[2,3- d]嘧啶-4-氟苯基)二甲基氧化膦乙酸鹽 EGFR_440
Figure 02_image089
 二甲基(2-((6-(4-(4-(4- 甲基呱嗪-1-基)呱啶-1-基)苯基)-7 H-吡咯並[2,3- d]嘧啶-4-基)胺基)苯基)氧化膦 EGFR_441
Figure 02_image091
 (4-氟-6-((6-(4-(4-(4-甲基呱嗪-1-基)呱啶-1-基)苯基)-7 H-吡咯並[2,3- d]嘧啶-4-基)胺基)苯基)二甲基氧化膦 EGFR_483
Figure 02_image093
 (2-氟-6-((6-(4-(4-(4-甲基呱嗪-1-基)呱啶-1-基)苯基)-7 H-吡咯並[2,3- d]嘧啶-4-基)胺基)苯基)二甲基氧化膦 EGFR_485
Figure 02_image095
 (2-((5-氯-2-(4-(4-(4-甲基呱嗪-1-基)呱啶-1-基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)苯基)二甲基氧化膦 EGFR_655
Figure 02_image097
 二甲基(2-((2-(3-(4-甲基呱嗪-1-基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)氧化膦乙酸鹽 EGFR_656
Figure 02_image099
 二甲基(2-((2-(4-嗎啉代苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)氧化膦甲酸鹽 EGFR_667
Figure 02_image101
 二甲基(2-((2-(4-(4-甲基呱嗪-1-基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)氧化膦甲酸鹽 EGFR_668
Figure 02_image103
 二甲基(2-((2-(4-(4-甲基-1,4-二氮雜環庚烷-1-基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)氧化膦甲酸鹽 EGFR_669
Figure 02_image105
 (2-((2-(4-((1-異丙基呱啶-4-基)胺基)苯基)-1 H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)二甲基氧化膦乙酸鹽 EGFR_743
Figure 02_image107
 (2-((2-(4-(4-(二甲基胺基)呱啶-1-基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)二甲基氧化膦乙酸鹽 EGFR_752
Figure 02_image109
 二甲基(2-((2-(4-(1-甲基呱啶-4-基)氧基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)氧化膦甲酸鹽 EGFR_774
Figure 02_image111
 (2-((2-(4-(2-(二甲基胺基)乙基(甲基)胺基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)二乙基氧化膦甲酸鹽 EGFR_795
Figure 02_image113
 二甲基(2-((2-(4-(1-甲基呱啶-4-基)胺基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)氧化膦乙酸鹽 EGFR_796
Figure 02_image115
 二甲基(2-((2-(4-(甲基(1-甲基呱啶-4-基)胺基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)氧化膦甲酸鹽 EGFR_797
Figure 02_image117
 (4-(4-((2-(二甲基磷醯基)苯基)胺基)-1 H-吡咯並[2,3- b]吡啶-2-基)苯基)(4-甲基呱嗪-1-基)甲酮甲酸鹽 EGFR_798
Figure 02_image119
 二甲基(2-((2-(4-((4-甲基呱嗪-1-基)甲基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)氧化膦甲酸鹽 EGFR_801
Figure 02_image121
 ( S)-二甲基(2-((2-(4-((1-甲基呱啶-3-基)胺基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)氧化膦乙酸鹽 EGFR_802
Figure 02_image123
 ( R)-二甲基(2-((2-(4-((1-甲基呱啶-3-基)胺基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)氧化膦乙酸鹽 EGFR_853
Figure 02_image125
 (2-氯-6-((2-(4-(4-(二甲基胺基)呱啶-1-基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)二甲基氧化膦甲酸鹽 EGFR_854
Figure 02_image127
 (2-((2-(4-(4-(二甲基胺基)呱啶-1-基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)-6-(三氟甲基)苯基)二甲基氧化膦甲酸鹽 EGFR_855
Figure 02_image129
 (6-((2-(4-(4-(二甲基胺基)呱啶-1-基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)-2,3-二氟苯基)二甲基氧化膦 EGFR_856
Figure 02_image131
 (2-((2-(4-(4-(二甲基胺基)呱啶-1-基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)-4-甲氧基苯基)二甲基氧化膦乙酸鹽 EGFR_857
Figure 02_image133
 (2-((2-(4-(4-(二甲基胺基)呱啶-1-基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)-4-(三氟甲氧基)苯基)二甲基氧化膦乙酸鹽 EGFR_858
Figure 02_image135
 (2-((2-(4-(4-(二甲基胺基)呱啶-1-基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)-4,6-二氟苯基)二甲基氧化膦乙酸鹽 EGFR_859
Figure 02_image137
 2-((2-(4-(4-(二甲基胺基)呱啶-1-基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)-4-氟苯基)二甲基氧化膦 EGFR_860
Figure 02_image139
 4-((2-(4-(4-(二甲基胺基)呱啶-1-基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)-3-(二甲基磷醯基)苄腈甲酸鹽 EGFR_862
Figure 02_image141
 (2-((2-(4-(4-(二甲基胺基)呱啶-1-基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)-6-氟苯基)二甲基氧化膦 EGFR_865
Figure 02_image143
 (2-((2-(4-(4-(二甲基胺基)呱啶-1-基)苯基)-5-氟-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)二甲基氧化膦甲酸鹽 EGFR_870
Figure 02_image145
 (2-((2-(4-(4-(二甲基胺基)呱啶-1-基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)-5-甲氧基苯基)二甲基氧化膦甲酸鹽 EGFR_871
Figure 02_image147
 (2-((2-(4-(4-(二甲基胺基)呱啶-1-基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)二乙基氧化膦乙酸鹽 EGFR_884
Figure 02_image149
 (2-((2-(4-(4-(二甲基胺基)呱啶-1-基)-2-(三氟甲氧基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)二甲基氧化膦乙酸鹽 EGFR_886
Figure 02_image151
 (2-((2-(4-(4-(二甲基胺基)呱啶-1-基)-2-甲基苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)二甲基氧化膦乙酸鹽 EGFR_887
Figure 02_image153
 2-((2-(4-(4-(二甲基胺基)呱啶-1-基)-3-甲基苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)二甲基氧化膦乙酸鹽 EGFR_896
Figure 02_image155
 (2-((2-(4-(4-(二甲基胺基)呱啶-1-基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)-6-甲氧基苯基)二甲基氧化膦乙酸鹽 EGFR_910
Figure 02_image157
 二乙基(2-((2-(4-((甲基(1-甲基呱啶-4-基)胺基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)氧化膦乙酸鹽 EGFR_912
Figure 02_image159
 二乙基(2-((2-(4-((1-甲基呱啶-4-基)氧基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)氧化膦乙酸鹽 EGFR_914
Figure 02_image161
 (2-((2-(4-(4-(二甲基胺基)呱啶-1-基)苯基)-5-甲基-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)二甲基氧化膦 EGFR_918
Figure 02_image163
 (2-甲氧基-6-((2-(4-((1-甲基呱啶-4-基)氧基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)二甲基氧化膦 EGFR_919
Figure 02_image165
 (2-氟-6-((2-(4-((1-甲基呱啶-4-基)氧基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)二甲基氧化膦甲酸鹽 EGFR_989
Figure 02_image167
 ( R)-(2-甲氧基-6-((2-(4-((1-甲基吡咯烷-3-基)氧基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)二甲基氧化膦 EGFR_990
Figure 02_image169
 ( S)-(2-甲氧基-6-((2-(4-((1-甲基吡咯烷-3-基)氧基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)二甲基氧化膦 EGFR_982
Figure 02_image171
 二環丙基(2-甲氧基-6-((2-(4-((1-甲基呱啶-4-基)氧基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)二甲基氧化膦 EGFR_985
Figure 02_image173
 (2-甲氧基-6-((2-(4-((2-甲基-2-氮雜雙環[2.2.1]庚烷-5-基)氧基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)二甲基氧化膦 EGFR_993
Figure 02_image175
 1-(4-(4-(4-((2-(二甲基磷醯基)-3-甲氧基苯基)胺基)-1 H-吡咯並[2,3- b]吡啶-2-基)苯氧基)呱啶-1-基)乙-1-酮 EGFR_994
Figure 02_image177
 2-(4-(4-(4-((2-(二甲基磷醯基)-3-甲氧基苯基)胺基)-1 H-吡咯並[2,3- b]吡啶-2-基)苯氧基)呱啶-1-基)- N, N-二甲基乙醯胺 EGFR_1006
Figure 02_image179
 (2-甲氧基甲氧基-6-((2-(4-((1-甲基呱啶-4-基)氧基)苯基)-1 H-吡咯並[2,3- b]吡啶-4-基)胺基)苯基)二甲基氧化膦乙酸鹽 本發明還涉及抑制受試者中表皮生長因子受體(EGFR)生物活性的方法，包括使EGFR激酶結構域與本文所述之化合物接觸。 EGFR抑制化合物可以用於製備用於治療本文所述任何病理狀態的藥物產品，例如，式I化合物、藥學上可接受的鹽、溶劑化物或立體異構體將可用於治療單獨或部分由EGFR活性介導的疾病或醫學狀態，例如腫瘤疾病。可以使用上述化合物治療的腫瘤疾病的實例包括但不限於膀胱癌、卵巢癌、宮頸癌、結腸直腸癌、乳腺癌、胰腺癌、頭頸癌、膠質瘤、成膠質細胞瘤、黑素瘤、前列腺癌、白血病、淋巴瘤、非霍奇金淋巴瘤、霍奇金淋巴瘤、肺癌(例如，非小細胞肺癌)、肝細胞癌、食道癌、胃癌、胃腸道間質瘤、甲狀腺癌、膽管癌、子宮內膜癌、腎癌、肝癌、間變性大細胞淋巴瘤、急性髓性白血病、多發性骨髓瘤、黑素瘤、間皮瘤、血液惡性腫瘤。 在一個實施方案中，本發明涉及藥物組合物，其包含至少一種本文所述之化合物或其藥學上可接受的鹽、溶劑化物、立體異構體和一種或多種藥學上可接受的賦形劑。在一個實施方案中，本發明涉及藥物組合物，其包含治療有效量的至少一種本文所述之化合物或其藥學上可接受的鹽、溶劑化物、立體異構體和一種或多種藥學上可接受的賦形劑。在另一個實施方案中，包含本發明化合物的藥物組合物用於預防或治療由EGFR啟動介導的疾病或病症。 在另一個實施方案中，包含本發明化合物的藥物組合物用於預防或治療由具有L858R突變和/或T790M突變和/或外顯子19缺失和/或C797S突變的EGFR啟動介導的疾病或病症。 在本發明的另一個實施方案中，包含本發明化合物的藥物組合物用於預防或治療腫瘤疾病，包括膀胱癌、卵巢癌、宮頸癌、結腸直腸癌、乳腺癌、胰腺癌、頭頸癌、膠質瘤、成膠質細胞瘤、黑素瘤、前列腺癌、白血病、淋巴瘤、非霍奇金淋巴瘤、霍奇金淋巴瘤、肺癌(例如，非小細胞肺癌)、肝細胞癌、食道癌、胃癌、胃腸道間質瘤、甲狀腺癌、膽管癌、子宮內膜癌、腎癌、肝癌、間變性大細胞淋巴瘤、急性髓性白血病、多發性骨髓瘤、黑素瘤、間皮瘤、血液惡性腫瘤。 在本發明的另一個實施方案中，包含本發明化合物的藥物組合物旨在預防或治療腫瘤疾病，其中所述腫瘤疾病是非小細胞肺癌。 本發明的藥物組合物包含例如約5重量%至約100重量%的活性成分，優選約10重量%至約60重量%的活性成分。應當理解，每個劑量單位可以不包含有效量的一種或多種活性成分，因為足夠的有效量可以通過施用多個劑量單位形式來實現。 典型的組合物通過將本發明的化合物與載體、稀釋劑或賦形劑混合來製備。合適的載體、稀釋劑和賦形劑是本領域技術人員公知的，包括諸如碳水化合物、蠟、水溶性和/或可溶脹聚合物、親水或疏水材料、明膠、油、溶劑、水等材料。所用的具體載體、稀釋劑或賦形劑將取決於本發明化合物應用的方式和目的。溶劑通常基於本領域技術人員認為可安全施用於哺乳動物的溶劑來選擇。通常，安全溶劑是水性溶劑，例如水和其它可溶于水或可與水混溶的溶劑。合適的水性溶劑包括水(作為主要成分)、乙醇、丙二醇、聚乙二醇(例如PEG400、PEG300)等，以及它們的混合物。組合物還可以包括一種或多種緩衝劑、穩定劑、表面活性劑、潤濕劑、潤滑劑、乳化劑、懸浮劑、防腐劑、抗氧化劑、遮光劑、助流劑、加工助劑、著色劑、甜味劑、芳香劑、調味劑和其它已知的添加劑，以提供藥物產品(即，本發明的化合物或其藥物組合物)的優雅外觀或有助於藥物產品(即，藥物產品)的製造。藥物組合物應優選按照GMP(良好的生產規範)要求生產。 藥物組合物還包括本發明化合物的溶劑化物和水合物，或化合物的穩定形式(例如，與環糊精衍生物或其它已知絡合劑的絡合物)。 本發明的藥物組合物可以配製成用於口服途徑給藥。口服給藥可以包括吞咽，使得化合物進入胃腸道，和/或口腔、舌或舌下給藥，通過這些給藥，化合物直接從口進入血流。 適於口服給藥的製劑包括固體、半固體和液體系統，例如片劑；含有多顆粒或納米顆粒、液體或粉末的軟膠囊或硬膠囊；顆粒；錠劑(包括液體填充的)；咀嚼物；凝膠；快速分散劑型；薄膜；ovules；噴霧劑；和頰/黏膜黏附貼劑。更優選的口服製劑包括片劑、顆粒劑和膠囊劑。 液體製劑包括懸浮液、溶液、糖漿和酏劑。這樣的製劑可以用作軟膠囊或硬膠囊(例如由明膠或羥丙基甲基纖維素製成)中的填充劑，並且通常包含載體，例如水、乙醇、聚乙二醇、丙二醇、甲基纖維素或合適的油，以及一種或多種乳化劑和/或懸浮劑。液體製劑也可以通過固體的重構，例如從小袋中重構來製備。 本發明的藥物組合物也可以腸胃外給藥。如本文所用，藥物組合物的“腸胃外施用”包括特徵在於物理破壞受試者的組織和通過組織中的缺口施用藥物組合物的任何施用途徑，因此通常導致直接施用到血流中、肌肉中或內部器官中。因此，腸胃外給藥尤其包括通過注射組合物、通過外科切口施用組合物、通過組織穿透非外科傷口施用組合物等來給藥藥物組合物。特別地，腸胃外給藥包括，尤其是，皮下、腹膜內、肌內、靜脈內、動脈內、鞘內、心室內、尿道內、顱內、滑膜內注射或輸注；和腎透析輸注技術。瘤內遞送，例如瘤內注射，也可能是有利的。還考慮了區域灌注。 適於腸胃外給藥的藥物組合物製劑通常包含與藥學上可接受的載體組合的活性成分，所述載體例如無菌水或無菌等滲鹽水。這樣的製劑可以以適於推注給藥或連續給藥的形式製備、包裝或銷售。可注射製劑可以單位劑型製備、包裝或銷售，例如在安瓿或在含有防腐劑的多劑量容器中。用於腸胃外給藥的製劑尤其包括混懸劑、溶液劑、在油性或水性媒介物中的乳劑、糊劑等。 本發明的化合物還可以鼻內或通過吸入給藥，通常以乾粉形式(單獨、作為混合物或作為混合組分顆粒，例如與合適的藥學上可接受的賦形劑混合)從乾粉吸入器、作為氣溶膠加壓容器、泵、噴霧劑、霧化器(優選使用電流體動力學產生細霧的霧化器)或霧化器(使用或不使用合適的拋射劑)或作為滴鼻劑給藥。 加壓容器、泵、噴霧器、霧化器或霧化器通常含有本發明化合物的溶液或懸浮液，其包含例如用於分散、增溶活性成分或延長活性成分釋放的合適試劑，作為溶劑的拋射劑。 在作為乾粉或混懸液使用之前，藥物產品通常被微粉化至適於通過吸入遞送的尺寸(通常小於5微米)。這可以通過任何合適的粉碎方法來實現，例如螺旋噴射研磨、流化床噴射研磨、超臨界流體加工以形成納米顆粒、高壓均化或噴霧乾燥。 用於吸入器或吹入器的膠囊、泡罩和藥筒可以配製成含有本發明化合物、合適的粉末基質和性能改性劑的粉末混合物。 用於使用電流體動力學產生細霧的霧化器的合適的溶液製劑可以含有每次驅動的合適劑量的本發明化合物，並且驅動體積可以例如為1μL至100μL。 可以將合適的矯味劑如薄荷醇和左薄荷醇，或甜味劑如糖精或糖精鈉加入本發明的那些旨在吸入/鼻內給藥的製劑中。 製劑可以配製成立即釋放和/或改進釋放。改進釋放製劑包括延遲、持續、脈衝、控制、靶向和程式化釋放。 在一個實施方案中，本發明涉及治療由EGFR活性介導的疾病或病症的方法，其包括以治療有效量向需要這種治療的受試者施用任何上述化合物或本發明的藥物組合物。 在另一個實施方案中，本發明涉及治療上述疾病或病症的方法，其中所述疾病或病症是具有L858R突變和/或T790M突變和/或外顯子19缺失和/或C797S突變的EGFR活性介導的疾病或病症。 在另一個實施方案中，本發明涉及治療上述疾病的方法，其中EGFR活性介導的疾病或病症是腫瘤學疾病。在另一個實施方案中，本發明涉及治療上述疾病的方法，其中所述腫瘤疾病選自膀胱癌、卵巢癌、宮頸癌、結腸直腸癌、乳腺癌、胰腺癌、頭頸癌、膠質瘤、成膠質細胞瘤、黑素瘤、前列腺癌、白血病、淋巴瘤、非霍奇金淋巴瘤、霍奇金淋巴瘤、肺癌(例如非小細胞肺癌)、肝細胞癌、食道癌、胃癌、胃腸道間質瘤、甲狀腺癌、膽管癌、子宮內膜癌、腎癌、肝癌、間變性大細胞淋巴瘤、急性髓性白血病、多發性骨髓瘤、黑素瘤、間皮瘤、血液惡性腫瘤。 在另一個實施方案中，本發明涉及用於治療上述癌症的方法，其中所述癌症是非小細胞肺癌。 在一個實施方案中，本發明涉及本發明化合物或上述藥物組合物在需要這種治療的受試者中治療由EGFR活性介導的疾病或病症的用途。 在另一個實施方案中，本發明涉及上述用途，其中所述疾病或病症是具有L858R突變和/或T790M突變和/或外顯子19缺失和/或C797S突變的EGFR活性介導的疾病或病症。 在另一個實施方案中，本發明涉及上述用途，其中EGFR活性介導的疾病或病症是腫瘤疾病。在另一個實施方案中，本發明涉及上述用途，其中所述腫瘤疾病選自膀胱癌、卵巢癌、宮頸癌、結腸直腸癌、乳腺癌、胰腺癌、頭頸癌、膠質瘤、成膠質細胞瘤、黑素瘤、前列腺癌、白血病、淋巴瘤、非霍奇金淋巴瘤、霍奇金淋巴瘤、肺癌(例如非小細胞肺癌)、肝細胞癌、食道癌、胃癌、胃腸道間質瘤、甲狀腺癌、膽管癌、子宮內膜癌、腎癌、肝癌、間變性大細胞淋巴瘤、急性髓性白血病、多發性骨髓瘤、黑素瘤、間皮瘤、血液惡性腫瘤。 在另一個實施方案中，本發明涉及上述用途，其中所述腫瘤疾病是非小細胞肺癌。 本發明的化合物可以單獨施用或與一種或多種其它藥物產品或抗體組合施用(或以其任何組合施用)。因此，本發明的藥物組合物、方法和用途還包括與其它活性劑組合(共同給藥)的實施方案。 如本文所用，術語“共同施用”、“共同給藥”和“與……組合”是指化合物與一種或多種其它治療劑一起，旨在表示並且確實是指並且包括以下各項： 當將本發明化合物和治療劑的這種組合一起配製成基本上同時向所述患者釋放所述組分的單一劑型時，向需要治療的患者同時給藥這種組合， 當將本發明化合物和治療劑的這種組合彼此分開配製成基本上同時被所述患者服用的獨立劑型時，將這種組合同時給予需要治療的患者，於是所述組分基本上同時釋放給所述患者， 當將本發明化合物和治療劑的這種組合彼此分開配製成單獨的劑型時，將這種組合依次給予需要治療的患者，所述劑型由所述患者在連續的時間服用，每次給藥之間有顯著的時間間隔，由此所述組分在基本上不同的時間釋放給所述患者；以及 當將本發明化合物和治療劑的這種組合配製成以受控方式釋放所述組分的單一劑型時，將這種組合依次給予需要治療的患者，其中所述組分在相同和/或不同時間同時、連續和/或重疊釋放給所述患者，其中各部分可以通過相同或不同途徑給予。 如本領域技術人員所熟知的，當藥物產品用於聯合治療時，治療有效劑量可以變化。文獻中已經描述了實驗確定用於聯合治療方案的藥物產品和其它藥劑的治療有效劑量的方法。例如，文獻中已經描述了使用節拍式給藥，即，提供更頻繁的更低劑量以使毒副作用最小化。組合治療還包括根據患者治療計畫在不同時間開始和停止的週期性治療。對於本專利中所述之聯合治療，共同給藥的化合物的劑量當然將根據所用的共同藥物的類型、所用的具體藥物、所治療的病症或障礙等而變化。 上述抗腫瘤治療可以作為獨立療法使用，或與手術、或放射療法、或藥物療法組合使用。這種治療可以與本發明化合物的治療同時、依次或分別施用，並且可以包括一種或多種下列類別的抗腫瘤劑：用於醫學腫瘤學的抗增殖/抗腫瘤藥物及其組合，例如烷化劑(例如順鉑、奧沙利鉑、卡鉑、環磷醯胺、氯甲嗪、美法侖、苯丁酸氮芥、白消安、曲舒凡、替莫唑胺、苯達莫司汀、丙司匹定、螺溴銨、潑尼松氮芥、雌莫司汀、帕芬淨、洛芬那醇、異環磷醯胺、馬磷胺、曲磷胺、葡磷胺和亞硝基脲，包括卡莫明、洛莫司汀、尼莫司汀、福莫司汀、阿拉鼻、鏈佐星)；抗代謝物(例如吉西他濱、氟尿嘧啶、氟尿苷、替加氟、雷替曲塞、甲氨蝶呤、三甲曲沙、培美曲塞、普拉曲沙、左亞葉酸鈣、阿糖胞苷、羥基脲、硫唑嘌呤、克拉屈濱、氟達拉濱、噴司他丁、巰嘌呤、奈拉濱、硫鳥嘌呤、福嘌呤、阿紮胞苷、卡培他濱、氟達拉濱、克拉屈濱、奈拉濱、硫唑嘌呤、氯法拉濱、阿糖胞苷、依諾濱、卡莫氟、吉西他濱、沙西他濱、依拉他濱、多昔尿苷)；抗腫瘤抗生素(例如博來黴素、阿黴素、柔紅黴素、表柔比星、伊達比星、絲裂黴素、更生黴素、光青黴素、紅諾黴素、卡柔比星、表柔比星、戊柔比星、佐柔比星、阿克拉黴素、吡柔比星、奈莫柔比星、氨柔比星、制癌菌素、鏈脲黴素、米托蒽醌)；抗有絲分裂劑(例如，長春花生物鹼，如長春新鹼、長春鹼、長春氟甯、長春地辛和長春瑞濱，紫杉烷類，如紫杉醇和多西他賽，卡巴他賽，特折紫杉醇，polo激酶抑制劑)；和拓撲異構酶抑制劑(例如，表鬼臼毒素，如依託泊苷和替尼泊苷、安吖啶、托泊替康、伊立替康、貝洛替康、伏立諾新、氨萘非特和喜樹鹼)；細胞抑制劑，例如抗雌激素(例如他莫昔芬、氯苯斯明、氟維司群、托瑞米芬、雷洛昔芬、屈洛昔芬和碘昔芬)、抗雄激素(例如比卡魯胺、氟他胺、尼魯米特、托吡魯胺、恩雜魯胺和醋酸環丙孕酮、氯地孕酮)、黃體生成素釋放激素(LHRH)拮抗劑或LHRH激動劑(例如戈舍瑞林、亮丙瑞林和布舍瑞林)、孕激素(例如氯地孕酮、己酸孕酮、甲羥孕酮、醋酸甲地孕酮)、芳香酶抑制劑(例如阿那曲唑、來曲唑、伏立唑和依西美坦)和5α-還原酶抑制劑(例如非那雄胺、度他胺、依普利特)；抗侵襲劑(例如，c-Src家族激酶抑制劑(例如，沙拉替尼、達沙替尼和博舒替尼)、金屬蛋白酶抑制劑(例如，馬立馬司他)、尿激酶啟動受體功能抑制劑(例如，纖溶酶原或抗乙醯肝素酶抗體)；生長因子抑制劑：例如，此類抑制劑包括抗生長因子抗體和抗生長因子受體抗體(例如，曲妥單抗、帕尼單抗、西妥昔單抗和Stern等人Critical reviews in oncology/ haematology, 2005, Vol. 54, p. 11-29中公開的任何抗生長因子/抗生長因子受體抗體；此類抑制劑還包括酪氨酸激酶抑制劑，包括表皮生長因子家族的抑制劑(例如EGFR酪氨酸激酶抑制劑，如吉非替尼、厄洛替尼、卡尼替尼(CI 1033)、阿法替尼、奧西替尼、羅西替尼、伊克替尼、達替尼、erbB2酪氨酸激酶抑制劑，如拉帕替尼、肝細胞生長因子家族的抑制劑；胰島素樣生長因子家族的抑制劑；血小板衍生生長因子家族的抑制劑，例如伊馬替尼、尼祿替尼；絲氨酸/蘇氨酸激酶抑制劑(例如，Ras/Raf途徑抑制劑，例如法尼基轉移酶抑制劑，例如索拉非尼、替比法尼和洛那法尼)，MEK-和/或AKT-激酶途徑抑制劑，c-kit抑制劑，abl激酶抑制劑，PI3激酶抑制劑，Plt3激酶抑制劑，CSF-1R激酶抑制劑，IGF受體(胰島素樣生長因子)激酶抑制劑；極光激酶抑制劑(例如巴拉塞替(AZD1152)、danusertib(РНА-739358)、陶紮色替(VX-680)、MLN8054、R763、МР235、МР529、VX-528和АХ39459)和細胞週期蛋白依賴性激酶抑制劑如CDK2和/或CDK4抑制劑；抗血管生成劑，例如抑制血管內皮生長因子作用的那些(例如貝伐單抗、凡德他尼、伐他拉尼、舒尼替尼、阿昔替尼、帕唑帕尼、克裡唑替尼和西地尼布(AZD2171)、林諾胺、整聯蛋白avp3功能抑制劑、制管張素、內皮抑素、沙利度胺、依維莫司、西羅莫司、伊曲康唑、蘇拉明、semaxanib、血小板反應蛋白、雷莫單抗、taschinmod、雷珠單抗、索拉非尼、國際申請WO 97/22596、WO 97/30035、WO 97/32856和WO 98/13354中公開的化合物)；血管損傷劑(例如考布他汀A4、ombrabulin和國際申請 WO 99/02166、WO 00/40529、WO 00/41669、 WO 01/92224、WO 02/04434和WO 02/08213中公開的化合物；內皮素受體拮抗劑(例如波生坦、西他生坦、安立生坦、BQ-123、BQ-788、馬西替坦、替唑生坦、齊波替生坦、阿曲生坦)；反義療法(例如針對上述靶的那些，例如ISIS 2503、反義抗ras、反義抗EGFR、庫替生、阿普托森、ISIS-STAT3Rx(ISIS 481464/AZD9150)、ISIS-ARRx (AZD5312)、曲貝德森(AP12009)、EZN-2968、LErafAON-ETU)；基因治療方法，包括例如置換異常基因的方法(例如異常的p53或異常的BRCA1或BRCA2，GDEPT(基因指導的酶前藥治療)方法，如使用胞嘧啶脫氨酶、胸苷激酶或細菌硝基還原酶的那些方法)，和增加患者對化療或放療耐受性的方法，如多藥抗性基因治療；和免疫治療方法，包括例如檢查點抑制劑，如PD-1/PD-L1(納武單抗、派姆單抗、阿替唑珠單抗、杜羅華單抗、阿瓦魯單抗、 pidilizumab等)，和靶向CTLA-4 (包括伊匹單抗、 tremelimumab)、OX-40、VISTA、ICOS、TIGIT、LAG-3、4-1BB、GITR、CD40、CCR 4等的藥物；其它體外和體內方法以增加患者腫瘤細胞的免疫原性，例如用細胞因子如白介素2、白介素4、白介素15或粒細胞-巨噬細胞集落刺激因數轉染，降低T-細胞無反應性的方法，使用轉染的免疫細胞如細胞因子轉染的樹突細胞的方法，使用細胞因子轉染的腫瘤細胞系的方法，使用抗獨特型抗體的方法，降低免疫抑制細胞如調節T-細胞、骨髓抑制細胞或表達IDO(吲哚胺2,3-去氧加氧酶)的樹突細胞的功能的方法，和使用由衍生自腫瘤相關抗原如NY-ESO-1、MAGE-3、WT1或Her 2/neu的蛋白或肽組成的癌症疫苗的方法。 因此，在本發明的另一個實施方案中，描述了一種藥物產品，其包含與如上定義的抗腫瘤劑組合的如上定義的式(I)化合物或其藥學上可接受的鹽、溶劑化物或立體異構體，用於聯合治療癌症。 可以調整劑量方案以提供最佳的期望反應。例如，可以施用單一劑量，可以隨時間施用若干分開的劑量，或者可以如治療情況的緊急情況所指示的那樣按比例減少或增加劑量。為了易於給藥和劑量的均勻性，將口服組合物配製成單位劑型是特別有利的。本文所用的單位劑型是指適合作為用於待治療的患者/受試者的單位元劑量的物理上離散的單位；每個單位含有經計算產生所需治療效果的預定量的活性化合物以及所需的藥物載體。本發明的單位劑型的規格通常由以下因素決定，並直接取決於(a)治療劑的獨特性質和要達到的特定治療或預防效果，和(b)配製用於治療患者敏感性的這種活性化合物的領域中固有的限制。 因此，基於本文提供的公開內容，技術人員將理解，根據治療領域中眾所周知的方法調整劑量和給藥方案。即，可以容易地建立最大可耐受劑量，並且還可以確定向患者提供可檢測的治療效果的有效量，以及可以確定施用每種藥劑以向患者提供可檢測的治療效果的時間要求。因此，儘管本文舉例說明瞭某些劑量和施用方案，但這些實施例決不限制在實施本發明的實施方案時可提供給患者的劑量和施用方案。 應注意，劑量值可隨待緩解的病症的類型和嚴重程度而變化，並且可包括單劑量或多劑量。此外，應當理解，對於任何特定的受試者，具體的劑量方案應當根據個體需要和施用或監督組合物施用的醫學專業人員的判斷隨時間進行調整，並且本說明書中闡述的劑量範圍僅是示例性的，並且不旨在限制要求保護的組合物的範圍或實踐。此外，使用本發明組合物的劑量方案可基於多種因素，包括疾病類型、年齡、體重、性別、患者的醫學狀況、狀況的嚴重程度、施用途徑和所用的本發明的特定化合物。因此，劑量方案可以廣泛地變化，但是可以使用標準方法常規地確定。例如，可以基於藥物動力學和藥效參數來調整劑量，所述藥物動力學和藥效參數可以包括臨床效果，例如毒性作用或實驗室值。因此，本發明包括由有資格的專家確定的患者內劑量遞增。確定適當劑量和方案的方法是本領域公知的，並且一旦提供本文公開的想法，技術人員將理解。 通常，成人的標準日劑量通常為0.02 mg至5000 mg或約1 mg至約1500 mg。 一旦患者狀況發生改善，如果需要，給予維持劑量。隨後，作為症狀的函數，可以將給藥劑量或頻率或兩者降低至保持改善的疾病、病症或病況的水準。然而，在症狀復發後，患者可能需要長期定期治療。 上述範圍僅僅是建議性的，因為關於個體治療方案的變數的數量是大的，並且從這些推薦值的相當大的偏離是常見的。這些劑量可以根據許多變數而改變，不限於所用化合物的活性、待治療的病症或病況、施用方法、個體受試者的要求、待治療的病症或病況的嚴重程度和醫師的判斷。 提供以下實施例以更好地理解本發明。這些實施例僅用於說明的目的，不應被解釋為以任何方式限制本發明的範圍。 本說明書中引用的所有出版物、專利和專利申請均通過引用併入本文。儘管為了清楚理解的目的，已經通過說明和實施例的方式相當詳細地描述了前述發明，但是本領域普通技術人員根據本發明的教導將容易地明白，在不背離所附實施方案的精神或範圍的情況下，可以對其進行某些改變和修改。 實施例 縮寫列表： 2-MeTHF-2-甲基四氫呋喃 THF-四氫呋喃 PTSA-對甲苯磺酸 Pd(dppf)Cl 2-[1,1'-雙(二苯基膦基)二茂鐵]鈀(II)氯化物 XPhos-2-二環己基膦基-2',4',6'-三異丙基聯苯 Pd 2(dba) 3-三(二亞苄基丙酮)二鈀(0) XantPhos-4,5-雙(二苯基膦基)-9,9-二甲基呫噸 DIPEA-二異丙基乙胺 TEA-三乙胺 TBAF-四丁基氟化銨 n-BuLi-正丁基鋰 TMEDA- N 1, N 1, N 2, N 2-四甲基乙二胺 NIS-N-碘代琥珀醯亞胺 NBS-N-溴代琥珀醯亞胺 LiHMDS-六甲基二矽氮烷鋰鹽 DCM-二氯甲烷 NMP-N-甲基吡咯烷酮 DMF-二甲基甲醯胺 RM-反應物質 R.t.-室溫 DBU-1,8-二氮雜雙環[5.4.0]十一碳-7-烯 LDA-二異丙基胺基鋰 Rac-BINAP-([1,1'-聯萘-2,2'-二基)雙(二苯基膦) EtOAc-乙酸乙酯 TFA-三氟乙酸 STAB-三乙醯氧基硼氫化鈉 MeOH-甲醇 MTBE-叔丁基甲醚 HBTU-3-[雙(二甲基胺基)甲基]-3H-苯並三唑-1-氧化物六氟磷酸鹽 B 2pin 2-雙(頻哪醇合)二硼 MeCN-乙腈 EtOH-乙醇 AcOH-乙酸 KOAc-乙酸鉀 實施例1.化合物1a的製備方法。
Figure 02_image181
在20℃下，將1a_1(10.0g，0.069 mol)在2-MeTHF(33 ml)中的溶液20分鐘加入到由Mg (5.85g，0.241 mol)和碘甲烷(14 ml，0.213 mol)獲得的碘化甲基鎂在2-MeTHF(40 ml，0.213 mol)中的溶液中。1小時後，將K2CO3的冰溶液加入到反應物料中。將所得懸浮液混合過夜。過濾沉澱，用MeOH洗滌，在旋轉蒸發器上濃縮所得溶液。通過矽膠柱色譜法，使用DCM/MeOH作為洗脫劑分離產物。1的產率是4.5g(84%)。 實施例1.1化合物1b的製備方法。
Figure 02_image183
與實施例1相似，用1b-1和乙基溴化鎂製備化合物1b，產率為3.4g(91%)。 實施例1.2製備化合物1d的方法。
Figure 02_image185
類似於實施例1，由1d-1和環丙基溴化鎂製備化合物1d，產率為2.4g(52%)。 實施例2.化合物2的製備方法。
Figure 02_image187
步驟1.化合物2_2的製備。 將 N 1, N 1, N 2--三甲基乙-1,2-二胺(7.68g，0.07 mol)加入到2_1 (10g，0.07 mol)的溶液中。將所得混合物在80℃的溫度下混合10小時。向反應混合物中加入己烷，過濾沉澱並乾燥。2_2的產率為15.6g(99%)。 步驟2.化合物2_3的製備。 將Ni-Raney的水懸浮液(8 ml)加入2_2(15.6g，0.06 mol)和水合肼(33.2g，0.66 mol)的EtOH(100 ml)溶液中。將RM攪拌過夜。過濾RM，用EtOH洗滌，並在旋轉蒸發器上濃縮。2_3的產率為12.8g(99%)。 步驟3.化合物2的製備。 在-10℃下將亞硝酸叔丁酯(4.36g，0.04 mol)緩慢加入到2_3(7.78g，0.04 mol)和HBF4(25.5g，0.14 mol)的THF (120 ml)溶液中。1小時後，過濾沉澱，用EtOAc洗滌並乾燥。將所得化合物溶於MeCN(120 ml)，在-25℃下加入B 2pin 2(9.39g，0.04 mol)和吡啶(11.6g，0.14 mol)1分鐘。將RM升至室溫並攪拌過夜。在旋轉蒸發器上濃縮所得溶液。通過矽膠柱色譜法，使用EtOAc/Et3N作為洗脫劑分離產物。2的產率為6.85g(62%)。 實施例3.化合物3b的製備方法。
Figure 02_image189
步驟1.化合物3b_2的製備。 在氮氣氣氛中將DIPEA(15.5 ml，0.10 mol)加入到2_1 (5.46g，0.04 mol)和呱啶-4-酮(7.21g，0.05 mol)的DMF(30 ml)溶液中。將RM在80℃攪拌5小時並倒入水中。過濾沉澱物，用水(50 ml)、乙醚洗滌，並乾燥。3b_2的產率為7.72g(92%)。 步驟2.化合物3b_3的製備。 在室溫下將3b_2(3.72g，0.02 mol)、1-甲基呱嗪(3.59 ml，0.03 mol)、AcOH(1 ml，0.02 mol)的DCM(56 ml)溶液混合1小時。加入STAB(7.12g，0.03 mol)，並將混合物攪拌16小時。在4小時內分批加入STAB(7.12g，0.03 mol)。將飽和NH4Cl溶液加入懸浮液中。用DCM洗滌所得懸浮液，中和水層，用DCM萃取。合併的有機相用Na2SO4乾燥，過濾並在旋轉蒸發器上濃縮。3b_3的產率為4.88g (99%)。 步驟3.化合物3b_4的製備。 在氫氣氛(5 atm)中，在5% Pd/C(5 mol%)存在下，將3b_3(0.91g，2.94 mmol)的MeOH(20 ml)溶液混合1小時。過濾RM，用MeOH洗滌，並在旋轉蒸發器上濃縮。3b_4的產率為0.8g (99%)。 步驟4.化合物3b的製備。 將在AcOH(21 ml，0.07 mol)中的PTSA加入到3b_4 (3.00g，9.84 mmol)在MeCN(10 ml)中的溶液中。在0℃下，將亞硝酸叔丁酯(2.15 ml，0.2 mol)的MeCN(10 ml)溶液加入到所得溶液中。3小時後，加入KI(12.2g，0.07 mol)在水(15 ml)中的溶液。將RM在70℃攪拌5小時，倒入Na2CO3水溶液中，然後用NaOH水溶液調節至pH 9。產物用DCM萃取。合併的有機相用Na2SO3飽和溶液洗滌，用Na2SO4乾燥，過濾並在旋轉蒸發器上濃縮。通過矽膠柱色譜法，使用DCM/MeOH/TEA作為洗脫劑分離產物。3b的產率為2.7g(71%)。 實施例3.1化合物3a的製備方法。
Figure 02_image191
類似於實施例3步驟4，由3a_1製備化合物3a，產率為3.1g(69%)。 實施例3.2 製備化合物3c的方法。
Figure 02_image193
類似於實施例3步驟4，由3c-1製備化合物3c，產率為1.29g(59%)。 實施例3.3化合物3d的製備方法。
Figure 02_image195
按照與實施例3步驟4相似的方式，由3d_1製備化合物3d，產率為1.38g(94%)。 實施例3.4化合物3e的製備方法。
Figure 02_image197
按照與實施例3步驟4相似的方式，由3e_1製備化合物3e，3e的產率為0.36g(40%)。 實施例3.5化合物3f的製備方法。
Figure 02_image199
按照與實施例3步驟4相似的方式，由3f_1製備化合物3f，產率為1.02g(75%)。 實施例3.6化合物3n的製備方法。
Figure 02_image201
步驟1.化合物3n_2的製備。 按照與實施例3步驟1相似的方式，由5-羥基-2-氮雜雙環[2.2.1]庚烷-2-甲酸叔丁酯製備化合物3n-2，產率為1.4g (94%)。 步驟2.化合物3n_3的製備。 將4N HCl的甲醇(15 ml)溶液加入3n_2(1.4g，0.004 mol)的1,4-二噁烷(7 ml)溶液中。在室溫下混合RM1小時，濃縮所得溶液，用飽和Na2CO3溶液調節至pH 9-10，並使用DCM萃取產物。合併的有機相用Na2SO4乾燥，過濾並在旋轉蒸發器上濃縮。3n_3的產率為1.0g(117%)。產物不經額外純化步驟用於下一步驟。 步驟3.化合物3n_4的製備。 將氰基硼氫化鈉(0.73g，3.28 mmol)和AcOH(0.2 ml)加入甲醛(0.50 ml，6.7 mmol)和3n_3(0.87g，3.3 mmol)在MeOH(20 ml)中的水溶液的混合物中，將所得RM在25℃下混合3小時。用3N NaOH水溶液將RM調節至pH 12，然後用DCM洗滌。合併的有機層用NaCl飽和水溶液洗滌，用Na2SO4乾燥，過濾並在旋轉蒸發器上濃縮。通過矽膠柱色譜法，使用DCM/MeOH/TEA作為洗脫劑分離產物。3n_4的產率為0.68g (82%)。 步驟4.化合物3n _5的製備。 按照與實施例3步驟3相似的方式，由3n_4製備化合物3n_5，產率為0.66g(99%)。 步驟5.化合物3n的製備。 按照與實施例3步驟4相似的方式，由3n_5製備化合物3n，產率為0.32g(34%)。 實施例3.7化合物3o的製備方法。
Figure 02_image203
步驟1.化合物3o_2的製備。 按照與實施例3.6步驟1相似的方式，由(R)-3-羥基吡咯烷-1-甲酸叔丁酯製備化合物3o_2，產率為8.5g(79%)。 步驟2.化合物3o_3的製備。 按照與實施例3.6步驟2相似的方式由3o_2製備化合物3o_3，產率為2.3g(117%)。 步驟3.化合物3o_4的製備。 按照與實施例3.6步驟3相似的方式由3o_3製備化合物3o_4，產率為2.2g(99%)。 步驟4.化合物3o_5的製備。 按照與實施例3步驟3相似的方式，由3o_4製備化合物3o_5，產率為1.5g (90%)。 步驟5.化合物3o的製備 按照與實施例3步驟4相似的方式，由3o_5製備化合物3o，產率為0.91g(86%)。 實施例3.8化合物3p的製備方法。
Figure 02_image205
步驟1.化合物3p_2的製備。 化合物3p_2按照與實施例3.6步驟1相同的方法，由(S)-3-羥基吡咯烷-1-甲酸叔丁酯製備，3p_2的產率為6.3g (77%)。 步驟2.化合物3p_3的製備。 按照與實施例3.6步驟2相似的方式，由3p_2製備化合物3p_3，產率為2.0g(104%)。 步驟3.化合物3p_4的製備。 按照與實施例3.6步驟3相似的方式，由3p_3製備化合物3p_4，3p_4的產率為1.7g(84%)。 步驟4.化合物3p_5的製備。 按照與實施例3步驟3相似的方式，由3p_4製備化合物3p_5，產率為1.5g(108%)。 步驟5.化合物3o的製備。 按照與實施例3步驟4相似的方式，由3p_5製備化合物3o，產率為1.13g (94%)。 實施例3.9化合物3q的製備方法
Figure 02_image207
步驟1.化合物3q_2的製備。 在室溫下將HBTU(3.14g，8.2 mmol)分批加入到3q_1 (1.2g，5.1 mmol)、AcOH(0.6 ml，10 mmol)、DIPEA(4.5 ml，26 mmol)的DMF(20 ml)溶液中。3小時後，加入水(150 ml)。在室溫下將RM混合1小時。使用EtOAc萃取產物。合併的有機層用水和NaCl飽和水溶液洗滌，用Na2SO4乾燥，過濾並在旋轉蒸發器上濃縮。通過矽膠柱色譜法使用DCM作為洗脫劑分離產物。3q_2的產率為2.34g(173%)。產物用於下一步驟而無需另外的純化步驟。 步驟2.化合物3q_3的製備。 化合物3q_3以類似於實施例3步驟3的方式，由3q_2製備。將產物溶解在1M HCl水溶液中，用DCM洗滌。用3N NaOH溶液將水層的pH值調節到11，然後用DCM洗滌。合併的有機層用NaCl飽和溶液洗滌，用Na2SO4乾燥，過濾並在旋轉蒸發器上濃縮。3q_3的產率為1.05g(101%)。 步驟3.化合物3q的製備。 按照與實施例3步驟3相似的方式，由3q_3製備化合物3q，產率為1.1g(94%)。 實施例3.10化合物3r的製備方法。
Figure 02_image209
步驟1.化合物3r_2的製備。 將3q-1(0.39g，2.0 mmol)、N,N-二甲基-2-氯乙醯胺(0.50g，2.6 mmol)和K 2CO 3(1.13g，8.0 mmol)在DMA(5 ml)中的懸浮液在室溫下混合16小時。將RM倒入NaCl的飽和水溶液中，並使用EtOAc萃取產物。合併的有機層用水、NaCl飽和水溶液洗滌，用Na2SO4乾燥，過濾並在旋轉蒸發器上濃縮。3r_2的產率為0.92g(149%)。產物用於下一步驟而無需另外的純化步驟。 步驟2.化合物3r_3的製備。 按照與實施例3步驟3相似的方式，由3r_2製備化合物3r_3，產率為0.36g (62%)。 步驟3.化合物3r的製備。 按照與實施例3步驟3相似的方式，由3r_3製備化合物3r，產率為0.4g(86%)。 實施例4.化合物3g的製備方法。
Figure 02_image211
步驟1.化合物3g_2的製備。 在氬氣氛中，將Pd 2(dba) 3(72 mg，0.07 mmol)和Rac-BINAP(0.14g，0.22 mmol)加入3g_1(0.70g，3.4 mmol)、1,4-二溴苯(2.5g，10 mmol)和DBU(0.94 ml，6.3 mmol)在甲苯(7.5 ml)中的溶液中。將混合物在100℃下混合1小時，加入叔丁醇鈉(0.85g，8.6 mmol)，將混合物在100℃下混合2小時，將所得RM在旋轉蒸發器上濃縮。通過矽膠柱色譜法，使用己烷/ MTBE作為洗脫劑分離產物。3g的產率是0.82g(67%)。 步驟2.化合物3g_3的製備。 將3g_2(0.3g，0.8 mmol)的TFA(3 ml)溶液在25℃下混合16小時。用飽和Na2CO3溶液中和RM，並用DCM洗滌。合併的有機相用Na2SO4乾燥，過濾並在旋轉蒸發器上濃縮。3g_3的產率為0.2g(99%)。 步驟3.化合物3g的製備。 將STAB (0.73g，3.28 mmol)和MeOH(1 ml)加入到甲醛(0.15 ml，2.0 mmol)和3g_3(0.22g，0.82 mmol)在THF(5 ml)中的水溶液的混合物中，將所得RM在25℃下混合16小時。用3N NaOH水溶液將RM調節至pH 12，然後用DCM洗滌。合併的有機層用NaCl飽和水溶液洗滌，有機層用Na2SO4乾燥，過濾並在旋轉蒸發器上濃縮。3g的產率是0.19g (87%)。 實施例4.1.化合物3h的製備方法。
Figure 02_image213
步驟1.化合物3h_2的製備。 按照與實施例4步驟1相似的方式，由3h_1製備化合物3h_2，產率為0.75g(62%)。 步驟2.化合物3h-3的製備。 按照與實施例4步驟2相似的方式，由3h_2製備化合物3h_3，產率為0.20g(98%)。 步驟3.化合物3h的製備。 按照與實施例4步驟3相似的方式，由3h-3製備化合物3h，產率為0.20g(87%)。 實施例4.2. 化合物3i的製備方法。
Figure 02_image215
按照與實施例4步驟1相似的方式，由3i_1製備化合物3i，產率為0.22g(33%)。 實施例4.3.化合物3j的製備方法。
Figure 02_image217
按照與實施例4步驟1相似的方式，由3j_1製備化合物3j，產率為0.42g(53%)。 實施例5.化合物4a的製備方法。
Figure 02_image219
將4a-1(0.47 g，1.69 mmol)、2(0.79 g，2.45 mmol)和Cs 2CO 3(2.42 g，7.35 mmol)在1,4-二噁烷/水(25 ml，20:1)混合物中的溶液用氬氣脫氣。在氬氣氛中加入Pd(dppf) Cl2(0.18g，0.2 mmol)。將混合物在80℃攪拌2小時。加入4a_1(0.25 g，0.8 mmol)。將混合物在80℃攪拌4小時。向反應混合物中加入EtOAc，用1N HCl水溶液洗滌有機層。水層用飽和Na2CO3溶液中和，用DCM洗滌。合併的有機相用Na2SO4乾燥，過濾並在旋轉蒸發器上濃縮。通過矽膠柱色譜法，使用DCM/MeOH作為洗脫劑分離產物。4a的產率為0.44g(55%)。 實施例6.化合物5a的製備方法。
Figure 02_image221
步驟1.化合物5a_2的製備。 將NIS(1.75g，7.60 mmol)加入到5a-1(0.68g，5.07 mmol)的DMF(4 ml)溶液中。在100℃下攪拌RM 3小時。在攪拌下向RM中加入水和飽和Na2S2O4溶液。濾出沉澱，用水洗滌並乾燥。5a_2的產率為0.83g(64%)。 步驟2.化合物5a_3的製備。 將5a-2(1.73g，6.43 mmol)、三甲基甲矽烷基乙炔(0.98g，9.65 mmol)和DIPEA(1.68g，12.9 mmol)的THF(30 ml)溶液用氬氣脫氣。在氬氣氛中加入CuI(0.25g，1.29 mmol)和Pd(Pph3) 2Cl2(0.46g，0.64 mmol)。將RM在70℃攪拌3小時，並在旋轉蒸發器上濃縮。通過矽膠柱色譜法，使用EtOAc/己烷作為洗脫劑分離產物。5a-3的產率為1.29g (89%)。 步驟3.化合物5a_4的製備。 將5a_3(0.30g，1.26 mmol)加入到1M TBAF的THF(2.5 ml，2.5 mmol)溶液中，將該混合物在室溫下混合2.5小時，將反應物料用水稀釋，用EtOAc萃取。有機相用10% Na2CO3、NaCl飽和溶液洗滌，用Na2SO4乾燥，過濾並在旋轉蒸發器上濃縮。5a-4的產率為0.19g(98%)。 步驟4.化合物5a_5的製備。 將5a_4(0.31g，0.89 mmol)、3a(0.45g，1.18 mmol)、DIPEA(0.31g，2.36 mmol)、CuI(0.02g，0.12 mmol)的THF (5 ml)溶液用氬氣脫氣。在氬氣氛中加入Pd(PPH3) 2Cl2 (0.42g，0.06 mmol)。將RM在室溫下攪拌過夜，用水稀釋，並用EtOAc萃取。有機相用飽和NaCl水溶液洗滌，用1M HCl水溶液萃取。用飽和NaHCO3溶液中和合併的水相，濾出沉澱並乾燥。5a_5的產率為0.33g(84%)。 步驟5.化合物5a的製備。 將5a_5(0.15g，0.45 mmol)、CuI (0.07g，0.36 mmol)和DBU(0.55 ml，3.6 mmol)在DMF(10 ml)中的溶液在100℃下混合24小時。用水和DCM稀釋RM，過濾，加入1M HCl水溶液。有機層用1M HCl水溶液萃取。用飽和NaHCO3溶液中和合併的水相，用DCM萃取。合併的有機相用Na2SO4乾燥，過濾並在旋轉蒸發器上濃縮。5a的產率為0.08g(57%)。 實施例6.1. 化合物5b的製備方法
Figure 02_image223
步驟1.化合物5b _1的製備。 按照與實施例6步驟4相似的方式，由5a_4和3b製備化合物5b_1，產率為0.65g(80%)。 步驟2.化合物5b的製備。 將5b_1(0.51g，1.4 mmol)和Cs2CO3(1.8g，5.2 mmol)在NMP(5 ml)中的懸浮液在87℃下混合2小時，通過矽膠柱色譜法使用CHCl 3/MeOH/TEA作為洗脫劑分離產物。5b的產率為0.35g (65%)。 實施例7.化合物6a的製備方法
Figure 02_image225
步驟1.化合物6a _2的製備。 在0℃下將NaH(0.10g，2.53 mmol)分批加入6a-1 (0.42g，2.11 mmol)的THF(10 ml)溶液中，將混合物攪拌10分鐘。在0℃分批加入對甲苯磺醯氯(0.42g，2.22 mmol)。將混合物在室溫下攪拌2小時，用NH4Cl飽和水溶液中和。產物用EtOAc萃取。合併的有機相用NaCl飽和水溶液洗滌，用Na2SO4乾燥，過濾並在旋轉蒸發器上濃縮。通過矽膠柱色譜法使用DCM /己烷作為洗脫劑分離產物。6a_2的產率為0.72g(99%)。 步驟2.化合物6a_3的製備。 在-30℃和氬氣氛下，將2M LDA的THF /庚烷/乙苯(1.15 ml，2.29 mmol)溶液緩慢加入6a_2(0.55g，1.53 mmol)的THF(10 ml)溶液中。1小時後，加入三丁基氯化錫(0.43 ml，1.53 mmol)。將混合物加熱至室溫1小時後，加入20% NH4Cl水溶液。產物用EtOAc萃取。合併的有機相用Na2SO4乾燥，過濾並在旋轉蒸發器上濃縮。通過矽膠柱色譜法，使用EtOAc/己烷作為洗脫劑分離產物。6a_2的產率為0.62g (64%)。 步驟3.化合物6a_4的製備。 在氬氣氛中，將Pd (PPh3) 2Cl2(0.11g，0.09 mmol)加入到6a_3(0.62g，0.92 mmol)、3a(0.23g，0.61 mmol)、CsF(0.19g，1.23 mmol)、CuI(0.04g，0.18 mmol)在DMF (10 ml)中的懸浮液中。將RM在80℃攪拌1小時，並在旋轉蒸發器上濃縮。通過矽膠柱色譜法，使用EtOAc/TEA作為洗脫劑分離產物。6a_4的產率為0.18g(57%)。 步驟4.化合物6a的製備。 將3N NaOH(2 ml)的水溶液加入6a-4(100 mg，0.18 mmol)的MeOH(4 ml)溶液中，將所得RM在70℃混合1小時。在旋轉蒸發器上濃縮RM，加入DMF，RM充滿水，濾出沉澱並乾燥。6a的產率是0.05g(72%)。 實施例7.1化合物6b的製備方法
Figure 02_image227
步驟1.化合物6b_2的製備。 按照與實施例7步驟3相似的方式，由6a_3和3b製備化合物6b_2，產率為0.89g (63%)。 步驟2.化合物6b的製備。 按照與實施例7步驟4相似的方式，由6b_2製備化合物6b，產率為0.46g(99%)。 實施例8.化合物4b的製備方法
Figure 02_image229
步驟1製備化合物4b_2。 按照與實施例7步驟1相似的方式，由4b_1製備化合物4b_2，產率為3.7g(97%)。 步驟2.化合物4b_3的製備。 按照與實施例7步驟2相似的方式，由4b_2製備化合物4b_3，產率為1.76g (30%)。 步驟3.化合物4b _4的製備。 按照與實施例7步驟3相似的方式，由4b_3製備化合物4b_4，3b的產率為0.11g(78%)。 步驟4.化合物4b的製備。 按照與實施例7步驟4相似的方式，由4b_4製備化合物4b，產率為0.06g(76%)。 實施例8.1.化合物4c的製備方法。 化合物4c以類似於實施例7步驟3步驟4的方式，自4b_3及3i經由4с_1(表1)製備。4с_1的產率是0.26g(52%)。4с產率是0.09g (64%)。 實施例8.2.化合物4d的製備方法。 化合物4d以類似於實施例7步驟3的方式由4b_3和3j(表1)製備。化合物4d_1未從RM分離。將Cs2CO3 (0.68g，2.1 mmol)和甲醇(3 ml)加入RM中，將混合物在60℃混合1小時。在旋轉蒸發器上濃縮RM。通過矽膠柱色譜法，使用DCM/MeOH/TEA作為洗脫劑分離產物。4d的產率為0.32g(82%，經過兩步的產率)。 實施例8.3.化合物4e的製備方法。 化合物4e以類似於實施例7步驟3步驟4的方式自4b_3及3c經由4e_1(表1)製備。4e-1的產率是0.36g(20%)。4e的產率是0.14g(83%)。 實施例8.4.化合物4f的製備方法。 化合物4f以類似於實施例7步驟3步驟4的方式，自4b_3及3d經由4f_1(表1)製備。4f_1的產率為0.10g(24%)。4f的產率是0.15g(57%)。 實施例8.5.化合物4g的製備方法。 化合物4g以類似於實施例7步驟3步驟4的方式自4b_3及3k經由4g_1(表1)製備。4g_1的產率為0.17g(48%)。4g的產率是0.07g (66%)。 實施例8.6.化合物4h的製備方法。 化合物4h以類似於實施例7步驟3步驟4的方式自4b_3及3e經由4h_1(表1)製備。4h_1的產率為0.23g(63%)。4h的產率為0.14g (94%)。 實施例8.7.化合物4i的製備方法。 化合物4i以類似於實施例7步驟3步驟4的方式，自4b_3及3l經由4i_1(表1)製備。4i-1的產率為0.36g (89%)。4i的產率為0.14g(75%)。 實施例8.8.化合物4j的製備方法。 化合物4j的製備方法類似於實施例7的步驟3，步驟4，由4b_3和3m通過4j_1進行(表1)。4j_1的產率為0.29g (67%)。4j的產率為0.20g(99%)。 實施例8.9.化合物4k的製備方法。 化合物4k以類似於實施例7步驟3步驟4的方式，自4b_3及3g經由4k_1(表1)製備。4k-1的產率為0.14g(50%)。4k的產率為0.04g(44%)。 實施例8.10.化合物4l的製備方法。 化合物4l以類似於實施例7步驟3步驟4的方式自4b_3及3小時經由4l_1(表1)製備。4l-1的產率為0.20g(55%)。4l的產率為0.06g(55%)。 實施例8.11.化合物4m的製備方法。 化合物4m以類似於實施例7步驟3步驟4的方式自4b_3及3f經由4m_1(表1)製備。4m-1的產率為0.67g(93%)。4m的產率是0.09g(23%)。 實施例8.12.化合物4n的製備方法。 化合物4n以類似於實施例7步驟3的方式自4b_3及3n經由4n_1(表1)製備。化合物4n_1未從RM中分離。將Cs2CO3(0.68g，2.1 mmol)和甲醇(3 ml)加入RM中，將混合物在60℃混合1小時。在旋轉蒸發器上濃縮RM。通過矽膠柱色譜法，使用DCM/MeOH/TEA作為洗脫劑分離產物。4n的產率為0.14g(83%，經過兩步的產率)。 實施例8.13.化合物4o的製備方法。 步驟1化合物4o_1的製備。 按照與實施例7步驟3相似的方式，由3o製備化合物4o_1，產率為0.45g (92%)。 步驟2.化合物4o的製備。 按照與實施例7步驟4相似的方式，由4o_1製備化合物4o，產率為0.15g(54%)。 實施例8.14.化合物4p的製備方法。 化合物4p以類似於實施例7步驟3的方式，從4b_3和3p經由4p_1(表1)製備。化合物4p_1未從RM中分離。將Cs2CO3(1.3g，4.0 mmol)和甲醇(5 ml)加入RM中，將混合物在室溫下混合16小時。在旋轉蒸發器上濃縮RM。通過矽膠柱色譜法，使用DCM/MeOH/TEA作為洗脫劑分離產物。4p的產率為0.12g(47%，經過兩步的產率)。 實施例8.15. 化合物4q的製備方法。 化合物4q以類似於實施例7步驟3的方式，由4b_3和3q經4q_1(表1)製備。化合物4q_1未從РМ分離。將Cs2CO3 (1.3g，4.0 mmol)和甲醇(5 ml)加入RM中，將混合物在室溫下混合16小時。在旋轉蒸發器上濃縮RM。通過矽膠柱色譜法，使用DCM/MeOH/TEA作為洗脫劑分離產物。4q的產率為0.13g(42%，經過兩步的產率)。 實施例8.16.化合物4r的製備方法。 化合物4r以類似於實施例7步驟3的方式，由4b_3和3r經4r_1(表1)製備。4r_1的產率為0.36g(78%)。4r的產率為0.03g (35%)。
Figure 02_image231
Figure 02_image233
Figure 02_image235
Figure 02_image237
實施例8.12化合物4s的製備方法。
Figure 02_image239
步驟1.化合物4s_2的製備。 在氬氣氛中，將Pd(dppf)Cl2 (0.06g，0.07 mmol)加入到4s-1(0.40g，1.57 mmol)、KOAc(0.40g，3.92 mmol)和B 2pin 2(0.61g，2.35 mmol)在1,4-二噁烷(8 ml)中的懸浮液中。將混合物在100℃攪拌1小時。4b-3(0.40g，1.57 mmol)、Na2CO3(0.42g，3.92 mmol)和水(1 ml)加入到RM中，將混合物在100℃混合3小時。在旋轉蒸發器上濃縮RM。通過矽膠柱色譜法，使用EtOAc/己烷作為洗脫劑分離產物。4s_2的產率為0.47g(77%)。 步驟2.化合物4s的製備。 將NaOH(0.36g，9.0 mmol)的水(2.5 ml)溶液滴加到4s-2(0.47g，0.90 mmol)的MeOH(5 ml)溶液中。將混合物在60℃攪拌2小時。加入水(10 ml)，濾出沉澱並在空氣中乾燥。4s的產率為0.2g(71%)。 實施例8.13化合物4t的製備方法。
Figure 02_image241
步驟1.化合物4t_2的製備。 按照與實施例8.12步驟1相似的方式，由4t_1製備化合物4t_2，產率為0.72g(58%)。 步驟2.化合物4t的製備。 按照與實施例8.12步驟2相似的方式，由4t_2製備化合物4t，產率為0.22g(52%)。 實施例8.14化合物4u的製備方法。
Figure 02_image243
步驟1.化合物4u_2的製備。 按照與實施例8.12步驟1相似的方式，由4u_1製備化合物4u_2，產率為0.32g(50%)。 步驟2.化合物4u的製備。 按照與實施例8.12步驟2相似的方式，由4u_2製備化合物4u，產率為0.40g(21%)。 實施例8.15化合物4v的製備方法
Figure 02_image245
步驟1製備化合物4v_2。 按照與實施例7步驟1相似的方式，由4v_1製備化合物4v_2，產率為1.8g(91%)。 步驟2.化合物4v_3的製備。 按照與實施例7步驟2相似的方式，由4v_2製備化合物4v_3，產率為1.21g(37%)。 步驟3.化合物4v_4的製備。 按照與實施例7步驟3相似的方式，由4v_3製備化合物4v_4，產率為0.11g(34%)。 步驟4.化合物4v的製備。 按照與實施例7步驟4相似的方式，由4v_4製備化合物4v，產率為0.06g(84%)。 實施例8.16化合物4w的製備方法
Figure 02_image247
步驟1製備化合物4w_2。 按照與實施例7步驟1相似的方式，由4w_1製備化合物4w_2，4w_2的產率為1.1g(36%)。 步驟2.化合物4的製備w_3。 按照與實施例7步驟2相似的方式，由4w_2製備化合物4w_3，產率為0.10g(38%)。 步驟3.化合物4的製備w_4。 按照與實施例7步驟3相似的方式，由4w_3製備化合物4w_4，產率為0.05g(33%)。 步驟4.化合物4w的製備。 按照與實施例7步驟4相似的方式，由4w_4製備化合物4w，產率為0.01g(3%)。 實施例9.化合物EGFR_48的製備方法。
Figure 02_image249
步驟1製備化合物7a_2。 在氬氣氛中，將Pd(OAc) 2(100 mg，0.50 mmol)和XantPhos(540 mg，0.90 mmol)加入到7a_1(2.04g，0.09 mol)、1a(0.90g，0.01 mol)、Cs2CO3(3.25g，0.01 mol)在1,4-二噁烷(20 ml)中的懸浮液中。將RM在110℃攪拌3小時，用DCM/MeOH混合物稀釋，濾出，用DCM/MeOH混合物洗滌，並在旋轉蒸發儀上濃縮。通過矽膠柱色譜法，使用DCM/MeOH作為洗脫劑分離產物。7a_2的產率為1.29g (83%)。 步驟2.候選物EGFR_48的製備。 在氬氣氛中，將Pd(OAc) 2(3 mg，0.02 mmol)和XPhos (14 mg，0.02 mmol)加入7a_2(30 mg，0.17 mmol)、4a(50 mg，0.14 mmol)、K2CO3(59 mg，0.42 mmol)在叔丁醇/ DM (3 ml)混合物中的懸浮液中。將RM在100℃攪拌5小時並濃縮。通過矽膠柱色譜法，使用DCM/MeOH/NH3作為洗脫劑分離產物。分離的產物通過製備色譜進一步純化。EGFR_48的產率是9 mg(14%)。 實施例9.1製備候選物EGFR_58的方法。 候選物EGFR_58以類似於實施例9的方式從7d_1,1a和4a(表2)製備，產率是40 mg(18%)。 實施例9.2製備候選物EGFR_65的方法。 候選物EGFR_65以類似於實施例9的方式從7c_1,1a和4a(表2)製備，產率是20mg(9%)。 實施例9.3：製備候選物EGFR_66的方法 以類似於實施例9的方式，從7b_1,1a和4a(表2)製備候選物EGFR_66，產率是10 mg(9%)。 實施例9.4：製備候選物EGFR_68的方法 候選物EGFR_68以類似於實施例9的方式從7e_1,1a和4a(表2)製備，產率是40 mg(26%)。 實施例9.5：製備候選物EGFR_69的方法 以類似於實施例9的方式，從7a_1,1a和5a(表2)製備候選物EGFR_69，產率是10 mg(14%)。 實施例9.6：製備候選物EGFR_79的方法 候選物EGFR_79以類似於實施例9步驟2的方式從8和4a(表2)製備，產率為70 mg(61%)。 實施例9.7：製備候選物EGFR_440的方法 候選物EGFR_440以類似於實施例9的方式從7a_1,1a和5b (表2)製備，產率是40 mg(40%)。 實施例9.8：製備候選物EGFR_441的方法 候選物EGFR_441以類似於實施例9的方式從7d_1,1a和5b(表2)製備，產率為25 mg(25%)。 實施例9.9：製備候選物EGFR_483的方法 以類似於實施例9的方式，從7b_1、1a和5b(表2)製備候選物EGFR_483，產率為90 mg(54%)。 實施例9.10：製備候選物EGFR_774的方法 以類似於實施例9的方式，從7f_1,1a和4a(表2)製備候選物EGFR_774，產率為90 mg(54%)。 實施例9.11：製備候選物EGFR_74的方法 候選物EGFR_74以類似於實施例9的方式從7a_1,1b和4a(表2)製備，產率是40 mg(69%)。 實施例9.12：製備候選物EGFR_76的方法 候選物EGFR_76以類似於實施例9的方式從7a_1，亞磷酸二甲酯和4a(表2)製備，產率是10 mg(11%)。 實施例9.13候選物EGFR_656的製備方法 候選物EGFR_656用類似於實施例9的方法從7a_1,1a和4s製備(表2)，產率是70 mg(55%)。 實施例9.14：製備候選物EGFR_667的方法 以類似於實施例9的方式，從7a_1,1a和4t製備候選物EGFR_667(表2)，產率為40 mg(34%)。 實施例9.15：製備候選物EGFR_668的方法 以類似於實施例9的方式從7a_1,1a和4c製備候選物EGFR_668(表2)，產率為40 mg(49%)。 實施例9.16：製備候選物EGFR_743的方法 以類似於實施例9的方式，從7a_1、1a和4e(表2)製備候選物EGFR_743，產率是40 mg(49%)。 實施例9.17：候選物EGFR_752的製備方法 候選物EGFR_752以類似於實施例9的方式從7a_1,1a和4f(表2)製備，產率是80 mg(77%)。 實施例9.18：製備候選物EGFR_796的方法 以類似於實施例9的方式，從7a_1,1a和4h(表2)製備候選物EGFR_796，產率是80 mg(68%)。 實施例9.19：製備候選物EGFR_797的方法 以類似於實施例9的方式，從7a_1,1a和4i(表2)製備候選物EGFR_797，產率是20 mg(27%)。 實施例9.20：製備候選物EGFR_798的方法 以類似於實施例9的方式，從7a_1,1a和4j(表2)製備候選物EGFR_798，產率是10 mg(10%)。 實施例9.21：製備候選物EGFR_853的方法 以類似於實施例9的方式，從7i_1、1a和4e(表2)製備候選物EGFR_853，在第一步中使用Pd(dppf)Cl2和KOAc代替Pd(OAc) 2和Cs2CO3，產率為10 mg (12%)。 實施例9.22：製備候選物EGFR_854的方法 候選物EGFR_854以類似於實施例9的方式從7j_1、1a和4e(表2)製備，在第一步使用Pd(dppf)Cl2和KOAc代替Pd (OAc) 2和Cs2CO3，產率為10 mg (14%)。 實施例9.23：製備候選物EGFR_855的方法 以類似於實施例9的方式，從7k_1、1a和4e (表2)製備候選物EGFR_855，在第一步中使用Pd(dppf)Cl2和KOAc代替Pd(OAc) 2和Cs2CO3，產率為40 mg(42%)。 實施例9.23：製備候選物EGFR_856的方法 以類似於實施例9的方式，從7l_1、1a和4e(表2)製備候選物EGFR_856，在第一步中使用Pd(dppf)Cl2代替Pd (OAc) 2，產率為4 mg(5%)。 實施例9.24：製備候選物EGFR_857的方法 以類似於實施例9的方式，從7m_1、1a和4e (表2)製備候選物EGFR_857，在第一步中使用Pd(dppf)Cl2代替Pd (OAc) 2，產率為20 mg(28%)。 實施例9.25：候選物EGFR_858的製備方法 以類似於實施例9的方式，從7n_1、1a和4e (表2)製備候選物EGFR_858，在第一步中使用Pd(dppf)Cl2和KOAc代替Pd(OAc) 2和Cs2CO3，產率為10 mg(17%)。 實施例9.26候選物EGFR_859的製備方法 以類似於實施例9的方式，從7d_1,1a和4e(表2)製備候選物EGFR_859，產率是44 mg(44%)。 實施例9.27：製備候選物EGFR_860的方法 候選物EGFR_860以與實施例9相似的方式從7o_1,1a和4e(表2)製備，產率為20 mg(13%)。 實施例9.28：候選物EGFR_862的製備方法 以類似於實施例9的方式，從7b_1,1a和4e(表2)製備候選物EGFR_862，產率為40 mg(28%)。 實施例9.29：製備候選物EGFR_870的方法 候選物EGFR_870的製備方法類似於實施例9，由7p_1,1a和4e(表2)製備，產率為23 mg(23%)。 實施例9.30製備候選物EGFR_871的方法 以類似於實施例9的方式，從7a_1、1b和4e(表2)製備 候選物EGFR_871，產率是17 mg(42%)。 實施例9.31：製備候選物EGFR_887的方法 以類似於實施例9的方式，從7a_1、1a和4m(表2)製備候選物EGFR_887，產率為8 mg(11%)。 實施例9.32製備候選物EGFR_896的方法 以類似於實施例9的方式，從7q_1、1a和4e(表2)製備候選物EGFR_896，在第一步中使用K2CO3代替Cs2CO3，產率為60 mg(55%)。 實施例9.33：製備候選物EGFR_910的方法 候選物EGFR_910以類似於實施例9的方式從7a_1,1b和4h製備(表2)，產率是10 mg(16%)。 實施例9.34：製備候選物EGFR_912的方法 候選物EGFR_912以類似於實施例9的方式從7a_1,1b和4f製備(表2)，產率是50 mg(36%)。 實施例9.35：製備候選物EGFR_918的方法 候選物EGFR_918按照類似於實施例9的方法，從7q_1,1a和4f(表2)製備，產率是50 mg(34%)。 實施例9.36：候選物EGFR_919的製備方法 以類似於實施例9的方式，從7b_1,1a和4f(表2)製備候選物EGFR_919，產率為40 mg(31%)。 實施例9.37：製備候選物EGFR_655的方法 以類似於實施例9的方式，從7a_1、1a和4u(表2)製備候選物EGFR_655，產率為10 mg(10%)。 實施例9.38：製備候選物EGFR_865的方法 候選物EGFR_865用與實施例9相似的方法從7a_1,1a和4v(表2)製備，產率是10 mg(25%)。 實施例9.39製備候選物EGFR_982的方法 以類似於實施例9的方式，從7q_1、1d和4f(表2)製備候選物EGFR_982，產率為13 mg (18%)。 實施例9.39製備候選物EGFR_985的方法 以類似於實施例9的方式，從7q_1、1a和4n(表2)製備候選物EGFR_985，在第二步使用叔丁醇/1,4-二噁烷的混合物作為溶劑，產率為6 mg(4%)。 實施例9.39：製備候選物EGFR_989的方法 以類似於實施例9的方式，從7q_1、1a和4o(表2)製備候選物EGFR_989，產率為28 mg(20%)。 實施例9.39候選物EGFR_990的製備方法 候選物EGFR_990以類似於實施例9的方式從7q_1、1a和4p(表2)製備，產率是13 mg(9%)。 實施例9.40：製備候選物EGFR_993的方法 候選物EGFR_993以類似於實施例9的方式從7q_1,1a和4q(表2)製備，產率是17 mg(20%)。 實施例9.41：製備候選物EGFR_994的方法 候選物EGFR_994以類似於實施例9的方式從7q_1,1a和4r(表2)製備，產率是9 mg (16%)。
Figure 02_image251
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Figure 02_image271
實施例10：製備候選物EGFR_70的方法
Figure 02_image273
將1M LiHMDS的THF溶液(0.51 ml，0.51 mmol)加入到6a(69 mg，0.17 mmol)和7a_2(91 mg，0.51 mol)的DMF (2 ml)懸浮液中。在氬氣氛中加入Pd 2(dba) 3(74 mg，0.08 mmol)和XPhos(75 mg，0.15 mmol)。將RM在100℃攪拌40小時並濃縮。通過矽膠柱色譜法，使用DCM/MeOH/NH3作為洗脫劑分離產物。分離的產物通過製備色譜進一步純化。EGFR_70的產率是3 mg(4%)。 實施例10.1：製備候選物EGFR_348的方法 以類似於實施例10的方式從7d_2和4b製備候選物EGFR_348，產率是30 mg(21%)。 實施例10.2：候選物EGFR_437的製備方法 以類似於實施例10的方式，從7d_2和5a製備候選物EGFR_437，產率是10 mg(9%)。 實施例10.3製備候選物EGFR_485的方法 以類似於實施例10的方式，從7a_2和6b製備候選物EGFR_485，產率是15 mg(16%)。 實施例10.4：製備候選物EGFR_669的方法 以類似於實施例10的方式，從7a_2和4d製備候選物EGFR_669，產率為21 mg(38%)。 實施例10.5：製備候選物EGFR_795的方法 以類似於實施例10的方式，從7a_2和4g製備候選物EGFR_795，產率是95 mg (71%)。 實施例10.6：製備候選物EGFR_801的方法 候選物EGFR_801是按照類似於實施例10的方式從7a _2和4k製備的，產率為40 mg (67%)。 實施例10.7：製備候選物EGFR_802的方法 候選物EGFR_802以類似於實施例10的方式從7a _2和4l製備，產率是30 mg (48%)。 實施例10.8：製備候選物EGFR_914的方法 候選物EGFR_914以類似於實施例10的方式從7a_2和4w製備，產率是10 mg(18%)。 實施例11.化合物EGFR_60的製備方法。
Figure 02_image275
步驟1.化合物9a_2的製備。 在氬氣氛中，將Pd 2(dba) 3(0.11g，0.11 mmol)和XPhos (0.16g，0.33 mmol)加入9a_1(0.70g，3.67 mmol)、 N 1, N 1, N 2--三甲基乙-1,2-二胺(0.57g，5.51 mmol)、叔丁醇鈉(0.90g，9.18 mmol)在甲苯(14 ml)中的懸浮液中。將RM在110℃攪拌3小時，濾出，並在旋轉蒸發器上濃縮。通過矽膠柱色譜法，使用EtOAc/TEA作為洗脫劑分離產物。9a_2的產率為0.31g(41%)。 步驟2.化合物9a_3的製備。 在0℃下，將NBS(0.28g，1.57 mmol)的MeCN(3 ml)溶液加入9a_2(0.31g，1.43 mmol)的MeCN(12 ml)溶液中。在室溫下攪拌RM2小時，濃縮，重新溶解在DCM中，用水洗滌並濃縮。通過矽膠柱色譜法，使用EtOAc/TEA作為洗脫劑分離產物。9a-3的產率為0.30g(73%)。 步驟3.化合物9a _4的製備。 在氬氣氛中，將Pd (dppf)Cl2(48.0 mg，0.06 mmol)加入到9a_3(0.23g，0.77 mmol)、4b_3(0.31g，0.64 mmol)、B 2pin 2(0.30g，1.15 mmol)、KOAC(0.19g，1.92 mmol)和K2CO3(0.22g，2.05 mmol)在1,4-二噁烷/水(7:2，9 ml)的混合物中的懸浮液中。反應物料在100℃攪拌3小時，產物通過矽膠柱色譜分離，用己烷/丙酮/TEA作為洗脫劑。9a_4的產率為0.30g (90%)。 步驟4.化合物9a_5的製備。 按照與實施例7步驟4相似的方式，由9a_4製備化合物9a_5，產率為0.14g(77%)。 步驟5.候選物EGFR_60的製備。 候選物EGFR_60以類似於實施例9步驟2的方式從9a_4和7a_2製備，產率是0.04g(22%)。 實施例11.1製備候選物EGFR_884的方法。
Figure 02_image277
步驟1.化合物9b_2的製備。 以類似於實施例11步驟1的方式，由9b_1和N,N-二甲基呱啶-4-胺製備化合物9b_2，產率為0.56g(48%)。 步驟2.化合物9b_3的製備。 按照與實施例11步驟2相似的方式，由9b_2製備化合物9b_3，產率為0.50g(90%)。 步驟3.化合物9b_4的製備。 按照與實施例11步驟3相似的方式，由9b_3和4b_3製備化合物9b_4，產率為0.06g(84%)。 步驟4.化合物9b_5的製備。 按照與實施例11步驟4相似的方式，由9b_4製備化合物9b_5，產率為0.06g(72%)。 步驟5.候選物EGFR_884的製備。 候選物EGFR_884以類似於實施例11步驟5的方式從9b_5製備，產率是0.04g(52%)。 實施例11.2製備候選物EGFR_886的方法。
Figure 02_image279
步驟1.化合物9c_2的製備。 以與實施例11步驟1相似的方式，由9c-1和N,N-二甲基呱啶-4-胺製備化合物9c-2，產率為0.57g(47%)。 步驟2.化合物9c_3的製備。 按照與實施例11步驟2類似的方式，由9c_2製備化合物9c_3，產率為0.61g (82%)。 步驟3.化合物9c_4的製備。 按照與實施例11步驟3相似的方式，由9c_3和4b_3製備化合物9c_4，產率為0.14g(24%)。 步驟4.化合物9c_5的製備。 按照與實施例11步驟4相似的方式，由9c_4製備化合物9c_5，產率為0.08g(91%)。 步驟5.候選物EGFR_886的製備。 候選物EGFR_886以類似於實施例11步驟5的方式從9c_5製備，產率是0.06g(58%)。 實施例12.化合物EGFR_59的製備方法。
Figure 02_image281
步驟1製備化合物10_2。 按照與實施例11步驟1相似的方式，由10_1製備化合物10_2，產率為2.47g(91%)。 步驟2.化合物10_3的製備。 在0℃和氬氣氛下，將NIS(0.28g，1.2 mmol)的DMF (2.5 ml)溶液緩慢加入到10_2(0.25g，1.14 mmol)的DMF (2.5 ml)溶液中。將混合物在室溫下攪拌30分鐘。將反應混合物倒入水中，用EtOAc萃取。合併的有機相用Na2SO4乾燥，過濾並在旋轉蒸發器上濃縮。通過矽膠柱色譜法，使用己烷/丙酮/TEA作為洗脫劑分離產物。10_3的產率是0.26g (67%)。 步驟3.化合物10_4的製備。 以類似於實施例7步驟3的方式，不同之處在於在70℃下，由4b_3和10_3製備化合物10_4，產率為0.17g(55%)。 步驟4.化合物10_5的製備。 按照與實施例7步驟4相似的方式，由10_4製備化合物10_5，產率為0.06g(76%)。 步驟5.候選物EGFR_59的製備。 候選物EGFR_59以類似於實施例11步驟5的方式從7a_2和10_5製備，產率是40 mg(63%)。 實施例13.候選物EGFR_338的製備方法。
Figure 02_image283
步驟1.化合物11_2的製備。 在氬氣氛中，將LiHMDS的THF溶液(1M，5.7 ml，5.7 mmol)加入到11_1(0.46g，2.85 mmol)的THF(10 ml)溶液中，在室溫下混合該混合物15分鐘。加入二碳酸二叔丁酯(0.7g，3.14 mmol)的THF(2 ml)溶液。將混合物在室溫下攪拌2小時，加入NH 4Cl飽和水溶液、NaCl飽和水溶液和EtOAc。有機相用Na2SO4乾燥，過濾並在旋轉蒸發器上濃縮。通過矽膠柱色譜法使用己烷/DCM/EtOAc作為洗脫劑分離產物。11_2的產率為0.68g(93%)。 步驟2.化合物11_3的製備。 在-78℃和氬氣氛下，將2.5M的正丁基鋰在己烷中的溶液(3.21 ml，8.03 mmol)緩慢加入到11_2(0.91g，3.21 mmol)和TMEDA(0.94g，8.03 mmol)的THF(22 ml)溶液中。將混合物在-78℃攪拌1小時，加入I 2(4.11g，0.02 mol)的THF(5 ml)溶液。使RM轉到r.t.；加入NaCl飽和水溶液、NaHSO4飽和水溶液，將混合物在室溫下混合30分鐘。產物用EtOAc萃取。合併的有機相用NaCl飽和水溶液洗滌，用Na2SO4乾燥，過濾並在旋轉蒸發器上濃縮。通過矽膠柱色譜法，使用EtOAc/己烷/DCM作為洗脫劑分離產物。11_3的產率為0.63g(52%)。 步驟3.化合物11_4的製備 將7N HCl在1,4-二噁烷(3 ml)、MeOH(1 ml)和水(0.1 ml)中的溶液加入到11_3(0.44g，11.0 mmol)在1,4-二噁烷(4 ml)中的溶液中。將所得溶液在60℃下混合1小時。濃縮RM，用Na2CO3的飽和水溶液中和，產物用EtOAc萃取。合併的有機相用NaCl飽和水溶液洗滌，用Na2SO4乾燥，過濾並在旋轉蒸發器上濃縮。11_4的產率為0.30g(98%)。 步驟4.化合物11_5的製備 化合物11_5以類似於實施例6步驟2的方式自11_4製備，產率為0.21g(93%)。 步驟5.化合物11_6的製備。 化合物11_6以類似於實施例6步驟3的方式自11_5製備。產物另外用矽膠柱色譜法使用EtOAc/己烷作為洗脫劑純化。11_6的產率為0.16g(83%)。 步驟6.化合物11_7的製備。 用與實施例6步驟4類似的方法，由11_6製備化合物11_7π。產物另外用矽膠柱色譜法使用EtOAc/MeOH/TEA作為洗脫劑純化。11_7的產率是0.18g(64%)。 步驟7.化合物11_8的製備。 將11_7(0.13g，0.36 mmol)和叔丁醇鉀(0.17g，1.4 mmol)在NMP(5 ml)中的溶液在80℃下混合5小時，加入水，並將產物用EtOAc萃取。合併的有機相用Na2SO4乾燥，過濾並在旋轉蒸發器上濃縮。通過矽膠柱色譜法，使用DCM/MeOH作為洗脫劑分離產物。11_8的產率為60 mg (47%)。 步驟8.候選物EGFR_338的製備。 候選物EGFR_338以類似於實施例10的方式從11_8和7a_2製備，產率是20 mg(32%)。 實施例14.候選物EGFR_1006的製備方法。
Figure 02_image285
步驟1.化合物7s_2的製備。 在0℃下，將甲氧基甲基氯(294 mg，3.47 mmol)的DCM(2 ml)溶液加入7s-1(645 mg，2.31 mmol)、DIPEA (550 mg，4.16 mmol)的DCM(15 ml)溶液中。45分鐘後，濃縮RM。通過矽膠柱色譜法，使用EtOAc/己烷作為洗脫劑分離產物。7s_2的產率為710 mg(99%)。 步驟2.化合物7s _3的製備。 將7s_2(680 mg，2.09 mmol)、Fe(354 mg，6.27 mmol)、CaCl 2(234 mg，2.09 mmol)在EtOH/水(4:1,15 ml)混合物中的懸浮液在80℃攪拌3小時，過濾並濃縮。通過矽膠柱色譜法，使用EtOAc/己烷作為梯度洗脫劑分離產物。7s_3的產率為548 mg (94%)。 步驟3.化合物7s_4的製備。 按照與實施例9步驟1相似的方式，由7s_3和1a製備化合物7s_4，產率為220 mg(53%)。 步驟4.候選物EGFR_1006的製備。 候選物EGFR_1006以類似於實施例9步驟2的方式從7s_4和4f製備，產率是20 mg(13%)。 實施例15.製備的化合物的分析。 通過色譜法/質譜法LC/MS和1H NMR光譜法證實所得化合物的純度和結構(表6)。 設備資料：
Figure 02_image287
Figure 02_image289
Figure 02_image291
Figure 02_image293
Figure 02_image295
Figure 02_image297
Figure 02_image299
Figure 02_image301
Figure 02_image303
Figure 02_image305
Figure 02_image307
實施例16.測定化合物在緩衝液中的濁度法溶解度。 在0.01M磷酸鈉緩衝液pH=7.4中測定化合物的溶解度。 將候選物的起始溶液(10 mM的DMSO溶液)用0.01M磷酸鈉緩衝液pH=7.4稀釋至100μM(測試溶液1)、80μM(測試溶液2)、60μM(測試溶液3)、50μM(測試溶液4)、40μM(測試溶液5)、30μM(測試溶液6)、20μM(測試溶液7)、10μM (測試溶液8)的濃度。將試驗溶液加入96-板(Corning 3635，UV板)的孔中。將含有測試溶液的板在熱振盪器(Biosan PST-60HL-4，Latvia)中孵育2小時。 使用Sunrise微板分光光度計(Tecan，澳大利亞)測定在620 nm波長的吸收。對光密度值與空白不同的樣品繪製溶液光密度作為濃度函數的圖，確定線性依賴方程，並計算溶解度值。
Figure 02_image309
實施例17.體外抗EGFR抑制活性。 本發明公開的化合物的IC 50值使用在非細胞系統中激酶活性抑制的生物化學試驗測定。 使用SignalChem激酶系統和ADP-Glo™激酶試驗(#V9102，Promega)檢測試劑盒測定EGFR野生型和EGFR L858R/T790M/C797S激酶活性的抑制。 使用以下製備必需的緩衝液： 1. H2O(LC-MS)。 2. 5X反應緩衝液A(ThermoFisher，#PV6135)。 3. 2 mM DTT(Sigma，#646563-10×5ML)。 4. Poly 4:1 Glu，Tyr肽(SignalChem，#P61-58-1MG)。 5. ATP(V915B，Promega)。 激酶緩衝液： 1. 4X激酶緩衝液(5X反應緩衝液A，200μM DTT，4% DMSO，H2O)。 2. 1X激酶緩衝液(4X激酶緩衝液，H2O)。 3. 混合物(2份Poly 4:1 Glu，Tyr肽，1份4X激酶緩衝液，1份100μM ATP)。 將激酶溶解在1X激酶緩衝液中。抑制劑從50μM開始以5的增量在具有12個濃度點的1X激酶緩衝液中滴定。 測量在384孔規格(Corning，#4513)中在5μl反應體積中進行。將激酶(2μL)和抑制劑(1μL)預孵育10分鐘。1X激酶緩衝液用作陰性對照。將2 ml混合物加入到激酶和抑制劑的混合物中的每一個(肽的終濃度為0.2 mg/ml，ATP的終濃度為10μM)，然後將板在400 rcf離心一分鐘，然後在25℃孵育1小時，使用ADP-Glo™檢測系統(Promega，#V9102)檢測在激酶反應過程中獲得的ADP的量。使用Spark 20M片劑多功能讀數器(Tecan，瑞士)測量發光信號。使用SparkControl Magellan V 3.0軟體(Tecan，瑞士)，通過用Levenberg-Marquardt優化的四參數模型來近似實驗點，計算IC50值：
Figure 02_image311
其中A是上漸近線；D是下漸近線；C是IC50，半最大抑制濃度，B是曲率(斜率)的參數。
Figure 02_image313
Figure 02_image315
本發明的化合物證明有效抑制具有靶EGFR突變L858R/T790M/C797S的激酶活性，並且還證明對野生型EGFR的低活性。 實施例18.抗Ba/F3 EGFR L858R/T790M/C797S細胞系的抗增殖活性。 在細胞試驗中，使用AlamarBlue活體染料(ThermoFisher，#DAL1100)對Ba/F3 EGFR L858R/T790M/ C797S細胞(鼠pro-B細胞系，KYinno，KC-0122)的連續培養物測定EGFR抑制劑的抗增殖活性。細胞在生長培養基（DMEM高葡萄糖（Gibco，#12800-082），補充10% FBS（Gibco，#16140-071））中培養，然後轉移到96孔培養板（Corning，#3599），每孔100毫升培養基中含有1.5×10 3個細胞。將測試化合物溶於DMSO中，用生長培養基稀釋至0-10μM的終濃度。接著，將100μl稀釋的化合物加入每個孔(DMSO的最終濃度不超過1%)，並在37℃下在具有5% CO2的孵育器中孵育72小時。孵育後，向每個孔中加入20 ml AlamarBlue試劑(ThermoFisher，#DAL1100)，將板的內容物在定軌搖床(Biosan，Latvia)上以550 rpm混合1分鐘，然後在37℃下在含有5% CO2的孵育器中另外孵育6小時。通過在540 nm的激發波長(lEx)和590 nm的發射波長(lEm)下測量螢光信號，在Spark 20M多模式讀板儀(Tecan，瑞士)上檢測活細胞的數目。使用SparkControl Magellan V 3.0軟體(Tecan，瑞士)，通過用Levenberg-Marquardt優化的四參數模型來近似實驗點，計算IC50值：
Figure 02_image317
其中A是上漸近線；D是下漸近線；C是IC50，半最大抑制濃度，B是曲率(斜率)的參數。
Figure 02_image319
本發明的化合物對Ba/F3 EGFR L858R/T790M/C797S細胞系顯示抗增殖活性。 實施例19.抗Ba/F3 EGFR Del19/T790M/C797S細胞系的抗增殖活性。 在細胞試驗中，使用AlamarBlue活體染料( ThermoFisher，#DAL1100)對Ba/F3 EGFR Del19/T790M/ C797S細胞(鼠pro-B細胞系，KYinno，KC-0116)的連續培養物測定EGFR抑制劑的抗增殖活性。細胞在生長培養基(DMEM高葡萄糖(Gibco，#12800-082)，補充10% FBS (Gibco，#16140-071))中培養，然後轉移到96孔培養板(Corning，#3599)，每孔100毫升培養基中含有1.5×10 3個細胞。將測試化合物溶於DMSO中，用生長培養基稀釋至0-10μM的終濃度。接著，將100μl稀釋的化合物加入每個孔(DMSO的最終濃度不超過1%)，並在37℃下在具有5% CO2的孵育器中孵育72小時。孵育後，向每個孔中加入20 ml AlamarBlue試劑(ThermoFisher，#DAL1100)，將板的內容物在定軌搖床(Biosan，Latvia)上以550 rpm混合1分鐘，然後在37℃下在含有5% CO2的孵育器中另外孵育6小時。通過在540 nm的激發波長(lEx)和590 nm的發射波長(lEm)下測量螢光信號，在Spark 20M多模式讀板儀(Tecan，瑞士)上檢測活細胞的數目。使用SparkControl Magellan V 3.0軟體(Tecan，瑞士)，通過用Levenberg-Marquardt優化的四參數模型來近似實驗點，計算IC50值：
Figure 02_image321
其中A是上漸近線；D是下漸近線；C是IC50，半最大抑制濃度，B是曲率(斜率)的參數。
Figure 02_image323
本發明的化合物對Ba/F3 EGFR Del19/T790M/C797S細胞系顯示抗增殖活性。 In one embodiment, the invention relates to compounds of formula I:
Figure 02_image003
or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, where L 1is a chemical bond or -NH-; x 1is -CH-, -N- or -C(R 6)-; each n, m is independently 0, 1, 2, 3 or 4; each R 1independently -H; -Hal; -C(Hal) 3;-CN;-NR 7R 8;-C(O)NR 9R 10;-C(O)OR 11;-C(O)R 12;-OR 13;-(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R 14replace;-(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R 14areplace; R 2for-P(O)((C 1-C 6)alkyl) 2, unsubstituted or replaced by one or more groups R 15replace; -P(O)((C 3-C 6)cycloalkyl) 2, unsubstituted or replaced by one or more groups R 15areplace; -P(O)((C 1-C 6)alkyl))((C 3-C 6) cycloalkyl), unsubstituted or replaced by one or more groups R 15bReplace; -P(O)(О(C 1-C 6)alkyl) 2, unsubstituted or replaced by one or more groups R 15cReplace; -P(O)(О(C 3-C 6)cycloalkyl) 2, unsubstituted or replaced by one or more groups R 15dreplace; -P(O)(О(C 1-C 6)Alkyl)(О(C 3-C 6) cycloalkyl), unsubstituted or replaced by one or more groups R 15ereplace; P(O)(О(C 1-C 6)alkyl)((C 3-C 6) cycloalkyl), unsubstituted or replaced by one or more groups R 15Replace; -P(O)(О(C 1-C 6)alkyl)((C 1-C 6)alkyl), unsubstituted or replaced by one or more groups R 15replace; -P(O)(О(C 3-C 6)cycloalkyl)((C 1-C 6)alkyl), unsubstituted or replaced by one or more groups R 15Replace; -P(O)(О(C 3-C 6)cycloalkyl)((C 3-C 6) cycloalkyl), unsubstituted or replaced by one or more groups R 15Replace; -SO 2(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R 15freplace; or -SO 2(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R 15greplace; R 3-H; -Hal; -CN; -C(Hal) 3;-NR 7aR 8a; -C(O)NR 9aR 10a;-C(O)OR 11a;-C(O)R 12a;-OR 13a;-(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R 16a substitution; -(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R 16breplace;-(C 6-C 12) aryl, unsubstituted or replaced by one or more groups R 16CSubstituted; 4-10 membered heteroaryl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or replaced by one or more groups R 16dreplace; each R 4independently -H; -Hal; -CN; -NR 7bR 8b;-C(Hal) 3;-C(O)NR 9bR 10b;-C(O)OR 11b;-C(O)R 12b;-OR 13b; -(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R 17areplace; -(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R 17bSubstituted; 4-10 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or О, unsubstituted or replaced by one or more groups R 17creplace; or -(C 6-C 12) aryl, unsubstituted or replaced by one or more groups R 17dreplace; R 5for: -NR 7сR 18;-NR 7dR 19;-W 1;-OW 2;-NR aW 3; -C(O)W 4; or -(CH 2)W 5; where each W 1, W 2, W 3, W 4or W 5Independently for -(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R 20Substituted; 4-7 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or replaced by one or more groups R 20replace, R 6-Hal, -CN, -C(Hal) 3、CH (Hal) 2、CH 2Hal, -NR 7eR 8C;-(C 1-C 6) alkyl, which is unsubstituted or is selected from one or more of -Hal, -NH 2, -OH, (=O) group substitution; each R 7, R 7a, R 7b, R 7e, R 8, R 8a, R 8b, R 8C, R 9, R 9a, R 9b, R 10, R 10a, R 10bindependently -H, -(C 1-C 6) alkyl, which is unsubstituted or is selected from one or more of -Hal, -NH 2, -OH, (=O) group substitution; -(C 3-C 6) cycloalkyl, which is unsubstituted or replaced by one or more selected from -Hal, -NH 2, -OH, (=O) group substitution; each R 7c, R 7d, R aindependently for -H, -(С 1-C 6)alkyl; R 18for-(С 1-C 10) alkyl, which is unsubstituted or is selected from one or more of -Hal, -OH, -NO 2, -NR twenty threeR twenty four, (=O) substituent substitution; R 19is a 2-10 membered heteroalkyl group with 1 or 2 heteroatoms selected from N, S or O, which is unsubstituted or replaced by one or more selected from -Hal, -OH, -NO 2, -NR twenty threeR twenty four, (=O) substituent substitution; each R 11, R 12, R 13, R 11a. R 12a. R 13a. R 11b, R 12b, R 13bindependently -H; -(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R twenty onereplace;-(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R twenty onea substitution; -(C 6-C 12) aryl, unsubstituted or replaced by one or more groups R 21bSubstituted, 4-10 membered heterocyclic group with 1 or 2 heteroatoms selected from N, S or О, unsubstituted or replaced by one or more groups R 21creplace; each R 14, R 14a, R 15, R 15a, R 15, R 15a, R 15b, R 15c, R 15d, R 15e, R 15f, R 15g, R 16, R 16a. R 16b, R 16C, R 16d, R 17, R 17a, R 17b, R 17c, R 17dindependently -Hal, -H, -OH, -NO 2, -NR twenty threeR twenty four,-(C 1-C 6) alkyl, which is unsubstituted or is selected from one or more of -Hal, -NH 2, -OH, (=O) group substitution; each R 20independently (=O), -NR 7fR 8d,-(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R twenty twoSubstituted, - 2-8 membered heteroalkyl with 1 or 2 heteroatoms selected from N, O or S, unsubstituted or replaced by one or more groups R 22areplace, -(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R 22bSubstituted, 4-10 membered heterocyclic group with 1 or 2 heteroatoms selected from N, S or О, unsubstituted or replaced by one or more groups R 22replace; each R 7f, R 8dindependently -H, -(C 1-C 6) alkyl, which is unsubstituted or is selected from one or more of -Hal, -NH 2, -OH, (=O) group substitution; -(C 3-C 6) cycloalkyl, which is unsubstituted or is selected from one or more -Hal, -NH 2, -OH, (=O) group substitution; each R twenty one, R twenty onea. R 21b, R twenty oneC, R twenty two, R 22a, R 22b, R 22independently -Hal, -H, -OH, -NO 2, -NR twenty threeR twenty four,-(C 1-C 6) alkyl, which is unsubstituted or is selected from one or more of -Hal, -NH 2, -O(C 1-C 6) alkyl, -ОH, (=O) group substitution; each R twenty three, R twenty fourindependently -H; -(C 1-C 6) alkyl, which is unsubstituted or replaced by one or more selected from (=О), -ОH, -NR 25R 26The group substitution; -(C 2-C 6) alkenyl, which is unsubstituted or replaced by one or more selected from (=О), -NR 25aR 26agroup substitution; each R 25, R 26, R 25a, R 26aindependently -H, -(C 1-C 6)alkyl; Hal is a fluorine, bromine, chlorine or iodine atom. In another embodiment, the invention relates to compounds of formula I, wherein L 1is a chemical bond, R 2for-P(O)((C 1-C 6)alkyl) 2, unsubstituted or replaced by one or more groups R 15replace; -P(O)((C 3-C 6)cycloalkyl) 2, unsubstituted or replaced by one or more groups R 15areplace; -P(O)((C 1-C 6)alkyl))((C 3-C 6) cycloalkyl), unsubstituted or replaced by one or more groups R 15breplace; -P(O)(О(C 1-C 6)alkyl) 2, unsubstituted or replaced by one or more groups R 15cReplace; -P(O)(О(C 3-C 6)cycloalkyl) 2, unsubstituted or replaced by one or more groups R 15dReplace; -P(O)(О(C 1-C 6)Alkyl)(О(C 3-C 6) cycloalkyl), unsubstituted or replaced by one or more groups R 15ereplace; P(O)(О(C 1-C 6)alkyl)((C 3-C 6) cycloalkyl), unsubstituted or replaced by one or more groups R 15replace; -P(O)(О(C 1-C 6)alkyl)((C 1-C 6)alkyl), unsubstituted or replaced by one or more groups R 15Replace; -P(O)(О(C 3-C 6) cycloalkyl) ((C 1-C 6)alkyl), unsubstituted or replaced by one or more groups R 15Replace; -P(O)(О(C 3-C 6)cycloalkyl)((C 3-C 6) cycloalkyl), unsubstituted or replaced by one or more groups R 15replace; P(O)(О(C 1-C 6)alkyl)((C 3-C 6) cycloalkyl), unsubstituted or replaced by one or more groups R 15Replace; -P(O)(О(C 1-C 6)alkyl)((C 1-C 6)alkyl), unsubstituted or replaced by one or more groups R 15Replace; -P(O)(О(C 3-C 6)cycloalkyl)((C 1-C 6)alkyl), unsubstituted or replaced by one or more groups R 15Replace; -P(O)(О(C 3-C 6)cycloalkyl)((C 3-C 6) cycloalkyl), unsubstituted or replaced by one or more groups R 15replace; or L 1for -NH-, R 2for-SO 2(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R 15freplace; or -SO 2(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R 15greplace, where each R 15, R 15a, R 15, R 15a, R 15b, R 15c, R 15d, R 15e, R 15f, R 15gindependently -Hal, -H, -OH, -NO 2, -NR twenty threeR twenty four, -(C 1-C 6) alkyl, which is unsubstituted or replaced by one or more selected from -Hal, -NH 2, -OH, (=O) group substitution; each R twenty three, R twenty fourindependently -H; -(C 1-C 6) alkyl, which is unsubstituted or replaced by one or more selected from (=О), -ОH, -NR 25R 26The group substitution; -(C 2-C 6) alkenyl, which is unsubstituted or replaced by one or more selected from (=О), -NR 25aR 26agroup substitution; each R 25, R 26, R 25a, R 26aindependently -H, -(C 1-C 6)alkyl, Hal is a fluorine, bromine, chlorine or iodine atom. In another embodiment, the present invention relates to compounds of formula I:
Figure 02_image005
or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, where L 1is a chemical bond or -NH-; x 1is -CH-, -N- or -C(R 6)-; each n, m is independently 0, 1, 2, 3 or 4; each R 1independently -H; -Hal; -C(Hal) 3;-CN;-NR 7R 8;-C(O)NR 9R 10;-C(O)OR 11;-C(O)R 12;-OR 13;-(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R 14replace;-(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R 14areplace; R 2for-P(O)((C 1-C 6)alkyl) 2, unsubstituted or replaced by one or more groups R 15replace; -P(O)((C 3-C 6)cycloalkyl) 2, unsubstituted or replaced by one or more groups R 15areplace; -P(O)((C 1-C 6)alkyl))((C 3-C 6) cycloalkyl), unsubstituted or replaced by one or more groups R 15breplace; -P(O)(О(C 1-C 6)alkyl) 2, unsubstituted or replaced by one or more groups R 15cReplace; -P(O)(О(C 3-C 6)cycloalkyl) 2, unsubstituted or replaced by one or more groups R 15dReplace; -P(O)(О(C 1-C 6)Alkyl)(О(C 3-C 6) cycloalkyl), unsubstituted or replaced by one or more groups R 15eReplace; -SO 2(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R 15freplace; P(O)(О(C 1-C 6)alkyl)((C 3-C 6) cycloalkyl), unsubstituted or replaced by one or more groups R 15replace; -P(O)(О(C 1-C 6)alkyl)((C 1-C 6)alkyl), unsubstituted or replaced by one or more groups R 15Replace; -P(O)(О(C 3-C 6)cycloalkyl)((C 1-C 6)alkyl), unsubstituted or replaced by one or more groups R 15Replace; -P(O)(О(C 3-C 6)cycloalkyl)((C 3-C 6) cycloalkyl), unsubstituted or replaced by one or more groups R 15replace; or -SO 2(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R 15greplace; R 3-H; -Hal; -CN; -C(Hal) 3;-NR 7aR 8a; -C(O)NR 9aR 10a;-C(O)OR 11a;-C(O)R 12a;-OR 13a;-(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R 16a substitution; -(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R 16breplace;-(C 6-C 12) aryl, unsubstituted or replaced by one or more groups R 16CSubstituted; 4-10 membered heteroaryl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or replaced by one or more groups R 16dreplace; each R 4independently -H; -Hal; -CN; -NR 7bR 8b;-C(Hal) 3;-C(O)NR 9bR 10b;-C(O)OR 11b;-C(O)R 12b;-OR 13b; -(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R 17areplace; -(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R 17bSubstituted; 4-10 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or О, unsubstituted or replaced by one or more groups R 17creplace; or -(C 6-C 12) aryl, unsubstituted or replaced by one or more groups R 17dreplace; R 5for: -NR 7сR 18;-NR 7dR 19;-W 1;-OW 2;-NR aW 3; -C(O)W 4; or -(CH 2)W 5; where each W 1, W 2, W 3, W 4or W 5Independently for -(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R 20Substituted; 4-7 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or replaced by one or more groups R 20replace; R 6-Hal, -CN, -C(Hal) 3、CH(Hal) 2、CH 2Hal, -NR 7eR 8C;-(C 1-C 6) alkyl, which is unsubstituted or is selected from one or more of -Hal, -NH 2, -OH, (=O) group substitution; each R 7, R 7a, R 7b, R 7e, R 8, R 8a, R 8b, R 8C, R 9, R 9a, R 9b, R 10, R 10a, R 10bindependently -H, -(C 1-C 6) alkyl, which is unsubstituted or is selected from one or more of -Hal, -NH 2, -OH, (=O) group substitution; -(C 3-C 6) cycloalkyl, which is unsubstituted or replaced by one or more selected from -Hal, -NH 2, -OH, (=O) group substitution; each R 7c, R 7d, R aindependently for -H, -(С 1-C 6)alkyl; R 18for-(С 1-C 10) alkyl, which is unsubstituted or is selected from one or more of -Hal, -OH, -NO 2, -NR twenty threeR twenty four, (=O) substituent substitution; R 19is a 2-10 membered heteroalkyl group with 1 or 2 heteroatoms selected from N, S or O, which is unsubstituted or replaced by one or more selected from -Hal, -OH, -NO 2, -NR twenty threeR twenty four, (=O) substituent substitution; each R 11, R 12, R 13, R 11a. R 12a. R 13a. R 11b, R 12b, R 13bindependently -H; -(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R twenty onereplace;-(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R twenty onea substitution; -(C 6-C 12) aryl, unsubstituted or replaced by one or more groups R 21bSubstituted, 4-10 membered heterocyclic group with 1 or 2 heteroatoms selected from N, S or О, unsubstituted or replaced by one or more groups R 21creplace; each R 14, R 14a, R 15, R 15a, R 15, R 15a, R 15b, R 15c, R 15d, R 15e, R 15f, R 15g, R 16, R 16a. R 16b, R 16C, R 16d, R 17, R 17a, R 17b, R 17c, R 17dindependently -Hal, -H, -OH, -NO 2, -NR twenty threeR twenty four,-(C 1-C 6) alkyl, which is unsubstituted or is selected from one or more of -Hal, -NH 2, -OH, (=O) group substitution; each R 20independently (=O), -NR 7fR 8d,-(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R twenty twoSubstituted, - 2-8 membered heteroalkyl with 1 or 2 heteroatoms selected from N, O or S, unsubstituted or replaced by one or more groups R 22areplace, -(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R 22bSubstituted, 4-10 membered heterocyclic group with 1 or 2 heteroatoms selected from N, S or О, unsubstituted or replaced by one or more groups R 22replace; each R 7f, R 8dindependently -H, -(C 1-C 6) alkyl, which is unsubstituted or is selected from one or more of -Hal, -NH 2, -OH, (=O) group substitution; -(C 3-C 6) cycloalkyl, which is unsubstituted or is selected from one or more -Hal, -NH 2, -OH, (=O) group substitution; each R twenty one, R twenty onea. R 21b, R twenty oneс, R twenty two, R 22a, R 22b, R 22independently -Hal, -H, -OH, -NO 2, -NR twenty threeR twenty four,-(C 1-C 6) alkyl, which is unsubstituted or is selected from one or more of -Hal, -NH 2, -O(C 1-C 6) alkyl, (=O), -ОH group substitution; each R twenty three, R twenty fourindependently -H; -(C 1-C 6) alkyl, which is unsubstituted or replaced by one or more selected from (=О), -ОH, -NR 25R 26The group substitution; -(C 2-C 6) alkenyl, which is unsubstituted or replaced by one or more selected from (=О), -NR 25aR 26agroup substitution; each R 25, R 26, R 25a, R 26aindependently -H, -(C 1-C 6)alkyl; Hal is a fluorine, bromine, chlorine or iodine atom. In another embodiment, the invention relates to compounds of formula I, wherein L 1is a chemical bond, R 2for-P(O)((C 1-C 6)alkyl) 2, unsubstituted or replaced by one or more groups R 15replace; -P(O)((C 3-C 6)cycloalkyl) 2, unsubstituted or replaced by one or more groups R 15areplace; -P(O)((C 1-C 6)alkyl))((C 3-C 6) cycloalkyl), unsubstituted or replaced by one or more groups R 15breplace; -P(O)(О(C 1-C 6)alkyl) 2, unsubstituted or replaced by one or more groups R 15cReplace; -P(O)(О(C 3-C 6)cycloalkyl) 2, unsubstituted or replaced by one or more groups R 15dReplace; -P(O)(О(C 1-C 6)Alkyl)(О(C 3-C 6) cycloalkyl), unsubstituted or replaced by one or more groups R 15ereplace; P(O)(О(C 1-C 6)alkyl)((C 3-C 6) cycloalkyl), unsubstituted or replaced by one or more groups R 15replace; -P(O)(О(C 1-C 6) Alkyl) ((C 1-C 6)alkyl), unsubstituted or replaced by one or more groups R 15Replace; -P(O)(О(C 3-C 6)cycloalkyl)((C 1-C 6)alkyl), unsubstituted or replaced by one or more groups R 15Replace; -P(O)(О(C 3-C 6)cycloalkyl)((C 3-C 6) cycloalkyl), unsubstituted or replaced by one or more groups R 15replace; or L 1for -NH-, R 2for-SO 2(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R 15freplace; or -SO 2(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R 15greplace, where each R 15, R 15a, R 15, R 15a, R 15b, R 15c, R 15d, R 15e, R 15f, R 15gindependently -Hal, -H, -OH, -NO 2, -NR twenty threeR twenty four, -(C 1-C 6) alkyl, which is unsubstituted or replaced by one or more selected from -Hal, -NH 2, -OH, (=O) group substitution; each R twenty three, R twenty fourindependently -H; -(C 1-C 6) alkyl, which is unsubstituted or replaced by one or more selected from (=О), -ОH, -NR 25R 26The group substitution; -(C 2-C 6) alkenyl, which is unsubstituted or replaced by one or more selected from (=О), -NR 25aR 26agroup substitution; each R 25, R 26, R 25a, R 26aindependently -H, -(C 1-C 6)alkyl. In another embodiment, the present invention relates to compounds of formula I.1
Figure 02_image007
or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, where L 1is a chemical bond or -NH-; x 1is -CH-, -N- or -C(R 6)-; m is 0, 1, 2, 3 or 4; each R 1a. R 1b.R 1c.R 1d is independently -H; -Hal; -C(Hal) 3;-CN;-NR 7R 8;-C(O)NR 9R 10;-C(O)OR 11; -C(O)R 12;-OR 13;-(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R 14replace;-(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R 14areplace; R 2for-P(O)((C 1-C 6)alkyl) 2, unsubstituted or replaced by one or more groups R 15replace; -P(O)((C 3-C 6)cycloalkyl) 2, unsubstituted or replaced by one or more groups R 15areplace; -P(O)((C 1-C 6)alkyl))((C 3-C 6) cycloalkyl), unsubstituted or replaced by one or more groups R 15bReplace; -P(O)(О(C 1-C 6)alkyl) 2, unsubstituted or replaced by one or more groups R 15creplace; -P(O)(О(C 3-C 6)cycloalkyl) 2, unsubstituted or replaced by one or more groups R 15dReplace; -P(O)(О(C 1-C 6)Alkyl)(О(C 3-C 6) cycloalkyl), unsubstituted or replaced by one or more groups R 15eReplace; -SO 2(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R 15freplace; P(O)(О(C 1-C 6)alkyl)((C 3-C 6) cycloalkyl), unsubstituted or replaced by one or more groups R 15replace; -P(O)(О(C 1-C 6)alkyl)((C 1-C 6)alkyl), unsubstituted or replaced by one or more groups R 15Replace; -P(O)(О(C 3-C 6)cycloalkyl)((C 1-C 6)alkyl), unsubstituted or replaced by one or more groups R 15Replace; -P(O)(О(C 3-C 6)cycloalkyl)((C 3-C 6) cycloalkyl), unsubstituted or replaced by one or more groups R 15replace; or -SO 2(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R 15greplace; R 3-H; -Hal; -CN; -C(Hal) 3;-NR 7aR 8a; -C(O)NR 9aR 10a;-C(O)OR 11a;-C(O)R 12a;-OR 13a;-(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R 16a substitution; -(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R 16breplace;-(C 6-C 12) aryl, unsubstituted or replaced by one or more groups R 16CSubstituted; 4-10 membered heteroaryl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or replaced by one or more groups R 16dreplace; each R 4independently -H; -Hal; -CN; -NR 7bR 8b;-C(Hal) 3;-C(O)NR 9bR 10b;-C(O)OR 11b;-C(O)R 12b;-OR 13b;-(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R 17areplace;-(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R 17bSubstituted; 4-10 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or О, unsubstituted or replaced by one or more groups R 17creplace; or -(C 6-C 12) aryl, unsubstituted or replaced by one or more groups R 17dreplace; R 5for: -NR 7сR 18;-NR 7dR 19;-W 1;-OW 2;-NR aW 3; -C(O)W 4; or -(CH 2)W 5; where each W 1, W 2, W 3, W 4or W 5Independently for -(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R 20Substituted; 4-7 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or replaced by one or more groups R 20replace; R 6-Hal, -CN, -C(Hal) 3、CH(Hal) 2、CH 2Hal, -NR 7eR 8C;-(C 1-C 6) alkyl, which is unsubstituted or is selected from one or more of -Hal, -NH 2, -OH, (=O) group substitution; each R 7, R 7a, R 7b, R 7e, R 8, R 8a, R 8b, R 8C, R 9, R 9a, R 9b, R 10, R 10a, R 10bindependently -H, -(C 1-C 6) alkyl, which is unsubstituted or is selected from one or more of -Hal, -NH 2, -OH, (=O) group substitution; -(C 3-C 6) cycloalkyl, which is unsubstituted or replaced by one or more selected from -Hal, -NH 2, -OH, (=O) group substitution; each R 7c, R 7dindependently for -H, -(С 1-C 6)alkyl; R18 is -(С 1-C 10) alkyl, which is unsubstituted or substituted by one or more substituents selected from -Hal, -OH, -NO2, -NR23R24, (=O); R19 is a 2-10 membered heteroalkyl group with 1 or 2 heteroatoms selected from N, S or O, which is unsubstituted or replaced by one or more selected from -Hal, -OH, -NO2, -NR23R24, (=O) is substituted by a substituent; Each R11, R12, R13, R11a, R12a, R13a, R11 b, R12 b, R13 bindependently -H, -(C1-C6)alkyl, unsubstituted or substituted by one or more groups R21, -(C 3-C6) cycloalkyl, unsubstituted or substituted by one or more groups R21a, -(C 6-C 12) aryl, unsubstituted or replaced by one or more groups R 21bSubstituted, 4-10 membered heterocyclic group with 1 or 2 heteroatoms selected from N, S or О, unsubstituted or replaced by one or more groups R 21creplace; Each of R14, R14a, R15, R15a, R15, R15a, R15b, R15C, R15d, R15e, R15f, R15g, R16, R16a, R16 b, R16 C, R16 d, R17, R17 a, R17 b, R 17c, R17 dindependently for -Hal, -H, -OH, -NO2, -NR23R24, -(C1-C6) alkyl, which is unsubstituted or replaced by one or more selected from -Hal, -NH 2, -OH, (=O) group substitution; Each R20 is independently (=O), -NR 7fR 8d, -(C1-C6)alkyl, which is unsubstituted or substituted by one or more groups R22, -2-8 membered heteroalkyl with 1 or 2 heteroatoms selected from N, O or S, which is unsubstituted or replaced by one or more groups R 22areplace, (C 3-C6) cycloalkyl, unsubstituted or by one or more groups R 22bSubstituted, a 4-10 membered heterocyclic group having 1 or 2 heteroatoms selected from N, S or О, which is unsubstituted or replaced by one or more groups R 22replace; each R 7f, R 8dare independently -H, -(C1-C6) alkyl, which are unsubstituted or replaced by one or more selected from -Hal, -NH 2, -OH, (=O) group substitution; -(C 3-C6) cycloalkyl, which is unsubstituted or is selected from one or more -Hal, -NH 2, -OH, (=O) group substitution; Each R21, R21a, R 21b, R21с, R22, R 22a, R 22b, R 22are independently -Hal, -H, -OH, -NO2, -NR23R24, -(C1-C6) alkyl, which are unsubstituted or replaced by one or more selected from -Hal, -NH 2, -O(C1-C6)alkyl, -ОH, (=O) group substitution; Each R23, R24 is independently -H; -(C1-C6) alkyl, which is unsubstituted or substituted by one or more groups selected from (=О), -ОH, -NR25R26; -(C 2-C 6) alkenyl, which is unsubstituted or replaced by one or more selected from (=О), -NR 25aR 26agroup substitution; Each R25, R26, R 25a, R 26aindependently -H, -(C1-C6) alkyl; Hal is a fluorine, bromine, chlorine or iodine atom. In another embodiment, the present invention relates to compounds of formula I.2
Figure 02_image009
or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, Where L1 is a chemical bond or -NH-; X1 is -CH-, -N- or -C(R6)-; n is 0, 1, 2, 3 or 4; each R1 is independently -H; -Hal; -C(Hal)3; -CN; -NR7R8; -C(O)NR9R10; -C(O)OR11; -C(O)R12; -OR13; -(C1-C6) alkyl, unsubstituted or substituted by one or more groups R14; -(C 3-C6) cycloalkyl, unsubstituted or substituted by one or more groups R14a; R2 is -P(O)((C1-C6)alkyl) 2, unsubstituted or substituted by one or more groups R15; -P(O)((C 3-C6)cycloalkyl) 2, unsubstituted or substituted by one or more groups R15a; -P(O)((C1-C6)alkyl))((C 3-C6) cycloalkyl), unsubstituted or by one or more groups R 15breplace; -P(O)(О(C1-C6)alkyl) 2, unsubstituted or substituted by one or more groups R15C; -P(O)(О(C 3-C6)cycloalkyl) 2, unsubstituted or substituted by one or more groups R15d; -P(O)(О(C1-C6)alkyl)(О(C 3-C6) cycloalkyl), which is unsubstituted or substituted by one or more groups R15e; -SO 2(C1-C6) alkyl, which is unsubstituted or substituted by one or more groups R15f; -P(O)(О(C1-C6)alkyl)((C 3-C6)cycloalkyl), unsubstituted or substituted by one or more groups R15; -P(O)(О(C1-C6)alkyl)((C1-C6)alkyl), unsubstituted or substituted by One or more groups R15 are substituted; -P(O)(О(C 3-C6)cycloalkyl)((C1-C6)alkyl), unsubstituted or substituted by one or more groups R15; -P(O)(О(C 3-C6)cycloalkyl)((C 3-C6) cycloalkyl), unsubstituted or substituted by one or more groups R15; or -SO 2(C 3-C6) cycloalkyl, unsubstituted or substituted by one or more groups R15g; R3 is -H; -Hal; -CN; -C(Hal)3; -NR7 aR8 a; -C(O)NR 9aR10 a;-C(O)OR11 a;-C(O)R12 a;-OR13 a;-(C1-C6)alkyl, unsubstituted or substituted by one or more groups R16a;-(C 3-C6) cycloalkyl, unsubstituted or by one or more groups R16 breplace;-(C 6-C 12) aryl, unsubstituted or by one or more groups R16 CSubstituted; 4-10 membered heteroaryl with 1 or 2 heteroatoms selected from N, S or O, which is unsubstituted or replaced by one or more groups R16 dreplace; each R 4a. R 4b.R 4c.R 4d is independently -H; -Hal; -CN; -NR7 bR8 b;-C(Hal)3;-C(O)NR9 bR10 b;-C(O)OR11 b; -C(O)R12 b;-OR13 b;-(C1-C6)alkyl, unsubstituted or by one or more groups R17 areplace;-(C 3-C6) cycloalkyl, unsubstituted or by one or more groups R17 bSubstituted; a 4-10 membered heterocyclic group having 1 or 2 heteroatoms selected from N, S or О, which is unsubstituted or replaced by one or more groups R 17creplace; or -(C 6-C 12) aryl, which is unsubstituted or replaced by one or more groups R17 dreplace; R 5for: -NR7сR18; -NR7 dR19; -W1; -OW2; -NR aW3; -C(O)W4; or -(CH 2)W5; wherein each W1, W2, W3, W4 or W5 is independently -(C 3-C6) cycloalkyl, which is unsubstituted or substituted by one or more groups R20; 4-7 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, which is unsubstituted Or substituted by one or more groups R20; R6 is -Hal, -CN, -C(Hal)3, CH(Hal)2, CH 2Hal, -NR7 eR8 C; -(C1-C6) alkyl, which is unsubstituted or is selected from one or more of -Hal, -NH 2, -OH, (=O) group substitution; Each R7, R7 a, R7 b, R7 e, R8, R8 a, R8 b, R8 C, R9, R 9a, R9 b, R10, R10 a, R10 bare independently -H, -(C1-C6) alkyl, which are unsubstituted or replaced by one or more selected from -Hal, -NH 2, -OH, (=O) group substitution; -(C 3-C6) cycloalkyl, which is unsubstituted or replaced by one or more selected from -Hal, -NH 2, -OH, (=O) group substitution; per R7 c, R7 dindependently for -H, -(С 1-C 6)alkyl; R18 is -(С 1-C 10) alkyl, which is unsubstituted or substituted by one or more substituents selected from -Hal, -OH, -NO2, -NR23R24, (=O); R19 is a 2-10 membered heteroalkyl group with 1 or 2 heteroatoms selected from N, S or O, which is unsubstituted or replaced by one or more selected from -Hal, -OH, -NO2, -NR23R24, (=O), -(С 1-C 6) substituent substitution of an alkyl group; Each R11, R12, R13, R11a, R12a, R13a, R11 b, R12 b, R13 bindependently -H, -(C1-C6)alkyl, unsubstituted or substituted by one or more groups R21, -(C 3-C6) cycloalkyl, unsubstituted or substituted by one or more groups R21a, -(C 6-C 12) aryl, unsubstituted or replaced by one or more groups R 21bSubstituted, 4-10 membered heterocyclic group with 1 or 2 heteroatoms selected from N, S or О, unsubstituted or replaced by one or more groups R 21creplace; Each of R14, R14a, R15, R15a, R15, R15a, R15b, R15C, R15d, R15e, R15f, R15g, R16, R16a, R16 b, R16 C, R16 d, R17, R17 a, R17 b, R 17c, R17 dindependently for -Hal, -H, -OH, -NO2, -NR23R24, -(C1-C6) alkyl, which is unsubstituted or replaced by one or more selected from -Hal, -NH 2, -OH, (=O) group substitution; each R 20independently (=O), -NR 7fR 8d,-(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R twenty twoSubstituted, - 2-8 membered heteroalkyl with 1 or 2 heteroatoms selected from N, O or S, unsubstituted or replaced by one or more groups R 22areplace, -(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R 22bSubstituted, 4-10 membered heterocyclic group with 1 or 2 heteroatoms selected from N, S or О, unsubstituted or replaced by one or more groups R 22replace; each R 7f, R 8dindependently -H, -(C 1-C 6) alkyl, which is unsubstituted or is selected from one or more of -Hal, -NH 2, -OH, (=O) group substitution; -(C 3-C 6) cycloalkyl, which is unsubstituted or replaced by one or more selected from -Hal, -NH 2, -OH, (=O) group substitution; each R twenty one, R twenty onea. R 21b, R twenty oneс, R twenty two, R 22a, R 22b, R 22independently -Hal, -H, -OH, -NO 2, -NR twenty threeR twenty four,-(C 1-C 6) alkyl, which is unsubstituted or is selected from one or more of -Hal, -NH 2, -OH, -O(C 1-C 6) alkyl group, (=O) group substitution; each R twenty three, R twenty fourindependently -H; -(C 1-C 6) alkyl, which is unsubstituted or replaced by one or more selected from (=О), -ОH, -NR 25R 26The group substitution; -(C 2-C 6) alkenyl, which is unsubstituted or replaced by one or more selected from (=О), -NR 25aR 26agroup substitution; each R 25, R 26, R 25a, R 26aindependently -H, -(C 1-C 6)alkyl; Hal is a fluorine, bromine, chlorine or iodine atom. In another embodiment, the present invention relates to compounds of formula I.3
Figure 02_image011
or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, where L 1is the chemical bond -NH-; x 1For -СH-, -N-, -C(R 6)-; each R 1a. R 1b.R 1c.R 1d is independently -H; -Hal; -C(Hal) 3;-CN;-NR 7R 8;-C(O)NR 9R 10;-C(O)OR 11; -C(O)R 12;-OR 13;-(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R 14replace;-(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R 14areplace; R 2for-P(O)((C 1-C 6)alkyl) 2, unsubstituted or replaced by one or more groups R 15replace; -P(O)((C 3-C 6)cycloalkyl) 2, unsubstituted or replaced by one or more groups R 15areplace; -P(O)((C 1-C 6)alkyl))((C 3-C 6) cycloalkyl), unsubstituted or replaced by one or more groups R 15breplace; -P(O)(О(C 1-C 6)alkyl) 2, unsubstituted or replaced by one or more groups R 15cReplace; -P(O)(О(C 3-C 6)cycloalkyl) 2, unsubstituted or replaced by one or more groups R 15dReplace; -P(O)(О(C 1-C 6)Alkyl)(О(C 3-C 6) cycloalkyl), unsubstituted or replaced by one or more groups R 15eReplace; -SO 2(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R 15freplace; P(O)(О(C 1-C 6)alkyl)((C 3-C 6) cycloalkyl), unsubstituted or replaced by one or more groups R 15replace; -P(O)(О(C 1-C 6)alkyl)((C 1-C 6)alkyl), unsubstituted or replaced by one or more groups R 15Replace; -P(O)(О(C 3-C 6)cycloalkyl)((C 1-C 6)alkyl), unsubstituted or replaced by one or more groups R 15Replace; -P(O)(О(C 3-C 6)cycloalkyl)((C 3-C 6) cycloalkyl), unsubstituted or replaced by one or more groups R 15replace; or -SO 2(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R 15greplace; R 3-H; -Hal; -CN; -C(Hal) 3;-NR 7aR 8a; -C(O)NR 9aR 10a;-C(O)OR 11a;-C(O)R 12a;-OR 13a;-(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R 16a substitution; -(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R 16breplace;-(C 6-C 12) aryl, unsubstituted or replaced by one or more groups R 16CSubstituted; 4-10 membered heteroaryl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or replaced by one or more groups R 16dreplace; each R 4a. R 4b.R 4c.R 4d is independently -H; -Hal; -CN; -NR 7bR 8b;-C(Hal) 3;-C(O)NR 9bR 10b;-C(O)OR 11b; -C(O)R 12b;-OR 13b;-(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R 17areplace;-(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R 17bSubstituted; 4-10 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or О, unsubstituted or replaced by one or more groups R 17creplace; or -(C 6-C 12) aryl, unsubstituted or replaced by one or more groups R 17dreplace; R 5for: -NR 7сR 18;-NR 7dR 19;-W 1;-OW 2;-NR aW 3; -C(O)W 4; or -(CH 2)W 5; where each W 1, W 2, W 3, W 4or W 5Independently for -(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R 20Substituted; 4-7 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or replaced by one or more groups R 20replace; R 6-Hal, -CN, -C(Hal) 3、CH (Hal) 2、CH 2Hal, -NR 7eR 8C;-(C 1-C 6) alkyl, which is unsubstituted or is selected from one or more of -Hal, -NH 2, -OH, (=O) group substitution; each R 7, R 7a, R 7b, R 7e, R 8, R 8a, R 8b, R 8C, R 9, R 9a, R 9b, R 10, R 10a, R 10bindependently -H, -(C 1-C 6) alkyl, which is unsubstituted or is selected from one or more of -Hal, -NH 2, -OH, (=O) group substitution; -(C 3-C 6) cycloalkyl, which is unsubstituted or replaced by one or more selected from -Hal, -NH 2, -OH, (=O) group substitution; each R 7c, R 7dindependently for -H, -(С 1-C 6)alkyl; R 18for-(С 1-C 10) alkyl, which is unsubstituted or is selected from one or more of -Hal, -OH, -NO 2, -NR twenty threeR twenty four, (=O) substituent substitution; R 19is a 2-10 membered heteroalkyl group with 1 or 2 heteroatoms selected from N, S or O, which is unsubstituted or replaced by one or more selected from -Hal, -OH, -NO 2, -NR twenty threeR twenty four, (=O), -(С 1-C 6) substituent substitution of an alkyl group; each R 11, R 12, R 13, R 11a. R 12a. R 13a. R 11b, R 12b, R 13bindependently -H; -(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R twenty onereplace;-(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R twenty onea substitution; -(C 6-C 12) aryl, unsubstituted or replaced by one or more groups R 21bSubstituted, 4-10 membered heterocyclic group with 1 or 2 heteroatoms selected from N, S or О, unsubstituted or replaced by one or more groups R 21creplace; each R 14, R 14a, R 15, R 15a, R 15, R 15a, R 15b, R 15c, R 15d, R 15e, R 15f, R 15g, R 16, R 16a. R 16b, R 16C, R 16d, R 17, R 17a, R 17b, R 17c, R 17dindependently -Hal, -H, -OH, -NO 2, -NR twenty threeR twenty four,-(C 1-C 6) alkyl, which is unsubstituted or is selected from one or more of -Hal, -NH 2, -OH, (=O) group substitution; each R 20independently (=O), -NR 7fR 8d,-(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R twenty twoSubstituted, - 2-8 membered heteroalkyl with 1 or 2 heteroatoms selected from N, O or S, unsubstituted or replaced by one or more groups R 22areplace, -(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R 22bSubstituted, 4-10 membered heterocyclic group with 1 or 2 heteroatoms selected from N, S or О, unsubstituted or replaced by one or more groups R 22replace; each R 7f, R 8dindependently -H, -(C 1-C 6) alkyl, which is unsubstituted or is selected from one or more of -Hal, -NH 2, -OH, (=O) group substitution; -(C 3-C 6) cycloalkyl, which is unsubstituted or is selected from one or more -Hal, -NH 2, -OH, (=O) group substitution; each R twenty one, R twenty onea. R 21b, R twenty oneс, R twenty two, R 22a, R 22b, R 22independently -Hal, -H, -OH, -NO 2, -NR twenty threeR twenty four,-(C 1-C 6) alkyl, which is unsubstituted or is selected from one or more of -Hal, -NH 2, -OH, -O(C 1-C 6) alkyl group, (=O) group substitution; each R twenty three, R twenty fourindependently -H; -(C 1-C 6) alkyl, which is unsubstituted or replaced by one or more selected from (=О), -ОH, -NR 25R 26The group substitution; -(C 2-C 6) alkenyl, which is unsubstituted or replaced by one or more selected from (=О), -NR 25aR 26agroup substitution; each R 25, R 26, R 25a, R 26aindependently -H, -(C 1-C 6)alkyl; Hal is a fluorine, bromine, chlorine or iodine atom. In one embodiment, the invention relates to compounds of formula I, wherein R 6-Hal, -CN, -C(Hal) 3、CH(Hal) 2、CH 2Hal. In one embodiment, the invention relates to compounds of formula I, wherein R 6-Hal, -CN, -CF 3, CHF2, CHCl2, CHBr 2、CH 2F. In another embodiment, the present invention relates to compounds of formula I, wherein each R 1independently is Hal; -C(Hal) 3,-O(CHal3);-CN; -O(С 1-C 6) alkyl, -O(CH 2) 2O-(С 1-C 6)alkyl. In another embodiment, the present invention relates to compounds of formula I, wherein each R 1independently -F, -Cl, -Br, -CF 3、-CCl 3, -O(CF 3), -O(CCl 3), -OCH 3、-OCH 2CH 3, -O(CH 2) 2O-СH3, -O(CH 2) 2O-СH2-СH3. In another embodiment, the present invention relates to compounds of formula I, wherein R 2for-P(O)((C 1-C 6)alkyl) 2,-P(O)((C 3-C 6)cycloalkyl) 2, -P(O)((C 1-C 6)alkyl))((C 3-C 6)cycloalkyl)), -P(O)(O(C 1-C 6)alkyl) 2,-P(O)(O(C 3-C 6)cycloalkyl) 2, -P(O)(O(C 1-C 6)alkyl)((C 3-C 6)cycloalkyl), P(O)(O(C 1-C 6)alkyl)((C 1-C 6) alkyl), P(O)(O(C 3-C 6)cycloalkyl)((C 1-C 6) alkyl), P(O)(O(C 3-C 6)cycloalkyl)((C 3-C 6) cycloalkyl), -SO 2(C 1-C 6)alkyl. In one embodiment of the invention, R 2is-P(O)(CH 3) 2, P(O)(CH 2CH 3) 2、-P(O)(CH 3)(CH 2CH 3), -P(O)(cyclopropyl) 2, -P(O)(CH 3)(cyclopropyl), -P(O)(CH 2CH 3)(cyclopropyl), -P(O)(OCH 3) 2、-P(O)(OCH 2CH 3) 2, -P(O)(OCH 3)(OCH 2CH 3), -P(O)(OCH 3)(CH 3), -P(O)(OCH 3)(CH 2CH 3), -P(O)(OCH 2CH 3)(CH 3), -P(O)(OCH 2CH 3)(CH 2CH 3), -P(O)(OCH 3)(cyclopropyl), -P(O)(OСH2CH 3)(cyclopropyl), -SO 2CH 3, SO 2CH 2CH 3. In another embodiment, the invention relates to compounds of formula I, wherein R 3-H; -Hal; -С(Hal)3, -CN; -NR 7aR 8a;-C(O)NR 9aR 10a;-CO(O)R 11a;-C(O)R 12a;-OR 13a;-(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R 16a substitution; -(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R 16bSubstituted; phenyl, unsubstituted or by one or more groups R 16Creplace, where each R 7a, R 8a, R 9a, R 10aindependently -H, -(C 1-C 6) alkyl, which is unsubstituted or is selected from one or more of -Hal, -NH 2, -OH, (=O) group substitution; each R 11a. R 12a. R 13a is independently -H; -(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R twenty onereplace;-(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R twenty onea substituted; -(C6-C12) aryl, unsubstituted or substituted by one or more groups R21b; -(C 4-C 8) heterocyclyl having 1 or 2 heteroatoms selected from N, S or О, unsubstituted or replaced by one or more groups R 21creplace; each R 16a. R 16b, R 16C, R twenty one, R twenty onea.R 21b, R twenty oneс is independently -H, -OH, -NO 2, -NR twenty threeR twenty four,-(C 1-C 6) alkyl, which is unsubstituted or is selected from one or more of -Hal, -NH 2, -OH, (=O), -O(C 1-C 6) group substitution of an alkyl group; each R twenty three, R twenty fourindependently -H; -(C 1-C 6) alkyl, which is unsubstituted or replaced by one or more selected from (=О), -ОH, -NR 25R 26The group substitution; -(C 2-C 6) alkenyl, which is unsubstituted or replaced by one or more selected from (=О), -NR 25aR 26agroup substitution; each R 25, R 26, R 25a, R 26aindependently -H, -(C 1-C 6)alkyl; Hal is a fluorine, bromine, chlorine or iodine atom. In another embodiment, the invention relates to compounds of formula I, wherein R 3-H; -Hal; -С(Hal)3, -CN; -NR 7aR 8a;-C(O)NR 9aR 10a;-CO(O)R 11a;-C(O)R 12a;-OR 13a;-(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R 16a substitution; -(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R 16bSubstituted; phenyl, unsubstituted or by one or more groups R 16Creplace, where each R 7a, R 8a, R 9a, R 10aindependently -H, -(C 1-C 6) alkyl, which is unsubstituted or is selected from one or more of -Hal, -NH 2, -OH, (=O) group substitution; each R 11a. R 12a. R 13a is independently -H; -(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R twenty onereplace;-(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R twenty onea substituted; -(C6-C12) aryl, unsubstituted or substituted by one or more groups R21b; -(C 4-C 8) heterocyclyl having 1 or 2 heteroatoms selected from N, S or О, unsubstituted or replaced by one or more groups R 21creplace; each R 16a. R 16b, R 16C, R twenty one, R twenty onea. R 21b, R twenty oneс is independently -H, -OH, -NO 2, -NR twenty threeR twenty four,-(C 1-C 6) alkyl, which is unsubstituted or is selected from one or more of -Hal, -NH 2, -OH, (=O), -O(C 1-C 6) group substitution of an alkyl group; each R twenty three, R twenty fourindependently -H; -(C 1-C 6) alkyl, which is unsubstituted or replaced by one or more selected from (=О), -ОH, -NR 25R 26The group substitution; -(C 2-C 6) alkenyl, which is unsubstituted or replaced by one or more selected from (=О), -NR 25aR 26agroup substitution; each R 25, R 26, R 25a, R 26aindependently -H, -(C 1-C 6)alkyl; Hal is a fluorine, bromine, chlorine or iodine atom. In one embodiment of the invention, R 3is -CN; phenyl, which is unsubstituted or replaced by a group R 16CSubstituted, selected from prop-2-enylamino], 3-hydroxyacrylamide, 3-(dimethylamino)acrylamide, wherein R 16Cis -Hal, -H, -OH, -NO 2, -NR twenty threeR twenty four,-(C 1-C 6) alkyl, which is unsubstituted or is selected from one or more of -Hal, -NH 2, -OH, (=O) group substitution. In another embodiment, the invention relates to compounds of formula I, each R 4independently -H; -Hal; -C(Hal) 3;-CN;-NR 7bR 8b; -C(O)NR 9bR 10b;-C(O)R 11b;-C(O)OR 12b;-OR 13b; -(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R 17areplace, where each R 7b, R 8b, R 9b, R 10bindependently -H, -(C 1-C 6) alkyl, which is unsubstituted or is selected from one or more of -Hal, -NH 2, -OH, (=O) group substitution; each R 11b, R 12b, R 13bindependently -H; -(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R twenty onereplace;-(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R twenty onea substituted; -(C6-C12) aryl, unsubstituted or substituted by one or more groups R21b; -(C 4-C 8) heterocyclyl having 1 or 2 heteroatoms selected from N, S or О, unsubstituted or replaced by one or more groups R 21creplace; each R 17a, R twenty one, R 21a, R 21b, R twenty oneс independently -H, -OH, -NO 2, -Hal, -NR twenty threeR twenty four,-(C 1-C 6) alkyl, which is unsubstituted or is selected from one or more of -Hal, -NH 2, -OH, (=O), -O(C 1-C 6) group substitution of an alkyl group; each R twenty three, R twenty fourindependently -H; -(C 1-C 6) alkyl, which is unsubstituted or replaced by one or more selected from (=О), -ОH, -NR 25R 26The group substitution; -(C 2-C 6) alkenyl, which is unsubstituted or replaced by one or more selected from (=О), -NR 25aR 26agroup substitution; each R 25, R 26, R 25a, R 26aindependently -H, -(C 1-C 6)alkyl; Hal is a fluorine, bromine, chlorine or iodine atom. In another embodiment, the invention relates to compounds of formula I, each R 4independently -H; -Hal; -C(Hal) 3;-CN;-NR 7bR 8b; -C(O)NR 9bR 10b;-C(O)R 11b;-C(O)OR 12b;-OR 13b; -(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R 17areplace, where each R 7b, R 8b, R 9b, R 10bindependently -H, -(C 1-C 6) alkyl, which is unsubstituted or is selected from one or more of -Hal, -NH 2, -OH, (=O) group substitution; each R 11b, R 12b, R 13bindependently -H; -(C 1-C 6) alkyl, unsubstituted or replaced by one or more groups R twenty onereplace;-(C 3-C 6) cycloalkyl, unsubstituted or replaced by one or more groups R twenty onea substituted; -(C6-C12) aryl, unsubstituted or substituted by one or more groups R21b; -(C 4-C 8) heterocyclyl having 1 or 2 heteroatoms selected from N, S or О, unsubstituted or replaced by one or more groups R 21creplace; each R 17a, R twenty one, R twenty onea. R 21b, R twenty oneс is independently -H, -OH, -NO 2, -NR twenty threeR twenty four,-(C 1-C 6) alkyl, which is unsubstituted or is selected from one or more of -Hal, -NH 2, -OH, -O(C 1-C 6) alkyl group, (=O) group substitution; Each R23, R24 is independently -H; -(C1-C6) alkyl, which is unsubstituted or substituted by one or more groups selected from (=О), -ОH, -NR25R26; -(C 2-C 6) alkenyl, which is unsubstituted or replaced by one or more selected from (=О), -NR 25aR 26agroup substitution; Each R25, R26, R 25a, R 26aindependently -H, -(C1-C6)alkyl. In one embodiment of the invention, each R 4independently -H; -(C1-C6) alkyl, -O(C1-C6) alkyl, which is unsubstituted or replaced by one or more selected from -Hal, -OH, -NO2, -NH 2group substitution. In another embodiment, the invention relates to compounds of formula I, wherein R 5for: -NR7сR18; -NR7 dR19; -W1; -OW2; -NR aW3; -C(O)W4; or -(CH 2)W5; wherein each W1, W2, W3, W4 or W5 is independently Unsubstituted or substituted by one or more groups R20 - (C 3-C6) cycloalkyl, selected from
Figure 02_image013
A 5-7 membered heterocyclic group having 1 or 2 heteroatoms selected from N, S or О, which is unsubstituted or substituted by one or more groups R20, selected from
Figure 02_image015
Figure 02_image017
Figure 02_image019
Figure 02_image021
where р is 0, 1, 2 or 3; each Y 1, Y 2independently for CH 2, СHR20, C(R20)2, NH, NR20, S or O; per R7 c, R7 dR aindependently for -H, -(С 1-C 6)alkyl; R18 is -(С 1-C 10) alkyl, which is unsubstituted or substituted by one or more substituents selected from -Hal, -OH, -NO2, -NR23R24, (=O); R19 is a 2-10 membered heteroalkyl group with 1 or 2 heteroatoms selected from N, S or O, which is unsubstituted or replaced by one or more selected from -Hal, -OH, Substituents of -NO2, -NR23R24, (=O) are substituted; Each R20 is independently (=O), -NR 7fR 8d, -(C1-C6) alkyl, which is unsubstituted or substituted by one or more groups R22, -(C with 1 or 2 heteroatoms selected from N, O or S 2-C 6) heteroalkyl, which is unsubstituted or replaced by one or more groups R 22areplace, -(C 3-C6) cycloalkyl, which is unsubstituted or replaced by one or more groups R 22breplace, -(C 4-C 8) heterocyclyl having 1 or 2 heteroatoms selected from N, S or О, unsubstituted or replaced by one or more groups R 22replace; each R 7f, R 8dH independently, - (C1-C6) alkyl, it is unsubstituted or by one or more selected from -Hal, -NH 2, -OH, (=O) group substitution; Each R22, R 22a, R 22b, R 22are independently -H, -OH, -NO2, -NR23R24, -(C1-C6) alkyl, which are unsubstituted or replaced by one or more selected from -Hal, -NH 2, -OH, (=O) group substitution; Each R23, R24 is independently -H; -(C1-C6) alkyl, which is unsubstituted or substituted by one or more groups selected from (=О), -ОH, -NR25R26; -(C 2-C 6) alkenyl, which is unsubstituted or replaced by one or more selected from (=О), -NR 25aR 26agroup substitution; Each R25, R26, R 25a, R 26aindependently -H, -(C1-C6) alkyl; Hal is a fluorine, bromine, chlorine or iodine atom. In another embodiment, the invention relates to compounds of formula I, wherein R 5for: -NR7сR18; -NR7 dR19; -W1; -OW2; -NR aW3; -C(O)W4; or -(CH 2)W5; wherein each W1, W2, W3, W4 or W5 is independently Unsubstituted or substituted by one or more groups R20 -(C 3-C6) cycloalkyl, selected from
Figure 02_image023
Figure 02_image025
A 5-7 membered heterocyclic group having 1 or 2 heteroatoms selected from N, S or О, which is unsubstituted or substituted by one or more groups R20, selected from
Figure 02_image027
Figure 02_image029
Figure 02_image031
Figure 02_image033
Figure 02_image035
Figure 02_image037
Figure 02_image039
Wherein q is selected from 0, 1 or 2, and the total number of ring system substituents is selected from 0, 1, 2 or 3; each Y 1, Y 2independently for CH 2, СHR20, C(R20)2, NH, NR20, S or O; per R7 c, R7 dindependently for -H, -(С 1-C 6)alkyl; R18 is -(С 1-C 10) alkyl, which is unsubstituted or substituted by one or more substituents selected from -Hal, -OH, -NO2, -NR23R24, (=O); R19 is a 2-10 membered heteroalkyl group with 1 or 2 heteroatoms selected from N, S or O, which is unsubstituted or replaced by one or more selected from -Hal, -OH, Substituents of -NO2, -NR23R24, (=O) are substituted; Each R20 is independently (=O), -NR 7fR 8d, -(C1-C6) alkyl, which is unsubstituted or substituted by one or more groups R22, -(C with 1 or 2 heteroatoms selected from N, O or S 2-C 6) heteroalkyl, which is unsubstituted or replaced by one or more groups R 22areplace, -(C 3-C6) cycloalkyl, which is unsubstituted or replaced by one or more groups R 22breplace, -(C 4-C 8) heterocyclyl having 1 or 2 heteroatoms selected from N, S or О, unsubstituted or replaced by one or more groups R 22replace; each R 7f, R 8dare independently H, -(C1-C6) alkyl, which are unsubstituted or replaced by one or more selected from -Hal, -NH 2, -OH, (=O) group substitution; Each R22, R 22a, R 22b, R 22are independently -H, -OH, -NO2, -NR23R24, -(C1-C6) alkyl, which are unsubstituted or replaced by one or more selected from -Hal, -NH 2, -OH, (=O) group substitution; Each R23, R24 is independently -H; -(C1-C6) alkyl, which is unsubstituted or substituted by one or more groups selected from (=О), -ОH, -NR25R26; -(C 2-C 6) alkenyl, which is unsubstituted or replaced by one or more selected from (=О), -NR 25aR 26agroup substitution; Each R25, R26, R 25a, R 26aindependently -H, -(C1-C6)alkyl. In another embodiment, the invention relates to compounds of formula I, wherein R 5for: -NR7сR18; -NR7 dR19; -W1; -OW2; -NR aW3; -C(O)W4; or -(CH 2)W5; wherein each W1, W2, W3, W4 or W5 is independently
Figure 02_image041
Figure 02_image043
Figure 02_image045
Figure 02_image047
Figure 02_image049
in p is 0, 1, 2 or 3; per R7 c, R7 dindependently for -H, -(С 1-C 6)alkyl; R18 is -(С 1-C 10) alkyl, which is unsubstituted or substituted by one or more substituents selected from -Hal, -OH, -NO2, -NR23R24, (=O); R19 is a 2-10 membered heteroalkyl group with 1 or 2 heteroatoms selected from N, S or O, which is unsubstituted or replaced by one or more selected from -Hal, -OH, -NO2, -NR23R24, (=O) is substituted by a substituent; Each R20 is independently (=O), -NR 7fR 8d, -(C1-C6) alkyl, which is unsubstituted or substituted by one or more groups R22, -(C with 1 or 2 heteroatoms selected from N, O or S 2-C 6) heteroalkyl, which is unsubstituted or replaced by one or more groups R 22areplace, -(C 3-C6) cycloalkyl, which is unsubstituted or replaced by one or more groups R 22breplace, -(C 4-C 8) heterocyclyl having 1 or 2 heteroatoms selected from N, S or О, unsubstituted or replaced by one or more groups R 22replace; each R 7f, R 8d, R aare independently H, -(C1-C6) alkyl, which are unsubstituted or replaced by one or more selected from -Hal, -NH 2, -OH, (=O) group substitution; Each R22, R 22a, R 22b, R 22are independently -H, -OH, -NO2, -NR23R24, -(C1-C6) alkyl, which are unsubstituted or replaced by one or more selected from -Hal, -NH 2, -OH, (=O) group substitution; Each R23, R24 is independently -H; -(C1-C6) alkyl, which is unsubstituted or substituted by one or more groups selected from (=О), -ОH, -NR25R26; -(C 2-C 6) alkenyl, which is unsubstituted or replaced by one or more selected from (=О), -NR 25aR 26agroup substitution; Each R25, R26, R 25a, R 26aindependently -H, -(C1-C6) alkyl; Hal is a fluorine, bromine, chlorine or iodine atom. In another embodiment, the invention relates to compounds of formula I, wherein R 5for: -NR7сR18; -NR7 dR19; -W1; -OW2; -NR aW3; -C(O)W4; or -(CH 2)W5; wherein each W1, W2, W3, W4 or W5 is independently
Figure 02_image051
Figure 02_image053
Figure 02_image055
Figure 02_image057
Wherein q is selected from 0, 1 or 2, and the total number of ring system substituents is selected from 0, 1, 2 or 3; per R7 c, R7 dindependently for -H, -(С 1-C 6)alkyl; R18 is -(С 1-C 10) alkyl, which is unsubstituted or substituted by one or more substituents selected from -Hal, -OH, -NO2, -NR23R24, (=O); R19 is a 2-10 membered heteroalkyl group with 1 or 2 heteroatoms selected from N, S or O, which is unsubstituted or replaced by one or more selected from -Hal, -OH, -NO2, -NR23R24, (=O), -(С 1-C 6) substituent substitution of an alkyl group; Each R20 is independently (=O), -NR 7fR 8d, -(C1-C6) alkyl, which is unsubstituted or substituted by one or more groups R22, -(C with 1 or 2 heteroatoms selected from N, O or S 2-C 6) heteroalkyl, which is unsubstituted or replaced by one or more groups R 22areplace, -(C 3-C6) cycloalkyl, which is unsubstituted or replaced by one or more groups R 22breplace, -(C 4-C 8) heterocyclyl having 1 or 2 heteroatoms selected from N, S or О, unsubstituted or replaced by one or more groups R 22replace; each R 7f, R 8dare independently H, -(C1-C6) alkyl, which are unsubstituted or replaced by one or more selected from -Hal, -NH 2, -OH, (=O) group substitution; Each R22, R 22a, R 22b, R 22are independently -H, -OH, -NO2, -NR23R24, -(C1-C6) alkyl, which are unsubstituted or replaced by one or more selected from -Hal, -NH 2, -OH, (=O) group substitution; Each R23, R24 is independently -H; -(C1-C6) alkyl, which is unsubstituted or substituted by one or more groups selected from (=О), -ОH, -NR25R26; -(C 2-C 6) alkenyl, which is unsubstituted or replaced by one or more selected from (=О), -NR 25aR 26agroup substitution; Each R25, R26, R 25a, R 26aindependently -H, -(C1-C6)alkyl. In one embodiment of the invention, R 5yes [2-(Dimethylamino)ethyl](methyl)amino, 4-(4-methylpiperazin-1-yl)piperidin-1-yl, 4-methylpiperazine-1- Base, 4-(dimethylamino)piperidin-1-yl, 4-morpholin-1-yl, 4-methyl-1,4-diazepan-1-yl, 1-iso Propylpiperidin-4-yl, (1-methylpiperidin-4-yl)oxy, (1-methylpiperidin-3-yl)amino, (1-methylpiperidin-4-yl ) amino, methyl (1-methylpiperidin-4-yl) amino, (4-methylpiperazin-1-yl) ketone, (4-methylpiperazin-1-yl) methyl , (2-methyl-2-azabicyclo[2.2.1]heptane-5-yl)oxyl group, (1-methylpyrrolidin-3-yl)oxyl group, (1-methylpiperidine- 4-yl)oxy, 1-acetylpiperidin-1-yl, piperidin-1-yl, 1-(2-(dimethylamino)-2-oxoethyl)piperidine. The compounds described in the present invention may be and/or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to: acid addition salts, obtained by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc. or with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, Trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2 -Hydroxyethanedisulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4 '-Methylenebis-3-hydroxy-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthalene Formic acid, salicylic acid, stearic acid, muconic acid and other reactions. The corresponding counterions of pharmaceutically acceptable salts can be analyzed and identified using various methods including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectroscopy, mass spectrometry or any combination thereof. The salt is recovered by using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, evaporation of the solvent, or in the case of an aqueous solution, lyophilization. It should be understood that references to pharmaceutically acceptable salts include solvent addition or crystal forms thereof, especially solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvents and may be formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described in this patent may be conveniently prepared or formed in the methods described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the compounds and methods provided herein. The compounds described herein may be provided in a variety of forms including, but not limited to, amorphous, milled, and nanoparticulate forms. Furthermore, the compounds described in the present invention include crystalline forms, also known as polymorphs. Polymorphs include different crystal packing arrangements of the same elemental composition of a compound. Polymorphs generally have different X-ray diffraction patterns, infrared spectra, melting points, different densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Various factors such as recrystallization solvent, crystallization rate, and storage temperature can cause one crystalline form to predominate. Screening and characterization of pharmaceutically acceptable salts, polymorphs and/or solvates can be accomplished using a variety of techniques including, but not limited to, thermal analysis, X-ray diffraction, spectroscopy, vapor adsorption and microscopy. Thermal analysis methods are devoted to the analysis of thermochemical degradation or thermophysical processes, including but not limited to polymorphic transitions, and such methods are used to analyze the relationship between polymorphic forms, to determine weight loss, to find the glass transition temperature , or for excipient compatibility studies. These methods include, but are not limited to, differential scanning calorimetry (DSC), modulated differential scanning calorimetry (MDCS), thermogravimetric analysis (TGA), thermogravimetric and infrared analysis (TG/IR). Crystallization methods include, but are not limited to, single crystal and powder diffractometers and synchrotron sources. The various spectroscopic techniques used include, but are not limited to, Raman (combined scattering), FTIR, UVIS, and NMR (liquid and solid state). Various microscopy techniques include, but are not limited to, polarized light microscopy, scanning electron microscopy (SEM) with energy dispersive X-ray analysis (EDX), environmental scanning electron microscopy with EDX (in a gas or water vapor atmosphere), IR microscopy, and Raman microscope. In another embodiment of the present invention relates to a compound selected from the group consisting of: coding structure name EGFR_48
Figure 02_image059
 (2-((2-(4-((2-(Dimethylamino)ethyl)(methyl)amino)phenyl)-1 H -pyrrolo[2,3- b ]pyridine-4 -yl)amino)phenyl)dimethylphosphine oxide formate EGFR_58
Figure 02_image061
 (2-((2-(4-((2-(Dimethylamino)ethyl)(methyl)amino)phenyl-1 H -pyrrolo[2,3- b ]pyridine-4- base) amino) -4-fluorophenyl) dimethyl phosphine oxide formate EGFR_59
Figure 02_image063
 (2-((2-(4-((2-(Dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)-1 H -pyrrolo[2,3 -b ]pyridin-4-yl)amino)phenyl)dimethylphosphine oxide acetate EGFR_60
Figure 02_image065
 (2-((2-(4-((2-(Dimethylamino)ethyl)(methyl)amino)-3-methoxyphenyl)-1 H -pyrrolo[2,3 -b ]pyridin-4-yl)amino)phenyl)dimethylphosphine oxide acetate EGFR_65
Figure 02_image067
 (2-((2-(4-((2-(Dimethylamino)ethyl)(methyl)amino)phenyl-1 H -pyrrolo[2,3- b ]pyridine-4- base) amino)-5-fluorophenyl) dimethylphosphine oxide acetate EGFR_66
Figure 02_image069
 (2-((2-(4-((2-(Dimethylamino)ethyl)(methyl)amino)phenyl-1 H -pyrrolo[2,3- b ]pyridine-4- base) amino) -6-fluorophenyl) dimethyl phosphine oxide formate EGFR_68
Figure 02_image071
 (2-((2-(4-((2-(Dimethylamino)ethyl)(methyl)amino)phenyl-1 H -pyrrolo[2,3- b ]pyridine-4- base)amino)-4-(trifluoromethyl)phenyl)dimethylphosphine oxide EGFR_69
Figure 02_image073
 (2-((6-(4-((2-(Dimethylamino)ethyl)(methyl)amino)phenyl- 7H -pyrrolo[2,3- d ]pyrimidine-4- base) amino) phenyl) dimethyl phosphine oxide EGFR_70
Figure 02_image075
 2-((5-chloro-2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)-1 H -pyrrolo[2,3- b ] Pyridin-4-yl)amino)phenyl)dimethylphosphine oxide formate EGFR_74
Figure 02_image077
 (2-((2-(4-((2-(Dimethylamino)ethyl)(methyl)amino)phenyl)-1 H -pyrrolo[2,3- b ]pyridine-4 -yl)amino)phenyl)diethylphosphine oxide EGFR_76
Figure 02_image079
 (2-((2-(4-((2-(Dimethylamino)ethyl)(methyl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridine-4- base) amino) phenyl) dimethyl phosphonate EGFR_79
Figure 02_image081
 N -(2-((2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)-1 H -pyrrolo[2,3- b ]pyrimidine -4-yl)amino)phenyl)methanesulfonamide formate EGFR_338
Figure 02_image083
 2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl-4-((2-dimethylphosphoryl)phenyl)amino)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile EGFR_348
Figure 02_image085
 (4-fluoro-2-((2-(4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-1 H -pyrrolo[2,3- b ] pyridin-4-yl) amino) phenyl) dimethyl phosphine oxide formate EGFR_437
Figure 02_image087
 (2-((6-(4-((2-(Dimethylamino)ethyl)(methyl)amino)phenyl)-7 H -pyrrolo[2,3- d ]pyrimidine-4 -Fluorophenyl) dimethylphosphine oxide acetate EGFR_440
Figure 02_image089
 Dimethyl(2-((6-(4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) -7H -pyrrolo[2,3- d ]pyrimidin-4-yl)amino)phenyl)phosphine oxide EGFR_441
Figure 02_image091
 (4-fluoro-6-((6-(4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-7 H -pyrrolo[2,3- d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide EGFR_483
Figure 02_image093
 (2-fluoro-6-((6-(4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-7 H -pyrrolo[2,3- d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide EGFR_485
Figure 02_image095
 (2-((5-chloro-2-(4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-1 H -pyrrolo[2,3- b ] pyridin-4-yl) phenyl) dimethyl phosphine oxide EGFR_655
Figure 02_image097
 Dimethyl(2-((2-(3-(4-methylpiperazin-1-yl)phenyl)-1 H -pyrrolo[2,3- b ]pyridin-4-yl)amino) Phenyl)phosphine oxide acetate EGFR_656
Figure 02_image099
 Dimethyl(2-((2-(4-morpholinophenyl) -1H -pyrrolo[2,3- b ]pyridin-4-yl)amino)phenyl)phosphine oxide formate EGFR_667
Figure 02_image101
 Dimethyl(2-((2-(4-(4-methylpiperazin-1-yl)phenyl)-1 H -pyrrolo[2,3- b ]pyridin-4-yl)amino) Phenyl)phosphine oxide formate EGFR_668
Figure 02_image103
 Dimethyl(2-((2-(4-(4-methyl-1,4-diazepan-1-yl)phenyl)-1 H -pyrrolo[2,3- b ] Pyridin-4-yl)amino)phenyl)phosphine oxide formate EGFR_669
Figure 02_image105
 (2-((2-(4-((1-isopropylpiperidin-4-yl)amino)phenyl)-1 H -pyrrolo[2,3-b]pyridin-4-yl)amine base) phenyl) dimethylphosphine oxide acetate EGFR_743
Figure 02_image107
 (2-((2-(4-(4-(Dimethylamino)piperidin-1-yl)phenyl)-1 H -pyrrolo[2,3- b ]pyridin-4-yl)amine base) phenyl) dimethylphosphine oxide acetate EGFR_752
Figure 02_image109
 Dimethyl(2-((2-(4-(1-methylpiperidin-4-yl)oxy)phenyl)-1 H -pyrrolo[2,3- b ]pyridin-4-yl) Amino)phenyl)phosphine oxide formate EGFR_774
Figure 02_image111
 (2-((2-(4-(2-(dimethylamino)ethyl(methyl)amino)phenyl)-1 H -pyrrolo[2,3- b ]pyridin-4-yl )amino)phenyl)diethylphosphine oxide formate EGFR_795
Figure 02_image113
 Dimethyl(2-((2-(4-(1-methylpiperidin-4-yl)amino)phenyl)-1 H -pyrrolo[2,3- b ]pyridin-4-yl) Amino)phenyl)phosphine oxide acetate EGFR_796
Figure 02_image115
 Dimethyl(2-((2-(4-(methyl(1-methylpiperidin-4-yl)amino)phenyl)-1 H -pyrrolo[2,3- b ]pyridine-4 -yl)amino)phenyl)phosphine oxide formate EGFR_797
Figure 02_image117
 (4-(4-((2-(Dimethylphosphoryl)phenyl)amino)-1 H -pyrrolo[2,3- b ]pyridin-2-yl)phenyl)(4-methyl Piperazin-1-yl)methanone formate EGFR_798
Figure 02_image119
 Dimethyl(2-((2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1 H -pyrrolo[2,3- b ]pyridin-4-yl )amino)phenyl)phosphine oxide formate EGFR_801
Figure 02_image121
 ( S )-Dimethyl(2-((2-(4-((1-methylpiperidin-3-yl)amino)phenyl)-1 H -pyrrolo[2,3- b ]pyridine -4-yl)amino)phenyl)phosphine oxide acetate EGFR_802
Figure 02_image123
 ( R )-Dimethyl(2-((2-(4-((1-methylpiperidin-3-yl)amino)phenyl)-1 H -pyrrolo[2,3- b ]pyridine -4-yl)amino)phenyl)phosphine oxide acetate EGFR_853
Figure 02_image125
 (2-Chloro-6-((2-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)-1 H -pyrrolo[2,3- b ]pyridine-4 -yl)amino)phenyl)dimethylphosphine oxide formate EGFR_854
Figure 02_image127
 (2-((2-(4-(4-(Dimethylamino)piperidin-1-yl)phenyl)-1 H -pyrrolo[2,3- b ]pyridin-4-yl)amine base)-6-(trifluoromethyl)phenyl)dimethylphosphine oxide formate EGFR_855
Figure 02_image129
 (6-((2-(4-(4-(Dimethylamino)piperidin-1-yl)phenyl)-1 H -pyrrolo[2,3- b ]pyridin-4-yl)amine base)-2,3-difluorophenyl) dimethylphosphine oxide EGFR_856
Figure 02_image131
 (2-((2-(4-(4-(Dimethylamino)piperidin-1-yl)phenyl)-1 H -pyrrolo[2,3- b ]pyridin-4-yl)amine base)-4-methoxyphenyl) dimethylphosphine oxide acetate EGFR_857
Figure 02_image133
 (2-((2-(4-(4-(Dimethylamino)piperidin-1-yl)phenyl)-1 H -pyrrolo[2,3- b ]pyridin-4-yl)amine base)-4-(trifluoromethoxy)phenyl)dimethylphosphine oxide acetate EGFR_858
Figure 02_image135
 (2-((2-(4-(4-(Dimethylamino)piperidin-1-yl)phenyl)-1 H -pyrrolo[2,3- b ]pyridin-4-yl)amine base)-4,6-difluorophenyl) dimethylphosphine oxide acetate EGFR_859
Figure 02_image137
 2-((2-(4-(4-(Dimethylamino)piperidin-1-yl)phenyl)-1 H -pyrrolo[2,3- b ]pyridin-4-yl)amino )-4-fluorophenyl)dimethylphosphine oxide EGFR_860
Figure 02_image139
 4-((2-(4-(4-(Dimethylamino)piperidin-1-yl)phenyl)-1 H -pyrrolo[2,3- b ]pyridin-4-yl)amino )-3-(Dimethylphosphoryl)benzonitrile formate EGFR_862
Figure 02_image141
 (2-((2-(4-(4-(Dimethylamino)piperidin-1-yl)phenyl)-1 H -pyrrolo[2,3- b ]pyridin-4-yl)amine base)-6-fluorophenyl) dimethylphosphine oxide EGFR_865
Figure 02_image143
 (2-((2-(4-(4-(Dimethylamino)piperidin-1-yl)phenyl)-5-fluoro-1 H -pyrrolo[2,3- b ]pyridine-4 -yl)amino)phenyl)dimethylphosphine oxide formate EGFR_870
Figure 02_image145
 (2-((2-(4-(4-(Dimethylamino)piperidin-1-yl)phenyl)-1 H -pyrrolo[2,3- b ]pyridin-4-yl)amine base)-5-methoxyphenyl)dimethylphosphine oxide formate EGFR_871
Figure 02_image147
 (2-((2-(4-(4-(Dimethylamino)piperidin-1-yl)phenyl)-1 H -pyrrolo[2,3- b ]pyridin-4-yl)amine base) phenyl) diethylphosphine oxide acetate EGFR_884
Figure 02_image149
 (2-((2-(4-(4-(Dimethylamino)piperidin-1-yl)-2-(trifluoromethoxy)phenyl)-1 H -pyrrolo[2,3 -b ]pyridin-4-yl)amino)phenyl)dimethylphosphine oxide acetate EGFR_886
Figure 02_image151
 (2-((2-(4-(4-(Dimethylamino)piperidin-1-yl)-2-methylphenyl)-1 H -pyrrolo[2,3- b ]pyridine- 4-yl)amino)phenyl)dimethylphosphine oxide acetate EGFR_887
Figure 02_image153
 2-((2-(4-(4-(Dimethylamino)piperidin-1-yl)-3-methylphenyl)-1 H -pyrrolo[2,3- b ]pyridine-4 -yl)amino)phenyl)dimethylphosphine oxide acetate EGFR_896
Figure 02_image155
 (2-((2-(4-(4-(Dimethylamino)piperidin-1-yl)phenyl)-1 H -pyrrolo[2,3- b ]pyridin-4-yl)amine base)-6-methoxyphenyl) dimethylphosphine oxide acetate EGFR_910
Figure 02_image157
 Diethyl(2-((2-(4-((methyl(1-methylpiperidin-4-yl)amino)phenyl)-1 H -pyrrolo[2,3- b ]pyridine- 4-yl)amino)phenyl)phosphine oxide acetate EGFR_912
Figure 02_image159
 Diethyl(2-((2-(4-((1-methylpiperidin-4-yl)oxy)phenyl)-1 H -pyrrolo[2,3- b ]pyridin-4-yl )amino)phenyl)phosphine oxide acetate EGFR_914
Figure 02_image161
 (2-((2-(4-(4-(Dimethylamino)piperidin-1-yl)phenyl)-5-methyl-1 H -pyrrolo[2,3- b ]pyridine- 4-yl)amino)phenyl)dimethylphosphine oxide EGFR_918
Figure 02_image163
 (2-methoxy-6-((2-(4-((1-methylpiperidin-4-yl)oxy)phenyl)-1 H -pyrrolo[2,3- b ]pyridine- 4-yl)amino)phenyl)dimethylphosphine oxide EGFR_919
Figure 02_image165
 (2-fluoro-6-((2-(4-((1-methylpiperidin-4-yl)oxy)phenyl)-1 H -pyrrolo[2,3- b ]pyridine-4- base) amino) phenyl) dimethyl phosphine oxide formate EGFR_989
Figure 02_image167
 ( R )-(2-methoxy-6-((2-(4-((1-methylpyrrolidin-3-yl)oxy)phenyl)-1 H -pyrrolo[2,3- b ] pyridin-4-yl) amino) phenyl) dimethylphosphine oxide EGFR_990
Figure 02_image169
 ( S )-(2-methoxy-6-((2-(4-((1-methylpyrrolidin-3-yl)oxy)phenyl)-1 H -pyrrolo[2,3- b ] pyridin-4-yl) amino) phenyl) dimethylphosphine oxide EGFR_982
Figure 02_image171
 Dicyclopropyl(2-methoxy-6-((2-(4-((1-methylpiperidin-4-yl)oxy)phenyl)-1 H -pyrrolo[2,3- b ] pyridin-4-yl) amino) phenyl) dimethylphosphine oxide EGFR_985
Figure 02_image173
 (2-methoxy-6-((2-(4-((2-methyl-2-azabicyclo[2.2.1]heptane-5-yl)oxy)phenyl)-1 H - pyrrolo[2,3- b ]pyridin-4-yl)amino)phenyl)dimethylphosphine oxide EGFR_993
Figure 02_image175
 1-(4-(4-(4-((2-(Dimethylphosphoryl)-3-methoxyphenyl)amino)-1 H -pyrrolo[2,3- b ]pyridine- 2-yl)phenoxy)piperidin-1-yl)ethan-1-one EGFR_994
Figure 02_image177
 2-(4-(4-(4-((2-(Dimethylphosphoryl)-3-methoxyphenyl)amino)-1 H -pyrrolo[2,3- b ]pyridine- 2-yl)phenoxy)piperidin-1-yl) -N , N -dimethylacetamide EGFR_1006
Figure 02_image179
 (2-methoxymethoxy-6-((2-(4-((1-methylpiperidin-4-yl)oxy)phenyl)-1 H -pyrrolo[2,3- b ]pyridin-4-yl)amino)phenyl)dimethylphosphine oxide acetate The invention also relates to a method of inhibiting the biological activity of epidermal growth factor receptor (EGFR) in a subject comprising contacting the EGFR kinase domain with a compound described herein. EGFR inhibiting compounds may be used in the preparation of pharmaceutical products for the treatment of any of the pathological conditions described herein, for example, compounds of formula I, pharmaceutically acceptable salts, solvates or stereoisomers will be useful in the treatment of mediated disease or medical condition, such as neoplastic disease. Examples of neoplastic diseases that can be treated using the above compounds include, but are not limited to, bladder cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, melanoma, prostate cancer , leukemia, lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, lung cancer (eg, non-small cell lung cancer), hepatocellular carcinoma, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, thyroid cancer, cholangiocarcinoma, Endometrial cancer, renal cancer, liver cancer, anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma, hematologic malignancies. In one embodiment, the present invention relates to a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, and one or more pharmaceutically acceptable excipients . In one embodiment, the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of at least one compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, and one or more pharmaceutically acceptable excipients. In another embodiment, a pharmaceutical composition comprising a compound of the invention is used for the prevention or treatment of a disease or condition mediated by EGFR activation. In another embodiment, the pharmaceutical composition comprising the compound of the present invention is used for preventing or treating diseases mediated by EGFR initiation with L858R mutation and/or T790M mutation and/or exon 19 deletion and/or C797S mutation or disease. In another embodiment of the present invention, the pharmaceutical composition comprising the compound of the present invention is used for the prevention or treatment of neoplastic diseases, including bladder cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, head and neck cancer, colloid tumor, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, lung cancer (eg, non-small cell lung cancer), hepatocellular carcinoma, esophageal cancer, gastric cancer , gastrointestinal stromal tumor, thyroid cancer, cholangiocarcinoma, endometrial cancer, kidney cancer, liver cancer, anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma, hematologic malignancies tumor. In another embodiment of the present invention, the pharmaceutical composition comprising the compound of the present invention is intended to prevent or treat a neoplastic disease, wherein said neoplastic disease is non-small cell lung cancer. The pharmaceutical composition of the present invention comprises, for example, about 5% to about 100% by weight of the active ingredient, preferably about 10% by weight to about 60% by weight of the active ingredient. It is to be understood that each dosage unit may contain no effective amount of one or more active ingredients, since a sufficient effective amount may be achieved by administering multiple dosage unit forms. Typical compositions are prepared by admixing a compound of the invention with a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like. The particular carrier, diluent or excipient used will depend on the manner and purpose for which the compound of the invention is to be used. Solvents are generally selected based on solvents considered safe for administration to mammals by those skilled in the art. Generally, safe solvents are aqueous solvents, such as water and other water-soluble or water-miscible solvents. Suitable aqueous solvents include water (as the main ingredient), ethanol, propylene glycol, polyethylene glycol (eg, PEG400, PEG300), etc., and mixtures thereof. The composition may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants , sweeteners, flavoring agents, flavoring agents and other known additives to provide an elegant appearance of the drug product (ie, the compound of the present invention or a pharmaceutical composition thereof) or to contribute to the appearance of the drug product (ie, the drug product) manufacture. The pharmaceutical composition should preferably be produced according to GMP (Good Manufacturing Practice) requirements. Pharmaceutical compositions also include solvates and hydrates of the compounds of the invention, or stabilized forms of the compounds (eg, complexes with cyclodextrin derivatives or other known complexing agents). The pharmaceutical compositions of the present invention may be formulated for oral administration. Oral administration can include swallowing, allowing the compound to enter the gastrointestinal tract, and/or buccal, lingual, or sublingual administration, whereby the compound enters the bloodstream directly from the mouth. Formulations suitable for oral administration include solid, semi-solid and liquid systems such as tablets; soft or hard capsules containing multiparticulate or nanoparticulate, liquid or powder; granules; lozenges (including liquid-filled); chewables gels; rapidly dispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesive patches. More preferred oral formulations include tablets, granules and capsules. Liquid preparations include suspensions, solutions, syrups and elixirs. Such formulations may be used as fillers in soft or hard capsules (made, for example, of gelatin or hydroxypropylmethylcellulose), and generally contain carriers such as water, ethanol, polyethylene glycol, propylene glycol, methyl Cellulose or a suitable oil, and one or more emulsifying and/or suspending agents. Liquid preparations can also be prepared by reconstitution of solids, eg, from sachets. The pharmaceutical compositions of the present invention can also be administered parenterally. As used herein, "parenteral administration" of a pharmaceutical composition includes any route of administration characterized by physical disruption of a subject's tissue and administration of the pharmaceutical composition through an opening in the tissue, thus typically resulting in direct administration into the bloodstream, muscle or internal organs. Thus, parenteral administration includes, inter alia, administration of the pharmaceutical composition by injection of the composition, administration of the composition through a surgical incision, administration of the composition by tissue penetration into a non-surgical wound, and the like. In particular, parenteral administration includes, inter alia, subcutaneous, intraperitoneal, intramuscular, intravenous, intraarterial, intrathecal, intraventricular, intraurethral, intracranial, intrasynovial injection or infusion; and renal dialysis infusion techniques . Intratumoral delivery, eg, intratumoral injection, may also be advantageous. Regional perfusion was also considered. Formulations of pharmaceutical compositions suitable for parenteral administration generally comprise the active ingredient in combination with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged or sold in a form suitable for bolus administration or continuous administration. Injectable formulations can be prepared, packaged, or sold in unit dosage form, eg, in ampoules or in multi-dose containers, with a preservative. Formulations for parenteral administration include suspensions, solutions, emulsions in oily or aqueous vehicles, pastes and the like, among others. The compounds of the invention can also be administered intranasally or by inhalation, usually in dry powder form (alone, as a mixture or as granules of mixed components, e.g. mixed with a suitable pharmaceutically acceptable excipient) from a dry powder inhaler, as Aerosol pressurized container, pump, spray, nebulizer (preferably one using electrohydrodynamically generated fine mist) or nebuliser (with or without a suitable propellant) or administered as nasal drops . Pressurized containers, pumps, nebulizers, nebulizers or nebulizers usually contain solutions or suspensions of the compounds of the invention comprising, for example, suitable agents for dispersing, solubilizing or prolonging the release of the active ingredient, as solvent propellants agent. Drug products are typically micronized to a size suitable for delivery by inhalation (typically less than 5 microns) prior to use as a dry powder or suspension. This can be achieved by any suitable comminution method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization or spray drying. Capsules, blisters and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of the compound of the invention, a suitable powder base and a property modifier. A suitable solution formulation for a nebulizer using electrohydrodynamics to generate a fine mist may contain a suitable dose of a compound of the invention per actuation, and the actuation volume may be, for example, 1 μL to 100 μL. Suitable flavoring agents, such as menthol and levomenthol, or sweetening agents, such as saccharin or sodium saccharin, may be added to those formulations of the invention intended for inhaled/intranasal administration. Formulations can be formulated to be immediate and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release. In one embodiment, the invention is directed to a method of treating a disease or condition mediated by EGFR activity comprising administering to a subject in need of such treatment any of the compounds described above or a pharmaceutical composition of the invention in a therapeutically effective amount. In another embodiment, the present invention relates to a method for treating the above-mentioned diseases or disorders, wherein said diseases or disorders are EGFR activity mediators with L858R mutation and/or T790M mutation and/or exon 19 deletion and/or C797S mutation leading diseases or conditions. In another embodiment, the present invention relates to a method of treating the aforementioned diseases, wherein the disease or condition mediated by EGFR activity is an oncological disease. In another embodiment, the present invention relates to a method of treating the above diseases, wherein said neoplastic disease is selected from bladder cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma Cell tumors, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, lung cancer (eg, non-small cell lung cancer), hepatocellular carcinoma, esophageal cancer, gastric cancer, gastrointestinal stromal cancer tumor, thyroid cancer, bile duct cancer, endometrial cancer, renal cancer, liver cancer, anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma, hematologic malignancies. In another embodiment, the present invention relates to a method for the treatment of the aforementioned cancer, wherein said cancer is non-small cell lung cancer. In one embodiment, the present invention relates to the use of a compound of the present invention or a pharmaceutical composition as described above for the treatment of a disease or condition mediated by EGFR activity in a subject in need of such treatment. In another embodiment, the present invention relates to the above use, wherein said disease or disorder is a disease or disorder mediated by EGFR activity with L858R mutation and/or T790M mutation and/or exon 19 deletion and/or C797S mutation . In another embodiment, the present invention relates to the above use, wherein the disease or condition mediated by EGFR activity is a neoplastic disease. In another embodiment, the present invention relates to the above use, wherein said neoplastic disease is selected from bladder cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, Melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, lung cancer (eg, non-small cell lung cancer), hepatocellular carcinoma, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, thyroid Carcinoma, bile duct cancer, endometrial cancer, kidney cancer, liver cancer, anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma, hematologic malignancies. In another embodiment, the present invention relates to the above use, wherein said neoplastic disease is non-small cell lung cancer. The compounds of the invention may be administered alone or in combination with one or more other pharmaceutical products or antibodies (or in any combination thereof). Accordingly, the pharmaceutical compositions, methods and uses of the present invention also include embodiments in combination (co-administration) with other active agents. As used herein, the terms "co-administration", "co-administration" and "in combination with" refer to a compound together with one or more other therapeutic agents and are intended to mean and do mean and include the following: When such combinations of a compound of the invention and a therapeutic agent are formulated together in a single dosage form that releases said components to said patient substantially simultaneously, the combination is administered simultaneously to a patient in need of treatment when the compound of the invention and the therapeutic agent are combined. When such a combination of the present invention is formulated separately from each other in separate dosage forms to be administered by said patient substantially simultaneously, such combination is administered simultaneously to the patient in need of treatment such that said components are released to said patient substantially simultaneously, when the present When such combinations of an inventive compound and therapeutic agent are formulated separately from each other in separate dosage forms, such combinations are sequentially administered to a patient in need of treatment, said dosage forms being taken by said patient at consecutive times with intervals between each administration. a significant time interval whereby the components are released to the patient at substantially different times; In a dosage form, the combination is administered sequentially to a patient in need of treatment, wherein said components are released to said patient simultaneously, sequentially and/or overlappingly at the same and/or different times, wherein the individual parts may be administered by the same or different routes. When pharmaceutical products are used in combination therapy, the therapeutically effective dosage may vary, as is well known to those skilled in the art. Methods for experimentally determining therapeutically effective doses of drug products and other agents for combination therapy regimens have been described in the literature. For example, the use of metronomic dosing has been described in the literature, ie, more frequent lower doses are given to minimize toxic side effects. Combination therapy also includes periodic therapy that starts and stops at different times according to the patient's treatment plan. For the combination therapies described in this patent, dosages of the co-administered compounds will of course vary depending on the type of co-drug employed, the particular drug employed, the condition or disorder being treated, and the like. The above-mentioned antitumor treatment can be used as an independent therapy, or used in combination with surgery, or radiation therapy, or drug therapy. Such treatment may be administered simultaneously, sequentially or separately from treatment with the compounds of the present invention and may include one or more of the following classes of antineoplastic agents: antiproliferative/antineoplastic agents used in medical oncology and combinations thereof such as alkylating agents (eg, cisplatin, oxaliplatin, carboplatin, cyclophosphamide, chlormethazine, melphalan, chlorambucil, busulfan, trosulfan, temozolomide, bendamustine, Pidine, spiroammonium bromide, prednisone nitrogen mustard, estramustine, pafungin, lofenarol, ifosfamide, mafosfamide, trofosfamide, glufosfamine, and nitrosoureas, including carmomin, lomustine, nimustine, fomustine, alabi, streptozocin); antimetabolites (such as gemcitabine, fluorouracil, floxuridine, tegafur, raltitrexed, Methotrexate, trimetrexate, pemetrexed, pralatrexate, levofolinate, cytarabine, hydroxyurea, azathioprine, cladribine, fludarabine, pentostatin, Mercaptopurine, nelarabine, thioguanine, fupurine, azacitidine, capecitabine, fludarabine, cladribine, nelarabine, azathioprine, clofarabine, cytarabine, Enoxabine, Camofur, Gemcitabine, Sacitabine, Eratabine, Doxiridine); antineoplastic antibiotics (such as bleomycin, doxorubicin, daunorubicin, epirubicin, Idarubicin, mitomycin, dactinomycin, photopenicillin, erythromycin, carrubicin, epirubicin, valrubicin, zorubicin, aclarubicin, pirarubicin , nemorubicin, amrubicin, carcinstatin, streptozotocin, mitoxantrone); antimitotic agents (eg, vinca alkaloids such as vincristine, vinblastine, vinflunine , vindesine and vinorelbine, taxanes such as paclitaxel and docetaxel, cabazitaxel, paclitaxel, polo kinase inhibitors); and topoisomerase inhibitors (eg, epipodophyllotoxin , such as etoposide and teniposide, amsacrine, topotecan, irinotecan, belotecan, vorinosin, thinafetide, and camptothecin); cytostatic agents, such as antiestrogens Hormones (eg, tamoxifen, clobesmin, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxifene), antiandrogens (eg, bicalutamide, fluta amines, nilutamide, topirutamide, enzalutamide and cyproterone acetate, chlormadinone), luteinizing hormone-releasing hormone (LHRH) antagonists or LHRH agonists (such as goserelin, leuprolide and buserelin), progestins (eg, chlormadinone, progesterone caproate, medroxyprogesterone, megestrol acetate), aromatase inhibitors (eg, anastrozole, letrozole, vorizole and exemestane) and 5α-reductase inhibitors (e.g., finasteride, dutamide, eprelide); anti-aggression agents (e.g., c-Src family kinase inhibitors (e.g., dasatinib, bosutinib), metalloproteinase inhibitors (eg, marimastat), inhibitors of urokinase-initiating receptor function (eg, plasminogen or anti-heparanase antibodies) Growth factor inhibitors: Examples of such inhibitors include anti-growth factor antibodies and anti-growth factor receptor antibodies (eg, trastuzumab, panitumumab, cetuximab and Stern et al. Critical reviews in oncology/ haematology, 2005, Vol. 54, p. Any of the anti-growth factor/anti-growth factor receptor antibodies disclosed in 11-29; such inhibitors also include tyrosine kinase inhibitors, including inhibitors of the epidermal growth factor family (e.g. EGFR tyrosine kinase inhibitors such as Gefitinib, Erlotinib, Carnitinib (CI 1033), Afatinib, Osimertinib, Rocitinib, Icotinib, Dafitinib, erbB2 tyrosine kinase inhibitors , such as lapatinib, inhibitors of the hepatocyte growth factor family; inhibitors of the insulin-like growth factor family; inhibitors of the platelet-derived growth factor family, such as imatinib, nilotinib; serine/threonine kinases Inhibitors (for example, Ras/Raf pathway inhibitors, such as farnesyltransferase inhibitors, such as sorafenib, tipifarnib and lonafarib), MEK- and/or AKT-kinase pathway inhibitors, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; Aurora kinase inhibitors (e.g. balasse (AZD1152), danusertib (РНА-739358), Tauzertib (VX-680), MLN8054, R763, МР235, МР529, VX-528 and АХ39459) and cyclin-dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors; anti-angiogenic agents such as those that inhibit the action of vascular endothelial growth factor (e.g., bevacizumab, vandetanib, vataranib, sunitinib, axitinib, pazopanib, Crizotinib and cediranib (AZD2171), linoxamide, integrin avp3 function inhibitor, angiostatin, endostatin, thalidomide, everolimus, sirolimus, Itraconazole, suramin, semaxanib, thrombospondin, ramucumab, taschinmod, ranibizumab, sorafenib, international applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354); vascular injury agents (such as combretastatin A4, ombrabulin and international applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02 Compounds disclosed in /08213; endothelin receptor antagonists (e.g. bosentan, sitaxsentan, ambrisentan, BQ-123, BQ-788, macitentan, tezosentan, zipotexan Atrasentan, Atrasentan); antisense therapies (such as those against the above-mentioned targets, such as ISIS 2503, antisense anti-ras, antisense anti-EGFR, curtisen, aptosen, ISIS-STAT3Rx (ISIS 481464/AZD9150 ), ISIS-ARRx (AZD5312), Qubedsen (AP120 09), EZN-2968, LErafAON-ETU); gene therapy methods, including, for example, methods of replacing abnormal genes (such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT (gene-directed enzyme prodrug therapy) methods, such as using cell pyrimidine deaminase, thymidine kinase, or bacterial nitroreductase), and approaches to increase patient resistance to chemotherapy or radiotherapy, such as multidrug resistance gene therapy; and immunotherapeutic approaches, including, for example, checkpoint inhibition agents, such as PD-1/PD-L1 (nivolumab, pembrolizumab, atezolizumab, durovolumab, avalumab, pidilizumab, etc.), and targeting CTLA-4 (including Ipilimumab, tremelimumab), OX-40, VISTA, ICOS, TIGIT, LAG-3, 4-1BB, GITR, CD40, CCR4other in vitro and in vivo methods to increase the immunogenicity of tumor cells in patients, such as transfection with cytokines such as interleukin 2, interleukin 4, interleukin 15 or granulocyte-macrophage colony-stimulating factor, to reduce T-cell Reactive methods, methods using transfected immune cells such as cytokine-transfected dendritic cells, methods using cytokine-transfected tumor cell lines, methods using anti-idiotypic antibodies, methods that reduce immunosuppressive cells such as regulatory T - methods for the function of cells, myelosuppressive cells or dendritic cells expressing IDO (indoleamine 2,3-deoxygenase), and using proteins derived from tumor-associated antigens such as NY-ESO-1, MAGE-3 , WT1 or Her 2A method for cancer vaccines composed of proteins or peptides/neu. Therefore, in another embodiment of the present invention there is described a pharmaceutical product comprising a compound of formula (I) as defined above or a pharmaceutically acceptable salt, solvate or stereo Isomers for combination therapy of cancer. Dosage regimens may be adjusted to provide the optimum desired response. For example, a single dose may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate oral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suitable as unitary dosages for the patient/subject to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in combination with the desired therapeutic effect. drug carrier. The specifications for the unit dosage forms of the invention are generally determined by, and are directly dependent upon (a) the unique properties of the therapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the formulation of such activity for the treatment of sensitivity in a patient limitations inherent in the field of compounds. Accordingly, based on the disclosure provided herein, the skilled artisan will appreciate that dosages and dosing regimens are adjusted according to methods well known in the therapeutic art. That is, a maximum tolerated dose can be readily established, and an effective amount to provide a detectable therapeutic effect in a patient can also be determined, as well as the time requirement for administering each agent to provide a detectable therapeutic effect in a patient can be determined. Thus, although certain dosages and administration regimens are illustrated herein, these examples in no way limit the dosages and administration regimens that can be provided to patients in practicing the embodiments of the invention. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated and may comprise single or multiple doses. Furthermore, it should be understood that for any particular subject, the specific dosage regimen should be adjusted over time according to the individual needs and the judgment of the medical professional administering or supervising the administration of the composition, and that the dosage ranges set forth in this specification are merely exemplary inclusive, and are not intended to limit the scope or practice of the claimed compositions. In addition, dosage regimens for the use of compositions of the invention can be based on a variety of factors including the type of disease, age, weight, sex, medical condition of the patient, severity of the condition, route of administration and the particular compound of the invention being used. Accordingly, dosage regimens can vary widely, but can be determined routinely using standard methods. For example, dosages may be adjusted based on pharmacokinetic and pharmacodynamic parameters, which may include clinical effects such as toxic effects or laboratory values. Accordingly, the invention includes intra-patient dose escalation as determined by a qualified expert. Methods of determining appropriate dosages and regimens are well known in the art and will be understood by the skilled artisan once provided with the ideas disclosed herein. In general, the standard daily dosage for an adult is usually 0.02 mg to 5000 mg or about 1 mg to about 1500 mg. Once the patient's condition improves, administer a maintenance dose, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced to a level that maintains the improved disease, disorder or condition as a function of symptoms. However, after symptoms recur, patients may require long-term regular treatment. The above ranges are suggestive only, as the number of variables with regard to individual treatment regimens is large and considerable deviations from these recommended values are common. These dosages may vary according to many variables not limited to the activity of the compound used, the disorder or condition being treated, the method of administration, the requirements of the individual subject, the severity of the disorder or condition being treated, and the judgment of the physician. The following examples are provided for a better understanding of the invention. These examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way. All publications, patents, and patent applications cited in this specification are hereby incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, those of ordinary skill in the art will, from the teachings of the invention, readily appreciate that, without departing from the spirit or scope of the appended embodiments, certain changes and modifications may be made. Example List of abbreviations: 2-MeTHF-2-Methyltetrahydrofuran THF-Tetrahydrofuran PTSA-p-toluenesulfonic acid Pd(dppf)Cl 2-[1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) chloride XPhos-2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl PD 2(dba) 3- Tris(dibenzylideneacetone)dipalladium(0) XantPhos-4,5-bis(diphenylphosphino)-9,9-dimethylxanthene DIPEA-Diisopropylethylamine TEA-triethylamine TBAF-tetrabutylammonium fluoride no-BuLi-n-Butyllithium TMEDA- N 1, N 1, N 2, N 2-Tetramethylethylenediamine NIS-N-iodosuccinimide NBS-N-Bromosuccinimide LiHMDS-Lithium Hexamethyldisilazane DCM-dichloromethane NMP-N-Methylpyrrolidone DMF-Dimethylformamide RM - reactive material R.t. - room temperature DBU-1,8-diazabicyclo[5.4.0]undec-7-ene LDA-lithium diisopropylamide Rac-BINAP-([1,1'-binaphthyl-2,2'-diyl)bis(diphenylphosphine) EtOAc-ethyl acetate TFA-trifluoroacetic acid STAB-sodium triacetyloxyborohydride MeOH-methanol MTBE-tert-butyl methyl ether HBTU-3-[bis(dimethylamino)methyl]-3H-benzotriazole-1-oxide hexafluorophosphate B 2pin 2-Bis(pinacolate)diboron MeCN-acetonitrile EtOH-ethanol AcOH-acetic acid KOAc-Potassium acetate Example 1. The preparation method of compound 1a.
Figure 02_image181
A solution of 1a-1 (10.0 g, 0.069 mol) in 2-MeTHF (33 ml) was added to a solution obtained from Mg (5.85 g, 0.241 mol) and iodomethane (14 ml, 0.213 mol) at 20 °C for 20 minutes. A solution of methylmagnesium iodide in 2-MeTHF (40 ml, 0.213 mol). After 1 h, an ice solution of K2CO3 was added to the reaction mass. The resulting suspension was mixed overnight. The precipitate was filtered, washed with MeOH, and the resulting solution was concentrated on a rotary evaporator. The product was isolated by silica gel column chromatography using DCM/MeOH as eluent. The yield of 1 was 4.5 g (84%). Example 1.1 Preparation method of compound 1b.
Figure 02_image183
Similar to Example 1, compound 1b was prepared from 1b-1 and ethylmagnesium bromide with a yield of 3.4 g (91%). Example 1.2 Method for preparing compound 1d.
Figure 02_image185
Similar to Example 1, compound 1d was prepared from 1d-1 and cyclopropylmagnesium bromide in a yield of 2.4 g (52%). Example 2. The preparation method of compound 2.
Figure 02_image187
Step 1. Preparation of compound 2_2. Will N 1, N 1, N 2--Trimethylethane-1,2-diamine (7.68g, 0.07 mol) was added to the solution of 2_1 (10g, 0.07 mol). The resulting mixture was mixed at a temperature of 80° C. for 10 hours. Hexane was added to the reaction mixture, and the precipitate was filtered and dried. The yield of 2_2 was 15.6 g (99%). Step 2. Preparation of compound 2_3. An aqueous suspension of Ni-Raney (8 ml) was added to a solution of 2_2 (15.6 g, 0.06 mol) and hydrazine hydrate (33.2 g, 0.66 mol) in EtOH (100 ml). The RM was stirred overnight. RM was filtered, washed with EtOH, and concentrated on a rotary evaporator. The yield of 2_3 was 12.8 g (99%). Step 3. Preparation of compound 2. tert-Butyl nitrite (4.36 g, 0.04 mol) was slowly added to a solution of 2_3 (7.78 g, 0.04 mol) and HBF4 (25.5 g, 0.14 mol) in THF (120 ml) at -10 °C. After 1 h, the precipitate was filtered, washed with EtOAc and dried. The resulting compound was dissolved in MeCN (120 ml), and B was added at -25 °C 2pin 2(9.39 g, 0.04 mol) and pyridine (11.6 g, 0.14 mol) for 1 min. The RM was warmed to room temperature and stirred overnight. The resulting solution was concentrated on a rotary evaporator. The product was isolated by silica gel column chromatography using EtOAc/Et3N as eluent. The yield of 2 was 6.85 g (62%). Example 3. The preparation method of compound 3b.
Figure 02_image189
Step 1. Preparation of compound 3b_2. DIPEA (15.5 ml, 0.10 mol) was added to a solution of 2_1 (5.46 g, 0.04 mol) and piperidin-4-one (7.21 g, 0.05 mol) in DMF (30 ml) under nitrogen atmosphere. The RM was stirred at 80 °C for 5 hours and poured into water. The precipitate was filtered, washed with water (50 ml), ether and dried. The yield of 3b_2 was 7.72 g (92%). Step 2. Preparation of compound 3b_3. A solution of 3b_2 (3.72 g, 0.02 mol), 1-methylpiperazine (3.59 ml, 0.03 mol), AcOH (1 ml, 0.02 mol) in DCM (56 ml) was mixed for 1 hour at room temperature. STAB (7.12 g, 0.03 mol) was added and the mixture was stirred for 16 hours. STAB (7.12 g, 0.03 mol) was added in portions over 4 hours. Saturated NH4Cl solution was added to the suspension. The resulting suspension was washed with DCM, the aqueous layer was neutralized and extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated on a rotary evaporator. The yield of 3b_3 was 4.88 g (99%). Step 3. Preparation of compound 3b_4. A solution of 3b_3 (0.91 g, 2.94 mmol) in MeOH (20 ml) was mixed in the presence of 5% Pd/C (5 mol%) in a hydrogen atmosphere (5 atm) for 1 h. RM was filtered, washed with MeOH, and concentrated on a rotary evaporator. The yield of 3b_4 was 0.8 g (99%). Step 4. Preparation of compound 3b. PTSA in AcOH (21 ml, 0.07 mol) was added to a solution of 3b_4 (3.00 g, 9.84 mmol) in MeCN (10 ml). A solution of tert-butyl nitrite (2.15 ml, 0.2 mol) in MeCN (10 ml) was added to the resulting solution at 0°C. After 3 hours, a solution of KI (12.2 g, 0.07 mol) in water (15 ml) was added. The RM was stirred at 70 °C for 5 h, poured into aqueous Na2CO3, and then adjusted to pH 9 with aqueous NaOH. The product was extracted with DCM. The combined organic phases were washed with saturated Na2SO3 solution, dried over Na2SO4, filtered and concentrated on a rotary evaporator. The product was isolated by silica gel column chromatography using DCM/MeOH/TEA as eluents. The yield of 3b was 2.7 g (71%). Example 3.1 Preparation of compound 3a.
Figure 02_image191
Similar to step 4 of Example 3, compound 3a was prepared from 3a_1 with a yield of 3.1 g (69%). Example 3.2 Method for the preparation of compound 3c.
Figure 02_image193
Similar to step 4 of Example 3, compound 3c was prepared from 3c-1 with a yield of 1.29 g (59%). Example 3.3 Preparation method of compound 3d.
Figure 02_image195
In a similar manner to step 4 of Example 3, compound 3d was prepared from 3d_1 with a yield of 1.38 g (94%). Example 3.4 Preparation of compound 3e.
Figure 02_image197
In a similar manner to step 4 of Example 3, compound 3e was prepared from 3e_1, and the yield of 3e was 0.36 g (40%). Example 3.5 Preparation method of compound 3f.
Figure 02_image199
In a similar manner to step 4 of Example 3, compound 3f was prepared from 3f_1 with a yield of 1.02 g (75%). Example 3.6 Preparation method of compound 3n.
Figure 02_image201
Step 1. Preparation of compound 3n_2. In a similar manner to Example 3, step 1, compound 3n-2 was prepared from 5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester with a yield of 1.4g (94%) . Step 2. Preparation of compound 3n_3. 4N HCl in methanol (15 ml) was added to a solution of 3n_2 (1.4 g, 0.004 mol) in 1,4-dioxane (7 ml). The RM was mixed at room temperature for 1 h, the resulting solution was concentrated, adjusted to pH 9-10 with saturated Na2CO3 solution, and the product was extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated on a rotary evaporator. The yield of 3n_3 was 1.0 g (117%). The product was used in the next step without additional purification steps. Step 3. Preparation of compound 3n_4. Sodium cyanoborohydride (0.73 g, 3.28 mmol) and AcOH (0.2 ml) were added to a mixture of formaldehyde (0.50 ml, 6.7 mmol) and an aqueous solution of 3n-3 (0.87 g, 3.3 mmol) in MeOH (20 ml), The resulting RM was mixed at 25°C for 3 hours. The RM was adjusted to pH 12 with 3N aqueous NaOH, then washed with DCM. The combined organic layers were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated on a rotary evaporator. The product was isolated by silica gel column chromatography using DCM/MeOH/TEA as eluents. The yield of 3n_4 was 0.68 g (82%). Step 4. Preparation of compound 3n_5. In a similar manner to step 3 of Example 3, compound 3n_5 was prepared from 3n_4 with a yield of 0.66 g (99%). Step 5. Preparation of compound 3n. In a manner similar to step 4 of Example 3, compound 3n was prepared from 3n_5 with a yield of 0.32 g (34%). Example 3.7 Preparation of compound 3o.
Figure 02_image203
Step 1. Preparation of compound 3o_2. In a similar manner to Example 3.6 Step 1, compound 3o_2 was prepared from (R)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester with a yield of 8.5 g (79%). Step 2. Preparation of compound 3o_3. Compound 3o_3 was prepared from 3o_2 in a similar manner to Example 3.6 Step 2 with a yield of 2.3 g (117%). Step 3. Preparation of compound 3o_4. Compound 3o_4 was prepared from 3o_3 in a similar manner to Example 3.6 Step 3 with a yield of 2.2 g (99%). Step 4. Preparation of compound 3o_5. In a similar manner to Example 3, step 3, compound 3o_5 was prepared from 3o_4 with a yield of 1.5 g (90%). Step 5. Preparation of compound 3o In a similar manner to step 4 of Example 3, compound 3o was prepared from 3o_5 with a yield of 0.91g (86%). Example 3.8 Preparation method of compound 3p.
Figure 02_image205
Step 1. Preparation of compound 3p_2. Compound 3p_2 was prepared from (S)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester according to the same method as in step 1 of Example 3.6, and the yield of 3p_2 was 6.3 g (77%). Step 2. Preparation of compound 3p_3. Compound 3p_3 was prepared from 3p_2 in a similar manner to step 2 of Example 3.6 with a yield of 2.0 g (104%). Step 3. Preparation of compound 3p_4. In a similar manner to Example 3.6 Step 3, compound 3p_4 was prepared from 3p_3, and the yield of 3p_4 was 1.7 g (84%). Step 4. Preparation of compound 3p_5. In a manner similar to step 3 of Example 3, compound 3p_5 was prepared from 3p_4 with a yield of 1.5 g (108%). Step 5. Preparation of compound 3o. In a similar manner to Example 3, step 4, compound 3o was prepared from 3p-5 with a yield of 1.13g (94%). The preparation method of embodiment 3.9 compound 3q
Figure 02_image207
Step 1. Preparation of compound 3q_2. HBTU (3.14 g, 8.2 mmol) was added portionwise to a solution of 3q_1 (1.2 g, 5.1 mmol), AcOH (0.6 ml, 10 mmol), DIPEA (4.5 ml, 26 mmol) in DMF (20 ml) at room temperature middle. After 3 hours, water (150 ml) was added. The RM was mixed for 1 hour at room temperature. The product was extracted using EtOAc. The combined organic layers were washed with water and saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated on a rotary evaporator. The product was isolated by silica gel column chromatography using DCM as eluent. The yield of 3q_2 was 2.34 g (173%). The product was used in the next step without additional purification steps. Step 2. Preparation of compound 3q_3. Compound 3q_3 was prepared from 3q_2 in a manner similar to Step 3 of Example 3. The product was dissolved in 1M aqueous HCl and washed with DCM. The pH of the aqueous layer was adjusted to 11 with 3N NaOH solution, then washed with DCM. The combined organic layers were washed with saturated NaCl solution, dried over Na2SO4, filtered and concentrated on a rotary evaporator. The yield of 3q_3 was 1.05 g (101%). Step 3. Preparation of compound 3q. In a manner similar to step 3 of Example 3, compound 3q was prepared from 3q_3 with a yield of 1.1 g (94%). Example 3.10 Preparation method of compound 3r.
Figure 02_image209
Step 1. Preparation of compound 3r_2. 3q-1 (0.39g, 2.0 mmol), N,N-dimethyl-2-chloroacetamide (0.50g, 2.6 mmol) and K 2CO 3(1.13 g, 8.0 mmol) in DMA (5 ml) was mixed at room temperature for 16 hours. The RM was poured into saturated aqueous NaCl and the product was extracted with EtOAc. The combined organic layers were washed with water, saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated on a rotary evaporator. The yield of 3r_2 was 0.92 g (149%). The product was used in the next step without additional purification steps. Step 2. Preparation of compound 3r_3. In a similar manner to Example 3, step 3, compound 3r_3 was prepared from 3r_2 with a yield of 0.36 g (62%). Step 3. Preparation of compound 3r. In a similar manner to step 3 of Example 3, compound 3r was prepared from 3r_3 with a yield of 0.4 g (86%). Example 4. The preparation method of compound 3g.
Figure 02_image211
Step 1. Preparation of compound 3g_2. In an argon atmosphere, the Pd 2(dba) 3(72 mg, 0.07 mmol) and Rac-BINAP (0.14 g, 0.22 mmol) were added with 3g_1 (0.70 g, 3.4 mmol), 1,4-dibromobenzene (2.5 g, 10 mmol) and DBU (0.94 ml, 6.3 mmol ) in a solution in toluene (7.5 ml). The mixture was mixed at 100°C for 1 hour, sodium tert-butoxide (0.85 g, 8.6 mmol) was added, the mixture was mixed at 100°C for 2 hours, and the resulting RM was concentrated on a rotary evaporator. The product was isolated by silica gel column chromatography using hexane/MTBE as eluent. The yield of 3g was 0.82g (67%). Step 2. Preparation of compound 3g_3. A solution of 3 g_2 (0.3 g, 0.8 mmol) in TFA (3 ml) was mixed at 25 °C for 16 h. The RM was neutralized with saturated Na2CO3 solution and washed with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated on a rotary evaporator. The yield of 3g_3 was 0.2g (99%). Step 3. Preparation of compound 3g. STAB (0.73 g, 3.28 mmol) and MeOH (1 ml) were added to a mixture of formaldehyde (0.15 ml, 2.0 mmol) and an aqueous solution of 3g-3 (0.22 g, 0.82 mmol) in THF (5 ml), and the resulting RM Mix for 16 hours at 25°C. The RM was adjusted to pH 12 with 3N aqueous NaOH, then washed with DCM. The combined organic layers were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated on a rotary evaporator. The yield of 3 g was 0.19 g (87%). Example 4.1. The preparation method of compound 3h.
Figure 02_image213
Step 1. Preparation of compound 3h_2. In a similar manner to step 1 of Example 4, compound 3h_2 was prepared from 3h_1 with a yield of 0.75 g (62%). Step 2. Preparation of compound 3h-3. In a similar manner to step 2 of Example 4, compound 3h_3 was prepared from 3h_2 with a yield of 0.20 g (98%). Step 3. Preparation of compound 3h. In a similar manner to step 3 of Example 4, compound 3h was prepared from 3h-3 with a yield of 0.20 g (87%). Example 4.2. The preparation method of compound 3i.
Figure 02_image215
In a similar manner to step 1 of Example 4, compound 3i was prepared from 3i_1 with a yield of 0.22 g (33%). Example 4.3. Preparation method of compound 3j.
Figure 02_image217
In a similar manner to step 1 of Example 4, compound 3j was prepared from 3j_1 with a yield of 0.42 g (53%). Example 5. Preparation method of compound 4a.
Figure 02_image219
4a-1 (0.47 g, 1.69 mmol), 2 (0.79 g, 2.45 mmol) and Cs 2CO 3(2.42 g, 7.35 mmol) in a 1,4-dioxane/water (25 ml, 20:1 ) mixture was degassed with argon. Pd(dppf)Cl2 (0.18 g, 0.2 mmol) was added under argon atmosphere. The mixture was stirred at 80°C for 2 hours. 4a_1 (0.25 g, 0.8 mmol) was added. The mixture was stirred at 80°C for 4 hours. EtOAc was added to the reaction mixture, and the organic layer was washed with 1N aqueous HCl. The aqueous layer was neutralized with saturated Na2CO3 solution and washed with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated on a rotary evaporator. The product was isolated by silica gel column chromatography using DCM/MeOH as eluent. The yield of 4a was 0.44 g (55%). Example 6. The preparation method of compound 5a.
Figure 02_image221
Step 1. Preparation of compound 5a_2. NIS (1.75 g, 7.60 mmol) was added to a solution of 5a-1 (0.68 g, 5.07 mmol) in DMF (4 ml). The RM was stirred at 100 °C for 3 hours. Water and saturated Na2S2O4 solution were added to RM with stirring. The precipitate was filtered off, washed with water and dried. The yield of 5a_2 was 0.83 g (64%). Step 2. Preparation of Compound 5a_3. A solution of 5a-2 (1.73 g, 6.43 mmol), trimethylsilylacetylene (0.98 g, 9.65 mmol) and DIPEA (1.68 g, 12.9 mmol) in THF (30 ml) was degassed with argon. Add CuI (0.25 g, 1.29 mmol) and Pd (Pph3) under argon atmosphere 2Cl2 (0.46 g, 0.64 mmol). The RM was stirred at 70 °C for 3 hours and concentrated on a rotary evaporator. The product was isolated by silica gel column chromatography using EtOAc/hexanes as eluent. The yield of 5a-3 was 1.29 g (89%). Step 3. Preparation of compound 5a_4. 5a_3 (0.30 g, 1.26 mmol) was added to 1M TBAF in THF (2.5 ml, 2.5 mmol), the mixture was mixed at room temperature for 2.5 hours, the reaction mass was diluted with water and extracted with EtOAc. The organic phase was washed with a saturated solution of 10% Na2CO3, NaCl, dried over Na2SO4, filtered and concentrated on a rotary evaporator. The yield of 5a-4 was 0.19 g (98%). Step 4. Preparation of compound 5a_5. A solution of 5a-4 (0.31 g, 0.89 mmol), 3a (0.45 g, 1.18 mmol), DIPEA (0.31 g, 2.36 mmol), CuI (0.02 g, 0.12 mmol) in THF (5 ml) was degassed with argon. Add Pd(PPH3) in argon atmosphere 2Cl2 (0.42 g, 0.06 mmol). The RM was stirred overnight at room temperature, diluted with water, and extracted with EtOAc. The organic phase was washed with saturated aqueous NaCl and extracted with 1M aqueous HCl. The combined aqueous phases were neutralized with saturated NaHCO3 solution, the precipitate was filtered off and dried. The yield of 5a_5 was 0.33 g (84%). Step 5. Preparation of compound 5a. A solution of 5a_5 (0.15 g, 0.45 mmol), CuI (0.07 g, 0.36 mmol) and DBU (0.55 ml, 3.6 mmol) in DMF (10 ml) was mixed at 100 °C for 24 hours. The RM was diluted with water and DCM, filtered, and 1M aq. HCl was added. The organic layer was extracted with 1M aqueous HCl. The combined aqueous phases were neutralized with saturated NaHCO3 solution and extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated on a rotary evaporator. The yield of 5a was 0.08 g (57%). Example 6.1. The preparation method of compound 5b
Figure 02_image223
Step 1. Preparation of compound 5b_1. In a similar manner to step 4 of Example 6, compound 5b_1 was prepared from 5a_4 and 3b with a yield of 0.65 g (80%). Step 2. Preparation of compound 5b. A suspension of 5b_1 (0.51 g, 1.4 mmol) and Cs2CO3 (1.8 g, 5.2 mmol) in NMP (5 ml) was mixed at 87 °C for 2 h and purified by silica gel column chromatography using CHCl 3/MeOH/TEA was used as eluent to isolate the product. The yield of 5b was 0.35 g (65%). Embodiment 7. The preparation method of compound 6a
Figure 02_image225
Step 1. Preparation of compound 6a_2. NaH (0.10 g, 2.53 mmol) was added portionwise to a solution of 6a-1 (0.42 g, 2.11 mmol) in THF (10 ml) at 0 °C, and the mixture was stirred for 10 min. p-Toluenesulfonyl chloride (0.42 g, 2.22 mmol) was added portionwise at 0°C. The mixture was stirred at room temperature for 2 hours and neutralized with saturated aqueous NH4Cl. The product was extracted with EtOAc. The combined organic phases were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated on a rotary evaporator. The product was isolated by silica gel column chromatography using DCM/hexane as eluent. The yield of 6a_2 was 0.72 g (99%). Step 2. Preparation of Compound 6a_3. A 2M solution of LDA in THF/heptane/ethylbenzene (1.15 ml, 2.29 mmol) was slowly added to a solution of 6a_2 (0.55 g, 1.53 mmol) in THF (10 ml) at -30°C under argon atmosphere. After 1 hour, tributyltin chloride (0.43 ml, 1.53 mmol) was added. After the mixture was warmed to room temperature for 1 h, 20% aqueous NH4Cl was added. The product was extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated on a rotary evaporator. The product was isolated by silica gel column chromatography using EtOAc/hexanes as eluent. The yield of 6a_2 was 0.62 g (64%). Step 3. Preparation of compound 6a_4. In an argon atmosphere, Pd (PPh3) 2Cl2 (0.11g, 0.09 mmol) was added to 6a_3 (0.62g, 0.92 mmol), 3a (0.23g, 0.61 mmol), CsF (0.19g, 1.23 mmol), CuI (0.04g, 0.18 mmol) in DMF (10 ml ) in the suspension. The RM was stirred at 80 °C for 1 hour and concentrated on a rotary evaporator. The product was isolated by silica gel column chromatography using EtOAc/TEA as eluent. The yield of 6a_4 was 0.18 g (57%). Step 4. Preparation of compound 6a. A solution of 3N NaOH (2 ml) in water was added to a solution of 6a-4 (100 mg, 0.18 mmol) in MeOH (4 ml) and the resulting RM was mixed at 70 °C for 1 h. The RM was concentrated on a rotary evaporator, DMF was added, the RM was filled with water, the precipitate was filtered off and dried. The yield of 6a was 0.05 g (72%). The preparation method of embodiment 7.1 compound 6b
Figure 02_image227
Step 1. Preparation of compound 6b_2. In a similar manner to Example 7, step 3, compound 6b_2 was prepared from 6a_3 and 3b with a yield of 0.89 g (63%). Step 2. Preparation of compound 6b. In a similar manner to step 4 of Example 7, compound 6b was prepared from 6b_2 with a yield of 0.46 g (99%). Embodiment 8. The preparation method of compound 4b
Figure 02_image229
Step 1 prepares compound 4b_2. Compound 4b_2 was prepared from 4b_1 in a similar manner to Step 1 of Example 7 with a yield of 3.7 g (97%). Step 2. Preparation of compound 4b_3. In a similar manner to Example 7, step 2, compound 4b_3 was prepared from 4b_2 with a yield of 1.76 g (30%). Step 3. Preparation of compound 4b-4. In a similar manner to step 3 of Example 7, compound 4b_4 was prepared from 4b_3, and the yield of 3b was 0.11 g (78%). Step 4. Preparation of compound 4b. In a similar manner to step 4 of Example 7, compound 4b was prepared from 4b_4 with a yield of 0.06 g (76%). Example 8.1. Preparation of compound 4c. Compound 4c was prepared from 4b_3 and 3i via 4с_1 (Table 1) in a manner similar to Example 7, step 3, step 4. The yield of 4с_1 was 0.26 g (52%). 4с Yield was 0.09 g (64%). Example 8.2. Preparation method of compound 4d. Compound 4d was prepared from 4b_3 and 3j (Table 1) in a similar manner to Example 7, step 3. Compound 4d_1 was not isolated from RM. Cs2CO3 (0.68 g, 2.1 mmol) and methanol (3 ml) were added to RM, and the mixture was mixed at 60° C. for 1 hour. RM was concentrated on a rotary evaporator. The product was isolated by silica gel column chromatography using DCM/MeOH/TEA as eluents. The yield of 4d was 0.32 g (82%, yield over two steps). Example 8.3. Preparation of Compound 4e. Compound 4e was prepared from 4b_3 and 3c via 4e_1 (Table 1) in a similar manner to Example 7, Step 3, Step 4. The yield of 4e-1 was 0.36 g (20%). The yield of 4e was 0.14 g (83%). Example 8.4. Preparation of Compound 4f. Compound 4f was prepared from 4b_3 and 3d via 4f_1 (Table 1) in a similar manner to Example 7, Step 3, Step 4. The yield of 4f_1 was 0.10 g (24%). The yield of 4f was 0.15 g (57%). Example 8.5. Preparation of compound 4g. Compound 4g was prepared from 4b_3 and 3k via 4g_1 (Table 1) in a similar manner to Example 7, Step 3, Step 4. The yield of 4g_1 was 0.17g (48%). The yield of 4 g was 0.07 g (66%). Example 8.6. Preparation of Compound 4h. Compound 4h was prepared from 4b_3 and 3e via 4h_1 (Table 1) in a similar manner to Example 7, Step 3, Step 4. The yield of 4h_1 was 0.23 g (63%). Yield at 4 h was 0.14 g (94%). Example 8.7. Preparation of compound 4i. Compound 4i was prepared from 4b_3 and 3l via 4i_1 (Table 1) in a manner analogous to Example 7, Step 3, Step 4. The yield of 4i-1 was 0.36 g (89%). The yield of 4i was 0.14 g (75%). Example 8.8. Preparation of compound 4j. The preparation method of compound 4j is similar to Step 3 and Step 4 of Example 7, from 4b_3 and 3m to 4j_1 (Table 1). The yield of 4j_1 was 0.29 g (67%). The yield of 4j was 0.20 g (99%). Example 8.9. Preparation of compound 4k. Compound 4k was prepared from 4b_3 and 3g via 4k_1 (Table 1) in a similar manner to Example 7, Step 3, Step 4. The yield of 4k-1 was 0.14 g (50%). The yield of 4k was 0.04 g (44%). Example 8.10. Preparation method of compound 4l. Compound 41 was prepared from 4b_3 and 3 hours via 41_1 (Table 1) in a manner similar to Example 7, step 3, step 4. The yield of 4l-1 was 0.20 g (55%). Yield of 41 was 0.06 g (55%). Example 8.11. Preparation of compound 4m. Compound 4m was prepared from 4b_3 and 3f via 4m_1 (Table 1) in a similar manner to Example 7, Step 3, Step 4. The yield of 4m-1 was 0.67 g (93%). The yield of 4m was 0.09g (23%). Example 8.12. Preparation method of compound 4n. Compound 4n was prepared from 4b_3 and 3n via 4n_1 (Table 1) in a similar manner to Example 7, Step 3. Compound 4n_1 was not isolated from RM. Cs2CO3 (0.68 g, 2.1 mmol) and methanol (3 ml) were added to RM, and the mixture was mixed at 60° C. for 1 hour. RM was concentrated on a rotary evaporator. The product was isolated by silica gel column chromatography using DCM/MeOH/TEA as eluents. The yield of 4n was 0.14 g (83%, yield over two steps). Example 8.13. Preparation of compound 4o. Step 1 Preparation of Compound 4o_1. In a similar manner to Example 7, step 3, compound 4o_1 was prepared from 3o with a yield of 0.45 g (92%). Step 2. Preparation of compound 4o. In a similar manner to step 4 of Example 7, compound 4o was prepared from 4o_1 with a yield of 0.15 g (54%). Example 8.14. Preparation of Compound 4p. Compound 4p was prepared from 4b_3 and 3p via 4p_1 (Table 1) in a similar manner to Example 7, Step 3. Compound 4p_1 was not isolated from RM. Cs2CO3 (1.3 g, 4.0 mmol) and methanol (5 ml) were added to RM, and the mixture was mixed at room temperature for 16 hours. RM was concentrated on a rotary evaporator. The product was isolated by silica gel column chromatography using DCM/MeOH/TEA as eluents. The yield of 4p was 0.12 g (47%, yield over two steps). Example 8.15. Preparation method of compound 4q. Compound 4q was prepared from 4b_3 and 3q via 4q_1 (Table 1) in a manner similar to Step 3 of Example 7. Compound 4q_1 was not isolated from РМ. Cs2CO3 (1.3 g, 4.0 mmol) and methanol (5 ml) were added to RM, and the mixture was mixed at room temperature for 16 hours. RM was concentrated on a rotary evaporator. The product was isolated by silica gel column chromatography using DCM/MeOH/TEA as eluents. The yield of 4q was 0.13 g (42%, yield over two steps). Example 8.16. Preparation method of compound 4r. Compound 4r was prepared from 4b_3 and 3r via 4r_1 (Table 1) in a manner similar to Step 3 of Example 7. The yield of 4r_1 was 0.36 g (78%). The yield of 4r was 0.03 g (35%).
Figure 02_image231
Figure 02_image233
Figure 02_image235
Figure 02_image237
Example 8.12 Preparation method of compound 4s.
Figure 02_image239
Step 1. Preparation of compound 4s_2. Under an argon atmosphere, Pd(dppf)Cl2 (0.06 g, 0.07 mmol) was added to 4s-1 (0.40 g, 1.57 mmol), KOAc (0.40 g, 3.92 mmol) and B 2pin 2(0.61 g, 2.35 mmol) in suspension in 1,4-dioxane (8 ml). The mixture was stirred at 100°C for 1 hour. 4b-3 (0.40 g, 1.57 mmol), Na2CO3 (0.42 g, 3.92 mmol) and water (1 ml) were added to RM, and the mixture was mixed at 100°C for 3 hours. RM was concentrated on a rotary evaporator. The product was isolated by silica gel column chromatography using EtOAc/hexanes as eluent. The yield of 4s_2 was 0.47 g (77%). Step 2. Preparation of compound 4s. A solution of NaOH (0.36 g, 9.0 mmol) in water (2.5 ml) was added dropwise to a solution of 4s-2 (0.47 g, 0.90 mmol) in MeOH (5 ml). The mixture was stirred at 60°C for 2 hours. Water (10 ml) was added, the precipitate was filtered off and dried in air. The yield of 4s was 0.2 g (71%). Example 8.13 Preparation of compound 4t.
Figure 02_image241
Step 1. Preparation of compound 4t_2. In a similar manner to Step 1 of Example 8.12, compound 4t_2 was prepared from 4t_1 with a yield of 0.72 g (58%). Step 2. Preparation of compound 4t. In a similar manner to step 2 of Example 8.12, compound 4t was prepared from 4t_2 with a yield of 0.22 g (52%). Example 8.14 Preparation of compound 4u.
Figure 02_image243
Step 1. Preparation of compound 4u_2. In a similar manner to Step 1 of Example 8.12, compound 4u_2 was prepared from 4u_1 with a yield of 0.32 g (50%). Step 2. Preparation of compound 4u. In a similar manner to step 2 of Example 8.12, compound 4u was prepared from 4u_2 with a yield of 0.40 g (21%). The preparation method of embodiment 8.15 compound 4v
Figure 02_image245
Step 1 prepares compound 4v_2. Compound 4v_2 was prepared from 4v_1 in a similar manner to step 1 of Example 7 with a yield of 1.8 g (91%). Step 2. Preparation of compound 4v_3. In a manner similar to step 2 of Example 7, compound 4v_3 was prepared from 4v_2 with a yield of 1.21 g (37%). Step 3. Preparation of compound 4v_4. In a similar manner to step 3 of Example 7, compound 4v_4 was prepared from 4v_3 with a yield of 0.11 g (34%). Step 4. Preparation of compound 4v. In a manner similar to step 4 of Example 7, compound 4v was prepared from 4v_4 with a yield of 0.06 g (84%). The preparation method of embodiment 8.16 compound 4w
Figure 02_image247
Step 1 prepares compound 4w_2. In a similar manner to step 1 of Example 7, compound 4w_2 was prepared from 4w_1, and the yield of 4w_2 was 1.1 g (36%). Step 2. Preparation of compound 4 w_3. In a similar manner to step 2 of Example 7, compound 4w_3 was prepared from 4w_2 with a yield of 0.10 g (38%). Step 3. Preparation of compound 4 w_4. In a similar manner to step 3 of Example 7, compound 4w_4 was prepared from 4w_3 with a yield of 0.05 g (33%). Step 4. Preparation of compound 4w. In a manner similar to step 4 of Example 7, compound 4w was prepared from 4w_4 with a yield of 0.01 g (3%). Example 9. The preparation method of compound EGFR_48.
Figure 02_image249
Step 1 prepares compound 7a_2. In an argon atmosphere, the Pd(OAc) 2(100 mg, 0.50 mmol) and XantPhos (540 mg, 0.90 mmol) were added to 7a_1 (2.04g, 0.09 mol), 1a (0.90g, 0.01 mol), Cs2CO3 (3.25g, 0.01 mol) in 1,4-di suspension in oxane (20 ml). The RM was stirred at 110 °C for 3 hours, diluted with a DCM/MeOH mixture, filtered off, washed with a DCM/MeOH mixture and concentrated on a rotary evaporator. The product was isolated by silica gel column chromatography using DCM/MeOH as eluent. The yield of 7a_2 was 1.29 g (83%). Step 2. Preparation of candidate EGFR_48. In an argon atmosphere, the Pd(OAc) 2(3 mg, 0.02 mmol) and XPhos (14 mg, 0.02 mmol) were added 7a_2 (30 mg, 0.17 mmol), 4a (50 mg, 0.14 mmol), K2CO3 (59 mg, 0.42 mmol) in tert-butanol/DM ( 3 ml) in suspension in the mixture. The RM was stirred at 100°C for 5 hours and concentrated. The product was isolated by silica gel column chromatography using DCM/MeOH/NH3 as eluent. The isolated product was further purified by preparative chromatography. The yield of EGFR_48 was 9 mg (14%). Example 9.1 Method of making candidate EGFR_58. Candidate EGFR_58 was prepared from 7d_1, 1a and 4a (Table 2) in a similar manner to Example 9 in a yield of 40 mg (18%). Example 9.2 Method of making candidate EGFR_65. Candidate EGFR_65 was prepared in a similar manner to Example 9 from 7c_1, 1a and 4a (Table 2) in a yield of 20 mg (9%). Example 9.3: Method for preparing candidate EGFR_66 Candidate EGFR_66 was prepared from 7b_1, 1a and 4a (Table 2) in a similar manner to Example 9 in a yield of 10 mg (9%). Example 9.4: Method for preparing candidate EGFR_68 Candidate EGFR_68 was prepared from 7e_1, 1a and 4a (Table 2) in a similar manner to Example 9 in a yield of 40 mg (26%). Example 9.5: Method for preparing candidate EGFR_69 Candidate EGFR_69 was prepared from 7a_1, 1a and 5a (Table 2) in a similar manner to Example 9 in a yield of 10 mg (14%). Example 9.6: Method for preparing candidate EGFR_79 Candidate EGFR_79 was prepared from 8 and 4a (Table 2) in a similar manner to Example 9, step 2, in a yield of 70 mg (61%). Example 9.7: Method for preparing candidate EGFR_440 Candidate EGFR_440 was prepared from 7a_1, 1a and 5b (Table 2) in a similar manner to Example 9 in a yield of 40 mg (40%). Example 9.8: Method for preparing candidate EGFR_441 Candidate EGFR_441 was prepared in a similar manner to Example 9 from 7d_1, 1a and 5b (Table 2) in a yield of 25 mg (25%). Example 9.9: Method for preparing candidate EGFR_483 Candidate EGFR_483 was prepared from 7b_1, 1a and 5b (Table 2) in a similar manner to Example 9 in a yield of 90 mg (54%). Example 9.10: Method of making candidate EGFR_774 Candidate EGFR_774 was prepared from 7f_1, 1a and 4a (Table 2) in a similar manner to Example 9 in a yield of 90 mg (54%). Example 9.11: Method for preparing candidate EGFR_74 Candidate EGFR_74 was prepared from 7a_1, 1b and 4a (Table 2) in a similar manner to Example 9 with a yield of 40 mg (69%). Example 9.12: Method for preparing candidate EGFR_76 Candidate EGFR_76 was prepared in a similar manner to Example 9 from 7a_1, dimethyl phosphite and 4a (Table 2) in a yield of 10 mg (11%). Example 9.13 Preparation method of candidate EGFR_656 Candidate EGFR_656 was prepared from 7a_1, 1a and 4s in a similar manner to Example 9 (Table 2) in a yield of 70 mg (55%). Example 9.14: Method for preparing candidate EGFR_667 Candidate EGFR_667 (Table 2) was prepared from 7a_1, 1a and 4t in a similar manner to Example 9 in a yield of 40 mg (34%). Example 9.15: Method for preparing candidate EGFR_668 Candidate EGFR_668 (Table 2) was prepared from 7a_1, 1a and 4c in a similar manner to Example 9 in a yield of 40 mg (49%). Example 9.16: Method for preparing candidate EGFR_743 Candidate EGFR_743 was prepared from 7a_1, 1a and 4e (Table 2) in a similar manner to Example 9 in a yield of 40 mg (49%). Example 9.17: Preparation method of candidate EGFR_752 Candidate EGFR_752 was prepared from 7a_1, 1a and 4f (Table 2) in a similar manner to Example 9 in a yield of 80 mg (77%). Example 9.18: Method for preparing candidate EGFR_796 Candidate EGFR_796 was prepared from 7a_1, 1a and 4h (Table 2) in a similar manner to Example 9 in a yield of 80 mg (68%). Example 9.19: Method for preparing candidate EGFR_797 Candidate EGFR_797 was prepared from 7a_1, 1a and 4i (Table 2) in a similar manner to Example 9 in a yield of 20 mg (27%). Example 9.20: Method for preparing candidate EGFR_798 Candidate EGFR_798 was prepared from 7a_1, 1a and 4j (Table 2) in a similar manner to Example 9 in a yield of 10 mg (10%). Example 9.21: Method for preparing candidate EGFR_853 Candidate EGFR_853 was prepared from 7i_1, 1a and 4e (Table 2) in a manner similar to Example 9, using Pd(dppf)Cl and KOAc instead of Pd(OAc) in the first step 2and Cs2CO3 in a yield of 10 mg (12%). Example 9.22: Method for preparing candidate EGFR_854 Candidate EGFR_854 was prepared from 7j_1, 1a and 4e (Table 2) in a similar manner to Example 9, using Pd(dppf)Cl and KOAc instead of Pd(OAc) in the first step 2and Cs2CO3 in a yield of 10 mg (14%). Example 9.23: Method for preparing candidate EGFR_855 Candidate EGFR_855 was prepared from 7k_1, 1a and 4e (Table 2) in a manner similar to Example 9, using Pd(dppf)Cl and KOAc instead of Pd(OAc) in the first step 2and Cs2CO3 in a yield of 40 mg (42%). Example 9.23: Method for preparing candidate EGFR_856 Candidate EGFR_856 was prepared from 7l_1, 1a and 4e (Table 2) in a manner similar to Example 9, using Pd(dppf)Cl instead of Pd(OAc) in the first step 2, yield 4 mg (5%). Example 9.24: Method for preparing candidate EGFR_857 Candidate EGFR_857 was prepared from 7m_1, 1a and 4e (Table 2) in a manner similar to Example 9, using Pd(dppf)Cl instead of Pd(OAc) in the first step 2, yield 20 mg (28%). Example 9.25: Preparation method of candidate EGFR_858 Candidate EGFR_858 was prepared from 7n_1, 1a and 4e (Table 2) in a manner similar to Example 9, using Pd(dppf)Cl and KOAc instead of Pd(OAc) in the first step 2and Cs2CO3 in a yield of 10 mg (17%). Example 9.26 Preparation method of candidate EGFR_859 Candidate EGFR_859 was prepared from 7d_1, 1a and 4e (Table 2) in a similar manner to Example 9 in a yield of 44 mg (44%). Example 9.27: Method for preparing candidate EGFR_860 Candidate EGFR_860 was prepared in a similar manner to Example 9 from 7o_1, 1a and 4e (Table 2) in a yield of 20 mg (13%). Example 9.28: Preparation method of candidate EGFR_862 Candidate EGFR_862 was prepared from 7b_1, 1a and 4e (Table 2) in a similar manner to Example 9 in a yield of 40 mg (28%). Example 9.29: Method for preparing candidate EGFR_870 Candidate EGFR_870 was prepared similarly to Example 9 from 7p_1, 1a and 4e (Table 2) in a yield of 23 mg (23%). Example 9.30 Method for preparing candidate EGFR_871 In a manner analogous to Example 9, prepared from 7a-1, 1b and 4e (Table 2) Candidate EGFR_871, yield was 17 mg (42%). Example 9.31: Method of making candidate EGFR_887 Candidate EGFR_887 was prepared from 7a_1, 1a and 4m (Table 2) in a similar manner to Example 9 in a yield of 8 mg (11%). Example 9.32 Method for preparing candidate EGFR_896 Candidate EGFR_896 was prepared from 7q_1, 1a and 4e (Table 2) in a similar manner to Example 9, using K2CO3 instead of Cs2CO3 in the first step in a yield of 60 mg (55%). Example 9.33: Method for preparing candidate EGFR_910 Candidate EGFR_910 was prepared from 7a_1, 1b and 4h in a similar manner to Example 9 (Table 2) in a yield of 10 mg (16%). Example 9.34: Method of making candidate EGFR_912 Candidate EGFR_912 was prepared from 7a_1, 1b and 4f in a similar manner to Example 9 (Table 2) in a yield of 50 mg (36%). Example 9.35: Method for preparing candidate EGFR_918 Candidate EGFR_918 was prepared in a similar manner to Example 9 from 7q_1, 1a and 4f (Table 2) in a yield of 50 mg (34%). Example 9.36: Preparation method of candidate EGFR_919 Candidate EGFR_919 was prepared from 7b_1, 1a and 4f (Table 2) in a similar manner to Example 9 in a yield of 40 mg (31%). Example 9.37: Method for preparing candidate EGFR_655 Candidate EGFR_655 was prepared from 7a_1, 1a and 4u (Table 2) in a similar manner to Example 9 in a yield of 10 mg (10%). Example 9.38: Method for preparing candidate EGFR_865 Candidate EGFR_865 was prepared from 7a_1, 1a and 4v (Table 2) in a similar manner to Example 9 in a yield of 10 mg (25%). Example 9.39 Method for preparing candidate EGFR_982 Candidate EGFR_982 was prepared from 7q_1, 1d and 4f (Table 2) in a similar manner to Example 9 in a yield of 13 mg (18%). Example 9.39 Method for preparing candidate EGFR_985 Candidate EGFR_985 was prepared from 7q_1, 1a and 4n (Table 2) in a manner similar to Example 9, using a mixture of tert-butanol/1,4-dioxane as solvent in the second step in a yield of 6 mg (4%). Example 9.39: Method for preparing candidate EGFR_989 Candidate EGFR_989 was prepared from 7q_1, 1a and 4o (Table 2) in a similar manner to Example 9 in a yield of 28 mg (20%). Preparation Method of Example 9.39 Candidate EGFR_990 Candidate EGFR_990 was prepared from 7q_1, 1a and 4p (Table 2) in a similar manner to Example 9 in a yield of 13 mg (9%). Example 9.40: Method of making candidate EGFR_993 Candidate EGFR_993 was prepared in a similar manner to Example 9 from 7q_1, 1a and 4q (Table 2) in a yield of 17 mg (20%). Example 9.41: Method for preparing candidate EGFR_994 Candidate EGFR_994 was prepared from 7q_1, 1a and 4r (Table 2) in a similar manner to Example 9 in a yield of 9 mg (16%).
Figure 02_image251
Figure 02_image253
Figure 02_image255
Figure 02_image257
Figure 02_image259
Figure 02_image261
Figure 02_image263
Figure 02_image265
Figure 02_image267
Figure 02_image269
Figure 02_image271
Example 10: Method for preparing candidate EGFR_70
Figure 02_image273
1M LiHMDS in THF (0.51 ml, 0.51 mmol) was added to a suspension of 6a (69 mg, 0.17 mmol) and 7a_2 (91 mg, 0.51 mol) in DMF (2 ml). Add Pd in argon atmosphere 2(dba) 3(74 mg, 0.08 mmol) and XPhos (75 mg, 0.15 mmol). The RM was stirred at 100°C for 40 hours and concentrated. The product was isolated by silica gel column chromatography using DCM/MeOH/NH3 as eluent. The isolated product was further purified by preparative chromatography. The yield of EGFR-70 was 3 mg (4%). Example 10.1: Method for preparing candidate EGFR_348 Candidate EGFR_348 was prepared from 7d_2 and 4b in a similar manner to Example 10 with a yield of 30 mg (21%). Example 10.2: Preparation method of candidate EGFR_437 Candidate EGFR_437 was prepared from 7d_2 and 5a in a similar manner to Example 10 in a yield of 10 mg (9%). Example 10.3 Method for preparing candidate EGFR_485 Candidate EGFR_485 was prepared from 7a_2 and 6b in a similar manner to Example 10 in a yield of 15 mg (16%). Example 10.4: Method for preparing candidate EGFR_669 Candidate EGFR_669 was prepared from 7a_2 and 4d in a similar manner to Example 10 in a yield of 21 mg (38%). Example 10.5: Method for preparing candidate EGFR_795 Candidate EGFR_795 was prepared from 7a_2 and 4g in a manner similar to Example 10 in a yield of 95 mg (71%). Example 10.6: Method for preparing candidate EGFR_801 Candidate EGFR_801 was prepared from 7a-2 and 4k in a similar manner to Example 10 in a yield of 40 mg (67%). Example 10.7: Method for preparing candidate EGFR_802 Candidate EGFR_802 was prepared from 7a-2 and 41 in a similar manner to Example 10 in a yield of 30 mg (48%). Example 10.8: Method for preparing candidate EGFR_914 Candidate EGFR_914 was prepared from 7a_2 and 4w in a similar manner to Example 10 in a yield of 10 mg (18%). Example 11. The preparation method of compound EGFR_60.
Figure 02_image275
Step 1. Preparation of Compound 9a_2. In an argon atmosphere, the Pd 2(dba) 3(0.11g, 0.11 mmol) and XPhos (0.16g, 0.33 mmol) were added to 9a_1 (0.70g, 3.67 mmol), N 1, N 1, N 2- Trimethylethane-1,2-diamine (0.57 g, 5.51 mmol), sodium tert-butoxide (0.90 g, 9.18 mmol) in suspension in toluene (14 ml). The RM was stirred at 110°C for 3 hours, filtered off, and concentrated on a rotary evaporator. The product was isolated by silica gel column chromatography using EtOAc/TEA as eluent. The yield of 9a_2 was 0.31 g (41%). Step 2. Preparation of compound 9a_3. A solution of NBS (0.28 g, 1.57 mmol) in MeCN (3 ml) was added to a solution of 9a_2 (0.31 g, 1.43 mmol) in MeCN (12 ml) at 0 °C. The RM was stirred at room temperature for 2 hours, concentrated, redissolved in DCM, washed with water and concentrated. The product was isolated by silica gel column chromatography using EtOAc/TEA as eluent. The yield of 9a-3 was 0.30 g (73%). Step 3. Preparation of Compound 9a-4. Under an argon atmosphere, Pd(dppf)Cl2 (48.0 mg, 0.06 mmol) was added to 9a_3 (0.23 g, 0.77 mmol), 4b_3 (0.31 g, 0.64 mmol), B 2pin 2(0.30g, 1.15 mmol), KOAC (0.19g, 1.92 mmol) and K2CO3 (0.22g, 2.05 mmol) in a suspension in a mixture of 1,4-dioxane/water (7:2, 9 ml) . The reaction mass was stirred at 100°C for 3 hours, and the product was separated by silica gel column chromatography using hexane/acetone/TEA as eluent. The yield of 9a-4 was 0.30 g (90%). Step 4. Preparation of compound 9a_5. In a similar manner to step 4 of Example 7, compound 9a_5 was prepared from 9a_4 with a yield of 0.14 g (77%). Step 5. Preparation of candidate EGFR_60. Candidate EGFR_60 was prepared from 9a_4 and 7a_2 in a similar manner to Example 9 step 2 in a yield of 0.04 g (22%). Example 11.1 Method of making candidate EGFR_884.
Figure 02_image277
Step 1. Preparation of compound 9b_2. In a manner similar to step 1 of Example 11, compound 9b_2 was prepared from 9b_1 and N,N-dimethylpiperidin-4-amine with a yield of 0.56 g (48%). Step 2. Preparation of compound 9b_3. In a similar manner to step 2 of Example 11, compound 9b_3 was prepared from 9b_2 with a yield of 0.50 g (90%). Step 3. Preparation of compound 9b_4. In a similar manner to step 3 of Example 11, compound 9b_4 was prepared from 9b_3 and 4b_3 with a yield of 0.06 g (84%). Step 4. Preparation of compound 9b_5. In a similar manner to step 4 of Example 11, compound 9b_5 was prepared from 9b_4 with a yield of 0.06 g (72%). Step 5. Preparation of candidate EGFR_884. Candidate EGFR_884 was prepared from 9b_5 in a similar manner to Example 11 step 5 in a yield of 0.04 g (52%). Example 11.2 Method of making candidate EGFR_886.
Figure 02_image279
Step 1. Preparation of compound 9c_2. In a similar manner to step 1 of Example 11, compound 9c-2 was prepared from 9c-1 and N,N-dimethylpiperidin-4-amine with a yield of 0.57 g (47%). Step 2. Preparation of compound 9c_3. In a similar manner to step 2 of Example 11, compound 9c_3 was prepared from 9c_2 with a yield of 0.61 g (82%). Step 3. Preparation of compound 9c_4. In a similar manner to step 3 of Example 11, compound 9c_4 was prepared from 9c_3 and 4b_3 with a yield of 0.14 g (24%). Step 4. Preparation of compound 9c_5. In a similar manner to step 4 of Example 11, compound 9c_5 was prepared from 9c_4 with a yield of 0.08 g (91%). Step 5. Preparation of candidate EGFR_886. Candidate EGFR_886 was prepared from 9c_5 in a similar manner to Example 11 step 5 in a yield of 0.06 g (58%). Example 12. The preparation method of compound EGFR_59.
Figure 02_image281
Step 1 prepares compound 10_2. In a similar manner to Example 11 Step 1, compound 10_2 was prepared from 10_1 with a yield of 2.47 g (91%). Step 2. Preparation of compound 10_3. A solution of NIS (0.28 g, 1.2 mmol) in DMF (2.5 ml) was slowly added to a solution of 10_2 (0.25 g, 1.14 mmol) in DMF (2.5 ml) at 0 °C under argon atmosphere. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated on a rotary evaporator. The product was isolated by silica gel column chromatography using hexane/acetone/TEA as eluents. The yield of 10_3 was 0.26 g (67%). Step 3. Preparation of compound 10_4. In a manner similar to step 3 of Example 7, except that compound 10_4 was prepared from 4b_3 and 10_3 at 70°C in a yield of 0.17 g (55%). Step 4. Preparation of compound 10_5. In a similar manner to Example 7, step 4, compound 10_5 was prepared from 10_4 with a yield of 0.06 g (76%). Step 5. Preparation of candidate EGFR_59. Candidate EGFR_59 was prepared from 7a_2 and 10_5 in a similar manner to Example 11 step 5 in a yield of 40 mg (63%). Example 13. Preparation method of candidate EGFR_338.
Figure 02_image283
Step 1. Preparation of compound 11_2. Under an argon atmosphere, LiHMDS in THF (1M, 5.7 ml, 5.7 mmol) was added to a THF (10 ml) solution of 11_1 (0.46 g, 2.85 mmol), and the mixture was mixed at room temperature for 15 min. A solution of di-tert-butyl dicarbonate (0.7 g, 3.14 mmol) in THF (2 ml) was added. The mixture was stirred at room temperature for 2 h, NH 4Cl sat aq, NaCl sat aq and EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated on a rotary evaporator. The product was isolated by silica gel column chromatography using hexane/DCM/EtOAc as eluent. The yield of 11_2 was 0.68 g (93%). Step 2. Preparation of Compound 11_3. A 2.5M solution of n-butyllithium in hexane (3.21 ml, 8.03 mmol) was slowly added to 11_2 (0.91 g, 3.21 mmol) and TMEDA (0.94 g, 8.03 mmol) at -78 °C under an argon atmosphere. in THF (22 ml) solution. The mixture was stirred at -78°C for 1 hour, and I 2(4.11 g, 0.02 mol) in THF (5 ml). The RM was turned to r.t.; saturated aqueous NaCl, saturated aqueous NaHSO4 were added and the mixture was mixed at room temperature for 30 min. The product was extracted with EtOAc. The combined organic phases were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated on a rotary evaporator. The product was isolated by silica gel column chromatography using EtOAc/hexane/DCM as eluent. The yield of 11_3 was 0.63 g (52%). Step 3. Preparation of compound 11_4 A solution of 7N HCl in 1,4-dioxane (3 ml), MeOH (1 ml) and water (0.1 ml) was added to 11_3 (0.44 g, 11.0 mmol) in 1,4-dioxane (4 ml) in solution. The resulting solution was mixed at 60°C for 1 hour. The RM was concentrated, neutralized with saturated aqueous Na2CO3, and the product was extracted with EtOAc. The combined organic phases were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated on a rotary evaporator. The yield of 11_4 was 0.30 g (98%). Step 4. Preparation of compound 11_5 Compound 11_5 was prepared from 11_4 in a similar manner to Example 6, Step 2, with a yield of 0.21 g (93%). Step 5. Preparation of compound 11_6. Compound 11_6 was prepared from 11_5 in a similar manner to Example 6, step 3. The product was additionally purified by silica gel column chromatography using EtOAc/hexanes as eluent. The yield of 11_6 was 0.16 g (83%). Step 6. Preparation of compound 11_7. Compound 11_7π was prepared from 11_6 in a similar manner to Step 4 of Example 6. The product was additionally purified by silica gel column chromatography using EtOAc/MeOH/TEA as eluent. The yield of 11_7 was 0.18 g (64%). Step 7. Preparation of Compound 11_8. A solution of 11_7 (0.13 g, 0.36 mmol) and potassium tert-butoxide (0.17 g, 1.4 mmol) in NMP (5 ml) was mixed at 80 °C for 5 h, water was added, and the product was extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated on a rotary evaporator. The product was isolated by silica gel column chromatography using DCM/MeOH as eluent. The yield of 11_8 was 60 mg (47%). Step 8. Preparation of candidate EGFR_338. Candidate EGFR_338 was prepared from 11_8 and 7a_2 in a similar manner to Example 10 with a yield of 20 mg (32%). Example 14. Preparation method of candidate EGFR_1006.
Figure 02_image285
Step 1. Preparation of compound 7s_2. At 0°C, a solution of methoxymethyl chloride (294 mg, 3.47 mmol) in DCM (2 ml) was added to 7s-1 (645 mg, 2.31 mmol), DIPEA (550 mg, 4.16 mmol) in DCM (15 ml) solution. After 45 minutes, the RM was concentrated. The product was isolated by silica gel column chromatography using EtOAc/hexanes as eluent. The yield of 7s_2 was 710 mg (99%). Step 2. Preparation of compound 7s_3. 7s_2 (680 mg, 2.09 mmol), Fe (354 mg, 6.27 mmol), CaCl 2(234 mg, 2.09 mmol) in a mixture of EtOH/water (4:1, 15 ml) was stirred at 80 °C for 3 hours, filtered and concentrated. The product was isolated by silica gel column chromatography using EtOAc/hexanes as gradient eluent. The yield of 7s_3 was 548 mg (94%). Step 3. Preparation of compound 7s_4. In a similar manner to Step 1 of Example 9, compound 7s_4 was prepared from 7s_3 and 1a with a yield of 220 mg (53%). Step 4. Preparation of candidate EGFR_1006. Candidate EGFR_1006 was prepared from 7s_4 and 4f in a similar manner to Example 9 step 2 in a yield of 20 mg (13%). Example 15. Analysis of prepared compounds. The purity and structure of the obtained compounds were confirmed by chromatography/mass spectrometry LC/MS and 1H NMR spectroscopy (Table 6). Equipment information:
Figure 02_image287
Figure 02_image289
Figure 02_image291
Figure 02_image293
Figure 02_image295
Figure 02_image297
Figure 02_image299
Figure 02_image301
Figure 02_image303
Figure 02_image305
Figure 02_image307
Example 16. Determination of turbidimetric solubility of compounds in buffer. Solubility of compounds was determined in 0.01 M sodium phosphate buffer pH=7.4. The starting solution of the candidate (10 mM in DMSO) was diluted with 0.01M sodium phosphate buffer pH=7.4 to 100 μM (test solution 1), 80 μM (test solution 2), 60 μM (test solution 3), 50 μM (test solution Concentrations of solution 4), 40 μM (test solution 5), 30 μM (test solution 6), 20 μM (test solution 7), 10 μM (test solution 8). The test solution was added to the wells of a 96-plate (Corning 3635, UV plate). Plates containing test solutions were incubated for 2 hours in a thermal shaker (Biosan PST-60HL-4, Latvia). Absorption at a wavelength of 620 nm was measured using a Sunrise microplate spectrophotometer (Tecan, Australia). Plot the solution optical density as a function of concentration for samples with optical density values different from the blank, determine the linear dependence equation, and calculate the solubility value.
Figure 02_image309
Example 17. Anti-EGFR inhibitory activity in vitro. IC of the compounds disclosed in the present invention 50Values are determined using biochemical assays for inhibition of kinase activity in a cell-free system. Inhibition of EGFR wild-type and EGFR L858R/T790M/C797S kinase activity was determined using the SignalChem Kinase System and the ADP-Glo™ Kinase Assay (#V9102, Promega) Assay Kit. Prepare the necessary buffers using: 1. H2O (LC-MS). 2. 5X Reaction Buffer A (ThermoFisher, #PV6135). 3. 2 mM DTT (Sigma, #646563-10×5ML). 4. Poly 4:1 Glu, Tyr peptide (SignalChem, #P61-58-1MG). 5. ATP (V915B, Promega). Kinase buffer: 1. 4X Kinase Buffer (5X Reaction Buffer A, 200μM DTT, 4% DMSO, H2O). 2. 1X Kinase Buffer (4X Kinase Buffer, H2O). 3. Mixture (2 parts Poly 4:1 Glu, Tyr Peptide, 1 part 4X Kinase Buffer, 1 part 100μM ATP). Dissolve kinase in 1X kinase buffer. Inhibitors were titrated in increments of 5 in 1X kinase buffer with 12 concentration points starting at 50 μΜ. Measurements were performed in a 5 μl reaction volume in a 384-well format (Corning, #4513). Kinase (2 μL) and inhibitor (1 μL) were pre-incubated for 10 min. 1X Kinase Buffer was used as a negative control. Add 2 ml of the mix to each of the kinase and inhibitor mixes (final concentration of 0.2 mg/ml for peptide and 10 μM for ATP) and centrifuge the plate at 400 rcf for one minute before incubating at 25 °C For 1 hour, the amount of ADP obtained during the kinase reaction was detected using the ADP-Glo™ detection system (Promega, #V9102). Luminescent signals were measured using a Spark 20M tablet multifunction reader (Tecan, Switzerland). IC50 values were calculated using SparkControl Magellan V 3.0 software (Tecan, Switzerland) by approximating the experimental points with a four-parameter model optimized by Levenberg-Marquardt:
Figure 02_image311
Among them, A is the upper asymptote; D is the lower asymptote; C is IC50, the half-maximum inhibitory concentration, and B is the parameter of the curvature (slope).
Figure 02_image313
Figure 02_image315
Compounds of the present invention demonstrate potent inhibition of kinase activity with the target EGFR mutation L858R/T790M/C797S, and also demonstrate low activity against wild-type EGFR. Example 18. Antiproliferative activity against Ba/F3 EGFR L858R/T790M/C797S cell line. In cell assays, Ba/F3 EGFR L858R/T790M/ Continuous cultures of C797S cells (murine pro-B cell line, KYinno, KC-0122) were used to determine the antiproliferative activity of EGFR inhibitors. Cells were cultured in growth medium (DMEM high glucose (Gibco, #12800-082), supplemented with 10% FBS (Gibco, #16140-071)) and then transferred to 96-well culture plates (Corning, #3599) at 100 mL medium contains 1.5 x 10 3cells. Test compounds were dissolved in DMSO and diluted with growth medium to a final concentration of 0-10 [mu]M. Next, 100 μl of the diluted compound was added to each well (final concentration of DMSO not to exceed 1%) and incubated at 37°C in an incubator with 5% CO2 for 72 hours. After incubation, 20 ml of AlamarBlue reagent (ThermoFisher, #DAL1100) was added to each well, the contents of the plate were mixed on an orbital shaker (Biosan, Latvia) at 550 rpm for 1 min, and then incubated at 37°C in a Incubate for an additional 6 hours in a 5% CO2 incubator. The number of viable cells was detected on a Spark 20M multimode plate reader (Tecan, Switzerland) by measuring the fluorescent signal at an excitation wavelength (IEx) of 540 nm and an emission wavelength (IEm) of 590 nm. IC50 values were calculated using SparkControl Magellan V 3.0 software (Tecan, Switzerland) by approximating the experimental points with a four-parameter model optimized by Levenberg-Marquardt:
Figure 02_image317
Among them, A is the upper asymptote; D is the lower asymptote; C is IC50, the half-maximum inhibitory concentration, and B is the parameter of the curvature (slope).
Figure 02_image319
The compounds of the present invention exhibit antiproliferative activity against the Ba/F3 EGFR L858R/T790M/C797S cell line. Example 19. Anti-proliferative activity against Ba/F3 EGFR Del 19/T790M/C797S cell line. In cell assays, use the AlamarBlue vital dye ( ThermoFisher, #DAL1100) assayed the antiproliferative activity of EGFR inhibitors on continuous cultures of Ba/F3 EGFR Del19/T790M/C797S cells (murine pro-B cell line, KYinno, KC-0116). Cells were cultured in growth medium (DMEM high glucose (Gibco, #12800-082) supplemented with 10% FBS (Gibco, #16140-071)) and transferred to 96-well culture plates (Corning, #3599) at 100 mL medium contains 1.5 x 10 3cells. Test compounds were dissolved in DMSO and diluted with growth medium to a final concentration of 0-10 [mu]M. Next, 100 μl of the diluted compound was added to each well (final concentration of DMSO not to exceed 1%) and incubated at 37°C in an incubator with 5% CO2 for 72 hours. After incubation, 20 ml of AlamarBlue reagent (ThermoFisher, #DAL1100) was added to each well, the contents of the plate were mixed on an orbital shaker (Biosan, Latvia) at 550 rpm for 1 min, and then incubated at 37°C in a Incubate for an additional 6 hours in a 5% CO2 incubator. The number of viable cells was detected on a Spark 20M multimode plate reader (Tecan, Switzerland) by measuring the fluorescent signal at an excitation wavelength (IEx) of 540 nm and an emission wavelength (IEm) of 590 nm. IC50 values were calculated using SparkControl Magellan V 3.0 software (Tecan, Switzerland) by approximating the experimental points with a four-parameter model optimized by Levenberg-Marquardt:
Figure 02_image321
Among them, A is the upper asymptote; D is the lower asymptote; C is IC50, the half-maximum inhibitory concentration, and B is the parameter of the curvature (slope).
Figure 02_image323
The compounds of the present invention exhibit antiproliferative activity on the Ba/F3 EGFR Del19/T790M/C797S cell line.

Figure 110149610-A0101-11-0003-3
Figure 110149610-A0101-11-0003-3

Claims (32)

一種式I之化合物或其藥學上可接受的鹽、溶劑化物或立體異構體，該化合物為：
Figure 03_image001
， 其中L 1為化學鍵或-NH-； X 1為-CH-、-N-或-C(R 6)-； 每個n、m獨立地為0、1、2、3或4； 每個R 1獨立地為-H；-Hal；-C(Hal) 3；-CN；-NR 7R 8；-C(O)NR 9R 10；-C(O)OR 11；-C(O)R 12；-OR 13；-(C 1-C 6)烷基，未取代或被一個或多個基團R 14取代；-(C 3-C 6)環烷基，未取代或被一個或多個基團R 14a取代； R 2為-P(O)((C 1-C 6)烷基) 2，未取代或被一個或多個基團R 15取代；-P(O)((C 3-C 6)環烷基) 2，未取代或被一個或多個基團R 15a取代；-P(O)((C 1-C 6)烷基))((C 3-C 6)環烷基)，未取代或被一個或多個基團R 15b取代； -P(O)(О(C 1-C 6)烷基) 2，未取代或被一個或多個基團R 15c取代；-P(O)(О(C 3-C 6)環烷基) 2，未取代或被一個或多個基團R 15d取代；-P(O)(О(C 1-C 6)烷基)(О(C 3-C 6)環烷基)，未取代或被一個或多個基團R 15e取代；P(O)(О(C 1-C 6)烷基)((C 3-C 6)環烷基)，未取代或被一個或多個基團R 15取代； -P(O)(О(C 1-C 6)烷基)((C 1-C 6)烷基)，未取代或被一個或多個基團R 15取代；-P(O)(О(C 3-C 6)環烷基)((C 1-C 6)烷基)，未取代或被一個或多個基團R 15取代；-P(O)(О(C 3-C 6)環烷基) ((C 3-C 6)環烷基)，未取代或被一個或多個基團R 15取代； -SO 2(C 1-C 6)烷基，未取代或被一個或多個基團R 15f取代；或-SO 2(C 3-C 6)環烷基，未取代或被一個或多個基團R 15g取代； R 3為-H；-Hal；-CN；-C(Hal) 3；-NR 7aR 8a； -C(O)NR 9aR 10a；-C(O)OR 11a；-C(O)R 12a；-OR 13a；-(C 1-C 6)烷基，未取代或被一個或多個基團R 16a取代；-(C 3-C 6)環烷基，未取代或被一個或多個基團R 16b取代；-(C 6-C 12)芳基，未取代或被一個或多個基團R 16C取代；具有1或2個選自N、S或O的雜原子的4-10元雜芳基，未取代或被一個或多個基團R 16d取代； 每個R 4獨立地為-H；-Hal；-CN；-NR 7bR 8b；-C(Hal) 3；-C(O)NR 9bR 10b；-C(O)OR 11b；-C(O)R 12b；-OR 13b； -(C 1-C 6)烷基，未取代或被一個或多個基團R 17a取代； -(C 3-C 6)環烷基，未取代或被一個或多個基團R 17b取代；具有1或2個選自N、S或О的雜原子的4-10元雜環基，未取代或被一個或多個基團R 17c取代；或-(C 6-C 12)芳基，未取代或被一個或多個基團R 17d取代； R 5為： -NR 7сR 18；-NR 7dR 19；-W 1；-OW 2；-NR aW 3； -C(O)W 4；或-(CH 2)W 5； 其中每個W 1、W 2、W 3、W 4或W 5獨立地為-(C 3-C 6)環烷基，未取代或被一個或多個基團R 20取代；具有1或2個選自N、S或O的雜原子的4-7元雜環基，未取代或被一個或多個基團R 20取代， R 6為-Hal、-CN、-C(Hal) 3、CH (Hal) 2、CH 2Hal、 -NR 7eR 8C；-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R 7、R 7a、R 7b、R 7e、R 8、R 8a、R 8b、R 8C、R 9、R 9a、R 9b、R 10、R 10a、R 10b獨立地為-H、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代；-(C 3-C 6)環烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R 7c、R 7d、R a獨立地為-H、-(С 1-С 6)烷基； R 18為-(С 1-С 10)烷基，其未被取代或被一個或多個選自-Hal、-OH、-NO 2、-NR 23R 24、(=O)的取代基取代； R 19為具有1或2個選自N、S或O的雜原子的2-10元雜烷基，其未被取代或被一個或多個選自-Hal、-OH、-NO 2、 -NR 23R 24、(=O)的取代基取代； 每個R 11、R 12、R 13、R 11a、R 12a、R 13a、R 11b、R 12b、R 13b獨立地為-H；-(C 1-C 6)烷基，未取代或被一個或多個基團R 21取代；-(C 3-C 6)環烷基，未取代或被一個或多個基團R 21a取代；-(C 6-C 12)芳基，未取代或被一個或多個基團R 21b取代，具有1或2個選自N、S或О的雜原子的4-10元雜環基，未取代或被一個或多個基團R 21c取代； 每個R 14、R 14a、R 15、R 15a、R 15、R 15a、R 15b、R 15c、R 15d、R 15e、R 15f、R 15g、R 16、R 16a、R 16b、R 16C、R 16d、R 17、R 17a、R 17b、R 17c、R 17d獨立地為-Hal、-H、-OH、 -NO 2、-NR 23R 24、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R 20獨立地為(=O)、-NR 7fR 8d、-(C 1-C 6)烷基，未取代或被一個或多個基團R 22取代，具有1或2個選自N、O或S的雜原子的2-8元雜烷基，未取代或被一個或多個基團R 22a取代，-(C 3-C 6)環烷基，未取代或被一個或多個基團R 22b取代，具有1或2個選自N、S或О的雜原子的4-10元雜環基，未取代或被一個或多個基團R 22с取代； 每個R 7f、R 8d獨立地為-H、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代；-(C 3-C 6)環烷基，其未被取代或被一個或多個選自 -Hal、-NH 2、-OH、(=O)的基團取代； 每個R 21、R 21a、R 21b、R 21с、R 22、R 22a、R 22b、R 22с獨立地為-Hal、-H、-OH、-NO 2、-NR 23R 24、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-O(C 1-C 6)烷基、-ОH、(=O)的基團取代； 每個R 23、R 24獨立地為-H；-(C 1-C 6)烷基，其未被取代或被一個或多個選自(=О)、-ОH、-NR 25R 26的基團取代；-(C 2-C 6)烯基，其未被取代或被一個或多個選自(=О)、-NR 25aR 26a的基團取代； 每個R 25、R 26、R 25a、R 26a獨立地為-H、-(C 1-C 6)烷基； Hal是氟、溴、氯或碘原子。 A compound of formula I or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, the compound is:
Figure 03_image001
, wherein L 1 is a chemical bond or -NH-; X 1 is -CH-, -N- or -C(R 6 )-; each n, m is independently 0, 1, 2, 3 or 4; each R 1 is independently -H; -Hal; -C(Hal) 3 ; -CN; -NR 7 R 8 ; -C(O)NR 9 R 10 ; -C(O)OR 11 ; R 12 ; -OR 13 ; -(C 1 -C 6 )alkyl, unsubstituted or substituted by one or more groups R 14 ; -(C 3 -C 6 )cycloalkyl, unsubstituted or substituted by one or Multiple groups R 14a are substituted; R 2 is -P(O)((C 1 -C 6 )alkyl) 2 , unsubstituted or substituted by one or more groups R 15 ; -P(O)(( C 3 -C 6 )cycloalkyl) 2 , unsubstituted or substituted by one or more groups R 15a ; -P(O)((C 1 -C 6 )alkyl))((C 3 -C 6 )cycloalkyl), unsubstituted or substituted by one or more groups R 15b ; -P(O)(О(C 1 -C 6 )alkyl) 2 , unsubstituted or substituted by one or more groups R 15c substituted; -P(O)(О(C 3 -C 6 )cycloalkyl) 2 , unsubstituted or substituted by one or more groups R 15d ; -P(O)(О(C 1 -C 6 )alkyl)(О(C 3 -C 6 )cycloalkyl), unsubstituted or substituted by one or more groups R 15e ; P(O)(О(C 1 -C 6 )alkyl)(( C 3 -C 6 )cycloalkyl), unsubstituted or substituted by one or more groups R 15 ; -P(O)(О(C 1 -C 6 )alkyl)((C 1 -C 6 ) Alkyl), unsubstituted or substituted by one or more groups R 15 ; -P(O)(О(C 3 -C 6 )cycloalkyl)((C 1 -C 6 )alkyl), unsubstituted Or substituted by one or more groups R 15 ; -P(O)(О(C 3 -C 6 )cycloalkyl) ((C 3 -C 6 )cycloalkyl), unsubstituted or substituted by one or more -SO 2 (C 1 -C 6 )alkyl, unsubstituted or substituted by one or more groups R 15f ; or -SO 2 (C 3 -C 6 )cycloalkyl, unsubstituted -C(Hal) 3 ; -NR 7a R 8a ; -C(O)NR 9a R 10a ; -C (O)OR 11a ; -C(O)R 12a ; -OR 13a ; -(C 1 -C 6 )alkyl, unsubstituted or substituted by one or more groups R 16 a ; -(C 3 -C 6 ) Cycloalkyl, unsubstituted or replaced by one or more groups R 16b -(C 6 -C 12 )aryl, unsubstituted or substituted by one or more groups R 16C ; 4-10 membered heteroaryl with 1 or 2 heteroatoms selected from N, S or O , unsubstituted or substituted by one or more groups R 16d ; each R 4 is independently -H; -Hal; -CN; -NR 7b R 8b ; -C(Hal) 3 ; -C(O)NR 9b R 10b ; -C(O)OR 11b ; -C(O)R 12b ; -OR 13b ; -(C 1 -C 6 )alkyl, unsubstituted or substituted by one or more groups R 17a ; (C 3 -C 6 )cycloalkyl, unsubstituted or substituted by one or more groups R 17b ; 4-10 membered heterocyclyl having 1 or 2 heteroatoms selected from N, S or О, unsubstituted substituted or substituted by one or more groups R 17c ; or -(C 6 -C 12 )aryl, unsubstituted or substituted by one or more groups R 17d ; R 5 is: -NR 7 сR 18 ;- NR 7d R 19 ; -W 1 ; -OW 2 ; -NR a W 3 ; -C(O)W 4 ; or -(CH 2 )W 5 ; wherein each of W 1 , W 2 , W 3 , W 4 or W 5 is independently -(C 3 -C 6 )cycloalkyl, unsubstituted or substituted by one or more groups R 20 ; 4- with 1 or 2 heteroatoms selected from N, S or O 7-membered heterocyclic group, unsubstituted or substituted by one or more groups R 20 , R 6 is -Hal, -CN, -C(Hal) 3 , CH (Hal) 2 , CH 2 Hal, -NR 7e R 8C ; -(C 1 -C 6 ) alkyl, which is unsubstituted or substituted by one or more groups selected from -Hal, -NH 2 , -OH, (=O); each R 7 , R 7a , R 7b , R 7e , R 8 , R 8a , R 8b , R 8C , R 9 , R 9a , R 9b , R 10 , R 10a , R 10b are independently -H, -(C 1 -C 6 ) alkyl, which is unsubstituted or substituted by one or more groups selected from -Hal, -NH 2 , -OH, (=O); -(C 3 -C 6 )cycloalkyl, which is not substituted by substituted or substituted by one or more groups selected from -Hal, -NH 2 , -OH, (=O); each R 7c , R 7d , R a is independently -H, -(С 1 -С 6 ) Alkyl; R 18 is -(С 1 -С 10 ) alkyl, which is unsubstituted or replaced by one or more selected from -Hal, -OH, -NO 2 , -NR 23 R 24 , (=O ) is substituted by a substituent; R 19 is a 2-10 membered heteroalkyl group having 1 or 2 heteroatoms selected from N, S or O, which Unsubstituted or substituted by one or more substituents selected from -Hal, -OH, -NO 2 , -NR 23 R 24 , (=O); each R 11 , R 12 , R 13 , R 11 a , R 12 a , R 13 a , R 11b , R 12b , R 13b are independently -H; -(C 1 -C 6 )alkyl, unsubstituted or substituted by one or more groups R 21 ; -( C 3 -C 6 )cycloalkyl, unsubstituted or substituted by one or more groups R 21a; - (C 6 -C 12 )aryl, unsubstituted or substituted by one or more groups R 21b , A 4-10 membered heterocyclic group having 1 or 2 heteroatoms selected from N, S or О, unsubstituted or substituted by one or more groups R 21c ; each of R 14 , R 14a , R 15 , R 15a , R 15 , R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , R 15g , R 16 , R 16a , R 16b , R 16c , R 16d , R 17 , R 17a , R 17b , R 17c , R 17d are independently -Hal, -H, -OH, -NO 2 , -NR 23 R 24 , -(C 1 -C 6 )alkyl, which are unsubstituted or selected by one or more Group substitution from -Hal, -NH 2 , -OH, (=O); each R 20 is independently (=O), -NR 7f R 8d , -(C 1 -C 6 )alkyl, not Substituted or substituted by one or more groups R22 , 2-8 membered heteroalkyl having 1 or 2 heteroatoms selected from N, O or S, unsubstituted or substituted by one or more groups R22a , -(C 3 -C 6 )cycloalkyl, unsubstituted or substituted by one or more groups R 22b , 4-10 membered heterocyclyl having 1 or 2 heteroatoms selected from N, S or О , unsubstituted or substituted by one or more groups R 22с ; each R 7f , R 8d is independently -H, -(C 1 -C 6 ) alkyl, which is unsubstituted or substituted by one or more selected Substituted by a group from -Hal, -NH 2 , -OH, (=O); -(C 3 -C 6 )cycloalkyl, which is unsubstituted or replaced by one or more groups selected from -Hal, -NH 2 , -OH, (=O) group substitution; each R 21 , R 21 a, R 21b , R 21 с, R 22 , R 22a , R 22b , R 22с are independently -Hal, -H, - OH, -NO 2 , -NR 23 R 24 , -(C 1 -C 6 )alkyl, which are unsubstituted or replaced by one or more selected from -Hal, -NH 2 , -O(C 1 -C 6 )Alkyl, -ОH, (=O) groups Substituted; each R 23 , R 24 is independently -H; -(C 1 -C 6 ) alkyl, which is unsubstituted or replaced by one or more selected from (=О), -ОH, -NR 25 R 26 ; -(C 2 -C 6 )alkenyl, which is unsubstituted or substituted by one or more groups selected from (=О), -NR 25a R 26a ; each R 25 , R 26 , R 25a , R 26a are independently -H, -(C 1 -C 6 )alkyl; Hal is a fluorine, bromine, chlorine or iodine atom. 如請求項1所述之化合物或其藥學上可接受的鹽、溶劑化物或立體異構體，其中 L 1為化學鍵，R 2為-P(O)((C 1-C 6)烷基) 2，未取代或被一個或多個基團R 15取代；-P(O)((C 3-C 6)環烷基) 2，未取代或被一個或多個基團R 15a取代；-P(O)((C 1-C 6)烷基))((C 3-C 6)環烷基)，未取代或被一個或多個基團R 15b取代； -P(O)(О(C 1-C 6)烷基) 2，未取代或被一個或多個基團R 15c取代；-P(O)(О(C 3-C 6)環烷基) 2，未取代或被一個或多個基團R 15d取代；-P(O)(О(C 1-C 6)烷基)(О(C 3-C 6)環烷基)，未取代或被一個或多個基團R 15e取代；P(O)(О(C 1-C 6)烷基)((C 3-C 6)環烷基)，未取代或被一個或多個基團R 15取代； -P(O)(О(C 1-C 6)烷基)((C 1-C 6)烷基)，未取代或被一個或多個基團R 15取代；-P(O)(О(C 3-C 6)環烷基)((C 1-C 6)烷基)，未取代或被一個或多個基團R 15取代；-P(O)(О(C 3-C 6)環烷基) ((C 3-C 6)環烷基)，未取代或被一個或多個基團R 15取代；P(O)(О(C 1-C 6)烷基)((C 3-C 6)環烷基)，未取代或被一個或多個基團R 15取代；-P(O)(О(C 1-C 6)烷基)((C 1-C 6)烷基)，未取代或被一個或多個基團R 15取代；-P(O)(О(C 3-C 6)環烷基) ((C 1-C 6)烷基)，未取代或被一個或多個基團R 15取代； -P(O)(О(C 3-C 6)環烷基)((C 3-C 6)環烷基)，未取代或被一個或多個基團R 15取代；或L 1為-NH-，R 2為-SO 2(C 1-C 6)烷基，未取代或被一個或多個基團R 15f取代；或-SO 2(C 3-C 6)環烷基，未取代或被一個或多個基團R 15g取代，其中 每個R 15、R 15a、R 15、R 15a、R 15b、R 15c、R 15d、R 15e、R 15f、R 15g獨立地為-Hal、-H、-OH、-NO 2、-NR 23R 24、 -(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、 -NH 2、-OH、(=O)的基團取代； 每個R 23、R 24獨立地為-H；-(C 1-C 6)烷基，其未被取代或被一個或多個選自(=О)、-ОH、-NR 25R 26的基團取代；-(C 2-C 6)烯基，其未被取代或被一個或多個選自(=О)、-NR 25aR 26a的基團取代； 每個R 25、R 26、R 25a、R 26a獨立地為-H、-(C 1-C 6)烷基， Hal是氟、溴、氯或碘原子。 The compound as described in Claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein L 1 is a chemical bond, R 2 is -P(O)((C 1 -C 6 )alkyl) 2 , unsubstituted or substituted by one or more groups R 15 ; -P(O)((C 3 -C 6 )cycloalkyl) 2 , unsubstituted or substituted by one or more groups R 15a ;- P(O)((C 1 -C 6 )alkyl))((C 3 -C 6 )cycloalkyl), unsubstituted or substituted by one or more groups R 15b ; -P(O)(О (C 1 -C 6 )alkyl) 2 , unsubstituted or substituted by one or more groups R 15c ; -P(O)(О(C 3 -C 6 )cycloalkyl) 2 , unsubstituted or substituted by One or more groups R 15d are substituted; -P(O)(О(C 1 -C 6 )alkyl)(О(C 3 -C 6 )cycloalkyl), unsubstituted or by one or more groups substituted by group R 15e ; P(O)(О(C 1 -C 6 )alkyl)((C 3 -C 6 )cycloalkyl), unsubstituted or substituted by one or more groups R 15 ; -P (O)(О(C 1 -C 6 )alkyl)((C 1 -C 6 )alkyl), unsubstituted or substituted by one or more groups R 15 ; -P(O)(О(C 3 -C 6 )cycloalkyl)((C 1 -C 6 )alkyl), unsubstituted or substituted by one or more groups R 15 ; -P(O)(О(C 3 -C 6 )ring Alkyl) ((C 3 -C 6 )cycloalkyl), unsubstituted or substituted by one or more groups R 15 ; P(O)(О(C 1 -C 6 )alkyl) ((C 3 -C 6 )cycloalkyl), unsubstituted or substituted by one or more groups R 15 ; -P(O)(О(C 1 -C 6 )alkyl)((C 1 -C 6 )alkyl ), unsubstituted or substituted by one or more groups R 15 ; -P(O)(О(C 3 -C 6 )cycloalkyl) ((C 1 -C 6 )alkyl), unsubstituted or substituted by One or more groups R 15 are substituted; -P(O)(О(C 3 -C 6 )cycloalkyl)((C 3 -C 6 )cycloalkyl), unsubstituted or by one or more groups Group R 15 substituted; or L 1 is -NH-, R 2 is -SO 2 (C 1 -C 6 ) alkyl, unsubstituted or substituted by one or more groups R 15f ; or -SO 2 (C 3 -C 6 ) cycloalkyl, unsubstituted or substituted by one or more groups R 15g , wherein each of R 15 , R 15a , R 15 , R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , R 15g are independently -Hal, -H, -OH, -NO 2 , -NR 23 R 24. -(C 1 -C 6 )alkyl, which is unsubstituted or substituted by one or more groups selected from -Hal, -NH 2 , -OH, (=O); each R 23 , R 24 is independently -H; -(C 1 -C 6 ) alkyl, which is unsubstituted or substituted by one or more groups selected from (=О), -ОH, -NR 25 R 26 ; -( C 2 -C 6 ) alkenyl, which is unsubstituted or substituted by one or more groups selected from (=О), -NR 25a R 26a ; each R 25 , R 26 , R 25a , R 26a independently H is -H, -(C 1 -C 6 )alkyl, and Hal is a fluorine, bromine, chlorine or iodine atom. 如請求項1所述之化合物或其藥學上可接受的鹽、溶劑化物或立體異構體，其中R 6為-Hal、-CN、 -C(Hal) 3、CH(Hal) 2、CH 2Hal。 The compound as described in Claim 1 or its pharmaceutically acceptable salt, solvate or stereoisomer, wherein R 6 is -Hal, -CN, -C(Hal) 3 , CH(Hal) 2 , CH 2 Hal. 如請求項1所述之化合物或其藥學上可接受的鹽、溶劑化物或立體異構體，其中R 1各自獨立地表示Hal；-C(Hal) 3；-O(CHal 3)；-CN；-O(С 1-С 6)烷基， -O(CH 2) 2O-(С 1-С 6)烷基。 The compound or pharmaceutically acceptable salt, solvate or stereoisomer thereof as claimed in item 1, wherein R 1 each independently represents Hal; -C(Hal) 3 ; -O(CHal 3 ); -CN ; -O(С 1 -С 6 )alkyl, -O(CH 2 ) 2 O-(С 1 -С 6 )alkyl. 如請求項1所述之化合物或其藥學上可接受的鹽、溶劑化物或立體異構體，其中R 1各自獨立地表示-F、-Cl、-Br、-CF 3、-CCl 3、-O(CF 3)、-O(CCl 3)、-OCH 3、-OCH 2CH 3、-O(CH 2) 2O-СН 3、-O(CH 2) 2O-СН 2-СН 3。 The compound as described in Claim 1 or its pharmaceutically acceptable salt, solvate or stereoisomer, wherein R 1 each independently represents -F, -Cl, -Br, -CF 3 , -CCl 3 , - O(CF 3 ), -O(CCl 3 ), -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 O-СН 3 , -O(CH 2 ) 2 O-СН 2 -СН 3 . 如請求項1所述之化合物或其藥學上可接受的鹽、溶劑化物或立體異構體，其中R 2為 -P(O)((C 1-C 6)烷基) 2、-P(O)((C 3-C 6)環烷基) 2、-P(O)((C 1-C 6)烷基))((C 3-C 6)環烷基))、-P(O)(O(C 1-C 6)烷基) 2、 -P(O)(O(C 3-C 6)環烷基) 2、-P(O)(O(C 1-C 6)烷基)((C 3-C 6)環烷基)、P(O)(O(C 1-C 6)烷基)((C 1-C 6)烷基)、P(O)(O(C 3-C 6)環烷基)((C 1-C 6)烷基)、P(O)(O(C 3-C 6)環烷基)((C 3-C 6)環烷基)、-SO 2(C 1-C 6)烷基。 The compound as described in Claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 2 is -P(O)((C 1 -C 6 )alkyl) 2 , -P( O)((C 3 -C 6 )cycloalkyl) 2 , -P(O)((C 1 -C 6 )alkyl))((C 3 -C 6 )cycloalkyl)), -P( O)(O(C 1 -C 6 )alkyl) 2 , -P(O)(O(C 3 -C 6 )cycloalkyl) 2 , -P(O)(O(C 1 -C 6 ) Alkyl)((C 3 -C 6 )cycloalkyl), P(O)(O(C 1 -C 6 )alkyl)((C 1 -C 6 )alkyl), P(O)(O (C 3 -C 6 )cycloalkyl)((C 1 -C 6 )alkyl), P(O)(O(C 3 -C 6 )cycloalkyl)((C 3 -C 6 )cycloalkane group), -SO 2 (C 1 -C 6 )alkyl. 如請求項6所述之化合物或其藥學上可接受的鹽、溶劑化物或立體異構體，其中R 2是-P(O)(CH 3) 2，P(O)(CH 2CH 3) 2，-P(O)(CH 3)(CH 2CH 3)，-P(O)(環丙基) 2， -P(O)(CH 3)(環丙基)，-P(O)(CH 2CH 3)(環丙基)， -P(O)(OCH 3) 2，-P(O)(OCH 2CH 3) 2， -P(O)(OCH 3)(OCH 2CH 3)，-P(O)(OCH 3)(CH 3)， -P(O)(OCH 3)(CH 2CH 3)，-P(O)(OCH 2CH 3)(CH 3)， -P(O)(OCH 2CH 3)(CH 2CH 3)，-P(O)(OCH 3)(環丙基)， -P(O)(OСH2CH 3)(環丙基)，-SO 2CH 3，SO 2CH 2CH 3。 The compound as described in claim 6 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 2 is -P(O)(CH 3 ) 2 , P(O)(CH 2 CH 3 ) 2 , -P(O)(CH 3 )(CH 2 CH 3 ), -P(O)(cyclopropyl) 2 , -P(O)(CH 3 )(cyclopropyl), -P(O) (CH 2 CH 3 )(cyclopropyl), -P(O)(OCH 3 ) 2 , -P(O)(OCH 2 CH 3 ) 2 , -P(O)(OCH 3 )(OCH 2 CH 3 ), -P(O)(OCH 3 )(CH 3 ), -P(O)(OCH 3 )(CH 2 CH 3 ), -P(O)(OCH 2 CH 3 )(CH 3 ), -P (O)(OCH 2 CH 3 )(CH 2 CH 3 ), -P(O)(OCH 3 )(cyclopropyl), -P(O)(OСH2CH 3 )(cyclopropyl), -SO 2 CH 3 , SO 2 CH 2 CH 3 . 如請求項1所述之化合物或其藥學上可接受的鹽、溶劑化物或立體異構體，其中R 3是-H；-Hal； -С(Hal) 3，-CN；-NR 7aR 8a；-C(O)NR 9aR 10a；-CO(O)R 11a； -C(O)R 12a；-OR 13a；-(C 1-C 6)烷基，未取代或被一個或多個基團R 16a取代；-(C 3-C 6)環烷基，未取代或被一個或多個基團R 16b取代；苯基，未取代或被一個或多個基團R 16C取代， 其中每個R 7a、R 8a、R 9a、R 10a獨立地為-H、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R 11a、R 12a、R 13a獨立地為-H；-(C 1-C 6)烷基，未取代或被一個或多個基團R 21取代；-(C 3-C 6)環烷基，未取代或被一個或多個基團R 21a取代；-(C 6-C 12)芳基，未取代或被一個或多個基團R 21b取代；-(C 4-C 8)雜環基，其具有1或2個選自N、S或О的雜原子，未取代或被一個或多個基團R 21c取代； 每個R 16a、R 16b、R 16C、R 21、R 21a、R 21b、R 21с獨立地為-H、-OH、-NO 2、-NR 23R 24、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)、-O(C 1-C 6)烷基的基團取代； 每個R 23、R 24獨立地為-H；-(C 1-C 6)烷基，其未被取代或被一個或多個選自(=О)、-ОH、-NR 25R 26的基團取代；-(C 2-C 6)烯基，其未被取代或被一個或多個選自(=О)、-NR 25aR 26a的基團取代； 每個R 25、R 26、R 25a、R 26a獨立地為-H、-(C 1-C 6)烷基； Hal是氟、溴、氯或碘原子。 The compound as claimed in item 1 or its pharmaceutically acceptable salt, solvate or stereoisomer, wherein R 3 is -H; -Hal; -С(Hal) 3 , -CN; -NR 7a R 8a ;-C(O)NR 9a R 10a ;-CO(O)R 11a ;-C(O)R 12a ; -OR 13a ; The group R 16 a is substituted; -(C 3 -C 6 )cycloalkyl, unsubstituted or substituted by one or more groups R 16b ; phenyl, unsubstituted or substituted by one or more groups R 16c , Wherein each R 7a , R 8a , R 9a , R 10a is independently -H, -(C 1 -C 6 )alkyl, which is unsubstituted or replaced by one or more selected from -Hal, -NH 2 , -OH, (=O) group substitution; each R 11 a, R 12 a, R 13 a is independently -H; -(C 1 -C 6 ) alkyl, unsubstituted or by one or more The group R 21 is substituted; -(C 3 -C 6 )cycloalkyl, unsubstituted or substituted by one or more groups R 21 a; -(C 6 -C 12 )aryl, unsubstituted or by one or Substituted by multiple groups R 21b ; -(C 4 -C 8 )heterocyclyl having 1 or 2 heteroatoms selected from N, S or О, unsubstituted or substituted by one or more groups R 21c ; each of R 16 a , R 16b , R 16C , R 21 , R 21 a, R 21b , R 21 с is independently -H, -OH, -NO 2 , -NR 23 R 24 , -(C 1 - C 6 ) alkyl, which is unsubstituted or substituted by one or more groups selected from -Hal, -NH 2 , -OH, (=O), -O(C 1 -C 6 ) alkyl; each R 23 and R 24 are independently -H; -(C 1 -C 6 ) alkyl, which is unsubstituted or replaced by one or more groups selected from (=О), -ОH, -NR 25 R 26 -(C 2 -C 6 )alkenyl, which is unsubstituted or substituted by one or more groups selected from (=О), -NR 25a R 26a ; each of R 25 , R 26 , R 25a and R 26a are independently -H, -(C 1 -C 6 )alkyl; Hal is a fluorine, bromine, chlorine or iodine atom. 如請求項1所述之化合物或其藥學上可接受的鹽、溶劑化物或立體異構體，其中R 3是-CN；苯基，其未被取代或被一個基團R 16C取代，選自丙-2-烯胺基、3-羥基丙醯胺基、3-(二甲基胺基)丙醯胺基，其中R 16C是 -Hal、-H、-OH、-NO 2、-NR 23R 24、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代。 A compound as claimed in claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 3 is -CN; phenyl, which is unsubstituted or substituted by a group R 16C selected from Prop-2-enylamino, 3-hydroxyacrylamide, 3-(dimethylamino)acrylamide, wherein R 16C is -Hal, -H, -OH, -NO 2 , -NR 23 R 24 , -(C 1 -C 6 )alkyl, which is unsubstituted or substituted by one or more groups selected from -Hal, -NH 2 , -OH, (=O). 如請求項1所述之化合物或其藥學上可接受的鹽、溶劑化物或立體異構體，其中每個R 4獨立地是-H；-Hal；-C(Hal) 3；-CN；-NR 7bR 8b；-C(O)NR 9bR 10b； -C(O)R 11b；-C(O)OR 12b；-OR 13b；-(C 1-C 6)烷基，未取代或被一個或多個基團R 17a取代，其中 每個R 7b、R 8b、R 9b、R 10b獨立地為-H、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R 11b、R 12b、R 13b獨立地為-H；-(C 1-C 6)烷基，未取代或被一個或多個基團R 21取代；-(C 3-C 6)環烷基，未取代或被一個或多個基團R 21a取代；-(C6-C12)芳基，未取代或被一個或多個基團R21b取代；-(C 4-C 8)雜環基，其具有1或2個選自N、S或О的雜原子，未取代或被一個或多個基團R 21c取代； 每個R 17a，R 21，R 21a，R 21b，R 21с獨立地為-H，-OH，-NO 2，-Hal，-NR 23R 24，-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal，-NH 2，-OH，(=O)，-O(C 1-C 6)烷基的基團取代； 每個R 23、R 24獨立地為-H；-(C 1-C 6)烷基，其未被取代或被一個或多個選自(=О)、-ОH、-NR 25R 26的基團取代；-(C 2-C 6)烯基，其未被取代或被一個或多個選自(=О)、-NR 25aR 26a的基團取代； 每個R 25、R 26、R 25a、R 26a獨立地為-H、-(C 1-C 6)烷基； Hal是氟、溴、氯或碘原子。 The compound as claimed in item 1 or its pharmaceutically acceptable salt, solvate or stereoisomer, wherein each R 4 is independently -H; -Hal; -C(Hal) 3 ; -CN; - NR 7b R 8b ; -C(O)NR 9b R 10b ; -C(O)R 11b ; -C(O)OR 12b ; -OR 13b ; -(C 1 -C 6 )alkyl, unsubstituted or One or more groups R 17a are substituted, wherein each R 7b , R 8b , R 9b , R 10b is independently -H, -(C 1 -C 6 )alkyl, which is unsubstituted or replaced by one or more A group selected from -Hal, -NH 2 , -OH, (=O) is substituted; each R 11b , R 12b , R 13b is independently -H; -(C 1 -C 6 ) alkyl, not Substituted or substituted by one or more groups R 21 ; -(C 3 -C 6 )cycloalkyl, unsubstituted or substituted by one or more groups R 21 a; -(C6-C12)aryl, unsubstituted Substituted or substituted by one or more groups R21b; -(C 4 -C 8 ) heterocyclyl, which has 1 or 2 heteroatoms selected from N, S or О, unsubstituted or substituted by one or more groups Group R 21c is substituted; each R 17a , R 21 , R 21a , R 21b , R 21 с are independently -H, -OH, -NO 2 , -Hal, -NR 23 R 24 , -(C 1 -C 6 ) Alkyl, which is unsubstituted or substituted by one or more groups selected from -Hal, -NH 2 , -OH, (=O), -O(C 1 -C 6 )alkyl; each R 23 and R 24 are independently -H; -(C 1 -C 6 )alkyl, which is unsubstituted or replaced by one or more groups selected from (=О), -ОH, -NR 25 R 26 Substituted; -(C 2 -C 6 )alkenyl, which is unsubstituted or substituted by one or more groups selected from (=О), -NR 25a R 26a ; each of R 25 , R 26 , R 25a , R 26a are independently -H, -(C 1 -C 6 )alkyl; Hal is a fluorine, bromine, chlorine or iodine atom. 如請求項10所述之化合物或其藥學上可接受的鹽、溶劑化物或立體異構體，其中每個R 4獨立地是-H；-(C 1-C 6)烷基、-O(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-OH、-NO 2、-NH 2的基團取代。 The compound as described in claim 10 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 4 is independently -H; -(C 1 -C 6 )alkyl, -O( C 1 -C 6 ) alkyl, which is unsubstituted or substituted by one or more groups selected from -Hal, -OH, -NO 2 , -NH 2 . 如請求項1所述之化合物或其藥學上可接受的鹽、溶劑化物或立體異構體，其中R 5是： -NR 7сR 18；-NR 7dR 19；-W 1；-OW 2；-NR aW 3； -C(O)W 4；或-(CH 2)W 5； 其中每個W 1、W 2、W 3、W 4或W 5獨立地為-(C 3-C 6)環烷基，其未被取代或被一個或多個基團R 20取代，選自
Figure 03_image003
具有1或2個選自N、S或О的雜原子的5-7元雜環基，其未被取代或被一個或多個基團R 20取代，選自
Figure 03_image005
Figure 03_image007
Figure 03_image009
Figure 03_image011
其中р是0、1、2或3； 每個Y 1、Y 2獨立地為CH 2、СHR 20、C(R 20) 2、NH、NR 20、S或O； 每個R 7c、R 7dR a獨立地為-H、-(С 1-С 6)烷基； R 18為-(С 1-С 10)烷基，其未被取代或被一個或多個選自-Hal、-OH、-NO 2、-NR 23R 24、(=O)的取代基取代； R 19為具有1或2個選自N、S或O的雜原子的2-10元雜烷基，其未被取代或被一個或多個選自-Hal、-OH、-NO 2、 -NR 23R 24、(=O)的取代基取代； 每個R 20獨立地為(=O)、-NR 7fR 8d、-(C 1-C 6)烷基，未取代或被一個或多個基團R 22取代，具有1或2個選自N、O或S的雜原子的-(C 2-C 6)雜烷基，未取代或被一個或多個基團R 22a取代，-(C 3-C 6)環烷基，未取代或被一個或多個基團R 22b取代，-(C 4-C 8)雜環基，其具有1或2個選自N、S或О的雜原子，未取代或被一個或多個基團R 22с取代； 每個R 7f、R 8d獨立地為H、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R 22、R 22a、R 22b、R 22с獨立地為-H、-OH、-NO 2、-NR 23R 24、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R 23、R 24獨立地為-H；-(C 1-C 6)烷基，其未被取代或被一個或多個選自(=О)、-ОH、-NR 25R 26的基團取代；-(C 2-C 6)烯基，其未被取代或被一個或多個選自(=О)、-NR 25aR 26a的基團取代； 每個R 25、R 26、R 25a、R 26a獨立地為-H、-(C 1-C 6)烷基； Hal是氟、溴、氯或碘原子。 The compound as claimed in claim 1 or its pharmaceutically acceptable salt, solvate or stereoisomer, wherein R 5 is: -NR 7 сR 18 ; -NR 7d R 19 ; -W 1 ; -OW 2 ; -NR a W 3 ; -C(O)W 4 ; or -(CH 2 )W 5 ; wherein each W 1 , W 2 , W 3 , W 4 or W 5 is independently -(C 3 -C 6 ) cycloalkyl, which is unsubstituted or substituted by one or more groups R 20 selected from
Figure 03_image003
A 5-7 membered heterocyclic group having 1 or 2 heteroatoms selected from N, S or О, which is unsubstituted or substituted by one or more groups R 20 selected from
Figure 03_image005
Figure 03_image007
Figure 03_image009
Figure 03_image011
wherein р is 0, 1, 2 or 3; each Y 1 , Y 2 is independently CH 2 , СHR 20 , C(R 20 ) 2 , NH, NR 20 , S or O; each R 7c , R 7d R a is independently -H, -(С 1 -С 6 ) alkyl; R 18 is - (С 1 -С 10 ) alkyl, which is unsubstituted or replaced by one or more selected from -Hal, -OH , -NO 2 , -NR 23 R 24 , (=O) are substituted by substituents; R 19 is a 2-10 membered heteroalkyl group having 1 or 2 heteroatoms selected from N, S or O, which is not substituted or substituted by one or more substituents selected from -Hal, -OH, -NO 2 , -NR 23 R 24 , (=O); each R 20 is independently (=O), -NR 7f R 8d , -(C 1 -C 6 )alkyl, unsubstituted or substituted by one or more groups R 22 , -(C 2 -C 6 with 1 or 2 heteroatoms selected from N, O or S ) heteroalkyl, unsubstituted or substituted by one or more groups R 22a , -(C 3 -C 6 )cycloalkyl, unsubstituted or substituted by one or more groups R 22b , -(C 4 - C 8 ) heterocyclic group, which has 1 or 2 heteroatoms selected from N, S or О, unsubstituted or substituted by one or more groups R 22с ; each R 7f , R 8d is independently H, -(C 1 -C 6 )alkyl, which is unsubstituted or substituted by one or more groups selected from -Hal, -NH 2 , -OH, (=O); each R 22 , R 22a , R 22b and R 22с are independently -H, -OH, -NO 2 , -NR 23 R 24 , -(C 1 -C 6 )alkyl, which are unsubstituted or replaced by one or more selected from -Hal, -NH 2 , -OH, (=O) group substitution; each R 23 , R 24 is independently -H; -(C 1 -C 6 ) alkyl, which is unsubstituted or replaced by one or more Substituted by a group selected from (=О), -ОH, -NR 25 R 26 ; -(C 2 -C 6 ) alkenyl, which is unsubstituted or replaced by one or more groups selected from (=О), -NR 25a R 26a is substituted by a group; each R 25 , R 26 , R 25a , R 26a is independently -H, -(C 1 -C 6 )alkyl; Hal is a fluorine, bromine, chlorine or iodine atom. 如請求項12所述之化合物或其藥學上可接受的鹽、溶劑化物或立體異構體，其中R 5是： -NR 7сR 18；-NR 7dR 19；-W 1；-OW 2；-NR aW 3； -C(O)W 4；或-(CH 2)W 5R； 其中每個W 1、W 2、W 3、W 4或W 5獨立地為
Figure 03_image013
Figure 03_image015
Figure 03_image017
Figure 03_image019
其中p是0、1、2或3； 每個R 7c、R 7d獨立地為-H、-(С 1-С 6)烷基； R 18為-(С 1-С 10)烷基，其未被取代或被一個或多個選自-Hal、-OH、-NO 2、-NR 23R 24、(=O)的取代基取代； R 19為具有1或2個選自N、S或O的雜原子的2-10元雜烷基，其未被取代或被一個或多個選自-Hal、-OH、-NO 2、 -NR 23R 24、(=O)的取代基取代； 每個R 20獨立地為(=O)、-NR 7fR 8d、-(C 1-C 6)烷基，未取代或被一個或多個基團R 22取代，具有1或2個選自N、O或S的雜原子的-(C 2-C 6)雜烷基，未取代或被一個或多個基團R 22a取代，-(C 3-C 6)環烷基，未取代或被一個或多個基團R 22b取代，-(C 4-C 8)雜環基，其具有1或2個選自N、S或О的雜原子，未取代或被一個或多個基團R 22с取代； 每個R 7f、R 8d、R a獨立地為H、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R 22、R 22a、R 22b、R 22с獨立地為-H、-OH、-NO 2、-NR 23R 24、-(C 1-C 6)烷基，其未被取代或被一個或多個選自-Hal、-NH 2、-OH、(=O)的基團取代； 每個R 23、R 24獨立地為-H；-(C 1-C 6)烷基，其未被取代或被一個或多個選自(=О)、-ОH、-NR 25R 26的基團取代；-(C 2-C 6)烯基，其未被取代或被一個或多個選自(=О)、-NR 25aR 26a的基團取代； 每個R 25、R 26、R 25a、R 26a獨立地為-H、-(C 1-C 6)烷基； Hal是氟、溴、氯或碘原子。 The compound as claimed in item 12 or its pharmaceutically acceptable salt, solvate or stereoisomer, wherein R 5 is: -NR 7 сR 18 ; -NR 7d R 19 ; -W 1 ; -OW 2 ; -NR a W 3 ; -C(O)W 4 ; or -(CH 2 )W 5 R; wherein each W 1 , W 2 , W 3 , W 4 or W 5 is independently
Figure 03_image013
Figure 03_image015
Figure 03_image017
Figure 03_image019
Wherein p is 0, 1, 2 or 3; each R 7c , R 7d is independently -H, -(С 1 -С 6 ) alkyl; R 18 is - (С 1 -С 10 ) alkyl, which Unsubstituted or substituted by one or more substituents selected from -Hal, -OH, -NO 2 , -NR 23 R 24 , (=O); R 19 has 1 or 2 substituents selected from N, S or A 2-10-membered heteroalkyl group of a heteroatom of O, which is unsubstituted or substituted by one or more substituents selected from -Hal, -OH, -NO 2 , -NR 23 R 24 , (=O); Each R 20 is independently (=O), -NR 7f R 8d , -(C 1 -C 6 )alkyl, unsubstituted or substituted by one or more groups R 22 , having 1 or 2 selected from -(C 2 -C 6 )heteroalkyl, unsubstituted or substituted by one or more groups R 22a , -(C 3 -C 6 )cycloalkyl, unsubstituted or Substituted by one or more groups R 22b , -(C 4 -C 8 )heterocyclyl having 1 or 2 heteroatoms selected from N, S or О, unsubstituted or by one or more groups R 22с is substituted; each R 7f , R 8d , R a is independently H, -(C 1 -C 6 ) alkyl, which is unsubstituted or is selected from one or more of -Hal, -NH 2 , - OH, (=O) group substitution; each R 22 , R 22a , R 22b , R 22с is independently -H, -OH, -NO 2 , -NR 23 R 24 , -(C 1 -C 6 ) alkyl, which is unsubstituted or substituted by one or more groups selected from -Hal, -NH 2 , -OH, (=O); each R 23 , R 24 is independently -H; -( C 1 -C 6 )alkyl, which is unsubstituted or substituted by one or more groups selected from (=О), -ОH, -NR 25 R 26 ; -(C 2 -C 6 )alkenyl, It is unsubstituted or substituted by one or more groups selected from (=O), -NR 25a R 26a ; each R 25 , R 26 , R 25a , R 26a is independently -H, -(C 1 -C 6 ) alkyl; Hal is a fluorine, bromine, chlorine or iodine atom. 如請求項12所述之化合物或其藥學上可接受的鹽、溶劑化物或立體異構體，其中R 5是： [2-(二甲基胺基)乙基](甲基)胺基，4-(4-甲基呱嗪-1-基)呱啶-1-基，4-甲基呱嗪-1-基，4-(二甲基胺基)呱啶-1-基，4-嗎啉-1-基，4-甲基-1,4-二氮雜環庚烷-1-基，1-異丙基呱啶-4-基，(1-甲基呱啶-4-基)氧基，(1-甲基呱啶-3-基)胺基，(1-甲基呱啶-4-基)胺基，甲基(1-甲基呱啶-4-基)胺基，(4-甲基呱嗪-1-基)甲酮，(4-甲基呱嗪-1-基)甲基，(2-甲基-2-氮雜雙環[2.2.1]庚烷-5-基)氧基，(1-甲基吡咯烷-3-基)氧基，(1-甲基呱啶-4-基)氧基，1-乙醯基呱啶-1-基，呱啶-1-基，1-(2-(二甲基胺基)-2-氧代乙基)呱啶。 The compound or pharmaceutically acceptable salt, solvate or stereoisomer thereof as claimed in item 12, wherein R 5 is: [2-(dimethylamino)ethyl](methyl)amino, 4-(4-methylpiperazin-1-yl)piperidin-1-yl, 4-methylpiperazin-1-yl, 4-(dimethylamino)piperidin-1-yl, 4- Morpholin-1-yl, 4-methyl-1,4-diazepan-1-yl, 1-isopropylpiperidin-4-yl, (1-methylpiperidin-4-yl ) Oxygen, (1-methylpiperidin-3-yl)amino, (1-methylpiperidin-4-yl)amino, methyl(1-methylpiperidin-4-yl)amino , (4-methylpiperazin-1-yl)methanone, (4-methylpiperazin-1-yl)methyl, (2-methyl-2-azabicyclo[2.2.1]heptane- 5-yl)oxyl, (1-methylpyrrolidin-3-yl)oxyl, (1-methylpiperidin-4-yl)oxyl, 1-acetylpiperidin-1-yl, piperidine Pyridin-1-yl, 1-(2-(dimethylamino)-2-oxoethyl)piperidine. 如請求項1至14中任一項所述之的化合物或其藥學上可接受的鹽、溶劑化物或立體異構體，該化合物為： (2-((2-(4-((2-(二甲基胺基)乙基)(甲基)胺基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)二甲基氧化膦甲酸鹽(EGFR_48)； (2-((2-(4-((2-(二甲基胺基)乙基)(甲基)胺基)苯基-1H-吡咯並[2,3-b]吡啶-4-基)胺基)-4-氟苯基)二甲基氧化膦甲酸鹽(EGFR_58)； (2-((2-(4-((2-(二甲基胺基)乙基)(甲基)胺基)-2-甲氧基苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)二甲基氧化膦乙酸鹽(EGFR_59)； (2-((2-(4-((2-(二甲基胺基)乙基)(甲基)胺基)-3-甲氧基苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)二甲基氧化膦乙酸鹽(EGFR_60)； (2-((2-(4-((2-(二甲基胺基)乙基)(甲基)胺基)苯基-1H-吡咯並[2,3-b]吡啶-4-基)胺基)-5-氟苯基)二甲基氧化膦乙酸鹽(EGFR_65)； (2-((2-(4-((2-(二甲基胺基)乙基)(甲基)胺基)苯基-1H-吡咯並[2,3-b]吡啶-4-基)胺基)-6-氟苯基)二甲基氧化膦甲酸鹽(EGFR_66)； (2-((2-(4-((2-(二甲基胺基)乙基)(甲基)胺基)苯基-1H-吡咯並[2,3-b]吡啶-4-基)胺基)-4-(三氟甲基)苯基)二甲基氧化膦(EGFR_68)； (2-((6-(4-((2-(二甲基胺基)乙基)(甲基)胺基)苯基-7H-吡咯並[2,3-d]嘧啶-4-基)胺基)苯基)二甲基氧化膦(EGFR_69)； 2-((5-氯-2-(4-((2-(二甲基胺基)乙基)(甲基)胺基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)二甲基氧化膦甲酸鹽(EGFR_70)； (2-((2-(4-((2-(二甲基胺基)乙基)(甲基)胺基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)二乙基氧化膦(EGFR_74)； (2-((2-(4-((2-(二甲基胺基)乙基)(甲基)胺基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)膦酸二甲酯(EGFR_76)； N-(2-((2-(4-((2-(二甲基胺基)乙基)(甲基)胺基)苯基)-1H-吡咯並[2,3-b]嘧啶-4-基)胺基)苯基)甲磺醯胺甲酸鹽(EGFR_79)； 2-(4-((2-(二甲基胺基)乙基)(甲基)胺基)苯基-4-((2-二甲基磷醯基)苯基)胺基)-1H-吡咯並[2,3-b]吡啶-5-甲腈(EGFR_338)； (4-氟-2-((2-(4-(4-(4-甲基呱嗪-1-基)呱啶-1-基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)二甲基氧化膦甲酸鹽(EGFR_348)； (2-((6-(4-((2-(二甲基胺基)乙基)(甲基)胺基)苯基)-7H-吡咯並[2,3-d]嘧啶-4-氟苯基)二甲基氧化膦乙酸鹽(EGFR_437)； 二甲基(2-((6-(4-(4-(4-甲基呱嗪-1-基)呱啶-1-基)苯基)-7H-吡咯並[2,3-d]嘧啶-4-基)胺基)苯基)氧化膦(EGFR_440)； (4-氟-6-((6-(4-(4-(4-甲基呱嗪-1-基)呱啶-1-基)苯基)-7H-吡咯並[2,3-d]嘧啶-4-基)胺基)苯基)二甲基氧化膦(EGFR_441)； (2-氟-6-((6-(4-(4-(4-甲基呱嗪-1-基)呱啶-1-基)苯基)-7H-吡咯並[2,3-d]嘧啶-4-基)胺基)苯基)二甲基氧化膦(EGFR_483)； (2-((5-氯-2-(4-(4-(4-甲基呱嗪-1-基)呱啶-1-基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)苯基)二甲基氧化膦(EGFR_485)； 二甲基(2-((2-(3-(4-甲基呱嗪-1-基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)氧化膦乙酸鹽(EGFR_655)； 二甲基(2-((2-(4-嗎啉代苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)氧化膦甲酸鹽(EGFR_656)； 二甲基(2-((2-(4-(4-甲基呱嗪-1-基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)氧化膦甲酸鹽(EGFR_667)； 二甲基(2-((2-(4-(4-甲基-1,4-二氮雜環庚烷-1-基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)氧化膦甲酸鹽(EGFR_668)； (2-((2-(4-((1-異丙基呱啶-4-基)胺基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)二甲基氧化膦乙酸鹽(EGFR_669)； (2-((2-(4-(4-(二甲基胺基)呱啶-1-基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)二甲基氧化膦乙酸鹽(EGFR_743)； 二甲基(2-((2-(4-(1-甲基呱啶-4-基)氧基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)氧化膦甲酸鹽(EGFR_752)； (2-((2-(4-(2-(二甲基胺基)乙基(甲基)胺基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)二乙基氧化膦甲酸鹽(EGFR_774)； 二甲基(2-((2-(4-(1-甲基呱啶-4-基)胺基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)氧化膦乙酸鹽(EGFR_795)； 二甲基(2-((2-(4-(甲基(1-甲基呱啶-4-基)胺基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)氧化膦甲酸鹽(EGFR_796)； (4-(4-((2-(二甲基磷醯基)苯基)胺基)-1H-吡咯並[2,3-b]吡啶-2-基)苯基)(4-甲基呱嗪-1-基)甲酮甲酸鹽(EGFR_797)； 二甲基(2-((2-(4-((4-甲基呱嗪-1-基)甲基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)氧化膦甲酸鹽(EGFR_798)； (S)-二甲基(2-((2-(4-((1-甲基呱啶-3-基)胺基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)氧化膦乙酸鹽(EGFR_801)； (R)-二甲基(2-((2-(4-((1-甲基呱啶-3-基)胺基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)氧化膦乙酸鹽(EGFR_802)； (2-氯-6-((2-(4-(4-(二甲基胺基)呱啶-1-基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)二甲基氧化膦甲酸鹽(EGFR_853)； (2-((2-(4-(4-(二甲基胺基)呱啶-1-基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)-6-(三氟甲基)苯基)二甲基氧化膦甲酸鹽(EGFR_854)； (6-((2-(4-(4-(二甲基胺基)呱啶-1-基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)-2,3-二氟苯基)二甲基氧化膦(EGFR_855)； (2-((2-(4-(4-(二甲基胺基)呱啶-1-基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)-4-甲氧基苯基)二甲基氧化膦乙酸鹽(EGFR_856)； (2-((2-(4-(4-(二甲基胺基)呱啶-1-基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)-4-(三氟甲氧基)苯基)二甲基氧化膦乙酸鹽(EGFR_857)； (2-((2-(4-(4-(二甲基胺基)呱啶-1-基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)-4,6-二氟苯基)二甲基氧化膦乙酸鹽(EGFR_858)； 2-((2-(4-(4-(二甲基胺基)呱啶-1-基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)-4-氟苯基)二甲基氧化膦(EGFR_859)； 4-((2-(4-(4-(二甲基胺基)呱啶-1-基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)-3-(二甲基磷醯基)苄腈甲酸鹽(EGFR_860)； (2-((2-(4-(4-(二甲基胺基)呱啶-1-基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)-6-氟苯基)二甲基氧化膦(EGFR_862)； (2-((2-(4-(4-(二甲基胺基)呱啶-1-基)苯基)-5-氟-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)二甲基氧化膦甲酸鹽(EGFR_865)； (2-((2-(4-(4-(二甲基胺基)呱啶-1-基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基) -5-甲氧基苯基)二甲基氧化膦甲酸鹽(EGFR_870)； (2-((2-(4-(4-(二甲基胺基)呱啶-1-基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)二乙基氧化膦乙酸鹽(EGFR_871)； (2-((2-(4-(4-(二甲基胺基)呱啶-1-基)-2-(三氟甲氧基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)二甲基氧化膦乙酸鹽(EGFR_884)； (2-((2-(4-(4-(二甲基胺基)呱啶-1-基)-2-甲基苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)二甲基氧化膦乙酸鹽(EGFR_886)； 2-((2-(4-(4-(二甲基胺基)呱啶-1-基)-3-甲基苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)二甲基氧化膦乙酸鹽(EGFR_887)； (2-((2-(4-(4-(二甲基胺基)呱啶-1-基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)-6-甲氧基苯基)二甲基氧化膦乙酸鹽(EGFR_896)； 二乙基(2-((2-(4-((甲基(1-甲基呱啶-4-基)胺基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)氧化膦乙酸鹽(EGFR_910)； 二乙基(2-((2-(4-((1-甲基呱啶-4-基)氧基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)氧化膦乙酸鹽(EGFR_912)； (2-((2-(4-(4-(二甲基胺基)呱啶-1-基)苯基)-5-甲基-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)二甲基氧化膦(EGFR_914)； (2-甲氧基-6-((2-(4-((1-甲基呱啶-4-基)氧基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)二甲基氧化膦(EGFR_918)； (2-氟-6-((2-(4-((1-甲基呱啶-4-基)氧基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)二甲基氧化膦甲酸鹽(EGFR_919)； (R)-(2-甲氧基-6-((2-(4-((1-甲基吡咯烷-3-基)氧基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)二甲基氧化膦(EGFR_989)； (S)-(2-甲氧基-6-((2-(4-((1-甲基吡咯烷-3-基)氧基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)二甲基氧化膦(EGFR_990)； 二環丙基(2-甲氧基-6-((2-(4-((1-甲基呱啶-4-基)氧基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)二甲基氧化膦(EGFR_982)； (2-甲氧基-6-((2-(4-((2-甲基-2-氮雜雙環[2.2.1]庚烷-5-基)氧基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)二甲基氧化膦(EGFR_985)； 1-(4-(4-(4-((2-(二甲基磷醯基)-3-甲氧基苯基)胺基)-1H-吡咯並[2,3-b]吡啶-2-基)苯氧基)呱啶-1-基)乙-1-酮(EGFR_993)； 2-(4-(4-(4-((2-(二甲基磷醯基) -3-甲氧基苯基)胺基)-1H-吡咯並[2,3-b]吡啶-2-基)苯氧基)呱啶-1-基)-N,N-二甲基乙醯胺(EGFR_994)； (2-甲氧基-6-((2-(4-((1-甲基呱啶-4-基)氧基)苯基)-1H-吡咯並[2,3-b]吡啶-4-基)胺基)苯基)二甲基氧化膦乙酸鹽(EGFR_1006)。 The compound as described in any one of claims 1 to 14 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, the compound is: (2-((2-(4-((2-(Dimethylamino)ethyl)(methyl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridine-4- Base) amino) phenyl) dimethyl phosphine oxide formate (EGFR_48); (2-((2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl )amino)-4-fluorophenyl) dimethylphosphine oxide formate (EGFR_58); (2-((2-(4-((2-(Dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)-1H-pyrrolo[2,3- b] pyridin-4-yl)amino)phenyl)dimethylphosphine oxide acetate (EGFR_59); (2-((2-(4-((2-(Dimethylamino)ethyl)(methyl)amino)-3-methoxyphenyl)-1H-pyrrolo[2,3- b] pyridin-4-yl)amino)phenyl)dimethylphosphine oxide acetate (EGFR_60); (2-((2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl )amino)-5-fluorophenyl) dimethylphosphine oxide acetate (EGFR_65); (2-((2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl )amino)-6-fluorophenyl) dimethylphosphine oxide formate (EGFR_66); (2-((2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl )amino)-4-(trifluoromethyl)phenyl)dimethylphosphine oxide (EGFR_68); (2-((6-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl )amino)phenyl)dimethylphosphine oxide (EGFR_69); 2-((5-chloro-2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridine -4-yl)amino)phenyl)dimethylphosphine oxide formate (EGFR_70); (2-((2-(4-((2-(Dimethylamino)ethyl)(methyl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridine-4- Base) amino) phenyl) diethylphosphine oxide (EGFR_74); (2-((2-(4-((2-(Dimethylamino)ethyl)(methyl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridine-4- Base) amino) phenyl) dimethyl phosphonate (EGFR_76); N-(2-((2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)-1H-pyrrolo[2,3-b]pyrimidine- 4-yl)amino)phenyl)methanesulfonamide formate (EGFR_79); 2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl-4-((2-dimethylphosphoryl)phenyl)amino)-1H -pyrrolo[2,3-b]pyridine-5-carbonitrile (EGFR_338); (4-fluoro-2-((2-(4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b ]pyridin-4-yl)amino)phenyl)dimethylphosphine oxide formate (EGFR_348); (2-((6-(4-((2-(Dimethylamino)ethyl)(methyl)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4- Fluorophenyl) dimethylphosphine oxide acetate (EGFR_437); Dimethyl(2-((6-(4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-7H-pyrrolo[2,3-d] Pyrimidin-4-yl)amino)phenyl)phosphine oxide (EGFR_440); (4-fluoro-6-((6-(4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-7H-pyrrolo[2,3-d ]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (EGFR_441); (2-fluoro-6-((6-(4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-7H-pyrrolo[2,3-d ]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (EGFR_483); (2-((5-chloro-2-(4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b ]pyridin-4-yl)phenyl)dimethylphosphine oxide (EGFR_485); Dimethyl(2-((2-(3-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)benzene base) phosphine oxide acetate (EGFR_655); Dimethyl(2-((2-(4-morpholinophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)phenyl)phosphine oxide formate (EGFR_656 ); Dimethyl(2-((2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)benzene base) phosphine oxide formate (EGFR_667); Dimethyl(2-((2-(4-(4-methyl-1,4-diazepan-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine -4-yl)amino)phenyl)phosphine oxide formate (EGFR_668); (2-((2-(4-((1-isopropylpiperidin-4-yl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino ) phenyl) dimethylphosphine oxide acetate (EGFR_669); (2-((2-(4-(4-(Dimethylamino)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino ) phenyl) dimethylphosphine oxide acetate (EGFR_743); Dimethyl(2-((2-(4-(1-methylpiperidin-4-yl)oxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amine Base) phenyl) phosphine oxide formate (EGFR_752); (2-((2-(4-(2-(dimethylamino)ethyl(methyl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl) Amino)phenyl)diethylphosphine oxide formate (EGFR_774); Dimethyl(2-((2-(4-(1-methylpiperidin-4-yl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amine Base) phenyl) phosphine oxide acetate (EGFR_795); Dimethyl(2-((2-(4-(methyl(1-methylpiperidin-4-yl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridine-4- Base) amino) phenyl) phosphine oxide formate (EGFR_796); (4-(4-((2-(Dimethylphosphoryl)phenyl)amino)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)(4-methyl Piperazin-1-yl)methanone formate (EGFR_797); Dimethyl(2-((2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl) Amino)phenyl)phosphine oxide formate (EGFR_798); (S)-Dimethyl(2-((2-(4-((1-methylpiperidin-3-yl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridine- 4-yl) amino) phenyl) phosphine oxide acetate (EGFR_801); (R)-Dimethyl(2-((2-(4-((1-methylpiperidin-3-yl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridine- 4-yl) amino) phenyl) phosphine oxide acetate (EGFR_802); (2-Chloro-6-((2-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-4- Base) amino) phenyl) dimethyl phosphine oxide formate (EGFR_853); (2-((2-(4-(4-(Dimethylamino)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino )-6-(trifluoromethyl)phenyl)dimethylphosphine oxide formate (EGFR_854); (6-((2-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino )-2,3-difluorophenyl) dimethylphosphine oxide (EGFR_855); (2-((2-(4-(4-(Dimethylamino)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino )-4-methoxyphenyl) dimethylphosphine oxide acetate (EGFR_856); (2-((2-(4-(4-(Dimethylamino)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino )-4-(trifluoromethoxy)phenyl)dimethylphosphine oxide acetate (EGFR_857); (2-((2-(4-(4-(Dimethylamino)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino )-4,6-difluorophenyl) dimethylphosphine oxide acetate (EGFR_858); 2-((2-(4-(4-(Dimethylamino)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) -4-fluorophenyl) dimethylphosphine oxide (EGFR_859); 4-((2-(4-(4-(Dimethylamino)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) -3-(Dimethylphosphoryl)benzonitrile formate (EGFR_860); (2-((2-(4-(4-(Dimethylamino)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino )-6-fluorophenyl) dimethylphosphine oxide (EGFR_862); (2-((2-(4-(4-(Dimethylamino)piperidin-1-yl)phenyl)-5-fluoro-1H-pyrrolo[2,3-b]pyridine-4- Base) amino) phenyl) dimethyl phosphine oxide formate (EGFR_865); (2-((2-(4-(4-(Dimethylamino)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino )-5-methoxyphenyl)dimethylphosphine oxide formate (EGFR_870); (2-((2-(4-(4-(Dimethylamino)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino ) phenyl) diethylphosphine oxide acetate (EGFR_871); (2-((2-(4-(4-(Dimethylamino)piperidin-1-yl)-2-(trifluoromethoxy)phenyl)-1H-pyrrolo[2,3- b] pyridin-4-yl)amino)phenyl)dimethylphosphine oxide acetate (EGFR_884); (2-((2-(4-(4-(Dimethylamino)piperidin-1-yl)-2-methylphenyl)-1H-pyrrolo[2,3-b]pyridine-4 -yl)amino)phenyl)dimethylphosphine oxide acetate (EGFR_886); 2-((2-(4-(4-(Dimethylamino)piperidin-1-yl)-3-methylphenyl)-1H-pyrrolo[2,3-b]pyridine-4- base) amino) phenyl) dimethylphosphine oxide acetate (EGFR_887); (2-((2-(4-(4-(Dimethylamino)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino )-6-methoxyphenyl) dimethylphosphine oxide acetate (EGFR_896); Diethyl(2-((2-(4-((methyl(1-methylpiperidin-4-yl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridine-4 -yl)amino)phenyl)phosphine oxide acetate (EGFR_910); Diethyl(2-((2-(4-((1-methylpiperidin-4-yl)oxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl) Amino)phenyl)phosphine oxide acetate (EGFR_912); (2-((2-(4-(4-(Dimethylamino)piperidin-1-yl)phenyl)-5-methyl-1H-pyrrolo[2,3-b]pyridine-4 -yl)amino)phenyl)dimethylphosphine oxide (EGFR_914); (2-methoxy-6-((2-(4-((1-methylpiperidin-4-yl)oxy)phenyl)-1H-pyrrolo[2,3-b]pyridine-4 -yl)amino)phenyl)dimethylphosphine oxide (EGFR_918); (2-fluoro-6-((2-(4-((1-methylpiperidin-4-yl)oxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl )amino)phenyl)dimethylphosphine oxide formate (EGFR_919); (R)-(2-methoxy-6-((2-(4-((1-methylpyrrolidin-3-yl)oxy)phenyl)-1H-pyrrolo[2,3-b ]pyridin-4-yl)amino)phenyl)dimethylphosphine oxide (EGFR_989); (S)-(2-methoxy-6-((2-(4-((1-methylpyrrolidin-3-yl)oxy)phenyl)-1H-pyrrolo[2,3-b ]pyridin-4-yl)amino)phenyl)dimethylphosphine oxide (EGFR_990); Dicyclopropyl(2-methoxy-6-((2-(4-((1-methylpiperidin-4-yl)oxy)phenyl)-1H-pyrrolo[2,3-b ]pyridin-4-yl)amino)phenyl)dimethylphosphine oxide (EGFR_982); (2-methoxy-6-((2-(4-((2-methyl-2-azabicyclo[2.2.1]heptane-5-yl)oxy)phenyl)-1H-pyrrole [2,3-b]pyridin-4-yl)amino)phenyl)dimethylphosphine oxide (EGFR_985); 1-(4-(4-(4-((2-(Dimethylphosphoryl)-3-methoxyphenyl)amino)-1H-pyrrolo[2,3-b]pyridine-2 -yl)phenoxy)piperidin-1-yl)ethan-1-one (EGFR_993); 2-(4-(4-(4-((2-(Dimethylphosphoryl)-3-methoxyphenyl)amino)-1H-pyrrolo[2,3-b]pyridine-2 -yl)phenoxy)piperidin-1-yl)-N,N-dimethylacetamide (EGFR_994); (2-methoxy-6-((2-(4-((1-methylpiperidin-4-yl)oxy)phenyl)-1H-pyrrolo[2,3-b]pyridine-4 -yl)amino)phenyl)dimethylphosphine oxide acetate (EGFR_1006). 一種抑制受試者中表皮生長因子受體(EGFR)生物活性之方法，該方法包括將EGFR的激酶結構域與如請求項1至15中任一項所述之化合物或其藥理學上可接受的鹽、溶劑化物或立體異構體接觸。A method for inhibiting the biological activity of epidermal growth factor receptor (EGFR) in a subject, the method comprising combining the kinase domain of EGFR with a compound as described in any one of claims 1 to 15 or pharmacologically acceptable salts, solvates or stereoisomers. 一種藥物組合物，其含有如請求項1至15中任一項所述之化合物或其藥學上可接受的鹽、溶劑化物或立體異構體，以及一種或多種藥學上可接受的賦形劑。A pharmaceutical composition, which contains the compound or pharmaceutically acceptable salt, solvate or stereoisomer thereof as described in any one of claims 1 to 15, and one or more pharmaceutically acceptable excipients . 如請求項17所述之藥物組合物，其用於預防或治療由EGFR活性介導的疾病或病症。The pharmaceutical composition according to claim 17, which is used for preventing or treating diseases or diseases mediated by EGFR activity. 如請求項18所述之藥物組合物，其中該特定疾病或病症是具有突變L858R和/或突變T790M和/或外顯子19缺失和/或突變C797S的EGFR活性介導的疾病或病症。The pharmaceutical composition according to claim 18, wherein the specific disease or disorder is a disease or disorder mediated by EGFR activity with mutation L858R and/or mutation T790M and/or exon 19 deletion and/or mutation C797S. 如請求項19所述之藥物組合物，其中由EGFR活性介導的疾病或病症是腫瘤疾病。The pharmaceutical composition according to claim 19, wherein the disease or disease mediated by EGFR activity is a tumor disease. 如請求項20所述之藥物組合物，其中該疾病或病症是膀胱癌、卵巢癌、宮頸癌、結腸直腸癌、乳腺癌、胰腺癌、頭頸癌、膠質瘤、成膠質細胞瘤、黑素瘤、前列腺癌、白血病、淋巴瘤、非霍奇金淋巴瘤、霍奇金淋巴瘤、肺癌、肝細胞癌、食管癌、胃癌、胃腸道間質瘤、甲狀腺癌、膽管癌、子宮內膜癌、腎癌、肝癌、間變性大細胞淋巴瘤、急性髓性白血病、多發性骨髓瘤、黑素瘤、間皮瘤、血液惡性腫瘤。The pharmaceutical composition according to claim 20, wherein the disease or disease is bladder cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, melanoma , prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, lung cancer, hepatocellular carcinoma, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, endometrial cancer, Renal cancer, liver cancer, anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma, hematologic malignancies. 如請求項20所述之藥物組合物，其中該腫瘤疾病是非小細胞肺癌。The pharmaceutical composition according to claim 20, wherein the tumor disease is non-small cell lung cancer. 一種治療由EGFR活性介導的疾病或病症的方法，其包括向需要此類治療的受試者施用治療有效量的如請求項1至15中任一項所述之化合物或其藥理學上可接受的鹽、溶劑化物或立體異構體，或如請求項17所述之藥物組合物。A method of treating a disease or disorder mediated by EGFR activity, comprising administering a therapeutically effective amount of a compound as described in any one of claims 1 to 15 or a pharmacologically acceptable amount thereof to a subject in need of such treatment The accepted salt, solvate or stereoisomer, or the pharmaceutical composition as described in claim 17. 如請求項23所述之方法，其中該特定疾病或病症是具有突變L858R和/或突變T790M和/或外顯子19缺失和/或突變C797S的EGFR活性介導的疾病或病症。The method according to claim 23, wherein the specific disease or condition is a disease or condition mediated by EGFR activity with mutation L858R and/or mutation T790M and/or exon 19 deletion and/or mutation C797S. 如請求項24所述之方法，其中該由EGFR活性介導的疾病或病症是腫瘤疾病。The method according to claim 24, wherein the disease or condition mediated by EGFR activity is a tumor disease. 如請求項25所述之方法，其中該疾病或病症是膀胱癌、卵巢癌、宮頸癌、結腸直腸癌、乳腺癌、胰腺癌、頭頸癌、膠質瘤、成膠質細胞瘤、黑素瘤、前列腺癌、白血病、淋巴瘤、非霍奇金淋巴瘤、霍奇金淋巴瘤、肺癌、肝細胞癌、食管癌、胃癌、胃腸道間質瘤、甲狀腺癌、膽管癌、子宮內膜癌、腎癌、肝癌、間變性大細胞淋巴瘤、急性髓性白血病、多發性骨髓瘤、黑素瘤、間皮瘤、血液惡性腫瘤。The method of claim 25, wherein the disease or condition is bladder cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, melanoma, prostate Cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, lung cancer, hepatocellular carcinoma, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, endometrial cancer, kidney cancer , liver cancer, anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma, hematologic malignancies. 如請求項26所述之方法，其中該腫瘤疾病是非小細胞肺癌。The method according to claim 26, wherein the tumor disease is non-small cell lung cancer. 如請求項1至15中任一項所述之化合物或其藥理學上可接受的鹽、溶劑化物或立體異構體或如請求項17所述之藥物組合物用於在需要這樣的治療的受試者中治療由EGFR活性介導的疾病或病症的用途。The compound as described in any one of claim items 1 to 15 or its pharmacologically acceptable salt, solvate or stereoisomer or the pharmaceutical composition as described in claim item 17 is used in need such treatment Use in a subject to treat a disease or condition mediated by EGFR activity. 如請求項28所述之化合物的用途，其中該特定疾病或病症是具有突變L858R和/或突變T790M和/或外顯子19中缺失和/或突變C797S的EGFR活性介導的疾病或病症。The use of the compound as claimed in claim 28, wherein the specific disease or disorder is a disease or disorder mediated by EGFR activity with mutation L858R and/or mutation T790M and/or deletion in exon 19 and/or mutation C797S. 如請求項29所述之化合物的用途，其中該由EGFR活性介導的疾病或病症是腫瘤疾病。The use of the compound as claimed in item 29, wherein the disease or disease mediated by EGFR activity is a tumor disease. 如請求項30所述之化合物的用途，其中該疾病或病症是膀胱癌、卵巢癌、宮頸癌、結腸直腸癌、乳腺癌、胰腺癌、頭頸癌、膠質瘤、成膠質細胞瘤、黑素瘤、前列腺癌、白血病、淋巴瘤、非霍奇金淋巴瘤、霍奇金淋巴瘤、肺癌、肝細胞癌、食管癌、胃癌、胃腸道間質瘤、甲狀腺癌、膽管癌、子宮內膜癌、腎癌、肝癌、間變性大細胞淋巴瘤、急性髓性白血病、多發性骨髓瘤、黑素瘤、間皮瘤、血液惡性腫瘤。Use of the compound as claimed in claim 30, wherein the disease or condition is bladder cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, melanoma , prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, lung cancer, hepatocellular carcinoma, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, endometrial cancer, Renal cancer, liver cancer, anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma, hematologic malignancies. 如請求項30所述之化合物的用途，其中該腫瘤疾病是非小細胞肺癌。The use of the compound as described in claim 30, wherein the tumor disease is non-small cell lung cancer.
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