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WO2018196757A1 - 4-aminopyrimidine compound, and preparation method therefor and application thereof - Google Patents

4-aminopyrimidine compound, and preparation method therefor and application thereof Download PDF

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Publication number
WO2018196757A1
WO2018196757A1 PCT/CN2018/084300 CN2018084300W WO2018196757A1 WO 2018196757 A1 WO2018196757 A1 WO 2018196757A1 CN 2018084300 W CN2018084300 W CN 2018084300W WO 2018196757 A1 WO2018196757 A1 WO 2018196757A1
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aminopyrimidin
amino
preparation
carboxamide
compound
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PCT/CN2018/084300
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French (fr)
Chinese (zh)
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赖宜生
郭毅
章颖溢
肖建虎
李月珍
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中国药科大学
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Publication of WO2018196757A1 publication Critical patent/WO2018196757A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention belongs to the field of medicine, and in particular to a 4-aminopyrimidine compound or a pharmaceutically acceptable salt thereof, a process for the preparation thereof, and their use as Bruton's tyrosine kinase inhibitor.
  • BTK Bruton's tyrosine kinase
  • BTK B-cell lymphoma and inflammation
  • BTK is overexpressed in a variety of B cell lymphomas (Blood, 2011, 117(23): 6287-6296; Leuk Res, 2013, 37(10): 1271-1277; Nature, 2010, 463 (7277) ): 88-92; Clin Pharmacol Ther, 2015, 97(5): 469-477).
  • BTK Tyr223 continues to autophosphorylate, resulting in excessive activation of BTK (Blood, 2013, 122(14): 2412-2424).
  • BTK is closely related to autoimmune diseases.
  • BTK is also involved in the regulation of other signaling pathways in vivo, such as the Fc ⁇ receptor signaling pathway (Nat Chem Biol, 2011, 7(1): 4-5) and the Toll-like (TLR) signaling pathway (J Leukoc Biol , 2014, 95(2): 243-250).
  • BTK inhibitors can reduce autoantibody levels and effectively control the occurrence and development of disease; in mouse MRL/lpr systemic lupus erythematosus model, BTK inhibitors can be reduced The production of antibodies and can reduce the risk of renal damage; the rat basophilic leukemia cell model treated with small interfering RNA (siRNA) and LFM-A13 reduced histamine content by 20-25% (Proc Natl Acad) Sci USA, 2010, 107(29): 13075-13080; Nat Chem Biol, 2011, 7(1): 41-50).
  • siRNA small interfering RNA
  • BTK has become an effective target in the field of treatment of B-cell lymphoma and inflammatory diseases.
  • BTK inhibitors such as BMS-986142, M-2951, CC-292, GDC-0853
  • Clinical trials of diseases such as syndrome, multiple sclerosis, systemic lupus erythematosus.
  • Ibrutinib is the only BTK inhibitor approved by the US FDA for the treatment of relapsed or refractory mantle cell lymphoma, treated chronic lymphocytic leukemia (CLL), CLL, Waldenstrom macroglobulinemia (WM), small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL) carrying a 17p deletion mutation.
  • CLL chronic lymphocytic leukemia
  • WM Waldenstrom macroglobulinemia
  • SLL small lymphocytic lymphoma
  • MZL marginal zone lymphoma
  • the technical problem to be solved by the present invention is to provide a 4-aminopyrimidine compound or a pharmaceutically acceptable salt thereof, a process for the preparation thereof, a pharmaceutical composition and use thereof.
  • the compounds of the present invention have good BTK inhibitory activity and can be used for the treatment and/or prevention of related diseases caused by BTK overactivation.
  • the present invention discloses a 4-aminopyrimidine compound represented by the formula (I) or a pharmaceutically acceptable salt thereof:
  • L represents C(O) or C(O)NH(CH 2 ) m ;
  • n an integer from 0 to 5;
  • A represents a benzene ring, a five-membered heterocyclic ring or a six-membered heterocyclic ring, wherein the heterocyclic ring may optionally comprise one or more other heteroatoms selected from O, S or N;
  • Each R 1 independently represents halogen, cyano, nitro, hydroxy, amino, trifluoromethyl, OR 3 , NHR 3 or (C 1 -C 8 )alkyl;
  • n an integer from 0 to 5;
  • Y is selected from: NH(C 1 -C 8 )alkylamino
  • R 2 represents a propionyl group, an acryloyl group, a 2-chloroacetyl group or a 2-butynyl group;
  • R 3 represents (C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy(C 1 -C 8 )alkyl, (C 6 -C 10 )aryl or (C 1 -C 10 ) An aromatic heterocyclic group; wherein said aromatic heterocyclic group may optionally contain one or more other heteroatoms selected from O, S or N; said aryl and aromatic heterocyclic groups may optionally be used Substituted to one to five groups: halogen, nitro, cyano, hydroxy, amino, (C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy or (C 3 -C 6 ) ring alkyl;
  • L represents C(O) or C(O)NH(CH 2 ) m ;
  • n an integer of 0 to 2;
  • A represents a benzene ring, a five-membered heterocyclic ring or a six-membered heterocyclic ring, wherein the heterocyclic ring may optionally comprise one or more other heteroatoms selected from O, S or N;
  • Each R 1 independently represents halogen, (C 1 -C 5 )alkyl, (C 1 -C 5 )alkoxy or phenoxy;
  • n is an integer from 0 to 2;
  • Y is selected from: NH(C 1 -C 8 )alkylamino
  • R 2 represents a propionyl group, an acryloyl group, a 2-chloroacetyl group or a 2-butynyl group;
  • L represents C(O) or C(O)NH(CH 2 ) m ;
  • n an integer of 0 to 2;
  • A represents a benzene ring, a five-membered heterocyclic ring or a six-membered heterocyclic ring, wherein the heterocyclic ring may optionally comprise one or more other heteroatoms selected from O, S or N;
  • Each R 1 independently represents halogen, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy or phenoxy;
  • n is an integer from 0 to 2;
  • Y is selected from: NH(C 1 -C 8 )alkylamino
  • R 2 represents a propionyl group, an acryloyl group, a 2-chloroacetyl group or a 2-butynyl group;
  • the 4-aminopyrimidine compound represented by the formula (I) is preferably selected from the following compounds:
  • Another object of the present invention is to provide a process for the preparation of a compound of the formula (I), characterized in that:
  • the compound of the formula (I) is prepared by using 4,6-dihydroxypyrimidine as a raw material, Vilsmeier-Haack reaction and chlorination reaction to obtain 4,6- Dichloro-5-pyrimidinecarboxaldehyde 1,1 is oxidized by sodium chlorite to obtain 4,6-dichloro-5-pyrimidinecarboxylic acid 2,2 and reacted with oxalyl chloride to obtain acid chloride, followed by Friedel-Crafts acylation with aromatic hydrocarbon
  • the intermediates 3, 3 are obtained by reacting with ammonia water to obtain intermediates 4 and 4, which are reacted with an amine compound to obtain 5-1 or 5-2, and 5-1 is deprotected with concentrated hydrochloric acid, and is the same as 5-2.
  • the compound of the formula (I) is obtained by reacting with an acid chloride or 2-butynoic acid:
  • n, A, R 1 and R 2 are as defined above.
  • the compound of the formula (I) is prepared by reacting the intermediate 2 with oxalyl chloride to obtain an acid chloride, and then condensing with an amine compound to form an amide 6, 6 reacting with ammonia to obtain intermediate 7,7 and amine compound (HY-Boc) to obtain 8,8 by concentrated hydrochloric acid to remove Boc to obtain 9, and finally 9 react with acid chloride or 2-butynoic acid to obtain general formula (I) Compound:
  • n, n, A, R 1 and R 2 are as defined above.
  • the pharmaceutically acceptable salts of the compounds of formula (I) can be synthesized by general chemical methods.
  • the preparation of the salt can be carried out by reacting the free base or acid with an equivalent stoichiometric or excess acid (inorganic or organic acid) or a base (inorganic or organic base) in a suitable solvent or solvent composition.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of an active ingredient and a pharmaceutically acceptable adjuvant; the active ingredient comprising a compound of formula (I) and pharmaceutically acceptable thereof One or more of the salts.
  • the adjuvant comprises a pharmaceutically acceptable carrier, diluent and/or excipient.
  • the pharmaceutical composition can be formulated into various types of dosage unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions and suspensions), depending on the purpose of the treatment, Preference is given to tablets, capsules, liquids, suspensions, and injections (solutions and suspensions).
  • any excipient known and widely used in the art can be used.
  • the solution or suspension may be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose or glycerin) to prepare an isotonic injection with blood.
  • Any of the commonly used carriers in the art can also be used in the preparation of the injection.
  • a usual solvent, a buffer, or the like may be added.
  • the content of the composition of the present invention in the pharmaceutical composition is not particularly limited and can be selected within a wide range, and is usually from 5 to 95% by mass, preferably from 30 to 85% by mass.
  • the administration method of the pharmaceutical composition of the present invention is not particularly limited. Formulations of various dosage forms can be selected depending on the age, sex and other conditions and symptoms of the patient.
  • the invention further provides the use of a compound of the formula (I), a pharmaceutically acceptable salt thereof or the pharmaceutical composition for the preparation of a BTK inhibitor.
  • the BTK inhibitors are useful in the treatment of thromboembolism, Waldenstrom's macroglobulinemia, inflammatory conditions, autoimmune diseases, and B cell lymphomas.
  • the inflammatory or autoimmune diseases include, but are not limited to, xenogeneic immune diseases, asthma, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, idiopathic thrombocytopenic purpura, autoimmune mediated One or more of hemolytic anemia, immune complex-mediated vasculitis, and psoriasis.
  • the B cell lymphoma includes, but is not limited to, chronic lymphocytic leukemia, acute lymphocytic leukemia, mantle cell lymphoma, follicular lymphoma, small lymphocytic lymphoma, diffuse large B-cell lymphoma, multiple bone marrow One or more of tumor, mucosa-associated lymphoid tissue lymphoma, Hodgkin's lymphoma, and B-cell non-Hodgkin's lymphoma.
  • the compound of the present invention and (R)-1-[3-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]amino]piperidin are detected by a radioisotope P 33 -ATP labeling method.
  • the radioisotope detection method is highly sensitive and the test results are very accurate, so it is considered to be the "gold standard" for the detection of protein kinase biochemical activity.
  • the experimental results show that some of the compounds of the present invention have a significant inhibitory effect on the activity of BTK kinase.
  • the inhibitory activities of the compounds A-1, A-2, A-8, A-9, A-10, B-2, and B-9 on BTK are equivalent to those of the compound b, and the compounds A-4 and A-6,
  • the activities of B-1, B-7, B-8, and B-11 were superior to those of compound b, and especially the activities of compounds A-6 and B-1 were significantly stronger than that of compound b.
  • the different stereoisomers of the compounds of the invention exhibit respective different activities.
  • compounds A-1 and A-2 are in the S configuration and the R configuration, respectively.
  • the former (S configuration) has a slightly stronger inhibitory activity against BTK than the latter (R configuration); for compound A-4 (R configuration)
  • the activity of the R configuration is significantly stronger than that of the S configuration; for the compounds A-6 (S configuration) and A-7 (R configuration).
  • the S configuration is 1800 times more active than the R configuration.
  • the activity of the compound B-1 was significantly 150 times stronger than that of the compound b, whereas the activity of the compound B-12 was unexpectedly 2600 times lower than that of the compound A-6.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to the field of medicines, and specifically relates to a 4-aminopyrimidine compound having a structural feature represented by formula (I), or pharmaceutically acceptable salts thereof, a preparation method for the compound, and a use of the compound and the salts as a Bruton tyrosine kinase (BTK) inhibitor. A result of experiments shows that the compound in the present invention has a significant inhibition effect on the BTK, and can be used for treating thromboembolism, inflammatory disorders, autoimmune diseases, Waldenstrom macroglobulinemia, B cell lymphomas, and other diseases.

Description

4-氨基嘧啶类化合物、其制备方法及应用4-aminopyrimidine compound, preparation method and application thereof 技术领域Technical field
本发明属于药物领域，具体涉及一种4-氨基嘧啶类化合物或其药学上可接受的盐、其制备方法、以及它们作为布鲁顿酪氨酸激酶抑制剂的用途。The present invention belongs to the field of medicine, and in particular to a 4-aminopyrimidine compound or a pharmaceutically acceptable salt thereof, a process for the preparation thereof, and their use as Bruton's tyrosine kinase inhibitor.
背景技术Background technique
布鲁顿酪氨酸激酶(BTK)是非受体酪氨酸蛋白激酶Tec家族的一员，由659个氨基酸组成，内含多个结构域，如Pleckstrin homology(PH)结构域、Tec homology(TH)结构域、Src homology 3(SH3)结构域、SH2和SH1结构域(Future Med Chem,2014,6(6):675-695)。研究表明，BTK作为B细胞受体(BCR)信号转导通路的重要组成部分，在B细胞的发育、成熟、分化和增殖等诸多生理过程中发挥极其重要的作用(Nature,1993,361(6409):226-233)。Bruton's tyrosine kinase (BTK) is a member of the Tec family of non-receptor tyrosine protein kinases. It consists of 659 amino acids and contains multiple domains, such as the Pleckstrin homology (PH) domain and Tec homology (TH). ) domain, Src homology 3 (SH3) domain, SH2 and SH1 domain (Future Med Chem, 2014, 6(6): 675-695). Studies have shown that BTK, as an important component of the B cell receptor (BCR) signal transduction pathway, plays an extremely important role in many physiological processes such as B cell development, maturation, differentiation and proliferation (Nature, 1993, 361 (6409) ): 226-233).
BTK的精确调控对维持B细胞的正常生理功能至关重要(Anticancer Agents Med Chem,2007,7(6):624-632)。BTK的过度活化会引起B细胞凋亡减慢，并且易发生自体免疫反应，从而诱导B细胞淋巴瘤和炎症等疾病的发生和发展(Int Rev Immunol,2012,31(2):119-132)。Precise regulation of BTK is critical for maintaining the normal physiological function of B cells (Anticancer Agents Med Chem, 2007, 7(6): 624-632). Excessive activation of BTK causes a decrease in apoptosis of B cells and is prone to autoimmune reactions, thereby inducing the development and progression of diseases such as B-cell lymphoma and inflammation (Int Rev Immunol, 2012, 31(2): 119-132) .
研究表明，BTK在多种B细胞淋巴瘤中均过度表达(Blood,2011,117(23):6287-6296；Leuk Res,2013,37(10):1271-1277；Nature,2010,463(7277):88-92；Clin Pharmacol Ther,2015,97(5):469-477)。如在慢性淋巴性白血病小鼠模型中，BTK的过度表达导致肿瘤发生率和死亡率增加(Am J Blood Res,2013,3(1):71-83)；在套细胞淋巴瘤细胞中，BTK Tyr223出现持续自动磷酸化，从而导致BTK过度活化(Blood,2013,122(14):2412-2424)。BTK功能获得型突变导致的过度活化也在急性淋巴细胞白血病(Leuk Lymphoma,2003,44(6):1011-1018)、急性髓性白血病(Expert Opin Ther Patents,2010,20(11):1457-1470)和慢性髓性白血病(Biochem Biophys Res Commun,2002,299(3):510-515)中得到确证。通过抑制BTK的活性能降低抗凋亡蛋白Bcl-2、Bcl-xL和Mcl-1的水平，从而促进B细胞淋巴瘤凋亡(Leuk Res,2013,37(10):1271-1277)。Studies have shown that BTK is overexpressed in a variety of B cell lymphomas (Blood, 2011, 117(23): 6287-6296; Leuk Res, 2013, 37(10): 1271-1277; Nature, 2010, 463 (7277) ): 88-92; Clin Pharmacol Ther, 2015, 97(5): 469-477). For example, in a mouse model of chronic lymphocytic leukemia, overexpression of BTK leads to increased tumor incidence and mortality (Am J Blood Res, 2013, 3(1): 71-83); in mantle cell lymphoma cells, BTK Tyr223 continues to autophosphorylate, resulting in excessive activation of BTK (Blood, 2013, 122(14): 2412-2424). Overactivation of BTK function-acquired mutations is also in acute lymphoblastic leukemia (Leuk Lymphoma, 2003, 44(6): 1011-1018), acute myeloid leukemia (Expert Opin Ther Patents, 2010, 20(11): 1457- 1470) was confirmed in chronic myeloid leukemia (Biochem Biophys Res Commun, 2002, 299(3): 510-515). By inhibiting the activity of BTK, the levels of anti-apoptotic proteins Bcl-2, Bcl-xL and Mcl-1 can be lowered, thereby promoting apoptosis of B cell lymphoma (Leuk Res, 2013, 37(10): 1271-1277).
此外，BTK与自身免疫性疾病密切相关。除BCR信号通路外，BTK还参与调控体内的其他信号通路，如Fcγ受体信号通路(Nat Chem Biol,2011,7(1):4-5)和Toll样(TLR)信号通路(J Leukoc Biol,2014,95(2):243-250)。Fcγ受体信号通路的激活最终导致TNFα、IL-1β和IL-6等炎症因子的释放(Drug Discov Today,2014,19(8):1200-1204)，而TLR信号通路的活化与转录因子NF-κB的激活、促炎/抗炎细胞因子的释放密切相关(J Clin Oncol,2014,32(17):1830-1839)。实验证明，在胶原蛋白诱导关节炎的小鼠模型中，BTK抑制剂可降低自 身抗体水平，有效控制疾病的发生与发展；在小鼠MRL/lpr系统性红斑狼疮模型中，BTK抑制剂可减少抗体的产生，并且能降低肾损害的风险；大鼠嗜碱性白血病细胞模型经小分子干扰核糖核酸(siRNA)和LFM-A13处理后，组胺的含量减少了20-25％(Proc Natl Acad Sci USA,2010,107(29):13075-13080；Nat Chem Biol,2011,7(1):41-50)。In addition, BTK is closely related to autoimmune diseases. In addition to the BCR signaling pathway, BTK is also involved in the regulation of other signaling pathways in vivo, such as the Fcγ receptor signaling pathway (Nat Chem Biol, 2011, 7(1): 4-5) and the Toll-like (TLR) signaling pathway (J Leukoc Biol , 2014, 95(2): 243-250). Activation of the Fcγ receptor signaling pathway ultimately leads to the release of inflammatory factors such as TNFα, IL-1β and IL-6 (Drug Discov Today, 2014, 19(8): 1200-1204), and activation of the TLR signaling pathway and transcription factor NF The activation of kappa B, the release of pro-inflammatory/anti-inflammatory cytokines is closely related (J Clin Oncol, 2014, 32(17): 1830-1839). Experiments have shown that in a mouse model of collagen-induced arthritis, BTK inhibitors can reduce autoantibody levels and effectively control the occurrence and development of disease; in mouse MRL/lpr systemic lupus erythematosus model, BTK inhibitors can be reduced The production of antibodies and can reduce the risk of renal damage; the rat basophilic leukemia cell model treated with small interfering RNA (siRNA) and LFM-A13 reduced histamine content by 20-25% (Proc Natl Acad) Sci USA, 2010, 107(29): 13075-13080; Nat Chem Biol, 2011, 7(1): 41-50).
文献还报道了BTK和异种免疫性疾病、血栓栓塞疾病的联系(Expert Opin Ther Patents,2010,20(11):1457-1470)。在骨髓移植的小鼠模型中，移植物抗宿主病(GVHD)预防处方添加BTK抑制剂可以显著改善异体骨髓移植的存活率。而X-连锁无丙种球蛋白血症(一种由BTK突变失活导致的先天性免疫缺陷疾病)患者体内，血小板响应于胶原或胶原相关肽的聚集、分泌能力明显降低。The literature also reports the association of BTK with xenogeneic immune diseases, thromboembolic diseases (Expert Opin Ther Patents, 2010, 20(11): 1457-1470). In a mouse model of bone marrow transplantation, graft-versus-host disease (GVHD) prophylaxis with the addition of BTK inhibitors can significantly improve the survival rate of allogeneic bone marrow transplantation. In patients with X-linked agammaglobulinemia (a congenital immunodeficiency disease caused by inactivation of BTK mutations), the ability of platelets to respond to the aggregation and secretion of collagen or collagen-related peptides is significantly reduced.
综上所述，BTK已成为目前B细胞淋巴瘤和炎性疾病治疗领域中的一个有效靶标。目前已有多个BTK抑制剂(如BMS-986142、M-2951、CC-292、GDC-0853)开展治疗B细胞淋巴瘤、类风湿性关节炎、
Figure PCTCN2018084300-appb-000001
综合征、多发性硬化症、系统性红斑狼疮等疾病的临床试验。其中，由Pharmacyclics和强生公司联合开发的Ibrutinib是目前唯一一个已获得美国FDA批准上市的BTK抑制剂，用于治疗复发性或难治性套细胞淋巴瘤、经治慢性淋巴细胞白血病(CLL)、携带17p删除突变的CLL、Waldenstrom巨球蛋白血症(WM)、小淋巴细胞淋巴瘤(SLL)、边缘区淋巴瘤(MZL)。然而，目前具有良好成药性的BTK抑制剂种类仍然较少，加上Ibrutinib在临床应用中已经出现耐药现象，因此研发新的BTK抑制剂具有重要的意义。 In summary, BTK has become an effective target in the field of treatment of B-cell lymphoma and inflammatory diseases. At present, there are several BTK inhibitors (such as BMS-986142, M-2951, CC-292, GDC-0853) for the treatment of B-cell lymphoma and rheumatoid arthritis.
Figure PCTCN2018084300-appb-000001
Clinical trials of diseases such as syndrome, multiple sclerosis, systemic lupus erythematosus. Among them, Ibrutinib, jointly developed by Pharmacyclics and Johnson & Johnson, is the only BTK inhibitor approved by the US FDA for the treatment of relapsed or refractory mantle cell lymphoma, treated chronic lymphocytic leukemia (CLL), CLL, Waldenstrom macroglobulinemia (WM), small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL) carrying a 17p deletion mutation. However, there are still few BTK inhibitors with good drug-forming properties, and Ibrutinib has been resistant in clinical applications. Therefore, the development of new BTK inhibitors is of great significance.
发明内容Summary of the invention
本发明所要解决的技术问题在于提供了一种4-氨基嘧啶类化合物或其药学上可接受的盐、其制备方法、药物组合物及应用。本发明的化合物具有良好的BTK抑制活性，可以用于治疗和/或预防BTK过度激活所引起的相关疾病。The technical problem to be solved by the present invention is to provide a 4-aminopyrimidine compound or a pharmaceutically acceptable salt thereof, a process for the preparation thereof, a pharmaceutical composition and use thereof. The compounds of the present invention have good BTK inhibitory activity and can be used for the treatment and/or prevention of related diseases caused by BTK overactivation.
本发明公开通式(I)所示的4-氨基嘧啶类化合物或其药学上可接受的盐：The present invention discloses a 4-aminopyrimidine compound represented by the formula (I) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2018084300-appb-000002
Figure PCTCN2018084300-appb-000002
其中：among them:
L代表C(O)或C(O)NH(CH 2) m； L represents C(O) or C(O)NH(CH 2 ) m ;
m代表0～5的整数；m represents an integer from 0 to 5;
A代表苯环、五元杂环或六元杂环，其中所述的杂环可任选地包含一个或多个选自O、S或N的其它杂原子；A represents a benzene ring, a five-membered heterocyclic ring or a six-membered heterocyclic ring, wherein the heterocyclic ring may optionally comprise one or more other heteroatoms selected from O, S or N;
各个R 1各自独立地代表卤素、氰基、硝基、羟基、氨基、三氟甲基、OR 3、NHR 3或(C 1-C 8)烷基； Each R 1 independently represents halogen, cyano, nitro, hydroxy, amino, trifluoromethyl, OR 3 , NHR 3 or (C 1 -C 8 )alkyl;
n代表0～5的整数；n represents an integer from 0 to 5;
Y任选自：NH(C 1-C 8)烷基氨基， Y is selected from: NH(C 1 -C 8 )alkylamino,
Figure PCTCN2018084300-appb-000003
Figure PCTCN2018084300-appb-000003
R 2代表丙酰基、丙烯酰基、2-氯乙酰基或2-丁炔酰基； R 2 represents a propionyl group, an acryloyl group, a 2-chloroacetyl group or a 2-butynyl group;
R 3代表(C 1-C 8)烷基、(C 1-C 8)烷氧基(C 1-C 8)烷基、(C 6-C 10)芳基或(C 1-C 10)芳杂环基；其中所述的芳杂环基团可任选地包含一个或多个选自O、S或N的其它杂原子；所述的芳基和芳杂环基可任选地用一个至五个以下基团取代：卤素、硝基、氰基、羟基、氨基、(C 1-C 8)烷基、(C 1-C 8)烷氧基或(C 3-C 6)环烷基； R 3 represents (C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy(C 1 -C 8 )alkyl, (C 6 -C 10 )aryl or (C 1 -C 10 ) An aromatic heterocyclic group; wherein said aromatic heterocyclic group may optionally contain one or more other heteroatoms selected from O, S or N; said aryl and aromatic heterocyclic groups may optionally be used Substituted to one to five groups: halogen, nitro, cyano, hydroxy, amino, (C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy or (C 3 -C 6 ) ring alkyl;
其中，下式(a-d)化合物除外：Wherein, except for the compound of the following formula (a-d):
Figure PCTCN2018084300-appb-000004
Figure PCTCN2018084300-appb-000004
进一步地，具有通式(I)的4-氨基嘧啶类化合物或其药学上可接受的盐，其特征在于：Further, a 4-aminopyrimidine compound of the formula (I) or a pharmaceutically acceptable salt thereof, characterized in that:
L代表C(O)或C(O)NH(CH 2) m； L represents C(O) or C(O)NH(CH 2 ) m ;
m代表0～2的整数；m represents an integer of 0 to 2;
A代表苯环、五元杂环或六元杂环，其中所述的杂环可任选地包含一个或多个选自O、S或N的其它杂原子；A represents a benzene ring, a five-membered heterocyclic ring or a six-membered heterocyclic ring, wherein the heterocyclic ring may optionally comprise one or more other heteroatoms selected from O, S or N;
各个R 1各自独立地代表卤素、(C 1-C 5)烷基、(C 1-C 5)烷氧基或苯氧基； Each R 1 independently represents halogen, (C 1 -C 5 )alkyl, (C 1 -C 5 )alkoxy or phenoxy;
n为0～2的整数；n is an integer from 0 to 2;
Y任选自：NH(C 1-C 8)烷基氨基， Y is selected from: NH(C 1 -C 8 )alkylamino,
Figure PCTCN2018084300-appb-000005
Figure PCTCN2018084300-appb-000005
R 2代表丙酰基、丙烯酰基、2-氯乙酰基或2-丁炔酰基； R 2 represents a propionyl group, an acryloyl group, a 2-chloroacetyl group or a 2-butynyl group;
更进一步地，具有通式(I)的4-氨基嘧啶类化合物或其药学上可接受的盐，其特征在于：Further, a 4-aminopyrimidine compound of the formula (I) or a pharmaceutically acceptable salt thereof, characterized in that:
L代表C(O)或C(O)NH(CH 2) m； L represents C(O) or C(O)NH(CH 2 ) m ;
m代表0～2的整数；m represents an integer of 0 to 2;
A代表苯环、五元杂环或六元杂环，其中所述的杂环可任选地包含一个或多个选自O、S或N的其它杂原子；A represents a benzene ring, a five-membered heterocyclic ring or a six-membered heterocyclic ring, wherein the heterocyclic ring may optionally comprise one or more other heteroatoms selected from O, S or N;
各个R 1各自独立地代表卤素、(C 1-C 3)烷基、(C 1-C 3)烷氧基或苯氧基； Each R 1 independently represents halogen, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy or phenoxy;
n为0～2的整数；n is an integer from 0 to 2;
Y任选自：NH(C 1-C 8)烷基氨基， Y is selected from: NH(C 1 -C 8 )alkylamino,
Figure PCTCN2018084300-appb-000006
Figure PCTCN2018084300-appb-000006
R 2代表丙酰基、丙烯酰基、2-氯乙酰基或2-丁炔酰基； R 2 represents a propionyl group, an acryloyl group, a 2-chloroacetyl group or a 2-butynyl group;
具体来说，通式(I)所示的4-氨基嘧啶类化合物优选自下列化合物：Specifically, the 4-aminopyrimidine compound represented by the formula (I) is preferably selected from the following compounds:
(S)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨甲基]哌啶-1-基]-2-丙烯-1-酮(A-1)；(S)-1-[3-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]aminomethyl]piperidin-1-yl]-2-propene-1 -ketone (A-1);
(R)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨甲基]哌啶-1-基]-2-丙烯-1-酮(A-2)；(R)-1-[3-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]aminomethyl]piperidin-1-yl]-2-propene-1 -ketone (A-2);
1-[2-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨甲基]哌啶-1-基]-2-丙烯-1-酮(A-3)；1-[2-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]aminomethyl]piperidin-1-yl]-2-propen-1-one (A -3);
(R)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨基]吡咯烷-1-基]-2-丙烯-1-酮(A-4)；(R)-1-[3-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]amino]pyrrolidin-1-yl]-2-propen-1-one (A-4);
(S)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨基]吡咯烷-1-基]-2-丙烯-1-酮(A-5)；(S)-1-[3-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]amino]pyrrolidin-1-yl]-2-propen-1-one (A-5);
(S)-1-[2-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨甲基]吡咯烷-1-基]-2-丙烯-1-酮(A-6)；(S)-1-[2-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]aminomethyl]pyrrolidin-1-yl]-2-propene-1 -ketone (A-6);
(R)-1-[2-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨甲基]吡咯烷-1-基]-2-丙烯-1-酮(A-7)；(R)-1-[2-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]aminomethyl]pyrrolidin-1-yl]-2-propene-1 -ketone (A-7);
1-[3-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨甲基]氮杂环丁烷-1-基]-2-丙烯-1-酮(A-8)；1-[3-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]aminomethyl]azetidin-1-yl]-2-propene-1- Ketone (A-8);
(R)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨基]哌啶-1-基]-2-氯乙烷-1-酮(A-9)；(R)-1-[3-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]amino]piperidin-1-yl]-2-chloroethane-1 -ketone (A-9);
(S)-1-[2-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨甲基]吡咯烷-1-基]-2-氯乙烷-1-酮(A-10)；(S)-1-[2-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]aminomethyl]pyrrolidin-1-yl]-2-chloroethane 1-ketone (A-10);
N-[2-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨基]乙基]丙烯酰胺(A-11)；N-[2-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]amino]ethyl]acrylamide (A-11);
(S)-1-[2-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨甲基]吡咯烷-1-基]丙烷-1-酮(A-12)；(S)-1-[2-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]aminomethyl]pyrrolidin-1-yl]propan-1-one ( A-12);
(S)-1-[2-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨甲基]吡咯烷-1-基]-2-丁炔-1-酮(A-13)；(S)-1-[2-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]aminomethyl]pyrrolidin-1-yl]-2-butyne- 1-ketone (A-13);
(R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-苯基甲酰胺(B-1)；(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-phenylcarboxamide (B-1);
(R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(4-溴苯基)甲酰胺(B-2)；(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(4-bromophenyl)carboxamide (B-2);
(R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(4-异丙基苯基)甲酰胺(B-3)；(R)-[4-[(1-Aroylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(4-isopropylphenyl)carboxamide (B-3 );
(R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(3-甲氧基-4-甲基苯基)甲酰胺(B-4)；(R)-[4-[(1-Aroylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(3-methoxy-4-methylphenyl) A Amide (B-4);
(R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(3,4-二甲氧基苯基)甲酰胺(B-5)；(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(3,4-dimethoxyphenyl)carboxamide ( B-5);
(R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(3,5-二甲氧基苯基)甲酰胺(B-6)；(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(3,5-dimethoxyphenyl)carboxamide ( B-6);
(R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(2-氟苯基)甲酰胺(B-7)；(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(2-fluorophenyl)carboxamide (B-7);
(R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(3-氟苯基)甲酰胺(B-8)；(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(3-fluorophenyl)carboxamide (B-8);
(R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(4-氟苯基)甲酰胺(B-9)；(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(4-fluorophenyl)carboxamide (B-9);
(R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-苄基甲酰胺(B-10)；(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-benzylformamide (B-10);
(R)-[4-[(1-丙烯酰基吡咯烷-3-基)氨基]-6-氨基嘧啶-5-基]-N-苯基甲酰胺(B-11)；(R)-[4-[(1-acryloylpyrrolidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-phenylformamide (B-11);
(S)-[4-[[(1-丙烯酰基吡咯烷-2-基)甲基]氨基]-6-氨基嘧啶-5-基]-N-苯基甲酰胺(B-12)；(S)-[4-[[(1-acryloylpyrrolidin-2-yl)methyl]amino]-6-aminopyrimidin-5-yl]-N-phenylcarboxamide (B-12);
(R)-[4-[(1-丙酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-苯基甲酰胺(B-13)。(R)-[4-[(1-propionylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-phenylformamide (B-13).
(R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(吡啶-2-基)甲酰胺(B-14)；(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(pyridin-2-yl)carboxamide (B-14);
(R)-[4-[[1-(2-丁炔酰基)哌啶-3-基]氨基]-6-氨基嘧啶-5-基]-N-(吡啶-2-基)甲酰胺(B-15)；(R)-[4-[[1-(2-butynyl)piperidin-3-yl]amino]-6-aminopyrimidin-5-yl]-N-(pyridin-2-yl)carboxamide ( B-15);
(R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(吡啶-3-基)甲酰胺(B-16)；(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(pyridin-3-yl)carboxamide (B-16);
(R)-[4-[[1-(2-丁炔酰基)哌啶-3-基]氨基]-6-氨基嘧啶-5-基]-N-(吡啶-3-基)甲酰胺(B-17)；(R)-[4-[[1-(2-butynyl)piperidin-3-yl]amino]-6-aminopyrimidin-5-yl]-N-(pyridin-3-yl)carboxamide ( B-17);
(R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(吡啶-4-基)甲酰胺(B-18)；(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(pyridin-4-yl)carboxamide (B-18);
(R)-[4-[[1-(2-丁炔酰基)哌啶-3-基]氨基]-6-氨基嘧啶-5-基]-N-(吡啶-4-基)甲酰胺(B-19)；(R)-[4-[[1-(2-butynyl)piperidin-3-yl]amino]-6-aminopyrimidin-5-yl]-N-(pyridin-4-yl)carboxamide ( B-19);
(R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(嘧啶-2-基)甲酰胺(B-20)；(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(pyrimidin-2-yl)carboxamide (B-20);
(R)-[4-[[1-(2-丁炔酰基)哌啶-3-基]氨基]-6-氨基嘧啶-5-基]-N-(嘧啶-2-基)甲酰胺(B-21)；(R)-[4-[[1-(2-butynyl)piperidin-3-yl]amino]-6-aminopyrimidin-5-yl]-N-(pyrimidin-2-yl)carboxamide ( B-21);
下面药理实验中涉及的化合物代号等同于此处代号所对应的化合物。The compound code referred to in the following pharmacological experiments is equivalent to the compound corresponding to the code herein.
本发明的另一目的在于提供通式(I)所示化合物的制备方法，其特征在于：Another object of the present invention is to provide a process for the preparation of a compound of the formula (I), characterized in that:
a)当L为C(O)时，通式(I)所示化合物的制备方法为：以4,6-二羟基嘧啶为原料，经Vilsmeier-Haack反应和氯代反应制得4,6-二氯-5-嘧啶甲醛1，1经亚氯酸钠氧化制得4,6-二氯-5-嘧啶羧酸2，2与草酰氯反应制得酰氯后与芳烃进行Friedel-Crafts酰基化反应制得中间体3，3与氨水反应制得中间体4，4与胺类化合物反应制得5-1或5-2，5-1经浓盐酸脱Boc保 护基后和5-2一样，可以与酰氯或2-丁炔酸反应制得通式(I)化合物：a) When L is C(O), the compound of the formula (I) is prepared by using 4,6-dihydroxypyrimidine as a raw material, Vilsmeier-Haack reaction and chlorination reaction to obtain 4,6- Dichloro-5-pyrimidinecarboxaldehyde 1,1 is oxidized by sodium chlorite to obtain 4,6-dichloro-5-pyrimidinecarboxylic acid 2,2 and reacted with oxalyl chloride to obtain acid chloride, followed by Friedel-Crafts acylation with aromatic hydrocarbon The intermediates 3, 3 are obtained by reacting with ammonia water to obtain intermediates 4 and 4, which are reacted with an amine compound to obtain 5-1 or 5-2, and 5-1 is deprotected with concentrated hydrochloric acid, and is the same as 5-2. The compound of the formula (I) is obtained by reacting with an acid chloride or 2-butynoic acid:
Figure PCTCN2018084300-appb-000007
Figure PCTCN2018084300-appb-000007
其中，n、A、R 1和R 2的定义如前所述。 Wherein n, A, R 1 and R 2 are as defined above.
b)当L为C(O)NH(CH 2) m时，通式(I)所示化合物的制备方法为：中间体2与草酰氯反应制得酰氯后与胺类化合物缩合生成酰胺6，6与氨水反应制得中间体7，7与胺类化合物(HY-Boc)反应制得8，8经浓盐酸脱Boc制得9，最后9与酰氯或2-丁炔酸反应制得通式(I)化合物： b) When L is C(O)NH(CH 2 ) m , the compound of the formula (I) is prepared by reacting the intermediate 2 with oxalyl chloride to obtain an acid chloride, and then condensing with an amine compound to form an amide 6, 6 reacting with ammonia to obtain intermediate 7,7 and amine compound (HY-Boc) to obtain 8,8 by concentrated hydrochloric acid to remove Boc to obtain 9, and finally 9 react with acid chloride or 2-butynoic acid to obtain general formula (I) Compound:
Figure PCTCN2018084300-appb-000008
Figure PCTCN2018084300-appb-000008
其中，m、n、A、R 1和R 2的定义如前所述。 Wherein, m, n, A, R 1 and R 2 are as defined above.
所述通式(I)化合物的药学上可接受的盐可通过一般的化学方法合成。The pharmaceutically acceptable salts of the compounds of formula (I) can be synthesized by general chemical methods.
一般情况下，盐的制备可以通过游离碱或酸与等化学当量或过量酸(无机酸或有机酸)或碱(无机碱或有机碱)在合适的溶剂或溶剂组合物中反应制得。In general, the preparation of the salt can be carried out by reacting the free base or acid with an equivalent stoichiometric or excess acid (inorganic or organic acid) or a base (inorganic or organic base) in a suitable solvent or solvent composition.
本发明还提供了一种药物组合物，其由治疗上有效量的活性组分和药学上可接受的辅料组成；所述的活性组分包括通式(I)化合物和其药学上可接受的盐中的一种或多种。所述药物组合物中，所述的辅料包括药学上可接受的载体、稀释剂和/或赋形剂。The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of an active ingredient and a pharmaceutically acceptable adjuvant; the active ingredient comprising a compound of formula (I) and pharmaceutically acceptable thereof One or more of the salts. In the pharmaceutical composition, the adjuvant comprises a pharmaceutically acceptable carrier, diluent and/or excipient.
根据治疗目的可将药物组合物制成各种类型的给药单位剂型，如片剂、丸剂、粉剂、液体、悬浮液、乳液、颗粒剂、胶囊、栓剂和针剂(溶液和悬浮液)等，优选片剂、胶囊、液体、悬浮液、和针剂(溶液和悬浮液)。The pharmaceutical composition can be formulated into various types of dosage unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions and suspensions), depending on the purpose of the treatment, Preference is given to tablets, capsules, liquids, suspensions, and injections (solutions and suspensions).
为了使片剂、丸剂或栓剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋形剂。In order to shape the pharmaceutical composition in the form of a tablet, pill or suppository, any excipient known and widely used in the art can be used.
为了制备针剂形式的药物组合物，可将溶液或悬浮液消毒后(最好加入适量的氯化钠，葡萄糖或甘油)，制成与血液等渗压的针剂。在制备针剂时，也可以使用本领域内任何常用的载体。例如：水、乙醇、丙二醇、乙氧基化的异硬脂醇、聚乙氧基化的异硬脂醇和聚乙烯脱水山梨醇的脂肪酸酯等。此外，还可以加入通常溶解剂和缓冲剂等。For the preparation of a pharmaceutical composition in the form of an injection, the solution or suspension may be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose or glycerin) to prepare an isotonic injection with blood. Any of the commonly used carriers in the art can also be used in the preparation of the injection. For example: water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyethoxylated isostearyl alcohol, and fatty acid esters of polyethylene sorbitan. Further, a usual solvent, a buffer, or the like may be added.
本发明所述的组合物在药物组合物中的含量无特殊限制，可在很宽的范围内进行选择，通常可为质量百分比的5～95％，优先为质量百分比的30～85％。The content of the composition of the present invention in the pharmaceutical composition is not particularly limited and can be selected within a wide range, and is usually from 5 to 95% by mass, preferably from 30 to 85% by mass.
本发明所述的药物组合物的给药方法没有特殊限制。可根据患者年龄、性别和其它条件及症状，选择各种剂型的制剂给药。The administration method of the pharmaceutical composition of the present invention is not particularly limited. Formulations of various dosage forms can be selected depending on the age, sex and other conditions and symptoms of the patient.
本发明另外提供了所述通式(I)化合物、其药学上可接受的盐或所述药物组合物在制备BTK抑制剂中的应用。所述的BTK抑制剂用于治疗血栓栓塞、华氏巨球蛋白血症、炎性病症、自身免疫性疾病和B细胞淋巴瘤。The invention further provides the use of a compound of the formula (I), a pharmaceutically acceptable salt thereof or the pharmaceutical composition for the preparation of a BTK inhibitor. The BTK inhibitors are useful in the treatment of thromboembolism, Waldenstrom's macroglobulinemia, inflammatory conditions, autoimmune diseases, and B cell lymphomas.
所述的炎性或自身免疫性疾病包括但不限于：异种免疫性疾病、哮喘、类风湿性关节炎、系统性红斑狼疮、多发性硬化、特发性血小板减少性紫癜、自身免疫介导的溶血性贫血、免疫复合体介导的脉管炎和银屑病中的一种或多种。The inflammatory or autoimmune diseases include, but are not limited to, xenogeneic immune diseases, asthma, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, idiopathic thrombocytopenic purpura, autoimmune mediated One or more of hemolytic anemia, immune complex-mediated vasculitis, and psoriasis.
所述的B细胞淋巴瘤包括但不限于：慢性淋巴细胞白血病、急性淋巴细胞白血病、套细胞淋巴瘤、滤泡性淋巴瘤、小淋巴细胞淋巴瘤、弥漫性大B细胞淋巴瘤、多发性骨髓瘤、黏膜相关淋巴组织淋巴瘤、霍奇金淋巴瘤和B细胞非霍奇金淋巴瘤中的一种或多种。The B cell lymphoma includes, but is not limited to, chronic lymphocytic leukemia, acute lymphocytic leukemia, mantle cell lymphoma, follicular lymphoma, small lymphocytic lymphoma, diffuse large B-cell lymphoma, multiple bone marrow One or more of tumor, mucosa-associated lymphoid tissue lymphoma, Hodgkin's lymphoma, and B-cell non-Hodgkin's lymphoma.
具体实施方式detailed description
为了进一步阐明本发明，下面给出一系列实施例，这些实施例完全是例证性的，它们仅用来对本发明具体描述，不应当理解为对本发明的限制。In order to further clarify the invention, a series of examples are given below, which are intended to be illustrative only and are not intended to limit the invention.
实施例1Example 1
4,6-二氯-5-嘧啶甲醛(1)的制备Preparation of 4,6-dichloro-5-pyrimidinecarboxaldehyde (1)
将DMF(5.50mL,71.34mmol)于冰浴下缓慢滴入POCl 3(17.00mL,185.71mmol)，搅拌反应1h，撤去冰浴，加入4,6-二羟基嘧啶(4.00g,35.68mmol)，升温回流3h，冷却至室温，倒入冰水中，二氯甲烷萃取，减压浓缩，石油醚-乙酸乙酯(P:E＝4:1(V:V))重结晶，得黄色固体4.74g，收率75.4％，mp 68-70℃。ESI-MS:177[M+H] +； 1H NMR(300MHz,CDCl 3)：δ(ppm):8.89(s,1H),10.43(s,1H)。 DMF (5.50 mL, 71.34 mmol) was slowly added dropwise to POCl 3 (17.00 mL, 185.71 mmol), and the reaction was stirred for 1 h, the ice bath was removed, and 4,6-dihydroxypyrimidine (4.00 g, 35.68 mmol) was added. The mixture was heated to reflux for 3 h, cooled to EtOAc EtOAc (mjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH , yield 75.4%, mp 68-70 ° C. ESI-MS: 177 [M + H] +; 1 H NMR (300MHz, CDCl 3): δ (ppm): 8.89 (s, 1H), 10.43 (s, 1H).
4,6-二氯-5-嘧啶羧酸(2)的制备Preparation of 4,6-dichloro-5-pyrimidinecarboxylic acid (2)
1(4.00g,22.72mmol)和NaH 2PO 4(9.55g,79.58mmol)溶于60mL叔丁醇和10mL水混合溶剂中，冰浴下加入NaClO 2(7.66g,84.69mmol)，反应1h，减压蒸去叔丁醇，倒入水中，盐酸调pH至5，乙酸乙酯萃取减压浓缩，得黄色固体3.12g，收率71.5％，mp 131-133℃。ESI-MS:190.9[M-H] -； 1H NMR(300MHz,DMSO-d 6):δ(ppm):9.00(s,1H). 1 (4.00 g, 22.72 mmol) and NaH 2 PO 4 (9.55 g, 79.58 mmol) were dissolved in a mixture of 60 mL of tert-butanol and 10 mL of water. NaClO 2 (7.66 g, 84.69 mmol) was added in an ice bath, and reacted for 1 h. The tert-butanol was distilled off, poured into water, and the mixture was adjusted to pH 5 with hydrochloric acid, and ethyl acetate was evaporated and evaporated to dryness to give a white solid, 3.12 g, yield 71.5%, mp 131-133 ° C. ESI-MS: 190.9 [MH] - ; 1 H NMR (300 MHz, DMSO-d 6 ): δ (ppm): 9.00 (s, 1H).
(4,6-二氯嘧啶-5-基)(4-苯氧苯基)甲酮(3)的制备Preparation of (4,6-dichloropyrimidin-5-yl)(4-phenoxyphenyl)methanone (3)
2(3.00g,15.63mmol)溶于20mL无水THF中，滴加草酰氯(4.00mL,46.87mmol)和2滴DMF，室温反应4h，减压蒸去溶剂和剩余的草酰氯，无水CH 2Cl 2溶解，移至恒压滴液漏斗，冰浴下滴加至二苯醚(12.40mL,8.31mmol)和AlCl 3(3.12g,23.46mmol)的无水CH 2Cl 2中，滴毕，回流反应3h，倒入冰水，浓盐酸调pH至2，CH 2Cl 2萃取，无水硫酸镁干燥，柱层析纯化[石油醚:乙酸乙酯(P:E)＝5:1(V:V)]，得白色固体3.82g，收率71.1％，mp 91-93℃。ESI-MS:345[M+H] +； 1H NMR(300MHz,CDCl 3):δ(ppm):7.07(d,J＝8.97Hz,2H),7.13(d,J＝9.72Hz,2H),7.26(t,J＝6.27Hz,1H),7.44(t,J＝7.53Hz,2H),7.80(d,J＝9.72Hz,2H),8.91(s,1H). 2 (3.00 g, 15.63 mmol) was dissolved in 20 mL of anhydrous THF, oxalyl chloride (4.00 mL, 46.87 mmol) and 2 D of DMF were added dropwise, and reacted at room temperature for 4 h, and the solvent and the remaining oxalyl chloride were evaporated under reduced pressure. 2 Cl 2 was dissolved, transferred to a constant pressure dropping funnel, and added dropwise to diphenyl ether (12.40 mL, 8.31 mmol) and AlCl 3 (3.12 g, 23.46 mmol) in anhydrous CH 2 Cl 2 under ice-cooling. , refluxing reaction for 3 h, poured into ice water, concentrated hydrochloric acid to pH 2, extracted with CH 2 Cl 2 , dried over anhydrous magnesium sulfate, purified by column chromatography [ petroleum ether: ethyl acetate (P: E) = 5:1 ( V: V)] gave a white solid 3.82 g, yield 71.1%, mp 91-93. ESI-MS: 345 [M+H] + ; 1 H NMR (300 MHz, CDCl 3 ): δ (ppm): 7.07 (d, J = 8.97 Hz, 2H), 7.13 (d, J = 9.72 Hz, 2H) , 7.26 (t, J = 6.27 Hz, 1H), 7.44 (t, J = 7.53 Hz, 2H), 7.80 (d, J = 9.72 Hz, 2H), 8.91 (s, 1H).
(4-氨基-6-氯嘧啶-5-基)(4-苯氧苯基)甲酮(4)的制备Preparation of (4-amino-6-chloropyrimidin-5-yl)(4-phenoxyphenyl)methanone (4)
3(1.0g,2.91mmol)加入25mL乙醇和氨水(8mL,52.0mmol)，室温反应24h，冰浴冷却，抽滤，干燥，得白色固体0.51g，收率53.9％，mp 264-266℃。ESI-MS:324[M-H] -； 1H NMR(300MHz,DMSO-d 6):δ(ppm):7.07(d,J＝8.82Hz,2H),7.16(d,J＝7.68Hz,2H),7.28(t,J＝7.35Hz,1H),7.35(s,2H),7.49(t,J＝7.86Hz,2H),7.84(d,J＝8.79Hz,2H),8.32(s,1H).(S)-3-[[6-氨基-5-(4-苯氧基苯甲酰基)嘧啶-4-基]氨甲基]哌啶-1-甲酸叔丁酯(5a)的制备 3 (1.0 g, 2.91 mmol) was added 25 mL of ethanol and aqueous ammonia (8 mL, 52.0 mmol), and the mixture was reacted at room temperature for 24 h, cooled in an ice bath, filtered, and dried to give a white solid, 0.51 g, mp 264-266 ° C. ESI-MS: 324 [MH] - ; 1 H NMR (300 MHz, DMSO-d 6 ): δ (ppm): 7.07 (d, J = 8.82 Hz, 2H), 7.16 (d, J = 7.68 Hz, 2H) , 7.28 (t, J = 7.35 Hz, 1H), 7.35 (s, 2H), 7.49 (t, J = 7.86 Hz, 2H), 7.84 (d, J = 8.79 Hz, 2H), 8.32 (s, 1H) . Preparation of (S)-3-[[6-amino-5-(4-phenoxybenzoyl)pyrimidin-4-yl]aminomethyl]piperidine-1-carboxylic acid tert-butyl ester (5a)
4(0.30g,0.92mmol)溶于20mL乙醇中，加入(S)-1-Boc-3-氨甲基哌啶(0.26g,1.20mmol)和DIPEA(0.18mL,1.01mmol)，回流反应48h，乙酸乙酯溶解，抽滤，柱层析纯化[P:E＝1:1(V:V)]，得淡黄色固体0.24g，收率51.8％。ESI-MS:504[M+H] +. 4 (0.30 g, 0.92 mmol) was dissolved in 20 mL of ethanol, (S)-1-Boc-3-aminomethylpiperidine (0.26 g, 1.20 mmol) and DIPEA (0.18 mL, 1.01 mmol). Ethyl acetate was dissolved, suction filtered, and purified by column chromatography [P: E = 1:1 (V:V)] to give a pale yellow solid, 0.24 g, yield 51.8%. ESI-MS: 504 [M+H] + .
(S)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨甲基]哌啶-1-基]-2-丙烯-1-酮(A-1)的制备(S)-1-[3-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]aminomethyl]piperidin-1-yl]-2-propene-1 - Preparation of ketone (A-1)
Figure PCTCN2018084300-appb-000009
Figure PCTCN2018084300-appb-000009
5a(0.20g,0.40mmol)溶于20mL CH 2Cl 2中，冰浴下加入浓盐酸(0.33mL,4.0mmol)，滴毕室温反应12h，减压浓缩后重新溶于四氢呋喃-水(THF:H 2O＝5:1(V:V))混合体系，加入NaHCO 3(0.10g,1.20mmol)，冰浴条件下滴加丙烯酰氯(0.04mL,0.46mmol)，室温反应过夜，减压蒸馏除去THF，剩余反应液加入适量水，CH 2Cl 2萃取，无水硫酸镁干燥，柱层析纯化[乙酸乙酯(EA)]，得黄色固体0.04g，收率17.6％。ESI-MS:458[M+H] +； 1H NMR(300MHz,DMSO-d 6):δ(ppm):8.01(s,1H),7.69(d,J＝8.2Hz,2H),7.44(t,J＝7.7Hz,2H),7.22(t,J＝7.4Hz,1H),7.10-6.99(m,4H),6.79-6.52(m,3H),6.02(d,J＝17.0Hz,1H),5.59(t,J＝13.1Hz,1H),4.20-3.69(m,3H),3.23(s,2H),3.08-2.95(m,1H),2.79(s,1H),1.61(s,3H),1.20(d,J＝31.9Hz,2H). 5a (0.20g, 0.40mmol) was dissolved in 20mL CH 2 Cl 2 in an ice bath was added concentrated hydrochloric acid (0.33mL, 4.0mmol), dropwise at rt 12h, concentrated under reduced pressure redissolved in tetrahydrofuran - water (THF: H 2 O=5:1 (V:V)) mixed system, NaHCO 3 (0.10 g, 1.20 mmol) was added, and acryloyl chloride (0.04 mL, 0.46 mmol) was added dropwise under ice-cooling, of THF was removed, the remaining amount of water was added to the reaction, CH 2 and extracted 2 Cl, dried over anhydrous magnesium sulfate, and purified by column chromatography [ethyl acetate (EA)], to give a yellow solid 0.04g, yield 17.6%. ESI-MS: 458 [M+H] + ; 1 H NMR (300 MHz, DMSO-d 6 ): δ (ppm): 8.01 (s, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.44 ( t, J = 7.7 Hz, 2H), 7.22 (t, J = 7.4 Hz, 1H), 7.10-6.99 (m, 4H), 6.79-6.52 (m, 3H), 6.02 (d, J = 17.0 Hz, 1H) ), 5.59 (t, J = 13.1 Hz, 1H), 4.20-3.69 (m, 3H), 3.23 (s, 2H), 3.08-2.95 (m, 1H), 2.79 (s, 1H), 1.61 (s, 3H), 1.20 (d, J = 31.9 Hz, 2H).
实施例2Example 2
(R)-3-[[6-氨基-5-(4-苯氧基苯甲酰基)嘧啶-4-基]氨甲基]哌啶-1-甲酸叔丁酯(5b)的制备Preparation of (R)-3-[[6-amino-5-(4-phenoxybenzoyl)pyrimidin-4-yl]aminomethyl]piperidine-1-carboxylic acid tert-butyl ester (5b)
参照5a的制备方法，由4和(R)-1-Boc-3-氨甲基哌啶反应得淡黄色固体，收率56.2％。ESI-MS:504[M+H] +. Referring to the preparation method of 5a, 4 and (R)-1-Boc-3-aminomethylpiperidine were reacted to give a pale yellow solid, yield 56.2%. ESI-MS: 504 [M+H] + .
(R)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨甲基]哌啶-1-基]-2-丙烯-1-酮(A-2)的制备(R)-1-[3-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]aminomethyl]piperidin-1-yl]-2-propene-1 - Preparation of ketone (A-2)
Figure PCTCN2018084300-appb-000010
Figure PCTCN2018084300-appb-000010
参照A-1的制备方法，由5b脱Boc保护基后与丙烯酰氯反应制得黄色固体，收率17.2％。ESI-MS:458[M+H] +； 1H NMR(300MHz,DMSO-d 6):δ(ppm):7.97(s,1H),7.65(d,J＝8.2Hz,2H),7.39(d,J＝8.7Hz,2H),7.19(s,1H),7.09-6.94(m,4H),6.64(s,3H),5.99(d,J＝16.7Hz,1H),5.57(s,1H),4.20-3.62(m,3H),3.18(s,2H),2.98(s,1H),2.74(s,1H),1.57(s,3H),1.16(d,J＝24.2Hz,2H). Referring to the preparation method of A-1, a yellow solid was obtained by reacting 5b with a Boc protecting group and reacting with acryloyl chloride, and the yield was 17.2%. ESI-MS: 458 [M + H] +; 1 H NMR (300MHz, DMSO-d 6): δ (ppm): 7.97 (s, 1H), 7.65 (d, J = 8.2Hz, 2H), 7.39 ( d, J=8.7 Hz, 2H), 7.19 (s, 1H), 7.09-6.94 (m, 4H), 6.64 (s, 3H), 5.99 (d, J = 16.7 Hz, 1H), 5.57 (s, 1H) ), 4.20-3.62 (m, 3H), 3.18 (s, 2H), 2.98 (s, 1H), 2.74 (s, 1H), 1.57 (s, 3H), 1.16 (d, J = 24.2 Hz, 2H) .
实施例3Example 3
[4-氨基-6-[(哌啶-2-甲基)氨基]嘧啶-5-基](4-苯氧苯基)甲酮(5c)的制备Preparation of [4-amino-6-[(piperidin-2-methyl)amino]pyrimidin-5-yl](4-phenoxyphenyl)methanone (5c)
参照5a的制备方法，由4和2-氨甲基哌啶反应得淡黄色固体，收率45.8％。ESI-MS:404[M+H] +. Referring to the preparation method of 5a, 4 and 2-aminomethylpiperidine were reacted to obtain a pale yellow solid in a yield of 45.8%. ESI-MS: 404 [M+H] + .
1-[2-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨甲基]哌啶-1-基]-2-丙烯-1-酮(A-3)的制备1-[2-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]aminomethyl]piperidin-1-yl]-2-propen-1-one (A -3) preparation
Figure PCTCN2018084300-appb-000011
Figure PCTCN2018084300-appb-000011
5c(0.23g,0.57mmol)溶于18mL四氢呋喃-水(THF:H 2O＝5:1(V:V))混合体系，加入NaHCO 3(0.14g,1.71mmol)，冰浴条件下滴加丙烯酰氯(0.06mL,0.68mmol)，室温反应过夜，减压蒸馏除去THF，剩余反应液加入适量水，CH 2Cl 2萃取，无水硫酸镁干燥，柱层析纯化[乙酸乙酯(EA)]，得黄色固体0.04g，收率16.0％。ESI-MS:458[M+H] +； 1H NMR(300MHz,DMSO-d 6):δ(ppm):8.04(s,1H),7.65(d,J＝8.3Hz,2H),7.45(t,J＝7.9Hz,2H),7.25(q,J＝8.6,7.4Hz,2H),7.11(d,J＝8.0Hz,2H),7.00(d,J＝8.4Hz,2H),6.65(dd,J＝16.4,10.6Hz,1H),6.50(s,2H),5.92(d,J＝16.3Hz,1H),5.46(d,J＝11.0Hz,1H),4.33(s,1H),3.62(s,2H),2.72(t,J＝13.1Hz,1H),1.64-1.47(m,5H),1.23(s,2H). 5c (0.23g, 0.57mmol) was dissolved in 18mL of tetrahydrofuran-water (THF:H 2 O=5:1 (V:V)) mixed system, added NaHCO 3 (0.14g, 1.71mmol), and added dropwise in ice bath acryloyl chloride (0.06mL, 0.68mmol), at room temperature overnight, THF was distilled off under reduced pressure, the remaining amount of water added to the reaction solution, CH 2 Cl 2 extracts, dried over anhydrous magnesium sulfate, and purified by column chromatography [ethyl acetate (EA) ], obtained a yellow solid 0.04 g, yield 16.0%. ESI-MS: 458 [M + H] +; 1 H NMR (300MHz, DMSO-d 6): δ (ppm): 8.04 (s, 1H), 7.65 (d, J = 8.3Hz, 2H), 7.45 ( t, J = 7.9 Hz, 2H), 7.25 (q, J = 8.6, 7.4 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 6.65 ( Dd, J = 16.4, 10.6 Hz, 1H), 6.50 (s, 2H), 5.92 (d, J = 16.3 Hz, 1H), 5.46 (d, J = 11.0 Hz, 1H), 4.33 (s, 1H), 3.62 (s, 2H), 2.72 (t, J = 13.1 Hz, 1H), 1.64-1.47 (m, 5H), 1.23 (s, 2H).
实施例4Example 4
(R)-3-[[6-氨基-5-(4-苯氧基苯甲酰基)嘧啶-4-基]氨基]吡咯烷-1-甲酸叔丁酯(5d)的制备Preparation of (R)-3-[[6-amino-5-(4-phenoxybenzoyl)pyrimidin-4-yl]amino]pyrrolidine-1-carboxylic acid tert-butyl ester (5d)
参照5a的制备方法，由4和(R)-1-Boc-3-氨基吡咯烷反应得淡黄色固体，收率57.1％。ESI-MS:476[M+H] +. Referring to the preparation method of 5a, 4 and (R)-1-Boc-3-aminopyrrolidine were reacted to obtain a pale yellow solid in a yield of 57.1%. ESI-MS: 476 [M+H] + .
(R)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨基]吡咯烷-1-基]-2-丙烯-1-酮(A-4)的制备(R)-1-[3-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]amino]pyrrolidin-1-yl]-2-propen-1-one Preparation of (A-4)
Figure PCTCN2018084300-appb-000012
Figure PCTCN2018084300-appb-000012
参照A-1的制备方法，由5d脱Boc保护基后与丙烯酰氯反应制得黄色固体，收率19.5％。ESI-MS:430[M+H] +； 1H NMR(300MHz,DMSO-d 6):δ(ppm):8.06(s,1H),7.64(dd,J＝8.8,2.5Hz,2H),7.45(t,J＝7.8Hz,2H),7.27-7.19(m,1H),7.11(td,J＝7.3,1.3Hz,2H),6.99-6.79(m, 5H),6.49(ddd,J＝16.8,10.3,3.6Hz,1H),6.11(dt,J＝16.8,2.5Hz,1H),5.63(ddd,J＝10.3,4.4,2.5Hz,1H),4.57(dq,J＝37.8,5.8Hz,1H),3.66(ddd,J＝67.6,11.7,6.4Hz,2H),3.21(dq,J＝9.5,5.9,5.4Hz,1H),2.15-1.91(m,1H),1.75(ddt,J＝33.0,12.9,6.0Hz,1H),1.31-1.12(m,1H). Referring to the preparation method of A-1, a yellow solid was obtained by reacting 5d with a Boc protecting group and then reacting with acryloyl chloride, and the yield was 19.5%. ESI-MS: 430 [M+H] + ; 1 H NMR (300 MHz, DMSO-d 6 ): δ (ppm): 8.06 (s, 1H), 7.64 (dd, J = 8.8, 2.5 Hz, 2H), 7.45 (t, J = 7.8 Hz, 2H), 7.27-7.19 (m, 1H), 7.11 (td, J = 7.3, 1.3 Hz, 2H), 6.99-6.79 (m, 5H), 6.49 (ddd, J = 16.8, 10.3, 3.6 Hz, 1H), 6.11 (dt, J = 16.8, 2.5 Hz, 1H), 5.63 (ddd, J = 10.3, 4.4, 2.5 Hz, 1H), 4.57 (dq, J = 37.8, 5.8 Hz) , 1H), 3.66 (ddd, J = 67.6, 11.7, 6.4 Hz, 2H), 3.21 (dq, J = 9.5, 5.9, 5.4 Hz, 1H), 2.15 - 1.91 (m, 1H), 1.75 (ddt, J =33.0, 12.9, 6.0 Hz, 1H), 1.31-1.12 (m, 1H).
实施例5Example 5
(S)-3-[[6-氨基-5-(4-苯氧基苯甲酰基)嘧啶-4-基]氨基]吡咯烷-1-甲酸叔丁酯(5e)的制备Preparation of (S)-3-[[6-Amino-5-(4-phenoxybenzoyl)pyrimidin-4-yl]amino]pyrrolidine-1-carboxylic acid tert-butyl ester (5e)
参照5a的制备方法，由4和(S)-1-Boc-3-氨基吡咯烷反应得淡黄色固体，收率52.8％。ESI-MS:476[M+H] +. Referring to the preparation method of 5a, 4 and (S)-1-Boc-3-aminopyrrolidine were reacted to give a pale yellow solid, yield 52.8%. ESI-MS: 476 [M+H] + .
(S)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨基]吡咯烷-1-基]-2-丙烯-1-酮(A-5)的制备(S)-1-[3-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]amino]pyrrolidin-1-yl]-2-propen-1-one Preparation of (A-5)
Figure PCTCN2018084300-appb-000013
Figure PCTCN2018084300-appb-000013
参照A-1的制备方法，由5e脱Boc保护基后与丙烯酰氯反应制得黄色固体，收率13.0％。ESI-MS:430[M+H] +； 1H NMR(300MHz,Chloroform-d):δ(ppm):8.59(s,1H),7.82-7.71(m,2H),7.41-7.27(m,2H),7.22-7.05(m,3H),7.05-6.93(m,2H),6.62(dd,J＝10.0,16.8Hz,1H),6.28(dd,J＝10.1,13.8Hz,1H),5.67(dd,J＝13.8,16.7Hz,1H),4.09(s,2H),3.88(dd,J＝6.9,9.4Hz,1H),3.62-3.37(m,3H),3.30(p,J＝6.9Hz,1H),2.24-2.06(m,1H),1.92-1.74(m,1H),0.93(s,1H). Referring to the preparation method of A-1, a yellow solid was obtained by reacting 5e with a Boc protecting group and then reacting with acryloyl chloride, and the yield was 13.0%. ESI-MS: 430 [M+H] + ; 1 H NMR (300 MHz, Chloroform-d): δ (ppm): 8.59 (s, 1H), 7.82-7.71 (m, 2H), 7.41-7.27 (m, 2H), 7.22-7.05 (m, 3H), 7.05-6.93 (m, 2H), 6.62 (dd, J = 10.0, 16.8 Hz, 1H), 6.28 (dd, J = 10.1, 13.8 Hz, 1H), 5.67 (dd, J = 13.8, 16.7 Hz, 1H), 4.09 (s, 2H), 3.88 (dd, J = 6.9, 9.4 Hz, 1H), 3.62-3.37 (m, 3H), 3.30 (p, J = 6.9) Hz, 1H), 2.24-2.06 (m, 1H), 1.92-1.74 (m, 1H), 0.93 (s, 1H).
实施例6Example 6
(S)-2-[[6-氨基-5-(4-苯氧基苯甲酰基)嘧啶-4-基]氨甲基]吡咯烷-1-甲酸叔丁酯(5f)的制备Preparation of (S)-2-[[6-amino-5-(4-phenoxybenzoyl)pyrimidin-4-yl]aminomethyl]pyrrolidine-1-carboxylic acid tert-butyl ester (5f)
参照5a的制备方法，由4和(S)-1-Boc-2-氨甲基吡咯烷反应得淡黄色固体，收率47.9％。ESI-MS:490[M+H] +. Referring to the preparation method of 5a, 4 and (S)-1-Boc-2-aminomethylpyrrolidine were reacted to give a pale yellow solid, yield 47.9%. ESI-MS: 490 [M+H] + .
(S)-1-[2-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨甲基]吡咯烷-1-基]-2-丙烯-1-酮(A-6)的制备(S)-1-[2-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]aminomethyl]pyrrolidin-1-yl]-2-propene-1 - Preparation of ketone (A-6)
Figure PCTCN2018084300-appb-000014
Figure PCTCN2018084300-appb-000014
参照A-1的制备方法，由5f脱Boc保护基后与丙烯酰氯反应制得黄色固体，收率18.6％。ESI-MS:444[M+H] +； 1H NMR(300MHz,DMSO-d 6):δ(ppm):8.08(s,1H),7.69(dd,J＝8.7,11.5Hz,3H),7.49-7.42(m,3H),7.24(dd,J＝1.5,7.5Hz,2H),7.09(dq,J＝1.1,7.5Hz,3H),7.05-6.99(m,3H),6.66-6.47(m,3H),6.11(ddd,J＝2.6,16.7,19.1Hz,1H),5.65(dt,J＝3.1,10.2Hz,1H),4.15(s,1H),1.76(d,J＝13.6Hz,2H),1.69(s,2H). Referring to the preparation method of A-1, a yellow solid was obtained by reacting 5f with a Boc protecting group and then reacting with acryloyl chloride, and the yield was 18.6%. ESI-MS: 444 [M+H] + ; 1 H NMR (300 MHz, DMSO-d 6 ): δ (ppm): 8.08 (s, 1H), 7.69 (dd, J = 8.7, 11.5 Hz, 3H), 7.49-7.42 (m, 3H), 7.24 (dd, J = 1.5, 7.5 Hz, 2H), 7.09 (dq, J = 1.1, 7.5 Hz, 3H), 7.05-6.99 (m, 3H), 6.66-6.47 ( m, 3H), 6.11 (ddd, J = 2.6, 16.7, 19.1 Hz, 1H), 5.65 (dt, J = 3.1, 10.2 Hz, 1H), 4.15 (s, 1H), 1.76 (d, J = 13.6 Hz) , 2H), 1.69 (s, 2H).
实施例7Example 7
(R)-2-[[6-氨基-5-(4-苯氧基苯甲酰基)嘧啶-4-基]氨甲基]吡咯烷-1-甲酸叔丁酯(5g)的制备Preparation of (R)-2-[[6-amino-5-(4-phenoxybenzoyl)pyrimidin-4-yl]aminomethyl]pyrrolidine-1-carboxylic acid tert-butyl ester (5 g)
参照5a的制备方法，由4和(R)-1-Boc-2-氨甲基吡咯烷反应得淡黄色固体，收率56.1％。ESI-MS:490[M+H] +. Referring to the preparation method of 5a, 4 and (R)-1-Boc-2-aminomethylpyrrolidine were reacted to obtain a pale yellow solid in a yield of 56.1%. ESI-MS: 490 [M+H] + .
(R)-1-[2-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨甲基]吡咯烷-1-基]-2-丙烯-1-酮(A-7)的制备(R)-1-[2-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]aminomethyl]pyrrolidin-1-yl]-2-propene-1 - Preparation of ketone (A-7)
Figure PCTCN2018084300-appb-000015
Figure PCTCN2018084300-appb-000015
参照A-1的制备方法，由5g脱Boc保护基后与丙烯酰氯反应制得黄色固体，收率18.9％。ESI-MS:444[M+H] +； 1H NMR(300MHz,DMSO-d 6):δ(ppm):8.08(s,1H),7.69(dd,J＝8.5,11.3Hz,3H),7.48-7.42(m,3H),7.24(d,J＝6.8Hz,2H),7.12-7.08(m,3H),7.02(dd,J＝5.3,8.6Hz,3H),6.64-6.47(m,3H),6.18-6.04(m,1H),5.67-5.62(m,1H),4.16(s,1H),1.77(d,J＝14.2Hz,2H),1.70(s,2H). Referring to the preparation method of A-1, a yellow solid was obtained by reacting 5 g of a deprotected group with acryloyl chloride, and the yield was 18.9%. ESI-MS: 444 [M+H] + ; 1 H NMR (300 MHz, DMSO-d 6 ): δ (ppm): 8.08 (s, 1H), 7.69 (dd, J = 8.5, 11.3 Hz, 3H), 7.48-7.42 (m, 3H), 7.24 (d, J = 6.8 Hz, 2H), 7.12-7.08 (m, 3H), 7.02 (dd, J = 5.3, 8.6 Hz, 3H), 6.64-6.47 (m, 3H), 6.18-6.04 (m, 1H), 5.67-5.62 (m, 1H), 4.16 (s, 1H), 1.77 (d, J = 14.2 Hz, 2H), 1.70 (s, 2H).
实施例8Example 8
3-[[6-氨基-5-(4-苯氧基苯甲酰基)嘧啶-4-基]氨甲基]氮杂环丁烷-1-甲酸叔丁酯(5h)的制备Preparation of tert-butyl 3-[[6-amino-5-(4-phenoxybenzoyl)pyrimidin-4-yl]aminomethyl]azetidin-1-carboxylate (5h)
参照5a的制备方法，由4和1-Boc-3-氨甲基氮杂环丁烷反应得淡黄色固体，收率59.7％。ESI-MS:476[M+H] +. Referring to the preparation method of 5a, 4 and 1-Boc-3-aminomethylazetidine were reacted to give a pale yellow solid in a yield of 59.7%. ESI-MS: 476 [M+H] + .
1-[3-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨甲基]氮杂环丁烷-1-基]-2-丙烯-1-酮(A-8)的制备1-[3-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]aminomethyl]azetidin-1-yl]-2-propene-1- Preparation of ketone (A-8)
Figure PCTCN2018084300-appb-000016
Figure PCTCN2018084300-appb-000016
参照A-1的制备方法，由5h脱Boc保护基后与丙烯酰氯反应制得黄色固体，收率16.9％。ESI-MS:430[M+H] +； 1H NMR(300MHz,Chloroform-d):δ(ppm):8.41(s,1H),7.84-7.73(m,2H),7.41-7.27(m,2H),7.22-7.05(m,3H),7.05-6.93(m,2H),6.62(dd,J＝10.0,16.8Hz,1H),6.27(dd,J＝10.1,13.8Hz,1H),5.69(dd,J＝13.8,16.8Hz,1H),5.07(s,1H),4.53(s,2H),3.99(dd,J＝7.0,11.2Hz,2H),3.61(dd,J＝7.0,11.2Hz,2H),3.24(d,J＝7.0Hz,2H),2.88(hept,J＝6.9Hz,1H). Referring to the preparation method of A-1, a yellow solid was obtained by reacting with acryloyl chloride after removing the Boc protecting group for 5 hours, and the yield was 16.9%. ESI-MS: 430 [M+H] + ; 1 H NMR (300 MHz, Chloroform-d): δ (ppm): 8.41 (s, 1H), 7.84-7.73 (m, 2H), 7.41-7.27 (m, 2H), 7.22-7.05 (m, 3H), 7.05-6.93 (m, 2H), 6.62 (dd, J = 10.0, 16.8 Hz, 1H), 6.27 (dd, J = 10.1, 13.8 Hz, 1H), 5.69 (dd, J = 13.8, 16.8 Hz, 1H), 5.07 (s, 1H), 4.53 (s, 2H), 3.99 (dd, J = 7.0, 11.2 Hz, 2H), 3.61 (dd, J = 7.0, 11.2) Hz, 2H), 3.24 (d, J = 7.0 Hz, 2H), 2.88 (hept, J = 6.9 Hz, 1H).
实施例9Example 9
(R)-3-[[6-氨基-5-(4-苯氧基苯甲酰基)嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(5i)的制备Preparation of (R)-3-[[6-amino-5-(4-phenoxybenzoyl)pyrimidin-4-yl]amino]piperidine-1-carboxylic acid tert-butyl ester (5i)
参照5a的制备方法，由4和(R)-1-Boc-3-氨基哌啶反应得淡黄色固体，收率67.5％，mp68-70℃。ESI-MS:512[M+Na] +；1H NMR(300MHz,DMSO-d6):δ(ppm):1.16(t,J＝6.96Hz,2H),1.22～1.24(m,2H),1.32(s,9H),1.49～1.51(m,1H),1.70～1.72(m,1H),2.24～2.26(m,1H),4.00～4.02(m,1H),6.76(s,2H),7.01(d,J＝8.70Hz,2H),7.16(d,J＝7.68Hz,3H),7.22(t,J＝7.41Hz,1H),7.44(t,J＝8.19Hz,2H),7.65(d,J＝8.64Hz,2H),8.02(s,1H). Referring to the preparation method of 5a, 4 and (R)-1-Boc-3-aminopiperidine were reacted to give a pale yellow solid (yield: 67.5%, mp 68 - 70 ° C). ESI-MS: 512 [M+Na] + ; 1H NMR (300 MHz, DMSO-d6): δ (ppm): 1.16 (t,J=6.96 Hz, 2H), 1.22 to 1.24 (m, 2H), 1.32 ( s, 9H), 1.49 to 1.51 (m, 1H), 1.70 to 1.72 (m, 1H), 2.24 to 2.26 (m, 1H), 4.00 to 4.02 (m, 1H), 6.76 (s, 2H), 7.01 ( d, J = 8.70 Hz, 2H), 7.16 (d, J = 7.68 Hz, 3H), 7.22 (t, J = 7.41 Hz, 1H), 7.44 (t, J = 8.19 Hz, 2H), 7.65 (d, J = 8.64 Hz, 2H), 8.02 (s, 1H).
(R)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨基]哌啶-1-基]-2-氯乙烷-1-酮(A-9)的制备(R)-1-[3-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]amino]piperidin-1-yl]-2-chloroethane-1 - Preparation of ketone (A-9)
Figure PCTCN2018084300-appb-000017
Figure PCTCN2018084300-appb-000017
参照A-1的制备方法，由5i脱Boc保护基后与氯乙酰氯反应制得黄色固体，收率19.7％。ESI-MS:466[M+H] +； 1H NMR(300MHz,Chloroform-d):δ(ppm):8.58(s,1H),7.82-7.72(m,2H),7.41-7.27(m,2H),7.18-7.04(m,3H),7.05-6.93(m,2H),4.51(d,J＝12.3Hz,1H),4.43-4.23(m,2H),4.05(s,2H),3.86(dd,J＝6.8,12.3Hz,1H),3.34-3.08(m,2H),2.89(dt,J＝7.0,12.5Hz,1H),2.13-1.95(m,1H),1.80-1.47(m,3H),1.07(s,1H). Referring to the preparation method of A-1, a yellow solid was obtained by reacting 5i with a Boc protecting group and reacting with chloroacetyl chloride in a yield of 19.7%. ESI-MS: 466 [M+H] + ; 1 H NMR (300 MHz, Chloroform-d): δ (ppm): 8.58 (s, 1H), 7.82-7.72 (m, 2H), 7.41-7.27 (m, 2H), 7.18-7.04 (m, 3H), 7.05-6.93 (m, 2H), 4.51 (d, J = 12.3 Hz, 1H), 4.43-4.23 (m, 2H), 4.05 (s, 2H), 3.86 (dd, J = 6.8, 12.3 Hz, 1H), 3.34 - 3.08 (m, 2H), 2.89 (dt, J = 7.0, 12.5 Hz, 1H), 2.13-1.95 (m, 1H), 1.80-1.47 (m , 3H), 1.07 (s, 1H).
实施例10Example 10
(S)-1-[2-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨甲基]吡咯烷-1-基]-2-氯乙烷-1-酮(A-10)的制备(S)-1-[2-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]aminomethyl]pyrrolidin-1-yl]-2-chloroethane Preparation of 1-ketone (A-10)
Figure PCTCN2018084300-appb-000018
Figure PCTCN2018084300-appb-000018
参照A-1的制备方法，由5f脱Boc保护基后与氯乙酰氯反应制得黄色固体，收率20.2％。ESI-MS:466[M+H] +； 1H NMR(300MHz,Chloroform-d):δ(ppm):8.54(s,1H),7.82-7.71(m,2H),7.41-7.27(m,2H),7.19-7.05(m,3H),7.05-6.93(m,2H),5.07(s,1H),4.74(d,J＝12.4Hz,1H),4.17(d,J＝12.4Hz,1H),4.16-3.97(m,1H),3.93(s,2H),3.90-3.66(m,3H),3.35(dt,J＝6.8,9.4Hz,1H),2.20-1.85(m,3H),1.90-1.69(m,1H). Referring to the preparation method of A-1, a yellow solid was obtained by reacting 5f with a Boc protecting group and then reacting with chloroacetyl chloride in a yield of 20.2%. ESI-MS: 466 [M+H] + ; 1 H NMR (300 MHz, Chloroform-d): δ (ppm): 8.54 (s, 1H), 7.82-7.71 (m, 2H), 7.41-7.27 (m, 2H), 7.19-7.05 (m, 3H), 7.05-6.93 (m, 2H), 5.07 (s, 1H), 4.74 (d, J = 12.4 Hz, 1H), 4.17 (d, J = 12.4 Hz, 1H) ), 4.16-3.97 (m, 1H), 3.93 (s, 2H), 3.90-3.66 (m, 3H), 3.35 (dt, J = 6.8, 9.4 Hz, 1H), 2.20 - 1.85 (m, 3H), 1.90-1.69 (m, 1H).
实施例11Example 11
[4-氨基-6-[(2-氨基乙基)氨基]嘧啶-5-基](4-苯氧苯基)甲酮(5j)的制备Preparation of [4-amino-6-[(2-aminoethyl)amino]pyrimidin-5-yl](4-phenoxyphenyl)methanone (5j)
参照5a的制备方法，由4和乙二胺反应得淡黄色固体，收率49.7％。ESI-MS:350[M+H] +.N-[2-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨基]乙基]丙烯酰胺(A-11)的制备 Referring to the preparation method of 5a, 4 and ethylenediamine were reacted to obtain a pale yellow solid in a yield of 49.7%. ESI-MS: 350 [M+H] + .N-[2-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]amino]ethyl]acrylamide (A Preparation of -11)
Figure PCTCN2018084300-appb-000019
Figure PCTCN2018084300-appb-000019
参照A-3的制备方法，由5j和丙烯酰氯反应得黄色固体，收率18.2％。ESI-MS:404[M+H] +； 1H NMR(300MHz,Chloroform-d):δ(ppm):8.57(s,1H),7.74-7.63(m,2H),7.41-7.27(m,2H),7.12(ddt,J＝2.1,6.3,8.3Hz,3H),7.05-6.93(m,2H),6.62(s,1H),6.48(dd,J＝10.1,16.7Hz,1H),6.07(dd,J＝10.1,13.8Hz,1H),5.79(dd,J＝13.8,16.6Hz,1H),5.07(s,1H),3.96-3.82(m,4H),3.51(t,J＝4.9Hz,2H). Referring to the preparation method of A-3, 5j and acryloyl chloride were reacted to obtain a yellow solid in a yield of 18.2%. ESI-MS: 404 [M+H] + ; 1 H NMR (300 MHz, Chloroform-d): δ (ppm): 8.57 (s, 1H), 7.74-7.63 (m, 2H), 7.41-7.27 (m, 2H), 7.12 (ddt, J=2.1, 6.3, 8.3 Hz, 3H), 7.05-6.93 (m, 2H), 6.62 (s, 1H), 6.48 (dd, J = 10.1, 16.7 Hz, 1H), 6.07 (dd, J = 10.1, 13.8 Hz, 1H), 5.79 (dd, J = 13.8, 16.6 Hz, 1H), 5.07 (s, 1H), 3.96-3.82 (m, 4H), 3.51 (t, J = 4.9) Hz, 2H).
实施例12Example 12
(S)-1-[2-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨甲基]吡咯烷-1-基]丙烷-1-酮(A-12)的制备(S)-1-[2-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]aminomethyl]pyrrolidin-1-yl]propan-1-one ( Preparation of A-12)
Figure PCTCN2018084300-appb-000020
Figure PCTCN2018084300-appb-000020
参照A-1的制备方法，由5f脱Boc保护基后与丙酰氯反应制得黄色固体，收率19.8％。ESI-MS:446[M+H] +； 1H NMR(300MHz,DMSO-d 6):δ(ppm):8.01(d,J＝8.8Hz,1H),7.69(dd,J＝8.7,10.2Hz,2H),7.50-7.41(m,2H),7.23(t,J＝7.6Hz,1H),7.17-7.08(m,2H),7.02(dd,J＝4.3,8.7Hz,2H),6.66(s,1H),6.59(s,1H),4.01(d,J＝8.7Hz,1H),3.45(dq,J＝6.0,7.0,12.7Hz,4H),2.43(dd,J＝5.3,7.5Hz,1H),2.23-2.13(m,1H),1.77(s,1H),1.66(s,1H),1.25-1.15(m,2H),1.02-0.88(m,4H). Referring to the preparation method of A-1, a yellow solid was obtained by reacting 5f with a Boc protecting group and propionyl chloride, and the yield was 19.8%. ESI-MS: 446 [M+H] + ; 1 H NMR (300 MHz, DMSO-d 6 ): δ (ppm): 8.01 (d, J = 8.8 Hz, 1H), 7.69 (dd, J = 8.7, 10.2 Hz, 2H), 7.50-7.41 (m, 2H), 7.23 (t, J = 7.6 Hz, 1H), 7.17-7.08 (m, 2H), 7.02 (dd, J = 4.3, 8.7 Hz, 2H), 6.66 (s, 1H), 6.59 (s, 1H), 4.01 (d, J = 8.7 Hz, 1H), 3.45 (dq, J = 6.0, 7.0, 12.7 Hz, 4H), 2.43 (dd, J = 5.3, 7.5 Hz, 1H), 2.23 - 2.13 (m, 1H), 1.77 (s, 1H), 1.66 (s, 1H), 1.25-1.15 (m, 2H), 1.02-0.88 (m, 4H).
实施例13Example 13
(4,6-二氯嘧啶-5-基)-N-苯基甲酰胺(6a)的制备Preparation of (4,6-dichloropyrimidin-5-yl)-N-phenylformamide (6a)
2(2.0g,10.36mmol)溶于20mL无水THF中，滴加草酰氯(2.65mL,31.09mmol)和2滴DMF，室温反应4h，减压蒸去溶剂和剩余的草酰氯，无水CH 2Cl 2溶解，移至恒压滴液 漏斗，冰浴下滴加至苯胺(1.04mL,11.39mmol)和三乙胺(3.14g,31.07mmol)的无水CH 2Cl 2中，滴毕，室温反应过夜，反应液倒入适量水中，CH 2Cl 2萃取，无水硫酸镁干燥，减压浓缩，抽滤，少量CH 2Cl 2洗涤，滤饼烘干后得到白色固体1.47g，收率52.9％。ESI-MS:268[M+H] +.(4-氨基-6-氯嘧啶-5-基)-N-苯基甲酰胺(7a)的制备 2 (2.0 g, 10.36 mmol) was dissolved in 20 mL of anhydrous THF, oxalyl chloride (2.65 mL, 31.09 mmol) and 2 drops of DMF were added dropwise, and reacted at room temperature for 4 h, and the solvent and the remaining oxalyl chloride were evaporated under reduced pressure. 2 Cl 2 was dissolved, transferred to a constant pressure dropping funnel, and added dropwise to aniline (1.04 mL, 11.39 mmol) and triethylamine (3.14 g, 31.07 mmol) in anhydrous CH 2 Cl 2 reaction at room temperature overnight, the reaction solution was poured into an appropriate amount of water, CH 2 Cl 2 extracts, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, filtered by suction, washed with a little CH 2 Cl 2, the filter cake was dried to give a white solid 1.47 g, yield 52.9%. ESI-MS: 268 [M+H] + . Preparation of (4-amino-6-chloropyrimidin-5-yl)-N-phenylcarboxamide (7a)
6a(1.0g,3.72mmol)加入25mL乙酸乙酯和氨水(10mL,67.1mmol)，室温反应24h，冰浴冷却，抽滤，干燥，得白色固体0.74g，收率79.8％。ESI-MS:249[M+H] +. 6a (1.0 g, 3.72 mmol) was added 25 mL of ethyl acetate and aq. EtOAc (10 mL, 67.1 mmol). ESI-MS: 249 [M+H] + .
(R)-3-[[6-氨基-5-(苯氨基甲酰基)嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(8a)的制备Preparation of (R)-3-[[6-amino-5-(phenylcarbamoyl)pyrimidin-4-yl]amino]piperidine-1-carboxylic acid tert-butyl ester (8a)
参照5a的制备方法，由7a与(R)-1-Boc-3-氨基哌啶反应得淡黄色固体，收率57.9％。ESI-MS:413[M+H] +. Referring to the preparation method of 5a, 7a was reacted with (R)-1-Boc-3-aminopiperidine to give a pale yellow solid in a yield of 57.9%. ESI-MS: 413 [M+H] + .
(R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-苯基甲酰胺(B-1)的制备Preparation of (R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-phenylformamide (B-1)
Figure PCTCN2018084300-appb-000021
Figure PCTCN2018084300-appb-000021
参照A-1的制备方法，由8a脱Boc保护基后与丙烯酰氯反应得黄色固体，收率18.9％。ESI-MS:367[M+H]+； 1H NMR(300MHz,DMSO-d 6):δ(ppm):9.93(s,1H),7.98(s,1H),7.70–7.62(m,2H),7.31(t,J＝7.8Hz,2H),7.06(t,J＝7.4Hz,1H),6.62(s,3H),6.05(dd,J＝2.4,16.8Hz,1H),5.62(dd,J＝2.4,10.4Hz,1H),4.31–3.75(m,2H),3.15(s,3H),1.91(s,1H),1.75-1.37(m,3H),1.24(s,1H). Referring to the preparation method of A-1, the Boc protecting group was removed from 8a and reacted with acryloyl chloride to obtain a yellow solid in a yield of 18.9%. ESI-MS: 367 [M+H]+; 1 H NMR (300 MHz, DMSO-d 6 ): δ (ppm): 9.93 (s, 1H), 7.78 (s, 1H), 7.70 - 7.62 (m, 2H) ), 7.31 (t, J = 7.8 Hz, 2H), 7.06 (t, J = 7.4 Hz, 1H), 6.62 (s, 3H), 6.05 (dd, J = 2.4, 16.8 Hz, 1H), 5.62 (dd , J=2.4, 10.4 Hz, 1H), 4.31–3.75 (m, 2H), 3.15 (s, 3H), 1.91 (s, 1H), 1.75-1.37 (m, 3H), 1.24 (s, 1H).
实施例14Example 14
(4,6-二氯嘧啶-5-基)-N-(4-溴苯基)甲酰胺(6b)的制备Preparation of (4,6-dichloropyrimidin-5-yl)-N-(4-bromophenyl)carboxamide (6b)
参照6a的制备方法，由2和4-溴苯胺反应得白色固体，收率53.8％。ESI-MS:346[M+H] +. Referring to the preparation method of 6a, 2 and 4-bromoaniline were reacted to obtain a white solid in a yield of 53.8%. ESI-MS: 346 [M+H] + .
(4-氨基-6-氯嘧啶-5-基)-N-(4-溴苯基)甲酰胺(7b)的制备Preparation of (4-amino-6-chloropyrimidin-5-yl)-N-(4-bromophenyl)carboxamide (7b)
参照7a的制备方法，由6b反应得白色固体，收率80.1％。ESI-MS:327[M+H] +. Referring to the preparation method of 7a, a white solid was obtained by the reaction of 6b in a yield of 80.1%. ESI-MS: 327 [M+H] + .
(R)-3-[[6-氨基-5-[(4-溴苯基)氨基甲酰基]嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(8b)的制备Preparation of (R)-3-[[6-amino-5-[(4-bromophenyl)carbamoyl]pyrimidin-4-yl]amino]piperidine-1-carboxylic acid tert-butyl ester (8b)
参照5a的制备方法，由7b与(R)-1-Boc-3-氨基哌啶反应得淡黄色固体，收率53.3％。ESI-MS:491[M+H] +. Referring to the preparation method of 5a, 7b was reacted with (R)-1-Boc-3-aminopiperidine to give a pale yellow solid in a yield of 53.3%. ESI-MS: 491 [M+H] + .
(R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(4-溴苯基)甲酰胺(B-2)的制备(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(4-bromophenyl)carboxamide (B-2) preparation
Figure PCTCN2018084300-appb-000022
Figure PCTCN2018084300-appb-000022
参照A-1的制备方法，由8b脱Boc保护基后与丙烯酰氯反应得黄色固体，收率17.5％。ESI-MS:445[M+H] +； 1H NMR(300MHz,Chloroform-d):δ(ppm):8.50(s,1H),8.07(s,1H),7.72-7.61(m,2H),7.55-7.45(m,2H),6.62(dd,J＝10.1,16.8Hz,1H),6.17(dd,J＝10.1,13.8Hz,1H),5.66(dd,J＝13.8,16.8Hz,1H),4.50(s,2H),4.28(dt,J＝7.0,12.5Hz,1H),3.69(dd,J＝6.9,12.4Hz,1H),3.32(dd,J＝7.0,12.4Hz,1H),3.16(p,J＝6.9Hz,1H),2.94(dt,J＝7.0,12.5Hz,1H),2.15-1.96(m,1H),1.81-1.46(m,3H),1.23(s,1H). Referring to the preparation method of A-1, the Boc protecting group was removed from 8b and reacted with acryloyl chloride to obtain a yellow solid in a yield of 17.5%. ESI-MS: 445 [M+H] + ; 1 H NMR (300 MHz, Chloroform-d): δ (ppm): 8.50 (s, 1H), 8.07 (s, 1H), 7.72-7.61 (m, 2H) , 7.55-7.45 (m, 2H), 6.62 (dd, J = 10.1, 16.8 Hz, 1H), 6.17 (dd, J = 10.1, 13.8 Hz, 1H), 5.66 (dd, J = 13.8, 16.8 Hz, 1H) ), 4.50 (s, 2H), 4.28 (dt, J = 7.0, 12.5 Hz, 1H), 3.69 (dd, J = 6.9, 12.4 Hz, 1H), 3.32 (dd, J = 7.0, 12.4 Hz, 1H) , 3.16 (p, J = 6.9 Hz, 1H), 2.94 (dt, J = 7.0, 12.5 Hz, 1H), 2.15 - 1.96 (m, 1H), 1.81-1.46 (m, 3H), 1.23 (s, 1H) ).
实施例15Example 15
(4,6-二氯嘧啶-5-基)-N-(4-异丙基苯基)甲酰胺(6c)的制备Preparation of (4,6-dichloropyrimidin-5-yl)-N-(4-isopropylphenyl)carboxamide (6c)
参照6a的制备方法，由2和4-异丙基苯胺反应得白色固体，收率62.3％。ESI-MS:310[M+H] +. Referring to the preparation method of 6a, 2 and 4-isopropylaniline were reacted to obtain a white solid in a yield of 62.3%. ESI-MS: 310 [M+H] + .
(4-氨基-6-氯嘧啶-5-基)-N-(4-异丙基苯基)甲酰胺(7c)的制备Preparation of (4-amino-6-chloropyrimidin-5-yl)-N-(4-isopropylphenyl)carboxamide (7c)
参照7a的制备方法，由6c反应得白色固体，收率83.1％。ESI-MS:291[M+H] +. Referring to the preparation method of 7a, a white solid was obtained by the reaction of 6c in a yield of 83.1%. ESI-MS: 291 [M+H] + .
(R)-3-[[6-氨基-5-[(4-异丙基苯基)氨基甲酰基]嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(8c)的制备Preparation of (R)-3-[[6-amino-5-[(4-isopropylphenyl)carbamoyl]pyrimidin-4-yl]amino]piperidine-1-carboxylic acid tert-butyl ester (8c)
参照5a的制备方法，由7c与(R)-1-Boc-3-氨基哌啶反应得淡黄色固体，收率66.5％。ESI-MS:455[M+H] +. Referring to the preparation method of 5a, 7c was reacted with (R)-1-Boc-3-aminopiperidine to give a pale yellow solid (yield: 66.5%). ESI-MS: 455 [M+H] + .
(R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(4-异丙基苯基)甲酰胺(B-3)的制备(R)-[4-[(1-Aroylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(4-isopropylphenyl)carboxamide (B-3 Preparation
Figure PCTCN2018084300-appb-000023
Figure PCTCN2018084300-appb-000023
参照A-1的制备方法，由8c脱Boc保护基后与丙烯酰氯反应得黄色固体，收率19.2％。ESI-MS:409[M+H] +； 1H NMR(300MHz,DMSO-d 6):δ(ppm):9.88(d,J＝14.8Hz,1H),7.97(s,1H),7.56(d,J＝8.5Hz,2H),7.17(d,J＝8.5Hz,2H),6.96(d,J＝30.9Hz,1H),6.80-6.53(m,3H),6.04(dd,J＝2.4,16.8Hz,1H),5.62(dd,J＝2.5,10.5Hz,1H),3.91(d,J＝37.9Hz,3H),3.14(dt,J＝8.1,19.1Hz,2H),2.89-2.80(m,1H),1.91(s,1H),1.59(dd,J＝10.3,18.0Hz,2H),1.50-1.40 (m,1H),1.18(d,J＝6.9Hz,6H). Referring to the preparation method of A-1, the Boc protecting group was removed from 8c and reacted with acryloyl chloride to obtain a yellow solid in a yield of 19.2%. ESI-MS: 409 [M + H] +; 1 H NMR (300MHz, DMSO-d 6): δ (ppm): 9.88 (d, J = 14.8Hz, 1H), 7.97 (s, 1H), 7.56 ( d, J = 8.5 Hz, 2H), 7.17 (d, J = 8.5 Hz, 2H), 6.96 (d, J = 30.9 Hz, 1H), 6.80 - 6.53 (m, 3H), 6.04 (dd, J = 2.4) , 16.8 Hz, 1H), 5.62 (dd, J = 2.5, 10.5 Hz, 1H), 3.91 (d, J = 37.9 Hz, 3H), 3.14 (dt, J = 8.1, 19.1 Hz, 2H), 2.89-2.80 (m, 1H), 1.91 (s, 1H), 1.59 (dd, J = 10.3, 18.0 Hz, 2H), 1.50-1.40 (m, 1H), 1.18 (d, J = 6.9 Hz, 6H).
实施例16Example 16
(4,6-二氯嘧啶-5-基)-N-(3-甲氧基-4-甲基苯基)甲酰胺(6d)的制备Preparation of (4,6-dichloropyrimidin-5-yl)-N-(3-methoxy-4-methylphenyl)carboxamide (6d)
参照6a的制备方法，由2和3-甲氧基-4-甲基苯胺反应得白色固体，收率49.9％。ESI-MS:312[M+H] +. Referring to the preparation method of 6a, 2 and 3-methoxy-4-methylaniline were reacted to give a white solid (yield: 49.9%). ESI-MS: 312 [M+H] + .
(4-氨基-6-氯嘧啶-5-基)-N-(3-甲氧基-4-甲基苯基)甲酰胺(7d)的制备Preparation of (4-amino-6-chloropyrimidin-5-yl)-N-(3-methoxy-4-methylphenyl)carboxamide (7d)
参照7a的制备方法，由6d反应得白色固体，收率81.8％。ESI-MS:293[M+H] +. Referring to the preparation method of 7a, a white solid was obtained by the reaction of 6d, and the yield was 81.8%. ESI-MS: 293 [M+H] + .
(R)-3-[[6-氨基-5-[(3-甲氧基-4-甲基苯基)氨基甲酰基]嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(8d)的制备(R)-3-[[6-Amino-5-[(3-methoxy-4-methylphenyl)carbamoyl]pyrimidin-4-yl]amino]piperidine-1-carboxylic acid tert-butyl ester Preparation of (8d)
参照5a的制备方法，由7d与(R)-1-Boc-3-氨基哌啶反应得淡黄色固体，收率53.9％。ESI-MS:457[M+H] +. Referring to the preparation method of 5a, 7d was reacted with (R)-1-Boc-3-aminopiperidine to give a pale yellow solid in a yield of 53.9%. ESI-MS: 457 [M+H] + .
(R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(3-甲氧基-4-甲基苯基)甲酰胺(B-4)的制备(R)-[4-[(1-Aroylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(3-methoxy-4-methylphenyl) A Preparation of amide (B-4)
Figure PCTCN2018084300-appb-000024
Figure PCTCN2018084300-appb-000024
参照A-1的制备方法，由8d脱Boc保护基后与丙烯酰氯反应得黄色固体，收率20.1％。ESI-MS:411[M+H]+； 1H NMR(300MHz,Chloroform-d):δ(ppm):8.11(s,1H),8.01(s,1H),7.50(d,J＝9.4Hz,1H),7.41(d,J＝8.1Hz,2H),7.21(d,J＝8.1Hz,2H),6.55(dd,J＝10.6,17.0Hz,1H),6.16(dd,J＝16.7,43.1Hz,1H),5.60(d,J＝10.2Hz,1H),5.45(d,J＝12.7Hz,2H),4.00(d,J＝14.0Hz,1H),3.30-3.13(m,2H),2.88(p,J＝6.9Hz,1H),2.02(s,1H),1.61(dq,J＝7.3,8.1,16.6Hz,3H),1.23(s,3H),1.21(s,3H). Referring to the preparation method of A-1, a 8c de Boc protecting group was reacted with acryloyl chloride to obtain a yellow solid in a yield of 20.1%. ESI-MS: 411 [M+H]+; 1 H NMR (300 MHz, Chloroform-d): δ (ppm): 8.11 (s, 1H), 8.01 (s, 1H), 7.50 (d, J = 9.4 Hz) , 1H), 7.41 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 8.1 Hz, 2H), 6.55 (dd, J = 10.6, 17.0 Hz, 1H), 6.16 (dd, J = 16.7, 43.1 Hz, 1H), 5.60 (d, J = 10.2 Hz, 1H), 5.45 (d, J = 12.7 Hz, 2H), 4.00 (d, J = 14.0 Hz, 1H), 3.30 - 3.13 (m, 2H) , 2.88 (p, J = 6.9 Hz, 1H), 2.02 (s, 1H), 1.61 (dq, J = 7.3, 8.1, 16.6 Hz, 3H), 1.23 (s, 3H), 1.21 (s, 3H).
实施例17Example 17
(4,6-二氯嘧啶-5-基)-N-(3,4-二甲氧基苯基)甲酰胺(6e)的制备Preparation of (4,6-dichloropyrimidin-5-yl)-N-(3,4-dimethoxyphenyl)carboxamide (6e)
参照6a的制备方法，由2和3,4-二甲氧基苯胺反应得白色固体，收率57.4％。ESI-MS:328[M+H] +. Referring to the preparation method of 6a, 2 and 3,4-dimethoxyaniline were reacted to obtain a white solid in a yield of 57.4%. ESI-MS: 328 [M+H] + .
(4-氨基-6-氯嘧啶-5-基)-N-(3,4-二甲氧基苯基)甲酰胺(7e)的制备Preparation of (4-amino-6-chloropyrimidin-5-yl)-N-(3,4-dimethoxyphenyl)carboxamide (7e)
参照7a的制备方法，由6e反应得白色固体，收率81.0％。ESI-MS:309[M+H] +. Referring to the preparation method of 7a, a white solid was obtained by the reaction of 6e in a yield of 81.0%. ESI-MS: 309 [M+H] + .
(R)-3-[[6-氨基-5-[(3,4-二甲氧基苯基)氨基甲酰基]嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(8e)的 制备(R)-3-[[6-Amino-5-[(3,4-dimethoxyphenyl)carbamoyl]pyrimidin-4-yl]amino]piperidine-1-carboxylic acid tert-butyl ester (8e Preparation
参照5a的制备方法，由7e与(R)-1-Boc-3-氨基哌啶反应得淡黄色固体，收率64.2％。ESI-MS:473[M+H] +. Referring to the preparation method of 5a, 7e was reacted with (R)-1-Boc-3-aminopiperidine to give a pale yellow solid in a yield of 64.2%. ESI-MS: 473 [M+H] + .
(R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(3,4-二甲氧基苯基)甲酰胺(B-5)的制备(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(3,4-dimethoxyphenyl)carboxamide ( Preparation of B-5)
Figure PCTCN2018084300-appb-000025
Figure PCTCN2018084300-appb-000025
参照A-1的制备方法，由8e脱Boc保护基后与丙烯酰氯反应得黄色固体，收率17.9％。ESI-MS:427[M+H] +； 1H NMR(300MHz,Chloroform-d):δ(ppm):9.80(d,J＝18.6Hz,1H),7.98(s,1H),7.40(s,1H),7.18-7.13(m,1H),7.04-6.87(m,2H),6.58(s,3H),6.05(dd,J＝2.5,16.7Hz,1H),5.63(d,J＝10.3Hz,1H),3.90(d,J＝43.9Hz,3H),3.73(d,J＝2.0Hz,6H),3.18(d,J＝36.3Hz,1H),1.95(d,J＝23.7Hz,1H),1.66(s,2H),1.46(s,1H),1.21(d,J＝18.8Hz,1H). Referring to the preparation method of A-1, the Boc protecting group was removed from 8e and reacted with acryloyl chloride to obtain a yellow solid in a yield of 17.9%. ESI-MS: 427 [M+H] + ; 1 H NMR (300 MHz, Chloroform-d): δ (ppm): 9.80 (d, J = 18.6 Hz, 1H), 7.78 (s, 1H), 7.40 (s) , 1H), 7.18-7.13 (m, 1H), 7.04-6.87 (m, 2H), 6.58 (s, 3H), 6.05 (dd, J = 2.5, 16.7 Hz, 1H), 5.63 (d, J = 10.3) Hz, 1H), 3.90 (d, J = 43.9 Hz, 3H), 3.73 (d, J = 2.0 Hz, 6H), 3.18 (d, J = 36.3 Hz, 1H), 1.95 (d, J = 23.7 Hz, 1H), 1.66 (s, 2H), 1.46 (s, 1H), 1.21 (d, J = 18.8 Hz, 1H).
实施例18Example 18
(4,6-二氯嘧啶-5-基)-N-(3,5-二甲氧基苯基)甲酰胺(6f)的制备Preparation of (4,6-dichloropyrimidin-5-yl)-N-(3,5-dimethoxyphenyl)carboxamide (6f)
参照6a的制备方法，由2和3,5-二甲氧基苯胺反应得白色固体，收率63.0％。ESI-MS:328[M+H] +. Referring to the preparation method of 6a, 2 and 3,5-dimethoxyaniline were reacted to obtain a white solid in a yield of 63.0%. ESI-MS: 328 [M+H] + .
(4-氨基-6-氯嘧啶-5-基)-N-(3,5-二甲氧基苯基)甲酰胺(7f)的制备Preparation of (4-amino-6-chloropyrimidin-5-yl)-N-(3,5-dimethoxyphenyl)carboxamide (7f)
参照7a的制备方法，由6f反应得白色固体，收率78.4％。ESI-MS:309[M+H] +. Referring to the preparation method of 7a, a white solid was obtained by the reaction of 6f, and the yield was 78.4%. ESI-MS: 309 [M+H] + .
(R)-3-[[6-氨基-5-[(3,5-二甲氧基苯基)氨基甲酰基]嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(8f)的制备(R)-3-[[6-Amino-5-[(3,5-dimethoxyphenyl)carbamoyl]pyrimidin-4-yl]amino]piperidine-1-carboxylic acid tert-butyl ester (8f Preparation
参照5a的制备方法，由7f与(R)-1-Boc-3-氨基哌啶反应得淡黄色固体，收率52.3％。ESI-MS:473[M+H] +. Referring to the preparation method of 5a, 7f was reacted with (R)-1-Boc-3-aminopiperidine to give a pale yellow solid in a yield of 52.3%. ESI-MS: 473 [M+H] + .
(R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(3,5-二甲氧基苯基)甲酰胺(B-6)的制备(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(3,5-dimethoxyphenyl)carboxamide ( Preparation of B-6)
Figure PCTCN2018084300-appb-000026
Figure PCTCN2018084300-appb-000026
参照A-1的制备方法，由8f脱Boc保护基后与丙烯酰氯反应得黄色固体，收率19.3％。ESI-MS:427[M+H] +； 1H NMR(300MHz,Chloroform-d):δ(ppm):8.43(s,1H),8.22(s,1H),6.82(d,J＝2.0Hz,2H),6.62(dd,J＝10.0,16.7Hz,1H),6.19(dd,J＝10.0,13.8Hz,1H),6.02(t,J＝2.0Hz,1H),5.67(dd,J＝13.8,16.7Hz,1H),4.84(s,2H),4.39(dt,J＝7.0,12.6Hz,1H),3.80(s,6H),3.75(dd,J＝7.0,12.5Hz,1H),3.45(dd,J＝7.0,12.5Hz,1H),3.16(p,J＝6.9Hz,1H),2.90(dt,J＝7.0,12.5Hz,1H),2.15-1.97(m,1H),1.81-1.46(m,3H),1.26(s,1H). Referring to the preparation method of A-1, the Boc protecting group was removed from 8f and reacted with acryloyl chloride to obtain a yellow solid in a yield of 19.3%. ESI-MS: 427 [M+H] + ; 1 H NMR (300 MHz, Chloroform-d): δ (ppm): 8.43 (s, 1H), 8.22 (s, 1H), 6.82 (d, J = 2.0 Hz) , 2H), 6.62 (dd, J = 10.0, 16.7 Hz, 1H), 6.19 (dd, J = 10.0, 13.8 Hz, 1H), 6.02 (t, J = 2.0 Hz, 1H), 5.67 (dd, J = 13.8, 16.7 Hz, 1H), 4.84 (s, 2H), 4.39 (dt, J = 7.0, 12.6 Hz, 1H), 3.80 (s, 6H), 3.75 (dd, J = 7.0, 12.5 Hz, 1H), 3.45 (dd, J = 7.0, 12.5 Hz, 1H), 3.16 (p, J = 6.9 Hz, 1H), 2.90 (dt, J = 7.0, 12.5 Hz, 1H), 2.15 - 1.97 (m, 1H), 1.81 -1.46(m,3H), 1.26(s,1H).
实施例19Example 19
(4,6-二氯嘧啶-5-基)-N-(2-氟苯基)甲酰胺(6g)的制备Preparation of (4,6-dichloropyrimidin-5-yl)-N-(2-fluorophenyl)carboxamide (6g)
参照6a的制备方法，由2和2-氟苯胺反应得白色固体，收率68.6％。ESI-MS:286[M+H] +. Referring to the preparation method of 6a, 2 and 2-fluoroaniline were reacted to obtain a white solid in a yield of 68.6%. ESI-MS: 286 [M+H] + .
(4-氨基-6-氯嘧啶-5-基)-N-(2-氟苯基)甲酰胺(7g)的制备Preparation of (4-amino-6-chloropyrimidin-5-yl)-N-(2-fluorophenyl)carboxamide (7g)
参照7a的制备方法，由6g反应得白色固体，收率82.3％。ESI-MS:267[M+H] +. Referring to the preparation method of 7a, 6 g of a white solid was obtained in a yield of 82.3%. ESI-MS: 267 [M+H] + .
(R)-3-[[6-氨基-5-[(2-氟苯基)氨基甲酰基]嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(8g)的制备Preparation of (R)-3-[[6-amino-5-[(2-fluorophenyl)carbamoyl]pyrimidin-4-yl]amino]piperidine-1-carboxylic acid tert-butyl ester (8 g)
参照5a的制备方法，由7g与(R)-1-Boc-3-氨基哌啶反应得淡黄色固体，收率52.2％。ESI-MS:431[M+H] +. Referring to the preparation method of 5a, 7 g of (R)-1-Boc-3-aminopiperidine was reacted to obtain a pale yellow solid in a yield of 52.2%. ESI-MS: 431 [M+H] + .
(R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(2-氟苯基)甲酰胺(B-7)的制备(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(2-fluorophenyl)carboxamide (B-7) preparation
Figure PCTCN2018084300-appb-000027
Figure PCTCN2018084300-appb-000027
参照A-1的制备方法，由8g脱Boc保护基后与丙烯酰氯反应得黄色固体，收率16.9％。ESI-MS:385[M+H] +； 1H NMR(300MHz,DMSO-d 6):δ(ppm):9.69(s,1H),7.95(d,J＝23.4Hz,3H),7.69(s,1H),7.18(s,3H),6.73(s,2H),6.03(d,J＝16.5Hz,1H),5.62(s,1H),4.25-4.16(m,1H),3.98(s,1H),3.79(s,1H),1.91(s,1H),1.62(s,2H),1.43(s,1H),1.21(s,1H),0.93-0.85(m,1H). Referring to the preparation method of A-1, 8 g of the deprotected Boc group was reacted with acryloyl chloride to obtain a yellow solid in a yield of 16.9%. ESI-MS: 385 [M+H] + ; 1 H NMR (300 MHz, DMSO-d 6 ): δ (ppm): 9.69 (s, 1H), 7.95 (d, J = 23.4 Hz, 3H), 7.69 ( s,1H),7.18(s,3H),6.73(s,2H),6.03(d,J=16.5Hz,1H),5.62(s,1H), 4.25-4.16(m,1H),3.98(s , 1H), 3.79 (s, 1H), 1.91 (s, 1H), 1.62 (s, 2H), 1.43 (s, 1H), 1.21 (s, 1H), 0.93-0.85 (m, 1H).
实施例20Example 20
(4,6-二氯嘧啶-5-基)-N-(3-氟苯基)甲酰胺(6h)的制备Preparation of (4,6-dichloropyrimidin-5-yl)-N-(3-fluorophenyl)carboxamide (6h)
参照6a的制备方法，由2和3-氟苯胺反应得白色固体，收率66.4％。ESI-MS:286[M+H] +. Referring to the preparation method of 6a, 2 and 3-fluoroaniline were reacted to obtain a white solid in a yield of 66.4%. ESI-MS: 286 [M+H] + .
(4-氨基-6-氯嘧啶-5-基)-N-(3-氟苯基)甲酰胺(7h)的制备Preparation of (4-amino-6-chloropyrimidin-5-yl)-N-(3-fluorophenyl)carboxamide (7h)
参照7a的制备方法，由6h反应得白色固体，收率80.2％。ESI-MS:267[M+H] +. Referring to the preparation method of 7a, a white solid was obtained by a reaction for 6 hours, and the yield was 80.2%. ESI-MS: 267 [M+H] + .
(R)-3-[[6-氨基-5-[(3-氟苯基)氨基甲酰基]嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(8h)的制备Preparation of (R)-3-[[6-amino-5-[(3-fluorophenyl)carbamoyl]pyrimidin-4-yl]amino]piperidine-1-carboxylic acid tert-butyl ester (8h)
参照5a的制备方法，由7h与(R)-1-Boc-3-氨基哌啶反应得淡黄色固体，收率50.7％。ESI-MS:431[M+H] +. Referring to the preparation method of 5a, it was reacted with (R)-1-Boc-3-aminopiperidine for 7 h to give a pale yellow solid, yield 50.7%. ESI-MS: 431 [M+H] + .
(R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(3-氟苯基)甲酰胺(B-8)的制备(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(3-fluorophenyl)carboxamide (B-8) preparation
Figure PCTCN2018084300-appb-000028
Figure PCTCN2018084300-appb-000028
参照A-1的制备方法，由8h脱Boc保护基后与丙烯酰氯反应得黄色固体，收率18.4％。ESI-MS:385[M+H] +； 1H NMR(300MHz,DMSO-d 6):δ(ppm):7.97(s,1H),7.65(dd,J＝4.8,9.4Hz,3H),7.14(t,J＝8.7Hz,2H),6.62(d,J＝15.9Hz,2H),6.03(d,J＝16.6Hz,1H),5.61(d,J＝10.4Hz,1H),4.21(t,J＝6.6Hz,1H),3.89(d,J＝42.3Hz,3H),1.90(s,1H),1.67-1.58(m,2H),1.37(dt,J＝8.6,14.7Hz,2H),1.19(d,J＝21.8Hz,1H),0.90(t,J＝7.5Hz,1H). Referring to the preparation method of A-1, the Boc protecting group was removed from 8 h and reacted with acryloyl chloride to obtain a yellow solid in a yield of 18.4%. ESI-MS: 385 [M+H] + ; 1 H NMR (300 MHz, DMSO-d 6 ): δ (ppm): 7.97 (s, 1H), 7.65 (dd, J = 4.8, 9.4 Hz, 3H), 7.14 (t, J = 8.7 Hz, 2H), 6.62 (d, J = 15.9 Hz, 2H), 6.03 (d, J = 16.6 Hz, 1H), 5.61 (d, J = 10.4 Hz, 1H), 4.21 ( t, J = 6.6 Hz, 1H), 3.89 (d, J = 42.3 Hz, 3H), 1.90 (s, 1H), 1.67-1.58 (m, 2H), 1.37 (dt, J = 8.6, 14.7 Hz, 2H) ), 1.19 (d, J = 21.8 Hz, 1H), 0.90 (t, J = 7.5 Hz, 1H).
实施例21Example 21
(4,6-二氯嘧啶-5-基)-N-(4-氟苯基)甲酰胺(6i)的制备Preparation of (4,6-dichloropyrimidin-5-yl)-N-(4-fluorophenyl)carboxamide (6i)
参照6a的制备方法，由2和4-氟苯胺反应得白色固体，收率67.5％。ESI-MS:286[M+H] +. Referring to the preparation method of 6a, 2 and 4-fluoroaniline were reacted to obtain a white solid in a yield of 67.5%. ESI-MS: 286 [M+H] + .
(4-氨基-6-氯嘧啶-5-基)-N-(4-氟苯基)甲酰胺(7i)的制备Preparation of (4-amino-6-chloropyrimidin-5-yl)-N-(4-fluorophenyl)carboxamide (7i)
参照7a的制备方法，由6i反应得白色固体，收率79.6％。ESI-MS:267[M+H] +. Referring to the preparation method of 7a, a white solid was obtained by 6i reaction, and the yield was 79.6%. ESI-MS: 267 [M+H] + .
(R)-3-[[6-氨基-5-[(4-氟苯基)氨基甲酰基]嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(8i)的制备Preparation of (R)-3-[[6-amino-5-[(4-fluorophenyl)carbamoyl]pyrimidin-4-yl]amino]piperidine-1-carboxylic acid tert-butyl ester (8i)
参照5a的制备方法，由7i与(R)-1-Boc-3-氨基哌啶反应得淡黄色固体，收率60.4％。ESI-MS:431[M+H] +. Referring to the preparation method of 5a, 7i was reacted with (R)-1-Boc-3-aminopiperidine to give a pale yellow solid in a yield of 60.4%. ESI-MS: 431 [M+H] + .
(R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(4-氟苯基)甲酰胺(B-9)的制备(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(4-fluorophenyl)carboxamide (B-9) preparation
Figure PCTCN2018084300-appb-000029
Figure PCTCN2018084300-appb-000029
参照A-1的制备方法，由8i脱Boc保护基后与丙烯酰氯反应得黄色固体，收率19.0％。ESI-MS:385[M+H] +； 1H NMR(300MHz,DMSO-d 6):δ(ppm): 1H NMR(300MHz,DMSO-d 6)δ7.98(s,1H),7.75-7.57(m,2H),7.40-7.26(m,2H),6.87(t,J＝8.3Hz,1H),6.65(d,J＝17.0Hz,2H),6.04(dd,J＝2.4,16.7Hz,1H),5.62(d,J＝10.3Hz,1H),4.21(t,J＝6.5Hz,1H),4.06-3.75(m,3H),1.90(s,1H),1.64(q,J＝7.1,7.6Hz,2H),1.41-1.32(m,1H),1.15(d,J＝7.1Hz,2H),0.90(t,J＝7.4Hz,1H). Referring to the preparation method of A-1, the Boc protecting group was removed from 8i and reacted with acryloyl chloride to obtain a yellow solid in a yield of 19.0%. ESI-MS: 385 [M+H] + ; 1 H NMR (300 MHz, DMSO-d 6 ): δ (ppm): 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.78 (s, 1H), 7.75 -7.57 (m, 2H), 7.40-7.26 (m, 2H), 6.87 (t, J = 8.3 Hz, 1H), 6.65 (d, J = 17.0 Hz, 2H), 6.04 (dd, J = 2.4, 16.7 Hz, 1H), 5.62 (d, J = 10.3 Hz, 1H), 4.21 (t, J = 6.5 Hz, 1H), 4.06 - 3.75 (m, 3H), 1.90 (s, 1H), 1.64 (q, J) = 7.1, 7.6 Hz, 2H), 1.41-1.32 (m, 1H), 1.15 (d, J = 7.1 Hz, 2H), 0.90 (t, J = 7.4 Hz, 1H).
实施例22Example 22
(4,6-二氯嘧啶-5-基)-N-苄基甲酰胺(6j)的制备Preparation of (4,6-dichloropyrimidin-5-yl)-N-benzylformamide (6j)
参照6a的制备方法，由2和苄胺反应得白色固体，收率54.4％。ESI-MS:282[M+H] +. Referring to the preparation method of 6a, 2 and benzylamine were reacted to obtain a white solid in a yield of 54.4%. ESI-MS: 282 [M+H] + .
(4-氨基-6-氯嘧啶-5-基)-N-苄基甲酰胺(7j)的制备Preparation of (4-amino-6-chloropyrimidin-5-yl)-N-benzylformamide (7j)
参照7a的制备方法，由6j反应得白色固体，收率80.9％。ESI-MS:263[M+H] +. Referring to the preparation method of 7a, a white solid was obtained from 6j, and the yield was 80.9%. ESI-MS: 263 [M+H] + .
(R)-3-[[6-氨基-5-(苄氨基甲酰基)嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(8j)的制备Preparation of (R)-3-[[6-Amino-5-(benzylcarbamoyl)pyrimidin-4-yl]amino]piperidine-1-carboxylic acid tert-butyl ester (8j)
参照5a的制备方法，由7j与(R)-1-Boc-3-氨基哌啶反应得淡黄色固体，收率55.6％。ESI-MS:427[M+H] +. Referring to the preparation method of 5a, 7j was reacted with (R)-1-Boc-3-aminopiperidine to give a pale yellow solid in a yield of 55.6%. ESI-MS: 427 [M+H] + .
(R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-苄基甲酰胺(B-10)的制备Preparation of (R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-benzylformamide (B-10)
Figure PCTCN2018084300-appb-000030
Figure PCTCN2018084300-appb-000030
参照A-1的制备方法，由8j脱Boc保护基后与丙烯酰氯反应得黄色固体，收率17.7％。ESI-MS:381[M+H] +； 1H NMR(300MHz,DMSO-d 6):δ(ppm):8.51(s,1H),7.95(s,1H),7.70(d,J＝8.6Hz,1H),7.32(d,J＝4.7Hz,4H),7.25(s,1H),7.08-6.57(m,2H),6.48(s,1H),6.06(d,J＝16.7Hz,1H),5.63(s,1H),4.41-4.38(m,1H),4.23(t,J＝6.5Hz,1H),3.94(s,1H),3.75(d,J＝12.9Hz,1H),3.24(d,J＝10.6Hz,1H),1.89(s,1H),1.65(t,J＝7.4Hz,2H),1.43-1.34(m,1H),1.21(d,J＝21.3Hz,1H),0.92(t,J＝7.4Hz,1H) Referring to the preparation method of A-1, the Boc protecting group was removed from 8j and reacted with acryloyl chloride to obtain a yellow solid in a yield of 17.7%. ESI-MS: 381 [M+H] + ; 1 H NMR (300 MHz, DMSO-d 6 ): δ (ppm): 8.51 (s, 1H), 7.95 (s, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.32 (d, J = 4.7 Hz, 4H), 7.25 (s, 1H), 7.08-6.57 (m, 2H), 6.48 (s, 1H), 6.06 (d, J = 16.7 Hz, 1H) ), 5.63 (s, 1H), 4.41-4.38 (m, 1H), 4.23 (t, J = 6.5 Hz, 1H), 3.94 (s, 1H), 3.75 (d, J = 12.9 Hz, 1H), 3.24 (d, J = 10.6 Hz, 1H), 1.89 (s, 1H), 1.65 (t, J = 7.4 Hz, 2H), 1.43-1.34 (m, 1H), 1.21 (d, J = 21.3 Hz, 1H) , 0.92 (t, J = 7.4 Hz, 1H)
实施例23Example 23
(R)-3-[[6-氨基-5-(苯氨基甲酰基)嘧啶-4-基]氨基]吡咯烷-1-甲酸叔丁酯(8k)的制备Preparation of (R)-3-[[6-amino-5-(phenylcarbamoyl)pyrimidin-4-yl]amino]pyrrolidine-1-carboxylic acid tert-butyl ester (8k)
参照5a的制备方法，由7a与(R)-1-Boc-3-氨基吡咯烷反应得淡黄色固体，收率59.8％。ESI-MS:399[M+H] +. Referring to the preparation method of 5a, 7a was reacted with (R)-1-Boc-3-aminopyrrolidine to give a pale yellow solid in a yield of 59.8%. ESI-MS: 399 [M+H] + .
(R)-[4-[(1-丙烯酰基吡咯烷-3-基)氨基]-6-氨基嘧啶-5-基]-N-苯基甲酰胺(B-11)的制备Preparation of (R)-[4-[(1-acryloylpyrrolidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-phenylcarboxamide (B-11)
Figure PCTCN2018084300-appb-000031
Figure PCTCN2018084300-appb-000031
参照A-1的制备方法，由8k脱Boc保护基后与丙烯酰氯反应得黄色固体，收率18.6％。ESI-MS:353[M+H] +； 1H NMR(300MHz,DMSO-d 6):δ(ppm):10.00(s,1H),8.00(s,1H),7.69-7.64(m,2H),7.30(t,J＝7.8Hz,2H),7.07(d,J＝7.8Hz,1H),6.64(s,2H),6.60-6.47(m,1H),6.12(dt,J＝2.7,16.9Hz,1H),4.69-4.51(m,1H),4.23(t,J＝6.5Hz,1H),3.68(td,J＝6.4,13.7,15.0Hz,1H),2.14(dq,J＝6.7,18.7Hz,1H),1.68-1.62(m,1H),1.44-1.33(m,2H),0.91(d,J＝7.4Hz,2H). Referring to the preparation method of A-1, a 8k de Boc protecting group was reacted with acryloyl chloride to obtain a yellow solid in a yield of 18.6%. ESI-MS: 353 [M+H] + ; 1 H NMR (300 MHz, DMSO-d 6 ): δ (ppm): 10.00 (s, 1H), 8.00 (s, 1H), 7.69-7.64 (m, 2H) ), 7.30 (t, J = 7.8 Hz, 2H), 7.07 (d, J = 7.8 Hz, 1H), 6.64 (s, 2H), 6.60-6.47 (m, 1H), 6.12 (dt, J = 2.7, 16.9 Hz, 1H), 4.69-4.51 (m, 1H), 4.23 (t, J = 6.5 Hz, 1H), 3.68 (td, J = 6.4, 13.7, 15.0 Hz, 1H), 2.14 (dq, J = 6.7) , 18.7 Hz, 1H), 1.68-1.62 (m, 1H), 1.44-1.33 (m, 2H), 0.91 (d, J = 7.4 Hz, 2H).
实施例24Example 24
(S)-2-[[6-氨基-5-(苯氨基甲酰基)嘧啶-4-基]氨甲基]吡咯烷-1-甲酸叔丁酯(8l)的制备Preparation of (S)-2-[[6-Amino-5-(phenylcarbamoyl)pyrimidin-4-yl]aminomethyl]pyrrolidine-1-carboxylic acid tert-butyl ester (8l)
参照5a的制备方法，由7a与(S)-1-Boc-2-氨甲基吡咯烷反应得淡黄色固体，收率54.1％。ESI-MS:413[M+H] +. Referring to the preparation method of 5a, 7a was reacted with (S)-1-Boc-2-aminomethylpyrrolidine to obtain a pale yellow solid in a yield of 54.1%. ESI-MS: 413 [M+H] + .
(S)-[4-[[(1-丙烯酰基吡咯烷-2-基)甲基]氨基]-6-氨基嘧啶-5-基]-N-苯基甲酰胺(B-12)的制备Preparation of (S)-[4-[[(1-acryloylpyrrolidin-2-yl)methyl]amino]-6-aminopyrimidin-5-yl]-N-phenylcarboxamide (B-12)
Figure PCTCN2018084300-appb-000032
Figure PCTCN2018084300-appb-000032
参照A-1的制备方法，由8l脱Boc保护基后与丙烯酰氯反应得黄色固体，收率19.4％。ESI-MS:367[M+H] +； 1H NMR(300MHz,DMSO-d 6):δ(ppm):8.04(d,J＝6.1Hz,1H),7.70(d,J＝7.7Hz,2H),7.32(t,J＝7.9Hz,3H),7.20(t,J＝5.6Hz,1H),7.07(t,J＝7.4Hz,1H),6.53(d,J＝5.3Hz,2H),6.20-5.99(m,1H),5.71-5.59(m,1H),4.23(t,J＝6.5Hz,2H),1.83(s,2H),1.68-1.61(m,1H),1.38(q,J＝6.5,7.4Hz,1H),1.21(d,J＝20.9Hz,2H),0.92(t,J＝7.4Hz,2H). Referring to the preparation method of A-1, 8 l of the Boc protecting group was reacted with acryloyl chloride to obtain a yellow solid, and the yield was 19.4%. ESI-MS: 367 [M+H] + ; 1 H NMR (300 MHz, DMSO-d 6 ): δ (ppm): 8.04 (d, J = 6.1 Hz, 1H), 7.70 (d, J = 7.7 Hz, 2H), 7.32 (t, J = 7.9 Hz, 3H), 7.20 (t, J = 5.6 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 6.53 (d, J = 5.3 Hz, 2H) , 6.20-5.99 (m, 1H), 5.71-5.59 (m, 1H), 4.23 (t, J = 6.5 Hz, 2H), 1.83 (s, 2H), 1.68-1.61 (m, 1H), 1.38 (q) , J = 6.5, 7.4 Hz, 1H), 1.21 (d, J = 20.9 Hz, 2H), 0.92 (t, J = 7.4 Hz, 2H).
实施例25Example 25
(R)-[4-[(1-丙酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-苯基甲酰胺(B-13)的制备Preparation of (R)-[4-[(1-propionylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-phenylformamide (B-13)
Figure PCTCN2018084300-appb-000033
Figure PCTCN2018084300-appb-000033
参照A-1的制备方法，由8a脱Boc保护基后与丙酰氯反应制得黄色固体，收率21.1％。ESI-MS:369[M+H] +； 1H NMR(300MHz,DMSO-d 6):δ(ppm):9.99(d,J＝3.7Hz,1H),7.98(d,J＝9.1Hz,1H),7.66(d,J＝8.0Hz,2H),7.31(t,J＝7.8Hz,2H),7.05(d,J＝7.1Hz,1H),6.63(d,J＝19.9Hz,2H),4.26-3.54(m,4H),2.86(dt,J＝11.3,48.2Hz,1H),2.35-2.24(m,2H),1.90(d,J＝11.2Hz,1H),1.68-1.55(m,2H),1.42-1.33(m,1H),1.18(t,J＝7.1Hz,1H),1.00-0.94(m,3H). Referring to the preparation method of A-1, a Boc protecting group was removed from 8a and reacted with propionyl chloride to obtain a yellow solid in a yield of 21.1%. ESI-MS: 369 [M+H] + ; 1 H NMR (300 MHz, DMSO-d 6 ): δ (ppm): 9.99 (d, J = 3.7 Hz, 1H), 7.98 (d, J = 9.1 Hz, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.31 (t, J = 7.8 Hz, 2H), 7.05 (d, J = 7.1 Hz, 1H), 6.63 (d, J = 19.9 Hz, 2H) , 4.26-3.54 (m, 4H), 2.86 (dt, J = 11.3, 48.2 Hz, 1H), 2.35-2.24 (m, 2H), 1.90 (d, J = 11.2 Hz, 1H), 1.68-1.55 (m , 2H), 1.42-1.33 (m, 1H), 1.18 (t, J = 7.1 Hz, 1H), 1.00-0.94 (m, 3H).
实施例26Example 26
(R)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(b)的制备(R)-1-[3-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]amino]piperidin-1-yl]-2-propen-1-one Preparation of (b)
参照A-1的制备方法，由5i脱Boc保护基后与丙烯酰氯反应制得黄色固体，收率23.7％。ESI-MS:444[M+H] +； 1H NMR(300MHz,DMSO-d 6):δ(ppm):8.04(s,1H),7.64(d,J＝6.21Hz,2H),7.45(t,J＝6.48Hz,2H),7.22(t,J＝7.08Hz,1H),7.09(d,J＝6.75Hz,2H),7.00(d,J＝8.34Hz,2H),6.76(s,2H),6.55(dd,J＝6.96,15.38Hz,1H),6.03(d,J＝16.32Hz,1H),5.62(d,J＝9.23Hz,1H),4.14-4.15(m,2H),3.74-3.76(m,1H),3.67-3.69(m,1H),1.77-1.79(m,1H),1.43-1.46(m,3H),1.23-1.25(m,2H). Referring to the preparation method of A-1, a yellow solid was obtained by reacting 5i with a Boc protecting group and acryloyl chloride, and the yield was 23.7%. ESI-MS: 444 [M + H] +; 1 H NMR (300MHz, DMSO-d 6): δ (ppm): 8.04 (s, 1H), 7.64 (d, J = 6.21Hz, 2H), 7.45 ( t, J = 6.48 Hz, 2H), 7.22 (t, J = 7.08 Hz, 1H), 7.09 (d, J = 6.75 Hz, 2H), 7.00 (d, J = 8.34 Hz, 2H), 6.76 (s, 2H), 6.55 (dd, J = 6.96, 15.38 Hz, 1H), 6.03 (d, J = 16.32 Hz, 1H), 5.62 (d, J = 9.23 Hz, 1H), 4.14 - 4.15 (m, 2H), 3.74-3.76 (m, 1H), 3.67-3.69 (m, 1H), 1.77-1.79 (m, 1H), 1.43-1.46 (m, 3H), 1.23-1.25 (m, 2H).
实施例27Example 27
(S)-1-[2-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨甲基]吡咯烷-1-基]2-丁炔-1-酮(A-13)的制备(S)-1-[2-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]aminomethyl]pyrrolidin-1-yl]2-butyne-1 - Preparation of ketone (A-13)
Figure PCTCN2018084300-appb-000035
Figure PCTCN2018084300-appb-000035
5f(195.6mg,0.40mmol)溶于20mL CH 2Cl 2中，冰浴下加入浓盐酸(0.33mL,4.0mmol)，滴毕室温反应12h，减压浓缩后重新溶于30mL CH 2Cl 2中，加入2-丁炔酸(4.8mmol)，EDCI(4.8mmol)，HOBt(4.8mmol)，滴加4滴三乙胺，室温反应过夜，剩余反应液加入适量水，CH 2Cl 2萃取，无水硫酸镁干燥，柱层析纯化[乙酸乙酯(EA)]，得黄色固体60.1mg，收率33.1％。ESI-MS:456[M+H] +； 1H NMR(300MHz,DMSO-d 6):δ(ppm)8.26(s,1H),8.17(d,J＝8.2Hz,3H),7.84(t,J＝7.7Hz,2H),7.80-7.62(m,2H),7.45(d,J＝6Hz,2H),6.55(s,2H),6.11(s,1H),3.05-2.94(m,5H),2.00-1.68(m,7H). 5f (195.6mg, 0.40mmol) was dissolved in 20mL CH 2 Cl 2 , concentrated hydrochloric acid (0.33mL, 4.0mmol) was added to the ice bath, and the reaction was carried out at room temperature for 12h, concentrated under reduced pressure and then redissolved in 30mL CH 2 Cl 2 Add 2-butynoic acid (4.8mmol), EDCI (4.8mmol), HOBt (4.8mmol), add 4 drops of triethylamine, and react at room temperature overnight, the remaining reaction solution is added with appropriate amount of water, CH 2 Cl 2 extraction, no The residue was dried over MgSO4q. ESI-MS: 456 [M+H] + ; 1 H NMR (300 MHz, DMSO-d 6 ): δ (ppm) 8.26 (s, 1H), 8.17 (d, J = 8.2 Hz, 3H), 7.84 (t , J=7.7Hz, 2H), 7.80-7.62 (m, 2H), 7.45 (d, J=6Hz, 2H), 6.55 (s, 2H), 6.11 (s, 1H), 3.05-2.94 (m, 5H) ), 2.00-1.68 (m, 7H).
实施例28Example 28
(4,6-二氯嘧啶-5-基)-N-(吡啶-2-基)甲酰胺(6m)的制备Preparation of (4,6-dichloropyrimidin-5-yl)-N-(pyridin-2-yl)carboxamide (6m)
参照6a的制备方法，由2和邻氨基吡啶反应得白色固体，收率55.6％。ESI-MS:270[M+H] +. Referring to the preparation method of 6a, 2 and o-aminopyridine were reacted to obtain a white solid in a yield of 55.6%. ESI-MS: 270 [M+H] + .
(4-氨基-6-氯嘧啶-5-基)-N-(吡啶-2-基)甲酰胺(7m)的制备Preparation of (4-amino-6-chloropyrimidin-5-yl)-N-(pyridin-2-yl)carboxamide (7m)
参照7a的制备方法，由6m反应得白色固体，收率80.1％。ESI-MS:250[M+H] +. Referring to the preparation method of 7a, a white solid was obtained by a reaction of 6 m in a yield of 80.1%. ESI-MS: 250 [M+H] + .
(R)-3-[[6-氨基-5-[(吡啶-2-基)氨基甲酰基]嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(8m)的制备Preparation of (R)-3-[[6-amino-5-[(pyridin-2-yl)carbamoyl]pyrimidin-4-yl]amino]piperidine-1-carboxylic acid tert-butyl ester (8 m)
参照5a的制备方法，由7m与(R)-1-Boc-3-氨基哌啶反应得淡黄色固体，收率53.3％。ESI-MS:413[M+H] +. Referring to the preparation method of 5a, 7m was reacted with (R)-1-Boc-3-aminopiperidine to give a pale yellow solid in a yield of 53.3%. ESI-MS: 413 [M+H] + .
(R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(吡啶-2-基)甲酰胺(B-14)的制备(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(pyridin-2-yl)carboxamide (B-14) preparation
Figure PCTCN2018084300-appb-000036
Figure PCTCN2018084300-appb-000036
参照A-1的制备方法，由8m脱Boc保护基后与丙烯酰氯反应得黄色固体，收率20.1％。ESI-MS:368[M+H] +； 1H NMR(300MHz,Chloroform-d):δ(ppm)10.83(s,1H),8.39(d,J＝10.1 Hz,2H),6.83-6.74(m,2H),6.33-6.28(m,2H),6.08(s,1H),6.03(s,2H),5.65-5.55(m,2H),4.25(s,J＝15Hz,2H),3.93-3.89(m,2H),3.07-2.98(m,1H),1.75-1.63(m,4H). Referring to the preparation method of A-1, a 8 m de Boc protecting group was reacted with acryloyl chloride to obtain a yellow solid in a yield of 20.1%. ESI-MS: 368 [M+H] + ; 1 H NMR (300 MHz, Chloroform-d): δ (ppm) 10.83 (s, 1H), 8.39 (d, J = 10.1 Hz, 2H), 6.83-6.74 ( m,2H),6.33-6.28(m,2H),6.08(s,1H),6.03(s,2H),5.65-5.55(m,2H), 4.25(s,J=15Hz,2H),3.93- 3.89 (m, 2H), 3.07-2.98 (m, 1H), 1.75-1.63 (m, 4H).
实施例29Example 29
(R)-[4-[[1-(2-丁炔酰基)哌啶-3-基]氨基]-6-氨基嘧啶-5-基]-N-(吡啶-2-基)甲酰胺(B-15)的制备(R)-[4-[[1-(2-butynyl)piperidin-3-yl]amino]-6-aminopyrimidin-5-yl]-N-(pyridin-2-yl)carboxamide ( Preparation of B-15)
Figure PCTCN2018084300-appb-000037
Figure PCTCN2018084300-appb-000037
参照A-13的制备方法，由8m脱Boc保护基后与2-丁炔酸反应得淡黄色固体，收率53.3％。ESI-MS:380[M+H] +. 1H NMR(300MHz,Chloroform-d):δ(ppm)8.33(s,1H),7.77(s,1H),7.75(s,1H),7.48(s,1H),7.26-7.23(m,1H),7.21-7.17(m,1H),6.01(s,2H),4.05-3.98(m,2H),2.25-2.22(m,1H),1.98-1.63(m,7H). Referring to the preparation method of A-13, a 8 m de Boc protecting group was reacted with 2-butynoic acid to obtain a pale yellow solid in a yield of 53.3%. ESI-MS: 380 [M + H] + 1 H NMR (300MHz, Chloroform-d):. Δ (ppm) 8.33 (s, 1H), 7.77 (s, 1H), 7.75 (s, 1H), 7.48 ( s, 1H), 7.26-7.23 (m, 1H), 7.21-7.17 (m, 1H), 6.01 (s, 2H), 4.05-3.98 (m, 2H), 2.25-2.22 (m, 1H), 1.98- 1.63 (m, 7H).
实施例30Example 30
(4,6-二氯嘧啶-5-基)-N-(吡啶-3-基)甲酰胺(6n)的制备Preparation of (4,6-dichloropyrimidin-5-yl)-N-(pyridin-3-yl)carboxamide (6n)
参照6a的制备方法，由2和间氨基吡啶反应得白色固体，收率42.3％。ESI-MS:270[M+H] +. Referring to the preparation method of 6a, 2 and m-aminopyridine were reacted to obtain a white solid in a yield of 42.3%. ESI-MS: 270 [M+H] + .
(4-氨基-6-氯嘧啶-5-基)-N-(吡啶-3-基)甲酰胺(7n)的制备Preparation of (4-amino-6-chloropyrimidin-5-yl)-N-(pyridin-3-yl)carboxamide (7n)
参照7a的制备方法，由6n反应得白色固体，收率77.8％。ESI-MS:250[M+H] +. Referring to the preparation method of 7a, a white solid was obtained by 6n reaction, and the yield was 77.8%. ESI-MS: 250 [M+H] + .
(R)-3-[[6-氨基-5-[(吡啶-3-基)氨基甲酰基]嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(8n)的制备Preparation of (R)-3-[[6-amino-5-[(pyridin-3-yl)carbamoyl]pyrimidin-4-yl]amino]piperidine-1-carboxylic acid tert-butyl ester (8n)
参照5a的制备方法，由7n与(R)-1-Boc-3-氨基哌啶反应得淡黄色固体，收率56.6％。ESI-MS:413[M+H] +. Referring to the preparation method of 5a, 7n was reacted with (R)-1-Boc-3-aminopiperidine to give a pale yellow solid in a yield of 56.6%. ESI-MS: 413 [M+H] + .
(R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(吡啶-3-基)甲酰胺(B-16)的制备(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(pyridin-3-yl)carboxamide (B-16) preparation
Figure PCTCN2018084300-appb-000038
Figure PCTCN2018084300-appb-000038
参照A-1的制备方法，由8n脱Boc保护基后与丙烯酰氯反应得黄色固体，收率23.6％。ESI-MS:368[M+H] +； 1H NMR(300MHz,Chloroform-d):δ(ppm)10.36(s,1H),8.72(s,1H),8.14 -8.11(m,2H),7.98(s,1H),7.50-7.47(m,1H),7.39-7.30(m,1H),6.55(s,2H),6.17-6.07(m,1H),5.96-5.86(m,1H),5.81-5.77(m,1H),4.13-3.97(m,4H),2.94-2.91(m,1H),1.68-1.58(m,4H). Referring to the preparation method of A-1, a 8c de Boc protecting group was reacted with acryloyl chloride to obtain a yellow solid in a yield of 23.6%. ESI-MS: 368 [M+H] + ; 1 H NMR (300 MHz, Chloroform-d): δ (ppm) 10.36 (s, 1H), 8.72 (s, 1H), 8.14 -8.11 (m, 2H), 7.98 (s, 1H), 7.50-7.47 (m, 1H), 7.39-7.30 (m, 1H), 6.55 (s, 2H), 6.17-6.07 (m, 1H), 5.96-5.86 (m, 1H), 5.81-5.77 (m, 1H), 4.13 - 3.97 (m, 4H), 2.94 - 2.91 (m, 1H), 1.68-1.58 (m, 4H).
实施例31Example 31
(R)-[4-[[1-(2-丁炔酰基)哌啶-3-基]氨基]-6-氨基嘧啶-5-基]-N-(吡啶-3-基)甲酰胺(B-17)的制备(R)-[4-[[1-(2-butynyl)piperidin-3-yl]amino]-6-aminopyrimidin-5-yl]-N-(pyridin-3-yl)carboxamide ( Preparation of B-17)
Figure PCTCN2018084300-appb-000039
Figure PCTCN2018084300-appb-000039
参照A-13的制备方法，由8n脱Boc保护基后与2-丁炔酸反应得淡黄色固体，收率53.3％。ESI-MS:380[M+H] +. 1H NMR(300MHz,Chloroform-d):δ(ppm)10.5(s,1H),7.96(s,2H),7.93(s,1H),7.70-7.66(m,1H),7.50-7.47(m,1H),7.38-7.35(m,1H),6.09(s,2H),4.05-3.97(m,4H),3.39-3.22(m,1H),1.97-1.73(m,7H). Referring to the preparation method of A-13, the 8n de Boc protecting group was reacted with 2-butynoic acid to obtain a pale yellow solid in a yield of 53.3%. ESI-MS: 380 [M+H] + . 1 H NMR (300 MHz, Chloroform-d): δ (ppm) 10.5 (s, 1H), 7.96 (s, 2H), 7.93 (s, 1H), 7.70- 7.66 (m, 1H), 7.50-7.47 (m, 1H), 7.38-7.35 (m, 1H), 6.09 (s, 2H), 4.05-3.97 (m, 4H), 3.39-3.22 (m, 1H), 1.97-1.73 (m, 7H).
实施例32Example 32
(4,6-二氯嘧啶-5-基)-N-(吡啶-4-基)甲酰胺(6o)的制备Preparation of (4,6-dichloropyrimidin-5-yl)-N-(pyridin-4-yl)carboxamide (6o)
参照6a的制备方法，由2和对氨基吡啶反应得白色固体，收率45.2％。ESI-MS:270[M+H] +. Referring to the preparation method of 6a, 2 and p-aminopyridine were reacted to obtain a white solid in a yield of 45.2%. ESI-MS: 270 [M+H] + .
(4-氨基-6-氯嘧啶-5-基)-N-(吡啶-4-基)甲酰胺(7o)的制备Preparation of (4-amino-6-chloropyrimidin-5-yl)-N-(pyridin-4-yl)carboxamide (7o)
参照7a的制备方法，由6o反应得白色固体，收率69.8％。ESI-MS:250[M+H] +. Referring to the preparation method of 7a, a white solid was obtained by a reaction of 6o, yield 69.8%. ESI-MS: 250 [M+H] + .
(R)-3-[[6-氨基-5-[(吡啶-4-基)氨基甲酰基]嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(8o)的制备Preparation of (R)-3-[[6-amino-5-[(pyridin-4-yl)carbamoyl]pyrimidin-4-yl]amino]piperidine-1-carboxylic acid tert-butyl ester (8o)
参照5a的制备方法，由7o与(R)-1-Boc-3-氨基哌啶反应得淡黄色固体，收率57.3％。ESI-MS:413[M+H] +. Referring to the preparation method of 5a, 7o was reacted with (R)-1-Boc-3-aminopiperidine to give a pale yellow solid in a yield of 57.3%. ESI-MS: 413 [M+H] + .
(R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(吡啶-4-基)甲酰胺(B-18)的制备(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(pyridin-4-yl)carboxamide (B-18) preparation
Figure PCTCN2018084300-appb-000040
Figure PCTCN2018084300-appb-000040
参照A-1的制备方法，由8o脱Boc保护基后与丙烯酰氯反应得黄色固体，收率24.2％。 ESI-MS:368[M+H] +； 1H NMR(300MHz,Chloroform-d):δ(ppm)8.19(s,1H),7.95-7.81(m,2H),7.78(s,1H),7.56-7.51(m,1H),7.44-7.32(m,1H),6.55(s,2H),6.17-6.05(m,1H),5.96-5.89(m,1H),5.81-5.77(m,1H),4.13-4.00(m,4H),2.97-2.91(m,1H),1.68-1.58(m,4H). Referring to the preparation method of A-1, a 8c de Boc protecting group was reacted with acryloyl chloride to obtain a yellow solid in a yield of 24.2%. ESI-MS: 368 [M+H] + ; 1 H NMR (300 MHz, Chloroform-d): δ (ppm) 8.19 (s, 1H), 7.95-7.81 (m, 2H), 7.78 (s, 1H), 7.56-7.51 (m, 1H), 7.44-7.32 (m, 1H), 6.55 (s, 2H), 6.17-6.05 (m, 1H), 5.96-5.89 (m, 1H), 5.81-5.77 (m, 1H) ), 4.13-4.00 (m, 4H), 2.97-2.91 (m, 1H), 1.68-1.58 (m, 4H).
实施例33Example 33
(R)-[4-[[1-(2-丁炔酰基)哌啶-3-基]氨基]-6-氨基嘧啶-5-基]-N-(吡啶-4-基)甲酰胺(B-19)的制备(R)-[4-[[1-(2-butynyl)piperidin-3-yl]amino]-6-aminopyrimidin-5-yl]-N-(pyridin-4-yl)carboxamide ( Preparation of B-19)
Figure PCTCN2018084300-appb-000041
Figure PCTCN2018084300-appb-000041
参照A-13的制备方法，由8o脱Boc保护基后与2-丁炔酸反应得淡黄色固体，收率37.9％。ESI-MS:380[M+H] +. 1H NMR(300MHz,Chloroform-d):δ(ppm)8.50(s,1H),7.84(s,1H),7.54(d,J＝6Hz,2H),6.64(s,1H),6.35-6.28(m,2H),6.22(s,2H),4.02-3.93(m,4H),2.96-2.90(m,1H),1.85-1.67(m,7H). Referring to the preparation method of A-13, the 8o de Boc protecting group was reacted with 2-butynoic acid to obtain a pale yellow solid in a yield of 37.9%. ESI-MS: 380 [M + H] + 1 H NMR (300MHz, Chloroform-d):. Δ (ppm) 8.50 (s, 1H), 7.84 (s, 1H), 7.54 (d, J = 6Hz, 2H ), 6.64 (s, 1H), 6.35-6.28 (m, 2H), 6.22 (s, 2H), 4.02-3.93 (m, 4H), 2.96-2.90 (m, 1H), 1.85-1.67 (m, 7H) ).
实施例34Example 34
(4,6-二氯嘧啶-5-基)-N-(嘧啶-2-基)甲酰胺(6p)的制备Preparation of (4,6-dichloropyrimidin-5-yl)-N-(pyrimidin-2-yl)carboxamide (6p)
参照6a的制备方法，由2和对氨基吡啶反应得白色固体，收率56.2％。ESI-MS:271[M+H] +. Referring to the preparation method of 6a, 2 and p-aminopyridine were reacted to obtain a white solid in a yield of 56.2%. ESI-MS: 271 [M+H] + .
(4-氨基-6-氯嘧啶-5-基)-N-(嘧啶-2-基)甲酰胺(7p)的制备Preparation of (4-amino-6-chloropyrimidin-5-yl)-N-(pyrimidin-2-yl)carboxamide (7p)
参照7a的制备方法，由6p反应得白色固体，收率70.2％。ESI-MS:251[M+H] +. Referring to the preparation method of 7a, a white solid was obtained by 6p reaction, and the yield was 70.2%. ESI-MS: 251 [M+H] + .
(R)-3-[[6-氨基-5-[(嘧啶-2-基)氨基甲酰基]嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(8p)的制备Preparation of (R)-3-[[6-amino-5-[(pyrimidin-2-yl)carbamoyl]pyrimidin-4-yl]amino]piperidine-1-carboxylic acid tert-butyl ester (8p)
参照5a的制备方法，由7p与(R)-1-Boc-3-氨基哌啶反应得淡黄色固体，收率51.3％。ESI-MS:414[M+H] +. Referring to the preparation method of 5a, 7p was reacted with (R)-1-Boc-3-aminopiperidine to give a pale yellow solid in a yield of 51.3%. ESI-MS: 414 [M+H] + .
(R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(嘧啶-2-基)甲酰胺(B-20)的制备(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(pyrimidin-2-yl)carboxamide (B-20) preparation
Figure PCTCN2018084300-appb-000042
Figure PCTCN2018084300-appb-000042
参照A-1的制备方法，由8p脱Boc保护基后与丙烯酰氯反应得黄色固体，收率26.9％。 ESI-MS:369[M+H] +； 1H NMR(300MHz,Chloroform-d):δ(ppm)10.50(s,1H),9.26(d,J＝6.0Hz,2H),8.82(s,1H),8.62-8.56(m,1H),8.28-8.19(m,1H),7.46(s,2H),6.03(s,1H),5.92-5.81(m,1H),5.76-5.61(m,1H),3.34-3.29(m,4H),2.98-2.96(m,1H),1.98-1.68(m,4H). Referring to the preparation method of A-1, a 8p de Boc protecting group was reacted with acryloyl chloride to obtain a yellow solid in a yield of 26.9%. ESI-MS: 369 [M+H] + ; 1 H NMR (300 MHz, Chloroform-d): δ (ppm) 10.50 (s, 1H), 9.26 (d, J = 6.0 Hz, 2H), 8.82 (s, 1H), 8.62-8.56 (m, 1H), 8.28-8.19 (m, 1H), 7.46 (s, 2H), 6.03 (s, 1H), 5.92-5.81 (m, 1H), 5.76-5.61 (m, 1H), 3.34 - 3.29 (m, 4H), 2.98-2.96 (m, 1H), 1.98-1.68 (m, 4H).
实施例35Example 35
(R)-[4-[[1-(2-丁炔酰基)哌啶-3-基]氨基]-6-氨基嘧啶-5-基]-N-(嘧啶-2-基)甲酰胺(B-21)的制备(R)-[4-[[1-(2-butynyl)piperidin-3-yl]amino]-6-aminopyrimidin-5-yl]-N-(pyrimidin-2-yl)carboxamide ( Preparation of B-21)
Figure PCTCN2018084300-appb-000043
Figure PCTCN2018084300-appb-000043
参照A-13的制备方法，由8p脱Boc保护基后与2-丁炔酸反应得淡黄色固体，收率35.7％。ESI-MS:381[M+H] +. 1H NMR(300MHz,Chloroform-d):δ(ppm)8.03(s,1H),7.70(d,J＝6.0Hz,2H),7.47(s,2H),7.43(s,1H),7.11-7.09(m,1H),6.53(s,2H),3.60-3.54(m,4H),2.38-2.31(m,1H),1.99-1.64(m,7H). Referring to the preparation method of A-13, the 8p de Boc protecting group was reacted with 2-butynoic acid to obtain a pale yellow solid in a yield of 35.7%. ESI-MS: 381 [M+H] + . 1 H NMR (300 MHz, Chloroform-d): δ (ppm) 8.03 (s, 1H), 7.70 (d, J = 6.0 Hz, 2H), 7.47 (s, 2H), 7.43 (s, 1H), 7.11-7.09 (m, 1H), 6.53 (s, 2H), 3.60-3.54 (m, 4H), 2.38-2.31 (m, 1H), 1.99-1.64 (m, 7H).
实施例36Example 36
BTK激酶活性的测试BTK kinase activity test
采用放射性同位素P 33-ATP标记方法检测本发明化合物以及(R)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨基]哌啶-1-基]-2-丙烯-1-酮(化合物b)对BTK激酶的抑制活性。放射性同位素检测方法的灵敏度很高，测试结果非常准确，因此被认为是蛋白激酶生化活性检测的“金标准”。 The compound of the present invention and (R)-1-[3-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]amino]piperidin are detected by a radioisotope P 33 -ATP labeling method. Inhibitory activity of pyridine-1-yl]-2-propen-1-one (compound b) against BTK kinase. The radioisotope detection method is highly sensitive and the test results are very accurate, so it is considered to be the "gold standard" for the detection of protein kinase biochemical activity.
具体由Reaction Biology Corp(Malvem PA)公司通过HotSpot法测试。首先将8nM重组人源BTK激酶(Invitrogen,Cat#PV3363)和0.2mg/mL底物pEY在缓冲液中(20mM Hepes pH7.5,10mM MgCl 2,1mM EGTA,0.02％Brij35,0.02mg/ml BSA,0.1mM Na 3VO 4,2mM DTT,1％DMSO)室温下混合，然后化合物溶解于指示剂量的100％DMSO中(从10μM不断稀释3倍)并通过Acoustic技术(Echo550；nanoliter range)递送到激酶反应的混合液中，接着于室温下保持20min。随后加入10μM的 33P-ATP(specifical activity 10μCi/μL)，反应开始，监测反应120min。激酶活性通过filter-binding法测定，IC 50值和曲线拟合由Prism(GraphPad Software)实现。实验结果如表1所示。IC 50值报告的范围为：A表示小于10 -7M，B表示10 - 5-10 -7M。 Specifically, it was tested by the Reaction Biology Corp (Malvem PA) company through the HotSpot method. First, 8 nM recombinant human BTK kinase (Invitrogen, Cat# PV3363) and 0.2 mg/mL substrate pEY in buffer (20 mM Hepes pH 7.5, 10 mM MgCl 2 , 1 mM EGTA, 0.02% Brij 35, 0.02 mg/ml BSA) , 0.1 mM Na 3 VO 4 , 2 mM DTT, 1% DMSO) mixed at room temperature, then the compound was dissolved in the indicated dose of 100% DMSO (continuously diluted 3 fold from 10 μM) and delivered to the Acoustic technique (Echo 550; nanoliter range) The mixture of kinase reactions was then kept at room temperature for 20 min. Subsequently, 10 μM of 33 P-ATP (specifical activity 10 μCi/μL) was added, the reaction was started, and the reaction was monitored for 120 min. Kinase activity by the filter-binding assay methods, IC 50 values and the curve fit is implemented by Prism (GraphPad Software). The experimental results are shown in Table 1. The IC 50 value report ranges from A for less than 10 -7 M and B for 10 - 5 -10 -7 M.
表1本发明化合物对BTK的抑制活性Table 1 Inhibitory activity of the compound of the present invention on BTK
Figure PCTCN2018084300-appb-000044
Figure PCTCN2018084300-appb-000044
Figure PCTCN2018084300-appb-000045
Figure PCTCN2018084300-appb-000045
Figure PCTCN2018084300-appb-000046
Figure PCTCN2018084300-appb-000046
Figure PCTCN2018084300-appb-000047
Figure PCTCN2018084300-appb-000047
Figure PCTCN2018084300-appb-000048
Figure PCTCN2018084300-appb-000048
Figure PCTCN2018084300-appb-000049
Figure PCTCN2018084300-appb-000049
实验结果表明，本发明的部分化合物对BTK激酶的活性具有显著的抑制作用。其中，化合物A-1、A-2、A-8、A-9、A-10、B-2、B-9对BTK的抑制活性与化合物b相当，而化合物A-4、A-6、B-1、B-7、B-8、B-11的活性则优于化合物b，尤其是化合物A-6和B-1的活性更是显著强于化合物b。另外，本发明化合物不同的立体异构体显示出各自不同的活性。例如，化合物A-1和A-2分别是S构型和R构型，前者(S构型)对BTK的抑制活性略强于后者(R构型)；对于化合物A-4(R构型)和A-5(S构型)来说，R构型的活性则显著强于S构型235倍；而对于化合物A-6(S构型)和A-7(R构型)而言，S构型的活性比R构型强1800倍。此外，化合物B-1的活性显著比化合物b强150倍，然而化合物B-12的活性却无法意料地比化合物A-6下降2600倍。The experimental results show that some of the compounds of the present invention have a significant inhibitory effect on the activity of BTK kinase. Among them, the inhibitory activities of the compounds A-1, A-2, A-8, A-9, A-10, B-2, and B-9 on BTK are equivalent to those of the compound b, and the compounds A-4 and A-6, The activities of B-1, B-7, B-8, and B-11 were superior to those of compound b, and especially the activities of compounds A-6 and B-1 were significantly stronger than that of compound b. In addition, the different stereoisomers of the compounds of the invention exhibit respective different activities. For example, compounds A-1 and A-2 are in the S configuration and the R configuration, respectively. The former (S configuration) has a slightly stronger inhibitory activity against BTK than the latter (R configuration); for compound A-4 (R configuration) For the type) and A-5 (S configuration), the activity of the R configuration is significantly stronger than that of the S configuration; for the compounds A-6 (S configuration) and A-7 (R configuration). The S configuration is 1800 times more active than the R configuration. Further, the activity of the compound B-1 was significantly 150 times stronger than that of the compound b, whereas the activity of the compound B-12 was unexpectedly 2600 times lower than that of the compound A-6.

Claims (10)

  1. 通式(I)所示的4-氨基嘧啶类化合物或其药学上可接受的盐：a 4-aminopyrimidine compound represented by the formula (I) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2018084300-appb-100001
    Figure PCTCN2018084300-appb-100001
    其中：among them:
    L代表C(O)或C(O)NH(CH 2) m； L represents C(O) or C(O)NH(CH 2 ) m ;
    m代表0～5的整数；m represents an integer from 0 to 5;
    A代表苯环、五元杂环或六元杂环，其中所述的杂环可任选地包含一个或多个选自O、S或N的其它杂原子；A represents a benzene ring, a five-membered heterocyclic ring or a six-membered heterocyclic ring, wherein the heterocyclic ring may optionally comprise one or more other heteroatoms selected from O, S or N;
    各个R 1各自独立地代表卤素、氰基、硝基、羟基、氨基、三氟甲基、OR 3、NHR 3或(C 1-C 8)烷基； Each R 1 independently represents halogen, cyano, nitro, hydroxy, amino, trifluoromethyl, OR 3 , NHR 3 or (C 1 -C 8 )alkyl;
    n代表0～5的整数；n represents an integer from 0 to 5;
    Y任选自：NH(C 1-C 8)烷基氨基， Y is selected from: NH(C 1 -C 8 )alkylamino,
    Figure PCTCN2018084300-appb-100002
    Figure PCTCN2018084300-appb-100002
    R 2代表丙酰基、丙烯酰基、2-氯乙酰基或2-丁炔酰基； R 2 represents a propionyl group, an acryloyl group, a 2-chloroacetyl group or a 2-butynyl group;
    R 3代表(C 1-C 8)烷基、(C 1-C 8)烷氧基(C 1-C 8)烷基、(C 6-C 10)芳基或(C 1-C 10)芳杂环基；其中所述的芳杂环基团可任选地包含一个或多个选自O、S或N的其它杂原子；所述的芳基和芳杂环基可任选地用一个至五个以下基团取代：卤素、硝基、氰基、羟基、氨基、(C 1-C 8)烷基、(C 1-C 8)烷氧基或(C 3-C 6)环烷基； R 3 represents (C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy(C 1 -C 8 )alkyl, (C 6 -C 10 )aryl or (C 1 -C 10 ) An aromatic heterocyclic group; wherein said aromatic heterocyclic group may optionally contain one or more other heteroatoms selected from O, S or N; said aryl and aromatic heterocyclic groups may optionally be used Substituted to one to five groups: halogen, nitro, cyano, hydroxy, amino, (C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy or (C 3 -C 6 ) ring alkyl;
    其中，下式(a-d)化合物除外：Wherein, except for the compound of the following formula (a-d):
    Figure PCTCN2018084300-appb-100003
    Figure PCTCN2018084300-appb-100003
  2. 根据权利要求1所述的4-氨基嘧啶类化合物或其药学上可接受的盐，其特征在于：The 4-aminopyrimidine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein:
    L代表C(O)或C(O)NH(CH 2) m； L represents C(O) or C(O)NH(CH 2 ) m ;
    m代表0～2的整数；m represents an integer of 0 to 2;
    A代表苯环、五元杂环或六元杂环，其中所述的杂环可任选地包含一个或多个选自O、S或N的其它杂原子；A represents a benzene ring, a five-membered heterocyclic ring or a six-membered heterocyclic ring, wherein the heterocyclic ring may optionally comprise one or more other heteroatoms selected from O, S or N;
    各个R 1各自独立地代表卤素、(C 1-C 5)烷基、(C 1-C 5)烷氧基或苯氧基； Each R 1 independently represents halogen, (C 1 -C 5 )alkyl, (C 1 -C 5 )alkoxy or phenoxy;
    n为0～2的整数；n is an integer from 0 to 2;
    Y任选自：NH(C 1-C 8)烷基氨基， Y is selected from: NH(C 1 -C 8 )alkylamino,
    Figure PCTCN2018084300-appb-100004
    Figure PCTCN2018084300-appb-100004
    R 2代表丙酰基、丙烯酰基、2-氯乙酰基或2-丁炔酰基。 R 2 represents a propionyl group, an acryloyl group, a 2-chloroacetyl group or a 2-butynoyl group.
  3. 根据权利要求2所述的4-氨基嘧啶类化合物或其药学上可接受的盐，其特征在于：The 4-aminopyrimidine compound or a pharmaceutically acceptable salt thereof according to claim 2, which is characterized in that:
    L代表C(O)或C(O)NH(CH 2) m； L represents C(O) or C(O)NH(CH 2 ) m ;
    m代表0～2的整数；m represents an integer of 0 to 2;
    A代表苯环、五元杂环或六元杂环，其中所述的杂环可任选地包含一个或多个选自O、S或N的其它杂原子；A represents a benzene ring, a five-membered heterocyclic ring or a six-membered heterocyclic ring, wherein the heterocyclic ring may optionally comprise one or more other heteroatoms selected from O, S or N;
    各个R 1各自独立地代表卤素、(C 1-C 3)烷基、(C 1-C 3)烷氧基或苯氧基； Each R 1 independently represents halogen, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy or phenoxy;
    n为0～2的整数；n is an integer from 0 to 2;
    Y任选自：NH(C 1-C 8)烷基氨基， Y is selected from: NH(C 1 -C 8 )alkylamino,
    Figure PCTCN2018084300-appb-100005
    Figure PCTCN2018084300-appb-100005
    R 2代表丙酰基、丙烯酰基、2-氯乙酰基或2-丁炔酰基； R 2 represents a propionyl group, an acryloyl group, a 2-chloroacetyl group or a 2-butynyl group;
  4. 根据权利要求1所述的4-氨基嘧啶类化合物或其药学上可接受的盐，其特征在于所述化合物优先选自：The 4-aminopyrimidine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is preferably selected from the group consisting of:
    (S)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨甲基]哌啶-1-基]-2-丙烯-1-酮；(S)-1-[3-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]aminomethyl]piperidin-1-yl]-2-propene-1 -ketone;
    (R)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨甲基]哌啶-1-基]-2-丙烯-1-酮；(R)-1-[3-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]aminomethyl]piperidin-1-yl]-2-propene-1 -ketone;
    1-[2-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨甲基]哌啶-1-基]-2-丙烯-1-酮；1-[2-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]aminomethyl]piperidin-1-yl]-2-propen-1-one;
    (R)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨基]吡咯烷-1-基]-2-丙烯-1-酮；(R)-1-[3-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]amino]pyrrolidin-1-yl]-2-propen-1-one ;
    (S)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨基]吡咯烷-1-基]-2-丙烯-1-酮；(S)-1-[3-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]amino]pyrrolidin-1-yl]-2-propen-1-one ;
    (S)-1-[2-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨甲基]吡咯烷-1-基]-2-丙烯-1-酮；(S)-1-[2-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]aminomethyl]pyrrolidin-1-yl]-2-propene-1 -ketone;
    (R)-1-[2-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨甲基]吡咯烷-1-基]-2-丙烯-1-酮；(R)-1-[2-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]aminomethyl]pyrrolidin-1-yl]-2-propene-1 -ketone;
    1-[3-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨甲基]氮杂环丁烷-1-基]-2-丙烯-1-酮；1-[3-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]aminomethyl]azetidin-1-yl]-2-propene-1- ketone;
    (R)-1-[3-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨基]哌啶-1-基]-2-氯乙烷-1-酮；(R)-1-[3-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]amino]piperidin-1-yl]-2-chloroethane-1 -ketone;
    (S)-1-[2-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨甲基]吡咯烷-1-基]-2-氯乙烷-1-酮；(S)-1-[2-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]aminomethyl]pyrrolidin-1-yl]-2-chloroethane -1-one;
    N-[2-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨基]乙基]丙烯酰胺；N-[2-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]amino]ethyl]acrylamide;
    (S)-1-[2-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨甲基]吡咯烷-1-基]丙烷-1-酮；(S)-1-[2-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]aminomethyl]pyrrolidin-1-yl]propan-1-one;
    (S)-1-[2-[[5-(4-苯氧基苯甲酰基)-6-氨基嘧啶-4-基]氨甲基]吡咯烷-1-基]-2-丁炔-1-酮；(S)-1-[2-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]aminomethyl]pyrrolidin-1-yl]-2-butyne- 1-ketone;
    (R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-苯基甲酰胺；(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-phenylformamide;
    (R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(4-溴苯基)甲酰胺；(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(4-bromophenyl)carboxamide;
    (R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(4-异丙基苯基)甲酰胺；(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(4-isopropylphenyl)carboxamide;
    (R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(3-甲氧基-4-甲基苯基)甲酰胺；(R)-[4-[(1-Aroylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(3-methoxy-4-methylphenyl) A Amide
    (R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(3,4-二甲氧基苯基)甲酰胺；(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(3,4-dimethoxyphenyl)carboxamide;
    (R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(3,5-二甲氧基苯基)甲酰胺；(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(3,5-dimethoxyphenyl)carboxamide;
    (R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(2-氟苯基)甲酰胺；(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(2-fluorophenyl)carboxamide;
    (R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(3-氟苯基)甲酰胺；(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(3-fluorophenyl)carboxamide;
    (R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(4-氟苯基)甲酰胺；(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(4-fluorophenyl)carboxamide;
    (R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-苄基甲酰胺；(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-benzylformamide;
    (R)-[4-[(1-丙烯酰基吡咯烷-3-基)氨基]-6-氨基嘧啶-5-基]-N-苯基甲酰胺；(R)-[4-[(1-acryloylpyrrolidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-phenylformamide;
    (S)-[4-[[(1-丙烯酰基吡咯烷-2-基)甲基]氨基]-6-氨基嘧啶-5-基]-N-苯基甲酰胺；(S)-[4-[[(1-acryloylpyrrolidin-2-yl)methyl]amino]-6-aminopyrimidin-5-yl]-N-phenylcarboxamide;
    (R)-[4-[(1-丙酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-苯基甲酰胺。(R)-[4-[(1-propionylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-phenylformamide.
    (R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(吡啶-2-基)甲酰胺；(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(pyridin-2-yl)carboxamide;
    (R)-[4-[[1-(2-丁炔酰基)哌啶-3-基]氨基]-6-氨基嘧啶-5-基]-N-(吡啶-2-基)甲酰胺；(R)-[4-[[1-(2-butynyl)piperidin-3-yl]amino]-6-aminopyrimidin-5-yl]-N-(pyridin-2-yl)carboxamide;
    (R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(吡啶-3-基)甲酰胺；(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(pyridin-3-yl)carboxamide;
    (R)-[4-[[1-(2-丁炔酰基)哌啶-3-基]氨基]-6-氨基嘧啶-5-基]-N-(吡啶-3-基)甲酰胺；(R)-[4-[[1-(2-butynyl)piperidin-3-yl]amino]-6-aminopyrimidin-5-yl]-N-(pyridin-3-yl)carboxamide;
    (R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(吡啶-4-基)甲酰胺；(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(pyridin-4-yl)carboxamide;
    (R)-[4-[[1-(2-丁炔酰基)哌啶-3-基]氨基]-6-氨基嘧啶-5-基]-N-(吡啶-4-基)甲酰胺；(R)-[4-[[1-(2-butynyl)piperidin-3-yl]amino]-6-aminopyrimidin-5-yl]-N-(pyridin-4-yl)carboxamide;
    (R)-[4-[(1-丙烯酰基哌啶-3-基)氨基]-6-氨基嘧啶-5-基]-N-(嘧啶-2-基)甲酰胺；(R)-[4-[(1-acryloylpiperidin-3-yl)amino]-6-aminopyrimidin-5-yl]-N-(pyrimidin-2-yl)carboxamide;
    (R)-[4-[[1-(2-丁炔酰基)哌啶-3-基]氨基]-6-氨基嘧啶-5-基]-N-(嘧啶-2-基)甲酰胺；(R)-[4-[[1-(2-butynyl)piperidin-3-yl]amino]-6-aminopyrimidin-5-yl]-N-(pyrimidin-2-yl)carboxamide;
  5. 根据权利要求1所述的4-氨基嘧啶类化合物的制备方法，其特征在于：The method for producing a 4-aminopyrimidine compound according to claim 1, wherein:
    a)当L为C(O)时，通式(I)所示化合物的制备方法为：以4,6-二羟基嘧啶为原料，经Vilsmeier-Haack反应和氯代反应制得4,6-二氯-5-嘧啶甲醛1，1经亚氯酸钠氧化制得4,6-二氯-5-嘧啶羧酸2，2与草酰氯反应制得酰氯后与芳烃进行Friedel-Crafts酰基化反应制得中间体3，3与氨水反应制得中间体4，4与胺类化合物反应制得5-1或5-2，5-1经浓盐酸脱Boc保护基后和5-2一样，可以与酰氯或2-丁炔酸反应制得通式(I)化合物：a) When L is C(O), the compound of the formula (I) is prepared by using 4,6-dihydroxypyrimidine as a raw material, Vilsmeier-Haack reaction and chlorination reaction to obtain 4,6- Dichloro-5-pyrimidinecarboxaldehyde 1,1 is oxidized by sodium chlorite to obtain 4,6-dichloro-5-pyrimidinecarboxylic acid 2,2 and reacted with oxalyl chloride to obtain acid chloride, followed by Friedel-Crafts acylation with aromatic hydrocarbon The intermediates 3, 3 are obtained by reacting with ammonia water to obtain intermediates 4 and 4, which are reacted with an amine compound to obtain 5-1 or 5-2, and 5-1 is deprotected with concentrated hydrochloric acid, and is the same as 5-2. The compound of the formula (I) is obtained by reacting with an acid chloride or 2-butynoic acid:
    Figure PCTCN2018084300-appb-100006
    Figure PCTCN2018084300-appb-100006
    其中，n、A、R 1和R 2的定义如前所述。 Wherein n, A, R 1 and R 2 are as defined above.
    b)当L为C(O)NH(CH 2) m时，通式(I)所示化合物的制备方法为：中间体2与草酰氯反应制得酰氯后与胺类化合物缩合生成酰胺6，6与氨水反应制得中间体7，7与胺类化合物(HY-Boc)反应制得8，8经浓盐酸脱Boc制得9，最后9与酰氯或2-丁炔酸反应制得通式(I)化合物： b) When L is C(O)NH(CH 2 ) m , the compound of the formula (I) is prepared by reacting the intermediate 2 with oxalyl chloride to obtain an acid chloride, and then condensing with an amine compound to form an amide 6, 6 reacting with ammonia to obtain intermediate 7,7 and amine compound (HY-Boc) to obtain 8,8 by concentrated hydrochloric acid to remove Boc to obtain 9, and finally 9 react with acid chloride or 2-butynoic acid to obtain general formula (I) Compound:
    Figure PCTCN2018084300-appb-100007
    Figure PCTCN2018084300-appb-100007
    其中，m、n、A、R 1和R 2的定义如前所述。 Wherein, m, n, A, R 1 and R 2 are as defined above.
  6. 一种药物组合物，其由治疗上有效量的活性组分和药学上可接受的辅料组成；所述的活性 组分包括如权利要求1-4中任一项所述的4-氨基嘧啶类化合物或其药学上可接受的盐；所述的药学上可接受的辅料包括药学上可接受的载体、稀释剂和/或赋形剂。A pharmaceutical composition comprising a therapeutically effective amount of an active ingredient and a pharmaceutically acceptable excipient; the active ingredient comprising the 4-aminopyrimidine of any one of claims 1-4 A compound or a pharmaceutically acceptable salt thereof; the pharmaceutically acceptable excipient comprising a pharmaceutically acceptable carrier, diluent and/or excipient.
  7. 权利要求1-4和6中任一项的化合物或其药学上可接受的盐在制备药物中的用途，所述药物用于抑制布鲁顿酪氨酸激酶的活性。Use of a compound according to any one of claims 1 to 4 and a pharmaceutically acceptable salt thereof for the preparation of a medicament for inhibiting the activity of Bruton's tyrosine kinase.
  8. 权利要求1-4和6中任一项的化合物或其药学上可接受的盐在制备布鲁顿酪氨酸激酶抑制剂药物中的应用，所述药物用于治疗血栓栓塞、炎性病症、自身免疫性疾病、B细胞淋巴瘤或华氏巨球蛋白血症。Use of a compound according to any one of claims 1 to 4 and a pharmaceutically acceptable salt thereof for the manufacture of a Bruton's tyrosine kinase inhibitor drug for the treatment of thromboembolism, inflammatory disorders, Autoimmune disease, B cell lymphoma or Waldenstrom's macroglobulinemia.
  9. 根据权利要求8所述的应用，其中所述的炎性或自身免疫性疾病为异种免疫性疾病、哮喘、类风湿性关节炎、系统性红斑狼疮、多发性硬化、特发性血小板减少性紫癜、自身免疫介导的溶血性贫血、免疫复合体介导的脉管炎或银屑病。The use according to claim 8, wherein the inflammatory or autoimmune disease is xenobiotic disease, asthma, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, idiopathic thrombocytopenic purpura Autoimmune-mediated hemolytic anemia, immune complex-mediated vasculitis, or psoriasis.
  10. 根据权利要求8所述的应用，其中所述的B细胞淋巴瘤为慢性淋巴细胞白血病、急性淋巴细胞白血病、套细胞淋巴瘤、滤泡性淋巴瘤、小淋巴细胞淋巴瘤、弥漫性大B细胞淋巴瘤、多发性骨髓瘤、黏膜相关淋巴组织淋巴瘤、霍奇金淋巴瘤或B细胞非霍奇金淋巴瘤。The use according to claim 8, wherein said B cell lymphoma is chronic lymphocytic leukemia, acute lymphocytic leukemia, mantle cell lymphoma, follicular lymphoma, small lymphocytic lymphoma, diffuse large B cell. Lymphoma, multiple myeloma, mucosa-associated lymphoid tissue lymphoma, Hodgkin's lymphoma, or B-cell non-Hodgkin's lymphoma.
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