TW201825490A - Pyrrolo[2,3-c]pyridine derivatives, preparation methods and pharmaceutical uses thereof - Google Patents
Pyrrolo[2,3-c]pyridine derivatives, preparation methods and pharmaceutical uses thereof Download PDFInfo
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Abstract
Description
本發明屬於醫藥領域，涉及吡咯並[2,3-c]吡啶類衍生物、其製備方法及含有該衍生物的醫藥組成物在醫藥研究上的應用，本發明公開了其作為BRD4抑制劑在治療癌症、炎症、慢性肝病、糖尿病、血脂異常等心血管疾病和AIDS等相關疾病的用途。 The invention belongs to the field of medicine, and relates to pyrrolo [2,3-c] pyridine derivatives, a preparation method thereof, and the application of a pharmaceutical composition containing the derivative in medical research. The invention discloses that it is used as a BRD4 inhibitor in Use for treating cardiovascular diseases such as cancer, inflammation, chronic liver disease, diabetes, dyslipidemia and related diseases such as AIDS.
腫瘤是嚴重危害人類生命的重大疾病之一，一半以上發生在發展中國家。我國惡性腫瘤發病率總體呈上升趨勢，發病率以年均3%~5%的速度遞增，預計到2020年，我國將有400萬人發生癌症，300萬人死於癌症，其主要原因是：老齡化、城鎮化、工業化及生活習慣改變。在中國醫院用藥市場，抗腫瘤藥物的銷售規模近幾年來一直穩步增長，2012年達到了664.2億元，同比增長了13.07%，預計到2017年，抗腫瘤藥物的市場規模將達到1055.7億元，同比增長7.57%。 Cancer is one of the major diseases that seriously endanger human life, and more than half of them occur in developing countries. The overall incidence of malignant tumors in China is on the rise. The incidence is increasing at an average annual rate of 3% to 5%. It is estimated that by 2020, 4 million people will develop cancer in China and 3 million will die from cancer. The main reasons are: Aging, urbanization, industrialization and changes in living habits. In the Chinese hospital drug market, the sales scale of anti-tumor drugs has been steadily increasing in recent years, reaching 66.42 billion yuan in 2012, an increase of 13.07% year-on-year. It is expected that by 2017, the market size of anti-tumor drugs will reach 105.57 billion yuan. An increase of 7.57% year-on-year.
由於惡性腫瘤的無限制生長與浸潤、轉移，現今臨床採用的三大常規治療方法(手術、放療和化療)無法完全切除或徹底殺滅腫瘤細胞，因此常出現腫瘤轉移或復發。腫瘤生物治療是應用現代生物技術及其相關產品進行腫瘤防治的新療法，因其安全、有效、不良反應低等特點，成為繼手術、放療、化療之後腫瘤治療的第四種模式，其藉由調動宿主的天然防禦機制或給予天然產生的靶向性很強的物質來獲得抗腫瘤的效應。 Due to the unlimited growth, invasion, and metastasis of malignant tumors, the three conventional treatment methods (surgery, radiation therapy, and chemotherapy) used in clinical practice today cannot completely remove or completely kill tumor cells, so tumor metastasis or recurrence often occurs. Tumor biotherapy is a new therapy using modern biotechnology and related products to prevent and treat tumors. Because of its safety, effectiveness, and low adverse reactions, it has become the fourth model of tumor treatment after surgery, radiotherapy, and chemotherapy. The natural defense mechanism of the host is mobilized or a naturally occurring highly targeted substance is given to obtain an antitumor effect.
溴結構蛋白4(BRD4)是溴結構域和超末端結構(bromodomain and extraterminal domain，BET)家族成員，BRD4藉由招募不同的轉錄調節因子，如Mediator、正性轉錄延伸因子b(positive transcription elongation factor b，P-TEFb)來調節靶基因的表達。作為一種在哺乳動物中廣泛表達的染色質“適配器，reader”，可以在整個有絲***過程中識別乙醯化的蛋白結合到染色體上，募集不同的染色質修飾蛋白，廣泛調控基因的表達，從而在調控細胞週期進程、轉錄、炎症等方面發揮重要作用。最近的研究表明BRD4的表達水準失調或功能紊亂與睾丸核蛋白中線癌(midline carcinoma with rearrangement of the nuclear protein intestis gene，NMC)、黑色素瘤、急性髓系白血病、結腸癌、乳腺癌等的發生有關。BRD4shRNA或BET抑制劑可以誘導上述腫瘤發生細胞週期阻滯、凋亡及細胞分化，顯示出強大的抗腫瘤活性。這些發現表明，BET蛋白有望成為上述腫瘤甚至其他腫瘤新的治療靶點。另外，藉 由工具化合物JQ1等研究發現，BRD4的抑制劑在病毒感染，糖尿病，代謝性疾病，肝臟疾病和老年癡呆症等多種疾病均可能有較廣泛的運用。公開的選擇性BRD4抑制劑的專利申請包括WO2013097052、WO2013158952、WO2014165127、WO2014206345、WO2016077378和WO2015081189等。 Bromine structural protein 4 (BRD4) is a member of the bromodomain and extraterminal domain (BET) family. BRD4 recruits different transcription regulators, such as Mediator, positive transcription elongation factor b b, P-TEFb) to regulate target gene expression. As a chromatin "adapter, reader" widely expressed in mammals, it can recognize acetylated proteins to bind to the chromosome throughout the mitosis process, recruit different chromatin-modified proteins, and widely regulate gene expression. It plays an important role in regulating cell cycle progress, transcription, and inflammation. Recent studies have shown that BRD4 expression dysregulation or dysfunction and the occurrence of midline carcinoma with rearrangement of the nuclear protein intestis gene (NMC), melanoma, acute myeloid leukemia, colon cancer, breast cancer, etc. related. BRD4shRNA or BET inhibitors can induce cell cycle arrest, apoptosis and cell differentiation of the above tumors, and show strong antitumor activity. These findings indicate that BET protein is expected to become a new therapeutic target for these tumors and even other tumors. In addition, studies such as the tool compound JQ1 have found that inhibitors of BRD4 may be widely used in various diseases such as viral infections, diabetes, metabolic diseases, liver diseases, and dementia. Published patent applications for selective BRD4 inhibitors include WO2013097052, WO2013158952, WO2014165127, WO2014206345, WO2016077378, and WO2015081189.
BRD4抑制劑作為藥物在醫藥行業具有良好的應用前景，目前還沒有上市的藥物，為了達到更好的治療效果的目的和滿足市場需求，我們希望能開發出新一代的高效低毒的選擇性BRD4抑制劑。 BRD4 inhibitors have good application prospects as pharmaceuticals in the pharmaceutical industry. There are currently no drugs on the market. In order to achieve better therapeutic effects and meet market demand, we hope to develop a new generation of highly selective and low toxicity BRD4. Inhibitor.
本發明的目的在於提供一種通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中通式(I)所示的化合物結構如下：
在本發明的一個較佳實施例方案中，該通式(I)所示的化合物，其為通式(II)所示的化合物：
在本發明的一個較佳實施例方案中，該通式(I)所示的化合物，其為通式(III)所示的化合物：
在本發明的一個較佳實施例方案中，該通式(I)所示的化合物，其為通式(IIA)和(IIB)所示的化合物：
在本發明的一個較佳實施例方案中，該通式(IV)和(IVA)所示的化合物，其為通式(V)、(VA)和(VB)所示的化合物：
在本發明的一個較佳實施例方案中，該通式(I)所示的化合物，其為通式(VI)所示的化合物：
其中：L選自O和NRv；較佳O或NH；Ra選自氫原子、鹵素、羥基、酮基、C1-8烷基、C1-8鹵烷基、C1-8烷氧基和C1-8鹵烷氧基；較佳為氫原子、鹵素、酮基、羥基、C1-6烷基和C1-6鹵烷基；更佳為氫原子、鹵素、羥基、C1-3烷基或C1-3鹵烷基；或者任意兩個Ra形成一個C3-8環烷基或3-10員的雜環基，其中該C3-8環烷基或3-10員的雜環基視需要進一步被選自C1-8烷基、鹵素、羥基、胺基、硝基、氰基、C1-8烷氧基或C1-8羥烷基中的一個或多個取代基所取代；R2選自C1-8烷基、C3-8環烷基、C1-8鹵烷基、C3-8鹵環烷基、3-10員雜環基或6-10員芳基，其中該C1-8烷基、C3-8環烷基、C1-8鹵烷基、C3-8鹵環烷基、3-10員雜環基 和6-10員芳基視需要進一步被選自C1-8烷基、鹵素、羥基、胺基、硝基、氰基、C1-8烷氧基、C3-8環烷基或C1-8羥烷基中的一個或多個取基所取；較佳為C1-6烷基、C1-6鹵烷基、C3-8環烷基、鹵C3-8環烷基或氰基取代的C3-8環烷基；更佳為C1-3烷基、C1-3鹵烷基、C3-6環烷基、鹵C3-6環烷基或氰基取代的C3-6環烷基；最佳為甲基、乙基、異丙基、環丙基、鹵環丙基、氰基取代的環丙基及其氘代物；R3選自氫原子、氘原子、C1-8烷基、C1-8鹵烷基、氰基、C3-8環烷基、鹵C3-8環烷基、氰基取的C3-8環烷基、-S(O)mR8和-C(O)R8；較佳為C1-6烷基、C1-6鹵烷基、C3-6環烷基、鹵C3-6環烷基或氰基取的C3-6環烷基；更佳為C1-3烷基、C1-3鹵烷基、C3-6環烷基、鹵C3-6環烷基或氰基取代的C3-6環烷基；最佳為甲基、乙基、異丙基、環丙基、鹵環丙基或氰基取代的環丙基；R4選自氫原子、C1-8烷基、C3-8環烷基、-C(O)OR8、-C(O)NR9R10或C1-8鹵烷基；其中該C1-8烷基、C3-8環烷基和C1-8鹵烷基視需要進一步被選自C1-8烷基、鹵素、羥基、胺基、硝基、氰基、C1-8烷氧基或C1-8羥烷基中的一個或多個取代基所取代，較佳為C1-6烷基或C1-6鹵烷基；更佳為C1-3烷基或C1-3鹵烷基；z為0或1的整數；且p為0、1、2、3、4或5的整數。 Wherein: L is selected from O and NR v; preferably O or NH; R a is selected from hydrogen, halogen, hydroxyl, keto, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy Oxygen and C 1-8 haloalkoxy; preferably a hydrogen atom, halogen, keto, hydroxy, C 1-6 alkyl and C 1-6 haloalkyl; more preferably hydrogen atom, halogen, hydroxy, C 1-3 alkyl or C 1-3 haloalkyl; or any two R a forming a C 3-8 cycloalkyl or 3-10 membered heterocyclyl, wherein the C 3-8 cycloalkyl or The 3-10 member heterocyclic group is further selected from C 1-8 alkyl, halogen, hydroxy, amine, nitro, cyano, C 1-8 alkoxy, or C 1-8 hydroxyalkyl, as necessary Substituted by one or more substituents; R 2 is selected from C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, C 3-8 halocycloalkyl, 3-10 members Heterocyclyl or 6-10 member aryl, wherein the C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, C 3-8 halocycloalkyl, 3-10 member hetero The cyclic group and the 6-10 membered aryl group are further selected from C 1-8 alkyl, halogen, hydroxyl, amine, nitro, cyano, C 1-8 alkoxy, and C 3-8 cycloalkyl, as necessary. Or one or more of C 1-8 hydroxyalkyl groups; preferably C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, halo C 3-8 cycloalkyl or cyano-substituted C 3-8 cycloalkyl; more preferably C 1-3 alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, halo C 3-6 cycloalkyl or cyano substituted C 3-6 cycloalkyl; most preferred are methyl, ethyl, isopropyl, cyclopropyl, Halocyclopropyl, cyano-substituted cyclopropyl, and deuterates thereof; R 3 is selected from hydrogen atom, deuterium atom, C 1-8 alkyl, C 1-8 haloalkyl, cyano, C 3-8 ring Alkyl, halo C 3-8 cycloalkyl, cyano C 3-8 cycloalkyl, -S (O) m R 8 and -C (O) R 8 ; preferably C 1-6 alkyl , C 1-6 haloalkyl, C 3-6 cycloalkyl, halo C 3-6 cycloalkyl or cyano C 3-6 cycloalkyl; more preferably C 1-3 alkyl, C 1 -3 haloalkyl, C 3-6 cycloalkyl, halo C 3-6 cycloalkyl or cyano substituted C 3-6 cycloalkyl; most preferred are methyl, ethyl, isopropyl, cyclopropyl Group, halocyclopropyl or cyano-substituted cyclopropyl; R 4 is selected from hydrogen atom, C 1-8 alkyl, C 3-8 cycloalkyl, -C (O) OR 8 , -C (O) NR 9 R 10 or C 1-8 haloalkyl; wherein the C 1-8 alkyl, C 3-8 cycloalkyl and C 1-8 haloalkyl are further selected from C 1-8 alkyl, Halogen, hydroxyl, amine, nitrate , One or more cyano, alkoxy, C 1-8 hydroxyalkyl or C 1-8 alkyl substituents, preferably C 1-6 alkyl or C 1-6 haloalkyl; more preferably Is C 1-3 alkyl or C 1-3 haloalkyl; z is an integer of 0 or 1; and p is an integer of 0, 1, 2, 3, 4 or 5.
在本發明的一個較佳實施例方案中，該通式(I)所示的化合物，其為通式(VII)所示的化合物：
其中：L選自O和NRv；較佳O或NH；Ra選自氫原子、鹵素、羥基、胺基、C1-8烷基、C1-8鹵烷基、C1-8烷氧基或C1-8羥烷基；較佳為氫原子、鹵素、C1-6烷基或C1-6羥烷基；更佳為氫原子、鹵素、或C1-3羥烷基；R2選自C1-8烷基、C3-8環烷基、C1-8鹵烷基、C3-8鹵環烷基、3-10員雜環基和6-10員芳基，其中該C1-8烷基、C3-8環烷基、C1-8鹵烷基、C3-8鹵環烷基、3-10員雜環基和6-10員芳基視需要進一步被選自C1-8烷基、鹵素、羥基、胺基、硝基、氰基、C1-8烷氧基、C3-8環烷基和C1-8羥烷基中的一個或多個取代基所取代；較佳為C1-6烷基、C1-6鹵烷基、C3-8環烷基、鹵C3-8環烷基或氰基取代的C3-8環烷基；更為C1-3烷基、C1-3鹵烷基、C3-6環烷基、鹵C3-6環烷基或氰基取代的C3-6環烷基；最佳為甲基、乙基、異丙基、環丙基、鹵環丙基、氰基取代的環丙基及其氘代物；R3選自氫原子、氘原子、C1-8烷基、C1-8鹵烷基、氰基、C3-8環烷基、鹵C3-8環烷基、氰基取代的C3-8環烷基、-S(O)mR8和-C(O)R8；較佳為C1-6烷基、C1-6鹵烷基、C3-6環烷基、鹵C3-6環烷基或氰基取代的C3-6環烷基；更佳為 C1-3烷基、C1-3鹵烷基、C3-6環烷基、鹵C3-6環烷基或氰基取代的C3-6環烷基；最佳為甲基、乙基、異丙基、環丙基、鹵環丙基或氰基取代的環丙基；R4選自氫原子、C1-8烷基、C3-8環烷基、C1-8鹵烷基、-C(O)OR8和-C(O)NR9R10；其中該C1-8烷基、C3-8環烷基和C1-8鹵烷基視需要進一步被選自C1-8烷基、鹵素、羥基、胺基、硝基、氰基、C1-8烷氧基或C1-8羥烷基中的一個或多個取代基所取代；較佳為C1-6烷基或C1-6鹵烷基；更佳為C1-3烷基或C1-3鹵烷基；z為0或1的整數；且p為0、1、2、3、4或5的整數。 Wherein: L is selected from O and NR v; preferably O or NH; R a is selected from hydrogen, halo, hydroxy, amino, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy Oxygen or C 1-8 hydroxyalkyl; preferably a hydrogen atom, halogen, C 1-6 alkyl or C 1-6 hydroxyalkyl; more preferably hydrogen atom, halogen, or C 1-3 hydroxyalkyl ; R 2 is selected from C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, C 3-8 halocycloalkyl, 3-10 membered heterocyclyl, and 6-10 membered aromatic Group, wherein the C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, C 3-8 halocycloalkyl, 3-10 membered heterocyclyl, and 6-10 membered aryl Optionally further selected from the group consisting of C 1-8 alkyl, halogen, hydroxyl, amine, nitro, cyano, C 1-8 alkoxy, C 3-8 cycloalkyl, and C 1-8 hydroxyalkyl Substituted with one or more substituents; preferably C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, halo C 3-8 cycloalkyl or cyano substituted C 3-8 cycloalkyl; more C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, halo C 3-6 cycloalkyl or cyano substituted C 3-6 ring alkyl group; most preferably methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl halides, cyano-substituted cyclopropyl and deuterated thereof; R 3 is selected from hydrogen Promoter, a deuterium atom, C 1-8 alkyl, C 1-8 haloalkyl, cyano, C 3-8 cycloalkyl, halo C 3-8 cycloalkyl, cyano C 3-8 cycloalkyl , -S (O) m R 8 and -C (O) R 8 ; preferably C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, halo C 3-6 C 3-6 cycloalkyl substituted by cycloalkyl or cyano; more preferably C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, halo C 3-6 cycloalkyl Or cyano-substituted C 3-6 cycloalkyl; most preferably methyl, ethyl, isopropyl, cyclopropyl, halocyclopropyl or cyano-substituted cyclopropyl; R 4 is selected from a hydrogen atom, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, -C (O) OR 8 and -C (O) NR 9 R 10 ; wherein the C 1-8 alkyl, C 3-8 cycloalkyl and C 1-8 haloalkyl are further optionally selected from C 1-8 alkyl, halogen, hydroxyl, amino, nitro, cyano, C 1-8 alkoxy, or C 1-8 hydroxyalkyl substituted with one or more substituents; preferably C 1-6 alkyl or C 1-6 haloalkyl; more preferably C 1-3 alkyl or C 1-3 halo Alkyl; z is an integer of 0 or 1; and p is an integer of 0, 1, 2, 3, 4 or 5.
在本發明的一個較佳實施例方案中，該通式(VI)所示的化合物，其為通式(VIII)所示的化合物：
其中：R2~R4、L、Ra和p如通式(VI)中所定義。 Wherein: R 2 ~ R 4, L , R a and p are as in formula (VI) as defined above.
在本發明的一個較佳實施例方案中，該通式(VII)所示的化合物，其為通式(IX)所示的化合物：
其中：R2~R4、L、Ra和p如通式(VII)中所定義。 Wherein: R 2 ~ R 4, L , R a and p are as in Formula (VII) as defined above.
在本發明的一個較佳實施例方案中，該通式(I)~(IX)所示的化合物，其中L選自O、S、NRv、-O(CH2)n-和-NH(CH2)n-；較佳為O、-OCH2-、NH或-NHCH2-。 In a preferred embodiment of the present invention, the compound represented by the general formulae (I) to (IX), wherein L is selected from O, S, NRv, -O (CH 2 ) n -and -NH (CH 2 ) n- ; preferably O, -OCH 2- , NH or -NHCH 2- .
在本發明的一個較佳實施例方案中，該通式(I)~(IX)所示的化合物，其中環A選自C3-8環烷基、3-10員雜環基和6-10員芳基；較佳為苯基、環丙基、環已基或吡喃基。 In a preferred embodiment of the present invention, the compound represented by the general formulae (I) to (IX), wherein the ring A is selected from a C 3-8 cycloalkyl group, a 3-10 member heterocyclic group, and a 6-membered heterocyclic group. 10-membered aryl; preferably phenyl, cyclopropyl, cyclohexyl or pyranyl.
在本發明的一個較佳實施例方案中，該通式(I)~(IX)所示的化合物，其中R2選自氫原子、C1-8烷基、C1-8鹵烷基、C1-8羥烷基、C3-8環烷基、3-10員雜環基和6-10員芳基，其中該C1-8烷基、C1-8鹵烷基、C1-8羥烷基、C3-8環烷基、3-10員雜環基和6-10員芳基視需要進一步被選自C1-8烷基、鹵素、羥基、胺基、氰基、C3-8環烷基、C1-8烷氧基、C1-8羥烷基、C3-8環烷基和3-10員雜環基中的一個或多個取代基所取代；較佳為氫原子、C1-6烷基、C1-6鹵烷基、C1-8羥烷基、氰基取代的C1-6烷基、C3-6環烷基、鹵C3-6環烷基、氰基取代的C3-6環烷基、C3-6羥基基取代的環烷基、4-6員雜環基或苯基。 In a preferred embodiment of the present invention, the compound represented by the general formulae (I) to (IX), wherein R 2 is selected from a hydrogen atom, a C 1-8 alkyl group, a C 1-8 haloalkyl group, C 1-8 hydroxyalkyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, and 6-10 membered aryl, wherein the C 1-8 alkyl, C 1-8 haloalkyl, C 1 -8Hydroxyalkyl , C 3-8 cycloalkyl, 3-10 membered heterocyclyl, and 6-10 membered aryl are further selected from C 1-8 alkyl, halogen, hydroxyl, amine, and cyano as necessary , C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 hydroxyalkyl, C 3-8 cycloalkyl, and 3-10 membered heterocyclyl ; Preferably a hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-8 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-6 cycloalkyl, halogen C 3-6 cycloalkyl, cyano substituted C 3-6 cycloalkyl, C 3-6 hydroxy substituted cycloalkyl, 4-6 membered heterocyclyl or phenyl.
在本發明的一個較佳實施例方案中，該通式(I)~(IX) 所示的化合物，其中R3選自氫原子、C1-8烷基、C1-8鹵烷基、氰基、-S(O)mR8和-C(O)R8；R8選自C1-8烷基、C2-8烯基和C3-8環烷基；R3較佳為氫原子、C1-6烷基、氰基、-S(O)mR8或-C(O)R8，R8較佳為C1-6烷基、C2-4烯基或C3-6環烷基。 In a preferred embodiment of the present invention, the compound represented by the general formulae (I) to (IX), wherein R 3 is selected from a hydrogen atom, a C 1-8 alkyl group, a C 1-8 haloalkyl group, Cyano, -S (O) m R 8 and -C (O) R 8 ; R 8 is selected from C 1-8 alkyl, C 2-8 alkenyl and C 3-8 cycloalkyl; R 3 is preferred Is a hydrogen atom, C 1-6 alkyl, cyano, -S (O) m R 8 or -C (O) R 8 , and R 8 is preferably C 1-6 alkyl, C 2-4 alkenyl or C 3-6 cycloalkyl.
在本發明的一個較佳實施例方案中，該通式(I)~(IX)所示的化合物，其中R4選自氫原子、C1-8烷基、-C(O)OR8和-C(O)NR9R10；較佳為氫原子、C1-6烷基、-C(O)OR8或-C(O)NR9R10，更佳為氫原子或甲基。 In a preferred embodiment of the present invention, the compound represented by the general formulae (I) to (IX), wherein R 4 is selected from a hydrogen atom, a C 1-8 alkyl group, -C (O) OR 8 and -C (O) NR 9 R 10 ; preferably a hydrogen atom, a C 1-6 alkyl group, -C (O) OR 8 or -C (O) NR 9 R 10 , more preferably a hydrogen atom or a methyl group.
在本發明的一個較佳實施例方案中，所示的式(I)化合物、其立體異構體或其藥學上可接受的鹽，包括選自如下化合物：
在本發明的一個較佳實施例方案中，所示的通式(I)化合物、其立體異構體或其藥學上可接受的鹽的中間體，其為通式(X)、通式(X-A)和通式(XI)所示的化合物：
在本發明的一個較佳實施例方案中，一種製備通式(I)化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式的鹽的方法，該方法包括：
通式(I-1)化合物經脫去胺基保護基，得到通式(I)化合物；其中：R1~R5、Ra、M、L、X和Y如通式(I)中所定義。 Formula (I-1) compound by removing the amine protective group, to give a compound of formula (I); wherein: the R 1 ~ R 5, R a , M, L, X and Y are as formula (I), definition.
在本發明的一個較佳實施例方案中，一種製備通式(II)化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式的鹽的方法，該方法包括：
通式(XI)化合物脫去胺基保護基，得到通式(II)化合物；其中：環A、R1~R4、Ra、L、z和y如通式(II)中所定義。本發明的另一方面涉及一種醫藥組成物，其含有治療有效劑量的通式(I)~通式(IX)任一所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或可藥用的鹽，以及一種或多種藥學上可接受的載體、稀釋劑或賦形劑。本發明還涉及一種製備上述組合物的方法，其包括將各通式所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽與藥學上可接受的載體、稀釋劑或賦形劑相混合。 Formula (XI) compound of removing amino protecting group, to give a compound of formula (II); wherein: ring A, R 1 ~ R 4, R a, L, z and y are as formula (II) as defined above. Another aspect of the present invention relates to a pharmaceutical composition containing a therapeutically effective dose of a compound represented by any one of the general formulae (I) to (IX) or a tautomer, meso, racemic Isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The present invention also relates to a method for preparing the above-mentioned composition, which comprises compound represented by each general formula or a tautomer, meso, racemate, enantiomer, diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier, diluent or excipient.
本發明進一步涉及通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或醫藥上可接受之鹽，或包含其的醫藥組成物在製備用於預防和/或治療預防作為BRD4抑制劑在治療癌症、炎症、慢性肝病、糖尿病、心血管疾病或AIDS的藥物中的用途。 The present invention further relates to a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a medicament An acceptable salt, or a pharmaceutical composition comprising the same, for use in the manufacture of a medicament for the prevention and / or therapeutic prevention of a BRD4 inhibitor in the treatment of cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease or AIDS.
本發明進一步涉及通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或醫藥上可接受之鹽，醫藥組成物在製備BRD4抑制劑藥物中的應用。 The present invention further relates to a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a medicament Acceptable salt, application of pharmaceutical composition in preparing BRD4 inhibitor medicine.
本發明進一步涉及通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或醫藥上可接受之鹽，醫藥組成物在製備治療癌症、炎症、慢性肝病、糖尿病、心血管疾病或AIDS的藥物中的應用。 The present invention further relates to a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a medicament Acceptable salt, application of medicinal composition in preparing medicine for treating cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease or AIDS.
本發明還涉及一種治療預防和/或治療預防BRD4介導的病理學特徵的疾病的方法，其包括向患者施用治療有效劑量的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或醫藥上可接受之鹽，或包含其的醫藥組成物。其中BRD4介導的病理學特徵的疾病包括癌症、炎症、慢性肝病、糖尿病、心血管疾病或AIDS的疾病。 The present invention also relates to a method for the treatment and / or treatment of diseases for preventing pathological features mediated by BRD4, which comprises administering to a patient a therapeutically effective dose of a compound represented by general formula (I) or a tautomer, Racemates, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts, or pharmaceutical compositions containing them. Diseases in which BRD4-mediated pathological features include cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease or AIDS.
本發明另一方面涉及一種治療癌症的方法，該方法包括向患者施用治療有效劑量的本發明的通式(I)所示的化 合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或醫藥上可接受之鹽。該方法顯示出突出的療效和較少的副作用。 Another aspect of the present invention relates to a method for treating cancer, which comprises administering to a patient a therapeutically effective dose of a compound represented by the general formula (I) of the present invention or a tautomer, a meso, a racemate thereof. , Enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts. This method shows outstanding efficacy and fewer side effects.
本發明另一方面涉及一種治療炎症的方法，該方法包括向患者施用治療有效劑量的本發明的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或醫藥上可接受之鹽。該方法顯示出突出的療效和較少的副作用。 Another aspect of the present invention relates to a method for treating inflammation, the method comprising administering to a patient a therapeutically effective dose of a compound represented by the general formula (I) of the present invention or a tautomer, a meso, or a racemate thereof. , Enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts. This method shows outstanding efficacy and fewer side effects.
本發明另一方面涉及一種治療慢性肝病的方法，該方法包括向患者施用治療有效劑量的本發明的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或醫藥上可接受之鹽。該方法顯示出突出的療效和較少的副作用。 Another aspect of the present invention relates to a method for treating chronic liver disease, the method comprising administering to a patient a therapeutically effective dose of a compound represented by the general formula (I) of the present invention or a tautomer, meso, racemic Isomers, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts. This method shows outstanding efficacy and fewer side effects.
本發明所述的癌症包括但不限於乳腺癌、宮頸癌、結腸癌、肺癌、胃癌、直腸癌、胰腺癌、腦癌、肝癌、實體瘤、神經膠質瘤、神經膠母細胞瘤、白血病、淋巴瘤、骨髓瘤和非小細胞肺癌。 The cancer described in the present invention includes, but is not limited to, breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, pancreatic cancer, brain cancer, liver cancer, solid tumor, glioma, glioblastoma, leukemia, lymph Tumors, myeloma, and non-small cell lung cancer.
本發明所述的慢性肝病選自原發性硬化(PBC)、腦髒性黃瘤症(CTX)、原發性硬化性膽囊炎(PSC)、藥物導致的膽汁鬱積、妊娠肝內膽汁淤積症、腸外吸收相關膽汁鬱積(PNAC)、細菌過度生長或膿血症膽汁鬱積、自身免疫肝炎、慢性病毒性肝炎、酒精性肝病、非酒精性脂肪肝疾病(NAFLD)、非酒精性脂肪性肝炎(NASH)、肝移植相關移植物抗宿主病、活供體肝移植再生、先天性肝纖維化、膽總 管結石、肉芽性肝病、肝內或外惡性腫瘤、Sjogren綜合症、結節病、Wilson's疾病、Gaucher's疾病、血色病和α1-抗膜蛋白酶缺乏症。 The chronic liver disease described in the present invention is selected from the group consisting of primary sclerosis (PBC), cerebral xanthomatosis (CTX), primary sclerosing cholecystitis (PSC), cholestasis caused by drugs, intrahepatic cholestasis of pregnancy , Parenteral absorption-related cholestasis (PNAC), bacterial overgrowth or septic cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis ( NASH), liver transplant-related graft-versus-host disease, live-donor liver transplantation regeneration, congenital liver fibrosis, common bile duct stones, granulomatous liver disease, intrahepatic or extramalignant tumor, Sjogren syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, and alpha 1 -antimembrane proteinase deficiency.
除非有相反陳述，在說明書和申請專利範圍中使用的術語具有下述含義。 Unless stated to the contrary, terms used in the specification and the scope of patent applications have the following meanings.
術語“烷基”指飽和脂肪族烴基團，其為包含1至20個碳原子的直鏈或支鏈基團，較佳含有1至8個碳原子的烷基，更佳1至6個碳原子的烷基，最更佳1至3個碳原子的烷基。非限制性實例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、第二丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及 其各種支鏈異構體等。烷基可以是取代的或非取代的，當被取代時，取代基可以在任何可使用的連接點上被取代，所述取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、酮基、羧基或羧酸酯基。 The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbons Atomic alkyl, most preferably 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, third butyl, second butyl, n-pentyl, 1,1-dimethylpropyl , 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 , 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl , 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-di Methylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl , 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4 -Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3 -Ethylhexyl 2,2-diethyl-pentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl and the various branched chain isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups, which are independently selected from Alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, keto, carboxyl or carboxylate.
術語“亞烷基”是指烷基的一個氫原子進一步被取代，例如：“亞甲基”指-CH2-、“亞乙基”指-(CH2)2-、“亞丙基”指-(CH2)3-、“亞丁基”指-(CH2)4-等。 The term "alkylene" means that a hydrogen atom of an alkyl group is further substituted, for example: "methylene" means -CH 2- , "ethylene" means-(CH 2 ) 2- , "propylene" Means-(CH 2 ) 3- , "butylene" means-(CH 2 ) 4- , and the like.
術語“烯基”指由至少由兩個碳原子和至少一個碳-碳雙鍵組成的如上定義的烷基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。 The term "alkenyl" refers to an alkyl group, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3 -Butenyl and the like.
術語“環烷基”指飽和或部分不飽和單環或多環環狀烴取代基，環烷基環包含3至20個碳原子，較佳包含3至8個碳原子，更佳包含3至6個碳原子。單環環烷基的非限制性實例包括環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環己二烯基、環庚基、環庚三烯基、環辛基等；多環環烷基包括螺環、稠環和橋環的環烷基，較佳為環丙基、環己基和環戊基。 The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20 carbon atoms, preferably contains 3 to 8 carbon atoms, and more preferably contains 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Polycyclocycloalkyl includes spiro, fused and bridged cycloalkyl, preferably cyclopropyl, cyclohexyl and cyclopentyl.
術語“螺環烷基”指5至20員的單環之間共用一個碳原子(稱螺原子)的多環基團，其可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統。較佳為6至14員，更佳為7至10員。根據環與環之間共用螺原子的數目 將螺環烷基分為單螺環烷基、雙螺環烷基或多螺環烷基，較佳為單螺環烷基和雙螺環烷基。更較佳為4員/4員、4員/5員、4員/6員、5員/5員或5員/6員單螺環烷基。螺環烷基的非限制性實例包括：
該環烷基環可以稠合於芳基、雜芳基或雜環烷基環上，其中與母體結構連接在一起的環為環烷基，非限制性實例包括茚滿基、四氫萘基、苯並環庚烷基等。環烷基可以是視需要取的或非取的，當被取時，取基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、酮基、羧基或羧酸酯基。 The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl , Benzocycloheptyl and the like. Cycloalkyl can be taken or not as needed. When taken, the radical is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, keto, carboxyl or carboxylate.
術語“雜環基”指飽和或部分不飽和單環或多環環狀烴取基，其包含3至20個環原子，其中一個或多個環原子為選自氮、氧或S(O)m(其中m是整數0至2)的雜原子，但不包括-O-O-、-O-S-或-S-S-的環部分，其餘環原子為碳。較佳包含3至12個環原子，其中1~4個是雜原子；更佳包 含3至8個環原子；最佳包含3至6個環原子。單環雜環基的非限制性實例包括吡咯烷基、咪唑烷基、四氫呋喃基、四氫噻吩基、二氫咪唑基、二氫呋喃基、二氫吡唑基、二氫吡咯基、哌啶基、哌嗪基、嗎啉基、硫嗎啉基、高哌嗪基、吡喃基等，較佳嗎啉基和吡喃基。多環雜環基包括螺環、稠環和橋環的雜環基。 The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon radical containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S (O) A heteroatom of m (where m is an integer from 0 to 2), excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 8 ring atoms; and most preferably 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidine Group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl and the like, and morpholinyl and pyranyl are preferred. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
該雜環基環可以稠合於芳基、雜芳基或環烷基環上，其中與母體結構連接在一起的環為雜環基，其非限制性實例包括：和等。 The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples thereof include: with Wait.
雜環基可以是視需要取的或非取的，當被取時，取基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、酮基、羧基或羧酸酯基。 The heterocyclic group may be optional or non-optional, and when taken, the group is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, keto, carboxyl or carboxylate.
術語“芳基”指具有共軛的π電子體系的6至14員全碳單環或稠合多環(也就是共用毗鄰碳原子對的環)基團，較佳為6至10員，例如苯基和萘基。更佳為苯基。該芳基環可以稠合於雜芳基、雜環基或環烷基環上，其中與母體結構連接在一起的環為芳基環，其非限制性實例包括：
芳基可以是取的或非取的，當被取時，取基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、羧基或羧酸酯基。 The aryl group may be taken or not. When taken, the taken group is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkylthio. , Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, carboxyl or carboxylate.
術語“雜芳基”指包含1至4個雜原子、5至14個環原子的雜芳族體系，其中雜原子選自氧、硫和氮。雜芳基較佳為5至10員，更佳為5員或6員，例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，較佳為咪唑基、吡唑基或嘧啶基、噻唑基；更有選嘧啶基。 The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 members, more preferably 5 or 6 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl , Pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrimidinyl.
雜芳基可以是視需要取的或非取的，當被取時，取基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、羧基或羧酸酯基。 Heteroaryl may be taken or not as needed. When taken, the taken group is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, carboxyl or carboxylate.
術語“烷氧基”指-O-(烷基)和-O-(非取的環烷基)，其中烷基的定義如上所述。烷氧基的非限制性實例包括：甲氧基、乙氧基、丙氧基、丁氧基、環丙氧基、環丁氧基、環戊氧基、環己氧基。烷氧基可以是視需要取的或非取的，當被取時，取基較佳為一個或多個以下基團，其獨立地選 自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、羧基或羧酸酯基。 The term "alkoxy" refers to -O- (alkyl) and -O- (non-selected cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group can be taken or not as required. When taken, the radical is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, carboxyl or carboxylate.
術語“鹵烷基”指被一個或多個鹵素取的烷基，其中烷基如上所定義。 The term "haloalkyl" refers to an alkyl group taken by one or more halogens, wherein alkyl is as defined above.
術語“鹵烷氧基”指被一個或多個鹵素取的烷氧基，其中烷氧基如上所定義。 The term "haloalkoxy" refers to an alkoxy group taken by one or more halogens, where alkoxy is as defined above.
術語“羥烷基”指被羥基取的烷基，其中烷基如上所定義。 The term "hydroxyalkyl" refers to an alkyl group taken by a hydroxyl group, wherein alkyl is as defined above.
術語“羥基”指-OH基團。 The term "hydroxy" refers to the -OH group.
術語“鹵素”指氟、氯、溴或碘。 The term "halogen" refers to fluorine, chlorine, bromine or iodine.
術語“胺基”指-NH2。 The term "amino" refers to -NH 2.
術語“氰基”指-CN。 The term "cyano" refers to -CN.
術語“硝基”指-NO2。 The term "nitro" refers to -NO 2.
術語“酮基”指=O。 The term "keto" refers to = 0.
術語“羧基”指-C(O)OH。 The term "carboxy" refers to -C (O) OH.
術語“苄氧羰基”指Cbz。 The term "benzyloxycarbonyl" refers to Cbz.
術語“第三丁氧羰基”指Boc。 The term "third butoxycarbonyl" refers to Boc.
術語“烯丙基羰基”指Alloc。 The term "allylcarbonyl" refers to Alloc.
術語“笏甲氧羰基”指Fmoc。 The term "watmethoxycarbonyl" refers to Fmoc.
術語“三甲基矽乙氧羰基”指Teoc。 The term "trimethylsilylethoxycarbonyl" refers to Teoc.
術語“鄰苯二甲醯基”指Pht。 The term "phthaloyl" refers to Pht.
術語“對甲苯磺醯基”指Ts。 The term "p-toluenesulfonyl" refers to Ts.
術語“三氟乙醯基”指Tfa。 The term "trifluoroacetamido" refers to Tfa.
術語“鄰(對)硝基苯磺醯基”指Ns。 The term "o- (p-nitrobenzenesulfonyl)" refers to Ns.
術語“三苯甲基”指Trt。 The term "trityl" refers to Trt.
術語“2,4-二甲氧基苄基”指Dmb。 The term "2,4-dimethoxybenzyl" refers to Dmb.
術語“甲氧基苄基”指PMB。 The term "methoxybenzyl" refers to PMB.
術語“苄基”指Bn。 The term "benzyl" refers to Bn.
術語“羧酸酯基”指-C(O)O(烷基)或-C(O)O(環烷基)，其中烷基如上所定義。 The term "carboxylate" refers to -C (O) O (alkyl) or -C (O) O (cycloalkyl), wherein alkyl is as defined above.
術語“醯鹵”指含有-C(O)-鹵素的基團的化合物。 The term "halogen halide" refers to a compound containing a -C (O) -halogen group.
“X選自A、B、或C”、“X選自A、B和C”、“X為A、B或C”、“X為A、B和C”等不同用語均表達了相同的意義，即表示X可以是A、B、C中的任意一種或幾種。 "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", "X is A, B, or C" and other terms all express the same Meaning, meaning that X can be any one or several of A, B, and C.
本發明的氫原子均可被其同位素氘所取代，本發明涉及的實施例化合物中的任一氫原子也均可被氘原子取代。 The hydrogen atom of the present invention may be replaced by its isotope deuterium, and any hydrogen atom in the compound of the embodiment of the present invention may be replaced by a deuterium atom.
“視需要”或“視需要地”意味著隨後所描述的事件或環境可以但不必發生，該說明包括該事件或環境發生或不發生的場合。例如，“視需要被烷基取代的雜環基團”意味著烷基可以但不必須存在，該說明包括雜環基團被烷基取代的情形和雜環基團不被烷基取代的情形。 "As needed" or "as needed" means that the event or environment described later can, but does not have to occur, and the description includes situations where the event or environment occurs or does not occur. For example, "heterocyclic group substituted with an alkyl group as necessary" means that the alkyl group may but need not exist, and the description includes a case where the heterocyclic group is substituted with an alkyl group and a case where the heterocyclic group is not substituted with an alkyl group .
“取代的”指基團中的一個或多個氫原子，較佳為最多5個，更佳為1~3個氫原子彼此獨立地被相應數目的取代基取代。不言而喻，取代基僅處在它們的可能的化學位置，本領域技術人員能夠在不付出過多努力的情況下確定(藉由實驗或理論)可能或不可能的取代。例如，具有游離氫的 胺基或羥基與具有不飽和(如烯屬)鍵的碳原子結合時可能是不穩定的。 "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amine or hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
“醫藥組成物”表示含有一種或多種本文所述化合物或其生理學上/可藥用的鹽或前體藥物與其他化學組分的混合物，以及其他組分例如生理學/可藥用的載體和賦形劑。 醫藥組成物的目的是促進對生物體的給藥，利於活性成分的吸收進而發揮生物活性。 "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiological / pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as physiological / pharmaceutically acceptable carriers And excipients. The purpose of the pharmaceutical composition is to promote the administration to the living body, which is beneficial to the absorption of the active ingredient and then exerts the biological activity.
“可藥用鹽”是指本發明化合物的鹽，這類鹽用於哺乳動物體內時具有安全性和有效性，且具有應有的生物活性。 "Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention. Such salts are safe and effective when used in mammals, and have due biological activity.
本發明化合物的合成方法Method for synthesizing compounds of the present invention
為了完成本發明的目的，本發明採用如下技術方案：本發明通式(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用的鹽的製備方法，包括以下步驟：
通式(II-1)化合物在鹼性和膦鈀類催化劑的條件下，與通式(IIA-9)化合物發生偶聯反應，得到通式(X-A)化合物； 得到的產物通式(X-A)進一步與通式(IIA-2)化合物在鹼性條件下反應得到通式(XI)化合物；得到的通式(XI)化合物在鹼性條件下脫保護，得到通式(II)化合物；
通式(X)化合物在鹼性和膦鈀類催化劑的條件下，與通式(IIA-9)化合物發生偶聯反應，得到通式(XI)化合物；得到的產物通式(XI)化合物在鹼性條件下脫保護，得到通式(II)化合物；本發明通式(IIA)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用的鹽的製備方法，包括以下步驟：
在高溫鹼性條件下(提供鹼性條件的試劑較佳為碳酸銫)，通式(IIA-1)化合物與通式(IIA-2)化合物發生反應，得到通式(IIA-3)化合物；通式(IIA-3)化合物在鹼性條件下(提供鹼性條件的試劑較佳為NaBH4)，發生還原反應，得到通式(IIA-4)化合物；將得到的通式(IIA-4)化合物在低溫條件下與PBr3反應，得到通式(IIA-5)化合物；得到的通式(IIA-5)化合物與R2SNa發生反應，得到通式(IIA-6)化合物；得到 的通式(IIA-6)化合物在低溫條件下，被氧化(提供氧化條件的試劑較佳為間氯過氧苯甲酸)得到通式(IIA-7)；通式(IIA-7)化合物在胺基甲酸銨和二乙酸碘苯的作用下，得到通式(IIA-8)化合物；得到的通式(IIA-8)化合物在鹼性(提供鹼性條件的試劑較佳為碳酸鈉)和膦鈀類催化劑的條件下，與通式(IIA-9)化合物發生偶聯反應，得到通式(IIA-10)化合物；得到的產物通式(IIA-10)視需要進一步與R3的鹵化物、硼酸或者硼酸酯反應得到通式(IIA-11)化合物；得到的產物通式(IIA-10)&通式(IIA-11)化合物在鹼性條件下脫保護，得到通式(IIA)化合物。 Under high temperature and alkaline conditions (the reagent providing the alkaline conditions is preferably cesium carbonate), the compound of the general formula (IIA-1) reacts with the compound of the general formula (IIA-2) to obtain the compound of the general formula (IIA-3); The compound of the general formula (IIA-3) undergoes a reduction reaction under basic conditions (the reagent providing the basic conditions is preferably NaBH 4 ) to obtain a compound of the general formula (IIA-4); ) The compound is reacted with PBr 3 under low temperature conditions to obtain a compound of the general formula (IIA-5); the obtained compound of the general formula (IIA-5) is reacted with R 2 SNa to obtain a compound of the general formula (IIA-6); The compound of the general formula (IIA-6) is oxidized under low temperature conditions (reagent providing oxidation conditions is preferably m-chloroperoxybenzoic acid) to obtain the general formula (IIA-7); Under the action of ammonium formate and iodobenzene diacetate, the compound of general formula (IIA-8) is obtained; the obtained compound of general formula (IIA-8) is basic (the reagent for providing basic conditions is preferably sodium carbonate) and phosphine Under the condition of a palladium-based catalyst, a coupling reaction with a compound of the general formula (IIA-9) is performed to obtain a compound of the general formula (IIA-10); the obtained product of the general formula (IIA-10) is further coupled with a halogen of R 3 as required. Compounds of general formula (IIA-11) are obtained by reacting compounds, boronic acid or boronic acid ester; the obtained products are compounds of general formula (IIA-10) & general formula (IIA-11) are deprotected under basic conditions to obtain general formula (IIA ) Compounds.
在鹼性條件下(提供鹼性條件的試劑較佳為氫氧化 鈉)，通式(IIA-a)化合物與鹵烷化合物發生反應，得到通式(IIA-c)化合物；或者通式(IIA-b)化合物在加熱條件下與含R2取代的硫烷發生還原反應，得到通式(IIA-c)化合物；將上述兩種方法得到的通式(IIA-c)化合物在低溫條件下，被氧化(提供氧化條件的試劑較佳為間氯過氧苯甲酸)得到通式(IIA-d)；得到的通式(IIA-d)化合物在酸性條件下，與疊氮化鈉反應，得到通式(IIA-e)化合物；得到的通式(IIA-e)化合物在鹼性(提供鹼性條件的試劑較佳為碳酸鈉)和膦鈀類催化劑的條件下，與通式(IIA-9)化合物發生偶聯反應，得到通式(IIA-10)化合物；得到的產物通式(IIA-10)視需要進一步與R3的鹵化物、硼酸或者硼酸酯反應得到通式(IIA-11)化合物；得到的產物通式(IIA-10)&通式(IIA-11)化合物在鹼性條件下脫保護，得到通式(IIA)化合物。 Under basic conditions (the reagent providing the basic conditions is preferably sodium hydroxide), the compound of the general formula (IIA-a) reacts with the haloalkane compound to obtain a compound of the general formula (IIA-c); or the general formula (IIA -b) the compound undergoes a reduction reaction with R 2 substituted sulfane under heating conditions to obtain a compound of general formula (IIA-c); and the compound of general formula (IIA-c) obtained by the above two methods under low temperature conditions, Oxidation (reagent providing oxidation conditions is preferably m-chloroperoxybenzoic acid) to obtain the general formula (IIA-d); the obtained compound of the general formula (IIA-d) is reacted with sodium azide under acidic conditions to obtain Compounds of general formula (IIA-e); the obtained compounds of general formula (IIA-e) are reacted with the general formula (IIA- 9) The compound undergoes a coupling reaction to obtain a compound of the general formula (IIA-10); the obtained product of the general formula (IIA-10) is further reacted with a halide, boric acid or a boronic acid ester of R 3 to obtain the general formula (IIA- 11) Compound; the obtained product is a compound of general formula (IIA-10) & general formula (IIA-11) is deprotected under basic conditions to obtain a compound of general formula (IIA).
本發明通式(IIB)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用的鹽的製備方法，包括以下步驟：
在鹼性條件下(提供鹼性條件的試劑較佳為碳酸銫)，通式(IIB-2)化合物與通式(IIA-2)化合物發生反應，得到通式(IIB-3)化合物；通式(IIB-3)化合物被還原(提供還原條件的試劑較佳為鐵粉)得到通式(IIB-4)化合物；將得到的通式(IIB-4)化合物在低溫條件下與亞硝酸鈉、碘化鉀反應，得到通式(IIB-5)化合物；得到的通式(IIB-5)化合物與含R2取代的硫烷酮發生反應，得到通式(IIB-6)化合物；得到的通式(IIB-6)化合物在鹼性(提供鹼性條件的試劑較佳為碳酸鈉)和膦鈀類催化劑的條件下，與通式(IIA-9)化合物發生偶聯反應，得到通式(IIB-7)化合物；得到的產物通式(IIB-7)化合物在鹼性條件下脫保護，得到通式(IIB-1)化合物。 Under basic conditions (the reagent providing the basic conditions is preferably cesium carbonate), the compound of the general formula (IIB-2) reacts with the compound of the general formula (IIA-2) to obtain the compound of the general formula (IIB-3); The compound of formula (IIB-3) is reduced (reagent providing reducing conditions is preferably iron powder) to obtain a compound of general formula (IIB-4); the obtained compound of general formula (IIB-4) is mixed with sodium nitrite under low temperature conditions. 1. Reaction of potassium iodide to obtain a compound of general formula (IIB-5); the obtained compound of general formula (IIB-5) reacts with R 2 substituted sulfanone to obtain a compound of general formula (IIB-6); (IIB-6) The compound undergoes a coupling reaction with a compound of the general formula (IIA-9) under the conditions of basicity (the reagent for providing basic conditions is preferably sodium carbonate) and a phosphine-palladium catalyst to obtain the general formula (IIB -7) compound; the obtained product, the compound of general formula (IIB-7) is deprotected under basic conditions to obtain the compound of general formula (IIB-1).
其中：方案一至方案五中涉及到的鹼性條件的試劑包 括有機鹼和無機鹼類，該有機鹼類包括但不限於三乙胺、N,N-二異丙基乙胺、正丁基鋰、二異丙基胺基鋰、醋酸鉀、第三丁醇鈉或第三丁醇鉀，該無機鹼類包括但不限於氫化鈉、磷酸鉀、碳酸鈉、碳酸鉀或碳酸銫；涉及到的膦鈀類催化劑包括但不限於2-二環己基膦-2,4,6-三異丙基聯苯、(±)-2,2’-雙-(二苯基膦)-1,1’-聯萘、三(二亞苄基丙酮)二鈀、醋酸鈀、[1,1'-雙(二苯基磷)二茂鐵]二氯化鈀、三苯基膦、四(三苯基膦)鈀；涉及到的B為硼酸或者硼酸酯；涉及到的G、G’為鹵素；涉及到的Pg為胺基保護基，選自苄氧羰基(Cbz)、第三丁氧羰基(Boc)、烯丙基羰基(Alloc)、笏甲氧羰基(Fmoc)、甲氧羰基、乙氧羰基、三甲基矽乙氧羰基(Teoc)、鄰苯二甲醯基(Pht)、對甲苯磺醯基(Ts)、三氟乙醯基(Tfa)、鄰(對)硝基苯磺醯基(Ns)、特戊醯基、苯甲醯基、三苯甲基(Trt)、2,4-二甲氧基苄基(Dmb)、對甲氧基苄基(PMB)或苄基(Bn)，較佳為對甲苯磺醯基(Ts)；環A、R2~R5、Ra、L、X、y和z如通式(I)中所定義。 Wherein, the reagents of alkaline conditions involved in schemes 1 to 5 include organic bases and inorganic bases, and the organic bases include, but are not limited to, triethylamine, N, N-diisopropylethylamine, n-butyllithium , Lithium diisopropylamino, potassium acetate, sodium tert-butoxide or potassium tert-butoxide, the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate or cesium carbonate; Phosphine-palladium catalysts include, but are not limited to, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, (±) -2,2'-bis- (diphenylphosphine) -1,1 ' -Binaphthyl, tris (dibenzylideneacetone) dipalladium, palladium acetate, [1,1'-bis (diphenylphosphonium) ferrocene] palladium dichloride, triphenylphosphine, tetrakis (triphenyl) Phosphine) Palladium; B involved is boronic acid or borate; G and G 'are involved; Pg is an amine protecting group selected from benzyloxycarbonyl (Cbz), third butoxycarbonyl ( Boc), Alloc, Allm, Fmoc, Methoxycarbonyl, Ethoxycarbonyl, Trimethylsilylethoxycarbonyl (Teoc), Phthalenyl (Pht), p-Toluene Sulfonyl (Ts), trifluoroethylsulfonyl (Tfa), o- (p-nitrobenzenesulfonyl) (Ns), terpentazone , Benzamidine, trityl (Trt), 2,4-dimethoxybenzyl (Dmb), p-methoxybenzyl (PMB) or benzyl (Bn), preferably p-toluene sulfo acyl (Ts of); the ring A, R 2 ~ R 5, are R a, L, X, y and z are as in formula (I) as defined above.
以下結合實施例進一步描述本發明，但這些實施例並非限制著本發明的範圍。 The present invention is further described below with reference to examples, but these examples do not limit the scope of the present invention.
化合物的結構是藉由核磁共振(NMR)或質譜(MS)來確定的。NMR的測定是用Bruker AVANCE-400核磁儀，測定溶劑為氘代二甲基亞碸(DMSO-d 6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，內標為四甲基矽烷(TMS)，化學位移是以10-6(ppm)作為單位給出。 The structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The NMR measurement was performed using Bruker AVANCE-400 nuclear magnetic analyzer. The measurement solvents were deuterated dimethylsulfine (DMSO- d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD). The internal standard was four. For methylsilane (TMS), chemical shifts are given in units of 10 -6 (ppm).
MS的測定用FINNIGAN LCQAd(ESI)質譜儀(生產商：Thermo，型號：Finnigan LCQ advantage MAX)。 MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
HPLC的測定使用安捷倫1200DAD高壓液相色譜儀(Sunfire C18 150×4.6mm色譜管柱)和Waters 2695-2996高壓液相色譜儀(Gimini C18 150×4.6mm色譜管柱)。 The HPLC was measured using an Agilent 1200 DAD high-pressure liquid chromatography (Sunfire C18 150 × 4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatography (Gimini C18 150 × 4.6 mm column).
激酶平均抑制率及IC50值的測定用NovoStar酶標儀(德國BMG公司)。 The average inhibition rate of the kinase and the IC 50 value were measured using a NovoStar microplate reader (BMG, Germany).
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0.15mm~0.2mm，薄層層析分離純化產物採用的規格是0.4mm~0.5mm矽膠板。 The thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silicone plate. The thin-layer chromatography (TLC) silicon plate uses a size of 0.15mm ~ 0.2mm. The thin-layer chromatography separation and purification product uses a size of 0.4mm. ~ 0.5mm silicone board.
管柱層析一般使用煙臺黃海200~300目矽膠為載體。 Column chromatography generally uses Yantai Yellow Sea 200-300 mesh silica gel as the carrier.
本發明的已知的起始原料可以採用或按照本領域已知的方法來合成，或可購買自ABCR GmbH & Co.KG，Acros Organnics，Aldrich Chemical Company，韶遠化學科技(Accela ChemBio Inc)、達瑞化學品等公司。 The known starting materials of the present invention can be synthesized by or in accordance with methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organnics, Aldrich Chemical Company, Accela ChemBio Inc, Dari Chemicals and other companies.
實施例中如無特殊說明，反應均在氬氣氛或氮氣氛下進行。 Unless otherwise specified in the examples, the reaction is performed under an argon atmosphere or a nitrogen atmosphere.
氬氣氛或氮氣氛是指反應瓶連接一個約1L容積的氬 氣或氮氣氣球。 An argon or nitrogen atmosphere means that the reaction flask is connected to an argon or 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。 The hydrogen atmosphere means that a reaction balloon is connected to a hydrogen gas balloon with a volume of about 1 L.
加壓氫化反應使用Parr 3916EKX型氫化儀和清藍QL-500型氫氣發生器或HC2-SS型氫化儀。 Pressurized hydrogenation reaction uses Parr 3916EKX type hydrogenation instrument and clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenation instrument.
氫化反應通常抽真空，充入氫氣，重複操作3次。 The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
微波反應使用CEM Discover-S 908860型微波反應器。 For the microwave reaction, a CEM Discover-S 908860 microwave reactor was used.
實施例中如無特殊說明，反應中的溶液是指水溶液。 Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.
實施例中如無特殊說明，反應的溫度為室溫。 Unless otherwise specified in the examples, the reaction temperature is room temperature.
室溫為最適宜的反應溫度，溫度範圍是20℃~30℃。 Room temperature is the most suitable reaction temperature, and the temperature range is 20 ° C ~ 30 ° C.
實施例中的反應進程的監測採用薄層色譜法(TLC)，反應所使用的展開劑的體系有：A：二氯甲烷和甲醇體系，B：正己烷和乙酸乙酯體系，C：石油醚和乙酸乙酯體系，D：丙酮，溶劑的體積比根據化合物的極性不同而進行調節。 The monitoring of the reaction progress in the examples uses thin layer chromatography (TLC). The developing systems used in the reaction are: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted according to the polarity of the compound.
純化化合物採用的管柱層析的洗脫劑的體系和薄層色譜法的展開劑的體系包括：A：二氯甲烷和甲醇體系，B：正己烷和乙酸乙酯體系，C：正己烷、乙酸乙酯和二氯甲烷體系，D：石油醚和乙酸乙酯體系，E：乙酸乙酯，溶劑的體積比根據化合物的極性不同而進行調節，也可以加入少量的三乙胺和酸性或鹼性試劑等進行調節。 The eluent system for column chromatography and the eluent system for thin-layer chromatography for purifying compounds include: A: dichloromethane and methanol systems, B: n-hexane and ethyl acetate systems, C: n-hexane, Ethyl acetate and dichloromethane system, D: petroleum ether and ethyl acetate system, E: ethyl acetate, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and acid or alkali can also be added Sex reagents and so on.
100mL三口瓶中依次加入2,4-二氟苯酚(1.47g,11.33mmol),3-溴-4-氟苯甲醛(2.30g,11.33mmol)，碳酸銫(4.05g,12.46mmol)，二甲基亞碸(10mL)。油浴加熱升溫至100℃，反應1小時後冷卻至室溫，反應液用乙酸乙酯(30mL)稀釋後用飽和食鹽水洗滌(10mLx3)，有機相經無水硫酸鈉乾燥，過濾，旋乾。粗產物用管柱層析分離(石油醚/乙酸乙酯：5/1)純化得到3-溴-4-(2,4-二氟苯氧基)苯甲醛(2.60g，淡黃色油狀物，產率：47%)。 In a 100 mL three-neck flask, 2,4-difluorophenol (1.47 g, 11.33 mmol), 3-bromo-4-fluorobenzaldehyde (2.30 g, 11.33 mmol), cesium carbonate (4.05 g, 12.46 mmol), and dimethyl carbonate were sequentially added. Chiazone (10 mL). The oil bath was heated to 100 ° C. and reacted for 1 hour and then cooled to room temperature. The reaction solution was diluted with ethyl acetate (30 mL) and washed with saturated brine (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was separated by column chromatography (petroleum ether / ethyl acetate: 5/1) and purified to obtain 3-bromo-4- (2,4-difluorophenoxy) benzaldehyde (2.60 g, pale yellow oil). , Yield: 47%).
3-溴-4-(2,4-二氟苯氧基)苯甲醛(2.60g，8.31mmol)溶於甲醇(10mL)與四氫呋喃(10mL)混合溶劑中，室溫下攪拌2-3分鐘後，加入硼氫化鈉(0.095g，2.49mmol)，加畢室溫條件下攪拌2小時，反應結束。將反應混合液旋乾，殘留物用乙酸乙酯(30mL)溶解，飽和食鹽水(10mL×3)洗滌，有機相經無水硫酸鈉乾燥，過濾，旋乾，得到粗產物 3-溴-4-(2,4-二氟苯氧基)苯甲醇(2.6g，白色固體)，直接用於下一步。 3-Bromo-4- (2,4-difluorophenoxy) benzaldehyde (2.60 g, 8.31 mmol) was dissolved in a mixed solvent of methanol (10 mL) and tetrahydrofuran (10 mL), and stirred at room temperature for 2-3 minutes Then, sodium borohydride (0.095 g, 2.49 mmol) was added, and the mixture was stirred at room temperature for 2 hours to complete the reaction. The reaction mixture was spin-dried, and the residue was dissolved in ethyl acetate (30 mL), washed with saturated brine (10 mL × 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product 3-bromo-4- (2,4-difluorophenoxy) benzyl alcohol (2.6 g, white solid) was used directly in the next step.
3-溴-4-(2,4-二氟苯氧基)苯甲醇(2.60g,8.25mmol)溶於二氯甲烷(20mL)中，冰浴冷卻至0~5℃，滴加三溴化磷(2.46g,9.08mmol)，加畢自然升溫至室溫，攪拌3小時反應結束。將反應液緩慢倒入冰水中，滴加飽和碳酸鈉溶液中和，分液，水相用二氯甲烷萃取(15mLx3)，合併有機相，有機相用飽和食鹽水(15mL×2)洗滌，無水硫酸鈉乾燥，過濾，旋乾，得到2-溴-4-(溴甲基)-1-(2,4-二氟苯氧基)苯(2.60g，白色固體)，直接用於下一步反應。 3-Bromo-4- (2,4-difluorophenoxy) benzyl alcohol (2.60g, 8.25mmol) was dissolved in dichloromethane (20mL), cooled in an ice bath to 0 ~ 5 ° C, and tribromide was added dropwise. Phosphorus (2.46 g, 9.08 mmol) was added to the room temperature, and the mixture was stirred for 3 hours to complete the reaction. The reaction solution was slowly poured into ice water, neutralized with saturated sodium carbonate solution dropwise, and the layers were separated. The aqueous phase was extracted with dichloromethane (15 mL x 3), and the organic phases were combined. The organic phase was washed with saturated brine (15 mL x 2), and anhydrous. Dry over sodium sulfate, filter, and spin dry to obtain 2-bromo-4- (bromomethyl) -1- (2,4-difluorophenoxy) benzene (2.60 g, white solid), which was used directly in the next reaction. .
100mL三口瓶中依次加入2-溴-4-(溴甲基)-1-(2,4-二氟苯氧基)苯(2.40g,6.35mmol)，乙硫醇鈉(0.53g,6.35mmol)，N,N-二甲基甲醯胺(40mL)，室溫攪拌4小時反應結束。反應液用乙酸乙酯(50mL)稀釋，經飽和食鹽水洗滌(10mLx5)，有機相用無水硫酸鈉乾燥，過濾，旋乾，管柱層析分離(石油醚/乙酸乙酯：5/1)，得到：3-溴-4-(2,4-二氟苯氧基)苄基乙基硫烷(1.30g，油狀物，收率57%)。 In a 100 mL three-necked flask, 2-bromo-4- (bromomethyl) -1- (2,4-difluorophenoxy) benzene (2.40 g, 6.35 mmol), and sodium ethyl mercaptan (0.53 g, 6.35 mmol) were sequentially added. ), N, N-dimethylformamide (40 mL), and stirred at room temperature for 4 hours. The reaction was completed. The reaction solution was diluted with ethyl acetate (50 mL), washed with saturated brine (10 mL x 5), and the organic phase was dried over anhydrous sodium sulfate, filtered, spin-dried, and separated by column chromatography (petroleum ether / ethyl acetate: 5/1). Obtained: 3-bromo-4- (2,4-difluorophenoxy) benzylethylsulfane (1.30 g, oil, 57% yield).
(3-溴-4-(2,4-二氟苯氧基)苯甲基)(乙基)硫烷(1.3g，3.6mmol)溶於二氯甲烷(20mL)中，乾冰/乙酸乙酯浴冷卻到-20℃，分批加入間氯過氧苯甲酸(0.69g,4.0mmol)，加畢撤去冰浴自然升至室溫後，攪拌30分鐘。LC-MS監測反應完全，向反應溶液中加入飽和碳酸鈉溶液(50mL)，然後用乙酸乙酯萃取(50mLx2)，混合有機相，用飽和氯化鈉溶液(80mL x2)洗滌，無水硫酸鈉乾燥，減壓濃縮得到2-溴-1-(2,4-二氟苯氧基)-4-((乙基亞硫醯基<亞磺醯>)甲基)苯(1.3g,96%)。 (3-Bromo-4- (2,4-difluorophenoxy) benzyl) (ethyl) sulfane (1.3 g, 3.6 mmol) was dissolved in dichloromethane (20 mL), and dry ice / ethyl acetate The bath was cooled to -20 ° C, and m-chloroperoxybenzoic acid (0.69 g, 4.0 mmol) was added in portions. After the addition was completed, the ice bath was removed and the temperature was raised to room temperature, followed by stirring for 30 minutes. LC-MS was used to monitor the completion of the reaction. To the reaction solution was added a saturated sodium carbonate solution (50 mL), followed by extraction with ethyl acetate (50 mL x 2). The organic phases were mixed, washed with saturated sodium chloride solution (80 mL x 2), and dried over anhydrous sodium sulfate. , And concentrated under reduced pressure to give 2-bromo-1- (2,4-difluorophenoxy) -4-((ethylthiosulfenyl <sulfenyl)> methyl) benzene (1.3 g, 96%) .
MS m/z(ESI)：375.0/377.0(50/50)[M+H]+. MS m / z (ESI): 375.0 / 377.0 (50/50) [M + H] +.
2-溴-1-(2,4-二氟苯氧基)-4-((乙基亞硫醯基<亞磺醯>)甲基)苯(300mg,0.78mmol)溶於甲醇(20mL)，依次加入胺基甲酸銨(252mg,3.24mmol)和二乙酸碘苯(753mg,2.34mmol)，室溫條件下攪拌1小時。停止反應，加入水(50mL)淬滅反應，用乙酸乙酯(50mLx2)萃取，合併有機相。有機相經飽和氯化鈉(50mL)洗滌，無水硫酸鈉乾燥，過濾，減 壓濃縮得到(3-溴-4-(2,4-二氟苯氧基)苯甲基)(乙基)(亞胺基)-λ﹁6-硫烷酮(300mg,95%)。 2-bromo-1- (2,4-difluorophenoxy) -4-((ethylsulfinyl <sulfenyl)) methyl) benzene (300 mg, 0.78 mmol) was dissolved in methanol (20 mL) Then, ammonium carbamate (252 mg, 3.24 mmol) and iodobenzene diacetate (753 mg, 2.34 mmol) were sequentially added, and the mixture was stirred at room temperature for 1 hour. The reaction was stopped, water (50 mL) was added to quench the reaction, extracted with ethyl acetate (50 mL x 2), and the organic phases were combined. The organic phase was washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (3-bromo-4- (2,4-difluorophenoxy) benzyl) (ethyl) ( Imino) -λ﹁6-sulfanone (300 mg, 95%).
MS m/z(ESI)：390.0/392.0(50/50)M+H]+. MS m / z (ESI): 390.0 / 392.0 (50/50) M + H] + .
在20mL微波管中將(3-溴-4-(2,4-二氟苯氧基)苯甲基)(乙基)(亞胺基)-λ6-硫烷酮(100mg,0.26mmol)，中間體Im(6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮)(109mg,0.26mmol)，四(三苯基膦)鈀(44mg,0.04mmol)，碳酸鈉(68mg,0.64mmol)溶於DME/H2O(4mL/4mL)，氮氣吹掃1-2分鐘後，微波120℃下反應30分鐘。停止反應，加入水(30mL)淬滅反應，用乙酸乙酯(30mL×2)萃取，合併有機相用飽和氯化鈉(30mL)洗滌，無水硫酸鈉乾燥，過濾，濃縮後製備薄層析分離得到4-(2-(2,4-二氟苯氧基)-5-(乙基磺亞胺醯基甲基)苯基)-6-甲基-1-甲苯磺醯 -1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(38mg,33%)。 (3-Bromo-4- (2,4-difluorophenoxy) benzyl) (ethyl) (imino) -λ6-sulfanone (100 mg, 0.26 mmol) in a 20 mL microwave tube, Intermediate Im (6-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-toluenesulfonium- 1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one) (109 mg, 0.26 mmol), tetrakis (triphenylphosphine) palladium (44 mg, 0.04 mmol), sodium carbonate (68 mg , 0.64 mmol) was dissolved in DME / H2O (4 mL / 4 mL). After purging with nitrogen for 1-2 minutes, the reaction was performed at 120 ° C for 30 minutes in the microwave. Stop the reaction, add water (30 mL) to quench the reaction, extract with ethyl acetate (30 mL x 2), combine the organic phases and wash with saturated sodium chloride (30 mL), dry over anhydrous sodium sulfate, filter, and concentrate to prepare a thin chromatography separation Obtain 4- (2- (2,4-difluorophenoxy) -5- (ethylsulfonyliminomethyl) phenyl) -6-methyl-1-toluenesulfonyl-1,6- Dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (38 mg, 33%).
MS m/z(ESI)：612.1[M+H]+. MS m / z (ESI): 612.1 [M + H] + .
4-(2-(2,4-二氟苯氧基)-5-(乙基磺亞胺醯基甲基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(30.0mg，0.05mmol)溶於乙醇(10mL)中，加入3mol/L的NaOH(3mL)，室溫條件下攪拌3h。停止反應，加入飽和碳酸氫鈉溶液(30mL)，用乙酸乙酯(30mLX2)萃取，合併有機相用飽和氯化鈉(30mL)洗滌，無水硫酸鈉乾燥，過濾，濃縮，用製備矽膠板分離，二氯甲烷/甲醇(10/1)，得4-(2-(2,4-二氟苯氧基)-5-(乙基磺亞胺醯基甲基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(16.6mg，產率72.6%)。 4- (2- (2,4-difluorophenoxy) -5- (ethylsulfonyliminomethyl) phenyl) -6-methyl-1-toluenesulfonyl-1,6-di Hydrogen-7H-pyrrolo [2,3-c] pyridin-7-one (30.0 mg, 0.05 mmol) was dissolved in ethanol (10 mL), 3 mol / L NaOH (3 mL) was added, and the mixture was stirred at room temperature for 3 h. The reaction was stopped, saturated sodium bicarbonate solution (30 mL) was added, and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated with a preparative silica gel plate. Dichloromethane / methanol (10/1) to give 4- (2- (2,4-difluorophenoxy) -5- (ethylsulfonyliminomethyl) phenyl) -6-methyl -1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (16.6 mg, yield 72.6%).
MS m/z(ESI)：458.0[M+H]+. MS m / z (ESI): 458.0 [M + H] + .
1H NMR(400MHz,CDCl3)δ 10.52(s,1 H),7.62(d,J=2.0Hz,1H),7.33-7.31(dd,J=8.4Hz,2.0Hz,1H),7.25(d,J=2.8Hz,1H),7.17(s,1H),7.00-6.88(m,2H),6.86-6.79(m,2H),6.43(t,J=2.0Hz,1H),4.41(d,J=12.8Hz,1H),4.30(d,J=12.8Hz,1H),3.68(s,3H),3.18(q,J=7.6Hz,2H), 1.48(t,J=7.6Hz,3H)； 1 H NMR (400MHz, CDCl 3 ) δ 10.52 (s, 1 H), 7.62 (d, J = 2.0Hz, 1H), 7.33-7.31 (dd, J = 8.4Hz, 2.0Hz, 1H), 7.25 (d , J = 2.8Hz, 1H), 7.17 (s, 1H), 7.00-6.88 (m, 2H), 6.86-6.79 (m, 2H), 6.43 (t, J = 2.0Hz, 1H), 4.41 (d, J = 12.8Hz, 1H), 4.30 (d, J = 12.8Hz, 1H), 3.68 (s, 3H), 3.18 (q, J = 7.6Hz, 2H), 1.48 (t, J = 7.6Hz, 3H) ;
4-(2-(2,4-二氟苯氧基)-5-(乙基磺亞胺醯基甲基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(65.0mg，0.11mmol)溶於吡啶(2mL)，加入環丙基磺醯氯(200mg，1.42mmol),DMAP(12mg，0.1mmol)在室溫條件下攪拌過夜。停止反應，加入1N鹽酸溶液(30mL)，用乙酸乙酯(30mLX2)萃取，合併有機相用飽和氯化鈉(30mL)洗滌，無水硫酸鈉乾燥，過濾，濃縮，用製備矽膠板分離，得N-((4-(2,4-二氟苯氧基)-3-(6-甲基-7-羰基-1-甲苯磺醯-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯甲基)(乙基)(羰基)-λ6-硫烷亞基)環丙磺醯胺(32.0mg，產率42.2%)。 4- (2- (2,4-difluorophenoxy) -5- (ethylsulfonyliminomethyl) phenyl) -6-methyl-1-toluenesulfonyl-1,6-di Hydrogen-7H-pyrrolo [2,3-c] pyridin-7-one (65.0mg, 0.11mmol) was dissolved in pyridine (2mL), cyclopropylsulfonyl chloride (200mg, 1.42mmol), DMAP (12mg, 0.1 mmol) was stirred at room temperature overnight. The reaction was stopped, 1N hydrochloric acid solution (30 mL) was added, and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated with a silica gel plate to obtain N. -((4- (2,4-difluorophenoxy) -3- (6-methyl-7-carbonyl-1-toluenesulfonium-6,7-dihydro-1H-pyrrolo [2,3 -c] pyridin-4-yl) benzyl) (ethyl) (carbonyl) -λ6-sulfanylidene) cyclopropanesulfonamide (32.0 mg, yield 42.2%).
MS m/z(ESI)：716.0[M+H]+. MS m / z (ESI): 716.0 [M + H] + .
以N-((4-(2,4-二氟苯氧基)-3-(6-甲基-7-羰基-1-甲苯磺醯-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯甲基)(乙基)(羰基)-λ6-硫烷亞基)環丙磺醯胺為起始原料，參照實施例1第八步得到N-((4-(2,4-二氟苯氧基)-3-(6-甲基-7-羰基-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯甲基)(乙基)(羰基)-λ-6-硫烷亞基)環丙磺醯胺。 N-((4- (2,4-difluorophenoxy) -3- (6-methyl-7-carbonyl-1-toluenesulfonium-6,7-dihydro-1H-pyrrolo [2 , 3-c] pyridin-4-yl) benzyl) (ethyl) (carbonyl) -λ6-sulfanylidene) cyclopropanesulfonamide as a starting material, and referring to the eighth step of Example 1, N- ((4- (2,4-difluorophenoxy) -3- (6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo [2,3-c] pyridine-4- Group) benzyl) (ethyl) (carbonyl) -λ-6-sulfanylidene) cyclopropanesulfonamide.
MS m/z(ESI)：562.0[M+H]+. MS m / z (ESI): 562.0 [M + H] + .
1H NMR(400MHz,CDCl3)δ 11.01(s,1 H),7.69(d,J=2.0Hz,1H),7.37-7.34(dd,J=8.4Hz,2.4Hz,1H),7.30(d,J=2.8Hz,1H),7.25(s,1H),7.02-6.90(m,2H),6.84-6.80(m,2H),6.42(t,J=2.0Hz,1H),4.78(d,J=14.4Hz,1H),4.70(d,J=14.4Hz,1H),3.73(s,3H),3.18(q,J=7.6Hz,2H),2.67-2.63(m,1H),1.48-1.45(t,J=7.6Hz,3H),1.28-1.24(m,2H),1.02-0.98(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ 11.01 (s, 1 H), 7.69 (d, J = 2.0Hz, 1H), 7.37-7.34 (dd, J = 8.4Hz, 2.4Hz, 1H), 7.30 (d , J = 2.8Hz, 1H), 7.25 (s, 1H), 7.02-6.90 (m, 2H), 6.84-6.80 (m, 2H), 6.42 (t, J = 2.0Hz, 1H), 4.78 (d, J = 14.4Hz, 1H), 4.70 (d, J = 14.4Hz, 1H), 3.73 (s, 3H), 3.18 (q, J = 7.6Hz, 2H), 2.67-2.63 (m, 1H), 1.48- 1.45 (t, J = 7.6Hz, 3H), 1.28-1.24 (m, 2H), 1.02-0.98 (m, 2H).
4-(2-(2,4-二氟苯氧基)-5-(乙基磺亞胺醯基甲基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(100mg,0.16mmol)，三甲基氧鎓四氟硼酸(121mg,0.82mmol)，二氯甲烷(5mL)置反應瓶中，室溫下攪拌15分鐘後，加入碳酸鈉(104mg,0.98mmol)，室溫反應過夜。停止反應，加入水(20mL)，用乙酸乙酯(30mLx2)萃取，合併有機相用飽和氯化鈉(30mL)洗滌，無水硫酸鈉乾燥，過濾，濾液濃縮，藉由製備矽膠板分離純化(展開劑：二氯甲烷/甲醇=10/1；洗脫劑：乙酸乙酯/甲醇=10/1)得4-(2-(2,4-二氟苯氧基)-5-((N-甲基乙基磺亞胺醯基)甲基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(32.0mg，產率42.2%)。 4- (2- (2,4-difluorophenoxy) -5- (ethylsulfonyliminomethyl) phenyl) -6-methyl-1-toluenesulfonyl-1,6-di Hydrogen-7H-pyrrolo [2,3-c] pyridin-7-one (100 mg, 0.16 mmol), trimethyloxonium tetrafluoroborate (121 mg, 0.82 mmol), and dichloromethane (5 mL) were placed in a reaction flask After stirring at room temperature for 15 minutes, sodium carbonate (104 mg, 0.98 mmol) was added and reacted at room temperature overnight. The reaction was stopped, water (20 mL) was added, and extraction was performed with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Agent: dichloromethane / methanol = 10/1; eluent: ethyl acetate / methanol = 10/1) to obtain 4- (2- (2,4-difluorophenoxy) -5-((N- Methylethylsulfonylimino) methyl) phenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7- Ketone (32.0 mg, 42.2% yield).
MS m/z(ESI)：626.0[M+H]+. MS m / z (ESI): 626.0 [M + H] + .
以4-(2-(2,4-二氟苯氧基)-5-((N-甲基乙基磺亞胺醯基)甲基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為起始原料，參照實施例1第八步水解得到4-(2-(2,4-二氟苯氧基)-5-((N-甲基乙基磺亞胺醯基)甲基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮。 4- (2- (2,4-difluorophenoxy) -5-((N-methylethylsulfimideamido) methyl) phenyl) -6-methyl-1-toluenesulfonate醯 -1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one was used as a starting material, and the eighth step of Example 1 was used to obtain 4- (2- (2,4-di Fluorophenoxy) -5-((N-methylethylsulfonylimino) methyl) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridine-7-one.
MS m/z(ESI)：472.0[M+H]+. MS m / z (ESI): 472.0 [M + H] +.
1H NMR(400MHz,CDCl3)δ 10.54(s,1 H),7.56(d,J=2.4Hz,1H),7.32-7.29(dd,J=8.4Hz,2.0Hz,1H),7.27(d,J=2.8Hz,1H),7.00(s,1H),6.98-6.88(m,2H),6.85-6.77(m,2H),6.44(t,J=2.4Hz,1H),4.36(s,2H),3.69(s,3H),3.03(q,J=7.6Hz,2H),2.84(s,3H),1.41(t,J=7.6Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ 10.54 (s, 1 H), 7.56 (d, J = 2.4Hz, 1H), 7.32-7.29 (dd, J = 8.4Hz, 2.0Hz, 1H), 7.27 (d , J = 2.8Hz, 1H), 7.00 (s, 1H), 6.98-6.88 (m, 2H), 6.85-6.77 (m, 2H), 6.44 (t, J = 2.4Hz, 1H), 4.36 (s, 2H), 3.69 (s, 3H), 3.03 (q, J = 7.6Hz, 2H), 2.84 (s, 3H), 1.41 (t, J = 7.6Hz, 3H).
3-氯-4-氟苯硫醇(1g，6.2mmol)和氫氧化鈉(246mg，6.2mmol)溶於甲醇(15ml)和水(1.5ml)，加入碘甲烷(873mg，6.2mmol)，反應在室溫攪拌下過夜。反應液蒸乾，乙酸乙酯萃取，飽和食鹽水洗滌，有機相乾燥蒸乾，得到(3-氯-4-氟苯基)(甲基)硫烷(720mg，產率66%)。 3-chloro-4-fluorobenzenethiol (1 g, 6.2 mmol) and sodium hydroxide (246 mg, 6.2 mmol) were dissolved in methanol (15 ml) and water (1.5 ml), and methyl iodide (873 mg, 6.2 mmol) was added to react Stir overnight at room temperature. The reaction solution was evaporated to dryness, extracted with ethyl acetate, washed with saturated brine, and the organic phase was dried and evaporated to dryness to obtain (3-chloro-4-fluorophenyl) (methyl) sulfane (720 mg, yield 66%).
1H NMR(400MHz,CDCl3)：δ 7.29(dd,J=6.7Hz,2.3Hz,1H),7.13(m,1H),7.06(t,J=8.7Hz,1H),2.47(s,3H)； 1 H NMR (400MHz, CDCl 3 ): δ 7.29 (dd, J = 6.7Hz, 2.3Hz, 1H), 7.13 (m, 1H), 7.06 (t, J = 8.7Hz, 1H), 2.47 (s, 3H );
(3-氯-4-氟苯基)(甲基)硫烷(690mg，3.9mmol)溶於二氯甲烷(10ml)中，在-30℃下加入間氯過氧苯甲酸(75% w/w，900mg，3.9mmol)的二氯甲烷(3ml)溶液。反應在-20℃下攪拌2小時，然後碳酸氫鈉飽和水溶液洗滌，二氯甲烷萃取。有機相分離，乾燥，蒸乾得到2-氯-1-氟-4-(甲基亞硫醯基<亞磺醯>)苯(620mg，產率86%)。 (3-Chloro-4-fluorophenyl) (methyl) sulfane (690 mg, 3.9 mmol) was dissolved in dichloromethane (10 ml), and m-chloroperoxybenzoic acid (75% w / w, 900 mg, 3.9 mmol) in dichloromethane (3 ml). The reaction was stirred at -20 ° C for 2 hours, then washed with a saturated aqueous solution of sodium bicarbonate, and extracted with dichloromethane. The organic phase was separated, dried, and evaporated to dryness to give 2-chloro-1-fluoro-4- (methylsulfinamido <sulfenimidine>) benzene (620 mg, yield 86%).
1H NMR(400MHz,CDCl3)：δ 7.75(dd,J=6.7Hz,2.2Hz,1H),7.56-7.50(m,1H),7.32(t,J=8.5Hz,1H),2.75(s,3H)； 1 H NMR (400MHz, CDCl3): δ 7.75 (dd, J = 6.7Hz, 2.2Hz, 1H), 7.56-7.50 (m, 1H), 7.32 (t, J = 8.5Hz, 1H), 2.75 (s, 3H);
2-氯-1-氟-4-(甲基亞硫醯基<亞磺醯>)苯(500mg，2.6mmol)和疊氮化鈉(338mg，5.2mmol)懸浮於氯仿(10ml)中，然後加入濃硫酸(0.85ml，15.6mmol)。反應液在45℃下攪拌16小時，然後冷卻到室溫，二氯甲烷萃取，飽和碳酸氫鈉水溶液洗滌，有機相乾燥，蒸乾，管柱分離(石油醚：乙酸乙酯=10：1)得到(3-氯-4-氟苯基)(亞胺基)(甲基)-λ6-硫烷酮(300mg，產率55%)。 2-Chloro-1-fluoro-4- (methylsulfinyl <sulfenimidine>) benzene (500 mg, 2.6 mmol) and sodium azide (338 mg, 5.2 mmol) were suspended in chloroform (10 ml), and then Concentrated sulfuric acid (0.85 ml, 15.6 mmol) was added. The reaction solution was stirred at 45 ° C for 16 hours, then cooled to room temperature, extracted with dichloromethane, washed with a saturated aqueous sodium hydrogen carbonate solution, the organic phase was dried, evaporated to dryness, and separated by column (petroleum ether: ethyl acetate = 10: 1) (3-chloro-4-fluorophenyl) (imino) (methyl) -λ6-sulfanone (300 mg, yield 55%) was obtained.
MS m/z(ESI)：208.0[M+H]+。 MS m / z (ESI): 208.0 [M + H] + .
1H NMR(400MHz,CDCl3)：δ 8.04(dd,J=6.7Hz,2.3Hz,1H),7.90-7.82(m,1H),7.25(t,J=8.5Hz,1H),3.06(s,3H),2.64-2.70(br,1H). 1 H NMR (400MHz, CDCl3): δ 8.04 (dd, J = 6.7Hz, 2.3Hz, 1H), 7.90-7.82 (m, 1H), 7.25 (t, J = 8.5Hz, 1H), 3.06 (s, 3H), 2.64-2.70 (br, 1H).
將(3-氯-4-氟苯基)(亞胺基)(甲基)-λ6-硫烷酮(100mg，0.48mmol)，中間體Im(250mg，0.58mmol)和碳酸鉀(200mg，1.44mmol)溶於乙醇，甲苯，水(v/v 9：3：1，5ml)，然後加入四三苯基膦鈀(56mg，48umol)。反應在120℃微波氮氣保護下攪拌0.5小時。反應液濃縮，管柱分離(二氯 甲烷：甲醇=98：2)得到4-(2-氟-5-(S-甲基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(80mg，產率35%)。 Add (3-chloro-4-fluorophenyl) (imino) (methyl) -λ 6 -sulfanone (100 mg, 0.48 mmol), intermediate Im (250 mg, 0.58 mmol) and potassium carbonate (200 mg, 1.44 mmol) was dissolved in ethanol, toluene, water (v / v 9: 3: 1, 5 ml), and then tetratriphenylphosphine palladium (56 mg, 48 umol) was added. The reaction was stirred under microwave nitrogen protection at 120 ° C for 0.5 hours. The reaction solution was concentrated and separated in a column (dichloromethane: methanol = 98: 2) to obtain 4- (2-fluoro-5- (S-methylsulfonylimino) phenyl) -6-methyl-1- Tosyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (80 mg, yield 35%).
MS m/z(ESI)：474.0[M+H]+。 MS m / z (ESI): 474.0 [M + H] + .
4-(2-氟-5-(S-甲基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(30mg，63.4umol)和2,4-二氟苯酚(20mg，152umol)溶於二甲基亞碸(1.5ml)，然後加入碳酸鉀(26mg，190umol)。反應在120℃氮氣保護下攪拌16小時，然後冷卻到室溫。二氯甲烷萃取，飽和食鹽水洗滌。有機相乾燥蒸乾，粗產物反相處層析分離(水：乙腈=3：2)，得到4-(2-(2,4-二氟苯氧基)-5-(S-甲基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(2.5mg，產率9%)。 4- (2-fluoro-5- (S-methylsulfonylimino) phenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2,3 -c] pyridin-7-one (30 mg, 63.4 umol) and 2,4-difluorophenol (20 mg, 152 umol) were dissolved in dimethyl sulfene (1.5 ml), and potassium carbonate (26 mg, 190 umol) was added. The reaction was stirred under nitrogen at 120 ° C for 16 hours, and then cooled to room temperature. Extracted with dichloromethane and washed with saturated brine. The organic phase was dried and evaporated to dryness, and the crude product was separated by reversed phase chromatography (water: acetonitrile = 3: 2) to obtain 4- (2- (2,4-difluorophenoxy) -5- (S-methylsulfinyl). Amine fluorenyl) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (2.5 mg, yield 9%).
MS m/z(ESI)：430.1[M+H]+。 MS m / z (ESI): 430.1 [M + H] + .
1H NMR(400MHz,CDCl3)：δ 10.44-10.57(s,1H),8.15-8.09(m,1H),7.94-7.88(m,1H),7.31-7.26(m,1H),7.15(s,1H),7.10-7.02(m,1H),7.01-6.94(m,1H),6.91-6.83(m,2H),6.40-6.37(m,1H),3.71(s,3H),3.20(s,3H)； 1 H NMR (400MHz, CDCl3): δ 10.44-10.57 (s, 1H), 8.15-8.09 (m, 1H), 7.94-7.88 (m, 1H), 7.31-7.26 (m, 1H), 7.15 (s, 1H), 7.10-7.02 (m, 1H), 7.01-6.94 (m, 1H), 6.91-6.83 (m, 2H), 6.40-6.37 (m, 1H), 3.71 (s, 3H), 3.20 (s, 3H);
以3-氯-4-氟苯硫醇(900mg,5.55mmol)為反應原料，參考實施例4第一步，用2-碘丙烷代替碘甲烷，得到化合物(3-氯-4-氟苯基)(異丙基)硫烷(產率66%)。 Using 3-chloro-4-fluorobenzenethiol (900mg, 5.55mmol) as the reaction raw material, the first step of Reference Example 4 was to replace 2-iodopropane with methyl iodide to obtain the compound (3-chloro-4-fluorophenyl ) (Isopropyl) sulfane (66% yield).
以(3-氯-4-氟苯基)(異丙基)硫烷為反應原料，參考實施例4第二步，得到化合物2-氯-1-氟-4-(異丙基亞硫醯基<亞磺醯>)苯(產率93%)。 Using (3-chloro-4-fluorophenyl) (isopropyl) sulfane as a reaction raw material, the second step of Reference Example 4 was used to obtain the compound 2-chloro-1-fluoro-4- (isopropylsulfenyl) (<Sulfinylpyrene>) benzene (yield 93%).
2-氯-1-氟-4-(異丙基亞硫醯基<亞磺醯>)苯(900.mg,4.09mmol)，溶於甲醇(15mL)，室溫下加胺基甲酸胺(1.27g,16.36mmol)，醋酸碘苯(3.95g,12.27mmol)，反應在室溫下攪拌半個小時，反應完全，將反應液濃縮，用乙酸乙酯(20ml)萃取，然後用水(20mL *2)和飽和食鹽水(20mL)洗滌，並用無水硫酸鈉乾燥，濃縮後管層析(二氯甲烷：甲醇=20：1)得到化合物(3-氯-4-氟苯基)(亞胺基)(異丙基)-硫烷酮(680mg，產率72%)。 2-Chloro-1-fluoro-4- (isopropylsulfenyl <sulfenimidine>) benzene (900.mg, 4.09mmol), dissolved in methanol (15mL), and amine carbamate ( 1.27g, 16.36mmol), iodobenzene acetate (3.95g, 12.27mmol), the reaction was stirred at room temperature for half an hour, the reaction was complete, the reaction solution was concentrated, extracted with ethyl acetate (20ml), and then water (20mL * 2) Washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated by tube chromatography (dichloromethane: methanol = 20: 1) to obtain the compound (3-chloro-4-fluorophenyl) (imino group) ) (Isopropyl) -sulfanone (680 mg, 72% yield).
MS m/z(ESI)：236.06[M+H]+。 MS m / z (ESI): 236.06 [M + H] + .
以(3-氯-4-氟苯基)(亞胺基)(異丙基)-硫烷酮為反應原料，參考實施例4第四步，得到化合物4-(2-氟-5-(丙烷-2-基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率33%)。 Using (3-chloro-4-fluorophenyl) (imino) (isopropyl) -sulfanone as a reaction raw material, refer to the fourth step of Example 4, to obtain compound 4- (2-fluoro-5- ( Propane-2-ylsulfonylimino) phenyl) -6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one ( Yield: 33%).
MS m/z(ESI)：502.1[M+H]+。 MS m / z (ESI): 502.1 [M + H] + .
4-(2-氟-5-(丙烷-2-基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(64.0mg,0.12mmol)，溶於DMF(2mL)中，加入環丙基甲醇(17.2mg,0.24mmol)，冰浴下加入鈉氫(10.0mg,0.24mmol)，0℃下攪拌十分鐘，然後45℃攪拌過夜，將反應用乙酸乙酯(10ml)萃取，然後用水(10mL *2)和飽和食鹽水(10mL)洗滌，並用無水硫酸鈉乾燥，濃縮後管柱層析(二氯甲烷：甲醇=20：1)得到化合物4-(2-(環丙基甲氧基)-5-(丙烷-2-基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(23.5mg，產率49%)。 4- (2-fluoro-5- (propane-2-ylsulfenimidofluorenyl) phenyl) -6-methyl-1-toluenesulfonamido-1,6-dihydro-7H-pyrrolo [2, 3-c] pyridine-7-one (64.0 mg, 0.12 mmol), dissolved in DMF (2 mL), cyclopropyl methanol (17.2 mg, 0.24 mmol) was added, and sodium hydrogen (10.0 mg, 0.24 mmol) was added under ice bath ), Stirred at 0 ° C for ten minutes, and then stirred at 45 ° C overnight. The reaction was extracted with ethyl acetate (10 ml), then washed with water (10 mL * 2) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. Column chromatography (dichloromethane: methanol = 20: 1) to give compound 4- (2- (cyclopropylmethoxy) -5- (propane-2-ylsulfenimido) phenyl) -6 -Methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (23.5 mg, yield 49%).
MS m/z(ESI)：400.1[M+H]+； MS m / z (ESI): 400.1 [M + H] + ;
1H NMR(400MHz,MeOD)δ 7.95(d,J=2.4Hz,1H),7.92(dd,J=8.6Hz,2.5Hz,1H),7.40-7.34(m,2H),7.31(d,J=8.7Hz,1H),6.28(d,J=2.9Hz,1H),4.01(d,J=6.8Hz,2H),3.73(s,3H),3.45-3.36(m,1H),1.33(d,J=6.8Hz,3H),1.30(d,J=6.8Hz,3H),1.26-1.11(m,1H),0.60-0.49(m,2H),0.37-0.26(m,2H). 1 H NMR (400MHz, MeOD) δ 7.95 (d, J = 2.4Hz, 1H), 7.92 (dd, J = 8.6Hz, 2.5Hz, 1H), 7.40-7.34 (m, 2H), 7.31 (d, J = 8.7Hz, 1H), 6.28 (d, J = 2.9Hz, 1H), 4.01 (d, J = 6.8Hz, 2H), 3.73 (s, 3H), 3.45-3.36 (m, 1H), 1.33 (d , J = 6.8Hz, 3H), 1.30 (d, J = 6.8Hz, 3H), 1.26-1.11 (m, 1H), 0.60-0.49 (m, 2H), 0.37-0.26 (m, 2H).
以4-(2-氟-5-(丙烷-2-基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，用2,4-二氟苯酚取代環丙基甲醇，參考實施例5第五步，得到化合物4-(2-(2,4-二氟苯氧基)-5-(丙烷-2-基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率39%)。 With 4- (2-fluoro-5- (propane-2-ylsulfimidofluorenyl) phenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2 , 3-c] pyridine-7-one as a raw material, and 2,4-difluorophenol was substituted for cyclopropyl methanol. The fifth step of Reference Example 5 was to obtain the compound 4- (2- (2,4-difluorobenzene). (Oxy) -5- (propane-2-ylsulfimimidino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7-one (Yield 39%).
MS m/z(ESI)：458.1[M+H]+。 MS m / z (ESI): 458.1 [M + H] + .
1H NMR(400MHz,CDCl3)：δ 8.21(s,1H),8.12(s,1H),7.52(m,1H),7.42(d,J=8.7Hz,1H),7.35(s,1H),7.21(t,J=9.4Hz,2H),7.08(d,J=2.9Hz,1H),6.40(s,1H),4.40-4.19(m,1H),3.76(s,3H),1.59(d,J=6.8Hz,3H),1.47(d,J=6.8Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ 8.21 (s, 1H), 8.12 (s, 1H), 7.52 (m, 1H), 7.42 (d, J = 8.7Hz, 1H), 7.35 (s, 1H) , 7.21 (t, J = 9.4Hz, 2H), 7.08 (d, J = 2.9Hz, 1H), 6.40 (s, 1H), 4.40-4.19 (m, 1H), 3.76 (s, 3H), 1.59 ( d, J = 6.8Hz, 3H), 1.47 (d, J = 6.8Hz, 3H).
以4-(2-氟-5-(丙烷-2-基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，用環己基甲醇取代環丙基甲醇，參考實施例5第五步，得到 化合物4-(2-(環己三烯並氧基)-5-(丙烷-2-基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率35%)。 With 4- (2-fluoro-5- (propane-2-ylsulfimidofluorenyl) phenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2 , 3-c] pyridine-7-one as a raw material, and cyclohexylmethanol was substituted for cyclopropylmethanol. The fifth step of Reference Example 5 was to obtain compound 4- (2- (cyclohexatrienoxy) -5- (Propan-2-ylsulfonylimino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (35% yield) .
MS m/z(ESI)：428.1[M+H]+； MS m / z (ESI): 428.1 [M + H] + ;
1H NMR(400MHz,CDCl3)δ 10.47(s,1H),7.99(d,J=2.4Hz,1H),7.88(dd,J==8.7Hz,2.4Hz,1H),7.26(s,1H),7.13(s,1H),7.09(d,J=8.9Hz,1H),6.28(t,J=2.4Hz,1H),4.51-4.37(m,1H),3.71(s,3H),3.42-3.30(m,1H),1.95-1.84(m,2H),1.70-1.57(m,2H),1.57-1.44(m,2H),1.43-1.15(m,10H). 1 H NMR (400MHz, CDCl 3 ) δ 10.47 (s, 1H), 7.99 (d, J = 2.4Hz, 1H), 7.88 (dd, J == 8.7Hz, 2.4Hz, 1H), 7.26 (s, 1H ), 7.13 (s, 1H), 7.09 (d, J = 8.9Hz, 1H), 6.28 (t, J = 2.4Hz, 1H), 4.51-4.37 (m, 1H), 3.71 (s, 3H), 3.42 -3.30 (m, 1H), 1.95-1.84 (m, 2H), 1.70-1.57 (m, 2H), 1.57-1.44 (m, 2H), 1.43-1.15 (m, 10H).
以4-(2-氟-5-(丙烷-2-基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為反應原料，用苯酚取代環丙基甲醇，參考實施例5第五步，得到化合物6-甲基-4-(2-苯氧基-5-(丙烷-2-基磺亞胺醯基)苯基)-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(7.9mg，產率22%)。 With 4- (2-fluoro-5- (propane-2-ylsulfimidofluorenyl) phenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2 , 3-c] pyridine-7-one as the reaction raw material, cyclophenol methanol was replaced with phenol, and the fifth step of Reference Example 5 was used to obtain the compound 6-methyl-4- (2-phenoxy-5- (propane) 2-ylsulfimidofluorenyl) phenyl) -1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (7.9 mg, yield 22%).
MS m/z(ESI)：422.1[M+H]+； MS m / z (ESI): 422.1 [M + H] + ;
1H NMR(400MHz,CDCl3)δ 10.48(br,1H),8.11(d,J= 2.4Hz,1H),7.85(dd,J=8.7Hz,2.4Hz,1H),7.41-7.31(m,2H),7.30-7.27(m,1H),7.23-7.11(m,2H),7.08-6.93(m,3H),6.42-6.30(m,1H),3.68(s,3H),3.48-3.33(m,1H),1.40(d,J=6.8Hz,3H),1.35(d,J=6.8Hz,3H). 1 H NMR (400MHz, CDCl3) δ 10.48 (br, 1H), 8.11 (d, J = 2.4Hz, 1H), 7.85 (dd, J = 8.7Hz, 2.4Hz, 1H), 7.41-7.31 (m, 2H ), 7.30-7.27 (m, 1H), 7.23-7.11 (m, 2H), 7.08-6.93 (m, 3H), 6.42-6.30 (m, 1H), 3.68 (s, 3H), 3.48-3.33 (m , 1H), 1.40 (d, J = 6.8Hz, 3H), 1.35 (d, J = 6.8Hz, 3H).
以4-(2-氟-5-(丙烷-2-基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為反應原料，用4,4-二氟環己基甲醇取代環丙基甲醇，參考實施例5第五步，得到化合物4-(2-((4,4-二氟環己基)酮基)-5-(丙烷-2-基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率19%)。 With 4- (2-fluoro-5- (propane-2-ylsulfimidofluorenyl) phenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2 , 3-c] pyridine-7-one as a reaction raw material, and cyclopropyl methanol was replaced with 4,4-difluorocyclohexyl methanol. The fifth step of Reference Example 5 was to obtain the compound 4- (2-((4,4 -Difluorocyclohexyl) keto) -5- (propane-2-ylsulfenimido) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c ] Pyridine-7-one (19% yield).
MS m/z(ESI)：464.1[M+H]+。 MS m / z (ESI): 464.1 [M + H] + .
1H NMR(400MHz,CDCl3)δ 10.49(br,1H),8.17-7.80(m,2H),7.79-7.67(m,1H),7.58-7.45(m,1H),7.21-6.96(m,1H),6.30-6.12(m,1H),4.71-4.57(m,1H),3.70(s,3H),3.61-3.42(m,1H),1.85-1.70(m,8H),1.42(d,J=6.3Hz,3H),1.36(d,J=6.6Hz,3H). 1 H NMR (400MHz, CDCl3) δ 10.49 (br, 1H), 8.17-7.80 (m, 2H), 7.79-7.67 (m, 1H), 7.58-7.45 (m, 1H), 7.21-6.96 (m, 1H ), 6.30-6.12 (m, 1H), 4.71-4.57 (m, 1H), 3.70 (s, 3H), 3.61-3.42 (m, 1H), 1.85-1.70 (m, 8H), 1.42 (d, J = 6.3Hz, 3H), 1.36 (d, J = 6.6Hz, 3H).
3-溴-4-氟苯胺(19g，0.1mol)和銅粉(0.96g，15mmol)溶於1,2-二乙基二硫烷(50ml)，將反應體系加熱至80攝氏度。緩慢的滴入亞硝酸異戊酯(15g,0.15mmol)以保持反應的內部溫度不高於90℃。滴加完畢反應在90℃下攪拌兩小時。反應液蒸乾，甲苯和稀鹽酸加入反應體系，分液，甲苯相分別使用稀鹽酸，水和飽和食鹽水洗滌，有機相乾燥蒸乾，殘留物藉由減壓蒸餾，收集蒸汽溫度60-70℃的餾分來得到的3-溴-4-氟苯基)(乙基)硫烷(15g，淡黃色油狀，產率63%)。 3-Bromo-4-fluoroaniline (19 g, 0.1 mol) and copper powder (0.96 g, 15 mmol) were dissolved in 1,2-diethyldisulfane (50 ml), and the reaction system was heated to 80 degrees Celsius. Isoamyl nitrite (15 g, 0.15 mmol) was slowly added dropwise to keep the internal temperature of the reaction not higher than 90 ° C. After the dropwise addition, the reaction was stirred at 90 ° C for two hours. The reaction solution was evaporated to dryness. Toluene and dilute hydrochloric acid were added to the reaction system. The liquid phase was separated. The toluene phase was washed with dilute hydrochloric acid, water and saturated brine. The organic phase was dried and evaporated to dryness. The residue was distilled under reduced pressure to collect steam temperature 60-70. A 3-bromo fraction was used to obtain 3-bromo-4-fluorophenyl) (ethyl) sulfane (15 g, pale yellow oil, 63% yield).
1H NMR(400MHz,CDCl3)：δ 7.53(dd,J=6.4Hz，2.0Hz,1H),7.27-7.23(m,1H),7.04(t,J=8.4Hz,1H),2.90(q,J=7.6Hz,2H),1.29(t,J=7.6Hz,3H)； 1 H NMR (400MHz, CDCl3): δ 7.53 (dd, J = 6.4Hz, 2.0Hz, 1H), 7.27-7.23 (m, 1H), 7.04 (t, J = 8.4Hz, 1H), 2.90 (q, J = 7.6 Hz, 2H), 1.29 (t, J = 7.6 Hz, 3H);
以(3-溴-4-氟苯基)(乙基)硫烷為反應原料，參考實施例4第二步，得到2-溴-1-氟-4-(乙基亞硫醯基<亞磺醯>) 苯(產率86%)。 Using (3-bromo-4-fluorophenyl) (ethyl) sulfane as a reaction raw material, refer to the second step of Example 4, to obtain 2-bromo-1-fluoro-4- (ethylthiosulfenyl group) Sulfonium>) benzene (86% yield).
以2-溴-1-氟-4-(乙基亞硫醯基<亞磺醯>)苯為反應原料，參考實施例5第三步，得到(3-溴-4-氟苯基)(亞胺基)(乙基)-λ6-硫烷酮(收率78%)。 Using 2-bromo-1-fluoro-4- (ethylsulfinyl <sulfenylsulfonium>) benzene as a reaction raw material, refer to the third step of Example 5 to obtain (3-bromo-4-fluorophenyl) ( Imino) (ethyl) -λ6-sulfanone (yield 78%).
MS m/z(ESI)：265.9/267.9(50/50)[M+H]+. MS m / z (ESI): 265.9 / 267.9 (50/50) [M + H] + .
(3-溴-4-氟苯基)(亞胺基)(乙基)-λ6-硫烷酮(266mg，1mmol)，中間體Im(428mg，1mmol)和碳酸鉀(270mg，2mmol)溶於1,4-二氧六環和水(v/v 9：1，10ml)，然後加入[1,1'-二(二苯基膦基)二茂鐵]二氯鈀(II)(140mg，0.2mmol)。反應在100℃氮氣保護下攪拌15小時。反應液濃縮，管柱分離(石油醚：乙酸乙酯=1：1~0：1)得到4-(5-(乙基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(160mg，產率30%)。 (3-Bromo-4-fluorophenyl) (imino) (ethyl) -λ 6 -sulfanone (266 mg, 1 mmol), intermediate Im (428 mg, 1 mmol) and potassium carbonate (270 mg, 2 mmol) were dissolved To 1,4-dioxane and water (v / v 9: 1, 10ml), then [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (140mg , 0.2 mmol). The reaction was stirred under nitrogen at 100 ° C for 15 hours. The reaction solution was concentrated and separated in a column (petroleum ether: ethyl acetate = 1: 1 to 0: 1) to obtain 4- (5- (ethylsulfonylimino) -2-fluorophenyl) -6-methyl. 1-Tosylsulfonium-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (160 mg, yield 30%).
MS m/z(ESI)：488.1[M+H]+. MS m / z (ESI): 488.1 [M + H] + .
2,4-二氟苯酚(800mg，0.6mmol)溶於1-甲基吡咯烷酮(1.5ml)，將氫化鈉(60% in mine oil，25mg,0.6mmol)加入反應體系中，室溫下攪拌10分鐘之後加入4-(5-(乙基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(50mg，0.1mmol)。反應體系密封之後置於180攝氏度的微波條件下反應半個小時，然後冷卻到室溫。乙酸乙酯萃取，飽和食鹽水洗滌。有機相乾燥蒸乾，粗產物製備板分離(二氯甲烷：甲醇==10：1)，得到4-(2-(2,4-二氟苯氧基)-5-(乙基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(30mg，產率67%)。 2,4-difluorophenol (800mg, 0.6mmol) was dissolved in 1-methylpyrrolidone (1.5ml), sodium hydride (60% in mine oil, 25mg, 0.6mmol) was added to the reaction system, and the mixture was stirred at room temperature for 10 minutes. After 4 minutes, 4- (5- (ethylsulfonylimidino) -2-fluorophenyl) -6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo [2, 3-c] pyridin-7-one (50 mg, 0.1 mmol). After the reaction system was sealed, it was placed under microwave conditions of 180 degrees Celsius for half an hour, and then cooled to room temperature. Extract with ethyl acetate and wash with saturated brine. The organic phase was dried and evaporated to dryness, and the crude product was separated on a plate (dichloromethane: methanol == 10: 1) to obtain 4- (2- (2,4-difluorophenoxy) -5- (ethylsulfimide). Fluorenyl) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (30 mg, yield 67%).
MS m/z(ESI)：444.1[M+H]+； MS m / z (ESI): 444.1 [M + H] + ;
1H NMR(400MHz,d4-MeOD)：δ 7.97(d,J=2.4Hz,1H),7.81(dd,J=8.8Hz,2.4Hz,1H),7.24-7.27(m,2H),7.10-7.12(m,2H),6.84-6.93(m,2H),6.27(d,J=2.8Hz,1H),3.60(s,3H),3.19(q,J=8.0Hz,2H),1.16(t,J=8.0Hz,3H)。 1 H NMR (400MHz, d 4-MeOD): δ 7.97 (d, J = 2.4Hz, 1H), 7.81 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.24-7.27 (m, 2H), 7.10 -7.12 (m, 2H), 6.84-6.93 (m, 2H), 6.27 (d, J = 2.8Hz, 1H), 3.60 (s, 3H), 3.19 (q, J = 8.0Hz, 2H), 1.16 ( t, J = 8.0 Hz, 3H).
以4-(5-(乙基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為反應原料，參考實施例10第五步，用環己醇取代2,4-二氟苯酚得到4-(2-(環己三烯並氧基)-5-(乙基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率21%)。 4- (5- (ethylsulfonylimino) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one is used as a reaction raw material. In the fifth step of Reference Example 10, cyclohexanol is used to replace 2,4-difluorophenol to obtain 4- (2- (cyclohexatrienoxy) -5- ( Ethylsulfimideamido) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (21% yield).
MS m/z(ESI)：414.1[M+H]+； MS m / z (ESI): 414.1 [M + H] + ;
1H NMR(400MHz,d4-MeOD)：δ 7.82-7.86(m,2H),7.23-7.24(m,2H),7.20(s,1H),6.16(d,J=2.8Hz,1H),4.47-4.48(m,1H),3.61(s,3H),3.24(q,J=7.2Hz,2H),1.79-1.82(m,2H),1.37-1.52(m,5H),1.24-1.33(m,3H),1.17(t,J=7.2Hz,3H). 1 H NMR (400MHz, d 4-MeOD): δ 7.82-7.86 (m, 2H), 7.23-7.24 (m, 2H), 7.20 (s, 1H), 6.16 (d, J = 2.8Hz, 1H), 4.47-4.48 (m, 1H), 3.61 (s, 3H), 3.24 (q, J = 7.2Hz, 2H), 1.79-1.82 (m, 2H), 1.37-1.52 (m, 5H), 1.24-1.33 ( m, 3H), 1.17 (t, J = 7.2Hz, 3H).
以4-(5-(乙基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為反應原料，參考實施例10第五步，用4,4-二氟環己醇取代2,4-二氟苯 酚，得到4-(2-((4,4-二氟環己基)酮基)-5-(乙基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率33%)。 4- (5- (ethylsulfonylimino) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one as the reaction raw material. In the fifth step of Reference Example 10, 2,4-difluorophenol was replaced with 4,4-difluorocyclohexanol to obtain 4- (2-((4,4- Difluorocyclohexyl) keto) -5- (ethylsulfonylimino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7 -Ketone (33% yield).
MS m/z(ESI)：450.1[M+H]+； MS m / z (ESI): 450.1 [M + H] + ;
1H NMR(400MHz,d4-MeOD)：δ 7.86-7.89(m,2H),7.30(d,J=9.6Hz,1H),7.25(d,J=2.8Hz,1H),7.18(s,1H),6.15(d,J=3.2Hz,1H),4.69-4.70(m,1H),3.61(s,3H),3.24(q,J=7.2Hz,2H),1.55-1.84(m,8H),1.17(t,J=7.2Hz,3H)。 1 H NMR (400MHz, d 4-MeOD): δ 7.86-7.89 (m, 2H), 7.30 (d, J = 9.6Hz, 1H), 7.25 (d, J = 2.8Hz, 1H), 7.18 (s, 1H), 6.15 (d, J = 3.2Hz, 1H), 4.69-4.70 (m, 1H), 3.61 (s, 3H), 3.24 (q, J = 7.2Hz, 2H), 1.55-1.84 (m, 8H ), 1.17 (t, J = 7.2 Hz, 3H).
以4-(5-(乙基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為反應原料，參考實施例10第五步，用對甲氧基環己醇取代2,4-二氟苯酚，得到4-(5-(乙基磺亞胺醯基)-2-((4-甲氧基環己基)酮基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率33%)。 4- (5- (ethylsulfonylimino) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one is used as a reaction raw material. In the fifth step of Reference Example 10, p-methoxycyclohexanol is used to replace 2,4-difluorophenol to obtain 4- (5- (ethylsulfimidine) ) -2-((4-methoxycyclohexyl) keto) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7-one ( Yield: 33%).
MS m/z(ESI)：444.1[M+H]+。 MS m / z (ESI): 444.1 [M + H] + .
1H NMR(400MHz,d6-DMSO)：δ 12.05(s,1H),7.84(dd,J=9.6Hz,2.4Hz,1H),7.78(d,J=8.8Hz,1H), 7.29-7.36(m,3H),6.15(dt,J=2.4,9.6Hz,1H),4.56-4.62(m,1H),4.05(s,1H),3.56(s,3H),3.09-3.22(m,5H),1.93-1.97(m,1H),1.58-1.78(m,4H),1.33-1.45(m,3H),1.10(t,J=7.2Hz,3H). 1 H NMR (400MHz, d6 -DMSO): δ 12.05 (s, 1H), 7.84 (dd, J = 9.6Hz, 2.4Hz, 1H), 7.78 (d, J = 8.8Hz, 1H), 7.29-7.36 ( m, 3H), 6.15 (dt, J = 2.4, 9.6 Hz, 1H), 4.56-4.62 (m, 1H), 4.05 (s, 1H), 3.56 (s, 3H), 3.09-3.22 (m, 5H) , 1.93-1.97 (m, 1H), 1.58-1.78 (m, 4H), 1.33-1.45 (m, 3H), 1.10 (t, J = 7.2Hz, 3H).
以3-溴-4-氟苯胺為反應原料，參考實施例10第一步，用二甲基二硫烷取代1,2-二乙基二硫烷，得到的(3-溴-4-氟苯基)(甲基)硫烷(淡黃色油狀物，產率63%)。 Using 3-bromo-4-fluoroaniline as the reaction raw material, the first step of Reference Example 10 was to replace 1,2-diethyldisulfane with dimethyldisulfane to obtain (3-bromo-4-fluoro Phenyl) (methyl) sulfane (light yellow oil, 63% yield).
1H NMR(400MHz,CDCl3)：δ 7.46-7.38(m,1H),7.21-7.12(m,1H),7.08-6.99(m,1H),2.46(s,3H)。 1 H NMR (400 MHz, CDCl3): δ 7.46-7.38 (m, 1H), 7.21-7.12 (m, 1H), 7.08-6.99 (m, 1H), 2.46 (s, 3H).
以(3-溴-4-氟苯基)(甲基)硫烷為反應原料，參考實施例4第二步，得到2-溴-1-氟-4-(甲基亞硫醯基<亞磺醯>) 苯(產率85%)。 Using (3-bromo-4-fluorophenyl) (methyl) sulfane as a reaction raw material, refer to the second step of Example 4, to obtain 2-bromo-1-fluoro-4- (methylthiosulfenyl group) Sulfonium>) benzene (85% yield).
MS m/z(ESI)：237.0[M+H]+,238.9[M+2+H]+。 MS m / z (ESI): 237.0 [M + H] + , 238.9 [M + 2 + H] + .
以2-溴-1-氟-4-(甲基亞硫醯基<亞磺醯>)苯為原料，參考實施例5第三步，得到(3-溴-4-氟苯基)(亞胺基)(甲基)-λ6-硫烷酮(產率90%)。 Using 2-bromo-1-fluoro-4- (methylthiosulfinyl <sulfenimidine>) benzene as a raw material, the third step of Reference Example 5 was used to obtain (3-bromo-4-fluorophenyl) ( Amine) (methyl) -λ6-sulfanone (yield 90%).
MS m/z(ESI)：251.9/253.9(50/50)[M+H]+. MS m / z (ESI): 251.9 / 253.9 (50/50) [M + H] + .
以(3-溴-4-氟苯基)(亞胺基)(甲基)-λ6-硫烷酮為原料，參考實施例4第四步得到4-(2-氟-5-(S-甲基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率58%)。 Using (3-bromo-4-fluorophenyl) (imino) (methyl) -λ6-sulfanone as a raw material, the fourth step of Reference Example 4 was to obtain 4- (2-fluoro-5- (S- Methanesulfonylimino) phenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7-one (yield 58 %).
MS m/z(ESI)：474.1[M+H]+。 MS m / z (ESI): 474.1 [M + H] + .
以4-(2-氟-5-(S-甲基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為反應原料，參考實施例10第五步，用環丙基甲醇取代2,4-二氟苯酚，得到4-(2-(環丙基甲氧基)-5-(S-甲基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮。 With 4- (2-fluoro-5- (S-methylsulfonylimino) phenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2, 3-c] pyridine-7-one as a reaction raw material. In the fifth step of Reference Example 10, 2,4-difluorophenol was replaced with cyclopropylmethanol to obtain 4- (2- (cyclopropylmethoxy)- 5- (S - methyl sulfonic acyl imine) phenyl) -6-methyl-1,6-dihydro -7 H - pyrrolo [2,3-c] pyridin-7-one.
MS m/z(ESI)：372.1[M+H]+。 MS m / z (ESI): 372.1 [M + H] + .
1H NMR(400MHz,CDCl3)：δ 11.33(s,1H),8.08(d,J=2.4Hz,1H),7.99(dd,J=8.7Hz,2.4Hz,1H),7.31(t,J=2.7Hz,1H),7.11(d,J=8.8Hz,1H),7.05(s,1H),6.24(t,J=2.4Hz,1H),4.62(s,1H),3.91(d,J=8Hz,2H),3.73(s,3H),3.20(s,3H),1.24-1.31(m,1H),0.58-0.49(m,2H),0.31-0.24(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ 11.33 (s, 1H), 8.08 (d, J = 2.4Hz, 1H), 7.99 (dd, J = 8.7Hz, 2.4Hz, 1H), 7.31 (t, J = 2.7Hz, 1H), 7.11 (d, J = 8.8Hz, 1H), 7.05 (s, 1H), 6.24 (t, J = 2.4Hz, 1H), 4.62 (s, 1H), 3.91 (d, J = 8Hz, 2H), 3.73 (s, 3H), 3.20 (s, 3H), 1.24-1.31 (m, 1H), 0.58-0.49 (m, 2H), 0.31-0.24 (m, 2H).
以4-(2-氟-5-(S-甲基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為反應原料，參考實施例10第五步，用4,4-二氟環己醇取代2,4-二氟苯 酚，得到4-(2-(4,4-二氟環己氧基)-5-(S-甲基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮。 With 4- (2-fluoro-5- (S-methylsulfonylimino) phenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2, 3-c] pyridine-7-one as the reaction raw material. In the fifth step of Reference Example 10, 2,4-difluorophenol was replaced with 4,4-difluorocyclohexanol to obtain 4- (2- (4,4 - difluoro-cyclohexyloxy) -5- (S - methyl sulfonic acyl imine) phenyl) -6-methyl-1,6-dihydro -7 H - pyrrolo [2,3-c] Pyridine-7-one.
MS m/z(ESI)：436.1[M+H]+。 MS m / z (ESI): 436.1 [M + H] + .
1H NMR(400MHz,CDCl3)：δ 11.08(s,1H),8.06(d,J=2.4Hz,1H),8.00(dd,J=8.7Hz,2.4Hz,1H),7.30(t,J=2.7Hz,1H),7.11(d,J=8.8Hz,1H),7.05(s,1H),6.24(t,J=2.4Hz,1H),4.62-4.61(m,1H),3.73(s,3H),3.20(s,3H),2.04-1.70(m,8H). 1 H NMR (400MHz, CDCl 3 ): δ 11.08 (s, 1H), 8.06 (d, J = 2.4Hz, 1H), 8.00 (dd, J = 8.7Hz, 2.4Hz, 1H), 7.30 (t, J = 2.7Hz, 1H), 7.11 (d, J = 8.8Hz, 1H), 7.05 (s, 1H), 6.24 (t, J = 2.4Hz, 1H), 4.62-4.61 (m, 1H), 3.73 (s , 3H), 3.20 (s, 3H), 2.04-1.70 (m, 8H).
以4-(2-氟-5-(S-甲基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為反應原料，參考實施例10第五步，用環己醇取代2,4-二氟苯酚，得到標題化合物4-(2-(環己氧基)-5-(S-甲基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮。 With 4- (2-fluoro-5- (S-methylsulfonylimino) phenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2, 3-c] pyridine-7-one as a reaction raw material. In the fifth step of Reference Example 10, 2,4-difluorophenol was replaced with cyclohexanol to obtain the title compound 4- (2- (cyclohexyloxy) -5. - (S - methyl sulfonic acyl imine) phenyl) -6-methyl-1,6-dihydro -7 H - pyrrolo [2,3-c] pyridin-7-one.
MS m/z(ESI)：400.1[M+H]+ MS m / z (ESI): 400.1 [M + H] +
1H NMR(400MHz,CDCl3)：δ 11.17(s,1H),8.05(d,J=2.4Hz,1H),7.95(dd,J=8.7Hz,2.4Hz,1H),7.30(t,J=2.6Hz,1H),7.12(s,1H),7.09(d,J=8.8Hz,1H),6.28(t,J=2.2Hz,1H),4.42-4.41(m,1H),3.73(s,3H),3.17(s,3H), 1.90-1.88(m,2H),1.61-1.60(m,2H),1.49-1.48(m,2H),1.34-1.32(m,4H). 1 H NMR (400MHz, CDCl 3 ): δ 11.17 (s, 1H), 8.05 (d, J = 2.4Hz, 1H), 7.95 (dd, J = 8.7Hz, 2.4Hz, 1H), 7.30 (t, J = 2.6Hz, 1H), 7.12 (s, 1H), 7.09 (d, J = 8.8Hz, 1H), 6.28 (t, J = 2.2Hz, 1H), 4.42-4.41 (m, 1H), 3.73 (s , 3H), 3.17 (s, 3H), 1.90-1.88 (m, 2H), 1.61-1.60 (m, 2H), 1.49-1.48 (m, 2H), 1.34-1.32 (m, 4H).
以4-(2-(環丙基甲氧基)-5-(S-甲基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為起始原料，參考實施例2第一步，得到標題化合物N-((4-(環丙基甲氧基)-3-(6-甲基-7-羰基-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基)(甲基)(羰基)-λ6-硫烷亞基)環丙磺醯胺。 To 4- (2- (cyclopropylmethoxy) -5- (S - methyl sulfonic acyl imine) phenyl) -6-methyl-1,6-dihydro -7 H - pyrrolo [ 2,3-c] pyridine-7-one as a starting material, and referring to the first step of Example 2, the title compound N -((4- (cyclopropylmethoxy) -3- (6-methyl- 7-carbonyl-6,7-dihydro-1 H -pyrrolo [2,3-c] pyridin-4-yl) phenyl) (methyl) (carbonyl) -λ 6 -sulfanylidene) cyclopropane Sulfonamide.
MS m/z(ESI)：476.1[M+H]+ MS m / z (ESI): 476.1 [M + H] +
1H NMR(400MHz,CDCl3)δ 10.62(s,1H),8.00(d,J=2.5Hz,1H),7.94(dd,J=8.8Hz,2.4Hz,1H),7.20(s,1H),7.14(s,1H),7.06(d,J=8.8Hz,1H),6.25(d,J=2.2Hz,1H),3.89(d,J=6.7Hz,2H),3.71(s,3H),3.37(s,3H),2.71-2.57(m,1H),1.24-1.18(m,4H),1.15-1.04(m,1H),1.00-0.90(m,2H),0.52-0.47(m,2H),0.23-0.19(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ 10.62 (s, 1H), 8.00 (d, J = 2.5Hz, 1H), 7.94 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.20 (s, 1H) , 7.14 (s, 1H), 7.06 (d, J = 8.8Hz, 1H), 6.25 (d, J = 2.2Hz, 1H), 3.89 (d, J = 6.7Hz, 2H), 3.71 (s, 3H) , 3.37 (s, 3H), 2.71-2.57 (m, 1H), 1.24-1.18 (m, 4H), 1.15-1.04 (m, 1H), 1.00-0.90 (m, 2H), 0.52-0.47 (m, 2H), 0.23-0.19 (m, 2H).
以4-(2-氟-5-(S-甲基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為反應原料，參考實施例10第五步，用3-胺基苯酚取代2,4-二氟苯酚，得到4-(2-(3-胺基苯氧基)-5-(S-甲基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮。 With 4- (2-fluoro-5- (S-methylsulfonylimino) phenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2, 3-c] pyridine-7-one as a reaction raw material. In the fifth step of Reference Example 10, 2,4-difluorophenol was replaced with 3-aminophenol to obtain 4- (2- (3-aminophenoxy). ) -5- (S-methylsulfonylimino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7-one.
MS m/z(ESI)：409.1[M+H]+ MS m / z (ESI): 409.1 [M + H] +
1H NMR(400MHz,DMSO-d 6 )：δ 12.16(s,1H),8.24(d,J=2.6Hz,1H),8.11(dd,J=8.9Hz,2.6Hz,1H),7.52(s,1H),7.47(t,J=8.0Hz,1H),7.32(t,J=2.8Hz,1H),7.24(d,J=8.9Hz,1H),7.13(d,J=7.7Hz,1H),7.06(s,1H),7.00(d,J=8.0Hz,1H),6.50-6.22(m,1H),4.01(s,3H),3.59(s,3H). 1 H NMR (400MHz, DMSO- d 6 ): δ 12.16 (s, 1H), 8.24 (d, J = 2.6Hz, 1H), 8.11 (dd, J = 8.9Hz, 2.6Hz, 1H), 7.52 (s , 1H), 7.47 (t, J = 8.0Hz, 1H), 7.32 (t, J = 2.8Hz, 1H), 7.24 (d, J = 8.9Hz, 1H), 7.13 (d, J = 7.7Hz, 1H ), 7.06 (s, 1H), 7.00 (d, J = 8.0Hz, 1H), 6.50-6.22 (m, 1H), 4.01 (s, 3H), 3.59 (s, 3H).
將二甲亞碸(5g，64mmol)溶於二氯甲烷(40mL)，0℃下加入疊氮化鈉(4.4g，68mmol)，滴加濃硫酸(13mL)。反應在35℃下攪拌過夜，將反應液倒入冰水中(100g)，分出水層，水相旋乾，加入乙醇(100mL)打漿30分鐘，過濾，濾液旋乾，加入二氯甲烷(100mL)打漿30分鐘，過濾，濾液旋乾得到亞胺基二甲基-λ6-硫烷酮(5.2g，產率87%)。 Dimethylarsin (5 g, 64 mmol) was dissolved in dichloromethane (40 mL), sodium azide (4.4 g, 68 mmol) was added at 0 ° C, and concentrated sulfuric acid (13 mL) was added dropwise. The reaction was stirred overnight at 35 ° C. The reaction solution was poured into ice water (100 g), the aqueous layer was separated, the aqueous phase was spin-dried, ethanol (100 mL) was added for beating for 30 minutes, filtered, the filtrate was spin-dried, and dichloromethane (100 mL) Beat for 30 minutes, filter, and spin-dry the filtrate to obtain iminodimethyl-λ6-sulfanone (5.2 g, yield 87%).
1H NMR(400MHz,CDCl3)δ 3.09(s,6H),2.68(brs,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 3.09 (s, 6H), 2.68 (brs, 1H).
將2-溴-1-氟-4硝基苯(2g，9mmol)，苯酚(0.9g，10mmol)溶於二甲亞碸(20mL)中，加入碳酸銫(3.3g，10mmol)。反應在100℃攪拌過夜，反應完全後，在25℃下加入水(50mL)，用乙酸乙酯(50mL)萃取，再用飽和氯化鈉水溶液(20mL)洗滌，分出乙酸乙酯，減壓脫除乙酸乙酯得到2-溴-4-硝基-1-苯氧基苯(2.7g，產率100%)。 2-Bromo-1-fluoro-4nitrobenzene (2 g, 9 mmol) and phenol (0.9 g, 10 mmol) were dissolved in dimethylarsine (20 mL), and cesium carbonate (3.3 g, 10 mmol) was added. The reaction was stirred at 100 ° C overnight. After the reaction was completed, water (50mL) was added at 25 ° C, and the mixture was extracted with ethyl acetate (50mL), and then washed with a saturated sodium chloride aqueous solution (20mL). The ethyl acetate was separated and the pressure was reduced. Removal of ethyl acetate gave 2-bromo-4-nitro-1-phenoxybenzene (2.7 g, yield 100%).
將2-溴-4-硝基-1-苯氧基苯(2.7g，9mmol)溶於乙醇(20mL)、四氫呋喃(20mL)、水(10mL)，加入鐵粉(2.5g，45mmol)、氯化銨(2.4g，45mmol)。升溫至75℃，攪拌1.5 小時，經矽藻土過濾，濾液脫除溶劑，加入二氯甲烷萃取，分層，乾燥，減壓脫除二氯甲烷得到3-溴-4-苯氧基苯胺(2.0g，產率83%)。 Dissolve 2-bromo-4-nitro-1-phenoxybenzene (2.7 g, 9 mmol) in ethanol (20 mL), tetrahydrofuran (20 mL), and water (10 mL), add iron powder (2.5 g, 45 mmol), and chlorine Ammonium (2.4 g, 45 mmol). The temperature was raised to 75 ° C, stirred for 1.5 hours, filtered through celite, the solvent was removed from the filtrate, dichloromethane was added for extraction, the layers were separated, and the dichloromethane was removed under reduced pressure to obtain 3-bromo-4-phenoxyaniline ( 2.0 g, yield 83%).
MS m/z(ESI)：264.0/266.0(50/50)[M+H]+. MS m / z (ESI): 264.0 / 266.0 (50/50) [M + H] + .
將3-溴-4-苯氧基苯胺(0.8g，3mmol)溶於乙腈(30mL)、水(5mL)，加入對甲苯磺酸一水合物(1.8g，10mmol)，在0℃下，滴加亞硝酸鈉(0.4g，6mmol)與碘化鉀(1.3g，8mmol)的水溶液(5mL)，在25℃下反應3小時，加入亞硫酸鈉飽和溶液(20mL)，蒸除有機溶劑，加入乙酸乙酯(100mL)萃取，乙酸乙酯旋乾管柱層析得到2-溴-4-碘-1-苯氧基苯(678mg，產率58%)。 3-Bromo-4-phenoxyaniline (0.8g, 3mmol) was dissolved in acetonitrile (30mL) and water (5mL), and p-toluenesulfonic acid monohydrate (1.8g, 10mmol) was added. Add an aqueous solution (5 mL) of sodium nitrite (0.4 g, 6 mmol) and potassium iodide (1.3 g, 8 mmol), and react at 25 ° C for 3 hours. Add a saturated solution of sodium sulfite (20 mL), evaporate the organic solvent, and add ethyl acetate ( 100mL) extraction, ethyl acetate spin-drying column chromatography to obtain 2-bromo-4-iodo-1-phenoxybenzene (678mg, yield 58%).
將2-溴-4-碘-1-苯氧基苯(300mg，0.8mmol)，亞胺基二甲基-λ6-硫烷酮(88mg，0.9mmol)溶於二氧六環(5mL)中，再加入碳酸銫(359mg，1.1mmol)、4,5-雙二苯基膦-9,9-二甲基氧雜蒽(34mg，0.06mmol)、三(二亞苄基丙酮)二鈀(22mg，0.02mmol)，氮氣置換並保護。在100℃攪拌3 小時，加入矽膠旋乾管柱層析得((3-溴-4-苯氧基苯基)亞胺基)二甲基-λ6-硫烷酮(160mg，產率59%)。 Dissolve 2-bromo-4-iodo-1-phenoxybenzene (300 mg, 0.8 mmol), iminodimethyl-λ6-sulfanone (88 mg, 0.9 mmol) in dioxane (5 mL) , And then add cesium carbonate (359mg, 1.1mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (34mg, 0.06mmol), tris (dibenzylideneacetone) dipalladium ( 22 mg, 0.02 mmol), replaced with nitrogen and protected. Stir at 100 ° C for 3 hours. Add silica gel spin-dry column chromatography to obtain ((3-bromo-4-phenoxyphenyl) imino) dimethyl-λ6-sulfanone (160mg, yield 59%). ).
將((3-溴-4-苯氧基苯基)亞胺基)二甲基-λ6-硫烷酮(160mg，0.5mmol)，中間體Im(262mg，0.6mmol)溶於二氧六環(5mL)與水(1mL)中，加入碳酸鉀(137mg，0.6mmol)，[1,1'-二(二苯基膦基)二茂鐵]二氯鈀(II)(40mg，0.05mmol)，氮氣置換並保護，在100℃下攪拌3小時，加入矽膠旋乾管柱層析得4-(5-((二甲基(羰基)-λ6-硫烷亞基)胺基)-2-苯氧基苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(100mg，產率38%)。 ((3-Bromo-4-phenoxyphenyl) imino) dimethyl-λ6-sulfanone (160 mg, 0.5 mmol), intermediate Im (262 mg, 0.6 mmol) was dissolved in dioxane (5 mL) and water (1 mL), potassium carbonate (137 mg, 0.6 mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (40 mg, 0.05 mmol) were added. , Nitrogen substitution and protection, stirring at 100 ° C for 3 hours, adding silica gel spin-dry column chromatography to obtain 4- (5-((dimethyl (carbonyl) -λ6-sulfanylidene) amino) -2- Phenoxyphenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (100 mg, yield 38%).
MS m/z(ESI)：562.1[M+H]+. MS m / z (ESI): 562.1 [M + H] + .
以4-(5-((二甲基(羰基)-λ6-硫烷亞基)胺基)-2-苯氧基 苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為起始原料，參考實施例1第八步水解，得到4-(5-((二甲基(羰基)-λ6-硫烷亞基)胺基)-2-苯氧基苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率17%)。 4- (5-((dimethyl (carbonyl) -λ6-sulfanylidene) amino) -2-phenoxyphenyl) -6-methyl-1-toluenesulfonyl-1,6- Dihydro-7H-pyrrolo [2,3-c] pyridin-7-one was used as a starting material, and the eighth step of Reference Example 1 was hydrolyzed to obtain 4- (5-((dimethyl (carbonyl) -λ6- Thiane subunit) amino) -2-phenoxyphenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7 -Ketone (17% yield).
MS m/z(ESI)：408.1[M+H]+. MS m / z (ESI): 408.1 [M + H] + .
1H NMR(400MHz,DMSO-d6)：δ 11.98(br,1H),7.19-7.26(m,4H),7.07(s,1H),6.93-6.95(m,3H),6.78(d,J=8Hz,2H),6.24(s,1H),3.47(s,3H),3.23(s,6H)。 1 H NMR (400MHz, DMSO-d6): δ 11.98 (br, 1H), 7.19-7.26 (m, 4H), 7.07 (s, 1H), 6.93-6.95 (m, 3H), 6.78 (d, J = 8Hz, 2H), 6.24 (s, 1H), 3.47 (s, 3H), 3.23 (s, 6H).
將2-溴-1-氟-4-硝基苯(5g，22.7mmol)、環丙基甲醇(2g，27.3mmol)溶於N,N-二甲基甲醯胺(20mL)中，在0℃下分批加入鈉氫(1.2g，29.5mmol)，攪拌2小時。加入水(60mL)，加入乙酸乙酯(100mL)萃取，減壓除去乙酸乙酯得2-溴-1-(環丙基甲氧基)-4-硝基苯(6g，產率96%)。 Dissolve 2-bromo-1-fluoro-4-nitrobenzene (5g, 22.7mmol) and cyclopropylmethanol (2g, 27.3mmol) in N, N-dimethylformamide (20mL) at 0 Sodium hydrogen (1.2 g, 29.5 mmol) was added in portions at ° C and stirred for 2 hours. Water (60 mL) was added, and ethyl acetate (100 mL) was added for extraction. The ethyl acetate was removed under reduced pressure to obtain 2-bromo-1- (cyclopropylmethoxy) -4-nitrobenzene (6 g, yield 96%). .
以2-溴-1-(環丙基甲氧基)-4-硝基苯為反應原料，參考實施例19第三步，管柱層析得3-溴-4-(環丙基甲氧基)苯胺(2.7g，產率50%)。 Using 2-bromo-1- (cyclopropylmethoxy) -4-nitrobenzene as the reaction raw material, in the third step of Reference Example 19, 3-bromo-4- (cyclopropylmethoxy) was obtained by column chromatography. ) Aniline (2.7 g, 50% yield).
以3-溴-4-(環丙基甲氧基)苯胺為反應原料，參考實施例19第四步，管柱層析得2-溴-1-(環丙基甲氧基)-4-碘苯(266mg，產率61%)。 Using 3-bromo-4- (cyclopropylmethoxy) aniline as the reaction raw material, in the fourth step of Reference Example 19, column chromatography gave 2-bromo-1- (cyclopropylmethoxy) -4- Iodobenzene (266 mg, yield 61%).
以2-溴-1-(環丙基甲氧基)-4-碘苯為反應原料，操作參考實施例19第五步，管柱層析得((3-溴-4-(環丙基甲氧基)苯基)亞胺基)二甲基-λ6-硫烷酮(產率46%)。 Using 2-bromo-1- (cyclopropylmethoxy) -4-iodobenzene as a reaction raw material, the fifth step of Reference Example 19 was operated, and column chromatography was used to obtain ((3-bromo-4- (cyclopropyl) Methoxy) phenyl) imino) dimethyl-λ6-sulfanone (46% yield).
以((3-溴-4-(環丙基甲氧基)苯基)亞胺基)二甲基-λ6-硫烷酮與中間體Im為反應原料，操作參考實施例19第六步，得4-(2-(環丙基甲氧基)-5-((二甲基(羰基)-λ6-硫烷亞基)胺基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮。 ((3-Bromo-4- (cyclopropylmethoxy) phenyl) imino) dimethyl-λ6-sulfanone and intermediate Im are used as the starting materials. For the operation, refer to the sixth step of Example 19. 4- (2- (Cyclopropylmethoxy) -5-((dimethyl (carbonyl) -λ6-sulfanylidene) amino) phenyl) -6-methyl-1-toluenesulfonium -1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one.
MS m/z(ESI)：540.1[M+H]+. MS m / z (ESI): 540.1 [M + H] + .
以4-(2-(環丙基甲氧基)-5-((二甲基(羰基)-λ6-硫烷亞基)胺基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為反應原料，操作參考實施例1第八步水解，得4-(2-(環丙基甲氧基)-5-((二甲基(羰基)-λ6-硫烷亞基)胺基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮。 4- (2- (cyclopropylmethoxy) -5-((dimethyl (carbonyl) -λ6-sulfanylidene) amino) phenyl) -6-methyl-1-toluenesulfonium -1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one was used as a reaction raw material. The eighth step of Reference Example 1 was hydrolyzed to obtain 4- (2- (cyclopropylmethoxy) Yl) -5-((dimethyl (carbonyl) -λ6-sulfanylidene) amino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c ] Pyridine-7-one.
MS m/z(ESI)：386.1[M+H]+. MS m / z (ESI): 386.1 [M + H] + .
1H NMR(400MHz,DMSO-d6)：δ 11.95(br,1H),7.26(t,J=2.4Hz,1H),7.24(s,1H),6.91-6.95(m,2H),6.83-6.86(m,1H),6.15(t,J=2.4Hz,1H),3.73(d,J=6.8,Hz 2H),3.55(s,3H),3.16(s,6H),0.99-1.08(m,1H),0.39-0.44(m,2H),0.16-0.20(m,2H). 1 H NMR (400MHz, DMSO-d6): δ 11.95 (br, 1H), 7.26 (t, J = 2.4Hz, 1H), 7.24 (s, 1H), 6.91-6.95 (m, 2H), 6.83-6.86 (m, 1H), 6.15 (t, J = 2.4Hz, 1H), 3.73 (d, J = 6.8, Hz 2H), 3.55 (s, 3H), 3.16 (s, 6H), 0.99-1.08 (m, 1H), 0.39-0.44 (m, 2H), 0.16-0.20 (m, 2H).
用2,4-二氟苯酚取代苯酚，反應操作參考實施例19第二步，以2,4-二氟苯酚取代苯酚，得2-溴-1-(2,4-二氟苯氧基)-4-硝基苯(產率100%)。 Use 2,4-difluorophenol to replace phenol, and refer to the second step of Reference Example 19 for the reaction operation. Replace 2,4-difluorophenol with phenol to obtain 2-bromo-1- (2,4-difluorophenoxy). 4-nitrobenzene (100% yield).
以2-溴-1-(2,4-二氟苯氧基)-4-硝基苯為反應原料，操作參考實施例19第三步，得3-溴-4-(2,4-二氟苯氧基)苯胺(收率100%)。 Using 2-bromo-1- (2,4-difluorophenoxy) -4-nitrobenzene as the reaction raw material, the third step of Reference Example 19 was operated to obtain 3-bromo-4- (2,4-di Fluorophenoxy) aniline (yield 100%).
MS m/z(ESI)：300.0[M+H]+. MS m / z (ESI): 300.0 [M + H] + .
以3-溴-4-(2,4-二氟苯氧基)苯胺為反應原料，操作參考實施例19第四步，得2-溴-1-(2,4-二氟苯氧基)-4-碘苯。 Using 3-bromo-4- (2,4-difluorophenoxy) aniline as a reaction raw material, the fourth step of Reference Example 19 was operated to obtain 2-bromo-1- (2,4-difluorophenoxy). -4-iodobenzene.
以2-溴-1-(2,4-二氟苯氧基)-4-碘苯為反應原料，操作參考實施例19第五步，得((3-溴-4-(2,4-二氟苯氧基)苯基)亞胺基)二甲基-λ6-硫烷酮。 Using 2-bromo-1- (2,4-difluorophenoxy) -4-iodobenzene as the reaction raw material, the fifth step of Reference Example 19 was operated to obtain ((3-bromo-4- (2,4- Difluorophenoxy) phenyl) imino) dimethyl-λ6-sulfanone.
以((3-溴-4-(2,4-二氟苯氧基)苯基)亞胺基)二甲基-λ6-硫烷酮與中間體Im為反應原料，操作參考實施例19第六步，得4-(2-(2,4-二氟苯氧基)-5-((二甲基(羰基)λ6-硫烷亞基)胺基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並 [2,3-c]吡啶-7-酮。 ((3-Bromo-4- (2,4-difluorophenoxy) phenyl) imino) dimethyl-λ6-sulfanone and intermediate Im were used as the starting materials. In six steps, 4- (2- (2,4-difluorophenoxy) -5-((dimethyl (carbonyl) λ6-sulfanylidene) amino) phenyl) -6-methyl- 1-Tosylate-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7-one.
MS m/z(ESI)：598.1[M+H]+. MS m / z (ESI): 598.1 [M + H] + .
以4-(2-(2,4-二氟苯氧基)-5-((二甲基(羰基)λ6-硫烷亞基)胺基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為反應原料，操作參考實施例1第八步水解，得4-(2-(2,4-二氟苯氧基)-5-((二甲基(羰基)-λ1-硫烷亞基)胺基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(7mg，產率47%)。 4- (2- (2,4-difluorophenoxy) -5-((dimethyl (carbonyl) λ6-sulfanylidene) amino) phenyl) -6-methyl-1-toluene Sulfonium-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one was used as the reaction raw material. The eighth step of Reference Example 1 was used to hydrolyze to obtain 4- (2- (2,4 -Difluorophenoxy) -5-((dimethyl (carbonyl) -λ1-sulfanylidene) amino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [ 2,3-c] pyridin-7-one (7 mg, 47% yield).
MS m/z(ESI)：444.1[M+H]+. MS m / z (ESI): 444.1 [M + H] + .
1H NMR(400MHz,CDCl3)：δ 10.06(br,1H),7.21(m,2H),7.10(s,1H),7.02(d,J=6.4Hz,1H),6.76-6.83(m,3H),6.66-6.68(m,1H),6.42(s,1H),3.63(s,3H),3.16(s,6H). 1 H NMR (400MHz, CDCl3): δ 10.06 (br, 1H), 7.21 (m, 2H), 7.10 (s, 1H), 7.02 (d, J = 6.4Hz, 1H), 6.76-6.83 (m, 3H ), 6.66-6.68 (m, 1H), 6.42 (s, 1H), 3.63 (s, 3H), 3.16 (s, 6H).
以環己醇取環丙基甲醇，反應操作參考實施例20第二步，以環己醇取環丙基甲醇，得標題化合物2-溴-1-(環己三烯並氧基)-4-硝基苯。 Cyclohexanol was used to take cyclopropyl methanol. For the reaction operation, refer to the second step of Example 20. Cyclohexanol was used to take cyclopropyl methanol to obtain the title compound 2-bromo-1- (cyclohexatrienoxy) -4. -Nitrobenzene.
以2-溴-1-(環己三烯並氧基)-4-硝基苯為反應原料，操作參考實施例19第三步，得3-溴-4-(環己三烯並氧基)苯胺(產率100%)。 Using 2-bromo-1- (cyclohexatrienoxy) -4-nitrobenzene as a reaction raw material, the third step of Reference Example 19 was operated to obtain 3-bromo-4- (cyclohexatrienoxy) ) Aniline (100% yield).
MS m/z(ESI)：270.0/272.0(50/50)[M+H]+. MS m / z (ESI): 270.0 / 272.0 (50/50) [M + H] + .
以3-溴-4-(環己三烯並氧基)苯胺為反應原料，操作同實施例19第四步，得2-溴-1-(環己三烯並氧基)-4-碘苯(產率35%)。 Using 3-bromo-4- (cyclohexatrienoxy) aniline as a reaction raw material, the same operation as in the fourth step of Example 19 was performed to obtain 2-bromo-1- (cyclohexatrienoxy) -4-iodine. Benzene (35% yield).
以2-溴-1-(環己三烯並氧基)-4-碘苯為反應原料，操作 參考實施例19第五步，得((3-溴-4-(環己三烯並氧基)苯基)亞胺基)二甲基-λ6-硫烷酮(產率100%)。 Using 2-bromo-1- (cyclohexatrienoxy) -4-iodobenzene as a reaction raw material, the fifth step of Reference Example 19 was operated to obtain ((3-bromo-4- (cyclohexatrienoxy) Phenyl) phenyl) imino) dimethyl-λ6-sulfanone (yield 100%).
MS m/z(ESI)：346.0/347.0(50/50)[M+H]+. MS m / z (ESI): 346.0 / 347.0 (50/50) [M + H] +.
以((3-溴-4-(環己三烯並氧基)苯基)亞胺基)二甲基-λ6-硫烷酮與中間體Im為反應原料，操作參考實施例19第六步，得4-(2-(環己三烯並氧基)-5-((二甲基(羰基)-λ6-硫烷亞基)胺基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(284mg，產率61%)。 Using ((3-bromo-4- (cyclohexatrienoxy) phenyl) imino) dimethyl-λ6-sulfanone and intermediate Im as the starting materials, refer to the sixth step of Example 19 for operation. To give 4- (2- (cyclohexatrienoxy) -5-((dimethyl (carbonyl) -λ6-sulfanylidene) amino) phenyl) -6-methyl-1-toluene Sulfo-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (284 mg, yield 61%).
MS m/z(ESI)：568.1[M+H]+. MS m / z (ESI): 568.1 [M + H] + .
以4-(2-(環己三烯並氧基)-5-((二甲基(羰基)-λ6-硫烷亞基)胺基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並 [2,3-c]吡啶-7-酮為反應原料，操作參考實施例1第八步，得4-(2-(環己三烯並氧基)-5-((二甲基(羰基)-λ6-硫烷亞基)胺基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(28%)。 4- (2- (cyclohexatrienoxy) -5-((dimethyl (carbonyl) -λ6-sulfanylidene) amino) phenyl) -6-methyl-1-toluenesulfonate Pyrene-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one was used as a reaction raw material. The eighth step of Reference Example 1 was operated to obtain 4- (2- (cyclohexatriene and (Oxy) -5-((dimethyl (carbonyl) -λ6-sulfanylidene) amino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridine-7-one (28%).
MS m/z(ESI)：414.1[M+H]+。 MS m / z (ESI): 414.1 [M + H] + .
1H NMR(400MHz,DMSO-d6)：δ 11.95(br,1H),7.26(t,J=2.4Hz,1H),7.24(s,1H),6.94-6.97(m,2H),6.83-6.86(m,1H),6.17(t,J=2.4Hz,1H),4.09-4.13(m,1H),3.55(s,3H),3.10(s,6H),1.72-1.75(m,2H),1.49-1.59(m,2H),1.15-1.40(m,6H). 1 H NMR (400MHz, DMSO-d6): δ 11.95 (br, 1H), 7.26 (t, J = 2.4Hz, 1H), 7.24 (s, 1H), 6.94-6.97 (m, 2H), 6.83-6.86 (m, 1H), 6.17 (t, J = 2.4Hz, 1H), 4.09-4.13 (m, 1H), 3.55 (s, 3H), 3.10 (s, 6H), 1.72-1.75 (m, 2H), 1.49-1.59 (m, 2H), 1.15-1.40 (m, 6H).
以實施例10第四步反應的產物4-(5-(乙基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(49mg，0.1mmol)與反式4-甲基環己胺(1.0mL)反應體系密封之後置於150℃的封管條件下反應12小時。冷卻到室溫。乙酸乙酯(10.0mL)稀釋，飽和食鹽水洗滌。有機相乾燥蒸乾，粗產物液相製備分離得到4-(5-(乙基磺亞胺醯基)-2-((反式-4-甲基環己基)胺基)苯 基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(15.4mg，產率36%)。 The product of the fourth step in Example 10 was 4- (5- (ethylsulfonylimino) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro- The reaction system of 7H-pyrrolo [2,3-c] pyridin-7-one (49mg, 0.1mmol) and trans 4-methylcyclohexylamine (1.0mL) was sealed and placed under a sealed tube at 150 ° C. 12 hours. Cool to room temperature. It was diluted with ethyl acetate (10.0 mL) and washed with saturated brine. The organic phase was dried and evaporated to dryness, and the crude product was prepared as a liquid phase to obtain 4- (5- (ethylsulfonylimido) -2-((trans-4-methylcyclohexyl) amino) phenyl) -6. -Methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (15.4 mg, yield 36%).
MS m/z(ESI)：427.2[M+H]+。 MS m / z (ESI): 427.2 [M + H] + .
1H NMR(400MHz,MeOD)δ 7.78(dd,J=8.8Hz,2.4Hz,1H),7.63(d,J=2.4Hz,1H),7.36(d,J=2.8Hz,1H),7.22(s,1H),6.91(d,J=9.0Hz,1H),6.13(d,J=2.8Hz,1H),3.71(s,3H),3.40(m,1H),3.23(q,J=7.4Hz,2H),2.02(s,2H),1.72(s,2H),1.36(s,1H),1.25(t,J=7.4Hz,3H),1.16-1.03(m,4H),0.92(d,J=6.5Hz,3H). 1 H NMR (400MHz, MeOD) δ 7.78 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.63 (d, J = 2.4Hz, 1H), 7.36 (d, J = 2.8Hz, 1H), 7.22 ( s, 1H), 6.91 (d, J = 9.0Hz, 1H), 6.13 (d, J = 2.8Hz, 1H), 3.71 (s, 3H), 3.40 (m, 1H), 3.23 (q, J = 7.4 Hz, 2H), 2.02 (s, 2H), 1.72 (s, 2H), 1.36 (s, 1H), 1.25 (t, J = 7.4Hz, 3H), 1.16-1.03 (m, 4H), 0.92 (d , J = 6.5Hz, 3H).
以實施例10第四步反應的產物4-(5-(乙基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為起始原料，用環庚胺代替反式4-甲基環己胺參考實施例23第一步得到4-(2-(環庚基胺基)-5-(乙基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率19%)。 The product of the fourth step in Example 10 was 4- (5- (ethylsulfonylimino) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro- 7H-pyrrolo [2,3-c] pyridin-7-one was used as the starting material, and cycloheptylamine was used instead of trans 4-methylcyclohexylamine. Reference Example 23 In the first step, 4- (2- (cyclo Heptylamino) -5- (ethylsulfimidoamido) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one ( 19% yield).
MS m/z(ESI)：427.2[M+H]+。 MS m / z (ESI): 427.2 [M + H] + .
1H NMR(400MHz,MeOD)：δ 7.69(dd,J=8.8Hz,2.4Hz,1H),7.53(d,J=2.4Hz,1H),7.26(d,J=2.8Hz,1H), 7.12(s,1H),6.71(d,J=9.0Hz,1H),6.02(d,J=2.8Hz,1H),3.60(s,3H),3.57-3.50(m,1H),3.11(q,J=7.4Hz,2H),1.82(s,2H),1.65-1.23(m,10H),1.13(t,J=7.4Hz,3H). 1 H NMR (400MHz, MeOD): δ 7.69 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.53 (d, J = 2.4Hz, 1H), 7.26 (d, J = 2.8Hz, 1H), 7.12 (s, 1H), 6.71 (d, J = 9.0Hz, 1H), 6.02 (d, J = 2.8Hz, 1H), 3.60 (s, 3H), 3.57-3.50 (m, 1H), 3.11 (q, J = 7.4Hz, 2H), 1.82 (s, 2H), 1.65-1.23 (m, 10H), 1.13 (t, J = 7.4Hz, 3H)
以實施例10第四步反應的產物4-(5-(乙基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為起始原料，用環丙基甲胺代替反式4-甲基環己胺，參考實施例23第一步得到4-(2-((環丙基甲基)胺基)-5-(乙基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(35mg，產率63%)。 The product of the fourth step in Example 10 was 4- (5- (ethylsulfonylimino) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro- 7H-pyrrolo [2,3-c] pyridin-7-one was used as the starting material, and cyclopropylmethylamine was used instead of trans 4-methylcyclohexylamine. Refer to Example 23 to obtain 4- (2 -((Cyclopropylmethyl) amino) -5- (ethylsulfonylimino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c ] Pyridine-7-one (35 mg, 63% yield).
MS m/z(ESI)：385.2[M+H]+. MS m / z (ESI): 385.2 [M + H] + .
1H NMR(400MHz,MeOD)：δ 7.90(dd,J=9.2Hz,2.8Hz,1H),7.72(d,J=2.4Hz,1H),7.38(d,J=3.2Hz,1H),7.28(s,1H),7.07(d,J=9.2Hz,1H),6.15(d,J=2.8Hz,1H),3.84(q,J=7.2Hz,2H),3.72(s,3H),3.16(d,J=7.2Hz,2H),1.38(t,J=7.2Hz,3H),1.09-1.06(m,1H),0.51-0.46(m,2H),0.23-0.19(m,2H). 1 H NMR (400MHz, MeOD): δ 7.90 (dd, J = 9.2Hz, 2.8Hz, 1H), 7.72 (d, J = 2.4Hz, 1H), 7.38 (d, J = 3.2Hz, 1H), 7.28 (s, 1H), 7.07 (d, J = 9.2Hz, 1H), 6.15 (d, J = 2.8Hz, 1H), 3.84 (q, J = 7.2Hz, 2H), 3.72 (s, 3H), 3.16 (d, J = 7.2Hz, 2H), 1.38 (t, J = 7.2Hz, 3H), 1.09-1.06 (m, 1H), 0.51-0.46 (m, 2H), 0.23-0.19 (m, 2H).
以實施例10第四步反應的產物4-(5-(乙基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，用4,4二甲基環己胺代替反式4-甲基環己胺，參考實施例23第一步，得到4-(2-((4,4-二甲基環己基)胺基)-5-(S-甲基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率46%)。 The product of the fourth step in Example 10 was 4- (5- (ethylsulfonylimino) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro- 7H-pyrrolo [2,3-c] pyridin-7-one was used as the raw material, and 4,4-dimethylcyclohexylamine was used instead of trans 4-methylcyclohexylamine. Referring to the first step of Example 23, 4 was obtained. -(2-((4,4-dimethylcyclohexyl) amino) -5- (S-methylsulfonylimino) phenyl) -6-methyl-1,6-dihydro-7H -Pyrrolo [2,3-c] pyridin-7-one (46% yield).
MS m/z(ESI)：441.2[M+H]+. MS m / z (ESI): 441.2 [M + H] + .
1H NMR(400MHz,MeOD)δ 7.78(dd,J=9.1Hz,2.5Hz,1H),7.60(d,J=2.5Hz,1H),7.27(d,J=2.8Hz,1H),7.17(s,1H),6.95(d,J=9.2Hz,1H),6.02(d,J=2.8Hz,1H),3.78(q,J=7.3Hz,2H),3.60(s,3H),3.46-3.32(m,1H),1.28(t,J=7.3Hz,3H),1.27-1.16(m,8H),0.83(s,3H),0.75(s,3H). 1 H NMR (400MHz, MeOD) δ 7.78 (dd, J = 9.1Hz, 2.5Hz, 1H), 7.60 (d, J = 2.5Hz, 1H), 7.27 (d, J = 2.8Hz, 1H), 7.17 ( s, 1H), 6.95 (d, J = 9.2Hz, 1H), 6.02 (d, J = 2.8Hz, 1H), 3.78 (q, J = 7.3Hz, 2H), 3.60 (s, 3H), 3.46- 3.32 (m, 1H), 1.28 (t, J = 7.3Hz, 3H), 1.27-1.16 (m, 8H), 0.83 (s, 3H), 0.75 (s, 3H).
以實施例10第四步反應的產物4-(5-(乙基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並 [2,3-c]吡啶-7-酮為原料，用哌啶代替反式4-甲基環己胺參考實施例23第一步，得到4-(5-(乙基磺亞胺醯基)-2-(哌啶-1-基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率44%)。 The product of the fourth step in Example 10 was 4- (5- (ethylsulfonylimino) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro- 7H-pyrrolo [2,3-c] pyridin-7-one was used as the starting material, and piperidine was used instead of trans 4-methylcyclohexylamine. The first step of Reference Example 23 gave 4- (5- (ethylsulfon Iminoamido) -2- (piperidin-1-yl) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (produced Rate 44%).
MS m/z(ESI)：399.2[M+H]+. MS m / z (ESI): 399.2 [M + H] + .
1H NMR(400MHz,MeOD)δ 7.86(dd,J=8.6Hz,2.4Hz,1H),7.82(d,J=2.4Hz,1H),7.42(s,1H),7.35(d,J=2.8Hz,1H),7.26(d,J=8.6Hz,1H),6.28(d,J=2.9Hz,1H),3.74(s,3H),3.25(q,J=7.4Hz,2H),3.05-2.90(m,4H),1.40-1.31(m,6H),1.25(t,J=7.4Hz,3H). 1 H NMR (400MHz, MeOD) δ 7.86 (dd, J = 8.6Hz, 2.4Hz, 1H), 7.82 (d, J = 2.4Hz, 1H), 7.42 (s, 1H), 7.35 (d, J = 2.8 Hz, 1H), 7.26 (d, J = 8.6 Hz, 1H), 6.28 (d, J = 2.9 Hz, 1H), 3.74 (s, 3H), 3.25 (q, J = 7.4 Hz, 2H), 3.05- 2.90 (m, 4H), 1.40-1.31 (m, 6H), 1.25 (t, J = 7.4Hz, 3H).
以實施例14第四步反應的產物4-(2-氟-5-(S-甲基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，用環辛胺代替反式4-甲基環己胺參考實施例23第一步，得到4-(2-(環辛基胺基)-5-(S-甲基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率18%)。 4- (2-fluoro-5- (S-methylsulfonylimino) phenyl) -6-methyl-1-toluenesulfon-1,6-di Hydrogen-7H-pyrrolo [2,3-c] pyridin-7-one was used as a raw material, and cyclooctylamine was used instead of trans 4-methylcyclohexylamine. Refer to the first step of Example 23 to obtain 4- (2- ( Cyclooctylamino) -5- (S-methylsulfonylimino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7 -Ketone (18% yield).
MS m/z(ESI)：427.2[M+H]+. MS m / z (ESI): 427.2 [M + H] + .
1H NMR(400MHz,MeOD)：δ 7.86(d,J=8.2Hz,1H),7.68(s,1H),7.28(d,J=2.4Hz,1H),7.19(s,1H),6.86(d,J=9.0Hz,1H),6.01(d,J=2.3Hz,1H),3.66(s,3H),3.61(s,3H),3.60-3.54(m,1H),1.78-1.64(m,2H),1.40-1.54(m,12H). 1 H NMR (400MHz, MeOD): δ 7.86 (d, J = 8.2Hz, 1H), 7.68 (s, 1H), 7.28 (d, J = 2.4Hz, 1H), 7.19 (s, 1H), 6.86 ( d, J = 9.0Hz, 1H), 6.01 (d, J = 2.3Hz, 1H), 3.66 (s, 3H), 3.61 (s, 3H), 3.60-3.54 (m, 1H), 1.78-1.64 (m , 2H), 1.40-1.54 (m, 12H).
以實施例14第四步反應的產物4-(2-氟-5-(S-甲基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，用環丙基甲胺代替反式4-甲基環己胺參考實施例23第一步，得到4-(2-((環丙基甲基)胺基)-5-(S-甲基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率33%)。 4- (2-fluoro-5- (S-methylsulfonylimino) phenyl) -6-methyl-1-toluenesulfon-1,6-di Hydrogen-7H-pyrrolo [2,3-c] pyridin-7-one was used as a raw material, and cyclopropylmethylamine was used instead of trans 4-methylcyclohexylamine. Refer to the first step of Example 23 to obtain 4- (2 -((Cyclopropylmethyl) amino) -5- (S-methylsulfonylimino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3 -c] pyridin-7-one (33% yield).
MS m/z(ESI)：371.2[M+H]+. MS m / z (ESI): 371.2 [M + H] + .
1H NMR(400MHz,DMSO)δ 7.81(dd,J=9.0Hz,2.5Hz,1H),7.66(d,J=2.5Hz,1H),7.31(s,1H),7.24(s,1H),6.13(s,1H),6.04(s,1H),3.73(s,3H),3.57(s,3H),3.10(d,J=5.7Hz,2H),1.09-0.95(m,1H),0.41-0.38(m,2H),0.23-0.12(m,2H). 1 H NMR (400MHz, DMSO) δ 7.81 (dd, J = 9.0Hz, 2.5Hz, 1H), 7.66 (d, J = 2.5Hz, 1H), 7.31 (s, 1H), 7.24 (s, 1H), 6.13 (s, 1H), 6.04 (s, 1H), 3.73 (s, 3H), 3.57 (s, 3H), 3.10 (d, J = 5.7Hz, 2H), 1.09-0.95 (m, 1H), 0.41 -0.38 (m, 2H), 0.23-0.12 (m, 2H).
以實施例14第四步反應的產物4-(2-氟-5-(S-甲基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮與反式4-甲基環己胺為原料，參考實施例23第一步，得到6-甲基-4-(2-((反式-4-甲基環己基)胺基)-5-(S-甲基磺亞胺醯基)苯基)-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率50%)。 4- (2-fluoro-5- (S-methylsulfonylimino) phenyl) -6-methyl-1-toluenesulfon-1,6-di Hydrogen-7H-pyrrolo [2,3-c] pyridin-7-one and trans 4-methylcyclohexylamine were used as raw materials. Referring to the first step of Example 23, 6-methyl-4- (2- ((Trans-4-methylcyclohexyl) amino) -5- (S-methylsulfonylimino) phenyl) -1,6-dihydro-7H-pyrrolo [2,3-c ] Pyridine-7-one (yield 50%).
MS m/z(ESI)：413.2[M+H]+. MS m / z (ESI): 413.2 [M + H] + .
1H NMR(400MHz,MeOD)δ 7.72(dd,J=8.8,2.4Hz,1H),7.57(d,J=2.4Hz,1H),7.25(d,J=2.8Hz,1H),7.11(s,1H),6.78(d,J=9.0Hz,1H),6.02(d,J=2.8Hz,1H),3.59(s,3H),3.32-3.23(m,1H),3.03(s,3H),1.95-1.85(m,2H),1.65-1.58(m,2H),1.26-1.24(m,1H),1.08-0.87(m,4H),0.80(d,J=6.5Hz,3H). 1 H NMR (400MHz, MeOD) δ 7.72 (dd, J = 8.8, 2.4 Hz, 1H), 7.57 (d, J = 2.4 Hz, 1H), 7.25 (d, J = 2.8 Hz, 1H), 7.11 (s , 1H), 6.78 (d, J = 9.0Hz, 1H), 6.02 (d, J = 2.8Hz, 1H), 3.59 (s, 3H), 3.32-3.23 (m, 1H), 3.03 (s, 3H) , 1.95-1.85 (m, 2H), 1.65-1.58 (m, 2H), 1.26-1.24 (m, 1H), 1.08-0.87 (m, 4H), 0.80 (d, J = 6.5Hz, 3H).
以實施例14第四步反應的產物4-(2-氟-5-(S-甲基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，用環庚胺代替反式4-甲基環己胺參考實施例23第一步，得到4-(2-(環庚基胺基)-5-(S-甲基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率50%)。 4- (2-fluoro-5- (S-methylsulfonylimino) phenyl) -6-methyl-1-toluenesulfon-1,6-di Hydrogen-7H-pyrrolo [2,3-c] pyridin-7-one was used as a raw material, and cycloheptylamine was used instead of trans 4-methylcyclohexylamine. Refer to the first step of Example 23 to obtain 4- (2- ( Cycloheptylamino) -5- (S-methylsulfonylimino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7 -Ketone (50% yield).
MS m/z(ESI)：413.2[M+H]+. MS m / z (ESI): 413.2 [M + H] + .
1H NMR(400MHz,MeOD)：δ 7.86(d,J=8.2Hz,1H),7.68(s,1H),7.28(d,J=2.4Hz,1H),7.19(s,1H),6.86(d,J=9.0Hz,1H),6.01(d,J=2.3Hz,1H),3.72(s,3H),3.70-3.62(m,1H),3.15(s,3H),2.10-2.02(m,2H),1.70-1.46(m,10H). 1 H NMR (400MHz, MeOD): δ 7.86 (d, J = 8.2Hz, 1H), 7.68 (s, 1H), 7.28 (d, J = 2.4Hz, 1H), 7.19 (s, 1H), 6.86 ( d, J = 9.0Hz, 1H), 6.01 (d, J = 2.3Hz, 1H), 3.72 (s, 3H), 3.70-3.62 (m, 1H), 3.15 (s, 3H), 2.10-2.02 (m , 2H), 1.70-1.46 (m, 10H).
以實施例5第四步反應的產物4-(2-氟-5-(丙烷-2-基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並 [2,3-c]吡啶-7-酮為原料，用環丙基甲胺代替反式4-甲基環己胺，參考實施例23第一步，得到4-(2-((環丙基甲基)胺基)-5-(丙烷-2-基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率46%)。 As the product of the fourth step in Example 5, 4- (2-fluoro-5- (propane-2-ylsulfinoimidofluorenyl) phenyl) -6-methyl-1-toluenesulfonyl-1,6- Dihydro-7H-pyrrolo [2,3-c] pyridin-7-one was used as the raw material, and cyclopropylmethylamine was used instead of trans 4-methylcyclohexylamine. Referring to the first step of Example 23, 4- (2-((Cyclopropylmethyl) amino) -5- (propane-2-ylsulfenimido) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [ 2,3-c] pyridine-7-one (46% yield).
MS m/z(ESI)：399.2[M+H]+. MS m / z (ESI): 399.2 [M + H] + .
1H NMR(400MHz,MeOD)δ 7.66(dd,J=9.1Hz,2.5Hz,1H),7.45(d,J=2.5Hz,1H),7.16(d,J=2.8Hz,1H),7.05(s,1H),6.87(d,J=9.1Hz,1H),5.93(d,J=2.8Hz,1H),3.95-3.75(m,1H),3.50(s,3H),2.94(d,J=6.9Hz,2H),1.29(d,J=6.7Hz,3H),1.21(d,J=6.8Hz,3H),0.85(dd,J=12.4,7.4Hz,1H),0.27(dd,J=8.0,1.3Hz,2H),-0.00(dd,J=7.6,2.7Hz,2H). 1 H NMR (400MHz, MeOD) δ 7.66 (dd, J = 9.1Hz, 2.5Hz, 1H), 7.45 (d, J = 2.5Hz, 1H), 7.16 (d, J = 2.8Hz, 1H), 7.05 ( s, 1H), 6.87 (d, J = 9.1Hz, 1H), 5.93 (d, J = 2.8Hz, 1H), 3.95-3.75 (m, 1H), 3.50 (s, 3H), 2.94 (d, J = 6.9Hz, 2H), 1.29 (d, J = 6.7Hz, 3H), 1.21 (d, J = 6.8Hz, 3H), 0.85 (dd, J = 12.4, 7.4Hz, 1H), 0.27 (dd, J = 8.0, 1.3Hz, 2H), -0.00 (dd, J = 7.6, 2.7Hz, 2H).
3L三口瓶中依次加入3-溴-4-氟苯胺(60g,315.6mmol)，乙腈(600mL)，水(600mL)，濃鹽酸(300mL)。冰浴冷卻至0-5℃，滴加亞硝酸鈉(23.4g，316mmol)的水 (300mL)溶液，維持體系溫度在0-5℃。反應1小時後加入尿素(3.6g，60mmol)淬滅多餘的亞硝酸鈉，攪拌10分鐘。1L的三口瓶中依次加入九水硫化鈉(100.8g，420mmol)，硫磺粉(13.2g，420mmol)，NaOH(17.4g，432mmol)，水(300mL)。油浴加熱至75℃反應1小時至溶液變澄清。將澄清溶液冷卻至室溫滴加到上述反應液中，並維持體系溫度為0-5℃。滴加完畢後，反應液用乙酸乙酯(1Lx2)萃取，過濾，無水硫酸鈉乾燥，旋乾得到粗產物1,2-二(3-溴-4-氟苯基)二硫烷(42g，黃色油狀物，產率64%)。 In a 3L three-neck flask, 3-bromo-4-fluoroaniline (60 g, 315.6 mmol), acetonitrile (600 mL), water (600 mL), and concentrated hydrochloric acid (300 mL) were added in this order. The solution was cooled to 0-5 ° C in an ice bath, and a solution of sodium nitrite (23.4 g, 316 mmol) in water (300 mL) was added dropwise to maintain the temperature of the system at 0-5 ° C. After 1 hour of reaction, urea (3.6 g, 60 mmol) was added to quench the excess sodium nitrite and stirred for 10 minutes. To a 1 L three-necked flask, sodium sulfide nonahydrate (100.8 g, 420 mmol), sulfur powder (13.2 g, 420 mmol), NaOH (17.4 g, 432 mmol), and water (300 mL) were sequentially added. The oil bath was heated to 75 ° C for 1 hour and the solution became clear. The clear solution was cooled to room temperature and added dropwise to the reaction solution, and the temperature of the system was maintained at 0-5 ° C. After the dropwise addition was completed, the reaction solution was extracted with ethyl acetate (1 Lx2), filtered, dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product of 1,2-bis (3-bromo-4-fluorophenyl) disulfane (42 g, Yellow oil, 64% yield).
3L三口瓶中依次加入1,2-二(3-溴-4-氟苯基)二硫烷(42g，101.9mmol)，甲醇(300mL)，四氫呋喃(1L)，氫氧化鈉(10.3g，257.5mmol)的水(300mL)溶液。室溫下分五批加入硼氫化鈉(11.1g，293.6mmol)。反應1小時後濃縮，加入氫氧化鈉(35g，875.0mmol)的水(300mL)溶液，用甲基第三丁基醚(500mLx2)洗。水相滴加到鹽酸(800mL，3mol/L)中，並維持體系溫度為0-5℃。反應液用甲基第三丁基醚(500mLx3)萃取，無水硫酸鈉乾燥，旋乾得到3-溴-4-氟苯硫醇(16g，黃色油狀物，產率38%)。 In a 3L three-neck flask, 1,2-bis (3-bromo-4-fluorophenyl) disulfane (42g, 101.9mmol), methanol (300mL), tetrahydrofuran (1L), sodium hydroxide (10.3g, 257.5) were added in this order. mmol) in water (300 mL). Sodium borohydride (11.1 g, 293.6 mmol) was added in five portions at room temperature. After reacting for 1 hour, the solution was concentrated, and a solution of sodium hydroxide (35 g, 875.0 mmol) in water (300 mL) was added, followed by washing with methyl tert-butyl ether (500 mL x 2). The aqueous phase was added dropwise to hydrochloric acid (800 mL, 3 mol / L), and the temperature of the system was maintained at 0-5 ° C. The reaction solution was extracted with methyl tert-butyl ether (500 mL × 3), dried over anhydrous sodium sulfate, and spin-dried to obtain 3-bromo-4-fluorobenzenethiol (16 g, yellow oil, 38% yield).
1H NMR(400MHz,CDCl3)：δ 7.50(dd,J=6.3,2.3Hz,1H),7.23-7.16(m,1H),7.00(t,J=8.4Hz,1H),3.48(s, 1H). 1 H NMR (400MHz, CDCl 3 ): δ 7.50 (dd, J = 6.3, 2.3Hz, 1H), 7.23-7.16 (m, 1H), 7.00 (t, J = 8.4Hz, 1H), 3.48 (s, 1H).
500mL三口瓶中依次加入3-溴-4-氟苯硫醇(14g,68.0mmol)，乙腈(200mL)。室溫下分五批加入碘苯二乙酸(21.9g，68.0mmol)。室溫反應1小時後加水(100mL)淬滅，濃縮，乙酸乙酯(100mL x2)萃取，無水硫酸鈉乾燥，管柱分離(石油醚)得到1,2-二(3-溴-4-氟苯基)二硫烷(14g，黃色油狀物，產率100%)。 In a 500 mL three-neck flask, 3-bromo-4-fluorobenzenethiol (14 g, 68.0 mmol), and acetonitrile (200 mL) were added in this order. Iodobenzenediacetic acid (21.9 g, 68.0 mmol) was added in five portions at room temperature. After reacting at room temperature for 1 hour, it was quenched by adding water (100 mL), concentrated, extracted with ethyl acetate (100 mL x 2), dried over anhydrous sodium sulfate, and separated by column (petroleum ether) to obtain 1,2-bis (3-bromo-4-fluoro). Phenyl) disulfane (14 g, yellow oil, 100% yield).
1H NMR(400MHz,CDCl3)：δ 7.72-7.63(m,1H),7.39-7.28(m,1H),7.13-7.04(m,1H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.72-7.63 (m, 1H), 7.39-7.28 (m, 1H), 7.13-7.04 (m, 1H).
250mL三口瓶中依次加入1,2-二(3-溴-4-氟苯基)二硫烷(8g,19.4mmol)，四氫呋喃(40mL)。氮氣保護下於零下70℃滴加環丙基溴化鎂(60mL，1M，60mmol)。反應1小時後加飽和NH4Cl(100mL)淬滅，乙酸乙酯(100mL x2)萃取，無水硫酸鈉乾燥，管柱分離(石油醚)得到(3-溴-4-氟苯基)(環丙基)硫烷(4.3g，黃色油狀物，產率51%)。 In a 250 mL three-neck flask, 1,2-bis (3-bromo-4-fluorophenyl) disulfane (8 g, 19.4 mmol), and tetrahydrofuran (40 mL) were added in this order. Cyclopropylmagnesium bromide (60 mL, 1 M, 60 mmol) was added dropwise at -70 ° C under a nitrogen atmosphere. After reacting for 1 hour, it was quenched with saturated NH 4 Cl (100 mL), extracted with ethyl acetate (100 mL x 2), dried over anhydrous sodium sulfate, and separated by column (petroleum ether) to obtain (3-bromo-4-fluorophenyl) (cyclic Propyl) sulfane (4.3 g, yellow oil, 51% yield).
1H NMR(400MHz,DMSO)：δ 7.65(m,1H),7.40- 7.31(m,2H),2.35(m,4.3Hz,1H),1.13-1.06(m,2H),0.63-0.56(m,2H). 1 H NMR (400MHz, DMSO): δ 7.65 (m, 1H), 7.40- 7.31 (m, 2H), 2.35 (m, 4.3Hz, 1H), 1.13-1.06 (m, 2H), 0.63-0.56 (m , 2H).
以(3-溴-4-氟苯基)(環丙基)硫烷為反應原料，參考實施例4第二步，得到2-溴-4-(環丙基亞硫醯基<亞磺醯>)-1-氟苯(產率47%)。 Using (3-bromo-4-fluorophenyl) (cyclopropyl) sulfane as a reaction raw material, refer to the second step of Example 4, to obtain 2-bromo-4- (cyclopropylthiosulfenyl group <sulfenylsulfonium >)-1-fluorobenzene (yield 47%).
1H NMR(400MHz,DMSO)：δ 8.01(dd,J=6.5,2.1Hz,1H),7.76(m,1H),7.61(t,J=8.6Hz,1H),2.55(m,1H),1.04-0.90(m,3H),0.88-0.80(m,1H). 1 H NMR (400MHz, DMSO): δ 8.01 (dd, J = 6.5, 2.1Hz, 1H), 7.76 (m, 1H), 7.61 (t, J = 8.6Hz, 1H), 2.55 (m, 1H), 1.04-0.90 (m, 3H), 0.88-0.80 (m, 1H).
以2-溴-4-(環丙基亞硫醯基<亞磺醯>)-1-氟苯為原料，參考實施例5第三步，得到(3-溴-4-氟苯基)(環丙基)(亞胺基)-λ6-硫烷酮(產率100%)。 Using 2-bromo-4- (cyclopropylthiosulfenylsulfinyl) sulfonium-1-fluorobenzene as a raw material, refer to the third step of Example 5 to obtain (3-bromo-4-fluorophenyl) ( Cyclopropyl) (imino) -λ 6 -sulfanone (yield 100%).
MS m/z(ESI)：278.0/280.0(50/50)[M+H]+. MS m / z (ESI): 278.0 / 280.0 (50/50) [M + H] + .
以(3-溴-4-氟苯基)(環丙基)(亞胺基)-λ6-硫烷酮為原料，參考實施例4第四步得到4-(5-(環丙磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率47%) Using (3-bromo-4-fluorophenyl) (cyclopropyl) (imino) -λ 6 -sulfanone as a raw material, the fourth step of Reference Example 4 was used to obtain 4- (5- (cyclopropanesulfinyl) Amine group) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7-one (yield 47 %)
MS m/z(ESI)：500.1[M+H]+ MS m / z (ESI): 500.1 [M + H] +
以4-(5-(環丙磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮與反式-4-甲基環己烷-1-胺為反應原料。參考實施例23第一步，得到4-(5-(環丙磺亞胺醯基)-2-((反式-4-甲基環己基)胺基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率34%)。 4- (5- (Cyclopropanesulfenimido) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridine-7-one and trans-4-methylcyclohexane-1-amine are used as the starting materials. Referring to the first step of Reference Example 23, 4- (5- (Cyclopropanesulfenimido) -2-((trans-4-methylcyclohexyl) amino) phenyl) -6-methyl- 1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (34% yield).
MS m/z(ESI)：439.2[M+H]+ MS m / z (ESI): 439.2 [M + H] +
1H NMR(400MHz,MeOD)δ 7.79(dd,J=8.8Hz,2.4Hz,1H),7.64(d,J=2.4Hz,1H),7.37(d,J=2.8Hz,1H),7.22(s, 1H),6.89(d,J=9.2Hz,1H),6.14(d,J=2.8Hz,1H),3.71(s,3H),3.44-3.37(m,1H),2.74-2.63(m,1H),2.08-1.97(m,2H),1.77-1.69(m,2H),1.36-1.28(m,2H),1.27-1.20(m,1H),1.15-1.05(m,5H),0.99-0.94(m,1H),0.92(d,J=6.4Hz,3H). 1 H NMR (400MHz, MeOD) δ 7.79 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.64 (d, J = 2.4Hz, 1H), 7.37 (d, J = 2.8Hz, 1H), 7.22 ( s, 1H), 6.89 (d, J = 9.2Hz, 1H), 6.14 (d, J = 2.8Hz, 1H), 3.71 (s, 3H), 3.44-3.37 (m, 1H), 2.74-2.63 (m , 1H), 2.08-1.97 (m, 2H), 1.77-1.69 (m, 2H), 1.36-1.28 (m, 2H), 1.27-1.20 (m, 1H), 1.15-1.05 (m, 5H), 0.99 -0.94 (m, 1H), 0.92 (d, J = 6.4Hz, 3H).
將4-(5-(環丙磺亞胺醯基)-2-((反式--4-甲基環己基)胺基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(30mg)手性製備得到(S)-4-(5-(環丙磺亞胺醯基)-2-((反式-4-甲基環己基)胺基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(13mg)和(R)-4-(5-(環丙磺亞胺醯基)-2-((反式--4-甲基環己基)胺基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(13mg)。 4- (5- (Cyclosulfanimidoamido) -2-((trans--4-methylcyclohexyl) amino) phenyl) -6-methyl-1,6-dihydro- Chiral preparation of 7H-pyrrolo [2,3-c] pyridin-7-one (30mg) to obtain (S) -4- (5- (cyclopropanesulfinoimidoamido) -2-((trans-4 -Methylcyclohexyl) amino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (13 mg) and (R) -4 -(5- (Cyclosulfanimidoamido) -2-((trans--4-methylcyclohexyl) amino) phenyl) -6-methyl-1,6-dihydro-7H- Pyrrolop [2,3-c] pyridin-7-one (13 mg).
手型製備條件：
(S)-構型化合物：t R =4.832min.MS m/z(ESI)：439.2[M+H]+ (S) -configuration compound: t R = 4.832min. MS m / z (ESI): 439.2 [M + H] +
1H NMR(400MHz,MeOD)δ 7.79(dd,J=8.8Hz,2.4Hz,1H),7.64(d,J=2.4Hz,1H),7.37(d,J=2.8Hz,1H),7.22(s,1H),6.89(d,J=9.2Hz,1H),6.14(d,J=2.8Hz,1H),3.71(s,3H),3.44-3.37(m,1H),2.74-2.63(m,1H),2.08-1.97(m,2H),1.77-1.69(m,2H),1.36-1.28(m,2H),1.27-1.20(m,1H),1.15-1.05(m,5H),0.99-0.94(m,1H),0.92(d,J=6.4Hz,3H). 1 H NMR (400MHz, MeOD) δ 7.79 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.64 (d, J = 2.4Hz, 1H), 7.37 (d, J = 2.8Hz, 1H), 7.22 ( s, 1H), 6.89 (d, J = 9.2Hz, 1H), 6.14 (d, J = 2.8Hz, 1H), 3.71 (s, 3H), 3.44-3.37 (m, 1H), 2.74-2.63 (m , 1H), 2.08-1.97 (m, 2H), 1.77-1.69 (m, 2H), 1.36-1.28 (m, 2H), 1.27-1.20 (m, 1H), 1.15-1.05 (m, 5H), 0.99 -0.94 (m, 1H), 0.92 (d, J = 6.4Hz, 3H).
(R)-構型化合物：t R =6.201min.MS m/z(ESI)：439.2[M+H]+ (R) -configuration compound: t R = 6.201min. MS m / z (ESI): 439.2 [M + H] +
1H NMR(400MHz,MeOD)δ 7.79(dd,J=8.8,2.4Hz,1H),7.64(d,J=2.4Hz,1H),7.37(d,J=2.8Hz,1H),7.22(s,1H),6.89(d,J=9.2Hz,1H),6.14(d,J=2.8Hz,1H),3.71(s, 3H),3.44-3.37(m,1H),2.74-2.63(m,1H),2.08-1.97(m,2H),1.77-1.69(m,2H),1.36-1.28(m,2H),1.27-1.20(m,1H),1.15-1.05(m,5H),0.99-0.94(m,1H),0.92(d,J=6.4Hz,3H). 1 H NMR (400MHz, MeOD) δ 7.79 (dd, J = 8.8, 2.4Hz, 1H), 7.64 (d, J = 2.4Hz, 1H), 7.37 (d, J = 2.8Hz, 1H), 7.22 (s , 1H), 6.89 (d, J = 9.2Hz, 1H), 6.14 (d, J = 2.8Hz, 1H), 3.71 (s, 3H), 3.44-3.37 (m, 1H), 2.74-2.63 (m, 1H), 2.08-1.97 (m, 2H), 1.77-1.69 (m, 2H), 1.36-1.28 (m, 2H), 1.27-1.20 (m, 1H), 1.15-1.05 (m, 5H), 0.99- 0.94 (m, 1H), 0.92 (d, J = 6.4Hz, 3H).
以實施例33第七步產物4-(5-(環丙磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，用環庚胺代替反式4-甲基環己胺參考實施例23第一步，得到4-(2-(環庚基胺基)-5-(環丙磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率45%)。 Take the product in the seventh step of Example 33 as 4- (5- (Cyclopropanesulfenimido) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H- Pyrrolop [2,3-c] pyridin-7-one was used as the starting material, and cycloheptylamine was used instead of trans 4-methylcyclohexylamine. The first step of Reference Example 23 was to obtain 4- (2- (cycloheptylamine) Yl) -5- (cyclopropanesulfenimido) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (yield 45 %).
MS m/z(ESI)：439.2[M+H]+. MS m / z (ESI): 439.2 [M + H] + .
1H NMR(400MHz,MeOD)：δ 7.68(dd,J=8.8Hz,2.4Hz,1H),7.53(d,J=2.4Hz,1H),7.26(d,J=2.8Hz,1H),7.11(s,1H),6.69(d,J=9.0Hz,1H),6.02(d,J=2.8Hz,1H),3.60(s,3H),2.59-2.53(m,1H),1.85-1.76(m,2H),1.59-1.26(m,8H),1.21(m,3H),1.18-1.10(m,1H),0.99-0.95(m,2H),0.92-0.73(m,1H). 1 H NMR (400MHz, MeOD): δ 7.68 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.53 (d, J = 2.4Hz, 1H), 7.26 (d, J = 2.8Hz, 1H), 7.11 (s, 1H), 6.69 (d, J = 9.0Hz, 1H), 6.02 (d, J = 2.8Hz, 1H), 3.60 (s, 3H), 2.59-2.53 (m, 1H), 1.85-1.76 ( m, 2H), 1.59-1.26 (m, 8H), 1.21 (m, 3H), 1.18-1.10 (m, 1H), 0.99-0.95 (m, 2H), 0.92-0.73 (m, 1H).
以實施例33第七步產物4-(5-(環丙磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，用N-甲基反式4-甲基環己胺代替反式4-甲基環己胺，參考實施例23第一步，得到4-(5-(環丙磺亞胺醯基)-2-(甲基(反式--4-甲基環己基)胺基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率47%)。 Take the product in the seventh step of Example 33 as 4- (5- (Cyclopropanesulfenimido) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H- Pyrrolop [2,3-c] pyridin-7-one was used as the raw material, and N-methyltrans 4-methylcyclohexylamine was used instead of trans 4-methylcyclohexylamine. Referring to the first step of Example 23, Obtain 4- (5- (cyclopropanesulfenimidoamido) -2- (methyl (trans--4-methylcyclohexyl) amino) phenyl) -6-methyl-1,6-di Hydrogen-7H-pyrrolo [2,3-c] pyridin-7-one (47% yield).
MS m/z(ESI)：453.2[M+H]+. MS m / z (ESI): 453.2 [M + H] + .
1H NMR(400MHz,MeOD)δ 7.83(dd,J=8.7Hz,2.5Hz,1H),7.77(d,J=2.4Hz,1H),7.37(d,J=2.8Hz,1H),7.27(s,1H),7.21(d,J=8.8Hz,1H),6.20(d,J=2.8Hz,1H),3.72(s,3H),3.25-3.15(m,1H),2.77-2.66(m,4H),1.58-1.51m,2H),1.46-1.37(m,2H),1.31-1.07(m,6H),1.02-0.95(m,1H),0.73(d,J=4.0Hz,3H),0.52-0.43(m,2H). 1 H NMR (400MHz, MeOD) δ 7.83 (dd, J = 8.7Hz, 2.5Hz, 1H), 7.77 (d, J = 2.4Hz, 1H), 7.37 (d, J = 2.8Hz, 1H), 7.27 ( s, 1H), 7.21 (d, J = 8.8Hz, 1H), 6.20 (d, J = 2.8Hz, 1H), 3.72 (s, 3H), 3.25-3.15 (m, 1H), 2.77-2.66 (m , 4H), 1.58-1.51m, 2H), 1.46-1.37 (m, 2H), 1.31-1.07 (m, 6H), 1.02-0.95 (m, 1H), 0.73 (d, J = 4.0Hz, 3H) , 0.52-0.43 (m, 2H).
以實施例33第七步產物4-(5-(環丙磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，用環丙基甲基胺代替反式4-甲基環己胺，參考實施例23第一步，得到4-(5-(環丙磺亞胺醯基)-2-((環丙基甲基)胺基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮的製備(產率40%)。 Take the product in the seventh step of Example 33 as 4- (5- (Cyclopropanesulfenimido) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H- Pyrrolop [2,3-c] pyridin-7-one was used as the raw material, and cyclopropylmethylamine was used instead of trans 4-methylcyclohexylamine. Referring to the first step of Example 23, 4- (5- ( Cyclopropanesulfenimido) -2-((cyclopropylmethyl) amino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine Preparation of -7-one (yield 40%).
MS m/z(ESI)：397.17[M+H]+. MS m / z (ESI): 397.17 [M + H] + .
1HNMR(400MHz,MeOD)δ 7.61(dd,J=9.2Hz,2.4Hz,1H),7.47(d,J=2.0Hz,1H),7.18(d,J=2.8Hz,1H),7.05(s,1H),6.70(d,J=8.8Hz,1H),5.98(d,J=2.8Hz,1H),3.53(s,3H),2.90(d,J=6.8Hz,2H),1.86-1.85(m,1H),1.45-1.43(m,1H),0.91-0.85(m,2H),0.75-0.71(m,2H),0.27-0.25(m,2H),0.17-0.15(m,2H). 1 HNMR (400MHz, MeOD) δ 7.61 (dd, J = 9.2Hz, 2.4Hz, 1H), 7.47 (d, J = 2.0Hz, 1H), 7.18 (d, J = 2.8Hz, 1H), 7.05 (s , 1H), 6.70 (d, J = 8.8Hz, 1H), 5.98 (d, J = 2.8Hz, 1H), 3.53 (s, 3H), 2.90 (d, J = 6.8Hz, 2H), 1.86-1.85 (m, 1H), 1.45-1.43 (m, 1H), 0.91-0.85 (m, 2H), 0.75-0.71 (m, 2H), 0.27-0.25 (m, 2H), 0.17-0.15 (m, 2H) .
以實施例33第七步產物4-(5-(環丙磺亞胺醯基)-2-氟 苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，用4,4-二甲基環己基胺代替反式4-甲基環己胺，參考實施例23第一步，得到4-(5-(環丙磺亞胺醯基)-2-((4,4-二甲基環己基)胺基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率24%)。 Take the product in the seventh step of Example 33 as 4- (5- (Cyclopropanesulfenimido) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H- Pyrrolop [2,3-c] pyridin-7-one was used as the raw material, and 4,4-dimethylcyclohexylamine was used instead of trans 4-methylcyclohexylamine. Referring to the first step of Example 23, 4- (5- (Cyclosulfanimidoamido) -2-((4,4-dimethylcyclohexyl) amino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (24% yield).
MS m/z(ESI)：453.2[M+H]+. MS m / z (ESI): 453.2 [M + H] + .
1H NMR(400MHz,MeOD)：δ 7.69(dd,J=8.8Hz,2.4Hz,1H),7.55(d,J=2.4Hz,1H),7.26(d,J=2.8Hz,1H),7.12(s,1H),6.79(d,J=9.0Hz,1H),6.04(d,J=2.8Hz,1H),3.60(s,3H),3.36-3.27(m,1H),2.72-2.64(m,1H),1.72-1.65(m,2H),1.37-1.13(m,7H),1.11-0.95(m,2H),0.93-0.88(m,1H),0.83(s,3H),0.75(s,3H). 1 H NMR (400MHz, MeOD): δ 7.69 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.55 (d, J = 2.4Hz, 1H), 7.26 (d, J = 2.8Hz, 1H), 7.12 (s, 1H), 6.79 (d, J = 9.0Hz, 1H), 6.04 (d, J = 2.8Hz, 1H), 3.60 (s, 3H), 3.36-3.27 (m, 1H), 2.72-2.64 ( m, 1H), 1.72-1.65 (m, 2H), 1.37-1.13 (m, 7H), 1.11-0.95 (m, 2H), 0.93-0.88 (m, 1H), 0.83 (s, 3H), 0.75 ( s, 3H).
以實施例33第七步產物4-(5-(環丙磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮與2,4-二氟苯酚為原料，參考實施例4第四步，得到4-(5-(環丙磺亞胺醯基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率44%)。 Take the product in the seventh step of Example 33 as 4- (5- (Cyclopropanesulfenimido) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H- Pyrrolop [2,3-c] pyridin-7-one and 2,4-difluorophenol are used as raw materials. The fourth step of Reference Example 4 is to obtain 4- (5- (cyclopropanesulfinoimidoamido) -2. -(2,4-difluorophenoxy) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (44% yield) .
MS m/z(ESI)：456.2[M+H]+ MS m / z (ESI): 456.2 [M + H] +
1H NMR(400MHz,MeOD)δ 7.98(d,J=2.4Hz,1H),7.81(dd,J=8.7Hz,2.4Hz,1H),7.27(s,1H),7.25(d,J=2.9Hz,1H),7.08-7.05(m,2H),6.89(dd,J=15.1,5.4Hz,2H),6.28(d,J=2.9Hz,1H),3.60(s,3H),2.67-2.64(m,1H),1.28-1.12(m,1H),1.04-0.98(m,2H),0.91-0.86(m,1H). 1 H NMR (400MHz, MeOD) δ 7.98 (d, J = 2.4Hz, 1H), 7.81 (dd, J = 8.7Hz, 2.4Hz, 1H), 7.27 (s, 1H), 7.25 (d, J = 2.9 Hz, 1H), 7.08-7.05 (m, 2H), 6.89 (dd, J = 15.1, 5.4Hz, 2H), 6.28 (d, J = 2.9Hz, 1H), 3.60 (s, 3H), 2.67-2.64 (m, 1H), 1.28-1.12 (m, 1H), 1.04-0.98 (m, 2H), 0.91-0.86 (m, 1H).
將4-(5-(環丙磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(60.0mg)以手性製備得(S)-4-(5-(環丙磺亞胺醯基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(24mg)和(S)-4-(5-(環丙磺亞胺醯基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(22mg)。 4- (5- (Cyclopropanesulfenimido) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3- c) Pyridine-7-one (60.0 mg) was prepared chiralally to (S) -4- (5- (cyclopropanesulfinoimidoamido) -2- (2,4-difluorophenoxy) phenyl ) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (24mg) and (S) -4- (5- (cyclopropanesulfonimide) Yl) -2- (2,4-difluorophenoxy) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (22 mg ).
手型製備條件：
(S)-構型化合物：t R =11.2min.MS m/z(ESI)：456.2[M+H]+. (S) -configuration compound: t R = 11.2min. MS m / z (ESI): 456.2 [M + H] + .
1H NMR(400MHz,MeOD)δ 7.98(d,J=2.4Hz,1H),7.81(dd,J=8.7Hz,2.4Hz,1H),7.27(s,1H),7.25(d,J=2.9Hz,1H),7.08-7.05(m,2H),6.89(dd,J=15.1,5.4Hz,2H),6.28(d,J=2.9Hz,1H),3.60(s,3H),2.67-2.64(m,1H),1.28-1.12(m,1H),1.04-0.98(m,2H),0.91-0.86(m,1H). 1 H NMR (400MHz, MeOD) δ 7.98 (d, J = 2.4Hz, 1H), 7.81 (dd, J = 8.7Hz, 2.4Hz, 1H), 7.27 (s, 1H), 7.25 (d, J = 2.9 Hz, 1H), 7.08-7.05 (m, 2H), 6.89 (dd, J = 15.1, 5.4Hz, 2H), 6.28 (d, J = 2.9Hz, 1H), 3.60 (s, 3H), 2.67-2.64 (m, 1H), 1.28-1.12 (m, 1H), 1.04-0.98 (m, 2H), 0.91-0.86 (m, 1H).
(R)-構型化合物：t R =11.6min.MS m/z(ESI)：456.2[M+H]+. (R) -configuration compound: t R = 11.6min. MS m / z (ESI): 456.2 [M + H] + .
1H NMR(400MHz,MeOD)δ 7.98(d,J=2.4Hz,1H),7.81(dd,J=8.7,2.4Hz,1H),7.27(s,1H),7.25(d,J=2.9Hz,1H),7.08-7.05(m,2H),6.89(dd,J=15.1,5.4Hz,2H),6.28(d,J=2.9Hz,1H),3.60(s,3H),2.67-2.64(m,1H),1.28-1.12(m,1H),1.04-0.98(m,2H),0.91-0.86(m,1H). 1 H NMR (400MHz, MeOD) δ 7.98 (d, J = 2.4Hz, 1H), 7.81 (dd, J = 8.7, 2.4Hz, 1H), 7.27 (s, 1H), 7.25 (d, J = 2.9Hz , 1H), 7.08-7.05 (m, 2H), 6.89 (dd, J = 15.1, 5.4Hz, 2H), 6.28 (d, J = 2.9Hz, 1H), 3.60 (s, 3H), 2.67-2.64 ( m, 1H), 1.28-1.12 (m, 1H), 1.04-0.98 (m, 2H), 0.91-0.86 (m, 1H).
25mL單口瓶中依次加入實施例33第五步產物2-溴-4-(環丙基亞硫醯基<亞磺醯>)-1-氟苯(260mg,1.0mmol),四氯化碳(5mL)。室溫下加入N-氯丁二醯亞胺(150mg，1.1mmol)。油浴加熱到60℃反應12小時後過濾，濾液濃縮管柱分離(石油醚/乙酸乙酯=5/1)得到2-溴-4-((1-氯環丙基)亞硫醯基<亞磺醯>)-1-氟苯(220mg，黃色油狀物，產率74%)。 In a 25 mL single-necked flask, 2-bromo-4- (cyclopropylsulfinylidene <sulfenimidine>)-1-fluorobenzene (260mg, 1.0mmol), carbon tetrachloride ( 5mL). N-chlorobutanediimide (150 mg, 1.1 mmol) was added at room temperature. The oil bath was heated to 60 ° C for 12 hours and then filtered. The filtrate was concentrated by column separation (petroleum ether / ethyl acetate = 5/1) to obtain 2-bromo-4-((1-chlorocyclopropyl) thiosulfenyl group < Sulfinyl>)-1-fluorobenzene (220 mg, yellow oil, 74% yield).
MS m/z(ESI)：296.9/298.9(50/50)[M+H]+. MS m / z (ESI): 296.9 / 298.9 (50/50) [M + H] +.
1H NMR(400MHz,CDCl3)δ 7.92(dd,J=6.3,2.1Hz,1H),7.64(m,1H),7.28(dd,J=13.0,4.5Hz,1H),1.67(dd,J=4.0,2.8Hz,2H),1.44-1.37(m,1H),1.28-1.22(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ 7.92 (dd, J = 6.3, 2.1Hz, 1H), 7.64 (m, 1H), 7.28 (dd, J = 13.0, 4.5Hz, 1H), 1.67 (dd, J = 4.0, 2.8Hz, 2H), 1.44-1.37 (m, 1H), 1.28-1.22 (m, 1H).
以2-溴-4-((1-氯環丙基)亞硫醯基<亞磺醯>)-1-氟苯為原料，參考實施例5第三步，得到(3-溴-4-氟苯基)(1-氯環丙基)(亞胺基)-λ6-硫烷酮(產率65%)。 Using 2-bromo-4-((1-chlorocyclopropyl) sulfenyl <sulfenylpyrene>)-1-fluorobenzene as a raw material, refer to the third step of Example 5 to obtain (3-bromo-4- Fluorophenyl) (1-chlorocyclopropyl) (imino) -λ 6 -sulfanone (65% yield).
MS m/z(ESI)：311.9/313.9(50/50)[M+H]+. MS m / z (ESI): 311.9 / 313.9 (50/50) [M + H] + .
1H NMR(400MHz,CDCl3)δ 8.27(dd,J=6.3,2.3Hz,1H),8.00(m,1H),7.31(dd,J=8.6,8.0Hz,1H),2.05-1.88(m,2H),1.55-1.38(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ 8.27 (dd, J = 6.3, 2.3Hz, 1H), 8.00 (m, 1H), 7.31 (dd, J = 8.6, 8.0Hz, 1H), 2.05-1.88 (m , 2H), 1.55-1.38 (m, 2H).
25mL單口瓶中依次加入(3-溴-4-氟苯基)(1-氯環丙基)(亞胺基)-λ6-硫烷酮(150mg,0.48mmol),2,4-二氟苯酚(195mg,1.5mmol)，碳酸銫(490mg,1.5mmol)，二甲基亞碸(5mL)。油浴加熱到80℃反應6小時後過濾，濾液濃縮管柱分離(石油醚/乙酸乙酯=3/1)得到(3-溴-4-(2,4-二氟苯氧基)苯基)(1-氯環丙基)(亞胺基)-λ6-硫烷酮(150mg，黃色油狀物，產率74%)。 (3-Bromo-4-fluorophenyl) (1-chlorocyclopropyl) (imino) -λ 6 -sulfanone (150 mg, 0.48 mmol), 2,4-difluoro Phenol (195 mg, 1.5 mmol), cesium carbonate (490 mg, 1.5 mmol), dimethylsulfene (5 mL). The oil bath was heated to 80 ° C for 6 hours and then filtered. The filtrate was concentrated by column separation (petroleum ether / ethyl acetate = 3/1) to obtain (3-bromo-4- (2,4-difluorophenoxy) phenyl. ) (1-chlorocyclopropyl) (imino) -λ 6 -sulfanone (150 mg, yellow oil, 74% yield).
MS m/z(ESI)：421.9/423.9(50/50)[M+H]+. MS m / z (ESI): 421.9 / 423.9 (50/50) [M + H] + .
以(3-溴-4-(2,4-二氟苯氧基)苯基)(1-氯環丙基)(亞胺基)-λ6-硫烷酮為原料，參考實施例4第四步得4-(5-(1-氯環丙烷-1-磺亞胺醯基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率43%)。 Using (3-bromo-4- (2,4-difluorophenoxy) phenyl) (1-chlorocyclopropyl) (imino) -λ 6 -sulfanone as a raw material, reference example 4 Four steps to get 4- (5- (1-chlorocyclopropane-1-sulfinimidofluorenyl) -2- (2,4-difluorophenoxy) phenyl) -6-methyl-1-toluenesulfonate Perylene-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (43% yield).
MS m/z(ESI)：644.1[M+H]+. MS m / z (ESI): 644.1 [M + H] + .
以4-(5-(1-氯環丙烷-1-磺亞胺醯基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，參考實施例1第八步得4-(5-(1-氯環丙烷-1-磺亞胺醯基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率47%)。 As 4- (5- (1-chlorocyclopropane-1-sulfinoimidofluorenyl) -2- (2,4-difluorophenoxy) phenyl) -6-methyl-1-toluenesulfonyl- 1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one was used as the raw material, and the eighth step of Reference Example 1 was to obtain 4- (5- (1-chlorocyclopropane-1-sulfinyl) Aminomethyl) -2- (2,4-difluorophenoxy) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7-one (47% yield).
MS m/z(ESI)：490.0[M+H]+。 MS m / z (ESI): 490.0 [M + H] + .
1H NMR(400MHz,MeOD)δ 8.05(d,J=2.4Hz,1H),7.87(dd,J=8.8Hz,2.4Hz,1H),7.32-7.23(m,2H),7.18-7.01(m,2H),6.96-6.84(m,2H),6.30(d,J=2.9Hz,1H),3.61(s,3H),1.92-1.79(m,2H),1.45-1.37(m,1H),1.36-1.29(m,1H). 1 H NMR (400MHz, MeOD) δ 8.05 (d, J = 2.4Hz, 1H), 7.87 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.32-7.23 (m, 2H), 7.18-7.01 (m , 2H), 6.96-6.84 (m, 2H), 6.30 (d, J = 2.9Hz, 1H), 3.61 (s, 3H), 1.92-1.79 (m, 2H), 1.45-1.37 (m, 1H), 1.36-1.29 (m, 1H).
氮氣保護下，25mL單口瓶中依次加入實施例41第二步產物(3-溴-4-氟苯基)(1-氯環丙基)(亞胺基)-λ6-硫烷酮(100mg,0.32mmol)，反式-4-甲基環己胺(1.0mL)。油浴加熱到80℃反應6小時後過濾，濾液濃縮管柱分離(石油醚/乙酸乙酯=3/1)得到(3-溴-4-((反式-4-甲基環己基)胺基)苯基)(1-氯環丙基)(亞胺基)-λ6-硫烷酮(100mg，黃色油狀物， 產率77%)。 Under nitrogen, a 25 mL single-necked flask was sequentially added with the product from the second step of Example 41 (3-bromo-4-fluorophenyl) (1-chlorocyclopropyl) (imino) -λ 6 -sulfanone (100 mg , 0.32 mmol), trans-4-methylcyclohexylamine (1.0 mL). The oil bath was heated to 80 ° C for 6 hours and then filtered. The filtrate was concentrated on a column and separated (petroleum ether / ethyl acetate = 3/1) to obtain (3-bromo-4-((trans-4-methylcyclohexyl) amine. (Phenyl) phenyl) (1-chlorocyclopropyl) (imino) -λ 6 -sulfanone (100 mg, yellow oil, 77% yield).
MS m/z(ESI)：405.0/407(50/50)[M+H]+. MS m / z (ESI): 405.0 / 407 (50/50) [M + H] + .
以(3-溴-4-((反式--4-甲基環己基)胺基)苯基)(1-氯環丙基)(亞胺基)-λ6-硫烷酮為原料，參考實施例4第四步得4-(5-(1-氯環丙烷-1-磺亞胺醯基)-2-((反式-4-甲基環己基)胺基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率58%)。 Using (3-bromo-4-((trans--4-methylcyclohexyl) amino) phenyl) (1-chlorocyclopropyl) (imino) -λ 6 -sulfanone as a raw material, Reference Example 4 In the fourth step, 4- (5- (1-chlorocyclopropane-1-sulfinimidofluorenyl) -2-((trans-4-methylcyclohexyl) amino) phenyl)- 6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (58% yield).
MS m/z(ESI)：627.1[M+H]+. MS m / z (ESI): 627.1 [M + H] + .
以4-(5-(1-氯環丙烷-1-磺亞胺醯基)-2-((反式-4-甲基環己基)胺基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯 並[2,3-c]吡啶-7-酮為原料，參考實施例1第八步得4-(5-(1-氯環丙烷-1-磺亞胺醯基)-2-((反式-)-4-甲基環己基)胺基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(52mg,產率76%)。 4- (5- (1-chlorocyclopropane-1-sulfinoimidofluorenyl) -2-((trans-4-methylcyclohexyl) amino) phenyl) -6-methyl-1- Tosylpyrene-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one was used as a raw material, and the eighth step of Reference Example 1 was to obtain 4- (5- (1-chlorocyclopropane- 1-sulfonylimido) -2-((trans-)-4-methylcyclohexyl) amino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2 , 3-c] pyridin-7-one (52 mg, yield 76%).
MS m/z(ESI)：473.1[M+H]+. MS m / z (ESI): 473.1 [M + H] + .
1H NMR(400MHz,MeOD)：δ 7.84(dd,J=8.9Hz,2.4Hz,1H),7.70(d,J=2.4Hz,1H),7.37(d,J=2.8Hz,1H),7.22(s,1H),6.91(d,J=9.0Hz,1H),6.17(d,J=2.8Hz,1H),3.72(s,3H),3.45-3.38(m,1H),2.07-1.98(m,2H),1.94-1.85(m,2H),1.74(d,J=7.7Hz,2H),1.50-1.30(m,3H),1.19-1.05(m,4H),0.92(d,J=6.5Hz,3H). 1 H NMR (400MHz, MeOD): δ 7.84 (dd, J = 8.9Hz, 2.4Hz, 1H), 7.70 (d, J = 2.4Hz, 1H), 7.37 (d, J = 2.8Hz, 1H), 7.22 (s, 1H), 6.91 (d, J = 9.0Hz, 1H), 6.17 (d, J = 2.8Hz, 1H), 3.72 (s, 3H), 3.45-3.38 (m, 1H), 2.07-1.98 ( m, 2H), 1.94-1.85 (m, 2H), 1.74 (d, J = 7.7Hz, 2H), 1.50-1.30 (m, 3H), 1.19-1.05 (m, 4H), 0.92 (d, J = 6.5Hz, 3H).
以實施例41第二步產物(3-溴-4-氟苯基)(1-氯環丙基)(亞胺基)-λ6-硫烷酮為原料，參考實施例42第一步得(3- 溴-4-(環庚基胺基)苯基)(1-氯環丙基)(亞胺基)-λ6-硫烷酮(產率76%)。 Using the product (3-bromo-4-fluorophenyl) (1-chlorocyclopropyl) (imino) -λ 6 -sulfanone in the second step of Example 41 as the starting material, (3-bromo-4- (cycloheptylamino) phenyl) (1-chlorocyclopropyl) (imino) -λ 6 -sulfanone (yield 76%).
MS m/z(ESI)：405.0/407.2(50/50)[M+H]+. MS m / z (ESI): 405.0 / 407.2 (50/50) [M + H] + .
以(3-溴-4-(環庚基胺基)苯基)(1-氯環丙基)(亞胺基)-λ6-硫烷酮為原料，參考實施例4第四步得4-(5-(1-氯環丙烷-1-磺亞胺醯基)-2-(環庚基胺基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率65%)。 Using (3-bromo-4- (cycloheptylamino) phenyl) (1-chlorocyclopropyl) (imino) -λ 6 -sulfanone as a raw material, refer to Example 4 in the fourth step to obtain 4 -(5- (1-chlorocyclopropane-1-sulfinimidofluorenyl) -2- (cycloheptylamino) phenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro -7H-pyrrolo [2,3-c] pyridin-7-one (65% yield).
MS m/z(ESI)：627.1[M+H]+. MS m / z (ESI): 627.1 [M + H] + .
以4-(5-(1-氯環丙烷-1-磺亞胺醯基)-2-(環庚基胺基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶 -7-酮為原料，參考實施例1第八步得4-(5-(1-氯環丙烷-1-磺亞胺醯基)-2-(環庚基胺基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(52mg，產率76%)。 4- (5- (1-chlorocyclopropane-1-sulfinoimidofluorenyl) -2- (cycloheptylamino) phenyl) -6-methyl-1-toluenesulfonyl-1,6- Dihydro-7H-pyrrolo [2,3-c] pyridin-7-one was used as a raw material, and the eighth step of Reference Example 1 was to obtain 4- (5- (1-chlorocyclopropane-1-sulfinimidofluorenyl). -2- (cycloheptylamino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (52 mg, yield 76%) .
MS m/z(ESI)：473.2[M+H]+. MS m / z (ESI): 473.2 [M + H] + .
1H NMR(400MHz,MeOD)δ 7.74(dd,J=8.8Hz,2.4Hz,1H),7.60(d,J=2.4Hz,1H),7.26(d,J=2.8Hz,1H),7.11(s,1H),6.71(d,J=9.0Hz,1H),6.05(d,J=2.8Hz,1H),3.61(s,3H),3.59-3.49(m,1H),1.92-1.76(m,4H),1.57-1.23(m,12H). 1 H NMR (400MHz, MeOD) δ 7.74 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.60 (d, J = 2.4Hz, 1H), 7.26 (d, J = 2.8Hz, 1H), 7.11 ( s, 1H), 6.71 (d, J = 9.0Hz, 1H), 6.05 (d, J = 2.8Hz, 1H), 3.61 (s, 3H), 3.59-3.49 (m, 1H), 1.92-1.76 (m , 4H), 1.57-1.23 (m, 12H).
以實施例33第七步產物4-(5-(環丙磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，用環己胺替代反式-4-甲基環己胺，參考實施例23第一步，得到4-(2-(環己基胺基)-5-(環丙磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(11mg,白色固體，產率22%)。 Take the product in the seventh step of Example 33 as 4- (5- (Cyclopropanesulfenimido) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H- As a raw material, pyrrolo [2,3-c] pyridin-7-one was substituted with cyclohexylamine for trans-4-methylcyclohexylamine. Referring to the first step of Example 23, 4- (2- (cyclohexyl) was obtained Amine) -5- (Cyclopropanesulfenimido) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (11 mg, White solid, 22% yield).
MS m/z(ESI)：425.2[M+H]+。 MS m / z (ESI): 425.2 [M + H] + .
1H NMR(400MHz,MeOD)δ 7.67(dd,J=8.8Hz,2.4Hz,1H),7.54(d,J=2.4Hz,1H),7.26(d,J=2.8Hz,1H),7.11(s, 1H),6.78(d,J=9.2Hz,1H),6.04(d,J=2.8Hz,1H),3.60(s,3H),3.41-3.33(m,1H),2.60-2.53(m,1H),1.90-1.81(m,2H),1.62-1.47(m,3H),1.37-1.26(m,2H),1.15-1.08(m,2H),1.06-0.93(m,4H),0.89-0.82(m,1H). 1 H NMR (400MHz, MeOD) δ 7.67 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.54 (d, J = 2.4Hz, 1H), 7.26 (d, J = 2.8Hz, 1H), 7.11 ( s, 1H), 6.78 (d, J = 9.2Hz, 1H), 6.04 (d, J = 2.8Hz, 1H), 3.60 (s, 3H), 3.41-3.33 (m, 1H), 2.60-2.53 (m , 1H), 1.90-1.81 (m, 2H), 1.62-1.47 (m, 3H), 1.37-1.26 (m, 2H), 1.15-1.08 (m, 2H), 1.06-0.93 (m, 4H), 0.89 -0.82 (m, 1H).
溴化甲基三苯基磷(22.9g,64mmol)溶於四氫呋喃(200mL)中，在0℃氮氣保護下分批加入第三丁醇鉀(7.2g，64mmol)，反應液在0℃攪拌1小時。1,4-二氧雜螺[4.5]癸烷-8-酮(5g，32mmol)溶於四氫呋喃(50mL)中，緩慢滴加入上述反應液中，反應緩慢升至室溫，攪拌18小時。反應液用水(100mL)淬滅，水相用乙酸乙酯(100mL×3)萃取，有機相經無水硫酸鈉乾燥，過濾，旋乾。粗產物用管柱層析分離(石油醚~石油醚/乙酸乙酯：10/1)純化得到8-亞甲基-1,4-二氧雜螺[4.5]癸烷(3.4g，無色液體，產率：69%)。 Methyltriphenylphosphonium bromide (22.9g, 64mmol) was dissolved in tetrahydrofuran (200mL), and potassium tert-butoxide (7.2g, 64mmol) was added in portions under nitrogen protection at 0 ° C. The reaction solution was stirred at 0 ° C for 1 hour. 1,4-Dioxaspiro [4.5] decane-8-one (5 g, 32 mmol) was dissolved in tetrahydrofuran (50 mL) and slowly added dropwise to the above reaction solution. The reaction was slowly raised to room temperature and stirred for 18 hours. The reaction solution was quenched with water (100 mL), the aqueous phase was extracted with ethyl acetate (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by column chromatography (petroleum ether ~ petroleum ether / ethyl acetate: 10/1) to obtain 8-methylene-1,4-dioxaspiro [4.5] decane (3.4 g, colorless liquid). , Yield: 69%).
1H NMR(400MHz,CDCl3)δ 4.67(s,2H),3.96(s,4H),2.32-2.24(m,4H),1.75-1.67(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ 4.67 (s, 2H), 3.96 (s, 4H), 2.32-2.24 (m, 4H), 1.75-1.67 (m, 4H).
8-亞甲基-1,4-二氧雜螺[4.5]癸烷(3.4g，22.1mmol)溶於甲苯(7mL)中，在-40℃氮氣保護下滴加二乙基鋅(55.2mL，55.2mmol)。反應在-40℃下攪拌10分鐘，然後緩慢加入二碘甲烷(29.4g，110mmol)，反應液在室溫下攪拌18小時。反應液倒入冰鎮的飽和氯化銨水溶液(30mL)淬滅，水相用乙酸乙酯(30mL×3)萃取，有機相經無水硫酸鈉乾燥，過濾，旋乾。粗產物用管柱層析分離(石油醚~石油醚/乙酸乙酯：20/1)純化得到7,10-二氧雜二螺[2.2.46.23]十二烷(2.8g，無色液體，產率：82%)。 8-Methylene-1,4-dioxaspiro [4.5] decane (3.4g, 22.1mmol) was dissolved in toluene (7mL), and diethylzinc (55.2mL) was added dropwise under nitrogen protection at -40 ° C. , 55.2 mmol). The reaction was stirred at -40 ° C for 10 minutes, then diiodomethane (29.4 g, 110 mmol) was slowly added, and the reaction solution was stirred at room temperature for 18 hours. The reaction solution was poured into iced saturated aqueous ammonium chloride solution (30 mL) and quenched. The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by column chromatography (petroleum ether ~ petroleum ether / ethyl acetate: 20/1) to obtain 7,10-dioxabisspiro [2.2.4 6 .2 3 ] dodecane (2.8 g, Colorless liquid, yield: 82%).
1H NMR(400MHz,CDCl3)δ 3.97(s,4H),2.32-2.24(m,4H),1.75-1.67(m,4H),0.28(s,4H). 1 H NMR (400MHz, CDCl 3 ) δ 3.97 (s, 4H), 2.32-2.24 (m, 4H), 1.75-1.67 (m, 4H), 0.28 (s, 4H).
7,10-二氧雜二螺[2.2.46.23]十二烷(2.8g，16.7mmol)溶於四氫呋喃(8mL)和水(8mL)中，加入三氟乙酸(3mL)。反應在室溫下攪拌2小時。反應液用2M的氫氧化鈉水溶液調pH至7。水相用甲基第三丁基醚(30mL×2)萃取，有 機相經無水硫酸鈉乾燥，過濾，低溫旋乾得到螺[2.5]辛烷-6-酮(1.8g，無色液體，產率：87%)。 7,10-dioxabisspiro [2.2.4 6 .2 3 ] dodecane (2.8 g, 16.7 mmol) was dissolved in tetrahydrofuran (8 mL) and water (8 mL), and trifluoroacetic acid (3 mL) was added. The reaction was stirred at room temperature for 2 hours. The reaction solution was adjusted to pH 7 with a 2M aqueous sodium hydroxide solution. The aqueous phase was extracted with methyl tert-butyl ether (30 mL x 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried at low temperature to obtain spiro [2.5] octane-6-one (1.8 g, colorless liquid, yield). : 87%).
螺[2.5]辛烷-6-酮(0.2g，1.6mmol)和(4-甲氧苯基)甲胺(0.24g，1.8mmol)溶於1,2二氯乙烷(10mL)，在0℃氮氣保護下加入乙酸(125mg，2.1mmol)。反應在0℃下攪拌十分鐘，加入三乙醯氧基硼氫化鈉(1.1g，5.3mmol)。反應在室溫下攪拌18小時。反應液用飽和碳酸氫鈉水溶液(20mL)淬滅，水相用二氯甲烷(30mL×3)萃取，有機相經無水硫酸鈉乾燥，過濾，旋乾。粗產物用管柱層析分離(石油醚~石油醚/乙酸乙酯：1/1)純化得到N-(4-甲氧苄基)螺[2.5]辛烷-6-胺(220mg，無色液體，產率：56%)。 Spiro [2.5] octane-6-one (0.2 g, 1.6 mmol) and (4-methoxyphenyl) methylamine (0.24 g, 1.8 mmol) were dissolved in 1,2 dichloroethane (10 mL) at 0 Acetic acid (125 mg, 2.1 mmol) was added under nitrogen protection at <0> C. The reaction was stirred at 0 ° C for ten minutes, and sodium triacetoxyborohydride (1.1 g, 5.3 mmol) was added. The reaction was stirred at room temperature for 18 hours. The reaction solution was quenched with a saturated aqueous sodium bicarbonate solution (20 mL), the aqueous phase was extracted with dichloromethane (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was separated by column chromatography (petroleum ether ~ petroleum ether / ethyl acetate: 1/1) and purified to obtain N- (4-methoxybenzyl) spiro [2.5] octane-6-amine (220mg, colorless liquid). , Yield: 56%).
1H NMR(400MHz,CDCl3)δ 7.25(d,J=7.6Hz,2H),6.86(d,J=8.7Hz,2H),3.80(s,3H),3.77(s,2H),2.60-2.52(m,1H),1.91-1.84(m,2H),1.70-1.63(m,2H),1.40-1.29(m,2H),1.00-0.92(m,2H),0.30-0.25(m,2H),0.23-0.16(m,2H). 1 H NMR (400MHz, CDCl3) δ 7.25 (d, J = 7.6Hz, 2H), 6.86 (d, J = 8.7Hz, 2H), 3.80 (s, 3H), 3.77 (s, 2H), 2.60-2.52 (m, 1H), 1.91-1.84 (m, 2H), 1.70-1.63 (m, 2H), 1.40-1.29 (m, 2H), 1.00-0.92 (m, 2H), 0.30-0.25 (m, 2H) , 0.23-0.16 (m, 2H).
N-(4-甲氧苄基)螺[2.5]辛烷-6-胺(1.1g，4.5mmol)和鈀碳(500mg)溶於甲醇(20mL)，在室溫氫氣球下攪拌18 小時。反應液過濾，濾餅用甲醇(10mL x5)洗，有機相旋乾得到螺[2.5]辛烷-6-胺(450mg g，無色液體，產率：80%)。 N- (4-methoxybenzyl) spiro [2.5] octane-6-amine (1.1 g, 4.5 mmol) and palladium on carbon (500 mg) were dissolved in methanol (20 mL) and stirred under a hydrogen balloon at room temperature for 18 hours. The reaction solution was filtered, the filter cake was washed with methanol (10 mL x 5), and the organic phase was spin-dried to obtain spiro [2.5] octane-6-amine (450 mg g, colorless liquid, yield: 80%).
1H NMR(400MHz,CDCl3)δ 2.79-2.68(m,1H),2.09(brs,2H),1.85-1.76(m,2H),1.76-1.64(m,2H),1.35-1.23(m,2H),0.96-0.89(m,2H),0.34-0.24(m,2H),0.24-0.16(m,2H). 1 H NMR (400MHz, CDCl3) δ 2.79-2.68 (m, 1H), 2.09 (brs, 2H), 1.85-1.76 (m, 2H), 1.76-1.64 (m, 2H), 1.35-1.23 (m, 2H ), 0.96-0.89 (m, 2H), 0.34-0.24 (m, 2H), 0.24-0.16 (m, 2H).
(3-溴-4-氟苯基)(環丙基)(亞胺基)-λ6-硫烷酮(110mg，0.4mmol)，螺[2.5]辛烷-6-胺(148mg，1.2mmol)和碳酸銫(325mg,1mmol)溶於二甲亞碸(10mL)，反應在80℃下攪拌18小時。反應液加水(50mL)，水相用乙酸乙酯(30mL×2)萃取，有機相經無水硫酸鈉乾燥，過濾，旋乾。粗產物用管柱層析分離(石油醚/乙酸乙酯：20/1~石油醚/乙酸乙酯：3/1)純化得到(3-溴-4-(螺[2.5]辛烷-6-基胺基)苯基)(環丙基)(亞胺基)-λ6-硫烷酮(100mg，無色固體，產率：65%)。 (3-bromo-4-fluorophenyl) (cyclopropyl) (imino) -λ 6 -sulfanone (110 mg, 0.4 mmol), spiro [2.5] octane-6-amine (148 mg, 1.2 mmol ) And cesium carbonate (325 mg, 1 mmol) were dissolved in dimethylarsine (10 mL), and the reaction was stirred at 80 ° C. for 18 hours. Water (50 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (30 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried. The crude product was separated by column chromatography (petroleum ether / ethyl acetate: 20/1 to petroleum ether / ethyl acetate: 3/1) and purified to obtain (3-bromo-4- (spiro [2.5] octane-6- Aminoamino) phenyl) (cyclopropyl) (imino) -λ 6 -sulfanone (100 mg, colorless solid, yield: 65%).
MS m/z(ESI)：383.0/385.0(50/50)[M+H]+. MS m / z (ESI): 383.0 / 385.0 (50/50) [M + H] + .
(3-溴-4-(螺[2.5]辛烷-6-基胺基)苯基)(環丙基)(亞胺基)-λ6-硫烷酮(50mg，0.13mmol)，6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(112mg，0.26mmol)，[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(19mg，0.026mmol)和碳酸鉀(45mg,0.33mmol)溶於1,4-二噁烷/水(5/1，2mL)，氮氣置換並保護，反應在90℃下攪拌2小時。反應液加水(10mL)，水相用乙酸乙酯(10mL×3)萃取，有機相經無水硫酸鈉乾燥，過濾，濃縮後用製備矽膠板分離(乙酸乙酯)，得到4-(5-(環丙磺亞胺醯基)-2-(螺[2.5]辛烷-6-基胺基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(30mg，棕色膠體，產率：38%)。 (3-bromo-4- (spiro [2.5] octane-6-ylamino) phenyl) (cyclopropyl) (imino) -λ 6 -sulfanone (50 mg, 0.13 mmol), 6- Methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-toluenesulfon-1,6-dihydro -7H-pyrrolo [2,3-c] pyridin-7-one (112 mg, 0.26 mmol), [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride (19 mg, 0.026 mmol) and potassium carbonate (45 mg, 0.33 mmol) were dissolved in 1,4-dioxane / water (5/1, 2 mL), replaced with nitrogen and protected, and the reaction was stirred at 90 ° C. for 2 hours. Water (10 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated and separated with a silica gel plate (ethyl acetate) to obtain 4- (5- ( Cyclopropanesulfenimido) -2- (spiro [2.5] octane-6-ylamino) phenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrole [2,3-c] pyridin-7-one (30 mg, brown colloid, yield: 38%).
MS m/z(ESI)：605.2[M+H]+ MS m / z (ESI): 605.2 [M + H] +
4-(5-(環丙磺亞胺醯基)-2-(螺[2.5]辛烷-6-基胺基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7- 酮(30mg，0.05mmol)溶於乙醇(5mL)，加入2M氫氧化鈉水溶液(5mL)，反應在30℃下攪拌0.5小時。反應液濃縮，旋乾後用高效液相色譜管柱分離，得到4-(5-(環丙磺亞胺醯基)-2-(螺[2.5]辛烷-6-基胺基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(6mg，白色固體，產率：27%)。 4- (5- (Cyclopropanesulfinolimino) -2- (spiro [2.5] octane-6-ylamino) phenyl) -6-methyl-1-toluenesulfon-1,6- Dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (30mg, 0.05mmol) was dissolved in ethanol (5mL), 2M aqueous sodium hydroxide solution (5mL) was added, and the reaction was stirred at 30 ° C for 0.5 hours. . The reaction solution was concentrated and spin-dried and separated by a high performance liquid chromatography column to obtain 4- (5- (cyclopropanesulfenimidoamido) -2- (spiro [2.5] octane-6-ylamino) phenyl. ) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (6 mg, white solid, yield: 27%).
MS m/z(ESI)：451.2[M+H]+ MS m / z (ESI): 451.2 [M + H] +
1H NMR(400MHz,MeOD)δ 7.78(dd,J=8.8Hz,2.3Hz,1H),7.64(d,J=2.4Hz,1H),7.36(d,J=2.8Hz,1H),7.22(s,1H),6.90(d,J=9.0Hz,1H),6.15(d,J=2.8Hz,1H),3.70(s,3H),3.56-3.48(m,1H),2.72-2.61(m,1H),2.00-1.88(m,2H),1.79-1.67(m,2H),1.36-1.24(m,4H),1.12-1.03(m,2H),1.00-0.94(m,2H),0.32-0.24(m,2H),0.21-0.13(m,2H). 1 H NMR (400MHz, MeOD) δ 7.78 (dd, J = 8.8Hz, 2.3Hz, 1H), 7.64 (d, J = 2.4Hz, 1H), 7.36 (d, J = 2.8Hz, 1H), 7.22 ( s, 1H), 6.90 (d, J = 9.0Hz, 1H), 6.15 (d, J = 2.8Hz, 1H), 3.70 (s, 3H), 3.56-3.48 (m, 1H), 2.72-2.61 (m , 1H), 2.00-1.88 (m, 2H), 1.79-1.67 (m, 2H), 1.36-1.24 (m, 4H), 1.12-1.03 (m, 2H), 1.00-0.94 (m, 2H), 0.32 -0.24 (m, 2H), 0.21-0.13 (m, 2H).
以(3-溴-4-氟苯基)(環丙基)(亞胺基)-λ6-硫烷酮為原料，參考實施例42第一步得(3-溴-4-((2,4-二氟苯基)胺基)苯基)(環丙基)(亞胺基)-λ6-硫烷酮(產率50%)。 Using (3-bromo-4-fluorophenyl) (cyclopropyl) (imino) -λ 6 -sulfanone as a raw material, (Step 3-bromo-4-((2 , 4-difluorophenyl) amino) phenyl) (cyclopropyl) (imino) -λ 6 - sulfur pyrrolidone (50% yield).
MS m/z(ESI)：386.9[M+H]+,388.9[M+2+H]+. MS m / z (ESI): 386.9 [M + H] + , 388.9 [M + 2 + H] + .
以(3-溴-4-((2,4-二氟苯基)胺基)苯基)(環丙基)(亞胺基)-λ6-硫烷酮為原料，參考實施例4第四步得4-(5-(環丙磺亞胺醯基)-2-((2,4-二氟苯基)胺基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率65%)。 Using (3-bromo-4-((2,4-difluorophenyl) amino) phenyl) (cyclopropyl) (imino) -λ 6 -sulfanone as a raw material, refer to Example 4 Four steps to get 4- (5- (cyclopropanesulfenimidoamido) -2-((2,4-difluorophenyl) amino) phenyl) -6-methyl-1-toluenesulfonyl-1 , 6-Dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (65% yield).
MS m/z(ESI)：609.1[M+H]+. MS m / z (ESI): 609.1 [M + H] + .
以4-(5-(環丙磺亞胺醯基)-2-((2,4-二氟苯基)胺基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，參考實施例1第八步得4-(5-(環丙磺亞胺醯基)-2-((2,4-二氟苯基)胺基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率65%)。 4- (5- (Cyclopropanesulfinoimidoamidinyl) -2-((2,4-difluorophenyl) amino) phenyl) -6-methyl-1-toluenesulfonyl-1,6 -Dihydro-7H-pyrrolo [2,3-c] pyridin-7-one as a raw material, and the eighth step of Reference Example 1 was to obtain 4- (5- (cyclopropanesulfinoimido) -2-(( 2,4-difluorophenyl) amino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (65% yield) .
MS m/z(ESI)：455.1[M+H]+。 MS m / z (ESI): 455.1 [M + H] + .
1H NMR(400MHz,MeOD)δ 7.69(d,J=2.4Hz,1H),7.65(m,1H),7.24(d,J=2.8Hz,1H),7.21(s,1H),7.18-7.11(m,1H),6.95-6.89(m,1H),6.83(d,J=9.2Hz,1H),6.74(m,1H),6.17(d,J=2.8Hz,1H),3.61(s,3H),2.63-2.59(m,1H),1.17-1.12(m,1H),1.04-0.98(m,2H),0.88(m,1H). 1 H NMR (400MHz, MeOD) δ 7.69 (d, J = 2.4Hz, 1H), 7.65 (m, 1H), 7.24 (d, J = 2.8Hz, 1H), 7.21 (s, 1H), 7.18-7.11 (m, 1H), 6.95-6.89 (m, 1H), 6.83 (d, J = 9.2Hz, 1H), 6.74 (m, 1H), 6.17 (d, J = 2.8Hz, 1H), 3.61 (s, 3H), 2.63-2.59 (m, 1H), 1.17-1.12 (m, 1H), 1.04-0.98 (m, 2H), 0.88 (m, 1H).
將4-(三氟甲基)環己烷-1-酮(9.7g，58.4mmol)溶於四氫呋喃(100mL)中，加入苄胺(6.3g，58.4mmol)，分批加入 三乙醯氧基硼氫化鈉(13.6g，64.2mmol)，在25℃攪拌16小時，加入飽和氯化銨水溶液(50mL)，乙酸乙酯(10mL)萃取，分出乙酸乙酯旋乾，過管柱純化得到N-苯甲基-4-(三氟甲基)環己烷-1-胺(10g)。 4- (trifluoromethyl) cyclohexane-1-one (9.7 g, 58.4 mmol) was dissolved in tetrahydrofuran (100 mL), benzylamine (6.3 g, 58.4 mmol) was added, and triethylamyloxy was added in portions. Sodium borohydride (13.6g, 64.2mmol), stirred at 25 ° C for 16 hours, added saturated ammonium chloride aqueous solution (50mL), and extracted with ethyl acetate (10mL). The ethyl acetate was separated and spin-dried. -Benzyl-4- (trifluoromethyl) cyclohexane-1-amine (10 g).
MS m/z(ESI)：258.1M+H]+. MS m / z (ESI): 258.1M + H] + .
1H NMR(400MHz,DMSO-d6)：δ 7.28-7.35(m,4H),3.66(s,2H),2.73-2.75(m,1H),2.19-2.22(m,1H),1.95(br,1H),1.65-1.78(m,4H),1.38-1.54(m,4H)； 1 H NMR (400MHz, DMSO-d6): δ 7.28-7.35 (m, 4H), 3.66 (s, 2H), 2.73-2.75 (m, 1H), 2.19-2.22 (m, 1H), 1.95 (br, 1H), 1.65-1.78 (m, 4H), 1.38-1.54 (m, 4H);
將N-苯甲基-4-(三氟甲基)環己烷-1-胺(5.0g，19.5mmol)溶於四氫呋喃(50mL)與乙醇(50mL)中，加入鈀炭(0.65g)，氫氣置換並保護，在25℃攪拌16小時，矽藻土過濾，旋乾，過管柱純化得到反-4-(三氟甲基)環己烷-1-胺(2g). N-benzyl-4- (trifluoromethyl) cyclohexane-1-amine (5.0 g, 19.5 mmol) was dissolved in tetrahydrofuran (50 mL) and ethanol (50 mL), and palladium on carbon (0.65 g) was added. Replace with hydrogen and protect, stir at 25 ° C for 16 hours, filter through celite, spin dry, and purify through a column to obtain trans-4- (trifluoromethyl) cyclohexane-1-amine (2g).
MS m/z(ESI)：168.1[M+H]+. MS m / z (ESI): 168.1 [M + H] + .
1H NMR(400MHz,DMSO-d6)：δ 3.06-3.09(m,1H),2.11-2.21(m,1H),1.67-1.78(m,2H),1.45-1.57(m,6H)； 1 H NMR (400MHz, DMSO-d6): δ 3.06-3.09 (m, 1H), 2.11-2.21 (m, 1H), 1.67-1.78 (m, 2H), 1.45-1.57 (m, 6H);
將實施例33第六步產物(3-溴-4-氟苯基)(環丙基)(亞胺基)-λ6-硫烷酮(140mg，0.5mmol)與反-4-(三氟甲基)環己胺-1-甲胺(1.0g)，在150℃下3小時後，管柱層析得到(3-溴-4-((反-4-(三氟甲基)環己基)胺基)苯基)(環丙基)(亞胺基)-λ6-硫烷酮(0.12g，收率56.6%)。 The product from the sixth step of Example 33 (3-bromo-4-fluorophenyl) (cyclopropyl) (imino) -λ 6 -sulfanone (140 mg, 0.5 mmol) and trans-4- (trifluoro (Methyl) cyclohexylamine-1-methylamine (1.0g). After 3 hours at 150 ° C, column chromatography gave (3-bromo-4-((trans-4- (trifluoromethyl) cyclohexyl) ) Amino) phenyl) (cyclopropyl) (imino) -λ6-sulfanone (0.12 g, yield 56.6%).
MS m/z(ESI)：425.0/427.0(50/50)[M+H]+. MS m / z (ESI): 425.0 / 427.0 (50/50) [M + H] + .
將(3-溴-4-((反-4-(三氟甲基)環己基)胺基)苯基)(環丙基)(亞胺基)-λ6-硫烷酮替實施例45第六步產物(3-溴-4-(螺[2.5]辛烷-6-基胺基)苯基)(環丙基)(亞胺基)-λ6-硫烷酮，參考實施例45第七步，得到4-(5-(環丙磺亞胺醯基)-2-((反-4-(三氟甲基)環己基)胺基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(收率48.6%)。 (3-Bromo-4-((trans-4- (trifluoromethyl) cyclohexyl) amino) phenyl) (cyclopropyl) (imino) -λ6-sulfanone was replaced by Example 45. Six-step product (3-bromo-4- (spiro [2.5] octane-6-ylamino) phenyl) (cyclopropyl) (imino) -λ 6 -sulfanone, refer to Example 45. Seven steps to give 4- (5- (cyclopropanesulfenimidoamido) -2-((trans-4- (trifluoromethyl) cyclohexyl) amino) phenyl) -6-methyl-1- Tosyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (48.6% yield).
MS m/z(ESI)：647.1[M+H]+. MS m / z (ESI): 647.1 [M + H] + .
將4-(5-(環丙磺亞胺醯基)-2-((反-4-(三氟甲基)環己基)胺基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為起始原料，參考實施例45第八步得到4-(5-(環丙磺亞胺醯基)-2-((反-4-(三氟甲基)環己基)胺基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮，收率86.6%)。 4- (5- (Cyclopropanesulfenimidoamidinyl) -2-((trans-4- (trifluoromethyl) cyclohexyl) amino) phenyl) -6-methyl-1-toluenesulfonium -1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one was used as a starting material, and the eighth step of Reference Example 45 was to obtain 4- (5- (cyclopropanesulfenimidoamidinyl ) -2-((trans-4- (trifluoromethyl) cyclohexyl) amino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine -7-one, yield 86.6%).
MS m/z(ESI)：493.1[M+H]+. MS m / z (ESI): 493.1 [M + H] + .
1H NMR(400MHz,DMSO-d6)：δ 12.17(br,1H),7.67(dd,J=8.8Hz,2.4Hz,1H),7.57(d,J=2.4Hz，1H),7.28-7.26(m,2H),6.83(d,J=8.8Hz,1H),6.07(t,J=2.0Hz,1H),4.75(d,J=6.4Hz,1H),3.78(s,1H),3.55(s,3H),2.61-2.55(m,1H),1.86-1.76(m,2H),1.64-1.54(m,4H),1.28-1.14(m,2H),1.10-1.00(m,2H),0.94-0.82(m,2H). 1 H NMR (400MHz, DMSO-d6): δ 12.17 (br, 1H), 7.67 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.57 (d, J = 2.4Hz, 1H), 7.28-7.26 ( m, 2H), 6.83 (d, J = 8.8Hz, 1H), 6.07 (t, J = 2.0Hz, 1H), 4.75 (d, J = 6.4Hz, 1H), 3.78 (s, 1H), 3.55 ( s, 3H), 2.61-2.55 (m, 1H), 1.86-1.76 (m, 2H), 1.64-1.54 (m, 4H), 1.28-1.14 (m, 2H), 1.10-1.00 (m, 2H), 0.94-0.82 (m, 2H).
以4-(5-(環丙磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯 磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，參考實施例4第四步，用4-三氟甲氧基苯酚取代2,4-二氟苯酚，得到4-(5-(環丙磺亞胺醯基)-2-(4-(三氟甲氧基)苯氧基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率44%)。 4- (5- (Cyclopropanesulfenimido) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one as a raw material. In the fourth step of Reference Example 4, 2,4-difluorophenol was replaced with 4-trifluoromethoxyphenol to obtain 4- (5- (cyclopropanesulfenimide) ) -2- (4- (trifluoromethoxy) phenoxy) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7-one (44% yield).
MS m/z(ESI)：504.1[M+H]+. MS m / z (ESI): 504.1 [M + H] + .
1H NMR(400MHz,MeOD)δ 8.10(d,J=2.4Hz,1H),7.96(dd,J=8.7Hz,2.4Hz,1H),7.34(d,J=2.9Hz,1H),7.31(s,1H),7.21(dd,J=8.5Hz,4.3Hz,3H),7.04-6.98(m,2H),6.35(d,J=2.9Hz,1H),3.65(s,3H),2.83-2.70(m,1H),1.21-1.07(m,2H),1.07-0.96(m,1H),0.95-0.85(m,1H). 1 H NMR (400MHz, MeOD) δ 8.10 (d, J = 2.4Hz, 1H), 7.96 (dd, J = 8.7Hz, 2.4Hz, 1H), 7.34 (d, J = 2.9Hz, 1H), 7.31 ( s, 1H), 7.21 (dd, J = 8.5Hz, 4.3Hz, 3H), 7.04-6.98 (m, 2H), 6.35 (d, J = 2.9Hz, 1H), 3.65 (s, 3H), 2.83 2.70 (m, 1H), 1.21-1.07 (m, 2H), 1.07-0.96 (m, 1H), 0.95-0.85 (m, 1H).
以4-(2-氟-5-(S-甲基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，參考實施例4第五步，用4-三氟甲氧基苯酚取代2,4-二氟苯酚，得到標題化合物6-甲基-4-(5-(S-甲基磺亞胺醯基)-2-(4-(三氟甲氧基)苯氧基)苯基)-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率43%)。 With 4- (2-fluoro-5- (S-methylsulfonylimino) phenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2, 3-c] pyridine-7-one as a raw material, and referring to the fifth step of Example 4, substituting 2,4-difluorophenol with 4-trifluoromethoxyphenol to obtain the title compound 6-methyl-4- (5 -(S-methylsulfonylimido) -2- (4- (trifluoromethoxy) phenoxy) phenyl) -1,6-dihydro-7H-pyrrolo [2,3-c ] Pyridin-7-one (43% yield).
MS m/z(ESI)：478.1[M+H]+. MS m / z (ESI): 478.1 [M + H] + .
1H NMR(400MHz,MeOD)δ 8.17(d,J=2.4Hz,1H),8.04(dd,J=8.7Hz,2.5Hz,1H),7.36(d,J=2.9Hz,1H),7.33(s,1H),7.24(t,J=8.6Hz,3H),7.06-6.99(m,2H),6.38(d,J=2.9Hz,1H),3.67(s,3H),3.24(s,3H). 1 H NMR (400MHz, MeOD) δ 8.17 (d, J = 2.4Hz, 1H), 8.04 (dd, J = 8.7Hz, 2.5Hz, 1H), 7.36 (d, J = 2.9Hz, 1H), 7.33 ( s, 1H), 7.24 (t, J = 8.6 Hz, 3H), 7.06-6.99 (m, 2H), 6.38 (d, J = 2.9 Hz, 1H), 3.67 (s, 3H), 3.24 (s, 3H ).
以(3-溴-4-氟苯基)(亞胺基)(甲基)-λ6-硫烷酮(100mg,0.4mmol)為反應原料，參考實施例47第六步，得到化合物(3-溴-4-(螺[2.5]辛烷-6-基胺基)苯基)(亞胺基)(甲基)-λ6-硫烷酮(40mg，產率28%)。 Using (3-bromo-4-fluorophenyl) (imino) (methyl) -λ 6 -sulfanone (100 mg, 0.4 mmol) as a reaction raw material, refer to the sixth step of Example 47 to obtain compound (3 - bromo-4- (spiro [2.5] octane-6-yl) phenyl) (imino) (meth) -λ 6 - sulfur pyrrolidone (40mg, 28% yield).
MS m/z(ESI)：357.0/359.0(50/50)[M+H]+. MS m / z (ESI): 357.0 / 359.0 (50/50) [M + H] +.
以(3-溴-4-(螺[2.5]辛烷-6-基胺基)苯基)(亞胺基)(甲基)-λ6-硫烷酮(40mg,0.11mmol)為反應原料，參考實施例45第七步，得到化合物6-甲基-4-(5-(S-甲基磺亞胺醯基)-2-(螺[2.5]辛烷-6-基胺基)苯基)-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(40mg，產率63%)。 (3-Bromo-4- (spiro [2.5] octane-6-ylamino) phenyl) (imino) (methyl) -λ 6 -sulfanone (40mg, 0.11mmol) as the reaction raw material Refer to the seventh step of Example 45 to obtain the compound 6-methyl-4- (5- (S-methylsulfonyliminoamido) -2- (spiro [2.5] octane-6-ylamino) benzene Yl) -1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (40 mg, yield 63%).
MS m/z(ESI)：579.2[M+H]+ MS m / z (ESI): 579.2 [M + H] +
6-甲基-4-(5-(S-甲基磺亞胺醯基)-2-(螺[2.5]辛烷-6-基胺基)苯基)-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(40mg，0.07mmol)溶於第三丁醇(5mL)和水(1mL)，加入氫氧化鉀(39mg，0.7mmol)，反應在60℃下攪拌18小時。反應液加水(10mL)，水相用乙酸乙酯(20mL)萃取，有機相經無水硫酸鈉乾燥，過濾，旋乾後用高效液相色譜管柱分離，得到6-甲基-4-(5-(S-甲基磺亞胺醯基)-2-(螺[2.5]辛烷-6-基胺基)苯基)-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7- 酮(2.2mg，白色固體，產率：7.6%)。 6-methyl-4- (5- (S-methylsulfimidofluorenyl) -2- (spiro [2.5] octane-6-ylamino) phenyl) -1-toluenesulfonyl-1, 6-Dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (40 mg, 0.07 mmol) was dissolved in tert-butanol (5 mL) and water (1 mL), and potassium hydroxide (39 mg, 0.7 mmol) and the reaction was stirred at 60 ° C for 18 hours. Water (10 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and separated by spin-drying using a high performance liquid chromatography column to obtain 6-methyl-4- (5 -(S-methylsulfonylimido) -2- (spiro [2.5] octane-6-ylamino) phenyl) -1,6-dihydro-7H-pyrrolo [2,3-c ] Pyridine-7-one (2.2 mg, white solid, yield: 7.6%).
MS m/z(ESI)：425.2[M+H]+ MS m / z (ESI): 425.2 [M + H] +
1H NMR(400MHz,MeOD)δ 7.83(dd,J=8.8Hz,2.4Hz,1H),7.68(d,J=2.4Hz,1H),7.36(d,J=2.8Hz,1H),7.23(s,1H),6.91(d,J=9.0Hz,1H),6.14(d,J=2.8Hz,1H),3.70(s,3H),3.57-3.46(m,1H),3.13(s,3H),2.07-2.00(m,1H),1.98-1.90(m,2H),1.78-1.68(m,2H),1.64-1.57(m,1H),1.01-0.93(m,2H),0.34-0.26(m,2H),0.20-0.15(m,2H). 1 H NMR (400MHz, MeOD) δ 7.83 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.68 (d, J = 2.4Hz, 1H), 7.36 (d, J = 2.8Hz, 1H), 7.23 ( s, 1H), 6.91 (d, J = 9.0Hz, 1H), 6.14 (d, J = 2.8Hz, 1H), 3.70 (s, 3H), 3.57-3.46 (m, 1H), 3.13 (s, 3H ), 2.07-2.00 (m, 1H), 1.98-1.90 (m, 2H), 1.78-1.68 (m, 2H), 1.64-1.57 (m, 1H), 1.01-0.93 (m, 2H), 0.34-0.26 (m, 2H), 0.20-0.15 (m, 2H).
以4-(2-氟-5-(S-甲基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為反應原料，參考實施例23第一步，用R-苯乙胺取代反-4-甲基環己胺，得到6-甲基-4-(5-(S-甲基磺亞胺醯基)-2-(((R)-1-苯基乙基)胺基)苯基)-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率25%)。 With 4- (2-fluoro-5- (S-methylsulfonylimino) phenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2, 3-c] pyridine-7-one as a reaction raw material. Referring to the first step of Example 23, trans-methyl-4-hexylamine was replaced with R-phenylethylamine to obtain 6-methyl-4- (5- ( S-methylsulfonylimido) -2-((((R) -1-phenylethyl) amino) phenyl) -1,6-dihydro-7H-pyrrolo [2,3-c ] Pyridine-7-one (25% yield).
MS m/z(ESI)：421.2[M+H]+. MS m / z (ESI): 421.2 [M + H] + .
1H NMR(400MHz,CDCl3)：δ 8.08(d,J=2.4Hz,1H),7.99(dd,J=8.7Hz,2.4Hz,1H),7.28-7.36(m,5H),7.31(t,J=2.7Hz,1H),7.11(d,J=8.8Hz,1H),7.05(s,1H),6.24(t,J =2.4Hz,1H),4.01-3.95(m,1H),3.73(s,3H),3.20(s,3H),1.41(d,J=2.4Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ 8.08 (d, J = 2.4Hz, 1H), 7.99 (dd, J = 8.7Hz, 2.4Hz, 1H), 7.28-7.36 (m, 5H), 7.31 (t , J = 2.7Hz, 1H), 7.11 (d, J = 8.8Hz, 1H), 7.05 (s, 1H), 6.24 (t, J = 2.4Hz, 1H), 4.01-3.95 (m, 1H), 3.73 (s, 3H), 3.20 (s, 3H), 1.41 (d, J = 2.4Hz, 3H).
以4-(2-氟-5-(S-甲基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為反應原料，參考實施例23第一步，用環己胺取反-4-甲基環己胺，得到4-(2-(環己基胺基)-5-(S-甲基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率33%)。 With 4- (2-fluoro-5- (S-methylsulfonylimino) phenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2, 3-c] pyridine-7-one as a reaction raw material. Referring to the first step of Example 23, using cyclohexylamine to take trans-4-methylcyclohexylamine to obtain 4- (2- (cyclohexylamino) -5 -(S-methylsulfonylimino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7-one (33% yield) .
MS m/z(ESI)：399.2[M+H]+. MS m / z (ESI): 399.2 [M + H] + .
1H NMR(400MHz,MeOD)：δ 7.86(d,J=8.2Hz,1H),7.68(s,1H),7.28(d,J=2.4Hz,1H),7.19(s,1H),6.86(d,J=9.0Hz,1H),6.01(d,J=2.3Hz,1H),3.66(s,3H),3.61(s,3H),2.60-2.41(m,1H),1.56-1.42(m,10H). 1 H NMR (400MHz, MeOD): δ 7.86 (d, J = 8.2Hz, 1H), 7.68 (s, 1H), 7.28 (d, J = 2.4Hz, 1H), 7.19 (s, 1H), 6.86 ( d, J = 9.0Hz, 1H), 6.01 (d, J = 2.3Hz, 1H), 3.66 (s, 3H), 3.61 (s, 3H), 2.60-2.41 (m, 1H), 1.56-1.42 (m , 10H).
以4-(5-(乙基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，用2-胺基吡啶取2,4-二甲基苯酚，參考實施例10第五步，得到4-(5-(乙基磺亞胺醯基)-2-(吡啶-2-基胺基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(白色固體，產率38%)。 4- (5- (ethylsulfonylimino) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one as a raw material, using 2, aminopyridine to take 2,4-dimethylphenol, and refer to the fifth step of Example 10 to obtain 4- (5- (ethylsulfonylimino)- 2- (pyridin-2-ylamino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (white solid, yield 38 %).
MS m/z(ESI)：408.1[M+H]+. MS m / z (ESI): 408.1 [M + H] + .
1H NMR(400MHz,MeOD)δ 8.18(d,J=8.8Hz,1H),8.05(d,J=4.0Hz,1H),7.84-7.74(m,2H),7.50-7.42(m,1H),7.23-7.14(m,2H),6.79-6.73(m,1H),6.69(d,J=8.4Hz,1H),6.03(d,J=2.8Hz,1H),3.61(s,3H),3.18(q,J=7.4Hz,2H),1.17(t,J=7.4Hz,3H). 1 H NMR (400MHz, MeOD) δ 8.18 (d, J = 8.8Hz, 1H), 8.05 (d, J = 4.0Hz, 1H), 7.84-7.74 (m, 2H), 7.50-7.42 (m, 1H) , 7.23-7.14 (m, 2H), 6.79-6.73 (m, 1H), 6.69 (d, J = 8.4Hz, 1H), 6.03 (d, J = 2.8Hz, 1H), 3.61 (s, 3H), 3.18 (q, J = 7.4Hz, 2H), 1.17 (t, J = 7.4Hz, 3H).
以4-(5-(乙基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，用2-羥基吡啶取2,4-二甲基苯酚，參考實施例10第五步，得到 4-(5-(乙基磺亞胺醯基)-2-(吡啶-2-羥基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(白色固體，產率3%)。 4- (5- (ethylsulfonylimino) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2,3- c] pyridine-7-one as a raw material, using 2, hydroxypyridine to take 2,4-dimethylphenol, and refer to the fifth step of Example 10 to obtain 4- (5- (ethylsulfonylimido) -2 -(Pyridine-2-hydroxy) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (white solid, 3% yield).
MS m/z(ESI)：409.1[M+H]+。 MS m / z (ESI): 409.1 [M + H] + .
1H NMR(400MHz,MeOD)δ8.11-8.00(m,2H),7.67(d,J=8.4Hz,1H),7.34(d,J=9.2Hz,2H),7.16(d,J=2.8Hz,1H),6.98(s,1H),6.40(d,J=9.2Hz,1H),6.16-6.11(m,2H),3.48(s,3H),3.30-3.26(m,2H),1.21(t,J=7.4Hz,3H). 1 H NMR (400MHz, MeOD) δ8.11-8.00 (m, 2H), 7.67 (d, J = 8.4Hz, 1H), 7.34 (d, J = 9.2Hz, 2H), 7.16 (d, J = 2.8 Hz, 1H), 6.98 (s, 1H), 6.40 (d, J = 9.2Hz, 1H), 6.16-6.11 (m, 2H), 3.48 (s, 3H), 3.30-3.26 (m, 2H), 1.21 (t, J = 7.4Hz, 3H).
5-溴-2-甲氧基-3-硝基吡啶(15g，64.3mmol)溶於四氫呋喃(150mL)中，在-78℃氮氣保護下慢慢滴加異烯丙基溴化鎂(385mL，192.9mmol，0.5M)。反應液在-78℃攪拌3小時，反應液用飽和氯化銨水溶液(100mL)淬滅，溶液用乙酸乙酯(100mL×2)萃取，有機相用飽和食鹽水(100 mL)洗滌，無水硫酸鈉乾燥。有機相乾燥旋乾，管柱分離(石油醚/乙酸乙酯=5/1)得到4-溴-7-甲氧基-2-甲基-1H-吡咯並[2,3-c]吡啶(5.5g，黃色油狀物，35%)。 5-Bromo-2-methoxy-3-nitropyridine (15g, 64.3mmol) was dissolved in tetrahydrofuran (150mL), and isoallylmagnesium bromide (385mL, 192.9 mmol, 0.5M). The reaction solution was stirred at -78 ° C for 3 hours. The reaction solution was quenched with a saturated aqueous ammonium chloride solution (100 mL). The solution was extracted with ethyl acetate (100 mL x 2). The organic phase was washed with saturated brine (100 mL), and anhydrous sulfuric acid Sodium is dried. The organic phase was dried and spin-dried, and separated by column (petroleum ether / ethyl acetate = 5/1) to obtain 4-bromo-7-methoxy-2-methyl-1H-pyrrolo [2,3-c] pyridine ( 5.5 g, yellow oil, 35%).
1H NMR(400MHz,CDCl3)δ 7.80(d,J=5.6Hz,1H),7.26(s,1H),4.06(s,3H),2.48(s,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.80 (d, J = 5.6 Hz, 1H), 7.26 (s, 1H), 4.06 (s, 3H), 2.48 (s, 3H).
4-溴-7-甲氧基-2-甲基-1H-吡咯並[2,3-c]吡啶(2.6g，11mmol)溶於N,N-二甲基甲醯胺(20mL)中，在0℃氮氣保護下分批加入氫化鈉(640mL，16mmol)。反應在室溫下攪拌15分鐘，然後在0℃氮氣保護下分批加入對甲基本磺醯氯(3.04g，16mmol)，反應液在室溫下攪拌16小時。反應液用飽和氯化銨水溶液(20mL)淬滅，溶液用乙酸乙酯(30mL×2)萃取，有機相用飽和食鹽水(20mL×3)洗滌，無水硫酸鈉乾燥。有機相乾燥旋乾，管柱分離(石油醚/乙酸乙酯=10/1)得到4-溴-7-甲氧基-2-甲基-1-甲苯磺醯-1H-吡咯並[2,3-c]吡啶(1.6g，黃色固體，37.5%)。 4-bromo-7-methoxy-2-methyl-1H-pyrrolo [2,3-c] pyridine (2.6 g, 11 mmol) was dissolved in N, N-dimethylformamide (20 mL), Sodium hydride (640 mL, 16 mmol) was added in portions under nitrogen at 0 ° C. The reaction was stirred at room temperature for 15 minutes, and then p-toluenesulfonyl chloride (3.04 g, 16 mmol) was added in portions under nitrogen protection at 0 ° C, and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was quenched with a saturated aqueous ammonium chloride solution (20 mL), the solution was extracted with ethyl acetate (30 mL × 2), and the organic phase was washed with saturated brine (20 mL × 3), and dried over anhydrous sodium sulfate. The organic phase was dried and spin-dried, and separated by column (petroleum ether / ethyl acetate = 10/1) to obtain 4-bromo-7-methoxy-2-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-c] pyridine (1.6 g, yellow solid, 37.5%).
MS m/z(ESI)：394.9/397.0(50/50)[M+H]+. MS m / z (ESI): 394.9 / 397.0 (50/50) [M + H] + .
4-溴-7-甲氧基-2-甲基-1-甲苯磺醯-1H-吡咯並[2,3-c]吡啶(1.6g，4.1mmol)於二噁烷(20mL)中，在室溫下加入鹽酸(20mL，4M)。反應在40℃下攪拌16小時。反應液濃縮，用二氯甲烷(20mL×2)萃取，有機相用飽和食鹽水(20mL)洗滌，無水硫酸鈉乾燥。有機相乾燥旋乾，管柱分離(石油醚/乙酸乙酯=2/1)得到4-溴-2-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(1.4g，白色固體，90.7%)。 4-bromo-7-methoxy-2-methyl-1-toluenesulfonium-1H-pyrrolo [2,3-c] pyridine (1.6 g, 4.1 mmol) in dioxane (20 mL). Hydrochloric acid (20 mL, 4M) was added at room temperature. The reaction was stirred at 40 ° C for 16 hours. The reaction solution was concentrated, extracted with dichloromethane (20 mL × 2), and the organic phase was washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The organic phase was dried and spin-dried and separated by a column (petroleum ether / ethyl acetate = 2/1) to obtain 4-bromo-2-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2 , 3-c] pyridin-7-one (1.4 g, white solid, 90.7%).
MS m/z(ESI)：380.9/382.9(50/50)[M+H]+. MS m / z (ESI): 380.9 / 382.9 (50/50) [M + H] + .
1H NMR(400MHz,CDCl3)δ 7.94(d,J=8.4Hz,2H),7.29(d,J=8.1Hz,2H),7.14(s,1H),6.34(d,J=0.9Hz,1H),2.79(d,J=0.7Hz,3H),2.41(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ 7.94 (d, J = 8.4Hz, 2H), 7.29 (d, J = 8.1Hz, 2H), 7.14 (s, 1H), 6.34 (d, J = 0.9Hz, 1H), 2.79 (d, J = 0.7Hz, 3H), 2.41 (s, 3H).
4-溴-2-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(1.4g，3.7mmol)溶於N,N-二甲基甲醯胺(20mL)中，在0℃氮氣保護下分批加入氫化鈉(180mL，4.5mmol，60%)。反應在室溫下攪拌15分鐘，然後在0℃氮氣保護下分批加入碘甲烷(620mg，4.5mmol)，反應液在室溫下攪拌3小時。反應液用飽和氯化銨水溶液(20mL)淬滅，溶液 用乙酸乙酯(30mL×2)萃取，有機相用飽和食鹽水(20mL×3)洗滌，無水硫酸鈉乾燥。有機相乾燥旋乾，管柱分離(石油醚/乙酸乙酯=2/1)得到4-溴-2,6-二甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(1.4g，黃色固體，96.5%)。 4-bromo-2-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (1.4 g, 3.7 mmol) was dissolved in N, N -In dimethylformamide (20 mL), sodium hydride (180 mL, 4.5 mmol, 60%) was added in portions under nitrogen protection at 0 ° C. The reaction was stirred at room temperature for 15 minutes, and then methyl iodide (620 mg, 4.5 mmol) was added in portions under nitrogen protection at 0 ° C, and the reaction solution was stirred at room temperature for 3 hours. The reaction solution was quenched with a saturated aqueous ammonium chloride solution (20 mL), and the solution was extracted with ethyl acetate (30 mL × 2). The organic phase was washed with saturated brine (20 mL × 3), and dried over anhydrous sodium sulfate. The organic phase was dried and spin-dried, and separated by a column (petroleum ether / ethyl acetate = 2/1) to obtain 4-bromo-2,6-dimethyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrole. [2,3-c] pyridin-7-one (1.4 g, yellow solid, 96.5%).
MS m/z(ESI)：394.9/397.0[M+H]+. MS m / z (ESI): 394.9 / 397.0 [M + H] + .
1H NMR(400MHz,CDCl3)δ7.99(d,J=8.4Hz,2H),7.31(d,J=8.1Hz,2H),7.18(s,1H),6.26(d,J=0.9Hz,1H),3.48(s,3H),2.76(d,J=0.8Hz,3H),2.41(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ7.99 (d, J = 8.4Hz, 2H), 7.31 (d, J = 8.1Hz, 2H), 7.18 (s, 1H), 6.26 (d, J = 0.9Hz , 1H), 3.48 (s, 3H), 2.76 (d, J = 0.8Hz, 3H), 2.41 (s, 3H).
4-溴-2,6-二甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(1.4g，3.5mmol)，頻哪醇硼酸酯(1.8g，7.0mmol)，三(二亞苄基丙酮)二鈀(84mg，0.091mmol)，乙酸鉀(877mg，8.75mmol)，2-二環己基磷-2,4,6-三異丙基聯苯(166mg，0.35mmol)溶於二噁烷(30mL)中，在90℃氮氣保護下攪拌2小時。反應液過濾，溶液用乙酸乙酯(30mL×2)萃取，有機相用飽和食鹽水(20mL)洗滌，無水硫酸鈉乾燥。有機相乾燥旋乾，管柱分離(石油醚/乙酸乙酯=1/1)得到2,6-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼 雜環戊烷-2-基)-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(1.4g，黃色油狀物，89%)。 4-bromo-2,6-dimethyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (1.4 g, 3.5 mmol), frequency Ninacol borate (1.8g, 7.0mmol), tris (dibenzylideneacetone) dipalladium (84mg, 0.091mmol), potassium acetate (877mg, 8.75mmol), 2-dicyclohexylphosphine-2,4, 6-Triisopropylbiphenyl (166 mg, 0.35 mmol) was dissolved in dioxane (30 mL), and stirred under nitrogen protection at 90 ° C for 2 hours. The reaction solution was filtered, and the solution was extracted with ethyl acetate (30 mL × 2). The organic phase was washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The organic phase was dried and spin-dried and separated by a column (petroleum ether / ethyl acetate = 1/1) to obtain 2,6-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl) -1-toluenesulfan-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (1.4 g, yellow oil (89%).
MS m/z(ESI)：443.2[M+H]+。 MS m / z (ESI): 443.2 [M + H] + .
實施例33第六步產物(3-溴-4-氟苯基)(環丙基)(亞胺基)-λ6-硫烷酮(500mg,1.75mmol)與反式-4-甲基環己烷胺(5.0mL)置25mL三口瓶中，氮氣保護下油浴加熱到90℃，反應5小時後冷卻至室溫，用乙酸乙酯(50mL)稀釋，經飽和氯化銨水溶液洗滌(25mL×2)，無水硫酸鈉乾燥，過濾。濾液濃縮後經管柱層析純化(石油醚/乙酸乙酯=3/1)得到(3-溴-4-((反式-4-甲基環己基)胺基)苯基)(環丙基)(亞胺基)-λ6-硫烷酮(500mg，黃色油狀物，產率75%)。 Example 33 Product of the sixth step (3-bromo-4-fluorophenyl) (cyclopropyl) (imino) -λ 6 -sulfanone (500 mg, 1.75 mmol) and trans-4-methyl ring Hexylamine (5.0mL) was placed in a 25mL three-necked flask. The oil bath was heated to 90 ° C under nitrogen protection. After 5 hours of reaction, it was cooled to room temperature, diluted with ethyl acetate (50mL), and washed with saturated ammonium chloride aqueous solution (25mL). × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 3/1) to obtain (3-bromo-4-((trans-4-methylcyclohexyl) amino) phenyl) (cyclopropyl ) (Imino) -λ 6 -sulfanone (500 mg, yellow oil, 75% yield).
MS m/z(ESI)：370.9/372.9(50/50)[M+H]+. MS m / z (ESI): 370.9 / 372.9 (50/50) [M + H] + .
(3-溴-4-((反式--4-甲基環己基)胺基)苯基)(環丙基)(亞胺基)-λ6-硫烷酮與2,6-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為反應原料，參考實施例4第四步得4-(5-(環丙磺亞胺醯基)-2-((反式-4-甲基環己基)胺基)苯基)-2,6-二甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率62%)。 (3-bromo-4-((trans--4-methylcyclohexyl) amino) phenyl) (cyclopropyl) (imino) -λ 6 -sulfanone with 2,6-dimethyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-toluenesulfonyl-1,6-dihydro- 7H-pyrrolo [2,3-c] pyridin-7-one is used as a reaction raw material, and the fourth step of Reference Example 4 is to obtain 4- (5- (cyclopropanesulfinoimidoamido) -2-((trans- 4-methylcyclohexyl) amino) phenyl) -2,6-dimethyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7- Ketone (62% yield).
MS m/z(ESI)：607.1[M+H]+. MS m / z (ESI): 607.1 [M + H] + .
以4-(5-(環丙磺亞胺醯基)-2-((反式-4-甲基環己基)胺基)苯基)-2,6-二甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，參考實施例1第八步得4-(5-(環丙磺亞胺醯基)-2-((反式-4-甲基環己基)胺基)苯基)-2,6-二甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率35%)。 4- (5- (Cyclopropanesulfenimide) -2-((trans-4-methylcyclohexyl) amino) phenyl) -2,6-dimethyl-1-toluenesulfonium -1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one was used as a raw material, and the eighth step of Reference Example 1 was to obtain 4- (5- (cyclopropanesulfinimide))- 2-((trans-4-methylcyclohexyl) amino) phenyl) -2,6-dimethyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7 -Ketone (35% yield).
MS m/z(ESI)：453.2[M+H]+。 MS m / z (ESI): 453.2 [M + H] + .
1H NMR(400MHz,MeOD)：δ 7.65(dd,J=8.8Hz,2.3Hz,1H),7.50(d,J=2.3Hz,1H),7.06(s,1H),6.75(d,J=8.9Hz,1H),5.73(s,1H),3.57(s,3H),3.26(d,J=3.9Hz,1H),2.59-2.51(m,1H),2.29(s,3H),1.93-1.89(m,2H), 1.64-1.60(m,2H),1.23-1.20(m,2H),1.16-1.09(m,1H),1.04-0.93(m,5H),0.85-0.83(m,1H),0.81(d,J=6.5Hz,3H). 1 H NMR (400MHz, MeOD): δ 7.65 (dd, J = 8.8Hz, 2.3Hz, 1H), 7.50 (d, J = 2.3Hz, 1H), 7.06 (s, 1H), 6.75 (d, J = 8.9Hz, 1H), 5.73 (s, 1H), 3.57 (s, 3H), 3.26 (d, J = 3.9Hz, 1H), 2.59-2.51 (m, 1H), 2.29 (s, 3H), 1.93 1.89 (m, 2H), 1.64-1.60 (m, 2H), 1.23-1.20 (m, 2H), 1.16-1.09 (m, 1H), 1.04-0.93 (m, 5H), 0.85-0.83 (m, 1H ), 0.81 (d, J = 6.5Hz, 3H).
以4-(5-(環丙磺亞胺醯基)-2-((反式-4-甲基環己基)胺基)苯基)-2,6-二甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，經拆分得4-(5-((S)-環丙磺亞胺醯基)-2-((反式-4-甲基環己基)胺基)苯基)-2,6-二甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率40%)和4-(5-((R)-環丙磺亞胺醯基)-2-((反式-4-甲基環己基)胺基)苯基)-2,6-二甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率40%)。 4- (5- (Cyclosulfanimidoamido) -2-((trans-4-methylcyclohexyl) amino) phenyl) -2,6-dimethyl-1,6-di Hydrogen-7H-pyrrolo [2,3-c] pyridin-7-one was used as a raw material, and 4- (5-((S) -cyclopropanesulfinoimidoamidinyl) -2-((trans -4-methylcyclohexyl) amino) phenyl) -2,6-dimethyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (yield 40 %) And 4- (5-((R) -cyclopropanesulfenimidoamido) -2-((trans-4-methylcyclohexyl) amino) phenyl) -2,6-dimethyl -1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (40% yield).
手型製備條件：
(S)-構型化合物：MS m/z(ESI)：453.2[M+H]+。 (S) -configuration compound: MS m / z (ESI): 453.2 [M + H] + .
1H NMR(400MHz,MeOD)δ 7.65(dd,J=8.8Hz,2.4Hz,1H),7.50(d,J=2.4Hz,1H),7.06(s,1H),6.75(d,J=8.9Hz,1H),5.73(s,1H),3.57(s,3H),3.26(d,J=3.6Hz,1H),2.59-2.51(m,1H),2.29(s,3H),1.93-1.89(m,2H),1.64-1.60(m,2H),1.23-1.20(m,2H),1.16-1.09(m,1H),1.04-0.93(m,5H),0.85-0.83(m,1H),0.81(d,J=6.5Hz,3H). 1 H NMR (400MHz, MeOD) δ 7.65 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.50 (d, J = 2.4Hz, 1H), 7.06 (s, 1H), 6.75 (d, J = 8.9 Hz, 1H), 5.73 (s, 1H), 3.57 (s, 3H), 3.26 (d, J = 3.6Hz, 1H), 2.59-2.51 (m, 1H), 2.29 (s, 3H), 1.93-1.89 (m, 2H), 1.64-1.60 (m, 2H), 1.23-1.20 (m, 2H), 1.16-1.09 (m, 1H), 1.04-0.93 (m, 5H), 0.85-0.83 (m, 1H) , 0.81 (d, J = 6.5Hz, 3H).
t R =7.054min(色譜管柱：CHIRALPAK IG 0.46×15cm；流動相：100% MeOH；管柱溫度：35℃；流速：1.0ml/min) t R = 7.054min (chromatographic column: CHIRALPAK IG 0.46 × 15cm; mobile phase: 100% MeOH; column temperature: 35 ° C; flow rate: 1.0ml / min)
(R)-構型化合物：MS m/z(ESI)：453.2[M+H]+。 (R) -configuration compound: MS m / z (ESI): 453.2 [M + H] + .
1H NMR(400MHz,MeOD)δ 7.65(dd,J=8.8Hz,2.3Hz,1H),7.50(d,J=2.3Hz,1H),7.06(s,1H),6.75(d,J=8.9Hz,1H),5.73(s,1H),3.57(s,3H),3.26(d,J=3.9Hz,1H),2.59-2.51(m,1H),2.29(s,3H),1.93-1.89(m,2H),1.64-1.60(m,2H),1.23-1.20(m,2H),1.16-1.09(m,1H), 1.04-0.93(m,5H),0.85-0.83(m,1H),0.81(d,J=6.5Hz,3H). 1 H NMR (400MHz, MeOD) δ 7.65 (dd, J = 8.8Hz, 2.3Hz, 1H), 7.50 (d, J = 2.3Hz, 1H), 7.06 (s, 1H), 6.75 (d, J = 8.9 Hz, 1H), 5.73 (s, 1H), 3.57 (s, 3H), 3.26 (d, J = 3.9Hz, 1H), 2.59-2.51 (m, 1H), 2.29 (s, 3H), 1.93-1.89 (m, 2H), 1.64-1.60 (m, 2H), 1.23-1.20 (m, 2H), 1.16-1.09 (m, 1H), 1.04-0.93 (m, 5H), 0.85-0.83 (m, 1H) , 0.81 (d, J = 6.5Hz, 3H).
t R =9.953min(色譜管柱：CHIRALPAK IG 0.46×15cm；流動相：100% MeOH；管柱溫度：35℃；流速：1.0ml/min) t R = 9.953min (chromatographic column: CHIRALPAK IG 0.46 × 15cm; mobile phase: 100% MeOH; column temperature: 35 ° C; flow rate: 1.0ml / min)
以實施例14第三步產物(3-溴-4-氟苯基)(亞胺基)(甲基)-λ6-硫烷酮與反式-4-甲基環己胺為起始原料，參考實施例57的第六步反應條件，得到(3-溴-4-((反式--4-甲基環己基)胺基)苯基)(甲基)(亞胺基)-λ6-硫烷酮(產率92%)。 The product from the third step of Example 14 (3-bromo-4-fluorophenyl) (imino) (methyl) -λ 6 -sulfanone and trans-4-methylcyclohexylamine were used as starting materials. With reference to the reaction conditions in the sixth step of Example 57, (3-bromo-4-((trans--4-methylcyclohexyl) amino) phenyl) (methyl) (imino) -λ 6 -sulfanone (yield 92%).
MS m/z(ESI)：345.1/347.1(50/50)[M+H]+. MS m / z (ESI): 345.1 / 347.1 (50/50) [M + H] + .
以(3-溴-4-((反式--4-甲基環己基)胺基)苯基)(甲基)(亞胺基)-λ6-硫烷酮替(3-溴-4-((反式-4-甲基環己基)胺基)苯基)(環丙基)(亞胺基)-λ6-硫烷酮，與2,6-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮反應，參考實施例55第七步，得2,6-二甲基-4-(2-((反式-4-甲基環己基)胺基)-5-(S-甲基磺亞胺醯基)苯基)-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率63%)。 Replace (3-bromo-4-((trans--4-methylcyclohexyl) amino) phenyl) (methyl) (imino) -λ 6 -sulfanone with (3-bromo-4 -((Trans-4-methylcyclohexyl) amino) phenyl) (cyclopropyl) (imino) -λ 6 -sulfanone, with 2,6-dimethyl-4- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2 , 3-c] pyridine-7-one reaction, referring to the seventh step of Example 55, to obtain 2,6-dimethyl-4- (2-((trans-4-methylcyclohexyl) amino)- 5- (S - methyl sulfonic acyl imine) phenyl) -1-acyl-1,6-dihydro-toluenesulfonic -7 H - pyrrolo [2,3- c] pyridin-7-one (yield 63%).
MS m/z(ESI)：581.2[M+H]+。 MS m / z (ESI): 581.2 [M + H] + .
以2,6-二甲基-4-(2-((反式-4-甲基環己基)胺基)-5-(S-甲基磺亞胺醯基)苯基)-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，參考實施例1第八步得2,6-二甲基-4-(2-((反式-4-甲基環己基)胺基)-5-(S-甲基磺亞胺醯基)苯基)-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率80%)。 2,6-Dimethyl-4- (2-((trans-4-methylcyclohexyl) amino) -5- ( S -methylsulfimimidino) phenyl) -1-toluene Sulfonil-1,6-dihydro-7 H -pyrrolo [2,3- c ] pyridin-7-one was used as the raw material, and the eighth step of Reference Example 1 was used to obtain 2,6-dimethyl-4- (2 -((Trans-4-methylcyclohexyl) amino) -5- ( S -methylsulfonylimino) phenyl) -1,6-dihydro-7 H -pyrrolo [2,3 -c ] pyridin-7-one (80% yield).
MS m/z(ESI)：427.2[M+H]+. MS m / z (ESI): 427.2 [M + H] + .
1H NMR(400MHz,DMSO)δ 7.78(dd,J=9.0Hz,2.4Hz,1H),7.62(d,J=2.5Hz,1H),7.20(s,1H),6.99(d,J=9.2Hz,1H),5.73(s,1H),3.71(s,3H),3.51(s,3H),3.29-3.22(m,1H),2.29(s,3H),2.06-1.94(m,1H),1.89-1.82(m,2H),1.69-1.61(m,2H),1.17-1.10(m,4H),0.86(d,J=6.5Hz,3H). 1 H NMR (400MHz, DMSO) δ 7.78 (dd, J = 9.0Hz, 2.4Hz, 1H), 7.62 (d, J = 2.5Hz, 1H), 7.20 (s, 1H), 6.99 (d, J = 9.2 Hz, 1H), 5.73 (s, 1H), 3.71 (s, 3H), 3.51 (s, 3H), 3.29-3.22 (m, 1H), 2.29 (s, 3H), 2.06-1.94 (m, 1H) , 1.89-1.82 (m, 2H), 1.69-1.61 (m, 2H), 1.17-1.10 (m, 4H), 0.86 (d, J = 6.5Hz, 3H).
將2,6-二甲基-4-(2-((反式-4-甲基環己基)胺基)-5-(S-甲基磺亞胺醯基)苯基)-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(98mg)以手性製備得2,6-二甲基-4-(2-((反式-4-甲基環己基)胺基)-5-((S)-S-甲基磺亞胺醯基)苯基)-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(48mg，收率49%)和2,6-二甲基-4-(2-((反式-4-甲基環己基)胺基)-5-((R)-S-甲基磺亞胺醯 基)苯基)-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(43mg，收率44%)。 2,6-Dimethyl-4- (2-((trans-4-methylcyclohexyl) amino) -5- (S-methylsulfimimidino) phenyl) -1,6 -Dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (98 mg) was prepared chiralally to obtain 2,6-dimethyl-4- (2-((trans-4-methyl Cyclohexyl) amino) -5-((S) -S-methylsulfimidoamido) phenyl) -1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7- Ketone (48mg, yield 49%) and 2,6-dimethyl-4- (2-((trans-4-methylcyclohexyl) amino) -5-((R) -S-methyl Sulfoimido) phenyl) -1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (43 mg, yield 44%).
手型製備條件：
(S)-構型化合物：MS m/z(ESI)：427.2[M+H]+. (S) -configuration compound: MS m / z (ESI): 427.2 [M + H] + .
1H NMR(400MHz,DMSO)δ 7.78(dd,J=9.0Hz,2.4Hz,1H),7.62(d,J=2.5Hz,1H),7.20(s,1H),6.99(d,J=9.2Hz,1H),5.73(s,1H),3.71(s,3H),3.51(s,3H),3.29-3.22(m,1H),2.29(s,3H),2.06-1.94(m,1H),1.89-1.82(m,2H),1.69-1.61(m,2H),1.17-1.10(m,4H),0.86(d,J=6.5Hz,3H). 1 H NMR (400MHz, DMSO) δ 7.78 (dd, J = 9.0Hz, 2.4Hz, 1H), 7.62 (d, J = 2.5Hz, 1H), 7.20 (s, 1H), 6.99 (d, J = 9.2 Hz, 1H), 5.73 (s, 1H), 3.71 (s, 3H), 3.51 (s, 3H), 3.29-3.22 (m, 1H), 2.29 (s, 3H), 2.06-1.94 (m, 1H) , 1.89-1.82 (m, 2H), 1.69-1.61 (m, 2H), 1.17-1.10 (m, 4H), 0.86 (d, J = 6.5Hz, 3H).
t R =6.803min(色譜管柱：CHIRALPAK IG 0.46×15cm；流動相：100% MeOH；管柱溫：35℃；流速：1.0ml/min) t R = 6.803min (chromatographic column: CHIRALPAK IG 0.46 × 15cm; mobile phase: 100% MeOH; column temperature: 35 ° C; flow rate: 1.0ml / min)
(R)-構型化合物：MS m/z(ESI)：427.2[M+H]+. (R) -configuration compound: MS m / z (ESI): 427.2 [M + H] + .
1H NMR(400MHz,DMSO)δ 7.78(dd,J=9.0Hz,2.4Hz, 1H),7.62(d,J=2.5Hz,1H),7.20(s,1H),6.99(d,J=9.2Hz,1H),5.73(s,1H),3.71(s,3H),3.51(s,3H),3.29-3.22(m,1H),2.29(s,3H),2.06-1.94(m,1H),1.89-1.82(m,2H),1.69-1.61(m,2H),1.17-1.10(m,4H),0.86(d,J=6.5Hz,3H). 1 H NMR (400MHz, DMSO) δ 7.78 (dd, J = 9.0Hz, 2.4Hz, 1H), 7.62 (d, J = 2.5Hz, 1H), 7.20 (s, 1H), 6.99 (d, J = 9.2 Hz, 1H), 5.73 (s, 1H), 3.71 (s, 3H), 3.51 (s, 3H), 3.29-3.22 (m, 1H), 2.29 (s, 3H), 2.06-1.94 (m, 1H) , 1.89-1.82 (m, 2H), 1.69-1.61 (m, 2H), 1.17-1.10 (m, 4H), 0.86 (d, J = 6.5Hz, 3H).
t R =9.284min(色譜管柱：CHIRALPAK IG 0.46×15cm；流動相：100% MeOH；管柱溫：35℃；流速：1.0ml/min). t R = 9.284min (chromatographic column: CHIRALPAK IG 0.46 × 15cm; mobile phase: 100% MeOH; column temperature: 35 ° C; flow rate: 1.0ml / min).
以實施例33第六步產物(3-溴-4-氟苯基)(環丙基)(亞胺基)-λ6-硫烷酮為起始原料，參考實施例4第五步反應，得到(3-溴-4-(2,4-二氟苯氧基))(環丙基)(亞胺基)-λ6-硫烷酮(收率76.8%). Taking the product of the sixth step of Example 33 (3-bromo-4-fluorophenyl) (cyclopropyl) (imino) -λ 6 -sulfanone as the starting material, and referring to the reaction in the fifth step of Example 4, (3-Bromo-4- (2,4-difluorophenoxy)) (cyclopropyl) (imino) -λ6-sulfanone (yield 76.8%) was obtained.
MS m/z(ESI)：388.0/390.0(50/50)[M+H]+. MS m / z (ESI): 388.0 / 390.0 (50/50) [M + H] +.
(3-溴-4-(2,4-二氟苯氧基))(環丙基)(亞胺基)-λ6-硫烷酮與2,6-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮反應，參考實施例55第七步，得到2,6-二甲基-4-(2-((反式-4-甲基環己基)胺基)-5-(環丙磺亞胺醯基)苯基)-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮，(產率56.8%)。 (3-bromo-4- (2,4-difluorophenoxy)) (cyclopropyl) (imino) -λ6-sulfanone and 2,6-dimethyl-4- (4,4 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2,3 -c] pyridine-7-one reaction, referring to the seventh step of Example 55 to obtain 2,6-dimethyl-4- (2-((trans-4-methylcyclohexyl) amino) -5- (Cyclopropanesulfinoimido) phenyl) -1-toluenesulfon-1,6-dihydro-7 H -pyrrolo [2,3- c ] pyridin-7-one, (yield 56.8%) .
MS m/z(ESI)：624.14[M+H]+. MS m / z (ESI): 624.14 [M + H] + .
以2,6-二甲基-4-(2-((反式-4-甲基環己基)胺基)-5-(環丙磺亞胺醯基)苯基)-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為起始原料，參考實施例1第八步得4-(5-(環丙磺亞胺醯基)-2-(2,4-二氟苯氧基)苯基)-2,6-二甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率76.2%)。 2,6-Dimethyl-4- (2-((trans-4-methylcyclohexyl) amino) -5- (cyclopropanesulfinoimido) phenyl) -1-toluenesulfonium -1,6-dihydro-7 H -pyrrolo [2,3- c ] pyridin-7-one was used as the starting material, and the eighth step of Reference Example 1 was used to obtain 4- (5- (cyclopropanesulfenimidine) Yl) -2- (2,4-difluorophenoxy) phenyl) -2,6-dimethyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7- Ketone (76.2% yield).
MS m/z(ESI)：470.1[M+H]+. MS m / z (ESI): 470.1 [M + H] + .
1H NMR(400MHz,DMSO-d6)：δ 11.87(br,1H),7.94(d,J=2.4Hz,1H),7.80(dd,J=8.4Hz,2.0Hz,1H),7.53-7.48(m,1H),7.40-7.37(m,2H),7.19-7.12(m,1H),6.93(d,J=8.8Hz,1H),6.0(s,1H),4.22(s,1H),3.56(s,3H),2.73-2.69(m,1H),2.30(s,3H),1.15-1.07(m,1H),1.00-0.85(m,3H). 1 H NMR (400MHz, DMSO-d6): δ 11.87 (br, 1H), 7.94 (d, J = 2.4Hz, 1H), 7.80 (dd, J = 8.4Hz, 2.0Hz, 1H), 7.53-7.48 ( m, 1H), 7.40-7.37 (m, 2H), 7.19-7.12 (m, 1H), 6.93 (d, J = 8.8Hz, 1H), 6.0 (s, 1H), 4.22 (s, 1H), 3.56 (s, 3H), 2.73-2.69 (m, 1H), 2.30 (s, 3H), 1.15-1.07 (m, 1H), 1.00-0.85 (m, 3H).
以(3-溴-4-(螺[2.5]辛烷-6-基胺基)苯基)(環丙基)(亞胺基)-λ6-硫烷酮(50mg,0.13mmol)與2,6-二甲基-4-4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮反應為反應原 料，參考實施例45第七步，得到化合物4-(5-(環丙磺亞胺醯基)-2-(螺[2.5]辛烷-6-基胺基)苯基)-2,6-二甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(60mg，產率75%)。 (3-Bromo-4- (spiro [2.5] octane-6-ylamino) phenyl) (cyclopropyl) (imino) -λ 6 -sulfanone (50mg, 0.13mmol) and 2 , 6-dimethyl-4-4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-toluenesulfonyl-1,6 -Dihydro-7H-pyrrolo [2,3-c] pyridin-7-one reaction is used as a reaction raw material, and the seventh step of Reference Example 45 is to obtain compound 4- (5- (cyclopropanesulfinimide))- 2- (spiro [2.5] octane-6-ylamino) phenyl) -2,6-dimethyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridine-7-one (60 mg, yield 75%).
MS m/z(ESI)：619.3[M+H]+ MS m / z (ESI): 619.3 [M + H] +
以4-(5-(環丙磺亞胺醯基)-2-(螺[2.5]辛烷-6-基胺基)苯基)-2,6-二甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為反應原料，參考實施例50第三步，得到化合物4-(5-(環丙磺亞胺醯基)-2-(螺[2.5]辛烷-6-基胺基)苯基)-2,6-二甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(白色固體，產率19%) 4- (5- (Cyclopropanesulfinolimido) -2- (spiro [2.5] octane-6-ylamino) phenyl) -2,6-dimethyl-1-toluenesulfonyl- 1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one as a reaction raw material, the third step of Reference Example 50 to obtain the compound 4- (5- (cyclopropanesulfenimidofluorenyl) ) -2- (spiro [2.5] octane-6-ylamino) phenyl) -2,6-dimethyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine- 7-one (white solid, 19% yield)
MS m/z(ESI)：465.2[M+H]+ MS m / z (ESI): 465.2 [M + H] +
1H NMR(400MHz,MeOD)δ 7.77(dd,J=8.8Hz,2.4Hz,1H),7.62(d,J=2.4Hz,1H),7.18(s,1H),6.88(d,J=8.9Hz,1H),5.86(s,1H),3.69(s,3H),3.57-3.46(m,1H),2.69-2.63(m,1H),2.40(s,3H),1.96-1.89(m,2H),1.73-1.64(m,2H),1.34-1.21(m,4H),1.08-0.93(m,4H),0.33-0.24(m,2H),0.21-0.14(m,2H). 1 H NMR (400MHz, MeOD) δ 7.77 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.62 (d, J = 2.4Hz, 1H), 7.18 (s, 1H), 6.88 (d, J = 8.9 Hz, 1H), 5.86 (s, 1H), 3.69 (s, 3H), 3.57-3.46 (m, 1H), 2.69-2.63 (m, 1H), 2.40 (s, 3H), 1.96-1.89 (m, 2H), 1.73-1.64 (m, 2H), 1.34-1.21 (m, 4H), 1.08-0.93 (m, 4H), 0.33-0.24 (m, 2H), 0.21-0.14 (m, 2H).
以(3-溴-4-((反式--4-甲基環己基)胺基)苯基)(1-氯環丙基)(亞胺基)-λ6-硫烷酮與2,6-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮反應為原料，參考實施例4第四步得4-(5-(1-氯環丙烷-1-磺亞胺醯基)-2-((反式-4-甲基環己基)胺基)苯基)-2,6-二甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率32%)。 With (3-bromo-4-((trans--4-methylcyclohexyl) amino) phenyl) (1-chlorocyclopropyl) (imino) -λ 6 -sulfanone with 2, 6-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-toluenesulfonium-1,6 -Dihydro-7H-pyrrolo [2,3-c] pyridin-7-one reaction was used as a raw material, and the fourth step of Reference Example 4 was to obtain 4- (5- (1-chlorocyclopropane-1-sulfimmine) Phenyl) -2-((trans-4-methylcyclohexyl) amino) phenyl) -2,6-dimethyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo [ 2,3-c] pyridin-7-one (32% yield).
MS m/z(ESI)：641.1[M+H]+. MS m / z (ESI): 641.1 [M + H] + .
以-(5-(1-氯環丙烷-1-磺亞胺醯基)-2-((反式-4-甲基環己基)胺基)苯基)-2,6-二甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，參考實施例1第八步得4-(5-(1-氯環丙烷-1-磺亞胺醯基)-2-((反式-4-甲基環己基)胺基)苯基)-2,6-二甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率25%)。 With-(5- (1-chlorocyclopropane-1-sulfinimidoamido) -2-((trans-4-methylcyclohexyl) amino) phenyl) -2,6-dimethyl- 1-Tosylate-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one was used as a raw material, and the eighth step of Reference Example 1 was to obtain 4- (5- (1-chlorocyclo Propane-1-sulfonylimido) -2-((trans-4-methylcyclohexyl) amino) phenyl) -2,6-dimethyl-1-toluenesulfon-1,6- Dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (yield 25%).
MS m/z(ESI)：487.2[M+H]+。 MS m / z (ESI): 487.2 [M + H] + .
1H NMR(400MHz,MeOD)：δ 7.72(dd,J=8.9Hz,2.4Hz,1H),7.56(d,J=2.4Hz,1H),7.06(s,1H),6.78(d,J=9.0Hz,1H),5.76(s,1H),3.58(s,3H),3.33-3.26(m,1H),2.30(s,3H),1.97-1.89(m,2H),1.82-1.76(m,1H),1.66-1.58(m,2H),1.30-1.16(m,5H),1.08-0.95(m,3H),0.81(d,J=6.5Hz,3H). 1 H NMR (400MHz, MeOD): δ 7.72 (dd, J = 8.9Hz, 2.4Hz, 1H), 7.56 (d, J = 2.4Hz, 1H), 7.06 (s, 1H), 6.78 (d, J = 9.0Hz, 1H), 5.76 (s, 1H), 3.58 (s, 3H), 3.33-3.26 (m, 1H), 2.30 (s, 3H), 1.97-1.89 (m, 2H), 1.82-1.76 (m , 1H), 1.66-1.58 (m, 2H), 1.30-1.16 (m, 5H), 1.08-0.95 (m, 3H), 0.81 (d, J = 6.5Hz, 3H).
以2-溴-1-氟-4-(異丙基亞硫醯基)苯(50mg,0.19mmol)為反應原料，參考實施例41第一步，得到化合物2-溴-4-((2-氯丙烷-2-基)亞硫醯基)-1-氟苯(40mg，無色膠體，產率71%) Using 2-bromo-1-fluoro-4- (isopropylthiosulfenyl) benzene (50 mg, 0.19 mmol) as a reaction raw material, refer to the first step of Example 41 to obtain the compound 2-bromo-4-((2 -Chloropropane-2-yl) sulfinyl) -1-fluorobenzene (40 mg, colorless colloid, yield 71%)
1H NMR(400MHz,CDCl3)δ 7.91(d,J=4.8Hz,1H),7.66-7.57(m,1H),7.20(t,J=8.2Hz,1H),1.82(s,3H),1.48(s,3H). 1 H NMR (400MHz, CDCl3) δ 7.91 (d, J = 4.8Hz, 1H), 7.66-7.57 (m, 1H), 7.20 (t, J = 8.2Hz, 1H), 1.82 (s, 3H), 1.48 (s, 3H).
以2-溴-4-((2-氯丙烷-2-基)亞硫醯基)-1-氟苯(200mg,0.67mmol)為反應原料，參考實施例5第三步，得到化合物(3-溴-4-氟苯基)(2-氯丙烷-2-基)(亞胺基)-λ6-硫烷酮(150mg，黃色固體，產率71%) Using 2-bromo-4-((2-chloropropane-2-yl) thiosulfenyl) -1-fluorobenzene (200 mg, 0.67 mmol) as a reaction raw material, refer to the third step of Example 5 to obtain compound (3 -Bromo-4-fluorophenyl) (2-chloropropane-2-yl) (imino) -λ 6 -sulfanone (150 mg, yellow solid, yield 71%)
MS m/z(ESI)：313.9/315.9(50/50)[M+H]+. MS m / z (ESI): 313.9 / 315.9 (50/50) [M + H] + .
以(3-溴-4-氟苯基)(2-氯丙烷-2-基)(亞胺基)-λ6-硫烷酮(150mg,0.49mmol)為反應原料，參考實施例45第七步，得到化合物4-(5-(2-氯丙烷-2-基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(170mg，無色膠體，產率66%) (3-Bromo-4-fluorophenyl) (2-chloropropane-2-yl) (imino) -λ 6 -sulfanone (150 mg, 0.49 mmol) was used as a reaction raw material. Reference Example 45 Step to obtain the compound 4- (5- (2-chloropropane-2-ylsulfenimidofluorenyl) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro- 7H-pyrrolo [2,3-c] pyridin-7-one (170mg, colorless colloid, yield 66%)
MS m/z(ESI)：536.0[M+H]+ MS m / z (ESI): 536.0 [M + H] +
以4-(5-(2-氯丙烷-2-基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(60mg,0.11mmol)為反應原料，參考實施例23第一步，得到化合 物4-(5-(2-氯丙烷-2-基磺亞胺醯基)-2-(((1r,4r)-4-甲基環己基)胺基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(7.6mg，白色固體，產率13%) 4- (5- (2-chloropropane-2-ylsulfenimido) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrole [2,3-c] pyridin-7-one (60 mg, 0.11 mmol) as the reaction raw material, the first step of Reference Example 23 was obtained to obtain the compound 4- (5- (2-chloropropane-2-ylsulfimide) Fluorenyl) -2-(((1r, 4r) -4-methylcyclohexyl) amino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c ] Pyridin-7-one (7.6 mg, white solid, 13% yield)
MS m/z(ESI)：475.2[M+H]+ MS m / z (ESI): 475.2 [M + H] +
1H NMR(400MHz,MeOD)δ 7.87(dd,J=8.9Hz,2.4Hz,1H),7.71(d,J=2.4Hz,1H),7.36(d,J=2.8Hz,1H),7.21(s,1H),6.92(d,J=9.1Hz,1H),6.14(d,J=2.8Hz,1H),3.71(s,3H),3.44-3.40(m,1H),2.05-1.99(m,2H),1.89(s,3H),1.86(s,3H),1.78-1.70(m,2H),1.37-1.32(m,1H),1.16-1.07(m,4H),0.92(d,J=6.5Hz,3H). 1 H NMR (400MHz, MeOD) δ 7.87 (dd, J = 8.9Hz, 2.4Hz, 1H), 7.71 (d, J = 2.4Hz, 1H), 7.36 (d, J = 2.8Hz, 1H), 7.21 ( s, 1H), 6.92 (d, J = 9.1Hz, 1H), 6.14 (d, J = 2.8Hz, 1H), 3.71 (s, 3H), 3.44-3.40 (m, 1H), 2.05-1.99 (m , 2H), 1.89 (s, 3H), 1.86 (s, 3H), 1.78-1.70 (m, 2H), 1.37-1.32 (m, 1H), 1.16-1.07 (m, 4H), 0.92 (d, J = 6.5Hz, 3H).
將4-溴-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(3.8g,10mmol)溶於200毫升四氫呋喃中，乾冰-丙酮浴冷卻至-78度，1M濃度二異丙基胺基鋰的四氫呋 喃溶液(15ML，15mmol)緩慢滴入反應體系，反應內溫保持在-70度以下。滴加完畢之後，反應升溫至-50度攪拌1小時。氯甲酸乙酯(1.63g,15mmol)的四氫呋喃溶液(10毫升)緩慢滴入反應體系，滴加完畢後在同樣溫度繼續反應2小時。飽和氯化銨溶液淬滅反應，升溫至室溫，乙酸乙酯萃取。合併有機相，水洗，飽和食鹽水洗，無水硫酸鈉乾燥。濾去乾燥劑，濾液旋乾，剩餘物使用矽膠管柱層析純化(石油醚：乙酸乙酯=1：1)得到乙基4-溴-6-甲基-7-羰基-1-甲苯磺醯-6,7-二氫-1H-吡咯並[2,3-c]吡啶-2-羧酸酯(2.6g,57%)。 4-Bromo-6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (3.8 g, 10 mmol) was dissolved in 200 ml of tetrahydrofuran In a dry ice-acetone bath, the solution was cooled to -78 degrees, and a tetrahydrofuran solution (15 ML, 15 mmol) of 1 M concentration of diisopropylamino lithium was slowly dropped into the reaction system, and the internal temperature of the reaction was kept below -70 degrees. After the dropwise addition was completed, the reaction was heated to -50 degrees and stirred for 1 hour. A tetrahydrofuran solution (10 ml) of ethyl chloroformate (1.63 g, 15 mmol) was slowly dropped into the reaction system, and the reaction was continued at the same temperature for 2 hours after the dropwise addition was completed. The reaction was quenched with saturated ammonium chloride solution, warmed to room temperature, and extracted with ethyl acetate. The organic phases were combined, washed with water, saturated brine, and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was spin-dried. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain ethyl 4-bromo-6-methyl-7-carbonyl-1-toluenesulfonate. Perylene-6,7-dihydro-1H-pyrrolo [2,3-c] pyridine-2-carboxylic acid ester (2.6 g, 57%).
MS m/z(ESI)：453.0/455.0(50/50)[M+H]+； MS m / z (ESI): 453.0 / 455.0 (50/50) [M + H] + ;
氬氣氣氛下，將乙基4-溴-6-甲基-7-羰基-1-甲苯磺醯-6,7-二氫-1H-吡咯並[2,3-c]吡啶-2-羧酸酯(2.6g,5.7mmol)，4,4,4',4',5,5,5',5'-八甲基-2,2'-聯(1,3,2-二氧雜硼雜環戊烷)(2.58g,11.4mmol)，氯(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯基)[2-(2'-胺基-1,1'-聯苯)]鈀(228mg,0.29mmol)，2-二環己基磷-2',4',6'-三異丙基聯苯(138mg,0.29mmol)和乙酸鉀(1.7g,17.1mmol)溶於100毫升預先 脫氣的無水1,4-二氧六環中，反應於80度條件下攪拌過夜。加水淬滅反應，乙酸乙酯萃取。合併有機相，水洗，飽和食鹽水洗，無水硫酸鈉乾燥。濾去乾燥劑，濾液旋乾，剩餘物使用矽膠管柱層析純化(石油醚：乙酸乙酯=1：2)得到乙基6-甲基-7-羰基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1-甲苯磺醯-6,7-二氫-1H-吡咯並[2,3-c]吡啶-2-羧酸酯(1.6g,56%)。 Under an argon atmosphere, ethyl 4-bromo-6-methyl-7-carbonyl-1-toluenesulfonium-6,7-dihydro-1H-pyrrolo [2,3-c] pyridine-2-carboxy Acid ester (2.6g, 5.7mmol), 4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2'-di (1,3,2-dioxa Boranepentane) (2.58g, 11.4mmol), chloro (2-dicyclohexylphosphino-2 ', 4', 6'-triisopropyl-1,1'-biphenyl) [2- (2'-Amino-1,1'-biphenyl)] Palladium (228 mg, 0.29 mmol), 2-dicyclohexylphosphine-2 ', 4', 6'-triisopropylbiphenyl (138 mg, 0.29 mmol) and potassium acetate (1.7 g, 17.1 mmol) were dissolved in 100 ml of previously degassed anhydrous 1,4-dioxane, and the reaction was stirred at 80 degrees overnight. The reaction was quenched by adding water and extracted with ethyl acetate. The organic phases were combined, washed with water, saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was spin-dried. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 2) to give ethyl 6-methyl-7-carbonyl-4- (4,4,5 , 5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-toluenesulfonium-6,7-dihydro-1H-pyrrolo [2,3-c ] Pyridine-2-carboxylic acid ester (1.6 g, 56%).
MS m/z(ESI)：501.2[M+H]+； MS m / z (ESI): 501.2 [M + H] + ;
25mL的微波管中加入實施例33中第五步的產物(3-溴-4-氟苯基)(環丙基)(亞胺基)-λ6-硫烷酮(1.39g,5mmol)及反式-4-甲基環己烷-1-胺(10mL)。反應體系密封之後置於150攝氏度的油浴下反應12小時，然後冷卻到室溫。乙酸乙酯萃取，飽和食鹽水洗滌。有機相乾燥蒸乾，粗產物矽膠管柱層析(石油醚：乙酸乙酯=1：1)得到(3-溴-4-((反-4-甲基環己基)胺基)苯基)(環丙基)(亞胺基)-16-硫烷酮(1.35g，產率72.8%)。 In a 25 mL microwave tube, add the product from the fifth step (3-bromo-4-fluorophenyl) (cyclopropyl) (imino) -λ 6 -sulfanone (1.39 g, 5 mmol) in Example 33 and Trans-4-methylcyclohexane-1-amine (10 mL). The reaction system was sealed and placed in an oil bath at 150 degrees Celsius for 12 hours, and then cooled to room temperature. Extract with ethyl acetate and wash with saturated brine. The organic phase was dried and evaporated to dryness, and the crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain (3-bromo-4-((trans-4-methylcyclohexyl) amino) phenyl) (Cyclopropyl) (imino) -16-sulfanone (1.35 g, 72.8% yield).
MS m/z(ESI)：371.1/373.1(50/50)[M+H]+ MS m / z (ESI): 371.1 / 373.1 (50/50) [M + H] +
氬氣氣氛下，將第二步得到的乙基6-甲基-7-羰基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1-甲苯磺醯-6,7-二氫-1H-吡咯並[2,3-c]吡啶-2-羧酸酯(500mg,1mmol)，第三步得到的(3-溴-4-(((1r,4r)-4-甲基環己基)胺基)苯基)(環丙基)(亞胺基)-16-硫烷酮(370mg,1mmol)，三(二亞苄基丙酮)二鈀(45mg,0.05mmol)，1,3,5,7-四甲基-6-苯基-2,4,8-三氧雜-6-磷醯金剛烷(29mg,0.1mmol)和無水磷酸三鉀(636mg,3mmol)溶於脫氣的20毫升四氫呋喃和5毫升水的混合溶劑中，反應升溫至60度攪拌3小時。加乙酸乙酯稀釋，分液，水相使用乙酸乙酯萃取。合併有機相，飽和食鹽水洗滌，無水硫酸鈉乾燥，過濾，旋乾。殘餘物使用矽膠管柱層析純化(石油醚：乙酸乙酯=0：1)得到(乙基4-(5-(環丙磺亞胺醯基)-2-((反-4-甲基環己基)胺基)苯基)-6-甲基-7-羰基-1-甲苯磺醯-6,7-二氫-1H-吡咯並[2,3-c]吡啶-2-羧酸酯(360mg,54%)。 Under an argon atmosphere, the ethyl 6-methyl-7-carbonyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane) obtained in the second step Alk-2-yl) -1-toluenesulfonium-6,7-dihydro-1H-pyrrolo [2,3-c] pyridine-2-carboxylic acid ester (500 mg, 1 mmol), obtained in the third step ( 3-bromo-4-(((1r, 4r) -4-methylcyclohexyl) amino) phenyl) (cyclopropyl) (imino) -16-sulfanone (370mg, 1mmol), three (Dibenzylideneacetone) dipalladium (45mg, 0.05mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoramantane ( 29 mg, 0.1 mmol) and anhydrous tripotassium phosphate (636 mg, 3 mmol) were dissolved in a degassed mixed solvent of 20 ml of tetrahydrofuran and 5 ml of water, and the reaction was heated to 60 degrees and stirred for 3 hours. Dilute with ethyl acetate, separate the layers, and extract the aqueous phase with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0: 1) to obtain (ethyl 4- (5- (cyclopropanesulfenimido))-2-((trans-4-methyl Cyclohexyl) amino) phenyl) -6-methyl-7-carbonyl-1-toluenesulfonium-6,7-dihydro-1H-pyrrolo [2,3-c] pyridine-2-carboxylic acid ester (360mg, 54%).
MS m/z(ESI)：665.2[M+H]+； MS m / z (ESI): 665.2 [M + H] + ;
將(乙基4-(5-(環丙磺亞胺醯基)-2-((反-4-甲基環己基)胺基)苯基)-6-甲基-7-羰基-1-甲苯磺醯-6,7-二氫-1H-吡咯並[2,3-c]吡啶-2-羧酸酯(67mg,0.1mmol)溶於2毫升乙醇和2毫升60%硫酸混合溶液中，之後反應回流過夜。冰水淬滅反應，PH值調至中性，乙酸乙酯萃取三次。合併有機相，水洗，飽和食鹽水洗，硫酸鈉乾燥，過濾，旋乾。殘餘物使用反相製備管柱純化得到乙基4-(5-(環丙磺亞胺醯基)-2-((反-4-甲基環己基)胺基)苯基)-6-甲基-7-羰基-6,7-二氫-1H-吡咯並[2,3-c]吡啶-2-羧酸酯(18.5mg,36%)。 (Ethyl 4- (5- (cyclopropanesulfenimido))-2-((trans-4-methylcyclohexyl) amino) phenyl) -6-methyl-7-carbonyl-1- Tosylate-6,7-dihydro-1H-pyrrolo [2,3-c] pyridine-2-carboxylic acid ester (67 mg, 0.1 mmol) was dissolved in 2 ml of ethanol and 2 ml of a 60% sulfuric acid mixed solution. The reaction was then refluxed overnight. The reaction was quenched with ice water, the pH was adjusted to neutral, and extracted with ethyl acetate three times. The organic phases were combined, washed with water, washed with saturated brine, dried over sodium sulfate, filtered, and spin-dried. The residue was prepared using a reverse-phase preparation tube Column purification gave ethyl 4- (5- (cyclopropanesulfenimido) -2-((trans-4-methylcyclohexyl) amino) phenyl) -6-methyl-7-carbonyl-6 , 7-dihydro-1H-pyrrolo [2,3-c] pyridine-2-carboxylic acid ester (18.5 mg, 36%).
MS m/z(ESI)：511.2[M+H]+； MS m / z (ESI): 511.2 [M + H] + ;
1H NMR(400MHz,d4-MeOD)：δ：7.68(dd,J=8.8Hz,2.4Hz,,1H),7.51(d,J=2.0Hz,1H),7.15(s,1H),6.79(d,J=8.8Hz,1H),6.58(s,1H),4.27(q,J=7.2Hz,2H),3.58(s,3H),3.28-3.27(m,1H),3.60-3.53(m,1H),1.92-1.88(m,2H),1.62-1.60(m,2H),1.28-1.19(m,5H),1.19-1.11(m,1H),1.02-0.97(m,5H),0.87-0.79(m,4H). 1 H NMR (400MHz, d 4-MeOD): δ: 7.68 (dd, J = 8.8Hz, 2.4Hz ,, 1H), 7.51 (d, J = 2.0Hz, 1H), 7.15 (s, 1H), 6.79 (d, J = 8.8Hz, 1H), 6.58 (s, 1H), 4.27 (q, J = 7.2Hz, 2H), 3.58 (s, 3H), 3.28-3.27 (m, 1H), 3.60-3.53 ( m, 1H), 1.92-1.88 (m, 2H), 1.62-1.60 (m, 2H), 1.28-1.19 (m, 5H), 1.19-1.11 (m, 1H), 1.02-0.97 (m, 5H), 0.87-0.79 (m, 4H).
以4-(5-(乙基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為反應原料，參考實施例10第五步，用1,4-二氧雜螺[4.5]癸烷-8-醇取2,4-二氟苯酚，得到4-(2-((1,4-二氧雜螺[4.5]癸烷-8-基)酮基)-5-(乙基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(收率63%)。 4- (5- (ethylsulfonylimino) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one is used as a reaction raw material. In the fifth step of Reference Example 10, 1,4-dioxaspiro [4.5] decane-8-ol is used to obtain 2,4-difluorophenol to obtain 4- ( 2-((1,4-dioxaspiro [4.5] decane-8-yl) keto) -5- (ethylsulfonylimino) phenyl) -6-methyl-1,6- Dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (63% yield).
MS m/z(ESI)：472.2[M+H]+； MS m / z (ESI): 472.2 [M + H] + ;
1H NMR(400MHz,d4-MeOD)：δ 7.86-7.81(m,2H),7.26-7.23(m,2H),7.19(s,1H),6.16(d,J=2.8Hz,1H),4.61-4.59(m,1H),3.80-3.74(m,4H),3.61(s,3H),3.16(q,J=7.6Hz,2H),1.77-1.75(m,4H),1.50-1.39(m,4H),1.15(t,J=7.6Hz,3H). 1 H NMR (400MHz, d 4-MeOD): δ 7.86-7.81 (m, 2H), 7.26-7.23 (m, 2H), 7.19 (s, 1H), 6.16 (d, J = 2.8Hz, 1H), 4.61-4.59 (m, 1H), 3.80-3.74 (m, 4H), 3.61 (s, 3H), 3.16 (q, J = 7.6Hz, 2H), 1.77-1.75 (m, 4H), 1.50-1.39 ( m, 4H), 1.15 (t, J = 7.6Hz, 3H).
以4-(5-(乙基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為反應原料，參考實施例10第五步，用1H-吲哚-5-酚取代2,4-二氟苯酚， 得到4-(2-((1H-吲哚-5-基)酮基)-5-(乙基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率25%)。 4- (5- (ethylsulfonylimino) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one is used as a reaction raw material. In the fifth step of Reference Example 10, 2,4-difluorophenol is replaced with 1H-indole-5-phenol to obtain 4- (2-((1H-indole- 5-yl) keto) -5- (ethylsulfonylimino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7- Ketone (25% yield).
MS m/z(ESI)：447.1[M+H]+； MS m / z (ESI): 447.1 [M + H] + ;
1H NMR(400MHz,d4-MeOD)：δ 8.08(d,J=2.4Hz,1H),7.85-7.82(dd,J=8.8Hz,2.4Hz,1H),7.44-7.39(m,3H),7.31-7.26(m,2H),7.00(d,J=8.8Hz,1H),6.87-6.84(m,1H),6.47-6.45(m,2H),3.72(s,3H),3.35(q,J=7.2Hz,2H),1.28(t,J=7.2Hz,3H)。 1 H NMR (400MHz, d 4-MeOD): δ 8.08 (d, J = 2.4Hz, 1H), 7.85-7.82 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.44-7.39 (m, 3H) , 7.31-7.26 (m, 2H), 7.00 (d, J = 8.8Hz, 1H), 6.87-6.84 (m, 1H), 6.47-6.45 (m, 2H), 3.72 (s, 3H), 3.35 (q , J = 7.2Hz, 2H), 1.28 (t, J = 7.2Hz, 3H).
以4-(5-(環丙磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，用4,4-二甲基環己醇取代環丙基甲醇，參考實施例5第五步，得到4-(5-(環丙磺亞胺醯基)-2-((4,4-二甲基環己基)酮基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(45%)。 4- (5- (Cyclopropanesulfenimido) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3- c] pyridine-7-one as a raw material, and cyclopropyl methanol was replaced with 4,4-dimethylcyclohexanol, and the fifth step of Reference Example 5 was to obtain 4- (5- (cyclopropanesulfenimide)) 2-((4,4-dimethylcyclohexyl) keto) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7-one (45%).
MS m/z(ESI)：454.2[M+H]+ MS m / z (ESI): 454.2 [M + H] +
1H NMR(400MHz,CDCl 3 )：δ 12.24(s,1H),8.20(d,J=2.4Hz,1H),7.96-7.93(dd,J=8.8,2.4Hz,1H),7.47(t,J=2.4Hz,1H),7.43(s,1H),7.25(d,J=8.8Hz,1H),6.38(t,J= 2.4Hz,1H),4.47(s,1H),3.82(s,3H),3.50-3.47(m,1H),2.09-2.04(m,1H),1.82-1.76(m,4H),1.68-1.50(m,4H),1.38-1.25(m,4H),0.90(s,3H),0.80(s,3H). 1 H NMR (400MHz, CDCl 3 ): δ 12.24 (s, 1H), 8.20 (d, J = 2.4Hz, 1H), 7.96-7.93 (dd, J = 8.8, 2.4Hz, 1H), 7.47 (t, J = 2.4Hz, 1H), 7.43 (s, 1H), 7.25 (d, J = 8.8Hz, 1H), 6.38 (t, J = 2.4Hz, 1H), 4.47 (s, 1H), 3.82 (s, 3H), 3.50-3.47 (m, 1H), 2.09-2.04 (m, 1H), 1.82-1.76 (m, 4H), 1.68-1.50 (m, 4H), 1.38-1.25 (m, 4H), 0.90 ( s, 3H), 0.80 (s, 3H).
將2-溴-1-氟-4-硝基苯(5g，22.7mmol)、環丙基甲醇(2g，27.3mmol)溶於N,N-二甲基甲醯胺(20mL)，在0℃下分批加入鈉氫(1.2g，29.5mmol)，4小時後，加入冰水(30mL)，乙酸乙酯(50mL)萃取，分出乙酸乙酯，抽乾得到2-溴-1-(環丙基甲氧基)-4-硝基苯(6.2g)，直接用作下一步。 Dissolve 2-bromo-1-fluoro-4-nitrobenzene (5g, 22.7mmol) and cyclopropylmethanol (2g, 27.3mmol) in N, N-dimethylformamide (20mL) at 0 ° C. Sodium hydrogen (1.2 g, 29.5 mmol) was added in batches. After 4 hours, ice water (30 mL) was added, and ethyl acetate (50 mL) was extracted. The ethyl acetate was separated and dried to obtain 2-bromo-1- (cyclo Propylmethoxy) -4-nitrobenzene (6.2 g) was used directly in the next step.
將2-溴-1-(環丙基甲氧基)-4-硝基苯(6.2g，22.7mmol)溶於乙醇(50mL)、四氫呋喃(50mL)與水(20mL)的混合溶劑中，加入鐵粉(6.4g，113.7mmol)、氯化銨(6.1g，113.7 mmol)，回流4小時，管柱層析純化得到3-溴-4-(環丙基甲氧基)苯胺(2.7g)。 2-Bromo-1- (cyclopropylmethoxy) -4-nitrobenzene (6.2 g, 22.7 mmol) was dissolved in a mixed solvent of ethanol (50 mL), tetrahydrofuran (50 mL) and water (20 mL), and added Iron powder (6.4 g, 113.7 mmol), ammonium chloride (6.1 g, 113.7 mmol), refluxed for 4 hours, and purified by column chromatography to obtain 3-bromo-4- (cyclopropylmethoxy) aniline (2.7 g) .
將3-溴-4-(環丙基甲氧基)苯胺(2.1g，8.8mmol)懸浮於乙腈(50mL)與水(50mL)中，加入對甲苯磺酸(5.0g，26.4mmol)，在0℃下滴加亞硝酸鈉(1.2g，17.6mmol)加入碘化鉀(3.7g，22.0mmol)，管柱層析得到2-溴-1-(環丙基甲氧基)-4-碘苯(1g)。 3-Bromo-4- (cyclopropylmethoxy) aniline (2.1 g, 8.8 mmol) was suspended in acetonitrile (50 mL) and water (50 mL), and p-toluenesulfonic acid (5.0 g, 26.4 mmol) was added. Sodium nitrite (1.2 g, 17.6 mmol) was added dropwise at 0 ° C, potassium iodide (3.7 g, 22.0 mmol) was added, and column chromatography gave 2-bromo-1- (cyclopropylmethoxy) -4-iodobenzene ( 1g).
將2-溴-1-(環丙基甲氧基)-4-碘苯(1g,2.8mmol)、硫代乙酸鉀(0.5g，4.2mmol)、碘化亞銅(54mg，0.28mmol)、1,10-菲囉啉(102mg，0.6mmol)至甲苯中(30mL)，氮氣保護，在100℃下攪拌3小時，管柱層析得到S-(3-溴-4-(環丙基甲氧基)苯基)乙硫酸酯(0.87g)。 2-bromo-1- (cyclopropylmethoxy) -4-iodobenzene (1 g, 2.8 mmol), potassium thioacetate (0.5 g, 4.2 mmol), cuprous iodide (54 mg, 0.28 mmol), 1,10-phenanthroline (102 mg, 0.6 mmol) into toluene (30 mL), protected by nitrogen, stirred at 100 ° C for 3 hours, and column chromatography was performed to obtain S- (3-bromo-4- (cyclopropylformyl) Oxy) phenyl) ethyl sulfate (0.87 g).
將S-(3-溴-4-(環丙基甲氧基)苯基)乙硫酸酯(0.87g，2.9mmol)溶於乙醇(10mL)與水(2mL)，加入氫氧化鈉 (143mg，3.6mmol)、溴乙腈(429mg，3.6mmol)，在25℃下攪拌2小時，管柱層析純化得到2-((3-溴-4-(環丙基甲氧基)苯基)硫基)乙醯腈(1g)。 S- (3-bromo-4- (cyclopropylmethoxy) phenyl) ethyl sulfate (0.87 g, 2.9 mmol) was dissolved in ethanol (10 mL) and water (2 mL), and sodium hydroxide (143 mg, 3.6mmol), bromoacetonitrile (429mg, 3.6mmol), stirred at 25 ° C for 2 hours, and purified by column chromatography to obtain 2-((3-bromo-4- (cyclopropylmethoxy) phenyl) thio group ) Acetonitrile (1 g).
反應操作同實施例4第二步，得到2-((3-溴-4-(環丙基甲氧基)苯基)亞硫醯基<亞磺醯>)乙醯腈(收率86.8%)。 The reaction was carried out in the same manner as in the second step of Example 4 to obtain 2-((3-bromo-4- (cyclopropylmethoxy) phenyl) sulfinyl <sulfenyl>) acetonitrile (yield 86.8%). ).
1H NMR(400MHz,CDCl3)：δ 7.91(d,J=2.4Hz,1H),7.68(dd,J=8.4Hz,2.0Hz,1H),7.04(d,J=8.4Hz,1H),3.92(d,J=6.8Hz,2H),3.72(d,J=15.6Hz,1H),3.64(d,J=15.6Hz,1H),1.29-1.24(m,1H),0.65-0.60(m,2H),0.39-0.35(m,2H). 1 H NMR (400MHz, CDCl3): δ 7.91 (d, J = 2.4Hz, 1H), 7.68 (dd, J = 8.4Hz, 2.0Hz, 1H), 7.04 (d, J = 8.4Hz, 1H), 3.92 (d, J = 6.8Hz, 2H), 3.72 (d, J = 15.6Hz, 1H), 3.64 (d, J = 15.6Hz, 1H), 1.29-1.24 (m, 1H), 0.65-0.60 (m, 2H), 0.39-0.35 (m, 2H).
將2-((3-溴-4-(環丙基甲氧基)苯基)亞硫醯基<亞磺醯>)乙醯腈(535mg，1.7mmol)溶於四氫呋喃(20mL)中，加入碳酸銫(1.7g，5.2mmol)、碘甲烷(0.73g，5.2mmol)，在25℃攪拌3小時，管柱層析純化得到得到2-((3-溴-4-(環丙基 甲氧基)苯基)亞硫醯基<亞磺醯>)-2-甲基丙腈(387mg，收率66.8%)。 Dissolve 2-((3-bromo-4- (cyclopropylmethoxy) phenyl) sulfinyl <sulfenimidine>) acetonitrile (535 mg, 1.7 mmol) in tetrahydrofuran (20 mL) and add Cesium carbonate (1.7g, 5.2mmol), methyl iodide (0.73g, 5.2mmol), stirred at 25 ° C for 3 hours, and purified by column chromatography to obtain 2-((3-bromo-4- (cyclopropylmethoxy) Phenyl) phenyl) sulfenyl sulfenyl <sulfinyl sulfonium>)-2-methylpropionitrile (387 mg, yield 66.8%).
以2-((3-溴-4-(環丙基甲氧基)苯基)亞硫醯基<亞磺醯>)-2-甲基丙腈為起始原料，反應操作同實施例4第三步，得到2-(3-溴-4-(環丙基甲氧基)苯基磺亞胺醯基)-2-甲基丙腈(收率56.3%)。 Using 2-((3-bromo-4- (cyclopropylmethoxy) phenyl) sulfenylsulfinyl <sulfenylhydrazone>)-2-methylpropionitrile as the starting material, the reaction operation was the same as in Example 4 In the third step, 2- (3-bromo-4- (cyclopropylmethoxy) phenylsulfimidoamido) -2-methylpropionitrile was obtained (yield 56.3%).
MS m/z(ESI)：357.0/359.0(50/50)[M+H]+. MS m / z (ESI): 357.0 / 359.0 (50/50) [M + H] + .
以2-(3-溴-4-(環丙基甲氧基)苯基磺亞胺醯基)-2-甲基丙腈與中間體Im為反應原料，操作參考實施例4第四步，得到2-(4-(環丙基甲氧基)-3-(6-甲基-7-羰基-1-甲苯磺醯-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基磺亞胺醯基)-2-甲基丙腈(收率36.8%)。 Using 2- (3-bromo-4- (cyclopropylmethoxy) phenylsulfimidoamido) -2-methylpropionitrile and intermediate Im as the starting materials, refer to the fourth step of Example 4, for operation. To give 2- (4- (cyclopropylmethoxy) -3- (6-methyl-7-carbonyl-1-toluenesulfonium-6,7-dihydro-1H-pyrrolo [2,3-c ] Pyridin-4-yl) phenylsulfimimidino) -2-methylpropionitrile (yield 36.8%).
MS m/z(ESI)：579.1[M+H]+. MS m / z (ESI): 579.1 [M + H] + .
將2-(4-(環丙基甲氧基)-3-(6-甲基-7-羰基-1-甲苯磺醯-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基磺亞胺醯基)-2-甲基丙腈(100mg，0.173mmol)溶於乙醇(2mL)中，加入乙醇鈉(38mg，0.52mmol)，在25℃攪拌2小時，管柱層析純化得到2-(4-(環丙基甲氧基)-3-(6-甲基-7-羰基-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基磺亞胺醯基)-2-甲基丙腈(30mg，收率40.9%)。 Add 2- (4- (cyclopropylmethoxy) -3- (6-methyl-7-carbonyl-1-toluenesulfonium-6,7-dihydro-1H-pyrrolo [2,3-c ] Pyridin-4-yl) phenylsulfonylimido) -2-methylpropionitrile (100 mg, 0.173 mmol) was dissolved in ethanol (2 mL), sodium ethoxide (38 mg, 0.52 mmol) was added, and the mixture was stirred at 25 ° C. 2 hours, purified by column chromatography to obtain 2- (4- (cyclopropylmethoxy) -3- (6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo [2,3 -c] pyridin-4-yl) phenylsulfimimidino) -2-methylpropionitrile (30 mg, yield 40.9%).
MS m/z(ESI)：425.1[M+H]+. MS m / z (ESI): 425.1 [M + H] + .
1H NMR(400MHz,CDCl3)：δ 10.71(br,1H),8.14(d,J=2.4Hz,1H),8.06(dd,J=2.4Hz,8.4Hz,1H),7.37(s,1H),7.25(s,1H),7.13(d,J=8.8Hz,1H),6.40(d,J=2Hz,1H),3.95(d,J=6.8Hz,2H),3.80(s,3H),1.76(s,3H),1.69(s,3H),0.91-0.86(m,1H),0.60-0.55(m,2H),0.31-0.27(m,2H). 1 H NMR (400MHz, CDCl3): δ 10.71 (br, 1H), 8.14 (d, J = 2.4Hz, 1H), 8.06 (dd, J = 2.4Hz, 8.4Hz, 1H), 7.37 (s, 1H) , 7.25 (s, 1H), 7.13 (d, J = 8.8Hz, 1H), 6.40 (d, J = 2Hz, 1H), 3.95 (d, J = 6.8Hz, 2H), 3.80 (s, 3H), 1.76 (s, 3H), 1.69 (s, 3H), 0.91-0.86 (m, 1H), 0.60-0.55 (m, 2H), 0.31-0.27 (m, 2H).
將3-溴-4-氟苯硫醇(1g，4.8mmol)溶於N,N-二甲基甲醯胺(15mL)，加入碳酸鉀(2g，14.5mmol)、碘化鈉(72mg，0.48mmol)、溴乙腈(1.74g，14.5mmol)，在25℃攪拌3小時，加入水(40mL)，乙酸乙酯(50mL)萃取，分出有機層旋乾，得到2-((3-溴-4-氟苯基)硫基)乙醯腈(0.82g，收率69.8%)。 3-Bromo-4-fluorobenzenethiol (1 g, 4.8 mmol) was dissolved in N, N-dimethylformamide (15 mL), and potassium carbonate (2 g, 14.5 mmol) and sodium iodide (72 mg, 0.48) were added. mmol), bromoacetonitrile (1.74 g, 14.5 mmol), stirred at 25 ° C for 3 hours, added water (40 mL), and extracted with ethyl acetate (50 mL). The organic layer was separated and spin-dried to give 2-((3-bromo- 4-fluorophenyl) thio) acetonitrile (0.82 g, yield 69.8%).
2-((3-溴-4-氟苯基)硫基)乙醯腈(0.82g,3.35mmol溶於二氯甲烷(20mL)中，0℃下滴加間氯過氧苯甲酸(0.88mg，5.1mmol)的二氯甲烷溶液(10mL)，在0℃下攪拌0.5小時，加入亞硫酸鈉攪拌5分鐘，加入飽和碳酸氫鈉水溶液(20mL)，分出有機層管柱層析得2-((3-溴-4-氟苯基)亞硫醯基<亞磺醯>)乙醯腈(0.84g，收率96.1%)。 2-((3-Bromo-4-fluorophenyl) thio) acetonitrile (0.82g, 3.35mmol dissolved in dichloromethane (20mL), m-chloroperoxybenzoic acid (0.88mg) was added dropwise at 0 ° C. , 5.1 mmol) of dichloromethane solution (10 mL), stirred at 0 ° C for 0.5 hours, added sodium sulfite and stirred for 5 minutes, added saturated sodium bicarbonate aqueous solution (20 mL), and separated the organic layer by column chromatography to obtain 2-(( 3-bromo-4-fluorophenyl) sulfenyl <sulfenimidine>) acetonitrile (0.84 g, yield 96.1%).
1H NMR(400MHz,CDCl3)：δ 7.99(dd,J=2Hz,6Hz,1H),7.69-7.73(m,1H),7.38(t,J=8.0Hz,1H),3.68-3.82(m,2H)； 1 H NMR (400MHz, CDCl3): δ 7.99 (dd, J = 2Hz, 6Hz, 1H), 7.69-7.73 (m, 1H), 7.38 (t, J = 8.0Hz, 1H), 3.68-3.82 (m, 2H);
以2-((3-溴-4-氟苯基)亞硫醯基<亞磺醯>)乙醯腈為起始原料，實施例68第七步，得到2-((3-溴-4-氟苯基)亞硫醯基<亞磺醯>)-2-甲基丙腈(收率76.2%)。 Using 2-((3-bromo-4-fluorophenyl) sulfenylidene <sulfinylpyrene>) acetonitrile as the starting material, the seventh step of Example 68 yielded 2-((3-bromo-4 -Fluorophenyl) sulfenyl <sulfenylpyrene>)-2-methylpropionitrile (yield 76.2%).
以2-((3-溴-4-氟苯基)亞硫醯基<亞磺醯>)-2-甲基丙腈為起始原料，參考實施例1第六步，得到2-(3-溴-4-氟苯基磺亞胺醯基)-2-甲基丙腈(收率：67.3%)。 Using 2-((3-bromo-4-fluorophenyl) sulfinyl <sulfenylsulfonium>)-2-methylpropionitrile as a starting material, refer to the sixth step of Example 1, to obtain 2- (3 -Bromo-4-fluorophenylsulfonylimino) -2-methylpropionitrile (yield: 67.3%).
MS m/z(ESI)：304.9/306.9(50/50)[M+H]+. MS m / z (ESI): 304.9 / 306.9 (50/50) [M + H] + .
以2-(3-溴-4-氟苯基磺亞胺醯基)-2-甲基丙腈與中間體Im為反應原料，參考實施例10第四步，得到2-(4-氟 -3-(6-甲基-7-羰基-1-甲苯磺醯-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基磺亞胺醯基)-2-甲基丙腈(收率：37.4%)。 Using 2- (3-bromo-4-fluorophenylsulfimidoamido) -2-methylpropionitrile and intermediate Im as the starting materials, refer to the fourth step of Example 10 to obtain 2- (4-fluoro- 3- (6-methyl-7-carbonyl-1-toluenesulfonium-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) phenylsulfimidinyl) 2-methylpropionitrile (yield: 37.4%).
MS m/z(ESI)：527.1[M+H]+。 MS m / z (ESI): 527.1 [M + H] + .
以2-(4-氟-3-(6-甲基-7-羰基-1-甲苯磺醯-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基磺亞胺醯基)-2-甲基丙腈為起始原料，用環丙基甲胺代替反-4-甲基環己烷胺，參考實施例23第一步，得到2-(4-((環丙基甲基)胺基)-3-(6-甲基-7-羰基-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基磺亞胺醯基)-2-甲基丙腈(收率：27.6%)。 2- (4-fluoro-3- (6-methyl-7-carbonyl-1-toluenesulfonium-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) Phenylsulfenimido) -2-methylpropionitrile was used as a starting material, and cyclopropylmethylamine was used instead of trans-4-methylcyclohexaneamine. Referring to the first step of Example 23, 2- ( 4-((cyclopropylmethyl) amino) -3- (6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) Phenylsulfenimido) -2-methylpropionitrile (yield: 27.6%).
MS m/z(ESI)：424.1[M+H]+. MS m / z (ESI): 424.1 [M + H] + .
1H NMR(400MHz,CDCl3)：δ 10.51(br,1H),7.92-7.89(m,1H),7.81(d,J=2.4Hz,1H),7.30(s,1H),7.04(s,1H),6.75(d,J=9.2Hz,1H),6.22(s,1H),4.64(s,1H),3.72(s,3H),3.04(d,J=7.2Hz,2H),1.74(s,3H),1.66(s,3H),1.00-0.94(m,1H),0.49-0.46(m,2H),0.17-0.14(m,2H)； 1 H NMR (400MHz, CDCl3): δ 10.51 (br, 1H), 7.92-7.89 (m, 1H), 7.81 (d, J = 2.4Hz, 1H), 7.30 (s, 1H), 7.04 (s, 1H ), 6.75 (d, J = 9.2Hz, 1H), 6.22 (s, 1H), 4.64 (s, 1H), 3.72 (s, 3H), 3.04 (d, J = 7.2Hz, 2H), 1.74 (s , 3H), 1.66 (s, 3H), 1.00-0.94 (m, 1H), 0.49-0.46 (m, 2H), 0.17-0.14 (m, 2H);
以2-(4-氟-3-(6-甲基-7-羰基-1-甲苯磺醯-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基磺亞胺醯基)-2-甲基丙腈與反式-4-甲基環己烷胺為原料，參考實施例23第一步，得到標題化合物2-甲基-2-(3-(6-甲基-7-羰基-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-4-((反式-4-甲基環己基)胺基)苯基磺亞胺醯基)丙腈(產率18%)。 2- (4-fluoro-3- (6-methyl-7-carbonyl-1-toluenesulfonium-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) Phenylsulfenimido) -2-methylpropionitrile and trans-4-methylcyclohexaneamine as raw materials. Refer to the first step of Example 23 to obtain the title compound 2-methyl-2- (3 -(6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) -4-((trans-4-methylcyclohexyl) Amine) phenylsulfimidoamido) propionitrile (18% yield).
MS m/z(ESI)：466.2[M+H]+. MS m / z (ESI): 466.2 [M + H] + .
1H NMR(400MHz,MeOD)δ 7.88(dd,J=8.9Hz,2.4Hz,1H),7.74(d,J=2.4Hz,1H),7.37(d,J=2.8Hz,1H),7.21(s,1H),6.94(d,J=9.0Hz,1H),6.18(d,J=2.8Hz,1H),3.71(s,3H),3.67-3.59(m,1H),1.95-1.85(m,2H),1.65-1.58(m,2H),1.69(s,3H),1.67(s,3H),1.26-1.24(m,1H),1.08-0.87(m,4H),0.92(d,J=6.4Hz,3H). 1 H NMR (400MHz, MeOD) δ 7.88 (dd, J = 8.9Hz, 2.4Hz, 1H), 7.74 (d, J = 2.4Hz, 1H), 7.37 (d, J = 2.8Hz, 1H), 7.21 ( s, 1H), 6.94 (d, J = 9.0Hz, 1H), 6.18 (d, J = 2.8Hz, 1H), 3.71 (s, 3H), 3.67-3.59 (m, 1H), 1.95-1.85 (m , 2H), 1.65-1.58 (m, 2H), 1.69 (s, 3H), 1.67 (s, 3H), 1.26-1.24 (m, 1H), 1.08-0.87 (m, 4H), 0.92 (d, J = 6.4Hz, 3H).
將2-((3-溴-4-氟苯基)亞硫醯基<亞磺醯>)乙醯腈(1.0g，3.8mmol)溶於四氫呋喃(30mL)中，加入碳酸銫、1,2-二溴乙烷，在70℃攪拌5小時，管柱層析純化得到1-((3-溴-4-氟苯基)亞硫醯基<亞磺醯>)環丙烷-1-甲腈(930mg，產率84%)。 Dissolve 2-((3-bromo-4-fluorophenyl) sulfinyl <sulfenimidine>) acetonitrile (1.0 g, 3.8 mmol) in tetrahydrofuran (30 mL), add cesium carbonate, 1,2 -Dibromoethane, stirred at 70 ° C for 5 hours, and purified by column chromatography to obtain 1-((3-bromo-4-fluorophenyl) sulfinyl <sulfenyl)> cyclopropane-1-carbonitrile (930 mg, yield 84%).
以1-((3-溴-4-氟苯基)亞硫醯基<亞磺醯>)環丙烷-1-甲腈為原料，參考參考實施例1第六步，得1-(3-溴-4-氟苯基磺亞胺醯基)環丙烷-1-甲腈(產率92%)。 Using 1-((3-bromo-4-fluorophenyl) sulfinyl <sulfenimidine>) cyclopropane-1-carbonitrile as a raw material, refer to the sixth step of Reference Example 1 to obtain 1- (3- Bromo-4-fluorophenylsulfonylimino) cyclopropane-1-carbonitrile (92% yield).
MS m/z(ESI)：302.9/304.9(50/50)[M+H]+. MS m / z (ESI): 302.9 / 304.9 (50/50) [M + H] + .
以1-(3-溴-4-氟苯基磺亞胺醯基)環丙烷-1-甲腈與中間體Im為原料，參考實施例10第四步，得1-(4-氟-3-(6-甲基-7-羰基-1-甲苯磺醯-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基磺亞胺醯基)環丙烷-1-甲腈(產率65%)。 Using 1- (3-bromo-4-fluorophenylsulfimideamido) cyclopropane-1-carbonitrile and intermediate Im as raw materials, refer to the fourth step of Example 10 to obtain 1- (4-fluoro-3 -(6-methyl-7-carbonyl-1-toluenesulfonium-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) phenylsulfimidinyl) ring Propane-1-carbonitrile (65% yield).
MS m/z(ESI)：525.1[M+H]+。 MS m / z (ESI): 525.1 [M + H] + .
以1-(4-氟-3-(6-甲基-7-羰基-1-甲苯磺醯-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基磺亞胺醯基)環丙烷-1-甲腈為原料，用環丙基甲胺代替反-4-甲基環己烷胺，參考實施例23第一步，得1-(4-((環丙基甲基)胺基)-3-(6-甲基-7-羰基-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基磺亞胺醯基)環丙烷-1-甲腈(產率12%)。 1- (4-fluoro-3- (6-methyl-7-carbonyl-1-toluenesulfonium-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) Phenylsulfenimido) cyclopropane-1-carbonitrile was used as the raw material, and cyclopropylmethylamine was used instead of trans-4-methylcyclohexaneamine. Referring to the first step of Example 23, 1- (4- ((Cyclopropylmethyl) amino) -3- (6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) phenyl Sulfoimido) cyclopropane-1-carbonitrile (12% yield).
MS m/z(ESI)：422.1[M+H]+. MS m / z (ESI): 422.1 [M + H] + .
1H NMR(400MHz,MeOD)δ 7.67(dd,J=8.9Hz,2.4Hz, 1H),7.55(d,J=2.4Hz,1H),7.16(d,J=2.8Hz,1H),7.04(s,1H),6.73(d,J=8.9Hz,1H),6.02(d,J=2.8Hz,1H),3.51(s,3H),2.91(d,J=6.8Hz,2H),1.57(m,3H),1.46-1.38(m,1H),0.85(s,1H),0.32-0.22(m,2H),0.00(dd,J=7.6,2.7Hz,2H). 1 H NMR (400MHz, MeOD) δ 7.67 (dd, J = 8.9Hz, 2.4Hz, 1H), 7.55 (d, J = 2.4Hz, 1H), 7.16 (d, J = 2.8Hz, 1H), 7.04 ( s, 1H), 6.73 (d, J = 8.9Hz, 1H), 6.02 (d, J = 2.8Hz, 1H), 3.51 (s, 3H), 2.91 (d, J = 6.8Hz, 2H), 1.57 ( m, 3H), 1.46-1.38 (m, 1H), 0.85 (s, 1H), 0.32-0.22 (m, 2H), 0.00 (dd, J = 7.6, 2.7Hz, 2H).
將2-溴-1-氟-4-硝基苯(5g，22.7mmol),2,4-二硝基苯酚(5.9g，45.4mmol)溶於乙腈(80mL)中，加入碳酸銫(14.8g,45.4mmol)，在60℃攪拌5小時，點板反應完成後，過濾，濃縮，管柱層析純化(石油醚/乙酸乙酯=30/1)得到2-溴-1-(2,4-二氟苯氧基)-4-硝基苯(7.5g,100%)。 Dissolve 2-bromo-1-fluoro-4-nitrobenzene (5g, 22.7mmol), 2,4-dinitrophenol (5.9g, 45.4mmol) in acetonitrile (80mL), and add cesium carbonate (14.8g) , 45.4 mmol), and stirred at 60 ° C for 5 hours. After the spot plate reaction was completed, it was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 30/1) to obtain 2-bromo-1- (2,4 -Difluorophenoxy) -4-nitrobenzene (7.5 g, 100%).
將2-溴-1-(2,4-二氟苯氧基)-4-硝基苯(7.5g，22.7 mmol)溶於乙醇(100mL)中，加入鐵粉(6.3g,114mmol)，氯化銨(12.3g，227mmol)，在80℃攪拌12小時，反應完成後，過濾，濃縮，管柱層析純化(石油醚/乙酸乙酯=5/1)得到3-溴-4-(2,4-二氟苯氧基)苯胺(5.6g,82%)。 Dissolve 2-bromo-1- (2,4-difluorophenoxy) -4-nitrobenzene (7.5 g, 22.7 mmol) in ethanol (100 mL), add iron powder (6.3 g, 114 mmol), chlorine Ammonium chloride (12.3g, 227mmol), and stirred at 80 ° C for 12 hours. After the reaction was completed, it was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5/1) to give 3-bromo-4- (2 , 4-difluorophenoxy) aniline (5.6 g, 82%).
MS m/z(ESI)：300.0/302.0(50/50)[M+H]+. MS m / z (ESI): 300.0 / 302.0 (50/50) [M + H] + .
將溴乙腈(8.4g,70mmol)，五水合硫代硫酸鈉(17.5g,70mmol)，五水合硫酸銅(750mg,3mmol)，2,2’-聯吡啶(468mg,3mmol)溶於甲醇(30毫升)和水(30毫升)的混合溶劑中，反應升溫至70度攪拌兩小時。之後，將3-溴-4-(2,4-二氟苯氧基)苯胺(3g,10mmol)加入，反應體系降至0度，亞硝酸第三丁酯(1.8g,15mmol)緩慢滴入反應體系，滴畢攪拌十分鐘，接著在室溫下攪拌半個小時後升溫至70度攪拌3小時。反應完成後，過濾，旋去有機相，水相用乙酸乙酯萃取。合併有機相，乾燥，過濾，濃縮，管柱層析純化(石油醚/乙酸乙酯=1/1)得到2-((3-溴-4-(2,4-二氟苯氧基)苯基)硫基)乙醯腈(1.5g,45%)。 Bromoacetonitrile (8.4g, 70mmol), sodium thiosulfate pentahydrate (17.5g, 70mmol), copper sulfate pentahydrate (750mg, 3mmol), 2,2'-bipyridine (468mg, 3mmol) were dissolved in methanol (30 Ml) and water (30 ml), the reaction was heated to 70 ° C and stirred for two hours. After that, 3-bromo-4- (2,4-difluorophenoxy) aniline (3g, 10mmol) was added, and the reaction system was lowered to 0 degree, and the third butyl nitrite (1.8g, 15mmol) was slowly added dropwise. The reaction system was stirred for 10 minutes after dripping, and then stirred at room temperature for half an hour, and then heated to 70 degrees for 3 hours. After the reaction was completed, the organic phase was filtered off, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 1/1) to give 2-((3-bromo-4- (2,4-difluorophenoxy) benzene Yl) thio) acetonitrile (1.5 g, 45%).
MS m/z(ESI)：355.9/357.9(50/50)[M+H]+. MS m / z (ESI): 355.9 / 357.9 (50/50) [M + H] + .
以2-((3-溴-4-(2,4-二氟苯氧基)苯基)硫基)乙醯腈為原料，參考實施例1第五步得2-((3-溴-4-(2,4-二氟苯氧基)苯基)亞硫醯基<亞磺醯>)乙醯腈(產率92%)。 Using 2-((3-bromo-4- (2,4-difluorophenoxy) phenyl) thio) acetonitrile as a raw material, the fifth step of Reference Example 1 was used to obtain 2-((3-bromo- 4- (2,4-difluorophenoxy) phenyl) sulfenylidene <sulfinylpyrene>) acetonitrile (92% yield).
MS m/z(ESI)：371.9/373.9(50/50)[M+H]+. MS m / z (ESI): 371.9 / 373.9 (50/50) [M + H] + .
以2-((3-溴-4-(2,4-二氟苯氧基)苯基)亞硫醯基<亞磺醯>)乙醯腈為原料，參考實施例70第一步得1-((3-溴-4-(2,4-二氟苯氧基)苯基)亞硫醯基<亞磺醯>)環丙烷-1-甲腈(產率85%)。 Using 2-((3-bromo-4- (2,4-difluorophenoxy) phenyl) sulfenylidene <sulfinylpyrene>) acetonitrile as a raw material, refer to Example 70 to obtain -((3-bromo-4- (2,4-difluorophenoxy) phenyl) sulfinyl <sulfenimidine>) cyclopropane-1-carbonitrile (85% yield).
MS m/z(ESI)：397.9/399.9(50/50)[M+H]+. MS m / z (ESI): 397.9 / 399.9 (50/50) [M + H] + .
以1-((3-溴-4-(2,4-二氟苯氧基)苯基)亞硫醯基<亞磺醯>)環丙烷-1-甲腈為原料，參考實施例1第六步得1-(3-溴-4-(2,4-二氟苯氧基)苯基磺亞胺醯基)環丙烷-1-甲腈(產 率81%)。 1-((3-bromo-4- (2,4-difluorophenoxy) phenyl) sulfinyl <sulfenyl) sulfopropane-1-carbonitrile is used as a raw material. In six steps, 1- (3-bromo-4- (2,4-difluorophenoxy) phenylsulfonylimino) cyclopropane-1-carbonitrile was obtained (81% yield).
MS m/z(ESI)：413.0/415.0(50/50)[M+H]+. MS m / z (ESI): 413.0 / 415.0 (50/50) [M + H] + .
以1-(3-溴-4-(2,4-二氟苯氧基)苯基磺亞胺醯基)環丙烷-1-甲腈為原料，參考實施例1第七步得1-(4-(2,4-二氟苯氧基)-3-(6-甲基-7-羰基-1-甲苯磺醯-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基磺亞胺醯基)環丙烷-1-甲腈(產率88%)。 1- (3-bromo-4- (2,4-difluorophenoxy) phenylsulfimideamido) cyclopropane-1-carbonitrile is used as a raw material, and the first step in Reference Example 1 is used to obtain 1- ( 4- (2,4-difluorophenoxy) -3- (6-methyl-7-carbonyl-1-toluenesulfonium-6,7-dihydro-1H-pyrrolo [2,3-c] Pyridine-4-yl) phenylsulfimimidino) cyclopropane-1-carbonitrile (88% yield).
MS m/z(ESI)：635.1[M+H]+. MS m / z (ESI): 635.1 [M + H] + .
以1-(4-(2,4-二氟苯氧基)-3-(6-甲基-7-羰基-1-甲苯磺醯-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基磺亞胺醯基)環丙烷-1-甲腈為原料，參考實施例1第八步得1-(4-(2,4- 二氟苯氧基)-3-(6-甲基-7-羰基-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基磺亞胺醯基)環丙烷-1-甲腈(產率73%)。 With 1- (4- (2,4-difluorophenoxy) -3- (6-methyl-7-carbonyl-1-toluenesulfonium-6,7-dihydro-1H-pyrrolo [2, 3-c] pyridin-4-yl) phenylsulfimidoamido) cyclopropane-1-carbonitrile as the raw material, and the eighth step of Reference Example 1 is to obtain 1- (4- (2,4-difluorophenoxy) Yl) -3- (6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) phenylsulfimimidino) cyclopropane- 1-carbonitrile (73% yield).
MS m/z(ESI)：481.1[M+H]+。 MS m / z (ESI): 481.1 [M + H] + .
1H NMR(400MHz,MeOD)δ 8.11(d,J=2.4Hz,1H),7.89(dd,J=8.8Hz,2.4Hz,1H),7.26-7.17(m,2H),7.17-7.04(m,2H),6.97-6.87(m,2H),6.36(d,J=2.8Hz,1H),3.61(s,3H),1.82-1.58(m,4H). 1 H NMR (400MHz, MeOD) δ 8.11 (d, J = 2.4Hz, 1H), 7.89 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.26-7.17 (m, 2H), 7.17-7.04 (m , 2H), 6.97-6.87 (m, 2H), 6.36 (d, J = 2.8Hz, 1H), 3.61 (s, 3H), 1.82-1.58 (m, 4H).
以4-(5-(乙基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，用4-氟苯硫酚取代2,4-二氟苯酚，參考實施例4第五步，得到標題化合物4-(5-(乙基磺亞胺醯基)-2-((4-氟苯基)硫基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率15%)。 4- (5- (ethylsulfonylimino) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one as a raw material, and 2,4-difluorophenol was replaced with 4-fluorothiophenol. The fifth step of Reference Example 4 gave the title compound 4- (5- (ethylsulfonyliminofluorenyl) ) -2-((4-fluorophenyl) thio) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (yield 15%).
MS m/z(ESI)：442.1[M+H]+. MS m / z (ESI): 442.1 [M + H] + .
1H NMR(400MHz,d4-MeOD)：δ 7.97(d,J=2.4Hz,1H),7.81(dd,J=8.8Hz,2.4Hz,1H),7.27-7.247(m,2H),7.12-7.10(m,3H),6.93-6.84(m,2H),6.27(d,J=2.8Hz,1H), 3.60(s,3H),3.19(q,J=8.0Hz,2H),1.16(t,J=8.0Hz,3H)。 1 H NMR (400MHz, d 4-MeOD): δ 7.97 (d, J = 2.4Hz, 1H), 7.81 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.27-7.247 (m, 2H), 7.12 -7.10 (m, 3H), 6.93-6.84 (m, 2H), 6.27 (d, J = 2.8Hz, 1H), 3.60 (s, 3H), 3.19 (q, J = 8.0Hz, 2H), 1.16 ( t, J = 8.0 Hz, 3H).
將2-溴-1-氟-4-硝基苯(3.33g，15mmol),4,4-二氟環己烷-1-醇(2.0g，15mmol)溶於乙腈(30mL)中，加入碳酸銫(9.75g,30mmol)，在60℃攪拌5小時，點板反應完成後，過濾，濃縮，管柱層析純化(石油醚/乙酸乙酯=5/1)得到2-溴-1-((4,4-二氟環己基)酮基)-4-硝基苯(4.5g，黃色固體，產率89%)。 Dissolve 2-bromo-1-fluoro-4-nitrobenzene (3.33 g, 15 mmol), 4,4-difluorocyclohexane-1-ol (2.0 g, 15 mmol) in acetonitrile (30 mL), and add carbonic acid Cesium (9.75 g, 30 mmol) was stirred at 60 ° C for 5 hours. After the spot reaction was completed, it was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5/1) to give 2-bromo-1- ( (4,4-difluorocyclohexyl) keto) -4-nitrobenzene (4.5 g, yellow solid, yield 89%).
將2-溴-1-((4,4-二氟環己基)酮基)-4-硝基苯為起始原料，參考實施例71第二步，得到3-溴-4-((4,4-二氟環己基)酮基)苯胺(產率95%)。 Using 2-bromo-1-((4,4-difluorocyclohexyl) keto) -4-nitrobenzene as a starting material, refer to the second step of Example 71 to obtain 3-bromo-4-((4 , 4-difluorocyclohexyl) keto) aniline (95% yield).
MS m/z(ESI)：306.1/308.1(50/50)[M+H]+ MS m / z (ESI): 306.1 / 308.1 (50/50) [M + H] +
以3-溴-4-((4,4-二氟環己基)酮基)苯胺為反應原料，參考實施例67第三步得到2-溴-1-((4,4-二氟環己基)酮基)-4-碘苯(黃色油狀物，產率41%)。 Using 3-bromo-4-((4,4-difluorocyclohexyl) keto) aniline as a reaction raw material, the third step of Reference Example 67 was to obtain 2-bromo-1-((4,4-difluorocyclohexyl ) Keto) -4-iodobenzene (yellow oil, 41% yield).
以2-溴-1-((4,4-二氟環己基)酮基)-4-碘苯為起始原料，參考實施例67第四步，得到S-(3-溴-4-((4,4-二氟環己基)酮基)苯基)乙硫酸酯(黃色油狀物，產率75%)。 Using 2-bromo-1-((4,4-difluorocyclohexyl) keto) -4-iodobenzene as a starting material, refer to the fourth step of Example 67 to obtain S- (3-bromo-4- ( (4,4-difluorocyclohexyl) keto) phenyl) ethyl sulfate (yellow oil, 75% yield).
將S-(3-溴-4-((4,4-二氟環己基)酮基)苯基)乙硫酸酯為起始原料，參考實施例67第五步，得到2-((3-溴-4-((4,4-二氟環己基)酮基)苯基)硫基)乙醯腈(黃色油狀物，產率88%)。 Using S- (3-bromo-4-((4,4-difluorocyclohexyl) keto) phenyl) ethyl sulfate as a starting material, refer to the fifth step of Example 67 to obtain 2-((3- Bromo-4-((4,4-difluorocyclohexyl) keto) phenyl) thio) acetonitrile (yellow oil, 88% yield).
MS m/z(ESI)：362.0/364.0(50/50)[M+H]+. MS m / z (ESI): 362.0 / 364.0 (50/50) [M + H] + .
以2-((3-溴-4-((4,4-二氟環己基)酮基)苯基)硫基)乙醯腈為原料，參考實施例1第五步得2-((3-溴-4-((4,4-二氟環己基)酮基)苯基)亞硫醯基<亞磺醯>)乙醯腈(產率83%)。 Using 2-((3-bromo-4-((4,4-difluorocyclohexyl) keto) phenyl) thio) acetonitrile as a raw material, refer to Example 5 in the fifth step to obtain 2-((3 -Bromo-4-((4,4-difluorocyclohexyl) keto) phenyl) sulfinyl (sulfinyl)> acetonitrile (yield 83%).
MS m/z(ESI)：378.0/380.0(50/50)[M+H]+. MS m / z (ESI): 378.0 / 380.0 (50/50) [M + H] + .
以2-((3-溴-4-((4,4-二氟環己基)酮基)苯基)亞硫醯基<亞磺醯>)乙醯腈為原料，參考實施例70第一步得1-((3-溴-4-((4,4-二氟環己基)酮基)苯基)亞硫醯基<亞磺醯>)環丙烷-1-甲腈(產率60%)。 Using 2-((3-bromo-4-((4,4-difluorocyclohexyl) keto) phenyl) phenyl) sulfinyl <sulfenyl>) acetonitrile as the raw material, reference example 70 first 1-((3-bromo-4-((4,4-difluorocyclohexyl) keto) phenyl) phenyl) sulfinyl <sulfenimidine>) cyclopropane-1-carbonitrile (yield 60) %).
以1-((3-溴-4-((4,4-二氟環己基)酮基)苯基)亞硫醯基<亞磺醯>)環丙烷-1-甲腈為原料，參考實施例1第六步得1-(3-溴-4-((4,4-二氟環己基)酮基)苯基磺亞胺醯基)環丙烷-1-甲腈(產率68%)。 Taking 1-((3-bromo-4-((4,4-difluorocyclohexyl) keto) phenyl) phenyl) sulfinyl <sulfenimidine>) cyclopropane-1-carbonitrile as a raw material, refer to the implementation Example 1 In the sixth step, 1- (3-bromo-4-((4,4-difluorocyclohexyl) keto) phenylsulfonylimino) cyclopropane-1-carbonitrile was obtained (yield 68%). .
MS m/z(ESI)：419.0/421.0(50/50)[M+H]+. MS m / z (ESI): 419.0 / 421.0 (50/50) [M + H] + .
以1-(3-溴-4-((4,4-二氟環己基)酮基)苯基磺亞胺醯基)環丙烷-1-甲腈為原料，參考實施例1第七步得1-(4-((4,4-二氟環己基)酮基)-3-(6-甲基-7-羰基-1-甲苯磺醯-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基磺亞胺醯基)環丙烷-1-甲腈(產率87%)。 Using 1- (3-bromo-4-((4,4-difluorocyclohexyl) keto) phenylsulfimidefluorenyl) cyclopropane-1-carbonitrile as the raw material, refer to the seventh step of Example 1 to obtain 1- (4-((4,4-difluorocyclohexyl) keto) -3- (6-methyl-7-carbonyl-1-toluenesulfonium-6,7-dihydro-1H-pyrrolo [ 2,3-c] pyridin-4-yl) phenylsulfimimidino) cyclopropane-1-carbonitrile (87% yield).
MS m/z(ESI)：641.1[M+H]+. MS m / z (ESI): 641.1 [M + H] + .
以1-(4-((4,4-二氟環己基)酮基)-3-(6-甲基-7-羰基-1-甲苯磺醯-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基磺亞胺醯基)環丙烷-1-甲腈為原料，參考實施例1第八步得1-(4-((4,4-二氟環己基)酮基)-3-(6-甲基-7-羰基-6,7-二氫 -1H-吡咯並[2,3-c]吡啶-4-基)苯基磺亞胺醯基)環丙烷-1-甲腈(產率25%)。 1- (4-((4,4-difluorocyclohexyl) keto) -3- (6-methyl-7-carbonyl-1-toluenesulfonium-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) phenylsulfimidofluorenyl) cyclopropane-1-carbonitrile was used as a raw material, and the eighth step of Reference Example 1 was used to obtain 1- (4-((4,4- Difluorocyclohexyl) keto) -3- (6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) phenylsulfimine (Fluorenyl) cyclopropane-1-carbonitrile (yield 25%).
MS m/z(ESI)：487.1[M+H]+. MS m / z (ESI): 487.1 [M + H] + .
1H NMR(400MHz,MeOD)δ 8.01-7.93(m,2H),7.35(d,J=8.8Hz,1H),7.25(d,J=2.8Hz,1H),7.20(s,1H),6.24(d,J=2.9Hz,1H),4.74-4.71(m,1H),3.61(s,3H),1.91-1.74(m,6H),1.72-1.48(m,6H). 1 H NMR (400MHz, MeOD) δ 8.01-7.93 (m, 2H), 7.35 (d, J = 8.8Hz, 1H), 7.25 (d, J = 2.8Hz, 1H), 7.20 (s, 1H), 6.24 (d, J = 2.9Hz, 1H), 4.74-4.71 (m, 1H), 3.61 (s, 3H), 1.91-1.74 (m, 6H), 1.72-1.48 (m, 6H).
以實施例33中的3-溴-4-氟苯硫酚(1g,5mmol)為原料，在氮氣氣氛保護下，將其與環丁基溴(810mg,6mmol)和碳酸鉀(1.36g，10mmol)在10毫升二甲亞碸中60度下反應過夜。體系用水稀釋，乙酸乙酯萃取，有機相水洗，飽和食鹽水洗滌，乾燥，濃縮，殘餘物使用矽膠管柱層析純化(石油醚：乙酸乙酯=10：1)得到化合物(3-溴-4-氟苯基)(環丁基)硫烷(1.2g,92%)。 Using 3-bromo-4-fluorothiophenol (1 g, 5 mmol) in Example 33 as a raw material, under a nitrogen atmosphere, this was mixed with cyclobutyl bromide (810 mg, 6 mmol) and potassium carbonate (1.36 g, 10 mmol). ) Reaction at 60 degrees in 10 ml of dimethylarsine overnight. The system was diluted with water, extracted with ethyl acetate, washed with organic phase, washed with saturated brine, dried, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain the compound (3-bromo- 4-fluorophenyl) (cyclobutyl) sulfane (1.2 g, 92%).
1H NMR(400MHz,d-CDCl3)：δ 7.47(dd,J=2.4,6.4Hz,1H),7.22-7.18(m,1H),7.07(t,J=8.4Hz,1H),3.35-3.47(m,1H),2.01-1.65(m,6H). 1 H NMR (400MHz, d -CDCl 3 ): δ 7.47 (dd, J = 2.4,6.4Hz, 1H), 7.22-7.18 (m, 1H), 7.07 (t, J = 8.4Hz, 1H), 3.35- 3.47 (m, 1H), 2.01-1.65 (m, 6H).
以(3-溴-4-氟苯基)(環丁基)硫烷為反應原料，參考實施例1第五步，得到2-溴-4-(環丙基亞硫醯基<亞磺醯>)-1-氟苯(產率77%)。 (3-Bromo-4-fluorophenyl) (cyclobutyl) sulfane was used as a reaction raw material, and the fifth step of Reference Example 1 was used to obtain 2-bromo-4- (cyclopropylthiosulfenyl group <sulfenylsulfonium >)-1-fluorobenzene (yield 77%).
MS m/z(ESI)：277.0/279.0(50/50)[M+H]+ MS m / z (ESI): 277.0 / 279.0 (50/50) [M + H] +
以2-溴-4-(環丁基亞硫醯基<亞磺醯>)-1-氟苯為原料，參考實施例1第六步，得到(3-溴-4-氟苯基)(環丁基)(亞胺基)-λ6-硫烷酮(產率88%)。 Using 2-bromo-4- (cyclobutylthiosulfinyl <sulfenyl)>-1-fluorobenzene as a raw material, refer to the sixth step of Example 1 to obtain (3-bromo-4-fluorophenyl) ( Cyclobutyl) (imino) -λ 6 -sulfanone (88% yield).
MS m/z(ESI)：292.0/294.0(50/50)[M+H]+. MS m / z (ESI): 292.0 / 294.0 (50/50) [M + H] + .
以(3-溴-4-氟苯基)(環丙基)(亞胺基)-λ6-硫烷酮與中間體Im為原料，參考實施例4第四步得到4-(5-(環丁磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率47%) Using (3-bromo-4-fluorophenyl) (cyclopropyl) (imino) -λ 6 -sulfanone and intermediate Im as raw materials, the fourth step of Reference Example 4 was to obtain 4- (5- ( Cyclobutanesulfinoimido) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7-one (Yield 47%)
MS m/z(ESI)：514.1[M+H]+ MS m / z (ESI): 514.1 [M + H] +
以4-(5-(環丁磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，4,4-二氟環己醇替代2,4-二氟苯酚，參考實施例10第五步反應條件，得到4-(5-(環丁磺亞胺醯基)-2-((4,4-二氟環己基)酮基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(收率：46.7%)。 4- (5- (Cyclobutanesulfinoimido) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridine-7-one as raw material, 4,4-difluorocyclohexanol replacing 2,4-difluorophenol, and the reaction conditions in the fifth step of Reference Example 10 were obtained to obtain 4- (5- (cyclobutanesulfimine) Fluorenyl) -2-((4,4-difluorocyclohexyl) keto) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7 -Ketone (yield: 46.7%).
MS m/z(ESI)：476.2[M+H]+. MS m / z (ESI): 476.2 [M + H] + .
1H NMR(400MHz,d4-MeOD)δ 7.98-7.92(m,2H),7.42(d,J=9.2Hz,1H),7.25(d,J=2.4Hz,1H),7.19(s,1H), 6.12(d,J=2.8Hz,1H),4.51-4.49(m,1H),3.60(s,3H),2.66-2.57(m,1H),2.45-2.35(m,2H),2.16-1.87(m,4H),1.84-1.53(m,8H). 1 H NMR (400MHz, d 4-MeOD) δ 7.98-7.92 (m, 2H), 7.42 (d, J = 9.2Hz, 1H), 7.25 (d, J = 2.4Hz, 1H), 7.19 (s, 1H ), 6.12 (d, J = 2.8Hz, 1H), 4.51-4.49 (m, 1H), 3.60 (s, 3H), 2.66-2.57 (m, 1H), 2.45-2.35 (m, 2H), 2.16- 1.87 (m, 4H), 1.84-1.53 (m, 8H).
將2-溴-1-氟-4-碘苯(18.0g，0.06mol)、Cu2O(36.0mg，0.25mmol)和KOH(5.6g，0.10mol)混合於1,4-二氧六環(20ml)中，氮氣保護下經注射器向體系內加入環戊硫醇(5.1g，0.05mol)，升溫至110℃反應過夜。反應液冷至室溫後，加入乙酸乙酯(30ml)，過濾，濾餅以乙酸乙酯(20ml)洗滌。合併濾液，減壓濃縮至乾。剩餘物經管柱層析分離得標題化合物(12.0g，產率72%)。 Mix 2-bromo-1-fluoro-4-iodobenzene (18.0 g, 0.06 mol), Cu2O (36.0 mg, 0.25 mmol), and KOH (5.6 g, 0.10 mol) in 1,4-dioxane (20 ml) ), Under the protection of nitrogen, cyclopentathiol (5.1 g, 0.05 mol) was added to the system through a syringe, and the temperature was raised to 110 ° C. for overnight reaction. After the reaction solution was cooled to room temperature, ethyl acetate (30 ml) was added, and the filter cake was washed with ethyl acetate (20 ml). The filtrates were combined and concentrated to dryness under reduced pressure. The residue was separated by column chromatography to obtain the title compound (12.0 g, yield 72%).
1H NMR(400MHz,CDCl3)δ 7.62-7.49(m,1H),7.34-7.20(m,1H),7.09-6.95(m,1H),3.52(td,J=7.2,3.6Hz,1H),2.08-1.92(m,2H),1.85-1.56(m,6H). 1 H NMR (400MHz, CDCl 3 ) δ 7.62-7.49 (m, 1H), 7.34-7.20 (m, 1H), 7.09-6.95 (m, 1H), 3.52 (td, J = 7.2,3.6Hz, 1H) , 2.08-1.92 (m, 2H), 1.85-1.56 (m, 6H).
以(3-溴-4-氟苯基)(環戊基)硫烷為原料，參考實施例4第二步，得標題化合物2-溴-4-(環戊基亞硫醯基<亞磺醯>)-1-氟苯(產率80%)。 Using (3-bromo-4-fluorophenyl) (cyclopentyl) sulfane as a raw material, and referring to the second step of Example 4, the title compound 2-bromo-4- (cyclopentylthiosulfenyl group <sulfenyl醯>)-1-fluorobenzene (yield 80%).
MS m/z(ESI)：291.0/293.0(50/50)[M+H]+。 MS m / z (ESI): 291.0 / 293.0 (50/50) [M + H] + .
以2-溴-4-(環戊基亞硫醯基<亞磺醯>)-1-氟苯為原料，參考實施例4第三步，得到標題化合物(3-溴-4-氟苯基)(環戊基)(亞胺基)-λ6-硫烷酮(產率78%)。 Using 2-bromo-4- (cyclopentylthiosulfenyl <sulfenylpyrene>)-1-fluorobenzene as a raw material, refer to the third step of Example 4 to obtain the title compound (3-bromo-4-fluorophenyl ) (Cyclopentyl) (imino) -λ6-sulfanone (yield 78%).
MS m/z(ESI)：306.0/308.0(50/50)[M+H]+. MS m / z (ESI): 306.0 / 308.0 (50/50) [M + H] + .
以(3-溴-4-氟苯基)(環戊基)(亞胺基)-λ6-硫烷酮為原料。參考實施例4第四步，得到標題化合物4-(5-(環戊磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡 咯並[2,3-c]吡啶-7-酮(產率31%)。 (3-Bromo-4-fluorophenyl) (cyclopentyl) (imino) -λ6-sulfanone was used as a raw material. The fourth step of Reference Example 4 gave the title compound 4- (5- (cyclopentanesulfenimido) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro -7H-pyrrolo [2,3-c] pyridin-7-one (31% yield).
MS m/z(ESI)：528.1[M+H]+. MS m / z (ESI): 528.1 [M + H] + .
以4-(5-(環戊磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，參考實施例5第五步，得到標題化合物4-(5-(環戊磺亞胺醯基)-2-(環丙基甲氧基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率44%)。 4- (5- (Cyclopentanesulfenimido) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one as a raw material, refer to the fifth step of Example 5, to obtain the title compound 4- (5- (cyclopentanesulfenimido) -2- (cyclopropylmethoxy) phenyl)- 6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (44% yield).
MS m/z(ESI)：426.2[M+H]+. MS m / z (ESI): 426.2 [M + H] + .
1H NMR(400MHz,MeOD)δ 8.02(dd,J=8.9,2.6Hz,1H),7.97(d,J=2.6Hz,1H),7.39(d,J=9.0Hz,1H),7.33-7.18(m,2H),6.13(d,J=2.9Hz,1H),4.47-4.24(m,1H),3.98(d,J=6.9Hz,2H),3.62(s,3H),2.27-2.10(m,2H),1.94-1.81(m,2H),1.77-1.56(m,4H),1.12-1.06(m,1H),0.52-0.34(m,2H),0.30-0.12(m,2H). 1 H NMR (400MHz, MeOD) δ 8.02 (dd, J = 8.9, 2.6 Hz, 1H), 7.97 (d, J = 2.6 Hz, 1H), 7.39 (d, J = 9.0 Hz, 1H), 7.33-7.18 (m, 2H), 6.13 (d, J = 2.9 Hz, 1H), 4.47-4.24 (m, 1H), 3.98 (d, J = 6.9 Hz, 2H), 3.62 (s, 3H), 2.27-2.10 ( m, 2H), 1.94-1.81 (m, 2H), 1.77-1.56 (m, 4H), 1.12-1.06 (m, 1H), 0.52-0.34 (m, 2H), 0.30-0.12 (m, 2H).
以4-(2-氟-5-(S-甲基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為反應原料，參考實施例10第五步，用4,4,-二甲基環己醇取代2,4-二氟苯酚，得到4-(2-((4,4-二甲基環己基)酮基)-5-(S-甲基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率22%)。 With 4- (2-fluoro-5- (S-methylsulfonylimino) phenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2, 3-c] pyridine-7-one as a reaction raw material. In the fifth step of Reference Example 10, 2,4-difluorophenol was replaced with 4,4, -dimethylcyclohexanol to obtain 4- (2-(( 4,4-dimethylcyclohexyl) keto) -5- (S-methylsulfonylimino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2, 3-c] pyridin-7-one (yield 22%).
MS m/z(ESI)：428.2[M+H]+. MS m / z (ESI): 428.2 [M + H] + .
1H NMR(400MHz,DMSO)δ 8.03(d,J=2.5Hz,1H),8.00(d,J=2.6Hz,1H),7.52(d,J=8.8Hz,1H),7.34(s,1H),7.32(t,J=2.8Hz,1H),6.26-6.08(m,1H),4.66-4.64(m,1H),3.80(s,3H),3.58(s,3H),2.05-1.94(m,2H),1.80-1.78(m,2H),1.66-1.38(m,4H),0.88(s,3H),0.77(s,3H). 1 H NMR (400MHz, DMSO) δ 8.03 (d, J = 2.5Hz, 1H), 8.00 (d, J = 2.6Hz, 1H), 7.52 (d, J = 8.8Hz, 1H), 7.34 (s, 1H ), 7.32 (t, J = 2.8Hz, 1H), 6.26-6.08 (m, 1H), 4.66-4.64 (m, 1H), 3.80 (s, 3H), 3.58 (s, 3H), 2.05-1.94 ( m, 2H), 1.80-1.78 (m, 2H), 1.66-1.38 (m, 4H), 0.88 (s, 3H), 0.77 (s, 3H).
將化合物4-(2-((1,4-二氧雜螺[4.5]癸烷-8-基)酮 基)-5-(乙基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(400mg,0.85mmol)溶於30毫升甲醇中，在攪拌條件下加入5毫升1M濃度的稀鹽酸。反應在室溫條件下攪拌過夜。減壓條件下除去溶劑，殘餘物用乙酸乙酯/水分液萃取，有機相經過乾燥，濃縮，管柱層析純化得到化合物4-(5-(乙基磺亞胺醯基)-2-((4-羰基環己基)酮基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(320mg,88%) The compound 4- (2-((1,4-dioxaspiro [4.5] decane-8-yl) keto) -5- (ethylsulfimidoamido) phenyl) -6-methyl -1,6-Dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (400 mg, 0.85 mmol) was dissolved in 30 ml of methanol, and 5 ml of a 1M diluted hydrochloric acid was added under stirring. The reaction was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was extracted with ethyl acetate / water solution. The organic phase was dried, concentrated, and purified by column chromatography to obtain compound 4- (5- (ethylsulfonylimino) -2- ( (4-carbonylcyclohexyl) keto) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7-one (320 mg, 88%)
MS m/z(ESI)：428.1[M+H]+. MS m / z (ESI): 428.1 [M + H] + .
1H NMR(400MHz,d4-MeOD)：δ 7.90-7.81(m,2H),7.36-7.19(m,3H),6.17-6.16(m,1H),4.89-4.87(m,1H),3.60(s,3H),3.21(q,J=7.3Hz,2H),2.14-1.94(m,5H),1.73-1.48(m,3H),1.16(t,J=7.3Hz,3H). 1 H NMR (400MHz, d 4-MeOD): δ 7.90-7.81 (m, 2H), 7.36-7.19 (m, 3H), 6.17-6.16 (m, 1H), 4.89-4.87 (m, 1H), 3.60 (s, 3H), 3.21 (q, J = 7.3Hz, 2H), 2.14-1.94 (m, 5H), 1.73-1.48 (m, 3H), 1.16 (t, J = 7.3Hz, 3H).
以4-(5-(乙基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為反應原料，參考實施例10第五步，用(2,2-二氟環丙基)甲醇取代2,4-二氟苯酚，得到4-(2-((2,2-二氟環丙基)甲氧基)-5-(乙基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7- 酮(收率32%)。 4- (5- (ethylsulfonylimino) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one is used as a reaction raw material. In the fifth step of Reference Example 10, 2,4-difluorophenol is replaced with (2,2-difluorocyclopropyl) methanol to obtain 4- (2-((2 , 2-difluorocyclopropyl) methoxy) -5- (ethylsulfonylimino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridine-7-one (32% yield).
MS m/z(ESI)：422.1[M+H]+； MS m / z (ESI): 422.1 [M + H] + ;
1H NMR(400MHz,d4-MeOD)：δ 8.03-7.99(m,2H),7.41(d,J=8.4Hz,1H),7.26-7.24(m,2H),6.15(t,J=2.8Hz,1H),4.30-4.25(m,1H),4.15-4.11(m,1H),3.84(q,J=7.2Hz,2H),3.60(s,3H),1.52-1.41(m,1H),1.30-1.19(m,5H). 1 H NMR (400MHz, d 4-MeOD): δ 8.03-7.99 (m, 2H), 7.41 (d, J = 8.4Hz, 1H), 7.26-7.24 (m, 2H), 6.15 (t, J = 2.8 Hz, 1H), 4.30-4.25 (m, 1H), 4.15-4.11 (m, 1H), 3.84 (q, J = 7.2Hz, 2H), 3.60 (s, 3H), 1.52-1.41 (m, 1H) , 1.30-1.19 (m, 5H).
以4-(5-(乙基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為反應原料，參考實施例10第五步，用4,4-二甲基環己醇取代2,4-二氟苯酚，得到4-(2-((4,4-二甲基環己基)酮基)-5-(乙基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(收率：35.5%)。 4- (5- (ethylsulfonylimino) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2,3- c] pyridine-7-one as the reaction raw material. In the fifth step of Reference Example 10, 2,4-difluorophenol was replaced with 4,4-dimethylcyclohexanol to obtain 4- (2-((4,4 -Dimethylcyclohexyl) keto) -5- (ethylsulfonylimino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine -7-one (yield: 35.5%).
MS m/z(ESI)：442.1[M+H]+. MS m / z (ESI): 442.1 [M + H] + .
1H NMR(400MHz,d4-MeOD)：δ 7.84-7.79(m,2H),7.23-7.17(m,3H),6.15(d,J=2.8Hz,1H),4.48-4.45(m,1H),3.60(s,3H),3.15(q,J=7.6Hz,2H),1.67-1.65(m,2H),1.52-1.51(m,2H),1.18-1.12(m,5H),1.07-1.01(m,2H), 0.79(s,3H),0.65(s,3H). 1 H NMR (400MHz, d 4-MeOD): δ 7.84-7.79 (m, 2H), 7.23-7.17 (m, 3H), 6.15 (d, J = 2.8Hz, 1H), 4.48-4.45 (m, 1H ), 3.60 (s, 3H), 3.15 (q, J = 7.6Hz, 2H), 1.67-1.65 (m, 2H), 1.52-1.51 (m, 2H), 1.18-1.12 (m, 5H), 1.07- 1.01 (m, 2H), 0.79 (s, 3H), 0.65 (s, 3H).
以4-(5-(乙基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，參考實施例10第五步，用對氟苯酚取代2,4-二氟苯酚，得到4-(5-(乙基磺亞胺醯基)-2-(4-氟苯氧基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率60%)。 4- (5- (ethylsulfonylimino) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one as a raw material. In the fifth step of Reference Example 10, 2,4-difluorophenol was replaced with p-fluorophenol to obtain 4- (5- (ethylsulfonylimino) -2- ( 4-fluorophenoxy) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (60% yield).
MS m/z(ESI)：426.1[M+H]+. MS m / z (ESI): 426.1 [M + H] + .
1H NMR(400MHz,MeOD)δ 8.24(d,J=2.6Hz,1H),8.11(dd,J=8.9Hz,2.6Hz,1H),7.49(s,1H),7.42(d,J=2.9Hz,1H),7.28-7.11(m,5H),6.40(d,J=2.9Hz,1H),4.09(q,J=7.3Hz,2H),3.74(s,3H),1.45(t,J=7.3Hz,3H). 1 H NMR (400MHz, MeOD) δ 8.24 (d, J = 2.6Hz, 1H), 8.11 (dd, J = 8.9Hz, 2.6Hz, 1H), 7.49 (s, 1H), 7.42 (d, J = 2.9 Hz, 1H), 7.28-7.11 (m, 5H), 6.40 (d, J = 2.9Hz, 1H), 4.09 (q, J = 7.3Hz, 2H), 3.74 (s, 3H), 1.45 (t, J = 7.3Hz, 3H).
將4-(5-(乙基磺亞胺醯基)-2-(4-氟苯氧基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(56.2mg,0.13mmol)溶於5毫升無水乙腈，在室溫條件下加入溴乙腈(16mg,0.15mmol)，接著在相同條件下攪拌過夜。加水淬滅反應，二氯甲烷萃取。有機相經過乾燥，濃縮，製備TLC板分離(二氯甲烷/甲醇=20：1)得到化合物N-(乙基(4-(4-氟苯氧基)-3-(6-甲基-7-羰基-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基)(羰基)-16-硫烷亞基)氰基醯胺(6.0mg，收率10%)。 4- (5- (Ethylsulfonylimido) -2- (4-fluorophenoxy) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3 -c] pyridine-7-one (56.2 mg, 0.13 mmol) was dissolved in 5 ml of anhydrous acetonitrile, and bromoacetonitrile (16 mg, 0.15 mmol) was added at room temperature, followed by stirring under the same conditions overnight. The reaction was quenched by adding water and extracted with dichloromethane. The organic phase was dried, concentrated, and separated on a TLC plate (dichloromethane / methanol = 20: 1) to obtain the compound N- (ethyl (4- (4-fluorophenoxy) -3- (6-methyl-7 -Carbonyl-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) phenyl) (carbonyl) -16-sulfanylidene) cyanamide (6.0 mg, collected Rate of 10%).
MS m/z(ESI)：451.1[M+H]+； MS m / z (ESI): 451.1 [M + H] + ;
1H NMR(400MHz,d4-MeOD)：δ 8.01(d,J=2.4Hz,1H),7.86(dd,J=8.8Hz,2.4Hz,1H),7.31(s,1H),7.26(d,J=2.8Hz,1H),7.00-7.08(m,5H),6.30(d,J=2.8Hz,1H),3.61-3.55(m,5H),1.26(t,J=7.2Hz,3H). 1 H NMR (400MHz, d 4-MeOD): δ 8.01 (d, J = 2.4Hz, 1H), 7.86 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.31 (s, 1H), 7.26 (d , J = 2.8Hz, 1H), 7.00-7.08 (m, 5H), 6.30 (d, J = 2.8Hz, 1H), 3.61-3.55 (m, 5H), 1.26 (t, J = 7.2Hz, 3H) .
以4-(5-(環丁磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為反應原料，參考實施例10第五步，用環丙基甲醇取代用2,4-二氟苯酚，得到4-(5-(環丁磺亞胺醯基)-2-(環丙基甲氧基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(收率：11%)。 4- (5- (Cyclobutanesulfinoimido) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one as the reaction raw material. In the fifth step of Reference Example 10, cyclopropylmethanol was used instead of 2,4-difluorophenol to obtain 4- (5- (cyclobutanesulfinoimidofluorenyl)- 2- (cyclopropylmethoxy) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7-one (yield: 11%).
MS m/z(ESI)：412.1[M+H]+； MS m / z (ESI): 412.1 [M + H] + ;
1H NMR(400MHz,d4-MeOD)δ 8.00(dd,J=9.2Hz,2.8,1H),7.95(d,J=2.8Hz,1H),7.39(d,J=9.2Hz,1H),7.28(s,1H),7.27(d,J=2.8Hz,1H),6.14(d,J=3.2Hz,1H),3.97(d,J=6.8Hz,2H),3.62(s,3H),2.71-1.91(m,7H),1.12-1.05(m,1H),0.47-0.42(m,2H),0.23-0.19(m,2H). 1 H NMR (400MHz, d 4-MeOD) δ 8.00 (dd, J = 9.2Hz, 2.8,1H), 7.95 (d, J = 2.8Hz, 1H), 7.39 (d, J = 9.2Hz, 1H), 7.28 (s, 1H), 7.27 (d, J = 2.8Hz, 1H), 6.14 (d, J = 3.2Hz, 1H), 3.97 (d, J = 6.8Hz, 2H), 3.62 (s, 3H), 2.71-1.91 (m, 7H), 1.12-1.05 (m, 1H), 0.47-0.42 (m, 2H), 0.23-0.19 (m, 2H).
以4-(5-(環丁磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮與2,4-二氟苯酚為反應原料，參考實施例10第五步，得到4-(5-(環丁磺亞胺醯基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(收率：26.6%)。 4- (5- (Cyclobutanesulfinoimido) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one and 2,4-difluorophenol are used as the starting materials. Refer to the fifth step of Example 10 to obtain 4- (5- (cyclobutanesulfenimido) -2- (2,4- Difluorophenoxy) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (yield: 26.6%).
MS m/z(ESI)：470.1[M+H]+； MS m / z (ESI): 470.1 [M + H] + ;
1H NMR(400MHz,d4-MeOD)δ 8.11(s,1H),8.00(d,J=8.4Hz,1H),7.41-6.94(m,6H),6.28(s,1H),3.65(s,3H),2.69-1.94(m,7H). 1 H NMR (400MHz, d 4-MeOD) δ 8.11 (s, 1H), 8.00 (d, J = 8.4Hz, 1H), 7.41-6.94 (m, 6H), 6.28 (s, 1H), 3.65 (s , 3H), 2.69-1.94 (m, 7H).
將氧雜環丁烷-3-醇(740mg,10mmol)和碳酸鉀(2.7g,20mmol)加入反應瓶中，再加入40毫升無水乙腈作用溶劑。在攪拌的狀況下分批加入對甲苯磺醯氯(2.3g,12mmol)固體，加完後反應升溫至70度攪拌過夜。用水淬滅反應，乙酸乙酯萃取，有機相經過乾燥，濃縮，剩餘物藉由矽膠管柱層析(石油醚：乙酸乙酯=20：1)得到化合物氧雜環丁烷-3-基4-甲基苯磺酸酯(1.8g，收率80%)。 Oxetane-3-ol (740 mg, 10 mmol) and potassium carbonate (2.7 g, 20 mmol) were added to the reaction flask, and 40 ml of anhydrous acetonitrile was added as a solvent. With stirring, p-toluenesulfonyl chloride (2.3 g, 12 mmol) was added in portions. After the addition, the reaction was heated to 70 ° C and stirred overnight. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was dried and concentrated. The residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1) to obtain the compound oxetane-3-yl 4 -Mesylate (1.8 g, yield 80%).
1H NMR(400MHz,d-CDCl3)δ 7.78(d,J=8.4Hz,2H),7.37(d,J=8.0Hz,2H),5.33-5.27(m,1H),4.74-4.65(m,4H),2.46(s,3H). 1 H NMR (400MHz, d-CDCl 3 ) δ 7.78 (d, J = 8.4Hz, 2H), 7.37 (d, J = 8.0Hz, 2H), 5.33-5.27 (m, 1H), 4.74-4.65 (m , 4H), 2.46 (s, 3H).
以3-溴-4-氟苯硫酚為原料，參考實施例74第一步，將環丁基溴更換為氧雜環丁烷-3-基4-甲基苯磺酸酯，得到化合物3-((3-溴-4-氟苯基)硫基)氧雜環丁烷(90%)。 Using 3-bromo-4-fluorothiophenol as a raw material, the first step of Reference Example 74 was to replace cyclobutyl bromide with oxetan-3-yl 4-methylbenzenesulfonate to obtain compound 3 -((3-bromo-4-fluorophenyl) thio) oxetane (90%).
1H NMR(400MHz,d-CDCl3)：δ 7.47(dd,J=2.4,6.4Hz,1H),7.22-7.18(m,1H),7.07(t,J=8.4Hz,1H),5.07(t,J=7.6Hz,1H),4.62(t,J=6.4Hz,2H),4.44-4.37(m,1H). 1 H NMR (400MHz, d -CDCl 3 ): δ 7.47 (dd, J = 2.4,6.4Hz, 1H), 7.22-7.18 (m, 1H), 7.07 (t, J = 8.4Hz, 1H), 5.07 ( t, J = 7.6 Hz, 1H), 4.62 (t, J = 6.4 Hz, 2H), 4.44-4.37 (m, 1H).
以(3-((3-溴-4-氟苯基)硫基)氧雜環丁烷為反應原料，參考實施例1第五步，得到2-溴-4-(環丙基亞硫醯基<亞磺醯>)-1-氟苯(產率73%)。 Using (3-((3-bromo-4-fluorophenyl) thio) oxetane as a reaction raw material, refer to the fifth step of Example 1 to obtain 2-bromo-4- (cyclopropylsulfinylsulfonium <Sulfinylpyrene>)-1-fluorobenzene (73% yield).
MS m/z(ESI)：279.0/281.0(50/50)[M+H]+ MS m / z (ESI): 279.0 / 281.0 (50/50) [M + H] +
以2-溴-4-(環丙基亞硫醯基<亞磺醯>)-1-氟苯為原 料，參考實施例1第六步，得到(3-溴-4-氟苯基)(亞胺基)(氧雜環丁烷-3-基)-I6-硫烷酮(產率75%)。 Using 2-bromo-4- (cyclopropylsulfinylidene <sulfenylpyrene>)-1-fluorobenzene as a raw material, refer to the sixth step of Example 1 to obtain (3-bromo-4-fluorophenyl) ( Imino) (oxetane-3-yl) -I6-sulfanone (75% yield).
MS m/z(ESI)：294.0/296.0(50/50)[M+H]+. MS m / z (ESI): 294.0 / 296.0 (50/50) [M + H] + .
以(3-溴-4-氟苯基)(亞胺基)(氧雜環丁烷-3-基)-I6-硫烷酮為原料，參考實施例10第四步得到4-(5-(環丁磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率39%) Using (3-bromo-4-fluorophenyl) (imino) (oxetan-3-yl) -I6-sulfanone as a raw material, the fourth step of Reference Example 10 was to obtain 4- (5- (Cyclobutanesulfinoimido) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7- Ketone (yield 39%)
MS m/z(ESI)：516.1[M+H]+. MS m / z (ESI): 516.1 [M + H] + .
以4-(5-(環丁磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮與4,4-二氟苯酚為原料，參考實施例10第五步得到4-(2-(2,4-二氟苯氧 基)-5-(氧雜環丁烷-3-磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(收率：21.2%)。 4- (5- (Cyclobutanesulfinoimido) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridine-7-one and 4,4-difluorophenol as raw materials, and the fifth step of Reference Example 10 is to obtain 4- (2- (2,4-difluorophenoxy) -5- (oxetan Alkane-3-sulfonylimido) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (yield: 21.2%).
MS m/z(ESI)：472.1[M+H]+ MS m / z (ESI): 472.1 [M + H] +
1H NMR(400MHz,d4-MeOD)δ 7.99(d,J=4.2Hz,1H),7.85-7.82(m,1H),7.26-7.24(m,2H),7.11-7.01(m,2H),6.93-6.92(m,2H),6.26-6.25(m,1H),4.86-4.78(m,3H),4.70-4.65(m,2H),3.60(s,3H). 1 H NMR (400MHz, d 4-MeOD) δ 7.99 (d, J = 4.2Hz, 1H), 7.85-7.82 (m, 1H), 7.26-7.24 (m, 2H), 7.11-7.01 (m, 2H) , 6.93-6.92 (m, 2H), 6.26-6.25 (m, 1H), 4.86-4.78 (m, 3H), 4.70-4.65 (m, 2H), 3.60 (s, 3H).
以4-(5-(環丁磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(52mg,0.1mmol)為反應原料，參考實施例10第五步，用環丙甲醇(46mg,0.6mmol)取代2,4-二氟苯酚，得到4-(2-(環丙基甲氧基)-5-(氧雜環丁烷-3-磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(4.5mg,10.9%)。 4- (5- (Cyclobutanesulfinoimido) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one (52 mg, 0.1 mmol) was used as a reaction raw material. In the fifth step of Reference Example 10, 2,4-difluorophenol was replaced with cyclopropanol (46 mg, 0.6 mmol) to obtain 4- (2- (Cyclopropylmethoxy) -5- (oxetan-3-sulfimimidino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3 -c] pyridin-7-one (4.5 mg, 10.9%).
MS m/z(ESI)：414.1[M+H]+； MS m / z (ESI): 414.1 [M + H] + ;
1H NMR(400MHz,d4-MeOD)：δ 7.87-7.85(m,2H),7.24-7.18(m,3H),6.15(d,J=2.8Hz,1H),4.82-4.77(m,3H),4.71-4.67(m,2H),3.89(d,J=6.8Hz,2H),3.61(s,3H), 0.82-0.78(m,1H),0.43-0.40(m,2H),0.19-0.17(m,2H)。 1 H NMR (400MHz, d 4-MeOD): δ 7.87-7.85 (m, 2H), 7.24-7.18 (m, 3H), 6.15 (d, J = 2.8Hz, 1H), 4.82-4.77 (m, 3H ), 4.71-4.67 (m, 2H), 3.89 (d, J = 6.8Hz, 2H), 3.61 (s, 3H), 0.82-0.78 (m, 1H), 0.43-0.40 (m, 2H), 0.19- 0.17 (m, 2H).
以4-(5-(環丙磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮與環丙基甲醇為原料，參考實施例5第五步，得到4-(5-(環丙磺亞胺醯基)-2-(環丙基甲氧基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率32.6%)。 4- (5- (Cyclopropanesulfenimido) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one and cyclopropylmethanol are used as raw materials, and the fifth step of Reference Example 5 is to obtain 4- (5- (cyclopropanesulfenimido) -2- (cyclopropylmethoxy) benzene Yl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (32.6% yield).
MS m/z(ESI)：398.1[M+H]+. MS m / z (ESI): 398.1 [M + H] + .
1H NMR(400MHz,MeOD)：δ 7.86(dd,J=11.2Hz,2.4,1H),7.81(d,J=2.4Hz,1H),7.24(t,J=6.8Hz,2H),7.16(d,J=8.8Hz,1H),6.17(d,J=2.8Hz,1H),3.88(d,J=6.8Hz,2H),3.61(s,3H),2.63-2.59(m,1H),1.08-0.85(m,5H),0.45-0.39(m,2H),0.20-0.16(m,2H). 1 H NMR (400MHz, MeOD): δ 7.86 (dd, J = 11.2Hz, 2.4, 1H), 7.81 (d, J = 2.4Hz, 1H), 7.24 (t, J = 6.8Hz, 2H), 7.16 ( d, J = 8.8Hz, 1H), 6.17 (d, J = 2.8Hz, 1H), 3.88 (d, J = 6.8Hz, 2H), 3.61 (s, 3H), 2.63-2.59 (m, 1H), 1.08-0.85 (m, 5H), 0.45-0.39 (m, 2H), 0.20-0.16 (m, 2H).
以4-(5-(環丙磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮與4,4-二氟環己醇為原料，參考實施例5第五步，得到4-(5-(環丙磺亞胺醯基)-2-((4,4-二氟環己基)酮基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率28.0%)。 4- (5- (Cyclopropanesulfenimido) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one and 4,4-difluorocyclohexanol as raw materials. Refer to the fifth step of Example 5, to obtain 4- (5- (cyclopropanesulfinoimido) -2-((4, 4-Difluorocyclohexyl) keto) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (28.0% yield).
MS m/z(ESI)：462.1[M+H]+. MS m / z (ESI): 462.1 [M + H] + .
1H NMR(400MHz,d-DMSO)：δ 12.05(s,1H),7.87(d,J=2.0Hz,1H),7.82(dd,J=8.8Hz,2.4,1H),7.39(d,J=8.8Hz,1H),7.31(s,1H),7.29(t,J=2.4Hz,1H),6.16(t,J=2.4Hz,1H),4.77(s,1H),4.10(s,1H),3.56(s,3H),2.70-2.51(m,2H),1.89-1.70(m,7H),1.12-1.07(m,1H),0.98-0.87(m,3H). 1 H NMR (400MHz, d -DMSO): δ 12.05 (s, 1H), 7.87 (d, J = 2.0Hz, 1H), 7.82 (dd, J = 8.8Hz, 2.4,1H), 7.39 (d, J = 8.8Hz, 1H), 7.31 (s, 1H), 7.29 (t, J = 2.4Hz, 1H), 6.16 (t, J = 2.4Hz, 1H), 4.77 (s, 1H), 4.10 (s, 1H ), 3.56 (s, 3H), 2.70-2.51 (m, 2H), 1.89-1.70 (m, 7H), 1.12-1.07 (m, 1H), 0.98-0.87 (m, 3H).
以3-溴-4-氟苯硫酚(1g,5mmol)為原料，參考實施例 74第一步，將環丁基溴更換為2,2-二甲基噁丙環(0.72g,10mmol)得到化合物1-((3-溴-4-氟苯基)硫基)-2-甲基丙烷-2-醇(1.18g,90%)。 Using 3-bromo-4-fluorothiophenol (1 g, 5 mmol) as the raw material, the first step of Reference Example 74 was to replace the cyclobutyl bromide with 2,2-dimethyloxapropane (0.72 g, 10 mmol). The compound 1-((3-bromo-4-fluorophenyl) thio) -2-methylpropane-2-ol (1.18 g, 90%) was obtained.
MS m/z(ESI)：279.0/281.0(50/50)[M+H]+ MS m / z (ESI): 279.0 / 281.0 (50/50) [M + H] +
以1-((3-溴-4-氟苯基)硫基)-2-甲基丙烷-2-醇為反應原料，參考實施例1第五步，得到1-((3-溴-4-氟苯基)亞硫醯基<亞磺醯>)-2-甲基丙烷-2-醇(產率85%)。 Using 1-((3-bromo-4-fluorophenyl) thio) -2-methylpropane-2-ol as a reaction raw material, refer to the fifth step of Example 1 to obtain 1-((3-bromo-4 -Fluorophenyl) sulfenyl <sulfenimidine>)-2-methylpropane-2-ol (yield 85%).
MS m/z(ESI)：295.0/297.0(50/50)[M+H]+ MS m / z (ESI): 295.0 / 297.0 (50/50) [M + H] +
以1-((3-溴-4-氟苯基)亞硫醯基<亞磺醯>)-2-甲基丙烷-2-醇為原料，參考實施例1第六步，得到(3-溴-4-氟苯基)(2-羥基-2-甲基丙基)(亞胺基)-I6-硫烷酮(產率91%)。 Using 1-((3-bromo-4-fluorophenyl) sulfinyl <sulfenimidine>)-2-methylpropane-2-ol as a raw material, refer to the sixth step of Example 1 to obtain (3- Bromo-4-fluorophenyl) (2-hydroxy-2-methylpropyl) (imino) -I6-sulfanone (91% yield).
MS m/z(ESI)：310.0/312.0(50/50)[M+H]+. MS m / z (ESI): 310.0 / 312.0 (50/50) [M + H] + .
以(3-溴-4-氟苯基)(2-羥基-2-甲基丙基)(亞胺基)-I6-硫烷酮為原料，參考實施例10第四步得到4-(2-氟-5-(2-羥基-2-甲基丙基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率49%) Using (3-bromo-4-fluorophenyl) (2-hydroxy-2-methylpropyl) (imino) -I6-sulfanone as a raw material, the fourth step of Reference Example 10 was to obtain 4- (2 -Fluoro-5- (2-hydroxy-2-methylpropylsulfonylimino) phenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2 , 3-c] pyridine-7-one (49% yield)
MS m/z(ESI)：532.1[M+H]+ MS m / z (ESI): 532.1 [M + H] +
反應管中加入環丙甲胺(76mg,1mmol)，4-(2-氟-5-(2-羥基-2-甲基丙基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(53mg,0.1mmol)和2毫升N-甲基吡咯烷酮。反應管密封之後加熱到100度反應10小時。之後體系冷卻到室溫，乙酸乙酯萃取，合併有機相飽和食鹽水洗滌，乾燥，蒸乾。粗產物液相製備分離 得到4-(2-((環丙基甲基)胺基)-5-(2-羥基-2-甲基丙基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(7.9mg，18.5%)。 Cyclopropylmethylamine (76 mg, 1 mmol), 4- (2-fluoro-5- (2-hydroxy-2-methylpropylsulfimideamido) phenyl) -6-methyl-1 was added to the reaction tube. -Tosylate-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7-one (53 mg, 0.1 mmol) and 2 ml of N-methylpyrrolidone. After the reaction tube was sealed, the reaction was heated to 100 degrees for 10 hours. After the system was cooled to room temperature, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried, and evaporated to dryness. The crude product was prepared by liquid phase separation to obtain 4- (2-((cyclopropylmethyl) amino) -5- (2-hydroxy-2-methylpropylsulfinoimido) phenyl) -6-formaldehyde -1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (7.9 mg, 18.5%).
MS m/z(ESI)：429.1[M+H]+ MS m / z (ESI): 429.1 [M + H] +
1H NMR(400MHz,d4-MeOD)δ 7.65(dd,J=8.8Hz,2.4Hz,1H),7.50(d,J=2.8Hz,1H),7.18(d,J=2.8Hz,1H),7.06(s,1H),6.71(d,J=8.8Hz,1H),5.98(d,J=2.8Hz,1H),3.53(s,3H),3.26-3.21(m,2H),2.90(d,J=6.8Hz,2H),2.02(t,J=7.2Hz,1H),1.29(s,3H),1.09(s,3H),0.29-0.24(m,2H),0.16-0.11(m,2H). 1 H NMR (400MHz, d 4-MeOD) δ 7.65 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.50 (d, J = 2.8Hz, 1H), 7.18 (d, J = 2.8Hz, 1H) , 7.06 (s, 1H), 6.71 (d, J = 8.8Hz, 1H), 5.98 (d, J = 2.8Hz, 1H), 3.53 (s, 3H), 3.26-3.21 (m, 2H), 2.90 ( d, J = 6.8Hz, 2H), 2.02 (t, J = 7.2Hz, 1H), 1.29 (s, 3H), 1.09 (s, 3H), 0.29-0.24 (m, 2H), 0.16-0.11 (m , 2H).
以3-溴-4-氟苯硫酚(1g,5mmol)為原料，參考實施例74第一步，將環丁基溴更換為2-(溴甲基)-1,3-二氧雜環戊烷(1.67g,10mmol)得到化合物2-(((3-溴-4-氟苯基)硫基)甲基)-1,3-二氧雜環戊烷(1.4g,95.6%)。 Using 3-bromo-4-fluorothiophenol (1 g, 5 mmol) as a raw material, the first step of Reference Example 74 was to replace cyclobutyl bromide with 2- (bromomethyl) -1,3-dioxane Pentane (1.67 g, 10 mmol) gave compound 2-(((3-bromo-4-fluorophenyl) thio) methyl) -1,3-dioxolane (1.4 g, 95.6%).
MS m/z(ESI)：293.0/295.0(50/50)[M+H]+. MS m / z (ESI): 293.0 / 295.0 (50/50) [M + H] + .
將2-(((3-溴-4-氟苯基)硫基)甲基)-1,3-二氧雜環戊烷(1.4g,4.8mmol)溶於30毫升甲苯，依次加入胺基甲酸銨(1.46g,19.2mmol)和二乙酸碘苯(4.63g,14.4mmol)。反應於室溫調價下攪拌過夜。旋乾溶劑，殘餘物用水稀釋，乙酸乙酯萃取。合併有機相水洗，飽和食鹽水洗，無水硫酸鈉乾燥。濾去乾燥劑，濾液旋乾，殘餘物使用矽膠管柱層析純化(石油醚：乙酸乙酯=1：1)得到(3-溴-4-氟苯基)(2-羥基-2-甲基丙基)(亞胺基)-I6-硫烷酮(1.16g,75%)。 Dissolve 2-(((3-bromo-4-fluorophenyl) thio) methyl) -1,3-dioxolane (1.4 g, 4.8 mmol) in 30 ml of toluene and add the amine group in sequence Ammonium formate (1.46 g, 19.2 mmol) and iodobenzene diacetate (4.63 g, 14.4 mmol). The reaction was stirred at room temperature for overnight. The solvent was spun off and the residue was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with water, saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was spin-dried. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain (3-bromo-4-fluorophenyl) (2-hydroxy-2-methyl). Propyl) (imino) -I6-sulfanone (1.16 g, 75%).
MS m/z(ESI)：324.0/326(50：50)[M+H]+. MS m / z (ESI): 324.0 / 326 (50:50) [M + H] + .
以(3-溴-4-氟苯基)(2-羥基-2-甲基丙基)(亞胺基)-I6-硫烷酮與中間體Im為原料，參考實施例10第四步得到 4-(5-(S-((1,3-二氧雜環戊烷-2-基)甲基)磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率49%)。 Using (3-bromo-4-fluorophenyl) (2-hydroxy-2-methylpropyl) (imino) -I6-sulfanone and intermediate Im as raw materials, refer to the fourth step of Example 10 to obtain 4- (5- (S-((1,3-dioxolane-2-yl) methyl) sulfonylimino) -2-fluorophenyl) -6-methyl-1-toluene Sulfo-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (49% yield).
MS m/z(ESI)：546.1[M+H]+ MS m / z (ESI): 546.1 [M + H] +
以4-(5-(S-((1,3-二氧雜環戊烷-2-基)甲基)磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮與4,4-二氟苯酚為起始原料，參考實施例10第五步反應，得到4-(5-(S-((1,3-二氧雜環戊烷-2-基)甲基)磺亞胺醯基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(26.9%)。 As 4- (5- (S-((1,3-dioxolane-2-yl) methyl) sulfonylimino) -2-fluorophenyl) -6-methyl-1- Tosyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one and 4,4-difluorophenol were used as starting materials. The fifth step of Reference Example 10 was used to obtain 4- (5- (S-((1,3-dioxolane-2-yl) methyl) sulfonyliminomethyl) -2- (2,4-difluorophenoxy) phenyl ) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (26.9%).
MS m/z(ESI)：502.1[M+H]+ MS m / z (ESI): 502.1 [M + H] +
1H NMR(400MHz,d-DMSO)δ 12.1(br,1H),7.99(d,J=2.0Hz,1H),7.83(dd,J=8.8Hz,2.4Hz,1H),7.54-7.48(m,1H),7.42-7.36(m,2H),7.31(t,J=2.8Hz,1H),7.18-7.14(m,1H),6.93(d,J=8.4Hz,1H),6.30(t,J=2.4Hz,1H),5.22(t,J=4.8Hz,1H),4.45(s,1H),3.81-3.72(m,4H),3.58(s,3H),3.54-3.52(m,2H). 1 H NMR (400MHz, d -DMSO) δ 12.1 (br, 1H), 7.99 (d, J = 2.0Hz, 1H), 7.83 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.54-7.48 (m , 1H), 7.42-7.36 (m, 2H), 7.31 (t, J = 2.8Hz, 1H), 7.18-7.14 (m, 1H), 6.93 (d, J = 8.4Hz, 1H), 6.30 (t, J = 2.4Hz, 1H), 5.22 (t, J = 4.8Hz, 1H), 4.45 (s, 1H), 3.81-3.72 (m, 4H), 3.58 (s, 3H), 3.54-3.52 (m, 2H ).
以4-(5-(環丙磺亞胺醯基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，參考實施例2第一步，用烯丙醯氯代替環丙基磺醯氯，得到N-(環丙基(4-(2,4-二氟苯氧基)-3-(6-甲基-7-羰基-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基)(羰基)-16-硫烷亞基)丙烯醯基醯胺(產率47%)。 4- (5- (Cyclopropanesulfinoimido) -2- (2,4-difluorophenoxy) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [ 2,3-c] pyridine-7-one as a raw material, referring to the first step of Example 2, replacing allylsulfonyl chloride with cyclopropylsulfonyl chloride to obtain N- (cyclopropyl (4- (2,4- Difluorophenoxy) -3- (6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) phenyl) (carbonyl)- 16-sulfanylidene) propenylfluorenamide (47% yield).
MS m/z(ESI)：510.1[M+H]+ MS m / z (ESI): 510.1 [M + H] +
1H NMR(400MHz,d6-DMSO)δ 12.14(br,1H),8.47(s,1H),7.94(d,J=2.4Hz,1H),7.81(dd,J=8.8Hz,2.4Hz,1H),7.45-7.56(m,3H),7.31(t,J=2.4Hz,1H),7.21-7.16(m,1H),6.99(d,J=8.8Hz,1H),6.28(t,J=2.0Hz,1H),6.18(t,J=2.4Hz,1H),5.73(dd,J=8.8,2.4Hz,1H),3.58(s,3H),3.21-3.14(m,1H),1.40-1.03(m,4H). 1 H NMR (400MHz, d 6-DMSO) δ 12.14 (br, 1H), 8.47 (s, 1H), 7.94 (d, J = 2.4Hz, 1H), 7.81 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.45-7.56 (m, 3H), 7.31 (t, J = 2.4Hz, 1H), 7.21-7.16 (m, 1H), 6.99 (d, J = 8.8Hz, 1H), 6.28 (t, J = 2.0Hz, 1H), 6.18 (t, J = 2.4Hz, 1H), 5.73 (dd, J = 8.8, 2.4Hz, 1H), 3.58 (s, 3H), 3.21-3.14 (m, 1H), 1.40 -1.03 (m, 4H).
將實施例63第五步得到的(乙基4-(5-(環丙磺亞胺醯基)-2-((反-4-甲基環己基)胺基)苯基)-6-甲基-7-羰基-1-甲苯磺醯-6,7-二氫-1H-吡咯並[2,3-c]吡啶-2-羧酸酯(67mg,1mmol)溶於2毫升35%乙胺的水溶液和2毫升乙醇中，體系加熱至30度攪拌過夜。旋去溶液，剩餘物使用反相製備得到產物4-(5-(環丙磺亞胺醯基)-2-((反-4-甲基環己基)胺基)苯基)-N-乙基-6-甲基-7-羰基-6,7-二氫-1H-吡咯並[2,3-c]吡啶-2-甲醯胺(4.5mg,9%)。 (Ethyl 4- (5- (cyclopropanesulfenimido) -2-((trans-4-methylcyclohexyl) amino) phenyl) -6-methyl obtained in the fifth step of Example 63 -7-carbonyl-1-toluenesulfonium-6,7-dihydro-1H-pyrrolo [2,3-c] pyridine-2-carboxylic acid ester (67 mg, 1 mmol) dissolved in 2 ml of 35% ethylamine In aqueous solution and 2 ml of ethanol, the system was heated to 30 degrees and stirred overnight. The solution was swirled off, and the residue was prepared by reversed phase to obtain the product 4- (5- (cyclopropanesulfinoimido) -2-((trans-4 -Methylcyclohexyl) amino) phenyl) -N-ethyl-6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo [2,3-c] pyridine-2-methyl Lamine (4.5 mg, 9%).
MS m/z(ESI)：510.3[M-H]+. MS m / z (ESI): 510.3 [MH] + .
1H NMR(400MHz,d4-MeOD)：δ 7.67(dd,J=8.8Hz,2.4Hz,1H),7.53(d,J=2.0Hz,1H),7.14(s,1H),6.78(d,J=8.8Hz,1H),6.62(s,1H),3.59(s,3H),3.25-3.31(m,3H),2.56-2.55(m,1H),1.92-1.88(m,2H),1.62-1.60(m,2H),1.23-1.19(m,3H),1.15-1.09(m,4H),1.01-0.97(m,4H),0.87-0.79(m,4H). 1 H NMR (400MHz, d 4-MeOD): δ 7.67 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.53 (d, J = 2.0Hz, 1H), 7.14 (s, 1H), 6.78 (d , J = 8.8Hz, 1H), 6.62 (s, 1H), 3.59 (s, 3H), 3.25-3.31 (m, 3H), 2.56-2.55 (m, 1H), 1.92-1.88 (m, 2H), 1.62-1.60 (m, 2H), 1.23-1.19 (m, 3H), 1.15-1.09 (m, 4H), 1.01-0.97 (m, 4H), 0.87-0.79 (m, 4H).
將4-(2-(環丙基甲氧基)-5-(S-甲基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(25mg)與三乙胺(8.8mg)溶於二氯甲烷(1.5ml)，冷卻至0-5℃。 4- (2- (Cyclopropylmethoxy) -5- (S-methylsulfonylimino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2 , 3-c] pyridin-7-one (25 mg) and triethylamine (8.8 mg) were dissolved in dichloromethane (1.5 ml) and cooled to 0-5 ° C.
加入丙烯醯氯(6.1mg)，室溫攪拌過夜。減壓濃縮至乾，經製備薄層層析分離得到N-((4-(環丙基甲氧基)-3-(6-甲基-7-羰基-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基)(甲基)(羰基)-16-硫烷亞基)丙烯醯基醯胺(6.5mg，產率24%)。 Add propylene chloride (6.1 mg) and stir at room temperature overnight. Concentrated to dryness under reduced pressure, and separated by preparative thin layer chromatography to obtain N-((4- (cyclopropylmethoxy) -3- (6-methyl-7-carbonyl-6,7-dihydro-1H- Pyrrolop [2,3-c] pyridin-4-yl) phenyl) (methyl) (carbonyl) -16-sulfanylidene) propenamidinium amine (6.5 mg, yield 24%).
MS m/z(ESI)：426.2[M+H]+. MS m / z (ESI): 426.2 [M + H] + .
1H NMR(400MHz,CDCl3)δ11.06(brs,1H),8.04(d,J=2.5Hz,1H),7.95(dd,J=8.8Hz,2.5Hz,1H),7.31(t,J=2.7Hz,1H),7.20(s,1H),7.11(d,J=8.8Hz,1H),6.40(dd,J=17.2Hz,1.9Hz,1H),6.32-6.22(m,2H),5.73(dd,J=10.0Hz,1.9Hz,1H),3.94(d,J=6.8Hz,2H),3.75(s,3H),3.42(s,3H),1.20-1.15(m,1H),0.65-0.48(m,2H),0.29-0.25(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ 11.06 (brs, 1H), 8.04 (d, J = 2.5Hz, 1H), 7.95 (dd, J = 8.8Hz, 2.5Hz, 1H), 7.31 (t, J = 2.7Hz, 1H), 7.20 (s, 1H), 7.11 (d, J = 8.8Hz, 1H), 6.40 (dd, J = 17.2Hz, 1.9Hz, 1H), 6.32-6.22 (m, 2H), 5.73 (dd, J = 10.0Hz, 1.9Hz, 1H), 3.94 (d, J = 6.8Hz, 2H), 3.75 (s, 3H), 3.42 (s, 3H), 1.20-1.15 (m, 1H), 0.65-0.48 (m, 2H), 0.29-0.25 (m, 2H).
以4-(5-(乙基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，參考實施例10第五步，用2,4-二氟苯硫酚取代2,4-二氟苯酚，得到標題化合物4-(2-((2,4-二氟苯基)硫基)-5-(乙基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率18%)。 4- (5- (ethylsulfonylimino) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one as a raw material, in the fifth step of Reference Example 10, replacing 2,4-difluorophenol with 2,4-difluorothiophenol to obtain the title compound 4- (2-((2,4 -Difluorophenyl) thio) -5- (ethylsulfonylimino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine- 7-one (yield 18%).
MS m/z(ESI)：460.1[M+H]+. MS m / z (ESI): 460.1 [M + H] + .
1H NMR(400MHz,DMSO)δ 7.90(d,J=2.1Hz,1H),7.86(dd,J=8.5Hz,2.2Hz,1H),7.70-7.64(m,1H),7.55-7.50(m,1H),7.41(s,1H),7.35(s,1H),7.26(dd,J=9.3Hz,7.1Hz,1H),7.09(d,J=8.5Hz,1H),6.11(s,1H),3.78(q,J=6.8Hz,2H),3.60(s,3H),1.19(t,J=7.3Hz,3H). 1 H NMR (400MHz, DMSO) δ 7.90 (d, J = 2.1Hz, 1H), 7.86 (dd, J = 8.5Hz, 2.2Hz, 1H), 7.70-7.64 (m, 1H), 7.55-7.50 (m , 1H), 7.41 (s, 1H), 7.35 (s, 1H), 7.26 (dd, J = 9.3Hz, 7.1Hz, 1H), 7.09 (d, J = 8.5Hz, 1H), 6.11 (s, 1H ), 3.78 (q, J = 6.8Hz, 2H), 3.60 (s, 3H), 1.19 (t, J = 7.3Hz, 3H).
以4-(2-氟-5-(S-甲基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為反應原料，參考實施例10第五步，用4-甲基環己醇(順反混合物)取代2,4-二氟苯酚，得到6-甲基-4-(2-((順式/反式-4-甲基環己基)酮基)-5-(S-甲基磺亞胺醯基)苯基)-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率22%)和6-甲基-4-(2-((反式/順式-4-甲基環己基)酮基)-5-(S-甲基磺亞胺醯基)苯基)-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(30%)。 With 4- (2-fluoro-5- (S-methylsulfonylimino) phenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2, 3-c] pyridine-7-one as a reaction raw material. In the fifth step of Reference Example 10, 4-methylcyclohexanol (cis-trans mixture) was used to replace 2,4-difluorophenol to obtain 6-methyl-4. -(2-((cis / trans-4-methylcyclohexyl) keto) -5- (S-methylsulfonylimino) phenyl) -1,6-dihydro-7H-pyrrole Benzo [2,3-c] pyridine-7-one (22% yield) and 6-methyl-4- (2-((trans / cis-4-methylcyclohexyl) keto) -5 -(S-methylsulfonylimino) phenyl) -1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (30%).
94-順式/反式Cis：MS m/z(ESI)：414.2[M+H]+. 94-cis / trans Cis: MS m / z (ESI): 414.2 [M + H] + .
1H NMR(400MHz,DMSO)δ 7.95(dd,J=4.6Hz,2.2Hz,2H),7.52-7.45(m,1H),7.27(s,1H),7.24(t,J=2.7Hz,1H),6.12-6.07(m,1H).4.55-4.40(m,1H),3.79(s,3H),3.51(s,3H),2.00-1.90(m,2H),1.62-1.60(m,2H),1.28-1.22(m,1H),1.22-1.17(m,2H),1.07-1.01(m,2H),0.80(d,J=6.5Hz,3H). 1 H NMR (400MHz, DMSO) δ 7.95 (dd, J = 4.6Hz, 2.2Hz, 2H), 7.52-7.45 (m, 1H), 7.27 (s, 1H), 7.24 (t, J = 2.7Hz, 1H ), 6.12-6.07 (m, 1H). 4.55-4.40 (m, 1H), 3.79 (s, 3H), 3.51 (s, 3H), 2.0-1.90 (m, 2H), 1.62-1.60 (m, 2H) ), 1.28-1.22 (m, 1H), 1.22-1.17 (m, 2H), 1.07-1.01 (m, 2H), 0.80 (d, J = 6.5Hz, 3H).
94-反式/順式：MS m/z(ESI)：414.2[M+H]+. 94-trans / cis: MS m / z (ESI): 414.2 [M + H] + .
1H NMR(400MHz,DMSO)δ 8.08(d,J=2.6Hz,1H),8.04(dd,J=8.9Hz,2.7Hz,1H),7.53(d,J=9.1Hz,1H),7.37(s,1H),7.33(t,J=2.8Hz,1H),6.31-6.15(m,1H),4.87-4.83(m,1H),3.91(s,3H),3.59(s,3H),1.92-1.73(m,2H),1.55(t,J=12.1Hz,2H),1.41-1.26(m,2H),1.26-1.22(m,1H),1.01-0.81(m,2H),0.70(d,J=6.3Hz,3H). 1 H NMR (400MHz, DMSO) δ 8.08 (d, J = 2.6Hz, 1H), 8.04 (dd, J = 8.9Hz, 2.7Hz, 1H), 7.53 (d, J = 9.1Hz, 1H), 7.37 ( s, 1H), 7.33 (t, J = 2.8 Hz, 1H), 6.31-6.15 (m, 1H), 4.87-4.83 (m, 1H), 3.91 (s, 3H), 3.59 (s, 3H), 1.92 -1.73 (m, 2H), 1.55 (t, J = 12.1Hz, 2H), 1.41-1.26 (m, 2H), 1.26-1.22 (m, 1H), 1.01-0.81 (m, 2H), 0.70 (d , J = 6.3Hz, 3H).
以4-(5-(環戊磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，參考實施例10第五步，用4,4-二氟環己醇取代2,4-二氟苯酚，得到標題化合物4-(5-(環戊磺亞胺醯基)-2-(環丙基甲氧基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率38%)。 4- (5- (Cyclopentanesulfenimido) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one as a raw material. In the fifth step of Reference Example 10, 2,4-difluorophenol was replaced with 4,4-difluorocyclohexanol to obtain the title compound 4- (5- (cyclopentanesulfinyl Aminomethyl) -2- (cyclopropylmethoxy) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7-one (yield 38%).
MS m/z(ESI)：490.2[M+H]+. MS m / z (ESI): 490.2 [M + H] + .
1H NMR(400MHz,MeOD)δ 8.06(dd,J=8.9Hz,2.6Hz,1H),8.00(d,J=2.6Hz,1H),7.51(d,J=9.1Hz,1H),7.28(d,J=2.8Hz,1H),7.25(s,1H),6.13(d,J=2.8Hz,1H),4.50-4.29(m,1H),3.63(s,3H),2.34-2.14(m,2H),1.99-1.51(m,15H). 1 H NMR (400MHz, MeOD) δ 8.06 (dd, J = 8.9Hz, 2.6Hz, 1H), 8.00 (d, J = 2.6Hz, 1H), 7.51 (d, J = 9.1Hz, 1H), 7.28 ( d, J = 2.8Hz, 1H), 7.25 (s, 1H), 6.13 (d, J = 2.8Hz, 1H), 4.50-4.29 (m, 1H), 3.63 (s, 3H), 2.34-2.14 (m , 2H), 1.99-1.51 (m, 15H).
以4-(5-(環戊磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮與2,4-二氟苯酚為原料，參考實施例10第五步，得到標題化合物4-(5-(環戊磺亞胺醯基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率33%)。 4- (5- (Cyclopentanesulfenimido) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one and 2,4-difluorophenol as raw materials, the fifth step of Reference Example 10, to obtain the title compound 4- (5- (cyclopentylsulfenimido) -2- (2,4 -Difluorophenoxy) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7-one (33% yield).
MS m/z(ESI)：484.1[M+H]+. MS m / z (ESI): 484.1 [M + H] + .
1H NMR(400MHz,MeOD)δ 8.12(d,J=2.6Hz,1H),8.00(dd,J=8.9Hz,2.6Hz,1H),7.33(s,1H),7.28(d,J=2.9Hz,1H),7.21(td,J=9.1,5.4Hz,1H),7.16-7.10(m,1H),7.09(d,J=7.9Hz,1H),7.00-6.92(m,1H),6.25(d,J=2.9Hz,1H),4.50-4.29(m,1H),3.62(s,3H),2.35-2.13(m,2H),1.99-1.80(m,2H),1.80-1.55(m,4H). 1 H NMR (400MHz, MeOD) δ 8.12 (d, J = 2.6Hz, 1H), 8.00 (dd, J = 8.9Hz, 2.6Hz, 1H), 7.33 (s, 1H), 7.28 (d, J = 2.9 Hz, 1H), 7.21 (td, J = 9.1, 5.4 Hz, 1H), 7.16-7.10 (m, 1H), 7.09 (d, J = 7.9 Hz, 1H), 7.00-6.92 (m, 1H), 6.25 (d, J = 2.9Hz, 1H), 4.50-4.29 (m, 1H), 3.62 (s, 3H), 2.35-2.13 (m, 2H), 1.99-1.80 (m, 2H), 1.80-1.55 (m , 4H).
以2-(4-氟-3-(6-甲基-7-羰基-1-甲苯磺醯-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基磺亞胺醯基)-2-甲基丙腈與2,4-二氟苯酚為原料，參考實施例10第五步，得到2-(4-(2,4-二氟苯氧基)-3-(6-甲基-7-羰基-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基磺亞胺醯基)-2-甲基丙腈(產率67%)。 2- (4-fluoro-3- (6-methyl-7-carbonyl-1-toluenesulfonium-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) Phenylsulfenimido) -2-methylpropionitrile and 2,4-difluorophenol as raw materials. Refer to the fifth step of Example 10 to obtain 2- (4- (2,4-difluorophenoxy) ) -3- (6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) phenylsulfimimidino) -2-methyl Propionitrile (67% yield).
MS m/z(ESI)：483.1[M+H]+. MS m / z (ESI): 483.1 [M + H] + .
1H NMR(400MHz,MeOD)δ 8.11(d,J=2.4Hz,1H),7.92(dd,J=8.8Hz,2.4Hz,1H),7.28(s,1H),7.25(d,J=2.9Hz,1H),7.19-7.12(m,1H),7.11-7.03(m,1H),6.97(d,J=8.7Hz,1H),6.90(t,J=7.5Hz,1H),6.34(d,J=2.9Hz,1H),3.60(s,3H),1.61(s,3H),1.59(s,3H). 1 H NMR (400MHz, MeOD) δ 8.11 (d, J = 2.4Hz, 1H), 7.92 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.28 (s, 1H), 7.25 (d, J = 2.9 Hz, 1H), 7.19-7.12 (m, 1H), 7.11-7.03 (m, 1H), 6.97 (d, J = 8.7Hz, 1H), 6.90 (t, J = 7.5Hz, 1H), 6.34 (d , J = 2.9Hz, 1H), 3.60 (s, 3H), 1.61 (s, 3H), 1.59 (s, 3H).
以2-(4-氟-3-(6-甲基-7-羰基-1-甲苯磺醯-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基磺亞胺醯基)-2-甲基丙腈與2-氟-4-溴苯酚為原料，參考實施例10第五步，得到標題化合物2-(4-(4-溴-2-氟苯氧基)-3-(6-甲基-7-羰基-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基磺亞胺醯基)-2-甲基丙腈(產率55%)。 2- (4-fluoro-3- (6-methyl-7-carbonyl-1-toluenesulfonium-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) Phenylsulfenimido) -2-methylpropionitrile and 2-fluoro-4-bromophenol as raw materials, refer to the fifth step of Example 10 to obtain the title compound 2- (4- (4-bromo-2- Fluorophenoxy) -3- (6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) phenylsulfimidinyl) 2-methylpropionitrile (55% yield).
MS m/z(ESI)：543.0/545.0(50/50)[M+H]+. MS m / z (ESI): 543.0 / 545.0 (50/50) [M + H] + .
1H NMR(400MHz,MeOD)δ 8.23(d,J=2.5Hz,1H),8.06(dd,J=8.8,2.5Hz,1H),7.54-7.49(m,2H),7.38(s,1H),7.36(d,J=2.9Hz,2H),7.19-7.11(m,1H),6.44(d,J=2.9Hz,1H),3.71(s,3H),1.73(s,3H),1.71(s,3H).. 1 H NMR (400MHz, MeOD) δ 8.23 (d, J = 2.5Hz, 1H), 8.06 (dd, J = 8.8, 2.5Hz, 1H), 7.54-7.49 (m, 2H), 7.38 (s, 1H) , 7.36 (d, J = 2.9Hz, 2H), 7.19-7.11 (m, 1H), 6.44 (d, J = 2.9Hz, 1H), 3.71 (s, 3H), 1.73 (s, 3H), 1.71 ( s, 3H) ..
以2-(4-氟-3-(6-甲基-7-羰基-1-甲苯磺醯-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基磺亞胺醯基)-2-甲基丙腈為原料，參考實施例10第五步，用2-氟-4-氯苯酚取代2,4-二氟苯酚，得到標題化合物2-(4-(4-氯-2-氟苯氧基)-3-(6-甲基-7-羰基-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基磺亞胺醯基)-2-甲基丙腈(產率58%)。 2- (4-fluoro-3- (6-methyl-7-carbonyl-1-toluenesulfonium-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) Phenylsulfenimido) -2-methylpropionitrile was used as a raw material. In the fifth step of Reference Example 10, 2,4-difluorophenol was replaced with 2-fluoro-4-chlorophenol to give the title compound 2- ( 4- (4-chloro-2-fluorophenoxy) -3- (6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl ) Phenylsulfimimidino) -2-methylpropionitrile (yield 58%).
MS m/z(ESI)：499.1[M+H]+. MS m / z (ESI): 499.1 [M + H] + .
1HNMR(400MHz,MeOD)δ 8.12(d,J=2.4Hz,1H),7.94(dd,J=8.8Hz,2.5Hz,1H),7.31-7.26(m,2H),7.25(d,J=2.9Hz,1H),7.14-7.06(m,2H),7.04(d,J=8.1Hz,1H),6.33(d,J=2.9Hz,1H),3.60(s,3H),1.62(s,3H)1.60(s,3H). 1 HNMR (400MHz, MeOD) δ 8.12 (d, J = 2.4Hz, 1H), 7.94 (dd, J = 8.8Hz, 2.5Hz, 1H), 7.31-7.26 (m, 2H), 7.25 (d, J = 2.9Hz, 1H), 7.14-7.06 (m, 2H), 7.04 (d, J = 8.1Hz, 1H), 6.33 (d, J = 2.9Hz, 1H), 3.60 (s, 3H), 1.62 (s, 3H) 1.60 (s, 3H).
以2-(4-氟-3-(6-甲基-7-羰基-1-甲苯磺醯-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基磺亞胺醯基)-2-甲基丙腈為原料，參考實施例23第一步，用6-氮雜螺[2.5]辛烷取反-4-甲基環己烷胺，得到標題化合物2-甲基-2-(3-(6-甲基-7-羰基-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-4-(6-氮雜螺[2.5]辛烷-6-基)苯基磺亞胺醯基)丙腈(產率40%)。 2- (4-fluoro-3- (6-methyl-7-carbonyl-1-toluenesulfonium-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) Phenylsulfenimido) -2-methylpropionitrile was used as a raw material. In the first step of Reference Example 23, 6-azaspiro [2.5] octane was used to obtain trans-4-methylcyclohexaneamine to obtain The title compound 2-methyl-2- (3- (6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) -4- ( 6-Azaspiro [2.5] octane-6-yl) phenylsulfimimidino) propionitrile (40% yield).
MS m/z(ESI)：464.2[M+H]+. MS m / z (ESI): 464.2 [M + H] + .
1H NMR(400MHz,MeOD)δ 7.96(dd,J=3.4Hz,2.3Hz,2H),7.43(s,1H),7.37(d,J=2.8Hz,1H),7.33(d,J=8.5Hz,1H),6.36(d,J=2.8Hz,1H),3.73(s,3H),3.20-3.05(m,4H),1.71(s,3H),1.69(s,3H),1.28-1.14(m,4H),0.29-0.25(m,4H). 1 H NMR (400MHz, MeOD) δ 7.96 (dd, J = 3.4Hz, 2.3Hz, 2H), 7.43 (s, 1H), 7.37 (d, J = 2.8Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 6.36 (d, J = 2.8Hz, 1H), 3.73 (s, 3H), 3.20-3.05 (m, 4H), 1.71 (s, 3H), 1.69 (s, 3H), 1.28-1.14 (m, 4H), 0.29-0.25 (m, 4H).
以4-(5-(環戊磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯 磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，參考實施例23第一步，用環丙甲胺替代反-4-甲基環己烷胺，得到標題化合物4-(5-(環戊磺亞胺醯基)-2-((環丙基甲基)胺基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(收率29.6%)。 4- (5- (Cyclopentanesulfenimido) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one as a raw material. In the first step of Reference Example 23, cyclopropylmethylamine was used in place of trans-4-methylcyclohexaneamine to obtain the title compound 4- (5- (cyclopentanesulfenimidine) ) -2-((cyclopropylmethyl) amino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7-one (received Rate 29.6%).
MS m/z(ESI)：425.2[M+H]+. MS m / z (ESI): 425.2 [M + H] + .
1H NMR(400MHz,MeOD)δ 7.69(dd,J=9.1Hz,2.6Hz,1H),7.50(d,J=2.5Hz,1H),7.17(d,J=2.8Hz,1H),7.06(s,1H),6.86(d,J=9.1Hz,1H),5.92(d,J=2.8Hz,1H),4.21-4.02(m,1H),3.50(s,3H),2.94(d,J=6.7Hz,2H),2.09-1.96(m,2H),1.88-1.71(m,2H),1.60-1.44(m,4H),0.88-0.81(m,1H),0.35-0.17(m,2H),0.07-0.09(m,2H). 1 H NMR (400MHz, MeOD) δ 7.69 (dd, J = 9.1Hz, 2.6Hz, 1H), 7.50 (d, J = 2.5Hz, 1H), 7.17 (d, J = 2.8Hz, 1H), 7.06 ( s, 1H), 6.86 (d, J = 9.1Hz, 1H), 5.92 (d, J = 2.8Hz, 1H), 4.21-4.02 (m, 1H), 3.50 (s, 3H), 2.94 (d, J = 6.7Hz, 2H), 2.09-1.96 (m, 2H), 1.88-1.71 (m, 2H), 1.60-1.44 (m, 4H), 0.88-0.81 (m, 1H), 0.35-0.17 (m, 2H ), 0.07-0.09 (m, 2H).
以4-(5-(乙基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，參考實施例10第五步，用鄰氟苯酚替代2，4-二氟苯酚，得4-(5-(乙基磺亞胺醯基)-2-(2-氟苯氧基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率14%)。 4- (5- (ethylsulfonylimino) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one as a raw material. In the fifth step of Reference Example 10, o-fluorophenol was used instead of 2,4-difluorophenol to obtain 4- (5- (ethylsulfonylimido) -2- ( 2-fluorophenoxy) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (14% yield).
MS m/z(ESI)：426.1[M+H]+. MS m / z (ESI): 426.1 [M + H] + .
1H NMR(400MHz,MeOD)δ 7.98(d,J=2.4Hz,1H),7.80(dd,J=8.7Hz,2.4Hz,1H),7.28(s,1H),7.25(d,J=2.9Hz,1H),7.16-7.00(m,4H),6.92(d,J=8.7Hz,1H),6.29(d,J=2.9Hz,1H),3.60(s,3H),3.17(d,J=8.0Hz,1H),1.15(d,J=7.4Hz,3H). 1 H NMR (400MHz, MeOD) δ 7.98 (d, J = 2.4Hz, 1H), 7.80 (dd, J = 8.7Hz, 2.4Hz, 1H), 7.28 (s, 1H), 7.25 (d, J = 2.9 Hz, 1H), 7.16-7.00 (m, 4H), 6.92 (d, J = 8.7 Hz, 1H), 6.29 (d, J = 2.9 Hz, 1H), 3.60 (s, 3H), 3.17 (d, J = 8.0Hz, 1H), 1.15 (d, J = 7.4Hz, 3H).
以4-(5-(乙基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，參考實施例10第五步，用第三丁基苯酚替代2，4-二氟苯酚，得4-(2-(4-(第三-丁基)苯氧基)-5-(乙基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率25%)。 4- (5- (ethylsulfonylimino) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one as a raw material, in the fifth step of Reference Example 10, replacing the 2,4-difluorophenol with a third butylphenol to obtain 4- (2- (4- (third-butyl) benzene (Oxy) -5- (ethylsulfonylimino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7-one (yield 25%).
MS m/z(ESI)：464.2[M+H]+. MS m / z (ESI): 464.2 [M + H] + .
1H NMR(400MHz,MeOD)δ 8.08(d,J=2.6Hz,1H),7.93(dd,J=8.9Hz,2.6Hz,1H),7.41-7.34(m,2H),7.31(s,1H),7.27(d,J=2.9Hz,1H),7.10(d,J=8.9Hz,1H),6.95-6.88(m,2H),6.27(d,J=2.9Hz,1H),3.84(q,J=7.3Hz,2H),3.60(s,3H),1.31(t,J=7.3Hz,3H),1.22(s,9H). 1 H NMR (400MHz, MeOD) δ 8.08 (d, J = 2.6Hz, 1H), 7.93 (dd, J = 8.9Hz, 2.6Hz, 1H), 7.41-7.34 (m, 2H), 7.31 (s, 1H ), 7.27 (d, J = 2.9Hz, 1H), 7.10 (d, J = 8.9Hz, 1H), 6.95-6.88 (m, 2H), 6.27 (d, J = 2.9Hz, 1H), 3.84 (q , J = 7.3Hz, 2H), 3.60 (s, 3H), 1.31 (t, J = 7.3Hz, 3H), 1.22 (s, 9H).
以2-溴-4-(溴甲基)-1-(2,4-二氟苯氧基)苯與甲硫醇鈉為起始原料，參考實施例1第四到第七步反應條件，得到4-(2-(2,4-二氟苯氧基)-5-((甲基磺亞胺醯基甲基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(4步總收率：10.5%)。 Using 2-bromo-4- (bromomethyl) -1- (2,4-difluorophenoxy) benzene and sodium methyl mercaptan as starting materials, referring to the reaction conditions in the fourth to seventh steps of Example 1, 4- (2- (2,4-difluorophenoxy) -5-((methylsulfonyliminomethyl) phenyl) -6-methyl-1,6-dihydro-7H- Pyrrolop [2,3-c] pyridin-7-one (total yield over 4 steps: 10.5%).
MS m/z(ESI)：444.0[M+H]+. MS m / z (ESI): 444.0 [M + H] + .
1H NMR(400MHz,MeOD)δ 7.61(d,J=2.3Hz,1H),7.43(dd,J=8.5Hz,2.3Hz,1H),7.25(d,J=3.2Hz,2H),7.05-6.96(m,2H),6.91(d,J=8.5Hz,1H),6.82(dd,J=2.8Hz,1.6Hz,1H),6.30(d,J=2.9Hz,1H),5.11-5.08(m,2H),3.59(s,3H),3.51(s,3H). 1 H NMR (400MHz, MeOD) δ 7.61 (d, J = 2.3Hz, 1H), 7.43 (dd, J = 8.5Hz, 2.3Hz, 1H), 7.25 (d, J = 3.2Hz, 2H), 7.05- 6.96 (m, 2H), 6.91 (d, J = 8.5Hz, 1H), 6.82 (dd, J = 2.8Hz, 1.6Hz, 1H), 6.30 (d, J = 2.9Hz, 1H), 5.11-5.08 ( m, 2H), 3.59 (s, 3H), 3.51 (s, 3H).
4-(2-(2,4-二氟苯氧基)-5-((甲基磺亞胺醯基甲基)苯 基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(50mg,0.13mmol)溶於二氯甲烷(3mL)中，加入溴乙腈(43mg,0.4mmol)和4-二甲胺基吡啶(50mg,0.4mmol)。反應在20℃下攪拌12小時，濃縮，HPLC分離得到N-((4-(2,4-二氟苯氧基)-3-(6-甲基-7-羰基-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯甲基)(甲基)(羰基)-λ-6-硫烷亞基)氰基醯胺(20mg,白色固體，收率38%)。 4- (2- (2,4-difluorophenoxy) -5-((methylsulfonyliminomethyl) phenyl) -6-methyl-1,6-dihydro-7H-pyrrole Benzo [2,3-c] pyridine-7-one (50 mg, 0.13 mmol) was dissolved in dichloromethane (3 mL), and bromoacetonitrile (43 mg, 0.4 mmol) and 4-dimethylaminopyridine (50 mg, 0.4 The reaction was stirred at 20 ° C for 12 hours, concentrated, and separated by HPLC to obtain N-((4- (2,4-difluorophenoxy) -3- (6-methyl-7-carbonyl-6,7 -Dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) benzyl) (methyl) (carbonyl) -λ- 6 -sulfanylidene) cyanoamidamine (20mg, white Solid, yield 38%).
MS m/z(ESI)：469.0[M+H]+. MS m / z (ESI): 469.0 [M + H] + .
1H NMR(400MHz,MeOD)δ 7.72(d,J=2.2Hz,1H),7.52(dd,J=8.5Hz,2.3Hz,1H),7.35(d,J=3.3Hz,2H),7.12-6.99(m,3H),6.87(s,1H),6.45(d,J=2.9Hz,1H),5.00-4.97(m,2H),3.70(s,3H),3.37(s,3H). 1 H NMR (400MHz, MeOD) δ 7.72 (d, J = 2.2Hz, 1H), 7.52 (dd, J = 8.5Hz, 2.3Hz, 1H), 7.35 (d, J = 3.3Hz, 2H), 7.12 6.99 (m, 3H), 6.87 (s, 1H), 6.45 (d, J = 2.9Hz, 1H), 5.00-4.97 (m, 2H), 3.70 (s, 3H), 3.37 (s, 3H).
2-溴-4-(溴甲基)-1-(2,4-二氟苯氧基)苯(100mg, 0.26mmol)溶於1-甲基-2吡咯烷酮(2mL)中，加入氫化鈉(28mg,0.6mmol)反應在20℃下攪拌30分鐘，然後乙基(亞胺基)(甲基)-λ-6-硫烷酮(70mg,0.6mmol)加入到上述反應液中，室溫下攪拌12小時。反應液用水淬滅，用乙酸乙酯萃取，乾燥、濃縮，管柱分離得到((3-溴-4-(2,4-二氟苯氧基)苯甲基)亞胺基)(乙基)(甲基)-λ-6-硫烷酮(80mg,白色固體，收率75%)。 2-bromo-4- (bromomethyl) -1- (2,4-difluorophenoxy) benzene (100 mg, 0.26 mmol) was dissolved in 1-methyl-2 pyrrolidone (2 mL), and sodium hydride ( (28 mg, 0.6 mmol) was stirred at 20 ° C for 30 minutes, and then ethyl (imino) (methyl) -λ- 6 -sulfanone (70 mg, 0.6 mmol) was added to the reaction solution at room temperature. Stir for 12 hours. The reaction solution was quenched with water, extracted with ethyl acetate, dried, concentrated, and separated by a column to obtain ((3-bromo-4- (2,4-difluorophenoxy) benzyl) imino) (ethyl ) (Methyl) -λ- 6 -sulfanone (80 mg, white solid, yield 75%).
MS m/z(ESI)：404.0/406.0(50/50)M+H]+. MS m / z (ESI): 404.0 / 406.0 (50/50) M + H] + .
以((3-溴-4-(2,4-二氟苯氧基)苯甲基)亞胺基)(乙基)(甲基)-λ-6-硫烷酮與中間體Im為原料，參考實施例4第四步得4-(2-(2,4-二氟苯氧基)-5-(((乙基(甲基)(羰基)-λ-6-硫烷亞基)胺基)甲基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率40%)。 ((3-Bromo-4- (2,4-difluorophenoxy) benzyl) imino) (ethyl) (methyl) -λ- 6 -sulfanone and intermediate Im as raw materials In the fourth step of Reference Example 4, 4- (2- (2,4-difluorophenoxy) -5-(((ethyl (methyl) (carbonyl) -λ- 6 -sulfanylidene) Amine) methyl) phenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7-one (yield 40%) .
MS m/z(ESI)：626.2[M+H]+. MS m / z (ESI): 626.2 [M + H] + .
以4-(2-(2,4-二氟苯氧基)-5-(((乙基(甲基)(羰基)-λ-6-硫烷亞基)胺基)甲基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，參考實施例1第八步得4-(2-(2,4-二氟苯氧基)-5-(((乙基(甲基)(羰基)-λ-6-硫烷亞基)胺基)甲基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率40%)。 4- (2- (2,4-difluorophenoxy) -5-(((ethyl (methyl) (carbonyl) -λ- 6 -sulfanylidene) amino) methyl) phenyl ) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one as a raw material, and the fourth step of Reference Example 1 is to obtain 4- ( 2- (2,4-difluorophenoxy) -5-(((ethyl (methyl) (carbonyl) -λ- 6 -sulfanylidene) amino) methyl) phenyl) -6- Methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (40% yield).
MS m/z(ESI)：472.1[M+H]+. MS m / z (ESI): 472.1 [M + H] + .
1H NMR(400MHz,MeOD)δ 7.50(d,J=2.2Hz,1H),7.34(dd,J=8.4Hz,2.2Hz,1H),7.25(d,J=2.8Hz,1H),7.20(s,1H),7.00-6.81(m,3H),6.79-6.72(m,1H),6.27(d,J=2.8Hz,1H),4.49(s,2H),3.92(q,J=7.5Hz,2H),3.68(s,3H),3.59(s,3H),1.44(t,J=7.3Hz,3H). 1 H NMR (400MHz, MeOD) δ 7.50 (d, J = 2.2Hz, 1H), 7.34 (dd, J = 8.4Hz, 2.2Hz, 1H), 7.25 (d, J = 2.8Hz, 1H), 7.20 ( s, 1H), 7.00-6.81 (m, 3H), 6.79-6.72 (m, 1H), 6.27 (d, J = 2.8Hz, 1H), 4.49 (s, 2H), 3.92 (q, J = 7.5Hz , 2H), 3.68 (s, 3H), 3.59 (s, 3H), 1.44 (t, J = 7.3Hz, 3H).
以4-(5-(環丙磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，參考實施例10第五步得4-(2-(4-溴-2-氟苯氧基)-5-(環丙磺亞胺醯 基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率20%)。 4- (5- (Cyclopropanesulfenimido) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one is used as the raw material, and the fifth step of Reference Example 10 is to obtain 4- (2- (4-bromo-2-fluorophenoxy) -5- (cyclopropaneiminofluorenyl) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (20% yield).
MS m/z(ESI)：516.0/518.0(50/50)[M+H]+. MS m / z (ESI): 516.0 / 518.0 (50/50) [M + H] + .
1H NMR(400MHz,MeOD)δ 8.00(d,J=2.4Hz,1H),7.84(dd,J=8.7Hz,2.4Hz,1H),7.38(dd,J=10.3Hz,2.3Hz,1H),7.28-7.19(m,3H),7.02-6.92(m,2H),6.27(d,J=2.9Hz,1H),3.60(s,3H),2.69-2.60(m,1H),1.25-1.17(m,1H),1.08-1.03(m,2H),0.94-0.88(m,1H). 1 H NMR (400MHz, MeOD) δ 8.00 (d, J = 2.4Hz, 1H), 7.84 (dd, J = 8.7Hz, 2.4Hz, 1H), 7.38 (dd, J = 10.3Hz, 2.3Hz, 1H) , 7.28-7.19 (m, 3H), 7.02-6.92 (m, 2H), 6.27 (d, J = 2.9Hz, 1H), 3.60 (s, 3H), 2.69-2.60 (m, 1H), 1.25-1.17 (m, 1H), 1.08-1.03 (m, 2H), 0.94-0.88 (m, 1H).
以4-(5-(乙基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，參考實施例10第五步得4-(2-(4-溴-2-氟苯氧基)-5-(乙基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率26%)。 4- (5- (ethylsulfonylimino) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one is used as the raw material. In the fifth step of Reference Example 10, 4- (2- (4-bromo-2-fluorophenoxy) -5- (ethylsulfonylimino) phenyl) is obtained. -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (26% yield).
MS m/z(ESI)：504.0/506.0(50/50)[M+H]+. MS m / z (ESI): 504.0 / 506.0 (50/50) [M + H] + .
1H NMR(400MHz,MeOD)δ 7.99(d,J=2.4Hz,1H),7.84(dd,J=8.7Hz,2.4Hz,1H),7.37(dd,J=10.3Hz,2.3Hz,1H),7.27-7.19(m,3H),7.03-6.93(m,2H),6.25(d,J=2.9Hz,1H),3.59(s,3H),3.19(q,J=7.2Hz,2H),1.17(t,J= 7.4Hz,3H). 1 H NMR (400MHz, MeOD) δ 7.99 (d, J = 2.4Hz, 1H), 7.84 (dd, J = 8.7Hz, 2.4Hz, 1H), 7.37 (dd, J = 10.3Hz, 2.3Hz, 1H) , 7.27-7.19 (m, 3H), 7.03-6.93 (m, 2H), 6.25 (d, J = 2.9Hz, 1H), 3.59 (s, 3H), 3.19 (q, J = 7.2Hz, 2H), 1.17 (t, J = 7.4Hz, 3H).
以4-(5-(乙基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，參考實施例10第五步得到4-(2-(4-氯-2-氟苯氧基)-5-(乙基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(收率38%)。 4- (5- (ethylsulfonylimino) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one as a raw material, and the fifth step of Reference Example 10 is to obtain 4- (2- (4-chloro-2-fluorophenoxy) -5- (ethylsulfonylimino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (38% yield).
MS m/z(ESI)：460.0[M+H]+. MS m / z (ESI): 460.0 [M + H] + .
1H NMR(400MHz,CD3Cl)：δ 10.92(br,1H),8.13(d,J=2H，1H),7.88(dd,J=8.8Hz,2.4Hz,1H),7.29(s,1H),7.23-7.18(m,2H),7.12-7.05(m,1H),6.99(t,J=8.4Hz,1H),6.92(d,J=8.4Hz,1H),6.37(s,1H),3.72(s,3H),3.28(q,J=7.2Hz,2H),1.33(t,J=7.2Hz,3H). 1 H NMR (400MHz, CD3Cl): δ 10.92 (br, 1H), 8.13 (d, J = 2H, 1H), 7.88 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.29 (s, 1H), 7.23-7.18 (m, 2H), 7.12-7.05 (m, 1H), 6.99 (t, J = 8.4Hz, 1H), 6.92 (d, J = 8.4Hz, 1H), 6.37 (s, 1H), 3.72 (s, 3H), 3.28 (q, J = 7.2Hz, 2H), 1.33 (t, J = 7.2Hz, 3H).
以4-(5-(環丙磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，參考實施例10第五步，得到4-(5-(環丙磺亞胺醯基)-2-(((1s,4s)-4-羥基環己基)酮基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(白色固體，產率15%)。 4- (5- (Cyclopropanesulfenimido) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one as a raw material, and referring to the fifth step of Example 10, 4- (5- (cyclopropanesulfenimidoamido) -2-(((1s, 4s) -4-hydroxycyclohexyl)) Keto) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (white solid, 15% yield).
MS m/z(ESI)：442.2[M+H]+. MS m / z (ESI): 442.2 [M + H] + .
1H NMR(400MHz,MeOD)δ 8.04-7.94(m,2H),7.39(d,J=8.9Hz,1H),7.29-7.22(m,2H),6.16(d,J=2.9Hz,1H),3.62(s,3H),3.58-3.51(m,1H),3.32-3.29(m,1H),2.68-2.60(m,1H),1.90-1.82(m,2H),1.66-1.45(m,5H),1.42-1.37(m,1H),1.35-1.25(m,2H),1.21-1.12(m,2H). 1 H NMR (400MHz, MeOD) δ 8.04-7.94 (m, 2H), 7.39 (d, J = 8.9Hz, 1H), 7.29-7.22 (m, 2H), 6.16 (d, J = 2.9Hz, 1H) , 3.62 (s, 3H), 3.58-3.51 (m, 1H), 3.32-3.29 (m, 1H), 2.68-2.60 (m, 1H), 1.90-1.82 (m, 2H), 1.66-1.45 (m, 5H), 1.42-1.37 (m, 1H), 1.35-1.25 (m, 2H), 1.21-1.12 (m, 2H).
將二乙基硫烷(2g，22.2mmol)溶於二氯甲烷(20mL) 中，在0℃下滴加間氯過氧苯甲酸(3.5g，15.5mmol)的二氯甲烷，0.5小時後，蒸除二氯甲烷，加入氫氧化鈉(1g)的水溶液(30mL)，蒸除水，加入二氯甲烷(30mL)，打漿過濾，母液蒸除二氯甲烷得(乙基亞硫醯基<亞磺醯>)乙烷(1.2g，產率51%)。 Diethylsulfane (2g, 22.2mmol) was dissolved in dichloromethane (20mL), and methylene chloride peroxybenzoic acid (3.5g, 15.5mmol) was added dropwise at 0 ° C. After 0.5 hours, Dichloromethane was distilled off, an aqueous solution (30 mL) of sodium hydroxide (1 g) was added, water was distilled off, dichloromethane (30 mL) was added, and the slurry was filtered. Sulfonium>) ethane (1.2 g, 51% yield).
1H NMR(400MHz,CD3Cl)：δ 2.66-2.77(m,4H),1.34(t,J=7.2Hz，6H). 1 H NMR (400MHz, CD3Cl): δ 2.66-2.77 (m, 4H), 1.34 (t, J = 7.2Hz, 6H).
將(乙基亞硫醯基<亞磺醯>)乙烷(1.1g，10.4mmol)溶於甲醇(30mL)中，在25℃下加胺基甲醯胺(3.2g，41.4mmol)、二乙醯氧基碘苯(10g，31.0mmol)，2小時後，蒸除甲醇，管柱層析得到二乙基(亞胺基)-λ6-硫烷酮(0.5g，產率40%)。 (Ethylthiosulfenyl sulfenyl) ethane (1.1 g, 10.4 mmol) was dissolved in methanol (30 mL), and aminoformamide (3.2 g, 41.4 mmol), diamine were added at 25 ° C. Acetyloxyiodobenzene (10 g, 31.0 mmol). After 2 hours, methanol was distilled off, and column chromatography was performed to obtain diethyl (imino) -λ6-sulfanone (0.5 g, yield 40%).
1H NMR(400MHz,CD3Cl)：δ 3.12-3.06(m,4H),2.06(s,1H),1.42(t,J=7.6Hz，6H) 1 H NMR (400MHz, CD3Cl): δ 3.12-3.06 (m, 4H), 2.06 (s, 1H), 1.42 (t, J = 7.6Hz, 6H)
以二乙基(亞胺基)-λ6-硫烷酮與2-溴-4-碘-1-苯氧基苯 為起始原料，反應操作參考實施例19第五至七步，得4-(5-((二乙基(羰基)-λ6-硫烷亞基)胺基)-2-苯氧基苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(38mg)。 Diethyl (imino) -λ6-sulfanone and 2-bromo-4-iodo-1-phenoxybenzene were used as starting materials. For the reaction operation, refer to the fifth to seventh steps of Example 19 to obtain 4- (5-((diethyl (carbonyl) -λ 6 -sulfanylidene) amino) -2-phenoxyphenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [ 2,3-c] pyridin-7-one (38 mg).
MS m/z(ESI)：436.1[M+H]+. MS m / z (ESI): 436.1 [M + H] +.
1H NMR(400MHz,DMSO-d6)：δ 11.97(br,1H),7.26-7.19(m,4H),7.09(d,J=2.8Hz,1H),6.97-6.90(m,3H),6.78-6.76(m,2H),6.23(t,J=2.0Hz,1H),3.47(s,3H),3.32-3.27(m,4H),1.28(t,J=7.6Hz,6H). 1 H NMR (400MHz, DMSO-d6): δ 11.97 (br, 1H), 7.26-7.19 (m, 4H), 7.09 (d, J = 2.8Hz, 1H), 6.97-6.90 (m, 3H), 6.78 -6.76 (m, 2H), 6.23 (t, J = 2.0Hz, 1H), 3.47 (s, 3H), 3.32-3.27 (m, 4H), 1.28 (t, J = 7.6Hz, 6H).
以2-((3-溴-4-((4,4-二氟環己基)酮基)苯基)亞硫醯基<亞磺醯>)乙醯腈為原料，參考實施例67第七步得2-((3-溴-4-((4,4-二氟環己基)酮基)苯基)亞硫醯基<亞磺醯>)-2-甲基丙腈(產率70%)。 Using 2-((3-bromo-4-((4,4-difluorocyclohexyl) keto) phenyl) phenyl) sulfinyl <sulfenyl>) acetonitrile as a raw material, reference example 67 2-((3-bromo-4-((4,4-difluorocyclohexyl) keto) phenyl) phenyl) sulfinyl <sulfenyl>)-2-methylpropionitrile (yield 70) %).
以2-((3-溴-4-((4,4-二氟環己基)酮基)苯基)亞硫醯基<亞磺醯>)-2-甲基丙腈為原料，參考實施例1第六步得2-(3-溴-4-((4,4-二氟環己基)酮基)苯基磺亞胺醯基)-2-甲基丙腈(產率68%)。 Using 2-((3-bromo-4-((4,4-difluorocyclohexyl) keto) phenyl) phenyl) sulfinyl <sulfenyl>)-2-methylpropionitrile as a raw material, refer to the implementation Example 1 In the sixth step, 2- (3-bromo-4-((4,4-difluorocyclohexyl) keto) phenylsulfimimidino) -2-methylpropionitrile was obtained (yield 68%). .
MS m/z(ESI)：421.0/423.0(50/50)[M+H]+. MS m / z (ESI): 421.0 / 423.0 (50/50) [M + H] + .
以2-(3-溴-4-((4,4-二氟環己基)酮基)苯基磺亞胺醯基)-2-甲基丙腈為原料，參考實施例1第七步得2-(4-((4,4-二氟環己基)酮基)-3-(6-甲基-7-羰基-1-甲苯磺醯-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基磺亞胺醯基)-2-甲基丙腈(產率87%)。 Using 2- (3-bromo-4-((4,4-difluorocyclohexyl) keto) phenylsulfimidofluorenyl) -2-methylpropionitrile as the raw material, refer to the seventh step of Example 1 to obtain 2- (4-((4,4-difluorocyclohexyl) keto) -3- (6-methyl-7-carbonyl-1-toluenesulfonium-6,7-dihydro-1H-pyrrolo [ 2,3-c] pyridin-4-yl) phenylsulfimimidino) -2-methylpropionitrile (87% yield).
MS m/z(ESI)：643.1[M+H]+. MS m / z (ESI): 643.1 [M + H] + .
以2-(4-((4,4-二氟環己基)酮基)-3-(6-甲基-7-羰基-1-甲苯磺醯-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基磺亞胺醯基)-2-甲基丙腈為原料，參考實施例1第八步得2-(4-((4,4-二氟環己基)酮基)-3-(6-甲基-7-羰基-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基磺亞胺醯基)-2-甲基丙腈(產率29%)。 2- (4-((4,4-difluorocyclohexyl) keto) -3- (6-methyl-7-carbonyl-1-toluenesulfonium-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) phenylsulfonylimino) -2-methylpropionitrile was used as a raw material, and the eighth step of Reference Example 1 was to obtain 2- (4-((4,4- Difluorocyclohexyl) keto) -3- (6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) phenylsulfimine Fluorenyl) -2-methylpropionitrile (29% yield).
MS m/z(ESI)：489.1[M+H]+. MS m / z (ESI): 489.1 [M + H] + .
1H NMR(400MHz,MeOD)δ 7.98(dd,J=10.9Hz,2.4Hz,2H),7.35(d,J=8.4Hz,1H),7.25(d,J=2.9Hz,1H),7.18(s,1H),6.22(d,J=2.9Hz,1H),4.75-4.70(m,1H),3.61(s,3H),1.92-1.78(m,4H),1.78-1.64(m,4H),1.61(s,3H),1.59(s,3H). 1 H NMR (400MHz, MeOD) δ 7.98 (dd, J = 10.9Hz, 2.4Hz, 2H), 7.35 (d, J = 8.4Hz, 1H), 7.25 (d, J = 2.9Hz, 1H), 7.18 ( s, 1H), 6.22 (d, J = 2.9 Hz, 1H), 4.75-4.70 (m, 1H), 3.61 (s, 3H), 1.92-1.78 (m, 4H), 1.78-1.64 (m, 4H) , 1.61 (s, 3H), 1.59 (s, 3H).
以1-(4-氟-3-(6-甲基-7-羰基-1-甲苯磺醯-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基磺亞胺醯基)環丙烷-1- 甲腈為原料，參考實施例23第一步，得到1-(3-(6-甲基-7-羰基-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-4-((反式-4-甲基環己基)胺基)苯基磺亞胺醯基)環丙烷-1-甲腈(白色固體，產率11%)。 1- (4-fluoro-3- (6-methyl-7-carbonyl-1-toluenesulfonium-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) Phenylsulfenimido) cyclopropane-1-carbonitrile was used as a raw material. Referring to the first step of Example 23, 1- (3- (6-methyl-7-carbonyl-6,7-dihydro-1H) was obtained. -Pyrrolo [2,3-c] pyridin-4-yl) -4-((trans-4-methylcyclohexyl) amino) phenylsulfimimidino) cyclopropane-1-carbonitrile ( White solid, yield 11%).
MS m/z(ESI)：464.2[M+H]+. MS m / z (ESI): 464.2 [M + H] + .
1H NMR(400MHz,MeOD)δ 7.75(dd,J=8.9Hz,2.4Hz,1H),7.62(d,J=2.4Hz,1H),7.25(d,J=2.8Hz,1H),7.11(s,1H),6.82(d,J=9.1Hz,1H),6.08(d,J=2.8Hz,1H),3.59(s,3H),3.35-3.27(m,1H),1.99-1.85(m,2H),1.74-1.61(m,4H),1.54-1.50(m,1H),1.25-1.16(m,2H),1.07-0.95(m,4H),0.81(d,J=6.5Hz,3H). 1 H NMR (400MHz, MeOD) δ 7.75 (dd, J = 8.9Hz, 2.4Hz, 1H), 7.62 (d, J = 2.4Hz, 1H), 7.25 (d, J = 2.8Hz, 1H), 7.11 ( s, 1H), 6.82 (d, J = 9.1Hz, 1H), 6.08 (d, J = 2.8Hz, 1H), 3.59 (s, 3H), 3.35-3.27 (m, 1H), 1.99-1.85 (m , 2H), 1.74-1.61 (m, 4H), 1.54-1.50 (m, 1H), 1.25-1.16 (m, 2H), 1.07-0.95 (m, 4H), 0.81 (d, J = 6.5Hz, 3H ).
以2-溴-1-(2,4-二氟苯氧基)-4-碘苯與二乙基(亞胺基)-λ6-硫烷酮為原料，反應操作參考實施例19第五至七步，得到4-(5-((二乙基(羰基)-λ6-硫烷亞基)胺基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(三步總收率8.5%)。 Using 2-bromo-1- (2,4-difluorophenoxy) -4-iodobenzene and diethyl (imino) -λ6-sulfanone as raw materials, refer to Example 19 Seven steps to give 4- (5-((diethyl (carbonyl) -λ 6 -sulfanylidene) amino) -2- (2,4-difluorophenoxy) phenyl) -6-methyl -1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (three step total yield 8.5%).
MS m/z(ESI)：472.1[M+H]+. MS m / z (ESI): 472.1 [M + H] +.
1H NMR(400MHz,DMSO-d6)：δ 12.00(br,1H),7.34-7.25(m,3H),7.07(d,J=2.8Hz,1H),6.97-6.91(m,3H),6.81-6.78(m,1H),6.21(t,J=2.0Hz,1H),3.51(s,3H),3.32-3.27(m,4H),1.26(t,J=7.6Hz,6H) 1 H NMR (400MHz, DMSO-d6): δ 12.00 (br, 1H), 7.34-7.25 (m, 3H), 7.07 (d, J = 2.8Hz, 1H), 6.97-6.91 (m, 3H), 6.81 -6.78 (m, 1H), 6.21 (t, J = 2.0Hz, 1H), 3.51 (s, 3H), 3.32-3.27 (m, 4H), 1.26 (t, J = 7.6Hz, 6H)
將3-溴-4-氟苯硫醇(1g，4.8mmol)、(溴甲基)環丙烷(1.9g，14.5mmol)、碳酸銫(4.7g，14.5mmol)、碘化鈉(72mg，0.5mmol)懸浮於二甲亞碸(20mL)中，在25℃下攪拌3小時，加入水(40mL)，乙酸乙酯(20mL)萃取，硫酸鈉乾燥，過濾旋乾得到(3-溴-4-氟苯基)(環丙基甲基)硫烷(1.5g)，直 接用做下一步。 3-Bromo-4-fluorobenzenethiol (1 g, 4.8 mmol), (bromomethyl) cyclopropane (1.9 g, 14.5 mmol), cesium carbonate (4.7 g, 14.5 mmol), sodium iodide (72 mg, 0.5 mmol) was suspended in dimethylarsine (20 mL), stirred at 25 ° C. for 3 hours, water (40 mL) was added, and ethyl acetate (20 mL) was added for extraction, dried over sodium sulfate, and filtered to give (3-bromo-4- Fluorophenyl) (cyclopropylmethyl) sulfane (1.5 g) was directly used as the next step.
以(3-溴-4-氟苯基)(環丙基甲基)硫烷為原料，參考實施例1第五步，得到2-溴-4-((環丙基甲基)亞硫醯基<亞磺醯>)-1-氟苯(收率86.3%)。 Using (3-bromo-4-fluorophenyl) (cyclopropylmethyl) sulfane as a raw material, the fifth step of Reference Example 1 was used to obtain 2-bromo-4-((cyclopropylmethyl) sulfinyl). Group <sulfinylpyrene>)-1-fluorobenzene (yield 86.3%).
1H NMR(400MHz,CDCl3)：δ 7.89(dd,J=2.4,6.4Hz,1H),7.59-7.55(m,1H),7.27(t,J=8.0Hz,1H),2.86-2.82(m,1H),2.70-2.65(m,1H),1.00-0.96(m,1H),0.68-0.65(m,2H),0.30-0.27(m,1H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.89 (dd, J = 2.4, 6.4 Hz, 1H), 7.59-7.55 (m, 1H), 7.27 (t, J = 8.0 Hz, 1H), 2.86-2.82 ( m, 1H), 2.70-2.65 (m, 1H), 1.00-0.96 (m, 1H), 0.68-0.65 (m, 2H), 0.30-0.27 (m, 1H).
以2-溴-4-((環丙基甲基)亞硫醯基<亞磺醯>)-1-氟苯為原料，參考實施例1第六步得到(3-溴-4-氟苯基)(環丙基甲基)(亞胺基)-λ6-硫烷酮(收率84.6%)。 Using 2-bromo-4-((cyclopropylmethyl) sulfenylsulfinyl <sulfenimidine>)-1-fluorobenzene as a raw material, the sixth step of Reference Example 1 was used to obtain (3-bromo-4-fluorobenzene (Cyclopropylmethyl) (imino) -λ6-sulfanone (yield 84.6%).
MS m/z(ESI)：292.0/294.0(50/50)[M+H]+。 MS m / z (ESI): 292.0 / 294.0 (50/50) [M + H] + .
以(3-溴-4-氟苯基)(環丙基甲基)(亞胺基)-λ6-硫烷酮與6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，參考參考實施例10第四步，得到4-(5-(S-(環丙基甲基)磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(收率36.3%)。 (3-Bromo-4-fluorophenyl) (cyclopropylmethyl) (imino) -λ6-sulfanone and 6-methyl-4- (4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl) -1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7-one As a raw material, refer to the fourth step of Reference Example 10 to obtain 4- (5- (S- (cyclopropylmethyl) sulfonylimino) -2-fluorophenyl) -6-methyl-1-toluene Sulfo-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (36.3% yield).
MS m/z(ESI)：514.1[M+H]+。 MS m / z (ESI): 514.1 [M + H] + .
以4-(5-(S-(環丙基甲基)磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮與2,4-二氟苯酚為原料，反應操作同實施例5第五步，得到4-(5-(S-(環丙基甲基)磺亞胺醯基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(收率29.6%)。 4- (5- (S- (Cyclopropylmethyl) sulfonylimino) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H- Pyrrolop [2,3-c] pyridin-7-one and 2,4-difluorophenol were used as raw materials. The reaction operation was the same as that in the fifth step of Example 5 to obtain 4- (5- (S- (cyclopropylmethyl) ) Sulfinoimido) -2- (2,4-difluorophenoxy) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine- 7-ketone (yield 29.6%).
MS m/z(ESI)：470.1[M+H]+. MS m / z (ESI): 470.1 [M + H] + .
1H NMR(400MHz,DMSO-d6)：δ 12.16(br,1H),8.12(d,J=2.8H，1H),7.99(dd,J=9.2Hz,2.8Hz,1H),7.59-7.45(m,3H),7.33(t,J=2.8Hz,1H),7.22-7.19(m,1H),7.12(d,J=8.4Hz,1H),6.30(t,J=2.0Hz,1H),4.01-3.93(m,2H),3.57(s,3H),1.03-0.98(m,1H),0.56-0.50(m,2H),0.26-0.21(m,1H),0.19-0.15(m,1H). 1 H NMR (400MHz, DMSO-d6): δ 12.16 (br, 1H), 8.12 (d, J = 2.8H, 1H), 7.99 (dd, J = 9.2Hz, 2.8Hz, 1H), 7.59-7.45 ( m, 3H), 7.33 (t, J = 2.8Hz, 1H), 7.22-7.19 (m, 1H), 7.12 (d, J = 8.4Hz, 1H), 6.30 (t, J = 2.0Hz, 1H), 4.01-3.93 (m, 2H), 3.57 (s, 3H), 1.03-0.98 (m, 1H), 0.56-0.50 (m, 2H), 0.26-0.21 (m, 1H), 0.19-0.15 (m, 1H ).
以4-(5-(S-(環丙基甲基)磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，反應操作同實施例5第五步，用環丙基甲醇替2,4-二氟苯酚，得到4-(2-(環丙基甲氧基)-5-(S-(環丙基甲基)磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(收率39.8%)。 4- (5- (S- (Cyclopropylmethyl) sulfonylimino) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H- Pyrrolop [2,3-c] pyridin-7-one was used as a raw material. The reaction operation was the same as that in the fifth step of Example 5. Cyclopropylmethanol was used instead of 2,4-difluorophenol to obtain 4- (2- (cyclopropane). Methoxy) -5- (S- (cyclopropylmethyl) sulfonylimino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c ] Pyridine-7-one (yield 39.8%).
MS m/z(ESI)：412.1[M+H]+. MS m / z (ESI): 412.1 [M + H] + .
1H NMR(400MHz,DMSO-d6)：δ 12.02(s,1H),7.85-7.81(m,2H),7.32(s,1H),7.29-7.25(m,2H),6.14(t,J=2.0Hz,1H),4.02(s,1H),3.96(d,J=6.8Hz,2H),3.58(s,3H),3.08(dd,J=7.2Hz,2.8Hz,2H),1.15-1.08(m,1H),0.93-0.86(m,1H),0.49-0.43(m,2H),0.40-0.37(m,2H), 0.29-0.25(m,2H),0.06-0.03(m,2H). 1 H NMR (400MHz, DMSO-d6): δ 12.02 (s, 1H), 7.85-7.81 (m, 2H), 7.32 (s, 1H), 7.29-7.25 (m, 2H), 6.14 (t, J = 2.0Hz, 1H), 4.02 (s, 1H), 3.96 (d, J = 6.8Hz, 2H), 3.58 (s, 3H), 3.08 (dd, J = 7.2Hz, 2.8Hz, 2H), 1.15-1.08 (m, 1H), 0.93-0.86 (m, 1H), 0.49-0.43 (m, 2H), 0.40-0.37 (m, 2H), 0.29-0.25 (m, 2H), 0.06-0.03 (m, 2H) .
以4-(5-(S-(環丙基甲基)磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，反應操作同實施例5第五步，用4,4-二氟環己醇替代2,4-二氟苯酚，得到4-(5-(S-(環丙基甲基)磺亞胺醯基)-2-((4,4-二氟環己基)酮基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(收率43.5%)。 4- (5- (S- (Cyclopropylmethyl) sulfonylimino) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H- Pyrrolop [2,3-c] pyridin-7-one was used as a raw material. The reaction operation was the same as that in the fifth step of Example 5. Substituting 4,4-difluorocyclohexanol for 2,4-difluorophenol gave 4- (4- 5- (S- (cyclopropylmethyl) sulfonylimino) -2-((4,4-difluorocyclohexyl) keto) phenyl) -6-methyl-1,6-dihydro -7H-pyrrolo [2,3-c] pyridin-7-one (43.5% yield).
MS m/z(ESI)：476.2[M+H]+. MS m / z (ESI): 476.2 [M + H] +.
1H NMR(400MHz,DMSO-d6)：δ 12.04(s,1H),7.88-7.83(m,2H),7.39(d,J=8.4Hz,1H),7.29-7.26(m,2H),6.13(t,J=2.0Hz,1H),4.77(s,1H),4.08-4.01(m,1H),3.56(s,3H),3.11-3.08(m,2H),1.86-1.66(m,8H),0.95-0.86(m,1H),0.42-0.38(m,2H),0.09-0.04(m,2H). 1H NMR (400MHz, DMSO-d6): δ 12.04 (s, 1H), 7.88-7.83 (m, 2H), 7.39 (d, J = 8.4Hz, 1H), 7.29-7.26 (m, 2H), 6.13 ( t, J = 2.0Hz, 1H), 4.77 (s, 1H), 4.08-4.01 (m, 1H), 3.56 (s, 3H), 3.11-3.08 (m, 2H), 1.86-1.66 (m, 8H) , 0.95-0.86 (m, 1H), 0.42-0.38 (m, 2H), 0.09-0.04 (m, 2H).
以2-((3-溴-4-(環丙基甲氧基)苯基)亞硫醯基<亞磺醯>)乙醯腈為原料，參考實施例70第一步反應條件，得到1-((3-溴-4-(環丙基甲氧基)苯基)亞硫醯基<亞磺醯>)環丙烷-1-甲腈(收率：65.8%)。 Using 2-((3-bromo-4- (cyclopropylmethoxy) phenyl) thiosulfinyl <sulfenimidine>) acetonitrile as a raw material, refer to the first reaction conditions in Example 70 to obtain 1 -((3-bromo-4- (cyclopropylmethoxy) phenyl) sulfinyl <sulfenimidine>) cyclopropane-1-carbonitrile (yield: 65.8%).
以1-((3-溴-4-(環丙基甲氧基)苯基)亞硫醯基<亞磺醯>)環丙烷-1-甲腈為原料，參考參考實施例1第六步，得到1-(3-溴-4-(環丙基甲氧基)苯基磺亞胺醯基)環丙烷-1-甲腈(收率：78.8%)。 Using 1-((3-bromo-4- (cyclopropylmethoxy) phenyl) sulfinyl <sulfenimidine>) cyclopropane-1-carbonitrile as a raw material, refer to the sixth step of Reference Example 1. Thus, 1- (3-bromo-4- (cyclopropylmethoxy) phenylsulfimidofluorenyl) cyclopropane-1-carbonitrile was obtained (yield: 78.8%).
MS m/z(ESI)：355.0/357.0(50/50)[M+H]+. MS m / z (ESI): 355.0 / 357.0 (50/50) [M + H] + .
以1-(3-溴-4-(環丙基甲氧基)苯基磺亞胺醯基)環丙烷-1-甲腈與中間體Im為原料，反應操作同實施例1第七步，得到1-(4-(環丙基甲氧基)-3-(6-甲基-7-羰基-1-甲苯磺醯-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基磺亞胺醯基)環丙烷-1-甲腈(收率：28.4%)。 Using 1- (3-bromo-4- (cyclopropylmethoxy) phenylsulfimidoamido) cyclopropane-1-carbonitrile and intermediate Im as raw materials, the reaction operation is the same as the seventh step in Example 1. 1- (4- (cyclopropylmethoxy) -3- (6-methyl-7-carbonyl-1-toluenesulfonium-6,7-dihydro-1H-pyrrolo [2,3-c ] Pyridin-4-yl) phenylsulfonylimido) cyclopropane-1-carbonitrile (yield: 28.4%).
MS m/z(ESI)：577.1[M+H]+. MS m / z (ESI): 577.1 [M + H] + .
以1-(4-(環丙基甲氧基)-3-(6-甲基-7-羰基-1-甲苯磺醯-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基磺亞胺醯基)環丙烷-1-甲腈為原料，參考實施例1第八步，得到1-(4-(環丙基甲氧基)-3-(6-甲基-7-羰基-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基磺亞胺醯基)環丙烷-1-甲腈(收率：55.6%)。 With 1- (4- (cyclopropylmethoxy) -3- (6-methyl-7-carbonyl-1-toluenesulfonium-6,7-dihydro-1H-pyrrolo [2,3-c ] Pyridin-4-yl) phenylsulfimidefluorenyl) cyclopropane-1-carbonitrile as a raw material, referring to the eighth step of Example 1, to obtain 1- (4- (cyclopropylmethoxy) -3- (6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) phenylsulfimimidino) cyclopropane-1-carbonitrile ( Yield: 55.6%).
MS m/z(ESI)：423.1[M+H]+. MS m / z (ESI): 423.1 [M + H] + .
1H NMR(400MHz,DMSO-d6)：δ 12.08(br,1H),7.93(d,J=2.0Hz,1H),7.89(dd,J=8.8Hz,2.4Hz,1H),7.35(d,J= 8.8Hz,1H),7.31-7.30(m,2H),6.25(s,1H),5.21(s,1H),4.01(d,J=6.8Hz,2H),3.58(s,3H),1.85-1.60(m,4H),1.19-1.12(m,1H),0.52-0.48(m,2H),0.33-0.29(m,2H). 1 H NMR (400MHz, DMSO-d6): δ 12.08 (br, 1H), 7.93 (d, J = 2.0Hz, 1H), 7.89 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.35 (d, J = 8.8Hz, 1H), 7.31-7.30 (m, 2H), 6.25 (s, 1H), 5.21 (s, 1H), 4.01 (d, J = 6.8Hz, 2H), 3.58 (s, 3H), 1.85-1.60 (m, 4H), 1.19-1.12 (m, 1H), 0.52-0.48 (m, 2H), 0.33-0.29 (m, 2H).
以實施例33第七步產物4-(5-(環丙磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮與2,4-二氟苯酚為原料，參考實施例4第四步，用2-氟苯酚替代2,4-二氟苯酚，得到4-(5-(環丙磺亞胺醯基)-2-(2-氟苯氧基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(收率：32.6%)。 Take the product in the seventh step of Example 33 as 4- (5- (Cyclopropanesulfenimido) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H- Pyrrolop [2,3-c] pyridin-7-one and 2,4-difluorophenol are used as raw materials. In the fourth step of Reference Example 4, 2-fluorophenol is used instead of 2,4-difluorophenol to obtain 4- (5- (Cyclopropanesulfinoimido) -2- (2-fluorophenoxy) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] Pyridine-7-one (yield: 32.6%).
MS m/z(ESI)：438.1[M+H]+. MS m / z (ESI): 438.1 [M + H] + .
1H NMR(400MHz,DMSO-d6)：δ 12.10(br,1H),7.97(d,J=2.4Hz,1H),7.82(dd,J=8.8Hz,2.4Hz,1H),7.44-7.38(m,2H),7.22(s,1H),7.33-7.24(m,3H),6.93(d,J=8.4Hz,1H),6.30(t,J=2.0Hz,1H),4.23(s,1H),3.58(s,3H),2.76-2.70(m,1H),0.98-0.94(m,1H),0.94-0.92(m,3H). 1 H NMR (400MHz, DMSO-d6): δ 12.10 (br, 1H), 7.97 (d, J = 2.4Hz, 1H), 7.82 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.44-7.38 ( m, 2H), 7.22 (s, 1H), 7.33-7.24 (m, 3H), 6.93 (d, J = 8.4Hz, 1H), 6.30 (t, J = 2.0Hz, 1H), 4.23 (s, 1H ), 3.58 (s, 3H), 2.76-2.70 (m, 1H), 0.98-0.94 (m, 1H), 0.94-0.92 (m, 3H).
以4-(5-(環丙磺亞胺醯基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，參考實施例2第一步，用乙基磺醯氯替代環丙基磺醯氯，得到N-(環丙基(4-(2,4-二氟苯氧基)-3-(6-甲基-7-羰基-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)苯基)(羰基)-λ6-硫烷亞基)乙醯胺(收率64.6%) 4- (5- (Cyclopropanesulfinoimido) -2- (2,4-difluorophenoxy) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [ 2,3-c] pyridine-7-one as a raw material. In the first step of Reference Example 2, ethylsulfonyl chloride was used instead of cyclopropylsulfonyl chloride to obtain N- (cyclopropyl (4- (2,4 -Difluorophenoxy) -3- (6-methyl-7-carbonyl-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) phenyl) (carbonyl) -λ6-sulfanylidene) acetamide (yield 64.6%)
MS m/z(ESI)：498.0[M+H]+. MS m / z (ESI): 498.0 [M + H] + .
1H NMR(400MHz,DMSO)δ 12.14(br,1H),8.48(s,1H),7.93(d,J=2.4Hz,1H),7.80(dd,J=8.8Hz,2.4Hz,1H),7.59-7.43(m,2H),7.40-7.29(m,1H),7.28-7.14(m,1H),6.97(d,J=8.7Hz,1H),6.28(s,1H),3.59(s,3H),3.15-3.05(m,1H),1.98(s,3H),1.38-0.90(m,4H). 1 H NMR (400MHz, DMSO) δ 12.14 (br, 1H), 8.48 (s, 1H), 7.93 (d, J = 2.4Hz, 1H), 7.80 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.59-7.43 (m, 2H), 7.40-7.29 (m, 1H), 7.28-7.14 (m, 1H), 6.97 (d, J = 8.7Hz, 1H), 6.28 (s, 1H), 3.59 (s, 3H), 3.15-3.05 (m, 1H), 1.98 (s, 3H), 1.38-0.90 (m, 4H).
以4-(5-(乙基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，參考實施例23第一步，用環辛胺替代反式-4甲基環己烷胺，得到4-(2-(環辛基胺基)-5-(乙基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(24mg)。 4- (5- (ethylsulfonylimino) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one as a raw material, in the first step of Reference Example 23, using cyclooctylamine to replace trans-4 methylcyclohexaneamine to obtain 4- (2- (cyclooctylamino) -5- (Ethylsulfenimido) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (24 mg).
MS m/z(ESI)：441.2[M+H]+. MS m / z (ESI): 441.2 [M + H] + .
1H NMR(400MHz,DMSO-d6)：δ 12.14(br,1H),7.67(dd,J=8.8Hz,2.0Hz,1H),7.57(d,J=2.4Hz,1H),7.30(t,J=2.4Hz,1H),7.23(s,1H),6.74(d,J=8.8Hz,1H),6.0(t,J=2.0Hz,1H),3.64-3.57(m,1H),3.56(s,3H),3.04(q,J=7.2Hz,2H),1.78-1.66(m,2H),1.60-1.40(m,12H),1.08(t,J=7.2Hz,3H). 1 H NMR (400MHz, DMSO-d6): δ 12.14 (br, 1H), 7.67 (dd, J = 8.8Hz, 2.0Hz, 1H), 7.57 (d, J = 2.4Hz, 1H), 7.30 (t, J = 2.4Hz, 1H), 7.23 (s, 1H), 6.74 (d, J = 8.8Hz, 1H), 6.0 (t, J = 2.0Hz, 1H), 3.64-3.57 (m, 1H), 3.56 ( s, 3H), 3.04 (q, J = 7.2Hz, 2H), 1.78-1.66 (m, 2H), 1.60-1.40 (m, 12H), 1.08 (t, J = 7.2Hz, 3H).
以4-(2-氟-5-(丙烷-2-基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(35mg,0.07mmol)為反應原料，參考實施例23第一步，得到化合物6-甲基-4-(2-((反-4-甲基環己基)胺基)-5-(丙烷-2-基磺亞胺醯基)苯基)-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(7.0 mg，白色固體，產率23%) With 4- (2-fluoro-5- (propane-2-ylsulfimidofluorenyl) phenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2 , 3-c] pyridine-7-one (35mg, 0.07mmol) as the reaction raw material, refer to the first step of Example 23 to obtain the compound 6-methyl-4- (2-((trans-4-methylcyclohexyl) ) Amino) -5- (propane-2-ylsulfimimidino) phenyl) -1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (7.0 mg, White solid, yield 23%)
MS m/z(ESI)：441.1[M+H]+ MS m / z (ESI): 441.1 [M + H] +
1H NMR(400MHz,MeOD)δ 7.74(dd,J=8.8Hz,2.4Hz,1H),7.58(d,J=2.3Hz,1H),7.35(d,J=2.8Hz,1H),7.19(s,1H),6.89(d,J=9.0Hz,1H),6.11(d,J=2.8Hz,1H),3.69(s,3H),3.42-3.35(m,1H),3.29-3.22(m,1H),2.02-1.95(m,2H),1.76-1.67(m,2H),1.37-1.25(m,7H),1.15-1.00(m,4H),0.91(d,J=6.8Hz,3H). 1 H NMR (400MHz, MeOD) δ 7.74 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.58 (d, J = 2.3Hz, 1H), 7.35 (d, J = 2.8Hz, 1H), 7.19 ( s, 1H), 6.89 (d, J = 9.0 Hz, 1H), 6.11 (d, J = 2.8 Hz, 1H), 3.69 (s, 3H), 3.42-3.35 (m, 1H), 3.29-3.22 (m , 1H), 2.02-1.95 (m, 2H), 1.76-1.67 (m, 2H), 1.37-1.25 (m, 7H), 1.15-1.00 (m, 4H), 0.91 (d, J = 6.8Hz, 3H ).
以4-(2-氟-5-(丙烷-2-基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(35mg,0.07mmol)為反應原料，參考實施例23第一步，得到化合物4-(2-(環庚基胺基)-5-(丙烷-2-基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(7.7mg，白色固體，產率25%)。 With 4- (2-fluoro-5- (propane-2-ylsulfimidofluorenyl) phenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2 , 3-c] pyridine-7-one (35mg, 0.07mmol) as the reaction raw material, refer to the first step of Example 23 to obtain the compound 4- (2- (cycloheptylamino) -5- (propane-2- Sulfinimide) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (7.7 mg, white solid, yield 25% ).
MS m/z(ESI)：441.2[M+H]+ MS m / z (ESI): 441.2 [M + H] +
1H NMR(400MHz,MeOD)δ 7.75(dd,J=8.8Hz,2.4Hz,1H),7.59(d,J=2.3Hz,1H),7.35(d,J=2.8Hz,1H),7.20(s, 1H),6.80(d,J=9.0Hz,1H),6.11(d,J=2.8Hz,1H),3.70(s,3H),3.68-3.60(m,1H),3.30-3.25(m,1H),1.96-1.85(m,2H),1.64-1.36(m,10H),1.28(t,J=7.1Hz,6H). 1 H NMR (400MHz, MeOD) δ 7.75 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.59 (d, J = 2.3Hz, 1H), 7.35 (d, J = 2.8Hz, 1H), 7.20 ( s, 1H), 6.80 (d, J = 9.0Hz, 1H), 6.11 (d, J = 2.8Hz, 1H), 3.70 (s, 3H), 3.68-3.60 (m, 1H), 3.30-3.25 (m , 1H), 1.96-1.85 (m, 2H), 1.64-1.36 (m, 10H), 1.28 (t, J = 7.1Hz, 6H).
以2-溴-1-(環丙基甲氧基)-4-碘苯與二乙基(亞胺基)-λ6-硫烷酮為起始原料，參考實施例19第五步至第七步反應條件，得到4-(2-(環丙基甲氧基)-5-((二乙基(羰基)-λ6-硫烷亞基)胺基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(75mg)。 Using 2-bromo-1- (cyclopropylmethoxy) -4-iodobenzene and diethyl (imino) -λ6-sulfanone as starting materials, refer to the fifth to seventh steps of Example 19 Reaction conditions to obtain 4- (2- (cyclopropylmethoxy) -5-((diethyl (carbonyl) -λ6-sulfanylidene) amino) phenyl) -6-methyl-1 , 6-Dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (75 mg).
MS m/z(ESI)：414.2[M+H]+. MS m / z (ESI): 414.2 [M + H] +.
1H NMR(400MHz,DMSO-d6)：δ 11.95(br,1H),7.26(t,J=2.8Hz,1H),7.24(s,1H),6.97(d,J=2.4Hz,1H),6.92-6.85(m,2H),6.14(t,J=2.8Hz,1H),3.73(d,J=6.8Hz,2H),3.55(s,3H),3.23(q,J=7.6Hz,4H),1.24(t,J=7.6Hz,6H),1.08-0.85(m,1H),0.45-0.36(m,2H),0.24-0.15(m,2H). 1 H NMR (400MHz, DMSO-d6): δ 11.95 (br, 1H), 7.26 (t, J = 2.8Hz, 1H), 7.24 (s, 1H), 6.97 (d, J = 2.4Hz, 1H), 6.92-6.85 (m, 2H), 6.14 (t, J = 2.8Hz, 1H), 3.73 (d, J = 6.8Hz, 2H), 3.55 (s, 3H), 3.23 (q, J = 7.6Hz, 4H ), 1.24 (t, J = 7.6Hz, 6H), 1.08-0.85 (m, 1H), 0.45-0.36 (m, 2H), 0.24-0.15 (m, 2H).
以4-(2-氟-5-(丙烷-2-基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為反應原料，參考實施例5第五步，用(2,2-二氟環丙基)甲醇替代環丙基甲醇，得到4-(2-((2,2-二氟環丙基)甲氧基)-5-(丙烷-2-基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(23.2mg，產率41%)。 With 4- (2-fluoro-5- (propane-2-ylsulfimidofluorenyl) phenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2 , 3-c] pyridine-7-one as a reaction raw material, in the fifth step of Reference Example 5, substituting (2,2-difluorocyclopropyl) methanol for cyclopropylmethanol to obtain 4- (2-((2 , 2-difluorocyclopropyl) methoxy) -5- (propane-2-ylsulfenimido) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2 , 3-c] pyridin-7-one (23.2 mg, yield 41%).
MS m/z(ESI)：436.1[M+H]+. MS m / z (ESI): 436.1 [M + H] + .
1H NMR(400MHz,CDCl3)δ 11.17(br,1H),8.11-7.99(m,1H),7.99-7.87(m,1H),7.35-7.29(m,1H),7.15(s,1H),7.11-7.01(m,1H),6.32-6.17(m,1H),4.24-4.06(m,2H),3.74(s,3H),3.37-3.22(m,1H),2.05-1.88(m,1H),1.58-1.44(m,1H),1.44-1.27(m,6H),1.29-1.13(m,1H). 1 H NMR (400MHz, CDCl3) δ 11.17 (br, 1H), 8.11-7.99 (m, 1H), 7.99-7.87 (m, 1H), 7.35-7.29 (m, 1H), 7.15 (s, 1H), 7.11-7.01 (m, 1H), 6.32-6.17 (m, 1H), 4.24-4.06 (m, 2H), 3.74 (s, 3H), 3.37-3.22 (m, 1H), 2.05-1.88 (m, 1H ), 1.58-1.44 (m, 1H), 1.44-1.27 (m, 6H), 1.29-1.13 (m, 1H).
以4-(2-氟-5-(丙烷-2-基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為反應原 料，參考實施例5第五步，用順-1，4-環己二醇替代環丙基甲醇，得到4-(2-((順-4-羥基環己基)酮基)-5-(丙烷-2-基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(2.0mg，產率5%)。 With 4- (2-fluoro-5- (propane-2-ylsulfimidofluorenyl) phenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2 , 3-c] pyridin-7-one as the reaction raw material, the fifth step of Reference Example 5 is to replace cyclopropyl methanol with cis-1,4-cyclohexanediol to obtain 4- (2-((cis-4 -Hydroxycyclohexyl) keto) -5- (propane-2-ylsulfimimidino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] Pyridine-7-one (2.0 mg, yield 5%).
MS m/z(ESI)：444.1[M+H]+. MS m / z (ESI): 444.1 [M + H] + .
1H NMR(400MHz,CDCl3)δ 10.36(br,1H),8.04-7.92(m,1H),7.92-7.81(m,1H),7.25-7.17(m,2H),7.16-7.11(m,1H),7.11-7.00(m,1H),6.29(br,1H),4.51(br,1H),3.79-3.71(m,1H),3.70(s,3H),3.43-3.32(m,1H),3.33-3.18(m,1H),2.08-1.98(m,2H),1.80-1.68(m,4H),1.55-1.41(m,2H),1.41-1.27(m,6H). 1 H NMR (400MHz, CDCl3) δ 10.36 (br, 1H), 8.04-7.92 (m, 1H), 7.92-7.81 (m, 1H), 7.25-7.17 (m, 2H), 7.16-7.11 (m, 1H ), 7.11-7.00 (m, 1H), 6.29 (br, 1H), 4.51 (br, 1H), 3.79-3.71 (m, 1H), 3.70 (s, 3H), 3.43-3.32 (m, 1H), 3.33-3.18 (m, 1H), 2.08-1.98 (m, 2H), 1.80-1.68 (m, 4H), 1.55-1.41 (m, 2H), 1.41-1.27 (m, 6H).
以4-(5-(乙基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為反應原料，參考實施例10第五步，用四氫呋喃-3-醇取代2,4-二氟苯酚，得到4-(5-(乙基磺亞胺醯基)-2-((四氫呋喃-3-基)酮基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率37%)。 4- (5- (ethylsulfonylimino) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one as a reaction raw material. In the fifth step of Reference Example 10, 2,4-difluorophenol was replaced with tetrahydrofuran-3-ol to obtain 4- (5- (ethylsulfonylimino)- 2-((tetrahydrofuran-3-yl) keto) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (37% yield ).
MS m/z(ESI)：402.1[M+H]+； MS m / z (ESI): 402.1 [M + H] + ;
1H NMR(400MHz,CDCl 3 )：δ 10.80(s,1H),8.02(d,J=2.4Hz,1H),7.96-7.93(dd,J=8.8Hz,2.4Hz,1H),7.29-7.26(dd,J=7.2,2.4Hz,1H),7.08(s,1H),7.02-7.00(d,J=8.8Hz,1H),6.21(s,1H),5.03-5.00(m,1H),4.03-3.99(m,1H),3.90-3.83(m,3H),3.80(s,3H),3.25(q,J=7.2Hz,2H),2.23-2.18(m,1H),2.05-2.03(m,1H),1.32(t,J=7.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ 10.80 (s, 1H), 8.02 (d, J = 2.4Hz, 1H), 7.96-7.93 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.29-7.26 (dd, J = 7.2, 2.4Hz, 1H), 7.08 (s, 1H), 7.02-7.00 (d, J = 8.8Hz, 1H), 6.21 (s, 1H), 5.03-5.00 (m, 1H), 4.03-3.99 (m, 1H), 3.90-3.83 (m, 3H), 3.80 (s, 3H), 3.25 (q, J = 7.2Hz, 2H), 2.23-2.18 (m, 1H), 2.05-2.03 ( m, 1H), 1.32 (t, J = 7.2Hz, 3H).
以4-(5-(乙基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為反應原料，參考實施例10第五步，用4-溴-2-氟苯酚取代2,4-二氟苯酚，得到4-(2-(4-溴-3-氟苯氧基)-5-(乙基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率18%)。 4- (5- (ethylsulfonylimino) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one is used as a reaction raw material. In the fifth step of Reference Example 10, 2,4-difluorophenol is replaced with 4-bromo-2-fluorophenol to obtain 4- (2- (4-bromo-3- Fluorophenoxy) -5- (ethylsulfonylimino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7-one ( Yield 18%).
MS m/z(ESI)：504.1/506.1(50/50)[M+H]+. MS m / z (ESI): 504.1 / 506.1 (50/50) [M + H] + .
1H NMR(400MHz,d4-MeOD)：δ 8.14(d,J=2.8Hz,1H),8.04-8.01(dd,J=8.8Hz,2.4Hz,1H),7.53-7.48(m,1H),7.32-7.27(m,3H),6.90-6.87(dd,J=9.6,2.8Hz,1H),6.74-6.71(m,1H),6.25(d,J=3.2Hz,1H),3.87(q,J=7.2Hz,2H),3.58(s,3H),1.32(t,J=7.2Hz,3H) 1 H NMR (400MHz, d 4-MeOD): δ 8.14 (d, J = 2.8Hz, 1H), 8.04-8.01 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.53-7.48 (m, 1H) , 7.32-7.27 (m, 3H), 6.90-6.87 (dd, J = 9.6, 2.8 Hz, 1H), 6.74-6.71 (m, 1H), 6.25 (d, J = 3.2 Hz, 1H), 3.87 (q , J = 7.2Hz, 2H), 3.58 (s, 3H), 1.32 (t, J = 7.2Hz, 3H)
以4-(5-(乙基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為反應原料，參考實施例10第五步，用(2,2-二氟環丙基)甲醇取代2,4-二氟苯酚，得到4-(5-(環丙磺亞胺醯基)-2-((2,2-二氟環丁基)甲氧基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率52%)。 4- (5- (ethylsulfonylimino) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one as a reaction raw material. In the fifth step of Reference Example 10, (2,2-difluorocyclopropyl) methanol was used to replace 2,4-difluorophenol to obtain 4- (5- (cyclopropane). Sulfoimido) -2-((2,2-difluorocyclobutyl) methoxy) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one (52% yield).
MS m/z(ESI)：436.1[M+H]+. MS m / z (ESI): 436.1 [M + H] + .
1H NMR(400MHz,CDCl 3 )：δ 10.51(s,1H),8.01(d,J=2.4Hz,1H),7.98-7.95(dd,J=8.8Hz,2.4Hz,1H),7.27(d,J=2.8Hz,1H),7.11-7.09(m,2H),6.17(t,J=2.4Hz,1H),4.09(d,J=4.2Hz,2H),3.70(s,3H),3.27(q,J=7.2Hz,2H),2.57-2.48(m,3H),2.37-2.27(m,2H),1.30(t,J=7.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ 10.51 (s, 1H), 8.01 (d, J = 2.4Hz, 1H), 7.98-7.95 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.27 (d , J = 2.8Hz, 1H), 7.11-7.09 (m, 2H), 6.17 (t, J = 2.4Hz, 1H), 4.09 (d, J = 4.2Hz, 2H), 3.70 (s, 3H), 3.27 (q, J = 7.2Hz, 2H), 2.57-2.48 (m, 3H), 2.37-2.27 (m, 2H), 1.30 (t, J = 7.2Hz, 3H).
以4-(5-(乙基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為反應原料，參考實施例10第五步，用4-甲氧基-2-氟苯酚取代2,4-二氟苯酚，得到4-(5-(乙基磺亞胺醯基)-2-(2-氟-4-甲氧基苯氧基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率21%)。 4- (5- (ethylsulfonylimino) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one is used as a reaction raw material. In the fifth step of Reference Example 10, 2,4-difluorophenol was replaced with 4-methoxy-2-fluorophenol to obtain 4- (5- (ethylsulfinyl Aminomethyl) -2- (2-fluoro-4-methoxyphenoxy) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine- 7-ketone (21% yield).
MS m/z(ESI)：456.1[M+H]+； MS m / z (ESI): 456.1 [M + H] + ;
1H NMR(400MHz,d4-MeOD)：δ 8.11(d,J=2.4Hz,1H),8.00-7.97(dd,J=8.8Hz,2.4Hz,1H),7.36(s,1H),7.28(d,J=2.8Hz,1H),7.08-7.02(m,2H),6.85-6.81(dd,J=12.4Hz,2.8Hz,1H),6.74-6.71(m,1H),6.29(d,J=3.2Hz,1H),3.97(q,J=7.2Hz,2H),3.72(s,3H),3.64(s,3H),1.32(t,J=7.2Hz,3H)。 1 H NMR (400MHz, d 4-MeOD): δ 8.11 (d, J = 2.4Hz, 1H), 8.00-7.97 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.36 (s, 1H), 7.28 (d, J = 2.8Hz, 1H), 7.08-7.02 (m, 2H), 6.85-6.81 (dd, J = 12.4Hz, 2.8Hz, 1H), 6.74-6.71 (m, 1H), 6.29 (d, J = 3.2Hz, 1H), 3.97 (q, J = 7.2Hz, 2H), 3.72 (s, 3H), 3.64 (s, 3H), 1.32 (t, J = 7.2Hz, 3H).
反應操作同實施例五第一步，得到(甲基亞硫醯基<亞磺醯>)乙烷(2.25g)。 The reaction was carried out in the same manner as in the first step of Example 5 to obtain (methylthiosulfinyl <sulfenimidine>) ethane (2.25 g).
反應操作同實施例五第二步，得到乙基(亞胺基)(甲基)-λ6-硫烷酮(1.5g)。 The reaction was carried out in the same manner as in the second step of Example 5 to obtain ethyl (imino) (methyl) -λ6-sulfanone (1.5 g).
以2-溴-1-(2,4-二氟苯氧基)-4-碘苯與乙基(亞胺基)(甲基)-λ6-硫烷酮為原料，反應操作參考實施例19第五至七步，得到4-(2-(2,4-二氟苯氧基)-5-((乙基(甲基)(羰基)-λ6-硫烷亞基)胺基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(三步總收率11.8%)。 Using 2-bromo-1- (2,4-difluorophenoxy) -4-iodobenzene and ethyl (imino) (methyl) -λ6-sulfanone as raw materials, refer to Example 19 for the reaction operation. Steps 5 to 7 give 4- (2- (2,4-difluorophenoxy) -5-((ethyl (methyl) (carbonyl) -λ6-sulfanylidene) amino) phenyl ) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (three-step total yield 11.8%).
MS m/z(ESI)：458.1[M+H]+. MS m / z (ESI): 458.1 [M + H] +.
1H NMR(400MHz,DMSO-d6)：δ 12.0(br,1H),7.35-7.25(m,3H)，7.06(s,1H),6.98-6.91(m,3H),6.81(d,J =8.4Hz,1H),6.22(t,J=2.0Hz,1H),3.52(s,3H),3.36(q,J=7.2Hz,2H),3.12(s,3H),1.30(t,J=7.2Hz,3H). 1 H NMR (400MHz, DMSO-d6): δ 12.0 (br, 1H), 7.35-7.25 (m, 3H), 7.06 (s, 1H), 6.98-6.91 (m, 3H), 6.81 (d, J = 8.4Hz, 1H), 6.22 (t, J = 2.0Hz, 1H), 3.52 (s, 3H), 3.36 (q, J = 7.2Hz, 2H), 3.12 (s, 3H), 1.30 (t, J = 7.2Hz, 3H).
以4-(5-(環丙磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，參考實施例5第五步，用(2,2-二氟環丙基)甲醇替代環丙基甲醇，得到4-(5-(環丙磺亞胺醯基)-2-((2,2-二氟環丙基)甲氧基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(43%)。 4- (5- (Cyclopropanesulfenimido) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one as a raw material. In the fifth step of Reference Example 5, cyclopropyl methanol was replaced with (2,2-difluorocyclopropyl) methanol to obtain 4- (5- (cyclopropanesulfenimide). Yl) -2-((2,2-difluorocyclopropyl) methoxy) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine- 7-one (43%).
MS m/z(ESI)：434.2[M+H]+； MS m / z (ESI): 434.2 [M + H] + ;
1H NMR(400MHz,CDCl 3 )：δ 7.89-7.87(m,2H),7.17-7.12(m,2H),7.05(s,1H),6.17(d,J=2.8Hz,1H),5.09-5.04(m,1H),4.28-4.23(m,1H),3.60(s,3H),2.58-2.52(m,1H),2.31-2.22(m,1H),1.52-0.98(m,6H). 1 H NMR (400MHz, CDCl 3 ): δ 7.89-7.87 (m, 2H), 7.17-7.12 (m, 2H), 7.05 (s, 1H), 6.17 (d, J = 2.8Hz, 1H), 5.09- 5.04 (m, 1H), 4.28-4.23 (m, 1H), 3.60 (s, 3H), 2.58-2.52 (m, 1H), 2.31-2.22 (m, 1H), 1.52-0.98 (m, 6H).
以4-(5-(環丙磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，參考實施例5第五步，得到4-(5-(環丙磺亞胺醯基)-2-((四氫-2H-吡喃-4-基)酮基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(48%)。 4- (5- (Cyclopropanesulfenimido) -2-fluorophenyl) -6-methyl-1-toluenesulfonium-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one as a raw material, referring to the fifth step of Example 5, to obtain 4- (5- (cyclopropanesulfenimidoamido) -2-((tetrahydro-2H-pyran-4-yl) Keto) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (48%).
MS m/z(ESI)：428.2[M+H]+ MS m / z (ESI): 428.2 [M + H] +
1H NMR(400MHz,CDCl 3 )：δ 10.81(s,1H),8.03(d,J=2.4Hz,1H),7.95-7.92(dd,J=8.8Hz,2.4Hz,1H),7.29-7.26(t,J=2.4Hz,1H),7.10(s,1H),7.10-7.08(d,J=8.8Hz,1H),6.26(t,J=2.4Hz,1H),4.62(t,J=3.6Hz,1H),3.80-3.73(m,5H),3.54-3.45(m,2H),2.65-2.62(m,2H),1.99-1.95(m,2H),1.72-1.68(m,2H),1.42-0.98(m,4H)。 1 H NMR (400MHz, CDCl 3 ): δ 10.81 (s, 1H), 8.03 (d, J = 2.4Hz, 1H), 7.95-7.92 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.29-7.26 (t, J = 2.4Hz, 1H), 7.10 (s, 1H), 7.10-7.08 (d, J = 8.8Hz, 1H), 6.26 (t, J = 2.4Hz, 1H), 4.62 (t, J = 3.6Hz, 1H), 3.80-3.73 (m, 5H), 3.54-3.45 (m, 2H), 2.65-2.62 (m, 2H), 1.99-1.95 (m, 2H), 1.72-1.68 (m, 2H) , 1.42-0.98 (m, 4H).
4-(5-(S-甲基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺 醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為反應原料，參考實施例10第五步，用順-1,4-二羥基環己烷替代2,4-二氟苯酚，得到4-(2-(順-4-羥基環己基)酮基)-5-(甲基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(收率10%.) 4- (5- (S-methylsulfonylimidino) -2-fluorophenyl) -6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo [2,3 -c] pyridine-7-one as a reaction raw material, refer to the fifth step of Example 10, and replace 2,4-difluorophenol with cis-1,4-dihydroxycyclohexane to obtain 4- (2- (cis- 4-Hydroxycyclohexyl) keto) -5- (methylsulfonylimido) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine- 7-keto (yield 10%.)
MS m/z(ESI)：416[M+H]+. MS m / z (ESI): 416 [M + H] + .
1H NMR(400MHz,DMSO)：δ 12.04(br,1H),7.85(d,J=2.4Hz,1H),7.75(d,J=8.4Hz,2.4Hz,1H),7.28(s,1H),7.25-7.22(m,2H),6.13(d,J=2.4Hz,1H),4.57-4.52(br,1H),4.42-4.32(br,1H),4.0(s,1H),3.51(s,3H),3.48-3.45(m,1H),3.0(s,3H),1.77-1.69(m,2H),1.55-1.39(m,4H),1.33-1.21(m,2H). 1 H NMR (400MHz, DMSO): δ 12.04 (br, 1H), 7.85 (d, J = 2.4Hz, 1H), 7.75 (d, J = 8.4Hz, 2.4Hz, 1H), 7.28 (s, 1H) , 7.25-7.22 (m, 2H), 6.13 (d, J = 2.4Hz, 1H), 4.57-4.52 (br, 1H), 4.42-4.32 (br, 1H), 4.0 (s, 1H), 3.51 (s , 3H), 3.48-3.45 (m, 1H), 3.0 (s, 3H), 1.77-1.69 (m, 2H), 1.55-1.39 (m, 4H), 1.33-1.21 (m, 2H).
將化合物4-(5-(乙基磺亞胺醯基)-2-((4-羰基環己基)酮基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(42.8mg,0.1mmol)溶於10毫升二氯甲烷中，冰水浴下加入硼氫化鈉(12mg,0.3mmol)。反應在室溫條件下攪拌2小時。減壓條件下除去溶劑，殘餘物用乙酸乙酯/水分液萃取，有機相經過乾燥，濃縮，製備TLC板分離(二氯甲烷/ 甲醇=20：1)得到化合物4-(5-(乙基磺亞胺醯基)-2-((4-羥基環己基)酮基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(21mg,49%)。 Compound 4- (5- (ethylsulfonylimido) -2-((4-carbonylcyclohexyl) keto) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (42.8 mg, 0.1 mmol) was dissolved in 10 ml of dichloromethane, and sodium borohydride (12 mg, 0.3 mmol) was added in an ice water bath. The reaction was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was extracted with ethyl acetate / water solution. The organic phase was dried, concentrated, and separated on a TLC plate (dichloromethane / methanol = 20: 1) to obtain compound 4- (5- (ethyl Sulfimidinyl) -2-((4-hydroxycyclohexyl) keto) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7 -Ketone (21 mg, 49%).
MS m/z(ESI)：430.1[M+H]+； MS m / z (ESI): 430.1 [M + H] + ;
1H NMR(400MHz,d4-MeOD)：δ 7.88-7.80(m,2H),7.25-7.16(m,3H),6.19-6.13(m,1H),4.56-4.44(m,1H),3.61-3.59(m,3H),3.55-3.49(m,1H),3.19-3.13(m,2H),1.98-1.29(m,8H),1.19-1.12(m,3H). 1 H NMR (400MHz, d 4-MeOD): δ 7.88-7.80 (m, 2H), 7.25-7.16 (m, 3H), 6.19-6.13 (m, 1H), 4.56-4.44 (m, 1H), 3.61 -3.59 (m, 3H), 3.55-3.49 (m, 1H), 3.19-3.13 (m, 2H), 1.98-1.29 (m, 8H), 1.19-1.12 (m, 3H).
將化合物4-(5-(乙基磺亞胺醯基)-2-((4-羰基環己基)酮基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(42.8mg,0.1mmol)溶於10毫升無水四氫呋喃中，-78℃條件下滴入1M濃度的甲基格式試劑四氫呋喃溶液(0.15mL,0.15mmol)。反應自然升溫至室溫並攪拌過夜。飽和氯化銨溶液淬滅反應，乙酸乙酯萃取，有機相經過乾燥，濃縮，製備TLC板分離(二氯甲烷/甲醇=20：1)得到化合物4-(5-(乙基磺亞胺醯基)-2-((4-羥基-4-甲基環己基)酮基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(10.5mg,49%) Compound 4- (5- (ethylsulfonylimido) -2-((4-carbonylcyclohexyl) keto) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (42.8mg, 0.1mmol) was dissolved in 10ml of anhydrous tetrahydrofuran, and a 1M concentration methyl form reagent tetrahydrofuran solution (0.15mL, 0.15mmol) was added dropwise at -78 ° C . The reaction was naturally warmed to room temperature and stirred overnight. The reaction was quenched with a saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried and concentrated to prepare a TLC plate for separation (dichloromethane / methanol = 20: 1) to obtain the compound 4- (5- (ethylsulfimide) ) -2-((4-hydroxy-4-methylcyclohexyl) keto) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine- 7-keto (10.5mg, 49%)
MS m/z(ESI)：444.2[M+H]+； MS m / z (ESI): 444.2 [M + H] + ;
1H NMR(400MHz,d4-MeOD)：δ 7.85-7.80(m,2H),7.24-7.16(m,3H),6.16-6.14(m,1H),4.63-4.38(m,1H),3.60(s,3H),3.55-3.49(m,1H),3.18-3.14(m,2H),1.82-1.35(m,7H),1.17-1.13(m,3H),1.01-0.83(m,3H). 1 H NMR (400MHz, d 4-MeOD): δ 7.85-7.80 (m, 2H), 7.24-7.16 (m, 3H), 6.16-6.14 (m, 1H), 4.63-4.38 (m, 1H), 3.60 (s, 3H), 3.55-3.49 (m, 1H), 3.18-3.14 (m, 2H), 1.82-1.35 (m, 7H), 1.17-1.13 (m, 3H), 1.01-0.83 (m, 3H) .
在氬氣氣氛下，4-甲基苯硫酚(651mg,5.25mmol)，2-溴-1-氟-4-碘苯(1.5g,5mmol)，氧化亞銅(36mg,0.25mmol)，氫氧化鉀(560mg,10mmol)和30毫升1,4-二氧六環加入圓底瓶中，反應加熱至回流攪拌過夜。反應用水稀釋，矽藻土過濾出去參與的銅催化劑，濾液用乙酸乙酯萃取三遍。合併有機相，水洗，飽和食鹽水洗，無水硫酸鈉乾燥。濾去乾燥劑，濾液旋乾。殘餘物矽膠管柱層析分離(石油醚：乙酸乙酯=2：1)得到(3-溴-4-氟苯基)(p-苯甲基)硫烷 (1.1g,74%)。 Under argon atmosphere, 4-methylthiophenol (651 mg, 5.25 mmol), 2-bromo-1-fluoro-4-iodobenzene (1.5 g, 5 mmol), cuprous oxide (36 mg, 0.25 mmol), hydrogen Potassium oxide (560 mg, 10 mmol) and 30 ml of 1,4-dioxane were added to the round bottom flask, and the reaction was heated to reflux and stirred overnight. The reaction was diluted with water, the participating copper catalyst was filtered off with celite, and the filtrate was extracted three times with ethyl acetate. The organic phases were combined, washed with water, saturated brine, and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was spin-dried. The residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain (3-bromo-4-fluorophenyl) (p-benzyl) sulfane (1.1 g, 74%).
以(3-溴-4-氟苯基)(p-苯甲基)硫烷為反應原料，參考實施例74第二步，得到2-溴-1-氟-4-(p-苯甲基亞硫醯基<亞磺醯>)苯(產率95%)。 Using (3-bromo-4-fluorophenyl) (p-benzyl) sulfane as a reaction raw material, refer to the second step of Example 74 to obtain 2-bromo-1-fluoro-4- (p-benzyl) Thiosulfinyl <sulfenimidine>) benzene (95% yield).
MS m/z(ESI)：313.0/315.0(50/50)[M+H]+ MS m / z (ESI): 313.0 / 315.0 (50/50) [M + H] +
以1-((3-溴-4-氟苯基)亞硫醯基<亞磺醯>)-2-甲基丙烷-2-醇為原料，參考實施例74第三步，得到(3-溴-4-氟苯基)(亞胺基)(p-苯甲基)-16-硫烷酮(產率63%)。 Using 1-((3-bromo-4-fluorophenyl) thiosulfenyl <sulfenaminium>)-2-methylpropane-2-ol as a raw material, refer to the third step of Example 74 to obtain (3- Bromo-4-fluorophenyl) (imino) (p-benzyl) -16-sulfanone (63% yield).
MS m/z(ESI)：328.0/330.0(50/50)[M+H]+. MS m / z (ESI): 328.0 / 330.0 (50/50) [M + H] + .
以(3-溴-4-氟苯基)(亞胺基)(p-苯甲基)-16-硫烷酮為原料，參考實施例74第四步得到4-(2-氟-5-(4-甲基苯基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(產率67%) Using (3-bromo-4-fluorophenyl) (imino) (p-benzyl) -16-sulfanone as a raw material, the fourth step of Reference Example 74 was used to obtain 4- (2-fluoro-5- (4-methylphenylsulfonylimino) phenyl) -6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridine-7- Ketone (67% yield)
MS m/z(ESI)：550.1[M+H]+ MS m / z (ESI): 550.1 [M + H] +
以4-(2-氟-5-(4-甲基苯基磺亞胺醯基)苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮與2,4-二氟苯酚為反應原料，參考實施例10第五步，得到4-(2-(2,4-二氟苯氧基)-5-(4-甲基苯基磺亞胺醯基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(52%)。 As 4- (2-fluoro-5- (4-methylphenylsulfonylimino) phenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [ 2,3-c] pyridin-7-one and 2,4-difluorophenol are used as the starting materials. Referring to the fifth step of Example 10, 4- (2- (2,4-difluorophenoxy) -5 is obtained. -(4-methylphenylsulfonylimino) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (52%) .
MS m/z(ESI)：506.1[M+H]+； MS m / z (ESI): 506.1 [M + H] + ;
1H NMR(400MHz,d6-DMSO)δ 12.10(brs,1H),8.01(d,J=2.8Hz,1H),7.85(d,J=8.4Hz,3H),7.51-7.45(m,1H), 7.37-7.34(m,5H),7.15-7.10(m,1H)6.88(d,J=8.8Hz,1H),6.19(t,J=2.4Hz,1H),4.90(s,1H),3.57(s,3H),2.34(s,3H). 1 H NMR (400MHz, d 6-DMSO) δ 12.10 (brs, 1H), 8.01 (d, J = 2.8Hz, 1H), 7.85 (d, J = 8.4Hz, 3H), 7.51-7.45 (m, 1H ), 7.37-7.34 (m, 5H), 7.15-7.10 (m, 1H) 6.88 (d, J = 8.8Hz, 1H), 6.19 (t, J = 2.4Hz, 1H), 4.90 (s, 1H), 3.57 (s, 3H), 2.34 (s, 3H).
以4-(5-(乙基磺亞胺醯基)-2-氟苯基)-6-甲基-1-甲苯磺醯-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮為原料，參考實施例10第五步，以3-羥甲基苯酚替代2,4-二氟苯酚，得到4-(5-(乙基磺亞胺醯基)-2-(3-(羥甲基)苯氧基)苯基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮(收率：8%)。 4- (5- (ethylsulfonylimino) -2-fluorophenyl) -6-methyl-1-toluenesulfon-1,6-dihydro-7H-pyrrolo [2,3- c] Pyridin-7-one as a raw material. In the fifth step of Reference Example 10, 3-hydroxymethylphenol was used instead of 2,4-difluorophenol to obtain 4- (5- (ethylsulfonylimino)-. 2- (3- (hydroxymethyl) phenoxy) phenyl) -6-methyl-1,6-dihydro-7H-pyrrolo [2,3-c] pyridin-7-one (yield: 8%).
MS m/z(ESI)：438.1[M+H]+； MS m / z (ESI): 438.1 [M + H] + ;
1H NMR(400MHz,d4-MeOD)δ 7.98(d,J=2.0Hz,1H),7.81(dd,J=8.8Hz,2.4Hz,1H),7.25-7.19(m,3H),7.06-7.00(m,2H),6.90(s,1H),6.78(d,J=9.6Hz,1H),6.28(d,J=3.2Hz,1H),4.45(s,2H),3.56(s,3H),3.18(q,J=7.6Hz,2H),1.17(t,J=7.6Hz,3H). 1 H NMR (400MHz, d 4-MeOD) δ 7.98 (d, J = 2.0Hz, 1H), 7.81 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.25-7.19 (m, 3H), 7.06- 7.00 (m, 2H), 6.90 (s, 1H), 6.78 (d, J = 9.6Hz, 1H), 6.28 (d, J = 3.2Hz, 1H), 4.45 (s, 2H), 3.56 (s, 3H ), 3.18 (q, J = 7.6Hz, 2H), 1.17 (t, J = 7.6Hz, 3H).
以下結合測試例進一步描述解釋本發明，但這些實施例並非意味著限制本發明的範圍。 The present invention is further described below in conjunction with test examples, but these examples are not meant to limit the scope of the present invention.
測試例1、本發明化合物對BRD4結合活性的測定Test example 1. Determination of BRD4 binding activity of the compound of the present invention
BRD4結合活性測試藉由以下的方法進行測試。 The BRD4 binding activity test was performed by the following method.
該方法用來測定本發明中的化合物對BRD4結合活性的抑制作用。 This method is used to determine the inhibitory effect of the compounds of the present invention on the BRD4 binding activity.
實驗步驟 Experimental steps
為了測試化合物對BRD4於乙醯化蛋白結合的的影響，本實驗採用螢光共振能量轉移(TR-FRET)的方法測試化合物對BRD4與乙醯化底物結合活性的抑制作用，並得出化合物對BRD4結合活性的半數抑制濃度IC50。 In order to test the effect of compounds on the binding of BRD4 to acetylated protein, this experiment uses fluorescence resonance energy transfer (TR-FRET) to test the inhibitory effect of compounds on the binding activity of BRD4 to acetylated substrates, and to obtain the compounds BRD4 binding activity for half maximal inhibitory concentration IC 50.
具體實驗操作如下：1、在384孔板中加入1~5ul BRD4酶溶液，酶終濃度為1~20nM；2、加入1~5ul梯度稀釋好的化合物溶液；3、加入1~5ul底物混合液包含乙醯化底物多肽終濃度2~50nM；4、室溫孵育0.5~3小時；5、加入10ul EDTA和含標記抗體的檢測液，室溫孵育1小時；6、酶標儀測定各板孔的665nm螢光信號值；7、藉由螢光信號值計算抑制率；8、根據不同濃度的抑制率藉由曲線擬合得出化合物的IC50。 The specific experimental operation is as follows: 1. Add 1 ~ 5ul BRD4 enzyme solution to a 384-well plate with a final enzyme concentration of 1 ~ 20nM; 2. Add 1 ~ 5ul gradient diluted compound solution; 3. Add 1 ~ 5ul substrate mixture The solution contains a final concentration of acetylated substrate polypeptide of 2 to 50 nM; 4. Incubate at room temperature for 0.5 to 3 hours; 5. Add 10 ul of EDTA and a detection solution containing a labeled antibody and incubate for 1 hour at room temperature; 6. Determine each 665nm fluorescent signal values plate hole; 7, by fluorescence signal value calculating inhibition rate; 8, obtained according to compound IC 50 inhibition rate of different concentration by curve fitting.
本發明中化合物對BRD4結合活性藉由以上的試驗進行測定，測得的IC50值見表1。 The binding activity of the compound of the present invention to BRD4 was determined by the above test, and the IC 50 values measured are shown in Table 1.
結論：本發明化合物對BRD4結合活性具有明顯的抑制作用。 Conclusion: The compounds of the present invention have a significant inhibitory effect on BRD4 binding activity.
測試例2、本發明化合物對結腸癌腫瘤細胞colo205增殖活性的測定Test example 2. Determination of the proliferative activity of the compound of the present invention on colon cancer tumor cell colo205
化合物對結腸癌腫瘤細胞colo205增殖活性藉由以下的方法進行測試。 The compound's proliferative activity against colon cancer tumor cells colo205 was tested by the following method.
該方法用來測定本發明中的化合物對結腸癌腫瘤細胞colo205增殖活性的抑制作用。 This method is used to determine the inhibitory effect of the compound of the present invention on the colon cancer tumor cell colo205 proliferation activity.
實驗步驟 Experimental steps
本實驗採用CellTiter-Glo的方法測試化合物對colo205細胞增殖的抑制作用，並得出化合物抑制細胞增殖活性的半數抑制濃度IC50。 The method of the present study, the inhibition of a test compound on the colo205 CellTiter-Glo cell proliferation, and to obtain the compound inhibited cell proliferation half maximal inhibitory concentration IC 50 activity.
1、在96孔細胞培養板中接種50~100μL的colo205細胞懸液，密度為1~5*104細胞/ml，將培養板於培養箱培養16~24小時(37℃，5% CO2)。 1. Inoculate 50 ~ 100 μL of colo205 cell suspension in a 96-well cell culture plate with a density of 1 ~ 5 * 104 cells / ml. Culture the plate in an incubator for 16 ~ 24 hours (37 ° C, 5% CO 2 ). .
2、向培養板細胞中加入梯度稀釋的不同濃度的待測化合物溶液，將培養板在培養箱孵育6天(37℃，5% CO2)。 2. Add gradient dilutions of different concentrations of the test compound solution to the cells in the culture plate, and incubate the culture plate in an incubator for 6 days (37 ° C, 5% CO 2 ).
3、每孔加入50~100μL CellTiter-Glo試劑，並振盪10分鐘，室溫靜置10分鐘。 3. Add 50 ~ 100μL CellTiter-Glo reagent to each well, shake for 10 minutes, and let stand at room temperature for 10 minutes.
4、酶標儀測定各板的化學發光信號值。 4. The microplate reader measures the chemiluminescence signal value of each plate.
5、藉由化學發光信號值計算抑制率。 5. Calculate the inhibition rate based on the value of the chemiluminescence signal.
6、根據不同濃度的抑制率藉由曲線擬合得出化合物的IC50。 6. The inhibition rate of different concentration of IC 50 obtained by curve fitting of the compound.
本發明中化合物對結腸癌腫瘤細胞colo205增殖活性的試驗進行測定，測得的IC50值見表2。 The compound of the present invention is tested for colon cancer tumor cell colo205 proliferation activity test, and the IC 50 values measured are shown in Table 2.
表2本發明中化合物對結腸癌腫瘤細胞colo205增殖 活性抑制IC50
結論：本發明化合物對結腸癌腫瘤細胞colo205增殖活性具有明顯的抑制作用。 Conclusion: The compound of the present invention has a significant inhibitory effect on the proliferation activity of colon cancer tumor cells colo205.
測試例3、本發明化合物對白血病細胞MV4-11增殖活性的影響Test Example 3, Effects of the compound of the present invention on the proliferative activity of leukemia cells MV4-11
化合物對白血病細胞MV4-11增殖活性的影響藉由以下的方法進行測試。 The effect of the compound on the proliferative activity of leukemia cells MV4-11 was tested by the following method.
該方法用來測定本發明中的化合物對白血病細胞MV4-11增殖活性的影響。 This method is used to determine the effects of the compounds of the present invention on the proliferative activity of leukemia cells MV4-11.
本實驗採用CellTiter-Glo的方法測試化合物對MV4-11細胞增殖的抑制作用，並得出化合物抑制細胞增殖活性的半數抑制濃度IC50。 This experiment uses the CellTiter-Glo method for testing compounds for inhibition of the proliferation of MV4-11 cells, the compounds inhibit cell proliferation and draw half maximal inhibitory concentration IC 50 activity.
實驗步驟： Experimental steps:
1、在96孔細胞培養板中接種50~100μL的MV4-11細胞懸液，密度為1~5*104細胞/ml，將培養板於培養箱培養16~24小時(37℃，5%CO2)。 1. Inoculate 50 ~ 100 μL of MV4-11 cell suspension in a 96-well cell culture plate with a density of 1 ~ 5 * 10 4 cells / ml. Culture the plate in an incubator for 16 ~ 24 hours (37 ° C, 5% CO 2 ).
2、向培養板細胞中加入梯度稀釋的不同濃度的待測化合物溶液，將培養板在培養箱孵育72小時(37℃，5%CO2)。 2. Add gradient dilutions of different concentrations of the test compound solution to the cells in the culture plate, and incubate the culture plate in an incubator for 72 hours (37 ° C, 5% CO 2 ).
3、每孔加入50~100μL CellTiter-Glo試劑，並振盪10分鐘，室溫靜置10分鐘。 3. Add 50 ~ 100μL CellTiter-Glo reagent to each well, shake for 10 minutes, and let stand at room temperature for 10 minutes.
4、酶標儀測定各板的化學發光信號值。 4. The microplate reader measures the chemiluminescence signal value of each plate.
5、藉由化學發光信號值計算抑制率。 5. Calculate the inhibition rate based on the value of the chemiluminescence signal.
6、根據不同濃度的抑制率藉由曲線擬合得出化合物的IC50。 6. The inhibition rate of different concentration of IC 50 obtained by curve fitting of the compound.
本發明中化合物對白血病細胞MV4-11增殖活性的試驗進行測定，測得的IC50值見表3。 The test of the compound of the present invention on the proliferative activity of leukemia cells MV4-11 was measured, and the IC 50 values measured are shown in Table 3.
結論：本發明化合物對白血病細胞MV4-11增殖活性具有明顯的抑制作用。 Conclusion: The compound of the present invention has a significant inhibitory effect on the proliferation activity of leukemia cells MV4-11.
測試例4、本發明化合物對小鼠的PK分析測試Test Example 4. PK analysis test of the compound of the present invention on mice
本發明較佳實施例的小鼠藥物代謝動力學試驗採用Balb/c小鼠(上海傑思捷實驗動物有限公司)進行。 The pharmacokinetics test of mice in the preferred embodiment of the present invention is performed using Balb / c mice (Shanghai Jiesijie Experimental Animal Co., Ltd.).
給藥方式：單次灌胃給藥 Mode of administration: single intragastric administration
給藥劑量：5毫克/10毫升/千克 Dosage: 5 mg / 10 ml / kg
製劑處方：0.5% CMC-Na和1% Tween 80，超聲溶解 Formulation: 0.5% CMC-Na and 1% Tween 80, sonicated
取樣點：給藥後0.5、1、2、4、6、8和24小時 Sampling points: 0.5, 1, 2, 4, 6, 8 and 24 hours after dosing
樣品處理：靜脈採血0.1mL，置於K2EDTA試管中，室溫1000~3000×g離心5~20min分離血漿，於-80℃保存。 Sample processing: 0.1mL of venous blood was collected, placed in a K2EDTA test tube, and the plasma was separated by centrifugation at 1000 ~ 3000 × g for 5-20min at room temperature, and stored at -80 ° C.
血漿樣品40uL加入160uL乙腈沉澱，混合後500~2000×g離心5~20分鐘。 Plasma samples of 40uL were added to 160uL of acetonitrile to precipitate. After mixing, centrifuge at 500 ~ 2000 × g for 5 ~ 20 minutes.
取處理後上清溶液100uL進行LC/MS/MS分析待測化合物的濃度，LC/MS/MS分析儀器：AB Sciex API 4000。 Take 100uL of the treated supernatant solution to analyze the concentration of the test compound by LC / MS / MS. LC / MS / MS analysis instrument: AB Sciex API 4000.
液相條件：Shimadzu LC-20AD泵 Liquid condition: Shimadzu LC-20AD pump
色譜管柱：phenomenex Gemiu 5μm C18 50×4.6mm Column: phenomenex Gemiu 5μm C18 50 × 4.6mm
移動相：A液為0.1%甲酸水溶液，B液為乙腈 Mobile phase: A solution is 0.1% formic acid aqueous solution, B solution is acetonitrile
流速：0.8mL/min Flow rate: 0.8mL / min
藥物代謝動力學：主要參數用WinNonlin 6.1計算得到，小鼠藥物代謝實驗結果見下表4 Pharmacokinetics: The main parameters are calculated using WinNonlin 6.1, and the results of mouse drug metabolism experiments are shown in Table 4 below.
從表中小鼠藥物代謝實驗結果可以看出：本發明實施例化合物表現出良好的代謝性質，暴露量AUC和最大血藥濃度Cmax都表現良好。 From the results of the mouse drug metabolism experiments in the table, it can be seen that the compounds of the examples of the present invention show good metabolic properties, and both the exposure AUC and the maximum blood concentration Cmax are good.
測試例5、本發明化合物對體內藥效試驗測試Test Example 5: Test of in vivo efficacy of the compound of the present invention
實驗目的：藉由體內藥效實驗篩選出藥效較為明顯且毒副作用較小的化合物。 Experimental purpose: To screen compounds with obvious efficacy and less toxic and side effects through in vivo pharmacodynamic experiments.
實驗主要儀器和試劑 The main instruments and reagents for the experiment
儀器： Instrument:
1、超淨工作臺(BSC-1300II A2，上海博訊實業有限公司醫療設備廠) 1. Ultra-clean bench (BSC-1300II A2, Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory)
2、CO2培養箱(Thermo) CO2 incubator (Thermo)
3、離心機(Centrifuge 5720R，Eppendorf) 3. Centrifuge (Centrifuge 5720R, Eppendorf)
4、全自動細胞計數儀(Countess II，Life) 4. Fully automatic cell counter (Countess II, Life)
5、移液器(10-20uL，Eppendorf) 5. Pipette (10-20uL, Eppendorf)
6、顯微鏡(TS100，尼康) 6.Microscope (TS100, Nikon)
6、遊標卡尺(500-196，日本三豐) 6. Vernier calipers (500-196, Mitutoyo, Japan)
7、細胞培養瓶(T25/T75/T225，Corning) 7. Cell culture flask (T25 / T75 / T225, Corning)
試劑： Reagent:
1、MEM培養基(11095-080，gibico) 1.MEM medium (11095-080, gibico)
2、胎牛血清(FBS)(10099-141，gibico) 2. Fetal bovine serum (FBS) (10099-141, gibico)
3、0.25%胰蛋白酶(25200-056，gibico) 3.0.25% trypsin (25200-056, gibico)
4、青鏈黴素雙抗(SV30010，GE) 4. Penicillin double antibody (SV30010, GE)
5、磷酸鹽緩衝液(PBS)(10010-023，gibico) 5. Phosphate buffered saline (PBS) (10010-023, gibico)
實驗步驟 Experimental steps
1、細胞培養及細胞懸液製備 1. Cell culture and cell suspension preparation
a,從細胞庫中取出一株Hep3B細胞，用MEM培養基(MEM+10%FBS+1%Glu+1%SP)復蘇細胞，復蘇後的細胞置細胞培養瓶中(在瓶壁標記好細胞種類、日期、培養人名字等)置於CO2培養箱中培養(培養箱溫度為37℃，CO2濃度為5%)。 a. Remove a Hep3B cell from the cell bank, resuscitate the cells with MEM medium (MEM + 10% FBS + 1% Glu + 1% SP), and place the recovered cells in a cell culture flask (label the cell type on the bottle wall) , Date, culture name, etc.) and cultured in a CO 2 incubator (incubator temperature is 37 ° C., CO 2 concentration is 5%).
b,待細胞鋪滿培養瓶底部80-90%後傳代，傳代後細胞繼續置於CO2培養箱中培養，重複該過程直到細胞數滿足體內藥效需求。 b. Passage the cells to 80-90% of the bottom of the culture flask. Passage the cells and continue to culture in a CO 2 incubator. Repeat this process until the number of cells meets the in vivo pharmacodynamic requirements.
c,收集培養好的細胞，用全自動細胞計數儀計數，根據計數結果用PBS重懸細胞，製成細胞懸液(密度7×107/mL)，置於冰盒中待用。 c. Collect the cultured cells, count with a full-automatic cell counter, and resuspend the cells with PBS according to the counting results to make a cell suspension (density 7 × 107 / mL) and put them in an ice box for use.
2、細胞接種、量瘤： 2. Cell inoculation and tumor measurement:
a,接種前用一次性大小鼠通用耳標標記裸鼠，並用75%醫用酒精消毒接種部位皮膚。 a. Mark nude mice with disposable ear and mouse ear tags before inoculation, and disinfect the skin of the inoculation site with 75% medical alcohol.
b,接種時混勻細胞懸液，用1mL注射器抽取0.1~1mL細胞懸液、排除氣泡，然後將注射器置於冰袋上待用。 b, mix the cell suspension during inoculation, withdraw 0.1 ~ 1mL cell suspension with a 1mL syringe, eliminate air bubbles, and then place the syringe on an ice bag for use.
c,依次給試驗裸鼠接種(接種部位位於裸鼠右側背部靠右肩位置皮下接種0.1mL細胞懸液)。 c. Inoculate the test nude mice in sequence (the inoculation site is subcutaneously inoculated with 0.1 mL of cell suspension on the right back and right shoulder of the nude mice).
3、荷瘤鼠量瘤、分組、給藥 3, tumor-bearing mice tumor measurement, grouping, administration
a,根據腫瘤生長情況，在接種後第14-16天量瘤、並計算腫瘤大小。 a. According to the tumor growth, measure the tumor on the 14-16 days after vaccination and calculate the tumor size.
腫瘤體積計算：腫瘤體積(mm3)=長(mm)×寬(mm)×寬(mm)/2 Tumor volume calculation: tumor volume (mm 3 ) = length (mm) × width (mm) × width (mm) / 2
b,根據腫瘤大小，採用隨機分組的方法進行分組。 b. According to tumor size, grouping is performed by random grouping.
c,根據分組結果，開始給予測試藥物(給藥方式：口服給藥，給藥劑量：30mg/kg，給藥體積：10mL/kg，給藥頻率：2次/天，給藥週期：14天，溶媒：0.5%CMC/1%吐溫80)。 c. According to the grouping results, start to give the test drug (administration method: oral administration, dosage: 30mg / kg, dosage volume: 10mL / kg, dosage frequency: 2 times / day, dosage period: 14 days , Solvent: 0.5% CMC / 1% Tween 80).
d,開始給予測試藥物後每週二次量瘤、稱重。 d. The tumor was weighed and weighed twice a week after starting the test drug administration.
e,實驗結束後安樂死動物。 e. Animals were euthanized after the experiment.
4、試驗資料： 4. Test data:
5、實驗結果 5. Experimental results
從上述結果中可以看出，本專利的上述實施例有較好的抑瘤率。 It can be seen from the above results that the above-mentioned embodiments of the present patent have a better tumor suppressing rate.
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| CN110776508B (en) * | 2018-07-27 | 2021-07-16 | 海创药业股份有限公司 | BRD4 inhibitor and preparation method and application thereof |
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