Movatterモバイル変換

[0]ホーム
URL:

WO2020221006A1 - Bet inhibitor, and preparation method and use thereof - Google Patents

Bet inhibitor, and preparation method and use thereofDownload PDF

Info

Publication number
WO2020221006A1
WO2020221006A1PCT/CN2020/084797CN2020084797WWO2020221006A1WO 2020221006 A1WO2020221006 A1WO 2020221006A1CN 2020084797 WCN2020084797 WCN 2020084797WWO 2020221006 A1WO2020221006 A1WO 2020221006A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
hydrogen
cycloalkyl
halogen
cyano
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CN2020/084797
Other languages
French (fr)
Chinese (zh)
Inventor
郑永勇
魏农农
金华
周峰
黄美花
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Xunhe Pharmaceutical Technology Co Ltd
Original Assignee
Shanghai Xunhe Pharmaceutical Technology Co Ltd
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 Shanghai Xunhe Pharmaceutical Technology Co LtdfiledCriticalShanghai Xunhe Pharmaceutical Technology Co Ltd
Publication of WO2020221006A1publicationCriticalpatent/WO2020221006A1/en
Anticipated expirationlegal-statusCritical
Ceasedlegal-statusCriticalCurrent

Links

Classifications

Definitions

Landscapes

Abstract

The present invention relates to the technical field of biomedicine, and specifically relates to a BET inhibitor, and a preparation method and use thereof. The present invention improves on the structure of prior art BET inhibitors to obtain a class of BET inhibitors having a new structure, better BET inhibition activity and good pharmacokinetics, and has prospects for development as a new highly efficient and low-toxicity BET inhibitor.

Description

Translated fromChinese
一种BET蛋白抑制剂、其制备方法及用途A BET protein inhibitor, its preparation method and application技术领域Technical field

本发明属于生物医药技术领域，具体涉及一种BET蛋白抑制剂、其制备方法及用途。The invention belongs to the technical field of biomedicine, and specifically relates to a BET protein inhibitor, a preparation method and application thereof.

背景技术Background technique

表观遗传学(Epigenetic)是当前非常热门的药物发现主题之一。组蛋白乙酰化是表观遗传研究的重要组成部分。Bromodomain(BRD)是一类能够特异性识别组蛋白中乙酰化赖氨酸(KAc)的保守蛋白结构域，通过与乙酰化赖氨酸结合促使蛋白富集于特定的基因转录位点，改变RNA聚合酶II的活性，调节基因的转录表达(Kuc和Allis，Bioessays,1998,20:615-626)。Epigenetic (Epigenetic) is currently one of the most popular drug discovery topics. Histone acetylation is an important part of epigenetic research. Bromodomain (BRD) is a class of conserved protein domains that can specifically recognize acetylated lysine (KAc) in histones. By binding to acetylated lysine, it promotes protein enrichment at specific gene transcription sites and changes RNA The activity of polymerase II regulates the transcriptional expression of genes (Kuc and Allis, Bioessays, 1998, 20:615-626).

目前，人体内发现的61种BRD结构域存在于42种蛋白中，根据母蛋白功能的不同，BRD蛋白划分为8大家族，BET蛋白家族是BRD蛋白家族的第2类。BET蛋白包括BRD2、BRD3、BRD4和BRDT四个成员(Wu和Chiang,J.Biol.chem.,2007,282:13141-13145)。前三种广泛表达于所有机体细胞，后者仅限表达于睾丸组织。At present, 61 types of BRD domains found in the human body are present in 42 types of proteins. According to the different functions of the parent protein, BRD proteins are divided into 8 major families, and the BET protein family is the second type of BRD protein family. BET protein includes four members of BRD2, BRD3, BRD4 and BRDT (Wu and Chiang, J. Biol. chem., 2007, 282: 13141-13145). The first three are widely expressed in all body cells, while the latter is only expressed in testicular tissues.

BET蛋白在多种肿瘤中发挥重要作用。如造血系统肿瘤(急性髓细胞白血病、淋巴瘤、多发性骨髓瘤、B细胞急性淋巴白血病等)，通过干扰BRD4与癌基因MYC的结合，可以抑制MYC的表达，进而引起肿瘤细胞凋亡。BET蛋白(BRD3或BRD4)和NUT(通常仅在睾丸中表达的蛋白)之间的融合导致鳞状细胞癌的攻击性形式，其被称作NUT中线癌(French，Cancer Genet，Cytogenet.,2010，203:16-20)。BET protein plays an important role in a variety of tumors. For example, hematopoietic tumors (acute myeloid leukemia, lymphoma, multiple myeloma, B-cell acute lymphoblastic leukemia, etc.) can inhibit the expression of MYC by interfering with the combination of BRD4 and the oncogene MYC, thereby causing tumor cell apoptosis. The fusion between the BET protein (BRD3 or BRD4) and NUT (a protein normally expressed only in the testis) results in an aggressive form of squamous cell carcinoma, which is called NUT midline carcinoma (French, Cancer Genet, Cytogenet., 2010 , 203:16-20).

在上皮瘤形成的高度恶性形式中发现涉及NUT(睾丸中的核蛋白)与BRD3或BRD4的反复移位形成新颖融合致癌基因BRD-NUT(French等人，Cancer Research 2003，63:304-307)。选择性减少此致癌基因可复原正常细胞分化且逆转致瘤表型(Fi1ippakopoulos等人，Nature2010，468:1068-1073)。已证实BRD2、BRD3和BRD4的基因剔除会损害多种血液学和实体肿瘤细胞的生长和活力(Zuber等人，Nature 2011，478:524-528；Delmore等人，Cell 2011，146:904-917)。除在癌症中的作用以外，BET蛋白还调控对细菌攻击的炎性反应，且BRD2亚等位基因小鼠模型显示显著较低水平的炎性细胞因子和防止肥胖诱导的糖尿病(Wang等人，Biochem J.2009，425:71-83)。另外，一些病毒利用这些BET蛋白将其基因组系栓于宿主细胞染色质作为病毒复制过程的一部分，或使用BET蛋白促进病毒基因转录和阻遏(You等人，Ce11 2004，117:349-360；Zhu等人，Cell Reports 2012，2:807-816)。In the highly malignant form of epithelioma formation, it was discovered that the repeated displacement of NUT (nucleoprotein in the testis) and BRD3 or BRD4 to form a novel fusion oncogene BRD-NUT (French et al., Cancer Research 2003, 63:304-307) . Selective reduction of this oncogene can restore normal cell differentiation and reverse the tumorigenic phenotype (Filippakopoulos et al., Nature 2010, 468:1068-1073). It has been confirmed that BRD2, BRD3 and BRD4 gene knockout can damage the growth and viability of a variety of hematology and solid tumor cells (Zuber et al., Nature 2011, 478:524-528; Delmore et al., Cell 2011, 146:904-917 ). In addition to its role in cancer, BET protein also regulates the inflammatory response to bacterial attack, and the BRD2 suballelic mouse model shows significantly lower levels of inflammatory cytokines and prevents obesity-induced diabetes (Wang et al., Biochem J. 2009, 425:71-83). In addition, some viruses use these BET proteins to tether their genomes to host cell chromatin as part of the virus replication process, or use BET proteins to promote viral gene transcription and repression (You et al., Ce11 2004, 117:349-360; Zhu Et al., Cell Reports 2012, 2:807-816).

综上所述，靶向这些蛋白对于发展靶向癌症，炎症和病毒感染的新的治疗策略可能是有益的。目前已有针对这一受体的小分子抑制剂进入临床阶段，其主要用于癌症及自身免疫疾病的治疗。目前公开了一系列BET抑制剂类专利申请，包括：WO2013158952、WO2014165127、WO2015075665、WO2016050821、WO2018188047、WO2018130174等。In summary, targeting these proteins may be beneficial for the development of new therapeutic strategies targeting cancer, inflammation and viral infections. At present, small molecule inhibitors targeting this receptor have entered the clinical stage and are mainly used for the treatment of cancer and autoimmune diseases. Currently, a series of BET inhibitor patent applications have been published, including: WO2013158952, WO2014165127, WO2015075665, WO2016050821, WO2018188047, WO2018130174, etc.

Abbive公司在WO2013097052A中公开了一类BET蛋白抑制剂，其中化合物ABBV-075具有开发前景，目前处于Ⅰ期临床试验阶段。Incyte公司在CN106414442A专利中公开了化合物INCB-057643，处于Ⅰ期临床试验阶段。Bristol-Myers Squibb公司在WO2015100282A中公开了另一类BET蛋白抑制剂，代表化合物BMS-986158处于Ⅰ期临床试验阶段。GlaxoSmithKline公司在WO2011054553A中公开了化合物I-BET762，该化合物正在开展肿瘤Ⅱ期临床试验。Abbive Company discloses a class of BET protein inhibitors in WO2013097052A. Among them, the compound ABBV-075 has development prospects and is currently in phase I clinical trials. Incyte company disclosed the compound INCB-057643 in the CN106414442A patent, which is in the phase I clinical trial. Bristol-Myers Squibb disclosed another type of BET protein inhibitor in WO2015100282A, representing that the compound BMS-986158 is in the phase I clinical trial. GlaxoSmithKline disclosed compound I-BET762 in WO2011054553A, which is currently undergoing tumor phase II clinical trials.

Figure PCTCN2020084797-appb-000001
Figure PCTCN2020084797-appb-000001

虽然没有上市药物，但BET蛋白抑制剂作为药物研发具有良好的应用前景。现阶段，更多用于治疗涉及溴结构域功能包括BET结构域功能的疾病和适应症的新型溴结构域抑制剂亟待开发。本发明化合物亦有助于满足此类临床需要，我们希望能开发出新一代高效低毒的BET蛋白抑制剂。Although there are no drugs on the market, BET protein inhibitors have good application prospects as drugs. At this stage, more novel bromodomain inhibitors for the treatment of diseases and indications involving the function of the bromodomain including the function of the BET domain are in urgent need of development. The compounds of the present invention also help to meet such clinical needs, and we hope to develop a new generation of BET protein inhibitors with high efficiency and low toxicity.

发明内容Summary of the invention

为了克服现有技术中所存在的问题，本发明的目的在于提供一种高效低毒的BET蛋白抑制剂。In order to overcome the problems in the prior art, the purpose of the present invention is to provide a BET protein inhibitor with high efficiency and low toxicity.

为了实现上述目的以及其他相关目的，本发明采用如下技术方案：In order to achieve the above objectives and other related objectives, the present invention adopts the following technical solutions:

一种BET蛋白抑制剂，其中所述抑制剂为式I化合物：A BET protein inhibitor, wherein the inhibitor is a compound of formula I:

Figure PCTCN2020084797-appb-000002
Figure PCTCN2020084797-appb-000002

或其药学上可接受的盐，其中，Or a pharmaceutically acceptable salt thereof, wherein

A选自

Figure PCTCN2020084797-appb-000003
A is selected from
Figure PCTCN2020084797-appb-000003

B环选自

Figure PCTCN2020084797-appb-000004
或被R11和/或R12取代的五元芳杂环；所述的“五元芳杂环”，是指5个原子的单环芳烃，并且含有1个或多个杂原子(例如N，O，S)，包括但不限于呋喃，咪唑，噻吩，吡唑等。其中：Ring B is selected from
Figure PCTCN2020084797-appb-000004
Or a five-membered aromatic heterocyclic ring substituted by R11 and/or R12 ; the "five-membered aromatic heterocyclic ring" refers to a monocyclic aromatic hydrocarbon of 5 atoms, and contains one or more heteroatoms (such as N , O, S), including but not limited to furan, imidazole, thiophene, pyrazole, etc. among them:

X为O、S或NR13；X is O, S or NR13 ;

Y为CH2、C＝O、NR1或Y不存在；Y is CH2 , C=O, NR1 or Y does not exist;

Z为CR14或N；Z is CR14 or N;

U为CH或N；U is CH or N;

W为O或NH；W is O or NH;

V为CH或N；V is CH or N;

R1为氢、C1-C6烷基、C3-C6环烷基、取代C1-C6烷基、取代C3-C6环烷基、C3-C6环烷基C1-C6烷基、C1-C6烷基-SO2-或C3-C6环烷基-SO2-；所述取代C1-C6烷基是指C1-C6烷基上的氢被一个或多个C3-C6环烷基取代；所述取代C3-C6环烷基是指C3-C6环烷基上的氢被一个或多个C1-C6烷基取代；R1 is hydrogen, C1 -C6 alkyl, C3 -C6 cycloalkyl, substituted C1 -C6 alkyl, substituted C3 -C6 cycloalkyl, C3 -C6 cycloalkyl C1 -C6 alkyl, C1 -C6 alkyl -SO2 -or C3 -C6 cycloalkyl -SO2 -; the substituted C1 -C6 alkyl refers to C1 -C6 alkane The hydrogen on the group is replaced by one or more C3 -C6 cycloalkyl; the substituted C3 -C6 cycloalkyl means that the hydrogen on the C3 -C6 cycloalkyl group is replaced by one or more C1 -C6 alkyl substitution;

R2为氢、C1-C6烷基、C1-C3烷氧基、卤素或氰基；R2 is hydrogen, C1 -C6 alkyl, C1 -C3 alkoxy, halogen or cyano;

R3为氢、C1-C6烷基、C1-C3烷氧基、卤素、氰基、-S(O)2R15、-S(O)2NR16R17或-N(R16)S(O)2R15；R3 is hydrogen, C1 -C6 alkyl, C1 -C3 alkoxy, halogen, cyano, -S(O)2 R15 , -S(O)2 NR16 R17 or -N( R16 )S(O)2 R15 ;

R4为氢、C1-C6烷基、C1-C3烷氧基、卤素或氰基；R4 is hydrogen, C1 -C6 alkyl, C1 -C3 alkoxy, halogen or cyano;

R5和R6各自独立地为氢或C1-C6烷基；R5 and R6 are each independently hydrogen or C1 -C6 alkyl;

R7、R8、R9和R10各自独立地为氢、卤素、氰基、C1-C3烷氧基或C1-C6烷基；R7 , R8 , R9 and R10 are each independently hydrogen, halogen, cyano, C1 -C3 alkoxy or C1 -C6 alkyl;

R11为氢或C1-C6烷基；R11 is hydrogen or C1 -C6 alkyl;

R12为氢或C1-C6烷基；R12 is hydrogen or C1 -C6 alkyl;

R13为氢或C1-C6烷基；R13 is hydrogen or C1 -C6 alkyl;

R14为氢、C1-C6烷基、卤素或氰基；R14 is hydrogen, C1 -C6 alkyl, halogen or cyano;

R15为C1-C6烷基；R15 is C1 -C6 alkyl;

R16为氢或C1-C6烷基；R16 is hydrogen or C1 -C6 alkyl;

R17为氢或C1-C6烷基；R17 is hydrogen or C1 -C6 alkyl;

上述卤素选自氟、氯、溴或碘。The aforementioned halogen is selected from fluorine, chlorine, bromine or iodine.

优选的，所述式I化合物中：Preferably, in the compound of formula I:

A选自

Figure PCTCN2020084797-appb-000005
A is selected from
Figure PCTCN2020084797-appb-000005

B环选自

Figure PCTCN2020084797-appb-000006
Ring B is selected from
Figure PCTCN2020084797-appb-000006

其中：among them:

X为O、S或NR13；X is O, S or NR13 ;

Y为CH2、C＝O、NR1或Y不存在；Y is CH2 , C=O, NR1 or Y does not exist;

Z为CR14或N；Z is CR14 or N;

U为CH或N；U is CH or N;

W为O或NH；W is O or NH;

V为CH或N；V is CH or N;

R1为氢、C1-C4烷基、C3-C6环烷基、取代C1-C4烷基、取代C3-C6环烷基、C3-C6环烷基C1-C3烷基、C1-C4烷基-SO2-或C3-C6环烷基-SO2-；所述取代C1-C4烷基是指C1-C4烷基上的氢被一个或多个C3-C6环烷基取代；所述取代C3-C6环烷基是指C3-C6环烷基上的氢被一个或多个C1-C4烷基取代；R1 is hydrogen, C1 -C4 alkyl, C3 -C6 cycloalkyl, substituted C1 -C4 alkyl, substituted C3 -C6 cycloalkyl, C3 -C6 cycloalkyl C1 -C3 alkyl, C1 -C4 alkyl -SO2 -or C3 -C6 cycloalkyl -SO2 -; the substituted C1 -C4 alkyl refers to C1 -C4 alkyl The hydrogen on the group is replaced by one or more C3 -C6 cycloalkyl; the substituted C3 -C6 cycloalkyl means that the hydrogen on the C3 -C6 cycloalkyl group is replaced by one or more C1 -C4 alkyl substitution;

R2为氢、C1-C4烷基、C1-C2烷氧基、卤素或氰基；R2 is hydrogen, C1 -C4 alkyl, C1 -C2 alkoxy, halogen or cyano;

R3为氢、C1-C4烷基、C1-C2烷氧基、卤素、氰基、-S(O)2R15、-S(O)2NR16R17或-N(R16)S(O)2R15；R3 is hydrogen, C1 -C4 alkyl, C1 -C2 alkoxy, halogen, cyano, -S(O)2 R15 , -S(O)2 NR16 R17 or -N( R16 )S(O)2 R15 ;

R4为氢、C1-C4烷基、C1-C3烷氧基、卤素或氰基；R4 is hydrogen, C1 -C4 alkyl, C1 -C3 alkoxy, halogen or cyano;

R5和R6各自独立地为氢或C1-C4烷基；R5 and R6 are each independently hydrogen or C1 -C4 alkyl;

R7、R8、R9和R10各自独立地为氢、卤素、氰基、C1-C3烷氧基或C1-C4烷基；R7 , R8 , R9 and R10 are each independently hydrogen, halogen, cyano, C1 -C3 alkoxy or C1 -C4 alkyl;

R11为氢或C1-C4烷基；R11 is hydrogen or C1 -C4 alkyl;

R12为氢或C1-C4烷基；R12 is hydrogen or C1 -C4 alkyl;

R13为氢或C1-C4烷基；R13 is hydrogen or C1 -C4 alkyl;

R14为氢、C1-C4烷基、卤素或氰基；R14 is hydrogen, C1 -C4 alkyl, halogen or cyano;

R15为C1-C4烷基；R15 is a C1 -C4 alkyl group;

R16为氢或C1-C4烷基；R16 is hydrogen or C1 -C4 alkyl;

R17为氢或C1-C4烷基；R17 is hydrogen or C1 -C4 alkyl;

上述卤素选自氟、氯、溴或碘。The aforementioned halogen is selected from fluorine, chlorine, bromine or iodine.

优选的，所述式I化合物中：Preferably, in the compound of formula I:

A选自

Figure PCTCN2020084797-appb-000007
A is selected from
Figure PCTCN2020084797-appb-000007

B环选自

Figure PCTCN2020084797-appb-000008
Ring B is selected from
Figure PCTCN2020084797-appb-000008

其中：among them:

X为O、S或NR13；X is O, S or NR13 ;

Y为CH2、C＝O、NR1或Y不存在；Y is CH2 , C=O, NR1 or Y does not exist;

Z为CR14或N；Z is CR14 or N;

U为CH或N；U is CH or N;

W为O或NH；W is O or NH;

V为CH或N；V is CH or N;

R1为氢、C1-C3烷基、C3-C6环烷基、取代C1-C3烷基、取代C3-C6环烷基、C3-C6环烷基C1-C3烷基、C1-C3烷基-SO2-或C3-C6环烷基-SO2-；所述取代C1-C3烷基是指C1-C3烷基上的氢被一个或多个C3-C6环烷基取代；所述取代C3-C6环烷基是指C3-C6环烷基上的氢被一个或多个C1-C3烷基取代；R1 is hydrogen, C1 -C3 alkyl, C3 -C6 cycloalkyl, substituted C1 -C3 alkyl, substituted C3 -C6 cycloalkyl, C3 -C6 cycloalkyl C1- C3 alkyl, C1 -C3 alkyl-SO2 -or C3 -C6 cycloalkyl-SO2 -; the substituted C1 -C3 alkyl refers to C1 -C3 alkyl The hydrogen on the group is replaced by one or more C3 -C6 cycloalkyl; the substituted C3 -C6 cycloalkyl means that the hydrogen on the C3 -C6 cycloalkyl group is replaced by one or more C1 -C3 alkyl substitution;

R2为氢、C1-C3烷基、C1-C2烷氧基、卤素或氰基；R2 is hydrogen, C1 -C3 alkyl, C1 -C2 alkoxy, halogen or cyano;

R3为氢、C1-C3烷基、C1-C2烷氧基、卤素、氰基、-S(O)2R15、-S(O)2NR16R17或-N(R16)S(O)2R15；R3 is hydrogen, C1 -C3 alkyl, C1 -C2 alkoxy, halogen, cyano, -S(O)2 R15 , -S(O)2 NR16 R17 or -N( R16 )S(O)2 R15 ;

R4为氢、C1-C3烷基、C1-C2烷氧基、卤素或氰基；R4 is hydrogen, C1 -C3 alkyl, C1 -C2 alkoxy, halogen or cyano;

R5和R6各自独立地为氢或C1-C3烷基；R5 and R6 are each independently hydrogen or C1 -C3 alkyl;

R7、R8、R9和R10各自独立地为氢、卤素、氰基、C1-C2烷氧基或C1-C3烷基；R7 , R8 , R9 and R10 are each independently hydrogen, halogen, cyano, C1 -C2 alkoxy or C1 -C3 alkyl;

R11为氢或C1-C3烷基；R11 is hydrogen or C1 -C3 alkyl;

R12为氢或C1-C3烷基；R12 is hydrogen or C1 -C3 alkyl;

R13为氢或C1-C3烷基；R13 is hydrogen or C1 -C3 alkyl;

R14为氢、C1-C3烷基、卤素或氰基；R14 is hydrogen, C1 -C3 alkyl, halogen or cyano;

R15为C1-C3烷基；R15 is C1 -C3 alkyl;

R16为氢或C1-C3烷基；R16 is hydrogen or C1 -C3 alkyl;

R17为氢或C1-C3烷基；R17 is hydrogen or C1 -C3 alkyl;

上述卤素选自氟、氯、溴或碘。The aforementioned halogen is selected from fluorine, chlorine, bromine or iodine.

本申请所述的“卤素”是指F、Cl、Br或I；所述的“C1-C3的烷基”是指甲基、乙基、正丙基或异丙基；所述的“C1-C2的烷氧基”是指甲氧基或乙氧基；所述的“环烷基”，除非另有说明，是指含有3-6个碳原子的饱和或者部分不饱和的环状烃。环烷基包括但不限于环丙基，环丁基，环戊基，环戊烯基，环己基，环己烯基。The “halogen” in this application refers to F, Cl, Br or I; the “C1 -C3 alkyl” refers to methyl, ethyl, n-propyl or isopropyl; "C1 -C2 alkoxy" means methoxy or ethoxy; the "cycloalkyl", unless otherwise specified, means saturated or partially unsaturated containing 3-6 carbon atoms Cyclic hydrocarbon. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl.

本发明的化合物可按照常规方法制备为药用盐的形式；包括其有机酸盐及无机酸盐：无机酸包括(但不限于)盐酸、硫酸、磷酸、二磷酸、氢溴酸、硝酸等，有机酸包括(但不限于)乙酸、马来酸、富马酸、酒石酸、琥珀酸、乳酸、对甲苯磺酸、水杨酸、草酸等。The compounds of the present invention can be prepared in the form of pharmaceutical salts according to conventional methods; including their organic acid salts and inorganic acid salts: inorganic acids include (but are not limited to) hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, nitric acid, etc., Organic acids include, but are not limited to, acetic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, lactic acid, p-toluenesulfonic acid, salicylic acid, oxalic acid and the like.

本发明的典型化合物包括，但不限于以下表1化合物：Typical compounds of the present invention include, but are not limited to the following compounds in Table 1:

Figure PCTCN2020084797-appb-000009
Figure PCTCN2020084797-appb-000009

Figure PCTCN2020084797-appb-000010
Figure PCTCN2020084797-appb-000010

Figure PCTCN2020084797-appb-000011
Figure PCTCN2020084797-appb-000011

Figure PCTCN2020084797-appb-000012
Figure PCTCN2020084797-appb-000012

Figure PCTCN2020084797-appb-000013
Figure PCTCN2020084797-appb-000013

本发明的第二目的在于提供了上述化合物的合成方法：The second objective of the present invention is to provide a synthetic method of the above compound:

Figure PCTCN2020084797-appb-000014
Figure PCTCN2020084797-appb-000014

通式IA化合物和通式IB化合物经催化偶联反应制得通式化合物I，各基团定义如前文所述。The compound of the general formula IA and the compound of the general formula IB are catalyzed and coupled to produce the compound I of the general formula, and the definition of each group is as described above.

本发明的第三目的在于提供上述化合物作为新型BET蛋白抑制剂在制备预防或治疗与BET蛋白相关疾病的药物中的用途。The third object of the present invention is to provide the use of the above compound as a novel BET protein inhibitor in the preparation of drugs for preventing or treating diseases related to BET protein.

具体的，所述与BET蛋白相关疾病指肿瘤疾病、良性增生、炎性疾病、自身免疫疾病、败血症、病毒感染、血管疾病和神经性疾病。进一步的，所述肿瘤疾病包括但不限于急性髓性白血病、淋巴瘤、多发性骨髓瘤、B细胞急性淋巴白血病、中线癌、神经胶质瘤、实体瘤、乳腺癌、结直肠癌、前列腺癌、宫颈癌、非小细胞肺癌、黑色素瘤等。Specifically, the diseases related to the BET protein refer to tumor diseases, benign hyperplasia, inflammatory diseases, autoimmune diseases, sepsis, viral infections, vascular diseases and neurological diseases. Further, the tumor diseases include, but are not limited to, acute myeloid leukemia, lymphoma, multiple myeloma, B-cell acute lymphoid leukemia, midline cancer, glioma, solid tumor, breast cancer, colorectal cancer, prostate cancer , Cervical cancer, non-small cell lung cancer, melanoma, etc.

本发明的衍生物在实施疾病治疗过程中，可以组合物的形成通过口服、注射等方式，用于治疗相关癌症及其他疾病。用于口服时，可将其制备成常规的固体制剂如片剂、粉剂或胶囊等；用于注射时，可将其制备成注射液。In the course of disease treatment, the derivatives of the present invention can be formed into a composition by oral, injection, etc., to treat related cancers and other diseases. When used for oral administration, it can be prepared into conventional solid preparations such as tablets, powders or capsules; when used for injection, it can be prepared into injections.

本发明的第四目的在于提供一种组合物，所述组合物包括治疗有效量的上述化合物或其可药用的盐和医学上可接受的载体。The fourth object of the present invention is to provide a composition comprising a therapeutically effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof and a medically acceptable carrier.

所述及的载体是指药学领域常规的载体，如：稀释剂、赋形剂如水等；粘合剂如纤维素衍生物、明胶、聚乙烯吡咯烷酮等；填充剂如淀粉等；崩裂剂如碳酸钙、碳酸氢钠；另外，还可以在组合物中加入其他辅助剂如香味剂和甜味剂。The carrier mentioned refers to the conventional carriers in the pharmaceutical field, such as diluents, excipients such as water, etc.; binders such as cellulose derivatives, gelatin, polyvinylpyrrolidone, etc.; fillers such as starch, etc.; disintegrating agents such as carbonic acid Calcium, sodium bicarbonate; in addition, other auxiliary agents such as flavoring and sweetening agents can also be added to the composition.

本发明的组合物的各种剂型可以采用医学领域常规的方法进行制备，其中活性成分的含量为0.1％～99.5％(重量比)。Various dosage forms of the composition of the present invention can be prepared by conventional methods in the medical field, and the content of the active ingredient is 0.1%-99.5% (weight ratio).

本发明的施用量可根据用药途径、患者的年龄、体重、所治疗的疾病的类型和严重程度等进行变化，其日剂量为0.005-30mg/kg体重(口服)或0.005-30mg/kg体重(注射)。The dosage of the present invention can be changed according to the route of administration, the age, weight of the patient, the type and severity of the disease to be treated, etc. The daily dosage is 0.005-30mg/kg body weight (oral) or 0.005-30mg/kg body weight ( injection).

与现有技术相比，本发明在现有BET蛋白抑制剂基础上进一步进行结构改进，得到一类新结构的BET蛋白抑制剂，其具有较好的BET蛋白抑制活性及良好的药代动力学性质，有望开发为新一代高效低毒的BET蛋白抑制剂。Compared with the prior art, the present invention further improves the structure on the basis of the existing BET protein inhibitor, and obtains a new structure of BET protein inhibitor, which has better BET protein inhibitory activity and good pharmacokinetics It is expected to be developed into a new generation of high-efficiency and low-toxicity BET protein inhibitor.

具体实施方式Detailed ways

下面将对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅是本发明的一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其它实施例，都属于本发明保护的范围。The technical solutions in the embodiments of the present invention will be described clearly and completely below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative work shall fall within the protection scope of the present invention.

参考例1：片段A1的合成路线。Reference example 1: Synthetic route of fragment A1.

Figure PCTCN2020084797-appb-000015
Figure PCTCN2020084797-appb-000015

步骤1：化合物A1-2的合成。Step 1: Synthesis of compound A1-2.

0℃下，向化合物A1-1(400mg，1.76mmol)的DMF(20mL)溶液中加入NaH(141mg，3.52mmol)。将混合物在该温度下搅拌10分钟并在0℃下加入TsCl(671mg，3.52mmol)。然后将混合物在室温下搅拌反应2小时。反应混合物用H2O(20mL)稀释，并用EA(30mL x 2)萃取。合并有机层，并用盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤并浓缩。残留物经硅胶柱层析(PE/EA＝2/1)，得到化合物A1-2(800mg， 95％产率)，为黄色固体。MS:382.0[M+H]+。At 0°C, NaH (141 mg, 3.52 mmol) was added to the DMF (20 mL) solution of compound A1-1 (400 mg, 1.76 mmol). The mixture was stirred at this temperature for 10 minutes and TsCl (671 mg, 3.52 mmol) was added at 0°C. Then the mixture was stirred and reacted at room temperature for 2 hours. The reaction mixture was diluted with H2 O (20 mL) and extracted with EA (30 mL x 2). The organic layers were combined, washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was subjected to silica gel column chromatography (PE/EA=2/1) to obtain compound A1-2 (800 mg, 95% yield) as a yellow solid. MS: 382.0 [M+H]+ .

步骤2：化合物A1-3的合成。Step 2: Synthesis of compound A1-3.

向化合物A1-2(800mg，2.1mmol)的二氧六环(10mL)溶液中加入4M HCl的二氧六环溶液(5mL)反应混合物在50℃下搅拌2小时。将反应混合物冷却至室温并浓缩，剩余物用H2O(20mL)稀释，并经EA(30mL x 2)萃取。合并有机层，有机层经盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤并浓缩，得到化合物A1-3(600mg，100％收率)，为黄色固体。MS:368.0[M+H]+。To the dioxane (10 mL) solution of compound A1-2 (800 mg, 2.1 mmol) was added 4M HCl in dioxane (5 mL), the reaction mixture was stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature and concentrated, and the residue was diluted with H2 O (20 mL) and extracted with EA (30 mL x 2). The organic layers were combined, and the organic layer was washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound A1-3 (600 mg, 100% yield) as a yellow solid. MS: 368.0 [M+H]+ .

步骤3：化合物A1-4的合成。Step 3: Synthesis of compound A1-4.

0℃下，向化合物A1-3(600mg，1.63mmol)的DMF(10mL)溶液中加入NaH(131mg，3.26mmol)。该混合物在此温度下搅拌10分钟并于冰浴中加入CH3I(671mg，3.52mmol)。混合物在室温下搅拌3小时。反应混合物经H2O(20mL)稀释，并经EA(30mL x 2)萃取。合并的有机层用盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤并浓缩。残留物经硅胶柱层析(PE/EA＝2/1)，得到化合物A1-4(450mg，72％产率)，为黄色固体。MS:382.0[M+H]+。At 0°C, NaH (131 mg, 3.26 mmol) was added to the DMF (10 mL) solution of compound A1-3 (600 mg, 1.63 mmol). The mixture was stirred at this temperature for 10 minutes and CH3 I (671 mg, 3.52 mmol) was added to the ice bath. The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with H2 O (20 mL) and extracted with EA (30 mL x 2). The combined organic layer was washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was subjected to silica gel column chromatography (PE/EA=2/1) to obtain compound A1-4 (450 mg, 72% yield) as a yellow solid. MS: 382.0 [M+H]+ .

步骤4：化合物A1的合成。Step 4: Synthesis of compound A1.

反应瓶中依次加入化合物A1-4(300mg，0.788mmol)，Pin2B2(400mg，1.57mmol)，KOAc(232mg，2.36mmol)，X-phos(38mg，0.08mmol)、Pd2(dba)3(73mg，0.08mmol)和二氧六环(20mL)。N2保护下，混合物在85℃搅拌3小时。反应混合物经H2O(20mL)稀释，并用DCM(30mL x 2)萃取。将合并的有机层用盐水(20mL)洗涤，无水硫酸钠干燥，过滤并浓缩，得到化合物A1-5粗品(500mg，100％产率)，为黄色固体。MS:429.0[M+H]+，1H NMR(400MHz,DMSO-d6)δ:8.11(s,1H),7.99-8.01(m,2H),7.92-7.93(d,J＝4.0Hz,1H),7.30-7.32(m,2H),6.50-6.51(d,J＝4.0Hz,1H),3.50(s,3H),2.40(s,3H),1.25(s,12H)。Compound A1-4 (300mg, 0.788mmol), Pin2 B2 (400mg, 1.57mmol), KOAc (232mg, 2.36mmol), X-phos (38mg, 0.08mmol), Pd2 (dba) were sequentially added to the reaction flask3 (73 mg, 0.08 mmol) and dioxane (20 mL). Under N2 protection, the mixture was stirred at 85°C for 3 hours. The reaction mixture was diluted with H2 O (20 mL) and extracted with DCM (30 mL x 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude compound A1-5 (500 mg, 100% yield) as a yellow solid. MS: 429.0[M+H]+ ,1 H NMR (400MHz, DMSO-d6 ) δ: 8.11 (s, 1H), 7.99-8.01 (m, 2H), 7.92-7.93 (d, J = 4.0 Hz, 1H), 7.30-7.32 (m, 2H), 6.50-6.51 (d, J=4.0 Hz, 1H), 3.50 (s, 3H), 2.40 (s, 3H), 1.25 (s, 12H).

参考例2-7：片段A2～A7。Reference example 2-7: Fragments A2～A7.

参照参考例1中步骤1-4的合成方法，合成下表2中各参考例：Referring to the synthesis method of steps 1-4 in Reference Example 1, synthesize each reference example in Table 2 below:

Figure PCTCN2020084797-appb-000016
Figure PCTCN2020084797-appb-000016

Figure PCTCN2020084797-appb-000017
Figure PCTCN2020084797-appb-000017

参考例8：片段A8的合成路线。Reference Example 8: Synthetic route of fragment A8.

Figure PCTCN2020084797-appb-000018
Figure PCTCN2020084797-appb-000018

反应瓶中依次加入化合物A8-1(150mg，0.95mmol)，Pin2B2(1.2g，4.73mmol)，KOAc(186mg，1.9mmol)，X-phos(91mg，0.19mmol)、Pd2(dba)3(87mg，0.095mmol)和二氧六环(10mL)。混合物在85℃下搅拌反应1小时。反应液冷至室温，加H2O(20mL)稀释，并用DCM(30mL×2)萃取。合并有机层，并经食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，得到粗产物A8-1(200mg，94％产率)，为黄色固体。MS:251.1[M+H]+。Compound A8-1 (150mg, 0.95mmol), Pin2 B2 (1.2g, 4.73mmol), KOAc (186mg, 1.9mmol), X-phos (91mg, 0.19mmol), Pd2 (dba )3 (87 mg, 0.095 mmol) and dioxane (10 mL). The mixture was stirred and reacted at 85°C for 1 hour. The reaction solution was cooled to room temperature, diluted with H2 O (20 mL), and extracted with DCM (30 mL×2). The organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product A8-1 (200 mg, 94% yield) as a yellow solid. MS: 251.1 [M+H]+ .

参考例9-11：片段A9～A11。Reference example 9-11: Fragment A9～A11.

参照参考例8的合成方法，合成下表3中各参考例:With reference to the synthesis method of Reference Example 8, each reference example in Table 3 below was synthesized:

Figure PCTCN2020084797-appb-000019
Figure PCTCN2020084797-appb-000019

Figure PCTCN2020084797-appb-000020
Figure PCTCN2020084797-appb-000020

参考例12：片段C1的合成路线。Reference Example 12: Synthetic route of fragment C1.

Figure PCTCN2020084797-appb-000021
Figure PCTCN2020084797-appb-000021

步骤1：化合物C1-2的合成。Step 1: Synthesis of compound C1-2.

向化合物C1-1(11g，0.05mol)的浓H2SO4(60mL)溶液中滴加入Br2(8g，0.05mol)，然后在冰水浴中加入HNO3(2.5mL)。反应液加热至90℃，保温反应5小时。反应冷至室温，加H2O(50mL)稀释，并用DCM(50mL×2)萃取。合并2次萃取液，再经饱和Na2S2O3(50mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩。剩余物通过硅胶柱层析(PE/EA＝2/1)纯化残余物，得到化合物C1-2(4.3g，29％收率)，为白色固体。MS:297.1[M-H]-。Br2 (8 g, 0.05 mol) was added dropwise to a solution of compound C1-1 (11 g, 0.05 mol) in concentrated H2 SO4 (60 mL), and then HNO3 (2.5 mL) was added to an ice water bath. The reaction solution was heated to 90°C and kept for 5 hours to react. The reaction was cooled to room temperature, diluted with H2 O (50 mL), and extracted with DCM (50 mL×2). The two extracts were combined, washed with saturated Na2 S2 O3 (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA=2/1) to obtain compound C1-2 (4.3 g, 29% yield) as a white solid. MS: 297.1 [MH]- .

步骤2：化合物C1-4的合成。Step 2: Synthesis of compound C1-4.

化合物C1-2(4.1g，13.8mmol)，4-氟-3-碘苯酚(3.45g，14.5mmol)和K2CO3(2g，14.5mmol)加入DMSO(120mL)中，该反应液在120℃下加热反应3小时。反应液冷至室温，加H2O(30mL)淬灭，并用EA(50mL x 2)萃取。将合并的有机层用食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩。剩余物通过硅胶柱层析(PE/EA＝2/1)纯化，得到化合物C1-4(5.4g，76％产率)，为黄色固体。MS:515.1[M-H]-。Compound C1-2 (4.1g, 13.8mmol), 4-fluoro-3-iodophenol (3.45g, 14.5mmol) and K2 CO3 (2g, 14.5mmol) were added to DMSO (120mL), the reaction solution was heated at 120 The reaction was heated at °C for 3 hours. The reaction solution was cooled to room temperature, quenched by adding H2 O (30 mL), and extracted with EA (50 mL x 2). The combined organic layer was washed with brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA=2/1) to obtain compound C1-4 (5.4 g, 76% yield) as a yellow solid. MS: 515.1 [MH]- .

步骤3：化合物C1-5的合成。Step 3: Synthesis of compound C1-5.

化合物C1-4(5.4g，10.5mmol)，Fe(2.0g，37mmol)和NH4Cl(334mg，6.3mmol)加入EtOH(100mL)和H2O(20mL)中，该混合液在90℃下搅拌反应3小时。反应液冷至室温，加H2O(50mL)稀释并用EA(80mL)萃取。分液，浓缩有机层，所得剩余物经硅胶柱层析(PE/EA＝2/1)纯化，得化合物C1-5(3.3g，64.7％产率)，为黄色固体。MS:485.1[M-H]-。Compound C1-4 (5.4g, 10.5mmol), Fe (2.0g, 37mmol) and NH4 Cl (334mg, 6.3mmol) were added to EtOH (100mL) and H2 O (20mL), and the mixture was heated at 90°C The reaction was stirred for 3 hours. The reaction solution was cooled to room temperature, diluted with H2 O (50 mL) and extracted with EA (80 mL). The layers were separated, the organic layer was concentrated, and the residue obtained was purified by silica gel column chromatography (PE/EA=2/1) to obtain compound C1-5 (3.3 g, 64.7% yield) as a yellow solid. MS: 485.1 [MH]- .

步骤4：化合物C1-6的合成。Step 4: Synthesis of compound C1-6.

化合物C1-5(500mg，1.03mmol)，Cs2CO3(1g，3.09mmol)，BINAP(128mg，0.2mmol)和Pd2(dba)3(192mg，0.2mmol)加入二氧六环(40mL)中，该反应液在80℃下搅拌反应过夜。反应液冷至室温，加H2O(50mL)稀释，并用EA(50mL×2)萃取。有机层经食盐水(30mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩。剩余物经硅胶柱层析(PE/EA＝2/1)纯化，得到化合物C1-6(290mg，37.6％产率)，为黄色固体。MS:357.2[M-H]-。Compound C1-5 (500mg, 1.03mmol), Cs2 CO3 (1g, 3.09mmol), BINAP (128mg, 0.2mmol) and Pd2 (dba)3 (192mg, 0.2mmol) were added with dioxane (40mL) In the reaction, the reaction solution was stirred overnight at 80°C. The reaction solution was cooled to room temperature, diluted with H2 O (50 mL), and extracted with EA (50 mL×2). The organic layer was washed with brine (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA=2/1) to obtain compound C1-6 (290 mg, 37.6% yield) as a yellow solid. MS: 357.2 [MH]- .

步骤5：化合物C1的合成。Step 5: Synthesis of compound C1.

冰浴下，向化合物5(660mg，0.02mol)、聚甲醛(166mg，5.53mmol)和DCM(20mL)的混合溶液中加入TFA(1.3mL)和Et3SiH(2.6mL)室温搅拌反应2小时。反应液加H2O(30mL)稀释，并用EA(50mL×2)萃取。合并有机层，并用食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩。剩余物经硅胶柱层析(PE/EA＝2/1)纯化，制得化合物C1(300mg，41％收率)，为黄色固体。MS:373.2[M+H]+，1H NMR(400MHz, CDCl3)δ:7.35(s,1H),7.00(s,1H),6.52-6.55(m,1H),6.38-6.42(m,1H),6.36(s,1H),3.35(s,3H),3.19(s,3H)。Under ice bath, to the mixed solution of compound 5 (660mg, 0.02mol), polyoxymethylene (166mg, 5.53mmol) and DCM (20mL) was added TFA (1.3mL) and Et3 SiH (2.6mL) and stirred at room temperature for 2 hours . The reaction solution was diluted with H2 O (30 mL), and extracted with EA (50 mL×2). The organic layers were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA=2/1) to obtain compound C1 (300 mg, 41% yield) as a yellow solid. MS: 373.2[M+H]+ ,1 H NMR(400MHz, CDCl3 )δ:7.35(s,1H),7.00(s,1H),6.52-6.55(m,1H),6.38-6.42(m, 1H), 6.36(s, 1H), 3.35(s, 3H), 3.19(s, 3H).

参考例13-53：片段C2～C42。Reference example 13-53: Fragment C2～C42.

参照参考例12中步骤1-5的合成方法，合成下表4中各参考例：Referring to the synthesis method of steps 1-5 in Reference Example 12, each reference example in Table 4 below was synthesized:

Figure PCTCN2020084797-appb-000022
Figure PCTCN2020084797-appb-000022

Figure PCTCN2020084797-appb-000023
Figure PCTCN2020084797-appb-000023

Figure PCTCN2020084797-appb-000024
Figure PCTCN2020084797-appb-000024

Figure PCTCN2020084797-appb-000025
Figure PCTCN2020084797-appb-000025

参考例54：片段C43和C44的合成路线。Reference Example 54: Synthetic route of fragments C43 and C44.

Figure PCTCN2020084797-appb-000026
Figure PCTCN2020084797-appb-000026

步骤1：化合物C43-3的合成。Step 1: Synthesis of compound C43-3.

化合物C43-1(2.51g，10.0mmol)，C43-2(1.65g，10.5mmol)和K2CO3(2.1g，15mmol)加入DMF(20mL)中，该反应液在100℃下加热反应3小时。反应液冷至室温，加H2O(30mL)淬灭，并用EA(50mL x 2)萃取。将合并的有机层用食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩。剩余物通过硅胶柱层析(PE/EA＝2/1)纯化，得到化合物C43-3(2.4g，62％产率)，为白色固体。MS:390.2[M+H]+。Compound C43-1 (2.51g, 10.0mmol), C43-2 (1.65g, 10.5mmol) and K2 CO3 (2.1g, 15mmol) were added to DMF (20mL), and the reaction solution was heated at 100°C for reaction 3. hour. The reaction solution was cooled to room temperature, quenched by adding H2 O (30 mL), and extracted with EA (50 mL x 2). The combined organic layer was washed with brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA=2/1) to obtain compound C43-3 (2.4 g, 62% yield) as a white solid. MS: 390.2 [M+H]+ .

步骤2：化合物C43的合成。Step 2: Synthesis of compound C43.

化合物C43-3(2.0g，5.1mmol)加入多聚磷酸(10mL)中，搅拌下加热至120℃反应3小时，反应液冷至室温，搅拌下加入冰水(30mL)搅拌30min，过滤，所得粗品经甲醇(10mL)重结晶，50℃真空干燥4h，得C43(1.54g，81％收率)，为类白色固体。MS:358.2[M+H]+，1H NMR(400MHz,CDCl3)δ:7.41(s,1H),7.05(s,1H),6.67(m,2H),6.58(m,1H),3.86(s,1H),3.35(s,3H)。Compound C43-3 (2.0g, 5.1mmol) was added to polyphosphoric acid (10mL), heated to 120°C for 3 hours with stirring, the reaction solution was cooled to room temperature, ice water (30mL) was added with stirring, stirred for 30min, filtered, and the result was The crude product was recrystallized from methanol (10 mL) and dried under vacuum at 50° C. for 4 hours to obtain C43 (1.54 g, 81% yield) as an off-white solid. MS: 358.2[M+H]+ ,1 H NMR (400MHz, CDCl3 ) δ: 7.41 (s, 1H), 7.05 (s, 1H), 6.67 (m, 2H), 6.58 (m, 1H), 3.86 (s, 1H), 3.35 (s, 3H).

步骤3：化合物C44的合成。Step 3: Synthesis of compound C44.

冰盐浴下向C43(1.0g，2.7mmol)的THF溶液(10mL)中滴加1N硼烷四氢呋喃溶液(2mL)，滴加完成后室温搅拌反应1h，再升温至回流反应2h。冷至室温，搅拌下滴加入无水乙醇(2mL)，滴加完成后减压浓缩至干，剩余物经二氯甲烷(10mL)/H2O(5mL)萃取、分液，有机层再经饱和食盐水(5mL)洗，分离、干燥、浓缩得C42粗品，该粗品经无水乙醇(5mL)重结晶，50℃真空干燥4h，得C44(0.82g，85％收率)，为类白色固体。MS:372.2[M+H]+，1H NMR(400MHz,CDCl3)δ:8.21(s,1H),8.05(s,1H),7.15-7.22(m,3H),3.34(s,3H)。1N Borane tetrahydrofuran solution (2 mL) was added dropwise to the THF solution (10 mL) of C43 (1.0 g, 2.7 mmol) under an ice-salt bath. After the addition was completed, the reaction was stirred at room temperature for 1 h, and then heated to reflux for 2 h. After cooling to room temperature, absolute ethanol (2mL) was added dropwise with stirring. After the addition was completed, it was concentrated to dryness under reduced pressure. The residue was extracted with dichloromethane (10mL)/H2 O (5mL) and separated. The organic layer Wash with saturated brine (5mL), separate, dry, and concentrate to obtain crude C42. The crude product is recrystallized with absolute ethanol (5mL) and dried under vacuum at 50°C for 4h to obtain C44 (0.82g, 85% yield), which is off-white solid. MS: 372.2[M+H]+ ,1 H NMR (400MHz, CDCl3 ) δ: 8.21 (s, 1H), 8.05 (s, 1H), 7.15 to 7.22 (m, 3H), 3.34 (s, 3H) .

参考例55-56：片段C45～C46。Reference example 55-56: Fragment C45～C46.

参照参考例54中步骤1-3的合成方法，合成下表5中各参考例：Refer to the synthesis method of steps 1-3 in Reference Example 54, to synthesize each reference example in Table 5 below:

Figure PCTCN2020084797-appb-000027
Figure PCTCN2020084797-appb-000027

参考例57：片段C47的合成路线。Reference Example 57: Synthetic route of fragment C47.

Figure PCTCN2020084797-appb-000028
Figure PCTCN2020084797-appb-000028

步骤1：化合物C47-2的合成。Step 1: Synthesis of compound C47-2.

化合物C47-1(2.51g，10.0mmol)，间氟苯硼酸(1.53g，11.0mmol)和K2CO3(3.45g，25.0mmol)加入DMF(20mL)中，该反应液N2气保护下，加热至100℃下加热反应3小时。反应液冷至室温，加H2O(30mL)/EtOAc(60mL)萃取，有机层用食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩。剩余物通过硅胶柱层析(PE/EA＝1/1)纯化，得到化合物C47-2(2.13g，80％产率)，为类白色固体。MS:267.3[M+H]+。Compound C47-1 (2.51g, 10.0mmol), m-fluorophenylboronic acid (1.53g, 11.0mmol) and K2 CO3 (3.45g, 25.0mmol) were added to DMF (20mL). The reaction solution was protected by N2 gas. , Heat to 100°C and react for 3 hours. The reaction solution was cooled to room temperature, and extracted with H2 O (30 mL)/EtOAc (60 mL). The organic layer was washed with brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA=1/1) to obtain compound C47-2 (2.13 g, 80% yield) as an off-white solid. MS: 267.3 [M+H]+ .

步骤2：化合物C47的合成。Step 2: Synthesis of compound C47.

敞口反应瓶中依次加入C47-2(2.1g，7.9mmol)、CuI(2.2g，11.8mmol)、特戊酸(0.8g，7.9mmol)和DMSO(10mL)，搅拌下加热至内温130℃反应12h。反应完成后，将EtOAc(30mL)加入到冷却的反应混合物中。依次加入氨水(15mL)和食盐水(15mL)洗涤、分液。有机层用无水硫酸钠干燥、过滤，并真空浓缩至干。所得剩余物通过硅胶柱层析(PE/EA＝10/1)纯化，得到化合物C47(1.78g，58％产率)，为类白色固体。MS:391.2[M+H]+，1H NMR(400MHz,CDCl3)δ:8.24(s,1H),8.15(s,1H),7.88(m,1H),7.13(m,1H),6.84(m,1H),3.32(s,1H)。Add C47-2 (2.1g, 7.9mmol), CuI (2.2g, 11.8mmol), pivalic acid (0.8g, 7.9mmol) and DMSO (10mL) to the open reaction flask, and heat to an internal temperature of 130 with stirring. Reaction at ℃ for 12h. After the reaction was completed, EtOAc (30 mL) was added to the cooled reaction mixture. Ammonia (15mL) and saline (15mL) were sequentially added for washing and liquid separation. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness in vacuo. The obtained residue was purified by silica gel column chromatography (PE/EA=10/1) to obtain compound C47 (1.78 g, 58% yield) as an off-white solid. MS: 391.2[M+H]+ ,1 H NMR (400MHz, CDCl3 ) δ: 8.24(s,1H), 8.15(s,1H), 7.88(m,1H), 7.13(m,1H), 6.84 (m,1H), 3.32(s,1H).

参考例58-60：片段C48-C50。Reference example 58-60: Fragment C48-C50.

参照参考例57中步骤1-2的合成方法，合成下表6中各参考例：Referring to the synthesis method of steps 1-2 in Reference Example 57, each reference example in Table 6 below was synthesized:

Figure PCTCN2020084797-appb-000029
Figure PCTCN2020084797-appb-000029

实施例1Example 1

合成路线：synthetic route:

Figure PCTCN2020084797-appb-000030
Figure PCTCN2020084797-appb-000030

步骤1：化合物I-1-1的合成Step 1: Synthesis of compound I-1-1

化合物A1(473mg,0.97mmol)、C1(180mg,0.485mmol)、CsF(221mg,1.45mmol)、Pd(dppf)Cl2(35mg,0.05mmol)、二氧六环(10mL)、H2O(2mL)依次加入反应瓶中，N2保护下加热升温至85℃反应12h。反应液冷至室温，加H2O(20mL)稀释，以DCM(30mL x 2)萃取，合并有机相。有机相经饱和食盐水(20mL)洗、分液。有机层用无水硫酸钠干燥、过滤，并真空浓缩至干。所得剩余物通过硅胶柱层析(PE/EA＝1/2)纯化，得到化合物I-1-1(178mg,62％产率)，为淡黄色固体。MS:594.6[M+H]+。Compound A1 (473mg, 0.97mmol), C1 (180mg, 0.485mmol), CsF (221mg, 1.45mmol), Pd(dppf)Cl2 (35mg, 0.05mmol), dioxane (10mL), H2 O ( 2mL) was added to the reaction flask one by one, heated to 85°C under N2 protection, and reacted for 12h. The reaction solution was cooled to room temperature, diluted with H2 O (20 mL), extracted with DCM (30 mL x 2), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL) and separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness in vacuo. The obtained residue was purified by silica gel column chromatography (PE/EA=1/2) to obtain compound I-1-1 (178 mg, 62% yield) as a pale yellow solid. MS: 594.6 [M+H]+ .

步骤2：化合物I-1的合成Step 2: Synthesis of compound I-1

I-1-1(160mg,0.27mmol)的甲醇溶液(10mL)中加入6M NaOH水溶液(5mL)，反应混合液加热至 80℃反应1h。反应液冷至室温，加H2O(20mL)稀释，以DCM(30mL x 2)萃取，合并有机相。有机相经饱和食盐水(20mL)洗、分液。有机层用无水硫酸钠干燥、过滤，并真空浓缩至干。所得剩余物通过硅胶柱层析(PE/EA＝1/2)纯化，得到化合物I-1(52mg,44％产率)，为白色固体。MS:440.5[M+H]+。1H NMR(400MHz,DMSO-d6)δ:12.11(s,1H),7.31-7.37(m,3H),7.14(s,1H),6.74-6.77(m,1H),6.44-6.52(m,2H),6.16(s,1H),3.59(s,3H),3.25(s,3H),3.17(s,3H).A 6M NaOH aqueous solution (5 mL) was added to the methanol solution (10 mL) of I-1-1 (160 mg, 0.27 mmol), and the reaction mixture was heated to 80° C. for 1 h. The reaction solution was cooled to room temperature, diluted with H2 O (20 mL), extracted with DCM (30 mL x 2), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL) and separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness in vacuo. The obtained residue was purified by silica gel column chromatography (PE/EA=1/2) to obtain compound I-1 (52 mg, 44% yield) as a white solid. MS: 440.5 [M+H]+ .1 H NMR (400MHz, DMSO-d6) δ: 12.11 (s, 1H), 7.31-7.37 (m, 3H), 7.14 (s, 1H), 6.74-6.77 (m, 1H), 6.44-6.52 (m, 2H), 6.16(s, 1H), 3.59(s, 3H), 3.25(s, 3H), 3.17(s, 3H).

参照实施例1中步骤1～2的合成方法，合成下表7中各实施例化合物：With reference to the synthetic methods of steps 1 to 2 in Example 1, the compounds of each example in Table 7 below were synthesized:

Figure PCTCN2020084797-appb-000031
Figure PCTCN2020084797-appb-000031

Figure PCTCN2020084797-appb-000032
Figure PCTCN2020084797-appb-000032

Figure PCTCN2020084797-appb-000033
Figure PCTCN2020084797-appb-000033

Figure PCTCN2020084797-appb-000034
Figure PCTCN2020084797-appb-000034

Figure PCTCN2020084797-appb-000035
Figure PCTCN2020084797-appb-000035

Figure PCTCN2020084797-appb-000036
Figure PCTCN2020084797-appb-000036

Figure PCTCN2020084797-appb-000037
Figure PCTCN2020084797-appb-000037

Figure PCTCN2020084797-appb-000038
Figure PCTCN2020084797-appb-000038

Figure PCTCN2020084797-appb-000039
Figure PCTCN2020084797-appb-000039

实施例56:I-56Example 56: I-56

合成路线：synthetic route:

Figure PCTCN2020084797-appb-000040
Figure PCTCN2020084797-appb-000040

化合物A12(200mg,2.06mmol)、C1(1533mg,4.12mmol)、K2CO3(568mg,4.12mmol)、Pd(OAc)2(46mg,0.2mmol)、二氧六环(20mL)、H2O(2mL)依次加入反应瓶中，N2保护下加热升温至85℃反应12h。反应液冷至室温，加H2O(20mL)稀释，以DCM(30mL x 2)萃取，合并有机相。有机相经饱和食盐水(20mL)洗、分液。有机层用无水硫酸钠干燥、过滤，并真空浓缩至干。所得剩余物通过硅胶柱层析(PE/EA＝1/1)纯化，得到化合物I-56(400mg,50％产率)，为淡黄色固体。MS:389.4[M+H]+。1H NMR(400MHz,DMSO-d6)δ:7.41(s,1H),7.05(s,1H),6.91(m,1H),6.50(m,2H),3.35(s,3H),3.20(s,3H),2.25(s,6H).Compound A12 (200mg, 2.06mmol), C1 (1533mg, 4.12mmol), K2 CO3 (568mg, 4.12mmol), Pd(OAc)2 (46mg, 0.2mmol), dioxane (20mL), H2 O (2mL) were added the reaction flask, was heated under N2 the reaction temperature was raised to 85 ℃ 12h. The reaction solution was cooled to room temperature, diluted with H2 O (20 mL), extracted with DCM (30 mL x 2), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL) and separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness in vacuo. The obtained residue was purified by silica gel column chromatography (PE/EA=1/1) to obtain compound I-56 (400 mg, 50% yield) as a pale yellow solid. MS: 389.4 [M+H]+ .1 H NMR (400MHz, DMSO-d6) δ: 7.41 (s, 1H), 7.05 (s, 1H), 6.91 (m, 1H), 6.50 (m, 2H), 3.35 (s, 3H), 3.20 (s) ,3H), 2.25(s,6H).

参照实施例56中合成方法，合成下表8中各实施例化合物：Refer to the synthesis method in Example 56, to synthesize the compound of each example in Table 8 below:

Figure PCTCN2020084797-appb-000041
Figure PCTCN2020084797-appb-000041

各实施例的NMR和MS数据汇总见下表9所示：The NMR and MS data of each example are summarized in Table 9 below:

Figure PCTCN2020084797-appb-000042
Figure PCTCN2020084797-appb-000042

Figure PCTCN2020084797-appb-000043
Figure PCTCN2020084797-appb-000043

Figure PCTCN2020084797-appb-000044
Figure PCTCN2020084797-appb-000044

Figure PCTCN2020084797-appb-000045
Figure PCTCN2020084797-appb-000045

Figure PCTCN2020084797-appb-000046
Figure PCTCN2020084797-appb-000046

测试例1、BRD4活性测试Test case 1, BRD4 activity test

结合反应过程:Combined reaction process:

(1)配制1×Assay buffer。(1) Prepare 1×Assay buffer.

(2)化合物浓度梯度的配制：受试化合物与阳性对照化合物AbbV-075、I-BET762测试终浓度均为1000nM起始，3倍稀释10个浓度，每个浓度设置二复孔测试。先将化合物以DMSO为溶剂梯度稀释成相应1000倍终浓度的溶液，然后用1×Assay buffer将相应浓度的DMSO溶液稀释100倍(此时DMSO浓度为1％)，用排枪转移2μL化合物1％DMSO溶液到384孔反应板中待测。Max孔中转移2μL的1％DMSO溶液，Min孔中转移2μL的AbbV-075最高浓度1％DMSO溶液。(2) Preparation of compound concentration gradient: the final concentration of the test compound and the positive control compound AbbV-075 and I-BET762 are all starting at 1000 nM, and the concentration is 3 times diluted to 10 concentrations, and each concentration is set for two multiple well tests. First, the compound was diluted with DMSO as the solvent to a solution of 1000 times the final concentration, and then the DMSO solution of the corresponding concentration was diluted 100 times with a 1×Assay buffer (the DMSO concentration was 1% at this time), and 2μL of the compound was transferred with a discharge gun. Transfer the DMSO solution to a 384-well reaction plate to be tested. Transfer 2 μL of 1% DMSO solution into the Max well, and transfer 2 μL of the AbbV-075 highest concentration 1% DMSO solution into the Min well.

(3)用1×反应溶液配制5×蛋白溶液。(3) Prepare 5× protein solution with 1× reaction solution.

(4)用1×反应溶液配制5×多肽溶液。(4) Prepare 5× peptide solution with 1× reaction solution.

(5)在各孔中加4μL的5×蛋白溶液，1000rpm离心1min，室温孵育15分钟。(5) Add 4 μL of 5× protein solution to each well, centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 15 minutes.

(6)反应板各孔中加入4μL的5×多肽溶液，1000rpm离心1min。(6) Add 4 μL of 5× polypeptide solution to each well of the reaction plate, and centrifuge at 1000 rpm for 1 min.

(7)加入10μL检测液，1000rpm离心60秒，轻轻振荡混匀后，室温孵育60分钟。(7) Add 10 μL of detection solution, centrifuge at 1000 rpm for 60 seconds, gently shake and mix, and incubate at room temperature for 60 minutes.

(8)用EnVision读数。(8) Read with EnVision.

数据分析:data analysis:

计算公式Calculation formula

Figure PCTCN2020084797-appb-000047
Figure PCTCN2020084797-appb-000047

拟合量效曲线Fitted dose-response curve

以浓度的log值作为X轴，百分比抑制率为Y轴，采用分析软件GraphPad Prism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线，从而得出化合物对蛋白结合抑制的IC50值。Take the log value of the concentration as the X-axis, and the percentage inhibition rate on the Y-axis. The log(inhibitor) vs.response-Variable slope of the analysis software GraphPad Prism 5 is used to fit the dose-response curve to obtain the IC50 of the compound's inhibition of protein binding. value.

测试例2、MV4-11细胞增殖实验Test Example 2. MV4-11 cell proliferation experiment

通过

Figure PCTCN2020084797-appb-000048
试剂(Invitrogen)测定细胞活力。by
Figure PCTCN2020084797-appb-000048
Reagent (Invitrogen) measures cell viability.

将MV4-11细胞(急性髓性白血病)以5000个细胞/孔的浓度接种在96孔微量滴定板上的100μL生长培养基(RPMI1640，10％FCS)中。在37℃下孵育过夜后，测定荧光值(C1值)。然后用多种物质稀释物处理板，并且在37℃下孵育72h，然后测定荧光值(C0值)。对于数据分析，从C0值扣除C1值，并且将用多种物质稀释物处理的或仅用缓冲溶液处理的细胞结果进行比较。从而计算IC50值。MV4-11 cells (acute myeloid leukemia) were seeded in 100 μL growth medium (RPMI1640, 10% FCS) on a 96-well microtiter plate at a concentration of 5000 cells/well. After incubating overnight at 37°C, the fluorescence value (C1 value) was measured. The plate was then treated with dilutions of various substances and incubated at 37°C for 72 hours, and then the fluorescence value (C0 value) was measured. For data analysis, the C1 value was subtracted from the C0 value, and the results of cells treated with multiple substance dilutions or only buffer solutions were compared. To calculate the IC50 value.

上述实验结果如表10所示。The above experimental results are shown in Table 10.

表10.测试结果：Table 10. Test results:

Figure PCTCN2020084797-appb-000049
Figure PCTCN2020084797-appb-000049

结论：本发明化合物对BRD4结合活性明显优于ABBV-075、INCB-057643；本发明化合物对白血病 细胞MV4-11增殖具有明显的抑制活性，抑制活性优于ABBV-075、INCB-057643。Conclusion: The compound of the present invention has significantly better BRD4 binding activity than ABBV-075 and INCB-057643; the compound of the present invention has obvious inhibitory activity on the proliferation of leukemia cells MV4-11, and the inhibitory activity is better than ABBV-075 and INCB-057643.

测试例3、本发明化合物药代动力学测试Test Example 3. Pharmacokinetic test of the compound of the present invention

以SD大鼠为受试动物，采用LC/MS/MS法测定大鼠灌胃给予ABBV-075和本发明优选实施例化合物后，测定其不同时刻血浆中的药物浓度，研究本发明化合物在大鼠体内药代动力学特征。Taking SD rats as the test animals, the LC/MS/MS method was used to determine that the rats were intragastrically administered ABBV-075 and the preferred embodiment compounds of the present invention, and then the drug concentration in the plasma at different times was measured to study the compounds of the present invention in Pharmacokinetic characteristics in rats.

SD大鼠来源：北京维通利华实验动物技术有限公司Source of SD rats: Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.

给药方式:单次灌胃给药Administration method: single intragastric administration

给药剂量及浓度：10mg/kg；1mg/mLDosage and concentration: 10mg/kg; 1mg/mL

制剂处方：0.5％methylcellulosePreparation prescription: 0.5% methylcellulose

取样点：5min，15min，30min，1h，2h，4h，8h，24h.Sampling points: 5min, 15min, 30min, 1h, 2h, 4h, 8h, 24h.

标准曲线和质控样本配制处理：取适量储备液用50％乙腈水稀释成0.04、0.10、0.20、0.40、1.00、2.00、4.00μg/mL的标准工作液，0.10、1.00、3.00μg/mL的质控工作液。分别取47.5μL空白大鼠血浆中加入2.50μL的标准曲线工作液和质控工作液，配置成含待测物浓度为2.00、5.00、10.00、20.00、50.00、100.00、200.00ng/mL的标曲和浓度为5.00、50.00和150.00ng/mL的质控样本，分别加入200μL的乙腈(含内标氯雷他定5ng/mL)，涡旋振荡3min后，15000rpm，4℃离心15min，取上清液100L进行LC-MS/MS分析。采用

Figure PCTCN2020084797-appb-000050
8.0计算实验结果。Standard curve and quality control sample preparation and processing: Take an appropriate amount of stock solution and dilute with 50% acetonitrile water into a standard working solution of 0.04, 0.10, 0.20, 0.40, 1.00, 2.00, 4.00 μg/mL, 0.10, 1.00, 3.00 μg/mL Quality control working fluid. Take 47.5μL of blank rat plasma and add 2.50μL of standard curve working solution and quality control working solution respectively, and configure the standard curve with the concentration of analyte at 2.00, 5.00, 10.00, 20.00, 50.00, 100.00, 200.00ng/mL Add 200μL of acetonitrile (containing the internal standard loratadine 5ng/mL) to the quality control samples with concentrations of 5.00, 50.00 and 150.00ng/mL, vortex for 3min, centrifuge at 15000rpm, 4℃ for 15min, and take the supernatant Liquid 100L was analyzed by LC-MS/MS. use
Figure PCTCN2020084797-appb-000050
8.0 Calculate the experimental results.

本发明优选化合物药代动力学参数如表11所示。The pharmacokinetic parameters of the preferred compounds of the present invention are shown in Table 11.

表11：优选化合物药代动力学参数Table 11: Pharmacokinetic parameters of preferred compounds

Figure PCTCN2020084797-appb-000051
Figure PCTCN2020084797-appb-000051

结论：本发明实施例化合物表现出良好的药代动力学性质，与ABBV-075相比，血药浓度、曲线面积较高，半衰期长，滞留时间短。Conclusion: The compounds of the examples of the present invention show good pharmacokinetic properties. Compared with ABBV-075, the blood concentration and curve area are higher, the half-life is longer, and the residence time is shorter.

测试例4、本发明化合物体内药效试验测试Test Example 4. In vivo efficacy test of the compound of the present invention

目的：测试受试化合物对MV4-11白血病裸鼠移植瘤体内生长的抑制作用。Objective: To test the inhibitory effect of the test compound on the growth of MV4-11 leukemia transplanted tumor in nude mice.

方法：BALB/c裸小鼠皮下接种MV4-11细胞，建立MV4-11裸鼠移植瘤模型。接种13天后(d13)，平均肿瘤体积约为215mm3，根据肿瘤体积大小采用随机区组法将荷瘤鼠分组，包括溶剂对照组、对照样品INCB-057643组、受试样品组，每组6只。各组均采用灌胃给药，给药剂量为30mg/kg，给药体积均为10ml/kg，每天给药一次，连续给药14天，溶剂对照组灌胃给予空白溶剂(50mM乳酸钠水溶液，PH4.0)。开始给予测试药物后每周二次量瘤、称重。实验结束后安乐死动物。Methods: BALB/c nude mice were inoculated subcutaneously with MV4-11 cells to establish a MV4-11 nude mouse xenograft model. 13 days after inoculation (d13), the average tumor volume is about 215mm3. According to the tumor volume, the tumor-bearing mice are divided into groups by random block method, including solvent control group, control sample INCB-057643 group, and test sample group, each with 6 only. Each group was given intragastric administration with a dose of 30mg/kg and a volume of 10ml/kg, once a day for 14 consecutive days. The solvent control group was given a blank solvent (50mM sodium lactate aqueous solution, PH4.0). Tumors were measured and weighed twice a week after the test drug was started. After the experiment, the animals were euthanized.

本发明优选化合物动物体内药效结果如表12所示。Table 12 shows the efficacy results of the preferred compounds of the present invention in animals.

表12：优选化合物动物体内药效Table 12: Pharmacodynamics of preferred compounds in animals

Figure PCTCN2020084797-appb-000052
Figure PCTCN2020084797-appb-000052

结论：本发明实施例化合物表现出良好抑瘤活性。与对照组INCB-057643相比抑瘤活性更加显著。Conclusion: The compounds of the examples of the present invention show good anti-tumor activity. Compared with the control group INCB-057643, the anti-tumor activity is more significant.

以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。The above descriptions are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the present invention. Within the scope of protection.

Claims (9)

Translated fromChinese
一种BET蛋白抑制剂，其特征在于，其结构如式I所示：A BET protein inhibitor, characterized in that its structure is shown in formula I:
Figure PCTCN2020084797-appb-100001
Figure PCTCN2020084797-appb-100001
或其药学上可接受的盐，其中，Or a pharmaceutically acceptable salt thereof, whereinA选自
Figure PCTCN2020084797-appb-100002
A is selected from
Figure PCTCN2020084797-appb-100002
B环选自
Figure PCTCN2020084797-appb-100003
或被R11和/或R12取代的五元芳杂环；Ring B is selected from
Figure PCTCN2020084797-appb-100003
Or a five-membered aromatic heterocyclic ring substituted by R11 and/or R12 ;其中：among them:X为O、S或NR13；X is O, S or NR13 ;Y为CH2、C＝O、NR1或Y不存在；Y is CH2 , C=O, NR1 or Y does not exist;Z为CR14或N；Z is CR14 or N;U为CH或N；U is CH or N;W为O或NH；W is O or NH;V为CH或N；V is CH or N;R1为氢、C1-C6烷基、C3-C6环烷基、取代C1-C6烷基、取代C3-C6环烷基、C3-C6环烷基C1-C6烷基、C1-C6烷基-SO2-或C3-C6环烷基-SO2-；R1 is hydrogen, C1 -C6 alkyl, C3 -C6 cycloalkyl, substituted C1 -C6 alkyl, substituted C3 -C6 cycloalkyl, C3 -C6 cycloalkyl C1 -C6 alkyl, C1 -C6 alkyl -SO2 -or C3 -C6 cycloalkyl -SO2 -;R2为氢、C1-C6烷基、C1-C3烷氧基、卤素或氰基；R2 is hydrogen, C1 -C6 alkyl, C1 -C3 alkoxy, halogen or cyano;R3为氢、C1-C6烷基、C1-C3烷氧基、卤素、氰基、-S(O)2R15、-S(O)2NR16R17或-N(R16)S(O)2R15；R3 is hydrogen, C1 -C6 alkyl, C1 -C3 alkoxy, halogen, cyano, -S(O)2 R15 , -S(O)2 NR16 R17 or -N( R16 )S(O)2 R15 ;R4为氢、C1-C6烷基、C1-C3烷氧基、卤素或氰基；R4 is hydrogen, C1 -C6 alkyl, C1 -C3 alkoxy, halogen or cyano;R5和R6各自独立地为氢或C1-C6烷基；R5 and R6 are each independently hydrogen or C1 -C6 alkyl;R7、R8、R9和R10各自独立地为氢、卤素、氰基、C1-C3烷氧基或C1-C6烷基；R7 , R8 , R9 and R10 are each independently hydrogen, halogen, cyano, C1 -C3 alkoxy or C1 -C6 alkyl;R11为氢或C1-C6烷基；R11 is hydrogen or C1 -C6 alkyl;R12为氢或C1-C6烷基；R12 is hydrogen or C1 -C6 alkyl;R13为氢或C1-C6烷基；R13 is hydrogen or C1 -C6 alkyl;R14为氢、C1-C6烷基、卤素或氰基；R14 is hydrogen, C1 -C6 alkyl, halogen or cyano;R15为C1-C6烷基；R15 is C1 -C6 alkyl;R16为氢或C1-C6烷基；R16 is hydrogen or C1 -C6 alkyl;R17为氢或C1-C6烷基；R17 is hydrogen or C1 -C6 alkyl;上述卤素选自氟、氯、溴或碘。The aforementioned halogen is selected from fluorine, chlorine, bromine or iodine.如权利要求1所述的BET蛋白抑制剂，其特征在于，A选自
Figure PCTCN2020084797-appb-100004
Figure PCTCN2020084797-appb-100005
The BET protein inhibitor of claim 1, wherein A is selected from
Figure PCTCN2020084797-appb-100004
Figure PCTCN2020084797-appb-100005
B环选自
Figure PCTCN2020084797-appb-100006
Ring B is selected from
Figure PCTCN2020084797-appb-100006
其中：among them:X为O、S或NR13；X is O, S or NR13 ;Y为CH2、C＝O、NR1或Y不存在；Y is CH2 , C=O, NR1 or Y does not exist;Z为CR14或N；Z is CR14 or N;U为CH或N；U is CH or N;W为O或NH；W is O or NH;V为CH或N；V is CH or N;R1为氢、C1-C4烷基、C3-C6环烷基、取代C1-C4烷基、取代C3-C6环烷基、C3-C6环烷基C1-C3烷基、C1-C4烷基-SO2-或C3-C6环烷基-SO2-；所述取代C1-C4烷基是指C1-C4烷基上的氢被一个或多个C3-C6环烷基取代；所述取代C3-C6环烷基是指C3-C6环烷基上的氢被一个或多个C1-C4烷基取代；R1 is hydrogen, C1 -C4 alkyl, C3 -C6 cycloalkyl, substituted C1 -C4 alkyl, substituted C3 -C6 cycloalkyl, C3 -C6 cycloalkyl C1 -C3 alkyl, C1 -C4 alkyl -SO2 -or C3 -C6 cycloalkyl -SO2 -; the substituted C1 -C4 alkyl refers to C1 -C4 alkyl The hydrogen on the group is replaced by one or more C3 -C6 cycloalkyl; the substituted C3 -C6 cycloalkyl means that the hydrogen on the C3 -C6 cycloalkyl group is replaced by one or more C1 -C4 alkyl substitution;R2为氢、C1-C4烷基、C1-C2烷氧基、卤素或氰基；R2 is hydrogen, C1 -C4 alkyl, C1 -C2 alkoxy, halogen or cyano;R3为氢、C1-C4烷基、C1-C2烷氧基、卤素、氰基、-S(O)2R15、-S(O)2NR16R17或-N(R16)S(O)2R15；R3 is hydrogen, C1 -C4 alkyl, C1 -C2 alkoxy, halogen, cyano, -S(O)2 R15 , -S(O)2 NR16 R17 or -N( R16 )S(O)2 R15 ;R4为氢、C1-C4烷基、C1-C3烷氧基、卤素或氰基；R4 is hydrogen, C1 -C4 alkyl, C1 -C3 alkoxy, halogen or cyano;R5和R6各自独立地为氢或C1-C4烷基；R5 and R6 are each independently hydrogen or C1 -C4 alkyl;R7、R8、R9和R10各自独立地为氢、卤素、氰基、C1-C3烷氧基或C1-C4烷基；R7 , R8 , R9 and R10 are each independently hydrogen, halogen, cyano, C1 -C3 alkoxy or C1 -C4 alkyl;R11为氢或C1-C4烷基；R11 is hydrogen or C1 -C4 alkyl;R12为氢或C1-C4烷基；R12 is hydrogen or C1 -C4 alkyl;R13为氢或C1-C4烷基；R13 is hydrogen or C1 -C4 alkyl;R14为氢、C1-C4烷基、卤素或氰基；R14 is hydrogen, C1 -C4 alkyl, halogen or cyano;R15为C1-C4烷基；R15 is a C1 -C4 alkyl group;R16为氢或C1-C4烷基；R16 is hydrogen or C1 -C4 alkyl;R17为氢或C1-C4烷基；R17 is hydrogen or C1 -C4 alkyl;上述卤素选自氟、氯、溴或碘。The aforementioned halogen is selected from fluorine, chlorine, bromine or iodine.如权利要求1所述的BET蛋白抑制剂，其特征在于，A选自
Figure PCTCN2020084797-appb-100007
Figure PCTCN2020084797-appb-100008
The BET protein inhibitor of claim 1, wherein A is selected from
Figure PCTCN2020084797-appb-100007
Figure PCTCN2020084797-appb-100008
B环选自
Figure PCTCN2020084797-appb-100009
Ring B is selected from
Figure PCTCN2020084797-appb-100009
其中：among them:X为O、S或NR13；X is O, S or NR13 ;Y为CH2、C＝O、NR1或Y不存在；Y is CH2 , C=O, NR1 or Y does not exist;Z为CR14或N；Z is CR14 or N;U为CH或N；U is CH or N;W为O或NH；W is O or NH;V为CH或N；V is CH or N;R1为氢、C1-C3烷基、C3-C6环烷基、取代C1-C3烷基、取代C3-C6环烷基、C3-C6环烷基C1-C3烷基、C1-C3烷基-SO2-或C3-C6环烷基-SO2-；所述取代C1-C3烷基是指C1-C3烷基上的氢被一个或多个C3-C6环烷基取代；所述取代C3-C6环烷基是指C3-C6环烷基上的氢被一个或多个C1-C3烷基取代；R1 is hydrogen, C1 -C3 alkyl, C3 -C6 cycloalkyl, substituted C1 -C3 alkyl, substituted C3 -C6 cycloalkyl, C3 -C6 cycloalkyl C1- C3 alkyl, C1 -C3 alkyl-SO2 -or C3 -C6 cycloalkyl-SO2 -; the substituted C1 -C3 alkyl refers to C1 -C3 alkyl The hydrogen on the group is replaced by one or more C3 -C6 cycloalkyl; the substituted C3 -C6 cycloalkyl means that the hydrogen on the C3 -C6 cycloalkyl group is replaced by one or more C1 -C3 alkyl substitution;R2为氢、C1-C3烷基、C1-C2烷氧基、卤素或氰基；R2 is hydrogen, C1 -C3 alkyl, C1 -C2 alkoxy, halogen or cyano;R3为氢、C1-C3烷基、C1-C2烷氧基、卤素、氰基、-S(O)2R15、-S(O)2NR16R17或-N(R16)S(O)2R15；R3 is hydrogen, C1 -C3 alkyl, C1 -C2 alkoxy, halogen, cyano, -S(O)2 R15 , -S(O)2 NR16 R17 or -N( R16 )S(O)2 R15 ;R4为氢、C1-C3烷基、C1-C2烷氧基、卤素或氰基；R4 is hydrogen, C1 -C3 alkyl, C1 -C2 alkoxy, halogen or cyano;R5和R6各自独立地为氢或C1-C3烷基；R5 and R6 are each independently hydrogen or C1 -C3 alkyl;R7、R8、R9和R10各自独立地为氢、卤素、氰基、C1-C2烷氧基或C1-C3烷基；R7 , R8 , R9 and R10 are each independently hydrogen, halogen, cyano, C1 -C2 alkoxy or C1 -C3 alkyl;R11为氢或C1-C3烷基；R11 is hydrogen or C1 -C3 alkyl;R12为氢或C1-C3烷基；R12 is hydrogen or C1 -C3 alkyl;R13为氢或C1-C3烷基；R13 is hydrogen or C1 -C3 alkyl;R14为氢、C1-C3烷基、卤素或氰基；R14 is hydrogen, C1 -C3 alkyl, halogen or cyano;R15为C1-C3烷基；R15 is C1 -C3 alkyl;R16为氢或C1-C3烷基；R16 is hydrogen or C1 -C3 alkyl;R17为氢或C1-C3烷基；R17 is hydrogen or C1 -C3 alkyl;上述卤素选自氟、氯、溴或碘。The aforementioned halogen is selected from fluorine, chlorine, bromine or iodine.如权利要求1所述的BET蛋白抑制剂，其特征在于，选自如下化合物：The BET protein inhibitor of claim 1, which is selected from the following compounds:
Figure PCTCN2020084797-appb-100010
Figure PCTCN2020084797-appb-100010
Figure PCTCN2020084797-appb-100011
Figure PCTCN2020084797-appb-100011
Figure PCTCN2020084797-appb-100012
Figure PCTCN2020084797-appb-100012
Figure PCTCN2020084797-appb-100013
Figure PCTCN2020084797-appb-100013
Figure PCTCN2020084797-appb-100014
Figure PCTCN2020084797-appb-100014
或其可药用的盐。Or its pharmaceutically acceptable salt.一种合成权利要求1～4任一项所述的化合物的方法，其特征在于反应式如下：A method for synthesizing the compound of any one of claims 1 to 4, characterized in that the reaction formula is as follows:
Figure PCTCN2020084797-appb-100015
Figure PCTCN2020084797-appb-100015
通式IA化合物和通式IB化合物经催化偶联反应制得通式化合物I，各基团定义如权利要求1～4任一项所述。The compound of the general formula IA and the compound of the general formula IB are subjected to a catalytic coupling reaction to prepare the compound of general formula I, and each group is defined as described in any one of claims 1 to 4.如权利要求1～4任一项所述的化合物在制备预防或治疗与BET蛋白相关疾病的药物中的用途。Use of the compound according to any one of claims 1 to 4 in the preparation of a medicine for preventing or treating diseases related to BET protein.如权利要求6所述的用途，其特征在于，所述与BET蛋白相关疾病指肿瘤疾病、良性增生、炎性疾病、自身免疫疾病、败血症、病毒感染、血管疾病或神经性疾病。The use according to claim 6, wherein the disease related to the BET protein refers to tumor disease, benign hyperplasia, inflammatory disease, autoimmune disease, sepsis, viral infection, vascular disease or neurological disease.如权利要求7所述的用途，其特征在于，所述肿瘤疾病包括但不限于急性髓性白血病、淋巴瘤、多发性骨髓瘤、B细胞急性淋巴白血病、中线癌、神经胶质瘤、实体瘤、乳腺癌、结直肠癌、前列腺癌、宫颈癌、非小细胞肺癌或黑色素瘤。The use according to claim 7, wherein the tumor diseases include but are not limited to acute myeloid leukemia, lymphoma, multiple myeloma, B-cell acute lymphoblastic leukemia, midline carcinoma, glioma, solid tumor , Breast cancer, colorectal cancer, prostate cancer, cervical cancer, non-small cell lung cancer or melanoma.一种组合物，所述组合物包括治疗有效量的权利要求1～4任一项所述的化合物或其可药用的盐和医学上可接受的载体。A composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof and a medically acceptable carrier.
PCT/CN2020/0847972019-04-302020-04-14Bet inhibitor, and preparation method and use thereofCeasedWO2020221006A1 (en)

Applications Claiming Priority (2)

Application NumberPriority DateFiling DateTitle
CN201910360142.1ACN110003204B (en)2019-04-302019-04-30 A kind of BET protein inhibitor, its preparation method and use
CN201910360142.12019-04-30

Publications (1)

Publication NumberPublication Date
WO2020221006A1true WO2020221006A1 (en)2020-11-05

Family

ID=67175217

Family Applications (1)

Application NumberTitlePriority DateFiling Date
PCT/CN2020/084797CeasedWO2020221006A1 (en)2019-04-302020-04-14Bet inhibitor, and preparation method and use thereof

Country Status (2)

CountryLink
CN (1)CN110003204B (en)
WO (1)WO2020221006A1 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication numberPriority datePublication dateAssigneeTitle
WO2023245297A1 (en)*2022-06-232023-12-28University Of OttawaFerroptosis inhibitors and uses thereof
WO2024229406A1 (en)2023-05-042024-11-07Revolution Medicines, Inc.Combination therapy for a ras related disease or disorder
WO2025034702A1 (en)2023-08-072025-02-13Revolution Medicines, Inc.Rmc-6291 for use in the treatment of ras protein-related disease or disorder
WO2025080946A2 (en)2023-10-122025-04-17Revolution Medicines, Inc.Ras inhibitors
WO2025171296A1 (en)2024-02-092025-08-14Revolution Medicines, Inc.Ras inhibitors

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication numberPriority datePublication dateAssigneeTitle
CN110003204B (en)*2019-04-302020-08-11上海勋和医药科技有限公司 A kind of BET protein inhibitor, its preparation method and use
CN113461538A (en)*2021-07-122021-10-01无锡双启科技有限公司Preparation method of 2-chloro-3-bromoaniline

Citations (10)

* Cited by examiner, † Cited by third party
Publication numberPriority datePublication dateAssigneeTitle
GB2301820A (en)*1995-06-071996-12-18Merck & Co Inc2-(dibenzofuranyl)-and 2-(dibenzothienyl)-carbapenems,compositions containing such compounds and methods of use
KR20140078144A (en)*2012-12-172014-06-25한국교통대학교산학협력단Phenylpyrazole derivatives and organoelectroluminescent device employing the same
WO2014134267A1 (en)*2013-02-272014-09-04Bristol-Myers Squibb CompanyCarbazole compounds useful as bromodomain inhibitors
WO2014164596A1 (en)*2013-03-112014-10-09The Regents Of The University Of MichiganBet bromodomain inhibitors and therapeutic methods using the same
WO2015100282A1 (en)*2013-12-242015-07-02Bristol-Myers Squibb CompanyTricyclic compounds as anticancer agents
WO2015164480A1 (en)*2014-04-232015-10-29Incyte Corporation1H-PYRROLO[2,3-c]PYRIDIN-7(6H)-ONES AND PYRAZOLO[3,4-c]PYRIDIN-7(6H)-ONES AS INHIBITORS OF BET PROTEINS
WO2016139361A1 (en)*2015-03-052016-09-09Boehringer Ingelheim International GmbhNew pyridinones and isoquinolinones as inhibitors of the bromodomain brd9
US9735378B2 (en)*2013-09-092017-08-15Universal Display CorporationOrganic electroluminescent materials and devices
WO2018033918A1 (en)*2016-08-182018-02-22Vidac Pharma Ltd.Piperazine derivatives, pharmaceutical compositions and methods of use thereof
CN110003204A (en)*2019-04-302019-07-12上海勋和医药科技有限公司A kind of BET protein inhibitor, preparation method and the usage

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication numberPriority datePublication dateAssigneeTitle
EP3110818B1 (en)*2014-02-282019-10-23The Regents of The University of Michigan9h-pyrimido[4,5-b]indoles and related analogs as bet bromodomain inhibitors
AU2016302400B2 (en)*2015-08-042020-10-15Catalyst Therapeutics Pty LtdBenzodiazepines as bromodomain inhibitors
US10918647B2 (en)*2016-07-262021-02-16University Of Southern CaliforniaSelective bromodomain inhibition of fungal Bdf1

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication numberPriority datePublication dateAssigneeTitle
GB2301820A (en)*1995-06-071996-12-18Merck & Co Inc2-(dibenzofuranyl)-and 2-(dibenzothienyl)-carbapenems,compositions containing such compounds and methods of use
KR20140078144A (en)*2012-12-172014-06-25한국교통대학교산학협력단Phenylpyrazole derivatives and organoelectroluminescent device employing the same
WO2014134267A1 (en)*2013-02-272014-09-04Bristol-Myers Squibb CompanyCarbazole compounds useful as bromodomain inhibitors
WO2014164596A1 (en)*2013-03-112014-10-09The Regents Of The University Of MichiganBet bromodomain inhibitors and therapeutic methods using the same
US9735378B2 (en)*2013-09-092017-08-15Universal Display CorporationOrganic electroluminescent materials and devices
WO2015100282A1 (en)*2013-12-242015-07-02Bristol-Myers Squibb CompanyTricyclic compounds as anticancer agents
WO2015164480A1 (en)*2014-04-232015-10-29Incyte Corporation1H-PYRROLO[2,3-c]PYRIDIN-7(6H)-ONES AND PYRAZOLO[3,4-c]PYRIDIN-7(6H)-ONES AS INHIBITORS OF BET PROTEINS
WO2016139361A1 (en)*2015-03-052016-09-09Boehringer Ingelheim International GmbhNew pyridinones and isoquinolinones as inhibitors of the bromodomain brd9
WO2018033918A1 (en)*2016-08-182018-02-22Vidac Pharma Ltd.Piperazine derivatives, pharmaceutical compositions and methods of use thereof
CN110003204A (en)*2019-04-302019-07-12上海勋和医药科技有限公司A kind of BET protein inhibitor, preparation method and the usage

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"CHEMCATS Database", COMPOUND CAS RN 2108886-42-4, 6 August 2017 (2017-08-06), DOI: 20200707121900X*
SHANMUGAM KARTHIK ET AL.: "Dibenzofuran and dibenzothiophene based palladium(II)/NHC catalysts –synthesis and applications in C–C bond formation", NEW JOURNAL OF CHEMISTRY, no. 42, 21 August 2018 (2018-08-21), XP055750718, DOI: 20200707122219X*

Cited By (5)

* Cited by examiner, † Cited by third party
Publication numberPriority datePublication dateAssigneeTitle
WO2023245297A1 (en)*2022-06-232023-12-28University Of OttawaFerroptosis inhibitors and uses thereof
WO2024229406A1 (en)2023-05-042024-11-07Revolution Medicines, Inc.Combination therapy for a ras related disease or disorder
WO2025034702A1 (en)2023-08-072025-02-13Revolution Medicines, Inc.Rmc-6291 for use in the treatment of ras protein-related disease or disorder
WO2025080946A2 (en)2023-10-122025-04-17Revolution Medicines, Inc.Ras inhibitors
WO2025171296A1 (en)2024-02-092025-08-14Revolution Medicines, Inc.Ras inhibitors

Also Published As

Publication numberPublication date
CN110003204A (en)2019-07-12
CN110003204B (en)2020-08-11

Similar Documents

PublicationPublication DateTitle
CN110003204B (en) A kind of BET protein inhibitor, its preparation method and use
ES2868355T3 (en) Bromodomain inhibitors
CN105636953B (en)1,4 dibasic pyridyl derivatives and its purposes for treating the illness related to SMN shortages
WO2020259432A1 (en)Kras-g12c inhibitor
EP3653620B9 (en)New heteroaryl amide derivatives as selective inhibitors of histone deacetylases 1 and 2 (hdac1-2)
WO2010139180A1 (en)Naphthalene carboxamide derivatives as inhibitors of protein kinase and histone deacetylase, preparation methods and uses thereof
CN108341813B (en)Substituted 1- (isoxazol-3-yl) -3- (3-fluoro-4-phenyl) urea derivative and preparation method and application thereof
OA13235A (en)Piperazine derivatives for the treatment of HIV infections.
CN103842350B (en)As five yuan of dihydro heterocyclic ketones derivatives and the application of DHODH inhibitor
CN111362967A (en)Benzoxadiazatetetradecene derivatives and use thereof
AU2017287553A1 (en)Imidazopyrazinamine phenyl derivative and use thereof
WO2011043359A1 (en)Pharmaceutical product containing aromatic heterocyclic compound
JP6916562B2 (en) Compounds, pharmaceutically acceptable salts thereof, solvates, stereoisomers and tautomers, and drug compositions, hyperproliferative disorder therapeutic agents, hyperproliferative disorder prophylaxis agents, drugs, cancer therapeutic agents, cancer Prophylactic agents and kinase signaling regulators
EP3844166B1 (en)Substituted macrocycles useful as kinase inhibitors
CN110240587B (en)Aryl difluoro benzyl ether compounds, preparation method and application
CN103965174B (en)The quinazoline based egfr tyrosine kinase inhibitor that contains zinc binding moiety
JP2022530866A (en) Diazanaphthalene derivative as a PRC2 inhibitor
CN113444069A (en)2-aryl-4- (1H-pyrazol-3-yl) pyridine LSD1/HDAC double-target inhibitor
CN113880772B (en)CDK kinase inhibitors and application thereof
CN115427407A (en)Novel N-heterocyclic BET bromodomain inhibitor, preparation method and medical application thereof
CN102827160B (en)PI3K or PI3K/m-TOR pathway inhibitor and the purposes in pharmacy thereof
CN111662275B (en) Benzenesulfonamide IDH mutant inhibitor, its preparation method and use
CN109879887B (en) Thieno[3,2-d]pyrimidine derivatives containing indole structure and their applications
CN109081818B (en)Novel indoleamine 2, 3-bis-oxidase inhibitors
WO2019029554A1 (en)Sulfonamide derivative, preparation method thereof, and use of same in medicine

Legal Events

DateCodeTitleDescription
121Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number:20799120

Country of ref document:EP

Kind code of ref document:A1

NENPNon-entry into the national phase

Ref country code:DE

122Ep: pct application non-entry in european phase

Ref document number:20799120

Country of ref document:EP

Kind code of ref document:A1
[8]ページ先頭
©2009-2025 Movatter.jp