WO2014089913A1

WO2014089913A1 - Bicyclic compound functioning as tyrosine kinase inhibitor

Info

Publication number: WO2014089913A1
Application number: PCT/CN2013/001555
Authority: WO
Inventors: 张倩; 张艳
Original assignee: 山东亨利医药科技有限责任公司
Priority date: 2012-12-12
Filing date: 2013-12-12
Publication date: 2014-06-19
Also published as: CN104968664A

Abstract

The present invention relates to a compound shown in a formula (I), a method for preparing the compound, a pharmaceutical composition containing the compound, and applications of the compound in preparing drugs for preventing and/or treating B-cell related leukemia, inflammatory diseases and autoimmune diseases, wherein X, W, ring A, ring B, L₁, L₂, R₁, R₂, R₃, ---, a, b, c, d, e, p and q are as defined in the specification.

Description

作为酪氨酸激晦抑制剂的并环化合物 Paracyclic compound as a tyrosine kinase inhibitor

1、技术领域 1. Technical field

本发明属于医药技术领域，具体涉及作为酪氨酸激酶抑制剂的并环化合物、其氘代物、其药学上可接受的盐或其立体异构体，所述化合物的制备方法，含有所述化合物的药物组合物，使用所述化合物预防和 /或治疗个体中 B 细胞相关的血癌（例如 B 细胞慢性淋巴细胞癌、非霍奇金淋巴瘤），炎性以及自身免疫性疾病 (例如类风湿性关节炎、系统性红斑狼疮等）的方法，以及所迷化合物在制备用于预防和 /或治疗 B 细胞相关的血癌（例如 B细胞慢性淋巴细胞癌、非霍奇金淋巴瘤），炎性以及自身免疫性疾病（例如类风湿性关节炎、 ***性红斑狼疮等）的药物中的应用。 The present invention relates to the field of medical technology, and particularly relates to a conjugated compound as a tyrosine kinase inhibitor, a progeny thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a method for producing the compound, which comprises the compound A pharmaceutical composition for preventing and/or treating B cell-associated blood cancer in an individual (eg, B cell chronic lymphocytic carcinoma, non-Hodgkin's lymphoma), inflammatory and autoimmune diseases (eg, rheumatoid) Methods of arthritis, systemic lupus erythematosus, etc., and the preparation of compounds for the prevention and/or treatment of B cell-associated blood cancer (eg, B-cell chronic lymphocytic carcinoma, non-Hodgkin's lymphoma), inflammatory and Use in drugs for autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and the like.

2、背景技术 2. Background technology

蛋白质激酶组成人类酶的最大家族之一，并且通过添加磷酸基团到蛋白质上来调节许多不同的信号传导过程 (T. Hunter, Cell 1987 50: 823-829)。特别地，酪氨酸激酶磷酸化蛋白盾在酪氨酸残基的羟基部分。酪氨酸激酶家族包括控制细胞生长、迁移和分化的成员。异常的激酶活性已经涉及许多人类疾病，包括癌症、自身免疫疾病和炎性疾病。由于蛋白质激酶属于细胞信号传导的关键调节剂，它们提供用小分子激酶抑制剂来调节细胞功能的目标，并且因此成为了良好的药物设计靶标。除了激酶介导的疾病过程的治疗，激酶活性的选择性和有效抑制剂还可用于研究细胞信号传导过程和鉴定其它具有治疗意义的细胞靶标。 Protein kinases constitute one of the largest families of human enzymes and regulate many different signaling processes by the addition of phosphate groups to proteins (T. Hunter, Cell 1987 50: 823-829). In particular, the tyrosine kinase phosphorylation protein is shielded in the hydroxyl portion of the tyrosine residue. The tyrosine kinase family includes members that control cell growth, migration, and differentiation. Abnormal kinase activity has been implicated in many human diseases, including cancer, autoimmune diseases, and inflammatory diseases. Since protein kinases are key regulators of cell signaling, they provide the goal of regulating cell function with small molecular kinase inhibitors and are therefore good drug design targets. In addition to the treatment of kinase-mediated disease processes, selective and potent inhibitors of kinase activity can be used to study cellular signaling processes and to identify other therapeutically significant cellular targets.

关于 B细胞在自身免疫和 /或炎性疾病的发病机制中的关键作用存在良好的证据。消耗 B细胞的基于蛋白质的治疗剂如 Rituxan针对自身抗体导致的炎性疾病如类风湿性关节炎是有效的（Rastetter 等， Annu Rev Med 2004 55: 477). 因此，在 B细胞活化中发挥作用的蛋白质激酶的抑制剂应该是对于 B 细胞介导的疾病病理如自身抗体生成有用的治疗剂。 There is good evidence that B cells play a key role in the pathogenesis of autoimmune and/or inflammatory diseases. B-cell-derived protein-based therapeutics such as Rituxan are effective against autoantibody-induced inflammatory diseases such as rheumatoid arthritis (Rastetter et al., Annu Rev Med 2004 55: 477). Therefore, play a role in B cell activation. Inhibitors of protein kinases should be useful therapeutic agents for B cell mediated pathology such as autoantibody production.

通过 B 细胞受体 (BCR)的信号传导控制一系列 B 细胞应答，包括增殖和分化到成熟的抗体生成细胞。 BCR是 B细胞活性的关键调节点并且异常的信号传导可以导致失调的 B 细胞增殖和病原性自身抗体的形成，其导致多种自身免疫疾病和 /或炎性疾病。布鲁顿 (Bruton's)酪氨酸蛋白激酶 (Btk)是在 BCR的膜近端和紧接下游的非 BCR相关的激酶。 Btk的缺乏已经显示阻断 BCR信号传导，并且因此 Btk的抑制可以是阻断 B细胞介导的疾病过程的有效治疗方法。 Signaling through the B cell receptor (BCR) controls a range of B cell responses, including proliferation and differentiation into mature antibody-producing cells. BCR is a key regulatory point for B cell activity and abnormal signaling can lead to dysregulated B cell proliferation and pathogenic autoantibodies Formation, which results in a variety of autoimmune diseases and/or inflammatory diseases. Bruton's tyrosine protein kinase (Btk) is a non-BCR-associated kinase proximal to and downstream of the membrane of BCR. The lack of Btk has been shown to block BCR signaling, and thus inhibition of Btk may be an effective treatment to block B cell mediated disease processes.

Btk是酪氨酸激酶 Tec家族的成员，并且显示是早期 B细胞形成以及成熟 B细胞活化和存活的关键调节剂（Khan等， Immunity 1995 3: 283; Ellmeier等， J. Exp. Med. 2000 192: 1611)。人的 Btk突变导致病症 X连锁丙球蛋白缺乏血症 (XLA)(Lindvall等 Immunol. Rev. 2005 203: 200)。这些患者是免疫受损的，并且显示受损的 B 细胞成熟，降低的免疫球蛋白和外周 B细胞水平，减少的不依赖 T细胞的免疫应答以及在 BCR 刺激后的减弱的钙动用。 Btk is a member of the Tec family of tyrosine kinases and has been shown to be a key regulator of early B cell formation and activation and survival of mature B cells (Khan et al, Immunity 1995 3: 283; Ellmeier et al, J. Exp. Med. 2000 192 : 1611). Human Btk mutations lead to the condition X-linked gamma globulin deficiency (XLA) (Lindvall et al Immunol. Rev. 2005 203: 200). These patients are immunocompromised and show impaired B cell maturation, decreased immunoglobulin and peripheral B cell levels, reduced T cell-independent immune response, and reduced calcium use following BCR stimulation.

关于 Btk在自身免疫疾病和炎性疾病中的作用的证据已经由 Btk- 缺陷型小鼠模型提供。在***性红斑狼疮 (SLE)的临床前鼠模型中， Btk 缺陷型小鼠显示疾病进展的显著改善。此外， Btk-缺陷型小鼠对胶原诱导的关节炎具有抗性 (Jansson和 Holmdahl Clin. Exp. Immunol. 1993 94: 459)。已经证明选择性 Btk抑制剂在小鼠关节炎模型中的剂量依赖性功效 (Z. Pan等， Chem. Med Chem. 2007 2: 58) 。 Evidence for the role of Btk in autoimmune diseases and inflammatory diseases has been provided by the Btk-deficient mouse model. Btk-deficient mice showed a significant improvement in disease progression in a preclinical mouse model of systemic lupus erythematosus (SLE). Furthermore, Btk-deficient mice are resistant to collagen-induced arthritis (Jansson and Holmdahl Clin. Exp. Immunol. 1993 94: 459). The dose-dependent efficacy of selective Btk inhibitors in the mouse arthritis model has been demonstrated (Z. Pan et al, Chem. Med Chem. 2007 2: 58).

Btk还有除了 B细胞之外可能涉及疾病过程的细胞表达。例如 Btk 由肥大细胞表达并且 Btk 缺陷型骨髓来源的肥大细胞显示受损的抗原诱导的脱粒 (Iwaki 等 J. Biol. Chem. 2005 280: 40261) 。这显示 Btk可以用于治疗病理性肥大细胞反应如***反应和哮喘。此外，其中缺乏 Btk活性的来自 XLA患者的单核细胞显示在刺激后减少的 TNFa生成 (Horwood 等 J Exp Med 2003 197: 1603)。因此， TNFa介导的炎症可以由小分子 Btk抑制剂调节。此外，已经报道的 Btk在细胞凋亡中发挥作用（Islam和 Smith Immunol. Rev. 2000 178: 49) ，并且因此 Btk抑制剂对于治疗某些 B细胞淋巴瘤和白血病将是有效的 (Feldhahn 等 J. Exp. Med. 2005 201 : 1837) 。 Btk also has cellular expression that may be involved in disease processes in addition to B cells. For example, Btk is expressed by mast cells and Btk-deficient bone marrow-derived mast cells show impaired antigen-induced degranulation (Iwaki et al. J. Biol. Chem. 2005 280: 40261). This shows that Btk can be used to treat pathological mast cell responses such as allergies and asthma. Furthermore, monocytes from XLA patients lacking Btk activity show reduced TNFa production following stimulation (Horwood et al J Exp Med 2003 197: 1603). Thus, TNFa-mediated inflammation can be modulated by small molecule Btk inhibitors. Furthermore, Btk has been reported to play a role in apoptosis (Islam and Smith Immunol. Rev. 2000 178: 49), and thus Btk inhibitors will be effective in the treatment of certain B cell lymphomas and leukemias (Feldhahn et al. Exp. Med. 2005 201 : 1837).

2006年上市的 Dasatinib是多靶点抑制剂，对 Btk具有较强抑制作用，用于治疗慢性骨髓性白血病；此外， 2013年 11 月被 FDA批准上市的 PCI-32765也是多靶点抑制剂，对 Btk抑制作用为不可逆性，用于治疗淋巴瘤、白血病及自身免疫疾病。

Dasatinib, which was launched in 2006, is a multi-target inhibitor that has a strong inhibitory effect on Btk and is used to treat chronic myelogenous leukemia. In addition, PCI-32765, which was approved by the FDA in November 2013, is also a multi-target inhibitor. Btk inhibition is irreversible and is used to treat lymphoma, leukemia and autoimmune diseases.

目前尚未有选择性的 Btk抑制剂上市，研究最快的药物是 CC-292 (又称 AVL-292 ), 2013年 10月底进入临床 II期研究，其作为不可逆的选择性抑制 Bt

At present, there is no selective Btk inhibitor listed. The fastest drug to be studied is CC-292 (also known as AVL-292). At the end of October 2013, it entered the clinical phase II study, which is an irreversible selective inhibition of Bt.

本发明的目的是提供优良的高选择性 Btk抑制剂，其能够用于预防和 /或治疗 B细胞相关的血癌、炎性和 /或自身免疫性疾病。 It is an object of the present invention to provide an excellent highly selective Btk inhibitor which can be used for the prevention and/or treatment of B cell-associated blood cancer, inflammatory and/or autoimmune diseases.

3、发明内容 3, the content of the invention

本发明提供了作为酪氨酸激酶抑制剂的并环化合物，所迷化合物是优良的 Btk 抑制剂，并且能够用于预防和 /或治疗 B 细胞相关的血癌、炎性和 /或自身免疫性疾病。 The present invention provides a bicyclic compound as a tyrosine kinase inhibitor, which is an excellent Btk inhibitor and can be used for the prevention and/or treatment of B cell-associated blood cancer, inflammatory and/or autoimmune diseases. .

本发明提供了下迷通式（I ) 所示的化合物、其氘代物、其药学上可接受的盐或其立体异构体： The present invention provides a compound represented by the formula (I), a deuterated compound thereof, a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

其中， X和 W分别独立的表示 C-Ra, C=0或 N-Rb， Where X and W respectively represent C-Ra, C=0 or N-Rb,

且 X和 W不同时为 C=0, And X and W are not C=0 at the same time.

Ra表示氢原子，卤素原子， -CN, -CF₃ , 被 1-2 个相同或不同的 (^取代或未被取代的 C_M烷基、 d.₄烷氧基 QM亚烷基、氨基、 C₃.₆环烷基 Q 亚烷基、苯基 CCM亚烷基、萘基 CQ.₄烷基、 5-10元杂芳基 QM 亚烷基或 -OH, Rb不存在，或者表示氢原子，被 1-2个相同或不同的（^取代或未被取代的 C ₄烷基、烷氧基 0)-₄亚烷基， C_3-6环烷基 Co_₄亚烷基，苯基 Q 亚烷基，萘基 Q 亚烷基或 5-10元杂芳基 QM亚烷基， Ra represents a hydrogen atom, a halogen atom, -CN, -CF ₃ , which is 1-2 identical or different (^ substituted or unsubstituted C _M alkyl, d. ₄ alkoxy QM alkylene, amino, C ₃ ₆ cycloalkyl Q alkylene, phenyl CCM alkylene, naphthyl CQ. ₄ alkyl, 5-10 membered heteroaryl QM alkylene or -OH, Rb is absent, or represents a hydrogen atom, is 1-2 identical or different (^ substituted or unsubstituted C ₄ alkyl, alkoxy 0) _-4 alkylene, C _3-6 cycloalkyl Co_ ₄ alkylene, phenyl Q alkylene, naphthyl Q alkylene or 5-10 membered heteroaryl QM alkylene,

表示 d-₄烷氧基，烷氧羰基，氨基甲酰基， C_1-3烷基氨基甲酰基， 3-8元环烷基或含有选自 N或 0的杂原子的 3-8元杂环基； And represents a d- ₄ alkoxy group, an alkoxycarbonyl group, a carbamoyl group, a C _1-3 alkylcarbamoyl group, a 3-8 membered cycloalkyl group or a 3-8 membered heterocyclic ring containing a hetero atom selected from N or 0. base;

R₂表示氢原子，卤素原子， -CF₃, C_M烷基，烷氧基，氨基或R ₂ represents a hydrogen atom, a halogen atom, -CF ₃ , C _M alkyl, alkoxy, amino or

-OH; -OH;

环 A和环 B分别独立的表示苯基， 3-8元环烷基，含有选 N、 0 和 S的杂原子的 3-8元杂环烷基， 4-7元杂芳基或 6-12元二环结构；和 L₂分别独立的表示共价键， -NH-, -N(C_1-3烷基) -, -0-， -S(0)_m-, -N(C_1-3 烷基） C(O)-， -QC N Cw 烷基） - , -N(C_1-3 烷基） S(0)₂-或- S(0)₂N(C_1-3烷基) -; Ring A and Ring B each independently represent a phenyl group, a 3-8 membered cycloalkyl group, a 3-8 membered heterocycloalkyl group containing a hetero atom selected from N, 0 and S, a 4-7 membered heteroaryl group or 6- 12-membered bicyclic structure; and L ₂ independently represent a covalent bond, -NH-, -N(C _1-3 alkyl) -, -0-, -S(0) _m -, -N(C _{1 -3} alkyl) C(O)-, -QC N Cw alkyl) - , -N(C _1-3 alkyl) S(0) ₂ - or - S(0) ₂ N(C _1-3 alkane Base) -;

a表示共价键，或未被取代或被 CM烷基取代的亚氨基； a represents a covalent bond, or an imino group which is unsubstituted or substituted by a CM alkyl group;

b表示 -CO-或 -S0₂-; b represents -CO- or -S0 ₂ -;

c表示未被取代或被一或两个甲基或三氟甲基取代的 1,3-亚丙二烯基、 1,1-或 1,2-亚乙烯基，亚乙炔基，或者未被取代或被一至四个甲基或三氟甲基取代的 1，3-丁二烯 -1 ,4-亚基； c represents 1,3-propylenediene, 1,1- or 1,2-vinylidene, ethynylene, or unsubstituted, which is unsubstituted or substituted by one or two methyl or trifluoromethyl groups a 1,3-butadiene-1,4-subunit substituted or substituted with one to four methyl or trifluoromethyl groups;

d表示共价键或 C_1-6亚烷基； d represents a covalent bond or a C _1-6 alkylene group;

e表示氢原子，。_1-4烷氧基，氨基， 3-7元环烷基， 6-12元二环结构， d.₄烷基氨基或二 - ( Cw烷基）氨基，其中烷基部分可相同或不同； 1^和 R₃分别独立的表示氢原子，卤素原子，氰基，硝基， C ₄烯基 C2-4块基或- - R45 e represents a hydrogen atom, . _1-4 alkoxy, amino, 3-7 membered cycloalkyl, 6-12 membered bicyclic structure, d. ₄ alkylamino or bis-(Cw alkyl)amino, wherein the alkyl moieties may be the same or different; 1^ and R ₃ independently represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, a C ₄ alkenyl group C2-4 block or - R45

L₃表示共价键， -NH-, -N(Ci_-3烷基) -, -0-, -O-Ci.3亚烷基-, -S-C_1-3 亚烷基-, -S(0)_m -, -C(0)-， -NHC(O)-, -N(C_1-3烷基) C(0)-， -C(0)NH -， -C(0)N(C,.₃ 烷基） -， -NHS(0)₂- , -N(Ci_-3 烷基） S(0)₂-， -S(0)₂NH -， -S(0)₂N(Ci.₃烷基) -， -OC(O)-或 -C(0)0-， L ₃ represents a covalent bond, -NH-, -N(Ci _-3 alkyl) -, -0-, -O-Ci.3 alkylene-, -SC _1-3 alkylene-, -S( 0) _m -, -C(0)-, -NHC(O)-, -N(C _1-3 alkyl) C(0)-, -C(0)NH -, -C(0)N( C,. ₃ alkyl) -, -NHS(0) ₂ - , -N(Ci _-3 alkyl) S(0) ₂ -, -S(0) ₂ NH -, -S(0) ₂ N( Ci. ₃ alkyl) -, -OC(O)- or -C(0)0-,

R₄表示氢原子， d-₄烷基， -N(C_{1 -3}烷基 )2 , -NHC C^CKCM烷基)， -OH, -0(C_1-4烷基）， -S(0)₂(Cw烷基）， 3-7元环烷基，苯基或 5-6元杂芳基； R ₄ represents a hydrogen atom, d- ₄ alkyl, -N(C _{1 -3} alkyl) 2 , -NHC C^CKCM alkyl), -OH, -0(C _1-4 alkyl), -S( 0) ₂ (Cw alkyl), 3-7 membered cycloalkyl, phenyl or 5-6 membered heteroaryl;

上述 c_1-3烷基和 c_1-4烷基中的烷基部分、环烷基、杂芳基可以进一步被 1-4个相同或不同的 Q₂取代， The alkyl moiety, cycloalkyl group, heteroaryl group in the above c _1-3 alkyl group and c _1-4 alkyl group may be further substituted by 1 to 4 identical or different Q ₂ groups,

(^表示素原子、 d.₃烷基、氨基、 d_₃烷基氨基、二 - ( Cw烷基）氨基、羟基、 d.₃烷氧基、 d_₃烷氧羰基、氨基甲酰基、烷基氨基甲酰基、二 - ( C_{I -3}烷基）氨基甲酰基或 3-6元环烷基，其中 Q₂可以相同或不同； (^ represents a prime atom, d. ₃ alkyl, amino, d_ ₃ alkylamino, di-(Cw alkyl) Amino, hydroxy, d. ₃ alkoxy, d- ₃ alkoxycarbonyl, carbamoyl, alkylcarbamoyl, bis-(C _{I -3} alkyl)carbamoyl or 3-6 membered cycloalkyl, wherein Q ₂ may be the same or different;

所述环烷基和二环结构的上碳原子可以被 1-4个相同或不同的 N、 NH、 N(C_1-3烷基）、 0、 S(0)_m、 C(O)替换； The upper carbon atom of the cycloalkyl and bicyclic structure may be replaced by 1-4 identical or different N, NH, N(C _1-3 alkyl), 0, S(0) _m , C(O) ;

所述杂芳基可以含有 1-4个杂原子，所述的杂原子分别独立的选自 N、 0或 S; The heteroaryl group may have 1 to 4 hetero atoms, and the hetero atoms are independently selected from N, 0 or S;

表示单键或双键； Represents a single or double bond;

m表示 0, 1或 2; m means 0, 1 or 2;

p和 q分别独立的表示 0, 1 , 2 , 3或 4。 p and q are independent representations of 0, 1, 2, 3 or 4.

在一个优选的实施方案中，本发明提供了上述通式（I )所示的化合物、其氘代物、其药学上可接受的盐或其立体异构体，其中： In a preferred embodiment, the present invention provides a compound represented by the above formula (I), a deuterated compound thereof, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein:

X表示 C-Ra或 N-Rb, X means C-Ra or N-Rb,

Ra表示氢原子，卤素原子， -CF₃，甲基，乙基，甲氧基，曱氧基乙基，氨基，环丙基，苯基，苄基，萘基，吡咯基，呋喃基或吡啶基， Rb不存在，或者表示氢原子，被 1-2个相同或不同的（^取代或未被取代的 d_₃烷基、 C_1-3烷氧基 Co.3亚烷基， C_3-6环烷基 C_Q-3亚烷基，苯基，苄基，萘基，吡咯基，四氢吡喃基，呋喃基或吡啶基， Ra represents a hydrogen atom, a halogen atom, -CF ₃ , methyl, ethyl, methoxy, methoxyethyl, amino, cyclopropyl, phenyl, benzyl, naphthyl, pyrrolyl, furyl or pyridine a group, Rb does not exist, or represents a hydrogen atom, which is 1-2 identical or different (^ substituted or unsubstituted d- ₃ alkyl, C _1-3 alkoxy Co. ₃ alkylene, C _{3- 6} cycloalkyl C _Q-3 alkylene, phenyl, benzyl, naphthyl, pyrrolyl, tetrahydropyranyl, furyl or pyridyl,

表示 d.₃烷氧基，烷氧羰基或含有选自 N或 0的杂原子的 5-7元杂环基； And represents a d. ₃ alkoxy group, an alkoxycarbonyl group or a 5-7 membered heterocyclic group containing a hetero atom selected from N or 0;

W表示 C=0; W means C=0;

R₂表示氢原子或氨基； R ₂ represents a hydrogen atom or an amino group;

环 A和环 B分别独立的表示苯基， 5-6元环烷基，含有选自 N、 0 和 S的杂原子的 5-6元杂环烷基， 5-6元杂芳基或 8-10元二环结构； 1^和 ₂分别独立的表示共价键， -NH-, -N(CH₃)-， -0-, -S(0)_m-，Ring A and Ring B each independently represent a phenyl group, a 5-6 membered cycloalkyl group, a 5-6 membered heterocycloalkyl group containing a hetero atom selected from N, 0 and S, a 5-6 membered heteroaryl group or 8 a -10-membered bicyclic structure; 1^ and ₂ independently represent a covalent bond, -NH-, -N(CH ₃ )-, -0-, -S(0) _m -,

-N(CH₃)C(0)-, -C(0)N(CH₃)-， -N(CH₃)S(0)₂-或 - S(0)₂N(CH₃) -N(CH ₃ )C(0)-, -C(0)N(CH ₃ )-, -N(CH ₃ )S(0) ₂ - or - S(0) ₂ N(CH ₃ )

a表示共价键，或未被取代或被 C 取代的亚氨基； a represents a covalent bond, or an imino group which is unsubstituted or substituted by C;

b表示 -CO-或 -S0₂-; b represents -CO- or -S0 ₂ -;

c 表示未被取代或被一或两个甲基取代的 1,2-亚乙烯基或亚乙炔基； c represents a 1,2-vinylidene or ethynylene group which is unsubstituted or substituted by one or two methyl groups;

d表示共价键或亚曱基； d represents a covalent bond or an anthracene group;

e表示氢原子，甲氧基，氨基，哌啶基，吗啉基， 6-9元螺环结构， 6-8元并环结构， 6-8元桥环结构，甲基氨基，哌嗪，吡咯烷基或二- (甲基）氨基； e represents a hydrogen atom, a methoxy group, an amino group, a piperidinyl group, a morpholinyl group, a 6-9 membered spiro ring structure, 6-8 membered ring structure, 6-8 membered bridged ring structure, methylamino, piperazine, pyrrolidinyl or bis-(methyl)amino group;

1^和1₃分别独立的表示氢原子，卤素原子，硝基或 -L₃-R₄，1^ and 1 ₃ independently represent a hydrogen atom, a halogen atom, a nitro group or -L ₃ -R ₄ ,

L₃表示共价键， -NH-, -N Cw烷基) -, -0-, -O-Cw亚烷基-, -S-C_1-3 亚烷基-, -S(0)_m-， -C(O)-, -NHC(O)-, -C(0)NH -， -NHS(0)₂-， - S(0)₂NH-,L ₃ represents a covalent bond, -NH-, -N Cw alkyl) -, -0-, -O-Cw alkylene-, -SC _1-3 alkylene-, -S(0) _m -, -C(O)-, -NHC(O)-, -C(0)NH -, -NHS(0) ₂ -, - S(0) ₂ NH-,

-OC(O)-或 -C(0)0-， -OC(O)- or -C(0)0-,

R₄表示氢原子， C_1-4烷基， -N Cw烷基 )₂, -NHC(0)0-(C_M烷基)，R ₄ represents a hydrogen atom, C _1-4 alkyl, -N Cw alkyl) ₂ , -NHC(0)0-(C _M alkyl),

-OH, -O CM烷基）， -S OWCw烷基）， 5-6元环烷基，苯基或 5-6元杂芳基； -OH, -O CM alkyl), -S OWCw alkyl), 5-6 membered cycloalkyl, phenyl or 5-6 membered heteroaryl;

上述 C_1-3烷基中的烷基部分、环烷基、杂芳基、螺环结构、并环结构和桥环结构可以进一步被 1-4个相同或不同的 Q₂取代， The alkyl moiety, cycloalkyl group, heteroaryl group, spiro ring structure, concentric ring structure and bridged ring structure in the above C _1-3 alkyl group may be further substituted by 1 to 4 identical or different Q ₂ groups,

Q₂表示！ ¾素原子、 C_1-3烷基、氨基、 d.₃烷基氨基、二 - (d.₃烷基）氨基、羟基、 d_₃烷氧基、烷氧羰基、氨基甲酰基、 C ₃烷基氨基甲酰基、二 - 烷基）氨基甲酰基或 5-6元环烷基，其中 Q₂可以相同或不同； Q ₂ means! ¾ prime atom, C _1-3 alkyl, amino, d ₃ alkylamino, di -. (. D ₃ alkyl) amino, hydroxy, d_ ₃ alkoxy, alkoxycarbonyl, carbamoyl, C ₃ alkyl Carbocarbyl, di-alkyl)carbamoyl or 5-6 membered cycloalkyl, wherein Q ₂ may be the same or different;

所述环烷基和二环结构上的碳原子可以被 4个相同或不同的 N、 NH、 N(C_1-3烷基）、 0、 S(0)_m、 C(O)替换； The carbon atoms on the cycloalkyl and bicyclic structures may be replaced by 4 identical or different N, NH, N(C _1-3 alkyl), 0, S(0) _m , C(O);

所迷螺环结构、并环结构和桥环结构可以含有 1-4个杂原子，所述的杂原子分别独立地选自 N、 ◦或 S; The spiro ring structure, the ring structure and the bridge ring structure may contain 1-4 hetero atoms, and the hetero atoms are independently selected from N, ◦ or S;

^表示单键或双键； ^ means single or double button;

m表示 0, 1或 2; m means 0, 1 or 2;

p和 q分别独立的表示 0, 1, 2, 3或 4。 p and q are independent representations of 0, 1, 2, 3 or 4.

在一个优选的实施方案中，本发明提供了上述通式（I)所示的化合物、其氘代物、其药学上可接受的盐或其立体异构体，其中： In a preferred embodiment, the present invention provides a compound represented by the above formula (I), a deuterated compound thereof, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein:

X表示 CH或 N-Rb, X means CH or N-Rb,

Rb不存在，或者表示氢原子，被 1-2个相同或不同的（^取代或未被取代的甲基、乙基、环丙烷基、环戊烷基或四氢吡喃基， Rb does not exist, or represents a hydrogen atom, which is 1-2 identical or different (^ substituted or unsubstituted methyl, ethyl, cyclopropyl, cyclopentyl or tetrahydropyranyl,

Q 表示烷氧基或含有选自 N或 0的杂原子的 5-6元杂环基； Q represents an alkoxy group or a 5-6 membered heterocyclic group containing a hetero atom selected from N or 0;

W表示 c=o; W means c=o;

环 A和环 B分别独立的表示苯基，含有 N杂原子的 5-6元杂环烷基或 5-6元杂芳基； 1^和 L₂分别独立的表示共价键， -NH-或 -N(CH₃)-; Ring A and Ring B each independently represent a phenyl group, a 5-6 membered heterocycloalkyl group having a N hetero atom or a 5-6 membered heteroaryl group; 1^ and L ₂ independently represent a covalent bond, -NH- or -N(CH ₃ )-;

a表示共价键或亚氨基； a represents a covalent bond or an imino group;

b表示 -CO-; b means -CO-;

c表示 1,2-亚乙烯基； c represents 1,2-vinylidene;

d表示共价鍵或亚甲基； d represents a covalent bond or a methylene group;

e表示氢原子，哌啶基，吗啉基，哌嗪，吡咯烷基或二- (甲基)氨基；表示氢原子，卤素原子，未被取代或被 1-4个相同或不同的卤素原子取代的甲基、甲氧基，曱基氨基或二- (甲基）氨基； e represents a hydrogen atom, piperidinyl, morpholinyl, piperazine, pyrrolidinyl or bis-(methyl)amino; represents a hydrogen atom, a halogen atom, is unsubstituted or is 1-4 identical or different halogen atoms Substituted methyl, methoxy, decylamino or bis-(methyl)amino;

R₃表示氢原子，卤素原子或 -L₃-R₄， R ₃ represents a hydrogen atom, a halogen atom or -L ₃ -R ₄ ,

L₃表示共价键， -NH-, -N(C_1-3烷基) -, -0-, -0-C_M亚烷基-, -S-d-3 亚烷基， -S(0)_m -, -C(O)-, -NHC(O)-, -C(0)NH-， -OC(O)-或 -C(0)0-，L ₃ represents a covalent bond, -NH-, -N(C _1-3 alkyl)-, -0-, -0-C _M alkylene-, -Sd-3 alkylene, -S(0) _m -, -C(O)-, -NHC(O)-, -C(0)NH-, -OC(O)- or -C(0)0-,

R₄表示氢原子，甲基，乙基， -N(C_1-3烷基 )₂, -NHC(0)0-C₃H₇, -0(CH₃), -0(CH₂CH₃), -0(C(C¾)₃)， -S(0)₂-C₃H₇, 环戊烷基，环己烷基，吡咯烷基，四氢呋喃基，哌啶基，吗啉基，哌嗪基，苯基，吡咯基，咪唑基，噻唑基，噁唑基，噻二唑基，吡啶基或嘧啶基； R ₄ represents a hydrogen atom, methyl, ethyl, -N(C _1-3 alkyl) ₂ , -NHC(0)0-C ₃ H ₇ , -0(CH ₃ ), -0(CH ₂ CH ₃ ), -0(C(C3⁄4) ₃ ), -S(0) ₂ -C ₃ H ₇ , cyclopentyl, cyclohexane, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, piperidine Azinyl, phenyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, pyridyl or pyrimidinyl;

所述环戊烷基、环己烷基、吡咯烷基、四氢呋喃基、哌啶基、吗啉基、哌嗪基，苯基、吡咯基、咪唑基、噻唑基、噁唑基、噻二唑基、吡啶基、嘧啶基可以进一步被 1-2个相同或不同的 Q₂取代， Cyclopentyl, cyclohexane, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, piperazinyl, phenyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, thiadiazole The base, pyridyl, pyrimidinyl group may be further substituted by 1-2 identical or different Q ₂ groups,

Q₂表示素原子、甲基、氨基、甲基氨基、二曱基氨基、羟基、曱氧基、曱氧羰基、氨基甲酰基、曱基氨基甲酰基或二- (甲基）氨基甲酰基； Q ₂ represents a sulfhydryl atom, a methyl group, an amino group, a methylamino group, a dinonylamino group, a hydroxyl group, a decyloxy group, a fluorenyloxycarbonyl group, a carbamoyl group, a decylcarbamoyl group or a bis-(methyl)carbamoyl group;

- ^表示单键或双键； - ^ means single or double button;

m表示 0, 1或 2; m means 0, 1 or 2;

p和 q分别独立的表示 0, 1或 2。 p and q stand independently for 0, 1 or 2.

X表示 CH或 N-Rb, X means CH or N-Rb,

Rb不存在，或者表示氢原子，环丙烷基，四氢吡喃基，被 1个（^ 取代或未被取代的甲基或乙基， Rb does not exist, or represents a hydrogen atom, a cyclopropyl group, a tetrahydropyranyl group, a methyl group or an ethyl group substituted with or without

表示曱氧基，吡咯烷酮基或吡咯烷基； Deriving to a decyloxy group, a pyrrolidinyl group or a pyrrolidinyl group;

W表示 00; W means 00;

R₂表示氢原子；环 A和环 B分别独立的表示苯基，吡唑基，咪唑基，异噁唑基，噁唑基，吡啶基或哌啶基； R ₂ represents a hydrogen atom; Ring A and Ring B each independently represent phenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, pyridyl or piperidinyl;

1^和 L₂分别独立的表示共价键， -NH-或 -N(CH₃); 1^ and L ₂ independently represent a covalent bond, -NH- or -N(CH ₃ );

a表示共价键或亚氨基； a represents a covalent bond or an imino group;

b表示 -CO-; b means -CO-;

c表示 1,2-亚乙烯基； c represents 1,2-vinylidene;

d表示共价键或亚甲基； d represents a covalent bond or a methylene group;

e 表示氢原子，哌啶基，吗啉基，哌嗪，吡咯烷基或二- (甲基）氨基； e represents a hydrogen atom, piperidinyl, morpholinyl, piperazine, pyrrolidinyl or bis-(methyl)amino;

R!表示氢原子，氟原子，氯原子，三氟甲基，甲氧基或三氟曱氧基； R! represents a hydrogen atom, a fluorine atom, a chlorine atom, a trifluoromethyl group, a methoxy group or a trifluorodecyloxy group;

R₃表示氢原子，氟原子，氯原子或 -L₃-R₄, R ₃ represents a hydrogen atom, a fluorine atom, a chlorine atom or -L ₃ -R ₄ ,

L₃表示共价键， -NH-, -N(C₃H₇) -, -0-， -0-CH₂CH₂-或 -S(0)_m-， R₄表示氢原子，曱基，乙基，二甲基氨基， -NHC(0)0-C₃H₇ ,L ₃ represents a covalent bond, -NH-, -N(C ₃ H ₇ ) -, -0-, -0-CH ₂ CH ₂ - or -S(0) _m -, R ₄ represents a hydrogen atom, a fluorenyl group , ethyl, dimethylamino, -NHC(0)0-C ₃ H ₇ ,

-0(CH₃)， -0(C(C¾)₃), -S(0)₂-C₃H₇, 吗啉基，苯基，吡咯基，咪唑基，噻唑基，噁唑基，噻二唑基或吡啶基， -0(CH ₃ ), -0(C(C3⁄4) ₃ ), -S(0) ₂ -C ₃ H ₇ , Morpholinyl, Phenyl, Pyrrolyl, Imidazolyl, Thiazolyl, Oxazolyl, Thio Diazolyl or pyridyl,

所述苯基、吡咯基、咪唑基、噻唑基、噁唑基、噻二唑基、吡啶基可以进一步被 1-2个相同或不同的 Q₂取代， The phenyl group, pyrrolyl group, imidazolyl group, thiazolyl group, oxazolyl group, thiadiazolyl group, pyridyl group may be further substituted by 1-2 identical or different Q ₂ groups,

Q₂表示氨基甲酰基、甲基氨基甲酰基或二- (甲基）氨基曱酰基；：表示单键或双键 ·， Q ₂ represents a carbamoyl group, a methylcarbamoyl group or a bis-(methyl)aminodecanoyl group; : represents a single bond or a double bond,

m表示 0， 1或 2; m means 0, 1 or 2;

p和 q分别独立的表示 0或 1。 p and q stand independently for 0 or 1.

X表示 N-Rb, X means N-Rb,

Rb 不存在，氢原子，甲基，环丙烷基，四氢吡喃基， C¾OCH₂CH₂-,

^ H; Rb is absent, hydrogen atom, methyl, cyclopropyl, tetrahydropyranyl, C3⁄4OCH ₂ CH ₂ -,

^ H;

W表示 c=o; W means c=o;

R₂表示氢原子； R ₂ represents a hydrogen atom;

环 A表示苯基；环 B表示苯基，吡啶基，吡唑基，咪唑基，异噁唑基或噁唑基；表示共价键； Ring A represents a phenyl group; Ring B represents phenyl, pyridyl, pyrazolyl, imidazolyl, isoxazolyl or oxazolyl; represents a covalent bond;

L₂分别独立的表示共价键， -NH-或 -N(C¾); L ₂ independently represents a covalent bond, -NH- or -N(C3⁄4);

a表示亚氨基； a represents an imino group;

b表示 -CO-; b means -CO-;

c表示 1,2-亚乙烯基； c represents 1,2-vinylidene;

表示氢原子； Represents a hydrogen atom;

R₃表示 -L₃-R₄, L₃表示共价键， 0或 -0-CH₂CH₂-， R₄表示 -0(CH₃), 二甲基氨基，吗啉基或吡啶基，所述吡啶基可以进一步被 1-2个相同或不同的 Q₂取代， Q₂表示氨基甲酰基、甲基氨基甲酰基或二- (甲基）氨基曱酰基； R ₃ represents -L ₃ -R ₄ , L ₃ represents a covalent bond, 0 or -0-CH ₂ CH ₂ -, R ₄ represents -0(CH ₃ ), dimethylamino, morpholinyl or pyridyl, The pyridyl group may be further substituted by 1-2 identical or different Q ₂ , and Q ₂ represents a carbamoyl group, a methylcarbamoyl group or a bis-(methyl)aminodecanoyl group;

表示单键； Represents a single key;

p表示 0; p means 0;

q表示 1。发明详述 q means 1. Detailed description of the invention

除非另有陈述，否则，应该了解，在本申请中使用的术语具有下列含义。 Unless otherwise stated, it should be understood that the terms used in this application have the following meanings.

本发明所述的 "C^烷基"是指含有 1-6个碳原子的直链或支链的烷基，其中包括 "d_₄烷基"、 "d_₃烷基"等，其实例包括但不限于例如曱基、乙基、正丙基、异丙基、正丁基、 2-甲基丙基、 1-曱基丙基、 1 ,1- 二甲基乙基等。术语" (：_1-4烷基"、 "Ci.₃烷基"指上述实例中的含有 1 至 4个、 1至 3个碳原子的具体实例。 The "C^alkyl group" as used in the present invention means a straight or branched alkyl group having 1 to 6 carbon atoms, and includes "d- ₄ alkyl group", "d- ₃ alkyl group" and the like, and examples thereof include However, it is not limited to, for example, anthracenyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, 1-mercaptopropyl, 1,1-dimethylethyl and the like. The term "(: _1-4 alkyl", "Ci. ₃ alkyl" refers to a specific example containing 1 to 4, 1 to 3 carbon atoms in the above examples.

本发明所迷的 "Ox亚烷基 "是指共价键（ C_Q亚烷基）或含有 1-6个碳原子（〇^₆亚烷基）的直链或支链的烷基去掉一个氢原子后的结构，其中包括" QM亚烷基"、 "Co_-3亚烷基，，、 "C_1-4亚烷基"、 "C_{1 -3}亚烷基 "等，其实例包括但不限于例如亚曱基（-CH₂- )、亚乙基（ -CH₂CH₂- )、亚丙基（ -CH₂CH₂C¾- )、亚丁基 ( -CH2CH2CH2CH2- ) 等。术语" C_M亚烷基"、 "Ci-3亚烷基"指上述实例中的含有 1至 4个、 1至 3个碳原子的具体实例。 The "Ox alkylene" as used in the present invention means a covalent bond (C _Q alkylene group) or a linear or branched alkyl group having 1 to 6 carbon atoms (〇^ ₆ alkylene group). a structure after a hydrogen atom, which includes "QM alkylene group", "Co _-3 alkylene group,", "C _1-4 alkylene group", "C _{1 -3} alkylene group", etc., examples of which include It is not limited to, for example, anthracenylene (-CH ₂ - ), ethylene (-CH ₂ CH ₂ - ), propylene (-CH ₂ CH ₂ C 3⁄4- ), butylene ( -CH ₂ CH ₂ CH ₂ CH ₂ ), and the like. _M alkylene", "Ci-3 alkylene" means a one having 1 to 4, 1 to 3 carbon atoms in the above examples. Body instance.

本发明所述的 "C₂₄烯基"是指含有键的碳原子数为 2-4的直链或支链烯基；其实例包括但不限于例如乙烯基、 1 -丙烯基、 2-丙烯基、 1 - 甲基乙烯基、 1 -丁烯基、 2-丁烯基、 3-丁烯基、 1 -甲基 - 1 -丙烯基、 2-曱基 - 1 -丙烯基、 1 -曱基 -2-丙烯基、 2-甲基 -2-丙烯基。 The "C ₂₄ alkenyl group" as used in the present invention means a linear or branched alkenyl group having 2 to 4 carbon atoms; and examples thereof include, but are not limited to, for example, a vinyl group, a 1-propenyl group, and a 2-propene group. 1, 1-methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-indolyl-1-propenyl, 1-indole Alkyl-2-propenyl, 2-methyl-2-propenyl.

本发明所述的 "C₂-₄炔基"是指含有叁键的碳原子数为 2-4的直链或支链的炔基；其实例包括但不限于例如乙炔基、 2-丙炔基、 2-丁炔基、 3-丁炔基、 1 -甲基 -2-丙炔基等。 The "C ₂ _-4 alkynyl group" as used in the present invention means a linear or branched alkynyl group having 2 to 4 carbon atoms containing a hydrazone bond; examples thereof include, but are not limited to, for example, ethynyl group, 2-propyne group Base, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, and the like.

本发明所述的 "C_M烷氧基"、 "C_{1 -4}烷氨基"、 "二 (C_M烷基)氨基"、 "C!.₄烷氧基羰基"、 "C_M烷基硫基"、 "CM烷基磺酰基"、 "C_M烷基亚磺酰基"、 "CM烷基氨基磺酰基"、 "( 烷基氨基亚磺酰基"，分别是指 "Ci_-4烷基 -0-"基团、 "C_1-4烷基 -NH-"基团、 "(C_M烷基 )₂N-，，基团、 "C_1-4 烷基 -O-C(O)-"基团、 "C_{1 -4}烷基 -S-"基团、 "C_{1 -4}烷基 -S0₂-，，基团、 "C_1-4 烷基 -SO-"基团、 "C_{1 -4}烷基 -S0₂-NH -"、 "C_M烷基 -SO-NH-"基团，其中 "CM烷基"如前文所定义。 "C _M alkoxy", "C _{1 -4} alkylamino", "di(C _M alkyl)amino", "C!. ₄ alkoxycarbonyl", "C _M alkyl sulfide" according to the invention ",""Ci _- alkylsulfonyl", "C _M alkylsulfinyl", "CM alkylsulfamoyl", "(alkylaminosulfinyl), respectively, means "Ci _-4 alkyl- 0-" group, "C _1-4 alkyl-NH-" group, "(C _M alkyl) ₂ N-,, group, "C _1-4 alkyl-OC(O)-" group a group, a "C _{1 -4} alkyl-S-" group, a "C _{1 -4} alkyl-S0 ₂ -, a group, a "C _1-4 alkyl-SO-" group, "C _{1 - a 4-} alkyl-S0 ₂ -NH -", "C _M alkyl-SO-NH-" group, wherein "CM alkyl" is as defined above.

本发明所述烷氧基 "指术语" 烷基"通过氧原子与其他结构相连接的基团，如曱氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基、仲丁氧基、戊氧基、新戊氧基、己氧基等。优选烷氧基，更优选烷氧基。术语 "d_₄烷氧基"、 "d_₃烷氧基" 指术语 "CM烷基"、 "C_{1 -3}烷基"通过氧原子与其他结构相连接的基团。 The alkoxy group of the present invention means a group which is bonded to another structure through an oxygen atom, such as a decyloxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, and an isobutyl group. group, tert-butoxy, sec-butoxy, pentyloxy, neo-pentyloxy, hexyloxy and the like. preferably the alkoxy group, more preferably an alkoxy group. The term "d_ ₄ alkoxy", "d_ ₃ alkoxy "refers to the term" CM alkyl "," C _{1 -3} alkyl "group via an oxygen atom to other connected structures.

本发明所述" 烷基酰氨基"是指" C_{1 -6}烷基"通过酰氨基与其他结构相连接的基团。 The "alkylamido" as used in the present invention means a group in which a "C _{1 -6} alkyl group" is bonded to another structure via an acylamino group.

本发明所述的 " 1¾素"是指氟原子、氯原子、溴原子或碘原子等。本发明所述的 "d-₄烷氧基 Q 亚烷基、 C_3-6环垸基 QM亚烷基、苯基 C()_₄亚烷基、萘基 Q 亚烷基、 5- 10元杂芳基 CQ-₄亚烷基"是指 C_1-4 烷氧基、环烷基、苯基、萘基、 5- 10元杂芳基通过 Co_₄亚烷基与其他结构相连接的基团，其中 "C(M亚烷基"如前文所定义。 The "13" element in the present invention means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. "d- ₄ alkoxy Q alkylene, C _3-6 cyclodecyl QM alkylene, phenyl C()- ₄ alkylene, naphthyl Q alkylene, 5- 10 according to the invention "heteroaryl CQ- ₄ alkylene" means that C _1-4 alkoxy, cycloalkyl, phenyl, naphthyl, 5- 10 -membered heteroaryl is bonded to other structures via a Co ₄ alkylene group. a group, wherein "C(M alkylene) is as defined above.

本发明所述的 "3-8元环烷基"是指环原子全部为碳原子，去除一个氢原子衍生的环状烷基基团，其中包括例如 "3-7元环烷基"、 "3-6元环烷基"、 "4-6元环烷基"" 5-7元环烷基"、 "5-6元环烷基", 其实例包括但不限于：环丙烷基、环丁烷基、环戊烷基、环己烷基、环庚烷基、环辛烷基等。本发明所述的 "3-8元杂环烷基"是指含有一至多个杂原子的 3-8元环状基团，所述"杂原子"是指氮原子、氧原子、硫原子等。优选 3-7元杂环基、 3-6元杂环基，更优选 5-7元杂环基、 5-6元杂环基。具体实例包括但不仅限于 2,5-二氢噻吩基、 4,5-二氢吡唑基、 3,4-二氢 -2 -吡喃基、 5,6-二氢 -4/ -1 ,3-噁嗪基、氮杂环丙烷基、氮杂环丁烷基、硫杂环丁烷基、四氢呋喃基、四氢吡咯基、咪唑烷基、吡唑烷基、四氢呋喃基、 1,4-二氧杂环己烷基、 1，3-二氧杂环己烷基、 1 ,3-二硫杂环己烷基、吗啉基、哌嗪基等。 The "3-8 membered cycloalkyl group" as used in the present invention means that the ring atoms are all carbon atoms, and a hydrogen atom-derived cyclic alkyl group is removed, including, for example, "3-7 membered cycloalkyl group", "3". -6 membered cycloalkyl group, "4-6 membered cycloalkyl group", "5-7 membered cycloalkyl group", "5-6 membered cycloalkyl group", examples of which include, but are not limited to: cyclopropane group, cyclobutene Alkyl, cyclopentyl, cyclohexane, cycloheptyl, cyclooctyl and the like. The "3-8 membered heterocycloalkyl group" as used in the present invention means a 3-8 membered cyclic group having one or more hetero atoms, and the "hetero atom" means a nitrogen atom, an oxygen atom, a sulfur atom, or the like. . A 3-7 membered heterocyclic group and a 3-6 membered heterocyclic group are preferred, and a 5-7 membered heterocyclic group and a 5-6 membered heterocyclic group are more preferred. Specific examples include, but are not limited to, 2,5-dihydrothiophenyl, 4,5-dihydropyrazolyl, 3,4-dihydro-2-pyranyl, 5,6-dihydro-4/-1, 3-oxazinyl, aziridine, azetidinyl, thietane, tetrahydrofuranyl, tetrahydropyrrolyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, 1,4- Dioxanyl group, 1,3-dioxanyl group, 1, 3-dithiacyclohexane group, morpholinyl group, piperazinyl group and the like.

"4-7元杂芳基"是指含有 4-7个环原子（其中至少含有一个杂原子）构成的芳香性基团，包括" 5-7 元杂芳基"、 "5-6 元杂芳基"，其具体实例包括但不限于例如呋喃、吡咯、噻吩、咪唑、噁唑、异噁唑、噻唑、吡啶、吡。秦，嘧咬、达。秦等。 "4-7-membered heteroaryl" means an aromatic group consisting of 4 to 7 ring atoms (having at least one hetero atom), including "5-7 membered heteroaryl" and "5-6 membered hetero "Aryl", specific examples thereof include, but are not limited to, furan, pyrrole, thiophene, imidazole, oxazole, isoxazole, thiazole, pyridine, pyridyl. Qin, pyridine bite, up. Qin and so on.

"6-12元二环结构"是指含有 6- 12个环原子构成的二环基团（可以不含有或者含有一个及一个以上的杂原子），包括" 7-10元二环结构"、 "8-10元二环结构"、 "6-9元螺环结构"、 "6-8元并环结构"、 "6-8元桥环结构 "等。其具体实例包括但不限于二环 [3. 1.0]己烷基、二环 [4.1.0] 庚烷基、二环 [2.2.0]己烷基、二环 [3.2.0]庚烷基、二环 [4.2.0]辛烷基、八氢并环戊二烯基、八氢茚基、十氢化萘基、十四氢菲基、双环 [3.1.0] 己 -2-婦基、双环 [4.1.0]庚 -3-烯基、双环 [3.2.0]庚 -3-烯基、双环 [4.2.0] 辛 -3-烯基、 l ,2，3，3a-四氢并环戊二烯基、 2,3，3a,4，7，7a-六氢 -1/7-茚基、 1,2,3,4,4α,5,6,8α-八氢化萘基、 1,2,4α,5,6,8 - 六氢化萘基、 1 ,2,3,4,5,6，7,8,9, 10-十氢菲基、环丁烷并四氢吡咯基、环戊烷并四氢吡咯基、氮杂环丁烷并咪唑烷基、 3-氧杂双环并 [3.1.0]己烷基、六氢呋喃 "6-12 membered bicyclic structure" means a bicyclic group consisting of 6 to 12 ring atoms (may not contain or contain one or more hetero atoms), including "7-10 membered bicyclic structure", "8-10 yuan two-ring structure", "6-9 yuan spiral ring structure", "6-8 yuan parallel ring structure", "6-8 yuan bridge ring structure" and so on. Specific examples thereof include, but are not limited to, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl Bicyclo[4.2.0]octyl, octahydrocyclopentadienyl, octahydroindenyl, decahydronaphthyl, tetradecahydrophenanyl, bicyclo[3.1.0]hex-2-yl, Bicyclo[4.1.0]hept-3-enyl, bicyclo[3.2.0]hept-3-enyl, bicyclo[4.2.0]oct-3-enyl, l,2,3,3a-tetrahydro Cyclopentadienyl, 2,3,3a,4,7,7a-hexahydro-1/7-fluorenyl, 1,2,3,4,4α,5,6,8α-octahydronaphthyl, 1 , 2,4α,5,6,8-hexahydronaphthyl, 1, 2,3,4,5,6,7,8,9, 10-decahydrophenanyl, cyclobutanetetrahydropyrrolyl, Cyclopentahydrotetrahydropyrrolyl, azetidinazolidinyl, 3-oxabicyclo[3.1.0]hexane, hexahydrofuran

[3,4-b][ l，4]二噁英基、六氢 -2/ -环戊烷并 [b][l ,4]二噁英基、 [3,4-b][ l,4]dioxinyl, hexahydro-2/-cyclopenta[b][l,4]dioxin,

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以及芳香性的二环结构，包括但不限于苯并呋喃基、苯并异呋喃基、苯并噻吩基、吲哚基、苯并噁唑基、苯并咪唑基、吲唑基、苯并***基、喹啉基、异喹啉基、吖啶基、菲啶基、苯并哒嗪基、酞嗪基、喹唑啉基、喹喔啉基、酚嗪基、喋啶基、嘌呤基、萘啶基、 1 ,3-二氢苯并呋喃基、苯并 [ [ 1.3]二氧杂环戊烯基、异吲哚啉基、色满基、 1 ,2,3,4-四氢吡咯并 [3,4-c]吡咯基、 5,6-二氢咪唑 [1.2- ]吡嗪 -7(8Λ 基、 5,6-二氢 -1 ,7-萘啶 -7(8 )-基、 5//-吡咯 [3.4-b]吡啶 -6(7 )-基、 7,8-二氢吡啶 [4. 嘧啶 -6(5/ )-基、 2,3,6,7-四氢吡唑 [4.3-cj吡啶 -5(4 /)-基、 6,7-二氢噻唑 [5.4-c]吡啶 -5(4//)-基等。

And an aromatic bicyclic structure, including but not limited to benzofuranyl, benzisofuranyl, benzothienyl, fluorenyl, benzoxazolyl, benzimidazolyl, oxazolyl, benzotrien Azyl, quinolyl, isoquinolyl, acridinyl, phenanthryl, benzoxazinyl, pyridazinyl, quinazolinyl, quinoxalinyl, phenolzinyl, acridinyl, fluorenyl , naphthyridinyl, 1 ,3-dihydrobenzofuranyl, benzo[ [1.3]dioxolyl, isoindolyl, chromanyl, 1,2,3,4-tetrahydrogen Pyrrolo[3,4-c]pyrrolyl, 5,6-dihydroimidazole [1.2- ]pyrazine-7 (8-mercapto, 5,6-dihydro-1,7-naphthyridin-7(8)- , 5//-pyrrole [3.4-b]pyridine-6(7)-yl, 7,8-dihydropyridine [4. pyrimidine-6(5/)-yl, 2,3,6,7-tetra Hydropyrazole [4.3-cjpyridine-5(4/)-yl, 6,7-dihydrothiazole [5.4-c]pyridine-5(4//)-yl and the like.

术语" 7-10元二环结构"、 "8-10元二环结构"指上述实例中的含有 7 至 10个、 8至 10个碳原子的具体实例。 The term "7-10 membered bicyclic structure" and "8-10 membered bicyclic structure" mean a specific example containing 7 to 10 and 8 to 10 carbon atoms in the above examples.

本发明所述" 6-9元螺环基"是指一类至少有两个环共享一个原子形成的 6-9元稠环结构。其具体实施例包括但不仅限于：螺 [3.3]庚烷基、螺 [3.4]辛烷基、螺 [3.5]壬烷基、螺 [4.4]壬烷基、螺 [3.4]辛 -6-烯基、螺 [3.5] 壬 -6-烯基、螺 [4.4]壬 -6-烯基、螺 [4.4]壬 -2，7-二烯基、 2-氧杂螺 [3.3]庚烷基、 6-氧杂螺 [2.5]辛烷基、 4-氧杂 -7-氨基螺 [2.5]辛烷基、 2-氨基螺 [3.3] 庚烷基、 2-氧杂 -6-氨基螺 [3.3]庚烷基、 2-氨基螺 [3.4]辛烷基、 6-氧杂 -2- 氨基螺 [3.4]辛烷基、 2-氧杂 -6-氨基螺 [3.4]辛烷基、 2-氧杂螺 [3.4]辛烷基、 5-氧杂螺 [3.5]壬烷基、 7-氨基螺 [3.5]壬烷基、 2-氨基螺 [4.4]壬烷基、 2- 氧杂 -7-氨基螺 [4.4]壬烷基、 2-氧杂螺 [4.4]壬烷基、 1，7-二氧杂螺 [4.4]壬烷基、 1 ,4,7-三氧杂螺 [4.4]壬烷基、 6-氨基螺 [3.4]辛 -7-烯基、 2-氧杂 -6- 氨基螺 [3.4]辛 -7-烯基、 7-氨基螺 [3.5]壬 -5-烯基、 2-氨基螺 [4.4]壬 -7-烯基等。 The "6-9 membered spiro group" as used in the present invention means a 6-9 membered fused ring structure in which at least two rings share one atom. Specific examples thereof include, but are not limited to, spiro[3.3]heptanyl, spiro[3.4]octylalkyl, spiro[3.5]decylalkyl, spiro[4.4]decylalkyl, spiro[3.4]oct-6-ene , snail [3.5] 壬-6-alkenyl, spiro[4.4] 壬-6-alkenyl, spiro[4.4] 壬-2,7-dienyl, 2-oxaspiro[3.3]heptanyl, 6-oxaspiro[2.5]octyl, 4-oxa-7-aminospiro[2.5]octyl, 2-aminospiro[3.3]heptanyl, 2-oxa-6-aminospiro[3.3 Heptylalkyl, 2-aminospiro[3.4]octyl, 6-oxa-2-aminospiro[3.4]octyl, 2-oxa-6-aminospiro[3.4]octyl, 2- Oxanspiro[3.4]octyl, 5-oxaspiro[3.5]decyl, 7-aminospiro[3.5]decyl, 2-aminospiro[4.4]decyl, 2-oxa-7 - aminospiro[4.4]decyl, 2-oxaspiro[4.4]decyl, 1,7-dioxaspiro[4.4]decyl, 1,4,7-trioxaspiro[4.4]壬alkyl, 6-aminospiro[3.4]oct-7-alkenyl, 2-oxa-6-aminospiro[3.4]oct-7-alkenyl, 7-aminospiro[3.5]indole-5-alkenyl 2-Aminospiro[4.4]dec-7-alkenyl.

本发明所述" 6 - 8元并环结构"是指由两个或两个以上环状结构彼此共用两个相邻的原子所形成的 6-8元环状基团，其具体实施例包括但不仅限于：二环 [3.1.0]己烷基、二环 [4.1.0]庚烷基、二环 [2.2.0]己烷基、二环 [3.2.0]庚烷基、二环 [4.2.0]辛烷基、双环 [3. 1.0]己 -2-烯基、汉环 [4. 1.0] 庚 -3-烯基、双环 [3.2.0]庚 -3-烯基、双环 [4.2.0]辛 -3-烯基、苯并呋喃基、苯并异呋喃基、苯并噻吩基、吲哚基、苯并噁唑基、苯并咪唑基、吲唑基、苯并***基、喹啉基、异喹啉基、吖啶基、菲啶基、苯并哒嗪基、酞嗪基、喹唑啉基、喹喔啉基、噻吩并 [2,3-b]噻吩基、噻吩并 [3,2-b] 噻吩基、苯并 [b]噻吩基、苯并 [0]噻唑基、环丁烷并四氢吡咯基、环戊烷并四氢吡咯基、氮杂环丁烷并咪唑烷基、 3-氧杂欢环并 [3.1.0]己烷基、六氢呋喃 [3,4-b][l,4]二噁英基、六氢 -2 -环戊烷并 [b][l,4]二噁英基等。 The "6- to 8-membered ring structure" as used in the present invention refers to a 6-8 membered cyclic group formed by two or more ring structures sharing two adjacent atoms with each other, and specific examples thereof include But not limited to: bicyclo [3.1.0] hexane, bicyclo [4.1.0] heptyl, bicyclo [2.2.0] hexane, bicyclo [3.2.0] heptyl, bicyclo [4.2.0] Octyl, bicyclo[3.1.0]hex-2-enyl, Hancyclo[4.1.0]hept-3-enyl, bicyclo[3.2.0]hept-3-enyl, bicyclo [4.2.0] Oct-3-enyl, benzofuranyl, benzoisofuranyl, benzothienyl, fluorenyl, benzoxazolyl, benzimidazolyl, anthracene Azolyl, benzotriazolyl, quinolyl, isoquinolinyl, acridinyl, phenanthryl, benzoxazinyl, pyridazinyl, quinazolinyl, quinoxalinyl, thieno[2] ,3-b]thienyl, thieno[3,2-b]thienyl, benzo[b]thienyl, benzo[0]thiazolyl, cyclobutanetetrahydropyrrolyl, cyclopentane Hydropyrrolyl, azetidinazolidinyl, 3-oxacyclo[3.1.0]hexane, hexahydrofuran [3,4-b][l,4]dioxin, hexa Hydrogen-2-cyclopentane[b][l,4]dioxin and the like.

本发明所述" 6-8元桥环结构 "是指由两个或两个以上环状结构彼此共用两个不相邻的原子所形成的 6-8元环 The "6-8 member bridged ring structure" as used in the present invention means a 6-8 membered ring formed by two or more ring structures sharing two non-adjacent atoms with each other.

本发明特别优选的化合物包括: Particularly preferred compounds of the invention include:

o/u/〇 ssssosld 26680ΗοίM

o/u/〇ssssosld 26680ΗοίM

下述反应方案中描迷的方法和 /或本领域普通技术人员已知的其它方法来合成，但不仅限于以下方法。 The methods described in the following reaction schemes and/or other methods known to those of ordinary skill in the art are synthesized, but are not limited to the following methods.

为方便起见，本发明使用众所周知的缩写代表多种化学化合物，包括但不限于 For convenience, the invention uses well-known abbreviations to represent a variety of chemical compounds, including but not limited to

DMF: N, V-二甲基甲酰胺； THF: 四氢呋喃； DIEA: TV,Y -二异丙基乙胺； DMA: 二甲胺； m-CPBA: 间氯过氧苯甲酸； LAH: 四氢铝锂等。 DMF: N, V-dimethylformamide; THF: tetrahydrofuran; DIEA: TV, Y-diisopropylethylamine; DMA: dimethylamine; m-CPBA: m-chloroperoxybenzoic acid; LAH: tetrahydrogen Aluminum lithium and the like.

反应方案 1: Reaction scheme 1:

反应步骤： Reaction steps:

步骤 1: 中间体 1的制备 Step 1: Preparation of intermediate 1

干燥的反应瓶中，加入原料 1 ( 1 当量），加入极性溶剂（如 DMF, DMA) 溶解，加入原料 2 ( 1 当量），碱（如碳酸钾）（2 当量），加热反应数小时，冷却至室温，将反应液倒入水水中，过滤，滤饼用冰水洗涤，真空干燥得中间体 1。 In a dry reaction flask, add 1 (1 equivalent) of the starting material, add a polar solvent (such as DMF, DMA) to dissolve, add the raw material 2 (1 equivalent), a base (such as potassium carbonate) (2 equivalents), and heat the reaction for several hours. After cooling to room temperature, the reaction liquid was poured into water, filtered, and the filter cake was washed with ice water and dried in vacuo to give Intermediate 1.

步骤 2: 中间体 2的制备 Step 2: Preparation of intermediate 2

干燥的反应瓶中，加入中间体 1(1 当量），加入四氢呋喃溶解， -78 °C下分批加入四氢铝锂（3-5 当量），滴加完毕后待温度升至室温，加入饱和的氯化铵水溶液，室温下搅拌半小时，过滤，滤液加入水，萃取，浓缩有机相，柱层析，得中间体 2。 In the dry reaction flask, add intermediate 1 (1 equivalent), add tetrahydrofuran to dissolve, add lithium tetrahydroaluminum (3-5 equivalents) in portions at -78 °C, add the temperature to room temperature, add saturation after the addition. The aqueous ammonium chloride solution was stirred at room temperature for half an hour, filtered, and the filtrate was added to water, extracted, and the organic phase was concentrated, and then purified to afford Intermediate 2.

步骤 3: 中间体 3的制备 Step 3: Preparation of intermediate 3

干燥的反应瓶中，加入中间体 2 ( 1 当量），二氯甲烷溶解，加入二氧化锰（ 20-40 当量），室温下搅拌反应过夜，过滤，用有机溶剂洗涤滤饼，旋干有机相，得中间体 3，直接用于下一步反应。 In a dry reaction flask, add intermediate 2 (1 eq.), dissolve in dichloromethane, add Manganese dioxide (20-40 equivalents), the reaction was stirred overnight at room temperature, filtered, and the filter cake was washed with an organic solvent, and the organic phase was evaporated to give intermediate 3 which was directly used for the next reaction.

步骤 4: 中间体 4的制备 Step 4: Preparation of intermediate 4

干燥反应瓶中，中间体 3 ( 1 当量）用极性溶剂（如曱醇）溶解，加入原料 3 ( 1.5-3当量），乙酸（最少 1.5当量），室温下搅拌反应数小时，加入硼氢化钠（2-5 当量），反应数小时，淬灭，有机溶剂萃取，浓缩有机相，柱层析，得中间体 4。也可以将亚胺后处理之后溶于四氢呋喃，用四氢锂铝还原。 In the dry reaction flask, intermediate 3 (1 eq.) is dissolved with a polar solvent (such as decyl alcohol), and the raw material 3 (1.5-3 equivalents), acetic acid (minimum 1.5 equivalents) is added, and the reaction is stirred at room temperature for several hours, and hydroboration is added. Sodium (2-5 equivalents), reacted for several hours, quenched, extracted with an organic solvent, concentrated organic phase, and purified by column chromatography to afford Intermediate 4. The imine may also be post-treated, dissolved in tetrahydrofuran, and reduced with lithium aluminum hydride.

步骤 5.· 中间体 5的制备 Step 5.· Preparation of Intermediate 5

干燥的反应器中，加入中间体 4 ( 1 当量），加入适当溶剂（如四氢呋喃，二氯甲烷）溶解，加入碱（如 DIEA ) ( 3 当量），冰水浴下加入原料 4 ( 0.5-1.5 当量），滴加完毕后继续反应，然后淬灭，用有机溶剂萃取，柱层析，得中间体 5。 In a dry reactor, add intermediate 4 (1 eq.), add a suitable solvent (such as tetrahydrofuran, dichloromethane) to dissolve, add a base (such as DIEA) (3 eq.), and add the raw material 4 (0.5-1.5 eq. After the completion of the dropwise addition, the reaction is continued, followed by quenching, extraction with an organic solvent, and column chromatography to give Intermediate 5.

步骤 6: 中间体 6的制备 Step 6: Preparation of intermediate 6

干燥的反应瓶中，加入中间体 5 ( 1 当量），加入适当溶剂（如二氯曱烷）溶解，冰水浴下，加入间氯过氧苯甲酸（ 1.5-3当量），升至室温继续反应，淬灭，用有机溶剂萃取，浓缩得中间体 6 直接用于下一步反应。 In a dry reaction flask, add intermediate 5 (1 eq.), add a suitable solvent (such as dichloromethane), dissolve in ice water, add m-chloroperoxybenzoic acid (1.5-3 equivalents), and continue to react at room temperature. , quenched, extracted with an organic solvent, and concentrated to give intermediate 6 for the next step.

步骤 7: 中间体 7的制备 Step 7: Preparation of intermediate 7

干燥的反应瓶中，加入中间体 6 ( 1 当量），加入适当溶剂（如叔戊醇）溶解，加入原料 5 ( 1-1.5当量），浓盐酸或三氟醋酸（0.5-1.5当量），回流反应，冷却至室温后淬灭，用有机溶剂萃取，浓缩，柱层析，得中间体 7。 In a dry reaction flask, add intermediate 6 (1 eq.), add a suitable solvent (such as tert-amyl alcohol) to dissolve, add the raw material 5 (1-1.5 eq.), concentrated hydrochloric acid or trifluoroacetic acid (0.5-1.5 eq.), reflux The reaction is quenched by cooling to room temperature, extracted with an organic solvent, concentrated, and then purified,

步骤 8: 中间体 8的制备 Step 8: Preparation of intermediate 8

将中间体 7(1 当量)加入适当溶剂（如二氯曱烷）溶解，加入溶剂量三氟乙酸，或者通入盐酸气，室温或冷却下搅拌反应至中间体 7 消失。浓缩，得中间体 8 , 直接用于下步反应。 Intermediate 7 (1 eq.) is dissolved in a suitable solvent (e.g., dichloromethane), solvent trifluoroacetic acid is added, or hydrochloric acid gas is added, and the reaction is stirred at room temperature or under cooling to afford intermediate 7 disappear. Concentration, intermediate 8 was obtained and used directly in the next step.

步骤 9: 式 I化合物的制备 Step 9: Preparation of a compound of formula I

将中间体 8(1 当量)溶于适当的溶剂（如四氢呋喃，二氯甲烷，丙酮， DMF, 或者为混合溶剂），加入 2-3 当量的碱 (如 DIEA), 冷却下（-20度到 -10度)，緩慢滴入原料 4 (0.9-1.1 当量)搅拌反应至中间体 8消失。淬灭反应，浓缩，柱层析或者中低压制备液相纯化得式 I化合物。反应方案 2: Dissolve intermediate 8 (1 eq.) in a suitable solvent (eg tetrahydrofuran, dichloromethane, acetone, DMF, or a mixed solvent), add 2-3 equivalents of base (eg DIEA), cool down (-20 ° to -10 degrees), slowly instilling the raw material 4 (0.9-1.1 equivalent) and stirring the reaction until the intermediate 8 disappears. The compound of formula I is purified by quenching, concentration, column chromatography or medium to low pressure preparative liquid phase purification. Reaction Scheme 2:

步骤 1 : 中间体 1的制备 Step 1: Preparation of intermediate 1

干燥的反应瓶中，加入原料 1 ( 1 当量），加入适当溶剂（如二氯甲烷）溶解，加入原料 2 ( 1.5当量），无氷醋酸铜（2当量），吡啶（2当量），在室温下反应过夜，过滤，滤液浓缩后硅胶柱层析得中间体 1。 In a dry reaction flask, add 1 (1 eq.) of the starting material, add the appropriate solvent (such as dichloromethane) to dissolve, add the raw material 2 (1.5 eq.), no ice copper acetate (2 eq.), pyridine (2 eq.), at room temperature The reaction was carried out overnight, filtered, and the filtrate was concentrated and then purified to silica.

步骤 2: 式 I化合物的制备 Step 2: Preparation of the compound of formula I

将中间体 1(1 当量)溶于适当的溶剂（如叔戊醇），加入原料 3 ( 1-1.5 当量），最后加入数滴浓盐酸，加热回流至中间体 2消失。冷却，浓缩，制备液相纯化得式 I化合物。 The intermediate 1 (1 equivalent) is dissolved in a suitable solvent (e.g., tert-amyl alcohol), and the starting material 3 (1 - 1.5 eq.) is added, and finally, a few drops of concentrated hydrochloric acid are added, and the mixture is heated to reflux until the intermediate 2 disappears. The compound of formula I is purified by cooling, concentration, and preparative liquid phase purification.

反应方案中的 X、 W、、 R₂、 R₃、 L₂、 a、 b、 c、 d、 e、 p、 q、 ^：、环 A和环 B如前文所述。本发明式（ I ) 化合物、其氘代物或其立体异构体可以以游离的形式或其药学上可接受的盐的形式使用。本发明式（ I ) 化合物显碱性，可以与无机酸或有机酸形成酸式盐。如盐酸盐、氢氟酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、三氟乙酸盐、苯磺酸盐、甲磺酸盐、三氟曱磺酸盐、乙磺酸盐、碳酸盐、硝酸盐、磷酸盐、亚磷酸盐、马来酸盐、酒石酸盐、柠檬酸盐、醋酸盐、苯甲酸盐、乙磺酸盐、富马酸盐、草酸盐、葡萄糖酸盐、羟基乙酸盐、羟乙磺酸、乳酸盐、乳糖酸盐、乳糖酸盐、苹果酸盐、曱磺酸盐、琥珀酸盐、对甲苯磺酸盐、甘氨酸盐、三甲基甘氨酸盐、精氨酸盐、鸟氨酸盐、谷氨酸盐、天冬氨酸盐等。 X, W, R ₂ , R ₃ , L ₂ , a, b, c, d, e, p, q, ^:, ring A and ring B in the reaction scheme are as described above. The compound of the formula (I), its progeny or a stereoisomer thereof of the present invention can be used in the form of a free form or a pharmaceutically acceptable salt thereof. The compound of the formula (I) of the present invention is basic and can form an acid salt with an inorganic acid or an organic acid. Such as hydrochloride, hydrofluoride, hydrochloride, hydrobromide, hydroiodide, sulfate, trifluoroacetate, besylate, methanesulfonate, trifluorosulfonate, Sulfonate, carbonate, nitrate, phosphate, phosphite, maleate, tartrate, citrate, acetate, benzoate, ethanesulfonate, fumarate, Oxalate, gluconate, glycolate, isethionate, lactate, lactobionate, lactobionate, malate, sulfonate, succinate, p-toluenesulfonate, glycine Salt, trimethylglycine, arginine, ornithine, glutamate, aspartate, and the like.

本发明式（ I ) 化合物或其氘代物、其药学上可接受的盐由于存在不对称碳原子，可以以一种旋光异构体形式存在，因此，本发明还包括这些旋光异构体及其混合物。 The compound of the formula (I) of the present invention or a protamine thereof, a pharmaceutically acceptable salt thereof, may exist in the form of an optical isomer due to the presence of an asymmetric carbon atom, and therefore, the present invention also includes these optical isomers and mixture.

本发明式（ I )化合物、其氘代物、其药学上可接受的盐或其立体异构体可以与一种或多种可药用载体组成药物组合物。在一个实施方案中，本发明提供了药物组合物，所述组合物含有如前所迷的本发明化合物、其氘代物、其药学上可接受的盐或其立体异构体和可药用载体。在另一个实施方案中，本发明提供了药物组合物，所述组合物含有如前所述的本发明化合物、其氘代物、其药学上可接受的盐或其立体异构体，以及选自抗肿瘤剂、免疫抑制剂和 /或抗炎药的第二治疗剂。所述药物组合物可以制成临床上使用的常规制剂，可以口服或肠胃外给药等方式施用于需要这种治疗的患者。如片剂、颗粒、胶嚢、粉末、注射剂、吸入剂、舌下给药制剂、糖浆、凝胶、油膏、栓剂、洗剂、鼻腔滴剂、喷雾剂、透皮制剂等。这些制剂可以通过常规方法，添加可药用载体如赋形剂、粘合剂、增湿剂、崩解剂、增稠剂等制备而成。 The compound of the formula (I), the deuterated compound, the pharmaceutically acceptable salt thereof or the stereoisomer thereof of the present invention may be combined with one or more pharmaceutically acceptable carriers to constitute a pharmaceutical composition. In one implementation In one aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, a progeny thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier, as hereinbefore described. In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention, a progeny thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, as defined above, and A second therapeutic agent for an antitumor agent, an immunosuppressive agent, and/or an anti-inflammatory agent. The pharmaceutical composition can be formulated into a conventional preparation for clinical use, and can be administered to a patient in need of such treatment by oral or parenteral administration. Such as tablets, granules, capsules, powders, injections, inhalants, sublingual preparations, syrups, gels, ointments, suppositories, lotions, nasal drops, sprays, transdermal preparations and the like. These preparations can be prepared by a conventional method by adding a pharmaceutically acceptable carrier such as an excipient, a binder, a moisturizing agent, a disintegrating agent, a thickening agent and the like.

本发明式（ I ) 化合物、其氘代物、其药学上可接受的盐或其立体异构体具有较好的 BTK激酶抑制作用，是较好具有优良的抗肿瘤作用以及自身免疫疾病治疗作用的药物。同时本发明式（ I ) 化合物、其氘代物、其药学上可接受的盐或其立体异构体在制备治疗 B 细胞相关的血癌（例如 B 细胞慢性淋巴细胞癌、非霍奇金淋巴瘤），以及自身免疫性疾病（例如类风湿性关节炎、 ***性红斑狼疮等）中起着重要作用。 The compound of the formula (I), the progeny thereof, the pharmaceutically acceptable salt thereof or the stereoisomer thereof thereof have good BTK kinase inhibitory action, and are excellent in antitumor action and therapeutic effect of autoimmune diseases. drug. At the same time, the compound of the formula (I), the progeny thereof, the pharmaceutically acceptable salt thereof or the stereoisomer thereof thereof are used for the preparation of a B cell-associated blood cancer (for example, B cell chronic lymphocytic carcinoma, non-Hodgkin's lymphoma). , and autoimmune diseases (such as rheumatoid arthritis, systemic lupus erythematosus, etc.) play an important role.

本发明式（ I )化合物、其氘代物、其药学上可接受的盐或其立体异构体是一种激酶抑制剂，特别是 Btk 抑制剂。这些抑制剂可以用于治疗哺乳动物中的一种或多种响应激酶抑制的疾病，包括响应 Btk 抑制和 /或 B细胞增殖的抑制的疾病。不希望束縛于任何特定的理论，相信本发明化合物与 Btk的相互作用导致 Btk活性的抑制，并因此得到这些化合物药学应用。因此，本发明包括用于治疗具有响应 Btk 活性的抑制和 /或抑制 B细胞增殖的疾病的哺乳动物，例如人的方法，该方法包括：向具有这样的疾病的哺乳动物给药有效量的至少一种在本文中描述的本发明化合物。可以在实险上例如通过测定化合物的血液浓度，或理论上通过计算生物利用度，确定有效浓度。除了 Btk之外，还可能受到影响的其它激酶包括但不限于，其它酪氨酸激酶和丝氨酸 / 苏氨酸激酶。 The compound of the formula (I), the progeny thereof, the pharmaceutically acceptable salt thereof or the stereoisomer thereof of the present invention is a kinase inhibitor, particularly a Btk inhibitor. These inhibitors can be used to treat one or more diseases that are responsive to kinase inhibition in a mammal, including diseases that respond to inhibition of Btk inhibition and/or B cell proliferation. Without wishing to be bound by any particular theory, it is believed that the interaction of the compounds of the invention with Btk results in inhibition of Btk activity and thus results in the pharmaceutical use of these compounds. Accordingly, the present invention includes a method for treating a mammal, such as a human, having a disease responsive to inhibition of Btk activity and/or inhibiting B cell proliferation, the method comprising: administering to a mammal having such a disease an effective amount of at least A compound of the invention as described herein. The effective concentration can be determined, for example, by measuring the blood concentration of the compound, or theoretically by calculating the bioavailability. Other kinases that may be affected in addition to Btk include, but are not limited to, other tyrosine kinases and serine/threonine kinases.

激酶在控制基本细胞过程如增殖、分化和死亡（细胞凋亡）的信号传导路径方面起着显著的作用。异常的激酶活性已经暗示于各种疾病中，所述的疾病包括多种癌症、自身免疫和 /或炎性疾病和急性炎性反应。激酶在关键细胞信号传导路径中的多面性作用提供识别靶向激酶和信号传导路径的新药物的显著机会。 Kinases play a significant role in controlling the signaling pathways of essential cellular processes such as proliferation, differentiation and death (apoptosis). Abnormal kinase activity has been implicated in various diseases In the case of the disease, the disease includes various cancers, autoimmune and/or inflammatory diseases, and acute inflammatory reactions. The multi-faceted role of kinases in key cell signaling pathways provides a significant opportunity to identify new drugs that target kinases and signaling pathways.

本发明一个实施方案包括使用本发明化合物或药物组合物治疗具有自身免疫和 /或炎性疾病或响应 Btk活性和 /或 B细胞增殖的抑制的急性炎性反应的患者的方法。 One embodiment of the invention encompasses a method of treating a patient having an autoimmune and/or inflammatory disease or a rapid inflammatory response in response to inhibition of Btk activity and/or B cell proliferation using a compound or pharmaceutical composition of the invention.

使用根据本发明的化合物和组合物可以影响的自身免疫和 /或炎性疾病包括但不限于：银屑病， ***反应，局限性肠炎，肠易激综合征，舍格伦病，组织移植物排斥反应和移植器官的超急性排斥反应，哮喘， ***性红斑狼疮（和相关的肾小球肾炎），皮肌炎，多发性硬化，硬皮病，血管炎（ ANCA-相关的和其它的血管炎），自身免疫溶血性和血小板减少性症状，古德帕斯综合征（和相关的肾小球肾炎和肺出血），动脉粥样硬化，类风湿性关节炎，慢性的特发性血小板减少性紫癜 ( ITP ), 艾迪生病，帕金森病，阿尔茨海默病，糖尿病，脓毒性休克和重症几无力。 Autoimmune and/or inflammatory diseases that can be affected by the use of the compounds and compositions according to the invention include, but are not limited to, psoriasis, allergies, localized enteritis, irritable bowel syndrome, Sjogren's disease, tissue grafts Rejection and hyperacute rejection of transplanted organs, asthma, systemic lupus erythematosus (and associated glomerulonephritis), dermatomyositis, multiple sclerosis, scleroderma, vasculitis (ANCA-related and other blood vessels) Inflammation, autoimmune hemolytic and thrombocytopenic symptoms, Goodpas syndrome (and associated glomerulonephritis and pulmonary hemorrhage), atherosclerosis, rheumatoid arthritis, chronic idiopathic thrombocytopenia Purpura (ITP), Edison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock and severe illness.

在本发明治疗方法中，可以将本文中提供的至少一种本发明化合物与抗炎药组合给药。抗炎药包括但不限于： NSAID , 非特异性和 COX-2 特异性环氧合酶酶抑制剂，金化合物，皮质类固醇类，甲氨蝶呤，肿瘤坏死因子受体（TNF ) 受体拮抗剂，免疫抑制剂和甲氨蝶呤。 In the method of treatment of the present invention, at least one of the compounds of the present invention provided herein can be administered in combination with an anti-inflammatory agent. Anti-inflammatory drugs include, but are not limited to: NSAID, non-specific and COX-2 specific cyclooxygenase inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptor antagonists , immunosuppressant and methotrexate.

NSAID的实例包括但不限于，布洛芬，氟比洛芬，萘普生和萘普生钠，双氯芬酸，双氯芬酸钠和米索前列醇的组合，舒林酸，苯曙丙酸，二氟尼柳，吡罗昔康，吲哚美辛，依托度酸，非诺洛芬钙，酮洛芬，萘丁美酮钠，柳氮磺吡啶，托美丁钠和羟氯喹。 NSAID的实例还包括 COX-2特异性抑制剂如塞来考昔，伐地考昔，芦米考昔和 /或艾托考昔。 Examples of NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, a combination of diclofenac sodium and misoprostol, sulindac, benzopyrene, diflunis Willow, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, nabumetone sodium, sulfasalazine, tolbutin sodium and hydroxychloroquine. Examples of NSAIDs also include COX-2 specific inhibitors such as celecoxib, valdecoxib, remiclox and/or etoricoxib.

在一个实施方案中，抗炎药是水杨酸酯或盐。水杨酸酯或盐包括但不限于乙酰基水杨酸或阿斯匹林，水杨酸钠以及水杨酸胆碱和水杨酸镁。 In one embodiment, the anti-inflammatory agent is a salicylate or a salt. Salicylates or salts include, but are not limited to, acetylsalicylic acid or aspirin, sodium salicylate, and choline salicylate and magnesium salicylate.

抗炎药还可以是皮质类固醇类。例如，皮质类固醇类可以是可的松， ***，甲泼尼龙， ***龙， ***龙磷酸钠，或***。 Anti-inflammatory drugs can also be corticosteroids. For example, the corticosteroid may be cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate, or prednisone.

在另外的实施方案中，抗炎药是金化合物如金硫丁二钠或金诺芬。本发明还包括其中抗炎药是代谢抑制剂如二氢叶酸还原酶抑制剂如曱氨蝶呤或二氢乳清酸盐脱氢酶抑制剂如来氟米特的实施方案。 In other embodiments, the anti-inflammatory agent is a gold compound such as gold thioudate or auranofin. The invention also includes wherein the anti-inflammatory agent is a metabolic inhibitor such as a dihydrofolate reductase inhibitor Embodiments such as methotrexate or dihydroorotate dehydrogenase inhibitors such as leflunomide.

在本发明的其它实施方案中，所述至少一种抗炎化合物是抗单克隆抗体（如依库珠单抗或培克珠单抗）， TNF 拮抗剂如依那西普 ( entanercept )或英利昔单抗，所述英利昔单抗是一种抗 TNFa单克隆抗体。 In other embodiments of the invention, the at least one anti-inflammatory compound is an anti-monoclonal antibody (such as eculizumab or pegizumab), a TNF antagonist such as entanercept or Yingli Infliximab, an anti-TNFa monoclonal antibody.

在本发明的其它实施方案中，所述至少一种抗炎药是免疫抑制剂化合物如选自甲氨蝶呤，来氟米特，环胞素，他克莫司，硫唑嘌呤和吗替麦考盼酯中的免疫抑制剂化合物的组合。 In other embodiments of the invention, the at least one anti-inflammatory agent is an immunosuppressive compound such as selected from the group consisting of methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine and morphine A combination of immunosuppressant compounds in mecopanate.

表达 Btk的 B细胞和 B细胞前体已经暗示于 B细胞恶性的病理学中， B细胞恶性包括但不限于 B细胞淋巴瘤，淋巴瘤（包括霍奇金和非霍奇金淋巴瘤），毛细胞淋巴瘤，多发性骨髓瘤，慢性的和急性的髓细胞源性白血病和慢性的和急性的淋巴细胞白血病。 B-cell and B-cell precursors that express Btk have been implicated in the pathology of B-cell malignancy, including B-cell lymphoma, including but not limited to B-cell lymphoma, lymphoma (including Hodgkin's and non-Hodgkin's lymphoma), hair Cellular lymphoma, multiple myeloma, chronic and acute myeloid leukemia and chronic and acute lymphocytic leukemia.

已经表明 Btk是在 B-系淋巴样细胞中 Fas/APO-l(CD-95)死亡诱导信号传导复合物 (DISC)的抑制剂。白血病 /淋巴瘤细胞的命运可能在于由 DISC活化的半胱天冬蛋白酶的反向前细胞凋亡作用和包括 Btk和 / 或其底物的上游抗细胞凋亡调节机理之间的平衡 (Vassilev 等， Biol. Chem. 1998, 274, 1646-1656) 。 Btk has been shown to be an inhibitor of Fas/APO-1 (CD-95) death-inducing signaling complex (DISC) in B-lineage lymphoid cells. The fate of leukemia/lymphoma cells may lie in the balance between the reverse pre-apoptotic effects of caspase-activated caspase and the upstream anti-apoptotic regulatory mechanisms including Btk and/or its substrates (Vassilev et al. , Biol. Chem. 1998, 274, 1646-1656).

还发现 Btk抑制剂可以用作化学敏化剂，因此可以用于与其它化学治疗药组合，所述的化学治疗药特别是诱导细胞凋亡的药，如抗肿瘤剂、免疫抑制剂等。可以与化学敏化抑制剂组合使用的其它化学治疗药的实例包括但不仅限于拓朴异构酶 I抑制剂（喜树碱或托泊替康），拓朴异构酶 II抑制剂（如道诺霉素和依托泊苷），烷化剂（如环磷酰胺，美法仑和 BCNU ), 微管蛋白导向的药剂（如泰素和长春碱）和生物制剂（例如抗体如抗 CD20抗体， IDEC8, 免疫毒素和细胞因子）。 It has also been found that Btk inhibitors can be used as chemical sensitizers, and thus can be used in combination with other chemical therapeutic agents, particularly those which induce apoptosis, such as anti-tumor agents, immunosuppressive agents and the like. Examples of other chemotherapeutic agents that can be used in combination with chemical sensitizers include, but are not limited to, topoisomerase I inhibitors (camptothecin or topotecan), topoisomerase II inhibitors (such as daunorubicin and Etoposide), alkylating agents (such as cyclophosphamide, melphalan and BCNU), tubulin-directed agents (such as Taxol and Vinblastine) and biological agents (eg antibodies such as anti-CD20 antibody, IDEC8, immunotoxin) And cytokines).

Btk 活性已经与一些表达由部分染色体 9 和 22 的易位导致的 bcr-abl 融合基因的白血病相关。这种异常通常在慢性髓细胞源性白血病中观察到。 Btk本质上由 bcr-abl激酶磷酸化，这引发在 bcr-abl细胞中防止细胞凋亡的下游生存信号（N.Feldhahn 等， J. Exp. Med. 2005, 201(11), 1837-1852) 。 Btk activity has been associated with some leukemias that express the bcr-abl fusion gene resulting from partial translocation of chromosomes 9 and 22. This abnormality is usually observed in chronic myeloid leukemia. Btk is essentially phosphorylated by bcr-abl kinase, which triggers a downstream survival signal that prevents apoptosis in bcr-abl cells (N. Feldhahn et al, J. Exp. Med. 2005, 201(11), 1837-1852) .

本发明化合物与最接近的现有技术相比，具有以下优点： The compounds of the invention have the following advantages over the closest prior art:

( 1 )本发明式（I )化合物、其药学上可接受的盐或其氘代物具有较好的 BTK激酶抑制作用； ( 2 )本发明式（I )化合物、其药学上可接受的盐或其氘代物副作用小，安全窗口大； (1) The compound of the formula (I), a pharmaceutically acceptable salt thereof or a progeny thereof of the present invention has a preferred BTK kinase inhibitory action; (2) The compound of the formula (I), the pharmaceutically acceptable salt thereof or the progeny thereof of the present invention has a small side effect and a large safety window;

( 3 )本发明化合物制备工艺简单，质量稳定，易于进行大规模工业生产。 (3) The compound of the present invention has a simple preparation process, stable quality, and is easy to carry out large-scale industrial production.

以下通过药理实验进一步阐述本发明化合物有益效果，但不应将此理解为本发明化合物仅具有下列有益效果。 The beneficial effects of the compounds of the present invention are further illustrated by pharmacological experiments below, but it should not be construed that the compounds of the present invention have only the following beneficial effects.

试验例本发明化合物的药理活性试验 Test Example Pharmacological activity test of the compound of the present invention

I 本发明化合物的体外抗布鲁顿酪氨酸激晦 ίΒΤΚ)活性测定 I In vitro anti-Bruton tyrosine 晦 ΒΤΚ 活性 activity assay of the compounds of the invention

供试品： testing sample:

本发明化合物：自制，其化学名称和结构式与制备方法见各化合物的制备实施例。 The compound of the present invention: self-made, the chemical name and structural formula and preparation method are shown in the preparation examples of the respective compounds.

对照化合物： CC-292 , 按照 WO2009158571A1 制得。 Control compound: CC-292, obtained according to WO2009158571A1.

实脸方法： Real face method:

1. 试验材料 Test material

HTRFR KinEASE™ -TK: 购自 Cisbio, 批号 62TK0PEB; BTK: 购自 Carna, Cat.No.08-080 ; ATP : 购自 Sigma, Cat. No. A7699, CAS No.34369-07-8 ; MgCl₂：购自 Sigma , CAS No. 7786-30-3, Lot. No. 101M8701 V； DMSO：购自 Sigma, CAS No.67-68-5, Lot. No. STBC0365V; 96孔板: 购自 Thermo, Cat. No. 249944, Lot. No. 1057825 ; 384孔板: 购自 Greiner, Cat. No. 784075, Lot. No. El 1 12Φ6Υ» HTRFR KinEASETM -TK: purchased from Cisbio, lot 62TK0PEB; BTK: purchased from Carna, Cat. No. 08-080; ATP: purchased from Sigma, Cat. No. A7699, CAS No. 34369-07-8; MgCl ₂ : purchased from Sigma, CAS No. 7786-30-3, Lot. No. 101M8701 V; DMSO: purchased from Sigma, CAS No. 67-68-5, Lot. No. STBC0365V; 96-well plate: purchased from Thermo, Cat. No. 249944, Lot. No. 1057825; 384-well plate: available from Greiner, Cat. No. 784075, Lot. No. El 1 12Φ6Υ»

2. 试验用试剂配制 2. Test reagent preparation

① 1 χ Kinase buffer ( 5 mM MgCl₂, lmM DTT, 50nM SEB );② DTT 将 DTT原液用灭菌注射用水稀释到 l OOmM作为储备液备用；③ ATP 用灭菌注射用水配制 5mM 的储备液备用； ④ 10mM 化合物溶液：采用 100% DMSO将化合物溶解配制成 10mM的化合物储备液备用。 1 1 χ Kinase buffer ( 5 mM MgCl ₂ , lmM DTT, 50 nM SEB ); 2 DTT DTT stock solution was diluted with sterile water for injection to 100 mM as a stock solution; 3 ATP 5 mM stock solution was prepared with sterile water for injection 4 10 mM compound solution: The compound was dissolved in 100% DMSO to make a 10 mM compound stock solution.

3.酶反应阶段 3. Enzymatic reaction stage

①将 10mM的化合物溶液用 100%DMSO稀释 20倍，再稀释 2倍后进行一系列的 3倍稀释，共 10个浓度梯度，再用 1 X激酶緩沖液（ kinase buffer ) 将每个浓度的溶液稀释 100倍作为试验用化合物浓度， 4μ17孔。 ②配制 5χ酶溶液 ( Enzyme solution ) ：将酶加入 1 χ激酶緩沖液， 2\xLI 孔。 ③ 25 °C 条件下孵育 30min。 ④配制 5 χΤΚ底物 -生物素 ( Substrate-biotin ) ：将 TK底物 -生物素加入 l x激酶緩冲液中， 2μ!7孔； ⑤配制 5χΑΤΡ: 将 ATP加入 1 χ激酶基本緩冲液（kinase base buffer )中， 2μΙ7孔； ⑥在 25 °C条件下孵育 40min。 1 Dilute 10 mM compound solution 20 times with 100% DMSO, dilute 2 times, perform a series of 3-fold dilutions, 10 concentration gradients, and then use 1 X kinase buffer to prepare each concentration solution. Dilute 100 times as the concentration of the test compound, 4μ17 well. 2 Prepare 5 Enzyme solution: Add the enzyme to 1 χ kinase buffer, 2\xLI well. Incubate for 30 min at 25 °C. 4 Preparation of 5 χΤΚ substrate - biotin (Substrate-biotin): TK substrate - biotin was added to lx kinase buffer, 2μ! 7 wells; 5 Preparation 5 χΑΤΡ: ATP was added to 1 χ kinase basic buffer (2 μΙ 7 wells; 6 incubated at 25 ° C for 40 min).

4. 检测反应阶段 4. Detection reaction stage

①配制 4χ链霉抗生物素蛋白（ Streptavidin ) -XL665 : 将链霉抗生物素蛋白 -XL665加入 HTRF®检测緩沖液（Detection buffer ) 中， 5μ17 孔。②每孔再加入 5μί TK Antibody-Cryptate。③ 25 °C条件下孵育 60 min。 1 Preparation 4 Streptavidin - XL665: Add streptavidin-XL665 to HTRF® Detection Buffer, 5μ17 well. 2 Add 5μί TK Antibody-Cryptate to each well. Incubate at 25 °C for 60 min.

5. 数据读取 5. Data reading

检测反应阶段完成后，用酶标仪分别检测检测样品在 615nm 和 665nm处的荧光值。 After the completion of the detection reaction phase, the fluorescence values of the detected samples at 615 nm and 665 nm were detected by a microplate reader.

6. 曲线拟合得出 IC₅₀ 6. Curve fitting yields IC ₅₀

采用 GraphPad 5.0 软件进行曲线拟合，拟合方程为 Y=Bottom + (Top-Bottom)/( l + 10^A((LogIC50-X)*HillSlope)) , 得出 IC₅₀值。 Curve fitting was performed using GraphPad 5.0 software, and the fitting equation was Y=Bottom + (Top-Bottom)/( l + 10 ^A ((LogIC50-X)*HillSlope)), and the IC ₅₀ value was obtained.

实验结果：本发明化合物（化合物 1 -24 )对体外抑制布鲁顿酪氨酸激酶 (BTK)的 IC₅₀ < 0.2μΜ。部分化合物的 IC₅₀如下、 '„：表 1 Experimental Results: The compound of the present invention (Compound 1-24) inhibited Bruton's tyrosine kinase (BTK) in vitro with an IC ₅₀ < 0.2 μΜ. The IC _{50 of} some compounds is as follows, '„: Table 1

化合物 Compound

CC-292 16.0 CC-292 16.0

化合物 1 2.5 Compound 1 2.5

化合物 2 1.35 Compound 2 1.35

化合物 3 0.91 Compound 3 0.91

化合物 4 2.46 Compound 4 2.46

化合物 5 1.05 Compound 5 1.05

化合物 6 0.62 Compound 6 0.62

化合物 7 0.52 Compound 7 0.52

化合物 8 1.26 Compound 8 1.26

化合物 11 1.06 Compound 11 1.06

化合物 12 0.97 Compound 12 0.97

化合物 13 13.05 Compound 13 13.05

化合物 14 1.72 Compound 14 1.72

化合物 16 11.83 Compound 16 11.83

化合物 18 1.09 Compound 18 1.09

化合物 19 7.34 Compound 19 7.34

化合物 20 1.96 Compound 20 1.96

实验结论：由表 1可见本发明化合物对 BTK激酶有较强的抑制活性。 Experimental results: It can be seen from Table 1 that the compound of the present invention has strong inhibitory activity against BTK kinase.

Π 本发明化合物对大鼠脾细胞 BTK酶占有率测定实验测定 Determination of BTK enzyme occupancy rate in rat spleen cells by the compound of the present invention

为了测定细胞或组织溶解产物中未被化合物占用 BTK的量，使用 ELISA方案，其利用一种只结合未被化合物占用 BTK的生物素化探针化合物,评价化合物在不同浓度下，在脾细胞中对 BTK 酶的占有率情况，计算⁰ /oBTK占有率（ BTK Occupancy )。 To determine the amount of BTK that is not occupied by a compound in a cell or tissue lysate, an ELISA protocol is used that evaluates the compound at different concentrations in spleen cells using a biotinylated probe compound that binds only to BTK that is not occupied by the compound. For the occupancy rate of BTK enzyme, calculate the ⁰ /oBTK occupancy rate (BTK Occupancy).

1、实验材料 1. Experimental materials

小鼠抗 BTK抗体 (Becton Dickinson);山羊抗小鼠 HRP抗体 (Becton Dickinson); 细胞裂解液 (Cell Signaling); 布鲁顿酪氨酸激酶（ BTK ) (Carna); 链霉亲和素包被的 96孔板 (Thermo); 大鼠淋巴细胞分离试剂盒 (LTS 1083PK , 天津市灏洋生物制品科技有限责任公司）；酶标仪 (victor4, PE) ；离心机 (5804R, Eppendorf); 显微镜 (CX31RTSF, 奥林巴斯）； MACS分选器 (midiMACS separation unit, MACS)。 Mouse anti-BTK antibody (Becton Dickinson); goat anti-mouse HRP antibody (Becton Dickinson); cell lysate (Cell Signaling); Bruton tyrosine kinase (BTK) (Carna); streptavidin coated 96-well plate (Thermo); rat lymphocyte isolation kit (LTS 1083PK, Tianjin Haoyang Biological Products Technology Co., Ltd.); microplate reader (victor4, PE); centrifuge (5804R, Eppendorf); microscope ( CX31RTSF, Olympus); MACS sorter (MACS).

2、实猃步骤 2, the actual steps

(1)试剂配制 (1) reagent preparation

探针化合物溶液（Probe ): 称取样品化合物 lmg，配制浓度为 ImM 的储备液，使用时用样品稀鋒液稀释；样品稀释液（ Sample diluents )：含 1 %牛血清白蛋白和 0.1 % Tween-20 的 PBS ; 洗涤液（Washing solution ): 含 0.05 % Tween-20的 PBS。 Probe compound solution (Probe): Weigh 1 mg of sample compound, prepare a stock solution with a concentration of 1 mM, and dilute with sample diluted solution. Sample diluents: 1% bovine serum albumin and 0.1% Tween -20 PBS; Washing solution: PBS containing 0.05% Tween-20.

(2) 大鼠脾脏单细胞制备 (2) Preparation of rat spleen single cells

将脾脏用 lmL的 PBS緩冲液沖洗（在脾脏的一端剪个小口，用注射器在脾脏另一端注入 1ml预冷 PBS冲洗），然后转移至 200 目无菌滤网，用手术剪剪碎，再用注射器研磨，注意边研磨边加预冷的 PBS緩冲液冲洗，共计用 5ml的 PBS緩冲液冲洗。 4°C , 400g离心 3min，去上清，加入 20ml细胞洗涤液 PBS , 4°C， 600Rpm, 离心 lOmin, 洗涤 3次。 Rinse the spleen with 1 mL of PBS buffer (smear a small opening at one end of the spleen and inject 1 ml of pre-cooled PBS into the spleen at the other end with a syringe), then transfer to a 200-mesh sterile filter and cut with a surgical scissors. Grind with a syringe, rinse with pre-cooled PBS buffer while grinding, and rinse with 5 ml of PBS buffer. After centrifugation at 400 °C for 3 min at 4 ° C, the supernatant was removed, and 20 ml of cell washing solution PBS was added at 4 ° C, 600 Rpm, centrifuged for 10 min, and washed 3 times.

(3) 化合物与细胞作用 (3) Compound and cell action

将细胞计数后，用 PBS 将细胞浓度稀释到 3 l07Cells/ml, 90μ1/ 孔。加入化合物 ΙΟμΙ/孔， 37°C孵育 lh。 20。C , 400g离心 20min, 弃掉上清。 After counting the cells, the cell concentration was diluted to 3 l07 Cells/ml, 90 μl/well with PBS. Add compound ΙΟμΙ/well and incubate for 1 h at 37 °C. 20. Centrifuge at 400 g for 20 min, discard the supernatant.

(4) 裂解细胞 (4) Lysis cells

将蛋白酶抑制剂 PMSF加入到细胞裂解液（ cell lysis buffer )中（注意 PMSF在裂解液使用前加入；)。将裂解液加入每管富集的细胞中混匀，根据裂解液说明书操作，冰上裂解 5min， 14000g离心 10min。取上清 ΙΟΟμΙ加入 96孔板中。 Add the protease inhibitor PMSF to the cell lysis buffer (Note) PMSF is added before the lysate is used;). The lysate was added to each tube-enriched cell and mixed, and lysed according to the lysate instructions, lysed on ice for 5 min, and centrifuged at 14,000 g for 10 min. Add the supernatant and add to the 96-well plate.

(5)ΒΤΚ测定实验步骤 (5) ΒΤΚ determination experimental steps

每孔加入 lOOul标准品或样品与 ΙΟμΙ 探针化合物溶液（终浓度为 Add lOOul of standard or sample to each well with ΙΟμΙ probe compound solution (final concentration is

ΙμΜ) 混合， 28°C震荡孵育 lh。孵育后，取 ΙΟΟμΙ加入到链霉亲和素包被的 ELISA 板上 ( Streptavidin-coatd ELISA plate), 28°C震荡孵育 lh。用洗涤液（ Washing sol ution ) 洗板 5次。向每孔中加入 ΙΟΟμΙ 纯化的小鼠抗人 ΒΤΚ 抗体 ( Purified mouse anti-human BTK antibody ) ( 1:1000倍稀释）。 28°C震荡孵育 lh。用洗涤液洗板 5次。向每孔中加入 ΙΟΟμΙ HRP标记的山羊抗小鼠抗体（HRP goat anti-mouse Ig)( 1:1000 稀释）。 28°C震荡孵育 lh。用洗涤液洗板 5次后向每孔加入 ΙΟΟμΙ底物 ΤΜΒ溶液， 28°C孵育 15min。每孔加入 50μ11M ¾S0₄终止反应。 ΙμΜ) Mix and incubate for 1 h at 28 °C. After incubation, ΙΟΟμΙ was added to a streptavidin-coated ELISA plate and incubated for 1 h at 28 °C with shaking. The plate was washed 5 times with Washing sol ution. Purified mouse anti-human BTK antibody (1:11000 dilution) was added to each well. Incubate for 1 h at 28 °C with shaking. The plate was washed 5 times with a washing solution. ΙΟΟμΙ HRP-labeled goat anti-mouse Ig (1:1000 dilution) was added to each well. Incubate for 1 h at 28 °C with shaking. After washing the plate with the washing solution 5 times, the ΙΟΟμΙ substrate ΤΜΒ solution was added to each well, and incubated at 28 ° C for 15 min. The reaction was stopped by adding 50 μl of ₁₁ M 3⁄4 S0 _{4 to} each well.

3、检测指标及检测方法 3. Detection indicators and detection methods

反应终止后，检测 450nm处的 OD值。根据 OD值，使用酶标仪中 A4参数逻辑曲线计算各样品中 BTK的量。 After the reaction was terminated, the OD value at 450 nm was detected. Based on the OD value, the amount of BTK in each sample was calculated using the A4 parameter logic curve in the microplate reader.

4、数据处理及结果 4, data processing and results

*%BTK占有率 = (对照组 BTK量-化合物组 BTK量） /对照组 BTK 量 χ100% *%BTK occupancy = (control group BTK amount - compound group BTK amount) / control group BTK amount χ100%

**变异系数 CV=S/x 100% **Coefficient of variation CV=S/x 100%

实验结果如表 2所示： The experimental results are shown in Table 2:

表 2 本发明化合物对大鼠脾细胞 BTK占有率实验结果 Table 2 Experimental results of BTK occupancy rate of rat spleen cells by the compound of the present invention

%BTK占有率 %BTK share

化合物 Compound

50nM 200nM 50nM 200nM

化合物 22 54.57 84.64 化合物 23 34.22 59.49 化合物 24 25.59 68.09 实验结论：由表 2可见，本发明化合物在大鼠脾细胞中的 BTK占有率较高，体现出较好的药效。 Compound 22 54.57 84.64 Compound 23 34.22 59.49 Compound 24 25.59 68.09 Experimental conclusion: As can be seen from Table 2, the compound of the present invention has a higher BTK occupancy rate in rat spleen cells, and exhibits better pharmacological effects.

4、具体实施方式 4, the specific implementation

以下通过实施例形式的具体实施方式，对本发明的上述内容作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下实施例。凡基于本发明上述内容所实现的技术均属于本发明的范围。 The above content of the present invention will be further described in detail below by way of specific embodiments in the form of embodiments. However, it should not be understood that the scope of the above-mentioned subject matter of the present invention is limited to The following example. Any technique implemented based on the above description of the present invention is within the scope of the present invention.

实施例 1 4-(4-(8-(3-丙烯酰氨基苯基) -6-甲基 -7-氧代 -5,6,7,8-四氢嘧啶并【4,5-ΑΠ嘧啶 -2-基氨基)苯氧基 V-甲基吡啶 -2-甲酰胺 (化合物 1) 的制备 Example 1 4-(4-(8-(3-acrylamidophenyl)-6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-purine Preparation of 2-ylamino)phenoxy V-methylpyridine-2-carboxamide (Compound 1)

( 1 ) 4-(3- (叔丁氧羰基氨基)苯氨基 )-2- (曱硫基)嘧啶 -5-甲酸乙酯的制 oc

(1) Preparation of ethyl 4-(3-(tert-butoxycarbonylamino)phenylamino)-2-(indolyl)pyrimidine-5-carboxylate

干燥的反应瓶中，加入 4-氯 -2- (曱硫基)嘧啶 -5-甲酸乙酯（6.99 g, 30.04 mmol ), 加入 100 mL DMF溶解，加入 3-氨基苯基氨基曱酸叔丁 II ( 6.26 g, 30.05 mmol ), 碳酸钾（ 8.293 g， 60 mmol ), 75 °C下反应 16小时，冷却至室温，将反应液倒入水水 500 mL中，析出固体，过滤，滤饼用水水洗涤，真空干燥得白色固体 11.7 g，收率为 96.3%。 Add 4-chloro-2-(indolyl)pyrimidine-5-carboxylic acid ethyl ester (6.99 g, 30.04 mmol) to a dry reaction flask, add 100 mL DMF, and add 3-aminophenylaminodecanoic acid tert-butyl II ( 6.26 g, 30.05 mmol ), potassium carbonate ( 8.293 g, 60 mmol ), react at 75 ° C for 16 hours, cool to room temperature, pour the reaction solution into 500 mL of water, precipitate solids, filter, filter cake with water The mixture was washed with water and dried in vacuo to give a white solid (11.7 g).

(2) 3-(5- (羟曱基) -2-(曱硫基)嘧啶 -4-基氨基)苯基氨基曱酸叔丁酯的制备

(2) Preparation of tert-butyl 3-(5-(hydroxyindenyl)-2-(indolyl)pyrimidin-4-ylamino)phenylaminodecanoate

千燥的反应瓶中，加入 4-(3- (叔丁氧羰基氨基)苯氨基 )-2- (甲硫基) 嘧啶 -5-曱酸乙酯（7.0 g, 17.31 mmol ), 加入四氢呋喃 100 mL溶解， -78 °C下滴加 2.5 M 的四氢铝锂的四氢呋喃溶液（ 16.62 mL , 41.55 mmol ), 滴加完毕后待温度升至室温，加入饱和的氯化铵水溶液 30 mL 淬灭，室温下搅拌半小时，过滤，滤液加入水，并用二氯甲烷萃取，浓缩滤液，过硅胶柱，乙酸乙酯：石油醚 =1 :2 , 过得白色固体 4.3 g, 收率为 68.5%。 To a dry reaction flask, ethyl 4-(3-(tert-butoxycarbonylamino)phenylamino)-2-(methylthio)pyrimidine-5-decanoate (7.0 g, 17.31 mmol) was added, and tetrahydrofuran 100 was added. Dissolve in mL, and add 2.5 M lithium tetrahydroaluminum tetrahydrofuran solution (16.62 mL, 41.55 mmol) at -78 °C. After the addition is complete, the temperature is raised to room temperature, and then saturated with 30 mL of aq. After stirring at room temperature for half an hour, it was filtered, and the filtrate was evaporated, evaporated, evaporated, evaporated.

(3) 3-(5-甲酰基 -2- (甲疏基)嘧啶 -4-基氨基)苯基氨基曱酸叔丁醋的制备 (3) Preparation of 3-(5-formyl-2-(methylamido)pyrimidin-4-ylamino)phenylaminodecanoic acid tert-butyl vinegar

干燥的反应瓶中，加入 3-(5- (羟甲基) -2- (甲硫基)嘧啶 -4-基氨基)苯基氨基曱酸叔丁酯（4.3 g, 11.86 mmol ), lOO mL二氯甲烷溶解，加入二氧化锰（10.31 g, 118.6 mmol ), 室温下搅拌反应 18小时，过滤，用二氯甲烷洗涤滤饼，旋干有机相，得灰色固体粗品 3.7 g, 直接用于下一步反应。 In a dry reaction flask, add tert-butyl 3-(5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-ylamino)phenylaminodecanoate (4.3 g, 11.86 mmol), lOO mL Dichloromethane was dissolved, manganese dioxide (10.31 g, 118.6 mmol) was added, the reaction was stirred at room temperature for 18 hours, filtered, and the filter cake was washed with dichloromethane, and the organic phase was evaporated to give 3.7 g of crude crude solid. One step reaction.

(4) 3-(5-((甲氨基)甲基) -2-(甲碗基)嘧啶 -4-基氨基)苯基氨基甲酸叔丁酯的制备 (4) Preparation of tert-butyl 3-(5-((methylamino)methyl)-2-(methylphenoxy)pyrimidin-4-ylamino)phenylcarbamate

干燥反应瓶中 , 加入 3-(5-甲酰基 -2- (甲硫基)嘧啶 -4-基氨基)苯基氨基曱酸叔丁酯的粗品 3.7 g, 用 100 mL甲醇溶解，同时加入醋酸钠（4.1 g, 50 mmol ), 甲胺盐酸盐（ 3.376 g, 50 mmol ), 室温下搅拌反应 16 小时，加入硼氢化钠（ 0.757 g, 20 mmol ), 反应半小时，加入饱和碳酸氢钠水溶液 50 mL和二氯甲烷 100 mL,分液，水相用二氯甲烷萃取，浓缩有机相，过硅胶柱（纯乙酸乙酯）得黄色固体 2.62 g, 两步的收率为 58.9%。 In a dry reaction flask, add 3.7 g of crude tert-butyl 3-(5-formyl-2-(methylthio)pyrimidin-4-ylamino)phenylaminodecanoate, dissolved in 100 mL of methanol, and added with acetic acid. Sodium (4.1 g, 50 mmol), methylamine hydrochloride ( 3.376 g, 50 mmol), stirred at room temperature 16 H, sodium borohydride (0.757 g, 20 mmol) was added, and the reaction was stirred for half an hour. A saturated aqueous solution of sodium bicarbonate (50 mL) and dichloromethane (100 mL) was then evaporated and evaporated. The column (pure ethyl acetate) gave 2.62 g of a yellow solid.

(5) 3-(3-曱基 -7- (曱硫基) -2-氧代 -3,4-二氢嘧啶并 [4,5- 嘧啶 -1(2 )- 基)苯基氨基曱酸叔丁酯的制 (5) 3-(3-Mercapto-7-(indolyl)-2-oxo-3,4-dihydropyrimido[4,5-pyrimidin-1(2)-yl)phenylaminopurine Preparation of t-butyl acid

干燥的反应器中，加入 3-(5-((甲氨基）曱基) -2-(曱硫基)嘧啶 -4-基氨基)苯基氨基甲酸叔丁酯（2.62 g, 6.98 mmol ), 加入四氢呋喃 100 mL 溶解，加入 DIEA ( 4 mL， 23 mmol ), 水水浴下滴加 0.2 M的三光气的四氢呋喃溶液 ( 12 mL, 2.4 mmol ), 滴加完毕后反应 10 min, 加入饱和碳酸氢钠溶液，用二氯曱烷萃取，浓缩有机相，过硅胶柱，乙酸乙酯：石油醚 =2: 1,得白色固体 1.9 g, 收率为 67.8%。 In a dry reactor, tert-butyl 3-(5-((methylamino)indenyl)-2-(indolyl)pyrimidin-4-ylamino)phenylcarbamate (2.62 g, 6.98 mmol), Add 100 mL of tetrahydrofuran, add DIEA (4 mL, 23 mmol), add 0.2 M of triphosgene in tetrahydrofuran (12 mL, 2.4 mmol), and add 10 mL of saturated sodium bicarbonate. The solution was extracted with dichloromethane, and the organic layer was evaporated,jjjjjjjj

(6) 3-(3-曱基 -7-(曱磺酰基）-2-氧代 -3,4-二氢嘧啶并 [4,5- 嘧啶 - 1 (2/ )-基)苯基氨基甲酸叔丁 (6) 3-(3-Mercapto-7-(indolyl)-2-oxo-3,4-dihydropyrimido[4,5-pyrimidin-1(2/)-yl)phenylamino Tert-butyl formate

干燥的反应瓶中，加入 3-(3-曱基 -7- (甲硫基) -2-氧代 -3,4-二氢嘧啶并 [4,5-ί ]嘧啶 -1(2 )-基)苯基氨基甲酸叔丁酯 ( 1.9 g， 4.73 mmol ), 二氯甲烷 50 mL, ；水水浴下，加入 85%间氯过氧苯甲酸（2.89 g, 14.2 mmol ), 反应升至室温，室温下反应 4小时，加入碳酸氢钠水溶液，用二氯甲烷萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩得白色固体粗品 2.3 g，直接用于下一步反应。 In a dry reaction flask, add 3-(3-mercapto-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4,5-ί]pyrimidine-1(2)- Tert-butyl phenylcarbamate (1.9 g, 4.73 mmol), dichloromethane (50 mL); water-water bath, 85% m-chloroperoxybenzoic acid (2.89 g, 14.2 mmol), The reaction was carried out for 4 hours at room temperature, then aqueous sodium hydrogen carbonate solution was added, and the organic layer was combined and evaporated.

(7) 3-(3-曱基 -7-(4-(2-(曱基氨基曱酰基) p比啶 -4-基氧基)苯氨基 )-2- 氧代 -3,4-二氢嘧啶并 [4,5- ]嘧啶 -1(2 )-基)苯基氨基曱酸叔丁酯的制备

(7) 3-(3-Mercapto-7-(4-(2-(decylaminodecanoyl) p-pyridin-4-yloxy)phenylamino)-2-oxo-3,4-di Preparation of tert-butyl hydropyrimido[4,5-]pyrimidin-1(2)-yl)phenylaminodecanoate

干燥的反应瓶中，加入 3-(3-甲基 -7- (甲磺酰基) -2-氧代 -3,4-二氢嘧啶并 [4,5-d]嘧啶 -1 (2H)-基)苯基氨基曱酸叔丁酯的粗品 2.3 g，特戊醇 50 mL, 4-(4-氨基苯氧基) -N-曱基吡啶甲酰胺（ 1.38 g， 5.67 mmol ), 三氟醋酸（ 0.539 g, 4.73 mmol ), 110 °C下反应 16小时，冷却至室温后，加入饱和碳酸氢钠水溶液，二氯曱烷萃取，浓缩有机相，过硅胶柱（纯乙酸乙酯）得黄色固体 1.13 g，上述两步的收率为 40.0%。 In a dry reaction flask, 3-(3-methyl-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1 (2H)- a crude product of tert-butyl phenylaminodecanoate 2.3 g, pentyl alcohol 50 mL, 4-(4-aminophenoxy)-N-mercaptopyridinecarboxamide ( 1.38 g, 5.67 mmol), trifluoroacetic acid (0.539 g, 4.73 mmol), mp. mp. 1.13 g, the yield of the above two steps was 40.0%.

(8) 4-(4-(8-(3-氨基苯基) -6-甲基 -7-氧代 -5,6，7,8-四氢嘧啶并 [4,5-ί ] 嘧啶 -2-基氨基)苯氧基) -2-甲酰胺的制备 (8) 4-(4-(8-(3-Aminophenyl)-6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-ί]pyrimidine- Preparation of 2-aminoamino)phenoxy)-2-carboxamide

干燥的反应瓶中，加入 3 -(3 -曱基 -7-(4-(2-(曱基氨基曱酰基)吡啶 -4- 基氧基)苯氨基 )-2-氧代 -3,4-二氢嘧啶并 [4,5- 嘧啶 -1(2//)-基)苯基氨基曱酸叔丁酯（ 298 mg, 0.5 mmol ), 二氯曱烷 5 mL和三氟醋酸 5 mL，冰水浴下搅拌 3小时，浓缩旋干，直接用于下一步反应。 In a dry reaction flask, add 3-(3-mercapto-7-(4-(2-(nonylaminodecanoyl)pyridin-4-yloxy)phenylamino)-2-oxo-3,4 -dihydropyrimido[4,5-pyrimidin-1(2//)-yl)phenylaminodecanoic acid tert-butyl ester (298 mg, 0.5 mmol), dichloromethane (5 mL) and trifluoroacetic acid 5 mL, Stir for 3 hours in an ice water bath, concentrate and spin dry, and use directly for the next reaction.

(9) 4-(4-(8-(3-丙烯酰氨基苯基) -6-曱基 -7-氧代 -5,6,7,8-四氢嘧啶并 [4,5-d]嘧啶 -2-基氨基)苯氧基) -N-甲基 p比啶 -2-甲酰胺的制备 (9) 4-(4-(8-(3-acrylamidophenyl)-6-indolyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d] Preparation of pyrimidin-2-ylamino)phenoxy)-N-methyl p-bipyridine-2-carboxamide

上一步反应粗品，加入四氢呋喃 20 mL, 用 DIEA调 pH至 9-10 , - 10 °C下滴加入丙烯酰氯（45 mg， 0.5 mmol ), 滴加完毕后反应 2小时，停止反应后，加入曱醇淬灭，拌样，制备液相纯化得黄色粉末状固体，用甲醇洗涤，干燥，得黄色粉末状固体 56 mg, 两步收率为 20.4%。 The crude product was reacted in the previous step, 20 mL of tetrahydrofuran was added, the pH was adjusted to 9-10 with DIEA, and acryloyl chloride (45 mg, 0.5 mmol) was added dropwise at -10 °C. After the addition was completed, the reaction was carried out for 2 hours. After the reaction was stopped, hydrazine was added. The alcohol was quenched, the mixture was combined, and purified to give a yellow powdery solid, which was washed with methanol and dried to give a yellow powdery solid of 56 mg.

分子式： C₂₉H₂₆N₈0₄ 分子量： 550.21 质谱 (m/e): 551.3 ^-NMRC^-DMSO, 400 MHz, δρρπι): δ 10.26 (1Η, s)， 9.57 (1Η, s), 8.75 (IH, q), 8.45 (IH, d)， 8.19 (IH, s), 7.66-7.59 (2H， m), 7.42 (IH, t), 7.37 (2H, d), 7.28 (IH, d), 7.02 (IH, dd), 6.98 (IH, d), 6,77 (2H, d), 6.31 (IH, dd), 6.12 (IH, d), 5.63 (IH, d), 4.49 (2H， s)， 2.96 (3H， s)， 2.77 (3H, d). Molecular formula: C ₂₉ H ₂₆ N ₈ 0 ₄ Molecular weight: 550.21 Mass spectrum (m/e): 551.3 ^-NMRC^-DMSO, 400 MHz, δρρπι): δ 10.26 (1Η, s), 9.57 (1Η, s), 8.75 (IH, q), 8.45 (IH, d), 8.19 (IH, s), 7.66-7.59 (2H, m), 7.42 (IH, t), 7.37 (2H, d), 7.28 (IH, d) , 7.02 (IH, dd), 6.98 (IH, d), 6,77 (2H, d), 6.31 (IH, dd), 6.12 (IH, d), 5.63 (IH, d), 4.49 (2H, s ), 2.96 (3H, s), 2.77 (3H, d).

实施例 2 W3-r -(4-(2-甲氧基乙氧基）笨氨基 )-3-甲基 -2-氧代 -3,4-二氢嘧啶并【4,5-cH嘧啶 -1(2 -基)苯基)丙烯酰胺 (化合物 2)的制备 Example 2 W3-r-(4-(2-methoxyethoxy)phenylamino)-3-methyl-2-oxo-3,4-dihydropyrimido[4,5-cH-pyrimidine- Preparation of 1(2-yl)phenyl)acrylamide (Compound 2)

( 1 ) 4-(3- (叔丁氧羰基氨基)笨氨基 )-2- (甲硫基)嘧啶 -5-甲酸乙酯的 (1) 4-(3-(tert-Butoxycarbonylamino)phenylamino)-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester

干燥的反应瓶中，加入 4-氯 -2-甲硫基嘧啶 -5-曱酸乙酯（35.0 g， 150 mmol ), 加入 500 mL DMA溶解，加入 3-氨基苯基氨基曱酸叔丁酯 ( 31.2 g, 150 mmol ), 碳酸钾（41.4 g, 300 mmol ), 75 °C下反应 16 小时，冷却至室温，将反应液倒入冰水 500 mL中，过滤，滤饼用冰水洗涤，真空干燥得白色固体 40.0 g, 收率为 66%。 In a dry reaction flask, add 4-chloro-2-methylthiopyrimidine-5-decanoic acid ethyl ester (35.0 g, 150 mmol), add 500 mL of DMA to dissolve, add tert-butyl 3-aminophenylaminodecanoate (31.2 g, 150 mmol), potassium carbonate (41.4 g, 300 mmol), reacted at 75 ° C for 16 hours, cooled to room temperature, poured into 500 mL of ice water, filtered, and the filter cake was washed with ice water. It was dried under vacuum to give 40.0 g of a white solid.

( 2 ) 3-(5- (羟甲基) -2- (甲硫基)嘧啶 -4-基氨基)苯基氨基甲酸叔丁酯的制备

(2) Preparation of tert-butyl 3-(5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-ylamino)phenylcarbamate

干燥的反应瓶中，加入 4-(3- (叔丁氧羰基氨基)苯氨基 )-2- (曱硫基) 嘧啶 -5-曱酸乙酯（40.0 g， 99 mmol ), 加入四氢呋喃 300 mL溶解， -78 °C下分批加入四氢铝锂（ 11.4 g, 300 mmol ), 滴加完毕后待温度升至室温，加入饱和的氯化铵水溶液，室温下搅拌半小时，过滤，滤液加入水，并用二氯曱烷萃取，过硅胶柱， PE:EA=2: 1，得白色固体 20.0 g, 收率为 55.8%。 In a dry reaction flask, add 4-(3-(tert-butoxycarbonylamino)phenylamino)-2-(indolyl)pyrimidine-5-decanoic acid ethyl ester (40.0 g, 99 mmol), add tetrahydrofuran 300 mL Dissolve, add lithium tetrahydrogenate (11. 4 g, 300 mmol) in portions at -78 °C. After the addition is complete, allow the temperature to rise to room temperature. Add saturated aqueous ammonium chloride solution, stir at room temperature for half an hour, filter, and add the filtrate. Water, and extracted with dichloromethane, passed through a silica gel column, EtOAc: EtOAc:

( 3 )3-(5-曱酰基 -2- (甲硫基)嘧啶 -4-基氨基)苯基氨基曱酸叔丁酯的制备 (3) Preparation of tert-butyl 3-(5-nonanoyl-2-(methylthio)pyrimidin-4-ylamino)phenylaminodecanoate

干燥的反应瓶中，加入 3-(5- (羟曱基) -2- (曱硫基)嘧啶 -4-基氨基)苯基氨基曱酸叔丁酯（20.0 g, 55.2 mmol ), 800 mL二氯曱烷溶解，加入二氧化锰（144 g, 1.66 mol ), 室温下搅拌反应 24小时，过滤，用二氯甲烷洗涤滤饼，旋干有机相，得灰色固体粗品 17.0 g, 直接用于下一步反应。 In a dry reaction flask, add tert-butyl 3-(5-(hydroxyindenyl)-2-(indolyl)pyrimidin-4-ylamino)phenylaminodecanoate (20.0 g, 55.2 mmol), 800 mL Dichlorosilane was dissolved, manganese dioxide (144 g, 1.66 mol) was added, and the reaction was stirred at room temperature for 24 hours, filtered, and the filter cake was washed with dichloromethane, and the organic phase was evaporated to give a crude solid (17.0 g). The next step is to react.

( 4 ) 3-(5-((曱氨基)曱基) -2-(曱硫基)嘧啶 -4-基氨基)苯基氨基甲酸叔丁酯的制备 (4) Preparation of 3-(5-((indolyl)indolyl)-2-(indolyl)pyrimidin-4-ylamino)phenylcarbamic acid tert-butyl ester

干燥反应瓶中，加入 3-(5-甲酰基 -2- (甲硫基)嘧啶 -4-基氨基)苯基氨基曱酸叔丁酯（2.50 g， 6.94 mmol ), 用 100 mL曱醇溶解，同时加入醋酸钠（ 1.39g， 16.9 mmol), 曱胺盐酸盐（ 1.14g， 16.9 mmol), 室温下搅拌反应 12小时，加入硼氢化钠（0.53 g, 14 mmol), 反应 12小时，加入饱和碳酸氢钠水溶液 50 mL和二氯甲烷，分液，水相用二氯甲烷萃取，浓缩有机相，过硅胶柱 (PE:EA=1:2)得淡黄色固体 2.38 g, 收率为 91.4%。 In a dry reaction flask, tert-butyl 3-(5-formyl-2-(methylthio)pyrimidin-4-ylamino)phenylaminodecanoate (2.50 g, 6.94 mmol) was dissolved in 100 mL of methanol , join at the same time Sodium acetate (1. 39 g, 16.9 mmol), decylamine hydrochloride (1. 14 g, 16.9 mmol), stirred at room temperature for 12 hours, sodium borohydride (0.53 g, 14 mmol), for 12 hr. The aqueous solution of sodium chloride (50 mL) and methylene chloride were separated, and the aqueous phase was extracted with methylene chloride. The organic phase was concentrated and evaporated to silica gel column (PE: EA = 1:2) to give a pale yellow solid, 2.38 g, yield 91.4%.

( 5 ) 3-(3-甲基 -7- (曱硫基) -2-氧代 -3,4-二氢嘧啶并 [4,5- ^嘧啶 - 1 (2 )-基)苯基氨基曱酸叔丁 (5) 3-(3-Methyl-7-(indolyl)-2-oxo-3,4-dihydropyrimido[4,5--pyrimidin-1(2)-yl)phenylamino Tert-butyl citrate

干燥的反应器中，加入 3-(5- ((曱氨基）曱基) -2- (曱硫基)嘧啶 -4-基氨基)苯基氨基曱酸叔丁酯（2.1 g, 5.59 mmol), 加入四氢呋喃 40mL溶解，加入 DIEA (2.17g, 16.8 mmol), 水水浴下滴加三光气（ 0.83 g, 2.80 mmol)的四氢呋喃溶液，滴加完毕后继续反应 2h，然后加入饱和碳酸氢钠溶液，用二氯曱烷萃取，过硅胶柱（乙酸乙酯：石油醚 =2:1 ), 得白色固体 1.85 g, 收率为 82.5%。 In a dry reactor, tert-butyl 3-(5-((indolyl)indenyl)-2-(indolyl)pyrimidin-4-ylamino)phenylaminodecanoate (2.1 g, 5.59 mmol) was added. Add 40 mL of tetrahydrofuran to dissolve, add DIEA (2.17 g, 16.8 mmol), and add a solution of triphosgene (0.83 g, 2.80 mmol) in tetrahydrofuran under a water bath. After the addition, continue to react for 2 h, then add saturated sodium bicarbonate solution. The mixture was extracted with methylene chloride (hexane) (ethyl acetate: petroleum ether = 2:1) to yield white solid 1.85 g.

(6) 3-(3-甲基 -7- (甲磺酰基) -2-氧代 -3,4-二氢嘧啶并 [4，5- 嘧啶 (6) 3-(3-Methyl-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimido[4,5-pyrimidine

- 1 (2 /)-基)苯基氨基曱酸叔丁 - 1 (2 /)-yl) phenylaminodecanoic acid tert-butyl

干燥的反应瓶中，加入 3-(3-曱基 -7- (曱硫基) -2-氧代 -3,4-二氢嘧啶并 [4,5-t ]嘧啶 -1(2 )-基)苯基氨基曱酸叔丁酯 ( 1.0 g, 2.49 mmol), 二氯曱烷 30mL, 水水浴下，加入间氯过氧苯曱酸（ 1.29 g, 7.47 mmol )，反应升至室温，室温下反应 2 小时，停止反应，然后加入饱和碳酸氢钠水溶液，用二氯甲烷萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到淡黄色固体直接用于下一步反应。 In a dry reaction flask, 3-(3-mercapto-7-(indolyl)-2-oxo-3,4-dihydropyrimido[4,5-t]pyrimidin-1(2)- Tert-butyl phenylaminodecanoate (1.0 g, 2.49 mmol), 30 mL of dichloromethane, water-water bath, m-chloroperoxybenzoic acid ( 1.29 g, 7.47 mmol), and allowed to warm to room temperature, room temperature After the reaction was continued for 2 hours, the reaction was quenched, and then aq.

( 7 )3-(7-(4-(2-甲氧基乙氧基)苯氨基 -2-氧代 -3 ,4-二氢嘧啶并 [4,5- 嘧啶 -2( 1//)-基)苯基氨基曱酸叔丁酯的制备

(7) 3-(7-(4-(2-methoxyethoxy)phenylamino-2-oxo-3,4-dihydropyrimido[4,5-pyrimidine-2( 1//) -Based Preparation of Tert-Butyl Phenylaminodecanoate

干燥的反应瓶中，加入上步得到的 3-(3-甲基 -7- (甲磺酰基) -2-氧代 -3,4-二氢嘧啶并 [4,5- 嘧啶 -1(2H 基)笨基氨基曱酸叔丁酯的粗品，叔戊醇 40mL, 4-(2-曱氧基乙氧基)苯胺（0.50g， 2.99 mmol ), 三氟醋酸 (0.28 g， 2.46 mmol), 110 °C油浴中回流反应 12小时，停止反应，冷却至室温后，加入饱和碳酸氢钠水溶液，二氯甲烷萃取，过硅胶柱 (PE:EA=1:2)得淡黄色固体 0.88 g, 上述两步的收率为 67.9%。 In the dried reaction flask, 3-(3-methyl-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimido[4,5-pyrimidine-1 (2H) obtained in the above step was added. a crude product of tert-butyl amino decanoate, tert-amyl alcohol 40 mL, 4-(2-decyloxyethoxy)aniline (0.50 g, 2.99 mmol), trifluoroacetic acid (0.28 g, 2.46 mmol), The reaction was refluxed for 12 hours in an oil bath at 110 ° C, and the reaction was quenched. After cooling to room temperature, a saturated aqueous solution of sodium hydrogencarbonate was added and dichloromethane was evaporated. The yield of the above two steps was 67.9%.

( 8) 1-(3-氨基苯基) -7-(4-(2-甲氧基乙氧基)苯氨基 )-3-甲基 -3,4-二氢嘧啶并 [4,5- 嘧啶 -2(1 -酮的制备 (8) 1-(3-Aminophenyl)-7-(4-(2-methoxyethoxy)phenylamino)-3-methyl-3,4-dihydropyrimido[4,5- Preparation of pyrimidine-2 (1-ketone)

千燥的反应瓶中，加入 3-(7-(4-(2-甲氧基乙氧基)苯氨基 -2-氧代 -3,4-二氢嘧啶并 [4,5- 嘧啶 -2(1 )_基)苯基氨基甲酸叔丁酯（0.88 mmol), 用 30.0 mL二氯甲烷溶解，在冰浴的条件下滴加三氟乙酸 15.0 mL，滴加完毕，室温继续搅拌，在 TLC检测下原料反应完全后，停止反应，然后减压浓缩，所得产物直接用于下一步反应。 In a dry reaction flask, 3-(7-(4-(2-methoxyethoxy)phenylamino-2-oxo-3,4-dihydropyrimido[4,5-pyrimidine-2 was added] (1) _ phenyl) phenylcarbamic acid tert-butyl ester (0.88 mmol), dissolved in 30.0 mL of dichloromethane, 15.0 mL of trifluoroacetic acid was added dropwise in an ice bath, the addition was completed, stirring was continued at room temperature, in TLC After the completion of the reaction of the starting material was confirmed, the reaction was stopped, and then concentrated under reduced pressure, and the obtained product was directly used for the next reaction.

( 9 ) TV-(3-(7-(4-(2-甲氧基乙氧基)苯氨基 )-3-甲基 -2-氧代 -3,4-二氢嘧啶并 [4,5- ]嘧啶 -1(2//)-基)苯基）丙烯酰胺的制备 (9) TV-(3-(7-(4-(2-methoxyethoxy)phenylamino)-3-methyl-2-oxo-3,4-dihydropyrimido[4,5 - Preparation of pyrimidine-1(2//)-yl)phenyl)acrylamide

干燥的反应瓶中加入上步得到的 1 -(3-氨基苯基) -7-(4-(2-曱氧基乙氧基)苯氨基 )-3-甲基 -3,4-二氢嘧啶并嘧啶 -2(1 /)-酮，加入四氢呋喃 30mL, 用 DIEA调 pH至 9-10， -10 °C下滴加入丙烯酰氯（ 0.31 g， The dry reaction flask was charged with 1-(3-aminophenyl)-7-(4-(2-decyloxyethoxy)phenylamino)-3-methyl-3,4-dihydrofurate obtained in the above step. Pyrimidopyrimidine-2(1/)-one, added to 30 mL of tetrahydrofuran, adjusted to pH 9-10 with DIEA, and added acryloyl chloride (0.31 g, dropwise) at -10 °C.

3.43 mmol), 滴加完毕后继续反应 0.5小时，停止反应后，加入曱醇淬灭，拌样，制备液相纯化（甲醇 /水 =40%)得黄色粉末状固体，用甲醇洗涤，得白色固体 150 mg, 两步收率为 18.7%。 3.43 mmol), after the completion of the dropwise addition, the reaction was continued for 0.5 hour. After the reaction was stopped, the mixture was quenched with decyl alcohol, and the mixture was mixed and purified by liquid phase (methanol/water = 40%) to obtain a yellow powdery solid which was washed with methanol. The solid was 150 mg in a two step yield of 18.7%.

分子式： C₂₅H₂₆N₆0₄ 分子量： 474.20 质 (m/e): 474.9 ^JH-NMR(^-DMSO, 400 ΜΗζ,δρριη): δ 10.29 (IH, s), 9.23 (IH, s), 8.13 (IH, s), 7.74 (IH, d), 7.62 (IH, s), 7.43 (IH, t), 7.15 (2H, d), 6.96 (IH d), 6.51 (2H, d), 6.42 (IH, dd), 6.23 (IH, dd), 5.74 (IH, dd), 4.45 (2H, s), 3.92 (2H, t), 3.58 (2H, t)， 3.28 (3H, s), 2.96 (3H, s). Molecular formula: C ₂₅ H ₂₆ N ₆ 0 ₄ Molecular weight: 474.20 Quality (m/e): 474.9 ^J H-NMR (^-DMSO, 400 ΜΗζ, δρριη): δ 10.29 (IH, s), 9.23 (IH, s), 8.13 (IH, s), 7.74 (IH, d), 7.62 (IH, s) , 7.43 (IH, t), 7.15 (2H, d), 6.96 (IH d), 6.51 (2H, d), 6.42 (IH, dd), 6.23 (IH, dd), 5.74 (IH, dd), 4.45 (2H, s), 3.92 (2H, t), 3.58 (2H, t), 3.28 (3H, s), 2.96 (3H, s).

实施例 3 4- -f8-(3-丙烯酰氨基 )-6-环丙基 -7-氧代 -5,6,7,8-四氢嘧啶并『4,5-</]嘧啶 -2-基氨基)苯氧基 WV-甲基吡啶 -2-甲酰胺 (化合物 3)的制备 Example 3 4--f8-(3-acrylamido)-6-cyclopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-</RTI> pyrimidine-2 Of -aminoamino)phenoxy WV-methylpyridine-2-carboxamide (Compound 3)

( 1 ) 3-(5- ((环丙基亚氨基）甲基) -2- (甲硫基)嘧啶 -4-基氨基)苯基氨基曱酸叔丁酯的制备 (1) Preparation of tert-butyl 3-(5-((cyclopropylimino)methyl)-2-(methylthio)pyrimidin-4-ylamino)phenylaminodecanoate

千燥反应瓶中，加入 3-(5-甲酰基 -2- (甲硫基)嘧啶 -4-基氨基)苯基氨基甲酸叔丁酯 (7.2 g， 20.0 mmol), 加入: 100 mL曱醇溶解，同时加入环丙胺 (5.71 g, 0.1 mol)和 1 mL水乙酸，室温下搅拌反应 16小时，旋千溶剂直接用于下一步。 To a dry reaction flask, add tert-butyl 3-(5-formyl-2-(methylthio)pyrimidin-4-ylamino)phenylcarbamate (7.2 g, 20.0 mmol), add: 100 mL sterol Dissolved, while adding cyclopropylamine (5.71 g, 0.1 mol) and 1 mL of water acetic acid, the reaction was stirred at room temperature for 16 hours, and the solvent was directly used in the next step.

( 2 ) 3-(5- ((环丙基氨基）曱基) -2- (甲硫基)嘧啶 -4-基氨基)苯基氨基甲酸叔丁酯的制备

(2) Preparation of tert-butyl 3-(5-((cyclopropylamino)indolyl)-2-(methylthio)pyrimidin-4-ylamino)phenylcarbamate

向上一步反应体系中加入 200 mL干燥的四氢呋喃， -78。C下分批加入四氢锂铝粉末 (3.8 g， 0.1 mol), 滴加完毕后待温度升至室温继续反应 5小时，加入饱和的氯化铵水溶液淬灭，室温下搅拌半小时，过滤，滤液加入水，并用二氯曱烷萃取，浓缩滤液，过硅胶柱 (石油醚一石油醚：乙酸乙酯 =1 : 1), 得到浅黄色固体 4.2 g, 两步合计收率 52.5%。 200 mL of dry tetrahydrofuran, -78, was added to the upper reaction system. Add lithium tetrahydrogen aluminum powder (3.8 g, 0.1 mol) in portions. After the dropwise addition, the reaction was allowed to proceed to room temperature for 5 hours, quenched with saturated aqueous ammonium chloride solution, stirred at room temperature for half an hour, and filtered. The filtrate was added to water and extracted with dichloromethane. The filtrate was concentrated and evaporated to silica gel column ( petroleum ether: petroleum ether: ethyl acetate = 1 : 1 ) to give a pale yellow solid of 4.2 g.

( 3 ) 3-(3-环丙基 -7- (甲硫基) -2-氧代 -3,4-二氢嘧啶并 [4,5-^]嘧啶 - 1 (2/ )-基)苯基氨基曱酸叔丁 (3) 3-(3-Cyclopropyl-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4,5-^]pyrimidine-1 (2/)-yl) Tert-butyl phenylaminodecanoate

干燥的反应器中，加入 3-(5- ((环丙基氨基)甲基) -2- (甲硫基)嘧啶 -4- 基氨基)苯基氨基甲酸叔丁酯 (4.02 g, 10.0 mmol),加入四氢呋喃 100 mL 溶解，加入 DIEA (4.96 mL, 28.5 mmol),冰水浴下滴加三光气（1.04 g, 3.5 mmol)的四氢呋喃溶液 10 mL，滴加完毕后反应 1小时，加入饱和碳酸氢钠溶液，二氯曱烷萃取，有机相浓缩，过硅胶柱 (石油醚一石油醚：乙酸乙酯 =1.5: 1), 得白色固体 3.03 g, 收率为 70.9%。 In a dry reactor, tert-butyl 3-(5-((cyclopropylamino)methyl)-2-(methylthio)pyrimidin-4-ylamino)phenylcarbamate (4.02 g, 10.0 mmol) Add 100 mL of tetrahydrofuran to dissolve, add DIEA (4.96 mL, 28.5 mmol), and add 10 mL of triphosgene (1.04 g, 3.5 mmol) in tetrahydrofuran solution in an ice water bath. After the dropwise addition, react for 1 hour, add saturated hydrogen carbonate. The sodium solution was extracted with dichloromethane, and the organic layer was concentrated. EtOAcjjjjjjjjj

( 4 ) 3-(3-环丙基 -7- (甲磺酰基) -2-氧代 -3,4-二氢嘧啶并 [4,5- 嘧啶 - 1 (2 /)-基)苯基氨基甲酸叔丁 (4) 3-(3-Cyclopropyl-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimido[4,5-pyrimidin-1(2/)-yl)phenyl Tert-butyl carbamate

干燥的反应瓶中，加入 3-(3-环丙基 -7- (甲硫基) -2-氧代 -3,4-二氢嘧啶并[4，5- 嘧啶-1(2//)-基)苯基氨基曱酸叔丁酯(2.13 g, 4.98 mmol), 二氯甲烷 30 mL, 水水浴下，加入间氯过氧苯甲酸 (2.59 g, 15.0 mmol), 反应升至室温，室温下反应 0.5小时，加入饱和碳酸氢钠水溶液，二氯甲烷萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩得白色固体粗品 2.3 g, 直接用于下一步反应。 In a dry reaction flask, add 3-(3-cyclopropyl-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4,5-pyrimidine-1 (2//) -yl) tert-butyl phenylaminodecanoate (2.13 g, 4.98 mmol), dichloromethane (30 mL), m.hyd. The reaction was warmed to room temperature, and the mixture was stirred at room temperature for 0.5 hr. EtOAc (EtOAc m. The next step is to react.

( 5 ) 3-(3-环丙基 -7-(4-(2- (曱基氨基曱酰基) p比啶 -4-基氧基）苯氨基) -2-氧代 -3，4-二氢嘧啶并 [4,5- 嘧啶 -1(2 )-基)苯基氨基曱酸叔丁酯的制备 (5) 3-(3-Cyclopropyl-7-(4-(2-(decylaminodecanoyl) p-pyridin-4-yloxy)phenylamino)-2-oxo-3,4- Preparation of tert-butyl dihydropyrimido[4,5-pyrimidin-1(2)-yl)phenylaminodecanoate

干燥的反应瓶中， 3-(3-环丙基 -7- (曱磺酰基) -2-氧代 -3,4-二氢嘧啶并 [4,5-ί/]嘧啶 -1(2 )-基)苯基氨基曱酸叔丁酯的粗品 2.3 g，叔戊醇 50 mL, 4-(4-氨基苯氧基) -TV-曱基吡啶 -2-曱酰胺 (1.34 g, 5.5 mmol), 三氟醋酸 (0.57 g, 5.0 mmol), 110°C下反应 24小时，浓缩，过硅胶柱 (石油醚一乙酸乙酯)得黄色固体 1.42 g, 上述两步的收率为 45.8%。 In a dry reaction flask, 3-(3-cyclopropyl-7-(indolyl)-2-oxo-3,4-dihydropyrimido[4,5-ί/]pyrimidin-1(2) -Glycol tert-butyl phenylaminodecanoate 2.3 g, tert-amyl alcohol 50 mL, 4-(4-aminophenoxy)-TV-mercaptopyridine-2-indoleamide (1.34 g, 5.5 mmol) Trifluoroacetic acid (0.57 g, 5.0 mmol) was reacted at 110 ° C for 24 hours, concentrated, and then purified to silica gel column ( petroleum ether ethyl acetate) to yield 1.42 g of a yellow solid. The yield of the above two steps was 45.8%.

( 6 ) 4-(4-(8-(3-氨基苯基） -6-环丙基 -7-氧代 -5,6,7,8-四氢嘧啶并 [4,5- ]嘧啶 -2-基氨基)苯 )- 曱基吡啶 -2-曱酰胺的制备 (6) 4-(4-(8-(3-Aminophenyl)-6-cyclopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-]pyrimidine- Preparation of 2-ylamino)phenyl)-hydrazinyl-2-carboxamide

干燥的反应瓶中 , 加入 3-(3-环丙基 -7-(4-(2- (甲基氨基甲酰基)吡啶 -4-基氧基)苯氨基 )-2-氧代 -3,4-二氢嘧啶并 [4，5-^]嘧啶 -1(2//)-基)苯基氨基曱酸叔丁酯 (0.311 g, 0.5 mmol), 二氯曱烷 5 mL和三氟醋酸 5 mL, 水水浴下搅拌 1小时，浓缩旋干，直接用于下一步反应。 In a dry reaction flask, 3-(3-cyclopropyl-7-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenylamino)-2-oxo-3 was added. 4-Dihydropyrimido[4,5-^]pyrimidin-1(2//)-yl)phenylaminodecanoic acid tert-butyl ester (0.311 g, 0.5 mmol), dichloromethane 5 mL and trifluoroacetic acid 5 mL, stirred for 1 hour in a water bath, concentrated and dried, and used directly for the next reaction.

( 7) 4-(4-(8-(3-丙烯酰氨基) -6-环丙基 -7-氧代 -5,6,7,8-四氢嘧啶并 [4,5-ί]嘧啶 -2-基氨基)苯曱基吡啶 -2-甲酰胺的制备 (7) 4-(4-(8-(3-acrylamido)-6-cyclopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-ί]pyrimidine Preparation of 2-ylamino)phenylhydrazinepyridine-2-carboxamide

上一步反应体系中加入四氢呋喃 20 mL, 用 DIEA调 pH至 9-10, -10 °C下滴加入丙烯酰氯 (45 mg, 0.5 mmol), 滴加完毕后反应 2小时，停止反应后，加入甲醇淬灭，制备液相纯化（曱醇 /水 =60% )得黄色粉末状固体，用甲醇洗涤，干燥，得黄色粉末状固体 71 mg，两步收率为 24.6%。 Add 20 mL of tetrahydrofuran to the reaction system of the previous step, and adjust the pH to 9-10 with DIEA. Add acryloyl chloride (45 mg, 0.5 mmol) dropwise at -10 °C, and react for 2 hours after the completion of the dropwise addition. After the reaction was stopped, it was quenched by the addition of methanol to prepare a liquid phase (sterol/water = 60%) to obtain a yellow powder. The solid was washed with methanol and dried to give a yellow powdery solid 71 mg.

分子式： C₃₁H₂₈N_s0₄ 分子量： 576.22 质谱 (m/e): 576.9 ^-NMR^-DMSO, 400 MHz, Sppm): δ 10.25 (IH, s), 9.59 (IH, s), 8.76 (1H， q), 8.45 (IH, d), 8.21 (IH, s)， 7.67-7.60 (2H, m), 7.49-7.35 (3H, m), 7.28 (IH, d), 7.03 (IH, dd), 6.98 (IH, dt), 6.78 (2H, d), 6.32 (IH, dd), 6.13 (IH, dd), 5.64 (IH, dd), 4.46 (2H, s)， 2.77 (3H, d), 2.72-2.63 (IH, m), 0.80-0.73 (2H, m), 0.72-0.66 (2H, m). Molecular formula: C ₃₁ H ₂₈ N _s 0 ₄ Molecular weight: 576.22 Mass spectrum (m/e): 576.9 ^-NMR^-DMSO, 400 MHz, Sppm): δ 10.25 (IH, s), 9.59 (IH, s), 8.76 (1H, q), 8.45 (IH, d), 8.21 (IH, s), 7.67-7.60 (2H, m), 7.49-7.35 (3H, m), 7.28 (IH, d), 7.03 (IH, dd ), 6.98 (IH, dt), 6.78 (2H, d), 6.32 (IH, dd), 6.13 (IH, dd), 5.64 (IH, dd), 4.46 (2H, s), 2.77 (3H, d) , 2.72-2.63 (IH, m), 0.80-0.73 (2H, m), 0.72-0.66 (2H, m).

实施例 4 4-f4-(8-(3-丙烯酰氨基苯基) -6-(2-甲氧基乙基) -7-氧代 -5,6,7,8-四氢嘧啶并 i4,5- 嘧啶 -2-基氨基)苯氧基 WV-曱基吡啶 -2-甲跣 (化合物 4)的制备 Example 4 4-f4-(8-(3-acrylamidophenyl)-6-(2-methoxyethyl)-7-oxo-5,6,7,8-tetrahydropyrimidine and i4 ,5-Pyridine-2-ylamino)phenoxy WV-mercaptopyridine-2-carboxamide (Compound 4)

( 1 ) 4-(3- (叔丁氧羰基氨基)苯氨基 )-2- (曱硫基)嘧啶 -5-曱酸乙酯的制备

(1) Preparation of ethyl 4-(3-(tert-butoxycarbonylamino)phenylamino)-2-(indolyl)pyrimidine-5-decanoate

干燥的反应瓶中，加入 4-氯 -2-曱硫基嘧啶 -5-曱酸乙酯（35.0 g, 150 mmol ), 加入 500 mL DMA溶解，加入 3-氨基苯基氨基曱酸叔丁酯 ( 31.2 g, 150 mmol ), 碳酸钾（41.4 g, 300 mmol ), 75 °C下反应 16 小时，冷却至室温，将反应液倒入冰水 500 mL中，过滤，滤饼用冰水洗涤，真空干燥得白色固体 40.0 g, 收率为 66%。 In a dry reaction flask, add 4-chloro-2-indolylpyrimidine-5-decanoic acid ethyl ester (35.0 g, 150 mmol), add 500 mL of DMA to dissolve, add tert-butyl 3-aminophenylaminodecanoate (31.2 g, 150 mmol), potassium carbonate (41.4 g, 300 mmol), reacted at 75 ° C for 16 hours, cooled to room temperature, poured into 500 mL of ice water, filtered, and the filter cake was washed with ice water. It was dried under vacuum to give 40.0 g of a white solid.

( 2 ) 3-(5- (羟曱基) -2- (甲硫基)嘧啶 -4-基氨基)苯基氨基曱酸叔丁酯的制备 (2) Preparation of tert-butyl 3-(5-(hydroxyindenyl)-2-(methylthio)pyrimidin-4-ylamino)phenylaminodecanoate

干燥的反应瓶中，加入 4-(3- (叔丁氧羰基氨基)苯氨基 )-2- (曱硫基) 嘧啶 -5-曱酸乙酯（40.0 g, 99 mmol ), 加入四氢呋喃 300 mL溶解， -78 °C下分批加入四氢铝锂（ 11.4 g， 300 mmol ), 滴加完毕后待温度升至室温，加入饱和的氯化铵水溶液，室温下搅拌半小时，过滤，滤液加入水，并用二氯甲烷萃取，过硅胶柱， PE:EA=2: 1 , 得白色固体 20.0 g，收率为 55.8%。 In a dry reaction flask, add 4-(3-(tert-butoxycarbonylamino)phenylamino)-2-(indolyl)pyrimidine-5-decanoic acid ethyl ester (40.0 g, 99 mmol), add tetrahydrofuran 300 mL Dissolve, add lithium tetrahydrogenate (11. 4 g, 300 mmol) in portions at -78 °C. After the addition is complete, allow the temperature to rise to room temperature. Add saturated aqueous ammonium chloride solution, stir at room temperature for half an hour, filter, and add the filtrate. Water, and extracted with dichloromethane, passed through a silica gel column, EtOAc: EtOAc: EtOAc:

( 3 )3-(5-曱酰基 -2- (曱硫基)嘧啶 -4-基氨基)苯基氨基曱酸叔丁酯的制备 (3) Preparation of tert-butyl 3-(5-nonanoyl-2-(indolyl)pyrimidin-4-ylamino)phenylaminodecanoate

干燥的反应瓶中，加入 3-(5- (羟曱基) -2- (曱硫基)嘧啶 -4-基氨基)苯基氨基曱酸叔丁酯（20.0 g, 55.2 mmol ), 800 mL二氯甲烷溶解，加入二氧化锰（ 144 g, 1.66 mol ), 室温下搅拌反应 24小时，过滤，用二氯甲烷洗涤滤饼，旋干有机相，得灰色固体粗品 17.0 g, 直接用于下一步反应。 In a dry reaction flask, add tert-butyl 3-(5-(hydroxyindenyl)-2-(indolyl)pyrimidin-4-ylamino)phenylaminodecanoate (20.0 g, 55.2 mmol), 800 mL Dichloromethane was dissolved, manganese dioxide (144 g, 1.66 mol) was added, and the reaction was stirred at room temperature for 24 hours, filtered, and the filter cake was washed with dichloromethane, and the organic phase was evaporated to give a crude solid (17.0 g). One step Reaction.

( 4 ) 3-(5-((2-甲氧基乙氨基）甲基) -2- (甲硫基)嘧啶 -4-基氨基)苯基氨基甲酸叔丁酯的制备 (4) Preparation of tert-butyl 3-(5-((2-methoxyethylamino)methyl)-2-(methylthio)pyrimidin-4-ylamino)phenylcarbamate

干燥反应瓶中，加入 3-(5-曱酰基 -2- (曱硫基)嘧啶 -4-基氨基)苯基氨基曱酸叔丁酯（2.50 g, 6.94 mmol ), 用 80 mL甲醇溶解，同时加入醋酸 8滴，曱氧基乙胺（2.09 g， 27.8 mmol ), 室温下搅拌反应 12小时，加入硼氢化钠（ 1.06 g, 28 mmol ), 反应 48小时，加入饱和碳酸氢钠水溶液和二氯甲烷，分液，水相用二氯甲烷萃取，浓缩有机相，过硅胶柱 (PE:EA=2: 1)得淡黄色固体 1.74 g，收率为 59.8 %。 In a dry reaction flask, tert-butyl 3-(5-nonanoyl-2-(indolyl)pyrimidin-4-ylamino)phenylaminodecanoate (2.50 g, 6.94 mmol) was added and dissolved in 80 mL methanol. At the same time, 8 drops of acetic acid, methoxyethylamine (2.09 g, 27.8 mmol) were added, and the reaction was stirred at room temperature for 12 hours, sodium borohydride (1.06 g, 28 mmol) was added, and the reaction was carried out for 48 hours, and a saturated aqueous solution of sodium hydrogencarbonate and The methyl chloride was separated, and the aqueous phase was extracted with methylene chloride. The organic layer was concentrated and evaporated to silica gel column (PE: EA = 2: 1) to yield 1.74 g of pale yellow solid.

( 5 )3-(3-(2-甲氧基乙基) -7- (曱硫基) -2-氧代 -3,4-二氢嘧啶并 [4,5-ί ] 嘧啶 -1(2 )-基)苯基氨基曱酸 (5) 3-(3-(2-Methoxyethyl)-7-(indolyl)-2-oxo-3,4-dihydropyrimido[4,5-ί]pyrimidine-1 ( 2)-yl)phenylaminononanoic acid

干燥的反应器中，加入 3-(5-((2-曱氧基乙氨基)甲基) -2- (甲硫基)嘧啶 -4-基氨基)苯基氨基甲酸叔丁酯（ 1.40 g， 3.34 mmol ), 加入四氢呋喃 40 mL溶解，加入 DIEA( 1.30 g, 10.1 mmol )，水水浴下滴加三光气（ 0.50 g， 1.68 mmol ) 的四氢呋喃溶液，滴加完毕后继续反应 1.5 h，然后加入饱和碳酸氢钠溶液，用二氯甲烷萃取，过硅胶柱，乙酸乙酯：石油醚 =2: 1，得白色固体 0.95 g，收率为 63.8%。 In a dry reactor, add tert-butyl 3-(5-((2-methoxyethyl)methyl)-2-(methylthio)pyrimidin-4-ylamino)phenylcarbamate ( 1.40 g , 3.34 mmol ), add 40 mL of tetrahydrofuran to dissolve, add DIEA ( 1.30 g, 10.1 mmol), add triphos (0.50 g, 1.68 mmol) in tetrahydrofuran solution under water bath, continue to react for 1.5 h after the addition, then add The mixture was diluted with EtOAc (EtOAc m.).

( 6 ) 3-(3-(2-曱氧基乙基) -7- (曱磺酰基) -2-氧代 -3,4-二氢嘧啶并 [4,5- 嘧啶 -1 (2 )-基)苯基氨基曱酸叔丁酯的制备

(6) 3-(3-(2-decyloxyethyl)-7-(indolyl)-2-oxo-3,4-dihydropyrimido[4,5-pyrimidine-1 (2) -Based Preparation of Tert-Butyl Phenylaminodecanoate

干燥的反应瓶中，加入 3 -(3 -(2-甲氧基乙基) -7-(甲疏基) -2-氧代 -3 ,4- 二氢嘧啶并 [4,5-^]嘧啶 -1(2 )-基)苯基氨基甲酸叔丁酯 ( 0.95 g， 2.13 mmol ), 二氯甲烷 30 mL，；水水浴下，加入间氯过氧苯曱酸（ 1.10 g, 6.37 mmol ), 反应升至室温，室温下反应 3小时，停止反应，然后加入饱和碳酸氢钠水溶液，用二氯曱烷萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到淡黄色固体（粗品） 1 g直接用于下一步反应。 In a dry reaction flask, add 3-(3-(2-methoxyethyl)-7-(methylamido)-2-oxo-3,4-dihydropyrimido[4,5-^] Pyrimidine-1(2)-yl)phenylcarbamic acid tert-butyl ester (0.95 g, 2.13 mmol), methylene chloride (30 mL), water-water bath, m-chloroperoxybenzoic acid (1.10 g, 6.37 mmol) The reaction was allowed to rise to room temperature, and the reaction was stirred at room temperature for 3 hours. The reaction was quenched, and then aq. NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Solid (crude) 1 g was used directly for the next reaction.

( 7 )3-(3-(2-甲氧基乙基) -7-(4-(2-(曱基氨基曱酰基)吡啶 -4-基氧基) 苯氨基 )-2-氧代 -3,4-二氢嘧啶并 [4,5 ^嘧啶 -1(2 /)-基)苯基氨基甲酸叔丁酯的制备 (7) 3-(3-(2-Methoxyethyl)-7-(4-(2-(indolylaminodecanoyl)pyridin-4-yloxy)phenylamino)-2-oxo- Preparation of tert-butyl 3,4-dihydropyrimido[4,5-pyrimidin-1(2 /)-yl)phenylcarbamate

干燥的反应瓶中，加入 3-(3-(2-甲氧基乙基) -7- (曱磺酰基) -2-氧代 -3,4-二氢嘧啶并 [4,5-ί ]嘧啶 -1(2H)-基)笨基氨基甲酸叔丁酯的粗品（ 1.0 g ), 叔戊醇 40 mL , 4-(4-氨基苯氧基) 甲基吡啶 -2-甲酰胺（0.56 g, 2.30 mmol ), 三氟醋酸（0.24 g， 2.1 1 mmol ), 110 °C油浴中回流反应 24 小时，停止反应，冷却至室温后，加入饱和碳酸氢钠水溶液，二氯甲烷萃取，浓缩有机相，过硅胶柱（ 100%乙酸乙酯）得淡黄色固体 0.38 _g, 上述两步的收率为 27.7%。 In a dry reaction flask, add 3-(3-(2-methoxyethyl)-7-(sulfonyl)-2-oxo-3,4-dihydropyrimido[4,5-ί ] Crude product of pyrimidine-1(2H)-yl)-tert-butylcarbamic acid tert-butyl ester (1.0 g), tert-amyl alcohol 40 mL, 4-(4-aminophenoxy)methylpyridine-2-carboxamide (0.56 g , 2.30 mmol ), trifluoroacetic acid (0.24 g, 2.1 1 mmol), refluxed in an oil bath of 110 ° C for 24 hours. The reaction was quenched. After cooling to room temperature, aq. The phase was passed through a silica gel column (100% ethyl acetate) to give a pale yellow solid (0.38 _g) . The yield of the above two steps was 27.7%.

( 8 ) 4-(4-(8-(3-氨基苯基) -6-(2-甲氧基乙基) -7-氧代 -5,6,7,8-四氢嘧啶并 [4,5- ]嘧啶 -2-基氨 -2-甲酰胺的制备 (8) 4-(4-(8-(3-Aminophenyl)-6-(2-methoxyethyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4 Of 5-pyrimidin-2-ylamino-2-carboxamide

干燥的反应瓶中，加入 3-(3-(2-甲氧基乙基) -7-(4-(2-(甲基氨基甲酰基) p比啶 -4-基氧基)苯氨基 )-2-氧代 -3，4-二氢嘧啶并 [4,5- 嘧啶 -1(2 )-基) 苯基氨基甲酸叔丁酯（0.38 g, 0.59 mmol ), 用 30.0 mL二氯甲烷溶解，在冰浴的条件下滴加三氟乙酸 15.0 mL，滴加完毕，室温继续搅拌，在 TLC 检测下原料反应完全后，停止反应，然后减压浓缩，所得产物直接用于下一步反应。

In a dry reaction flask, 3-(3-(2-methoxyethyl)-7-(4-(2-(methylcarbamoyl) p-pyridin-4-yloxy)phenylamino) was added. 2-Oxo-3,4-dihydropyrimido[4,5-pyrimidin-1(2)-yl) tert-butyl phenylcarbamate (0.38 g, 0.59 mmol), dissolved in 30.0 mL dichloromethane 15.0 mL of trifluoroacetic acid was added dropwise under ice-cooling. After the dropwise addition was completed, stirring was continued at room temperature. After the reaction of the starting material was completed by TLC, the reaction was stopped, and then concentrated under reduced pressure, and the obtained product was directly used for the next reaction.

( 9 ) 4-(4-(8-(3-丙烯酰氨基苯基 )-6-(2-曱氧基乙基 )-7-氧代 -5,6,7,8-四氢嘧啶并 [4，5-d]嘧啶 -2-基氨基）苯氧基) 甲基吡啶 -2-甲酰 (9) 4-(4-(8-(3-Acrylamidophenyl)-6-(2-decyloxyethyl)-7-oxo-5,6,7,8-tetrahydropyrimidine [4,5-d]pyrimidin-2-ylamino)phenoxy)methylpyridine-2-formyl

干燥的反应瓶中加入上步得到的 4-(4-(8-(3-氨基苯基) -6-(2-甲氧基乙基) -7-氧代 -5,6,7,8-四氢嘧啶并 [4，5- 嘧啶 -2-基氨基)笨氧基) 甲基吡啶 -2-曱酰胺，加入四氢呋喃 30 mL，用 DIEA调 PH至 9-10， -10 °C 下滴加入丙烯酰氯（0.1 1 g， 1.22 mmol ), 滴加完毕后继续反应 0.5小时，停止反应后，加入甲醇淬灭，拌样，制备色谱纯化（甲醇 /水 =55% ) 得黄色粉末状固体，用甲醇洗涤，得白色固体 105 mg，两步收率为 30.5%。 The dry reaction flask was charged with 4-(4-(8-(3-aminophenyl)-6-(2-methoxyethyl)-7-oxo-5,6,7,8 obtained in the above step. -tetrahydropyrimido[4,5-pyrimidin-2-ylamino)phenyloxy)methylpyridine-2-indoleamide, added to 30 mL of tetrahydrofuran, adjusted to pH 9-10 with DIEA, drip at -10 °C Add acryloyl chloride (0.1 1 g, 1.22 mmol), and continue to react for 0.5 hour after the completion of the dropwise addition. After the reaction is stopped, the mixture is quenched with methanol, and the mixture is subjected to preparative chromatography (methanol/water = 55%) to obtain a yellow powdery solid. Washing with methanol gave 105 mg of a white solid.

分子式： C₃₁H₃₀N₈O₅ 分子量： 594.23 质谱 (m/e): 594.9 'H-NMR^-DMSO, 400 MHz, 5ppm): δ 10.24 (IH, s), 9.60 (IH, s), 8.75 ( I H, q), 8.45 ( 1H， d), 8.20 ( 1H， s), 7.68-7.61 (2H, m), 7.43 (1H， t), 7.39 (2H, d), 7.29 (IH, d), 7.02 (IH, dd), 6.99 ( IH, d), 6.79 (2H, d), 6.32 (IH, dd), 6.13 (IH, d), 5.64 (IH, d), 4.58 (2H, s), 3.57 (4H, s), 3.29 (3H, s), 2.77 (3H, d). Molecular formula: C ₃₁ H ₃₀ N ₈ O ₅ Molecular weight: 594.23 Mass (m/e): 594.9 'H-NMR^-DMSO, 400 MHz, 5 ppm): δ 10.24 (IH, s), 9.60 (IH, s), 8.75 ( IH, q), 8.45 ( 1H, d), 8.20 ( 1H, s), 7.68-7.61 (2H, m), 7.43 (1H, t), 7.39 (2H, d), 7.29 (IH, d) , 7.02 (IH, dd), 6.99 ( IH, d), 6.79 (2H, d), 6.32 (IH, dd), 6.13 (IH, d), 5.64 (IH, d), 4.58 (2H, s), 3.57 (4H, s), 3.29 (3H, s), 2.77 (3H, d).

实施例 5 4-(4-ί8- -丙烯酰氨基) -7-氧代 -6- (四氢 -2 吡喃 -4- 基) -5,6,7,8-四氢嘧啶并『4,5-^]嘧啶 -2-基氨基)苯氧基 WV-甲基吡啶 -2-甲跣胺 (化合物 5)的制备

Example 5 4-(4-ί8--acrylamido)-7-oxo-6-(tetrahydro-2-pyran-4-yl)-5,6,7,8-tetrahydropyrimidine ,5-^]pyrimidin-2-ylamino)phenoxy WV-methylpyridine-2-carboxamide (Compound 5)

( 1 ) 3-(2- (甲硫基) -5- ((四氢 -2//-吡喃 -4-基亚氨基）甲基)嘧啶 -4-基氨基)苯基氨基甲酸叔丁酯的 (1) 3-(2-(Methylthio)-5-((tetrahydro-2//-pyran-4-ylimino)methyl)pyrimidin-4-ylamino)phenylcarbamic acid tert-butyl Ester

干燥反应瓶中，加入 3-(5-甲酰基 -2- (曱硫基)嘧啶 -4-基氨基)苯基氨基甲酸叔丁酯 (7.2 g， 20.0 mmol)，加入 100 mL甲醇溶解，同时加入四氢 -2 /-吡喃 -4-胺盐酸盐（13.76 g, 0.1 mol)和乙酸钠 (8.2 g， 0.1 mol), 室温下搅拌反应 24小时，旋千溶剂直接用于下一步。 In a dry reaction flask, tert-butyl 3-(5-formyl-2-(indolyl)pyrimidin-4-ylamino)phenylcarbamate (7.2 g, 20.0 mmol) was added and dissolved in 100 mL of methanol. Tetrahydro-2/-pyran-4-amine hydrochloride (13.76 g, 0.1 mol) and sodium acetate (8.2 g, 0.1 mol) were added, and the reaction was stirred at room temperature for 24 hours, and the solvent was directly applied to the next step.

( 2 ) 3-(2- (甲硫基) -5- ((四氢 -2/ -吡喃 -4-基氨基）甲基)嘧啶 -4-基氨基)苯基氨基甲酸叔丁酯的制备 (2) tert-butyl 3-(2-(methylthio)-5-((tetrahydro-2/-pyran-4-ylamino)methyl)pyrimidin-4-ylamino)phenylcarbamate Preparation

向上一步反应体系中加入 200 mL干燥的四氢呋喃， -78°C下分批加入四氢锂铝固体 (3.8 g, 0.1 mol), 滴加完毕后待温度升至室温继续反应 5小时，加入饱和的氯化铵水溶液淬灭，室温下搅拌半小时，过滤，滤液加入水，并用二氯甲烷萃取，浓缩滤液，过硅胶柱 (石油醚一石油醚：乙酸乙酯 =1 : 1), 得到浅黄色固体 4.2 g，两步合计收率 47.2%。 ( 3 ) 3-(7- (曱硫基) -2-氧代 -3- (四氢 -2 -吡喃 -4-基) -3,4-二氢嘧啶并 [4,5- 嘧啶- 1 (2 / 基)苯基氨备 200 mL of dry tetrahydrofuran was added to the upper reaction system, and tetrahydrogen lithium aluminum solid (3.8 g, 0.1 mol) was added in portions at -78 ° C. After the completion of the dropwise addition, the reaction was allowed to proceed to room temperature for 5 hours, and saturated. The aqueous solution of ammonium chloride was quenched, stirred at room temperature for half an hour, filtered, and the filtrate was added to water and extracted with dichloromethane. The filtrate was concentrated and evaporated to silica gel ( petroleum ether: petroleum ether: ethyl acetate = 1 : 1) to give pale yellow The solid was 4.2 g, and the total yield of the two steps was 47.2%. (3) 3-(7-(Indolyl)-2-oxo-3-(tetrahydro-2-pyran-4-yl)-3,4-dihydropyrimido[4,5-pyrimidine- 1 (2 / yl) phenylamine

干燥的反应器中，加入 3-(2- (曱硫基) -5- ((四氢 -2//-吡喃 -4-基氨基) 甲基)嘧啶 -4-基氨基)苯基氨基甲酸叔丁酯 (4.46 g， 10.0 mmol), 加入四氢呋喃 lOO mL溶解，力口入 DIEA (4.96 mL, 28.5 mmol), ；水水浴下滴加三光气（1.04 g, 3.5 mmol)的四氢呋喃溶液 10 mL, 滴加完毕后反应 1小时，加入饱和碳酸氢钠溶液，二氯曱烷萃取，有机相浓缩，过硅胶柱 (石油醚一石油醚：乙酸乙酯 =1 : 1), 得白色固体 2.97 g, 收率为 63%。 In a dry reactor, 3-(2-(indolyl)-5-((tetrahydro-2//-pyran-4-ylamino)methyl)pyrimidin-4-ylamino)phenylamino Tert-butyl formate (4.46 g, 10.0 mmol), dissolved in 100 mL of tetrahydrofuran, and digested into DIEA (4.96 mL, 28.5 mmol); and added a solution of triphosgene (1.04 g, 3.5 mmol) in tetrahydrofuran 10 mL under water bath. After the completion of the dropwise addition, the reaction was carried out for 1 hour, and a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was extracted with dichloromethane, and the organic phase was concentrated, and then passed through a silica gel column (petrole ether- petroleum ether: ethyl acetate = 1 : 1) to obtain a white solid of 2.97 g. , the yield was 63%.

( 4 ) 3-(7- (甲磺酰基) -2-氧代 -3- (四氢 -2//-吡喃 -4-基) -3,4-二氢嘧啶并 [4，5- ]嘧啶 -1(2 /)-基)苯基制备 (4) 3-(7-(Methanesulfonyl)-2-oxo-3-(tetrahydro-2//-pyran-4-yl)-3,4-dihydropyrimido[4,5- Pyrimidine-1(2/)-yl)phenyl preparation

干燥的反应瓶中，加入 3-(7- (甲硫基) -2-氧代 -3- (四氢 -2/ -吡喃 -4- 基) -3,4-二氢嘧啶并 [4,5-c ]嘧啶 -1(2/ )-基)苯基氨基曱酸叔丁酯 (2.36 g, 5.0 mmol), 二氯甲烷 30 mL, 冰水浴下，加入间氯过氧苯甲酸 (2.59 g, 15.0 mmol), 反应升至室温，室温下反应 0.5小时，加入饱和碳酸氢钠水溶液，二氯甲烷萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩得白色固体粗品 2.5 g，直接用于下一步反应。 In a dry reaction flask, add 3-(7-(methylthio)-2-oxo-3-(tetrahydro-2/-pyran-4-yl)-3,4-dihydropyrimidine [4 ,5-c]pyrimidine-1(2/)-yl)phenylaminodecanoic acid tert-butyl ester (2.36 g, 5.0 mmol), dichloromethane 30 mL, ice-water bath, m-chloroperoxybenzoic acid (2.59) g, 15.0 mmol), the reaction was allowed to warm to room temperature, and the mixture was stirred at room temperature for 0.5 hr. EtOAc (EtOAc m. 2.5 g, used directly in the next reaction.

( 5 ) 3-(7-(4-(2- (曱基氨基甲酰基)吡啶 -4-基氧基)苯氨基 )-2-氧代 -3- (四氢 -2/ -吡喃 -4-基) -3,4-二氢嘧啶并 [4,5-ί ]嘧啶 -1(2//)-基)苯基氨基曱酸叔丁酯的制备 (5) 3-(7-(4-(2-(Mercaptocarbamoyl)pyridin-4-yloxy)phenylamino)-2-oxo-3-(tetrahydro-2/-pyran- Preparation of 4-yl)-3,4-dihydropyrimido[4,5-ί]pyrimidin-1(2//)-yl)phenylaminodecanoic acid tert-butyl ester

干燥的反应瓶中， 3-(7- (曱磺酰基） -2-氧代 -3- (四氢 -2 -吡喃 -4- 基) -3,4-二氢嘧啶并 [4,5-t ]嘧啶 -1(2/ )-基）苯基氨基曱酸叔丁酯的粗品 2.5 g,叔戊醇 50 mL，4-(4-氨基苯氧基) -N-曱基吡啶 -2-甲酰胺（1.34 g, 5.5 mmol) , 三氟醋酸 (0.57 g, 5.0 mmol) , 110。C下反应 48小时，浓缩，过硅胶柱（100%石油酸一 100%乙酸乙酯)得黄色固体 1.8 g, 上述两步的收率为 54°/。。 In a dry reaction flask, 3-(7-(sulfonyl)-2-oxo-3-(tetrahydro-2-pyran-4-yl)-3,4-dihydropyrimido[4,5 -t ] crude product of pyrimidine-1(2/)-yl)phenylaminodecanoic acid tert-butyl ester 2.5 g, tert-amyl alcohol 50 mL, 4-(4-aminophenoxy)-N-mercaptopyridine-2-carboxamide (1.34 g, 5.5 mmol), trifluoroacetic acid (0.57 g, 5.0 mmol), 110 . The reaction was carried out for 48 hours under C, concentrated, and then applied to a silica gel column (100% petroleum acid - 100% ethyl acetate) to obtain a yellow solid (1.8 g). .

( 6 ) 4-(4-(8-(3-氨基苯基) -7-氧代 -6- (四氢 -2/ -吡喃 -4-基) -5,6，7,8- 四氢嘧啶并 [4，5- 嘧啶 -2- 啶 -2-甲酰胺的制备 (6) 4-(4-(8-(3-Aminophenyl)-7-oxo-6-(tetrahydro-2/-pyran-4-yl)-5,6,7,8- Preparation of Hydropyrimido[4,5-pyrimidin-2-pyridine-2-carboxamide

干燥的反应瓶中，加入 3-(7-(4-(2- (甲基氨基曱酰基)吡啶 -4-基氧基) 苯氨基）-2-氧代 -3- (四氢 -2H-吡喃 -4-基）-3 ,4-二氢嘧啶并 [4,5- 嘧啶 -1(2 )-基)苯基氨基曱酸叔丁酯 (0.333 g, 0.5 mmol) , 二氯甲烷 5 mL和三氟醋酸 5 mL, 冰水浴下搅拌 1小时，浓缩旋干，直接用于下一步反应。 In a dry reaction flask, 3-(7-(4-(2-(methylaminodecanoyl)pyridin-4-yloxy)phenylamino)-2-oxo-3-(tetrahydro-2H-) tert-Butyl pyran-4-yl)-3,4-dihydropyrimido[4,5-pyrimidin-1(2)-yl)phenylaminodecanoate (0.333 g, 0.5 mmol), methylene chloride 5 5 mL of trifluoroacetic acid and 5 ml of trifluoroacetic acid were stirred for 1 hour in an ice water bath, concentrated and dried, and used directly for the next reaction.

( 7 )4-(4-(8-(3-丙烯酰氨基) -7-氧代 -6- (四氢 -2 -吡喃 -4-基) -5,6,7,8- 四氢嘧啶并 [4，5-ί ]嘧啶 -2- 啶 -2-甲酰胺的制备 (7) 4-(4-(8-(3-acrylamido)-7-oxo-6-(tetrahydro-2-pyran-4-yl)-5,6,7,8-tetrahydro Preparation of pyrimido[4,5-ί]pyrimidine-2-pyridine-2-carboxamide

上一步反应体系中加入四氢呋喃 20 mL，用 DIEA调 pH至 9-10， -10。C下滴加入丙浠酰氯 (45 mg, 0.5 mmol) , 滴加完毕后反应 2小时，停止反应后，加入甲醇淬灭，制备液相纯化（甲醇：水 =65%)得黄色粉固体，用甲醇洗涤，干燥，得黄色粉末状固体 62 mg, 两步收率为

20 mL of tetrahydrofuran was added to the reaction system of the previous step, and the pH was adjusted to 9-10, -10 with DIEA. Propionyl chloride (45 mg, 0.5 mmol) was added dropwise to C. After the completion of the dropwise addition, the reaction was carried out for 2 hours. After the reaction was stopped, methanol was added to quench it, and liquid phase purification (methanol: water = 65%) was obtained to obtain a yellow powder solid. Washed with methanol, dried to give a yellow powdery solid, 62 mg.

分子式： C₃₃H₃₂N₈0₅ 分子量： 620.25 质谱 (m/e): 620.9 ^-NMRC^-DMSO, 400 MHz, 5ppm): δ 10.24 (1H, s), 9.60 (1H, s), 8.76 ( 1H, q), 8.46 (1H, m), 8.23 ( 1 H, s), 7.72-7.57 (2H, m), 7.50-7.22 (4H, m), 7.03 (2H, m), 6.88-6.74 (2H, m), 6.32 (1H, dd), 6.13 (1 H, d), 5.64 (1H, d), 4.52-4.33 (3H, m), 3.95 (2H, m), 3.46-3.36 (2H, m), 2.78 (3H, d), 2.03-1.82 (2H, m), 1.68-1.58 (2H, m). Molecular formula: C ₃₃ H ₃₂ N ₈ 0 ₅ Molecular weight: 620.25 Mass (m/e): 620.9 ^-NMRC^-DMSO, 400 MHz, 5 ppm): δ 10.24 (1H, s), 9.60 (1H, s), 8.76 (1H, q), 8.46 (1H, m), 8.23 ( 1 H, s), 7.72-7.57 (2H, m), 7.50-7.22 (4H, m), 7.03 (2H, m), 6.88-6.74 ( 2H, m), 6.32 (1H, dd), 6.13 (1 H, d), 5.64 (1H, d), 4.52-4.33 (3H, m), 3.95 (2H, m), 3.46-3.36 (2H, m ), 2.78 (3H, d), 2.03-1.82 (2H, m), 1.68-1.58 (2H, m).

实施例 6 iV-(3-i3-环丙基 -7-(6-(2-甲氧基乙氧基）吡啶 -3-基氨基) -2-氧代 -3,4-二氢嘧啶并『4,5- 嘧啶 -1(2^ -基)苯基）丙烯酰胺 (化合物 6)的制备 Example 6 iV-(3-i3-cyclopropyl-7-(6-(2-methoxyethoxy)pyridin-3-ylamine Preparation of 2-oxo-3,4-dihydropyrimido-,4,5-pyrimidin-1(2^-yl)phenyl)acrylamide (Compound 6)

(1) 3-(3-环丙基 -7-(6-(2-曱氧基乙氧基）吡啶 -3-基氨基 )-2-氧代 -3,4-二氢嘧啶并 [4，5-d]嘧啶 -1(2H)-基)苯基氨基甲酸叔丁酯的制备 (1) 3-(3-Cyclopropyl-7-(6-(2-decyloxyethoxy)pyridin-3-ylamino)-2-oxo-3,4-dihydropyrimido[4] ,5-d]Preparation of pyridyl-1(2H)-yl)phenylcarbamic acid tert-butyl ester

千燥反应瓶中，加入 3-(3-环丙基 -7- (曱磺酰基) -2-氧代 -3,4-二氢嘧啶并 [4,5- ]嘧啶 -1 (2H 基)苯基氨基曱酸叔丁酯 (0.919 g, 2.0 mmol), 叔戊醇 30 mL, 6-(2-曱氧基乙氧基)吡啶 -3-胺 (0.37 g, 2.2 mmol), 三氟醋酸 (0.228 g, 2.0 mmol), 110°C下反应 12小时，浓缩，过硅胶柱 (石油醚一石油醚：乙酸乙酯 =1 :2)得黄色固体 0.67 g，收率为 61%。 In a dry reaction flask, 3-(3-cyclopropyl-7-(indolyl)-2-oxo-3,4-dihydropyrimido[4,5-]pyrimidine-1 (2H group) was added. tert-Butyl phenylaminodecanoate (0.919 g, 2.0 mmol), 30 mL of tert-amyl alcohol, 6-(2-decyloxyethoxy)pyridin-3-amine (0.37 g, 2.2 mmol), trifluoroacetic acid (0.228 g, 2.0 mmol), mp. EtOAc (EtOAc:EtOAc)

(2) 1-(3-氨基苯基) -3-环丙基 -7-(6-(2-曱氧基乙氧基）吡啶 -3-基氨基) -3,4-二氢嘧啶并 [4,5-c ] -2(1//)-酮的制备 (2) 1-(3-Aminophenyl)-3-cyclopropyl-7-(6-(2-decyloxyethoxy)pyridin-3-ylamino)-3,4-dihydropyrimidine Preparation of [4,5-c]-2(1//)-one

干燥的反应瓶中，加入 3-(3-环丙基 -7-(6-(2-甲氧基乙氧基)吡啶 -3- 基氨基 )-2-氧代 -3,4-二氢嘧啶并 [4,5-ί ]嘧啶 -1(2//)-基)苯基氨基甲酸叔丁酯 (0.67 g, 1.22 mmol), 二氯甲烷 5 mL和三氟醋酸 5 mL, 水水浴下搅拌 1小时，浓缩旋干，直接用于下一步反应。 In a dry reaction flask, 3-(3-cyclopropyl-7-(6-(2-methoxyethoxy)pyridin-3-ylamino)-2-oxo-3,4-dihydro was added. Pyrimido[4,5-ί]pyrimidin-1(2//)-yl)phenylcarbamic acid tert-butyl ester (0.67 g, 1.22 mmol), dichloromethane 5 mL and trifluoroacetic acid 5 mL, water bath Stir for 1 hour, concentrate and spin dry, and use directly for the next reaction.

(3) N-(3-(3-环丙基 -7-(6-(2-甲氧基乙氧基)吡啶 -3-基氨基 )-2-氧代 -3,4-二氢嘧啶并 [4,5-ί ]嘧啶 -1(2//)-基)苯基）丙烯酰胺的制备

(3) N-(3-(3-Cyclopropyl-7-(6-(2-methoxyethoxy)pyridin-3-ylamino)-2-oxo-3,4-dihydropyrimidine Preparation of [4,5-ί]pyrimidin-1(2//)-yl)phenyl)acrylamide

将上一步得到的粗品溶于 15 mL四氢呋喃溶解，用 DIEA调 pH至 9-10, 水水浴下滴加入丙烯酰氯 (110 mg, 1.22 mmol), 滴加完毕后反应 1小时，停止反应后，加入曱醇淬灭，过硅胶柱（100%乙酸乙酯)得黄色粉末状固体，用甲醇洗涤，干燥，得黄色粉末状固体 210 mg, 两步收率为 34.4%。 The crude product obtained in the previous step was dissolved in 15 mL of tetrahydrofuran, and the pH was adjusted to 9-10 with DIEA. acryloyl chloride (110 mg, 1.22 mmol) was added dropwise to the water bath, and the reaction was completed for 1 hour after the completion of the dropwise addition. The title compound was obtained as a yellow powdery solid (yield: EtOAc).

分子式： C₂₆H₂₇N₇0₄ 分子量： 501.21 质谱（m/e ): 501.9 !H-NMR -DMSO, 400 MHz, Sppm): 10.31 (IH, s), 9.31 (IH, s), 8.15 (IH, s), 7.97 (IH, s), 7.70-7.56 (3H, m), 7.41 (1H， t), 6.95 (IH, d), 6.41 (IH, dd), 6.38-6.28 (IH, m), 6.23 (IH, dd), 5.74 (IH, dd), 4.42 (2H, s) 4.20 (2H, t), 3.57 (2H, t)， 3.25 (3H， s), 2.70-2.61 (IH, m), 0.80-0.71 (2H, m), 0.70-0.63 (2H, m). Molecular formula: C ₂₆ H ₂₇ N ₇ 0 ₄ Molecular weight: 501.21 Mass spectrum (m/e): 501.9 !H-NMR -DMSO, 400 MHz, Sppm): 10.31 (IH, s), 9.31 (IH, s), 8.15 ( IH, s), 7.97 (IH, s), 7.70-7.56 (3H, m), 7.41 (1H, t), 6.95 (IH, d), 6.41 (IH, dd), 6.38-6.28 (IH, m) , 6.23 (IH, dd), 5.74 (IH, dd), 4.42 (2H, s) 4.20 (2H, t), 3.57 (2H, t), 3.25 (3H, s), 2.70-2.61 (IH, m) , 0.80-0.71 (2H, m), 0.70-0.63 (2H, m).

实施例 7 iV-(3-(3-环丙基 -7-ί6-曱氧基吡啶 -3-基氨基 )-2-氧代 -3,4- 二氢 -1(2^ -基)苯基)丙烯酰胺 (化合物 7)的制备 Example 7 iV-(3-(3-Cyclopropyl-7-ί6-decyloxypyridin-3-ylamino)-2-oxo-3,4-dihydro-1(2^-yl)benzene Preparation of acrylamide (compound 7)

(1) 3-(3-环丙基 -7-(6-曱氧基吡啶 -3-基氨基 )-2-氧代 -3,4-二氢嘧啶并 [4，5- 嘧啶 -1(2 /)-基)苯基备 (1) 3-(3-Cyclopropyl-7-(6-decyloxypyridin-3-ylamino)-2-oxo-3,4-dihydropyrimido[4,5-pyrimidine-1 ( 2 /)-based) phenyl preparation

干燥反应瓶中，加入 3-(3-环丙基 -7- (曱基磺酰基 )-2-氧代 -3,4-二氢嘧啶并 [4，5- ]嘧啶 -1(2/ )-基)苯基氨基曱酸叔丁酯 (0.919 g, 2.0 mmol), 叔戊醇 30 mL， 6-甲氧基 -3-氨基吡啶 (0.273 g, 2.2 mmol),三氟醋酸 (0.228 g, 2.0 mmol) , 110°C下反应 12小时，浓缩，过硅胶柱 (石油醚一石油醚：乙酸乙酯 =1 : 1 )得黄色固体 0.4 g, 收率为 39.7%。 In a dry reaction flask, 3-(3-cyclopropyl-7-(mercaptosulfonyl)-2-oxo-3,4-dihydropyrimido[4,5-]pyrimidin-1 (2/) was added. -yl) tert-butyl phenylaminodecanoate (0.919 g, 2.0 mmol), 30 mL of tert-amyl alcohol, 6-methoxy-3-aminopyridine (0.273 g, 2.2 mmol), trifluoroacetic acid (0.228 g, 2.0 mmol), reacted at 110 ° C for 12 hours, concentrated, passed through silica gel column (oil Ether-petroleum ether: ethyl acetate = 1 : 1 ) gave a yellow solid, 0.4 g, yield 39.7%.

(2) 1-(3-氨基苯基) -3-环丙基 -7-(6-甲氧基吡啶 -3-基氨基 )-3,4-二氢嘧啶并 [4,5- 嘧啶 -2(1//)-酮 (2) 1-(3-Aminophenyl)-3-cyclopropyl-7-(6-methoxypyridin-3-ylamino)-3,4-dihydropyrimido[4,5-pyrimidine- 2(1//)-ketone

干燥的反应瓶中，加入 3-(3-环丙基 -7-(6-甲氧基吡啶 -3-基氨基 )-2- 氧代 -3,4-二氢嘧啶并 [4,5-c ]嘧啶 -1(2//)-基)苯基氨基甲酸叔丁酯 (0.4 g, 0.794 mmol), 二氯甲烷 5 mL和三氟醋酸 5 mL, ；水水浴下搅拌 1小时，浓缩旋干，直接用于下一步反应。 In a dry reaction flask, 3-(3-cyclopropyl-7-(6-methoxypyridin-3-ylamino)-2-oxo-3,4-dihydropyrimidine [4,5- c] pyrimidine-1 (2//)-yl) phenylcarbamic acid tert-butyl ester (0.4 g, 0.794 mmol), dichloromethane 5 mL and trifluoroacetic acid 5 mL, stirred in water water for 1 hour, concentrated Dry, used directly in the next reaction.

(3) N-(3-(3-环丙基 -7-(6-甲氧基吡啶 -3-基氨基 )-2-氧代 -3,4-二氢嘧啶并 [4,5- 嘧啶 -1 (2 />基)苯 (3) N-(3-(3-Cyclopropyl-7-(6-methoxypyridin-3-ylamino)-2-oxo-3,4-dihydropyrimido[4,5-pyrimidine -1 (2 yl) benzene

将上一步得到的粗品用 15 mL四氢呋喃溶解，用 DIEA调 pH至 9-10 , 冰水浴下滴加入丙烯酰氯 (72 mg, 0.794 mmol), 滴加完毕后反应 1小时，停止反应后，加入甲醇淬灭，过硅胶柱（100%石油醚一石油瞇：乙酸乙酯 =1 :2)得类白色粉末状固体，用甲醇洗涤，干燥，得类白色粉末状固体 1 12 mg，两步收率为 30.9%。 The crude product obtained in the previous step was dissolved in 15 mL of tetrahydrofuran, adjusted to pH 9-10 with DIEA, and acryloyl chloride (72 mg, 0.794 mmol) was added dropwise in an ice water bath. After the dropwise addition, the reaction was carried out for 1 hour. After the reaction was stopped, methanol was added. Quenching, a silica gel column (100% petroleum ether: EtOAc: EtOAc: EtOAc: EtOAc) It is 30.9%.

分子式： C₂₄H₂₃N₇0₃ 分子量： 457. 19 质谱（m/e ): 457.9 ^-NMR^-DMSO, 400 MHz, 5ppm): 10.31 ( 1H， s)， 9.29 (IH, s),Molecular formula: C ₂₄ H ₂₃ N ₇ 0 ₃ Molecular weight: 457. 19 Mass (m/e ): 457.9 ^-NMR^-DMSO, 400 MHz, 5 ppm): 10.31 (1H, s), 9.29 (IH, s),

8.15 (IH, s), 7.99 (IH, s), 7.70-7.56 (3H, m), 7.41 (IH, t), 6.94 (IH, d)， 6.41 ( IH, dd), 6.37-6.28 (IH, m), 6.23 (1H， d), 5.74 (IH, d), 4.42 (2H, s), 3.70 (3H, s), 2.69-2.61 (I H, m), 0.80-0.71 (2H, m), 0.70-0.63 (2H, m). 8.15 (IH, s), 7.99 (IH, s), 7.70-7.56 (3H, m), 7.41 (IH, t), 6.94 (IH, d), 6.41 ( IH, dd), 6.37-6.28 (IH, m), 6.23 (1H, d), 5.74 (IH, d), 4.42 (2H, s), 3.70 (3H, s), 2.69-2.61 (IH, m), 0.80-0.71 (2H, m), 0.70 -0.63 (2H, m).

实施例 8 V-i3-i3-环丙基 (二甲氨基)吡啶 -3-基氨基 )-2-氧代 -3,4-二氢嘧啶并【4,5-^]嘧啶 -Ii2 基)苯基)丙烯酰胺 (化合物 8)的制备

Example 8 V-i3-i3-cyclopropyl(dimethylamino)pyridin-3-ylamino)-2-oxo-3,4-dihydropyrimido[4,5-^]pyrimidine-Ii2 group) Preparation of phenyl)acrylamide (compound 8)

(1) 4-(3- (叔丁氧羰基氨基)笨氨基 )-2- (甲磺酰基)嘧啶 -5-甲酸乙酉的制备 (1) Preparation of 4-(3-(tert-butoxycarbonylamino)phenylamino)-2-(methylsulfonyl)pyrimidine-5-carboxylate

干燥的反应瓶中，加入 4-(3- (叔丁氧羰基氨基)苯氨基 )-2- (曱硫基) 嘧啶 -5-甲酸乙酯 (6 g， 14.8 mmol) , 二氯甲烷 300 mL, 水水浴下，加入间氯过氧苯甲酸 (7.66 g, 44.4 mmol) , 反应升至室温，室温下反应 1小时，加入饱和碳酸氢钠水溶液淬灭，二氯甲烷萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩得白色固体粗品 6.3 g, 直接用于下一步反应。 Add 4-(3-(tert-Butoxycarbonylamino)phenylamino)-2-(indolyl)pyrimidine-5-carboxylic acid ethyl ester (6 g, 14.8 mmol) to dichloromethane (300 mL) The mixture was stirred in a water-bath, and the mixture was stirred at room temperature for 1 hour. The mixture was washed with brine, dried over anhydrous sodium sulfate

(2) 4-(3- (叔丁氧羰基氨基)笨氨基 )-2-(6- (二甲氨基) p比啶 -3-基氨基) 嘧啶 -5-甲酸乙酯的制备 (2) Preparation of ethyl 4-(3-(tert-butoxycarbonylamino)phenylamino)-2-(6-(dimethylamino) p-pyridin-3-ylamino)pyrimidine-5-carboxylate

干燥的反应瓶中，加入 4-(3- (叔丁氧羰基氨基)苯氨基 )-2- (甲磺酰基) 嘧啶 -5-甲酸乙酯的粗品 6.3 g，叔戊醇 200 mL, N²,?^-二曱基吡啶 -2,5- 二胺 (2.23 g, 16.3 mmol), 三氟醋酸（1.69 g， 14.8 mmol), 110°C下反应 16小时，浓缩，过硅胶柱 (石油醚一石油醚：乙酸乙酯 =2: 1)得黄色固体 3.1 g, 上述两步的收率为 42.4%。 In a dry reaction flask, add 6.3 g of crude ethyl 4-(3-(tert-butoxycarbonylamino)phenylamino)-2-(methylsulfonyl)pyrimidine-5-carboxylate, tert-amyl alcohol 200 mL, N ² ,?^-dimercaptopyridine-2,5- The diamine (2.23 g, 16.3 mmol), trifluoroacetic acid (1.69 g, 14.8 mmol), was reacted at 110 ° C for 16 hours, concentrated, and passed through a silica gel column ( petroleum ether: petroleum ether: ethyl acetate = 2:1) The yellow solid was 3.1 g, and the yield of the above two steps was 42.4%.

(3) 3-(2-(6- (二曱氨基) p比啶 -3-基氨基 )-5- (羟曱基)嘧啶 -4-基氨基)苯基氨基曱酸叔丁酯的制备 (3) Preparation of tert-butyl 3-(2-(6-(diamino)p-pyridin-3-ylamino)-5-(hydroxyindenyl)pyrimidin-4-ylamino)phenylaminodecanoate

干燥的反应瓶中，加入 4-(3- (叔丁氧羰基氨基)苯氨基 )-2-(6- (二甲氨基)吡啶 -3-基氨基)嘧啶 -5-甲酸乙酯 (3.1 g, 6.28 mmol), 加入四氢呋喃 lOO mL溶解， -78 下分批加入四氢锂铝固体（1.19 g, 31.3 mmol), 温度緩慢升至室温后继续反应 5 小时，加入十水硫酸钠固体淬灭，充分搅拌后过滤，滤饼用乙酸乙酯洗涤，浓缩滤液，过硅胶柱 (石油醚一石油瞇：乙酸乙酯 =1.5: 1)，得到浅黄色固体 2.4 g, 收率 84.7%。 Add 4-(3-(tert-Butoxycarbonylamino)phenylamino)-2-(6-(dimethylamino)pyridin-3-ylamino)pyrimidine-5-carboxylic acid ethyl ester (3.1 g) to a dry reaction flask , 6.28 mmol), dissolved in 100 mL of tetrahydrofuran, and added lithium tetrahydrogen aluminum solid (1.19 g, 31.3 mmol) in portions at -78. The temperature was slowly raised to room temperature, and the reaction was continued for 5 hours, and quenched with sodium sulfate decahydrate. After thoroughly stirring, the mixture was filtered, and the filtered cake was washed with ethyl acetate, and the filtrate was evaporated to silica gel column ( petroleum ether: petroleum oil: ethyl acetate = 1.5:1) to give a pale yellow solid (2.4 g, yield: 84.7%).

(4) 3-(2-(6- (二曱氨基) p比啶 -3-基氨基 )-5-曱酰基嘧啶 -4-基氨基)笨基氨基甲酸叔丁酯的制备 (4) Preparation of tert-butyl 3-(2-(6-(diamino)p-pyridin-3-ylamino)-5-nonylpyrimidin-4-ylamino)phenylaminocarbamate

干燥的反应瓶中，加入 3-(2-(6- (二曱氨基)吡啶 -3-基氨基 )-5- (羟甲基)嘧啶 -4-基氨基)苯基氨基甲酸叔丁酯 (2.4 g, 5.32 mmol), 100 mL二氯甲烷溶解，加入二氧化锰 (9.26 g， 107 mmol), 升温至 35°C反应 18小时，过滤，用二氯甲烷洗涤滤饼，旋干有机相，得黄色粗品 2.4 g，直接用于下一步反应。 In a dry reaction flask, tert-butyl 3-(2-(6-(diamino)pyridin-3-ylamino)-5-(hydroxymethyl)pyrimidin-4-ylamino)phenylcarbamate was added ( 2.4 g, 5.32 mmol), dissolved in 100 mL of dichloromethane, added manganese dioxide (9.26 g, 107 mmol), warmed to 35 ° C for 18 hours, filtered, washed with dichloromethane, and dried organic phase. A crude yellow product of 2.4 g was obtained and used directly for the next reaction.

(5) 3-(5- ((环丙基亚氛基）曱基) -2-(6- (二曱氨基) p比啶 -3-基氨基)嘧啶 -4-基氨基)苯基氨基曱酸叔

(5) 3-(5-((cyclopropylarylene)indolyl)-2-(6-(diamino)p-pyridin-3-ylamino)pyrimidin-4-ylamino)phenylamino Uncle

干燥反应瓶中，加入 3-(2-(6- (二甲氨基)吡啶 -3-基氨基 )-5-甲酰基嘧啶 -4-基氨基)苯基氨基甲酸叔丁酯的粗品 2.4 g，加入 100 mL曱醇溶解，同时加入环丙胺（1.43 g, 25 mmol)和数滴冰乙酸，室温下搅拌反应 48 小时，旋干溶剂直接用于下一步。 In a dry reaction flask, add 2.4 g of crude tert-butyl 3-(2-(6-(dimethylamino)pyridin-3-ylamino)-5-formylpyrimidin-4-ylamino)phenylcarbamate, Add 100 mL of sterol to dissolve, At the same time, cyclopropylamine (1.43 g, 25 mmol) and a few drops of glacial acetic acid were added, and the reaction was stirred at room temperature for 48 hours, and the solvent was evaporated to the next step.

(6) 3-(5- ((环丙基氨基）曱基) -2-(6- (二曱氨基) p比啶 -3-基氨基)嘧啶 -4-基氨基)苯基氨基甲酸 (6) 3-(5-((Cyclopropylamino)indolyl)-2-(6-(diguanidino)p-pyridin-3-ylamino)pyrimidin-4-ylamino)phenylcarbamic acid

向上一步反应体系中加入 100 mL干燥的四氢呋喃， -78。C下分批加入四氢锂铝固体（1.01 g, 26.6 mmol), 滴加完毕后待温度升至室温继续反应 6 小时，加入十水石克酸钠固体淬灭，过滤，滤饼用乙酸乙酯洗涤，浓缩滤液，过硅胶柱 (石油醚一石油醚：乙酸乙酯 =1 :3) , 得到浅黄色固体 1.4 g, 以上三步合计收率 53.6%。 100 mL of dry tetrahydrofuran, -78, was added to the upper one-step reaction system. Add lithium tetrahydrogen aluminum solid (1.01 g, 26.6 mmol) in portions, and then continue to react for 6 hours after the dropwise addition. Add the sodium sulphate solids to quench, filter, and filter cake with ethyl acetate. After washing, the filtrate was concentrated and dried over silica gel column ( petroleum ether: petroleum ether: ethyl acetate = 1 : 3) to give a pale yellow solid (yield: 1.4 g).

(7) 3-(3-环丙基 -7-(6- (二甲氨基)吡啶 -3-基氨基 )-2-氧代 -3，4-二氢嘧啶并 [4,5- 嘧啶- 1 (2 )-基)苯的制备 (7) 3-(3-Cyclopropyl-7-(6-(dimethylamino)pyridin-3-ylamino)-2-oxo-3,4-dihydropyrimido[4,5-pyrimidine- Preparation of 1 (2 )-yl)benzene

干燥的反应器中，加入 3-(5- ((环丙基氨基）甲基) -2-(6- (二甲氨基) 吡啶 -3-基氨基)嘧啶 -4-基氨基)苯基氨基曱酸叔丁酯（1.4 g, 2.85 mmol), 加入四氢呋喃 20 mL溶解，加入 DIEA (1.5 mL, 8.6 mmol) , 冰水浴下滴加三光气 (0.423 g, 1.43 mmol)的四氢呋喃溶液 5 mL, 滴加完毕后反应 1 小时，加入饱和碳酸氢钠溶液，二氯甲烷萃取，有机相浓缩，过硅胶柱 (石油醚一石油醚：乙酸乙酯 =1 :5) ,得白色固体 0.83 g,收率为 56.5%。 In a dry reactor, 3-(5-((cyclopropylamino)methyl)-2-(6-(dimethylamino)pyridin-3-ylamino)pyrimidin-4-ylamino)phenylamino tert-Butyl phthalate (1.4 g, 2.85 mmol), dissolved in 20 mL of tetrahydrofuran, added DIEA (1.5 mL, 8.6 mmol), and added 3 mL of phosgene (0.423 g, 1.43 mmol) in tetrahydrofuran under ice-water bath. After the addition was completed, the reaction was carried out for 1 hour, a saturated sodium hydrogencarbonate solution was added, and dichloromethane was evaporated. The organic phase was concentrated and evaporated to silica gel column ( petroleum ether: petroleum ether: ethyl acetate = 1:5) to give white solids: It is 56.5%.

(8) 1 -(3-氨基苯基) -3-环丙基 -7-(6- (二甲氨基) p比啶 -3-基氨基 )-3,4- 二氢嘧啶并 [4,5- 嘧啶 -2( 1 -酮的制备 (8) 1-(3-Aminophenyl)-3-cyclopropyl-7-(6-(dimethylamino)p-pyridin-3-ylamino)-3,4-dihydropyrimido[4, Preparation of 5-pyrimidine-2 (1-ketone)

干燥的反应瓶中，加入 3-(3-环丙基 -7-(6- (二甲氨基）吡啶 -3-基氨基) -2-氧代 -3,4-二氢嘧啶并 [4,5-^]嘧啶 -1(2//)-基)苯基氨基甲酸叔丁酯 (0.83 g, 1.61 mmol) , 二氯曱烷 10 mL和三氟醋酸 10 mL, 冰水浴下搅拌 1小时，浓缩旋干，直接用于下一步反应。 In a dry reaction flask, 3-(3-cyclopropyl-7-(6-(dimethylamino)pyridin-3-ylamino)-2-oxo-3,4-dihydropyrimidine [4, 4-^]pyrimidine-1(2//)-yl)phenylcarbamic acid tert-butyl ester (0.83 g, 1.61 mmol), dichloromethane (10 mL) and trifluoroacetic acid 10 mL, stirred in ice water bath Mix for 1 hour, concentrate and spin dry, and use directly for the next reaction.

(9) N-(3-(3-环丙基 -7-(6- (二甲氨基）吡啶 -3-基氨基 )-2-氧代 -3,4-二氢嘧啶并 [4,5-t ]嘧啶 -1(2//)- 制备 (9) N-(3-(3-Cyclopropyl-7-(6-(dimethylamino)pyridin-3-ylamino)-2-oxo-3,4-dihydropyrimido[4,5 -t ]pyrimidine-1(2//)- preparation

将上步得到的粗品用 20 mL四氢呋喃溶解，用 DIEA调 pH至 9-10 , 水水浴下滴加入丙烯酰氯（146 mg， 1.61 mmol), 滴加完毕后反应 0.5小时，停止反应后，加入曱醇淬灭，拌样过硅胶柱（乙酸乙酯)得到粗品黄色粉末 330 mg, 制备液相纯化（曱醇：水 =70%)得黄色粉末状固体，用乙酸乙酯 /***混合溶剂重结晶，得黄色固体 91 mg ,两步收率为 11.8%。 The crude product obtained in the previous step was dissolved in 20 mL of tetrahydrofuran, adjusted to pH 9-10 with DIEA, and acryloyl chloride (146 mg, 1.61 mmol) was added dropwise to the water bath. After the completion of the dropwise addition, the reaction was carried out for 0.5 hour. The alcohol was quenched, and the mixture was applied to a silica gel column (ethyl acetate) to obtain a crude yellow powder (yield: 330 mg), which was purified by liquid phase (methanol: water = 70%) to obtain a yellow powdery solid which was recrystallized from ethyl acetate/diethyl ether. , a yellow solid 91 mg was obtained in a two step yield of 11.8%.

分子式： C₂₅H₂₆N₈0₂ 分子量： 470.22 质谱（m/e ): 471.2 lH^MR(CDCl₃, 400 MHz, 5ppm): 7.99 (IH, s)， 7.94 (IH, s), 7.72 (IH, s), 7.61 ( IH, s), 7.51 -7.37 (3H, m), 7.00 (IH, d), 6.64 ( IH, s), 6.39 (IH, dd), 6.32-6.24 (IH, m), 6.19 (I H, dd), 5.74 (I H, d), 4.41 (2H, s), 3.00 (6H, s), 2.74-2.65 (I H, m), 0.93-0.85 (2H, m), 0.79-0.72 (2H, m). Molecular formula: C ₂₅ H ₂₆ N ₈ 0 ₂ Molecular weight: 470.22 Mass spectrum (m/e ): 471.2 lH^MR (CDCl ₃ , 400 MHz, 5 ppm): 7.99 (IH, s), 7.94 (IH, s), 7.72 ( IH, s), 7.61 ( IH, s), 7.51 -7.37 (3H, m), 7.00 (IH, d), 6.64 ( IH, s), 6.39 (IH, dd), 6.32-6.24 (IH, m) , 6.19 (IH, dd), 5.74 (IH, d), 4.41 (2H, s), 3.00 (6H, s), 2.74-2.65 (IH, m), 0.93-0.85 (2H, m), 0.79-0.72 (2H, m).

实施例 9 4-(4-(8-(3-丙烯跣氨基苯基) -7-氧代 -6- - (吡咯烷 -1-基) 乙基) -5,6,7,8-四氢嘧啶并【4,5-^1嘧啶 -2-基氨基)苯氧基 V-甲基吡啶 -2- 曱酰胺 (化合物 9)的制备 Example 9 4-(4-(8-(3-Propylaminophenyl)-7-oxo-6-(pyrrolidin-1-yl)ethyl)-5,6,7,8-tetra Preparation of Hydropyrimido[4,5-^1pyrimidin-2-ylamino)phenoxy V-methylpyridine-2-carboxamide (Compound 9)

( 1 ) 4-(3- (叔丁氧羰基氨基)苯氨基 )-2- (曱磺酰基)嘧啶 -5-甲酸乙的制备 (1) Preparation of 4-(3-(tert-butoxycarbonylamino)phenylamino)-2-(indolyl)pyrimidine-5-carboxylic acid

干燥的反应瓶中，加入 4-(3- (叔丁氧羰基氨基)苯氨基 )-2- (甲硫基) 嘧啶 -5-甲酸乙酯 (6 g, 14.8 mmol)，二氯甲烷 300 mL，冰水浴下，加入间氯过氧苯甲酸 (7.66 g, 44.4 mmol), 反应升至室温，室温下反应 1 小时，加入饱和碳酸氢钠水溶液淬灭，二氯甲烷萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩得白色固体粗品 6.3 g，直接用于下一步反应。 ( 2 )4-(3- (叔丁氧羰基氨基)苯氨基 )-2-(4-(2- (曱基氨基曱酰基) p比啶 -4-基氧基)苯氨基)嘧啶 - -甲酸乙酯的制备 To a dry reaction flask, add ethyl 4-(3-(tert-butoxycarbonylamino)phenylamino)-2-(methylthio)pyrimidine-5-carboxylate (6 g, 14.8 mmol), m. Add the m-chloroperoxybenzoic acid (7.66 g, 44.4 mmol), and then react to room temperature, and react at room temperature for 1 hour, quench with saturated aqueous sodium hydrogencarbonate, extract with dichloromethane, and then The mixture was washed with brine, dried over anhydrous sodium sulfate (2) 4-(3-(tert-Butoxycarbonylamino)phenylamino)-2-(4-(2-(indolylaminodecanoyl)p-pyridin-4-yloxy)phenylamino)pyrimidine- - Preparation of ethyl formate

干燥的反应瓶中，加入 4-(3- (叔丁氧羰基氨基)苯氨基 )-2- (曱磺酰基) 嘧啶 -5-曱酸乙酯的粗品 6.3 g, 叔戊醇 200 mL, 4-(4-氨基苯氧基) 甲基吡啶 -2-甲酰胺 (3.97 g, 16.3 mmol), 三氟醋酸（1.69 g， 14.8 mmol), 110°C下反应 12小时，浓缩，过硅胶柱 (石油醚一石油醚：乙酸乙酯 =1 :2) 得黄色固体 3.85 g, 上述两步的收率为 43.4%。 In a dry reaction flask, add 6.3 g of crude 4-(3-(tert-butoxycarbonylamino)phenylamino)-2-(indolyl) pyrimidine-5-decanoate, tert-amyl alcohol 200 mL, 4 -(4-Aminophenoxy)methylpyridine-2-carboxamide (3.97 g, 16.3 mmol), trifluoroacetic acid (1.69 g, 14.8 mmol), mp. Petroleum ether- petroleum ether: ethyl acetate = 1:2) gave 3.85 g of a yellow solid. The yield of the above two steps was 43.4%.

( 3 ) 3-(5- (羟曱基) -2-(4-(2- (曱基氨基甲酰基) p比啶 -4-基氧基)笨氨基)嘧啶 -4-基氨基)苯基 (3) 3-(5-(Hydroxymethyl)-2-(4-(2-(decylcarbamoyl) p-pyridin-4-yloxy)phenylaminopyrimidin-4-ylamino)benzene Base

干燥的反应瓶中，加入 4-(3- (叔丁氧羰基氨基)苯氨基 )-2-(4-(2- (甲基氨基甲酰基）吡啶 -4-基氧基）笨氨基）嘧啶 -5-甲酸乙酯 (3.85 g, 6.42 mmol), 加入四氢呋喃 100 mL溶解， -78°C下分批加入四氢锂铝固体 (1.22 g, 32.1 mmol), 温度緩慢升至室温后继续反应 3小时，加入十水硫酸钠固体淬灭，充分搅拌后过滤，滤饼用乙酸乙酯洗涤，浓缩滤液，过硅胶柱（100%乙酸乙酯），得到类白色固体 2.8 g, 收率 78.2%。 In a dry reaction flask, 4-(3-(tert-butoxycarbonylamino)phenylamino)-2-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenylamino)pyrimidine was added. -5-ethyl formate (3.85 g, 6.42 mmol), dissolved in 100 mL of tetrahydrofuran, and added lithium tetrahydrogen aluminum solid (1.22 g, 32.1 mmol) in portions at -78 ° C. The temperature was slowly raised to room temperature and the reaction was continued. The mixture was quenched with EtOAc EtOAc (EtOAc)EtOAc.

( 4 ) 3-(5-曱酰基 -2-(4-(2- (曱基氨基甲酰基)吡啶 -4-基氧基)苯氨基) 嘧啶 -4-基氨基)苯基氨基 (4) 3-(5-decanoyl-2-(4-(2-(indolylcarbamoyl)pyridine-4-yloxy)phenylamino)pyrimidin-4-ylamino)phenylamino

干燥的反应瓶中，加入 3-(5- (羟曱基) -2-(4-(2- (曱基氨基曱酰基)吡啶 -4-基氧基)苯氨基)嘧啶 -4-基氨基)苯基氨基曱酸叔丁酯 (2.8 g, 5.02 mmol), 100 mL二氯甲烷溶解，加入二氧化锰 (8.73 g， 100.5 mmol), 升温至 35°C反应 48小时，过滤，用二氯甲烷洗涤滤饼，旋干有机相，得浅黄色粗品 2.8 g，直接用于下一步反应。 In a dry reaction flask, add 3-(5-(hydroxyindenyl)-2-(4-(2-(indolylaminodecanoyl)pyridin-4-yloxy)phenylamino)pyrimidin-4-ylamino tert-Butyl phenylaminodecanoate (2.8 g, 5.02 mmol), dissolved in 100 mL of dichloromethane, and added manganese dioxide (8.73 g, 100.5 mmol). The mixture was warmed to 35 ° C for 48 hours, filtered, and the filter cake was washed with dichloromethane, and the organic phase was evaporated to give 2.8 g of pale yellow crude material which was directly used for the next reaction.

( 5 ) 3-(2-(4-(2- (甲基氨基曱酰基)吡啶 -4-基氧基)苯氨基 )-5-((2-(P比咯烷 -1-基）乙基亚氨基）甲基)嘧啶 -4-基氨基)苯基氨基曱酸叔丁酯的制备 (5) 3-(2-(4-(2-(methylaminodecanoyl)pyridin-4-yloxy)phenylamino)-5-((2-(P-pyrrolidin-1-yl)) Preparation of tert-butyl (meth)amino)methyl)pyrimidin-4-ylamino)phenylaminodecanoate

干燥反应瓶中，加入 3-(5-甲酰基 -2-(4-(2- (甲基氨基甲酰基)吡啶 -4- 基氧基)苯氨基)嘧啶 -4-基氨基)苯基氨基甲酸叔丁酯的粗品 2.8 g, 加入 100 mL甲醇溶解，同时加入 2- (吡咯烷 -1-基）乙胺 (2.86 g, 25 mmol)和数滴水乙酸，室温下搅拌反应 48小时，旋干溶剂直接用于下一步。 In a dry reaction flask, 3-(5-formyl-2-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenylamino)pyrimidin-4-ylamino)phenylamino The crude product of tert-butyl formate was 2.8 g, dissolved in 100 mL of methanol, and 2-(pyrrolidin-1-yl)ethylamine (2.86 g, 25 mmol) and a few drops of acetic acid were added, and the reaction was stirred at room temperature for 48 hours, and dried. The solvent was used directly in the next step.

( 6 ) 3-(2-(4-(2- (甲基氨基甲酰基)吡啶 -4-基氧基)苯氨基 )-5-((2- (吡咯烷- 1 -基）乙氨基)曱基 -4-基氨基)苯基氨基甲酸叔丁酯的制备 (6) 3-(2-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenylamino)-5-((2-(pyrrolidin-1-yl)ethylamino) Preparation of tert-butyl mercapto-4-ylamino)phenylcarbamate

向上一步反应体系中加入 100 mL干燥的四氢呋喃， -78°C下分批加入四氢锂铝固体 (0.954 g, 25.1 mmol), 滴加完毕后待温度升至室温继续反应 4 小时，加入十水硫酸钠固体淬灭，过滤，滤饼用乙酸乙酯洗涤，浓缩滤液，过硅胶柱（乙酸乙酯：甲醇 =100: 1)，得到浅黄色固体 1.1 g, 以上三步合计收率 33.5%。 100 mL of dry tetrahydrofuran was added to the upper reaction system, and lithium tetrahydrogen aluminum solid (0.954 g, 25.1 mmol) was added in portions at -78 ° C. After the completion of the dropwise addition, the reaction was allowed to proceed to room temperature for 4 hours, and 10 water was added. The sodium sulphate solid was quenched, filtered, and the filtered cake was washed with ethyl acetate. The filtrate was concentrated and evaporated to silica gel column (ethyl acetate:methanol = 100:1) to give a pale yellow solid (1.1 g).

( 7 ) 3-(7-(4-(2- (甲基氨基甲酰基)吡啶 -4-基氧基)苯氨基 )-2-氧代 -3-(2- (吡咯烷 -1-基）乙基) -3,4-二氢嘧啶并 [4,5-if]嘧啶 -1(2 )-基）苯基氨基甲酸叔丁酯的制备

(7) 3-(7-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenylamino)-2-oxo-3-(2-(pyrrolidin-1-yl) Preparation of tert-butyl ester of ethyl)-3,4-dihydropyrimido[4,5-if]pyrimidin-1(2)-yl)phenylcarbamate

干燥的反应器中，加入 3-(2-(4-(2- (甲基氨基甲酰基)吡啶 -4-基氧基) 苯氨基 )-5-((2- (吡咯烷 -1-基）乙氨基）甲基)嘧啶 -4-基氨基)苯基氨基甲酸叔丁酯（1.1 g, 1.68 mmol)，加入四氢呋喃 15 mL溶解，加入 DIEA (650 mg, 5.03 mmol), ；水水浴下滴加三光气 (0.249 g, 0.84 mmol)的四氢呋喃溶液 5 mL, 滴加完毕后反应 1小时，加入甲醇，浓缩，过硅胶柱（乙酸乙酯），得白色固体 0.33 g, 收率为 28.9%。 In a dry reactor, 3-(2-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenylamino)-5-((2-(pyrrolidin-1-yl)) tert-Butyl ethylamino)methyl)pyrimidin-4-ylamino)phenylcarbamate (1.1 g, 1.68 mmol), dissolved in 15 mL of tetrahydrofuran, added DIEA (650 mg, 5.03 mmol); 5 mL of a solution of triphosgene (0.249 g, 0.84 mmol) in tetrahydrofuran was added. After the dropwise addition, the mixture was reacted for 1 hour, then methanol was added, and the mixture was concentrated to give a white solid (0.33 g,yield: 28.9%).

( 8 ) 4-(4-(8-(3-氨基苯基 )-7-氧代 -6-(2-(吡咯烷小基）乙基) -5，6,7，8-四氢嘧啶并 [4,5- ]嘧啶 -2-基氨基)苯氧基) 甲基吡啶 -2-甲酰胺的制备 (8) 4-(4-(8-(3-Aminophenyl)-7-oxo-6-(2-(pyrrolidinyl)ethyl)-5,6,7,8-tetrahydropyrimidine Preparation of [4,5-]pyrimidin-2-ylamino)phenoxy)methylpyridine-2-carboxamide

干燥的反应瓶中，加入 3-(7-(4-(2- (甲基氨基曱酰基)吡啶 -4-基氧基) 苯氨基 )-2-氧代 -3-(2-(P比咯烷 -1 -基）乙基) -3,4-二氢嘧啶并 [4,5-c ]嘧啶 - 1(2//)-基)苯基氨基甲酸叔丁酯 (0.33 g, 0.485 mmol), 二氯甲烷 5 mL和三氟醋酸 5mL, 水水浴下搅拌 2小时，浓缩旋千溶剂，直接用于下一步反应。 In a dry reaction flask, 3-(7-(4-(2-(methylaminodecanoyl)pyridin-4-yloxy)phenylamino)-2-oxo-3-(2-(P ratio) R-Alkyl-1 -yl)ethyl)-3,4-dihydropyrimido[4,5-c]pyrimidine- 1(2//)-yl)phenylcarbamic acid tert-butyl ester (0.33 g, 0.485 mmol 5 mL of dichloromethane and 5 mL of trifluoroacetic acid were stirred in a water bath for 2 hours, and the solvent was concentrated and used directly for the next reaction.

( 9 ) 4-(4-(8-(3-丙烯酰氨基苯基) -7-氧代 -6-(2- (吡咯烷 - 1 -基）乙基) -5，6,7，8-四氢嘧啶并 [4,5- ^嘧啶 -2-基氨基）苯氧基) 甲基吡啶 -2-甲酰胺的制备 (9) 4-(4-(8-(3-acrylamidophenyl)-7-oxo-6-(2-(pyrrolidin-1-yl)ethyl)-5,6,7,8 -Preparation of tetrahydropyrimido[4,5-pyrimidin-2-ylamino)phenoxy)methylpyridine-2-carboxamide

将上步得到的粗品用 5 mL四氢呋喃溶解，用 DIEA调 pH至 9-10, ；氷水浴下滴加入丙烯酰氯 (44 mg, 0.486 mmol), 滴加完毕后反应 0.5小时，停止反应后，加入甲醇淬灭，高压制备液相純化（乙腈：水 =60%) 得黄色粉末状固体 11 mg, 两步收率为 3.6%。

The crude product obtained in the previous step was dissolved in 5 mL of tetrahydrofuran, and the pH was adjusted to 9-10 with DIEA. The acryloyl chloride (44 mg, 0.486 mmol) was added dropwise in an ice water bath, and the reaction was completed for 0.5 hour after the completion of the dropwise addition. The methanol was quenched and purified by high pressure (yield: acetonitrile: water = 60%) to afford 11 mg as a yellow powdery solid.

分子式： C₃₄H₃₅N₉0₄ 分子量： 633.28 质谱（M+H ): 634.3Molecular formula: C ₃₄ H ₃₅ N ₉ 0 ₄ Molecular weight: 633.28 Mass spectrometry (M+H ): 634.3

^-NMRC^-DMSO, 400 MHz, 5ppm): δ 10.25 (IH, s), 9.60 (IH, s), 8.76 (IH, q), 8.46 (1H， d), 8.20 (IH, s), 7.68 (IH, s), 7.62 (IH, d), 7.43 (IH, t), 7.41-7.35 (2H， m), 7.29 (IH, d), 7.03 (1H， dd), 6.99 (1H， d)， 6.79 (2H, d), 6.33 (IH, dd), 6.13 (IH, dd), 5.64 (IH, dd), 4.58 (2H, s), 2.77 (3H, d), 2.69-2.62 (4H, m), 2.34-2.29 (4H, m), 1.76-1.68 (4H, m), 1.49-1.40 (4H m). ^-NMRC^-DMSO, 400 MHz, 5 ppm): δ 10.25 (IH, s), 9.60 (IH, s), 8.76 (IH, q), 8.46 (1H, d), 8.20 (IH, s), 7.68 (IH, s), 7.62 (IH, d), 7.43 (IH, t), 7.41-7.35 (2H, m), 7.29 (IH, d), 7.03 (1H, dd), 6.99 (1H, d), 6.79 (2H, d), 6.33 (IH, dd), 6.13 (IH, dd), 5.64 (IH, dd), 4.58 (2H, s), 2.77 (3H, d), 2.69-2.62 (4H, m) , 2.34-2.29 (4H, m), 1.76-1.68 (4H, m), 1.49-1.40 (4H m).

实施例 10 4-ί4-(8-(3-丙烯酰氨基苯基 V7-氧代 -6-ί2-ί2-氧代吡咯烷 -1-基）乙基) -5,6,7,8-四氢嘧啶并『4,5-rf]嘧啶 -2-基氨基)苯氧基 )- V-曱 Example 10 4-ί4-(8-(3-acrylamidophenyl V7-oxo-6-ί2-ί2-oxopyrrolidin-1-yl)ethyl)-5,6,7,8- Tetrahydropyrimido-[4,5-rf]pyrimidin-2-ylamino)phenoxy)-V-曱

-2-甲酰胺 (化合物 10)的制备 Preparation of 2-formamide (Compound 10)

( 1 ) 2-(2-氧代吡咯烷 -1-基）备

干燥反应瓶中，加入 20 mL无水乙腈， N,N-二甲基甲酰胺 (0.876 g, 12 mmol), 维持 0。C, 向体系中緩慢加入三氯氧磷 (1.69 g, 11 mmol), 继续搅拌 1 小时，分批加入 2-(2-氧代吡咯烷小基）乙酰胺 (1.42 g, 10 mmol),升温至 50 °C反应 3小时，冷却至 0°C,緩慢加入吡啶 (1.74 g, 22 mmol), 搅拌 20分钟后加入 l mL浓盐酸，向反应液中加水，分出有机相，水相二氯曱烷萃取三次，合并有机相，用饱和食盐水洗涤，干燥，浓缩，得到黄色粗品 1.4 g, 直接用于下一步反应。 (1) 2-(2-oxopyrrolidin-1-yl)

Dry the reaction flask and add 20 mL of anhydrous acetonitrile, N,N-dimethylformamide (0.876 g, 12 mmol). C, slowly add phosphorus oxychloride (1.69 g, 11 mmol) to the system, continue stirring for 1 hour, add 2-(2-oxopyrrolidine small) acetamide (1.42 g, 10 mmol) in portions, and heat up. The reaction was carried out at 50 ° C for 3 hours, cooled to 0 ° C, and pyridine (1.74 g, 22 mmol) was slowly added. After stirring for 20 minutes, 1 mL of concentrated hydrochloric acid was added, water was added to the reaction mixture, and the organic phase was separated. The decane was extracted three times, and the organic layer was combined, washed with brine, dried and evaporated

( 2 ) 1-(2-氨基乙基)吡咯 -2-酮盐酸盐的制备

(2) Preparation of 1-(2-aminoethyl)pyrrol-2-one hydrochloride

向上一步得到的粗品 1.4 g中加入 10 mL甲醇，加入 1 g雷尼镍，之后緩慢滴加含有硼氢化钠 (0.76 g, 20 mmol)的 8 M氢氧化钠水溶液 (2.5 mL, 20 mmol), 室温下反应 2小时，过滤，滤饼用少许甲醇洗涤一次，滤液浓缩，得到的白色固体加入到 20 mL***中，滴加盐酸的异丙醇溶液，调 pH至 5左右，过滤，滤饼干燥，得到的产品直接用于下一步反应。 10 g of methanol was added to the crude product obtained in the previous step, 10 mL of methanol was added, 1 g of Raney nickel was added, and then an aqueous solution of sodium borohydride (0.76 g, 20 mmol) in 8 M sodium hydroxide (2.5 mL, 20 mmol) was slowly added dropwise. The reaction was carried out for 2 hours at room temperature, filtered, and the filter cake was washed once with a little methanol. The filtrate was concentrated, and the obtained white solid was added to 20 mL of diethyl ether. The solution of hydrochloric acid in isopropanol was added dropwise, the pH was adjusted to about 5, filtered, and the filter cake was dried. , the obtained product is directly used for the next reaction.

( 3 ) 3-(2- (甲硫基) -5-((2-(2-氧代吡咯烷 -1-基）乙基亚氨基）曱基) 嘧啶 -4-基氨基)苯基甲酸叔 (3) 3-(2-(Methylthio)-5-((2-(2-oxopyrrolidin-1-yl)ethylimino)indolyl)pyrimidin-4-ylamino)phenylcarboxylic acid uncle

千燥反应瓶中 , 加入 3-(5-曱酰基 -2- (曱硫基)嘧啶 -4-基氨基)苯基氨基甲酸叔丁酯 (3.6 g, 10.0 mmol), 加入 50 mL甲醇溶解，同时加入上一步得到的粗品和乙酸钠 (0.82 g, 10.0 mmol), 室温下搅拌反应 48小时，旋干溶剂直接用于下一步。 In a dry reaction flask, tert-butyl 3-(5-nonanoyl-2-(indolyl)pyrimidin-4-ylamino)phenylcarbamate (3.6 g, 10.0 mmol) was added and dissolved in 50 mL of methanol. The crude product obtained in the previous step and sodium acetate (0.82 g, 10.0 mmol) were added at the same time, and the reaction was stirred at room temperature for 48 hours, and the solvent was evaporated to the next step.

( 4 ) 3-(2-(曱硫基) -5-((2-(2-氧代吡咯烷- 1 -基）乙氨基）甲基)嘧啶 -4- 基氨基)苯基甲酸叔丁酯的制备

(4) 3-(2-(Indolylthio)-5-((2-(2-oxopyrrolidine-1-yl)ethylamino)methyl)pyrimidin-4-ylamino)phenylcarboxylic acid tert-butyl Preparation of ester

向上一步反应体系中加入 50 mL干燥的四氢呋喃，水水浴下分批加入硼氢化钠（1.9 g, 50 mmol), 室温反应 12小时后，继续补加硼氢化钠 (3.8 g， 0. 1 mol)，继续反应 72小时，加入 50 mL甲醇，浓缩，过硅胶柱（100%乙酸乙酯），得到浅黄色固体 1.6 g, 四步合计收率 33.9%。 50 mL of dry tetrahydrofuran was added to the reaction system, and sodium borohydride (1.9 g, 50 mmol) was added in a water bath. After reacting for 12 hours at room temperature, sodium borohydride (3.8 g, 0.1 mol) was further added. The reaction was continued for 72 hours, 50 mL of methanol was added, and the mixture was concentrated and evaporated to silica gel column (100% ethyl acetate) to afford 1.6 g of pale yellow solid.

( 5 ) 3-(7- (甲硫基) -2-氧代 -3-(2-(2-氧代 p比咯烷 -1 -基）乙基) -3,4-二氢嘧啶并 [4,5-d]嘧啶 - 1(2//)-基) 制备 (5) 3-(7-(Methylthio)-2-oxo-3-(2-(2-oxo-p-rrolidin-1-yl)ethyl)-3,4-dihydropyrimidine [4,5-d]pyrimidine-1 (2//)-yl) Preparation

干燥的反应器中，加入 3-(2- (甲硫基) -5-((2-(2-氧代吡咯烷 -1-基）乙氨基）甲基)嘧啶 -4-基氨基)苯基甲酸叔丁酯（1.6 g, 3.39 mmol),加入四氢呋喃 30 mL溶解，加入 DIEA (1.31 g, 10.1 mmol), 冰水浴下滴加三光气 (0.505 g， 1.7 mmol)的四氢呋喃溶液 10 mL, 滴加完毕后反应 1小时，加入饱和碳酸氢钠溶液，二氯甲烷萃取，浓缩有机相，过硅胶柱（100% 乙酸乙酯），得浅黄色固体 1.03 g, 收率为 61.1 %。 In a dry reactor, 3-(2-(methylthio)-5-((2-(2-oxopyrrolidin-1-yl)ethylamino)methyl)pyrimidin-4-ylamino)benzene was added. Tert-butyl carboxylic acid (1.6 g, 3.39 mmol), dissolved in 30 mL of tetrahydrofuran, added DIEA (1.31 g, 10.1 mmol), and added 10 mL of triphosgene (0.505 g, 1.7 mmol) in tetrahydrofuran under ice-water bath. After the addition was completed, the reaction was carried out for 1 hour, and then a saturated aqueous solution of sodium hydrogencarbonate and dichloromethane was evaporated, and the organic layer was evaporated to silica gel column (100% ethyl acetate).

( 6 ) 3-(7- (甲基磺酰基 )-2-氧代 -3-(2-(2-氧代吡咯垸 -1-基）乙基) -3,4- 二氢嘧啶并 [4，5-d]嘧啶 -1(2/ -基)笨基甲酸叔丁酯的制备 (6) 3-(7-(Methylsulfonyl)-2-oxo-3-(2-(2-oxopyrrolidin-1-yl)ethyl)-3,4-dihydropyrimido[ Preparation of 4,5-d]pyrimidine-1(2/-yl)-tert-butyl tert-butylate

干燥的反应瓶中，加入 3-(7- (曱硫基) -2-氧代 -3-(2-(2-氧代吡咯烷 -1- 基）乙基) -3,4-二氢嘧啶并 [4,5-d]嘧啶 - 1(2A 基)苯基甲酸叔丁酯（1.03 g, 2.07 mmol), 二氯甲烷 20 mL，；水水浴下，加入间氯过氧苯曱酸 (1.07 g, 6.2 mmol), 反应 2小时，加入饱和碳酸氢钠水溶液，二氯曱烷萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩得白色固体粗品 1.1 g, 直接用于下一步反应。 In a dry reaction flask, 3-(7-(indolylthio)-2-oxo-3-(2-(2-oxopyrrolidin-1-yl)ethyl)-3,4-dihydrogen was added. Pyrimido[4,5-d]pyrimidin- 1 (2A)phenylcarboxylic acid tert-butyl ester (1.03 g, 2.07 mmol), dichloromethane 20 mL, water-water bath, m-chloroperoxybenzoic acid ( 1.07 g, 6.2 mmol), EtOAc (2 mL, EtOAc, m. The crude product 1.1 g was used directly in the next reaction.

( 7 ) 3-(7-(4-(2- (曱基氨基甲酰基)吡啶 -4-基氧基)苯氨基 )-2-氧代 -3-(2-(2-氧代吡咯烷 - 1-基）乙基) -3,4-二氢嘧啶并 [4,5-d]嘧啶 -1(2//)-基) 苯基氨基甲酸叔丁酯的 (7) 3-(7-(4-(2-(Mercaptocarbamoyl)pyridin-4-yloxy)phenylamino)-2-oxo-3-(2-(2-oxopyrrolidine) -1-yl)ethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2//)-yl) tert-butyl phenylcarbamate

千燥的反应瓶中，加入上步的得到的粗品 1.1 g, 叔戊醇 20 mL, 4-(4-氨基苯氧基; V-曱基吡啶 -2-甲酰胺 (0.553 g, 2.27 mmol), 三氟醋酸 (0.236 g, 2.07 mmol), 110°C下反应 12小时，浓缩，过硅胶柱 (二氯甲烷:甲醇 =30: 1 )得黄色固体 0.35 g, 上述两步的收率为 24.3%。 In a dry reaction flask, add 1.1 g of the crude product obtained in the previous step, 20 mL of tert-amyl alcohol, 4-(4-aminophenoxy; V-decylpyridin-2-carboxamide (0.553 g, 2.27 mmol) Trifluoroacetic acid (0.236 g, 2.07 mmol), was reacted at 110 ° C for 12 hours, concentrated, and passed through a silica gel column (dichloromethane:methanol = 30:1) to give a yellow solid (0.35 g). %.

( 8 ) 4-(4-(8-(3-氨基苯基) -7-氧代 -6-(2-(2-氧代吡咯烷 -1-基）乙基) -5,6，7，8-四氢嘧啶并 [4,5-d]嘧啶 -2-基氨基)苯氧基) 曱基吡啶 -2-甲酰胺的制备 (8) 4-(4-(8-(3-Aminophenyl)-7-oxo-6-(2-(2-oxopyrrolidin-1-yl)ethyl)-5,6,7 Of 8-(4-hydropyrimido[4,5-d]pyrimidin-2-ylamino)phenoxy)mercaptopyridine-2-carboxamide

千燥的反应瓶中，加入 3-(7-(4-(2- (曱基氨基甲酰基)吡啶 -4-基氧基) 苯氨基 )-2-氧代 -3-(2-(2-氧代吡咯烷 - 1-基）乙基) -3,4-二氢嘧啶并 [4,5-d] 嘧啶 -1(2/ )-基)苯基氨基甲酸叔丁酯 (0.35 g, 0.504 mmol), 二氯甲烷 5 mL和三氟醋酸 5 mL，水水浴下搅拌 1小时，浓缩旋干，直接用于下一步反应。 In a dry reaction flask, 3-(7-(4-(2-(decylcarbamoyl)pyridin-4-yloxy)phenylamino)-2-oxo-3-(2-(2) -oxopyrrolidino-1-yl)ethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2/)-yl)phenylcarbamic acid tert-butyl ester (0.35 g, 0.504 mmol), 5 mL of dichloromethane and 5 mL of trifluoroacetic acid were stirred in water and water for 1 hour, concentrated and dried, and used directly for the next reaction.

( 9 ) 4-(4-(8-(3-丙烯酰氨基苯基) -7-氧代 -6-(2-(2-氧代吡咯烷 - 1-基) 乙基) -5,6,7,8-四氢嘧啶并 [4,5-d]嘧啶 -2-基氨基）苯氧基) 甲基吡啶 -2- 甲酰胺的制备将上步得到的粗品溶于 N-甲基吡咯烷酮 10 mL，用 DIEA调 pH至 9-10, -10。C下滴加入丙烯酰氯 (46 mg, 0.508 mmol), 滴加完毕后反应 1小时，继续补加丙烯酰氯 (46 mg, 0.508 mmol), LC-MS显示反应完全后，加入甲醇淬灭，浓缩体系，过硅胶柱 (二氯甲烷:甲醇 =30:1)得黄色固体，用甲醇洗涤，干燥，得黄色粉末状固体 85 mg, 两步收率为 26%。 (9) 4-(4-(8-(3-acrylamidophenyl)-7-oxo-6-(2-(2-oxopyrrolidin-1-yl)ethyl)-5,6 Of 7,7-tetrahydropyrimido[4,5-d]pyrimidin-2-ylamino)phenoxy)methylpyridine-2-carboxamide The crude product obtained in the previous step was dissolved in 10 mL of N-methylpyrrolidone, and the pH was adjusted to 9-10, -10 with DIEA. Acryloyl chloride (46 mg, 0.508 mmol) was added dropwise to C. After the dropwise addition, the reaction was continued for 1 hour, and acryloyl chloride (46 mg, 0.508 mmol) was further added. After LC-MS showed that the reaction was completed, it was quenched with methanol and concentrated. A silica gel column (dichloromethane:methanol = 30:1) was obtained as a yellow solid.

分子式： C₃₄H₃₃N₉0₅ 分子量： 647.26 质谱（M+H): 648.3Molecular formula: C ₃₄ H ₃₃ N ₉ 0 ₅ Molecular weight: 647.26 Mass spectrometry (M+H): 648.3

^-NMRC^-DMSO, 400 MHz, 5ppm): δ 10.25 (IH, s), 9.60 (IH, s), 8.76 (IH, q), 8.45 (IH, d), 8.21 (IH, s), 7.68-7.60 (2H, m)， 7.43 (IH, t), 7.41-7.34 (2H, m), 7.29 (IH, d), 7.02 (IH, dd), 6.94 (IH, d), 6.78 (2H, d), 6.32 (IH, dd), 6.12 (IH, dd), 5.63 (IH, dd), 4.57 (2H, s), 3.56 (2H, t)， 3.46 (2H, t), 3.39 (2H, t), 2.77 (3H, d), 2.16 (2H, t), 1.85 (2H, quintet). ^-NMRC^-DMSO, 400 MHz, 5 ppm): δ 10.25 (IH, s), 9.60 (IH, s), 8.76 (IH, q), 8.45 (IH, d), 8.21 (IH, s), 7.68 -7.60 (2H, m), 7.43 (IH, t), 7.41-7.34 (2H, m), 7.29 (IH, d), 7.02 (IH, dd), 6.94 (IH, d), 6.78 (2H, d ), 6.32 (IH, dd), 6.12 (IH, dd), 5.63 (IH, dd), 4.57 (2H, s), 3.56 (2H, t), 3.46 (2H, t), 3.39 (2H, t) , 2.77 (3H, d), 2.16 (2H, t), 1.85 (2H, quintet).

实施例 11 7Υ-ί3-ί3-环丙基甲基 -1 吡唑 -4-基氨基 )-2-氧代 -3,4-二氢嘧啶并【4,5-<f嘧啶 -1(2^-基)苯基)丙烯酰胺 (化合物 11)的制备 Example 11 7Υ-ί3-ί3-cyclopropylmethyl-1pyrazol-4-ylamino)-2-oxo-3,4-dihydropyrimido[4,5-<f-pyrimidine-1 (2 Preparation of ^-yl)phenyl)acrylamide (Compound 11)

( 1 ) 3-(3-环丙基 -7-(l-甲基吡唑 -4-基氨基 )-2-氧代 -3,4-二氢嘧啶并 [4,5- 嘧啶 -1(2//)-基)苯基氨基曱酸叔丁酯的制备 (1) 3-(3-Cyclopropyl-7-(l-methylpyrazol-4-ylamino)-2-oxo-3,4-dihydropyrimido[4,5-pyrimidine-1 ( Preparation of 2//)-yl)phenylaminodecanoic acid tert-butyl ester

干燥的反应瓶中，加入 3-(3-环丙基 -7- (甲磺酰基) -2-氧代 -3,4-二氢嘧啶并 [4,5-d]嘧啶 -1(2 )-基)苯基氨基甲酸叔丁酯（0.46 g, l.Ommol) 和 1-甲基吡唑 -4胺（117mg, 1.20 mmol), 用 20mL叔戊醇溶解，加入三氟醋酸（0.114 g, l.Ommol), 100°C油浴中回流反应 4小时，停止反应，冷却至室温后，减压浓缩柱层析（PE:EA=1:2)得到 0.4 g淡黄色固体，收率为 83.9 %。 In a dry reaction flask, add 3-(3-cyclopropyl-7-(methylsulfonyl)-2-oxo-3,4-dihydro Pyrimido[4,5-d]pyrimidin-1(2)-yl)phenylcarbamic acid tert-butyl ester (0.46 g, 1.0 mmol) and 1-methylpyrazol-4amine (117 mg, 1.20 mmol), Dissolve with 20 mL of tert-amyl alcohol, add trifluoroacetic acid (0.114 g, 1.0 mmol), reflux in a 100 ° C oil bath for 4 hours, stop the reaction, cool to room temperature, and concentrate under reduced pressure column chromatography (PE: EA = 1:2) 0.4 g of a pale yellow solid was obtained with a yield of 83.9%.

(2) 1-(3-氨基苯基) -3-环丙基 -7-(1-曱基吡唑 -4-基氨基 )-3，4- 二氢嘧啶并 [4,5-ί]嘧啶 -2(1/ -酮的制备 (2) 1-(3-Aminophenyl)-3-cyclopropyl-7-(1-indolylpyrazol-4-ylamino)-3,4-dihydropyrimido[4,5-ί] Preparation of pyrimidine-2 (1/ketone)

干燥的反应瓶中，加入 3-(3-环丙基 -7-(1-曱基吡唑 -4-基氨基) -2-氧代 -3,4-二氢嘧啶并 [4,5- 嘧啶 -1(2 /)-基)苯基氨基甲酸叔丁酯 (0.40g, 0.839 mmol), 用 20.0 mL二氯甲烷溶解，在冰浴下滴加三氟乙酸 10.0 mL, 滴加完毕，室温继续搅拌，在 TLC检测下原料反应完全后，停止反应，然后减压浓缩，所得油状物直接用于下一步反应。 In a dry reaction flask, 3-(3-cyclopropyl-7-(1-mercaptopyrazole-4-ylamino)-2-oxo-3,4-dihydropyrimido[4,5- Pyrimidine-1(2/)-yl)phenylcarbamic acid tert-butyl ester (0.40 g, 0.839 mmol), dissolved in 20.0 mL of dichloromethane, 10.0 mL of trifluoroacetic acid was added dropwise in an ice bath, and the addition was completed at room temperature. Stirring was continued. After the reaction of the starting material was completed by TLC, the reaction was stopped, then concentrated under reduced pressure, and the obtained oil was directly used for the next reaction.

( 3 )V-(3-(3-环丙基 -7-(1-曱基吡唑 -4-基氨基 )-2-氧代 -3,4-二氢嘧啶并 [4,5- 嘧啶 - 1 (2 )-基) 备 (3) V-(3-(3-Cyclopropyl-7-(1-indolylpyrazol-4-ylamino)-2-oxo-3,4-dihydropyrimido[4,5-pyrimidine - 1 (2)-base)

干燥的反应瓶中加入上步得到的粗品，加入四氢呋喃 15 mL, 用 DIEA调 pH至 9-10， 0 °C下滴加入丙烯酰氯（ 152 mg， 1.678 mmol), 滴加完毕后继续反应 15 min, 停止反应后，加入甲醇淬灭，硅胶柱层析（ 100%EA), 得淡黄色粉末状固体，用曱醇和***洗固体得到白色固体 120mg, 两步收率为 33.2%。 Add the crude product obtained in the above step to a dry reaction flask, add 15 mL of tetrahydrofuran, adjust the pH to 9-10 with DIEA, and add acryloyl chloride (152 mg, 1.678 mmol) dropwise at 0 °C. Continue the reaction for 15 min after the addition. After the reaction was quenched, the title compound was obtained from mjjjjjjjjjjjjj

分子式： C₂₂H₂₂N₈0₂ 分子量： 430.2 质谱（M+H): 431.2 ^-NMR^-DMSO, 400 MHz, 5ppm): δ 10.34 (IH, s), 9.36 (IH，s), 8.12 (IH, s), 7.78 (IH, d), 7.62 (IH, s), 7.50 (IH, t), 7.05-6.95 (2H, m)， 6.61 (IH, br), 6.42 (IH, dd), 6.24 (IH, dd), 5.75 (IH, dd), 4.42 (2H, s), 3.46 (3H, s), 2.67 (1H, m), 0.79-0.72 (2H, m), 0.72-0.64 (2H, m). Molecular formula: C ₂₂ H ₂₂ N ₈ 0 ₂ Molecular weight: 430.2 Mass (M+H): 431.2 ^-NMR^-DMSO, 400 MHz, 5 ppm): δ 10.34 (IH, s), 9.36 (IH, s), 8.12 (IH, s), 7.78 (IH, d), 7.62 (IH, s), 7.50 (IH, t), 7.05-6.95 (2H, m), 6.61 (IH, br), 6.42 (IH, dd), 6.24 (IH, dd), 5.75 (IH, dd), 4.42 (2H, s), 3.46 (3H, s), 2.67 (1H, m), 0.79-0.72 (2H, m), 0.72-0.64 (2H, m).

实施例 12 iV-i3-(3-环丙基 7-(1-甲基 -1 吡唑 -5-基氨基 )-2-氧代 - -二氢嘧啶并【4,5-^1嘧啶 -lG -基)苯基)丙烯酰胺 f化合物 12)的制备 Example 12 iV-i3-(3-cyclopropyl 7-(1-methyl-1 pyrazol-5-ylamino)-2-oxo-dihydropyrimido[4,5-^1 pyrimidine- Preparation of lG-yl)phenyl)acrylamide f compound 12)

( 1 ) 3-(3-环丙基 -7-(1-曱基吡唑 -5-基氨基 )-2-氧代 -3,4-二氢嘧啶并 [4,5- 嘧啶- 1 (2/ )-基) 酯的制备 (1) 3-(3-Cyclopropyl-7-(1-mercaptopyrazole-5-ylamino)-2-oxo-3,4-dihydropyrimido[4,5-pyrimidine- 1 ( Preparation of 2/)-yl) ester

干燥的反应瓶中，加入 1-曱基 -5-氨基吡唑（ 117 mg, 1.20 mmol), 用 20 mL四氢呋喃溶解，加入钠氢（80 mg, 2.0 mmol )在 50°C油浴中搅拌 1小时，再加入 3-(3-环丙基 -7- (甲磺酰基) -2-氧代 -3,4-二氢嘧啶并 [4,5-d]嘧啶 -1(2 )-基)苯基氨基甲酸叔丁酯（0.46 g, l.Ommol)在 100°C 油浴中回流反应 4 小时，停止反应，冷却至室温后，减压浓缩柱层析 (PE:EA=1:3 )得到 102 mg淡黄色固体，收率为 21.4 %。 In a dry reaction flask, add 1-mercapto-5-aminopyrazole (117 mg, 1.20 mmol), dissolve in 20 mL of tetrahydrofuran, add sodium hydrogen (80 mg, 2.0 mmol) and stir in a 50 ° C oil bath. In an hour, add 3-(3-cyclopropyl-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2)-yl) Tert-butyl phenylcarbamate (0.46 g, 1.0 mmol) was refluxed in an oil bath at 100 ° C for 4 hours, the reaction was stopped, cooled to room temperature, and concentrated under reduced pressure (PE: EA = 1:3) 102 mg of a pale yellow solid were obtained in a yield of 21.4%.

( 2 ) 1-(3-氨基苯基) -3-环丙基 -7-(1-曱基吡唑 -5-基氨基 )-3,4- 二氢嘧啶并 [4,5-ί/]嘧啶 -2(1 / ( 2 ) 1-(3-Aminophenyl)-3-cyclopropyl-7-(1-mercaptopyrazole-5-ylamino)-3,4-dihydropyrimido[4,5-ί/ Pyrimidine-2 (1 /

干燥的反应瓶中，加入 3-(3-环丙基 -7-(1-甲基吡唑 -5-基氨基) -2-氧代 -3,4-二氢嘧啶并 [4,5- 嘧啶 -1(2 /)-基)苯基氨基曱酸叔丁酯 ( 102 mg, 0.214 mmol), 用 10.0 mL二氯甲烷溶解，在冰浴的条件下滴加三氟乙酸 5.0 mL，滴加完毕，室温继续搅拌，在 TLC检测下原料反应完全后，停止反应，然后减压浓缩，所得油状物直接用于下一步反应。 In a dry reaction flask, add 3-(3-cyclopropyl-7-(1-methylpyrazol-5-ylamino)-2-oxo-3,4-dihydropyrimidine [4,5- Pyrimidine-1(2/)-yl)phenylaminodecanoic acid tert-butyl ester (102 mg, 0.214 mmol), dissolved in 10.0 mL dichloromethane, in ice bath 5.0 mL of trifluoroacetic acid was added dropwise, and the addition was completed. Stirring was continued at room temperature. After the reaction of the starting material was completed by TLC, the reaction was stopped, then concentrated under reduced pressure, and the obtained oil was directly used for the next reaction.

( 3 )N-(3-(3-环丙基 -7-(1-甲基吡唑 -5-基氨基 )-2-氧代 -3,4-二氢嘧啶并 [4,5- ]嘧啶 -1(2//)-基) 制备 (3) N-(3-(3-Cyclopropyl-7-(1-methylpyrazol-5-ylamino)-2-oxo-3,4-dihydropyrimido[4,5- ] Pyrimidine-1 (2//)-yl) preparation

干燥的反应瓶中加入上步得到的粗品，加入四氢呋喃 8 mL，用 DIEA调 pH至 9-10， 0 °C下滴加入丙烯酰氯（ 39 mg， 0.428 mmol ), 滴加完毕后继续反应 15 mm, 停止反应后，加入曱醇淬灭，硅胶柱层析（ 100%EA ) 得白色粉末状固体 20 mg, 两步收率为 21.7 %。 Add the crude product obtained in the above step to the dry reaction flask, add 8 mL of tetrahydrofuran, adjust the pH to 9-10 with DIEA, and add acryloyl chloride (39 mg, 0.428 mmol) dropwise at 0 °C. Continue to react 15 mm after the addition. After the reaction was stopped, it was quenched by the addition of methanol, and purified by silica gel column chromatography (100% EtOAc)

分子式： C₂₂H₂₂N₈0₂ 分子量： 430.2 质谱（M+H ): 431.2

400 MHz, 5ppm): δ 10.25 (IH, s), 9.18 (IH, br), 8.16 (IH, s), 7.66-7.56 (2H, m), 7.37 (IH, t), 7.00 (IH, br), 6.93 (IH, d), 6.42 (IH, dd), 6.23 (IH, d), 5.75 (IH, d), 5.66 (IH, s), 4.43 (2H, s), 3.53 (3H, s), 2.66 (IH, m), 0.79-0.72 (2H, m), 0.70-0.62 (2H, m). Molecular formula: C ₂₂ H ₂₂ N ₈ 0 ₂ Molecular weight: 430.2 Mass spectrometry (M+H): 431.2

400 MHz, 5ppm): δ 10.25 (IH, s), 9.18 (IH, br), 8.16 (IH, s), 7.66-7.56 (2H, m), 7.37 (IH, t), 7.00 (IH, br) , 6.93 (IH, d), 6.42 (IH, dd), 6.23 (IH, d), 5.75 (IH, d), 5.66 (IH, s), 4.43 (2H, s), 3.53 (3H, s), 2.66 (IH, m), 0.79-0.72 (2H, m), 0.70-0.62 (2H, m).

实施例 13 jV-(3-(3-环丙基 -7- (异噻唑 -5-基氨基 )-2-氧代 -3,4-二氢嘧啶并【4,5- 嘧啶 -K2^ -基)苯基)丙烯酰胺 ί化合物 13)的制备 Example 13 jV-(3-(3-cyclopropyl-7-(isothiazol-5-ylamino)-2-oxo-3,4-dihydropyrimido[4,5-pyrimidine-K2^ - Preparation of phenyl)acrylamide ί compound 13)

( 1 ) 3-(3-环丙基 -7- (异噻唑 -5-基氨基 )-2-氧代 -3，4-二氢嘧啶并 [4,5- 嘧啶 -1 (2/ )-基)苯基氨基甲酸叔丁酯的制备

(1) 3-(3-Cyclopropyl-7-(isothiazol-5-ylamino)-2-oxo-3,4-dihydropyrimido[4,5-pyrimidine-1 (2/)- Of tert-butyl phenylcarbamate

干燥反应瓶中，加入 5-氨基异噁唑 (0,504 g, 6.0 mmol) ，干燥的四氢呋喃 10 mL，室温下加入氢化钠 (60%, 0.48 g, 12.0 mmol), 氮气保护，搅拌十分钟后，升温至 50°C反应 1小时，加入 3-(3-环丙基 -7- (甲基磺酰基) -2-氧代 -3,4-二氢嘧啶并 [4,5- ]嘧啶 -1(2 )-基)苯基氨基曱酸叔丁酯（1.38 g, 3.0 mmol)， 80°C下反应 2小时，浓缩，过硅胶柱 (二氯甲烷一二氯曱烷：甲醇 =50: 1 )得黄色固体 0.483 g, 收率为 34.8%。 In a dry reaction flask, 5-aminoisoxazole (0,504 g, 6.0 mmol), 10 mL of dry tetrahydrofuran was added, and sodium hydride (60%, 0.48 g, 12.0 mmol) was added at room temperature, and the mixture was stirred for ten minutes. The temperature was raised to 50 ° C for 1 hour, and 3-(3-cyclopropyl-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimido[4,5-]pyrimidine-1 was added. (2)-Phenylaminodecanoic acid tert-butyl ester (1.38 g, 3.0 mmol), reacted at 80 ° C for 2 hours, concentrated, passed through a silica gel column (dichlorodichloromethane: methanol = 50: 1 The yellow solid was 0.483 g, and the yield was 34.8%.

( 2 ) 1-(3-氨基苯基) -3-环丙基 -7- (异噻唑 -5-基氨基 )-3,4-二氢嘧啶并 [4,5-c ]嘧啶 -2(1 )-酮的制 (2) 1-(3-Aminophenyl)-3-cyclopropyl-7-(isothiazol-5-ylamino)-3,4-dihydropyrimido[4,5-c]pyrimidine-2 ( 1)-ketone system

干燥的反应瓶中，加入 3-(3-环丙基 -7- (异噻唑 -5-基氨基 )-2-氧代 -3,4-二氢嘧啶并 [4,5-c ]嘧啶 -1(2 )-基）苯基氨基甲酸叔丁酯 (0.483 g, 1.04 mmol), 二氯甲烷 5 mL和三氟醋酸 5 mL，；水水浴下搅拌 1小时，旋干，直接用于下一步反应。 In a dry reaction flask, 3-(3-cyclopropyl-7-(isothiazol-5-ylamino)-2-oxo-3,4-dihydropyrimido[4,5-c]pyrimidine- tert-Butyl 1(2)-yl)phenylcarbamate (0.483 g, 1.04 mmol), 5 mL of dichloromethane and 5 mL of trifluoroacetic acid, stirred in water and water for 1 hour, then dried and used directly reaction.

( 3 ) N-(3-(3-环丙基 -7- (异噻唑 -5-基氨基 )-2-氧代 -3,4-二氢嘧啶并 [4,5-α]嘧啶- 1 (2/ )-基)苯基）丙 (3) N-(3-(3-Cyclopropyl-7-(isothiazol-5-ylamino)-2-oxo-3,4-dihydropyrimido[4,5-α]pyrimidine-1 (2/)-yl)phenyl)propyl

将上一步得到的粗品用 5 mL 四氢呋喃溶解，用 DIEA调 pH至 9-10 , 水水浴下滴加入丙烯酰氯（113 mg, 1.25 mmol), 滴加完毕后反应 10分钟，停止反应后，加入甲醇淬灭，制备液相纯化（甲醇：水 =50%) 得白色固体 75 mg，两步收率为 17.3%。 The crude product obtained in the previous step was dissolved in 5 mL of tetrahydrofuran, adjusted to pH 9-10 with DIEA, and acryloyl chloride (113 mg, 1.25 mmol) was added dropwise to the water bath. After the dropwise addition, the reaction was carried out for 10 minutes. After the reaction was stopped, methanol was added. Quenching, preparative liquid phase purification (methanol: water = 50%) gave a white solid, 75 mg.

分子式： C₂₁H₁₉N₇0₃ 分子量： 417.2 质谱（M+H ): 472.2 ^-NM^^-DMSO, 400 MHz, 5ppm): δ 11.13 (1H, s)， 10.27 (1H, s), 8.28 (IH, s)， 7.99 (IH, d), 7.67 (IH, d), 7.62 (IH, m)， 7.44 (IH, t), 6.99 (IH, d), 6.41 (1H， dd), 6.23 (IH, dd), 5.75 (IH, dd), 5.12 (IH, s), 4.49 (2H, s), 2.72-2.62 (IH, m), 0.80-0.73 (2H, m), 0.72-0.63 (2H, m). Molecular formula: C ₂₁ H ₁₉ N ₇ 0 ₃ Molecular weight: 417.2 Mass spectrum (M+H): 472.2^-NM^^-DMSO, 400 MHz, 5 ppm): δ 11.13 (1H, s), 10.27 (1H, s), 8.28 (IH, s), 7.99 (IH, d), 7.67 (IH, d), 7.62 (IH, m), 7.44 (IH, t), 6.99 (IH, d), 6.41 (1H, dd), 6.23 (IH, dd), 5.75 (IH, dd), 5.12 (IH, s), 4.49 (2H, s), 2.72-2.62 (IH, m), 0.80-0.73 (2H, m), 0.72-0.63 (2H , m).

实施例 14 7V-i3-(3-环丙基 1-7- (异噁唑 -4-基氨基 )-2-氧代 -3,4-二氢嘧啶并【4,5- ^嘧啶 -U2^ -基)苯基)丙烯酰胺 f化合物 14)的制备 Example 14 7V-i3-(3-cyclopropyl 1-7-(isoxazol-4-ylamino)-2-oxo-3,4-dihydropyrimido[4,5--pyrimidine-U2 Preparation of ^-yl)phenyl)acrylamide f compound 14)

4-硝基异噁唑的制备

Preparation of 4-nitroisoxazole

干燥的反应瓶中，加入异噁唑（5.01 g, 72.5 mmol )和三氟乙酸酐 ( 53.3 g, 253.8 mmol ), 在水浴下分批慢慢加入硝酸铵（ 8.99 g, 112.4 mmol ), 加完室温搅拌 4h , 然后向体系加入水，二氯甲烷萃取水相，干燥并浓缩有机相柱层析 (PE:EA=5: 1)純化得到淡黄色固体 1.05 g，收率为 12.7%。 In a dry reaction flask, add isoxazole (5.01 g, 72.5 mmol) and trifluoroacetic anhydride (53.3 g, 253.8 mmol), and gradually add ammonium nitrate (8.99 g, 112.4 mmol) in a water bath. After stirring at room temperature for 4 hours, water was added to the mixture, and the aqueous layer was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

( 2 )异噁唑 -4-胺的制备

(2) Preparation of isoxazole-4-amine

干燥的反应瓶中，加入 4-硝基异噁唑（1.05 g， 9.20 mmol )和氯化铵（9.84 g, 184 mmol )加入水 70 mL, 冰浴下慢慢加入锌粉（ 5.98 g, 91.4 mmol ), 加完毕后 0°C搅拌过夜，过滤掉锌粉，用 EA萃取氷相，干燥并浓缩有机相得到 0.4 g暗红色油状物，收率为 51.7%。 In a dry reaction flask, add 4-nitroisoxazole (1.05 g, 9.20 mmol) and ammonium chloride (9.84 g, 184 mmol) to 70 mL of water. Slowly add zinc powder (5.98 g, 91.4) in an ice bath. After the addition, the mixture was stirred at 0 ° C overnight, the zinc powder was filtered off, the ice phase was extracted with EA, and the organic phase was dried and concentrated to give 0.4 g of dark red oil, yield 51.7%.

( 3 ) 3-(3-环丙基 -7- (甲基磺酰基 )-2-氧代 -3,4-二氢嘧啶并 [4,5- 嘧啶- 1 (2 )-基)笨基氨基曱酸叔丁酯的制备 P T/CN2013/001555

(3) 3-(3-Cyclopropyl-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimido[4,5-pyrimidin-1(2)-yl) Preparation of tert-butyl aminoguanate PT/CN2013/001555

干燥的反应瓶中，加入 3-(3-环丙基 -7- (甲硫基) -2-氧代 -3,4-二氢嘧啶并 [4,5-d]嘧啶 -1(2 /)-基)苯基氨基曱酸叔丁酯 (5.0 g, 11.7 mmol), 二氯甲烷和曱醇各 50 mL, 水水浴下加入间氯过氧苯甲酸（6.04 g, 35.1 mmol ), 加完升至室温反应 2 小时，停止反应，减压浓缩，柱层析 (PE:EA=1:2) 得到 4.01 g淡黄色固体, 收率为 74.6%。 In a dry reaction flask, add 3-(3-cyclopropyl-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidine-1 (2 / Tert-butyl p-phenylaminodecanoate (5.0 g, 11.7 mmol), 50 mL each of dichloromethane and methanol, and m-chloroperoxybenzoic acid (6.04 g, 35.1 mmol) The mixture was allowed to react to room temperature for 2 hours, and the reaction was quenched. EtOAc (EtOAc:EtOAc:EtOAc:

(4 ) 3-(3-环丙基 -7- (异噁唑 -4-基氨基 )-2-氧代 -3，4-二氢嘧啶并 (4) 3-(3-Cyclopropyl-7-(isoxazol-4-ylamino)-2-oxo-3,4-dihydropyrimidine

[4,5- 嘧啶- 1 (2 )-基)苯基氨备 [4,5-pyrimidine-1 (2)-yl)phenylamine

干燥的反应瓶中，加入 3-(3-环丙基 -7- (甲基磺酰基 )-2-氧代 -3,4-二氢嘧啶并 [4,5- 嘧啶 -1(2 /)-基)苯基氨基甲酸叔丁酯（ 0.46 g, l.Ommol ) 和异噁唑 -4-胺（ 101 mg, 1.20 mmol), 用 20 mL叔戊醇溶解，然后加入三氟醋酸（0.114 g, l.Ommol), 100 °C油浴中回流反应 12小时，停止反应，冷却至室温后，减压浓缩柱层析（PE:EA=1:2)得到 0.24g淡黄色固体，收率为 51.8%。 In a dry reaction flask, add 3-(3-cyclopropyl-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimido[4,5-pyrimidine-1 (2 /) Tert-butyl phenylcarbamate (0.46 g, 1.0 mmol) and isoxazol-4-amine (101 mg, 1.20 mmol), dissolved in 20 mL of tert-amyl alcohol, then trifluoroacetic acid (0.114 g) , l.Ommol), refluxing in a 100 ° C oil bath for 12 hours, the reaction was stopped, cooled to room temperature, and concentrated under reduced pressure column chromatography (PE: EA = 1:2) to give 0.24 g of pale yellow solid. 51.8%.

( 5 ) 1-(3-氨基苯基) -3-环丙基 -7- (异噁唑 -4-基氨基 )-3,4-二氢嘧啶并 [4,5-c ]嘧啶 -2(1/)-酮的制备 (5) 1-(3-Aminophenyl)-3-cyclopropyl-7-(isoxazol-4-ylamino)-3,4-dihydropyrimido[4,5-c]pyrimidine-2 Preparation of (1/)-ketone

千燥的反应瓶中，加入 3-(3-环丙基 -7- (异噁唑 -4-基氨基 )-2-氧代 -3,4-二氢嘧啶并 [4,5- 嘧啶 -1(2//)-基)苯基氨基曱酸叔丁酯 (0.24 g, 0.518 mmol), 用 20.0 mL二氯甲烷溶解，在;水浴的条件下滴加三氟乙酸 10.0 mL, 滴加完毕，室温搅拌，在 TLC检测下原料反应完全后，停止反应，然后减压浓缩，所得油状物直接用于下一步反应。 In a dry reaction flask, add 3-(3-cyclopropyl-7-(isoxazol-4-ylamino)-2-oxo-3,4-dihydropyrimido[4,5-pyrimidine- 1(2//)-yl) tert-butyl phenylaminodecanoate (0.24 g, 0.518 mmol), dissolved in 20.0 mL of dichloromethane, 10.0 mL of trifluoroacetic acid was added dropwise in a water bath, and the addition was completed. After stirring at room temperature, after the reaction of the starting material was completed by TLC, the reaction was stopped, then concentrated under reduced pressure, and the obtained oil was directly used for the next reaction.

( 6 ) N-(3-(3-环丙基 1-7- (异噁唑 -4-基氨基 )-2-氧代 -3,4-二氢嘧啶并 [4,5-c ]嘧啶- 1 (2//)-基)苯基）丙 (6) N-(3-(3-Cyclopropyl 1-7-(isoxazol-4-ylamino)-2-oxo-3,4-dihydropyrimidine [4,5-c ]pyrimidine-1 (2//)-yl)phenyl)propyl

干燥的反应瓶中加入上步得到的粗品，加入四氢呋喃 20 mL, 用 DIEA调 pH至 9-10, 0 °C下滴加入丙烯酰氯（ 94 mg, 1.04 mmol ), 滴加完毕后继续反应 15 min, 停止反应后，加入甲醇淬灭，拌样，制备液相纯化（甲醇 /水 =45% )得淡黄色粉末状固体 120 mg, 两步收率为 55.4%。 Add the crude product obtained in the above step to the dry reaction flask, add 20 mL of tetrahydrofuran, adjust the pH to 9-10 with DIEA, add acryloyl chloride (94 mg, 1.04 mmol) dropwise at 0 °C, continue the reaction for 15 min after the addition. After the reaction was stopped, it was quenched by the addition of methanol, and the mixture was mixed and purified by liquid phase (methanol/water = 45%) to obtain a pale yellow powdery solid 120 mg. The yield in two steps was 55.4%.

分子式： C₂₁H₁₉N₇0₃ 分子量： 417.2 质谱（M+H ): 418.2 ^-NMRC^-DMSO, 400 MHz, : δ 10.33 (IH, s), 9.60 (IH, br), 8.30-8.15 (2H, m), 7.72 (IH, br), 7.67 (IH, d), 7.60-7.51 (IH, m), 7.48 (IH t), 7.00 (IH, d), 6.41 (IH, dd), 6.23 (IH, dd), 5.75 (IH, dd), 4.45 (2H, s),Molecular formula: C ₂₁ H ₁₉ N ₇ 0 ₃ Molecular weight: 417.2 Mass spectrum (M+H): 418.2 ^-NMRC^-DMSO, 400 MHz, : δ 10.33 (IH, s), 9.60 (IH, br), 8.30-8.15 (2H, m), 7.72 (IH, br), 7.67 (IH, d), 7.60-7.51 (IH, m), 7.48 (IH t), 7.00 (IH, d), 6.41 (IH, dd), 6.23 (IH, dd), 5.75 (IH, dd), 4.45 (2H, s),

2.67 (IH, m), 0.80-0.71 (2H, m), 0.71-0.65 (2H， m). 2.67 (IH, m), 0.80-0.71 (2H, m), 0.71-0.65 (2H, m).

实施例 15 A^3-(3-环丙基 -7- 6-曱氧基吡啶 -3-基)（甲基)氨基) -2- 氧代 -3,4-二氢嘧啶并 i4,5-dl嘧啶 -K2iy)-基)苯基）丙烯酜胺 (化合物 15) 的制备 Example 15 A^3-(3-cyclopropyl-7-6-methoxypyridin-3-yl)(methyl)amino)-2-oxo-3,4-dihydropyrimidine and i4,5 Preparation of -dl-pyrimidine-K2iy)-yl)phenyl)propenylamine (Compound 15)

( 1 ) 6-甲氧基 -N-曱基吡啶 -3-胺的制备 (1) Preparation of 6-methoxy-N-mercaptopyridine-3-amine

干燥反应瓶中，加入 10 mL 无水四氢呋喃和二异丙基胺（1.01 g, 10.0 mmol), -78。C下滴加正丁基锂的己烷溶液（2.4 M, 4.16 mL, 10.0 mmol),搅拌十分钟后，冰水浴继续搅拌二十分钟，再次降温至 -78。C ，加入 6-曱氧基 -3-氨基吡啶（1.24 g， 10.0 mmol)的四氢呋喃溶液 10 mL, 升温至 0。C反应 1小时，再次降温至 -78 。C, 滴加碘曱烷（1.42 g， 10.0 mmol), 保持 -78 °C反应 2小时，之后緩慢升至室温继续反应 18小时，加入饱和氯化铵溶液淬灭反应，乙酸乙酯萃取三次，合并有机相，干燥，浓缩，过硅胶柱 (石油醚一石油醚：乙酸乙酯 =10: 1)得椋红色油状物 0.31 g, 收率为 22.5%。 Dry the reaction flask and add 10 mL of anhydrous tetrahydrofuran and diisopropylamine (1.01 g, 10.0 mmol), -78. A solution of n-butyllithium in hexane (2.4 M, 4.16 mL, 10.0 mmol) was added dropwise over C. After stirring for ten minutes, the ice water bath was further stirred for twenty minutes and then cooled again to -78. C, adding 10 mL of 6-decyloxy-3-aminopyridine (1.24 g, 10.0 mmol) in tetrahydrofuran, Warm up to 0. C reacted for 1 hour and cooled again to -78. C, dropwise addition of iododecane (1.42 g, 10.0 mmol), maintaining the reaction at -78 °C for 2 hours, then slowly increasing to room temperature and continuing the reaction for 18 hours. The reaction was quenched by the addition of a saturated The organic phase was combined, dried and evaporated tolulululululululululululululululululululu

( 2 ) 3-(3-环丙基 -7-((6-甲氧基吡啶 -3-基 )(甲基)氨基) -2-氧代 -3,4- 二氢嘧啶并 [4，5-d]嘧啶 -1(2 丁酯的制备 (2) 3-(3-Cyclopropyl-7-((6-methoxypyridin-3-yl)(methyl)amino)-2-oxo-3,4-dihydropyrimido[4, Preparation of 5-d]pyrimidine-1 (2 butyl ester)

干燥反应瓶中，加入 3-(3-环丙基 -7- (曱基磺酰基 )-2-氧代 -3,4-二氢嘧啶并 [4,5-ί ]嘧啶 -1(2//)-基)苯基氨基甲酸叔丁酯 (0.937 g, 2.04 mmol), 叔戊醇 20 mL， 6-甲氧基曱基吡啶 -3-胺 (0.31 g, 2.25 mmol), 三氟醋酸 (0.233 g, 2.04 mmol), 110 °C下反应 12小时，浓缩，过硅胶柱 (石油醚一石油醚：乙酸乙酯 =1 :2)得深红色油状物 0.39 g, 收率为 37%。 In a dry reaction flask, 3-(3-cyclopropyl-7-(indolylsulfonyl)-2-oxo-3,4-dihydropyrimido[4,5-ί]pyrimidine-1 (2/) was added. /)-yl) tert-butyl phenylcarbamate (0.937 g, 2.04 mmol), tert-amyl alcohol 20 mL, 6-methoxymercaptopyridine-3-amine (0.31 g, 2.25 mmol), trifluoroacetic acid ( The reaction was carried out for 12 hours at 110 ° C. EtOAc (EtOAc:EtOAc)

( 3 ) 1 -(3-氨基苯基) -3-环丙基 -7-((6-甲氧基吡啶 -3-基)（甲基)氨基) -3,4-二氢嘧啶并 [4,5-d] -2(1 )-酮的制备 (3) 1-(3-Aminophenyl)-3-cyclopropyl-7-((6-methoxypyridin-3-yl)(methyl)amino)-3,4-dihydropyrimido[ Preparation of 4,5-d]-2(1)-one

干燥的反应瓶中，加入 3-(3-环丙基 -7-((6-甲氧基吡啶 -3-基 )（曱基) 氨基) -2-氧代 -3,4-二氢嘧啶并 [4,5-d]嘧啶 -1(2/ )-基)苯基氨基曱酸叔丁酯 (0.39 g, 0.754 mmol), 二氯曱烷 5 mL和三氟醋酸 5 mL, 冰水浴下搅拌 1小时，浓缩旋干，直接用于下一步反应。 In a dry reaction flask, 3-(3-cyclopropyl-7-((6-methoxypyridin-3-yl)(indolyl)amino)-2-oxo-3,4-dihydropyrimidine was added. And [4,5-d]pyrimidin-1(2/)-yl)phenylaminodecanoic acid tert-butyl ester (0.39 g, 0.754 mmol), dichloromethane 5 mL and trifluoroacetic acid 5 mL, ice water bath Stir for 1 hour, concentrate and spin dry, and use directly for the next reaction.

( ) ΛΚ3-(3-环丙基 -7-((6-甲氧基吡啶 -3-基)（曱基)氨基) -2-氧代 ( ) 3-(3-cyclopropyl-7-((6-methoxypyridin-3-yl)(fluorenyl)amino)-2-oxo

-3,4-二氢嘧啶并 [4,5-d]嘧啶 - -基)笨基）丙烯酰胺的制备 Preparation of -3,4-dihydropyrimido[4,5-d]pyrimidin-yl)phenyl)acrylamide

将上一步得到的粗品用 10 mL四氢呋喃溶解，用 DIEA调 pH至 9-10, 水水浴下滴加入丙烯酰氯 (82 mg, 0.905 mmol), 滴加完毕后反应 1小时，停止反应后，加入甲醇淬灭，过硅胶柱（100%石油醚一石油醚：乙酸乙酯 =1 :3)得浅黄色固体 70 mg，两步收率为 19.6%。 The crude product obtained in the previous step was dissolved in 10 mL of tetrahydrofuran, and the pH was adjusted with DIEA. 9-10, acryloyl chloride (82 mg, 0.905 mmol) was added dropwise to the water bath, and the reaction was completed for 1 hour after the completion of the dropwise addition. After the reaction was stopped, the mixture was quenched with methanol, and passed through a silica gel column (100% petroleum ether- petroleum ether: acetic acid Ester = 1 : 3) gave a pale yellow solid (yield: 70 mg).

分子式： C₂₅H₂₅N₇0₃ 分子量： 471.2 质谱（M+H ): 472.2 ^-NMR^-DMSO, 400 MHz, 6ppm): δ 10.19 (IH, s), 8.09 (IH, s), 7.92 (IH, d), 7.57 (1H， t), 7.53 (IH, d), 7.46 (IH, dd), 7.29 (IH, t), 6.85 (IH, d), 6.53 (IH, d), 6.42 (IH, dd), 6.23 (IH, dd), 5.75 (IH, dd), 4.39 (2H s), 3.77 (3H, s), 3.16 (3H, s), 2.70-2.61 (IH, m), 0.78-0.71 (2H, m), 0.68-0.61 (2H, m). Molecular formula: C ₂₅ H ₂₅ N ₇ 0 ₃ Molecular weight: 471.2 Mass spectrum (M+H): 472.2^-NMR^-DMSO, 400 MHz, 6 ppm): δ 10.19 (IH, s), 8.09 (IH, s), 7.92 (IH, d), 7.57 (1H, t), 7.53 (IH, d), 7.46 (IH, dd), 7.29 (IH, t), 6.85 (IH, d), 6.53 (IH, d), 6.42 ( IH, dd), 6.23 (IH, dd), 5.75 (IH, dd), 4.39 (2H s), 3.77 (3H, s), 3.16 (3H, s), 2.70-2.61 (IH, m), 0.78- 0.71 (2H, m), 0.68-0.61 (2H, m).

实施例 16 V-O- -环丙基 -7-(5-甲氧基吡啶 -2-基氨基 )-2-氧代 -3,4-二氢嘧啶并【4,5-rfl嘧啶 -1(2^)-基)苯基)丙烯酰胺 ί化合物 16)的制备 Example 16 VO--cyclopropyl-7-(5-methoxypyridin-2-ylamino)-2-oxo-3,4-dihydropyrimido[4,5-rfl-pyrimidine-1 (2 Preparation of ^)-yl)phenyl)acrylamide ί compound 16)

( 1 ) 3-(3-环丙基 -7-(5-甲氧基吡啶 -2-基氨基 )-2-氧代 -3,4-二氢嘧啶并 [4,5- ]嘧啶 -1(2 )-基)苯基氨基甲酸叔丁酯的制备 (1) 3-(3-Cyclopropyl-7-(5-methoxypyridin-2-ylamino)-2-oxo-3,4-dihydropyrimido[4,5-]pyrimidine-1 Preparation of (2)-yl)phenylcarbamic acid tert-butyl ester

干燥反应瓶中，加入 5-曱氧基吡啶 -2-胺 (0.149 g, 1.2 mmol) ，干燥的四氢呋喃 10 mL，室温下加入氢化钠（60%, 96 mg, 2.4 mmol)，氮气保护，升温至 60。C反应 1 小时，加入 3-(3-环丙基 -7- (甲基磺酰基 )-2- 氧代 -3,4-二氢嘧啶并 [4,5- ]嘧啶 -1(2 )-基)苯基氨基甲酸叔丁酯 (0.551 g, 1.2 mmol), 80°C下反应 2小时，浓缩，过硅胶柱 (二氯曱烷一二氯甲烷：甲醇 =100: 1)得黄色固体 0.23 g, 进一步制备液相纯化（甲醇：水 =60%)得白色固体 0.14 g，收率为 23.2%。 Dry the reaction flask, add 5-methoxypyridin-2-amine (0.149 g, 1.2 mmol), dry 10 mL of tetrahydrofuran, add sodium hydride (60%, 96 mg, 2.4 mmol) at room temperature, protect with nitrogen, warm To 60. C reaction for 1 hour, adding 3-(3-cyclopropyl-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimido[4,5-]pyrimidin-1(2)- Tert-butyl phenylcarbamate (0.551 g, 1.2 mmol), was reacted at 80 ° C for 2 hours, concentrated, and purified by silica gel column (dichloromethane-dichloromethane:methanol = 100:1) g, Further preparative liquid phase purification (methanol: water = 60%) gave a white solid, 0.14 g, yield 23.2%.

( 2 )1-(3-氨基苯基) -3-环丙基 -7-(5-曱氧基吡啶 -2-基氨基 )-3,4-二氢嘧啶并 [4,5-0嘧啶 -2(1/ )- (2) 1-(3-Aminophenyl)-3-cyclopropyl-7-(5-decyloxypyridin-2-ylamino)-3,4-dihydro Pyrimido[4,5-0 pyrimidine-2(1/)-

千燥的反应瓶中，加入 3-(3-环丙基 -7-(5-甲氧基吡啶 -2-基氨基 )-2- 氧代 -3,4-二氢嘧啶并 [4,5- 嘧啶 -1(2 /)-基)苯基氨基曱酸叔丁酯 (0.14 g, 0.278 mmol) , 二氯曱烷 4 mL和三氟醋酸 3 mL, 冰水浴下搅拌 1小时，旋干，直接用于下一步反应。 In a dry reaction flask, add 3-(3-cyclopropyl-7-(5-methoxypyridin-2-ylamino)-2-oxo-3,4-dihydropyrimidine [4,5 - pyrimidine-1 (2 /)-yl) phenylaminodecanoic acid tert-butyl ester (0.14 g, 0.278 mmol), 4 mL of dichloromethane and 3 mL of trifluoroacetic acid, stirred for 1 hour in ice-water bath, and dried. Used directly in the next step.

( 3 )N-(3-(3-环丙基 -7-(5-曱氧基吡啶 -2-基氨基 )-2-氧代 -3,4-二氢嘧啶并 [4,5-d]嘧啶- 1 (2 )-基)苯 (3) N-(3-(3-Cyclopropyl-7-(5-decyloxypyridin-2-ylamino)-2-oxo-3,4-dihydropyrimido[4,5-d Pyrimidine-1 (2)-yl)benzene

将上一步得到的粗品用 5 mL四氢呋喃溶解，用 DIEA调 pH至 The crude product obtained in the previous step was dissolved in 5 mL of tetrahydrofuran, and the pH was adjusted with DIEA.

9-10, 水水浴下滴加入丙烯酰氯 (30 mg, 0.334 mmol)，滴加完毕后反应 10分钟，停止反应后，加入甲醇淬灭，旋干反应液得到黄色粗品，甲醇洗涤，过滤，滤饼干燥得到浅黄色固体 45 mg，两步收率为 35.3%。 9-10, acryloyl chloride (30 mg, 0.334 mmol) was added dropwise to the water bath. After the completion of the dropwise addition, the reaction was carried out for 10 minutes. After the reaction was stopped, the mixture was quenched with methanol, and the reaction mixture was evaporated to give a crude yellow product, washed with methanol, filtered and filtered. The cake was dried to give a pale yellow solid of 45 mg.

分子式： C₂₄H₂₃N₇0₃ 分子量： 457.2 质谱（M+H ): 458.2 'H-NMR^-DMSO, 400 MHz, 6ppm): δ 10.30 (IH, s), 9.39 (IH, s),Molecular formula: C ₂₄ H ₂₃ N ₇ 0 ₃ Molecular weight: 457.2 Mass spectrum (M+H): 458.2 'H-NMR^-DMSO, 400 MHz, 6 ppm): δ 10.30 (IH, s), 9.39 (IH, s),

8.20 ( IH, s), 7.85 (IH, d), 7.75 (IH, d)， 7.60 ( IH, s), 7.46 (IH, t), 7.22 (IH, d), 6.98 (IH, d), 6.77 (IH, dd), 6.41 (IH, dd), 6.23 (IH, dd), 5.74 (IH, dd), 4.46 (2H, s), 3.70 (3H, s), 2.72-2.63 (IH, m), 0.81 -0.72 (2H, m), 0.72-0.65 (2H, m). 8.20 ( IH, s), 7.85 (IH, d), 7.75 (IH, d), 7.60 ( IH, s), 7.46 (IH, t), 7.22 (IH, d), 6.98 (IH, d), 6.77 (IH, dd), 6.41 (IH, dd), 6.23 (IH, dd), 5.74 (IH, dd), 4.46 (2H, s), 3.70 (3H, s), 2.72-2.63 (IH, m), 0.81 -0.72 (2H, m), 0.72-0.65 (2H, m).

实施例 17 ； V-(3-(3-环丙基 -7- (噁唑 -2-基氨基 )-2-氧代 -3,4-二氢嘧啶并 i4,5-ffl嘧啶 -1 (2 -基)苯基)丙烯酰胺 (化合物 17)的制备 Example 17; V-(3-(3-cyclopropyl-7-(oxazol-2-ylamino)-2-oxo-3,4-dihydropyrimido and i4,5-ffl pyrimidine-1 ( Preparation of 2-phenyl)phenyl)acrylamide (Compound 17)

( 1 ) 3-(3-环丙基 -7- (噁唑 -2-基氨基 )-2-氧代 -3,4-二氢嘧啶并 [4,5-ί ] 嘧啶 - 1(2 / 基)苯基氨基甲酸 (1) 3-(3-Cyclopropyl-7-(oxazol-2-ylamino)-2-oxo-3,4-dihydropyrimido[4,5-ί]pyrimidine-1 (2 / Phenyl carbamate

将 168 mg (2 mmol) 2-氨基噁唑溶于 20 mL四氢呋喃中，加入 80 mg(2mmol)60^o/ 々NaH， 50°C搅拌 1.5h，加入 459 mg ( 1 mmol ) sm, 80°C反应 5h, 旋千，柱层析（DCM:MeOH=20: 1 ), 制备液相纯化得白色固体 55 mg, 收率 11.9% Dissolve 168 mg (2 mmol) of 2-aminooxazole in 20 mL of tetrahydrofuran, add 80 mg (2 mmol) of 60 ^o / 々NaH, stir at 50 °C for 1.5 h, add 459 mg (1 mmol) sm, 80 °C Reaction 5h, Cyclone, column chromatography (DCM: MeOH = 20: 1), purified in liquid phase to give a white solid, 55 mg, yield 11.9%

( 2 ) 1-(3-氨基苯基) -3-环丙基 -7- (噁唑 -2-基氨基 )-3 ,4-二氢嘧啶并 [4,5- 嘧啶 -2(1/7)-酮的制备 (2) 1-(3-Aminophenyl)-3-cyclopropyl-7-(oxazol-2-ylamino)-3,4-dihydropyrimido[4,5-pyrimidine-2 (1/ 7) Preparation of ketone

将 55 mg (0.12 mmol) 3-(3-环丙基 -7- (噁唑 -2-基氨基 )-2-氧代 -3,4- 二氢嘧啶并 [4,5- ]嘧啶 -1(2/)-基)苯基氨基曱酸叔丁酯溶于 3 mL DCM 中，加入 2 mL三氟乙酸，室温反应 4 h, TLC监测反应结束，旋干溶剂，直接用于下步反应。 55 mg (0.12 mmol) 3-(3-cyclopropyl-7-(oxazol-2-ylamino)-2-oxo-3,4-dihydropyrimido[4,5-]pyrimidine-1 (2/)-yl) tert-butyl p-phenylaminodecanoate was dissolved in 3 mL of DCM, added with 2 mL of trifluoroacetic acid, and reacted at room temperature for 4 h. The reaction was terminated by TLC. The solvent was evaporated and used directly for the next step.

( 3 ) AK3-(3-环丙基 -7- (噁唑 -2-基氨基 )-2-氧代 -3,4-二氢嘧啶并 [4,5-ί/]嘧啶- 1 (2/)-基)苯基)丙烯酰胺的制备

(3) AK3-(3-cyclopropyl-7-(oxazol-2-ylamino)-2-oxo-3,4-dihydropyrimido[4,5-ί/]pyrimidine-1 (2) Preparation of /)-yl)phenyl)acrylamide

将上步反应产物溶于 5 mL THF中，加入 65 mg ( 0.5 mmol ) DIEA, 水浴下加入 11 mg ( 0.12 mmol )丙烯酰氯，反应 0.5 h完毕。旋干溶剂，制备液相纯化得白色固体 7 mg，以上两步收率 14%。 The reaction product of the above step was dissolved in 5 mL of THF, 65 mg (0.5 mmol) of DIEA was added, and 11 mg (0.12 mmol) of acryloyl chloride was added in a water bath, and the reaction was completed for 0.5 h. The solvent was dried and the liquid phase was purified to give a white solid (yield: 7 mg).

分子式： C₂₁H₁₉N₇0₃分子量： 417.2 质谱 (M+H): 418.2 Molecular formula: C ₂₁ H ₁₉ N ₇ 0 ₃ Molecular weight: 417.2 Mass spectrometry (M+H): 418.2

^-NMRCDMSO-^, 400 MHz, 6ppm): δ 10.22 (IH, s), 10.19 (IH, s), 8.18 (IH, s), 7.63 (1H， d), 7.58 (IH, s), 7.53 (IH, s), 7.35 (IH, t), 6.96-6.91 (2H, m), 6.42 (IH, dd), 6.24 (IH, d), 5.75 (IH, d), 4.45 (2H, s), 2.69-2.61 (IH, m), 0.79-0.71 (2H, m), 0.69-0.63 (2H, m). ^-NMRC DMSO-^, 400 MHz, 6 ppm): δ 10.22 (IH, s), 10.19 (IH, s), 8.18 (IH, s), 7.63 (1H, d), 7.58 (IH, s), 7.53 ( IH, s), 7.35 (IH, t), 6.96-6.91 (2H, m), 6.42 (IH, dd), 6.24 (IH, d), 5.75 (IH, d), 4.45 (2H, s), 2.69 -2.61 (IH, m), 0.79-0.71 (2H, m), 0.69-0.63 (2H, m).

实施例 18 iV-i3-(3-环丙基 -7-ί6-曱氧基吡啶 -3-基氨基 )-2-氧代 Example 18 iV-i3-(3-cyclopropyl-7-ί6-decyloxypyridin-3-ylamino)-2-oxo

-3,4-二氢嘧啶并【4,5-^1嘧啶 -Κ2Η)-基)苯基) -4- (二甲氨基)丁 -2-烯酰胺 -3,4-dihydropyrimido[4,5-^1 pyrimidine-Κ2Η)-yl)phenyl)-4-(dimethylamino)butan-2-enamide

( 1 )1-(3-氨基苯基) -3-环丙基 -7-(6-曱氧基吡啶 -3-基氨基 )-3,4-二氢嘧啶并 [4,5- ^嘧啶 -2(1/ )-酮 (1) 1-(3-Aminophenyl)-3-cyclopropyl-7-(6-decyloxypyridin-3-ylamino)-3,4-dihydropyrimido[4,5--pyrimidine -2(1/ )-ketone

干燥的反应瓶中，加入 3-(3-环丙基 -7-(6-曱氧基吡啶 -3-基氨基 )-2- 氧代 -3,4-二氢嘧啶并 [4，5- ^嘧啶 -1(2 /)-基）苯基氨基甲酸叔丁酯 (0.504 g, 1.0 mmol), 二氯甲烷 15 mL和三氟醋酸 10 mL, 水水浴下搅拌 1小时，旋干，直接用于下一步反应。 In a dry reaction flask, 3-(3-cyclopropyl-7-(6-decyloxy-3-ylamino)-2-oxo-3,4-dihydropyrimidine [4,5- Pyrimidine-1(2/)-yl)phenyl carbamic acid tert-butyl ester (0.504 g, 1.0 mmol), dichloromethane 15 mL and trifluoroacetic acid 10 mL, stirred in water and water 1 When it is dried, it is used directly for the next reaction.

( 2 ) 4-溴丁 -2-烯酰氯的制

(2) Preparation of 4-bromobut-2-enoyl chloride

千燥的反应瓶中，加入 4-溴巴豆酸（0.165 g, 1.0 mmol), 二氯甲烷 10 mL, 滴加数滴 DMF, 室温下加入草酰氯 (0.191 g， 1.5 mmol), 室温下搅拌 1小时，浓缩旋干，直接用于下一步反应。 In a dry reaction flask, add 4-bromo crotonic acid (0.165 g, 1.0 mmol), 10 mL of dichloromethane, add a few drops of DMF, add oxalyl chloride (0.191 g, 1.5 mmol) at room temperature, stir at room temperature 1 In the hour, concentrate and spin dry and use directly for the next reaction.

( 3 ) 4-溴 - (3-(3-环丙基 -7-(6-甲氧基吡啶 -3-基氨基 )-2-氧代 -3,4- 二氢嘧啶并 [4,5- 嘧啶 -1(2 )- -2-烯酰胺的制备 (3) 4-Bromo-(3-(3-cyclopropyl-7-(6-methoxypyridin-3-ylamino)-2-oxo-3,4-dihydropyrimido[4,5 - Preparation of pyrimidine-1(2)--2-enamide

将第一步得到的 1 -(3-氨基苯基) -3-环丙基 -7-(6-曱氧基吡啶 -3-基氨基) -3,4-二氢嘧啶并 [4,5-ί/]嘧啶 -2(1//)-酮粗品用 10 mL四氢呋喃和 5 mL NMP溶解，加入 3 mL DIEA, 冰水浴下滴加入第二步反应所得 4-溴丁 -2-烯酰氯的四氢呋喃溶液 5 mL，滴加完毕后反应 30分钟，直接用于下一步反应。 1-(3-Aminophenyl)-3-cyclopropyl-7-(6-decyloxypyridin-3-ylamino)-3,4-dihydropyrimidine [4,5] obtained in the first step -ί/]pyrimidine-2(1//)-ketone crude was dissolved in 10 mL of tetrahydrofuran and 5 mL of NMP, 3 mL of DIEA was added, and the 4-bromobut-2-enoyl chloride obtained in the second step was added dropwise in an ice water bath. 5 mL of tetrahydrofuran solution was reacted for 30 minutes after the completion of the dropwise addition, and used directly for the next reaction.

( 4 ) ΛΚ3-(3-环丙基 -7-(6-曱氧基吡啶 -3-基氨基 )-2-氧代 -3,4-二氢嘧啶并 [4，5- 嘧啶 -1(2Η)-基) -4- (二甲氨基)丁 -2-烯酰胺的制备 (4) ΛΚ3-(3-Cyclopropyl-7-(6-decyloxypyridin-3-ylamino)-2-oxo-3,4-dihydropyrimido[4,5-pyrimidine-1 ( Preparation of 2Η)-yl)-4-(dimethylamino)but-2-enamide

称取二曱胺的盐酸盐 (0.816 g, 10.0 mmol)加入到上步的反应体系中，室温下反应 48小时，减压蒸出大部分溶剂，加入 100 mL乙酸乙酯，饱和食盐水洗涤三次，有机相干燥，浓缩，过硅胶柱 (二氯曱烷一二氯甲烷：甲醇 =15:1)得到浅黄色固体 115 mg, 总体收率 22.3%。 The hydrochloride salt of diammoniumamine (0.816 g, 10.0 mmol) was added to the reaction system of the previous step, and the reaction was carried out for 48 hours at room temperature. Most of the solvent was evaporated under reduced pressure, and 100 mL of ethyl acetate was added and washed with saturated brine. After three times, the organic phase was dried (EtOAc m.

分子式： C₂₇¾。N₈0₃ 分子量： 514.2 质谱（M+H ): 515.3 ^-NMR^-DMSO, 400 MHz, 5ppm): δ 10.51 (IH, s), 9.32 (IH, s), 8.16 (IH, s), 8.01 (IH, s), 7.71 (IH, d), 7.67-7.58 (2H, m), 7.43 (IH, t), 6.97 (IH, d), 6.74 (IH, dt), 6.44 (IH, d), 6.39-6.28 (IH, m), 4.43 (2H, s), 3.85-3.76 (2H, m), 3.71 (3H, s), 2.73-2.62 (7H, m), 0.80-0.72 (2H, m)， 0.72-0.63 (2H, m). 实施例 19 7V-i3-i3-环丙基 -7-ί6-甲氧基吡啶 -3-基氨基 )-2-氧代 -3,4-二氢嘧啶并【4,5- 嘧啶 - 2H 基)苯基) -4-吗啉丁 -2-烯跣胺 (化合物 Molecular formula: C ₂₇ 3⁄4. N ₈ 0 ₃ Molecular Weight: 514.2 Mass Spectrum (M+H): 515.3^-NMR^-DMSO, 400 MHz, 5 ppm): δ 10.51 (IH, s), 9.32 (IH, s), 8.16 (IH, s), 8.01 (IH, s), 7.71 (IH, d), 7.67-7.58 (2H, m), 7.43 (IH, t), 6.97 (IH, d), 6.74 (IH, dt), 6.44 (IH, d) , 6.39-6.28 (IH, m), 4.43 (2H, s), 3.85-3.76 (2H, m), 3.71 (3H, s), 2.73-2.62 (7H, m), 0.80-0.72 (2H, m) , 0.72-0.63 (2H, m). Example 19 7V-i3-i3-cyclopropyl-7-ί6-methoxypyridin-3-ylamino)-2-oxo-3,4-dihydropyrimido[4,5-pyrimidine-2H Phenyl)-4-morpholin-2-eneamine (compound)

( 1 ) 1-(3-氨基苯基) -3-环丙基 -7-(6-甲氧基吡啶 -3-基氨基 )-3,4-二氢嘧啶并 [4,5-ί ]嘧啶 -2(1/ )- (1) 1-(3-Aminophenyl)-3-cyclopropyl-7-(6-methoxypyridin-3-ylamino)-3,4-dihydropyrimido[4,5-ί ] Pyrimidine-2(1/ )-

干燥的反应瓶中，加入 3-(3-环丙基 -7-(6-甲氧基吡啶 -3-基氨基 )-2- 氧代 -3,4-二氢嘧啶并 [4,5- 嘧啶 -1(2 )-基)苯基氨基曱酸叔丁酯 (0.504 g, 1.0 mmol), 二氯甲烷 15 mL和三氟醋酸 10 mL, 水水浴下搅拌 1小时，旋千，直接用于下一步反应。 In a dry reaction flask, 3-(3-cyclopropyl-7-(6-methoxypyridin-3-ylamino)-2-oxo-3,4-dihydropyrimidine [4,5- Pyrimidine-1(2)-yl)phenylaminodecanoic acid tert-butyl ester (0.504 g, 1.0 mmol), dichloromethane 15 mL and trifluoroacetic acid 10 mL, stirred in water and water for 1 hour, rotary, used directly The next step is to react.

( 2 ) 4-溴丁 -2-烯酰氯的制

(2) Preparation of 4-bromobut-2-enoyl chloride

干燥的反应瓶中，加入 4-溴巴豆酸（0.165 g, 1.0 mmol), 二氯甲烷 10 mL, 滴加数滴 DMF，室温下加入草酰氯 (0.191 g, 1.5 mmol)，室温下搅拌 1小时，浓缩旋干，直接用于下一步反应。 In a dry reaction flask, add 4-bromo crotonic acid (0.165 g, 1.0 mmol), 10 mL of dichloromethane, add a few drops of DMF, add oxalyl chloride (0.191 g, 1.5 mmol) at room temperature, and stir at room temperature for 1 hour. , concentrated and spin dry, used directly in the next reaction.

( 3 ) 4-溴 -N-(3-(3-环丙基 -7-(6-甲氧基吡啶 -3-基氨基 )-2-氧代 -3,4- 二氢嘧啶并 [4,5 嘧啶 -1(2/ )-基)苯基)丁 -2-烯酰胺的制备

(3) 4-Bromo-N-(3-(3-cyclopropyl-7-(6-methoxypyridin-3-ylamino)-2-oxo-3,4-dihydropyrimido[4] Of 5-pyrimidin-1(2/)-yl)phenyl)but-2-enamide

将第一步得到的 1-(3-氨基苯基) -3-环丙基 -7-(6-曱氧基吡啶 -3-基氨基) -3,4-二氢嘧啶并 [4,5- 嘧啶 -2(1/ )-酮粗品用 10 mL四氢呋喃和 5 mL NMP溶解，用 DIEA调 pH至 9-10, ；水水浴下滴加入第二步反应所得 4-溴丁 -2-烯酰氯的四氢呋喃溶液 5 mL, 滴加完毕后反应 30分钟，直接用于下一步反应。 1-(3-Aminophenyl)-3-cyclopropyl-7-(6-decyloxypyridin-3-ylamino)-3,4-dihydropyrimidine[4,5 obtained in the first step - Pyrimidine-2(1/)-ketone crude was dissolved in 10 mL of tetrahydrofuran and 5 mL of NMP. The pH was adjusted to 9-10 with DIEA. The 4-bromobut-2-enoyl chloride obtained in the second step was added dropwise in a water bath. 5 mL of the tetrahydrofuran solution was reacted for 30 minutes after the completion of the dropwise addition, and used directly for the next reaction.

( 4 )N-(3-(3-环丙基 -7-(6-曱氧基吡啶 -3-基氨基 )-2-氧代 -3,4-二氢嘧啶并 [4,5-ί]嘧啶 -1(2H)-基)苯 -4-吗啉丁 -2-烯酰胺的制备 (4) N-(3-(3-Cyclopropyl-7-(6-decyloxy-3-ylamino)-2-oxo-3,4-dihydropyrimido[4,5-ί Preparation of pyrimidine-1(2H)-yl)benzene-4-morpholinbut-2-enamide

称取吗啉 (0.261 g, 3.0 mmol)加入到上步的反应体系中，室温下反应 24小时，减压蒸出大部分溶剂，加入 100 mL乙酸乙酯，饱和食盐水洗涤三次，有机相干燥，浓缩，过硅胶柱 (二氯甲烷一二氯甲烷：甲醇 =25:1)得到浅黄色固体 270 mg，总体收率 48.5%。 Weigh morpholine (0.261 g, 3.0 mmol) into the reaction system of the previous step, react at room temperature for 24 hours, distill off most of the solvent under reduced pressure, add 100 mL of ethyl acetate, wash the brine three times, and dry the organic phase. Concentration, through a silica gel column (dichloromethane-dichloromethane:methanol = 25:1) afforded 270 mg as pale yellow solid.

分子式： C₂₉H₃₂N₈0₄ 分子量： 556.3 质谱（M+H): 557.3Molecular formula: C ₂₉ H ₃₂ N ₈ 0 ₄ Molecular weight: 556.3 Mass spectrometry (M+H): 557.3

¹H-NMR ( ₆-DMSO, 400 MHz, 5ppm): δ 10.18 (1H, s), 9.31 (1H, s), 8.16 (1H, s), 8.01 (1H, s), 7.68-7.58 (3H， m), 7.40 (1H, t), 6.93 (1H， d), 6.75-6.63 (1H, m), 6.40-6.29 (1H, m), 6.26 (1H, d), 4.43 (2H, s), 3.71 (3H, s), 3.57 (4H, t), 3.10 (2H, d), 2.71-2.63 (1H, m), 2.40-2.33 (4H, m), 0.80-0.72 (2H, m), 0.72-0.64 (2H, m). ¹ H-NMR ( ₆ -DMSO, 400 MHz, 5 ppm): δ 10.18 (1H, s), 9.31 (1H, s), 8.16 (1H, s), 8.01 (1H, s), 7.68-7.58 (3H, m), 7.40 (1H, t), 6.93 (1H, d), 6.75-6.63 (1H, m), 6.40-6.29 (1H, m), 6.26 (1H, d), 4.43 (2H, s), 3.71 (3H, s), 3.57 (4H, t), 3.10 (2H, d), 2.71-2.63 (1H, m), 2.40-2.33 (4H, m), 0.80-0.72 (2H, m), 0.72-0.64 (2H, m).

实施例 20 7ν-ί3- -环丙基 -7-(6-甲氧基吡啶 -3-基氨基 )-2-氧代 -3,4-二氢嘧啶并 i4,5- 嘧啶 -K2H)-基)苯基 4- (吡咯烷 -1-基)丁 -2-烯酰胺 (化合物 20)的制备

Example 20 7ν-ί3- -cyclopropyl-7-(6-methoxypyridin-3-ylamino)-2-oxo-3,4-dihydropyrimido and i4,5-pyrimidine-K2H)- Preparation of phenyl 4-(pyrrolidin-1-yl)but-2-enamide (Compound 20)

( 1 ) 1 -(3-氨基苯基) -3-环丙基 -7-(6-甲氧基吡啶- -基氨基) -3,4-二氢嘧啶并 [4,5-ί ]嘧啶 -2(1//)-酮 (1) 1-(3-Aminophenyl)-3-cyclopropyl-7-(6-methoxypyridyl-ylamino)-3,4-dihydropyrimido[4,5-ί]pyrimidine -2(1//)-ketone

干燥的反应瓶中，加入 3-(3-环丙基 -7-(6-曱氧基吡啶 -3-基氨基 )-2- 氧代 -3,4-二氢嘧啶并 [4，5-^]嘧啶 -1(2/ )-基)苯基氨基甲酸叔丁酯 (0.504 g, 1.0 mmol), 二氯曱烷 15 mL和三氟醋酸 10 mL, 水水浴下搅拌 1小时，旋干，直接用于下一步反应。 In a dry reaction flask, 3-(3-cyclopropyl-7-(6-decyloxy-3-ylamino)-2-oxo-3,4-dihydropyrimidine [4,5- ^] pyrimidine-1(2/)-yl)phenylcarbamic acid tert-butyl ester (0.504 g, 1.0 mmol), dichloromethane (15 mL) and trifluoroacetic acid 10 mL, stirred in water and water for 1 hour, and dried. Used directly in the next step.

( 2 ) 4-溴丁 -2-烯酰氯的制

(2) Preparation of 4-bromobut-2-enoyl chloride

干燥的反应瓶中，加入 4-溴巴豆酸（0.165 g, 1.0 mmol)，二氯甲烷 10 mL, 滴加数滴 DMF, 室温下加入草酰氯 (0.191 g, 1.5 mmol), 室温下搅拌 1小时，浓缩旋干，直接用于下一步反应。 In a dry reaction flask, add 4-bromo crotonic acid (0.165 g, 1.0 mmol), 10 mL of dichloromethane, add a few drops of DMF, add oxalyl chloride (0.191 g, 1.5 mmol) at room temperature, and stir at room temperature for 1 hour. , concentrated and spin dry, used directly in the next reaction.

( 3 ) 4-溴 -ΛΚ3-(3-环丙基 -7-(6-甲氧基吡啶 -3-基氨基 )-2-氧代 -3,4- 二氢嘧啶并 [4,5-J]嘧啶 -1(2 /)-基)苯基)丁 -2-烯酰胺的制备 (3) 4-Bromo-indole 3-(3-cyclopropyl-7-(6-methoxypyridin-3-ylamino)-2-oxo-3,4-dihydropyrimido[4,5- Preparation of J]pyrimidine-1(2 /)-yl)phenyl)but-2-enamide

将第一步得到的 1 -(3-氨基苯基) -3-环丙基 -7-(6-甲氧基吡啶 -3-基氨基) -3,4-二氢嘧啶并 [4,5- 嘧啶 -2(1/ )-酮粗品用 10 mL四氢呋喃和 5 mL NMP溶解，用 DIEA调 pH至 9-10 , ；水水浴下滴加入第二步反应所得 4-溴丁 -2-烯酰氯的四氢呋喃溶液 5 mL，滴加完毕后反应 30分钟，直接用于下一步反应。 1-(3-Aminophenyl)-3-cyclopropyl-7-(6-methoxypyridin-3-ylamino)-3,4-dihydropyrimidine[4,5 obtained in the first step - Pyrimidine-2(1/)-ketone crude was dissolved in 10 mL of tetrahydrofuran and 5 mL of NMP, adjusted to pH 9-10 with DIEA, and added to the second step by water bath. A solution of 4-bromobut-2-enoyl chloride in tetrahydrofuran (5 mL) was reacted for 30 minutes after the dropwise addition, and used directly for the next reaction.

( 4 )N-(3-(3-环雨基 -7-(6-甲氧基吡啶 -3-基氨基 )-2-氧代 -3,4-二氢嘧啶并 [4,5- 嘧啶 -1 (2H)-基)苯 -4- (吡咯烷 -1 -基)丁 -2-烯酰胺的制备 (4) N-(3-(3-Cyclodyl-7-(6-methoxypyridin-3-ylamino)-2-oxo-3,4-dihydropyrimido[4,5-pyrimidine Preparation of -1 (2H)-yl)benzene-4-(pyrrolidin-1 -yl)but-2-enamide

称取吡咯烷 (0.213 g, 3.0 mmol)加入到上步的反应体系中，室温下反应 24小时，减压蒸出大部分溶剂，加入 100 mL乙酸乙酯，饱和食盐水洗涤三次，有机相干燥，浓缩，过硅胶柱 (二氯甲烷一二氯甲烷：甲醇 =10: 1 )得到黄色固体 220 mg, 总体收率 40.7%。 Pyrrolidine (0.213 g, 3.0 mmol) was added to the reaction system of the previous step, and the reaction was carried out for 24 hours at room temperature. Most of the solvent was evaporated under reduced pressure. Concentration, passing through a silica gel column (dichloromethane-dichloromethane:methanol = 10:1) afforded a white solid, 220 mg.

分子式： C₂₉H₃₂N₈0₃ 分子量： 540.3 质谱（M+H ): 541.3 ^-NMR^-DMSO+DsO, 400 MHz, 5ppm): δδ. 15 (】Η， s)， 7.99 (1 Η, s), 7.68-7.60 (3H, m), 7.40 (1H, t), 6.93 (1H, d), 6.74 (1H, dt), 6.38-6.23 (2H, m), 4.42 (2H, s), 3.70 (3H, s), 3.38-3.30 (2H, m), 2.69-2.62 (1H, m), 2.62-2.55 (4H, m), 1.76-1.68 (4H， m), 0.79-0.72 (2H, m), 0.69-0.63 (2H, m). Molecular formula: C ₂₉ H ₃₂ N ₈ 0 ₃ Molecular weight: 540.3 Mass spectrum (M+H): 541.3^-NMR^-DMSO+DsO, 400 MHz, 5 ppm): δδ. 15 (]Η, s), 7.99 (1 Η , s), 7.68-7.60 (3H, m), 7.40 (1H, t), 6.93 (1H, d), 6.74 (1H, dt), 6.38-6.23 (2H, m), 4.42 (2H, s), 3.70 (3H, s), 3.38-3.30 (2H, m), 2.69-2.62 (1H, m), 2.62-2.55 (4H, m), 1.76-1.68 (4H, m), 0.79-0.72 (2H, m ), 0.69-0.63 (2H, m).

实施例 21 N-(3-(3-环丙基 -7-f6-曱氧基吡啶 -3-基氨基 )-2-氧代 -3,4-二氢嘧啶并【4，5-f l嘧啶基)苯基) -4- (哌嗪 -1-基)丁 -2-烯酰胺 Example 21 N-(3-(3-Cyclopropyl-7-f6-decyloxypyridin-3-ylamino)-2-oxo-3,4-dihydropyrimido[4,5-fluoripyridine Phenyl)-4-(piperazin-1-yl)but-2-enamide

( 1 ) l -(3-氨基苯基) -3-环丙基 -7-(6-甲氧基吡啶 -3-基氨基 )-3,4-二氢嘧啶并 [4,5- ]嘧啶 -2(1//)-酮的制备

(1) l-(3-Aminophenyl)-3-cyclopropyl-7-(6-methoxypyridin-3-ylamino)-3,4-dihydropyrimido[4,5-]pyrimidine Preparation of -2(1//)-one

干燥的反应瓶中，加入 3-(3-环丙基 -7-(6-甲氧基吡啶 -3-基氨基 )-2- 氧代 -3 ,4-二氢嘧啶并 [4,5-ii]嘧啶 -1(2//)-基）苯基氨基甲酸叔丁酯 (0.504 g, 1.0 mmol), 二氯曱烷 15 mL和三氟醋酸 10 mL, 水水浴下搅拌 1小时，旋千，直接用于下一步反应。 In a dry reaction flask, 3-(3-cyclopropyl-7-(6-methoxypyridin-3-ylamino)-2-oxo-3,4-dihydropyrimido[4,5- Ii] pyrimidine-1(2//)-yl)phenylcarbamic acid tert-butyl ester (0.504 g, 1.0 mmol), dichloromethane 15 mL and trifluoroacetic acid 10 mL, stirred in water and water for 1 hour, , used directly in the next step.

( 2 ) 4-溴丁 -2-烯酰氯的制

(2) Preparation of 4-bromobut-2-enoyl chloride

干燥的反应瓶中，加入 4-溴巴豆酸（0.165 g, 1.0 mmol), 二氯甲烷 10 mL, 滴加数滴 DMF , 室温下加入草酰氯 (0.191 g, 1.5 mmol), 室温下搅拌 1小时，浓缩旋干，直接用于下一步反应。 In a dry reaction flask, add 4-bromo crotonic acid (0.165 g, 1.0 mmol), 10 mL of dichloromethane, add a few drops of DMF, add oxalyl chloride (0.191 g, 1.5 mmol) at room temperature, and stir at room temperature for 1 hour. , concentrated and spin dry, used directly in the next reaction.

( 3 ) 4-溴 -N-(3-(3-环丙基 -7-(6-甲氧基吡啶 -3-基氨基 )-2-氧代 -3,4- 二氢嘧啶并 [4,5-t ]嘧啶 -1(2/ -基)苯基)丁 -2-烯酰胺的制备 (3) 4-Bromo-N-(3-(3-cyclopropyl-7-(6-methoxypyridin-3-ylamino)-2-oxo-3,4-dihydropyrimido[4] Of 5-,5-pyrimidine-1(2/-yl)phenyl)but-2-enamide

将第一步得到的 1-(3-氨基苯基) -3-环丙基 -7-(6-曱氧基吡啶 -3-基氨基) -3,4-二氢嘧啶并 [4，5-ί ]嘧啶 -2(1//)-酮粗品用 10 mL四氢呋喃和 5 mL NMP溶解，用 DIEA调 pH至 9-10 , 冰水浴下滴加入第二步反应所得 4-溴丁 -2-烯酰氯的四氢呋喃溶液 5 mL, 滴加完毕后反应 30分钟，直接用于下一步反应。 1-(3-Aminophenyl)-3-cyclopropyl-7-(6-decyloxypyridin-3-ylamino)-3,4-dihydropyrimidine[4,5 obtained in the first step -ί ] pyrimidine-2(1//)-ketone crude was dissolved in 10 mL of tetrahydrofuran and 5 mL of NMP, adjusted to pH 9-10 with DIEA, and added to the second step of 4-bromobutan-2- in the ice bath. 5 mL of a solution of the enoyl chloride in tetrahydrofuran was reacted for 30 minutes after the dropwise addition, and used directly for the next reaction.

( 4 )4-(4-(3-(3-环丙基 -7-(6-甲氧基吡啶 -3-基氨基 )-2-氧代 -3,4-二氢嘧啶并 [4,5-d]嘧啶 -1(2 基)苯氨基 )-4-氧代丁 -2-烯基)哌嗪 -1-曱酸叔丁酯的制备 (4) 4-(4-(3-(3-Cyclopropyl-7-(6-methoxypyridin-3-ylamino)-2-oxo-3,4-dihydropyrimido[4, Preparation of 5-d]pyrimidine-1(2-yl)phenylamino)-4-oxobut-2-enyl)piperazine-1-decanoic acid tert-butyl ester

称取哌嗪 -1-甲酸叔丁酯（0.558 g, 3.0 mmol)加入到上步的反应体系中，室温下反应 24小时，减压蒸出大部分溶剂，加入 100 mL乙酸乙酯，饱和食盐水洗涤三次，有机相干燥，浓缩，过硅胶柱 (二氯曱烷一二氯曱烷：曱醇 =25： 1 )得到浅黄色固体 490 mg，三步合计收率 74.7%。 Piper piperazine-1-carboxylic acid tert-butyl ester (0.558 g, 3.0 mmol) was added to the reaction of the previous step. In the system, the reaction was carried out for 24 hours at room temperature. Most of the solvent was evaporated under reduced pressure. EtOAc (EtOAc)EtOAc Sterol = 25: 1 ) A pale yellow solid of 490 mg was obtained in a three-step total yield of 74.7%.

( 5 )N-(3-(3-环丙基 -7-(6-甲氡基吡啶 -3-基氨基 )-2-氧代 -3，4-二氢嘧啶并 [4,5-d]嘧啶 -1(2//)-基) -4- (哌嗪 -1 -基)丁 -2-烯酰胺的制备 (5) N-(3-(3-cyclopropyl-7-(6-methylpyridin-3-ylamino)-2-oxo-3,4-dihydropyrimido[4,5-d Preparation of pyrimidine-1(2//)-yl)-4-(piperazin-1-yl)but-2-enamide

千燥的反应瓶中，加入 4-(4-(3-(3-环丙基 -7-(6-曱氧基吡啶 -3-基氨基) -2-氧代 -3，4-二氢嘧啶并 [4,5-d]嘧啶 -1(2 /)-基)苯氨基 )-4-氧代丁 -2-烯基)哌嗪 - 1 -甲酸叔丁酯 (0.49 g, 0.747 mmol) , 二氯甲烷 10 mL和三氟醋酸 15 mL, 室温下搅拌 1小时，用氢氧化钠水溶液调节 pH至弱碱性，浓缩旋干，得到的粗品用甲醇洗涤，过滤，滤饼干燥，得到类白色固体 0.21 g，收率 50.5%。 In a dry reaction flask, 4-(4-(3-(3-cyclopropyl-7-(6-decyloxy-3-ylamino)-2-oxo-3,4-dihydro) was added. Pyrimido[4,5-d]pyrimidin-1(2/)-yl)phenylamino)-4-oxobut-2-enyl)piperazine-1-carboxylic acid tert-butyl ester (0.49 g, 0.747 mmol) 10 mL of dichloromethane and 15 mL of trifluoroacetic acid were stirred at room temperature for 1 hour. The pH was adjusted to be weakly basic with aqueous sodium hydroxide solution, and concentrated to dryness. The obtained crude product was washed with methanol, filtered, and dried. White solid 0.21 g, yield 50.5%.

分子式： C₂₉H₃₃N₉0₃ 分子量： 555.3 质谱（M+H ): 556.3 ]H-NMR(6 -DMSO, 400 MHz, 6ppm): δ 10.17 (1Η， s), 9.30 (1 Η, s)， 8. 16 (1H, s), 8.01 ( 1H, s), 7.68-7.58 (3H, m), 7.39 (1H， t)， 6.93 (1H_} d), 6.70 (1 H, dt), 6.34 (1H, d), 6.24 ( 1 H, d), 4.43 (2H, s), 3.71 (3H, s)， 3.05 (2H, d), 2.72-2.63 (5H, m)， 2.32-2.24 (4H, m), 0.80-0.71 (2H, m), 0.71-0.64 (2H, m). Molecular formula: C ₂₉ H ₃₃ N ₉ 0 ₃ Molecular weight: 555.3 Mass spectrum (M+H): 556.3 ]H-NMR (6-DMSO, 400 MHz, 6 ppm): δ 10.17 (1 Η, s), 9.30 (1 Η, s ), 8. 16 (1H, s), 8.01 ( 1H, s), 7.68-7.58 (3H, m), 7.39 (1H, t), 6.93 (1H _} d), 6.70 (1 H, dt), 6.34 (1H, d), 6.24 ( 1 H, d), 4.43 (2H, s), 3.71 (3H, s), 3.05 (2H, d), 2.72-2.63 (5H, m), 2.32-2.24 (4H, m), 0.80-0.71 (2H, m), 0.71-0.64 (2H, m).

实施例 22 7V-i3-i3-环丙基 -7-(l-甲基 -li -吡唑 -3-基氨基 )-2-氧代 -3,4-二氢嘧啶并 ί4,5-^Ί嘧啶 -U2H)-基)苯基)丙烯跣胺 (化合物 22)的制备 Example 22 7V-i3-i3-cyclopropyl-7-(l-methyl-li-pyrazol-3-ylamino)-2-oxo-3,4-dihydropyrimidine ί4,5-^ Preparation of pyrimidine-U2H)-yl)phenyl)propenylamine (Compound 22)

( 1 ) 3-(3-环丙基 -7- (甲磺酰基) -2-氧代 -3,4-二氢嘧啶并 [4,5-i ]嘧啶 - 1 (2//>基)苯基氨基曱酸叔丁 (1) 3-(3-Cyclopropyl-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimido[4,5-i]pyrimidine - 1 (2/yl) phenylaminodecanoic acid tert-butyl

干燥的反应瓶中，加入 3-(3-环丙基 -7- (甲疏基) -2-氧代 -3,4-二氢嘧啶并 [4,5-d]嘧啶 -1(2 )-基)苯基氨基甲酸叔丁酯 (9.0 g, 21.05 mmol), 用二氯甲烷 lOOmL 和甲醇各 50 mL，冰水浴下加入间氯过氧苯甲酸 ( 10.89 g, 63.15 mmol), 室温反应 2.5小时，停止反应，然后减压浓缩柱层析（PE:EA=1:2) 得到 9.05 g白色固体，收率为 93.6%。 In a dry reaction flask, add 3-(3-cyclopropyl-7-(methylamido)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2) tert-Butyl phenylcarbamate (9.0 g, 21.05 mmol), with 50 mL of dichloromethane and 50 mL of methanol, m-chloroperoxybenzoic acid (10.89 g, 63.15 mmol). The reaction was stopped, and then concentrated under reduced pressure column chromatography (PE: EA = 1:2) to yield 9.05 g of white solid.

( 2 ) 3-(3-环丙基 -7-(1-曱基吡唑 -3-基氨基 )-2-氧代 -3,4-二氢嘧啶并 [4,5-ί ]嘧啶- 1 (2/)-基)苯的制备 (2) 3-(3-Cyclopropyl-7-(1-indolylpyrazol-3-ylamino)-2-oxo-3,4-dihydropyrimido[4,5-ί]pyrimidine- Preparation of 1 (2/)-yl)benzene

干燥的反应瓶中，加入 3-(3-环丙基 -7- (曱基磺酰基 )-2-氧代 -3,4-二氢嘧啶并 [4,5- 嘧啶 -1(2//)-基)苯基氨基曱酸叔丁酯（0.46 g, l.Ommol) 和 1_曱基吡唑 _3胺（ 117mg， 1.20 mmol), 用 40 mL叔戊醇溶解，然后加入三氟醋酸（0.114g, l.Ommol), 100 °C油浴中回流反应 12小时，停止反应，冷却至室温后，减压浓缩柱层析（PE:EA=1:2)得到 190 mg淡黄色固体，收率为 39.9%。 In a dry reaction flask, 3-(3-cyclopropyl-7-(mercaptosulfonyl)-2-oxo-3,4-dihydropyrimido[4,5-pyrimidine-1 (2//) was added. Tert-butyl phenylaminodecanoate (0.46 g, 1.0 mmol) and 1 - mercaptopyrazole-3 amine (117 mg, 1.20 mmol), dissolved in 40 mL of tert-amyl alcohol, then trifluoroacetic acid (0.114 g, 1.0 mmol), the reaction was refluxed for 12 hours in an oil bath at 100 ° C, and the reaction was stopped. After cooling to room temperature, EtOAc (EtOAc: EtOAc: The yield was 39.9%.

( 3 ) 1-(3-氨基笨基) -3-环丙基 -7-(1-甲基吡唑 -3-基氨基 )-3,4- 二氢嘧啶并 [4,5-^]嘧啶 -2(1//-酮的制备 (3) 1-(3-Aminophenyl)-3-cyclopropyl-7-(1-methylpyrazol-3-ylamino)-3,4-dihydropyrimido[4,5-^] Preparation of pyrimidine-2 (1//-ketone)

干燥的反应瓶中，加入 3-(3-环丙基 -7-(1-曱基吡唑 -3-基氨基) -2-氧代 -3,4-二氢嘧啶并 [4，5- ^嘧啶 -1(2 )-基)苯基氨基曱酸叔丁酯 (0.19g, 0.399 mmol), 用 15.0 mL二氯甲烷溶解，在水浴的条件下滴加三氟乙酸 7.0mL, 滴加完毕，室温继续搅拌 1.5h, 停止反应，然后减压浓缩，所得油状物直接用于下一步反应。 In a dry reaction flask, 3-(3-cyclopropyl-7-(1-indolylpyrazol-3-ylamino)-2-oxo-3,4-dihydropyrimidine [4,5- Pyrimidine-1(2)-yl)phenylaminodecanoic acid tert-butyl ester (0.19 g, 0.399 mmol), dissolved in 15.0 mL of dichloromethane, and then dropwise Stir at room temperature for 1.5 h, stop the reaction, then Concentrated under reduced pressure, the obtained oil was used directly to the next reaction.

( 4 )/^-(3-(3-环丙基-7-(1-甲基-1 /-吡唑-3-基氨基)-2-氧代-3,4-二氢嘧啶并 [4,5- 嘧啶- 1 (2H)-基) 备 (4)/^-(3-(3-Cyclopropyl-7-(1-methyl-1/-pyrazol-3-ylamino)-2-oxo-3,4-dihydropyrimido[ 4,5-pyrimidine-1 (2H)-yl)

干燥的反应瓶中加入上一步得到的粗品，加入四氢呋喃〗5 mL, 用 Add the crude product obtained in the previous step to the dried reaction flask, add 4 mL of tetrahydrofuran, and use

DIEA调 pH至 9-10, 0 °C下滴加入丙烯酰氯（ 72 mg, 0.798 mmol ), 滴加完毕后继续反应 15 min, 停止反应后，加入甲醇淬灭，然后減压浓缩柱层析（DCM:MeOH=50: 1 ) 得淡黄色固体，然后用少量二氯甲烷和曱醇溶解，加入大量***析出固体，抽滤得到 60 mg白色固体，收率为 34.9 %。 The pH of the DIEA was adjusted to 9-10, and acryloyl chloride (72 mg, 0.798 mmol) was added dropwise at 0 °C. After the completion of the dropwise addition, the reaction was continued for 15 min. After the reaction was stopped, the mixture was quenched with methanol, and then concentrated under reduced pressure. DCM: MeOH = 50: 1) EtOAc (EtOAc: EtOAc)

分子式： C₂₂H₂₂N₈0₂ 分子量： 430.2 质谱（M+H ): 431.2 ^-NMRC^-DMSO, 400 MHz, 5ppm): δ 10.23 (IH, s), 9.47 (IH, s), 8.12 (IH, s), 7.70 (IH, d), 7.55 (IH, t), 7.40 (IH, t), 7.09 (IH, s), 6.95 (1H， d), 6.41 (IH, dd), 6.23 (IH, dd), 5.74 (IH, dd), 5.55-5.45 (IH, m), 4.41 (2H, s), 3.58 (3H, s), 2.70-2.62 (IH, m), 0.80-0.71 (2H, m), 0.70-0.63 (2H, m). Molecular formula: C ₂₂ H ₂₂ N ₈ 0 ₂ Molecular weight: 430.2 Mass spectrum (M+H): 431.2^-NMRC^-DMSO, 400 MHz, 5 ppm): δ 10.23 (IH, s), 9.47 (IH, s), 8.12 (IH, s), 7.70 (IH, d), 7.55 (IH, t), 7.40 (IH, t), 7.09 (IH, s), 6.95 (1H, d), 6.41 (IH, dd), 6.23 ( IH, dd), 5.74 (IH, dd), 5.55-5.45 (IH, m), 4.41 (2H, s), 3.58 (3H, s), 2.70-2.62 (IH, m), 0.80-0.71 (2H, m), 0.70-0.63 (2H, m).

实施例 23 V-i3- -环丙基 -7-il-甲基 -I -吡唑 -4-基氨基 )-2-氧代 -3,4-二氢嘧啶并【4，5-f/1嘧啶 -l(2Jy)-基)苯基 4 二甲氨基）丁 -2-烯酰胺 Example 23 V-i3-cyclopropyl-7-il-methyl-I-pyrazol-4-ylamino)-2-oxo-3,4-dihydropyrimido[4,5-f/ 1 pyrimidine-l(2Jy)-yl)phenyl 4 dimethylamino)but-2-enamide

( 1 ) 3-(3-环丙基 -7-(l-曱基吡唑 -4-基氨基 )-2-氧代 -3,4-二氢嘧啶并 [4,5- 嘧啶- 1 (2//)-基)苯的制备 (1) 3-(3-Cyclopropyl-7-(l-decylpyrazol-4-ylamino)-2-oxo-3,4-dihydropyrimidine Preparation of pyridyl[4,5-pyrimidin-1 (2//)-yl)benzene

干燥的反应瓶中，加入 3-(3-环丙基 -7- (甲磧酰基) -2-氧代 -3,4-二氢嘧啶并 [4,5-d]嘧啶 -1(2 /)-基)苯基氨基甲酸叔丁酯 (3.15 g, 6.86 mmol ) 和 1-曱基吡唑 -4胺（ 799 mg, 8.23 mmol ), 用 100 mL叔戊醇溶解，加入三氟醋酸（ 0.782 g, 6.86 mmol), 100°C油浴中回流反应 5小时，停止反应，冷却至室温，减压浓缩柱层析（PE:EA=1:2)得到 3.20g淡黄色固体，收率为 97.9%。 In a dry reaction flask, add 3-(3-cyclopropyl-7-(carbamoyl)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidine-1 (2 / tert-Butyl phenylcarbamate (3.15 g, 6.86 mmol) and 1-mercaptopyrazole-4amine (799 mg, 8.23 mmol), dissolved in 100 mL of tert-amyl alcohol, added trifluoroacetic acid (0.782) g, 6.86 mmol), refluxing for 5 hours in a 100 ° C oil bath, quenched, cooled to room temperature, concentrated under reduced pressure column chromatography (PE: EA = 1:2) to give 3.20 g of pale yellow solid. %.

( 2 ) 1-(3-氨基笨基) -3-环丙基 -7-(1-甲基吡唑 -4-基氨基 )-3,4- 二氢嘧啶并 [4,5- 嘧啶 -2(1 ·酮的制备 (2) 1-(3-Aminophenyl)-3-cyclopropyl-7-(1-methylpyrazol-4-ylamino)-3,4-dihydropyrimido[4,5-pyrimidine- 2 (1 · Preparation of ketone

干燥的反应瓶中，加入 3-(3-环丙基 -7-(1-甲基吡唑 -4-基氨基) -2-氧代 -3,4-二氢嘧啶并 [4，5- 嘧啶 -1(2 )-基）苯基氨基甲酸叔丁酯 ( 0.953 g, 2.0 mmol ), 用 30.0 mL二氯甲烷溶解，在水浴下滴加三氟乙酸 12.0 mL，滴加完毕，室温继续搅拌 lh,停止反应，然后减压浓缩，所得油状物直接用于第四步反应。 In a dry reaction flask, add 3-(3-cyclopropyl-7-(1-methylpyrazol-4-ylamino)-2-oxo-3,4-dihydropyrimidine [4,5- Pyrimidine-1(2)-yl)phenylcarbamic acid tert-butyl ester (0.953 g, 2.0 mmol), dissolved in 30.0 mL of dichloromethane, 12.0 mL of trifluoroacetic acid was added dropwise in a water bath, the addition was completed, and stirring was continued at room temperature. Lh, the reaction was stopped, and then concentrated under reduced pressure, and the obtained oil was directly used for the fourth step.

(3) 4-溴丁 -2-烯酰氯的制备 (3) Preparation of 4-bromobut-2-enoyl chloride

、ci Ci

千燥的反应瓶中加入 4-溴巴豆酸（ 330 mg, 2.0 mmol ), 用二氯甲烷 30mL溶解，在冰浴下滴加草酰氯（381 mg, 3.0 mmol), 滴加完毕后室温反应 l h, 停止反应后，减压浓缩，所得油状物直接用于下一步反应。 4-bromo crotonic acid (330 mg, 2.0 mmol) was added to a dry reaction flask, dissolved in 30 mL of dichloromethane, and oxalyl chloride (381 mg, 3.0 mmol) was added dropwise in an ice bath. After the reaction was stopped, it was concentrated under reduced pressure, and the obtained oil was used directly to the next reaction.

( 4 ) 4-溴 - -(3-(3-环丙基 -7-(1-甲基吡唑 -4-基氨基 )-2-氧代 -3,4-二氢嘧啶并 [4，5-ί]嘧啶 -1(2//)-基)苯基)丁 -2-烯酰胺的制备

(4) 4-Bromo-(3-(3-cyclopropyl-7-(1-methylpyrazol-4-ylamino)-2-oxo-3,4-dihydropyrimido[4, Preparation of 5-ί]pyrimidine-1(2//)-yl)phenyl)but-2-enamide

干燥的反应瓶中，加入 1-(3-氨基苯基) -3-环丙基 -7-(1-曱基吡唑 -4-基氨基 )-3，4-二氢嘧啶并 [4,5-tf]嘧啶 -2(1/ )-酮粗品用 30 mL四氢呋喃和 8 mL NMP溶解，然后用 DIEA调体系 pH至碱性，在冰浴条件下滴加 4-溴丁 -2-烯酰氯的四氢呋喃溶液，滴加完后继续冰浴搅拌 1 h, 停止反应，所得体系直接用于下一步反应。 In a dry reaction flask, add 1-(3-aminophenyl)-3-cyclopropyl-7-(1-indolylpyrazol-4-ylamino)-3,4-dihydropyrimidine [4, The crude 5-tf]pyrimidine-2(1/)-one was dissolved in 30 mL of tetrahydrofuran and 8 mL of NMP, then the pH was adjusted to basic with DIEA, and 4-bromobut-2-enoyl chloride was added dropwise under ice bath. The tetrahydrofuran solution was added to the ice bath for 1 h after the dropwise addition, the reaction was stopped, and the obtained system was directly used for the next reaction.

( 5 )vV-(3-(3-环丙基 -7-(1-甲基 -1 7-吡唑 -4-基氨基 )-2-氧代 -3,4-二氢嘧啶并 [4,5- ]嘧啶- 1 (2 /)-基)苯基) -4- (二曱氨基)丁 -2-烯酰胺的制备 (5) vV-(3-(3-cyclopropyl-7-(1-methyl-1 7-pyrazol-4-ylamino)-2-oxo-3,4-dihydropyrimido[4 ,5-]pyrimidine-1 (2/)-yl)phenyl)-4-(diamino)but-2-enamide

取 10 mL二甲胺水溶液，用 20 mL二氯甲烷萃取一遍，并且干燥有机相，然后取第四步反应体系的一半，向其中加入二曱胺的二氯曱烷溶液 2 mL, 然后加入催化量的捵化鉀，避光水浴的条件下反应 48 h, 减压浓缩柱层析（DCM:MeOH=5: 1 )得到浅黄色固体，再将其用少量曱醇溶解，加入大量***析出固体，抽滤得到淡黄色固体 65 mg。 Take 10 mL of dimethylamine aqueous solution, extract once with 20 mL of dichloromethane, and dry the organic phase, then take half of the fourth reaction system, add 2 mL of diammonium chloride solution, and then add catalysis. Amount of potassium telluride, reacted in a dark water bath for 48 h, concentrated under reduced pressure column chromatography (DCM: MeOH = 5: 1) to give a pale-yellow solid, which was then dissolved in a small amount of decyl alcohol. , suction filtration gave a pale yellow solid 65 mg.

分子式： C₂₅H₂₉N₉0₂ 分子量： 487.2 质谱（M+H ): 488.2Molecular formula: C ₂₅ H ₂₉ N ₉ 0 ₂ Molecular weight: 487.2 Mass spectrometry (M+H): 488.2

^-NMR^-DMSO, 400 MHz, 5ppm): δ 10.93 (IH, s)， 9.35 (IH, s)， 8.11 (IH, s), 7.89 (IH, m), 7.67 (IH, s), 7.49 (1H， t ), 7.15-6.90 (2H, m), 6.80 (IH, dt), 6.72-6.50 (2H, m), 4.41 (2H, s), 3.93-3.76 (2H, m), 3.46 (3H s), 2.80-2.62 (7H, m), 0.85-0.64 (4H, m). ^-NMR^-DMSO, 400 MHz, 5 ppm): δ 10.93 (IH, s), 9.35 (IH, s), 8.11 (IH, s), 7.89 (IH, m), 7.67 (IH, s), 7.49 (1H, t), 7.15-6.90 (2H, m), 6.80 (IH, dt), 6.72-6.50 (2H, m), 4.41 (2H, s), 3.93-3.76 (2H, m), 3.46 (3H s), 2.80-2.62 (7H, m), 0.85-0.64 (4H, m).

实施例 24 7V-(3-(3-环丙基 -7-(l-甲基 -li -吡唑 -4-基氨基 )-2-氧代 Example 24 7V-(3-(3-Cyclopropyl-7-(l-methyl-li-pyrazole-4-ylamino)-2-oxo

-3,4-二氢嘧啶【4,5- 嘧啶 -lO^ 基)苯基) -4- (吡咯烷 -1-基）丁 -2-烯酰胺 ί化合物 24)的制备

-3,4-Dihydropyrimidine [4,5-pyrimidin-lO^yl)phenyl)-4-(pyrrolidin-1-yl)but-2-enamide Compound 24)

( 1 ) 3-(3-环丙基 -7-(l-甲基吡唑 -4-基氨基 )-2-氧代 -3,4-二氢嘧啶并 [4，5- 嘧啶 - 1 (2 / 基)苯的制备 (1) 3-(3-Cyclopropyl-7-(l-methylpyrazol-4-ylamino)-2-oxo-3,4-dihydropyrimido[4,5-pyrimidine- 1 ( 2 / base) preparation of benzene

干燥的反应瓶中，加入 3-(3-环丙基 -7- (曱磺酰基) -2-氧代 -3,4-二氢 ^π密啶并 [4,5-d]嘧啶 -1(2 )-基)苯基氨基甲酸叔丁酯（3.15g, 6.86 mmol ) 和 1-甲基吡唑 -4胺（ 799 mg， 8.23 mmol ), 用 100 mL叔戊醇溶解, 加入三氟醋酸（0.782 g, 6.86 mmol), 100°C油浴中回流反应 5小时，停止反应，冷却至室温，减压浓缩柱层析（PE:EA=1:2)得到 3.20g淡黄色固体，收率为 97.9%。 Dried reaction flask was added 3- (3-cyclopropyl-7- (Yue-sulfonyl) -2-oxo-3,4-dihydro-pyrido adhesion ^π [4,5-d] pyrimidin-l ( 2)-Phenylcarbamic acid tert-butyl ester (3.15 g, 6.86 mmol) and 1-methylpyrazol-4amine (799 mg, 8.23 mmol) were dissolved in 100 mL of tert-amyl alcohol and added trifluoroacetic acid ( 0.782 g, 6.86 mmol), the reaction was refluxed for 5 hours in a 100 ° C oil bath, the reaction was quenched, cooled to room temperature, and concentrated under reduced pressure column chromatography (PE: EA = 1:2) to give 3.20 g of pale yellow solid. 97.9%.

(2) 1-(3-氨基苯基) -3-环丙基 -7-(1-甲基吡唑 -4-基氨基 )-3,4- 二氢嘧啶并 [4，5-tJ嘧啶 -2(1 /)- (2) 1-(3-Aminophenyl)-3-cyclopropyl-7-(1-methylpyrazol-4-ylamino)-3,4-dihydropyrimido[4,5-tJ pyrimidine -2(1 /)-

干燥的反应瓶中，加入 3-(3-环丙基 -7-(1-甲基吡唑 -4-基氨基) -2-氧代 -3,4-二氢嘧啶并 [4,5- ^嘧啶 -1(2 )-基)苯基氨基曱酸叔丁酯 ( 0.953 g, 2.0 mmol ), 用 30.0 mL二氯曱烷溶解，在;水浴下滴加三氟乙酸 12.0 mL，滴加完毕，室温继续搅拌 lh,停止反应，然后减压浓缩，所得油状物直接用于第四步反应。 In a dry reaction flask, add 3-(3-cyclopropyl-7-(1-methylpyrazol-4-ylamino)-2-oxo-3,4-dihydropyrimidine [4,5- Pyrimidine-1(2)-yl)phenylaminodecanoic acid tert-butyl ester (0.953 g, 2.0 mmol), dissolved in 30.0 mL of dichloromethane, 12.0 mL of trifluoroacetic acid was added dropwise in a water bath, and the addition was completed. Stirring was continued for 1 h at room temperature, the reaction was stopped, and then concentrated under reduced pressure. The obtained oil was used directly for the next step.

(3) 4-溴丁 -2-烯酰氯的制备

(3) Preparation of 4-bromobut-2-enoyl chloride

干燥的反应瓶中加入 4-溴巴豆酸（ 330 mg, 2.0 mmol ), 用二氯甲烷 30mL溶解，在;水浴下滴加草酰氯（381 mg, 3.0 mmol), 滴加完毕后室温反应 l h，停止反应后，减压浓缩，所得油状物直接用于下一步反应。 4-bromo crotonic acid (330 mg, 2.0 mmol) was added to the dried reaction flask, and dissolved in 30 mL of dichloromethane. The oxalyl chloride (381 mg, 3.0 mmol) was added dropwise in a water bath, and the mixture was reacted at room temperature for 1 h. After the reaction was stopped, it was concentrated under reduced pressure, and the obtained oil was used directly to the next reaction.

( 4 ) 4-渙 - (3-(3-环丙基 -7-(1-甲基吡唑 -4-基氨基 )-2-氧代 -3,4-二氢嘧啶并 [4,5- 嘧啶 - -基)苯基)丁 -2-烯酰胺的制备 (4) 4-涣-(3-(3-Cyclopropyl-7-(1-methylpyrazol-4-ylamino)-2-oxo-3,4-dihydropyrimido[4,5 - Preparation of pyrimidine-yl)phenyl)but-2-enamide

干燥的反应瓶中，加入 1-(3-氨基苯基) -3-环丙基 -7-(1-甲基吡唑 -4-基氨基 )-3,4-二氢嘧啶并 [4,5-ύ?]嘧啶 -2(1//)-酮粗品用 30 mL四氢呋喃和 8mLNMP溶解，然后用 DIEA调体系 pH至碱性，在冰浴条件下滴加 4-溴丁 -2-烯酰氯的四氢呋喃溶液，滴加完后继续冰浴搅拌 1 h，停止反应，所得体系直接用于下一步反应。 In a dry reaction flask, add 1-(3-aminophenyl)-3-cyclopropyl-7-(1-methylpyrazol-4-ylamino)-3,4-dihydropyrimidine [4, 5-ύ?]pyrimidine-2(1//)-one crude was dissolved in 30 mL of tetrahydrofuran and 8 mL of NMP, then the pH was adjusted to basic with DIEA, and 4-bromobut-2-enoyl chloride was added dropwise under ice bath. The tetrahydrofuran solution was added to the ice bath for 1 h after the dropwise addition, the reaction was stopped, and the obtained system was directly used for the next reaction.

( 5 )N-(3-(3-环丙基 -7-(1-曱基 -1 7-吡唑 -4-基氨基 )-2-氧代 -3,4-二氢嘧啶 [4,5- ]嘧啶 -1(2/)-基) -4- (吡咯烷 -1-基)丁 -2-烯酰胺的制备 (5) N-(3-(3-cyclopropyl-7-(1-mercapto-1 7-pyrazol-4-ylamino)-2-oxo-3,4-dihydropyrimidine [4, Preparation of 5- ]pyrimidine-1(2/)-yl)-4-(pyrrolidin-1-yl)but-2-enamide

取第四步反应体系的一半，向其中加入吡咯烷（213 mg, 3.0 mmol), 加入催化量的碘化钾，避光水浴的条件下反应 48 h, 减压浓缩柱层析 (DCM:MeOH=5: 1 )得到浅黄色固体，再将其用少量曱醇溶解，加入大量***析出固体，抽滤得到淡黄色固体 165 mg, 然后进一步用高压制备液相纯化（乙腈 /水 =35%) 得到 11 mg白色固体。 Take half of the reaction system in the fourth step, add pyrrolidine (213 mg, 3.0 mmol), add a catalytic amount of potassium iodide, react for 48 h in the dark water bath, and concentrate the column under reduced pressure (DCM: MeOH = 5). : 1) A pale yellow solid is obtained, which is dissolved in a small amount of decyl alcohol, and a large amount of diethyl ether is added to precipitate a solid, which is filtered to give a pale yellow solid 165 mg, which is further purified by high-pressure preparative liquid phase (acetonitrile/water = 35%). Mg white solid.

分子式： C₂₇H₃₁N₉0₂ 分子量： 513.3 质谱（M+H): 514.3

400 MHz, 5ppm): δ 10.43 (1Η, s), 9.35 (1H, s), 8.12 (1H, s)， 7.87-7.45 (3H, m), 7.09-6.95 (2H, m), 6.75 (1H, dt), 6.66-6.50 (1H, m), 6.38 (1H, d), 4.42 (2H, s), 3.85-3.65 (2H， m), 3.47 (3H, s), 3.15-2.87 (4H, m), 2.71 -2.62 (1H， m), 1.92-1.80 (4H, m), 0.80-0.64 (4H, m). Molecular formula: C ₂₇ H ₃₁ N ₉ 0 ₂ Molecular weight: 513.3 Mass spectrometry (M+H): 514.3

400 MHz, 5 ppm): δ 10.43 (1Η, s), 9.35 (1H, s), 8.12 (1H, s), 7.87-7.45 (3H, m), 7.09-6.95 (2H, m), 6.75 (1H, Dt), 6.66-6.50 (1H, m), 6.38 (1H, d), 4.42 (2H, s), 3.85-3.65 (2H, m), 3.47 (3H, s), 3.15-2.87 (4H, m), 2.71 - 2.62 (1H, m), 1.92-1.80 (4H, m), 0.80-0.64 (4H, m).

使用类似于上述的制备方法，还制备了以下化合物： Using the preparation method similar to the above, the following compounds were also prepared:

£I6680/ 0Z OAV £I6680/ 0Z OAV

Claims

权利要求 Rights request

1. 通式（I )所示的化合物、其氘代物、其药学上可接受的盐或其立体异构体： A compound represented by the formula (I), a deuterated compound thereof, a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

其中， X和 W分别独立的表示 C-Ra， CO或 N-Rb， Where X and W respectively represent C-Ra, CO or N-Rb,

且 X和 W不同时为 C=0, And X and W are not C=0 at the same time.

Ra表示氢原子，鹵素原子， -CN， -CF₃ , 被 1-2 个相同或不同的 Qi取代或未被取代的 C_1-4烷基、 C_1-4烷氧基 QM亚烷基、氨基、环烷基 QM亚烷基、苯基 QM亚烷基、萘基 CG_₄亚烷基、 5-10元杂芳基 C₀-4亚烷基或 -OH, Ra represents a hydrogen atom, a halogen atom, -CN, -CF ₃ , a C _1-4 alkyl group substituted or unsubstituted with 1-2 identical or different Qi, a C _1-4 alkoxy QM alkylene group, Amino, cycloalkyl QM alkylene, phenyl QM alkylene, naphthyl CG ₄ alkylene, 5-10 membered heteroaryl C ₀ -4 alkylene or -OH,

Rb不存在，或者表示氢原子，被 1 -2个相同或不同的（^取代或未被取代的（3_1-4烷基、 C_M烷氧基 C( 亚烷基， C_3-6环烷基 C(M亚烷基，苯基 CG_-4亚烷基，萘基 C(M亚烷基或 5- 10元杂芳基 Co.4亚烷基， Rb is absent, or represents a hydrogen atom, which is 1 - 2 identical or different (^ substituted or unsubstituted (3 _1-4 alkyl, C _M alkoxy C (alkylene, C _3-6 ring) Alkyl C (M alkylene, phenyl CG _-4 alkylene, naphthyl C (M alkylene or 5- 10 membered heteroaryl Co. 4 alkylene,

Qi表示 d- ^氧基， C_1-3烷氧羰基，氨基曱酰基， C_1-3烷基氨基甲酰基， 3-8元环烷基或含有选自 N或 0的杂原子的 3-8元杂环基； Qi represents d-oxy, C _1-3 alkoxycarbonyl, aminodecanoyl, C _1-3 alkylcarbamoyl, 3-8 membered cycloalkyl or 3-containing a hetero atom selected from N or 0. 8-membered heterocyclic group;

R₂表示氢原子，卤素原子， -CF₃， CM烷基，〇_1-4烷氧基，氨基或R ₂ represents a hydrogen atom, a halogen atom, -CF ₃ , CM alkyl, 〇 _1-4 alkoxy, amino or

-OH; -OH;

环 A和环 B分别独立的表示苯基， 3-8元环烷基，含有选 N、 0 和 S的杂原子的 3-8元杂环烷基， 4-7元杂芳基或 6-12元二环结构； Ring A and Ring B each independently represent a phenyl group, a 3-8 membered cycloalkyl group, a 3-8 membered heterocycloalkyl group containing a hetero atom selected from N, 0 and S, a 4-7 membered heteroaryl group or 6- 12-membered two-ring structure;

L]和 L₂分别独立的表示共价键， -NH -， -N d.3烷基) -0-， -S(0)_m -, -N(Ci_-3 烷基） C(0)-， -C(0)N(C_1-3 烷基） -， -N(Ci_-3 烷基） S(0)₂-或- S O^N Cw烷基) -; L] and L ₂ each independently represent a covalent bond, -NH -, -N d.3 alkyl) -0-, -S(0) _m -, -N(Ci _-3 alkyl) C(0) -, -C(0)N(C _1-3 alkyl) -, -N(Ci _-3 alkyl) S(0) ₂ - or - SO^N Cw alkyl) -;

a表示共价键，或未被取代或被 C_M烷基取代的亚氨基； a represents a covalent bond, or an imino group which is unsubstituted or substituted with a C _M alkyl group;

b表示 -CO-或 -S0₂-; b represents -CO- or -S0 ₂ -;

c表示未被取代或被一或两个甲基或三氟甲基取代的 1,3-亚丙二烯基、 1 , 1 -或 1 ,2-亚乙烯基，亚乙炔基，或者未被取代或被一至四个曱基或三氟曱基取代的 1 ,3-丁二烯 -1 ,4-亚基； c represents 1,3-propylenediene, 1,1 - or 1,2-vinylidene, ethynylene, or unsubstituted, which is unsubstituted or substituted by one or two methyl or trifluoromethyl groups Replace or be one to four thiol Or a trifluoromethyl substituted 1,3-butadiene-1,4-subunit;

e表示氢原子， C_1-4烷氧基，氨基， 3-7元环烷基， 6-12元二环结构， CM烷基氨基或二 - ( CM烷基）氨基，其中烷基部分可相同或不同；e represents a hydrogen atom, a C _1-4 alkoxy group, an amino group, a 3-7 membered cycloalkyl group, a 6-12 membered bicyclic structure, a CM alkylamino group or a bis-(CM alkyl)amino group, wherein the alkyl moiety is Same or different;

1^和 R₃分别独立的表示氢原子，鹵素原子，氰基，硝基， C₂_₄烯基， C₂_₄炔基或 -L₃-R4， 1^ and R ₃ independently represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, a C ₂ _ ₄ alkenyl group, a C ₂ _ alkynyl group or a -L ₃ -R ₄ group,

表示共价键， -NH-, -N(Ci_-3烷基) -, -0-, -0-Ci.₃亚烷基-, -S-Ci.3 亚烷基-, -S(0)_m -, -C(O)-, -NHC(O)-, -N(C_1-3烷基) C(O)-, -C(0)NH -， -C(0)N(C_1-3 烷基） - , -NHS(0)₂-， -N(C_1-3 烷基） S(0)₂-， -S(0)₂NH- , -S(0)₂N(Ci_-3烷基) -, -OC(O)-或 -C(0)0-， Represents a covalent bond, -NH-, -N(Ci _-3 alkyl) -, -0-, -0-Ci. ₃ alkylene-, -S-Ci.3 alkylene-, -S(0 _m -, -C(O)-, -NHC(O)-, -N(C _1-3 alkyl) C(O)-, -C(0)NH -, -C(0)N(C _1-3 alkyl) - , -NHS(0) ₂ -, -N(C _1-3 alkyl) S(0) ₂ -, -S(0) ₂ NH- , -S(0) ₂ N( Ci _-3 alkyl) -, -OC(O)- or -C(0)0-,

R₄表示氢原子， d.₄烷基， -N(d.₃烷基 )₂， -NHC(0)0-(CM烷基), -OH, -0(C_1-4烷基）， -S(0)₂(C_1-3烷基）， 3-7元环烷基，苯基或 5-6元杂芳基； R ₄ represents a hydrogen atom, d. ₄ alkyl, -N(d. ₃ alkyl) ₂ , -NHC(0)0-(CM alkyl), -OH, -0(C _1-4 alkyl), -S(0) ₂ (C _1-3 alkyl), 3-7 membered cycloalkyl, phenyl or 5-6 membered heteroaryl;

上述 c_1-3烷基和 C_M烷基中的烷基部分、环烷基、杂芳基可以进一步被 1-4个相同或不同的 Q₂取代， The alkyl moiety, cycloalkyl group, heteroaryl group in the above c _1-3 alkyl group and C _M alkyl group may be further substituted by 1 to 4 identical or different Q ₂ groups,

(^表示卤素原子、 d_₃烷基、氨基、烷基氨基、二 - ( Cw烷基）氨基、羟基、烷氧基、 d.₃烷氧羰基、氨基曱酰基、 d.₃烷基氨基甲酰基、二- ( d-₃烷基）氨基甲酰基或 3-6元环烷基，其中 Q₂可以相同或不同； (^ Represents a halogen atom, d_ ₃ alkyl, amino, alkylamino, di -.. (Cw alkyl) amino, hydroxy, alkoxy, d ₃ alkoxycarbonyl group, an amino group Yue, d ₃ alkylcarbamoyl An acyl group, a bis-(d- ₃ alkyl)carbamoyl group or a 3-6 membered cycloalkyl group, wherein Q ₂ may be the same or different;

所述环烷基和二环结构上的碳原子可以被 1-4个相同或不同的 N、 NH、 N(C_1-3烷基）、 0、 S(0)_m、 C(O)替换； The carbon atoms on the cycloalkyl and bicyclic structures may be replaced by 1-4 identical or different N, NH, N(C _1-3 alkyl), 0, S(0) _m , C(O) ;

所述杂芳基可以含有 1 -4个杂原子，所述的杂原子分别独立的选自 N、 0或 S; The heteroaryl group may have 1 to 4 hetero atoms, and the hetero atoms are independently selected from N, 0 or S;

- 表示单键或双键； - indicates a single or double button;

m表示 0 , 1或 2; m means 0, 1 or 2;

p和 q分别独立的表示 0， 1 , 2 , 3或 4。 p and q are independent representations of 0, 1, 2, 3 or 4.

2. 如权利要求 1 所述的化合物、其氘代物、其药学上可接受的盐或其立体异构体： 2. A compound according to claim 1 or a prodrug thereof, a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

其中， X表示 C-Ra或 N-Rb, Where X represents C-Ra or N-Rb,

Ra表示氢原子，卤素原子， -CF₃ , 甲基，乙基，甲氧基，甲氧基乙基，氨基，环丙基，苯基，苄基，萘基，吡咯基，呋喃基或吡啶基， Rb不存在，或者表示氢原子，被 1-2个相同或不同的（^取代或未被取代的烷基、 d-₃烷氧基 C_G-3亚烷基， C_3-6环烷基 Co_-3亚烷基，苯基，苄基，萘基，吡咯基，四氢吡喃基，呋喃基或吡啶基， Ra represents a hydrogen atom, a halogen atom, -CF ₃ , methyl, ethyl, methoxy, methoxyethyl, amino, cyclopropyl, phenyl, benzyl, naphthyl, pyrrolyl, furyl or pyridine Base, Rb does not exist, or represents a hydrogen atom, is replaced by 1-2 identical or different (^ or not Substituted alkyl, d- ₃ alkoxy C _G-3 alkylene, C _3-6 cycloalkyl Co _-3 alkylene, phenyl, benzyl, naphthyl, pyrrolyl, tetrahydropyran Base, furanyl or pyridyl,

表示烷氧基，烷氧羰基或含有选自 N或 0的杂原子的 Representing an alkoxy group, an alkoxycarbonyl group or a hetero atom selected from N or 0

5- 7元杂环基； 5- 7 membered heterocyclic group;

W表示 c=o; W means c=o;

环 A和环 B分别独立的表示苯基， 5-6元环烷基，含有选自 N、 0 和 S的杂原子的 5-6元杂环烷基， 5-6元杂芳基或 8-10元二环结构； Ring A and Ring B each independently represent a phenyl group, a 5-6 membered cycloalkyl group, a 5-6 membered heterocycloalkyl group containing a hetero atom selected from N, 0 and S, a 5-6 membered heteroaryl group or 8 -10 yuan two-ring structure;

L P L₂分别独立的表示共价键， -NH-, -N(CH₃)-, -0-， -S(0)_M -, -N(CH₃)C(0)-, -C(0)N(CH₃)-, -N(CH₃)S(0)₂-或 - S(0)₂N(CH₃)-; LPL ₂ independently represents a covalent bond, -NH-, -N(CH ₃ )-, -0-, -S(0) _M -, -N(CH ₃ )C(0)-, -C(0 N(CH ₃ )-, -N(CH ₃ )S(0) ₂ - or - S(0) ₂ N(CH ₃ )-;

a表示共价键，或未被取代或被 CH₃取代的亚氨基； a represents a covalent bond, or an imino group which is unsubstituted or substituted with CH ₃ ;

b表示 -CO-或 -S0₂-; b represents -CO- or -S0 ₂ -;

c 表示未被取代或被一或两个曱基取代的 1,2-亚乙烯基或亚乙炔基； c represents a 1,2-vinylidene or ethylene group which is unsubstituted or substituted by one or two thiol groups;

e表示氢原子，甲氧基，氨基，哌啶基，吗啉基， 6-9元螺环结构， e represents a hydrogen atom, a methoxy group, an amino group, a piperidinyl group, a morpholinyl group, a 6-9 membered spiro ring structure,

6- 8元并环结构， 6-8元桥环结构，甲基氨基，哌嗪，吡咯烷基或二 -(甲基）氨基； 6- to 8-membered ring structure, 6-8 membered bridged ring structure, methylamino, piperazine, pyrrolidinyl or bis-(methyl)amino;

1^和1₃分别独立的表示氢原子，卤素原子，硝基或 -L₃-R₄,1^ and 1 ₃ independently represent a hydrogen atom, a halogen atom, a nitro group or -L ₃ -R ₄ ,

L₃表示共价键， -NH-, -N(C_1-3烷基) -, -0-, -0-C_1-3亚烷基-， -S-C_1-3 亚烷基-, -S(0)_M -, -C(O)-, -NHC(O)-, -C(0)NH-, -NHS(0)₂-， - S(0)₂NH -，L ₃ represents a covalent bond, -NH-, -N(C _1-3 alkyl)-, -0-, -0-C _1-3 alkylene-, -SC _1-3 alkylene-, - S(0) _M -, -C(O)-, -NHC(O)-, -C(0)NH-, -NHS(0) ₂ -, - S(0) ₂ NH -,

-OC(O)-或 -C(0)0-， -OC(O)- or -C(0)0-,

R₄表示氢原子， C_1-4烷基， -N(C_1-3烷基 )₂, -NHC(0)0-(C_1-4烷基)，R ₄ represents a hydrogen atom, C _1-4 alkyl, -N(C _1-3 alkyl) ₂ , -NHC(0)0-(C _1-4 alkyl),

-OH, -O CM烷基）, -S O Cw烷基）， 5-6元环烷基，苯基或 5-6元杂芳基； -OH, -O CM alkyl), -S O Cw alkyl), 5-6 membered cycloalkyl, phenyl or 5-6 membered heteroaryl;

上述 d_₃烷基中的烷基部分、环烷基、杂芳基、螺环结构、并环结构和桥环结构可以进一步被 1-4个相同或不同的 Q₂取代， The alkyl moiety, cycloalkyl group, heteroaryl group, spiro ring structure, concentric ring structure and bridged ring structure in the above d- ₃ alkyl group may be further substituted by 1 to 4 identical or different Q ₂ groups,

Q₂表示！ ¾素原子、 d.₃烷基、氨基、烷基氨基、二 -(Cw烷基）氨基、羟基、烷氧基、 d_₃烷氧羰基、氨基甲酰基、 d.₃烷基氨基曱酰基、二- (C_1-3烷基）氨基曱酰基或 5-6元环烷基，其中 Q₂可以相同或不同； Q ₂ means! _3⁄4 atom, d. ₃ alkyl, amino, alkylamino, bis-(Cw alkyl)amino, hydroxy, alkoxy, d- ₃ alkoxycarbonyl, carbamoyl, d. ₃ alkylaminodecanoyl, a bis-(C _1-3 alkyl)aminodecanoyl group or a 5-6 membered cycloalkyl group, wherein Q ₂ may be the same or different;

所述环烷基和二环结构上的碳原子可以被 1-4个相同或不同的 N、 NH、 N(Ci_-3烷基）、 0、 S(0)_m、 C(O)替换； The carbon atoms on the cycloalkyl and bicyclic structures may be 1-4 identical or different N, NH, N(Ci _-3 alkyl), 0, S(0) _m , C(O) substitution;

所述螺环结构、并环结构和桥环结构可以含有 1-4个杂原子，所述的杂原子分别独立地选自 N、 0或 S; The spiro ring structure, the concentric ring structure and the bridged ring structure may contain 1-4 heteroatoms, each of which is independently selected from N, 0 or S;

-表示单键或双键； - indicates a single or double button;

m表示 0， 1或 2; m means 0, 1 or 2;

p和 q分别独立的表示 0， 1 , 2, 3或 4。 p and q are independent representations of 0, 1, 2, 3 or 4.

3. 如权利要求 2所述的化合物、其氘代物、其药学上可接受的盐或其立体异构体： 3. A compound according to claim 2, a deuterated compound thereof, a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

其中， X表示 CH或 N-Rb， Where X represents CH or N-Rb,

Q!表示 d.₃烷氧基或含有选自 N或 0的杂原子的 5-6元杂环基；Q! represents a d. ₃ alkoxy group or a 5-6 membered heterocyclic group containing a hetero atom selected from N or 0;

W表示 00; W means 00;

环 A和环 B分别独立的表示苯基，含有 N杂原子的 5-6元杂环烷基或 5-6元杂芳基； Ring A and ring B each independently represent a phenyl group, a 5-6 membered heterocycloalkyl group having a N hetero atom or a 5-6 membered heteroaryl group;

和 L₂分别独立的表示共价键， -NH-或 -N(C¾)-; And L ₂ independently represent a covalent bond, -NH- or -N(C3⁄4)-;

a表示共价键或亚氨基； a represents a covalent bond or an imino group;

b表示 -C0-; b means -C0-;

c表示 1,2-亚乙烯基； c represents 1,2-vinylidene;

e表示氢原子，哌啶基，吗啉基，哌嗪，吡咯烷基或二- (曱基)氨基；表示氢原子，卤素原子，未被取代或被 1-4个相同或不同的卤素原子取代的甲基、甲氧基，甲基氨基或二- (甲基）氨基； e represents a hydrogen atom, piperidinyl, morpholinyl, piperazine, pyrrolidinyl or bis-(indenyl)amino; represents a hydrogen atom, a halogen atom, is unsubstituted or is 1-4 identical or different halogen atoms Substituted methyl, methoxy, methylamino or bis-(methyl)amino;

R₃表示氢原子，卤素原子或 -L₃-R₄, R ₃ represents a hydrogen atom, a halogen atom or -L ₃ -R ₄ ,

L₃表示共价键， -NH-, -N(C_1-3烷基) -, -0-, -0-C_1-3亚烷基-, -S-Ci.3 亚烷基， -S(0)_m-， -C(0)-， -NHC(O)-, -C(0)NH-, -0C(0)-或 -C(0)0-，L ₃ represents a covalent bond, -NH-, -N(C _1-3 alkyl)-, -0-, -0-C _1-3 alkylene-, -S-Ci.3 alkylene, - S(0) _m -, -C(0)-, -NHC(O)-, -C(0)NH-, -0C(0)- or -C(0)0-,

R₄表示氢原子，甲基，乙基， -N(Cw烷基 )₂， -NHC(0)0-C₃H₇, -0(CH₃)， -0(CH₂CH₃), -0(C(CH₃)₃)， -S(0)₂-C₃H₇, 环戊烷基，环己烷基，吡咯烷基，四氢呋喃基，哌啶基，吗啉基，哌嗪基，苯基，吡咯基，咪唑基，噻唑基，噁唑基，噻二唑基，吡啶基或嘧啶基； R ₄ represents a hydrogen atom, methyl, ethyl, -N(Cw alkyl) ₂ , -NHC(0)0-C ₃ H ₇ , -0(CH ₃ ), -0(CH ₂ CH ₃ ), - 0(C(CH ₃ ) ₃ ), -S(0) ₂ -C ₃ H ₇ , cyclopentyl, cyclohexane, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, piperazinyl , phenyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, pyridyl or pyrimidinyl;

所述环戊烷基、环己烷基、吡咯烷基、四氢呋喃基、哌啶基、吗啉基、哌嗪基，苯基、吡咯基、咪唑基、噻唑基、噁唑基、噻二唑基、吡啶基、嘧啶基可以进一步被 1-2个相同或不同的 Q₂取代， The cyclopentyl group, cyclohexane group, pyrrolidinyl group, tetrahydrofuranyl group, piperidinyl group, Alkyl, piperazinyl, phenyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, pyridyl, pyrimidinyl may be further substituted by 1-2 identical or different Q ₂ ,

Q₂表示素原子、甲基、氨基、甲基氨基、二甲基氨基、羟基、甲氧基、甲氧羰基、氨基甲酰基、曱基氨基甲酰基或二- (曱基）氨基甲酰基； Q ₂ represents a sulfhydryl atom, a methyl group, an amino group, a methylamino group, a dimethylamino group, a hydroxyl group, a methoxy group, a methoxycarbonyl group, a carbamoyl group, a decylcarbamoyl group or a bis-(indenyl)carbamoyl group;

表示单键或双键； Represents a single or double bond;

m表示 0， 1或 2; m means 0, 1 or 2;

4. 如权利要求 3所述的化合物、其氘代物、其药学上可接受的盐或其立体异构体： 4. A compound according to claim 3, a progeny thereof, a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

其中， X表示 CH或 N-Rb， Where X represents CH or N-Rb,

表示甲氧基，吡咯烷酮基或吡咯烷基； Represents methoxy, pyrrolidinyl or pyrrolidinyl;

W表示 c=o; W means c=o;

R₂表示氢原子； R ₂ represents a hydrogen atom;

环 A和环 B分别独立的表示苯基，吡唑基，咪唑基，异噁唑基，噁唑基，吡啶基或哌啶基； Ring A and ring B each independently represent a phenyl group, a pyrazolyl group, an imidazolyl group, an isoxazolyl group, an oxazolyl group, a pyridyl group or a piperidinyl group;

L]和 L₂分别独立的表示共价键， -NH-或 -N(CH₃); L] and L ₂ independently represent a covalent bond, -NH- or -N(CH ₃ );

a表示共价键或亚氨基； a represents a covalent bond or an imino group;

b表示 -CO-; b means -CO-;

c表示 1，2-亚乙烯基； c represents 1,2-vinylidene;

表示氢原子，氟原子，氯原子，三氟甲基，甲氧基或三氟甲氧基； Represents a hydrogen atom, a fluorine atom, a chlorine atom, a trifluoromethyl group, a methoxy group or a trifluoromethoxy group;

R₃表示氢原子，氟原子，氯原子或 -L R₄, R ₃ represents a hydrogen atom, a fluorine atom, a chlorine atom or -LR ₄ ,

L₃表示共价键， -NH-, -N(C₃H₇) -, -0-, -0-CH₂CH₂-或 -S(0)_m -, R₄表示氢原子，甲基，乙基，二甲基氨基， -NHC(0)0-C₃H₇，L ₃ represents a covalent bond, -NH-, -N(C ₃ H ₇ ) -, -0-, -0-CH ₂ CH ₂ - or -S(0) _m -, R ₄ represents a hydrogen atom, methyl , ethyl, dimethylamino, -NHC(0)0-C ₃ H ₇ ,

-0(CH₃), -0(C(CH₃)₃), -S(0)₂-C₃H₇, 吗啉基，苯基，吡咯基，咪唑基，噻唑基，噁唑基，噻二唑基或吡啶基，所述苯基、吡咯基、咪唑基、噻唑基、噁唑基、噻二唑基、吡啶基可以进一步被 1-2个相同或不同的 Q₂取代， -0(CH ₃ ), -0(C(CH ₃ ) ₃ ), -S(0) ₂ -C ₃ H ₇ , morpholinyl, phenyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, Thiadiazolyl or pyridyl, The phenyl group, pyrrolyl group, imidazolyl group, thiazolyl group, oxazolyl group, thiadiazolyl group, pyridyl group may be further substituted by 1-2 identical or different Q ₂ groups,

Q₂表示氨基甲酰基、甲基氨基甲酰基或二- (甲基）氨基甲酰基； -表示单键或双键； Q ₂ represents a carbamoyl group, a methylcarbamoyl group or a bis-(methyl)carbamoyl group; - represents a single bond or a double bond;

m表示 0， 1或 2; m means 0, 1 or 2;

p和 q分别独立的表示 0或 1 。 p and q are independent of 0 or 1 respectively.

5. 如权利要求 4所述的化合物、其氘代物、其药学上可接受的盐或其立体异构体： 5. A compound according to claim 4, a progeny thereof, a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

其中， X表示 N-Rb， Where X represents N-Rb,

基，环丙烷基，四氢吡喃基，

Base, cyclopropane, tetrahydropyranyl,

W表示 C=0; W means C=0;

R₂表示氢原子； R ₂ represents a hydrogen atom;

环 A表示苯基； Ring A represents a phenyl group;

环 B表示苯基，吡啶基，吡唑基，咪唑基，异噁唑基或噁唑基；表示共价键； Ring B represents phenyl, pyridyl, pyrazolyl, imidazolyl, isoxazolyl or oxazolyl; represents a covalent bond;

L₂分别独立的表示共价键， -NH-或 -N(CH₃); L ₂ independently represents a covalent bond, -NH- or -N(CH ₃ );

a表示亚氨基； a represents an imino group;

b表示 -CO-; b means -CO-;

c表示 1,2-亚乙烯基； c represents 1,2-vinylidene;

表示氢原子； Represents a hydrogen atom;

R₃表示 -L₃-R₄， L₃表示共价键， 0或 -0-CH₂CH₂-， R₄表示 -0(CH₃)，二甲基氨基，吗啉基或吡啶基，所述吡啶基可以进一步被 1-2个相同或不同的 Q₂取代， Q₂表示氨基甲酰基、甲基氨基曱酰基或二 -（甲基）氨基甲酰基； R ₃ represents -L ₃ -R ₄ , L ₃ represents a covalent bond, 0 or -0-CH ₂ CH ₂ -, R ₄ represents -0(CH ₃ ), dimethylamino, morpholinyl or pyridyl, The pyridyl group may be further substituted by 1-2 identical or different Q ₂ , and Q ₂ represents a carbamoyl group, a methylaminodecanoyl group or a bis-(methyl)carbamoyl group;

- ^表示单键； - ^ means a single key;

p表示 0; q表示 1。 p represents 0; q means 1.

6. 选自下列的化合物、其氘代物、其药学上可接受的盐或其立体异构体： 6. A compound selected from the group consisting of the following, a progeny thereof, a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

7. 制备权利要求 1-6任一项所述的化合物、其氘代物、其药学上可接受的盐或其立体异构体的方法，其特征在于，所述方法包括将式 ( III ) 所示化合物与式（IV ) 所示化合物反应制备得到式（ II ) 所示化合物 7. Process for the preparation of a compound according to any one of claims 1 to 6, a progeny thereof, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, characterized in that the method comprises the formula (III) The compound of the formula (IV) is reacted to prepare a compound of the formula (II).

其

q如权利要求 1所定义。 its

q as defined in claim 1.

8. 药物组合物，所述组合物含有权利要求 1-6任一项所述的化合物、其氘代物、其药学上可接受的盐或其立体异构体和可药用载体。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 6, a progeny thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.

9. 药物组合物，所述组合物含有权利要求 1-6任一项所述的化合物、其氘代物、其药学上可接受的盐或其立体异构体，以及选自抗肿瘤剂、免疫抑制剂和 /或抗炎药的第二治疗剂。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 6, a progeny thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and an antitumor agent, immunized A second therapeutic agent for an inhibitor and/or an anti-inflammatory agent.

10. 权利要求 8-9任一项所述的药物组合物，其中所述药物组合物为药学上可接受的任一剂型。 The pharmaceutical composition according to any one of claims 8-9, wherein the pharmaceutical composition is in any of pharmaceutically acceptable dosage forms.

11. 如权利要求 1-6任一项所述的化合物、其药学上可接受的盐或其立体异构体或者如权利要求 8-10任一项所述的药物组合物在制备用于预防和 /或治疗 B细胞相关的血癌的药物中的应用。 The compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the pharmaceutical composition according to any one of claims 8 to 10, which is prepared for prevention And/or use in the treatment of B cell-associated blood cancer drugs.

12. 如权利要求 1-6任一项所述的化合物、其氘代物、其药学上可接受的盐或其立体异构体或者如权利要求 8-10任一项所述的药物组合物在制备用于预防和 /或治疗 B 细胞炎性和 /或自身免疫性疾病的药物中的应用。 12. A compound according to any one of claims 1 to 6, a progeny thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition according to any one of claims 8 to 10 Use in the preparation of a medicament for the prevention and/or treatment of B cell inflammatory and/or autoimmune diseases.

13. 预防和 /或治疗个体中 B细胞相关的血癌的方法，所迷方法包括给所迷个体施用如权利要求 1 -6任一项所述的化合物、其药学上可接受的盐或其立体异构体或者如权利要求 8- 10 任一项所迷的药物组合物。 13. A method of preventing and/or treating B cell-associated blood cancer in an individual, the method comprising administering to the individual a compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof or a stereo Isomer or a pharmaceutical composition according to any one of claims 8-10.

14. 预防和 /或治疗个体中 B细胞相关的炎性和 /或自身免疫性疾病的方法，所述方法包括给所述个体施用如权利要求 1 -6任一项所述的化合物、其药学上可接受的盐或其立体异构体或者如权利要求 8-10任一项所述的药物组合物。 A method of preventing and/or treating a B cell-associated inflammatory and/or autoimmune disease in an individual, the method comprising administering to the individual a compound according to any one of claims 1 to 6, a pharmaceutically acceptable form thereof An acceptable salt or a stereoisomer thereof or a pharmaceutical composition according to any one of claims 8-10.