TWI786742B - Pyridone compounds and their preparation methods and applications - Google Patents
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
本發明公開一種吡啶酮類化合物及其製備方法及應用。具體地，本發明涉及式I化合物，其可用於治療與腸易激綜合症（IBS）和其他胃腸道障礙相關的疾病，以及治療RET和/或TRK功能性障礙或調節RET和/或TRK活性的癌症、炎症性腸病、神經退化性疾病、慢性疼痛、急性疼痛、炎性疾病、克氏錐蟲感染、與骨重建調節失衡有關的疾病。The invention discloses a pyridone compound, a preparation method and application thereof. In particular, the present invention relates to compounds of formula I, which are useful for the treatment of diseases associated with irritable bowel syndrome (IBS) and other gastrointestinal disorders, as well as for the treatment of RET and/or TRK functional disorders or for the regulation of RET and/or TRK activity Cancer, inflammatory bowel disease, neurodegenerative disease, chronic pain, acute pain, inflammatory disease, Trypanosoma cruzi infection, diseases related to imbalances in the regulation of bone remodeling.
Description
本發明屬於藥物領域，具體地，涉及吡啶酮類化合物及其製備方法和應用。The invention belongs to the field of medicines, and in particular relates to pyridone compounds and their preparation methods and applications.
轉染期間重排(RET)是神經生長因子受體酪胺酸激酶，對腎臟、腸神經系統的發育，神經、內分泌、造血、雄性生殖系統等的穩態維持具有重要作用。RET的結構分為胞外區、跨膜區和胞內激酶區。其訊號傳導由神經膠質細胞系衍生的神經營養因子（GDNF）和家族配體(GFL)的可溶性蛋白質的結合介導，其神經營養因子（GDNF）家族配體不直接與RET結合，而是先與GDNF家族受體α形成複合物GFL–GFRα，繼而催化RET同源二聚，使RET在胞內區域自磷酸化，繼而招募銜接蛋白和通路蛋白來激活包括MAPK、PI3K、JAK-STAT、PKA和PKC在內的多種訊號通路，從而參與細胞增殖、神經傳導、細胞遷移和細胞分化（Alexander Drilon, Nature Reviews Clinical Oncology, 2018, 15:151–167）。這些傳導訊息在調節細胞存活、分化、增殖，遷移和趨化性上起到重要作用。Rearrangement during transfection (RET) is a nerve growth factor receptor tyrosine kinase that plays an important role in the development of the kidney and enteric nervous system, and the maintenance of homeostasis in the nervous, endocrine, hematopoietic, and male reproductive systems. The structure of RET is divided into extracellular region, transmembrane region and intracellular kinase region. Its signaling is mediated by the binding of soluble proteins of glial cell line-derived neurotrophic factor (GDNF) and family ligands (GFL), whose ligands of the neurotrophic factor (GDNF) family do not directly bind to RET, but first Form a complex GFL–GFRα with GDNF family receptor α, and then catalyze RET homodimerization, make RET autophosphorylate in the intracellular region, and then recruit adapter proteins and pathway proteins to activate including MAPK, PI3K, JAK-STAT, PKA Various signaling pathways, including PKC, are involved in cell proliferation, nerve conduction, cell migration and cell differentiation (Alexander Drilon, Nature Reviews Clinical Oncology, 2018, 15:151–167). These transmitted messages play an important role in regulating cell survival, differentiation, proliferation, migration and chemotaxis.
RET在皮膚和腸的傳入疼痛感受器的生長和存活中起到重要作用。RET激酶敲除小鼠缺乏腸內神經元，並存在其他神經系統異常，這表明神經系統正常發育可能需要功能性的RET激酶蛋白產物（Taraviras，S.等人，1999,126:2785-2797)。以結腸梗阻為特徵的Hirschsprung病患者的人群研究中，出現較高比例的家族性和散發性RET缺失突變（Butler Tjaden N.,等人，Transl. Res.，2013,162:1-15)。RET plays an important role in the growth and survival of afferent nociceptors in the skin and intestine. RET kinase knockout mice lack enteric neurons and have other neurological abnormalities, suggesting that a functional RET kinase protein product may be required for normal nervous system development (Taraviras, S. et al., 1999, 126:2785-2797) . A high proportion of familial and sporadic RET deletion mutations has been reported in population-based studies of Hirschsprung disease patients characterized by colonic obstruction (Butler Tjaden N., et al., Transl. Res., 2013, 162:1-15).
RET基因的染色體重排可能導致RET基因斷裂，斷裂後RET基因的3'端可以與KIF5B、TRIM33、CCDC6或NCOA4等不同的基因發生融合，形成融合基因，表達的融合蛋白表現為持續激活，驅動腫瘤的發生。據報導，RET基因融合存在於約10-20%的PTC（甲狀腺乳頭狀癌）患者中，主要為CCDC6-RET以及NCOA4-RET融合。約1%～2%的肺腺癌患者的體內存在RET融合基因，主要為KIF5B-RET、CCDC6-RET、TRIM33-RET、NCOA4-RET這四種，其中KIF5B-RET最為常見(Rosell R，and Karachaliou N，Lancet Oncol.，2016，17:1623-1625)。The chromosomal rearrangement of the RET gene may lead to breakage of the RET gene. After the breakage, the 3' end of the RET gene can be fused with different genes such as KIF5B, TRIM33, CCDC6 or NCOA4 to form a fusion gene. The expressed fusion protein is continuously activated and drives Tumor occurrence. According to reports, RET gene fusions exist in about 10-20% of PTC (papillary thyroid carcinoma) patients, mainly CCDC6-RET and NCOA4-RET fusions. About 1% to 2% of patients with lung adenocarcinoma have RET fusion genes in their bodies, mainly including four types: KIF5B-RET, CCDC6-RET, TRIM33-RET, and NCOA4-RET, among which KIF5B-RET is the most common (Rosell R, and Karachaliou N, Lancet Oncol., 2016, 17:1623-1625).
編碼RET蛋白的基因位於人類10號染色體長臂，其異常(基因融合、突變等)可引起多種疾病，包括甲狀腺乳頭狀癌(PTC)、甲狀腺髓樣癌(MTC)、先天性巨結腸、肺腺癌，腸易激綜合症等。The gene encoding RET protein is located on the long arm of human chromosome 10, and its abnormality (gene fusion, mutation, etc.) can cause a variety of diseases, including papillary thyroid carcinoma (PTC), medullary thyroid carcinoma (MTC), Hirschsprung cancer, pulmonary Adenocarcinoma, irritable bowel syndrome, etc.
目前已有兩個RET靶向藥上市，分別是Loxo Oncology公司的LOXO-292 (selpercatinib/LY3527723)以及Blurprint公司的BLU-667 (pralsetinib/Gavreto)。這兩個靶向藥對於RET融合或突變陽性的患者表現出理想的療效及安全性，特別是RET融合陽性的非小細胞肺癌(non small cell lung cancer, NSCLC)和RET突變陽性的髓樣甲狀腺癌(medullary thyroid cancer, MTC)。Currently, there are two RET-targeted drugs on the market, namely Loxo Oncology's LOXO-292 (selpercatinib/LY3527723) and Blurprint's BLU-667 (pralsetinib/Gavreto). These two targeted drugs have shown ideal efficacy and safety for RET fusion or mutation-positive patients, especially RET fusion-positive non-small cell lung cancer (NSCLC) and RET mutation-positive medullary thyroid. Cancer (medullary thyroid cancer, MTC).
Trk是由稱為神經營養素(NT)的一組可溶性生長因子激活的高親和性受體酪胺酸激酶。Trk受體家族具有3個成員，即Trk A、Trk B和Trk C。Trk A為神經生長因子（以下簡稱為NGF)的高親和性受體，Trk B為腦源性神經營養因子(BDNF)和神經營養素（以下簡稱為NT)-4/5的高親和性受體，Trk C為NT-3的高親和性受體。所有Trk受體在神經組織中高表達並參與神經細胞功能的分化和維持。Trks are high affinity receptor tyrosine kinases activated by a group of soluble growth factors called neurotrophins (NT). The Trk receptor family has three members, Trk A, Trk B and Trk C. Trk A is a high-affinity receptor for nerve growth factor (hereinafter referred to as NGF), and Trk B is a high-affinity receptor for brain-derived neurotrophic factor (BDNF) and neurotrophin (hereinafter referred to as NT)-4/5 , Trk C is a high-affinity receptor for NT-3. All Trk receptors are highly expressed in nerve tissue and participate in the differentiation and maintenance of nerve cell function.
已有文獻報導Trk牽涉於骨關節炎、慢性腰背痛、風濕性關節炎、骨折、間質性膀胱炎和慢性胰腺炎的傷害性疼痛、神經性疼痛以及伴有兩種上述疼痛類型的癌症疼痛中。此外，Trk受體表達於癌細胞（例如膠質瘤、肝膽管型肝癌、乳頭狀甲狀腺癌、結腸癌、非小細胞肺癌、頭頸部鱗狀細胞癌、胰腺癌、肉瘤和黑色素成神經細胞瘤、***癌和胰腺癌）、炎性細胞（例如肥大細胞和嗜酸性粒細胞）、免疫活性細胞（例如T細胞和B細胞）和角蛋白細胞，且據報導可能參與癌細胞的增殖、遷移和轉移、炎性疾病(例如潰瘍性結腸炎和克羅恩氏病）、過敏性疾病（例如哮喘、鼻炎和特應性皮炎)和其他疾病(例如銀屑病）。Trk has been reported to be involved in osteoarthritis, chronic low back pain, rheumatoid arthritis, fractures, nociceptive pain in interstitial cystitis and chronic pancreatitis, neuropathic pain, and cancer with both of the above pain types in pain. In addition, Trk receptors are expressed in cancer cells such as glioma, hepatic cholangiocarcinoma, papillary thyroid carcinoma, colon cancer, non-small cell lung cancer, squamous cell carcinoma of the head and neck, pancreatic cancer, sarcoma and melanoblastoma, prostate and pancreatic cancer), inflammatory cells (such as mast cells and eosinophils), immunocompetent cells (such as T cells and B cells), and keratinocytes, and have been reported to be involved in cancer cell proliferation, migration, and metastasis , inflammatory diseases (such as ulcerative colitis and Crohn's disease), allergic diseases (such as asthma, rhinitis and atopic dermatitis) and other diseases (such as psoriasis).
因此，具有Trk抑制活性的化合物可用於治療傷害性疼痛、神經性疼痛和組合這兩類疼痛的疼痛、癌症、炎性疾病、過敏性疾病和銀屑病。Compounds having Trk inhibitory activity are therefore useful in the treatment of nociceptive pain, neuropathic pain and pain combining these two types of pain, cancer, inflammatory diseases, allergic diseases and psoriasis.
腸易激綜合症(IBS)是一種常見的功能性疾病，有10-20%的個體受其影響，並且以異常腸排便、胃氣脹、腹痛和內臟超敏感反應為特徵。目前大多數研究認為IBS病因是由於腦和胃腸道之間的障礙，腸道微生物的干擾或者炎症的增加導致的，以至於影響腸道傳輸功能，從而導致腹瀉、便秘。有些患者隨意服用藥物，更進一步導致腸道菌群失調，加重了疾病。這些研究表明，抑制RET和/或TRK可能是一種有效的策略，可能用於治療與腸易激綜合症（IBS）、炎症性腸病、其他胃腸道障礙相關疾病、神經退化性疾病、慢性疼痛、急性疼痛、炎性疾病，以及治療RET和/或TRK功能性障礙或調節RET和/或TRK活性的癌症。Irritable bowel syndrome (IBS) is a common functional disorder affecting 10-20% of individuals and is characterized by abnormal bowel movements, bloating, abdominal pain, and visceral hypersensitivity. At present, most studies believe that the cause of IBS is due to the barrier between the brain and gastrointestinal tract, the interference of intestinal microorganisms or the increase of inflammation, which affects the intestinal transmission function, resulting in diarrhea and constipation. Some patients take drugs at will, which further leads to the imbalance of intestinal flora and aggravates the disease. These studies suggest that inhibition of RET and/or TRK may be an effective strategy for the treatment of diseases associated with irritable bowel syndrome (IBS), inflammatory bowel disease, other gastrointestinal disorders, neurodegenerative diseases, chronic pain , acute pain, inflammatory diseases, and cancers that treat RET and/or TRK dysfunction or modulate RET and/or TRK activity.
本發明目的是提供一種RET和TRK激酶抑制劑，其可用於治療與腸易激綜合症（IBS）、炎症性腸病、其他胃腸道障礙相關疾病、神經退化性疾病、慢性疼痛、急性疼痛、炎性疾病，以及治療RET和/或TRK功能性障礙或調節RET和/或TRK活性的癌症。The purpose of the present invention is to provide a RET and TRK kinase inhibitor, which can be used for the treatment of diseases related to irritable bowel syndrome (IBS), inflammatory bowel disease, other gastrointestinal disorders, neurodegenerative diseases, chronic pain, acute pain, Inflammatory diseases, and treatment of RET and/or TRK dysfunction or cancers that modulate RET and/or TRK activity.
本發明的第一方面，提供一種式Ⅰ化合物或其藥學上可接受的鹽、水合物、溶劑化物、同位素化合物或前藥；
式中，In the formula,
各R1
獨立地為H、鹵素或選自取代或未取代的羥基、胺基、C1-C6烷基、R'-O-(
R'、R"各自獨立地選自取代或未取代的C1-C6烷基、C3-C6環烷基、3-6員雜環基、C6-C10芳基、5-10員雜芳基，其中，所述取代是指被一個或多個選自下組的基團取代：鹵素、羥基、C1-C6烷基；R', R" are each independently selected from substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, Wherein, the substitution refers to being substituted by one or more groups selected from the following group: halogen, hydroxyl, C1-C6 alkyl;
或當兩個R1 連接至環上相鄰的兩個原子時，其可以稠合形成取代或未取代的C4-C8環烯基、4-8員雜環基、C6-C10芳基、5-10員雜芳基；Or when two R 1 are connected to two adjacent atoms on the ring, they can be fused to form substituted or unsubstituted C4-C8 cycloalkenyl, 4-8 membered heterocyclyl, C6-C10 aryl, 5 -10-membered heteroaryl;
各R2
獨立地為H、鹵素、氰基、硝基或選自取代或未取代的羥基、胺基、R8
C(O)O-(
或當兩個R2 連接至環上相鄰的兩個原子時，其可以稠合形成取代或未取代的C4-C8環烯基、4-8員雜環基、C6-C10芳基、5-10員雜芳基；Or when two R 2 are connected to two adjacent atoms on the ring, they can be fused to form substituted or unsubstituted C4-C8 cycloalkenyl, 4-8 membered heterocyclyl, C6-C10 aryl, 5 -10-membered heteroaryl;
各Rb
獨立地為鹵素、氰基、硝基或選自取代或未取代的胺基、R8
C(O)O-(
各Ra
獨立地選自鹵素、氰基、羥基、C1-C6烷基、鹵代C1-C6烷基、C1-C6烷氧基、鹵代C1-C6烷氧基、-NR7
R'7
(
R6 、R7 和R'7 各自獨立地選自H、C1-C6烷基、鹵代C1-C6烷基、C3-C6環烷基、鹵代C3-C6環烷基、3-8員環雜烷基；R 6 , R 7 and R' 7 are independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, 3-8 members Cycloheteroalkyl;
R5
為氫、氰基、鹵素、硝基或選自取代或未取代的醛基、R8
C(O)-(
或者Rb 和R5 位於相鄰的兩個C原子時，與其連接的C原子稠合形成取代或未取代的C4-C8環烯基、4-8員環雜基、C6-C10芳基、5-10員雜芳基；Or when R b and R 5 are located at two adjacent C atoms, the C atoms connected to them are fused to form substituted or unsubstituted C4-C8 cycloalkenyl, 4-8 membered cycloheteroyl, C6-C10 aryl, 5-10 member heteroaryl;
R8 、R10 、R'10 、R11 、R'11 和R"11 各自獨立地為H或選自取代或未取代的C1-C6烷基、C1-C6烷氧基、C3-C6環烷基、3-6員環雜烷基、C6-C10芳基、5-10員雜芳基，所述取代是指被一個或多個選自下組的基團取代：鹵素、羥基、C1-C6烷基、N(R'13 )(R"13 )；R'13 和R"13 各自獨立選自H、鹵素、C1-C6烷基；R 8 , R 10 , R' 10 , R 11 , R' 11 and R" 11 are each independently H or selected from substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, C3-C6 ring Alkyl, 3-6 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl, the substitution refers to being substituted by one or more groups selected from the following group: halogen, hydroxyl, C1 -C6 alkyl, N(R' 13 )(R" 13 ); R' 13 and R" 13 are each independently selected from H, halogen, C1-C6 alkyl;
或者R10 和R'10 與其連接的N原子一起形成取代或未取代的3-8員雜環基；Or R 10 and R' 10 form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom to which it is connected;
或者R'11 和R"11 與其連接的N原子一起形成取代或未取代的3-8員雜環基；Or R' 11 and R " 11 form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom it is connected to;
R9
和R'9
各自獨立地為H、氰基或選自取代或未取代的醛基、C1-C6烷基、-NR12
R'12
(
或者R9 和R'9 與其連接的N原子一起形成取代或未取代的3-8員雜環基；Or R 9 and R' 9 form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom to which they are attached;
如無特別說明，所述取代是指被一個或多個R取代；Unless otherwise specified, the substitution refers to substitution by one or more R;
各R獨立地選自鹵素、氰基、醛基、羥基、胺基、C1-C6烷基、C1-C6烷氧基；Each R is independently selected from halogen, cyano, aldehyde, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;
各L1
和L2
獨立地選自：-CRf
Rg
-(
r為1、2或3；r is 1, 2 or 3;
m和p各自獨立地為1、2、3、4、5或6；m and p are each independently 1, 2, 3, 4, 5 or 6;
n為0、1或2；n is 0, 1 or 2;
n'為0、1、2或3；n' is 0, 1, 2 or 3;
n"為0、1、2或3。n" is 0, 1, 2 or 3.
在另一優選例中，
在另一優選例中，所述的式Ⅰ化合物或其藥學上可接受的鹽、水合物、溶劑化物、同位素化合物或前藥，其具有式I'所示的結構：
式中，In the formula,
R1 選自H、鹵素、羥基、胺基、C1-C6烷基、鹵代C1-C6烷基、C1-C6烷氧基、鹵代C1-C6烷氧基、C3-C6環烷基、鹵代C3-C6環烷基、C3-C6環烷氧基、鹵代C3-C6環烷氧基、(C1-C6烷基)NH-、(C1-C6烷基)(C1-C6烷基)N-；R is selected from H, halogen, hydroxyl, amino, C1 -C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, Halogenated C3-C6 cycloalkyl, C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy, (C1-C6 alkyl) NH-, (C1-C6 alkyl) (C1-C6 alkyl )N-;
各R2 獨立地選自H、鹵素、羥基、胺基、氰基、硝基、C1-C6烷基、鹵代C1-C6烷基、C3-C6環烷基、鹵代C3-C6環烷基；Each R is independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C1 - C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkane base;
R3
和R4
各自獨立地選自H、鹵素、羥基、胺基、氰基、C1-C6烷基、鹵代C1-C6烷基、C3-C6環烷基、3-8員環雜烷基、C6-C10芳基、5-10員雜芳基、-OR6
(
R6 、R7 和R'7 各自獨立地選自H、C1-C6烷基、鹵代C1-C6烷基、C3-C6環烷基、鹵代C3-C6環烷基、3-8員環雜烷基；R 6 , R 7 and R' 7 are independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, 3-8 members Cycloheteroalkyl;
R5
選自：氫、氰基、醛基、R8
C(O)-(
R8 、R10 、R'10 、R11 、R'11 和R"11 各自獨立地選自H、C1-C6烷基、鹵代C1-C6烷基、C1-C6烷氧基、C3-C6環烷基、3-6員環雜烷基、C6-C10芳基、5-10員雜芳基；R 8 , R 10 , R' 10 , R 11 , R' 11 and R" 11 are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3- C6 cycloalkyl, 3-6 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl;
或者R10 和R'10 與其連接的N原子一起形成取代或未取代的3-8員雜環基，其中，所述取代是指被一個或多個選自下組的基團取代：鹵素、氰基、-CHO、羥基、胺基、C1-C6烷基、C1-C6烷氧基、N(R'13 )(R"13 )；R'13 和R"13 各自獨立選自H、鹵素或C1-C6烷基；Or R 10 and R' 10 form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom it is connected to, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of: halogen, Cyano, -CHO, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, N(R' 13 )(R" 13 ); R' 13 and R" 13 are each independently selected from H, halogen or C1-C6 alkyl;
R9
和R'9
各自獨立地選自氰基、醛基、C1-C6烷基、-NR12
R'12
(
或者R9 和R'9 與其連接的N原子一起形成取代或未取代的3-8員雜環基，其中，所述取代是指被一個或多個選自下組的基團取代：鹵素、氰基、醛基、羥基、胺基、C1-C6烷基、C1-C6烷氧基；Or R 9 and R' 9 form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom they are connected to, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of: halogen, Cyano, aldehyde, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;
L1
和L2
各自獨立地為-CRf
Rg
-(
n為0、1或2；n is 0, 1 or 2;
m和p各自獨立地為1、2、3、4、5或6。m and p are each independently 1, 2, 3, 4, 5 or 6.
在另一優選例中，R1 選自：C1-C6烷氧基、鹵代C1-C6烷氧基、C3-C6環烷氧基、鹵代C3-C6環烷氧基；In another preferred example, R is selected from: C1 -C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy;
R5
選自氰基、醛基、R8
C(O)-(
R8 、R10 、R'10 、R11 、R'11 和R"11 各自獨立地選自H、C1-C6烷基、鹵代C1-C6烷基、C1-C6烷氧基、C3-C6環烷基、C3-C6環雜烷基、C6-C10芳基、5-10員雜芳基；R 8 , R 10 , R' 10 , R 11 , R' 11 and R" 11 are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3- C6 cycloalkyl, C3-C6 cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl;
或者R10 和R'10 與其連接的N原子一起形成取代或未取代的3-8員雜環基，其中，所述取代是指被一個或多個選自下組的基團取代：鹵素、氰基、醛基、羥基、胺基、C1-C6烷基、C1-C6烷氧基、N(R'13 )(R"13 )；R'13 和R"13 各自獨立選自H、鹵素、C1-C6烷基；Or R 10 and R' 10 form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom it is connected to, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of: halogen, Cyanide, aldehyde, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, N(R' 13 )(R" 13 ); R' 13 and R" 13 are each independently selected from H, halogen , C1-C6 alkyl;
R9
和R'9
各自獨立地選自氰基、醛基、C1-C6烷基、-NR12
R'12
(
或者R9 和R'9 與其連接的N原子一起形成取代或未取代的3-8員雜環基，其中，所述取代是指被一個或多個選自下組的基團取代：鹵素、氰基、醛基、羥基、胺基、C1-C6烷基、C1-C6烷氧基；Or R 9 and R' 9 form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom they are connected to, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of: halogen, Cyano, aldehyde, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;
L1
和L2
各自獨立地為-CRf
Rg
-(
m和p各自獨立地為1、2、3、4、5或6；m and p are each independently 1, 2, 3, 4, 5 or 6;
各R2 獨立地選自鹵素、氰基、硝基、C1-C6烷基、鹵代C1-C6烷基；Each R is independently selected from halogen, cyano, nitro, C1 - C6 alkyl, halogenated C1-C6 alkyl;
R3 和R4 各自獨立地選自H、鹵素、羥基、胺基、氰基、C1-C6烷基、鹵代C1-C6烷基。R 3 and R 4 are each independently selected from H, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl.
在另一優選例中，R1 選自：C1-C6烷氧基、鹵代C1-C6烷氧基、C3-C6環烷氧基、鹵代C3-C6環烷氧基。In another preferred example, R 1 is selected from: C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy.
在另一優選例中，R5
選自氰基、醛基、R8
C(O)-(
R8 、R10 、R'10 、R11 、R'11 和R"11 各自獨立地選自H、C1-C6烷基、鹵代C1-C6烷基、C1-C6烷氧基、C3-C6環烷基、C3-C6環雜烷基、C6-C10芳基、5-10員雜芳基；R 8 , R 10 , R' 10 , R 11 , R' 11 and R" 11 are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3- C6 cycloalkyl, C3-C6 cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl;
或者R10 和R'10 與其連接的N原子一起形成取代或未取代的3-8員雜環基，其中，所述取代是指被一個或多個選自下組的基團取代：鹵素、氰基、醛基、羥基、胺基、C1-C6烷基、C1-C6烷氧基、N(R'13 )(R"13 )；R'13 和R"13 各自獨立選自H、鹵素、C1-C6烷基；Or R 10 and R' 10 form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom it is connected to, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of: halogen, Cyanide, aldehyde, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, N(R' 13 )(R" 13 ); R' 13 and R" 13 are each independently selected from H, halogen , C1-C6 alkyl;
R9
和R'9
各自獨立地選自氰基、醛基、C1-C6烷基、-NR12
R'12
(
或者R9 和R'9 與其連接的N原子一起形成取代或未取代的3-8員雜環基，其中，所述取代是指被一個或多個選自下組的基團取代：鹵素、氰基、醛基、羥基、胺基、C1-C6烷基、C1-C6烷氧基；Or R 9 and R' 9 form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom they are connected to, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of: halogen, Cyano, aldehyde, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;
L1
和L2
各自獨立地為-CRf
Rg
-(
m和p各自獨立地為1、2、3、4、5或6。m and p are each independently 1, 2, 3, 4, 5 or 6.
在另一優選例中，各R2 獨立地選自鹵素、氰基、硝基、C1-C6烷基、鹵代C1-C6烷基。In another preferred example, each R 2 is independently selected from halogen, cyano, nitro, C1-C6 alkyl, and halogenated C1-C6 alkyl.
在另一優選例中，R3 和R4 各自獨立地選自H、鹵素、羥基、胺基、氰基、C1-C6烷基、鹵代C1-C6烷基。 In another preferred example, R3 and R4 are each independently selected from H, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, and halogenated C1-C6 alkyl.
在另一優選例中，所述式I化合物具有式I"所示的結構：
式中，In the formula,
Rc為選自取代或未取代的C1-C6烷基，所述的取代是指被一個或多個選自鹵素、氰基、羥基中的基團取代；Rc is selected from substituted or unsubstituted C1-C6 alkyl, said substitution refers to being substituted by one or more groups selected from halogen, cyano, and hydroxyl;
X選自鹵素、氰基、硝基、鹵代C1-C6烷基；X is selected from halogen, cyano, nitro, halogenated C1-C6 alkyl;
R5 的定義如上所述。R 5 is as defined above.
在另一優選例中，R5
選自
在另一優選例中，R5
為-C(O)OR8
(
在另一優選例中，R5
為-(L1
)p
-N(R9
)(R'9
) (
在另一優選例中，R5
為-C(O)-N(R10
)(R'10
)(
在另一優選例中，R5
為-C(O)-NH-CH2
CH2
-N(R'11
)(R"11
)(
在另一優選例中，R1 、R2 、R3 、R4 、R5 為實施例中各具體化合物相對應的具體基團。In another preferred example, R 1 , R 2 , R 3 , R 4 , and R 5 are specific groups corresponding to specific compounds in the embodiments.
在另一優選例中，所述化合物選自
在另一優選例中，所述化合物選自實施例中所示的化合物。In another preferred example, the compound is selected from the compounds shown in the Examples.
本發明第二方面，提供一種藥物組合物，其包含第一方面所述的化合物或其藥學上可接受的鹽、水合物、溶劑化物、同位素化合物或前藥；和藥用載體或稀釋劑。The second aspect of the present invention provides a pharmaceutical composition, which comprises the compound described in the first aspect or its pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug; and a pharmaceutical carrier or diluent.
在另一優選例中，所述的藥物組合物還包括一種或多種其他治療劑，所述的其他治療劑選自胺基水楊酸製劑（如柳氮磺吡啶）、糖皮質激素（如氫化可的松、***等）、PD-1抑制劑(如納武單抗、派姆單抗、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10、BAT1306、AK105、LZM 009或上述藥物的生物類似藥等)、PD-L1抑制劑(如德瓦魯單抗、阿特珠單抗、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003、KL-A167、F 520、GR1405、MSB2311或上述藥物的生物類似藥等)、CD20抗體(如利妥昔單抗、奧濱尤妥珠單抗、奧法木單抗、托西莫單抗、替伊莫單抗等)、CD47抗體(如Hu5F9-G4、CC-90002、TTI-621、TTI-622、OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制劑(如色瑞替尼、艾樂替尼、布加替尼、勞拉替尼、奧卡替尼)、PI3K抑制劑(如艾代拉裡斯、Dactolisib、Taselisib、Buparlisib等)、BTK抑制劑(如依魯替尼、Tirabrutinib、Acalabrutinib等)、EGFR抑制劑(如阿法替尼、吉非替尼、厄洛替尼、拉帕替尼、達克替尼、埃克替尼、卡奈替尼等)、VEGFR抑制劑(如索拉非尼、帕唑帕尼、瑞伐替尼、卡博替尼、舒尼替尼、多納非尼等)、HDAC抑制劑(如Givinostat、Droxinostat、恩替諾特、達西司特、泰克地那林等)、CDK抑制劑(如帕博西尼、瑞博西尼、Abemaciclib、Lerociclib等)、MEK抑制劑(如司美替尼(AZD6244)、曲美替尼(GSK1120212)、PD0325901、U0126、AS-703026、PD184352(CI-1040)等)、Akt抑制劑(如MK-2206、Ipatasertib、Capivasertib、Afuresertib、Uprosertib等)、mTOR抑制劑(如Vistusertib等)、SHP2抑制劑(如RMC-4630、JAB-3068、TNO155等)、IGF-1R抑制劑(如Ceritinib、奧卡替尼、linsitinib、BMS-754807、GSK1838705A等)。In another preferred example, the pharmaceutical composition further includes one or more other therapeutic agents selected from aminosalicylic acid preparations (such as sulfasalazine), glucocorticoids (such as hydrogenated Cortisone, dexamethasone, etc.), PD-1 inhibitors (such as nivolumab, pembrolizumab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226 , STW204, HX008, HLX10, BAT1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, CS1001, KN035, HLX20, SHR- 1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, offa Timomab, tositumomab, imomoumab, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lorlatinib, ocatinib), PI3K inhibitors (such as alectinib Dailaris, Dactolisib, Taselisib, Buparlisib, etc.), BTK inhibitors (such as ibrutinib, Tirabrutinib, Acalabrutinib, etc.), EGFR inhibitors (such as afatinib, gefitinib, erlotinib, lapa Tini, dacomitinib, icotinib, canertinib, etc.), VEGFR inhibitors (such as sorafenib, pazopanib, ravatinib, cabozantinib, sunitinib, Donafenib, etc.), HDAC inhibitors (such as Givinostat, Droxinostat, Entinostat, Dacilast, Teikedinaline, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, Lerociclib, etc.), MEK inhibitors (such as selumetinib (AZD6244), trametinib (GSK1120212), PD0325901, U0126, AS-703026, PD184352 (CI-1040), etc.), Akt inhibitors (such as MK-2206 , Ipatasertib, Capivasertib, Afuresertib, Uprosertib, etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.), IGF-1R inhibitors (such as Ceritinib, Ocatinib , linsitini b. BMS-754807, GSK1838705A, etc.).
本發明第三方面，提供一種第一方面所述的化合物或其藥學上可接受的鹽、水合物、溶劑化物、同位素化合物或前藥在製備治療腸易激綜合症、其他腸道相關疾病和/或癌症的藥物中的用途。In the third aspect of the present invention, there is provided a compound described in the first aspect or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug in the preparation of treating irritable bowel syndrome, other intestinal-related diseases and and/or use in medicines for cancer.
在另一優選例中，所述的藥學上可接受的鹽為包括但不限於下組的鹽：醋酸鹽、己二酸鹽、海藻酸鹽、抗壞血酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、硫酸氫鹽、硼酸鹽、丁酸鹽、檸檬酸鹽、樟腦鹽、樟腦磺酸鹽、環戊烷丙酸鹽、二甘醇酸鹽、十二烷基硫酸鹽、乙烷磺酸鹽、延胡索酸鹽、葡庚糖酸鹽、甘油磷酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、鹽酸鹽、氫溴酸鹽、氫碘酸鹽、羥基乙磺酸鹽、乳酸鹽、馬來酸鹽、甲磺酸鹽、萘磺酸鹽、菸酸鹽、硝酸鹽、草酸鹽、果膠酸鹽、過硫酸鹽、苯丙酸鹽、磷酸鹽、苦味酸鹽、新戊酸鹽、丙酸鹽、水楊酸鹽、琥珀酸鹽、硫酸鹽、磺酸鹽、酒石酸鹽、硫氰酸鹽、甲苯磺酸鹽、十二烷酸鹽。In another preferred example, the pharmaceutically acceptable salts include but are not limited to the following groups: acetate, adipate, alginate, ascorbate, aspartate, benzoic acid Salt, Benzene Sulfonate, Bisulfate, Borate, Butyrate, Citrate, Camphor Salt, Camphor Sulfonate, Cyclopentane Propionate, Diglycolate, Lauryl Sulfate, Ethanesulfonate, Fumarate, Glucoheptonate, Glycerophosphate, Hemisulfate, Heptanoate, Hexanoate, Hydrochloride, Hydrobromide, Hydroiodide, Isethionate , lactate, maleate, methanesulfonate, naphthalenesulfonate, nicotinate, nitrate, oxalate, pectate, persulfate, phenylpropionate, phosphate, picrate , Pivalate, Propionate, Salicylate, Succinate, Sulfate, Sulfonate, Tartrate, Thiocyanate, Toluenesulfonate, Dodecanoate.
在另一優選例中，所述腸易激綜合症為腹瀉主導型腸易激綜合症、便秘主導型腸易激綜合症、混合型腸易激綜合症、未定型腸易激綜合症。In another preferred example, the irritable bowel syndrome is diarrhea-predominant irritable bowel syndrome, constipation-predominant irritable bowel syndrome, mixed irritable bowel syndrome, and unspecified irritable bowel syndrome.
在另一優選例中，所述其他腸道相關疾病為功能性胃氣脹、功能性便秘、非特異性功能性腸紊亂、功能性腹痛綜合症、慢性特發性便秘、功能性胃十二指腸病。In another preferred example, the other intestinal-related diseases are functional flatulence, functional constipation, non-specific functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional gastroduodenal disease .
在另一優選例中，所述腸易激綜合症包括：腹瀉主導型、便秘主導型或交替排便模式、功能性胃氣脹、功能性便秘、非特異性功能性腸紊亂、功能性腹痛綜合症、慢性特發性便秘、功能性胃十二指腸病。In another preferred example, the irritable bowel syndrome includes: diarrhea-dominant, constipation-dominant or alternating defecation patterns, functional flatulence, functional constipation, non-specific functional bowel disorder, functional abdominal pain syndrome syndrome, chronic idiopathic constipation, and functional gastroduodenal disease.
在另一優選例中，所述癌症包括：膀胱癌、卵巢癌、腺癌、胃癌、胰腺癌、***癌、結腸癌、肺癌、骨癌、腦癌、神經細胞瘤、直腸癌、家族性腺瘤性息肉性癌、遺傳性非息肉性結直腸癌、食管癌、唇癌、喉癌、下嚥癌、舌癌、唾液腺癌、甲狀腺髓樣癌、乳頭狀甲狀腺癌、腎癌、腎實質癌、子宮頸癌、子宮體癌、子宮內膜癌、絨毛膜癌、睾丸癌、泌尿癌、黑素瘤、急性淋巴性白血病、慢性淋巴性白血病、急性骨髓性白血病、慢性粒細胞白血病、肝細胞癌、膽囊癌、支氣管癌、小細胞肺癌、非小細胞肺癌、多發性骨髓瘤。In another preferred example, the cancer includes: bladder cancer, ovarian cancer, adenocarcinoma, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neurocytoma, rectal cancer, familial adenoma Sexual polypoid carcinoma, hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, Cervical cancer, uterine body cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary cancer, melanoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, hepatocellular carcinoma , gallbladder cancer, bronchial cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma.
在另一優選例中，所述癌症為非小細胞肺癌、膠質瘤、多發性骨髓瘤、肝膽管型肝癌、甲狀腺髓樣癌、甲狀腺乳頭狀腫瘤、神經母細胞瘤、結腸癌、頭頸部鱗狀細胞癌、胰腺癌、肉瘤、黑色素瘤、纖維肉瘤、胰腺腫瘤、軟組織肉瘤、高度實性腫瘤、乳腺腫瘤或膽管癌。In another preferred example, the cancer is non-small cell lung cancer, glioma, multiple myeloma, hepatobiliary liver cancer, medullary thyroid cancer, thyroid papillary tumor, neuroblastoma, colon cancer, squamous cell carcinoma of the head and neck Stem cell carcinoma, pancreatic cancer, sarcoma, melanoma, fibrosarcoma, pancreatic tumor, soft tissue sarcoma, high-solid tumor, breast tumor, or cholangiocarcinoma.
本發明第四方面，提供第一方面所述的化合物或其藥學上可接受的鹽、水合物、溶劑化物、同位素化合物或前藥在製備治療神經退化性疾病、慢性疼痛、急性疼痛、炎性疾病、炎症性腸病、克氏錐蟲感染或與骨重建調節失衡有關的疾病的藥物中的用途。The fourth aspect of the present invention provides the compound described in the first aspect or its pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug in the preparation of treatment of neurodegenerative diseases, chronic pain, acute pain, inflammatory Use in medicine for diseases, inflammatory bowel disease, Trypanosoma cruzi infection or diseases associated with imbalances in the regulation of bone remodeling.
本發明第五方面，提供一種GSK-3179106和/或BOS-589，或其藥學上可接受的鹽、水合物、溶劑化物、同位素化合物或前藥在製備治療神經退化性疾病、慢性疼痛、急性疼痛、炎性疾病、炎症性腸病、克氏錐蟲感染或與骨重建調節失衡有關的疾病的藥物中的用途；
本發明第六方面，提供一種第一方面所述的化合物或其藥學上可接受的鹽、水合物、溶劑化物、同位素化合物或前藥，或第二方面所述的藥物組合物在製備用於抑制細胞或受試者中的RET激酶和/或TRK激酶活性的藥物中的用途。The sixth aspect of the present invention provides the compound described in the first aspect or its pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug, or the pharmaceutical composition described in the second aspect in preparation for Use in a medicament for inhibiting RET kinase and/or TRK kinase activity in a cell or a subject.
本發明第七方面，提供一種GSK-3179106和/或BOS-589，或其藥學上可接受的鹽、水合物、溶劑化物、同位素化合物或前藥在製備用於抑制細胞或受試者中的RET激酶和/或TRK激酶活性的藥物中的用途。In the seventh aspect of the present invention, there is provided a kind of GSK-3179106 and/or BOS-589, or its pharmaceutically acceptable salt, hydrate, solvate, isotope compound or prodrug in the preparation for inhibiting cell or subject Use in medicines for RET kinase and/or TRK kinase activity.
本發明第八方面，提供一種治療RET和/或TRK相關疾病的方法，所述方法包括給予被鑒定或診斷為具有RET和/或TRK相關疾病的受試者治療有效量的如第一方面所述的化合物或其藥學上可接受的鹽、水合物、溶劑化物、同位素化合物或前藥，如第二方面所述的藥物組合物，GSK-3179106或其藥學上可接受的鹽、水合物、溶劑化物、同位素化合物或前藥，或BOS-589或其藥學上可接受的鹽、水合物、溶劑化物、同位素化合物或前藥。The eighth aspect of the present invention provides a method for treating RET and/or TRK-related diseases, the method comprising administering a therapeutically effective amount of the RET and/or TRK-related diseases to a subject identified or diagnosed as described in the first aspect The compound or its pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug, the pharmaceutical composition as described in the second aspect, GSK-3179106 or its pharmaceutically acceptable salt, hydrate, Solvate, isotope compound or prodrug, or BOS-589 or its pharmaceutically acceptable salt, hydrate, solvate, isotope compound or prodrug.
本發明第九方面，提供一種用於抑制細胞或受試者中的RET和/或TRK激酶活性的方法，所述方法包括使所述細胞接觸或向所述受試者施用第一方面所述的化合物或其藥學上可接受的鹽、水合物、溶劑化物、同位素化合物或前藥，第二方面所述的藥物組合物，GSK-3179106或其藥學上可接受的鹽、水合物、溶劑化物、同位素化合物或前藥、或BOS-589或其藥學上可接受的鹽、水合物、溶劑化物、同位素化合物或前藥的步驟。In the ninth aspect of the present invention, there is provided a method for inhibiting RET and/or TRK kinase activity in a cell or a subject, the method comprising contacting the cell or administering to the subject the method described in the first aspect. The compound or its pharmaceutically acceptable salt, hydrate, solvate, isotope compound or prodrug, the pharmaceutical composition described in the second aspect, GSK-3179106 or its pharmaceutically acceptable salt, hydrate, solvate , an isotope compound or a prodrug, or BOS-589 or a pharmaceutically acceptable salt, hydrate, solvate, isotope compound or prodrug thereof.
在另一優選例中，所述細胞為哺乳動物細胞。In another preferred embodiment, the cells are mammalian cells.
在另一優選例中，所述受試者為哺乳動物，優選為人。In another preferred example, the subject is a mammal, preferably a human.
本發明第十方面，提供一種第一方面所述的化合物或其藥學上可接受的鹽、水合物、溶劑化物、同位素化合物或前藥的製備方法，包括步驟：
1）將式M化合物與式N化合物反應，得到式A化合物；
2）將式A化合物與酸反應，得到式I化合物；2) reacting the compound of formula A with an acid to obtain the compound of formula I;
其中，Y選自OH、鹵素；Wherein, Y is selected from OH, halogen;
其他各基團如第一方面所定義。Other groups are as defined in the first aspect.
本發明第十一方面，提供一種製備式1-2化合物的方法，包括步驟：
化合物1-1在濃硫酸條件下，慢慢滴加濃硝酸，或者發煙硝酸進行硝化反應，得到化合物1-2，Rb 、n"如第一方面所定義。Compound 1-1 is slowly added with concentrated nitric acid or fuming nitric acid for nitration under the condition of concentrated sulfuric acid to obtain compound 1-2, R b , n" are as defined in the first aspect.
應理解，在本發明範圍內中，本發明的上述各技術特徵和在下文(如實施例)中具體描述的各技術特徵之間都可以互相組合，從而構成新的或優選的技術方案。限於篇幅，在此不再一一累述。It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, we will not repeat them here.
本發明人經過廣泛而深入的研究，意外地發現了一類SF5取代的吡啶酮類化合物具有較好的RET和TRK激酶抑制活性，同時對VEGFR2激酶具有較好的選擇性的化合物。此外，所述化合物具有較好藥效學/藥代動力學性能。在此基礎上，完成了本發明。After extensive and in-depth research, the present inventors unexpectedly discovered a class of SF5-substituted pyridone compounds that have better RET and TRK kinase inhibitory activity, and have better selectivity for VEGFR2 kinase. In addition, the compounds have better pharmacodynamic/pharmacokinetic properties. On this basis, the present invention has been accomplished.
術語the term
在本發明中，除非特別指出，所用術語具有本領域技術人員周知的一般含義。In the present invention, unless otherwise specified, the terms used have the usual meanings known to those skilled in the art.
當通過從左向右書寫的常規化學式描述取代基時，該取代基也同樣包括從右向左書寫結構式時所得到的在化學上等同的取代基。舉例而言，-CH2 O-等同於-OCH2 -。When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH 2 O- is equivalent to -OCH 2 -.
術語“烷基”本身或作為另一取代基的一部分，是指具有指定的碳原子數的直鏈或支鏈烴基(即，C1-C6是指一個至六個碳原子)。烷基的實例包括但不限於甲基、乙基、正丙基、異丙基、正丁基、第三丁基、異丁基、第二丁基、正戊基、正己基及其類似烷基。烷基中的一個或多個位置被取代，尤其是1-4個取代基，可在任何位置上取代。The term "alkyl" by itself or as part of another substituent refers to a straight or branched chain hydrocarbon group having the indicated number of carbon atoms (ie, C1-C6 means one to six carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, s-butyl, n-pentyl, n-hexyl, and the like base. One or more positions in the alkyl group are substituted, especially 1-4 substituents, which can be substituted at any position.
術語“C1-C6烷氧基”本身或作為另一取代基的一部分，是指具有1至6個碳原子的直鏈或支鏈或環狀烷氧基(如C3-C6環烷氧基)，代表性的例子包括(但並不限於)：甲氧基、乙氧基、丙氧基、異丙氧基和丁氧基等。優選為C1-C3烷氧基。The term "C1-C6 alkoxy" by itself or as part of another substituent means a straight or branched or cyclic alkoxy group having 1 to 6 carbon atoms (such as C3-C6 cycloalkoxy) , representative examples include (but are not limited to): methoxy, ethoxy, propoxy, isopropoxy, and butoxy, and the like. Preference is given to C1-C3 alkoxy.
術語“雜烷基”本身或作為另一取代基的一部分，是指烷基中的碳原子被1、2、3個選自N、O、S、Si或P的雜原子取代的基團，且其中，氮和硫原子任選地被氧化，本發明中“3-8員雜烷基”是指包含1-6（即1、2、3、4、5或6）個碳原子，和1或2個選自N、O、S或P的雜原子的基團，代表性的例子包括(但並不限於)：CH3 OCH2 -、CH3 SCH2 -、CH3 CH2 OCH2 -等。The term "heteroalkyl" by itself or as part of another substituent means a group in which the carbon atoms in the alkyl group are replaced by 1, 2, 3 heteroatoms selected from N, O, S, Si or P, And wherein, nitrogen and sulfur atoms are optionally oxidized, "3-8 membered heteroalkyl" in the present invention refers to containing 1-6 (ie 1, 2, 3, 4, 5 or 6) carbon atoms, and A group of 1 or 2 heteroatoms selected from N, O, S or P, representative examples include (but are not limited to): CH 3 OCH 2 -, CH 3 SCH 2 -, CH 3 CH 2 OCH 2 -Wait.
術語“環烷基”本身或作為另一取代基的一部分，是指包括飽和單環、雙環或多環的環狀烷基，例如C3-C8或C3-C12環烷基。C3-C8環烷基指包括C3、C4、C5、C6、C7、或C8環烷基。環烷基還可包括螺環、橋環、并環等結構的環烷基。本發明的代表性的環烷基包括但不限於：環丙基、環丁基、環戊基、環己基和降莰烷基。應理解，取代或未取代的環烷基，例如支化環烷基（如1-甲基環丙基和2-甲基環丙基），均包括在“環烷基”的定義中。The term "cycloalkyl" by itself or as part of another substituent refers to cyclic alkyl groups including saturated monocyclic, bicyclic or polycyclic, eg C3-C8 or C3-C12 cycloalkyl. C3-C8 cycloalkyl refers to C3, C4, C5, C6, C7, or C8 cycloalkyl. Cycloalkyl groups may also include cycloalkyl groups with structures such as spiro rings, bridged rings, and parallel rings. Representative cycloalkyl groups of the invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. It is to be understood that substituted or unsubstituted cycloalkyl groups, such as branched cycloalkyl groups (eg, 1-methylcyclopropyl and 2-methylcyclopropyl), are included within the definition of "cycloalkyl".
術語“環雜烷基”本身或作為另一取代基的一部分，是指具有指定的環頂點(或成員)數且具有一至五個選自N、O和S的雜原子分別取代環骨架中碳原子，且其中，氮和硫原子任選地被氧化，且氮原子任選被季銨化的環烷基環。環雜烷基通常為4－12員環。環雜烷基可為單環、雙環或多環系統。環雜烷基例子包括但並不限於：吡咯烷基、咪唑烷基、吡唑烷基、丁內醯胺基、戊內醯胺基、咪唑烷酮基、乙內醯脲基、二氧雜環戊烷基、鄰苯二甲醯亞胺基、哌啶基、1,4-二氧六環基、嗎啉基、硫代嗎啉基、硫代嗎啉-S-氧化物、硫代嗎啉-S,S-氧化物、哌𠯤基、哌喃基、吡啶酮基、3-吡咯啉基、噻喃基、吡喃酮基、四氫呋喃基、四氫噻吩基、奎寧環及其類似物。The term "cycloheteroalkyl" by itself or as part of another substituent means having the specified number of ring vertices (or members) and having one to five heteroatoms selected from N, O, and S replacing carbons in the ring backbone respectively. atom, and wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized cycloalkyl ring. Cycloheteroalkyl groups are typically 4-12 membered rings. Cycloheteroalkyl groups can be monocyclic, bicyclic or polycyclic ring systems. Examples of cycloheteroalkyl groups include, but are not limited to: pyrrolidinyl, imidazolidinyl, pyrazolidinyl, butyrolactamyl, valerolactylamide, imidazolidinonyl, hydantoinyl, dioxalactyl Cyclopentyl, phthalimino, piperidinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholine-S-oxide, thio Morpholine-S, S-oxide, piperyl, pyranyl, pyridonyl, 3-pyrrolinyl, thiopyranyl, pyranone, tetrahydrofuryl, tetrahydrothiophenyl, quinuclidinyl, and analog.
術語“烯基”本身或作為另一取代基的一部分，表示含一個或多個雙鍵且通常長度為2至20個碳原子(或C2-C8)的直鏈或支鏈的烴基。例如，本發明中，“C2-C6烯基”含有兩個至六個碳原子。烯基包括但不限於例如乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基等。The term "alkenyl" by itself or as part of another substituent denotes a straight or branched chain hydrocarbon group containing one or more double bonds and generally having a length of 2 to 20 carbon atoms (or C2-C8). For example, in the present invention, "C2-C6 alkenyl" contains two to six carbon atoms. Alkenyl groups include, but are not limited to, eg vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.
術語“芳基”，單獨或作為較大部分諸如“芳烷基”、“芳烷氧基”或“芳基氧基烷基”的部分，是指具有總計5至15個環成員的單環、二環或三環的環系統(優選6-10員芳環)，其中所述系統中的至少一個環為芳族的且其中所述系統中的每個環含有3至7個環成員。“芳基”可以是取代的或者未取代的。在本發明的某些實施方案中，“芳基”是指芳族環系統，其包括但不限於苯基、聯苯基、茚滿基、1-萘基、2-萘基和四氫萘基。稠合的芳基可在環烷基環或芳族環的合適位置上連接至另一基團。從環系統中畫出的連接線表明鍵可連接至任意合適的環原子。The term "aryl", alone or as part of a larger moiety such as "aralkyl", "aralkoxy" or "aryloxyalkyl", refers to a single ring having a total of 5 to 15 ring members , a bicyclic or tricyclic ring system (preferably a 6-10 membered aromatic ring), wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. "Aryl" can be substituted or unsubstituted. In certain embodiments of the invention, "aryl" refers to an aromatic ring system which includes, but is not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthalene base. A fused aryl group can be attached to another group at a suitable position on the cycloalkyl ring or aromatic ring. Connecting lines drawn from ring systems indicate that bonds may be attached to any suitable ring atom.
術語“雜芳基”本身或作為另一取代基的一部分，指包含1-4個雜原子、5-14個環原子的雜芳族體系，其中，雜原子選自氧、氮和硫。雜芳基優選5至10員環，更優選為5員或6員，例如吡咯基、吡唑基、咪唑基、㗁唑基、異㗁唑基、噻唑基、噻二唑基、異噻唑基、呋喃基、吡啶基、吡𠯤基、嘧啶基、嗒𠯤基、三氮𠯤基、三氮唑基及四氮唑基等。“雜芳基”可以是取代的或者未取代的，當被取代時，取代基優選為一個或多個以下基團，其獨立地選自烷基、氘代烷基、鹵代烷基、烷氧基、鹵代烷氧基、烯基、炔基、烷硫基、烷基胺基、鹵素、胺基、硝基、羥基、巰基、氰基、環烷基、雜環基、芳基、雜芳基、環烷硫基、氧代基、羧基和羧酸酯基。The term "heteroaryl" by itself or as part of another substituent refers to a heteroaromatic system containing 1-4 heteroatoms, 5-14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur. Heteroaryl is preferably a 5 to 10 membered ring, more preferably 5 or 6 membered, e.g. pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl , furyl, pyridyl, pyridyl, pyrimidinyl, pyridyl, triazolyl, triazolyl and tetrazolyl, etc. "Heteroaryl" may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy , haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amine, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, Cycloalkylthio, oxo, carboxyl and carboxylate groups.
優選地，各“5-10員雜芳基”獨立地為含1、2或3個選自N、O或S的雜原子的5-10員雜芳基。Preferably, each "5-10 membered heteroaryl" is independently a 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S.
術語“雜環”、“雜環基”或“雜環基團”本身或作為另一取代基的一部分，指穩定的3員、4員、5員、或7員單環或二環或7員、8員、9員、10員、11員、12員、13員或14員多環雜環，包括稠環、螺環和/或橋環結構，其為飽和的、部分不飽和的或完全不飽和的，且其含有碳原子和1個、2個、3個或4個獨立地選自N、O和S的雜原子。該術語還包括雜環與芳環（如苯環）稠合所形成的多環基團。“雜環”可以是取代的或者未取代的。作為環原子的氮和硫雜原子可任選地被氧化。氮原子為取代的或未取代的(即N或NR，其中R為H或如果被定義，則為另一取代基)。雜環可在得到穩定結構的任何雜原子或碳原子處連接至其側基。如果所得化合物是穩定的，則本文所述的雜環基可在碳或氮原子上被取代。雜環中的氮可任選地被季銨化。優選地，當雜環中S和O原子的總數超過1時，則這些雜原子彼此不相鄰。優選地，雜環中S和O原子的總數不大於1。當使用術語“雜環”時，其意欲包括雜芳基。雜環的實施例包括但不限於吖啶基、氮雜環丁基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并噻吩基、苯并㗁唑基、苯并㗁唑啉基、苯并噻唑基、苯并***基、苯并四唑基、苯并異㗁唑基、苯并異噻唑基、苯并咪唑啉基、哢唑基、4aH
-咔唑基、咔啉基、𠳭基、𠳭烯基、噌啉基、十氫喹啉基、2H
,6H
-1,5,2-二噻𠯤基、二氫呋喃并[2,3-b
]四氫呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H
-吲唑基、咪唑并吡啶基、假吲哚基(indolenyl)、二氫吲哚基、吲𠯤基、吲哚基、3H
-吲哚基、靛紅醯基(isatinoyl)、異苯并呋喃基、異𠳭基、異吲唑基、異二氫吲哚基、異吲哚基、異喹啉基、異噻唑基、異噻唑并吡啶基、異㗁唑基、異㗁唑并吡啶基、亞甲基二氧基苯基、嗎啉基、二氮雜萘基、八氫異喹啉基、㗁二唑基、1,2,3-㗁二唑基、1,2,4-㗁二唑基、1,2,5-㗁二唑基、1,3,4-㗁二唑基、㗁唑烷基、㗁唑基、㗁唑并吡啶基、㗁唑烷基、萘嵌間二氮雜苯基、羥吲哚基、嘧啶基、菲啶基、菲咯啉基、吩𠯤基、吩噻𠯤基、吩㗁噻基、吩㗁𠯤基、酞𠯤基、哌𠯤基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、喋啶基、嘌呤基、吡喃基、吡𠯤基、吡唑烷基、吡唑啉基、吡唑并吡啶基、吡唑基、嗒𠯤基、吡啶并㗁唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2-吡咯烷酮基、2H
-吡咯基、吡咯基、喹唑啉基、喹啉基、4H
-喹𠯤基、喹㗁啉基、奎寧環基、四唑基、四氫呋喃基、四氫異喹啉基、四氫喹啉基、6H
-1,2,5-噻二𠯤基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻唑并吡啶基、噻吩并噻唑基、噻吩并㗁唑基、噻吩并咪唑基、噻吩基、三𠯤基、1,2,3-***基、1,2,4-***基、1,2,5-***基、1,3,4-***基和𠮿
優選地，各“3-6員雜環基”為含1、2或3個選自N、O或S的雜原子的3-6員雜環基。術語“4-8員雜環基”、“3-6員環雜烷基”、“3-8員雜環基”、“4-8員環雜基”、“C3-C6環雜烷基”具有類似含義。Preferably, each "3-6 membered heterocyclic group" is a 3-6 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S. The terms "4-8 membered heterocyclyl", "3-6 membered cycloheteroalkyl", "3-8 membered heterocyclyl", "4-8 membered cycloheteroyl", "C3-C6 cycloheteroalkyl " has a similar meaning.
術語“C4-C8環烯基”是指含1、2或3個烯鍵的環狀4-8員環。在本發明中，上述的烷基、鹵代烷基、烷氧基、環烷基、芳基、雜芳基、環雜烷基、烯基、炔烴、雜環、雜環基等中各基團可以是取代的或未取代的。The term "C4-C8 cycloalkenyl" refers to a cyclic 4-8 membered ring containing 1, 2 or 3 ethylenic bonds. In the present invention, each group in the above-mentioned alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, alkenyl, alkyne, heterocycle, heterocyclyl, etc. Can be substituted or unsubstituted.
在本發明中，術語“取代”指特定的基團上的一個或多個氫原子被特定的取代基所取代。特定的取代基為在前文中相應描述的取代基，或各實施例中所出現的取代基。除非特別說明，某個取代的基團可以在該基團的任何可取代的位點上具有一個選自特定組的取代基，所述的取代基在各個位置上可以是相同或不同的。本領域技術人員應理解，本發明所預期的取代基的組合是那些穩定的或化學上可實現的組合。典型的取代包括但不限於一個或多個以下基團：如氫、氘、鹵素(例如，單鹵素取代基或多鹵素取代基，後者如三氟甲基或包含Cl3
的烷基)、腈基、硝基、氧代(如=O)、三氟甲基、三氟甲氧基、環烷基、烯基、炔基、雜環、芳環、-ORa
、-SRa
、-S(=O)Re
、-S(=O)2
Re
、-P(=O)2
Re
、-S(=O)2
ORe
，-P(=O)2
ORe
、-NRb
Rc
(
除非另外說明，假定任何不滿價態的雜原子有足夠的氫原子補充其價態。Unless otherwise stated, it is assumed that any heteroatom with a dissatisfied valence has sufficient hydrogen atoms to fill its valence.
當取代基為非末端取代基時，其為相應基團的亞基，例如烷基對應於亞烷基、環烷基對應亞環烷基、雜環基對亞雜環基、烷氧基對應亞烷氧基等。When the substituent is a non-terminal substituent, it is the subunit of the corresponding group, for example, alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclyl corresponds to heterocyclylene, alkoxy corresponds to Alkyleneoxy, etc.
術語“鹵代”或“鹵素”包括氟、氯、溴和碘。The term "halo" or "halogen" includes fluorine, chlorine, bromine and iodine.
術語“PMB”是指對甲氧基苄基。The term "PMB" refers to p-methoxybenzyl.
術語“醛基”具有結構-CHO。The term "aldehyde group" has the structure -CHO.
活性成分active ingredient
如本文所用，術語“本發明的化合物”或“本發明的活性成分”可互換使用，指式I化合物、或其藥學上可接受的鹽、水合物、溶劑化物、同位素化合物(如氘代化合物)或前藥。該術語還包括外消旋體、光學異構體。As used herein, the term "compound of the present invention" or "active ingredient of the present invention" is used interchangeably and refers to a compound of formula I, or a pharmaceutically acceptable salt, hydrate, solvate, isotope compound (such as a deuterated compound) ) or prodrugs. The term also includes racemates, optical isomers.
本發明中，所述的式I化合物具有如下結構：
式中，In the formula,
R1 、R2 、R5 、Rb 、n、r、n'和n"的定義如上所述。R 1 , R 2 , R 5 , R b , n, r, n' and n" are as defined above.
優選地，所述式I化合物具有式I'所示的結構：
式中，R1 、R2 、R3 、R4 、R5 和n的定義如上所述。In the formula, the definitions of R 1 , R 2 , R 3 , R 4 , R 5 and n are as above.
優選地，式I和式I'中，R1 選自C1-C6烷氧基、鹵代C1-C6烷氧基、C3-C6環烷氧基、鹵代C3-C6環烷氧基。Preferably, in formula I and formula I', R 1 is selected from C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy.
優選地，式I和式I'中，R5
選自氰基、醛基、C1-C6烷基、鹵代C1-C6烷基、3-8員雜烷基、C1-C6烷基-OH、C2-C6烯基、C2-C6炔基、-C(O)OR8
(
R8 、R10 、R'10 、R11 、R'11 和R"11 各自獨立地選自H、C1-C6烷基、鹵代C1-C6烷基、C1-C6烷氧基、C3-C6環烷基、C3-C6環雜烷基、C6-C10芳基、5-10員雜芳基；R 8 , R 10 , R' 10 , R 11 , R' 11 and R" 11 are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3- C6 cycloalkyl, C3-C6 cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl;
或者R10 和R'10 與其連接的N原子一起形成取代或未取代的3-8員雜環基，其中，所述取代是指被一個或多個選自下組的基團取代：鹵素、氰基、-CHO、羥基、胺基、C1-C6烷基、C1-C6烷氧基；Or R 10 and R' 10 form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom it is connected to, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of: halogen, Cyano, -CHO, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;
R9
和R'9
各自獨立地選自：氰基、醛基、-NR12
R'12
(
或者R9 和R'9 與其連接的N原子一起形成取代或未取代的3-8員雜環基，其中，所述取代是指被一個或多個選自下組的基團取代：鹵素、氰基、醛基、羥基、胺基、C1-C6烷基、C1-C6烷氧基；Or R 9 and R' 9 form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom they are connected to, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of: halogen, Cyano, aldehyde, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;
L1
和L2
各自獨立地為-CRf
Rg
-(
m和p各自獨立地為1、2、3、4、5或6。m and p are each independently 1, 2, 3, 4, 5 or 6.
優選地，式I和式I'中，各R2 獨立地選自：鹵素、氰基、硝基、C1-C6烷基、鹵代C1-C6烷基。Preferably, in formula I and formula I', each R 2 is independently selected from: halogen, cyano, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl.
優選地，所述式I化合物具有式I"所示的結構：
式中，In the formula,
Rc為選自取代或未取代的C1-C6烷基，所述的取代是指被一個或多個鹵素、氰基、羥基取代；Rc is selected from substituted or unsubstituted C1-C6 alkyl, said substitution refers to being substituted by one or more halogen, cyano, hydroxyl;
X選自鹵素、氰基、硝基、鹵代C1-C6烷基；X is selected from halogen, cyano, nitro, halogenated C1-C6 alkyl;
R5 的定義如上所述。R 5 is as defined above.
優選地，式I、I'、I"中，R5
選自
優選地，式I、I'、I"中，R5
為-C(O)OR8
(
優選地，式I、I'、I"中，R5
為-(L1
)p
-N(R9
)(R'9
) (
優選地，式I、I'、I"中，R5
為-C(O)-N(R10
)(R'10
) (
優選地，式I、I'、I"中，R5
為-C(O)-NH-CH2
CH2
-N(R'11
)(R"11
)(
代表性地，本發明提供了一種式Ⅰ化合物或其藥學上可接受的鹽、水合物、溶劑化物、同位素化合物或前藥；
式中，In the formula,
各R1 獨立地選自取代或未取代的下組基團：H、鹵素、羥基、胺基、C1-C6烷基、R'-O-、C3-C6環烷基、C6-C10芳基、5-10員雜芳基、R'NH-或R'R"N-；Each R1 is independently selected from the group consisting of substituted or unsubstituted groups: H, halogen, hydroxyl, amino, C1-C6 alkyl, R'-O-, C3-C6 cycloalkyl, C6-C10 aryl , 5-10 membered heteroaryl, R'NH- or R'R"N-;
R'、R"各自獨立選自取代或未取代的下組基團：C1-C6烷基、C3-C6環烷基、3-6員雜環基、C6-C10芳基、5-10員雜芳基，所述取代是指被選自下組的一個或多個基團取代：鹵素、羥基、C1-C6烷基；R', R" are independently selected from the following groups of substituted or unsubstituted groups: C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, C6-C10 aryl, 5-10 membered Heteroaryl, the substitution refers to being substituted by one or more groups selected from the following group: halogen, hydroxyl, C1-C6 alkyl;
或當兩個R1 連接至環上相鄰的兩個原子時，其可以稠合形成取代或未取代的下組基團：C4-C8環烯基、4-8員雜環基、C6-C10芳基、5-10員雜芳基；Or when two R 1 are connected to two adjacent atoms on the ring, they can be fused to form substituted or unsubstituted following groups: C4-C8 cycloalkenyl, 4-8 membered heterocyclyl, C6- C10 aryl, 5-10 membered heteroaryl;
各R2 獨立地選自取代或未取代的下組基團：H、鹵素、羥基、胺基、氰基、硝基、R8 C(O)O-、R8 C(O)-、R8 S(O)2 、C1-C6烷基、C3-C6環烷基；Each R 2 is independently selected from the group consisting of substituted or unsubstituted groups: H, halogen, hydroxyl, amino, cyano, nitro, R 8 C(O)O-, R 8 C(O)-, R 8 S(O) 2 , C1-C6 alkyl, C3-C6 cycloalkyl;
或當兩個R2 連接至環上相鄰的兩個原子時，其可以稠合形成取代或未取代的下組基團：C4-C8環烯基、4-8員雜環基、C6-C10芳基、5-10員雜芳基；Or when two R 2 are connected to two adjacent atoms on the ring, they can be fused to form substituted or unsubstituted following groups: C4-C8 cycloalkenyl, 4-8 membered heterocyclyl, C6- C10 aryl, 5-10 membered heteroaryl;
各Rb 獨立地選自取代或未取代的下組基團：鹵素、胺基、氰基、硝基、R8 C(O)O-、R8 C(O)-、R8 S(O)2 、C1-C6烷基、C3-C6環烷基、3-8員環雜烷基、C6-C10芳基、5-10員雜芳基、-OR6 、-CONR7 R'7 ，其中，所述取代是指被一個或多個Ra 取代：Each R b is independently selected from the group consisting of substituted or unsubstituted groups: halogen, amine, cyano, nitro, R 8 C(O)O-, R 8 C(O)-, R 8 S(O ) 2 , C1-C6 alkyl, C3-C6 cycloalkyl, 3-8 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl, -OR 6 , -CONR 7 R' 7 , Wherein, the substitution refers to being substituted by one or more R a :
各Ra 獨立地選自：鹵素、氰基、羥基、C1-C6烷基、鹵代C1-C6烷基、C1-C6烷氧基、鹵代C1-C6烷氧基或-NR7 R'7 ；Each R a is independently selected from: halogen, cyano, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy or -NR 7 R'7;
R6 、R7 和R'7 各自獨立選自：H、C1-C6烷基、鹵代C1-C6烷基、C3-C6環烷基、鹵代C3-C6環烷基、3-8員環雜烷基；R 6 , R 7 and R' 7 are each independently selected from: H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, 3-8 members Cycloheteroalkyl;
R5 選自取代或未取代的下組基團：-H、-CN、-CHO、硝基、R8 C(O)-、R8 S(O)2 、-NH2 、-OH、鹵素、C1-C6烷基、3-8員雜烷基、C1-C6烷氧基、C3-C6環烷基、3-8員雜環基、C2-C6烯基、C2-C6炔基、-C(O)OR8 、-(L1 )p -N(R9 )(R'9 )、-C(O)-N(R10 )(R'10 )、-C(O)-N(R11 )-(L2 )m -N(R'11 )(R"11 )；R 5 is selected from the group consisting of substituted or unsubstituted groups: -H, -CN, -CHO, nitro, R 8 C(O)-, R 8 S(O) 2 , -NH 2 , -OH, halogen , C1-C6 alkyl, 3-8 membered heteroalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl, - C(O)OR 8 , -(L 1 ) p -N(R 9 )(R' 9 ), -C(O)-N(R 10 )(R' 10 ), -C(O)-N( R 11 )-(L 2 ) m -N(R' 11 )(R" 11 );
或者Rb 和R5 位於相鄰的兩個C原子時，與其連接的C原子稠合形成取代或未取代的下組基團：C4-C8環烯基、4-8員環雜基、C6-C10芳基、5-10員雜芳基；Or when R b and R 5 are located at two adjacent C atoms, the C atoms connected to them are fused to form the following groups of substituted or unsubstituted groups: C4-C8 cycloalkenyl, 4-8 membered cycloheteroyl, C6 -C10 aryl, 5-10 membered heteroaryl;
R8 、R10 、R'10 、R11 、R'11 和R"11 各自獨立選自取代或未取代的下組基團：H、C1-C6烷基、C1-C6烷氧基、C3-C6環烷基、3-6員環雜烷基、C6-C10芳基、5-10員雜芳基，所述取代是指被選自下組的一個或多個基團取代：鹵素、羥基、C1-C6烷基；R 8 , R 10 , R' 10 , R 11 , R' 11 and R" 11 are each independently selected from substituted or unsubstituted groups from the following groups: H, C1-C6 alkyl, C1-C6 alkoxy, C3 -C6 cycloalkyl, 3-6 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl, the substitution refers to being substituted by one or more groups selected from the group: halogen, Hydroxy, C1-C6 alkyl;
或者R10 和R'10 與其連接的N原子一起形成取代或未取代的3-8員雜環基；Or R 10 and R' 10 form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom to which it is connected;
或者R'11 和R"11 與其連接的N原子一起形成取代或未取代的3-8員雜環基；Or R' 11 and R " 11 form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom it is connected to;
R9 和R'9 各自獨立選自取代或未取代的下組基團：H、-CN、-CHO、-NR12 R'12 、-OH、3-8員雜烷基、3-8員雜環基、C6-C10芳基、5-10員雜芳基，其中，R12 和R'12 各自獨立選自：C1-C6烷基、鹵代C1-C6烷基、C1-C6烷氧基、C3-C6環烷基、C3-C6環雜烷基；R 9 and R' 9 are each independently selected from the following substituted or unsubstituted groups: H, -CN, -CHO, -NR 12 R' 12 , -OH, 3-8-membered heteroalkyl, 3-8-membered Heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, wherein, R 12 and R' 12 are each independently selected from: C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy Base, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl;
或者R9 和R'9 與其連接的N原子一起形成取代或未取代的3-8員雜環基；Or R 9 and R' 9 form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom to which they are attached;
如無特別說明，所述取代是指被一個或多個R取代；Unless otherwise specified, the substitution refers to substitution by one or more R;
各R獨立地選自：鹵素、氰基、-CHO、羥基、胺基、C1-C6烷基、C1-C6烷氧基；Each R is independently selected from: halogen, cyano, -CHO, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;
各L1 和L2 獨立地選自：-CRf Rg -、CO、SO2 ；其中，Rf 和Rg 各自獨立地選自下組：H、C1-C6烷基、鹵素、氰基、羥基、胺基；Each L 1 and L 2 are independently selected from: -CR f R g -, CO, SO 2 ; wherein, R f and R g are each independently selected from the following group: H, C1-C6 alkyl, halogen, cyano , hydroxyl, amino;
r為1、2或3；r is 1, 2 or 3;
m和p各自獨立地為1、2、3、4、5或6；m and p are each independently 1, 2, 3, 4, 5 or 6;
n為0、1或2；n is 0, 1 or 2;
n'為0、1、2或3；n' is 0, 1, 2 or 3;
n"為0、1、2或3。n" is 0, 1, 2 or 3.
在另一優選例中，
在另一優選例中，所述的式Ⅰ化合物或其藥學上可接受的鹽、水合物、溶劑化物、同位素化合物或前藥，其具有式I'所示的結構：
式中，In the formula,
R1 選自：H、鹵素、羥基、胺基、C1-C6烷基、鹵代C1-C6烷基、C1-C6烷氧基、鹵代C1-C6烷氧基、C3-C6環烷基、鹵代C3-C6環烷基、C3-C6環烷氧基、鹵代C3-C6環烷氧基、(C1-C6烷基)NH-或(C1-C6烷基)(C1-C6烷基)N-；R1 is selected from: H, halogen, hydroxyl, amino, C1 -C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl , halogenated C3-C6 cycloalkyl, C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy, (C1-C6 alkyl) NH- or (C1-C6 alkyl) (C1-C6 alkane Base) N-;
各R2 獨立地選自：H、鹵素、羥基、胺基、氰基、硝基、C1-C6烷基、鹵代C1-C6烷基、C3-C6環烷基、鹵代C3-C6環烷基；Each R is independently selected from: H, halogen, hydroxyl, amino, cyano, nitro, C1 - C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 ring alkyl;
R3 和R4 各自獨立地選自：H、鹵素、羥基、胺基、氰基、C1-C6烷基、鹵代C1-C6烷基、C3-C6環烷基、3-8員環雜烷基、C6-C10芳基、5-10員雜芳基、-OR6 、-CONR7 R'7 ，其中，所述C1-C6烷基任選地被選自下組的一個或多個基團取代：氰基、羥基、C1-C6烷氧基、鹵代C1-C6烷氧基和-NR7 R'7 ，所述C6-C10芳基或者5-10員雜芳基任選地被選自下組的一個或多個基團取代：鹵素、C1-C6烷基、鹵代C1-C6烷基；R 3 and R 4 are each independently selected from: H, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, 3-8 membered cyclohetero Alkyl, C6-C10 aryl, 5-10 membered heteroaryl, -OR 6 , -CONR 7 R' 7 , wherein the C1-C6 alkyl is optionally selected from one or more of the following group Group substitution: cyano, hydroxyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy and -NR 7 R' 7 , the C6-C10 aryl or 5-10 membered heteroaryl is optionally Substituted by one or more groups selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl;
R6 、R7 和R'7 各自獨立地選自：H、C1-C6烷基、鹵代C1-C6烷基、C3-C6環烷基、鹵代C3-C6環烷基、3-8員環雜烷基；R 6 , R 7 and R' 7 are each independently selected from: H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, 3-8 Member cycloheteroalkyl;
R5 選自：-H、-CN、-CHO、-NH2 、-OH、鹵素、C1-C6烷基、3-8員雜烷基、鹵代C1-C6烷基、C1-C6烷基-OH、C1-C6烷氧基、C3-C6環烷基、C2-C6烯基、C2-C6炔基、-C(O)OR8 、-(L1 )p -N(R9 )(R'9 )、-C(O)-N(R10 )(R'10 )、-C(O)-N(R11 )-(L2 )m -N(R'11 )(R"11 )；R 5 is selected from: -H, -CN, -CHO, -NH 2 , -OH, halogen, C1-C6 alkyl, 3-8 membered heteroalkyl, halogenated C1-C6 alkyl, C1-C6 alkyl -OH, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C(O)OR 8 , -(L 1 ) p -N(R 9 )( R' 9 ), -C(O)-N(R 10 )(R' 10 ), -C(O)-N(R 11 )-(L 2 ) m -N(R' 11 )(R" 11 );
R8 、R10 、R'10 、R11 、R'11 和R"11 各自獨立地選自：H、C1-C6烷基、鹵代C1-C6烷基、C1-C6烷氧基、C3-C6環烷基、3-6員環雜烷基、C6-C10芳基、5-10員雜芳基；R 8 , R 10 , R' 10 , R 11 , R' 11 and R" 11 are each independently selected from: H, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3 -C6 cycloalkyl, 3-6 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl;
或者R10 和R'10 與其連接的N原子一起形成取代或未取代的3-8員雜環基，其中，所述取代是指被一個或多個選自下組的基團取代：鹵素、氰基、-CHO、羥基、胺基、C1-C6烷基、C1-C6烷氧基；Or R 10 and R' 10 form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom it is connected to, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of: halogen, Cyano, -CHO, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;
R9 和R'9 各自獨立地選自：-CN、-CHO、-NR12 R'12 、-OH、3-8員雜烷基、3-8員雜環基、5-10雜芳基，其中，R12 和R'12 各自獨立地選自：C1-C6烷基、鹵代C1-C6烷基、C1-C6烷氧基、C3-C6環烷基、C3-C6環雜烷基；R 9 and R' 9 are each independently selected from: -CN, -CHO, -NR 12 R' 12 , -OH, 3-8-membered heteroalkyl, 3-8-membered heterocyclyl, 5-10-membered heteroaryl , wherein, R 12 and R' 12 are each independently selected from: C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl ;
或者R9 和R'9 與其連接的N原子一起形成取代或未取代的3-8員雜環基，其中，所述取代是指被一個或多個選自下組的基團取代：鹵素、氰基、-CHO、羥基、胺基、C1-C6烷基、C1-C6烷氧基；Or R 9 and R' 9 form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom they are connected to, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of: halogen, Cyano, -CHO, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;
L1 和L2 各自獨立地為-CRf Rg -，其中，所述Rf 和Rg 各自獨立地選自：H、C1-C6烷基、鹵素、氰基、羥基、胺基；L 1 and L 2 are each independently -CR f R g -, wherein each of said R f and R g is independently selected from: H, C1-C6 alkyl, halogen, cyano, hydroxyl, amino;
n為0、1或2；n is 0, 1 or 2;
m和p各自獨立地為1、2、3、4、5或6。m and p are each independently 1, 2, 3, 4, 5 or 6.
在另一優選例中，R1 選自：C1-C6烷氧基、鹵代C1-C6烷氧基、C3-C6環烷氧基、鹵代C3-C6環烷氧基。In another preferred example, R 1 is selected from: C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy.
在另一優選例中，R5 選自：-CN、-CHO、C1-C6烷基、鹵代C1-C6烷基、3-8員雜烷基、C1-C6烷基-OH、C2-C6烯基、C2-C6炔基、-C(O)OR8 、-(L1 )p -N(R9 )(R'9 )、-C(O)-N(R10 )(R'10 )、-C(O)-N(R11 )-(L2 )m -N(R'11 )(R"11 )；In another preferred example, R 5 is selected from: -CN, -CHO, C1-C6 alkyl, halogenated C1-C6 alkyl, 3-8 membered heteroalkyl, C1-C6 alkyl-OH, C2- C6 alkenyl, C2-C6 alkynyl, -C(O)OR 8 , -(L 1 ) p -N(R 9 )(R' 9 ), -C(O)-N(R 10 )(R' 10 ), -C(O)-N(R 11 )-(L 2 ) m -N(R' 11 )(R" 11 );
R8 、R10 、R'10 、R11 、R'11 和R"11 各自獨立地選自：H、C1-C6烷基、鹵代C1-C6烷基、C1-C6烷氧基、C3-C6環烷基、C3-C6環雜烷基、C6-C10芳基、5-10員雜芳基；R 8 , R 10 , R' 10 , R 11 , R' 11 and R" 11 are each independently selected from: H, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3 -C6 cycloalkyl, C3-C6 cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl;
或者R10 和R'10 與其連接的N原子一起形成取代或未取代的3-8員雜環基，其中，所述取代是指被一個或多個選自下組的基團取代：鹵素、氰基、-CHO、羥基、胺基、C1-C6烷基、C1-C6烷氧基；Or R 10 and R' 10 form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom it is connected to, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of: halogen, Cyano, -CHO, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;
R9 和R'9 各自獨立地選自：-CN、-CHO、-NR12 R'12 、-OH、3-8員雜烷基、3-8員雜環基、5-10雜芳基，其中，R12 和R'12 各自獨立地選自：C1-C6烷基、鹵代C1-C6烷基、C1-C6烷氧基、C3-C6環烷基、C3-C6環雜烷基；R 9 and R' 9 are each independently selected from: -CN, -CHO, -NR 12 R' 12 , -OH, 3-8-membered heteroalkyl, 3-8-membered heterocyclyl, 5-10-membered heteroaryl , wherein, R 12 and R' 12 are each independently selected from: C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl ;
或者R9 和R'9 與其連接的N原子一起形成取代或未取代的3-8員雜環基，其中，所述取代是指被一個或多個選自下組的基團取代：鹵素、氰基、-CHO、羥基、胺基、C1-C6烷基、C1-C6烷氧基；Or R 9 and R' 9 form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom they are connected to, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of: halogen, Cyano, -CHO, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;
L1 和L2 各自獨立地為-CRf Rg -，其中，所述Rf 和Rg 各自獨立地選自：H、C1-C6烷基、鹵素、氰基、羥基、胺基；L 1 and L 2 are each independently -CR f R g -, wherein each of said R f and R g is independently selected from: H, C1-C6 alkyl, halogen, cyano, hydroxyl, amino;
m和p各自獨立地為1、2、3、4、5或6。m and p are each independently 1, 2, 3, 4, 5 or 6.
在另一優選例中，“-(L1 )p -”和“-(L2 )m -”為-CH2 CH2 -。In another preferred example, "-(L 1 ) p -" and "-(L 2 ) m -" are -CH 2 CH 2 -.
在另一優選例中，m為1、2、3或4。In another preferred example, m is 1, 2, 3 or 4.
在另一優選例中，p為1、2、3或4。In another preferred example, p is 1, 2, 3 or 4.
在另一優選例中，各R2 獨立地選自：鹵素、氰基、硝基、C1-C6烷基、鹵代C1-C6烷基。In another preferred example, each R 2 is independently selected from: halogen, cyano, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl.
在另一優選例中，R3 和R4 各自獨立地選自：H、鹵素、羥基、胺基、氰基、C1-C6烷基、鹵代C1-C6烷基。 In another preferred example, R3 and R4 are each independently selected from: H, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl.
在另一優選例中，所述式I化合物具有式I"所示的結構：
式中，In the formula,
Rc為選自取代或未取代的C1-C6烷基，所述的取代是指被一個或多個鹵素、氰基、羥基取代；Rc is selected from substituted or unsubstituted C1-C6 alkyl, said substitution refers to being substituted by one or more halogen, cyano, hydroxyl;
X選自：鹵素、氰基、硝基、鹵代C1-C6烷基；X is selected from: halogen, cyano, nitro, halogenated C1-C6 alkyl;
R5 的定義如上所述。R 5 is as defined above.
在另一優選例中，R5
選自：
在另一優選例中，R5 為-C(O)OR8 ，其中，R8 選自：甲基、乙基、異丙基、第三丁基。In another preferred example, R 5 is -C(O)OR 8 , wherein R 8 is selected from: methyl, ethyl, isopropyl, and tert-butyl.
在另一優選例中，R5 為-(L1 )p -N(R9 )(R'9 )，其中，p為1、2、3；R9 和R'9 的定義如上所述。In another preferred example, R 5 is -(L 1 ) p -N(R 9 )(R' 9 ), wherein p is 1, 2, or 3; the definitions of R 9 and R' 9 are as above.
在另一優選例中，R5 為-C(O)-N(R10 )(R'10 )，其中，R10 和R'10 各自獨立地選自：H、甲基、乙基、異丙基、第三丁基、C3-C6環烷基（如環丙基、環丁基、環戊基、環己基）、3-6員雜環烷烴（如四氫呋喃基、四氫吡咯基、嗎啉基），或者R10 和R'10 與其連接的N原子一起形成5-6員雜環基。In another preferred example, R 5 is -C(O)-N(R 10 )(R' 10 ), wherein R 10 and R' 10 are each independently selected from: H, methyl, ethyl, iso Propyl, tertiary butyl, C3-C6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 3-6 membered heterocycloalkane (such as tetrahydrofuryl, tetrahydropyrrolyl, Linyl), or R 10 and R' 10 form a 5-6 membered heterocyclic group together with the N atom to which they are attached.
在另一優選例中，R5 為-C(O)-NH-CH2 CH2 -N(R'11 )(R"11 )，其中，R'11 和R"11 各自獨立地選自：H、甲基、乙基、異丙基、第三丁基、C3-C6環烷基（如環丙基、環丁基、環戊基、環己基）、3-6員雜環烷烴（如四氫呋喃基、四氫吡咯基、嗎啉基）。In another preferred example, R 5 is -C(O)-NH-CH 2 CH 2 -N(R' 11 )(R" 11 ), wherein R' 11 and R" 11 are each independently selected from: H, methyl, ethyl, isopropyl, tertiary butyl, C3-C6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 3-6 membered heterocycloalkane (such as tetrahydrofuranyl, tetrahydropyrrolyl, morpholinyl).
在另一優選例中，R1 、R2 、R3 、R4 、R5 為實施例中各具體化合物相對應的具體基團。In another preferred example, R 1 , R 2 , R 3 , R 4 , and R 5 are specific groups corresponding to specific compounds in the embodiments.
本發明中的化合物可能形成的鹽也是屬於本發明的範圍。除非另有說明，本發明中的化合物被理解為包括其鹽類。在此使用的術語“鹽”，指用無機或有機酸和鹼形成酸式或鹼式的鹽。此外，當本發明中的化合物含一個鹼性片段時，它包括但不限於吡啶或咪唑，含一個酸性片段時，包括但不限於羧酸，可能形成的兩性離子(“內鹽”)包含在術語“鹽”的範圍內。藥學上可接受的(即無毒，生理可接受的)鹽是首選，雖然其他鹽類也有用，例如可以用在製備過程中的分離或純化步驟。本發明的化合物可能形成鹽，例如，化合物I與一定量如等當量的酸或鹼反應，在介質中鹽析出來，或在水溶液中冷凍乾燥得來。The salts that may be formed by the compounds of the present invention also belong to the scope of the present invention. Unless otherwise stated, the compounds of the present invention are understood to include their salts. The term "salt" as used herein refers to an acidic or basic salt formed with an inorganic or organic acid and a base. In addition, when a compound of the present invention contains a basic moiety, which includes but is not limited to pyridine or imidazole, and an acidic moiety, including but not limited to carboxylic acid, zwitterions ("inner salts") that may be formed are contained in within the term "salt". Pharmaceutically acceptable (ie, non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in isolation or purification steps during preparation. The compound of the present invention may form a salt, for example, compound I reacts with a certain amount, such as an equivalent amount of acid or base, and salts it out in a medium, or freeze-dries it in an aqueous solution.
本發明中的化合物含有的鹼性片段，包括但不限於胺或吡啶或咪唑環，可能會和有機或無機酸形成鹽。可以成鹽的典型的酸包括醋酸鹽(如用醋酸或三鹵代醋酸，如三氟乙酸)、己二酸鹽、海藻酸鹽、抗壞血酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、硫酸氫鹽、硼酸鹽、丁酸鹽、檸檬酸鹽、樟腦鹽、樟腦磺酸鹽、環戊烷丙酸鹽、二甘醇酸鹽、十二烷基硫酸鹽、乙烷磺酸鹽、延胡索酸鹽、葡庚糖酸鹽、甘油磷酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、鹽酸鹽、氫溴酸鹽、氫碘酸鹽、羥基乙磺酸鹽(如，2-羥基乙磺酸鹽)、乳酸鹽、馬來酸鹽、甲磺酸鹽、萘磺酸鹽(如，2-萘磺酸鹽)、菸酸鹽、硝酸鹽、草酸鹽、果膠酸鹽、過硫酸鹽、苯丙酸鹽(如3-苯丙酸鹽)、磷酸鹽、苦味酸鹽、新戊酸鹽、丙酸鹽，水楊酸鹽、琥珀酸鹽、硫酸鹽(如與硫酸形成的)、磺酸鹽、酒石酸鹽、硫氰酸鹽、甲苯磺酸鹽如對甲苯磺酸鹽、十二烷酸鹽等等。Basic moieties contained in the compounds of the present invention, including but not limited to amines or pyridine or imidazole rings, may form salts with organic or inorganic acids. Typical acids from which salts can be formed include acetate (e.g. with acetic acid or a trihaloacetic acid such as trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, benzoate, benzoate Sulfonate, Bisulfate, Borate, Butyrate, Citrate, Camphor Salt, Camphor Sulfonate, Cyclopentane Propionate, Diglycolate, Lauryl Sulfate, Ethane Sulfonate salt, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, isethionate (eg, 2-Hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (eg, 2-naphthalenesulfonate), nicotinate, nitrate, oxalate, pectin salts, persulfates, phenylpropionates (such as 3-phenylpropionate), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonate, dodecanoate, etc.
本發明的某些化合物可能含有的酸性片段，包括但不限於羧酸，可能會和各種有機或無機鹼形成鹽。典型的鹼形成的鹽包括銨鹽、鹼金屬鹽如鈉、鋰、鉀鹽，鹼土金屬鹽如鈣、鎂鹽和有機鹼形成的鹽(如有機胺)，如苄星、二環己基胺、海巴胺(與N,N -二(去氫松香基)乙二胺形成的鹽)、N -甲基-D-葡糖胺、N -甲基-D-葡糖醯胺、第三丁基胺，以及和胺基酸如精胺酸、離胺酸等等形成的鹽。鹼性含氮基團可以與鹵化物季銨鹽，如小分子烷基鹵化物(如甲基、乙基、丙基和丁基的氯化物、溴化物及碘化物)，二烷基硫酸鹽(如，硫酸二甲酯、二乙酯、二丁酯和二戊酯)，長鏈鹵化物(如癸基、十二烷基、十四烷基和十四烷基的氯化物、溴化物及碘化物)，芳烷基鹵化物(如苄基和苯基溴化物)等等。Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical salts formed with bases include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts and salts formed with organic bases (such as organic amines), such as benzathine, dicyclohexylamine, Hipamine (salt with N,N -di(dehydroabietyl)ethylenediamine), N -methyl-D-glucosamine, N -methyl-D-glucosamide, butyl Base amines, and salts formed with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and dipentyl sulfates), long-chain halides (e.g., decyl, dodecyl, tetradecyl, and tetradecyl chlorides, bromides and iodides), aralkyl halides (such as benzyl and phenyl bromides) and the like.
如本文所用，術語“藥學上可接受的鹽”指本發明化合物與酸或鹼所形成的適合用作藥物的鹽。藥學上可接受的鹽包括無機鹽和有機鹽。一類優選的鹽是本發明化合物與酸形成的鹽。適合形成鹽的酸包括但並不限於：鹽酸、氫溴酸、氫氟酸、硫酸、硝酸、磷酸等無機酸；甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富馬酸、馬來酸、乳酸、蘋果酸、酒石酸、檸檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、對甲苯磺酸、苯磺酸、萘磺酸等有機酸；以及脯胺酸、***酸、天冬胺酸、麩胺酸等胺基酸。As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with an acid or a base which is suitable for use as a medicine. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts are the salts of the compounds of the invention with acids. Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid and other organic acids; Amino acids such as amino acid, phenylalanine, aspartic acid, and glutamic acid.
另一類優選的鹽是本發明化合物與鹼形成的鹽，例如鹼金屬鹽(例如鈉鹽或鉀鹽)、鹼土金屬鹽(例如鎂鹽或鈣鹽)、銨鹽(如低級的烷醇銨鹽以及其它藥學上可接受的胺鹽)，例如甲胺鹽、乙胺鹽、丙胺鹽、二甲基胺鹽、三甲基胺鹽、二乙基胺鹽、三乙基胺鹽、第三丁基胺鹽、乙二胺鹽、羥乙胺鹽、二羥乙胺鹽、三羥乙胺鹽，以及分別由嗎啉、哌𠯤、離胺酸形成的胺鹽。Another preferred class of salts are the salts of the compounds of the invention with bases, such as alkali metal salts (e.g. sodium or potassium salts), alkaline earth metal salts (e.g. magnesium or calcium salts), ammonium salts (e.g. lower alkanolammonium salts) and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tributylamine salts, amine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperamide, and lysine, respectively.
術語“溶劑合物”指本發明化合物與溶劑分子配位形成特定比例的配合物。“水合物”是指本發明化合物與水進行配位形成的配合物。The term "solvate" refers to a complex in which a compound of the present invention coordinates with solvent molecules to form a specific ratio. "Hydrate" refers to a complex formed by coordination between the compound of the present invention and water.
本發明中化合物的前藥及溶劑合物也在涵蓋的範圍之內。此處術語“前藥”是指一種化合物，在治療相關疾病時，經過代謝或化學過程的化學轉化而產生本發明中的化合物、鹽、或溶劑合物。本發明的化合物包括溶劑合物，如水合物。Prodrugs and solvates of the compounds of the present invention are also contemplated. The term "prodrug" here refers to a compound that undergoes metabolic or chemical transformation during the treatment of related diseases to produce the compound, salt, or solvate of the present invention. The compounds of the present invention include solvates, such as hydrates.
本發明中的化合物、鹽或溶劑合物，可能存在的互變異構形式(例如醯胺和亞胺醚)。所有這些互變異構體都是本發明的一部分。Compounds, salts or solvates of the present invention, possible tautomeric forms (such as amides and imino ethers). All such tautomers are part of the present invention.
所有化合物的立體異構體(例如，那些由於對各種取代可能存在的不對稱碳原子)，包括其對映體形式和非對映形式，都屬於本發明的設想範圍。本發明中的化合物獨立的立體異構體可能不與其他異構體同時存在(例如，作為一個純的或者實質上是純的光學異構體具有特殊的活性)，或者也可能是混合物，如消旋體，或與所有其他立體異構體或其中的一部分形成的混合物。本發明的手性中心有S或R兩種構型，由理論與應用化學國際聯合會(IUPAC)1974年建議定義。外消旋形式可通過物理方法解決，例如分步結晶，或通過衍生為非對映異構體分離結晶，或通過手性柱色譜法分離。單個的光學異構體可通過合適的方法由外消旋體得到，包括但不限於傳統的方法，例如與光學活性酸成鹽後再結晶。Stereoisomers of all compounds (for example, those due to possible asymmetric carbon atoms for various substitutions), including enantiomeric and diastereomeric forms thereof, are contemplated by the present invention. The individual stereoisomers of the compounds of the present invention may not exist simultaneously with other isomers (for example, as a pure or substantially pure optical isomer having a specific activity), or may be a mixture, such as Racemates, or mixtures with all other stereoisomers or parts thereof. The chiral center of the present invention has two configurations of S or R, which are defined by the 1974 proposal of the International Union of Theoretical and Applied Chemistry (IUPAC). The racemic forms can be resolved by physical methods such as fractional crystallization, or by derivatization into diastereoisomers, or by separation by chiral column chromatography. Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to conventional methods such as salt formation with optically active acids followed by crystallization.
本發明中的化合物，依次通過製備、分離純化獲得的該化合物其重量含量等於或大於90%，例如，等於或大於95%，等於或大於99%(“非常純”的化合物)，在正文描述列出。此處這種“非常純”本發明的化合物也作為本發明的一部分。The compound in the present invention, the weight content of the compound obtained by preparation, separation and purification in sequence is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compound), described in the main text listed. Such "very pure" compounds of the invention are also included herein as part of the invention.
本發明的化合物所有的構型異構體都在涵蓋的範圍之內，無論是混合物、純的或非常純的形式。在本發明化合物的定義包含順式(Z )和反式(E )兩種烯烴異構體，以及碳環和雜環的順式和反式異構體。All configurational isomers of the compounds of the invention are contemplated, whether in admixture, pure or very pure form. The definitions of the compounds of the present invention include both cis ( Z ) and trans ( E ) olefinic isomers, as well as carbocyclic and heterocyclic cis and trans isomers.
在整個說明書中，基團和取代基可以被選擇以提供穩定的片段和化合物。Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.
特定官能團和化學術語定義都詳細介紹如下。對本發明來說，化學元素與元素週期表，CAS version，Handbook of Chemistry and Physics ，75th Ed.中定義的一致。特定官能團的定義也在其中描述。此外，有機化學的基本原則以及特定官能團和反應性在“Organic Chemistry”，Thomas Sorrell，University Science Books，Sausalito: 1999，也有說明，其全部內容納入參考文獻之列。Definitions of specific functional groups and chemical terms are detailed below. For purposes of this invention, the chemical elements are as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics , 75 th Ed. Definitions of specific functional groups are also described therein. In addition, the basic principles of organic chemistry as well as specific functional groups and reactivity are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, the entire contents of which are incorporated by reference.
本發明的某些化合物可能存在於特定的幾何或立體異構體形式。本發明涵蓋所有的化合物，包括其順式和反式異構體、R和S對映異構體、非對映體、(D)型異構體、(L)型異構體、外消旋混合物和其它混合物。另外不對稱碳原子可表示取代基，如烷基。所有異構體以及它們的混合物，都包含在本發明中。Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic spin mixtures and other mixtures. Alternatively an asymmetric carbon atom may represent a substituent, such as an alkyl group. All isomers, as well as mixtures thereof, are included in the present invention.
按照本發明，同分異構體的混合物含有異構體的比率可以是多樣的。例如，在只有兩個異構體的混合物可以有以下組合：50:50，60:40，70:30，80:20，90:10，95:5，96:4，97:3，98:2，99:1，或100:0，異構體的所有比率都在本發明範圍之內。本專業內一般技術人員容易理解的類似的比率，及為更複雜的異構體的混合物的比率也在本發明範圍之內。According to the present invention, the mixture of isomers may contain various ratios of isomers. For example, in a mixture of only two isomers you can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: 2, 99:1, or 100:0, all ratios of isomers are within the scope of the present invention. Similar ratios, as well as ratios that are mixtures of more complex isomers, readily understood by one of ordinary skill in the art, are also within the scope of the invention.
本發明還包括同位素標記的化合物，等同於原始化合物在此公開。不過實際上對一個或更多的原子被與其原子量或質量序數不同的原子取代通常會出現。可以列為本發明的化合物同位素的例子包括氫、碳、氮、氧、磷、硫、氟和氯同位素，分別如2 H、3 H、13 C、11 C、14 C、15 N、18 O、17 O、31 P、32 P、35 S、18 F和36 Cl。本發明中的化合物，或對映體，非對映體，異構體，或藥學上可接受的鹽或溶劑化物，其中含有上述化合物的同位素或其他同位素原子都在本發明的範圍之內。本發明中某些同位素標記化合物，例如3 H和14 C的放射性同位素也在其中，在藥物和底物的組織分佈實驗中是有用的。氚，即3 H和碳-14，即14 C，它們的製備和檢測比較容易。是同位素中的首選。此外，較重同位素取代如氘，即2 H，由於其很好的代謝穩定性在某些療法中有優勢，例如在體內增加半衰期或減少用量，因此，在某些情況下可以優先考慮。同位素標記的化合物可以用一般的方法，通過用易得的同位素標記試劑替換為非同位素的試劑，用批露在示例中的方案可以製備。The invention also includes isotopically labeled compounds equivalent to the original compounds disclosed herein. In practice, however, substitution of one or more atoms by an atom with a different atomic mass or mass number usually occurs. Examples of isotopes that may be included in compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, respectively , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl. The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the above compounds are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as 3 H and 14 C radioactive isotopes, are useful in tissue distribution assays for drugs and substrates. Tritium, namely 3 H, and carbon-14, namely 14 C, are relatively easy to prepare and detect. is the first choice among isotopes. In addition, substitution of heavier isotopes such as deuterium, ie 2 H, may be preferred in some cases due to its good metabolic stability, which has advantages in certain therapies, such as increased half-life in vivo or reduced dosage. Isotopically-labeled compounds can be prepared in general manner by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent, using the protocols disclosed in the Examples.
如果要設計一個本發明的化合物特定的對映體的合成，它可以不對稱合成製備，或用手性輔劑衍生化，將所產生的非對映混合物分離，再除去手性輔劑而得到純的對映體。另外，如果分子中含有一個鹼性官能團，如胺基酸，或酸性官能團，如羧基，可以用合適的光學活性的酸或鹼的與之形成非對映異構體鹽，再通過分離結晶或色譜等常規手段分離，然後就得到了純的對映體。If the synthesis of a specific enantiomer of a compound of the present invention is to be designed, it can be prepared by asymmetric synthesis, or derivatized with a chiral auxiliary, the resulting diastereomeric mixture is separated, and the chiral auxiliary is removed to obtain pure enantiomers. In addition, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, a diastereoisomeric salt can be formed with a suitable optically active acid or base, and then crystallized by separation or The pure enantiomers are then obtained by separation by conventional means such as chromatography.
如本文所述，本發明中的化合物可與任何數量取代基或官能團取而擴大其包含範圍。通常，術語“取代”不論在術語“可選”前面或後面出現，在本發明配方中包括取代基的通式，是指用指定結構取代基，代替氫自由基。當特定結構中的多個在位置被多個特定的取代基取代時，取代基每一個位置可以是相同或不同。本文中所使用的術語“取代”包括所有允許有機化合物取代。從廣義上講，允許的取代基包括非環狀的、環狀的、支鏈的非支鏈的、碳環的和雜環的，芳環的和非芳環的有機化合物。在本發明中，如雜原子氮可以有氫取代基或任何允許的上文所述的有機化合物來補充其價態。此外，本發明是無意以任何方式限制允許取代有機化合物。本發明認為取代基和可變基團的組合在以穩定化合物形式在疾病的治療上是很好的。此處術語“穩定”是指具有穩定的化合物，在足夠長的時間內檢測足以維持化合物結構的完整性，最好是在足夠長的時間內都在效，本文在此用於上述目的。As described herein, the compounds of the present invention may be supplemented with any number of substituents or functional groups to extend their scope. Generally, whether the term "substitution" appears before or after the term "optional", the general formula including the substituent in the formula of the present invention means that the hydrogen radical is replaced by the specified structural substituent. When multiple positions in a specific structure are substituted with multiple specific substituents, the substituents may be the same or different for each position. The term "substitution" as used herein includes all permissible organic compound substitutions. Broadly speaking, the permissible substituents include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds. In the present invention eg heteroatom nitrogen may have hydrogen substituents or any permissible organic compound as described above to complement its valence. Furthermore, this invention is not intended to be limiting in any way to the organic compounds permissible to be substituted. Combinations of substituents and variables are considered by the present invention to be beneficial in the treatment of diseases in the form of stable compounds. The term "stable" herein means having a compound that is stable, detectable for a sufficient period of time to maintain the structural integrity of the compound, preferably active for a sufficient period of time, and is used herein for the above purposes.
本申請所涉及的化合物及其藥學可接受的鹽的代謝產物，以及可以在體內轉變為本申請所涉及的化合物及其藥學可接受的鹽的結構的前藥，也包含在本申請的申請專利範圍中。The metabolites of the compounds involved in the application and their pharmaceutically acceptable salts, as well as the prodrugs that can be transformed into the structures of the compounds involved in the application and their pharmaceutically acceptable salts in vivo, are also included in the patent application of the application in range.
藥物組合物和施用方法Pharmaceutical compositions and methods of administration
本發明所述的藥物組合物用於預防和/或治療以下疾病：腸易激綜合症和/或癌症。The pharmaceutical composition of the present invention is used for preventing and/or treating the following diseases: irritable bowel syndrome and/or cancer.
通式(I)所述化合物可以與已知的治療或改進相似病狀的其他藥物聯用。聯合給藥時，原來藥物的給藥方式和劑量可以保持不變，而同時或隨後服用式I的化合物。當式I化合物與其它一種或幾種藥物同時服用時，可以優選使用同時含有一種或幾種已知藥物和式I化合物的藥用組合物。藥物聯用也包括在重疊的時間段服用式I化合物與其它一種或幾種已知藥物。當式I化合物與其它一種或幾種藥物進行藥物聯用時，式I化合物或已知藥物的劑量可能比它們單獨用藥的劑量低。The compound of general formula (I) can be used in combination with other known drugs for treating or improving similar diseases. In the case of combined administration, the administration method and dosage of the original drug can be kept unchanged, and the compound of formula I can be taken simultaneously or subsequently. When the compound of formula I is taken together with one or several other drugs, the pharmaceutical composition containing one or several known drugs and the compound of formula I can be preferably used. Drug combinations also include administration of a compound of formula I and one or more other known drugs for overlapping periods of time. When the compound of formula I is used in combination with one or several other drugs, the dosage of the compound of formula I or known drugs may be lower than that of their single administration.
可以與通式(I)所述化合物進行藥物聯用的藥物或活性成分包括但不局限為：胺基水楊酸製劑（如柳氮磺吡啶）、糖皮質激素（如氫化可的松、***等）、PD-1抑制劑(如納武單抗、派姆單抗、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10、BAT1306、AK105、LZM 009或上述藥物的生物類似藥等)、PD-L1抑制劑(如德瓦魯單抗、阿特珠單抗、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003、KL-A167、F 520、GR1405、MSB2311或上述藥物的生物類似藥等)、CD20抗體(如利妥昔單抗、奧濱尤妥珠單抗、奧法木單抗、托西莫單抗、替伊莫單抗等)、CD47抗體(如Hu5F9-G4、CC-90002、TTI-621、TTI-622、OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制劑(如色瑞替尼、艾樂替尼、布加替尼、勞拉替尼、奧卡替尼)、PI3K抑制劑(如艾代拉裡斯、Dactolisib、Taselisib、Buparlisib等)、BTK抑制劑(如依魯替尼、Tirabrutinib、Acalabrutinib等)、EGFR抑制劑(如阿法替尼、吉非替尼、厄洛替尼、拉帕替尼、達克替尼、埃克替尼、卡奈替尼等)、VEGFR抑制劑(如索拉非尼、帕唑帕尼、瑞伐替尼、卡博替尼、舒尼替尼、多納非尼等)、HDAC抑制劑(如Givinostat、Droxinostat、恩替諾特、達西司特、泰克地那林等)、CDK抑制劑(如帕博西尼、瑞博西尼、Abemaciclib、Lerociclib等)、MEK抑制劑(如司美替尼(AZD6244)、曲美替尼(GSK1120212)、PD0325901、U0126、AS-703026、PD184352(CI-1040)等)、Akt抑制劑(如MK-2206、Ipatasertib、Capivasertib、Afuresertib、Uprosertib等)、mTOR抑制劑(如Vistusertib等)、SHP2抑制劑(如RMC-4630、JAB-3068、TNO155等)、IGF-1R抑制劑(如Ceritinib、奧卡替尼、linsitinib、BMS-754807、GSK1838705A等)或它們的任意組合。Drugs or active ingredients that can be combined with the compound described in general formula (I) include but are not limited to: aminosalicylic acid preparations (such as sulfasalazine), glucocorticoids (such as hydrocortisone, Semethasone, etc.), PD-1 inhibitors (such as nivolumab, pembrolizumab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333 , JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, simotumumab, icomomab, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR -1603, IBI188, IMM01), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lorlatinib, ocatinib), PI3K inhibitors (such as Idelaris, Dactolisib , Taselisib, Buparlisib, etc.), BTK inhibitors (such as ibrutinib, Tirabrutinib, Acalabrutinib, etc.), EGFR inhibitors (such as afatinib, gefitinib, erlotinib, lapatinib, dac Icotinib, Icotinib, Canertinib, etc.), VEGFR inhibitors (such as Sorafenib, Pazopanib, Ravatinib, Cabozantinib, Sunitinib, Donafenib, etc. ), HDAC inhibitors (such as Givinostat, Droxinostat, entinostat, dalcylast, tecdinaline, etc.), CDK inhibitors (such as palbociclib, ribociclib, Abemaciclib, Lerociclib, etc.), MEK Inhibitors (such as selumetinib (AZD6244), trametinib (GSK1120212), PD0325901, U0126, AS-703026, PD184352 (CI-1040), etc.), Akt inhibitors (such as MK-2206, Ipatasertib, Capivasertib, Afuresertib, Uprosertib, etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.), IGF-1R inhibitors (such as Ceritinib, ocatinib, linsitinib, BMS -754807, GSK1838705A, etc.) or any combination of them.
本發明藥物組合物的劑型包括(但並不限於)：注射劑、片劑、膠囊劑、氣霧劑、栓劑、膜劑、滴丸劑、外用擦劑、控釋型、緩釋型或奈米製劑。The dosage form of the pharmaceutical composition of the present invention includes (but not limited to): injection, tablet, capsule, aerosol, suppository, film, drop pill, external liniment, controlled release type, sustained release type or nanometer preparation .
本發明的藥物組合物包含安全有效量範圍內的本發明化合物或其藥理上可接受的鹽及藥理上可以接受的賦形劑或載體。其中“安全有效量”指的是：化合物的量足以明顯改善病情，而不至於產生嚴重的副作用。通常，藥物組合物含有1-2000 mg本發明化合物/劑，更佳地，含有10-1000 mg本發明化合物/劑。較佳地，所述的“一劑”為一個膠囊或藥片。The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof within a safe and effective amount range and a pharmaceutically acceptable excipient or carrier. Wherein, "safe and effective dose" refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.
“藥學上可以接受的載體”指的是：一種或多種相容性固體或液體填料或凝膠物質，它們適合於人使用，而且必須有足夠的純度和足夠低的毒性。“相容性”在此指的是組合物中各組份能和本發明的化合物以及它們之間相互摻和，而不明顯降低化合物的藥效。藥學上可以接受的載體部分例子有纖維素及其衍生物(如羧甲基纖維素鈉、乙基纖維素鈉、纖維素乙酸酯等)、明膠、滑石、固體潤滑劑(如硬脂酸、硬脂酸鎂)、硫酸鈣、植物油(如豆油、芝麻油、花生油、橄欖油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化劑(如吐溫®)、潤濕劑(如十二烷基硫酸鈉)、著色劑、調味劑、穩定劑、抗氧化劑、防腐劑、無熱原水等。"Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low enough toxicity. "Compatibility" herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Examples of pharmaceutically acceptable carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween®), moisturizers Wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
本發明化合物或藥物組合物的施用方式沒有特別限制，代表性的施用方式包括(但並不限於)：口服、瘤內、直腸、腸胃外(靜脈內、肌肉內或皮下)、和局部給藥。The mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
用於口服給藥的固體劑型包括膠囊劑、片劑、丸劑、散劑和顆粒劑。在這些固體劑型中，活性化合物與至少一種常規惰性賦形劑(或載體)混合，如檸檬酸鈉或磷酸二鈣，或與下述成分混合：(a) 填料或增容劑，例如，澱粉、乳糖、蔗糖、葡萄糖、甘露醇和矽酸；(b) 黏合劑，例如，羥甲基纖維素、海藻酸鹽、明膠、聚乙烯基吡咯烷酮、蔗糖和***膠；(c) 保濕劑，例如，甘油；(d) 崩解劑，例如，瓊脂、碳酸鈣、馬鈴薯澱粉或木薯澱粉、海藻酸、某些複合矽酸鹽、和碳酸鈉；(e) 緩溶劑，例如石蠟；(f) 吸收加速劑，例如，季胺化合物；(g) 潤濕劑，例如鯨蠟醇和單硬脂酸甘油酯；(h) 吸附劑，例如，高嶺土；和(i) 潤滑劑，例如，滑石、硬脂酸鈣、硬脂酸鎂、固體聚乙二醇、十二烷基硫酸鈉，或其混合物。膠囊劑、片劑和丸劑中，劑型也可包含緩衝劑。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with: (a) fillers or extenders, for example, starch , lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants such as, Glycerin; (d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slowing agents such as paraffin; (f) absorption acceleration (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, stearic acid Calcium, magnesium stearate, polyethylene glycol solid, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.
固體劑型如片劑、糖丸、膠囊劑、丸劑和顆粒劑可採用包衣和殼材製備，如腸衣和其它本領域周知的材料。它們可包含不透明劑，並且，這種組合物中活性化合物或化合物的釋放可以延遲的方式在消化道內的某一部分中釋放。可採用的包埋組分的實例是聚合物質和蠟類物質。必要時，活性化合物也可與上述賦形劑中的一種或多種形成微膠囊形式。Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner. Examples of usable embedding components are polymeric substances and waxy substances. The active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
用於口服給藥的液體劑型包括藥學上可接受的乳液、溶液、懸浮液、糖漿或酊劑。除了活性化合物外，液體劑型可包含本領域中常規採用的惰性稀釋劑，如水或其它溶劑，增溶劑和乳化劑，例知，乙醇、異丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲醯胺以及油，特別是棉籽油、花生油、玉米胚油、橄欖油、蓖麻油和芝麻油或這些物質的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
除了這些惰性稀釋劑外，組合物也可包含助劑，如潤濕劑、乳化劑和懸浮劑、甜味劑、矯味劑和香料。Besides such inert diluents, the compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
除了活性化合物外，懸浮液可包含懸浮劑，例如，乙氧基化異十八烷醇、聚氧乙烯山梨醇和脫水山梨醇酯、微晶纖維素、甲醇鋁和瓊脂或這些物質的混合物等。Suspensions, in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
用於腸胃外注射的組合物可包含生理上可接受的無菌含水或無水溶液、分散液、懸浮液或乳液和用於重新溶解成無菌的可注射溶液或分散液的無菌粉末。適宜的含水和非水載體、稀釋劑、溶劑或賦形劑包括水、乙醇、多元醇及其適宜的混合物。Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
用於局部給藥的本發明化合物的劑型包括軟膏劑、散劑、貼劑、噴射劑和吸入劑。活性成分在無菌條件下與生理上可接受的載體及任何防腐劑、緩衝劑，或必要時可能需要的推進劑一起混合。Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.
本發明治療方法可以單獨施用，或者與其它治療手段或者治療藥物聯用。The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.
使用藥物組合物時，是將安全有效量的本發明化合物適用於需要治療的哺乳動物(如人)，其中施用時劑量為藥學上認為的有效給藥劑量，對於60 kg體重的人而言，日給藥劑量通常為1～2000 mg，優選50～1000 mg。當然，具體劑量還應考慮給藥途徑、病人健康狀況等因素，這些都是熟練醫師技能範圍之內的。When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered. For a person with a body weight of 60 kg, The daily dosage is usually 1-2000 mg, preferably 50-1000 mg. Of course, factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
本發明還提供了一種藥物組合物的製備方法，包括步驟：將藥學上可接受的載體與本發明所述通式(I)化合物或其晶型、藥學上可接受的鹽、水合物或溶劑合物進行混合，從而形成藥物組合物。The present invention also provides a preparation method of a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of general formula (I) or its crystal form, pharmaceutically acceptable salt, hydrate or solvent of the present invention compounds are mixed to form a pharmaceutical composition.
本發明還提供了一種治療方法，它包括步驟：給需要治療的對象施用本發明中所述通式(I)化合物，或其晶型、藥學上可接受的鹽、水合物或溶劑合物，或施用本發明所述的藥物組合物，用於選擇性地抑制RET。The present invention also provides a treatment method, which includes the steps of: administering the compound of general formula (I) described in the present invention, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate to the subject in need of treatment, Or administer the pharmaceutical composition of the present invention for selectively inhibiting RET.
製備方法Preparation
以下方案和實例中描述了製備式I的化合物的方法。原料和中間體從商業來源購買，由已知步驟製備，或以其他方式說明。在某些情況下，可以改變執行反應方案的步驟的順序，以促進反應或避免不需要的副反應產物。Methods of preparing compounds of Formula I are described in the following Schemes and Examples. Starting materials and intermediates were purchased from commercial sources, prepared by known procedures, or otherwise illustrated. In some cases, the order in which the steps of a reaction scheme are performed can be altered to facilitate a reaction or to avoid undesired side reaction products.
下面更具體地描述本發明式I結構化合物的製備方法，但這些具體方法不對本發明構成任何限制。本發明化合物還可以任選將在本說明書中描述的或本領域已知的各種合成方法組合起來而方便的製得，這樣的組合可由本發明所屬領域的技術人員容易的進行。The preparation method of the compound of formula I of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compound of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in the specification or known in the art. Such a combination can be easily performed by those skilled in the art to which the present invention belongs.
通常，在製備流程中，各反應通常惰性氣體保護下，適當溶劑中，在0到90℃下進行，反應時間通常為2-24小時。Usually, in the preparation process, each reaction is usually carried out in an appropriate solvent under the protection of an inert gas at a temperature of 0 to 90° C., and the reaction time is usually 2-24 hours.
優選地，本發明式I化合物的製備方法包括如下步驟：Preferably, the preparation method of the compound of formula I of the present invention comprises the following steps:
(s1) 化合物1-1在濃硫酸條件下，慢慢滴加濃硝酸，或者發煙硝酸進行硝化反應，得到化合物1-2；(s1) Compound 1-1 is slowly added dropwise with concentrated nitric acid or fuming nitric acid under the condition of concentrated sulfuric acid for nitration reaction to obtain compound 1-2;
(s2) 化合物1-2經官能團轉換及還原步驟得到化合物I1；(s2) compound 1-2 undergoes functional group conversion and reduction steps to obtain compound I1;
(s3) 化合物2-1在惰性溶劑中，鹼性條件下反應生成化合物2-2；(s3) Compound 2-1 reacts in an inert solvent under basic conditions to generate Compound 2-2;
(s4) 化合物2-2經偶聯等反應生成化合物I2；(s4) compound 2-2 generates compound I2 through coupling and other reactions;
(s5) 在惰性溶劑中，催化劑存在下，式I1和式I2化合物發生反應，得到式3-1化合物；(s5) In an inert solvent, in the presence of a catalyst, the compound of formula I1 and formula I2 reacts to obtain the compound of formula 3-1;
(s6) 在惰性溶劑中，酸性條件下，式3-1化合物發生反應，得到式I化合物；
式中，Y選自OH、鹵素；In the formula, Y is selected from OH and halogen;
R1 、R2 、R5 、Rb 、r、n、n'和n"的定義如上所述。R 1 , R 2 , R 5 , R b , r, n, n' and n" are as defined above.
優選地，步驟(s3)、(s5)、(s6)中，所述的惰性溶劑為吡啶、DMF、DMSO、三乙胺、DCM、1,2-二氯乙烷、四氫呋喃、1,6-二氧六烷。Preferably, in steps (s3), (s5), and (s6), the inert solvent is pyridine, DMF, DMSO, triethylamine, DCM, 1,2-dichloroethane, tetrahydrofuran, 1,6- Dioxane.
優選地，步驟(s5)中，所述的催化劑為丙基磷酸酐(T3 P)。Preferably, in step (s5), the catalyst is propylphosphoric anhydride (T 3 P).
優選地，步驟(s6)中，所述的酸為TFA。Preferably, in step (s6), the acid is TFA.
優選地，本發明化合物可通過如下步驟獲得：
式中，R1 、R5 的定義如上所述；In the formula, the definitions of R 1 and R 5 are as above;
優選地，R1
為-O-R'(
優選地，R5
選自-C(O)-N(R10
)(R'10
)(
(i)在濃硫酸條件下，慢慢滴加濃硝酸，或者發煙硝酸進行硝化反應，得到化合物2；(i) under the condition of concentrated sulfuric acid, slowly add concentrated nitric acid or fuming nitric acid for nitration reaction to obtain compound 2;
(ii)酸在氯化亞碸或者草醯氯和催化劑（例如，DMF）作用轉化為醯氯，在鹼性（例如，Et3 N，DIEA）條件下，醯氯和胺快速反應生成化合物3；(ii) Acid is converted to acyl chloride by the action of phosphide chloride or oxalyl chloride and a catalyst (for example, DMF). Under alkaline (for example, Et 3 N, DIEA) conditions, acyl chloride and amine rapidly react to form compound 3 ;
(iii)在酸性（例如：HCl）條件下，鐵還原硝基，得到化合物4；(iii) Under acidic (for example: HCl) conditions, iron reduces the nitro group to obtain compound 4;
(iv)在鹼性條件下（如碳酸鉀），化合物5與碘代烷基反應生成化合物6；(iv) Under basic conditions (such as potassium carbonate), compound 5 reacts with iodoalkyl to generate compound 6;
(v)在鹼性條件下（如氫氧化鉀），化合物6與對甲氧基苯基甲醇反應生成化合物7；(v) Under alkaline conditions (such as potassium hydroxide), compound 6 reacts with p-methoxyphenylcarbinol to generate compound 7;
(vi)在鹼性條件下（如碳酸銫），化合物7與2-（2-氟-4-（4,4,5,5-四甲基-1,3,2-二氧硼雜環戊烷-2-基）苯基）乙酸甲酯偶聯生成化合物8；(vi) Under basic conditions (such as cesium carbonate), compound 7 and 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborine Pentan-2-yl) phenyl) methyl acetate is coupled to generate compound 8;
(vii)在鹼性條件下（如氫氧化鋰），化合物8脫甲基生成化合物9；(vii) Under alkaline conditions (such as lithium hydroxide), compound 8 is demethylated to generate compound 9;
(viii)在鹼性（例如，吡啶）以及酸酐條件下，化合物4與化合物9進行縮合成醯胺，生成化合物10；(viii) Under basic (for example, pyridine) and acid anhydride conditions, compound 4 and compound 9 are condensed to form an amide to generate compound 10;
(ix)化合物10在酸性（例如：TFA）條件下，脫去苄氧基，最終得到化合物11；(ix) Compound 10 is removed from benzyloxy group under acidic (eg TFA) conditions to finally obtain Compound 11;
以上反應步驟中，反應溶劑、反應溫度、反應時間、催化劑等可以根據具體的反應物進行選擇。In the above reaction steps, the reaction solvent, reaction temperature, reaction time, catalyst, etc. can be selected according to the specific reactants.
以上反應步驟中，反應原料和試劑可以通過商購或文獻報導路線合成。In the above reaction steps, the reaction raw materials and reagents can be synthesized through commercially available or literature-reported routes.
本發明具有以下主要優點：The present invention has the following main advantages:
(1)本發明化合物對RET激酶具有優良的抑制能力，以及對RET激酶具有優良選擇性，對VEGFR2等其他激酶的抑制活性低；(1) The compound of the present invention has excellent inhibitory ability to RET kinase, and has excellent selectivity to RET kinase, and has low inhibitory activity to other kinases such as VEGFR2;
(2)本發明化合物對TRK激酶具有優良的抑制能力，以及對突變型TRK激酶具有更強的抑制能力；(2) The compound of the present invention has excellent inhibitory ability to TRK kinase, and has stronger inhibitory ability to mutant TRK kinase;
(3)本發明中部分化合物具有更好的細胞抑制活性作用，且在IBS模型（醋酸誘導的腸超敏模型）中表現出更好的藥效作用。(3) Some compounds in the present invention have better cytostatic activity, and show better pharmacodynamic effects in the IBS model (acetic acid-induced intestinal hypersensitivity model).
下面結合具體實施例，進一步闡述本發明。應理解，這些實施例僅用於說明本發明而不用於限制本發明的範圍。下列實施例中未註明具體條件的實驗方法，通常按照常規條件，或按照製造廠商所建議的條件。除非另外說明，否則百分比和份數按重量計算。Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. For the experimental methods without specific conditions indicated in the following examples, the conventional conditions or the conditions suggested by the manufacturer are usually followed. Percentages and parts are by weight unless otherwise indicated.
除非另行定義，文中所使用的所有專業與科學用語與本領域熟練人員所熟悉的意義相同。此外，任何與所記載內容相似或均等的方法及材料皆可應用於本發明方法中。文中所述的較佳實施方法與材料僅作示範之用。Unless otherwise defined, all professional and scientific terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be applied to the method of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.
本發明的化合物結構是通過核磁共振(NMR)和液質聯用色譜(LC-MS)來確定的。The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass chromatography (LC-MS).
NMR是使用Bruker AVANCE-400和Bruker AVANCE-500核磁儀檢測的，測定溶劑包含氘代二甲亞碸(DMSO-d 6 )、氘代丙酮(CD3 COCD3 )、氘代氯仿(CDCl3 )及氘代甲醇(CD3 OD)等，內標採用四甲基矽烷(TMS)，化學位移以百萬分之一(ppm)的單位計量。NMR was detected using Bruker AVANCE-400 and Bruker AVANCE-500 nuclear magnetic instruments, and the determination solvents included deuterated dimethyl sulfide (DMSO- d 6 ), deuterated acetone (CD 3 COCD 3 ), deuterated chloroform (CDCl 3 ) and deuterated methanol (CD 3 OD), etc., the internal standard is tetramethylsilane (TMS), and the chemical shift is measured in parts per million (ppm).
液質聯用色譜(LC-MS) 是使用Agilent 1260質譜儀檢測的。HPLC的測定使用Agilent 1100高壓色譜儀(Microsorb 5 micron C18 100 × 3.0 mm)，製備薄層色譜採用的是0.4 mm-0.5 mm。柱層析一般使用青島矽膠200-300目矽膠作為載體。Liquid chromatography-mass chromatography (LC-MS) was detected using an Agilent 1260 mass spectrometer. Agilent 1100 high-pressure chromatograph (Microsorb 5 micron C18 100 × 3.0 mm) was used for HPLC determination, and 0.4 mm-0.5 mm was used for preparative thin-layer chromatography. Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as the carrier.
本發明實施例中的起始原料都是已知並有市售的，或者可以採用或按照本領域已報導的文獻資料合成的。The starting materials in the examples of the present invention are all known and commercially available, or can be adopted or synthesized according to literatures reported in the art.
除特殊說明外，本發明所有反應均在乾燥的惰性氣體(如氮氣或氬氣)保護下通過連續磁力攪拌進行，反應溫度均為攝氏度。Unless otherwise specified, all reactions in the present invention are carried out under the protection of dry inert gas (such as nitrogen or argon) by continuous magnetic stirring, and the reaction temperatures are all in degrees Celsius.
下列簡寫詞的使用貫穿本發明The following abbreviations are used throughout this specification
THF：四氫呋喃THF: Tetrahydrofuran
DCM：二氯甲烷DCM: dichloromethane
Fe：鐵粉Fe: iron powder
H2 SO4 ：硫酸H 2 SO 4 : sulfuric acid
HNO3 ：硝酸HNO 3 : nitric acid
SOCl2 ：氯化亞碸SOCl 2 : Phosphorus chloride
HCl：鹽酸HCl: hydrochloric acid
H2 O：水 H2O : water
TEA：三乙胺TEA: Triethylamine
DIEA：N ,N -二異丙基乙胺DIEA: N , N -Diisopropylethylamine
DMF：N ,N -二甲基甲醯胺DMF: N , N -Dimethylformamide
Cs2 CO3 ：碳酸銫Cs 2 CO 3 : cesium carbonate
LiOH：氫氧化鋰LiOH: lithium hydroxide
EA：乙酸乙酯EA: ethyl acetate
Pd(dppf)Cl2 ：[1,1'-雙(二苯基膦)二茂鐵]二氯化鈀Pd(dppf)Cl 2 : [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
T3 P：丙基磷酸酐T 3 P: Propyl phosphoric anhydride
中間體1 3- 硝基-5-( 五氟硫代) 苯甲酸的合成 
將3-(五氟硫代)苯甲酸（1.0 g, 4.03 mmol）加入到單口瓶中，然後慢慢加入濃硫酸（12 mL），該混合液攪拌並降溫至0℃，再緩慢加入濃硝酸（2 mL），攪拌10分鐘，然後升溫至80℃反應12 h，反應完全後，冷卻，反應液慢慢倒入冰水中，EA萃取，有機相再用飽和碳酸氫鈉中和，乾燥，過濾，濃縮，得到3-硝基-5-(五氟硫代)苯甲酸0.9 g。Add 3-(pentafluorothio)benzoic acid (1.0 g, 4.03 mmol) into a single-necked flask, then slowly add concentrated sulfuric acid (12 mL), stir the mixture and cool it down to 0°C, then slowly add concentrated nitric acid (2 mL), stirred for 10 minutes, then heated to 80°C for 12 h, after the reaction was complete, cooled, the reaction solution was slowly poured into ice water, extracted with EA, the organic phase was neutralized with saturated sodium bicarbonate, dried, and filtered , and concentrated to obtain 0.9 g of 3-nitro-5-(pentafluorothio)benzoic acid.
中間體2 3- 胺基-N
-(2-( 二甲基胺基) 乙基)-5-( 五氟硫代) 苯甲醯胺的合成 
步驟1step 1 合成N -(2-(Synthesis of N -(2-( 二甲基胺基)Dimethylamino) 乙基)-3-Ethyl)-3- 硝基-5-(Nitro-5-( 五氟硫代)Pentafluorothio) 苯甲醯胺benzamide
將3-硝基-5-(五氟硫代)苯甲酸（0.5 g, 1.71 mmol）溶解在SOCl2 （10 mL)中，再加入幾滴DMF，然後回流反應2小時，反應完全後旋乾反應液，將醯基氯溶於DCM（15 mL）中，將混合物冷卻至0℃，然後加入三乙胺（0.52 g, 5.12 mmol），接著加入N ,N -二甲基乙二胺（0.23 g, 2.56 mmol），在0℃下繼續反應半小時，反應完全後，加入水淬滅反應，分液，有機相濃縮，柱層析得到N -(2-(二甲基胺基)乙基)-3-硝基-5-(五氟硫代)苯甲醯胺0.55 g，MS m/z（ESI）：363.3[M+H]+ 。Dissolve 3-nitro-5-(pentafluorothio)benzoic acid (0.5 g, 1.71 mmol) in SOCl 2 (10 mL), add a few drops of DMF, then reflux for 2 hours, spin dry after the reaction is complete For the reaction solution, dissolve acyl chloride in DCM (15 mL), cool the mixture to 0 °C, then add triethylamine (0.52 g, 5.12 mmol), then add N , N -dimethylethylenediamine (0.23 g, 2.56 mmol), continue the reaction at 0°C for half an hour, after the reaction is complete, add water to quench the reaction, separate the liquids, concentrate the organic phase, and obtain N- (2-(dimethylamino)ethyl )-3-nitro-5-(pentafluorothio)benzamide 0.55 g, MS m/z (ESI): 363.3[M+H] + .
步驟2step 2 合成3-Synthetic 3- 胺基-N -(2-(Amino- N -(2-( 二甲基胺基)Dimethylamino) 乙基)-5-(Ethyl)-5-( 五氟硫代)Pentafluorothio) 苯甲醯胺benzamide
將N -(2-(二甲基胺基)乙基)-3-硝基-5-(五氟硫代)苯甲醯胺（0.5 g, 1.38 mmol）加入到甲醇（10 mL）中,再加入鐵粉（1.5 g），然後再慢慢加入鹽酸（1 mL, 12 mol/L），混合物在72℃下攪拌反應2小時，監測反應完全後，冷卻，抽濾，反應液旋乾，柱層析得到3-胺基-N -(2-(二甲基胺基)乙基)-5-(五氟硫代)苯甲醯胺0.38 g，MS m/z（ESI）：333.9[M+H]+ 。Add N- (2-(dimethylamino)ethyl)-3-nitro-5-(pentafluorothio)benzamide (0.5 g, 1.38 mmol) into methanol (10 mL), Iron powder (1.5 g) was added, and then hydrochloric acid (1 mL, 12 mol/L) was slowly added, and the mixture was stirred and reacted at 72°C for 2 hours. After monitoring the completion of the reaction, it was cooled, filtered with suction, and the reaction solution was spin-dried. Column chromatography gave 0.38 g of 3-amino- N- (2-(dimethylamino)ethyl)-5-(pentafluorothio)benzamide, MS m/z (ESI): 333.9[ M+H] + .
中間體3 2-(4-(4- 乙氧基-6-((4- 甲氧基苄基) 氧基) 吡啶-3- 基)-2- 氟苯基) 乙酸的合成 
步驟1step 1 合成5-Synthetic 5- 溴-4-Bromo-4- 乙氧基-2Ethoxy-2 （（4-((4- 甲氧基苄基）氧基）吡啶Methoxybenzyl)oxy)pyridine
室溫下，向5-溴-2-氯-4-乙氧基吡啶（2.5 g, 10.6 mmol）在甲苯（30 mL）的混合液中加入（4-甲氧基苯基）甲醇（1.75 g, 12.7 mmol）、KOH(1.2 g, 21.2 mmol)和18-冠醚-6（0.28 g, 1.06 mmol），混合物在120℃下反應3小時，反應完全後，旋乾反應液，加入水（15 mL），然後再用EA（30 mL*2）萃取，有機相乾燥，旋乾，柱層析，得到5-溴-4-乙氧基-2（（4-甲氧基苄基）氧基）吡啶3.0 g。MS m/z（ESI）：339.1[M+H]+ 。Add (4-methoxyphenyl)methanol (1.75 g , 12.7 mmol), KOH (1.2 g, 21.2 mmol) and 18-crown-6 (0.28 g, 1.06 mmol), the mixture was reacted at 120°C for 3 hours, after the reaction was complete, the reaction solution was spin-dried, and water (15 mL), and then extracted with EA (30 mL*2), the organic phase was dried, spin-dried, and column chromatographed to obtain 5-bromo-4-ethoxy-2((4-methoxybenzyl)oxy ) pyridine 3.0 g. MS m/z (ESI): 339.1 [M+H] + .
步驟2step 2 合成2-Synthetic 2- （4-(4- （4-(4- 乙氧基-6-Ethoxy-6- （（4-((4- 甲氧基苄基）氧基）吡啶-3-Methoxybenzyl)oxy)pyridine-3- 基）-2-Base) -2- 氟苯基）乙酸甲酯Fluorophenyl) methyl acetate
在氮氣保護下，將5-溴-4-乙氧基-2（（4-甲氧基苄基）氧基）吡啶（1.9 g, 5.62 mmol）、2-（2-氟-4-（4,4,5,5-四甲基-1,3,2-二氧硼雜環戊烷-2-基）苯基）乙酸甲酯（1.82 g, 6.18 mmol），PdCl2 (dppf)(0.45 g, 0.56 mmol)和碳酸銫（3.65 g, 11.2 mmol）加入到單口瓶中，再加入1,4-二氧六環（30 mL）和水（10 mL），混合物在95℃下反應3小時。反應完全後，用EA（40 mL*2）萃取，有機相乾燥，旋乾，柱層析得到2-（4-（4-乙氧基-6-（（4-甲氧基苄基）氧基）吡啶-3-基）-2-氟苯基）乙酸甲酯1.8 g。MS m/z（ESI）：426.3[M+H]+ 。Under nitrogen protection, 5-bromo-4-ethoxy-2((4-methoxybenzyl)oxy)pyridine (1.9 g, 5.62 mmol), 2-(2-fluoro-4-(4 ,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (1.82 g, 6.18 mmol), PdCl 2 (dppf) (0.45 g, 0.56 mmol) and cesium carbonate (3.65 g, 11.2 mmol) were added to a one-necked bottle, then 1,4-dioxane (30 mL) and water (10 mL) were added, and the mixture was reacted at 95°C for 3 hours . After the reaction was complete, it was extracted with EA (40 mL*2), the organic phase was dried, spin-dried, and column chromatography gave 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy base) pyridin-3-yl)-2-fluorophenyl) methyl acetate 1.8 g. MS m/z (ESI): 426.3 [M+H] + .
步驟3step 3 合成2-Synthetic 2- （4-(4- （4-(4- 乙氧基-6-Ethoxy-6- （（4-((4- 甲氧基苄基）氧基）吡啶-3-Methoxybenzyl)oxy)pyridine-3- 基）-2-Base) -2- 氟苯基）乙酸Fluorophenyl)acetic acid
將2-（4-（4-乙氧基-6-（（4-甲氧基苄基）氧基）吡啶-3-基）-2-氟苯基）乙酸甲酯（2.4 g, 5.63 mmol）溶解在THF（15 mL）中，然後再將溶解了氫氧化鋰（0.3 g, 12.4 mmol）水溶液加入其中，混合物在60℃下攪拌反應4小時。反應完全後，旋乾大部分有機相，然後再用稀鹽酸調pH=7，析出白色固體，抽濾，濾餅再用水洗，烘乾，得到2-（4-（4-乙氧基-6-（（4-甲氧基苄基）氧基）吡啶-3-基）-2-氟苯基）乙酸2.1 g，MS m/z（ESI）：412.2[M+H]+ 。2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid methyl ester (2.4 g, 5.63 mmol ) was dissolved in THF (15 mL), and then an aqueous solution of lithium hydroxide (0.3 g, 12.4 mmol) was added to it, and the mixture was stirred and reacted at 60°C for 4 hours. After the reaction is complete, spin dry most of the organic phase, then adjust the pH to 7 with dilute hydrochloric acid, precipitate a white solid, filter with suction, wash the filter cake with water, and dry to obtain 2-(4-(4-ethoxy- 6-((4-Methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid 2.1 g, MS m/z (ESI): 412.2 [M+H] + .
實施例1N
-(2-( 二甲基胺基) 乙基)-3- （2- （4- （4- 乙氧基-6- 氧代-1,6- 二氫吡啶-3- 基-2- 氟苯基）乙醯胺基-5-( 五氟硫代) 苯甲醯胺的合成 
步驟1step 1 合成N -Synthetic N- （2-(2- （二甲基胺基）乙基）-3-(Dimethylamino)ethyl)-3- （2-(2- （4-(4- （4-(4- 乙氧基-6-Ethoxy-6- （（4-((4- 甲氧基苄基）氧基）吡啶-3-Methoxybenzyl)oxy)pyridine-3- 基）-2-Base) -2- 氟苯基）乙醯胺基）-5-Fluorophenyl) acetamido) -5- （五氟硫代）苯甲醯胺(Pentafluorothio)benzamide
將2-（4-（4-乙氧基-6-（（4-甲氧基苄基）氧基）吡啶-3-基）-2-氟苯基）乙酸（0.6 g, 1.45 mmol）加入到吡啶（5 mL）中，然後再加入3-胺基-N -（2-（二甲基胺基）乙基）-5-(五氟硫代)苯甲醯胺（0.48 g, 1.75 mmol）和T3 P(0.55 g, 1.75 mmol)，混合物在室溫下反應12小時。反應完全後直接旋乾反應液，然後柱層析得到N -（2-（二甲基胺基）乙基）-3-（2-（4-（4-乙氧基-6-（（4-甲氧基苄基）氧基）吡啶-3-基）-2-氟苯基）乙醯胺基）-5-（五氟硫代）苯甲醯胺0.82 g，MS m/z（ESI）：727.5[M+H]+ 。2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (0.6 g, 1.45 mmol) was added into pyridine (5 mL), and then added 3-amino- N- (2-(dimethylamino)ethyl)-5-(pentafluorothio)benzamide (0.48 g, 1.75 mmol ) and T 3 P (0.55 g, 1.75 mmol), the mixture was reacted at room temperature for 12 hours. After the reaction is complete, the reaction solution is directly spin-dried, and then column chromatography is obtained to obtain N- (2-(dimethylamino)ethyl)-3-(2-(4-(4-ethoxy-6-((4 -methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)-5-(pentafluorothio)benzamide 0.82 g, MS m/z (ESI ): 727.5[M+H] + .
步驟2step 2 合成N -(2-(Synthesis of N -(2-( 二甲基胺基)Dimethylamino) 乙基)-3-Ethyl)-3- （2-(2- （4-(4- （4-(4- 乙氧基-6-Ethoxy-6- 氧代-1,6-Oxo-1,6- 二氫吡啶-3-Dihydropyridine-3- 基-2-base-2- 氟苯基）乙醯胺基-5-(Fluorophenyl) acetamido-5-( 五氟硫代)Pentafluorothio) 苯甲醯胺benzamide
將N -（2-（二甲基胺基）乙基）-3-（2-（4-（4-乙氧基-6-（（4-甲氧基苄基）氧基）吡啶-3-基）-2-氟苯基）乙醯胺基）-5-（五氟硫代）苯甲醯胺（0.82 g, 1.13 mmol）溶解在DCM（10 mL）中，然後加入TFA（2 mL），混合物室溫下攪拌反應2小時。反應完全後，濃縮反應液，再用碳酸鈉水溶液調至中性，DCM（20 mL*2）萃取，有機相旋乾，柱層析得到N -(2-(二甲基胺基)乙基)-3-（2-（4-（4-乙氧基-6-氧代-1,6-二氫吡啶-3-基-2-氟苯基）乙醯胺基-5-(五氟硫代)苯甲醯胺（化合物 1 ） 0.48 g。MS m/z（ESI）：607.3[M+H]+ 。1 H NMR (400 MHz, DMSO) δ 11.38 (s, 1H), 10.85 (s, 1H), 8.78 (s, 1H), 8.45 (s, 1H), 8.24 (s, 1H), 8.01 (s, 1H), 7.40 – 7.30 (m, 2H), 7.28 – 7.17 (m, 2H), 5.80 (s, 1H), 4.02 (dt,J = 6.8, 2.1 Hz, 4H), 3.78 (s, 2H), 2.43 (t,J = 6.5 Hz, 2H), 2.19 (s, 6H), 1.27 (t,J = 6.9 Hz, 3H). N- (2-(dimethylamino)ethyl)-3-(2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridine-3 -yl)-2-fluorophenyl)acetamido)-5-(pentafluorothio)benzamide (0.82 g, 1.13 mmol) was dissolved in DCM (10 mL), then TFA (2 mL ), and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated, then adjusted to neutrality with aqueous sodium carbonate, extracted with DCM (20 mL*2), the organic phase was spin-dried, and column chromatography gave N- (2-(dimethylamino)ethyl )-3-(2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl-2-fluorophenyl)acetamido-5-(pentafluoro Thio)benzamide (Compound 1 ) 0.48 g. MS m/z (ESI): 607.3[M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.38 (s, 1H), 10.85 (s , 1H), 8.78 (s, 1H), 8.45 (s, 1H), 8.24 (s, 1H), 8.01 (s, 1H), 7.40 – 7.30 (m, 2H), 7.28 – 7.17 (m, 2H), 5.80 (s, 1H), 4.02 (dt, J = 6.8, 2.1 Hz, 4H), 3.78 (s, 2H), 2.43 (t, J = 6.5 Hz, 2H), 2.19 (s, 6H), 1.27 (t , J = 6.9 Hz, 3H).
實施例2 3- （2- （4- （4- 乙氧基-6- 氧代-1,6- 二氫吡啶基-3- 基）-2- 氟苯基）乙醯胺基）-N ,N
- 二甲基-5- （五氟硫代）苯甲醯胺的合成 
步驟1step 1 合成N synthetic N ,N -, N - 二甲基-3-Dimethyl-3- 硝基-5-Nitro-5- （五氟硫代）苯甲醯胺(Pentafluorothio)benzamide
將3-硝基-5-(五氟硫代)苯甲酸（0.3 g, 1.02 mmol）溶解在SOCl2 （10 mL)中，再加入幾滴DMF，然後回流反應2小時。反應完全後旋乾反應液，將醯基氯溶於DCM（10 mL）中，將混合物冷卻至0℃，然後加入三乙胺（0.32 g, 3.07 mmol），接著加入二甲胺（0.07 g, 1.56 mmol），在0℃下繼續反應半小時。反應完全後，加入水淬滅反應，分液，有機相濃縮，柱層析得到N ,N -二甲基-3-硝基-5-（五氟硫代）苯甲醯胺0.26 g。MS m/z（ESI）：321.5[M+H]+ 。Dissolve 3-nitro-5-(pentafluorothio)benzoic acid (0.3 g, 1.02 mmol) in SOCl 2 (10 mL), add a few drops of DMF, and then reflux for 2 hours. After the reaction was complete, the reaction solution was spin-dried, and the acyl chloride was dissolved in DCM (10 mL), and the mixture was cooled to 0°C, then triethylamine (0.32 g, 3.07 mmol) was added, followed by dimethylamine (0.07 g, 1.56 mmol), the reaction was continued for half an hour at 0°C. After the reaction was complete, water was added to quench the reaction, the layers were separated, the organic phase was concentrated, and column chromatography gave 0.26 g of N , N -dimethyl-3-nitro-5-(pentafluorothio)benzamide. MS m/z (ESI): 321.5 [M+H] + .
步驟2step 2 合成3-Synthetic 3- 胺基-N Amino- N ,N -, N - 二甲基-5-Dimethyl-5- （五氟硫代）苯甲醯胺(Pentafluorothio)benzamide
將N ,N -二甲基-3-硝基-5-（五氟硫代）苯甲醯胺（0.26 g, 0.8 mmol）加入到甲醇（10 mL）中，再加入鐵粉（0.8 g），然後再慢慢加入鹽酸（1 mL, 12 mol/L），混合物在72℃下攪拌反應2小時。監測反應完全後，冷卻，抽濾，反應液旋乾，柱層析得到3-胺基-N ,N -二甲基-5-（五氟硫代）苯甲醯胺0.17 g。MS m/z（ESI）：291.1[M+H]+ 。Add N , N -dimethyl-3-nitro-5-(pentafluorothio)benzamide (0.26 g, 0.8 mmol) into methanol (10 mL), and then iron powder (0.8 g) , and then slowly added hydrochloric acid (1 mL, 12 mol/L), and the mixture was stirred and reacted at 72°C for 2 hours. After monitoring the completion of the reaction, cool, filter with suction, spin the reaction solution to dryness, and obtain 0.17 g of 3-amino- N , N -dimethyl-5-(pentafluorothio)benzamide through column chromatography. MS m/z (ESI): 291.1 [M+H] + .
步驟3step 3 合成3-Synthetic 3- （2-(2- （4-(4- （4-(4- 乙氧基-6-Ethoxy-6- （（4-((4- 甲氧基苄基）氧基）吡啶-3-Methoxybenzyl)oxy)pyridine-3- 基）-2-Base) -2- 氟苯基）乙醯胺基）-N Fluorophenyl) acetamido) - N ,N -, N - 二甲基-5-Dimethyl-5- （五氟硫代）苯甲醯胺(Pentafluorothio)benzamide
將2-（4-（4-乙氧基-6-（（4-甲氧基苄基）氧基）吡啶-3-基）-2-氟苯基）乙酸（0.2 g, 0.49 mmol）加入到吡啶（5 mL）中，然後再加入3-胺基-N ,N -二甲基-5-（五氟硫代）苯甲醯胺（0.17 g, 0.58 mmol）和T3 P(0.19 g, 0.58 mmol)，混合物在室溫下反應12小時。反應完全後直接旋乾反應液，然後柱層析得到3-（2-（4-（4-乙氧基-6-（（4-甲氧基苄基）氧基）吡啶-3-基）-2-氟苯基）乙醯胺基）-N ,N -二甲基-5-（五氟硫代）苯甲醯胺0.22 g。MS m/z（ESI）：684.3[M+H]+ 。2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (0.2 g, 0.49 mmol) was added into pyridine (5 mL), and then added 3-amino- N , N -dimethyl-5-(pentafluorothio)benzamide (0.17 g, 0.58 mmol) and T 3 P (0.19 g , 0.58 mmol), the mixture was reacted at room temperature for 12 hours. After the reaction was complete, the reaction solution was directly spin-dried, and then column chromatography was used to obtain 3-(2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl) -2-fluorophenyl)acetamido) -N , N -dimethyl-5-(pentafluorothio)benzamide 0.22 g. MS m/z (ESI): 684.3 [M+H] + .
步驟4 合成3- （2- （4- （4- 乙氧基-6- 氧代-1,6- 二氫吡啶基-3- 基）-2- 氟苯基）乙醯胺基）-N ,N - 二甲基-5- （五氟硫代）苯甲醯胺 將3-（2-（4-（4-乙氧基-6-（（4-甲氧基苄基）氧基）吡啶-3-基）-2-氟苯基）乙醯胺基）-N ,N -二甲基-5-（五氟硫代）苯甲醯胺（0.22 g, 0.32 mmol）溶解在DCM（6 mL）中，然後加入TFA（1 mL），混合物室溫下攪拌反應2小時。反應完全後，濃縮反應液，再用碳酸鈉水溶液調至中性，DCM（10 mL*2）萃取，有機相旋乾，柱層析得到3-（2-（4-（4-乙氧基-6-氧代-1,6-二氫吡啶基-3-基）-2-氟苯基）乙醯胺基）-N ,N -二甲基-5-（五氟硫代）苯甲醯胺（化合物 2 ） 0.11 g。MS m/z（ESI）：564.5[M+H]+ 。1 H NMR (500 MHz, DMSO) δ 11.39 (s, 1H), 10.76 (s, 1H), 8.29 (t,J = 2.0 Hz, 1H), 7.85 (s, 1H), 7.59 (dd,J = 1.9, 1.3 Hz, 1H), 7.40 – 7.32 (m, 2H), 7.28 – 7.20 (m, 2H), 5.81 (s, 1H), 4.04 (q,J = 7.0 Hz, 2H), 3.78 (s, 2H), 2.99 (s, 3H), 2.90 (s, 3H), 1.28 (t,J = 7.0 Hz, 3H). Step 4 Synthesis of 3- (2- (4- (4- ethoxy-6- oxo-1,6- dihydropyridyl-3 -yl)-2- fluorophenyl)acetamido) -N , N - Dimethyl-5- (pentafluorothio)benzamide 3-(2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy) Pyridin-3-yl)-2-fluorophenyl)acetamido) -N , N -dimethyl-5-(pentafluorothio)benzamide (0.22 g, 0.32 mmol) was dissolved in DCM ( 6 mL), then TFA (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated, adjusted to neutrality with aqueous sodium carbonate, extracted with DCM (10 mL*2), the organic phase was spin-dried, and column chromatography gave 3-(2-(4-(4-ethoxy -6-oxo-1,6-dihydropyridinyl-3-yl)-2-fluorophenyl)acetamido) -N , N -dimethyl-5-(pentafluorothio)benzyl Amide (Compound 2 ) 0.11 g. MS m/z (ESI): 564.5 [M+H] + . 1 H NMR (500 MHz, DMSO) δ 11.39 (s, 1H), 10.76 (s, 1H), 8.29 (t, J = 2.0 Hz, 1H), 7.85 (s, 1H), 7.59 (dd, J = 1.9 , 1.3 Hz, 1H), 7.40 – 7.32 (m, 2H), 7.28 – 7.20 (m, 2H), 5.81 (s, 1H), 4.04 (q, J = 7.0 Hz, 2H), 3.78 (s, 2H) , 2.99 (s, 3H), 2.90 (s, 3H), 1.28 (t, J = 7.0 Hz, 3H).
實施例3N
- （2- （二乙胺基）乙基）-3- （2- （4- （4- 乙氧基-6- 氧代-1,6- 二氫吡啶-3- 基）-2- 氟苯基）乙醯胺基）-5- （五氟硫代）苯甲醯胺的合成 
步驟1 合成N - （2- （二乙胺基）乙基）-3- 硝基-5-( 五氟硫代) 苯甲醯胺 將3-硝基-5-(五氟硫代)苯甲酸（0.3 g, 1.02 mmol）溶解在SOCl2 （10 mL)中，再加入幾滴DMF，然後回流反應2小時。反應完全後旋乾反應液，將醯基氯溶於DCM（10 mL）中，將混合物冷卻至0℃，然後加入三乙胺（0.32 g, 3.07 mmol），接著加入N,N -二乙基乙二胺（0.18 g, 1.56 mmol），在0℃下繼續反應半小時。反應完全後，加入水淬滅反應，分液，有機相濃縮，柱層析，得到N -（2-（二乙胺基）乙基）-3-硝基-5-(五氟硫代)苯甲醯胺0.32 g。MS m/z（ESI）：392.1[M+H]+ 。 Step 1 synthesizes N- (2- (diethylamino)ethyl)-3 -nitro- 5-( pentafluorothio ) benzamide by converting 3-nitro-5-(pentafluorothio)benzene Formic acid (0.3 g, 1.02 mmol) was dissolved in SOCl 2 (10 mL), and a few drops of DMF were added, followed by reflux for 2 hours. After the reaction was complete, the reaction solution was spin-dried, and the acyl chloride was dissolved in DCM (10 mL), and the mixture was cooled to 0°C, then triethylamine (0.32 g, 3.07 mmol) was added, followed by N,N -diethyl Ethylenediamine (0.18 g, 1.56 mmol), continue to react at 0°C for half an hour. After the reaction is complete, add water to quench the reaction, separate the layers, concentrate the organic phase, and perform column chromatography to obtain N- (2-(diethylamino)ethyl)-3-nitro-5-(pentafluorothio) Benzamide 0.32 g. MS m/z (ESI): 392.1 [M+H] + .
步驟2step 2 合成3-Synthetic 3- 胺基-N -Amino- N - （2-(2- （二乙胺基）乙基）-5-((Diethylamino) ethyl) -5-( 五氟硫代)Pentafluorothio) 苯甲醯胺benzamide
將N -（2-（二乙胺基）乙基）-3-硝基-5-(五氟硫代)苯甲醯胺（0.32g, 0.82 mmol）加入到甲醇（10 mL）中,再加入鐵粉（0.8 g），然後再慢慢加入鹽酸（1 mL, 12 mol/L），混合物在72℃下攪拌反應2小時。監測反應完全後，冷卻，抽濾，反應液旋乾，柱層析得到3-胺基-N -（2-（二乙胺基）乙基）-5-（(五氟硫代)苯甲醯胺0.25 g,MS m/z（ESI）：362.2[M+H]+ 。Add N- (2-(diethylamino)ethyl)-3-nitro-5-(pentafluorothio)benzamide (0.32 g, 0.82 mmol) into methanol (10 mL), and then Iron powder (0.8 g) was added, and then hydrochloric acid (1 mL, 12 mol/L) was added slowly, and the mixture was stirred and reacted at 72°C for 2 hours. After monitoring the completion of the reaction, cool, filter with suction, spin the reaction solution to dryness, and obtain 3-amino- N- (2-(diethylamino)ethyl)-5-((pentafluorothio)benzyl Amide 0.25 g, MS m/z (ESI): 362.2 [M+H] + .
步驟3step 3 合成N -Synthetic N- （2-(2- （二乙胺基）乙基）-3-(Diethylamino)ethyl)-3- （2-(2- （4-(4- （4-(4- 乙氧基-6-Ethoxy-6- （（4-((4- 甲氧基苄基）氧基）吡啶-3-Methoxybenzyl)oxy)pyridine-3- 基）-2-Base) -2- 氟苯基）乙醯胺基）-5-Fluorophenyl) acetamido) -5- （五氟硫代）苯甲醯胺(Pentafluorothio)benzamide
將2-（4-（4-乙氧基-6-（（4-甲氧基苄基）氧基）吡啶-3-基）-2-氟苯基）乙酸（0.25 g, 0.61 mmol）加入到吡啶（5 mL）中，然後再加入3-胺基-N -（2-（二乙胺基）乙基）-5-(五氟硫代)苯甲醯胺（0.26 g, 0.73 mmol）和T3 P(0.28 g, 0.72 mmol)，混合物在室溫下反應12小時。反應完全後直接旋乾反應液，然後柱層析，得到N -（2-（二乙胺基）乙基）-3-（2-（4-（4-乙氧基-6-（（4-甲氧基苄基）氧基）吡啶-3-基）-2-氟苯基）乙醯胺基）-5-（五氟硫代）苯甲醯胺0.19 g,MS m/z（ESI）：755.6[M+H]+ 。2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (0.25 g, 0.61 mmol) was added into pyridine (5 mL), and then added 3-amino- N- (2-(diethylamino)ethyl)-5-(pentafluorothio)benzamide (0.26 g, 0.73 mmol) and T 3 P (0.28 g, 0.72 mmol), the mixture was reacted at room temperature for 12 hours. After the reaction is complete, the reaction solution is directly spin-dried, and then column chromatography is obtained to obtain N- (2-(diethylamino)ethyl)-3-(2-(4-(4-ethoxy-6-((4 -Methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)-5-(pentafluorothio)benzamide 0.19 g, MS m/z (ESI ): 755.6[M+H] + .
步驟4 合成N - （2- （二乙胺基）乙基）-3- （2- （4- （4- 乙氧基-6- 氧代-1,6- 二氫吡啶-3- 基）-2- 氟苯基）乙醯胺基）-5- （五氟硫代）苯甲醯胺 將N -（2-（二乙胺基）乙基）-3-（2-（4-（4-乙氧基-6-（（4-甲氧基苄基）氧基）吡啶-3-基）-2-氟苯基）乙醯胺基）-5-（五氟硫代）苯甲醯胺（0.19 g, 0.25 mmol）溶解在DCM（5 mL）中，然後加入TFA（1 mL），混合物室溫下攪拌反應2小時，反應完全後，濃縮反應液，再用碳酸鈉水溶液調至中性，DCM（10 mL*2）萃取，有機相旋乾，柱層析，得到N -（2-（二乙胺基）乙基）-3-（2-（4-（4-乙氧基-6-氧代-1,6-二氫吡啶-3-基）-2-氟苯基）乙醯胺基）-5-（五氟硫代）苯甲醯胺（化合物 3 ） 0.081 g。MS m/z（ESI）：635.1[M+H]+ 。1 H NMR (400 MHz, DMSO) δ 11.58 (s, 1H), 10.75 (s, 1H), 8.67 (s, 1H), 8.45 (s, 1H), 8.24 (s, 1H), 8.05 (s, 1H), 7.40 – 7.32 (m, 2H), 7.28 – 7.11 (m, 2H), 5.83 (s, 1H), 4.02 (dt,J = 5.8, 2.1 Hz, 2H), 3.78 (s, 4H), 2.43 (t,J = 6.5 Hz, 4H), 2.19(s,2H),1.17-1.35 (t, 9H). Step 4 Synthesis of N- (2- (diethylamino)ethyl)-3- (2- (4- (4- ethoxy-6- oxo-1,6- dihydropyridin-3 -yl) -2- fluorophenyl)acetamido)-5- ( pentafluorothio)benzamide N- (2-(diethylamino)ethyl)-3-(2-(4-( 4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)-5-(pentafluorothio)benzyl Amide (0.19 g, 0.25 mmol) was dissolved in DCM (5 mL), then TFA (1 mL) was added, the mixture was stirred and reacted at room temperature for 2 hours, after the reaction was complete, the reaction solution was concentrated, and then adjusted to Neutral, extracted with DCM (10 mL*2), spin-dried the organic phase, and column chromatography to obtain N- (2-(diethylamino)ethyl)-3-(2-(4-(4-ethoxy yl-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamido)-5-(pentafluorothio)benzamide (compound 3 ) 0.081 g . MS m/z (ESI): 635.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.58 (s, 1H), 10.75 (s, 1H), 8.67 (s, 1H), 8.45 (s, 1H), 8.24 (s, 1H), 8.05 (s, 1H ), 7.40 – 7.32 (m, 2H), 7.28 – 7.11 (m, 2H), 5.83 (s, 1H), 4.02 (dt, J = 5.8, 2.1 Hz, 2H), 3.78 (s, 4H), 2.43 ( t, J = 6.5 Hz, 4H), 2.19(s,2H),1.17-1.35 (t, 9H).
實施例4N
-(2-( 二甲基胺基) 乙基)-3-(2-(4-(4- 乙氧基-6- 氧代-1,6- 二氫吡啶-3- 基)-2- 氟苯基) 乙醯胺基)-N
- 甲基-5-( 五氟硫代) 苯甲醯胺的合成 
步驟1step 1 合成N -(2-(Synthesis of N -(2-( 二甲基胺基)Dimethylamino) 乙基)-N -Ethyl)- N - 甲基-3-Methyl-3- 硝基-5-(Nitro-5-( 五氟硫代)Pentafluorothio) 苯甲醯胺benzamide
將3-硝基-5-(五氟硫代)苯甲酸(500 mg, 1.71 mmol)溶解在SOCl2 (5 mL)中，再加入幾滴DMF，然後回流反應2小時，反應完全後旋乾反應液，將醯基氯溶於DCM(5 mL)中，將混合物滴加到三乙胺(517 mg, 5.12 mmol)和N1 ,N1 ,N2 -三甲基乙烷-1,2-二胺(226 mg, 2.22 mmol)的DCM(5 mL)溶液中，在0℃下繼續反應半小時。反應完全後，加入水淬滅反應，分液，有機相濃縮，柱層析得到N -(2-(二甲基胺基)乙基)-N -甲基-3-硝基-5-(五氟硫代)苯甲醯胺460 mg。MS m/z(ESI)：378[M+H]+ 。Dissolve 3-nitro-5-(pentafluorothio)benzoic acid (500 mg, 1.71 mmol) in SOCl 2 (5 mL), add a few drops of DMF, then reflux for 2 hours, spin dry after the reaction is complete For the reaction solution, dissolve acyl chloride in DCM (5 mL), and add the mixture dropwise to triethylamine (517 mg, 5.12 mmol) and N 1 , N 1 , N 2 -trimethylethane-1,2 - In a solution of diamine (226 mg, 2.22 mmol) in DCM (5 mL), continue to react at 0° C. for half an hour. After the reaction is complete, add water to quench the reaction, separate the layers, concentrate the organic phase, and obtain N- (2-(dimethylamino)ethyl) -N -methyl-3-nitro-5-( Pentafluorothio)benzamide 460 mg. MS m/z (ESI): 378 [M+H] + .
步驟2step 2 合成3-Synthetic 3- 胺基-N -(2-(Amino- N -(2-( 二甲基胺基)Dimethylamino) 乙基)-N -Ethyl)- N - 甲基-5-(Methyl-5-( 五氟硫代)Pentafluorothio) 苯甲醯胺benzamide
將N -(2-(二甲基胺基)乙基)-N -甲基-3-硝基-5-(五氟硫代)苯甲醯胺(460 mg, 1.22 mmol)、FeCl3 (20 mg, 0.12 mmo)、活性炭(100 mg)加入到乙醇(10 mL)中，然後向反應體系中緩慢加入水合肼(244 mg, 4.88 mmol)，混合物在80℃下攪拌反應過夜。監測反應完全後，冷卻，抽濾，反應液旋乾，柱層析得到3-胺基-N -(2-(二甲基胺基)乙基)-N -甲基-5-(五氟硫代)苯甲醯胺400 mg。MS m/z(ESI)：348[M+H]+ 。 N- (2-(dimethylamino)ethyl) -N -methyl-3-nitro-5-(pentafluorothio)benzamide (460 mg, 1.22 mmol), FeCl 3 ( 20 mg, 0.12 mmol), activated carbon (100 mg) were added to ethanol (10 mL), and then hydrazine hydrate (244 mg, 4.88 mmol) was slowly added to the reaction system, and the mixture was stirred and reacted at 80°C overnight. After monitoring that the reaction is complete, cool, filter with suction, spin the reaction solution to dryness, and obtain 3-amino- N- (2-(dimethylamino)ethyl) -N -methyl-5-(pentafluoro Thio)benzamide 400 mg. MS m/z (ESI): 348 [M+H] + .
步驟3step 3 合成N -(2-(Synthesis of N -(2-( 二甲基胺基)Dimethylamino) 乙基)-3-(2-(4-(4-Ethyl)-3-(2-(4-(4- 乙氧基-6-((4-Ethoxy-6-((4- 甲氧基苄基)Methoxybenzyl) 氧基)oxygen) 吡啶-3-Pyridine-3- 基)-2-base)-2- 氟苯基)Fluorophenyl) 乙醯胺基)-N -Acetylamino)- N - 甲基-5-(Methyl-5-( 五氟硫代)Pentafluorothio) 苯甲醯胺benzamide
將2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸(474 mg, 1.15 mmol)溶解到DMF中，然後再加入HATU(482 mg, 1.27 mmol)、DMAP(14 Mg, 0.115 mmol)、DIEA(446 mg, 3.46 mmol)、3-胺基-N -(2-(二甲基胺基)乙基)-N -甲基-5-(五氟硫代)苯甲醯胺(400 mg, 1.15 mmol)，混合物在室溫下反應過夜。反應完全後，加入水淬滅反應，然後再用EA(20 mL*2)萃取，有機相乾燥，旋乾，柱層析得到N -(2-(二甲基胺基)乙基)-3-(2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙醯胺基)-N -甲基-5-(五氟硫代)苯甲醯胺380 mg。MS m/z(ESI)：741[M+H]+ 。2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (474 mg, 1.15 mmol) was dissolved To DMF, then add HATU (482 mg, 1.27 mmol), DMAP (14 Mg, 0.115 mmol), DIEA (446 mg, 3.46 mmol), 3-amino- N- (2-(dimethylamino ) ethyl) -N -methyl-5-(pentafluorothio)benzamide (400 mg, 1.15 mmol), and the mixture was reacted overnight at room temperature. After the reaction was complete, water was added to quench the reaction, and then extracted with EA (20 mL*2), the organic phase was dried, spin-dried, and column chromatography gave N- (2-(dimethylamino)ethyl)-3 -(2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)- N - Methyl-5-(pentafluorothio)benzamide 380 mg. MS m/z (ESI): 741 [M+H] + .
步驟4step 4 合成N -(2-(Synthesis of N -(2-( 二甲基胺基)Dimethylamino) 乙基)-3-(2-(4-(4-Ethyl)-3-(2-(4-(4- 乙氧基-6-Ethoxy-6- 氧代-1,6-Oxo-1,6- 二氫吡啶-3-Dihydropyridine-3- 基)-2-base)-2- 氟苯基)Fluorophenyl) 乙醯胺基)-N -Acetylamino)- N - 甲基-5-(Methyl-5-( 五氟硫代)Pentafluorothio) 苯甲醯胺benzamide
將N -(2-(二甲基胺基)乙基)-3-(2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙醯胺基)-N -甲基-5-(五氟硫代)苯甲醯胺(380 mg, 0.514 mmol)溶解在DCM(10 mL)中，然後加入TFA(2 mL)，混合物室溫下攪拌反應2小時。反應完全後，濃縮反應液，再用碳酸鈉水溶液調至中性，DCM(20 mL*2)萃取，有機相旋乾，柱層析得到N -(2-(二甲基胺基)乙基)-3-(2-(4-(4-乙氧基-6-氧代-1,6-二氫吡啶-3-基)-2-氟苯基)乙醯胺基)-N -甲基-5-(五氟硫代)苯甲醯胺（化合物 4 ） 180 mg。MS m/z(ESI)：621[M+H]+ 。1 H NMR (400 MHz, DMSO-d 6 ) δ 11.39 (s, 1H), 10.79 (s, 1H), 8.29 (s, 1H), 7.85 (s, 1H), 7.56 (s, 1H), 7.41 – 7.32 (m, 2H), 7.29 – 7.21 (m, 2H), 5.81 (s, 1H), 4.05 (q,J = 6.9 Hz, 2H), 3.79 (s, 2H), 3.58 (s, 1H), 3.24 (s, 1H), 2.94 (d,J = 22.5 Hz, 3H), 2.59 (s, 1H), 2.37 (s, 1H), 2.30 (s, 3H), 1.95 (s, 3H), 1.29 (t,J = 6.9 Hz, 3H). N- (2-(dimethylamino)ethyl)-3-(2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridine-3 -yl)-2-fluorophenyl)acetamido) -N -methyl-5-(pentafluorothio)benzamide (380 mg, 0.514 mmol) was dissolved in DCM (10 mL), then TFA (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated, then adjusted to neutrality with aqueous sodium carbonate, extracted with DCM (20 mL*2), the organic phase was spin-dried, and column chromatography gave N- (2-(dimethylamino)ethyl )-3-(2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamido) -N -form Cyl-5-(pentafluorothio)benzamide (compound 4 ) 180 mg. MS m/z (ESI): 621 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.39 (s, 1H), 10.79 (s, 1H), 8.29 (s, 1H), 7.85 (s, 1H), 7.56 (s, 1H), 7.41 – 7.32 (m, 2H), 7.29 – 7.21 (m, 2H), 5.81 (s, 1H), 4.05 (q, J = 6.9 Hz, 2H), 3.79 (s, 2H), 3.58 (s, 1H), 3.24 (s, 1H), 2.94 (d, J = 22.5 Hz, 3H), 2.59 (s, 1H), 2.37 (s, 1H), 2.30 (s, 3H), 1.95 (s, 3H), 1.29 (t, J = 6.9 Hz, 3H).
實施例5 2-(4-(4- 乙氧基-6- 氧代-1,6- 二氫吡啶-3- 基)-2- 氟苯基)-N
-(3-( 五氟硫代)-5-( 吡咯烷-1- 羰基) 苯基) 乙醯胺的合成 
步驟1step 1 合成(3-Synthesis (3- 硝基-5-(Nitro-5-( 五氟硫代)Pentafluorothio) 苯基)(Phenyl)( 吡咯烷-1-pyrrolidine-1- 基)base) 甲酮ketone
將3-硝基-5-(五氟硫代)苯甲酸(500 mg, 1.71 mmol)溶解在二氯亞碸(15 mL)中，向體系中滴入兩滴DMF，加熱至80℃回流2h。反應完全後將體系旋乾，用1 mL DCM將溶解醯氯產物。吡咯烷(243 mg, 3.41 mmol)和三乙胺(517 mg, 5.12 mmol)溶於二氯甲烷中，冰浴下向上述體系緩慢滴加醯氯產物，完畢後將冰浴撤去，該反應液在室溫反30 min。加水洗滌，二氯甲烷萃取，合併有機相，乾燥有機相，旋乾，粗產品用EA/PE=1:3進行矽膠柱層析得到產物(3-硝基-5-(五氟硫代)苯基)(吡咯烷-1-基)甲酮480 mg. MS m/z(ESI)：347.3 [M+H]+ 。Dissolve 3-nitro-5-(pentafluorothio)benzoic acid (500 mg, 1.71 mmol) in dichlorosulfone (15 mL), drop two drops of DMF into the system, heat to 80°C and reflux for 2h . After the reaction was complete, the system was spin-dried, and the acyl chloride product was dissolved with 1 mL of DCM. Pyrrolidine (243 mg, 3.41 mmol) and triethylamine (517 mg, 5.12 mmol) were dissolved in dichloromethane, and the acyl chloride product was slowly added dropwise to the above system under ice bath, and the ice bath was removed after completion, and the reaction solution Incubate at room temperature for 30 min. Wash with water, extract with dichloromethane, combine the organic phases, dry the organic phases, spin dry, and carry out silica gel column chromatography on the crude product with EA/PE=1:3 to obtain the product (3-nitro-5-(pentafluorothio) Phenyl)(pyrrolidin-1-yl)methanone 480 mg. MS m/z (ESI): 347.3 [M+H] + .
步驟2step 2 合成(3-Synthesis (3- 胺基-5-(Amino-5-( 五氟硫代)Pentafluorothio) 苯基)(Phenyl)( 吡咯烷-1-pyrrolidine-1- 基)base) 甲酮ketone
氮氣保護下，向雙口瓶加入(3-硝基-5-(五氟硫代)苯基)(吡咯烷-1-基)甲酮(480 mg, 1.39 mmol)、無水三氯化鐵(22.5 mg, 0.14 mmol)、活性炭(96 mg, 6.0 mmol)，加入乾燥的乙醇(20 mL)，80℃下回流，然後緩慢滴加水合肼(278 mg, 5.54 mmol)，繼續反應2 h。監測反應完全後，將體系過濾，旋乾。粗產品用EA/PE=1:1進行矽膠柱層析，得到純品產物(3-胺基-5-(五氟硫代)苯基)(吡咯烷-1-基)甲酮376 mg. MS m/z(ESI)：333.3 [M+H]+ 。Under nitrogen protection, (3-nitro-5-(pentafluorothio)phenyl)(pyrrolidin-1-yl)methanone (480 mg, 1.39 mmol), anhydrous ferric chloride ( 22.5 mg, 0.14 mmol), activated carbon (96 mg, 6.0 mmol), added dry ethanol (20 mL), refluxed at 80°C, then slowly added hydrazine hydrate (278 mg, 5.54 mmol) dropwise, and continued the reaction for 2 h. After monitoring the completion of the reaction, the system was filtered and spin-dried. The crude product was subjected to silica gel column chromatography with EA/PE=1:1 to obtain the pure product (3-amino-5-(pentafluorothio)phenyl)(pyrrolidin-1-yl)methanone 376 mg. MS m/z (ESI): 333.3 [M+H] + .
步驟3step 3 合成2-(4-(4-Synthesis of 2-(4-(4- 乙氧基-6-(((4-Ethoxy-6-(((4- 甲氧基苄基)Methoxybenzyl) 氧基)oxygen) 吡啶-3-Pyridine-3- 基)-2-base)-2- 氟苯基)-N -(3-(Fluorophenyl)- N -(3-( 五氟硫代)-5-(Pentafluorothio)-5-( 吡咯烷-1-pyrrolidine-1- 羰基)Carbonyl) 苯基)phenyl) 乙醯胺Acetamide
將2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸(370 mg, 0.90 mmol)溶於乾燥的DMF(10 mL)中，加入HATU (376 mg, 0.99 mmol)、(3-胺基-5-(五氟硫代)苯基)(吡咯烷-1-基)甲酮 (300 mg, 0.90 mmol)、DMAP(11 mg, 0.09 mmol)，最後加入DIPEA(465 mg, 3.60 mmol)，室溫攪拌2h。監測反應完全後，將體系倒入冰水中，EA萃取，合併有機相，旋乾。粗產品用EA/PE=1:1進行矽膠柱層析，得到純產物2-(4-(4-乙氧基-6-(((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)-N -(3-(五氟硫代)-5-(吡咯烷-1-羰基)苯基)乙醯胺370 mg. MS m/z(ESI)：710.7 [M+H]+ 。2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (370 mg, 0.90 mmol) was dissolved In dry DMF (10 mL), add HATU (376 mg, 0.99 mmol), (3-amino-5-(pentafluorothio)phenyl)(pyrrolidin-1-yl)methanone (300 mg , 0.90 mmol), DMAP (11 mg, 0.09 mmol), and finally DIPEA (465 mg, 3.60 mmol), and stirred at room temperature for 2h. After monitoring the completion of the reaction, the system was poured into ice water, extracted with EA, the organic phases were combined, and spin-dried. The crude product was subjected to silica gel column chromatography with EA/PE=1:1 to obtain the pure product 2-(4-(4-ethoxy-6-(((4-methoxybenzyl)oxy)pyridine-3 -yl)-2 - fluorophenyl)-N-(3-(pentafluorothio)-5-(pyrrolidine-1-carbonyl)phenyl)acetamide 370 mg. MS m/z(ESI): 710.7 [M+H] + .
步驟4step 4 合成2-(4-(4-Synthesis of 2-(4-(4- 乙氧基-6-Ethoxy-6- 氧代-1,6-Oxo-1,6- 二氫吡啶-3-Dihydropyridine-3- 基)-2-base)-2- 氟苯基)-N -(3-(Fluorophenyl)- N -(3-( 五氟硫代)-5-(Pentafluorothio)-5-( 吡咯烷-1-pyrrolidine-1- 羰基)Carbonyl) 苯基)phenyl) 乙醯胺Acetamide
將2-(4-(4-乙氧基-6-(((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)-N -(3-(五氟硫代)-5-(吡咯烷-1-羰基)苯基)乙醯胺(370 mg, 0.52 mmol)溶於DCM中，加入TFA(2 ml)，室溫反應30 min，TLC監測反應進程，反應完全後，將體系旋乾，加水，二氯甲烷萃取合併有機相，乾燥旋乾。粗產品用EA/PE=2:1進行矽膠柱層析，得到純產物2-(4-(4-乙氧基-6-氧代-1,6-二氫吡啶-3-基)-2-氟苯基)-N -(3-(五氟硫代)-5-(吡咯烷-1-基)羰基)苯基)乙醯胺（化合物5 ） 153.6 mg. MS m/z(ESI)：590.6 [M+H]+ 。1 H NMR (500 MHz, DMSO) δ 11.36 (s, 1H), 10.75 (s, 1H), 8.28 (t,J = 2.0 Hz, 1H), 7.98 (s, 1H), 7.66(s, 1H), 7.37(d,J = 8.2 Hz, 1H), 7.33(d,J = 4.3 Hz, 1H), 7.25 (d,J = 11.4 Hz, 1H), 7.22 (dd,J = 7.9, 1.7 Hz, 1H), 5.80 (s, 1H), 4.03 (q,J = 7.0 Hz, 2H), 3.78 (s, 1H), 3.46 (t,J =6.6 Hz, 2H), 3.36 (t,J =6.3 Hz, 2H), 1.84 (dt,J = 18.4, 6.5 Hz, 3H), 1.35-1.14 (m, 4H).2-(4-(4-ethoxy-6-(((4-methoxybenzyl)oxy)pyridin-3-yl)-2 - fluorophenyl)-N-(3-(penta Fluorothio)-5-(pyrrolidine-1-carbonyl)phenyl)acetamide (370 mg, 0.52 mmol) was dissolved in DCM, TFA (2 ml) was added, reacted at room temperature for 30 min, TLC monitored the reaction progress , after the reaction was complete, the system was spin-dried, added water, dichloromethane extracted the combined organic phase, dried and spin-dried. The crude product was chromatographed on silica gel with EA/PE=2:1 to obtain the pure product 2-(4-(4 -Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2 - fluorophenyl)-N-(3-(pentafluorothio)-5-(pyrrolidin-1- yl)carbonyl)phenyl)acetamide (Compound 5 ) 153.6 mg. MS m/z (ESI): 590.6 [M+H] + . 1 H NMR (500 MHz, DMSO) δ 11.36 (s, 1H), 10.75 (s, 1H), 8.28 (t, J = 2.0 Hz, 1H), 7.98 (s, 1H), 7.66(s, 1H), 7.37(d, J = 8.2 Hz, 1H), 7.33(d, J = 4.3 Hz, 1H), 7.25 (d, J = 11.4 Hz, 1H), 7.22 (dd, J = 7.9, 1.7 Hz, 1H), 5.80 (s, 1H), 4.03 (q, J = 7.0 Hz, 2H), 3.78 (s, 1H), 3.46 (t, J =6.6 Hz, 2H), 3.36 (t, J = 6.3 Hz, 2H), 1.84 (dt, J = 18.4, 6.5 Hz, 3H), 1.35-1.14 (m, 4H).
實施例6 2-(4-(4- 乙氧基-6- 氧代-1,6- 二氫吡啶-3- 基)-2- 氟苯基)-N
-(3-( 五氟硫代)-5-( 哌啶-1- 基) 羰基) 苯基) 乙醯胺的合成 
步驟1step 1 ：合成(3-: Synthesis (3- 硝基-5-(Nitro-5-( 五氟硫代)Pentafluorothio) 苯基)(Phenyl)( 哌啶-1-piperidine-1- 基)base) 甲酮ketone
將3-硝基-5-(五氟硫代)苯甲酸(500 mg, 1.71 mmol)溶解在二氯亞碸(15 mL)中，然後往體系中滴入兩滴DMF，加熱至80℃，回流反應2h。反應完全後將體系中的液體旋乾，用1 mL DCM將醯氯產物溶解。哌啶(290 mg, 3.41 mmol)和三乙胺(517 mg, 5.12 mmol)溶於二氯甲烷中，冰浴下將醯氯產物緩慢滴加進上述體系，完畢後將冰浴撤去，在室溫反應30 min。加水洗滌，二氯甲烷萃取，合併有機相，乾燥，減壓濃縮，粗產品用EA/PE=1:3進行矽膠柱層析得到產物(3-硝基-5-(五氟硫代)苯基)(哌啶-1-基)甲酮350 mg. MS m/z(ESI)：361.3 [M+H]+ 。Dissolve 3-nitro-5-(pentafluorothio)benzoic acid (500 mg, 1.71 mmol) in dichlorosulfone (15 mL), then add two drops of DMF to the system, heat to 80°C, Reflux reaction 2h. After the reaction was complete, the liquid in the system was spin-dried, and the acyl chloride product was dissolved in 1 mL of DCM. Piperidine (290 mg, 3.41 mmol) and triethylamine (517 mg, 5.12 mmol) were dissolved in dichloromethane, and the acyl chloride product was slowly added dropwise into the above system under ice bath, and the ice bath was removed after completion, and the Warm reaction for 30 min. Wash with water, extract with dichloromethane, combine the organic phases, dry, and concentrate under reduced pressure. The crude product is subjected to silica gel column chromatography with EA/PE=1:3 to obtain the product (3-nitro-5-(pentafluorothio)benzene yl)(piperidin-1-yl)methanone 350 mg. MS m/z (ESI): 361.3 [M+H] + .
步驟2step 2 ：合成(3-: Synthesis (3- 胺基-5-(Amino-5-( 五氟硫代)Pentafluorothio) 苯基)(Phenyl)( 哌啶-1-piperidine-1- 基)base) 甲酮ketone
氮氣保護下向雙口瓶中加入(3-硝基-5-(五氟硫代)苯基)(哌啶-1-基)甲酮 (485 mg, 1.35 mmol)、氯化亞鐵(21.83 mg, 0.13 mmol)、活性炭(97 mg, 6.06 mmol)，加入乾燥的乙醇(20 mL)，80℃下回流，然後緩慢滴加水合肼 (270.3 mg, 5.40 mmol)，繼續反應2 h。監測反應完全後，將體系過濾，旋乾。粗產品用EA/PE=1:1進行矽膠柱層析，得到純品產物(3-胺基-5-(五氟硫代)苯基)(哌啶-1-基)甲酮404 mg. MS m/z(ESI)：347.3 [M+H]+ 。Add (3-nitro-5-(pentafluorothio)phenyl)(piperidin-1-yl)methanone (485 mg, 1.35 mmol), ferrous chloride (21.83 mg, 0.13 mmol), activated carbon (97 mg, 6.06 mmol), added dry ethanol (20 mL), refluxed at 80°C, then slowly added hydrazine hydrate (270.3 mg, 5.40 mmol) dropwise, and continued the reaction for 2 h. After monitoring the completion of the reaction, the system was filtered and spin-dried. The crude product was subjected to silica gel column chromatography with EA/PE=1:1 to obtain the pure product (3-amino-5-(pentafluorothio)phenyl)(piperidin-1-yl)methanone 404 mg. MS m/z (ESI): 347.3 [M+H] + .
步驟3step 3 ：合成2-(4-(4-: Synthesis of 2-(4-(4- 乙氧基-6-(((4-Ethoxy-6-(((4- 甲氧基苄基)Methoxybenzyl) 氧基)oxygen) 吡啶-3-Pyridine-3- 基)-2-base)-2- 氟苯基)-N -(3-(Fluorophenyl)- N -(3-( 五氟硫代)-5-(Pentafluorothio)-5-( 哌啶-1-piperidine-1- 羰基)Carbonyl) 苯基)phenyl) 乙醯胺Acetamide
將2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸(300 mg, 0.73 mmol)溶於乾燥的DMF(10 mL)中，加入HATU (305 mg, 0.8 mmol)、(3-胺基-5-(五氟硫代)苯基)(哌啶-1-基)甲酮(241 mg, 0.73 mmol)、DMAP(9 mg, 0.07 mmol)，最後加入DIPEA(377 mg, 2.92 mmol)，室溫攪拌2h。監測反應完全後，將體系倒入冰水中，EA萃取，合併有機相，旋乾。粗產品用EA/PE=1:1進行矽膠柱層析，得到純產物2-(4-(4-乙氧基-6-(((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)-N -(3-(五氟硫代)-5-(哌啶-1-羰基)苯基)乙醯胺340 mg. MS m/z(ESI)：724.7 [M+H]+ 。2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (300 mg, 0.73 mmol) was dissolved In dry DMF (10 mL), add HATU (305 mg, 0.8 mmol), (3-amino-5-(pentafluorothio)phenyl)(piperidin-1-yl)methanone (241 mg , 0.73 mmol), DMAP (9 mg, 0.07 mmol), and finally DIPEA (377 mg, 2.92 mmol), and stirred at room temperature for 2h. After monitoring the completion of the reaction, the system was poured into ice water, extracted with EA, the organic phases were combined, and spin-dried. The crude product was subjected to silica gel column chromatography with EA/PE=1:1 to obtain the pure product 2-(4-(4-ethoxy-6-(((4-methoxybenzyl)oxy)pyridine-3 -yl)-2 - fluorophenyl)-N-(3-(pentafluorothio)-5-(piperidine-1-carbonyl)phenyl)acetamide 340 mg. MS m/z(ESI): 724.7 [M+H] + .
步驟4step 4 ：合成2-(4-(4-: Synthesis of 2-(4-(4- 乙氧基-6-Ethoxy-6- 氧代-1,6-Oxo-1,6- 二氫吡啶-3-Dihydropyridine-3- 基)-2-base)-2- 氟苯基)-N -(3-(Fluorophenyl)- N -(3-( 五氟硫代)-5-(Pentafluorothio)-5-( 哌啶-1-piperidine-1- 基)base) 羰基)Carbonyl) 苯基)phenyl) 乙醯胺Acetamide
將2-(4-(4-乙氧基-6-(((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)-N -(3-(五氟硫代)-5-(哌啶-1-羰基)苯基)乙醯胺(113 mg, 0.16 mmol)溶於DCM中，加入TFA(2 ml)，室溫反應30 min。TLC監測反應進程，反應完全後，將體系旋乾，加水，二氯甲烷萃取合併有機相，乾燥有機相，旋乾。粗產品用EA/PE=2:1進行矽膠柱層析，得到純產物2-(4-(4-乙氧基-6-氧代-1,6-二氫吡啶-3-基)-2-氟苯基)-N -(3-(五氟硫代)-5-(哌啶-1-基) 羰基)苯基)乙醯胺（化合物6 ） 53.3 mg. MS m/z(ESI)：604.6 [M+H]+ 。1 H NMR (500 MHz, DMSO) δ 11.36 (s, 1H), 10.76 (s, 1H), 8.27 (t,J = 1.9 Hz, 1H), 7.83 (s, 1H), 7.54 (s, 1H), 7.37(d,J = 8.1 Hz, 1H), 7.33 (d,J = 3.7 Hz, 1H), 7.25 (d,J = 11.4Hz, 1H), 7.30-7.20 (m, 1H), 5.80 (s, 1H), 4.03 (q,J = 6.9 Hz, 2H), 3.78 (s, 2H), 3.57 (s, 2H), 3.24 (s, 2H), 1.60-1.46 (m, 4H), 1.29-1.22 (m, 6H).2-(4-(4-ethoxy-6-(((4-methoxybenzyl)oxy)pyridin-3-yl)-2 - fluorophenyl)-N-(3-(penta Fluorothio)-5-(piperidine-1-carbonyl)phenyl)acetamide (113 mg, 0.16 mmol) was dissolved in DCM, TFA (2 ml) was added and reacted at room temperature for 30 min. TLC monitored the reaction progress , after the reaction was complete, the system was spin-dried, added water, dichloromethane extracted the combined organic phase, dried the organic phase, and spin-dried. The crude product was chromatographed on a silica gel column with EA/PE=2:1 to obtain the pure product 2-(4 -(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2 - fluorophenyl)-N-(3-(pentafluorothio)-5-(piperidine -1-yl)carbonyl)phenyl)acetamide (Compound 6 ) 53.3 mg. MS m/z (ESI): 604.6 [M+H] + . 1 H NMR (500 MHz, DMSO) δ 11.36 (s, 1H), 10.76 (s, 1H), 8.27 (t, J = 1.9 Hz, 1H), 7.83 (s, 1H), 7.54 (s, 1H), 7.37(d, J = 8.1 Hz, 1H), 7.33 (d, J = 3.7 Hz, 1H), 7.25 (d, J = 11.4Hz, 1H), 7.30-7.20 (m, 1H), 5.80 (s, 1H ), 4.03 (q, J = 6.9 Hz, 2H), 3.78 (s, 2H), 3.57 (s, 2H), 3.24 (s, 2H), 1.60-1.46 (m, 4H), 1.29-1.22 (m, 6H).
實施例7N
-(3-(3-( 二甲基胺基) 氮雜環丁烷-1- 羰基)-5-( 五氟硫代) 苯基)-2-(4-(4- 乙氧基-6- 氧代-1,6- 二氫吡啶-3- 基)-2- 氟苯基) 乙醯胺的合成 
步驟1step 1 合成 (3-(Synthetic (3-( 二甲基胺基)Dimethylamino) 氮雜環丁烷-1-Azetidine-1- 基)(3-Base) (3- 硝基-5-(Nitro-5-( 五氟硫代)Pentafluorothio) 苯基)phenyl) 甲酮ketone
將3-硝基-5-(五氟硫代)苯甲酸(500 mg, 1.71 mmol)溶解在SOCl2 (5 mL)中，再加入幾滴DMF，然後回流反應2小時，反應完全後旋乾反應液，將醯基氯溶於DCM(5 mL)中，將混合物滴加到三乙胺(517 mg, 5.12 mmol)和N ,N -二甲基氮雜環丁烷-3-胺(222 mg, 2.22 mmol)的DCM(5 mL)溶液中，在0℃下繼續反應半小時。反應完全後，加入水淬滅反應，分液，有機相濃縮，柱層析得到(3-(二甲基胺基)氮雜環丁烷-1-基)(3-硝基-5-(五氟硫代)苯基)甲酮 460 mg。MS m/z(ESI)：376[M+H]+ 。Dissolve 3-nitro-5-(pentafluorothio)benzoic acid (500 mg, 1.71 mmol) in SOCl 2 (5 mL), add a few drops of DMF, then reflux for 2 hours, spin dry after the reaction is complete For the reaction solution, dissolve acyl chloride in DCM (5 mL), and add the mixture dropwise to triethylamine (517 mg, 5.12 mmol) and N , N -dimethylazetidin-3-amine (222 mg, 2.22 mmol) in DCM (5 mL), the reaction was continued at 0°C for half an hour. After the reaction is complete, add water to quench the reaction, separate the liquids, concentrate the organic phase, and obtain (3-(dimethylamino)azetidin-1-yl)(3-nitro-5-( Pentafluorothio)phenyl)methanone 460 mg. MS m/z (ESI): 376 [M+H] + .
步驟2step 2 合成(3-Synthesis (3- 胺基-5-(Amino-5-( 五氟硫代)Pentafluorothio) 苯基)(3-(Phenyl) (3-( 二甲基胺基)Dimethylamino) 氮雜環丁烷-1-Azetidine-1- 基)base) 甲酮ketone
將(3-(二甲基胺基)氮雜環丁烷-1-基)(3-硝基-5-(五氟硫代)苯基)甲酮(460 mg, 1.23 mmol)、FeCl3 (20 mg, 0.12 mmol)、活性炭(100 mg)加入到乙醇(10 mL)中，然後再慢慢加入水合肼(244 mg, 4.88 mmol)，混合物在80℃下攪拌反應過夜。監測反應完全後，冷卻，抽濾，反應液旋乾，柱層析得到(3-胺基-5-(五氟硫代)苯基)(3-(二甲基胺基)氮雜環丁烷-1-基)甲酮330 mg。MS m/z(ESI)：346[M+H]+ 。(3-(Dimethylamino)azetidin-1-yl)(3-nitro-5-(pentafluorothio)phenyl)methanone (460 mg, 1.23 mmol), FeCl 3 (20 mg, 0.12 mmol), activated carbon (100 mg) were added to ethanol (10 mL), and then hydrazine hydrate (244 mg, 4.88 mmol) was added slowly, and the mixture was stirred and reacted overnight at 80°C. After monitoring that the reaction is complete, cool, filter with suction, spin the reaction solution to dryness, and obtain (3-amino-5-(pentafluorothio)phenyl)(3-(dimethylamino)azetidine Alk-1-yl)methanone 330 mg. MS m/z (ESI): 346 [M+H] + .
步驟3step 3 合成N -(3-(3-(Synthesis of N -(3-(3-( 二甲基胺基)Dimethylamino) 氮雜環丁烷-1-Azetidine-1- 羰基)-5-(Carbonyl)-5-( 五氟硫代)Pentafluorothio) 苯基)-2-(4-(4-Phenyl)-2-(4-(4- 乙氧基-6-((4-Ethoxy-6-((4- 甲氧基苄基)Methoxybenzyl) 氧基)oxygen) 吡啶-3-Pyridine-3- 基)-2-base)-2- 氟苯基)Fluorophenyl) 乙醯胺Acetamide
將2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸(393 mg, 0.957 mmol)溶解到DMF 中，加入HATU(400 mg, 1.05 mmol)、DMAP(12 mg, 0.095 mmol)、DIEA(370 mg, 2.87 mmol)、(3-胺基-5-(五氟硫代)苯基)(3-(二甲基胺基)氮雜環丁烷-1-基)甲酮(330 mg, 0.957 mmol)，混合物在室溫下反應過夜。反應完全後，加入水淬滅反應，然後再用EA(20 mL*2)萃取，有機相乾燥，旋乾，柱層析得到N -(3-(3-(二甲基胺基)氮雜環丁烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙醯胺300 mg。MS m/z(ESI)：739[M+H]+ 。2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (393 mg, 0.957 mmol) was dissolved To DMF, add HATU (400 mg, 1.05 mmol), DMAP (12 mg, 0.095 mmol), DIEA (370 mg, 2.87 mmol), (3-amino-5-(pentafluorothio)phenyl) ( 3-(Dimethylamino)azetidin-1-yl)methanone (330 mg, 0.957 mmol), and the mixture was reacted at room temperature overnight. After the reaction was complete, water was added to quench the reaction, and then extracted with EA (20 mL*2), the organic phase was dried, spin-dried, and column chromatography gave N- (3-(3-(dimethylamino)azepine Cyclobutane-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridine- 3-yl)-2-fluorophenyl)acetamide 300 mg. MS m/z (ESI): 739 [M+H] + .
步驟4step 4 合成N -(3-(3-(Synthesis of N -(3-(3-( 二甲基胺基)Dimethylamino) 氮雜環丁烷-1-Azetidine-1- 羰基)-5-(Carbonyl)-5-( 五氟硫代)Pentafluorothio) 苯基)-2-(4-(4-Phenyl)-2-(4-(4- 乙氧基-6-Ethoxy-6- 氧代-1,6-Oxo-1,6- 二氫吡啶-3-Dihydropyridine-3- 基)-2-base)-2- 氟苯基)Fluorophenyl) 乙醯胺Acetamide
將N -(3-(3-(二甲基胺基)氮雜環丁烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙醯胺(300 mg, 0.407 mmol)溶解在DCM(10 mL)中，然後加入TFA(2 mL)，混合物室溫下攪拌反應2小時。反應完全後，濃縮反應液，再用碳酸鈉水溶液調至中性，DCM(20 mL*2)萃取，有機相旋乾，柱層析得到N -(3-(3-(二甲基胺基)氮雜環丁烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-氧代-1,6-二氫吡啶-3-基)-2-氟苯基)乙醯胺（化合物 7 ） 85 mg。MS m/z(ESI)：619[M+H]+ 。1 H NMR (500 MHz, DMSO-d 6 ) δ 11.40 (s, 1H), 10.80 (s, 1H), 8.40 (t,J = 2.0 Hz, 1H), 8.05 (t,J = 1.5 Hz, 1H), 7.71 (t,J = 1.6 Hz, 1H), 7.40 – 7.32 (m, 2H), 7.28 – 7.20 (m, 2H), 5.81 (s, 1H), 4.30 (t,J = 8.0 Hz, 1H), 4.05 (dq,J = 14.0, 7.5, 7.0 Hz, 4H), 3.85 (dd,J = 10.5, 5.1 Hz, 1H), 3.79 (s, 2H), 3.14 – 3.07 (m, 1H), 2.08 (s, 6H), 1.28 (t,J = 6.9 Hz, 3H). N- (3-(3-(dimethylamino)azetidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy -6-((4-Methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (300 mg, 0.407 mmol) was dissolved in DCM (10 mL) and added TFA (2 mL), the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated, then adjusted to neutrality with aqueous sodium carbonate, extracted with DCM (20 mL*2), the organic phase was spin-dried, and column chromatography gave N- (3-(3-(dimethylamino )azetidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridine-3 -yl)-2-fluorophenyl)acetamide (compound 7 ) 85 mg. MS m/z (ESI): 619 [M+H] + . 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.40 (s, 1H), 10.80 (s, 1H), 8.40 (t, J = 2.0 Hz, 1H), 8.05 (t, J = 1.5 Hz, 1H) , 7.71 (t, J = 1.6 Hz, 1H), 7.40 – 7.32 (m, 2H), 7.28 – 7.20 (m, 2H), 5.81 (s, 1H), 4.30 (t, J = 8.0 Hz, 1H), 4.05 (dq, J = 14.0, 7.5, 7.0 Hz, 4H), 3.85 (dd, J = 10.5, 5.1 Hz, 1H), 3.79 (s, 2H), 3.14 – 3.07 (m, 1H), 2.08 (s, 6H), 1.28 (t, J = 6.9 Hz, 3H).
實施例8 2-(4-(4- 乙氧基-6- 氧代-1,6- 二氫吡啶-3- 基)-2- 氟苯基)-N
-(3-( 嗎啉-4- 羰基)-5-( 五氟硫代) 苯基) 乙醯胺的合成 
步驟1step 1 合成嗎啉代(3-Synthesis of morpholino (3- 硝基-5-(Nitro-5-( 五氟硫代)Pentafluorothio) 苯基)phenyl) 甲酮ketone
將3-硝基-5-(五氟硫代)苯甲酸(500 mg, 1.71 mmol)溶解在二氯亞碸(15 mL)中，向體系中滴入兩滴DMF，加熱至80℃回流2h。反應完全後將體系旋乾，用1 mL DCM溶解醯氯產物。嗎啉(298 mg, 3.41 mmol)和三乙胺(517 mg, 5.12 mmol)溶於二氯甲烷中，冰浴下向上述體系緩慢滴加醯氯產物，完畢後將冰浴撤去，在室溫反30 min。加水洗滌，二氯甲烷萃取，合併有機相，乾燥旋乾，粗產品用EA/PE=1:3進行矽膠柱層析得到產物嗎啉代(3-硝基-5-(五氟硫代)苯基)甲酮354 mg. MS m/z(ESI)：363.3 [M+H]+ 。Dissolve 3-nitro-5-(pentafluorothio)benzoic acid (500 mg, 1.71 mmol) in dichlorosulfone (15 mL), drop two drops of DMF into the system, heat to 80°C and reflux for 2h . After the reaction was complete, the system was spin-dried, and the acyl chloride product was dissolved in 1 mL DCM. Morpholine (298 mg, 3.41 mmol) and triethylamine (517 mg, 5.12 mmol) were dissolved in dichloromethane, and the acyl chloride product was slowly added dropwise to the above system under ice bath, and the ice bath was removed after completion, at room temperature Wait for 30 minutes. Washed with water, extracted with dichloromethane, combined organic phase, dried and spin-dried, the crude product was subjected to silica gel column chromatography with EA/PE=1:3 to obtain the product morpholino (3-nitro-5-(pentafluorothio) Phenyl)methanone 354 mg. MS m/z (ESI): 363.3 [M+H] + .
步驟2step 2 合成嗎啉代(3-Synthesis of morpholino (3- 胺基-5-(Amino-5-( 五氟硫代)Pentafluorothio) 苯基)phenyl) 甲酮ketone
氮氣保護下向雙口瓶中加入嗎啉代(3-胺基-5-(五氟硫代)苯基)甲酮(354 mg, 0.98 mmol)、無水三氯化鐵(15.9 mg, 0.10 mmol)、活性炭(70.8 mg, 4.42 mmol)、乾燥的乙醇(20 mL)，80℃下回流，然後緩慢滴加水合肼 (196 mg, 3.91 mmol)，繼續反應2 h。監測反應完全後，將體系過濾，旋乾。粗產品用EA/PE=1:1進行矽膠柱層析，得到純品產物嗎啉代(3-胺基-5-(五氟硫代)苯基)甲酮307 mg. MS m/z(ESI)：349.3 [M+H]+ 。Add morpholino(3-amino-5-(pentafluorothio)phenyl)methanone (354 mg, 0.98 mmol), anhydrous ferric chloride (15.9 mg, 0.10 mmol) into a two-necked flask under nitrogen protection ), activated carbon (70.8 mg, 4.42 mmol), dry ethanol (20 mL), reflux at 80°C, then slowly dropwise add hydrazine hydrate (196 mg, 3.91 mmol), and continue the reaction for 2 h. After monitoring the completion of the reaction, the system was filtered and spin-dried. The crude product was subjected to silica gel column chromatography with EA/PE=1:1 to obtain pure product morpholino(3-amino-5-(pentafluorothio)phenyl)methanone 307 mg. MS m/z( ESI): 349.3 [M+H] + .
步驟3step 3 合成2-(4-(4-Synthesis of 2-(4-(4- 乙氧基-6-(((4-Ethoxy-6-(((4- 甲氧基苄基)Methoxybenzyl) 氧基)oxygen) 吡啶-3-Pyridine-3- 基)-2-base)-2- 氟苯基)-N -(3-(Fluorophenyl)- N -(3-( 嗎啉-4-Morpholine-4- 羰基)-5-(Carbonyl)-5-( 五氟硫代)Pentafluorothio) 苯基)phenyl) 乙醯胺Acetamide
將2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸(362 mg, 0.88 mmol)溶於乾燥的DMF(10 mL)中，加入HATU (368 mg, 0.97 mmol)、嗎啉代(3-胺基-5-(五氟硫代)苯基)甲酮 (307 mg, 0.88 mmol)、DMAP(10.8 mg, 0.09 mmol)，最後加入DIPEA(455 mg, 3.52 mmol)，室溫攪拌2h。監測反應完全後，將體系倒入冰水中，EA萃取，合併有機相，旋乾。粗產品用EA/PE=1:1進行矽膠柱層析，得到純產物2-(4-(4-乙氧基-6-(((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)-N -(3-(嗎啉-4-羰基)-5-(五氟硫代)苯基)乙醯胺600 mg. MS m/z(ESI)：726.7 [M+H]+ 。2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (362 mg, 0.88 mmol) was dissolved In dry DMF (10 mL), add HATU (368 mg, 0.97 mmol), morpholino (3-amino-5-(pentafluorothio)phenyl)methanone (307 mg, 0.88 mmol), DMAP (10.8 mg, 0.09 mmol) and finally DIPEA (455 mg, 3.52 mmol) were added and stirred at room temperature for 2h. After monitoring the completion of the reaction, the system was poured into ice water, extracted with EA, the organic phases were combined, and spin-dried. The crude product was subjected to silica gel column chromatography with EA/PE=1:1 to obtain the pure product 2-(4-(4-ethoxy-6-(((4-methoxybenzyl)oxy)pyridine-3 -yl)-2 - fluorophenyl)-N-(3-(morpholine-4-carbonyl)-5-(pentafluorothio)phenyl)acetamide 600 mg. MS m/z(ESI): 726.7 [M+H] + .
步驟4step 4 合成2-(4-(4-Synthesis of 2-(4-(4- 乙氧基-6-Ethoxy-6- 氧代-1,6-Oxo-1,6- 二氫吡啶-3-Dihydropyridine-3- 基)-2-base)-2- 氟苯基)-N -(3-(Fluorophenyl)- N -(3-( 嗎啉-4-Morpholine-4- 羰基)-5-(Carbonyl)-5-( 五氟硫代)Pentafluorothio) 苯基)phenyl) 乙醯胺Acetamide
將2-(4-(4-乙氧基-6-(((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)-N -(3-(嗎啉-4-羰基)-5-(五氟硫代)苯基)乙醯胺(600 mg, 0.83 mmol)溶於DCM中，加入TFA(2 mL)，室溫反應30 min。TLC監測反應進程，反應完全後，將體系旋乾，加水，二氯甲烷萃取合併有機相，乾燥旋乾。粗產品用EA/PE=2:1進行矽膠柱層析，得到純產物2-(4-(4-乙氧基-6-氧代-1,6-二氫吡啶-3-基)-2-氟苯基)-N -(3-(五氟硫代)-5-(吡咯烷-1-基)羰基)苯基)乙醯胺（化合物8 ） 225 mg. MS m/z(ESI)：606.6 [M+H]+ 。1 H NMR (500 MHz, DMSO) δ 11.37 (s, 1H), 10.77 (s, 1H), 8.29 (d,J = 1.9 Hz, 1H), 7.84 (s, 1H), 7.61 (s, 1H), 7.37(d,J = 8.1 Hz, 1H), 7.33 (d,J = 3.6 Hz, 1H), 7.25 (d,J = 11.5 Hz, 1H), 7.20 (m, 1H), 5.80 (s, 1H), 4.03 (q,J = 6.9 Hz, 2H), 3.78 (s, 1H), 3.62-3.56 (m, 4H), 1.37-1.18 (m, 3H).2-(4-(4-ethoxy-6-(((4-methoxybenzyl)oxy)pyridin-3-yl)-2 - fluorophenyl)-N-(3-( Phenyl-4-carbonyl)-5-(pentafluorothio)phenyl)acetamide (600 mg, 0.83 mmol) was dissolved in DCM, TFA (2 mL) was added and reacted at room temperature for 30 min. TLC monitored the reaction progress , after the reaction was complete, the system was spin-dried, added water, dichloromethane extracted the combined organic phase, dried and spin-dried. The crude product was chromatographed on silica gel with EA/PE=2:1 to obtain the pure product 2-(4-(4 -Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2 - fluorophenyl)-N-(3-(pentafluorothio)-5-(pyrrolidin-1- yl)carbonyl)phenyl)acetamide (Compound 8 ) 225 mg. MS m/z (ESI): 606.6 [M+H] + . 1 H NMR (500 MHz, DMSO) δ 11.37 (s, 1H), 10.77 (s, 1H), 8.29 (d, J = 1.9 Hz, 1H), 7.84 (s, 1H), 7.61 (s, 1H), 7.37(d, J = 8.1 Hz, 1H), 7.33 (d, J = 3.6 Hz, 1H), 7.25 (d, J = 11.5 Hz, 1H), 7.20 (m, 1H), 5.80 (s, 1H), 4.03 (q, J = 6.9 Hz, 2H), 3.78 (s, 1H), 3.62-3.56 (m, 4H), 1.37-1.18 (m, 3H).
實施例9N
-(3-(3-( 二甲基胺基) 吡咯烷-1- 羰基)-5-( 五氟硫代) 苯基)-2-(4-(4- 乙氧基-6- 氧代-1,6- 二氫吡啶-3- 基)-2- 氟苯基) 乙醯胺的合成 
步驟1step 1 合成(3-(Synthetic (3-( 二甲胺基)Dimethylamino) 吡咯烷-1-pyrrolidine-1- 基)(3-Base) (3- 硝基-5-(Nitro-5-( 五氟硫代)Pentafluorothio) 苯基)phenyl) 甲酮ketone
將3-硝基-5-(五氟硫代)苯甲酸(500 mg, 1.71 mmol)溶解在SOCl2 (5 mL)中，加入幾滴DMF，然後回流反應2小時，反應完全後旋乾反應液。將醯基氯溶於DCM(5 mL)中，將混合物滴加到三乙胺(517 mg, 5.12 mmol)和N ,N -二甲基吡咯烷丁-3-胺(253 mg, 2.22 mmol)的DCM(5 mL)溶液中，在0℃下反應半小時。反應完全後，加入水淬滅反應，分液，有機相濃縮，柱層析得到((3-(二甲胺基)吡咯烷-1-基)(3-硝基-5-(五氟硫代)苯基)甲酮 480 mg。MS m/z(ESI)：390[M+H]+ 。Dissolve 3-nitro-5-(pentafluorothio)benzoic acid (500 mg, 1.71 mmol) in SOCl 2 (5 mL), add a few drops of DMF, then reflux for 2 hours, spin dry after the reaction is complete liquid. Acyl chloride was dissolved in DCM (5 mL), and the mixture was added dropwise to triethylamine (517 mg, 5.12 mmol) and N , N -dimethylpyrrolidinium butan-3-amine (253 mg, 2.22 mmol) DCM (5 mL) solution at 0°C for half an hour. After the reaction is complete, add water to quench the reaction, separate the layers, concentrate the organic phase, and obtain ((3-(dimethylamino)pyrrolidin-1-yl)(3-nitro-5-(pentafluorosulfur) by column chromatography Substitute) phenyl) ketone 480 mg. MS m/z (ESI): 390 [M+H] + .
步驟2step 2 合成(3-Synthesis (3- 胺基-5-(Amino-5-( 五氟硫代)Pentafluorothio) 苯基)(3-(Phenyl) (3-( 二甲基胺基)Dimethylamino) 吡咯烷-1-pyrrolidine-1- 基)base) 甲酮ketone
將(3-(二甲胺基)吡咯烷-1-基)(3-硝基-5-(五氟硫代)苯基)甲酮(480 mg, 1.23 mmol)、FeCl3 (20 mg, 0.12 mmol)、活性炭(100 mg)加入到乙醇(10 mL)中，向體系中緩慢加入水合肼(247 mg, 4.93 mmol)，混合物在80℃下攪拌反應過夜。監測反應完全後，冷卻，抽濾，反應液旋乾，柱層析得到(3-胺基-5-(五氟硫代)苯基)(3-(二甲基胺基)吡咯烷-1-基)甲酮375 mg。MS m/z(ESI)：360[M+H]+ 。(3-(Dimethylamino)pyrrolidin-1-yl)(3-nitro-5-(pentafluorothio)phenyl)methanone (480 mg, 1.23 mmol), FeCl 3 (20 mg, 0.12 mmol), activated carbon (100 mg) were added to ethanol (10 mL), and hydrazine hydrate (247 mg, 4.93 mmol) was slowly added to the system, and the mixture was stirred and reacted at 80°C overnight. After monitoring that the reaction is complete, cool, filter with suction, spin the reaction solution to dryness, and obtain (3-amino-5-(pentafluorothio)phenyl)(3-(dimethylamino)pyrrolidine-1 -yl) Methanone 375 mg. MS m/z (ESI): 360 [M+H] + .
步驟3step 3 合成N -(3-(3-(Synthesis of N -(3-(3-( 二甲基胺基)Dimethylamino) 吡咯烷-1-pyrrolidine-1- 羰基)-5-(Carbonyl)-5-( 五氟硫代)Pentafluorothio) 苯基)-2-(4-(4-Phenyl)-2-(4-(4- 乙氧基-6-((4-Ethoxy-6-((4- 甲氧基苄基)Methoxybenzyl) 氧基)oxygen) 吡啶-3-Pyridine-3- 基)-2-base)-2- 氟苯基)Fluorophenyl) 乙醯胺Acetamide
將2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸(429 mg, 1.045 mmol)溶解到DMF 中，然後加入HATU(437 mg, 1.15 mmol)、DMAP(13 mg, 0.104 mmol)、DIEA(404 mg, 3.13 mmol)、(3-胺基-5-(五氟硫代)苯基)(3-(二甲基胺基)吡咯烷-1-基)甲酮(375 mg, 1.045 mmol)，混合物在室溫下反應過夜，反應完全後。加入水淬滅反應，然後再用EA(20 mL*2)萃取，有機相乾燥，旋乾，柱層析得到N -(3-(3-(二甲基胺基)吡咯烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙醯胺320 mg。MS m/z(ESI)：753[M+H]+ 。2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (429 mg, 1.045 mmol) was dissolved to DMF, then added HATU (437 mg, 1.15 mmol), DMAP (13 mg, 0.104 mmol), DIEA (404 mg, 3.13 mmol), (3-amino-5-(pentafluorothio)phenyl) (3-(Dimethylamino)pyrrolidin-1-yl)methanone (375 mg, 1.045 mmol), the mixture was reacted at room temperature overnight, after the reaction was complete. Water was added to quench the reaction, and then extracted with EA (20 mL*2), the organic phase was dried, spin-dried, and column chromatography gave N- (3-(3-(dimethylamino)pyrrolidine-1-carbonyl )-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2- Fluorophenyl) acetamide 320 mg. MS m/z (ESI): 753 [M+H] + .
步驟4step 4 合成N -(3-(3-(Synthesis of N -(3-(3-( 二甲基胺基)Dimethylamino) 吡咯烷-1-pyrrolidine-1- 羰基)-5-(Carbonyl)-5-( 五氟硫代)Pentafluorothio) 苯基)-2-(4-(4-Phenyl)-2-(4-(4- 乙氧基-6-Ethoxy-6- 氧代-1,6-Oxo-1,6- 二氫吡啶-3-Dihydropyridine-3- 基)-2-base)-2- 氟苯基)Fluorophenyl) 乙醯胺Acetamide
將N -(3-(3-(二甲基胺基)吡咯烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙醯胺(320 mg, 0.426 mmol)溶解在DCM(10 mL)中，然後加入TFA(2 mL)，混合物室溫下攪拌反應2小時。反應完全後，濃縮反應液，再用碳酸鈉水溶液調至中性，DCM(20 mL*2)萃取，有機相旋乾，柱層析得到N -(3-(3-(二甲基胺基)吡咯烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-氧代-1,6-二氫吡啶-3-基)-2-氟苯基)乙醯胺（化合物 9 ） 200 mg。MS m/z(ESI)：633[M+H]+ 。1 H NMR (400 MHz, DMSO-d 6 ) δ 11.40 (s, 1H), 10.89 (s, 1H), 8.31 (q,J = 3.0, 1.9 Hz, 1H), 8.03 (d,J = 14.1 Hz, 1H), 7.69 (s, 1H), 7.36 (d,J = 10.5 Hz, 2H), 7.29 – 7.21 (m, 2H), 5.82 (s, 1H), 4.05 (q,J = 7.0 Hz, 2H), 3.90 (dd,J = 12.6, 7.1 Hz, 1H), 3.80 (s, 2H), 3.53 (q,J = 17.8, 14.1 Hz, 4H), 2.68 (d,J = 60.3 Hz, 6H), 2.27 (s, 1H), 2.08 (s, 1H), 1.29 (t,J = 6.9 Hz, 3H). N- (3-(3-(dimethylamino)pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy-6- ((4-Methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (320 mg, 0.426 mmol) was dissolved in DCM (10 mL), then TFA (2 mL), the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated, then adjusted to neutrality with aqueous sodium carbonate, extracted with DCM (20 mL*2), the organic phase was spin-dried, and column chromatography gave N- (3-(3-(dimethylamino )pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) acetamide (compound 9 ) 200 mg. MS m/z (ESI): 633 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.40 (s, 1H), 10.89 (s, 1H), 8.31 (q, J = 3.0, 1.9 Hz, 1H), 8.03 (d, J = 14.1 Hz, 1H), 7.69 (s, 1H), 7.36 (d, J = 10.5 Hz, 2H), 7.29 – 7.21 (m, 2H), 5.82 (s, 1H), 4.05 (q, J = 7.0 Hz, 2H), 3.90 (dd, J = 12.6, 7.1 Hz, 1H), 3.80 (s, 2H), 3.53 (q, J = 17.8, 14.1 Hz, 4H), 2.68 (d, J = 60.3 Hz, 6H), 2.27 (s , 1H), 2.08 (s, 1H), 1.29 (t, J = 6.9 Hz, 3H).
實施例10N
-(2-( 二甲基胺基) 乙基)-3-(2-(2- 氟-4-(4- 異丁氧基-6- 氧代-1,6- 二氫吡啶-3- 基) 苯基) 乙醯胺基)-5-( 五氟硫代) 苯甲醯胺的合成 
步驟1step 1 合成2-Synthetic 2- 氯-4-Chloro-4- 異丁氧基吡啶Isobutoxypyridine
將異丁醇(4.68 g, 63.29 mmol)溶解在THF(50 mL)中，冰浴下加入NaH(60%) (3.16 g, 79.11 mmol)攪拌30分鐘。然後加入2-氯-4-硝基吡啶(5 g, 31.65 mmol)，反應攪拌過夜。反應完全後，旋乾反應液，乙酸乙酯萃取，乾燥，旋乾，柱層析得到2-氯-4-異丁氧基吡啶3.6 g。MS m/z(ESI)：186[M+H]+ 。Dissolve isobutanol (4.68 g, 63.29 mmol) in THF (50 mL), add NaH (60%) (3.16 g, 79.11 mmol) under ice cooling and stir for 30 minutes. 2-Chloro-4-nitropyridine (5 g, 31.65 mmol) was then added and the reaction was stirred overnight. After the reaction was complete, the reaction solution was spin-dried, extracted with ethyl acetate, dried, spin-dried, and column chromatographed to obtain 3.6 g of 2-chloro-4-isobutoxypyridine. MS m/z (ESI): 186 [M+H] + .
步驟2step 2 合成5-Synthetic 5- 溴-2-Bromo-2- 氯-4-Chloro-4- 異丁氧基吡啶Isobutoxypyridine
將2-氯-4-異丁氧基吡啶(3.6 g, 19.46 mmol)溶解在濃硫酸(20 mL)中，然後向體系中緩慢分批加入NBS(5.2 g, 29.19 mmol)，加完後反應液升溫至80℃反應4小時。反應完全後，冷卻，將反應液倒入冰水中，經EA(50 mL*3)萃取，有機相乾燥旋乾，柱層析得到5-溴-2-氯-4-異丁氧基吡啶1.1 g產物。MS m/z(ESI)：264[M+H]+ 。Dissolve 2-chloro-4-isobutoxypyridine (3.6 g, 19.46 mmol) in concentrated sulfuric acid (20 mL), then slowly add NBS (5.2 g, 29.19 mmol) in batches to the system, and react The temperature of the solution was raised to 80° C. for 4 hours. After the reaction is complete, cool down, pour the reaction solution into ice water, extract with EA (50 mL*3), dry the organic phase and spin to dry, and obtain 5-bromo-2-chloro-4-isobutoxypyridine 1.1 by column chromatography g product. MS m/z (ESI): 264 [M+H] + .
步驟3step 3 合成5-Synthetic 5- 溴-4-Bromo-4- 異丁氧基-2-((4-Isobutoxy-2-((4- 甲氧基苄基)Methoxybenzyl) 氧基)oxygen) 吡啶pyridine
室溫下，向5-溴-2-氯-4-乙氧基吡啶(1.1 g, 4.18 mmol)在甲苯(20 mL)的混合液中加入(4-甲氧基苯基)甲醇(693 mg, 5.02 mmol)、KOH(469 mg, 8.37 mmol)和18-冠醚-6(110 mg, 0.42 mmol)，混合物在120℃下反應3小時。反應完全後，減壓濃縮反應液，加入水(15 mL)，然後再用EA(20 mL*2)萃取，有機相乾燥，旋乾，柱層析得到5-溴-4-異丁氧基-2-((4-甲氧基苄基)氧基)吡啶950 mg。MS m/z(ESI)：366[M+H]+ 。To a mixture of 5-bromo-2-chloro-4-ethoxypyridine (1.1 g, 4.18 mmol) in toluene (20 mL) was added (4-methoxyphenyl)methanol (693 mg , 5.02 mmol), KOH (469 mg, 8.37 mmol) and 18-crown-6 (110 mg, 0.42 mmol), the mixture was reacted at 120°C for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, water (15 mL) was added, and then extracted with EA (20 mL*2), the organic phase was dried, spin-dried, and column chromatography gave 5-bromo-4-isobutoxy -2-((4-methoxybenzyl)oxy)pyridine 950 mg. MS m/z (ESI): 366 [M+H] + .
步驟4step 4 合成2-(2-Synthesis of 2-(2- 氟-4-(4-Fluoro-4-(4- 異丁氧基-6-((4-Isobutoxy-6-((4- 甲氧基苄基)Methoxybenzyl) 氧基)oxygen) 吡啶-3-Pyridine-3- 基)base) 苯基)phenyl) 乙酸甲酯Methyl acetate
在氮氣保護下將5-溴-4-異丁氧基-2-((4-甲氧基苄基)氧基)吡啶(950 mg, 2.6 mmol)、2-(2-氟-4-(4,4,5,5-四甲基-1, 3, 2-二氧硼雜環戊烷-2-基)苯基)乙酸甲酯(842 mg, 2.86 mmol)、Pd(dppf)Cl2 (212 mg, 0.26 mmol)和碳酸銫(1.7 g, 5.2 mmol)加入到單口瓶中，再加入1, 4-二氧六環(15 mL)和水(5 mL)，混合物在95℃下反應3小時。反應完全後，用EA(20 mL*2)萃取，有機相乾燥，減壓濃縮旋乾，柱層析得到2-(2-氟-4-(4-異丁氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)苯基)乙酸甲酯980 mg。MS m/z(ESI)：454[M+H]+ 。Under nitrogen protection, 5-bromo-4-isobutoxy-2-((4-methoxybenzyl)oxy)pyridine (950 mg, 2.6 mmol), 2-(2-fluoro-4-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid methyl ester (842 mg, 2.86 mmol), Pd(dppf)Cl 2 (212 mg, 0.26 mmol) and cesium carbonate (1.7 g, 5.2 mmol) were added to a one-necked bottle, and then 1,4-dioxane (15 mL) and water (5 mL) were added, and the mixture was reacted at 95°C 3 hours. After the reaction was complete, it was extracted with EA (20 mL*2), the organic phase was dried, concentrated under reduced pressure and spin-dried, and column chromatography gave 2-(2-fluoro-4-(4-isobutoxy-6-((4 -Methoxybenzyl)oxy)pyridin-3-yl)phenyl)methyl acetate 980 mg. MS m/z (ESI): 454 [M+H] + .
步驟5step 5 合成2-(2-Synthesis of 2-(2- 氟-4-(4-Fluoro-4-(4- 異丁氧基-6-((4-Isobutoxy-6-((4- 甲氧基苄基)Methoxybenzyl) 氧基)oxygen) 吡啶-3-Pyridine-3- 基)base) 苯基)phenyl) 乙酸Acetic acid
將2-(2-氟-4-(4-異丁氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)苯基)乙酸甲酯(980 mg, 2.16 mmol)溶解在THF(15 mL)中，然後再將氫氧化鋰(182 mg, 4.33 mmol)水溶液加入反應體系中，混合物在60℃下攪拌反應4小時。反應完全後，減壓濃縮去除大部分有機相，加入稀鹽酸將體系pH調至7，析出白色固體，抽濾，水洗濾餅，烘乾，得到2-(2-氟-4-(4-異丁氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)苯基)乙酸670 mg。MS m/z(ESI)：440[M+H]+ 。Methyl 2-(2-fluoro-4-(4-isobutoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)phenyl)acetate (980 mg, 2.16 mmol) was dissolved in THF (15 mL), and then lithium hydroxide (182 mg, 4.33 mmol) aqueous solution was added to the reaction system, and the mixture was stirred and reacted at 60°C for 4 hours. After the reaction is complete, concentrate under reduced pressure to remove most of the organic phase, add dilute hydrochloric acid to adjust the pH of the system to 7, a white solid precipitates, filter with suction, wash the filter cake with water, and dry to obtain 2-(2-fluoro-4-(4- Isobutoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)phenyl)acetic acid 670 mg. MS m/z (ESI): 440 [M+H] + .
步驟6step 6 合成N -(2-(Synthesis of N -(2-( 二甲胺基)Dimethylamino) 乙基)-3-(2-(2-Ethyl)-3-(2-(2- 氟-4-(4-Fluoro-4-(4- 異丁氧基-6-((4-Isobutoxy-6-((4- 甲氧基苄基)Methoxybenzyl) 氧基)oxygen) 吡啶-3-Pyridine-3- 基)base) 苯基)phenyl) 乙醯胺基)-5 -(Acetylamino)-5 -( 五氟硫代)Pentafluorothio) 苯甲醯胺benzamide
將2-(2-氟-4-(4-異丁氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)苯基)乙酸(670 mg, 1.53 mmol)溶解到DMF 中，然後再加入HATU(638 mg, 1.68 mmol)、DMAP(19 mg, 0.153 mmol)、DIEA(636 mg, 4.58 mmol)、3-胺基-N -(2-(二甲基胺基)乙基)-5-(五氟硫代)苯甲醯胺(508 mg, 1.53 mmol)，混合物在室溫下反應過夜，反應完全後，加入水淬滅反應，然後再用EA(20 mL*2)萃取，有機相乾燥，旋乾，柱層析得到N -(2-(二甲胺基)乙基)-3-(2-(2-氟-4-(4-異丁氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)苯基)乙醯胺基)-5-(五氟硫代)苯甲醯胺380 mg。MS m/z(ESI)：755[M+H]+ 。2-(2-Fluoro-4-(4-isobutoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)phenyl)acetic acid (670 mg, 1.53 mmol) Dissolved in DMF, then added HATU (638 mg, 1.68 mmol), DMAP (19 mg, 0.153 mmol), DIEA (636 mg, 4.58 mmol), 3-amino- N- (2-(dimethylamine Base) ethyl)-5-(pentafluorothio)benzamide (508 mg, 1.53 mmol), the mixture was reacted overnight at room temperature, after the reaction was complete, the reaction was quenched by adding water, and then EA (20 mL*2) extraction, the organic phase was dried, spin-dried, and column chromatography gave N- (2-(dimethylamino)ethyl)-3-(2-(2-fluoro-4-(4-isobutoxy yl-6-((4-methoxybenzyl)oxy)pyridin-3-yl)phenyl)acetamido)-5-(pentafluorothio)benzamide 380 mg. MS m/z (ESI): 755 [M+H] + .
步驟7step 7 合成N -(2-(Synthesis of N -(2-( 二甲基胺基)Dimethylamino) 乙基)-3-(2-(2-Ethyl)-3-(2-(2- 氟-4-(4-Fluoro-4-(4- 異丁氧基-6-Isobutoxy-6- 氧代-1,6-Oxo-1,6- 二氫吡啶-3-Dihydropyridine-3- 基)base) 苯基)phenyl) 乙醯胺基)-5-(Acetylamino)-5-( 五氟硫代)Pentafluorothio) 苯甲醯胺benzamide
將N -(2-(二甲胺基)乙基)-3-(2-(2-氟-4-(4-異丁氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)苯基)乙醯胺基)-5-(五氟硫代)苯甲醯胺(380 mg, 0.504 mmol)溶解在DCM(10 mL)中，然後加入TFA(2 mL)，混合物室溫下攪拌反應2小時。反應完全後，濃縮反應液，再用碳酸鈉水溶液調至中性，DCM(20 mL*2)萃取，減壓濃縮去除有機相，柱層析得到N -(2-(二甲基胺基)乙基)-3-(2-(2-氟-4-(4-異丁氧基-6-氧代-1,6-二氫吡啶-3-基)苯基)乙醯胺基)-5-(五氟硫代)苯甲醯胺（化合物 10 ） 190 mg。MS m/z(ESI)：635[M+H]+ 。1 H NMR (400 MHz, DMSO-d 6 ) δ 11.39 (s, 1H), 10.86 (s, 1H), 8.79 (t,J = 5.7 Hz, 1H), 8.45 (t,J = 2.0 Hz, 1H), 8.26 (d,J = 1.6 Hz, 1H), 8.03 (t,J = 1.7 Hz, 1H), 7.42 – 7.34 (m, 2H), 7.28 – 7.21 (m, 2H), 5.81 (s, 1H), 3.80 (s, 2H), 3.77 (d,J = 6.3 Hz, 2H), 3.40 (q,J = 6.4 Hz, 4H), 2.24 (s, 6H), 1.97 (dt,J = 13.2, 6.6 Hz, 1H), 0.92 (d,J = 6.7 Hz, 6H). N- (2-(dimethylamino)ethyl)-3-(2-(2-fluoro-4-(4-isobutoxy-6-((4-methoxybenzyl)oxy )pyridin-3-yl)phenyl)acetamido)-5-(pentafluorothio)benzamide (380 mg, 0.504 mmol) was dissolved in DCM (10 mL), then TFA (2 mL ), the mixture was stirred and reacted at room temperature for 2 hours. After the reaction was complete, the reaction liquid was concentrated, adjusted to neutrality with aqueous sodium carbonate, extracted with DCM (20 mL*2), concentrated under reduced pressure to remove the organic phase, and obtained N- (2-(dimethylamino) Ethyl)-3-(2-(2-fluoro-4-(4-isobutoxy-6-oxo-1,6-dihydropyridin-3-yl)phenyl)acetamido)- 5-(Pentafluorothio)benzamide (compound 10 ) 190 mg. MS m/z (ESI): 635 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.39 (s, 1H), 10.86 (s, 1H), 8.79 (t, J = 5.7 Hz, 1H), 8.45 (t, J = 2.0 Hz, 1H) , 8.26 (d, J = 1.6 Hz, 1H), 8.03 (t, J = 1.7 Hz, 1H), 7.42 – 7.34 (m, 2H), 7.28 – 7.21 (m, 2H), 5.81 (s, 1H), 3.80 (s, 2H), 3.77 (d, J = 6.3 Hz, 2H), 3.40 (q, J = 6.4 Hz, 4H), 2.24 (s, 6H), 1.97 (dt, J = 13.2, 6.6 Hz, 1H ), 0.92 (d, J = 6.7 Hz, 6H).
實施例11N
-(2-( 二甲基胺基) 乙基)-3-(2-(4-(5- 乙氧基-6- 氧代-1,6- 二氫吡啶-3- 基)-2- 氟苯基) 乙醯胺基)-5-( 五氟硫代) 苯甲醯胺的合成 
步驟1step 1 合成化合物 5-Synthetic compound 5- 溴-2-Bromo-2- 氯-3-Chloro-3- 乙氧基吡啶Ethoxypyridine
將5-溴-2-氯吡啶-3-醇(1 g, 4.83 mmol)、碘乙烷(980 mg, 6.28 mmol)、碘化鉀(80 mg, 0.483 mmol)和碳酸鉀(1.33 g, 9.67 mmol)溶解在DMF(20 mL)中，混合液50℃反應過夜。反應完全後，將反應液倒入冰水中，用乙酸乙酯萃取，乾燥有機相，旋乾，柱層析得到5-溴-2-氯-3-乙氧基吡啶1.1 g。MS m/z(ESI)：236[M+H]+ 。5-Bromo-2-chloropyridin-3-ol (1 g, 4.83 mmol), ethyl iodide (980 mg, 6.28 mmol), potassium iodide (80 mg, 0.483 mmol) and potassium carbonate (1.33 g, 9.67 mmol) It was dissolved in DMF (20 mL), and the mixture was reacted overnight at 50°C. After the reaction was complete, the reaction solution was poured into ice water, extracted with ethyl acetate, and the organic phase was dried, spin-dried, and column chromatographed to obtain 1.1 g of 5-bromo-2-chloro-3-ethoxypyridine. MS m/z (ESI): 236 [M+H] + .
步驟2step 2 合成5-Synthetic 5- 溴-3-Bromo-3- 乙氧基-2-((4-Ethoxy-2-((4- 甲氧基苄基)Methoxybenzyl) 氧基)oxygen) 吡啶pyridine
將5-溴-2-氯-3-乙氧基吡啶(1.21 g, 5.12 mmol)、(4-甲氧基苯基)甲醇(848 mg, 6.14 mmol)、18-冠醚-6 (135 mg, 0.51 mmol)、氫氧化鉀(574 mg, 5.23 mmol)溶解在甲苯(15 mL)中，加熱至120℃反應5 h。反應完全後往體系中加水淬滅，EA萃取，合併有機相，乾燥有機相，旋乾，粗產品用EA/PE=1:3進行矽膠柱層析得到產物5-溴-3-乙氧基-2-((4-甲氧基苄基)氧基)吡啶1.26 g。MS m/z(ESI)：339.2 [M+H]+ 。5-Bromo-2-chloro-3-ethoxypyridine (1.21 g, 5.12 mmol), (4-methoxyphenyl)methanol (848 mg, 6.14 mmol), 18-crown-6 (135 mg , 0.51 mmol), potassium hydroxide (574 mg, 5.23 mmol) were dissolved in toluene (15 mL), heated to 120°C for 5 h. After the reaction is complete, add water to the system to quench, extract with EA, combine the organic phases, dry the organic phases, spin dry, and perform silica gel column chromatography on the crude product with EA/PE=1:3 to obtain the product 5-bromo-3-ethoxy - 2-((4-methoxybenzyl)oxy)pyridine 1.26 g. MS m/z (ESI): 339.2 [M+H] + .
步驟3step 3 合成2-(4-(5-Synthesis of 2-(4-(5- 乙氧基-6-(((4-Ethoxy-6-(((4- 甲氧基苄基)Methoxybenzyl) 氧基)oxygen) 吡啶-3-Pyridine-3- 基)-2-base)-2- 氟苯基)Fluorophenyl) 乙酸甲酯Methyl acetate
將5-溴-3-乙氧基-2-((4-甲氧基苄基)氧基)吡啶(1.26 g, 3.73 mmol)、2-(2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼雜環戊烷-2-基)苯基)乙酸甲酯(1.21 g, 4.10 mmol)、Pd(dppf)Cl2 (270 mg, 0.37 mmol)、Cs2 CO3 (2.43 g, 7.45 mmol)溶解在1,4-二氧六環/H2 O(40 mL, 3:1)的混合溶液中，加熱至85℃回流反應過夜。反應完全後加水淬滅，EA萃取，合併有機相，乾燥旋乾，粗產品用EA/PE=1:2進行矽膠柱層析得到產物2-(4-(5-乙氧基-6-(((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸甲酯1.34 g。MS m/z(ESI)：426.5 [M+H]+ 。5-Bromo-3-ethoxy-2-((4-methoxybenzyl)oxy)pyridine (1.26 g, 3.73 mmol), 2-(2-fluoro-4-(4,4,5 ,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid methyl ester (1.21 g, 4.10 mmol), Pd(dppf)Cl 2 (270 mg, 0.37 mmol), Cs 2 CO 3 (2.43 g, 7.45 mmol) were dissolved in a mixed solution of 1,4-dioxane/H 2 O (40 mL, 3:1), heated to 85°C and refluxed overnight. After the reaction is complete, add water to quench, extract with EA, combine the organic phases, dry and spin dry, and carry out silica gel column chromatography on the crude product with EA/PE=1:2 to obtain the product 2-(4-(5-ethoxy-6-( Methyl ((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetate 1.34 g. MS m/z (ESI): 426.5 [M+H] + .
步驟4step 4 合成2-(4-(5-Synthesis of 2-(4-(5- 乙氧基-6-(((4-Ethoxy-6-(((4- 甲氧基苄基)Methoxybenzyl) 氧基)oxygen) 吡啶-3-Pyridine-3- 基)-2-base)-2- 氟苯基)Fluorophenyl) 乙酸Acetic acid
將2-(4-(5-乙氧基-6-(((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸甲酯 (1.34 g, 3.15 mmol)、氫氧化鋰(260 mg, 6.30 mmol)溶解在MeOH/H2 O(20 mL, 3:1 )中，室溫反應2 h。監測反應完全後，將體系旋乾，加水洗滌，稀鹽酸調節pH至弱酸性，EA萃取。合併有機相，旋乾。粗產品用EA/PE=1:1進行矽膠柱層析，得到純品產物2-(4-(5-乙氧基-6-(((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸1.25 g。MS m/z(ESI)：412.4 [M+H]+ 。Methyl 2-(4-(5-ethoxy-6-(((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetate (1.34 g, 3.15 mmol), lithium hydroxide (260 mg, 6.30 mmol) were dissolved in MeOH/H 2 O (20 mL, 3:1 ), and reacted at room temperature for 2 h. After monitoring the completion of the reaction, the system was spin-dried, washed with water, diluted Adjust the pH to weak acidity with hydrochloric acid, and extract with EA. The organic phases are combined and spin-dried. The crude product is subjected to silica gel column chromatography with EA/PE=1:1 to obtain the pure product 2-(4-(5-ethoxy-6 -(((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid 1.25 g. MS m/z (ESI): 412.4 [M+H] + .
步驟5step 5 ：合成N -(2-(: Synthetic N -(2-( 二甲基胺基)Dimethylamino) 乙基)-3-(2-(4-(5-Ethyl)-3-(2-(4-(5- 乙氧基-6-((4-Ethoxy-6-((4- 甲氧基苄基)Methoxybenzyl) 氧基)oxygen) 吡啶-3-Pyridine-3- 基)-2-base)-2- 氟苯基)Fluorophenyl) 乙醯胺基)-5-(Acetylamino)-5-( 五氟硫代)Pentafluorothio) 苯甲醯胺benzamide
將2-(4-(5-乙氧基-6-(((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸(300 mg, 0.73 mmol)溶於乾燥的DMF(10 mL)中，加入HATU (305 mg, 0.8 mmol)、3-胺基-N -(2-(二甲基胺基)乙基)-5-(五氟硫代)苯甲醯胺 (243 mg, 0.73 mmol)、DMAP(9.0 mg, 0.07 mmol)，最後加入DIPEA (377 mg, 2.92 mmol)，室溫攪拌2h。監測反應完全後，將體系倒入冰水中，EA萃取，合併有機相，旋乾。粗產品用DCM/MeOH= 10:1進行矽膠柱層析，得到純產物N -(2-(二甲基胺基)乙基)-3-(2-(4-(5-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙醯胺基)-5-(五氟硫代)苯甲醯胺237 mg。MS m/z(ESI)：727.7 [M+H]+ 。2-(4-(5-Ethoxy-6-(((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (300 mg, 0.73 mmol) Dissolve in dry DMF (10 mL), add HATU (305 mg, 0.8 mmol), 3-amino- N- (2-(dimethylamino)ethyl)-5-(pentafluorothio) Benzamide (243 mg, 0.73 mmol), DMAP (9.0 mg, 0.07 mmol), and finally DIPEA (377 mg, 2.92 mmol) were added and stirred at room temperature for 2 h. After monitoring the completion of the reaction, the system was poured into ice water, EA Extraction, combined organic phase, spin-drying. Thick product carries out silica gel column chromatography with DCM/MeOH=10:1, obtains pure product N- (2-(dimethylamino) ethyl)-3-(2-( 4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)-5-(pentafluorothio ) benzamide 237 mg. MS m/z (ESI): 727.7 [M+H] + .
步驟6step 6 ：合成N -(2-(: Synthetic N -(2-( 二甲基胺基)Dimethylamino) 乙基)-3-(2-(4-(5-Ethyl)-3-(2-(4-(5- 乙氧基-6-Ethoxy-6- 氧代-1,6-Oxo-1,6- 二氫吡啶-3-Dihydropyridine-3- 基)-2-base)-2- 氟苯基)Fluorophenyl) 乙醯胺基)-5-(Acetylamino)-5-( 五氟硫代)Pentafluorothio) 苯甲醯胺benzamide
將N -(2-(二甲基胺基)乙基)-3-(2-(4-(5-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙醯胺基)-5-(五氟硫代)苯甲醯胺 (191 mg, 0.26 mmol)溶於DCM中，加入TFA(2 mL)，室溫反應30 min。TLC監測反應進程，反應完全後，將體系旋乾，加水，二氯甲烷萃取合併有機相，乾燥旋乾。粗產品用DCM/MeOH=10:1進行矽膠柱層析，得到純產物N -(2-(二甲基胺基)乙基)-3-(2-(4-(5-乙氧基-6-氧代-1,6-二氫吡啶-3-基)-2-氟苯基)乙醯胺基)-5-(五氟硫代)苯甲醯胺（化合物11 ） 22 mg。MS m/z(ESI)：607.6 [M+H]+ 。1 H NMR (500 MHz, DMSO) δ 11.84 (s, 1H), 10.83 (s, 1H), 8.81 (s, 1H), 8.43 (s, 1H), 8.25 (s, 1H), 8.01 (s, 1H), 7.47 (d,J = 12.0 Hz, 1H), 7.40 (d,J = 5.4 Hz, 1H), 7.36 (d,J = 9.0 Hz, 1H), 7.14 (d,J = 2.1 Hz, 1H), 4.03 (q,J = 7.0 Hz, 2H), 3.78 (s, 2H), 2.63 (m, 2H), 2.31 (s, 4H), 1.48-1.15 (m, 4H). N- (2-(dimethylamino)ethyl)-3-(2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridine-3 -yl)-2-fluorophenyl)acetamido)-5-(pentafluorothio)benzamide (191 mg, 0.26 mmol) was dissolved in DCM, TFA (2 mL) was added and reacted at room temperature 30 min. The reaction progress was monitored by TLC. After the reaction was complete, the system was spin-dried, water was added, and the combined organic phase was extracted with dichloromethane, dried and spin-dried. The crude product was subjected to silica gel column chromatography with DCM/MeOH=10:1 to obtain the pure product N- (2-(dimethylamino)ethyl)-3-(2-(4-(5-ethoxy- 6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamido)-5-(pentafluorothio)benzamide (compound 11 ) 22 mg. MS m/z (ESI): 607.6 [M+H] + . 1 H NMR (500 MHz, DMSO) δ 11.84 (s, 1H), 10.83 (s, 1H), 8.81 (s, 1H), 8.43 (s, 1H), 8.25 (s, 1H), 8.01 (s, 1H ), 7.47 (d, J = 12.0 Hz, 1H), 7.40 (d, J = 5.4 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 7.14 (d, J = 2.1 Hz, 1H), 4.03 (q, J = 7.0 Hz, 2H), 3.78 (s, 2H), 2.63 (m, 2H), 2.31 (s, 4H), 1.48-1.15 (m, 4H).
實施例12 (S
)-N
-(3-(3-( 二甲基胺基) 吡咯烷-1- 羰基)-5-( 五氟硫代) 苯基)-2-(4-(4- 乙氧基-6- 氧代-1,6- 二氫吡啶-3- 基)-2- 氟苯基) 乙醯胺的合成 
步驟1step 1 合成(S )-(3-(Synthesis of ( S )-(3-( 二甲基胺基)Dimethylamino) 吡咯烷-1-pyrrolidine-1- 基)(3-Base) (3- 硝基-5-(Nitro-5-( 五氟硫代)Pentafluorothio) 苯基)phenyl) 甲酮ketone
將3-硝基-5-(五氟硫代)苯甲酸(500 mg, 1.71 mmol)溶解在SOCl2 (5 mL)中，加入幾滴DMF，回流反應2小時。反應完全後旋乾反應液，將醯基氯溶於DCM(5 mL)中，將混合物滴加到三乙胺(517 mg, 5.12 mmol)和(S )-N ,N -二甲基吡咯烷基-3-胺(253 mg, 2.22 mmol)的DCM(5 mL)溶液中，在0℃下繼續反應半小時。反應完全後，加入水淬滅反應，分液，有機相濃縮，柱層析得到(S )-(3-(二甲基胺基)吡咯烷-1-基)(3-硝基-5-(五氟硫代)苯基)甲酮 470 mg。MS m/z(ESI)：390[M+H]+ 。Dissolve 3-nitro-5-(pentafluorothio)benzoic acid (500 mg, 1.71 mmol) in SOCl 2 (5 mL), add a few drops of DMF, and react under reflux for 2 hours. After the reaction was complete, the reaction solution was spin-dried, the acyl chloride was dissolved in DCM (5 mL), and the mixture was added dropwise to triethylamine (517 mg, 5.12 mmol) and ( S ) -N , N -dimethylpyrrolidine In a DCM (5 mL) solution of 3-yl-3-amine (253 mg, 2.22 mmol), the reaction was continued at 0°C for half an hour. After the reaction is complete, add water to quench the reaction, separate the layers, concentrate the organic phase, and obtain ( S )-(3-(dimethylamino)pyrrolidin-1-yl)(3-nitro-5- (Pentafluorothio)phenyl)methanone 470 mg. MS m/z (ESI): 390 [M+H] + .
步驟2step 2 合成(S )-(3-Synthesis of ( S )-(3- 胺基-5-(Amino-5-( 五氟硫代)Pentafluorothio) 苯基)(3-(Phenyl) (3-( 二甲胺基)Dimethylamino) 吡咯烷-1-pyrrolidine-1- 基)base) 甲酮ketone
將(S )-(3-(二甲基胺基)吡咯烷-1-基)(3-硝基-5-(五氟硫代)苯基)甲酮(470 mg, 1.23 mmol)、FeCl3 (20 mg, 0.12 mmol)、活性炭(100 mg)加入到乙醇(10 mL)中，向體系中緩慢加入水合肼(242 mg, 4.83 mmol)，混合物在80℃下攪拌反應過夜。監測反應完全後，冷卻，抽濾，反應液旋乾，柱層析得到(S )-(3-胺基-5-(五氟硫代)苯基)(3-(二甲胺基)吡咯烷-1-基)甲酮360 mg。MS m/z(ESI)：360[M+H]+ 。( S )-(3-(dimethylamino)pyrrolidin-1-yl)(3-nitro-5-(pentafluorothio)phenyl)methanone (470 mg, 1.23 mmol), FeCl 3 (20 mg, 0.12 mmol), activated carbon (100 mg) were added to ethanol (10 mL), and hydrazine hydrate (242 mg, 4.83 mmol) was slowly added to the system, and the mixture was stirred and reacted at 80°C overnight. After monitoring that the reaction is complete, cool, filter with suction, spin the reaction solution to dryness, and obtain ( S )-(3-amino-5-(pentafluorothio)phenyl)(3-(dimethylamino)pyrrole Alk-1-yl)methanone 360 mg. MS m/z (ESI): 360 [M+H] + .
步驟3step 3 合成(S )-N -(3-(3-(Synthesis ( S )- N -(3-(3-( 二甲基胺基)Dimethylamino) 吡咯烷-1-pyrrolidine-1- 羰基)-5-(Carbonyl)-5-( 五氟硫代)Pentafluorothio) 苯基)-2-(4-(4-Phenyl)-2-(4-(4- 乙氧基-6-((4-Ethoxy-6-((4- 甲氧基苄基)Methoxybenzyl) 氧基)oxygen) 吡啶-3-Pyridine-3- 基)-2-base)-2- 氟苯基)Fluorophenyl) 乙醯胺Acetamide
將2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸(412 mg, 1.003 mmol)溶解到DMF中，然後再加入HATU(419 mg, 1.103 mmol)、DMAP(12 mg, 0.100 mmol)、DIEA(388 mg, 3.008 mmol)、(S )-(3-胺基-5-(五氟硫代)苯基)(3-(二甲胺基)吡咯烷-1-基)甲酮(360 mg, 1.003 mmol)，混合物在室溫下反應過夜。反應完全後，加入水淬滅反應，然後再用EA(20 mL*2)萃取，有機相乾燥，旋乾，柱層析得到(S )-N -(3-(3-(二甲基胺基)吡咯烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙醯胺310 mg。MS m/z(ESI)：753[M+H]+ 。2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (412 mg, 1.003 mmol) was dissolved To DMF, then add HATU (419 mg, 1.103 mmol), DMAP (12 mg, 0.100 mmol), DIEA (388 mg, 3.008 mmol), ( S )-(3-Amino-5-(pentafluorosulfur Substitute) phenyl) (3-(dimethylamino) pyrrolidin-1-yl) ketone (360 mg, 1.003 mmol), the mixture was reacted overnight at room temperature. After the reaction was complete, water was added to quench the reaction, and then extracted with EA (20 mL*2), the organic phase was dried, spin-dried, and column chromatography gave ( S ) -N- (3-(3-(dimethylamine Base) pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridine -3-yl)-2-fluorophenyl)acetamide 310 mg. MS m/z (ESI): 753 [M+H] + .
步驟4step 4 合成(S )-N -(3-(3-(Synthesis ( S )- N -(3-(3-( 二甲基胺基)Dimethylamino) 吡咯烷-1-pyrrolidine-1- 羰基)-5-(Carbonyl)-5-( 五氟硫代)Pentafluorothio) 苯基)-2-(4-(4-Phenyl)-2-(4-(4- 乙氧基-6-Ethoxy-6- 氧代-1, 6-Oxo-1, 6- 二氫吡啶-3-Dihydropyridine-3- 基)-2-base)-2- 氟苯基)Fluorophenyl) 乙醯胺Acetamide
將(S )-N -(3-(3-(二甲基胺基)吡咯烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙醯胺(310 mg, 0.412 mmol)溶解在DCM(10 mL)中，然後加入TFA(2 mL)，混合物室溫下攪拌反應2小時。反應完全後，濃縮反應液，再用碳酸鈉水溶液調至中性，DCM(20 mL*2)萃取，有機相旋乾，柱層析得到(S )-N -(3-(3-(二甲基胺基)吡咯烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-氧代-1, 6-二氫吡啶-3-基)-2-氟苯基)乙醯胺（化合物 12 ） 170 mg。MS m/z(ESI)：633[M+H]+ 。1 H NMR (400 MHz, DMSO-d 6 ) δ 11.40 (s, 1H), 10.91 (s, 1H), 8.36 – 8.30 (m, 1H), 8.02 (d, J = 13.8 Hz, 1H), 7.69 (d, J = 2.6 Hz, 1H), 7.37 (d, J = 10.5 Hz, 2H), 7.29 – 7.21 (m, 2H), 5.82 (s, 1H), 4.05 (q, J = 6.9 Hz, 2H), 3.86 (d, J = 5.2 Hz, 1H), 3.81 (s, 2H), 3.56 – 3.46 (m, 4H), 2.63 (s, 3H), 2.46 (s, 3H), 2.20 (d, J = 13.1 Hz, 1H), 2.00 (s, 1H), 1.29 (t, J = 7.0 Hz, 3H).( S )-N-(3-(3-( dimethylamino )pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy Ethyl-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (310 mg, 0.412 mmol) was dissolved in DCM (10 mL), then TFA (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated, then adjusted to neutrality with aqueous sodium carbonate, extracted with DCM (20 mL*2), the organic phase was spin-dried, and column chromatography gave ( S ) -N- (3-(3-(di Methylamino)pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridine- 3-yl)-2-fluorophenyl)acetamide (compound 12 ) 170 mg. MS m/z (ESI): 633 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.40 (s, 1H), 10.91 (s, 1H), 8.36 – 8.30 (m, 1H), 8.02 (d, J = 13.8 Hz, 1H), 7.69 ( d, J = 2.6 Hz, 1H), 7.37 (d, J = 10.5 Hz, 2H), 7.29 – 7.21 (m, 2H), 5.82 (s, 1H), 4.05 (q, J = 6.9 Hz, 2H), 3.86 (d, J = 5.2 Hz, 1H), 3.81 (s, 2H), 3.56 – 3.46 (m, 4H), 2.63 (s, 3H), 2.46 (s, 3H), 2.20 (d, J = 13.1 Hz , 1H), 2.00 (s, 1H), 1.29 (t, J = 7.0 Hz, 3H).
實施例13 (R
)-N
-(3-(3-( 二甲基胺基) 吡咯烷-1- 羰基)-5-( 五氟硫代) 苯基)-2-(4-(4- 乙氧基-6- 氧代-1, 6- 二氫吡啶-3- 基)-2- 氟苯基) 乙醯胺的合成 
步驟1step 1 合成(R )-(3-(Synthesis of ( R )-(3-( 二甲基胺基)Dimethylamino) 吡咯烷-1-pyrrolidine-1- 基)(3-Base) (3- 硝基-5-(Nitro-5-( 五氟硫代)Pentafluorothio) 苯基)phenyl) 甲酮ketone
將3-硝基-5-(五氟硫代)苯甲酸(500 mg, 1.71 mmol)溶解在SOCl2 (5 mL)中，再加入幾滴DMF，回流反應2小時。反應完全後旋乾反應液，將醯基氯溶於DCM(5 mL)中，將混合物滴加到三乙胺(517 mg, 5.12 mmol)和(R )-N ,N -二甲基吡咯烷基-3-胺(253 mg, 2.22 mmol)的DCM(5 mL)溶液中，在0℃下繼續反應半小時。反應完全後，加入水淬滅反應，分液，有機相濃縮，柱層析得到(R )-(3-(二甲基胺基)吡咯烷-1-基)(3-硝基-5-(五氟硫代)苯基)甲酮 560 mg。MS m/z(ESI)：390[M+H]+ 。Dissolve 3-nitro-5-(pentafluorothio)benzoic acid (500 mg, 1.71 mmol) in SOCl 2 (5 mL), add a few drops of DMF, and react under reflux for 2 hours. After the reaction was complete, the reaction solution was spin-dried, the acyl chloride was dissolved in DCM (5 mL), and the mixture was added dropwise to triethylamine (517 mg, 5.12 mmol) and ( R ) -N , N -dimethylpyrrolidine In a DCM (5 mL) solution of 3-yl-3-amine (253 mg, 2.22 mmol), the reaction was continued at 0°C for half an hour. After the reaction is complete, add water to quench the reaction, separate the layers, concentrate the organic phase, and obtain ( R )-(3-(dimethylamino)pyrrolidin-1-yl)(3-nitro-5- (Pentafluorothio)phenyl)methanone 560 mg. MS m/z (ESI): 390 [M+H] + .
步驟2step 2 合成(R )-(3-Synthesis of ( R )-(3- 胺基-5-(Amino-5-( 五氟硫代)Pentafluorothio) 苯基)(3-(Phenyl) (3-( 二甲胺基)Dimethylamino) 吡咯烷-1-pyrrolidine-1- 基)base) 甲酮ketone
將(R )-(3-(二甲基胺基)吡咯烷-1-基)(3-硝基-5-(五氟硫代)苯基)甲酮(560 mg, 1.23 mmol)、FeCl3(23 mg, 0.14 mmol)、活性炭(100 mg)加入到乙醇(10 mL)中，然後再慢慢加入水合肼(288 mg, 5.76 mmol)，混合物在80℃下攪拌反應過夜，監測反應完全後，冷卻，抽濾，反應液旋乾，柱層析得到(R )-(3-胺基-5-(五氟硫代)苯基)(3-(二甲胺基)吡咯烷-1-基)甲酮420 mg。MS m/z(ESI)：360[M+H]+ 。( R )-(3-(dimethylamino)pyrrolidin-1-yl)(3-nitro-5-(pentafluorothio)phenyl)methanone (560 mg, 1.23 mmol), FeCl3 (23 mg, 0.14 mmol), activated carbon (100 mg) were added to ethanol (10 mL), and then hydrazine hydrate (288 mg, 5.76 mmol) was added slowly, and the mixture was stirred and reacted overnight at 80°C. After the reaction was completed, the , cooled, suction filtered, the reaction solution was spin-dried, and column chromatography gave ( R )-(3-amino-5-(pentafluorothio)phenyl)(3-(dimethylamino)pyrrolidine-1- base) Methanone 420 mg. MS m/z (ESI): 360 [M+H] + .
步驟3step 3 合成(R )-N -(3-(3-(Synthesis of ( R )- N -(3-(3-( 二甲基胺基)Dimethylamino) 吡咯烷-1-pyrrolidine-1- 羰基)-5-(Carbonyl)-5-( 五氟硫代)Pentafluorothio) 苯基)-2-(4-(4-Phenyl)-2-(4-(4- 乙氧基-6-((4-Ethoxy-6-((4- 甲氧基苄基)Methoxybenzyl) 氧基)oxygen) 吡啶-3-Pyridine-3- 基)-2-base)-2- 氟苯基)Fluorophenyl) 乙醯胺Acetamide
將2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸(481 mg, 1.17 mmol)溶解到DMF 中，然後再加入HATU(489 mg, 1.29 mmol)、DMAP(14 mg, 0.117 mmol)、DIEA(453 mg, 3.51 mmol)、(R )-(3-胺基-5-(五氟硫代)苯基)(3-(二甲胺基)吡咯烷-1-基)甲酮(420 mg, 1.17 mmol)，混合物在室溫下反應過夜。反應完全後，加入水淬滅反應，然後再用EA(20 mL*2)萃取，有機相乾燥，旋乾，柱層析得到(R )-N -(3-(3-(二甲基胺基)吡咯烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙醯胺350 mg。MS m/z(ESI)：753[M+H]+ 。2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (481 mg, 1.17 mmol) was dissolved To DMF, then add HATU (489 mg, 1.29 mmol), DMAP (14 mg, 0.117 mmol), DIEA (453 mg, 3.51 mmol), ( R )-(3-Amino-5-(pentafluorosulfur Substitute) phenyl) (3-(dimethylamino) pyrrolidin-1-yl) ketone (420 mg, 1.17 mmol), the mixture was reacted overnight at room temperature. After the reaction was complete, water was added to quench the reaction, and then extracted with EA (20 mL*2), the organic phase was dried, spin-dried, and column chromatography gave ( R )-N-(3-(3-( dimethylamine Base) pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridine -3-yl)-2-fluorophenyl)acetamide 350 mg. MS m/z (ESI): 753 [M+H] + .
步驟4step 4 合成(R )-N -(3-(3-(Synthesis of ( R )- N -(3-(3-( 二甲基胺基)Dimethylamino) 吡咯烷-1-pyrrolidine-1- 羰基)-5-(Carbonyl)-5-( 五氟硫代)Pentafluorothio) 苯基)-2-(4-(4-Phenyl)-2-(4-(4- 乙氧基-6-Ethoxy-6- 氧代-1,6-Oxo-1,6- 二氫吡啶-3-Dihydropyridine-3- 基)-2-base)-2- 氟苯基)Fluorophenyl) 乙醯胺Acetamide
將(R )-N -(3-(3-(二甲基胺基)吡咯烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙醯胺(350 mg, 0.465 mmol)溶解在DCM(10 mL)中，然後加入TFA(2 mL)，混合物室溫下攪拌反應2小時。反應完全後，濃縮反應液，再用碳酸鈉水溶液調至中性，DCM(20 mL*2)萃取，有機相旋乾，柱層析得到(R )-N -(3-(3-(二甲基胺基)吡咯烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-氧代-1,6-二氫吡啶-3-基)-2-氟苯基)乙醯胺（化合物 13 ） 200 mg。MS m/z(ESI)：633[M+H]+ 。1 H NMR (400 MHz, DMSO-d 6 ) δ 11.40 (s, 1H), 10.87 (s, 1H), 8.29 (t, J = 2.1 Hz, 1H), 8.04 (d, J = 13.0 Hz, 1H), 7.70 (s, 1H), 7.41 – 7.33 (m, 2H), 7.30 – 7.21 (m, 2H), 5.82 (s, 1H), 4.05 (q, J = 6.9 Hz, 2H), 3.95 – 3.86 (m, 1H), 3.80 (s, 2H), 3.73 – 3.47 (m, 4H), 2.75 (d, J = 50.1 Hz, 6H), 2.29 (s, 1H), 2.10 (t, J = 8.8 Hz, 1H), 1.29 (t, J = 6.9 Hz, 3H).( R )-N-(3-(3-( dimethylamino )pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy Dimethyl-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (350 mg, 0.465 mmol) was dissolved in DCM (10 mL), then TFA (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated, then adjusted to neutrality with aqueous sodium carbonate, extracted with DCM (20 mL*2), the organic phase was spin - dried, and column chromatography gave ( R )-N-(3-(3-(di Methylamino)pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridine- 3-yl)-2-fluorophenyl)acetamide (compound 13 ) 200 mg. MS m/z (ESI): 633 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.40 (s, 1H), 10.87 (s, 1H), 8.29 (t, J = 2.1 Hz, 1H), 8.04 (d, J = 13.0 Hz, 1H) , 7.70 (s, 1H), 7.41 – 7.33 (m, 2H), 7.30 – 7.21 (m, 2H), 5.82 (s, 1H), 4.05 (q, J = 6.9 Hz, 2H), 3.95 – 3.86 (m , 1H), 3.80 (s, 2H), 3.73 – 3.47 (m, 4H), 2.75 (d, J = 50.1 Hz, 6H), 2.29 (s, 1H), 2.10 (t, J = 8.8 Hz, 1H) , 1.29 (t, J = 6.9 Hz, 3H).
生物活性測試例1Biological Activity Test Example 1 ：:
(a)(a) 體外篩選實驗-HTRFIn vitro screening test-HTRF 方法檢測化合物對RETMethod for detection of compounds against RET 的抑制活性Inhibitory activity of
方法如下：
1. 1x激酶緩衝液的配製：5x酶緩衝液與蒸餾水以1：4混勻，終濃度是5 mM氯化鎂; 1 mM二硫蘇糖醇。
2. 用100%二甲基亞碸將測試化合物(5 mM儲液)稀釋5倍至1 mM，在384孔稀釋板中以1:3進行等比稀釋10個濃度。
3. 使用Echo 550移液系統將0.2 μL梯度稀釋的化合物加到384孔板中，每個濃度2個複孔，二甲基亞碸終濃度為0.5%(v/v)。測試化合物的梯度濃度為5000、1666.7、555.5、185.18、61.72、20.57、6.858、2.286、0.764、0.254 nM。
4. 用1x激酶緩衝液配製2x RET(0.1 ng/μL)。
5. 在384孔板加入5 μL的2x RET，1000 g離心30 s，室溫孵育10 min。
6. 用1x激酶緩衝液配製2x酪胺酸激酶-生物素標記的底物(2 μM)和腺嘌呤核苷三磷酸(20 μM)混合液。
7. 加入5 μL酪胺酸激酶-生物素標記的底物和腺嘌呤核苷三磷酸混合液以啟動反應。1000 g離心30 s，封板，室溫孵育30 min。
8. 用均相時間分辨螢光技術檢測緩衝液配製2x Sa-XL 665(註：一種試劑)(125 μM)和酪胺酸激酶-抗體-穴狀化合物混合液。
9. 每孔加入10 μL Sa-XL 665和酪胺酸激酶-抗體-穴狀化合物混合液，1000 g離心30 s，室溫孵育1 h。
10. Envision 2104酶標儀615 nm和665 nm讀板，計算比率 (665/615 nm)。
11. 抑制率計算如下：
（b(b ）體外篩選實驗-HTRF) in vitro screening test - HTRF 方法method 檢測化合物抑制VEGFR2Test compounds inhibit VEGFR2 活性測試activity test
實驗步驟：
1. 1x激酶緩衝液配製：5x酶緩衝液與蒸餾水以1：4混勻，終濃度是5 mM 氯化鎂; 1 mM二硫蘇糖醇;1 mM氯化錳。
2. 用100%二甲基亞碸將測試化合物(5 mM儲液)稀釋5倍至1 mM，在384孔稀釋板中以1:3進行等比稀釋10個濃度。
3. 使用Echo 550移液系統將0.2 μL梯度稀釋的化合物加到384孔細胞培養板(Corning，3570)中，每個濃度2個複孔，二甲基亞碸終濃度為0.5%(v/v)。測試化合物的梯度濃度為5000、1666.7、555.5、185.18、61.72、20.57、6.858、2.286、0.764、0.254 nM。
4. 用1x激酶緩衝液配製2x VEGFR2(0.02 ng/μL)。
5. 在384孔板加入5 μL的2x VEGFR2，1000 g離心30 s，室溫孵育10 min。
6. 用1x激酶緩衝液配製2x酪胺酸激酶-生物素標記的底物(2 μM)和ATP(8 μM)混合液。
7. 加入5 μL酪胺酸激酶-生物素標記的底物和腺嘌呤核苷三磷酸混合液以啟動反應。1000 g離心30 s，封板，室溫孵育40 min。
8. 用均相時間分辨螢光技術檢測緩衝液配製2x Sa-XL 665(125 μM)和酪胺酸激酶-抗體-穴狀化合物混合液。
9. 每孔加入10μL Sa-XL 665和酪胺酸激酶-抗體-穴狀化合物混合液，1000 g離心30 s，室溫孵育1 h。
10. Envision 2104酶標儀615 nm和665 nm讀板，計算比率(665/615nm)。
11. 抑制率計算如下:
（c(c ）體外篩選實驗-CellTiter-Glo) In vitro screening experiment-CellTiter-Glo 發光法檢測化合物抑制Ba/F3-KIF5B-RETLuminescence Detection of Compounds Inhibiting Ba/F3-KIF5B-RET 細胞活力測試Cell Viability Test
實驗步驟： 1. 利用Neon®轉染系統方法將包含人源KIF5B-RET cDNA的哺乳動物細胞表達載體導入Ba/F3細胞，經嘌呤黴素篩選過後存活的選殖株進行細胞生長抑制功能實驗和蛋白免疫印跡法驗證RET穩定高表達的細胞系。 2. 細胞培養於RPMI 1640培養液、10%胎牛血清、1%青黴素-鏈黴素、2 μg/mL嘌呤黴素的培養基中，置於37℃、5%二氧化碳細胞培養箱中培養。 3. 用100%二甲基亞碸將測試化合物(5 mM儲液)稀釋2.5倍至2 mM，在384孔稀釋板中以1:3進行等比稀釋10個濃度。 4. 使用Echo 550移液系統將0.2μL梯度稀釋的化合物加到384孔細胞培養板(Corning，3570)中，每個濃度2個複孔，二甲基亞碸終濃度為0.5%(v/v)。測試化合物的梯度濃度為5000、1666.7、555.5、185.18、61.72、20.57、6.858、2.286、0.764、0.254 nM。 5. 每孔加入40 μL含800個Ba/F3-KIF5B-RET細胞懸液，於5%二氧化碳細胞培養箱培養72 h。 6. 按每孔20 μL Cell Titer-Glo試劑加入細胞培養板，震盪混勻2 min以裂解細胞，然後室溫孵育30 min，用Envision 2104酶標儀讀取螢光訊號值。 7. 數據由XLfit 5.0按4參數公式： Y=Bottom+(Top-Bottom)/(1+10^((LogIC50 -X)*HillSlope))擬合計算IC50 值。Experimental steps: 1. Using the Neon® transfection system method, the mammalian cell expression vector containing human KIF5B-RET cDNA was introduced into Ba/F3 cells, and the surviving clones were selected by puromycin for cell growth inhibition function experiments and The cell lines with stable and high expression of RET were verified by western blotting. 2. Cells were cultured in RPMI 1640 culture medium, 10% fetal bovine serum, 1% penicillin-streptomycin, 2 μg/mL puromycin, and cultured in a 37°C, 5% carbon dioxide cell incubator. 3. Dilute the test compound (5 mM stock solution) 2.5-fold to 2 mM with 100% dimethylsulfoxide, and dilute 10 concentrations at 1:3 in a 384-well dilution plate. 4. Use the Echo 550 pipetting system to add 0.2 μL of the serially diluted compound to a 384-well cell culture plate (Corning, 3570), with 2 duplicate wells for each concentration, and the final concentration of dimethylsulfoxide is 0.5% (v/ v). The gradient concentrations of test compounds were 5000, 1666.7, 555.5, 185.18, 61.72, 20.57, 6.858, 2.286, 0.764, 0.254 nM. 5. Add 40 μL of 800 Ba/F3-KIF5B-RET cell suspension to each well and incubate in a 5% carbon dioxide incubator for 72 h. 6. Add 20 μL of Cell Titer-Glo reagent per well to the cell culture plate, shake and mix for 2 minutes to lyse the cells, then incubate at room temperature for 30 minutes, and read the fluorescence signal value with an Envision 2104 microplate reader. 7. The data were fitted by XLfit 5.0 according to the 4-parameter formula: Y=Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)*HillSlope)) to calculate the IC 50 value.
（d(d ）體外篩選實驗-CellTiter-Glo) In vitro screening experiment-CellTiter-Glo 發光法檢測化合物抑制TTLuminescent detection of compounds that inhibit TT （人甲狀腺髓樣癌細胞）細胞活力(Human Medullary Thyroid Cancer Cell) Cell Viability
實驗步驟： 1. 細胞培養於384孔細胞培養板(Corning, 3570)中，含F12K培養基、20%胎牛血清、1%青黴素-鏈黴素的培養基中，置於37℃、5% CO2 細胞培養箱中培養過夜。 2. 用100% DMSO將測試化合物（5 mM儲液）稀釋2.5倍至2 mM，在384孔稀釋板中以1:3進行等比稀釋10個濃度。 3. 使用Echo 550將0.2 μL梯度稀釋的化合物加到384孔細胞，每個濃度2個複孔，DMSO終濃度為0.5%（v/v）。測試化合物的梯度濃度為1000，333.33，111.11，37.04，12.35，4.12，1.37，0.46，0.15，0.05 nM。於5%二氧化碳細胞培養箱培養72 h。 4. 按每孔30 μL Cell Titer-Glo Reagent加入細胞培養板，震盪混勻2 min以裂解細胞，然後室溫避光孵育30 min，用Envision 2104讀取luminescence訊號值。 5. 數據由XLfit 5.0按4參數公式：Y=Bottom+(Top-Bottom)/(1+10^((LogIC50 -X)*HillSlope))擬合計算IC50 值。Experimental steps: 1. Cells were cultured in a 384-well cell culture plate (Corning, 3570) in a medium containing F12K medium, 20% fetal bovine serum, and 1% penicillin-streptomycin at 37°C and 5% CO 2 Incubate overnight in the cell culture incubator. 2. Dilute the test compound (5 mM stock solution) 2.5 times to 2 mM with 100% DMSO, and dilute 10 concentrations at 1:3 in a 384-well dilution plate. 3. Use Echo 550 to add 0.2 μL of serially diluted compounds to 384-well cells, with 2 replicate wells for each concentration, and the final concentration of DMSO is 0.5% (v/v). The gradient concentrations of test compounds were 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0.05 nM. Cultured in a 5% carbon dioxide incubator for 72 h. 4. Add 30 μL Cell Titer-Glo Reagent to each well of the cell culture plate, shake and mix for 2 minutes to lyse the cells, then incubate at room temperature in the dark for 30 minutes, and use Envision 2104 to read the luminescence signal value. 5. The data were fitted by XLfit 5.0 according to the 4-parameter formula: Y=Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)*HillSlope)) to calculate the IC 50 value.
測試結果如表1所示
【表1】
(e)(e) 體外篩選實驗-HTRFIn vitro screening test-HTRF 方法檢測化合物對TRKMethod to detect compounds against TRK 的抑制活性Inhibitory activity of
方法如下：
1. 1x激酶緩衝液的配製：5x酶緩衝液與蒸餾水以1：4混勻，終濃度是5 mM氯化鎂; 1 mM二硫蘇糖醇。
2. 用100%二甲基亞碸將測試化合物(5 mM儲液)稀釋5倍至1 mM，在384孔稀釋板中以1:3進行等比稀釋10個濃度。
3. 使用Echo 550移液系統將0.2 μL梯度稀釋的化合物加到384孔板中，每個濃度2個複孔，二甲基亞碸終濃度為0.5%(v/v)。測試化合物的梯度濃度為5000、1666.7、555.5、185.18、61.72、20.57、6.858、2.286、0.764、0.254 nM。
4. 用1x激酶緩衝液配製2x TRK A/TRK B/TRK C/TRK A G595R/TRK A G667C。
5. 在384孔板加入5 μL的2x TRK A/TRK B/TRK C/TRK A G595R/TRK A G667C，1000 g離心30 s，室溫孵育10 min。
6. 用1x激酶緩衝液配製2x蘇胺酸蛋白磷酸酶-生物素標記的底物和腺嘌呤核苷三磷酸混合液。
7. 加入5 μL酪胺酸激酶-生物素標記的底物和腺嘌呤核苷三磷酸混合液以啟動反應。1000 g離心30 s，封板，室溫孵育40 min。
8. 用均相時間分辨螢光技術檢測緩衝液配製4x Sa-XL 665(註：一種試劑)和酪胺酸激酶-抗體-穴狀化合物混合液。
9. 每孔加入5 μL Sa-XL 665和5 μL蘇胺酸蛋白磷酸酶-抗體-穴狀化合物混合液，1000 g離心30 s，室溫孵育1 h。
10. Envision 2104酶標儀615 nm和665 nm讀板，計算比率 (665/615 nm)。
11. 抑制率計算如下：
測試結果如表2所示:
【表2】
從上述數據可以看出，本發明所列舉的化合物對Trk A, Trk B, Trk C,及其部分突變株具有良好的抑制活性。It can be seen from the above data that the compounds listed in the present invention have good inhibitory activity on Trk A, Trk B, Trk C, and some mutants thereof.
（f(f ）體內藥效評估-) In vivo efficacy evaluation- 化合物在遙測腸易激綜合症(IBS)Compounds in Telemetry for Irritable Bowel Syndrome (IBS) 模型中的效果effect in the model
實驗動物：正常SD大鼠，280-350 g；Experimental animals: normal SD rats, 280-350 g;
受測化合物：化合物1（10 mg/kg）、BOS-589（10 mg/kg）；Tested compounds: Compound 1 (10 mg/kg), BOS-589 (10 mg/kg);
實驗步驟： 1. 50 mg/kg戊巴比妥鈉麻醉動物，腹外斜肌埋置DSI遙測植入子，記錄EMG訊號； 2. 定義給藥當天為實驗第1天（D1），D1-D3，每天灌胃給藥2次；D3.5，上午給藥及直腸給予醋酸刺激1小時後進行直腸擴張實驗，氣囊壓力設置為60 mmHg，記錄EMG訊號，檢測持續10分鐘。Experimental steps: 1. Animals were anesthetized with 50 mg/kg pentobarbital sodium, and DSI telemetry implants were embedded in the external oblique muscle to record EMG signals; 2. Define the day of administration as the first day of the experiment (D1), D1-D3, intragastric administration twice a day; D3.5, rectal dilation test after administration in the morning and acetic acid stimulation in the rectum for 1 hour, and the balloon pressure setting When the temperature is 60 mmHg, the EMG signal is recorded and the detection lasts for 10 minutes.
數據分析：原始數據由DSI系統Ponemah軟體採集，用NeuroScore軟體和Spike2分析。計算所記錄EMG訊號的，每個壓力值統計10分鐘。實驗數據由平均值（Mean）表示，採用t-檢驗進行統計分析，p ＜ 0.05表示有統計學意義，p ＜ 0.01表示有顯著性差異，p ＜ 0.001表示有極顯著性差異。Data analysis: The original data were collected by the DSI system Ponemah software, and analyzed by NeuroScore software and Spike2. For calculating the recorded EMG signal, each pressure value is counted for 10 minutes. The experimental data is represented by the mean value (Mean), and the t-test is used for statistical analysis. P < 0.05 indicates statistical significance, p < 0.01 indicates significant difference, and p < 0.001 indicates extremely significant difference.
實驗結果：
本實驗結果表明，在給藥後進行直腸擴張實驗，化合物1（10 mg/kg）組腹外斜肌EMG訊號burst number均顯著減少。說明化合物1對醋酸誘導的大鼠內臟敏感模型有一定療效，且同劑量下化合物1的治療效果比BOS-589更顯著。The results of this experiment showed that the EMG signal burst number of the external oblique muscle in the compound 1 (10 mg/kg) group was significantly reduced in the rectal dilation test after administration. It shows that compound 1 has a certain curative effect on the acetic acid-induced visceral sensitivity model in rats, and the therapeutic effect of compound 1 at the same dose is more significant than that of BOS-589.
BOS 589的結構如下：
LOXO-195的結構如下：
GSK-3179106的結構如下：
綜上，本發明的化合物具有較好的RET激酶抑制活性和TRK激酶抑制活性；發明人通過研究也意外的發現BOS 589、GSK-3179106同樣具備一定的TRK激酶抑制活性。In summary, the compounds of the present invention have good RET kinase inhibitory activity and TRK kinase inhibitory activity; the inventors also unexpectedly found that BOS 589 and GSK-3179106 also have certain TRK kinase inhibitory activity through research.
與化合物BOS 589相比，本發明的化合物的Ba/F3-KIF5B-RET細胞活性提高6倍，TT細胞活性提升12倍；與LOXO-195相比，本發明的化合物對於突變型TRK激酶（如TRK A G595R/TRK A G667C）有更強的抑制活性；本發明的化合物在IBS模型（醋酸誘導的腸超敏模型）中的治療效果顯著優於相同劑量的BOS-589（部分化合物的實驗結果未示出）。本發明請求保護的化合物的上述意料不到的技術效果，發明人推測可能原因是化合物中的五氟化硫官能團使其具有獨特的物理化學性質與三維空間結構，能更好的結合RET/TRK蛋白的相應口袋，使得本發明化合物的具有更好的RET/TRK激酶抑制活性。Compared with compound BOS 589, the Ba/F3-KIF5B-RET cell activity of the compound of the present invention increases 6 times, and the TT cell activity improves 12 times; TRK A G595R/TRK A G667C) has stronger inhibitory activity; the therapeutic effect of the compound of the present invention in the IBS model (acetic acid-induced intestinal hypersensitivity model) is significantly better than the same dose of BOS-589 (experimental results of some compounds not shown). The inventor speculates that the possible reason for the unexpected technical effect of the compound claimed in the present invention is that the sulfur pentafluoride functional group in the compound makes it have unique physical and chemical properties and three-dimensional space structure, which can better combine RET/TRK The corresponding pocket of the protein makes the compound of the present invention have better RET/TRK kinase inhibitory activity.
在本發明提及的所有文獻都在本申請中引用作為參考，就如同每一篇文獻被單獨引用作為參考那樣。此外應理解，在閱讀了本發明的上述講授內容之後，本領域技術人員可以對本發明作各種改動或修改，這些等價形式同樣落於本申請所附申請專利範圍所限定的範圍。All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended patent scope of the present application.
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| CN105051027A (en) * | 2013-03-15 | 2015-11-11 | 葛兰素史密斯克莱知识产权发展有限公司 | Pyridine derivatives as rearranged during transfection (RET) kinase inhibitors |
| CN107074768A (en) * | 2014-09-10 | 2017-08-18 | 葛兰素史克知识产权发展有限公司 | The Pyridione derivatives of (RET) kinase inhibitor are reset as transfection |
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| US20110034461A1 (en) * | 2008-02-05 | 2011-02-10 | Sanofi-Aventis | Sf5 derivatives as par1 inhibitors, production thereof, and use as medicaments |
| CN105051027A (en) * | 2013-03-15 | 2015-11-11 | 葛兰素史密斯克莱知识产权发展有限公司 | Pyridine derivatives as rearranged during transfection (RET) kinase inhibitors |
| CN107074768A (en) * | 2014-09-10 | 2017-08-18 | 葛兰素史克知识产权发展有限公司 | The Pyridione derivatives of (RET) kinase inhibitor are reset as transfection |
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