TWI768781B - TRANSFORMING GROWTH FACTOR-β RECEPTOR INHIBITOR - Google Patents

TRANSFORMING GROWTH FACTOR-β RECEPTOR INHIBITOR Download PDF

Info

Publication number
TWI768781B
TWI768781B TW110110282A TW110110282A TWI768781B TW I768781 B TWI768781 B TW I768781B TW 110110282 A TW110110282 A TW 110110282A TW 110110282 A TW110110282 A TW 110110282A TW I768781 B TWI768781 B TW I768781B
Authority
TW
Taiwan
Prior art keywords
cancer
alkyl
compound
halogenated
cycloalkyl
Prior art date
Application number
TW110110282A
Other languages
Chinese (zh)
Other versions
TW202144347A (en
Inventor
俞智勇
李剛
王坤瑤
邱慶崇
季彬
孫釗
Original Assignee
大陸商杭州阿諾生物醫藥科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 大陸商杭州阿諾生物醫藥科技有限公司 filed Critical 大陸商杭州阿諾生物醫藥科技有限公司
Publication of TW202144347A publication Critical patent/TW202144347A/en
Application granted granted Critical
Publication of TWI768781B publication Critical patent/TWI768781B/en

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/4353Heterocyclic 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 ortho- or peri-condensed with heterocyclic ring systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • A61P37/06Immunosuppressants, e.g. drugs for graft rejection
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Epidemiology (AREA)
  • Transplantation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

The present invention provides a compound of formula (I) and a pharmaceutical composition thereof. The compound of formula (I) of the present invention can be used as TGF-β receptor inhibitors, especially TGFβRI inhibitors, and can be used to prevent or treat, for example, various related diseases mediated by TGFβRI (ALK5).

Description

轉化生長因子-β受體抑制劑 Transforming growth factor-beta receptor inhibitor

本發明提供了一類新型雜環化合物,其製備方法及其作為TGF-β受體(特別是TGFβRI)拮抗劑的應用。 The present invention provides a new type of heterocyclic compound, its preparation method and its application as a TGF-beta receptor (especially TGFbetaRI) antagonist.

轉化生長因子-β(transforming growth factor-β,TGF-β)是一種多功能的生長因子和細胞因子,與活化素(activins)、抑制素(inhibins)、繆勒氏管抑制質(Mullerian inhibitor substance,MIS)和骨形成蛋白(bone morpho-genetic proteins,BMPs)等多種相關蛋白組成轉化生長因子-β超家族。它能夠參與調節多種生物過程,包括細胞的增殖、分化、發育以及細胞外基質的修飾(包括腫瘤基質和免疫抑制、血管生成和纖維組織生成)。 Transforming growth factor-β (TGF-β) is a multifunctional growth factor and cytokine, which is closely related to activins, inhibins, and Mullerian inhibitor substances. , MIS) and bone morpho-genetic proteins (BMPs) and other related proteins constitute the transforming growth factor-β superfamily. It is involved in the regulation of a variety of biological processes, including cell proliferation, differentiation, development, and modification of the extracellular matrix (including tumor stroma and immunosuppression, angiogenesis, and fibrogenesis).

TGF-β主要有三種細胞受體,分別是I型(TGFβRI)、II型(TGFβRII)和III型(TGFβRIII)。TGF-β信號通路中的信號傳導主要是通過TGF-β配體與細胞表面的絲氨酸/蘇氨酸激酶受體TGFβRI(ALK5)和TGFβRII結合形成一個異源四聚體複合物,然後TGFβRII對TGFβRI的甘氨酸/絲氨酸區域(GS region)進行磷酸化並啟動TGFβRI磷酸化與其連接的細胞內信號傳導蛋白Smad蛋白分子──Smad2/Smad3。磷酸化的Smad2和Smad3蛋白與Smad4結合形成的複合物轉移到細胞核,結合不同的轉錄因子和轉錄共啟動劑或共抑制劑,來調節靶基因的轉錄,引起各種各樣的轉錄反應,從而導致基因表達的改變。而轉化生長因子-β III型受體(TGFβRIII)則本身不能傳遞信號,但它能通過結合TGF-β並將其 傳遞給TGFβRII來增強TGF-β配體與TGF-βII型受體的結合,從而間接的影響信號的傳導。在生物體內,細胞因子、生長因子、微環境條件、激素、磷酸化和去磷酸化激酶等都能影響和控制TGF-β信號通路中的信號傳導。 There are three main cellular receptors for TGF-β, namely type I (TGFβRI), type II (TGFβRII) and type III (TGFβRIII). Signal transduction in the TGF-β signaling pathway is mainly through the binding of TGF-β ligands to the serine/threonine kinase receptors TGFβRI (ALK5) and TGFβRII on the cell surface to form a heterotetrameric complex, and then TGFβRII interacts with TGFβRI. The glycine/serine region (GS region) of TGFβRI phosphorylates and initiates the phosphorylation of TGFβRI to the intracellular signaling protein Smad protein molecule - Smad2/Smad3. The complexes formed by phosphorylated Smad2 and Smad3 proteins combined with Smad4 are translocated to the nucleus, where they bind to different transcription factors and transcriptional co-initiators or co-repressors to regulate the transcription of target genes and cause a variety of transcriptional responses, resulting in Changes in gene expression. The transforming growth factor-β type III receptor (TGFβRIII) itself cannot transmit signals, but it can bind TGF-β and Delivered to TGFβRII to enhance the binding of TGF-β ligands to TGF-β type II receptors, thereby indirectly affecting signal transduction. In vivo, cytokines, growth factors, microenvironmental conditions, hormones, phosphorylation and dephosphorylation kinases, etc. can all affect and control the signal transduction in the TGF-β signaling pathway.

研究表明,TGF-β在心、肝、肺、腎等不同器官系統纖維化的發生和進展中起著關鍵作用。異常的TGF-β信號和許多人類疾病有關,比如癌症、心血管疾病、炎症、器官纖維化疾病、胰腺疾病等。在人的腫瘤中,TGF-β信號的失調很常見,能促進腫瘤細胞生長和分化、調節細胞外基質和上皮間質轉換。目前,隨著腫瘤免疫療法研究的不斷深入,TGF-β已經被證實對調節抗腫瘤免疫有重要作用。TGF-β對T淋巴細胞的分化有很強的抑制作用,對樹狀細胞、CD8+T細胞和NK細胞有明顯的負影響,同時它能增強免疫抑制Treg和骨髓源性抑制細胞(Myeloid-derived suppressor cells,MDSC)的活性,從而為腫瘤生長和轉移提供有利的腫瘤微環境。因此,抑制TGF-β信號通路中某個環節的信號傳導有可能成為治療腫瘤的有效方法之一。 Studies have shown that TGF-β plays a key role in the occurrence and progression of fibrosis in different organ systems such as the heart, liver, lung, and kidney. Aberrant TGF-β signaling has been implicated in many human diseases, such as cancer, cardiovascular disease, inflammation, organ fibrosis, and pancreatic disease. Dysregulation of TGF-β signaling is common in human tumors, promoting tumor cell growth and differentiation, and regulating the extracellular matrix and epithelial-mesenchymal transition. At present, with the deepening of tumor immunotherapy research, TGF-β has been confirmed to play an important role in regulating anti-tumor immunity. TGF-β has a strong inhibitory effect on the differentiation of T lymphocytes, and has a significant negative effect on dendritic cells, CD8 + T cells and NK cells, and it can enhance immunosuppressive T reg and myeloid-derived suppressor cells (Myeloid cells). -derived suppressor cells, MDSCs), thereby providing a favorable tumor microenvironment for tumor growth and metastasis. Therefore, inhibiting the signal transduction of a certain link in the TGF-β signaling pathway may become one of the effective methods for the treatment of tumors.

TGFβRI(ALK5)作為TGF-β信號通路中的一個重要節點被認為是治療腫瘤的一個重要靶點,通過阻止TGFβRI與配體的結合,來抑制ALK5對其下游信號蛋白(Smad2或Smad3)的磷酸化,從而影響或者阻斷TGF-β信號的傳導,以實現預防和治療各種由ALK5介導的相關疾病。 TGFβRI (ALK5), as an important node in the TGF-β signaling pathway, is considered to be an important target for tumor therapy. By preventing the binding of TGFβRI to ligands, it inhibits the phosphorylation of ALK5 to its downstream signaling proteins (Smad2 or Smad3). Therefore, it can affect or block the transduction of TGF-β signaling to achieve the prevention and treatment of various related diseases mediated by ALK5.

目前,國際專利申請公開號WO2000/061576、WO2002/066462、WO2004/111036、WO2004/048382、WO2009/087224、WO2009/013335、WO2012/002680、WO2016/057278、WO2017/015425、WO2017/215506、WO2018/017633等和中國專利申請公開號CN107663206A等公開了用作TGF-β受體拮抗劑的化合物。然而,仍需要對TGF-β受體,尤其是對TGFβRI(ALK5)具有更好抑制效果 的抑制劑;特別地,能夠選擇性抑制ALK5的拮抗劑具有重要的臨床價值和治療意義,但是目前對其報導很少。現有技術中迫切需要具有更好抑制效果的ALK5抑制劑,特別是能夠選擇性抑制ALK5的新型拮抗劑化合物。 目前,國際專利申請公開號WO2000/061576、WO2002/066462、WO2004/111036、WO2004/048382、WO2009/087224、WO2009/013335、WO2012/002680、WO2016/057278、WO2017/015425、WO2017/215506、WO2018/017633 et al. and Chinese Patent Application Publication No. CN107663206A et al. disclose compounds useful as TGF-beta receptor antagonists. However, there is still a need for better inhibitory effects on TGF-β receptors, especially TGFβRI (ALK5) In particular, antagonists that can selectively inhibit ALK5 have important clinical value and therapeutic significance, but there are few reports on them. In the prior art, there is an urgent need for ALK5 inhibitors with better inhibitory effect, especially novel antagonist compounds capable of selectively inhibiting ALK5.

經過長期而深入的研究,我們意外地發現了一類具有良好的ALK5抑制活性的雜環化合物。 After long-term and in-depth research, we unexpectedly discovered a class of heterocyclic compounds with good ALK5 inhibitory activity.

基於上述發現,在本發明的第一個方面,提供了式(I)化合物或其藥學上可接受的鹽、前藥、同位素衍生物、異構體、溶劑化物、或其代謝產物, Based on the above findings, in a first aspect of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt, prodrug, isotopic derivative, isomer, solvate, or metabolite thereof,

Figure 110110282-A0202-12-0003-4
Figure 110110282-A0202-12-0003-4

其中: in:

Cy表示被0、1、2或3個取代基所取代的C6-C10芳基或者5-10元雜芳基,其中所述的取代基選自:鹵素、C1-C6烷基、C3-C6環烷基、鹵代C1-C6烷基、-ORa、氰基、硝基、NRaRb、-SO2Ra、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-P(O)RaRbCy represents a C 6 -C 10 aryl group or a 5-10-membered heteroaryl group substituted by 0, 1, 2 or 3 substituents, wherein the substituents are selected from: halogen, C 1 -C 6 alkyl , C 3 -C 6 cycloalkyl, halogenated C 1 -C 6 alkyl, -OR a , cyano, nitro, NR a R b , -SO 2 R a , -C(O)R a , - C(O)OR a , -C(O)NR a R b , -P(O)R a R b ;

R1表示氫、鹵素、C1-C6烷基、C3-C6環烷基、羥基(C1-C6烷基)、鹵代C1-C6烷基; R 1 represents hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, hydroxy (C 1 -C 6 alkyl), halogenated C 1 -C 6 alkyl;

R2表示氫、C1-C6烷基、C3-C6環烷基、羥基(C1-C6烷基)、鹵代C1-C6烷基、-ORa、氰基、硝基、NRaRb、-SO2Ra、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Rb、-SO2NRaRb、-NRaSO2RbR 2 represents hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, hydroxy (C 1 -C 6 alkyl), halogenated C 1 -C 6 alkyl, -OR a , cyano, Nitro, NR a R b , -SO 2 R a , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R b , -SO 2 NR a R b , -NR a SO 2 R b ;

R3表示氫、鹵素、C1-C6烷基、C3-C6環烷基、羥基 (C1-C6烷基)、鹵代C1-C6烷基、-ORa、氰基、硝基、NRaRb、-SO2Ra、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Rb、-SO2NRaRb、-NRaSO2RbR 3 represents hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, hydroxy (C 1 -C 6 alkyl), halogenated C 1 -C 6 alkyl, -OR a , cyano group, nitro, NR a R b , -SO 2 R a , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R b , -SO 2 NR a R b , -NR a SO 2 R b ;

R4表示氫、C1-C6烷基、C2-C6烯基、C3-C6環烷基、鹵代C1-C6烷基、-ORa、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、羥基(C1-C6烷基);R5表示氫、C1-C6烷基、C2-C6烯基、C3-C6環烷基、鹵代C1-C6烷基;或者R4、R5連同其共同相連的原子一起形成5-8元飽和和不飽和環,該環中還可以任意地含有0、1或2個選自N、O、S的雜原子; R 4 represents hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, halogenated C 1 -C 6 alkyl, -OR a , -C(O)R a , -C(O)OR a , -C(O)NR a R b , hydroxyl (C 1 -C 6 alkyl); R 5 represents hydrogen, C 1 -C 6 alkyl, C 2 - C 6 alkene group, C 3 -C 6 cycloalkyl, halogenated C 1 -C 6 alkyl; or R 4 , R 5 together with the atoms to which they are connected together form a 5-8 membered saturated and unsaturated ring, which can also optionally contains 0, 1 or 2 heteroatoms selected from N, O, S;

其中,Ra、Rb分別各自獨立地表示氫、C1-C6烷基、C2-C6烯基、C3-C6環烷基、鹵代C1-C6烷基;或者Ra、Rb與其所連接的原子一起形成5-8元環,該環中還可以任意地含有0、1或2個選自N、O、S的雜原子; wherein, R a and R b each independently represent hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, halogenated C 1 -C 6 alkyl; or R a and R b together with the atoms to which they are attached form a 5-8 membered ring, and the ring may optionally contain 0, 1 or 2 heteroatoms selected from N, O and S;

其中n表示0、1、2或3。 where n represents 0, 1, 2 or 3.

優選地,所述式(I)化合物具有以下式(II)結構: Preferably, the compound of formula (I) has the following structure of formula (II):

Figure 110110282-A0202-12-0004-58
Figure 110110282-A0202-12-0004-58

其中: in:

R1、R3、R4、R5、Ra、Rb和n具有如請求項1所述的定義; R 1 , R 3 , R 4 , R 5 , R a , R b and n are as defined in claim 1;

R2表示氫、C1-C6烷基、C3-C6環烷基、羥基(C1-C6烷基)、鹵代C1-C6烷基; R 2 represents hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, hydroxy (C 1 -C 6 alkyl), halogenated C 1 -C 6 alkyl;

W表示CRL或者N; W represents CR L or N;

R6表示氫、鹵素、C1-C6烷基、C3-C6環烷基、鹵代C1- C6烷基、-ORa、氰基、硝基、NRaRb、-SO2Ra、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-P(O)RaRbR 6 represents hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogenated C 1 -C 6 alkyl, -OR a , cyano, nitro, NR a R b , - SO 2 R a , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -P(O)R a R b ;

RL表示氫、鹵素、C1-C6烷基、C3-C6環烷基、鹵代C1-C6烷基、-ORa、氰基、硝基、NRaRb、-SO2Ra、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-P(O)RaRbR L represents hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogenated C 1 -C 6 alkyl, -OR a , cyano, nitro, NR a R b , - SO 2 R a , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -P(O)R a R b ;

o表示0、1、2或3。 o means 0, 1, 2 or 3.

優選地,本發明的化合物選自以下結構: Preferably, the compounds of the present invention are selected from the following structures:

Figure 110110282-A0202-12-0005-6
Figure 110110282-A0202-12-0005-6

Figure 110110282-A0202-12-0006-7
Figure 110110282-A0202-12-0006-7

本發明的化合物也可製備成可藥用鹽的形式,所述可藥用鹽可以使用例如以下的無機酸或有機酸而形成:鹽酸、氫溴酸、硫酸、磷酸、硝酸、乙酸、乙醇酸、乳酸、丙酮酸、丙二酸、琥珀酸、戊二酸、富馬酸、蘋果酸、扁桃酸、酒石酸、檸檬酸、抗壞血酸、棕櫚酸、馬來酸、羥基馬來酸、苯甲酸、羥基苯甲酸、苯乙酸、肉桂酸、水楊酸、甲磺酸、苯磺酸或甲苯磺酸。 The compounds of the present invention can also be prepared in the form of pharmaceutically acceptable salts which can be formed using, for example, the following inorganic or organic acids: hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, acetic, glycolic acid , lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxy Benzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid.

本發明的可藥用鹽可通過常規方法製備,例如通過將本發明的化合物溶解于與水可混溶的有機溶劑(例如丙酮、甲醇、乙醇和乙腈)中,向其中添加過量的有機酸或無機酸水溶液,以使得鹽從所得混合物中沉澱,從中除去溶劑和剩餘的游離酸,然後分離所沉澱的鹽即可。 The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example, by dissolving the compound of the present invention in a water-miscible organic solvent such as acetone, methanol, ethanol and acetonitrile, adding thereto an excess of an organic acid or Aqueous mineral acid solution to precipitate the salt from the resulting mixture, removing the solvent and remaining free acid therefrom, and isolating the precipitated salt.

本發明化合物(或其可藥用鹽)可包括溶劑化物形式,優選地,所述溶劑化物為水合物。 The compounds of the present invention (or pharmaceutically acceptable salts thereof) may include the form of solvates, preferably, the solvates are hydrates.

本發明還提供了本發明的化合物在製備用於預防或治療可通過抑制ALK5活性來調節之疾病的藥物中的用途。優選地,所述疾病選自癌症、腫瘤、炎症性疾病、自身免疫性疾病和免疫介導性疾病。 The present invention also provides the use of the compounds of the present invention in the manufacture of a medicament for the prevention or treatment of diseases that can be modulated by inhibiting the activity of ALK5. Preferably, the disease is selected from cancer, tumor, inflammatory disease, autoimmune disease and immune-mediated disease.

此外,本發明提供了用於預防或治療癌症、腫瘤、炎症性疾病、自身免疫性疾病、神經退行性疾病、注意力相關疾病或免疫介導性疾病的藥物組合物,其包含本發明的式(I)化合物作為活性成分。 Furthermore, the present invention provides a pharmaceutical composition for preventing or treating cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease or immune-mediated disease, comprising the formula of the present invention (I) The compound as an active ingredient.

此外,本發明提供了一種用於預防或治療癌症、腫瘤、炎症性疾病、自身免疫性疾病、神經退行性疾病、注意力相關 疾病或免疫介導性疾病的方法,其包括向有此需要的哺乳動物施用本發明的化合物。 In addition, the present invention provides a method for preventing or treating cancer, tumors, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, attention-related diseases A method of disease or immune-mediated disease comprising administering to a mammal in need thereof a compound of the present invention.

癌症或腫瘤的代表性實例可包括但不限於,皮膚癌、膀胱癌、卵巢癌、乳腺癌、胃癌、胰腺癌、前列腺癌、結腸癌、肺癌、骨癌、腦癌、神經細胞瘤、直腸癌、結腸癌、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、胃癌、腺癌、甲狀腺髓樣癌、乳頭狀甲狀腺癌、腎癌、腎實質癌、卵巢癌、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、腦腫瘤諸如成膠質細胞瘤、星形細胞瘤、腦膜瘤、成神經管細胞瘤和外周神經外胚層腫瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、急性淋巴性白血病(Acute lymphoblastic leukemia,ALL)、慢性淋巴性白血病(Chronic lymphocytic leukemia,CLL)、急性骨髓性白血病(Acute myeloid leukemia,AML)、慢性粒細胞白血病(CML)、成人T細胞白血病淋巴瘤、彌漫性大B細胞淋巴瘤(Diffuse large B cell lymphomas,DLBCL)、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、基底細胞瘤、畸胎瘤、成視網膜細胞瘤、脈絡膜黑素瘤、精原細胞瘤、橫紋肌肉瘤、顱咽管瘤、骨肉瘤、軟骨肉瘤、肌肉瘤、脂肪肉瘤、纖維肉瘤、尤因肉瘤或漿細胞瘤。 Representative examples of cancers or tumors may include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neurocytoma, rectal cancer , colon cancer, familial adenomatous polyposis cancer, hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, Papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, endometrial cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary cancer, melanoma, brain tumors such as glioblastoma, astrocytes Cytoblastoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphoblastic leukemia (ALL), Chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (Diffuse large B-cell lymphoma) cell lymphomas, DLBCL), hepatocellular carcinoma, gallbladder carcinoma, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, spermatogonia cell tumor, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, sarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, or plasmacytoma.

當將本發明化合物或其可藥用鹽與另外的用於治療癌症或腫瘤的抗癌劑或檢查點抑制劑組合施用時,本發明化合物或其可藥用鹽可提供增強的抗癌作用。 The compounds of the present invention or pharmaceutically acceptable salts thereof may provide enhanced anticancer effects when administered in combination with additional anticancer agents or checkpoint inhibitors for the treatment of cancer or tumors.

用於治療癌症或腫瘤的抗癌劑的代表性實例可包括但不限於細胞信號轉導抑制劑、苯丁酸氮芥、美法侖、環磷醯胺、異環磷醯胺、白消安、卡莫司汀、洛莫司汀、鏈脲佐菌素、順鉑、卡鉑、奧沙利鉑、達卡巴嗪、替莫唑胺、丙卡巴肼、甲氨蝶呤、氟尿嘧啶、阿糖胞苷、吉西他濱、巰基嘌呤、氟達拉濱、長春堿、長春新堿、 長春瑞濱、紫杉醇、多西紫杉醇、拓撲替康、伊立替康、依託泊苷、曲貝替定、更生黴素、多柔比星、表柔比星、道諾黴素、米托蒽醌、博來黴素、絲裂黴素C、伊沙匹隆、他莫昔芬、氟他胺、戈那瑞林類似物、甲地孕酮、強的松、地塞米松、甲潑尼龍、沙利度胺、干擾素α、亞葉酸鈣、西羅莫司、西羅莫司脂化物、依維莫司、阿法替尼、alisertib、amuvatinib、阿帕替尼、阿西替尼、硼替佐米、波舒替尼、布立尼布、卡博替尼、西地尼布、crenolanib、克卓替尼、達拉菲尼、達可替尼、達努塞替、達沙替尼、多維替尼、厄洛替尼、foretinib、ganetespib、吉非替尼、依魯替尼、埃克替尼、伊馬替尼、iniparib、拉帕替尼、lenvatinib、linifanib、linsitinib、馬賽替尼、momelotinib、莫替沙尼、來那替尼、尼祿替尼、niraparib、oprozomib、olaparib、帕唑帕尼、pictilisib、普納替尼、quizartinib、瑞格菲尼、rigosertib、rucaparib、盧梭利替尼、塞卡替尼、saridegib、索拉非尼、舒尼替尼、替拉替尼、tivantinib、替沃紮尼、托法替尼、曲美替尼、凡德他尼、維利帕尼、威羅菲尼、維莫德吉、volasertib、阿侖單抗、貝伐單抗、貝倫妥單抗維多汀、卡妥索單抗、西妥昔單抗、地諾單抗、吉妥珠單抗、伊匹單抗、尼妥珠單抗、奧法木單抗、帕尼單抗、利妥昔單抗、托西莫單抗、曲妥珠單抗;檢查點抑制劑,包括但不局限於抗PD-1抗體、抗PD-L1抗體、LAG3抗體、TIM-3抗體以及抗CTLA-4抗體或它們的任意組合。 Representative examples of anticancer agents for treating cancer or tumors may include, but are not limited to, cell signaling inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan , carmustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, Gemcitabine, mercaptopurine, fludarabine, periwinkle, periwinkle, Vinorelbine, Paclitaxel, Docetaxel, Topotecan, Irinotecan, Etoposide, Trabectedin, Dactomycin, Doxorubicin, Epirubicin, Daunomycin, Mitoxantrone , bleomycin, mitomycin C, ixabepilone, tamoxifen, flutamide, gonarelin analogues, megestrol, prednisone, dexamethasone, methylprednisolone, Thalidomide, interferon alfa, leucovorin, sirolimus, temsirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, boron Tezomib, bosutinib, brinyb, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danucetib, dasatinib, multivitamin tinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motisanib, neratinib, nerotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, rosolitinib, Catinib, saridegib, sorafenib, sunitinib, tiratinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, velotinib Fini, vemodagi, volasertib, alemtuzumab, bevacizumab, belemtuzumab vedotin, catumuzumab, cetuximab, denosumab, gemtuzumab Anti-, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumumab, trastuzumab; checkpoint inhibitors, including but not Limited to anti-PD-1 antibody, anti-PD-L1 antibody, LAG3 antibody, TIM-3 antibody and anti-CTLA-4 antibody or any combination thereof.

炎症性疾病、自身免疫性疾病和免疫介導性疾病的代表性實例可包括但不限於,關節炎、類風濕性關節炎、脊柱關節炎、痛風性關節炎、骨關節炎、幼年型關節炎、其他關節炎性病症、狼瘡、系統性紅斑狼瘡(Systemic Lupus Erythematosus,SLE)、皮膚相關疾病、銀屑病、濕疹、皮炎、過敏性皮膚炎、疼痛、肺病、肺部炎症、成人呼吸窘迫綜合征(Acute respiratory distress syndrome,ARDS)、肺結節病、慢性肺部炎症性疾病、慢性阻塞性肺病(Chronic Obstructive Pulmonary Disease,COPD)、心血管疾病、動脈粥樣硬化、心肌梗塞、充血性心力衰竭、心肌缺血再灌注損傷、炎性腸病、克羅恩病、潰瘍性結腸炎、腸易激綜合征、哮喘、乾燥綜合征、自身免疫甲狀腺疾病、蕁麻疹(風疹)、多發性硬化、硬皮症、器官移植排斥、異種移植、特發性血小板減少性紫癜(Idiopathic thrombocytopenic purpura,ITP)、帕金森病、阿爾茲海默病、糖尿病相關疾病、炎症、盆腔炎性疾病、過敏性鼻炎、過敏性支氣管炎、過敏性鼻竇炎、白血病、淋巴瘤、B細胞淋巴瘤、T細胞淋巴瘤、骨髓瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性髓性白血病(AML)、慢性髓性白血病(CML)、毛細胞白血病、何傑金氏病、非何傑金淋巴瘤、多發性骨髓瘤、骨髓增生異常綜合征(Myelodysplastic syndromes,MDS)、骨髓增生性腫瘤(Myeloproliferative neoplasm,MPN)、彌漫性大B細胞淋巴瘤和濾泡性淋巴瘤。 Representative examples of inflammatory, autoimmune, and immune-mediated diseases may include, but are not limited to, arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis , other arthritic conditions, lupus, systemic lupus erythematosus (SLE), skin-related disorders, psoriasis, eczema, dermatitis, atopic dermatitis, pain, lung disease, lung inflammation, adult respiratory distress Acute respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease (chronic obstructive pulmonary disease) Pulmonary Disease, COPD), cardiovascular disease, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia-reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome , Asthma, Sjögren's syndrome, autoimmune thyroid disease, urticaria (rubella), multiple sclerosis, scleroderma, organ transplant rejection, xenotransplantation, idiopathic thrombocytopenic purpura (ITP), Parkinson's disease disease, Alzheimer's disease, diabetes-related diseases, inflammation, pelvic inflammatory disease, allergic rhinitis, allergic bronchitis, allergic sinusitis, leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma , acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hairy cell leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, Multiple myeloma, myelodysplastic syndromes (Myelodysplastic syndromes, MDS), myeloproliferative neoplasms (Myeloproliferative neoplasm, MPN), diffuse large B-cell lymphoma and follicular lymphoma.

當將本發明化合物或其可藥用鹽與另外的用於治療炎症性疾病、自身免疫性疾病和免疫介導性疾病的治療劑組合施用時,本發明化合物或其可藥用鹽可提供增強的治療作用。 The compounds of the present invention, or pharmaceutically acceptable salts thereof, may provide enhancement when administered in combination with additional therapeutic agents useful in the treatment of inflammatory, autoimmune, and immune-mediated diseases therapeutic effect.

用於治療炎症性疾病、自身免疫性疾病和免疫介導性疾病的治療劑的代表性實例可包括但不限於,甾體藥物(例如,強的松、氫化波尼松、甲基氫化波尼松、可的松、羥基可的松、倍他米松、地塞米松等)、甲氨蝶呤、來氟米特、抗TNFα劑(例如,依那西普、英夫利昔單抗、阿達利單抗等)、鈣調神經磷酸酶抑制劑(例如,他克莫司、吡美莫司等)和抗組胺藥(例如,苯海拉明、羥嗪、氯雷他定、依巴斯汀、酮替芬、西替利嗪、左西替利嗪、非索非那定等),並且選自其中的至少一種治療劑可包含于本發明藥物組合物中。 Representative examples of therapeutic agents for the treatment of inflammatory diseases, autoimmune diseases, and immune-mediated diseases may include, but are not limited to, steroidal drugs (eg, prednisone, prednisone, methylhydroponil) sone, cortisone, hydroxycortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNFα agents (eg, etanercept, infliximab, adalix monoclonal antibodies, etc.), calcineurin inhibitors (eg, tacrolimus, pimecrolimus, etc.), and antihistamines (eg, diphenhydramine, hydroxyzine, loratadine, ebaz) Cetirizine, ketotifen, cetirizine, levocetirizine, fexofenadine, etc.), and at least one therapeutic agent selected from them may be included in the pharmaceutical composition of the present invention.

本發明的化合物或其可藥用鹽可作為活性成分通過口服或腸胃外施用,其有效量的範圍為在哺乳動物包括人(體重約70kg)的情況下0.1至2,000mg/kg體重/天、優選1至1,000mg/kg體 重/天,並且每天以單次或4次分次劑量,或者遵循/不遵循預定時間施用。活性成分的劑量可根據多個相關因素(例如待治療物件的情況、疾病類型和嚴重性、施用速率和醫生意見)進行調整。在某些情況下,小於以上劑量的量可能是合適的。如果不引起有害的副作用則可使用大於以上劑量的量並且該量可以每天以分次劑量施用。 The compound of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally as an active ingredient in an effective amount ranging from 0.1 to 2,000 mg/kg body weight/day, in mammals including humans (about 70 kg body weight), Preferably 1 to 1,000 mg/kg body weight/day, and administered in single or 4 divided doses per day, or on/off schedule. The dosage of the active ingredient can be adjusted according to a number of relevant factors, such as the condition of the item being treated, the type and severity of the disease, the rate of administration, and the opinion of the physician. In some cases, amounts less than the above doses may be appropriate. An amount greater than the above dose may be used if it does not cause adverse side effects and the amount may be administered in divided doses per day.

可根據常規方法中的任何一種將本發明藥物組合物配製成用於口服施用或腸胃外施用(包括肌內、靜脈內和皮下途徑)的劑型,例如片劑、顆粒、粉末、膠囊、糖漿、乳劑、微乳劑、溶液或混懸液。 The pharmaceutical compositions of the present invention can be formulated according to any of conventional methods into dosage forms such as tablets, granules, powders, capsules, syrups for oral administration or parenteral administration (including intramuscular, intravenous and subcutaneous routes) , emulsion, microemulsion, solution or suspension.

用於口服施用的本發明藥物組合物可通過將活性成分與例如以下的載體混合來製備:纖維素、矽酸鈣、玉米澱粉、乳糖、蔗糖、右旋糖、磷酸鈣、硬脂酸、硬脂酸鎂、硬脂酸鈣、明膠、滑石、表面活性劑、助懸劑、乳化劑和稀釋劑。在本發明的注射組合物中採用的載體的實例是水、鹽溶液、葡萄糖溶液、葡萄糖樣溶液、醇、二醇、醚(例如,聚乙二醇400)、油、脂肪酸、脂肪酸酯、甘油酯、表面活性劑、助懸劑和乳化劑。 Pharmaceutical compositions of the present invention for oral administration can be prepared by mixing the active ingredient with a carrier such as: cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, hard Magnesium fatty acid, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers and diluents. Examples of carriers employed in the injectable compositions of the present invention are water, saline solutions, dextrose solutions, dextrose-like solutions, alcohols, glycols, ethers (eg, polyethylene glycol 400), oils, fatty acids, fatty acid esters, Glycerides, surfactants, suspending and emulsifying agents.

本發明描述示例性實施方案的過程中,本發明的其它特徵將變得顯而易見,給出所述實施方案用於說明本發明而不意欲成為其限制,以下實施例使用本發明所公開的方法製備、分離和表徵。 Other features of this invention will become apparent in the course of describing exemplary embodiments of this invention, which are given to illustrate the invention and not to limit it, and the following examples were prepared using the methods disclosed in this invention. , isolation and characterization.

可以用有機合成領域的技術人員已知的多種方式來製備本發明的化合物,可使用有機合成化學領域中已知的合成方法或通過本領域技術人員所瞭解的其變化形式來合成本發明化合物。可以在適用於所使用試劑盒材料和適用於所實現轉變的溶劑或溶劑混合物中實施所需反應。 The compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis, using synthetic methods known in the art of synthetic organic chemistry or by variations thereof known to those skilled in the art. The desired reactions can be carried out in solvents or solvent mixtures suitable for the kit materials used and for the transformation being effected.

本發明人經過長期而深入的研究,發現了一類具有TGF-β受體抑制活性、尤其是ALK5抑制活性的如式(I)所示的雜環化合物。基於上述發現,發明人完成了本發明。 After long-term and in-depth research, the present inventors discovered a class of heterocyclic compounds represented by formula (I) with TGF-β receptor inhibitory activity, especially ALK5 inhibitory activity. Based on the above findings, the inventors have completed the present invention.

術語the term

如果無另外說明,用於本發明申請,包括說明書和權利要求書中的術語,定義如下。必須注意,在說明書和所附的權利要求書中,如果文中無另外清楚指示,無數詞修飾的名詞通常包括其複數意義。如果無另外說明,使用質譜、核磁、(High performance liquid chromatography,HPLC)、蛋白化學、生物化學、重組DNA技術和藥理的常規方法。 Unless otherwise stated, terms used in the present application, including the specification and claims, are defined as follows. It must be noted that in the specification and the appended claims, nouns modified by innumerable words generally include their plural meanings unless the context clearly dictates otherwise. If not stated otherwise, conventional methods of mass spectrometry, nuclear magnetic resonance (High performance liquid chromatography, HPLC), protein chemistry, biochemistry, recombinant DNA techniques and pharmacology were used.

在說明書和權利要求書中,給定化學式或名稱應涵蓋所有立體和光學異構體及其中存在上述異構體的外消旋物。除非另外指明,否則所有手性(對映異構體和非對映異構體)和外消旋形式均在本發明範圍內。所述化合物中還可存在C=C雙鍵、C=N雙鍵、環系統等的許多幾何異構體,且所有上述穩定異構體均涵蓋于本發明內。本發明描述了本發明化合物的順式-和反式-(或E-和Z-)幾何異構體,且其可分離成異構體的混合物或分開的異構體形式。本發明化合物可以光學活性或外消旋形式加以分離。用於製備本發明化合物和其中製備的中間體的所有方法均視為本發明的部分。在製備對映異構體或非對映異構體產物時,其可通過常規方法(例如通過色譜或分段結晶)進行分離。取決於方法條件,以游離(中性)或鹽形式獲得本發明的終產物。這些終產物的游離形式和鹽均在本發明的範圍內。如果需要的話,則可將化合物的一種形式轉化成另一種形式。可將游離堿或酸轉化成鹽;可將鹽轉化成游離化合物或另一種鹽;可將本發明異構體化合物的混合物分離成單獨的異構體。本發明化合物、其游離形式和 鹽可以多種互變異構體形式存在,其中氫原子轉置到分子的其它部分上且由此分子的原子之間的化學鍵發生重排。應當理解的是,可存在的所有互變異構體形式均包括在本發明內。 In the specification and claims, a given chemical formula or name shall encompass all stereo and optical isomers and racemates in which such isomers exist. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the present invention. Numerous geometric isomers of C=C double bonds, C=N double bonds, ring systems, etc. may also exist in the compounds, and all of the above stable isomers are encompassed by the present invention. The present invention describes cis- and trans- (or E- and Z- ) geometric isomers of the compounds of the present invention, and which may be isolated as a mixture of isomers or as separate isomeric forms. The compounds of the present invention can be isolated in optically active or racemic forms. All methods used to prepare the compounds of the present invention and intermediates prepared therein are considered part of this invention. In the preparation of enantiomeric or diastereomeric products, they can be separated by conventional methods, eg by chromatography or fractional crystallization. Depending on the process conditions, the final product of the invention is obtained in free (neutral) or salt form. Both free forms and salts of these final products are within the scope of the present invention. If desired, one form of a compound can be converted into another. The free halide or acid can be converted into a salt; a salt can be converted into a free compound or another salt; a mixture of isomeric compounds of the present invention can be separated into individual isomers. The compounds of the present invention, their free forms and salts, may exist in various tautomeric forms in which hydrogen atoms are transposed to other parts of the molecule and the chemical bonds between the atoms of the molecule are thereby rearranged. It is to be understood that all tautomeric forms that may exist are encompassed by the present invention.

除非另有定義,否則當取代基被標注為“任選取代的”時,所述取代基選自例如以下取代基,諸如烷基、環烷基、芳基、雜環基、鹵素、羥基、烷氧基、氧代、烷醯基、芳基氧基、烷醯基氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺基團(其中2個氨基取代基選自烷基、芳基或芳基烷基)、烷醯基氨基、芳醯基氨基、芳烷醯基氨基、取代的烷醯基氨基、取代的芳基氨基、取代的芳烷醯基氨基、硫基、烷基硫基、芳基硫基、芳基烷基硫基、芳基硫羰基、芳基烷基硫羰基、烷基磺醯基、芳基磺醯基、芳基烷基磺醯基、磺醯氨基例如-SO2NH2、取代的磺醯氨基、硝基、氰基、羧基、氨基甲醯基例如-CONH2、取代的氨基甲醯基例如-CONH烷基、-CONH芳基、-CONH芳基烷基或在氮上具有兩個選自烷基、芳基或芳基烷基的取代基的情況、烷氧基羰基、芳基、取代的芳基、胍基、雜環基,例如吲哚基、咪唑基、呋喃基、噻吩基、噻唑基、吡咯烷基、吡啶基、嘧啶基、吡咯烷基、呱啶基、嗎啉基、呱嗪基、高呱嗪基等和取代的雜環基。 Unless otherwise defined, when a substituent is annotated as "optionally substituted", the substituent is selected from, for example, substituents such as alkyl, cycloalkyl, aryl, heterocyclyl, halogen, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine groups (wherein 2 amino groups are substituted group is selected from the group consisting of alkyl, aryl or arylalkyl), alkanolamino, aralkylamino, aralkylamino, substituted alkylamino, substituted arylamino, substituted aralkylamino Amino, thio, alkylthio, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, alkylsulfonyl, arylsulfonyl, arylalkyl Sulfonyl, sulfonamido such as -SO 2 NH 2 , substituted sulfoamino, nitro, cyano, carboxyl, carbamate such as -CONH 2 , substituted carbamate such as -CONH alkyl, - CONH aryl, -CONH arylalkyl or with two substituents on nitrogen selected from alkyl, aryl or arylalkyl, alkoxycarbonyl, aryl, substituted aryl, guanidino , Heterocyclyl such as indolyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrrolidinyl, oxidyl, morpholinyl, oxazinyl, homoquanyl oxazinyl etc. and substituted heterocyclyl.

本文使用的術語“烷基”或“亞烷基”意欲包括具有指定碳原子數的支鏈或直鏈飽和脂族烴基團。例如,“C1-C6烷基”表示具有1個至6個碳原子的烷基。烷基的實例包括但不限於甲基(Me)、乙基(Et)、丙基(例如正丙基和異丙基)、丁基(例如正丁基、異丁基、叔丁基)和戊基(例如正戊基、異戊基、新戊基)。優選的烷基是C1-C6烷基,更優選的烷基是C1-C4烷基。 The terms "alkyl" or "alkylene" as used herein are intended to include branched or straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms. For example, " C1 - C6 alkyl" means an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (eg n-propyl and isopropyl), butyl (eg n-butyl, isobutyl, tert-butyl) and Pentyl (eg n-pentyl, isopentyl, neopentyl). Preferred alkyl groups are C1 - C6 alkyl groups, more preferred alkyl groups are C1 - C4 alkyl groups.

術語“烯基”表示含一個或多個雙鍵且通常長度為2至20個碳原子的直鏈或支鏈的烴基。例如,“C2-C8烯基”含有兩個至八個碳原子。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、庚烯基、辛烯基等。優選的烯基是C2-C8烯基,更優選的烯基是C2-C6烯基。 The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing one or more double bonds and usually 2 to 20 carbon atoms in length. For example, "C2 - C8 alkenyl" contains from two to eight carbon atoms. Alkenyl groups include, but are not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like. Preferred alkenyl groups are C2 - C8 alkenyl groups, more preferred alkenyl groups are C2 - C6 alkenyl groups.

術語“炔基”表示含一個或多個三鍵且通常長度為2至20個碳原子的直鏈或支鏈的烴基。例如,“C2-C8炔基”含有兩個至八個碳原子。優選的炔基是C2-C8炔基,更優選的烯基是C2-C6炔基。代表性炔基包括但不限於例如乙炔基、1-丙炔基、1-丁炔基、庚炔基、辛炔基等。 The term "alkynyl" refers to a straight or branched chain hydrocarbon group containing one or more triple bonds and usually 2 to 20 carbon atoms in length. For example, "C2 - C8alkynyl" contains from two to eight carbon atoms. Preferred alkynyl groups are C 2 -C 8 alkynyl groups, and more preferred alkenyl groups are C 2 -C 6 alkynyl groups. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

術語“烷氧基”或“烷基氧基”是指-O-烷基。“C1-C6烷氧基”(或烷基氧基)意欲包括C1、C2、C3、C4、C5和C6烷氧基。優選的烷氧基是C1-C6烷氧基,更優選的烷氧基是C1-C4烷氧基。烷氧基的實例包括但不限於甲氧基、乙氧基、丙氧基(例如正丙氧基和異丙氧基)和叔丁氧基。類似地,“烷基硫基”或“硫代烷氧基”表示具有指定數量碳原子的經硫橋連接的如上文所定義的烷基;例如甲基-S-和乙基-S-。 The term "alkoxy" or "alkyloxy" refers to -O-alkyl. "C 1 -C 6 alkoxy" (or alkyloxy) is intended to include C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy. Preferred alkoxy groups are C 1 -C 6 alkoxy groups, and more preferred alkoxy groups are C 1 -C 4 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy), and t-butoxy. Similarly, "alkylthio" or "thioalkoxy" represents an alkyl group, as defined above, having the indicated number of carbon atoms attached through a sulfur bridge; eg, methyl-S- and ethyl-S-.

術語“羰基”是指由碳和氧兩種原子通過雙鍵連接而成的有機官能團(C=O)。 The term "carbonyl" refers to an organic functional group (C=O) composed of two atoms, carbon and oxygen, linked by a double bond.

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12個環成員的單環、二環或三環的環系統,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。單環的芳香基指的是苯基,二環及二環以上的芳香基指萘基、蒽基等,同時此芳基二環也可為苯環融合了一個環烷基、或融合一個環烯基、或融合一個環炔基。優選的芳基是C6-C12芳基。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。術語“芳烷基”或“芳基烷基”是指連接至芳基環的烷基殘基。非限制性實例包括苄基、苯乙基等。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。例從環系統中畫出的箭 頭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 12 ring members , bicyclic or tricyclic ring systems, wherein at least one ring in the system is aromatic and wherein each ring in the system contains from 3 to 7 ring members. Monocyclic aromatic group refers to phenyl group, bicyclic and more than bicyclic aromatic groups refer to naphthyl, anthracenyl, etc. At the same time, the aryl bicyclic ring can also be fused with a cycloalkyl group or a ring with a benzene ring. alkenyl, or fused to a cycloalkynyl. Preferred aryl groups are C 6 -C 12 aryl groups. In certain embodiments of the present invention, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthalene base. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring. Non-limiting examples include benzyl, phenethyl, and the like. A fused aryl group can be attached to another group at a suitable position on the cycloalkyl or aromatic ring. For example, an arrowed line drawn from a ring system indicates that the bond may be attached to any suitable ring atom.

術語“環烷基”是指單環或二環的環狀烷基。單環的環狀烷基指C3-C8的環狀烷基,包括但不限於環丙基、環丁基、環戊基、環己基和降莰烷基。支化環烷基諸如1-甲基環丙基和2-甲基環丙基包括在“環烷基”的定義中。二環的環狀烷基包括橋環、螺環或融合環的環烷基。優選的環烷基是C3-C6環烷基。 The term "cycloalkyl" refers to a monocyclic or bicyclic cyclic alkyl group. A monocyclic cyclic alkyl group refers to a C3 - C8 cyclic alkyl group, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and norbornyl. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". Bicyclic cyclic alkyl groups include bridged, spiro or fused ring cycloalkyl groups. Preferred cycloalkyls are C3 - C6 cycloalkyls.

術語“環烯基”是指單環或二環的環狀烯基。單環的環狀烯基指C3-C8的環狀烯基,包括但不限於環丙烯基、環丁烯基、環戊烯基、環己烯基和降莰烯基。支化環烯基諸如1-甲基環丙烯基和2-甲基環丙烯基包括在“環烯基”的定義中。二環的環狀烯基包括橋環、螺環或融合環的環狀烯基。 The term "cycloalkenyl" refers to a monocyclic or bicyclic cyclic alkenyl group. Monocyclic cyclic alkenyl refers to C3 - C8 cyclic alkenyl, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and norbornyl. Branched cycloalkenyl groups such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl". Bicyclic cyclic alkenyl groups include bridged, spiro or fused ring cyclic alkenyl groups.

術語“羥基烷基”是指具有指定碳原子數的支鏈和直鏈飽和脂族烴基團且烴基的碳原子上至少連接一個-OH。羥基烷基的實例包括但不限於羥甲基、羥乙基、1-羥基丙基、2-羥基丙基。 The term "hydroxyalkyl" refers to branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms with at least one -OH attached to the carbon atoms of the hydrocarbon group. Examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl.

“鹵代”或“鹵素”包括氟、氯、溴和碘。“鹵代烷基”意欲包括具有指定碳原子數且取代有1個或多個鹵素的支鏈和直鏈飽和脂族烴基團。鹵代烷基的實例包括但不限於氟甲基、二氟甲基、三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。鹵代烷基的實例還包括意欲包括具有指定碳原子數且取代有1個或多個氟原子的支鏈和直鏈飽和脂族烴基團的“氟烷基”。 "Halo" or "halogen" includes fluorine, chlorine, bromine and iodine. "Haloalkyl" is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms and substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoroethyl propyl and heptachloropropyl. Examples of haloalkyl groups also include "fluoroalkyl groups" which are intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms and substituted with one or more fluorine atoms.

“鹵代烷氧基”或“鹵代烷基氧基”表示具有指定數量碳原子的經氧橋連接的如上文所定義的鹵代烷基。例如,“C1-C6鹵代烷氧基”意欲包括C1、C2、C3、C4、C5和C6鹵代烷氧基。鹵代烷氧基的實例包括但不限於三氟甲氧基、2,2,2-三氟乙氧基和五氟乙氧基。類似地,“鹵代烷基硫基”或“硫代鹵代烷氧基”表示具有指定數量碳原子的經硫橋連接的如上文所定義的鹵代烷基;例如三氟甲基-S-和五氟乙基-S-。 "Haloalkoxy" or "haloalkyloxy" means a haloalkyl group, as defined above, having the indicated number of carbon atoms attached through an oxygen bridge. For example, "C 1 -C 6 haloalkoxy" is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , and C 6 haloalkoxy. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" represents a haloalkyl group, as defined above, having the indicated number of carbon atoms attached through a sulfur bridge; eg, trifluoromethyl-S- and pentafluoroethyl -S-.

術語“雜芳基”意指穩定的3元、4元、5元、6元、或7元芳香單環或芳香二環或7元、8元、9元、10元、11元、12元、13元或14元芳香多環雜環,其為完全不飽和的、部分不飽和的,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;且包括任何以下多環基團,其中上文所定義的任意雜環與苯環稠合。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。優選的雜芳基是5-12元雜芳基。雜芳基的實例包括但不限於吖啶基、氮雜環丁基、吖辛因基、苯並咪唑基、苯並呋喃基、苯並硫代呋喃基、苯並噻吩基、苯並噁唑基、苯並噁唑啉基、苯並噻唑基、苯並三唑基、苯並四唑基、苯並異噁唑基、苯並異噻唑基、苯並咪唑啉基、哢唑基、4aH-哢唑基、哢啉基、色滿基、色烯基、噌啉基、十氫喹啉基、2H,6H-1,5,2-二噻嗪基、二氫呋喃並[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、咪唑並吡啶基、假吲哚基(indolenyl)、二氫吲哚基、吲嗪基、吲哚基、3H-吲哚基、靛紅醯基(isatinoyl)、異苯並呋喃基、異色滿基、異吲唑基、異二氫吲哚基、異吲哚基、異喹啉基、異噻唑基、異噻唑並吡啶基、異噁唑基、異噁唑並吡啶基、亞甲基二氧基苯基、嗎啉基、二氮雜萘基、八氫異喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、噁唑並吡啶基、噁唑烷基、萘嵌間二氮雜苯基、羥吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、吩噁噻基、吩噁嗪基、酞嗪基、呱嗪基、呱啶基、呱啶酮基、4-呱啶酮基、胡椒基、喋啶基、嘌呤基、吡喃基、 吡嗪基、吡唑烷基、吡唑啉基、吡唑並吡啶基、吡唑基、噠嗪基、吡啶並噁唑基、吡啶並咪唑基、吡啶並噻唑基、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-喹嗪基、喹喔啉基、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-噻二嗪基、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、噻唑並吡啶基、噻吩並噻唑基、噻吩並噁唑基、噻吩並咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫噸基、喹啉基、異喹啉基、酞嗪基、喹唑啉基、吲哚基、異吲哚基、二氫吲哚基、1H-吲唑基、苯並咪唑基、1,2,3,4-四氫喹啉基、1,2,3,4-四氫異喹啉基、5,6,7,8-四氫-喹啉基、2,3-二氫-苯並呋喃基、色滿基、1,2,3,4-四氫-喹喔啉基和1,2,3,4-四氫-喹唑啉基。本發明還包括含有例如上述雜環的稠環和螺環化合物。 The term "heteroaryl" means a stable 3-, 4-, 5-, 6-, or 7-membered aromatic monocyclic or aromatic bicyclic or 7-, 8-, 9-, 10-, 11-, 12-membered , 13- or 14-membered aromatic polycyclic heterocycles, which are fully unsaturated, partially unsaturated, and which contain carbon atoms and 1, 2, 3, or 4 independently selected from N, O, and S and includes any of the following polycyclic groups in which any of the heterocycles defined above are fused to a benzene ring. Nitrogen and sulfur heteroatoms can optionally be oxidized. Nitrogen atoms are substituted or unsubstituted (ie, N or NR, where R is H or, if defined, another substituent). Heterocycles can be attached to their pendant groups at any heteroatom or carbon atom that results in a stable structure. The heterocyclyl groups described herein may be substituted on a carbon or nitrogen atom if the resulting compound is stable. The nitrogens in the heterocycle may be optionally quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is not greater than one. Preferred heteroaryl groups are 5-12 membered heteroaryl groups. Examples of heteroaryl groups include, but are not limited to, acridinyl, azetidinyl, acridine, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothienyl, benzoxazole base, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, oxazolyl, 4aH - azolyl, quinolinyl, chromanyl, chromenyl, cinnoline, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3 -b] tetrahydrofuranyl, furanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridyl, indolenyl, indolyl, indolyl Azinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl, isoindolyl, isoquinoline olinyl, isothiazolyl, isothiazolopyridyl, isoxazolyl, isoxazolopyridyl, methylenedioxyphenyl, morpholinyl, naphthinyl, octahydroisoquinolinyl , oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridyl, oxazolidinyl, rylene, oxindole, pyrimidinyl, phenanthridine, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxthiyl, phenoxazinyl, phthalazinyl, oxazinyl, quaridinyl, oxidyl, 4-oxidyl, piperonyl, pteridyl, purinyl, pyridyl Ranyl, Pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinyl, 2-pyrrolidone, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinazinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, Tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl , 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthryl, thiazolyl, thienyl, thiazolopyridyl, thienothiazolyl, thienooxazolyl, thiophene Imidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indoline, 1H-indazolyl, benzimidazolyl, 1 ,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro- Benzofuranyl, chromanyl, 1,2,3,4-tetrahydro-quinoxalinyl and 1,2,3,4-tetrahydro-quinazolinyl. The present invention also includes fused and spiro compounds containing, for example, the heterocycles described above.

本文使用的術語“雜環烷基”指的是一個單環雜環烷基體系,或為一個二環雜環烷基體系,同時還包括螺雜環或橋雜環烷基。單環的雜環烷基指的是3-8元、且至少含一個選自O、N、S、P的飽和或不飽和但不為芳香性的環狀烷基體系。二環雜環烷基體系指的是一個雜環烷基融合到一個苯基、或一個環烷基、或一個環烯基、或一個雜環烷基、或一個雜芳基。優選的雜環烷基是3-12元雜環烷基。 The term "heterocycloalkyl" as used herein refers to a monocyclic heterocycloalkyl system, or a bicyclic heterocycloalkyl system, and also includes spiroheterocycles or bridged heterocycloalkyls. Monocyclic heterocycloalkyl refers to a 3-8 membered cyclic alkyl system containing at least one saturated or unsaturated but non-aromatic alkyl group selected from O, N, S, P. Bicyclic heterocycloalkyl systems refer to a heterocycloalkyl group fused to a phenyl group, or a cycloalkyl group, or a cycloalkenyl group, or a heterocycloalkyl group, or a heteroaryl group. Preferred heterocycloalkyl groups are 3-12 membered heterocycloalkyl groups.

本文中所用的術語“取代”意指至少一個氫原子被非氫基團替代,條件是維持正常化合價且所述取代得到穩定的化合物。本文所用的環雙鍵為在兩個相鄰環原子之間形成的雙鍵(例如C=C、C=N或N=N)。 The term "substituted" as used herein means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that normal valences are maintained and the substitution results in a stable compound. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (eg, C=C, C=N, or N=N).

在本發明化合物上存在氮原子(例如胺)的情形下,可通過使用氧化劑(例如m-CPBA和/或過氧化氫)進行處理來將這些氮原子轉化成N-氧化物以獲得本發明的其它化合物。因此,所顯示 和要求保護的氮原子視為均涵蓋所顯示氮及其N-氧化物以獲得本發明衍生物。 Where nitrogen atoms such as amines are present on the compounds of the invention, these nitrogen atoms can be converted to N-oxides by treatment with oxidizing agents such as m -CPBA and/or hydrogen peroxide to obtain the compounds of the invention. other compounds. Accordingly, both shown and claimed nitrogen atoms are considered to encompass both the shown nitrogen and its N -oxides to obtain the derivatives of the invention.

當任何變數在化合物的任何組成或式中出現一次以上時,其每次出現時的定義均獨立於其在其它每種情況下出現時的定義。因此,例如如果顯示基團取代有0、1、2或3個R,則所述基團可任選地取代有至多三個R基團,且在每次出現時R獨立地選自R的定義。此外,取代基和/或變數的組合僅在上述組合可產生穩定的化合物時才容許存在。 When any variable occurs more than once in any composition or formula of a compound, its definition at each occurrence is independent of its definition at each other occurrence. Thus, for example, if a group is shown to be substituted with 0, 1, 2 or 3 R groups, the group may be optionally substituted with up to three R groups, and at each occurrence R is independently selected from the group consisting of R's definition. Furthermore, combinations of substituents and/or variables are only permissible if such combinations result in stable compounds.

術語“溶劑化物”意指本發明化合物與一個或多個溶劑分子(無論有機的還是無機的)的物理締合。該物理締合包括氫鍵。在某些情形中,例如當一個或多個溶劑分子納入結晶固體的晶格中時,溶劑化物將能夠被分離。溶劑化物中的溶劑分子可按規則排列和/或無序排列存在。溶劑化物可包含化學計量或非化學計量的溶劑分子。“溶劑合物”涵蓋溶液相和可分離的溶劑化物。示例性溶劑化物包括但不限於水合物、乙醇合物、甲醇合物和異丙醇合物。溶劑化方法是本領域公知的。 The term "solvate" means a physical association of a compound of the present invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances, such as when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid, the solvate will be capable of isolation. Solvent molecules in a solvate may exist in regular and/or disordered arrangements. Solvates may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses both solution phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

本文使用的術語“患者”是指通過本發明的方法進行治療的有機體。這類有機體優選包括但不限於哺乳動物(例如鼠類、猿/猴、馬、牛、豬、犬、貓等)且最優選是指人類。 The term "patient" as used herein refers to an organism treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (eg, murine, simian/monkey, equine, bovine, porcine, canine, feline, etc.) and most preferably refer to humans.

本文使用的術語“有效量”意指將會引起例如研究人員或臨床醫師所尋求的組織、系統、動物或人的生物學或醫學回應的藥物或藥劑(即本發明化合物)的量。此外,術語“治療有效量”意指這樣的量:與未接受上述量的相應受試者相比,所述量導致改善的治療、治癒、預防或減輕疾病、病症或副作用,或降低在疾病或病症的進展速度。有效量可以一個或多個給藥、施用或劑量給予且不意欲被特定的製劑或給藥途徑限制。該術語還包括在其範圍內的增強正常生理機能的有效量。 As used herein, the term "effective amount" means the amount of a drug or agent (ie, a compound of the invention) that will elicit a biological or medical response, eg, in a tissue, system, animal or human being sought by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means an amount that results in improved treatment, cure, prevention or alleviation of a disease, disorder or side effect, or a reduction in the incidence of a disease, as compared to a corresponding subject not receiving such amounts or the rate of progression of the disease. An effective amount can be administered in one or more administrations, administrations or doses and is not intended to be limited by a particular formulation or route of administration. The term also includes within its scope an amount effective to enhance normal physiology.

本文使用的術語“治療”包括導致改善病症、疾病、障礙等的任何效果,例如減輕、減少、調節、改善或消除,或改善其症狀。如本文所用,某一化合物或藥物組合物,在給藥後可以使某一疾病、症狀或情況得到改善,尤指其嚴重度得到改善,延遲發病,減緩病情進展,或減少病情持續時間。無論固定給藥或臨時給藥、持續給藥或斷續給藥,可以歸因於或與給藥有關的情況。本文使用的術語“預防”是指在疾病或症狀發生之前防止、阻斷、消除疾病發生或者干擾或減緩病程發展。 As used herein, the term "treating" includes any effect that results in amelioration of a condition, disease, disorder, etc., eg, alleviation, reduction, modulation, amelioration or elimination, or amelioration of symptoms thereof. As used herein, a compound or pharmaceutical composition, upon administration, results in amelioration, especially improvement in severity, delay in onset, slow progression, or reduction in duration of a disease, symptom or condition. Whether fixed or temporary, continuous or intermittent, conditions may be attributable to or associated with the administration. The term "preventing" as used herein refers to preventing, blocking, eliminating the onset of a disease or interfering with or slowing the progression of a disease before it occurs.

本文使用的術語“藥物組合物”是指活性劑與惰性或活性的載體的組合,使得所述組合物尤其適用於體內或離體診斷或治療。堿的實例包括但不限於鹼金屬(例如鈉)氫氧化物、鹼土金屬(例如鎂)氫氧化物、氨等。對於治療用途,本發明化合物的鹽對於治療用途,本發明化合物的鹽預期為是藥用的。然而,非藥用的酸和堿的鹽也可用於例如藥用化合物的製備或純化中。 The term "pharmaceutical composition" as used herein refers to the combination of an active agent with an inert or active carrier, making the composition particularly suitable for use in in vivo or ex vivo diagnosis or therapy. Examples of quiniums include, but are not limited to, alkali metal (eg, sodium) hydroxides, alkaline earth metal (eg, magnesium) hydroxides, ammonia, and the like. For therapeutic use, salts of compounds of the present invention For therapeutic use, salts of compounds of the present invention are intended to be pharmaceutically acceptable. However, non-pharmaceutically acceptable salts of acids and quiniums can also be used, for example, in the preparation or purification of pharmaceutically acceptable compounds.

術語“藥用”在本文中用於指如下那些化合物、物質、組合物和/或劑型:在合理醫學判斷的範圍內,其適於與人類和動物的組織接觸使用而無過高毒性、刺激性、過敏反應和/或其它問題或併發症,並與合理的益處/風險比相稱。 The term "pharmaceutically acceptable" is used herein to refer to those compounds, substances, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without unduly toxic, irritating sexual, allergic reactions and/or other problems or complications and are commensurate with a reasonable benefit/risk ratio.

本文使用的短語“藥學上可接受的載體”、“可藥用載體”意指藥用物質、組合物或媒介物,諸如液體或固體填充劑、稀釋劑、賦形劑、製造助劑(例如潤滑劑、滑石、硬脂酸鎂、硬脂酸鈣或硬脂酸鋅或硬脂酸)或溶劑包囊物質,其涉及將活性化合物從一個器官或身體的部分攜帶或運送至另一個器官或身體的部分。每種載體在與製劑的其它成分相容和對患者無害的意義上必須是“可接受的”。 As used herein, the phrase "pharmaceutically acceptable carrier", "pharmaceutically acceptable carrier" means a pharmaceutical substance, composition or vehicle such as a liquid or solid filler, diluent, excipient, manufacturing aid ( such as lubricants, talc, magnesium stearate, calcium stearate or zinc stearate or stearic acid) or solvent encapsulating substances, which are involved in carrying or transporting the active compound from one organ or part of the body to another or body parts. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

特定藥學及醫學術語Certain Pharmacy and Medical Terms

術語“可接受的”,如本文所用,指一個處方組分或活性成分對一般治療目標的健康沒有過分的有害影響。 The term "acceptable", as used herein, refers to a formulation component or active ingredient that does not have undue deleterious effects on the health of the general target of treatment.

術語“癌症”,如本文所用,指一種不能控制的細胞的異常生長,並且在某種條件下能夠轉移(傳播)。這種類型的癌症包括但不限於,實體腫瘤(如膀胱、腸、腦、胸、子宮、心臟、腎、肺、淋巴組織(淋巴瘤)、卵巢、胰腺或其它內分泌器官(如甲狀腺)、前列腺、皮膚(黑色素瘤)或血液瘤(如非白血性白血病)。 The term "cancer", as used herein, refers to an abnormal growth of cells that is uncontrollable and, under certain conditions, is capable of metastasizing (spreading). Cancers of this type include, but are not limited to, solid tumors (eg, bladder, bowel, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (eg, thyroid), prostate , skin (melanoma), or blood tumor (eg, nonleukemic leukemia).

術語“聯合給藥”或其類似術語,如本文所用,指將幾種所選的治療藥物給一個病人用藥,以相同或不同的給藥方式在相同或不同的時間給藥。 The term "co-administration" or similar terms, as used herein, refers to the administration of several selected therapeutic agents to a patient, administered in the same or different administrations at the same or different times.

術語“增強”或“能增強”,如本文所用,指預期的結果能夠在效價或是持續時間方面都有增加或延長。因此,在增強藥物的治療效果方面,術語“能增強”指藥物在系統中有提高或延長效價或持續時間的能力。本文所用的“增效值”,指在理想的系統中,能夠最大限度地的增強另外一個治療藥物的能力。 The term "enhancing" or "enhancing", as used herein, refers to the ability of a desired result to be increased or prolonged, either in potency or duration. Thus, in enhancing the therapeutic effect of a drug, the term "enhancer" refers to the drug's ability to increase or prolong the potency or duration of the drug in the system. As used herein, "potentiation value" refers to the ability to maximize the ability of another therapeutic agent in an ideal system.

術語“免疫性疾病”指對內源性或外源性抗原產生的不良或有害反應的疾病或症狀。結果通常會造成細胞的功能障礙、或因此而破壞並造成機能障礙、或破壞可能產生免疫症狀的器官或組織。 The term "immune disease" refers to a disease or condition of an adverse or deleterious response to an endogenous or exogenous antigen. The result is usually the dysfunction of cells, or the destruction and dysfunction of the cells, or the destruction of organs or tissues that may produce immune symptoms.

術語“試劑盒”與“產品包裝”是同義詞。 The terms "kit" and "product packaging" are synonymous.

術語“受試者”或“對象”包括哺乳動物和非哺乳動物。哺乳動物包括但不限於,哺乳類:人、非人靈長類如猩猩、猿及猴類;農業動物如牛、馬、山羊、綿羊、豬;家畜如兔、狗;實驗動物包括齧齒類,如大鼠、小鼠及豚鼠等。非哺乳類動物包括但不限於,鳥、魚等。在一優選例中,所選哺乳動物是人。 The term "subject" or "subject" includes mammals and non-mammals. Mammals include, but are not limited to, mammals: humans, non-human primates such as orangutans, apes and monkeys; agricultural animals such as cattle, horses, goats, sheep, pigs; livestock such as rabbits, dogs; laboratory animals including rodents, such as Rats, mice and guinea pigs, etc. Non-mammalian animals include, but are not limited to, birds, fish, and the like. In a preferred embodiment, the selected mammal is a human.

給藥途徑Route of administration

適合的給藥途徑包括但不限於,口服、靜脈注射、直腸、氣霧劑、非腸道給藥、眼部給藥、肺部給藥、經皮給藥、陰道給藥、耳道給藥、鼻腔給藥及局部給藥。此外,僅作舉例說明,腸道外給藥,包括肌肉 注射、皮下注射、靜脈注射、髓內注射、心室注射、腹膜內注射、淋巴管內注射、及鼻內注射。 Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, ear canal , nasal administration and topical administration. In addition, by way of example only, parenteral administration, including intramuscular Injection, subcutaneous injection, intravenous injection, intramedullary injection, ventricular injection, intraperitoneal injection, intralymphatic injection, and intranasal injection.

在一方面,此處描述的化合物給藥方式是局部的而不是全身性的給藥方式。在特定的具體實施例中,長效製劑通過植入給藥(例如皮下或肌肉)或通過肌肉注射。此外,在另一具體化實施例中,藥物通過靶向藥物給藥系統來給藥。例如,由器官特異性抗體包裹的脂質體。在這種具體實施例中,所述脂質體被選擇性的導向特定器官並吸收。 In one aspect, the compounds described herein are administered locally rather than systemically. In certain specific embodiments, the depot formulation is administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in another embodiment, the drug is administered by a targeted drug delivery system. For example, liposomes encapsulated by organ-specific antibodies. In this particular embodiment, the liposomes are selectively targeted to specific organs and absorbed.

藥物組合物和劑量Pharmaceutical composition and dosage

本發明還提供藥用組合物,其包含治療有效量的與一種或多種藥用載體(添加劑)和/或稀釋劑一起配製的一種或多種本發明的化合物,和任選的一種或多種上述其它治療劑。可通過任意合適方式給予本發明化合物以用於任意上述用途,例如口服,諸如片劑、丸劑、粉劑、顆粒劑、酏劑、酊劑、懸浮液(包括納米懸浮液、微懸浮液、噴霧乾燥的分散液)、糖漿和乳液;經舌下;含服;經腸胃外,諸如通過皮下、靜脈內、肌內或胸骨內注射或輸注技術(例如以無菌可注射水性或非水性溶液或懸浮液形式);經鼻,包括向鼻膜給藥,諸如通過吸入噴霧;局部,諸如以乳膏劑或軟膏劑形式;或經直腸,諸如以栓劑形式。它們可單獨給藥,但通常使用基於所選給藥途徑和標準藥學實踐選擇的藥物載體給藥。 The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of the present invention formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents, and optionally one or more of the other aforementioned therapeutic agent. The compounds of the present invention may be administered for any of the above uses by any suitable means, eg orally, such as tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups and emulsions; sublingual; buccal; parenterally, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (eg, in the form of sterile injectable aqueous or non-aqueous solutions or suspensions ); nasally, including administration to nasal membranes, such as by inhalation spray; topical, such as in the form of a cream or ointment; or rectally, such as in the form of a suppository. They can be administered alone, but are usually administered using a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

根據本領域技術人員認識範圍內的諸多因素來調配藥用載體。這些因素包括,但不限於:所調配活性劑的類型和性質;含有活性劑的組合物所要給藥的受試者;組合物的預期給藥途徑;及所靶向的治療適應症。藥用載體包括水性和非水性液體介質及各種固體和半固體劑型。 Pharmaceutically acceptable carriers are formulated according to a number of factors within the purview of those skilled in the art. These factors include, but are not limited to: the type and nature of the active agent being formulated; the subject to which the composition containing the active agent is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid media and various solid and semisolid dosage forms.

上述載體可包括除活性劑外的諸多不同成分和添加劑,上述其它成分出於本領域技術人員公知的各種原因包括於製劑中, 例如穩定活性劑、粘合劑等。關於合適的藥用載體和載體選擇中所涉及的因素的描述可參見多個容易獲得的來源,例如Allen L.V.Jr.et al.Remington:The Science and Practice of Pharmacy(2 Volumes),22nd Edition(2012),Pharmaceutical Press。 The above-mentioned carrier may include many different components and additives in addition to the active agent, and the above-mentioned other components are included in the formulation for various reasons well known to those skilled in the art, Examples are stabilized active agents, binders, and the like. A description of suitable pharmaceutical carriers and factors involved in carrier selection can be found in a number of readily available sources such as Allen L.V.Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012 ), Pharmaceutical Press.

當然,本發明化合物的劑量方案取決於已知因素而有所變化,諸如具體藥劑的藥效學特性及其給藥模式和途徑;接受者的物種、年齡、性別、健康狀況、醫學病狀和重量;症狀的性質和程度;同時治療的種類;治療頻率;給藥途徑、患者的腎和肝功能及期望效應。根據一般指導,當用於指定效應時,各活性成分的日口服劑量應為約0.001mg/天至約10-5000mg/天,優選地為約0.01mg/天至約1000mg/天,且最優選地為約0.1mg/天至約250mg/天。在恒速輸注期間,靜脈內最優選劑量應為約0.01mg/kg/分鐘至約10mg/kg/分鐘。本發明化合物可以單一日劑量給藥,或可以每日兩次、三次或四次的分開劑量給藥總日劑量。 Of course, dosage regimens for the compounds of the present invention will vary depending on known factors, such as the pharmacodynamic properties of the particular agent and its mode and route of administration; the recipient's species, age, sex, health, medical condition, and Weight; nature and extent of symptoms; type of concurrent treatment; frequency of treatment; route of administration, renal and hepatic function of the patient, and desired effect. According to general guidance, the daily oral dose of each active ingredient should be from about 0.001 mg/day to about 10-5000 mg/day, preferably from about 0.01 mg/day to about 1000 mg/day, and most preferably, when used for the indicated effect Typically from about 0.1 mg/day to about 250 mg/day. During constant rate infusion, the most preferred intravenous dose should be from about 0.01 mg/kg/minute to about 10 mg/kg/minute. The compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily.

所述化合物通常以與根據預期給藥形式(例如口服片劑、膠囊劑、酏劑和糖漿劑)適當地選擇且與常規藥學實踐相符合的合適藥物稀釋劑、賦形劑或載體(在本文中統稱為藥物載體)的混合物形式進行給藥。 The compounds are usually in the form of suitable pharmaceutical diluents, excipients or carriers (herein) appropriately selected according to the intended form of administration (eg, oral tablets, capsules, elixirs and syrups) and consistent with conventional pharmaceutical practice. are administered in the form of a mixture of drug carriers).

適於給藥的劑型(藥物組合物)可含有約1毫克至約2000毫克活性成分/劑量單位。在這些醫藥組合物中,以組合物的總重量計,活性成分通常將以約0.1-95重量%的量存在。 Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 mg to about 2000 mg of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will generally be present in an amount of about 0.1-95% by weight, based on the total weight of the composition.

用於口服給藥的典型膠囊劑含有至少一種本發明化合物(250mg)、乳糖(75mg)和硬脂酸鎂(15mg)。使該混合物穿過60目網篩,並包裝成1號明膠膠囊。 A typical capsule for oral administration contains at least one compound of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture was passed through a 60 mesh screen and packaged into size 1 gelatin capsules.

典型的可注射製劑可如下製備:以無菌方式將至少一種本發明化合物(250mg)置於瓶中、以無菌方式凍幹並密封。為進行使用,將瓶內容物與2mL生理鹽水混合,以產生可注射製劑。 A typical injectable formulation can be prepared by aseptically placing at least one compound of the invention (250 mg) in a vial, aseptically lyophilizing and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline to produce an injectable formulation.

本發明範圍包括(單獨或與藥物載體組合)包含治療有效量的至少一種本發明化合物作為活性成分的藥物組合物。任選地,本發明化合物可單獨使用、與本發明其它化合物組合使用或與一種或多種其它治療劑(例如抗癌劑或其它藥學活性物質)組合使用。 Within the scope of the present invention are pharmaceutical compositions comprising, either alone or in combination with a pharmaceutical carrier, a therapeutically effective amount of at least one compound of the present invention as an active ingredient. Optionally, the compounds of the present invention may be used alone, in combination with other compounds of the present invention, or in combination with one or more other therapeutic agents (eg, anticancer agents or other pharmaceutically active substances).

不考慮所選擇的給藥路徑,通過本領域技術人員已知的常規方法來將本發的化合物(其可以合適的水合形式使用)和/或本發明的藥物組合物配製成藥用劑量形式。 Regardless of the route of administration chosen, the compounds of the present invention (which may be used in a suitable hydrated form) and/or the pharmaceutical compositions of the present invention are formulated into pharmaceutical dosage forms by conventional methods known to those skilled in the art .

可改變活性成分在本發明的藥物組合物中的實際劑量水準,從而獲得對於實現特定患者的期望的治療回應、組成和給藥模式有效的而對患者無毒的活性成分量。 The actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention can be varied to obtain an amount of active ingredient that is effective in achieving the desired therapeutic response, composition and mode of administration for a particular patient, without being toxic to the patient.

選定的劑量水準會取決於多種因素,包括所用的本發明的特定化合物或其酯、鹽或醯胺的活性;給藥路徑;給藥時間;所用的特定化合物的排泄速率;吸收速率和程度;治療的持續時間;與所用的特定化合物組合使用的其它藥物、化合物和/或物質;所治療的患者的年齡、性別、重量、狀況、一般健康和先前的醫學史等醫學領域公知的因素。 The dose level selected will depend on a variety of factors, including the activity of the particular compound of the invention or its ester, salt or amide employed; the route of administration; the time of administration; the rate of excretion of the particular compound employed; the rate and extent of absorption; Duration of treatment; other drugs, compounds and/or substances used in combination with the particular compound used; age, sex, weight, condition, general health and previous medical history of the patient being treated, factors well known in the medical arts.

具有本領域普通技術的醫生或獸醫可容易地確定並開出有效量的所需藥物組合物。例如,為了達到所期望的治療效果,醫師或獸醫可在低於所需的水準開始藥物組合物中所用的本發明化合物的較量,並逐步增加劑量直至實現所期望的效果。通常,合適日劑量的本發明化合物將是有效產生治療效果的最低劑量的化合物的量。此種有效劑量通常取決於上述因素。通常,口服、靜脈內、腦室內和皮下劑量的用於患者的本發明化合物的範圍為約0.01至約50mg/kg體重/天。如果需要的話,有效日劑量的活性化合物可以兩個、三個、四個、五個、六個或更多個亞劑量在一天當中的適當的間隔分別給藥,任選地呈單位劑型形式。在本發明的某些方面中,服藥為每天一次給藥。 A physician or veterinarian having ordinary skill in the art can readily determine and prescribe an effective amount of the desired pharmaceutical composition. For example, in order to achieve the desired therapeutic effect, a physician or veterinarian may initiate a test of a compound of the present invention used in a pharmaceutical composition at a level below that required and gradually increase the dosage until the desired effect is achieved. In general, a suitable daily dose of a compound of the present invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend on the factors discussed above. Typically, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of the invention for patients will range from about 0.01 to about 50 mg/kg body weight/day. If desired, an effective daily dose of the active compound may be administered separately in two, three, four, five, six or more sub-doses at appropriate intervals throughout the day, optionally in unit dosage form. In certain aspects of the invention, the dosing is once a day.

雖然本發明化合物可單獨給藥,但優選以藥物製劑(組合物)形式給予化合物。 Although the compounds of the present invention may be administered alone, it is preferred to administer the compounds in the form of a pharmaceutical formulation (composition).

試劑盒/產品包裝Kit/Product Packaging

為了用於上述適應症的治療,試劑盒/產品包裝也在此進行描述。這些試劑盒可以由輸送器、藥包或容器盒組成,容器盒可被劃分成多格,以容納一種或多種容器,如管形瓶、試管及類似物等,每個容器中包含所述方法中的單獨一種成分。合適的容器包括瓶子,管形瓶,注射器和試管等。容器由可接受的玻璃或塑膠等材料製作而成。 Kits/product packaging are also described herein for use in the treatment of the above-mentioned indications. These kits may consist of transporters, packs, or boxes of containers, which may be divided into compartments to accommodate one or more containers, such as vials, test tubes, and the like, each containing the method a single ingredient in . Suitable containers include bottles, vials, syringes and test tubes, among others. Containers are made of acceptable materials such as glass or plastic.

舉例來講,容器可裝有一種或多種在此所述的化合物,化合物可能以藥物組分形式存在,也可能與在本文中所述的其它成分組成混合物體存在。容器可有一個無菌輸出口(例如容器可為靜脈輸液包或瓶,瓶塞可被皮下注射器針頭刺破)。這樣的試劑盒可帶有一種化合物,及本文中所述的使用方法的說明、標籤或操作說明。 For example, the container may contain one or more of the compounds described herein, which may be present as pharmaceutical components or in admixture with other ingredients described herein. The container may have a sterile outlet (eg, the container may be an IV pack or bottle, the stopper being pierced by a hypodermic needle). Such kits may carry a compound, along with instructions for use, labeling, or operating instructions as described herein.

一個典型的試劑盒可包括一種或多種容器,為適應商業推廣和使用者對化合物使用的需求,每個容器裝有一種或多種材料(如試劑,也可以是濃縮的母液,和/或器械)。這些材料包括但不局限於緩衝液,稀釋液,濾器,針頭,注射器,輸送器,包,容器,瓶和/或試管,附有內容清單和/或使用說明書,內置包裝也附有說明書。整套的說明都要包括在內。 A typical kit may include one or more containers, each containing one or more materials (eg, reagents, or concentrated stock solutions, and/or instruments) to suit commercial promotion and user needs for the use of the compound. . These materials include, but are not limited to, buffers, diluents, filters, needles, syringes, dispensers, bags, containers, vials and/or tubes, with a list of contents and/or instructions for use, and instructions for the inner packaging. The entire set of instructions is to be included.

標籤可顯示在容器上或與容器緊密相關。標籤出現在容器上即指標籤字母、數位或其它特徵被粘貼、鑄模、刻在容器上;標籤也可出現在裝有多種容器的容器盒或運輸盒內,如在產品插頁中。一個標籤可用來提示內容物的某種特定治療用途。標籤也可標示內容物使用說明,諸如在上述方法中描述的。 Labels can be displayed on or closely associated with the container. The presence of a label on a container means that the label letters, numbers or other features are affixed, molded, or engraved on the container; the label may also appear in a container box or shipping box containing a variety of containers, such as in product inserts. A label may be used to indicate a specific therapeutic use of the contents. The label may also indicate instructions for use of the contents, such as described in the above method.

在本說明書中被描述的所有特徵(包括任何所述的權利要求、摘要和圖),和/或任何方法或過程中涉及的所有步驟,均有可能以任意一種組合存在,除非某些特徵或步驟在同一組合中是相互排斥的。 All features described in this specification (including any stated claims, abstract and figures), and/or all steps involved in any method or process, may be present in any combination unless certain features or Steps are mutually exclusive in the same combination.

本發明提到的上述特徵,或實施例提到的特徵可以任意組合。本案說明書所揭示的所有特徵可與任何組合物形式並用,說明書中所揭示的各個特徵,可以任何可提供相同、均等或相似目的的替代性特徵取代。因此除有特別說明,所揭示的特徵僅為均等或相似特徵的一般性例子。 The above features mentioned in the present invention or the features mentioned in the embodiments can be combined arbitrarily. All the features disclosed in this specification can be used in combination with any composition, and each feature disclosed in the specification can be replaced by any alternative features that serve the same, equivalent or similar purpose. Therefore, unless otherwise stated, the disclosed features are only general examples of equivalent or similar features.

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。下列實施例中未注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,否則所有的百分數、比率、比例、或份數按重量計。 The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. In the following examples, the experimental methods without specific conditions are usually in accordance with conventional conditions or in accordance with the conditions suggested by the manufacturer. All percentages, ratios, ratios, or parts are by weight unless otherwise indicated.

本發明中的重量體積百分比中的單位是本領域技術人員所熟知的,例如是指在100毫升的溶液中溶質的重量。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于本發明方法中。文中所述的較佳實施方法與材料僅作示範之用。 The unit in the weight volume percentage in the present invention is well known to those skilled in the art, for example, it refers to the weight of the solute in 100 ml of the solution. Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be used in the methods of the present invention. Methods and materials for preferred embodiments described herein are provided for illustrative purposes only.

在本發明的優選例中,提供但不局限於以下化合物: In a preferred example of the present invention, the following compounds are provided but not limited to:

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。下列實施例中未注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。 The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. In the following examples, the experimental methods without specific conditions are usually in accordance with conventional conditions, or in accordance with the conditions suggested by the manufacturer. Percentages and parts are by weight unless otherwise indicated.

具體實施例specific embodiment

當未包括製備途徑時,相關中間體是市售的(例如來自Sigma Aldrich,Alfa)。 When preparative routes are not included, relevant intermediates are commercially available (eg from Sigma Aldrich, Alfa).

通用過程Generic process

使用市售試劑而不需進一步純化。1H-NMR譜在Bruker儀器上於500MHz記錄。化學位移值以百萬分率表示,即δ值。以下簡寫用 於NMR信號的多重性:s=單峰,brs=寬峰,d=二重峰,t=三重峰,m=多重峰。耦合常數以J值列出,以Hz測量。NMR和質譜結果根據背景峰校正。色譜是指使用100篩目矽膠進行並在氮氣壓力(快速色譜)條件下完成的柱色譜。用於監測反應的TLC指使用特定流動相和來自Merck的矽膠F254作為固定相進行的TLC。 Commercially available reagents were used without further purification. 1 H-NMR spectra were recorded on a Bruker instrument at 500 MHz. Chemical shift values are expressed in parts per million, ie, delta values. The following abbreviations are used for the multiplicity of NMR signals: s=singlet, brs=broad, d=doublet, t=triplet, m=multiplet. Coupling constants are listed in J values, measured in Hz. NMR and mass spectral results were corrected for background peaks. Chromatography refers to column chromatography using 100 mesh silica gel and performed under nitrogen pressure (flash chromatography). TLC for monitoring the reaction refers to TLC performed using a specific mobile phase and silica gel F254 from Merck as the stationary phase.

LC-MS實驗在以下條件下測量:LC-MS experiments were measured under the following conditions:

儀器:Thermo U3000,ALLtech ELSD,MSQ,UV檢測器結合ELSD和MSD(流出比為4:1)。柱:Waters X-Bridge C-18,3.5μm,4.6x50mm;柱溫:30℃。梯度【時間(min)/溶劑B在A中(%)】:0.00/5.0,0.70/95,1.40/95,1.41/5,1.50/5。(溶劑A=0.01%三氟乙酸在水中;溶劑B=0.01%三氟乙酸在乙腈中)。UV檢測:214/254/280/300nm;DAD檢測:200-400nm;流速:4mL/min;MS:ESI,100-1500m/z Instrumentation: Thermo U3000, ALLtech ELSD, MSQ, UV detector combined ELSD and MSD (efflux ratio 4:1). Column: Waters X-Bridge C-18, 3.5 μm, 4.6×50 mm; column temperature: 30°C. Gradient [time (min)/solvent B in A (%)]: 0.00/5.0, 0.70/95, 1.40/95, 1.41/5, 1.50/5. (Solvent A = 0.01% trifluoroacetic acid in water; Solvent B = 0.01% trifluoroacetic acid in acetonitrile). UV detection: 214/254/280/300nm; DAD detection: 200-400nm; flow rate: 4mL/min; MS: ESI, 100-1500m/z

製備型HPLC通常使用酸性方法(乙腈和水的梯度,各含有0.1%甲酸)用Thermo U3000 AFC-3000;柱:Globalsil C-18 12nm,250 x 20mm,10μm,或相當;流速:20mL/min,進行分離。 Preparative HPLC typically uses an acidic method (gradient of acetonitrile and water, each containing 0.1% formic acid) with a Thermo U3000 AFC-3000; column: Globalsil C-18 12nm, 250 x 20mm, 10μm, or equivalent; flow rate: 20mL/min, to separate.

中間體的合成Synthesis of Intermediates

化合物INT-1的製備:Preparation of compound INT-1 :

Figure 110110282-A0202-12-0026-8
Figure 110110282-A0202-12-0026-8

在回流條件下,將混有4-氟苯乙酮(2.5g,18mmol)和N,N-二甲基甲醯胺二甲基縮醛(2.4g,20mmol)攪拌4小時;反應液濃縮後,粗品用乙醇溶解(10mL),隨後加入水合肼(1.1g,18mmol,80%w/w)。所得反應液在80℃條件下攪拌2小時,反應液濃縮後,所得粗品用矽膠柱層析(石油醚/乙酸乙酯=4/1~1/1)得到黃色固體INT-1a(1.84g,收率:62.7%)。MS(ESI):m/z 163.2(M+H)+. Under reflux conditions, the mixture of 4-fluoroacetophenone (2.5g, 18mmol) and N , N -dimethylformamide dimethyl acetal (2.4g, 20mmol) was stirred for 4 hours; the reaction solution was concentrated after , the crude product was dissolved in ethanol (10 mL), followed by the addition of hydrazine hydrate (1.1 g, 18 mmol, 80% w/w). The obtained reaction solution was stirred at 80° C. for 2 hours. After the reaction solution was concentrated, the obtained crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=4/1~1/1) to obtain yellow solid INT-1a (1.84 g, Yield: 62.7%). MS(ESI): m/z 163.2(M+H) + .

在室溫條件下,將N-溴代丁二醯亞胺(549mg,3.1mmol)加入至溶有化合物INT-1a(500mg,3.1mmol)的N,N-二甲基甲醯胺(5mL)中,所得反應液在相同溫度下攪拌1.5小時。反應液倒入水(50mL)中,並用乙酸乙酯萃取(50mL×3);合併有機相用水和飽和食鹽水(各100mL)洗滌,無水硫酸鈉乾燥,濃縮。所得粗品用矽膠柱層析(石油醚/乙酸乙酯=4/1)得到白色固體INT-1b(553mg,收率:74.4%)。1H NMR(500MHz,Chloroform-d)δ 7.81-7.74(m,2H),7.63(s,1H),7.18-7.11(m,2H);MS(ESI):m/z 241.2(M+H)+. At room temperature, N -bromosuccinimide (549 mg, 3.1 mmol) was added to a solution of compound INT-1a (500 mg, 3.1 mmol) in N , N -dimethylformamide (5 mL) , the resulting reaction solution was stirred at the same temperature for 1.5 hours. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL×3); the combined organic phases were washed with water and saturated brine (100 mL each), dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to obtain INT-1b (553 mg, yield: 74.4%) as a white solid. 1 H NMR (500 MHz, Chloroform- d ) δ 7.81-7.74 (m, 2H), 7.63 (s, 1H), 7.18-7.11 (m, 2H); MS (ESI): m/z 241.2 (M+H) + .

在0℃條件下,將鈉氫(38mg,0.95mmol,60% w/w在煤油)加入至溶有化合物INT-1c(200mg,0.83mmol)的無水四氫呋喃(8mL)溶液中,所得反應液在相同條件下攪拌20分鐘;隨後加入2-(三甲基矽烷基)乙氧甲基氯(207mg,1.24mmol),所得反應液在室溫條件下進一步攪拌2小時。反應液加少許水淬滅後,倒入至水(50mL)中,並用乙酸乙酯萃取(50mL×3);合併有機相用水和飽和食鹽水(各100mL)洗滌,無水硫酸鈉乾燥,濃縮。所得粗品用矽膠柱層析(石油醚/乙酸乙酯=10/1)得到無色油狀物INT-1(298mg,收率:96.7%)。 At 0°C, sodium hydrogen (38 mg, 0.95 mmol, 60% w/w in kerosene) was added to a solution of compound INT-1c (200 mg, 0.83 mmol) in anhydrous tetrahydrofuran (8 mL), and the resulting reaction solution was in The mixture was stirred under the same conditions for 20 minutes; then 2-(trimethylsilyl)ethoxymethyl chloride (207 mg, 1.24 mmol) was added, and the resulting reaction solution was further stirred at room temperature for 2 hours. The reaction solution was quenched with a little water, poured into water (50 mL), and extracted with ethyl acetate (50 mL×3); the combined organic phases were washed with water and saturated brine (100 mL each), dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to obtain INT-1 (298 mg, yield: 96.7%) as a colorless oil.

化合物INT-2的製備:Preparation of compound INT-2 :

Figure 110110282-A0202-12-0027-10
Figure 110110282-A0202-12-0027-10

將環丙甲基酮(160mg,1.9mmol)加入至混有鈉氫(37mg,1.6mmol,60% w/w在煤油)的四氫呋喃(10mL)溶液中,所得反應液在室溫條件下攪拌半小時後加熱升至回流;隨後滴加預先溶有4-氟苯乙酮(250mg,1.6mmol)的四氫呋喃(3mL)溶液。所得反應液在回流狀態下進一步攪拌半小時。冷卻至室溫後,將反應液倒入至1M鹽酸水溶液,調節pH至7-8;並用乙酸乙酯萃取(30mL×2)。合併有機相用水和飽和食鹽水(各50mL)洗滌,無水硫酸鈉乾燥,濃縮。所得粗品用矽膠柱層析(石油醚/乙酸乙酯=20/1~10/1)得到淡黃色油狀物INT-2a(250mg,收率:74.8%)。MS(ESI):m/z 207.4(M+H)+ Cyclopropyl methyl ketone (160 mg, 1.9 mmol) was added to a solution of sodium hydrogen (37 mg, 1.6 mmol, 60% w/w in kerosene) in tetrahydrofuran (10 mL), and the resulting reaction was stirred at room temperature for half a It was heated to reflux after 1 hour; then a solution of 4-fluoroacetophenone (250 mg, 1.6 mmol) in tetrahydrofuran (3 mL) pre-dissolved was added dropwise. The resulting reaction solution was further stirred for half an hour under reflux. After cooling to room temperature, the reaction solution was poured into 1M aqueous hydrochloric acid solution to adjust pH to 7-8; and extracted with ethyl acetate (30 mL×2). The combined organic phases were washed with water and saturated brine (50 mL each), dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=20/1~10/1) to obtain INT-2a (250 mg, yield: 74.8%) as a pale yellow oil. MS(ESI): m/z 207.4(M+H) +

在回流條件下,將溶有化合物INT-2a(250mg,1.2mmol),水合肼(103mg,2.7mmol,80%w/w)的乙醇(5mL)溶液攪拌4小時。反應液冷卻至室溫後濃縮,所得粗品用二氯甲烷(30mL)溶解,並用水和飽和食鹽水(各30mL)洗滌,無水硫酸鈉乾燥,濃縮得到白色固體INT-2b(200mg,收率:81.6%)。MS(ESI):m/z 203.5(M+H)+ Under reflux, a solution of compound INT-2a (250 mg, 1.2 mmol) and hydrazine hydrate (103 mg, 2.7 mmol, 80% w/w) in ethanol (5 mL) was stirred for 4 hours. The reaction solution was cooled to room temperature and concentrated. The obtained crude product was dissolved in dichloromethane (30 mL), washed with water and saturated brine (30 mL each), dried over anhydrous sodium sulfate, and concentrated to obtain a white solid INT-2b (200 mg, yield: 81.6%). MS(ESI): m/z 203.5(M+H) +

在冰浴條件下,將N-碘代丁二醯亞胺(270mg,1.2mmol)加入至溶有化合物INT-2b(200mg,1.0mmol)的N,N-二甲基甲醯胺(5mL)中;所得反應液加熱至90℃條件下攪拌16小時。反應液中加入二氯甲烷和飽和碳酸氫鈉溶液(各30mL);有機相用水和飽和食鹽水(各30mL)洗滌,無水硫酸鈉乾燥,濃縮得到淡黃色油狀物INT-2c(300mg,收率:92.5%)。MS(ESI):m/z 329.2(M+H)+ Under ice bath condition, N -iodosuccinimide (270 mg, 1.2 mmol) was added to N , N -dimethylformamide (5 mL) dissolved with compound INT-2b (200 mg, 1.0 mmol) The resulting reaction solution was heated to 90°C and stirred for 16 hours. Dichloromethane and saturated sodium bicarbonate solution (30 mL each) were added to the reaction solution; the organic phase was washed with water and saturated brine (30 mL each), dried over anhydrous sodium sulfate, and concentrated to give a pale yellow oil INT-2c (300 mg, collected rate: 92.5%). MS(ESI): m/z 329.2(M+H) +

從化合物INT-2c起,參考化合物INT-1合成中的最 後一步,得到化合物INT-2。MS(ESI):m/z 459.1(M+H)+ Starting from compound INT-2c , referring to the last step in the synthesis of compound INT-1 , compound INT-2 is obtained. MS (ESI): m/z 459.1 (M+H) +

化合物INT-3的製備:Preparation of compound INT-3 :

Figure 110110282-A0202-12-0028-11
Figure 110110282-A0202-12-0028-11

從乙酸乙酯和4-氟苯乙酮起,參考化合物INT-2a的合成得到化合物INT-3aFrom ethyl acetate and 4-fluoroacetophenone, the synthesis of reference compound INT-2a gave compound INT-3a .

從化合物INT-3a起,參考化合物INT-2的合成得到化合物INT-3。MS(ESI):m/z 433.0(M+H)+From compound INT-3a , compound INT-3 is obtained by referring to the synthesis of compound INT-2 . MS (ESI): m/z 433.0 (M+H) + .

化合物INT-4的製備:Preparation of compound INT-4 :

Figure 110110282-A0202-12-0028-13
Figure 110110282-A0202-12-0028-13

將2,4-二硝基苯基羥胺(3.1g,15.4mmol)加入至溶有4-(叔丁氧羰基氨基)吡啶(3.0g,15.4mmol)的2-甲基四氫呋喃(15mL)溶液;所得反應液在40℃條件下攪拌4小時,隨後冷卻至室溫後攪拌 過夜。反應液過濾得到黃色固體INT-4a(6.1g,收率:99.6%)。 2,4-Dinitrophenylhydroxylamine (3.1 g, 15.4 mmol) was added to a solution of 4-(tert-butoxycarbonylamino)pyridine (3.0 g, 15.4 mmol) in 2-methyltetrahydrofuran (15 mL); The resulting reaction solution was stirred at 40°C for 4 hours, then cooled to room temperature and stirred overnight. The reaction solution was filtered to obtain yellow solid INT-4a (6.1 g, yield: 99.6%).

將混有化合物INT-4a(1.0g,2.5mmol),丙炔酸乙酯(249mg,2.5mmol)和碳酸鉀(703mg,5.0mmol)的N,N-二甲基甲醯胺(8mL)在室溫條件下攪拌過夜。所得反應液倒入水(80mL)中,並用乙酸乙酯萃取(60mL×3)。合併有機相用水和飽和食鹽水(各 150mL)洗滌,無水硫酸鈉乾燥,濃縮。所得粗品用矽膠柱層析(石油醚/乙酸乙酯=4/1)得到黃色固體INT-4b(378mg,收率:48.7%)。MS(ESI):m/z 306.1(M+H)+. N , N -dimethylformamide (8 mL) was mixed with compound INT-4a (1.0 g, 2.5 mmol), ethyl propiolate (249 mg, 2.5 mmol) and potassium carbonate (703 mg, 5.0 mmol). Stir overnight at room temperature. The resulting reaction solution was poured into water (80 mL), and extracted with ethyl acetate (60 mL×3). The combined organic phases were washed with water and saturated brine (150 mL each), dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to obtain yellow solid INT-4b (378 mg, yield: 48.7%). MS(ESI): m/z 306.1(M+H) + .

將溶有化合物INT-4b(378mg,1.24mmol)和三氟乙酸(1.41g,12.4mmol)的二氯甲烷(12mL)溶液在室溫條件下攪拌過夜。所得反應液倒入水(30mL)中,用二氯甲烷萃取(20mL×2)。合併有機相用飽和碳酸氫鈉,水和飽和食鹽水(各50mL)洗滌,無水硫酸鈉乾燥,濃縮得到黃色固體INT-4c(254mg,收率:100%)。MS(ESI):m/z 206.5(M+H)+. A solution of compound INT-4b (378 mg, 1.24 mmol) and trifluoroacetic acid (1.41 g, 12.4 mmol) in dichloromethane (12 mL) was stirred at room temperature overnight. The obtained reaction solution was poured into water (30 mL), and extracted with dichloromethane (20 mL×2). The combined organic phases were washed with saturated sodium bicarbonate, water and saturated brine (50 mL each), dried over anhydrous sodium sulfate, and concentrated to give yellow solid INT-4c (254 mg, yield: 100%). MS(ESI): m/z 206.5(M+H) + .

在冰浴條件下,將亞硝酸鈉(128mg,1.86mmol)加入至溶有化合物INT-4c(254mg,1.24mmol)的溴化氫水溶液(5mL,48% w/w),並維持5分鐘;隨後在相同條件下加入溴化亞銅(355mg,2.48mmol),並進一步維持10分鐘。所得反應液慢慢加熱攪拌至50℃,反應20分鐘。反應液倒入水(20mL)中,用乙酸乙酯萃取(30mL×2)。合併有機相用飽和碳酸氫鈉,水和飽和食鹽水(各50mL)洗滌,無水硫酸鈉乾燥,濃縮。所得粗品用矽膠柱層析(石油醚/乙酸乙酯=4/1)得到黃色固體INT-4(272mg,收率:81.7%)。1H NMR(500MHz,DMSO-d 6 )δ8.86(d,J=7.5Hz,1H),8.48(s,1H),8.24-8.20(m,1H),7.34(d,J=7.5Hz,1H),4.32(q,J=7.0Hz,2H),1.34(t,J=7.0Hz,3H);MS(ESI):m/z 269.3(M+H)+. Under ice bath conditions, sodium nitrite (128 mg, 1.86 mmol) was added to a solution of compound INT-4c (254 mg, 1.24 mmol) in aqueous hydrogen bromide (5 mL, 48% w/w), and maintained for 5 minutes; Cuprous bromide (355 mg, 2.48 mmol) was then added under the same conditions and maintained for a further 10 minutes. The obtained reaction solution was slowly heated and stirred to 50° C., and reacted for 20 minutes. The reaction solution was poured into water (20 mL) and extracted with ethyl acetate (30 mL×2). The combined organic phases were washed with saturated sodium bicarbonate, water and saturated brine (50 mL each), dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to obtain INT-4 as a yellow solid (272 mg, yield: 81.7%). 1 H NMR (500MHz, DMSO- d 6 ) δ 8.86(d, J =7.5Hz, 1H), 8.48(s, 1H), 8.24-8.20(m, 1H), 7.34(d, J =7.5Hz, 1H), 4.32(q, J =7.0Hz, 2H), 1.34(t, J =7.0Hz, 3H); MS(ESI): m/z 269.3(M+H) + .

化合物INT-5的製備:Preparation of compound INT-5 :

Figure 110110282-A0202-12-0029-14
Figure 110110282-A0202-12-0029-14

將溶有化合物INT-4(100mg,0.37mmol)的硫酸水溶液(40% w/w,5mL)在100℃條件下攪拌5小時。反應液冷卻至室溫後倒入水(20mL)中,並用乙酸乙酯(30mL×2)萃取。合併有機相用飽和碳酸氫 鈉,水和飽和食鹽水(各50mL)洗滌,無水硫酸鈉乾燥,濃縮得到黃色油狀物INT-5(77mg,收率:94.6%)。MS(ESI):m/z 197.3(M+H)+. An aqueous sulfuric acid solution (40% w/w, 5 mL) in which compound INT-4 (100 mg, 0.37 mmol) was dissolved was stirred at 100° C. for 5 hours. The reaction solution was cooled to room temperature, poured into water (20 mL), and extracted with ethyl acetate (30 mL×2). The combined organic phases were washed with saturated sodium bicarbonate, water and saturated brine (50 mL each), dried over anhydrous sodium sulfate, and concentrated to obtain INT-5 (77 mg, yield: 94.6%) as a yellow oil. MS(ESI): m/z 197.3(M+H) + .

化合物INT-6的製備:Preparation of compound INT-6 :

Figure 110110282-A0202-12-0030-15
Figure 110110282-A0202-12-0030-15

在冰浴條件下,將鈉氫(72mg,1.8mmol,60% w/w在煤油)加入至溶有化合物INT-1b(300mg,1.24mmol)的四氫呋喃(8mL)溶液中,並維持20分鐘;隨後在相同條件下加入碘甲烷(353mg,2.5mmol)。所得反應液在攪拌中緩慢升至室溫,並在室溫條件下攪拌過夜。反應液用少許水淬滅,倒入水(40mL)中,並用乙酸乙酯萃取(40mL×2)。合併有機相濃縮後用製備HPLC分離得到黃色固體INT-6(149mg,收率:46.9%)。1H NMR(500MHz,Chloroform-d)δ 7.88-7.81(m,2H),7.45(s,1H),7.15-7.07(m,2H),3.92(s,3H). Under ice bath conditions, sodium hydrogen (72 mg, 1.8 mmol, 60% w/w in kerosene) was added to a solution of compound INT-1b (300 mg, 1.24 mmol) in tetrahydrofuran (8 mL) and maintained for 20 minutes; Iodomethane (353 mg, 2.5 mmol) was then added under the same conditions. The resulting reaction solution was slowly warmed to room temperature with stirring, and stirred at room temperature overnight. The reaction solution was quenched with a little water, poured into water (40 mL), and extracted with ethyl acetate (40 mL×2). The combined organic phases were concentrated and separated by preparative HPLC to obtain INT-6 as a yellow solid (149 mg, yield: 46.9%). 1 H NMR (500MHz, Chloroform- d )δ 7.88-7.81(m,2H), 7.45(s,1H), 7.15-7.07(m,2H), 3.92(s,3H).

化合物INT-7的製備:Preparation of compound INT-7 :

Figure 110110282-A0202-12-0031-16
Figure 110110282-A0202-12-0031-16

在0℃條件下,將溶有1H-吡唑-3-硼酸頻哪酯(500mg,2.6mmol)和N,N-二異丙基乙胺(333mg,2.6mmol)的二氯甲烷(10mL)溶液攪拌半小時,隨後加入2-(三甲基矽烷基)乙氧甲基氯(430mg,2.6mmol)。反應液在攪拌下緩慢升至室溫,並在室溫條件下繼續攪拌過夜。反應液用二氯甲烷(40mL)稀釋,並用飽和碳酸氫鈉和飽和食鹽水(各50mL)洗滌,無水硫酸鈉乾燥,濃縮。所得粗品用矽膠柱層析(二氯甲烷/甲醇=20/1)分離得到淡黃色油狀物INT-7a(500mg,收率:59.8%)。 At 0°C, 1H-pyrazole-3-boronic acid pinacol (500 mg, 2.6 mmol) and N , N -diisopropylethylamine (333 mg, 2.6 mmol) were dissolved in dichloromethane (10 mL) The solution was stirred for half an hour before 2-(trimethylsilyl)ethoxymethyl chloride (430 mg, 2.6 mmol) was added. The reaction solution was slowly warmed to room temperature with stirring, and continued stirring at room temperature overnight. The reaction solution was diluted with dichloromethane (40 mL), washed with saturated sodium bicarbonate and saturated brine (50 mL each), dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was separated by silica gel column chromatography (dichloromethane/methanol=20/1) to obtain INT-7a (500 mg, yield: 59.8%) as a pale yellow oil.

在氮氣氣氛下,將混有化合物INT-7a(150mg,0.46mmol),2-溴-6-甲基吡啶(88mg,0.51mmol),Pd(PPh3)4(53mg,0.046mmol)和碳酸鉀(192mg,1.38mmol)的1,4-二氧六環和水的混合溶液(3.3mL,v/v=10/1)在90℃條件下攪拌16小時。反應液冷卻後用乙酸乙酯(30mL)稀釋,矽藻土過濾。濾液濃縮後用矽膠柱層析(石油醚/乙酸乙酯=5/1)分離得到黃色油狀物INT-7b(120mg,收率:89.6%)。MS(ESI):m/z 290.5(M+H)+ Under nitrogen atmosphere, compound INT-7a (150 mg, 0.46 mmol), 2-bromo-6-methylpyridine (88 mg, 0.51 mmol), Pd(PPh 3 ) 4 (53 mg, 0.046 mmol) and potassium carbonate were mixed (192 mg, 1.38 mmol) of a mixed solution of 1,4-dioxane and water (3.3 mL, v/v=10/1) was stirred at 90° C. for 16 hours. The reaction solution was cooled, diluted with ethyl acetate (30 mL), and filtered through celite. The filtrate was concentrated and separated by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to obtain INT-7b (120 mg, yield: 89.6%) as a yellow oil. MS(ESI): m/z 290.5(M+H) +

從化合物INT-7b起,參照化合物INT-1b的合成得到化合物INT-7。MS(ESI):m/z 368.3(M+H)+ From compound INT-7b , compound INT-7 was obtained by referring to the synthesis of compound INT-1b . MS(ESI): m/z 368.3(M+H)+

化合物INT-8的製備:Preparation of compound INT-8 :

Figure 110110282-A0202-12-0032-17
Figure 110110282-A0202-12-0032-17

從化合物INT-7a和2-溴-6-三氟甲基吡啶起,參照化合物INT-7的合成得到化合物INT-8。MS(ESI):m/z 422.1(M+H)+ Starting from compound INT-7a and 2-bromo-6-trifluoromethylpyridine, compound INT -8 was obtained by referring to the synthesis of compound INT-7 . MS(ESI): m/z 422.1(M+H) +

化合物INT-9的製備:Preparation of compound INT-9 :

Figure 110110282-A0202-12-0032-18
Figure 110110282-A0202-12-0032-18

從化合物INT-7a和2-溴-6-二氟甲基吡啶起,參照化合物INT-7的合成得到化合物INT-9。MS(ESI):m/z 404.1(M+H)+ Starting from compound INT-7a and 2-bromo-6-difluoromethylpyridine, compound INT-9 was obtained by referring to the synthesis of compound INT-7 . MS(ESI): m/z 404.1(M+H) +

化合物INT-10的製備:Preparation of compound INT-10 :

Figure 110110282-A0202-12-0032-19
Figure 110110282-A0202-12-0032-19

從6-三氟甲基吡啶-2-甲酸甲酯起,參照化合物INT-2的合成得到化合物INT-10。MS(ESI):m/z 510.2(M+H)+ Compound INT-10 was obtained by referring to the synthesis of compound INT-2 from methyl 6-trifluoromethylpyridine-2-carboxylate. MS (ESI): m/z 510.2 (M+H) +

化合物INT-11的製備:Preparation of compound INT-11 :

Figure 110110282-A0202-12-0033-24
Figure 110110282-A0202-12-0033-24

從6-甲基吡啶-2-甲酸甲酯起,參照化合物INT-2的合成得到化合物INT-11。MS(ESI):m/z 456.1(M+H)+ Starting from methyl 6-methylpyridine-2-carboxylate, compound INT-11 was obtained by referring to the synthesis of compound INT-2 . MS(ESI): m/z 456.1(M+H) +

化合物INT-12的製備:Preparation of compound INT-12 :

Figure 110110282-A0202-12-0033-22
Figure 110110282-A0202-12-0033-22

從4-氟苯乙酮和環戊甲基酮起,參照化合物INT-2的合成得到化合物INT-12。MS(ESI):m/z 487.0(M+H)+ Starting from 4-fluoroacetophenone and cyclopentanmethyl ketone, compound INT-12 was obtained by referring to the synthesis of compound INT-2 . MS(ESI): m/z 487.0(M+H) +

化合物INT-13的製備:Preparation of compound INT-13 :

Figure 110110282-A0202-12-0033-20
Figure 110110282-A0202-12-0033-20

從化合物INT-4a和3-炔基-2-丁酮起,參照化合物INT-4的合成得到化合物INT-13。MS(ESI):m/z 239.0(M+H)+ From compound INT-4a and 3-alkynyl-2-butanone, compound INT-13 was obtained by referring to the synthesis of compound INT-4 . MS(ESI): m/z 239.0(M+H) +

化合物INT-14的製備:Preparation of compound INT-14 :

Figure 110110282-A0202-12-0034-25
Figure 110110282-A0202-12-0034-25

將草酸二乙酯(554mg,3.8mmol)加入至混有鈉氫(74mg,3.2mmol,60% w/w在煤油)的四氫呋喃(20mL)溶液中,所得反應液在室溫條件下攪拌半小時後加熱升至回流;隨後滴加預先溶有4-氟苯乙酮(500mg,3.6mmol)的四氫呋喃(6mL)溶液。所得反應液在回流狀態下進一步攪拌半小時。冷卻至室溫後,將反應液倒入至1M鹽酸水溶液,調節pH至7-8;並用乙酸乙酯萃取(30mL×2)。合併有機相用水和飽和食鹽水(各50mL)洗滌,無水硫酸鈉乾燥,濃縮。所得粗品用矽膠柱層析(石油醚/乙酸乙酯=20/1~10/1)得到淡黃色油狀物INT-14a(386mg,收率:45.1%)。MS(ESI):m/z 239.3(M+H)+ Diethyl oxalate (554 mg, 3.8 mmol) was added to a solution of sodium hydrogen (74 mg, 3.2 mmol, 60% w/w in kerosene) in tetrahydrofuran (20 mL), and the resulting reaction was stirred at room temperature for half an hour After heating to reflux; a solution of 4-fluoroacetophenone (500 mg, 3.6 mmol) in tetrahydrofuran (6 mL) was then added dropwise. The resulting reaction solution was further stirred for half an hour under reflux. After cooling to room temperature, the reaction solution was poured into 1M aqueous hydrochloric acid solution to adjust pH to 7-8; and extracted with ethyl acetate (30 mL×2). The combined organic phases were washed with water and saturated brine (50 mL each), dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=20/1~10/1) to obtain INT-14a (386 mg, yield: 45.1%) as a pale yellow oil. MS (ESI): m/z 239.3 (M+H) +

從化合物INT-14a起,參照化合物INT-2的合成得 到化合物INT-14。MS(ESI):m/z 491.2(M+H)+ From compound INT-14a , compound INT-14 was obtained by referring to the synthesis of compound INT- 2 . MS(ESI): m/z 491.2(M+H) +

化合物INT-15的製備Preparation of compound INT-15

Figure 110110282-A0202-12-0034-26
Figure 110110282-A0202-12-0034-26

從4-氟苯乙酮和1,1-二氟乙酸乙酯起,參照化合物INT-14的合成得到化合物INT-15。MS(ESI):m/z 469.4(M+H)+ Starting from 4-fluoroacetophenone and ethyl 1,1-difluoroacetate, compound INT-15 was obtained by referring to the synthesis of compound INT-14 . MS (ESI): m/z 469.4 (M+H) +

實施例化合物的合成Synthesis of Example Compounds

實施例1:Example 1:

Figure 110110282-A0202-12-0035-27
Figure 110110282-A0202-12-0035-27

在氮氣氛圍下,將混有化合物INT-4(10mg,37μmol),聯硼酸頻那醇酯(9.9mg,39μmol),Pd(PPh3)2Cl2(2.6mg,3.7μmol)和醋酸鉀(10.9mg,111μmol)的1,4-二氧六環溶液(5mL)在90℃條件下攪拌2小時。隨後在反應液中加入化合物INT-1(15mg,40μmol),Pd(PPh3)4(4.7mg,4.0μmol)磷酸鉀(25.7mg,121μmol)和水(0.5mL);所得混合液用氮氣置換三次,並在100℃條件和氮氣氣氛下攪拌過夜。反應液冷卻至室溫,矽藻土過濾,濃縮。所得粗品用製備型薄層層析板(石油醚/乙酸乙酯=3/1)得到黃色油狀物1a(16.7mg,收率:86.0%)。MS(ESI):m/z 481.0(M+H)+. Under nitrogen atmosphere, compound INT-4 (10 mg, 37 μmol), pinacol diboronate (9.9 mg, 39 μmol), Pd(PPh 3 ) 2 Cl 2 (2.6 mg, 3.7 μmol) and potassium acetate ( A solution of 10.9 mg, 111 μmol) in 1,4-dioxane (5 mL) was stirred at 90° C. for 2 hours. Then compound INT-1 (15 mg, 40 μmol), Pd(PPh 3 ) 4 (4.7 mg, 4.0 μmol) potassium phosphate (25.7 mg, 121 μmol) and water (0.5 mL) were added to the reaction solution; the resulting mixture was replaced with nitrogen three times and stirred overnight at 100°C under nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered through celite, and concentrated. The obtained crude product was subjected to preparative thin layer chromatography (petroleum ether/ethyl acetate=3/1) to obtain a yellow oily substance 1a (16.7 mg, yield: 86.0%). MS(ESI): m/z 481.0(M+H) + .

將溶有化合物1a(16.7mg,35μmol)的三氟乙酸和二氯甲烷的混合溶液(2mL,v/v=1/1)溶液在室溫下攪拌2小時。反應液中加入乙酸乙酯和水(各15mL),然後分液;有機相進一步用飽和碳酸氫鈉和飽和食鹽水洗滌(各10mL),濃縮。所得粗品用製備HPLC分離得到白色固體1(2.0mg,收率:16.4%)。1H NMR(500MHz,DMSO-d6)δ 13.33(s,1H),8.78(d,J=7.3Hz,1H),8.37(s,1H),7.84(s,1H),7.57-7.45(m,3H),7.38-7.16(m,3H),7.09-7.02(m,1H),4.15(q,J=7.1Hz,2H),1.15(t,J=7.1Hz,3H);MS(ESI):m/z 351.2(M+H)+. A mixed solution (2 mL, v/v=1/1) of compound 1a (16.7 mg, 35 μmol) dissolved in trifluoroacetic acid and dichloromethane was stirred at room temperature for 2 hours. Ethyl acetate and water (15 mL each) were added to the reaction solution, followed by liquid separation; the organic phase was further washed with saturated sodium bicarbonate and saturated brine (10 mL each), and concentrated. The obtained crude product was separated by preparative HPLC to give 1 (2.0 mg, yield: 16.4%) as a white solid. 1 H NMR (500MHz, DMSO- d 6) δ 13.33(s, 1H), 8.78(d, J =7.3Hz, 1H), 8.37(s, 1H), 7.84(s, 1H), 7.57-7.45(m ,3H),7.38-7.16(m,3H),7.09-7.02(m,1H),4.15(q, J =7.1Hz,2H),1.15(t, J =7.1Hz,3H); MS(ESI) : m/z 351.2(M+H) + .

實施例2:Example 2:

Figure 110110282-A0202-12-0036-28
Figure 110110282-A0202-12-0036-28

從化合物INT-5起,參照化合物1的合成得到化合物21H NMR(500MHz,DMSO-d6)δ 13.25(s,1H),8.57(d,J=7.2Hz,1H),8.03(brs,1H),7.93(d,J=2.0Hz,1H),7.58-7.43(m,3H),7.30-7.17(m,2H),6.66-6.62(m,1H),6.51-6.48(m,1H);MS(ESI):m/z 279.3(M+H)+. From compound INT-5 , compound 2 was obtained by referring to the synthesis of compound 1 . 1 H NMR (500MHz, DMSO- d 6)δ 13.25(s, 1H), 8.57(d, J =7.2Hz, 1H), 8.03(brs, 1H), 7.93(d, J =2.0Hz, 1H), 7.58-7.43(m,3H), 7.30-7.17(m,2H), 6.66-6.62(m,1H), 6.51-6.48(m,1H); MS(ESI): m/z 279.3(M+H) + .

實施例3:Example 3:

Figure 110110282-A0202-12-0036-29
Figure 110110282-A0202-12-0036-29

將氫氧化鈉水溶液(3M,1mL)加入至溶有化合物1a(147mg,0.31mmol)的甲醇(5mL)溶液;所得反應液在60℃條件下攪拌2小時。反應液冷卻至室溫後,用1M鹽酸水溶液調節pH至3-4,並用乙酸乙酯萃取(20mL×2)。合併有機相用飽和碳酸氫鈉和飽和食鹽水洗滌(各30mL),無水硫酸鈉乾燥,濃縮後得到黃色油狀物3a(122mg,收率:88.1%)。MS(ESI):m/z 453.2(M+H)+. Aqueous sodium hydroxide solution (3M, 1 mL) was added to a solution of compound 1a (147 mg, 0.31 mmol) in methanol (5 mL); the resulting reaction solution was stirred at 60°C for 2 hours. After the reaction solution was cooled to room temperature, the pH was adjusted to 3-4 with 1M aqueous hydrochloric acid, and extracted with ethyl acetate (20 mL×2). The combined organic phases were washed with saturated sodium bicarbonate and saturated brine (30 mL each), dried over anhydrous sodium sulfate, and concentrated to obtain a yellow oil 3a (122 mg, yield: 88.1%). MS(ESI): m/z 453.2(M+H) + .

在溶有化合物3a(122mg,0.27mmol)的1,4-二氧六環(4mL)溶液中加入N,N-二異丙基乙胺(70mg,0.54mmol),HATU(123mg,0.32mmol)和氨(0.4M在1,4-二氧六環中,5mL);所得反應液在50℃條件下攪拌4小時。反應液濃縮,所得粗品用矽膠柱層析(石油醚/乙酸乙酯=1/1)得到淡黃色油狀物3b(100mg,收率: 82.2%)。 To a solution of compound 3a (122 mg, 0.27 mmol) in 1,4-dioxane (4 mL) was added N , N -diisopropylethylamine (70 mg, 0.54 mmol), HATU (123 mg, 0.32 mmol) and ammonia (0.4M in 1,4-dioxane, 5 mL); the resulting reaction was stirred at 50°C for 4 hours. The reaction solution was concentrated, and the obtained crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain a pale yellow oily substance 3b (100 mg, yield: 82.2%).

從化合物3b起,參照化合物1的最後一步反應得到化合物31H NMR(500MHz,Chloroform-d)δ 8.32-8.27(m,1H),8.27-8.23(m,1H),8.20(d,J=2.6Hz,1H),7.84(brs,1H),7.45-7.37(m,2H),7.28-7.24(m,2H),7.09-7.00(m,2H),6.71-6.65(m,1H);MS(ESI):m/z 322.3(M+H)+. Starting from compound 3b , referring to the last step of compound 1 , compound 3 is obtained. 1 H NMR (500MHz, Chloroform- d )δ 8.32-8.27(m,1H), 8.27-8.23(m,1H), 8.20(d, J =2.6Hz,1H), 7.84(brs,1H), 7.45- 7.37(m,2H), 7.28-7.24(m,2H), 7.09-7.00(m,2H), 6.71-6.65(m,1H); MS(ESI): m/z 322.3(M+H) + .

實施例4:Example 4:

Figure 110110282-A0202-12-0037-31
Figure 110110282-A0202-12-0037-31

從化合物INT-5和化合物INT-7起,參照化合物2的合成得到化合物41H NMR(500MHz,DMSO-d6)δ 8.61-8.56(m,1H),8.30(s,1H),7.95(s,1H),7.81(s,1H),7.73(t,J=7.5Hz,1H),7.27-7.22(m,1H),6.90-6.83(m,1H),6.53(s,1H),2.44(s,3H);MS(ESI):m/z 276.3(M+H)+. From compound INT-5 and compound INT-7 , compound 4 was obtained by referring to the synthesis of compound 2 . 1 H NMR (500MHz, DMSO- d 6) δ 8.61-8.56(m, 1H), 8.30(s, 1H), 7.95(s, 1H), 7.81(s, 1H), 7.73(t, J =7.5Hz ,1H),7.27-7.22(m,1H),6.90-6.83(m,1H),6.53(s,1H),2.44(s,3H); MS(ESI): m/z 276.3(M+H) + .

實施例5:Example 5:

Figure 110110282-A0202-12-0037-30
Figure 110110282-A0202-12-0037-30

從化合物INT-5和化合物INT-8起,參照化合物2的合成得到化合物51H NMR(500MHz,DMSO-d6)δ 8.57(d,J=7.5Hz,1H),8.22(s,1H),8.16(t,J=8.0Hz,1H),8.11(d,J=8.0Hz,1H),7.98-7.94(m,1H),7.89-7.84(m,2H),6.89(d,J=7.5Hz,1H),6.50(s,1H);MS(ESI):m/z 330.3(M+H)+. From compound INT-5 and compound INT-8 , compound 5 was obtained by referring to the synthesis of compound 2 . 1 H NMR (500MHz, DMSO- d 6) δ 8.57(d, J =7.5Hz, 1H), 8.22(s, 1H), 8.16(t, J =8.0Hz, 1H), 8.11(d, J =8.0 Hz, 1H), 7.98-7.94(m, 1H), 7.89-7.84(m, 2H), 6.89(d, J =7.5Hz, 1H), 6.50(s, 1H); MS(ESI): m/z 330.3(M+H) + .

實施例6:Example 6:

Figure 110110282-A0202-12-0038-33
Figure 110110282-A0202-12-0038-33

從化合物INT-4和化合物6a起,參照化合物1a的合成得到化合物6a。MS(ESI):m/z 365.3(M+H)+. From compound INT-4 and compound 6a , compound 6a was obtained by referring to the synthesis of compound 1a . MS(ESI): m/z 365.3(M+H) + .

從化合物6a起,參照化合物3b的合成得到化合物61H NMR(500MHz,DMSO-d6)δ 8.67(d,J=7.1Hz,1H),8.49(s,1H),8.20(s,1H),8.11(s,1H),7.64(brs,1H),7.51-7.41(m,2H),7.26-7.16(m,2H),7.03(brs,1H),6.78-6.72(m,1H),3.93(s,3H);MS(ESI):m/z 336.3(M+H)+. From compound 6a , compound 6 was obtained by referring to the synthesis of compound 3b . 1 H NMR (500MHz, DMSO- d 6)δ 8.67(d, J =7.1Hz,1H), 8.49(s,1H), 8.20(s,1H), 8.11(s,1H), 7.64(brs,1H) ), 7.51-7.41(m, 2H), 7.26-7.16(m, 2H), 7.03(brs, 1H), 6.78-6.72(m, 1H), 3.93(s, 3H); MS(ESI): m/ z 336.3(M+H) + .

實施例7:Example 7:

Figure 110110282-A0202-12-0038-34
Figure 110110282-A0202-12-0038-34

從化合物INT-4和化合INT-2起,參照化合物1a的合成得到化合物7a。MS(ESI):m/z 521.5(M+H)+. From compound INT-4 and compound INT-2 , compound 7a was obtained by referring to the synthesis of compound 1a . MS(ESI): m/z 521.5(M+H) + .

從化合物7a起,參照化合物3的合成得到化合物71H NMR(500MHz,DMSO-d6)δ 12.88(brs,1H),8.70(d,J=7.0Hz,1H),8.52(s,1H),8.20(s,1H),7.69(s,1H),7.48-7.38(m,2H),7.19(t,J=9.0Hz,2H),7.02(s,1H),6.81-6.73(m,1H),1.95-1.83(m,1H),0.98-0.83(m,4H);MS(ESI):m/z 362.0(M+H)+. From compound 7a , compound 7 was obtained by referring to the synthesis of compound 3 . 1 H NMR (500MHz, DMSO- d 6) δ 12.88(brs,1H), 8.70(d, J =7.0Hz,1H), 8.52(s,1H), 8.20(s,1H), 7.69(s,1H) ), 7.48-7.38(m, 2H), 7.19(t, J =9.0Hz, 2H), 7.02(s, 1H), 6.81-6.73(m, 1H), 1.95-1.83(m, 1H), 0.98- 0.83 (m, 4H); MS (ESI): m/z 362.0 (M+H) + .

實施例8:Example 8:

Figure 110110282-A0202-12-0039-37
Figure 110110282-A0202-12-0039-37

從化合物INT-4和化合INT-3起,參照化合物7的合成得到化合物81H NMR(500MHz,Methanol-d4)δ 8.51(d,J=7.2Hz,1H),8.44(s,1H),8.15(s,1H),7.45-7.38(m,2H),7.07(s,2H),6.73(s,1H),4.62(s,2H),2.40(s,3H);MS(ESI):m/z 336.2(M+H)+. From compound INT-4 and compound INT-3 , compound 8 was obtained by referring to the synthesis of compound 7 . 1 H NMR(500MHz,Methanol- d 4)δ 8.51(d, J =7.2Hz,1H),8.44(s,1H),8.15(s,1H),7.45-7.38(m,2H),7.07(s , 2H), 6.73(s, 1H), 4.62(s, 2H), 2.40(s, 3H); MS(ESI): m/z 336.2(M+H) + .

實施例9:Example 9:

Figure 110110282-A0202-12-0039-36
Figure 110110282-A0202-12-0039-36

從化合物INT-4和化合INT-7起,參照化合物7的合成得到化合物91H NMR(500MHz,DMSO-d6)δ 13.35(brs,1H),8.66(s,1H),8.48(s,1H),8.40-8.24(m,1H),7.73(t,J=7.5Hz,1H),7.63(s,1H),7.22(s,1H),7.15-6.92(m,2H),2.39(s,3H);MS(ESI):m/z 319.1(M+H)+. From compound INT-4 and compound INT-7 , compound 9 was obtained by referring to the synthesis of compound 7 . 1 H NMR (500MHz, DMSO- d 6) δ 13.35(brs,1H), 8.66(s,1H), 8.48(s,1H), 8.40-8.24(m,1H), 7.73(t, J =7.5Hz ,1H),7.63(s,1H),7.22(s,1H),7.15-6.92(m,2H),2.39(s,3H); MS(ESI): m/z 319.1(M+H) + .

實施例10:Example 10:

Figure 110110282-A0202-12-0039-35
Figure 110110282-A0202-12-0039-35

從化合物INT-4和化合INT-8起,參照化合物7的合成得到化合物101H NMR(500MHz,methanol-d4)δ 8.51(d,J=7.0Hz,1H), 8.42(s,1H),8.21(s,1H),8.10-7.98(m,3H),7.75-7.70(m,1H),7.14(d,J=7.0Hz,1H);MS(ESI):m/z 373.2(M+H)+. From compound INT-4 and compound INT-8 , compound 10 was obtained by referring to the synthesis of compound 7 . 1 H NMR(500MHz, methanol- d 4)δ 8.51(d, J =7.0Hz,1H), 8.42(s,1H), 8.21(s,1H), 8.10-7.98(m,3H), 7.75-7.70 (m,1H),7.14(d, J =7.0Hz,1H); MS(ESI): m/z 373.2(M+H) + .

實施例11:Example 11:

Figure 110110282-A0202-12-0040-38
Figure 110110282-A0202-12-0040-38

從化合物INT-4和化合INT-9起,參照化合物7的合成得到化合物111H NMR(500MHz,Methanol-d4)δ 8.52(d,J=7.0Hz,1H),8.42(s,1H),8.38(s,1H),8.05(s,1H),8.00(t,J=8.0Hz,1H),7.90-7.83(m,1H),7.65(d,J=7.5Hz,1H),7.12-7.08(m,1H),6.65(t,J=45Hz,1H);MS(ESI):m/z 355.0(M+H)+. From compound INT-4 and compound INT-9 , compound 11 was obtained by referring to the synthesis of compound 7 . 1 H NMR(500MHz,Methanol- d 4)δ 8.52(d, J =7.0Hz,1H),8.42(s,1H),8.38(s,1H),8.05(s,1H),8.00(t, J =8.0Hz, 1H), 7.90-7.83(m, 1H), 7.65(d, J =7.5Hz, 1H), 7.12-7.08(m, 1H), 6.65(t, J =45Hz, 1H); MS( ESI): m/z 355.0(M+H) + .

實施例12:Example 12:

Figure 110110282-A0202-12-0040-39
Figure 110110282-A0202-12-0040-39

從化合物INT-4和化合INT-10起,參照化合物7的合成得到化合物121H NMR(500MHz,Methanol-d4)δ 8.54(d,J=7.5Hz,1H),8.45(s,1H),8.27(s,1H),7.98(t,J=7.5Hz,1H),7.65(d,J=7.5Hz,1H),7.04-6.99(m,1H),2.02-1.93(m,1H),1.04-0.95(m,2H),0.91-0.85(m,2H);MS(ESI):m/z 413.3(M+H)+. From compound INT-4 and compound INT-10 , compound 12 was obtained by referring to the synthesis of compound 7 . 1 H NMR(500MHz,Methanol- d 4)δ 8.54(d, J =7.5Hz,1H),8.45(s,1H),8.27(s,1H),7.98(t, J =7.5Hz,1H), 7.65(d, J =7.5Hz,1H), 7.04-6.99(m,1H), 2.02-1.93(m,1H), 1.04-0.95(m,2H), 0.91-0.85(m,2H); MS( ESI): m/z 413.3(M+H) + .

實施例13:Example 13:

Figure 110110282-A0202-12-0041-42
Figure 110110282-A0202-12-0041-42

從化合物INT-4和化合INT-11起,參照化合物7的合成得到化合物131H NMR(500MHz,Methanol-d4)δ 8.70-8.42(m,2H),8.33(s,1H),7.72-7.55(m,1H),7.49-7.07(m,2H),7.01-6.85(m,1H),2.59-2.30(m,3H),2.09-1.81(m,1H),1.08-0.85(m,4H);MS(ESI):m/z 359.3(M+H)+. From compound INT-4 and compound INT-11 , compound 13 was obtained by referring to the synthesis of compound 7 . 1 H NMR(500MHz, Methanol- d 4)δ 8.70-8.42(m, 2H), 8.33(s, 1H), 7.72-7.55(m, 1H), 7.49-7.07(m, 2H), 7.01-6.85( m,1H), 2.59-2.30(m,3H), 2.09-1.81(m,1H), 1.08-0.85(m,4H); MS(ESI): m/z 359.3(M+H) + .

實施例14:Example 14:

Figure 110110282-A0202-12-0041-41
Figure 110110282-A0202-12-0041-41

從化合物INT-4和化合INT-10起,參照化合物12的合成,將氨換成二甲胺得到化合物141H NMR(500MHz,Methanol-d4)δ 8.53(s,1H),8.26(s,1H),8.12-7.93(m,3H),7.64(s,1H),7.03-7.00(m,1H),3.20(s,6H),2.05-1.97(m,1H),1.05-0.95(m,2H),0.92-0.85(m,2H);MS(ESI):m/z 441.2(M+H)+. Starting from compound INT-4 and compound INT-10 , referring to the synthesis of compound 12 , compound 14 was obtained by replacing ammonia with dimethylamine. 1 H NMR(500MHz, Methanol- d 4)δ 8.53(s,1H), 8.26(s,1H), 8.12-7.93(m,3H), 7.64(s,1H), 7.03-7.00(m,1H) ,3.20(s,6H),2.05-1.97(m,1H),1.05-0.95(m,2H),0.92-0.85(m,2H); MS(ESI): m/z 441.2(M+H) + .

實施例15:Example 15:

Figure 110110282-A0202-12-0041-40
Figure 110110282-A0202-12-0041-40

從化合物INT-4和化合INT-10起,參照化合物12的合成,將氨換成甲胺得到化合物151H NMR(500MHz,Methanol-d4)δ 8.52(s, 1H),8.36(s,1H),8.27(s,1H),8.06-7.94(m,2H),7.64(d,J=7.5Hz,1H),7.00(dd,J=7.0,2.0Hz,1H),2.90(s,3H),1.99(s,1H),1.00(s,2H),0.91-0.84(m,2H);MS(ESI):m/z 427.2(M+H)+. Starting from compound INT-4 and compound INT-10 , referring to the synthesis of compound 12 , ammonia was replaced with methylamine to obtain compound 15 . 1 H NMR(500MHz, Methanol- d 4)δ 8.52(s, 1H), 8.36(s, 1H), 8.27(s, 1H), 8.06-7.94(m, 2H), 7.64(d, J=7.5Hz) ,1H),7.00(dd,J=7.0,2.0Hz,1H),2.90(s,3H),1.99(s,1H),1.00(s,2H),0.91-0.84(m,2H); MS( ESI): m/z 427.2(M+H) + .

實施例16:Example 16:

Figure 110110282-A0202-12-0042-44
Figure 110110282-A0202-12-0042-44

從化合物INT-4和化合INT-2起,參照化合物7的合成,將氨換成乙醇胺得到化合物161H NMR(500MHz,Methanol-d4)δ 8.50(d,J=7.0Hz,1H),8.42(s,1H),8.31(s,1H),7.44-7.39(m,2H),7.08(t,J=8.5Hz,2H),6.78(d,J=7.0Hz,1H),3.71(t,J=6.0Hz,2H),3.49(t,J=6.0Hz,2H),2.04-1.96(m,1H),1.05-0.96(m,2H),0.92-0.85(m,2H);m/z 405.7(M+H)+. Starting from compound INT-4 and compound INT-2 , referring to the synthesis of compound 7 , ammonia was replaced with ethanolamine to obtain compound 16 . 1 H NMR(500MHz,Methanol- d 4)δ 8.50(d,J=7.0Hz,1H),8.42(s,1H),8.31(s,1H),7.44-7.39(m,2H),7.08(t ,J=8.5Hz,2H),6.78(d,J=7.0Hz,1H),3.71(t,J=6.0Hz,2H),3.49(t,J=6.0Hz,2H),2.04-1.96(m ,1H),1.05-0.96(m,2H),0.92-0.85(m,2H); m/z 405.7(M+H) + .

實施例17:Example 17:

Figure 110110282-A0202-12-0042-45
Figure 110110282-A0202-12-0042-45

從化合物INT-4和化合INT-2起,參照化合物7的合成得到化合物171H NMR(500MHz,Methanol-d4)δ 8.51(d,J=7.0Hz,1H),8.44(s,1H),8.17(s,1H),7.42-7.38(m,2H),7.05(t,J=8.5Hz,2H),6.73(d,J=8.0Hz,1H),2.13-2.01(m,2H),1.89-1.71(m,5H),1.71-1.63(m,2H);m/z 389.7(M+H)+. From compound INT-4 and compound INT-2 , compound 17 was obtained by referring to the synthesis of compound 7 . 1 H NMR(500MHz, Methanol- d 4)δ 8.51(d,J=7.0Hz,1H),8.44(s,1H),8.17(s,1H),7.42-7.38(m,2H),7.05(t ,J=8.5Hz,2H),6.73(d,J=8.0Hz,1H),2.13-2.01(m,2H),1.89-1.71(m,5H),1.71-1.63(m,2H); m/ z 389.7(M+H) + .

實施例18:Example 18:

Figure 110110282-A0202-12-0043-47
Figure 110110282-A0202-12-0043-47

從化合物INT-13和化合物INT-2起,參照化合物1的合成得到化合物181H NMR(500MHz,Methanol-d4)δ 8.60(d,J=7.2Hz,1H),8.55(s,1H),8.38(s,1H),7.42(m,2H),7.15-7.05(m,2H),6.96(s,1H),2.55(s,3H),2.12-1.96(m,1H),0.99(m,4H);m/z 361.2(M+H)+. From compound INT-13 and compound INT-2 , compound 18 was obtained by referring to the synthesis of compound 1 . 1 H NMR(500MHz,Methanol- d 4)δ 8.60(d,J=7.2Hz,1H),8.55(s,1H),8.38(s,1H),7.42(m,2H),7.15-7.05(m ,2H),6.96(s,1H),2.55(s,3H),2.12-1.96(m,1H),0.99(m,4H); m/z 361.2(M+H) + .

實施例19:Example 19:

Figure 110110282-A0202-12-0043-46
Figure 110110282-A0202-12-0043-46

從化合物7a起,參照化合物1合成中的最後一步得到化合物19a。m/z 391.2(M+H)+. Starting from compound 7a , referring to the last step in the synthesis of compound 1 , compound 19a was obtained. m/z 391.2(M+H) + .

在冰浴條件下,將二異丁基氫化鋁(83μL,2M在甲苯中)滴加至溶有化合物19a(40mg,0.10mmol)的二氯甲烷(1mL)溶液中;所得混合液液在相同條件下攪拌半小時。反應液隨後加入到酒石酸鉀鈉溶液中(5mL,1M水溶液),經乙酸乙酯萃取;有機相減壓濃縮後,所得粗品用製備HPLC分離得到白色固體19(5.2mg,收率:14.6%)。1H NMR(500MHz,Methanol-d4)δ 8.44(d,J=7.2Hz,1H),7.95(s,1H),7.70(s,1H),7.44(dd,J=8.5,5.4Hz,2H),7.08(m,2H),6.71(m,1H),4.76(s,2H),2.01(m,1H),0.94(m,4H);m/z 349.3(M+H)+. In an ice bath, diisobutylaluminum hydride (83 μL, 2M in toluene) was added dropwise to a solution of compound 19a (40 mg, 0.10 mmol) in dichloromethane (1 mL); the resulting mixture was in the same Stir for half an hour. The reaction solution was then added to potassium sodium tartrate solution (5 mL, 1M aqueous solution), extracted with ethyl acetate; after the organic phase was concentrated under reduced pressure, the obtained crude product was separated by preparative HPLC to obtain white solid 19 (5.2 mg, yield: 14.6%) . 1 H NMR(500MHz,Methanol- d 4)δ 8.44(d,J=7.2Hz,1H),7.95(s,1H),7.70(s,1H),7.44(dd,J=8.5,5.4Hz,2H ), 7.08(m, 2H), 6.71(m, 1H), 4.76(s, 2H), 2.01(m, 1H), 0.94(m, 4H); m/z 349.3(M+H) + .

實施例20:Example 20:

Figure 110110282-A0202-12-0044-50
Figure 110110282-A0202-12-0044-50

從化合物INT-14和化合物INT-4起,參照化合物1和化合物3的合成得到化合物20a。m/z 394.3(M+H)+. From compound INT-14 and compound INT-4 , compound 20a was obtained by referring to the synthesis of compound 1 and compound 3 . m/z 394.3(M+H) + .

從化合物20a起,參照化合物19的最後一步合成得到化合物201H NMR(500MHz,Methanol-d4)δ 13.31(s,1H),8.69(d,J=7.0Hz,1H),8.53-8.48(m,1H),8.09(s,1H),7.49-7.38(m,2H),7.29-7.13(m,2H),7.01-6.75(m,1H),4.49(s,2H);m/z 352.2(M+H)+. Starting from compound 20a , compound 20 was synthesized with reference to the last step of compound 19 . 1 H NMR(500MHz, Methanol- d 4)δ 13.31(s,1H),8.69(d,J=7.0Hz,1H),8.53-8.48(m,1H),8.09(s,1H),7.49-7.38 (m,2H), 7.29-7.13(m,2H), 7.01-6.75(m,1H), 4.49(s,2H); m/z 352.2(M+H) + .

實施例21:Example 21:

Figure 110110282-A0202-12-0044-51
Figure 110110282-A0202-12-0044-51

從化合物INT-15和化合物INT-4起,參照化合物1和化合物3的合成得到化合物211HNMR(500MHz,Methanol-d4)δ 8.56(d,J=7.0Hz,1H),8.44(s,1H),8.23(s,1H),7.42(dd,J=8.5,5.0Hz,2H),7.13(t,J=8.5Hz,2H),6.90-6.83(m,1H),1.36-1.19(m,1H);m/z 372.3(M+H)+. From compound INT-15 and compound INT-4 , compound 21 was obtained by referring to the synthesis of compound 1 and compound 3 . 1 HNMR(500MHz,Methanol- d 4)δ 8.56(d,J=7.0Hz,1H),8.44(s,1H),8.23(s,1H),7.42(dd,J=8.5,5.0Hz,2H) ,7.13(t,J=8.5Hz,2H),6.90-6.83(m,1H),1.36-1.19(m,1H); m/z 372.3(M+H) + .

測試實施例Test Example

化合物對TGFβRI激酶(ALK5)活性抑制作用的測定:Determination of Inhibitory Effect of Compounds on TGFβRI Kinase (ALK5) Activity:

TGFβRI激酶購買自Carna(Cat # 09-141)。在384孔板(Greiner,Cat #784075)中加入2μl用激酶緩衝液(40mM Tris PH 7.5,20mM MgCl2,1mM DTT,1mg/ml BSA)配製的酶溶液(TGFβRI激酶在最終反應體系中為25nM)。對於陰性對照則加入2μl激酶緩衝液。將化合物用DMSO配製成10mM的儲存液,在檢測化合物之前根據起始濃度的需要,用DMSO對化合物進行二次稀釋。取2.5μl化合物加入47.5μl ddH2O中,按照3倍稀釋方法進行稀釋,每個化合物設置10個濃度點。化合物稀釋完成後,取1μl加入酶溶液中。充分混勻後室溫孵育10min(最終反應體系中DMSO濃度為1%)。對於陰性對照和陽性對照,則加入1μl含5%DMSO的水溶液。最後加入2μl含有ATP以及TGFβRI激酶多肽底物(Signalchem,Cat # T36-58)的混合液(ATP最終濃度為3.5μM,底物最終濃度為0.1μg/ul),充分混勻後置於28度反應120min。最後使用ADP-Glo Kinase Assay Kit(Promega,Cat # V9102)進行檢測。使用Molecular Devices,SpectraMax i3x.讀取最終化學發光信號。採用XLFIT對所得到的資料進行4參數曲線擬合併計算IC50TGFβRI kinase was purchased from Carna (Cat # 09-141). To a 384-well plate (Greiner, Cat #784075) was added 2 μl of enzyme solution (TGFβRI kinase 25 nM in the final reaction) in kinase buffer (40 mM Tris pH 7.5, 20 mM MgCl 2 , 1 mM DTT, 1 mg/ml BSA) ). For negative controls 2 μl of kinase buffer was added. Compounds were prepared as 10 mM stock solutions in DMSO, and compounds were diluted a second time in DMSO as needed for the starting concentration prior to assaying the compound. 2.5 μl of compound was added into 47.5 μl of ddH 2 O, and diluted according to the 3-fold dilution method, and 10 concentration points were set for each compound. After compound dilution was completed, 1 μl was added to the enzyme solution. After thorough mixing, incubate at room temperature for 10 min (the DMSO concentration in the final reaction system is 1%). For negative and positive controls, 1 μl of 5% DMSO in water was added. Finally, 2 μl of a mixture containing ATP and TGFβRI kinase polypeptide substrate (Signalchem, Cat # T36-58) was added (the final concentration of ATP was 3.5 μM, and the final concentration of substrate was 0.1 μg/ul), and the mixture was thoroughly mixed and placed at 28°C. The reaction was carried out for 120 min. Finally, the ADP-Glo Kinase Assay Kit (Promega, Cat # V9102) was used for detection. The final chemiluminescent signal was read using Molecular Devices, SpectraMax i3x. A 4-parameter curve fit was performed on the obtained data using XLFIT and IC50 was calculated.

化合物對p38α激酶活性抑制作用的測定:Determination of the inhibitory effect of compounds on p38α kinase activity:

p38α激酶購買自SignalChem(Cat # M39-10BG)。在384孔板(Greiner,Cat #784075)中加入2μl用激酶緩衝液(40mM Tris PH 7.5,20mM MgCl2,0.05mM DTT,0.1mg/ml BSA)配製的酶溶液(p38α激酶在最終反應體系中為0.8ng/ul)。對於陰性對照則加入2μl激酶緩衝液。將化合物用DMSO配製成10mM的儲存液,在檢測化合物之前根據起始濃度的需要,用DMSO對化合物進行二次稀釋。取2.5μl化合物加入47.5μl ddH2O中,按照3倍稀釋方法進行稀釋,每個化合物設置10個濃度點。化合物稀釋完成後,取1μl加入酶溶液中。充分 混勻後室溫孵育10min(最終反應體系中DMSO濃度為1%)。對於陰性對照和陽性對照,則加入1μl含5%DMSO的水溶液。最後加入2μl含有ATP以及p38激酶多肽底物(Signalchem,Cat #P03-58)的混合液(ATP最終濃度為50μM,底物最終濃度為0.125μg/μl),充分混勻後置於25度反應120min。最後使用ADP-Glo Kinase Assay Kit(Promega,Cat # V9102)進行檢測。使用Molecular Devices,SpectraMax i3x.讀取最終化學發光信號。採用XLFIT對所得到的資料進行4參數曲線擬合併計算IC50p38α kinase was purchased from SignalChem (Cat # M39-10BG). Add 2 μl of enzyme solution (p38α kinase in the final reaction) in kinase buffer (40 mM Tris pH 7.5, 20 mM MgCl 2 , 0.05 mM DTT, 0.1 mg/ml BSA) in a 384-well plate (Greiner, Cat #784075). is 0.8ng/ul). For negative controls 2 μl of kinase buffer was added. Compounds were prepared as 10 mM stock solutions in DMSO, and compounds were diluted a second time in DMSO as needed for the starting concentration prior to assaying the compound. 2.5 μl of compound was added into 47.5 μl of ddH 2 O, and diluted according to the 3-fold dilution method, and 10 concentration points were set for each compound. After compound dilution was completed, 1 μl was added to the enzyme solution. After thorough mixing, incubate at room temperature for 10 min (the DMSO concentration in the final reaction system is 1%). For negative and positive controls, 1 μl of 5% DMSO in water was added. Finally, 2 μl of a mixture containing ATP and p38 kinase polypeptide substrate (Signalchem, Cat #P03-58) was added (the final concentration of ATP was 50 μM, and the final concentration of the substrate was 0.125 μg/μl), and the mixture was thoroughly mixed and placed at 25 degrees for reaction 120min. Finally, the ADP-Glo Kinase Assay Kit (Promega, Cat # V9102) was used for detection. The final chemiluminescent signal was read using Molecular Devices, SpectraMax i3x. A 4-parameter curve fit was performed on the obtained data using XLFIT and IC50 was calculated.

實施例中所列化合物對於ALK5和p38α的激酶活性抑制作用的結果: Results of the inhibition of the kinase activity of ALK5 and p38α by the compounds listed in the Examples:

Figure 110110282-A0202-12-0046-52
Figure 110110282-A0202-12-0046-52

化合物對TGFβRI受體Smad信號通路的抑制活性的測定:Determination of Inhibitory Activity of Compounds on TGFβRI Receptor Smad Signaling Pathway:

收集HEK-Blue TGFβ cells(Invivogen,Cat# hkb-tgfb),並用10% FBS的DMEM調整細胞密度為1.25×106cells/ml,並以每孔40μl加入96孔板中。將化合物用DMSO配製成10mM的儲存液,在檢測化合物之前根據起始濃度的需要,用DMSO對化合物進行二次稀釋。取2.5μl化合物加入1ml完全培養基中,吹打混勻,用含0.25% DMSO的DMEM培養基對化合物進行3倍稀釋(100μl體系中DMSO濃度為0.1%)。取40μl配製好的化合物至96孔細胞板中,陽性對照以及陰性對照中加入40ul含0.25%DMSO的培養基,於37℃ 5% CO2培養箱中孵育2小時。每孔加入20μl人重組TGFβ1(Invivogen,cat#Rcyc-htgfb1),其最終濃度為0.1ng/ml。置於37℃ 5% CO2中培養24小時。24小時後取60μl上清用於分泌型鹼性磷酸酶(SEAP)檢測,細胞板中補加60ul/well的培養基用於細胞活性檢測。SEAP檢測採用Great EscApe SEAP chemiluminescence KIT(Clontech,Cat#631738)進行檢測,細胞活性檢測採用CellTiter-Glo Luminescent Cell Viability Assay(Promega,Cat# G7573)進行檢測。使用Molecular Devices,SpectraMax i3x.讀取最終化學發光信號。採用XLFIT對所得到的資料進行4參數曲線擬合併計算IC50HEK-Blue TGFβ cells (Invivogen, Cat# hkb-tgfb) were collected and adjusted to a cell density of 1.25×10 6 cells/ml with 10% FBS in DMEM, and 40 μl per well was added to a 96-well plate. Compounds were prepared as 10 mM stock solutions in DMSO, and compounds were diluted a second time in DMSO as needed for the starting concentration prior to assaying the compound. 2.5 μl of compound was added to 1 ml of complete medium, mixed by pipetting, and the compound was diluted 3-fold with DMEM medium containing 0.25% DMSO (the concentration of DMSO in 100 μl system was 0.1%). Take 40 μl of the prepared compound into a 96-well cell plate, add 40 μl of medium containing 0.25% DMSO to the positive control and negative control, and incubate in a 37°C 5% CO 2 incubator for 2 hours. 20 μl of human recombinant TGFβ1 (Invivogen, cat#Rcyc-htgfb1) was added to each well at a final concentration of 0.1 ng/ml. Incubate for 24 hours at 37°C in 5% CO 2 . 24 hours later, 60 μl of the supernatant was taken for secreted alkaline phosphatase (SEAP) detection, and 60 μl/well of medium was added to the cell plate for cell activity detection. The SEAP assay was performed with the Great EscApe SEAP chemiluminescence KIT (Clontech, Cat#631738), and the cell viability assay was performed with the CellTiter-Glo Luminescent Cell Viability Assay (Promega, Cat# G7573). The final chemiluminescent signal was read using Molecular Devices, SpectraMax i3x. A 4-parameter curve fit was performed on the obtained data using XLFIT and IC50 was calculated.

實施例中所列化合物對於TGFβRI受體Smad信號通路的抑制活性的結果: Results of the inhibitory activity of the compounds listed in the Examples on the TGFβRI receptor Smad signaling pathway:

Figure 110110282-A0202-12-0047-53
Figure 110110282-A0202-12-0047-53

Figure 110110282-A0202-12-0048-54
Figure 110110282-A0202-12-0048-54

Claims (8)

一種式(I)化合物或其藥學上可接受的鹽或異構體,其中所述式(I)化合物具有以下結構:
Figure 110110282-A0305-02-0051-1
其中,Cy表示被0、1、2、3個取代基所取代的C6-C10芳基或者5-10元雜芳基,其中所述的取代基選自:鹵素、C1-C6烷基、C3-C6環烷基、鹵代C1-C6烷基、-ORa、氰基、硝基、NRaRb、-SO2Ra、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-P(O)RaRb;R1表示氫、鹵素、C1-C6烷基、C3-C6環烷基、羥基(C1-C6烷基)、鹵代C1-C6烷基;R2表示氫、C1-C6烷基、C3-C6環烷基、羥基(C1-C6烷基)、鹵代C1-C6烷基、-ORa、氰基、硝基、NRaRb、-SO2Ra、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Rb、-SO2NRaRb、-NRaSO2Rb;R3表示氫、鹵素、C1-C6烷基、C3-C6環烷基、羥基(C1-C6烷基)、鹵代C1-C6烷基、-ORa、氰基、硝基、NRaRb、-SO2Ra、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Rb、-SO2NRaRb、-NRaSO2Rb;R4表示氫、C1-C6烷基、C2-C6烯基、C3-C6環烷基、鹵代C1-C6烷基、-ORa、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、羥基(C1-C6烷基);R5表示氫、C1-C6烷基、C2-C6烯基、C3-C6環烷基、鹵代C1-C6烷基;或者R4、R5與其所連接的原子一起形成5-8元飽和或不飽和環,該環中還可以任意地含有0、1或2個選自N、O、S的雜原子;其中,Ra、Rb分別各自獨立地表示氫、C1-C6烷基、C2-C6烯基、 C3-C6環烷基、鹵代C1-C6烷基;或者Ra、Rb與其所連接的原子一起形成5-8元環,該環中還可以任意地含有0、1或2個選自N、O、S的雜原子;n表示0、1、2或3。
A compound of formula (I) or a pharmaceutically acceptable salt or isomer thereof, wherein said compound of formula (I) has the following structure:
Figure 110110282-A0305-02-0051-1
Wherein, Cy represents a C 6 -C 10 aryl group or a 5-10-membered heteroaryl group substituted by 0, 1, 2, and 3 substituents, wherein the substituents are selected from: halogen, C 1 -C 6 Alkyl, C 3 -C 6 cycloalkyl, halogenated C 1 -C 6 alkyl, -OR a , cyano, nitro, NR a R b , -SO 2 R a , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -P(O)R a R b ; R 1 represents hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 ring Alkyl, hydroxyl (C 1 -C 6 alkyl), halogenated C 1 -C 6 alkyl; R 2 represents hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, hydroxyl (C 1 -C 6 alkyl), halogenated C 1 -C 6 alkyl, -OR a , cyano, nitro, NR a R b , -SO 2 R a , -C(O)R a , -C(O ) OR a , -C(O)NR a R b , -NR a C(O) R b , -SO 2 NR a R b , -NR a SO 2 R b ; R 3 represents hydrogen, halogen, C 1 - C 6 alkyl, C 3 -C 6 cycloalkyl, hydroxy (C 1 -C 6 alkyl), halogenated C 1 -C 6 alkyl, -OR a , cyano, nitro, NR a R b , -SO 2 R a , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R b , -SO 2 NR a R b , -NR a SO 2 R b ; R 4 represents hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, halogenated C 1 -C 6 alkyl, -OR a , -C(O)R a , -C(O)OR a , -C(O)NR a R b , hydroxyl (C 1 -C 6 alkyl); R 5 represents hydrogen, C 1 -C 6 alkane base, C 2- C 6 alkenyl, C 3 -C 6 cycloalkyl, halogenated C 1 -C 6 alkyl; or R 4 , R 5 together with the atoms to which they are attached form a 5-8 membered saturated or unsaturated ring, the ring may optionally contain 0, 1 or 2 heteroatoms selected from N, O, S; wherein, R a and R b each independently represent hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, halogenated C 1 -C 6 alkyl; or R a , R b and the atoms to which they are attached together form a 5-8-membered ring, which can also Optionally contains 0, 1 or 2 heteroatoms selected from N, O, S; n represents 0, 1, 2 or 3.
如請求項1所述的式(I)化合物或其藥學上可接受的鹽或異構體,其中所述式(I)化合物具有以下式(II)結構:
Figure 110110282-A0305-02-0052-2
其中,R1、R3、R4、R5、Ra、Rb和n具有如請求項1所述的定義;R2表示氫、C1-C6烷基、C3-C6環烷基、羥基(C1-C6烷基)、鹵代C1-C6烷基;W表示CRL或者N;R6表示氫、鹵素、C1-C6烷基、C3-C6環烷基、鹵代C1-C6烷基、-ORa、氰基、硝基、NRaRb、-SO2Ra、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-P(O)RaRb;其中,RL表示氫、鹵素、C1-C6烷基、C3-C6環烷基、鹵代C1-C6烷基、-ORa、氰基、硝基、NRaRb、-SO2Ra、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-P(O)RaRb;其中,o表示0、1、2或3。
The compound of formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt or isomer thereof, wherein the compound of formula (I) has the following structure of formula (II):
Figure 110110282-A0305-02-0052-2
wherein, R 1 , R 3 , R 4 , R 5 , R a , R b and n have the definitions as described in claim 1; R 2 represents hydrogen, C 1 -C 6 alkyl, C 3 -C 6 ring Alkyl, hydroxy (C 1 -C 6 alkyl), halogenated C 1 -C 6 alkyl; W represents CR L or N; R 6 represents hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogenated C 1 -C 6 alkyl, -OR a , cyano, nitro, NR a R b , -SO 2 R a , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -P(O)R a R b ; wherein, RL represents hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogenated C 1 -C 6 alkyl, -OR a , cyano, nitro, NR a R b , -SO 2 R a , -C(O)R a , -C(O)OR a , -C(O) NR a R b , -P(O)R a R b ; wherein o represents 0, 1, 2 or 3.
如請求項1-2任一項所述的式(I)化合物或其藥學上可接受的鹽或異構體,其中所述式(I)化合物選自:
Figure 110110282-A0305-02-0053-3
The compound of formula (I) or a pharmaceutically acceptable salt or isomer thereof according to any one of claims 1-2, wherein the compound of formula (I) is selected from:
Figure 110110282-A0305-02-0053-3
一種藥物組合物,其包含權利要求1至3任一項所述的式(I)化合物或其藥學上可接受的鹽或異構體,以及任選的藥學上可接受的載體。 A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or isomer thereof, and an optional pharmaceutically acceptable carrier. 如請求項4所述的藥物組合物,其進一步包含另外的治療劑和/或 檢查點抑制劑,所述另外的治療劑優選地選自苯丁酸氮芥、美法侖、環磷醯胺、異環磷醯胺、白消安、卡莫司汀、洛莫司汀、鏈脲佐菌素、順鉑、卡鉑、奧沙利鉑、達卡巴嗪、替莫唑胺、丙卡巴肼、甲氨蝶呤、氟尿嘧啶、阿糖胞苷、吉西他濱、巰基嘌呤、氟達拉濱、長春堿、長春新堿、長春瑞濱、紫杉醇、多西紫杉醇、拓撲替康、伊立替康、依託泊苷、曲貝替定、更生黴素、多柔比星、表柔比星、道諾黴素、米托蒽醌、博來黴素、絲裂黴素C、伊沙匹隆、他莫昔芬、氟他胺、戈那瑞林類似物、甲地孕酮、強的松、地塞米松、甲潑尼龍、沙利度胺、干擾素α、亞葉酸鈣、西羅莫司、西羅莫司脂化物、依維莫司、阿法替尼、alisertib、amuvatinib、阿帕替尼、阿西替尼、硼替佐米、波舒替尼、布立尼布、卡博替尼、西地尼布、crenolanib、克卓替尼、達拉菲尼、達可替尼、達努塞替、達沙替尼、多維替尼、厄洛替尼、foretinib、ganetespib、吉非替尼、依魯替尼、埃克替尼、伊馬替尼、iniparib、拉帕替尼、lenvatinib、linifanib、linsitinib、馬賽替尼、momelotinib、莫替沙尼、來那替尼、尼祿替尼、niraparib、oprozomib、olaparib、帕唑帕尼、pictilisib、普納替尼、quizartinib、瑞格菲尼、rigosertib、rucaparib、盧梭利替尼、塞卡替尼、saridegib、索拉非尼、舒尼替尼、替拉替尼、tivantinib、替沃紮尼、托法替尼、曲美替尼、凡德他尼、維利帕尼、威羅菲尼、維莫德吉、volasertib、阿侖單抗、貝伐單抗、貝倫妥單抗維多汀、卡妥索單抗、西妥昔單抗、地諾單抗、吉妥珠單抗、伊匹單抗、尼妥珠單抗、奧法木單抗、帕尼單抗、利妥昔單抗、托西莫單抗、曲妥珠單抗;所述的檢查點抑制劑優選地選自抗PD-1抗體、抗PD-L1抗體、LAG3抗體、TIM-3抗體及抗CTLA-4抗體。 The pharmaceutical composition of claim 4, further comprising additional therapeutic agents and/or Checkpoint inhibitor, the additional therapeutic agent is preferably selected from the group consisting of chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinca Chlorine, Vinorelbine, Vinorelbine, Paclitaxel, Docetaxel, Topotecan, Irinotecan, Etoposide, Trabectedin, Dactomycin, Doxorubicin, Epirubicin, Daunomycin pyridoxine, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxifen, flutamide, gonarelin analogs, megestrol, prednisone, dexamethasone Metasone, methylprednisolone, thalidomide, interferon alfa, calcium folinate, sirolimus, temsirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, britinib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danucetib, Dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motisanib, neratinib, nerotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, Roxolitinib, cicatinib, saridegib, sorafenib, sunitinib, tiratinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, vitamin Lipanib, vemurafenib, vemodagi, volasertib, alemtuzumab, bevacizumab, belemumab vedotin, catulumumab, cetuximab, denosumab anti, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumumab, trastuzumab; described The checkpoint inhibitor is preferably selected from anti-PD-1 antibody, anti-PD-L1 antibody, LAG3 antibody, TIM-3 antibody and anti-CTLA-4 antibody. 如請求項1-3任一項所述的式(I)化合物或其藥學上可接受的鹽或異構體或者如請求項4-5任一項所述的藥物組合物在製備用於通過抑制TGF-β受體來預防或治療的腫瘤、病毒感染、器官移植排斥、神經退行性疾病、注意力缺陷相關疾病或自身免疫性疾病的藥物中的用途, 其中所述TGF-β受體優選選自TGFβRI(ALK5)受體。 The compound of formula (I) or a pharmaceutically acceptable salt or isomer thereof according to any one of claims 1-3 or the pharmaceutical composition according to any one of claims 4-5 is prepared for use by Use in a medicament for inhibiting TGF-beta receptors for the prevention or treatment of tumors, viral infections, organ transplant rejection, neurodegenerative diseases, attention deficit related disorders or autoimmune diseases, Wherein the TGF-beta receptor is preferably selected from the TGFbetaRI (ALK5) receptor. 如請求項6所述的用途,其中,所述腫瘤選自皮膚癌、膀胱癌、卵巢癌、乳腺癌、胃癌、胰腺癌、前列腺癌、結腸癌、肺癌、骨癌、腦癌、神經細胞瘤、直腸癌、結腸癌、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、胃癌、腺癌、甲狀腺髓樣癌、乳頭狀甲狀腺癌、腎癌、腎實質癌、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、腦腫瘤諸如成膠質細胞瘤、星形細胞瘤、腦膜瘤、成神經管細胞瘤和外周神經外胚層腫瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性骨髓性白血病(AML)、慢性粒細胞白血病(CML)、成人T細胞白血病淋巴瘤、彌漫性大B細胞淋巴瘤(DLBCL)、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、基底細胞瘤、畸胎瘤、成視網膜細胞瘤、精原細胞瘤、橫紋肌肉瘤、顱咽管瘤、骨肉瘤、軟骨肉瘤、肌肉瘤、脂肪肉瘤、纖維肉瘤、尤因肉瘤和漿細胞瘤。 The use according to claim 6, wherein the tumor is selected from skin cancer, bladder cancer, ovarian cancer, breast cancer, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neurocytoma , rectal cancer, colon cancer, familial adenomatous polyposis cancer, hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, thyroid medullary cancer cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, cervical cancer, endometrial cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary cancer, melanoma, brain tumors such as glioblastoma, astrocytes Cytocytoma, Meningioma, Medulloblastoma and Peripheral Neuroectodermal Tumors, Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Burkitt Lymphoma, Acute Lymphatic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder carcinoma, bronchial carcinoma, small cell Lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, sarcoma, liposarcoma, Fibrosarcoma, Ewing's sarcoma, and plasmacytoma. 如請求項6所述的用途,其中,所述腫瘤為脈絡膜黑素瘤。 The use according to claim 6, wherein the tumor is choroidal melanoma.
TW110110282A 2020-03-24 2021-03-22 TRANSFORMING GROWTH FACTOR-β RECEPTOR INHIBITOR TWI768781B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010212752 2020-03-24
CN202010212752.X 2020-03-24

Publications (2)

Publication Number Publication Date
TW202144347A TW202144347A (en) 2021-12-01
TWI768781B true TWI768781B (en) 2022-06-21

Family

ID=77891775

Family Applications (1)

Application Number Title Priority Date Filing Date
TW110110282A TWI768781B (en) 2020-03-24 2021-03-22 TRANSFORMING GROWTH FACTOR-β RECEPTOR INHIBITOR

Country Status (2)

Country Link
TW (1) TWI768781B (en)
WO (1) WO2021190425A1 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114853754B (en) * 2022-05-23 2023-04-18 云白药征武科技(上海)有限公司 Thioamide derivative and preparation method and application thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018017633A1 (en) * 2016-07-21 2018-01-25 Bristol-Myers Squibb Company TGF Beta RECEPTOR ANTAGONISTS

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT3470409T (en) * 2016-06-13 2020-05-11 Genfleet Therapeutics Shanghai Inc Benzotriazole-derived and unsaturated amide compound used as tgf- r1 inhibitor
US11466003B2 (en) * 2016-07-29 2022-10-11 Shanghai Yingli Pharmaceutical Co., Ltd Nitrogenous heterocyclic aromatic compound, preparation method therefor, pharmaceutical composition thereof, and application thereof
CN110066277B (en) * 2018-01-24 2021-07-23 上海璎黎药业有限公司 Aromatic heterocyclic substituted olefin compound, preparation method, pharmaceutical composition and application thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018017633A1 (en) * 2016-07-21 2018-01-25 Bristol-Myers Squibb Company TGF Beta RECEPTOR ANTAGONISTS

Also Published As

Publication number Publication date
TW202144347A (en) 2021-12-01
WO2021190425A1 (en) 2021-09-30

Similar Documents

Publication Publication Date Title
KR20220092920A (en) Helios small molecule degrading agent and method of use
KR20240019867A (en) Tlr7/8 antagonists and uses thereof
CN111989313A (en) A2A and/or A2B receptor antagonists
CN111548343B (en) Preparation method of high-activity CSF1R inhibitor compound
WO2022089398A1 (en) High activity hpk1 kinase inhibitor
JP7281834B2 (en) PD-L1 antagonist compounds
CN112028891B (en) Adenosine receptor antagonists
TWI768781B (en) TRANSFORMING GROWTH FACTOR-β RECEPTOR INHIBITOR
CN115066423A (en) PD-L1 antagonist compounds
CN112592354B (en) Preparation method of isoxazolo-pyrimidine heterocyclic compound
CN111440148B (en) Preparation method of adenosine receptor antagonist
LU505117B1 (en) A pan-KRAS inhibitor compound
WO2022214008A1 (en) Highly active hpk1 kinase inhibitor
WO2024022365A1 (en) Wnt pathway inhibitor compound
WO2022199561A1 (en) Hpk1 kinase inhibitor compound
WO2023215471A1 (en) Tetrahydroisoquinoline heterobifunctional bcl-xl degraders
CN118047799A (en) Pan-KRAS inhibitor compound

Legal Events

Date Code Title Description
MM4A Annulment or lapse of patent due to non-payment of fees