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CN114920744A - Non-covalent BTK kinase inhibitor and biological application thereof - Google Patents

Non-covalent BTK kinase inhibitor and biological application thereof Download PDF

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CN114920744A
CN114920744A CN202111391888.2A CN202111391888A CN114920744A CN 114920744 A CN114920744 A CN 114920744A CN 202111391888 A CN202111391888 A CN 202111391888A CN 114920744 A CN114920744 A CN 114920744A
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韩进松
施芳芳
黄慧
刘宇航
缪顺童
倪伟伟
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Abstract

本发明属于医药化学领域，具体涉及式I所示的一类具有抑制BTK活性的化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，含有这些化合物的药物组合物，以及这些化合物或组合物在药物制备中的应用。本发明的化合物对BTK具有明显的抑制作用，为以BTK为治疗靶点的疾病如恶性肿瘤疾病或自身免疫性疾病等的治疗提供新的方案，可用于制备治疗相关疾病的药物。

Figure RE-DDA0003454953890000011
The invention belongs to the field of medicinal chemistry, and specifically relates to a class of compounds with inhibitory BTK activity shown in formula I or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, Metabolites, pharmaceutically acceptable salts or prodrugs, pharmaceutical compositions containing these compounds, and the use of these compounds or compositions in the manufacture of medicaments. The compound of the present invention has obvious inhibitory effect on BTK, provides a new solution for the treatment of diseases with BTK as the therapeutic target, such as malignant tumor diseases or autoimmune diseases, and can be used to prepare medicines for the treatment of related diseases.
Figure RE-DDA0003454953890000011

Description

一种非共价BTK激酶抑制剂及其生物用途A kind of non-covalent BTK kinase inhibitor and biological use thereof

技术领域technical field

本发明涉及医药技术领域，特别是涉及一种作为BTK激酶抑制剂的化合物及其用途。The present invention relates to the technical field of medicine, in particular to a compound as a BTK kinase inhibitor and use thereof.

背景技术Background technique

BTK(Bruton's tyrosine kinase，布鲁顿酪氨酸激酶)存在于细胞质中，作为Tec激酶家族的一员，是一种非受体酪氨酸激酶(NRTK)。人类BTK激酶发生功能性缺失突变可导致遗传性疾病——X连锁的无球蛋白血症(XLA)，造成体内成熟外周B细胞缺失和血清免疫球蛋白水平降低，在儿童身上表现为早期反复发作的细菌感染和败血症，这一现象最早由Ogdon Bruton医生发现。BTK在B细胞受体(B cell receptor，BCR)信号通路中发挥重要的信号转导作用，在B细胞激活、增殖、分化和存活过程中有着重要的作用，与多种B细胞肿瘤及自身免疫性疾病密切相关。BTK (Bruton's tyrosine kinase, Bruton's tyrosine kinase) exists in the cytoplasm. As a member of the Tec kinase family, it is a non-receptor tyrosine kinase (NRTK). Loss-of-function mutations in human BTK kinase lead to an inherited disorder called X-linked aglobulinemia (XLA), resulting in loss of mature peripheral B cells in vivo and reduced serum immunoglobulin levels, manifesting as early recurrent episodes in children bacterial infection and sepsis, a phenomenon first discovered by Dr. Ogdon Bruton. BTK plays an important signal transduction role in the B cell receptor (BCR) signaling pathway and plays an important role in the activation, proliferation, differentiation and survival of B cells. sexually transmitted diseases are closely related.

BTK激酶由五个区域组成：pleckstrin同源(PH)结构域、Tec同源(TH)结构域、Src同源3(SH3)结构域、Src同源2(SH2)结构域和具有酪氨酸激酶活性的C末端区或Src同源1结构域(TK/SH1)。其中PH结构域包括转录因子BAP-135/TFII-I的结合位点，同时可介导第二信使与PIP3的相互作用；TK/SH1结构域除了具有实现BTK初始激活的活化环外，还包含有ATP结合位点和变构抑制片段；SH2、SH3结构域则包含BTK激酶的自磷酸化位点，在完成BTK的完全激活方面发挥了重要作用。The BTK kinase consists of five domains: the pleckstrin homology (PH) domain, the Tec homology (TH) domain, the Src homology 3 (SH3) domain, the Src homology 2 (SH2) domain and the Kinase-active C-terminal region or Src homology 1 domain (TK/SH1). The PH domain includes the binding site of the transcription factor BAP-135/TFII-I, and can mediate the interaction between the second messenger and PIP3; the TK/SH1 domain, in addition to the activation loop that realizes the initial activation of BTK, also contains There are ATP binding sites and allosteric inhibitory fragments; SH2 and SH3 domains contain the autophosphorylation site of BTK kinase, which plays an important role in the complete activation of BTK.

BTK激酶作为调控BCR通路信号转导和下游蛋白表达的重要因子，当其水平异常时，往往会导致包括非霍奇金淋巴瘤(NHL)、B细胞慢性淋巴性白血病(CLL)和多发性骨髓瘤(MM)等在内的各种B细胞衍生的恶性肿瘤和类风湿性关节炎、红斑性狼疮等自身免疫性疾病的发生。BTK kinase is an important factor regulating the signal transduction and downstream protein expression of the BCR pathway. When its level is abnormal, it often leads to non-Hodgkin's lymphoma (NHL), B-cell chronic lymphocytic leukemia (CLL) and multiple myeloid The occurrence of various B cell-derived malignant tumors including MM and other autoimmune diseases such as rheumatoid arthritis and lupus erythematosus.

现今已经批准上市的BTK抑制剂分子，如Ibrutinib、Acalabrutinib、Orelabrutinib等均为通过选择性地与关键半胱氨酸残基Cys481形成共价键发挥抑制作用的共价抑制剂分子，然而这类抑制剂无法规避BTK突变引起的活性下降，即Ibrutinib耐药性，这一临床需求使得靶向抑制BTK-C481S突变型的可逆抑制剂有望克服Ibrutinib耐药性，为该类患者提供新的治疗方案。The currently approved BTK inhibitor molecules, such as Ibrutinib, Acalabrutinib, Orelabrutinib, etc. are all covalent inhibitor molecules that selectively form covalent bonds with the key cysteine residue Cys481 to exert inhibition. However, such inhibition This clinical need makes reversible inhibitors that target the BTK-C481S mutant to overcome Ibrutinib resistance and provide new treatment options for these patients.

发明内容SUMMARY OF THE INVENTION

本发明主要解决的技术问题是提供一种化合物，能够有效抑制突变型BTK激酶。The main technical problem to be solved by the present invention is to provide a compound that can effectively inhibit mutant BTK kinase.

为解决上述技术问题，本发明采用的以下技术方案：In order to solve the above-mentioned technical problems, the following technical solutions adopted in the present invention:

本发明的第一方面中，提供了式(Ⅰ)所示的化合物，In the first aspect of the present invention, there is provided a compound represented by formula (I),

Figure BDA0003367826790000021
Figure BDA0003367826790000021

或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，其中：or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:

X1为O或S；X 1 is O or S;

X2为O，S或NH；X 2 is O, S or NH;

Ra、Rb独立地选自：氢、卤素、腈基、硝基、羟基、羧基、取代或未取代的C1-6酰基、取代或未取代的氨基、取代或未取代的C1-6烷基、取代或未取代的C1-6烷氧基，可以为单、双或多取代；所述C1-6酰基、氨基、C1-6烷基、C1-6烷氧基的取代是指被下列一个或多个取代基所取代：C1-5烷基、C2-5烯基、C2-5炔基、C1-5烷氧基、卤素、硝基、氰基、羟基、氨基、羧基和氧代；R a , R b are independently selected from: hydrogen, halogen, nitrile, nitro, hydroxyl, carboxyl, substituted or unsubstituted C 1-6 acyl, substituted or unsubstituted amino, substituted or unsubstituted C 1- 6 alkyl, substituted or unsubstituted C 1-6 alkoxy, which can be mono-, di- or polysubstituted; the C 1-6 acyl, amino, C 1-6 alkyl, C 1-6 alkoxy Substituted means substituted by one or more of the following substituents: C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 1-5 alkoxy, halogen, nitro, cyano group, hydroxyl, amino, carboxyl and oxo;

X3为CH或N；X 3 is CH or N;

X4为O，S，CHRd或NRe；X 4 is O, S, CHR d or NR e ;

X5为O，NH，S，CH2，CHRd或NRe；X 5 is O, NH, S, CH 2 , CHR d or NR e ;

Rc可以相同或不同，各自独立地为-(CH2)fNR1R2，R1-S(＝O)g-，R1-S(＝O)gO-，R1-OS(＝O)g-，R1-C(＝O)-，R1-C(＝O)O(CH2)f-，R1-(CH2)fOC(＝O)-，R1-(CH2)fN(R1)C(＝O)-，R1-(CH2)fC(＝O)N(R1)-，R1-(CH2)fOC(＝O)N(R1)-，醚烷基，羟基取代的烷基，氢，氧代(＝O)，氟，氯，溴，碘，羟基，烷基，卤代烷基，杂烷基，烷氧基，烷氨基，烯基，炔基，环烷基，杂环基，卤代杂环基，氨基，硝基，羧基,氰基，芳基，卤代芳基，杂芳基，卤代杂芳基，芳基烷基，杂芳基烷基，氨基磺酰基，氨基甲酰基，芳基氨基，杂芳基氨基，芳基烷氨基，杂芳基烷氨基，杂环基氨基，杂环基烷氨基，芳基氧基，杂芳基氧基，杂芳基氧基，芳基烷氧基，杂芳基烷氧基，杂环基氧基或杂环基烷氧基；R c may be the same or different, and are each independently -(CH2) f NR 1 R 2 , R 1 -S(=O) g -, R 1 -S(=O) g O-, R 1 -OS(= O) g -, R 1 -C(=O)-, R 1 -C(=O)O(CH 2 ) f -, R 1 -(CH 2 ) f OC(=O)-, R 1 -( CH 2 ) f N(R 1 )C(=O)-, R 1 -(CH 2 ) f C(=O)N(R 1 )-, R 1 -(CH 2 ) f OC(=O)N (R 1 )-, ether alkyl, hydroxy substituted alkyl, hydrogen, oxo(=O), fluoro, chloro, bromo, iodo, hydroxy, alkyl, haloalkyl, heteroalkyl, alkoxy, alkane amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, haloheterocyclyl, amino, nitro, carboxyl, cyano, aryl, haloaryl, heteroaryl, haloheteroaryl, Arylalkyl, heteroarylalkyl, aminosulfonyl, carbamoyl, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heterocyclylamino, heterocyclylalkylamino, Aryloxy, heteroaryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy, heterocyclyloxy or heterocyclylalkoxy;

Rd为-(CH2)fNR1R2，R1-S(＝O)g-，R1-S(＝O)gO-，R1-OS(＝O)g-，R1-C(＝O)-，R1-C(＝O)O(CH2)f-，R1-(CH2)fOC(＝O)-，R1-(CH2)fN(H)C(＝O)-，R1-(CH2)f C(＝O)N(R1)-，R1-(CH2)fOC(＝O)N(R1)-，醚烷基，羟基取代的烷基，氢，氧代(＝O)，氟，氯，溴，碘，羟基，烷基，卤代烷基，杂烷基，烷氧基，烷氨基，烯基，炔基，环烷基，杂环基，卤代杂环基，氨基，硝基，羧基，氰基，芳基，卤代芳基，杂芳基，卤代杂芳基，芳基烷基，杂芳基烷基，氨基磺酰基，氨基甲酰基，芳基氨基，杂芳基氨基，芳基烷氨基，杂芳基烷氨基，杂环基氨基，杂环基烷氨基，芳基氧基，杂芳基氧基，杂芳基氧基，芳基烷氧基，杂芳基烷氧基，杂环基氧基或杂环基烷氧基；R d is -(CH2) f NR 1 R 2 , R 1 -S(=O) g -, R 1 -S(=O) g O-, R 1 -OS(=O) g -, R 1 - C(=O)-, R 1 -C(=O)O(CH 2 ) f -, R 1 -(CH 2 ) f OC(=O)-, R 1 -(CH 2 ) f N(H) C(=O)-, R 1 -(CH 2 ) f C(=O)N(R 1 )-, R 1 -(CH 2 ) f OC(=O)N(R 1 )-, ether alkyl , hydroxy-substituted alkyl, hydrogen, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxy, alkyl, haloalkyl, heteroalkyl, alkoxy, alkylamino, alkenyl, alkynyl, ring Alkyl, Heterocyclyl, Haloheterocyclyl, Amino, Nitro, Carboxyl, Cyano, Aryl, Haloaryl, Heteroaryl, Haloheteroaryl, Arylalkyl, Heteroarylalkane group, aminosulfonyl, carbamoyl, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heterocyclylamino, heterocyclylalkylamino, aryloxy, heteroaryloxy group, heteroaryloxy, arylalkoxy, heteroarylalkoxy, heterocyclyloxy or heterocyclylalkoxy;

Re为-(CH2)fNR1R2，R1-S(＝O)g-，R1-S(＝O)gO-，R1-OS(＝O)g-，R1-C(＝O)-，R1-C(＝O)O(CH2)f-，R1-(CH2)fOC(＝O)-，R1-(CH2)f N(H)C(＝O)-，R1-(CH2)fC(＝O)N(R1)-，R1-(CH2)fOC(＝O)N(R1)-，醚烷基，羟基取代的烷基，氢，氧代(＝O)，氟，氯，溴，碘，羟基，烷基，卤代烷基，杂烷基，烷氧基，烷氨基，烯基，炔基，环烷基，杂环基，卤代杂环基，氨基，硝基，羧基，氰基，芳基，卤代芳基，杂芳基，卤代杂芳基，芳基烷基，杂芳基烷基，氨基磺酰基，氨基甲酰基，芳基氨基，杂芳基氨基，芳基烷氨基，杂芳基烷氨基，杂环基氨基，杂环基烷氨基，芳基氧基，杂芳基氧基，杂芳基氧基，芳基烷氧基，杂芳基烷氧基，杂环基氧基或杂环基烷氧基； Re is -(CH2) f NR 1 R 2 , R 1 -S(=O) g -, R 1 -S(=O) g O-, R 1 -OS(=O) g -, R 1 - C(=O)-, R 1 -C(=O)O(CH 2 ) f -, R 1 -(CH 2 ) f OC(=O)-, R 1 -(CH 2 ) f N(H) C(=O)-, R 1 -(CH 2 ) f C(=O)N(R 1 )-, R 1 -(CH 2 ) f OC(=O)N(R 1 )-, ether alkyl , hydroxy-substituted alkyl, hydrogen, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxy, alkyl, haloalkyl, heteroalkyl, alkoxy, alkylamino, alkenyl, alkynyl, ring Alkyl, Heterocyclyl, Haloheterocyclyl, Amino, Nitro, Carboxyl, Cyano, Aryl, Haloaryl, Heteroaryl, Haloheteroaryl, Arylalkyl, Heteroarylalkane group, aminosulfonyl, carbamoyl, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heterocyclylamino, heterocyclylalkylamino, aryloxy, heteroaryloxy group, heteroaryloxy, arylalkoxy, heteroarylalkoxy, heterocyclyloxy or heterocyclylalkoxy;

各R1和R2独立地为氢，烷基，环烷基，芳基烷基，杂芳基烷基，卤代烷基，杂环基，芳基或杂芳基；Each R1 and R2 is independently hydrogen , alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, haloalkyl, heterocyclyl, aryl or heteroaryl;

各g独立地为0，1或2；each g is independently 0, 1 or 2;

各n，m，f独立地为0，1，2，3，4或5；each of n, m, f is independently 0, 1, 2, 3, 4 or 5;

当n＝2时，且两个Rc连在同一碳原子上，那么两个Rc与之相连的碳原子一起可形成3-8元杂环。When n=2, and the two R c are attached to the same carbon atom, then the two R c and the carbon atom to which they are attached together can form a 3-8 membered heterocycle.

在某些优选的实施方案中，公开了式(Ⅰ)所示的化合物，或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，其中：In certain preferred embodiments, compounds of formula (I), or stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites thereof, are disclosed , a pharmaceutically acceptable salt or prodrug wherein:

X1为O或S；X 1 is O or S;

X2为O，S或NH；X 2 is O, S or NH;

Ra、Rb独立地选自：氢、卤素、腈基、硝基、羟基、羧基，可以为单、双或多取代；优选的，Ra、Rb独立地选自：氢、卤素R a and R b are independently selected from: hydrogen, halogen, nitrile, nitro, hydroxyl, carboxyl, which can be mono-, di- or polysubstituted; preferably, R a and R b are independently selected from: hydrogen, halogen

其中，

Figure BDA0003367826790000041
结构单元选自以下子结构：in,
Figure BDA0003367826790000041
Structural units are selected from the following substructures:

Figure BDA0003367826790000042
Figure BDA0003367826790000042

其中，in,

X5为O，NH，S，CH2，CHRd或NRe；X 5 is O, NH, S, CH 2 , CHR d or NR e ;

R3可以相同或不同，各自独立地为-(CH2)fNR1R2，R1-S(＝O)g-，R1-S(＝O)gO-，R1-OS(＝O)g-，R1-C(＝O)-，R1-C(＝O)O(CH2)f-，R1-(CH2)fOC(＝O)-，R1-(CH2)fN(H)C(＝O)-，R1-(CH2)fC(＝O)N(R1)-，R1-(CH2)fOC(＝O)N(R1)-，C2-10醚烷基，羟基取代的C1-10烷基，氟，氯，溴，碘，C1-6烷基，C1-6卤代烷基，C1-6烷氨基，C1-6杂烷基，C1-6烷氧基，C1-6烷氨基，C2-6烯基，C2-6炔基，C3-8环烷基，C2-10杂环基，C2-10卤代杂环基，氨基，硝基，羧基，氰基，C6-10芳基，C6-10卤代芳基，C1-9杂芳基，C1-9卤代杂芳基，C6-10芳基C1-6烷基，C1-9杂芳基C1-6烷基，氨基磺酰基，氨基甲酰基，C6-10芳基氨基，C1-9杂芳基氨基，C6-10芳基C1-6烷氨基，C1-9杂芳基氨基，C6-10芳基C1-6烷氨基，C1-9杂芳基C1-6烷氨基，C2-10杂环基氨基，C2-10杂环基C1-6烷氨基，C6-10芳基氧基，C1-9杂芳基氧基，C6-10芳基C1-6烷氧基，C1-9杂芳基C1-6烷氧基，C2-10杂环基氧基或C2-10杂环基C1-6烷氧基；R 3 may be the same or different, and each independently is -(CH2) f NR 1 R 2 , R 1 -S(=O) g -, R 1 -S(=O) g O-, R 1 -OS(= O) g -, R 1 -C(=O)-, R 1 -C(=O)O(CH 2 ) f -, R 1 -(CH 2 ) f OC(=O)-, R 1 -( CH 2 ) f N(H)C(=O)-, R 1 -(CH 2 ) f C(=O)N(R 1 )-, R 1 -(CH 2 ) f OC(=O)N( R 1 )-, C 2-10 ether alkyl, hydroxy substituted C 1-10 alkyl, fluorine, chlorine, bromine, iodine, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkane Amino, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 2- 10 heterocyclyl, C 2-10 haloheterocyclyl, amino, nitro, carboxyl, cyano, C 6-10 aryl, C 6-10 haloaryl, C 1-9 heteroaryl, C 1-9 haloheteroaryl, C 6-10 aryl C 1-6 alkyl, C 1-9 heteroaryl C 1-6 alkyl, aminosulfonyl, carbamoyl, C 6-10 aryl Amino, C 1-9 Heteroarylamino, C 6-10 Aryl, C 1-6 Alkylamino, C 1-9 Heteroarylamino, C 6-10 Aryl, C 1-6 Alkylamino, C 1-9 Heteroaryl C 1-6 alkylamino, C 2-10 heterocyclylamino, C 2-10 heterocyclyl C 1-6 alkylamino, C 6-10 aryloxy, C 1-9 heteroaryloxy base, C 6-10 aryl C 1-6 alkoxy, C 1-9 heteroaryl C 1-6 alkoxy, C 2-10 heterocyclyloxy or C 2-10 heterocyclyl C 1 -6 alkoxy;

R4可以相同或不同，各自独立地为-(CH2)fNR1R2，R1-S(＝O)g-，R1-S(＝O)gO-，R1-OS(＝O)g-，R1-C(＝O)-，R1-C(＝O)O(CH2)f-，R1-(CH2)fOC(＝O)-，R1-(CH2)fN(H)C(＝O)-，R1-(CH2)fC(＝O)N(R1)-，R1-(CH2)fOC(＝O)N(R1)-，C2-10醚烷基，羟基取代的C1-10烷基，氟，氯，溴，碘，C1-6烷基，C1-6卤代烷基，C1-6烷氨基，C1-6杂烷基，C1-6烷氧基，C1-6烷氨基，C2-6烯基，C2-6炔基，C3-8环烷基，C2-10杂环基，C2-10卤代杂环基，氨基，硝基，羧基，氰基，C6-10芳基，C6-10卤代芳基，C1-9杂芳基，C1-9卤代杂芳基，C6-10芳基C1-6烷基，C1-9杂芳基C1-6烷基，氨基磺酰基，氨基甲酰基，C6-10芳基氨基，C1-9杂芳基氨基，C6-10芳基C1-6烷氨基，C1-9杂芳基氨基，C6-10芳基C1-6烷氨基，C1-9杂芳基C1-6烷氨基，C2-10杂环基氨基，C2-10杂环基C1-6烷氨基，C6-10芳基氧基，C1-9杂芳基氧基，C6-10芳基C1-6烷氧基，C1-9杂芳基C1-6烷氧基，C2-10杂环基氧基或C2-10杂环基C1-6烷氧基；R 4 may be the same or different, and each independently is -(CH2) f NR 1 R 2 , R 1 -S(=O) g -, R 1 -S(=O) g O-, R 1 -OS(= O) g -, R 1 -C(=O)-, R 1 -C(=O)O(CH 2 ) f -, R 1 -(CH 2 ) f OC(=O)-, R 1 -( CH 2 ) f N(H)C(=O)-, R 1 -(CH 2 ) f C(=O)N(R 1 )-, R 1 -(CH 2 ) f OC(=O)N( R 1 )-, C 2-10 ether alkyl, hydroxy substituted C 1-10 alkyl, fluorine, chlorine, bromine, iodine, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkane Amino, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 2- 10 heterocyclyl, C 2-10 haloheterocyclyl, amino, nitro, carboxyl, cyano, C 6-10 aryl, C 6-10 haloaryl, C 1-9 heteroaryl, C 1-9 haloheteroaryl, C 6-10 aryl C 1-6 alkyl, C 1-9 heteroaryl C 1-6 alkyl, aminosulfonyl, carbamoyl, C 6-10 aryl Amino, C 1-9 Heteroarylamino, C 6-10 Aryl, C 1-6 Alkylamino, C 1-9 Heteroarylamino, C 6-10 Aryl, C 1-6 Alkylamino, C 1-9 Heteroaryl C 1-6 alkylamino, C 2-10 heterocyclylamino, C 2-10 heterocyclyl C 1-6 alkylamino, C 6-10 aryloxy, C 1-9 heteroaryloxy base, C 6-10 aryl C 1-6 alkoxy, C 1-9 heteroaryl C 1-6 alkoxy, C 2-10 heterocyclyloxy or C 2-10 heterocyclyl C 1 -6 alkoxy;

Rd为-(CH2)fNR1R2，R1-S(＝O)g-，R1-S(＝O)gO-，R1-OS(＝O)g-，R1-C(＝O)-，R1-C(＝O)O(CH2)f-，R1-(CH2)fOC(＝O)-，R1-(CH2)fN(H)C(＝O)-，R1-(CH2)fC(＝O)N(R1)-，R1-(CH2)fOC(＝O)N(R1)-，C2-10醚烷基，羟基取代的C1-10烷基，氟，氯，溴，碘，C1-6烷基，C1-6卤代烷基，C1-6烷氨基，C1-6杂烷基，C1-6烷氧基，C1-6烷氨基，C2-6烯基，C2-6炔基，C3-8环烷基，C2-10杂环基，C2-10卤代杂环基，氨基，硝基，羧基，氰基，C6-10芳基，C6-10卤代芳基，C1-9杂芳基，C1-9卤代杂芳基，C6-10芳基C1-6烷基，C1-9杂芳基C1-6烷基，氨基磺酰基，氨基甲酰基，C6-10芳基氨基，C1-9杂芳基氨基，C6-10芳基C1-6烷氨基，C1-9杂芳基氨基，C6-10芳基C1-6烷氨基，C1-9杂芳基C1-6烷氨基，C2-10杂环基氨基，C2-10杂环基C1-6烷氨基，C6-10芳基氧基，C1-9杂芳基氧基，C6-10芳基C1-6烷氧基，C1-9杂芳基C1-6烷氧基，C2-10杂环基氧基或C2-10杂环基C1-6烷氧基；R d is -(CH2) f NR 1 R 2 , R 1 -S(=O) g -, R 1 -S(=O) g O-, R 1 -OS(=O) g -, R 1 - C(=O)-, R 1 -C(=O)O(CH 2 ) f -, R 1 -(CH 2 ) f OC(=O)-, R 1 -(CH 2 ) f N(H) C(=O)-, R 1 -(CH 2 ) f C(=O)N(R 1 )-, R 1 -(CH 2 ) f OC(=O)N(R 1 )-, C 2- 10 ether alkyl, hydroxy substituted C 1-10 alkyl, fluorine, chlorine, bromine, iodine, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylamino, C 1-6 heteroalkane base, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 2-10 heterocyclyl, C 2- 10 halogenated heterocyclyl, amino, nitro, carboxyl, cyano, C6-10 aryl, C6-10 halogenated aryl, C1-9 heteroaryl, C1-9 halogenated heteroaryl , C 6-10 aryl C 1-6 alkyl, C 1-9 heteroaryl C 1-6 alkyl, aminosulfonyl, carbamoyl, C 6-10 arylamino, C 1-9 heteroaryl base amino, C 6-10 aryl C 1-6 alkylamino, C 1-9 heteroarylamino, C 6-10 aryl C 1-6 alkylamino, C 1-9 heteroaryl C 1-6 alkyl Amino, C 2-10 heterocyclylamino, C 2-10 heterocyclyl, C 1-6 alkylamino, C 6-10 aryloxy, C 1-9 heteroaryloxy, C 6-10 aryl C 1-6 alkoxy, C 1-9 heteroaryl C 1-6 alkoxy, C 2-10 heterocyclyloxy or C 2-10 heterocyclyl C 1-6 alkoxy;

Re为-(CH2)fNR1R2，R1-S(＝O)g-，R1-S(＝O)gO-，R1-OS(＝O)g-，R1-C(＝O)-，R1-C(＝O)O(CH2)f-，R1-(CH2)fOC(＝O)-，R1-(CH2)fN(H)C(＝O)-，R1-(CH2)fC(＝O)N(R1)-，R1-(CH2)fOC(＝O)N(R1)-，C2-10醚烷基，羟基取代的C1-10烷基，氟，氯，溴，碘，C1-6烷基，C1-6卤代烷基，C1-6杂烷基，C1-6烷氧基，C1-6烷氨基，C2-6烯基，C2-6炔基，C3-8环烷基，C2-10杂环基C2-10卤代杂环基，氨基，硝基，羧基，氰基，C6-10芳基，C6-10卤代芳基，C1-9杂芳基，C1-9卤代杂芳基，C6-10芳基C1-6烷基，C1-9杂芳基C1-6烷基，氨基磺酰基，氨基甲酰基，C6-10芳基氨基，C1-9杂芳基氨基，C6-10芳基C1-6烷氨基，C1-9杂芳基氨基，C6-10芳基C1-6烷氨基，C1-9杂芳基C1-6烷氨基，C2-10杂环基氨基，C2-10杂环基C1-6烷氨基，C6-10芳基氧基，C1-9杂芳基氧基，C6-10芳基C1-6烷氧基，C1-9杂芳基C1-6烷氧基，C2-10杂环基氧基或C2-10杂环基C1-6烷氧基； Re is -(CH2) f NR 1 R 2 , R 1 -S(=O) g -, R 1 -S(=O) g O-, R 1 -OS(=O) g -, R 1 - C(=O)-, R 1 -C(=O)O(CH 2 ) f -, R 1 -(CH 2 ) f OC(=O)-, R 1 -(CH 2 ) f N(H) C(=O)-, R 1 -(CH 2 ) f C(=O)N(R 1 )-, R 1 -(CH 2 ) f OC(=O)N(R 1 )-, C 2- 10 ether alkyl, hydroxy substituted C 1-10 alkyl, fluorine, chlorine, bromine, iodine, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 1-6 alkane Oxy group, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 2-10 heterocyclyl, C 2-10 haloheterocyclyl, amino , nitro, carboxyl, cyano, C 6-10 aryl, C 6-10 haloaryl, C 1-9 heteroaryl, C 1-9 haloheteroaryl, C 6-10 aryl C 1-6 alkyl, C 1-9 heteroaryl C 1-6 alkyl, aminosulfonyl, carbamoyl, C 6-10 arylamino, C 1-9 heteroarylamino, C 6-10 aryl base C 1-6 alkylamino, C 1-9 heteroarylamino, C 6-10 aryl C 1-6 alkylamino, C 1-9 heteroaryl C 1-6 alkylamino, C 2-10 heterocycle base amino, C 2-10 heterocyclyl C 1-6 alkylamino, C 6-10 aryloxy, C 1-9 heteroaryloxy, C 6-10 aryl C 1-6 alkoxy, C 1-9 heteroaryl C 1-6 alkoxy, C 2-10 heterocyclyloxy or C 2-10 heterocyclyl C 1-6 alkoxy;

各R1和R2独立地为氢，C1-6烷基，C3-8环烷基，C6-10芳基C1-6烷基，C1-9杂芳基C1-6烷基，卤代C1-6烷基，C2-10杂环基，C6-10芳基或C1-9杂芳基；Each R 1 and R 2 is independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl C 1-6 alkyl, C 1-9 heteroaryl C 1-6 Alkyl, halogenated C 1-6 alkyl, C 2-10 heterocyclyl, C 6-10 aryl or C 1-9 heteroaryl;

各g独立地为0，1或2；each g is independently 0, 1 or 2;

各n，m，f独立地为0，1，2，3，4或5；each of n, m, f is independently 0, 1, 2, 3, 4 or 5;

当n＝2时，且两个Rc连在同一碳原子上，那么两个Rc与之相连的碳原子一起可形成3-8元杂环。When n=2, and the two R c are attached to the same carbon atom, then the two R c and the carbon atom to which they are attached together can form a 3-8 membered heterocycle.

在某些更优选的实施方案中，公开了式(Ⅰ)所示的化合物，或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，其中：In certain more preferred embodiments, compounds of formula (I), or stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites thereof, are disclosed A product, pharmaceutically acceptable salt or prodrug, wherein:

X1为O或S；X 1 is O or S;

X2为O，S或NH；X 2 is O, S or NH;

Ra、Rb独立地选自：氢、卤素，可以为单、双或多取代；R a and R b are independently selected from: hydrogen, halogen, which can be mono-, di- or polysubstituted;

其中，

Figure BDA0003367826790000061
结构单元选自以下子结构：in,
Figure BDA0003367826790000061
Structural units are selected from the following substructures:

Figure BDA0003367826790000062
Figure BDA0003367826790000062

其中，X5为O，NH，S，CH2，CHRd或NRe；Wherein, X 5 is O, NH, S, CH 2 , CHR d or NR e ;

R3可以相同或不同，各自独立地为-(CH2)fNR1R2，R1-C(＝O)-，R1-C(＝O)O(CH2)f-，R1-(CH2)fOC(＝O)-，R1-(CH2)fN(H)C(＝O)-，R1-(CH2)fC(＝O)N(R1)-，R1-(CH2)fOC(＝O)N(R1)-，羟基取代的C1-10烷基，氢，氧代(＝O)，氟，氯，溴，碘，羟基，甲基，乙基，丙基，丁基，异丙基，三氟甲基，三氟乙基，甲氧基，乙氧基，丙氧基，二甲基氨基，二乙基氨基，乙烯基，乙炔基，环丙基，环丁基，环戊基，氨基，硝基，羧基，氰基，苯基，氟代苯基，氯代苯基，溴代苯基，甲氧基苯基，甲基苯基，咪唑基，吡唑基，吡啶基，嘧啶基或苄基；R 3 may be the same or different, and each independently is -(CH2) f NR 1 R 2 , R 1 -C(=O)-, R 1 -C(=O)O(CH 2 ) f -, R 1 - (CH 2 ) f OC(=O)-, R 1 -(CH 2 ) f N(H)C(=O)-, R 1 -(CH 2 ) f C(=O)N(R 1 )- , R 1 -(CH 2 ) f OC(=O)N(R 1 )-, hydroxy substituted C 1-10 alkyl, hydrogen, oxo(=O), fluorine, chlorine, bromine, iodine, hydroxyl, Methyl, Ethyl, Propyl, Butyl, Isopropyl, Trifluoromethyl, Trifluoroethyl, Methoxy, Ethoxy, Propoxy, Dimethylamino, Diethylamino, Vinyl , ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, amino, nitro, carboxyl, cyano, phenyl, fluorophenyl, chlorophenyl, bromophenyl, methoxyphenyl, methylphenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl or benzyl;

R4可以相同或不同，各自独立地为-(CH2)fNR1R2，R1-C(＝O)-，R1-C(＝O)O(CH2)f-，R1-(CH2)fOC(＝O)-，R1-(CH2)fN(H)C(＝O)-，R1-(CH2)fC(＝O)N(R1)-，R1-(CH2)fOC(＝O)N(R1)-，羟基取代的C1-10烷基，氢，氧代(＝O)，氟，氯，溴，碘，羟基，甲基，乙基，丙基，丁基，异丙基，三氟甲基，三氟乙基，甲氧基，乙氧基，丙氧基，二甲基氨基，二乙基氨基，乙烯基，乙炔基，环丙基，环丁基，环戊基，氨基，硝基，羧基，氰基，苯基，氟代苯基，氯代苯基，溴代苯基，甲氧基苯基，甲基苯基，咪唑基，吡唑基，吡啶基，嘧啶基或苄基；R 4 may be the same or different, and each independently is -(CH2) f NR 1 R 2 , R 1 -C(=O)-, R 1 -C(=O)O(CH 2 ) f -, R 1 - (CH 2 ) f OC(=O)-, R 1 -(CH 2 ) f N(H)C(=O)-, R 1 -(CH 2 ) f C(=O)N(R 1 )- , R 1 -(CH 2 ) f OC(=O)N(R 1 )-, hydroxy substituted C 1-10 alkyl, hydrogen, oxo(=O), fluorine, chlorine, bromine, iodine, hydroxyl, Methyl, Ethyl, Propyl, Butyl, Isopropyl, Trifluoromethyl, Trifluoroethyl, Methoxy, Ethoxy, Propoxy, Dimethylamino, Diethylamino, Vinyl , ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, amino, nitro, carboxyl, cyano, phenyl, fluorophenyl, chlorophenyl, bromophenyl, methoxyphenyl, methylphenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl or benzyl;

Rd为-(CH2)fNR1R2，R1-C(＝O)-，R1-C(＝O)O(CH2)f-，R1-(CH2)fOC(＝O)-，R1-(CH2)fN(H)C(＝O)-，R1-(CH2)fC(＝O)N(R1)-，R1-(CH2)fOC(＝O)N(R1)-，羟基取代的C1-10烷基，氢，氧代(＝O)，氟，氯，溴，碘，羟基，甲基，乙基，丙基，丁基，异丙基，三氟甲基，三氟乙基，甲氧基，乙氧基，丙氧基，二甲基氨基，二乙基氨基，乙烯基，乙炔基，环丙基，环丁基，环戊基，氨基，硝基，羧基，氰基，苯基，氟代苯基，氯代苯基，溴代苯基，甲氧基苯基，甲基苯基，咪唑基，吡唑基，吡啶基，嘧啶基或苄基；R d is -(CH2) f NR 1 R 2 , R 1 -C(=O)-, R 1 -C(=O)O(CH 2 ) f -, R 1 -(CH 2 ) f OC(= O)-, R 1 -(CH 2 ) f N(H)C(=O)-, R 1 -(CH 2 ) f C(=O)N(R 1 )-, R 1 -(CH 2 ) f OC(=O)N(R 1 )-, hydroxy substituted C 1-10 alkyl, hydrogen, oxo(=O), fluoro, chloro, bromo, iodo, hydroxy, methyl, ethyl, propyl , butyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, propoxy, dimethylamino, diethylamino, vinyl, ethynyl, cyclopropyl, Cyclobutyl, cyclopentyl, amino, nitro, carboxyl, cyano, phenyl, fluorophenyl, chlorophenyl, bromophenyl, methoxyphenyl, methylphenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl or benzyl;

Re为-(CH2)fNR1R2，R1-C(＝O)-，R1-C(＝O)O(CH2)f-，R1-(CH2)fOC(＝O)-，R1-(CH2)fN(H)C(＝O)-，R1-(CH2)fC(＝O)N(R1)-，R1-(CH2)fOC(＝O)N(R1)-，羟基取代的C1-10烷基，氢，氧代(＝O)，氟，氯，溴，碘，羟基，甲基，乙基，丙基，丁基，异丙基，三氟甲基，三氟乙基，甲氧基，乙氧基，丙氧基，二甲基氨基，二乙基氨基，乙烯基，乙炔基，环丙基，环丁基，环戊基，氨基，硝基，羧基，氰基，苯基，氟代苯基，氯代苯基，溴代苯基，甲氧基苯基，甲基苯基，咪唑基，吡唑基，吡啶基，嘧啶基或苄基； Re is -(CH2) f NR 1 R 2 , R 1 -C(=O)-, R 1 -C(=O)O(CH 2 ) f -, R 1 -(CH 2 ) f OC(= O)-, R 1 -(CH 2 ) f N(H)C(=O)-, R 1 -(CH 2 ) f C(=O)N(R 1 )-, R 1 -(CH 2 ) f OC(=O)N(R 1 )-, hydroxy substituted C 1-10 alkyl, hydrogen, oxo(=O), fluoro, chloro, bromo, iodo, hydroxy, methyl, ethyl, propyl , butyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, propoxy, dimethylamino, diethylamino, vinyl, ethynyl, cyclopropyl, Cyclobutyl, cyclopentyl, amino, nitro, carboxyl, cyano, phenyl, fluorophenyl, chlorophenyl, bromophenyl, methoxyphenyl, methylphenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl or benzyl;

各R1和R2独立地为氢，甲基，乙基，丙基，丁基，异丙基，环丙基，环丁基，环戊基，三氟甲基，苄基，吗啉基，哌嗪基，苯基，吡唑基，咪唑基，吡啶基，嘧啶基；Each R1 and R2 is independently hydrogen , methyl, ethyl, propyl, butyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, trifluoromethyl, benzyl, morpholinyl , piperazinyl, phenyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl;

各g独立地为0，1或2；each g is independently 0, 1 or 2;

各n，m，f独立地为0，1，2，3，4或5；each of n, m, f is independently 0, 1, 2, 3, 4 or 5;

当n＝2时，且两个Rc连在同一碳原子上，那么两个Rc与之相连的碳原子一起可形成3-8元杂环。When n=2, and the two R c are attached to the same carbon atom, then the two R c and the carbon atom to which they are attached together can form a 3-8 membered heterocycle.

在某些更优选的实施方案中，公开了式(Ⅰ)所示的化合物，或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，其中：In certain more preferred embodiments, compounds of formula (I), or stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites thereof, are disclosed A product, pharmaceutically acceptable salt or prodrug, wherein:

X1为O或S；X 1 is O or S;

X2为O，S或NH；X 2 is O, S or NH;

Ra、Rb独立地选自：氢、卤素；R a , R b are independently selected from: hydrogen, halogen;

Figure BDA0003367826790000071
Figure BDA0003367826790000071

结构单元选自以下子结构：Structural units are selected from the following substructures:

Figure BDA0003367826790000081
Figure BDA0003367826790000081

其中，R1a选自氢、羰基、酰胺基、酯基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C3-7杂环基、C6-10芳基或C5-10杂芳基；Wherein, R 1a is selected from hydrogen, carbonyl, amide, ester, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-7 heterocyclyl, C 6-10 Aryl or C 5-10 heteroaryl;

R1b选自氢、卤素、羟基、氨基酰基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C3-7杂环基、C6-10芳基或C5-10杂芳基；R 1b is selected from hydrogen, halogen, hydroxy, aminoacyl, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl , C 1-6 alkoxy, C 3-7 heterocyclyl, C 6-10 aryl or C 5-10 heteroaryl;

R1c选自氢、羟基、羰基、酯基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C3-7杂环基、C6-10芳基或C5-10杂芳基；R 1c is selected from hydrogen, hydroxyl, carbonyl, ester, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-7 heterocyclyl, C 6-10 aryl or C 5-10 heteroaryl;

R可以相同或不同，各自独立地选自氢、卤素、腈基、硝基、羟基、醛基、羧基、酰胺基、氨基酰基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C3-7杂环基、C6-10芳基或C5-10杂芳基；R may be the same or different, each independently selected from hydrogen, halogen, nitrile, nitro, hydroxyl, aldehyde, carboxyl, amide, aminoacyl, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-7 heterocyclyl, C 6-10 aryl or C 5-10 hetero Aryl;

或者相同原子或相邻原子上的两个R基团可以一起形成C3-7环烷基、C3-7杂环烷基、C6-10芳基或C5-10杂芳基；Or two R groups on the same atom or on adjacent atoms can be taken together to form a C 3-7 cycloalkyl, C 3-7 heterocycloalkyl, C 6-10 aryl or C 5-10 heteroaryl;

p为0，1，2，3，4或5；p is 0, 1, 2, 3, 4 or 5;

q为0，1或2；q is 0, 1 or 2;

所述的卤素为F，Cl，或Br；Described halogen is F, Cl, or Br;

所述的取代是指被下列一个或多个取代基所取代：C1-5烷基、C2-5烯基、C2-5炔基、C1-5烷氧基、卤素、硝基、氰基、羟基、氨基、羧基和氧代。The substitution refers to being substituted by one or more of the following substituents: C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 1-5 alkoxy, halogen, nitro , cyano, hydroxyl, amino, carboxyl and oxo.

在某些更优选的实施方案中，本发明的化合物是如下表1中的任一化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药。表1为本发明的部分化合物：In certain more preferred embodiments, the compound of the present invention is any of the compounds in Table 1 below, or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate thereof , metabolites, pharmaceutically acceptable salts or prodrugs. Table 1 is some compounds of the present invention:

Figure BDA0003367826790000082
Figure BDA0003367826790000082

Figure BDA0003367826790000091
Figure BDA0003367826790000091

Figure BDA0003367826790000101
Figure BDA0003367826790000101

Figure BDA0003367826790000111
Figure BDA0003367826790000111

Figure BDA0003367826790000121
Figure BDA0003367826790000121

Figure BDA0003367826790000131
Figure BDA0003367826790000131

在又一方面，本发明提供了药物组合物，包含本发明的化合物，或它们的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，或任选的药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物或它们的组合。其中一些实施例为，这些化合物是蛋白质激酶抑制剂，另外一些实施例为，这些化合物是BTK激酶抑制剂。In yet another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention, or their stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites , a pharmaceutically acceptable salt or prodrug, or an optional pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof. In some embodiments, the compounds are protein kinase inhibitors, and in other embodiments, the compounds are BTK kinase inhibitors.

在又一方面，本发明提供了如式(C)所示的化合物的制备方法，包括如下步骤：In another aspect, the present invention provides the preparation method of the compound shown as formula (C), comprises the steps:

Figure BDA0003367826790000132
Figure BDA0003367826790000132

其中，X3，X4，X5，Rc，m和n如权利要求1所述；wherein, X 3 , X 4 , X 5 , R c , m and n are as described in claim 1;

所述制备方法具体包括以下步骤：The preparation method specifically comprises the following steps:

首先，以化合物A为原料，通过与正丁基锂发生卤素-金属交换反应形成有机锂化合物，再与4-苯氧基苯甲酸酯发生亲核加成反应，得到化合物B；然后以弱碱作为缚酸剂，化合物B与取代的杂环发生亲核取代反应，得到目标化合物C。First, compound A is used as a raw material to form an organolithium compound through a halogen-metal exchange reaction with n-butyllithium, and then a nucleophilic addition reaction with 4-phenoxybenzoate to obtain compound B; then a weak The base acts as an acid binding agent, and the compound B undergoes a nucleophilic substitution reaction with the substituted heterocycle to obtain the target compound C.

本发明另一方面提供了本发明的化合物或包含本发明的化合物的药物组合物在制备用于治疗自身免疫性疾病、炎性疾病、血栓栓塞疾病、过敏症、感染性疾病、增生性疾病和癌症中的任意一种或多种疾病的药物中的用途。Another aspect of the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention in the manufacture of a compound for the treatment of autoimmune diseases, inflammatory diseases, thromboembolic diseases, allergies, infectious diseases, proliferative diseases and Use in the medicament of any one or more diseases in cancer.

在具体实施方案中，所述疾病选自：关节炎、类风湿性关节炎、荨麻疹、白癜风、器官移植排斥、溃疡性结肠炎、克罗恩病、皮炎、哮喘、干燥综合征、系统性红斑狼疮、多发性硬化、特发性血小板减少性紫癜、皮疹、抗嗜中性白细胞胞质抗体血管炎、天胞疮、寻常性天胞疮、慢性阻塞性肺疾病、银屑病；乳腺癌、套细胞淋巴瘤、卵巢癌、食道癌、喉癌、成胶质细胞瘤、成神经细胞瘤、胃癌、肝细胞癌、胶质瘤、子宫内膜癌、黑色素瘤、肾癌、膀胱癌、胆道癌、胰腺癌、淋巴瘤、毛细胞癌、鼻咽癌、大肠癌、直肠癌、脑和中枢神经系统癌症、宫颈癌、前列腺癌、睾丸癌、泌尿生殖道癌、肺癌、肺小细胞癌、小细胞癌、肺腺癌、骨癌、结肠癌、腺瘤、胰腺癌、甲状腺癌、滤泡性癌、霍奇金白血病、支气管癌、子宫体癌、子宫颈癌、多发性骨髓瘤、急性髓细胞源性白血病、慢性髓细胞源性白血病、淋巴细胞白血病、慢性淋巴样白血病、骨髓性白血病、非霍奇金淋巴瘤、原发性巨球蛋白血症。In specific embodiments, the disease is selected from the group consisting of: arthritis, rheumatoid arthritis, urticaria, vitiligo, organ transplant rejection, ulcerative colitis, Crohn's disease, dermatitis, asthma, Sjögren's syndrome, systemic lupus erythematosus, multiple sclerosis, idiopathic thrombocytopenic purpura, rash, anti-neutrophil cytoplasmic antibody vasculitis, pemphigus, pemphigus vulgaris, chronic obstructive pulmonary disease, psoriasis; breast cancer , mantle cell lymphoma, ovarian cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, hepatocellular carcinoma, glioma, endometrial cancer, melanoma, kidney cancer, bladder cancer, Biliary tract cancer, pancreatic cancer, lymphoma, hair cell cancer, nasopharyngeal cancer, colorectal cancer, rectal cancer, brain and central nervous system cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, lung cancer, small cell lung cancer , small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, thyroid cancer, follicular cancer, Hodgkin's leukemia, bronchial cancer, endometrial cancer, cervical cancer, multiple myeloma, Acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, chronic lymphoid leukemia, myeloid leukemia, non-Hodgkin lymphoma, primary macroglobulinemia.

本发明另一方面提供了本发明的化合物或包含本发明的化合物的药物组合物在制备用于治疗致使BTK激酶过度表达的疾病中的药物中的用途。Another aspect of the present invention provides the use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention in the manufacture of a medicament for the treatment of a disease resulting in overexpression of BTK kinase.

本发明另一方面提供了本发明的化合物或包含本发明的化合物的药物组合物在制备用于治疗BTK激酶过度表达所致疾病的药物中的用途。Another aspect of the present invention provides the use of a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention in the manufacture of a medicament for treating a disease caused by overexpression of BTK kinase.

定义definition

化学定义chemical definition

下面更详细地描述具体官能团和化学术语的定义。Definitions of specific functional groups and chemical terms are described in more detail below.

像本发明所描述的，本发明中的化合物可以任选地被一个或多个取代基所取代，如本发明的通式化合物，或者像实施例中特殊的例子、子类，和本发明所包含的一类化合物。应了解“任选取代的”这个术语与“取代与非取代的”这个术语可以交换使用。一般而言，术语“任选地”不论是否位于术语“取代的”之前，表示所给结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表明，一个任选的取代基团可以有一个取代基在基团各个可取代的位置进行取代。当所给出的结构式中不止一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。其中所述的取代基可以是，但并不限于，羟基，羟基烷基，氨基，卤素，氰基，氧代(＝O)，芳基，杂芳基，烷氧基，烷基，卤代烷基，氨基烷基，烷基氨基，烯基，炔基，杂环基，巯基，硝基，芳基氧基或芳基烷基等等。As described herein, compounds of the present invention may be optionally substituted with one or more substituents, such as compounds of the general formula of the present invention, or specific examples, subclasses, and A class of compounds contained. It is to be understood that the term "optionally substituted" is used interchangeably with the term "substituted and unsubstituted". In general, the term "optionally" whether or not preceded by the term "substituted" means that one or more hydrogen atoms in a given structure have been replaced with a specified substituent. Unless otherwise indicated, an optional substituent group may have a substituent at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position identically or differently. The substituents described therein may be, but are not limited to, hydroxy, hydroxyalkyl, amino, halogen, cyano, oxo(=O), aryl, heteroaryl, alkoxy, alkyl, haloalkyl , aminoalkyl, alkylamino, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy or arylalkyl and the like.

本发明使用的术语“脂肪族的”或“脂肪族基团”，表示直链(即非支链)或支链，取代或费取代的完全饱和或含有一个或多个不饱和度的烃链。除非另外详细说明，脂肪族基团含有1-20个碳原子，其中一些实施例为，脂肪族基团含有1-10个碳原子，另外一些实施例Wie，脂肪族基团含有1-8个碳原子，另外一些实施例为，脂肪族基团含有1-6个碳原子，另外一些实施例为，脂肪族基团含有1-4个碳原子。合适的脂肪族基团包括但不限于，直链或支链，取代或非取代的烷基，亚烷基，烯基或炔基基团，如甲基，乙基，异丙基，叔丁基，乙烯基等。The term "aliphatic" or "aliphatic group", as used herein, refers to a straight (ie, unbranched) or branched, substituted or substituted hydrocarbon chain that is fully saturated or contains one or more degrees of unsaturation . Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms, with some examples where aliphatic groups contain 1-10 carbon atoms, and other examples, where aliphatic groups contain 1-8 carbon atoms Carbon atoms, in other embodiments, the aliphatic group contains 1-6 carbon atoms, and in other embodiments, the aliphatic group contains 1-4 carbon atoms. Suitable aliphatic groups include, but are not limited to, straight or branched chain, substituted or unsubstituted alkyl, alkylene, alkenyl or alkynyl groups such as methyl, ethyl, isopropyl, tert-butyl base, vinyl, etc.

本发明使用的术语“烷基”包括1-20个碳原子饱和直链或支链的单价烃基，其中烷基可以独立任选地被一个或多个本发明所描述的取代基所取代。其中一些实施例为，烷基含有1-10个碳原子，另外一些实施例为，烷基含有1-8个碳原子，另外一些实施例为，烷基含有1-6个碳原子，另外一些实施例为，烷基含有1-4个碳原子。烷基基团更进一步的实例包括，但并不限于，甲基(Me，-CH3)，乙基(Et，-CH2CH3)，正丙基(n-Pr，-CH2CH2CH3)，异丙基(i-Pr，-CH(CH3)2)，正丁基(n-Bu，-CH2CH2CH2CH3)，异丁基(i-Bu，-CH2CH(CH3)2)，仲丁基(s-Bu，-CH(CH3)CH2CH3)，叔丁基(t-Bu，-C(CH3)3)，正戊基(-CH2CH2CH2CH2CH3)，2-戊基(-CH(CH3)CH2CH2CH3)，3-戊基(-CH(CH2CH3)2)，2-甲基-2-丁基(-C(CH3)2CH2CH3)，3-甲基2-丁基(-CH(CH3)CH(CH3)2)，3-甲基-1-丁基(-CH2CH2CH(CH3)2)，2-甲基-1丁基(-CH2CH(CH3)CH2CH3)，正己基，正庚基，等等。术语“烷基”和其前缀“烷”在此处使用，都包含直链和支链的饱和碳链。The term "alkyl" as used herein includes saturated straight or branched monovalent hydrocarbon groups of 1 to 20 carbon atoms, wherein the alkyl group may be independently optionally substituted with one or more substituents described herein. In some embodiments, the alkyl group contains 1-10 carbon atoms, in other embodiments, the alkyl group contains 1-8 carbon atoms, in other embodiments, the alkyl group contains 1-6 carbon atoms, and in some other embodiments, the alkyl group contains 1-6 carbon atoms. As an example, the alkyl group contains 1-4 carbon atoms. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH3 ), ethyl (Et, -CH2CH3), n - propyl (n - Pr, -CH2CH2 ) CH3 ), isopropyl (i-Pr, -CH( CH3 ) 2 ), n-butyl (n - Bu, -CH2CH2CH2CH3 ) , isobutyl (i - Bu, -CH 2 CH(CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl ( -CH2CH2CH2CH2CH3 ), 2 -pentyl (-CH( CH3 ) CH2CH2CH3 ) , 3 -pentyl (-CH( CH2CH3 ) 2 ) , 2- Methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl 2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1 -Butyl ( -CH2CH2CH ( CH3 ) 2 ), 2 -methyl- 1 -butyl (-CH2CH( CH3 ) CH2CH3 ) , n-hexyl, n-heptyl, and the like. The term "alkyl" and its prefix "alk", as used herein, both encompass straight and branched saturated carbon chains.

本发明使用的术语“卤代烷烃”表示烷基被一个或多个相同或不同的卤原子所取代，其中烷基具有本发明所述的含义，卤原子即氟、氯、溴或碘，这样的实例包括，但不限于三氟甲基、三氟乙基等。The term "halogenated alkane" as used in the present invention means that an alkyl group is substituted by one or more same or different halogen atoms, wherein the alkyl group has the meaning described in the present invention, the halogen atom being fluorine, chlorine, bromine or iodine, such Examples include, but are not limited to, trifluoromethyl, trifluoroethyl, and the like.

本发明使用的术语“羟基取代的烷基”表示烷基被一个或多个羟基基团所取代，其中烷基具有本发明所述的含义，这样的实例包括，但不限于羟甲基，(R)-羟乙基，(S)-羟乙基，(R)-羟丙基，(S)-羟丙基，2-羟基丙基，2-羟基-2丙基，3-羟基3-戊基等。The term "hydroxy-substituted alkyl" as used herein means that an alkyl group is substituted with one or more hydroxyl groups, wherein the alkyl group has the meaning described herein, such examples include, but are not limited to, hydroxymethyl, ( R)-Hydroxyethyl, (S)-Hydroxyethyl, (R)-Hydroxypropyl, (S)-Hydroxypropyl, 2-Hydroxypropyl, 2-Hydroxy-2propyl, 3-Hydroxy3- Amyl etc.

本发明使用的术语“醚烷基”表示烷基中含有一个或多个O或S，并由碳原子与其余分子相连，其中烷基具有本发明所述的含义，这样的实例包括，但不限于甲氧基甲基，乙氧基乙基，丙氧基丙基，乙氧基乙氧基乙基等。The term "ether alkyl" as used in the present invention means that the alkyl group contains one or more O or S and is attached to the rest of the molecule by a carbon atom, wherein the alkyl group has the meaning described in the present invention, such examples include, but do not Limited to methoxymethyl, ethoxyethyl, propoxypropyl, ethoxyethoxyethyl, etc.

术语“烯基”表示2-12个碳原子直链或支链的一价烃基，其中至少一个位置为不饱和状态，即一个C-C为sp2双键，其中链烯基的基团可以独立任选地被一个或多个本发明所描述的取代基所取代，包括基团有“反”“正”或“E”“Z”的定位，其中具体的实例包括，但并不限于，乙烯基(-CH＝CH2)，烯丙基(-CH2CH＝CH2)，丙烯基(CH3CH＝CH-)等等。The term "alkenyl" refers to a linear or branched monovalent hydrocarbon group of 2-12 carbon atoms, wherein at least one position is unsaturated, that is, one CC is a sp double bond, wherein the alkenyl group can be independently any Optionally substituted by one or more substituents described herein, including groups having "trans", "n" or "E""Z" orientations, specific examples of which include, but are not limited to, vinyl (-CH= CH2 ), allyl (-CH2CH = CH2 ) , propenyl (CH3CH=CH-) and the like.

术语“炔基”表示2-12个碳原子直链或支链的一价烃基，其中至少一个位置为不饱和状态，即一个C-C为sp三键，其中炔基基团可以独立任选地被一个或多个本发明所描述的取代基所取代，具体的实例包括，但并不限于，乙炔基(-C三CH)，炔丙基(-CH2C三CH)等等。The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group of 2-12 carbon atoms, wherein at least one position is unsaturated, i.e., one CC is an sp triple bond, wherein the alkynyl group can be independently optionally Substituted by one or more substituents described in the present invention, specific examples include, but are not limited to, ethynyl (-CtriCH), propargyl ( -CH2CtriCH ) and the like.

术语“碳环基”或“环烷基”是指一价或多价，非芳香族，饱和或部分不饱和环，包括3-12个碳原子的单环或7-12个碳原子的二环。具有7-12个院子的双碳环可以是二环[4,5]，[5,5]，[5,6]或[6,6]体系，同时具有9或10个原子的双碳环可以是二环[5,6]或[6,6]体系。合适的碳环基包括，但并不限于，环烷基，环烯基和环炔基。碳环基的实例进一步包括，但绝不限于，环丙基，环丁基，1-环戊基-1-烯基，1-环戊基-2-烯基，1-环戊基-3-烯基，环己基，1-环己基-1-烯基，1-环己基-2-烯基，1-环己基-3-烯基，环己二烯基，环庚基，环辛基，等等。并且，所述“碳环基”或“环烷基”可以是取代或费取代的，其中取代基可以是，但并不限于，羟基，氨基，卤素，氰基，芳基，杂芳基，烷氧基，烷基，烯基，炔基，杂环基，巯基，硝基，芳基氧基，芳基烷基等等。The term "carbocyclyl" or "cycloalkyl" refers to a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated ring, including a monocyclic ring of 3-12 carbon atoms or a dicyclic ring of 7-12 carbon atoms ring. Bicarbocycles with 7-12 yards can be bicyclic [4,5], [5,5], [5,6] or [6,6] systems, while bicarbocycles with 9 or 10 atoms Can be a bicyclic [5,6] or [6,6] system. Suitable carbocyclyl groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples of carbocyclyl groups further include, but are in no way limited to, cyclopropyl, cyclobutyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3 -Alkenyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl ,and many more. And, the "carbocyclyl" or "cycloalkyl" may be substituted or substituted, wherein the substituent may be, but not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, Alkoxy, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, arylalkyl and the like.

术语“环烷基氧基”或“碳环基氧基”包括任选取代的环烷基，如本发明所定义的连接到氧原子上，并且由氧原子与其余分子相连，这样的实例包括，但并不限于环丙基氧基，环戊基氧基，环己基氧基，羟基取代的环丙基氧基等。The term "cycloalkyloxy" or "carbocyclyloxy" includes an optionally substituted cycloalkyl, as defined herein, attached to an oxygen atom and through the oxygen atom to the rest of the molecule, examples of which include , but not limited to cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, hydroxy-substituted cyclopropyloxy, etc.

术语“烷氧基”包括任选取代的烷基，如本发明所定义的，连接到氧原子上，并且由氧原子与其余分子相连，这样的实例包括，但并不限于甲氧基，乙氧基，丙氧基等。The term "alkoxy" includes an optionally substituted alkyl group, as defined herein, attached to an oxygen atom and through the oxygen atom to the rest of the molecule, examples of which include, but are not limited to, methoxy, ethyl oxy, propoxy, etc.

术语“烷氨基”包括“N-烷基氨基”和“N,N-二烷基氨基”，其中氨基基团分别独立地被一个或两个烷基基团所取代，其中烷基基团具有如本发明所述的含义。其中一些实施例为，烷基氨基是一个或两个C1-6烷基连接到氮原子上的较低及的烷基氨基基团。另外一些实施例为，烷基氨基是C1-3的较低级的烷基氨基基团。合适的烷基氨基基团可以是单烷基氨基或二烷基氨基，这样的实施例包括，但并不限于，N-甲氨基，N-乙氨基，N,N-二甲氨基，N,N-二乙氨基等。The term "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino" wherein the amino group is independently substituted with one or two alkyl groups, wherein the alkyl group has meaning as described in the present invention. In some embodiments, alkylamino is a lower alkylamino group with one or two C1-6 alkyl groups attached to a nitrogen atom. In other embodiments, the alkylamino group is a C 1-3 lower alkylamino group. Suitable alkylamino groups may be monoalkylamino or dialkylamino, such examples include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N, N-diethylamino, etc.

术语“杂烷基”表示为烷基上一个或多个原子可以独立地任选地被杂原子所取代，烷基如本发明所定义的，并且由碳原子与其余分子相连，其中一些实施例为，“杂烷基”是1-10个原子的支链或直链(1-9个碳原子和选自N，O，S，P的1-3个杂原子，在此S或P任选地被一个或多个氧原子所取代得到像SO2，SO，PO，PO2的基团)，这样的实例包括，但并不限于氨基甲基，甲氧基乙基等。The term "heteroalkyl" means that one or more atoms of an alkyl group may be independently optionally substituted with a heteroatom, as defined herein, and attached to the remainder of the molecule by a carbon atom, some examples of which For, "heteroalkyl" is a branched or straight chain of 1-10 atoms (1-9 carbon atoms and 1-3 heteroatoms selected from N, O, S, P, where S or P is any optionally substituted with one or more oxygen atoms to give groups like SO2, SO, PO, PO2 ) , examples of which include, but are not limited to, aminomethyl, methoxyethyl, and the like.

术语“杂环”或“杂环基”在此处可交换使用，都是指单环，双环，或三环体系，其中环上一个或多个原子可以独立任选地被杂原子所取代，环可以是完全饱和的或包含一个或多个不饱和度，但绝不是芳香族类，有一个或多个连接点连接到其他分子上去。一个或多个环上的氢原子独立任选地一个或多个本发明所描述的取代基所取代。其中一些实施例为，“杂环”或“杂环基”基团是3-7元环的单环(1-6个碳原子和选自N，O，S，P的1-3个杂原子，在此S或P任选地被一个或多个氧原子所取代得到像SO2，SO，PO，PO2的基团，当所述的环为三元环时，其中只有一个杂原子)，或7-10元的双环(4-9个碳原子和选自N，O，S，P的1-3个杂原子，在此S或P任选地被一个或多个氧原子所取代得到像SO2，SO，PO，PO2的基团).The terms "heterocycle" or "heterocyclyl" are used interchangeably herein to refer to a monocyclic, bicyclic, or tricyclic ring system wherein one or more atoms in the ring may be independently optionally substituted with a heteroatom, Rings may be fully saturated or contain one or more degrees of unsaturation, but are never aromatic, having one or more points of attachment to other molecules. One or more ring hydrogen atoms are independently optionally substituted with one or more substituents described herein. In some embodiments, a "heterocycle" or "heterocyclyl" group is a 3-7 membered monocyclic ring (1-6 carbon atoms and 1-3 heterocycles selected from N, O, S, P) atoms, where S or P are optionally substituted by one or more oxygen atoms to give groups like SO 2 , SO, PO, PO 2 , when the ring is a three-membered ring, in which there is only one heteroatom ), or a 7-10 membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, S, P, where S or P are optionally replaced by one or more oxygen atoms Substitution gives groups like SO 2 , SO, PO, PO 2 ).

杂环基可以是碳基或杂原子基。“杂环基”同样也包括杂环基团与饱和或部分不饱和环或杂环稠和所形成的的基团。杂环的实例包括，但并不限于，吡咯烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，四氢吡喃基，二氢吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，噻噁烷基，哌嗪基，高哌嗪基，氮杂环丁基，氧杂环丁基，硫杂环丁基，高哌啶基，环氧丙基，氮杂环庚基，氧杂环庚基，硫杂环庚基，氧氮杂卓基，二氮杂卓基，硫氮杂卓基，2-吡咯啉基，3-吡咯啉基，二氢吲哚基，2H-吡喃基，4H-吡喃基，二氧杂环己基，1,3-二氧戊基，吡唑啉基，二噻烷基，二噻茂烷基，二氢噻吩基，吡唑烷基咪唑啉基，咪唑烷基，1,2,3,4-四氢异喹啉基，3-氮杂双环[3.1.0]己基，3-氮杂双环[4.1.0]庚基，氮杂双环[2.2.2]己基,3H-吲哚基喹啉基和N-吡啶基尿素。杂环基团的实例还包括，1,1-二氧硫代吗啉基，和其中换上两个碳原子被氧原子所取代如嘧啶二酮基。并且所述杂环基可以是取代或非取代的，其中取代基可以是，但并不限于，羟基，氨基，卤素，氰基，芳基，杂芳基，烷氧基，烷基，烯基，炔基，杂环基，巯基，硝基，芳基氧基，芳基烷基等等。The heterocyclyl group can be a carbon group or a heteroatom group. "Heterocyclyl" also includes a heterocyclic group fused to a saturated or partially unsaturated ring or heterocyclic ring. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, Morpholinyl, Thiomorpholinyl, Thioxanyl, Piperazinyl, Homopiperazinyl, Azacyclobutyl, Oxetanyl, Thietanyl, Homopiperidinyl, Glycidol Base, Azacycloheptyl, Oxeptyl, Thiepanyl, Oxazepinyl, Diazepanyl, Thiazepinyl, 2-Pyrrolino, 3-Pyrrolino, Indoline, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxopentyl, pyrazolinyl, dithianyl, dithiazolinyl, dithionyl Hydrothienyl, pyrazolidinyl imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1 .0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinolinyl and N-pyridylurea. Examples of heterocyclic groups also include, 1,1-dioxothiomorpholinyl, and pyrimidinedione groups in which two carbon atoms are replaced by oxygen atoms. And the heterocyclic group can be substituted or unsubstituted, wherein the substituent can be, but not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl , alkynyl, heterocyclyl, mercapto, nitro, aryloxy, arylalkyl, etc.

术语“不饱和杂环”表示的是杂环基包含一个或多个不饱和度，但绝不是芳香类，有一个或多个连接点连接到其他分子上去；其中杂环基具有本发明所述的含义，这样的实例包括，但并不限于，2H-吡喃基，4H-吡喃基等。The term "unsaturated heterocycle" means that a heterocyclyl group contains one or more degrees of unsaturation, but is by no means aromatic, having one or more points of attachment to other molecules; The meaning of , such examples include, but are not limited to, 2H-pyranyl, 4H-pyranyl, and the like.

术语“杂环基氧基”包括任选取代的杂环基，如本发明所定义的，连接到氧原子上，其中氧原子与分子其余部分相连，这样的实例包括，但并不限于吡咯-2-氧基，吡咯-3-氧基，哌啶-2氧基，哌啶-3-氧基，哌嗪-2-氧基，哌啶-4-氧基等。The term "heterocyclyloxy" includes an optionally substituted heterocyclyl, as defined herein, attached to an oxygen atom that is attached to the rest of the molecule, examples of which include, but are not limited to, pyrrole- 2-oxy, pyrrole-3-oxy, piperidine-2-oxy, piperidine-3-oxy, piperazine-2-oxy, piperidine-4-oxy and the like.

术语“杂环基氨基”表示氨基基团被一个或两个杂环基团所取代，其中氮原子与分子其余部分相连，并且杂环基具有如本发明所述的含义，这样的实例包括，但并不限于吡咯-2-氨基，吡咯-3-氨基，哌啶-2-氨基，哌啶-3-氨基，哌啶-4-氨基，哌嗪-2-氨基，二吡咯-2-氨基等。The term "heterocyclylamino" means that the amino group is substituted with one or two heterocyclic groups, wherein the nitrogen atom is attached to the rest of the molecule, and the heterocyclyl group has the meaning as described herein, examples of which include, But not limited to pyrrole-2-amino, pyrrole-3-amino, piperidine-2-amino, piperidine-3-amino, piperidine-4-amino, piperazine-2-amino, dipyrrole-2-amino Wait.

术语“杂环烷基”包括杂环基取代的烷基；术语“杂环基烷氧基”包括杂环基取代的烷氧基，其中氧原子与分子的其余部分相连；术语“杂环基烷氨基”包括杂环基取代的烷氨基，其中氮原子与分子的其余部分相连；其中杂环基、烷基、烷氧基和烷氨基基团具有如本发明所述的含义。这样的实例包括，但并不限于吡咯-2-甲基，吗啉-4-甲基，吡咯-2甲氧基，哌啶-2-乙氧基，哌嗪-2-乙氨基，吗啉-4-丙氧基，吗啉-4-乙氨基等。The term "heterocycloalkyl" includes heterocyclyl-substituted alkyl groups; the term "heterocyclylalkoxy" includes heterocyclyl-substituted alkoxy groups in which the oxygen atom is attached to the remainder of the molecule; the term "heterocyclyl group" "Alkylamino" includes a heterocyclyl-substituted alkylamino group in which the nitrogen atom is attached to the remainder of the molecule; wherein the heterocyclyl, alkyl, alkoxy and alkylamino groups have the meanings as described herein. Such examples include, but are not limited to, pyrrole-2-methyl, morpholine-4-methyl, pyrrole-2methoxy, piperidine-2-ethoxy, piperazine-2-ethylamino, morpholine -4-Propoxy, morpholine-4-ethylamino, etc.

术语“杂原子”表示一个或多个O，S，N，P和Si，包括N，S和P任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N(像3,4-二氢-2H-吡咯基中的N)，NH(像吡咯烷基中的NH)或NR(像N-取代的吡咯烷基中的NR)。The term "heteroatom" means one or more of O, S, N, P, and Si, including N, S, and P in any oxidation state; in the form of primary, secondary, tertiary amines, and quaternary ammonium salts; or nitrogen in a heterocyclic ring The form in which the hydrogen on the atom is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrolidine), NH (like NH in pyrrolidinyl), or NR (like N-substituted pyrrolidine NR in the base).

术语“卤素”或前缀“卤”，是指F，Cl，Br或I。The term "halogen" or the prefix "halo" refers to F, Cl, Br or I.

本发明所使用的术语“不饱和的”表示部分含有一个或多个不饱和度。The term "unsaturated" as used herein means that a moiety contains one or more degrees of unsaturation.

术语“芳基”可以单独使用或作为“芳烷基”“芳烷氧基””或“芳氧基烷基”的一大部分，表示共含有6-14元环的单环，双环和三环的碳环体系，其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7元环，且只有一个附着点与分子的其他部分相连。术语“芳基”可以和术语“芳香环”交换使用，如方向华可以包括苯基，萘基和蔥。并且所述芳基可以是取代或非取代的，其中取代基可以是，但并不限于，羟基，氨基，卤素，氰基，芳基，杂芳基，烷氧基，烷基，烯基，炔基，杂环基，巯基，硝基，芳基氧基，芳基烷基等等。The term "aryl" may be used alone or as part of "aralkyl", "aralkoxy" or "aryloxyalkyl" to denote monocyclic, bicyclic and tricyclic rings containing a total of 6-14 membered rings. Carbocyclic ring systems of rings, wherein at least one ring system is aromatic, wherein each ring system comprises a 3-7 membered ring and has only one point of attachment to the rest of the molecule. The term "aryl" may be used in conjunction with the term "aryl" "Aromatic ring" is used interchangeably, such as direction Hua can include phenyl, naphthyl and onion. And the aryl group can be substituted or unsubstituted, wherein the substituent can be, but not limited to, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, arylalkyl and the like.

术语“芳基烷基”表示烷基被一个或多个芳基基团所取代，其中烷基和芳基基团具有本发明所述的含义，这样的实例包括，但并不限于苯甲基，苯乙基，对甲苯乙基，苯乙烯基等。The term "arylalkyl" means an alkyl group substituted with one or more aryl groups, wherein the alkyl and aryl groups have the meanings described herein, examples of which include, but are not limited to, benzyl , phenethyl, p-tolueneethyl, styryl, etc.

术语“芳基氧基”包括任选取代的芳基，如本发明所定义的，连接到氧原子上，并且由氧原子分子其余部分相连，其中芳基基团具有本发明所述的汉语，这样的实例包括，但并不限于对甲苯氧基，对乙苯氧基等。The term "aryloxy" includes an optionally substituted aryl group, as defined herein, attached to an oxygen atom and connected by the remainder of the oxygen atom molecule, wherein the aryl group has the Chinese language of the present invention, Such examples include, but are not limited to, p-tolyloxy, p-ethylphenoxy, and the like.

术语“芳基氨基”表示氨基基团被一个或两个芳基基团所取代，其中芳基具有本发明所述的含义，这样的实例包括，但并不限于苯基氨基，二苯基氨基，二甲苯基氨基等。The term "arylamino" means that an amino group is substituted with one or two aryl groups, wherein aryl has the meaning set forth herein, examples of which include, but are not limited to, phenylamino, diphenylamino , Xylylamino, etc.

术语“芳基烷氧基”包括烷氧基基团被一个或多个芳基基团所取代，其中芳基、烷氧基具有本发明所述的含义，并且由氧原子分子其余部分相连，这样的实例包括，但并不限于苯甲氧基，对甲苯乙氧基，对乙苯乙氧基等。The term "arylalkoxy" includes an alkoxy group substituted with one or more aryl groups, wherein aryl, alkoxy have the meanings described herein, and are attached to the remainder of the molecule by an oxygen atom, Such examples include, but are not limited to, benzyloxy, p-tolueneethoxy, p-ethylphenethoxy, and the like.

术语“芳基烷氨基”表示烷氨基基团被一个或多个芳基基团所取代，其中芳基、烷氨基具有本发明所述的含义，并且由氮原子分子其余部分相连，这样的实例包括，但并不限于苯基甲氨基，二苯基乙氨基等。The term "arylalkylamino" means that an alkylamino group is substituted with one or more aryl groups, wherein aryl, alkylamino have the meanings described herein, and are attached to the remainder of the molecule by a nitrogen atom, such as Including, but not limited to, phenylmethylamino, diphenylethylamino, and the like.

术语“杂芳基”可以单独使用或作为“杂芳基烷基”或“杂芳基烷氧基”的一大部分，，表示共含有5-14元环的单环，双环，和三环体系，其中至少一个环体系是芳香族的，且至少一个环体系包含一个或多个杂原子，其中每一个环体系包含3-7元环，且只有一个附着点与分子其余部分相连。术语“杂芳基”可以与术语“芳杂环”或“杂芳族化合物”交换使用。并且所述杂芳基可以是取代或非取代的，，其中取代基可以是，但并不限于，羟基，氨基，卤素，氰基，芳基，杂芳基，烷氧基，烷基，烯基，炔基，杂环基，巯基，硝基，芳基氧基，芳基烷基等等。The term "heteroaryl" may be used alone or as part of a "heteroarylalkyl" or "heteroarylalkoxy", to mean monocyclic, bicyclic, and tricyclic rings containing a total of 5-14 membered rings systems wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a 3-7 membered ring and has only one point of attachment to the rest of the molecule. The term "heteroaryl" is used interchangeably with the terms "aromatic heterocycle" or "heteroaromatic". And the heteroaryl group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, alkene alkynyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, arylalkyl and the like.

另外一些实施例为，芳杂环包括以下的单环，但并不限于这些单环：2-呋喃基，3-呋喃基，N-咪唑基，2-咪唑基，4-咪唑基，5-咪唑基，3-异噁唑基，4-异噁唑基，5-异噁唑基，2-噁唑基，4-噁唑基，5-噁唑基，N-吡咯基，2-吡咯基，3-吡咯基，2-吡啶基，3-吡啶基，4-吡啶基，2-嘧啶基，4-嘧啶基，5-嘧啶基，哒嗪基(如3-哒嗪基)，2-噻唑基，4-噻唑基，5-噻唑基，四唑基(如5-四唑基)，三唑基(如2-三唑基和5-三唑基)，2-噻吩基，3-噻吩基，吡唑基，(如2-吡唑基)，异噻唑基，1,2,3-噁二唑基，1,2,5-噁二唑基，1,2,4-噁二唑基，1,2,3-三唑基，1,2,3,-硫代二唑基，1,3,4-硫代二唑基，1,2,5-硫代二唑基，吡嗪基，1,3,5-三嗪基；也包括以下的双环，但绝不限于这些双环：苯并咪唑基，苯并呋喃基，苯并噻吩基，吲哚基(如2-吲哚基)，嘌呤基，喹啉基(如2-喹啉基，3-喹啉基，4-喹啉基)，异喹啉基(如1-异喹啉基，3-异喹啉基或4-异喹啉基)等。In other embodiments, the aromatic heterocycle includes, but is not limited to, the following monocycles: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- Imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrole base, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2 - Thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3 -Thienyl, pyrazolyl, (eg 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl oxadiazolyl, 1,2,3-triazolyl, 1,2,3,-thiooxadiazolyl, 1,3,4-thiooxadiazolyl, 1,2,5-thiooxadiazolyl , pyrazinyl, 1,3,5-triazinyl; also including, but in no way limited to, the following bicyclic rings: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (such as 2- indolyl), purinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl) group or 4-isoquinolyl) etc.

术语“杂芳基烷基”表示烷基基团被一个或多个杂芳基基团所取代，其中烷基基团和杂芳基基团具有如本发明所述的含义，这样的实例包括，但并不限于吡啶-2-乙基，噻唑-2-甲基，咪唑-2-乙基，嘧啶-2-丙基等。The term "heteroarylalkyl" means that an alkyl group is substituted with one or more heteroaryl groups, wherein the alkyl group and the heteroaryl group have the meanings as described herein, examples of which include , but not limited to pyridine-2-ethyl, thiazole-2-methyl, imidazole-2-ethyl, pyrimidine-2-propyl, etc.

术语“杂芳基氧基”包括任选取代的杂芳基，如本发明所定义的，连接到氧原子上，并且由氧原子与分子其余部分相连，其中杂芳基基团具有如本发明所述的含义，这样的实例包括，但并不限于吡啶-2-氧基，噻唑-2-氧基，咪唑-2-氧基，嘧啶-2-氧基等。The term "heteroaryloxy" includes an optionally substituted heteroaryl group, as defined herein, attached to an oxygen atom and by the oxygen atom to the remainder of the molecule, wherein the heteroaryl group has the same properties as the present invention By the meaning, such examples include, but are not limited to, pyridine-2-oxy, thiazol-2-oxy, imidazol-2-oxy, pyrimidine-2-oxy, and the like.

术语“杂芳基氨基”表示氨基基团被一个或两个杂芳基基团所取代，其中杂芳基基团具有如本发明所述的含义，这样的实例包括，但并不限于吡啶-2-氨基，噻唑-2-氨基，咪唑-2-氨基，嘧啶-2-氨基等。The term "heteroarylamino" means that an amino group is substituted with one or two heteroaryl groups, wherein the heteroaryl groups have the meanings described herein, examples of which include, but are not limited to, pyridine- 2-amino, thiazole-2-amino, imidazole-2-amino, pyrimidine-2-amino, etc.

术语“杂芳基烷氧基”包括含有氧原子的杂芳基烷基基团通过氧原子与分子其余部分相连，其中杂芳基和烷氧基基团具有如本发明所述的含义。这样的实例包括，但并不限于吡啶基-2-甲氧基，吡啶基-4-乙氧基，噻唑基-2-乙氧基，咪唑-3-丙氧基等。The term "heteroarylalkoxy" includes a heteroarylalkyl group containing an oxygen atom attached to the remainder of the molecule through the oxygen atom, wherein the heteroaryl and alkoxy groups have the meanings as described herein. Such examples include, but are not limited to, pyridyl-2-methoxy, pyridyl-4-ethoxy, thiazolyl-2-ethoxy, imidazole-3-propoxy, and the like.

术语“杂芳基烷氨基”表示烷氨基基团被一个或多个杂芳基基团所取代，其中杂芳基和烷氨基具有如本发明所述的含义，并且由氮原子与分子其余部分相连，这样的实例包括，但并不限于吡啶基-2-甲氨基，吡啶基-4-乙氨基，噻唑基-2-乙氨基，咪唑-3-丙氨基等。The term "heteroarylalkylamino" means that an alkylamino group is substituted with one or more heteroaryl groups, wherein heteroaryl and alkylamino have the meanings as described herein, and are composed of a nitrogen atom and the remainder of the molecule. Linked, such examples include, but are not limited to, pyridyl-2-methylamino, pyridyl-4-ethylamino, thiazolyl-2-ethylamino, imidazole-3-propylamino, and the like.

术语“氨基磺酰基”表示氨基取代的磺酰基基团，形成氨磺酰基(-SO2NH2)。The term "aminosulfonyl" refers to an amino-substituted sulfonyl group forming a sulfamoyl group ( -SO2NH2 ) .

术语“氨基甲酰基”表示氨基取代的甲酰基基团，形成氨甲酰基(-CONH2)。The term "carbamoyl" refers to an amino-substituted formyl group, forming a carbamoyl group ( -CONH2 ).

术语“羧基”，无论是单独使用还是和其他术语连用，如“羧烷基”，表示-COOH。The term "carboxy", whether used alone or in combination with other terms, such as "carboxyalkyl", means -COOH.

像本发明所描述的，取代基画一个键连接到中心的环上形成的环体系(如a所示)代表Rc可以在环上任何可取代的位置都可以取代。例如a代表W环上任何可能被取代的位置均可被Rc取代。As described in the present invention, the substituents draw a bond to the central ring to form a ring system (shown as a) representing that R c can be substituted at any substitutable position on the ring. For example, a represents that any possible substituted position on the W ring can be substituted by R c .

Figure BDA0003367826790000211
Figure BDA0003367826790000211

除非其他方面表明，本发明所描述的结构式包括所有的同分异构形式(如对映异构、非对映异构，和几何异构(或构象异构))；例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体，和(Z)、(E)的构象异构体。因此，本发明的化合物的单个立体化学异构体或其对映异构体，非对映异构体，或几何异构体(或构象异构体)的混合物都属于本发明的范围。Unless otherwise indicated, the structural formulae described herein include all isomeric forms (eg, enantiomeric, diastereomeric, and geometric (or conformational)); for example, those containing asymmetric centers R, S configuration, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Accordingly, individual stereochemical isomers or enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers) of the compounds of the present invention are within the scope of the present invention.

其它定义Other definitions

本发明中所述的“药学上可接受的”是指包括任意不干扰活性成分的生物活性的有效性且对它被给予的宿主无毒性的物质。"Pharmaceutically acceptable" as used herein is meant to include any substance that does not interfere with the effectiveness of the biological activity of the active ingredient and is non-toxic to the host to which it is administered.

本发明所述药学上可接受的辅料，是药物中除主药以外的一切附加材料的总称，辅料应当具备如下性质：(1)对人体无毒害作用，几无副作用；(2)化学性质稳定，不易手温度、pH、保存时间等的影响；(3)与主药无配伍禁忌，不影响主药的疗效和质量检查；(4)不与包装材料相互发生作用。本发明中辅料包括但不限于填充剂(稀释剂)、润滑剂(助流剂或抗粘着剂)、分散剂、润湿剂、粘合剂、调节剂、增溶剂、抗氧剂、抑菌剂、乳化剂、崩解剂等。粘合剂包括糖浆、阿拉伯胶、明胶、山梨醇、黄芪胶、纤维素及其衍生物(如微晶纤维素、羧甲基纤维素钠、乙基纤维素或羟丙基纤维素等)、明胶浆、糖浆淀粉浆或聚乙烯吡咯烷酮等；填充剂包含乳糖、糖粉、糊精、淀粉及其衍生物、纤维素及其衍生物、无机钙盐(如硫酸钙、磷酸钙、磷酸氢钙、沉降碳酸钙等)、山梨醇或甘氨酸等；润滑剂包含微粉硅胶、硬脂酸镁、滑石粉、氢氧化铝、硼酸、氢化植物油、聚乙二醇等；崩解剂包含淀粉及其衍生物(如羧甲基淀粉钠、淀粉乙醇酸钠、预胶化淀粉、改良淀粉、羟丙基淀粉、玉米淀粉等)、聚乙烯吡咯烷酮或微晶纤维素等，润湿剂包含十二烷基硫酸钠、水或醇等；抗氧剂白喊亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠、二丁基苯酸等；抑菌剂包含0.5％苯酚、0.3％甲酚、0.5％三氯叔丁醇等；调节剂包含盐枸橼酸、氢氧化钾(钠)、枸橼酸钠及缓冲剂(包括磷酸氢二钠和磷酸二氢钠)等；乳化剂包含聚山梨酯-80、没酸山梨坦、普流罗尼克F-68、卵磷脂、豆磷脂等；增溶剂包含吐温-80、胆汁、甘油等。术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。上述酸碱为广义的路易斯酸碱。适合形成盐的酸包括但不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸、苯磺酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸。The pharmaceutically acceptable adjuvant of the present invention is a general term for all additional materials in the drug except the main drug, and the adjuvant should have the following properties: (1) it has no toxic effect on the human body, and has almost no side effects; (2) its chemical properties are stable , It is not easy to be affected by temperature, pH, storage time, etc.; (3) It has no incompatibility with the main drug, and does not affect the efficacy and quality inspection of the main drug; (4) It does not interact with packaging materials. The auxiliary materials in the present invention include but are not limited to fillers (diluents), lubricants (glidants or anti-adherents), dispersants, wetting agents, adhesives, regulators, solubilizers, antioxidants, bacteriostatic agents agent, emulsifier, disintegrant, etc. Binders include syrup, acacia, gelatin, sorbitol, tragacanth, cellulose and its derivatives (such as microcrystalline cellulose, sodium carboxymethyl cellulose, ethyl cellulose or hydroxypropyl cellulose, etc.), Gelatin syrup, syrup starch syrup or polyvinylpyrrolidone, etc.; fillers include lactose, sugar powder, dextrin, starch and its derivatives, cellulose and its derivatives, inorganic calcium salts (such as calcium sulfate, calcium phosphate, calcium hydrogen phosphate) , precipitated calcium carbonate, etc.), sorbitol or glycine, etc.; lubricants include micropowder silica gel, magnesium stearate, talc, aluminum hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol, etc.; disintegrants include starch and its derivatives (such as sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch, corn starch, etc.), polyvinylpyrrolidone or microcrystalline cellulose, etc., the wetting agent contains dodecyl Sodium sulfate, water or alcohol, etc; etc.; regulators include salt citric acid, potassium hydroxide (sodium), sodium citrate and buffers (including disodium hydrogen phosphate and sodium dihydrogen phosphate), etc.; emulsifying agents include polysorbate-80, sorbitan disate Tan, Pluronic F-68, lecithin, soybean lecithin, etc.; solubilizers include Tween-80, bile, glycerol, etc. The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with an acid or base suitable for use as a medicament. The above acids and bases are Lewis acids and bases in a broad sense. Acids suitable for forming salts include, but are not limited to, inorganic acids such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, nitric, phosphoric, formic, acetic, propionic, oxalic, malonic, succinic, fumaric, Organic acids such as lactic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenemethanesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

本发明所使用的术语“前药”，代表一个化合物在体内转化为式Ⅰ所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。As used herein, the term "prodrug" refers to the conversion of a compound to a compound of formula I in vivo. Such conversion is effected by hydrolysis of the prodrug in blood or enzymatic conversion to the parent structure in blood or tissue. The prodrug compounds of the present invention can be esters. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonate esters , carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, which can be acylated to give the compound in prodrug form. Other prodrug forms include phosphates, such as these phosphates are phosphorylated by the hydroxyl group on the parent.

除非其他方面表明，本发明的化合物的所有互变异构形式都包含在本发明的范围之内。另外，除非其他方面表明，本发明所描述的化合物的结构式包括一个或多个不同的原子的富集同位素。Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are included within the scope of the present invention. Additionally, unless otherwise indicated, the structural formulae of the compounds described herein include enriched isotopes of one or more different atoms.

“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰胺化，脱酰胺作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。"Metabolite" refers to a product obtained by metabolism of a specific compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art. Such products may be obtained by subjecting the administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

本发明的化合物可以包含不对称中心或手性中心，因此存在不同的立体异构体。本发明的化合物所有的立体异构形式，包括但绝不限于，非对映体，对映异构体，阻转异构体，和它们的混合物，如外消旋混合物，组成了本发明的一部分。很多有机化合物都以光学活性形式存在，，即它们有能力旋转平面偏振光的平面。在描述光学活性化合物时，前缀D、L或R、S用来表示分子手性中心的绝对构型。前缀d、l或(+)、(-)用来命名化合物平面偏振光旋转的符号，前缀(-)或l是指化合物是左旋的，前缀(+)或d是指化合物是右旋的。这些立体异构体的化学结构是相同的，但是它们的立体结构不一样。特定的立体异构体可以是对映体，异构体的混合物通常称为对映异构体混合物。50:50的对映体混合物被称为外消旋混合物或外消旋体，这可能导致化学反应过程中没有立体选择性或立体定向性。术语“外消旋混合物”和“外消旋体”是指等摩尔的两个对映异构体的混合物，缺乏光学活性。The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including, but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the part. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D, L or R, S are used to denote the absolute configuration of the chiral center of the molecule. The prefix d, l or (+), (-) is used to designate the symbol of the plane-polarized light rotation of the compound, the prefix (-) or l means that the compound is levorotatory, and the prefix (+) or d means that the compound is dextrorotatory. The chemical structures of these stereoisomers are the same, but their steric structures are not the same. A specific stereoisomer may be an enantiomer, and a mixture of isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can result in no stereoselectivity or stereospecificity during chemical reactions. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers, devoid of optical activity.

术语“互变异构体”或“互变异构的形式”是指不同能量的结构的同分异构体可以通过低能垒互相转化。这样的实例包括，但并不限于，质子互变异构体((即质子移变的互变异构体)包括通过质子迁移的互变，如酮式-烯醇式和亚胺-烯胺的同分异构化作用。原子价(化合价)互变异构体包括一些成键电子的重组互变。The term "tautomer" or "tautomeric form" means that isomers of structures of different energies can be interconverted through a low energy barrier. Examples of such include, but are not limited to, proton tautomers (ie, proton tautomers) including interconversion by proton migration, such as keto-enol and imine-enamine Isomerization.Atomic (valence) tautomers include some recombination interconversion of bonding electrons.

本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸，氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。A "solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association in which the solvent molecule is water.

术语“保护基团”或“Pg”是指一个取代基与别的官能团起反应的时候，通常用来阻断或保护特殊的功能性。例如，“氨基的保护基团”是指一个取代基与氨基基团相连来阻断或保护化合物中氨基的功能性，合适的氨基保护基团包括乙酰基，三氟乙酰基，叔丁氧羰基(Boc)，苄氧羰基(CBZ)和9-芴亚甲氧羰基(Fmoc)。相似地，“羟基保护基团”是指羟基的取代基用来阻断或保护羟基的功能性，合适的保护基团包括乙酰基和甲硅烷基。“羧基保护基团”是指羧基的取代基用来阻断或保护羧基的功能性，一般的羧基保护基包括-CH2CH2SO2Ph，氰基乙基，2-(三甲基硅烷基)乙基，2-(三甲基硅烷基)乙氧基甲基，2-(对甲苯磺酰基)乙基，2-(对硝基苯磺酰基)乙基，2-(二苯基膦基)乙基，硝基乙基，等等。The term "protecting group" or "Pg" refers to a substituent that is commonly used to block or protect a particular functionality when it reacts with another functional group. For example, "amino protecting group" refers to a substituent attached to the amino group to block or protect the functionality of the amino group in the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxyl protecting group" refers to a substituent of a hydroxy group used to block or protect the functionality of the hydroxy group, suitable protecting groups include acetyl and silyl. "Carboxyl protecting group" means that the substituent of the carboxyl group is used to block or protect the functionality of the carboxyl group. General carboxyl protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilane) yl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl) phosphino)ethyl, nitroethyl, and the like.

给药dosing

本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)、和局部给药。The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include, but are not limited to: oral, parenteral (intravenous, intramuscular or subcutaneous), and topical.

用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增溶剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐和碳酸钠；(e)缓溶剂，例如，石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如，鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or solubilizers, for example, starch , lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants such as, Glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption acceleration agents, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, stearin Calcium acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其他本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.

用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域常规采用的惰性稀释剂，如水或其他溶剂，增溶剂和乳化剂，例如，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3 - butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances and the like.

除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。Besides these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.

用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.

本发明化合物同样可以用于注射制剂。其中，所述注射剂选自液体注射剂(水针)、注射用无菌粉末(粉针)或注射用片剂(系指药物用无菌操作法制成的模印片或机压片，临用是用注射用水溶解，供皮下或肌肉注射之用)。The compounds of the present invention may likewise be used in the preparation of injections. Wherein, the injection is selected from liquid injection (water injection), sterile powder for injection (powder injection) or tablet for injection (referring to a molded tablet or a machine-compressed tablet made by aseptic operation of medicine, and it is Dissolve with water for injection for subcutaneous or intramuscular injection).

其中，所述注射用粉剂的中除含有上述化合物外，还至少含有赋形剂。本发明中所述赋形剂，为有意加到药物中的成分，其在所用的量上不应具有药理学特性，但是，赋形剂可以有助于药物的加工、溶解或溶出、通过靶向给药途径或有助于稳定性。Wherein, in addition to the above-mentioned compound, the powder for injection also contains at least an excipient. The excipients described in the present invention are ingredients that are intentionally added to the drug and should not have pharmacological properties in the amount used, however, the excipients can aid in the processing, dissolution or dissolution of the drug, through the target Route of administration may contribute to stability.

本发明提供了一系列具有抑制BTK活性的化合物，通过试验表明其对BTK具有明显的抑制作用，为以BTK为治疗靶点的疾病如恶性肿瘤疾病或自身免疫性疾病等的治疗提供新的方案，可用于制备治疗相关疾病的药物，具有开阔的应用前景。The present invention provides a series of compounds with BTK inhibitory activity, which have obvious inhibitory effect on BTK through experiments, and provide a new solution for the treatment of diseases with BTK as a therapeutic target, such as malignant tumor diseases or autoimmune diseases, etc. , which can be used to prepare medicines for the treatment of related diseases, and has broad application prospects.

具体实施方式Detailed ways

提供以下实施例以便为领域技术人员提供如何实施、制备和评估本文请求保护的方法和化合物的完整公开和说明，旨在仅仅示例本发明而非限制本发明的范围。The following examples are provided to provide those skilled in the art with a complete disclosure and description of how to practice, prepare, and evaluate the methods and compounds claimed herein, and are intended only to illustrate the invention and not to limit its scope.

本发明中，化合物的结构是通过质谱(MS)和/或核磁共振(1HNMR)设备来确定的。化学缩写简称具有以下意义：In the present invention, the structure of the compound is determined by mass spectrometry (MS) and/or nuclear magnetic resonance ( 1 HNMR) equipment. The chemical abbreviations have the following meanings:

DMF：N,N-二甲基甲酰胺DMF: N,N-Dimethylformamide

n-BuLi：正丁基锂n-BuLi: n-butyllithium

THF：四氢呋喃THF: Tetrahydrofuran

DIPEA：N,N-二异丙基乙胺DIPEA: N,N-Diisopropylethylamine

PE：石油醚PE: petroleum ether

EA：乙酸乙酯EA: Ethyl acetate

DCM：二氯甲烷DCM: dichloromethane

MeOH：甲醇MeOH: methanol

HBTU：苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐HBTU: benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate

TFA：三氟乙酸TFA: trifluoroacetic acid

合成方法resolve resolution

本发明化合物可按照本领域常规方法，并使用合适的试剂、原料和本领域技术人员已知的纯化方法制备。The compounds of the present invention can be prepared according to routine methods in the art using suitable reagents, starting materials and purification methods known to those skilled in the art.

下面更具体地描述本发明化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。The preparation methods of the compounds of the present invention are described in more detail below, but these specific methods do not constitute any limitation of the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention pertains.

实施例1制备(2-氯-4-苯氧基苯基)(4-(4-甲基哌嗪-1-基)-7H吡咯并[2,3-d]嘧Example 1 Preparation of (2-chloro-4-phenoxyphenyl)(4-(4-methylpiperazin-1-yl)-7H pyrrolo[2,3-d]pyrimidine 啶-5-基)甲酮(化合物1)pyridin-5-yl)methanone (Compound 1)

Figure BDA0003367826790000261
Figure BDA0003367826790000261

步骤1：中间体1-3的合成Step 1: Synthesis of Intermediates 1-3

向反应瓶中加入原料化合物1-1(10.00g，53.03mmol)，1-2(5.99g，63.63mmol)，DMF(80mL)，搅拌中加入碳酸钾(14.66g，106.05mmol)，90℃下搅拌反应3小时，TLC显示反应完全。反应体系倒入水中，用乙酸乙酯萃取两次，合并乙酸乙酯层，水洗两次，饱和食盐水洗涤，无水Na2SO4干燥，减压浓缩，粗品经硅胶柱层析(PE:EA＝20:1)纯化得到无色透明油状液体12g产物1-3，收率：86.15％。The raw compound 1-1 (10.00 g, 53.03 mmol), 1-2 (5.99 g, 63.63 mmol), DMF (80 mL) were added to the reaction flask, potassium carbonate (14.66 g, 106.05 mmol) was added while stirring, and the mixture was stirred at 90°C. The reaction was stirred for 3 hours, TLC showed the reaction was complete. The reaction system was poured into water, extracted twice with ethyl acetate, the ethyl acetate layers were combined, washed twice with water, washed with saturated brine, dried over anhydrous Na 2 SO 4 , concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (PE: EA=20:1) Purification to obtain 12 g of product 1-3 as a colorless transparent oily liquid, yield: 86.15%.

步骤2：中间体1-5的合成Step 2: Synthesis of Intermediates 1-5

向三口反应瓶中加入中间体1-4(5.00g，21.51mmol)，氮气置换，加入无水四氢呋喃(20mL)，反应液冷却至-78℃，向反应瓶内滴加n-BuLi四氢呋喃溶液(17.90mL，2.4M)，搅拌反应1小时后，加入中间体1-3(6.22g，23.66mmol)的四氢呋喃溶液，继续-78℃反应2小时，TLC显示反应完全。将反应液升至室温，加入饱和氯化铵溶液淬灭反应，加入乙酸乙酯萃取两次，合并乙酸乙酯层，水洗两次，饱和食盐水洗涤，无水Na2SO4干燥，减压浓缩，粗品经硅胶柱层析(PE:EA＝5:1)纯化得到5.00g白色固体产物1-5，收率：60.50％。Intermediate 1-4 (5.00g, 21.51mmol) was added to the three-necked reaction flask, nitrogen was replaced, anhydrous tetrahydrofuran (20mL) was added, the reaction solution was cooled to -78°C, and n-BuLi tetrahydrofuran solution ( 17.90 mL, 2.4M), and after stirring the reaction for 1 hour, the tetrahydrofuran solution of intermediate 1-3 (6.22 g, 23.66 mmol) was added, and the reaction was continued at -78°C for 2 hours. TLC showed that the reaction was complete. The reaction solution was warmed to room temperature, saturated ammonium chloride solution was added to quench the reaction, ethyl acetate was added for extraction twice, the ethyl acetate layers were combined, washed twice with water, washed with saturated brine, dried over anhydrous Na 2 SO 4 , and reduced pressure. Concentrated, and the crude product was purified by silica gel column chromatography (PE:EA=5:1) to obtain 5.00 g of white solid product 1-5, yield: 60.50%.

步骤3：化合物1的合成Step 3: Synthesis of Compound 1

向反应瓶中加入中间体1-5(100.00mg，0.26mmol)，1-6(39.10mg，0.39mmol)，三乙胺(52.68mg，0.52mmol)和二氯甲烷(3mL)，室温下搅拌反应过夜，TLC显示反应完全。减压浓缩，粗品经硅胶柱层析(DCM：MeOH＝40：1)纯化再冻干得到52mg产物1，收率：44.60％。Intermediates 1-5 (100.00 mg, 0.26 mmol), 1-6 (39.10 mg, 0.39 mmol), triethylamine (52.68 mg, 0.52 mmol) and dichloromethane (3 mL) were added to the reaction flask, and stirred at room temperature The reaction was carried out overnight, and TLC showed that the reaction was complete. Concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (DCM:MeOH=40:1) and lyophilized to obtain 52 mg of product 1, yield: 44.60%.

1H NMR(400MHz，DMSO-d6)δ12.66(1H，brs)，8.32(1H，s)，7.62(1H，s)，7.60(1H，d，J＝8Hz)，7.48(2H，t，J＝8Hz)，7.26(1H，t，J＝8Hz)，7.19(2H，d，J＝8Hz)，7.16(1H，d，J＝2.36Hz)，7.03(1H，dd，J1＝8.5Hz，J2＝2.4Hz)，3.57(4H,s)，2.40(4H，t，J＝5Hz)，2.19(3H，s).；LC/MS：m/z＝447.15[M+H]+。 1 H NMR (400MHz, DMSO-d 6 ) δ 12.66 (1H, brs), 8.32 (1H, s), 7.62 (1H, s), 7.60 (1H, d, J=8Hz), 7.48 (2H, t) , J=8Hz), 7.26 (1H, t, J=8Hz), 7.19 (2H, d, J=8Hz), 7.16 (1H, d, J=2.36Hz), 7.03 (1H, dd, J1=8.5Hz) , J2=2.4Hz), 3.57 (4H, s), 2.40 (4H, t, J=5Hz), 2.19 (3H, s).; LC/MS: m/z=447.15 [M+H] + .

实施例2制备(2-氯-4-苯氧基苯基)(4-(3,4-二甲基哌嗪-1-基)-7H吡咯并[2,3-Example 2 Preparation of (2-chloro-4-phenoxyphenyl)(4-(3,4-dimethylpiperazin-1-yl)-7H pyrrolo[2,3- d]嘧啶-5-基)甲酮(化合物2)d]pyrimidin-5-yl)methanone (compound 2)

参照实施例1的方法，以中间体1-5为原料，制得化合物2：1H NMR(400MHz，DMSO-d6)δ12.64(1H，brs)，8.30(1H，s)，7.63(1H，s)，7.61(1H，d，J＝8Hz)，7.46(2H，t，J＝8Hz)，7.31(1H，t，J＝8Hz)，7.22(2H，d，J＝8Hz)，7.19(1H，d，J＝2.36Hz)，7.02(1H，dd，J1＝8.5Hz，J2＝2.4Hz)，3.87-3.81(2H，m)，3.77-3.74(1H，m)，3.26-3.18(1H，m)，3.59-3.55(1H，m)，3.01-3.08(2H，m)，2.18(3H，s)，1.15(3H，d，J＝7.0Hz)；LC/MS：m/z＝461.17[M+H]+。Referring to the method of Example 1, using intermediates 1-5 as raw materials, compound 2 was prepared: 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.64 (1H, brs), 8.30 (1H, s), 7.63 ( 1H, s), 7.61 (1H, d, J=8Hz), 7.46 (2H, t, J=8Hz), 7.31 (1H, t, J=8Hz), 7.22 (2H, d, J=8Hz), 7.19 (1H, d, J=2.36Hz), 7.02 (1H, dd, J1=8.5Hz, J2=2.4Hz), 3.87-3.81 (2H, m), 3.77-3.74 (1H, m), 3.26-3.18 ( 1H, m), 3.59-3.55 (1H, m), 3.01-3.08 (2H, m), 2.18 (3H, s), 1.15 (3H, d, J=7.0 Hz); LC/MS: m/z= 461.17[M+H] + .

实施例3制备(2-氯-4-苯氧基苯基)(4-(4-嘧啶-2-基)哌嗪-1-基)-7H吡咯并[2,Example 3 Preparation of (2-chloro-4-phenoxyphenyl)(4-(4-pyrimidin-2-yl)piperazin-1-yl)-7H pyrrolo[2, 3-d]嘧啶-5-基)甲酮(化合物3)3-d]pyrimidin-5-yl)methanone (Compound 3)

参照实施例1的方法，以中间体1-5为原料，制得化合物3：1H NMR(400MHz，DMSO-d6)δ12.65(1H，brs)，8.42(2H，d，J＝4.6Hz)，8.33(1H，s)，7.67(1H，s)，7.65(1H，d，J＝8Hz)，7.43(2H，t，J＝8Hz)，7.35(1H，t，J＝8Hz)，7.20(2H，d，J＝8Hz)，7.18(1H，d，J＝2.4Hz)，7.10(1H，dd，J1＝8.5Hz，J2＝2.4Hz)，6.71(1H，t，J＝4.4Hz)，3.63(4H，m)，2.44(4H，m)；LC/MS：m/z＝511.15[M+H]+。Referring to the method of Example 1, using intermediates 1-5 as raw materials, compound 3 was prepared: 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.65 (1H, brs), 8.42 (2H, d, J=4.6 Hz), 8.33 (1H, s), 7.67 (1H, s), 7.65 (1H, d, J=8Hz), 7.43 (2H, t, J=8Hz), 7.35 (1H, t, J=8Hz), 7.20 (2H, d, J=8Hz), 7.18 (1H, d, J=2.4Hz), 7.10 (1H, dd, J1=8.5Hz, J2=2.4Hz), 6.71 (1H, t, J=4.4Hz) ), 3.63 (4H, m), 2.44 (4H, m); LC/MS: m/z=511.15 [M+H] + .

实施例4制备(2-氯-4-苯氧基苯基)(4-(4-氯苯基)哌嗪-1-基)-7H吡咯并[2,3-d]Example 4 Preparation of (2-chloro-4-phenoxyphenyl)(4-(4-chlorophenyl)piperazin-1-yl)-7H pyrrolo[2,3-d] 嘧啶-5-基)甲酮(化合物4)Pyrimidine-5-yl)methanone (Compound 4)

参照实施例1的方法，以中间体1-5为原料，制得化合物4：LC/MS：m/z＝543.12[M+H]+。Referring to the method of Example 1, using intermediates 1-5 as raw materials, compound 4 was prepared: LC/MS: m/z=543.12 [M+H] + .

实施例5制备(2-氯-4-苯氧基苯基)(4-(4-(4-氟苯基)哌嗪-1-基)-7H吡咯并[2,Example 5 Preparation of (2-chloro-4-phenoxyphenyl)(4-(4-(4-fluorophenyl)piperazin-1-yl)-7H pyrrolo[2, 3-d]嘧啶-5-基)甲酮(化合物5)3-d]pyrimidin-5-yl)methanone (Compound 5)

参照实施例1的方法，以中间体1-5为原料，制得化合物5：LC/MS：m/z＝527.14[M+H]+。Referring to the method of Example 1, using intermediates 1-5 as raw materials, compound 5 was prepared: LC/MS: m/z=527.14 [M+H] + .

实施例6制备(2-氯-4-苯氧基苯基)(4-(4-(对甲苯基)哌嗪-1-基)-7H吡咯并[2,Example 6 Preparation of (2-chloro-4-phenoxyphenyl)(4-(4-(p-tolyl)piperazin-1-yl)-7H pyrrolo[2, 3-d]嘧啶-5-基)甲酮(化合物6)3-d]pyrimidin-5-yl)methanone (Compound 6)

参照实施例1的方法，以中间体1-5为原料，制得化合物6：LC/MS：m/z＝523.17[M+H]+。Referring to the method of Example 1, using intermediates 1-5 as raw materials, compound 6 was prepared: LC/MS: m/z=523.17 [M+H] + .

实施例7制备(2-氯-4-苯氧基苯基)(4-(4-(4-甲氧基苯基)哌嗪-1-基)-7H吡咯并Example 7 Preparation of (2-chloro-4-phenoxyphenyl)(4-(4-(4-methoxyphenyl)piperazin-1-yl)-7H pyrrolo [2,3-d]嘧啶-5-基)甲酮(化合物7)[2,3-d]pyrimidin-5-yl)methanone (Compound 7)

参照实施例1的方法，以中间体1-5为原料，制得化合物7：LC/MS：m/z＝539.17[M+H]+。Referring to the method of Example 1, using intermediates 1-5 as raw materials, compound 7 was prepared: LC/MS: m/z=539.17 [M+H] + .

实施例8制备(2-氯-4-苯氧基苯基)(4-(4-(2-甲氧基苯基)哌嗪-1-基)-7H吡咯并Example 8 Preparation of (2-chloro-4-phenoxyphenyl)(4-(4-(2-methoxyphenyl)piperazin-1-yl)-7H pyrrolo [2,3-d]嘧啶-5-基)甲酮(化合物8)[2,3-d]pyrimidin-5-yl)methanone (Compound 8)

参照实施例1的方法，以中间体1-5为原料，制得化合物8：LC/MS：m/z＝539.17[M+H]+。Referring to the method of Example 1, using intermediates 1-5 as raw materials, compound 8 was prepared: LC/MS: m/z=539.17 [M+H] + .

实施例9制备(2-氯-4-苯氧基苯基)(4-吗啉-7H-吡咯[2,3-d]嘧啶-5-基)甲酮(化Example 9 Preparation of (2-chloro-4-phenoxyphenyl)(4-morpholine-7H-pyrro[2,3-d]pyrimidin-5-yl)methanone (Cl 合物9)Compound 9)

参照实施例1的方法，以中间体1-5为原料，制得化合物9：1H NMR(400MHz，DMSO-d6)δ12.74(1H，brs)，8.36(1H，s)，7.65(1H，s)，7.60(1H，d，J＝8.4Hz)，7.48(2H，t，J＝8Hz)，7.26(1H，t，J＝7.4Hz)，7.18(2H，d，J＝7.5Hz)，7.16(1H，d，J＝2.4Hz)，7.03(1H，dd，J1＝8.5Hz，J2＝2.4Hz)，3.72(4H，t，J＝4Hz)，3.54(4H，t，J＝5.2Hz)；LC/MS：m/z＝434.12[M+H]+。Referring to the method of Example 1, using intermediates 1-5 as raw materials, compound 9 was prepared: 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.74 (1H, brs), 8.36 (1H, s), 7.65 ( 1H, s), 7.60 (1H, d, J=8.4Hz), 7.48 (2H, t, J=8Hz), 7.26 (1H, t, J=7.4Hz), 7.18 (2H, d, J=7.5Hz) ), 7.16 (1H, d, J=2.4Hz), 7.03 (1H, dd, J1=8.5Hz, J2=2.4Hz), 3.72 (4H, t, J=4Hz), 3.54 (4H, t, J= 5.2 Hz); LC/MS: m/z=434.12 [M+H] + .

实施例10制备(2-氯-4-苯氧基苯基)(4-(2-甲基吗啉)-7H吡咯[2,3-d]嘧啶-5-Example 10 Preparation of (2-chloro-4-phenoxyphenyl)(4-(2-methylmorpholine)-7Hpyrro[2,3-d]pyrimidine-5- 基)甲酮(化合物10)yl) ketone (compound 10)

参照实施例1的方法，以中间体1-5为原料，制得化合物10：LC/MS：m/z＝448.13[M+H]+。Referring to the method of Example 1, using intermediates 1-5 as raw materials, compound 10 was prepared: LC/MS: m/z=448.13 [M+H] + .

实施例11制备(2-氯-4-苯氧基苯基)(4-(2,6-二甲基吗啉)-7H-吡咯并[2,3-d]嘧Example 11 Preparation of (2-chloro-4-phenoxyphenyl)(4-(2,6-dimethylmorpholine)-7H-pyrrolo[2,3-d]pyrimidine 啶-5-基)甲酮(化合物11)Perid-5-yl)methanone (Compound 11)

参照实施例1的方法，以中间体1-5为原料，制得化合物11：LC/MS：m/z＝462.16[M+H]+。Referring to the method of Example 1, using intermediates 1-5 as raw materials, compound 11 was prepared: LC/MS: m/z=462.16 [M+H] + .

实施例12制备(2-氯-4-苯氧基苯基)(4-(2,2-二甲基吗啉)-7H-吡咯[2,3-d]嘧Example 12 Preparation of (2-chloro-4-phenoxyphenyl)(4-(2,2-dimethylmorpholine)-7H-pyrro[2,3-d]pyrimidine 啶-5-基)甲酮(化合物12)Perid-5-yl)methanone (Compound 12)

参照实施例1的方法，以中间体1-5为原料，制得化合物12：LC/MS：m/z＝462.16[M+H]+。Referring to the method of Example 1, using intermediates 1-5 as raw materials, compound 12 was prepared: LC/MS: m/z=462.16 [M+H] + .

实施例13制备(2-氯-4-苯氧基苯基)(4-(2-乙基吗啉)-7H-吡咯[2,3-d]嘧啶-5-Example 13 Preparation of (2-chloro-4-phenoxyphenyl)(4-(2-ethylmorpholine)-7H-pyrro[2,3-d]pyrimidine-5- 基)甲酮(化合物13)yl) ketone (compound 13)

参照实施例1的方法，以中间体1-5为原料，制得化合物13：LC/MS：m/z＝462.15[M+H]+。Referring to the method of Example 1, using intermediates 1-5 as raw materials, compound 13 was prepared: LC/MS: m/z=462.15 [M+H] + .

实施例14制备(2-氯-4-苯氧基苯基)(4-(2-(羟甲基)吗啉)-7H-吡咯[2,3-d]嘧Example 14 Preparation of (2-chloro-4-phenoxyphenyl)(4-(2-(hydroxymethyl)morpholine)-7H-pyrro[2,3-d]pyrimidine 啶-5-基)甲酮(化合物14)Perid-5-yl)methanone (Compound 14)

参照实施例1的方法，以中间体1-5为原料，制得化合物14：LC/MS：m/z＝464.13[M+H]+。Referring to the method of Example 1, using intermediates 1-5 as raw materials, compound 14 was prepared: LC/MS: m/z=464.13 [M+H] + .

实施例15制备1-(5-(2-氯-4-苯氧基苯甲酰基)-7H-吡咯[2,3-d]嘧啶-4-基)吡咯Example 15 Preparation of 1-(5-(2-Chloro-4-phenoxybenzoyl)-7H-pyrro[2,3-d]pyrimidin-4-yl)pyrrole 烷-3-羧酸乙酯(化合物15)Ethyl alkane-3-carboxylate (Compound 15)

Figure BDA0003367826790000291
Figure BDA0003367826790000291

步骤1：中间体15-2的合成Step 1: Synthesis of Intermediate 15-2

在反应瓶中加入原料化合物15-1(430mg，2.00mmol)，三氟乙酸(2mL)，二氯甲烷(10mL)，室温下搅拌反应1小时，减压浓缩，得到230mg淡黄色液体产物-中间体15-2，收率：100％。The starting compound 15-1 (430 mg, 2.00 mmol), trifluoroacetic acid (2 mL), and dichloromethane (10 mL) were added to the reaction flask, and the reaction was stirred at room temperature for 1 hour, and concentrated under reduced pressure to obtain 230 mg of pale yellow liquid product-intermediate Body 15-2, yield: 100%.

步骤2：中间体15-3的合成Step 2: Synthesis of Intermediate 15-3

在反应瓶中加入中间体15-2(230mg，2.00mmol)，浓盐酸(2mL)，无水乙醇(20mL)，加热回流过夜，反应完毕减压浓缩得到280mg淡黄色液体产物-中间体15-3，收率：97.89％。Intermediate 15-2 (230 mg, 2.00 mmol), concentrated hydrochloric acid (2 mL), absolute ethanol (20 mL) were added to the reaction flask, heated to reflux overnight, the reaction was completed and concentrated under reduced pressure to obtain 280 mg of pale yellow liquid product-Intermediate 15- 3. Yield: 97.89%.

步骤3：化合物15的合成Step 3: Synthesis of Compound 15

在反应瓶中加入中间体1-5(100.00mg，0.260mmol)，15-3(55.90mg,0.390mmol)，碳酸钾(71.94mg，0.520mmol)和N,N-二甲基甲酰胺(5mL)，120℃回流过夜，TLC显示反应完全，反应体系倒入水中，用乙酸乙酯萃取两次，合并乙酸乙酯层，水洗两次，饱和食盐水洗涤，无水Na2SO4干燥，减压浓缩，粗品经硅胶柱层析(PE:EA＝1:1)纯化并冻干得到37mg白色固体产物15，收率：28.96％。Intermediates 1-5 (100.00 mg, 0.260 mmol), 15-3 (55.90 mg, 0.390 mmol), potassium carbonate (71.94 mg, 0.520 mmol) and N,N-dimethylformamide (5 mL) were added to the reaction flask ), refluxed at 120 °C overnight, TLC showed that the reaction was complete, the reaction system was poured into water, extracted twice with ethyl acetate, the ethyl acetate layers were combined, washed twice with water, washed with saturated brine, dried over anhydrous Na 2 SO 4 , and then reduced It was concentrated under pressure, and the crude product was purified by silica gel column chromatography (PE:EA=1:1) and lyophilized to obtain 37 mg of white solid product 15, yield: 28.96%.

1H NMR(300MHz，DMSO-d6)δ12.49(1H，brs)，8.20(1H，s)，7.65(1H，d，J＝8.5Hz)，7.52-7.46(3H，m)，7.26(1H，t，J＝7.4Hz)，7.20(2H，d，J＝7.5Hz)，7.16(1H，d，J＝2.4Hz)，7.03(1H，dd，J1＝8.4Hz，J2＝2.4Hz)，4.05(2H，q，J＝7.0Hz)，3.91(2H，d，J＝7.1Hz)，3.82-3.67(2H，m)，3.19-3.08(1H，m)，2.18-1.95(2H，m)，1.13(3H，t，J＝7.2Hz)；LC/MS：m/z＝490.14[M+H]+。 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.49 (1H, brs), 8.20 (1H, s), 7.65 (1H, d, J=8.5Hz), 7.52-7.46 (3H, m), 7.26 ( 1H, t, J=7.4Hz), 7.20 (2H, d, J=7.5Hz), 7.16 (1H, d, J=2.4Hz), 7.03 (1H, dd, J1=8.4Hz, J2=2.4Hz) , 4.05 (2H, q, J=7.0Hz), 3.91 (2H, d, J=7.1Hz), 3.82-3.67 (2H, m), 3.19-3.08 (1H, m), 2.18-1.95 (2H, m) ), 1.13 (3H, t, J=7.2 Hz); LC/MS: m/z=490.14 [M+H] + .

实施例16制备1-(5-(2-氯-4-苯氧基苯甲酰基)-7H-吡咯并[2,3-d]嘧啶-4-基)吡Example 16 Preparation of 1-(5-(2-Chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridine 咯烷-3-羧酸(化合物16)rolidine-3-carboxylic acid (compound 16)

Figure BDA0003367826790000301
Figure BDA0003367826790000301

向反应瓶中加入化合物15(100mg，0.204mmol)，氢氧化钠(16.29mg，0.407mmol)，甲醇(5mL)，水(2mL)，40℃下回流反应3小时，TLC显示反应完全，减压浓缩，加水，滴加浓盐酸调节pH至5.5，固体析出，用水和正己烷漂洗得到92mg白色固体产物16，收率：97.58％。Compound 15 (100 mg, 0.204 mmol), sodium hydroxide (16.29 mg, 0.407 mmol), methanol (5 mL), water (2 mL) were added to the reaction flask, and the reaction was refluxed at 40°C for 3 hours. TLC showed that the reaction was complete, and the pressure was reduced. Concentrate, add water, add concentrated hydrochloric acid dropwise to adjust the pH to 5.5, a solid is precipitated, rinsed with water and n-hexane to obtain 92 mg of white solid product 16, yield: 97.58%.

1H NMR(400MHz，DMSO-d6)δ12.48(1H，brs)，8.19(1H，s)，7.65(1H，d，J＝8.4Hz)，7.49(2H，t，J＝7.4Hz)，7.44(1H，s)，7.26(1H，t，J＝7.4Hz)，7.19(2H，d，J＝7.5Hz)，7.16(1H，d，J＝2.4Hz)，7.03(1H，dd，J1＝8.5Hz，J2＝2.4Hz)，3.89(2H，d，J＝7.1Hz)，3.76-3.70(2H，m)，3.07-2.99(1H，m)，2.13-1.96(2H，m)；LC/MS：m/z＝462.12[M+H]+。 1 H NMR (400MHz, DMSO-d 6 ) δ 12.48 (1H, brs), 8.19 (1H, s), 7.65 (1H, d, J=8.4Hz), 7.49 (2H, t, J=7.4Hz) , 7.44 (1H, s), 7.26 (1H, t, J=7.4Hz), 7.19 (2H, d, J=7.5Hz), 7.16 (1H, d, J=2.4Hz), 7.03 (1H, dd, J1=8.5Hz, J2=2.4Hz), 3.89 (2H, d, J=7.1Hz), 3.76-3.70 (2H, m), 3.07-2.99 (1H, m), 2.13-1.96 (2H, m); LC/MS: m/z=462.12 [M+H] + .

实施例17制备(1-(5-(2-氯-4-苯氧基苯甲酰基)-7H-吡咯并[2,3-d]嘧啶-4-基)Example 17 Preparation of (1-(5-(2-Chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) 吡咯烷酮-3-基)(4-甲基哌嗪-1-基)甲酮(化合物17)Pyrrolidone-3-yl)(4-methylpiperazin-1-yl)methanone (Compound 17)

Figure BDA0003367826790000311
Figure BDA0003367826790000311

在反应瓶中加入化合物16(50mg，0.108mmol)，1-6(12.98mg，0.130mmol)，N,N-二异丙基乙胺(16.75mg，0.130mmol)，二氯甲烷(5mL)，35℃下回流过夜反应，TLC显示反应完全，减压浓缩，粗品经硅胶柱层析(DCM:MeOH＝40:1)纯化并冻干得到17mg白色固体产物17，收率：28.88％。Compound 16 (50 mg, 0.108 mmol), 1-6 (12.98 mg, 0.130 mmol), N,N-diisopropylethylamine (16.75 mg, 0.130 mmol), dichloromethane (5 mL) were added to the reaction flask, The reaction was refluxed at 35°C overnight, TLC showed that the reaction was complete, concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (DCM:MeOH=40:1) and lyophilized to obtain 17 mg of white solid product 17, yield: 28.88%.

1H NMR(400MHz，DMSO-d6)δ12.44(1H，brs)，8.18(1H，s)，7.66(1H，d，J＝8.4Hz)，7.49(2H，t，J＝7.5Hz)，7.44(1H，s)，7.27(1H，t，J＝7.5Hz)，7.19(2H，d，J＝7.6Hz)，7.17(1H，d，J＝2.5Hz)，7.02(1H，dd，J1＝8.5Hz，J2＝2.4Hz)，3.93-3.88(1H，m)，3.80-3.72(3H，m)，3.50-3.36(5H，m)，2.30-2.15(4H，m)，2.13(3H，s)，2.06-1.94(2H，m)；LC/MS：m/z＝544.20[M+H]+。 1 H NMR (400MHz, DMSO-d 6 ) δ 12.44 (1H, brs), 8.18 (1H, s), 7.66 (1H, d, J=8.4Hz), 7.49 (2H, t, J=7.5Hz) , 7.44 (1H, s), 7.27 (1H, t, J=7.5Hz), 7.19 (2H, d, J=7.6Hz), 7.17 (1H, d, J=2.5Hz), 7.02 (1H, dd, J1=8.5Hz, J2=2.4Hz), 3.93-3.88(1H,m), 3.80-3.72(3H,m), 3.50-3.36(5H,m), 2.30-2.15(4H,m), 2.13(3H) , s), 2.06-1.94 (2H, m); LC/MS: m/z=544.20 [M+H] + .

实施例18制备(1-(5-(2-氯-4-苯氧基苯甲酰基)-7H-吡咯并[2,3-d]嘧啶-4-基)Example 18 Preparation of (1-(5-(2-Chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) 吡咯烷酮-3-基)(哌嗪-1-基)甲酮(化合物18)Pyrrolidone-3-yl)(piperazin-1-yl)methanone (Compound 18)

Figure BDA0003367826790000312
Figure BDA0003367826790000312

步骤1：中间体18-2的合成Step 1: Synthesis of Intermediate 18-2

向反应瓶中加入化合物16(50mg，0.108mmol)，18-1(24.14mg，0.130mmol)，N,N-二异丙基乙胺(16.75mg，0.130mmol)，二氯甲烷(5mL)，35℃下回流过夜反应，TLC显示反应完全，减压浓缩，粗品经硅胶柱层析(DCM:MeOH＝40:1)纯化得到24mg白色固体产物18-2，收率：35.20％。To the reaction flask was added compound 16 (50 mg, 0.108 mmol), 18-1 (24.14 mg, 0.130 mmol), N,N-diisopropylethylamine (16.75 mg, 0.130 mmol), dichloromethane (5 mL), The reaction was refluxed at 35°C overnight, TLC showed that the reaction was complete, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH=40:1) to obtain 24 mg of white solid product 18-2, yield: 35.20%.

步骤2：化合物18的合成Step 2: Synthesis of Compound 18

向反应瓶中加入中间体18-2(50mg，0.079mmol)，盐酸/1,4-二氧六环(5mL)，室温搅拌反应1小时，TLC显示反应完全，减压浓缩，加水(5mL)，用饱和碳酸氢钠溶液调节pH至8，固体析出，过滤，干燥得到33mg白色固体产物18，收率：78.44％。Intermediate 18-2 (50 mg, 0.079 mmol), hydrochloric acid/1,4-dioxane (5 mL) was added to the reaction flask, and the reaction was stirred at room temperature for 1 hour. TLC showed that the reaction was complete, concentrated under reduced pressure, and added water (5 mL) , the pH was adjusted to 8 with saturated sodium bicarbonate solution, the solid was precipitated, filtered and dried to obtain 33 mg of white solid product 18, yield: 78.44%.

1H NMR(400MHz，DMSO-d6)δ12.43(1H，brs)，8.17(1H，s)，7.65(1H，d，J＝8.5Hz)，7.48(2H，t，J＝7.5Hz)，7.44(1H，s)，7.26(1H，t，J＝7.5Hz)，7.21(2H，d，J＝7.4Hz)，7.16(1H，d，J＝2.5Hz)，7.02(1H，dd，J1＝8.4Hz，J2＝2.4Hz)，3.94-3.85(1H，m)，3.79-3.70(3H，m)，3.55-3.23(9H，m)，2.06-1.94(2H，m)，1.90(1H，m)；LC/MS：m/z＝530.18[M+H]+。 1 H NMR (400MHz, DMSO-d 6 ) δ 12.43 (1H, brs), 8.17 (1H, s), 7.65 (1H, d, J=8.5Hz), 7.48 (2H, t, J=7.5Hz) , 7.44 (1H, s), 7.26 (1H, t, J=7.5Hz), 7.21 (2H, d, J=7.4Hz), 7.16 (1H, d, J=2.5Hz), 7.02 (1H, dd, J1=8.4Hz, J2=2.4Hz), 3.94-3.85(1H,m), 3.79-3.70(3H,m), 3.55-3.23(9H,m), 2.06-1.94(2H,m), 1.90(1H) , m); LC/MS: m/z=530.18 [M+H] + .

实施例19制备(1-(5-(2-氯-4-苯氧基苯甲酰基)-7H-吡咯并[2,3-d]嘧啶-4-基)Example 19 Preparation of (1-(5-(2-Chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) 吡咯烷-3-基)(吗啉)甲酮(化合物19)Pyrrolidin-3-yl)(morpholino)methanone (Compound 19)

参照实施例17的方法，以化合物16为原料，制得化合物19：LC/MS：m/z＝531.18[M+H]+。Referring to the method of Example 17, using compound 16 as a raw material, compound 19 was prepared: LC/MS: m/z=531.18 [M+H] + .

实施例20制备1-(5-(2-氯-4-苯氧基苯甲酰基)-7H-吡咯并[2,3-d]嘧啶-4-基)哌Example 20 Preparation of 1-(5-(2-Chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine 啶-4-羧酸乙酯(化合物20)Ethyl pyridine-4-carboxylate (Compound 20)

参照实施例15的方法，以中间体1-5为原料，制得化合物20：1H NMR(300MHz，DMSO-d6)δ12.67(1H，brs)，8.32(1H，s)，7.62-7.59(3H，m)，7.49(2H，t，J＝7.4Hz)，7.26(1H，t，J＝7.4Hz)，7.19(2H，d，J＝7.5Hz)，7.16(1H，d，J＝2.3Hz)，7.03(1H，dd，J1＝8.4Hz，J2＝2.4Hz)，4.15(2H，d，J＝15.0Hz)，4.07(2H，q，J＝7.1Hz)，3.04(2H，t，J＝11.2Hz)，2.63-2.56(1H，m)，1.86-1.63(4H，m)，1.18(3H，t，J＝7.1Hz)；LC/MS：m/z＝504.16[M+H]+。Referring to the method of Example 15, using intermediates 1-5 as raw materials, compound 20 was prepared: 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.67 (1H, brs), 8.32 (1H, s), 7.62- 7.59 (3H, m), 7.49 (2H, t, J=7.4Hz), 7.26 (1H, t, J=7.4Hz), 7.19 (2H, d, J=7.5Hz), 7.16 (1H, d, J = 2.3Hz), 7.03 (1H, dd, J1=8.4Hz, J2=2.4Hz), 4.15 (2H, d, J=15.0Hz), 4.07 (2H, q, J=7.1Hz), 3.04 (2H, t, J=11.2 Hz), 2.63-2.56 (1H, m), 1.86-1.63 (4H, m), 1.18 (3H, t, J=7.1 Hz); LC/MS: m/z=504.16 [M+ H] + .

实施例21制备1-(5-(2-氯-4-苯氧基苯甲酰基)-7H-吡咯并[2,3-d]嘧啶-4-基)哌Example 21 Preparation of 1-(5-(2-Chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine 啶-4-羧酸(化合物21)Pyridin-4-carboxylic acid (Compound 21)

参照实施例16的方法，以化合物20为原料，制得化合物21：1H NMR(400MHz，DMSO-d6)δ12.61(1H，brs)，8.34(1H，s)，7.61(2H，d，J＝7.9Hz)，7.49(2H，t，J＝7.5Hz)，7.26(1H，t，J＝7.4Hz)，7.19(2H，d，J＝7.5Hz)，7.16(1H，d，J＝2.4Hz)，7.03(1H，dd，J1＝8.5Hz，J2＝2.4Hz)，4.14(2H，d，J＝13.1Hz)，3.08-3.02(2H，m)，1.85-1.62(4H，m)；LC/MS：m/z＝476.13[M+H]+。Referring to the method of Example 16, using compound 20 as raw material, compound 21 was prepared: 1 H NMR (400 MHz, DMSO-d 6 )δ 12.61 (1H, brs), 8.34 (1H, s), 7.61 (2H, d , J=7.9Hz), 7.49 (2H, t, J=7.5Hz), 7.26 (1H, t, J=7.4Hz), 7.19 (2H, d, J=7.5Hz), 7.16 (1H, d, J = 2.4Hz), 7.03 (1H, dd, J1=8.5Hz, J2=2.4Hz), 4.14 (2H, d, J=13.1Hz), 3.08-3.02 (2H, m), 1.85-1.62 (4H, m ); LC/MS: m/z=476.13 [M+H] + .

实施例22制备(1-(5-(2-氯-4-苯氧基苯甲酰基)-7H-吡咯并[2,3-d]嘧啶-4-基)Example 22 Preparation of (1-(5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) 哌啶-4-基)(4-甲基哌嗪-1-基)甲酮(化合物22)Piperidin-4-yl)(4-methylpiperazin-1-yl)methanone (Compound 22)

参照实施例17的方法，以化合物21为原料，制得化合物22：1H NMR(300MHz，DMSO-d6)δ12.61(1H，brs)，8.31(1H，s)，7.61(2H，d，J＝8.4Hz)，7.49(2H，t，J＝7.4Hz)，7.26(1H，t，J＝7.4Hz)，7.19(2H，d，J＝7.5Hz)，7.16(1H，d，J＝2.4Hz)，7.02(1H，dd，J1＝8.4Hz，J2＝2.4Hz)，4.26(2H，d，J＝12.8Hz)，3.51-3.43(5H，m)，3.05-2.86(3H，m)，2.29-2.21(4H，m)，2.17(3H，s)，1.73-1.58(4H，m)；LC/MS：m/z＝558.20[M+H]+。Referring to the method of Example 17, using compound 21 as raw material, compound 22 was prepared: 1 H NMR (300 MHz, DMSO-d 6 )δ 12.61 (1H, brs), 8.31 (1H, s), 7.61 (2H, d , J=8.4Hz), 7.49 (2H, t, J=7.4Hz), 7.26 (1H, t, J=7.4Hz), 7.19 (2H, d, J=7.5Hz), 7.16 (1H, d, J = 2.4Hz), 7.02 (1H, dd, J1=8.4Hz, J2=2.4Hz), 4.26 (2H, d, J=12.8Hz), 3.51-3.43 (5H, m), 3.05-2.86 (3H, m ), 2.29-2.21 (4H, m), 2.17 (3H, s), 1.73-1.58 (4H, m); LC/MS: m/z=558.20 [M+H] + .

实施例23制备(1-(5-(2-氯-4-苯氧基苯甲酰基)-7H-吡咯并[2,3-d]嘧啶-4-基)Example 23 Preparation of (1-(5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) 哌啶-4-基)(哌嗪-1-基)甲酮(化合物23)Piperidin-4-yl)(piperazin-1-yl)methanone (Compound 23)

参照实施例18的方法，以化合物21为原料，制得化合物23：LC/MS：m/z＝544.20[M+H]+。Referring to the method of Example 18, using compound 21 as a raw material, compound 23 was prepared: LC/MS: m/z=544.20 [M+H] + .

实施例24制备(1-(5-(2-氯-4-苯氧基苯甲酰基)-7H-吡咯并[2,3-d]嘧啶-4-基)Example 24 Preparation of (1-(5-(2-Chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) 哌啶-4-基)(吗啉)甲酮(化合物24)Piperidin-4-yl)(morpholino)methanone (Compound 24)

参照实施例17的方法，以化合物21为原料，制得化合物24：LC/MS：m/z＝545.18[M+H]+。Referring to the method of Example 17, using compound 21 as a raw material, compound 24 was prepared: LC/MS: m/z=545.18 [M+H] + .

实施例25制备1-(5-(2-氯-4-苯氧基苯甲酰基)-7H-吡咯并[2,3-d]嘧啶-4-基)哌Example 25 Preparation of 1-(5-(2-Chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine 啶-3-羧酸乙酯(化合物25)Ethyl pyridine-3-carboxylate (Compound 25)

参照实施例15的方法，以中间体1-5为原料，制得化合物25：1H NMR(300MHz，DMSO-d6)δ12.66(1H，brs)，8.33(1H，s)，7.62(1H，s)，7.58(1H，d，J＝8.5Hz)，7.49(2H，t，J＝7.4Hz)，7.26(1H，t，J＝7.4Hz)，7.21-7.16(3H，m)，7.03(1H，dd，J1＝8.4Hz，J2＝2.4Hz)，4.30(1H，d，J＝13.3Hz)，4.09(1H，d，J＝13.0Hz)，4.03-3.91(2H，m)，3.16-3.02(2H，m)，2.69-2.61(1H，m)，2.00-1.97(1H，m)，1.73-1.53(3H，m)，1.05(3H，t，J＝7.1Hz)；LC/MS：m/z＝504.16[M+H]+。Referring to the method of Example 15, using intermediates 1-5 as raw materials, compound 25 was prepared: 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.66 (1H, brs), 8.33 (1H, s), 7.62 ( 1H, s), 7.58 (1H, d, J=8.5Hz), 7.49 (2H, t, J=7.4Hz), 7.26 (1H, t, J=7.4Hz), 7.21-7.16 (3H, m), 7.03 (1H, dd, J1=8.4Hz, J2=2.4Hz), 4.30 (1H, d, J=13.3Hz), 4.09 (1H, d, J=13.0Hz), 4.03-3.91 (2H, m), 3.16-3.02 (2H, m), 2.69-2.61 (1H, m), 2.00-1.97 (1H, m), 1.73-1.53 (3H, m), 1.05 (3H, t, J=7.1 Hz); LC/ MS: m/z=504.16 [M+H] + .

实施例26制备1-(5-(2-氯-4-苯氧基苯甲酰基)-7H-吡咯并[2,3-d]嘧啶-4-基)哌Example 26 Preparation of 1-(5-(2-Chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine 啶-3-羧酸(化合物26)Pyridin-3-carboxylic acid (Compound 26)

参照实施例16的方法，以化合物25为原料，制得化合物26：1H NMR(400MHz，DMSO-d6)δ12.63(1H，brs)，8.32(1H，s)，7.59(1H，s)，7.57(1H，d，J＝8.5Hz)，7.48(2H，t，J＝7.4Hz)，7.26(1H，t，J＝7.4Hz)，7.19(2H，d，J＝7.5Hz)，7.15(1H，d，J＝2.4Hz)，7.02(1H，dd，J1＝8.5Hz，J2＝2.5Hz)，4.30(1H，d，J＝13.4Hz)，4.15(1H，d，J＝12.6Hz)，3.05-2.93(2H，m)，2.58-2.53(1H，m)，2.01-1.99(1H，m)，1.70-1.53(3H，m)；LC/MS：m/z＝476.13[M+H]+。Referring to the method of Example 16, using compound 25 as raw material, compound 26 was prepared: 1 H NMR (400MHz, DMSO-d 6 )δ12.63 (1H, brs), 8.32 (1H, s), 7.59 (1H, s) ), 7.57 (1H, d, J=8.5Hz), 7.48 (2H, t, J=7.4Hz), 7.26 (1H, t, J=7.4Hz), 7.19 (2H, d, J=7.5Hz), 7.15 (1H, d, J=2.4Hz), 7.02 (1H, dd, J1=8.5Hz, J2=2.5Hz), 4.30 (1H, d, J=13.4Hz), 4.15 (1H, d, J=12.6 Hz), 3.05-2.93 (2H, m), 2.58-2.53 (1H, m), 2.01-1.99 (1H, m), 1.70-1.53 (3H, m); LC/MS: m/z=476.13 [M +H] + .

实施例27制备(1-(5-(2-氯-4-苯氧基苯甲酰基)-7H-吡咯并[2,3-d]嘧啶-4-基)Example 27 Preparation of (1-(5-(2-Chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) 哌啶-3-基)(4-甲基哌嗪-1-基)甲酮(化合物27)Piperidin-3-yl)(4-methylpiperazin-1-yl)methanone (Compound 27)

参照实施例17的方法，以化合物26为原料，制得化合物27：1H NMR(300MHz，DMSO-d6)δ12.61(1H，brs)，8.31(1H，s)，7.62-7.59(2H，m)，7.49(2H，t，J＝7.4Hz)，7.26(1H，t，J＝7.4Hz)，7.19(2H，d，J＝7.5Hz)，7.16(1H，d，J＝2.4Hz)，7.02(1H，dd，J1＝8.4Hz，J2＝2.4Hz)，4.26(2H，d，J＝12.8Hz)，3.51-3.43(5H，m)，3.05-2.86(3H，m)，2.29-2.21(4H，m)，2.17(3H，s)，1.74-1.58(4H，m)；LC/MS：m/z＝558.21[M+H]+。Referring to the method of Example 17, using compound 26 as raw material, compound 27 was prepared: 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.61 (1H, brs), 8.31 (1H, s), 7.62-7.59 (2H) , m), 7.49 (2H, t, J=7.4Hz), 7.26 (1H, t, J=7.4Hz), 7.19 (2H, d, J=7.5Hz), 7.16 (1H, d, J=2.4Hz) ), 7.02 (1H, dd, J1=8.4Hz, J2=2.4Hz), 4.26 (2H, d, J=12.8Hz), 3.51-3.43 (5H, m), 3.05-2.86 (3H, m), 2.29 -2.21 (4H, m), 2.17 (3H, s), 1.74-1.58 (4H, m); LC/MS: m/z=558.21 [M+H] + .

实施例28制备(1-(5-(2-氯-4-苯氧基苯甲酰基)-7H-吡咯并[2,3-d]嘧啶-4-基)Example 28 Preparation of (1-(5-(2-Chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) 哌啶-3-基)(哌嗪-1-基)甲酮(化合物28)Piperidin-3-yl)(piperazin-1-yl)methanone (Compound 28)

参照实施例18的方法，以化合物26为原料，制得化合物28：LC/MS：m/z＝544.20[M+H]+。Referring to the method of Example 18, using compound 26 as a raw material, compound 28 was prepared: LC/MS: m/z=544.20 [M+H] + .

实施例29制备(1-(5-(2-氯-4-苯氧基苯甲酰基)-7H-吡咯并[2,3-d]嘧啶-4-基)Example 29 Preparation of (1-(5-(2-Chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) 哌啶-3-基)(吗啉)甲酮(化合物29)Piperidin-3-yl)(morpholino)methanone (Compound 29)

参照实施例17的方法，以化合物26为原料，制得化合物29：LC/MS：m/z＝545.17[M+H]+。Referring to the method of Example 17, using compound 26 as a raw material, compound 29 was prepared: LC/MS: m/z=545.17 [M+H] + .

实施例30制备(2-氯-4-苯氧基苯基)(4-(3-羟基吡咯烷-1-基)-7H-吡咯并[2,3-Example 30 Preparation of (2-chloro-4-phenoxyphenyl)(4-(3-hydroxypyrrolidin-1-yl)-7H-pyrrolo[2,3- d]嘧啶-5-基)甲酮(化合物30)d]pyrimidin-5-yl)methanone (Compound 30)

参照实施例1的方法，以中间体1-5为原料，制得化合物30：1H NMR(300MHz，DMSO-d6)δ12.42(1H，brs)，8.17(1H，s)，7.66(1H，d，J＝8.4Hz)，7.49(2H，t，J＝8.6Hz)，7.27(1H，t，J＝7.4Hz)，7.20(2H，d，J＝7.6Hz)，7.17(1H，d，J＝2.4Hz)，7.03(1H，dd，J1＝8.4Hz，J2＝2.4Hz)，4.89(1H，s)，4.25(1H，s)，3.88-3.79(2H，m)，3.70-3.62(1H，m)，3.54(1H，d，J＝12.3Hz)，1.93-1.75(2H，m)；LC/MS：m/z＝434.11[M+H]+。Referring to the method of Example 1, using intermediates 1-5 as raw materials, compound 30 was prepared: 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.42 (1H, brs), 8.17 (1H, s), 7.66 ( 1H, d, J=8.4Hz), 7.49 (2H, t, J=8.6Hz), 7.27 (1H, t, J=7.4Hz), 7.20 (2H, d, J=7.6Hz), 7.17 (1H, d, J=2.4Hz), 7.03 (1H, dd, J1=8.4Hz, J2=2.4Hz), 4.89 (1H, s), 4.25 (1H, s), 3.88-3.79 (2H, m), 3.70- 3.62 (1H, m), 3.54 (1H, d, J=12.3 Hz), 1.93-1.75 (2H, m); LC/MS: m/z=434.11 [M+H] + .

实施例31制备(2-氯-4-苯氧基苯基)(4-(3-(羟甲基)吡咯烷-1-基)-7H-吡咯并Example 31 Preparation of (2-chloro-4-phenoxyphenyl)(4-(3-(hydroxymethyl)pyrrolidin-1-yl)-7H-pyrrolo [2,3-d]嘧啶-5-基)甲酮(化合物31)[2,3-d]pyrimidin-5-yl)methanone (Compound 31)

参照实施例1的方法，以中间体1-5为原料，制得化合物31：1H NMR(300MHz，DMSO-d6)δ12.41(1H，brs)，8.16(1H，s)，7.65(1H，d，J＝8.5Hz)，7.48(2H，t，J＝8.7Hz)，7.42(1H，s)，7.26(1H，t，J＝7.4Hz)，7.20(2H，d，J＝7.4Hz)，7.16(1H，d，J＝2.4Hz)，7.02(1H，dd，J1＝8.4Hz，J2＝2.4Hz)，4.67(1H，s)，3.79-3.64(3H，m)，3.53-3.46(1H，m)，2.31-2.22(1H，m)，1.95-1.84(1H，m)，1.66-1.54(1H，m)；LC/MS：m/z＝448.13[M+H]+。Referring to the method of Example 1, using intermediates 1-5 as raw materials, compound 31 was prepared: 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.41 (1H, brs), 8.16 (1H, s), 7.65 ( 1H, d, J=8.5Hz), 7.48 (2H, t, J=8.7Hz), 7.42 (1H, s), 7.26 (1H, t, J=7.4Hz), 7.20 (2H, d, J=7.4 Hz), 7.16 (1H, d, J=2.4Hz), 7.02 (1H, dd, J1=8.4Hz, J2=2.4Hz), 4.67 (1H, s), 3.79-3.64 (3H, m), 3.53- 3.46 (1H,m), 2.31-2.22 (1H,m), 1.95-1.84 (1H,m), 1.66-1.54 (1H,m); LC/MS: m/z=448.13 [M+H] + .

实施例32制备(2-氯-4-苯氧基苯基)(4-(4-羟基哌啶-1-基)-7H-吡咯并[2,3-d]Example 32 Preparation of (2-chloro-4-phenoxyphenyl)(4-(4-hydroxypiperidin-1-yl)-7H-pyrrolo[2,3-d] 嘧啶-5-基)甲酮(化合物34)Pyrimidine-5-yl)methanone (Compound 34)

参照实施例1的方法，以中间体1-5为原料，制得化合物34：LC/MS：m/z＝448.13[M+H]+。Referring to the method of Example 1, using intermediates 1-5 as raw materials, compound 34 was prepared: LC/MS: m/z=448.13 [M+H] + .

实施例33制备(2-氯-4-苯氧基苯基)(4-(4-羟甲基)哌啶-1-基)-7H-吡咯并[2,3-Example 33 Preparation of (2-chloro-4-phenoxyphenyl)(4-(4-hydroxymethyl)piperidin-1-yl)-7H-pyrrolo[2,3- d]嘧啶-5-基)甲酮(化合物35)d]pyrimidin-5-yl)methanone (Compound 35)

参照实施例1的方法，以中间体1-5为原料，制得化合物35：LC/MS：m/z＝462.15[M+H]+。Referring to the method of Example 1, using intermediates 1-5 as raw materials, compound 35 was prepared: LC/MS: m/z=462.15 [M+H] + .

实施例34制备(2-氯-4-苯氧基苯基)(4-(3-羟基哌啶-1-基)-7H-吡咯并[2,3-d]Example 34 Preparation of (2-chloro-4-phenoxyphenyl)(4-(3-hydroxypiperidin-1-yl)-7H-pyrrolo[2,3-d] 嘧啶-5-基)甲酮(化合物38)Pyrimidin-5-yl)methanone (Compound 38)

参照实施例1的方法，以中间体1-5为原料，制得化合物38：1H NMR(400MHz，DMSO-d6)δ12.59(1H，brs)，8.28(1H，s)，7.61(1H，d，J＝8.4Hz)，7.57(1H，s)，7.48(2H，t，J＝8.7Hz)，7.26(1H，t，J＝7.4Hz)，7.19(2H，d，J＝7.5Hz)，7.16(1H，d，J＝2.4Hz)，7.03(1H，dd，J1＝8.4Hz，J2＝2.4Hz)，4.79(1H，s)，4.20(1H，d，J＝12.5Hz)，3.99(1H，d，J＝13.0Hz)，3.57-3.50(1H，m)，3.06-2.99(1H，m)，2.83-2.78(1H，m)，1.91-1.87(1H，m)，1.69-1.64(1H，m)，1.53-1.44(1H，m)，1.39-1.30(1H，m)；LC/MS：m/z＝448.12[M+H]+。Referring to the method of Example 1, using intermediates 1-5 as raw materials, compound 38 was prepared: 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.59 (1H, brs), 8.28 (1H, s), 7.61 ( 1H, d, J=8.4Hz), 7.57 (1H, s), 7.48 (2H, t, J=8.7Hz), 7.26 (1H, t, J=7.4Hz), 7.19 (2H, d, J=7.5 Hz), 7.16 (1H, d, J=2.4Hz), 7.03 (1H, dd, J1=8.4Hz, J2=2.4Hz), 4.79 (1H, s), 4.20 (1H, d, J=12.5Hz) , 3.99 (1H, d, J=13.0Hz), 3.57-3.50 (1H, m), 3.06-2.99 (1H, m), 2.83-2.78 (1H, m), 1.91-1.87 (1H, m), 1.69 -1.64 (1H, m), 1.53-1.44 (1H, m), 1.39-1.30 (1H, m); LC/MS: m/z=448.12 [M+H] + .

实施例35制备(2-氯-4-苯氧基苯基)(4-(3-(羟甲基)哌啶-1-基)-7H-吡咯并[2,Example 35 Preparation of (2-chloro-4-phenoxyphenyl)(4-(3-(hydroxymethyl)piperidin-1-yl)-7H-pyrrolo[2, 3-d]嘧啶-5-基)甲酮(化合物39)3-d]pyrimidin-5-yl)methanone (Compound 39)

参照实施例1的方法，以中间体1-5为原料，制得化合物39：1H NMR(300MHz，DMSO-d6)δ12.52(1H，brs)，8.28(1H，s)，7.59(1H，d，J＝8.5Hz)，7.55(1H，s)，7.48(2H，t，J＝8.7Hz)，7.26(1H，t，J＝7.4Hz)，7.19(2H，d，J＝7.4Hz)，7.16(1H，d，J＝2.4Hz)，7.02(1H，dd，J1＝8.4Hz，J2＝2.4Hz)，4.48(1H，s)，4.27-4.15(2H，m)，3.27-3.23(2H，m)，2.96-2.69(2H，m)，1.76-1.13(4H，m)；LC/MS：m/z＝462.15[M+H]+。Referring to the method of Example 1, using intermediates 1-5 as raw materials, compound 39 was prepared: 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.52 (1H, brs), 8.28 (1H, s), 7.59 ( 1H, d, J=8.5Hz), 7.55 (1H, s), 7.48 (2H, t, J=8.7Hz), 7.26 (1H, t, J=7.4Hz), 7.19 (2H, d, J=7.4 Hz), 7.16 (1H, d, J=2.4Hz), 7.02 (1H, dd, J1=8.4Hz, J2=2.4Hz), 4.48 (1H, s), 4.27-4.15 (2H, m), 3.27- 3.23 (2H, m), 2.96-2.69 (2H, m), 1.76-1.13 (4H, m); LC/MS: m/z=462.15 [M+H] + .

实施例36制备叔丁基(1-(5-(2-氯-4-苯氧基苯甲酰基)-7H-吡咯并[2,3-d]嘧啶-Example 36 Preparation of tert-butyl(1-(5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-基)吡咯烷酮-3-基)氨基甲酸酯(化合物32)4-yl)pyrrolidone-3-yl)carbamate (Compound 32)

参照实施例1的方法，以中间体1-5为原料，制得化合物32：1H NMR(300MHz，DMSO-d6)δ12.49(1H，brs)，8.18(1H，s)，7.63(1H，d，J＝8.6Hz)，7.49(2H，t，J＝7.8Hz)，7.42(1H，s)，7.26(1H，t，J＝7.3Hz)，7.19(2H，d，J＝7.9Hz)，7.16(1H，d，J＝2.4Hz)，7.14-7.11(1H，m)，7.02(1H，dd，J1＝8.4Hz，J2＝2.5Hz)，3.95-3.55(5H，m)，2.08-1.75(2H，m)，1.34(9H，s)；LC/MS：m/z＝533.18[M+H]+。Referring to the method of Example 1, using intermediates 1-5 as raw materials, compound 32 was prepared: 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.49 (1H, brs), 8.18 (1H, s), 7.63 ( 1H, d, J=8.6Hz), 7.49 (2H, t, J=7.8Hz), 7.42 (1H, s), 7.26 (1H, t, J=7.3Hz), 7.19 (2H, d, J=7.9 Hz), 7.16 (1H, d, J=2.4Hz), 7.14-7.11 (1H, m), 7.02 (1H, dd, J1=8.4Hz, J2=2.5Hz), 3.95-3.55 (5H, m), 2.08-1.75 (2H, m), 1.34 (9H, s); LC/MS: m/z=533.18 [M+H] + .

实施例37制备(4-(3-氨基吡咯烷-1-基)-7H-吡咯并[2,3-d]嘧啶-5-基)(2-氯-4-Example 37 Preparation of (4-(3-aminopyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4- 苯氧基苯基)甲酮(化合物33)Phenoxyphenyl)methanone (Compound 33)

Figure BDA0003367826790000361
Figure BDA0003367826790000361

向反应瓶中加入化合物32(50mg，0.094mmol)，盐酸/1,4-二氧六环(5mL)，室温搅拌反应1小时，TLC显示反应完全，减压浓缩，加水(5mL)，用饱和碳酸氢钠溶液调节pH至8，固体析出，过滤，干燥得到35mg白色固体产物18，收率：86.15％。Compound 32 (50 mg, 0.094 mmol), hydrochloric acid/1,4-dioxane (5 mL) was added to the reaction flask, the reaction was stirred at room temperature for 1 hour, TLC showed that the reaction was complete, concentrated under reduced pressure, added water (5 mL), saturated with The sodium bicarbonate solution was adjusted to pH 8, the solid was precipitated, filtered and dried to obtain 35 mg of white solid product 18, yield: 86.15%.

LC/MS：m/z＝433.13[M+H]+。LC/MS: m/z=433.13 [M+H] + .

实施例38制备叔丁基(1-(5-(2-氯-4-苯氧基苯甲酰基)-7H-吡咯并[2,3-d]嘧啶-Example 38 Preparation of tert-butyl(1-(5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-基)哌啶-4-基)氨基甲酸酯(化合物36)4-yl)piperidin-4-yl)carbamate (Compound 36)

参照实施例1的方法，以中间体1-5为原料，制得化合物36：LC/MS：m/z＝547.20[M+H]+。Referring to the method of Example 1, using intermediates 1-5 as raw materials, compound 36 was prepared: LC/MS: m/z=547.20 [M+H] + .

实施例39制备(4-(4-氨基哌啶-1-基)-7H-吡咯并[2,3-d]嘧啶-5-基)(2-氯-4-苯Example 39 Preparation of (4-(4-aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-benzene 氧基苯基)甲酮(化合物37)Oxyphenyl)methanone (Compound 37)

参照实施例37的方法，以化合物36为原料，制得化合物37：LC/MS：m/z＝447.16[M+H]+。Referring to the method of Example 37, using compound 36 as a raw material, compound 37 was prepared: LC/MS: m/z=447.16 [M+H] + .

实施例40制备叔丁基(1-(5-(2-氯-4-苯氧基苯甲酰基)-7H-吡咯并[2,3-d]嘧啶-Example 40 Preparation of tert-butyl(1-(5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-基)哌啶-3-基)氨基甲酸酯(化合物40)4-yl)piperidin-3-yl)carbamate (Compound 40)

参照实施例1的方法，以中间体1-5为原料，制得化合物40：LC/MS：m/z＝547.20[M+H]+。Referring to the method of Example 1, using intermediates 1-5 as raw materials, compound 40 was prepared: LC/MS: m/z=547.20 [M+H] + .

实施例41制备(4-(3-氨基哌啶-1-基)-7H-吡咯并[2,3-d]嘧啶-5-基)(2-氯-4-苯Example 41 Preparation of (4-(3-aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-benzene 氧基苯基)甲酮(化合物41)Oxyphenyl)methanone (Compound 41)

参照实施例37的方法，以化合物40为原料，制得化合物41：LC/MS：m/z＝447.16[M+H]+。Referring to the method of Example 37, using compound 40 as a raw material, compound 41 was prepared: LC/MS: m/z=447.16 [M+H] + .

生物活性测试Biological activity test

(一)化合物进行体外细胞增殖(SU-DHL-4)抑制活性的测定(1) Determination of in vitro cell proliferation (SU-DHL-4) inhibitory activity of compounds

1：细胞系1: Cell Lines

表2为进行体外细胞增殖的细胞系信息Table 2 provides cell line information for in vitro cell proliferation

细胞系cell line 细胞类型cell type 细胞数量/孔Number of cells/well 培养基culture medium SU-DHL-4SU-DHL-4 悬浮Suspended 1000010000 RPMI-1640+10％FBSRPMI-1640+10%FBS

置于37℃、5％CO2、95％湿度条件下培养。Incubate at 37°C, 5% CO 2 , and 95% humidity.

2：化合物配制2: Compound preparation

待测化合物分别用DMSO稀释配成终浓度为10mM母液备用。The compounds to be tested were diluted with DMSO to prepare a stock solution with a final concentration of 10 mM.

3：细胞培养和接种3: Cell Culture and Seeding

(1)收获处于对数生长期的细胞并采用细胞计数仪进行细胞计数。用台盼蓝排斥法检测细胞活力，确保细胞活力在90％以上；(1) Cells in logarithmic growth phase were harvested and counted using a cell counter. Cell viability was detected by trypan blue exclusion method to ensure cell viability was above 90%;

(2)调整细胞浓度：分别添加50μL细胞悬浮液至96孔板中；(2) Adjust the cell concentration: add 50 μL of cell suspension to the 96-well plate respectively;

(3)将96孔板中的细胞置于37℃、5％CO2、95％湿度条件下培养过夜。(3) The cells in the 96-well plate were cultured overnight at 37° C., 5% CO 2 , and 95% humidity.

4：药物稀释和加药4: Drug dilution and dosing

(1)配制浓度为5μM和0.5μM的药物溶液，在接种的96孔板中每孔加入50μL相应浓度的药物溶液，每个药物浓度设置三个复孔，对照组DMSO浓度为0.2％。(1) Prepare drug solutions with concentrations of 5 μM and 0.5 μM, add 50 μL of drug solutions of corresponding concentrations to each well of the inoculated 96-well plate, and set up three duplicate wells for each drug concentration. The concentration of DMSO in the control group is 0.2%.

(2)将已加药的96孔板中的细胞置于37℃、5％CO2、95％湿度条件下继续培养72小时。(2) The cells in the medicated 96-well plate were placed under the conditions of 37° C., 5% CO 2 , and 95% humidity for further cultivation for 72 hours.

5：CCK-8活力检测5: CCK-8 Viability Detection

给药后培养72小时后，每孔加入10μL CCK-8溶液和10μL RPMI-1640培养基，后将96孔板放置于培养箱中，继续培养2小时后取出。After culturing for 72 hours after administration, 10 μL of CCK-8 solution and 10 μL of RPMI-1640 medium were added to each well, and then the 96-well plate was placed in an incubator and taken out after culturing for 2 hours.

6：测吸光度并计算抑制率6: Measure the absorbance and calculate the inhibition rate

将96孔板置于酶标仪中，检测波长为450nm处的吸光值。以每3个复孔吸光度的平均值计算其相对抑制率。每组样品要做3次平行实验。The 96-well plate was placed in a microplate reader, and the absorbance at a wavelength of 450 nm was detected. The relative inhibition rate was calculated as the average value of the absorbance of each 3 replicate wells. Three parallel experiments were performed for each group of samples.

450nm读数，计算细胞存活率，根据结果计算抑制率，结果如下表3。450nm reading, calculate the cell viability, calculate the inhibition rate according to the results, the results are shown in Table 3 below.

表3.本发明部分化合物对SU-DHL-4细胞增殖抑制活性Table 3. Inhibitory activity of some compounds of the present invention on SU-DHL-4 cell proliferation

Figure BDA0003367826790000381
Figure BDA0003367826790000381

Figure BDA0003367826790000391
Figure BDA0003367826790000391

(二)体外BTK激酶抑制活性试验(2) In vitro BTK kinase inhibitory activity test

1：化合物配制1: Compound preparation

将化合物粉末溶解在100％DMSO中，配制成10mM储存液。于-20℃避光冻存。Compound powders were dissolved in 100% DMSO to make 10 mM stock solutions. Store frozen at -20°C in the dark.

2：激酶反应过程2: Kinase reaction process

(1)配制4X kinase buffer和1X kinase buffer；(1) Prepare 4X kinase buffer and 1X kinase buffer;

(2)化合物的配制：受测试的化合物浓度为50μM，率先稀释成100倍终浓度的100％DMSO溶液，利用4X kinase buffer稀释成5倍终浓度的5％DMSO溶液，分液器转移1μL到384孔板，每个化合物两复孔；(2) Compound preparation: The concentration of the tested compound is 50 μM, firstly diluted to 100 times the final concentration of 100% DMSO solution, and then diluted to 5 times the final concentration of 5% DMSO solution with 4X kinase buffer, and the dispenser transfers 1 μL to 384-well plate, two duplicate wells per compound;

(3)利用4X kinase buffer配制2.5倍终浓度的激酶溶液；(3) Use 4X kinase buffer to prepare 2.5 times the final concentration of kinase solution;

(4)在化合物和阳性对照孔加入2μL的2.5倍终浓度的激酶溶液，阴性对照孔加入3μL的1X kinase buffer；(4) Add 2 μL of 2.5 times final concentration of kinase solution to compound and positive control wells, and add 3 μL of 1X kinase buffer to negative control wells;

(5)反应板震荡混匀后室温孵育10分钟；(5) Incubate at room temperature for 10 minutes after the reaction plate is shaken and mixed;

(6)利用4X kinase buffer配制2.5倍终浓度的ATP和Kinase substrate的混合溶液；(6) Use 4X kinase buffer to prepare a mixed solution of 2.5 times the final concentration of ATP and Kinase substrate;

(7)加入2μL的ATP和Kinase substrate的混合溶液，起始反应；(7) Add 2 μL of a mixed solution of ATP and Kinase substrate to initiate the reaction;

(8)震荡混匀后室温孵育60分钟；(8) Incubate at room temperature for 60 minutes after shaking and mixing;

(9)加入5μL ADP-Glo试剂，震荡混匀，终止反应，并室温孵育60min消耗残余的ATP；(9) Add 5 μL of ADP-Glo reagent, shake and mix to stop the reaction, and incubate at room temperature for 60 minutes to consume residual ATP;

(10)加入10μLkinase detection reagent，震荡混匀，室温孵育40min；(10) Add 10 μL kinase detection reagent, shake and mix, and incubate at room temperature for 40 minutes;

(11)用酶标仪读取数据，计算抑制率。(11) Read the data with a microplate reader and calculate the inhibition rate.

3：数据分析3: Data Analysis

计算公式：Calculation formula:

Figure BDA0003367826790000401
Figure BDA0003367826790000401

其中：Conversion％_sample是样品的转化率读数；Conversion％_min：阴性对照孔均值，代表没有酶活孔的转化率读数；Conversion％_max：阴性对照孔比值均值，代表没有化合物抑制孔的转化率读数。结果如下表4。Where: Conversion%_sample is the conversion rate reading of the sample; Conversion%_min: the mean value of the negative control wells, representing the conversion rate readings of the wells without enzymatic activity; Conversion%_max: the mean ratio of the negative control wells, representing the conversion rate readings of the wells without compound inhibition . The results are shown in Table 4 below.

表4.本发明部分化合物对BTK激酶抑制活性Table 4. BTK kinase inhibitory activity of some compounds of the present invention

Figure BDA0003367826790000402
Figure BDA0003367826790000402

Figure BDA0003367826790000411
Figure BDA0003367826790000411

由以上实施例可知，本发明作为BTK蛋白激酶抑制剂的部分化合物对BTK激酶有很强的抑制作用，细胞活性和激酶活性可观，可用于制备治疗BTK激酶过度表达所致疾病的药物。It can be seen from the above examples that some compounds of the present invention as BTK protein kinase inhibitors have a strong inhibitory effect on BTK kinase with considerable cellular activity and kinase activity, and can be used to prepare medicines for treating diseases caused by overexpression of BTK kinase.

尽管已经示出了和描述了本发明的实施例，对于本领域的普通技术人员而言，可以理解在不脱离本发明的原理和精神的情况下可以对这些实施例进行多种变化、修改、替换和变型，本发明的范围由所附权利要求及其等同物限定。Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, Alternatives and modifications, the scope of the invention is defined by the appended claims and their equivalents.

Claims (12)

1.一种如式Ⅰ所示的化合物：1. A compound of formula I:
Figure FDA0003367826780000011
Figure FDA0003367826780000011
 或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，其中：or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein: X1为O或S；X 1 is O or S; X2为O，S或NH；X 2 is O, S or NH; Ra、Rb独立地选自：氢、卤素、腈基、硝基、羟基、羧基、取代或未取代的C1-6酰基、取代或未取代的氨基、取代或未取代的C1-6烷基、取代或未取代的C1-6烷氧基，可以为单、双或多取代；所述C1-6酰基酰基、氨基、C1-6烷基、C1-6烷氧基的取代是指被下列一个或多个取代基所取代：C1-5烷基、C2-5烯基、C2-5炔基、C1-5烷氧基、卤素、硝基、氰基、羟基、氨基、羧基和氧代；R a , R b are independently selected from: hydrogen, halogen, nitrile, nitro, hydroxyl, carboxyl, substituted or unsubstituted C 1-6 acyl, substituted or unsubstituted amino, substituted or unsubstituted C 1- 6 alkyl, substituted or unsubstituted C 1-6 alkoxy, which can be mono-, di- or polysubstituted; the C 1-6 acyl acyl, amino, C 1-6 alkyl, C 1-6 alkoxy Substitution of radicals refers to substitution by one or more of the following substituents: C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 1-5 alkoxy, halogen, nitro, cyano, hydroxyl, amino, carboxyl and oxo; X3为CH或N；X 3 is CH or N; X4为O，S，CHRd或NRe；X 4 is O, S, CHR d or NR e ; X5为O，NH，S，CH2，CHRd或NRe；X 5 is O, NH, S, CH 2 , CHR d or NR e ; Rc可以相同或不同，各自独立地为-(CH2)fNR1R2，R1-S(＝O)g-，R1-S(＝O)gO-，R1-OS(＝O)g-，R1-C(＝O)-，R1-C(＝O)O(CH2)f-，R1-(CH2)f OC(＝O)-，R1-(CH2)fN(R1)C(＝O)-，R1-(CH2)f C(＝O)N(R1)-，R1-(CH2)f OC(＝O)N(R1)-，醚烷基，羟基取代的烷基，氢，氧代(＝O)，氟，氯，溴，碘，羟基，烷基，卤代烷基，杂烷基，烷氧基，烷氨基，烯基，炔基，环烷基，杂环基，卤代杂环基，氨基，硝基，羧基,氰基，芳基，卤代芳基，杂芳基，卤代杂芳基，芳基烷基，杂芳基烷基，氨基磺酰基，氨基甲酰基，芳基氨基，杂芳基氨基，芳基烷氨基，杂芳基烷氨基，杂环基氨基，杂环基烷氨基，芳基氧基，杂芳基氧基，杂芳基氧基，芳基烷氧基，杂芳基烷氧基，杂环基氧基或杂环基烷氧基；R c may be the same or different, and are each independently -(CH2) f NR 1 R 2 , R 1 -S(=O) g -, R 1 -S(=O) g O-, R 1 -OS(= O) g -, R 1 -C(=O)-, R 1 -C(=O)O(CH 2 ) f -, R 1 -(CH 2 ) f OC(=O)-, R 1 -( CH 2 ) f N(R 1 )C(=O)-, R 1 -(CH 2 ) f C(=O)N(R 1 )-, R 1 -(CH 2 ) f OC(=O)N (R 1 )-, ether alkyl, hydroxy substituted alkyl, hydrogen, oxo(=O), fluoro, chloro, bromo, iodo, hydroxy, alkyl, haloalkyl, heteroalkyl, alkoxy, alkane amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, haloheterocyclyl, amino, nitro, carboxyl, cyano, aryl, haloaryl, heteroaryl, haloheteroaryl, Arylalkyl, heteroarylalkyl, aminosulfonyl, carbamoyl, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heterocyclylamino, heterocyclylalkylamino, Aryloxy, heteroaryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy, heterocyclyloxy or heterocyclylalkoxy; Rd为-(CH2)fNR1R2，R1-S(＝O)g-，R1-S(＝O)gO-，R1-OS(＝O)g-，R1-C(＝O)-，R1-C(＝O)O(CH2)f-，R1-(CH2)f OC(＝O)-，R1-(CH2)f N(H)C(＝O)-，R1-(CH2)fC(＝O)N(R1)-，R1-(CH2)fOC(＝O)N(R1)-，醚烷基，羟基取代的烷基，氢，氧代(＝O)，氟，氯，溴，碘，羟基，烷基，卤代烷基，杂烷基，烷氧基，烷氨基，烯基，炔基，环烷基，杂环基，卤代杂环基，氨基，硝基，羧基，氰基，芳基，卤代芳基，杂芳基，卤代杂芳基，芳基烷基，杂芳基烷基，氨基磺酰基，氨基甲酰基，芳基氨基，杂芳基氨基，芳基烷氨基，杂芳基烷氨基，杂环基氨基，杂环基烷氨基，芳基氧基，杂芳基氧基，杂芳基氧基，芳基烷氧基，杂芳基烷氧基，杂环基氧基或杂环基烷氧基；R d is -(CH2) f NR 1 R 2 , R 1 -S(=O) g -, R 1 -S(=O) g O-, R 1 -OS(=O) g -, R 1 - C(=O)-, R 1 -C(=O)O(CH 2 ) f -, R 1 -(CH 2 ) f OC(=O)-, R 1 -(CH 2 ) f N(H) C(=O)-, R 1 -(CH 2 ) f C(=O)N(R 1 )-, R 1 -(CH 2 ) f OC(=O)N(R 1 )-, ether alkyl , hydroxy-substituted alkyl, hydrogen, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxy, alkyl, haloalkyl, heteroalkyl, alkoxy, alkylamino, alkenyl, alkynyl, ring Alkyl, Heterocyclyl, Haloheterocyclyl, Amino, Nitro, Carboxyl, Cyano, Aryl, Haloaryl, Heteroaryl, Haloheteroaryl, Arylalkyl, Heteroarylalkane group, aminosulfonyl, carbamoyl, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heterocyclylamino, heterocyclylalkylamino, aryloxy, heteroaryloxy group, heteroaryloxy, arylalkoxy, heteroarylalkoxy, heterocyclyloxy or heterocyclylalkoxy; Re为-(CH2)fNR1R2，R1-S(＝O)g-，R1-S(＝O)gO-，R1-OS(＝O)g-，R1-C(＝O)-，R1-C(＝O)O(CH2)f-，R1-(CH2)f OC(＝O)-，R1-(CH2)fN(H)C(＝O)-，R1-(CH2)fC(＝O)N(R1)-，R1-(CH2)f OC(＝O)N(R1)-，醚烷基，羟基取代的烷基，氢，氧代(＝O)，氟，氯，溴，碘，羟基，烷基，卤代烷基，杂烷基，烷氧基，烷氨基，烯基，炔基，环烷基，杂环基，卤代杂环基，氨基，硝基，羧基，氰基，芳基，卤代芳基，杂芳基，卤代杂芳基，芳基烷基，杂芳基烷基，氨基磺酰基，氨基甲酰基，芳基氨基，杂芳基氨基，芳基烷氨基，杂芳基烷氨基，杂环基氨基，杂环基烷氨基，芳基氧基，杂芳基氧基，杂芳基氧基，芳基烷氧基，杂芳基烷氧基，杂环基氧基或杂环基烷氧基； Re is -(CH2) f NR 1 R 2 , R 1 -S(=O) g -, R 1 -S(=O) g O-, R 1 -OS(=O) g -, R 1 - C(=O)-, R 1 -C(=O)O(CH 2 ) f -, R 1 -(CH 2 ) f OC(=O)-, R 1 -(CH 2 ) f N(H) C(=O)-, R 1 -(CH 2 ) f C(=O)N(R 1 )-, R 1 -(CH 2 ) f OC(=O)N(R 1 )-, ether alkyl , hydroxy-substituted alkyl, hydrogen, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxy, alkyl, haloalkyl, heteroalkyl, alkoxy, alkylamino, alkenyl, alkynyl, ring Alkyl, Heterocyclyl, Haloheterocyclyl, Amino, Nitro, Carboxyl, Cyano, Aryl, Haloaryl, Heteroaryl, Haloheteroaryl, Arylalkyl, Heteroarylalkane group, aminosulfonyl, carbamoyl, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heterocyclylamino, heterocyclylalkylamino, aryloxy, heteroaryloxy group, heteroaryloxy, arylalkoxy, heteroarylalkoxy, heterocyclyloxy or heterocyclylalkoxy; 各R1和R2独立地为氢，烷基，环烷基，芳基烷基，杂芳基烷基，卤代烷基，杂环基，芳基或杂芳基；Each R1 and R2 is independently hydrogen , alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, haloalkyl, heterocyclyl, aryl or heteroaryl; 各g独立地为0，1或2；each g is independently 0, 1 or 2; 各n，m，f独立地为0，1，2，3，4或5；each of n, m, f is independently 0, 1, 2, 3, 4 or 5; 当n＝2时，且两个Rc连在同一碳原子上，那么两个Rc与之相连的碳原子一起可形成3-8元杂环。When n=2, and the two R c are attached to the same carbon atom, then the two R c and the carbon atom to which they are attached together can form a 3-8 membered heterocycle. 2.根据权利要求1所述的化合物，或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，其中：2. The compound of claim 1, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or pro- medicine, which: X1为O或S；X 1 is O or S; X2为O，S或NH；X 2 is O, S or NH; Ra、Rb独立地选自：氢、卤素、腈基、硝基、羟基、羧基，可以为单、双或多取代；R a and R b are independently selected from: hydrogen, halogen, nitrile, nitro, hydroxyl, and carboxyl, which can be mono-, di- or polysubstituted; 其中，
Figure FDA0003367826780000031
结构单元选自以下子结构：in,
Figure FDA0003367826780000031
Structural units are selected from the following substructures:
Figure FDA0003367826780000032
Figure FDA0003367826780000032
 其中，in, X5为O，NH，S，CH2，CHRd或NRe；X 5 is O, NH, S, CH 2 , CHR d or NR e ; R3可以相同或不同，各自独立地为-(CH2)fNR1R2，R1-S(＝O)g-，R1-S(＝O)gO-，R1-OS(＝O)g-，R1-C(＝O)-，R1-C(＝O)O(CH2)f-，R1-(CH2)fOC(＝O)-，R1-(CH2)fN(H)C(＝O)-，R1-(CH2)fC(＝O)N(R1)-，R1-(CH2)fOC(＝O)N(R1)-，C2-10醚烷基，羟基取代的C1-10烷基，氟，氯，溴，碘，C1-6烷基，C1-6卤代烷基，C1-6烷氨基，C1-6杂烷基，C1-6烷氧基，C1-6烷氨基，C2-6烯基，C2-6炔基，C3-8环烷基，C2-10杂环基，C2-10卤代杂环基，氨基，硝基，羧基，氰基，C6-10芳基，C6-10卤代芳基，C1-9杂芳基，C1-9卤代杂芳基，C6-10芳基C1-6烷基，C1-9杂芳基C1-6烷基，氨基磺酰基，氨基甲酰基，C6-10芳基氨基，C1-9杂芳基氨基，C6-10芳基C1-6烷氨基，C1-9杂芳基氨基，C6-10芳基C1-6烷氨基，C1-9杂芳基C1-6烷氨基，C2-10杂环基氨基，C2-10杂环基C1-6烷氨基，C6-10芳基氧基，C1-9杂芳基氧基，C6-10芳基C1-6烷氧基，C1-9杂芳基C1-6烷氧基，C2-10杂环基氧基或C2-10杂环基C1-6烷氧基；R 3 may be the same or different, and each independently is -(CH2) f NR 1 R 2 , R 1 -S(=O) g -, R 1 -S(=O) g O-, R 1 -OS(= O) g -, R 1 -C(=O)-, R 1 -C(=O)O(CH 2 ) f -, R 1 -(CH 2 ) f OC(=O)-, R 1 -( CH 2 ) f N(H)C(=O)-, R 1 -(CH 2 ) f C(=O)N(R 1 )-, R 1 -(CH 2 ) f OC(=O)N( R 1 )-, C 2-10 ether alkyl, hydroxy substituted C 1-10 alkyl, fluorine, chlorine, bromine, iodine, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkane Amino, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 2- 10 heterocyclyl, C 2-10 haloheterocyclyl, amino, nitro, carboxyl, cyano, C 6-10 aryl, C 6-10 haloaryl, C 1-9 heteroaryl, C 1-9 haloheteroaryl, C 6-10 aryl C 1-6 alkyl, C 1-9 heteroaryl C 1-6 alkyl, aminosulfonyl, carbamoyl, C 6-10 aryl Amino, C 1-9 Heteroarylamino, C 6-10 Aryl, C 1-6 Alkylamino, C 1-9 Heteroarylamino, C 6-10 Aryl, C 1-6 Alkylamino, C 1-9 Heteroaryl C 1-6 alkylamino, C 2-10 heterocyclylamino, C 2-10 heterocyclyl C 1-6 alkylamino, C 6-10 aryloxy, C 1-9 heteroaryloxy base, C 6-10 aryl C 1-6 alkoxy, C 1-9 heteroaryl C 1-6 alkoxy, C 2-10 heterocyclyloxy or C 2-10 heterocyclyl C 1 -6 alkoxy; R4可以相同或不同，各自独立地为-(CH2)fNR1R2，R1-S(＝O)g-，R1-S(＝O)gO-，R1-OS(＝O)g-，R1-C(＝O)-，R1-C(＝O)O(CH2)f-，R1-(CH2)f OC(＝O)-，R1-(CH2)fN(H)C(＝O)-，R1-(CH2)f C(＝O)N(R1)-，R1-(CH2)fOC(＝O)N(R1)-，C2-10醚烷基，羟基取代的C1-10烷基，氟，氯，溴，碘，C1-6烷基，C1-6卤代烷基，C1-6烷氨基，C1-6杂烷基，C1-6烷氧基，C1-6烷氨基，C2-6烯基，C2-6炔基，C3-8环烷基，C2-10杂环基，C2-10卤代杂环基，氨基，硝基，羧基，氰基，C6-10芳基，C6-10卤代芳基，C1-9杂芳基，C1-9卤代杂芳基，C6-10芳基C1-6烷基，C1-9杂芳基C1-6烷基，氨基磺酰基，氨基甲酰基，C6-10芳基氨基，C1-9杂芳基氨基，C6-10芳基C1-6烷氨基，C1-9杂芳基氨基，C6-10芳基C1-6烷氨基，C1-9杂芳基C1-6烷氨基，C2-10杂环基氨基，C2-10杂环基C1-6烷氨基，C6-10芳基氧基，C1-9杂芳基氧基，C6-10芳基C1-6烷氧基，C1-9杂芳基C1-6烷氧基，C2-10杂环基氧基或C2-10杂环基C1-6烷氧基；R 4 may be the same or different, and each independently is -(CH2) f NR 1 R 2 , R 1 -S(=O) g -, R 1 -S(=O) g O-, R 1 -OS(= O) g -, R 1 -C(=O)-, R 1 -C(=O)O(CH 2 ) f -, R 1 -(CH 2 ) f OC(=O)-, R 1 -( CH 2 ) f N(H)C(=O)-, R 1 -(CH 2 ) f C(=O)N(R 1 )-, R 1 -(CH 2 ) f OC(=O)N( R 1 )-, C 2-10 ether alkyl, hydroxy substituted C 1-10 alkyl, fluorine, chlorine, bromine, iodine, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkane Amino, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 2- 10 heterocyclyl, C 2-10 haloheterocyclyl, amino, nitro, carboxyl, cyano, C 6-10 aryl, C 6-10 haloaryl, C 1-9 heteroaryl, C 1-9 haloheteroaryl, C 6-10 aryl C 1-6 alkyl, C 1-9 heteroaryl C 1-6 alkyl, aminosulfonyl, carbamoyl, C 6-10 aryl Amino, C 1-9 Heteroarylamino, C 6-10 Aryl, C 1-6 Alkylamino, C 1-9 Heteroarylamino, C 6-10 Aryl, C 1-6 Alkylamino, C 1-9 Heteroaryl C 1-6 alkylamino, C 2-10 heterocyclylamino, C 2-10 heterocyclyl C 1-6 alkylamino, C 6-10 aryloxy, C 1-9 heteroaryloxy base, C 6-10 aryl C 1-6 alkoxy, C 1-9 heteroaryl C 1-6 alkoxy, C 2-10 heterocyclyloxy or C 2-10 heterocyclyl C 1 -6 alkoxy; Rd为-(CH2)fNR1R2，R1-S(＝O)g-，R1-S(＝O)gO-，R1-OS(＝O)g-，R1-C(＝O)-，R1-C(＝O)O(CH2)f-，R1-(CH2)f OC(＝O)-，R1-(CH2)fN(H)C(＝O)-，R1-(CH2)fC(＝O)N(R1)-，R1-(CH2)f OC(＝O)N(R1)-，C2-10醚烷基，羟基取代的C1-10烷基，氟，氯，溴，碘，C1-6烷基，C1-6卤代烷基，C1-6烷氨基，C1-6杂烷基，C1-6烷氧基，C1-6烷氨基，C2-6烯基，C2-6炔基，C3-8环烷基，C2-10杂环基，C2-10卤代杂环基，氨基，硝基，羧基，氰基，C6-10芳基，C6-10卤代芳基，C1-9杂芳基，C1-9卤代杂芳基，C6-10芳基C1-6烷基，C1-9杂芳基C1-6烷基，氨基磺酰基，氨基甲酰基，C6-10芳基氨基，C1-9杂芳基氨基，C6-10芳基C1-6烷氨基，C1-9杂芳基氨基，C6-10芳基C1-6烷氨基，C1-9杂芳基C1-6烷氨基，C2-10杂环基氨基，C2-10杂环基C1-6烷氨基，C6-10芳基氧基，C1-9杂芳基氧基，C6-10芳基C1-6烷氧基，C1-9杂芳基C1-6烷氧基，C2-10杂环基氧基或C2-10杂环基C1-6烷氧基；R d is -(CH2) f NR 1 R 2 , R 1 -S(=O) g -, R 1 -S(=O) g O-, R 1 -OS(=O) g -, R 1 - C(=O)-, R 1 -C(=O)O(CH 2 ) f -, R 1 -(CH 2 ) f OC(=O)-, R 1 -(CH 2 ) f N(H) C(=O)-, R 1 -(CH 2 ) f C(=O)N(R 1 )-, R 1 -(CH 2 ) f OC(=O)N(R 1 )-, C 2- 10 ether alkyl, hydroxy substituted C 1-10 alkyl, fluorine, chlorine, bromine, iodine, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylamino, C 1-6 heteroalkane base, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 2-10 heterocyclyl, C 2- 10 halogenated heterocyclyl, amino, nitro, carboxyl, cyano, C6-10 aryl, C6-10 halogenated aryl, C1-9 heteroaryl, C1-9 halogenated heteroaryl , C 6-10 aryl C 1-6 alkyl, C 1-9 heteroaryl C 1-6 alkyl, aminosulfonyl, carbamoyl, C 6-10 arylamino, C 1-9 heteroaryl base amino, C 6-10 aryl C 1-6 alkylamino, C 1-9 heteroarylamino, C 6-10 aryl C 1-6 alkylamino, C 1-9 heteroaryl C 1-6 alkyl Amino, C 2-10 heterocyclylamino, C 2-10 heterocyclyl, C 1-6 alkylamino, C 6-10 aryloxy, C 1-9 heteroaryloxy, C 6-10 aryl C 1-6 alkoxy, C 1-9 heteroaryl C 1-6 alkoxy, C 2-10 heterocyclyloxy or C 2-10 heterocyclyl C 1-6 alkoxy; Re为-(CH2)fNR1R2，R1-S(＝O)g-，R1-S(＝O)gO-，R1-OS(＝O)g-，R1-C(＝O)-，R1-C(＝O)O(CH2)f-，R1-(CH2)f OC(＝O)-，R1-(CH2)f N(H)C(＝O)-，R1-(CH2)fC(＝O)N(R1)-，R1-(CH2)fOC(＝O)N(R1)-，C2-10醚烷基，羟基取代的C1-10烷基，氟，氯，溴，碘，C1-6烷基，C1-6卤代烷基，C1-6杂烷基，C1-6烷氧基，C1-6烷氨基，C2-6烯基，C2-6炔基，C3-8环烷基，C2-10杂环基C2-10卤代杂环基，氨基，硝基，羧基，氰基，C6-10芳基，C6-10卤代芳基，C1-9杂芳基，C1-9卤代杂芳基，C6-10芳基C1-6烷基，C1-9杂芳基C1-6烷基，氨基磺酰基，氨基甲酰基，C6-10芳基氨基，C1-9杂芳基氨基，C6-10芳基C1-6烷氨基，C1-9杂芳基氨基，C6-10芳基C1-6烷氨基，C1-9杂芳基C1-6烷氨基，C2-10杂环基氨基，C2-10杂环基C1-6烷氨基，C6-10芳基氧基，C1-9杂芳基氧基，C6-10芳基C1-6烷氧基，C1-9杂芳基C1-6烷氧基，C2-10杂环基氧基或C2-10杂环基C1-6烷氧基； Re is -(CH2) f NR 1 R 2 , R 1 -S(=O) g -, R 1 -S(=O) g O-, R 1 -OS(=O) g -, R 1 - C(=O)-, R 1 -C(=O)O(CH 2 ) f -, R 1 -(CH 2 ) f OC(=O)-, R 1 -(CH 2 ) f N(H) C(=O)-, R 1 -(CH 2 ) f C(=O)N(R 1 )-, R 1 -(CH 2 ) f OC(=O)N(R 1 )-, C 2- 10 ether alkyl, hydroxy substituted C 1-10 alkyl, fluorine, chlorine, bromine, iodine, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 1-6 alkane Oxy group, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 2-10 heterocyclyl, C 2-10 haloheterocyclyl, amino , nitro, carboxyl, cyano, C 6-10 aryl, C 6-10 haloaryl, C 1-9 heteroaryl, C 1-9 haloheteroaryl, C 6-10 aryl C 1-6 alkyl, C 1-9 heteroaryl C 1-6 alkyl, aminosulfonyl, carbamoyl, C 6-10 arylamino, C 1-9 heteroarylamino, C 6-10 aryl base C 1-6 alkylamino, C 1-9 heteroarylamino, C 6-10 aryl C 1-6 alkylamino, C 1-9 heteroaryl C 1-6 alkylamino, C 2-10 heterocycle base amino, C 2-10 heterocyclyl C 1-6 alkylamino, C 6-10 aryloxy, C 1-9 heteroaryloxy, C 6-10 aryl C 1-6 alkoxy, C 1-9 heteroaryl C 1-6 alkoxy, C 2-10 heterocyclyloxy or C 2-10 heterocyclyl C 1-6 alkoxy; 各R1和R2独立地为氢，C1-6烷基，C3-8环烷基，C6-10芳基C1-6烷基，C1-9杂芳基C1-6烷基，卤代C1-6烷基，C2-10杂环基，C6-10芳基或C1-9杂芳基；Each R 1 and R 2 is independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl C 1-6 alkyl, C 1-9 heteroaryl C 1-6 Alkyl, halogenated C 1-6 alkyl, C 2-10 heterocyclyl, C 6-10 aryl or C 1-9 heteroaryl; 各g独立地为0，1或2；each g is independently 0, 1 or 2; 各n，m，f独立地为0，1，2，3，4或5；each of n, m, f is independently 0, 1, 2, 3, 4 or 5; 当n＝2时，且两个Rc连在同一碳原子上，那么两个Rc与之相连的碳原子一起可形成3-8元杂环。When n=2, and the two R c are attached to the same carbon atom, then the two R c and the carbon atom to which they are attached together can form a 3-8 membered heterocycle. 3.根据权利要求2所述的化合物，或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，其中：3. The compound of claim 2, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or pro- medicine, which: X1为O或S；X 1 is O or S; X2为O，S或NH；X 2 is O, S or NH; Ra、Rb独立地选自：氢、卤素，可以为单、双或多取代；R a and R b are independently selected from: hydrogen, halogen, which can be mono-, di- or polysubstituted; 其中，
Figure FDA0003367826780000051
结构单元选自以下子结构：in,
Figure FDA0003367826780000051
Structural units are selected from the following substructures:
Figure FDA0003367826780000052
Figure FDA0003367826780000052
 其中，X5为O，NH，S，CH2，CHRd或NRe；Wherein, X 5 is O, NH, S, CH 2 , CHR d or NR e ; R3可以相同或不同，各自独立地为-(CH2)fNR1R2，R1-C(＝O)-，R1-C(＝O)O(CH2)f-，R1-(CH2)f OC(＝O)-，R1-(CH2)fN(H)C(＝O)-，R1-(CH2)fC(＝O)N(R1)-，R1-(CH2)f OC(＝O)N(R1)-，羟基取代的C1-10烷基，氢，氧代(＝O)，氟，氯，溴，碘，羟基，甲基，乙基，丙基，丁基，异丙基，三氟甲基，三氟乙基，甲氧基，乙氧基，丙氧基，二甲基氨基，二乙基氨基，乙烯基，乙炔基，环丙基，环丁基，环戊基，氨基，硝基，羧基，氰基，苯基，氟代苯基，氯代苯基，溴代苯基，甲氧基苯基，甲基苯基，咪唑基，吡唑基，吡啶基，嘧啶基或苄基；R 3 may be the same or different, and each independently is -(CH2) f NR 1 R 2 , R 1 -C(=O)-, R 1 -C(=O)O(CH 2 ) f -, R 1 - (CH 2 ) f OC(=O)-, R 1 -(CH 2 ) f N(H)C(=O)-, R 1 -(CH 2 ) f C(=O)N(R 1 )- , R 1 -(CH 2 ) f OC(=O)N(R 1 )-, hydroxy substituted C 1-10 alkyl, hydrogen, oxo(=O), fluorine, chlorine, bromine, iodine, hydroxyl, Methyl, Ethyl, Propyl, Butyl, Isopropyl, Trifluoromethyl, Trifluoroethyl, Methoxy, Ethoxy, Propoxy, Dimethylamino, Diethylamino, Vinyl , ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, amino, nitro, carboxyl, cyano, phenyl, fluorophenyl, chlorophenyl, bromophenyl, methoxyphenyl, methylphenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl or benzyl; R4可以相同或不同，各自独立地为-(CH2)fNR1R2，R1-C(＝O)-，R1-C(＝O)O(CH2)f-，R1-(CH2)f OC(＝O)-，R1-(CH2)fN(H)C(＝O)-，R1-(CH2)fC(＝O)N(R1)-，R1-(CH2)f OC(＝O)N(R1)-，羟基取代的C1-10烷基，氢，氧代(＝O)，氟，氯，溴，碘，羟基，甲基，乙基，丙基，丁基，异丙基，三氟甲基，三氟乙基，甲氧基，乙氧基，丙氧基，二甲基氨基，二乙基氨基，乙烯基，乙炔基，环丙基，环丁基，环戊基，氨基，硝基，羧基，氰基，苯基，氟代苯基，氯代苯基，溴代苯基，甲氧基苯基，甲基苯基，咪唑基，吡唑基，吡啶基，嘧啶基或苄基；R 4 may be the same or different, and each independently is -(CH2) f NR 1 R 2 , R 1 -C(=O)-, R 1 -C(=O)O(CH 2 ) f -, R 1 - (CH 2 ) f OC(=O)-, R 1 -(CH 2 ) f N(H)C(=O)-, R 1 -(CH 2 ) f C(=O)N(R 1 )- , R 1 -(CH 2 ) f OC(=O)N(R 1 )-, hydroxy substituted C 1-10 alkyl, hydrogen, oxo(=O), fluorine, chlorine, bromine, iodine, hydroxyl, Methyl, Ethyl, Propyl, Butyl, Isopropyl, Trifluoromethyl, Trifluoroethyl, Methoxy, Ethoxy, Propoxy, Dimethylamino, Diethylamino, Vinyl , ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, amino, nitro, carboxyl, cyano, phenyl, fluorophenyl, chlorophenyl, bromophenyl, methoxyphenyl, methylphenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl or benzyl; Rd为-(CH2)fNR1R2，R1-C(＝O)-，R1-C(＝O)O(CH2)f-，R1-(CH2)f OC(＝O)-，R1-(CH2)f N(H)C(＝O)-，R1-(CH2)f C(＝O)N(R1)-，R1-(CH2)f OC(＝O)N(R1)-，羟基取代的C1-10烷基，氢，氧代(＝O)，氟，氯，溴，碘，羟基，甲基，乙基，丙基，丁基，异丙基，三氟甲基，三氟乙基，甲氧基，乙氧基，丙氧基，二甲基氨基，二乙基氨基，乙烯基，乙炔基，环丙基，环丁基，环戊基，氨基，硝基，羧基，氰基，苯基，氟代苯基，氯代苯基，溴代苯基，甲氧基苯基，甲基苯基，咪唑基，吡唑基，吡啶基，嘧啶基或苄基；R d is -(CH2) f NR 1 R 2 , R 1 -C(=O)-, R 1 -C(=O)O(CH 2 ) f -, R 1 -(CH 2 ) f OC(= O)-, R 1 -(CH 2 ) f N(H)C(=O)-, R 1 -(CH 2 ) f C(=O)N(R 1 )-, R 1 -(CH 2 ) f OC(=O)N(R 1 )-, hydroxy substituted C 1-10 alkyl, hydrogen, oxo(=O), fluoro, chloro, bromo, iodo, hydroxy, methyl, ethyl, propyl , butyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, propoxy, dimethylamino, diethylamino, vinyl, ethynyl, cyclopropyl, Cyclobutyl, cyclopentyl, amino, nitro, carboxyl, cyano, phenyl, fluorophenyl, chlorophenyl, bromophenyl, methoxyphenyl, methylphenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl or benzyl; Re为-(CH2)fNR1R2，R1-C(＝O)-，R1-C(＝O)O(CH2)f-，R1-(CH2)f OC(＝O)-，R1-(CH2)f N(H)C(＝O)-，R1-(CH2)f C(＝O)N(R1)-，R1-(CH2)fOC(＝O)N(R1)-，羟基取代的C1-10烷基，氢，氧代(＝O)，氟，氯，溴，碘，羟基，甲基，乙基，丙基，丁基，异丙基，三氟甲基，三氟乙基，甲氧基，乙氧基，丙氧基，二甲基氨基，二乙基氨基，乙烯基，乙炔基，环丙基，环丁基，环戊基，氨基，硝基，羧基，氰基，苯基，氟代苯基，氯代苯基，溴代苯基，甲氧基苯基，甲基苯基，咪唑基，吡唑基，吡啶基，嘧啶基或苄基； Re is -(CH2) f NR 1 R 2 , R 1 -C(=O)-, R 1 -C(=O)O(CH 2 ) f -, R 1 -(CH 2 ) f OC(= O)-, R 1 -(CH 2 ) f N(H)C(=O)-, R 1 -(CH 2 ) f C(=O)N(R 1 )-, R 1 -(CH 2 ) f OC(=O)N(R 1 )-, hydroxy substituted C 1-10 alkyl, hydrogen, oxo(=O), fluoro, chloro, bromo, iodo, hydroxy, methyl, ethyl, propyl , butyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, propoxy, dimethylamino, diethylamino, vinyl, ethynyl, cyclopropyl, Cyclobutyl, cyclopentyl, amino, nitro, carboxyl, cyano, phenyl, fluorophenyl, chlorophenyl, bromophenyl, methoxyphenyl, methylphenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl or benzyl; 各R1和R2独立地为氢，甲基，乙基，丙基，丁基，异丙基，环丙基，环丁基，环戊基，三氟甲基，苄基，吗啉基，哌嗪基，苯基，吡唑基，咪唑基，吡啶基，嘧啶基；Each R1 and R2 is independently hydrogen , methyl, ethyl, propyl, butyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, trifluoromethyl, benzyl, morpholinyl , piperazinyl, phenyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl; 各g独立地为0，1或2；each g is independently 0, 1 or 2; 各n，m，f独立地为0，1，2，3，4或5；each of n, m, f is independently 0, 1, 2, 3, 4 or 5; 当n＝2时，且两个Rc连在同一碳原子上，那么两个Rc与之相连的碳原子一起可形成3-8元杂环。When n=2, and the two R c are attached to the same carbon atom, then the two R c and the carbon atom to which they are attached together can form a 3-8 membered heterocycle. 4.根据权利要求3所述的化合物，或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，其中：4. The compound of claim 3, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or pro- medicine, which: X1为O或S；X 1 is O or S; X2为O，S或NH；X 2 is O, S or NH; Ra、Rb独立地选自：氢、卤素；R a , R b are independently selected from: hydrogen, halogen;
Figure FDA0003367826780000061
Figure FDA0003367826780000061
 结构单元选自以下子结构：Structural units are selected from the following substructures:
Figure FDA0003367826780000062
Figure FDA0003367826780000071
Figure FDA0003367826780000062
Figure FDA0003367826780000071
 其中，R1a选自氢、羰基、酰胺基、酯基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C3-7杂环基、C6-10芳基或C5-10杂芳基；Wherein, R 1a is selected from hydrogen, carbonyl, amide, ester, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-7 heterocyclyl, C 6-10 Aryl or C 5-10 heteroaryl; R1b选自氢、卤素、羟基、氨基酰基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C3-7杂环基、C6-10芳基或C5-10杂芳基；R 1b is selected from hydrogen, halogen, hydroxy, aminoacyl, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl , C 1-6 alkoxy, C 3-7 heterocyclyl, C 6-10 aryl or C 5-10 heteroaryl; R1c选自氢、羟基、羰基、酯基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C3-7杂环基、C6-10芳基或C5-10杂芳基；R 1c is selected from hydrogen, hydroxyl, carbonyl, ester, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-7 heterocyclyl, C 6-10 aryl or C 5-10 heteroaryl; R可以相同或不同，各自独立地选自氢、卤素、腈基、硝基、羟基、醛基、羧基、酰胺基、氨基酰基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C3-7杂环基、C6-10芳基或C5-10杂芳基；R may be the same or different, each independently selected from hydrogen, halogen, nitrile, nitro, hydroxyl, aldehyde, carboxyl, amide, aminoacyl, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-7 heterocyclyl, C 6-10 aryl or C 5-10 hetero Aryl; 或者相同原子或相邻原子上的两个R基团可以一起形成C3-7环烷基、C3-7杂环烷基、C6-10芳基或C5-10杂芳基；Or two R groups on the same atom or on adjacent atoms can be taken together to form a C 3-7 cycloalkyl, C 3-7 heterocycloalkyl, C 6-10 aryl or C 5-10 heteroaryl; p为0，1，2，3，4或5；p is 0, 1, 2, 3, 4 or 5; q为0，1或2；q is 0, 1 or 2; 所述的卤素为F，Cl，或Br；Described halogen is F, Cl, or Br; 所述的取代是指被下列一个或多个取代基所取代：C1-5烷基、C2-5烯基、C2-5炔基、C1-5烷氧基、卤素、硝基、氰基、羟基、氨基、羧基和氧代。The substitution refers to being substituted by one or more of the following substituents: C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 1-5 alkoxy, halogen, nitro , cyano, hydroxyl, amino, carboxyl and oxo. 5.根据权利要求4所述的化合物，或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，所述化合物选自：5. The compound of claim 4, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or pro- medicine, the compound is selected from:
Figure FDA0003367826780000072
Figure FDA0003367826780000072
Figure FDA0003367826780000081
Figure FDA0003367826780000081
Figure FDA0003367826780000091
Figure FDA0003367826780000091
Figure FDA0003367826780000101
Figure FDA0003367826780000101
Figure FDA0003367826780000111
Figure FDA0003367826780000111
Figure FDA0003367826780000121
Figure FDA0003367826780000121
 6.式C所示的化合物的制备方法，其特征在于，所述制备方法的反应式如下：6. the preparation method of the compound shown in formula C, is characterized in that, the reaction formula of described preparation method is as follows:
Figure FDA0003367826780000122
Figure FDA0003367826780000122
 其中，X3，X4，X5，Rc，m和n如权利要求1所述；wherein, X 3 , X 4 , X 5 , R c , m and n are as described in claim 1; 所述制备方法具体包括以下步骤：The preparation method specifically comprises the following steps: 首先，以化合物A为原料，通过与正丁基锂发生卤素-金属交换反应形成有机锂化合物，再与4-苯氧基苯甲酸酯发生亲核加成反应，得到化合物B；然后以弱碱作为缚酸剂，化合物B与取代的杂环发生亲核取代反应，得到目标化合物C。First, compound A is used as a raw material to form an organolithium compound through a halogen-metal exchange reaction with n-butyllithium, and then a nucleophilic addition reaction with 4-phenoxybenzoate to obtain compound B; then a weak The base acts as an acid binding agent, and the compound B undergoes a nucleophilic substitution reaction with the substituted heterocycle to obtain the target compound C. 7.一种药物组合物，该组合物含有权利要求1-5任一项所述的化合物，或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药。7. A pharmaceutical composition comprising the compound of any one of claims 1-5, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, Solvates, metabolites, pharmaceutically acceptable salts or prodrugs. 8.如权利要求1-5任一项所述的化合物，或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，在制备蛋白质激酶抑制剂中的用途；所述激酶抑制剂为BTK抑制剂。8. The compound of any one of claims 1-5, or its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable Use of the accepted salt or prodrug in the preparation of a protein kinase inhibitor; the kinase inhibitor is a BTK inhibitor. 9.如权利要求1-5任一项所述的化合物，或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，在制备用于治疗自身免疫性疾病、炎性疾病、血栓栓塞疾病、过敏症、感染性疾病、增生性疾病或癌症中的任意一种或多种疾病的药物中的用途。9. The compound of any one of claims 1-5, or its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable Accepted salts or prodrugs in the manufacture of a medicament for the treatment of any one or more of autoimmune disease, inflammatory disease, thromboembolic disease, allergy, infectious disease, proliferative disease or cancer use. 10.根据权利要求9所述的用途，其特征在于，所述疾病选自：关节炎、类风湿性关节炎、荨麻疹、白癜风、器官移植排斥、溃疡性结肠炎、克罗恩病、皮炎、哮喘、干燥综合征、系统性红斑狼疮、多发性硬化、特发性血小板减少性紫癜、皮疹、抗嗜中性白细胞胞质抗体血管炎、天胞疮、寻常性天胞疮、慢性阻塞性肺疾病、银屑病；乳腺癌、套细胞淋巴瘤、卵巢癌、食道癌、喉癌、成胶质细胞瘤、成神经细胞瘤、胃癌、肝细胞癌、胶质瘤、子宫内膜癌、黑色素瘤、肾癌、膀胱癌、胆道癌、胰腺癌、淋巴瘤、毛细胞癌、鼻咽癌、大肠癌、直肠癌、脑和中枢神经系统癌症、宫颈癌、前列腺癌、睾丸癌、泌尿生殖道癌、肺癌、肺小细胞癌、小细胞癌、肺腺癌、骨癌、结肠癌、腺瘤、胰腺癌、甲状腺癌、滤泡性癌、霍奇金白血病、支气管癌、子宫体癌、子宫颈癌、多发性骨髓瘤、急性髓细胞源性白血病、慢性髓细胞源性白血病、淋巴细胞白血病、慢性淋巴样白血病、骨髓性白血病、非霍奇金淋巴瘤、原发性巨球蛋白血症。10. The use according to claim 9, wherein the disease is selected from the group consisting of: arthritis, rheumatoid arthritis, urticaria, vitiligo, organ transplant rejection, ulcerative colitis, Crohn's disease, dermatitis , asthma, Sjögren's syndrome, systemic lupus erythematosus, multiple sclerosis, idiopathic thrombocytopenic purpura, rash, anti-neutrophil cytoplasmic antibody vasculitis, pemphigus vulgaris, chronic obstructive Lung disease, psoriasis; breast cancer, mantle cell lymphoma, ovarian cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, hepatocellular carcinoma, glioma, endometrial cancer, Melanoma, kidney cancer, bladder cancer, biliary tract cancer, pancreatic cancer, lymphoma, hair cell cancer, nasopharyngeal cancer, colorectal cancer, rectal cancer, brain and central nervous system cancer, cervical cancer, prostate cancer, testicular cancer, urogenital cancer Tract cancer, lung cancer, small cell lung cancer, small cell cancer, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, thyroid cancer, follicular cancer, Hodgkin's leukemia, bronchial cancer, uterine body cancer, Cervical cancer, multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, chronic lymphoid leukemia, myeloid leukemia, non-Hodgkin lymphoma, primary macroglobulinemia disease. 11.权利要求1-5任一项所述化合物，或其立体异构体、溶剂化物、水合物、药学上可接受的盐或共晶在制备用于治疗致使BTK激酶过度表达的疾病的药物中的用途。11. The compound of any one of claims 1-5, or a stereoisomer, solvate, hydrate, pharmaceutically acceptable salt or co-crystal thereof in the manufacture of a medicament for the treatment of a disease causing overexpression of BTK kinase use in. 12.权利要求1-5任一项所述化合物，或其立体异构体、溶剂化物、水合物、药学上可接受的盐或共晶在制备用于治疗BTK激酶过度表达所致疾病的药物中的用途。12. The compound of any one of claims 1-5, or a stereoisomer, solvate, hydrate, pharmaceutically acceptable salt or co-crystal thereof in the preparation of a medicament for the treatment of diseases caused by overexpression of BTK kinase use in.
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