WO2017054702A1

WO2017054702A1 - Biphenyl derivative and preparation method and use thereof in medicine

Info

Publication number: WO2017054702A1
Application number: PCT/CN2016/100307
Authority: WO
Inventors: 郑苏欣; 张国彪; 张晓波; 王文晶; 李航; 杜勇; 邱关鹏; 魏用刚
Original assignee: 四川海思科制药有限公司
Priority date: 2015-09-28
Filing date: 2016-09-27
Publication date: 2017-04-06
Also published as: CN107849047B; CN107849047A

Abstract

The present invention relates to a biphenyl derivative and a preparation method and a use thereof in medicine, in particular relates to a compound shown by general formula (I) or a stereomer, a hydrate, a metabolite, a solvate, a pharmaceutically acceptable salt, an eutectic or a prodrug thereof, and a preparation method and a use in the preparation of drugs for treating obstructive airways disorders, wherein the compound of formula (I) is as shown in the figure. The definitions of the substituents are the same as defined in the description.

Description

一种联苯衍生物及其制备方法和在医药上的用途Biphenyl derivative, preparation method thereof and use in medicine

技术领域Technical field

本发明涉及一种联苯衍生物及其制备方法和在医药上的应用，具体是一种具有蕈毒碱受体拮抗活性的新颖哌啶衍生物或其立体异构体、水合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药、其药物组合物以及其制备方法和在医药上的应用。The invention relates to a biphenyl derivative, a preparation method thereof and application in medicine, in particular to a novel piperidine derivative having muscarinic receptor antagonistic activity or a stereoisomer, hydrate or solvate thereof. , metabolites, pharmaceutically acceptable salts, eutectic or prodrugs, pharmaceutical compositions thereof, as well as methods for their preparation and use in medicine.

背景技术Background technique

支气管扩张剂对于呼吸疾病例如慢性阻塞性肺疾病(COPD)及哮喘等的治疗起重要作用。蕈毒碱受体(M受体)拮抗剂通过降低气道平滑肌的迷走神经胆碱能水平来发挥支气管扩张的效力。基于治疗的效果和副作用，首选吸入的M受体拮抗剂，而非口服。目前临床中使用的吸入M受体拮抗剂包括异丙托溴铵、氧托溴铵、格隆溴铵、噻托溴铵、阿地溴胺和芜地溴胺。其中异丙托溴铵和氧托溴铵为短效药物，需要每天多次给药，给患者带来不便，由于频繁给药可能导致顺应性差，从而有治疗不充分的风险。阿地溴胺每天给药两次，可能会引起严重的不良反应，其中包括矛盾性支气管痉挛、新发窄角型青光眼或加重、新发尿潴留或加重，并且不宜用于18岁以下的患者。部分M受体拮抗剂通过吸入给药，也有部分药物进入循环***，从而导致***副作用如口干、胃肠道症状、尿潴留以及***等。这类药物如格隆溴铵和噻托溴铵。Bronchodilators play an important role in the treatment of respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma. A muscarinic receptor (M receptor) antagonist exerts potency in bronchiectasis by reducing the level of vagal cholinergic energy in airway smooth muscle. Based on the effects and side effects of the treatment, the inhaled M receptor antagonist is preferred, but not orally. Inhaled M receptor antagonists currently used in the clinic include ipratropium bromide, oxitropium bromide, glycopyrrolate, tiotropium bromide, adiponium bromide and indole bromide. Among them, ipratropium bromide and oxitropium bromide are short-acting drugs, which need to be administered several times a day, which brings inconvenience to patients, and frequent administration may result in poor compliance, and thus there is a risk of inadequate treatment. Adipramine is administered twice daily and may cause serious adverse reactions, including contradictory bronchospasm, new-angled glaucoma or aggravation, new urinary retention or exacerbation, and should not be used in patients under 18 years of age. . Some M receptor antagonists are administered by inhalation, and some drugs enter the circulatory system, leading to systemic side effects such as dry mouth, gastrointestinal symptoms, urinary retention, and urinary tract infections. Such drugs are glycopyrrolate and tiotropium bromide.

目前，临床中使用的M受体拮抗剂对M受体的亚型(M1,M2,M3,M4和M5)的选择性不高，其进入循环***后，引发不良反应。如M2受体在心脏中也广泛地表达，产生负性心率和负性肌力的作用，抑制心脏M2受体可引发心脏有关的疾病。因此，对于哮喘和COPD等气道阻塞性疾病而言，更佳的M受体拮抗剂应当是对M1和M3亲和性较高，对M2的亲和性较差。At present, the M receptor antagonists used in the clinic are not highly selective for the M receptor subtypes (M1, M2, M3, M4 and M5), and after entering the circulatory system, an adverse reaction is caused. For example, the M2 receptor is also widely expressed in the heart, producing a negative heart rate and a negative inotropic effect, and inhibition of the cardiac M2 receptor can cause a heart-related disease. Therefore, for airway obstructive diseases such as asthma and COPD, a better M receptor antagonist should have a higher affinity for M1 and M3 and a lower affinity for M2.

因此，有必要开发新颖的具有M受体拮抗活性药物，特别是通过吸入给药具有高效价、作用时间长、减少***副作用和/或高选择性M1/M2、M3/M2的新型M受体拮抗活性药物。为患者提供更多的临床用药选择。Therefore, it is necessary to develop novel M receptor-reactive active drugs, especially by inhalation of novel M receptors with high titer, long acting time, reduced system side effects and/or high selectivity M1/M2, M3/M2. Antagonistic active drugs. Provide patients with more clinical medication options.

WO2005087737A1中描述了一类联苯衍生物，具有M受体拮抗活性的化合物，其通式为

与本发明的不同。WO2005087737A1 describes a class of biphenyl derivatives, compounds having M receptor antagonistic activity, which have the general formula

Different from the present invention.

WO2005087736A1中描述了一类联苯衍生物，具有M受体拮抗活性的化合物，其通式为

与本发明不同。WO2005087736A1 describes a class of biphenyl derivatives, compounds having M receptor antagonistic activity, the general formula of which is

Different from the present invention.

发明内容Summary of the invention

本发明提供一种通式(I)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，The present invention provides a compound represented by the formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof.

其中：among them:

a选自0、1、2、3、4或5；a is selected from 0, 1, 2, 3, 4 or 5;

b选自0、1、2、3或4；b is selected from 0, 1, 2, 3 or 4;

c选自0、1或2；c is selected from 0, 1 or 2;

d或e各自独立选自0或1；d or e are each independently selected from 0 or 1;

R¹、R²每个各自独立的选自F、Cl、Br、I、CF₃、氰基、C_1-4烷基、C_2-4烯基、C_2-4炔基、C_3-6环烷基、-OR^1a、-C(O)OR^1b、-SR^1c、-S(＝O)R^1d、-S(＝O)₂R^1e或-NR^1fR^1g；R ¹ and R ² are each independently selected from the group consisting of F, Cl, Br, I, CF ₃ , cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _{3- 6} cycloalkyl, -OR ^1a , -C(O)OR ^1b , -SR ^1c , -S(=O)R ^1d , -S(=O) ₂ R ^1e or -NR ^1f R ^1g ;

R^1a、R^1b、R^1c、R^1d、R^1e、R^1f和R^1g各自独立的选自H或C_1-4烷基；R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f and R ^1g are each independently selected from H or C _1-4 alkyl;

W选自-O-、-NH-或者-NC_1-4烷基-；W is selected from -O-, -NH- or -NC _1-4 alkyl-;

环A选自

且N对位的碳原子与W直接相连，所述的

任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、CF₃、OH、氰基、C_1-4烷基或C_1-4烷氧基的取代基所取代；Ring A is selected from

And the N-position carbon atom is directly connected to W, said

Optionally further substituted by 0, 1, ₂ , ₃ , 4 or 5 selected from F, Cl, Br, I, CF ₃ , OH, cyano, C _1-4 alkyl or C _1-4 alkoxy Substituted by

Q选自键、-O-、-C(＝O)-、-C(＝O)NR^q-、-NR^qC(＝O)-、-OC(＝O)NR^q-或-NR^qC(＝O)O-；Q is selected from a bond, -O-, -C(=O)-, -C(=O)NR ^q -, -NR ^q C(=O)-, -OC(=O)NR ^q - or -NR ^q C(=O)O-;

R^q各自独立的选自H、C_1-4烷基或者C_3-6环烷基；R ^{q is} independently selected from H, C _1-4 alkyl or C _3-6 cycloalkyl;

环B选自C_6-12碳环或5至12元杂环，所述的碳环或杂环可以是单环，也可以是双环，所述的碳环或杂环任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、CF₃、＝O、OH、氰基、NH₂、C_1-4烷基、C_1-4烷氧基或C_2-4炔基的取代基所取代，且所述的杂环含有1、2或3个任选自N、O或S的杂原子；Ring B is selected from a C _6-12 carbocyclic ring or a 5 to 12 membered heterocyclic ring, and the carbocyclic or heterocyclic ring may be a monocyclic ring or a bicyclic ring, and the carbocyclic or heterocyclic ring may be further further 0. 1, 2, 3, 4 or 5 are selected from the group consisting of F, Cl, Br, I, CF ₃ , =0, OH, cyano, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy or C Substituted with a substituent of _2-4 alkynyl, and said heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S;

环C选自4至10元的含氮杂环，所述的含杂氮杂任选进一步被0、1、2、3、4或5个选自R^c的取代基所取代，且所述含氮杂环含有1、2或3个任选自N、O或S的杂原子； Ring C is selected from a 4 to 10 membered nitrogen-containing heterocyclic ring, and said aza-containing heterocyclic ring is optionally further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from R ^c , and said The nitrogen-containing heterocycle contains 1, 2 or 3 heteroatoms selected from N, O or S;

R^c各自独立的选自＝O、F、Cl、Br、I、CF₃、OH、氰基、NH₂、C_1-4烷基、C_3-6环烷基、C_1-4烷氧基、C_1-4烷硫基、-C(＝O)C_1-4烷基、-NHC_1-4烷基或-N(C_1-4烷基)₂；R ^{c is} independently selected from the group consisting of =O, F, Cl, Br, I, CF ₃ , OH, cyano, NH ₂ , C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 alkoxy a group, C _1-4 alkylthio, -C(=O)C _1-4 alkyl, -NHC _1-4 alkyl or -N(C _1-4 alkyl) ₂ ;

R³各自独立的选自OH、C_1-4烷基、C_3-6环烷基、C_1-4烷氧基、-NR^3aR^3b或-C_1-4烷基-NR^3aR^3b；R ^{3 is} independently selected from OH, C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, -NR ^3a R ^3b or -C _1-4 alkyl-NR ^3a R ^3b ;

R^3a、R^3b各自独立的选自H、C_1-4烷基或C_3-6环烷基；R ^3a and R ^3b are each independently selected from H, C _1-4 alkyl or C _3-6 cycloalkyl;

作为选择，R^3a、R^3b与其连接的原子一起形成一个3至6元的含氮杂环，或者R^3a与R^c直接相连形成一个3至6元的含氮杂环；Alternatively, R ^3a , R ^3b together with the atoms to which they are attached form a 3 to 6 membered nitrogen-containing heterocyclic ring, or R ^3a is directly bonded to R ^c to form a 3 to 6 membered nitrogen-containing heterocyclic ring;

条件是，当环A选自

且环B选自苯环或单环杂环，同时R³选自-NR^3aR^3b，R^3a与R^c不直接相连形成一个3至6元的含氮杂环时，环C不能为

q选自0、1、2或3；Condition is when ring A is selected from

And ring B is selected from a benzene ring or a monocyclic hetero ring, and R ^{3 is} selected from -NR ^3a R ^3b , and when R ^3a and R ^{c are} not directly bonded to form a 3 to 6 membered nitrogen-containing hetero ring, ring C cannot be

q is selected from 0, 1, 2 or 3;

本发明的一种优选方案，提供一种通式(II)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药：According to a preferred embodiment of the present invention, there is provided a compound of the formula (II): or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof:

其中：among them:

a选自0、1、2、3、4或5；a is selected from 0, 1, 2, 3, 4 or 5;

b选自0、1、2、3或4；b is selected from 0, 1, 2, 3 or 4;

c选自0、1或2；c is selected from 0, 1 or 2;

R¹、R²每个各自独立的选自F、Cl、Br、I、CF₃、氰基、C_1-4烷基、C_2-4烯基、C_2-4炔基、C_3-6环烷基、-OR^1a、-C(O)OR^1b、-SR^1c、-S(＝O)R^1d、-S(＝O)₂R^1e或-NR^1fR^1g，优选F、Cl、Br、I、CF₃、氰基、-OR^1a、甲基、乙基、乙炔基、环丙基或环丁基；R ¹ and R ² are each independently selected from the group consisting of F, Cl, Br, I, CF ₃ , cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _{3- 6} cycloalkyl, -OR ^1a , -C(O)OR ^1b , -SR ^1c , -S(=O)R ^1d , -S(=O) ₂ R ^1e or -NR ^1f R ^1g , preferably F, Cl , Br, I, CF ₃ , cyano, -OR ^1a , methyl, ethyl, ethynyl, cyclopropyl or cyclobutyl;

R^1a、R^1b、R^1c、R^1d、R^1e、R^1f和R^1g各自独立的选自H或C_1-4烷基，优选H、甲基或乙基；R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f and R ^1g are each independently selected from H or C _1-4 alkyl, preferably H, methyl or ethyl;

W选自-O-、-NH-或者-NC_1-4烷基-，优选-O-、-NH-或-NCH₃-；W is selected from -O-, -NH- or -NC _1-4 alkyl-, preferably -O-, -NH- or -NCH ₃ -;

环A选自

且N对位的碳原子与W直接相连，所述的

任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、CF₃、 OH、氰基、C_1-4烷基或C_1-4烷氧基的取代基所取代，优选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、CF₃、OH、氰基、甲基、乙基、甲氧基或乙氧基的取代基所取代；Ring A is selected from

And the N-position carbon atom is directly connected to W, said

Optionally further substituted by 0, 1, ₂ , ₃ , 4 or 5 selected from F, Cl, Br, I, CF ₃ , OH, cyano, C _1-4 alkyl or C _1-4 alkoxy Substituted, preferably further 0, 1, ₂ , ₃ , 4 or 5 selected from the group consisting of F, Cl, Br, I, CF ₃ , OH, cyano, methyl, ethyl, methoxy or ethoxy Substituted by a substituent;

R^q各自独立的选自H、C_1-4烷基或者C_3-6环烷基，优选H、甲基、乙基、丙基、环丙基或者环丁基；R ^{q is} independently selected from H, C _1-4 alkyl or C _3-6 cycloalkyl, preferably H, methyl, ethyl, propyl, cyclopropyl or cyclobutyl;

环C选自

所述的

任选进一步被0、1、2、3、4或5个选自R^c的取代基所取代；Ring C is selected from

Said

Optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from R ^c ;

R^c各自独立的选自＝O、F、Cl、Br、I、CF₃、OH、氰基、NH₂、C_1-4烷基、C_3-6环烷基、C_1-4烷氧基、C_1-4烷硫基、-C(＝O)C_1-4烷基、-NHC_1-4烷基或-N(C_1-4烷基)₂优选＝O、F、Cl、Br、I、CF₃、OH、氰基、NH₂、甲基、乙基、环丙基、环丁基、甲氧基、乙氧基、甲硫基、-C(＝O)CH₃、-C(＝O)CH₂CH₃、-NHCH₃、-N(CH₃)₂、-NHCH₂CH₃或-N(CH₂CH₃)₂、；R ^{c is} independently selected from the group consisting of =O, F, Cl, Br, I, CF ₃ , OH, cyano, NH ₂ , C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 alkoxy , C _1-4 alkylthio, -C(=O)C _1-4 alkyl, -NHC _1-4 alkyl or -N(C _1-4 alkyl) ₂ preferably =O, F, Cl, Br, I, CF ₃ , OH, cyano, NH ₂ , methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, methylthio, -C(=O)CH ₃ , -C(=O)CH ₂ CH ₃ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH ₂ CH ₃ or -N(CH ₂ CH ₃ ) ₂ ,;

Ar¹选自苯环、噻吩环、呋喃环或吡咯环，优选苯环，所述的苯环、噻吩环、呋喃环或吡咯环任选进一步被0、1、2、3或4个选自F、Cl、Br、I、CF₃、OH、氰基、NH₂、C_1-4烷基、C_1-4烷氧基或C_2-4炔基的取代基所取代，优选进一步被0、1、2、3或4个F、Cl、Br、I、CF₃、OH、氰基、NH₂、甲基、乙基、甲氧基、乙氧基或乙炔基的取代基所取代；Ar ^{1 is} selected from a benzene ring, a thiophene ring, a furan ring or a pyrrole ring, preferably a benzene ring, and the benzene ring, thiophene ring, furan ring or pyrrole ring is optionally further selected from 0, 1, 2, 3 or 4 Substituted with a substituent of F, Cl, Br, I, CF ₃ , OH, cyano, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy or C _2-4 alkynyl, preferably further Substituting 1, 1, 2, 3 or 4 substituents of F, Cl, Br, I, CF ₃ , OH, cyano, NH ₂ , methyl, ethyl, methoxy, ethoxy or ethynyl;

R³各自独立的选自OH、C_1-4烷基、C_3-6环烷基、C_1-4烷氧基、-NR^3aR^3b或-C_1-4烷基-NR^3aR^3b，优选OH、甲基、乙基、环丙基、环丁基、甲氧基、乙氧基、-NR^3aR^3b、-CH₂-NR^3aR^3b或-CH₂CH₂-NR^3aR^3b；R ^{3 is} independently selected from OH, C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, -NR ^3a R ^3b or -C _1-4 alkyl-NR ^3a R ^3b Preferred is OH, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, -NR ^3a R ^3b , -CH ₂ -NR ^3a R ^3b or -CH ₂ CH ₂ -NR ^3a R ^3b ;

R^3a、R^3b各自独立的选自H、C_1-4烷基或C_3-6环烷基，优选H、甲基、乙基、环丙基或环丁基；R ^3a and R ^3b are each independently selected from H, C _1-4 alkyl or C _3-6 cycloalkyl, preferably H, methyl, ethyl, cyclopropyl or cyclobutyl;

条件是，当环A选自

Condition is when ring A is selected from

本发明的一种优选方案，一种通式(II)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药：A preferred embodiment of the invention, a compound of the formula (II) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof:

a、b均为0；a, b are 0;

c选自0、1或2；c is selected from 0, 1 or 2;

W选自-O-、-NH-或-NCH₃-；W is selected from -O-, -NH- or -NCH ₃ -;

环A选自

且N对位的碳原子与W直接相连；Ring A is selected from

And the N-position carbon atom is directly connected to W;

R^q各自独立的选自H、甲基、乙基、丙基、环丙基或者环丁基；R ^{q is} independently selected from H, methyl, ethyl, propyl, cyclopropyl or cyclobutyl;

环C选自

所述的

任选进一步被0、1、2、3、4或5个选自R^c的取代基所取代，当环C选自

时，N直接与

连接；Ring C is selected from

Said

Optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from R ^c when ring C is selected from

When N is directly

connection;

R^c各自独立的选自＝O、F、Cl、Br、I、CF₃、OH、氰基、NH₂、甲基、乙基、环丙基、环丁基、甲氧基、乙氧基、甲硫基、-C(＝O)CH₃、-C(＝O)CH₂CH₃、-NHCH₃、-N(CH₃)₂、-NHCH₂CH₃或-N(CH₂CH₃)₂；R ^{c is} independently selected from the group consisting of =O, F, Cl, Br, I, CF ₃ , OH, cyano, NH ₂ , methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy. , methylthio, -C(=O)CH ₃ , -C(=O)CH ₂ CH ₃ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH ₂ CH ₃ or -N(CH ₂ CH ₃ ₂ ) ;

Ar¹选自苯环、噻吩环、呋喃环或吡咯环，优选苯环，所述的苯环、噻吩环、呋喃环或吡咯环任选进一步被0、1、2、3或4个选自F、Cl、Br、I、CF₃、OH、氰基、NH₂、甲基、乙基、甲氧基、乙氧基或乙炔基的取代基所取代；Ar ^{1 is} selected from a benzene ring, a thiophene ring, a furan ring or a pyrrole ring, preferably a benzene ring, and the benzene ring, thiophene ring, furan ring or pyrrole ring is optionally further selected from 0, 1, 2, 3 or 4 Substituted with a substituent of F, Cl, Br, I, CF ₃ , OH, cyano, NH ₂ , methyl, ethyl, methoxy, ethoxy or ethynyl;

R³各自独立的选自OH、甲基、乙基、环丙基、环丁基、甲氧基、乙氧基、-NR^3aR^3b、-CH₂-NR^3aR^3b或-CH₂CH₂-NR^3aR^3b；R ^{3 is} independently selected from OH, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, -NR ^3a R ^3b , -CH ₂ -NR ^3a R ^3b or -CH ₂ CH ₂ -NR ^3a R ^3b ;

R^3a、R^3b各自独立的选自H、甲基、乙基、环丙基或环丁基；R ^3a and R ^3b are each independently selected from the group consisting of H, methyl, ethyl, cyclopropyl or cyclobutyl;

条件是，当环A选自

Condition is when ring A is selected from

本发明的一种优选方案，提供一种通式(III)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药：According to a preferred embodiment of the present invention, there is provided a compound of the formula (III): or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof:

其中：among them:

a选自0、1、2、3、4或5；a is selected from 0, 1, 2, 3, 4 or 5;

b选自0、1、2、3或4；b is selected from 0, 1, 2, 3 or 4;

c选自0、1或2；c is selected from 0, 1 or 2;

n选自0、1、2或3；n is selected from 0, 1, 2 or 3;

R^1a、R^1b、R^1c、R^1d、R^1e、R^1f和R^1g各自独立的选自H或C_1-4烷基，优选H、甲基或乙基； R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f and R ^1g are each independently selected from H or C _1-4 alkyl, preferably H, methyl or ethyl;

环A选自

且N对位的碳原子与W直接相连，所述的

任选进一步被被0、1、2、3、4或5个选自F、Cl、Br、I、CF₃、OH、氰基、C_1-4烷基或C_1-4烷氧基的取代基所取代，优选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、CF₃、OH、氰基、甲基、乙基、甲氧基或乙氧基的取代基所取代；Ring A is selected from

And the N-position carbon atom is directly connected to W, said

Optionally further being 0, 1, ₂ , ₃ , 4 or 5 selected from the group consisting of F, Cl, Br, I, CF ₃ , OH, cyano, C _1-4 alkyl or C _1-4 alkoxy Substituted by a substituent, preferably further selected from 0, 1, ₂ , ₃ , 4 or 5 selected from the group consisting of F, Cl, Br, I, CF ₃ , OH, cyano, methyl, ethyl, methoxy or ethoxy Substituted by a substituent of the group;

环D选自C_4-7碳环或者4至7元杂环，所述的碳环或者杂环任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、CF₃、＝O、OH、NH₂、氰基、C_1-4烷基、C_1-4烷氧基或C_2-4炔基的取代基所取代，优选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、CF₃、＝O、OH、NH₂、氰基、甲基、乙基、甲氧基、乙氧基或乙炔基的取代基所取代，所述的杂环含有1、2或3个任选自N、O或S的杂原子；Ring D is selected from a C _4-7 carbocyclic ring or a 4 to 7 membered heterocyclic ring, and the carbocyclic or heterocyclic ring is optionally further 0, 1, 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br, Substituting for a substituent of I, CF ₃ , =O, OH, NH ₂ , cyano, C _1-4 alkyl, C _1-4 alkoxy or C _2-4 alkynyl, preferably further by 0, 1. 2, 3, 4 or 5 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , =O, OH, NH ₂ , cyano, methyl, ethyl, methoxy, ethoxy or ethynyl Substituted, the heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O or S;

R⁴各自独立的选自F、Cl、Br、I、CF₃、OH、NH₂、氰基、C_1-4烷基、C_1-4烷氧基或C_2-4炔基，优选F、Cl、Br、I、CF₃、OH、氰基、NH₂、甲基、乙基、甲氧基、乙氧基或乙炔基；R ^{4 is} independently selected from the group consisting of F, Cl, Br, I, CF ₃ , OH, NH ₂ , cyano, C _1-4 alkyl, C _1-4 alkoxy or C _2-4 alkynyl, preferably F , Cl, Br, I, CF ₃ , OH, cyano, NH ₂ , methyl, ethyl, methoxy, ethoxy or ethynyl;

环C选自

所述的

任选进一步被0、1、2、3、4或5个选自R^c的取代基所取代，且所述含氮杂环含有1、2或3个任选自N、O或S的杂原子； Ring C is selected from

Said

Optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from R ^c , and the nitrogen-containing heterocycle contains 1, 2 or 3 heterologously selected from N, O or S atom;

R^c各自独立的选自F、Cl、Br、I、CF₃、OH、氰基、NH₂、C_1-4烷基、C_3-6环烷基、C_1-4烷氧基、C_1-4烷硫基、-NHC_1-4烷基或-N(C_1-4烷基)₂，优选F、Cl、Br、I、CF₃、OH、氰基、NH₂、甲基、乙基、环丙基、环丁基、甲氧基、乙氧基、甲硫基、-NHCH₃、-N(CH₃)₂、-NHCH₂CH₃或-N(CH₂CH₃)₂；R ^{c is} independently selected from the group consisting of F, Cl, Br, I, CF ₃ , OH, cyano, NH ₂ , C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, C _1-4 alkylthio, -NHC _1-4 alkyl or -N(C _1-4 alkyl) ₂ , preferably F, Cl, Br, I, CF ₃ , OH, cyano, NH ₂ , methyl, Ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, methylthio, -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH ₂ CH ₃ or -N(CH ₂ CH ₃ ) ₂ ;

R³各自独立的选自OH、C_1-4烷基、C_3-6环烷基、C_1-4烷氧基、-NR^3aR^3b或-C_1-4烷基-NR^3aR^3b，优选OH、甲基、乙基、环丙基、环丁基、甲氧基、乙氧基、-NR^3aR^3b、-CH₂-NR^3aR^3b或-CH₂CH₂-NR^3aR^3b；R ^{3 is} independently selected from OH, C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, -NR ^3a R ^3b or -C _1-4 alkyl-NR ^3a R ^3b , preferably OH, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ^{^{_{ethoxy, -NR 3a R 3b, -CH 2}}} -NR 3a R 3b or -CH _₂ CH ₂ -NR ^3a R ^3b ;

作为选择，R^3a、R^3b与其连接的原子一起形成一个3至6元的含氮杂环，或者R^3a与R^c直接相连形成一个3至6元的含氮杂环。Alternatively, R ^3a , R ^3b together with the atoms to which they are attached form a 3 to 6 membered nitrogen-containing heterocyclic ring, or R ^3a and R ^{c are} directly bonded to form a 3 to 6 membered nitrogen-containing heterocyclic ring.

本发明的一种优选方案，一种通式(III)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药：A preferred embodiment of the invention, a compound of the formula (III) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof:

a、b均为0；a, b are 0;

c选自0、1或2；c is selected from 0, 1 or 2;

n选自0、1、2或3；n is selected from 0, 1, 2 or 3;

W选自-O-、-NH-或-NCH₃-；W is selected from -O-, -NH- or -NCH ₃ -;

环A选自

且N对位的碳原子与W直接相连；Ring A is selected from

And the N-position carbon atom is directly connected to W;

环D选自C_4-7碳环或者4至7元杂环，优选4至7元杂环，所述的碳环或者杂环任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、CF₃、＝O、OH、氰基、NH₂、甲基、乙基、甲氧基、乙氧基或乙炔基的取代基所取代，所述的杂环含有1、2或3个任选自N、O或S的杂原子；Ring D is selected from a C _4-7 carbocyclic ring or a 4 to 7 membered heterocyclic ring, preferably a 4 to 7 membered heterocyclic ring, optionally further 0, 1, 2, 3, 4 or 5 Substituted with a substituent selected from the group consisting of F, Cl, Br, I, CF ₃ , =0, OH, cyano, NH ₂ , methyl, ethyl, methoxy, ethoxy or ethynyl, said hetero The ring contains 1, 2 or 3 heteroatoms selected from N, O or S;

R⁴各自独立的选自F、Cl、Br、I、CF₃、OH、氰基、NH₂、甲基、乙基、甲氧基、乙氧基或乙炔基；R ^{4 is} each independently selected from the group consisting of F, Cl, Br, I, CF ₃ , OH, cyano, NH ₂ , methyl, ethyl, methoxy, ethoxy or ethynyl;

环C选自

所述的

任选进一步被0至5个选自R^c的取代基所取代；Ring C is selected from

Said

Optionally further substituted with 0 to 5 substituents selected from R ^c ;

R^c各自独立的选自F、Cl、Br、I、CF₃、OH、氰基、NH₂、甲基、乙基、环丙基、环丁基、甲氧基、乙氧基、甲硫基、-NHCH₃、-N(CH₃)₂、-NHCH₂CH₃或-N(CH₂CH₃)₂；R ^{c is} independently selected from the group consisting of F, Cl, Br, I, CF ₃ , OH, cyano, NH ₂ , methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, methylthio a group, -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH ₂ CH ₃ or -N(CH ₂ CH ₃ ) ₂ ;

R³各自独立的选自OH、甲基、乙基、环丙基、环丁基、甲氧基、乙氧基、-NR^3aR^3b、-CH₂-NR^3aR^3b或-CH₂CH₂-NR^3aR^3b；R ^{3 is} independently selected from OH, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, -NR ^3a R ^3b , -CH ₂ -NR ^3a R ^3b or -CH ₂ CH ₂ -NR ^3a R ^3b;

R^3a、R^3b各自独立的选自H、甲基、乙基、环丙基或者环丁基；R ^3a and R ^3b are each independently selected from the group consisting of H, methyl, ethyl, cyclopropyl or cyclobutyl;

本发明优选方案，提供一种通式(IV)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，According to a preferred embodiment of the present invention, there is provided a compound of the formula (IV): or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof;

其中：among them:

a选自0、1、2、3、4或5；a is selected from 0, 1, 2, 3, 4 or 5;

b选自0、1、2、3或4；b is selected from 0, 1, 2, 3 or 4;

c选自0、1或2；c is selected from 0, 1 or 2;

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

m为0、1、2或3；m is 0, 1, 2 or 3;

Ar²选自苯环、噻吩环、呋喃环或吡咯环，优选苯环，所述的苯环、噻吩环、呋喃环或吡咯环任选进一步被0、1、2、3或4个选自F、Cl、Br、I、CF₃、OH、氰基、NH₂、C_1-4烷基、C_1-4烷氧基或C_2-4炔基的取代基所取代，优选进一步被0、1、2、3或4个选自F、Cl、Br、I、CF₃、OH、氰基、NH₂、甲基、乙基、甲氧基、乙氧基或乙炔基的取代基所取代；Ar ^{2 is} selected from a benzene ring, a thiophene ring, a furan ring or a pyrrole ring, preferably a benzene ring, and the benzene ring, thiophene ring, furan ring or pyrrole ring is optionally further selected from 0, 1, 2, 3 or 4 Substituted with a substituent of F, Cl, Br, I, CF ₃ , OH, cyano, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy or C _2-4 alkynyl, preferably further 1, 2, 3 or 4 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , OH, cyano, NH ₂ , methyl, ethyl, methoxy, ethoxy or ethynyl Replace

R⁵选自F、Cl、Br、I、CF₃、OH、氰基、NH₂、C_1-4烷基、C_3-6环烷基、C_1-4烷氧基、C_1-4烷硫基、-NHC_1-4烷基或-N(C_1-4烷基)₂，优选F、Cl、Br、I、CF₃、OH、氰基、NH₂、甲基、乙基、环丙基、环丁基、甲氧基、乙氧基、甲硫基、-NHCH₃、-N(CH₃)₂、-NHCH₂CH₃或-N(CH₂CH₃)₂；R ^{5 is} selected from the group consisting of F, Cl, Br, I, CF ₃ , OH, cyano, NH ₂ , C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, C _1-4 Alkylthio, -NHC _1-4 alkyl or -N(C _1-4 alkyl) ₂ , preferably F, Cl, Br, I, CF ₃ , OH, cyano, NH ₂ , methyl, ethyl, Cyclopropyl, cyclobutyl, methoxy, ethoxy, methylthio, -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH ₂ CH ₃ or -N(CH ₂ CH ₃ ) ₂ ;

作为选择，R^3a、R^3b与其连接的原子一起形成一个3至6元的含氮杂环，或者R^3a与R⁵直接相连形成一个3至6元的含氮杂环。Alternatively, R ^3a , R ^3b together with the atoms to which they are attached form a 3 to 6 membered nitrogen-containing heterocyclic ring, or R ^3a and R ^{5 are} directly bonded to form a 3 to 6 membered nitrogen-containing heterocyclic ring.

本发明优选方案，一种通式(IV)或者(V)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药：A preferred embodiment of the invention, a compound of the formula (IV) or (V) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof:

a、b均为0；a, b are 0;

c选自0、1或2；c is selected from 0, 1 or 2;

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

m为0、1、2或3； m is 0, 1, 2 or 3;

W选自-O-、-NH-或-NCH₃-；W is selected from -O-, -NH- or -NCH ₃ -;

R^q各自独立的选自H、甲基、乙基、丙基、环丙基或环丁基；R ^q is independently selected from H, methyl, ethyl, propyl, cyclopropyl or cyclobutyl;

Ar²选自苯环、噻吩环、呋喃环或吡咯环，优选苯环，所述的苯环、噻吩环、呋喃环或吡咯环任选进一步被0、1、2、3或4个选自F、Cl、Br、I、CF₃、OH、氰基、NH₂、甲基、乙基、甲氧基、乙氧基或乙炔基的取代基所取代；Ar ^{2 is} selected from a benzene ring, a thiophene ring, a furan ring or a pyrrole ring, preferably a benzene ring, and the benzene ring, thiophene ring, furan ring or pyrrole ring is optionally further selected from 0, 1, 2, 3 or 4 Substituted with a substituent of F, Cl, Br, I, CF ₃ , OH, cyano, NH ₂ , methyl, ethyl, methoxy, ethoxy or ethynyl;

R⁵选自F、Cl、Br、I、CF₃、OH、氰基、NH₂、甲基、乙基、环丙基、环丁基、甲氧基、乙氧基、甲硫基、-NHCH₃、-N(CH₃)₂、-NHCH₂CH₃或-N(CH₂CH₃)₂；R ^{5 is} selected from the group consisting of F, Cl, Br, I, CF ₃ , OH, cyano, NH ₂ , methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, methylthio, - NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH ₂ CH ₃ or -N(CH ₂ CH ₃ ) ₂ ;

本发明优选方案，本发明所涉及的化合物包括但不限于：In a preferred embodiment of the invention, the compounds of the invention include, but are not limited to:

本发明还涉及提供一种药物组合物，所述的药物组合物含有治疗有效剂量的通式(I)、(II)、(III)或(IV)任一项所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，以及药学上可接受的载体、稀释剂、佐剂、媒介物或赋形剂；所述的组合物还可进一步包括一种或多种其他治疗剂；优选的，其中所述其他治疗剂选自PDE4抑制剂、蕈毒碱受体拮抗剂、皮质类固醇和β-肾上腺素能受体激动剂中的一种或多种。The invention further relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of formula (I), (II), (III) or (IV) or a stereoisod thereof a construct, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug, and a pharmaceutically acceptable carrier, diluent, adjuvant, vehicle or excipient; combinations thereof The composition may further comprise one or more additional therapeutic agents; preferably, wherein the other therapeutic agent One or more selected from the group consisting of a PDE4 inhibitor, a muscarinic receptor antagonist, a corticosteroid, and a β-adrenergic receptor agonist.

本发明还涉及提供通式(I)、(II)、(III)或(IV)所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，或所述药物组合物在制备用于治疗气道阻塞性疾病的药物中的应用，优选的，在制备用于治疗哮喘、慢性阻塞性肺疾病或支气管炎的药物中的应用。The present invention also relates to providing a compound of the formula (I), (II), (III) or (IV) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt thereof, or a total of Crystal or prodrug, or use of the pharmaceutical composition in the preparation of a medicament for treating an airway obstructive disease, preferably, in the preparation of a medicament for treating asthma, chronic obstructive pulmonary disease or bronchitis .

本发明还涉及治疗气道阻塞性疾病的方法，所述方法包括给药通式(I)、(II)、(III)或(IV)所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药及上述的药物组合物。The present invention also relates to a method of treating an airway obstructive disease, the method comprising administering a compound of the formula (I), (II), (III) or (IV) or a stereoisomer thereof, a hydrate thereof, Metabolites, solvates, pharmaceutically acceptable salts, eutectic or prodrugs, and pharmaceutical compositions as described above.

本发明还涉及治疗哮喘、慢性阻塞性肺疾病或支气管炎的方法，所述方法包括给药通式(I)、(II)、(III)或(IV)所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药及上述的药物组合物。The invention also relates to a method of treating asthma, chronic obstructive pulmonary disease or bronchitis, comprising administering a compound of the formula (I), (II), (III) or (IV) or a stereoisomer thereof A body, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug and a pharmaceutical composition as described above.

本发明提供一种制备通式(I)、(II)、(III)或(IV)的所示化合物或其立体异构体的中间体，该中间体选自通式(V)所示的化合物或者其立体异构体中间体：The present invention provides an intermediate for preparing the compound of the formula (I), (II), (III) or (IV) or a stereoisomer thereof, which is selected from the group consisting of the formula (V) a compound or a stereoisomer intermediate thereof:

a选自0、1、2、3、4或5；a is selected from 0, 1, 2, 3, 4 or 5;

b选自0、1、2、3或4；b is selected from 0, 1, 2, 3 or 4;

环A选自

且N对位的碳原子与W直接相连，所述的

任选进一步被0至5个选自F、Cl、Br、I、CF₃、OH、氰基、C_1-4烷基或C_1-4烷氧基的取代基所取代；Ring A is selected from

And the N-position carbon atom is directly connected to W, said

Optionally further substituted with 0 to 5 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , OH, cyano, C _1-4 alkyl or C _1-4 alkoxy;

M选自H、

M is selected from H,

条件是环A选自

M选自

The condition is that ring A is selected from

M is selected from

c选自0、1或2；c is selected from 0, 1 or 2;

R^q各自独立的选自H、C_1-4烷基或C_3-6环烷基；R ^{q is} independently selected from H, C _1-4 alkyl or C _3-6 cycloalkyl;

环D选自C_4-7碳环或者4至7元杂环，所述的碳环或者杂环任选进一步被0至5个选自F、Cl、Br、I、CF₃、＝O、OH、NH₂、氰基、C_1-4烷基、C_1-4烷氧基或C_2-4炔基的取代基所取代，所述的杂环含有1至3个任选自N、O或S的杂原子；Ring D is selected from a C _4-7 carbocyclic ring or a 4 to 7 membered heterocyclic ring, and the carbocyclic or heterocyclic ring is optionally further further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, CF ₃ , =0, Substituted by a substituent of OH, NH ₂ , cyano, C _1-4 alkyl, C _1-4 alkoxy or C _2-4 alkynyl, said heterocyclic ring containing from 1 to 3, optionally selected from N, a hetero atom of O or S;

R⁴各自独立的选自F、Cl、Br、I、CF₃、OH、NH₂、氰基、C_1-4烷基、C_1-4烷氧基或C_2-4炔基；R ^{4 is} each independently selected from the group consisting of F, Cl, Br, I, CF ₃ , OH, NH ₂ , cyano, C _1-4 alkyl, C _1-4 alkoxy or C _2-4 alkynyl;

n选自0、1、2或3；n is selected from 0, 1, 2 or 3;

Ar²选自苯环、噻吩环、呋喃环或吡咯环，所述的苯环、噻吩环、呋喃环或吡咯环任选进一步被0至4个选自F、Cl、Br、I、CF₃、OH、氰基、NH₂、C_1-4烷基、C_1-4烷氧基或C_2-4炔基的取代基所取代；Ar ^{2 is} selected from a benzene ring, a thiophene ring, a furan ring or a pyrrole ring, and the benzene ring, thiophene ring, furan ring or pyrrole ring is optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, CF ₃ Substituted with a substituent of OH, cyano, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy or C _2-4 alkynyl;

R^m选自-CHO、-CH₂OH或者-CH₂OP；R ^{m is} selected from -CHO, -CH ₂ OH or -CH ₂ OP;

P选自羟基保护基。P is selected from a hydroxy protecting group.

本发明的一种优选方案，中间体通式(V)所示的化合物或者其立体异构体中间体任选自如下结构之一：In a preferred embodiment of the present invention, the compound represented by the formula (V) or the stereoisomer intermediate thereof is selected from one of the following structures:

除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。Terms used in the specification and claims have the following meanings unless stated to the contrary.

本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括¹²C、¹³C和¹⁴C，氢的同位素包括氕(H)、氘(D，又称为重氢)、氚(T，又称为超重氢)，氧的同位素包括¹⁶O、¹⁷O和¹⁸O，硫的同位素包括³²S、³³S、³⁴S和³⁶S，氮的同位素包括¹⁴N和¹⁵N，氟的同位素¹⁹F，氯的同位素包括³⁵Cl和³⁷Cl，溴的同位素包括⁷⁹Br和⁸¹Br。The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, and the groups and compounds involved in the present invention. The nitrogen or halogen is optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include ¹² C, ¹³ C, and ¹⁴ C, and the hydrogen isotopes include helium (H), helium (D, also known as heavy hydrogen ), tritium (T, also known as tritium), oxygen isotopes include ¹⁶ O, ¹⁷ O and ¹⁸ O, comprising sulfur, ³² S, ³³ S, ³⁴ S and ³⁶ S, the nitrogen isotopes ¹⁴ N and ¹⁵ comprising N, the fluorine isotope ¹⁹ F, the chlorine isotope includes ³⁵ Cl and ³⁷ Cl, and the bromine isotopes include ⁷⁹ Br and ⁸¹ Br.

“烷基”是指直链和支链的一价饱和烃基，主链包括1至10个碳原子，优选为1至8个碳原子，进一步优选为1至6个碳原子，更优选为1至4个碳原子的直链与支链基团，最优选1至2个碳原子，烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、正己基、正庚基、正辛基、正壬基和正癸基等；所述的烷基可以任选进一步被0至5个选自F、Cl、Br、I、＝O、-CH₂F、-CHF₂、-CF₃、羟基、-SR¹⁹、硝基、氰基、异氰基、烷基、羟基烷基、烷氧基、碳环基、杂环基、C_2-8烯基、C_2-8炔基、-(CH₂)_a-C(＝O)-R¹⁹、-(CH₂)_k-C(＝O)-O-R¹⁹、-(CH₂)_k-C(＝O)-NR¹⁹R^19a、-(CH₂)_k-S(＝O)_j-R¹⁹、-O-C(＝O)-O-R¹⁹或者-NR¹⁹R^19a的取代基所取代，其中R¹⁹和R^19a各自独立选自H、羟基、氨基、羧基、C_1-8烷基、C_1-8烷氧基、C_2-8烯基、C_2-8炔基、3至10元碳环基、4至10元杂环基、3至10元碳环基氧基或者4至10元杂环基氧基，k选自0、1、2、3、4或者5，j选自0、1或者2。本文中出现的烷基、k、j或R¹⁹和R^19a，其定义如上所述。"Alkyl" means a straight-chain and branched monovalent saturated hydrocarbon group, and the main chain includes 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, further preferably 1 to 6 carbon atoms, more preferably 1 Straight and branched groups of up to 4 carbon atoms, most preferably 1 to 2 carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, n-hexyl, n-glycol a base, an n-octyl group, a n-decyl group, a n-decyl group, etc.; the alkyl group may optionally be further from 0 to 5 selected from the group consisting of F, Cl, Br, I, =0, -CH ₂ F, -CHF ₂ , -CF ₃ , hydroxy, -SR ¹⁹ , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C _2-8 alkenyl, C _2-8 Alkynyl, -(CH ₂ ) _a -C(=O)-R ¹⁹ , -(CH ₂ ) _k -C(=O)-OR ¹⁹ , -(CH ₂ ) _k -C(=O)-NR ¹⁹ Substituting R ^19a , -(CH ₂ ) _k -S(=O) _j -R ¹⁹ , -OC(=O)-OR ¹⁹ or -NR ¹⁹ R ^19a , wherein R ¹⁹ and R ^19a are each independently selected from H, hydroxyl, amino, carboxyl, C _1-8 Group, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, 3-10 yuan carbocyclyl 4 to 10-membered heterocyclic, 3-10 yuan carbocyclyl group, or 4 to 10 membered heterocyclyloxy group, k is selected from 0, 1, 2, 3, 4 or 5, and j is selected from 0, 1, or 2. The alkyl, k, j or R ¹⁹ and R ^19a appearing herein are as defined above.

“环烷基”是指饱和环状烷基，环上包括3至10个碳原子，优选为3至8个碳原子，进一步优选为3至6个碳原子，环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基和环庚基等；所述的的环烷基可以任选进一步被0至5个选自F、Cl、Br、I、＝O、-CH₂F、-CHF₂、-CF₃、羟基、-SR¹⁹、硝基、氰基、异氰基、烷基、羟基烷基、烷氧基、碳环基、杂环基、C_2-8烯基、C_2-8炔基、-(CH₂)_a-C(＝O)-R¹⁹、-(CH₂)_k-C(＝O)-O-R¹⁹、-(CH₂)_k-C(＝O)-NR¹⁹R^19a、-(CH₂)_k-S(＝O)_j-R¹⁹、-O-C(＝O)-O-R¹⁹或者-NR¹⁹R^19a的取代基所取代，本文中出现的环烷基，其定义如上所述。"Cycloalkyl" means a saturated cyclic alkyl group having from 3 to 10 carbon atoms, preferably from 3 to 8 carbon atoms, further preferably from 3 to 6 carbon atoms, examples of cycloalkyl groups including but not Limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, etc.; the cycloalkyl group may optionally be further from 0 to 5 selected from the group consisting of F, Cl, Br, I, =0, -CH ₂ F, -CHF ₂ , -CF ₃ , hydroxy, -SR ¹⁹ , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C _{2 -8} alkenyl, C _2-8 alkynyl, -(CH ₂ ) _a -C(=O)-R ¹⁹ , -(CH ₂ ) _k -C(=O)-OR ¹⁹ , -(CH ₂ ) _k -C(=O)-NR ¹⁹ R ^19a , -(CH ₂ ) _k -S(=O) _j -R ¹⁹ , -OC(=O)-OR ¹⁹ or a substituent of -NR ¹⁹ R ^19a , The cycloalkyl groups appearing herein are as defined above.

“烷氧基”是指O-烷基的一价基团，其中，烷基如本文所定义，烷氧基实施例包括但不限于甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-1-丙氧基、2-丁氧基、2-甲基-2-丙氧基、1-戊氧基、2-戊氧基、3-戊氧基、2-甲基-2-丁氧基、3-甲基-2-丁氧基、3-甲基-1-丁氧基和2-甲基-1-丁氧基等。"Alkoxy" means a monovalent group of an O-alkyl group, wherein alkyl is as defined herein, and alkoxy embodiments include, but are not limited to, methoxy, ethoxy, 1-propoxy, 2 -propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, 1-pentyloxy, 2-pentyloxy , 3-pentyloxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy, 3-methyl-1-butoxy and 2-methyl-1-butoxy Wait.

“烯基”是指直链和支链的一价不饱和烃基，其具有至少1个，通常有1、2或3个碳碳双键，主链包括2至10个碳原子，进一步优选2至6个碳原子，更优选在主链上有2至4个碳原子，烯基实施例包括但不限于乙烯基、烯丙基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基、2-甲基-3-丁烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、1-庚烯基、2-庚烯基、3-庚烯基、4-庚烯基、1-辛烯基、3-辛烯基、1-壬烯基、3-壬烯基、1-癸烯基、4-癸烯基、1,3-丁二烯、1,3-戊二烯、1,4-戊二烯和1,4-己二烯等；所述的烯基可以任选进一步被0至5个选自F、Cl、Br、I、＝O、-CH₂F、-CHF₂、-CF₃、羟基、-SR¹⁹、硝基、氰基、异氰基、烷基、羟基烷基、烷氧基、碳环基、杂环基、C_2-8烯基、C_2-8炔基、-(CH₂)_a-C(＝O)-R¹⁹、-(CH₂)_k-C(＝O)-O-R¹⁹、-(CH₂)_k-C(＝O)-NR¹⁹R^19a、-(CH₂)_k-S(＝O)_j-R¹⁹、-O-C(＝O)-O-R¹⁹或者-NR¹⁹R^19a的取代基所取代。本文中出现的烯基，其定义如上所述。"Alkenyl" means a straight-chain or branched monovalent unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon double bonds, the main chain comprising 2 to 10 carbon atoms, further preferably 2 Up to 6 carbon atoms, more preferably 2 to 4 carbon atoms in the main chain, and alkenyl examples include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl , 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2- Methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octene , 3-octenyl, 1-decenyl, 3-decenyl, 1-decenyl, 4-nonenyl, 1,3-butadiene, 1,3-pentadiene, 1, 4-pentadiene and 1,4-hexadiene, etc.; the alkenyl group may optionally be further from 0 to 5 selected from the group consisting of F, Cl, Br, I, =0, -CH ₂ F, -CHF ₂ , -CF ₃ , hydroxy, -SR ¹⁹ , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbon Cyclo, heterocyclyl, C _2-8 alkenyl, C _2-8 alkynyl, -(CH ₂ ) _a -C(=O)-R ¹⁹ , -(CH ₂ ) _k -C(=O)- OR ¹⁹ , -(CH ₂ ) _k -C(=O)-NR ¹⁹ R ^19a , -(CH ₂ ) _k -S(=O) _j -R ¹⁹ , -OC(=O)-OR ¹⁹ or -NR Substituted by a substituent of ¹⁹ R ^19a . The alkenyl groups appearing herein are as defined above.

“炔基”是指直链和支链的一价不饱和烃基，其具有至少1个，通常有1、2或3个碳碳三键，主链包括2至10个碳原子，进一步优选2至6个碳原子，更优选在主链上有2至4个碳原子，炔基实施例包括但不限于乙炔基、1-丙炔基、2-丙炔基、丁炔基、2-丁炔基、3-丁炔基、1-甲基-2-丙炔基、4-戊炔基、3-戊炔基、1-甲基-2-丁炔基、2-己炔基、3-己炔基、2-庚炔基、3-庚炔基、4-庚炔基、3-辛炔基、3-壬炔基和4-癸炔基等；所述的炔基可以任选进一步被0至5个选自F、Cl、Br、I、＝O、-CH₂F、-CHF₂、-CF₃、羟基、-SR¹⁹、硝基、氰基、异氰基、烷基、羟基烷基、烷氧基、碳环基、杂环基、C_2-8烯基、C_2-8炔基、-(CH₂)_a-C(＝O)-R¹⁹、-(CH₂)_k-C(＝O)-O-R¹⁹、-(CH₂)_k-C(＝O)-NR¹⁹R^19a、-(CH₂)_k-S(＝O)_j-R¹⁹、-O-C(＝O)-O-R¹⁹或者-NR¹⁹R^19a的取代基所取代。本文中出现的炔基，其定义如上所述。"Alkynyl" means a straight-chain or branched monovalent unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, the main chain comprising 2 to 10 carbon atoms, further preferably 2 Up to 6 carbon atoms, more preferably 2 to 4 carbon atoms in the main chain, examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butyl Alkynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3 -hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-decynyl and 4-decynyl, etc.; the alkynyl group may be optionally Further from 0 to 5 selected from the group consisting of F, Cl, Br, I, =O, -CH ₂ F, -CHF ₂ , -CF ₃ , hydroxy, -SR ¹⁹ , nitro, cyano, isocyano, alkyl , hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C _2-8 alkenyl, C _2-8 alkynyl, -(CH ₂ ) _a -C(=O)-R ¹⁹ , -(CH ₂ ) _k -C(=O)-OR ¹⁹ , -(CH ₂ ) _k -C(=O)-NR ¹⁹ R ^19a , -(CH ₂ ) _k -S(=O) _j -R ¹⁹ , -OC (=O)-OR ¹⁹ or a substituent of -NR ¹⁹ R ^19a is substituted. The alkynyl groups appearing herein are as defined above.

“碳环”或者“碳环基”是指饱和或者不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至10元的单环、4至12元双环或者10至15元三环体系，碳环基可以连接有桥环或者螺环，非限制性实施例包括环丙基、环丁基、环戊基、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基、苯基、萘基、

所述的碳环基可以任选进一步被0至5个选自F、Cl、Br、I、＝O、-CH₂F、-CHF₂、-CF₃、羟基、-SR¹⁹、硝基、氰基、异氰基、烷基、羟基烷基、烷氧基、碳环基、杂环基、C_2-8烯基、C_2-8炔基、-(CH₂)_a-C(＝O)-R¹⁹、-(CH₂)_k-C(＝O)-O-R¹⁹、-(CH₂)_k-C(＝O)-NR¹⁹R^19a、-(CH₂)_k-S(＝O)_j-R¹⁹、-O-C(＝O)-O-R¹⁹或者-NR¹⁹R^19a的取代基所取代。本文中出现的碳环基，其定义如上所述。"Carbocycle" or "carbocyclyl" means a saturated or unsaturated aromatic or non-aromatic ring. The aromatic or non-aromatic ring may be a 3 to 10 membered monocyclic ring, a 4 to 12 membered bicyclic ring or a 10 to 15 membered member. A tricyclic system, a carbocyclic group may be bonded to a bridged ring or a spiro ring, and non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl -2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, cyclohexadienyl , cycloheptyl, cyclooctyl, cyclodecyl, cyclodecyl, cycloundecyl, cyclododecyl, phenyl, naphthyl,

The carbocyclic group may be further optionally 0 to 5 selected from the group consisting of F, Cl, Br, I, =O, -CH ₂ F, -CHF ₂ , -CF ₃ , hydroxy, -SR ¹⁹ , nitro, Cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C _2-8 alkenyl, C _2-8 alkynyl, -(CH ₂ ) _a -C(= O)-R ¹⁹ , -(CH ₂ ) _k -C(=O)-OR ¹⁹ , -(CH ₂ ) _k -C(=O)-NR ¹⁹ R ^19a , -(CH ₂ ) _k -S(= O) Substituted by a substituent of _j -R ¹⁹ , -OC(=O)-OR ¹⁹ or -NR ¹⁹ R ^19a . The carbocyclic group appearing herein is defined as described above.

“杂环基”是指饱和或不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至10元的单环、4至12元双环或者10至15元三环体系，且包含1至4个选自N、O或S的杂原子，优选4至8元杂环基，杂环基的环中选择性取代的N、S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上，杂环基可以连接有桥环或者螺环，非限制性实施例包括环氧乙基、环氧丙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、硫杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、氧杂环庚基、硫杂环庚基、氧氮杂卓基、二氮杂卓基、硫氮杂卓基、吡啶基、哌啶基、高哌啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、高哌嗪基、咪唑基、哌啶基、哌叮基、吗啉基、硫代吗啉基、噻噁烷基、1,3-二噻基、二氢呋喃基、二氢吡喃基、二噻戊环基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己基、1,3-二氧戊基、吡唑啉基、二噻烷基、二噻茂烷基、二氢噻吩基、吡唑烷基、咪唑啉基、咪唑烷基、1,2,3,4-四氢异喹啉基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、氮杂双环[2.2.2]己基、3H-吲哚基喹嗪基、N-吡啶基尿素、1,1-二氧硫代吗啉基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。所述的杂环基可以任选进一步被0至5个选自F、Cl、Br、I、＝O、-CH₂F、-CHF₂、 -CF₃、羟基、-SR¹⁹、硝基、氰基、异氰基、烷基、羟基烷基、烷氧基、碳环基、杂环基、C_2-8烯基、C_2-8炔基、-(CH₂)_a-C(＝O)-R¹⁹、-(CH₂)_k-C(＝O)-O-R¹⁹、-(CH₂)_k-C(＝O)-NR¹⁹R^19a、-(CH₂)_k-S(＝O)_j-R¹⁹、-O-C(＝O)-O-R¹⁹或者-NR¹⁹R^19a的取代基所取代。本文中出现的杂环基，其定义如上所述。"Heterocyclyl" means a saturated or unsaturated aromatic or non-aromatic ring, and the aromatic or non-aromatic ring may be a 3 to 10 membered monocyclic, 4 to 12 membered bicyclic or 10 to 15 membered tricyclic system, and It contains 1 to 4 hetero atoms selected from N, O or S, preferably a 4 to 8 membered heterocyclic group, and N, S which are optionally substituted in the ring of the heterocyclic group can be oxidized to various oxidation states. The heterocyclic group may be bonded to a hetero atom or a carbon atom, and the heterocyclic group may be bonded to a bridged or spiro ring, and non-limiting examples include an epoxyethyl group, a glycidyl group, an azacyclopropyl group, and an oxocyclic ring. Butyl, azetidinyl, thioheterobutyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxolyl, azacycloheptyl , oxetanyl, thiaheptyl, oxazepine, diazepine, thiazepine, pyridyl, piperidinyl, homopiperidinyl, furyl, thienyl, pyr Cyclo, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl , thiazolidine, 1,3-dithia, dihydrofuranyl, dihydropyranyl, dithylpentyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl , tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, 2-pyrroline, 3-pyrroline, indanyl, 2H-pyranyl , 4H-pyranyl, dioxolane, 1,3-dioxolanyl, pyrazolinyl, dithiaalkyl, dithialimyl, dihydrothienyl, pyrazolidinyl, imidazoline Base, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[ 2.2.2] Hexyl, 3H-nonylquinazinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octyl, azabicyclo [5.2.0] decyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl. The heterocyclic group may be further optionally 0 to 5 selected from the group consisting of F, Cl, Br, I, =O, -CH ₂ F, -CHF ₂ , -CF ₃ , hydroxy, -SR ¹⁹ , nitro, Cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C _2-8 alkenyl, C _2-8 alkynyl, -(CH ₂ ) _a -C(= O)-R ¹⁹ , -(CH ₂ ) _k -C(=O)-OR ¹⁹ , -(CH ₂ ) _k -C(=O)-NR ¹⁹ R ^19a , -(CH ₂ ) _k -S(= O) Substituted by a substituent of _j -R ¹⁹ , -OC(=O)-OR ¹⁹ or -NR ¹⁹ R ^19a . The heterocyclic group appearing herein is as defined above.

“羟基保护基”是指用于氨基保护的基团，该基团适用于保护氨基，使氨基不进行化学反应，但是在分子的其它部分完成所需化学反应之后该基团容易除去。包括但不限于以下基团：-C(＝O)C₁～C₆烷基、-Si(C₁～C₆烷基)₃和-O(CH₂)OC₁～C₆烷基，优选地，选自如下基团：乙酰基、三甲基硅基、三乙基硅基、二甲基叔丁基硅基、异丙基硅基、甲氧基甲基或乙氧基甲基。"Hydroxy protecting group" refers to a group for amino protection which is useful for protecting an amino group such that the amino group does not undergo a chemical reaction, but the group is readily removed after completion of the desired chemical reaction in other portions of the molecule. Including but not limited to the following groups: -C(=O)C ₁ -C ₆ alkyl, -Si(C ₁ -C ₆ alkyl) ₃ and -O(CH ₂ )OC ₁ -C ₆ alkyl, preferably Ground, selected from the group consisting of acetyl, trimethylsilyl, triethylsilyl, dimethyl-tert-butylsilyl, isopropylsilyl, methoxymethyl or ethoxymethyl.

“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生，该说明包括该事件或环境发生或不发生的场合。如：“任选被F取代的烷基”指烷基可以但不必须被F取代，说明包括烷基被F取代的情形和烷基不被F取代的情形。"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "alkyl group optionally substituted by F" means that the alkyl group may, but need not, be substituted by F, indicating a case where the alkyl group is substituted by F and a case where the alkyl group is not substituted by F.

“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐与其他组成成分的混合物，其中其它组分包含生理学/药学上可接受的载体和赋形剂。"Pharmaceutical composition" means a mixture of one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt thereof, with other components, wherein the other components comprise physiologically/pharmaceutically acceptable carriers and excipients.

“载体”指的是不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的载体或稀释剂。"Carrier" refers to a carrier or diluent that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.

“赋形剂”指的是加入到药物组合物中以进一步依赖于化合物给药的惰性物质。赋形剂的实例包括但不限于碳酸钙、磷酸钙、各种糖和不同类型的淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂、崩解剂等。"Excipient" refers to an inert substance that is added to a pharmaceutical composition to further depend on the administration of the compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, Granules, lubricants, binders, disintegrators, and the like.

“前药”是指可以在生理条件下或通过溶剂解转化为具有生物活性的本发明化合物的化合物。本发明的前药通过修饰本发明化合物中的功能基团来制备，该修饰可以通过常规的操作或者在体内被除去，而得到母体化合物。"Prodrug" means a compound that can be converted to a biologically active compound of the invention under physiological conditions or by solvolysis. Prodrugs of the invention are prepared by modifying functional groups in the compounds of the invention which can be removed by conventional procedures or in vivo to provide the parent compound.

“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。"Stereoisomer" refers to isomers resulting from the spatial arrangement of atoms in a molecule, including cis and trans isomers, enantiomers and conformational isomers.

“有效剂量”指引起组织、***或受试者生理或医学反应的化合物的量，此量是所寻求的，包括在受治疗者身上施用时足以预防受治疗的疾患或病症的一种或几种症状发生或使其减轻至某种程度的化合物的量。"Effective dose" refers to the amount of a compound that causes a physiological or medical response to a tissue, system or subject, which amount is sought, and includes one or more of the conditions or conditions sufficient to prevent treatment when administered to a subject. The amount of a compound that occurs or reduces it to some extent.

“溶剂化物”指本发明化合物或其盐，它们还包括以分子间非共价力结合的化学计量或非化学计量的溶剂。当溶剂为水时，则为水合物。"Solvate" means a compound of the invention or a salt thereof, which also includes a stoichiometric or non-stoichiometric amount of solvent bound by intermolecular non-covalent forces. When the solvent is water, it is a hydrate.

具体实施方式 detailed description

以下通过具体实施例详细说明本发明的实施过程和产生的有益效果，旨在帮助阅读者更好地理解本发明的实质和特点，不作为对本案可实施范围的限定。The embodiments of the present invention and the beneficial effects thereof are described in detail below by way of specific examples, which are intended to provide a better understanding of the nature and characteristics of the present invention.

化合物的结构是通过核磁共振(NMR)或(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 Avance III 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)。MS的测定用(Agilent 6120B(ESI)和Agilent6120B(APCI))。HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm)。薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.20mm，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。本发明的己知的起始原料可以采用或按照本领域已知的方法来合成，或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司。氮气氛是指反应瓶连接一个约1L容积的氮气气球。氢气氛是指反应瓶连接一个约1L容积的氢气气球。氢化反应通常抽真空，充入氢气，反复操作3次。实施例中无特殊说明，反应在氮气氛下进行。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。实施例中无特殊说明，M是摩尔每升。室温为最适宜的反应温度，为20℃～30℃。Bn：是指苄基。TBS：是指叔丁基二甲基。Boc：是指叔丁基氧基羰基。The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 ^-6 (ppm). The NMR was measured using a (Bruker Avance III 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). The measurement of MS was carried out (Agilent 6120B (ESI) and Agilent 6120B (APCI)). The HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm). Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.20mm. The specification for thin layer chromatography separation and purification is 0.4mm. ~0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier. The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anheji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies. The nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon having a volume of about 1 L. The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume. The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times. Unless otherwise stated in the examples, the reaction was carried out under a nitrogen atmosphere. Unless otherwise stated in the examples, the solution means an aqueous solution. There is no particular description in the examples, and the reaction temperature is room temperature. There is no special description in the examples, and M is a mole per liter. The room temperature is an optimum reaction temperature of 20 ° C to 30 ° C. Bn: means benzyl. TBS: refers to tert-butyldimethyl. Boc: means a tert-butyloxycarbonyl group.

中间体1：1-丙烯酰基二氢吲哚-5-醛Intermediate 1:1-acryloylindolin-5-aldehyde

1-prop-2-enoylindoline-5-carbaldehyde1-prop-2-enoylindoline-5-carbaldehyde

取5-甲酰基二氢吲哚-1-碳酸叔丁酯(1a)(742mg,3mmol)(参考WO2007129745制备得到)置于25mL圆底烧瓶中，加入二氯甲烷(10mL)，将体系冷却至0℃，滴加三氟乙酸(5mL)，滴加完毕后，升至室温反应1小时。反应结束后，将体系减压浓缩，残留物加入到二氯甲烷(10mL)中，于0℃条件下，向体系滴加三乙胺(0.83mL，6mmol)，搅拌均匀后，滴加丙烯酰氯(0.36mL，4.5mmol)的二氯甲烷(5mL)溶液，自然升至室温反应30分钟，加入饱和碳酸氢钠溶液(20mL)淬灭反应，二氯甲烷(20mL×2)萃取，合并有机相，饱和食盐水(30mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱层析纯化(石油醚/乙酸乙酯(v/v)＝2:1)，得到标题产物1-丙烯酰基二氢吲哚-5-醛(中间体1)，淡黄色固体(0.36g,产率60％)。 Taking 5-formylindoline-1-carbonate tert-butyl ester (1a) (742 mg, 3 mmol) (prepared by reference to WO2007129745) was placed in a 25 mL round bottom flask, dichloromethane (10 mL) was added, and the system was cooled to Trifluoroacetic acid (5 mL) was added dropwise at 0 ° C, and after the addition was completed, the mixture was allowed to react at room temperature for 1 hour. After the reaction was completed, the system was concentrated under reduced pressure, and the residue was added to dichloromethane (10 mL), and then triethylamine (0.83mL, 6mmol) was added dropwise to the system at 0 ° C. After stirring, acryloyl chloride was added dropwise. (0.36 mL, 4.5 mmol) in methylene chloride (5 mL), EtOAc (EtOAc) (EtOAc) The mixture was washed with saturated brine (30 mL×1). The title product 1-acryloylindolin-5-aldehyde (Intermediate 1) was obtained as a pale yellow solid (0.36 g, yield 60%).

LCMS m/z＝202.1[M+1]。LCMS m/z = 202.1 [M + 1].

中间体2:3-乙基-5,6-二氢-4H-吡咯[3,4-d]咪唑-2-甲酰胺(中间体2)Intermediate 2: 3-ethyl-5,6-dihydro-4H-pyrrole [3,4-d]imidazole-2-carboxamide (Intermediate 2)

3-ethyl-5,6-dihydro-4H-pyrrolo[3,4-d]imidazole-2-carboxamide3-ethyl-5,6-dihydro-4H-pyrrolo[3,4-d]imidazole-2-carboxamide

第一步：6-氧杂-3-氮杂双环并[3.1.0]己烷-3-甲酸叔丁酯(2b)First step: 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (2b)

tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylateTert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate

将N-叔丁氧羰基-吡咯啉(2a)(100g,0.59mol)溶于二氯甲烷(600mL)中，分批加入间氯过氧苯甲酸(198.70g,0.88mol)，室温下搅拌17小时。将反应液缓慢加入浓度为17％的硫代硫酸钠溶液(46.64g,0.29mol)中，充分搅拌，用硅藻土过滤，将滤液分液，水相用二氯甲烷(400mL×3)萃取，合并有机相，分别用饱和碳酸钾溶液(500mL×1)、饱和氯化钠溶液(1000mL×1)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题产物6-氧杂-3-氮杂双环并[3.1.0]己烷-3-甲酸叔丁酯(2b)，黄色油状物，直接用于下一步。N-tert-Butoxycarbonyl-pyrroline (2a) (100 g, 0.59 mol) was dissolved in dichloromethane (600 mL), and m-chloroperoxybenzoic acid (198.70 g, 0.88 mol) was added portionwise and stirred at room temperature. hour. The reaction solution was slowly added to a 17% sodium thiosulfate solution (46.64 g, 0.29 mol), stirred well, filtered over Celite, and the filtrate was separated and the aqueous phase was extracted with dichloromethane (400 mL×3) The organic phase was combined and washed with a saturated aqueous solution of sodium carbonate (500 mL×1) and saturated sodium chloride (1000 mL×1). Oxy-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (2b) was obtained as a yellow oil.

LCMS m/z＝208.1[M+23]。 LCMS m/z = 208.1 [M+23].

第二步：3-叠氮基-4-羟基吡咯烷基-1-甲酸叔丁酯(2c)Second step: 3-azido-4-hydroxypyrrolidinyl-1-carboxylic acid tert-butyl ester (2c)

tert-butyl 3-azido-4-hydroxypyrrolidine-1-carboxylateTert-butyl 3-azido-4-hydroxypyrrolidine-1-carboxylate

将6-氧杂-3-氮杂双环并[3.1.0]己烷-3-甲酸叔丁酯(2b)(109.32g,0.59mol)溶于二氧六环(800mL)和水(260mL)的混合溶剂中，加入叠氮化钠(115.24g,1.77mol)，升温至105℃回流反应60小时。将反应液冷至室温，加入饱和氯化钠溶液(3000mL)，水相用二氯甲烷(2000mL×4)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题产物3-叠氮基-4-羟基吡咯烷基-1-甲酸叔丁酯(2c)，棕色油状物，直接用于下一步。6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (2b) (109.32 g, 0.59 mol) was dissolved in dioxane (800 mL) and water (260 mL) A sodium azide (115.24 g, 1.77 mol) was added to the mixed solvent, and the mixture was heated to 105 ° C for reflux for 60 hours. The reaction solution was cooled to room temperature, a saturated aqueous sodium chloride solution (3000 mL) was added, and the aqueous phase was extracted with methylene chloride (2000 mL × 4). The product 3-azido-4-hydroxypyrrolidinyl-1-carboxylic acid tert-butyl ester (2c) was obtained as a brown oil.

LCMS m/z＝251.1[M+23]。LCMS m/z = 251.1 [M+23].

第三步：3-叠氮基-4-((甲磺酰基)氧基)吡咯烷基-1-甲酸叔丁酯(2d)The third step: 3-azido-4-((methylsulfonyl)oxy)pyrrolidinyl-1-carboxylic acid tert-butyl ester (2d)

tert-butyl 3-azido-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylateTert-butyl 3-azido-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate

氮气氛下，将3-叠氮基-4-羟基吡咯烷基-1-甲酸叔丁酯(2c)(134.72g,0.59mol)溶于二氯甲烷(3400mL)，冷却至0℃，依次加入三乙胺(89.70g,0.88mol)、甲基磺酰氯(87.99g,0.76mol)，加毕，自然升至室温反应17小时。反应液用饱和氯化钠溶液(1500mL×3)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题产物3-叠氮基-4-((甲磺酰基)氧基)吡咯烷基-1-甲酸叔丁酯(2d)，黄色油状物，直接用于下一步。3-Azido-4-hydroxypyrrolidinyl-1-carboxylic acid tert-butyl ester (2c) (134.72 g, 0.59 mol) was dissolved in dichloromethane (3400 mL), cooled to 0 ° C, and then added sequentially. Triethylamine (89.70 g, 0.88 mol) and methanesulfonyl chloride (87.99 g, 0.76 mol) were added, and the mixture was allowed to react to room temperature for 17 hours. The reaction mixture was washed with aq. EtOAc (EtOAc m. Pyrrolidin-1-carboxylic acid tert-butyl ester (2d), yellow oil, used directly in the next step.

第四步：3,4-二叠氮基吡咯烷基-1-甲酸叔丁酯(2e)Fourth step: tert-butyl 3,4-diazidopyrrolidin-1-carboxylate (2e)

tert-butyl 3,4-diazidopyrrolidine-1-carboxylateTert-butyl 3,4-diazidopyrrolidine-1-carboxylate

将3-叠氮基-4-((甲磺酰基)氧基)吡咯烷基-1-甲酸叔丁酯(2d)(181.02g,0.59mol)溶于N’N-二甲基甲酰胺(3370mL)中，加入叠氮化钠(115.23g,1.77mol)，升温至90℃搅拌60小时。向反应液中加入水(12L)，用甲基叔丁基醚(2000mL×5)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题产物3,4-二叠氮基吡咯烷基-1-甲酸叔丁酯(2e)，棕色油状物，直接用于下一步。tert-Butyl 3-azido-4-((methylsulfonyl)oxy)pyrrolidinyl-1-carboxylate (2d) (181.02 g, 0.59 mol) was dissolved in N'N-dimethylformamide ( To 3370 mL), sodium azide (115.23 g, 1.77 mol) was added, and the mixture was heated to 90 ° C and stirred for 60 hours. Water (12 L) was added to the reaction mixture, and the mixture was evaporated, evaporated, evaporated, evaporated Azidopyrrolidinyl-1-carboxylic acid tert-butyl ester (2e), as a brown oil, was taken directly to next.

LCMS m/z＝276[M+23]。 LCMS m/z = 276 [M+23].

第五步：叔丁基3,4-二氨基吡咯烷基-1-甲酸酯盐酸盐(2f)Step 5: tert-butyl 3,4-diaminopyrrolidinyl-1-carboxylate hydrochloride (2f)

tert-butyl 3,4-diaminopyrrolidine-1-carboxylate hydrochlorideTert-butyl 3,4-diaminopyrrolidine-1-carboxylate hydrochloride

将3,4-二叠氮基吡咯烷基-1-甲酸叔丁酯(2e)(130g,0.51mol)溶于甲苯(2340mL)，加入三苯基膦(404.32g,1.54mol)，升温至115℃回流1小时，降至室温，加入四氢呋喃(468mL)和水(65mL)，回流17小时。向反应液中加入水(600mL)，冰浴降温，用稀盐酸(1mol/L)调节溶液pH至5，乙酸乙酯(500mL×3)萃取，将水相减压浓缩，得到标题产物叔丁基3,4-二氨基吡咯烷基-1-甲酸酯盐酸盐(2f)，白色粉末状物(85.0g,产率69.6％)。3,4-Diazidopyrrolidinyl-1-carboxylic acid tert-butyl ester (2e) (130 g, 0.51 mol) was dissolved in toluene (2340 mL), triphenylphosphine (404.32 g, 1.54 mol) was added and the mixture was warmed to After refluxing at 115 ° C for 1 hour, the temperature was lowered to room temperature, and tetrahydrofuran (468 mL) and water (65 mL) were added and refluxed for 17 hours. Water (600 mL) was added to the reaction mixture, and the mixture was cooled in an ice-cooled mixture, and the mixture was adjusted to pH 5 with dilute hydrochloric acid (1 mol/L), ethyl acetate (500 mL×3), and the aqueous phase was concentrated under reduced pressure to give the title product 3,4-Diaminopyrrolidinyl-1-carboxylate hydrochloride (2f), white powder (85.0 g, yield 69.6%).

¹H NMR(400MHz,DMSO-d₆)δ5.71(brs,4H),3.54(d,4H),3.22-3.20(s,2H),1.40(s,9H)。 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.71 (brs, 4H), 3.54 (d, 4H), 3.22-3.20 (s, 2H), 1.40 (s, 9H).

第六步：5-叔丁基2-乙基3a,4,6,6a-四氢吡咯并[3,4-d]咪唑-2,5(1H)-二甲酸酯(2h)Step 6: 5-tert-Butyl 2-ethyl 3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate (2h)

5-tert-butyl 2-ethyl 3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate5-tert-butyl 2-ethyl 3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate

将叔丁基3,4-二氨基吡咯烷基-1-甲酸酯盐酸盐(2f)(980mg,4.126mmoL)溶于六氟异丙醇(10mL)中，搅拌下加入2-乙氧基-2-亚氨基乙酸乙酯盐酸盐(2g)(886mg,4.538mmoL)，50℃搅拌16小时。将反应液浓缩旋干，加入饱和食盐水(50mL)，用稀盐酸调节pH值至2～3，用乙酯乙酯(50mL×2)萃取。收集水相，并用饱和碳酸氢钠溶液调pH值7～8，用乙酯乙酯(50mL×4)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝20:1)，得到标题产物5-叔丁基2-乙基3a,4,6,6a-四氢吡咯并[3,4-d]咪唑-2,5(1H)-二甲酸酯(2h)，白色固体(700mg,产率60％)。tert-Butyl 3,4-diaminopyrrolidinyl-1-carboxylate hydrochloride (2f) (980 mg, 4.126 mmol) was dissolved in hexafluoroisopropanol (10 mL) and 2-ethoxylated was added with stirring. Ethyl-2-iminoacetate hydrochloride (2 g) (886 mg, 4.538 mmol) was stirred at 50 ° C for 16 hours. The reaction solution was concentrated to dryness, and brine (50 mL) was evaporated, and the mixture was adjusted to pH 2-3 with dilute hydrochloric acid, and ethyl acetate (50mL×2). The aqueous phase was collected, and the pH was adjusted to 7 to 8 with a saturated aqueous solution of sodium bicarbonate, and ethyl acetate (50mL×4) was used to extract the organic phase, dried over anhydrous sodium sulfate, filtered and concentrated. Separation and purification (dichloromethane/methanol (v/v) = 20:1) to give the title product 5-t-butyl 2-ethyl 3a, 4,6,6a-tetrahydropyrrolo[3,4-d] Imidazole-2,5(1H)-dicarboxylate (2h), white solid (700mg, yield 60%).

LCMS m/z＝284.1[M+1]。LCMS m/z = 284.1 [M + 1].

¹H NMR(400MHz,CDCl₃)δ4.64(s,2H),4.37-4.33(q,2H),3.72-3.69(d,2H),3.55-3.50(dd,2H),1.44(s,9H),1.40-1.37(t,3H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ4.64 (s, 2H), 4.37-4.33 (q, 2H), 3.72-3.69 (d, 2H), 3.55-3.50 (dd, 2H), 1.44 (s, 9H ), 1.40-1.37 (t, 3H).

第七步：5-叔丁基2-乙基4,6-二氢吡咯并[3,4-d]咪唑-2,5-二甲酸酯(2i)Step 7: 5-tert-Butyl 2-ethyl 4,6-dihydropyrrolo[3,4-d]imidazole-2,5-dicarboxylate (2i)

5-tert-butyl 2-ethyl 4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate 5-tert-butyl 2-ethyl 4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate

将草酰氯(652.5mg,5.14mmoL)溶于干燥的二氯甲烷(15mL)中，用干冰丙酮浴降温到-78℃，搅拌下滴加干燥的二甲基亚砜(803.96mg,10.29mmoL)，搅拌30分钟。向反应液中滴加5-叔丁基2-乙基3a,4,6,6a-四氢吡咯并[3,4-d]咪唑-2,5(1H)-二甲酸酯(2h)(970mg,3.43mmoL)的二氯甲烷(5mL)溶液，继续搅拌20分钟。-78℃下滴加二异丙基乙胺(2.216g,17.15mmoL)，自然升到室温反应2小时。向反应液中加入饱和氯化铵溶液(50mL)、饱和氯化钠溶液(50mL)和二氯甲烷(50mL)，分液，水相用二氯甲烷用(50mL×3)萃取，合并有机相，饱和氯化钠溶液(50mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1:1)得到标题产物5-叔丁基2-乙基4,6-二氢吡咯并[3,4-d]咪唑-2,5-二甲酸酯(2i)，白色固体(520mg,产率54％)。Oxalyl chloride (652.5 mg, 5.14 mmoL) was dissolved in dry dichloromethane (15 mL), cooled to -78 ° C with dry ice acetone bath, and dried dimethyl sulfoxide (803.96 mg, 10.29mmoL) was added dropwise with stirring. Stir for 30 minutes. To the reaction solution was added dropwise 5-tert-butyl 2-ethyl 3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate (2h) A solution of (970 mg, 3.43 mmol) in dichloromethane (5 mL) was stirred for 20 min. Diisopropylethylamine (2.216 g, 17.15 mmol) was added dropwise at -78 ° C, and naturally allowed to react to room temperature for 2 hours. A saturated ammonium chloride solution (50 mL), a saturated sodium chloride solution (50 mL), and dichloromethane (50 mL) were added to the mixture, and the mixture was separated, and the aqueous phase was extracted with dichloromethane (50 mL×3). The mixture was washed with a saturated sodium chloride solution (50 mL×3), dried over anhydrous sodium sulfate, filtered and evaporated. The title product 5-tert-butyl 2-ethyl 4,6-dihydropyrrolo[3,4-d]imidazole-2,5-dicarboxylate (2i), white solid (520 mg, yield 54%) .

LCMS m/z＝282.1[M+1]。LCMS m/z = 282.1 [M + 1].

¹H NMR(400MHz,CDCl₃)δ4.54(s,2H),4.47(s,2H),4.46-4.41(q,2H),1.51(s,9H),1.44-1.41(t,3H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.54 (s, 2H), 4.47 (s, 2H), 4.46-4.41 (q, 2H), 1.51 (s, 9H), 1.44-1.41 (t, 3H).

第八步：5-叔丁基2-乙基1-乙基-4,6-二氢吡咯并[3,4-d]咪唑-2,5(1H)-二甲酸酯(2j)Step 8: 5-tert-Butyl 2-ethyl 1-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate (2j)

5-tert-butyl 2-ethyl 1-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate5-tert-butyl 2-ethyl 1-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate

将5-叔丁基2-乙基4,6-二氢吡咯并[3,4-d]咪唑-2,5-二甲酸酯(2i)(600mg,2.13mmoL)加入N,N-二甲基甲酰胺(8mL)中搅拌溶清，加入碳酸钾(590mg,4.26mmoL)，0℃搅拌下滴加碘乙烷(1000mg,6.4mmoL)，室温下搅拌反应6小时。将水(20mL)和甲基叔丁基醚(20mL)加入至反应液中，静置分层。水相用甲基叔丁基醚(20mL×1)萃取，合并有机相，依次用水(20mL×1)、饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩，得到标题产物5-叔丁基2-乙基1-乙基-4,6-二氢吡咯并[3,4-d]咪唑-2,5(1H)-二甲酸酯(2j)，黄色油状物(500mg,产率75.8％)。Add 5-tert-butyl 2-ethyl 4,6-dihydropyrrolo[3,4-d]imidazole-2,5-dicarboxylate (2i) (600 mg, 2.13 mmoL) to N,N-di Methylformamide (8 mL) was stirred and dissolved, and potassium carbonate (590 mg, 4.26 mmol) was added thereto, and ethyl iodide (1000 mg, 6.4 mmol) was added dropwise with stirring at 0 ° C, and the reaction was stirred at room temperature for 6 hours. Water (20 mL) and methyl tert-butyl ether (20 mL) were added to the reaction mixture, and the layers were allowed to stand. The aqueous phase was extracted with methyl tert-butyl ether (20 mL × 1), and the organic layer was washed with water (20 mL×1), brine (20 mL×2), dried over anhydrous sodium sulfate Product 5-tert-Butyl 2-ethyl 1-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate (2j), yellow oil (500 mg, yield 75.8%).

第九步：2-甲酰胺基-3-乙基-4,6-二氢吡咯[3,4-d]咪唑-5-甲酸叔丁酯(2k)Step 9: 2-formamido-3-ethyl-4,6-dihydropyrrole [3,4-d]imidazole-5-carboxylic acid tert-butyl ester (2k)

tert-butyl 2-carbamoyl-3-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5-carboxylate Tert-butyl 2-carbamoyl-3-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5-carboxylate

将5-叔丁基2-乙基1-乙基-4,6-二氢吡咯并[3,4-d]咪唑-2,5(1H)-二甲酸酯(11.0g，0.036mol)，氨甲醇溶液(30mL，7.0mol)加入100mL的高压反应釜中搅拌并加热到80℃-90℃反应6小时。将反应液浓缩至干，加入醋酸异丙酯(80mL)并回流0.5小时，冷至室温，过滤，滤饼用醋酸异丙酯(20mL×2)洗涤，将滤饼烘干得到2-甲酰胺基-3-乙基-4,6-二氢吡咯[3,4-d]咪唑-5-甲酸叔丁酯，白色固体(9.2g，收率：92.3％)。5-tert-Butyl 2-ethyl 1-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate (11.0 g, 0.036 mol) Ammonia methanol solution (30 mL, 7.0 mol) was added to a 100 mL autoclave and stirred and heated to 80 ° C - 90 ° C for 6 hours. The reaction solution was concentrated to dryness. EtOAc (EtOAc) (EtOAc)EtOAc. Tert-butyl 3-ethyl-4,6-dihydropyrrole [3,4-d]imidazole-5-carboxylate, white solid (9.2 g, yield: 92.3%).

LCMS m/z＝281.1[M+1]。LCMS m/z = 281.1 [M + 1].

第十步：3-乙基-5,6-二氢-4H-吡咯[3,4-d]咪唑-2-甲酰胺(中间体2)Step 10: 3-Ethyl-5,6-dihydro-4H-pyrrole [3,4-d]imidazole-2-carboxamide (Intermediate 2)

将2-甲酰胺基-3-乙基-4,6-二氢吡咯[3,4-d]咪唑-5-甲酸叔丁酯(9.0g，0.032mol)和醋酸异丙酯(100mL)依次加入反应瓶中，加入苯磺酸一水合物(11.31g，0.064mol)，加毕于85℃～90℃间反应1小时。反应液冷却到室温后，过滤，滤饼用醋酸异丙酯(400mL)洗涤并抽滤干，烘干得到3-乙基-5,6-二氢-4H-吡咯[3,4-d]咪唑-2-甲酰胺二苯磺酸盐，白色固体(14.2g，收率89.3％)。取白色固体2g悬浮于二氯甲烷(30mL)中，再加入三乙胺(2g)反应液呈浑浊，于室温搅拌1小时后，过滤，得3-乙基-5,6-二氢-4H-吡咯[3,4-d]咪唑-2-甲酰胺(中间体2)，白色固体(0.7g，收率96.4％)。2-Carboxamido-3-ethyl-4,6-dihydropyrrole [3,4-d]imidazole-5-carboxylic acid tert-butyl ester (9.0 g, 0.032 mol) and isopropyl acetate (100 mL) The reaction mixture was placed in a reaction flask, and benzenesulfonic acid monohydrate (11.31 g, 0.064 mol) was added thereto, and the mixture was reacted at 85 ° C to 90 ° C for 1 hour. After the reaction solution was cooled to room temperature, it was filtered, and the filter cake was washed with isopropyl acetate (400 mL) and filtered and dried to give 3-ethyl-5,6-dihydro-4H-pyrrole [3,4-d] Imidazole-2-carboxamide diphenyl sulfonate, white solid (14.2 g, yield 89.3%). 2 g of a white solid was suspended in dichloromethane (30 mL), and then the reaction mixture was added to triethylamine (2 g) to be turbid, stirred at room temperature for 1 hour, and then filtered to give 3-ethyl-5,6-dihydro-4H. Pyrrole [3,4-d]imidazole-2-carboxamide (Intermediate 2), white solid (0.7 g, yield 96.4%).

LCMS m/z＝181.1[M+1]。LCMS m/z = 181.1 [M + 1].

¹H NMR(400MHz,CD₃OD)δ4.44-4.43(q,2H),4.05(s,2H),3.88(s,2H),1.39-1.36(t,3H)。 ¹ H NMR (400 MHz, CD ₃ OD) δ 4.44 - 4.43 (q, 2H), 4.05 (s, 2H), 3.88 (s, 2H), 1.39-1.36 (t, 3H).

中间体3:3-甲基-2-(1-甲基-1H-四唑-5-基)-5,6-二氢-4H-吡咯并[3,4-d]咪唑苯磺酸盐Intermediate 3: 3-methyl-2-(1-methyl-1H-tetrazol-5-yl)-5,6-dihydro-4H-pyrrolo[3,4-d]imidazolebenzenesulfonate

3-methyl-2-(1-methyltetrazol-5-yl)-5,6-dihydro-4H-pyrrolo[3,4-d]imidazole benzenesulfonic acid3-methyl-2-(1-methyltetrazol-5-yl)-5,6-dihydro-4H-pyrrolo[3,4-d]imidazole benzenesulfonic acid

第一步：2-氰基-3-甲基-4,6-二氢吡咯并[3,4-d]咪唑-5-羧酸叔丁酯(3b)First step: 2-cyano-3-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5-carboxylic acid tert-butyl ester (3b)

tert-butyl 2-cyano-3-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5-carboxylateTert-butyl 2-cyano-3-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5-carboxylate

将2-氨基甲酰基-3-甲基-4,6-二氢吡咯[3,4-d]咪唑-5-羧酸叔丁酯(3a)(350g,1.3moL)与二氯甲烷(3500mL)混合，加入三乙胺(345.5g,3.4moL)，搅拌并降温到0℃，保持体系内温在-2℃～0℃下滴加三氟乙酸酐(359.2g,1.7moL)。加毕保持温度不超过10℃搅拌反应2小时。搅拌下将反应液慢慢加入冰水(8000mL)中，加入适量食盐使之半饱和状态，分液，水相用二氯甲烷(150mL×3)萃取，合并有机相，并用半饱和食盐水(2000mL×3)洗涤。有机相用无水硫酸钠干燥，过滤，浓缩至约200mL溶剂残留时，加入石油醚(2000mL)搅拌30分钟，过滤，滤饼用石油醚(300mL×3)洗涤，烘干，得白色固体状的2-氰基-3-甲基-4,6-二氢吡咯并[3,4-d]咪唑-5-羧酸叔丁酯(3b)(325.6g,收率99.7％)。2-carbamoyl-3-methyl-4,6-dihydropyrrole [3,4-d]imidazole-5-carboxylic acid tert-butyl ester (3a) (350 g, 1.3 mol) and dichloromethane (3500 mL) After mixing, triethylamine (345.5 g, 3.4 moL) was added, stirred and cooled to 0 ° C, and trifluoroacetic anhydride (359.2 g, 1.7 moL) was added dropwise at -2 ° C to 0 ° C while maintaining the internal temperature of the system. The reaction was stirred for 2 hours while maintaining the temperature not exceeding 10 °C. The reaction solution was slowly added to ice water (8000 mL) with stirring, and an appropriate amount of salt was added to make it semi-saturated. The liquid phase was separated, and the aqueous phase was extracted with dichloromethane (150 mL×3), and the organic phase was combined with a half-saturated brine. 2000 mL × 3) washing. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to ethyl acetate (200 mL). The mixture was stirred for 30 mins with petroleum ether (2000 mL), filtered, filtered, washed with petroleum ether (300 mL×3) and dried to give a white solid. 2-Cyano-3-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5-carboxylic acid tert-butyl ester (3b) (325.6 g, yield 99.7%).

第二步：3-甲基-2-(1H-四唑-5-基)-4,6-二氢吡咯并[3,4-d]咪唑-5-羧酸叔丁酯(3c)Second step: 3-methyl-2-(1H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5-carboxylic acid tert-butyl ester (3c)

tert-butyl 3-methyl-2-(1H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5-carboxylateTert-butyl 3-methyl-2-(1H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5-carboxylate

将2-氰基-3-甲基-4,6-二氢吡咯并[3,4-d]咪唑-5-羧酸叔丁酯(3b)(324.5g,1.3moL)溶于N,N-二甲基甲酰胺(3200mL)中，加入叠氮钠(187.1g,2.9moL)和三乙胺盐酸盐(396.2g,2.9moL)，于120℃下搅拌反应2小时。将反应液冷却到室温，加入冰水(5.4L)，冰盐浴下用盐酸溶液(3mol/L)调pH值至2-3，析出白色固体，过滤，滤饼用水(1000mL×3)洗涤，烘干，得白色固体状的3-甲基-2-(1H-四唑-5-基)-4,6-二氢吡咯并[3,4-d]咪唑-5-羧酸叔丁酯(3c)(381g,收率85.9％)。2-Chloro-3-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5-carboxylic acid tert-butyl ester (3b) (324.5 g, 1.3 moL) was dissolved in N, N To the dimethylformamide (3200 mL), sodium azide (187.1 g, 2.9 mol) and triethylamine hydrochloride (396.2 g, 2.9 mol) were added, and the reaction was stirred at 120 ° C for 2 hours. The reaction solution was cooled to room temperature, ice water (5.4 L) was added, and the pH was adjusted to 2-3 with a hydrochloric acid solution (3 mol/L) in an ice salt bath to precipitate a white solid, which was filtered, and the filter cake was washed with water (1000 mL×3). , dried to give 3-methyl-2-(1H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5-carboxylic acid tert-butyl as a white solid. Ester (3c) (381 g, yield 85.9%).

第三步：3-甲基-2-(1-甲基-1H-四唑-5-基)-4,6-二氢吡咯并[3,4-d]咪唑-5-羧酸叔丁酯(3d) 与叔丁基1-甲基-2-(2-甲基-2H-四唑-5-基)-4,6-二氢吡咯并[3,4-d]咪唑-5-羧酸叔丁酯(3e)的混合物The third step: 3-methyl-2-(1-methyl-1H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5-carboxylic acid tert-butyl Ester (3d) And tert-butyl 1-methyl-2-(2-methyl-2H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5-carboxylic acid tert-butyl a mixture of esters (3e)

tert-butyl 3-methyl-2-(1-methyltetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5-carboxylate(3d)Tert-butyl 3-methyl-2-(1-methyltetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5-carboxylate(3d)

tert-butyl 3-methyl-2-(2-methyltetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5-carboxylate(3e)Tert-butyl 3-methyl-2-(2-methyltetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5-carboxylate(3e)

将3-甲基-2-(1H-四唑-5-基)-4,6-二氢吡咯并[3,4-d]咪唑-5-羧酸叔丁酯(3c)(65g,0.2moL)溶于N,N-二甲基乙酰胺(650mL)中，降温到0℃，搅拌下将N,N-二异丙乙胺(34.68g,0.268mol)加入反应液中，加毕搅拌10分钟，保持反应液内温于-5℃～5℃，将硫酸二甲酯(30.9g,0.245mol)的N,N-二甲基乙酰胺(100mL)溶液滴加入反应液中，加毕于-5℃～5℃继续反应4小时。反应结束，在内温小于0℃下将水(1.3L)滴加至反应液中，搅拌，析出类白色固体。搅拌30分钟，过滤，滤饼依次用水(200mL×3)和石油醚(200mL×2)洗涤，抽滤，红外干燥，得白色固体化合物3-甲基-2-(1-甲基-1H-四唑-5-基)-4,6-二氢吡咯并[3,4-d]咪唑-5-羧酸叔丁酯(3d)与叔丁基1-甲基-2-(2-甲基-2H-四唑-5-基)-4,6-二氢吡咯并[3,4-d]咪唑-5-羧酸叔丁酯(3e)的混合物，其中化合物3d含量85％(62g,产率91％)。3-methyl-2-(1H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5-carboxylic acid tert-butyl ester (3c) (65 g, 0.2 moL) was dissolved in N,N-dimethylacetamide (650 mL), cooled to 0 ° C, and N,N-diisopropylethylamine (34.68 g, 0.268 mol) was added to the reaction mixture under stirring, and the mixture was stirred. 10 minutes, maintaining the internal temperature of the reaction solution at -5 ° C ~ 5 ° C, a solution of dimethyl sulfate (30.9g, 0.245 mol) of N, N-dimethylacetamide (100mL) was added dropwise to the reaction solution, added The reaction was continued at -5 ° C to 5 ° C for 4 hours. After completion of the reaction, water (1.3 L) was added dropwise to the reaction liquid at an internal temperature of less than 0 ° C, and stirred to precipitate a white solid. After stirring for 30 minutes, the filter cake was washed with water (200 mL×3) and petroleum ether (200 mL×2), filtered, and dried in vacuo to give white solid compound 3-methyl-2-(1-methyl-1H- Tetrabutyl-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5-carboxylic acid tert-butyl ester (3d) with tert-butyl 1-methyl-2-(2-methyl a mixture of benzyl-2H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5-carboxylic acid tert-butyl ester (3e), wherein the compound 3d content is 85% (62 g) , yield 91%).

LCMS m/z＝306.1[M+1]。LCMS m/z = 306.1 [M + 1].

¹H NMR(400MHz,DMSO-d6):δ4.58-4.54(d,2H),4.40-4.37(d,2H),4.34(d,3H),3.99(s,3H),1.48-1.47(d,9H)。 ^{1 H NMR (400MHz, DMSO-} d6): δ4.58-4.54 (d, 2H), 4.40-4.37 (d, 2H), 4.34 (d, 3H), 3.99 (s, 3H), 1.48-1.47 (d , 9H).

第四步：3-甲基-2-(1-甲基-1H-四唑-5-基)-5,6-二氢-4H-吡咯并[3,4-d]咪唑苯磺酸盐(中间体3)Fourth step: 3-methyl-2-(1-methyl-1H-tetrazol-5-yl)-5,6-dihydro-4H-pyrrolo[3,4-d]imidazolium sulfonate (Intermediate 3)

将3-甲基-2-(1-甲基-1H-四唑-5-基)-4,6-二氢吡咯并[3,4-d]咪唑-5-羧酸叔丁酯(3d)与叔丁基1-甲基-2-(2-甲基-2H-四唑-5-基)-4,6-二氢吡咯并[3,4-d]咪唑-5-羧酸叔丁酯(3e)的混合物(111.4g,0.37moL，其中化合物3d含量80％以上)和甲醇(1200mL)加入反应瓶中，加入苯磺酸.1.5H₂O(128.6g,0.73moL)，加毕，于60℃～70℃反应4小时。反应结束，将反应液冷却到室温，加入乙酸异丙酯(600mL)搅拌20分钟，过滤，滤饼用乙酸异丙酯(400mL)洗涤，抽滤，烘干，得白色固体状的3-甲基-2-(1-甲基-1H-四唑-5-基)-5,6-二氢-4H-吡咯并[3,4-d]咪唑苯磺酸盐(中间体3)(107g,收率80.7％,HPLC:99.13％)。3-methyl-2-(1-methyl-1H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5-carboxylic acid tert-butyl ester (3d And t-butyl 1-methyl-2-(2-methyl-2H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5-carboxylic acid A mixture of butyl ester (3e) (111.4 g, 0.37 mol, wherein the compound 3d content is 80% or more) and methanol (1200 mL) were added to the reaction flask, and benzenesulfonic acid .1.5H ₂ O (128.6 g, 0.73 mol) was added. After completion, the reaction was carried out at 60 ° C to 70 ° C for 4 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and then added with isopropyl acetate (600 mL), and the mixture was stirred for 20 minutes, filtered, and the filter cake was washed with isopropyl acetate (400 mL), filtered, and dried to give a white solid. 2-(1-methyl-1H-tetrazol-5-yl)-5,6-dihydro-4H-pyrrolo[3,4-d]imidazolebenzenesulfonate (Intermediate 3) (107 g , yield 80.7%, HPLC: 99.13%).

LCMS m/z＝206.2[M+1]；LCMS m/z = 206.2 [M + 1];

¹H NMR(400MHz,DMSO-d6):δ9.87(s,2H),7.61-7.59(m,2H),7.32-7.30(m,3H),4.55(s,2H),4.35(s,2H),4.32(s,3H),4.0(s,3H)。 ¹ H NMR (400 MHz, DMSO-d6): δ 9.87 (s, 2H), 7.61 - 7.59 (m, 2H), 7.32-7.30 (m, 3H), 4.55 (s, 2H), 4.35 (s, 2H) ), 4.32 (s, 3H), 4.0 (s, 3H).

中间体4：二甲基2-(溴甲基)苯基-1,4-二羧酸酯Intermediate 4: dimethyl 2-(bromomethyl)phenyl-1,4-dicarboxylate

dimethyl 2-(bromomethyl)benzene-1,4-dicarboxylateDimethyl 2-(bromomethyl)benzene-1,4-dicarboxylate

称取2-甲基-1,4-苯二甲酸二甲酯(1a,6.24g,30.0mmol)，置于250mL圆底烧瓶中，向反应瓶中加入氯苯(150mL)。向反应瓶中依次加入N-溴代丁二酰亚胺(5.6g,31.5mmol)，过氧化苯甲酰(0.07,0.3mmol)，反应升值至85℃下搅拌4小时。待反应冷至室温，减压浓缩除去大部分反应溶剂，向残余物中加入碳酸氢钠水溶液(100mL)，乙酸乙酯(200mL×2)萃取，合并后的有机相用饱和食盐水洗(100mL)，无水硫酸钠干燥后，减压浓缩柱层析分离[(石油醚/乙酸乙酯(v/v)＝15:1)]得到白色固体状的二甲基2-(溴甲基)苯基-1,4-二羧酸酯(中间体4)(4.8g,产率56％)。Dimethyl 2-methyl-1,4-phthalic acid (1a, 6.24 g, 30.0 mmol) was weighed and placed in a 250 mL round bottom flask, and chlorobenzene (150 mL) was added to the reaction flask. N-bromosuccinimide (5.6 g, 31.5 mmol), benzoyl peroxide (0.07, 0.3 mmol) was added to the reaction flask, and the mixture was stirred at 85 ° C for 4 hours. The reaction mixture was cooled to room temperature, and the residue was evaporated to dryness crystals crystalssssssssssssssssssssssssss After drying over anhydrous sodium sulfate, EtOAc (EtOAc/EtOAc (v/v) = 15:1) Base-1,4-dicarboxylate (Intermediate 4) (4.8 g, yield 56%).

¹H NMR(400MHz,CDCl₃)δ8.11(s,1H),7.99-7.98(d,2H),4.94(s,2H),3.95(s,3H),3.93(s,3H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.11 (s, 1H), 7.99-7.98 (d, 2H), 4.94 (s, 2H), 3.95 (s, 3H), 3.93 (s, 3H).

实施例1：[1-[3-[5-[(4-氨基甲酰基-1-哌啶基)甲基]二氢吲哚-1-基]-3-氧代-丙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物1)Example 1: [1-[3-[5-[(4-carbamoyl-1-piperidyl)methyl]indan-1-yl]-3-oxo-propyl]-4 -piperidinyl]N-(2-phenylphenyl)carbamate (Compound 1)

[1-[3-[5-[(4-carbamoyl-1-piperidyl)methyl]indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate[1-[3-[5-[(4-carbamoyl-1-piperidyl)methyl]indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

第一步：[1-[3-(5-甲酰基二氢吲哚-1-基)-3-氧代-丙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(1B)First step: [1-[3-(5-formylindan-1-yl)-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl) Amino Acid ester (1B)

[1-[3-(5-formylindolin-1-yl)-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate[1-[3-(5-formylindolin-1-yl)-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

取4-哌啶基N-(2-苯基苯基)氨基甲酸酯(1A)(参考WO2012009166制备得到)(0.15g，0.5mmol)和1-丙烯酰基二氢吲哚-5-醛(中间体1)(0.10g，0.5mmol)置于25mL圆底烧瓶中，加入四氢呋喃(10mL)，室温反应24小时。反应完全后，反应液直接减压浓缩，残留物用硅胶柱层析纯化(三乙胺/乙酸乙酯(v/v)＝1:100)，得到标题产物[1-[3-(5-甲醛二氢吲哚-1-基)-3-氧代-丙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(1B)，浅黄色固体(0.22g,产率88％)。4-piperidinyl N-(2-phenylphenyl)carbamate (1A) (prepared by reference to WO2012009166) (0.15 g, 0.5 mmol) and 1-acryloylindolin-5-aldehyde ( Intermediate 1) (0.10 g, 0.5 mmol) was placed in a 25 mL round bottom flask, and tetrahydrofuran (10 mL) was added and allowed to react at room temperature for 24 hours. After the completion of the reaction, the reaction mixture was evaporated to drynesshhhhhhhhhhhhhhhhhhhh Formaldehyde indoline-1-yl)-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (1B), light yellow solid (0.22 g , yield 88%).

LCMS m/z＝498.1[M+1]。LCMS m/z = 498.1 [M + 1].

第二步：[1-[3-[5-[(4-氨基甲酰基-1-哌啶基)甲基]二氢吲哚-1-基]-3-氧代-丙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物1)Second step: [1-[3-[5-[(4-carbamoyl-1-piperidyl)methyl]indan-1-yl]-3-oxo-propyl]-4 -piperidinyl]N-(2-phenylphenyl)carbamate (Compound 1)

取[1-[3-(5-甲醛二氢吲哚-1-基)-3-氧代-丙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(1B)(0.35g，0.7mmol)和4-哌啶甲酰胺(1C)(0.18g，1.4mmol)置于50mL圆底烧瓶中，加入异丙醇(20mL)，60℃条件下搅拌30分钟后，60℃减压浓缩1小时后，向残留物中加入异丙醇(20mL)、无水硫酸钠(0.20g,1.4mmol)和乙酸(0.24mL,4.2mmol)，搅拌均匀后，于0℃条件下加入三乙酰氧基硼氢化钠(0.45g，3.1mmol)，升至室温反应3小时。反应结束后，反应液加入饱和碳酸氢钠溶液(30mL)淬灭反应，二氯甲烷(30mL×2)萃取，合并有机相，有机相依次用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱层析纯化((二氯甲烷/甲醇(v/v)＝1:8)，得到标题[1-[3-[5-[(4-氨基甲酰基-1-哌啶基)甲基]二氢吲哚-1-基]-3-氧代-丙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物1)，白色固体(0.19g，收率44％)。Taking [1-[3-(5-formaldehydedihydroindol-1-yl)-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (1B) (0.35g, 0.7mmol) and 4-piperidinecarboxamide (1C) (0.18g, 1.4mmol) were placed in a 50mL round bottom flask, isopropyl alcohol (20mL) was added, and stirred at 60 ° C for 30 minutes After concentrating under reduced pressure at 60 ° C for 1 hour, isopropyl alcohol (20 mL), anhydrous sodium sulfate (0.20 g, 1.4 mmol) and acetic acid (0.24 mL, 4.2 mmol) were added to the residue. Sodium triacetoxyborohydride (0.45 g, 3.1 mmol) was added at ° C, and the mixture was allowed to react at room temperature for 3 hr. After the reaction was completed, the reaction mixture was evaporated and evaporated, evaporated, evaporated, evaporated The residue was purified with EtOAc EtOAcjjjjjjjjjjj )methyl]indoline-1-yl]-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (compound 1), white solid (0.19 g, yield 44%).

LCMS m/z＝305.7[M/2+1]。LCMS m/z = 305.7 [M/2 + 1].

¹H NMR(400MHz,DMSO-d6)δ8.67(s,1H),8.04(d,J＝8.1Hz,1H),7.54–7.31(m,8H),7.20(s,2H),7.09(d,J＝8.4Hz,1H),6.74(s,1H),4.51(s,1H),4.15(m,2H),3.42(m,2H), 3.18(s,2H),2.84(d,J＝11.4Hz,2H),2.65(s,5H),2.24(s,2H),2.08(m,1H),1.94(m,2H),1.81m,2H),1.70(m,2H),1.57(m,4H),1.30(s,2H)。 ^{1 H NMR (400MHz, DMSO-} d6) δ8.67 (s, 1H), 8.04 (d, J = 8.1Hz, 1H), 7.54-7.31 (m, 8H), 7.20 (s, 2H), 7.09 (d , J = 8.4 Hz, 1H), 6.74 (s, 1H), 4.51 (s, 1H), 4.15 (m, 2H), 3.42 (m, 2H), 3.18 (s, 2H), 2.84 (d, J = 11.4 Hz, 2H), 2.65 (s, 5H), 2.24 (s, 2H), 2.08 (m, 1H), 1.94 (m, 2H), 1.81 m, 2H), 1.70 (m, 2H), 1.57 (m) , 4H), 1.30 (s, 2H).

实施例2：[1-[3-[5-[(2-氨基甲酰基-3-乙基-4,6-二氢吡咯[3,4-d]咪唑-5-基)甲基]二氢吲哚-1-基]-3-氧代-丙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物2)Example 2: [1-[3-[5-[(2-carbamoyl-3-ethyl-4,6-dihydropyrrole[3,4-d]imidazol-5-yl)methyl]) Hydroquinone-1-yl]-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (Compound 2)

[1-[3-[5-[(2-carbamoyl-3-ethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-yl)methyl]indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate[1-[3-[5-[(2-carbamoyl-3-ethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-yl)methyl]indolin-1-yl]-3-oxo- Propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

取[1-[3-(5-甲醛二氢吲哚-1-基)-3-氧代-丙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(1B)(0.35g，0.7mmol)和3-乙基-5,6-二氢-4H-吡咯[3,4-d]咪唑-2-甲酰胺(中间体2)(0.25g，1.4mmol)置于50mL圆底烧瓶中，加入异丙醇(20mL)，温度升至60℃下搅拌30分钟后，60℃减压浓缩1小时，向残留物中加入异丙醇(20mL)、无水硫酸钠(0.20g,1.4mmol)和乙酸(0.24mL,4.2mmol)，搅拌均匀后，于0℃条件下加入三乙酰氧基硼氢化钠(0.45g，3.1mmol)，升至室温反应3小时。反应结束后，反应液加入饱和碳酸氢钠溶液(30mL)淬灭反应，二氯甲烷(30mL×2)萃取，合并有机相，有机相依次用无水硫酸钠干燥，减压浓缩，残留物经硅胶柱层析纯化(二氯甲烷/甲醇(v/v)＝1:8)，得到标题化合物[1-[3-[5-[(2-氨基甲酰基-3-乙基-4,6-二氢吡咯[3,4-d]咪唑-5-基)甲基]二氢吲哚-1-基]-3-氧代-丙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物2),白色固体(0.31g，收率67％)。Taking [1-[3-(5-formaldehydedihydroindol-1-yl)-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (1B) (0.35 g, 0.7 mmol) and 3-ethyl-5,6-dihydro-4H-pyrrole[3,4-d]imidazole-2-carboxamide (Intermediate 2) (0.25 g, 1.4 mmol Placed in a 50 mL round bottom flask, add isopropanol (20 mL), stir at a temperature of 60 ° C for 30 minutes, then concentrate at 60 ° C for 1 hour under reduced pressure, and add isopropanol (20 mL) to the residue. Sodium sulphate (0.20 g, 1.4 mmol) and acetic acid (0.24 mL, 4.2 mmol) were stirred, and then sodium triacetoxyborohydride (0.45 g, 3.1 mmol) was added at 0 ° C, and allowed to react to room temperature for 3 hours. . After the reaction was completed, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The title compound [1-[3-[5-[(2-carbamoyl-3-ethyl-4,6) was obtained. -dihydropyrrole[3,4-d]imidazol-5-yl)methyl]indan-1-yl]-3-oxo-propyl]-4-piperidinyl]N-(2- Phenylphenyl)carbamate (Compound 2), white solid (0.31 g, yield 67%).

LCMS m/z＝662.3[M+1]。LCMS m/z = 662.3 [M + 1].

¹H NMR(400MHz,DMSO-d6)δ8.62(s,1H),8.02(d,J＝8.2Hz,1H),7.62(s,1H),7.47–7.21(m,11H),7.15(d,J＝8.0Hz,1H),4.46(s,1H),4.41–4.30(m,2H),4.12(t,J＝8.4Hz,2H),4.04(d,J＝7.1Hz,1H),3.89(s,2H),3.81(s,2H),3.67(s,2H),3.14(t,J＝8.4Hz,2H),2.61(s,6H),2.19(s,2H),2.00(s,1H),1.72(s,2H),1.45(s,2H)。 ^{1 H NMR (400MHz, DMSO-} d6) δ8.62 (s, 1H), 8.02 (d, J = 8.2Hz, 1H), 7.62 (s, 1H), 7.47-7.21 (m, 11H), 7.15 (d , J=8.0Hz, 1H), 4.46(s,1H), 4.41–4.30(m,2H), 4.12(t,J=8.4Hz,2H),4.04(d,J=7.1Hz,1H),3.89 (s, 2H), 3.81 (s, 2H), 3.67 (s, 2H), 3.14 (t, J = 8.4 Hz, 2H), 2.61 (s, 6H), 2.19 (s, 2H), 2.00 (s, 1H), 1.72 (s, 2H), 1.45 (s, 2H).

实施例3：[(3aS,5r,6aR)-2-[2-[[4-[(4-氨基甲酰基-1-哌啶基)甲基]苯甲酰]-甲基-胺基]乙基]-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(化合物3)Example 3: [(3aS,5r,6aR)-2-[2-[[4-[(4-carbamoyl-1-piperidyl)methyl]benzoyl]-methyl-amino] Ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ( Compound 3)

[(3aS,5r,6aR)-2-[2-[[4-[(4-carbamoyl-1-piperidyl)methyl]benzoyl]-methyl-amino]ethyl]-3,3 a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate[(3aS,5r,6aR)-2-[2-[[4-[(4-carbamoyl-1-piperidyl)methyl]benzoyl]-methyl-amino]ethyl]-3,3 a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

第一步：[(3aS,5r,6aR)-1,2,3,3a,4,5,6,6a-八氢环戊二烯并[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(3B)First step: [(3aS,5r,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2- Phenylphenyl)carbamate (3B)

[(3aS,5r,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate[(3aS,5r,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

取(3aS,5r,6aR)-5-羟基-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯-2-羧酸叔丁基酯(3A)(参考CN102146084制备得到)(2.27g，10mmol)和2-苯基苯基异氰酸酯(1.95g，10mmol)置于100mL圆底烧瓶中，加入四氢呋喃(40mL)和三乙胺(2.77mL，20mmol)，加热至回流反应6小时。反应液冷却至室温，减压浓缩，残留物加入到二氯甲烷(20mL)中，冷却至0℃，滴加三氟乙酸(10mL)，室温反应1小时后，将体系减压浓缩，加入二氯甲烷(20mL)，三乙胺调至碱性，加入饱和碳酸氢钠溶液(20mL)，二氯甲烷(30mL×2)萃取，合并有机相，有机相依次用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱层析纯化(二氯甲烷/甲醇(v/v)＝1:15)，得到[(3aS,5r,6aR)-1,2,3,3a,4,5,6,6a-八氢环戊二烯并[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(3B),棕黄色固体(1.91g，产率59％)。(3aS,5r,6aR)-5-hydroxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester (3A (prepared by reference to CN102146084) (2.27g, 10mmol) and 2-phenylphenylisocyanate (1.95g, 10mmol) were placed in a 100mL round bottom flask, tetrahydrofuran (40mL) and triethylamine (2.77mL, 20mmol) Heat to reflux for 6 hours. The reaction mixture was cooled to room temperature, and the mixture was evaporated. EtOAcjjjjjjjjjjjjjjjj Methyl chloride (20 mL), triethylamine was added to EtOAc (3 mL), EtOAc (EtOAc) The filtrate was concentrated under reduced pressure. EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 5,6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (3B), brown solid (1.91 g, yield 59 %).

LCMS m/z＝323.3[M+1]。LCMS m/z = 323.3 [M + 1].

第二步：[(3aS,5r,6aR)-2-(2-甲基氨乙基)-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯-5-基] N-(2-苯基苯基)氨基甲酸酯(3D)Second step: [(3aS,5r,6aR)-2-(2-methylaminoethyl)-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadienyl[c] Pyrrole-5-yl] N-(2-phenylphenyl)carbamate (3D)

[(3aS,5r,6aR)-2-(2-methylaminoethyl)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate[(3aS,5r,6aR)-2-(2-methylaminoethyl)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl) Carbamate

取[(3aS,5r,6aR)-1,2,3,3a,4,5,6,6a-八氢环戊二烯并[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(3B)(0.97g,3mmol)和N-甲基-N-(2-氧乙基)氨基甲酸苄基酯(3C)(0.62g，3mmol)(参考WO2012009166制备得到)置于50mL圆底烧瓶中，加入甲醇(20mL)，室温搅拌1小时后，加入三乙酰氧基硼氢化钠(1.90g，9mmol)，继续反应3小时，反应结束后，饱和碳酸氢钠溶液(30mL)淬灭反应，二氯甲烷(30mL×2)萃取，合并有机相，有机相用依次用饱和食盐水(40mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，向残留物中加入甲醇(20mL)和10％(w/w)钯碳(0.1g)，氢气氛围下室温反应6小时，硅藻土过滤，减压浓缩，残留物经硅胶柱层析纯化(二氯甲烷/甲醇(v/v)＝1:10)，得到标题化合物[(3aS,5r,6aR)-2-(2-甲基氨乙基)-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(3D)，透明油状液体(0.70g，产率61％)。Taking [(3aS,5r,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene Carbamate (3B) (0.97 g, 3 mmol) and benzyl N-methyl-N-(2-oxoethyl)carbamate (3C) (0.62 g, 3 mmol) (prepared by reference to WO2012009166) The mixture was placed in a 50 mL round bottom flask, and methanol (20 mL) was added. After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (1.90 g, 9 mmol) was added and the reaction was continued for 3 hours. After completion of the reaction, a saturated sodium hydrogencarbonate solution ( The reaction was quenched with EtOAc (3 mL, EtOAc) (EtOAc) Methanol (20 mL) and 10% (w/w) palladium on carbon (0.1 g) were added, and the mixture was reacted for 6 hours at room temperature under a hydrogen atmosphere, filtered over Celite, and evaporated. Methane/methanol (v/v) = 1 : 10) gave the title compound [(3aS,5r,6aR)-2-(2-methylaminoethyl)-3,3a,4,5,6,6a- Hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (3D), a clear oily liquid (0.70 g, yield 61%).

LCMS m/z＝380.2[M+1]。LCMS m/z = 380.2 [M + 1].

第三步：[(3aS,5r,6aR)-2-[2-[(4-甲酰基苯甲酰基)-甲基-胺基]乙基]-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(3E)The third step: [(3aS,5r,6aR)-2-[2-[(4-formylbenzoyl)-methyl-amino]ethyl]-3,3a,4,5,6,6a -Hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (3E)

[(3aS,5r,6aR)-2-[2-[(4-formylbenzoyl)-methyl-amino]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate[(3aS,5r,6aR)-2-[2-[(4-formylbenzoyl)-methyl-amino]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol- 5-yl]N-(2-phenylphenyl)carbamate

取[(3aS,5r,6aR)-2-(2-甲基氨乙基)-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(3D)(0.43g，1.08mmol)和4-甲酰基苯甲酸(0.16g，1.08mmol)置于2-甲基四氢呋喃(20mL)中，室温搅拌30分钟后，加入4-(4,6-二甲氧基三嗪)-4-甲基吗啉盐酸盐(0.35g，1.19mmol)，继续反应4小时。反应结束后，反应液直接减压浓缩，残留物通过硅胶柱层析纯化(三乙胺/乙酸乙酯(v/v)＝1:100)，得到标题化合物[(3aS,5r,6aR)-2-[2-[(4-甲酰基苯甲酰基)-甲基-胺基]乙基]-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(3E)，透明油状液体(0.41g,产率:74％)。Taking [(3aS,5r,6aR)-2-(2-methylaminoethyl)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5 -N-(2-phenylphenyl)carbamate (3D) (0.43 g, 1.08 mmol) and 4-formylbenzoic acid (0.16 g, 1.08 mmol) in 2-methyltetrahydrofuran (20 mL) After stirring at room temperature for 30 minutes, 4-(4,6-dimethoxytriazine)-4-methylmorpholine hydrochloride (0.35 g, 1.19 mmol) was added, and the reaction was continued for 4 hours. After completion of the reaction, the reaction mixture was evaporated to mjjjjjjjjjjjjjjjj 2-[2-[(4-formylbenzoyl)-methyl-amino]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadienyl[c Pyrrole-5-yl]N-(2-phenylphenyl)carbamate (3E), a clear oily liquid (0.41 g, yield: 74%).

LCMS m/z＝512.0[M+1]。 LCMS m/z = 512.0 [M + 1].

第四步：[(3aS,5r,6aR)-2-[2-[[4-[(4-氨基甲酰基-1-哌啶基)甲基]苯甲酰基]-甲基-胺基]乙基]-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(化合物3)Fourth step: [(3aS,5r,6aR)-2-[2-[[4-[(4-carbamoyl-1-piperidyl)methyl]benzoyl]-methyl-amino] Ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ( Compound 3)

[(3aS,5r,6aR)-2-[2-[[4-[(4-carbamoyl-1-piperidyl)methyl]benzoyl]-methyl-amino]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate[(3aS,5r,6aR)-2-[2-[[4-[(4-carbamoyl-1-piperidyl)methyl]benzoyl]-methyl-amino]ethyl]-3,3a,4,5,6, 6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

取[(3aS,5r,6aR)-2-[2-[(4-甲酰基苯甲酰基)-甲基-胺基]乙基]-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(3E)(0.41g，0.8mmol)和4-哌啶甲酰胺(1C)(0.21g，1.6mmol)置于50mL圆底烧瓶中，加入异丙醇(20mL)，60℃条件下搅拌30分钟后，60℃减压浓缩1小时，向残留物中加入异丙醇(20mL)、无水硫酸钠(0.23g,1.6mmol)和乙酸(0.27mL,4.8mmol)，搅拌均匀后，于0℃条件下加入三乙酰氧基硼氢化钠(0.51g，2.4mmol)，升至室温反应3小时。反应结束后饱和碳酸氢钠溶液(30mL)淬灭反应，二氯甲烷(30mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经硅胶柱层析纯化(二氯甲烷/甲醇(v/v)＝1:8)，得到标题化合物[(3aS,5r,6aR)-2-[2-[[4-[(4-氨基甲酰基-1-哌啶基)甲基]苯甲酰基]-甲基-胺基]乙基]-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(化合物3)，白色固体(0.31g,产率:67％)。Taking [(3aS,5r,6aR)-2-[2-[(4-formylbenzoyl)-methyl-amino]ethyl]-3,3a,4,5,6,6a-hexahydro -1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (3E) (0.41 g, 0.8 mmol) and 4-piperidinecarboxamide (1C (0.21 g, 1.6 mmol) was placed in a 50 mL round bottom flask, isopropanol (20 mL) was added, and the mixture was stirred at 60 ° C for 30 minutes, and then concentrated under reduced pressure at 60 ° C for 1 hour, and isopropyl alcohol was added to the residue ( 20 mL), anhydrous sodium sulfate (0.23 g, 1.6 mmol) and acetic acid (0.27 mL, 4.8 mmol). After stirring well, sodium triacetoxyborohydride (0.51 g, 2.4 mmol) was added at 0 ° C, liter The reaction was carried out for 3 hours at room temperature. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:8) gave the title compound [(3aS,5r,6aR)-2-[2-[[4-[(4-carbamoyl-1-piperidine) Methyl]benzoyl]-methyl-amino]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl N-(2-Phenylphenyl)carbamate (Compound 3), white solid (0.31 g, yield: 67%).

LCMS m/z＝312.7[M/2+1]。LCMS m/z = 312.7 [M/2+1].

¹H NMR(400MHz,DMSO-d6)δ8.49(s,1H),7.47–7.25(m,11H),7.18(s,1H),6.69(s,1H),4.66(m,2H),3.52(m,1H),3.46(s,2H),2.94(s,3H),2.79(d,J＝11.1Hz,2H),2.46–2.27(m,4H),2.17(m,2H),1.98(m,6H),1.58(m,4H),1.24(s,5H)。 ^{1 H NMR (400MHz, DMSO-} d6) δ8.49 (s, 1H), 7.47-7.25 (m, 11H), 7.18 (s, 1H), 6.69 (s, 1H), 4.66 (m, 2H), 3.52 (m, 1H), 3.46 (s, 2H), 2.94 (s, 3H), 2.79 (d, J = 11.1 Hz, 2H), 2.46 - 2.27 (m, 4H), 2.17 (m, 2H), 1.98 ( m, 6H), 1.58 (m, 4H), 1.24 (s, 5H).

实施例4：[(3aS,5s,6aR)-2-[2-[[4-[(4-氨基甲酰基-1-哌啶基)甲基]苯甲酰基]-甲基-胺基]乙基]-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(化合物4)Example 4: [(3aS,5s,6aR)-2-[2-[[4-[(4-carbamoyl-1-piperidyl)methyl]benzoyl]-methyl-amino] Ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ( Compound 4)

[(3aS,5s,6aR)-2-[2-[[4-[(4-carbamoyl-1-piperidyl)methyl]benzoyl]-methyl-amino]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate[(3aS,5s,6aR)-2-[2-[[4-[(4-carbamoyl-1-piperidyl)methyl]benzoyl]-methyl-amino]ethyl]-3,3a,4,5,6, 6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

第一步：[(3aS,5s,6aR)-1,2,3,3a,4,5,6,6a-八氢环戊二烯并[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(4B)First step: [(3aS,5s,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2- Phenylphenyl)carbamate (4B)

[(3aS,5s,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate[(3aS,5s,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

取(3aS,5s,6aR)-5-羟基-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯-2-羧酸叔丁酯(4A)(参考CN102146084制备得到)(4.56g，20mmol)和2-苯基苯基异氰酸酯(3.90g，20mmol)置于250mL圆底烧瓶中，加入四氢呋喃(80mL)和三乙胺(5.54mL，40mmol)，将体系加热至回流条件下，反应6小时。反应结束后，将体系减压浓缩，残留物加入到二氯甲烷(40mL)中，冷却至0℃，滴加三氟乙酸(20mL)，室温反应1小时后将体系减压浓缩，加入二氯甲烷(40mL)，三乙胺调至碱性，加入饱和碳酸氢钠溶液(60mL)，二氯甲烷(60mL×2)萃取，合并有机相，有机相依次用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱层析纯化(二氯甲烷/甲醇(v/v)＝1:15)，得到标题产物[(3aS,5s,6aR)-1,2,3,3a,4,5,6,6a-八氢环戊二烯并[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(4B)，棕黄色固体(5.0g，产率77％)。(3aS,5s,6aR)-5-hydroxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester (4A) (Prepared by reference to CN102146084) (4.56g, 20mmol) and 2-phenylphenylisocyanate (3.90g, 20mmol) were placed in a 250mL round bottom flask, tetrahydrofuran (80mL) and triethylamine (5.54mL, 40mmol). The system was heated to reflux and allowed to react for 6 hours. After completion of the reaction, the system was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjj Methane (40 mL), triethylamine was adjusted to basic. EtOAc (EtOAc) (EtOAc) The organic layer was concentrated under reduced EtOAcqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH ,5,6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (4B), brownish yellow solid (5.0 g, yield 77%).

LCMS m/z＝323.3[M+1]。LCMS m/z = 323.3 [M + 1].

第二步：[(3aS,5s,6aR)-2-(2-甲基胺乙基)-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(4C)Second step: [(3aS,5s,6aR)-2-(2-methylaminoethyl)-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadienyl[c] Pyrrol-5-yl]N-(2-phenylphenyl)carbamate (4C)

[(3aS,5s,6aR)-2-(2-methylaminoethyl)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate [(3aS,5s,6aR)-2-(2-methylaminoethyl)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl) Carbamate

取[(3aS,5s,6aR)-1,2,3,3a,4,5,6,6a-八氢环戊二烯并[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(4B)(1.73g，5.4mmol)和N-甲基-N-(2-氧乙基)氨基甲酸苄基酯(3C)(1.08g，5.4mmol)(参考WO2012009166制备得到)置于100mL圆底烧瓶中，加入甲醇(30mL)，室温搅拌1小时后，加入三乙酰氧基硼氢化钠(3.4g，16mmol)，继续反应3小时，反应结束后，饱和碳酸氢钠溶液(50mL)淬灭反应，二氯甲烷(50mL×2)萃取，合并有机相，有机相依次用饱和食盐水(60mL×1)洗涤，无水硫酸钠干燥，减压浓缩，向残留物中加入甲醇(30mL)和10％(w/w)钯碳(0.2g)，氢气氛围下室温反应6小时，硅藻土过滤，滤液减压浓缩，残留物经硅胶柱层析纯化((二氯甲烷/甲醇(v/v)＝1:10))后，得到标题化合物[(3aS,5s,6aR)-2-(2-甲基胺乙基)-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(4C)，透明油状物(0.92g，产率45％)。Taking [(3aS,5s,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene Carbamate (4B) (1.73 g, 5.4 mmol) and N-methyl-N-(2-oxoethyl)carbamate (3C) (1.08 g, 5.4 mmol) (Prepared by reference to WO2012009166) The solution was placed in a 100 mL round bottom flask, and methanol (30 mL) was added. After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (3.4 g, 16 mmol) was added to continue the reaction for 3 hours. After the reaction, saturated sodium hydrogencarbonate was added. The solution was quenched (50 mL), EtOAc (EtOAc m. Methanol (30 mL) and 10% (w/w) palladium on carbon (0.2 g) were added, and the mixture was reacted for 6 hours at room temperature under a hydrogen atmosphere, filtered over Celite, and the filtrate was evaporated. The title compound [(3aS,5s,6aR)-2-(2-methylaminoethyl)-3,3a,4,5,6, after methane/methanol (v/v) = 1 : 10), 6a-Hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (4C), transparent oil (0.92 g, yield 45%) ).

LCMS m/z＝380.2[M+1]。LCMS m/z = 380.2 [M + 1].

第三步：[(3aS,5s,6aR)-2-[2-[(4-甲酰基苯甲酰基)-甲基-氨基]乙基]-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(4D)The third step: [(3aS,5s,6aR)-2-[2-[(4-formylbenzoyl)-methyl-amino]ethyl]-3,3a,4,5,6,6a- Hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (4D)

[(3aS,5s,6aR)-2-[2-[(4-formylbenzoyl)-methyl-amino]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate[(3aS,5s,6aR)-2-[2-[(4-formylbenzoyl)-methyl-amino]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol- 5-yl]N-(2-phenylphenyl)carbamate

取[(3aS,5s,6aR)-2-(2-甲基氨乙基)-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(4C)(0.45g，1.2mmol)和4-甲酰基苯甲酸(0.21g，1.4mmol)置于2-甲基四氢呋喃(20mL)中，室温搅拌30分钟后，加入4-(4,6-二甲氧基三嗪)-4-甲基吗啉盐酸盐(0.38g，1.3mmol)，继续反应4小时。反应结束后，反应液减压浓缩，残留物用硅胶柱层析纯化(三乙胺/乙酸乙酯(v/v)＝1:100)，得到标题化合物[(3aS,5s,6aR)-2-[2-[(4-甲酰基苯甲酰基)-甲基-氨基]乙基]-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(4D)，透明油状物(0.46g，产率76％)。Taking [(3aS,5s,6aR)-2-(2-methylaminoethyl)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5 -N-(2-phenylphenyl)carbamate (4C) (0.45 g, 1.2 mmol) and 4-formylbenzoic acid (0.21 g, 1.4 mmol) in 2-methyltetrahydrofuran (20 mL) After stirring at room temperature for 30 minutes, 4-(4,6-dimethoxytriazine)-4-methylmorpholine hydrochloride (0.38 g, 1.3 mmol) was added, and the reaction was continued for 4 hr. After completion of the reaction, the reaction mixture was evaporated.jjjjjjjjjjjjjjjjj -[2-[(4-formylbenzoyl)-methyl-amino]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole -5-yl]N-(2-phenylphenyl)carbamate (4D), viscous oil (0.46 g, yield 76%).

LCMS m/z＝512.0[M+1]。LCMS m/z = 512.0 [M + 1].

第四步：[(3aS,5s,6aR)-2-[2-[[4-[(4-氨基甲酰基-1-哌啶基)甲基]苯甲酰基]-甲基-胺基]乙基]-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(化合物4) Fourth step: [(3aS,5s,6aR)-2-[2-[[4-[(4-carbamoyl-1-piperidyl)methyl]benzoyl]-methyl-amino] Ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ( Compound 4)

取[(3aS,5s,6aR)-2-[2-[(4-甲酰基苯甲酰基)-甲基-氨基]乙基]-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(4D)(0.37g，0.72mmol)和4-哌啶甲酰胺(1C)(0.19g，1.5mmol)置于50mL圆底烧瓶中，加入异丙醇(20mL)，60℃条件下搅拌30分钟后，60℃减压浓缩1小时，向残留物中加入异丙醇(20mL)、无水硫酸钠(0.20g,1.4mmol)和乙酸(0.25mL,4.3mmol)，搅拌均匀后，于0℃条件下加入三乙酰氧基硼氢化钠(0.46g，2.2mmol)，升至室温反应3小时。反应结束后，向反应液中加入饱和碳酸氢钠溶液(30mL)淬灭反应，二氯甲烷(30mL×2)萃取，合并有机相，有机相依次用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱层析纯化(二氯甲烷/甲醇(v/v)＝1:8)，得到标题产物[(3aS,5s,6aR)-2-[2-[[4-[(4-氨基甲酰基-1-哌啶基)甲基]苯甲酰基]-甲基-胺基]乙基]-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(化合物4),白色固体(0.18g，产率40％)。Taking [(3aS,5s,6aR)-2-[2-[(4-formylbenzoyl)-methyl-amino]ethyl]-3,3a,4,5,6,6a-hexahydro- 1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (4D) (0.37 g, 0.72 mmol) and 4-piperidinecarboxamide (1C) (0.19 g, 1.5 mmol) was placed in a 50 mL round bottom flask, and isopropyl alcohol (20 mL) was added thereto, and the mixture was stirred at 60 ° C for 30 minutes, and then concentrated under reduced pressure at 60 ° C for 1 hour, and isopropyl alcohol (20 mL) was added to the residue. Anhydrous sodium sulphate (0.20 g, 1.4 mmol) and acetic acid (0.25 mL, 4.3 mmol), and stirred, and then added sodium triacetoxyborohydride (0.46 g, 2.2 mmol) at 0 ° C, The reaction was carried out for 3 hours at room temperature. After the reaction was completed, a saturated aqueous solution of sodium hydrogencarbonate (30 mL) was added to the mixture, and the mixture was evaporated. The residue was purified with EtOAc EtOAc EtOAcjjjjjjjj 4-carbamoyl-1-piperidinyl)methyl]benzoyl]-methyl-amino]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentane Alkeno[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 4), white solid (0.18 g, yield 40%).

LCMS m/z＝624.3[M+1]。LCMS m/z = 624.3 [M + 1].

¹H NMR(400MHz,DMSO-d6)δ8.51(s,1H),7.55–7.23(m,11H),7.18(s,1H),6.69(s,1H),4.95(s,1H),3.46(m,3H),2.93(s,3H),2.80(m,2H),2.20(s,2H),2.04(m,2H),1.94(m,2H),1.83–1.39(m,8H),1.24(s,1H)。 ^{1 H NMR (400MHz, DMSO-} d6) δ8.51 (s, 1H), 7.55-7.23 (m, 11H), 7.18 (s, 1H), 6.69 (s, 1H), 4.95 (s, 1H), 3.46 (m, 3H), 2.93 (s, 3H), 2.80 (m, 2H), 2.20 (s, 2H), 2.04 (m, 2H), 1.94 (m, 2H), 1.83 - 1.39 (m, 8H), 1.24 (s, 1H).

实施例5：[1-[2-[[4-[(5,6-二甲氧基异吲哚啉-2-基)甲基]苯甲酰基]-甲基-胺基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物5)Example 5: [1-[2-[[4-[(5,6-Dimethoxyisoindolin-2-yl)methyl]benzoyl]-methyl-amino]ethyl] 4-piperidinyl]N-(2-phenylphenyl)carbamate (compound 5)

[1-[2-[[4-[(5,6-dimethoxyisoindolin-2-yl)methyl]benzoyl]-methyl-amino]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate[1-[2-[[4-[(5,6-dimethoxyisoindolin-2-yl)methyl]benzoyl]-methyl-amino]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

取[1-[2-[(4-甲酰基苯甲酰基)-甲基-胺基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(5A)(0.964g，2mmol)和5,6-二甲氧基异吲哚啉(5B)(0.717g，4mmol)置于50mL圆底烧瓶中，加入异丙醇(30mL)，60℃减压浓缩，至溶液澄清，再加入异丙醇(30mL)，60℃减压浓缩，溶液澄清后，残留物约20mL，冷至0℃，加入乙酸(0.72g，12mmol)、无水硫酸钠(0.15g)，搅拌均匀后，最后加入三乙酰氧基硼氢化钠(1.27g，6mmol)，升至室温反应2.5小时。反应结束后，反应液加入饱和碳酸氢钠溶液(30mL)淬灭反应，二氯甲烷(30mL×2)萃取，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经硅胶柱层析纯化(二氯甲烷:甲醇(v/v)＝1:0～10:1)，得到标题产物[1-[2-[[4-[(5,6-二甲氧基异吲哚啉-2-基)甲基]苯甲酰基]-甲基-胺基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物5)，黄色固体(1.1g，产率85.3％)。Taking [1-[2-[(4-formylbenzoyl)-methyl-amino]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (5A (0.964g, 2mmol) and 5,6-dimethoxyisoindoline (5B) (0.717g, 4mmol) were placed in a 50mL round bottom flask, isopropanol (30mL) was added, concentrated at 60 ° C under reduced pressure To the solution, clarify, add isopropanol (30 mL), concentrate under reduced pressure at 60 ° C. After clarification of the solution, the residue is about 20 mL, cooled to 0 ° C, acetic acid (0.72 g, 12 mmol), anhydrous sodium sulfate (0.15 g) After stirring well, sodium triacetoxyborohydride (1.27 g, 6 mmol) was finally added, and the mixture was allowed to react at room temperature for 2.5 hours. After the reaction was completed, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane:methanol (v/v) = 1:0 to 10:1) to give the title product [1-[2-[[4-[(5,6-dimethoxyisoindoline-2) -yl)methyl]benzoyl]-methyl-amino]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (compound 5), yellow solid (1.1 g, yield 85.3%).

LCMS m/z＝649.3[M+1]。LCMS m/z = 649.3 [M + 1].

¹H NMR(400MHz,CDCl₃)δ8.08(s,1H),7.52–7.42(m,4H),7.42–7.39(m,2H),7.39–7.31(m,4H),7.21(dd,J＝7.6,1.5Hz,1H),7.13(dd,J＝10.7,4.2Hz,1H),6.73(s,2H),6.58(s,1H),4.74(s,1H),3.93(s,2H),3.90(s,4H),3.84(s,6H),3.66(s,1H),3.38(s,1H),3.02(s,3H),2.82(s,1H),2.68(s,1H),2.47(s,4H),2.19–1.81(m,4H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.08 (s, 1H), 7.52-7.42 (m, 4H), 7.42-7.39 (m, 2H), 7.39-7.31 (m, 4H), 7.21 (dd, J = 7.6, 1.5 Hz, 1H), 7.13 (dd, J = 10.7, 4.2 Hz, 1H), 6.73 (s, 2H), 6.58 (s, 1H), 4.74 (s, 1H), 3.93 (s, 2H) , 3.90 (s, 4H), 3.84 (s, 6H), 3.66 (s, 1H), 3.38 (s, 1H), 3.02 (s, 3H), 2.82 (s, 1H), 2.68 (s, 1H), 2.47 (s, 4H), 2.19 - 1.81 (m, 4H).

实施例6：[1-[2-[[4-[[(3aS,5r,6aR)-5-氨基甲酰基-3,3a,4,5,6,6a-六氢-1H-环戊二烯[c]吡咯-2-基]甲基]苯甲酰基]-甲基-胺基]乙基]哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物6)Example 6: [1-[2-[[4-[[(3aS,5r,6aR)-5-carbamoyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopentane Alkene [c]pyrrol-2-yl]methyl]benzoyl]-methyl-amino]ethyl]piperidinyl]N-(2-phenylphenyl)carbamate (Compound 6)

[1-[2-[[4-[[(3aS,5r,6aR)-5-carbamoyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]methyl]benzoyl]-methyl-amino]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate[1-[2-[[4-[[(3aS,5r,6aR)-5-carbamoyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl] Methyl]benzoyl]-methyl-amino]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

(3aR,5r,6aS)-2-[[4-甲基-[2-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]乙基]氨基甲酰基]苯基]甲基]-3,3a,4,5,6,6a-六氢-环戊二烯[c]吡咯-5-羧酸(化合物7)(3aR,5r,6aS)-2-[[4-methyl-[2-[4-[(2-phenylphenyl)carbamoyloxy)-1-piperidinyl]ethyl]amino Acyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-cyclopentadiene[c]pyrrole-5-carboxylic acid (compound 7)

(3aR,5r,6aS)-2-[[4-[methyl-[2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl]carbamoyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-carboxylic acid(3aR,5r,6aS)-2-[[4-[methyl-[2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl]carbamoyl]phenyl]methyl]-3,3a,4 ,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-carboxylic acid

第一步：(3aS,5r,6aR)-5-氰基-3,3a,4,5,6,6a-六氢-1H-环戊二烯[c]吡咯羧酸叔丁酯(6B)First step: (3aS, 5r, 6aR)-5-cyano-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadienyl[c]pyrrolecarboxylic acid tert-butyl ester (6B)

tert-butyl(3aS,5r,6aR)-5-cyano-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate(6B)Tert-butyl(3aS,5r,6aR)-5-cyano-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate(6B)

干冰浴下，将5-氧代-1,3,3a,4,6,6a-六氢环戊二烯[c]吡咯-2-羧酸叔丁酯(6A)(9.0g，40mmol)和对甲苯磺酰甲基异腈(15g，76.4mmol)溶解于乙二醇二甲醚(80mL)中，滴加叔丁醇钾(9.0g，80mmol)的叔丁醇(80mL)溶液，0℃下搅拌反应2小时，室温搅拌反应12小时。将反应液过滤，滤液减压浓缩，残余物用硅胶柱层析纯化(石油醚/乙酸乙酯(v/v)＝1:8～1:4)，得到标题产物(3aS,5r,6aR)-5-氰基-3,3a,4,5,6,6a-六氢-1H-环戊二烯[c]吡咯羧酸叔丁酯(6B)。5-Oxo-1,3,3a,4,6,6a-hexahydrocyclopentadienyl[c]pyrrole-2-carboxylic acid tert-butyl ester (6A) (9.0 g, 40 mmol) and dry ice bath p-Toluenesulfonylmethyl isocyanide (15 g, 76.4 mmol) was dissolved in ethylene glycol dimethyl ether (80 mL), and a solution of potassium t-butoxide (9.0 g, 80 mmol) in tert-butanol (80 mL) The reaction was stirred for 2 hours, and the reaction was stirred at room temperature for 12 hours. The reaction mixture was filtered, and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ -5-Cyano-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadienyl[c]pyrrolecarboxylic acid tert-butyl ester (6B).

¹H NMR(400MHz,CD₃Cl)δ3.52(m,2H),3.15(dd,2H),2.97(m,1H),2.88(m,2H),2.14–2.21(m,2H),1.89-1.95(m,2H),1.45(s,9H)。 ¹ H NMR (400 MHz, CD ₃ Cl) δ 3.52 (m, 2H), 3.15 (dd, 2H), 2.97 (m, 1H), 2.88 (m, 2H), 2.14 - 2.21 (m, 2H), 1.89 -1.95 (m, 2H), 1.45 (s, 9H).

LCMS m/z＝259.1[M+Na]。LCMS m/z = 259.1 [M+Na].

第二步：(3aS,5r,6aR)-1,2,3,3a,4,5,6,6a-八氢环戊二烯[c]吡咯-5-甲酰胺(6C)Second step: (3aS, 5r, 6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopentadiene [c]pyrrole-5-carboxamide (6C)

(3aS,5r,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-carboxamide(3aS,5r,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-carboxamide

(3aS,5r,6aR)-1,2,3,3a,4,5,6,6a-八氢环戊二烯[c]吡咯-5-羧酸(6D)(3aS,5r,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopentadiene [c]pyrrole-5-carboxylic acid (6D)

(3aS,5r,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-carboxylic acid(3aS,5r,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-carboxylic acid

将(3aS,5r,6aR)-5-氰基-3,3a,4,5,6,6a-六氢-1H-环戊二烯[c]吡咯羧酸叔丁酯(6B)(0.6g， 2.5mmol)置于5mL圆底烧瓶中，冰浴下缓慢滴加浓盐酸(2mL)，加完5分钟后，升至50℃反应2小时，降至50℃，缓慢滴加氢氧化钠(1.2g)，调pH约10～11，用乙酸乙酯(8mL×3)萃取，水相再用氯仿/甲醇(v/v＝7:3)(8mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液经减压浓缩后，得到(3aS,5r,6aR)-1,2,3,3a,4,5,6,6a-八氢环戊二烯[c]吡咯-5-甲酰胺(6C)和(3aS,5r,6aR)-1,2,3,3a,4,5,6,6a-八氢环戊二烯[c]吡咯-5-羧酸(6D)的混合物，不用分离，直接用于下一步。(3aS,5r,6aR)-5-cyano-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadienyl[c]pyrrolecarboxylic acid tert-butyl ester (6B) (0.6g , 2.5 mmol) was placed in a 5 mL round bottom flask. Concentrated hydrochloric acid (2 mL) was slowly added dropwise in an ice bath. After 5 minutes, the reaction was allowed to rise to 50 ° C for 2 hours, dropped to 50 ° C, and sodium hydroxide was slowly added dropwise (1.2). g), adjust the pH to about 10 to 11, extract with ethyl acetate (8mL × 3), the aqueous phase is extracted with chloroform / methanol (v / v = 7:3) (8mL × 3), the organic phase is combined, anhydrous Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to give (3aS, 5r, 6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopentadiene [c]pyrrole-5 -formamide (6C) and (3aS,5r,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopentadiene [c]pyrrole-5-carboxylic acid (6D) The mixture, without isolation, was used directly in the next step.

6C:LCMS m/z＝155.3[M+1]。6C: LCMS m/z = 155.3 [M + 1].

6D:LCMS m/z＝156.2[M+1]。6D: LCMS m/z = 156.2 [M + 1].

第三步：[1-[2-[[4-[[(3aS,5r,6aR)-5-氨基甲酰基-3,3a,4,5,6,6a-六氢-1H-环戊二烯[c]吡咯-2-基]甲基]苯甲酰基]-甲基-胺基]乙基]哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物6)The third step: [1-[2-[[4-[[(3aS,5r,6aR)-5-carbamoyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopentane Alkene [c]pyrrol-2-yl]methyl]benzoyl]-methyl-amino]ethyl]piperidinyl]N-(2-phenylphenyl)carbamate (Compound 6)

(3aS,5r,6aR)-2-[[4-甲基-[2-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]乙基]氨基甲酰基]苯基]甲基]-3,3a,4,5,6,6a-六氢-环戊二烯[c]吡咯-5-羧酸(化合物7)(3aS,5r,6aR)-2-[[4-methyl-[2-[4-[(2-phenylphenyl)carbamoyloxy)-1-piperidinyl]ethyl]amino Acyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-cyclopentadiene[c]pyrrole-5-carboxylic acid (compound 7)

(3aS,5r,6aR)-2-[[4-[methyl-[2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl]carbamoyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-carboxylic acid(3aS,5r,6aR)-2-[[4-[methyl-[2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl]carbamoyl]phenyl]methyl]-3,3a,4 ,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-carboxylic acid

称取[1-[2-[(4-甲酰基苯甲酰基)-甲基-胺基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(5A)(参考WO2012009166A1实施例3制备得到)(0.25g,0.5mmol)，置于100mL圆底烧瓶中，向反应瓶中加入异丙醇(9.0mL)。向反应瓶中依次加入(3aS,5r,6aR)-1,2,3,3a,4,5,6,6a-八氢环戊二烯[c]吡咯-5-甲酰胺(6C)和(3aS,5r,6aR)-1,2,3,3a,4,5,6,6a-八氢环戊二烯[c]吡咯-5-羧酸(6D)的混合物(0.26g)、无水硫酸钠(0.254g)和乙酸(0.28mL,5.0mmol)。反应在室温下搅拌30分钟后，加入三乙酰氧基硼氢化钠(0.54g,2.6mmol)，室温搅拌2小时后，反应结束。减压浓缩除去大部分反应溶剂，向残余物中缓慢滴加饱和碳酸氢钠水溶液(50mL)，水相用二氯甲烷(100mL×2)萃取，合并有机相，依次用饱和食盐水(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱层析分析提纯(二氯甲烷/甲醇(v/v)＝15:1)，得到[1-[2-[[4-[[(3aS,5r,6aR)-5-氨基甲酰基-3,3a,4,5,6,6a-六氢-1H-环戊二烯[c]吡咯-2-基]甲基]苯甲酰基]-甲基-胺基]乙基]哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物6)，白色固体(0.03g,产率9.3％)和(3aS,5r,6aR)-2-[[4-甲基-[2-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]乙基]氨基甲酰基]苯基]甲基]-3,3a,4,5,6,6a-六氢-环戊二烯[c]吡咯-5-羧酸(化合物7)，白色固体(0.1g,产率31％)。Weighing [1-[2-[(4-formylbenzoyl)-methyl-amino]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate ( 5A) (prepared in Example 3 of WO2012009166A1) (0.25 g, 0.5 mmol), placed in a 100 mL round bottom flask, and isopropanol (9.0 mL) was added to the reaction flask. (3aS, 5r, 6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopentadiene [c]pyrrole-5-carboxamide (6C) and (in order) were added to the reaction flask. a mixture of 3aS, 5r, 6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopentadiene [c]pyrrole-5-carboxylic acid (6D) (0.26 g), anhydrous Sodium sulfate (0.254 g) and acetic acid (0.28 mL, 5.0 mmol). After the reaction was stirred at room temperature for 30 minutes, sodium triacetoxyborohydride (0.54 g, 2.6 mmol) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure to dryness, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated. 1) Washing, drying with anhydrous sodium sulfate, filtration, and concentrating the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 15:1) to give [1-[2- [[4-[[(3aS,5r,6aR)-5-carbamoyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadiene[c]pyrrol-2-yl] Methyl]benzoyl]-methyl-amino]ethyl]piperidinyl]N-(2-phenylphenyl)carbamate (Compound 6), white solid (0.03 g, yield 9.3%) And (3aS,5r,6aR)-2-[[4-methyl-[2-[4-[(2-phenylphenyl)carbamoyloxy) Iso-1-piperidinyl]ethyl]carbamoyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-cyclopentadiene [c]pyrrole-5-carboxylate Acid (Compound 7), white solid (0.1 g, yield 31%).

化合物6：¹H NMR(400MHz,CD₃OD)δ7.33-7.70(m,14H),4.50(m,3H),3.48-3.97(m,10H),2.89-3.15(m,9H),1.86-2.17(m,9H)。Compound ^{6: 1 H NMR (400MHz,} CD 3 OD) δ7.33-7.70 (m, 14H), 4.50 (m, 3H), 3.48-3.97 (m, 10H), 2.89-3.15 (m, 9H), 1.86 -2.17 (m, 9H).

LCMS m/z＝624.4[M+1]。LCMS m/z = 624.4 [M + 1].

化合物7：¹H NMR(400MHz,CD₃OD)δ7.36-7.63(m,14H),4.34(s,2H),3.88(m,2H),3.54-3.58(m,3H),2.87-3.26(m,12H),1.86-5-2.05(m,7H),1.66(d,1H),1.47-1.49(m,2H),1.320(m,1H)。Compound ^{7: 1 H NMR (400MHz,} CD 3 OD) δ7.36-7.63 (m, 14H), 4.34 (s, 2H), 3.88 (m, 2H), 3.54-3.58 (m, 3H), 2.87-3.26 (m, 12H), 1.86-5-2.05 (m, 7H), 1.66 (d, 1H), 1.47-1.49 (m, 2H), 1.320 (m, 1H).

LCMS m/z＝625.3[M+1]。LCMS m/z = 625.3 [M + 1].

实施例7：[1-[2-[[4-[(2-甲酰胺基-3-乙基-4,6-二氢吡咯[3,4-d]咪唑-5-基)甲基]苯甲酰基]-甲基-胺基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物8)[1-[2-[[4-[(2-carbamoyl-3-ethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-yl)methyl]benzoyl]-methyl-amino]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamateExample 7: [1-[2-[[4-[(2-carboxamido-3-ethyl-4,6-dihydropyrrole[3,4-d]imidazol-5-yl)methyl]] Benzoyl]-methyl-amino]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (Compound 8) [1-[2-[[4-[ (2-carbamoyl-3-ethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-yl)methyl]benzoyl]-methyl-amino]ethyl]-4-piperidyl]N-(2-phenylphenyl) Carbamate

称取[1-[2-[(4-甲酰基苯甲酰基)-甲基-胺基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(5A)(0.60g,1.2mmol)，置于100mL圆底烧瓶中，向反应瓶中加入异丙醇(15mL)和3-乙基-5,6-二氢-4H-吡咯[3,4-d]咪唑-2-甲酰胺(中间体2)(0.45g,2.5mmol)。室温下搅拌30分钟后，再依次加入乙酸(0.42mL,7.2mmol)，三乙酰氧基硼氢化钠(0.79g,3.6mmol)，室温反应2小时。反应液直接减压浓缩除去大部分反应溶剂，向残余物中缓慢滴加饱和碳酸氢钠水溶液(50mL)，水相用二氯甲烷萃取(100mL×2)，合并有机相，饱和食盐水(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱层析分离提纯(二氯甲烷/甲醇(v/v)＝15:1)，得到标题产物[1-[2-[[4-[(2-甲酰胺基-3-乙基-4,6-二氢吡咯[3,4-d]咪唑-5-基)甲基]苯甲酰基]-甲基-胺基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物8)，白色固体(0.75g,产率96％)。Weighing [1-[2-[(4-formylbenzoyl)-methyl-amino]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate ( 5A) (0.60 g, 1.2 mmol), placed in a 100 mL round bottom flask, isopropyl alcohol (15 mL) and 3-ethyl-5,6-dihydro-4H-pyrrole [3,4- d] Imidazole-2-carboxamide (Intermediate 2) (0.45 g, 2.5 mmol). After stirring at room temperature for 30 minutes, acetic acid (0.42 mL, 7.2 mmol), sodium triacetoxyborohydride (0.79 g, 3.6 mmol) The reaction mixture was concentrated under reduced pressure to dryness, and the solvent was evaporated, evaporated, evaporated, evaporated, evaporated. ×1) Washed, dried over anhydrous sodium sulfate, filtered, EtOAcjjjjjjjjjjjjjjj [2-[[4-[(2-carboxamido-3-ethyl-4,6-dihydropyrrole[3,4-d]imidazol-5-yl)methyl]benzoyl]-methyl -Amino]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (Compound 8), white solid (0.75 g, yield 96%).

¹H NMR(400MHz,CDCl₃)δ8.08(s,1H),7.44-7.37(m,10H),7.15-7.09(m,2H),6.59(s,1H),5.25(s,2H),4.72(br,1H),4.43-4.39(m,2H),4.01(s,2H),3.83-3.63(m,4H),3.37(br,1H),3.02-2.99(m,3H),2.66-1.54(m,11H),1.38-1.35(m,3H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.08 (s, 1H), 7.44-7.37 (m, 10H), 7.15-7.09 (m, 2H), 6.59 (s, 1H), 5.25 (s, 2H), 4.72 (br, 1H), 4.43-4.39 (m, 2H), 4.01 (s, 2H), 3.83-3.63 (m, 4H), 3.37 (br, 1H), 3.02-2.99 (m, 3H), 2.66- 1.54 (m, 11H), 1.38-1.35 (m, 3H).

LCMS m/z＝650.3[M+1]。LCMS m/z = 650.3 [M + 1].

实施例8：[1-[2-[6-[(4-甲酰胺基-1-哌啶基)甲基]-1-氧代-3,4-二氢异喹啉-2-基]乙基]-4- 哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物9)Example 8: [1-[2-[6-[(4-carboxamido-1-piperidyl)methyl]-1-oxo-3,4-dihydroisoquinolin-2-yl] Ethyl]-4- Piperidinyl]N-(2-phenylphenyl)carbamate (Compound 9)

[1-[2-[6-[(4-carbamoyl-1-piperidyl)methyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate[1-[2-[6-[(4-carbamoyl-1-piperidyl)methyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl) Carbamate

第一步：6-溴-3,4-二氢-2H-异喹啉-1-酮(9B)First step: 6-bromo-3,4-dihydro-2H-isoquinolin-1-one (9B)

6-bromo-3,4-dihydro-2H-isoquinolin-1-one6-bromo-3,4-dihydro-2H-isoquinolin-1-one

称取5-溴-1-茚酮(9A)(1.08g,5.1mmol)，置于100mL圆底烧瓶中。0℃下，向反应瓶中依次加入二氯甲烷(30mL)、甲磺酸(15mL)和叠氮化钠(0.5g,7.7mmol)，温度升至室温搅拌3小时。向反应液中滴加1.0M氢氧化钠水溶液(50mL)淬灭反应，水相用二氯甲烷(100mL×1)萃取，合并有机相，依次用饱和食盐水洗(40mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱层析分离提纯(石油醚/乙酸乙酯(v/v)＝3:1)，得到标题产物6-溴-3,4-二氢-2H-异喹啉-1-酮(9B)，灰色固体(0.45g,产率39％)。5-Bromo-1-indolone (9A) (1.08 g, 5.1 mmol) was weighed and placed in a 100 mL round bottom flask. Methylene chloride (30 mL), methanesulfonic acid (15 mL) and sodium azide (0.5 g, 7.7 mmol) were sequentially added to the reaction mixture at 0 ° C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with aq. EtOAc (EtOAc) (EtOAc) (EtOAc) The organic layer was dried (MgSO4), filtered, evaporated. Hydrogen-2H-isoquinolin-1-one (9B), a gray solid (0.45 g, yield 39%).

¹H NMR(400MHz,CDCl₃)δ7.91-7.89(m,1H),7.48-7.46(m,1H),7.38(s,1H),7.15(br,1H),3.58-3.54(m,2H),2.98-2.94(m,2H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.91-7.89 (m, 1H), 7.48-7.46 (m, 1H), 7.38 (s, 1H), 7.15 (br, 1H), 3.58-3.54 (m, 2H) ), 2.98-2.94 (m, 2H).

第二步：2-烯丙基-6-溴-3,4-二氢异喹啉-1-酮(9C) The second step: 2-allyl-6-bromo-3,4-dihydroisoquinolin-1-one (9C)

2-allyl-6-bromo-3,4-dihydroisoquinolin-1-one2-allyl-6-bromo-3,4-dihydroisoquinolin-1-one

将N,N-二甲基甲酰胺(25mL)加入250mL圆底烧瓶中。0℃下，向反应瓶中加入氢化钠(1.8g,33.0mmol,60％(w/w))，然后滴加6-溴-3,4-二氢-2H-异喹啉-1-酮(9B)(5.0g,22.0mmol)的N,N-二甲基甲酰胺(20mL)溶液，搅拌20分钟后，滴加3-溴丙烯(4.0g,33mmol)。温度升至室温搅拌4小时。向反应液中滴加水(100mL)淬灭反应，乙酸乙酯(200mL×2)萃取，合并有机相用，依次用饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱层析分离(石油醚/乙酸乙酯(v/v)＝10:1)提纯，得到标题产物2-烯丙基-6-溴-3,4-二氢异喹啉-1-酮(9C),黄色液体(4.80g,产率82％)。N,N-dimethylformamide (25 mL) was added to a 250 mL round bottom flask. Sodium hydride (1.8 g, 33.0 mmol, 60% (w/w)) was added to the reaction flask at 0 ° C, and then 6-bromo-3,4-dihydro-2H-isoquinolin-1-one was added dropwise. (9B) (5.0 g, 22.0 mmol), EtOAc (EtOAc) The temperature was raised to room temperature and stirred for 4 hours. The reaction mixture was added dropwise with water (100 mL), and the mixture was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjj The residue was purified by silica gel column chromatography (EtOAc/EtOAc (EtOAc) Quinolin-1-one (9C), yellow liquid (4.80 g, yield 82%).

¹H NMR(400MHz,CDCl₃)δ7.94-7.92(m,1H),7.45-7.43(m,1H),7.32(s,1H),5.84-5.78(m,1H),5.25-5.19(m,2H),4.17-4.16(m,2H),3.49-3.48(m,2H),2.96-2.93(m,2H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.94-7.92 (m, 1H), 7.45-7.43 (m, 1H), 7.32 (s, 1H), 5.84-5.78 (m, 1H), 5.25-5.19 (m , 2H), 4.17-4.16 (m, 2H), 3.49-3.48 (m, 2H), 2.96-2.93 (m, 2H).

第三步：2-烯丙基-1-羰基-3,4-二氢异喹啉-6-甲醛(9D)The third step: 2-allyl-1-carbonyl-3,4-dihydroisoquinoline-6-formaldehyde (9D)

2-allyl-1-oxo-3,4-dihydroisoquinoline-6-carbaldehyde2-allyl-1-oxo-3,4-dihydroisoquinoline-6-carbaldehyde

称取2-烯丙基-6-溴-3,4-二氢异喹啉-1-酮(9C)(0.80g,3.0mmol)置于50mL圆底烧瓶中。-78℃下，向反应瓶中依次加入四氢呋喃(20mL)和N,N-二甲基甲酰胺(0.33g,4.5mmol)，滴加叔丁基锂(4.5mL,6.0mmol,1.3M正己烷溶液)。-78℃下搅拌1小时后，滴加乙酸(5mL)淬灭反。残余物中加入乙酸乙酯(100mL)和饱和食盐水(50mL)，萃取，水相用乙酸乙酯(100mL×1)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用柱层析分离(石油醚/乙酸乙酯(v/v)＝2:1)提纯，得到标题产物2-烯丙基-1-羰基-3,4-二氢异喹啉-6-甲醛(9D)，黄色液体(0.28g,43％)。2-Allyl-6-bromo-3,4-dihydroisoquinolin-1-one (9C) (0.80 g, 3.0 mmol) was weighed and placed in a 50 mL round bottom flask. Tetrahydrofuran (20 mL) and N,N-dimethylformamide (0.33 g, 4.5 mmol) were added to the reaction flask at -78 ° C, and t-butyllithium (4.5 mL, 6.0 mmol, 1.3 M n-hexane) was added dropwise. Solution). After stirring at -78 ° C for 1 hour, acetic acid (5 mL) was added dropwise to quench. Ethyl acetate (100 mL) and brine (50 mL) were evaporated, evaporated, evaporated, evaporated. The residue was purified by column chromatography (EtOAc/EtOAc (EtOAc:EtOAc) - Formaldehyde (9D), yellow liquid (0.28 g, 43%).

¹H NMR(400MHz,CDCl₃)δ10.05(s,1H),8.27-8.25(d,1H),7.84-7.82(d,1H),7.72-7.71(m,1H),5.90-5.81(m,1H),5.29-5.23(m,2H),4.23-4.21(m,2H),3.57-3.55(m,2H),3.09-3.06(m,2H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.05 (s, 1H), 8.27-8.25 (d, 1H), 7.84-7.82 (d, 1H), 7.72-7.71 (m, 1H), 5.90-5.81 (m) , 1H), 5.29-5.23 (m, 2H), 4.23-4.21 (m, 2H), 3.57-3.55 (m, 2H), 3.09-3.06 (m, 2H).

第四步：2-烯丙基-6-(羟基甲基)-3,4-二氢异喹啉-1-酮(9E)Fourth step: 2-allyl-6-(hydroxymethyl)-3,4-dihydroisoquinolin-1-one (9E)

2-allyl-6-(hydroxymethyl)-3,4-dihydroisoquinolin-1-one2-allyl-6-(hydroxymethyl)-3,4-dihydroisoquinolin-1-one

称取2-烯丙基-1-羰基-3,4-二氢异喹啉-6-甲醛(9D)(0.28g,1.3mmol)，置于50mL圆底烧瓶中。向反应瓶中加入甲醇(10mL)，分批加入硼氢化钠(0.1g,2.0mmol)，室温下搅拌2小时。滴加水(5mL)淬灭反应，用乙酸乙酯(50mL×2)萃取合并有机相，依次用饱和食盐水(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后得到标题产物2-烯丙基-6-(羟基甲基)-3,4-二氢异喹啉-1-酮(9E)，黄色液体(0.26g,92％)。2-Allyl-1-carbonyl-3,4-dihydroisoquinoline-6-carbaldehyde (9D) (0.28 g, 1.3 mmol) was weighed and placed in a 50 mL circle In the bottom flask. Methanol (10 mL) was added to the reaction mixture, and sodium borohydride (0.1 g, 2.0 mmol) was added portionwise and stirred at room temperature for 2 hr. The reaction was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) Product 2-Allyl-6-(hydroxymethyl)-3,4-dihydroisoquinolin-1-one (9E), yellow liquid (0.26 g, 92%).

¹H NMR(400MHz,CDCl₃)δ8.05-8.04(d,1H),7.29-7.27(d,1H),7.20(s,1H),5.88-5.80(m,1H),5.26-5.19(m,2H),4.72(s,2H),4.20-4.18(m,2H),3.52-3.49(m,2H),2.99-2.95(m,2H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.05-8.04 (d, 1H), 7.29-7.27 (d, 1H), 7.20 (s, 1H), 5.88-5.80 (m, 1H), 5.26-5.19 (m , 2H), 4.72 (s, 2H), 4.20-4.18 (m, 2H), 3.52-3.49 (m, 2H), 2.99-2.95 (m, 2H).

第五步：2-烯丙基-6-[[叔丁基(二甲基)硅基]氧基甲基]-3,4-二氢异喹啉-1-酮(9F)Step 5: 2-allyl-6-[[tert-butyl(dimethyl)silyl]oxymethyl]-3,4-dihydroisoquinolin-1-one (9F)

2-allyl-6-[[tert-butyl(dimethyl)silyl]oxymethyl]-3,4-dihydroisoquinolin-1-one2-allyl-6-[[tert-butyl(dimethyl)silyl]oxymethyl]-3,4-dihydroisoquinolin-1-one

将2-烯丙基-6-(羟基甲基)-3,4-二氢异喹啉-1-酮(9E)(0.26g,1.2mmol)溶于二氯甲烷(15mL)中。依次加入三乙胺(0.48mL,3.6mmol)、叔丁基二甲基氯硅烷(0.27g,1.8mmol)和4-二甲胺基吡啶(0.015g,0.12mmol)。室温下搅拌2小时后。反应液直接减压浓缩，残留物用硅胶柱层析分离提纯(石油醚/乙酸乙酯(v/v)＝2:1)，得到标题产物2-烯丙基-6-(羟基甲基)-3,4-二氢异喹啉-1-酮(9F)，黄色液体(0.4g,100％)。2-Allyl-6-(hydroxymethyl)-3,4-dihydroisoquinolin-1-one (9E) (0.26 g, 1.2 mmol) was dissolved in dichloromethane (15 mL). Triethylamine (0.48 mL, 3.6 mmol), tert-butyldimethylsilyl chloride (0.27 g, 1.8 mmol) and 4-dimethylaminopyridine (0.015 g, 0.12 mmol) were added sequentially. After stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. -3,4-Dihydroisoquinolin-1-one (9F), yellow liquid (0.4 g, 100%).

¹H NMR(400MHz,CDCl₃)δ8.05-8.03(d,1H),7.27-7.25(d,1H),7.15(s,1H),5.89-5.81(m,1H),5.26-5.19(m,2H),4.75(s,2H),4.20-4.19(m,2H),3.52-3.49(m,2H),2.99-2.96(m,2H),0.95(s,9H),0.11(s,6H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.05-8.03 (d, 1H), 7.27-7.25 (d, 1H), 7.15 (s, 1H), 5.89-5.81 (m, 1H), 5.26-5.19 (m , 2H), 4.75 (s, 2H), 4.20-4.19 (m, 2H), 3.52-3.49 (m, 2H), 2.99-2.96 (m, 2H), 0.95 (s, 9H), 0.11 (s, 6H) ).

第六步：2-[6-[[叔丁基(二甲基)硅基]氧基甲基]-1-氧代-3,4-二氢异喹啉-2-基]乙醛(9G)Step 6: 2-[6-[[tert-Butyl(dimethyl)silyl]oxymethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]acetaldehyde ( 9G)

2-[6-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]acetaldehyde2-[6-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]acetaldehyde

将2-烯丙基-6-[[叔丁基(二甲基)硅基]氧基甲基]-3,4-二氢异喹啉-1-酮(9F)(0.33g,1.0mmol)溶于四氢呋喃(12mL)与水(3mL)的混合溶剂中。0℃下，依次加入二水合锇酸钾(0.07g,0.2mmol)和高碘酸钠(1.05g,5.0mmol)。反温度升至室温下搅拌2小时。滴加饱和硫代硫酸钠水溶液(30mL)淬灭反应，乙酸乙酯(50mL×2)萃取合并有机相，依次用饱和食盐水(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱层析分离提纯(石油醚/乙酸乙酯(v/v)＝1:1)，得到标题产物2-[6-[[叔丁基(二甲基)硅基]氧基甲基]-1-氧代-3,4-二氢异喹啉-2-基]乙醛(9G)，黄色液体(0.21g,64％)。2-Allyl-6-[[tert-butyl(dimethyl)silyl]oxymethyl]-3,4-dihydroisoquinolin-1-one (9F) (0.33 g, 1.0 mmol) It was dissolved in a mixed solvent of tetrahydrofuran (12 mL) and water (3 mL). Potassium phthalate dihydrate (0.07 g, 0.2 mmol) and sodium periodate (1.05 g, 5.0 mmol) were added sequentially at 0 °C. The temperature was raised to room temperature and stirred for 2 hours. The reaction was quenched with aq. EtOAc (EtOAc) The mixture was concentrated under reduced pressure. EtOAc mjjjjjjjjj ]oxymethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]acetaldehyde (9G), yellow liquid (0.21 g, 64%).

¹H NMR(400MHz,CDCl₃)δ9.69(s,1H),8.04-8.02(d,1H),7.29-7.27(d,1H),7.18(s,1H),4.77(s,2H),4.39(s,2H),3.64-3.60(m,2H),3.09-3.06(m,2H),0.95(s,9H),0.11(s,6H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.69 (s, 1H), 8.04-8.02 (d, 1H), 7.29-7.27 (d, 1H), 7.18 (s, 1H), 4.77 (s, 2H), 4.39 (s, 2H), 3.64-3.60 (m, 2H), 3.09-3.06 (m, 2H), 0.95 (s, 9H), 0.11 (s, 6H).

第七步：[1-[2-[6-[[叔丁基(二甲基)硅基]氧基甲基]-1-氧代-3,4-二氢异喹啉-2-基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(9H)Step 7: [1-[2-[6-[[tert-Butyl(dimethyl)silyl]oxymethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl) ]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (9H)

[1-[2-[6-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate[1-[2-[6-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl) Carbamate

将2-[6-[[叔丁基(二甲基)硅基]氧基甲基]-1-氧代-3,4-二氢异喹啉-2-基]乙醛(9G)(0.33g,1.0mmol)溶于二氯甲烷(10mL)中。向其中加入4-哌啶基N-(2-苯基苯基)氨基甲酸酯(参考WO2012009166制备例1得到)(0.3g,1.0mmol)。室温搅拌1小时后，加入三乙酰氧基硼氢化钠(0.63g,3.0mmol)，继续搅拌2小时。滴加饱和碳酸氢钠水溶液(40mL)淬灭反应，二氯甲烷(50mL×2)萃取合并有机相，依次用饱和食盐水(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱层析分离提纯(二氯甲烷/甲醇(v/v)＝15:1)得到[1-[2-[6-[[叔丁基(二甲基)硅基]氧基甲基]-1-氧代-3,4-二氢异喹啉-2-基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(9H)(0.41g,67％)。2-[6-[[tert-Butyl(dimethyl)silyl]oxymethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]acetaldehyde (9G) ( 0.33 g, 1.0 mmol) was dissolved in dichloromethane (10 mL). To this was added 4-piperidinyl N-(2-phenylphenyl)carbamate (refer to Preparation Example 1 of WO2012009166) (0.3 g, 1.0 mmol). After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (0.63 g, 3.0 mmol) was added and stirring was continued for 2 hr. The reaction was quenched with saturated aqueous sodium hydrogen sulfate (40 mL), EtOAc (EtOAc m. The residue was concentrated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 15:1) to give [1-[2-[6-[[ter-butyl(dimethyl)silyl]] Oxymethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate ( 9H) (0.41 g, 67%).

¹H NMR(400MHz,CDCl₃)δ8.10-8.08(d,1H),8.02-8.00(d,1H),7.43-7.37(m,6H),7.20-7.10(m,4H),6.59(s,1H),4.76-4.74(m,3H),3.68-3.58(m,4H),2.98-2.95(m,2H),2.76-2.74(m,2H),2.60-2.58(m,2H),2.32-2.30(m,2H),1.93-1.91(m,2H),1.68-1.64(m,2H),0.95(s,9H),0.11(s,6H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.10-8.08 (d, 1H), 8.02-8.00 (d, 1H), 7.43-7.37 (m, 6H), 7.20-7.10 (m, 4H), 6.59 (s , 1H), 4.76-4.74 (m, 3H), 3.68-3.58 (m, 4H), 2.98-2.95 (m, 2H), 2.76-2.74 (m, 2H), 2.60-2.58 (m, 2H), 2.32 -2.30 (m, 2H), 1.93-1.91 (m, 2H), 1.68-1.64 (m, 2H), 0.95 (s, 9H), 0.11 (s, 6H).

LCMS m/z＝614.4[M+1]。LCMS m/z = 614.4 [M + 1].

第八步：[1-[2-(6-羟基甲基)-1-氧代-3,4-二氢异喹啉-2-基]乙基]-4-哌啶基]N-(2-苯基苯基)碳酸铵(9I)Step 8: [1-[2-(6-Hydroxymethyl)-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidinyl]N-( 2-phenylphenyl)ammonium carbonate (9I)

[1-[2-[6-(hydroxymethyl)-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate[1-[2-[6-(hydroxymethyl)-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

将[1-[2-[6-[[叔丁基(二甲基)硅基]氧基甲基]-1-氧代-3,4-二氢异喹啉-2-基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(9H)(0.31g,0.5mmol)溶于四氢呋喃(10mL)中，加入四丁基氟化铵(0.26g,1.0mmol)，室温搅拌2小时后。将反应液直接减压浓缩后，残留物用硅胶柱层析分离提纯(二氯甲烷/甲醇(v/v)＝15:1)，得到标题产物[1-[2-(6-羟基甲基)-1-氧代-3,4-二氢异喹啉-2-基]乙基]-4-哌啶基]N-(2-苯基苯基)碳酸铵(9I)(0.20g,80％)。 [1-[2-[6-[[tert-Butyl(dimethyl)silyl]oxymethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl ]-4-piperidinyl]N-(2-phenylphenyl)carbamate (9H) (0.31 g, 0.5 mmol) was dissolved in tetrahydrofuran (10 mL) and tetrabutylammonium fluoride (0.26 g) , 1.0 mmol), stirred at room temperature for 2 hours. After the reaction mixture was concentrated under reduced pressure, the residue was purified (jjjjjjjjjjjjjjjj )-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidinyl]N-(2-phenylphenyl)ammonium carbonate (9I) (0.20 g, 80%).

LCMS m/z＝500.3[M+1]。LCMS m/z = 500.3 [M + 1].

第九步：[1-[2-(6-甲醛基-1-氧代-3,4-二氢异喹啉-2-基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(9J)Step 9: [1-[2-(6-Formaldehyde-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidinyl]N-(2- Phenylphenyl)carbamate (9J)

[1-[2-(6-formyl-1-oxo-3,4-dihydroisoquinolin-2-yl)ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate[1-[2-(6-formyl-1-oxo-3,4-dihydroisoquinolin-2-yl)ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

将[1-[2-(6-羟基甲基)-1-氧代-3,4-二氢异喹啉-2-基]乙基]-4-哌啶基]N-(2-苯基苯基)碳酸铵(9I)(0.20g,0.4mmol)溶于二氯甲烷(10mL)中。0℃下，加入戴斯-马丁氧化剂(0.4g,1.0mmol)。温度升至室温下搅拌2小时。滴加饱和碳酸氢钠水溶液(40mL)淬灭反应，残余物用二氯甲烷(50mL×2)萃取，合并有机相，依次用饱和食盐水(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱层析分离提纯(二氯甲烷/甲醇(v/v)＝15:1)，得到标题产物[1-[2-(6-甲醛基-1-氧代-3,4-二氢异喹啉-2-基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(9J)(0.15g,75％)。[1-[2-(6-Hydroxymethyl)-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidinyl]N-(2-benzene Phenylphenyl)ammonium carbonate (9I) (0.20 g, 0.4 mmol) was dissolved in dichloromethane (10 mL). Dess-Martin periodinane (0.4 g, 1.0 mmol) was added at 0 °C. The temperature was raised to room temperature and stirred for 2 hours. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. The filtrate was concentrated under reduced pressure, and the residue was purified mjjjjjjjjjjjjjjjjjjjjj 3,4-Dihydroisoquinolin-2-yl]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (9J) (0.15 g, 75%) .

LCMS m/z＝498.3[M+1]。LCMS m/z = 498.3 [M + 1].

第十步：[1-[2-[6-[(4-甲酰胺基-1-哌啶基)甲基]-1-氧代-3,4-二氢异喹啉-2-基]乙基]-4-哌啶基]N-(2-苯基苯基)碳酸铵(化合物9)Step 10: [1-[2-[6-[(4-carboxamido-1-piperidyl)methyl]-1-oxo-3,4-dihydroisoquinolin-2-yl] Ethyl]-4-piperidinyl]N-(2-phenylphenyl)ammonium carbonate (Compound 9)

[1-[2-[[4-[(2-carbamoyl-3-ethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-yl)methyl]benzoyl]-methyl-amino]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate[1-[2-[[4-[(2-carbamoyl-3-ethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-yl)methyl]benzoyl]-methyl-amino]ethyl]- 4-piperidyl]N-(2-phenylphenyl)carbamate

将[1-[2-(6-甲醛基-1-氧代-3,4-二氢异喹啉-2-基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(9J)(0.15g,0.3mmol)溶于异丙醇(15mL)中，加入4-哌啶甲酰胺(1C)(0.12g,1.0mmol)。室温搅拌30分钟后，依次向加入乙酸(0.5mL)和三乙酰氧基硼氢化钠(0.2g,1.0mmol)，室温反应2小时。减压浓缩除去大部分反应溶剂，向残余物中缓慢滴加饱和碳酸氢钠水溶液(50mL)，水相用二氯甲烷萃取(100mL×2)，合并有机相，依次用饱和食盐水(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱层析分离提纯(二氯甲烷/甲醇(v/v)＝15:1)，得到标题产物[1-[2-[6-[(4-甲酰胺基-1-哌啶基)甲基]-1-氧代-3,4-二氢异喹啉-2-基]乙基]-4-哌啶基]N-(2-苯基苯基)碳酸铵(化合物9)，白色固体 (0.10g,产率53％)。[1-[2-(6-Formaldehyde-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidinyl]N-(2-phenylbenzene) The carbamate (9J) (0.15 g, 0.3 mmol) was dissolved in isopropyl alcohol (15 mL), then 4-piperidinecarboxamide (1C) (0.12 g, 1.0 mmol). Acetic acid (0.5 mL) and sodium triacetoxyborohydride (0.2 g, 1.0 mmol) were successively added, and the mixture was reacted at room temperature for 2 hours, and concentrated under reduced pressure to remove most of the solvent, and a saturated aqueous solution of sodium hydrogencarbonate was slowly added dropwise to the residue. (50 mL), the aqueous phase was extracted with methylene chloride (100 mL×2), and the organic phase was combined, washed with saturated brine (50 mL×1), dried over anhydrous sodium sulfate, filtered and evaporated. Purification by column chromatography (dichloromethane/methanol (v/v) = 15:1) gave the title product [1-[2-[6-[(4-carbamido-1-piperidyl)methyl) ]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidinyl]N-(2-phenylphenyl)ammonium carbonate (compound 9), white solid (0.10 g, yield 53%).

¹H NMR(400MHz,CDCl₃)δ8.10-8.08(d,1H),8.00-7.98(d,1H),7.48-7.36(m,6H),7.23-7.11(m,4H),6.58(s,1H),5.49(s,1H),5.29(s,1H),4.76-4.72(m,1H),3.69-3.66(m,2H),3.62-3.59(m,2H),3.51(s,2H),2.96-2.94(m,4H),2.79-2.77(m,2H),2.64-2.61(m,2H),2.35(br,2H),1.86-1.66(m,10H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.10-8.08 (d, 1H), 8.00-7.98 (d, 1H), 7.48-7.36 (m, 6H), 7.23-7.11 (m, 4H), 6.58 (s , 1H), 5.49 (s, 1H), 5.29 (s, 1H), 4.76-4.72 (m, 1H), 3.69-3.66 (m, 2H), 3.62-3.59 (m, 2H), 3.51 (s, 2H) ), 2.96-2.94 (m, 4H), 2.79-2.77 (m, 2H), 2.64-2.61 (m, 2H), 2.35 (br, 2H), 1.86-1.66 (m, 10H).

LCMS m/z＝610.3[M+1]。LCMS m/z = 610.3 [M + 1].

实施例10：[1-[2-[[5-[(4-甲酰胺-1-哌啶基)甲基]-1-氧代-异氢化吲哚-2-基]乙基]-4-哌啶基]-N-(2-苯基苯基)氨基甲酸酯(化合物10)Example 10: [1-[2-[[5-[(4-carboxamide-1-piperidyl)methyl]-1-oxo-isohydroindol-2-yl]ethyl]-4 -piperidinyl]-N-(2-phenylphenyl)carbamate (Compound 10)

[1-[2-[5-[(4-carbamoyl-1-piperidyl)methyl]-1-oxo-isoindolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate[1-[2-[5-[(4-carbamoyl-1-piperidyl)methyl]-1-oxo-isoindolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

第一步：[1-[2-(叔丁氧羰基胺基)乙基]-4-哌啶]N-(2-苯基苯基)氨基甲酸酯(10B)First step: [1-[2-(tert-butoxycarbonylamino)ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (10B)

[1-[2-(tert-butoxycarbonylamino)ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate[1-[2-(tert-butoxycarbonylamino)ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

将4-哌啶基N-(2-苯基苯基)氨基甲酸酯(参考WO2012009166A1制备)(10A)(2.96g,10.0mmol)溶于乙腈(60mL)中。向其中依次加入N-叔丁氧羰基-溴乙胺(2.24g,10.0mmol)，N,N-二异丙基乙胺(3.56mL，20.0mmol)。反应在50℃下搅拌24小时。减压浓缩除去反应溶剂，向残余物中加入饱和碳酸氢钠水溶液(100mL)，用二氯甲烷(150mL ×2)萃取，合并后的有机相用饱和食盐水(100mL)洗，无水硫酸钠干燥，减压浓缩后得到黄色液体状的[1-[2-(叔丁氧羰基胺基)乙基]-4-哌啶]N-(2-苯基苯基)氨基甲酸酯(10B)(4.4g,100％)。4-piperidinyl N-(2-phenylphenyl)carbamate (prepared by reference to WO2012009166A1) (10A) (2.96 g, 10.0 mmol) was dissolved in acetonitrile (60 mL). N-tert-Butoxycarbonyl-bromoethylamine (2.24 g, 10.0 mmol), N,N-diisopropylethylamine (3.56 mL, 20.0 mmol). The reaction was stirred at 50 ° C for 24 hours. The reaction solvent was concentrated under reduced pressure. EtOAc m. ×2), the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate ]-4-Piperidine]N-(2-phenylphenyl)carbamate (10B) (4.4 g, 100%).

LCMS m/z＝440.3[M+1]。LCMS m/z = 440.3 [M + 1].

第二步：[1-(2-胺基乙基)-4-哌啶]N-(2-苯基苯基)氨基甲酸酯(10C)Second step: [1-(2-Aminoethyl)-4-piperidine]N-(2-phenylphenyl)carbamate (10C)

[1-(2-aminoethyl)-4-piperidyl]N-(2-phenylphenyl)carbamate[1-(2-aminoethyl)-4-piperidyl]N-(2-phenylphenyl)carbamate

将[1-[2-(叔丁氧羰基胺基)乙基]-4-哌啶]N-(2-苯基苯基)氨基甲酸酯(10B)(4.4g,10.0mmol)溶于二氯甲烷(50mL)中，向其中加入三氟乙酸(10mL)，室温搅拌3小时。减压浓缩除去反应溶剂，向残余物中加入二氯甲烷(200mL)，饱和碳酸氢钠水溶液(100mL)，萃取,水相用二氯甲烷(100mL)萃取，合并后的有机相用无水硫酸钠干燥，减压浓缩后柱层析分离(二氯甲烷/甲醇(v/v)＝10:1)得到黄色固体状的[1-(2-胺基乙基)-4-哌啶]N-(2-苯基苯基)氨基甲酸酯(10C)(2.1g,62.0％)。Dissolve [1-[2-(tert-butoxycarbonylamino)ethyl]-4-piperidine]N-(2-phenylphenyl)carbamate (10B) (4.4 g, 10.0 mmol) Trifluoroacetic acid (10 mL) was added to dichloromethane (50 mL) and stirred at room temperature for 3 hr. The reaction solvent was concentrated under reduced pressure. dichloromethane (EtOAc) (EtOAc) Drying with sodium, concentrating under reduced pressure, EtOAc (EtOAc/MeOH (MeOH) -(2-Phenylphenyl)carbamate (10C) (2.1 g, 62.0%).

LCMS m/z＝340.1[M+1]。LCMS m/z = 340.1 [M + 1].

第三步：1-氧代-2-[2-[4-[(2-苯基苯基)胺基甲酰基氧]-1-哌啶基]乙基]异吲哚啉-5-羧酸甲酯(10D)The third step: 1-oxo-2-[2-[4-[(2-phenylphenyl)aminocarbonyloxy]-1-piperidinyl]ethyl]isoindoline-5-carboxylate Methyl ester (10D)

methyl 1-oxo-2-[2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl]isoindoline-5-carboxylateMethyl 1-oxo-2-[2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl]isoindoline-5-carboxylate

将[1-(2-胺基乙基)-4-哌啶]N-(2-苯基苯基)氨基甲酸酯(10C)(3.4g,10.0mmol)溶于四氢呋喃(50mL)中，向其中依次加入二甲基2-(溴甲基)苯基-1,4-二碳酸酯(中间体4)(2.9g,10.0mmol)，三乙胺(2.1mL,15.0mmol)。反应在50℃下搅拌12小时后后终止。待反应冷至室温，减压浓缩除去反应溶剂，向残余物中加入二氯甲烷(200mL)，饱和碳酸氢钠水溶液(100mL)，萃取，水相用二氯甲烷(100mL)萃取，合并后的有机相用无水硫酸钠干燥，减压浓缩后柱层析分离(二氯甲烷/甲醇(v/v)＝15:1)得到白色固体状的1-氧代-2-[2-[4-[(2-苯基苯基)胺基甲酰基氧]-1-哌啶基]乙基]异吲哚啉-5-羧酸甲酯(10D)(4.0g,77.8％)。[1-(2-Aminoethyl)-4-piperidine]N-(2-phenylphenyl)carbamate (10C) (3.4 g, 10.0 mmol) was dissolved in tetrahydrofuran (50 mL) Dimethyl 2-(bromomethyl)phenyl-1,4-dicarbonate (Intermediate 4) (2.9 g, 10.0 mmol), triethylamine (2.1 mL, 15.0 mmol) was added sequentially. The reaction was stirred at 50 ° C for 12 hours and then terminated. The reaction was cooled to room temperature, and the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The organic phase was dried over anhydrous sodium sulfate (MgSO4). Methyl [[2-phenylphenyl)carbamoyloxy]-1-piperidinyl]ethyl]isoindoline-5-carboxylate (10D) (4.0 g, 77.8%).

第四步：[1-[2-[5-(羟基甲基)-1-氧代-异吲哚啉-2-基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(10E) Fourth step: [1-[2-[5-(hydroxymethyl)-1-oxo-isoindol-2-yl]ethyl]-4-piperidinyl]N-(2-phenyl Phenyl)carbamate (10E)

[1-[2-[5-(hydroxymethyl)-1-oxo-isoindolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate[1-[2-[5-(hydroxymethyl)-1-oxo-isoindolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

将1-氧代-2-[2-[4-[(2-苯基苯基)胺基甲酰基氧]-1-哌啶基]乙基]异吲哚啉-5-羧酸甲酯(10D)(0.85g,1.7mmol)溶于二氯甲烷(30mL)中，-78℃下，滴加二异丁基氢化铝的甲苯溶液(2M,1.7mL,3.4mmol)，滴加完毕后，-78℃搅拌3小时。滴加10％酒石酸钠钾水溶液(30mL)淬灭反应，待反应升至室温后，萃取，水相用二氯甲烷(50mL)萃取，合并后的有机相用无水硫酸钠干燥，减压浓缩后柱层析分离(二氯甲烷/甲醇(v/v)＝15:1)得到黄色固体状的[1-[2-[5-(羟基甲基)-1-氧代-异吲哚啉-2-基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(10E)[(0.6g,75％)。Methyl 1-oxo-2-[2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidinyl]ethyl]isoindoline-5-carboxylate (10D) (0.85 g, 1.7 mmol) was dissolved in dichloromethane (30 mL), and a solution of diisobutylaluminum hydride in toluene (2M, 1.7 mL, 3.4 mmol) was added dropwise at -78 ° C. Stir at -78 ° C for 3 hours. The reaction was quenched with aq. EtOAc (EtOAc) (EtOAc) After column chromatography (dichloromethane/methanol (v/v) = 15:1) gave [1-[2-[5-(hydroxymethyl)-1-oxo-isoporphyrin as a yellow solid. 2-yl]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (10E) [(0.6 g, 75%).

LCMS m/z＝486.3[M+1]。LCMS m/z = 486.3 [M + 1].

第五步：[1-[2-(5-甲酰基-1-氧代-异吲哚啉-2-基)乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(10F)Step 5: [1-[2-(5-Formyl-1-oxo-isoindol-2-yl)ethyl]-4-piperidinyl]N-(2-phenylphenyl) Carbamate (10F)

[1-[2-(5-formyl-1-oxo-isoindolin-2-yl)ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate[1-[2-(5-formyl-1-oxo-isoindolin-2-yl)ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

将[1-[2-[5-(羟基甲基)-1-氧代-异吲哚啉-2-基]乙基]-4-哌啶基]-N-(2-苯基苯基)氨基甲酸酯(10E)(0.6g,1.2mmol)溶于二氯甲烷(20mL)中，0℃下，向其中滴加戴斯-马丁氧化剂(0.79g,1.9mmol)，0℃搅拌2小时。滴加饱和碳酸氢钠水溶液(30mL)淬灭反应，用二氯甲烷(50mL×2)萃取，合并后的有机相用无水硫酸钠干燥，减压浓缩后柱层析分离(二氯甲烷/甲醇(v/v)＝15:1)得到黄色固体状的[1-[2-(5-甲酰基-1-氧代-异吲哚啉-2-基)乙基]-4-哌啶基]-N-(2-苯基苯基)氨基甲酸酯(10F)[(0.45g,75％)。[1-[2-[5-(Hydroxymethyl)-1-oxo-isoindol-2-yl]ethyl]-4-piperidinyl]-N-(2-phenylphenyl) The carbamate (10E) (0.6 g, 1.2 mmol) was dissolved in dichloromethane (20 mL). EtOAc (0.79 g, 1.9 mmol) was added dropwise at 0 ° C, stirring at 0 ° C 2 hour. The reaction was quenched with EtOAc EtOAc (EtOAc m. Methanol (v/v) = 15:1) gave [1-[2-(5-formyl-1-oxo-isoindol-2-yl)ethyl]-4-piperidine as a yellow solid ]]-N-(2-phenylphenyl)carbamate (10F) [(0.45 g, 75%).

LCMS m/z＝484.3[M+1]。LCMS m/z = 484.3 [M + 1].

第六步：[1-[2-[[5-[(4-甲酰胺-1-哌啶基)甲基]-1-氧代-异氢化吲哚-2-基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物10)The sixth step: [1-[2-[[5-[(4-carboxamide-1-piperidyl)methyl]-1-oxo-isohydroindol-2-yl]ethyl]-4 -piperidinyl]N-(2-phenylphenyl)carbamate (Compound 10)

[1-[2-[5-[(4-carbamoyl-1-piperidyl)methyl]-1-oxo-isoindolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate [1-[2-[5-[(4-carbamoyl-1-piperidyl)methyl]-1-oxo-isoindolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

将[1-[2-(5甲酰基-1-氧代-异吲哚啉-2-基)乙基]-4-哌啶基]-N-(2-苯基苯基)碳酸铵(10F)(0.45g,0.93mmol)溶于异丙醇(15mL)中，向其中加入4-哌啶甲酰胺(0.24g,1.9mmol)。室温下搅拌30分钟后，依次向加入乙酸(0.32mL)，三乙酰氧基硼氢化钠(0.59g,2.8mmol)，2小时后终止反应。减压浓缩除去大部分反应溶剂，向残余物中缓慢滴加饱和碳酸氢钠水溶液(50mL)，水相用二氯甲烷萃取(100mL×2)，合并后的有机相用饱和食盐水洗(50mL)，无水硫酸钠干燥后，减压浓缩柱层析分离[(二氯甲烷/甲醇(v/v)＝10:1)]得到白色固体状的[1-[2-[[5-[(4-甲酰胺-1-哌啶基)甲基]-1-氧代-异氢化吲哚-2-基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物10)(0.4g,产率72％)。[1-[2-(5-Formyl-1-oxo-isoindol-2-yl)ethyl]-4-piperidinyl]-N-(2-phenylphenyl)ammonium carbonate ( 10F) (0.45 g, 0.93 mmol) was dissolved in isopropyl alcohol (15 mL), and 4-piperidinecarboxamide (0.24 g, 1.9 mmol) was added. After stirring at room temperature for 30 minutes, acetic acid (0.32 mL) and sodium triacetoxyborohydride (0.59 g, 2.8 mmol) were sequentially added, and the reaction was terminated after 2 hours. The reaction mixture was concentrated under reduced pressure to dryness crystals crystalsssssssssssssssssssssssssssssssssssssssss After drying over anhydrous sodium sulfate, the residue was purified by column chromatography under reduced pressure [dichloromethane/methanol (v/v) = 10:1) to give [1-[2-[[5-[( 4-carboxamide-1-piperidinyl)methyl]-1-oxo-isohydroindol-2-yl]ethyl]-4-piperidinyl]N-(2-phenylphenyl)amino Formate (Compound 10) (0.4 g, yield 72%).

¹H NMR(400MHz,CDCl₃)δ8.10-8.08(d,1H),7.76-7.74(d,1H),7.50-7.37(m,8H),7.21-7.14(m,1H),7.11-7.07(m,1H),6.58(s,1H),5.50(s,1H),5.45(s,1H),4.74-4.70(m,1H),4.46(s,2H),3.73-3.69(m,2H),3.58(s,2H),3.48(m,2H),2.91-2.59(d,2H),2.78-2.76(m,2H),2.63-2.60(m,2H),2.32-2.30(m,2H),2.15-1.62(m,7H)。 ¹ H NMR (400MHz, CDCl ₃ ) δ 8.10-8.08 (d, 1H), 7.76-7.74 (d, 1H), 7.50-7.37 (m, 8H), 7.21-7.14 (m, 1H), 7.11-7.07 (m, 1H), 6.58 (s, 1H), 5.50 (s, 1H), 5.45 (s, 1H), 4.74 - 4.70 (m, 1H), 4.46 (s, 2H), 3.73 - 3.69 (m, 2H) ), 3.58 (s, 2H), 3.48 (m, 2H), 2.91-2.59 (d, 2H), 2.78-2.76 (m, 2H), 2.63-2.60 (m, 2H), 2.32-2.30 (m, 2H) ), 2.15 - 1.62 (m, 7H).

LCMS m/z＝596.4[M+1]。LCMS m/z = 596.4 [M + 1].

实施例11：[1-[3-[5-[(4-氨甲酰基-1-哌啶基)甲基]-6-甲氧基-吲哚啉-1-基]-3-氧代-丙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物11)Example 11: [1-[3-[5-[(4-carbamoyl-1-piperidyl)methyl]-6-methoxy-indololin-1-yl]-3-oxo -propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (Compound 11)

[1-[3-[5-[(4-carbamoyl-1-piperidyl)methyl]-6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate[1-[3-[5-[(4-carbamoyl-1-piperidyl)methyl]-6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl) Carbamate

第一步：6-甲氧基二氢吲哚(11B)First step: 6-methoxydihydroanthracene (11B)

6-methoxyindoline6-methoxyindoline

将6-甲氧基吲哚(11A)(5.0g,33.97mmol)溶于乙酸(50mL)中，氮气保护，将氰基硼氢化钠(5.34g,84.94mmol)加到反应液中，25℃反应2小时。反应液加入水(80mL)，冷却到0℃，小心加入氢氧化钠调节pH至12～13。加入乙酸乙酯(80mL)，萃取分层，水相用乙酸乙酯(30mL×2)萃取，合并有机相。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后残留物用硅胶柱色谱分离提纯(乙酸乙酯：石油醚(v/v)＝0:1～1:4)，得到标题化合物6-甲氧基二氢吲哚(11B)，黄色油状(4.4g，产率87％)。6-Methoxyindole (11A) (5.0 g, 33.97 mmol) was dissolved in acetic acid (50 mL), EtOAc (EtOAc m. Reaction for 2 hours. The reaction solution was added with water (80 mL) and cooled to 0 ° C. Ethyl acetate (80 mL) was added, and the layers were separated and evaporated, ethyl acetate The organic phase was dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, evaporated -Methoxy indoline (11B), yellow oil (4.4 g, yield 87%).

¹H NMR(400MHz,CDCl₃)δ7.00(dd,1H),6.28–6.24(m,2H),3.76(s,4H),3.56(t,2H),2.97(t,2H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.00 (dd, 1H), 6.28 - 6.24 (m, 2H), 3.76 (s, 4H), 3.56 (t, 2H), 2.97 (t, 2H).

LCMS m/z＝150.1[M+1]。LCMS m/z = 150.1 [M + 1].

第二步：5-溴-6-甲氧基二氢吲哚(11C)Second step: 5-bromo-6-methoxyindoline (11C)

5-bromo-6-methoxyindoline5-bromo-6-methoxyindoline

将6-甲氧基二氢吲哚(11B)(22g,147.46mmol)溶于乙酸乙酯(200mL)中，在0℃下加入1,3-二溴-5,5-二甲基海因(CAS:77-48-5)(21.08g,73.73mmol)，0℃反应2小时。向反应液中加入15％的碳酸钾溶液(250mL)，充分搅拌后萃取分层，有机相无水硫酸钠干燥，过滤，滤液减压浓缩后残留物用硅胶柱色谱分离提纯(乙酸乙酯：石油醚(v/v)＝0:1～1:9)，得到标题化合物5-溴-6-甲氧基二氢吲哚(11C)，紫色液体(16g，产率47.57％)。6-Methoxydihydroindole (11B) (22 g, 147.46 mmol) was dissolved in ethyl acetate (200 mL) and 1,3-dibromo-5,5-dimethylhydan was added at 0 °C. (CAS: 77-48-5) (21.08 g, 73.73 mmol), reaction at 0 ° C for 2 hours. A 15% potassium carbonate solution (250 mL) was added to the reaction mixture, and the mixture was stirred and evaporated to dryness. Petroleum ether (v/v) = 0:1 to 1:9) gave the title compound 5-bromo-6-methoxyindoline (11C) as a purple liquid (16 g, yield 47.57%).

¹H NMR(400MHz,CDCl₃)δ7.19(t,1H),6.26(s,1H),3.80(s,3H),3.56(t,2H),2.95(t,2H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.19 (t, 1H), 6.26 (s, 1H), 3.80 (s, 3H), 3.56 (t, 2H), 2.95 (t, 2H).

LCMS m/z＝228.1[M+1]。LCMS m/z = 228.1 [M + 1].

第三步：5-溴-6-甲氧基二氢吲哚-1-氨基羧酸叔丁酯(11D)The third step: 5-bromo-6-methoxyindoline-1-aminocarboxylic acid tert-butyl ester (11D)

tert-butyl 5-bromo-6-methoxyindoline-1-carboxylateTert-butyl 5-bromo-6-methoxyindoline-1-carboxylate

将5-溴-6-甲氧基二氢吲哚(11C)(16g,70.15mmol)溶于四氢呋喃(70mL)中，加入二碳酸二叔丁酯(22.97g,105.22mmol)和4-二甲氨基吡啶(1.71g,14.03mol)，室温反应2小时。向反应液中加入水(50mL)和乙酸乙酯(50mL)，萃取分层。水相用乙酸乙酯(30 mL)，合并有机相。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后残留物用硅胶柱色谱分离提纯(乙酸乙酯：石油醚(v/v)＝0:1～1:19)，得到标题化合物5-溴-6-甲氧基二氢吲哚-1-氨基羧酸叔丁酯(11D)，紫白色固体(17g，产率74％)。5-Bromo-6-methoxyindoline (11C) (16 g, 70.15 mmol) was dissolved in tetrahydrofuran (70 mL), di-tert-butyl dicarbonate (22.97 g, 105.22 mmol) and 4-dimethyl Aminopyridine (1.71 g, 14.03 mol) was reacted at room temperature for 2 hours. Water (50 mL) and ethyl acetate (50 mL) were added to the mixture, and the layers were separated. Water phase with ethyl acetate (30 mL), combined organic phase. The organic phase was dried over anhydrous sodium sulfate (MgSO4), EtOAcjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH -Bromo-6-methoxyindoline-1-aminocarboxylic acid tert-butyl ester (11D), purple-white solid (17 g, yield 74%).

¹H NMR(400MHz,CDCl₃)δ7.70–7.50(m,1H),7.25(s,1H),3.97(t,2H),3.89(s,3H),3.01(t,2H),1.56(s,9H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.70-7.50 (m, 1H), 7.25 (s, 1H), 3.97 (t, 2H), 3.89 (s, 3H), 3.01 (t, 2H), 1.56 ( s, 9H).

LCMS m/z＝350.0[M+23]。LCMS m/z = 350.0 [M+23].

第四步：5-甲酰基-6-甲氧基二氢吲哚-1-氨基羧酸叔丁酯(11E)The fourth step: 5-formyl-6-methoxyindoline-1-aminocarboxylic acid tert-butyl ester (11E)

tert-butyl 5-formyl-6-methoxyindoline-1-carboxylateTert-butyl 5-formyl-6-methoxyindoline-1-carboxylate

将5-溴-6-甲氧基二氢吲哚-1-氨基甲酸叔丁基酯(11D)(17g,51.80mmol)溶于四氢呋喃(300mL)中，氮气保护，-78℃加入2.5M正丁基锂的正己烷溶液(22.8mL,56.98mmol)，保持此温度反应30分钟。-78℃加入N,N-二甲基甲酰胺(18.93g,259mmol)，逐渐升至室温反应1小时。向反应液中加入水(200mL)和加入乙酸乙酯(100mL)，萃取分层。水相用乙酸乙酯(100mL)萃取一次，合并有机相。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后残留物用硅胶柱色谱分离提纯(乙酸乙酯：石油醚(v/v)＝0:1～1:4)，得到标题化合物5-甲酰基-6-甲氧基二氢吲哚-1-氨基羧酸叔丁酯(11E)，黄色固体(8.6g，产率60％)。5-Bromo-6-methoxyindoline-1-carbamic acid tert-butyl ester (11D) (17 g, 51.80 mmol) was dissolved in tetrahydrofuran (300 mL). A solution of butyllithium in n-hexane (22.8 mL, 56.98 mmol) was maintained at this temperature for 30 min. N,N-dimethylformamide (18.93 g, 259 mmol) was added at -78 ° C, and the mixture was gradually warmed to room temperature for 1 hour. Water (200 mL) was added to the reaction mixture, and ethyl acetate (100 mL) was added, and the mixture layered. The aqueous phase was extracted once with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate (MgSO4), EtOAcjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH -Formyl-6-methoxyindoline-1-aminocarboxylic acid tert-butyl ester (11E), yellow solid (8.6 g, yield 60%).

¹H NMR(400MHz,CDCl₃)δ10.29(s,1H),7.56(d,2H),4.02(t,2H),3.93(s,3H),3.03(t,2H),1.58(s,9H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ10.29 (s, 1H), 7.56 (d, 2H), 4.02 (t, 2H), 3.93 (s, 3H), 3.03 (t, 2H), 1.58 (s, 9H).

LCMS m/z＝278.1[M+Na]。LCMS m/z = 278.1 [M+Na].

第五步：6-甲氧基二氢吲哚-5-甲醛(11F)Step 5: 6-Methoxydihydroindole-5-formaldehyde (11F)

6-methoxyindoline-5-carbaldehyde6-methoxyindoline-5-carbaldehyde

将5-甲酰基-6-甲氧基二氢吲哚-1-氨基甲酸叔丁酯(11E)(8.6g,31mmol)溶于二氯甲烷(50mL)中，加入三氟乙酸(18g,160mmol)，室温反应3小时。反应液减压浓缩，加入氨水调节pH至9，加入水(100mL)和二氯甲烷(100mL)，萃取。水相用二氯甲烷(50mL)萃取一次，合并有机相。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。残留物用硅胶柱色谱分离提纯(乙酸乙酯：石油醚(v/v)＝1:9～4:1)，得到标题化合物6-甲氧基二氢吲哚-5-甲醛(11F)，黄色固体(2.7g，产率49％)。 tert-Butyl 5-formyl-6-methoxyindoline-1-carbamate (11E) (8.6 g, 31 mmol) was dissolved in dichloromethane (50 mL). ), reacted at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. aqueous EtOAc (EtOAc)EtOAc. The aqueous phase was extracted once with dichloromethane (50 mL). The organic phase was dried over anhydrous sodium sulfate and filtered and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:EtOAc (EtOAc:EtOAc) Yellow solid (2.7 g, yield 49%).

¹H NMR(400MHz,CDCl₃)δ10.13(s,1H),7.55(s,1H),6.08(s,1H),4.44(s,1H),3.83(s,3H),3.68(t,2H),2.99(t,2H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ10.13 (s, 1H), 7.55 (s, 1H), 6.08 (s, 1H), 4.44 (s, 1H), 3.83 (s, 3H), 3.68 (t, 2H), 2.99 (t, 2H).

LCMS m/z＝178.1[M+1]。LCMS m/z = 178.1 [M + 1].

第六步：6-甲氧基-1-丙基-2-烯酰-吲哚啉-5-甲醛(11G)Step 6: 6-Methoxy-1-propyl-2-enoyl-porphyrin-5-formaldehyde (11G)

6-methoxy-1-prop-2-enoyl-indoline-5-carbaldehyde6-methoxy-1-prop-2-enoyl-indoline-5-carbaldehyde

将6-甲氧基二氢吲哚-5-甲醛(11F)(0.100g,0.564mmol)溶于乙酸乙酯(10mL)中，加入三乙胺(0.428g,4.23mmol)，氮气保护。滴加丙烯酸(0.102g,1.41mmol)。升至40℃再滴加1-丙基磷酸酐(0.449g,1.41mmol)，40℃反应，4小时。反应液加入乙酸乙酯(20mL)，依次用2M盐酸溶液(20mL)和3％氢氧化钠溶液(20mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物6-甲氧基-1-丙基-2-烯酰-吲哚啉-5-甲醛(11G)，黄色固体(0.08g，产率61％)。6-Methoxydihydroindole-5-carboxaldehyde (11F) (0.100 g, 0.564 mmol) was dissolved in ethyl acetate (10 mL) and triethylamine (0.428 g, 4. Acrylic acid (0.102 g, 1.41 mmol) was added dropwise. The mixture was further added to a solution of 1-propylphosphoric anhydride (0.449 g, 1.41 mmol) at 40 ° C, and reacted at 40 ° C for 4 hours. The reaction mixture was added with EtOAc EtOAc (EtOAc)EtOAc. Methoxy-1-propyl-2-enoyl-porphyrin-5-carbaldehyde (11G), yellow solid (0.08 g, yield 61%).

¹H NMR(400MHz,CDCl₃)δ10.33(s,1H),8.06(s,1H),7.65(s,1H),6.58(t,2H),5.88(dd,1H),4.23(t,2H),3.95(s,3H),3.17(t,2H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ10.33 (s, 1H), 8.06 (s, 1H), 7.65 (s, 1H), 6.58 (t, 2H), 5.88 (dd, 1H), 4.23 (t, 2H), 3.95 (s, 3H), 3.17 (t, 2H).

LCMS m/z＝232.1[M+1]。LCMS m/z = 232.1 [M + 1].

第七步：[1-[3-(5-甲酰基-6-甲氧基-吲哚啉-1-基)-3-氧代-丙基]-4哌啶基]N-(2-苯基苯基)氨基甲酸酯(11H)Step 7: [1-[3-(5-Formyl-6-methoxy-indololin-1-yl)-3-oxo-propyl]-4piperidinyl]N-(2- Phenylphenyl)carbamate (11H)

[1-[3-(5-formyl-6-methoxy-indolin-1-yl)-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate[1-[3-(5-formyl-6-methoxy-indolin-1-yl)-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

将6-甲氧基-1-丙基-2-烯酰-吲哚-5-甲醛(11G)(0.608g,2.63mmol)溶于2-甲基四氢呋喃(10mL)中，加入4-哌啶基N-(2-苯基苯基)氨基甲酸酯(1A)(0.600g,2.02mmol)，加入乙酸(0.243g,4.05mmol)，100℃微波反应1小时。反应液浓缩，加入二氯甲烷(20mL)和饱和碳酸氢钠溶液(20mL)，萃取分层。水相用二氯甲烷(20mL×2)萃取，无水硫酸钠干燥，过滤，滤液减压浓缩后残留物用硅胶柱色谱分离提纯(乙酸乙酯：石油醚(v/v)＝1:1～1:0，甲醇：二氯甲烷(v/v)＝3:97)，得到标题化合物[1-[3-(5-甲酰基-6-甲氧基-吲哚啉-1-基)-3-氧代-丙基]-4哌啶基]N-(2-苯基苯基)氨基甲酸酯(11H)，黄色固体(0.72g，产率67.4％)。 6-Methoxy-1-propyl-2-enoyl-indole-5-carbaldehyde (11G) (0.608 g, 2.63 mmol) was dissolved in 2-methyltetrahydrofuran (10 mL). N-(2-Phenylphenyl)carbamate (1A) (0.600 g, 2.02 mmol), acetic acid (0.243 g, 4.05 mmol) was added, and the mixture was stirred at 100 ° C for 1 hour. The reaction mixture was concentrated, dichloromethane (20 mL) and EtOAc. The aqueous layer was extracted with methylene chloride (20 mL×2), dried over anhydrous sodium sulfate. ～1:0, methanol: dichloromethane (v/v) = 3:97) to give the title compound [1-[3-(5-formyl-6-methoxy-indololin-1-yl) 3-Oxo-propyl]-4piperidinyl]N-(2-phenylphenyl)carbamate (11H), yellow solid (0.72 g, yield 67.4%).

¹H NMR(400MHz,CDCl₃)δ10.32(s,1H),8.08(d,1H),7.97(s,1H),7.64(s,1H),7.50(t,2H),7.45–7.39(m,1H),7.39–7.33(m,3H),7.23(dd,1H),7.14(td,1H),6.61(s,1H),4.82(s,1H),4.13(t,2H),3.92(s,3H),3.15(t,2H),2.97(s,2H),2.80(s,4H),2.54(s,2H),2.13–1.98(m,2H),1.82(s,2H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ10.32 (s, 1H), 8.08 (d, 1H), 7.97 (s, 1H), 7.64 (s, 1H), 7.50 (t, 2H), 7.45-7.39 ( m,1H), 7.39–7.33 (m, 3H), 7.23 (dd, 1H), 7.14 (td, 1H), 6.61 (s, 1H), 4.82 (s, 1H), 4.13 (t, 2H), 3.92 (s, 3H), 3.15 (t, 2H), 2.97 (s, 2H), 2.80 (s, 4H), 2.54 (s, 2H), 2.13 - 1.98 (m, 2H), 1.82 (s, 2H).

LCMS m/z＝528.1[M+1]。LCMS m/z = 528.1 [M + 1].

第八步:[1-[3-[5-[(4-氨甲酰基-1-哌啶基)甲基]-6-甲氧基-吲哚啉-1-基]-3-氧代-丙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物11)Step 8: [1-[3-[5-[(4-carbamoyl-1-piperidyl)methyl]-6-methoxy-indololin-1-yl]-3-oxo -propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (Compound 11)

取[1-[3-(5-甲酰基-6-甲氧基-吲哚啉-1-基)-3-氧代-丙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(11H)(0.53g，1.0mmol)和4-哌啶甲酰胺(0.26g，2.0mmol)置于50mL圆底烧瓶中，加入异丙醇(20mL)，60℃条件下搅拌30分钟后，60℃减压浓缩1小时，向残留物中加入异丙醇(20mL)、无水硫酸钠(0.28g,2.0mmol)和乙酸(0.28mL,5.0mmol)，搅拌均匀后，于0℃条件下加入三乙酰氧基硼氢化钠(0.63g，3.0mmol)，升至室温反应3小时。反应结束后饱和碳酸氢钠溶液(30mL)淬灭反应，二氯甲烷(30mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经硅胶柱层析纯化(二氯甲烷/甲醇(v/v)＝1:8)，得到标题化合物[1-[3-[5-[(4-氨甲酰基-1-哌啶基)甲基]-6-甲氧基-吲哚啉-1-基]-3-氧代-丙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物11),白色固体(0.27g,产率:42％)。Taking [1-[3-(5-formyl-6-methoxy-indololin-1-yl)-3-oxo-propyl]-4-piperidinyl]N-(2-phenyl Phenyl)carbamate (11H) (0.53 g, 1.0 mmol) and 4-piperidinecarboxamide (0.26 g, 2.0 mmol) were placed in a 50 mL round bottom flask and isopropyl alcohol (20 mL) was added at 60 ° C After stirring for 30 minutes, it was concentrated under reduced pressure at 60 ° C for 1 hour, and isopropyl alcohol (20 mL), anhydrous sodium sulfate (0.28 g, 2.0 mmol) and acetic acid (0.28 mL, 5.0 mmol) Sodium triacetoxyborohydride (0.63 g, 3.0 mmol) was added at 0 ° C, and the mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:8) gave the title compound [1-[3-[5-[(4-carbamoyl-1-piperidyl)methyl]-6- Oxy-porphyrin-1-yl]-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (Compound 11), white solid (0.27 g, yield: 42%).

LCMS m/z＝640.3[M+1]。LCMS m/z = 640.3 [M + 1].

¹H NMR(400MHz,DMSO-d6)δ8.60(s,1H),7.81(s,1H),7.47–7.23(m,9H),7.15(s,1H),7.11(s,1H),6.66(s,1H),4.44(dd,J＝8.2,4.2Hz,1H),4.09(t,J＝8.4Hz,2H),,3.70(s,3H),3.29(s,4H),3.04(t,J＝8.3Hz,2H),2.79(d,J＝11.4Hz,2H),2.59(s,6H),2.17(m,2H),2.01(m,1H),1.98(s,1H),1.90(t,J＝10.4Hz,2H),1.70(m,2H),1.62(m,2H),1.53(m,2H),1.41(m,3H),1.23(s,2H),1.16(dd,J＝15.0,7.9Hz,1H)。 ^{1 H NMR (400MHz, DMSO-} d6) δ8.60 (s, 1H), 7.81 (s, 1H), 7.47-7.23 (m, 9H), 7.15 (s, 1H), 7.11 (s, 1H), 6.66 (s, 1H), 4.44 (dd, J = 8.2, 4.2 Hz, 1H), 4.09 (t, J = 8.4 Hz, 2H), 3.70 (s, 3H), 3.29 (s, 4H), 3.04 (t , J = 8.3 Hz, 2H), 2.79 (d, J = 11.4 Hz, 2H), 2.59 (s, 6H), 2.17 (m, 2H), 2.01 (m, 1H), 1.98 (s, 1H), 1.90 (t, J = 10.4 Hz, 2H), 1.70 (m, 2H), 1.62 (m, 2H), 1.53 (m, 2H), 1.41 (m, 3H), 1.23 (s, 2H), 1.16 (dd, J = 15.0, 7.9 Hz, 1H).

实施例12：[1-[3-[5-[(2-氨甲酰基-3-乙基-4,6-二氢吡咯[3,4-d]咪唑-5-基)甲基]-6-甲氧基-吲哚啉-1-基]-3-氧代-丙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物12)Example 12: [1-[3-[5-[(2-carbamoyl-3-ethyl-4,6-dihydropyrrole[3,4-d]imidazol-5-yl)methyl]- 6-Methoxy-porphyrin-1-yl]-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (Compound 12)

[1-[3-[5-[(2-carbamoyl-3-ethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-yl)methyl]-6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate [1-[3-[5-[(2-carbamoyl-3-ethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-yl)methyl]-6-methoxy-indolin-1-yl] -3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

取[1-[3-(5-甲酰基-6-甲氧基-吲哚啉-1-基)-3-氧代-丙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(11A)(0.53g，1.0mmol)和3-乙基-5,6-二氢-4H-吡咯[3,4-d]咪唑-2-甲酰胺(中间体2)(0.36g，2.0mmol)置于50mL圆底烧瓶中，加入异丙醇(20mL)，60℃条件下搅拌30分钟后，60℃减压浓缩1小时，向残留物中加入异丙醇(20mL)、无水硫酸钠(0.28g,2.0mmol)和乙酸(0.28mL,5.0mmol)，搅拌均匀后，于0℃条件下加入三乙酰氧基硼氢化钠(0.63g，3.0mmol)，升至室温反应3小时。反应结束后饱和碳酸氢钠溶液(30mL)淬灭反应，二氯甲烷(30mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经硅胶柱层析纯化(二氯甲烷/甲醇(v/v)＝1:8)，得到标题化合物[1-[3-[5-[(2-氨甲酰基-3-乙基-4,6-二氢吡咯[3,4-d]咪唑-5-基)甲基]-6-甲氧基-吲哚啉-1-基]-3-氧代-丙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物12),白色固体(0.34g,产率:49％)。Taking [1-[3-(5-formyl-6-methoxy-indololin-1-yl)-3-oxo-propyl]-4-piperidinyl]N-(2-phenyl Phenyl)carbamate (11A) (0.53 g, 1.0 mmol) and 3-ethyl-5,6-dihydro-4H-pyrrole[3,4-d]imidazole-2-carboxamide (Intermediate 2 (0.36 g, 2.0 mmol) was placed in a 50 mL round bottom flask, isopropanol (20 mL) was added, and the mixture was stirred at 60 ° C for 30 minutes, and then concentrated under reduced pressure at 60 ° C for 1 hour, and isopropyl alcohol was added to the residue ( 20 mL), anhydrous sodium sulfate (0.28 g, 2.0 mmol) and acetic acid (0.28 mL, 5.0 mmol). After stirring well, sodium triacetoxyborohydride (0.63 g, 3.0 mmol) was added at 0 ° C, liter The reaction was carried out for 3 hours at room temperature. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:8) gave the title compound [1-[3-[5-[(2-carbamoyl-3-ethyl-4,6-dihydropyrrole [ 3,4-d]imidazol-5-yl)methyl]-6-methoxy-porphyrin-1-yl]-3-oxo-propyl]-4-piperidinyl]N-(2 -Phenylphenyl)carbamate (Compound 12), white solid (0.34 g, yield: 49%).

LCMS m/z＝346.8[M/2+1]。LCMS m/z = 346.8 [M/2+1].

¹H NMR(400MHz,DMSO-d6)δ8.61(s,1H),7.85(s,1H),7.60(s,1H),7.49–7.19(m,10H),5.75(s,1H),4.45(s,1H),4.35(q,J＝7.1Hz,2H),4.12(t,J＝8.4Hz,2H),3.87(s,2H),3.84(s,2H),3.75(s,3H),3.68(s,2H),3.07(t,J＝8.3Hz,2H),2.60(s,5H),2.18(t,J＝9.5Hz,2H),1.71(s,2H),1.43(m,2H),1.25(m,4H)。 ^{1 H NMR (400MHz, DMSO-} d6) δ8.61 (s, 1H), 7.85 (s, 1H), 7.60 (s, 1H), 7.49-7.19 (m, 10H), 5.75 (s, 1H), 4.45 (s, 1H), 4.35 (q, J = 7.1 Hz, 2H), 4.12 (t, J = 8.4 Hz, 2H), 3.87 (s, 2H), 3.84 (s, 2H), 3.75 (s, 3H) , 3.68 (s, 2H), 3.07 (t, J = 8.3 Hz, 2H), 2.60 (s, 5H), 2.18 (t, J = 9.5 Hz, 2H), 1.71 (s, 2H), 1.43 (m, 2H), 1.25 (m, 4H).

实施例13：[1-[2-[[4-(2,8-二氮杂螺[4.5]癸-8-基甲基)苯甲酰基]-甲基-氨基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物13)Example 13: [1-[2-[[4-(2,8-diazaspiro[4.5]dec-8-ylmethyl)benzoyl]-methyl-amino]ethyl]-4- Piperidinyl]N-(2-phenylphenyl)carbamate (Compound 13)

[1-[2-[[4-(2,8-diazaspiro[4.5]decan-8-ylmethyl)benzoyl]-methyl-amino]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate [1-[2-[[4-(2,8-diazaspiro[4.5]decan-8-ylmethyl)benzoyl]-methyl-amino]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

第一步：8-[[4-[甲基-[2-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]乙基]氨甲酰基]苯基]甲基]-2,8-二氮杂螺[4.5]癸-2-羧酸叔丁酯(13A)First step: 8-[[4-[methyl-[2-[4-[(2-phenylphenyl)carbamoyloxy)-1-piperidinyl]ethyl]carbamoyl]benzene Methyl]-2,8-diazaspiro[4.5]indole-2-carboxylic acid tert-butyl ester (13A)

tert-butyl 8-[[4-[methyl-[2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl]carbamoyl]phenyl]methyl]-2,8-diazaspiro[4.5]decane-2-carboxylateTert-butyl 8-[[4-[methyl-[2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl]carbamoyl]phenyl]methyl]-2,8-diazaspiro[4.5]decane- 2-carboxylate

将[1-[2-[(4-甲酰基苯甲酰基)-甲基-胺基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(5A)(1.3g,2.7mmol)溶于二氯甲烷(20mL)和甲醇(6mL)的混合溶剂中。向其中加入2,8-二氮杂螺[4.5]癸-2-羧酸叔丁酯(0.34g,1.0mmol)，室温下搅拌30分钟后加入三乙酰氧基硼氢化钠(1.7g,8.0mmol)，室温搅拌3小时。向其中加入饱和碳酸氢钠水溶液(50mL)淬灭反应，残余物用二氯甲烷(100mL×5)萃取，合并后的有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后硅胶柱层析分离(二氯甲烷：甲醇(v/v)＝1:0～8:1)得白色固体状的8-[[4-[甲基-[2-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]乙基]氨甲酰基]苯基]甲基]-2,8-二氮杂螺[4.5]癸-2-碳酸叔丁酯(13A)(1.3g,产率68％)。[1-[2-[(4-Formylbenzoyl)-methyl-amino]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (5A (1.3 g, 2.7 mmol) was dissolved in a mixed solvent of dichloromethane (20 mL) and methanol (6 mL). 2,8-Diazaspiro[4.5]indole-2-carboxylic acid tert-butyl ester (0.34 g, 1.0 mmol) was added thereto, and stirred at room temperature for 30 minutes, then sodium triacetoxyborohydride (1.7 g, 8.0) was added. Methyl), stirred at room temperature for 3 hours. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. Separation and separation (dichloromethane:methanol (v/v) = 1:0 to 8:1) afforded 8-[[4-[methyl-[2-[4-[(2-phenylbenzene) Carbamoyloxy]-1-piperidinyl]ethyl]carbamoyl]phenyl]methyl]-2,8-diazaspiro[4.5]indole-2-carbonate tert-butyl ester (13A (1.3 g, yield 68%).

第二步：[1-[2-[[4-(2,8-二氮杂螺[4.5]癸-8-基甲基)苯甲酰基]-甲基-氨基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物13)The second step: [1-[2-[[4-(2,8-diazaspiro[4.5]癸-8-ylmethyl)benzoyl]-methyl-amino]ethyl]-4- Piperidinyl]N-(2-phenylphenyl)carbamate (Compound 13)

[1-[2-[[4-(2,8-diazaspiro[4.5]decan-8-ylmethyl)benzoyl]-methyl-amino]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate[1-[2-[[4-(2,8-diazaspiro[4.5]decan-8-ylmethyl)benzoyl]-methyl-amino]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

将8-[[4-[甲基-[2-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]乙基]氨甲酰基]苯基]甲基]-2,8-二氮杂螺[4.5]癸-2-羧酸叔丁酯(13A)(1.3g,1.8mmol)溶于二氯甲烷(15mL)中。室温下，向反应滴加三氟乙酸(5mL)，搅拌4小时后终止。减压浓缩除去反应溶剂，加入二氯甲烷(20mL)，滴加三乙胺调至碱性，加入饱和碳酸氢钠溶液(30mL)，二氯甲烷(30 mL×2)萃取两次，合并有机相，有机相依次用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经用硅胶柱层析纯化得到白色固体状的[1-[2-[[4-(2,8-二氮杂螺[4.5]癸-8-基甲基)苯甲酰基]-甲基-氨基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物13)(0.26g,产率23％)。8-[[4-[Methyl-[2-[4-[(2-phenylphenyl)carbamoyloxy)-1-piperidinyl]ethyl]carbamoyl]phenyl]- Tert-butyl-2,8-diazaspiro[4.5]indole-2-carboxylate (13A) (1.3 g, 1.8 mmol) was dissolved in dichloromethane (15 mL). Trifluoroacetic acid (5 mL) was added dropwise to the reaction at room temperature, and stirred for 4 hr. The reaction solvent was concentrated under reduced pressure. dichloromethane (20 mL) was added, and then triethylamine was added dropwise to the mixture, and saturated sodium hydrogen carbonate solution (30 mL), dichloromethane (30) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; [4-(2,8-diazaspiro[4.5]decyl-8-ylmethyl)benzoyl]-methyl-amino]ethyl]-4-piperidinyl]N-(2-phenyl Phenyl) carbamate (compound 13) (0.26 g, yield 23%).

¹H NMR(400MHz,DMSO-d6)δ8.60(m,1H),7.28-7.43(m,13H),4.40(s,1H),3.44-3.47(m,3H),3.27(s,1H),2.92(s,3H),2.81-2.84(t,2H),2.58(s,2H),2.18-2.31(m,7H),1.96(m,2H),1.30-1.62(m,11H)。 ^{1 H NMR (400MHz, DMSO-} d6) δ8.60 (m, 1H), 7.28-7.43 (m, 13H), 4.40 (s, 1H), 3.44-3.47 (m, 3H), 3.27 (s, 1H) , 2.92 (s, 3H), 2.81-2.84 (t, 2H), 2.58 (s, 2H), 2.18-2.31 (m, 7H), 1.96 (m, 2H), 1.30-1.62 (m, 11H).

LCMS m/z＝611.4[M+2]。LCMS m/z = 611.4 [M+2].

实施例14：[1-[2-[[4-[(2-乙酰基-2,8-二氮杂螺[4.5]癸-8-基)甲基)苯甲酰基]-甲基-氨基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物14)Example 14: [1-[2-[[4-[(2-acetyl-2,8-diazaspiro[4.5]]-8-yl)methyl)benzoyl]-methyl-amino ]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (Compound 14)

[1-[2-[[4-[(2-acetyl-2,8-diazaspiro[4.5]decan-8-yl)methyl]benzoyl]-methyl-amino]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate[1-[2-[[4-[(2-acetyl-2,8-diazaspiro[4.5]decan-8-yl)methyl]benzoyl]-methyl-amino]ethyl]-4-piperidyl]N-(2 -phenylphenyl)carbamate

将[1-[2-[[4-(2,8-二氮杂螺[4.5]癸-8-基甲基)苯甲酰基]-甲基-氨基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物13)(0.15g,0.25mmol)溶于二氯甲烷(20mL)中。室温下，依次向反应瓶中加入三乙胺(0.12g,1.2mmol)，乙酸(0.022g,0.37mmol)，HATU(0.14g,0.37mmol)，室温下搅拌2小时后终止反应。滴加饱和碳酸氢钠水溶液(50mL)淬灭反应，残余物用二氯甲烷(100mL×2)萃取，合并后的有机相用饱和食盐水(50mL)洗，无水硫酸钠干燥，减压浓缩后柱层析分离(二氯甲烷/甲醇(v/v)＝15:1)得到白色固体状的[1-[2-[[4-[(2-乙酰基-2,8-二氮杂螺[4.5]癸-8-基)甲基)苯甲酰基]-甲基-氨基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物14)(0.11g,产率69％)。[1-[2-[[4-(2,8-Diazaspiro[4.5]癸-8-ylmethyl)benzoyl]-methyl-amino]ethyl]-4-piperidinyl) N-(2-Phenylphenyl)carbamate (Compound 13) (0.15 g, 0.25 mmol) was dissolved in dichloromethane (20 mL). Triethylamine (0.12 g, 1.2 mmol), acetic acid (0.022 g, 0.37 mmol), HATU (0.14 g, 0.37 mmol) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 2 hr. The reaction was quenched with EtOAc EtOAc (EtOAc m. After column chromatography (dichloromethane/methanol (v/v) = 15:1) gave [1-[2-[[4-[(2-acetyl-2,8-diaza) Spiro[4.5]dec-8-yl)methyl)benzoyl]-methyl-amino]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (Compound 14 (0.11 g, yield 69%).

¹H NMR(400MHz,DMSO-d6)δ8.59(S,1H),7.28-7.41(m,13H),4.41(s,1H),3.55(s,3H),3.41-3.45(t,2H),3.27-3.31(t,2H),3.23(s,1H),3.12(s,1H),3.00-3.06(q,2H),2.92(s,3H),2.32-2.45(m,7H),1.99(s,1H),1.89-1.90(m,3H),1.71-1.74(t,2H),1.62-1.66(t,2H),1.50-1.51(m,4H)。 ^{1 H NMR (400MHz, DMSO-} d6) δ8.59 (S, 1H), 7.28-7.41 (m, 13H), 4.41 (s, 1H), 3.55 (s, 3H), 3.41-3.45 (t, 2H) , 3.27-3.31(t,2H), 3.23(s,1H), 3.12(s,1H), 3.00-3.06(q,2H), 2.92(s,3H),2.32-2.45(m,7H),1.99 (s, 1H), 1.89-1.90 (m, 3H), 1.71-1.74 (t, 2H), 1.62-1.66 (t, 2H), 1.50-1.51 (m, 4H).

LCMS m/z＝652.5[M+1]。LCMS m/z = 652.5 [M + 1].

实施例15:[1-[2-[[4-(2,7-二氮杂螺[3.5]壬-2-基甲基)苯甲酰基]-甲基-氨基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物15)Example 15: [1-[2-[[4-(2,7-diazaspiro[3.5]indol-2-ylmethyl)benzoyl]-methyl-amino]ethyl]-4- Piperidinyl]N-(2-phenylphenyl)carbamate (Compound 15)

[1-[2-[[4-(2,7-diazaspiro[3.5]nonan-2-ylmethyl)benzoyl]-methyl-amino]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate [1-[2-[[4-(2,7-diazaspiro[3.5]nonan-2-ylmethyl)benzoyl]-methyl-amino]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

第一步：2-[[4-[甲基-[2-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]乙基]氨甲酰基]苯基]甲基]-2,7-二氮杂螺[3.5]壬-7-羧酸叔丁酯(15A)First step: 2-[[4-[methyl-[2-[4-[(2-phenylphenyl)carbamoyloxy)-1-piperidinyl]ethyl]carbamoyl]benzene Methyl]-2,7-diazaspiro[3.5]indole-7-carboxylic acid tert-butyl ester (15A)

tert-butyl 2-[[4-[methyl-[2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl]carbamoyl]phenyl]methyl]-2,7-diazaspiro[3.5]nonane-7-carboxylateTert-butyl 2-[[4-[methyl-[2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl]carbamoyl]phenyl]methyl]-2,7-diazaspiro[3.5]nonane- 7-carboxylate

将[1-[2-[(4-甲酰基苯甲酰基)-甲基-胺基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(5A)(1.3g,2.7mmol)溶于二氯甲烷(20mL)和甲醇(6mL)的混合溶剂中。向其中加入2,7-二氮杂螺[3.5]壬-7-羧酸叔丁酯(0.61g,2.7mmol)，室温下搅拌30分钟后加入三乙酰氧基硼氢化钠(1.7g,8.0mmol)，室温搅拌3小时。向其中加入饱和碳酸氢钠水溶液(50mL)淬灭反应，残余物用二氯甲烷(100mL×2)萃取，合并后的有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后柱层析分离(二氯甲烷：甲醇(v/v)＝1:0～8:1)得到白色固体状的2-[[4-[甲基-[2-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]乙基]氨甲酰基]苯基]甲基]-2,7-二氮杂螺[3.5]壬-7-羧酸叔丁酯(15A)(1.2g,产率64％)。[1-[2-[(4-Formylbenzoyl)-methyl-amino]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (5A (1.3 g, 2.7 mmol) was dissolved in a mixed solvent of dichloromethane (20 mL) and methanol (6 mL). 2,7-diazaspiro[3.5]indole-7-carboxylic acid tert-butyl ester (0.61 g, 2.7 mmol) was added thereto, and stirred at room temperature for 30 minutes, then sodium triacetoxyborohydride (1.7 g, 8.0) was added. Methyl), stirred at room temperature for 3 hours. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. Separation (dichloromethane:methanol (v/v) = 1:0 to 8:1) to give 2-[[4-[methyl-[2-[4-[(2-phenylphenyl) Carbamoyloxy]-1-piperidinyl]ethyl]carbamoyl]phenyl]methyl]-2,7-diazaspiro[3.5]indole-7-carboxylic acid tert-butyl ester (15A) ) (1.2 g, yield 64%).

第二步：[1-[2-[[4-(2,7-二氮杂螺[3.5]壬-2-基甲基)苯甲酰基]-甲基-氨基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物15)The second step: [1-[2-[[4-(2,7-diazaspiro[3.5]indol-2-ylmethyl)benzoyl]-methyl-amino]ethyl]-4- Piperidinyl]N-(2-phenylphenyl)carbamate (Compound 15)

[1-[2-[[4-(2,7-diazaspiro[3.5]nonan-2-ylmethyl)benzoyl]-methyl-amino]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate[1-[2-[[4-(2,7-diazaspiro[3.5]nonan-2-ylmethyl)benzoyl]-methyl-amino]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

将2-[[4-[甲基-[2-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]乙基]氨甲酰基]苯基]甲基]-2,7-二氮杂螺[3.5]壬-7-羧酸叔丁酯(15B)(1.2g,1.7mmol)溶于二氯甲烷(15mL)中。室温下，向反应滴加三氟乙酸(5mL)，搅拌4小时后终止。减压浓缩除去反应溶剂，加入二氯甲烷(20mL)，滴加三乙胺调至碱性，加入饱和碳酸氢钠溶液(30mL)，二氯甲烷(30mL×2)萃取两次，合并有机相，有机相依次用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经用硅胶柱层析纯化得到白色固体状的[1-[2-[[4-(2,7-二氮杂螺[3.5]壬-2-基甲基)苯甲酰基]-甲基-氨基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物15)(0.45g,产率44％)。2-[[4-[Methyl-[2-[4-[(2-phenylphenyl)carbamoyloxy)-1-piperidinyl]ethyl]carbamoyl]phenyl]- Tert-butyl-2,7-diazaspiro[3.5]indole-7-carboxylate (15B) (1.2 g, 1.7 mmol) was dissolved in dichloromethane (15 mL). Trifluoroacetic acid (5 mL) was added dropwise to the reaction at room temperature, and stirred for 4 hr. The reaction solvent was concentrated under reduced pressure, dichloromethane (20 mL) was added, and then triethylamine was added dropwise to the mixture, and the mixture was added with saturated sodium hydrogen carbonate solution (30 mL), dichloromethane (30 mL×2), and the organic phase was combined. The organic phase was dried over anhydrous sodium sulfate (MgSO4), EtOAcjjjjjjjjjjj Spiro[3.5]non-2-ylmethyl)benzoyl]-methyl-amino]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (Compound 15) (0.45 g, yield 44%).

¹H NMR(400MHz,DMSO-d₆)δ8.60(m,1H),7.29-7.41(m,13H),4.41(s,1H),3.27-3.47(m,5H),3.27(s,1H),2.85-2.92(m,4H),2.67(s,1H),2.24-2.35(m,7H),1.99(m,2H),1.60-1.72(m,6H),1.36(m,2H),1.16-1.19(t,2H)。 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.60 (m, 1H), 7.29-7.41 (m, 13H), 4.41 (s, 1H), 3.27-3.47 (m, 5H), 3.27 (s, 1H) ), 2.85-2.92 (m, 4H), 2.67 (s, 1H), 2.24-2.35 (m, 7H), 1.99 (m, 2H), 1.60-1.72 (m, 6H), 1.36 (m, 2H), 1.16-1.19(t, 2H).

LCMS m/z＝596.4[M+1]。LCMS m/z = 596.4 [M + 1].

实施例16：[(3aS,5s,6aR)-2-[2-[6-[(4-氨甲酰-1-哌啶基)甲基]-1-氧-3,4-二氢异喹啉-2-基]乙基]-3,3a,4,5,6,6a-六氢-1H-环戊二烯[C]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(化合物16)Example 16: [(3aS,5s,6aR)-2-[2-[6-[(4-carbamoyl-1-piperidyl)methyl]-1-oxo-3,4-dihydroiso Quinoline-2-yl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadiene[C]pyrrole-5-yl]N-(2-phenylphenyl Carbamate (Compound 16)

[(3aS,5s,6aR)-2-[2-[6-[(4-carbamoyl-1-piperidyl)methyl]-1-oxo-3,4-dihydroisoquinolin-2-y l]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate[(3aS,5s,6aR)-2-[2-[6-[(4-carbamoyl-1-piperidyl)methyl]-1-oxo-3,4-dihydroisoquinolin-2-y l]ethyl]-3, 3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

第一步：[(3aS,5s,6aR)-2-[2-[6-[[叔丁基(二甲基)硅基]甲氧基]-1-氧-3,4-二氢异喹啉-2-基]乙基]-3,3a,4,5,6,6a-六氢-1H-环戊二烯[C]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(16A)First step: [(3aS, 5s, 6aR)-2-[2-[6-[[tert-butyl(dimethyl)silyl]methoxy]-1-oxo-3,4-dihydroiso Quinoline-2-yl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadiene[C]pyrrole-5-yl]N-(2-phenylphenyl Carbamate (16A)

[(3aS,5s,6aR)-2-[2-[6-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate[(3aS,5s,6aR)-2-[2-[6-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-3,3a ,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

将[(3aS,5s,6aR)-1,2,3,3a,4,5,6,6a-八氢环戊二烯并[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(4B)(0.96g,3.0mmol)溶于二氯甲烷(20mL)和甲醇(6mL)的混合溶剂中。向其中加入2-[6-[[叔丁基(二甲基)硅基]氧基甲基]-1-氧代-3,4-二氢异喹啉-2-基]乙醛(9G)(1.05g,3.15 mmol)，室温下搅拌30分钟后加入三乙酰氧基硼氢化钠(2.1g,9.9mmol),室温搅拌3小时。向其中加入饱和碳酸氢钠水溶液(50mL)淬灭反应，残余物用二氯甲烷(100mL×2)萃取，合并后的有机相用无水硫酸钠干燥，减压浓缩后柱层析分离(二氯甲烷：甲醇(v/v)＝1:0～8:1)得到黄色液体状的[(3aS,5s,6aR)-2-[2-[6-[[叔丁基(二甲基)硅基]甲氧基]-1-氧-3,4-二氢异喹啉-2-基]乙基]-3,3a,4,5,6,6a-六氢-1H-环戊二烯[C]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(16A)(0.6g,产率30％)。[(3aS,5s,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene The carbamate (4B) (0.96 g, 3.0 mmol) was dissolved in a mixed solvent of dichloromethane (20 mL) and methanol (6 mL). 2-[6-[[tert-Butyl(dimethyl)silyl]oxymethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]acetaldehyde (9G) was added thereto. ) (1.05g, 3.15) After stirring for 30 minutes at room temperature, sodium triacetoxyborohydride (2.1 g, 9.9 mmol) was added and stirred at room temperature for 3 hr. The reaction mixture was quenched with aq. EtOAc (EtOAc) Methyl chloride: methanol (v/v) = 1:0 to 8:1) to give [(3aS,5s,6aR)-2-[2-[6-[[tert-butyl(dimethyl))) as a yellow liquid Silyl]methoxy]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentane Alkene [C]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (16A) (0.6 g, yield 30%).

第二步：[(3aS,5s,6aR)-2-[2-[6-(羟甲基)-1-氧-3,4-二氢异喹啉-2-基]乙基]-3,3a,4,5,6,6a-六氢-1H-环戊二烯[C]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(16B)Second step: [(3aS,5s,6aR)-2-[2-[6-(hydroxymethyl)-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-3 ,3a,4,5,6,6a-hexahydro-1H-cyclopentadienyl[C]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (16B)

[(3aS,5s,6aR)-2-[2-[6-(hydroxymethyl)-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate[(3aS,5s,6aR)-2-[2-[6-(hydroxymethyl)-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

[(3aS,5s,6aR)-2-[2-[6-[[叔丁基(二甲基)硅基]甲氧基]-1-氧-3,4-二氢异喹啉-2-基]乙基]-3,3a,4,5,6,6a-六氢-1H-环戊二烯[C]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(16A)(0.60g,0.94mmol)溶于四氢呋喃(10mL)中。向其中加入四丁基氟化铵(0.49g,1.9mmol)，室温搅拌2小时。将反应液减压浓缩后柱层析分离(二氯甲烷/甲醇(v/v)＝15:1)得到黄色液体状的[(3aS,5s,6aR)-2-[2-[6-(羟甲基)-1-氧-3,4-二氢异喹啉-2-基]乙基]-3,3a,4,5,6,6a-六氢-1H-环戊二烯[C]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(16B)(0.49g,99％)。[(3aS,5s,6aR)-2-[2-[6-[[tert-butyl(dimethyl)silyl]methoxy]-1-oxo-3,4-dihydroisoquinoline-2 -yl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadienyl[C]pyrrole-5-yl]N-(2-phenylphenyl)carbamic acid The ester (16A) (0.60 g, 0.94 mmol) was dissolved in tetrahydrofurane (10 mL). Tetrabutylammonium fluoride (0.49 g, 1.9 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and then purified (jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Hydroxymethyl)-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadiene [C Pyrrolo-5-yl]N-(2-phenylphenyl)carbamate (16B) (0.49 g, 99%).

第三步：[(3aS,5s,6aR)-2-[2-(6-甲酰基-1-氧-3,4-二氢异喹啉-2-基]乙基]-3,3a,4,5,6,6a-六氢-1H-环戊二烯[C]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(16C)The third step: [(3aS, 5s, 6aR)-2-[2-(6-formyl-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-3,3a, 4,5,6,6a-hexahydro-1H-cyclopentadienyl[C]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (16C)

[(3aS,5s,6aR)-2-[2-(6-formyl-1-oxo-3,4-dihydroisoquinolin-2-yl)ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate[(3aS,5s,6aR)-2-[2-(6-formyl-1-oxo-3,4-dihydroisoquinolin-2-yl)ethyl]-3,3a,4,5,6,6a-hexahydro- 1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

将[(3aS,5s,6aR)-2-[2-[6-(羟甲基)-1-氧-3,4-二氢异喹啉-2-基]乙基]-3,3a,4,5,6,6a-六氢-1H-环戊二烯[C]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(16B)(0.49g,0.93mmol)溶于二氯甲烷(10mL)中。0℃下，向其中加入戴斯-马丁氧化剂(0.59g,1.4mmol)。室温搅拌2小时。滴加饱和碳酸氢钠水溶液(40mL)淬灭反应，残余物用二氯甲烷(50mL×2)萃取，合并后的有机相用饱和食盐水(50mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩后柱层析分离(二氯甲烷/甲醇(v/v)＝15:1)得到黄色液体状的[(3aS,5s,6aR)-2-[2-(6-甲酰基-1-氧 -3,4-二氢异喹啉-2-基]乙基]-3,3a,4,5,6,6a-六氢-1H-环戊二烯[C]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(16C)(0.30g,61％)。[(3aS,5s,6aR)-2-[2-[6-(Hydroxymethyl)-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-3,3a, 4,5,6,6a-hexahydro-1H-cyclopentadienyl[C]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (16B) (0.49 g, 0.93 mmol) Dissolved in dichloromethane (10 mL). Dess-Martin periodinane (0.59 g, 1.4 mmol) was added thereto at 0 °C. Stir at room temperature for 2 hours. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. After concentration under reduced pressure, the residue was purified (jjjjjjjjjjjjjjjjjjjjjjjjj - oxygen -3,4-dihydroisoquinolin-2-yl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadienyl[C]pyrrole-5-yl]N -(2-Phenylphenyl)carbamate (16C) (0.30 g, 61%).

LCMS m/z＝524.3[M+1]。LCMS m/z = 524.3 [M + 1].

第四步：[(3aS,5s,6aR)-2-[2-[6-[(4-氨甲酰-1-哌啶基)甲基]-1-氧-3,4-二氢异喹啉-2-基]乙基]-3,3a,4,5,6,6a-六氢-1H-环戊二烯[C]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(化合物16)The fourth step: [(3aS,5s,6aR)-2-[2-[6-[(4-carbamoyl-1-piperidyl)methyl]-1-oxo-3,4-dihydroiso Quinoline-2-yl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadiene[C]pyrrole-5-yl]N-(2-phenylphenyl Carbamate (Compound 16)

[(3aS,5s,6aR)-2-[2-[6-[(4-carbamoyl-1-piperidyl)methyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate[(3aS,5s,6aR)-2-[2-[6-[(4-carbamoyl-1-piperidyl)methyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-3,3a ,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

将[(3aS,5s,6aR)-2-[2-(6-甲酰基-1-氧-3,4-二氢异喹啉-2-基]乙基]-3,3a,4,5,6,6a-六氢-1H-环戊二烯[C]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(16C)(0.22g,0.42mmol)溶于异丙醇(15mL)中，向其中加入4-哌啶甲酰胺(0.089g,0.69mmol)。室温下搅拌30分钟后，依次向加入乙酸(0.5mL)，三乙酰氧基硼氢化钠(0.25g,1.2mmol)，2小时后终止反应。减压浓缩除去大部分反应溶剂，向残余物中缓慢滴加饱和碳酸氢钠水溶液(50mL)，水相用二氯甲烷萃取(100mL×2)，合并后的有机相用饱和食盐水洗(50mL)，无水硫酸钠干燥后，减压浓缩柱层析分离[(二氯甲烷/甲醇(v/v)＝15:1)]得到白色固体状的[(3aS,5s,6aR)-2-[2-[6-[(4-氨甲酰-1-哌啶基)甲基]-1-氧-3,4-二氢异喹啉-2-基]乙基]-3,3a,4,5,6,6a-六氢-1H-环戊二烯[C]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(化合物16)(0.18g,产率67％)。[(3aS,5s,6aR)-2-[2-(6-Formyl-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-3,3a,4,5 ,6,6a-hexahydro-1H-cyclopentadien[C]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (16C) (0.22 g, 0.42 mmol) 4-propanidinecarboxamide (0.089 g, 0.69 mmol) was added to propanol (15 mL). After stirring at room temperature for 30 minutes, acetic acid (0.5 mL) was added successively, sodium triacetoxyborohydride (0.25 g) The reaction was quenched after 2 hours, and the reaction mixture was evaporated to dryness. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate. (3aS,5s,6aR)-2-[2-[6-[(4-carbamoyl-1-piperidyl)methyl]-1-oxo-3,4-dihydroisoquinoline-2- Ethyl]ethyl,-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadien[C]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 16) (0.18 g, yield 67%).

¹H NMR(400MHz,DMSO-d6)δ8.47(s,1H),7.78(d,J＝7.9Hz,1H),7.44–7.38(m,2H),7.38–7.20(m,9H),7.18(s,2H),6.68(s,1H),4.93–4.86(m,1H),3.55(t,J＝6.5Hz,4H),3.44(s,2H),3.31(m,6H),2.95–2.87(m,4H),2.79(d,J＝11.1Hz,3H),2.23(s,2H),1.92(t,J＝11.0Hz,2H),1.69(m,2H),1.54–1.45(m,3H)。 ^{1 H NMR (400MHz, DMSO-} d6) δ8.47 (s, 1H), 7.78 (d, J = 7.9Hz, 1H), 7.44-7.38 (m, 2H), 7.38-7.20 (m, 9H), 7.18 (s, 2H), 6.68 (s, 1H), 4.93 - 4.86 (m, 1H), 3.55 (t, J = 6.5 Hz, 4H), 3.44 (s, 2H), 3.31 (m, 6H), 2.95 - 2.87 (m, 4H), 2.79 (d, J = 11.1 Hz, 3H), 2.23 (s, 2H), 1.92 (t, J = 11.0 Hz, 2H), 1.69 (m, 2H), 1.54 - 1.45 (m) , 3H).

LCMS m/z＝636.5[M+1]。LCMS m/z = 636.5 [M + 1].

实施例17：[1-[2-[[4-[(4-乙酰哌嗪-1-基)甲基]苯甲酰基]-甲基-氨基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物17)Example 17: [1-[2-[[4-[(4-acetylpiperazin-1-yl)methyl]benzoyl]-methyl-amino]-4-piperidinyl]N-(2 -phenylphenyl)carbamate (compound 17)

[1-[2-[[4-[(4-acetylpiperazin-1-yl)methyl]benzoyl]-methyl-amino]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate[1-[2-[[4-[(4-acetylpiperazin-1-yl)methyl]benzoyl]-methyl-amino]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

取[1-[2-[(4-甲酰基苯甲酰基)-甲基-胺基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯 (5A)(0.5g，1.03mmol)和4-乙酰哌嗪(17A)(0.26g，2.06mmol)置于50mL圆底烧瓶中，加入异丙醇(20mL)，60℃条件下搅拌30分钟后，60℃减压浓缩1小时后，向残留物中加入异丙醇(20mL)、无水硫酸钠(0.20g,1.4mmol)和乙酸(0.24mL,4.2mmol)，搅拌均匀后，于0℃条件下加入三乙酰氧基硼氢化钠(0.45g，3.1mmol)，升至室温反应3小时。反应结束后，反应液加入饱和碳酸氢钠溶液(30mL)淬灭反应，二氯甲烷(30mL×2)萃取，合并有机相，有机相依次用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱层析纯化(二氯甲烷/甲醇(v/v)＝1:8)，得到白色固体状的[1-[2-[[4-[(4-乙酰哌嗪-1-基)甲基]苯甲酰基]-甲基-氨基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物17)(0.1g，收率17％)。Taking [1-[2-[(4-formylbenzoyl)-methyl-amino]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (5A) (0.5g, 1.03mmol) and 4-acetylpiperazine (17A) (0.26g, 2.06mmol) were placed in a 50mL round bottom flask, isopropyl alcohol (20mL) was added, and stirred at 60 ° C for 30 minutes. After concentrating under reduced pressure at 60 ° C for 1 hour, isopropyl alcohol (20 mL), anhydrous sodium sulfate (0.20 g, 1.4 mmol) and acetic acid (0.24 mL, 4.2 mmol) were added to the residue, and the mixture was stirred at 0 ° C. Sodium triacetoxyborohydride (0.45 g, 3.1 mmol) was added thereto, and the mixture was allowed to react at room temperature for 3 hours. After the reaction was completed, the reaction mixture was evaporated and evaporated, evaporated, evaporated, evaporated The residue was purified by EtOAc EtOAcjjjjjjjjjj Methyl]benzoyl]-methyl-amino]-4-piperidinyl]N-(2-phenylphenyl)carbamate (Compound 17) (0.1 g, yield 17%).

LCMS m/z＝299.8[M/2+1]。LCMS m/z = 299.8 [M/2+1].

¹H NMR(400MHz,CDCl3)δ8.16(s,1H),7.21-7.49(m,12H),6.64(s,1H),3.45-3.53(m,12H),2.86-2.94(m,6H),2.41-2.44(m,5H),2.03-2.08(m,6H)。 ¹ H NMR (400 MHz, CDCl 3 ) δ 8.16 (s, 1H), 7.21-7.49 (m, 12H), 6.64 (s, 1H), 3.45-3.53 (m, 12H), 2.86-2.94 (m, 6H) , 2.41-2.44 (m, 5H), 2.03-2.08 (m, 6H).

实施例18：[(3aS,5s,6aR)-2-[3-[[4-[(4-氨基甲酰基-1-哌啶基)甲基]苯基]氨基-3-氧代-丙基]-3,3a,4,5,6,6a-六氢-1H-环戊烷[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(化合物18)Example 18: [(3aS,5s,6aR)-2-[3-[[4-[(4-carbamoyl-1-piperidyl)methyl]phenyl]amino-3-oxo-propyl -3,3a,4,5,6,6a-hexahydro-1H-cyclopentane[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate (Compound 18)

[(3aS,5s,6aR)-2-[3-[[4-[(4-carbamoyl-1-piperidyl)methyl]phenyl]amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate[(3aS,5s,6aR)-2-[3-[[4-[(4-carbamoyl-1-piperidyl)methyl]phenyl]amino]-3-oxo-propyl]-3,3a,4,5, 6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

第一步：[(3aS,5s,6aR)-2-[3-[4-(羟基甲基)苯胺基]-3-氧代-丙基]-3,3a,4,5,6,6a-六氢-1H-环戊二烯[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(18A)First step: [(3aS,5s,6aR)-2-[3-[4-(hydroxymethyl)anilino]-3-oxo-propyl]-3,3a,4,5,6,6a -Hexahydro-1H-cyclopentadienyl[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (18A)

[(3aR,5s,6aS)-2-[3-[4-(hydroxymethyl)anilino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate[(3aR,5s,6aS)-2-[3-[4-(hydroxymethyl)anilino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c] Pyrrol-5-yl]N-(2-phenylphenyl)carbamate

将[(3aS,5s,6aR)-1,2,3,3a,4,5,6,6a-八氢环戊二烯并[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(4B)(0.96g,3.0mmol),溶于四氢呋喃(10mL)和甲醇(2mL)的混合溶剂中。依次向其中加入N-(4-(羟基甲基)苯基)丙烯酰胺(US20050113417,Example 2,step 1)(0.63g,3.6mmol),三乙胺(0.83mL,6.0mmol)。反应在60℃下搅拌4小时后终止。待反应冷至室温,减压浓缩,柱层析分离(二氯甲烷/甲醇(v/v)＝15:1)得到黄色固体状的[(3aS,5s,6aR)-2-[3-[4-(羟基甲基)苯胺基]-3-氧代-丙基]-3,3a,4,5,6,6a-六氢-1H-环戊二烯[c]吡咯-5-基]-N-(2-苯基苯基)氨基甲酸酯(18A)(0.80g,产率54％)。[(3aS,5s,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene The carbamate (4B) (0.96 g, 3.0 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and methanol (2 mL). N-(4-(Hydroxymethyl)phenyl)acrylamide (US20050113417, Example 2, step 1) (0.63 g, 3.6 mmol), triethylamine (0.83 mL, 6.0 mmol) was added. The reaction was terminated after stirring at 60 ° C for 4 hours. After the reaction was cooled to room temperature, concentrated under reduced pressure and purified by chromatography (dichloromethane/methanol (v/v) = 15:1) to give [(3aS,5s,6aR)-2-[3-[ 4-(Hydroxymethyl)anilino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadienyl[c]pyrrole-5-yl] -N-(2-Phenylphenyl)carbamate (18A) (0.80 g, yield 54%).

LCMS m/z＝500.3[M+1]。LCMS m/z = 500.3 [M + 1].

第二步：[(3aS,5s,6aR)-2-[3-(4-(甲酰基苯胺基)-3-氧代-丙基]-3,3a,4,5,6,6a-六氢-1H-环戊二烯[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(18B)Second step: [(3aS,5s,6aR)-2-[3-(4-(formylanilino)-3-oxo-propyl]-3,3a,4,5,6,6a-six Hydrogen-1H-cyclopentadienyl[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (18B)

[(3aR,5s,6aS)-2-[3-(4-formylanilino)-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate[(3aR,5s,6aS)-2-[3-(4-formylanilino)-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5 -yl]N-(2-phenylphenyl)carbamate

将[(3aS,5s,6aR)-2-[3-[4-(羟基甲基)苯胺基]-3-氧代-丙基]-3,3a,4,5,6,6a-六氢-1H-环戊二烯[c]吡咯-5-基]-N-(2-苯基苯基)氨基甲酸酯(18A)(0.80g,1.6mmol)溶于二氯甲烷(15mL)中。0℃下,向反应中加入戴斯马丁氧化剂(1.4g,3.2mmol),并在该温度下搅拌2小时。向反应瓶中滴加饱和碳酸氢钠水溶液(50mL)淬灭反应,用二氯甲烷(50mL×2)萃取,合并后的有机相用无水硫酸钠干燥,减压浓缩后得到黄色固体状的[(3aS,5s,6aR)-2-[3-(4-(甲酰基苯胺基)-3-氧代-丙基]-3,3a,4,5,6,6a-六氢-1H-环戊二烯[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(18B)(0.60g,产率75％)。[(3aS,5s,6aR)-2-[3-[4-(Hydroxymethyl)anilino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro -1H-cyclopentadienyl [c]pyrrole-5-yl]-N-(2-phenylphenyl)carbamate (18A) (0.80 g, 1.6 mmol) dissolved in dichloromethane (15 mL) . Dess Martin oxidizing agent (1.4 g, 3.2 mmol) was added to the reaction at 0 ° C, and stirred at this temperature for 2 hours. The reaction mixture was stirred with EtOAc EtOAc (EtOAc m. [(3aS,5s,6aR)-2-[3-(4-(formylanilino)-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H- Cyclopentadiene [c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (18B) (0.60 g, yield 75%).

LCMS m/z＝498.2[M+1].LCMS m/z = 498.2 [M + 1].

第三步：[(3aS,5s,6aR)-2-[3-[[4-[(4-氨基甲酰基-1-哌啶基)甲基]苯基]氨基-3-氧代-丙基]-3,3a,4,5,6,6a-六氢-1H-环戊烷[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(化合物18)The third step: [(3aS,5s,6aR)-2-[3-[[4-[(4-carbamoyl-1-piperidyl)methyl]phenyl]amino-3-oxo-propyl -3,3a,4,5,6,6a-hexahydro-1H-cyclopentane[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate (Compound 18)

取[(3aS,5s,6aR)-2-[3-[(4-苯甲醛基)氨基]-3-氧-丙基]-3,3a,4,5,6,6a-六氢化-1H-环戊并烷 [c]吡咯l-5-基]N-(2-苯基苯基)氨基甲酸酯(18B)(0.4g，0.8mmol)和4-哌啶甲酰胺(18C)(0.18g，1.4mmol)置于50mL圆底烧瓶中，加入异丙醇(20mL)，60℃条件下搅拌30分钟后，60℃减压浓缩1小时后，向残留物中加入异丙醇(20mL)、无水硫酸钠(0.20g,1.4mmol)和乙酸(0.24mL,4.2mmol)，搅拌均匀后，于0℃条件下加入三乙酰氧基硼氢化钠(0.45g，3.1mmol)，升至室温反应3小时。反应结束后，反应液加入饱和碳酸氢钠溶液(30mL)淬灭反应，二氯甲烷(30mL×2)萃取，合并有机相，有机相依次用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱层析纯化(二氯甲烷/甲醇(v/v)＝1:8)，得到白色固体状的[(3aS,5s,6aR)-2-[3-[[4-[(4-氨基甲酰基-1-哌啶基)甲基]苯基]氨基-3-氧代-丙基]-3,3a,4,5,6,6a-六氢-1H-环戊烷[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(化合物18)(0.1g，收率20％)。[[3aS,5s,6aR)-2-[3-[(4-Benzaldehyde)amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H -cyclopentane [c]pyrrole l-5-yl]N-(2-phenylphenyl)carbamate (18B) (0.4 g, 0.8 mmol) and 4-piperidinecarboxamide (18C) (0.18 g, 1.4 mmol The mixture was placed in a 50 mL round bottom flask, isopropanol (20 mL) was added, and the mixture was stirred at 60 ° C for 30 minutes. After concentration at 60 ° C for 1 hour under reduced pressure, isopropyl alcohol (20 mL) and anhydrous sulfuric acid were added to the residue. Sodium (0.20 g, 1.4 mmol) and acetic acid (0.24 mL, 4.2 mmol) were stirred. After the reaction was completed, the reaction mixture was evaporated and evaporated, evaporated, evaporated, evaporated The residue was purified with EtOAc EtOAcjjjjjjjjjj 4-carbamoyl-1-piperidinyl)methyl]phenyl]amino-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentane [ c] Pyrrol-5-yl]N-(2-phenylphenyl)carbamate (Compound 18) (0.1 g, yield 20%).

LCMS m/z＝305.8[M/2+1]。LCMS m/z = 305.8 [M/2 + 1].

¹H NMR(400MHz,CD₃OD)δ7.7-7.72(m,2H),7.55(s,1H),7.29–7.46(m,11H),5.2(s,1H),4.26(s,2H),3.75(s,1H),3.53-3.55(m,5H),3.31.3.35(m,4H),2.75-3.26(m,8H),2.52(s,1H),1.25(s,1H)。 ¹ H NMR (400 MHz, CD ₃ OD) δ 7.7-7.72 (m, 2H), 7.55 (s, 1H), 7.29 - 7.46 (m, 11H), 5.2 (s, 1H), 4.26 (s, 2H) , 3.75 (s, 1H), 3.53-3.55 (m, 5H), 3.31.3.35 (m, 4H), 2.75-3.26 (m, 8H), 2.52 (s, 1H), 1.25 (s, 1H).

实施例19：[(3aS,5r,6aR)-2-[2-[[4-[(2-氨基甲酰基-3-乙基-3a,4,6,6a-四氢吡咯[3,4-d]咪唑-5-基)甲基]苯甲酰基]-甲基-氨基]乙基]-3,3a,4,5,6,6a-六氢-1H-环戊并烷[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(化合物19)Example 19: [(3aS,5r,6aR)-2-[2-[[4-[(2-carbamoyl-3-ethyl-3a,4,6,6a-tetrahydropyrrole [3,4] -d]imidazol-5-yl)methyl]benzoyl]-methyl-amino]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentane [c] Pyrrol-5-yl]N-(2-phenylphenyl)carbamate (Compound 19)

[(3aS,5r,6aR)-2-[2-[[4-[(2-carbamoyl-3-ethyl-3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazol-5-yl)methyl]benzoyl]-methyl-amino]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate[(3aS,5r,6aR)-2-[2-[[4-[(2-carbamoyl-3-ethyl-3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazol-5-yl) Methyl]benzoyl]-methyl-amino]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

取[(3aS,5r,6aR)-2-[2-[(4-甲酰基苯甲酰基)-甲基-胺基]乙基]-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(3E)(0.25g，0.5mmol)和3-乙基-5,6-二氢-4H-吡咯[3,4-d]咪唑-2-甲酰胺(中间体2)(0.1g，0.55mmol)置于50mL圆底烧瓶中，加入异丙醇(20mL)，60℃条件下搅拌30分钟后，60℃减压浓缩1小时后，向残留物中加入异丙醇(20mL)、无水硫酸钠(0.20g,1.4mmol)和乙酸(0.24mL,4.2mmol)，搅拌均匀后，于0℃条件下加入三乙酰氧基硼氢化钠(0.45g，3.1mmol)，升至室温反应3小时。反应结束后，反应液加入饱和碳酸氢钠溶液(30mL)淬灭反应，二氯甲烷(30mL×2)萃取，合并有机相，有机相依次用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱层析纯化(二氯甲烷/甲醇(v/v)＝1:8)，得到白色固体状的[(3aS,5r,6aR)-2-[2-[[4-[(2-氨基甲酰基-3-乙基-3a,4,6,6a-四氢吡咯[3,4-d]咪唑-5-基)甲基]苯甲酰基]-甲基-氨基]乙基]-3,3a,4,5,6,6a-六氢-1H-环戊并烷 [c]吡咯-5-基]N-(2-苯基苯基)氨基甲酸酯(化合物19)(0.07g，收率21％)。Taking [(3aS,5r,6aR)-2-[2-[(4-formylbenzoyl)-methyl-amino]ethyl]-3,3a,4,5,6,6a-hexahydro -1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (3E) (0.25 g, 0.5 mmol) and 3-ethyl-5,6 -Dihydro-4H-pyrrole [3,4-d]imidazole-2-carboxamide (Intermediate 2) (0.1 g, 0.55 mmol) was placed in a 50 mL round bottom flask, isopropyl alcohol (20 mL), 60 ° C After stirring for 30 minutes, the mixture was concentrated under reduced pressure at 60 ° C for 1 hour, and then isopropyl alcohol (20 mL), anhydrous sodium sulfate (0.20 g, 1.4 mmol) and acetic acid (0.24 mL, After homogenization, sodium triacetoxyborohydride (0.45 g, 3.1 mmol) was added at 0 ° C, and the mixture was allowed to react at room temperature for 3 hours. After the reaction was completed, the reaction mixture was evaporated and evaporated, evaporated, evaporated, evaporated The residue was purified with EtOAc EtOAcjjjjjjjjjjjjjj 2-carbamoyl-3-ethyl-3a,4,6,6a-tetrahydropyrrole[3,4-d]imidazol-5-yl)methyl]benzoyl]-methyl-amino]ethyl ]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentane [c] Pyrrol-5-yl]N-(2-phenylphenyl)carbamate (Compound 19) (0.07 g, yield 21%).

LCMS m/z＝338.8[M/2+1]。LCMS m/z = 338.8 [M/2+1].

¹H NMR(400MHz,CD₃OD)δ7.18-7.7(m,13H),5.19(s,1H),4.71.4.75(m,4H),4.42-4.49(m,4H),4.07(s,1H),2.8-3.83(m,12H),1.82-2.19(m,4H),1.29-1.38(m,4H)。 ^{_{1 H NMR (400MHz, CD 3}} OD) δ7.18-7.7 (m, 13H), 5.19 (s, 1H), 4.71.4.75 (m, 4H), 4.42-4.49 (m, 4H), 4.07 (s, 1H), 2.8-3.83 (m, 12H), 1.82-2.19 (m, 4H), 1.29-1.38 (m, 4H).

实施例20:[1-[2-[[4-[(2-氨基甲酰基-3-甲基-4,6-二氢吡咯[3,4-d]咪唑-5-基)甲基]苯甲酰基]-甲基-氨基]乙基]-4-哌啶基]N-(2-苯基苯基)基氨基甲酸酯(化合物20)Example 20: [1-[2-[[4-[(2-carbamoyl-3-methyl-4,6-dihydropyrrole[3,4-d]imidazol-5-yl)methyl]] Benzoyl]-methyl-amino]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (Compound 20)

[1-[2-[[4-[(2-carbamoyl-3-methyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-yl)methyl]benzoyl]-methyl-amino]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate[1-[2-[[4-[(2-carbamoyl-3-methyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-yl)methyl]benzoyl]-methyl-amino]ethyl]- 4-piperidyl]N-(2-phenylphenyl)carbamate

第一步：1-甲基-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-甲酰胺(20B)First step: 1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide (20B)

1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide

取2-甲酰胺基-3-甲基-4,6-二氢吡咯[3,4-d]咪唑-5-甲酸叔丁酯(20A)(0.58g，2.17mmol)于乙酸乙酯(20mL)中，再加入苯磺酸(0.7675g，4.36mmol)，升至60℃反应6小时。反应结束，加入水(40mL)，再用三乙胺调pH至8。再加入乙酸乙酯(100mL)，分液，水相用乙酸乙酯(100mL×1)萃取，合并有机相，有机相用饱和食盐水(150mL×1)洗涤。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物1-甲基-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-甲酰胺(20B)，白色油状物(0.36g，产率100％)。2-Carboxamido-3-methyl-4,6-dihydropyrrole [3,4-d]imidazole-5-carboxylic acid tert-butyl ester (20A) (0.58 g, 2.17 mmol) in ethyl acetate (20 mL) In addition, benzenesulfonic acid (0.7675 g, 4.36 mmol) was further added, and the reaction was carried out at 60 ° C for 6 hours. At the end of the reaction, water (40 mL) was added and the pH was adjusted to 8 with triethylamine. Ethyl acetate (100 mL) was added, and the mixture was evaporated. The organic phase was dried over anhydrous sodium sulfate (MgSO4), filtered,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 20B), white oil (0.36 g, yield 100%).

第二步：[1-[2-[[4-[(2-氨基甲酰基-3-甲基-4,6-二氢吡咯[3,4-d]咪唑-5-基)甲基]苯甲酰基]-甲基-氨基]乙基]-4-哌啶基]N-(2-苯基苯基)基氨基甲酸酯(化合物20)Second step: [1-[2-[[4-[(2-carbamoyl-3-methyl-4,6-dihydropyrrole[3,4-d]imidazol-5-yl)methyl]] Benzoyl]-methyl-amino]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (Compound 20)

取[1-[2-[(4-甲酰基苯甲酰基)-甲基-胺基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(5A)(0.704g，1.45mmol)和1-甲基-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-甲酰胺(20B)(0.36g，2.17mmol)置于50mL圆底烧瓶中，加入异丙醇(30mL)，旋转蒸发仪减压浓缩(60℃)，至溶液澄清，再加入异丙醇(30mL)，旋转蒸发仪减压浓缩(60℃)，溶液澄清后，残留物约20mL，冷至0℃，加入乙酸(0.52g，8.86mmol)、无水硫酸钠(0.15g)，搅拌均匀后，最后加入三乙酰氧基硼氢化钠(0.92g，4.34mmol)，升至室温反应2.5小时。反应结束后饱和碳酸氢钠水溶液(30mL)淬灭反应，二氯甲烷萃取(30mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经硅胶柱层析纯化后得到标题化合物[1-[2-[[4-[(2-氨基甲酰基-3-甲基-4,6-二氢吡咯[3,4-d]咪唑-5-基)甲基]苯甲酰基]-甲基-氨基]乙基]-4-哌啶基]N-(2-苯基苯基)基氨基甲酸酯(化合物20)，白色固体(0.74g，产率80.3％)。Taking [1-[2-[(4-formylbenzoyl)-methyl-amino]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (5A (0.704 g, 1.45 mmol) and 1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide (20B) (0.36 g, 2.17 mmol) In a 50 mL round bottom flask, isopropanol (30 mL) was added, and concentrated under reduced pressure (60 ° C) on a rotary evaporator to clarify the solution, then isopropyl alcohol (30 mL) was added, and concentrated (60 ° C) under reduced pressure on a rotary evaporator. After the solution was clarified, the residue was about 20 mL, cooled to 0 ° C, acetic acid (0.52 g, 8.86 mmol), anhydrous sodium sulfate (0.15 g) was added, and after stirring, finally, sodium triacetoxyborohydride (0.92 g, 4.34 mmol), and allowed to react to room temperature for 2.5 hours. After completion of the reaction, the mixture was evaporated to drynessnessnessnessnessnessnessnessnessnessness [1-[2-[[4-[(2-carbamoyl-3-methyl-4,6-dihydropyrrole[3,4-d]imidazol-5-yl)methyl]benzoyl] -Methyl-amino]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (Compound 20), white solid (0.74 g, yield 80.3%).

¹H NMR(400MHz,CDCl₃)δ8.09(d,J＝6.8Hz,1H),7.49(t,J＝7.3Hz,2H),7.45–7.39(m,4H),7.38–7.31(m,3H),7.22(dd,J＝7.6,1.6Hz,1H),7.13(td,J＝7.5,1.1Hz,1H),7.02(d,J＝19.0Hz,1H),6.59(s,1H),5.24(s,1H),4.72(s,1H),4.01(s,2H),3.92(s,3H),3.81(s,4H),3.67(s,1H),3.37(s,1H),3.05(d,J＝20.0Hz,3H),2.81(s,1H),2.66(s,1H),2.46(s,2H),2.39–2.23(m,1H),2.14(d,J＝25.9Hz,1H),1.86(s,2H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.09 (d, J = 6.8Hz, 1H), 7.49 (t, J = 7.3Hz, 2H), 7.45-7.39 (m, 4H), 7.38-7.31 (m, 3H), 7.22 (dd, J = 7.6, 1.6 Hz, 1H), 7.13 (td, J = 7.5, 1.1 Hz, 1H), 7.02 (d, J = 19.0 Hz, 1H), 6.59 (s, 1H), 5.24(s,1H), 4.72(s,1H),4.01(s,2H),3.92(s,3H),3.81(s,4H),3.67(s,1H),3.37(s,1H),3.05 (d, J = 20.0 Hz, 3H), 2.81 (s, 1H), 2.66 (s, 1H), 2.46 (s, 2H), 2.39 - 2.23 (m, 1H), 2.14 (d, J = 25.9 Hz, 1H), 1.86 (s, 2H).

LCMS m/z＝636.3[M+1]。LCMS m/z = 636.3 [M + 1].

实施例21：[1-[2-[甲基-[4-[(1-氧代-2,8-二氮杂螺[4.5]癸-8-基)甲基]苯甲酰]氨基]乙基]-4-哌啶基]N-(2-苯基苯基)基氨基甲酸酯(化合物21)Example 21: [1-[2-[methyl-[4-[(1-oxo-2,8-diazaspiro[4.5]dec-8-yl)methyl]benzoyl]amino] Ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (Compound 21)

[1-[2-[methyl-[4-[(1-oxo-2,8-diazaspiro[4.5]decan-8-yl)methyl]benzoyl]amino]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate[1-[2-[methyl-[4-[(1-oxo-2,8-diazaspiro[4.5]decan-8-yl)methyl]benzoyl]amino]ethyl]-4-piperidyl]N-(2- Phenylphenyl)carbamate

第一步：1-叔丁基4-甲基4-(氰甲基)哌啶-1,4-二羧酸酯(21B)First step: 1-tert-butyl 4-methyl 4-(cyanomethyl)piperidine-1,4-dicarboxylate (21B)

1-tert-butyl 4-methyl4-(cyanomethyl)piperidine-1,4-dicarboxylate 1-tert-butyl 4-methyl4-(cyanomethyl)piperidine-1,4-dicarboxylate

取1-叔丁基4-甲基哌啶-1,4-二羧酸酯(5g，20.6mmol)溶于四氢呋喃(20mL)中，氮气保护下冷至-78℃，滴加二异丙基氨基锂(14.4mL，28.8mmol)，加完后维持温度继续反应1.5小时。再滴加溴乙腈(3.7g，30.9mmol)的四氢呋喃溶液30mL，保持温度继续反应1小时。再自然升至室温反应2小时。反应结束，加入乙酸乙酯(100mL)和水(100mL)，分液，水相用乙酸乙酯(100mL×1)萃取，合并有机相，有机相用饱和食盐水(150mL×1)洗涤。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到1-叔丁基4-甲基4-(氰甲基)哌啶-1,4-二羧酸酯(21B)，黄色油状(2.9g，产率50％)。1-tert-Butyl 4-methylpiperidine-1,4-dicarboxylate (5 g, 20.6 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to -78 ° C under nitrogen, and diisopropyl was added dropwise. Lithium amide (14.4 mL, 28.8 mmol) was reacted for 1.5 hours while maintaining the temperature. Further, 30 mL of a solution of bromoacetonitrile (3.7 g, 30.9 mmol) in tetrahydrofuran was added dropwise, and the reaction was continued for one hour while maintaining the temperature. The reaction was naturally raised to room temperature for 2 hours. After the reaction was completed, ethyl acetate (100 mL) and water (100 mL) was evaporated, and the mixture was evaporated to ethyl acetate (100 mL×1). The organic phase was combined and the organic phase was washed with saturated brine (150 mL×1). The organic phase was dried over anhydrous sodium sulfate, filtered, and then evaporated. 2.9 g, yield 50%).

¹H NMR(400MHz,CDCl₃)δ3.79(s,3H),3.08(t,J＝11.2Hz,2H),2.61(s,2H),2.16(ddd,J＝7.8,6.0,3.0Hz,2H),2.04(s,1H),1.62–1.52(m,2H),1.44(d,J＝11.5Hz,9H),1.26(t,J＝7.1Hz,1H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ3.79 (s, 3H), 3.08 (t, J = 11.2Hz, 2H), 2.61 (s, 2H), 2.16 (ddd, J = 7.8,6.0,3.0Hz, 2H), 2.04 (s, 1H), 1.62 - 1.52 (m, 2H), 1.44 (d, J = 11.5 Hz, 9H), 1.26 (t, J = 7.1 Hz, 1H).

LCMSm/z＝305.1[M+23]。LCMS m/z = 305.1 [M+23].

第二步：叔丁基1-氧代-2,8-二氮杂螺[4.5]癸烷-8-羧酸酯(21C)Step 2: tert-Butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (21C)

tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylateTert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate

取1-叔丁基4-甲基4-(氰甲基)哌啶-1,4-二羧酸酯(21B)(5g，20.6mmol)于250mL高压釜中，加入甲醇(60mL)中，镍(2.5g)，再加入氨水(5mL)，充20Mpa氢气升至50℃反应18小时。反应结束，冷至室温，硅藻土过滤，再用50mL甲醇洗涤，旋去甲醇。加入二氯甲烷(50mL)和水(50mL)，分液，水相用二氯甲烷(50mL×1)萃取，合并有机相，有机相用100mL饱和食盐水(100mL×1)洗涤。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经硅胶柱层析纯化(石油醚：乙酸乙酯＝1:0到2:1)后得到叔丁基1-氧代-2,8-二氮杂螺[4.5]癸烷-8-羧酸酯(21C)，1.4g白色固体，产率55.1％。1-tert-Butyl 4-methyl 4-(cyanomethyl)piperidine-1,4-dicarboxylate (21B) (5 g, 20.6 mmol) was taken in a 250 mL autoclave and added to methanol (60 mL). Nickel (2.5 g), then add ammonia (5 mL), and add 20 Mpa of hydrogen to 50 ° C for 18 hours. After completion of the reaction, it was cooled to room temperature, filtered through Celite, washed with 50 mL of methanol and then evaporated. Dichloromethane (50 mL) and water (50 mL) were added and the mixture was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The organic phase was dried over anhydrous sodium sulfate (MgSO4), filtered, evaporated. 2,8-Diazaspiro[4.5]decane-8-carboxylate (21C), 1.4 g of a white solid, yield 55.1%.

LCMS m/z＝277.1[M+23]。LCMS m/z = 277.1 [M+23].

第三步：2,8-二氮杂螺[4.5]癸基-1-酮(21D)The third step: 2,8-diazaspiro[4.5]decyl-1-one (21D)

2,8-diazaspiro[4.5]decan-1-one2,8-diazaspiro[4.5]decan-1-one

取叔丁基1-氧代-2,8-二氮杂螺[4.5]癸烷-8-羧酸酯(1.4g，5.5mmol)于10mL二氯甲烷中，加入2M盐酸的四氢呋喃(20mL)室温反应3d。反应结束，硅藻土过滤，再用甲醇洗涤(50mL)，旋去甲醇。加入饱和碳酸氢钠水溶液调pH值至8，二氯甲烷(50mL×2)萃取，合并有机相，有机相用100mL饱和食盐水(100mL×1)洗涤。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物2,8-二氮杂螺[4.5]癸基-1-酮(21D)，白色固体(0.8g，产率94.5％)。tert-Butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (1.4 g, 5.5 mmol) was taken in 10 mL of dichloromethane, and 2M hydrochloric acid in tetrahydrofuran (20 mL) The reaction was carried out for 3 days at room temperature. After completion of the reaction, the mixture was filtered over Celite, and then washed with methanol (50mL) After adding a saturated aqueous solution of sodium hydrogencarbonate, the mixture was adjusted to pH 8 and dichloromethane (50 mL×2) was evaporated. The organic phase was dried over anhydrous sodium sulfate (MgSO4jjjjjjjjjjjjjj ).

LCMSm/z＝155.2[M+1]。LCMS m/z = 155.2 [M + 1].

第四步：[1-[2-[甲基-[4-[(1-氧代-2,8-二氮杂螺[4.5]癸-8-基)甲基]苯甲酰]氨基]乙基]-4-哌啶基]N-(2-苯基苯基)基氨基甲酸酯(化合物21)The fourth step: [1-[2-[methyl-[4-[(1-oxo-2,8-diazaspiro[4.5]dec-8-yl)methyl]benzoyl]amino] Ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (Compound 21)

取[1-[2-[(4-甲酰基苯甲酰基)-甲基-胺基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(5A)(0.728g，1.5mmol)和2,8-二氮杂螺[4.5]癸基-1-酮(21D)(0.347g，2.25mmol)置于50mL圆底烧瓶中，加入异丙醇(30mL)，旋转蒸发仪减压浓缩(60℃)，至溶液澄清，再加入异丙醇(30mL)，旋转蒸发仪减压浓缩(60℃)，溶液澄清后，残留物约20mL，冷至0℃，加入乙酸(0.54g，9mmol)、无水硫酸钠(0.12g)，搅拌均匀后，最后加入三乙酰氧基硼氢化钠(0.954g，4.5mmol)，升至室温反应2.5小时。反应结束后饱和碳酸氢钠水溶液(30mL)淬灭反应，二氯甲烷萃取(30mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经硅胶柱层析纯化后得到目标化合物[1-[2-[甲基-[4-[(1-氧代-2,8-二氮杂螺[4.5]癸-8-基)甲基]苯甲酰]氨基]乙基]-4-哌啶基]N-(2-苯基苯基)基氨基甲酸酯(化合物21)，白色固体(0.87g，产率93％)。Taking [1-[2-[(4-formylbenzoyl)-methyl-amino]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (5A (0.728 g, 1.5 mmol) and 2,8-diazaspiro[4.5]decyl-1-one (21D) (0.347 g, 2.25 mmol) were placed in a 50 mL round bottom flask, and isopropanol (30 mL) was added. ), the rotary evaporator was concentrated under reduced pressure (60 ° C), until the solution was clarified, then isopropanol (30 mL) was added, and concentrated under reduced pressure (60 ° C) by rotary evaporator. After the solution was clarified, the residue was about 20 mL, and cooled to 0 ° C. Acetic acid (0.54 g, 9 mmol) and anhydrous sodium sulfate (0.12 g) were added, and the mixture was stirred well, and finally sodium triacetoxyborohydride (0.954 g, 4.5 mmol) was added, and the mixture was allowed to react at room temperature for 2.5 hours. After completion of the reaction, the reaction mixture was evaporated to drynessnessnessnessnessnessnessnessnessnessnessnessnessness [1-[2-[Methyl-[4-[(1-oxo-2,8-diazaspiro[4.5]dec-8-yl)methyl]benzoyl]amino]ethyl]- 4-piperidinyl]N-(2-phenylphenyl)carbamate (Compound 21), white solid (0.87 g, yield 93%).

¹H NMR(400MHz,CDCl₃)δ8.09(d,J＝7.9Hz,1H),7.49(t,J＝7.3Hz,2H),7.45–7.39(m,1H),7.39–7.31(m,6H),7.21(dd,J＝7.6,1.6Hz,1H),7.13(td,J＝7.5,1.0Hz,1H),6.58(s,1H),5.52(s,1H),4.73(s,1H),3.64(s,1H),3.51(d,J＝17.8Hz,2H),3.36(s,1H),3.30(t,J＝6.8Hz,2H),3.03(d,J＝22.8Hz,3H),2.80(s,2H),2.63(s,1H),2.45(s,2H),2.34(s,1H),2.12(s,3H),2.06–2.00(m,4H),2.00–1.92(m,4H),1.84(s,1H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.09 (d, J = 7.9Hz, 1H), 7.49 (t, J = 7.3Hz, 2H), 7.45-7.39 (m, 1H), 7.39-7.31 (m, 6H), 7.21 (dd, J=7.6, 1.6 Hz, 1H), 7.13 (td, J=7.5, 1.0 Hz, 1H), 6.58 (s, 1H), 5.52 (s, 1H), 4.73 (s, 1H) ), 3.64 (s, 1H), 3.51 (d, J = 17.8 Hz, 2H), 3.36 (s, 1H), 3.30 (t, J = 6.8 Hz, 2H), 3.03 (d, J = 22.8 Hz, 3H) ), 2.80 (s, 2H), 2.63 (s, 1H), 2.45 (s, 2H), 2.34 (s, 1H), 2.12 (s, 3H), 2.06 - 2.00 (m, 4H), 2.00 - 1.92 ( m, 4H), 1.84 (s, 1H).

LCMSm/z＝312.8[M/2+1]。LCMS m/z = 312.8 [M/2 + 1].

实施例22：[1-[2-[[4-[(5-氨基甲酰异吲哚啉-2-基)甲基]本甲酰基]-甲基-氨基]乙基]-4-哌啶]N-(2-苯基苯基)氨基甲酸酯(化合物22) Example 22: [1-[2-[[4-[(5-carbamoylisoindol-2-yl)methyl]]-formyl]-methyl-amino]ethyl]-4-piperidin Acridine]N-(2-phenylphenyl)carbamate (Compound 22)

[1-[2-[[4-[(5-carbamoylisoindolin-2-yl)methyl]benzoyl]-methyl-amino]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate[1-[2-[[4-[(5-carbamoylisoindolin-2-yl)methyl]benzoyl]-methyl-amino]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

第一步：3,4-双(溴代甲基)苯甲酸甲酯(22B)First step: methyl 3,4-bis(bromomethyl)benzoate (22B)

methyl 3,4-bis(bromomethyl)benzoateMethyl 3,4-bis(bromomethyl)benzoate

取3，4-二甲基苯甲酸甲酯(3.28g，20mmol)溶于80mL四氯化碳中，加入N-溴代丁二酰亚胺(7.83g，44mmol)，再加偶氮二异丁腈(290mg，1.2mmol)，升至80度反应6h。反应结束，加入饱和碳酸氢钠水溶液淬灭反应，再加入水(50mL)和二氯甲烷(50mL)，分液，水相用二氯甲烷(50mL×1)萃取，合并有机相，有机相用饱和食盐水(100mL×1)洗涤。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物3,4-双(溴代甲基)苯甲酸甲酯(22B)，黄色油状(6.4g，产率99.5％)。Methyl 3,4-dimethylbenzoate (3.28 g, 20 mmol) was dissolved in 80 mL of carbon tetrachloride, and N-bromosuccinimide (7.83 g, 44 mmol) was added, followed by azo diiso Nitrile (290 mg, 1.2 mmol) was raised to 80 ° for 6 h. After completion of the reaction, the reaction was quenched with saturated aqueous sodium hydrogen sulfate, and water (50 mL) and dichloromethane (50 mL) was evaporated. Saturated saline (100 mL × 1) was washed. The organic phase was dried over anhydrous sodium sulfate (MgSO4), filtered,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

第二步：2-苄基异二氢吲哚-5-甲酸甲酯(22C)Step 2: 2-Benzylisoindoline-5-carboxylic acid methyl ester (22C)

methyl 2-benzylisoindoline-5-carboxylateMethyl 2-benzylisoindoline-5-carboxylate

取3,4-双(溴代甲基)苯甲酸甲酯(0.322g，1mmol)于四氢呋喃(15mL)中，加入三乙胺(0.277mL，2mmol)，滴加苄胺(0.108g，1mmol)的四氢呋喃溶液(5mL)，室温反应5小时。反应结束，旋去溶剂。加入水(50mL)，用乙酸乙酯(50mL×2)萃取，合并有机相，有机相用饱和食盐水(100mL×1)洗涤。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到化合物2-苄基异二氢吲哚-5-甲酸甲酯(22C)，0.2g棕色固体，产率74.9％。Methyl 3,4-bis(bromomethyl)benzoate (0.322 g, 1 mmol) in tetrahydrofuran (15 mL), triethylamine (0.277 mL, 2 mmol), benzylamine (0.108 g, 1 mmol) The tetrahydrofuran solution (5 mL) was reacted at room temperature for 5 hours. At the end of the reaction, the solvent was removed. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered, and then evaporated tolulululululululululululululululululululululululululululu

LCMSm/z＝268.2[M+1]。 LCMS m/z = 268.2 [M + 1].

第三步：异吲哚-5-甲酸甲酯(22D)The third step: isoindole-5-carboxylic acid methyl ester (22D)

methyl isoindoline-5-carboxylateMethyl isoindoline-5-carboxylate

取2-苄基异二氢吲哚-5-甲酸甲酯(1.33g，5mmol)于甲醇(20mL)中，加入钯碳(0.4g)氢气氛置换三次，室温反应4天。反应结束，硅藻土过滤，再用甲醇(50mL)洗涤，减压浓缩，残留物经硅胶柱层析纯化(二氯甲烷：甲醇(v/v)＝1:0～20:1)得到化合物异吲哚-5-甲酸甲酯(22D)，黄色固体(0.5g，产率56.7％)。Methyl 2-benzylisoindoline-5-carboxylate (1.33 g, 5 mmol) was taken in methanol (20 mL After completion of the reaction, the mixture was filtered over Celite (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHH Isoindole-5-carboxylic acid methyl ester (22D), yellow solid (0.5 g, yield 56.7%).

LCMSm/z＝178.1[M+1]。LCMS m/z = 178.1 [M + 1].

第四步：2-叔丁基5-甲基异吲哚啉-2,5-二羧酸酯(22E)Fourth step: 2-tert-butyl 5-methylisoindoline-2,5-dicarboxylate (22E)

2-tert-butyl 5-methyl isoindoline-2,5-dicarboxylate2-tert-butyl 5-methyl isoindoline-2,5-dicarboxylate

取异吲哚-5-甲酸甲酯(0.5g，2.82mmol)于二氯甲烷(10mL)中，加入三乙胺(0.59mL，4.23mmol)，再缓慢加入二碳酸二叔丁酯(677mg，3.1mmol)，室温反应2小时。反应结束，加入饱和碳酸氢钠水溶液(30mL)淬灭反应，再加入二氯甲烷(20mL)，分液。水相用二氯甲烷(40mL×1)萃取，合并有机相，有机相用饱和食盐水(50mL×1)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到化合物2-叔丁基5-甲基异吲哚啉-2,5-二羧酸酯(22E)，棕色油状(0.782g，产率100％)。Methyl isodec-5-carboxylate (0.5 g, 2.82 mmol) was added to dichloromethane (10 mL), triethylamine (0.59 mL, 4.23 mmol) was added, and then di-tert-butyl dicarbonate (677 mg, 3.1 mmol), reacted at room temperature for 2 hours. After completion of the reaction, the reaction was quenched with saturated aqueous sodium hydrogen sulfate (30 mL). The aqueous phase was extracted with dichloromethane (40 mL×1), and the organic layer was evaporated. tert-Butyl 5-methylisoindoline-2,5-dicarboxylate (22E), brown oil (0.782 g, yield 100%).

第五步：2-(叔丁氧羰基)异二氢吲哚-5-羧酸(22F)Step 5: 2-(tert-Butoxycarbonyl)isoindoline-5-carboxylic acid (22F)

2-(tert-butoxycarbonyl)isoindoline-5-carboxylic acid2-(tert-butoxycarbonyl)isoindoline-5-carboxylic acid

取2-叔丁基5-甲基异吲哚啉-2,5-二羧酸酯(22E)(0.782g，2.82mmol)于30mL甲醇中，加入1M氢氧化钠水溶液(5.6mL，5.64mmol)60℃反应4小时。反应结束，旋去甲醇。加入5％柠檬酸水溶液(20mL)，用乙酸乙酯(30mL×2)萃取，合并有机相。有机相用饱和食盐水(50mL×1)洗涤。有相机用无水硫酸钠干燥。过滤，滤液减压浓缩，得到化合物2-(叔丁氧羰基)异二氢吲哚-5-羧酸(22F)，棕色固体(0.7g，产率94.3％)。2-tert-Butyl 5-methylisoindoline-2,5-dicarboxylate (22E) (0.782 g, 2.82 mmol) was taken in 30 mL of MeOH. The reaction was carried out at 60 ° C for 4 hours. At the end of the reaction, the methanol was spun off. A 5% aqueous citric acid solution (20 mL) was added, and extracted with ethyl acetate (30 mL×2). The organic phase was washed with saturated brine (50 mL×1). The camera was dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure gave compound 2-(t-butoxycarbonyl)isoindoline-5-carboxylic acid (22F) as a brown solid (0.7 g, yield 94.3%).

LCMSm/z＝286.2[M+23]。LCMS m/z = 286.2 [M+23].

第六步：叔丁基5-氨甲酰基异吲哚啉-2-羧酸酯(22G)Step 6: tert-Butyl 5-carbamoylisoindoline-2-carboxylate (22G)

tert-butyl 5-carbamoylisoindoline-2-carboxylate Tert-butyl 5-carbamoylisoindoline-2-carboxylate

取2-(叔丁氧羰基)异二氢吲哚-5-苯甲酸(22F)(0.7g，2.66mmol)于N,N-二甲基甲酰胺(20mL)中，依次加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.51g，3.99mmol)、三乙胺(0.77mL，5.32mmol)，再加入氨水(5mL)，室温反应2小时。反应结束，加入水(50mL)，用乙酸乙酯(50mL×2)萃取，合并有机相。有机相用饱和食盐水(100mL×1)洗涤。有相机用无水硫酸钠干燥。减压浓缩，得到化合物叔丁基5-氨甲酰基异吲哚啉-2-羧酸酯(22G)，0.655g无色油状，产率95.4％。2-(tert-Butoxycarbonyl)isoindoline-5-benzoic acid (22F) (0.7 g, 2.66 mmol) in N,N-dimethylformamide (20 mL). -azozotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.51 g, 3.99 mmol), triethylamine (0.77 mL, 5.32 mmol), then added with aqueous ammonia (5 mL), react at room temperature for 2 hours. After completion of the reaction, water (50 mL) was added, and ethyl acetate (50 mL×2) The organic phase was washed with saturated brine (100 mL×1). The camera was dried over anhydrous sodium sulfate. Concentration under reduced pressure gave compound t-butyl-5-carbamoylisoindoline-2-carboxylate (22G).

¹H NMR(400MHz,CDCl₃)δ7.72(dd,J＝16.0,6.5Hz,2H),7.32(dd,J＝15.2,8.1Hz,1H),4.72(s,2H),4.68(d,J＝5.6Hz,2H),1.52(s,9H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.72 (dd, J = 16.0,6.5Hz, 2H), 7.32 (dd, J = 15.2,8.1Hz, 1H), 4.72 (s, 2H), 4.68 (d, J = 5.6 Hz, 2H), 1.52 (s, 9H).

LCMSm/z＝285.3[M+23]。LCMS m/z = 285.3 [M+23].

第七步：异吲哚啉-5-甲酰胺(22H)Step 7: Isoporphyrin-5-carboxamide (22H)

isoindoline-5-carboxamideIsoindoline-5-carboxamide

取叔丁基5-氨甲酰基异吲哚啉-2-羧酸酯(22G)(0.655g，2.5mmol)于二氯甲烷(20mL)中，加入三氟乙酸(10mL)，室温反应2小时。反应结束，加入饱和碳酸氢钠水溶液调pH到8，加入水(30mL)和二氯甲烷(50mL)，分液。水相用二氯甲烷(50mL×1)萃取，合并有机相。有机相用饱和食盐水(100mL×1)洗涤。有相机用无水硫酸钠干燥，过滤，滤液减压浓缩，得到化合物异吲哚啉-5-甲酰胺(22H)，无色油状(0.16g，产率39.5％)。tert-Butyl 5-carbamoylisoindoline-2-carboxylate (22G) (0.655 g, 2.5 mmol) in dichloromethane (20 mL), trifluoroacetic acid (10 mL) . After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added and the mixture was adjusted to pH 8 and water (30mL) and dichloromethane (50mL) were added. The aqueous phase was extracted with dichloromethane (50 mL x 1) and organic phases were combined. The organic phase was washed with saturated brine (100 mL×1). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated.

LCMSm/z＝185.3[M+23]。LCMS m/z = 185.3 [M+23].

第八步：[1-[2-[[4-[(5-氨基甲酰异吲哚啉-2-基)甲基]本甲酰基]-甲基-氨基]乙基]-4-哌啶]N-(2-苯基苯基)氨基甲酸酯(化合物22)Step 8: [1-[2-[[4-[(5-carbamoylisoindol-2-yl)methyl] benzoyl]-methyl-amino]ethyl]-4-piperidin Acridine]N-(2-phenylphenyl)carbamate (Compound 22)

取[1-[2-[(4-甲酰基苯甲酰基)-甲基-胺基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(5A)(0.4g，0.822mmol)和异吲哚啉-5-甲酰胺(22H)(0.16g，0.986mmol)置于50mL圆底烧瓶中，加入异丙醇(30mL)，旋转蒸发仪减压浓缩(60℃)，至溶液澄清，再加入异丙醇(30mL)，旋转蒸发仪减压浓缩(60℃)，溶液澄清后，残留物约20mL，冷至0℃，加入乙酸(0.296g， 4.932mmol)、无水硫酸钠(0.12g)，搅拌均匀后，加入三乙酰氧基硼氢化钠(0.5226g，2.466mmol)，升至室温反应2.5小时。反应结束后饱和碳酸氢钠水溶液(30mL)淬灭反应，用二氯甲烷萃取(30mL×2)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经硅胶柱层析纯化后得到目标化合物[1-[2-[[4-[(5-氨基甲酰异吲哚啉-2-基)甲基]本甲酰基]-甲基-氨基]乙基]-4-哌啶]N-(2-苯基苯基)氨基甲酸酯(化合物22)，白色固体(0.32g，产率61.7％)。Taking [1-[2-[(4-formylbenzoyl)-methyl-amino]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (5A (0.4 g, 0.822 mmol) and isoindolin-5-carboxamide (22H) (0.16 g, 0.986 mmol) were placed in a 50 mL round bottom flask, isopropyl alcohol (30 mL) was added, (60 ° C), until the solution was clarified, then add isopropanol (30 mL), concentrated under reduced pressure on a rotary evaporator (60 ° C), the solution was clarified, the residue was about 20 mL, cooled to 0 ° C, and added acetic acid (0.296 g, 4.932 mmol) and anhydrous sodium sulfate (0.12 g). After stirring well, sodium triacetoxyborohydride (0.5226 g, 2.466 mmol) was added, and the mixture was allowed to react to room temperature for 2.5 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ After purification, the title compound [1-[2-[[4-[(5-carbamoylisoindol-2-yl)methyl]]-formyl]-methyl-amino]ethyl]-4 - piperidine] N-(2-phenylphenyl)carbamate (Compound 22), white solid (0.32 g, yield 61.7%).

¹H NMR(400MHz,CDCl₃)δ8.07(s,1H),7.66(d,J＝8.0Hz,2H),7.53–7.31(m,9H),7.25–7.18(m,2H),7.14(td,J＝7.5,1.0Hz,1H),6.58(s,1H),4.83–4.60(m,1H),3.97(s,2H),3.93(s,3H),3.69(s,1H),3.38(s,1H),3.06–2.94(m,2H),2.45(s,2H),2.05(s,2H),1.86(d,J＝19.0Hz,2H),1.62(s,6H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.07 (s, 1H), 7.66 (d, J = 8.0Hz, 2H), 7.53-7.31 (m, 9H), 7.25-7.18 (m, 2H), 7.14 ( Td, J=7.5, 1.0 Hz, 1H), 6.58 (s, 1H), 4.83–4.60 (m, 1H), 3.97 (s, 2H), 3.93 (s, 3H), 3.69 (s, 1H), 3.38 (s, 1H), 3.06 - 2.94 (m, 2H), 2.45 (s, 2H), 2.05 (s, 2H), 1.86 (d, J = 19.0 Hz, 2H), 1.62 (s, 6H).

LCMSm/z＝632.4[M+1]。LCMS m/z = 632.4 [M + 1].

实施例23：[1-[3-[5-[(4-氨基甲酰基-1-哌啶基)甲基]吲唑-1-基]丙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物23)Example 23: [1-[3-[5-[(4-carbamoyl-1-piperidyl)methyl]oxazol-1-yl]propyl]-4-piperidinyl]N-( 2-phenylphenyl)carbamate (compound 23)

[1-[3-[5-[(4-carbamoyl-1-piperidyl)methyl]indazol-1-yl]propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate[1-[3-[5-[(4-carbamoyl-1-piperidyl)methyl]indazol-1-yl]propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

第一步：1-(3-羟丙基)吲唑-5-甲醛(23B)First step: 1-(3-hydroxypropyl)carbazole-5-carbaldehyde (23B)

1-(3-hydroxypropyl)indazole-5-carbaldehyde1-(3-hydroxypropyl)indazole-5-carbaldehyde

将1H-吲唑-5-甲醛(23A)(14.6g,99.9mmol)置于N,N二甲基甲酰胺中(25mL)中。依次向其中加入溴丙醇(20.8g,150mmol),碳酸钾(65.1g g,200mmol)以及催化量的碘化钾(1.66g,9.9mmol)。反应在80℃下搅拌4小时后终止。待反应冷至室温后,减压除去溶剂，向反应中加入水(50mL)，用乙酸乙酯(100mL×2)萃取，合并后的有机相用无水硫酸钠干燥，减压浓缩后柱层析分离(石油醚/乙酸乙酯(v/v)＝4:1)得到黄色液体状1-(3-羟丙基)吲唑-5-甲醛(23B)(9.0g,产率44％)。1H-indazole-5-carbaldehyde (23A) (14.6 g, 99.9 mmol) was taken in N, N-dimethylformamide (25 mL). Bromopropanol (20.8 g, 150 mmol), potassium carbonate (65.1 g, 200 mmol) and a catalytic amount of potassium iodide (1.66 g, 9.9 mmol) were sequentially added thereto. The reaction was terminated after stirring at 80 ° C for 4 hours. After the reaction was cooled to room temperature, the solvent was removed under reduced pressure. Water (50 mL) was added to the reaction, and the mixture was evaporated. v) = 4: 1) 1-(3-hydroxypropyl)oxazol-5-carbaldehyde (23B) (9.0 g, yield 44%) was obtained as a yellow liquid.

LCMS m/z＝205.1[M+1]。LCMS m/z = 205.1 [M + 1].

第二步：3-(5-甲酰基吲唑-1-基)丙基甲磺酸酯(23C)Step 2: 3-(5-formylindazol-1-yl)propyl methanesulfonate (23C)

3-(5-formylindazol-1-yl)propyl methanesulfonate3-(5-formylindazol-1-yl)propyl methanesulfonate

将1-(3-羟丙基)吲唑-5-甲醛(23B)(3.07g,15.0mmol)置于二氯甲烷(100mL)中，降至0℃。依次向其中加入三乙胺(3.04g,30.1mmol)，甲磺酰氯(2.58g,22.5mmol)。反应在0℃下搅拌4小时。待反应冷至室温后，向反应中依次加入水(50mL)和二氯甲烷(100mL),萃取，有机相和水相分离，水相用乙酸乙酯(100mL×1)萃取，合并后的有机相用无水硫酸钠干燥，减压浓缩后得到黄色液体状3-(5-甲醛吲唑-1-基)丙基甲磺酸酯(23C)(4.24g,产率100％)。1-(3-Hydroxypropyl)oxazol-5-carbaldehyde (23B) (3.07 g, 15.0 mmol) was taken in dichloromethane (100 mL). Triethylamine (3.04 g, 30.1 mmol), methanesulfonyl chloride (2.58 g, 22.5 mmol) was added thereto in order. The reaction was stirred at 0 ° C for 4 hours. After the reaction was cooled to room temperature, water (50 mL) and dichloromethane (100 mL) were successively added to the reaction, and the organic phase and aqueous phase were separated, and the aqueous phase was extracted with ethyl acetate (100 mL×1). The organic layer was dried over anhydrous sodium sulfate and evaporatedielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielieliel

LCMS m/z＝283.1[M+1]。LCMS m/z = 283.1 [M + 1].

第三步：[1-[3-(5-甲酰基吲唑-1-基)丙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(23D)The third step: [1-[3-(5-formylindazol-1-yl)propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (23D)

[1-[3-(5-formylindazol-1-yl)propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate[1-[3-(5-formylindazol-1-yl)propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

将4-哌啶基N-(2-苯基苯基)氨基甲酸酯(2.96g,9.99mmol)置于加入(60mL)乙腈和四氢呋喃(v/v＝2/1)的混合溶剂中。依次向其中加入3-(5-甲醛吲唑-1-基)丙基甲磺酸酯(23C)(2.82g,9.99mmol)，三乙胺(1.31g,13.0mmol)。60℃下搅拌4小时。待反应冷至室温后，减压除去溶剂，向反应中加入水(50mL)，用乙酸乙酯(100mL×2)，萃取，合并后的有机相用无水硫酸钠干燥，减压浓缩后柱层析分离(二氯甲烷/甲醇(v/v)＝15:1)得到黄色液体状[1-[3-(5-甲酰基吲唑-1-基)丙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(23D)(1.8g,产率37％)。4-piperidinyl N-(2-phenylphenyl)carbamate (2.96 g, 9.99 mmol) was placed in a mixed solvent of (60 mL) acetonitrile and tetrahydrofuran (v/v = 2/1). 3-(5-Formaldehyde oxazol-1-yl)propyl methanesulfonate (23C) (2.82 g, 9.99 mmol), triethylamine (1.31 g, 13.0 mmol) was added. Stir at 60 ° C for 4 hours. After the reaction mixture was cooled to room temperature, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. Chromatography (dichloromethane/methanol (v/v) = 15:1) afforded [1-[3-(5-formylindazol-1-yl)propyl]-4-piperidinyl as a yellow liquid. N-(2-Phenylphenyl)carbamate (23D) (1.8 g, yield 37%).

LCMS m/z＝483.3[M+1]。LCMS m/z = 483.3 [M + 1].

第四步：[1-[3-[5-[(4-氨基甲酰基-1-哌啶基)甲基]吲唑-1-基]丙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物23)The fourth step: [1-[3-[5-[(4-carbamoyl-1-piperidyl)methyl]oxazol-1-yl]propyl]-4-piperidinyl]N-( 2-phenylphenyl)carbamate (compound 23)

[1-[3-[5-[(4-carbamoyl-1-piperidyl)methyl]indazol-1-yl]propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate [1-[3-[5-[(4-carbamoyl-1-piperidyl)methyl]indazol-1-yl]propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

将[1-[3-(5-甲酰基吲唑-1-基)丙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(23D)(0.482g,0.99mmol)置于100mL圆底烧瓶中，向反应瓶中加入异丙醇(30.0mL)。向反应瓶中依次加入哌啶4-甲酰胺(0.256g,2.0mmol)，60℃减压除去溶剂，重复两次，再加入异丙醇(15mL)、无水硫酸钠(0.567g)和乙酸(0.36g,5.99mmol)。反应在室温下搅拌30分钟后，加入三乙酰氧基硼氢化钠(0.0.64g,3.00mmol)，室温搅拌2小时。减压浓缩除去大部分反应溶剂，向残余物中缓慢滴加饱和碳酸氢钠水溶液(50mL)，水相用二氯甲烷萃取(100mL×2)，合并后的有机相用饱和食盐水(50mL×1)洗涤，无水硫酸钠干燥后，过滤，滤液减压浓缩经硅胶柱层析分离(二氯甲烷/甲醇(v/v)＝15:1)提纯，得到白色固体状的[1-[3-[5-[(4-氨基甲酰基-1-哌啶基)甲基]吲唑-1-基]丙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物23)(0.08g,产率10％)。[1-[3-(5-Formylindazol-1-yl)propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (23D) (0.482 g, 0.99 mmol) was placed in a 100 mL round bottom flask, and isopropanol (30.0 mL) was added to the reaction flask. Piperidine 4-carboxamide (0.256 g, 2.0 mmol) was added to the reaction flask in turn, and the solvent was removed under reduced pressure at 60 ° C twice, then isopropanol (15 mL), anhydrous sodium sulfate (0.567 g) and acetic acid. (0.36 g, 5.99 mmol). After stirring at room temperature for 30 minutes, sodium triacetoxyborohydride (0.0.64 g, 3.00 mmol) was added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure to dryness, and the mixture was evaporated, evaporated, evaporated, evaporated. 1) Washing, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure on silica gel column chromatography (dichloromethane/methanol (v/v) = 15:1) to give [1-[ 3-[5-[(4-carbamoyl-1-piperidinyl)methyl]oxazol-1-yl]propyl]-4-piperidinyl]N-(2-phenylphenyl)amino Formate (Compound 23) (0.08 g, yield 10%).

¹H NMR(400MHz,CD₃OD)δ7.98(d,J＝0.8Hz,1H),7.66(s,1H),7.55(d,J＝8.7Hz,2H),7.48–7.14(m,9H),4.63–4.48(m,1H),4.44(t,J＝6.5Hz,2H),3.62(s,2H),2.93(dd,J＝14.1,9.6Hz,3H),2.52(s,2H),2.29–2.11(m,5H),2.11–1.99(m,4H),1.85–1.67(m,6H),1.65–1.51(m,2H)。 ¹ H NMR (400 MHz, CD ₃ OD) δ 7.98 (d, J = 0.8 Hz, 1H), 7.66 (s, 1H), 7.55 (d, J = 8.7 Hz, 2H), 7.48 - 7.14 (m, 9H) ), 4.63 - 4.48 (m, 1H), 4.44 (t, J = 6.5 Hz, 2H), 3.62 (s, 2H), 2.93 (dd, J = 14.1, 9.6 Hz, 3H), 2.52 (s, 2H) , 2.29–2.11 (m, 5H), 2.11–1.99 (m, 4H), 1.85–1.67 (m, 6H), 1.65–1.51 (m, 2H).

LCMS m/z＝595.3[M+1]。LCMS m/z = 595.3 [M + 1].

实施例24：[1-[2-[7-[(4-甲酰胺-1-哌啶基)甲基]-1-氧代-3,4-二氢异喹啉-2-基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物24)Example 24: [1-[2-[7-[(4-carboxamide-1-piperidyl)methyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]B 4-thiazolidinyl]N-(2-phenylphenyl)carbamate (compound 24)

[1-[2-[7-[(4-carbamoyl-1-piperidyl)methyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate[1-[2-[7-[(4-carbamoyl-1-piperidyl)methyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl) Carbamate

第一步：2-烯丙基-7-溴-3,4-二氢异喹啉-1-酮(24B)First step: 2-allyl-7-bromo-3,4-dihydroisoquinolin-1-one (24B)

2-allyl-7-bromo-3,4-dihydroisoquinolin-1-one2-allyl-7-bromo-3,4-dihydroisoquinolin-1-one

将N,N-二甲基甲酰胺(200mL)，置于1000mL圆底烧瓶中。0℃下，向反应瓶中加入氢化钠(12g,300mmol,60％)，通过恒压漏斗向反应瓶中滴加7-溴-3,4-二氢-2H-异喹啉-1-酮(24A)(33.9g,150mmol)的N,N-二甲基甲酰胺(150mL)溶液，搅拌20分钟后，向反应瓶中滴加3-溴丙烯(27.2g,225mmol)。反应升至室温搅拌4小时后终止。向反应液中滴加水(100mL)淬灭反应，残余物用乙酸乙酯萃取(200mL×5)，合并后的有机相用饱和食盐水洗(100mL×2),无水硫酸钠干燥，减压浓缩后柱层析分离(石油醚/乙酸乙酯(v/v)＝10:1)得到黄色液体状的2-烯丙基-7-溴-3,4-二氢异喹啉-1-酮(24B)(29.0g,产率73％)。N,N-dimethylformamide (200 mL) was placed in a 1000 mL round bottom flask. Sodium hydride (12 g, 300 mmol, 60%) was added to the reaction flask at 0 ° C, and 7-bromo-3,4-dihydro-2H-isoquinolin-1-one was added dropwise to the reaction via a constant pressure funnel. (24A) (33.9 g, 150 mmol) in N,N-dimethylformamide (150 mL). After stirring for 20 min, 3-bromopropene (27.2 g, 225 mmol) was added dropwise to the reaction flask. The reaction was allowed to warm to room temperature and stirred for 4 hours and then quenched. The reaction mixture was diluted with water (100 mL), and the mixture was evaporated. After column chromatography (petroleum ether / ethyl acetate (v / v) = 10:1) to give 2- allyl-7-bromo-3,4-dihydroisoquinolin-1-one as a yellow liquid. (24B) (29.0 g, yield 73%).

第二步：2-烯丙基-1-氧代-3,4-二氢异喹啉-7-甲腈(24C)Second step: 2-allyl-1-oxo-3,4-dihydroisoquinoline-7-carbonitrile (24C)

2-allyl-1-oxo-3,4-dihydroisoquinoline-7-carbonitrile2-allyl-1-oxo-3,4-dihydroisoquinoline-7-carbonitrile

将2-烯丙基-7-溴-3,4-二氢异喹啉-1-酮(24B)(29.0g,108.9mmol)置于1000mL圆底烧瓶中，加入N,N-二甲基甲酰胺(250mL)、氰化亚铜(20.1g,244.8mmol)。反应升至160℃搅拌10小时后终止。向反应液中加入水(300mL)，用乙酸乙酯萃取(200mL×3)，合并后的有机相用饱和食盐水洗(100mL×2)，无水硫酸钠干燥，减压浓缩后柱层析分离(石油醚/乙酸乙酯(v/v)＝10:1)得到黄色固体状的2-烯丙基-1-氧代-3,4-二氢异喹啉-7-甲腈(24C)(15.6g,产率68％)。2-Allyl-7-bromo-3,4-dihydroisoquinolin-1-one (24B) (29.0 g, 108.9 mmol) was placed in a 1000 mL round bottom flask and N,N-dimethyl was added. Formamide (250 mL), cuprous cyanide (20.1 g, 244.8 mmol). The reaction was raised to 160 ° C and stirred for 10 hours and then terminated. Water (300 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL×3). The combined organic phase was washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate (petroleum ether/ethyl acetate (v/v) = 10:1) to give 2-allyl-1-oxo-3,4-dihydroisoquinolin-7-carbonitrile as a yellow solid (24C) (15.6 g, yield 68%).

LCMS m/z＝213.1[M+1]。LCMS m/z = 213.1 [M + 1].

第三步：2-烯丙基-1-羰基-3,4-二氢异喹啉-6-苯甲醛(24D)The third step: 2-allyl-1-carbonyl-3,4-dihydroisoquinoline-6-benzaldehyde (24D)

2-allyl-1-oxo-3,4-dihydroisoquinoline-7-carbaldehyde2-allyl-1-oxo-3,4-dihydroisoquinoline-7-carbaldehyde

将2-烯丙基-1-氧代-3,4-二氢异喹啉-7-甲腈(24C)(15.6g,73.5mmol)置于1000mL圆底烧瓶中，加入乙醇(250mL)，镍(5.0g,85mmol)，甲酸(10.0g,217mmol)。反应升至160℃搅拌10小时后终止。将混合物用硅藻土过滤，滤液减压浓缩后得到黄色液体状的2-烯丙基-1-羰基-3,4-二氢异喹啉-6-苯甲醛(24D)(8.5g,产率54％)。2-Allyl-1-oxo-3,4-dihydroisoquinoline-7-carbonitrile (24C) (15.6 g, 73.5 mmol) was placed in a 1000 mL round bottom flask and ethanol (250 mL) was added. Nickel (5.0 g, 85 mmol), formic acid (10.0 g, 217 mmol). The reaction was raised to 160 ° C and stirred for 10 hours and then terminated. The mixture was filtered through celite, and the filtrate was evaporated to dryness crystals crystalssssssssssssssssssssss Rate 54%).

LCMS m/z＝216.1[M+1]。LCMS m/z = 216.1 [M + 1].

第四步：2-烯丙基-7-(羟基甲基)-3,4-二氢异喹啉-1-酮(24E) Fourth step: 2-allyl-7-(hydroxymethyl)-3,4-dihydroisoquinolin-1-one (24E)

2-allyl-7-(hydroxymethyl)-3,4-dihydroisoquinolin-1-one2-allyl-7-(hydroxymethyl)-3,4-dihydroisoquinolin-1-one

将2-烯丙基-1-羰基-3,4-二氢异喹啉-6-苯甲醛(24D)(8.5g,39mmol)，置于500mL圆底烧瓶中。向反应瓶中加入甲醇(100mL)，分批加入硼氢化钠(1.9g,51mmol)，反应在室温下搅拌2小时后终止。滴加水(15mL)淬灭反应。残余物用乙酸乙酯(200mL)萃取，水相用乙酸乙酯(150mL)反萃，合并后的有机相用饱和食盐水(50mL)洗，无水硫酸钠干燥，减压浓缩后得到黄色液体状的2-烯丙基-7-(羟基甲基)-3,4-二氢异喹啉-1-酮(24E)(3.8g,44％)。2-Allyl-1-carbonyl-3,4-dihydroisoquinolin-6-benzaldehyde (24D) (8.5 g, 39 mmol) was placed in a 500 mL round bottom flask. Methanol (100 mL) was added to the reaction flask, sodium borohydride (1.9 g, 51 mmol) was added portionwise, and the mixture was stirred at room temperature for 2 hr. The reaction was quenched by dropwise addition of water (15 mL). The residue was extracted with EtOAc (EtOAc) (EtOAc)EtOAc. 2-Allyl-7-(hydroxymethyl)-3,4-dihydroisoquinolin-1-one (24E) (3.8 g, 44%).

LCMS m/z＝218.1[M+1]。LCMS m/z = 218.1 [M + 1].

第五步：2-烯丙基-7-[[叔丁基(二甲基)硅基]氧亚甲基]-3,4-二氢异喹啉-1-酮(24F)Step 5: 2-allyl-7-[[tert-butyl(dimethyl)silyl]oxymethylene]-3,4-dihydroisoquinolin-1-one (24F)

2-allyl-7-[[tert-butyl(dimethyl)silyl]oxymethyl]-3,4-dihydroisoquinolin-1-one2-allyl-7-[[tert-butyl(dimethyl)silyl]oxymethyl]-3,4-dihydroisoquinolin-1-one

将2-烯丙基-7-(羟基甲基)-3,4-二氢异喹啉-1-酮(24E)(3.8g,17.5mmol)溶于二氯甲烷(50mL)中。依次向其中加入三乙胺(7.5g,74mmol)，叔丁基二甲基氯硅烷(4.35g,28.9mmol)，4-二甲胺基吡啶(0.8g,7mmol)。反应在室温下搅拌1小时后终止。反应液减压浓缩后柱层析分离(石油醚/乙酸乙酯(v/v)＝10:1)得到黄色液体状的2-烯丙基-7-[[叔丁基(二甲基)硅基]氧亚甲基]-3,4-二氢异喹啉-1-酮(24F)(5.8g,100％)。2-Allyl-7-(hydroxymethyl)-3,4-dihydroisoquinolin-1-one (24E) (3.8 g, 17.5 mmol) was dissolved in dichloromethane (50 mL). Triethylamine (7.5 g, 74 mmol), tert-butyldimethylsilyl chloride (4.35 g, 28.9 mmol), 4-dimethylaminopyridine (0.8 g, 7 mmol) were added thereto in that order. The reaction was quenched after stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by chromatography (ethyl ether / ethyl acetate (v/v) = 10:1) to afford 2- allyl-7-[[t-butyl(dimethyl) Silyl]oxymethylene]-3,4-dihydroisoquinolin-1-one (24F) (5.8 g, 100%).

第六步：2-[7-[[叔丁基(二甲基)硅基]氧亚甲基]-1-氧代-3,4-二氢异喹啉-2-基]乙醛(24G)Step 6: 2-[7-[[tert-Butyl(dimethyl)silyl]oxymethylene]-1-oxo-3,4-dihydroisoquinolin-2-yl]acetaldehyde ( 24G)

2-[7-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]acetaldehyde2-[7-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]acetaldehyde

将2-烯丙基-7-[[叔丁基(二甲基)硅基]氧亚甲基]-3,4-二氢异喹啉-1-酮(24F)(2.9g,8.7mmol)溶于四氢呋喃(28mL)，水(7mL)中。0℃下，依次向其中加入二水合锇酸钾(0.5g,1.0mmol)，高碘酸钠(9.24g,43.2mmol)。反应升至室温下搅拌6小时后终止。滴加饱和硫代硫酸钠水溶液(80mL)淬灭反应，残余物用乙酸乙酯(150mL)萃取，水相用乙酸乙酯(150mL)反萃，合并后的有机相用饱和食盐水(50mL)洗，无水硫酸钠干燥，减压浓缩后柱层析分离(石油醚/乙酸乙酯(v/v)＝1:1)得到黄色液体状的2-[7-[[叔丁基(二甲基)硅基]氧亚甲基]-1-氧代-3,4-二氢异喹啉-2-基]乙醛(24G)(2.2g,75％)。2-Allyl-7-[[tert-butyl(dimethyl)silyl]oxymethylene]-3,4-dihydroisoquinolin-1-one (24F) (2.9 g, 8.7 mmol) ) Dissolved in tetrahydrofuran (28 mL) in water (7 mL). Potassium phthalate dihydrate (0.5 g, 1.0 mmol) and sodium periodate (9.24 g, 43.2 mmol) were sequentially added thereto at 0 °C. The reaction was allowed to warm to room temperature and stirred for 6 hours and then quenched. The reaction was quenched with EtOAc EtOAc (EtOAc) Washed, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography (ethyl ether / ethyl acetate (v/v) = 1:1) to give 2-[7-[[ter-butyl] Methyl)silyl]oxymethylene]-1-oxo-3,4-dihydroisoquinolin-2-yl]acetaldehyde (24G) (2.2 g, 75%).

LCMS m/z＝334.1[M+1]。LCMS m/z = 334.1 [M + 1].

第七步：[1-[2-[7-[[叔丁基(二甲基)硅基]氧亚甲基]-1-氧代-3,4-二氢异喹啉-2-基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(24H)Step 7: [1-[2-[7-[[tert-Butyl(dimethyl)silyl]oxymethylene]-1-oxo-3,4-dihydroisoquinolin-2-yl ] B 4--4-piperidinyl]N-(2-phenylphenyl)carbamate (24H)

[1-[2-[7-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate[1-[2-[7-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl) Carbamate

将2-[7-[[叔丁基(二甲基)硅基]氧亚甲基]-1-氧代-3,4-二氢异喹啉-2-基]乙醛(24G)(2.2g,6.6mmol)溶于二氯甲烷(100mL)中。向其中加入4-哌啶基N-(2-苯基苯基)氨基甲酸酯(1A)(2.0g,6.75mmol)。反应在室温下搅拌1小时后加入三乙酰氧基硼氢化钠(3.5g,17mmol)，继续搅拌2小时后终止反应。滴加饱和碳酸氢钠水溶液(80mL)淬灭反应，残余物用二氯甲烷(150mL)萃取，水相用二氯甲烷(150mL)反萃，合并后的有机相用饱和食盐水(50mL)洗，无水硫酸钠干燥，减压浓缩后柱层析分离(二氯甲烷/甲醇(v/v)＝15:1)得到[1-[2-[7-[[叔丁基(二甲基)硅基]氧亚甲基]-1-氧代-3,4-二氢异喹啉-2-基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(24H)(0.92g,23％)。2-[7-[[tert-Butyl(dimethyl)silyl]oxymethylene]-1-oxo-3,4-dihydroisoquinolin-2-yl]acetaldehyde (24G) ( 2.2 g, 6.6 mmol) was dissolved in dichloromethane (100 mL). 4-piperidinyl N-(2-phenylphenyl)carbamate (1A) (2.0 g, 6.75 mmol) was added thereto. After the reaction was stirred at room temperature for 1 hour, sodium triacetoxyborohydride (3.5 g, 17 mmol) was added, and stirring was continued for 2 hr. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. Drying under anhydrous sodium sulfate, concentrating under reduced pressure and then purified by column chromatography (dichloromethane/methanol (v/v) = 15:1) to give [1-[2-[7-[[ )silyl]oxymethylene]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidinyl]N-(2-phenylphenyl)amino Formate (24H) (0.92 g, 23%).

第八步：[1-[2-(7-羟基亚甲基)-1-氧代-3,4-二氢异喹啉-2-基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(24I)Step 8: [1-[2-(7-Hydroxymethylene)-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidinyl]N- (2-phenylphenyl)carbamate (24I)

[1-[2-[7-(hydroxymethyl)-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate[1-[2-[7-(hydroxymethyl)-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

将[1-[2-[7-[[叔丁基(二甲基)硅基]氧亚甲基]-1-氧代-3,4-二氢异喹啉-2-基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(24H)(0.92g,1.5mmol)溶于四氢呋喃(20mL)中。向其中加入四丁基氟化铵(0.65g,2.5mmol)，在室温下搅拌2小时后终止反应。将反应液减压浓缩后柱层析分离(二氯甲烷/甲醇(v/v)＝15:1)得到[1-[2-(7-羟基亚甲基)-1-氧代-3,4-二氢异喹啉-2-基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(24I)(0.67g,89％)。[1-[2-[7-[[tert-Butyl(dimethyl)silyl]oxymethylene]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl ]-4-piperidinyl]N-(2-phenylphenyl)carbamate (24H) (0.92 g, 1.5 mmol) was dissolved in THF (20 mL). Tetrabutylammonium fluoride (0.65 g, 2.5 mmol) was added thereto, and the reaction was terminated after stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and then purified (jjjjjjjjjjjjjjjjjjjjj 4-Dihydroisoquinolin-2-yl]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (24I) (0.67 g, 89%).

LCMS m/z＝500.3[M+1]。LCMS m/z = 500.3 [M + 1].

第九步：[1-[2-(7-甲醛基-1-氧代-3,4-二氢异喹啉-2-基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(24J)Step 9: [1-[2-(7-Formaldehyde-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidinyl]N-(2- Phenylphenyl)carbamate (24J)

[1-[2-(7-formyl-1-oxo-3,4-dihydroisoquinolin-2-yl)ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate[1-[2-(7-formyl-1-oxo-3,4-dihydroisoquinolin-2-yl)ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

将[1-[2-(7-羟基亚甲基)-1-氧代-3,4-二氢异喹啉-2-基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(24I)(0.67g,1.33mmol)溶于二氯甲烷(10mL)中。0℃下，向其中加入戴斯-马丁氧化剂(0.68g,1.6mmol)。反应在室温下搅拌2小时后后终止。滴加饱和碳酸氢钠水溶液(40mL)淬灭反应，残余物用二氯甲烷(50mL)萃取，水相用二氯甲烷(50mL)反萃，合并后的有机相用饱和食盐水(50mL)洗，无水硫酸钠干燥，减压浓缩后柱层析分离(二氯甲烷/甲醇(v/v)＝15:1)得到黄色液体状的[1-[2-(7-甲醛基-1-氧代-3,4-二氢异喹啉-2-基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(24J)(0.58g,87％)。[1-[2-(7-Hydroxymethylene)-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidinyl]N-(2- Phenylphenyl)carbamate (24I) (0.67 g, 1.33 mmol) was dissolved in dichloromethane (10 mL). Dess-Martin periodinane (0.68 g, 1.6 mmol) was added thereto at 0 °C. The reaction was stirred at room temperature for 2 hours and then terminated. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. Drying under anhydrous sodium sulfate, concentrating under reduced pressure and then purified by column chromatography (dichloromethane/methanol (v/v) = 15:1) to give [1-[2-(7-carbamoyl-1-) Oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (24J) (0.58 g, 87% ).

第十步：[1-[2-[7-[(4-甲酰胺-1-哌啶基)甲基]-1-氧代-3,4-二氢异喹啉-2-基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物24)Step 10: [1-[2-[7-[(4-carboxamide-1-piperidyl)methyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]B 4-thiazolidinyl]N-(2-phenylphenyl)carbamate (compound 24)

将[1-[2-(7-甲醛基-1-氧代-3,4-二氢异喹啉-2-基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(24J)(0.29g,0.58mmol)溶于异丙醇(15mL)中，向其中加入4-哌啶甲酰胺(0.15g,1.2mmol)。室温下搅拌30分钟后，依次向加入乙酸(0.18g,3.0mmol)，三乙酰氧基硼氢化钠(0.4g,1.9mmol)，2小时后终止反应。减压浓缩除去大部分反应溶剂，向残余物中缓慢滴加饱和碳酸氢钠水溶液(50mL)，水相用二氯甲烷萃取(100mL×2),合并后的有机相用饱和实验水洗(50mL)，无水硫酸钠干燥后,减压浓缩柱层析分离[(二氯甲烷/甲醇(v/v)＝15:1)]得到白色固体状的[1-[2-[7-[(4-甲酰胺-1-哌啶基)甲基]-1-氧代-3,4-二氢异喹啉-2-基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(化合物24)(0.046g,产率13％)。[1-[2-(7-Formaldehyde-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidinyl]N-(2-phenylbenzene) The carbamate (24 J) (0.29 g, 0.58 mmol) was dissolved in isopropyl alcohol (15 mL), and 4-piperidinecarboxamide (0.15 g, 1.2 mmol) was added thereto. After stirring at room temperature for 30 minutes, Acetic acid (0.18 g, 3.0 mmol) and sodium triacetoxyborohydride (0.4 g, 1.9 mmol) were added successively, and the reaction was terminated after 2 hours. The reaction solvent was concentrated under reduced pressure to remove most of the solvent. The aqueous sodium hydrogencarbonate solution (50 mL) was extracted with dichloromethane (100 mL×2), and the combined organic phase was washed with saturated water (50 mL), dried over anhydrous sodium sulfate Methylene chloride/methanol (v/v) = 15:1)] gave [1-[2-[7-[(4-carboxamide-1-piperidyl)methyl]-1-oxyl as a white solid 3,4-Dihydroisoquinolin-2-yl]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (Compound 24) (0.046 g, yield 13%).

¹H NMR(400MHz,DMSO-d₆)δ8.58(s,1H),7.77(s,1H),7.41–7.29(m,10H),7.22(d,J＝7.7Hz,1H),7.17(s,1H),6.68(s,1H),4.47–4.40(m,1H),3.55(t,J＝6.5Hz,4H),3.44(s,2H),2.91(t,J＝6.5Hz,2H),2.78(d,J＝11.3Hz,2H),2.62-2.69(m,2H),2.18(t,J＝9.5Hz,2H),2.06-1.99(m,2H),1.87-1.93(m,2H),1.76–1.59(m,5H),1.58–1.50(m,2H),1.40-1.35(m,2H)。 ^{1 H NMR (400MHz, DMSO-} d 6) δ8.58 (s, 1H), 7.77 (s, 1H), 7.41-7.29 (m, 10H), 7.22 (d, J = 7.7Hz, 1H), 7.17 ( s, 1H), 6.68 (s, 1H), 4.47 - 4.40 (m, 1H), 3.55 (t, J = 6.5 Hz, 4H), 3.44 (s, 2H), 2.91 (t, J = 6.5 Hz, 2H) ), 2.78 (d, J = 11.3 Hz, 2H), 2.62 - 2.69 (m, 2H), 2.18 (t, J = 9.5 Hz, 2H), 2.06-1.99 (m, 2H), 1.87-1.93 (m, 2H), 1.76 - 1.59 (m, 5H), 1.58 - 1.50 (m, 2H), 1.40-1.35 (m, 2H).

LCMS m/z＝610.3[M+1]。LCMS m/z = 610.3 [M + 1].

实施例25：4-氨基-1-[[4-[甲基-[2-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]乙基]氨甲酰]苯基]甲基]哌啶-4-羧酸甲酯(化合物25)Example 25: 4-Amino-1-[[4-[methyl-[2-[4-[(2-phenylphenyl)carbamoyloxy)-1-piperidinyl]ethyl]ammonium Methyl formyl]phenyl]methyl]piperidine-4-carboxylate (compound 25)

methyl 4-amino-1-[[4-[methyl-[2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl]carbamoyl]phenyl]methyl]piperidine-4-carboxylate Methyl 4-amino-1-[[4-[methyl-[2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl]carbamoyl]phenyl]methyl]piperidine-4-carboxylate

第一步：4-(叔丁氧羰基氨基)-1-[[4-[甲基-[2-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]乙基]氨甲酰]苯基]甲基]哌啶-4-羧酸甲酯(25B)First step: 4-(tert-butoxycarbonylamino)-1-[[4-[methyl-[2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidine) Methyl]ethyl]carbamoyl]phenyl]methyl]piperidine-4-carboxylic acid methyl ester (25B)

methyl 4-(tert-butoxycarbonylamino)-1-[[4-[methyl-[2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl]carbamoyl]phenyl]methyl]piperidine-4-carboxylateMethyl 4-(tert-butoxycarbonylamino)-1-[[4-[methyl-[2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl]carbamoyl]phenyl]methyl]piperidine-4-carboxylate

将[1-[2-[(4-甲醛基苯甲酰基)-甲基-氨基]乙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(5A)(1.7g,3.5mmol)溶于二氯甲烷(25mL)的溶剂中，加入4-(叔丁氧羰基氨基)哌啶-4-羧酸甲酯(25A)(0.995g,3.85mmol)，加入乙酸(0.21g,3.5mmol)，室温下搅拌1h后，加入三乙酰氧基硼氢化钠(2.23g,10.5mmol),室温搅拌3小时。向其中加入饱和碳酸氢钠水溶液(50mL)淬灭反应，残余物用二氯甲烷(100mL×2)萃取，合并后的有机相用无水硫酸钠干燥，减压浓缩后柱层析分离(二氯甲烷：甲醇(v/v)＝1:0～8:1)得到黄色固体状的4-(叔丁氧羰基氨基)-1-[[4-[甲基-[2-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]乙基]氨甲酰]苯基]甲基]哌啶-4-羧酸甲酯(25B)(2.0g,产率78％)。[1-[2-[(4-Mercaptobenzoyl)-methyl-amino]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (5A) (1.7 g, 3.5 mmol) was dissolved in dichloromethane (25 mL) EtOAc (EtOAc (EtOAc) Acetic acid (0.21 g, 3.5 mmol) was stirred at room temperature for 1 h then sodium triacetoxyborohydride (2.23 g, 10.5 mmol). The reaction mixture was quenched with aq. EtOAc (EtOAc) Methyl chloride:methanol (v/v) = 1:0 to 8:1) to give 4-(tert-butoxycarbonylamino)-1-[[4-[methyl-[2-[4-[ Methyl (2-phenylphenyl)carbamoyloxy-1-phenylpiperidinyl]ethyl]carbamoyl]phenyl]methyl]piperidine-4-carboxylate (25B) (2.0 g, Yield 78%).

LCMS m/z＝728.3[M+1]。LCMS m/z = 728.3 [M + 1].

第二步：4-氨基-1-[[4-[甲基-[2-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]乙基]氨甲酰]苯基]甲基]哌啶-4-羧酸甲酯(化合物25)Second step: 4-amino-1-[[4-[methyl-[2-[4-[(2-phenylphenyl)carbamoyloxy)-1-piperidinyl]ethyl]ammonium Methyl formyl]phenyl]methyl]piperidine-4-carboxylate (compound 25)

methyl 4-amino-1-[[4-[methyl-[2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl]carbamoyl]phenyl]methyl]piperidine-4-carboxylateMethyl 4-amino-1-[[4-[methyl-[2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl]carbamoyl]phenyl]methyl]piperidine-4-carboxylate

将4-(叔丁氧羰基氨基)-1-[[4-[甲基-[2-[4-[(2-联苯基)氨基甲酰氧基]-1-哌啶基]乙基]氨甲酰]苯基]甲基]哌啶-4-羧酸甲酯(25B)(2.0g,2.7mmol)溶于二氯甲烷(15mL)中。室温下，向反应滴加三氟乙酸(5mL)，搅拌4小时后。减压浓缩除去反应溶剂，向残余物中加入甲苯(10mL)，减压浓缩后，残余物用硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝15/1)，得到白色泡沫状固体4-氨基-1-[[4-[甲基-[2-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]乙基]氨甲酰]苯基]甲基]哌啶-4-羧酸甲酯(化合物25)(1.7g,产率100％)。4-(tert-Butoxycarbonylamino)-1-[[4-[methyl-[2-[4-[(2-biphenyl)carbamoyloxy)-1-piperidinyl]ethyl Methylcarbamoyl]phenyl]methyl]piperidine-4-carboxylate (25B) (2.0 g, 2.7 mmol) was dissolved in dichloromethane (15 mL). Trifluoroacetic acid (5 mL) was added dropwise to the reaction at room temperature and stirred for 4 hr. The reaction solvent was concentrated under reduced pressure, and a residue was added to the residue. Benzene (10 mL), EtOAc (EtOAc m. -[Methyl-[2-[4-[(2-phenylphenyl)carbamoyloxy)-1-piperidinyl]ethyl]carbamoyl]phenyl]methyl]piperidine-4 Methyl carboxylate (compound 25) (1.7 g, yield 100%).

LCMS m/z＝628.3[M+1]。LCMS m/z = 628.3 [M + 1].

¹H NMR(400MHz,CD₃OD)δ7.74–6.97(m,13H),3.92(d,J＝20.9Hz,3H),3.81(s,3H),3.34(s,7H),3.13–2.70(m,8H),2.36–2.18(m,2H),2.08(s,2H),1.91(dd,J＝8.8,5.4Hz,4H)。 ¹ H NMR (400 MHz, CD ₃ OD) δ 7.74 - 6.97 (m, 13H), 3.92 (d, J = 20.9 Hz, 3H), 3.81 (s, 3H), 3.34 (s, 7H), 3.13 - 2.70 (m, 8H), 2.36 - 2.18 (m, 2H), 2.08 (s, 2H), 1.91 (dd, J = 8.8, 5.4 Hz, 4H).

实施例26：4-氨基-1-[[4-[甲基-[2-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]乙基]氨基甲酰]苯基]甲基]哌啶-4-羧酸三氟乙酸盐(化合物26)Example 26: 4-Amino-1-[[4-[methyl-[2-[4-[(2-phenylphenyl)carbamoyloxy)-1-piperidinyl]ethyl]amino Formyl]phenyl]methyl]piperidine-4-carboxylic acid trifluoroacetate (Compound 26)

4-amino-1-[[4-[methyl-[2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl]carbamoyl]phenyl]methyl]piperidine-4-carboxylic acid trifluoroacetic acid4-amino-1-[[4-[methyl-[2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl]carbamoyl]phenyl]methyl]piperidine-4-carboxylic acid trifluoroacetic acid

将甲基4-(叔丁氧羰基氨基)-1-[[4-[甲基-[2-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]乙基]氨甲酰]苯基]甲基]哌啶-4-甲酸酯(化合物25)(0.126g,0.20mmol)置于反应瓶中，溶于5ml水，加入氢氧化钠固体(0.032g,0.80mmol)，室温搅拌24h。减压除去溶剂，残余物用液相制备(液相制备条件：制备柱：Xbridge C18,5um,19×250mm，流动相为含0.05％TFA的去离子水(A)，含0.05％TFA的乙腈(B)，梯度洗脱B/(A+B)＝5％～60％，洗脱时间16.5min，流速12mL/min，柱温：30℃)分离得到白色固体状的4-氨基-1-[[4-[甲基-[2-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]乙基]氨基甲酰]苯基]甲基]哌啶-4-羧酸三氟乙酸盐(化合物26)的(0.06g,50％)。4-(tert-Butoxycarbonylamino)-1-[[4-[methyl-[2-[4-[(2-phenylphenyl)carbamoyloxy)-1-piperidinyl) Ethyl]carbamoyl]phenyl]methyl]piperidine-4-carboxylate (Compound 25) (0.126 g, 0.20 mmol) was placed in a reaction flask, dissolved in 5 ml of water, and sodium hydroxide solid was added ( 0.032 g, 0.80 mmol), stirred at room temperature for 24 h. The solvent was removed under reduced pressure and the residue was purified using liquid phase (yield: mp. (B), gradient elution B / (A + B) = 5% ~ 60%, elution time 16.5min, flow rate 12mL / min, column temperature: 30 ° C) isolated to obtain 4-amino-1- white solid [[4-[Methyl-[2-[4-[(2-phenylphenyl)carbamoyloxy)-1-piperidinyl]ethyl]carbamoyl]phenyl]methyl]piper (0.06 g, 50%) of the pyridine-4-carboxylic acid trifluoroacetate (Compound 26).

LCMS m/z＝614.2[M+1]。LCMS m/z = 614.2 [M + 1].

¹H NMR(400MHz,CD₃OD)δ8.11–6.71(m,13H),4.45(s,2H),3.92(s,2H),3.73(d,J＝56.9Hz,2H),3.56(s,4H),3.44(s,2H),3.13(s,2H),3.04(s,3H),2.50(d,J＝14.1Hz,2H),2.33–2.17(m,2H),2.04(s,2H),1.29(s,1H),0.94–0.78(m,2H)。 ¹ H NMR (400 MHz, CD ₃ OD) δ 8.11 - 6.71 (m, 13H), 4.45 (s, 2H), 3.92 (s, 2H), 3.73 (d, J = 56.9 Hz, 2H), 3.56 (s) , 4H), 3.44 (s, 2H), 3.13 (s, 2H), 3.04 (s, 3H), 2.50 (d, J = 14.1 Hz, 2H), 2.33 - 2.17 (m, 2H), 2.04 (s, 2H), 1.29 (s, 1H), 0.94 - 0.78 (m, 2H).

生物测试例Biological test case

测试例1：对人毒蕈碱M1、M2和M3受体的抑制活性Test Example 1: Inhibitory activity against human muscarinic M1, M2 and M3 receptors

稳定表达人毒蕈碱受体1、2或3(hM1、hM2、hM3)和apo-Aequorin的CHO细胞(PerkinElmer，ES-212-AF)培养于含10％胎牛血清(FBS)(Gibico 10099-141)，400μg/mL G418(sigma G5013)和250μg/ml Zeocin(invivogen ant-zn-5p)的Ham’S F12培养基(Invitrogen 12500-062)中，在37℃，5％CO₂条件下培养，达到90－100％融合。以PBS/5mM EDTA冲洗分离细胞，离心收集，以含0.1％BSA(BOVOGEN BSAS 100)无酚红Ham’s F12培养基(Invitrogen 11039-021)重悬细胞并计数，调整细胞浓度至1×10⁶cells/ml。将15ml细胞悬液加入50ml离心管，加入Coelenterazine-h(promega S2011)至终浓度为5μM。用锡纸包裹避光，于旋转摇床20℃下孵育4小时。再以0.1％BSA/无酚红Ham’s F12培养基稀释细胞至终浓度为5.0×10⁵cells/ml，将细胞置于旋转摇床上低速转动，室温下孵育至少1小时。实施例的化合物用DMSO溶解配制为10mM母液，0.1％BSA/无酚红Ham’s F12培养基梯度稀释(log(M):-7,-8,-9.-10.-11)，加入96孔板，每孔50μl。每孔再加入50μl细胞悬液(25000细胞/孔)，室温孵育15分钟。将96孔板放入酶标仪(Perkin Elmer，Envision)，以酶标仪加样器每孔加入50μL氯化乙酰胆碱(Sigma A6625)溶液，其浓度为31.2nM(hM1)、3.69μM(hM2)或112.92nM(hM3)，记录发光20秒，使用origin7.5计算和分析IC₅₀。本发明化合物人毒蕈碱受体的抑制活性通过以上的实验进行测定，测得的IC₅₀值见下表1。CHO cells (PerkinElmer, ES-212-AF) stably expressing human muscarinic receptor 1, 2 or 3 (hM1, hM2, hM3) and apo-Aequorin were cultured in 10% fetal bovine serum (FBS) (Gibico 10099) -141), 400 μg/mL G418 (sigma G5013) and 250 μg/ml Zeocin (invivogen ant-zn-5p) in Ham'S F12 medium (Invitrogen 12500-062), cultured at 37 ° C, 5% CO ₂ , Achieve 90-100% integration. The cells were washed with PBS/5 mM EDTA, collected by centrifugation, resuspended in 0.1% BSA (BOVOGEN BSAS 100) phenol red-free Ham's F12 medium (Invitrogen 11039-021) and counted, and the cell concentration was adjusted to 1 × 10 ⁶ cells. /ml. 15 ml of the cell suspension was added to a 50 ml centrifuge tube and Coelenterazine-h (promega S2011) was added to a final concentration of 5 μM. It was wrapped in tin foil and protected from light and incubated for 4 hours at 20 ° C in a rotary shaker. The cells were diluted with 0.1% BSA/phenol red-free Ham's F12 medium to a final concentration of 5.0×10 ⁵ cells/ml, and the cells were placed on a rotary shaker at low speed and incubated at room temperature for at least 1 hour. The compound of the example was dissolved in DMSO to prepare a 10 mM mother liquor, and 0.1% BSA/phenol red free Ham's F12 medium was diluted (log (M): -7, -8, -9.-10.-11), and added to 96 wells. Plate, 50 μl per well. An additional 50 μl of cell suspension (25,000 cells/well) was added to each well and incubated for 15 minutes at room temperature. A 96-well plate was placed in a microplate reader (Perkin Elmer, Envision), and 50 μL of acetylcholine chloride (Sigma A6625) solution was added to each well at a concentration of 31.2 nM (hM1) and 3.69 μM (hM2). Or 112.92 nM (hM3), the luminescence was recorded for 20 seconds, and the IC _{50 was} calculated and analyzed using origin 7.5. The inhibitory activity of the muscarinic receptor of the compound of the present invention was measured by the above experiment, and the measured IC ₅₀ values are shown in Table 1 below.

表1：化合物对hM1、hM2和hM3活性数据Table 1: Compound vs. hM1, hM2 and hM3 activity data

结论：本发明化合物对人毒蕈碱M1和M3受体有显著抑制活性，部分化合物M1/M2、 M3/M2的选择性指数较高。Conclusion: The compound of the present invention has significant inhibitory activity on human muscarinic M1 and M3 receptors, and some compounds M1/M2. The selectivity index of M3/M2 is higher.

测试例2：乙酰甲胆碱诱导的豚鼠支气管收缩抑制作用Test Example 2: Methotrexate-induced inhibition of bronchial contraction in guinea pigs

8周龄全雄豚鼠购置于维通利华，适应3天后开始实验。待测化合物用83％无水乙醇+17％吐温80配制成0.6mM储备液。于给药前用水稀释500倍使用。给药前，使用小动物麻醉机(Matrx；VME2)给予5％异氟烷麻醉动物，麻醉时间为1.5～2分钟。待豚鼠麻醉后，将豚鼠固定于气管插管操作平台上，使用大鼠液体气溶胶给药套装(penn-century；MSA-250-R)气管内给药，每只豚鼠给药体积250μl。给药后，于4小时，24小时，使用全体积描计仪(DSI；GS220A12-R7B)测量豚鼠增强呼气间歇(enhanced pause；PenH)值。雾化给予3mg/ml乙酰甲胆碱(Mch)，雾化时间36秒，记录时间7分钟。计算PenH平均值。(参考文献J Pharmacol Exp Ther 345:260-270.)。实验结果见表3。Eight-week old male guinea pigs were purchased in Vitalivic, and the experiment was started after 3 days of adaptation. The test compound was formulated into a 0.6 mM stock solution using 83% absolute ethanol + 17% Tween 80. It was diluted 500 times with water before administration. Prior to administration, the animals were anesthetized with 5% isoflurane using a small animal anesthesia machine (Matrx; VME2) for an anesthesia time of 1.5 to 2 minutes. After guinea pig anesthesia, the guinea pigs were fixed on an tracheal intubation operating platform and intratracheally administered using a rat liquid aerosol administration kit (penn-century; MSA-250-R), and each guinea pig was administered with a volume of 250 μl. After administration, the guinea pig enhanced exhalation pause (PenH) value was measured using a full volume oximeter (DSI; GS220A12-R7B) at 4 hours and 24 hours. 3 mg/ml methacholine (Mch) was administered by nebulization, the atomization time was 36 seconds, and the recording time was 7 minutes. Calculate the PenH average. (Reference J Pharmacol Exp Ther 345: 260-270.). The experimental results are shown in Table 3.

PenH计算公式：PenH＝PEP/PIP*Pause；Pause＝(Te-Tr)/Tr；Te：呼气相时间(s)；Tr：松弛相时间(s)；PEP：呼气峰流速(ml/s)；PIP：吸气峰流速(ml/s)PenH calculation formula: PenH=PEP/PIP*Pause; Pause=(Te-Tr)/Tr; Te: expiratory time (s); Tr: relaxation phase time (s); PEP: expiratory peak flow rate (ml/ s); PIP: inspiratory peak flow rate (ml/s)

表3化合物对乙酰甲胆碱诱导的豚鼠支气管收缩抑制作用结果Table 3 results of inhibition of methacholine-induced bronchial contraction in guinea pigs

结论：本发明化合物对乙酰甲胆碱诱导的豚鼠支气管收缩抑制作用优于阳性对照，且在给药24小时后，部分化合物仍具有良好的支气管收缩抑制效果。 Conclusion: The compounds of the present invention have a better inhibitory effect on methacholine-induced bronchial contraction in guinea pigs than the positive control, and some compounds still have a good bronchoconstriction inhibitory effect after 24 hours of administration.

Claims

一种通式(I)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药：A compound of the formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof:

其中：among them:

a选自0、1、2、3、4或5；a is selected from 0, 1, 2, 3, 4 or 5;

b选自0、1、2、3或4；b is selected from 0, 1, 2, 3 or 4;

c选自0、1或2；c is selected from 0, 1 or 2;

d或e各自独立选自0或1；d or e are each independently selected from 0 or 1;

R¹、R²每个各自独立的选自F、Cl、Br、I、CF₃、氰基、C_1-4烷基、C_2-4烯基、C_2-4炔基、C_3-6环烷基、-OR^1a、-C(O)OR^1b、-SR^1c、-S(＝O)R^1d、-S(＝O)₂R^1e或-NR^1fR^1g；R ¹ and R ² are each independently selected from the group consisting of F, Cl, Br, I, CF ₃ , cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _{3- 6} cycloalkyl, -OR ^1a , -C(O)OR ^1b , -SR ^1c , -S(=O)R ^1d , -S(=O) ₂ R ^1e or -NR ^1f R ^1g ;

R^1a、R^1b、R^1c、R^1d、R^1e、R^1f和R^1g各自独立的选自H或C_1-4烷基；R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f and R ^1g are each independently selected from H or C _1-4 alkyl;

W选自-O-、-NH-或者-NC_1-4烷基-；W is selected from -O-, -NH- or -NC _1-4 alkyl-;

环A选自
且N对位的碳原子与W直接相连，所述的
任选进一步被0至5个选自F、Cl、Br、I、CF₃、OH、氰基、C_1-4烷基或C_1-4烷氧基的取代基所取代；Ring A is selected from
And the N-position carbon atom is directly connected to W, said
Optionally further substituted with 0 to 5 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , OH, cyano, C _1-4 alkyl or C _1-4 alkoxy;

Q选自键、-O-、-C(＝O)-、-C(＝O)NR^q-、-NR^qC(＝O)-、-OC(＝O)NR^q-或-NR^qC(＝O)O-；Q is selected from a bond, -O-, -C(=O)-, -C(=O)NR ^q -, -NR ^q C(=O)-, -OC(=O)NR ^q - or -NR ^q C(=O)O-;

R^q各自独立的选自H、C_1-4烷基或C_3-6环烷基；R ^{q is} independently selected from H, C _1-4 alkyl or C _3-6 cycloalkyl;

环B选自C_6-12碳环或5至12元杂环，所述的碳环或杂环可以是单环，也可以是双环，所述的碳环或杂环任选进一步被0至5个选自F、Cl、Br、I、CF₃、＝O、OH、氰基、NH₂、C_1-4烷基、C_1-4烷氧基或C_2-4炔基的取代基所取代，且所述的杂环含有1至3个任选自N、O或S的杂原子；Ring B is selected from a C _6-12 carbocyclic ring or a 5 to 12 membered heterocyclic ring, and the carbocyclic or heterocyclic ring may be a monocyclic ring or a bicyclic ring, and the carbocyclic or heterocyclic ring may be further further 0 to 5 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , =O, OH, cyano, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy or C _2-4 alkynyl Substituted, and the heterocyclic ring contains 1 to 3 heteroatoms selected from N, O or S;

环C选自4至10元的含氮杂环，所述的含杂氮杂任选进一步被0至5个选自R^c的取代基所取代，且所述含氮杂环含有1至3个任选自N、O或S的杂原子；Ring C is selected from a 4 to 10 membered nitrogen-containing heterocyclic ring, and said aza-containing heterocyclic ring is optionally further substituted with 0 to 5 substituents selected from R ^c , and said nitrogen-containing heterocyclic ring contains 1 to 3 a hetero atom selected from N, O or S;

R^c各自独立的选自＝O、F、Cl、Br、I、CF₃、OH、氰基、NH₂、C_1-4烷基、C_3-6环烷基、C_1-4烷氧基、C_1-4烷硫基、-C(＝O)-C_1-4烷基、-NHC_1-4烷基或-N(C_1-4烷基)₂； R ^{c is} independently selected from the group consisting of =O, F, Cl, Br, I, CF ₃ , OH, cyano, NH ₂ , C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 alkoxy a group, C _1-4 alkylthio, -C(=O)-C _1-4 alkyl, -NHC _1-4 alkyl or -N(C _1-4 alkyl) ₂ ;

R³各自独立的选自OH、C_1-4烷基、C_3-6环烷基、C_1-4烷氧基、-NR^3aR^3b或-C_1-4烷基-NR^3aR^3b；R ^{3 is} independently selected from OH, C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, -NR ^3a R ^3b or -C _1-4 alkyl-NR ^3a R ^3b ;

R^3a、R^3b各自独立的选自H、C_1-4烷基或C_3-6环烷基；R ^3a and R ^3b are each independently selected from H, C _1-4 alkyl or C _3-6 cycloalkyl;

作为选择，R^3a、R^3b与其连接的原子一起形成一个3至6元的含氮杂环，或者R^3a与R^c直接相连形成一个3至6元的含氮杂环；Alternatively, R ^3a , R ^3b together with the atoms to which they are attached form a 3 to 6 membered nitrogen-containing heterocyclic ring, or R ^3a is directly bonded to R ^c to form a 3 to 6 membered nitrogen-containing heterocyclic ring;

条件是，当环A选自
且环B选自苯环或单环杂环，同时R³选自-NR^3aR^3b，R^3a与R^c不直接相连形成一个3至6元的含氮杂环时，环C不能为
q选自0、1、2或3。Condition is when ring A is selected from
And ring B is selected from a benzene ring or a monocyclic hetero ring, and R ^{3 is} selected from -NR ^3a R ^3b , and when R ^3a and R ^{c are} not directly bonded to form a 3 to 6 membered nitrogen-containing hetero ring, ring C cannot be
q is selected from 0, 1, 2 or 3.
根据权利要求1所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，其中该化合物选自通式(II)所示的化合物：The compound according to claim 1 or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein the compound is selected from the group consisting of the formula (II) Compound:

a、b、c、d、e、R¹、R²、W、环A、Q、R³的定义与权利要求1一致；The definitions of a, b, c, d, e, R ¹ , R ² , W, ring A, Q, R ³ are consistent with claim 1;

环C选自

所述的

任选进一步被0至5个选自R^c的取代基所取代；Ring C is selected from

Said

Optionally further substituted with 0 to 5 substituents selected from R ^c ;

R^c各自独立的选自＝O、F、Cl、Br、I、CF₃、OH、氰基、NH₂、C_1-4烷基、C_3-6环烷基、 C_1-4烷氧基、C_1-4烷硫基、-C(＝O)-C_1-4烷基、-NHC_1-4烷基或-N(C_1-4烷基)₂；R ^{c is} independently selected from the group consisting of =O, F, Cl, Br, I, CF ₃ , OH, cyano, NH ₂ , C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 alkoxy a group, C _1-4 alkylthio, -C(=O)-C _1-4 alkyl, -NHC _1-4 alkyl or -N(C _1-4 alkyl) ₂ ;

Ar¹选自苯环、噻吩环、呋喃环或吡咯环，所述的苯环、噻吩环、呋喃环或吡咯环任选进一步被0至4个选自F、Cl、Br、I、CF₃、OH、氰基、NH₂、C_1-4烷基、C_1-4烷氧基或C_2-4炔基的取代基所取代；Ar ^{1 is} selected from a benzene ring, a thiophene ring, a furan ring or a pyrrole ring, and the benzene ring, thiophene ring, furan ring or pyrrole ring is optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, CF ₃ Substituted with a substituent of OH, cyano, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy or C _2-4 alkynyl;

作为选择，R^3a、R^3b与其连接的原子一起形成一个3至6元的含氮杂环，或者R^3a与R^c直接相连形成一个3至6元的含氮杂环；Alternatively, R ^3a , R ^3b together with the atoms to which they are attached form a 3 to 6 membered nitrogen-containing heterocyclic ring, or R ^3a is directly bonded to R ^c to form a 3 to 6 membered nitrogen-containing heterocyclic ring;

条件是，当环A选自
且环B选自苯环或单环杂环，同时R³选自-NR^3aR^3b，R^3a与R^c不直接相连形成一个3至6元的含氮杂环时，环C不能为
Condition is when ring A is selected from
And ring B is selected from a benzene ring or a monocyclic hetero ring, and R ^{3 is} selected from -NR ^3a R ^3b , and when R ^3a and R ^{c are} not directly bonded to form a 3 to 6 membered nitrogen-containing hetero ring, ring C cannot be
根据权利要求2所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，其中：A compound according to claim 2, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

W选自-O-、-NH-或-NCH₃-；W is selected from -O-, -NH- or -NCH ₃ -;

环A选自
且N对位的碳原子与W直接相连；Ring A is selected from
And the N-position carbon atom is directly connected to W;

R^q各自独立的选自H、甲基、乙基、丙基、环丙基或者环丁基；R ^{q is} independently selected from H, methyl, ethyl, propyl, cyclopropyl or cyclobutyl;

R^c各自独立的选自＝O、F、Cl、Br、I、CF₃、OH、氰基、NH₂、甲基、乙基、环丙基、环丁基、甲氧基、乙氧基、甲硫基、-C(＝O)CH₃、C(＝O)CH₂CH₃、-NHCH₃、-N(CH₃)₂、-NHCH₂CH₃或-N(CH₂CH₃)₂；R ^{c is} independently selected from the group consisting of =O, F, Cl, Br, I, CF ₃ , OH, cyano, NH ₂ , methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy. , methylthio, -C(=O)CH ₃ , C(=O)CH ₂ CH ₃ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH ₂ CH ₃ or -N(CH ₂ CH ₃ ) ₂ ;

Ar¹选自苯环，所述的苯环任选进一步被0至4个选自F、Cl、Br、I、CF₃、OH、氰基、NH₂、甲基、乙基、甲氧基、乙氧基或乙炔基的取代基所取代；Ar ^{1 is} selected from a benzene ring, and the benzene ring is optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, CF ₃ , OH, cyano, NH ₂ , methyl, ethyl, methoxy. Substituted by a substituent of an ethoxy or ethynyl group;

R³各自独立的选自OH、甲基、乙基、环丙基、环丁基、甲氧基、乙氧基、-NR^3aR^3b、-CH₂-NR^3aR^3b或-CH₂CH₂-NR^3aR^3b；R ^{3 is} independently selected from OH, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, -NR ^3a R ^3b , -CH ₂ -NR ^3a R ^3b or -CH ₂ CH ₂ -NR ^3a R ^3b;

R^3a、R^3b各自独立的选自H、甲基、乙基、环丙基或环丁基；R ^3a and R ^3b are each independently selected from the group consisting of H, methyl, ethyl, cyclopropyl or cyclobutyl;

作为选择，R^3a、R^3b与其连接的原子一起形成一个3至6元的含氮杂环，或者R^3a与R^c直接相连形成一个3至6元的含氮杂环；Alternatively, R ^3a , R ^3b together with the atoms to which they are attached form a 3 to 6 membered nitrogen-containing heterocyclic ring, or R ^3a is directly bonded to R ^c to form a 3 to 6 membered nitrogen-containing heterocyclic ring;

a、b均为0。Both a and b are 0.
根据权利要求1所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，其中该化合物选自通式(III)所示的化合物： The compound according to claim 1 or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein the compound is selected from the group consisting of the formula (III) Compound:

a、b、c、d、e、R¹、R²、W、环A、环C、Q、R³的定义与权利要求1一致；The definitions of a, b, c, d, e, R ¹ , R ² , W, ring A, ring C, Q, R ³ are consistent with claim 1;

环D选自C_4-7碳环或者4至7元杂环，所述的碳环或者杂环任选进一步被0至5个选自F、Cl、Br、I、CF₃、＝O、OH、NH₂、氰基、C_1-4烷基、C_1-4烷氧基或C_2-4炔基的取代基所取代，所述的杂环含有1至3个任选自N、O或S的杂原子；Ring D is selected from a C _4-7 carbocyclic ring or a 4 to 7 membered heterocyclic ring, and the carbocyclic or heterocyclic ring is optionally further further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, CF ₃ , =0, Substituted by a substituent of OH, NH ₂ , cyano, C _1-4 alkyl, C _1-4 alkoxy or C _2-4 alkynyl, said heterocyclic ring containing from 1 to 3, optionally selected from N, a hetero atom of O or S;

R⁴各自独立的选自F、Cl、Br、I、CF₃、OH、NH₂、氰基、C_1-4烷基、C_1-4烷氧基或C_2-4炔基；R ^{4 is} each independently selected from the group consisting of F, Cl, Br, I, CF ₃ , OH, NH ₂ , cyano, C _1-4 alkyl, C _1-4 alkoxy or C _2-4 alkynyl;

作为选择，R^3a、R^3b与其连接的原子一起形成一个3至6元的含氮杂环，或者R^3a与R^c直接相连形成一个3至6元的含氮杂环；Alternatively, R ^3a , R ^3b together with the atoms to which they are attached form a 3 to 6 membered nitrogen-containing heterocyclic ring, or R ^3a is directly bonded to R ^c to form a 3 to 6 membered nitrogen-containing heterocyclic ring;

n选自0、1、2或3。n is selected from 0, 1, 2 or 3.
根据权利要求4所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，其中：A compound according to claim 4, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

环C选自

所述的

任选进一步被0至5个选自R^c的取代基所取代；Ring C is selected from

Said

Optionally further substituted with 0 to 5 substituents selected from R ^c ;

R^c各自独立的选自F、Cl、Br、I、CF₃、OH、氰基、NH₂、C_1-4烷基、C_3-6环烷基、C_1-4烷氧基、C_1-4烷硫基、-NHC_1-4烷基或-N(C_1-4烷基)₂。R ^{c is} independently selected from the group consisting of F, Cl, Br, I, CF ₃ , OH, cyano, NH ₂ , C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, C _1-4 alkylthio, -NHC _1-4 alkyl or -N(C _1-4 alkyl) ₂ .
根据权利要求5所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，其中：A compound according to claim 5, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein:

W选自-O-、-NH-或-NCH₃-； W is selected from -O-, -NH- or -NCH ₃ -;

环A选自
且N对位的碳原子与W直接相连；Ring A is selected from
And the N-position carbon atom is directly connected to W;

R^q各自独立的选自H、甲基、乙基、丙基、环丙基或者环丁基；R ^{q is} independently selected from H, methyl, ethyl, propyl, cyclopropyl or cyclobutyl;

环D选自C_4-7碳环或者4至7元杂环，所述的碳环或者杂环任选进一步被0至5个选自F、Cl、Br、I、CF₃、＝O、OH、氰基、NH₂、甲基、乙基、甲氧基、乙氧基或乙炔基，所述的杂环含有1至3个任选自N、O或S的杂原子；Ring D is selected from a C _4-7 carbocyclic ring or a 4 to 7 membered heterocyclic ring, and the carbocyclic or heterocyclic ring is optionally further further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, CF ₃ , =0, OH, cyano, NH ₂ , methyl, ethyl, methoxy, ethoxy or ethynyl, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, O or S;

R⁴各自独立的选自F、Cl、Br、I、CF₃、OH、氰基、NH₂、甲基、乙基、甲氧基、乙氧基或乙炔基；R ^{4 is} each independently selected from the group consisting of F, Cl, Br, I, CF ₃ , OH, cyano, NH ₂ , methyl, ethyl, methoxy, ethoxy or ethynyl;

R^c各自独立的选自F、Cl、Br、I、CF₃、OH、氰基、NH₂、甲基、乙基、环丙基、环丁基、甲氧基、乙氧基、甲硫基、-NHCH₃、-N(CH₃)₂、-NHCH₂CH₃或-N(CH₂CH₃)₂；R ^{c is} independently selected from the group consisting of F, Cl, Br, I, CF ₃ , OH, cyano, NH ₂ , methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, methylthio a group, -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH ₂ CH ₃ or -N(CH ₂ CH ₃ ) ₂ ;

R³各自独立的选自OH、甲基、乙基、环丙基、环丁基、甲氧基、乙氧基、-NR^3aR^3b、-CH₂-NR^3aR^3b或-CH₂CH₂-NR^3aR^3b；R ^{3 is} independently selected from OH, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, -NR ^3a R ^3b , -CH ₂ -NR ^3a R ^3b or -CH ₂ CH ₂ -NR ^3a R ^3b;

R^3a、R^3b各自独立的选自H、甲基、乙基、环丙基或者环丁基；R ^3a and R ^3b are each independently selected from the group consisting of H, methyl, ethyl, cyclopropyl or cyclobutyl;

作为选择，R^3a、R^3b与其连接的原子一起形成一个3至6元的含氮杂环，或者R^3a与R^c直接相连形成一个3至6元的含氮杂环；Alternatively, R ^3a , R ^3b together with the atoms to which they are attached form a 3 to 6 membered nitrogen-containing heterocyclic ring, or R ^3a is directly bonded to R ^c to form a 3 to 6 membered nitrogen-containing heterocyclic ring;

a、b均为0。Both a and b are 0.
根据权利要求1所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，其中该化合物选自通式(IV)所示的化合物：The compound according to claim 1 or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein the compound is selected from the group consisting of the formula (IV) Compound:

a、b、c、d、e、R¹、R²、W、Q、R³的定义与权利要求1一致；The definitions of a, b, c, d, e, R ¹ , R ² , W, Q, R ³ are consistent with claim 1;

Ar²选自苯环、噻吩环、呋喃环或吡咯环，所述的苯环、噻吩环、呋喃环或吡咯环任选进一步被0至4个选自F、Cl、Br、I、CF₃、OH、氰基、NH₂、C_1-4烷基、C_1-4烷氧基或C_2-4炔基的取代基所取代；Ar ^{2 is} selected from a benzene ring, a thiophene ring, a furan ring or a pyrrole ring, and the benzene ring, thiophene ring, furan ring or pyrrole ring is optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, CF ₃ Substituted with a substituent of OH, cyano, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy or C _2-4 alkynyl;

R⁵选自F、Cl、Br、I、CF₃、OH、氰基、NH₂、C_1-4烷基、C_3-6环烷基、C_1-4烷氧基、C_1-4烷硫基、-NHC_1-4烷基或-N(C_1-4烷基)₂；R ^{5 is} selected from the group consisting of F, Cl, Br, I, CF ₃ , OH, cyano, NH ₂ , C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, C _1-4 Alkylthio, -NHC _1-4 alkyl or -N(C _1-4 alkyl) ₂ ;

作为选择，R^3a、R^3b与其连接的原子一起形成一个3至6元的含氮杂环，或者R^3a与R⁵直接相连形成一个3至6元的含氮杂环；Alternatively, R ^3a , R ^3b together with the atoms to which they are attached form a 3 to 6 membered nitrogen-containing heterocyclic ring, or R ^3a is directly bonded to R ⁵ to form a 3 to 6 membered nitrogen-containing heterocyclic ring;

m为0、1、2或3； m is 0, 1, 2 or 3;

f为0、1、2、3、4或5。f is 0, 1, 2, 3, 4 or 5.
根据权利要求7所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，其中：A compound according to claim 7 or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein:

W选自-O-、-NH-或-NCH₃-；W is selected from -O-, -NH- or -NCH ₃ -;

R^q各自独立的选自H、甲基、乙基、丙基、环丙基或环丁基；R ^q is independently selected from H, methyl, ethyl, propyl, cyclopropyl or cyclobutyl;

Ar²选自苯环，所述的苯环任选进一步被0至4个选自F、Cl、Br、I、CF₃、OH、氰基、NH₂、甲基、乙基、甲氧基、乙氧基或乙炔基的取代基所取代；Ar ^{2 is} selected from a benzene ring, and the benzene ring is optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, CF ₃ , OH, cyano, NH ₂ , methyl, ethyl, methoxy. Substituted by a substituent of an ethoxy or ethynyl group;

R³各自独立的选自OH、甲基、乙基、环丙基、环丁基、甲氧基、乙氧基、-NR^3aR^3b、-CH₂-NR^3aR^3b或-CH₂CH₂-NR^3aR^3b；R ^{3 is} independently selected from OH, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, -NR ^3a R ^3b , -CH ₂ -NR ^3a R ^3b or -CH ₂ CH ₂ -NR ^3a R ^3b;

R^3a、R^3b各自独立的选自H、甲基、乙基、环丙基或环丁基；R ^3a and R ^3b are each independently selected from the group consisting of H, methyl, ethyl, cyclopropyl or cyclobutyl;

R⁵选自F、Cl、Br、I、CF₃、OH、氰基、NH₂、甲基、乙基、环丙基、环丁基、甲氧基、乙氧基、甲硫基、-NHCH₃、-N(CH₃)₂、-NHCH₂CH₃或-N(CH₂CH₃)₂；R ^{5 is} selected from the group consisting of F, Cl, Br, I, CF ₃ , OH, cyano, NH ₂ , methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, methylthio, - NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH ₂ CH ₃ or -N(CH ₂ CH ₃ ) ₂ ;

作为选择，R^3a、R^3b与其连接的原子一起形成一个3至6元的含氮杂环，或者R^3a与R⁵直接相连形成一个3至6元的含氮杂环；Alternatively, R ^3a , R ^3b together with the atoms to which they are attached form a 3 to 6 membered nitrogen-containing heterocyclic ring, or R ^3a is directly bonded to R ⁵ to form a 3 to 6 membered nitrogen-containing heterocyclic ring;

a、b均为0。Both a and b are 0.
根据权利要求1所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，其中，所述的化合物选自如下结构之一：The compound according to claim 1 or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein the compound is selected from one of the following structures:
一种药物组合物，所述的药物组合物含有治疗有效剂量的根据利要求1～9中任一项所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，以及药学上可接受的载体、稀释剂、佐剂、媒介物或赋形剂；所述的组合物还可进一步包括一种或多种其他治疗剂。A pharmaceutical composition, which comprises a therapeutically effective amount of a compound according to any one of claims 1 to 9, or a stereoisomer, hydrate, metabolite, solvate thereof, pharmaceutically acceptable Accepted salt, eutectic or prodrug, and a pharmaceutically acceptable carrier, diluent, adjuvant, vehicle or excipient; said composition also One or more additional therapeutic agents can be further included.
根据权利要求10所述的药物组合物，其中所述其他治疗剂选自PDE4抑制剂、蕈毒碱受体拮抗剂、皮质类固醇和β-肾上腺素能受体激动剂中的一种或多种。The pharmaceutical composition according to claim 10, wherein the other therapeutic agent is one or more selected from the group consisting of a PDE4 inhibitor, a muscarinic receptor antagonist, a corticosteroid, and a β-adrenergic receptor agonist. .
权利要求1～9中任一项所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，或权利要求10或11中所述的药物组合物在制备用于治疗气道阻塞性疾病的药物中的应用。A compound according to any one of claims 1 to 9, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, or in claim 10 or Use of the pharmaceutical composition described in the manufacture of a medicament for the treatment of an airway obstructive disease.
权利要求1～9中任一项所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，或权利要求10或11中所述的药物组合物在制备用于治疗哮喘、慢性阻塞性肺疾病或支气管炎的药物中的应用。A compound according to any one of claims 1 to 9, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, or in claim 10 or Use of the pharmaceutical composition described for the manufacture of a medicament for the treatment of asthma, chronic obstructive pulmonary disease or bronchitis.
一种治疗气道阻塞性疾病的方法，所述方法包括给药权利要求1～9中任一项所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，或权利要求10或11所述的药物组合物。A method of treating an airway obstructive disease, the method comprising administering a compound according to any one of claims 1 to 9, or a stereoisomer, hydrate, metabolite, solvate thereof, pharmaceutically acceptable a salt, eutectic or prodrug, or a pharmaceutical composition according to claim 10 or 11.
根据权利要求14所述的治疗气道阻塞性疾病的方法，其中，所述治疗气道阻塞性疾病包括治疗哮喘、慢性阻塞性肺疾病或支气管炎。The method of treating an airway obstructive disease according to claim 14, wherein the treating an airway obstructive disease comprises treating asthma, chronic obstructive pulmonary disease or bronchitis.
一种制备通式(I)、(II)、(III)或(IV)的所示化合物或其立体异构体的中间体，该中间体选自通式(V)所示的化合物或者其立体异构体：An intermediate for the preparation of a compound of the formula (I), (II), (III) or (IV) or a stereoisomer thereof, which is selected from a compound of the formula (V) or a compound thereof Stereoisomers:

a选自0、1、2、3、4或5；a is selected from 0, 1, 2, 3, 4 or 5;

b选自0、1、2、3或4；b is selected from 0, 1, 2, 3 or 4;

R¹、R²每个各自独立的选自F、Cl、Br、I、CF₃、氰基、C_1-4烷基、C_2-4烯基、C_2-4炔基、C_3-6环烷基、-OR^1a、-C(O)OR^1b、-SR^1c、-S(＝O)R^1d、-S(＝O)₂R^1e或-NR^1fR^1g；R ¹ and R ² are each independently selected from the group consisting of F, Cl, Br, I, CF ₃ , cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _{3- 6} cycloalkyl, -OR ^1a , -C(O)OR ^1b , -SR ^1c , -S(=O)R ^1d , -S(=O) ₂ R ^1e or -NR ^1f R ^1g ;

R^1a、R^1b、R^1c、R^1d、R^1e、R^1f和R^1g各自独立的选自H或C_1-4烷基；R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f and R ^1g are each independently selected from H or C _1-4 alkyl;

W选自-O-、-NH-或者-NC_1-4烷基-；W is selected from -O-, -NH- or -NC _1-4 alkyl-;

环A选自
且N对位的碳原子与W直接相连，所述的
任选进一步被0至5个选自F、Cl、Br、I、CF₃、OH、氰基、C_1-4烷基或C_1-4烷氧基的取代基所取代； Ring A is selected from
And the N-position carbon atom is directly connected to W, said
Optionally further substituted with 0 to 5 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , OH, cyano, C _1-4 alkyl or C _1-4 alkoxy;

M选自H、

M is selected from H,

条件是环A选自
M选自
The condition is that ring A is selected from
M is selected from

c选自0、1或2；c is selected from 0, 1 or 2;

Q选自键、-O-、-C(＝O)-、-C(＝O)NR^q-、-NR^qC(＝O)-、-OC(＝O)NR^q-或-NR^qC(＝O)O-；Q is selected from a bond, -O-, -C(=O)-, -C(=O)NR ^q -, -NR ^q C(=O)-, -OC(=O)NR ^q - or -NR ^q C(=O)O-;

R^q各自独立的选自H、C_1-4烷基或C_3-6环烷基；R ^{q is} independently selected from H, C _1-4 alkyl or C _3-6 cycloalkyl;

环D选自C_4-7碳环或者4至7元杂环，所述的碳环或者杂环任选进一步被0至5个选自F、Cl、Br、I、CF₃、＝O、OH、NH₂、氰基、C_1-4烷基、C_1-4烷氧基或C_2-4炔基的取代基所取代，所述的杂环含有1至3个任选自N、O或S的杂原子；Ring D is selected from a C _4-7 carbocyclic ring or a 4 to 7 membered heterocyclic ring, and the carbocyclic or heterocyclic ring is optionally further further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, CF ₃ , =0, Substituted by a substituent of OH, NH ₂ , cyano, C _1-4 alkyl, C _1-4 alkoxy or C _2-4 alkynyl, said heterocyclic ring containing from 1 to 3, optionally selected from N, a hetero atom of O or S;

R⁴各自独立的选自F、Cl、Br、I、CF₃、OH、NH₂、氰基、C_1-4烷基、C_1-4烷氧基或C_2-4炔基；R ^{4 is} each independently selected from the group consisting of F, Cl, Br, I, CF ₃ , OH, NH ₂ , cyano, C _1-4 alkyl, C _1-4 alkoxy or C _2-4 alkynyl;

n选自0、1、2或3；n is selected from 0, 1, 2 or 3;

Ar²选自苯环、噻吩环、呋喃环或吡咯环，所述的苯环、噻吩环、呋喃环或吡咯环任选进一步被0至4个选自F、Cl、Br、I、CF₃、OH、氰基、NH₂、C_1-4烷基、C_1-4烷氧基或C_2-4炔基的取代基所取代；Ar ^{2 is} selected from a benzene ring, a thiophene ring, a furan ring or a pyrrole ring, and the benzene ring, thiophene ring, furan ring or pyrrole ring is optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, CF ₃ Substituted with a substituent of OH, cyano, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy or C _2-4 alkynyl;

R^m选自-CHO、-CH₂OH或者-CH₂OP；R ^{m is} selected from -CHO, -CH ₂ OH or -CH ₂ OP;

P选自羟基保护基。P is selected from a hydroxy protecting group.
根据权利要求16所述的中间体，该中间体任选自如下所示的化合物或者其立体异构体之一：The intermediate according to claim 16, which is selected from the group consisting of a compound shown below or one of its stereoisomers: