TW202214600A - Pyrmidyl derivatives, preparation methods and uses thereof - Google Patents
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Abstract
Description
本發明涉及醫藥技術領域，特別是一種嘧啶基衍生物、其製備方法及其用途。The present invention relates to the technical field of medicine, in particular to a pyrimidine derivative, a preparation method and use thereof.
細胞週期蛋白依賴性激酶(CDKs)是調控轉錄(CDKs 7-13和19-20)或細胞週期進程(CDKs 1-6和14-18)的絲胺酸/蘇胺酸蛋白激酶。幾乎所有已知的CDKs都是通過(i)與細胞週期蛋白結合和(ii)CDK啟動激酶(CAK)磷酸化其T-環而被啟動。CAK是一種由CDK7、cyclin H和環指蛋白MAT1組成的三聚體複合物，使CDK7獨特地參與轉錄和細胞週期的調控，CDK7在其T-環的Thr170位點發生自磷酸化並與cyclin H結合後被啟動。另有研究表明，CDKs也是一類在癌細胞增殖和解除控制的致癌轉錄過程中起重要調控作用的激酶。CDK7與cyclin H和MATI結合形成三聚體細胞週期蛋白活化激酶(CDK)，通過磷酸化參與細胞週期調控其他CDKs來發揮其功能。這些複合物控制著細胞週期中M期和S期兩個階段之間的特定轉變。CDK7涉及調控細胞週期的時間控制和轉錄活性，通過RNA聚合酶II (RNAPII)的Rbpl亞基磷酸化參與轉錄起始過程。不受控制的細胞增殖和轉錄失調是癌症的標誌。CDK7異常過剩已在多種癌症類型中被檢測到，並與侵襲性臨床病理特徵和不良預後相關。有研究證實，CDK7在肝細胞癌、胃癌和結直腸癌(CRC)中擴增。例如，胃癌標本免疫組化分析顯示，173例胃癌標本CDK7水準升高，且與腫瘤分級相關。類似地，CDK7在口腔鱗狀細胞癌樣本中大量過表達，表明其作為預後標誌物的效用；乳腺癌組織中與相鄰的正常乳腺組織相比，CDK7的蛋白和mRNA水準也上調；CDK7的高表達與三陰性乳腺癌(TNBC)患者的不良臨床結果有關。選擇性靶向CDK7具有同時抑制活性轉錄和細胞週期進展的優勢。Cyclin-dependent kinases (CDKs) are serine/threonine protein kinases that regulate transcription (CDKs 7-13 and 19-20) or cell cycle progression (CDKs 1-6 and 14-18). Almost all known CDKs are initiated by (i) binding to cyclins and (ii) phosphorylating their T-loops by CDK-initiating kinases (CAKs). CAK is a trimeric complex composed of CDK7, cyclin H, and the RING finger protein MAT1, which makes CDK7 uniquely involved in the regulation of transcription and cell cycle. CDK7 autophosphorylates at the Thr170 site of its T-loop and interacts with cyclin It is activated after H binding. Other studies have shown that CDKs are also a class of kinases that play important regulatory roles in cancer cell proliferation and uncontrolled oncogenic transcription. CDK7 combines with cyclin H and MATI to form a trimeric cyclin-activated kinase (CDK), which exerts its function by participating in the regulation of other CDKs in the cell cycle by phosphorylation. These complexes control specific transitions between the two phases of the cell cycle, the M and S phases. CDK7 is involved in the regulation of temporal control and transcriptional activity of the cell cycle, and is involved in transcription initiation through the phosphorylation of the Rbpl subunit of RNA polymerase II (RNAPII). Uncontrolled cell proliferation and transcriptional dysregulation are hallmarks of cancer. Aberrant excess of CDK7 has been detected in multiple cancer types and is associated with aggressive clinicopathological features and poor prognosis. Studies have confirmed that CDK7 is amplified in hepatocellular carcinoma, gastric cancer, and colorectal cancer (CRC). For example, immunohistochemical analysis of gastric cancer specimens showed that CDK7 levels were elevated in 173 gastric cancer specimens and correlated with tumor grade. Similarly, CDK7 was significantly overexpressed in oral squamous cell carcinoma samples, indicating its utility as a prognostic marker; protein and mRNA levels of CDK7 were also upregulated in breast cancer tissues compared to adjacent normal breast tissues; High expression is associated with poor clinical outcomes in triple-negative breast cancer (TNBC) patients. Selective targeting of CDK7 has the advantage of simultaneously inhibiting active transcription and cell cycle progression.
因此，CDK7是治療癌症，特別是侵襲性和難治性癌症的一個有希望的靶點。提供具有選擇性的CDK7抑制劑，用於細胞增殖失調的治療，如癌症，具有十分重要的意義。Therefore, CDK7 is a promising target for the treatment of cancer, especially aggressive and refractory cancers. It is of great significance to provide selective CDK7 inhibitors for the treatment of cell proliferation disorders, such as cancer.
本領域仍然需要對CDK7具有良好的抑制活性和選擇性的化合物。There is still a need in the art for compounds with good inhibitory activity and selectivity for CDK7.
基於此，有必要提供一種嘧啶基衍生物。該嘧啶基衍生物可以作為具有選擇性的CDK7抑制劑，解決多種癌症的有效治療需求，尤其是轉錄失調的癌症。Based on this, it is necessary to provide a pyrimidinyl derivative. The pyrimidinyl derivatives can be used as selective CDK7 inhibitors to address the need for effective treatment of various cancers, especially cancers with dysregulated transcription.
具體技術方案如下：The specific technical solutions are as follows:
具有通式(I)所示結構的嘧啶基衍生物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥：
在另外一個具體的實施方案中，環A還可以選自其它環烷基、雜環基、芳基和雜芳基。In another specific embodiment, Ring A can also be selected from other cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups.
作為優選地，環A選自如下基團中的一個，環A上的H被1至3個R
0取代：
在其中一個優選的實施例中，環A選自如下基團中的一個，環A上的H被1至3個R
0取代：
在其中一個優選的實施例中，R 0各自獨立地選自-H、甲基、乙基、羥基、-NH 2和-NH-CH 3。 In one of the preferred embodiments, each R 0 is independently selected from -H, methyl, ethyl, hydroxyl, -NH 2 and -NH-CH 3 .
在其中一個具體的實施方案中，R 1選自-H、鹵素、氰基、C 1-C 3鹵代烷基、3-5元飽和環烷基、C 1-C 3烷基、C 1-C 3烷氧基和C 1-C 3鹵代烷氧基。 In one specific embodiment, R 1 is selected from -H, halogen, cyano, C 1 -C 3 haloalkyl, 3-5 membered saturated cycloalkyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy and C 1 -C 3 haloalkoxy.
在另外一個具體的實施方案中，R 1還可以選自其它烷基、環烷基、烷氧基和它們的鹵代形式，也可以選自環烷基、雜環基、芳基、雜芳基和它們的鹵代形式。 In another specific embodiment, R 1 can also be selected from other alkyl groups, cycloalkyl groups, alkoxy groups and their halogenated forms, and can also be selected from cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups bases and their halogenated forms.
作為優選地，R 1選自C 1-C 3鹵代烷基。具體地，R 1為-CF 3。 Preferably, R 1 is selected from C 1 -C 3 haloalkyl. Specifically, R 1 is -CF 3 .
在其中一個具體的實施方案中，R 2、R 3各自獨立地選自-H、鹵素、氰基、-C(O)NH(C 1-C 4烷基)、-C(O)N(C 1-C 4烷基) 2、5-6元雜芳基、C 1-C 4烷基、C 1-C 4烷氧基、C 1-C 4鹵代烷基和C 1-C 4鹵代烷氧基。 In one specific embodiment, R 2 , R 3 are each independently selected from -H, halogen, cyano, -C(O)NH(C 1 -C 4 alkyl), -C(O)N( C 1 -C 4 alkyl) 2 , 5-6 membered heteroaryl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl and C 1 -C 4 haloalkoxy base.
在另外一個具體的實施方案中，R 2、R 3還可以各自獨立地選自其它烷基、環烷基、烷氧基和它們的鹵代形式，也可以選自環烷基、雜環基、芳基、雜芳基和它們的鹵代形式。 In another specific embodiment, R 2 and R 3 can also be independently selected from other alkyl groups, cycloalkyl groups, alkoxy groups and their halogenated forms, and can also be selected from cycloalkyl groups, heterocyclic groups , aryl, heteroaryl and their halogenated forms.
作為優選地，R 2選自-H、鹵素或氰基。具體地，R 2為-H、-F或-CN。 Preferably, R 2 is selected from -H, halogen or cyano. Specifically, R 2 is -H, -F or -CN.
作為優選地，R 3為-H。 Preferably, R 3 is -H.
在其中一個具體的實施方案中，X選自CH和N。作為優選地，X選自CH。In one specific embodiment, X is selected from CH and N. Preferably, X is selected from CH.
在另外一個具體的實施方案中，R
4選自如下基團：
進一步地，在其中一個具體的實施方案中，R
4為
更進一步地，R 5、R 6為甲基。 Furthermore, R 5 and R 6 are methyl groups.
在另一個具體的實施方案中，R
4為
更進一步地，R 5為甲基；R 6為-H。 Further, R 5 is methyl; R 6 is -H.
在另一個具體的實施方案中，R
4為
更進一步地，R 5、R 6為甲基。 Furthermore, R 5 and R 6 are methyl groups.
在另一個具體的實施方案中，R
4為
更進一步地，R
5為甲基、
在另外一個具體的實施方案中，R 5、R 6還可以各自獨立地選自其它烷基、環烷基、烷氧基和它們的鹵代形式，也可以選自環烷基、雜環基、芳基、雜芳基和它們的鹵代形式。R 5和R 6不連接或連接成其它環烷基、雜環基、芳基或雜芳基環系。 In another specific embodiment, R 5 and R 6 can also be independently selected from other alkyl groups, cycloalkyl groups, alkoxy groups and their halogenated forms, and can also be selected from cycloalkyl groups, heterocyclic groups , aryl, heteroaryl and their halogenated forms. R5 and R6 are not linked or linked to other cycloalkyl, heterocyclyl, aryl or heteroaryl ring systems.
在其中一個實施例中，R
4為
在其中一個實施例中，R 1為-CF 3。 In one of these embodiments, R 1 is -CF 3 .
在其中一個實施例中，R 2為-H、-F或-CN。 In one of these embodiments, R 2 is -H, -F or -CN.
在其中一個實施例中，R 3為-H。 In one of these embodiments, R3 is -H.
在其中一個實施例中，所述嘧啶基衍生物選自以下化合物中的一種：
進一步，所述嘧啶基衍生物選自以下化合物中的一種：
本發明還提供所述的嘧啶基衍生物的製備方法，包括如下步驟：
本發明還提供一種藥物組合物，所述藥物組合物包含如上所述的嘧啶基衍生物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，以及藥學上可接受的輔料、稀釋劑或載體。The present invention also provides a pharmaceutical composition comprising the above-mentioned pyrimidine derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives thereof Derivatives or prodrugs, and pharmaceutically acceptable excipients, diluents or carriers.
在其中一個實施例中，所述藥物組合物還包括聯用藥劑；所述聯用藥劑選自抗增殖劑、抗癌劑、免疫抑制劑和疼痛緩解劑中的至少一種。In one embodiment, the pharmaceutical composition further comprises a combined agent; the combined agent is selected from at least one of an anti-proliferative agent, an anti-cancer agent, an immunosuppressant and a pain relief agent.
本發明還提供如上所述的嘧啶基衍生物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥或如上所述的藥物組合物在製備用於預防或治療與異常的CDK7活性相關的癌症、良性贅生物、血管生成、炎症性疾病、自身炎症性疾病、自身免疫性疾病或感染性疾病的藥物中的用途。The present invention also provides the pyrimidinyl derivatives as described above, their optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs or drugs as described above Use of the composition in the manufacture of a medicament for preventing or treating cancer, benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, autoimmune disease or infectious disease associated with abnormal CDK7 activity.
在其中一個實施例中，本發明涉及嘧啶基衍生物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥或包含其的藥物組合物，其用於預防或治療與異常的CDK7活性相關的癌症、良性贅生物、血管生成、炎症性疾病、自身炎症性疾病、自身免疫性疾病或感染性疾病。In one of these embodiments, the present invention relates to pyrimidinyl derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives or prodrugs thereof, or containing the same A pharmaceutical composition for preventing or treating cancer, benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, autoimmune disease or infectious disease associated with abnormal CDK7 activity.
其中一個實施例中，本發明涉及一種預防或治療與異常的CDK7活性相關的癌症、良性贅生物、血管生成、炎症性疾病、自身炎症性疾病、自身免疫性疾病或感染性疾病的方法，包括向需要的受試者給藥所述的嘧啶基衍生物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥或包含其的藥物組合物。在其中一個實施例中，所述與異常的CDK7活性相關的癌症選自乳腺癌、卵巢癌、直腸癌、肝癌、肺癌、胃癌、腦癌、膽管癌、宮頸癌、子宮內膜癌、頭頸癌、膀胱癌、骨癌、腸癌、腎癌、喉癌、淋巴瘤、白血病、慢性淋巴細胞性白血病(CLL)、急性成淋巴細胞性白血病(ALL)、T細胞急性成淋巴細胞性白血病(T-ALL)、慢性骨髓性白血病(CML)、急性骨髓性白血病(AML)、多發性骨髓瘤、黑色素瘤、間皮瘤、骨髓瘤、神經內分泌癌、食管癌、陰莖癌、***癌、皮膚癌、軟組織肉瘤癌、脊髓癌、睾丸癌、甲狀腺癌和子宮癌中的一種或幾種。In one embodiment, the present invention relates to a method of preventing or treating cancer, benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, autoimmune disease or infectious disease associated with abnormal CDK7 activity, comprising: Administering described pyrimidinyl derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives or prodrugs thereof or comprising the same to a subject in need thereof pharmaceutical composition. In one embodiment, the cancer associated with aberrant CDK7 activity is selected from the group consisting of breast cancer, ovarian cancer, rectal cancer, liver cancer, lung cancer, stomach cancer, brain cancer, bile duct cancer, cervical cancer, endometrial cancer, head and neck cancer , bladder cancer, bone cancer, bowel cancer, kidney cancer, throat cancer, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T -ALL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), multiple myeloma, melanoma, mesothelioma, myeloma, neuroendocrine cancer, esophageal cancer, penile cancer, prostate cancer, skin cancer , one or more of soft tissue sarcoma cancer, spinal cord cancer, testicular cancer, thyroid cancer and uterine cancer.
與現有技術相比較，本發明具有如下有益效果中的一種或多種：Compared with the prior art, the present invention has one or more of the following beneficial effects:
本發明提供了一種嘧啶基衍生物，其可以作為新型的選擇性CDK7抑制劑，通過抑制CDK7的異常活性來誘導細胞凋亡和/或抑制轉錄，相對於其它細胞週期蛋白依賴性激酶亞型具有較高的選擇性和較高的激酶抑制活性，用來治療患有增殖性疾病的受試者，解決多種癌症的有效治療需求，尤其是轉錄失調的癌症。經試驗研究表明，本發明化合物對CDK7具有良好的抑制活性和選擇性。The present invention provides a pyrimidine-based derivative, which can be used as a novel selective CDK7 inhibitor to induce apoptosis and/or inhibit transcription by inhibiting the abnormal activity of CDK7. Higher selectivity and higher kinase inhibitory activity for the treatment of subjects with proliferative diseases, addressing the need for effective treatment of a variety of cancers, especially those with dysregulated transcription. Experimental studies show that the compounds of the present invention have good inhibitory activity and selectivity to CDK7.
以下結合具體實施例對本發明的嘧啶基衍生物、其製備方法及其應用作進一步詳細的說明。本發明可以以許多不同的形式來實現，並不限於本文所描述的實施方式。相反地，提供這些實施方式的目的是使對本發明公開內容理解更加透徹全面。The pyrimidinyl derivatives of the present invention, their preparation methods and their applications will be described in further detail below with reference to specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that a thorough and complete understanding of the present disclosure is provided.
除非另有定義，本文所使用的所有的技術和科學術語與屬於本發明的技術領域的技術人員通常理解的含義相同。本文中在本發明的說明書中所使用的術語只是為了描述具體的實施方案的目的，不是旨在於限制本發明。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terms used herein in the description of the present invention are for the purpose of describing specific embodiments only, and are not intended to limit the present invention.
術語“光學異構體”如果沒有特殊說明，應包括所有異構體中的一種或它們的混合物，例如，雙鍵、環中的幾何異構體(E型、Z型、順式的(cis)、反式的(trans))，直鏈烷基和支鏈烷基中由存在不對稱碳原子等而產生的光學異構體(R型、S型)及它們任意比例的混合物。外消旋混合物以及所有的由互變異構體產生的異構體均包括在本發明中。另外，每種化合物結構均可以為具有相同分子式的不同立體異構體，其中的立體異構體還包括對映異構體和非對映異構體，對映異構體即為光學異構體，非對映異構體為不成手性對映的立體異構體，與本發明化合物具有相同分子式的不同異構體也在本發明的保護範圍內。The term "optical isomer", unless otherwise specified, shall include one of all isomers or their mixtures, for example, double bonds, geometric isomers in rings (E, Z, cis (cis) ), trans (trans)), optical isomers (R-type, S-type) arising from the presence of asymmetric carbon atoms in straight-chain alkyl and branched-chain alkyl groups, and mixtures thereof in any ratio. Racemic mixtures and all isomers resulting from tautomers are included in the present invention. In addition, each compound structure can be different stereoisomers with the same molecular formula, among which stereoisomers also include enantiomers and diastereomers, and enantiomers are optical isomers Diastereomers are stereoisomers of achiral enantiomers, and different isomers with the same molecular formula as the compounds of the present invention are also within the protection scope of the present invention.
術語“藥學上可接受的鹽”是指化合物可以通過傳統的方法轉化為相應的鹽，其在化學上或物理上與構成某藥物劑型的其它成分相相容，並在生理上與受體相相容。該鹽可以為化合物與無機和/或有機酸和/或與無機和/或堿形成的酸式和/或鹼式鹽，也包括兩性離子鹽(內鹽)，還包括季銨鹽，例如烷基銨鹽。這些鹽可以是在化合物的最後分離和純化中直接得到。也可以是通過將本發明的化合物或其立體異構體或溶劑合物與一定量的酸或堿適當混合而得到的。這些鹽可能在溶液中形成沉澱，然後以過濾方法收集，或在溶劑蒸發後回收而得到，或在水介質中反應後冷卻乾燥制得。具體地，鹽優選為水溶性的藥學上可接受的無毒酸加成鹽，實例為胺基與無機酸(如鹽酸、氫溴酸、磷酸、硫酸以及高氯酸)或與有機酸(如乙酸、草酸、順丁烯二酸、酒石酸、檸檬酸、琥珀酸或丙二酸)形成的鹽，或通過使用本領域中傳統的其他方法(例如離子交換法)形成的鹽。其他藥學上可接受的鹽包括己二酸鹽、藻酸鹽、抗壞血酸鹽、天冬胺酸鹽、苯磺酸鹽、苯甲酸鹽、硫酸氫鹽、硼酸鹽、丁酸鹽、樟腦酸鹽、樟腦磺酸鹽、檸檬酸鹽、環戊烷丙酸鹽、二葡糖酸鹽、十二烷基硫酸鹽、乙烷磺酸鹽、甲酸鹽、富馬酸鹽、葡庚糖酸鹽、甘油磷酸鹽、葡糖酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、氫碘化物、2-羥基-乙烷磺酸鹽、乳糖酸鹽、乳酸鹽、月桂酸鹽、月桂基硫酸鹽、蘋果酸鹽、馬來酸鹽、丙二酸鹽、甲烷磺酸鹽、2-萘磺酸鹽、煙酸鹽、硝酸鹽、油酸鹽、草酸鹽、棕櫚酸鹽、雙羥萘酸鹽、果膠酸鹽、過硫酸鹽、3-苯基丙酸鹽、磷酸鹽、苦味酸鹽、新戊酸鹽、丙酸鹽、硬脂酸鹽、琥珀酸鹽、硫酸鹽、酒石酸鹽、硫氰酸鹽、對-甲苯磺酸鹽、十一烷酸鹽、戊酸鹽等。適當時，另外的藥學上可接受的鹽還可以包括衍生自適當堿的鹽，包括鹼金屬鹽、鹼土金屬鹽以及銨鹽。代表性鹼金屬或鹼土金屬鹽包括鈉鹽、鋰鹽、鉀鹽、鈣鹽、鎂鹽等。適當時，另外的藥學上可接受的鹽包括使用如鹵離子、氫氧根、羧酸根、硫酸根、磷酸根、硝酸根、低級烷基磺酸根以及芳基磺酸根等平衡離子形成的無毒銨、季銨以及胺陽離子。The term "pharmaceutically acceptable salts" refers to compounds that can be converted by conventional methods into the corresponding salts which are chemically or physically compatible with the other ingredients that make up a pharmaceutical dosage form and which are physiologically compatible with the receptor. compatible. The salts may be acid and/or base salts of compounds with inorganic and/or organic acids and/or with inorganic and/or halides, also include zwitterionic salts (inner salts), and also include quaternary ammonium salts such as alkanes base ammonium salt. These salts can be obtained directly in the final isolation and purification of the compounds. It can also be obtained by appropriately mixing the compound of the present invention or its stereoisomer or solvate with a certain amount of acid or phosphonium. These salts may form precipitates in solution and then be collected by filtration, or recovered after evaporation of the solvent, or by reaction in an aqueous medium followed by cooling and drying. Specifically, the salt is preferably a water-soluble pharmaceutically acceptable non-toxic acid addition salt, exemplified by an amine group with an inorganic acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or with an organic acid (such as acetic acid) , oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid), or by using other methods conventional in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate , camphorsulfonate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate , Glycerophosphate, Gluconate, Hemisulfate, Heptanoate, Caproate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lactobate, Lactate, Laurate, Lauryl Sulfate salt, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate acid salt, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate , thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Additional pharmaceutically acceptable salts may also include salts derived from suitable phosphoniums, including alkali metal, alkaline earth metal, and ammonium salts, as appropriate. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include non-toxic ammonium formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate, and arylsulfonate, as appropriate , quaternary ammonium and amine cations.
術語“溶劑合物”也可以稱為“溶劑化合物”、“溶劑化物”，指的是含有溶劑的化合物，其中溶劑分子可以以包括配位鍵、共價鍵、范德華力、離子鍵、氫鍵等方式與化合物分子相結合。The term "solvate" may also be referred to as "solvate", "solvate", and refers to a compound containing a solvent, wherein the solvent molecule can include coordinate bonds, covalent bonds, van der Waals forces, ionic bonds, hydrogen bonds and other ways to combine with compound molecules.
術語“前藥”是指當被施用至生物體時由於自發化學反應、酶催化的化學反應、光解和/或代謝化學反應而產生藥物，即活性成分的任何化合物。前藥因此是治療活性化合物的共價改性的類似物或潛在形式。合適的實例包括但不限於：化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、碸酯、亞碸酯、胺基化合物、胺基甲酸鹽、偶氮化合物、磷醯胺、葡萄糖苷、醚、乙縮醛等形式。The term "prodrug" refers to any compound that, when administered to an organism, produces a drug, ie, an active ingredient, as a result of spontaneous chemical reactions, enzyme-catalyzed chemical reactions, photolysis, and/or metabolic chemical reactions. A prodrug is thus a covalently modified analog or latent form of a therapeutically active compound. Suitable examples include, but are not limited to, carboxylate, carbonate, phosphate, nitrate, sulphate, sulfite, sulfite, amine compounds, carbamates, azo compounds, phosphamides of compounds , glucoside, ether, acetal and other forms.
術語“阻轉異構體”是一類立體異構體，其中兩種異構體的原子空間排列不同。阻轉異構體由於大基團圍繞中心鍵的旋轉受阻引起的受限制的旋轉而存在。The term "atropisomer" is a class of stereoisomers in which the atoms of the two isomers are arranged differently in space. Atropisomers exist due to restricted rotation caused by hindered rotation of the large group about the central bond.
術語“同位素標記的化合物”等同於本發明所述的化合物，但一個或多個原子被原子品質或質量數不同於自然界常見的原子品質或質量數的原子所代替。可以引入本發明化合物中的同位素的實例包括氫、碳、氮、氧、磷、硫、氟和氯的同位素，分別例如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。含有上述同位素和/或其它原子的其它同位素的本發明化合物、其前體藥物和所述化合物或所述前體藥物的藥學上可接受的鹽都屬於本發明的範圍。 The term "isotopically labeled compound" is equivalent to a compound described herein except that one or more atoms are replaced by an atom having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen , carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, 3H , 13C , 11C , 14C , 15N , 18 , respectively O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl. Compounds of the invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or said prodrugs containing the above isotopes and/or other isotopes of other atoms are within the scope of the present invention.
術語“烷基”是指包含伯(正)碳原子、或仲碳原子、或叔碳原子、或季碳原子、或其組合的飽和烴基。包含該術語的短語，例如，“C 1-C 3烷基”是指包含1~3個碳原子的烷基，每次出現時，可以互相獨立地為C 1烷基、C 2烷基、C 3烷基。優選的烷基為C 1-C 6烷基、C 1-C 5烷基、C 1-C 4烷基和C 1-C 3烷基。合適的實例包括但不限於：甲基(Me、-CH 3)、乙基(Et、-CH 2CH 3)、1-丙基(n-Pr、n-丙基、-CH 2CH 2CH 3)、2-丙基(i-Pr、i-丙基、-CH(CH 3) 2)。 The term "alkyl" refers to a saturated hydrocarbon group containing primary (normal) carbon atoms, or secondary carbon atoms, or tertiary carbon atoms, or quaternary carbon atoms, or a combination thereof. Phrases containing this term, for example, "C 1 -C 3 alkyl" refers to an alkyl group containing 1 to 3 carbon atoms, and each occurrence may independently be C 1 alkyl, C 2 alkyl , C 3 alkyl. Preferred alkyl groups are C 1 -C 6 alkyl, C 1 -C 5 alkyl, C 1 -C 4 alkyl and C 1 -C 3 alkyl. Suitable examples include, but are not limited to: methyl (Me, -CH3 ), ethyl (Et, -CH2CH3), 1 -propyl (n-Pr, n - propyl, -CH2CH2CH ) 3 ), 2-propyl (i-Pr, i-propyl, -CH( CH3 ) 2 ).
術語“亞烷基”是指是指除去烷基的另一個氫而形成的二價基團，並且可以是取代或未取代的。在一些實施方案中，C 1-C 4亞烷基、C 2-C 4亞烷基和C 1-C 3亞烷基是優選的。 The term "alkylene" refers to a divalent group formed by removal of another hydrogen from an alkyl group, and may be substituted or unsubstituted. In some embodiments, C1 - C4 alkylene, C2 - C4 alkylene, and C1 - C3 alkylene are preferred.
術語“鹵代烷基”是指上述烷基，其被一個或多個鹵素基團取代。The term "haloalkyl" refers to the aforementioned alkyl groups, which are substituted with one or more halogen groups.
術語“羥基”是指-OH。The term "hydroxy" refers to -OH.
術語“氰基”是指-CN。The term "cyano" refers to -CN.
術語“飽和環烷基”是指包含環碳原子的非芳香族環狀烴基，可以為單環烷基或橋環烷基。包含該術語的短語，例如，“4-7元飽和環烷基”是指包含4~7個環碳原子的環烷基，每次出現時，可以互相獨立地為C 4環烷基、C 5環烷基、C 6環烷基、C 7環烷基。優選的飽和環烷基為3-8元環烷基、3-7元環烷基、3-6元環烷基和5-6元環烷基。合適的實例包括但不限於：環丙基、環丁基、環戊基、環己基和環庚基。相應地，術語“飽和含氮雜環基”是指，環系中至少一個環碳原子被N取代的非芳香族環狀烴基；術語“飽和含氮螺環基”是指環系為螺環結構且環系中至少一個環碳原子被N取代的飽和含氮雜環基。優選的飽和含氮雜環基為3-8元含氮雜環基、3-6元含氮雜環基或4-6元含氮雜環基。 The term "saturated cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group containing ring carbon atoms, which may be monocyclic or bridged. Phrases containing this term, for example, "4-7 membered saturated cycloalkyl" refers to a cycloalkyl group containing 4 to 7 ring carbon atoms, each occurrence of which may independently be C4cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, C 7 cycloalkyl. Preferred saturated cycloalkyls are 3-8 membered cycloalkyl, 3-7 membered cycloalkyl, 3-6 membered cycloalkyl and 5-6 membered cycloalkyl. Suitable examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Correspondingly, the term "saturated nitrogen-containing heterocyclic group" refers to a non-aromatic cyclic hydrocarbon group in which at least one ring carbon atom in the ring system is substituted by N; the term "saturated nitrogen-containing spirocyclic group" refers to the ring system as a spiro ring structure A saturated nitrogen-containing heterocyclic group in which at least one ring carbon atom in the ring system is substituted by N. Preferred saturated nitrogen-containing heterocyclic groups are 3-8 membered nitrogen-containing heterocyclic groups, 3-6 membered nitrogen-containing heterocyclic groups or 4-6 membered nitrogen-containing heterocyclic groups.
術語“鹵素”是指-F、-Cl、-Br或-I。相應地，“鹵代”是指以-F、-Cl、-Br或-I替代相應基團中的-H。The term "halogen" refers to -F, -Cl, -Br or -I. Correspondingly, "halo" refers to the substitution of -F, -Cl, -Br or -I for -H in the corresponding group.
術語“烷氧基”是指具有-O-烷基的基團，即如上所定義的烷基經由氧原子連接至母核結構。包含該術語的短語，例如，“C 1-C 3烷氧基”是指烷基部分包含1~3個碳原子。 The term "alkoxy" refers to a group having an -O-alkyl group, ie an alkyl group as defined above is attached to the core structure via an oxygen atom. Phrases containing this term, for example, " C1 -C3alkoxy" means that the alkyl moiety contains 1 to 3 carbon atoms.
術語“芳基”是指在芳香環化合物的基礎上除去一個氫原子衍生的芳族烴基，可以為單環芳基、稠環芳基或多環芳基。對於多環狀基團，至少一個是芳族環系。包含該術語的短語，例如，“5-6元芳基”是指芳香環系包含5-6個環原子的基團。優選的芳基為6-10元芳基，作為實例可以選自苯基和萘基。The term "aryl" refers to an aromatic hydrocarbon group derived from an aromatic ring compound by removing one hydrogen atom, which may be a single-ring aryl group, a condensed-ring aryl group or a polycyclic aryl group. For polycyclic groups, at least one is an aromatic ring system. Phrases containing this term, eg, "5-6 membered aryl" refer to groups whose aromatic ring systems contain 5-6 ring atoms. Preferred aryl groups are 6-10 membered aryl groups, which can be selected from phenyl and naphthyl as examples.
術語“雜芳基”是指含有雜原子的芳基，可為單環或稠合環狀基團，並且所述雜原子獨立地選自N、O和S。雜芳基優選為5-12元雜芳基，更優選為5-6元雜芳基。雜芳基的實例包括但不限於吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、異噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、噠嗪基、喹啉基、異喹啉基、***基、四氫吡咯基。在某一方案中，雜芳基典型地為含1個或多個獨立選自N、O和S的雜原子的5-6元單環雜芳基。除非另外說明，“5-元雜芳基”為包含一個雜原子的示例性5-元雜芳基基團，實例包括但不限於，吡咯基、呋喃基以及噻吩基；包含兩個雜原子的示例性5-元雜芳基基團包括但不限於，咪唑基、吡唑基、噁唑啉基、異噁唑啉基、噻唑基以及異噻唑基；包含三個雜原子的示例性5-元雜芳基基團包括但不限於，***基、噁二唑基以及噻二唑基；包含四個雜原子的示例性5-元雜芳基基團包括但不限於，四唑基。The term "heteroaryl" refers to an aryl group containing a heteroatom, which may be a monocyclic or fused cyclic group, and the heteroatom is independently selected from N, O, and S. The heteroaryl group is preferably a 5-12 membered heteroaryl group, more preferably a 5-6 membered heteroaryl group. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinoline base, isoquinolyl, triazolyl, tetrahydropyrrolyl. In one embodiment, heteroaryl is typically a 5-6 membered monocyclic heteroaryl containing 1 or more heteroatoms independently selected from N, O and S. Unless otherwise specified, "5-membered heteroaryl" is an exemplary 5-membered heteroaryl group containing one heteroatom, examples including, but not limited to, pyrrolyl, furanyl, and thienyl; two heteroatoms containing Exemplary 5-membered heteroaryl groups include, but are not limited to, imidazolyl, pyrazolyl, oxazolinyl, isoxazolinyl, thiazolyl, and isothiazolyl; exemplary 5-membered Membered heteroaryl groups include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl; exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl.
術語“雜環基”是指構成環的一個或多個原子是雜原子且其餘為碳的非芳香環狀基團，所述的雜原子包括而不限於氮原子、氧原子和硫原子等。 優選的雜環基為3-10元飽和雜環基。除非本說明書中另外特別指明，否則雜環基可以是單環的(“單環的雜環基”)，或者是雙環、三環或更多環的雜環狀體系，其可包括並環的(稠合的)、橋聯的(橋環的)或螺的環系統(例如二環系統(“二環的雜環烷基”)。雜環烷基二環的環系統可以在一個或兩個環中包括一個或多個雜原子；並且是飽和的。示例性3-元雜環基基團包括但不限於，氮雜環丙基、環氧乙烷基以及硫雜環丙烷基，或者其立體異構體；示例性4-元雜環基基團包括但不限於，氮雜環丁烷基，環氧丙烷基，硫雜環丁烷基，或者其同分異構體和立體異構體；示例性5-元雜環基基團包括但不限於，四氫呋喃基，四氫噻吩基，吡咯烷基，噻唑烷基，異噻唑烷基，噁唑烷基，異噁唑烷基，咪唑烷基，吡唑烷基，二氧戊環基，氧雜硫呋喃基，二硫呋喃基，或者其同分異構體和立體異構體。示例性6-元雜環基基團包括但不限於，呱啶基，四氫吡喃基，硫化環戊烷基，嗎啉基，硫代嗎啉基，二噻烷基，二噁烷基，呱嗪基，三嗪烷基，或者其同分異構體和立體異構體；示例性7-元雜環基基團包括但不限於，氮雜環庚烷基，氧雜環庚烷基，硫雜環庚烷基，以及二氮雜環庚基，或者其同分異構體和立體異構體。在某一方案中，典型的含1個或多個獨立選自N、O和S的雜原子的5-6元單環雜環基。方案中，“雜環烷基”為4-6元雜環烷基，其中雜原子選自N、O和S中的一種或多種，雜原子數為1、2或3個。The term "heterocyclyl" refers to a non-aromatic cyclic group in which one or more atoms constituting the ring are heteroatoms including, but not limited to, nitrogen, oxygen, sulfur, and the like, and the remainder is carbon. Preferred heterocyclyl groups are 3-10 membered saturated heterocyclyl groups. Unless specifically stated otherwise in this specification, a heterocyclyl group may be monocyclic ("monocyclic heterocyclyl"), or a bicyclic, tricyclic or more cyclic heterocyclic system, which may include cycloheterocyclic (fused), bridged (bridged ring), or spiro ring systems (eg, bicyclic ring systems ("bicyclic heterocycloalkyl"). Heterocycloalkyl bicyclic ring systems may be in one or two and is saturated. Exemplary 3-membered heterocyclyl groups include, but are not limited to, aziridyl, oxiranyl, and thiirane, or Stereoisomers thereof; exemplary 4-membered heterocyclyl groups include, but are not limited to, azetidinyl, propylene oxide, thietane, or isomers and stereoisomers thereof Constructs; exemplary 5-membered heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, Imidazolidinyl, pyrazolidinyl, dioxolanyl, oxathiofuranyl, dithiofuranyl, or isomers and stereoisomers thereof. Exemplary 6-membered heterocyclyl groups include but not limited to, oxidyl, tetrahydropyranyl, cyclopentanyl sulfide, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, oxazinyl, triazinyl, or Isomers and stereoisomers thereof; exemplary 7-membered heterocyclyl groups include, but are not limited to, azepanyl, oxepanyl, thiepanyl, and dicycloheptyl Azacycloheptyl, or its isomers and stereoisomers. In one embodiment, typically a 5-6 membered unit containing 1 or more heteroatoms independently selected from N, O, and S Cyclic heterocyclyl. In the scheme, "heterocycloalkyl" is a 4-6 membered heterocycloalkyl, wherein the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3 .
在本發明的各部分，描述了連接取代基。當該結構清楚地需要連接基團時，針對該基團所列舉的馬庫什變數應理解為連接基團。例如，如果該結構需要連接基團並且針對該變數的馬庫什基團定義列舉了“烷基”或“芳基”，則應該理解，該“烷基”或“芳基”分別代表連接的亞烷基基團或亞芳基基團。在一些具體的結構中，當烷基基團清楚地表示為連接基團時，則該烷基基團代表連接的亞烷基基團，例如，基團“-C 1-C 3鹵代烷基”中的烷基應當理解為亞烷基。 In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for that group should be understood to be the linking group. For example, if the structure requires a linking group and the definition of a Markush group for that variable recites "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" respectively represents the linking An alkylene group or an arylene group. In some specific structures, when an alkyl group is clearly represented as a linking group, the alkyl group represents the alkylene group to which it is attached, eg, the group " -C1 - C3 haloalkyl" Alkyl in should be understood to mean alkylene.
除非另有規定，本文使用的所有技術術語和科學術語具有要求保護主題所屬領域的標準含義。倘若對於某術語存在多個定義，則以本文定義為准。應該理解，在本發明中使用的單數形式，如“一種”，包括複數指代，除非另有規定。Unless otherwise defined, all technical and scientific terms used herein have the standard meaning in the art to which the claimed subject matter belongs. If more than one definition exists for a term, the definitions herein prevail. It should be understood that singular forms such as "a" used in the present invention include plural referents unless stated otherwise.
此外，術語“包括”是開放性限定並非封閉式，即包括本發明所指明的內容，但並不排除其他方面的內容。In addition, the term "comprising" is an open definition rather than a closed one, that is, it includes the contents specified in the present invention, but does not exclude other aspects.
除非另有說明，本發明採用質譜、核磁等傳統方法鑒定化合物，各步驟和條件可參照本領域常規的操作步驟和條件。Unless otherwise specified, the present invention adopts traditional methods such as mass spectrometry and nuclear magnetic resonance to identify compounds, and each step and condition can refer to the routine operation steps and conditions in the art.
除非另有指明，本發明採用分析化學、有機合成化學和光學的標準命名及標準實驗室步驟和技術。在某些情況下，標準技術被用於化學合成、化學分析、發光器件性能檢測。Unless otherwise indicated, the present invention employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry, and optics. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and performance testing of light-emitting devices.
另外，需要說明的是，除非以其他方式明確指出，在本發明中所採用的描述方式“…獨立地”應做廣義理解，是指所描述的各個個體之間是相互獨立的，可以獨立地為相同或不同的具體基團。更詳細地，描述方式“…獨立地”既可以是指在不同基團中，相同符號之間所表達的具體選項之間互相不影響；也可以表示在相同的基團中，相同符號之間所表達的具體選項之間互相不影響。In addition, it should be noted that, unless clearly stated otherwise, the description mode "...independently" used in the present invention should be understood in a broad sense, meaning that the described individuals are independent of each other and can independently are the same or different specific groups. In more detail, the description mode "...independently" can either mean that in different groups, the specific options expressed between the same symbols do not affect each other; it can also mean that in the same group, between the same symbols The specific options expressed do not affect each other.
本領域技術人員可以理解，根據本領域中使用的慣例，本申請描述基團的結構式中所使用的“
本發明所用試劑和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.
本發明涉及如下實施方案。The present invention relates to the following embodiments.
在一個實施方案中，本發明涉及具有通式(I)所示結構的嘧啶基衍生物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥：
在一個實施方案中，本發明涉及上述具有通式(I)所示結構的嘧啶基衍生物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，其特徵在於，
R
4為
在一個實施方案中，本發明涉及上述具有通式(I)所示結構的嘧啶基衍生物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，其特徵在於，R
4為
在一個實施方案中，本發明涉及上述具有通式(I)所示結構的嘧啶基衍生物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，其特徵在於，
R
4為
在一個實施方案中，本發明涉及上述具有通式(I)所示結構的嘧啶基衍生物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，其特徵在於，R
4為
在一個實施方案中，本發明涉及上述具有通式(I)所示結構的嘧啶基衍生物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，其特徵在於，
R
4為
在一個實施方案中，本發明涉及上述具有通式(I)所示結構的嘧啶基衍生物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，其特徵在於，R 1為-CF 3。 In one embodiment, the present invention relates to the above-mentioned pyrimidinyl derivatives having the structure represented by the general formula (I), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopic labels thereof The derivative or prodrug, characterized in that R 1 is -CF 3 .
在一個實施方案中，本發明涉及上述具有通式(I)所示結構的嘧啶基衍生物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，其特徵在於，R 2為-H、-F或-CN。 In one embodiment, the present invention relates to the above-mentioned pyrimidinyl derivatives having the structure represented by the general formula (I), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopic labels thereof The derivative or prodrug, characterized in that R 2 is -H, -F or -CN.
在一個實施方案中，本發明涉及上述具有通式(I)所示結構的嘧啶基衍生物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，其特徵在於，R 3為-H。 In one embodiment, the present invention relates to the above-mentioned pyrimidinyl derivatives having the structure represented by the general formula (I), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopic labels thereof The derivative or prodrug, characterized in that R 3 is -H.
在一個實施方案中，本發明涉及上述具有通式(I)所示結構的嘧啶基衍生物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，其特徵在於，環A選自如下基團中的一個且環A上的H被1至3個R
0取代：
在一個實施方案中，本發明涉及上述具有通式(I)所示結構的嘧啶基衍生物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，其特徵在於，環A選自如下基團中的一個且環A上的H被1至3個R
0取代：
在一個實施方案中，本發明涉及上述具有通式(I)所示結構的嘧啶基衍生物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，其特徵在於，R 0各自獨立地選自-H、甲基、乙基、羥基、-NH 2和-NH-CH 3。 In one embodiment, the present invention relates to the above-mentioned pyrimidinyl derivatives having the structure represented by the general formula (I), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopic labels thereof The derivative or prodrug of , wherein each R 0 is independently selected from -H, methyl, ethyl, hydroxyl, -NH 2 and -NH-CH 3 .
在一個實施方案中，本發明涉及具有通式(a)的化合物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥：
在一個實施方案中，本發明涉及上述具有通式(a)的化合物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，其中： R 7各自獨立地選自-H、鹵素、氰基、C 1-4烷基、鹵代C 1-4烷基和-P(=O)R 5R 6； R 5和R 6各自獨立地選自-H和C 1-4烷基； R 8選自鹵素、氰基和鹵代C 1-4烷基； R 9和R 10各自獨立地選自-H和C 1-4烷基； R 11選自-H、-NR’R’’、-NHC(O)OC 1-4烷基、-NHC(O)NHC 1-4烷基和-NHC(O)N(C 1-4烷基) 2；其中所述C 1-4烷基任選被1-3個選自羥基、巰基和-NR’R’’的取代基取代； R’和R’’各自獨立地選自-H、C 1-4烷基和鹵代C 1-4烷基； m1、m2、n1和n2各自獨立地為0、1或2； p選自0、1和2; t選自1和2； 條件是R 7中至少一個為-P(=O)R 5R 6。 In one embodiment, the present invention relates to the above-described compounds of formula (a), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives or prodrugs thereof , wherein: R 7 is each independently selected from -H, halogen, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl and -P(=O)R 5 R 6 ; R 5 and R 6 Each is independently selected from -H and C 1-4 alkyl; R 8 is selected from halogen, cyano and halogenated C 1-4 alkyl; R 9 and R 10 are each independently selected from -H and C 1-4 Alkyl; R 11 is selected from -H, -NR'R'', -NHC(O)OC 1-4 alkyl, -NHC(O)NHC 1-4 alkyl and -NHC(O)N(C 1 -4 alkyl) 2 ; wherein the C 1-4 alkyl is optionally substituted by 1-3 substituents selected from hydroxyl, mercapto and -NR'R'';R' and R'' are independently selected From -H, C 1-4 alkyl and halogenated C 1-4 alkyl; m1, m2, n1 and n2 are each independently 0, 1 or 2; p is selected from 0, 1 and 2; t is selected from 1 and 2; provided that at least one of R 7 is -P(=O)R 5 R 6 .
在一個實施方案中，本發明涉及上述具有通式(a)的化合物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，其中： R 7各自獨立地選自鹵素、氰基和-P(=O)R 5R 6； R 5和R 6各自獨立地為C 1-4烷基； R 8為鹵代C 1-4烷基； R 9和R 10各自獨立地為-H； R 11選自H和-NR’R’’； R’和R’’各自獨立地選自-H和C 1-4烷基； m1、m2、n1和n2各自獨立地為1或2； p為0; t選自1和2； 條件是R 7中至少一個為-P(=O)R 5R 6。 In one embodiment, the present invention relates to the above-described compounds of formula (a), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives or prodrugs thereof , wherein: R 7 is independently selected from halogen, cyano and -P(=O)R 5 R 6 ; R 5 and R 6 are each independently C 1-4 alkyl; R 8 is halogenated C 1- 4 alkyl; R 9 and R 10 are each independently -H; R 11 is selected from H and -NR'R'';R' and R'' are each independently selected from -H and C 1-4 alkyl; m1, m2, n1 and n2 are each independently 1 or 2; p is 0; t is selected from 1 and 2 ; provided that at least one of R7 is -P(=0) R5R6 .
在一個實施方案中，本發明涉及上述具有通式(a)的化合物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，其中： R 7為-P(=O)R 5R 6； R 5和R 6各自獨立地為C 1-4烷基； R 8為鹵代C 1-4烷基，優選為-CF 3； R 9和R 10各自獨立地為-H； R 11為-NR’R’’； R’和R’’各自獨立地為-H； m1、m2、n1和n2各自獨立地為1； p為0； t為1。 In one embodiment, the present invention relates to the above-described compounds of formula (a), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives or prodrugs thereof , wherein: R 7 is -P(=O)R 5 R 6 ; R 5 and R 6 are each independently C 1-4 alkyl; R 8 is halogenated C 1-4 alkyl, preferably -CF 3 ; R 9 and R 10 are each independently -H; R 11 is -NR'R'';R' and R'' are each independently -H; m1, m2, n1 and n2 are each independently 1; p is 0; t is 1.
在一個實施方案中，本發明涉及具有通式(b)的化合物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，
在一個實施方案中，本發明涉及上述具有通式(b)的化合物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，其中： R 7各自獨立地選自-H、鹵素、氰基、C 1-4烷基、鹵代C 1-4烷基和-P(=O)R 5R 6； R 5和R 6各自獨立地選自-H和C 1-4烷基； R 8選自鹵素、氰基和鹵代C 1-4烷基； R 11選自-H、-C(O)OC 1-4烷基、-C(O)NHC 1-4烷基和-C(O)N(C 1-4烷基) 2；其中所述C 1-4烷基任選被1-3個選自羥基、巰基和-NR’R’’的取代基取代； R’和R’’各自獨立地選自-H和C 1-6烷基； m1、m2、n1和n2各自獨立地為0、1或2； t選自1和2； p選自0和1； 條件是R 7中至少一個為-P(=O)R 5R 6。 In one embodiment, the present invention relates to the above-described compounds of general formula (b), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives or prodrugs thereof , wherein: R 7 is each independently selected from -H, halogen, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl and -P(=O)R 5 R 6 ; R 5 and R 6 Each is independently selected from -H and C 1-4 alkyl; R 8 is selected from halogen, cyano and halogenated C 1-4 alkyl; R 11 is selected from -H, -C(O)OC 1-4 alkane group, -C(O)NHC 1-4 alkyl and -C(O)N(C 1-4 alkyl) 2 ; wherein the C 1-4 alkyl is optionally selected by 1-3 groups selected from hydroxyl, Substituent substitution of mercapto and -NR'R'';R' and R'' are each independently selected from -H and C 1-6 alkyl; m1, m2, n1 and n2 are each independently 0, 1 or 2 t is selected from 1 and 2; p is selected from 0 and 1; provided that at least one of R 7 is -P(=0)R 5 R 6 .
在一個實施方案中，本發明涉及上述具有通式(b)的化合物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，其中： R 7各自獨立地選自-H、鹵素、氰基和-P(=O)R 5R 6； R 5和R 6各自獨立地為C 1-4烷基； R 8為鹵代C 1-4烷基； R 11為H或-C(O)OC 1-4烷基；其中所述C 1-4烷基任選被1-2個羥基取代； m1、m2、n1和n2各自獨立地為1或2； t選自1和2； p選自0和1； 條件是R 7中至少一個為-P(=O)R 5R 6。 In one embodiment, the present invention relates to the above-described compounds of general formula (b), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives or prodrugs thereof , wherein: R 7 is each independently selected from -H, halogen, cyano and -P(=O)R 5 R 6 ; R 5 and R 6 are each independently C 1-4 alkyl; R 8 is halo C 1-4 alkyl; R 11 is H or -C(O)OC 1-4 alkyl; wherein said C 1-4 alkyl is optionally substituted with 1-2 hydroxyl groups; m1, m2, n1 and n2 each independently is 1 or 2; t is selected from 1 and 2; p is selected from 0 and 1; provided that at least one of R 7 is -P(=0)R 5 R 6 .
在一個實施方案中，本發明涉及具有通式(b-1)的化合物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，
在一個實施方案中，本發明涉及上述具有通式(b-1)的化合物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，其中： R 7選自-H、鹵素、氰基、C 1-4烷基和鹵代C 1-4烷基； R 5和R 6各自獨立地選自-H和C 1-4烷基； R 8選自鹵素、氰基和鹵代C 1-4烷基； R 11選自-H、-C(O)OC 1-4烷基、-C(O)NHC 1-4烷基和-C(O)N(C 1-4烷基) 2；其中所述C 1-4烷基任選被1-3個選自羥基、巰基和-NR’R’’的取代基取代； R’和R’’各自獨立地選自-H和C 1-6烷基； m1、m2、n1和n2各自獨立地為0、1或2。 In one embodiment, the present invention relates to the above-mentioned compounds of general formula (b-1), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives thereof, or A prodrug, wherein: R 7 is selected from -H, halogen, cyano, C 1-4 alkyl and halogenated C 1-4 alkyl; R 5 and R 6 are each independently selected from -H and C 1-4 Alkyl; R 8 is selected from halogen, cyano and halogenated C 1-4 alkyl; R 11 is selected from -H, -C(O)OC 1-4 alkyl, -C(O)NHC 1-4 alkyl and -C(O)N(C 1-4 alkyl) 2 ; wherein the C 1-4 alkyl is optionally substituted with 1-3 substituents selected from hydroxyl, mercapto and -NR'R''R' and R'' are each independently selected from -H and C 1-6 alkyl; m1, m2, n1 and n2 are each independently 0, 1 or 2.
在一個實施方案中，本發明涉及上述具有通式(b-1)的化合物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，其中： R 7選自-H、鹵素和氰基； R 5和R 6各自獨立地為C 1-4烷基； R 8為鹵代C 1-4烷基； R 11為H或-C(O)OC 1-4烷基; 其中所述C 1-4烷基任選被1-2個羥基取代； m1、m2、n1和n2各自獨立地為1或2。 In one embodiment, the present invention relates to the above-mentioned compounds of general formula (b-1), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives thereof, or A prodrug, wherein: R 7 is selected from -H, halogen and cyano; R 5 and R 6 are each independently C 1-4 alkyl; R 8 is halogenated C 1-4 alkyl; R 11 is H or -C(O)OC 1-4 alkyl; wherein said C 1-4 alkyl is optionally substituted with 1-2 hydroxyl groups; m1, m2, n1 and n2 are each independently 1 or 2.
在一個實施方案中，本發明涉及上述具有通式(b-1)的化合物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，其中： R 7為-H； R 5和R 6各自獨立地為C 1-4烷基； R 8為鹵代C 1-4烷基，優選為-CF 3； R 11為-C(O)OC 1-4烷基; 其中所述C 1-4烷基任選被1-2個羥基取代； m1、m2、n1和n2各自獨立地為1。 In one embodiment, the present invention relates to the above-mentioned compounds of general formula (b-1), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives thereof, or Prodrugs, wherein: R 7 is -H; R 5 and R 6 are each independently C 1-4 alkyl; R 8 is halogenated C 1-4 alkyl, preferably -CF 3 ; R 11 is -C (O) OC 1-4 alkyl; wherein said C 1-4 alkyl is optionally substituted with 1-2 hydroxyl groups; m1, m2, n1 and n2 are each independently 1.
在一個實施方案中，本發明涉及通式(b-2)的化合物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，
在一個實施方案中，本發明涉及上述具有通式(b-2)的化合物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，其中： R 7選自-H、鹵素、氰基、C 1-4烷基和鹵代C 1-4烷基； R 5和R 6各自獨立地選自-H和C 1-4烷基； R 8選自鹵素、氰基和鹵代C 1-4烷基； R 15為C 1-4烷基，其任選被1-3個選自羥基、巰基和-NR’R’’的取代基取代； R’和R’’各自獨立地選自-H和C 1-6烷基； m1、m2、n1和n2各自獨立地為0、1或2。 In one embodiment, the present invention relates to the above-described compounds of general formula (b-2), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives thereof, or A prodrug, wherein: R 7 is selected from -H, halogen, cyano, C 1-4 alkyl and halogenated C 1-4 alkyl; R 5 and R 6 are each independently selected from -H and C 1-4 Alkyl; R 8 is selected from halogen, cyano and halogenated C 1-4 alkyl; R 15 is C 1-4 alkyl, which is optionally surrounded by 1-3 selected from hydroxyl, mercapto and -NR'R' Substituent substitution of ';R' and R'' are each independently selected from -H and C 1-6 alkyl; m1, m2, n1 and n2 are each independently 0, 1 or 2.
在一個實施方案中，本發明涉及上述具有通式(b-2)的化合物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，其中： R 7選自-H、鹵素和氰基； R 5和R 6各自獨立地為C 1-4烷基； R 8為鹵代C 1-4烷基； R 15為C 1-4烷基；其任選被1-2個羥基取代； m1、m2、n1和n2各自獨立地為1或2。 In one embodiment, the present invention relates to the above-described compounds of general formula (b-2), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives thereof, or A prodrug, wherein: R 7 is selected from -H, halogen and cyano; R 5 and R 6 are each independently C 1-4 alkyl; R 8 is halo-C 1-4 alkyl; R 15 is C 1 -4 alkyl; it is optionally substituted with 1-2 hydroxyl groups; m1, m2, n1 and n2 are each independently 1 or 2.
在一個實施方案中，本發明涉及上述具有通式(b-2)的化合物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，其中： R 7為-H； R 5和R 6各自獨立地為C 1-4烷基； R 8為鹵代C 1-4烷基，優選為-CF 3； R 11為-C(O)OC 1-4烷基; 其中所述C 1-4烷基任選被1-2個羥基取代； m1、m2、n1和n2各自獨立地為1。 In one embodiment, the present invention relates to the above-described compounds of general formula (b-2), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives thereof, or Prodrugs, wherein: R 7 is -H; R 5 and R 6 are each independently C 1-4 alkyl; R 8 is halogenated C 1-4 alkyl, preferably -CF 3 ; R 11 is -C (O) OC 1-4 alkyl; wherein said C 1-4 alkyl is optionally substituted with 1-2 hydroxyl groups; m1, m2, n1 and n2 are each independently 1.
在一個實施方案中，本發明涉及具有通式(c)的化合物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，
在一個實施方案中，本發明涉及上述具有通式(c)的化合物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，其中：
R
8為鹵代C
1-6烷基；
R
13和R
14各自獨立地選自H和C
1-6烷基；
R
15各自獨立地選自-H、鹵素、氰基、
在一個實施方案中，本發明涉及上述具有通式(c)的化合物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，其中：
R
8為鹵代C
1-4烷基；
R
13和R
14各自獨立地為C
1-4烷基；
R
15各自獨立地選自-H、鹵素、氰基和
在一個實施方案中，本發明涉及上述具有通式(c)的化合物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，其中：
R
8為鹵代C
1-4烷基，優選為-CF
3；
R
13和R
14各自獨立地為C
1-4烷基；
R
15選自鹵素和
在一個實施方案中，本發明涉及具有通式(c-1)的化合物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，
在一個實施方案中，本發明涉及上述具有通式(c-1)的化合物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，其中： R 8為鹵代C 1-4烷基； R 13和R 14各自獨立地選自-H和C 1-4烷基； R 15選自-H、鹵素和氰基； R 5’選自-H和C 1-4烷基； R 6’選自-H、氰基和C 1-4烷基； s和q各自獨立地選自0和1。 In one embodiment, the present invention relates to the above-mentioned compounds of general formula (c-1), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives thereof, or A prodrug, wherein: R 8 is halogenated C 1-4 alkyl; R 13 and R 14 are each independently selected from -H and C 1-4 alkyl; R 15 is selected from -H, halogen and cyano; R 5' is selected from -H and C 1-4 alkyl; R 6' is selected from -H, cyano and C 1-4 alkyl; s and q are each independently selected from 0 and 1.
在一個實施方案中，本發明涉及上述具有通式(c-1)的化合物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，其中： R 8為鹵代C 1-4烷基，優選為-CF 3； R 13和R 14各自獨立地選自-H和C 1-4烷基； R 15選自-H和鹵素； R 5’為C 1-4烷基； R 6’選自-H和氰基； s和q各自獨立地為1。 In one embodiment, the present invention relates to the above-mentioned compounds of general formula (c-1), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives thereof, or A prodrug, wherein: R 8 is halogenated C 1-4 alkyl, preferably -CF 3 ; R 13 and R 14 are each independently selected from -H and C 1-4 alkyl; R 15 is selected from -H and halogen; R 5' is C 1-4 alkyl; R 6' is selected from -H and cyano; s and q are each independently 1.
具體地，所述嘧啶基衍生物選自以下化合物中的一種：
在一個實施方案中，所述嘧啶基衍生物選自以下化合物中的一種：
在一個實施方案中，本發明提供嘧啶基衍生物的製備方法，其特徵在於，包括如下步驟：
在其中一個具體的實施方案中，將基團w反應形成R 4的方法包括如下步驟： 基團w為鹵素，基團w與R 4-H進行取代反應，形成R 4；或 基團w為-S-R 5，基團w進行氧化反應，形成R 4；或 基團w為-NO 2，基團w進行還原反應生成-NH 2，-NH 2進行縮合反應，形成R 4；R 1、R 2、R 3、R 4、w、x和A如說明書中所定義。 In one specific embodiment, the method for reacting group w to form R 4 comprises the following steps: the group w is halogen, and the group w is substituted with R 4 -H to form R 4 ; or the group w is -SR 5 , group w undergoes oxidation reaction to form R 4 ; or group w is -NO 2 , group w undergoes reduction reaction to generate -NH 2 , -NH 2 undergoes condensation reaction to form R 4 ; R 1 , R 2 , R3 , R4, w, x and A are as defined in the specification.
在一個實施方案中，本發明涉及一種藥物組合物，其特徵在於，所述藥物組合物包含如本發明所述的嘧啶基衍生物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，以及藥學上可接受的輔料、稀釋劑或載體。In one embodiment, the present invention relates to a pharmaceutical composition, characterized in that the pharmaceutical composition comprises the pyrimidinyl derivative according to the present invention, its optical isomer, pharmaceutically acceptable salt, solvate compounds, atropisomers, isotopically-labeled derivatives or prodrugs, and pharmaceutically acceptable excipients, diluents or carriers.
在一個實施方案中，所述藥物組合物還包括聯用藥劑；所述聯用藥劑選自抗增殖劑、抗癌劑、免疫抑制劑和疼痛緩解劑中的至少一種。In one embodiment, the pharmaceutical composition further comprises a combined agent; the combined agent is selected from at least one of an antiproliferative agent, an anticancer agent, an immunosuppressant, and a pain relief agent.
在一個實施方案中，本發明涉及所述嘧啶基衍生物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥或所述藥物組合物在製備用於預防或治療與異常的CDK7活性相關的癌症、良性贅生物、血管生成、炎症性疾病、自身炎症性疾病、自身免疫性疾病或感染性疾病的藥物中的用途。In one embodiment, the present invention relates to said pyrimidinyl derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof or said Use of a pharmaceutical composition in the preparation of a medicament for preventing or treating cancer, benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, autoimmune disease or infectious disease associated with abnormal CDK7 activity.
在一個實施方案中，所述與異常的CDK7活性相關的癌症選自乳腺癌、卵巢癌、直腸癌、肝癌、肺癌、胃癌、腦癌、膽管癌、宮頸癌、子宮內膜癌、頭頸癌、膀胱癌、骨癌、腸癌、腎癌、喉癌、淋巴瘤、白血病、慢性淋巴細胞性白血病、急性成淋巴細胞性白血病、T細胞急性成淋巴細胞性白血病、慢性骨髓性白血病、急性骨髓性白血病、多發性骨髓瘤、黑色素瘤、間皮瘤、骨髓瘤、神經內分泌癌、食管癌、陰莖癌、***癌、皮膚癌、軟組織肉瘤癌、脊髓癌、睾丸癌、甲狀腺癌和子宮癌中的一種或幾種。In one embodiment, the cancer associated with aberrant CDK7 activity is selected from the group consisting of breast cancer, ovarian cancer, rectal cancer, liver cancer, lung cancer, gastric cancer, brain cancer, bile duct cancer, cervical cancer, endometrial cancer, head and neck cancer, Bladder cancer, bone cancer, bowel cancer, kidney cancer, throat cancer, lymphoma, leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic myeloid leukemia, acute myeloid leukemia of leukemia, multiple myeloma, melanoma, mesothelioma, myeloma, neuroendocrine, esophageal, penile, prostate, skin, soft tissue sarcoma, spinal cord, testicular, thyroid and uterine cancers one or more.
在一個實施方案中，本發明涉及所述嘧啶基衍生物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥或所述藥物組合物，其用於預防或治療與異常的CDK7活性相關的癌症、良性贅生物、血管生成、炎症性疾病、自身炎症性疾病、自身免疫性疾病或感染性疾病。In one embodiment, the present invention relates to said pyrimidinyl derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof or said A pharmaceutical composition for preventing or treating cancer, benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, autoimmune disease or infectious disease associated with abnormal CDK7 activity.
在一個實施方案中，所述與異常的CDK7活性相關的癌症選自乳腺癌、卵巢癌、直腸癌、肝癌、肺癌、胃癌、腦癌、膽管癌、宮頸癌、子宮內膜癌、頭頸癌、膀胱癌、骨癌、腸癌、腎癌、喉癌、淋巴瘤、白血病、慢性淋巴細胞性白血病、急性成淋巴細胞性白血病、T細胞急性成淋巴細胞性白血病、慢性骨髓性白血病、急性骨髓性白血病、多發性骨髓瘤、黑色素瘤、間皮瘤、骨髓瘤、神經內分泌癌、食管癌、陰莖癌、***癌、皮膚癌、軟組織肉瘤癌、脊髓癌、睾丸癌、甲狀腺癌和子宮癌中的一種或幾種。In one embodiment, the cancer associated with aberrant CDK7 activity is selected from the group consisting of breast cancer, ovarian cancer, rectal cancer, liver cancer, lung cancer, gastric cancer, brain cancer, bile duct cancer, cervical cancer, endometrial cancer, head and neck cancer, Bladder cancer, bone cancer, bowel cancer, kidney cancer, throat cancer, lymphoma, leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic myeloid leukemia, acute myeloid leukemia of leukemia, multiple myeloma, melanoma, mesothelioma, myeloma, neuroendocrine, esophageal, penile, prostate, skin, soft tissue sarcoma, spinal cord, testicular, thyroid and uterine cancers one or more.
在一個實施方案中，本發明涉及一種預防或治療與異常的CDK7活性相關的癌症、良性贅生物、血管生成、炎症性疾病、自身炎症性疾病、自身免疫性疾病或感染性疾病的方法，包括向需要的受試者給藥本發明所述的嘧啶基衍生物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥或所述藥物組合物。In one embodiment, the present invention relates to a method of preventing or treating cancer, benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, autoimmune disease or infectious disease associated with aberrant CDK7 activity, comprising Administer the pyrimidinyl derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs of the present invention to a subject in need thereof. the pharmaceutical composition.
在該治療方法的一個實施方案中，所述與異常的CDK7活性相關的癌症選自乳腺癌、卵巢癌、直腸癌、肝癌、肺癌、胃癌、腦癌、膽管癌、宮頸癌、子宮內膜癌、頭頸癌、膀胱癌、骨癌、腸癌、腎癌、喉癌、淋巴瘤、白血病、慢性淋巴細胞性白血病、急性成淋巴細胞性白血病、T細胞急性成淋巴細胞性白血病、慢性骨髓性白血病、急性骨髓性白血病、多發性骨髓瘤、黑色素瘤、間皮瘤、骨髓瘤、神經內分泌癌、食管癌、陰莖癌、***癌、皮膚癌、軟組織肉瘤癌、脊髓癌、睾丸癌、甲狀腺癌和子宮癌中的一種或幾種。In one embodiment of the method of treatment, the cancer associated with aberrant CDK7 activity is selected from the group consisting of breast cancer, ovarian cancer, rectal cancer, liver cancer, lung cancer, gastric cancer, brain cancer, bile duct cancer, cervical cancer, endometrial cancer , head and neck cancer, bladder cancer, bone cancer, bowel cancer, kidney cancer, throat cancer, lymphoma, leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic myelogenous leukemia , acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma, myeloma, neuroendocrine, esophageal, penile, prostate, skin, soft tissue sarcoma, spinal cord, testicular, thyroid and One or more of uterine cancers.
本發明的實施例還提供一種藥物組合物，所述藥物組合物包含如上所述的嘧啶基衍生物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，以及藥學上可接受的輔料、稀釋劑或載體。Embodiments of the present invention also provide a pharmaceutical composition comprising the above-mentioned pyrimidinyl derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, Isotopically labeled derivatives or prodrugs, and pharmaceutically acceptable excipients, diluents or carriers.
在其中一個具體的實施方案中，所述藥物組合物還包括聯用藥劑；所述聯用藥劑選自抗增殖劑、抗癌劑、抗糖尿病劑、抗炎劑、免疫抑制劑、以及疼痛緩解劑中的至少一種。在某些實施方式中，所述聯用藥劑為一種或多種抗癌劑。所述聯用藥劑選自小有機分子，如藥物化合物(例如《美國聯邦法規(Code of Federal Regulations)》(CFR)中所提供的由美國食品和藥物管理局(U .S .Foodand Drug Administration)批准的化合物)，以及肽、蛋白質、碳水化合物、單糖、低聚糖、多糖、核蛋白、粘蛋白、脂蛋白、合成多肽或蛋白質、與蛋白質連接的小分子、糖蛋白、類固醇、核酸、DNA、RNA、核苷酸、核苷、寡核苷酸、反義寡核苷酸、脂質、激素、維生素以及細胞等。In one specific embodiment, the pharmaceutical composition further comprises a combined agent; the combined agent is selected from the group consisting of anti-proliferative agents, anti-cancer agents, anti-diabetic agents, anti-inflammatory agents, immunosuppressive agents, and pain relief agents at least one of the agents. In certain embodiments, the combination agent is one or more anticancer agents. The combination agent is selected from small organic molecules, such as pharmaceutical compounds (eg, as provided in the Code of Federal Regulations (CFR) by the U.S. Food and Drug Administration) approved compounds), and peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells, etc.
可以理解地，所述藥物組合物還可以包括藥學上可接受的載體或稀釋劑。It is understood that the pharmaceutical composition may also include a pharmaceutically acceptable carrier or diluent.
本發明還提供如上所述的嘧啶基衍生物、其光學異構體、藥學上可接受的鹽、溶劑合物、阻轉異構體、同位素標記的衍生物或前藥，或如上所述的藥物組合物在製備用於預防或治療CDK7介導的疾病或病症的藥物中的應用。具體地，所述CDK7介導的疾病或病症是指哺乳動物(尤其是人)中CDK7介導的疾病或病症。The present invention also provides pyrimidinyl derivatives as described above, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof, or as described above Use of a pharmaceutical composition in the preparation of a medicament for preventing or treating a CDK7-mediated disease or condition. Specifically, the CDK7-mediated disease or disorder refers to a CDK7-mediated disease or disorder in mammals (especially humans).
在其中一個具體的實施方案中，所述CDK7介導的疾病或病症是指異常的CDK7活性相關的增殖性疾病(如癌症)、良性贅生物、血管生成、炎症性疾病、自身炎症性疾病、自身免疫性疾病、感染性疾病或過敏性疾病。In one specific embodiment, the CDK7-mediated disease or disorder refers to aberrant CDK7 activity-related proliferative diseases (such as cancer), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, Autoimmune disease, infectious disease or allergic disease.
在其中一個具體的實施方案中，所述與異常的CDK7活性相關的癌症選自乳腺癌(尤其是三陰乳腺癌)、卵巢癌、直腸癌、肝癌、肺癌、胃癌、腦癌、膽管癌、宮頸癌、子宮內膜癌、頭頸癌、膀胱癌、骨癌、腸癌、腎癌、喉癌、淋巴瘤、白血病、慢性淋巴細胞性白血病(CLL)、急性成淋巴細胞性白血病(ALL)、T細胞急性成淋巴細胞性白血病(T-ALL)、慢性骨髓性白血病(CML)、急性骨髓性白血病(AML)、多發性骨髓瘤、黑色素瘤、間皮瘤、骨髓瘤、神經內分泌癌、食管癌、陰莖癌、***癌、皮膚癌、軟組織肉瘤癌、脊髓癌、睾丸癌、甲狀腺癌和子宮癌中的一種或幾種。In one specific embodiment, the cancer associated with abnormal CDK7 activity is selected from breast cancer (especially triple negative breast cancer), ovarian cancer, rectal cancer, liver cancer, lung cancer, stomach cancer, brain cancer, bile duct cancer, Cervical cancer, endometrial cancer, head and neck cancer, bladder cancer, bone cancer, bowel cancer, kidney cancer, laryngeal cancer, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), multiple myeloma, melanoma, mesothelioma, myeloma, neuroendocrine carcinoma, esophagus One or more of cancer, penile cancer, prostate cancer, skin cancer, soft tissue sarcoma cancer, spinal cord cancer, testicular cancer, thyroid cancer and uterine cancer.
以下為具體的實施方案。下列實施例中未注明具體條件的實驗方法，按照常規方法和條件，可以由本領域技術人員通過傳統的優化程式來確定。The following are specific embodiments. The experimental methods that do not specify specific conditions in the following examples can be determined by those skilled in the art through traditional optimization programs according to conventional methods and conditions.
化合物的結構是通過核磁共振 (NMR)和/或質譜(MS)來確定的。NMR位移(δ)以10 -6(ppm)的單位給出。NMR的測定是用(Bruker Avance III 400和Bruker Avance 300) 核磁儀，測定溶劑為氘代二甲基亞碸 (DMSO-d 6)，氘代氯仿 (CDCl 3)，氘代甲醇 (CD 3OD)，內標為四甲基矽烷(TMS)。 The structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10<" 6 > (ppm). NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instruments, and the solvents were deuterated dimethylsulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) ), the internal standard is tetramethylsilane (TMS).
MS的測定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))。For MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI)).
HPLC的測定使用安捷倫1260DAD高壓液相色譜儀 (Zorbax SB-C18 100×4.6 mm)。The HPLC measurement was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm).
薄層層析矽膠板使用煙臺黃海HSGF254 或青島GF254 矽膠板，薄層色譜法 (TLC) 使用的矽膠板採用的規格是0.15 mm~0.20 mm，薄層層析分離純化產品採用的規格是0.4 mm~0.5 mm。The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15 mm~0.20 mm, and the size of the TLC separation and purification products is 0.4 mm. ~0.5 mm.
柱層析一般使用煙臺黃海矽膠200~300目矽膠為載體。Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.
本發明的己知的起始原料可以採用或按照本領域已知的方法來合成，或可購買於泰坦科技、安耐吉化學、上海德默、成都科龍化工、韶遠化學科技、百靈威科技等公司。The known starting materials of the present invention can be synthesized by using or according to methods known in the art, or can be purchased from Titan Technology, Annagy Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Bailingwei Technology and other companies.
氮氣氛是指反應瓶連接一個約1L容積的氮氣氣球。Nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon with a volume of about 1 L.
氫氣氛是指反應瓶連接一個約1L容積的氫氣氣球。Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
氫化反應通常抽真空，充入氫氣，反復操作3次。The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
實施例中無特殊說明，反應在氮氣氛下進行。There is no special description in the examples, and the reaction is carried out under nitrogen atmosphere.
實施例中無特殊說明，溶液是指水溶液。There is no special description in the examples, and the solution refers to an aqueous solution.
實施例中無特殊說明，反應的溫度為室溫。There is no special description in the examples, and the reaction temperature is room temperature.
室溫為最適宜的反應溫度，為20℃~30℃。Room temperature is the most suitable reaction temperature, ranging from 20°C to 30°C.
化學合成相關縮寫： Boc 2O：一縮二碳酸二叔丁基酯 DIEA：N,N-二異丙基乙胺 Xantphos：4,5-雙(二苯基膦基)-9,9-二甲基氧雜蒽 Johnphos：2-(二叔丁基膦)聯苯 Pd(OAc) 2：醋酸鈀 Pd(PPh 3) 4：四(三苯基膦)鈀 Pd(Pd(PPh 3) 2Cl 2：雙苯基磷二氯化鈀 Pd(dppf)Cl 2：[1,1'-雙(二苯基磷)二茂鐵]二氯化鈀 Pd 2(dba) 3：三(二亞苄基丙酮)二鈀 Pd/C：鈀炭催化劑 NaOtBu：叔丁醇鈉 PE：石油醚； EA：乙酸乙酯； DMF：N, N-二甲基甲醯胺； DCM：二氯甲烷； THF：四氫呋喃 MeOH：甲醇 Prep-HPLC：高壓製備液相色譜 Rf：比移值； g：克 mg：毫克 h：小時 rt：室溫 mol：摩爾 mmol：毫摩爾 mL：毫升 M：摩爾/升 SEMCl：氯甲基三甲基矽乙基醚 TFA：三氟乙酸 TFAA：三氟乙酸酐 Abbreviations related to chemical synthesis: Boc 2 O: di-tert-butyl dicarbonate DIEA: N,N-diisopropylethylamine Xantphos: 4,5-bis(diphenylphosphino)-9,9-di Methylxanthene Johnphos: 2-(di-tert-butylphosphine)biphenyl Pd(OAc) 2 : Palladium acetate Pd(PPh 3 ) 4 : Tetrakis(triphenylphosphine)palladium Pd(Pd(PPh 3 ) 2 Cl 2 : bisphenylphosphonium palladium dichloride Pd(dppf)Cl 2 : [1,1'-bis(diphenylphosphonium)ferrocene]dichloropalladium Pd 2 (dba) 3 : tris(dibenzylidene) acetone) dipalladium Pd/C: palladium carbon catalyst NaOtBu: sodium tert-butoxide PE: petroleum ether; EA: ethyl acetate; DMF: N,N-dimethylformamide; DCM: dichloromethane; THF: Tetrahydrofuran MeOH: methanol Prep-HPLC: high pressure preparative liquid chromatography Rf: ratio shift; g: grams mg: mg h: hours rt: room temperature mol: moles mmol: millimoles mL: milliliters M: mol/L SEMCl: chlorine Methyltrimethylsilyl ethyl ether TFA: trifluoroacetic acid TFAA: trifluoroacetic anhydride
中間體 1：7-溴-1H-吲哚-6-甲腈
第一步：7-溴-1H-吲哚-6-羧酸1b
將乙烯基溴化鎂(1mol/L，320mL)加入到200mL無水THF中，降溫至-78℃，向其中慢慢滴加化合物2-溴-3-硝基苯甲酸1a(20g, 81.3mmol)溶解在320mL無水THF的溶液。滴加完成後，升至室溫攪拌過夜。反應液用150mL飽和NH4Cl溶液淬滅，用1mol/L的鹽酸溶液調節pH至2左右，接著用EtOAc(3x200mL)萃取。有機相用飽和NaCl溶液洗滌，無水Na 2SO 4乾燥，真空旋幹得固體粗品。向粗品中加入適量DCM進行打漿純化，得到棕色固體產品1b(16g，收率：82%)。 Vinylmagnesium bromide (1 mol/L, 320 mL) was added to 200 mL of anhydrous THF, cooled to -78°C, and the compound 2-bromo-3-nitrobenzoic acid 1a (20 g, 81.3 mmol) was slowly added dropwise thereto. Dissolve a solution in 320 mL of anhydrous THF. After the dropwise addition was completed, the mixture was warmed to room temperature and stirred overnight. The reaction solution was quenched with 150 mL of saturated NH 4 Cl solution, adjusted to pH about 2 with 1 mol/L hydrochloric acid solution, and then extracted with EtOAc (3×200 mL). The organic phase was washed with saturated NaCl solution, dried over anhydrous Na 2 SO 4 , and dried in vacuo to obtain a solid crude product. An appropriate amount of DCM was added to the crude product for beating and purification to obtain a brown solid product 1b (16 g, yield: 82%).
MS m/z (ESI)：240.1 [M+1]。MS m/z (ESI): 240.1 [M+1].
第二步：7-溴-1H-吲哚-6-羧醯胺1c
將化合物1b(16g，66.9mmol)溶於150mL無水DMF中，降溫至0℃，加入CDI(21.7g，134mmol)，0℃下攪拌1h。LC-MS監測化合物1b已消耗掉。接著向其中加入96 mL氨水，繼續在0℃下反應1h。反應液加水淬滅，用THF(3x100mL)萃取。有機相用飽和NaCl溶液洗滌，無水Na 2SO 4乾燥，真空旋幹。粗品通過矽膠柱(洗脫劑：二氯甲烷/甲醇=70/1)純化後得到黃色固體產品1c(11g，收率：69%)。 Compound 1b (16 g, 66.9 mmol) was dissolved in 150 mL of anhydrous DMF, cooled to 0 °C, CDI (21.7 g, 134 mmol) was added, and stirred at 0 °C for 1 h. LC-MS monitored that compound 1b was consumed. Then, 96 mL of ammonia water was added thereto, and the reaction was continued at 0 °C for 1 h. The reaction was quenched with water and extracted with THF (3×100 mL). The organic phase was washed with saturated NaCl solution, dried over anhydrous Na 2 SO 4 and spun dry in vacuo. The crude product was purified by silica gel column (eluent: dichloromethane/methanol=70/1) to obtain yellow solid product 1c (11 g, yield: 69%).
MS m/z (ESI)：239.1 [M+1]。MS m/z (ESI): 239.1 [M+1].
第三步：7-溴-1H-吲哚-6-甲腈(中間體1)
將化合物1c(11g，46.2mmol)溶於50mL無水DCM中，降溫至0℃。加入三乙胺(9.3g，92.4mmol)，攪拌5min，接著向其中緩慢滴加TFAA(三氟乙酸酐)(19.4g，92.4mmol)。添加完成後，反應液於0℃下攪拌1h。反應加水淬滅，接著用DCM萃取。有機相用飽和NaCl溶液洗滌，無水Na 2SO 4乾燥，真空旋幹得到粗品。粗品通過矽膠柱(洗脫劑：石油醚/乙酸乙酯=15/1)純化得淺黃色固體產品7-溴-1H-吲哚-6-甲腈(中間體1)(2.0g，收率：20%)。 Compound 1c (11 g, 46.2 mmol) was dissolved in 50 mL of anhydrous DCM and cooled to 0 °C. Triethylamine (9.3 g, 92.4 mmol) was added, stirred for 5 min, and then TFAA (trifluoroacetic anhydride) (19.4 g, 92.4 mmol) was slowly added dropwise thereto. After the addition was completed, the reaction solution was stirred at 0 °C for 1 h. The reaction was quenched with water, followed by extraction with DCM. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na 2 SO 4 , and dried in vacuo to obtain the crude product. The crude product was purified by silica gel column (eluent: petroleum ether/ethyl acetate=15/1) to obtain 7-bromo-1H-indole-6-carbonitrile (intermediate 1) as a light yellow solid product (2.0 g, yield : 20%).
1H-NMR (400 MHz, CDCl 3) δ 8.61 (brs, 1 H), 7.64 (d, 1 H), 7.48 (t, 1 H), 7.36 (d, 1 H), 6.72 (dd, 1 H)。 1H-NMR (400 MHz, CDCl 3 ) δ 8.61 (brs, 1 H), 7.64 (d, 1 H), 7.48 (t, 1 H), 7.36 (d, 1 H), 6.72 (dd, 1 H) .
中間體 2：順式-N
1-甲基環己烷-1,3-二胺
第一步：((1R,3S)-環己烷-1,3-二基)二胺基甲酸二苄酯2b
將化合物(1R,3S)-環己烷-1,3-二羧酸(2a)(5g，1eq)、DPPA(16g，2eq)和Et 3N(6g，2eq)在甲苯(25mL)中的混合物在60 oC攪拌0.5h。然後在加入BnOH(6.4g，2eq)後，將最終混合物在100℃下再攪拌3小時。TLC顯示原料已耗盡。將反應混合物通過添加10mL水稀釋，有機層用乙酸乙酯(20ml×3)萃取，有機相用鹽水洗滌，用無水硫酸鈉乾燥。減壓濃縮有機相得到粗化合物。粗品通過矽膠柱色譜法純化，用(MeOH/DCM＝0至5%)洗脫，得到((1R,3S)-環己烷-1,3-二基)二胺基甲酸二苄酯2b(3g，27%)。 Compound (1R,3S)-cyclohexane-1,3-dicarboxylic acid (2a) (5g, 1eq), DPPA (16g, 2eq) and Et3N (6g, 2eq) in toluene (25mL) The mixture was stirred at 60 ° C for 0.5h. Then after addition of BnOH (6.4 g, 2 eq), the final mixture was stirred at 100°C for an additional 3 hours. TLC showed starting material was consumed. The reaction mixture was diluted by adding 10 mL of water, the organic layer was extracted with ethyl acetate (20 ml×3), the organic phase was washed with brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude compound. The crude product was purified by silica gel column chromatography, eluting with (MeOH/DCM = 0 to 5%) to give ((1R,3S)-cyclohexane-1,3-diyl)dicarbamate dibenzyl ester 2b ( 3g, 27%).
1H NMR (400 MHz, DMSO-D6) δ 7.39 – 7.29 (m, 10H), 7.26 (s, 1H), 7.24 (s, 1H), 5.00 (s, 4H), 2.00 – 1.62 (m, 5H), 1.35 – 0.93 (m, 5H)1H NMR (400 MHz, DMSO-D6) δ 7.39 – 7.29 (m, 10H), 7.26 (s, 1H), 7.24 (s, 1H), 5.00 (s, 4H), 2.00 – 1.62 (m, 5H), 1.35 – 0.93 (m, 5H)
第二步：順式-(3-(((苄氧基)羰基)胺基)環己基)(甲基)胺基甲酸苄基酯2c
在0℃下，向2b(380mg，1mmol)的DMF(5mL)混合物中加入NaH(40mg，1mmol)。將混合物在0℃下攪拌0.5h。加入CH 3I(142mg，1mmol)。將混合物在25℃攪拌2h。加入10mL水稀釋反應混合物，將有機層用乙酸乙酯(20ml×3)萃取，將有機相用鹽水洗滌，用無水硫酸鈉乾燥。將混合物在減壓下濃縮得到粗品。通過矽膠上的柱色譜法純化所述粗品，用(乙酸乙酯/石油醚＝0至50%)洗脫，得到順式-(3-(((苄氧基)羰基)胺基)環己基)(甲基)胺基甲酸苄基酯(2c)(120mg)，為黃色油狀物。 To a mixture of 2b (380 mg, 1 mmol) in DMF (5 mL) at 0 °C was added NaH (40 mg, 1 mmol). The mixture was stirred at 0 °C for 0.5 h. CH3I (142 mg, 1 mmol) was added. The mixture was stirred at 25 °C for 2 h. 10 mL of water was added to dilute the reaction mixture, the organic layer was extracted with ethyl acetate (20 ml×3), the organic phase was washed with brine, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography on silica gel eluting with (ethyl acetate/petroleum ether = 0 to 50%) to give cis-(3-(((benzyloxy)carbonyl)amino)cyclohexyl ) benzyl (methyl)carbamate (2c) (120 mg) as a yellow oil.
MS m/z (ESI): 397.1[M+1]。MS m/z (ESI): 397.1 [M+1].
第三步：順式-N
1-甲基環己烷-1,3-二胺(中間體2)
將Pd/C(32mg，0.1eq)加入到2c(120mg，1eq)的MeOH(5mL)溶液中，在室溫攪拌2h。TLC顯示原料消耗完後，將反應混合物過濾。將固體用MeOH(10ml×2)洗滌。減壓濃縮濾液，得到化合物順式-N 1-甲基環己烷-1,3-二胺(中間體2)(30mg，77.3%)，為淺黃色固體。 Pd/C (32 mg, 0.1 eq) was added to a solution of 2c (120 mg, 1 eq) in MeOH (5 mL) and stirred at room temperature for 2 h. After TLC showed that the starting material was consumed, the reaction mixture was filtered. The solid was washed with MeOH (10 ml x 2). The filtrate was concentrated under reduced pressure to give compound cis-N 1 -methylcyclohexane-1,3-diamine (Intermediate 2) (30 mg, 77.3%) as a pale yellow solid.
中間體 3：(2s,3as,5s,6as)-八氫並環戊二烯-2,5-二胺
第一步：(2r,3ar,5r,6ar)-八氫並環戊二烯-2,5-二醇 3b
將四氫並環戊二烯-2,5(1H,3H)-二酮3a (10 g, 72.38 mmol )溶於乾燥的乙酸乙酯 (300 mL) 中並用N 2置換空氣3次。降至0 oC, 加入1mol/L三叔丁氧基氫化鋰鋁 (217 ml，217 mmol)。添加完成後自然升溫至室溫，攪拌18個小時。向反應液中加入飽和氯化銨(300ml)淬滅，分液，水相用乙酸乙酯 (300 mL × 2) 萃取，合併有機相。有機相用飽和食鹽水 (100 mL × 2) 洗滌，室溫無水硫酸鈉乾燥，過濾，濃縮。殘留物用矽膠柱色譜分離提純(石油醚/乙酸乙酯 (v/v) = 5:1) 得到白色固體(2r,3ar,5r,6ar)-八氫並環戊二烯-2,5-二醇 3b (6.2 g, 產率60.24%)。 Tetrahydrocyclopentadiene-2,5(1H,3H)-dione 3a (10 g, 72.38 mmol) was dissolved in dry ethyl acetate (300 mL) and the air was replaced with N2 3 times. The temperature was lowered to 0 o C, and 1 mol/L tri-tert-butoxy lithium aluminum hydride (217 ml, 217 mmol) was added. After the addition was completed, the temperature was naturally raised to room temperature, and the mixture was stirred for 18 hours. Saturated ammonium chloride (300 ml) was added to the reaction solution to quench, and the layers were separated. The aqueous phase was extracted with ethyl acetate (300 mL × 2), and the organic phases were combined. The organic phase was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate at room temperature, filtered and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 5:1) to obtain (2r,3ar,5r,6ar)-octahydrocyclopentadiene-2,5- as a white solid Diol 3b (6.2 g, 60.24% yield).
第二步：(2r,3ar,5r,6ar)-二甲磺酸八氫並環戊二烯-2,5-二基酯 3c
將(2r,3ar,5r,6ar)-八氫並環戊二烯-2,5-二醇 3b (6.2 g，43.6 mmol) 和三乙胺(17.65 g，174.4 mmol)溶於乾燥的二氯甲烷 (100 mL) 中並用N 2置換空氣3次。0℃加入MsCl (12.49 g，109 mmol)，攪拌反應一個小時。向反應液中加入二氯甲烷(100ml)和冰水 (100 mL)，分液。水相用二氯甲烷 (100 mL × 2) 萃取，合併有機相。有機相用飽和食鹽水 (20 mL × 2) 洗滌，室溫用無水硫酸鈉乾燥，過濾，濃縮。殘留物用矽膠柱色譜分離提純(石油醚/乙酸乙酯 (v/v) = 3:1) 得到淡白色固體狀的化合物(2r,3ar,5r,6ar)-二甲磺酸八氫並環戊二烯-2,5-二基酯3c (5.8 g, 產率44.58%)。 (2r,3ar,5r,6ar)-octahydrocyclopentadiene-2,5-diol 3b (6.2 g, 43.6 mmol) and triethylamine (17.65 g, 174.4 mmol) were dissolved in dry dichloro in methane (100 mL) and replacing the air with N 2 3 times. MsCl (12.49 g, 109 mmol) was added at 0°C and the reaction was stirred for one hour. Dichloromethane (100 mL) and ice water (100 mL) were added to the reaction solution, and the layers were separated. The aqueous phase was extracted with dichloromethane (100 mL × 2), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate at room temperature, filtered and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3:1) to obtain the compound (2r,3ar,5r,6ar)-dimethanesulfonic acid octahydrocyclohexanol as a pale white solid Pentadiene-2,5-diyl ester 3c (5.8 g, 44.58% yield).
第三步：(2s,3as,5s,6as)-2,5-二疊氮基八氫並環戊二烯 3d
將(2r,3ar,5r,6ar)-二甲磺酸八氫並環戊二烯-2,5-二基酯3c (2.5 g, 8.38 mmol) 和疊氮鈉 (5.45 g, 83.79 mmol) 溶於N,N-二甲基甲醯胺(20 ml)中, N 2置換3次，然後加熱至80℃反應四個小時。向反應液中加入乙酸乙酯(60ml)和冰水 (100 mL)，分液。水相用乙酸乙酯 (100 mL × 2) 萃取，合併有機相。有機相用飽和食鹽水 (20 mL × 2) 洗滌，室溫用無水硫酸鈉乾燥，過濾，濃縮得到殘留物。殘留物用矽膠柱色譜分離提純(石油醚/乙酸乙酯 (v/v) = 10:1) 得到淡黃色油狀的化合物(2s,3as,5s,6as)-2,5-二疊氮基八氫並環戊二烯3d (1.6 g, 產率99%)。 (2r,3ar,5r,6ar)-dimethanesulfonic acid octahydrocyclopentadiene-2,5-diyl ester 3c (2.5 g, 8.38 mmol) and sodium azide (5.45 g, 83.79 mmol) were dissolved In N,N-dimethylformamide (20 ml), N 2 was replaced 3 times, then heated to 80 °C for four hours. Ethyl acetate (60 ml) and ice water (100 mL) were added to the reaction solution, and the layers were separated. The aqueous phase was extracted with ethyl acetate (100 mL × 2), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate at room temperature, filtered, and concentrated to obtain a residue. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 10:1) to obtain the compound (2s,3as,5s,6as)-2,5-diazide as light yellow oil Octahydrocyclopentadiene 3d (1.6 g, 99% yield).
第四步：(2s,3as,5s,6as)-八氫並環戊二烯-2,5-二胺 (中間體3)
將(2s,3as,5s,6as)-2,5-二疊氮基八氫並環戊二烯3d (1.6 g, 8.32 mmol)溶於無水四氫呋喃 (20 mL) 中，加入Pd/C (160 mg), H 2置換3次，室溫反應6個小時。過濾，減壓濃縮得棕色油狀殘留物。殘留物用矽膠柱色譜分離提純(石油醚/乙酸乙酯 (v/v) = 3:1) 得到棕色油狀的化合物(2s,3as,5s,6as)-八氫並環戊二烯-2,5-二胺(中間體3) (1.1 g，產率94%)。 (2s,3as,5s,6as)-2,5-diazidooctahydrocyclopentadiene 3d (1.6 g, 8.32 mmol) was dissolved in dry tetrahydrofuran (20 mL) and Pd/C (160 mmol) was added. mg), replaced by H 3 times, and reacted at room temperature for 6 hours. Filtration and concentration under reduced pressure gave a brown oily residue. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3:1) to obtain the compound (2s,3as,5s,6as)-octahydrocyclopentadiene-2 as a brown oil ,5-Diamine (Intermediate 3) (1.1 g, 94% yield).
中間體 4：3-(2-氯-5-(三氟甲基)嘧啶-4-基)-6-氟-7-(甲硫基)-1H-吲哚
第一步：(2-氟-6-硝基苯基)(甲基)硫烷 4b
將2,3-二氟硝基苯 4a(20 g, 0.126 mol) 溶於DMSO (200 mL) 中，向其中加入甲硫醇鈉 (9.7 g, 0.138 mol)，室溫攪拌過夜。向反應液中加入水(600 mL)淬滅，用乙酸乙酯 (300 mL × 2) 萃取得到有機相。有機相用飽和食鹽水 (100 mL) 洗滌，無水硫酸鈉乾燥，過濾，濃縮旋幹得到殘留物。殘留物通過矽膠柱 (石油醚/乙酸乙酯 (v/v) = 10/1) 純化後得到棕色油狀化合物(2-氟-6-硝基苯基)(甲基)硫烷 4b(12 g, 產率51%)。 2,3-Difluoronitrobenzene 4a (20 g, 0.126 mol) was dissolved in DMSO (200 mL), sodium methanethiolate (9.7 g, 0.138 mol) was added thereto, and the mixture was stirred at room temperature overnight. Water (600 mL) was added to the reaction solution to quench, and the organic phase was obtained by extraction with ethyl acetate (300 mL × 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated and spin-dried to obtain a residue. The residue was purified by silica gel column (petroleum ether/ethyl acetate (v/v) = 10/1) to give (2-fluoro-6-nitrophenyl)(methyl)sulfane 4b (12) as a brown oily compound g, 51% yield).
MS m/z (ESI)：188.1 [M+1]MS m/z (ESI): 188.1 [M+1]
第二步：6-氟-7-(甲硫基)-1H-吲哚
4c 
將(2-氟-6-硝基苯基)(甲基)硫烷 4b(10 g, 0.0535 mol) 溶於乾燥的四氫呋喃 (170 mL) 中並用N 2置換空氣3次。然後降至-78 oC, 加入1.5 mol/L的乙烯基溴化鎂 (169 mL，0.254 mol)。添加完成後自然升溫至室溫並攪拌3個小時。向反應液中加入飽和氯化銨(200 mL)淬滅，接著用乙酸乙酯 (100 mL × 2) 萃取，合併有機相。有機相用飽和食鹽水 (100 mL) 洗滌，無水硫酸鈉乾燥，過濾，濃縮旋幹得到殘留物。殘留物過矽膠柱 (石油醚/乙酸乙酯 (v/v) = 10/1) 純化後得到棕色油狀化合物6-氟-7-(甲硫基)-1H-吲哚 4c(4.5 g, 產率46%)。 (2-Fluoro-6-nitrophenyl)(methyl)sulfane 4b (10 g, 0.0535 mol) was dissolved in dry tetrahydrofuran (170 mL) and the air was replaced with N2 3 times. Then it was lowered to -78 ° C, and 1.5 mol/L of vinylmagnesium bromide (169 mL, 0.254 mol) was added. After the addition was completed, the temperature was naturally warmed to room temperature and stirred for 3 hours. The reaction solution was quenched by adding saturated ammonium chloride (200 mL), followed by extraction with ethyl acetate (100 mL × 2), and the organic phases were combined. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated and spin-dried to obtain a residue. The residue was purified by silica gel column (petroleum ether/ethyl acetate (v/v) = 10/1) to give 6-fluoro-7-(methylthio)-1H-indole 4c (4.5 g, yield 46%).
MS m/z (ESI)：182.1 [M+1]MS m/z (ESI): 182.1 [M+1]
第三步：3-(2-氯-5-(三氟甲基)嘧啶-4-基)-6-氟-7-(甲硫基)-1H-吲哚 (中間體4)
將2,4-二氯-5-(三氟甲基)嘧啶 (8.0 g，37.29 mmol) 溶於乾燥的1,2-二氯乙烷 (30 mL) 中並用N 2置換空氣3次。加入無水三氯化鋁 (4.98 g，37.29 mmol)，然後加熱至80℃攪拌半個小時。將6-氟-7-(甲硫基)-1H-吲哚 4c(4.5 g, 24.86 mmol)的1,2-二氯乙烷溶液(10 ml)緩慢加入反應體系，保持80℃繼續攪拌2個小時。降至室溫，向反應液中加入二氯甲烷(30 mL)、冰水 (30 mL)，分液，水相用二氯甲烷 (20 mL × 2) 萃取。合併有機相，有機相用飽和食鹽水 (20 mL × 2) 洗滌，無水硫酸鈉乾燥，過濾，濃縮得到殘留物。殘留物通過矽膠柱 (石油醚/乙酸乙酯 (v/v) = 3/1) 純化後得到淡黃色固體化合物3-(2-氯-5-(三氟甲基)嘧啶-4-基)-6-氟-7-(甲硫基)-1H-吲哚 ( 中間體 4)(4.8 g, 產率54%)。 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (8.0 g, 37.29 mmol) was dissolved in dry 1,2-dichloroethane (30 mL) and the air was replaced with N2 3 times. Anhydrous aluminum trichloride (4.98 g, 37.29 mmol) was added, then heated to 80°C and stirred for half an hour. A solution of 6-fluoro-7-(methylthio)-1H-indole 4c (4.5 g, 24.86 mmol) in 1,2-dichloroethane (10 ml) was slowly added to the reaction system, and kept stirring at 80 °C for 2 Hours. The temperature was lowered to room temperature, dichloromethane (30 mL) and ice water (30 mL) were added to the reaction solution, and the layers were separated. The aqueous phase was extracted with dichloromethane (20 mL × 2). The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column (petroleum ether/ethyl acetate (v/v) = 3/1) to give a pale yellow solid compound 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl) -6-Fluoro-7-(methylthio)-1H-indole ( Intermediate 4) (4.8 g, 54% yield).
MS m/z (ESI)：360.1 [M-1]MS m/z (ESI): 360.1 [M-1]
中間體 5：3-(2-氯-5-(三氟甲基)嘧啶-4-基)-7-(甲硫基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚
第一步：7-(甲硫基)-1H-吲哚 5b
將7-溴-1H-吲哚5a (4.0 g, 20.4 mmol)溶於二甲苯 (15 mL) 中，加入硫代丁酸S-酸甲酯(12.0 g, 102 mmol)、二氯化鈀 (1.0 g, 5.65 mmol)、叔丁醇鉀 (8.5 g, 75.9 mmol)、9,9-二甲基-4,5-雙(二苯基膦)雜蒽 (1.0 g, 5.65 mmol), N 2置換3次，升溫至140℃反應12個小時。加入水 (50 mL)和乙酸乙酯(150 ml)，分液，保留有機相。水相再用乙酸乙酯 (10 mL × 2) 萃取，合併有機相。將有機相用飽和食鹽水 (20 mL × 2) 洗滌，無水硫酸鈉乾燥，過濾，濃縮得到粗品。粗品通過矽膠柱(石油醚/乙酸乙酯 = 5/1)純化後得到黃色油狀化合物7-(甲硫基)-1H-吲哚5b (2.6 g，產率79%)。 7-Bromo-1H-indole 5a (4.0 g, 20.4 mmol) was dissolved in xylene (15 mL), S-acid methyl thiobutyrate (12.0 g, 102 mmol), palladium dichloride ( 1.0 g, 5.65 mmol), potassium tert-butoxide (8.5 g, 75.9 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (1.0 g, 5.65 mmol), N 2 The replacement was performed three times, and the temperature was raised to 140° C. to react for 12 hours. Water (50 mL) and ethyl acetate (150 mL) were added, the layers were separated, and the organic phase was retained. The aqueous phase was extracted with ethyl acetate (10 mL × 2), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column (petroleum ether/ethyl acetate = 5/1) to obtain compound 7-(methylthio)-1H-indole 5b (2.6 g, yield 79%) as yellow oil.
MS m/z (ESI)：164.1 [M+1]MS m/z (ESI): 164.1 [M+1]
第二步：3-(2-氯-5-(三氟甲基)嘧啶-4-基)-7-(甲硫基)-1H-吲哚5c
將2,4-二氯-5-(三氟甲基)嘧啶 (8.0 g, 37.0 mmol)溶於無水二氯乙烷 (50 mL) 中，加入無水三氯化鋁(4.8 g，36.0 mmol)，N 2置換3次。然後升溫至80℃，反應30分鐘。加入7-(甲硫基)-1H-吲哚5b(2 g, 12.3 mmol)，反應1個小時。加入水 (100 mL)和乙酸乙酯(150 ml)，分液，保留有機相。水相用乙酸乙酯 (30 mL × 2) 萃取，合併有機相。將有機相用飽和食鹽水 (30 mL × 2) 洗滌，無水硫酸鈉乾燥，過濾，濃縮得到粗品。粗品通過矽膠柱(石油醚/乙酸乙酯 = 5/1)純化後得到黃色固體化合物3-(2-氯-5-(三氟甲基)嘧啶-4-基)-7-(甲硫基)-1H-吲哚 5c(1.0 g，產率24%)。 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (8.0 g, 37.0 mmol) was dissolved in dry dichloroethane (50 mL) and anhydrous aluminum trichloride (4.8 g, 36.0 mmol) was added , N 2 is replaced 3 times. Then, the temperature was raised to 80°C, and the reaction was carried out for 30 minutes. 7-(Methylthio)-1H-indole 5b (2 g, 12.3 mmol) was added and reacted for 1 hour. Water (100 mL) and ethyl acetate (150 mL) were added, the layers were separated, and the organic phase was retained. The aqueous phase was extracted with ethyl acetate (30 mL × 2), and the organic phases were combined. The organic phase was washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column (petroleum ether/ethyl acetate = 5/1) to obtain a yellow solid compound 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-(methylthio) )-1H-indole 5c (1.0 g, 24% yield).
MS m/z (ESI)：344.1 [M+1]MS m/z (ESI): 344.1 [M+1]
第三步：3-(2-氯-5-(三氟甲基)嘧啶-4-基)-7-(甲硫基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚(中間體5)
將3-(2-氯-5-(三氟甲基)嘧啶-4-基)-7-(甲硫基)-1H-吲哚 5c(1.0 g, 2.92 mmol)溶於N,N-二甲基甲醯胺(10 mL) 中，N 2置換3次。然後降至0度，加入鈉氫 (180 mg, 4.38 mmol)，反應30分鐘。然後加入(2-(氯甲氧基)乙基)三甲基矽烷 (540 mg, 4.10 mmol)，升溫至室溫，反應4個小時。加入水(20 mL)和乙酸乙酯(15 mL)，分液，保留有機相。水相再用乙酸乙酯 (10 mL × 2) 萃取，合併有機相。將有機相用飽和食鹽水 (20 mL × 2) 洗滌，無水硫酸鈉乾燥，過濾，濃縮得到粗品。粗品通過矽膠柱(石油醚/乙酸乙酯 = 5/1)純化後得到黃色油狀化合物3-(2-氯-5-(三氟甲基)嘧啶-4-基)-7-(甲硫基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚 中間體 5(600 mg，產率43%)。 3-(2-Chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-(methylthio)-1H-indole 5c (1.0 g, 2.92 mmol) was dissolved in N,N-di In methylformamide (10 mL), N 2 was replaced 3 times. Then it was lowered to 0 degrees, sodium hydrogen (180 mg, 4.38 mmol) was added, and the reaction was carried out for 30 minutes. Then (2-(chloromethoxy)ethyl)trimethylsilane (540 mg, 4.10 mmol) was added, the temperature was raised to room temperature, and the reaction was carried out for 4 hours. Water (20 mL) and ethyl acetate (15 mL) were added, the layers were separated, and the organic phase was retained. The aqueous phase was extracted with ethyl acetate (10 mL × 2), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column (petroleum ether/ethyl acetate = 5/1) to obtain the yellow oily compound 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-(methylthio) yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole Intermediate 5 (600 mg, 43% yield).
MS m/z (ESI)：474.1 [M+1]MS m/z (ESI): 474.1 [M+1]
中間體 6：1-(胺甲基)-5-氮雜螺[2.4]庚烷-5-羧酸叔丁酯
第一步：1-(羥甲基)-5-氮雜螺[2.4]庚烷-5-羧酸叔丁酯 6b
將5-(叔丁氧羰基)-5-氮雜螺[2.4]庚烷-1-羧酸 6a (900 mg, 3.73 mmol)溶於無水四氫呋喃 (20 mL) 中，N 2置換3次。降溫至0℃，加入硼烷四氫呋喃(1mol/L)(7.5 ml, 7.5mmol), 升溫至室溫，反應3個小時。加入水 (20 mL)和乙酸乙酯(15 ml)，分液。水相用乙酸乙酯 (10 mL × 2) 萃取，合併有機相。將有機相用飽和食鹽水 (20 mL × 2) 洗滌，無水硫酸鈉乾燥，過濾，濃縮得到油狀的化合物1-(羥甲基)-5-氮雜螺[2.4]庚烷-5-羧酸叔丁酯6b (920 mg，粗品)，直接用於下一步反應。 5-(tert-Butoxycarbonyl)-5-azaspiro[2.4]heptane-1-carboxylic acid 6a (900 mg, 3.73 mmol) was dissolved in dry tetrahydrofuran (20 mL) and replaced with N 2 three times. The temperature was lowered to 0° C., borane tetrahydrofuran (1 mol/L) (7.5 ml, 7.5 mmol) was added, the temperature was raised to room temperature, and the reaction was carried out for 3 hours. Water (20 mL) and ethyl acetate (15 mL) were added to separate the layers. The aqueous phase was extracted with ethyl acetate (10 mL × 2), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain an oily compound 1-(hydroxymethyl)-5-azaspiro[2.4]heptane-5-carboxylate tert-Butyl acid 6b (920 mg, crude) was used directly in the next reaction.
MS m/z (ESI)：228.4 [M+1]MS m/z (ESI): 228.4 [M+1]
第二步：1-(((甲基磺醯基)氧基)甲基)-5-氮雜螺[2.4]庚烷-5-羧酸叔丁酯 6c
將1-(羥甲基)-5-氮雜螺[2.4]庚烷-5-羧酸叔丁酯6b (920 mg, 4.05 mmol)溶於二氯甲烷 (20 mL) 中，加入三乙胺(1.23 g，12.16mmol)，N 2置換3次。降溫至0℃，滴加甲基磺醯氯(923mg，8.1mmol), 升溫至室溫，反應3個小時。加入水 (20 mL)和乙酸乙酯(15 ml)，分液，水相用乙酸乙酯 (10 mL × 2) 萃取，合併有機相。有機相用飽和食鹽水 (20 mL × 2) 洗滌，無水硫酸鈉乾燥，過濾，濃縮得到固體狀的化合物1-(((甲基磺醯基)氧基)甲基)-5-氮雜螺[2.4]庚烷-5-羧酸叔丁酯6c (1 g，產率81.3%)。 1-(Hydroxymethyl)-5-azaspiro[2.4]heptane-5-carboxylate tert-butyl ester 6b (920 mg, 4.05 mmol) was dissolved in dichloromethane (20 mL) and triethylamine was added (1.23 g, 12.16 mmol), replaced by N 3 times. The temperature was lowered to 0°C, methylsulfonyl chloride (923 mg, 8.1 mmol) was added dropwise, the temperature was raised to room temperature, and the reaction was carried out for 3 hours. Water (20 mL) and ethyl acetate (15 ml) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (10 mL × 2), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a solid compound 1-(((methylsulfonyl)oxy)methyl)-5-azaspiro [2.4] Heptane-5-carboxylate tert-butyl ester 6c (1 g, 81.3% yield).
MS m/z (ESI)：306.4 [M+1]MS m/z (ESI): 306.4 [M+1]
第三步：1-(疊氮甲基)-5-氮雜螺[2.4]庚烷-5-羧酸叔丁酯6d
將1-(((甲基磺醯基)氧基)甲基)-5-氮雜螺[2.4]庚烷-5-羧酸叔丁酯6c (1g, 3.97 mmol)溶於N,N-二甲基甲醯胺(10 mL) 中，加入疊氮化鈉(774 mg，11.9mmol)，N 2置換3次。升溫至80℃，反應16個小時。加入水 (20 mL)和乙酸乙酯(15 ml)，分液，水相用乙酸乙酯 (10 mL × 2) 萃取，合併有機相。有機相用飽和食鹽水 (20 mL × 2) 洗滌，無水硫酸鈉乾燥，過濾，濃縮得到油狀的化合物1-(疊氮甲基)-5-氮雜螺[2.4]庚烷-5-羧酸叔丁酯6d (900 mg，粗品)，直接用於下一步反應。 1-(((Methylsulfonyl)oxy)methyl)-5-azaspiro[2.4]heptane-5-carboxylate tert-butyl ester 6c (1 g, 3.97 mmol) was dissolved in N,N- To dimethylformamide (10 mL), sodium azide (774 mg, 11.9 mmol) was added and replaced with N 2 three times. The temperature was raised to 80°C, and the reaction was carried out for 16 hours. Water (20 mL) and ethyl acetate (15 ml) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (10 mL × 2), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain an oily compound 1-(azidomethyl)-5-azaspiro[2.4]heptane-5-carboxylate tert-Butyl acid 6d (900 mg, crude) was used directly in the next reaction.
MS m/z (ESI)：253.3 [M+1]MS m/z (ESI): 253.3 [M+1]
第四步：1-(胺甲基)-5-氮雜螺[2.4]庚烷-5-羧酸叔丁酯(中間體6)
將1-(疊氮甲基)-5-氮雜螺[2.4]庚烷-5-羧酸叔丁酯6d (900 mg, 3.57 mmol)溶於無水甲醇 (20 mL) 中，加入10%鈀炭(100 mg)，氫氣置換3次，室溫反應5個小時。將反應混合物用矽藻土過濾，濃縮得到油狀的化合物1-(胺甲基)-5-氮雜螺[2.4]庚烷-5-羧酸叔丁酯中間體6 (800 mg，產率99%)。1-(Azidomethyl)-5-azaspiro[2.4]heptane-5-carboxylate tert-butyl ester 6d (900 mg, 3.57 mmol) was dissolved in anhydrous methanol (20 mL) and 10% palladium was added Carbon (100 mg) was replaced with hydrogen for 3 times, and the reaction was carried out at room temperature for 5 hours. The reaction mixture was filtered through celite and concentrated to give compound 1-(aminomethyl)-5-azaspiro[2.4]heptane-5-carboxylate tert-butyl ester Intermediate 6 (800 mg, yield) as an oil 99%).
MS m/z (ESI)：227.4 [M+1]MS m/z (ESI): 227.4 [M+1]
中間體 7： 6-((4-(7-(二甲基磷醯基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-氮雜螺[3.3]庚烷-2-羧酸叔丁基酯
第一步：6-((4-(7-溴-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-氮雜螺[3.3]庚烷-2-羧酸叔丁基酯 7b
將7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吲哚1B (450 mg, 1.19 mmol ) 和6-胺基-2-氮雜螺[3.3]庚烷-2-羧酸叔丁酯(303 mg, 1.43 mmol)溶解在四氫呋喃 (10 mL) 中，加入DIEA (462 mg, 3.57 mmol )，氮氣置換，升溫至70℃，反應2小時。反應液降至室溫，濃縮旋幹得到殘留物。該殘留物通過反相柱(ACN:H2O=5:95到95:5)純化後得到黃色固體產物6-((4-(7-溴-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-氮雜螺[3.3]庚烷-2-羧酸叔丁基酯 7b (400 mg，收率60%)。7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole 1B (450 mg, 1.19 mmol) and 6-amino-2-azaspiro [3.3] Heptane-2-carboxylate tert-butyl ester (303 mg, 1.43 mmol) was dissolved in tetrahydrofuran (10 mL), DIEA (462 mg, 3.57 mmol) was added, nitrogen was replaced, the temperature was raised to 70 °C, and the reaction was carried out for 2 hours . The reaction solution was cooled to room temperature, concentrated and spin-dried to obtain a residue. The residue was purified by reverse phase column (ACN:H2O=5:95 to 95:5) to give the product 6-(((4-(7-bromo-1H-indol-3-yl)-5-() as a yellow solid Trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester 7b (400 mg, 60% yield).
MS m/z (ESI)：552.1 [M+1]MS m/z (ESI): 552.1 [M+1]
第二步： 6-((4-(7-(二甲基磷醯基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-氮雜螺[3.3]庚烷-2-羧酸叔丁基酯 (中間體7)
氮氣保護下，將6-((4-(7-溴-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-氮雜螺[3.3]庚烷-2-羧酸叔丁基酯 7b (240 mg，0.43 mmol)溶解在DMF (5 mL)中, 加入二甲基氧化膦(170 mg，2.15 mmol)、醋酸鈀(20 mg，0.08 mmol)、磷酸鉀(184 mg，0.86 mmol)和4,5-雙二苯基膦-9,9-二甲基氧雜蒽(75 mg，0.13 mmol)，微波中150℃反應1小時。降至室溫，加入乙酸乙酯，用飽和的食鹽水水洗滌。分離有幾層，用無水硫酸鈉乾燥，然後濃縮得到殘留物。殘留物過矽膠柱(石油醚/乙酸乙酯 (v/v) =1/1)純化後得到淡黃色固體化合物6-((4-(7-(二甲基磷醯基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-氮雜螺[3.3]庚烷-2-羧酸叔丁基酯中間體7(110 mg，收率47%)。Under nitrogen protection, 6-((4-(7-bromo-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[ 3.3] Heptane-2-carboxylate tert-butyl ester 7b (240 mg, 0.43 mmol) was dissolved in DMF (5 mL), dimethylphosphine oxide (170 mg, 2.15 mmol) and palladium acetate (20 mg, 2.15 mmol) were added. 0.08 mmol), potassium phosphate (184 mg, 0.86 mmol) and 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (75 mg, 0.13 mmol), react in microwave at 150 °C for 1 hour. The temperature was lowered to room temperature, ethyl acetate was added, and the mixture was washed with saturated brine. The layers were separated, dried over anhydrous sodium sulfate, and concentrated to give a residue. The residue was purified by silica gel column (petroleum ether/ethyl acetate (v/v) = 1/1) to obtain a pale yellow solid compound 6-((4-(7-(dimethylphosphoryl)-1H-indone Indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester Intermediate 7 (110 mg , the yield is 47%).
MS m/z (ESI)：550.1 [M+1]MS m/z (ESI): 550.1 [M+1]
中間體 8：6-((4-(6-氰基-7-(二甲基磷醯基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-氮雜螺[3.3]庚烷-2-羧酸叔丁基酯
第一步：6-((4-(7-溴-6-氰基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-氮雜螺[3.3]庚烷-2 -羧酸叔丁基酯 8b
將7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲腈3A (2.00 g, 5.0 mmol ) 和6-胺基-2-氮雜螺[3.3]庚烷-2-羧酸叔丁酯(1.30 g,6.00 mmol)溶解在異丙醇(40 mL) 中，加入DIEA(1.94 g, 15.0 mmol )，氮氣置換，升溫至100℃，反應2小時。降至室溫，直接濃縮，殘留物通過反相柱(ACN:H2O=5:95到95:5)純化後得到固體化合物6-((4-(7-溴-6-氰基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-氮雜螺[3.3]庚烷-2-羧酸叔丁基酯 8b (1.30 g白色固體，收率45.1%)。7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile 3A (2.00 g, 5.0 mmol) and 6-amino- 2-Azaspiro[3.3]heptane-2-carboxylate tert-butyl ester (1.30 g, 6.00 mmol) was dissolved in isopropanol (40 mL), DIEA (1.94 g, 15.0 mmol) was added, nitrogen was replaced, and the temperature was increased. to 100°C, and reacted for 2 hours. It was cooled to room temperature, concentrated directly, and the residue was purified by reverse phase column (ACN:H2O=5:95 to 95:5) to obtain solid compound 6-((4-(7-bromo-6-cyano-1H- Indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester 8b (1.30 g white solid, yield 45.1%).
MS m/z (ESI)：577.1 [M+1]MS m/z (ESI): 577.1 [M+1]
第二步： 6-((4-(6-氰基-7-(二甲基磷醯基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-氮雜螺[3.3]庚烷-2-羧酸叔丁基酯(中間體8)
將6-((4-(7-溴-6-氰基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-氮雜螺[3.3]庚烷-2 -羧酸叔丁基酯 8b (200 mg， 0.34 mmol )溶解在DMF (10 mL)中，加入二甲基氧化膦(135 mg, 1.73 mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(254 mg, 0.34 mmol)、磷酸鉀(368 mg, 1.70 mmol)和4,5-雙二苯基膦-9,9-二甲基氧雜蒽(200 mg, 0.34 mmol)，氮氣保護，微波反應，於150℃反應1小時。降至室溫，加入乙酸乙酯，用飽和的食鹽水水洗，合併有機層。乾燥有機層，然後濃縮，殘留物通過矽膠柱(石油醚/乙酸乙酯 (v/v) =1/1)純化後得到淡黃色固體化合物6-((4-(6-氰基-7-(二甲基磷醯基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-氮雜螺[3.3]庚烷-2-羧酸叔丁基酯中間體8 (112 mg，產率56.3%)。6-((4-(7-Bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro [3.3] Heptane-2-carboxylate tert-butyl ester 8b (200 mg, 0.34 mmol) was dissolved in DMF (10 mL), dimethylphosphine oxide (135 mg, 1.73 mmol), [1,1' -Bis(diphenylphosphino)ferrocene]palladium dichloride (254 mg, 0.34 mmol), potassium phosphate (368 mg, 1.70 mmol) and 4,5-bisdiphenylphosphine-9,9-di Methylxanthene (200 mg, 0.34 mmol), nitrogen protection, microwave reaction, reaction at 150 ℃ for 1 hour. The temperature was lowered to room temperature, ethyl acetate was added, the mixture was washed with saturated brine, and the organic layers were combined. The organic layer was dried, then concentrated, and the residue was purified by silica gel column (petroleum ether/ethyl acetate (v/v) = 1/1) to obtain a pale yellow solid compound 6-((4-(6-cyano-7- (Dimethylphosphoronyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2- tert-Butyl Carboxylate Intermediate 8 (112 mg, 56.3% yield).
MS m/z (ESI)：575.1 [M+1]MS m/z (ESI): 575.1 [M+1]
實施例Example 11
(S)-二甲基((3-(2-( 呱啶-3-基胺基)-5-(三氟甲基) -嘧啶-4-基)-1H -吲哚-7-基)亞胺基)-λ
6-亞碸的製備(化合物1)
第一步：7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吲哚 1B
向2,4-二氯-5-(三氟甲基)嘧啶(3.98g, 15.3mmol)的DCE(30mL)溶液中在氮氣保護下添加三氯化鋁(3.06g, 22.95mmol)，由此產生的混合物在80℃下攪拌30分鐘。反應混合物冷卻到室溫，加入7-溴-吲哚1A(3g、15.3mmol)。將得到的混合物在80℃下繼續攪拌3h，隨著時間的推移，溶液變紅。然後將混合物倒入碎冰和乙酸乙酯中，分層分離。將合併的有機層用無水硫酸鈉乾燥，過濾，減壓濃縮得到粗品殘留物。粗品殘留物經矽膠(乙酸乙酯/石油醚=0~50%)洗脫後柱層析純化，得到7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吲哚1B(2.8g, 48.59%)。To a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (3.98 g, 15.3 mmol) in DCE (30 mL) was added aluminum trichloride (3.06 g, 22.95 mmol) under nitrogen, thereby The resulting mixture was stirred at 80°C for 30 minutes. The reaction mixture was cooled to room temperature and 7-bromo-indole 1A (3 g, 15.3 mmol) was added. The resulting mixture was stirred for a further 3 h at 80°C, the solution turned red over time. The mixture was then poured into crushed ice and ethyl acetate and the layers were separated. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue. The crude residue was eluted with silica gel (ethyl acetate/petroleum ether=0~50%) and purified by column chromatography to obtain 7-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidine-4- base)-1H-indole 1B (2.8 g, 48.59%).
第二步：(S)-3-((4-(7-溴-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-甲酸叔丁酯 1C
將1B(500mg, 1.33mmol)、DIEA(458.9mg, 3.98mmol)、(S)-3-胺基呱啶-1-羧酸叔丁酯(319mg, 1.59mmol)與DCM(30mL)的混合物在氮氣保護下在25℃下攪拌18h。當TLC顯示原料消耗後，加入40mL水稀釋反應混合物，用100mLx3的乙酸乙酯萃取有機層，用鹽水洗滌有機相，用無水硫酸鈉乾燥。將混合物減壓濃縮得到粗品化合物。將粗品化合物用矽膠(乙酸乙酯/石油醚=0-50%)洗脫得到(S)-3-((4-(7-溴-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-甲酸叔丁酯1C(350mg, 48.78%)。A mixture of 1B (500 mg, 1.33 mmol), DIEA (458.9 mg, 3.98 mmol), (S)-tert-butyl 3-aminopyridine-1-carboxylate (319 mg, 1.59 mmol) and DCM (30 mL) was mixed in Stir at 25 °C for 18 h under nitrogen protection. When TLC showed that the starting material was consumed, 40 mL of water was added to dilute the reaction mixture, the organic layer was extracted with 100 mL x 3 of ethyl acetate, the organic phase was washed with brine, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to give the crude compound. The crude compound was eluted with silica gel (ethyl acetate/petroleum ether=0-50%) to give (S)-3-((4-(7-bromo-1H-indol-3-yl)-5-(tris Fluoromethyl)pyrimidin-2-yl)amino)ciridine-1-carboxylate tert-butyl ester 1C (350 mg, 48.78%).
第三步： (S)-3-((4-(7-溴-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2- 胺基)呱啶-1-羧酸叔丁基酯 1D
在0℃下向1C(150mg, 0.277mmol)的THF(15mL)溶液中加入氫化鈉(16.6mg,0.416mmol)，氮氣氣氛下攪拌30分鐘。添加SEMCl(55.5mg,0.333mmol)。反應混合物在氮氣氣氛下在25℃下繼續攪拌2h。加水稀釋後用乙酸乙酯(2x100ml)萃取。有機相合併後用鹽水清洗，乾燥(Na 2SO 4)和減壓濃縮。得到的粗品通過矽膠過濾提純，用0%到50%的乙酸乙酯/石油醚洗脫，得到 (S)-3-((4-(7-溴-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁基酯1D(107mg，57.48%)。 To a solution of 1C (150 mg, 0.277 mmol) in THF (15 mL) was added sodium hydride (16.6 mg, 0.416 mmol) at 0°C, followed by stirring under nitrogen atmosphere for 30 minutes. SEMCl (55.5 mg, 0.333 mmol) was added. The reaction mixture was stirred for a further 2 h at 25 °C under nitrogen atmosphere. After dilution with water, it was extracted with ethyl acetate (2x100ml). The combined organic phases were washed with brine, dried ( Na2SO4 ) and concentrated under reduced pressure. The resulting crude product was purified by silica gel filtration, eluting with 0% to 50% ethyl acetate/petroleum ether to give (S)-3-((4-(7-bromo-1-((2-(trimethyl) Silyl)ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)quamidine-1-carboxylate tert-butyl ester 1D (107 mg, 57.48%).
第四步： (S)-3-((4-(7-((二甲基(氧代)-λ
6-硫亞基)胺基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3- 烷基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-甲酸叔丁基酯 1E
將1D(107mg, 0.159mmol)、Pd 2(dba)3(14.6mg, 0.015mmol)、Johnphos(9.52mg, 0.031mmol)、NaOtBu(46mg, 0.478mmol)、亞胺基二甲基-λ 6-亞碸(29.7mg, 0.319mmol)溶於1,4-二氧六環(10mL)中，在80℃和在氮氣保護條件下攪拌4小時。當TLC顯示原料消耗盡後，加入30mL水稀釋反應混合物，用50mLx3的乙酸乙酯提取有機層，用鹽水洗滌有機相，用無水硫酸鈉乾燥。將混合物減壓濃縮，得到粗品，矽膠柱層析純化(乙酸乙酯/石油醚=0-50%)，得到(S)-3-((4-(7-((二甲基(氧代)-λ 6-亞硫烷基)胺基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-甲酸叔丁基酯1E(58mg, 53.23%)。 1D (107 mg, 0.159 mmol), Pd 2 (dba) 3 (14.6 mg, 0.015 mmol), Johnphos (9.52 mg, 0.031 mmol), NaOtBu (46 mg, 0.478 mmol), iminodimethyl-λ 6 - Substance (29.7 mg, 0.319 mmol) was dissolved in 1,4-dioxane (10 mL) and stirred at 80 °C for 4 h under nitrogen protection. When TLC showed that the starting material was consumed, 30 mL of water was added to dilute the reaction mixture, the organic layer was extracted with 50 mL×3 of ethyl acetate, the organic phase was washed with brine, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate/petroleum ether=0-50%) to obtain (S)-3-((4-(7-((dimethyl(oxo) )-λ 6 -sulfinyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-5-(trimethylsilyl)- Fluoromethyl)pyrimidin-2-yl)amino)ciridine-1-carboxylic acid tert-butyl ester 1E (58 mg, 53.23%).
第五步：(S)-二甲基((3-(2-( 呱啶-3-基胺基)-5-(三氟甲基) -嘧啶-4-基)-1H -吲哚-7-基)亞胺基)-λ
6-亞碸的製備 (化合物1)
在1E(58mg,0.084mmol)的DCM(8ml)溶液中加入三氟乙酸(5mL)。反應混合物在室溫下攪拌2小時。混合物在減壓下濃縮。在殘液中加入THF(8mL)和NH 4OH(4mL)，室溫攪拌2h。殘液用水(20mL)稀釋，乙酸乙酯(2x40mL)提取。所得有機層用Na 2SO 4乾燥，減壓濃縮，得到殘留粗品。用Prep-HPLC(儀器:Gilson；Flow:25mL/min；流動相A:0.1%NH 4OH inwater，流動相B:CAN；A與B的體積比為45%)對殘留粗品進行純化，得到化合物1(2mg,10.27%)白色固體。 To a solution of 1E (58 mg, 0.084 mmol) in DCM (8 ml) was added trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. THF (8 mL) and NH 4 OH (4 mL) were added to the residue, and the mixture was stirred at room temperature for 2 h. The residue was diluted with water (20 mL) and extracted with ethyl acetate (2 x 40 mL). The resulting organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure to obtain a residual crude product. The residual crude product was purified by Prep-HPLC (instrument: Gilson; Flow: 25 mL/min; mobile phase A: 0.1% NH 4 OH inwater, mobile phase B: CAN; the volume ratio of A to B was 45%) to obtain the compound 1 (2 mg, 10.27%) as a white solid.
MS m/z (ESI): 453.1[M+1]；MS m/z (ESI): 453.1[M+1];
1H NMR (400 MHz, DMSO-D6) δ 11.37 (d, 1 H), 8.52 (d, 1 H), 7.92 (dd, 1 H), 7.66 (d, 2 H), 6.98 (t, 1 H), 6.84 (d, 1 H), 3.91 (d, 1 H), 3.27 (s, 6 H), 3.05 (d, 1 H), 2.79 (d, 1 H), 2.45 (d, 2 H), 2.03 – 1.87 (m, 1 H), 1.64 (d, 1 H), 1.56 – 1.37 (m, 2 H)。1H NMR (400 MHz, DMSO-D6) δ 11.37 (d, 1 H), 8.52 (d, 1 H), 7.92 (dd, 1 H), 7.66 (d, 2 H), 6.98 (t, 1 H) , 6.84 (d, 1 H), 3.91 (d, 1 H), 3.27 (s, 6 H), 3.05 (d, 1 H), 2.79 (d, 1 H), 2.45 (d, 2 H), 2.03 – 1.87 (m, 1 H), 1.64 (d, 1 H), 1.56 – 1.37 (m, 2 H).
實施例Example 22
反式-(3-(2-((3-胺基環己基)胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)二甲基氧化膦 (化合物2)
第一步：反式-N
1-(4-(7-溴-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)環己烷-1,3-二胺 2A
將1B(50mg，0.132mmol)、DIEA(51mg，0.398mmol)、反式-1,3-環己烷二胺(18.19mg，0.159mmol)在DCM(8ml)中的混合物在氮氣氣氛下於25℃攪拌18小時。TLC顯示原料已消耗後，通過添加40mL水稀釋反應混合物。有機層用乙酸乙酯(50ml×3)萃取，有機相用鹽水洗滌，用無水硫酸鈉乾燥。將混合物在減壓下濃縮得到粗制化合物，將其通過矽膠柱色譜法純化，用(乙酸乙酯/石油醚=0-50%)洗脫，得到反式-N 1-(4-(7-溴-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)環己烷-1,3-二胺2A(55mg，91.18%)。 A mixture of 1B (50 mg, 0.132 mmol), DIEA (51 mg, 0.398 mmol), trans-1,3-cyclohexanediamine (18.19 mg, 0.159 mmol) in DCM (8 ml) was added under nitrogen at 25 °C was stirred for 18 hours. After TLC showed that the starting material had been consumed, the reaction mixture was diluted by adding 40 mL of water. The organic layer was extracted with ethyl acetate (50 ml×3), and the organic phase was washed with brine and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to give the crude compound, which was purified by silica gel column chromatography eluting with (ethyl acetate/petroleum ether=0-50%) to give trans-N1-(4-( 7 -Bromo-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)cyclohexane-1,3-diamine 2A (55 mg, 91.18%).
第二步：反式-(3-((4-(7-溴-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)環己基)胺基甲酸叔丁基酯 2B
在25℃下向2A(55mg，0.121mmol)和DIEA(46.9mg，0.363mmol)的DCM(10mL)溶液中加入Boc 2O(52.8mg，0.242mmol)。將反應混合物在氮氣氣氛下在25℃攪拌18小時。減壓濃縮反應物。殘餘物用水稀釋，並用乙酸乙酯萃取(2×100ml)。有機相用鹽水洗滌，無水硫酸鈉乾燥，濃縮，殘餘物通過矽膠柱色譜純化，用(乙酸乙酯/石油醚= 0-50%)洗脫，得到反式-(3-((4-(7-溴-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)環己基)胺基甲酸叔丁基酯 2B(60mg，89.39%)。 To a solution of 2A (55 mg, 0.121 mmol) and DIEA (46.9 mg, 0.363 mmol) in DCM (10 mL) at 25 °C was added Boc2O (52.8 mg , 0.242 mmol). The reaction mixture was stirred at 25°C for 18 hours under nitrogen atmosphere. The reaction was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (2 x 100 ml). The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography, eluting with (ethyl acetate/petroleum ether=0-50%) to give trans-(3-((4-( 7-Bromo-lH-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclohexyl)carbamate tert-butyl ester 2B (60 mg, 89.39%).
第三步：反式-(3-((4-(7-(二甲基磷醯基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)環己基)胺基甲酸叔丁基酯 2C
將化合物2B(60mg，0.108mmol)、二甲基氧化膦(12.67mg，0.162mmol)、Pd(OAc) 2(2.4mg，0.01mmol)、K 3PO 4(68.92mg，0.324mmol)、Xantphos(6.2mg, 0.01mmol)加入到DMF(8ml)溶液中，於150°C攪拌2 h，並用氮氣保護。TLC顯示原料耗盡後，將反應混合物用10mL水稀釋。有機層用乙酸乙酯(20ml×3)萃取，有機相用鹽水洗滌，用無水硫酸鈉乾燥。減壓濃縮，得到粗化合物。將其通過矽膠柱色譜純化，用(乙酸乙酯/石油醚= 0-50%)洗脫，得到反式- (3-((4-(7-(二甲基磷醯基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)環己基)胺基甲酸叔丁基酯2C(43mg，72.04%)。 Compound 2B (60 mg, 0.108 mmol), dimethylphosphine oxide (12.67 mg, 0.162 mmol), Pd(OAc) 2 (2.4 mg, 0.01 mmol), K 3 PO 4 (68.92 mg, 0.324 mmol), Xantphos ( 6.2 mg, 0.01 mmol) was added to a solution of DMF (8 ml), stirred at 150 °C for 2 h, and protected with nitrogen. After TLC showed consumption of starting material, the reaction mixture was diluted with 10 mL of water. The organic layer was extracted with ethyl acetate (20 ml×3), and the organic phase was washed with brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave crude compound. It was purified by silica gel column chromatography eluting with (ethyl acetate/petroleum ether=0-50%) to give trans-(3-((4-(7-(dimethylphosphoryl)-1H- Indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclohexyl)carbamate tert-butyl ester 2C (43 mg, 72.04%).
第四步：反式-(3-(2-((3-胺基環己基)胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)二甲基氧化膦 （化合物2）
將化合物2C(43mg，0.077mmol)和TFA(1ml)在DCM(8ml)中的混合物在25℃下在氮氣保護下攪拌1h。TLC顯示原料耗盡後，通過添加30mL水稀釋反應混合物。有機層用乙酸乙酯(30ml×3)萃取，有機相用鹽水洗滌，用無水硫酸鈉乾燥。將混合物在減壓下濃縮得到粗品，通過在矽膠上進行柱色譜法來純化，用(DCM/MeOH= 0-10%)洗脫，得到反式-(3-(2-((3-胺基環己基)胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)二甲基氧化膦(化合物2)(20mg，56.8%)。A mixture of compound 2C (43 mg, 0.077 mmol) and TFA (1 ml) in DCM (8 ml) was stirred at 25 °C for 1 h under nitrogen protection. After TLC showed consumption of starting material, the reaction mixture was diluted by adding 30 mL of water. The organic layer was extracted with ethyl acetate (30 ml×3), and the organic phase was washed with brine and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel eluting with (DCM/MeOH=0-10%) to give trans-(3-(2-((3-amine) (ylcyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (compound 2) (20 mg, 56.8%).
MS m/z (ESI): 452.2[M+1]；MS m/z (ESI): 452.2[M+1];
1H NMR (400 MHz, DMSO-D6) δ 8.61 (s, 1 H), 8.29 (s, 1 H), 7.92 (s, 1 H), 7.50 (dd, J= 13.1, 7.5 Hz, 1 H), 7.28 (t, J= 6.8 Hz, 1 H), 4.38 (s, 1 H), 3.39 (s, 2 H), 2.12 (s, 1 H), 1.76 (dd, J= 44.7, 27.7 Hz, 12 H), 1.44 (d, J= 38.8 Hz, 2 H), 1.25 – 1.11 (m, 2 H)。 1 H NMR (400 MHz, DMSO-D6) δ 8.61 (s, 1 H), 8.29 (s, 1 H), 7.92 (s, 1 H), 7.50 (dd, J = 13.1, 7.5 Hz, 1 H) , 7.28 (t, J = 6.8 Hz, 1 H), 4.38 (s, 1 H), 3.39 (s, 2 H), 2.12 (s, 1 H), 1.76 (dd, J = 44.7, 27.7 Hz, 12 H), 1.44 (d, J = 38.8 Hz, 2 H), 1.25 – 1.11 (m, 2 H).
化合物2的拆分：化合物2(20mg)用Chiral-HPLC製備色譜分離純化(CHIRALCEL®OD4.6×250mm 5μm，流動相A：正己烷，流動相B：EtOH(0.1%DEA)，A與B的體積比為80:20，流速：1mL/min，分離時間20分鐘)，獲得化合物2A (7 mg)和化合物2B (6 mg)。
化合物2A：在色譜柱中保留時間8.57min；Compound 2A: retention time in chromatographic column 8.57min;
MS m/z (ESI): 452.0[M+1]；MS m/z (ESI): 452.0[M+1];
化合物2B：在色譜柱中保留時間10.29min；Compound 2B: retention time in chromatographic column 10.29min;
MS m/z (ESI): 452.1[M+1]。MS m/z (ESI): 452.1 [M+1].
實施例Example 33
反式-3-(2-((3-胺基環己基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷醯基)-1H-吲哚-6-甲腈 (化合物3)
第一步：7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲腈3A
將7-溴-1H-吲哚-6-甲腈中間體1(200mg, 0.91 mmol )、2,4-二氯-5-(三氟甲基)嘧啶(393 mg，1.82mmol)溶於乾燥的1,2-二氯乙烷(10mL)中並N2置換空氣3次。加入無水三氯化鋁 (363mg，2.73 mmol) 並於封管中加熱至110℃，攪拌9個小時。降至室溫，向反應液中加入二氯甲烷(10ml)和冰水(10mL)，分液，水相用二氯甲烷(10 mL×2)萃取，合併有機相。有機相用飽和食鹽水(20mL×2)洗滌，室溫無水硫酸鈉乾燥，過濾，濃縮得到殘留物。將殘留物用矽膠柱色譜分離提純(石油醚/乙酸乙酯(v/v) = 3:1)得到淡黃色固體狀的化合物7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲腈3A (70 mg, 產率19%)。7-Bromo-1H-indole-6-carbonitrile Intermediate 1 (200 mg, 0.91 mmol), 2,4-dichloro-5-(trifluoromethyl)pyrimidine (393 mg, 1.82 mmol) was dissolved in dry of 1,2-dichloroethane (10 mL) and N2 replaced the air 3 times. Anhydrous aluminum trichloride (363 mg, 2.73 mmol) was added and heated to 110°C in a sealed tube and stirred for 9 hours. The temperature was lowered to room temperature, dichloromethane (10 ml) and ice water (10 mL) were added to the reaction solution, and the layers were separated. The aqueous phase was extracted with dichloromethane (10 mL×2), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate at room temperature, filtered, and concentrated to obtain a residue. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3:1) to obtain compound 7-bromo-3-(2-chloro-5-(trifluoromethyl) as a pale yellow solid yl)pyrimidin-4-yl)-1H-indole-6-carbonitrile 3A (70 mg, 19% yield).
MS m/z (ESI)：400.8 [M-1]。MS m/z (ESI): 400.8 [M-1].
第二步：反式-3-(2-((3-胺基環己基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-溴-1H-吲哚-6-甲腈3B
將7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲腈3A(70mg, 0.18 mmol)溶於無水四氫呋喃(3mL)中，加入反式-環己烷-1,3-二胺(114mg, 1mmol)，N 2置換3次。升溫至60℃，反應12個小時。降至室溫，減壓濃縮得類棕色油狀物粗品，其為反式-3-(2-((3-胺基環己基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-溴-1H-吲哚-6-甲腈3B (140 mg，粗品)。 7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile 3A (70 mg, 0.18 mmol) was dissolved in dry tetrahydrofuran (3 mL) To this, trans-cyclohexane-1,3-diamine (114 mg, 1 mmol) was added and replaced with N 3 times. The temperature was raised to 60°C, and the reaction was carried out for 12 hours. It was cooled to room temperature and concentrated under reduced pressure to obtain a crude brown oil, which was trans-3-(2-((3-aminocyclohexyl)amino)-5-(trifluoromethyl)pyrimidine-4 -yl)-7-bromo-1H-indole-6-carbonitrile 3B (140 mg, crude).
MS m/z (ESI)：479.3 [M+1]。MS m/z (ESI): 479.3 [M+1].
第三步：反式-(3-((4-(7-溴-6-氰基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)環己基)胺基甲酸叔丁基酯3C
將粗品3B(140mg, 0.29mmol)溶於四氫呋喃(3ml)中，加入N,N-二異丙基乙胺(113mg，0.89mmol)和一縮二碳酸二叔丁酯(194 mg，0.89 mmol)，N 2置換3次，室溫反應一個小時。將反應液濃縮，乙酸乙酯溶解後用製備板分離提純 (石油醚/乙酸乙酯(v/v)=3:1)，濃縮得淡黃色固體，其為反式-(3-((4-(7-溴-6-氰基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)環己基)胺基甲酸叔丁基酯3C (25 mg，產率15%)。 Crude 3B (140 mg, 0.29 mmol) was dissolved in tetrahydrofuran (3 ml), N,N-diisopropylethylamine (113 mg, 0.89 mmol) and di-tert-butyl dicarbonate (194 mg, 0.89 mmol) were added , replaced by N 3 times, and reacted at room temperature for one hour. The reaction solution was concentrated, and after dissolving the ethyl acetate, it was separated and purified with a preparation plate (petroleum ether/ethyl acetate (v/v)=3:1), and concentrated to obtain a pale yellow solid, which was trans-(3-((4 -(7-Bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclohexyl)carbamate tert-butyl ester 3C ( 25 mg, 15% yield).
MS m/z (ESI)：579.4 [M+1]。MS m/z (ESI): 579.4 [M+1].
第四步：反式-(3-((4-(6-氰基-7-(二甲基磷醯基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)環己基)胺基甲酸叔丁基酯 3D
將3C(25mg, 0.04mmol)、磷酸三鉀(46mg, 0.22mmol)、4,5-雙二苯基膦-9,9-二甲基氧雜蒽(23mg, 0.04 mmol)、醋酸鈀(9mg, 0.04mmol)、二甲基氧化膦(17mg, 0.22mmol) 溶於乾燥N,N-二甲基甲醯胺(2mL)中，升至150℃反應2小時。將反應液冷卻至室溫，加入水(10mL)和乙酸乙酯(10ml)，分液，水相用乙酸乙酯(10mL×2)萃取。將合併的有機相用飽和食鹽水(20mL×2)洗滌，無水硫酸鈉乾燥，過濾，濃縮。所得殘留物用製備板分離提純 (石油醚/乙酸乙酯(v/v) =1：1，) 得到類白色固體狀的化合物，其為反式-(3-((4-(6-氰基-7-(二甲基磷醯基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)環己基)胺基甲酸叔丁基酯3D (15 mg，產率60%)。3C (25mg, 0.04mmol), Tripotassium Phosphate (46mg, 0.22mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (23mg, 0.04mmol), Palladium acetate (9mg , 0.04 mmol) and dimethylphosphine oxide (17 mg, 0.22 mmol) were dissolved in dry N,N-dimethylformamide (2 mL), and the temperature was raised to 150° C. for 2 hours. The reaction solution was cooled to room temperature, water (10 mL) and ethyl acetate (10 mL) were added, the layers were separated, and the aqueous phase was extracted with ethyl acetate (10 mL×2). The combined organic phases were washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was separated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v) = 1:1,) to give the compound as an off-white solid, which was trans-(3-((4-(6-cyano) tert-butyl-7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclohexyl)carbamate 3D (15 mg, 60% yield).
MS m/z (ESI)：577.3 [M+1]。MS m/z (ESI): 577.3 [M+1].
第五步：反式-3-(2-((3-胺基環己基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷醯基)-1H-吲哚-6-甲腈 (化合物3)
將3D (15 mg, 0.026 mmol)溶於二氯甲烷(1 mL)中，加入三氟乙酸(0.5 ml)，室溫反應一個小時。將反應混合物減壓濃縮，殘留物加碳酸鈉水溶液調製鹼性。加入水 (10 mL)和乙酸乙酯(10 ml)，分液，水相用乙酸乙酯(10mL×2)萃取。將合併的有機相用飽和食鹽水(20 mL×2)洗滌，無水硫酸鈉乾燥，過濾，濃縮。將殘留物用甲醇溶解並用製備板分離提純(二氯甲烷/甲醇(v/v)=8:1)得到白色固體狀的化合物，其為反式-3-(2-((3-胺基環己基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷醯基)-1H-吲哚-6-甲腈 (化合物3) (3 mg，產率24%)。3D (15 mg, 0.026 mmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.5 ml) was added, and the reaction was carried out at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, and the residue was made alkaline by adding an aqueous sodium carbonate solution. Water (10 mL) and ethyl acetate (10 mL) were added, the solution was separated, and the aqueous phase was extracted with ethyl acetate (10 mL×2). The combined organic phases were washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was dissolved in methanol and purified by preparative plate separation (dichloromethane/methanol (v/v)=8:1) to give the compound as a white solid, which was trans-3-(2-((3-amino Cyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carbonitrile (compound 3) (3 mg, yield 24%).
MS m/z (ESI)：477.0 [M+1]；MS m/z (ESI): 477.0 [M+1];
1H NMR (400 MHz, CD 3OD) δ 8.58 (m, 2 H), 8.17 (s, 1 H), 7.65 (m, 1 H), 4.59 (m, 1 H), 4.41 (m, 1 H), 2.14 (s, 3 H), 2.11 (s, 3 H), 1.90 (m, 1 H), 1.78 (m, 4 H), 1.52 – 1.40 (m, 1 H), 1.29 (m, 2 H)。 1 H NMR (400 MHz, CD 3 OD) δ 8.58 (m, 2 H), 8.17 (s, 1 H), 7.65 (m, 1 H), 4.59 (m, 1 H), 4.41 (m, 1 H) ), 2.14 (s, 3 H), 2.11 (s, 3 H), 1.90 (m, 1 H), 1.78 (m, 4 H), 1.52 – 1.40 (m, 1 H), 1.29 (m, 2 H) ).
實施例Example 44
順式-3-(2-((3-胺基環己基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷醯基)-1H-吲哚-6-甲腈 (化合物4)
參照實施例3的合成方法，按照上面的步驟，以順式-1,3-環己二胺鹽酸鹽為原料，合成得到化合物4。Referring to the synthesis method of Example 3, following the above steps, using cis-1,3-cyclohexanediamine hydrochloride as a raw material, compound 4 was synthesized.
MS m/z (ESI)：477.1 [M+1]；MS m/z (ESI): 477.1 [M+1];
1H NMR (400 MHz, CD 3OD) δ 8.53 (m, 2 H), 8.05 (s, 1 H), 7.51 (s, 1 H), 2.45 (m, 1 H), 2.22 – 2.15 (m, 1 H), 2.08 (s, 3 H), 2.05 (s, 3 H), 2.03 – 1.95 (m, 2 H), 1.65 – 1.43 (m, 2 H), 1.38 – 1.34 (m, 2 H), 1.33 (s, 2 H)。 1 H NMR (400 MHz, CD 3 OD) δ 8.53 (m, 2 H), 8.05 (s, 1 H), 7.51 (s, 1 H), 2.45 (m, 1 H), 2.22 – 2.15 (m, 1 H), 2.08 (s, 3 H), 2.05 (s, 3 H), 2.03 – 1.95 (m, 2 H), 1.65 – 1.43 (m, 2 H), 1.38 – 1.34 (m, 2 H), 1.33 (s, 2H).
實施例Example 55
順式-(3-(2-((3-胺基環己基)胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)二甲基氧化膦 (化合物5)
參照實施例2的合成方法，按照上面的步驟，以順式-1,3-環己二胺鹽酸鹽為原料，合成得到化合物5。Referring to the synthesis method of Example 2, following the above steps, using cis-1,3-cyclohexanediamine hydrochloride as a raw material, compound 5 was synthesized.
MS m/z (ESI)：452.1 [M+1]；MS m/z (ESI): 452.1 [M+1];
1H NMR (400 MHz, CD 3OD) δ 8.54 (s, 2 H), 7.96 (s, 1 H), 7.50 (dd, 1 H), 7.33 (s, 1 H), 4.11 (m, 1 H), 3.19 (m, 1 H), 2.45 (m, 1 H), 2.02 (m, 4 H), 1.93 (s, 3 H), 1.90 (s, 3 H), 1.59 – 1.29 (m, 4 H)。 1 H NMR (400 MHz, CD 3 OD) δ 8.54 (s, 2 H), 7.96 (s, 1 H), 7.50 (dd, 1 H), 7.33 (s, 1 H), 4.11 (m, 1 H) ), 3.19 (m, 1 H), 2.45 (m, 1 H), 2.02 (m, 4 H), 1.93 (s, 3 H), 1.90 (s, 3 H), 1.59 – 1.29 (m, 4 H) ).
實施例Example 66
順式-二甲基(3-(2-((3-(甲基胺基)環己基)胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)氧化膦 (化合物6)
參照實施例2的合成方法，按照上面的步驟，以中間體2為原料，合成得到化合物6。Referring to the synthesis method of Example 2, following the above steps, using intermediate 2 as a raw material, compound 6 was synthesized.
MS m/z (ESI)：466.0 [M+1]；MS m/z (ESI): 466.0 [M+1];
1H NMR (400 MHz, CD 3OD) δ 8.55 (m, 3 H), 7.96 (s, 1 H), 7.50 (dd, 1 H), 7.33 (m, 1 H), 4.08 (m, 1 H), 3.13 (m, 1 H), 2.78 – 2.62 (m, 3 H), 2.53 (d, 1 H), 2.15 (m, 2H), 2.02 (m, 2 H), 1.93 (s, 3 H), 1.89 (s, 3 H), 1.45 – 1.27 (m, 4 H)。 1 H NMR (400 MHz, CD 3 OD) δ 8.55 (m, 3 H), 7.96 (s, 1 H), 7.50 (dd, 1 H), 7.33 (m, 1 H), 4.08 (m, 1 H) ), 3.13 (m, 1 H), 2.78 – 2.62 (m, 3 H), 2.53 (d, 1 H), 2.15 (m, 2H), 2.02 (m, 2 H), 1.93 (s, 3 H) , 1.89 (s, 3 H), 1.45 – 1.27 (m, 4 H).
實施例Example 77
(S)-((6-氟-3-(2-(呱啶-3-基胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)亞胺基)二甲基-λ
6-亞碸(化合物7)
第一步：7-溴-6-氟-1H-吲哚7B
將2-溴-1-氟-3-硝基苯7A(10g, 45.67mmol)溶於乾燥的四氫呋喃(30mL)中並用N 2置換空氣3次，降至-78 oC。加入1.5mol/L乙烯基溴化鎂(91ml，136.99 mmol), 添加完成後自然升溫至室溫攪拌3個小時。向反應液中加入飽和氯化銨(100ml)淬滅，然後加入乙酸乙酯(100mL)，分液。水相用乙酸乙酯(50mL×2)萃取，合併有機相。有機相用飽和食鹽水(100mL×2)洗滌，室溫無水硫酸鈉乾燥，過濾，濃縮。所得殘留物用矽膠柱色譜分離提純(石油醚/乙酸乙酯(v/v) = 30:1) 得到棕色油狀物7-溴-6-氟-1H-吲哚7B (2 g, 產率21%)。 2-Bromo-1-fluoro-3-nitrobenzene 7A (10 g, 45.67 mmol) was dissolved in dry tetrahydrofuran (30 mL) and the air was replaced 3 times with N 2 to -78 ° C. 1.5 mol/L vinylmagnesium bromide (91 ml, 136.99 mmol) was added, and after the addition was completed, the temperature was naturally raised to room temperature and stirred for 3 hours. Saturated ammonium chloride (100 mL) was added to the reaction solution to quench, and then ethyl acetate (100 mL) was added to separate the layers. The aqueous phase was extracted with ethyl acetate (50 mL×2), and the organic phases were combined. The organic phase was washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate at room temperature, filtered and concentrated. The obtained residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 30:1) to give 7-bromo-6-fluoro-1H-indole 7B as a brown oil (2 g, yield twenty one%).
MS m/z (ESI)：214.1 [M+1]。MS m/z (ESI): 214.1 [M+1].
第二步：7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-6-氟-1H-吲哚7C
將2,4-二氯-5-(三氟甲基)嘧啶(3g，13.89mmol)溶於乾燥的1,2-二氯乙烷 (30 mL)中並N 2置換空氣3次。加入無水三氯化鋁 (1.9g，14.29 mmol)並加熱至85℃，攪拌半個小時。將7-溴-6-氟-1H-吲哚7B (2g, 9.39mmol)的1,2-二氯乙烷溶液(10 ml)緩慢加入反應體系中，保持85℃繼續攪拌2個小時。降至室溫後，向反應液中加入二氯甲烷(30ml)和冰水(30mL)，分液，水相用二氯甲烷(20mL×2) 萃取。將合併的有機相用飽和食鹽水(20mL×2)洗滌。在室溫用無水硫酸鈉乾燥，過濾，濃縮。將所得殘留物用矽膠柱色譜分離提純(石油醚/乙酸乙酯(v/v)=3:1)得到淡黃色固體狀的化合物7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-6-氟-1H-吲哚7C (1.7 g, 產率46%)。 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (3 g, 13.89 mmol) was dissolved in dry 1,2-dichloroethane (30 mL) and N 2 replaced air 3 times. Anhydrous aluminum trichloride (1.9 g, 14.29 mmol) was added and heated to 85°C and stirred for half an hour. A solution of 7-bromo-6-fluoro-1H-indole 7B (2 g, 9.39 mmol) in 1,2-dichloroethane (10 ml) was slowly added to the reaction system, and stirring was continued at 85° C. for 2 hours. After cooling to room temperature, dichloromethane (30 ml) and ice water (30 mL) were added to the reaction solution, and the layers were separated, and the aqueous phase was extracted with dichloromethane (20 mL×2). The combined organic phases were washed with saturated brine (20 mL×2). Dry over anhydrous sodium sulfate at room temperature, filter, and concentrate. The obtained residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=3:1) to obtain the compound 7-bromo-3-(2-chloro-5-(trifluoro) as a pale yellow solid Methyl)pyrimidin-4-yl)-6-fluoro-1H-indole 7C (1.7 g, 46% yield).
MS m/z (ESI)：391.4 [M-1]。MS m/z (ESI): 391.4 [M-1].
第三步：7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-6-氟-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚7D
將7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-6-氟-1H-吲哚7C(1.3g, 3.3mmol) 溶於N,N-二甲基甲醯胺(20ml)中，降溫至0 oC, N 2置換3次。然後加入氫化鈉(60%)(160 mg，3.98 mmol)，反應一個小時。接著加入2-(三甲基甲矽烷基)乙氧甲基氯，室溫繼續反應兩個小時。向反應液中加入乙酸乙酯(30ml)和冰水(30mL)，分液。水相用乙酸乙酯(20 mL×2)萃取。將合併的有機相用飽和食鹽水(20mL×2) 洗滌，於室溫用無水硫酸鈉乾燥，過濾，濃縮。將所得殘留物用矽膠柱色譜分離提純(石油醚/乙酸乙酯(v/v) =10:1)得到淡黃色固體狀的化合物7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-6-氟-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚7D (500 mg, 產率29%)。 7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-6-fluoro-1H-indole 7C (1.3 g, 3.3 mmol) was dissolved in N,N-di In methylformamide (20ml), the temperature was lowered to 0 o C, and N 2 was replaced 3 times. Then sodium hydride (60%) (160 mg, 3.98 mmol) was added and reacted for one hour. Then, 2-(trimethylsilyl)ethoxymethyl chloride was added, and the reaction was continued for two hours at room temperature. Ethyl acetate (30 ml) and ice water (30 mL) were added to the reaction solution, and the layers were separated. The aqueous phase was extracted with ethyl acetate (20 mL×2). The combined organic phases were washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate at room temperature, filtered and concentrated. The obtained residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 10:1) to obtain compound 7-bromo-3-(2-chloro-5-(trifluoro) as a pale yellow solid Methyl)pyrimidin-4-yl)-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole 7D (500 mg, 29% yield) .
MS m/z (ESI)：524.4 [M+1]。MS m/z (ESI): 524.4 [M+1].
第四步：(S)-3-((4-(7-溴-6-氟-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁基酯7E
將7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-6-氟-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚7D (400mg, 0.765 mmol)溶於無水四氫呋喃(8mL)中，加入3-胺基呱啶-1-羧酸叔丁基酯(306 mg, 1.53 mmol)和N,N-二異丙基乙胺 (396mg, 3.07 mmol), N 2置換3次。升溫至60℃，反應4個小時。降至室溫，減壓濃縮，將所得殘留物用矽膠柱色譜分離提純(石油醚/乙酸乙酯(v/v) =3:1) 得到淡黃色固體狀的化合物7E (300 mg，產率57%)。 7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methan [ - Diisopropylethylamine (396 mg, 3.07 mmol), replaced with N 3 times. The temperature was raised to 60°C, and the reaction was carried out for 4 hours. It was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3:1) to obtain compound 7E as a pale yellow solid (300 mg, yield 57%).
第五步：(S)-3-((4-(7-((二甲基(氧代)-λ
6-硫亞基)胺基)-6-氟-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁基酯7F
將(S)-3-((4-(7-溴-6-氟-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁基酯7E (50mg, 0.074 mmol)、三[二亞苄基丙酮]二鈀(13.6 mg, 0.014mmol)、2-(二叔丁基膦)聯苯(4.45 mg, 0.014mmol)、叔丁醇鈉(14.3mg, 0.14mmol)、二甲基亞胺基碸(20.8mg, 0.223 mmol)溶於乾燥1.4-二氧六環(5mL)中，升至80℃反應2小時。將反應液冷卻至室溫，濃縮，加入水(10mL)和乙酸乙酯(15ml)，分液，水相用乙酸乙酯(10mL×2)萃取。將合併的有機相用飽和食鹽水(20 mL×2)洗滌，無水硫酸鈉乾燥，過濾，濃縮。將所得殘留物用製備板分離提純(石油醚/乙酸乙酯 (v/v) = 1：1，) 得到類白色固體狀的化合物，其為(S)-3-((4-(7-((二甲基(氧代)- λ 6-硫亞基)胺基)-6-氟-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁基酯7F (46 mg，產率90%)。 (S)-3-((4-(7-Bromo-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl )-5-(trifluoromethyl)pyrimidin-2-yl)amino)ciridine-1-carboxylate tert-butyl ester 7E (50 mg, 0.074 mmol), tris[dibenzylideneacetone]dipalladium (13.6 mg, 0.014 mmol), 2-(di-tert-butylphosphine)biphenyl (4.45 mg, 0.014 mmol), sodium tert-butoxide (14.3 mg, 0.14 mmol), dimethyliminothio (20.8 mg, 0.223 mmol) ) was dissolved in dry 1.4-dioxane (5 mL), raised to 80°C and reacted for 2 hours. The reaction solution was cooled to room temperature, concentrated, water (10 mL) and ethyl acetate (15 ml) were added, the layers were separated, and the aqueous phase was extracted with ethyl acetate (10 mL×2). The combined organic phases were washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was separated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v) = 1:1,) to give the compound as an off-white solid, which was (S)-3-((4-(7- ((Dimethyl(oxo)-λ 6 -sulfanylidene)amino)-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indium Indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridine-1-carboxylate tert-butyl ester 7F (46 mg, 90% yield).
MS m/z (ESI)：701.4 [M+1]。MS m/z (ESI): 701.4 [M+1].
第六步：(S) -((6-氟-1-(羥甲基)-3-(2-(呱啶-3-基胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)亞胺基)二甲基-λ
6-亞碸7G
將(S)-3-((4-(7-((二甲基(氧代)-λ 6-硫亞基)胺基)-6-氟-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁基酯7F(46mg, 0.065mmol)溶於二氯甲烷(3ml)和三氟乙酸(3ml)中，室溫攪拌反應一個小時。將反應混合物減壓濃縮，得到棕色油狀物粗品，其為(S)-((6-氟-1-(羥甲基)-3-(2-(呱啶-3-基胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)亞胺基)二甲基-λ 6-亞碸7G (24 mg，產率73%)。 (S)-3-((4-(7-((dimethyl(oxo)-λ 6 -sulfanylidene)amino)-6-fluoro-1-(((2-(trimethylmethyl) Silyl)ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)quamidine-1-carboxylate tert-butyl ester 7F (46 mg, 0.065 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (3 ml), and the reaction was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure to give a crude brown oil as (S)-((6-fluoro-1-(hydroxymethyl)-3-(2-(guaidin-3-ylamino)- 5-(Trifluoromethyl)pyrimidin-4-yl)-1H-indol- 7 -yl)imino)dimethyl-λ6-arylene 7G (24 mg, 73% yield).
第七步：(S)-((6-氟-3-(2-(呱啶-3-基胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)亞胺基)二甲基-λ
6-亞碸(化合物7)
將粗品(S)-((6-氟-1-(羥甲基)-3-(2-(呱啶-3-基胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)亞胺基)二甲基-λ 6-亞碸7G(24 mg, 0.047 mmol)溶於四氫呋喃(3 mL)中，加入氨水(1ml), 室溫反應三十分鐘。將反應混合物減壓濃縮，殘留物加甲醇溶解，然後通過製備型HPLC製備分離提純(儀器：Gilson. 流量：25mL /min，流動相A：水中含有0.1%NH 4OH，流動相B：ACN, A:B(V/V) = 45%) 得到白色固體狀的化合物(S)-((6-氟-3-(2-(呱啶-3-基胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)亞胺基)二甲基-λ 6-亞碸，其為化合物7 (6 mg，產率26%)。 The crude (S)-((6-fluoro-1-(hydroxymethyl)-3-(2-(quaridin-3-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl) -1H-Indol-7-yl)imino)dimethyl-λ 6 -sulfite 7G (24 mg, 0.047 mmol) was dissolved in tetrahydrofuran (3 mL), ammonia water (1 mL) was added, and the reaction was carried out at room temperature for three ten minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol, and then preparatively separated and purified by preparative HPLC (apparatus: Gilson. Flow rate: 25 mL/min, mobile phase A: 0.1% NH 4 OH in water, mobile phase B: ACN, A:B(V/V) = 45%) to obtain compound (S)-((6-fluoro-3-(2-(guaridin-3-ylamino)-5-(trifluoromethane) as a white solid yl)pyrimidin-4-yl)-1H-indol-7-yl)imino)dimethyl-λ6-sulfite, which was compound 7 ( 6 mg, 26% yield).
MS m/z (ESI)：471.1 [M+1]；MS m/z (ESI): 471.1 [M+1];
1H NMR (400 MHz, DMSO-D6) δ11.46 (s, 1 H), 8.53 (d, 1 H), 7.95 (ddd, 1 H), 7.76 – 7.65 (m, 2 H), 6.96 (dd, 1 H), 3.91 (m, 1 H), 3.26 (s, 6 H), 3.05 (d, 1 H), 2.79 (d, 1 H), 2.44 (m, 2 H), 1.96 (m, 1 H), 1.64 (m, 1 H), 1.52 – 1.38 (m, 2 H)。 1 H NMR (400 MHz, DMSO-D6) δ11.46 (s, 1 H), 8.53 (d, 1 H), 7.95 (ddd, 1 H), 7.76 – 7.65 (m, 2 H), 6.96 (dd , 1 H), 3.91 (m, 1 H), 3.26 (s, 6 H), 3.05 (d, 1 H), 2.79 (d, 1 H), 2.44 (m, 2 H), 1.96 (m, 1 H), 1.64 (m, 1 H), 1.52 – 1.38 (m, 2 H).
實施例Example 88
反式-((3-(2-((3-胺基環己基)胺基)-5-(三氟甲基)嘧啶-4-基)-6-氟-1H-吲哚-7-基)亞胺基)二甲基-λ
6-亞碸(化合物8)
參照實施例7的合成方法，按照上面的步驟，以反式-1,3-環己二胺為原料，合成得到化合物8。Referring to the synthesis method of Example 7, following the above steps, using trans-1,3-cyclohexanediamine as a raw material, compound 8 was synthesized.
MS m/z (ESI)：485.2 [M+1]；MS m/z (ESI): 485.2 [M+1];
1H NMR (400 MHz, DMSO-D6) δ 11.53 (s, 1 H), 8.56 (d, 1 H), 8.08 – 7.68 (m, 3 H), 6.97 (m, 1 H), 4.37 (m, 1 H), 3.27 (s, 6 H), 1.99 (m, 1 H), 1.72 (m, 6 H), 1.49 – 1.33 (m, 1 H), 1.25 (m, 1 H)。 1 H NMR (400 MHz, DMSO-D6) δ 11.53 (s, 1 H), 8.56 (d, 1 H), 8.08 – 7.68 (m, 3 H), 6.97 (m, 1 H), 4.37 (m, 1 H), 3.27 (s, 6 H), 1.99 (m, 1 H), 1.72 (m, 6 H), 1.49 – 1.33 (m, 1 H), 1.25 (m, 1 H).
實施例Example 99
(S)-N-(3-(2-(呱啶-3-基胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)甲磺醯胺(化合物9)
第一步：3-(2-氯-5-(三氟甲基)嘧啶-4-基)-7-硝基-1H-吲哚9B
將三氯化鋁(2.40g, 18.0mmol)和2,4-二氯-5-(三氟甲基)嘧啶(7.90g,36.5mmol)溶解在DCE(50mL)中，氮氣置換，升溫至80℃，反應30分鐘。然後加入7-硝基-1H-吲哚1(2.0g, 12.3mmol ), 反應12小時。降至室溫，向反應液裡加入乙酸乙酯(200mL)，用飽和食鹽水(200mL×3)洗滌。將所得有機相用無水硫酸鈉乾燥，過濾，濃縮。將所得殘留物用矽膠柱色譜分離提純(石油醚/乙酸乙酯(v/v)=1:15~1:8)得到固體化合物3-(2-氯-5-(三氟甲基)嘧啶-4-基)-7-硝基-1H-吲哚9B(1.70g，產率40.4%)。Aluminum trichloride (2.40 g, 18.0 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (7.90 g, 36.5 mmol) were dissolved in DCE (50 mL), replaced with nitrogen, and the temperature was raised to 80 ℃, the reaction was carried out for 30 minutes. Then 7-nitro-1H-indole 1 (2.0 g, 12.3 mmol) was added, and the reaction was carried out for 12 hours. The temperature was lowered to room temperature, ethyl acetate (200 mL) was added to the reaction solution, and the mixture was washed with saturated brine (200 mL×3). The resulting organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1:15~1:8) to obtain the solid compound 3-(2-chloro-5-(trifluoromethyl)pyrimidine) -4-yl)-7-nitro-1H-indole 9B (1.70 g, 40.4% yield).
MS m/z (ESI)：343.0 [M+1]。MS m/z (ESI): 343.0 [M+1].
第二步：(S)-3-((4-(7-硝基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁酯9C
將3-(2-氯-5-(三氟甲基)嘧啶-4-基)-7-硝基-1H-吲哚9B(1.70g, 4.95mmol)溶解在異丙醇(30mL)中，加入DIEA(1.60g, 12.44mmol)和(S)-3-胺基呱啶-1-羧酸叔丁酯(1.20g, 6.00mmol)，於100℃反應12小時。降至室溫，濃縮。將所得殘留物用矽膠柱色譜分離提純(石油醚/乙酸乙酯(v/v)=1:5~1:1)得到白色固體化合物(S)-3-((4-(7-硝基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁酯9C(900 mg，產率36.4%)。3-(2-Chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-nitro-1H-indole 9B (1.70 g, 4.95 mmol) was dissolved in isopropanol (30 mL), DIEA (1.60 g, 12.44 mmol) and (S)-3-aminopyridine-1-carboxylate tert-butyl ester (1.20 g, 6.00 mmol) were added, and the mixture was reacted at 100° C. for 12 hours. Cooled to room temperature and concentrated. The obtained residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1:5~1:1) to obtain a white solid compound (S)-3-((4-(7-nitro -1H-Indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)quaridine-1-carboxylate tert-butyl ester 9C (900 mg, 36.4% yield).
MS m/z (ESI)：507.1 [M+1]。MS m/z (ESI): 507.1 [M+1].
第三步：(S)-3-((4-(7-胺基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁酯 9D
將(S)-3-((4-(7-硝基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁酯9C(900mg， 1.77mmol)溶解在乙醇(10mL)和飽和的氯化銨水溶液(10mL)中，加入鐵粉(5g, 89.28 mmol)，氮氣保護，於80℃反應2小時。降至室溫，過濾，濃縮。將所得殘留物用矽膠柱色譜分離提純(石油醚/乙酸乙酯 (v/v)=1:5~1:1)得到灰色固體化合物(S)-3-((4-(7-胺基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁酯9D(800mg)。(S)-3-((4-(7-Nitro-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)quamidine-1-carboxylate Acid tert-butyl ester 9C (900 mg, 1.77 mmol) was dissolved in ethanol (10 mL) and saturated aqueous ammonium chloride solution (10 mL), iron powder (5 g, 89.28 mmol) was added, and the reaction was carried out at 80 °C for 2 hours under nitrogen protection. Cooled to room temperature, filtered and concentrated. The obtained residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1:5~1:1) to obtain gray solid compound (S)-3-((4-(7-amino) -1H-Indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)ciridine-1-carboxylate tert-butyl ester 9D (800 mg).
MS m/z (ESI)：477.1 [M+1]。MS m/z (ESI): 477.1 [M+1].
第四步：(S)-3-((4-(7-(甲基磺醯胺基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-甲酸叔丁酯 9E
將(S)-3-((4-(7-胺基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁酯9D(300mg，0.63mmol)和三乙胺(127mg，1.26mmol)溶解在二氯甲烷(5mL)中，加入甲基磺醯氯(86mg, 0.75mmol)，氮氣保護，室溫反應2小時。將反應液濃縮除去溶劑，殘留物用矽膠柱色譜分離提純(石油醚/乙酸乙酯(v/v) = 1:2~1:1)得到油狀化合物(S)-3-((4-(7-(甲基磺醯胺基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-甲酸叔丁酯 9E (120 mg)。(S)-3-((4-(7-Amino-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)quamidine-1-carboxylate Acid tert-butyl ester 9D (300 mg, 0.63 mmol) and triethylamine (127 mg, 1.26 mmol) were dissolved in dichloromethane (5 mL), methylsulfonyl chloride (86 mg, 0.75 mmol) was added, and the reaction was carried out at room temperature under nitrogen protection. 2 hours. The reaction solution was concentrated to remove the solvent, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1:2~1:1) to obtain an oily compound (S)-3-((4- (7-(Methylsulfonamido)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridine-1-carboxylate tert-butyl ester 9E ( 120 mg).
MS m/z (ESI)：555.1 [M+1]。MS m/z (ESI): 555.1 [M+1].
第五步：(S)-N-(3-(2-(呱啶-3-基胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)甲磺醯胺(化合物9)
將(S)-3-((4-(7-(甲基磺醯胺基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-甲酸叔丁酯 9E (120 mg, 0.21 mmol) 溶於3N的鹽酸甲醇溶液 (2 mL) 中，室溫反應2小時。將反應液濃縮旋幹，將所得粗品經prep-HPLC(甲酸方法)純化。凍幹得白色固體狀的化合物(S)-N-(3-(2-(呱啶-3-基胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)甲磺醯胺甲酸鹽(化合物9)(69 mg，產率70.4%)。(S)-3-((4-(7-(methylsulfonamido)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino) The tert-butyl pyridine-1-carboxylate 9E (120 mg, 0.21 mmol) was dissolved in 3N hydrochloric acid methanol solution (2 mL), and the reaction was carried out at room temperature for 2 hours. The reaction solution was concentrated and spun dry, and the resulting crude product was purified by prep-HPLC (formic acid method). Freeze-dried compound (S)-N-(3-(2-(guaridin-3-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole as white solid -7-yl)methanesulfonamidocarboxylate (compound 9) (69 mg, 70.4% yield).
MS m/z (ESI)：455.1 [M+1]；MS m/z (ESI): 455.1 [M+1];
1H-NMR (400 MHz, DMSO-D6) δ 11.77 (s, 1 H), 8.58 (d, 1 H), 8.31 (s, 1 H), 8.28-8.06 (dd, 1 H), 7.84 (m, 2 H), 7.16 (m, 2 H), 4.04 (m, 1 H), 3.17 (m, 1 H), 3.01(s, 3 H), 2.97 (m, 1 H), 2.67-2.51 (m, 2 H), 2.02 (m, 1 H), 1.75 (m, 1 H), 1.60-1.46 (m, 2 H)。 1 H-NMR (400 MHz, DMSO-D6) δ 11.77 (s, 1 H), 8.58 (d, 1 H), 8.31 (s, 1 H), 8.28-8.06 (dd, 1 H), 7.84 (m , 2 H), 7.16 (m, 2 H), 4.04 (m, 1 H), 3.17 (m, 1 H), 3.01(s, 3 H), 2.97 (m, 1 H), 2.67-2.51 (m , 2 H), 2.02 (m, 1 H), 1.75 (m, 1 H), 1.60-1.46 (m, 2 H).
實施例Example 1010
(S)-1-環丙基-N-(3-(2-(呱啶-3-基胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)甲磺醯胺(化合物10)
第一步：(S)-3-((4-(7-((環丙基甲基)磺醯胺基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-甲酸叔丁酯10A
將(S)-3-((4-(7-胺基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁酯9D(140mg , 0.29mmol)和三乙胺(90 mg, 0.87 mmol)溶解在二氯甲烷(6 mL)中，然後加入環丙基甲磺醯氯(89 mg, 0.58mmol)，室溫攪拌2h。將反應液倒入水中，水相用乙酸乙酯萃取，合併的有機相經無水硫酸鈉乾燥、真空濃縮旋幹得到粗品。粗品經prep-TLC純化後得到(S)-3-((4-(7-((環丙基甲基)磺醯胺基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-甲酸叔丁酯 10A(80 mg，收率：45.8%，淡綠色固體)。(S)-3-((4-(7-Amino-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)quamidine-1-carboxylate tert-Butyl acid 9D (140 mg, 0.29 mmol) and triethylamine (90 mg, 0.87 mmol) were dissolved in dichloromethane (6 mL), then cyclopropylmethanesulfonyl chloride (89 mg, 0.58 mmol) was added, Stir at room temperature for 2h. The reaction solution was poured into water, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, concentrated in vacuo and spun to dryness to obtain the crude product. The crude product was purified by prep-TLC to give (S)-3-((4-(7-((cyclopropylmethyl)sulfonamido)-1H-indol-3-yl)-5-(trifluoro Methyl)pyrimidin-2-yl)amino)ciridine-1-carboxylate tert-butyl ester 10A (80 mg, yield: 45.8%, pale green solid).
LCMS(ESI)：595.0 [M+1]。LCMS (ESI): 595.0 [M+1].
第二步：(S)-1-環丙基-N-(3-(2-(呱啶-3-基胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)甲磺醯胺 (化合物10)
將(S)-3-((4-(7-((環丙基甲基)磺醯胺基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-甲酸叔丁酯 10A(80 mg，0.13 mmol)溶於HCl/二氧六環溶液(5 mL)中，室溫下反應1h，然後將反應液真空旋幹，經prep-HPLC純化後得到(S)-1-環丙基-N-(3-(2-(呱啶-3-基胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)甲磺醯胺 (化合物10) (24 mg，收率：36.1%，白色固體)。(S)-3-((4-(7-((cyclopropylmethyl)sulfonamido)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidine-2- (80 mg, 0.13 mmol) was dissolved in HCl/dioxane solution (5 mL), reacted at room temperature for 1 h, and then the reaction solution was vacuum-dried , purified by prep-HPLC to give (S)-1-cyclopropyl-N-(3-(2-(quaridin-3-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl )-1H-indol-7-yl)methanesulfonamide (Compound 10) (24 mg, yield: 36.1%, white solid).
LC-MS (ESI)：495.1 [M+1]；LC-MS (ESI): 495.1 [M+1];
1H-NMR (400 MHz, DMSO-D6) δ 11.73 (s, 1 H), 8.58 (d, 1 H), 8.36 (s, 1 H), 8.23-8.01 (dd, 1 H), 7.85 (m, 2 H), 7.20 (m, 1 H), 7.12 (m, 1 H), 4.07 (m, 1 H), 3.19 (m, 1 H), 3.10 (d, 2 H), 2.97 (m, 1 H), 2.67-2.51 (m, 2 H), 2.02 (m, 1 H), 1.75 (m, 1 H), 1.56 (m, 2 H), 1.00 (m, 1 H), 0.52 (m, 2 H), 0.24 (m, 2 H)。 1 H-NMR (400 MHz, DMSO-D6) δ 11.73 (s, 1 H), 8.58 (d, 1 H), 8.36 (s, 1 H), 8.23-8.01 (dd, 1 H), 7.85 (m , 2 H), 7.20 (m, 1 H), 7.12 (m, 1 H), 4.07 (m, 1 H), 3.19 (m, 1 H), 3.10 (d, 2 H), 2.97 (m, 1 H), 2.67-2.51 (m, 2 H), 2.02 (m, 1 H), 1.75 (m, 1 H), 1.56 (m, 2 H), 1.00 (m, 1 H), 0.52 (m, 2 H), 0.24 (m, 2 H).
實施例Example 1111
3-(2-(((2s,3aR,5r,6aS)-5-胺基八氫並環戊二烯-2-基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷醯基)-1H-吲哚-6-甲腈 (化合物11)
第一步：3-(2-(((2s,3aR,5r,6aS)-5-胺基八氫並環戊二烯-2-基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-溴-1H-吲哚-6-甲腈
11A 
將7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲腈 3A(300 mg, 0.74 mmol)、(2s,3as,5s,6as)-八氫並環戊二烯-2,5-二胺 ( 中間體 3)(157 mg, 1.1 mmol)和DIEA (289 mg, 2.24 mmol)溶於乾燥四氫呋喃 (20 mL) 中，升至60℃反應16個小時。反應液冷卻至室溫，濃縮，殘留物用製備板分離提純 (二氯甲烷/甲醇 (v/v) = 10：1) 得到淡黃色固體狀的化合物3-(2-(((2s,3aR,5r,6aS)-5-胺基八氫並環戊二烯-2-基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-溴-1H-吲哚-6-甲腈 11A(1232 mg，產率61%)。 7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile 3A (300 mg, 0.74 mmol), (2s,3as, 5s,6as)-octahydrocyclopentadiene-2,5-diamine ( intermediate 3) (157 mg, 1.1 mmol) and DIEA (289 mg, 2.24 mmol) were dissolved in dry tetrahydrofuran (20 mL), The reaction was raised to 60°C for 16 hours. The reaction solution was cooled to room temperature, concentrated, and the residue was separated and purified with a preparative plate (dichloromethane/methanol (v/v) = 10:1) to obtain compound 3-(2-((((2s,3aR) as a pale yellow solid. ,5r,6aS)-5-aminooctahydrocyclopentadien-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-bromo-1H-indole- 6-Carbononitrile 11A (1232 mg, 61% yield).
MS m/z (ESI)：505.7 [M+1]MS m/z (ESI): 505.7 [M+1]
第二步： ((2s,3aR,5r,6aS)-5-((4-(7-溴-6-氰基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基 )八氫並環戊二烯-2-基)胺基甲酸叔丁基酯 11B
將3-(2-(((2s,3aR,5r,6aS)-5-胺基八氫並環戊二烯-2-基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-溴-1H-吲哚-6-甲腈 11A(232 mg, 0.45 mmol)和DIEA (178 mg, 1.38 mmol) 溶於四氫呋喃(10 ml)中, 加入一縮二碳酸二叔丁酯 (150 mg, 0.68 mmol)，室溫攪拌反應一個小時。減壓濃縮，殘餘物用矽膠柱色譜分離提純(石油醚/乙酸乙酯 (v/v) = 1:1) 得到棕色固狀物，其為((2s,3aR,5r,6aS)-5-((4-(7-溴-6-氰基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)八氫並環戊二烯-2-基)胺基甲酸叔丁基酯 11B(132 mg，產率47%)。 3-(2-(((2s,3aR,5r,6aS)-5-aminooctahydrocyclopentadien-2-yl)amino)-5-(trifluoromethyl)pyrimidine-4- yl)-7-bromo-1H-indole-6-carbonitrile 11A (232 mg, 0.45 mmol) and DIEA (178 mg, 1.38 mmol) were dissolved in tetrahydrofuran (10 ml) and di-tert-butyl dicarbonate was added The ester (150 mg, 0.68 mmol) was stirred at room temperature for one hour. Concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1:1) to obtain a brown solid, which was ((2s,3aR,5r,6aS)-5- ((4-(7-Bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)octahydrocyclopentadiene-2 -yl) tert-butyl carbamate 11B (132 mg, 47% yield).
MS m/z (ESI)：605.2 [M+1]MS m/z (ESI): 605.2 [M+1]
第三步：((2s,3aR,5r,6aS)-5-((4-(6-氰基-7-(二甲基磷醯基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)八氫並環戊二烯-2-基)胺基甲酸叔丁基酯
11C 
將((2s,3aR,5r,6aS)-5-((4-(7-溴-6-氰基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基 )八氫並環戊二烯-2-基)胺基甲酸叔丁基酯 11B(132 mg, 0.218 mmol)、4,5-雙(二苯基膦)-9,9-二甲基氧雜蒽 (126 mg, 0.218 mmol)、1,1'-雙二苯基膦二茂鐵二氯化鈀 (159 mg, 0.218 mmol)、K 3PO 4(138 mg, 0.65 mmol)和二甲基氧化膦 (85 mg, 0.65 mmol) 溶於乾燥的N,N-二甲基甲醯胺(8 mL) 中，升溫至150℃，反應一個小時。減壓濃縮，殘留物通過製備板分離提純(PE/EA (v/v) = 1：1得到黃色固體狀的化合物 ((2s,3aR,5r,6aS)-5-((4-(6-氰基-7-(二甲基磷醯基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)八氫並環戊二烯-2-基)胺基甲酸叔丁基酯 11C(55 mg，產率41%) ((2s,3aR,5r,6aS)-5-((4-(7-bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidine-2- yl)amino)octahydrocyclopentadien-2-yl)carbamate tert-butyl ester 11B (132 mg, 0.218 mmol), 4,5-bis(diphenylphosphine)-9,9-di Methylxanthene (126 mg, 0.218 mmol), 1,1'-bisdiphenylphosphinoferrocene palladium dichloride (159 mg, 0.218 mmol), K 3 PO 4 (138 mg, 0.65 mmol) and Dimethylphosphine oxide (85 mg, 0.65 mmol) was dissolved in dry N,N-dimethylformamide (8 mL), the temperature was raised to 150 °C, and the reaction was performed for one hour. Concentrated under reduced pressure, the residue was purified by preparative plate separation (PE/EA (v/v) = 1:1 to obtain compound ((2s,3aR,5r,6aS)-5-((4-(6- Cyano-7-(dimethylphosphoronyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)octahydrocyclopentadiene-2 -yl) tert-butyl carbamate 11C (55 mg, 41% yield)
MS m/z (ESI)：603.4 [M+1]MS m/z (ESI): 603.4 [M+1]
第四步：3-(2-(((2s,3aR,5r,6aS)-5-胺基八氫並環戊二烯-2-基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷醯基)-1H-吲哚-6-甲腈
( 化合物 11) 
將((2s,3aR,5r,6aS)-5-((4-(6-氰基-7-(二甲基磷醯基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基 )胺基)八氫並環戊二烯-2-基)胺基甲酸叔丁基酯 11C(55 mg, 0.091 mmol)溶於DCM (3 mL) 和三氟乙酸(3 mL)中，室溫反應三個小時。減壓濃縮，殘留物通過製備板分離提純(DCM/MeOH (v/v) = 10：1)得到白色固體狀的化合物3-(2-(((2s,3aR,5r,6aS)-5-胺基八氫並環戊二烯-2-基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷醯基)-1H-吲哚-6-甲腈 化合物 11(4 mg，產率8.7%)。 ((2s,3aR,5r,6aS)-5-((4-(6-cyano-7-(dimethylphosphoronyl)-1H-indol-3-yl)-5-(trifluoro Methyl)pyrimidin-2-yl)amino)octahydrocyclopentadien-2-yl)carbamate tert-butyl ester 11C (55 mg, 0.091 mmol) in DCM (3 mL) and trifluoroacetic acid (3 mL) at room temperature for three hours. Concentrated under reduced pressure, the residue was purified by preparative plate separation (DCM/MeOH (v/v) = 10:1) to give compound 3-(2-(((2s,3aR,5r,6aS)-5- as a white solid Aminooctahydrocyclopentadien-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6 -carbonitrile Compound 11 (4 mg, 8.7% yield).
MS m/z (ESI)：503.0 [M+1]MS m/z (ESI): 503.0 [M+1]
1H NMR (400 MHz, DMSO-D6) δ 8.73 – 8.63 (m, 1 H), 8.59 (d, 1 H), 8.21 (s, 1 H), 7.96 (d, 1 H), 7.67 (dd, 1 H), 4.37 (s, 1 H), 3.42 (m, 2 H), 2.67 (m, 2 H), 2.05 (s, 3 H), 2.02 (s, 3 H), 1.78 – 1.67 (m, 6 H), 1.50 (m, 2 H).1H NMR (400 MHz, DMSO-D6) δ 8.73 – 8.63 (m, 1 H), 8.59 (d, 1 H), 8.21 (s, 1 H), 7.96 (d, 1 H), 7.67 (dd, 1 H), 4.37 (s, 1 H), 3.42 (m, 2 H), 2.67 (m, 2 H), 2.05 (s, 3 H), 2.02 (s, 3 H), 1.78 – 1.67 (m, 6 H), 1.50 (m, 2 H).
實施例Example 1212
(3-(2-(((2s,3aR,5r,6aS)-5-胺基八氫並環戊二烯-2-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)二甲基二甲基氧化膦 (化合物12)
第一步：(2s,3aR,5r,6aS)-N2-(4-(7-溴-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)八氫並環戊二烯-2,5-二胺
12A 
將7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吲哚 1B(210 mg, 0.56 mmol)和(2s,3as,5s,6as)-八氫並環戊二烯-2,5-二胺溶解在異丙醇(5 mL)中，然後加入DIEA(217 mg, 1.68 mmol)，氮氣置換，於100℃下反應16小時。將反應液倒入水中，水相用乙酸乙酯萃取。合併的有機相經飽和食鹽水洗滌，無水硫酸鈉乾燥，真空旋幹得到粗品(2s,3aR,5r,6aS)-N2-(4-(7-溴-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)八氫並環戊二烯-2,5-二胺 12A(289 mg)，粗品直接用於下一步反應。 7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole 1B (210 mg, 0.56 mmol) and (2s,3as,5s,6as)- Octahydrocyclopentadiene-2,5-diamine was dissolved in isopropanol (5 mL), then DIEA (217 mg, 1.68 mmol) was added, nitrogen was replaced, and the reaction was carried out at 100° C. for 16 hours. The reaction solution was poured into water, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried in vacuo to obtain crude product (2s, 3aR, 5r, 6aS)-N2-(4-(7-bromo-1H-indol-3-yl)- 5-(Trifluoromethyl)pyrimidin-2-yl)octahydrocyclopentadiene-2,5-diamine 12A (289 mg) was used crude in the next reaction.
LC-MS：480.1 [M+H]+LC-MS: 480.1 [M+H]+
第二步：((2s,3aR,5r,6aS)-5-((4-(7-溴-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)八氫並環戊二烯-2-基)胺基甲酸叔丁基酯
12B 
將(2s,3aR,5r,6aS)-N2-(4-(7-溴-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)八氫並環戊二烯-2,5-二胺 12A(289 mg, 0.603 mmol)溶解在二氯甲烷(10 mL)中加入一縮二碳酸二叔丁酯(197 mg, 0.903 mmol)和三乙胺(122 mg, 1.21 mmol)，氮氣置換後，室溫下反應6小時。反應液真空旋除溶劑得到粗品。粗品經矽膠柱層析(乙酸乙酯/石油醚 = 1/10)純化後得到 ((2s,3aR,5r,6aS)-5-((4-(7-溴-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)八氫並環戊二烯-2-基)胺基甲酸叔丁基酯 12B(140 mg，收率40%，黃色油狀物)。 (2s,3aR,5r,6aS)-N2-(4-(7-bromo-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)octahydrocyclopenta Diene-2,5-diamine 12A (289 mg, 0.603 mmol) was dissolved in dichloromethane (10 mL) was added di-tert-butyl dicarbonate (197 mg, 0.903 mmol) and triethylamine (122 mg , 1.21 mmol), after nitrogen replacement, the reaction was carried out at room temperature for 6 hours. The reaction solution was spun off to remove the solvent in vacuo to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=1/10) to obtain ((2s,3aR,5r,6aS)-5-(((4-(7-bromo-1H-indole-3- yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)octahydrocyclopentadien-2-yl)carbamate tert-butyl ester 12B (140 mg, 40% yield, yellow oil).
LC-MS：580.1 [M+H]+LC-MS: 580.1 [M+H]+
第三步：((2s,3aR,5r,6aS)-5-((4-(7-(二甲基磷醯基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)八氫並環戊二烯 -2-基)胺基甲酸叔丁基酯12C
將((2s,3aR,5r,6aS)-5-((4-(7-溴-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)八氫並環戊二烯-2-基)胺基甲酸叔丁基酯 12B(140 mg, 0.242 mmol)溶解在N,N-二甲基甲醯胺(5 mL)中，加入二甲基氧化膦(94 mg, 1.21 mmol)、磷酸鉀(103 mg, 0.484 mmol)、4,5-雙(二苯基膦)-9,9-二甲基氧雜蒽(28 mg, 0.0484 mmol)和1,1'-雙二苯基膦二茂鐵二氯化鈀(35 mg, 0.0478 mmol)，氮氣置換後，微波150℃下反應1小時。將反應液倒入水中，水相用乙酸乙酯萃取，合併的有機相經飽和食鹽水洗滌、無水硫酸鈉乾燥、真空旋除溶劑得到粗品。粗品經矽膠柱層析(甲醇：二氯甲烷=1:15)分離純化得到 ((2s,3aR,5r,6aS)-5-((4-(7-(二甲基磷醯基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)八氫並環戊二烯-2-基胺基甲酸叔丁基酯 12C(69 mg，收率50%，黃色油狀物)。 ((2s,3aR,5r,6aS)-5-((4-(7-bromo-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino) Octahydrocyclopentadien-2-yl)carbamate tert-butyl ester 12B (140 mg, 0.242 mmol) was dissolved in N,N-dimethylformamide (5 mL) and added with dimethyl oxide Phosphine (94 mg, 1.21 mmol), potassium phosphate (103 mg, 0.484 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (28 mg, 0.0484 mmol) and 1 , 1'-bisdiphenylphosphinoferrocene palladium dichloride (35 mg, 0.0478 mmol), after nitrogen replacement, the reaction was carried out at 150° C. for 1 hour by microwave. The reaction solution was poured into water, the aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (methanol:dichloromethane=1:15) to obtain ((2s,3aR,5r,6aS)-5-((4-(7-(dimethylphosphoryl)-1H -Indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)octahydrocyclopentadien-2-ylcarbamate tert-butyl ester 12C (69 mg, received rate 50%, yellow oil).
LC-MS：578.2 [M+H] + LC-MS: 578.2 [M+H] +
第四步：3-(2-(((2s,3aR,5r,6aS)-5-胺基八氫並環戊二烯-2-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)二甲基氧化膦
( 化合物 12) 
將((2s,3aR,5r,6aS)-5-((4-(7-(二甲基磷醯基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)八氫並環戊二烯-2-基胺基甲酸叔丁基酯 12C(69 mg, 0.12 mmol)溶解在二氯甲烷(4 mL)中，加入三氟乙酸(1 mL)，室溫下反應1小時。反應液真空旋除溶劑得到粗品。粗品經製備型HPLC純化後凍幹得到白色固體 ( 化合物 12)(14 mg，收率25%)。 ((2s,3aR,5r,6aS)-5-((4-(7-(dimethylphosphoronyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidine- 2-yl)amino)octahydrocyclopentadien-2-ylcarbamate tert-butyl ester 12C (69 mg, 0.12 mmol) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (1 mL), reacted at room temperature for 1 hour. The reaction solution was vacuumed to remove the solvent to obtain the crude product. The crude product was purified by preparative HPLC and lyophilized to obtain a white solid ( compound 12) (14 mg, yield 25%).
LC-MS：478.0 [M+H] + LC-MS: 478.0 [M+H] +
1H NMR (400 MHz, CD 3OD) δ 8.56 (d, 1 H), 8.51 (m, 1 H), 7.95 (s, 1 H), 7.49 (dd, 1 H), 7.31 (td, 1 H), 4.52 (m, 1 H), 3.66 (m, 1 H), 2.88 (m, 2 H), 2.00-1.78 (m, 14 H). 1H NMR (400 MHz, CD 3 OD) δ 8.56 (d, 1 H), 8.51 (m, 1 H), 7.95 (s, 1 H), 7.49 (dd, 1 H), 7.31 (td, 1 H) , 4.52 (m, 1 H), 3.66 (m, 1 H), 2.88 (m, 2 H), 2.00-1.78 (m, 14 H).
實施例Example 1313
3-(2-(((1R,3s,5S)-8-氮雜雙環[3.2.1]辛烷-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷醯基)-1H-吲哚-6-甲腈 (化合物13)
第一步：(1R,3s,5S)-3-((叔丁氧羰基)胺基)-8-氮雜雙環[3.2.1]辛烷-8-羧酸苄基酯
13B 
將((1R,3s,5S)-8-氮雜雙環[3.2.1]辛烷-3-基)胺基甲酸叔丁基酯 13A(200 mg, 0.885 mmol )溶於乾燥的二氯甲烷 (10 mL) 中並加入三乙胺(268 mg，2.65 mmol)，N 2置換空氣3次。然後降至0℃, 加入氯甲酸苄酯(225 mg，1.3 mmol)。添完完成後自然升溫至室溫攪拌1個小時。向反應液中加入乙酸乙酯 (100 mL)，分液，水相用乙酸乙酯 (50 mL × 2) 萃取。將合併的有機相在室溫用無水硫酸鈉乾燥，過濾，濃縮，殘留物用TLC板提純(石油醚/乙酸乙酯 (v/v) = 2:1) 得到(1R,3s,5S)-3-((叔丁氧羰基)胺基)-8-氮雜雙環[3.2.1]辛烷-8-羧酸苄基酯 13B(300 mg, 產率94%)。 ((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)carbamate tert-butyl ester 13A (200 mg, 0.885 mmol) was dissolved in dry dichloromethane ( 10 mL) and added triethylamine (268 mg, 2.65 mmol), replacing the air with N 3 times. It was then lowered to 0°C and benzyl chloroformate (225 mg, 1.3 mmol) was added. After the addition was completed, the temperature was naturally raised to room temperature and stirred for 1 hour. Ethyl acetate (100 mL) was added to the reaction solution, the layers were separated, and the aqueous phase was extracted with ethyl acetate (50 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate at room temperature, filtered, concentrated, and the residue was purified with a TLC plate (petroleum ether/ethyl acetate (v/v) = 2:1) to give (1R,3s,5S)- 3-((tert-Butoxycarbonyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate benzyl ester 13B (300 mg, 94% yield).
MS m/z (ESI)：361 [M+1]MS m/z (ESI): 361 [M+1]
第二步：(1R,3s,5S)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羧酸苄基酯13C
向(1R,3s,5S)-3-((叔丁氧羰基)胺基)-8-氮雜雙環[3.2.1]辛烷-8-羧酸苄基酯 13B(300 mg, 0.83 mmol)中加入鹽酸的乙酸乙酯溶液(5 ml)，攪拌1個小時。向反應液中加入飽和碳酸氫鈉(30ml)和水 (30 mL)，分液，水相用乙酸乙酯 (20 mL × 2) 萃取。將合併的有機相在室溫用無水硫酸鈉乾燥，過濾，濃縮得到(1R,3s,5S)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羧酸苄基酯 13C(140 mg, 產率64%)。 To (1R,3s,5S)-3-((tert-butoxycarbonyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate benzyl ester 13B (300 mg, 0.83 mmol) An ethyl acetate solution of hydrochloric acid (5 ml) was added thereto, followed by stirring for 1 hour. Saturated sodium bicarbonate (30 mL) and water (30 mL) were added to the reaction solution, the layers were separated, and the aqueous phase was extracted with ethyl acetate (20 mL×2). The combined organic phases were dried over anhydrous sodium sulfate at room temperature, filtered, and concentrated to give (1R,3s,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylic acid benzyl Ester 13C (140 mg, 64% yield).
MS m/z (ESI)：261 [M+1]MS m/z (ESI): 261 [M+1]
第三步：(1R,3s,5S)-3-((4-(7-溴-6-氰基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-8-氮雜雙環[3.2.1]辛烷-8-羧酸苄基酯13D
將(1R,3s,5S)-3-胺基-8-氮雜雙環[3.2.1]辛烷-8-羧酸苄基酯 13C(140 mg, 0.583 mmol)和7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲腈(100 mg，0.249 mmol)溶於四氫呋喃(5 ml)中，加入N,N-二異丙基乙胺(80 mg，0.62 mmol)，升溫至60℃, N 2置換3次，反應兩個小時。向反應液中加入乙酸乙酯(30ml)和水 (30 mL)，分液，水相用乙酸乙酯 (20 mL × 2) 萃取。將合併的有機相在室溫用無水硫酸鈉乾燥，過濾，濃縮，殘留物用矽膠柱色譜分離提純(石油醚/乙酸乙酯 (v/v) = 5:1) 得到(1R,3s,5S)-3-((4-(7-溴-6-氰基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-8-氮雜雙環[3.2.1]辛烷-8-羧酸苄基酯 13D(60 mg, 產率28%)。 Combine (1R,3s,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate benzyl ester 13C (140 mg, 0.583 mmol) and 7-bromo-3-( 2-Chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile (100 mg, 0.249 mmol) was dissolved in tetrahydrofuran (5 ml) and N,N-dicarbonitrile was added Isopropylethylamine (80 mg, 0.62 mmol), warmed to 60 °C, replaced by N 3 times, and reacted for two hours. Ethyl acetate (30 mL) and water (30 mL) were added to the reaction solution, the layers were separated, and the aqueous phase was extracted with ethyl acetate (20 mL×2). The combined organic phases were dried over anhydrous sodium sulfate at room temperature, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 5:1) to give (1R,3s,5S) )-3-((4-(7-Bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-8-aza Bicyclo[3.2.1]octane-8-carboxylate benzyl ester 13D (60 mg, 28% yield).
MS m/z (ESI)：625 [M+1]MS m/z (ESI): 625 [M+1]
第四步：(1R,3r,5S)-3-((4-(6-氰基-7-(二甲基磷醯基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-8-氮雜雙環[3.2.1]辛烷-8-羧酸苄基酯
13E 
將(1R,3s,5S)-3-((4-(7-溴-6-氰基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-8-氮雜雙環[3.2.1]辛烷-8-羧酸苄基酯 13D(60 mg, 0.096 mmol)、4,5-雙(二苯基膦)-9,9-二甲基氧雜蒽(12 mg，0.02 mmol)、醋酸鈀(5 mg，0.02 mmol)和磷酸鉀(102 mg，0.48 mmol)溶於N,N-二甲基甲醯胺 (8 mL) 中，加入二甲基氧化膦(37.5 mg，0.48 mmol)，N 2置換3次，升溫至150 ℃，反應1個小時。降至室溫，減壓濃縮，殘留物用矽膠柱色譜分離提純(石油醚/乙酸乙酯 (v/v) = 2:1) 得到(1R,3r,5S)-3-((4-(6-氰基-7-(二甲基磷醯基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-8-氮雜雙環[3.2.1]辛烷-8-羧酸苄基酯 13E(10 mg，產率17%)。 (1R,3s,5S)-3-((4-(7-Bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amine yl)-8-azabicyclo[3.2.1]octane-8-carboxylate benzyl ester 13D (60 mg, 0.096 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyl Xanthene (12 mg, 0.02 mmol), palladium acetate (5 mg, 0.02 mmol) and potassium phosphate (102 mg, 0.48 mmol) were dissolved in N,N-dimethylformamide (8 mL) and added Dimethylphosphine oxide (37.5 mg, 0.48 mmol), replaced with N 2 three times, heated to 150 °C, and reacted for 1 hour. It was cooled to room temperature, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2:1) to obtain (1R,3r,5S)-3-((4-( 6-cyano-7-(dimethylphosphoronyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-8-azabicyclo[ 3.2.1] Benzyl octane-8-carboxylate 13E (10 mg, 17% yield).
MS m/z (ESI)：623 [M+1]MS m/z (ESI): 623 [M+1]
第五步：3-(2-(((1R,3r,5S)-8-氮雜雙環[3.2.1]辛烷-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷醯基)-1H-吲哚-6-甲腈(化合物13)
將(1R,3r,5S)-3-((4-(6-氰基-7-(二甲基磷醯基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-8-氮雜雙環[3.2.1]辛烷-8-羧酸苄基酯 13E(10 mg, 0.016 mmol)和鈀炭(2 mg)溶於乙酸乙酯(10 mL) 中，在氫氣下反應2小時。將反應混合物過濾，濃縮，加入水 (10 mL)和乙酸乙酯(15 ml)，分液，水相用乙酸乙酯 (10 mL × 2) 萃取。將合併的有機相用無水硫酸鈉乾燥，過濾，濃縮，殘留物用製備板分離提純 (二氯甲烷/無水甲醇 (v/v) = 10：1，) 得到類白色固體狀的化合物3-(2-(((1R,3r,5S)-8-氮雜雙環[3.2.1]辛烷-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷醯基)-1H-吲哚-6-甲腈(化合物13) (1 mg，產率13%)。 (1R,3r,5S)-3-((4-(6-cyano-7-(dimethylphosphoronyl)-1H-indol-3-yl)-5-(trifluoromethyl) Pyrimidine-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate benzyl ester 13E (10 mg, 0.016 mmol) and palladium on carbon (2 mg) were dissolved in ethyl acetate (10 mL) under hydrogen for 2 hours. The reaction mixture was filtered, concentrated, water (10 mL) and ethyl acetate (15 ml) were added, the layers were separated, and the aqueous phase was extracted with ethyl acetate (10 mL×2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified with a preparative plate (dichloromethane/anhydrous methanol (v/v) = 10:1,) to give compound 3-( as an off-white solid. 2-(((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7- (Dimethylphosphoryl)-1H-indole-6-carbonitrile (Compound 13) (1 mg, 13% yield).
MS m/z (ESI)：489.1 [M+1]MS m/z (ESI): 489.1 [M+1]
實施例Example 1414
(6-氟-3-(2-(((S)-呱啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)(亞胺基)(甲基)-λ
6-亞碸 (化合物14-P1和化合物14-P2)
第一步：(S)-3-((4-(6-氟-7-(甲硫基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁酯
14A 
將3-(2-氯-5-(三氟甲基)嘧啶-4-基)-6-氟-7-(甲硫基)-1H-吲哚 ( 中間體 4)(4.8 g, 13.2 mmol) 溶於無水四氫呋喃 (50 mL)中，加入(S)-1-叔丁氧羰基-3胺基呱啶(3.36 g, 16.8 mmol)、N,N-二異丙基乙胺 (4.3 g, 33.6 mmol), N2置換3次，升溫至60℃，反應3個小時。降至室溫，減壓濃縮得棕色油狀物。將所得殘留物通過反相柱(ACN:H2O=5:95到95:5)純化後得到淡黃色固體狀的化合物(S)-3-((4-(6-氟-7-(甲硫基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁酯 14A(3.0 g, 產率43%)。 3-(2-Chloro-5-(trifluoromethyl)pyrimidin-4-yl)-6-fluoro-7-(methylthio)-1H-indole ( Intermediate 4) (4.8 g, 13.2 mmol) ) was dissolved in anhydrous tetrahydrofuran (50 mL), and (S)-1-tert-butoxycarbonyl-3-aminopyridine (3.36 g, 16.8 mmol), N,N-diisopropylethylamine (4.3 g, 33.6 mmol), replaced by N 3 times, heated to 60 °C, and reacted for 3 hours. It was cooled to room temperature and concentrated under reduced pressure to give a brown oil. The obtained residue was purified by reverse phase column (ACN:H2O=5:95 to 95:5) to give compound (S)-3-((4-(6-fluoro-7-(methylthio) as a pale yellow solid. (yl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)quamidine-1-carboxylate tert-butyl ester 14A (3.0 g, 43% yield) .
MS m/z (ESI)：526.1 [M+1]MS m/z (ESI): 526.1 [M+1]
第二步：(S)-3-((4-(6-氟-7-(甲硫基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁基酯
14B 
將(S)-3-((4-(6-氟-7-(甲硫基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁酯 14A(3.0 g, 5.70 mmol) 溶於N,N-二甲基甲醯胺(20 mL)中，降溫0 oC, N2置換3次。加入氫化鈉(60%) (383 mg，9.57 mmol)，反應半小時，然後加入2-(三甲基甲矽烷基)乙氧甲基氯 (1.14 g，6.84 mmol)，室溫繼續反應兩個小時。向反應液中加入乙酸乙酯(30 mL)和冰水 (30 mL)，分液，水相用乙酸乙酯 (20 mL × 2) 萃取，合併有機相。有機相用飽和食鹽水 (20 mL) 洗滌，無水硫酸鈉乾燥，過濾，濃縮旋幹。殘留物通過矽膠柱 (石油醚/乙酸乙酯 (v/v) = 10/1) 純化後得到類白色固體狀的化合物(S)-3-((4-(6-氟-7-(甲硫基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁基酯 14B(3.8 g，產率100%)。 (S)-3-((4-(6-Fluoro-7-(methylthio)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino ) pyridine-1-carboxylate tert-butyl ester 14A (3.0 g, 5.70 mmol) was dissolved in N,N-dimethylformamide (20 mL), the temperature was lowered to 0 ° C, and N2 was replaced 3 times. Sodium hydride (60%) (383 mg, 9.57 mmol) was added and reacted for half an hour, then 2-(trimethylsilyl)ethoxymethyl chloride (1.14 g, 6.84 mmol) was added, and the reaction was continued at room temperature for two Hour. Ethyl acetate (30 mL) and ice water (30 mL) were added to the reaction solution, and the layers were separated. The aqueous phase was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and spin-dried. The residue was purified by silica gel column (petroleum ether/ethyl acetate (v/v) = 10/1) to give compound (S)-3-((4-(6-fluoro-7-(methyl) as an off-white solid. Thio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl) Amino) pyridine-1-carboxylate tert-butyl ester 14B (3.8 g, 100% yield).
MS m/z (ESI)：656.1 [M+1]MS m/z (ESI): 656.1 [M+1]
第三步：(3S)-3-((4-(6-氟-7-(S-甲基亞胺亞碸基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁基酯
14C 
將(S)-3-((4-(6-氟-7-(甲硫基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁基酯 14B(500 mg, 0.763 mmol)、(二乙醯氧基碘)苯(983 mg, 3.05 mmol)、碳酸銨 (220 mg, 2.29 mmol)溶於甲醇 (5 mL)中，反應0.5個小時。平行投8個該反應。合併反應液，室溫濃縮旋幹，殘留物用製備板分離提純 (石油醚/乙酸乙酯 (v/v) = 2/1)，得到白色固體化合物 (3S)-3-((4-(6-氟-7-(S-甲基亞胺亞碸基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁基酯 14C(2.2 g，產率55%)。 (S)-3-((4-(6-Fluoro-7-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole -3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)ciridine-1-carboxylate tert-butyl ester 14B (500 mg, 0.763 mmol), (diacetoxyiodide) ) benzene (983 mg, 3.05 mmol) and ammonium carbonate (220 mg, 2.29 mmol) were dissolved in methanol (5 mL) and reacted for 0.5 hours. Roll 8 of this reaction in parallel. The reaction solutions were combined, concentrated and rotated to dryness at room temperature, and the residue was separated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v) = 2/1) to obtain a white solid compound (3S)-3-((4-( 6-Fluoro-7-(S-methyliminoidene)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)- 5-(Trifluoromethyl)pyrimidin-2-yl)amino)quamidine-1-carboxylate tert-butyl ester 14C (2.2 g, 55% yield).
MS m/z (ESI)：687.1 [M+1]MS m/z (ESI): 687.1 [M+1]
將上述得到的2.2克消旋體 14C進行手性拆分，分別得到 14C-P1(保留時間：1.45 min)和 14C-P2(保留時間：1.74 min)各1.0 g。 The 2.2 g racemate 14C obtained above was subjected to chiral separation to obtain 1.0 g each of 14C-P1 (retention time: 1.45 min) and 14C-P2 (retention time: 1.74 min).
手性拆分的具體條件如下表所示：The specific conditions for chiral resolution are shown in the following table:
第四步：(6-氟-3-(2-(((S)-呱啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)(亞胺基)(甲基)- λ
6-亞碸
( 化合物 14-P1) 
將(3S)-3-((4-(6-氟-7-(S-甲基亞胺亞碸基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁基酯 14C-P1(1.0 g, 1.46 mmol) 溶於二氯甲烷(10 mL)和三氟乙酸(5 mL)中，室溫攪拌反應一個小時，減壓濃縮旋幹。殘留物溶於四氫呋喃(5 mL) 中，加入氨水(2 mL)，室溫反應三十分鐘，減壓濃縮旋幹得粗品。粗品經製備型HPLC純化後凍幹得白色固體產品(6-氟-3-(2-(((S)-呱啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)(亞胺基)(甲基)-λ 6-亞碸 ( 化合物 14-P1)(262 mg，產率39%)。 (3S)-3-((4-(6-Fluoro-7-(S-methyliminoidene)-1-((2-(trimethylsilyl)ethoxy)methyl )-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)quamidine-1-carboxylate tert-butyl ester 14C-P1 (1.0 g, 1.46 mmol) Dissolve in dichloromethane (10 mL) and trifluoroacetic acid (5 mL), stir the reaction at room temperature for one hour, concentrate under reduced pressure and spin dry. The residue was dissolved in tetrahydrofuran (5 mL), ammonia water (2 mL) was added, the reaction was carried out at room temperature for 30 minutes, concentrated under reduced pressure and spin-dried to obtain the crude product. The crude product was purified by preparative HPLC and lyophilized to give a white solid product (6-fluoro-3-(2-(((S)-pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidine- 4-yl)-1H-indol-7-yl)(imino)(methyl)-λ 6 -thylene ( compound 14-P1) (262 mg, 39% yield).
MS m/z (ESI)：457.1 [M+1]MS m/z (ESI): 457.1 [M+1]
1HNMR (400 MHz, DMSO-D6) δ 11.66 (s, 1H), 8.72-8.40 (m, 2H), 7.95-7.80 (m, 2H), 7.19 (q, 1H), 5.15 (s, 1H), 3.90-3.80 (m, 1H), 3.36 (s, 3H), 3.10-3.00 (m, 1H), 2.85-2.75 (m, 1H), 2.48-2.38 (m, 2H), 2.00-1.90 (m, 1H), 1.70-1.60 (m, 1H), 1.55-1.35 (m, 2H).1HNMR (400 MHz, DMSO-D6) δ 11.66 (s, 1H), 8.72-8.40 (m, 2H), 7.95-7.80 (m, 2H), 7.19 (q, 1H), 5.15 (s, 1H), 3.90 -3.80 (m, 1H), 3.36 (s, 3H), 3.10-3.00 (m, 1H), 2.85-2.75 (m, 1H), 2.48-2.38 (m, 2H), 2.00-1.90 (m, 1H) , 1.70-1.60 (m, 1H), 1.55-1.35 (m, 2H).
(6-氟-3-(2-(((S)-呱啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)(亞胺基)(甲基)-λ
6-亞碸
( 化合物 14-P2)
將(3S)-3-((4-(6-氟-7-(S-甲基亞胺亞碸基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁基酯 14C-P2(1.0 g, 1.46 mmol)溶於二氯甲烷(10 mL)和三氟乙酸(5 mL)中，室溫攪拌反應一個小時，減壓濃縮旋幹。殘留物溶於四氫呋喃(5 mL) 中，加入氨水(2 mL)，室溫反應三十分鐘。減壓濃縮旋幹反應混合物得粗品。粗品經製備型HPLC純化後凍幹得白色固體產品(6-氟-3-(2-(((S)-呱啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)(亞胺基)(甲基)-λ 6-亞碸 ( 化合物 14-P2)(186 mg，產率28%)。 (3S)-3-((4-(6-Fluoro-7-(S-methyliminoidene)-1-((2-(trimethylsilyl)ethoxy)methyl )-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)quamidine-1-carboxylate tert-butyl ester 14C-P2 (1.0 g, 1.46 mmol) Dissolve in dichloromethane (10 mL) and trifluoroacetic acid (5 mL), stir the reaction at room temperature for one hour, concentrate under reduced pressure and spin dry. The residue was dissolved in tetrahydrofuran (5 mL), ammonia water (2 mL) was added, and the reaction was carried out at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and spin-dried to obtain crude product. The crude product was purified by preparative HPLC and lyophilized to give a white solid product (6-fluoro-3-(2-(((S)-pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidine- 4-yl)-1H-indol-7-yl)(imino)(methyl)-λ 6 -thylene ( compound 14-P2) (186 mg, 28% yield).
MS m/z (ESI)：457.0 [M+1]MS m/z (ESI): 457.0 [M+1]
1HNMR (400 MHz, CDCl 3) δ 10.74 (s, 1 H), 8.58 (m, 1 H), 8.49 (dd, 1 H), 7.85 (s, 1 H), 7.11 (t, 1 H), 5.96 (s, 1 H), 4.13 (m, 1 H), 3.42 (s, 3 H), 3.22-3.19 (m, 1 H), 2.89-2.80 (m, 3 H), 1.95 (m, 1 H), 1.81 (m, 1 H), 1.69-1.60 (m, 2H). 1HNMR (400 MHz, CDCl 3 ) δ 10.74 (s, 1 H), 8.58 (m, 1 H), 8.49 (dd, 1 H), 7.85 (s, 1 H), 7.11 (t, 1 H), 5.96 (s, 1 H), 4.13 (m, 1 H), 3.42 (s, 3 H), 3.22-3.19 (m, 1 H), 2.89-2.80 (m, 3 H), 1.95 (m, 1 H) , 1.81 (m, 1H), 1.69-1.60 (m, 2H).
實施例Example 1515
N-((3-(2-(((S)-6,6-二甲基呱啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)(甲基)(氧代)- λ
6-硫亞基)氰胺 (化合物15)
第一步：(S)-N-(6,6-二甲基呱啶-3-基)-4-(7-(甲硫基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-胺
15A 
將3-(2-氯-5-(三氟甲基)嘧啶-4-基)-7-(甲硫基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚 ( 中間體 5)(600 mg, 1.27 mmol) 溶於異丙醇(10 mL)中，加入(S)-6,6-二甲基呱啶-3-胺(420 mg，3.81 mmol)、N,N-二異丙基乙胺 (670 mg, 4.87 mmol)，氮氣置換3次，升至90℃，反應15個小時。反應液冷卻至室溫，濃縮旋幹得到油狀化合物(S)-N-(6,6-二甲基呱啶-3-基)-4-(7-(甲硫基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-胺 15A(500 mg，產率70%)。 3-(2-Chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl yl)-1H-indole ( Intermediate 5) (600 mg, 1.27 mmol) was dissolved in isopropanol (10 mL) and added (S)-6,6-dimethylpyridin-3-amine (420 mg, 3.81 mmol), N,N-diisopropylethylamine (670 mg, 4.87 mmol), replaced with nitrogen three times, raised to 90° C., and reacted for 15 hours. The reaction solution was cooled to room temperature, concentrated and spin-dried to obtain an oily compound (S)-N-(6,6-dimethylpyridin-3-yl)-4-(7-(methylthio)-1-( (2-(Trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine 15A (500 mg, yield 70 %).
MS m/z (ESI)：566.3 [M+1]MS m/z (ESI): 566.3 [M+1]
第二步：(S)-2,2-二甲基-5-((4-(7-(甲硫基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁基酯
15B 
將(S)-N-(6,6-二甲基呱啶-3-基)-4-(7-(甲硫基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-胺15A (500 mg, 0.88mmol) 溶於二氯甲烷 (10 mL)中，加入三乙胺 (300 mg, 2.66 mmol)和一縮二碳酸二叔丁酯 (347 mg, 1.76 mmol), N2置換3次，室溫反應1個小時。減壓濃縮，殘留物用製備板分離提純(石油醚/乙酸乙酯 (v/v) = 3/1) 得到類白色固體化合物(S)-2,2-二甲基-5-((4-(7-(甲硫基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁基酯15B (380 mg，產率72%)。(S)-N-(6,6-Dimethylpyridin-3-yl)-4-(7-(methylthio)-1-((2-(trimethylsilyl)ethoxy (yl)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine 15A (500 mg, 0.88 mmol) was dissolved in dichloromethane (10 mL) and added with trifluoromethyl Ethylamine (300 mg, 2.66 mmol) and di-tert-butyl dicarbonate (347 mg, 1.76 mmol), replaced with N2 three times, and reacted at room temperature for 1 hour. Concentrated under reduced pressure, the residue was separated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v) = 3/1) to obtain off-white solid compound (S)-2,2-dimethyl-5-((4 -(7-(Methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoromethyl) Pyrimidin-2-yl)amino)ciridine-1-carboxylate tert-butyl ester 15B (380 mg, 72% yield).
MS m/z (ESI)：666.4 [M+1]MS m/z (ESI): 666.4 [M+1]
第三步：(5S)-2,2-二甲基-5-((4-(7-(S-甲基亞氨亞碸基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁基酯
15C 
將(S)-2,2-二甲基-5-((4-(7-(甲硫基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁基酯 15B(380 mg, 0.571 mmol) 溶於甲醇(5 mL)中，加入(二乙醯氧基碘)苯(460 mg, 1.43 mmol)和碳酸銨 (170 mg, 1.97 mmol)，空氣氛圍中反應半個小時。反應液直接用製備板分離提純(石油醚/乙酸乙酯 (v/v) = 1:1) 得到類白色固體化合物(5S)-2,2-二甲基-5-((4-(7-(S-甲基亞胺亞碸基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁基酯 15C(280 mg，產率71%)。 (S)-2,2-dimethyl-5-((4-(7-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-Indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)quamidine-1-carboxylate tert-butyl ester 15B (380 mg, 0.571 mmol) in methanol ( 5 mL), added (diacetoxyiodo)benzene (460 mg, 1.43 mmol) and ammonium carbonate (170 mg, 1.97 mmol), and reacted for half an hour in an air atmosphere. The reaction solution was directly separated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v) = 1:1) to obtain an off-white solid compound (5S)-2,2-dimethyl-5-((4-(7 -(S-Methyliminoidene)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoro Methyl)pyrimidin-2-yl)amino)ciridine-1-carboxylate tert-butyl ester 15C (280 mg, 71% yield).
MS m/z (ESI)：697.4 [M+1]MS m/z (ESI): 697.4 [M+1]
第四步：(5S)-5-((4-(7-(N-氰基-S-甲基亞胺亞碸基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2,2-二甲基呱啶-1-羧酸叔丁基酯
15D 
將(5S)-2,2-二甲基-5-((4-(7-(S-甲基亞胺亞碸基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁基酯 15C(50 mg, 0.07 mmol) 溶於二氯甲烷(5 mL)中，加入氰化溴(15 mg, 0.14 mmol)和4-二甲胺基吡啶 (18 mg, 0.14 mmol)，室溫反應過夜。過濾反應液，減壓濃縮，殘留物用製備板分離提純 (石油醚/乙酸乙酯 (v/v) = 2/1) 得到白色固體化合物(5S)-5-((4-(7-(N-氰基-S-甲基亞胺亞碸基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2,2-二甲基呱啶-1-羧酸叔丁基酯 15D(30 mg，產率59%)。 (5S)-2,2-dimethyl-5-((4-(7-(S-methyliminoidene)-1-((2-(trimethylsilyl)ethoxy) (yl)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)ciridine-1-carboxylate tert-butyl ester 15C (50 mg, 0.07 mmol) was dissolved in dichloromethane (5 mL), bromine cyanide (15 mg, 0.14 mmol) and 4-dimethylaminopyridine (18 mg, 0.14 mmol) were added, and the reaction was carried out at room temperature overnight. The reaction solution was filtered, concentrated under reduced pressure, and the residue was separated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v) = 2/1) to obtain a white solid compound (5S)-5-((4-(7-( N-Cyano-S-methyliminosilylidene)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-5- (Trifluoromethyl)pyrimidin-2-yl)amino)-2,2-dimethylpyridine-1-carboxylate tert-butyl ester 15D (30 mg, 59% yield).
MS m/z (ESI)：722.3 [M+1]MS m/z (ESI): 722.3 [M+1]
第五步：N-((3-(2-(((S)-6,6-二甲基呱啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)(甲基)(氧代)-λ
6-硫亞基)氰胺
( 化合物 15) 
將(5S)-5-((4-(7-(N-氰基-S-甲基亞胺亞碸基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2,2-二甲基呱啶-1-羧酸叔丁基酯 15D(30 mg, 0.04 mmol)溶於二氯甲烷(2 mL)和三氟乙酸(1 mL)中，室溫攪拌反應4小時。反應液濃縮旋幹，殘留物溶於四氫呋喃 (2 mL)中。加入氨水(1 mL)，室溫攪拌反應30分鐘。濃縮旋幹，殘留物用製備板分離提純 (二氯甲烷/甲醇 (v/v) = 10：1，)得到白色固體化合物N-((3-(2-(((S)-6,6-二甲基呱啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)(甲基)(氧代)-λ 6-硫亞基)氰胺 ( 化合物 15)(3.1 mg，產率16%)。 (5S)-5-((4-(7-(N-cyano-S-methyliminoidene)-1-((2-(trimethylsilyl)ethoxy)methyl (yl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2,2-dimethylpyridine-1-carboxylate tert-butyl ester 15D (30 mg, 0.04 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL), and the reaction was stirred at room temperature for 4 hours. The reaction solution was concentrated and spun dry, and the residue was dissolved in tetrahydrofuran (2 mL). Aqueous ammonia (1 mL) was added, and the reaction was stirred at room temperature for 30 minutes. Concentrated and spin-dried, the residue was separated and purified with a preparative plate (dichloromethane/methanol (v/v) = 10:1,) to obtain a white solid compound N-((3-(2-((((S)-6,6) -Dimethylpyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)(methyl)(oxo)-λ 6 -Sulfurylidene)cyanamide ( Compound 15) (3.1 mg, 16% yield).
MS m/z (ESI)：492.1 [M+1]MS m/z (ESI): 492.1 [M+1]
1HNMR (400 MHz, CD 3OD) δ 8.84-8.59 (m, 2H), 7.98 (m, 1 H), 7.91 (d, 1 H), 7.50 (t, 1 H), 4.09 (m, 1 H), 3.63 (d, 2 H), 3.25 (m, 2 H), 2.90 (t, 1 H), 2.02 (m, 1 H), 1.85-1.67 (m, 2 H), 1.59 (m, 1 H), 1.26 (s, 6 H). 1HNMR (400 MHz, CD 3 OD) δ 8.84-8.59 (m, 2H), 7.98 (m, 1 H), 7.91 (d, 1 H), 7.50 (t, 1 H), 4.09 (m, 1 H) , 3.63 (d, 2 H), 3.25 (m, 2 H), 2.90 (t, 1 H), 2.02 (m, 1 H), 1.85-1.67 (m, 2 H), 1.59 (m, 1 H) , 1.26 (s, 6 H).
實施例Example 1616
(S)-7-((二甲基(氧代)-λ
6-亞硫基)胺基)-3-(2-(呱啶-3-基胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲腈 (化合物16)
第一步：7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-6-甲腈
16A 
將7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲腈 3A(250 mg, 0.625 mmol) 溶於N,N-二甲基甲醯胺(8 ml)中，降溫至0 oC, N2置換3次, 加入氫化鈉(60%)(50 mg，1.25 mmol)，反應一個小時。然後加入2-(三甲基甲矽烷基)乙氧甲基氯(208 mg，1.25 mmol)，室溫繼續反應兩個小時。向反應液中加入乙酸乙酯(10ml)和冰水 (10 mL)，分液，水相用乙酸乙酯 (10 mL × 2) 萃取，合併有機相。有機相用飽和食鹽水 (10 mL × 2) 洗滌，室溫用無水硫酸鈉乾燥，過濾，濃縮。殘留物用矽膠柱色譜分離提純(石油醚/乙酸乙酯 (v/v) = 10:1) 得到淡黃色固體狀的化合物7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-6-甲腈 16A(70 mg, 產率21%)。 7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile 3A (250 mg, 0.625 mmol) was dissolved in N,N- In dimethylformamide (8 ml), the temperature was lowered to 0 o C, replaced by N2 three times, sodium hydride (60%) (50 mg, 1.25 mmol) was added, and the reaction was carried out for one hour. Then 2-(trimethylsilyl)ethoxymethyl chloride (208 mg, 1.25 mmol) was added and the reaction was continued for two hours at room temperature. Ethyl acetate (10 mL) and ice water (10 mL) were added to the reaction solution, and the layers were separated. The aqueous phase was extracted with ethyl acetate (10 mL × 2), and the organic phases were combined. The organic phase was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate at room temperature, filtered and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 10:1) to obtain compound 7-bromo-3-(2-chloro-5-(trifluoromethyl) as a pale yellow solid )pyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-6-carbonitrile 16A (70 mg, 21% yield).
MS m/z (ESI)：531.8 [M+1]MS m/z (ESI): 531.8 [M+1]
第二步：(S)-3-((4-(7-溴-6-氰基-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁基酯
16B 
將7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-6-甲腈 16A(70 mg, 0.132 mmol)溶於無水四氫呋喃 (5 mL)中，加入3-胺基呱啶-1-羧酸叔丁基酯 (53 mg, 0.264 mmol)和N,N-二異丙基乙胺 (52 mg, 0.4 mmol), N2置換3次，升溫至60℃，反應4個小時。降至室溫，減壓濃縮。殘留物用矽膠柱色譜分離提純(石油醚/乙酸乙酯 (v/v) = 3:1) 得到類白色固體狀的化合物(S)-3-((4-(7-溴-6-氰基-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁基酯 16B(60 mg，產率65%)。 7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H -Indole-6-carbonitrile 16A (70 mg, 0.132 mmol) was dissolved in dry tetrahydrofuran (5 mL), tert-butyl 3-aminopyridine-1-carboxylate (53 mg, 0.264 mmol) and N,N-diisopropylethylamine (52 mg, 0.4 mmol), replaced with N2 three times, heated to 60°C, and reacted for 4 hours. It was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3:1) to obtain compound (S)-3-((4-(7-bromo-6-cyano) as an off-white solid yl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino ) pyridine-1-carboxylate tert-butyl ester 16B (60 mg, 65% yield).
MS m/z (ESI)：695.6 [M+1]MS m/z (ESI): 695.6 [M+1]
第三步：(S)-3-((4-(6-氰基-7-((二甲基(氧代)-λ
6-亞硫基)胺基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁基酯
16C 
將(S)-3-((4-(7-溴-6-氰基-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁基酯 16B(58 mg, 0.083 mmol)、三[二亞苄基丙酮]二鈀 (15.3 mg, 0.016 mmol)、2-(二叔丁基膦)聯苯 (9.5 mg, 0.032 mmol)、叔丁醇鈉 (16 mg, 0.16 mmol)和二甲基亞胺基亞碸 (38.8 mg, 0.416 mmol) 溶於乾燥1.4-二氧六環 (5 mL) 中，升至80℃反應16個小時。將反應液冷卻至室溫，矽藻土過濾濃縮。殘留物用製備板分離提純 (石油醚/乙酸乙酯 (v/v) = 1：1，) 得到淡黃色油狀的化合物(S)-3-((4-(6-氰基-7-((二甲基(氧代)-λ 6-亞硫基)胺基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁基酯 16C(9 mg，產率15%)。 (S)-3-((4-(7-Bromo-6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3- yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)quamidine-1-carboxylate tert-butyl ester 16B (58 mg, 0.083 mmol), tris[dibenzylideneacetone]dipalladium (15.3 mg, 0.016 mmol), 2-(di-tert-butylphosphine)biphenyl (9.5 mg, 0.032 mmol), sodium tert-butoxide (16 mg, 0.16 mmol) and dimethyliminosulfite (38.8 mg , 0.416 mmol) was dissolved in dry 1.4-dioxane (5 mL) and heated to 80 °C for 16 hours. The reaction solution was cooled to room temperature, filtered through celite and concentrated. The residue was separated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v) = 1:1,) to give compound (S)-3-((4-(6-cyano-7-) as pale yellow oil ((dimethyl(oxo)-λ 6 -sulfinyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3- (9 mg , 15% yield).
MS m/z (ESI)：708.2 [M+1]MS m/z (ESI): 708.2 [M+1]
第四步：(S)-7-((二甲基(氧代)-λ
6-亞硫基)胺基)-1-(羥甲基)-3-(2-(呱啶-3-基胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲腈 16D
將(S)-3-((4-(6-氰基-7-((二甲基(氧代)- λ 6-亞硫基)胺基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)呱啶-1-羧酸叔丁基酯 16C(9 mg, 0.013 mmol)，溶於二氯甲烷(2ml)和三氟乙酸(0.5ml)中，室溫攪拌反應一個小時。減壓濃縮反應混合物得到粗品棕色油狀物(S)-7-((二甲基(氧代)- λ 6-亞硫基)胺基)-1-(羥甲基)-3-(2-(呱啶-3-基胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲腈 16D(12 mg，粗品)，直接用於下一步反應。 (S)-3-((4-(6-cyano-7-((dimethyl(oxo)-λ 6 -thiosulfinyl)amino)-1-((2-(trimethyl Silyl)ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)quamidine-1-carboxylate tert-butyl ester 16C (9 mg, 0.013 mmol) was dissolved in dichloromethane (2 ml) and trifluoroacetic acid (0.5 ml), and the reaction was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure to give crude brown oil (S)-7-((dimethyl(oxo)-λ 6 -thiosulfinyl)amino)-1-(hydroxymethyl)-3-(2 -(Quaridin-3-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile 16D (12 mg, crude), used directly in the next reaction .
MS m/z (ESI)：508.5 [M+1]MS m/z (ESI): 508.5 [M+1]
第五步：(S)-7-((二甲基(氧代)-λ
6-亞硫基)胺基)-3-(2-(呱啶-3-基胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲腈
( 化合物 16) 
將粗品(S)-7-((二甲基(氧代)-λ 6-亞硫基)胺基)-1-(羥甲基)-3-(2-(呱啶-3-基胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲腈 16D(12 mg, 0.023 mmol)，溶於四氫呋喃(2 mL) 中，加入氨水 (1ml), 室溫反應三十分鐘。減壓濃縮反應混合物。殘留物中加甲醇溶解，通過製備板分離提純(二氯甲烷/甲醇 (v/v) = 7：1得到白色固體狀的化合物(S)-7-((二甲基(氧代)-λ 6-亞硫基)胺基)-3-(2-(呱啶-3-基胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲腈 ( 化合物 16)(2 mg，產率18%)。 The crude (S)-7-((dimethyl(oxo)-λ 6 -thiosulfinyl)amino)-1-(hydroxymethyl)-3-(2-(guaidin-3-ylamine) yl)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile 16D (12 mg, 0.023 mmol), dissolved in tetrahydrofuran (2 mL), ammonia (1 mL) was added , at room temperature for thirty minutes. The reaction mixture was concentrated under reduced pressure. Add methanol to the residue to dissolve, and separate and purify by preparative plate (dichloromethane/methanol (v/v) = 7:1 to obtain compound (S)-7-((dimethyl(oxo)-λ) as a white solid 6 -Sulfanyl)amino)-3-(2-(quaridin-3-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile ( Compound 16) (2 mg, 18% yield).
MS m/z (ESI)：478.0 [M+1]MS m/z (ESI): 478.0 [M+1]
1H NMR (400 MHz, CD 3OD) δ 8.58 (s, 1 H), 7.95 (m, 2 H), 7.44-7.14 (m, 1 H), 4.26 (m, 1 H), 3.63-3.48 (m, 2 H), 3.34 (s, 6 H) 2.94-2.89 (m, 2 H), 2.21-2.17 (m, 1H), 2.02 (m, 1 H), 1.75-1.60 (m, 2 H). 1H NMR (400 MHz, CD 3 OD) δ 8.58 (s, 1 H), 7.95 (m, 2 H), 7.44-7.14 (m, 1 H), 4.26 (m, 1 H), 3.63-3.48 (m , 2 H), 3.34 (s, 6 H) 2.94-2.89 (m, 2 H), 2.21-2.17 (m, 1H), 2.02 (m, 1 H), 1.75-1.60 (m, 2 H).
實施例Example 1717
(3-(2-(((5-氮雜螺[2.4]庚烷-1-基)甲基)胺基)-5-(三氟甲基)嘧啶-4-基)-6-氟-1H-吲哚-7-基)二甲基氧化膦 (化合物17)
第一步： 1-(((4-(7-溴-6-氟-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)甲基)-5-氮雜螺[2.4]庚烷-5-羧酸叔丁基酯
17A 
將7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-6-氟-1H-吲哚 7C(150 mg, 0.38mmol)溶於無水四氫呋喃 (5 mL)中，加入1-(氨甲基)-5-氮雜螺[2.4]庚烷-5-羧酸叔丁酯 ( 中間體 6)(172 mg, 0.76mmol)、N,N-二異丙基乙胺 (245 mg, 1.9 mmol), N2置換3次，升溫至60℃，反應4個小時。降至室溫，減壓濃縮，殘留物用製備板分離提純(石油醚/乙酸乙酯 (v/v) = 3:1) 得到類白色色固體狀的化合物1-(((4-(7-溴-6-氟-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)甲基)-5-氮雜螺[2.4]庚烷-5-羧酸叔丁基酯 17A(120 mg，產率54%)。 7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-6-fluoro-1H-indole 7C (150 mg, 0.38 mmol) was dissolved in dry tetrahydrofuran (5 mL) ), add 1-(aminomethyl)-5-azaspiro[2.4]heptane-5-carboxylate tert-butyl ester ( intermediate 6) (172 mg, 0.76 mmol), N,N-diisopropyl Ethylamine (245 mg, 1.9 mmol), replaced with N2 three times, heated to 60 °C, and reacted for 4 hours. It was cooled to room temperature, concentrated under reduced pressure, and the residue was separated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v) = 3:1) to obtain compound 1-(((4-(7 as an off-white solid. -Bromo-6-fluoro-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)-5-azaspiro[2.4]heptane-5 - tert-butyl carboxylate 17A (120 mg, 54% yield).
MS m/z (ESI)：584.4 [M+1]MS m/z (ESI): 584.4 [M+1]
第二步：1-(((4-(7-(二甲基磷醯基)-6-氟-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)甲基)-5-氮雜螺[2.4]庚烷-5-羧酸叔丁基酯
17B 
將1-((4-(7-溴-6-氟-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)甲基)-5-氮雜螺[2.4]庚烷-5-羧酸叔丁基酯 17A(102 mg, 0.174 mmol)、1,1'-雙二苯基膦二茂鐵二氯化鈀 (127 mg, 0.174 mmol)、4,5-雙(二苯基膦)-9,9-二甲基氧雜蒽 (100 mg, 0.174 mmol)、磷酸三鉀 (184 mg, 0.87 mmol)和二甲基氧化膦 (68 mg, 0.87 mmol) 溶於乾燥N,N-二甲基甲醯胺(3 mL) 中，升至150℃反應1個小時。將反應液冷卻至室溫，加入水 (10 mL)和乙酸乙酯(15 ml)，分液，水相用乙酸乙酯 (10 mL × 2) 萃取。將合併的有機相用飽和食鹽水 (20 mL × 2) 洗滌，無水硫酸鈉乾燥，過濾，濃縮。殘留物用製備板分離提純 (石油醚/乙酸乙酯 (v/v) = 1：1，) 得到黃色固體狀的化合物1-(((4-(7-(二甲基磷醯基)-6-氟-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)甲基)-5-氮雜螺[2.4]庚烷-5-羧酸叔丁基酯 17B(20 mg，產率20%)。 1-((4-(7-Bromo-6-fluoro-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)-5-nitrogen Heterospiro[2.4]heptane-5-carboxylate tert-butyl ester 17A (102 mg, 0.174 mmol), 1,1'-bisdiphenylphosphinoferrocene palladium dichloride (127 mg, 0.174 mmol), 4,5-Bis(diphenylphosphine)-9,9-dimethylxanthene (100 mg, 0.174 mmol), tripotassium phosphate (184 mg, 0.87 mmol) and dimethylphosphine oxide (68 mg, 0.87 mmol) was dissolved in dry N,N-dimethylformamide (3 mL), heated to 150 °C and reacted for 1 hour. The reaction solution was cooled to room temperature, water (10 mL) and ethyl acetate (15 ml) were added, the layers were separated, and the aqueous phase was extracted with ethyl acetate (10 mL×2). The combined organic phases were washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v) = 1:1,) to give compound 1-(((4-(7-(dimethylphosphoryl)- 6-Fluoro-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-Butyl ester 17B (20 mg, 20% yield).
MS m/z (ESI)：582.4 [M+1]MS m/z (ESI): 582.4 [M+1]
第三步：(3-(2-(((5-氮雜螺[2.4]庚烷-1-基)甲基)胺基)-5-(三氟甲基)嘧啶-4-基)-6-氟-1H-吲哚-7-基)二甲基氧化膦
( 化合物 17) 
將1-(((4-(7-(二甲基磷醯基)-6-氟-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)甲基)-5-氮雜螺[2.4]庚烷-5-羧酸叔丁基酯 17B(20 mg, 0.03 mmol)溶於二氯甲烷(2ml)和三氟乙酸(1ml)中，於室溫攪拌反應一個小時。將反應混合物減壓濃縮，得到粗品棕色油狀物。向其中加入乙酸乙酯(10ml)和碳酸鈉飽和溶液調至鹼性，分層，水相用乙酸乙酯(10ml)萃取。將合併的有機相用飽和食鹽水 (10 mL × 2) 洗滌，無水硫酸鈉乾燥，過濾，濃縮。殘留物用製備板分離提純 (二氯甲烷/甲醇 (v/v) = 8：1，)得到白色固體狀的化合物(3-(2-(((5-氮雜螺[2.4]庚烷-1-基)甲基)胺基)-5-(三氟甲基)嘧啶-4-基)-6-氟-1H-吲哚-7-基)二甲基氧化膦 ( 化合物 17)(11 mg，產率67%)。 1-(((4-(7-(Dimethylphosphoronyl)-6-fluoro-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino )methyl)-5-azaspiro[2.4]heptane-5-carboxylate tert-butyl ester 17B (20 mg, 0.03 mmol) was dissolved in dichloromethane (2 ml) and trifluoroacetic acid (1 ml) in The reaction was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure to give a crude brown oil. Ethyl acetate (10 ml) and saturated sodium carbonate solution were added thereto to make basic, the layers were separated, and the aqueous phase was extracted with ethyl acetate (10 ml). The combined organic phases were washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified with a preparative plate (dichloromethane/methanol (v/v) = 8:1,) to give the compound (3-(2-(((5-azaspiro[2.4]heptane-) as a white solid. 1-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-6-fluoro-1H-indol-7-yl)dimethylphosphine oxide ( Compound 17) (11 mg, 67% yield).
MS m/z (ESI)：482.1 [M+1]MS m/z (ESI): 482.1 [M+1]
1H NMR (400 MHz, CD 3OD) δ 8.59 (d, 2 H), 7.95 (s, 1 H), 7.11-7.05 (m, 1 H), 3.60 (m, 1 H), 3.51-3.35 (m, 4 H), 3.27-3.11 (m, 1 H), 2.09 – 2.04 (m, 1 H), 1.97 (s, 3 H), 1.93 (m, 4 H), 1.58-1.49 (m, 1 H), 1.01-0.97 (m, 1 H), 0.73-0.70 (m, 1 H). 1H NMR (400 MHz, CD 3 OD) δ 8.59 (d, 2 H), 7.95 (s, 1 H), 7.11-7.05 (m, 1 H), 3.60 (m, 1 H), 3.51-3.35 (m , 4 H), 3.27-3.11 (m, 1 H), 2.09 – 2.04 (m, 1 H), 1.97 (s, 3 H), 1.93 (m, 4 H), 1.58-1.49 (m, 1 H) , 1.01-0.97 (m, 1 H), 0.73-0.70 (m, 1 H).
實施例Example 1818
3-(2-(((5-氮雜螺[2.4]庚烷-1-基)甲基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷醯基)-1H-吲哚-6-甲腈 (化合物18)
第一步：1-(((4-(7-溴-6-氰基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)甲基)-5-氮雜螺[2.4]庚烷-5-羧酸叔丁基酯
18A 
將7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲腈(230 mg, 0.575mmol) 溶於無水四氫呋喃 (2 mL) 中，加入1-(氨甲基)-5-氮雜螺[2.4]庚烷-5-羧酸叔丁酯(中間體6) (260 mg, 1.15mmol)和三乙胺 (121mg, 1.19 mmol), N2置換3次，升溫至80℃，反應1.5個小時。降至室溫，減壓濃縮，殘留物用製備板分離提純(石油醚/乙酸乙酯 (v/v) = 1：1) 得到類白色固體狀的化合物1-(((4-(7-溴-6-氰基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)甲基)-5-氮雜螺[2.4]庚烷-5-羧酸叔丁基酯 18A(130 mg，產率37%)。 7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile (230 mg, 0.575 mmol) was dissolved in dry tetrahydrofuran (2 mL) ), was added tert-butyl 1-(aminomethyl)-5-azaspiro[2.4]heptane-5-carboxylate (Intermediate 6) (260 mg, 1.15 mmol) and triethylamine (121 mg, 1.19 mmol), replaced by N 3 times, heated to 80°C, and reacted for 1.5 hours. It was cooled to room temperature, concentrated under reduced pressure, and the residue was separated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v) = 1:1) to obtain compound 1-((((4-(7- bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)-5-azaspiro[2.4]heptane-5 - tert-butyl carboxylate 18A (130 mg, 37% yield).
MS m/z (ESI)：591.4 [M+1]MS m/z (ESI): 591.4 [M+1]
第二步：1-(((4-(6-氰基-7-(二甲基磷醯基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)甲基)-5-氮雜螺[2.4]庚烷-5-羧酸叔丁基酯
18B 
將1-(((4-(7-溴-6-氰基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)甲基)-5-氮雜螺[2.4]庚烷-5-羧酸叔丁基酯 18A(123 mg, 0.21mmol)、1,1'-雙二苯基膦二茂鐵二氯化鈀 (149.7 mg, 0.208 mmol)、4,5-雙(二苯基膦)-9,9-二甲基氧雜蒽 (120.5 mg, 0.208 mmol)、磷酸三鉀 (98 mg, 1.04mmol)和二甲基氧化膦 (81 mg, 1.04 mmol) 溶於乾燥N,N-二甲基甲醯胺(2 mL)中，升至150℃反應1個小時。將反應液冷卻至室溫，加入水 (10 mL)和乙酸乙酯(15 ml)，分液，水相用乙酸乙酯 (10 mL × 2) 萃取。將合併的有機相用飽和食鹽水 (20 mL × 2) 洗滌，無水硫酸鈉乾燥，過濾，濃縮。將所得殘留物用製備板分離提純 (石油醚/乙酸乙酯 (v/v) = 1：1，) 得到黃色固體狀的化合物1-(((4-(6-氰基-7-(二甲基磷醯基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)甲基)-5-氮雜螺[2.4]庚烷-5-羧酸叔丁基酯 18B(50 mg，產率40%)。 1-(((4-(7-Bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)-5 - Azaspiro[2.4]heptane-5-carboxylate tert-butyl ester 18A (123 mg, 0.21 mmol), 1,1'-bisdiphenylphosphinoferrocene palladium dichloride (149.7 mg, 0.208 mmol) ), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (120.5 mg, 0.208 mmol), tripotassium phosphate (98 mg, 1.04 mmol) and dimethylphosphine oxide (81 mg, 1.04 mmol) was dissolved in dry N,N-dimethylformamide (2 mL), heated to 150 °C and reacted for 1 hour. The reaction solution was cooled to room temperature, water (10 mL) and ethyl acetate (15 ml) were added, the layers were separated, and the aqueous phase was extracted with ethyl acetate (10 mL×2). The combined organic phases were washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was separated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v) = 1:1,) to obtain compound 1-((((4-(6-cyano-7-(di) as a yellow solid. Methylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)-5-azaspiro[2.4]heptane-5 - tert-butyl carboxylate 18B (50 mg, 40% yield).
MS m/z (ESI)：589.4[M+1]MS m/z (ESI): 589.4[M+1]
第三步：3-(2-(((5-氮雜螺[2.4]庚烷-1-基)甲基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷醯基)-1H-吲哚-6-甲腈
( 化合物 18) 
將1-(((4-(6-氰基-7-(二甲基磷醯基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)甲基)-5-氮雜螺[2.4]庚烷-5-羧酸叔丁基酯 18B(50 mg, 0.086 mmol) 溶於二氯甲烷(2ml)和三氟乙酸(1ml)中，室溫攪拌反應一個小時。將反應混合物減壓濃縮，得到粗品棕色油狀物。向其中加入乙酸乙酯(10ml)，然後加入碳酸鈉飽和溶液調至鹼性，分層，水相用乙酸乙酯(10ml)萃取。將合併的有機相用飽和食鹽水 (10 mL × 2) 洗滌，無水硫酸鈉乾燥，過濾，濃縮。所得殘留物用製備板分離提純 (二氯甲烷/甲醇 (v/v) = 10：1，)得到白色固體狀的化合物3-(2-(((5-氮雜螺[2.4]庚烷-1-基)甲基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷醯基)-1H-吲哚-6-甲腈 ( 化合物 18)(10 mg，產率24%)。 1-(((4-(6-cyano-7-(dimethylphosphoronyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amine (yl)methyl)-5-azaspiro[2.4]heptane-5-carboxylate tert-butyl ester 18B (50 mg, 0.086 mmol) was dissolved in dichloromethane (2 ml) and trifluoroacetic acid (1 ml), The reaction was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure to give a crude brown oil. Ethyl acetate (10 ml) was added thereto, then a saturated solution of sodium carbonate was added to make it basic, the layers were separated, and the aqueous phase was extracted with ethyl acetate (10 ml). The combined organic phases were washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was separated and purified with a preparative plate (dichloromethane/methanol (v/v) = 10:1,) to give compound 3-(2-(((5-azaspiro[2.4]heptane- 1-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carbonitrile ( Compound 18) (10 mg, 24% yield).
MS m/z (ESI)：489.2 [M+1]MS m/z (ESI): 489.2 [M+1]
1H NMR (400 MHz, CD 3OD) δ 8.59 (d, 2 H), 7.95 (s, 1 H), 7.11-7.05 (m, 1 H), 3.60 (m, 1 H), 3.51-3.35 (m, 4 H), 3.27-3.11 (m, 1 H), 2.09 – 2.04 (m, 1 H), 1.97 (s, 3 H), 1.93 (m, 4 H), 1.58-1.49 (m, 1 H), 1.01-0.97 (m, 1 H), 0.73-0.70 (m, 1 H). 1H NMR (400 MHz, CD 3 OD) δ 8.59 (d, 2 H), 7.95 (s, 1 H), 7.11-7.05 (m, 1 H), 3.60 (m, 1 H), 3.51-3.35 (m , 4 H), 3.27-3.11 (m, 1 H), 2.09 – 2.04 (m, 1 H), 1.97 (s, 3 H), 1.93 (m, 4 H), 1.58-1.49 (m, 1 H) , 1.01-0.97 (m, 1 H), 0.73-0.70 (m, 1 H).
實施例Example 1919
(3-(2-((2-氮雜螺[3.3]庚烷-6-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)二甲基氧化膦 (化合物19)
將6-((4-(7-(二甲基磷醯基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-氮雜螺[3.3]庚烷-2-羧酸叔丁酯 ( 中間體 7)(50 mg, 0.09 mmol)溶於二氯甲烷(2ml)和三氟乙酸(1ml)中，於室溫攪拌反應一個小時。減壓濃縮，得到粗品棕色油狀物。向其中加入乙酸乙酯(10ml)，然後加入碳酸鈉飽和溶液調至鹼性，分層。水相用乙酸乙酯(10ml)萃取。將合併的有機相用飽和食鹽水 (10 mL × 2) 洗滌，無水硫酸鈉乾燥，過濾，濃縮。殘留物用製備板分離提純 (二氯甲烷/甲醇 (v/v) = 8：1，)得到白色固體狀的化合物(3-(2-((2-氮雜螺[3.3]庚烷-6-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)二甲基氧化膦 ( 化合物 19)(16 mg，產率39%)。 6-((4-(7-(Dimethylphosphoronyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-nitrogen Heteraspiro[3.3]heptane-2-carboxylate tert-butyl ester ( Intermediate 7) (50 mg, 0.09 mmol) was dissolved in dichloromethane (2 ml) and trifluoroacetic acid (1 ml), and the reaction was stirred at room temperature for a Hour. Concentration under reduced pressure gave crude brown oil. Ethyl acetate (10 ml) was added thereto, then a saturated solution of sodium carbonate was added to make it basic, and the layers were separated. The aqueous phase was extracted with ethyl acetate (10 ml). The combined organic phases were washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified with a preparative plate (dichloromethane/methanol (v/v) = 8:1,) to give compound (3-(2-((2-azaspiro[3.3]heptane-6) as a white solid. -yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-lH-indol-7-yl)dimethylphosphine oxide ( compound 19) (16 mg, 39% yield).
MS m/z (ESI)：450 [M+1]MS m/z (ESI): 450 [M+1]
1H NMR (400 MHz, CD 3OD) δ 8.53 (s, 2 H), 7.94 (s, 1 H), 7.52-7.47 (m, 1 H), 7.33 (m, 1 H), 4.43 (m, 1 H), 4.15-4.05 (m, 4 H), 2.81-2.76 (m, 2 H), 2.38-2.33 (m, 2 H), 1.93 (s, 3 H), 1.89 (s, 3 H). 1 H NMR (400 MHz, CD 3 OD) δ 8.53 (s, 2 H), 7.94 (s, 1 H), 7.52-7.47 (m, 1 H), 7.33 (m, 1 H), 4.43 (m, 1 H), 4.15-4.05 (m, 4 H), 2.81-2.76 (m, 2 H), 2.38-2.33 (m, 2 H), 1.93 (s, 3 H), 1.89 (s, 3 H).
實施例Example 2020
(3-(2-((2-氮雜螺[3.3]庚烷-6-基)胺基)-5-(三氟甲基)嘧啶-4-基)-6-氟-1H-吲哚-7-基)二甲基氧化膦 (化合物20)
第一步：6-((4-(7-溴-6-氟-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-氮雜螺[3.3]庚烷-2-羧酸叔丁基酯 20A
將7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-6-氟-1H-吲哚 7C(300 mg, 0.76 mmol)溶於無水四氫呋喃 (5 mL) 中，加入6-胺基-2-氮雜螺[3.3]庚烷-2-羧酸叔丁酯(243 mg, 1.15mmol)和N,N-二異丙基乙胺 (490 mg, 3.8 mmol), N 2置換3次，升溫至60℃，反應4個小時。降至室溫，減壓濃縮，殘留物用製備板分離提純(石油醚/乙酸乙酯 (v/v) = 3:1) 得到類白色固體狀的化合物 20A(150 mg，產率35%)。 7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-6-fluoro-1H-indole 7C (300 mg, 0.76 mmol) was dissolved in dry tetrahydrofuran (5 mL) ), add 6-amino-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester (243 mg, 1.15 mmol) and N,N-diisopropylethylamine (490 mg, 3.8 mmol), replaced by N 3 times, heated to 60 °C, and reacted for 4 hours. It was cooled to room temperature, concentrated under reduced pressure, and the residue was separated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v) = 3:1) to obtain compound 20A (150 mg, yield 35%) as an off-white solid. .
MS m/z (ESI)：570.4 [M+1]MS m/z (ESI): 570.4 [M+1]
第二步：6-((4-(7-(二甲基磷醯基)-6-氟-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-氮雜螺[3.3]庚烷-2-羧酸叔丁酯
20B 
將6-((4-(7-溴-6-氟-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-氮雜螺[3.3]庚烷-2-羧酸叔丁基酯 20A(150 mg, 0.263 mmol)、1,1'-雙二苯基膦二茂鐵二氯化鈀 (192 mg, 0.263 mmol)、4,5-雙(二苯基膦)-9,9-二甲基氧雜蒽 (152 mg, 0.263 mmol)、磷酸三鉀 (167 mg, 0.79 mmol)和二甲基氧化膦 (102 mg, 1.315 mmol) 溶於乾燥N,N-二甲基甲醯胺(5 mL) 中，升至150℃反應1個小時。將反應液冷卻至室溫，加入水 (10 mL)和乙酸乙酯(15 ml)，分液，水相用乙酸乙酯 (10 mL × 2) 萃取。合併的有機相用飽和食鹽水 (20 mL × 2) 洗滌，無水硫酸鈉乾燥，過濾，濃縮。殘留物用製備板分離提純 (石油醚/乙酸乙酯 (v/v) = 1：1，) 得到黃色固體狀的化合物6-((4-(7-(二甲基磷醯基)-6-氟-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-氮雜螺[3.3]庚烷-2-羧酸叔丁酯 20B(100 mg，產率66%)。 6-((4-(7-Bromo-6-fluoro-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[ 3.3] Heptane-2-carboxylate tert-butyl ester 20A (150 mg, 0.263 mmol), 1,1'-bisdiphenylphosphinoferrocene palladium dichloride (192 mg, 0.263 mmol), 4,5 -Bis(diphenylphosphine)-9,9-dimethylxanthene (152 mg, 0.263 mmol), tripotassium phosphate (167 mg, 0.79 mmol) and dimethylphosphine oxide (102 mg, 1.315 mmol) Dissolve in dry N,N-dimethylformamide (5 mL), raise to 150°C and react for 1 hour. The reaction solution was cooled to room temperature, water (10 mL) and ethyl acetate (15 ml) were added, the layers were separated, and the aqueous phase was extracted with ethyl acetate (10 mL×2). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v) = 1:1,) to obtain compound 6-((4-(7-(dimethylphosphoryl)-6 as a yellow solid -Fluoro-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester 20B (100 mg, 66% yield).
MS m/z (ESI)：567.5 [M+1]MS m/z (ESI): 567.5 [M+1]
第三步：(3-(2-((2-氮雜螺[3.3]庚烷-6-基)胺基)-5-(三氟甲基)嘧啶-4-基)-6-氟-1H-吲哚-7-基)二甲基氧化膦
( 化合物 20) 
將6-((4-(7-(二甲基磷醯基)-6-氟-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-氮雜螺[3.3]庚烷-2-羧酸叔丁酯 20B(100 mg, 0.176 mmol)溶於二氯甲烷(2ml)和三氟乙酸(1ml)中，於室溫攪拌反應一個小時。減壓濃縮，得到粗品棕色油狀物。向其中加入乙酸乙酯(10ml)，然後加入碳酸鈉飽和溶液調至鹼性，分層。水相用乙酸乙酯(10ml)萃取。合併的有機相用飽和食鹽水 (10 mL × 2) 洗滌，無水硫酸鈉乾燥，過濾，濃縮。殘留物用製備板分離提純 (二氯甲烷/甲醇 (v/v) = 10：1，)得到白色固體狀的化合物(3-(2-((2-氮雜螺[3.3]庚烷-6-基)胺基)-5-(三氟甲基)嘧啶-4-基)-6-氟-1H-吲哚-7-基)二甲基氧化膦 ( 化合物 20)(27 mg，產率33%)。 6-((4-(7-(Dimethylphosphoronyl)-6-fluoro-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino) -2-Azaspiro[3.3]heptane-2-carboxylate tert-butyl ester 20B (100 mg, 0.176 mmol) was dissolved in dichloromethane (2 ml) and trifluoroacetic acid (1 ml), and the reaction was stirred at room temperature for one Hour. Concentration under reduced pressure gave crude brown oil. Ethyl acetate (10 ml) was added thereto, then a saturated solution of sodium carbonate was added to make it basic, and the layers were separated. The aqueous phase was extracted with ethyl acetate (10 ml). The combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified with a preparative plate (dichloromethane/methanol (v/v) = 10:1,) to give compound (3-(2-((2-azaspiro[3.3]heptane-6) as a white solid. -yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-6-fluoro-1H-indol-7-yl)dimethylphosphine oxide ( compound 20) (27 mg, yield 33%).
MS m/z (ESI)：468.1 [M+1]MS m/z (ESI): 468.1 [M+1]
1H NMR (400 MHz, CD 3OD) δ 8.67-8.51 (m, 2 H), 7.94 (s, 1 H), 7.07 (s, 1 H), 4.39 (m, 1 H), 3.88 – 3.77 (m, 4 H), 2.71 (m, 2 H), 2.25 (m, 2 H), 1.97 (s, 3 H), 1.93 (s, 3 H). 1H NMR (400 MHz, CD 3 OD) δ 8.67-8.51 (m, 2 H), 7.94 (s, 1 H), 7.07 (s, 1 H), 4.39 (m, 1 H), 3.88 – 3.77 (m , 4 H), 2.71 (m, 2 H), 2.25 (m, 2 H), 1.97 (s, 3 H), 1.93 (s, 3 H).
實施例Example 21twenty one
6-((4-(7-(二甲基磷醯基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-氮雜螺[3.3]庚烷-2-羧酸2-羥基-2-甲基丙基酯 (化合物21)
將化合物(3-(2-((2-氮雜螺[3.3]庚烷-6-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)二甲基氧化膦 ( 化合物 19)(400 mg，0.89 mmol)溶於1,4-二氧六環(5 mL)中，於攪拌下加入4,4-二甲基-1,3-二氧戊環-2-酮(200 mg, 1.78 mmol)和碳酸銫(725 mg, 2.23 mmol)，將混合物在50℃下攪拌16小時。反應結束後濃縮，通過製備型HPLC純化，凍幹得到白色固體化合物6-((4-(7-(二甲基磷醯基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-氮雜螺[3.3]庚烷-2-羧酸2-羥基-2-甲基丙基酯 (化合物21)(53 mg，收率10%)。 Compound (3-(2-((2-azaspiro[3.3]heptan-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-7 -yl)dimethylphosphine oxide ( compound 19) (400 mg, 0.89 mmol) was dissolved in 1,4-dioxane (5 mL), 4,4-dimethyl-1,3 was added with stirring -Dioxolane-2-one (200 mg, 1.78 mmol) and cesium carbonate (725 mg, 2.23 mmol), the mixture was stirred at 50 °C for 16 hours. After the reaction, it was concentrated, purified by preparative HPLC, and lyophilized to obtain a white solid compound 6-((4-(7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoro) Methyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid 2-hydroxy-2-methylpropyl ester (compound 21) (53 mg, yield 10 %).
MS m/z (ESI)：566.6 [M+1]MS m/z (ESI): 566.6 [M+1]
1H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1 H), 8.61 - 8.43 (m, 2 H), 8.20 (t, 1 H), 7.92 (d, 1 H), 7.51-7.48 (m, 1 H), 7.33-7.26 (m, 1 H), 4.51 (s, 1 H), 4.35-4.31 (m, 1 H), 3.99-3.90 (m, 4 H), 3.72 (s, 2 H), 2.58-2.56 (m, 2 H), 2.25 (m, 2 H), 1.83 (s, 3 H), 1.79 (s, 3 H), 1.07 (s, 6 H). 1 H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1 H), 8.61 - 8.43 (m, 2 H), 8.20 (t, 1 H), 7.92 (d, 1 H), 7.51-7.48 ( m, 1 H), 7.33-7.26 (m, 1 H), 4.51 (s, 1 H), 4.35-4.31 (m, 1 H), 3.99-3.90 (m, 4 H), 3.72 (s, 2 H) ), 2.58-2.56 (m, 2 H), 2.25 (m, 2 H), 1.83 (s, 3 H), 1.79 (s, 3 H), 1.07 (s, 6 H).
實施例Example 22twenty two
6-((4-(7-(二甲基磷醯基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-氮雜螺[3.3]庚烷-2-羧酸2-羥乙基酯 (化合物22)
將(3-(2-((2-氮雜螺[3.3]庚烷-6-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)二甲基氧化膦 ( 化合物 19)(100 mg, 0.22 mmol) 溶於甲苯(6 mL) 中，加入碳酸銫(144 mg, 0.44 mmol)和碳酸乙烯酯(18 mg, 0.22 mmol)，加熱至100℃反應2小時。將反應液濃縮旋幹，然後加入二氯甲烷 (15 mL)，過濾。濾液濃縮旋幹得到粗品。粗品經製備型HPLC純化後凍幹得白色固體化合物6-((4-(7-(二甲基磷醯基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-氮雜螺[3.3]庚烷-2-羧酸2-羥乙基酯 ( 化合物 22)(12 mg，收率10%)。 (3-(2-((2-Azaspiro[3.3]heptan-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-7- base) dimethylphosphine oxide ( compound 19) (100 mg, 0.22 mmol) was dissolved in toluene (6 mL), cesium carbonate (144 mg, 0.44 mmol) and ethylene carbonate (18 mg, 0.22 mmol) were added, and heated The reaction was carried out at 100°C for 2 hours. The reaction solution was concentrated and spin-dried, then dichloromethane (15 mL) was added and filtered. The filtrate was concentrated and spin-dried to obtain crude product. The crude product was purified by preparative HPLC and then lyophilized to obtain a white solid compound 6-((4-(7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidine -2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid 2-hydroxyethyl ester ( compound 22) (12 mg, 10% yield).
MS m/z (ESI)：538.3 [M+1]MS m/z (ESI): 538.3 [M+1]
1HNMR (400 MHz, DMSO-D6) δ 11.55 (s, 1 H), 8.58-8.43 (m, 2 H), 8.19 (t, 1 H), 7.91 (d, 1 H), 7.48 (m, 1 H), 7.32-7.26 (m, 1 H), 4.72 (s, 1 H), 4.35-4.33 (m, 1 H), 3.95-3.88 (m, 6 H), 3.52-3.51 (m, 2 H), 2.60-2.58 (m, 2 H), 2.23 (m, 2 H), 1.83 (s, 3 H), 1.79 (s, 3 H). 1 HNMR (400 MHz, DMSO-D6) δ 11.55 (s, 1 H), 8.58-8.43 (m, 2 H), 8.19 (t, 1 H), 7.91 (d, 1 H), 7.48 (m, 1 H), 7.32-7.26 (m, 1 H), 4.72 (s, 1 H), 4.35-4.33 (m, 1 H), 3.95-3.88 (m, 6 H), 3.52-3.51 (m, 2 H) , 2.60-2.58 (m, 2 H), 2.23 (m, 2 H), 1.83 (s, 3 H), 1.79 (s, 3 H).
實施例Example 23twenty three
3-(2-((2-氮雜螺[3.3]庚烷-6-基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷醯基)-1H-吲哚-6-甲腈 (化合物23)
將6-((4-(6-氰基-7-(二甲基磷醯基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-氮雜螺[3.3]庚烷-2-羧酸叔丁基酯 ( 中間體 8)(670 mg, 1.16 mmol) 溶於二氯甲烷溶液(27 mL)中，加入三氟乙酸(3 mL)，室溫反應2小時。濃縮反應液，殘留物加入氨水調節至弱鹼性，然後過反相柱(ACN:H2O=5:95到95:5)純化後得到3-(2-((2-氮雜螺[3.3]庚烷-6-基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷醯基)-1H-吲哚-6-甲腈 ( 化合物 23)(420 mg，產率76%)。 6-((4-(6-cyano-7-(dimethylphosphoronyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino )-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester ( Intermediate 8) (670 mg, 1.16 mmol) was dissolved in dichloromethane solution (27 mL), trifluoroacetic acid ( 3 mL) and reacted at room temperature for 2 hours. The reaction solution was concentrated, the residue was adjusted to weakly alkaline by adding ammonia water, and then purified by reversed-phase column (ACN:H2O=5:95 to 95:5) to obtain 3-(2-((2-azaspiro[3.3] Heptan-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carbonitrile ( Compound 23) (420 mg, 76% yield).
MS m/z (ESI)：475.1 [M+1]MS m/z (ESI): 475.1 [M+1]
1H NMR (400 MHz, DMSO-D6) δ 8.76 (dd, 1 H), 8.61 (m, 1 H), 8.52 (m, 1 H), 8.30 (m, 1 H), 8.19 (d, 1 H), 7.82-7.69 (m, 1 H), 4.33-4.24 (m, 1 H), 4.02 (d, 2 H), 3.91 (d, 2 H), 2.66-2.64 (m, 2 H), 2.33-2.20 (m, 2 H), 2.06 (s, 3 H), 2.02 (s, 3 H). 1 H NMR (400 MHz, DMSO-D6) δ 8.76 (dd, 1 H), 8.61 (m, 1 H), 8.52 (m, 1 H), 8.30 (m, 1 H), 8.19 (d, 1 H) ), 7.82-7.69 (m, 1 H), 4.33-4.24 (m, 1 H), 4.02 (d, 2 H), 3.91 (d, 2 H), 2.66-2.64 (m, 2 H), 2.33- 2.20 (m, 2 H), 2.06 (s, 3 H), 2.02 (s, 3 H).
實施例Example 24twenty four
6-((4-(6-氰基-7-(二甲基磷醯基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-氮雜螺[3.3]庚烷-2-羧酸2-羥乙基酯 (化合物24)
將3-(2-((2-氮雜螺[3.3]庚烷-6-基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷醯基)-1H-吲哚-6-甲腈 ( 化合物 23)(200 mg, 0.37 mmol) 溶於甲苯(15 mL) 中，加入碳酸銫(410 mg, 1.25 mmol)和碳酸乙烯酯(73 mg, 0.83 mmol)，油浴鍋加熱反應，於100℃反應2小時。濃縮反應液，然後加入二氯甲烷(15 mL)，然後過濾，得到濾液，濃縮。所得殘餘物通過製備型HPLC純化，凍幹得白色固體化合物6-((4-(6-氰基-7-(二甲基磷醯基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-氮雜螺[3.3]庚烷-2-羧酸2-羥乙基酯(化合物24) (40 mg，產率17%)。 3-(2-((2-azaspiro[3.3]heptan-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl) yl)-1H-indole-6-carbonitrile ( compound 23) (200 mg, 0.37 mmol) was dissolved in toluene (15 mL), cesium carbonate (410 mg, 1.25 mmol) and ethylene carbonate (73 mg, 1.25 mmol) were added. 0.83 mmol), heated in an oil bath, and reacted at 100 °C for 2 hours. The reaction solution was concentrated, and then dichloromethane (15 mL) was added, followed by filtration to obtain a filtrate, which was concentrated. The resulting residue was purified by preparative HPLC and lyophilized to give a white solid compound 6-((4-(6-cyano-7-(dimethylphosphoronyl)-1H-indol-3-yl)-5- (Trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate 2-hydroxyethyl ester (Compound 24) (40 mg, 17% yield) .
MS m/z (ESI)：563.2 [M+1]MS m/z (ESI): 563.2 [M+1]
1H NMR (400 MHz, DMSO-D6) δ 12.12 (s, 1 H), 8.72-8.51 (m, 2 H), 8.29 (d, 1 H),8.18 (d, 1 H), 7.75 (dd, 1 H), 4.74 (s, 1 H), 4.35-4.26 (m, 1 H), 3.98-3.88 (m, 6 H), 3.52 (m, 2 H), 2.60-2.55 (m, 2 H), 2.24 (m, 2 H), 2.05 (s, 3 H), 2.02 (s, 3 H). 1 H NMR (400 MHz, DMSO-D6) δ 12.12 (s, 1 H), 8.72-8.51 (m, 2 H), 8.29 (d, 1 H), 8.18 (d, 1 H), 7.75 (dd, 1 H), 4.74 (s, 1 H), 4.35-4.26 (m, 1 H), 3.98-3.88 (m, 6 H), 3.52 (m, 2 H), 2.60-2.55 (m, 2 H), 2.24 (m, 2H), 2.05 (s, 3H), 2.02 (s, 3H).
測試例：Test case:
測試例test case 11 、, CDKCDK 激酶抑制活性的Kinase inhibitory activity 測定Determination
使用Caliper/LabChip EZ Reader (PerkinElmer，Waltham，MA)開發的每種CDK的激酶測定法測定本發明化合物對CDK7、CDK9、CDK12和CDK2活性的抑制作用。這些測定測量磷酸化肽底物的量，該磷酸化肽底物在27℃孵育期後，作為總肽的一部分產生，其含有以下成分：測試化合物(可變濃度從10μM降至0 .508nM，在一系列3倍的系列稀釋液中)、活性CDK激酶蛋白(具有下文列出的每種CDK的指示的細胞週期蛋白)、ATP(2mM)和底物肽(如下所列)，在下列緩衝液中：2-(N-嗎啉代)乙磺酸鹽(MES緩衝液，20mM)，pH 6.75，0.01%(v/v)吐溫20清潔劑，0.05mg/mL牛血清白蛋白(BSA)。具體地，CDK7抑制測定使用CDK7/細胞週期蛋白H/MAT1複合物(6nM)和“5-FAMCDK7tide”肽底物(2μM，合成的螢光團標記的肽，具有以下序列：5-FAM-YSPTSPSYSPTSPSYSPTSPSKKKK(SEQ ID No.1)，其中“5-FAM”是指5-羧基螢光素)，且在上面列出的緩衝液組合物中含有6mM MgCl 2。此外，CDK9抑制測定使用CDK9/細胞週期蛋白T1複合物(8nM)和“5-FAM-CDK9tide”肽底物(2μM，合成的螢光團標記的肽，具有以下序列：5-FAM-GSRTPMY(SEQ ID No.2)-NH 2，5-FAM如上所定義且NH 2表示C-端醯胺)，且在上面列出的緩衝液組合物中含有10mM MgCl 2。CDK12抑制測定使用CDK12(aa686-1082)/細胞週期蛋白K複合物(50nM)和如上定義的“5-FAM-CDK9tide”(2μM)，且在上面列出的緩衝液組合物中含有2mM MgCl 2。此外，CDK2抑制測定使用CDK2/細胞週期蛋白E1複合物(0.5nM)和如上定義的“5-FAM-CDK7tide”(2μM)，且在上面列出的緩衝液組合物中含有2mM MgCl 2。選擇每種CDK抑制試驗在27℃下的孵育期，使得每次試驗中產生的磷酸化肽產物相對於總肽濃度的比例對於未抑制的激酶約為20%(±5%)(對於CDK7，35分鐘，對於CDK2，35分鐘，對於CDK12，3小時，對於CDK9，15分鐘)。在測試化合物滴定並導致肽產物形成抑制的情況下，這些資料擬合產生最佳擬合IC50值。 The inhibition of CDK7, CDK9, CDK12 and CDK2 activity by compounds of the invention was determined using a kinase assay for each CDK developed by the Caliper/LabChip EZ Reader (PerkinElmer, Waltham, MA). These assays measure the amount of phosphorylated peptide substrate, produced as part of the total peptide after an incubation period at 27°C, containing the following components: test compound (variable concentrations from 10 μM to 0.508 nM, in a series of 3-fold serial dilutions), active CDK kinase protein (cyclins with the indicated cyclins for each CDK listed below), ATP (2 mM) and substrate peptides (listed below) in the following buffers In solution: 2-(N-morpholino)ethanesulfonate (MES buffer, 20 mM), pH 6.75, 0.01% (v/v) Tween 20 detergent, 0.05 mg/mL bovine serum albumin (BSA) ). Specifically, the CDK7 inhibition assay used the CDK7/Cyclin H/MAT1 complex (6 nM) and the "5-FAMCDK7tide" peptide substrate (2 μM, a synthetic fluorophore-labeled peptide with the following sequence: 5-FAM-YSPTSPSYSPTSPSYSPTSPSKKKK (SEQ ID No. 1), wherein "5-FAM" refers to 5-carboxyluciferin), and contained 6 mM MgCl2 in the buffer composition listed above. In addition, CDK9 inhibition assays used the CDK9/cyclin T1 complex (8 nM) and the "5-FAM-CDK9tide" peptide substrate (2 μM, a synthetic fluorophore-labeled peptide with the following sequence: 5-FAM-GSRTPMY ( SEQ ID No. 2) - NH2 , 5-FAM is as defined above and NH2 represents a C-terminal amide) with 10 mM MgCl2 in the buffer compositions listed above. The CDK12 inhibition assay used CDK12 (aa686-1082)/cyclin K complex (50 nM) and "5-FAM-CDK9tide" (2 μM) as defined above with 2 mM MgCl in the buffer composition listed above . In addition, CDK2 inhibition assays used CDK2/Cyclin El complex (0.5 nM) and "5-FAM-CDK7tide" (2 μM) as defined above with 2 mM MgCl2 in the buffer composition listed above. The incubation period at 27°C for each CDK inhibition assay was chosen such that the ratio of phosphorylated peptide product produced in each assay relative to the total peptide concentration was approximately 20% (±5%) for uninhibited kinase (for CDK7, 35 minutes, 35 minutes for CDK2, 3 hours for CDK12, 15 minutes for CDK9). Fitting of these data resulted in best fit IC50 values where test compounds were titrated and resulted in inhibition of peptide product formation.
這些測定的結果如下表1所示，其中“A”代表計算的IC 50大於1nM小於或等於10nM；“B”表示計算的IC 50大於10nM小於或等於100nM；“C”表示計算的IC 50大於100nM小於或等於1000nM；“D”表示計算的IC 50大於1000nM；“NT”表示未在指定的測定中測試指定的化合物。 The results of these assays are shown in Table 1 below, where "A" represents a calculated IC50 greater than 1 nM and less than or equal to 10 nM; "B" represents a calculated IC50 greater than 10 nM and less than or equal to 100 nM; "C" represents a calculated IC50 greater than 100 nM 100 nM is less than or equal to 1000 nM; "D" indicates that the calculated IC50 is greater than 1000 nM; "NT" indicates that the indicated compound was not tested in the indicated assay.
表1 .本發明的化合物對CDK2、CDK7、CDK9和CDK12的抑制活性。
以上的結果表明本發明的化合物對CDK7具有良好的抑制活性和選擇性。The above results show that the compounds of the present invention have good inhibitory activity and selectivity to CDK7.
以上所述實施例的各技術特徵可以進行任意的組合，為使描述簡潔，未對上述實施例中的各個技術特徵所有可能的組合都進行描述，然而，只要這些技術特徵的組合不存在矛盾，都應當認為是本說明書記載的範圍。The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity, all possible combinations of the technical features in the above-described embodiments are not described. However, as long as there is no contradiction between the combinations of these technical features, All should be regarded as the scope described in this specification.
以上所述實施例僅表達了本發明的幾種實施方式，其描述較為具體和詳細，但並不能因此而理解為對發明專利範圍的限制。應當指出的是，對於本領域的普通技術人員來說，在不脫離本發明構思的前提下，還可以做出若干變形和改進，這些都屬於本發明的保護範圍。因此，本發明專利的保護範圍應以所附申請專利範圍為准。The above-mentioned embodiments only represent several embodiments of the present invention, and the descriptions thereof are more specific and detailed, but should not be construed as a limitation on the scope of the invention patent. It should be pointed out that for those skilled in the art, without departing from the concept of the present invention, several modifications and improvements can be made, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the scope of the appended patent application.
無none
無。none.
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