CN114057770A - Bifunctional compounds targeting EGFR protein degradation - Google Patents

Bifunctional compounds targeting EGFR protein degradation Download PDF

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CN114057770A
CN114057770A CN202110889913.3A CN202110889913A CN114057770A CN 114057770 A CN114057770 A CN 114057770A CN 202110889913 A CN202110889913 A CN 202110889913A CN 114057770 A CN114057770 A CN 114057770A
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李进
潘飞
陈迪
兰燕
汤若风
辛艳飞
张登友
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Hitgen Inc
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Abstract

本发明提供一种新的双功能化合物,或其立体异构体、药学上可接受的盐及其在制备药物中的用途。本发明的双功能化合物是一种蛋白靶向联合体,能够选择性促进EGFR蛋白泛素化并降解,可用于多种癌症/肿瘤的治疗。The present invention provides a novel bifunctional compound, or a stereoisomer, a pharmaceutically acceptable salt thereof, and its use in preparing a medicine. The bifunctional compound of the present invention is a protein targeting combination, which can selectively promote the ubiquitination and degradation of EGFR protein, and can be used for the treatment of various cancers/tumors.

Description

靶向EGFR蛋白降解的双功能化合物Bifunctional compounds targeting EGFR protein degradation

技术领域technical field

本发明属于医药领域,具体涉及一种靶向EGFR蛋白降解的双功能化合物及其在制备药物中的用途。The invention belongs to the field of medicine, in particular to a bifunctional compound targeting EGFR protein degradation and its use in preparing medicine.

背景技术Background technique

EGFR(Epidermal Growth Factor Receptor)是跨膜蛋白酪氨酸激酶erbB受体家族的一员。通过与其配体-例如表皮生长因子(EGF)的结合,EGFR在细胞膜上可以形成同源二聚体,或者与家族中其他的受体(比如erbB2,erbB3,或erbB4)形成异源二聚体。这些二聚体的形成,可引起EGFR细胞内关键的酪氨酸残基磷酸化,从而激活细胞内多个下游的信号通路。这些细胞内信号通路在细胞增殖、生存及抗凋亡中起重要作用。EGFR信号传导通路失调,包括配体及受体的表达增高、EGFR基因扩增以及突变等,可促进细胞向恶性转化,并在肿瘤细胞的增殖、侵袭、转移以及血管形成中起重要作用。因此EGFR被认为是抗癌药物开发的靶点。EGFR (Epidermal Growth Factor Receptor) is a member of the transmembrane protein tyrosine kinase erbB receptor family. EGFR can form homodimers on the cell membrane by binding to its ligands, such as epidermal growth factor (EGF), or heterodimers with other receptors in the family (such as erbB2, erbB3, or erbB4) . The formation of these dimers can cause phosphorylation of key tyrosine residues in EGFR cells, thereby activating multiple downstream signaling pathways in cells. These intracellular signaling pathways play important roles in cell proliferation, survival and anti-apoptosis. Dysregulation of the EGFR signaling pathway, including increased expression of ligands and receptors, EGFR gene amplification, and mutation, can promote the malignant transformation of cells and play an important role in tumor cell proliferation, invasion, metastasis, and angiogenesis. Therefore, EGFR is considered as a target for anticancer drug development.

泛素蛋白(Ubiquitin)自身由76个氨基酸残基所组成,分子量约8.5kDa,以“泛素”为名是因为它在真核生物体中广泛存在。泛素化(Ubiquitination)是指泛素分子在一系列特殊的酶作用下,将细胞内的蛋白质分类,从中选出靶蛋白分子,对靶蛋白进行特异性修饰的过程,形成靶蛋白多聚泛素链。这些特殊的酶包括泛素活化酶(E1),泛素结合酶(E2)、泛素连结酶(E3)等。泛素化与肿瘤、心血管、自身免疫等疾病的发病密切相关。泛素-蛋白酶体系统降解蛋白是蛋白质选择性降解的重要途径,可以简单地分为三个步骤:首先由一种连接酶给目标蛋白加上泛素标签,然后经过多轮泛素化后就有了多个泛素标签,多聚泛素化之后的蛋白会被一种蛋白酶体识别并被降解。通过构建双功能化合物,一头是靶向目标蛋白的结构;另一头是可以结合蛋白降解体系比如E3连结酶,中间通过合适的连接链连接,可以有效促进靶点蛋白的降解。Ubiquitin itself consists of 76 amino acid residues with a molecular weight of about 8.5kDa. It is named "ubiquitin" because it is widely present in eukaryotic organisms. Ubiquitination refers to the process in which ubiquitin molecules classify intracellular proteins under the action of a series of special enzymes, select target protein molecules, and specifically modify the target protein to form target protein polyubiquitination. prime chain. These special enzymes include ubiquitin activating enzyme (E1), ubiquitin conjugating enzyme (E2), ubiquitin ligase (E3), etc. Ubiquitination is closely related to the pathogenesis of tumors, cardiovascular, autoimmunity and other diseases. Degradation of proteins by the ubiquitin-proteasome system is an important pathway for selective protein degradation, which can be simply divided into three steps: first, a ligase adds a ubiquitin tag to the target protein, and then after multiple rounds of ubiquitination With multiple ubiquitin tags, the polyubiquitinated protein is recognized by a proteasome and degraded. By constructing a bifunctional compound, one end is a structure targeting the target protein; the other end is a protein degradation system such as E3 ligase, and the middle is connected by a suitable connecting chain, which can effectively promote the degradation of the target protein.

已上市的EGFR抑制剂药物在治疗后大多会产生对小分子抑制剂的抗药性。其耐药机制包括EGFR继发突变、旁通路激活等。目前还没有通过构建双功能化合物降解EGFR蛋白的药物上市。开发能够泛素化降解EGFR蛋白的双功能化合物可能成为一种新的治疗肿瘤或癌症的方法,具有广阔的应用前景。Most of the marketed EGFR inhibitor drugs develop resistance to small molecule inhibitors after treatment. The drug resistance mechanisms include EGFR secondary mutations, bypass pathway activation and so on. There are no drugs on the market that degrade EGFR proteins by constructing bifunctional compounds. The development of bifunctional compounds that can degrade EGFR protein by ubiquitination may become a new method for the treatment of tumors or cancers, which has broad application prospects.

发明内容SUMMARY OF THE INVENTION

本发明提供了一种式I所示的双功能化合物,或其立体异构体、药学上可接受的盐:The present invention provides a bifunctional compound shown in formula I, or a stereoisomer or a pharmaceutically acceptable salt thereof:

Figure BDA0003199064950000021
Figure BDA0003199064950000021

其中,in,

R1选自氢、卤素、=O、-C1~6烷基、卤素取代的-C1~6烷基、-OR、-NRR、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);R 1 is selected from hydrogen, halogen, =O, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OR, -NRR, -C 0-2 alkylene-(3-10 yuan cycloalkyl), -C 0-2 alkylene-(3-10 membered heterocycloalkyl);

R2选自氢、卤素、氰基、硝基、-C1~6烷基、卤素取代的-C1~6烷基、-OR、-NRR、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);R 2 is selected from hydrogen, halogen, cyano, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OR, -NRR, -C 0-2 alkylene-(3 ~10-membered cycloalkyl), -C 0-2 alkylene-(3-10-membered heterocycloalkyl);

X1、X2分别独立选自O、S、NRx1、CRx1Rx2X 1 and X 2 are independently selected from O, S, NR x1 , CR x1 R x2 ;

Rx1、Rx2分别独立选自氢、-C1~6烷基、卤素取代的-C1~6烷基、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);R x1 and R x2 are independently selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene-(3-10 membered cycloalkyl), - C 0-2 alkylene-(3-10-membered heterocycloalkyl);

Y选自N或CRY1Y is selected from N or CR Y1 ;

RY1选自氢、C1~10烷基、卤素取代的-C1~6烷基、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);R Y1 is selected from hydrogen, C 1-10 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene-(3-10 membered cycloalkyl), -C 0-2 alkylene base-(3-10 membered heterocycloalkyl);

A环选自苯环、5~6元芳杂环;其中苯环、芳杂环可进一步被一个、两个或三个RA取代;Ring A is selected from benzene ring and 5-6 membered aromatic heterocycle; wherein benzene ring and aromatic heterocycle can be further substituted by one, two or three R A ;

每个RA分别独立选自氢、卤素、氰基、硝基、-C1~6烷基、卤素取代的-C1~6烷基、-OR、-NRR、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);Each R A is independently selected from hydrogen, halogen, cyano, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OR, -NRR, -C 0-2 alkylene base-(3-10-membered cycloalkyl), -C 0-2 alkylene-(3-10-membered heterocycloalkyl);

R4、R5分别独立有0、1、2或3个;R 4 and R 5 are independently 0, 1, 2 or 3 respectively;

R4、R5分别独立选自氢、卤素、氰基、硝基、-C1~6烷基、卤素取代的-C1~6烷基、-OR、-NRR、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);R 4 and R 5 are independently selected from hydrogen, halogen, cyano, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OR, -NRR, -C 0-2 alkylene Alkyl-(3-10-membered cycloalkyl), -C 0-2 alkylene-(3-10-membered heterocycloalkyl);

Z1、Z2、Z3、Z4分别独立选自CH或N;Z 1 , Z 2 , Z 3 , Z 4 are independently selected from CH or N;

B环选自5~6元环烷基、5~6元杂环烷基、5~6元芳环、5~6元芳杂环;其中环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个RB取代;Ring B is selected from 5-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aromatic ring, 5-6 membered aromatic heterocycle; wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic ring The heterocycle may be further substituted with one, two or three R ;

每个RB分别独立选自氢、卤素、氰基、硝基、=O、=S、-C1~6烷基、卤素取代的-C1~6烷基、-OR、-NRR、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);Each R B is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OR, -NRR, - C 0-2 alkylene-(3-10-membered cycloalkyl), -C 0-2 alkylene-(3-10-membered heterocycloalkyl);

L为-(LA)q-;L is -(L A ) q -;

q为大于或等于1的整数,小于等于100的整数;q is an integer greater than or equal to 1, and an integer less than or equal to 100;

每个LA分别独立选自CRR、C(O)、O、S、S(O)、S(O)2、NR、-CR=CR-、-C≡C-、P(O)R、P(O)OR、3~10元环烷烃、3~10元杂环烷烃、5~10元芳环、5~10元芳杂环、5~12元螺环、5~12元螺杂环、5~12元桥环、5~12元桥杂环;其中环烷烃、杂环烷烃、芳环、芳杂环、螺环、螺杂环、桥环、桥杂环可进一步被一个、两个或三个RLA取代;Each LA is independently selected from CRR, C (O), O, S, S(O), S(O) 2 , NR, -CR=CR-, -C≡C-, P(O)R, P(O)OR, 3-10-membered cycloalkane, 3-10-membered heterocycloalkane, 5-10-membered aromatic ring, 5-10-membered aromatic heterocycle, 5-12-membered spirocycle, 5-12-membered spiroheterocycle , 5-12-membered bridged ring, 5-12-membered bridged heterocyclic ring; wherein cycloalkane, heterocycloalkane, aromatic ring, aromatic heterocyclic ring, spirocyclic ring, spiro heterocyclic ring, bridged ring, bridged heterocyclic ring can be further replaced by one, two one or three R LA substitutions;

每个RLA分别独立选自氢、卤素、=O、氰基、硝基、-C1~6烷基、卤素取代的-C1~6烷基、-OR、-NRR、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);Each R LA is independently selected from hydrogen, halogen, =O, cyano, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OR, -NRR, -C 0- 2 alkylene-(3-10-membered cycloalkyl), -C 0-2 alkylene-(3-10-membered heterocycloalkyl);

每个R分别独立选自氢、C1~10烷基、卤素取代的-C1~6烷基、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)。Each R is independently selected from hydrogen, C 1-10 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene-(3-10 membered cycloalkyl), -C 0- 2 -alkylene-(3- to 10-membered heterocycloalkyl).

进一步地,further,

B环选自

Figure BDA0003199064950000031
Figure BDA0003199064950000032
Ring B is selected from
Figure BDA0003199064950000031
or
Figure BDA0003199064950000032

进一步地,further,

L为-LA1-LA2-LA3-LA4-LA5-LA6-LA7-;L is -L A1 -L A2 -L A3 -L A4 -L A5 -L A6 -L A7 -;

其中,LA1一端与

Figure BDA0003199064950000033
相连,另一端与LA2相连;Among them, one end of L A1 is connected to
Figure BDA0003199064950000033
connected, and the other end is connected to L A2 ;

LA7一端与LA6相连,另一端与

Figure BDA0003199064950000034
相连;One end of L A7 is connected to L A6 , and the other end is connected to
Figure BDA0003199064950000034
connected;

LA1选自-(C0~2亚烷基)-;L A1 is selected from -(C 0-2 alkylene)-;

LA2选自-NR-、-(5~6元杂环烷基)-或无;L A2 is selected from -NR-, -(5-6 membered heterocycloalkyl)- or none;

LA3选自-(5~6元杂环烷基)-、-(5~10元桥杂环)-、-(6~9元螺杂环)-、-(C1~10亚烷基)-NR-、-(5~6元杂环烷基)-NR-、-(5~10元桥杂环)-NR-、-(6~9元螺杂环)-NR-、-(C0~10亚烷基)-;L A3 is selected from -(5-6-membered heterocycloalkyl)-, -(5-10-membered bridged heterocycle)-, -(6-9 membered spiro heterocycle)-, -(C 1-10 alkylene )-NR-, -(5~6 membered heterocycloalkyl)-NR-, -(5~10 membered bridged heterocycle)-NR-, -(6~9 membered spiro heterocycle)-NR-, -( C 0~10 alkylene)-;

LA4选自-C(O)-、-(5~6元杂环烷基)-或无;L A4 is selected from -C(O)-, -(5-6 membered heterocycloalkyl)- or none;

LA5选自-(C0~10亚烷基)-或-C(O)-;L A5 is selected from -(C 0-10 alkylene)- or -C(O)-;

LA6选自-O-、-NR-或无;L A6 is selected from -O-, -NR- or none;

LA7选自-(CH≡CH)-、-(3~6元环烷烃)-、-(3~6元杂环)-、-(5~6元芳杂环)-、-(6~9元螺环)-、-(6~9元螺杂环)-、-(C0~10亚烷基)-或无;L A7 is selected from -(CH≡CH)-, -(3-6 membered cycloalkane)-, -(3-6 membered heterocycle)-, -(5-6 membered aromatic heterocycle)-, -(6- 9-membered spirocycle)-, -(6-9 membered spiroheterocycle)-, -(C 0-10 alkylene)- or none;

每个R分别独立选自氢、C1~10烷基。Each R is independently selected from hydrogen, C 1-10 alkyl.

更进一步地,go a step further,

LA3选自

Figure BDA0003199064950000041
Figure BDA0003199064950000042
L A3 is selected from
Figure BDA0003199064950000041
Figure BDA0003199064950000042

LA7选自-(CH≡CH)-、-(C0~10亚烷基)-、

Figure BDA0003199064950000043
Figure BDA0003199064950000044
或无。L A7 is selected from -(CH≡CH)-, -(C 0-10 alkylene)-,
Figure BDA0003199064950000043
Figure BDA0003199064950000044
or none.

进一步地,further,

R1选自甲基;R2选自甲基;X1选自O;X2选自CH2;Y选自N;R 1 is selected from methyl; R 2 is selected from methyl; X 1 is selected from O; X 2 is selected from CH 2 ; Y is selected from N;

A环选自吡唑或吡啶;其中吡唑或吡啶可进一步被一个、两个或三个RA取代;每个RA分别独立选自氢、甲基;Ring A is selected from pyrazole or pyridine; wherein pyrazole or pyridine can be further substituted by one, two or three RAs ; each RA is independently selected from hydrogen, methyl;

R4、R5分别独立选自氢。R 4 and R 5 are each independently selected from hydrogen.

进一步地,所述式I的化合物如式IIa所示:Further, the compound of the formula I is shown in the formula IIa:

Figure BDA0003199064950000045
Figure BDA0003199064950000045

其中,in,

R1选自氢、卤素、=O、-C1~6烷基、卤素取代的-C1~6烷基、-OR、-NRR、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);R 1 is selected from hydrogen, halogen, =O, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OR, -NRR, -C 0-2 alkylene-(3-10 yuan cycloalkyl), -C 0-2 alkylene-(3-10 membered heterocycloalkyl);

R2选自氢、卤素、氰基、硝基、-C1~6烷基、卤素取代的-C1~6烷基、-OR、-NRR、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);R 2 is selected from hydrogen, halogen, cyano, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OR, -NRR, -C 0-2 alkylene-(3 ~10-membered cycloalkyl), -C 0-2 alkylene-(3-10-membered heterocycloalkyl);

X1、X2分别独立选自O、S、NRx1、CRx1Rx2X 1 and X 2 are independently selected from O, S, NR x1 , CR x1 R x2 ;

Rx1、Rx2分别独立选自氢、-C1~6烷基、卤素取代的-C1~6烷基、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);R x1 and R x2 are independently selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene-(3-10 membered cycloalkyl), - C 0-2 alkylene-(3-10-membered heterocycloalkyl);

Y选自N或CRY1Y is selected from N or CR Y1 ;

RY1选自氢、C1~10烷基、卤素取代的-C1~6烷基、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);R Y1 is selected from hydrogen, C 1-10 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene-(3-10 membered cycloalkyl), -C 0-2 alkylene base-(3-10 membered heterocycloalkyl);

A环选自苯环、5~6元芳杂环;其中苯环、芳杂环可进一步被一个、两个或三个RA取代;Ring A is selected from benzene ring and 5-6 membered aromatic heterocycle; wherein benzene ring and aromatic heterocycle can be further substituted by one, two or three R A ;

每个RA分别独立选自氢、卤素、氰基、硝基、-C1~6烷基、卤素取代的-C1~6烷基、-OR、-NRR、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);Each R A is independently selected from hydrogen, halogen, cyano, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OR, -NRR, -C 0-2 alkylene base-(3-10-membered cycloalkyl), -C 0-2 alkylene-(3-10-membered heterocycloalkyl);

R4、R5分别独立有0、1、2或3个;R 4 and R 5 are independently 0, 1, 2 or 3 respectively;

R4、R5分别独立选自氢、卤素、氰基、硝基、-C1~6烷基、卤素取代的-C1~6烷基、-OR、-NRR、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);R 4 and R 5 are independently selected from hydrogen, halogen, cyano, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OR, -NRR, -C 0-2 alkylene Alkyl-(3-10-membered cycloalkyl), -C 0-2 alkylene-(3-10-membered heterocycloalkyl);

Z1、Z2、Z3、Z4分别独立选自CH或N;Z 1 , Z 2 , Z 3 , Z 4 are independently selected from CH or N;

L为-(LA)q-;L is -(L A ) q -;

q为大于或等于1的整数;q is an integer greater than or equal to 1;

每个LA分别独立选自CRR、C(O)、O、S、S(O)、S(O)2、NR、-CR=CR-、-C≡C-、P(O)R、P(O)OR、3~10元环烷基、3~10元杂环烷基、5~10元芳环、5~10元芳杂环、5~12元螺环、5~12元螺杂环、5~12元桥环、5~12元桥杂环;其中环烷基、杂环烷基、芳环、芳杂环、螺环、螺杂环、桥环、桥杂环可进一步被一个、两个或三个RLA取代;Each LA is independently selected from CRR, C (O), O, S, S(O), S(O) 2 , NR, -CR=CR-, -C≡C-, P(O)R, P(O)OR, 3-10-membered cycloalkyl, 3-10-membered heterocycloalkyl, 5-10-membered aromatic ring, 5-10-membered aromatic heterocycle, 5-12-membered spiro, 5-12-membered spiro Heterocycle, 5-12-membered bridged ring, 5-12-membered bridged heterocycle; wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle, spirocycle, spiroheterocycle, bridged ring, bridged heterocycle can be further replaced by one, two or three R LAs ;

每个RLA分别独立选自氢、卤素、=O、氰基、硝基、-C1~6烷基、卤素取代的-C1~6烷基、-OR、-NRR、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);Each R LA is independently selected from hydrogen, halogen, =O, cyano, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OR, -NRR, -C 0- 2 alkylene-(3-10-membered cycloalkyl), -C 0-2 alkylene-(3-10-membered heterocycloalkyl);

每个R分别独立选自氢、C1~10烷基、卤素取代的-C1~6烷基、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)。Each R is independently selected from hydrogen, C 1-10 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene-(3-10 membered cycloalkyl), -C 0- 2 -alkylene-(3- to 10-membered heterocycloalkyl).

进一步地,所述式I的化合物如式IIb所示:Further, the compound of formula I is shown in formula IIb:

Figure BDA0003199064950000061
Figure BDA0003199064950000061

其中,in,

R1选自氢、卤素、=O、-C1~6烷基、卤素取代的-C1~6烷基、-OR、-NRR、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);R 1 is selected from hydrogen, halogen, =O, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OR, -NRR, -C 0-2 alkylene-(3-10 yuan cycloalkyl), -C 0-2 alkylene-(3-10 membered heterocycloalkyl);

R2选自氢、卤素、氰基、硝基、-C1~6烷基、卤素取代的-C1~6烷基、-OR、-NRR、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);R 2 is selected from hydrogen, halogen, cyano, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OR, -NRR, -C 0-2 alkylene-(3 ~10-membered cycloalkyl), -C 0-2 alkylene-(3-10-membered heterocycloalkyl);

X1、X2分别独立选自O、S、NRx1、CRx1Rx2X 1 and X 2 are independently selected from O, S, NR x1 , CR x1 R x2 ;

Rx1、Rx2分别独立选自氢、-C1~6烷基、卤素取代的-C1~6烷基、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);R x1 and R x2 are independently selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene-(3-10 membered cycloalkyl), - C 0-2 alkylene-(3-10-membered heterocycloalkyl);

Y选自N或CRY1Y is selected from N or CR Y1 ;

RY1选自氢、C1~10烷基、卤素取代的-C1~6烷基、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);R Y1 is selected from hydrogen, C 1-10 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene-(3-10 membered cycloalkyl), -C 0-2 alkylene base-(3-10 membered heterocycloalkyl);

A环选自苯环、5~6元芳杂环;其中苯环、芳杂环可进一步被一个、两个或三个RA取代;Ring A is selected from benzene ring and 5-6 membered aromatic heterocycle; wherein benzene ring and aromatic heterocycle can be further substituted by one, two or three R A ;

每个RA分别独立选自氢、卤素、氰基、硝基、-C1~6烷基、卤素取代的-C1~6烷基、-OR、-NRR、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);Each R A is independently selected from hydrogen, halogen, cyano, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OR, -NRR, -C 0-2 alkylene base-(3-10-membered cycloalkyl), -C 0-2 alkylene-(3-10-membered heterocycloalkyl);

R4、R5分别独立有0、1、2或3个;R 4 and R 5 are independently 0, 1, 2 or 3 respectively;

R4、R5分别独立选自氢、卤素、氰基、硝基、-C1~6烷基、卤素取代的-C1~6烷基、-OR、-NRR、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);R 4 and R 5 are independently selected from hydrogen, halogen, cyano, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OR, -NRR, -C 0-2 alkylene Alkyl-(3-10-membered cycloalkyl), -C 0-2 alkylene-(3-10-membered heterocycloalkyl);

Z1、Z2、Z3、Z4分别独立选自CH或N;Z 1 , Z 2 , Z 3 , Z 4 are independently selected from CH or N;

RB选自氢、卤素、氰基、硝基、=O、=S、-C1~6烷基、卤素取代的-C1~6烷基、-OR、-NRR、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);R B is selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OR, -NRR, -C 0-2 Alkylene-(3-10-membered cycloalkyl), -C 0-2 alkylene-(3-10-membered heterocycloalkyl);

L为-(LA)q-;L is -(L A ) q -;

q为大于或等于1的整数;q is an integer greater than or equal to 1;

每个LA分别独立选自CRR、C(O)、O、S、S(O)、S(O)2、NR、-CR=CR-、-C≡C-、P(O)R、P(O)OR、3~10元环烷基、3~10元杂环烷基、5~10元芳环、5~10元芳杂环、5~12元螺环、5~12元螺杂环、5~12元桥环、5~12元桥杂环;其中环烷基、杂环烷基、芳环、芳杂环、螺环、螺杂环、桥环、桥杂环可进一步被一个、两个或三个RLA取代;Each LA is independently selected from CRR, C (O), O, S, S(O), S(O) 2 , NR, -CR=CR-, -C≡C-, P(O)R, P(O)OR, 3-10-membered cycloalkyl, 3-10-membered heterocycloalkyl, 5-10-membered aromatic ring, 5-10-membered aromatic heterocycle, 5-12-membered spiro, 5-12-membered spiro Heterocycle, 5-12-membered bridged ring, 5-12-membered bridged heterocycle; wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle, spirocycle, spiroheterocycle, bridged ring, bridged heterocycle can be further replaced by one, two or three R LAs ;

每个RLA分别独立选自氢、卤素、=O、氰基、硝基、-C1~6烷基、卤素取代的-C1~6烷基、-OR、-NRR、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);Each R LA is independently selected from hydrogen, halogen, =O, cyano, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OR, -NRR, -C 0- 2 alkylene-(3-10-membered cycloalkyl), -C 0-2 alkylene-(3-10-membered heterocycloalkyl);

每个R分别独立选自氢、C1~10烷基、卤素取代的-C1~6烷基、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)。Each R is independently selected from hydrogen, C 1-10 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene-(3-10 membered cycloalkyl), -C 0- 2 -alkylene-(3- to 10-membered heterocycloalkyl).

进一步地,所述式I的化合物如式IIc所示:Further, the compound of formula I is shown in formula IIc:

Figure BDA0003199064950000071
Figure BDA0003199064950000071

其中,in,

R1选自氢、卤素、=O、-C1~6烷基、卤素取代的-C1~6烷基、-OR、-NRR、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);R 1 is selected from hydrogen, halogen, =O, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OR, -NRR, -C 0-2 alkylene-(3-10 yuan cycloalkyl), -C 0-2 alkylene-(3-10 membered heterocycloalkyl);

R2选自氢、卤素、氰基、硝基、-C1~6烷基、卤素取代的-C1~6烷基、-OR、-NRR、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);R 2 is selected from hydrogen, halogen, cyano, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OR, -NRR, -C 0-2 alkylene-(3 ~10-membered cycloalkyl), -C 0-2 alkylene-(3-10-membered heterocycloalkyl);

X1、X2分别独立选自O、S、NRx1、CRx1Rx2X 1 and X 2 are independently selected from O, S, NR x1 , CR x1 R x2 ;

Rx1、Rx2分别独立选自氢、-C1~6烷基、卤素取代的-C1~6烷基、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);R x1 and R x2 are independently selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene-(3-10 membered cycloalkyl), - C 0-2 alkylene-(3-10-membered heterocycloalkyl);

Y选自N或CRY1Y is selected from N or CR Y1 ;

RY1选自氢、C1~10烷基、卤素取代的-C1~6烷基、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);R Y1 is selected from hydrogen, C 1-10 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene-(3-10 membered cycloalkyl), -C 0-2 alkylene base-(3-10 membered heterocycloalkyl);

A环选自苯环、5~6元芳杂环;其中苯环、芳杂环可进一步被一个、两个或三个RA取代;Ring A is selected from benzene ring and 5-6 membered aromatic heterocycle; wherein benzene ring and aromatic heterocycle can be further substituted by one, two or three R A ;

每个RA分别独立选自氢、卤素、氰基、硝基、-C1~6烷基、卤素取代的-C1~6烷基、-OR、-NRR、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);Each R A is independently selected from hydrogen, halogen, cyano, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OR, -NRR, -C 0-2 alkylene base-(3-10-membered cycloalkyl), -C 0-2 alkylene-(3-10-membered heterocycloalkyl);

R4、R5分别独立有0、1、2或3个;R 4 and R 5 are independently 0, 1, 2 or 3 respectively;

R4、R5分别独立选自氢、卤素、氰基、硝基、-C1~6烷基、卤素取代的-C1~6烷基、-OR、-NRR、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);R 4 and R 5 are independently selected from hydrogen, halogen, cyano, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OR, -NRR, -C 0-2 alkylene Alkyl-(3-10-membered cycloalkyl), -C 0-2 alkylene-(3-10-membered heterocycloalkyl);

Z1、Z2、Z3、Z4分别独立选自CH或N;Z 1 , Z 2 , Z 3 , Z 4 are independently selected from CH or N;

W选自C(O)、CRR、NR;W is selected from C(O), CRR, NR;

L为-(LA)q-;L is -(L A ) q -;

q为大于或等于1的整数;q is an integer greater than or equal to 1;

每个LA分别独立选自CRR、C(O)、O、S、S(O)、S(O)2、NR、-CR=CR-、-C≡C-、P(O)R、P(O)OR、3~10元环烷基、3~10元杂环烷基、5~10元芳环、5~10元芳杂环、5~12元螺环、5~12元螺杂环、5~12元桥环、5~12元桥杂环;其中环烷基、杂环烷基、芳环、芳杂环、螺环、螺杂环、桥环、桥杂环可进一步被一个、两个或三个RLA取代;Each LA is independently selected from CRR, C (O), O, S, S(O), S(O) 2 , NR, -CR=CR-, -C≡C-, P(O)R, P(O)OR, 3-10-membered cycloalkyl, 3-10-membered heterocycloalkyl, 5-10-membered aromatic ring, 5-10-membered aromatic heterocycle, 5-12-membered spiro, 5-12-membered spiro Heterocycle, 5-12-membered bridged ring, 5-12-membered bridged heterocycle; wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle, spirocycle, spiroheterocycle, bridged ring, bridged heterocycle can be further replaced by one, two or three R LAs ;

每个RLA分别独立选自氢、卤素、=O、氰基、硝基、-C1~6烷基、卤素取代的-C1~6烷基、-OR、-NRR、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);Each R LA is independently selected from hydrogen, halogen, =O, cyano, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OR, -NRR, -C 0- 2 alkylene-(3-10-membered cycloalkyl), -C 0-2 alkylene-(3-10-membered heterocycloalkyl);

每个R分别独立选自氢、C1~10烷基、卤素取代的-C1~6烷基、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)。Each R is independently selected from hydrogen, C 1-10 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene-(3-10 membered cycloalkyl), -C 0- 2 -alkylene-(3- to 10-membered heterocycloalkyl).

进一步具体地,More specifically,

L选自如下基团:L is selected from the following groups:

-(C0~2亚烷基)-(5~6元杂环烷基)-(C0~10亚烷基)-(CH≡CH)-、-(C 0-2 alkylene)-(5-6 membered heterocycloalkyl)-(C 0-10 alkylene)-(CH≡CH)-,

-(C0~2亚烷基)-(5~6元杂环烷基)-(C0~10亚烷基)-、-(C 0-2 alkylene)-(5-6 membered heterocycloalkyl)-(C 0-10 alkylene)-,

-(C0~2亚烷基)-(5~6元杂环烷基)-(C0~10亚烷基)-(C0~10亚烷基)-、-(C 0-2 alkylene)-(5-6 membered heterocycloalkyl)-(C 0-10 alkylene)-(C 0-10 alkylene)-,

-(C0~2亚烷基)-(5~6元杂环烷基)-(C0~10亚烷基)-(3~6元环烷烃)-、-(C 0-2 alkylene)-(5-6 membered heterocycloalkyl)-(C 0-10 alkylene)-(3-6 membered cycloalkane)-,

-(C0~2亚烷基)-(5~6元杂环烷基)-(C0~10亚烷基)-(3~6元杂环)-、-(C 0-2 alkylene)-(5-6 membered heterocycloalkyl)-(C 0-10 alkylene)-(3-6 membered heterocycle)-,

-(C0~2亚烷基)-(5~6元杂环烷基)-(C0~10亚烷基)-(5~6元芳杂环)-、-(C 0-2 alkylene)-(5-6 membered heterocycloalkyl)-(C 0-10 alkylene)-(5-6 membered aromatic heterocycle)-,

-(C0~2亚烷基)-(5~6元杂环烷基)-(5~6元杂环烷基)-(C0~10亚烷基)--(C 0-2 alkylene)-(5-6 membered heterocycloalkyl)-(5-6 membered heterocycloalkyl)-(C 0-10 alkylene)-

-(C0~2亚烷基)-(5~6元杂环烷基)-(5~6元杂环烷基)-(C0~10亚烷基)-(5~6元芳杂环)-、-(C 0-2 alkylene)-(5-6 membered heterocycloalkyl)-(5-6 membered heterocycloalkyl)-(C 0-10 alkylene)-(5-6 membered aromatic hetero ring)-,

-(C0~2亚烷基)-(5~6元杂环烷基)-(C0~2亚烷基)-(5~6元杂环烷基)-(C0~10亚烷基)-(5~6元芳杂环)-、-(C 0-2 alkylene)-(5-6 membered heterocycloalkyl)-(C 0-2 alkylene)-(5-6 membered heterocycloalkyl)-(C 0-10 alkylene base)-(5-6 membered aromatic heterocycle)-,

-(C0~2亚烷基)-(5~6元杂环烷基)-(C0~10亚烷基)-O-、-(C 0-2 alkylene)-(5-6 membered heterocycloalkyl)-(C 0-10 alkylene)-O-,

-(C0~2亚烷基)-(5~6元杂环烷基)-(C0~10亚烷基)-O-(3~6元环烷烃)-、-(C 0-2 alkylene)-(5-6 membered heterocycloalkyl)-(C 0-10 alkylene)-O-(3-6 membered cycloalkane)-,

-(C0~2亚烷基)-(5~6元杂环烷基)-(C0~10亚烷基)-O-(C0~10亚烷基)-、-(C 0-2 alkylene)-(5-6 membered heterocycloalkyl)-(C 0-10 alkylene)-O-(C 0-10 alkylene)-,

-(C0~2亚烷基)-(5~6元杂环烷基)-(C0~10亚烷基)-(6~9元螺杂环)-、-(C 0-2 alkylene)-(5-6 membered heterocycloalkyl)-(C 0-10 alkylene)-(6-9 membered spiroheterocycle)-,

-(C0~2亚烷基)-(5~6元杂环烷基)-C(O)-(C0~10亚烷基)-(CH≡CH)-、-(C 0-2 alkylene)-(5-6 membered heterocycloalkyl)-C(O)-(C 0-10 alkylene)-(CH≡CH)-,

-(C0~2亚烷基)-(5~6元杂环烷基)-C(O)-(C0~10亚烷基)-、-(C 0-2 alkylene)-(5-6 membered heterocycloalkyl)-C(O)-(C 0-10 alkylene)-,

-(C0~2亚烷基)-(5~6元杂环烷基)-(5~6元杂环烷基)-C(O)-(C0~10亚烷基)-、-(C 0-2 alkylene)-(5-6 membered heterocycloalkyl)-(5-6 membered heterocycloalkyl)-C(O)-(C 0-10 alkylene)-,

-(C0~2亚烷基)-(5~6元杂环烷基)-(C0~2亚烷基)-(5~6元杂环烷基)-C(O)-(C0~2亚烷基)-O-、-(C 0-2 alkylene)-(5-6 membered heterocycloalkyl)-(C 0-2 alkylene)-(5-6 membered heterocycloalkyl)-C(O)-(C 0~2 alkylene)-O-,

-(C0~2亚烷基)-(5~6元杂环烷基)-C(O)-(C0~10亚烷基)-(3~6元环烷烃)-、-(C 0-2 alkylene)-(5-6 membered heterocycloalkyl)-C(O)-(C 0-10 alkylene)-(3-6 membered cycloalkane)-,

-(C0~2亚烷基)-(5~6元杂环烷基)-C(O)-(C0~10亚烷基)-(3~6元杂环)-、-(C 0-2 alkylene)-(5-6 membered heterocycloalkyl)-C(O)-(C 0-10 alkylene)-(3-6 membered heterocycle)-,

-(C0~2亚烷基)-(5~6元杂环烷基)-C(O)-(C0~10亚烷基)-(5~6元芳杂环)-。-(C 0-2 alkylene)-(5-6 membered heterocycloalkyl)-C(O)-(C 0-10 alkylene)-(5-6 membered aromatic heterocycle)-.

更进一步具体地,More specifically,

R1选自甲基;R2选自甲基;X1选自O;X2选自CH2;Y选自N;R 1 is selected from methyl; R 2 is selected from methyl; X 1 is selected from O; X 2 is selected from CH 2 ; Y is selected from N;

A环选自吡唑或吡啶;其中吡唑或吡啶可进一步被一个、两个或三个RA取代;每个RA分别独立选自氢、甲基;Ring A is selected from pyrazole or pyridine; wherein pyrazole or pyridine can be further substituted by one, two or three RAs ; each RA is independently selected from hydrogen, methyl;

R4、R5分别独立选自氢;R 4 and R 5 are independently selected from hydrogen;

W选自C(O)、CH2、NH;W is selected from C(O), CH2 , NH;

RB选自甲基;R B is selected from methyl;

L选自如下连接基团:L is selected from the following linking groups:

-(C0~1亚烷基)-(哌嗪)-(C0~10亚烷基)-(CH≡CH)-、-(C 0-1 alkylene)-(piperazine)-(C 0-10 alkylene)-(CH≡CH)-,

-(C0~1亚烷基)-(哌嗪)-(C0~10亚烷基)-、-(C 0-1 alkylene)-(piperazine)-(C 0-10 alkylene)-,

-(C0~1亚烷基)-(哌嗪)-(C0~10亚烷基)-(C0~10亚烷基)-、-(C 0-1 alkylene)-(piperazine)-(C 0-10 alkylene)-(C 0-10 alkylene)-,

-(C0~1亚烷基)-(哌嗪)-(哌嗪)-(C0~10亚烷基)-、-(C 0-1 alkylene)-(piperazine)-(piperazine)-(C 0-10 alkylene)-,

-(C0~1亚烷基)-(哌嗪)-(哌嗪)-(C0~10亚烷基)-(吡唑)-、-(C 0-1 alkylene)-(piperazine)-(piperazine)-(C 0-10 alkylene)-(pyrazole)-,

-(C0~1亚烷基)-(哌嗪)-(C0~2亚烷基)-(哌嗪)-(C0~10亚烷基)-(吡唑)-、-(C 0-1 alkylene)-(piperazine)-(C 0-2 alkylene)-(piperazine)-(C 0-10 alkylene)-(pyrazole)-,

-(C0~1亚烷基)-哌嗪)-(环丁烷)-、-(C 0-1 alkylene)-piperazine)-(cyclobutane)-,

-(C0~1亚烷基)-(哌嗪)-(环丁胺)-、-(C 0-1 alkylene)-(piperazine)-(cyclobutylamine)-,

-(C0~1亚烷基)-(1.2.5.6-四氢吡啶)-(C0~10亚烷基)-、-(C 0-1 alkylene)-(1.2.5.6-tetrahydropyridine)-(C 0-10 alkylene)-,

-(C0~1亚烷基)-(哌啶)-(C0~10亚烷基)-、-(C 0-1 alkylene)-(piperidine)-(C 0-10 alkylene)-,

-(C0~1亚烷基)-(哌嗪)-(C0~10亚烷基)-(哌啶)--(C 0-1 alkylene)-(piperazine)-(C 0-10 alkylene)-(piperidine)-

-(C0~1亚烷基)-(哌嗪)-(哌嗪)-C(O)-(C0~10亚烷基)--(C 0-1 alkylene)-(piperazine)-(piperazine)-C(O)-(C 0-10 alkylene)-

-(C0~1亚烷基)-(哌嗪)-(C0~10亚烷基)-(四氢吡咯)-C(O)-(C0~10亚烷基)-O-、-(C 0-1 alkylene)-(piperazine)-(C 0-10 alkylene)-(tetrahydropyrrole)-C(O)-(C 0-10 alkylene)-O-,

-(C0~1亚烷基)-(哌嗪)-C(O)-(C0~10亚烷基)-(CH≡CH)-、-(C 0-1 alkylene)-(piperazine)-C(O)-(C 0-10 alkylene)-(CH≡CH)-,

-(C0~1亚烷基)-(哌嗪)-C(O)-(C0~10亚烷基)-、-(C 0-1 alkylene)-(piperazine)-C(O)-(C 0-10 alkylene)-,

-(C0~1亚烷基)-(哌嗪)-(C0~10亚烷基)-(吡唑)-、-(C 0-1 alkylene)-(piperazine)-(C 0-10 alkylene)-(pyrazole)-,

-(C0~1亚烷基)-(哌嗪)-C(O)-(C0~10亚烷基)-(吡唑)-、-(C 0-1 alkylene)-(piperazine)-C(O)-(C 0-10 alkylene)-(pyrazole)-,

-(C0~1亚烷基)-(哌嗪)-(C0~10亚烷基)-O-、-(C 0-1 alkylene)-(piperazine)-(C 0-10 alkylene)-O-,

-(C0~1亚烷基)-(哌嗪)-(C0~10亚烷基)-O-(C1~10亚烷基)、-(C 0-1 alkylene)-(piperazine)-(C 0-10 alkylene)-O-(C 1-10 alkylene),

-(C0~1亚烷基)-(哌嗪)-(C0~10亚烷基)-O-(3~4元环烷烃)-、-(C 0-1 alkylene)-(piperazine)-(C 0-10 alkylene)-O-(3-4 membered cycloalkane)-,

-(C0~1亚烷基)-(哌嗪)-(C0~10亚烷基)-(2-氮杂螺[3.3]庚烷)-。-(C 0-1 alkylene)-(piperazine)-(C 0-10 alkylene)-(2-azaspiro[3.3]heptane)-.

更具体地,L选自如下连接基团:More specifically, L is selected from the following linking groups:

Figure BDA0003199064950000101
Figure BDA0003199064950000101

Figure BDA0003199064950000111
Figure BDA0003199064950000111

Figure BDA0003199064950000121
Figure BDA0003199064950000121

上述结构中的1端与

Figure BDA0003199064950000131
相连;上述结构中的2端与
Figure BDA0003199064950000132
相连。In the above structure, the 1 end and
Figure BDA0003199064950000131
Connected; 2 ends in the above structure are connected with
Figure BDA0003199064950000132
connected.

在本发明的一些具体实施方案中,所述化合物具体为:In some specific embodiments of the present invention, the compound is specifically:

Figure BDA0003199064950000133
Figure BDA0003199064950000133

Figure BDA0003199064950000141
Figure BDA0003199064950000141

Figure BDA0003199064950000151
Figure BDA0003199064950000151

Figure BDA0003199064950000161
Figure BDA0003199064950000161

Figure BDA0003199064950000171
Figure BDA0003199064950000171

Figure BDA0003199064950000181
Figure BDA0003199064950000181

Figure BDA0003199064950000191
Figure BDA0003199064950000191

Figure BDA0003199064950000201
Figure BDA0003199064950000201

Figure BDA0003199064950000211
Figure BDA0003199064950000211

Figure BDA0003199064950000221
Figure BDA0003199064950000221

Figure BDA0003199064950000231
Figure BDA0003199064950000231

Figure BDA0003199064950000241
Figure BDA0003199064950000241

Figure BDA0003199064950000251
Figure BDA0003199064950000251

Figure BDA0003199064950000261
Figure BDA0003199064950000261

Figure BDA0003199064950000271
Figure BDA0003199064950000271

Figure BDA0003199064950000281
Figure BDA0003199064950000281

Figure BDA0003199064950000291
Figure BDA0003199064950000291

Figure BDA0003199064950000301
Figure BDA0003199064950000301

Figure BDA0003199064950000311
Figure BDA0003199064950000311

Figure BDA0003199064950000321
Figure BDA0003199064950000321

Figure BDA0003199064950000331
Figure BDA0003199064950000331

本发明还提供了上述的双功能化合物,或者其立体异构体、药学上可接受的盐在制备治疗肿瘤或癌症的药物中的用途。The present invention also provides the use of the above-mentioned bifunctional compound, or a stereoisomer or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of tumor or cancer.

本发明还提供了一种组合物,包含上述任一的双功能化合物,或者其立体异构体、药学上可接受的盐,以及药学上可接受的载体。The present invention also provides a composition comprising any of the above-mentioned bifunctional compounds, or a stereoisomer thereof, a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社,Columbus,OH)命名系统命名。The compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。Definitions of terms used in the present invention: Unless otherwise specified, the initial definitions of groups or terms provided herein apply to the group or term throughout the specification; for terms that are not specifically defined herein, the content and context of the disclosure should be used. , give their meanings that those skilled in the art can give them.

“取代”是指分子中的氢原子被其它不同的原子或分子所替换。"Substitution" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.

“可进一步被取代”是指“取代”可以但不必须发生,该说明包括发生或不发生的情形。"May be further substituted" means that "substitution" may but need not occur, and the description includes instances where it occurs or not.

碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,前缀Ca~b烷基表明任何含“a”至“b”个碳原子的烷基。因此,例如,“C1~4烷基”是指包含1~4个碳原子的烷基。Minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, eg, the prefix C a-b alkyl denotes any alkyl group containing "a" to "b" carbon atoms. Thus, for example, "C 1-4 alkyl" refers to an alkyl group containing 1 to 4 carbon atoms.

“烷基”是指具有指定数目的成员原子的饱和烃链。例如,C16烷基是指具有1至6个成员原子,例如1至4个成员原子的烷基基团。烷基基团可以是直链或支链的。代表性的支链烷基基团具有一个、两个或三个支链。烷基基团可任选地被一个或多个如本文所定义的取代基取代。烷基包括甲基、乙基、丙基(正丙基和异丙基)、丁基(正丁基、异丁基和叔丁基)、戊基(正戊基、异戊基和新戊基)和己基。烷基基团也可以是其他基团的一部分,所述其他基团为例如C16烷氧基。"Alkyl" refers to a saturated hydrocarbon chain having the specified number of member atoms. For example, C1-6 alkyl refers to an alkyl group having 1 to 6 member atoms, eg, 1 to 4 member atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two or three branches. Alkyl groups may be optionally substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) base) and hexyl. Alkyl groups can also be part of other groups such as C1-6alkoxy .

本发明中所述的“亚烷基”是指具有1至10个碳原子和在一些实施方案中1至6个碳原子的二价饱和脂族烃基。“(Ca~Cb)亚烷基”是指具有a至b个碳原子的亚烷基基团。亚烷基基团包括支链和直链烃基基团。例如,“(C1~C6)亚烷基”意在包括亚甲基、亚乙基、亚丙基、2-甲基亚丙基、二甲基亚乙基、亚戊基等等。因此,术语“亚丙基”可以通过下列结构例举:

Figure BDA0003199064950000341
同样地,术语“二甲基亚丁基”可以例如通过下列结构的任一种例举:
Figure BDA0003199064950000342
Figure BDA0003199064950000343
此外,术语“(C1~C6)亚烷基”意在包括此类支链烃基基团,诸如环丙基亚甲基,其可以通过下列结构例举:
Figure BDA0003199064950000344
"Alkylene" as used herein refers to a divalent saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms and in some embodiments 1 to 6 carbon atoms. "(C a -C b )alkylene" refers to an alkylene group having a to b carbon atoms. Alkylene groups include branched and straight chain hydrocarbyl groups. For example, "( C1 - C6 )alkylene" is intended to include methylene, ethylene, propylene, 2-methylpropylene, dimethylethylene, pentylene, and the like. Thus, the term "propylene" can be exemplified by the following structures:
Figure BDA0003199064950000341
Likewise, the term "dimethylbutylene" can be exemplified, for example, by any of the following structures:
Figure BDA0003199064950000342
or
Figure BDA0003199064950000343
Furthermore, the term "(C 1 -C 6 )alkylene" is intended to include such branched chain hydrocarbyl groups, such as cyclopropylmethylene, which can be exemplified by the following structures:
Figure BDA0003199064950000344

本发明中所述的“环烷基”、“环烷烃”是指具有多个碳原子且没有环杂原子且具有单个环或多个环(包括稠合、桥连、螺环和金刚烷体系)的饱和或部分饱和的环状基团。对于具有不含环杂原子的芳族和非芳族环的多环体系,当连接点位于非芳族碳原子时,适用术语“环烷基”(例如5,6,7,8,-四氢化萘-5-基)。术语“环烷基”包括环烯基基团,诸如环己烯基。环烷基基团的实例包括例如,金刚烷基、环丙基、环丁基、环己基、环戊基、环辛基、环戊烯基和环己烯基。包括多双环烷基环体系的环烷基基团的实例是双环己基、双环戊基、双环辛基等。下面例举并命名两种此类双环烷基多环结构:

Figure BDA0003199064950000351
双环己基和
Figure BDA0003199064950000352
双环己基。金刚烷基包括但不限于以下结构:
Figure BDA0003199064950000353
In the present invention, "cycloalkyl" and "cycloalkane" refer to having multiple carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused, bridged, spiro and adamantane systems ) saturated or partially saturated cyclic group. For polycyclic systems having aromatic and non-aromatic rings containing no ring heteroatoms, the term "cycloalkyl" applies when the point of attachment is at a non-aromatic carbon atom (eg 5,6,7,8,-tetra Hydronaphthalene-5-yl). The term "cycloalkyl" includes cycloalkenyl groups such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of cycloalkyl groups including polybicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, and the like. Two such bicycloalkyl polycyclic structures are exemplified and named below:
Figure BDA0003199064950000351
dicyclohexyl and
Figure BDA0003199064950000352
Dicyclohexyl. Adamantyl includes but is not limited to the following structures:
Figure BDA0003199064950000353

“烯基”是指具有2至10个碳原子和在一些实施方案中2至6个碳原子或2至4个碳原子且具有至少1个乙烯基不饱和位点(>C=C<)的直链或支链烃基基团。例如,(Ca-Cb)烯基是指具有a至b个碳原子的烯基基团并且意在包括例如乙烯基、丙烯基、异丙烯基、1,3-丁二烯基等。"Alkenyl" means having 2 to 10 carbon atoms and in some embodiments 2 to 6 carbon atoms or 2 to 4 carbon atoms and having at least 1 site of vinyl unsaturation (>C=C<) straight or branched chain hydrocarbon groups. For example, (Ca-Cb)alkenyl refers to an alkenyl group having a to b carbon atoms and is intended to include, for example, vinyl, propenyl, isopropenyl, 1,3-butadienyl, and the like.

本发明中所述的“亚烯基”是指具有2至10个碳原子、至少一个双键和两个不饱和化学价的烃链。例如,(C3-C6)亚烯基包括>C=CH-CH2-、-CH-CH=CH-CH2-等。"Alkenylene" as used in the present invention refers to a hydrocarbon chain having 2 to 10 carbon atoms, at least one double bond and two unsaturated valences. For example, (C3 - C6 )alkenylene includes >C= CH -CH2-, -CH-CH= CH -CH2-, and the like.

“炔基”是指含有至少一个三键的直链一价烃基或支链一价烃基。术语“炔基”还意在包括具有一个三键和一个双键的那些烃基基团。例如,(C2-C6)炔基意在包括乙炔基、丙炔基等。"Alkynyl" means a straight-chain monovalent hydrocarbon group or a branched-chain monovalent hydrocarbon group containing at least one triple bond. The term "alkynyl" is also intended to include those hydrocarbyl groups having one triple bond and one double bond. For example, (C2-C6)alkynyl is intended to include ethynyl, propynyl, and the like.

本发明中所述的“亚炔基”是指具有2至10个碳原子和至少一个三键的二价烃链。The "alkynylene group" as used in the present invention refers to a divalent hydrocarbon chain having 2 to 10 carbon atoms and at least one triple bond.

“卤素”为氟、氯、溴或碘。"Halogen" is fluorine, chlorine, bromine or iodine.

“卤素烷基”、“卤素取代的烷基”指烷基中的氢原子可被一个或多个卤素原子取代。例如C1~4卤素烷基指氢原子被一个或多个卤素原子取代的包含1~4个碳原子的烷基。"Haloalkyl", "halogen-substituted alkyl" means that the hydrogen atoms in the alkyl group may be replaced by one or more halogen atoms. For example, C 1-4 haloalkyl refers to an alkyl group containing 1 to 4 carbon atoms in which hydrogen atoms are replaced by one or more halogen atoms.

本发明中所述的“-OR”、“-NRR”等是指R基团与氧原子或氮原子以单键相连。"-OR", "-NRR" and the like mentioned in the present invention mean that the R group is connected to an oxygen atom or a nitrogen atom by a single bond.

本发明中所述的“-C(O)R”、“-S(O)2R”等中的氧原子是与碳原子或硫原子以双键相连。The oxygen atom in "-C(O)R", "-S(O) 2 R" and the like described in the present invention is connected to a carbon atom or a sulfur atom by a double bond.

本发明中所述的“羰基”是指氧原子通过双键取代,即“=O”。The "carbonyl group" in the present invention means that the oxygen atom is substituted by a double bond, that is, "=O".

本发明中所述的“杂环”、“杂环烷基”、“杂环烷烃”是指包含至少一个杂原子的饱和环或非芳香性的不饱和环;其中杂原子指氮原子、氧原子、硫原子等。通常表示多个环原子的一价饱和或部分不饱和单环或二环环系统、优选3至9个环原子的一价饱和或部分不饱和单环或二环环系统,其包含1、2或3个选自N、O和S的环杂原子,其余的环原子是碳。二环表示由共有两个环原子的两个环组成的,即将两个环分开的桥是单键或是一个或两个环原子的链。单环饱和杂环烷基的实例是氧杂环丁基、氮杂环丁基、吡咯烷基、2-氧代-吡咯烷-3-基、四氢呋喃基、四氢-噻吩基、吡唑烷基、咪唑烷基、噻唑烷基、哌啶基、四氢吡喃基、四氢噻喃基、哌嗪基、吗啉基、

Figure BDA0003199064950000361
硫代吗啉基、1,1-二氧代-硫代吗啉-4-基、氮杂环庚基、二氮杂环庚基、高哌嗪基或氧杂氮杂环庚基。二环饱和杂环烷基的实例是8-氮杂-二环[3.2.1]辛基、奎宁环基、8-氧杂-3-氮杂-二环[3.2.1]辛基、9-氮杂-二环[3.3.1]壬基、
Figure BDA0003199064950000362
部分不饱和杂环烷基的实例是二氢呋喃基、咪唑啉基、四氢-吡啶基或二氢吡喃基。In the present invention, "heterocycle", "heterocycloalkyl" and "heterocycloalkane" refer to a saturated ring or a non-aromatic unsaturated ring containing at least one heteroatom; atoms, sulfur atoms, etc. Typically represents a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of multiple ring atoms, preferably a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 3 to 9 ring atoms, comprising 1, 2 or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Bicyclic means consisting of two rings that share two ring atoms, i.e. the bridge separating the two rings is a single bond or a chain of one or two ring atoms. Examples of monocyclic saturated heterocycloalkyl are oxetanyl, azetidine, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidine base, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl,
Figure BDA0003199064950000361
Thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl or oxazepanyl. Examples of bicyclic saturated heterocycloalkyl groups are 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl,
Figure BDA0003199064950000362
Examples of partially unsaturated heterocycloalkyl groups are dihydrofuranyl, imidazolinyl, tetrahydro-pyridyl or dihydropyranyl.

本发明中所述的“芳环”、“芳基”是指具有多个碳原子的芳烃基团。芳基通常是具有5-20个碳原子的单环、二环或三环芳基。此外,本文所用的术语“芳基”是指可以是单个芳环或稠合在一起的多个芳环的芳族取代基。非限制性实例包括苯基、萘基或四氢萘基。The "aromatic ring" and "aryl group" described in the present invention refer to an aromatic hydrocarbon group having a plurality of carbon atoms. Aryl groups are typically monocyclic, bicyclic or tricyclic aryl groups having 5 to 20 carbon atoms. Furthermore, the term "aryl" as used herein refers to an aromatic substituent which may be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl.

本发明中所述的“芳杂环”、“芳杂环基”是指包含至少一个杂原子的芳香性不饱和环;其中杂原子指氮原子、氧原子、硫原子等。通常包含多个环原子的、其中一个或多个环原子选自O、N、S的杂原子的芳族单环或双环烃。优选地有一到三个杂原子。杂环芳基例如代表:吡啶基、吲哚基、喹噁啉基、喹啉基、异喹啉基、苯并噻吩基、苯并呋喃基、苯并噻吩基、苯并吡喃基、苯并噻吡喃基、呋喃基、吡咯基、噻唑基、噁唑基、异噁唑基、三唑基、四唑基、吡唑基、咪唑基、噻吩基、噁二唑基、苯并咪唑基、苯并噻唑基、苯并噁唑基。In the present invention, "aromatic heterocycle" and "aromatic heterocyclic group" refer to an aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to nitrogen atom, oxygen atom, sulfur atom and the like. Aromatic monocyclic or bicyclic hydrocarbons generally containing multiple ring atoms, one or more of which are heteroatoms selected from O, N, S. There are preferably one to three heteroatoms. Heterocyclic aryl groups represent, for example: pyridyl, indolyl, quinoxolinyl, quinolyl, isoquinolyl, benzothienyl, benzofuranyl, benzothienyl, benzopyranyl, benzene Thiapyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazole base, benzothiazolyl, benzoxazolyl.

“立体异构体”包括对映异构体和非对映异构体;"Stereoisomer" includes enantiomers and diastereomers;

术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料,和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容,并在生理上与受体相兼容。The term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients that make up a pharmaceutical dosage form, and is physiologically Compatible with receptors.

术语“盐”和“药学上可接受的盐”是指上述化合物或其立体异构体,与无机和/或有机酸和碱形成的酸式和/或碱式盐,也包括两性离子盐(内盐),还包括季铵盐,例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物,或其立体异构体,与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集,或在溶剂蒸发后回收而得到,或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。The terms "salt" and "pharmaceutically acceptable salt" refer to the above-mentioned compounds or their stereoisomers, acid and/or base salts with inorganic and/or organic acids and bases, and also include zwitterionic salts ( inner salts), also including quaternary ammonium salts such as alkyl ammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. It can also be obtained by mixing the above-mentioned compound, or a stereoisomer thereof, with a certain amount of acid or base as appropriate (for example, an equivalent amount). These salts may be precipitated in solution and collected by filtration, recovered after evaporation of the solvent, or obtained by lyophilization after reaction in an aqueous medium. The salts described in the present invention can be hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate of the compound salt, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.

显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。Obviously, according to the above-mentioned content of the present invention, according to the common technical knowledge and conventional means in the field, without departing from the above-mentioned basic technical idea of the present invention, other various forms of modification, replacement or change can also be made.

附图说明Description of drawings

图1为本发明化合物形成EGFR-PROTAC-CRBN/DDB1三元复合物的荧光检测结果图。Figure 1 is a graph showing the results of fluorescence detection of the compounds of the present invention to form EGFR-PROTAC-CRBN/DDB1 ternary complexes.

具体实施方式Detailed ways

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再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的实例。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 through the specific implementation in the form of examples. However, this should not be construed as limiting the scope of the above-mentioned subject matter of the present invention only to the following examples. All technologies implemented based on the above content of the present invention belong to the scope of the present invention.

本发明的已知的起始原料可以采用或按照本领域已知的方法来合成,或可购买于安耐吉化学、成都科龙化工、韶远化学科技、百灵威科技等公司。The known starting materials of the present invention can be synthesized by using or according to methods known in the art, or can be purchased from companies such as Annagy Chemical, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Bailingwei Technology and the like.

实施例中所述试剂缩写如下:AIBN:偶氮二异丁氰;NBS:N-溴代丁二酰亚胺;DMP:DESS-MARTIN PERIODINANE戴斯-马丁氧化剂;DIPEA:N,N-二异丙基乙胺;TEMPO:2,2,6,6-四甲基哌啶氧化物;MTBE:甲基叔丁基醚;NaHMDS:双(三甲基硅基)氨基钠;DIAD:偶氮二甲酸二异丙酯;DPPA:叠氮磷酸二苯酯;TBTU:2-(1H-苯并三偶氮L-1-基)-1,1,3,3-四甲基脲四氟硼酸酯;TEA:三乙胺;SEMCl:2-(三甲基硅烷基)乙氧甲基氯;BINAP:1,1'-联萘-2,2'-双二苯膦;X-Phos:2-二环己基磷-2,4,6-三异丙基联苯;DMF:N,N-二甲基甲酰胺;DCM:二氯甲烷;DCE:1,2-二氯乙烷;TFA:三氟醋酸;EA:乙酸乙酯;PE:石油醚;BPO:过氧化苯甲酰。The abbreviations of the reagents described in the examples are as follows: AIBN: azobisisobutyl cyanide; NBS: N-bromosuccinimide; DMP: DESS-MARTIN PERIODINANE Dess-Martin oxidant; DIPEA: N,N-diisobutylene Propylethylamine; TEMPO: 2,2,6,6-tetramethylpiperidine oxide; MTBE: methyl tert-butyl ether; NaHMDS: sodium bis(trimethylsilyl)amide; DIAD: azobis Diisopropyl formate; DPPA: Diphenylphosphoric azide; TBTU: 2-(1H-benzotriazo L-1-yl)-1,1,3,3-tetramethylurea tetrafluoroboric acid ester; TEA: triethylamine; SEMCl: 2-(trimethylsilyl)ethoxymethyl chloride; BINAP: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine; X-Phos: 2 - Dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl; DMF: N,N-dimethylformamide; DCM: dichloromethane; DCE: 1,2-dichloroethane; TFA: Trifluoroacetic acid; EA: ethyl acetate; PE: petroleum ether; BPO: benzoyl peroxide.

实施例中无特殊说明,反应在氮气氛围下进行。实施例中无特殊说明,溶液是指水溶液。实施例中无特殊说明,反应的温度为室温。室温为最适宜的反应温度,为20℃~30℃。实施例中无特殊说明,M是摩尔每升。There is no special description in the examples, and the reaction is carried out under nitrogen atmosphere. There is no special description in the examples, and the solution refers to an aqueous solution. There is no special description in the examples, and the reaction temperature is room temperature. Room temperature is the most suitable reaction temperature, which is 20°C to 30°C. There is no special description in the examples, and M is moles per liter.

化合物的结构是通过核磁共振(NMR)和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker AvanceIII 400和Bruker Avance 300)核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),内标为四甲基硅烷(TMS)。LC-MS的测定使用岛津液质联用仪(Shimadzu LC-MS 2020(ESI))。HPLC的测定使用岛津高压液相色谱仪(Shimadzu LC-20A)。MPLC(中压制备色谱)使用Gilson GX-281反相制备色谱仪。薄层层析硅胶板用烟台黄海HSGF254或青岛GF254硅胶板,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。The structures of the compounds were determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10-6 (ppm). NMR was measured with (Bruker AvanceIII 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) , the internal standard is tetramethylsilane (TMS). For the measurement of LC-MS, a Shimadzu LC-MS 2020 (ESI) was used. For the HPLC measurement, a Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A) was used. MPLC (medium pressure preparative chromatography) used a Gilson GX-281 reverse phase preparative chromatograph. The thin layer chromatography silica gel plate is made of Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specifications of the thin layer chromatography separation and purification products are 0.4mm ~ 0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

中间体Z-1的合成Synthesis of Intermediate Z-1

Figure BDA0003199064950000381
Figure BDA0003199064950000381

步骤1、1-a的合成Step 1, Synthesis of 1-a

向2-甲基-3-溴苯甲酸甲酯(51g,222.64mmol)的1,2-二氯乙烷(560mL)溶液中加入AIBN(3.66g,22.26mmol)和NBS(47.55g,267.17mmol)。反应液加热至85℃反应4小时。反应完成后,浓缩反应液得到1-a(65g,211.06mmol,94.80%收率,粗品),未经纯化直接用于下一步。MS(ESI)m/z=306[M+1]+To a solution of methyl 2-methyl-3-bromobenzoate (51 g, 222.64 mmol) in 1,2-dichloroethane (560 mL) was added AIBN (3.66 g, 22.26 mmol) and NBS (47.55 g, 267.17 mmol) ). The reaction solution was heated to 85°C and reacted for 4 hours. After the reaction was completed, the reaction solution was concentrated to obtain 1-a (65 g, 211.06 mmol, 94.80% yield, crude product), which was used in the next step without purification. MS(ESI) m/z=306[M+1] + .

步骤2、1-b的合成Step 2. Synthesis of 1-b

向1-a(42g,136.38mmol)和3-氨基哌啶-2,6-二酮盐酸盐(17.47g,136.38mmol)的乙腈(210mL)溶液中加入DIPEA(21.15g,163.65mmol,28.51mL),反应液升温至90℃并在此温度搅拌3小时,反应完成后,浓缩混合液得到粗品,粗品经水洗后过滤得到化合物1-b(35.6g,110.17mmol,80.78%收率)。MS(ESI)m/z=324[M+1]+To a solution of 1-a (42 g, 136.38 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (17.47 g, 136.38 mmol) in acetonitrile (210 mL) was added DIPEA (21.15 g, 163.65 mmol, 28.51 mmol) mL), the reaction solution was heated to 90° C. and stirred at this temperature for 3 hours. After the reaction was completed, the mixture was concentrated to obtain a crude product, which was washed with water and filtered to obtain compound 1-b (35.6 g, 110.17 mmol, 80.78% yield). MS(ESI) m/z=324[M+1] + .

步骤3、1-c的合成Step 3. Synthesis of 1-c

向1-b(3g,9.28mmol)的DMF(30mL)溶液中依次加入4-戊炔-1-醇(1.56g,13.93mmol),碘化亚铜(265.22mg,1.39mmol),Pd(Ph3P)2Cl2(488.10mg,696.29μmol)和DIPEA(2.82g,27.85mmol,3.88mL)。反应液在N2保护下于80℃搅拌18小时,用水稀释,乙酸乙酯萃取,分离的有机相用水和食盐水洗涤,干燥后旋干。粗品加入乙酸乙酯,有棕色固体析出,过滤后收集滤饼,得目标化合物1-c(1.6g,4.51mmol,48.65%收率)。MS(ESI)m/z=355[M+1]+To a solution of 1-b (3 g, 9.28 mmol) in DMF (30 mL) were sequentially added 4-pentyn-1-ol (1.56 g, 13.93 mmol), cuprous iodide (265.22 mg, 1.39 mmol), Pd (Ph 3 P) 2 Cl 2 (488.10 mg, 696.29 μmol) and DIPEA (2.82 g, 27.85 mmol, 3.88 mL). The reaction solution was stirred at 80°C for 18 hours under the protection of N 2 , diluted with water, extracted with ethyl acetate, and the separated organic phase was washed with water and brine, dried and then spin-dried. The crude product was added with ethyl acetate, and a brown solid was precipitated. After filtration, the filter cake was collected to obtain the target compound 1-c (1.6 g, 4.51 mmol, 48.65% yield). MS(ESI) m/z=355[M+1] + .

步骤4、1-d的合成Step 4. Synthesis of 1-d

向1-c(200mg,0.61mmol)的MeOH(80mL)/THF(20mL)/EtOAc(20mL)的混合溶液中加入Pd/C(200mg)。混合液用氢气置换后,在氢气保护下于室温搅拌18小时。反应完成后,过滤除掉Pd/C,滤液浓缩得到1-d(162mg,0.49mmol,80%收率,粗品)。To a mixed solution of 1-c (200 mg, 0.61 mmol) in MeOH (80 mL)/THF (20 mL)/EtOAc (20 mL) was added Pd/C (200 mg). After the mixture was replaced with hydrogen, it was stirred at room temperature for 18 hours under the protection of hydrogen. After the reaction was completed, Pd/C was removed by filtration, and the filtrate was concentrated to give 1-d (162 mg, 0.49 mmol, 80% yield, crude).

步骤5、中间体Z-1的合成Step 5. Synthesis of Intermediate Z-1

向化合物1-d(300mg,881.39μmol)的DCM(3mL)和DMF(3mL)的混合溶液中加入戴斯马丁试剂(560.75mg,1.32mmol)。悬浊液在室温下搅拌1小时。反应完成后,混合液过滤,滤液浓缩旋干,粗品加入乙酸乙酯稀释,有棕色固体析出,过滤收集固体,用反相C18柱分离纯化,得到中间体化合物Z-1(200mg,591.09μmol,67.06%收率)。MS(ESI)m/z=339[M+1]+To a mixed solution of compound 1-d (300 mg, 881.39 μmol) in DCM (3 mL) and DMF (3 mL) was added Dess Martin’s reagent (560.75 mg, 1.32 mmol). The suspension was stirred at room temperature for 1 hour. After the reaction was completed, the mixed solution was filtered, the filtrate was concentrated and spin-dried, the crude product was diluted with ethyl acetate, a brown solid was precipitated, the solid was collected by filtration, and separated and purified with a reverse-phase C18 column to obtain the intermediate compound Z-1 (200 mg, 591.09 μmol, 67.06% yield). MS(ESI) m/z=339[M+1] + .

中间体Z-2的合成Synthesis of Intermediate Z-2

Figure BDA0003199064950000391
Figure BDA0003199064950000391

按照中间体Z-1的合成方法中的步骤2至步骤5,步骤1使用的2-溴甲基-4-溴苯甲酸甲酯为原料,其余条件不变,得到Z-2。MS(ESI)m/z=339[M+1]+According to step 2 to step 5 in the synthesis method of intermediate Z-1, the methyl 2-bromomethyl-4-bromobenzoate used in step 1 is used as the raw material, and other conditions remain unchanged to obtain Z-2. MS(ESI) m/z=339[M+1] + .

中间体Z-3的合成Synthesis of Intermediate Z-3

Figure BDA0003199064950000392
Figure BDA0003199064950000392

按照中间体Z-1的合成方法中的步骤1至步骤5,将步骤1中的2-甲基-3-溴苯甲酸甲酯替换为2-甲基-5-溴苯甲酸甲酯,其余条件不变,得到Z-3。MS(ESI)m/z=339[M+1]+According to steps 1 to 5 in the synthetic method of intermediate Z-1, the methyl 2-methyl-3-bromobenzoate in step 1 is replaced with methyl 2-methyl-5-bromobenzoate, and the rest With the conditions unchanged, Z-3 is obtained. MS(ESI) m/z=339[M+1] + .

中间体Z-4到Z-12的合成Synthesis of Intermediates Z-4 to Z-12

按照中间体Z-1的合成方法中的步骤1至步骤5,分别将步骤1中的2-甲基-3-溴苯甲酸甲酯替换为表中SM-Br,将步骤3中的4-戊炔-1-醇替换为表中对应的SM-ene,其余条件不变,得到表中相应的Z-4搭配Z-12的结构。According to step 1 to step 5 in the synthetic method of intermediate Z-1, respectively replace methyl 2-methyl-3-bromobenzoate in step 1 with SM-Br in the table, and replace 4- The pentyn-1-ol was replaced with the corresponding SM-ene in the table, and the other conditions remained unchanged to obtain the corresponding structure of Z-4 and Z-12 in the table.

Figure BDA0003199064950000401
Figure BDA0003199064950000401

Figure BDA0003199064950000411
Figure BDA0003199064950000411

中间体Z-13的合成Synthesis of Intermediate Z-13

Figure BDA0003199064950000412
Figure BDA0003199064950000412

零度下,向中间体化合物1-c(500mg,1.53mmol)的DMF(4mL)/DCM(40mL)混合溶液中加入DMP(974.75mg,2.30mmol),反应混合液缓慢升至室温并搅拌3小时,反应完成后,加入1mL甲醇,旋干反应混合液,残留物用m-HPLC分离纯化得到中间体化合物Z-13(133mg,410.08μmol,26.77%收率)。MS(ESI)m/z=325[M+1]+At zero temperature, DMP (974.75 mg, 2.30 mmol) was added to a mixed solution of intermediate compound 1-c (500 mg, 1.53 mmol) in DMF (4 mL)/DCM (40 mL), and the reaction mixture was slowly warmed to room temperature and stirred for 3 hours After the reaction was completed, 1 mL of methanol was added, the reaction mixture was spin-dried, and the residue was separated and purified by m-HPLC to obtain the intermediate compound Z-13 (133 mg, 410.08 μmol, 26.77% yield). MS(ESI) m/z=325[M+1] + .

中间体Z-14的合成Synthesis of Intermediate Z-14

Figure BDA0003199064950000421
Figure BDA0003199064950000421

参照化合物Z-13的合成方法,将其中的原料1-c替换为2-c,其余方法不变,得到Z-14。MS(ESI)m/z=325[M+1]+Referring to the synthesis method of compound Z-13, the raw material 1-c is replaced by 2-c, and the other methods remain unchanged to obtain Z-14. MS(ESI) m/z=325[M+1] + .

中间体Z-15的合成Synthesis of Intermediate Z-15

Figure BDA0003199064950000422
Figure BDA0003199064950000422

参照化合物Z-13的合成方法,将其中的原料1-c替换为3-c,其余方法不变,得到Z-15。MS(ESI)m/z=325[M+1]+Referring to the synthesis method of compound Z-13, the raw material 1-c is replaced by 3-c, and the other methods remain unchanged to obtain Z-15. MS(ESI) m/z=325[M+1] + .

中间体Z-16到Z-27的合成Synthesis of Intermediates Z-16 to Z-27

按照中间体Z-13的合成方法,将其中的原料1-c替换为对应的原料中间体编号,其余方法不变,得到表中对应的Z-16到Z-27。According to the synthesis method of the intermediate Z-13, the raw material 1-c in it is replaced with the corresponding raw material intermediate number, and the other methods remain unchanged to obtain the corresponding Z-16 to Z-27 in the table.

Figure BDA0003199064950000423
Figure BDA0003199064950000423

Figure BDA0003199064950000431
Figure BDA0003199064950000431

Figure BDA0003199064950000441
Figure BDA0003199064950000441

中间体Z-25的合成Synthesis of Intermediate Z-25

Figure BDA0003199064950000442
Figure BDA0003199064950000442

向1-c(1g,3.06mmol)的乙腈(66.67mL)/水(133.33mL)混合溶液中加入TEMPO(191.51mg,1.23mmol)和碘苯二乙酸(3.95g,12.26mmol)。反应混合液于室温搅拌过夜,反应完成后,浓缩反应液,粗品用正相硅胶柱分离纯化(DCM:MEOH=33:1)得到中间体化合物Z-25(248mg,728.71μmol,23.78%收率)。MS(ESI)m/z=341[M+1]+To a mixed solution of 1-c (1 g, 3.06 mmol) in acetonitrile (66.67 mL)/water (133.33 mL) were added TEMPO (191.51 mg, 1.23 mmol) and iodobenzenediacetic acid (3.95 g, 12.26 mmol). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated, and the crude product was separated and purified by a normal phase silica gel column (DCM:MEOH=33:1) to obtain the intermediate compound Z-25 (248 mg, 728.71 μmol, 23.78% yield). ). MS(ESI) m/z=341[M+1] + .

中间体Z-26的合成Synthesis of Intermediate Z-26

Figure BDA0003199064950000443
Figure BDA0003199064950000443

向中间体Z-25(160mg,0.47mmol)的MeOH(10mL)的溶液中,加入Pd/C(30mg)。反应液用氢气置换,然后在氢气保护下室温搅拌1小时,反应完成后,滤除Pd/C,滤液旋干,得中间体化合物Z-26(150mg,93%收率)。MS(ESI)m/z=345[M+1]+ To a solution of intermediate Z-25 (160 mg, 0.47 mmol) in MeOH (10 mL) was added Pd/C (30 mg). The reaction solution was replaced with hydrogen, and then stirred at room temperature for 1 hour under the protection of hydrogen. After the reaction was completed, the Pd/C was filtered off, and the filtrate was spin-dried to obtain the intermediate compound Z-26 (150 mg, 93% yield). MS(ESI)m/z=345[M+1] +

中间体Z-27的合成Synthesis of Intermediate Z-27

Figure BDA0003199064950000451
Figure BDA0003199064950000451

步骤1、27-a的合成Step 1, Synthesis of 27-a

向delta-戊内酯(10g,99.88mmol)的甲苯(100mL)溶液中加入BnBr(68.32g,399.54mmol)和KOH(16.81g,299.65mmol)的水(100mL),混合液升温至115℃反应过夜。反应完成后,降至室温,加入7g KOH,分液,分离的水相用MTBE洗2次,然后用浓盐酸调pH=2-3,乙酸乙酯萃取,得到的有机相经干燥后浓缩,得到中间体化合物27-a(5.4g,25.93mmol,25.96%收率),MS(ESI)m/z=207[M+1]+ To a solution of delta-valerolactone (10 g, 99.88 mmol) in toluene (100 mL) was added BnBr (68.32 g, 399.54 mmol) and KOH (16.81 g, 299.65 mmol) in water (100 mL), and the mixture was heated to 115 °C for reaction overnight. After the reaction was completed, it was cooled to room temperature, 7g of KOH was added, the liquid was separated, the separated aqueous phase was washed twice with MTBE, then adjusted to pH=2-3 with concentrated hydrochloric acid, extracted with ethyl acetate, and the obtained organic phase was dried and concentrated. Obtained intermediate compound 27-a (5.4 g, 25.93 mmol, 25.96% yield), MS (ESI) m/z=207[M+1] +

步骤2、27-b的合成Step 2. Synthesis of 27-b

零度下,向27-a(2g,9.60mmol)的DCM(100mL)溶液中加入1滴DMF,然后缓慢滴加(COCl)2(2.44g,19.21mmol),升至室温反应一小时,反应完成后,将反应液浓缩,得到化合物27-b(2.1g,9.26mmol,96.46%收率)。At zero degrees, 1 drop of DMF was added to a solution of 27-a (2 g, 9.60 mmol) in DCM (100 mL), then (COCl) 2 (2.44 g, 19.21 mmol) was slowly added dropwise, and the reaction was completed at room temperature for one hour. After that, the reaction solution was concentrated to obtain compound 27-b (2.1 g, 9.26 mmol, 96.46% yield).

步骤3、27-c的合成Step 3. Synthesis of 27-c

将(R)-4-苄基-2-噁唑烷酮(5.77g,32.55mmol)溶于THF(80mL)中,氮气保护下降温至-78℃,加入n-BuLi(16mL),保温反应30分钟,然后加入27-b(7.38g,32.55mmol)的THF溶液,滴毕,保温反应1小时。反应完成后,将反应倒入饱和氯化铵水溶液中淬灭,分液,(R)-4-benzyl-2-oxazolidinone (5.77g, 32.55mmol) was dissolved in THF (80mL), the temperature was lowered to -78°C under nitrogen protection, n-BuLi (16mL) was added, and the reaction was incubated After 30 minutes, the THF solution of 27-b (7.38 g, 32.55 mmol) was added, the dropping was completed, and the reaction was incubated for 1 hour. After the reaction was completed, the reaction was poured into a saturated aqueous ammonium chloride solution to quench, and the liquids were separated.

有机相浓缩干,残余物用正相硅胶柱分离纯化(PE/EA=3/1)得到27-c(7.04g,19.16mmol,58.85%收率)。MS(ESI)m/z=368[M+1]+ The organic phase was concentrated to dryness, and the residue was separated and purified by normal phase silica gel column (PE/EA=3/1) to obtain 27-c (7.04 g, 19.16 mmol, 58.85% yield). MS(ESI)m/z=368[M+1] +

步骤4、27-d的合成Step 4. Synthesis of 27-d

-78℃,氮气保护下,向27-c(7.04g,19.16mmol)的THF(50mL)中,逐滴加入NaHMDS(12.5mL),保温反应30分钟,然后滴入MeI(16.32g,114.96mmol)的THF溶液,滴毕,撤去外浴,室温反应1小时,反应完成后,将反应液倒入饱和氯化铵水溶液中淬灭,分液,有机相浓缩,残余物用正相硅胶柱分离纯化(MTBE/PE=1/1)得到27-d(5.4g,14.16mmol,73.88%收率)。MS(ESI)m/z=382[M+1]+ -78°C, under nitrogen protection, to 27-c (7.04g, 19.16mmol) in THF (50mL), NaHMDS (12.5mL) was added dropwise, the reaction was incubated for 30 minutes, and then MeI (16.32g, 114.96mmol) was added dropwise ) in THF solution, the dripping was completed, the external bath was removed, and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into a saturated aqueous ammonium chloride solution to quench, the layers were separated, the organic phase was concentrated, and the residue was separated by a normal-phase silica gel column. Purification (MTBE/PE=1/1) gave 27-d (5.4 g, 14.16 mmol, 73.88% yield). MS(ESI)m/z=382[M+1] +

步骤5、27-e的合成Step 5. Synthesis of 27-e

零度下,向27-d(5.4g,14.16mmol)的THF(100mL)中,加入LiAlH4(15mL),升至室温反应2小时。反应完成后,将反应液浓缩干,残余物用正相硅胶柱分离纯化(MTBE/PE=1/2)得到27-e(2.4g,11.52mmol,81.39%收率),MS(ESI)m/z=209[M+1]+ At zero temperature, LiAlH 4 (15 mL) was added to 27-d (5.4 g, 14.16 mmol) in THF (100 mL), and the reaction was raised to room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to dryness, and the residue was separated and purified by normal phase silica gel column (MTBE/PE=1/2) to obtain 27-e (2.4 g, 11.52 mmol, 81.39% yield), MS (ESI) m /z=209[M+1] +

步骤6、27-f的合成Step 6, Synthesis of 27-f

将27-e(2.4g,11.52mmol)溶于THF(100mL)中,氮气保护下依次加入PPh3(6.04g,23.04mmol),DIAD(4.65g,23.04mmol)和DPPA(6.34g,23.04mmol),室温搅拌过夜,反应完成后,将反应液浓缩干,残余物用正相硅胶柱分离纯化(8%MTBE in PE)得到27-f(1.97g,8.44mmol,73.28%收率)。MS(ESI)m/z=234[M+1]+ 27-e (2.4 g, 11.52 mmol) was dissolved in THF (100 mL), PPh 3 (6.04 g, 23.04 mmol), DIAD (4.65 g, 23.04 mmol) and DPPA (6.34 g, 23.04 mmol) were added successively under nitrogen protection ), stirred at room temperature overnight, after completion of the reaction, the reaction solution was concentrated to dryness, and the residue was separated and purified by normal phase silica gel column (8% MTBE in PE) to obtain 27-f (1.97 g, 8.44 mmol, 73.28% yield). MS(ESI)m/z=234[M+1] +

步骤7、27-g的合成Step 7, Synthesis of 27-g

向27-f(2g,8.57mmol)的MeOH(50mL)中加入2滴浓盐酸,再加入Pd/C(0.5g)。氢气置换后,室温搅拌2小时。反应完成后,滤除Pd/C,滤液浓缩干,得到27-g(1g,8.53mmol,99.54%收率)。MS(ESI)m/z=118[M+1]+ To 27-f (2 g, 8.57 mmol) in MeOH (50 mL) was added 2 drops of concentrated hydrochloric acid followed by Pd/C (0.5 g). After hydrogen substitution, the mixture was stirred at room temperature for 2 hours. After the reaction was completed, Pd/C was filtered off, and the filtrate was concentrated to dryness to obtain 27-g (1 g, 8.53 mmol, 99.54% yield). MS(ESI)m/z=118[M+1] +

步骤8、27-h的合成Step 8, Synthesis of 27-h

向27-g(1g,8.53mmol)的DMF(20mL)溶液中,依次加入K2CO3(2.36g,17.07mmol)和2-氟-4-溴硝基苯(1.88g,8.53mmol),升温至60℃并搅拌过夜,反应完成后,浓缩反应液,残余物用正相硅胶柱分离纯化(PE/EA=5/1)得到27-h(2g,6.31mmol,73.89%收率)。MS(ESI)m/z=318[M+1]+ To a solution of 27-g (1 g, 8.53 mmol) in DMF (20 mL) was added K 2 CO 3 (2.36 g, 17.07 mmol) followed by 2-fluoro-4-bromonitrobenzene (1.88 g, 8.53 mmol), The temperature was raised to 60°C and stirred overnight. After the reaction was completed, the reaction solution was concentrated, and the residue was separated and purified by normal phase silica gel column (PE/EA=5/1) to obtain 27-h (2 g, 6.31 mmol, 73.89% yield). MS(ESI)m/z=318[M+1] +

步骤9、27-i的合成Step 9, Synthesis of 27-i

零度下,向27-h(465mg,1.47mmol)的DCM(10mL)溶液中,依次加入TEA(222.52mg,2.20mmol,306.72μL)和MsCl(201.52mg,1.76mmol),零度下搅拌1小时,反应完成后,加入饱和碳酸氢钠水溶液,分液,分离的有机相依次用水洗,饱和食盐水洗涤,无水硫酸钠干燥后,经浓缩,得到27-i(0.57g,1.44mmol,98.36%收率),粗品未经纯化直接用以下一步反应。MS(ESI)m/z=397[M+1]+ At zero temperature, to a solution of 27-h (465 mg, 1.47 mmol) in DCM (10 mL), TEA (222.52 mg, 2.20 mmol, 306.72 μL) and MsCl (201.52 mg, 1.76 mmol) were added in sequence, and the mixture was stirred at zero temperature for 1 hour, After the completion of the reaction, saturated aqueous sodium bicarbonate solution was added to separate the layers. The separated organic phase was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and concentrated to obtain 27-i (0.57 g, 1.44 mmol, 98.36% yield), the crude product was directly used in the next reaction without purification. MS(ESI)m/z=397[M+1] +

步骤10、27-j的合成Synthesis of Steps 10, 27-j

将27-i(579mg,1.46mmol),甲基2-(5-羟基-1-甲基-1H-吡唑-4-yl)-6-甲基异烟酸酯(362.18mg,1.46mmol)和K2CO3(505.37mg,3.66mmol)溶于DMF(15mL)中,反应升至60℃反应搅拌过夜,反应完成后,冷却至室温,加入MTBE,混合液用水洗2次,分离的有机相浓缩,残余物用硅胶柱分离纯化(60%EA in PE),得到27-j(254mg,464.85μmol,31.73%收率)。MS(ESI)m/z=548[M+1]+ 27-i (579 mg, 1.46 mmol), methyl 2-(5-hydroxy-1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinate (362.18 mg, 1.46 mmol) and K 2 CO 3 (505.37 mg, 3.66 mmol) were dissolved in DMF (15 mL), the reaction was raised to 60 ° C and the reaction was stirred overnight. After the reaction was completed, it was cooled to room temperature, MTBE was added, the mixture was washed twice with water, and the separated organic The phases were concentrated and the residue was purified by silica gel column separation (60% EA in PE) to give 27-j (254 mg, 464.85 μmol, 31.73% yield). MS(ESI)m/z=548[M+1] +

步骤11、27-k的合成Step 11, Synthesis of 27-k

零度下,向27-j(254mg,464.85μmol)的MeOH(10mL)中,依次加入NH4OH(3mL)和Na2S2O4(404.42mg,2.32mmol),室温搅拌1小时,反应完成后,加水洗石,用乙酸乙酯萃取,合并的有机相依次用水、饱和食盐水洗涤,干燥,浓缩后得到27-k(170mg,329.18μmol,70.81%收率),粗品未经纯化,直接用于下一步反应。MS(ESI)m/z=518[M+1]+ To 27-j (254 mg, 464.85 μmol) in MeOH (10 mL) at zero temperature, NH 4 OH (3 mL) and Na 2 S 2 O 4 (404.42 mg, 2.32 mmol) were sequentially added, and the reaction was completed by stirring at room temperature for 1 hour. Then, washed with water and extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine successively, dried, and concentrated to obtain 27-k (170 mg, 329.18 μmol, 70.81% yield). The crude product was not purified and was directly used for the next reaction. MS(ESI)m/z=518[M+1] +

步骤12、27-l的合成Synthesis of Step 12, 27-1

向27-k(170mg,329.18μmol)的DCM(10mL)/t-BuOH(3mL)混合溶液中,加入CNBr(41.87mg,395.02μmol),室温搅拌过夜。反应完成后,加入饱和碳酸氢钠水溶液,搅拌10分钟,分液,有机相用依次用户饱和碳酸氢钠水溶液、水、盐水洗涤,无水硫酸钠干燥,浓缩有机相,得到27-l(177mg,326.91μmol,99.31%收率)。MS(ESI)m/z=541[M+1]+ To a mixed solution of 27-k (170 mg, 329.18 μmol) in DCM (10 mL)/t-BuOH (3 mL), CNBr (41.87 mg, 395.02 μmol) was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, a saturated aqueous sodium bicarbonate solution was added, stirred for 10 minutes, and the layers were separated. The organic phase was washed with a saturated aqueous sodium bicarbonate solution, water, and brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain 27-1 (177 mg , 326.91 μmol, 99.31% yield). MS(ESI)m/z=541[M+1] +

步骤13、27-m的合成Step 13, Synthesis of 27-m

向27-l(177mg,326.91μmol)的THF(5mL)/H2O(5mL)中,加入NaOH(52.31mg,1.31mmol),室温搅拌1小时,反应完成后,浓缩反应液,加水稀释,用1M HCl调pH=4-5,有固体析出,过滤,滤饼用水洗涤,干燥后得27-m(172mg,326.12μmol,99.76%收率)。MS(ESI)m/z=541[M+1]+ To 27-1 (177 mg, 326.91 μmol) of THF (5 mL)/H 2 O (5 mL), NaOH (52.31 mg, 1.31 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated and diluted with water. The pH was adjusted to 4-5 with 1M HCl, a solid was precipitated, filtered, and the filter cake was washed with water, and dried to obtain 27-m (172 mg, 326.12 μmol, 99.76% yield). MS(ESI)m/z=541[M+1] +

步骤14、Z-27的合成Step 14. Synthesis of Z-27

向27-m(172mg,326.12μmol)的DCM(5mL)中,依次加入TEA(132.00mg,1.30mmol,181.94uL)和TBTU(100.14mg,391.34μmol),室温搅拌15分钟,反应完成后,加水稀释,分液,浓缩有机相,所得残余物用硅胶柱分离纯化(DCM/MeOH=10/1)得到中间Z-27(113mg,221.83μmol,68.02%收率)。MS(ESI)m/z=511[M+1]+1H NMR(400MHz,DMSO-d6)δ12.83(s,1H),8.49–8.33(m,1H),7.92(d,J=1.4Hz,2H),7.56(d,J=1.2Hz,1H),7.46(d,J=8.4Hz,1H),7.38(dd,J=8.5,1.8Hz,1H),4.35(dt,J=9.7,4.9Hz,1H),4.14(dd,J=13.7,3.2Hz,1H),4.04–3.90(m,2H),3.73(s,3H),2.79(s,1H),2.69(s,1H),2.55(s,3H),2.28–2.13(m,1H),1.95(d,J=14.5Hz,1H),1.22(s,1H),0.81(d,J=6.5Hz,3H).To 27-m (172 mg, 326.12 μmol) in DCM (5 mL), TEA (132.00 mg, 1.30 mmol, 181.94 uL) and TBTU (100.14 mg, 391.34 μmol) were sequentially added, and stirred at room temperature for 15 minutes. After the reaction was completed, water was added. The organic phase was diluted, separated, and the organic phase was concentrated, and the obtained residue was separated and purified by silica gel column (DCM/MeOH=10/1) to obtain intermediate Z-27 (113 mg, 221.83 μmol, 68.02% yield). MS(ESI) m/z=511[M+1] + , 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.83(s, 1H), 8.49-8.33(m, 1H), 7.92(d, J =1.4Hz,2H),7.56(d,J=1.2Hz,1H),7.46(d,J=8.4Hz,1H),7.38(dd,J=8.5,1.8Hz,1H),4.35(dt,J =9.7,4.9Hz,1H),4.14(dd,J=13.7,3.2Hz,1H),4.04–3.90(m,2H),3.73(s,3H),2.79(s,1H),2.69(s, 1H), 2.55(s, 3H), 2.28–2.13(m, 1H), 1.95(d, J=14.5Hz, 1H), 1.22(s, 1H), 0.81(d, J=6.5Hz, 3H).

中间体Z-28的合成Synthesis of Intermediate Z-28

Figure BDA0003199064950000481
Figure BDA0003199064950000481

步骤1、28-a的合成Step 1, Synthesis of 28-a

向中间体27(493.00mg,967.81μmol)的DMF(30mL)溶液中加入DIPEA(375.24mg,2.90mmol,505.71μL)和SEMCl(242.44mg,1.45mmol),反应混合液升温至在60℃搅拌过夜,反应完成后,浓缩反应液,残余物用水稀释,乙酸乙酯萃取,合并的有机相用依次用水、饱和食盐水洗涤,无水硫酸钠干燥,浓缩后,残余物用正相硅胶柱分离纯化(100%EA)得到28-a(373mg,583.13μmol,60.25%收率)。MS(ESI)m/z=639[M+1]+To a solution of intermediate 27 (493.00 mg, 967.81 μmol) in DMF (30 mL) was added DIPEA (375.24 mg, 2.90 mmol, 505.71 μL) and SEMCl (242.44 mg, 1.45 mmol), and the reaction mixture was warmed to 60 °C and stirred overnight , after the completion of the reaction, the reaction solution was concentrated, the residue was diluted with water, extracted with ethyl acetate, the combined organic phases were washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and after concentration, the residue was separated and purified with a normal phase silica gel column (100% EA) to give 28-a (373 mg, 583.13 μmol, 60.25% yield). MS(ESI) m/z=639[M+1] + .

步骤2、28-b的合成Step 2. Synthesis of 28-b

向28-a(718mg,1.12mmol)的二氧六环(20mL)/水(2mL)混合溶液中,加入4-N-Boc哌嗪1-甲基三氟化硼钾盐(515.51mg,1.68mmol)、X-Phos(106.86mg,224.50μmol)、Pd(OAc)2(25.14mg,112.25μmol)和Cs2CO3(1.10g,3.37mmol),混合液用氮气置换几次,然后在氮气保护下升温至100℃并搅拌15h。反应完成后,浓缩反应液,残余物用水稀释,乙酸乙酯萃取,合并的有机相用水、饱和食盐水洗涤,无水硫酸钠干燥,浓缩后残余物用正相硅胶柱分离纯化(100%EA)得到28-b(607mg,799.71μmol,71.25%收率)。MS(ESI)m/z=759[M+1]+1HNMR(400MHz,DMSO-d6)δ12.83(s,1H),8.49–8.33(m,1H),7.92(d,J=1.4Hz,2H),7.56(d,J=1.2Hz,1H),7.46(d,J=8.4Hz,1H),7.38(dd,J=8.5,1.8Hz,1H),4.35(m,1H),4.14(dd,J=13.7,3.2Hz,1H),4.04–3.90(m,2H),3.73(s,3H),2.79(s,1H),2.69(s,1H),2.55(s,3H),2.28–2.13(m,1H),1.95(d,J=14.5Hz,1H),1.43-1.47(m,1H),1.22(s,1H),0.81(d,J=6.5Hz,3H).To a mixed solution of 28-a (718 mg, 1.12 mmol) in dioxane (20 mL)/water (2 mL) was added 4-N-Boc piperazine 1-methylboron trifluoride potassium salt (515.51 mg, 1.68 g mmol), X-Phos (106.86 mg, 224.50 μmol), Pd(OAc) 2 (25.14 mg, 112.25 μmol) and Cs 2 CO 3 (1.10 g, 3.37 mmol), the mixture was replaced with nitrogen several times, and then heated under nitrogen The temperature was raised to 100 °C under protection and stirred for 15 h. After the reaction was completed, the reaction solution was concentrated, the residue was diluted with water, extracted with ethyl acetate, the combined organic phases were washed with water and saturated brine, and dried over anhydrous sodium sulfate. After concentration, the residue was separated and purified by normal phase silica gel column (100% EA). ) to give 28-b (607 mg, 799.71 μmol, 71.25% yield). MS(ESI) m/z=759[M+1] + , 1 HNMR (400MHz, DMSO-d 6 ) δ 12.83(s, 1H), 8.49-8.33(m, 1H), 7.92(d, J= 1.4Hz, 2H), 7.56(d, J=1.2Hz, 1H), 7.46(d, J=8.4Hz, 1H), 7.38(dd, J=8.5, 1.8Hz, 1H), 4.35(m, 1H) ,4.14(dd,J=13.7,3.2Hz,1H),4.04–3.90(m,2H),3.73(s,3H),2.79(s,1H),2.69(s,1H),2.55(s,3H) ), 2.28-2.13(m, 1H), 1.95(d, J=14.5Hz, 1H), 1.43-1.47(m, 1H), 1.22(s, 1H), 0.81(d, J=6.5Hz, 3H) .

步骤3、Z-28的合成Step 3. Synthesis of Z-28

向28-b(671mg,884.03μmol)的DCM(5mL)中,加入TFA(5mL),反应液室温搅拌1小时。反应完成后,浓缩干反应液,得到Z-28(452mg,855.01μmol,96.72%收率),未经纯化直接用于下一步反应。MS(ESI)m/z=529[M+1]+To 28-b (671 mg, 884.03 μmol) in DCM (5 mL), TFA (5 mL) was added, and the reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the dry reaction solution was concentrated to obtain Z-28 (452 mg, 855.01 μmol, 96.72% yield), which was directly used in the next reaction without purification. MS(ESI) m/z=529[M+1] + .

中间体Z-29的合成Synthesis of Intermediate Z-29

Figure BDA0003199064950000491
Figure BDA0003199064950000491

参照Z-27的合成方法中的步骤8到步骤14,仅在步骤8中用2-氟-5-溴硝基苯代替2-氟-4-溴硝基苯,其余方法相同,即可得Z-29。MS(ESI)m/z=509[M+1]+Referring to step 8 to step 14 in the synthesis method of Z-27, only in step 8, 2-fluoro-5-bromonitrobenzene is used instead of 2-fluoro-4-bromonitrobenzene, and the rest of the methods are the same, and the obtained Z-29. MS(ESI) m/z=509[M+1] + .

中间体Z-30的合成Synthesis of Intermediate Z-30

Figure BDA0003199064950000492
Figure BDA0003199064950000492

参照Z-28的合成方法步骤1到步骤3的方法,用Z-29替代步骤1中Z-27,其余方法步骤相同,得到Z-30。MS(ESI)m/z=529[M+1]+Referring to the methods from step 1 to step 3 of the synthesis method of Z-28, Z-29 is used to replace Z-27 in step 1, and the remaining method steps are the same to obtain Z-30. MS(ESI) m/z=529[M+1] + .

中间体Z-31的合成Synthesis of Intermediate Z-31

Figure BDA0003199064950000493
Figure BDA0003199064950000493

步骤1、中间体31-a的合成Step 1. Synthesis of Intermediate 31-a

向Z-27(493.00mg,967.81μmol)的DMF(30mL)溶液中依次加入DIPEA(375.24mg,2.90mmol,505.71μL)和SEMCl(242.44mg,1.45mmol),反应混合液升温至60℃并搅拌12h,反应完成后,浓缩反应液,残余物加水稀释,用乙酸乙酯萃取,合并的有机相依次用水、饱和食盐水洗涤,无水硫酸钠干燥,旋干后用正相硅胶柱分离纯化(100%乙酸乙酯),得31-a(373mg,583.13μmol,60.25%收率)。MS(ESI)m/z=639[M+1]+To a solution of Z-27 (493.00 mg, 967.81 μmol) in DMF (30 mL), DIPEA (375.24 mg, 2.90 mmol, 505.71 μL) and SEMCl (242.44 mg, 1.45 mmol) were sequentially added, and the reaction mixture was heated to 60° C. and stirred 12h, after the completion of the reaction, the reaction solution was concentrated, the residue was diluted with water, extracted with ethyl acetate, the combined organic phases were washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and then spin-dried and separated and purified with a normal phase silica gel column ( 100% ethyl acetate) to give 31-a (373 mg, 583.13 μmol, 60.25% yield). MS(ESI) m/z=639[M+1] + .

步骤2、中间体31-b的合成Step 2. Synthesis of Intermediate 31-b

向31-a(50mg,78.17μmol)的甲苯(3mL)溶液中加入1-叔丁氧羰基哌嗪(14.56mg,78.17μmol),BINAP(9.73mg,15.63μmol),Pd(OAc)2(1.75mg,7.82μmol)和Cs2CO3(50.81mg,156.33μmol)。氮气保护,升温至120℃并在此温度下搅拌反应15小时。反应完成后,混合液用乙酸乙酯稀释,加水洗涤,浓缩有机相得粗品,粗品用反相硅胶柱分离纯化得31-b(30mg,40.27μmol,51.52%收率),MS(ESI)m/z=745[M+1]+To a solution of 31-a (50 mg, 78.17 μmol) in toluene (3 mL) was added 1-tert-butoxycarbonylpiperazine (14.56 mg, 78.17 μmol), BINAP (9.73 mg, 15.63 μmol), Pd(OAc) 2 (1.75 mg, 7.82 μmol) and Cs 2 CO 3 (50.81 mg, 156.33 μmol). Under nitrogen, the temperature was raised to 120°C and the reaction was stirred at this temperature for 15 hours. After the reaction was completed, the mixture was diluted with ethyl acetate, washed with water, and the organic phase was concentrated to obtain a crude product. The crude product was separated and purified by a reverse-phase silica gel column to obtain 31-b (30 mg, 40.27 μmol, 51.52% yield). MS (ESI) m /z=745[M+1] + .

步骤3、中间体Z-31的合成Step 3. Synthesis of Intermediate Z-31

向31-b(30mg,40.27μmol)的DCM(3mL)溶液中加入TFA(2mL),混合液室温搅拌1小时。然后浓缩反应液,用油泵旋除残余的TFA,得到Z-31(50mg,43.8%纯度),未经纯化直接用于下一步反应。MS(ESI)m/z=515[M+1]+To a solution of 31-b (30 mg, 40.27 μmol) in DCM (3 mL) was added TFA (2 mL), and the mixture was stirred at room temperature for 1 hour. Then, the reaction solution was concentrated, and the residual TFA was spun off with an oil pump to obtain Z-31 (50 mg, 43.8% purity), which was directly used in the next reaction without purification. MS(ESI) m/z=515[M+1] + .

中间体Z-32的合成Synthesis of Intermediate Z-32

Figure BDA0003199064950000501
Figure BDA0003199064950000501

参照Z-31合成方法中的步骤1到步骤3,用Z-29替代步骤1中的Z-27,经相同的方法得Z-32。MS(ESI)m/z=515[M+1]+Referring to steps 1 to 3 in the synthesis method of Z-31, Z-29 was used to replace Z-27 in step 1, and Z-32 was obtained by the same method. MS(ESI) m/z=515[M+1] + .

中间体Z-33的合成Synthesis of Intermediate Z-33

Figure BDA0003199064950000502
Figure BDA0003199064950000502

步骤1、中间体33-a的合成Step 1. Synthesis of Intermediate 33-a

室温下,向4-溴-2-甲基氨基苯胺(7.6g,37.8mmol)的THF(200mL)溶液中加入CDI(7.4g,45.6mmol)。混合液回流16小时,反应液冷却至室温,加水(500mL)稀释,室温搅拌30分钟。产生的沉淀经过滤收集,并用水洗涤,滤饼干燥后得6-溴-1-甲基-1,3-二氢-2H-苯并咪唑-2-酮,即33-a(7g,72%收率)黄色固体,MS(ESI)m/z=227.10,229.10[M+1]+To a solution of 4-bromo-2-methylaminoaniline (7.6 g, 37.8 mmol) in THF (200 mL) was added CDI (7.4 g, 45.6 mmol) at room temperature. The mixture was refluxed for 16 hours, the reaction solution was cooled to room temperature, diluted with water (500 mL), and stirred at room temperature for 30 minutes. The resulting precipitate was collected by filtration, washed with water, and the filter cake was dried to give 6-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one, namely 33-a (7 g, 72 % yield) yellow solid, MS (ESI) m/z = 227.10, 229.10 [M+1] + .

步骤2、中间体33-b的合成Step 2. Synthesis of Intermediate 33-b

冰浴且氮气保护下,向3-溴哌啶-2,6-二酮(10g,52.08mmol),4-甲氧基苄醇(7.92g,57.29mmol)和PPh3(13.66g,52.08mmol)的混合溶液中滴加DEAD(9.06g,52.08mmol),反应混合液在零度下搅拌2小时,反应完成后,加水淬灭反应,混合液用乙酸乙酯萃取,合并的有机相浓缩得到粗品,经硅胶柱分离纯化(PE/EA=3/1和DCM/PE=1/1,v/v)得到中间体33-b(4.88g,15.63mmol,30.02%收率)。MS(ESI)m/z=312,314[M+1]+To 3-bromopiperidine-2,6-dione (10 g, 52.08 mmol), 4-methoxybenzyl alcohol (7.92 g, 57.29 mmol) and PPh3 (13.66 g, 52.08 mmol) under an ice bath under nitrogen ) was added dropwise to the mixed solution of DEAD (9.06g, 52.08mmol), the reaction mixture was stirred at zero degrees for 2 hours, after the reaction was completed, water was added to quench the reaction, the mixed solution was extracted with ethyl acetate, and the combined organic phase was concentrated to obtain the crude product , separated and purified by silica gel column (PE/EA=3/1 and DCM/PE=1/1, v/v) to obtain intermediate 33-b (4.88 g, 15.63 mmol, 30.02% yield). MS(ESI) m/z=312,314[M+1] + .

步骤3、中间体33-c的合成Step 3. Synthesis of Intermediate 33-c

将33-a(4.0g,17.7mmol)的THF(50mL)溶液冷却至0℃,加入t-BuOK(2.38g,21.2mmol),混合液零度下搅拌30分钟,然后加入33-b(8.26g,26.5mmol),混合液室温搅拌过夜,旋除溶剂,粗品用硅胶柱分离纯化(EtOAc:DCM=1:1)得到33-c(2.9g,6.33mmol,收率:36%),MS(ESI)m/z=458[M+1]+The solution of 33-a (4.0 g, 17.7 mmol) in THF (50 mL) was cooled to 0 °C, t-BuOK (2.38 g, 21.2 mmol) was added, the mixture was stirred at zero temperature for 30 minutes, and then 33-b (8.26 g) was added. , 26.5 mmol), the mixture was stirred at room temperature overnight, the solvent was removed, and the crude product was separated and purified by silica gel column (EtOAc:DCM=1:1) to obtain 33-c (2.9 g, 6.33 mmol, yield: 36%), MS ( ESI)m/z=458[M+1] + .

步骤4、中间体Z-33的合成Step 4. Synthesis of Intermediate Z-33

室温下,向33-c(2.0g,4.37mmol)的甲苯(20mL)溶液中加入MeSO3H(10mL),反应混合液升温至110℃并在此温度下搅拌2h。冷却至室温,混合液减压浓缩,粗品用冰水稀释,析出的固体经过滤收集,然后正己烷洗涤,干燥后得中间体Z-33(0.8g,收率54%),MS(ESI)m/z=339[M+1]+To a solution of 33-c (2.0 g, 4.37 mmol) in toluene (20 mL) was added MeSO3H (10 mL) at room temperature, and the reaction mixture was warmed to 110 °C and stirred at this temperature for 2 h. Cooled to room temperature, the mixture was concentrated under reduced pressure, the crude product was diluted with ice water, the precipitated solid was collected by filtration, washed with n-hexane, and dried to obtain intermediate Z-33 (0.8 g, yield 54%), MS (ESI) m/z=339[M+1] + .

中间体Z-34的合成Synthesis of Intermediate Z-34

Figure BDA0003199064950000511
Figure BDA0003199064950000511

步骤1、中间体34-a的合成Step 1. Synthesis of Intermediate 34-a

参照中间体Z-33步骤1中33-a的合成方法,将原料4-溴-2-甲基氨基苯胺替换为5-溴-2-甲基氨基苯胺,其余操作不变,可得中间体34-a。MS(ESI)m/z=227.10,229.10[M+1]+Referring to the synthetic method of 33-a in the step 1 of the intermediate Z-33, the raw material 4-bromo-2-methylaminoaniline is replaced with 5-bromo-2-methylaminoaniline, and the remaining operations are unchanged, and the intermediate can be obtained 34-a. MS(ESI) m/z = 227.10, 229.10 [M+1] + .

步骤2、中间体34-b的合成Step 2. Synthesis of Intermediate 34-b

零度下,向四氢-5-氧代-2-呋喃羧酸(12g,92mmol)中缓慢加入SOCl2(25g,207mmol)。混合液升温至85℃,并搅拌3小时,然后反应液冷却至室温,继续搅拌6小时。原料反应完全后,混合液减压浓缩。氮气保护下,粗品溶解在零度干燥的DCM中,然后加入Et3N(18.7g,184mmol)和4-甲氧基苄胺(10.1g,74mmol),混合液室温搅拌3小时。完成后,加水稀释,混合液用DCM萃取,合并的有机相依次用0.5M HCl(50mL)水溶液和饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤旋干后,粗品用硅胶柱分离纯化,得到34-b(10.5g,45.6%收率),MS(ESI)m/z=272.0[M+Na]+To tetrahydro-5-oxo-2-furancarboxylic acid (12 g, 92 mmol) was slowly added SOCl 2 (25 g, 207 mmol) at zero degrees. The mixture was heated to 85°C and stirred for 3 hours, then the reaction solution was cooled to room temperature and stirred for 6 hours. After the reaction of the raw materials was completed, the mixture was concentrated under reduced pressure. Under nitrogen protection, the crude product was dissolved in zero-degree dry DCM, then Et 3 N (18.7 g, 184 mmol) and 4-methoxybenzylamine (10.1 g, 74 mmol) were added, and the mixture was stirred at room temperature for 3 hours. After completion, diluted with water, the mixture was extracted with DCM, the combined organic phases were washed with 0.5M aqueous HCl (50 mL) and saturated brine (50 mL) successively, dried over anhydrous sodium sulfate, filtered and spin-dried, and the crude product was separated with a silica gel column Purification gave 34-b (10.5 g, 45.6% yield), MS (ESI) m/z = 272.0 [M+Na] + .

步骤3、中间体34-c的合成Step 3. Synthesis of Intermediate 34-c

34-b(10.5g,47.9mmol)的无水THF(120mL)冷却至-78℃,然后氮气保护且-78℃下,逐滴加入t-BuOK(5.4g,48.4mmol)的无水THF(100mL),反应混合液在-40℃搅拌反应1小时,反应完成后,混合液用饱和NH4Cl溶液淬灭,加乙酸乙酯萃取,合并的有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤后浓缩,醋瓶用硅胶柱分离纯化得到中间体34-c(10.9g,43.73mmol,77.7%收率)。MS(ESI)m/z=250.0[M+1]+34-b (10.5 g, 47.9 mmol) in anhydrous THF (120 mL) was cooled to -78 °C, then under nitrogen protection and at -78 °C, t-BuOK (5.4 g, 48.4 mmol) in anhydrous THF ( 100 mL), the reaction mixture was stirred at -40 °C for 1 hour, after the reaction was completed, the mixture was quenched with saturated NH 4 Cl solution, extracted with ethyl acetate, the combined organic phases were washed with saturated brine, and anhydrous sodium sulfate was added. After drying, filtration and concentration, the vinegar flask was separated and purified by silica gel column to obtain intermediate 34-c (10.9 g, 43.73 mmol, 77.7% yield). MS(ESI) m/z=250.0[M+1] + .

步骤4、中间体34-d的合成Step 4. Synthesis of intermediate 34-d

零度下,向34-c(10.9g,43.73mmol)和吡啶(6.92g,87.46mmol)的DCM(100mL)溶液中逐滴加入三氟甲磺酸酐(18.51g,65.59mmol),氮气保护下,混合液在0-10℃搅拌1.5小时。反应完成后,浓缩混合液,粗品用硅胶柱分离纯化得到34-d(8.17g,21.43mmol,49%收率),MS(ESI)m/z=382[M+1]+Trifluoromethanesulfonic anhydride (18.51 g, 65.59 mmol) was added dropwise to a solution of 34-c (10.9 g, 43.73 mmol) and pyridine (6.92 g, 87.46 mmol) in DCM (100 mL) at zero temperature, under nitrogen protection, The mixture was stirred at 0-10°C for 1.5 hours. After the reaction was completed, the mixture was concentrated, and the crude product was separated and purified by silica gel column to obtain 34-d (8.17 g, 21.43 mmol, 49% yield), MS (ESI) m/z=382 [M+1] + .

步骤5、中间体34-e的合成Step 5. Synthesis of Intermediate 34-e

零度下,向34-a(4.86g,21.43mmol)的THF(100mL)溶液中加入t-BuOK(2.89g,25.7mmol),混合液0℃下搅拌0.5h,然后,逐滴加入34-d(8.17g,21.43mmol)的THF(50mL)溶液,反应液在氮气保护下室温搅拌0.5h。反应完成后,反应液用饱和NH4Cl(40mL)淬灭,加乙酸乙酯萃取,合并的有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤浓缩后,粗品用mHPLC分离纯化,得到34-e(4.91g,10.71mmol,55%收率)。MS(ESI)m/z=459[M+1]+At zero degrees, t-BuOK (2.89 g, 25.7 mmol) was added to a solution of 34-a (4.86 g, 21.43 mmol) in THF (100 mL), the mixture was stirred at 0 °C for 0.5 h, and then 34-d was added dropwise (8.17 g, 21.43 mmol) in THF (50 mL) solution, the reaction solution was stirred at room temperature for 0.5 h under nitrogen protection. After the reaction was completed, the reaction solution was quenched with saturated NH 4 Cl (40 mL), extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was separated and purified by mHPLC to obtain 34-e (4.91 g, 10.71 mmol, 55% yield). MS(ESI) m/z=459[M+1] + .

步骤6、中间体Z-34的合成Step 6. Synthesis of Intermediate Z-34

参照中间体Z-33的步骤4,将步骤中的底物33-c换成34-e,其余操作步骤相同,可得到中间体Z-34,MS(ESI)m/z=338,340[M+1]+Referring to step 4 of intermediate Z-33, replace the substrate 33-c with 34-e in the step, and the rest of the operation steps are the same to obtain intermediate Z-34, MS(ESI) m/z=338,340[M+ 1] + .

中间体Z-35的合成Synthesis of Intermediate Z-35

Figure BDA0003199064950000531
Figure BDA0003199064950000531

参照中间体Z-33的合成路线中,步骤1到步骤4的方法,在步骤1中用3-溴-2-甲基氨基苯胺代替4-溴-2-甲基氨基苯胺为起始原料,其余操作相同,经历相同的步骤,即可得中间体Z-35,MS(ESI)m/z=338,340[M+1]+Referring to the synthetic route of intermediate Z-33, the method from step 1 to step 4, in step 1, 3-bromo-2-methylaminoaniline is used instead of 4-bromo-2-methylaminoaniline as the starting material, The remaining operations are the same and go through the same steps to obtain the intermediate Z-35, MS(ESI) m/z=338,340[M+1] + .

中间体Z-36的合成Synthesis of Intermediate Z-36

Figure BDA0003199064950000532
Figure BDA0003199064950000532

步骤1、中间体36-a的合成Step 1. Synthesis of Intermediate 36-a

4-吡唑硼酸频哪醇酯(5g,25.77mmol)和3-苄氧基溴丙烷(8.86g,38.65mmol)混溶于DMF(20mL)溶液中,然后加入K2CO3(8.90g,64.42mmol),KI(427.76mg,2.58mmol)。反应混合液升温至80℃,并搅拌17小时。反应完成后,浓缩反应液得到的粗品,用硅胶柱分离纯化(PE:EA=8:1,v/v),得到中间体36-a(6.4g,18.70mmol,72.57%收率),MS(ESI)m/z=343[M+H]+4-Pyrazole boronic acid pinacol ester (5 g, 25.77 mmol) and 3-benzyloxybromopropane (8.86 g, 38.65 mmol) were mixed in DMF (20 mL) solution, then K 2 CO 3 (8.90 g, 64.42 mmol), KI (427.76 mg, 2.58 mmol). The reaction mixture was warmed to 80°C and stirred for 17 hours. After the reaction was completed, the crude product obtained by concentrating the reaction solution was separated and purified by silica gel column (PE:EA=8:1, v/v) to obtain intermediate 36-a (6.4 g, 18.70 mmol, 72.57% yield), MS (ESI) m/z=343 [M+H] + .

步骤2、中间体36-b的合成Step 2. Synthesis of Intermediate 36-b

36-a(2g,5.84mmol)和1-b(1.89g,5.84mmol)混溶于DMF(20mL)中,加入Na2CO3(1.86g,17.53mmol)和Pd(dppf)Cl2(213.80mg,292.19umol),混合液用氮气置换几次,然后在氮气的保护下升温至100℃,并搅拌过夜。反应完成后,冷却至室温,加水稀释,乙酸乙酯萃取,合并的有机相经饱和食盐水洗涤后,浓缩,粗品经硅胶柱分离纯化(100%EA),得到中间体36-b(1.6g,3.49mmol,59.71%收率),MS(ESI)m/z=459[M+H]+36-a (2 g, 5.84 mmol) and 1-b (1.89 g, 5.84 mmol) were mixed in DMF (20 mL), Na 2 CO 3 (1.86 g, 17.53 mmol) and Pd(dppf)Cl 2 (213.80 were added) mg, 292.19 umol), the mixture was replaced with nitrogen several times, then heated to 100° C. under the protection of nitrogen, and stirred overnight. After the reaction was completed, it was cooled to room temperature, diluted with water, extracted with ethyl acetate, the combined organic phases were washed with saturated brine, concentrated, and the crude product was separated and purified by silica gel column (100% EA) to obtain intermediate 36-b (1.6 g). , 3.49 mmol, 59.71% yield), MS (ESI) m/z=459 [M+H] + .

步骤3、中间体36-c的合成Step 3. Synthesis of Intermediate 36-c

向36-b(840mg,1.83mmol)的MeOH(100mL)溶液中加入10%Pd/C(840mg,1.83mmol),混合液氢气置换,在氢气保护下,室温下搅拌24小时。反应完成后,滤除Pd/C,滤液浓缩得到36-c(367mg,996.24μmol,54.38%收率)。MS(ESI)m/z=369[M+H]+To a solution of 36-b (840 mg, 1.83 mmol) in MeOH (100 mL) was added 10% Pd/C (840 mg, 1.83 mmol), the mixture was replaced with hydrogen, and the mixture was stirred at room temperature for 24 hours under the protection of hydrogen. After the reaction was completed, Pd/C was filtered off, and the filtrate was concentrated to obtain 36-c (367 mg, 996.24 μmol, 54.38% yield). MS (ESI) m/z = 369 [M+H] + .

步骤4、中间体Z-36的合成Step 4. Synthesis of Intermediate Z-36

向36-c(100mg,271.45μmol)的DCM(30mL)溶液中加入DMP(230.19mg,542.91μmol),反应混合液室温下搅拌2小时。反应完成后,过滤反应液,滤液浓缩,得到的粗品经硅胶柱分离纯化(DCM/MeOH=10/1)得到Z-36(85mg,232.01μmol,85.47%收率)。MS(ESI)m/z=367[M+H]+To a solution of 36-c (100 mg, 271.45 μmol) in DCM (30 mL) was added DMP (230.19 mg, 542.91 μmol) and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated, and the obtained crude product was separated and purified by silica gel column (DCM/MeOH=10/1) to obtain Z-36 (85 mg, 232.01 μmol, 85.47% yield). MS (ESI) m/z = 367 [M+H] + .

中间体Z-37的合成Synthesis of Intermediate Z-37

Figure BDA0003199064950000541
Figure BDA0003199064950000541

步骤1、中间体37-a的合成Step 1. Synthesis of intermediate 37-a

向4-吡唑硼酸频哪醇酯(6.0g,30.92mmol)的乙腈(60ml)中加入CsF(470mg,3.09mmol)和丙烯酸叔丁酯(5.82mL,40.2mmol)。反应混合液升温至80℃,并在此温度下搅拌过夜。反应完成后,冷却至室温,减压浓缩,粗品加水和乙酸乙酯萃取,合并分离的有机相,用水和饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液浓缩,得到的粗品经硅胶柱分离纯化(正己烷/乙酸乙酯=1/1,v/v)得到37-a(9.37g,29.07mmol,收率94%)。MS(ESI)m/z=323[M+H]+To pinacol 4-pyrazoleboronic acid (6.0 g, 30.92 mmol) in acetonitrile (60 ml) was added CsF (470 mg, 3.09 mmol) and tert-butyl acrylate (5.82 mL, 40.2 mmol). The reaction mixture was warmed to 80°C and stirred at this temperature overnight. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, and the crude product was extracted with water and ethyl acetate. The separated organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The obtained crude product was passed through a silica gel column. Separation and purification (n-hexane/ethyl acetate=1/1, v/v) gave 37-a (9.37 g, 29.07 mmol, yield 94%). MS (ESI) m/z = 323 [M+H] + .

步骤2、中间体37-b的合成Step 2. Synthesis of Intermediate 37-b

向37-a(500mg,1.55mmol)和1-b(455.86mg,1.41mmol)的DMF(12mL)/H2O(3mL)溶液中加入K3PO4(416.73mg,1.98mmol),S-phos(69.41mg,169.29μmol)和Pd(OAc)2(22.61mg,98.75μmol),混合液氮气置换后在氮气的保护下升温至100℃,并在此温度下搅拌15小时,反应完成后。冷却至室温,过滤,浓缩滤液,粗品加水稀释,加乙酸乙酯萃取,合并的有机相用水和饱和食盐水洗涤,无水硫酸钠干燥,浓缩,粗品用硅胶柱分离纯化(PE/EA=0/1,v/v),得到37-b(100mg,228.06μmol,16.17%收率)淡黄色固体。MS(ESI)m/z=439[M+H]+To a solution of 37-a (500 mg, 1.55 mmol) and 1-b (455.86 mg, 1.41 mmol) in DMF (12 mL)/H 2 O (3 mL) was added K 3 PO 4 (416.73 mg, 1.98 mmol), S- phos (69.41 mg, 169.29 μmol) and Pd(OAc) 2 (22.61 mg, 98.75 μmol), the mixture was replaced with nitrogen and then heated to 100° C. under the protection of nitrogen, and stirred at this temperature for 15 hours, after the reaction was completed. Cooled to room temperature, filtered, concentrated the filtrate, the crude product was diluted with water, extracted with ethyl acetate, the combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated and purified by silica gel column (PE/EA=0 /1, v/v) to give 37-b (100 mg, 228.06 μmol, 16.17% yield) as a pale yellow solid. MS (ESI) m/z = 439 [M+H] + .

步骤3、中间体Z-37的合成Step 3. Synthesis of Intermediate Z-37

室温下,向37-b(100mg,228.06μmol)的DCM(2mL)溶液中加入TFA(1.54g,13.51mmol,1mL),混合液室温下搅拌2小时。反应完成后,浓缩干燥反应液得到Z-37(92mg,185.34μmol,81.27%收率),未经纯化直接用于下一步反应。MS(ESI)m/z=383[M+H]+To a solution of 37-b (100 mg, 228.06 μmol) in DCM (2 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated and dried to obtain Z-37 (92 mg, 185.34 μmol, 81.27% yield), which was directly used in the next reaction without purification. MS (ESI) m/z = 383 [M+H] + .

中间体Z-38的合成Synthesis of Intermediate Z-38

Figure BDA0003199064950000551
Figure BDA0003199064950000551

步骤1、中间体38-a的合成Step 1. Synthesis of Intermediate 38-a

向2-甲基5-碘苯甲酸甲酯(10g,36.22mmol)的CCl4(100mL)溶液中加入NBS(6.77g,38.03mmol)和过氧化苯甲酰(4.38g,18.11mmol),混合液升温至80℃并搅拌反应4小时。反应完成后,冷却至室温,过滤,浓缩滤液得到38-a(12g,33.81mmol,93.33%收率),橙色油状物,未经进一步的纯化直接用于下一步反应。To a solution of methyl 2-methyl 5-iodobenzoate (10 g, 36.22 mmol) in CCl 4 (100 mL) was added NBS (6.77 g, 38.03 mmol) and benzoyl peroxide (4.38 g, 18.11 mmol), and mixed The temperature of the liquid was raised to 80°C and the reaction was stirred for 4 hours. After the reaction was completed, it was cooled to room temperature, filtered, and the filtrate was concentrated to obtain 38-a (12 g, 33.81 mmol, 93.33% yield) as an orange oil, which was used in the next reaction without further purification.

步骤2、中间体38-b的合成Step 2. Synthesis of Intermediate 38-b

向38-a(12g,33.81mmol)的DMF(150mL)溶液中加入3-氨基-2,6-哌啶二酮盐酸盐(6.12g,37.19mmol)和K2CO3(14.02g,101.42mmol)。反应混合液升温至70℃并搅拌反应18h。反应完成后,冷却反应液至室温,加水稀释,搅拌10min,过滤,滤饼经石油醚和乙酸乙酯洗涤,收集滤饼,干燥后得38-b(6.5g,17.56mmol,51.95%收率).MS(ESI)m/z=371[M+H]+To a solution of 38-a (12 g, 33.81 mmol) in DMF (150 mL) was added 3 -amino-2,6-piperidinedione hydrochloride (6.12 g, 37.19 mmol) and K2CO3 (14.02 g , 101.42 mmol). The reaction mixture was heated to 70 °C and stirred for 18 h. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water, stirred for 10 min, filtered, the filter cake was washed with petroleum ether and ethyl acetate, the filter cake was collected, and dried to obtain 38-b (6.5 g, 17.56 mmol, 51.95% yield). ). MS (ESI) m/z=371 [M+H] + .

步骤3、中间体38-c的合成Step 3. Synthesis of Intermediate 38-c

向38-b(400mg,1.08mmol)和2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H-吡唑-1-基)乙酸叔丁酯(366.34mg,1.19mmol)的二氧六环(5mL)/H2O(0.5mL)溶液中加入K3PO4(320.74mg,1.51mmol),S-phos(53.17mg,129.68μmol)和Pd(OAc)2(17.32mg,75.65μmol),混合液氮气置换几次,然后在氮气保护下升温至100℃,搅拌过夜。反应完成后,冷却至室温,加水稀释,加乙酸乙酯萃取,合并的有机相用水,饱和食盐水洗涤,无水硫酸钠干燥,浓缩后的粗品,经DMF/H2O的混合液重结晶得到38-c(200mg,471.20μmol,43.60%收率),浅黄色固体。MS(ESI)m/z=425[M+H]+To 38-b (400 mg, 1.08 mmol) and 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)-1H-pyrazole -1-yl) tert-butyl acetate (366.34 mg, 1.19 mmol) in dioxane (5 mL)/H2O (0.5 mL) was added K 3 PO 4 (320.74 mg, 1.51 mmol), S-phos (53.17 mg, 129.68 μmol) and Pd(OAc) 2 (17.32 mg, 75.65 μmol), the mixture was replaced with nitrogen several times, then heated to 100° C. under nitrogen protection, and stirred overnight. After the reaction was completed, it was cooled to room temperature, diluted with water, extracted with ethyl acetate, the combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was recrystallized from a mixture of DMF/H 2 O 38-c (200 mg, 471.20 μmol, 43.60% yield) was obtained as a pale yellow solid. MS (ESI) m/z = 425 [M+H] + .

步骤4、中间体Z-38的合成Step 4. Synthesis of Intermediate Z-38

室温下,向38-c(200mg,471.20μmol)的DCM(3mL)溶液中加入TFA(53.73mg,471.20μmol,35.12μL),反应混合液室温下搅拌2小时。反应完成后,浓缩反应液,粗品干燥后得Z-38(200mg,414.62μmol,87.99%收率,TF),未经进一步纯化直接用于下一步反应。To a solution of 38-c (200 mg, 471.20 μmol) in DCM (3 mL) was added TFA (53.73 mg, 471.20 μmol, 35.12 μL) at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated, and the crude product was dried to obtain Z-38 (200 mg, 414.62 μmol, 87.99% yield, TF), which was directly used in the next reaction without further purification.

中间体Z-39的合成Synthesis of Intermediate Z-39

Figure BDA0003199064950000561
Figure BDA0003199064950000561

步骤1、中间体39-a的合成Step 1. Synthesis of Intermediate 39-a

向中间体38-b(1g,2.70mmol)和36-a(1.02g,2.97mmol)在二氧六环(20mL)/H2O(1mL)的混合液中加入Na2CO3(400.93mg,3.78mmol),S-phos(132.92mg,324.20μmol)和Pd(OAc)2(43.31mg,189.12μmol),混合液氮气置换几次,在氮气的保护下反应混合液升温至60℃,在60℃搅拌反应过夜。反应完成后,过滤反应液,浓缩滤液,所得粗品加水稀释,乙酸乙酯萃取,合并的有机相用水和饱和食盐水洗涤,无水硫酸钠干燥,旋干后得粗品用pre-HPLC分离纯化得到中间体39-a(130mg,283.53μmol,10.49%收率)白色固体。MS(ESI)m/z=284[M+H]+To a mixture of intermediates 38-b (1 g, 2.70 mmol) and 36-a (1.02 g, 2.97 mmol) in dioxane (20 mL)/H 2 O (1 mL) was added Na 2 CO 3 (400.93 mg) , 3.78mmol), S-phos (132.92mg, 324.20μmol) and Pd(OAc) 2 (43.31mg, 189.12μmol), the mixture was replaced with nitrogen several times, and the reaction mixture was warmed to 60° C. under the protection of nitrogen. The reaction was stirred at 60°C overnight. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated, the obtained crude product was diluted with water, extracted with ethyl acetate, the combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product by pre-HPLC separation and purification to obtain Intermediate 39-a (130 mg, 283.53 μmol, 10.49% yield) as a white solid. MS(ESI) m/z=284[M+H] + .

步骤2、中间体39-b的合成Step 2. Synthesis of Intermediate 39-b

向39-a(410mg,894.20μmol)的MeOH(150mL)和THF(30mL)混合液中加入Pd/C(1.09g,894.20μmol,10%纯度),反应液氢气置换几次,然后在氢气的保护下室温搅拌15h,反应完成后,过滤,滤液浓缩干燥得中间体39-b的粗品(310mg),未经纯化直接用于下一步反应。Pd/C (1.09 g, 894.20 μmol, 10% purity) was added to a mixture of 39-a (410 mg, 894.20 μmol) in MeOH (150 mL) and THF (30 mL), the reaction solution was replaced with hydrogen several times, and then added under hydrogen The mixture was stirred at room temperature for 15 h under protection, filtered, and the filtrate was concentrated and dried to obtain the crude product (310 mg) of intermediate 39-b, which was directly used in the next reaction without purification.

步骤3、中间体Z-39的合成Step 3. Synthesis of Intermediate Z-39

室温下,向39-b(150mg,0.41mmol)的DCM(3mL)/DMF(1mL)的混合液中加入DMP(345mg,0.81mmol),反应混合液室温下搅拌反应1小时。反应完成后,过滤反应液,滤液浓缩,得到的粗品经硅胶柱分离纯化得到Z-39(110mg,0.3mmol,73%收率)。MS(ESI)m/z=367[M+H]+DMP (345 mg, 0.81 mmol) was added to a mixture of 39-b (150 mg, 0.41 mmol) in DCM (3 mL)/DMF (1 mL) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated, and the obtained crude product was separated and purified by silica gel column to obtain Z-39 (110 mg, 0.3 mmol, 73% yield). MS (ESI) m/z = 367 [M+H] + .

中间体Z-40的合成Synthesis of Intermediate Z-40

Figure BDA0003199064950000571
Figure BDA0003199064950000571

步骤1、中间体40-a的合成Step 1. Synthesis of Intermediate 40-a

冰浴下,向2-b(10.0g,30.9mmol)和DBU(10.4mL,69mmol)的DMF(95mL)溶液中加入SEMCl(9.9mL,56mmol),混合液缓慢升至室温并搅拌反应6h。反应完成后,反应液用饱和NH4Cl(250mL)淬灭,加乙酸乙酯萃取,合并的有机相用无水硫酸钠干燥,过滤,滤液浓缩得粗品,粗品用乙酸乙酯/乙醚/正己烷的混合液重结晶,得中间体40-a(9.5g,30.95mmol,67.7%收率)类白色固体。Under ice bath, SEMCl (9.9 mL, 56 mmol) was added to a solution of 2-b (10.0 g, 30.9 mmol) and DBU (10.4 mL, 69 mmol) in DMF (95 mL), the mixture was slowly warmed to room temperature and the reaction was stirred for 6 h. After the completion of the reaction, the reaction solution was quenched with saturated NH 4 Cl (250 mL), extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was washed with ethyl acetate/diethyl ether/n-hexane The alkane mixture was recrystallized to obtain intermediate 40-a (9.5 g, 30.95 mmol, 67.7% yield) as an off-white solid.

步骤2、中间体40-b的合成Step 2. Synthesis of Intermediate 40-b

向40-a(1g,2.21mmol)和36-a(830.31mg,2.43mmol)的二氧六环(5.00mL)/H2O(5.00mL)混合液中加入Na2CO3(327.30mg,3.09mmol),S-phos(108.51mg,264.67μmol)和Pd(OAc)2(35.35mg,154.39μmol),混合液氮气置换几次,然后在氮气保护下升温至60℃,并在此温度下搅拌反应15h,反应完成后,过滤反应液,浓缩滤液,所得粗品加水稀释,乙酸乙酯萃取,合并的有机相用水和饱和食盐水洗涤,无水硫酸钠干燥,旋干后得粗品用硅胶柱分离纯化(PE/EA=1/1)得到中间体40-b(200mg,339.69μmol,15.40%收率)白色固体。MS(ESI)m/z=589[M+H]+To a mixture of 40-a (1 g, 2.21 mmol) and 36-a (830.31 mg, 2.43 mmol) in dioxane (5.00 mL)/H 2 O (5.00 mL) was added Na 2 CO 3 (327.30 mg, 3.09 mmol), S-phos (108.51 mg, 264.67 μmol) and Pd(OAc) 2 (35.35 mg, 154.39 μmol), the mixture was replaced with nitrogen several times, and then heated to 60 ° C under nitrogen protection, and at this temperature The reaction was stirred for 15 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated. The obtained crude product was diluted with water, extracted with ethyl acetate, the combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product using a silica gel column. Isolation and purification (PE/EA=1/1) gave intermediate 40-b (200 mg, 339.69 μmol, 15.40% yield) as a white solid. MS (ESI) m/z = 589 [M+H] + .

步骤3和步骤4、中间体Z-40的合成Synthesis of step 3 and step 4, intermediate Z-40

参照中间体Z-39合成方法中步骤2和步骤3的方法,以40-b为原料,经Pd/C还原,DMP氧化可得中间体Z-40,MS(ESI)m/z=497[M+H]+Referring to the method of step 2 and step 3 in the synthesis method of intermediate Z-39, using 40-b as raw material, through Pd/C reduction and DMP oxidation, intermediate Z-40 can be obtained, MS(ESI) m/z=497[ M+H] + .

中间体Z-41的合成Synthesis of Intermediate Z-41

Figure BDA0003199064950000572
Figure BDA0003199064950000572

步骤1、中间体41-a的合成Step 1. Synthesis of Intermediate 41-a

向中间体40-a(469.02mg,1.46mmol)和37-a(600mg,1.32mmol)的DMF(8mL)/H2O(2mL)混合液中加入K3PO4(393.32mg,1.85mmol),S-phos(65.19mg,159.01μmol)和Pd(OAc)2(21.21mg,92.63μmol),混合液氮气置换几次,在氮气的保护下升温至100℃,并在此温度下搅拌反应15h。反应完成后,过滤反应液,滤液浓缩,所得粗品加水稀释,乙酸乙酯萃取,合并的有机相用水和饱和食盐水洗涤,无水硫酸钠干燥,旋干后得粗品用硅胶柱分离纯化(PE/EA=2/1)得到中间体41-a(130mg,228.58μmol,17.27%收率)白色固体。MS(ESI)m/z=383[M+H]+To a mixture of intermediates 40-a (469.02 mg, 1.46 mmol) and 37-a (600 mg, 1.32 mmol) in DMF (8 mL)/H 2 O (2 mL) was added K 3 PO 4 (393.32 mg, 1.85 mmol) , S-phos (65.19mg, 159.01μmol) and Pd(OAc) 2 (21.21mg, 92.63μmol), the mixture was replaced with nitrogen several times, heated to 100°C under the protection of nitrogen, and stirred for 15h at this temperature . After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated, the obtained crude product was diluted with water, extracted with ethyl acetate, the combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product with silica gel column separation and purification (PE /EA=2/1) to obtain intermediate 41-a (130 mg, 228.58 μmol, 17.27% yield) as a white solid. MS (ESI) m/z = 383 [M+H] + .

步骤2、中间体Z-41的合成Step 2. Synthesis of Intermediate Z-41

室温下,向41-a(90mg,158.25μmol)的DCM(2mL)溶液中加入TFA(18.04mg,158.25μmol),混合液室温下搅拌反应2小时,反应完成后,浓缩反应液,粗品重新溶解在DCM(5mL)中,然后室温加TEA(16.01mg,158.25μmol,22.07μL),混合液室温下搅拌30分钟。再次浓缩反应液并用pre-HPLC分离纯化,得到中间体Z-41(50mg,130.76μmol,82.63%收率)白色固体。At room temperature, TFA (18.04 mg, 158.25 μmol) was added to a solution of 41-a (90 mg, 158.25 μmol) in DCM (2 mL), and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated and the crude product was redissolved. In DCM (5 mL), TEA (16.01 mg, 158.25 μmol, 22.07 μL) was added at room temperature, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated again and separated and purified by pre-HPLC to obtain intermediate Z-41 (50 mg, 130.76 μmol, 82.63% yield) as a white solid.

中间体Z-42的合成Synthesis of Intermediate Z-42

Figure BDA0003199064950000581
Figure BDA0003199064950000581

步骤1、中间体42-a的合成Step 1. Synthesis of Intermediate 42-a

向3-(4-羟基-1-氧代-1,3-二氢异吲哚-2-基)哌啶-2,6-二酮(500mg,1.92mmol)的DMF(8mL)溶液中加入4-溴丁基氧基-叔丁基二甲基硅烷(514mg,1.92mmol),KHCO3(570mg,5.76mmol)和催化量的KI,混合液升温至70℃,在此温度下搅拌反应15h。反应完成后,反应液加水稀释,加乙酸乙酯萃取,合并的有机相用水、饱和食盐水洗涤,无水硫酸钠干燥,过滤旋干得粗品,粗品用mHPLC分离纯化,得到中间体42-a(160mg,0.48mmol,25%收率)。MS(ESI)m/z=333[M+H]+To a solution of 3-(4-hydroxy-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione (500 mg, 1.92 mmol) in DMF (8 mL) was added 4-Bromobutyloxy-tert-butyldimethylsilane (514mg, 1.92mmol), KHCO 3 (570mg, 5.76mmol) and a catalytic amount of KI, the mixture was heated to 70°C, and the reaction was stirred at this temperature for 15h . After the completion of the reaction, the reaction solution was diluted with water, extracted with ethyl acetate, the combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and spin-dried to obtain the crude product, which was separated and purified by mHPLC to obtain intermediate 42-a (160 mg, 0.48 mmol, 25% yield). MS (ESI) m/z = 333 [M+H] + .

步骤2、中间体Z-42的合成Step 2. Synthesis of Intermediate Z-42

向42-a(80mg,240.71μmol)的DCM(10mL)溶液中加入DMP(204.12mg,481.42μmol),混合液室温搅拌反应1小时。反应完成后,过滤反应液,滤液浓缩,粗品用硅胶柱分离纯化(DCM/MeOH=10/1),得到中间体Z-42(75mg,227.04μmol,94.32%收率)。MS(ESI)m/z=331[M+H]+To a solution of 42-a (80 mg, 240.71 μmol) in DCM (10 mL) was added DMP (204.12 mg, 481.42 μmol), and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated, and the crude product was separated and purified by silica gel column (DCM/MeOH=10/1) to obtain intermediate Z-42 (75 mg, 227.04 μmol, 94.32% yield). MS (ESI) m/z=331 [M+H] + .

中间体Z-43的合成Synthesis of Intermediate Z-43

Figure BDA0003199064950000591
Figure BDA0003199064950000591

步骤1、中间体43-b的合成Step 1. Synthesis of Intermediate 43-b

向43-a(5.0g,50.94mmol)溶于DMF(100mL)溶液中,氮气保护下降温至0℃,加入NaH(2.04g,50.94mmol),保温反应30分钟,加入3-苄氧基溴丙烷(9.34g,40.76mmol),反应混合液升温至25℃并搅拌2h,反应完成后,加入饱和氯化铵水溶液淬灭,加水稀释,用EA萃取,合并的有机相依次用水、饱和食盐水洗涤,无水硫酸钠干燥,旋干后用硅胶柱分离纯化(PE/EA=20/1),得43-b(2.5g,10.15mmol,19.92%收率)。MS(ESI)m/z=247[M+1]+43-a (5.0 g, 50.94 mmol) was dissolved in DMF (100 mL) solution, the temperature was lowered to 0 °C under nitrogen protection, NaH (2.04 g, 50.94 mmol) was added, the reaction was incubated for 30 minutes, and 3-benzyloxy bromide was added. Propane (9.34 g, 40.76 mmol), the reaction mixture was heated to 25°C and stirred for 2 h. After the reaction was completed, saturated aqueous ammonium chloride solution was added to quench, diluted with water, and extracted with EA. The combined organic phases were successively water and saturated brine. Washed, dried over anhydrous sodium sulfate, spin-dried, separated and purified by silica gel column (PE/EA=20/1) to obtain 43-b (2.5 g, 10.15 mmol, 19.92% yield). MS(ESI) m/z=247[M+1] + .

步骤2、中间体43-c的合成Step 2. Synthesis of Intermediate 43-c

向1-b(20.0g,61.89mmol)溶于DMF(500mL)溶液中,氮气保护下降温至0℃,加入NaH(2.72g,68.08mmol),保温反应30分钟,加入SEMCl(12.66g,75.83mmol),反应混合液升温至25℃并搅拌12h,反应完成后,加入饱和氯化铵水溶液淬灭,加水稀释,用EA萃取,合并的有机相依次用水、饱和食盐水洗涤,无水硫酸钠干燥,旋干后得粗品43-c(28g,61.76mmol,99.78%收率)。MS(ESI)m/z=453[M+1]+,直接用于下一步。1-b (20.0 g, 61.89 mmol) was dissolved in DMF (500 mL) solution, the temperature was lowered to 0 °C under nitrogen protection, NaH (2.72 g, 68.08 mmol) was added, the reaction was incubated for 30 minutes, and SEMCl (12.66 g, 75.83 mmol) was added. mmol), the reaction mixture was heated to 25 °C and stirred for 12 h. After the reaction was completed, saturated aqueous ammonium chloride solution was added to quench, diluted with water, extracted with EA, the combined organic phases were washed with water and saturated brine in turn, and anhydrous sodium sulfate After drying and spin drying, crude product 43-c (28 g, 61.76 mmol, 99.78% yield) was obtained. MS (ESI) m/z = 453 [M+1] + , used directly in the next step.

步骤3、中间体43-d的合成Step 3. Synthesis of Intermediate 43-d

向43-c(6.91g,15.24mmol)的DMF(100mL)溶液中依次加入43-b(4.13g,16.76mmol),CuI(435.38mg,2.29mmol),Pd(Ph3P)2Cl2(801.24mg,1.14mmol)和TEA(4.63g,45.72mmol,6.37mL)。反应液在N2保护下于85℃搅拌12小时,用水稀释,EA萃取,分离的有机相用水和食盐水洗涤,干燥后旋干。粗品用硅胶柱分离纯化(PE/EA=1/1),得到中间体43-d(6.66g,10.76mmol,70.62%收率)。MS(ESI)m/z=619[M+H]+To a solution of 43-c (6.91 g, 15.24 mmol) in DMF (100 mL) was added 43-b (4.13 g, 16.76 mmol), CuI (435.38 mg, 2.29 mmol), Pd(Ph 3 P) 2 Cl 2 ( 801.24 mg, 1.14 mmol) and TEA (4.63 g, 45.72 mmol, 6.37 mL). The reaction solution was stirred at 85°C for 12 hours under the protection of N 2 , diluted with water, extracted with EA, and the separated organic phase was washed with water and brine, dried and then spin-dried. The crude product was separated and purified by silica gel column (PE/EA=1/1) to obtain intermediate 43-d (6.66 g, 10.76 mmol, 70.62% yield). MS (ESI) m/z=619 [M+H] + .

步骤4、中间体43-e的合成Step 4. Synthesis of Intermediate 43-e

向43-d(1000mg,1.62mmol)的MeOH(20mL)溶液中加入Pd/C(0.1g,10%纯度),反应液氢气置换后,在氢气的保护下室温搅拌12h,反应完成后,过滤,滤液浓缩干燥得中间体43-e的粗品(600mg,1.13mmol,69.70%收率),直接用于下一步反应。MS(ESI)m/z=533[M+H]+Pd/C (0.1 g, 10% purity) was added to a solution of 43-d (1000 mg, 1.62 mmol) in MeOH (20 mL), the reaction solution was replaced with hydrogen, and stirred at room temperature for 12 h under the protection of hydrogen. After the reaction was completed, filter , the filtrate was concentrated and dried to obtain the crude product of intermediate 43-e (600 mg, 1.13 mmol, 69.70% yield), which was directly used in the next reaction. MS (ESI) m/z = 533 [M+H] + .

步骤5、中间体Z-43的合成Step 5. Synthesis of Intermediate Z-43

向43-e(200mg,375.42μmol)的DCM(10mL)溶液中加入DMP(238.76mg,563.12μmol),混合液室温搅拌反应1小时。反应完成后,过滤反应液,滤液浓缩,粗品用硅胶柱分离纯化(DCM/MeOH=10/1),得到中间体Z-43(199mg,374.96μmol,99.88%收率)。MS(ESI)m/z=531[M+H]+To a solution of 43-e (200 mg, 375.42 μmol) in DCM (10 mL) was added DMP (238.76 mg, 563.12 μmol), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was filtered, the filtrate was concentrated, and the crude product was separated and purified by silica gel column (DCM/MeOH=10/1) to obtain intermediate Z-43 (199 mg, 374.96 μmol, 99.88% yield). MS (ESI) m/z = 531 [M+H] + .

中间体Z-44的合成Synthesis of Intermediate Z-44

Figure BDA0003199064950000601
Figure BDA0003199064950000601

参照中间体Z-43的合成路线中,步骤1到步骤5的方法,在步骤1中用4-戊炔基-1-醇代替5-己炔基-1-醇基苯胺为起始原料,其余操作相同,经历相同的步骤,即可得中间体Z-44,MS(ESI)m/z=517[M+1]+Referring to the synthetic route of intermediate Z-43, the method from step 1 to step 5, in step 1, 4-pentynyl-1-ol was used instead of 5-hexynyl-1-ol aniline as the starting material, The remaining operations are the same and go through the same steps to obtain the intermediate Z-44, MS(ESI) m/z=517[M+1] + .

中间体Z-45的合成Synthesis of Intermediate Z-45

Figure BDA0003199064950000611
Figure BDA0003199064950000611

步骤1、中间体45-b的合成Step 1. Synthesis of Intermediate 45-b

向28-a(50mg,78.17μmol)的DMF(5mL)/H2O(0.5mL)溶液中依次加入45-a(24.17mg,78.17mmol),K2CO3(32.36mg,234.5μmol),Pd(dppf)Cl2(5.71mg,7.82μmol)。反应液在N2保护下于90℃搅拌12小时,用水稀释,乙酸乙酯萃取,分离的有机相用水和食盐水洗涤,干燥后旋干。粗品用pre-TLC分离纯化(100%EA),得到中间体45-b(57mg,76.82mmol,98.28%收率)。MS(ESI)m/z=742[M+H]+To a solution of 28-a (50 mg, 78.17 μmol) in DMF (5 mL)/H 2 O (0.5 mL) was sequentially added 45-a (24.17 mg, 78.17 mmol), K 2 CO 3 (32.36 mg, 234.5 μmol), Pd(dppf)Cl2 (5.71 mg , 7.82 μmol). The reaction solution was stirred at 90°C for 12 hours under the protection of N 2 , diluted with water, extracted with ethyl acetate, and the separated organic phase was washed with water and brine, dried and then spin-dried. The crude product was isolated and purified by pre-TLC (100% EA) to give intermediate 45-b (57 mg, 76.82 mmol, 98.28% yield). MS(ESI) m/z=742[M+H] + .

步骤2、中间体Z-45的合成Step 2. Synthesis of Intermediate Z-45

室温下,向45-b(32mg,43.13μmol)的DCM(2mL)溶液中加入TFA(18.04mg,158.25μmol),混合液室温下搅拌反应2小时,反应完成后,浓缩反应液,得到粗品中间体Z-45(22mg,43.00μmol,99.71%收率),直接用于下一步。At room temperature, TFA (18.04 mg, 158.25 μmol) was added to a solution of 45-b (32 mg, 43.13 μmol) in DCM (2 mL), and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain the intermediate crude product. Body Z-45 (22 mg, 43.00 μmol, 99.71% yield) was used directly in the next step.

中间体Z-46的合成Synthesis of Intermediate Z-46

Figure BDA0003199064950000612
Figure BDA0003199064950000612

步骤1、中间体46-a的合成Step 1. Synthesis of Intermediate 46-a

向45-b(32mg,43.13μmol)的MeOH(5mL)溶液中加入Pd/C(3mg,10%纯度),反应液氢气置换几次,然后在氢气的保护下室温搅拌12h,反应完成后,过滤,滤液浓缩干燥得中间体46-a的粗品(32mg,43.01μmol,99.73%收率),未经纯化直接用于下一步反应。MS(ESI)m/z=744[M+H]+Pd/C (3 mg, 10% purity) was added to a solution of 45-b (32 mg, 43.13 μmol) in MeOH (5 mL), the reaction solution was replaced with hydrogen several times, and then stirred at room temperature for 12 h under the protection of hydrogen. After the reaction was completed, After filtration, the filtrate was concentrated and dried to obtain the crude product of intermediate 46-a (32 mg, 43.01 μmol, 99.73% yield), which was directly used in the next reaction without purification. MS (ESI) m/z = 744 [M+H] + .

步骤2、中间体Z-46的合成Step 2. Synthesis of Intermediate Z-46

室温下,向46-a(33mg,44.35μmol)的DCM(2mL)溶液中加入TFA(18.04mg,158.25μmol),混合液室温下搅拌反应2小时,反应完成后,浓缩反应液,得到粗品中间体Z-46(22mg,42.83μmol,96.57%收率),直接用于下一步。At room temperature, TFA (18.04 mg, 158.25 μmol) was added to a solution of 46-a (33 mg, 44.35 μmol) in DCM (2 mL), and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain the intermediate crude product. Body Z-46 (22 mg, 42.83 μmol, 96.57% yield) was used directly in the next step.

中间体Z-47的合成Synthesis of Intermediate Z-47

Figure BDA0003199064950000621
Figure BDA0003199064950000621

步骤1、中间体Z-47的合成Step 1. Synthesis of Intermediate Z-47

向47-a(200mg,431.35μmol)的DCM(10mL)溶液中加入DMP(267.98mg,632.03μmol),混合液室温搅拌反应1小时。反应完成后,过滤反应液,滤液浓缩,粗品用硅胶柱分离纯化(PE/EA=1/2),得到中间体Z-47(198mg,418.92μmol,99.42%收率)。MS(ESI)m/z=473[M+H]+To a solution of 47-a (200 mg, 431.35 μmol) in DCM (10 mL) was added DMP (267.98 mg, 632.03 μmol), and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated, and the crude product was separated and purified by silica gel column (PE/EA=1/2) to obtain intermediate Z-47 (198 mg, 418.92 μmol, 99.42% yield). MS (ESI) m/z = 473 [M+H] + .

中间体Z-48的合成Synthesis of Intermediate Z-48

Figure BDA0003199064950000622
Figure BDA0003199064950000622

步骤1、中间体48-c的合成Step 1. Synthesis of Intermediate 48-c

向48-a(200mg,724.06μmol)的NMP(10mL)溶液中加入48-b(100.07mg,838.87μmol),DIPEA(280.73mg,2.17mmol,378.35μL),混合液氮气保护下升温至90℃反应12小时。反应完成后,加水,EA萃取,有机相浓缩,粗品用硅胶柱分离纯化(PE/EA=1/4),得到中间体48-c(200mg,538.52μmol,74.38%收率)。MS(ESI)m/z=372[M+H]+To the NMP (10 mL) solution of 48-a (200 mg, 724.06 μmol) was added 48-b (100.07 mg, 838.87 μmol), DIPEA (280.73 mg, 2.17 mmol, 378.35 μL), and the mixture was heated to 90 ° C under nitrogen protection The reaction was carried out for 12 hours. After the reaction was completed, water was added, extracted with EA, the organic phase was concentrated, and the crude product was separated and purified by silica gel column (PE/EA=1/4) to obtain intermediate 48-c (200 mg, 538.52 μmol, 74.38% yield). MS (ESI) m/z = 372 [M+H] + .

步骤2、中间体Z-48的合成Step 2. Synthesis of Intermediate Z-48

向48-c(200mg,538.52μmol)的DCM(10mL)溶液中加入DMP(342.50mg,807.78μmol),混合液室温搅拌反应1小时。反应完成后,过滤反应液,滤液浓缩,粗品用硅胶柱分离纯化(PE/EA=1/4),得到中间体Z-48(134mg,362.78μmol,67.37%收率)。MS(ESI)m/z=370[M+H]+To a solution of 48-c (200 mg, 538.52 μmol) in DCM (10 mL) was added DMP (342.50 mg, 807.78 μmol), and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated, and the crude product was separated and purified by silica gel column (PE/EA=1/4) to obtain intermediate Z-48 (134 mg, 362.78 μmol, 67.37% yield). MS (ESI) m/z = 370 [M+H] + .

中间体Z-49的合成Synthesis of Intermediate Z-49

Figure BDA0003199064950000631
Figure BDA0003199064950000631

步骤1、中间体49-a的合成Step 1. Synthesis of Intermediate 49-a

向2-b(3.0g,9.28mmol)溶于DMF(50mL)溶液中,氮气保护下降温至0℃,加入NaH(445.63mg,11.14mmol),保温反应30分钟,加入SEMCl(1.86g,11.14mmol),反应混合液升温至25℃并搅拌12h,反应完成后,加入饱和氯化铵水溶液淬灭,加水稀释,用乙酸乙酯萃取,合并的有机相依次用水、饱和食盐水洗涤,无水硫酸钠干燥,旋干,粗品用硅胶柱分离纯化(PE/EA=1/1),得到中间体49-a(2.97g,6.55mmol,70.56%收率)。MS(ESI)m/z=453[M+1]+2-b (3.0 g, 9.28 mmol) was dissolved in DMF (50 mL) solution, the temperature was lowered to 0 °C under nitrogen protection, NaH (445.63 mg, 11.14 mmol) was added, the reaction was incubated for 30 minutes, SEMCl (1.86 g, 11.14 mmol) was added. mmol), the reaction mixture was heated to 25 °C and stirred for 12 h. After the reaction was completed, saturated aqueous ammonium chloride solution was added to quench, diluted with water, extracted with ethyl acetate, the combined organic phases were washed with water and saturated brine successively, and anhydrous Dry over sodium sulfate, spin dry, and separate and purify the crude product with silica gel column (PE/EA=1/1) to obtain intermediate 49-a (2.97 g, 6.55 mmol, 70.56% yield). MS(ESI) m/z=453[M+1] + .

步骤2、中间体49-c的合成Step 2. Synthesis of Intermediate 49-c

将49-a(0.2g,441.11μmol),49-b(127.97mg,529.33μmol),Pd(OAc)2(3.96mg,17.64μmol),BINAP(21.97mg,35.29μmol),Cs2CO3(286.72mg,882.22μmol)溶于甲苯(10mL)和t-BuOH(1mL)的混合溶剂中,氮气置换后,加热至100℃反应12小时。反应完成后,加水,EA萃取,有机相依次用水、饱和食盐水洗涤,无水硫酸钠干燥,旋干,粗品用硅胶柱分离纯化(100%EA),得到中间体49-c(40mg,69.23μmol,15.69%收率)。MS(ESI)m/z=578[M+1]+49-a (0.2 g, 441.11 μmol), 49-b (127.97 mg, 529.33 μmol), Pd(OAc) 2 (3.96 mg, 17.64 μmol), BINAP (21.97 mg, 35.29 μmol), Cs 2 CO 3 ( 286.72 mg, 882.22 μmol) was dissolved in a mixed solvent of toluene (10 mL) and t-BuOH (1 mL), replaced with nitrogen, and heated to 100° C. to react for 12 hours. After the completion of the reaction, water was added, extracted with EA, the organic phase was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, spin-dried, and the crude product was separated and purified with a silica gel column (100% EA) to obtain intermediate 49-c (40 mg, 69.23 μmol, 15.69% yield). MS(ESI) m/z=578[M+1] + .

步骤3、中间体49-d的合成Step 3. Synthesis of Intermediate 49-d

向49-c(45mg,77.88μmol)的MeOH(5mL)溶液中加入Pd/C(5mg,10%纯度),反应液氢气置换几次,然后在氢气的保护下室温搅拌4h,反应完成后,过滤,滤液浓缩干燥得中间体49-d的粗品(36mg,73.82μmol,94.87%收率),未经纯化直接用于下一步反应。MS(ESI)m/z=488[M+H]+Pd/C (5 mg, 10% purity) was added to a solution of 49-c (45 mg, 77.88 μmol) in MeOH (5 mL), the reaction solution was replaced with hydrogen several times, and then stirred at room temperature for 4 h under the protection of hydrogen. After the reaction was completed, After filtration, the filtrate was concentrated and dried to obtain the crude product of intermediate 49-d (36 mg, 73.82 μmol, 94.87% yield), which was directly used in the next reaction without purification. MS (ESI) m/z=488 [M+H] + .

步骤4、中间体Z-49的合成Step 4. Synthesis of Intermediate Z-49

向49-d(36mg,73.82μmol)的DCM(3mL)溶液中加入DMP(46.95mg,110.73μmol),混合液室温搅拌反应1小时。反应完成后,过滤反应液,滤液浓缩,粗品用硅胶柱分离纯化(100%EA),得到中间体Z-49(31mg,63.83μmol,86.47%收率)。MS(ESI)m/z=486[M+H]+To a solution of 49-d (36 mg, 73.82 μmol) in DCM (3 mL) was added DMP (46.95 mg, 110.73 μmol), and the mixture was stirred for 1 hour at room temperature. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated, and the crude product was separated and purified by silica gel column (100% EA) to obtain intermediate Z-49 (31 mg, 63.83 μmol, 86.47% yield). MS (ESI) m/z = 486 [M+H] + .

中间体Z-50的合成Synthesis of Intermediate Z-50

Figure BDA0003199064950000641
Figure BDA0003199064950000641

步骤1、50-a的合成Step 1, Synthesis of 50-a

零度下,向27-g(3.0g,25.64mmol)的THF(100mL)/H2O(50mL)溶液中,依次加入碳酸钾(10.62g,76.92mmol)和Cbz-OSu(12.82g,51.28mmol),室温搅拌1小时,反应完成后,加入饱和碳酸氢钠水溶液,加入EA萃取分液,分离的有机相依次用水洗,饱和食盐水洗涤,无水硫酸钠干燥后浓缩,残余物用硅胶柱分离纯化(50%EA in PE),得到50-a(5.1g,20.29mmol,79.13%收率)。MS(ESI)m/z=252[M+1]+ To a solution of 27-g (3.0 g, 25.64 mmol) in THF (100 mL)/H 2 O (50 mL) at zero degrees, potassium carbonate (10.62 g, 76.92 mmol) and Cbz-OSu (12.82 g, 51.28 mmol) were sequentially added ), and stirred at room temperature for 1 hour. After the reaction was completed, saturated aqueous sodium bicarbonate solution was added, and EA was added to extract and separate the layers. The separated organic phase was washed with water and saturated brine successively, dried over anhydrous sodium sulfate and concentrated. The residue was washed with silica gel column. Isolation and purification (50% EA in PE) gave 50-a (5.1 g, 20.29 mmol, 79.13% yield). MS(ESI)m/z=252[M+1] +

步骤2、50-b的合成Step 2. Synthesis of 50-b

零度下,向50-a(5.1g,20.29mmol)的DCM(100mL)溶液中,依次加入TEA(6.16g,60.88mmol,8.49mL)和MsCl(3.49g,30.44mmol),零度下搅拌1小时,反应完成后,加入饱和碳酸氢钠水溶液,分液,分离的有机相依次用水洗,饱和食盐水洗涤,无水硫酸钠干燥后,经浓缩,得到50-b(6.66g,20.22mmol,99.63%收率),粗品未经纯化直接用以下一步反应。MS(ESI)m/z=330[M+1]+ At zero temperature, to a solution of 50-a (5.1 g, 20.29 mmol) in DCM (100 mL), TEA (6.16 g, 60.88 mmol, 8.49 mL) and MsCl (3.49 g, 30.44 mmol) were sequentially added, and stirred at zero temperature for 1 hour After the reaction was completed, saturated aqueous sodium bicarbonate solution was added to separate the layers, and the separated organic phase was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and concentrated to obtain 50-b (6.66 g, 20.22 mmol, 99.63 % yield), the crude product was directly used in the next reaction without purification. MS(ESI)m/z=330[M+1] +

步骤3、50-d的合成Step 3, Synthesis of 50-d

将50-b(6.68g,20.28mmol),50-c(5.52g,22.31mmol),NaI(303.96mg,2.03mmol)和K2CO3(8.40g,60.84mmol)溶于DMF(100mL)中,反应升至80℃反应搅拌过夜,反应完成后,冷却至室温,加入EA,混合液用水洗2次,分离的有机相浓缩,残余物用硅胶柱分离纯化(50%EA in PE),得到50-d(3.3g,6.87mmol,33.86%收率)。MS(ESI)m/z=481[M+1]+ 50-b (6.68 g, 20.28 mmol), 50-c (5.52 g, 22.31 mmol), NaI ( 303.96 mg, 2.03 mmol) and K2CO3 (8.40 g , 60.84 mmol) were dissolved in DMF (100 mL) , the reaction was raised to 80°C and the reaction was stirred overnight. After the reaction was completed, it was cooled to room temperature, EA was added, the mixture was washed twice with water, the separated organic phase was concentrated, and the residue was separated and purified with a silica gel column (50% EA in PE) to obtain 50-d (3.3 g, 6.87 mmol, 33.86% yield). MS(ESI)m/z=481[M+1] +

步骤4、中间体50-e的合成Step 4. Synthesis of Intermediate 50-e

向50-d(3.3g,6.87mmol)的MeOH(60mL)溶液中加入Pd/C(1.0g,10%纯度),反应液氢气置换几次,然后在氢气的保护下室温搅拌4h,反应完成后,过滤,滤液浓缩干燥得中间体50-e的粗品(2.16g,6.24mmol,90.80%收率),未经纯化直接用于下一步反应。MS(ESI)m/z=347[M+H]+Pd/C (1.0 g, 10% purity) was added to the solution of 50-d (3.3 g, 6.87 mmol) in MeOH (60 mL), the reaction solution was replaced with hydrogen several times, and then stirred at room temperature for 4 h under the protection of hydrogen, the reaction was completed After that, it was filtered, and the filtrate was concentrated and dried to obtain the crude product of intermediate 50-e (2.16 g, 6.24 mmol, 90.80% yield), which was directly used in the next reaction without purification. MS (ESI) m/z = 347 [M+H] + .

步骤5、50-g的合成Step 5, Synthesis of 50-g

冰浴下,向50-e(2.16g,6.24mmol)的DCM(50mL)溶液中,依次加入DIPEA(2.42g,18.71mmol)和50-f(1.20g,6.24mmol),室温搅拌过夜,反应完成后,浓缩反应液,残余物用正相硅胶柱分离纯化(PE/EA=1/1)得到50-g(3.0g,5.96mmol,95.66%收率)。MS(ESI)m/z=503[M+1]+ In an ice bath, to a solution of 50-e (2.16 g, 6.24 mmol) in DCM (50 mL), DIPEA (2.42 g, 18.71 mmol) and 50-f (1.20 g, 6.24 mmol) were sequentially added, and the reaction was stirred overnight at room temperature. After completion, the reaction solution was concentrated, and the residue was separated and purified by normal phase silica gel column (PE/EA=1/1) to obtain 50-g (3.0 g, 5.96 mmol, 95.66% yield). MS(ESI)m/z=503[M+1] +

步骤6、50-h的合成Step 6, Synthesis of 50-h

向50-g(3.82g,7.60mmol)的EtOH(60mL)/H2O(10mL)中,依次加入NH4Cl(4.03g,75.95mmol)和Fe(2.55g,45.57mmol),80℃搅拌12小时,反应完成后,过滤,滤液用EA淋洗,浓缩后得到50-h(3.15g,6.66mmol,87.69%收率),粗品未经纯化,直接用于下一步反应。MS(ESI)m/z=473[M+1]+ To 50-g (3.82 g, 7.60 mmol) of EtOH (60 mL)/H 2 O (10 mL), NH 4 Cl (4.03 g, 75.95 mmol) and Fe (2.55 g, 45.57 mmol) were sequentially added, and stirred at 80 °C After 12 hours, the reaction was completed, filtered, the filtrate was rinsed with EA, and concentrated to obtain 50-h (3.15 g, 6.66 mmol, 87.69% yield). The crude product was used for the next reaction without purification. MS(ESI)m/z=473[M+1] +

步骤7、50-i的合成Step 7, Synthesis of 50-i

向50-h(100mg,211.43μmol)的EtOH(3mL)混合溶液中,加入CNBr(111.06mg,1.06mmol),60℃搅拌过夜。反应完成后,加入饱和碳酸氢钠水溶液,搅拌10分钟,分液,有机相用依次用户饱和碳酸氢钠水溶液、水、盐水洗涤,无水硫酸钠干燥,浓缩有机相,所得残余物用硅胶柱分离纯化(DCM/MeOH=10/1)得到50-i(90mg,180.73μmol,85.48%收率)。MS(ESI)m/z=498[M+1]+ To a mixed solution of 50-h (100 mg, 211.43 μmol) in EtOH (3 mL), CNBr (111.06 mg, 1.06 mmol) was added, and the mixture was stirred at 60° C. overnight. After the reaction was completed, a saturated aqueous sodium bicarbonate solution was added, stirred for 10 minutes, and the layers were separated. The organic phase was washed with a saturated aqueous sodium bicarbonate solution, water, and brine in this order, dried over anhydrous sodium sulfate, and the organic phase was concentrated. The obtained residue was washed with a silica gel column. Isolation and purification (DCM/MeOH=10/1) gave 50-i (90 mg, 180.73 μmol, 85.48% yield). MS(ESI)m/z=498[M+1] +

步骤8、50-j的合成Step 8, Synthesis of 50-j

向50-i(2.0g,4.02mmol)的THF(50mL)/H2O(50mL)中,加入NaOH(642.60mg,16.07mmol),室温搅拌1小时,反应完成后,浓缩反应液,加水稀释,用1M HCl调pH=4-5,有固体析出,过滤,滤饼用水洗涤,干燥后得50-j(1.2g,2.48mmol,61.74%收率)。MS(ESI)m/z=484[M+1]+To 50-i (2.0 g, 4.02 mmol) in THF (50 mL)/H 2 O (50 mL), NaOH (642.60 mg, 16.07 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated and diluted with water. , adjusted to pH=4-5 with 1M HCl, a solid was precipitated, filtered, and the filter cake was washed with water, and dried to obtain 50-j (1.2 g, 2.48 mmol, 61.74% yield). MS(ESI) m/z=484[M+1] + .

步骤9、50-k的合成Step 9, Synthesis of 50-k

向50-j(1.23g,2.54mmol)的DCM(5mL)中,依次加入TEA(1.03g,10.17mmol,1.42mL)和TBTU(979.02mg,3.05mmol),室温搅拌15分钟,反应完成后,加水稀释,分液,浓缩有机相,所得残余物用硅胶柱分离纯化(DCM/MeOH=10/1)得到中间50-k(1.0g,2.15mmol,84.44%收率)。MS(ESI)m/z=466[M+1]+To 50-j (1.23 g, 2.54 mmol) in DCM (5 mL), TEA (1.03 g, 10.17 mmol, 1.42 mL) and TBTU (979.02 mg, 3.05 mmol) were sequentially added, and stirred at room temperature for 15 minutes. After the reaction was completed, Add water to dilute, separate the layers, and concentrate the organic phase. The obtained residue is separated and purified by silica gel column (DCM/MeOH=10/1) to obtain the intermediate 50-k (1.0 g, 2.15 mmol, 84.44% yield). MS(ESI) m/z=466[M+1] + .

步骤10、中间体50-l的合成Step 10, the synthesis of intermediate 50-1

向50-k(1.0g,2.15mmol)的DMF(30mL)溶液中依次加入DIPEA(832.12mg,6.44mmol,1.12mL)和SEMCl(358.42mg,2.15mmol),反应混合液升温至60℃并搅拌12h,反应完成后,浓缩反应液,残余物加水稀释,用乙酸乙酯萃取,合并的有机相依次用水、饱和食盐水洗涤,无水硫酸钠干燥,旋干后用正相硅胶柱分离纯化(100%乙酸乙酯),得50-l(630mg,1.06mmol,49.24%收率)。MS(ESI)m/z=596[M+1]+To a solution of 50-k (1.0 g, 2.15 mmol) in DMF (30 mL), DIPEA (832.12 mg, 6.44 mmol, 1.12 mL) and SEMCl (358.42 mg, 2.15 mmol) were sequentially added, and the reaction mixture was warmed to 60 °C and stirred 12h, after the reaction was completed, the reaction solution was concentrated, the residue was diluted with water, extracted with ethyl acetate, the combined organic phases were washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and then spin-dried and separated and purified with a normal-phase silica gel column ( 100% ethyl acetate) to give 50-l (630 mg, 1.06 mmol, 49.24% yield). MS(ESI) m/z=596[M+1] + .

步骤11、中间体50-m的合成Step 11. Synthesis of Intermediate 50-m

向50-l(300mg,503.19μmol)的甲苯(4mL)/叔丁醇(1mL)溶液中加入1-叔丁氧羰基哌嗪(140.58mg,754.79μmol),BINAP(25.07mg,40.26μmol),Pd(OAc)2(4.51mg,20.13μmol)和Cs2CO3(327.07mg,1.01mmol)。氮气保护,升温至120℃并在此温度下搅拌反应15小时。反应完成后,混合液用乙酸乙酯稀释,加水洗涤,浓缩有机相得粗品,粗品用反相硅胶柱分离纯化得50-m(370mg,495.99μmol,98.57%收率),MS(ESI)m/z=746[M+1]+To a solution of 50-l (300 mg, 503.19 μmol) in toluene (4 mL)/tert-butanol (1 mL) was added 1-tert-butoxycarbonylpiperazine (140.58 mg, 754.79 μmol), BINAP (25.07 mg, 40.26 μmol), Pd(OAc) 2 (4.51 mg, 20.13 μmol) and Cs 2 CO 3 (327.07 mg, 1.01 mmol). Under nitrogen, the temperature was raised to 120°C and the reaction was stirred at this temperature for 15 hours. After the reaction was completed, the mixture was diluted with ethyl acetate, washed with water, and the organic phase was concentrated to obtain a crude product. The crude product was separated and purified by a reverse-phase silica gel column to obtain 50-m (370 mg, 495.99 μmol, 98.57% yield). MS (ESI) m /z=746[M+1] + .

步骤12、中间体Z-50的合成Step 12. Synthesis of Intermediate Z-50

向50-m(390mg,522.80μmol)的DCM(10mL)溶液中加入TFA(10mL),混合液室温搅拌1小时。然后浓缩反应液,用油泵旋除残余的TFA,得到Z-50(269mg,521.71μmol,99.79%收率),未经纯化直接用于下一步反应。MS(ESI)m/z=516[M+1]+To a solution of 50-m (390 mg, 522.80 μmol) in DCM (10 mL) was added TFA (10 mL), and the mixture was stirred at room temperature for 1 hour. Then, the reaction solution was concentrated, and the residual TFA was removed with an oil pump to obtain Z-50 (269 mg, 521.71 μmol, 99.79% yield), which was directly used in the next reaction without purification. MS(ESI) m/z=516[M+1] + .

中间体Z-51的合成Synthesis of Intermediate Z-51

Figure BDA0003199064950000661
Figure BDA0003199064950000661

步骤1、中间体51-a的合成Step 1. Synthesis of Intermediate 51-a

零度下,向1-b(16g,49.51mmol)的DMF(470mL)溶液中加入NaH(1.43g,59.42mmol),混合液零度下搅拌反应1小时,然后加入SEMCl(9.08g,54.47mmol)。滴毕,混合液室温反应12h。反应完成后,加水稀释,加EtOAc萃取,合并的有机相用水,食盐水洗涤,无水硫酸钠干燥,浓缩后得51-a粗品(22g,48.52mmol,98.00%收率)。MS(ESI)m/z=425[M-27]+At zero temperature, NaH (1.43 g, 59.42 mmol) was added to a solution of 1-b (16 g, 49.51 mmol) in DMF (470 mL), and the mixture was stirred for 1 hour at zero temperature, and then SEMCl (9.08 g, 54.47 mmol) was added. After dripping, the mixture was reacted at room temperature for 12h. After the reaction was completed, it was diluted with water, extracted with EtOAc, the combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to obtain crude 51-a (22 g, 48.52 mmol, 98.00% yield). MS(ESI) m/z=425[M-27] + .

步骤2到步骤4、中间体Z-51的合成Step 2 to Step 4, Synthesis of Intermediate Z-51

参照中间体Z-1的合成路线步骤3、4和5的操作,用中间体51-a替代中间体1-b,其余操作相同,可得中间体Z-51。MS(ESI)m/z=445[M+1]+Referring to the operations of steps 3, 4 and 5 of the synthetic route of intermediate Z-1, intermediate 1-b is replaced by intermediate 51-a, and the remaining operations are the same to obtain intermediate Z-51. MS(ESI) m/z=445[M+1] + .

中间体Z-52的合成Synthesis of Intermediate Z-52

Figure BDA0003199064950000671
Figure BDA0003199064950000671

参照中间体Z-42的合成方法,在步骤1中用4-溴戊基氧基-叔丁基二甲基硅烷替代4-溴丁基氧基-叔丁基二甲基硅烷,其余操作相同,可得中间体Z-52。MS(ESI)m/z=345[M+1]+Referring to the synthesis method of intermediate Z-42, in step 1, 4-bromobutyloxy-tert-butyldimethylsilane was replaced with 4-bromobutyloxy-tert-butyldimethylsilane, and the rest of the operations were the same , the intermediate Z-52 can be obtained. MS(ESI) m/z=345[M+1] + .

中间体Z-53的合成Synthesis of Intermediate Z-53

Figure BDA0003199064950000672
Figure BDA0003199064950000672

参照中间体Z-50合成路线中步骤11和12的方法,在步骤11中用1-Boc-4-(哌啶-4-基)-哌嗪代替1-叔丁氧羰基哌嗪,其余操作相同,可得中间体Z-53,MS(ESI)m/z=599[M+1]+Referring to the methods of steps 11 and 12 in the synthetic route of intermediate Z-50, in step 11, 1-Boc-4-(piperidin-4-yl)-piperazine was used instead of 1-tert-butoxycarbonylpiperazine, and the remaining operations The same, intermediate Z-53 can be obtained, MS(ESI) m/z=599[M+1] + .

中间体Z-54的合成Synthesis of Intermediate Z-54

Figure BDA0003199064950000673
Figure BDA0003199064950000673

参照中间体Z-50合成路线中步骤11和12的方法,在步骤11中用中间体28-a替代中间体50-l,同时用4-哌嗪-1-基哌啶-1-羧酸叔丁酯替代1-叔丁氧羰基哌嗪,其余操作相同,可得中间体Z-54,MS(ESI)m/z=598[M+1]+Referring to the method of steps 11 and 12 in the synthetic route of intermediate Z-50, in step 11, intermediate 28-a is used instead of intermediate 50-1, and 4-piperazin-1-ylpiperidine-1-carboxylic acid is used at the same time The tert-butyl ester was replaced with 1-tert-butoxycarbonylpiperazine, and other operations were the same to obtain the intermediate Z-54, MS(ESI) m/z=598[M+1] + .

中间体Z-55的合成Synthesis of Intermediate Z-55

Figure BDA0003199064950000681
Figure BDA0003199064950000681

参照中间体Z-50路线中步骤5到步骤12的操作,步骤5中用2,4-二氯-5-硝基吡啶替换2,6-二氯-3-硝基吡啶,在步骤11中用4-哌嗪-1-基哌啶-1-羧酸叔丁酯替换1-叔丁氧羰基哌嗪,其余操作相同,可得中间体Z-55。MS(ESI)m/z=598[M+1]+Referring to the procedure of steps 5 to 12 in the route of intermediate Z-50, in step 5, replace 2,6-dichloro-3-nitropyridine with 2,4-dichloro-5-nitropyridine, in step 11 Substitute 4-piperazin-1-ylpiperidine-1-carboxylic acid tert-butyl ester for 1-tert-butoxycarbonylpiperazine, and the other operations are the same to obtain intermediate Z-55. MS(ESI) m/z=598[M+1] + .

中间体Z-56的合成Synthesis of Intermediate Z-56

Figure BDA0003199064950000682
Figure BDA0003199064950000682

参照中间体Z-50的合成路线中步骤11和步骤12的方法,在步骤11中用4-哌嗪-1-基哌啶-1-羧酸叔丁酯替换1-叔丁氧羰基哌嗪,其余操作相同,可得中间体Z-56。MS(ESI)m/z=599[M+1]+Referring to the method of step 11 and step 12 in the synthetic route of intermediate Z-50, in step 11, replace 1-tert-butoxycarbonylpiperazine with tert-butyl 4-piperazin-1-ylpiperidine-1-carboxylate , and other operations are the same to obtain the intermediate Z-56. MS(ESI) m/z=599[M+1] + .

中间体Z-57的合成Synthesis of Intermediate Z-57

Figure BDA0003199064950000691
Figure BDA0003199064950000691

参照中间体Z-50的合成路线中步骤11和步骤12的操作,用中间体28-a替换中间体50-l,同时用4-[(哌嗪-1-基)甲基]哌啶-1-羧酸叔丁酯替换1-叔丁氧羰基哌嗪,其余操作相同,可得中间体Z-57。MS(ESI)m/z=612[M+1]+。Referring to the operation of step 11 and step 12 in the synthetic route of intermediate Z-50, intermediate 50-1 was replaced with intermediate 28-a, and 4-[(piperazin-1-yl)methyl]piperidine- Substitute 1-tert-butoxycarbonylpiperazine with 1-tert-butyl carboxylate, and the other operations are the same to obtain intermediate Z-57. MS(ESI) m/z=612[M+1]+.

中间体Z-58的合成Synthesis of Intermediate Z-58

Figure BDA0003199064950000692
Figure BDA0003199064950000692

参照中间体Z-55的合成路线中步骤7和步骤8的操作,用1-叔丁氧羰基哌嗪替换4-哌嗪-1-基哌啶-1-羧酸叔丁酯,其余操作相同,可得中间体Z-58。MS(ESI)m/z=516[M+1]+Referring to the operations of step 7 and step 8 in the synthetic route of intermediate Z-55, replace 4-piperazin-1-ylpiperidine-1-carboxylate tert-butyl ester with 1-tert-butoxycarbonylpiperazine, and the remaining operations are the same , the intermediate Z-58 can be obtained. MS(ESI) m/z=516[M+1] + .

中间体Z-59的合成Synthesis of Intermediate Z-59

Figure BDA0003199064950000693
Figure BDA0003199064950000693

步骤1、中间体59-a的合成Step 1. Synthesis of Intermediate 59-a

参照中间体Z-25的合成方法,用4-c替代中间体1-c,其余操作条件相同,可得中间体59-a。Referring to the synthesis method of intermediate Z-25, using 4-c instead of intermediate 1-c, and other operating conditions are the same, intermediate 59-a can be obtained.

步骤2、中间体Z-59的合成Step 2. Synthesis of Intermediate Z-59

参照中间体Z-26的合成方法,用59-a替代Z-25做起始原料,相同的操作和条件,可得中间体Z-59。Referring to the synthesis method of the intermediate Z-26, using 59-a instead of Z-25 as the starting material, the same operation and conditions, the intermediate Z-59 can be obtained.

中间体Z-60的合成Synthesis of Intermediate Z-60

Figure BDA0003199064950000701
Figure BDA0003199064950000701

参照中间体Z-43合成路线步骤1到步骤4的方法,在步骤1中用7辛炔醇替换43-a为起始原料,其余操作步骤相同,可得中间体Z-60,MS(ESI)m/z=559[M+1]+Referring to the method from step 1 to step 4 of the synthetic route of intermediate Z-43, in step 1, 43-a was replaced with 7 octynyl alcohol as the starting material, and the rest of the operation steps were the same to obtain intermediate Z-60, MS (ESI )m/z=559[M+1] + .

中间体Z-61的合成Synthesis of Intermediate Z-61

Figure BDA0003199064950000702
Figure BDA0003199064950000702

参照实施例Z-1合成路线步骤2到步骤4的方法,在起始步骤中用10-十一炔醇替换4-戊炔-1-醇,其余操作步骤相同,可得中间体Z-61。MS(ESI)m/z=543[M+1]+Referring to the method from step 2 to step 4 of the synthetic route of Example Z-1, in the initial step, 10-undenyl alcohol was used to replace 4-pentyn-1-ol, and the rest of the operation steps were the same to obtain intermediate Z-61 . MS(ESI) m/z=543[M+1] + .

中间体Z-62的合成Synthesis of Intermediate Z-62

Figure BDA0003199064950000703
Figure BDA0003199064950000703

参照中间体Z-50合成路线中步骤11和步骤12,在起始步骤中用3-(哌嗪-1-基甲基)吡咯烷-1-羧酸叔丁酯替换1-叔丁氧羰基哌嗪,其余操作步骤相同,可得中间体Z-62。MS(ESI)m/z=599[M+1]+Referring to steps 11 and 12 in the synthetic route of intermediate Z-50, in the initial step, 3-(piperazin-1-ylmethyl)pyrrolidine-1-carboxylate tert-butyl ester was used to replace 1-tert-butoxycarbonyl group Piperazine, the remaining operation steps are the same, and intermediate Z-62 can be obtained. MS(ESI) m/z=599[M+1] + .

中间体Z-63的合成Synthesis of Intermediate Z-63

Figure BDA0003199064950000711
Figure BDA0003199064950000711

步骤1step 1

Z-63-1a(2g,9.2mmol)和吡唑(755mg,11mmol)混溶于乙腈(20ml),冰水浴降温(0℃-5℃)滴加入乙酰氯(872mg,11mmol),然后室温反应17h,次日直接向反应液中加入Z-63-1b(1.5g,9.2mmol),吡唑(1.4g,19.3mmol)和亚磷酸三苯酯(3.4g,11mmol),然后加热85℃反应17h,反应完成后,冷却至室温,向反应液中加入水,有固体析出,过滤出固体并用水洗1次,乙酸乙酯洗1次,然后固体过滤,旋干,直接用于下一步。Z-63-1a (2g, 9.2mmol) and pyrazole (755mg, 11mmol) were mixed in acetonitrile (20ml), cooled in an ice-water bath (0℃-5℃), and acetyl chloride (872mg, 11mmol) was added dropwise, and then reacted at room temperature 17h, Z-63-1b (1.5g, 9.2mmol), pyrazole (1.4g, 19.3mmol) and triphenyl phosphite (3.4g, 11mmol) were directly added to the reaction solution the next day, and then heated at 85°C to react 17h, after the reaction was completed, cooled to room temperature, water was added to the reaction solution, a solid was precipitated, the solid was filtered and washed once with water and once with ethyl acetate, then the solid was filtered, spin-dried, and used directly in the next step.

步骤2Step 2

Z-63-1c(1.58g,4.5mmol)溶于DMF,冰水浴降温(0℃-5℃),加入氢化钠(130mg,5.4mmol),保持该温度反应1h,随后缓慢滴加入SEMCl(906mg,5.4mmol),升至室温反应3h,反应完后加入水,用乙酸乙酯萃取3次,有机层饱和食盐水洗涤一次,无水硫酸钠干燥,浓缩,直接用于下一步。Z-63-1c (1.58g, 4.5mmol) was dissolved in DMF, cooled in an ice-water bath (0°C-5°C), sodium hydride (130mg, 5.4mmol) was added, the reaction was maintained at this temperature for 1h, and then SEMCl (906mg) was slowly added dropwise , 5.4 mmol), warmed to room temperature and reacted for 3 h. After the reaction, water was added, extracted three times with ethyl acetate, the organic layer was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and used directly in the next step.

步骤3Step 3

Z-63-1d(500mg,1.04mmol)和4-戊炔-1-醇(105mg,1.25mmol)混溶于DMF,然后加入Pd(pph3)2Cl2(55mg,0.078mmol),CuI(30mg,0.156mmol)和TEA(315mg,3.12mmol),加热80℃反应17小时,反应完成后,加入水,加入EA萃取分液,分离的有机相依次用水洗,饱和食盐水洗涤,无水硫酸钠干燥后浓缩,粗品用硅胶柱分离纯化(50%EA in PE),得到Z-63-1e(240mg,0.496mmol,47.8%收率)。MS(ESI)m/z=484[M+1]+ Z-63-1d (500 mg, 1.04 mmol) and 4-pentyn-1-ol (105 mg, 1.25 mmol) were dissolved in DMF, then Pd(pph 3 ) 2 Cl 2 (55 mg, 0.078 mmol), CuI ( 30mg, 0.156mmol) and TEA (315mg, 3.12mmol), heated at 80°C for 17 hours, after the reaction was completed, water was added, EA was added to extract the liquid, the separated organic phase was washed with water in turn, washed with saturated brine, and anhydrous sulfuric acid. After drying over sodium, it was concentrated, and the crude product was separated and purified by silica gel column (50% EA in PE) to give Z-63-1e (240 mg, 0.496 mmol, 47.8% yield). MS(ESI)m/z=484[M+1] +

步骤4Step 4

Z-63-1e(240mg,0.496mmol)溶于甲醇,加入10%钯碳(35mg),在氢气保护下室温反应17h,反应完后过滤,滤液旋干直接用于下一步,得到Z-63-1f(220mg,0.451mmol,90.1%收率)MS(ESI)m/z=488[M+1]+ Z-63-1e (240 mg, 0.496 mmol) was dissolved in methanol, 10% palladium on carbon (35 mg) was added, and the reaction was carried out at room temperature for 17 h under the protection of hydrogen. -1f (220 mg, 0.451 mmol, 90.1% yield) MS (ESI) m/z=488[M+1] +

步骤5Step 5

Z-63-1f(220mg,0.451mmol)溶于二氯甲烷,冰浴降温,加入DMP(229mg,0.54mmol),然后升至室温反应4h,反应完成后,滤出固体,滤液旋干,粗品过柱纯化(PE:EA=2:1),得到化合物Z-63(120mg,0.246mmol,52%收率),MS(ESI)m/z=486[M+1]+ Z-63-1f (220mg, 0.451mmol) was dissolved in dichloromethane, cooled in an ice bath, DMP (229mg, 0.54mmol) was added, then warmed to room temperature and reacted for 4h. After the reaction was completed, the solid was filtered out, the filtrate was spin-dried, and the crude product After column purification (PE:EA=2:1), compound Z-63 (120 mg, 0.246 mmol, 52% yield) was obtained, MS (ESI) m/z=486[M+1] +

中间体Z-64的合成Synthesis of Intermediate Z-64

Figure BDA0003199064950000721
Figure BDA0003199064950000721

向2-(2,6-二氧代-哌啶-3-基)-4-羟基-异吲哚-1,3-二酮(1.57g,5.7mmol)的DMF(50mL)溶液中加入碳酸钾(1.19g,8.58mmol)和溴乙酸叔丁酯(1.1g,5.71mmol)。室温反应2h后,旋蒸除掉DMF,乙酸乙酯溶解后加水洗,有机相旋干。粗品经硅胶柱纯化(石油醚/乙酸乙酯=2/1)得到中间体2-(2,6-二氧代-哌啶-3-基)-4-羟基乙酸叔丁酯-异吲哚-1,3-二酮(2g,5.1mmol)。将其溶解在二氯甲烷(15mL)中,加入三氟乙酸(10mL),室温反应1h,然后旋干溶剂得到目标化合物Z-64(1.6g)。To a solution of 2-(2,6-dioxo-piperidin-3-yl)-4-hydroxy-isoindole-1,3-dione (1.57 g, 5.7 mmol) in DMF (50 mL) was added carbonic acid Potassium (1.19 g, 8.58 mmol) and tert-butyl bromoacetate (1.1 g, 5.71 mmol). After reacting at room temperature for 2 h, DMF was removed by rotary evaporation, ethyl acetate was dissolved, washed with water, and the organic phase was rotary dried. The crude product was purified by silica gel column (petroleum ether/ethyl acetate=2/1) to obtain the intermediate 2-(2,6-dioxo-piperidin-3-yl)-4-hydroxyacetic acid tert-butyl ester-isoindole -1,3-Dione (2 g, 5.1 mmol). It was dissolved in dichloromethane (15 mL), trifluoroacetic acid (10 mL) was added, reacted at room temperature for 1 h, and then the solvent was spin-dried to obtain the target compound Z-64 (1.6 g).

中间体Z-65的合成Synthesis of Intermediate Z-65

按照Z-63的合成方法,将起始原料2-胺基6-溴苯甲酸更换成2-胺基-5-溴苯甲酸,其它试剂及操作方法相同,得到中间体Z-65。According to the synthesis method of Z-63, the starting material 2-amino-6-bromobenzoic acid was replaced with 2-amino-5-bromobenzoic acid, and other reagents and operation methods were the same to obtain intermediate Z-65.

Figure BDA0003199064950000731
Figure BDA0003199064950000731

中间体Z-66的合成Synthesis of Intermediate Z-66

Figure BDA0003199064950000732
Figure BDA0003199064950000732

参照中间体Z-1合成路线中步骤3到步骤5的方法,在起始步骤中用3-丁炔-1-醇替换4-戊炔-1-醇,其余操作步骤相同,可得中间体Z-66。MS(ESI)m/z=315[M+1]+Referring to the method from step 3 to step 5 in the synthetic route of intermediate Z-1, in the initial step, 3-butyn-1-ol was used to replace 4-pentyn-1-ol, and the rest of the operation steps were the same to obtain the intermediate Z-66. MS(ESI) m/z=315[M+1] + .

中间体Z-67的合成Synthesis of Intermediate Z-67

Figure BDA0003199064950000733
Figure BDA0003199064950000733

参照中间体Z-36合成路线步骤1到步骤4的方法,在起始步骤中用2-苄氧基溴乙烷替换3-苄氧基溴丙烷,其余操作步骤相同,可得中间体Z-67。MS(ESI)m/z=353[M+1]+Referring to the method from step 1 to step 4 of the synthetic route of intermediate Z-36, in the initial step, 2-benzyloxybromoethane was used to replace 3-benzyloxybromopropane, and the rest of the operation steps were the same to obtain intermediate Z- 67. MS(ESI) m/z=353[M+1] + .

中间体Z-68的合成Synthesis of Intermediate Z-68

Figure BDA0003199064950000734
Figure BDA0003199064950000734

参照中间体Z-25的合成方法,用3-c代替1-c,其余试剂和操作相同,可得中间体Z-68。MS(ESI)m/z=341[M+1]+Referring to the synthesis method of intermediate Z-25, substituting 3-c for 1-c, and other reagents and operations are the same, intermediate Z-68 can be obtained. MS(ESI) m/z=341[M+1] + .

实施例1、化合物1的合成Example 1. Synthesis of compound 1

Figure BDA0003199064950000741
Figure BDA0003199064950000741

向Z-28(30mg,56.75μmol)的MeOH(2mL)中,加TEA至pH=9-10,然后加入Z-2(18.63mg,56.75μmol),室温搅拌30分钟,然后加醋酸调pH=4-5。搅拌5分钟后,一次性加入NaBH3CN(10.73mg,170.25μmol),反应混合液室温过夜。反应完成后,过滤反应液,滤液经Pre.HPLC分离纯化,得到实施例1(1.42mg,1.59μmol,2.80%收率,94%纯度)。MS(ESI)m/z=837[M+1]+1H NMR(400MHz,DMSO-d6)δ8.43(s,1H),7.96(s,1H),7.69–7.62(m,1H),7.58(d,J=1.2Hz,1H),7.53–7.45(m,4H),7.44(s,1H),7.39–7.31(m,2H),7.23–7.15(m,1H),5.12–5.01(m,1H),4.49–4.25(m,3H),4.25–4.15(m,2H),4.09–3.85(m,3H),3.73(s,4H),3.56(s,2H),2.97–2.82(m,2H),2.82–2.72(m,1H),2.73–2.59(m,4H),2.56(s,3H),2.49–2.29(m,5H),2.30–2.16(m,3H),2.08–1.89(m,4H),1.69–1.55(m,2H),1.44(t,J=7.4Hz,3H),1.26(dd,J=14.6,7.1Hz,2H),0.80(d,J=6.5Hz,3H).To Z-28 (30mg, 56.75μmol) in MeOH (2mL), add TEA to pH=9-10, then add Z-2 (18.63mg, 56.75μmol), stir at room temperature for 30 minutes, then add acetic acid to adjust pH= 4-5. After stirring for 5 minutes, NaBH 3 CN (10.73 mg, 170.25 μmol) was added in one portion and the reaction mixture was overnight at room temperature. After the reaction was completed, the reaction solution was filtered, and the filtrate was separated and purified by Pre.HPLC to obtain Example 1 (1.42 mg, 1.59 μmol, 2.80% yield, 94% purity). MS(ESI) m/z=837[M+1] + , 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.43(s, 1H), 7.96(s, 1H), 7.69-7.62(m, 1H ), 7.58(d, J=1.2Hz, 1H), 7.53-7.45(m, 4H), 7.44(s, 1H), 7.39-7.31(m, 2H), 7.23-7.15(m, 1H), 5.12- 5.01(m,1H),4.49–4.25(m,3H),4.25–4.15(m,2H),4.09–3.85(m,3H),3.73(s,4H),3.56(s,2H),2.97– 2.82 (m, 2H), 2.82–2.72 (m, 1H), 2.73–2.59 (m, 4H), 2.56 (s, 3H), 2.49–2.29 (m, 5H), 2.30–2.16 (m, 3H), 2.08–1.89 (m, 4H), 1.69–1.55 (m, 2H), 1.44 (t, J=7.4Hz, 3H), 1.26 (dd, J=14.6, 7.1Hz, 2H), 0.80 (d, J= 6.5Hz, 3H).

实施例2、化合物2的合成Example 2, the synthesis of compound 2

Figure BDA0003199064950000742
Figure BDA0003199064950000742

Z-28(46.60mg,88.15μmol)和Z-25(30mg,88.15μmol)混溶于DMF(5mL)中,然后依次加入DIPEA(56.96mg,440.75μmol,76.77μL)和HATU(40.22mg,105.78μmol)。反应液在室温下搅拌4小时,反应完成后,加入1mL MeOH,浓缩反应液得到的粗品经Pre.HPLC分离纯化得到实施例2(1.32mg,1.37μmol,1.55%收率)。MS(ESI)m/z=851[M+1]+1H NMR(400MHz,CD3OD)δ8.86(s,1H),8.24(s,1H),8.01(s,1H),7.78–7.68(m,2H),7.62–7.55(m,2H),7.49(d,J=7.6Hz,1H),7.38(d,J=8.2Hz,1H),5.18(dd,J=13.3,5.2Hz,1H),4.57–4.29(m,6H),4.13(s,1H),3.96–3.76(m,6H),2.99–2.71(m,10H),2.50(m,1H),2.33(m,1H),2.24–2.12(m,1H),2.06(m,2H),1.57(m,1H),0.90(d,J=5.4Hz,3H).Z-28 (46.60mg, 88.15μmol) and Z-25 (30mg, 88.15μmol) were mixed in DMF (5mL), then DIPEA (56.96mg, 440.75μmol, 76.77μL) and HATU (40.22mg, 105.78μL) were added sequentially μmol). The reaction solution was stirred at room temperature for 4 hours. After the reaction was completed, 1 mL of MeOH was added, and the crude product obtained by concentrating the reaction solution was separated and purified by Pre.HPLC to obtain Example 2 (1.32 mg, 1.37 μmol, 1.55% yield). MS(ESI) m/z=851[M+1] + , 1 H NMR (400 MHz, CD 3 OD) δ 8.86(s, 1H), 8.24(s, 1H), 8.01(s, 1H), 7.78 –7.68(m,2H),7.62–7.55(m,2H),7.49(d,J=7.6Hz,1H),7.38(d,J=8.2Hz,1H),5.18(dd,J=13.3,5.2 Hz, 1H), 4.57–4.29 (m, 6H), 4.13 (s, 1H), 3.96–3.76 (m, 6H), 2.99–2.71 (m, 10H), 2.50 (m, 1H), 2.33 (m, 1H), 2.24–2.12(m, 1H), 2.06(m, 2H), 1.57(m, 1H), 0.90(d, J=5.4Hz, 3H).

实施例3、化合物3的合成Example 3, the synthesis of compound 3

Figure BDA0003199064950000751
Figure BDA0003199064950000751

参照实施例1的合成方法,用中间体化合物Z-28和Z-16为原料经还原胺化,得到实施例3。MS(ESI)m/z=851[M+1]+1H NMR(400MHz,DMSO-d6)δ8.43(s,1H),7.95(s,1H),7.76–7.69(m,1H),7.67–7.60(m,1H),7.58(s,1H),7.58–7.51(m,1H),7.54–7.45(m,4H),7.23–7.15(m,2H),5.12(dd,J=13.2,5.1Hz,1H),4.52–4.42(m,2H),4.40–4.27(m,3H),4.25–4.15(m,2H),4.05–3.96(m,1H),3.73(s,3H),3.57(s,4H),2.82–2.67(m,1H),2.56(s,4H),2.47–2.28(m,16H),2.27–2.12(m,1H),2.10–1.87(m,5H),1.67–1.52(m,9H),1.53–1.40(m,2H),1.32–1.18(m,7H),0.90–0.81(m,1H),0.80(d,J=6.4Hz,3H).Referring to the synthesis method of Example 1, using intermediate compounds Z-28 and Z-16 as raw materials, through reductive amination, Example 3 was obtained. MS(ESI) m/z=851[M+1] + , 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.43(s, 1H), 7.95(s, 1H), 7.76-7.69(m, 1H ), 7.67–7.60 (m, 1H), 7.58 (s, 1H), 7.58–7.51 (m, 1H), 7.54–7.45 (m, 4H), 7.23–7.15 (m, 2H), 5.12 (dd, J = 13.2, 5.1Hz, 1H), 4.52–4.42 (m, 2H), 4.40–4.27 (m, 3H), 4.25–4.15 (m, 2H), 4.05–3.96 (m, 1H), 3.73 (s, 3H) ), 3.57(s, 4H), 2.82–2.67(m, 1H), 2.56(s, 4H), 2.47–2.28(m, 16H), 2.27–2.12(m, 1H), 2.10–1.87(m, 5H ), 1.67–1.52 (m, 9H), 1.53–1.40 (m, 2H), 1.32–1.18 (m, 7H), 0.90–0.81 (m, 1H), 0.80 (d, J=6.4Hz, 3H).

实施例4、化合物4的合成Example 4, the synthesis of compound 4

Figure BDA0003199064950000761
Figure BDA0003199064950000761

参照实施例1的合成方法,以中间体Z-14和中间体Z-28为原料,经还原胺化得到实施例4。MS(ESI)m/z=837[M+1]+1H NMR(400MHz,DMSO-d6)δ8.43(s,1H),7.95(s,1H),7.63(s,1H),7.57(d,J=1.2Hz,1H),7.55–7.45(m,4H),7.19(dd,J=8.3,1.3Hz,1H),5.08(dd,J=13.2,5.1Hz,1H),4.50–4.40(m,2H),4.40–4.28(m,2H),4.25–4.15(m,1H),4.04–3.87(m,2H),3.73(s,3H),3.61(s,1H),3.57(s,3H),2.97–2.82(m,1H),2.82–2.72(m,2H),2.71–2.57(m,2H),2.56(s,3H),2.52–2.43(m,4H),2.44–2.30(m,10H),2.26–2.15(m,2H),2.10–1.85(m,4H),1.79–1.65(m,3H),1.52–1.41(m,2H),0.81(d,J=6.5Hz,3H).Referring to the synthesis method of Example 1, using intermediate Z-14 and intermediate Z-28 as raw materials, through reductive amination to obtain Example 4. MS(ESI) m/z=837[M+1] + , 1 H NMR (400MHz, DMSO-d 6 )δ8.43(s,1H),7.95(s,1H),7.63(s,1H), 7.57(d,J=1.2Hz,1H),7.55–7.45(m,4H),7.19(dd,J=8.3,1.3Hz,1H),5.08(dd,J=13.2,5.1Hz,1H),4.50 –4.40(m,2H),4.40–4.28(m,2H),4.25–4.15(m,1H),4.04–3.87(m,2H),3.73(s,3H),3.61(s,1H),3.57 (s, 3H), 2.97–2.82 (m, 1H), 2.82–2.72 (m, 2H), 2.71–2.57 (m, 2H), 2.56 (s, 3H), 2.52–2.43 (m, 4H), 2.44 –2.30(m,10H),2.26-2.15(m,2H),2.10-1.85(m,4H),1.79-1.65(m,3H),1.52-1.41(m,2H),0.81(d,J= 6.5Hz, 3H).

实施例5、化合物5的合成Example 5, the synthesis of compound 5

Figure BDA0003199064950000762
Figure BDA0003199064950000762

参照实施例2的合成方法,以中间体Z-26和Z-28为原料用HATU为缩合剂,经缩合反应得到实施例5。MS(ESI)m/z=855[M+1]+,1H NMR(400MHz,DMSO)δ12.71(s,1H),11.00(s,1H),8.43(s,1H),7.92(s,1H),7.64–7.31(m,5H),7.18(d,J=8.4Hz,1H),5.14(dd,J=13.3,5.1Hz,1H),4.46(d,J=17.1Hz,1H),4.33(dd,J=23.3,11.0Hz,2H),4.20(d,J=11.2Hz,1H),4.10–3.87(m,6H),3.73(s,4H),3.57(s,2H),3.43(s,5H),3.00–2.85(m,2H),2.80(s,2H),2.71–2.61(m,3H),2.56(s,3H),2.38–2.25(m,6H),2.21(s,1H),2.09–1.87(m,3H),1.67–1.42(m,5H),0.81(d,J=6.4Hz,2H).Referring to the synthesis method of Example 2, using intermediates Z-26 and Z-28 as raw materials and using HATU as a condensing agent, Example 5 is obtained through condensation reaction. MS(ESI) m/z=855[M+1] + , 1 H NMR(400MHz, DMSO)δ12.71(s,1H),11.00(s,1H),8.43(s,1H),7.92(s ,1H),7.64–7.31(m,5H),7.18(d,J=8.4Hz,1H),5.14(dd,J=13.3,5.1Hz,1H),4.46(d,J=17.1Hz,1H) ,4.33(dd,J=23.3,11.0Hz,2H),4.20(d,J=11.2Hz,1H),4.10–3.87(m,6H),3.73(s,4H),3.57(s,2H), 3.43(s, 5H), 3.00–2.85(m, 2H), 2.80(s, 2H), 2.71–2.61(m, 3H), 2.56(s, 3H), 2.38–2.25(m, 6H), 2.21( s, 1H), 2.09–1.87 (m, 3H), 1.67–1.42 (m, 5H), 0.81 (d, J=6.4Hz, 2H).

实施例6、化合物6的合成Example 6, the synthesis of compound 6

Figure BDA0003199064950000771
Figure BDA0003199064950000771

参照实施例1的合成方法,以Z-1和Z-28为原料,经还原胺化得到实施例6,MS(ESI)m/z=841[M+1]+1H NMR(400MHz,DMSO)δ12.70(s,1H),10.99(s,1H),8.42(s,1H),7.92(s,1H),7.65–7.52(m,2H),7.51–7.35(m,4H),7.16(d,J=8.9Hz,1H),5.13(dd,J=13.2,5.1Hz,1H),4.45(d,J=17.2Hz,1H),4.33(dd,J=25.6,10.8Hz,2H),4.19(d,J=11.0Hz,1H),3.98(d,J=16.6Hz,2H),3.73(s,3H),3.54(s,2H),3.01–2.85(m,1H),2.79(s,1H),2.63(m,3H),2.56(s,3H),2.44–2.27(m,7H),2.28–2.12(m,4H),2.06–1.85(m,3H),1.67–1.53(m,2H),1.44(m,3H),1.37–1.25(m,2H),0.80(d,J=6.5Hz,3H).Referring to the synthesis method of Example 1, using Z-1 and Z-28 as raw materials, through reductive amination to obtain Example 6, MS (ESI) m/z=841[M+1] + , 1 H NMR (400MHz, DMSO)δ12.70(s,1H),10.99(s,1H),8.42(s,1H),7.92(s,1H),7.65–7.52(m,2H),7.51–7.35(m,4H), 7.16(d,J=8.9Hz,1H),5.13(dd,J=13.2,5.1Hz,1H),4.45(d,J=17.2Hz,1H),4.33(dd,J=25.6,10.8Hz,2H) ),4.19(d,J=11.0Hz,1H),3.98(d,J=16.6Hz,2H),3.73(s,3H),3.54(s,2H),3.01–2.85(m,1H),2.79 (s, 1H), 2.63 (m, 3H), 2.56 (s, 3H), 2.44–2.27 (m, 7H), 2.28–2.12 (m, 4H), 2.06–1.85 (m, 3H), 1.67–1.53 (m, 2H), 1.44 (m, 3H), 1.37–1.25 (m, 2H), 0.80 (d, J=6.5Hz, 3H).

实施例7~27、化合物7~27的合成Synthesis of Examples 7-27 and Compounds 7-27

参照实施例1的还原胺化方法,同时以表中相应的SM-醛替代步骤中的Z-2。以SM-胺替代步骤中的Z-28,其余方法相同,即可得下表实施例7至27:Referring to the reductive amination method of Example 1, Z-2 in the step was replaced with the corresponding SM-aldehyde in the table. Substitute Z-28 in the step with SM-amine, and the remaining methods are the same to obtain the following examples 7 to 27:

Figure BDA0003199064950000772
Figure BDA0003199064950000772

Figure BDA0003199064950000781
Figure BDA0003199064950000781

Figure BDA0003199064950000791
Figure BDA0003199064950000791

Figure BDA0003199064950000801
Figure BDA0003199064950000801

Figure BDA0003199064950000811
Figure BDA0003199064950000811

Figure BDA0003199064950000821
Figure BDA0003199064950000821

Figure BDA0003199064950000831
Figure BDA0003199064950000831

Figure BDA0003199064950000841
Figure BDA0003199064950000841

Figure BDA0003199064950000851
Figure BDA0003199064950000851

实施例27、化合物27的合成Example 27, the synthesis of compound 27

Figure BDA0003199064950000852
Figure BDA0003199064950000852

步骤1、中间体27-1的合成Step 1. Synthesis of Intermediate 27-1

向中间体Z-35(0.9g,2.66mmol)的DMF(10mL)溶液中加入4-戊炔-1-醇(448mg,5.32mmol),TEA(806mg,7.98mmol),CuI(101mg,0.5mmol)和Pd(PPh3)2Cl2(187mg,0.27mmol),混合液氮气置换几次,然后在N2的保护下升温至90℃,并再次温度下搅拌反应12h。反应完成后,浓缩反应液,粗品加水稀释,加乙酸乙酯萃取,合并的有机相用水、饱和食盐水洗涤,无水硫酸钠干燥,浓缩后的粗品用硅胶柱分离纯化(100%EA),得到27-1(190mg,0.56mmol,21%收率),MS(ESI)m/z=342[M+1]+To a solution of intermediate Z-35 (0.9 g, 2.66 mmol) in DMF (10 mL) was added 4-pentyn-1-ol (448 mg, 5.32 mmol), TEA (806 mg, 7.98 mmol), CuI (101 mg, 0.5 mmol) ) and Pd(PPh 3 ) 2 Cl 2 (187 mg, 0.27 mmol), the mixture was replaced with nitrogen several times, then heated to 90° C. under the protection of N 2 , and the reaction was stirred for 12 h at the temperature again. After the reaction was completed, the reaction solution was concentrated, the crude product was diluted with water, extracted with ethyl acetate, the combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was separated and purified by silica gel column (100% EA), 27-1 was obtained (190 mg, 0.56 mmol, 21% yield), MS (ESI) m/z = 342 [M+1] + .

步骤2、中间体27-2的合成Step 2. Synthesis of Intermediate 27-2

向27-1(190mg,0.56mmol)的DCM(30mL)溶液中加入DMP(476mg,1.12mmol),反应混合液室温下搅拌2小时。反应完成后,过滤反应液,滤液浓缩,得到的粗品经硅胶柱分离纯化(DCM/MeOH=10/1)得到27-2(134mg,0.39mmol,71%收率)。MS(ESI)m/z=340[M+H]+To a solution of 27-1 (190 mg, 0.56 mmol) in DCM (30 mL) was added DMP (476 mg, 1.12 mmol) and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated, and the obtained crude product was separated and purified by silica gel column (DCM/MeOH=10/1) to obtain 27-2 (134 mg, 0.39 mmol, 71% yield). MS (ESI) m/z=340 [M+H] + .

步骤3、化合物27的合成Step 3. Synthesis of compound 27

向中间体Z-28(70mg,0.13mmol)的DCM(7mL)中加入27-2(58.4mg,0.17mmol)和催化量的醋酸,混合液室温搅拌1h,然后加入NaBH(OAc)3(84mg,0.397mmol),继续室温搅拌反应4h。反应完成后,浓缩反应液,粗品用水稀释,乙酸乙酯萃取,合并的有机相用水和饱和食盐水洗涤,无水硫酸钠干燥,浓缩后的粗品用mHPLC分离纯化得到化合物27(45mg,0.05mmol,收率40%)。MS(ESI)m/z=852[M+H]+27-2 (58.4 mg, 0.17 mmol) and catalytic amount of acetic acid were added to intermediate Z-28 (70 mg, 0.13 mmol) in DCM (7 mL), the mixture was stirred at room temperature for 1 h, and then NaBH(OAc) 3 (84 mg) was added. , 0.397mmol), and continued to stir the reaction at room temperature for 4h. After the reaction was completed, the reaction solution was concentrated, the crude product was diluted with water, extracted with ethyl acetate, the combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was separated and purified by mHPLC to obtain compound 27 (45 mg, 0.05 mmol). , the yield is 40%). MS (ESI) m/z = 852 [M+H] + .

实施例28、化合物28的合成Example 28, the synthesis of compound 28

Figure BDA0003199064950000861
Figure BDA0003199064950000861

参照实施例27合成中步骤1到步骤3的方法,在步骤1中用中间体Z-33代替中间体Z-35,其余方法不变,可得化合物28。MS(ESI)m/z=852[M+H]+Referring to the method of step 1 to step 3 in the synthesis of Example 27, in step 1, intermediate Z-33 is used instead of intermediate Z-35, and the other methods remain unchanged, and compound 28 can be obtained. MS (ESI) m/z = 852 [M+H] + .

实施例29、化合物29的合成Example 29, the synthesis of compound 29

Figure BDA0003199064950000871
Figure BDA0003199064950000871

参照实施例27合成中步骤1到步骤3的方法,在步骤1中用中间体Z-34代替中间体Z-35,其余方法不变,可得化合物29。MS(ESI)m/z=852[M+H]+Referring to the method of step 1 to step 3 in the synthesis of Example 27, in step 1, intermediate Z-34 is used instead of intermediate Z-35, and the other methods remain unchanged, and compound 29 can be obtained. MS (ESI) m/z = 852 [M+H] + .

实施例30至实施例38、化合物30~化合物38的合成Synthesis of Example 30 to Example 38 and Compound 30 to Compound 38

参照实施例27合成中步骤3还原胺化的方法,同时以表中相应的SM-醛替代步骤中的27-2。以SM-胺替代步骤中的Z-30,其余方法相同,即可得下表实施例30至38:Refer to the method for reductive amination of step 3 in the synthesis of Example 27, and replace 27-2 in the step with the corresponding SM-aldehyde in the table. Substitute SM-amine for Z-30 in the step, and the remaining methods are the same to obtain the following examples 30 to 38:

Figure BDA0003199064950000872
Figure BDA0003199064950000872

Figure BDA0003199064950000881
Figure BDA0003199064950000881

Figure BDA0003199064950000891
Figure BDA0003199064950000891

实施例39、化合物39的合成Example 39, the synthesis of compound 39

Figure BDA0003199064950000892
Figure BDA0003199064950000892

步骤1、中间体39-1的合成Step 1. Synthesis of Intermediate 39-1

向27-1(230mg,0.67mmol)的MeOH(15mL)/THF(5mL)的混合溶液中加入Pd/C(200mg)。混合液用氢气置换后,在氢气保护下于室温搅拌反应16小时。反应完成后,过滤除掉Pd/C,滤液浓缩得到39-1(181mg,0.52mmol,78%收率,粗品)。To a mixed solution of 27-1 (230 mg, 0.67 mmol) in MeOH (15 mL)/THF (5 mL) was added Pd/C (200 mg). After the mixture was replaced with hydrogen, the reaction was stirred at room temperature for 16 hours under the protection of hydrogen. After the reaction was completed, Pd/C was removed by filtration, and the filtrate was concentrated to give 39-1 (181 mg, 0.52 mmol, 78% yield, crude product).

步骤2、中间体39-2的合成Step 2. Synthesis of Intermediate 39-2

向化合物39-1(181mg,0.52mmol)的DCM(6mL)溶液中加入DMP(331mg,0.78mmol)。悬浊液在室温下搅拌1.5小时。反应完成后,混合液过滤,滤液浓缩旋干,粗品加入乙酸乙酯稀释,有棕色固体析出,过滤收集固体,用反相C18柱分离纯化,得到中间体化合物39-2(116mg,0.34mmol,65%收率)。MS(ESI)m/z=344[M+1]+To a solution of compound 39-1 (181 mg, 0.52 mmol) in DCM (6 mL) was added DMP (331 mg, 0.78 mmol). The suspension was stirred at room temperature for 1.5 hours. After the reaction was completed, the mixture was filtered, the filtrate was concentrated and spin-dried, the crude product was diluted with ethyl acetate, a brown solid was precipitated, the solid was collected by filtration, and separated and purified with a reverse-phase C18 column to obtain an intermediate compound 39-2 (116 mg, 0.34 mmol, 65% yield). MS(ESI) m/z=344[M+1] + .

步骤3、化合物39的合成Step 3. Synthesis of compound 39

参照实施例27步骤3的方法,用中间体39-2代替27-2,其余操作方法一致(即在NaBH(AcO)3为试剂,DCM加催化量醋酸为溶剂,还原胺化),可得化合物39。MS(ESI)m/z=856[M+1]+Referring to the method of step 3 of Example 27, the intermediate 39-2 was used instead of 27-2, and the remaining operation methods were the same (i.e. NaBH(AcO) 3 was used as a reagent, DCM was added with catalytic amount of acetic acid as a solvent, and reductive amination was performed), and the obtained Compound 39. MS(ESI) m/z=856[M+1] + .

实施例40、化合物40的合成Example 40, the synthesis of compound 40

Figure BDA0003199064950000901
Figure BDA0003199064950000901

参照实施例39合成中步骤1到步骤3的方法,在步骤1中用中间体40-2代替中间体39-2,其余方法不变,可得化合物28。MS(ESI)m/z=856[M+H]+Referring to the method of step 1 to step 3 in the synthesis of Example 39, in step 1, intermediate 40-2 is used instead of intermediate 39-2, and the other methods remain unchanged, and compound 28 can be obtained. MS(ESI) m/z=856 [M+H] + .

实施例41、化合物41的合成Example 41, the synthesis of compound 41

Figure BDA0003199064950000902
Figure BDA0003199064950000902

参照实施例39合成中步骤1到步骤3的方法,在步骤1中用中间体29-1代替中间体27-1,其余方法不变,可得化合物41。MS(ESI)m/z=856[M+H]+Referring to the methods from step 1 to step 3 in the synthesis of Example 39, in step 1, intermediate 27-1 is replaced by intermediate 29-1, and the other methods remain unchanged, and compound 41 can be obtained. MS(ESI) m/z=856 [M+H] + .

实施例42至实施例50、化合物42~化合物50的合成Synthesis of Example 42 to Example 50 and Compound 42 to Compound 50

参照实施例27合成中步骤3还原胺化的方法,同时以表中相应的SM-醛替代步骤中的27-2。以SM-胺替代步骤中的Z-30,其余方法相同,即可得下表实施例42至50:Refer to the method for reductive amination of step 3 in the synthesis of Example 27, and replace 27-2 in the step with the corresponding SM-aldehyde in the table. Substitute SM-amine for Z-30 in the step, and the remaining methods are the same to obtain the following examples 42 to 50:

Figure BDA0003199064950000903
Figure BDA0003199064950000903

Figure BDA0003199064950000911
Figure BDA0003199064950000911

Figure BDA0003199064950000921
Figure BDA0003199064950000921

Figure BDA0003199064950000931
Figure BDA0003199064950000931

实施例51、化合物51的合Z-28成Example 51, synthesis of compound 51 Z-28

Figure BDA0003199064950000941
Figure BDA0003199064950000941

步骤1、中间体51-1的合成Step 1. Synthesis of Intermediate 51-1

向Z-28(42.58mg,80.54μmol)和Z-40(42.58mg,80.54μmol)的DCM(2mL)混合液中滴加TFA,调节pH至5~6,搅拌30min后,然后加入NaBH(OAc)3(51.21mg,241.63μmol),混合液室温搅拌反应15小时。反应完成后,加水稀释反应液,DCM萃取,合并的有机相用水,饱和食盐水洗涤,无水硫酸钠干燥,浓缩后的粗品用pre-HPLC分离纯化,得到51-1(12mg,11.89μmol,14.76%收率)黄色固体。To a mixture of Z-28 (42.58 mg, 80.54 μmol) and Z-40 (42.58 mg, 80.54 μmol) in DCM (2 mL), TFA was added dropwise to adjust the pH to 5-6, and after stirring for 30 min, NaBH (OAc ) 3 (51.21 mg, 241.63 μmol), the mixture was stirred and reacted at room temperature for 15 hours. After the completion of the reaction, the reaction solution was diluted with water, extracted with DCM, the combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was separated and purified by pre-HPLC to obtain 51-1 (12 mg, 11.89 μmol, 14.76% yield) as a yellow solid.

步骤2、化合物51的合成Step 2. Synthesis of compound 51

室温下,向51-1(12mg,11.89μmol)的DCM(2mL)溶液中加入TFA(1.36mg,11.89μmol,2mL),混合液室温搅拌1小时。反应完成后,浓缩反应液,所得粗品重新溶解于DCM(2mL)中,室温加TEA(725.50mg,7.17mmol,1mL),搅拌反应30分钟。浓缩混合液,粗品用pre-HPLC分离纯化得51(1.14mg,1.14umol,9.56%收率,99%纯度,TF)黄色固体。MS(ESI)m/z=879[M+H]+。核磁谱图:1H NMR(400MHz,DMSO-d6)δ12.81(s,1H),10.99(s,1H),8.46(s,1H),8.34(s,1H),8.05(s,1H),7.97(s,1H),7.81(s,1H),7.72(d,J=3.1Hz,2H),7.57(d,J=30.4Hz,3H),7.25(s,1H),5.11(dd,J=13.3,5.2Hz,1H),4.46(d,J=17.2Hz,1H),4.34(d,J=17.4Hz,2H),4.29–4.15(m,3H),4.02(s,1H),3.74(s,4H),3.43(s,28H),2.80(s,3H),2.58(s,7H),2.17(s,4H),1.96(d,J=36.6Hz,4H),1.46(s,1H),1.06(t,J=7.0Hz,2H),0.82(d,J=6.4Hz,3H).To a solution of 51-1 (12 mg, 11.89 μmol) in DCM (2 mL) was added TFA (1.36 mg, 11.89 μmol, 2 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated, the obtained crude product was redissolved in DCM (2 mL), TEA (725.50 mg, 7.17 mmol, 1 mL) was added at room temperature, and the reaction was stirred for 30 minutes. The mixture was concentrated, and the crude product was separated and purified by pre-HPLC to obtain 51 (1.14 mg, 1.14 umol, 9.56% yield, 99% purity, TF) as a yellow solid. MS (ESI) m/z = 879 [M+H] + . Nuclear magnetic spectrum: 1 H NMR (400MHz, DMSO-d6)δ12.81(s,1H), 10.99(s,1H), 8.46(s,1H), 8.34(s,1H), 8.05(s,1H) ,7.97(s,1H),7.81(s,1H),7.72(d,J=3.1Hz,2H),7.57(d,J=30.4Hz,3H),7.25(s,1H),5.11(dd, J=13.3, 5.2Hz, 1H), 4.46 (d, J=17.2Hz, 1H), 4.34 (d, J=17.4Hz, 2H), 4.29–4.15 (m, 3H), 4.02 (s, 1H), 3.74(s, 4H), 3.43(s, 28H), 2.80(s, 3H), 2.58(s, 7H), 2.17(s, 4H), 1.96(d, J=36.6Hz, 4H), 1.46(s ,1H),1.06(t,J=7.0Hz,2H),0.82(d,J=6.4Hz,3H).

实施例52、化合物52的合成Example 52, the synthesis of compound 52

Figure BDA0003199064950000942
Figure BDA0003199064950000942

参照化合物51合成步骤1和步骤2,用中间体Z-30替代步骤1中的Z-28为起始原料,其余操作方法相同,可得化合物52。MS(ESI)m/z=879[M+H]+。核磁谱图:1H NMR(400MHz,DMSO-d6)δ12.87(s,1H),8.48(s,1H),8.34(s,1H),8.02(d,J=20.8Hz,2H),7.86–7.50(m,6H),7.33(d,J=8.3Hz,1H),5.11(dd,J=13.2,5.1Hz,1H),4.47(d,J=17.2Hz,1H),4.41–4.30(m,2H),4.22(q,J=5.7,5.2Hz,3H),4.08–3.90(m,4H),3.75(s,5H),2.92(ddd,J=18.2,13.8,5.6Hz,4H),2.80(s,2H),2.60(s,5H),2.40(td,J=13.3,4.7Hz,2H),2.19(d,J=28.0Hz,3H),2.06–1.90(m,3H),1.46(s,1H),1.23(s,1H),0.82(d,J=6.4Hz,3H).Referring to the synthesis steps 1 and 2 of compound 51, using intermediate Z-30 instead of Z-28 in step 1 as the starting material, and the rest of the operation method is the same, compound 52 can be obtained. MS (ESI) m/z = 879 [M+H] + . Nuclear magnetic spectrum: 1 H NMR (400MHz, DMSO-d 6 )δ12.87(s, 1H), 8.48(s, 1H), 8.34(s, 1H), 8.02(d, J=20.8Hz, 2H), 7.86–7.50 (m, 6H), 7.33 (d, J=8.3Hz, 1H), 5.11 (dd, J=13.2, 5.1Hz, 1H), 4.47 (d, J=17.2Hz, 1H), 4.41–4.30 (m, 2H), 4.22 (q, J=5.7, 5.2Hz, 3H), 4.08–3.90 (m, 4H), 3.75 (s, 5H), 2.92 (ddd, J=18.2, 13.8, 5.6Hz, 4H ), 2.80(s, 2H), 2.60(s, 5H), 2.40(td, J=13.3, 4.7Hz, 2H), 2.19(d, J=28.0Hz, 3H), 2.06–1.90(m, 3H) ,1.46(s,1H),1.23(s,1H),0.82(d,J=6.4Hz,3H).

实施例53、化合物53的合成Example 53, the synthesis of compound 53

Figure BDA0003199064950000951
Figure BDA0003199064950000951

参照实施例51步骤1的合成方法,以Z-28和Z-36为原料进行还原胺化,可得化合物53,MS(ESI)m/z=879[M+H]+。核磁谱图:1H NMR(400MHz,DMSO-d6)δ12.84(s,1H),11.04(s,1H),8.50(s,1H),8.26(s,1H),8.03(d,J=4.5Hz,2H),7.89(dd,J=7.6,1.2Hz,1H),7.67(s,1H),7.64–7.59(m,2H),7.59–7.52(m,2H),7.30–7.24(m,1H),5.26–5.15(m,1H),4.65–4.54(m,3H),4.46–4.32(m,5H),4.30–4.18(m,5H),4.07–3.97(m,3H),3.94–3.82(m,2H),3.75(s,4H),3.05–2.89(m,4H),2.86–2.73(m,2H),2.70–2.62(m,1H),2.62(s,3H),2.29–2.09(m,5H),2.09–1.84(m,4H),1.51–1.38(m,1H),0.82(d,J=6.5Hz,3H).Referring to the synthesis method of step 1 in Example 51, Z-28 and Z-36 were used as raw materials for reductive amination to obtain compound 53, MS (ESI) m/z=879 [M+H] + . Nuclear magnetic spectrum: 1 H NMR (400MHz, DMSO-d 6 )δ12.84(s,1H), 11.04(s,1H), 8.50(s,1H), 8.26(s,1H), 8.03(d,J =4.5Hz,2H),7.89(dd,J=7.6,1.2Hz,1H),7.67(s,1H),7.64-7.59(m,2H),7.59-7.52(m,2H),7.30-7.24( m, 1H), 5.26–5.15 (m, 1H), 4.65–4.54 (m, 3H), 4.46–4.32 (m, 5H), 4.30–4.18 (m, 5H), 4.07–3.97 (m, 3H), 3.94–3.82 (m, 2H), 3.75 (s, 4H), 3.05–2.89 (m, 4H), 2.86–2.73 (m, 2H), 2.70–2.62 (m, 1H), 2.62 (s, 3H), 2.29–2.09 (m, 5H), 2.09–1.84 (m, 4H), 1.51–1.38 (m, 1H), 0.82 (d, J=6.5Hz, 3H).

实施例54到实施例62、化合物54至化合物62的合成Synthesis of Example 54 to Example 62, Compound 54 to Compound 62

参照实施例51步骤1的方法,以下表中的SM-醛和SM-胺为原料,经还原胺化可得表中相应实施例化合物。Referring to the method of step 1 of Example 51, the SM-aldehyde and SM-amine in the following table are used as raw materials, and the corresponding example compounds in the table can be obtained by reductive amination.

Figure BDA0003199064950000952
Figure BDA0003199064950000952

Figure BDA0003199064950000961
Figure BDA0003199064950000961

Figure BDA0003199064950000971
Figure BDA0003199064950000971

Figure BDA0003199064950000981
Figure BDA0003199064950000981

实施例63、化合物63的合成Example 63, the synthesis of compound 63

Figure BDA0003199064950000991
Figure BDA0003199064950000991

向Z-28(30mg,56.75μmol)的DMF(2mL)溶液中加入Z-37(21.70mg,56.75μmol),DIPEA(36.67mg,283.74μmol,49.42μL)和HATU(21.56mg,56.75μmol),反应混合液室温搅拌过夜。To a solution of Z-28 (30 mg, 56.75 μmol) in DMF (2 mL) was added Z-37 (21.70 mg, 56.75 μmol), DIPEA (36.67 mg, 283.74 μmol, 49.42 μL) and HATU (21.56 mg, 56.75 μmol), The reaction mixture was stirred at room temperature overnight.

反应完成后,过滤反应液,滤液浓缩后经pre-HPLC分离纯化得到化合物63(9.38mg,0.009mmol,16%收率,99.4%纯度,TF)黄色固体,MS(ESI)m/z=893[M+H]+After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated and separated and purified by pre-HPLC to obtain compound 63 (9.38 mg, 0.009 mmol, 16% yield, 99.4% purity, TF) as a yellow solid, MS (ESI) m/z=893 [M+H] + .

1H NMR(400MHz,Methanol-d4)δ8.89(s,1H),8.27(s,1H),8.06(d,J=13.1Hz,2H),7.78(t,J=6.6Hz,2H),7.70–7.59(m,3H),7.51(t,J=7.3Hz,1H),7.39(d,J=6.9Hz,1H),5.25–5.16(m,1H),4.67–4.39(m,8H),4.31(d,J=13.8Hz,1H),3.90(d,J=11.8Hz,1H),3.85(d,J=1.3Hz,4H),3.05(s,4H),2.83(s,4H),2.77(s,2H),2.58(tt,J=13.3,6.7Hz,2H),2.32(s,1H),2.23–2.15(m,1H),2.03(d,J=12.2Hz,2H),1.55(d,J=10.3Hz,1H),0.85(t,J=6.5Hz,3H).1H NMR(400MHz,Methanol-d 4 )δ8.89(s,1H),8.27(s,1H),8.06(d,J=13.1Hz,2H),7.78(t,J=6.6Hz,2H), 7.70–7.59 (m, 3H), 7.51 (t, J=7.3Hz, 1H), 7.39 (d, J=6.9Hz, 1H), 5.25–5.16 (m, 1H), 4.67–4.39 (m, 8H) ,4.31(d,J=13.8Hz,1H),3.90(d,J=11.8Hz,1H),3.85(d,J=1.3Hz,4H),3.05(s,4H),2.83(s,4H) , 2.77(s, 2H), 2.58(tt, J=13.3, 6.7Hz, 2H), 2.32(s, 1H), 2.23–2.15(m, 1H), 2.03(d, J=12.2Hz, 2H), 1.55(d, J=10.3Hz, 1H), 0.85(t, J=6.5Hz, 3H).

实施例64到实施例74、化合物64至化合物74的合成Synthesis of Example 64 to Example 74, Compound 64 to Compound 74

参照实施例63的方法,以下表中的SM-胺和SM-酸为原料,经相同条件缩合反应可得表中相应实施例化合物。Referring to the method of Example 63, SM-amine and SM-acid in the following table are used as raw materials, and the corresponding example compounds in the table can be obtained through condensation reaction under the same conditions.

Figure BDA0003199064950000992
Figure BDA0003199064950000992

Figure BDA0003199064950001001
Figure BDA0003199064950001001

Figure BDA0003199064950001011
Figure BDA0003199064950001011

Figure BDA0003199064950001021
Figure BDA0003199064950001021

实施例75、化合物75的合成Example 75, the synthesis of compound 75

Figure BDA0003199064950001022
Figure BDA0003199064950001022

向Z-30(50mg,94.58μmol)的DCM(4mL)溶液中加入Z-42(31.24mg,94.58μmol),反应混合液室温搅拌30min,然后滴入AcOH调节反应液pH至3到4。再加入NaBH(AcO)3(60.14mg,283.74μmol),混合液室温搅拌5小时。反应完成后,反应液加水稀释,加乙酸乙酯萃取,合并的有机相用水,饱和食盐水洗涤,无水硫酸钠干燥,浓缩后得到的粗品用Pre.HPLC分离纯化,得到化合物75(33.8mg,35.32μmol,37.34%收率,TF),MS(ESI)m/z=843[M+H]+。核磁谱图:1H NMR(400MHz,DMSO)δ12.86(s,1H),10.99(s,1H),8.50(s,1H),8.01(s,1H),7.65(d,J=8.2Hz,2H),7.51(dd,J=19.0,11.2Hz,2H),7.33(d,J=7.5Hz,2H),7.25(d,J=8.2Hz,1H),5.13(dd,J=13.3,5.0Hz,1H),4.37(dd,J=11.1,6.1Hz,5H),4.30–4.11(m,10H),3.98(dd,J=27.2,16.7Hz,7H),3.75(s,4H),3.01–2.86(m,3H),2.80(s,2H),2.71–2.55(m,5H),2.23(s,2H),2.06–1.88(m,4H),1.79(s,5H),1.46(s,1H),0.82(d,J=6.4Hz,3H).Z-42 (31.24 mg, 94.58 μmol) was added to a solution of Z-30 (50 mg, 94.58 μmol) in DCM (4 mL), the reaction mixture was stirred at room temperature for 30 min, and then AcOH was added dropwise to adjust the pH of the reaction solution to 3 to 4. Then NaBH(AcO) 3 (60.14 mg, 283.74 μmol) was added, and the mixture was stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate, the combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the crude product obtained after concentration was separated and purified by Pre.HPLC to obtain compound 75 (33.8 mg , 35.32 μmol, 37.34% yield, TF), MS (ESI) m/z=843 [M+H]+. Nuclear magnetic spectrum: 1 H NMR (400MHz, DMSO) δ12.86(s, 1H), 10.99(s, 1H), 8.50(s, 1H), 8.01(s, 1H), 7.65(d, J=8.2Hz ,2H),7.51(dd,J=19.0,11.2Hz,2H),7.33(d,J=7.5Hz,2H),7.25(d,J=8.2Hz,1H),5.13(dd,J=13.3, 5.0Hz, 1H), 4.37 (dd, J=11.1, 6.1Hz, 5H), 4.30–4.11 (m, 10H), 3.98 (dd, J=27.2, 16.7Hz, 7H), 3.75 (s, 4H), 3.01–2.86 (m, 3H), 2.80 (s, 2H), 2.71–2.55 (m, 5H), 2.23 (s, 2H), 2.06–1.88 (m, 4H), 1.79 (s, 5H), 1.46 ( s,1H),0.82(d,J=6.4Hz,3H).

实施例76至实施例78、化合物76至化合物的合成Synthesis of Example 76 to Example 78, Compound 76 to Compound

参照实施例75的方法,以下表中的SM-胺和Z-42为原料,经相同条件还原胺化反应可得表中相应实施例化合物。Referring to the method of Example 75, SM-amine and Z-42 in the following table are used as raw materials, and the corresponding example compounds in the table can be obtained through reductive amination reaction under the same conditions.

Figure BDA0003199064950001031
Figure BDA0003199064950001031

Figure BDA0003199064950001041
Figure BDA0003199064950001041

实施例79至实施例81,化合物79至化合物81的合成Example 79 to Example 81, Synthesis of Compound 79 to Compound 81

参照实施例75的方法,以中间体Z-28为原料分别和下表中相应结构的醛为原料,经相同条件的还原胺化反应可得表中相应实施例化合物。Referring to the method of Example 75, using the intermediate Z-28 as the raw material and the aldehyde of the corresponding structure in the following table as the raw material, the corresponding example compounds in the table can be obtained through reductive amination reaction under the same conditions.

Figure BDA0003199064950001042
Figure BDA0003199064950001042

Figure BDA0003199064950001051
Figure BDA0003199064950001051

实施例82,化合物82的合成Example 82, Synthesis of Compound 82

参照实施例63的方法,以中间体Z-28和下表中的SM-酸为原料,经相同条件缩合反应可得实施例化合物82。Referring to the method of Example 63, using the intermediate Z-28 and the SM-acid in the following table as raw materials, the compound 82 of Example can be obtained by condensation reaction under the same conditions.

Figure BDA0003199064950001052
Figure BDA0003199064950001052

实施例83至实施例85,化合物83至化合物85的合成Example 83 to Example 85, Synthesis of Compound 83 to Compound 85

参照实施例75的方法,以中间体Z-30为原料分别和下表中相应结构的醛为原料,经相同条件的还原胺化反应可得表中相应实施例化合物。Referring to the method of Example 75, using the intermediate Z-30 as the raw material and the aldehyde of the corresponding structure in the following table as the raw material, the corresponding example compounds in the table can be obtained through reductive amination reaction under the same conditions.

Figure BDA0003199064950001061
Figure BDA0003199064950001061

Figure BDA0003199064950001071
Figure BDA0003199064950001071

实施例86至实施例91,化合物86至化合物91的合成Example 86 to Example 91, Synthesis of Compound 86 to Compound 91

参照实施例75的方法,以中间体Z-31为原料分别和下表中相应结构的醛为原料,经相同条件的还原胺化反应可得表中相应实施例化合物。Referring to the method of Example 75, using the intermediate Z-31 as the raw material and the aldehyde of the corresponding structure in the following table as the raw material, the corresponding example compounds in the table can be obtained through reductive amination reaction under the same conditions.

Figure BDA0003199064950001072
Figure BDA0003199064950001072

Figure BDA0003199064950001081
Figure BDA0003199064950001081

Figure BDA0003199064950001091
Figure BDA0003199064950001091

实施例91,化合物91的合成Example 91, the synthesis of compound 91

参照实施例63的方法,以中间体Z-31和下表中的SM-酸为原料,经相同条件缩合反应可得实施例化合物91。Referring to the method of Example 63, using the intermediate Z-31 and the SM-acid in the following table as raw materials, the compound 91 of Example can be obtained by condensation reaction under the same conditions.

Figure BDA0003199064950001092
Figure BDA0003199064950001092

Figure BDA0003199064950001101
Figure BDA0003199064950001101

实施例92、实施例93,化合物92、化合物93的合成Example 92, Example 93, Synthesis of Compound 92 and Compound 93

参照实施例75的方法,以中间体Z-32为原料分别和下表中相应结构的醛为原料,经相同条件的还原胺化反应可得表中相应实施例化合物。Referring to the method of Example 75, using the intermediate Z-32 as the raw material and the aldehyde of the corresponding structure in the following table as the raw material, the corresponding example compounds in the table can be obtained through reductive amination reaction under the same conditions.

Figure BDA0003199064950001102
Figure BDA0003199064950001102

Figure BDA0003199064950001111
Figure BDA0003199064950001111

实施例94、化合物94的合成Example 94, the synthesis of compound 94

Figure BDA0003199064950001112
Figure BDA0003199064950001112

步骤1、中间体94-a的合成Step 1. Synthesis of Intermediate 94-a

向Z-31(36mg,67.83μmol)的DCM(2mL)中,加TEA至pH=9-10,然后加入Z-43(41.89mg,81.40μmol),室温搅拌30分钟,然后加醋酸调pH=4-5。搅拌5分钟后,一次性加入NaBH(OAc)3(43.13mg,203.49μmol),反应混合液室温过夜。反应完成后,加水,加入DCM萃取,有机相水洗,盐水洗,干燥,浓缩,粗品经过Pre-TLC(DCM/MeOH=10/1)分离纯化,得到中间体94-a(69mg,67.03μmol,98.82%收率)。MS(ESI)m/z=1029[M+1]+To Z-31 (36 mg, 67.83 μmol) in DCM (2 mL), add TEA to pH=9-10, then add Z-43 (41.89 mg, 81.40 μmol), stir at room temperature for 30 minutes, and then add acetic acid to adjust pH= 4-5. After stirring for 5 minutes, NaBH(OAc) 3 (43.13 mg, 203.49 μmol) was added in one portion, and the reaction mixture was left at room temperature overnight. After the reaction was completed, water was added, DCM was added for extraction, the organic phase was washed with water, washed with brine, dried, concentrated, and the crude product was separated and purified by Pre-TLC (DCM/MeOH=10/1) to obtain intermediate 94-a (69 mg, 67.03 μmol, 98.82% yield). MS(ESI) m/z=1029[M+1] + .

步骤2、化合物94的合成Step 2. Synthesis of compound 94

室温下,向94-a(70mg,68.00μmol)的DCM(2mL)溶液中加入TFA(18.04mg,158.25μmol),混合液室温下搅拌反应2小时,反应完成后,浓缩反应液,粗品用pre-HPLC分离纯化得94;(30.88mg,28.96μmol,42.58%收率,95%纯度,TF)黄色固体。MS(ESI)m/z=899[M+H]+。核磁谱图:1H NMR(400MHz,Methanol-d4)δ8.86(s,1H),8.24(s,1H),8.01(s,1H),7.65–7.58(m,1H),7.47–7.41(m,3H),7.16(d,J=2.1Hz,1H),7.05(d,J=8.7Hz,1H),5.20–5.12(m,1H),4.56–4.44(m,3H),4.35–4.26(m,1H),4.16–4.08(m,1H),3.95–3.86(m,2H),3.84(s,3H),3.79–3.67(m,2H),3.57(t,J=5.6Hz,2H),3.46(t,J=6.3Hz,2H),3.18–3.04(m,2H),2.96–2.80(m,2H),2.80(s,3H),2.73–2.66(m,2H),2.57–2.49(m,1H),2.37–2.29(m,1H),2.20–2.13(m,1H),2.11–1.99(m,4H),1.74–1.64(m,2H),1.63–1.56(m,2H),1.46–1.37(m,4H),0.87(dd,J=6.6,3.2Hz,3H).At room temperature, TFA (18.04 mg, 158.25 μmol) was added to a solution of 94-a (70 mg, 68.00 μmol) in DCM (2 mL), and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated, and the crude product was treated with pre -HPLC separation and purification gave 94; (30.88 mg, 28.96 μmol, 42.58% yield, 95% purity, TF) as a yellow solid. MS (ESI) m/z = 899 [M+H] + . Nuclear magnetic spectrum: 1H NMR (400MHz, Methanol-d4)δ8.86(s,1H), 8.24(s,1H), 8.01(s,1H), 7.65–7.58(m,1H), 7.47–7.41(m ,3H),7.16(d,J=2.1Hz,1H),7.05(d,J=8.7Hz,1H),5.20–5.12(m,1H),4.56–4.44(m,3H),4.35–4.26( m, 1H), 4.16–4.08 (m, 1H), 3.95–3.86 (m, 2H), 3.84 (s, 3H), 3.79–3.67 (m, 2H), 3.57 (t, J=5.6Hz, 2H) ,3.46(t,J=6.3Hz,2H),3.18-3.04(m,2H),2.96-2.80(m,2H),2.80(s,3H),2.73-2.66(m,2H),2.57-2.49 (m, 1H), 2.37–2.29 (m, 1H), 2.20–2.13 (m, 1H), 2.11–1.99 (m, 4H), 1.74–1.64 (m, 2H), 1.63–1.56 (m, 2H) ,1.46–1.37(m,4H),0.87(dd,J=6.6,3.2Hz,3H).

实施例95到实施例101、化合物95至化合物101的合成Synthesis of Example 95 to Example 101, Compound 95 to Compound 101

参照实施例94步骤1到步骤2的方法,以下表中的SM-醛和SM-胺为原料,经还原胺化可得表中相应实施例化合物。Referring to the method from step 1 to step 2 of Example 94, the SM-aldehyde and SM-amine in the following table are used as raw materials, and the corresponding example compounds in the table can be obtained by reductive amination.

Figure BDA0003199064950001121
Figure BDA0003199064950001121

Figure BDA0003199064950001131
Figure BDA0003199064950001131

Figure BDA0003199064950001141
Figure BDA0003199064950001141

Figure BDA0003199064950001151
Figure BDA0003199064950001151

Figure BDA0003199064950001161
Figure BDA0003199064950001161

Figure BDA0003199064950001171
Figure BDA0003199064950001171

Figure BDA0003199064950001181
Figure BDA0003199064950001181

Figure BDA0003199064950001191
Figure BDA0003199064950001191

Figure BDA0003199064950001201
Figure BDA0003199064950001201

Figure BDA0003199064950001211
Figure BDA0003199064950001211

Figure BDA0003199064950001221
Figure BDA0003199064950001221

Figure BDA0003199064950001231
Figure BDA0003199064950001231

为了说明本发明的有益效果,本发明提供以下试验例。In order to illustrate the beneficial effects of the present invention, the present invention provides the following test examples.

试验例1、EGFR激酶活性检测Test Example 1. Detection of EGFR Kinase Activity

EGFR激酶活性通过检测底物的磷酸化水平来表征,磷酸化抗体和生物素标记的多肽底物之间FRET信号强度与酶活性成正比。检测所需试剂除蛋白外均包含在

Figure BDA0003199064950001232
KinEASETM试剂盒(CISBIO)中,具体操作如下:在384孔板中加入125pM EGFR(T790M/C797S/L858R)激酶蛋白,300nM TK Substrate-biotin,0.8μM ATP,反应总体积10μL,混匀后室温孵育40分钟;再加入37.5nM Streptavidin-XL665和5μL/孔TK Antibody-Cryptate,反应终体积20μL,混匀后室温孵育60分钟,用酶标仪检测激发波长320nM发射波长620nM和665nM的荧光强度,计算FRET信号强度(665nM荧光强度/620nM荧光强度*10000)。检测化合物对激酶活性抑制时,化合物先与激酶蛋白室温预孵育15~60分钟,再加入底物和ATP进行反应。活性数据如下表:EGFR kinase activity was characterized by detecting the phosphorylation level of the substrate, and the intensity of the FRET signal between the phosphorylated antibody and the biotin-labeled polypeptide substrate was proportional to the enzyme activity. The reagents required for the detection are included in the
Figure BDA0003199064950001232
KinEASE TM kit (CISBIO), the specific operation is as follows: add 125pM EGFR (T790M/C797S/L858R) kinase protein, 300nM TK Substrate-biotin, 0.8μM ATP to a 384-well plate, and mix at room temperature Incubate for 40 minutes; then add 37.5nM Streptavidin-XL665 and 5μL/well TK Antibody-Cryptate, the final reaction volume is 20μL, after mixing, incubate for 60 minutes at room temperature, and use a microplate reader to detect the fluorescence intensity of excitation wavelength 320nM emission wavelength 620nM and 665nM, Calculate the FRET signal intensity (665nM fluorescence intensity/620nM fluorescence intensity*10000). When detecting the inhibition of the kinase activity by the compound, the compound is pre-incubated with the kinase protein for 15-60 minutes at room temperature, and then the substrate and ATP are added for the reaction. The activity data are as follows:

Figure BDA0003199064950001241
Figure BDA0003199064950001241

Figure BDA0003199064950001251
Figure BDA0003199064950001251

试验例2、EGFR-PROTAC-CRBN/DDB1三元复合物形成检测Test example 2. Detection of EGFR-PROTAC-CRBN/DDB1 ternary complex formation

在384孔板中加入系列浓度实施例化合物和EGFR(T790M/C797S/L858R)重组蛋白以及CRBN/DDB1重组蛋白复合物,反应缓冲液为1×PBS pH 7.4,室温孵育120分钟,再加入5nM Anti GST-Eu cryptate和6.67nM,Ant 6His-XL665,混匀后室温孵育60分钟,用酶标仪检测激发波长320nM发射波长620nM和665nM的荧光强度,计算FRET信号强度(665nM荧光强度/620nM荧光强度*10000)。实验结果如附图1所示,本发明化合物能够形成三元复合物。A series of concentrations of example compounds, EGFR (T790M/C797S/L858R) recombinant protein and CRBN/DDB1 recombinant protein complex were added to a 384-well plate. The reaction buffer was 1×PBS pH 7.4, incubated at room temperature for 120 minutes, and then 5nM Antibody was added. GST-Eu cryptate and 6.67nM, Ant 6His-XL665 were mixed and incubated at room temperature for 60 minutes, the fluorescence intensity of excitation wavelength 320nM emission wavelength 620nM and 665nM was detected by a microplate reader, and the FRET signal intensity was calculated (665nM fluorescence intensity/620nM fluorescence intensity *10000). The experimental results are shown in FIG. 1 , the compound of the present invention can form a ternary complex.

试验例3、细胞水平EGFR降解检测Test Example 3. Detection of EGFR degradation at the cellular level

96孔透明底黑板经胶原蛋白和纤连蛋白包被处理后,接种Ba/F3-EGFR(T790M/C797S/L858R)过表达细胞(2*10^4个细胞每孔)并于37℃,5%CO2培养箱中培养过夜。次日,移除细胞中的培养基,先加入150μL新鲜培养基,再加入50μL含有4倍终浓度实施例化合物的培养基,放入培养箱中,在37℃及5%CO2条件下继续培养16小时。之后,移除细胞中的培养基,使用4%多聚甲醛固定细胞,每孔150μL,室温孵育15min。细胞固定后使用0.1%(v/v)Triton X-100通透细胞,每孔150μL,室温孵育15min。细胞使用1%封闭试剂(罗氏,货号:11096176001)封闭,每孔100μL,室温孵育60min。封闭后每孔加入50μL使用1%(w/v)封闭试剂稀释后的EGFR抗体(CST,货号:4267S,稀释比例为1:250),室温孵育2小时。移除孔中的EGFR抗体,使用0.05%(v/v)PBST洗细胞,每孔200μL,重复4次。然后加入1%(w/v)封闭试剂稀释的羊抗兔荧光二抗(Invitrogen,货号:A32731)和DAPI染液(Thermofisher,货号:62247)(荧光二抗稀释比例为1:250,DAPI的稀释比例为1:2000),每孔50μL,室温环境下于振荡器上300rpm避光孵育2小时。然后移除孔中的抗体,使用0.05%(v/v)PBST洗细胞,每孔200μL,重复4次(最后一次保留孔内的洗液)。使用高内涵成像分析系统(GE,In CellAnalyzer,型号:2200)获取数据,每孔扫描9个视野,FITC通道曝光时间设置为0.5s,DAPI通道曝光时间设置为0.05s。使用In cell analyzer workstation软件分析数据,获得细胞内的EGFR荧光信号值和细胞周围的背景值。使用Excel对获得的数据进行后续的处理,首先将细胞内的EGFR荧光信号值减去细胞周围的背景值获得标准化后的细胞内的EGFR荧光信号值。其次,计算化合物处理后相对于DMSO对照的EGFR相对水平(DMSO处理计为100%),使用GraphPad Prism软件对EGFR相对水平进行分析,并得到DC50值和拟合曲线。96-well transparent bottom black plates were treated with collagen and fibronectin, and then seeded with Ba/F3-EGFR (T790M/C797S/L858R) overexpressing cells (2*10^4 cells per well) and incubated at 37°C for 5 Incubate overnight in a %CO 2 incubator. The next day, remove the medium from the cells, add 150 μL of fresh medium first, then add 50 μL of medium containing 4 times the final concentration of the example compounds, put in an incubator, and continue at 37 °C and 5% CO Incubate for 16 hours. After that, the medium in the cells was removed, and the cells were fixed with 4% paraformaldehyde, 150 μL per well, and incubated at room temperature for 15 min. After the cells were fixed, the cells were permeabilized with 0.1% (v/v) Triton X-100, 150 μL per well, and incubated at room temperature for 15 min. Cells were blocked with 1% blocking reagent (Roche, catalog number: 11096176001), 100 μL per well, and incubated at room temperature for 60 min. After blocking, 50 μL of EGFR antibody diluted with 1% (w/v) blocking reagent (CST, Cat. No.: 4267S, dilution ratio of 1:250) was added to each well, and incubated at room temperature for 2 hours. The EGFR antibody in the wells was removed, and the cells were washed with 0.05% (v/v) PBST, 200 μL per well, 4 times. Then add 1% (w/v) blocking reagent diluted goat anti-rabbit fluorescent secondary antibody (Invitrogen, Cat. No. A32731) and DAPI staining solution (Thermofisher, Cat. No. 62247) (fluorescent secondary antibody dilution ratio 1:250, DAPI The dilution ratio is 1:2000), 50 μL per well, and incubated at room temperature on a shaker at 300 rpm in the dark for 2 hours. Antibodies in the wells were then removed, and cells were washed with 0.05% (v/v) PBST, 200 μL per well, repeated 4 times (the last wash was retained in the wells). Data were acquired using a high-content imaging analysis system (GE, In CellAnalyzer, model: 2200), 9 fields of view were scanned per well, and the exposure time of the FITC channel was set to 0.5s, and the exposure time of the DAPI channel was set to 0.05s. The data were analyzed using the In cell analyzer workstation software to obtain intracellular EGFR fluorescence signal values and surrounding background values. Use Excel to perform subsequent processing on the acquired data. First, the intracellular EGFR fluorescence signal value is subtracted from the background value around the cell to obtain the normalized intracellular EGFR fluorescence signal value. Next, the relative levels of EGFR after compound treatment were calculated relative to the DMSO control (DMSO treatment counted as 100%), the relative levels of EGFR were analyzed using GraphPad Prism software, and DC 50 values and fitted curves were obtained.

Figure BDA0003199064950001261
Figure BDA0003199064950001261

实验结果表明,本发明化合物能够抑制和降解EGFR蛋白,可能成为一种靶向EGFR蛋白降解的药物。The experimental results show that the compound of the present invention can inhibit and degrade the EGFR protein, and may become a drug targeting the degradation of the EGFR protein.

Claims (13)

1. A bifunctional compound of formula I, or a stereoisomer, pharmaceutically acceptable salt thereof:
Figure FDA0003199064940000011
wherein,
R1selected from hydrogen, halogen, ═ O, -C1~6Alkyl, halogen substituted-C1~6Alkyl, -OR, -NRR, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl);
R2selected from hydrogen, halogen, cyano, nitro, -C1~6Alkyl, halogen substituted-C1~6Alkyl, -OR, -NRR, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl);
X1、X2each independently selected from O, S, NRx1、CRx1Rx2
Rx1、Rx2Each independently selected from hydrogen and-C1~6Alkyl, halogen substituted-C1~6Alkyl, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl);
y is selected from N or CRY1
RY1Selected from hydrogen, C1~10Alkyl, halogen substituted-C1~6Alkyl, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl);
the ring A is selected from a benzene ring and a 5-6-membered aromatic heterocycle; wherein the benzene ringThe aromatic heterocyclic ring may be further substituted by one, two or three RASubstitution;
each RAAre respectively and independently selected from hydrogen, halogen, cyano, nitro and-C1~6Alkyl, halogen substituted-C1~6Alkyl, -OR, -NRR, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl);
R4、R50, 1,2 or 3 are respectively independent;
R4、R5are respectively and independently selected from hydrogen, halogen, cyano, nitro and-C1~6Alkyl, halogen substituted-C1~6Alkyl, -OR, -NRR, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl);
Z1、Z2、Z3、Z4each independently selected from CH or N;
the B ring is selected from 5-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aromatic ring, 5-6 membered aromatic heterocycle; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl may be further substituted by one, two or three RBSubstitution;
each RBAre independently selected from hydrogen, halogen, cyano, nitro, ═ O, ═ S and-C1~6Alkyl, halogen substituted-C1~6Alkyl, -OR, -NRR, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl);
l is- (L)A)q-;
q is an integer greater than or equal to 1;
each LAAre respectively and independently selected from CRR, C (O), O, S, S (O), S (O)2NR, -CR ═ CR-, -C.ident.C-, P (O) R, P (O) OR, 3-to 10-membered cycloalkane, 3-to 10-membered heterocycloalkane, 5-to 10-membered aromatic ring, 5-to 10-membered aromatic heterocycle, 5-to 12-membered spiro ring, 5-to 12-membered bridged heterocycle; wherein the cycloalkane, heterocycloalkane, aromatic ring, aromatic heterocycle, spiro ring, spiro heterocycle, bridged ring, bridged heterocycle may be further substituted with one, two or three RLASubstitution;
each RLAAre each independently selected from hydrogen, halogen, ═ O, cyano, nitro, -C1~6Alkyl, halogen substituted-C1~6Alkyl, -OR, -NRR, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl);
each R is independently selected from hydrogen and C1~10Alkyl, halogen substituted-C1~6Alkyl, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl).
2. The bifunctional compound of claim 1, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein:
ring B is selected from
Figure FDA0003199064940000021
3. The bifunctional compound of claim 1, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein:
l is-LA1-LA2-LA3-LA4-LA5-LA6-LA7-;
LA1Is selected from- (C)0~2Alkylene) -;
LA2selected from-NR-, - (5-6 membered heterocycloalkyl) -or none;
LA3selected from- (5-6 membered heterocycloalkyl) -, - (5-10 membered bridged heterocycle) -, - (6-9 membered spiroheterocycle) -, - (C)1~10Alkylene) -NR-, - (5-to 6-membered heterocycloalkyl) -NR-, - (5-to 10-membered bridged heterocycle) -NR-, - (6-to 9-membered spiroheterocycle) -NR-, - (C)0~10Alkylene) -;
LA4selected from-C (O) -, - (5-6 membered heterocycloalkyl) -or none;
LA5is selected from- (C)0~10Alkylene) -or-c (o) -;
LA6selected from-O-, -NR-, or none;
LA7selected from the group consisting of- (CH ≡ CH) -, - (3-to 6-membered cycloalkane) -, - (3-to 6-membered heterocycle) -, - (5-to 6-membered heteroaromatic ring) -, - (6-to 9-membered spirocyclic) -, - (C-to 9-membered spiroheterocyclic ring) -, - (C-to 9-membered spirocyclic ring) -, and0~10alkylene) -or none;
each R is independently selected from hydrogen and C1~10An alkyl group.
4. The bifunctional compound of claim 3, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein:
LA3is selected from
Figure FDA0003199064940000031
Figure FDA0003199064940000032
LA7Is selected from- (CH ≡ CH) -, - (C)0~10Alkylene) -, or,
Figure FDA0003199064940000033
Figure FDA0003199064940000034
Or none.
5. The bifunctional compound of claim 1, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein:
R1is selected from methyl; r2Is selected from methyl; x1Is selected from O; x2Is selected from CH2(ii) a Y is selected from N;
ring A is selected from pyrazole or pyridine; wherein the pyrazole or pyridine may be further substituted by one, two or three RASubstitution; each RAEach independently selected from hydrogen and methyl;
R4、R5each independently selected from hydrogen.
6. The bifunctional compound of claim 1, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein: the compound of formula I is represented by formula IIa:
Figure FDA0003199064940000035
wherein,
R1selected from hydrogen, halogen, ═ O, -C1~6Alkyl, halogen substituted-C1~6Alkyl, -OR, -NRR, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl);
R2selected from hydrogen, halogen, cyano, nitro, -C1~6Alkyl, halogen substituted-C1~6Alkyl, -OR, -NRR, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl);
X1、X2each independently selected from O, S, NRx1、CRx1Rx2
Rx1、Rx2Each independently selected from hydrogen and-C1~6Alkyl, halogen substituted-C1~6Alkyl, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl);
y is selected from N or CRY1
RY1Selected from hydrogen, C1~10Alkyl, halogen substituted-C1~6Alkyl, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl);
the ring A is selected from a benzene ring and a 5-6-membered aromatic heterocycle; wherein the benzene ring and the aromatic heterocyclic ring can be further substituted by one, two or three RASubstitution;
each RAAre respectively and independently selected from hydrogen, halogen, cyano, nitro and-C1~6Alkyl, halogen substituted-C1~6Alkyl, -OR, -NRR, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl);
R4、R50, 1,2 or 3 are respectively independent;
R4、R5are respectively and independently selected from hydrogen, halogen, cyano, nitro and-C1~6Alkyl, halogen substituted-C1~6Alkyl, -OR, -NRR, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl);
Z1、Z2、Z3、Z4each independently selected from CH or N;
l is- (L)A)q-;
q is an integer greater than or equal to 1;
each LAAre respectively and independently selected from CRR, C (O), O, S, S (O), S (O)2NR, -CR ═ CR-, -C.ident.C-, P (O) R, P (O) OR, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, 5-to 10-membered aromatic ring, 5-to 10-membered aromatic heterocycle, 5-to 12-membered spiro ring, 5-to 12-membered bridged heterocycle; wherein the cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle, spiro heterocycle, bridged ring, bridged heterocycle may be further substituted with one, two or three RLASubstitution;
each RLAAre each independently selected from hydrogen, halogen, ═ O, cyano, nitro, -C1~6Alkyl, halogen substituted-C1~6Alkyl, -OR, -NRR, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl);
each R is independently selected from hydrogen and C1~10Alkyl, halogen substituted-C1~6Alkyl, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl).
7. The bifunctional compound of claim 1, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein: the compound of formula I is represented by formula IIb:
Figure FDA0003199064940000051
wherein,
R1selected from hydrogen, halogen, ═ O, -C1~6Alkyl, halogen substituted-C1~6Alkyl, -OR, -NRR, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl);
R2selected from hydrogen, halogen, cyano, nitro, -C1~6Alkyl, halogen substituted-C1~6Alkyl, -OR, -NRR, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl);
X1、X2each independently selected from O, S, NRx1、CRx1Rx2
Rx1、Rx2Each independently selected from hydrogen and-C1~6Alkyl, halogen substituted-C1~6Alkyl, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl);
y is selected from N or CRY1
RY1Selected from hydrogen, C1~10Alkyl, halogen substituted-C1~6Alkyl, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl);
the ring A is selected from a benzene ring and a 5-6-membered aromatic heterocycle; wherein the benzene ring and the aromatic heterocyclic ring can be further substituted by one, two or three RASubstitution;
each RAAre respectively and independently selected from hydrogen, halogen, cyano, nitro and-C1~6Alkyl, halogen substituted-C1~6Alkyl, -OR, -NRR, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl);
R4、R50, 1,2 or 3 are respectively independent;
R4、R5are respectively and independently selected from hydrogen, halogen, cyano, nitro and-C1~6Alkyl, halogen substituted-C1~6Alkyl, -OR, -NRR, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl);
Z1、Z2、Z3、Z4each independently selected from CH or N;
RBselected from hydrogen, halogen, cyano, nitro, ═ O, ═ S and-C1~6Alkyl, halogen substituted-C1~6Alkyl, -OR, -NRR, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl);
l is- (L)A)q-;
q is an integer greater than or equal to 1;
each LAAre respectively and independently selected from CRR, C (O), O, S, S (O), S (O)2NR, -CR ═ CR-, -C.ident.C-, P (O) R, P (O) OR, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, 5-to 10-membered aromatic ring, 5-to 10-membered aromatic heterocycle, 5-to 12-membered spiro ring, 5-to 12-membered bridged heterocycle; wherein the cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle, spiro heterocycle, bridged ring, bridged heterocycle may be further substituted with one, two or three RLASubstitution;
each RLAAre each independently selected from hydrogen, halogen, ═ O, cyano, nitro, -C1~6Alkyl, halogen substituted-C1~6Alkyl, -OR, -NRR, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl);
each R is independently selected from hydrogen and C1~10Alkyl, halogen substituted-C1~6Alkyl, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl).
8. The bifunctional compound of claim 1, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein: the compound of formula I is represented by formula IIc:
Figure FDA0003199064940000061
wherein,
R1selected from hydrogen, halogen, ═ O, -C1~6Alkyl, halogen substituted-C1~6Alkyl, -OR, -NRR, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl);
R2selected from hydrogen, halogen, cyano, nitro, -C1~6Alkyl, halogen substituted-C1~6Alkyl, -OR, -NRR, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl);
X1、X2each independently selected from O, S, NRx1、CRx1Rx2
Rx1、Rx2Each independently selected from hydrogen and-C1~6Alkyl, halogen substituted-C1~6Alkyl, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl);
y is selected from N or CRY1
RY1Selected from hydrogen, C1~10Alkyl, halogen substituted-C1~6Alkyl, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl);
the ring A is selected from a benzene ring and a 5-6-membered aromatic heterocycle; wherein the benzene ring and the aromatic heterocyclic ring can be further substituted by one, two or three RASubstitution;
each RAAre respectively and independently selected from hydrogen, halogen, cyano, nitro and-C1~6Alkyl, halogen substituted-C1~6Alkyl, -OR, -NRR, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl);
R4、R50, 1,2 or 3 are respectively independent;
R4、R5are respectively and independently selected from hydrogen, halogen, cyano, nitro and-C1~6Alkyl, halogen substituted-C1~6Alkyl, -OR, -NRR, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl);
Z1、Z2、Z3、Z4each independently selected from CH or N;
w is selected from C (O), CRR, NR;
l is- (L)A)q-;
q is an integer greater than or equal to 1;
each LAAre respectively and independently selected from CRR, C (O), O, S, S (O), S (O)2NR, -CR ═ CR-, -C.ident.C-, P (O) R, P (O) OR, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, 5-to 10-membered aromatic ring, 5-to 10-membered aromatic heterocycle, 5-to 12-membered spiro ring, 5-to 12-membered bridged heterocycle; wherein the cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle, spiro heterocycle, bridged ring, bridged heterocycle may be further substituted with one, two or three RLASubstitution;
each RLAAre each independently selected from hydrogen, halogen, ═ O, cyano, nitro, -C1~6Alkyl, halogen substituted-C1~6Alkyl, -OR, -NRR, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl);
each R is independently selected from hydrogen and C1~10Alkyl, halogen substituted-C1~6Alkyl, -C0~2Alkylene- (3-to 10-membered cycloalkyl), -C0~2Alkylene- (3-to 10-membered heterocycloalkyl).
9. A bifunctional compound as claimed in claims 6-8, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein:
l is selected from the following groups:
-(C0~2alkylene) - (5-to 6-membered heterocycloalkyl) - (C0~10Alkylene) - (CH ≡ CH) -, C,
-(C0~2Alkylene) - (5-to 6-membered heterocycloalkyl) - (C0~10Alkylene) -, or,
-(C0~2Alkylene) - (5-to 6-membered heterocycloalkyl) - (C0~10Alkylene group) - (C0~10Alkylene) -, or,
-(C0~2Alkylene) - (5-to 6-membered heterocycloalkyl) - (C0~10Alkylene group) - (3-to 6-membered cycloalkane) -, or,
-(C0~2Alkylene) - (5-to 6-membered heterocycloalkyl) - (C0~10Alkylene group) - (3-to 6-membered heterocycle) -, or,
-(C0~2Alkylene) - (5-to 6-membered heterocycloalkyl) - (C0~10Alkylene group) - (5-to 6-membered aromatic heterocycle) -, or,
-(C0~2Alkylene group) - (5-to 6-membered heterocycloalkyl) - (C0~10Alkylene) compounds
-(C0~2Alkylene group) - (5-to 6-membered heterocycloalkyl) - (C0~10Alkylene group) - (5-to 6-membered aromatic heterocycle) -, or,
-(C0~2Alkylene) - (5-to 6-membered heterocycloalkyl) - (C0~2Alkylene) - (5-to 6-membered heterocycloalkyl) - (C0~10Alkylene group) - (5-to 6-membered aromatic heterocycle) -, or,
-(C0~2Alkylene) - (5-to 6-membered heterocycloalkyl) - (C0~10Alkylene) -O-),
-(C0~2Alkylene) - (5-to 6-membered heterocycloalkyl) - (C0~10Alkylene) -O- (3-to 6-membered cycloalkane) -, and,
-(C0~2Alkylene) - (5-to 6-membered heterocycloalkyl) - (C0~10Alkylene) -O- (C)0~10Alkylene) -, or,
-(C0~2Alkylene) - (5-to 6-membered heterocycloalkyl) - (C0~10Alkylene group) - (6-to 9-membered spiroheterocycle) -, or,
-(C0~2Alkylene) - (5-to 6-membered heterocycloalkyl) -C (O) - (C)0~10Alkylene) - (CH ≡ CH) -, C,
-(C0~2Alkylene) - (5-to 6-membered heterocycloalkyl) -C (O) - (C)0~10Alkylene) -, or,
-(C0~2Alkylene) - (5-to 6-membered heterocycloalkyl) -C (O) - (C)0~10Alkylene) -, or,
-(C0~2Alkylene) - (5-to 6-membered heterocycloalkyl) - (C0~2Alkylene) - (5-to 6-membered heterocycloalkyl) -C (O) - (C)0~2Alkylene) -O-),
-(C0~2Alkylene) - (5-to 6-membered heterocycloalkyl) -C (O) - (C)0~10Alkylene group) - (3-to 6-membered cycloalkane) -, or,
-(C0~2Alkylene) - (5-to 6-membered heterocycloalkyl) -C (O) - (C)0~10Alkylene group) - (3-to 6-membered heterocycle) -, or,
-(C0~2Alkylene) - (5-to 6-membered heterocycloalkyl) -C (O) - (C)0~10Alkylene) - (5-to 6-membered aromatic heterocycle) -.
10. The bifunctional compound of claim 9, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein: the method is characterized in that:
R1is selected from methyl; r2Is selected from methyl; x1Is selected from O; x2Is selected from CH2(ii) a Y is selected from N;
ring A is selected from pyrazole or pyridine; wherein the pyrazole or pyridine may be further substituted by one, two or three RASubstitution; each RAEach independently selected from hydrogen and methyl;
R4、R5each independently selected from hydrogen;
w is selected from C (O), CH2、NH;
RBIs selected from methyl;
l is selected from the following linking groups:
-(C0~1alkylene) - (piperazine) - (C0~10Alkylene) - (CH ≡ CH) -, C,
-(C0~1Alkylene) - (piperazine) - (C0~10Alkylene) -, or,
-(C0~1Alkylene) - (piperazine) - (C0~10Alkylene group) - (C0~10Alkylene) -, or,
-(C0~1Alkylene) - (piperazine) - (C0~10Alkylene) -, or,
-(C0~1Alkylene) - (piperazine) - (C0~10Alkylene) - (pyrazole) -,
-(C0~1alkylene) - (piperazine) - (C0~2Alkylene) - (piperazine) - (C0~10Alkylene) - (pyrazole) -,
-(C0~1alkylene) -piperazine-cyclobutane-s,
-(C0~1Alkylene) - (piperazine) - (cyclobutylamine) -,
-(C0~1alkylene) - (1.2.5.6-tetrahydropyridine) - (C)0~10Alkylene) -, or,
-(C0~1Alkylene) - (piperidine) - (C)0~10Alkylene) -, or,
-(C0~1Alkylene) - (piperazine) - (C0~10Alkylene) - (piperidine) -
-(C0~1Alkylene) - (piperazine) -C (O) - (C)0~10Alkylene) compounds
-(C0~1Alkylene) - (piperazine) - (C0~10Alkylene) - (tetrahydropyrrole) -C (O) - (C)0~10Alkylene) -O-),
-(C0~1Alkylene) - (piperazine) -C (O) - (C)0~10Alkylene) - (CH ≡ CH) -, C,
-(C0~1Alkylene) - (piperazine) -C (O) - (C)0~10Alkylene) -, or,
-(C0~1Alkylene) - (piperazine) - (C0~10Alkylene) - (pyrazole) -,
-(C0~1alkylene) - (piperazine) -C (O) - (C)0~10Alkylene) - (pyrazole) -,
-(C0~1alkylene) - (piperazine) - (C0~10Alkylene) -O-),
-(C0~1Alkylene) - (piperazine) - (C0~10Alkylene) -O- (C)1~10Alkylene) s (a),
-(C0~1Alkylene) - (piperazine) - (C0~10Alkylene) -O- (3-to 4-membered cycloalkane) -, and,
-(C0~1Alkylene) - (piperazine) - (C0~10Alkylene) - (2-azaspiro [ 3.3)]Heptane) -.
11. A bifunctional compound as claimed in claims 1-5, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein: the compound is specifically:
Figure FDA0003199064940000091
Figure FDA0003199064940000101
Figure FDA0003199064940000111
Figure FDA0003199064940000121
Figure FDA0003199064940000131
Figure FDA0003199064940000141
Figure FDA0003199064940000151
Figure FDA0003199064940000161
Figure FDA0003199064940000171
Figure FDA0003199064940000181
Figure FDA0003199064940000191
Figure FDA0003199064940000201
Figure FDA0003199064940000211
Figure FDA0003199064940000221
Figure FDA0003199064940000231
Figure FDA0003199064940000241
Figure FDA0003199064940000251
Figure FDA0003199064940000261
Figure FDA0003199064940000271
Figure FDA0003199064940000281
Figure FDA0003199064940000291
12. use of the bifunctional compound of any one of claims 1-11, or a stereoisomer, a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a tumor or cancer.
13. A composition comprising a bifunctional compound of any one of claims 1-11, or a stereoisomer, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
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