CN109721601B

CN109721601B - Preparation and medical application of tetrahydro carboline-tetrahydroisoquinoline compounds

Info

Publication number: CN109721601B
Application number: CN201811266399.2A
Authority: CN
Inventors: 刘站柱; 陈晓光; 鲁向冉; 潘璇; 季鸣; 贯宝和
Original assignee: Institute of Materia Medica of CAMS
Current assignee: Institute of Materia Medica of CAMS
Priority date: 2017-10-27
Filing date: 2018-10-29
Publication date: 2022-09-16
Anticipated expiration: 2038-10-29
Also published as: CN109721601A

Abstract

The invention discloses structural analogues of an anti-tumor marine natural product ecteinascidins. The invention also relates to a pharmaceutical composition containing the compound of the general formula I and a preparation method thereof, and application of the compound and the pharmaceutical composition in the aspect of tumor resistance.

Description

Preparation and medical application of tetrahydro carboline-tetrahydroisoquinoline compounds

Technical Field

The invention relates to the technical field of medicines, and relates to structural analogs of an antitumor marine natural product ecteinascidin, pharmaceutically acceptable salts thereof, and an antitumor preparation containing the compounds and the pharmaceutically acceptable salts thereof.

Background

Cancer is one of malignant diseases seriously harming human health, the number of people died due to cancer is more than 500 million worldwide every year, the incidence of tumors is on the rise year by year in recent years, and the mortality is the first of various diseases. Chemotherapy is a commonly used and effective cancer treatment means in clinic at present, however, due to the multidrug resistance of cancer cells and the serious toxic and side effects of the existing anticancer drugs, a new anticancer drug with good curative effect and light side effects is urgently needed in clinic.

The bis-tetrahydroisoquinoline alkaloid is a natural product family which is composed of more than 60 compounds and has strong antitumor activity, wherein the natural product family comprises ecteinascidins, renieramycins, saframycins and the like, wherein the ecteinascidins are tetrahydroisoquinoline alkaloids which are separated from ascidian Ecteinascidia turbinata and have the strongest antitumor activity in the alkaloids. Among such bis-tetrahydroisoquinoline alkaloids of ecteinascidins, ecteinascidin 743 (abbreviated as Et-743, trade name trabectedin, Yondelis) is the most potent one, and its antitumor activity in vitro is 1-3 orders higher than that of Taxol, Camptothecin, Adriamycin, Mitomycin C, Cisplatin, Bleomycin and Etopside currently used clinically. Has been marketed in germany in 2007 as the first marine drug to be successfully developed for the treatment of advanced soft tissue tumors, and subsequently has also been approved for this indication in the european community. It was marketed in korea in 2008 for the treatment of advanced soft tissue tumors. 11 months of 2009 was approved for the treatment of ovarian cancer in the european community 27 and in three countries, norway, icelandic and liechtenstein.

Because the bistetrahydroisoquinoline natural products have extremely strong antitumor activity, novel and complex chemical structures and unique multiple antitumor mechanisms, and simultaneously have extremely low content in nature (for example, the content of Et-743 in ascidians is only 0.0001%), the medicine is difficult to provide by natural extraction, and the current clinical medicine is provided by semisynthesis through 21 steps of reaction by using Cynosafracin B as a raw material. Therefore, the total synthesis and structural modification of the bis-tetrahydroisoquinoline natural product become the hotspot field of research and development of novel antitumor drugs.

The structure transformation method for the bistetrahydroisoquinoline alkaloid in the world mainly comprises the following three methods:

the first kind of structural modification is to simplify the substituent of the molecular skeleton and summarize the structure-activity relationship of a series of natural products on the premise of keeping the pentacyclic molecular skeleton and the antitumor key pharmacophore, and the specific method can refer to e.j.corey, et al, proc.natl.acad.sci.1999,96,3496; myers, et al, j.am.chem.soc.2001,123, 5114; s.aubry, m.mail, et al, Bioorganic & Medicinal Chemistry letters.2007,17,2598; avendano, et al, Bioorganic & Medicinal Chemistry 2007,15, 112; liu, et al, Bioorganic & Medicinal Chemistry letters.2006,16,1282; liu, et al, European Journal of Medicinal chemistry.2013,62,670.

The second kind of structural modification is to maintain pentacyclic molecular skeleton and antitumor key pharmacophore, change the topological structure of molecular skeleton and summarize its influence on antiedema activity. The change of the configuration of C-1,3,11,13 chiral centers in the pentacyclic skeleton can cause the corresponding change of the topological configuration of the pentacyclic skeleton, thereby affecting the antitumor activity of the pentacyclic skeleton. The literature z.z.liu, et al, tetrahedron.2015,71,4296 reports that the dominant conformations are calculated by optimization using the natural product (-) -renieramycin G, whose topological conformations are L-type and 11,13-epi- (+) -renieramycin G and 11,13-epi- (-) -renieramycin G are S-type. In vitro antitumor activity data show that the antitumor activity of the (+) -renieramycin G is equivalent to that of the natural product (-) -renieramycin G and is obviously superior to that of 11,13-epi- (+) -renieramycin G and 11,13-epi- (-) -renieramycin G, so that the topological configuration is an important factor influencing the antitumor effect of (-) -renieramycin G.

The third kind of structural modification idea is to maintain the key antitumor pharmacophore and simplify the pentacyclic skeleton of bis-tetrahydroisoquinoline into tricyclic skeleton containing only one tetrahydroisoquinoline unit. The tricyclic simplifier has simple structure and low synthesis difficulty, and is widely concerned internationally. Document c.avedano, et al, Bioorganic & Medicinal Chemistry 2007,15, 112; avendano, et al, Bioorganic & Medicinal Chemistry,2008,16, 9065; avedano, et al, Bioorganic & Medicinal Chemistry,2010,18, 6813; saito, et al, Tetrahedron,2014,70,6529 successively reported tricyclic simplifications of the bis-tetrahydroisoquinoline natural products, and a potent antitumor compound with a simple structure was sought by simplifying a ring system of the natural product with a complicated molecular skeleton. In vitro activity shows that the activity of the tricyclic simplexes is at the mu M level.

Disclosure of Invention

The technical problem to be solved by the invention is to provide ecteinascidin structural analogs with a general formula I and pharmaceutically acceptable salts thereof;

another technical problem to be solved by the present invention is to provide a pharmaceutical composition comprising a compound of formula I and pharmaceutically acceptable salts thereof;

the invention aims to solve the technical problem of providing the application of the compound shown in the general formula I and the pharmaceutically acceptable salt thereof in preparing the antitumor drugs.

The compound with the general formula I and the pharmaceutically acceptable salt thereof have the structural characteristics that one of the structural characteristics is that the compound has more B rings than natural products, namely ecteinascidins, renieramycins and saframycins; another structural feature of the class of compounds to which the present invention relates is that the carboxylic acid at position 26 is an arylcarboxylic acid, an arylacrylic acid, and a fatty acid.

The chiral centers at 1,3, 14, 16 and 24 positions in the molecules of the compound with the general formula I are consistent with the absolute configuration of related natural product ecteinascidins molecules, and are photoactive.

Wherein R is ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₆ 、R ₇ 、R ₈ Independently of each other selected from: H. halogen, OH, SH, NH ₂ 、COOH、CF ₃ Aldehyde group, carbamoyl group, NO ₂ 、CN、C ₁ -C ₈ Linear or branched alkyl of (2), C ₂ -C ₈ Alkenyl of, C ₂ -C ₈ Alkynyl of (A), C ₆ -C ₈ Aryl of (C) ₄ -C ₈ Heteroaryl of (A), C ₁ -C ₈ Alkoxy group of (a);

R ₉ independently of each other selected from: h, C ₁ -C ₈ Linear or branched alkyl of (2), C ₂ -C ₈ Alkenyl of, C ₂ -C ₈ Alkynyl of (A), C ₆ -C ₈ Aryl of (C) ₄ -C ₈ Heteroaryl of (A), C ₁ -C ₈ Alkyl acyl of (2), C ₁ -C ₈ Sulfonyl group of (A), C ₁ -C ₈ An alkoxyacyl group of (a);

y is selected from CN, OH, halogen, SH, NH ₂ ；

R ₁₀ Is selected from C ₆ -C ₁₀ Aryl of (C) ₄ -C ₁₀ Heteroaryl of (A), C ₆ -C ₁₀ Aryl substituted C ₁ -C ₄ Alkyl radical, C ₄ -C ₁₀ Heteroaryl substituted C ₁ -C ₄ Alkyl radical, C ₆ -C ₁₀ Aryl substituted C ₀ -C ₄ Alkyl vinyl radical, C ₁ -C ₁₀ Linear or branched alkyl of (2), C ₅ -C ₆ A cycloalkyl-and phenyl group; these aryl, heteroaryl, C ₅ -C ₆ The cycloalkylphenyl group may have one or more substituents selected from H, OH, SH, NH ₂ 、COOH、CF ₃ Aldehyde group, carbamoyl group, halogen, NO ₂ 、CN、C ₁ -C ₈ Straight-chain or branched alkyl, C ₁ -C ₈ Alkoxy radical, C ₁ -C ₈ Alkylamino radical, C ₁ -C ₈ Alkoxy C ₁ -C ₈ Alkyl, C ₂ -C ₈ Alkenyl radical, C ₂ -C ₈ Alkynyl, C ₆ -C ₈ Aryl of (C) ₄ -C ₈ The heterocyclic aryl group of (a);

x is selected from O, NH, S, CH ₂ N; when X is selected from N, N is directly related to R ₁₁ Are connected to form C ₆ -C ₁₀ Aryl five-membered dicarboximide ring or C ₄ -C ₁₀ A heteroaryl and five membered dicarboximide ring; these aryl and heteroaryl groups may have one or more substituents selected from H, OH, SH, NH ₂ 、COOH、CF ₃ Aldehyde group, carbamoyl group, halogen, NO ₂ 、CN、C ₁ -C ₃ Straight-chain or branched alkyl, C ₁ -C ₃ Alkoxy radical, C ₁ -C ₃ Alkylamino radical, C ₁ -C ₃ Alkoxy C ₁ -C ₃ Alkyl radical, C ₂ -C ₃ Alkenyl radical, C ₂ -C ₃ Alkynyl.

Preferred R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₆ 、R ₇ 、R ₈ Independently of each other selected from: H. halogen, OH, SH, NH ₂ 、COOH、CF ₃ Aldehyde group, carbamoyl group, NO ₂ 、CN、C ₁ -C ₆ Linear or branched alkyl of (2), C ₂ -C ₆ Alkenyl of, C ₂ -C ₆ Alkynyl of (A), C ₆ -C ₈ Aryl of (C) ₄ -C ₈ Heteroaryl of (A), C ₁ -C ₆ Alkoxy group of (a);

R ₉ independently of each other, are selected from: h, C ₁ -C ₆ Linear or branched alkyl of (2), C ₂ -C ₆ Alkenyl of, C ₂ -C ₆ Alkynyl of (A), C ₆ -C ₈ Aryl of (C) ₄ -C ₈ Heteroaryl of (A), C ₁ -C ₆ Alkyl acyl of (2), C ₁ -C ₆ Sulfonyl group of (A), C ₁ -C ₆ An alkoxyacyl group of (a);

y is selected from CN, OH, halogen, SH, NH ₂ ；

R ₁₀ Is selected from C ₆ -C ₁₀ Aryl of (C) ₄ -C ₁₀ Heteroaryl of (A), C ₆ -C ₁₀ Aryl substituted C ₁ -C ₂ Alkyl radical, C ₄ -C ₁₀ Heteroaryl substituted C ₁ -C ₂ Alkyl radical, C ₆ -C ₈ Aryl substituted C ₀ -C ₂ Alkyl vinyl radical, C ₁ -C ₆ Linear or branched alkyl of (2), C ₅ -C ₆ A cycloalkyl-and phenyl group; these aryl, heteroaryl, C ₅ -C ₆ The cycloalkylphenyl group may have one or more substituents selected from H, OH, SH, NH ₂ 、COOH、CF ₃ Aldehyde group, carbamoyl group, halogen, NO ₂ 、CN、C ₁ -C ₆ Straight-chain or branched alkyl, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₆ Alkylamino radical, C ₁ -C ₆ Alkoxy C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₆ -C ₈ Aryl of (C) ₄ -C ₈ The heterocyclic aryl group of (1);

x is selected from O, NH, CH ₂ N; when X is selected from N, N is directly related to R ₁₁ Are connected to form C ₆ -C ₁₀ Aryl and five-membered dicarboximide ring of (A) or (C) ₄ -C ₁₀ The heteroaryl and five membered dicarboximide ring of (a); these aryl and heteroaryl groups may have one or more substituents selected from the group consisting of H, OH, SH, NH ₂ 、COOH、CF ₃ Aldehyde group, carbamoyl group, halogen, NO ₂ 、CN、C ₁ -C ₃ Straight-chain or branched alkyl, C ₁ -C ₃ Alkoxy radical, C ₁ -C ₃ Alkylamino radical, C ₁ -C ₃ Alkoxy C ₁ -C ₃ Alkyl radical, C ₂ -C ₃ Alkenyl radical, C ₂ -C ₃ Alkynyl.

More preferred R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₆ 、R ₇ 、R ₈ Independently of each other selected from: H. halogen, OH, SH, NH ₂ 、COOH、CF ₃ Aldehyde group, carbamoyl group, NO ₂ 、CN、C ₁ -C ₄ Linear or branched alkyl of (2), C ₂ -C ₄ Alkenyl of, C ₂ -C ₄ Alkynyl of (A), C ₆ -C ₈ Aryl of (C) ₄ -C ₈ Heteroaryl of (A), C ₁ -C ₄ Alkoxy group of (a);

R ₉ independently of each other selected from: h, C ₁ -C ₄ Linear or branched alkyl of (2), C ₂ -C ₄ Alkenyl of, C ₂ -C ₄ Alkynyl of (A), C ₆ -C ₈ Aryl of (C) ₄ -C ₈ Heteroaryl of (A), C ₁ -C ₄ Alkyl acyl of (2), C ₁ -C ₄ Sulfonyl group of (A), C ₁ -C ₄ An alkoxyacyl group of (a);

y is selected from CN, OH, halogenElement, SH, NH ₂ ；

R ₁₀ Is selected from C ₆ -C ₁₀ Aryl of (C) ₄ -C ₁₀ Heteroaryl of (A), C ₆ -C ₁₀ Aryl substituted C ₁ -C ₂ Alkyl radical, C ₄ -C ₁₀ Heteroaryl substituted C ₁ -C ₂ Alkyl radical, C ₆ -C ₈ Aryl substituted C ₀ -C ₂ Alkyl vinyl radical, C ₁ -C ₄ Linear or branched alkyl of (2), C ₅ -C ₆ A cycloalkyl-and phenyl group; the aryl is as follows: phenyl, naphthyl; the heteroaryl is as follows: furyl, thienyl, pyridyl, quinolyl, indolyl, benzothienyl, benzofuryl; said C ₅ -C ₆ Cycloalkyl-and phenyl radicals such as: tetrahydronaphthyl; these aryl, heteroaryl, C ₅ -C ₆ The cycloalkylphenyl group may have one or more substituents selected from H, OH, SH, NH ₂ 、COOH、CF ₃ Aldehyde group, carbamoyl group, halogen, NO ₂ 、CN、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Alkylamino radical, C ₁ -C ₄ Alkoxy C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkenyl radical, C ₂ -C ₄ Alkynyl, C ₆ -C ₈ Aryl of (C) ₄ -C ₈ The heterocyclic aryl group of (a);

x is selected from O, NH, CH ₂ N; when X is selected from N, N is directly related to R ₁₁ Are connected to form C ₆ -C ₁₀ Aryl and five-membered dicarboximide ring of (1) or C ₄ -C ₁₀ The heteroaryl and five membered dicarboximide ring of (a); these aryl and heteroaryl groups may have one or more substituents selected from the group consisting of H, OH, SH, NH ₂ 、COOH、CF ₃ Aldehyde group, carbamoyl group, halogen, NO ₂ 、CN、C ₁ -C ₃ Straight-chain or branched alkyl, C ₁ -C ₃ Alkoxy radical, C ₁ -C ₃ Alkylamino radical, C ₁ -C ₃ Alkoxy C ₁ -C ₃ Alkyl radical, C ₂ -C ₃ Alkenyl radical, C ₂ -C ₃ Alkynyl.

Most preferred R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₆ 、R ₇ 、R ₈ Independently of each other selected from: H. halogen, OH, SH, NH ₂ 、COOH、CF ₃ Aldehyde group, carbamoyl group, NO ₂ CN, methyl, ethyl, ethenyl, ethynyl, C ₆ -C ₈ Aryl of (C) ₄ -C ₈ Heteroaryl of (A), C ₁ -C ₂ Alkoxy group of (a);

R ₉ independently of each other, are selected from: h, methyl, ethyl, ethenyl, ethynyl, C ₆ -C ₈ Aryl of (C) ₄ -C ₈ Heteroaryl of (A), C ₁ -C ₂ Alkyl acyl of (2), C ₁ -C ₂ Sulfonyl group of (A), C ₁ -C ₂ An alkoxyacyl group of (a);

y is selected from CN, OH, halogen, SH, NH ₂ ；

R ₁₀ Is selected from C ₆ -C ₁₀ Aryl of (C) ₄ -C ₁₀ Heteroaryl of (A), C ₆ -C ₁₀ Aryl substituted C ₁ -C ₂ Alkyl radical, C ₄ -C ₁₀ Heteroaryl substituted C ₁ -C ₂ Alkyl radical, C ₆ -C ₈ Aryl substituted C ₀ -C ₂ Alkyl vinyl radical, C ₁ -C ₄ Linear or branched alkyl of (2), C ₅ -C ₆ A cycloalkyl-and phenyl group; the aryl is as follows: phenyl, naphthyl; the heteroaryl is as follows: furyl, thienyl, pyridyl, quinolyl, indolyl, benzothienyl, benzofuryl; said C ₅ -C ₆ Cycloalkylacenyl radicals are, for example: a tetrahydronaphthyl group; these aryl, heteroaryl, C ₅ -C ₆ The cycloalkylphenylphenyl group may have one or more substituents selected from H, OH, SH, NH ₂ 、COOH、CF ₃ Aldehyde group, carbamoyl group, halogen, NO ₂ 、CN、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Alkyl radicalAmino group, C ₁ -C ₄ Alkoxy C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkenyl radical, C ₂ -C ₄ Alkynyl, C ₆ -C ₈ Aryl of (C) ₄ -C ₈ The heterocyclic aryl group of (a);

x is selected from O, NH, CH ₂ N; when X is selected from N, N is directly related to R ₁₁ Are connected to form C ₆ -C ₁₀ Aryl and five-membered dicarboximide ring of (A) or (C) ₄ -C ₁₀ The heteroaryl and five membered dicarboximide ring of (a); these aryl and heteroaryl groups may have one or more substituents selected from H, OH, SH, NH ₂ 、COOH、CF ₃ Aldehyde group, carbamoyl group, halogen, NO ₂ 、CN、C ₁ -C ₃ Straight-chain or branched alkyl, C ₁ -C ₃ Alkoxy radical, C ₁ -C ₃ Alkylamino radical, C ₁ -C ₃ Alkoxy C ₁ -C ₃ Alkyl radical, C ₂ -C ₃ Alkenyl radical, C ₂ -C ₃ Alkynyl.

Most preferred inventive compounds are selected from the following group:

R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₆ 、R ₇ 、R ₈ independently of each other selected from: H. halogen, OH, SH, NH ₂ COOH, aldehyde group, carbamoyl group, NO ₂ 、CN、-CH ₃ 、-C ₂ H ₅ 、-OCH ₃ ；

R ₉ Independently of each other, are selected from: h, -CH ₃ 、-COCH ₃ 、-COOC(CH ₃ ) ₃ ；

Y is selected from CN and OH;

x is selected from O, NH and N; when X is selected from N, N is directly related to R ₁₁ Are connected to form C ₆ -C ₁₀ Aryl and five-membered dicarboximide ring of (A) or (C) ₄ -C ₁₀ The heteroaryl and five membered dicarboximide ring of (a); these aryl and heteroaryl groups may have one or more substituents selected from H, OH, SH, NH ₂ 、COOH、CF ₃ Aldehyde group, carbamoyl group, halogen, NO ₂ 、CN、C ₁ -C ₃ Straight-chain or branched alkyl, C ₁ -C ₃ Alkoxy radical, C ₁ -C ₃ Alkylamino radical, C ₁ -C ₃ Alkoxy C ₁ -C ₃ Alkyl radical, C ₂ -C ₃ Alkenyl radical, C ₂ -C ₃ Alkynyl. R ₁₀ May be taken from the following groups, respectively:

1. phenyl-: the substituents on the benzene ring may be one or more; for example, the benzene ring may be mono-substituted, di-substituted or tri-substituted; the substitution position on the monosubstituted benzene ring is 2-, 3-or 4-position; the position of the substituent on the disubstituted benzene ring is 2, 4-, 3,4-, 2, 3-or 3, 4-; the substitution position of the trisubstituted benzene ring is 2,3, 4-or 3,4, 5-position; these substituents are each independently selected from the following substituents:

H、OH、SH、NH ₂ 、COOH、CF ₃ aldehyde group, carbamoyl group, F, Cl, Br, I, NO ₂ 、CN、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Alkylamino radical, C ₁ -C ₄ Alkoxy C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkenyl radical, C ₂ -C ₄ An alkynyl group; when the substituents on the disubstituted benzene ring are adjacent positions, two adjacent substituents may be bonded to each other to form C ₅ -C ₆ A cycloalkylo-phenyl group, the substituent being selected from-CH ₂ CH ₂ -、-CH ₂ -. Such as: tetrahydronaphthyl.

2. 2-pyridyl group: the substituents on the 2-pyridine ring may be one or more; for example, the pyridine ring may be mono-or di-substituted; the positions of the substituent on the monosubstituted pyridine ring are 4-position and 6-position; the positions of the substituents on the disubstituted pyridine ring are 3, 5-, 3, 4-and 3, 6-positions, and the substituents are respectively independent and selected from the following substituents:

H、OH、SH、NH ₂ 、COOH、CF ₃ aldehyde group, carbamoyl group, F, Cl, Br, I, NO ₂ 、CN、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Alkylamino radical, C ₁ -C ₄ Alkoxy C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkenyl radical, C ₂ -C ₄ An alkynyl group;

3. 4-pyridyl group: the substituents on the 4-pyridine ring may be one or more; for example, the pyridine ring may be mono-or di-substituted; the positions of the substituent on the monosubstituted pyridine ring are 2-and 3-positions; the positions of the substituent groups on the disubstituted pyridine ring are 2,3-, 3, 5-and 2, 6-positions, and the substituent groups are respectively independent and are selected from the following substituent groups:

4. 3-pyridyl group: the substituents on the 3-pyridine ring may be one or more; for example, the pyridine ring may be mono-or di-substituted; the 2-, 4-, 5-and 6-positions of the substituent on the monosubstituted pyridine ring; the positions of the substituent groups on the disubstituted pyridine ring are 4, 6-positions and 5, 6-positions, and the substituent groups are respectively independent and are selected from the following substituent groups:

5.α -naphthyl group: the substituents on the α -naphthyl ring may be one or more; for example, a single substituent at the 4-, 5-, or 8-position on the naphthalene ring; the disubstituted group is 4, 5-, 4, 8-or 5, 8-position on naphthalene ring, and the substituents are respectively independent and selected from the following substituents:

6.β -naphthyl group: the substituents on the β -naphthyl ring may be one or more; for example, a single substituent at the 1-, 4-, 5-, or 8-position on the naphthalene ring; the disubstituted group is 1, 4-, 4, 5-, 4, 8-or 5, 8-position on the naphthalene ring, and the substituted groups are respectively independent and are selected from the following substituted groups:

H、OH、SH、NH ₂ 、COOH、CF ₃ aldehyde group, carbamoyl group, F, Cl, Br, I, NO ₂ 、CN、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ Alkoxy radical、C ₁ -C ₄ Alkylamino radical, C ₁ -C ₄ Alkoxy C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkenyl radical, C ₂ -C ₄ An alkynyl group;

7. 4-quinolyl group: the substituents on the 4-quinoline ring may be one or more; for example, a single substituent at the 2-, 5-, 6-, 7-, or 8-position on the quinoline ring; the disubstituted group is a5, 6-, 5, 7-, 5, 8-or 6, 7-position on a quinoline ring, and the substituted groups are respectively independent and are selected from the following substituted groups:

8. 3-quinolyl group: the substituents on the 3-quinoline ring may be one or more; for example, a single substituent at the 2-, 4-, 5-, 6-, 7-, or 8-position of the quinoline ring; the disubstituted group is a5, 6-, 5, 7-, 5, 8-or 6, 7-position on a quinoline ring, and the substituted groups are respectively independent and are selected from the following substituted groups:

9. 2-quinolyl group: the substituents on the 2-quinoline ring may be one or more; for example, a single substituent at the 3-, 4-, 5-, 6-, 7-, or 8-position of the quinoline ring; the disubstituted group is a5, 6-, 5, 7-, 5, 8-or 6, 7-position on a quinoline ring, and the substituted groups are respectively independent and are selected from the following substituted groups:

10. 3-indolyl group: the substituents on the 3-indole ring may be one or more; for example, a single substituent at the 2-, 4-, 5-, 6-, or 7-position of the indole ring; the disubstituent is 4, 5-, 5, 6-, 5, 7-, 4, 6-, 4, 7-or 6, 7-position on indole ring, and the substituent is independently selected from the following substituent groups:

H、OH、SH、NH ₂ 、COOH、CF ₃ aldehyde group, carbamoyl group, F, Cl, Br, I, NO ₂ 、CN、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Alkylamino radical, C ₁ -C ₄ Alkoxy C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkenyl radical, C ₂ -C ₄ An alkynyl group; r' is H, C ₁ -C ₄ Straight or branched chain alkyl.

11. 2-indolyl group: the substituents on the 2-indole ring may be one or more; for example, a single substituent at the 3-, 4-, 5-, 6-, or 7-position of the indole ring; the disubstituent is 4, 5-, 5, 6-, 5, 7-, 4, 6-, 4, 7-or 6, 7-position on indole ring, and the substituent is independently selected from the following substituent groups:

12. 2-benzofuranyl: the substituents on the 2-benzofuran ring may be one or more; for example, a single substituent at the 3-, 4-, 5-, 6-, or 7-position of the benzofuran ring; the disubstituent is 4, 5-, 5, 6-, 5, 7-, 4, 6-, 4, 7-or 6, 7-position on benzofuran ring, and the substituent is independently selected from the following substituent groups:

13. 3-benzofuranyl: the substituents on the 3-benzofuran ring may be one or more; for example, a single substituent at the 2-, 4-, 5-, 6-, or 7-position of the benzofuran ring; the disubstituent is 4, 5-, 5, 6-, 5, 7-, 4, 6-, 4, 7-or 6, 7-position on benzofuran ring, and the substituent is independently selected from the following substituent groups:

14. 2-benzothienyl: the substituents on the 2-benzothiophene ring may be one or more; for example, a single substituent at the 3-, 4-, 5-, 6-, or 7-position of the benzothiophene ring; the disubstituent is 4, 5-, 5, 6-, 5, 7-, 4, 6-, 4, 7-or 6, 7-position on benzothiophene ring, and the substituent is selected from the following substituent groups:

15. 3-benzothienyl: the substituents on the 3-benzothiophene ring can be one or more; for example, a single substituent at the 2-, 4-, 5-, 6-, or 7-position of the benzothiophene ring; the disubstituent is 4, 5-, 5, 6-, 5, 7-, 4, 6-, 4, 7-or 6, 7-position on benzothiophene ring, and the substituent is selected from the following substituent groups:

16. 2-furyl group: the substituents on the 2-furan ring may be one or more; for example, a single substituent at the 3-, 4-, or 5-position of the furan ring; the disubstituted group is a3, 4-, 3, 5-or 4, 5-position on the furan ring, and the substituted groups are respectively independent and are selected from the following substituted groups: H. OH, SH, NH ₂ 、COOH、CF ₃ Aldehyde group, carbamoyl group, F, Cl, Br, I, NO ₂ 、CN、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Alkylamino radical, C ₁ -C ₄ Alkoxy C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkenyl radical, C ₂ -C ₄ An alkynyl group;

17. 3-furyl group: the substituent on the 3-furan ring may be one or more; for example, a single substituent at the 2-, 4-, or 5-position of the furan ring; the disubstituted group is 2, 4-, 2, 5-or 4, 5-position on furan ring, and the substituents are respectively independent and selected from the following substituents: H. OH, SH, NH ₂ 、COOH、CF ₃ Aldehyde group, carbamoyl group, F, Cl, Br, I, NO ₂ 、CN、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Alkylamino radical, C ₁ -C ₄ Alkoxy C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkenyl radical, C ₂ -C ₄ An alkynyl group;

18. 2-thienyl: the substituents on the 2-thiophene ring may be one or more; for example, a single substituent at the 3-, 4-, or 5-position of the thiophene ring; the disubstituted group is a3, 4-, 3, 5-or 4, 5-position on the thiophene ring, and the substituents are respectively independent and are selected from the following substituents: H. OH, SH, NH ₂ 、COOH、CF ₃ Aldehyde group, carbamoyl group, F, Cl, Br, I, NO ₂ 、CN、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Alkylamino radical, C ₁ -C ₄ Alkoxy C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkenyl radical, C ₂ -C ₄ An alkynyl group;

19. 3-thienyl: the substituents on the 3-thiophene ring may be one or more; for example, a single substituent at the 2-, 4-, or 5-position of the thiophene ring; the disubstituent is 2, 4-, 2, 5-or 4, 5-position on thiophene ring, and the substitutents are respectively independent and selected from the following substitutents: H. OH, SH, NH ₂ 、COOH、CF ₃ Aldehyde group, carbamoyl group, F, Cl, Br, I, NO ₂ 、CN、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Alkylamino radical, C ₁ -C ₄ Alkoxy C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkenyl radical, C ₂ -C ₄ An alkynyl group;

20. styryl-: the alkene carbon-carbon double bond can be in Z-configuration or E-configuration; the substituents on the benzene ring may be one or more; for example, the benzene ring may be mono-substituted, di-substituted or tri-substituted; the substitution position on the mono-substituted benzene ring is 2-, 3-or 4-position; the position of the substituent on the disubstituted benzene ring is 2, 4-, 3,4-, 2, 3-or 3, 4-; the substitution position of the trisubstituted benzene ring is 2,3, 4-or 3,4, 5-position; these substituents are each independently selected from the following substituents:

H、OH、SH、NH ₂ 、COOH、CF ₃ aldehyde group, carbamoyl group, F, Cl, Br, I, NO ₂ 、CN、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Alkylamino radical, C ₁ -C ₄ Alkoxy C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkenyl radical, C ₂ -C ₄ An alkynyl group; when the position of the substituent on the disubstituted benzene ring is 2, 3-or 3,4-, two adjacent substituents can be mutually connected to form a five-membered ring or a six-membered ring, and the substituent is selected from-CH ₂ CH ₂ -、-CH ₂ -。

21. Alkyl-: c ₁ -C ₄ Linear or branched alkyl of (a); for example, methyl, ethyl, isopropyl, tert-butyl, and the like.

Most preferred compounds of formula I include, but are not limited to, compounds represented by I C

Said

Selected from phenyl, pyridyl, furyl, thienyl, naphthyl, quinolyl, indolyl, benzofuryl, benzothienyl, styryl, C ₁ -C ₆ Linear or branched alkyl of (a);

R ₁₃ represents one or more substituents which may be substituted or unsubstituted

Attached at any suitable position, and the substituents are independently selected from H, OH, SH, NH ₂ COOH, aldehyde group, carbamoyl group, halogen, NO ₂ 、CN、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Alkylamino radical, C ₁ -C ₄ Alkoxy C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkenyl radical, C ₂ -C ₄ Alkynyl. Most preferred compounds of formula I C include, but are not limited to, the compounds of formula I C1

R ₁₃₁ Selected from H, OH, SH, NH ₂ 、COOH、CF ₃ Aldehyde group, carbamoyl group, F, Cl, Br, I, NO ₂ 、CN、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Alkylamino radical, C ₁ -C ₄ Alkoxy C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkenyl radical, C ₂ -C ₄ An alkynyl group; when the substituents on the disubstituted benzene ring are adjacent positions, two adjacent substituents may be bonded to each other to form C ₅ -C ₆ A cycloalkylo-phenyl group, the substituent being selected from-CH ₂ CH ₂ -、-CH ₂ -. Such as: tetrahydronaphthyl.

Most preferred compounds of formula I C include, but are not limited to, the compounds of formula I C2

R ₁₃₂ Selected from H, OH, SH, NH ₂ 、COOH、CF ₃ Aldehyde group, carbamoyl group, F, Cl, Br, I, NO ₂ 、CN、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Alkylamino radical, C ₁ -C ₄ Alkoxy C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkenyl radical, C ₂ -C ₄ Alkynyl.

Most preferred compounds of formula I C include, but are not limited to, the compounds of formula I C3

R ₁₃₃ Selected from H, OH, SH, NH ₂ 、COOH、CF ₃ Aldehyde group, carbamoyl group, F, Cl, Br, I, NO ₂ 、CN、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Alkylamino radical, C ₁ -C ₄ Alkoxy C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkenyl radical, C ₂ -C ₄ Alkynyl.

Most preferred compounds of formula I C include, but are not limited to, compounds represented by formula I C4

R ₁₃₄ Selected from H, OH, SH, NH ₂ 、COOH、CF ₃ Aldehyde group, carbamoyl group, F, Cl, Br, I, NO ₂ 、CN、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Alkylamino radical, C ₁ -C ₄ Alkoxy C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkenyl radical, C ₂ -C ₄ Alkynyl.

Most preferred compounds of formula I C include, but are not limited to, the compounds of formula I C5

R ₁₃₅ Selected from H, OH, SH, NH ₂ 、COOH、CF ₃ Aldehyde group, carbamoyl group, F, Cl, Br, I, NO ₂ 、CN、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Alkylamino radical, C ₁ -C ₄ Alkoxy C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkenyl radical, C ₂ -C ₄ Alkynyl.

Most preferred compounds of formula I C include, but are not limited to, the compounds of formula I C6

R ₁₃₆ Selected from H, OH, SH, NH ₂ 、COOH、CF ₃ Aldehyde group, carbamoyl group, F, Cl, Br, I, NO ₂ 、CN、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Alkylamino radical, C ₁ -C ₄ Alkoxy C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkenyl radical, C ₂ -C ₄ Alkynyl.

Most preferred compounds of formula I C include, but are not limited to, the compounds of formula I C7

R ₁₃₇ Selected from H, OH, SH, NH ₂ 、COOH、CF ₃ Aldehyde group, carbamoyl group, F, Cl, Br, I, NO ₂ 、CN、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Alkylamino radical, C ₁ -C ₄ Alkoxy C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkenyl radical, C ₂ -C ₄ An alkynyl group;

r' is H, C ₁ -C ₄ Straight or branched chain alkyl.

Most preferred compounds of formula I C include, but are not limited to, compounds represented by formula I C8

R ₁₃₈ Selected from H, OH, SH, NH ₂ 、COOH、CF ₃ Aldehyde group, carbamoyl group, F, Cl, Br, I, NO ₂ 、CN、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Alkylamino radical, C ₁ -C ₄ Alkoxy C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkenyl radical, C ₂ -C ₄ Alkynyl.

Most preferred compounds of formula I C include, but are not limited to, compounds represented by formula I C9

R ₁₃₉ Selected from H, OH, SH, NH ₂ 、COOH、CF ₃ Aldehyde group, carbamoyl group, F, Cl, Br, I, NO ₂ 、CN、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Alkylamino radical, C ₁ -C ₄ Alkoxy C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkenyl radical, C ₂ -C ₄ Alkynyl.

Most preferred compounds of formula I C include, but are not limited to, compounds represented by formula I C10

R ₁₃₁₀ Selected from H, OH, SH, NH ₂ 、COOH、CF ₃ Aldehyde group, carbamoyl group, F, Cl, Br, I, NO ₂ 、CN、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Alkylamino radical, C ₁ -C ₄ Alkoxy C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkenyl radical, C ₂ -C ₄ Alkynyl.

Most preferred compounds of formula I C include, but are not limited to, the compounds of formula I C11

R ₁₃₁₁ Is selected from C ₁ -C ₆ Linear or branched alkyl of (a); for example, methyl, ethyl, isopropyl, tert-butyl, and the like.

Most preferred compounds of formula I include, but are not limited to, compounds represented by I D

R ₁₄ Represents one or more substituents which may be attached at any suitable position on the aromatic ring of the phthalimide group, the substituents being independently selected from H, OH, SH, NH ₂ COOH, aldehyde group, carbamoyl group, halogen, NO ₂ 、CN、C ₁ -C ₃ Straight-chain or branched alkyl, C ₁ -C ₃ Alkoxy radical, C ₁ -C ₃ Alkylamino radical, C ₁ -C ₃ Alkoxy C ₁ -C ₃ Alkyl radical, C ₂ -C ₃ Alkenyl radical, C ₂ -C ₃ Alkynyl.

Wherein the 27-position carbon atom may be substituted with R ₁₀ Attached at any suitable position on the aryl or heteroaryl group.

C of the invention ₁ -C ₈ Preferred among the linear or branched alkyl groups is C ₁ -C ₆ Straight or branched chain alkyl. C of the invention ₁ -C ₆ Preferred among the linear or branched alkyl groups is C ₁ -C ₄ Straight or branched chain alkyl. C of the invention ₁ -C ₄ Preferred among the linear or branched alkyl groups is methyl or ethyl. C of the invention ₂ -C ₈ Preferred among alkenyl groups is C ₂ -C ₆ An alkenyl group. C of the invention ₂ -C ₆ Preferred among alkenyl groups is C ₂ -C ₄ An alkenyl group. C of the invention ₂ -C ₄ Preferred among alkenyl groups is vinyl.

C of the invention ₂ -C ₈ Preferred of alkynyl is C ₂ -C ₆ Alkynyl. C of the invention ₂ -C ₆ Preferred of alkynyl is C ₂ -C ₄ Alkynyl. C of the invention ₂ -C ₄ Preferred among alkynyl groups is ethynyl.

Preferred C ₁ -C ₆ The linear or branched alkyl is selected from methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, pentyl, isopentyl.

It is preferably C ₁ -C ₄ The linear or branched alkyl is selected from methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl.

Preferred aryl groups are selected from phenyl, naphthyl.

Preferred heteroaryl groups are selected from pyridyl, furyl, thienyl, quinolyl, indolyl, benzothienyl, benzofuryl. The halogen is selected from F, Cl, Br and I.

The pharmaceutically acceptable salt of the above-mentioned preferred compound with an acid also forms a part of the present invention, and the basic nitrogen atom in the molecule of the compound in the present invention may form a salt with an acid, and is not particularly limited as long as it can form a salt with a base and is a pharmaceutically acceptable acid. Examples thereof include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid, and organic acids such as oxalic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, methanesulfonic acid and p-toluenesulfonic acid.

The synthesis of certain steps of ecteinascidins analogs having general formula (I) and pharmaceutically acceptable salts thereof according to the present invention is described in the following references, Corey, E.J. et al.J. am. chem. Soc.1996,118, 9202; fukuyama, t.et al, j.am.chem.soc.2002,124, 6552; cuevas, c.et al, org.lett.2000,2,2545; cuevas, c.et al, j.org.chem.2003,68,8859; zhu, j.et al, j.am.chem.soc.2006,128, 87; danishefsky, s.j.et al, angelw.chem.int.ed.2006, 45,1754; chandrasekhar, s.et al, Tetrahedron,2006,62, 12098; williams, r.m.et al, org.lett.2006,8,3299; williams, r.m.et al, j.org.chem.2008,73,9594; avenano, c.et al, Tetrahedron,2005,61, 7447; avenano, c.et al, Tetrahedron,2009,65, 2201; liu, z.z.et al, Tetrahedron lett.2003,44,7091; liu, z.z.et al, bioorg.med.chem.lett.2006,16,1282.

The specific preparation route is as follows:

1. reacting a tetrahydrocarboline precursor compound A and a carboxylic acid precursor compound B in anhydrous dichloromethane for 48 hours at room temperature under the action of BOPCl to obtain an intermediate compound 1; suitable condensing agents include DCC, EDCI, HATU; the proper reaction temperature is-30 ℃ to 30 ℃; the optimal reaction temperature is 25 ℃; solvents of choice for the reaction include dichloromethane, dimethylformamide, dimethyl sulfoxide, acetone;

2. using intermediate compound 1 in (Boc) ₂ Under the action of O, introducing a protecting group into a nitrogen atom of an indole ring to obtain an intermediate compound 2;

3. removing a tert-butyl dimethyl silicon-based protective group of an oxygen atom from the intermediate compound 2 under the action of tetrabutylammonium fluoride to obtain an intermediate compound 3;

4. obtaining an intermediate compound 4 by adopting the intermediate compound 3 and a Swern oxidation method;

5. removing a tert-butoxycarbonyl protecting group on a nitrogen atom by using an intermediate compound 4 under the action of trifluoroacetic acid, trifluoromethanesulfonic acid, glacial acetic acid, anhydrous formic acid and Lewis acid, and then carrying out intramolecular PS (polystyrene) cyclization reaction to obtain an intermediate compound 5;

6. methylating nitrogen atoms by using an intermediate compound 5 under the action of formaldehyde aqueous solution and sodium cyanoborohydride to obtain an intermediate compound 6;

7. introducing hydrogen into the intermediate compound 6 under the catalysis of 10 percent palladium hydroxide/carbon, and removing a benzyl protecting group on an oxygen atom at room temperature under the pressure of 50psi to obtain an intermediate compound 7;

8. reducing the intermediate compound 7 by lithium aluminum hydride, and carrying out cyanation reaction under the conditions of trimethyl cyano silane and boron trifluoride diethyl etherate to obtain an intermediate compound 8;

9. the intermediate compound 8 is adopted to perform Mitsunobu reaction under the action of diisopropyl azodicarboxylate, triphenylphosphine and phthalimide to obtain an intermediate compound 9, namely a target product with a general formula of I D. (ii) a

10. Adopting an intermediate compound 9 to allow the phthalimide group to generate hydrazinolysis under the action of hydrazine hydrate to obtain precursor amine C;

11. with the precursor amine C, under the action of the condensing agent EDCI, and the substituent R ₁₀ The carboxylic acids listed for formula I above are subjected to dehydration condensation to give the desired product having formula I C. R ₁₀ The definitions of (a) are the same as above.

In a further aspect, the invention relates to pharmaceutical compositions comprising as active ingredient a compound of the invention. The pharmaceutical composition may be prepared according to methods well known in the art. The compounds of the invention may be formulated into any dosage form suitable for human or animal use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The compounds of the present invention are generally present in the pharmaceutical compositions in an amount of from 0.1 to 95% by weight.

The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by enteral or parenteral routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ophthalmic, pulmonary and respiratory, dermal, vaginal, rectal, and the like.

The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.

The compound can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle drug delivery systems.

For tableting the compounds of the present invention, a wide variety of excipients well known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.

The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.

To encapsulate the administration units, the active ingredient of the compounds of the invention can be mixed with diluents and glidants and the mixture can be placed directly into hard or soft capsules. Or the effective component of the compound of the invention can be prepared into granules or pellets with diluent, adhesive and disintegrating agent, and then placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, glidants used to prepare the compound tablets of the present invention may also be used to prepare capsules of the compound of the present invention.

In order to prepare the compound of the invention into injection, water, ethanol, isopropanol, propylene glycol or a mixture thereof can be used as a solvent, and a proper amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator which are commonly used in the field can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol and glucose can be added as proppant for preparing lyophilized powder for injection.

In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.

For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method. The compounds of the invention may be used in the treatment of tumours with other anti-cancer drugs, which are also part of the invention, including: taxol, paclitaxel, taxotere, docetaxel, vincristine, vinblastine, 5-fluoroouracil, cytarabine, gemcitabine, pentastatin, methotrexane, cyclophosphamide, ifosfamide, adriamycin, doxorubicin, pharmorubicin, epirubicin, etoposide, tamoxifen, flutamide, leuprolide, goserelin, cyromote, octreotide, hereptin, cis-platin, carboplatin, oxapaletin, dexamethasone, etc.

The compounds of the invention may also be used in combination with compounds belonging to the following classes of antineoplastic agents, which also form part of the present invention: taxol, podophyllotoxins, vinblastine, nitrogen mustard, anthraquinones, estrogens, antiestrogens, androgens, antiandrogens, antibody derivatives, platins, matrix protease inhibitors, etc.

The compounds of the invention may also be used in combination with compounds belonging to the following classes of antineoplastic agents, which also form part of the present invention: tubulin modulators, antimetabolites, alkylating drugs, DNA-targeted antineoplastic drugs, topoisomerase-targeted drugs, hormones and hormone agonists or antagonists, cancer intracellular signaling-targeted drugs, gene therapy or antisense therapy drugs, antibody therapy drugs, marine-derived active compounds, hormone analogs, anti-inflammatory drugs, or antiemetic drugs.

The compound of the invention can be used alone or used as a medicinal active ingredient for treating patients suffering from leukemia, melanoma, gastric cancer, lung cancer, breast cancer, renal cancer, liver cancer, oral epidermoid carcinoma, cervical cancer, ovarian cancer, pancreatic cancer, prostatic cancer, colon cancer and the like. The dosage of the pharmaceutical composition of the compound of the present invention to be administered may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route and dosage form of administration, and the like. Generally, a suitable daily dosage range for a compound of the invention is from 0.001 to 150mg/Kg body weight, preferably from 0.1 to 100mg/Kg body weight, more preferably from 1 to 60mg/Kg body weight, and most preferably from 2 to 30mg/Kg body weight. The above-described dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.

The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention is used in a synergistic manner with other therapeutic agents, the dosage thereof should be adjusted according to the actual circumstances.

Detailed Description

The present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Preparation of Compounds 1-17

Can be prepared by one-step acylation reaction of common precursor amine C, and the precursor amine C is prepared by multi-step reaction of tetrahydrocarboline intermediate A and carboxylic acid intermediate B. Among them, the carboxylic acid intermediate B can be prepared by the method described in Liu, z.z.et al, bioorg.med.chem.lett.2006,16,1282.

1. Preparation of tetrahydrocarboline intermediate A:

a:SOCl ₂ ,MeOH,reflux；b:BnOCH ₂ CHO,TFA,CH ₂ Cl ₂ ；c:LiAlH ₄ ,THF；d:TBSCl,Imidazole,CH ₂ Cl ₂

preparation of intermediate A-1: dissolving 20g of L-tryptophan in 500ml of methanol, cooling to 0 ℃ in an ice bath, slowly dropwise adding 18ml of thionyl chloride, heating to reflux after dropwise adding, and reacting for 5 hours. Evaporating the solvent under reduced pressure, dissolving the residual solid with ethyl acetate, and dissolving with saturated NaHCO ₃ Adjusting pH to 8 with aqueous solution, sequentially adding saturated NaHCO ₃ The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, slurried with petroleum ether, and filtered to give 19g of crude product, which was used directly in the next reaction.

Preparation of intermediate A-2: 66g of intermediate A-1 are dissolved in 700ml of dichloromethane, 50g of benzyloxyacetaldehyde and 5g of the powder are added

Cooling to 0 deg.C in ice bath, slowly dropping 12ml trifluoroacetic acid, stirring at 0 deg.C for 1 hr, slowly dropping 25ml trifluoroacetic acid, and stirring at 0 deg.C for 4 hr. Filtering, adjusting pH to 8 with saturated sodium bicarbonate solution, washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, evaporating under reduced pressure, and performing silica gel column chromatography to obtain brownish red67g of oily liquid, yield 63%. [ alpha ] of] _D ²¹ ＝-58.3(c0.6,CH ₃ OH)；HRMS calcd.for C ₂₁ H ₂₃ N ₂ O ₃ [M+H] ⁺ 351.1703,found 351.1697； ¹ H NMR(400MHz,Chloroform-d)δ8.46(s,1H),7.49(d,J＝7.8Hz,1H),7.38(m,5H),7.29(d,J＝7.8Hz,1H),7.16(t,J＝7.5Hz,1H),7.11(d,J＝7.5Hz,1H),4.65(s,2H),4.43(br s,1H),3.84(m,5H),3.67(t,J＝8.7Hz,1H),3.16(dd,J＝15.0,3.6Hz,1H),2.91–2.78(m,1H),2.01(s,1H).

Preparation of intermediate A-3: 23g of intermediate A-2 was dissolved in 200ml of anhydrous tetrahydrofuran, cooled to 0 ℃ in an ice bath, and 2.5g of lithium aluminum hydride was slowly added and reacted at 0 ℃ for 5 minutes. Slowly dropwise adding saturated sodium bicarbonate aqueous solution under ice bath to quench reaction, performing suction filtration, performing reduced pressure distillation on the filtrate to remove most tetrahydrofuran, dissolving the residue with dichloromethane, washing with saturated saline solution, drying with anhydrous sodium sulfate, performing reduced pressure distillation, and performing silica gel column chromatography to obtain 14g of white solid with the yield of 65%. [ alpha ] to] _D ²³ ＝-55.5(c 0.75,CH ₃ OH)；HRMS calcd.for C ₂₀ H ₂₃ N ₂ O ₂ [M+H] ⁺ 323.1754,found 323.1747； ¹ H NMR(400MHz,DMSO-d ₆ )δ10.62(s,1H),7.31(m,7H),6.99(t,J＝7.8Hz,1H),6.91(t,J＝7.8Hz,1H),4.80(t,J＝5.3Hz,1H),4.57(s,2H),4.23(br s,1H),3.97(dd,J＝9.1,3.7Hz,1H),3.63–3.49(m,2H),3.48–3.35(m,1H),3.01–2.84(m,1H),2.72–2.52(m,2H),2.28–2.13(m,1H).

Preparation of tetrahydrocarboline intermediate A: 28g of intermediate A-3 was dissolved in 300ml of methylene chloride, 21g of imidazole was added thereto, and the mixture was stirred at room temperature for 5 minutes, 26g of t-butyldimethylsilyl chloride was added thereto, and the mixture was stirred at room temperature for 4 hours. After the reaction, the mixture was washed with saturated brine, evaporated to dryness under reduced pressure, and subjected to silica gel column chromatography to obtain 35g of a brownish red oily liquid with a yield of 92%. [ alpha ] to] _D ²³ ＝-15.1(c 0.7,CH ₃ OH)；HRMScalcd.for C ₂₆ H ₃₇ N ₂ O ₂ Si[M+H] ⁺ 437.2619,found 437.2614； ¹ H NMR(400MHz,Chloroform-d)δ8.49(s,1H),7.51(d,J＝7.6Hz,1H),7.47–7.34(m,5H),7.31(d,J＝7.6Hz,1H),7.17(t,J＝7.3Hz,1H),7.12(d,J＝7.3Hz,1H),4.68(m,2H),4.47–4.36(m,1H),3.93–3.85(m,1H),3.84–3.77(m,1H),3.75–3.66(m,2H),3.27–3.12(m,1H),2.77–2.66(m,1H),2.59–2.42(m,1H),2.24(br s,1H),0.97(s,9H),0.15(s,6H).

2. Preparation of precursor amine C:

a:BOPCl,Et ₃ N,CH ₂ Cl ₂ ；b:(Boc) ₂ O,DMAP,Et ₃ N,CH ₂ Cl ₂ ；c:TBAF,THF；d:(COCl) ₂ ,DMSO,Et ₃ N,CH ₂ Cl ₂ ,-78℃；e:TFA；f:HCHO(37％),NaBH ₃ CN,CH ₃ COOH,CH ₃ OH；g:Pd(OH) ₂ ,H ₂ (50psi),CH ₃ COOH,CH ₃ OH；h:LiAlH ₄ ,THF；i:TMSCN,BF ₃ ·OEt ₂ ,CH ₂ Cl ₂ ；j:Phthalimide,(Ph) ₃ P,DIAD,THF；k:N ₂ H ₄ ·H ₂ O

preparation of intermediate 1: dissolving 20g of tetrahydrocarboline intermediate A and 15g of carboxylic acid intermediate B in 200ml of dichloromethane, sequentially adding 14g of BOPCl and 13ml of triethylamine, stirring for three days at room temperature under the protection of argon. The reaction solution was diluted with dichloromethane and saturated NaHCO ₃ The reaction was quenched with an aqueous solution, washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and chromatographed on silica gel column to give 10g of a reddish-brown oily liquid with a yield of 31%. [ alpha ] to] _D ¹⁸ ＝+145.3(c 0.15,CH ₃ OH)；HRMS calcd.forC ₄₂ H ₅₇ N ₃ O ₇ SiNa[M+Na] ⁺ 766.3863,found 766.3807； ¹ H NMR(400MHz,DMSO-d ₆ )δ10.90–10.51(m,1H),7.41–7.36(m,1H),7.32–7.21(m,6H),7.04(t,J＝6.9Hz,1H),6.94(t,J＝7.4Hz,1H),6.82–6.73(m,3H),6.64(d,J＝8.5Hz,1H),5.40(br s,1H),4.54(s,2H),4.29–4.15(m,1H),3.81–3.74(m,1H),3.69–3.65(m,2H),3.65–3.44(m,8H),2.88–2.77(m,3H),2.39–2.31(m,1H),1.33(s,6H),1.14(s,3H),0.77(s,3H),0.71(s,6H),-0.07–-0.22(m,6H).

Preparation of intermediate 2: in 10g ofIntermediate 1 was dissolved in 150ml of methylene chloride, and 5g of (Boc) was added ₂ O,0.33g DMAP and 5ml triethylamine were stirred at room temperature for 5 hours. Saturated NaHCO ₃ Washing, washing with saturated NaCl, drying with anhydrous sodium sulfate, and evaporating to dryness under reduced pressure to obtain a crude product of the brownish red oily liquid intermediate 2, wherein the product is directly used for the next reaction without purification.

Preparation of intermediate 3: 11.5g of the crude intermediate 2 were dissolved in 200ml of tetrahydrofuran, and 27ml (1 mol. L) of tetrahydrofuran was added thereto ^-1 ) Tetrabutylammonium fluoride in tetrahydrofuran, and reacted at room temperature for 2 hours. Adding saturated ammonium chloride aqueous solution to quench reaction, distilling under reduced pressure to remove most tetrahydrofuran, adding dichloromethane to dissolve concentrate, washing with saturated NaCl, drying with anhydrous sodium sulfate, evaporating under reduced pressure to dryness, and performing silica gel column chromatography to obtain light yellow oily liquid 8.5g, with a total yield of two steps of 81%. [ alpha ] to] _D ²⁰ ＝+154.7(c 0.15,CH ₃ OH)；HRMScalcd.for C ₄₁ H ₅₂ N ₃ O ₉ [M+H] ⁺ 730.3704,found 730.3606； ¹ H NMR(400MHz,CDCl ₃ )δ8.08(d,J＝8.5Hz,1H),7.33–7.18(m,8H),6.73–6.58(m,3H),6.53(d,J＝8.0Hz,1H),5.51(d,J＝8.0Hz,1H),5.22–5.12(m,1H),4.62(d,J＝12.0Hz,1H),4.47(d,J＝12.0Hz,1H),4.38–4.27(m,1H),4.02(d,J＝7.3Hz,1H),3.84(br s,1H),3.80–3.73(m,1H),3.68(s,3H),3.66–3.58(m,4H),3.58–3.49(m,1H),2.99(d,J＝6.4Hz,2H),2.36(d,J＝16.4Hz,1H),2.16–2.05(m,1H),1.62(s,9H),1.44(s,9H).

Preparation of intermediate 4: dissolving 1.25ml of oxalyl chloride in 200ml of anhydrous dichloromethane, reducing the temperature to-78 ℃ under the protection of argon, diluting 2.1ml of dimethyl sulfoxide with 20ml of dichloromethane, slowly dropwise adding a dichloromethane solution of dimethyl sulfoxide, after the dropwise addition, reacting for 30 minutes, diluting 6g of intermediate 3 with 20ml of dichloromethane, slowly dropwise adding a dichloromethane solution of intermediate 3, reacting for 1 hour after the dropwise addition, dropwise adding 5.3ml of triethylamine, reacting for 30 minutes, and slowly raising the temperature to room temperature. Washing with saturated NaCl, drying with anhydrous sodium sulfate, evaporating to dryness under reduced pressure, and directly using the product in the next reaction without purification.

Preparation of intermediate 5: 6g of crude intermediate 4 was dissolved in 15ml of trifluoroacetic acid in an ice bath, stirred for 1 hour in the ice bath, warmed to room temperature and reacted for 6 hours. After the reaction, most of trifluoroacetic acid is distilled off, and saturated NaHCO is obtained by diluting with ethyl acetate ₃ Adjusting the pH value of the reaction solution to 8, washing with saturated NaCl, drying with anhydrous sodium sulfate, evaporating to dryness under reduced pressure, and performing silica gel column chromatography to obtain 1g of white solid with the total yield of the two steps of 28%. [ alpha ] to] _D ¹⁹ ＝+157.3(c 0.15,CH ₃ OH)；HRMS calcd.for C ₃₁ H ₃₂ N ₃ O ₄ [M+H] ⁺ 510.2393,found 510.2378； ¹ H NMR(600MHz,CDCl ₃ )δ8.16(s,1H),7.55(d,J＝7.7Hz,1H),7.33(d,J＝8.0Hz,1H),7.25–7.20(m,3H),7.18(t,J＝8.0Hz,1H),7.14(t,J＝8.0Hz,1H),7.04(m,2H),6.65(s,1H),6.63(s,1H),5.38(dd,J＝8.1,3.3Hz,1H),4.29(d,J＝11.9Hz,1H),4.20–4.14(m,2H),4.07(d,J＝6.7Hz,1H),4.05–4.01(m,1H),3.94(dd,J＝8.5,3.3Hz,1H),3.89(s,3H),3.85(s,3H),3.21(dd,J＝17.0,6.7Hz,1H),3.10(dd,J＝14.3,3.0Hz,1H),3.00(d,J＝17.0Hz,1H),2.96(t,J＝8.3Hz,1H),2.63(dd,J＝14.3,12.3Hz,1H)； ¹³ C NMR(150MHz,CDCl ₃ ) δ 171.94,148.80,146.81,138.24,135.91,132.93,129.91,128.27,127.49,127.28,126.03,124.71,121.74,119.56,117.84,111.74,111.65,111.33,107.68,73.21,72.41,61.83,56.25,55.85,54.93,54.61,51.28,33.84,24.68 preparation of intermediate 6: 1g of intermediate 5 was dissolved in 20ml of anhydrous methanol, and 0.5ml of 37% aqueous formaldehyde solution, 0.26g of sodium cyanoborohydride and 0.2ml of glacial acetic acid were successively added thereto and reacted at room temperature for 30 minutes. After the reaction, saturated Na was added under ice bath ₂ CO ₃ Quenching the reaction, adjusting the pH to 9, extracting with ethyl acetate, washing with saturated NaCl, drying with anhydrous sodium sulfate, evaporating to dryness under reduced pressure, and performing silica gel column chromatography to obtain a white solid with the yield of 87 percent, wherein the white solid is 0.9 g. [ alpha ] to] _D ²⁰ ＝+166.8(c 0.15,CH ₃ OH)；HRMS calcd.for C ₃₂ H ₃₄ N ₃ O ₄ [M+H] ⁺ 524.2549,found 524.2555； ¹ H NMR(500MHz,CDCl ₃ )δ8.20(s,1H),7.55(d,J＝7.6Hz,1H),7.33(d,J＝7.8Hz,1H),7.25–7.11(m,5H),7.06–7.01(m,2H),6.65(s,1H),6.63(s,1H),5.42–5.33(m,1H),4.30(d,J＝11.9Hz,1H),4.22–4.09(m,2H),3.99–3.95(m,1H),3.91(s,3H),3.87–3.81(m,4H),3.77(d,J＝6.4Hz,1H),3.28(dd,J＝17.3,6.7Hz,1H),3.10–2.96(m,2H),2.82(d,J＝17.3Hz,1H),2.61(t,J＝13.1Hz,1H),2.49(s,3H)； ¹³ C NMR(125MHz,CDCl ₃ )δ172.46,148.88,147.15,138.41,136.10,133.09,128.39,127.58,127.37,126.21,125.46,122.69,121.83,119.64,117.95,112.73,111.44,111.42,108.09,73.33,72.51,61.51,60.72,58.62,56.35,55.95,51.46,40.03,28.26,24.62.

Preparation of intermediate 7: placing 2g of intermediate 6 into a hydrogenation bottle, adding 30ml of anhydrous methanol for dissolving, and sequentially adding 0.2g of Pd (OH) ₂ C and 1ml glacial acetic acid, and reacting for 24 hours under 50psi pressure by introducing hydrogen. Filtering, and adding saturated Na to the filtrate under ice bath ₂ CO ₃ Adjusting pH to 9, removing most of methanol, dissolving in ethyl acetate, washing with saturated NaCl, evaporating under reduced pressure, and performing silica gel column chromatography to obtain white solid 1g with yield of 61%. [ alpha ] to] _D ²³ ＝+190.7(c 0.15,CH ₃ OH)；HRMS calcd.for C ₂₅ H ₂₈ N ₃ O ₄ [M+H] ⁺ 434.2080,found 434.2069； ¹ H NMR(400MHz,DMSO-d ₆ )δ10.92(s,1H),7.48(d,J＝7.5Hz,1H),7.31(d,J＝7.8Hz,1H),7.09–6.91(m,2H),6.82(s,1H),6.72(s,1H),5.15–5.03(m,1H),4.60(t,J＝5.2Hz,1H),3.93–3.82(m,2H),3.77(s,3H),3.72(s,3H),3.62–3.49(m,2H),3.23–3.07(m,2H),2.80–2.66(m,1H),2.60(d,J＝17.3Hz,1H),2.43–2.21(m,4H)； ¹³ CNMR(125MHz,DMSO-d ₆ )δ171.36,148.05,146.36,135.71,133.33,125.72,125.20,123.01,120.36,118.31,117.51,113.34,111.41,111.35,107.06,63.56,59.80,59.72,58.28,55.85,55.27,52.66,27.77,23.73,14.07.

Preparation of intermediate 8: dissolving 1g of the intermediate 7 in 20ml of anhydrous tetrahydrofuran, cooling to-17 ℃, slowly adding 0.18g of lithium aluminum hydride, reacting at-17 ℃ for 1 hour under the protection of argon, heating to 0 ℃ for reacting for 1 hour, and heating to room temperature for reacting for 1 hour. Saturated NaHCO in ice bath ₃ Quenching reaction, extracting with ethyl acetate for multiple times, washing with saturated NaCl, drying with anhydrous sodium sulfate, and evaporating to dryness under reduced pressure. The crude product is dissolved in 20ml of dry dichloromethane, the temperature is reduced to-30 ℃,0.3 ml of boron trifluoride diethyl etherate is dripped under the protection of argon, after stirring for 5 minutes, 0.9ml of trimethylcyanosilane is dripped, and the reaction is carried out for 3 hours at-30 ℃. Saturated NaHCO in ice bath ₃ Aqueous quenchingAfter the reaction, an organic layer was separated, washed with saturated NaCl, evaporated to dryness under reduced pressure, and subjected to silica gel column chromatography to obtain 0.8g of a white solid with a yield of 78%. [ alpha ] to] _D ²⁰ ＝+135.0(c 0.20,CH ₃ OH)；HRMS calcd.for C ₂₆ H ₂₉ N ₄ O ₃ [M+H] ⁺ 445.2240,found 445.2224； ¹ H NMR(400MHz,CDCl ₃ )δ8.33(s,1H),7.49(d,J＝7.7Hz,1H),7.33(d,J＝7.9Hz,1H),7.24–7.04(m,2H),6.57(d,J＝3.4Hz,2H),4.03–3.75(m,8H),3.64(br s,1H),3.58(d,J＝10.5Hz,1H),3.54–3.39(m,2H),3.33(d,J＝7.3Hz,1H),3.06(dd,J＝17.8,7.9Hz,1H),2.83(d,J＝12.5Hz,1H),2.54–2.44(m,1H),2.42–2.29(m,4H)； ¹³ C NMR(125MHz,CDCl ₃ )δ148.59,146.85,136.48,130.32,126.37,126.12,123.68,122.03,119.55,118.22,117.91,113.49,111.24,110.68,108.34,63.41,59.98,58.50,56.66,56.37,56.02,55.44,53.56,41.79,25.98,24.05.

Preparation of intermediate 9 (compound 17): dissolving 0.5g of the intermediate 8 in 10ml of anhydrous tetrahydrofuran, adding 0.23g of phthalimide and 0.93g of triphenylphosphine, cooling to-25 ℃, diluting 0.48ml of diisopropyl azodicarboxylate with 3ml of anhydrous tetrahydrofuran, slowly dropwise adding a tetrahydrofuran solution of diisopropyl azodicarboxylate under the protection of argon, reacting at-25 ℃ for 2 hours after dropwise adding, and heating to 0 ℃ for reacting for 1 hour. Saturated NaHCO in ice bath ₃ Quenching the reaction by aqueous solution, extracting by ethyl acetate, washing by saturated NaCl, evaporating to dryness under reduced pressure, and performing silica gel column chromatography to obtain a light yellow solid of 0.48g with a yield of 74%. [ alpha ] to] _D ²³ ＝+15.0(c0.27,CH ₃ OH)；HRMS calcd.for C ₃₄ H ₃₂ N ₅ O ₄ [M+H] ⁺ 574.2449,found 574.2425； ¹ H NMR(500MHz,Acetone-d ₆ )δ9.96(s,1H),7.83–7.69(m,4H),7.42(d,J＝7.8Hz,1H),7.27(d,J＝8.0Hz,1H),7.03(t,J＝7.4Hz,1H),6.97(t,J＝7.4Hz,1H),6.73(s,1H),6.68(s,1H),4.72–4.66(m,1H),4.31–4.25(m,1H),3.98–3.85(m,2H),3.78(s,3H),3.75(s,3H),3.70(br s,1H),3.53(d,J＝7.6Hz,1H),3.32–3.25(m,1H),3.11(dd,J＝17.9,7.9Hz,1H),2.96–2.86(m,2H),2.39–2.26(m,4H)； ¹³ C NMR(150MHz,Acetone-d ₆ )δ206.07,168.54,149.41,147.55,137.88,134.81,132.94,132.08,128.09,127.29,124.86,123.72,121.93,119.43,118.65,118.59,114.89,112.16,111.88,108.68,63.85,60.93,58.63,58.40,56.46,56.38,56.02,42.60,41.60,25.77,25.00.

Preparation of precursor amine C: 0.48g of intermediate 9 is dissolved in anhydrous 15ml of anhydrous ethanol, 0.2ml of hydrazine hydrate is added, the temperature is raised to 50 ℃, and the reaction is carried out for 1 hour. Most of the solvent was distilled off under reduced pressure, dissolved in ethyl acetate, washed with saturated NaCl, dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and chromatographed on silica gel column to give 0.3g of white solid with a yield of 81%. [ alpha ] to] _D ²⁰ ＝+118.0(c 0.10,CH ₃ OH)；HRMScalcd.for C ₂₆ H ₃₀ N ₅ O ₂ [M+H] ⁺ 444.2400,found 444.2377； ¹ H NMR(400MHz,CDCl ₃ )δ8.42(s,1H),7.44(d,J＝7.6Hz,1H),7.30(d,J＝7.9Hz,1H),7.15(t,J＝7.2Hz,1H),7.09(t,J＝7.2Hz,1H),6.58(s,2H),3.98–3.86(m,5H),3.83(s,3H),3.64(br s,1H),3.50–3.42(m,1H),3.33(d,J＝7.4Hz,1H),3.08(dd,J＝17.8,7.9Hz,1H),2.90–2.80(m,2H),2.80–2.70(m,1H),2.52–2.38(m,2H),2.35(s,3H)； ¹³ C NMR(150MHz,CDCl ₃ )δ148.26,146.42,136.33,130.14,126.23,126.19,123.69,121.96,119.45,117.88,117.78,113.26,111.09,110.39,108.86,63.29,59.69,56.29,56.20,55.85,55.32,41.70,29.68,25.92,23.92,18.43.

2. Preparation of Compounds 1-16

Preparation of compound 1:

10mg of the precursor amine C are dissolved in 2ml of dichloromethane and 3.5mg of 2-furancarboxylic acid, 6mg of EDCI and 8.5mg of DMAP are added at room temperature and reacted at room temperature for 30 minutes under argon. The reaction solution was diluted with dichloromethane and saturated NaHCO ₃ Washing with water solution, evaporating to dryness under reduced pressure, and performing silica gel column chromatography to obtain white solid 10mg with yield of 83%. [ alpha ] to] _D ²⁰ ＝+116.0(c 0.32,CH ₃ OH)；HRMScalcd.for C ₃₁ H ₃₂ N ₅ O ₄ [M+H] ⁺ 538.2454,found 538.2431； ¹ H NMR(400MHz,Acetone-d ₆ )δ9.99(s,1H),7.39(d,J＝7.4Hz,1H),7.33–7.22(m,2H),7.07–6.83(m,3H),6.73–6.58(m,2H),6.45–6.28(m,2H),4.63(br s,1H),4.25(br s,1H),4.12–3.98(m,1H),3.86(s,3H),3.81(br s,1H),3.75–3.60(m,4H),3.52(d,J＝6.9Hz,1H),3.44(d,J＝10.6Hz,1H),3.16(dd,J＝17.9,7.4Hz,1H),3.02(d,J＝14.9Hz,1H),2.77–2.69(m,1H),2.65–2.53(m,1H),2.36(s,3H)； ¹³ C NMR(150MHz,Acetone-d ₆ )δ157.28,148.60,147.86,146.76,144.20,136.81,130.29,126.98,126.34,124.04,121.18,118.61,117.68,114.09,112.83,111.36,111.01,110.94,108.45,63.05,59.20,57.11,56.87,55.48,55.40,54.87,40.86,40.07,25.22,23.73.

Preparation of compound 2:

the method for producing compound 2 is the same as that for compound 1. [ alpha ] to] _D ²⁰ ＝+123.0(c 0.16,CH ₃ OH)；HRMS calcd.for C ₃₄ H ₃₃ F ₃ N ₅ O ₃ [M+H] ⁺ 616.2535,found 616.2500； ¹ H NMR(400MHz,Acetone-d ₆ )δ10.01(s,1H),7.82(s,1H),7.73(d,J＝7.2Hz,1H),7.50–7.36(m,2H),7.28(d,J＝7.7Hz,1H),7.13–6.78(m,5H),6.47(br s,1H),4.68(br s,1H),4.27(br s,1H),4.08–3.72(m,6H),3.61–3.36(m,5H),3.14–2.98(m,2H),2.80–2.73(m,1H),2.67–2.55(m,1H),2.33(s,3H)； ¹³ C NMR(150MHz,Acetone-d ₆ )δ164.89,148.49,146.70,136.89,135.22,130.48,129.91(q,J＝32.2Hz),129.36,129.14,127.31(q,J＝4.5Hz),127.07,126.47,124.08(q,J＝3.9Hz),123.99,121.20,118.63,117.71,114.01,111.01,110.96,110.66,108.36,108.31,63.01,59.17,57.41,56.82,55.41,55.39,54.60,40.82,40.74,24.95,24.01.

Preparation of compound 3:

the preparation method of the compound 3 is the same as that of the compoundCompound 1. [ alpha ] to] _D ²⁰ ＝+83.0(c 0.16,CH ₃ OH)；HRMS calcd.forC ₃₃ H ₃₃ ClN ₅ O ₃ [M+H] ⁺ 582.2272,found 582.2249； ¹ H NMR(500MHz,Acetone-d ₆ )δ9.99(s,1H),7.39(d,J＝7.8Hz,1H),7.32–7.20(m,3H),7.05–6.97(m,3H),6.97–6.87(m,2H),6.54(br s,2H),4.65(br s,1H),4.27(br s,1H),4.02(dd,J＝13.9,6.9Hz,1H),3.89(s,3H),3.84–3.78(m,1H),3.59–3.49(m,4H),3.49–3.40(m,1H),3.19–2.99(m,2H),2.79–2.70(m,2H),2.67–2.55(m,1H),2.34(s,3H)； ¹³ C NMR(150MHz,Acetone-d ₆ )δ164.85,148.61,146.79,136.85,136.43,132.70,130.34,128.18,128.07,127.05,126.40,124.07,121.20,118.61,117.70,117.65,114.19,110.99,110.68,108.34,63.00,59.08,57.20,56.75,55.52,55.36,54.54,40.82,40.50,25.07,23.94.

Preparation of compound 4:

the method for producing compound 4 is the same as that for compound 1. [ alpha ] to] _D ²⁰ ＝+78.0(c 0.4,CH ₃ OH)；HRMS calcd.forC ₃₃ H ₃₄ N ₅ O ₃ [M+H] ⁺ 548.2662,found 548.2640； ¹ H NMR(500MHz,Acetone-d ₆ )δ10.00(s,1H),7.37(t,J＝8.5Hz,2H),7.29–7.17(m,3H),7.05(d,J＝7.5Hz,2H),7.00(t,J＝7.4Hz,1H),6.97–6.88(m,2H),6.58(s,1H),6.56–6.47(m,1H),4.71–4.64(m,1H),4.28(br s,1H),4.08(dd,J＝13.9,7.5Hz,1H),3.88(s,3H),3.86–3.75(m,2H),3.59–3.50(m,4H),3.49–3.40(m,1H),3.13(dd,J＝18.1,8.0Hz,1H),3.05(dd,J＝15.0,3.2Hz,1H),2.77–2.72(m,1H),2.69–2.57(m,1H),2.34(s,3H)； ¹³ C NMR(150MHz,Acetone-d ₆ )δ165.67,148.78,146.91,136.86,133.91,130.85,130.47,128.09,127.02,126.41,126.35,124.08,121.18,118.60,117.67,114.22,111.00,110.78,108.27,63.08,59.13,57.31,56.83,55.54,55.40,54.71,40.87,40.55,25.19,23.97.

Preparation of compound 5:

the method for producing compound 5 is the same as that for compound 1. [ alpha ] to] _D ²⁰ ＝+73.0(c 0.24,CH ₃ OH)；HRMS calcd.forC ₃₄ H ₃₆ N ₅ O ₄ [M+H] ⁺ 578.2767,found 578.2751； ¹ H NMR(400MHz,Acetone-d ₆ )δ10.00(s,1H),7.38(d,J＝7.5Hz,1H),7.26(d,J＝7.3Hz,1H),7.07–6.86(m,5H),6.74(d,J＝8.0Hz,2H),6.60(s,1H),6.35(br s,1H),4.66(br s,1H),4.27(br s,1H),4.16–4.02(m,1H),3.91(s,3H),3.87–3.77(m,4H),3.77–3.67(m,1H),3.63–3.50(m,4H),3.50–3.41(m,1H),3.22–3.01(m,2H),2.78–2.71(m,1H),2.69–2.58(m,1H),2.35(s,3H)； ¹³ C NMR(150MHz,Acetone-d ₆ )δ161.84,148.76,146.91,136.81,130.49,128.00,127.01,126.35,126.11,124.12,121.15,118.56,117.66,117.65,114.17,113.23,110.98,110.93,110.76,108.21,63.06,59.07,57.26,57.23,56.79,55.54,55.35,54.67,40.85,40.40,25.21,23.92.

Preparation of compound 6:

the method for producing compound 6 is the same as that for compound 1. [ alpha ] to] _D ²⁰ ＝+116.0(c 0.16,CH ₃ OH)；HRMS calcd.for C ₃₂ H ₃₃ N ₆ O ₃ [M+H] ⁺ 549.2614,found 549.2587； ¹ H NMR(400MHz,Acetone-d ₆ )δ10.03(s,1H),8.20(br s,1H),7.93–7.68(m,3H),7.48–7.33(m,2H),7.29(d,J＝7.8Hz,1H),7.08–6.89(m,2H),6.81(s,1H),6.55(s,1H),4.63(br s,1H),4.28(br s,1H),4.01–3.80(m,5H),3.76(br s,1H),3.62(s,3H),3.51(d,J＝7.1Hz,1H),3.40(d,J＝10.9Hz,1H),3.09(dd,J＝17.8,7.8Hz,1H),3.02–2.92(m,1H),2.77–2.69(m,1H),2.68–2.55(m,1H),2.32(s,3H)； ¹³ C NMR(150MHz,Acetone-d ₆ )δ163.71,149.64,148.44,148.06,146.62,136.91,136.86,130.37,126.93,126.47,125.77,123.95,121.24,121.16,118.63,117.71,117.70,113.96,110.99,110.89,108.82,63.09,59.30,57.41,57.38,57.06,55.42,54.76,40.87,40.45,25.14,23.90.

Preparation of compound 7:

a method for producing compound 7 is the same as that of compound 1. [ alpha ] to] _D ²² ＝-13.3(c 0.15,CH ₃ OH)；HRMS calcd.for C ₃₆ H ₃₅ N ₆ O ₃ [M+H] ⁺ 599.2771,found 599.2758； ¹ H NMR(500MHz,Acetone-d ₆ )δ10.08(s,1H),8.34(d,J＝8.4Hz,1H),7.98(d,J＝8.4Hz,1H),7.93(d,J＝8.1Hz,2H),7.74(t,J＝7.4Hz,1H),7.67–7.55(m,2H),7.51(d,J＝7.7Hz,1H),7.33(d,J＝8.0Hz,1H),7.06(t,J＝7.4Hz,1H),7.00(t,J＝7.4Hz,1H),6.59(s,1H),6.46(s,1H),4.65–4.59(m,1H),4.35(br s,1H),4.15–4.03(m,1H),3.81–3.73(m,1H),3.70(br s,1H),3.55(s,3H),3.52–3.45(m,4H),3.43–3.34(m,1H),3.11–2.96(m,2H),2.78–2.67(m,2H),2.24(s,3H)； ¹³ C NMR(150MHz,Acetone-d ₆ )δ164.85,150.24,148.96,147.19,146.88,138.05,137.92,131.13,130.78,130.25,129.93,128.64,128.44,127.54,127.49,124.72,122.18,119.67,118.87,118.69,118.59,114.25,111.98,111.60,110.45,63.97,60.41,58.62,58.03,56.25,55.80,55.41,41.73,41.46,25.97,25.06.

Preparation of compound 8:

the method for producing compound 8 is the same as that for compound 1. [ alpha ] to] _D ²⁰ ＝-5.0(c 0.10,CH ₃ OH)；HRMS calcd.for C ₃₅ H ₃₄ N ₅ O ₃ S[M+H] ⁺ 604.2382,found 604.2354； ¹ H NMR(400MHz,Acetone-d ₆ )δ10.01(s,1H),7.92–7.81(m,2H),7.46–7.31(m,3H),7.28(d,J＝7.9Hz,1H),7.01(t,J＝7.2Hz,1H),6.96–6.85(m,3H),6.63(s,2H),4.70(br s,1H),4.29(br s,1H),4.07(dd,J＝13.7,6.9Hz,1H),3.87(s,3H),3.83(br s,1H),3.55(d,J＝7.3Hz,1H),3.59–3.35(m,4H),3.14(dd,J＝18.0,7.8Hz,1H),3.08–3.01(m,1H),2.82–2.75(m,2H),2.70–2.59(m,1H),2.35(s,3H)； ¹³ C NMR(150MHz,Acetone-d ₆ )δ161.12,148.70,146.83,140.56,139.25,138.99,136.86,130.25,127.08,126.01,125.31,124.58,124.09,123.72,122.29,121.19,118.61,117.71,117.63,114.25,111.02,110.96,110.80,108.50,63.06,59.09,57.24,56.88,55.51,55.38,54.50,40.85,40.54,25.10,24.00.

Preparation of compound 9:

a method for producing compound 9, and compound 1. [ alpha ] of] _D ²² ＝+28.7(c 0.15,CH ₃ OH)；HRMS calcd.for C ₃₇ H ₃₆ N ₅ O ₃ [M+H] ⁺ 598.2818,found 598.2798； ¹ H NMR(500MHz,Acetone-d ₆ )δ10.04(s,1H),7.95(s,1H),7.86(d,J＝8.0Hz,1H),7.81–7.76(m,1H),7.73(d,J＝8.6Hz,1H),7.58–7.45(m,2H),7.40(d,J＝7.8Hz,1H),7.28(d,J＝8.1Hz,1H),7.09–6.98(m,2H),6.97–6.84(m,3H),6.44(s,1H),4.72(brs,1H),4.29(br s,1H),4.06–3.93(m,2H),3.85(s,3H),3.81(br s,1H),3.54(d,J＝7.6Hz,1H),3.48–3.40(m,1H),3.28(s,3H),3.13–2.99(m,2H),2.78–2.75(m,1H),2.72–2.60(m,1H),2.32(s,3H)； ¹³ C NMR(150MHz,Acetone-d ₆ )δ167.14,149.51,147.64,137.77,135.36,133.35,132.45,131.54,129.71,128.74,128.36,128.31,128.17,127.89,127.39,127.31,124.86,123.81,122.03,119.49,118.56,118.52,115.07,111.89,111.58,109.14,63.94,59.98,58.39,57.76,56.38,56.29,55.28,41.73,41.62,25.91,24.98.

Preparation of compound 10:

a method for producing compound 10 is the same as that of compound 1. [ alpha ] to] _D ²⁰ ＝+60.7(c 0.15,CH ₃ OH)；HRMS calcd.for C ₃₁ H ₃₂ N ₅ O ₃ S[M+H] ⁺ 554.2226,found 554.2214； ¹ H NMR(500MHz,Acetone-d ₆ )δ9.99(s,1H),7.49(d,J＝4.8Hz,1H),7.39(d,J＝7.8Hz,1H),7.27(d,J＝8.0Hz,1H),7.01(t,J＝7.4Hz,1H),6.98–6.83(m,3H),6.63(s,1H),6.56–6.47(m,1H),6.40(d,J＝3.2Hz,1H),4.66(br s,1H),4.26(br s,1H),4.01(dd,J＝13.7,7.6Hz,1H),3.87(s,3H),3.82(br s,1H),3.79–3.73(m,1H),3.63(s,3H),3.54(d,J＝7.7Hz,1H),3.49–3.39(m,1H),3.14(dd,J＝18.1,8.1Hz,1H),3.04(dd,J＝15.0,3.1Hz,1H),2.78–2.73(m,1H),2.66–2.55(m,1H),2.34(s,3H)； ¹³ C NMR(150MHz,Acetone-d ₆ )δ161.63,149.78,147.89,140.14,137.72,131.29,130.73,128.24,127.91,127.67,127.26,124.99,122.07,119.49,118.55,118.49,115.21,111.89,111.79,109.17,63.90,59.91,58.07,57.72,56.46,56.25,55.71,41.71,41.40,26.01,24.80.

Preparation of compound 11:

a method for producing compound 11 is the same as that of compound 1. [ alpha ] to] _D ²² ＝-47.0(c 0.24,CH ₃ OH)；HRMS calcd.forC ₃₆ H ₃₅ F ₃ N ₅ O ₃ [M+H] ⁺ 642.2692,found 642.2662； ¹ H NMR(400MHz,Acetone-d ₆ )δ10.00(s,1H),7.81–7.55(m,4H),7.47–7.36(m,2H),7.29(d,J＝7.8Hz,1H),7.05(t,J＝7.1Hz,1H),6.98(d,J＝7.2Hz,1H),6.85(s,1H),6.63(s,1H),6.38(br s,1H),6.11(d,J＝15.6Hz,1H),4.67(br s,1H),4.16(br s,1H),3.98(d,J＝13.6Hz,1H),3.88–3.67(m,5H),3.56–3.35(m,5H),3.08(dd,J＝17.8,7.5Hz,1H),2.97(d,J＝14.9Hz,1H),2.81–2.75(m,1H),2.64–2.51(m,1H),2.34(s,3H)； ¹³ CNMR(150MHz,Acetone-d ₆ )δ164.54,148.54,146.64,137.70,136.90,136.22,130.75,130.62,129.65,127.46,126.56,125.58(q,J＝3.7Hz),124.51(q,J＝4.7Hz),124.14,123.33,121.18,118.66,117.72,117.63,114.37,111.06,111.02,110.97,108.21,63.04,58.94,57.16,56.62,55.54,55.47,54.72,40.87,40.23,24.87,23.78.

Preparation of compound 12:

a method for producing compound 12 is the same as that of compound 1. [ alpha ] to] _D ²⁰ ＝+90.0(c 0.20,CH ₃ OH)；HRMScalcd.for C ₃₃ H ₃₃ FN ₅ O ₃ [M+H] ⁺ 566.2567,found 566.2540； ¹ H NMR(500MHz,Acetone-d ₆ )δ9.99(s,1H),7.38(d,J＝7.8Hz,1H),7.27(d,J＝8.0Hz,1H),7.10–6.89(m,6H),6.58(s,1H),6.47(br s,1H),4.69–4.63(m,1H),4.27(br s,1H),4.04(dd,J＝13.8,7.3Hz,1H),3.89(s,3H),3.85–3.76(m,2H),3.61–3.49(m,4H),3.48–3.41(m,1H),3.13(dd,J＝18.1,8.0Hz,1H),3.06(dd,J＝15.1,3.2Hz,1H),2.78–2.72(m,2H),2.67–2.56(m,1H),2.34(s,3H)； ¹³ C NMR(150MHz,Acetone-d ₆ )δ165.56,165.06(d,J＝247.4Hz),149.50,147.69,137.72,131.26,129.70(d,J＝8.9Hz),127.96,127.26,125.00,122.06,119.47,118.56,118.54,115.70(d,J＝22.0Hz),115.04,111.87,111.81,111.62,109.18,63.90,59.99,58.12,57.65,56.38,56.24,55.48,41.70,41.43,26.00,24.80.

Preparation of compound 13:

a method for producing compound 13 is the same as that of compound 1. [ alpha ] to] _D ²⁰ ＝+97.4(c 0.27,CH ₃ OH)；HRMS calcd.for C ₃₅ H ₃₈ N ₅ O ₃ [M+H] ⁺ 576.2975,found 576.2955； ¹ H NMR(500MHz,Acetone-d ₆ )δ10.01(s,1H),7.38(d,J＝7.8Hz,1H),7.25(d,J＝8.0Hz,1H),7.06(d,J＝7.9Hz,2H),7.03–6.87(m,5H),6.59(s,1H),6.51–6.41(m,1H),4.67(br s,1H),4.28(br s,1H),4.09(dd,J＝13.9,7.5Hz,1H),3.89(s,3H),3.83(br s,1H),3.81–3.72(m,1H),3.61–3.50(m,4H),3.50–3.41(m,1H),3.13(dd,J＝18.0,8.0Hz,1H),3.06(dd,J＝15.1,3.2Hz,1H),2.75(d,J＝18.1Hz,1H),2.71–2.53(m,3H),2.34(s,3H),1.19(t,J＝7.6Hz,3H)； ¹³ C NMR(150MHz,Acetone-d ₆ )δ165.61,148.81,147.30,146.94,136.85,131.35,130.50,127.55,127.00,126.46,126.40,124.09,121.18,118.60,117.67,114.25,111.01,110.78,108.23,63.09,59.10,57.30,56.82,55.57,55.39,54.68,40.88,40.48,28.28,25.22,23.97,14.58.

Preparation of compound 14:

a method for producing compound 14 is the same as that of compound 1. [ alpha ] to] _D ²⁰ ＝-21.7(c 0.35,CH ₃ OH)；HRMS calcd.for C ₃₅ H ₃₆ N ₅ O ₃ [M+H] ⁺ 574.2818,found 574.2807； ¹ H NMR(500MHz,Acetone-d ₆ )δ9.99(s,1H),7.45(d,J＝6.4Hz,2H),7.40(d,J＝7.8Hz,1H),7.38–7.31(m,4H),7.28(d,J＝8.0Hz,1H),7.03(t,J＝7.4Hz,1H),6.96(t,J＝7.4Hz,1H),6.86(s,1H),6.63(s,1H),6.38–6.30(m,1H),5.97(d,J＝15.6Hz,1H),4.72–4.63(m,1H),4.15(br s,1H),3.96–3.87(m,1H),3.86–3.73(m,5H),3.51(d,J＝7.5Hz,1H),3.48–3.37(m,4H),3.09(dd,J＝18.1,7.9Hz,1H),2.96(dd,J＝15.1,3.4Hz,1H),2.79–2.75(m,1H),2.63–2.51(m,1H),2.35(s,3H)； ¹³ C NMR(150MHz,Acetone-d ₆ )δ165.79,149.53,147.58,140.32,137.75,135.91,131.60,130.16,129.56,128.50,128.25,127.42,125.02,122.05,122.02,119.52,118.56,118.46,115.27,111.88,108.92,63.94,59.74,58.01,57.47,56.45,56.35,55.67,41.76,41.07,25.78,24.66.

Preparation of compound 15:

a method for producing compound 15 is the same as that of compound 1. [ alpha ] to] _D ²⁵ ＝+5.0(c 0.20,CH ₃ OH)；HRMScalcd.for C ₃₅ H ₃₅ N ₆ O ₃ [M+H] ⁺ 587.2771,found 587.2746； ¹ H NMR(500MHz,Acetone-d ₆ )δ10.36(s,1H),9.99(s,1H),7.69(d,J＝7.9Hz,1H),7.38(d,J＝8.2Hz,1H),7.33(d,J＝7.8Hz,1H),7.26(d,J＝8.0Hz,1H),7.13(t,J＝7.5Hz,1H),7.07–6.93(m,3H),6.89(t,J＝7.4Hz,1H),6.73(s,1H),6.55–6.45(m,1H),5.70(s,1H),4.69(br s,1H),4.28(br s,1H),4.21–4.11(m,1H),3.92–3.81(m,4H),3.77–3.67(m,1H),3.60–3.50(m,4H),3.48–3.40(m,1H),3.18(dd,J＝18.0,7.9Hz,1H),3.08–2.95(m,1H),2.79–2.75(m,1H),2.67–2.54(m,1H),2.36(s,3H)； ¹³ C NMR(150MHz,Acetone-d ₆ )δ161.41,149.84,147.94,137.68,137.40,131.61,131.23,128.57,127.86,127.22,125.05,124.37,122.98,121.99,120.65,119.44,118.54,115.19,112.62,111.83,111.77,109.30,102.07,63.97,60.01,58.22,57.78,56.43,56.26,55.65,41.75,41.08,26.13,24.82.

Preparation of compound 16:

10mg of the precursor amine C are dissolved in 2ml of dichloromethane, and 2.7mg of acetic anhydride, 3mg of triethylamine and 0.6mg of DMAP are added at room temperature, and the reaction is carried out for 30 minutes at room temperature under the protection of argon. The reaction solution was diluted with dichloromethane and saturated NaHCO ₃ Washing with water solution, evaporating to dryness under reduced pressure, and performing silica gel column chromatography to obtain white solid 10mg with yield of 91%. [ alpha ] to] _D ²² ＝+111.7(c 0.30,CH ₃ OH)；HRMScalcd.for C ₂₈ H ₃₂ N ₅ O ₃ [M+H] ⁺ 486.2505,found 486.2493； ¹ H NMR(500MHz,Acetone-d ₆ )δ9.92(s,1H),7.43(d,J＝7.7Hz,1H),7.27(d,J＝7.95Hz,1H),7.04(t,J＝7.4Hz,1H),6.98(t,J＝7.6Hz,1H),6.84(s,1H),6.72(s,1H),6.32–6.24(m,1H),4.56(br s,1H),4.04(br s,1H),3.95–3.86(m,1H),3.83(s,3H),3.77(s,3H),3.73(br s,1H),3.50–3.40(m,2H),3.39–3.31(m,1H),3.04(dd,J＝17.9,7.9Hz,1H),2.94(dd,J＝14.9,3.2Hz,1H),2.80–2.76(m,1H),2.60–2.46(m,1H),2.34(s,3H),1.43(s,3H)； ¹³ C NMR(150MHz,Acetone-d ₆ )δ169.35,148.61,146.68,136.91,130.85,127.55,126.61,124.23,121.13,118.65,117.70,117.68,114.41,111.27,111.00,108.15,63.05,58.98,57.39,56.66,55.59,55.51,55.15,40.86,39.95,24.74,23.86,21.84.

See intermediate 9 for preparation of compound 17 and data.

Pharmacological experiment

Experimental example 1: in vitro activity studies:

experimental materials:

the colon cancer cell strain (HCT-116), the liver cancer cell strain (HepG2), the gastric cancer cell strain (BGC-823), the lung cancer cell strain (A549), the ovarian cancer cell strain (A2780), the breast cancer cell strain (MCF7) and the colon cancer cell strain (HT-29) are preserved and passaged by the cell center of the institute of basic medicine of Chinese academy of medicine and sciences. DMEM medium and pancreatin (Trypsin) were purchased from Gibco, Fetal Calf Serum (FCS) was a product of Hyclone, 100U/ml penicillin and 100g/ml streptomycin were purchased from Lonza; MTT was purchased from Sigma. The experimental method comprises the following steps:

determination of in vitro antitumor activity by MTT method:

selecting a human solid tumor cell strain: colon cancer cell line (HCT-116), liver cancer cell line (HepG2), gastric cancer cell line (BGC-823), lung cancer cell line (A549), ovarian cancer cell line (A2780), breast cancer cell line (MCF7) and colon cancer cell line (HT-29), culturing with DMEM containing 10% serum at 37 deg.C and 5% CO ₂ The cells cultured under the conditions are digested with 0.25% pancreatin, counted and added into a 96-well plate (37 ℃, 5% CO) ₂ ) And culturing for 24 h. Samples were dissolved in DMSO and diluted to working night concentration with 10% serum RPMI1640 medium and added to 96-well plates at final concentrations of 100, 10, 1. mu.M. After the drug was contacted with the cells for 96h, MTT (0.05%) was added at 37 ℃ with 5% CO ₂ Incubate for 4h under conditions and add DMSO. The BIO-RAD 450 type enzyme-linked analyzer detects the optical density at the dual wavelength of 450-570nm and calculates the IC ₅₀ The value is obtained.

The experimental results are as follows:

TABLE 1 in vitro inhibitory Activity of the Compounds on seven human tumor cell lines

Analysis and discussion of in vitro activity study results:

the antitumor activity of the compound is mainly 10 ^-7 ～10 ^-8 The mol/L range, wherein the selective inhibitory activity of the compounds 5,6 and 11 on several tumor cell strains can reach 10 ^-9 mol/L, is a selective potent antitumor compound; the activity data show that compared with the bis-tetrahydro isoquinoline pentacyclic simplified compound, the compound taking the tetrahydro carboline-tetrahydro isoquinoline heterozygous structure as the matrix has certain improvement on the antitumor activity, and the introduction of the tetrahydro carboline structure has certain superiority in improving the antitumor activity.

The change of the C-25 substituent of the compound has obvious influence on the antitumor activity, wherein the C-25 is the aromatic heterocyclic formamide and the substituted benzoyl compound both have better antitumor activity; for the substituted benzamide compounds, the change of the electrical property and steric hindrance of the substituent on the benzene ring has little influence on the antitumor activity; in addition, the activity of the compounds with aryl acrylamide and fatty amides at the C-25 position is obviously lower than that of the compounds with aromatic heterocyclic formamide and benzoyl. Thus, the C-25 position is a key anti-tumor structural modification site for the compound.

The compound has stronger activity on colon cancer cell strains HCT-116 and liver cancer cell strains HepG2, has the strongest inhibitory activity on ovarian cancer cell strains, and therefore, the compound 6 with the strongest activity is selected for evaluating the in-vivo anti-tumor activity of ovarian cancer cells A2780.

Experimental example 2: in vivo activity studies:

the in vivo antitumor effect of compound 6 single drug against human ovarian cancer A2780 was evaluated on a nude mouse subcutaneous allograft tumor model.

Experimental materials:

balb/c nude mice, 17-19g, SPF grade, female, supplied by Spbefu Biotechnology, Inc., quality certification number 11401300045101 for the experimental animal.

The experimental method comprises the following steps:

collecting human ovarian cancer A2780 tumor cells under aseptic condition, and adjusting cell density to 1 × 10 with sterilized normal saline ⁷ Taking 0.2ml per ml, inoculating to the subcutaneous layer of the axillary back of the nude mouse, taking out under aseptic condition when the tumor grows to the size of 1cm in diameter, cutting into tumor blocks of 1mm multiplied by 1mm, and uniformly inoculating to the subcutaneous layer of the axillary back of the nude mouse. 7 days later, the tumor grows to 100-300 mm ³ Thereafter, animals were randomized and dosing was initiated (day 0). The test compound is administered intraperitoneally daily; cisplatin was administered intraperitoneally 1 time per week. Body weights were weighed twice weekly and tumor lengths and widths were measured with a vernier caliper, nude mice were dislocated and sacrificed 21 days after dosing, tumor tissues were stripped, weighed and photographed. And finally, calculating the tumor inhibition rate, and evaluating the anti-tumor effect intensity by using the tumor inhibition rate.

The experimental results are as follows:

TABLE 2 growth inhibition of Compound 6 against human ovarian carcinoma A2780 nude mouse subcutaneous xenograft tumors

After administration for 14 days, the dose was adjusted from 0.5mg/kg to 5mg/kg

In the contrast group, 1 nude mouse had no tumor growth

NA is not applicable.

Claims

1. A compound represented by the following general formula I:

wherein R is ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₈ 、R ₉ Selected from: h, R ₆ 、R ₇ Independently of each other selected from: c ₁ -C ₈ Alkoxy group of (a); y is selected from CN;

R ₁₀ is selected from C ₆ -C ₁₀ Aryl of (C) ₄ -C ₁₀ Heteroaryl of (A), C ₆ -C ₁₀ Aryl substituted C ₀ -C ₄ Alkyl vinyl radical, C ₁ -C ₁₀ Linear or branched alkyl of (a); the aryl and the heteroaryl have one or more substituents selected from H, CF ₃ Halogen, C ₁ -C ₈ Straight-chain or branched alkyl, C ₁ -C ₈ An alkoxy group;

x is selected from NH and N; when X is selected from N, N and R ₁₀ Are connected to form C ₆ -C ₁₀ Aryl five-membered dicarboximide ring or C ₄ -C ₁₀ A heteroaryl and five-membered dicarboximide ring.

2. A compound of formula I according to claim 1, wherein:

R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₈ 、R ₉ selected from: h, R ₆ 、R ₇ Independently of each other selected from: c ₁ -C ₆ Alkoxy group of (a);

y is selected from CN;

R ₁₀ is selected from C ₆ -C ₁₀ Aryl of (C) ₄ -C ₁₀ Heteroaryl of (A), C ₆ -C ₈ Aryl substituted C ₀ -C ₂ Alkyl vinyl radical, C ₁ -C ₆ Linear or branched alkyl of (a); the aryl and the heteroaryl have one or more substituents selected from H, CF ₃ Halogen, C ₁ -C ₆ Straight-chain or branched alkyl, C ₁ -C ₆ An alkoxy group;

x is selected from NH and N; when X is selected from N, N and R ₁₀ Are connected to form C ₆ -C ₁₀ Aryl and five-membered dicarboximide ring of (A) or (C) ₄ -C ₁₀ The heteroaryl and five-membered dicarboximide ring of (a).

3. A compound according to any one of claims 1-2, wherein said compound is of formula IA, and pharmaceutically acceptable salts thereof

Said

Selected from phenyl, pyridyl, furyl, thienyl, naphthyl, quinolyl, indolyl, benzofuryl, benzothienyl, styryl;

R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₈ 、R ₉ selected from: h, R ₆ 、R ₇ Independently of each other selected from: -OCH ₃ ；

X is selected from NH;

y is selected from CN;

R ₁₁ represents one or more substituents and

the middle aromatic ring or the heteroaromatic ring is connected at any suitable position, and the substituents are independently selected from H, CF ₃ Halogen, C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ An alkoxy group.

4. A compound according to claim 3, wherein said compound is of formula IA1, and pharmaceutically acceptable salts thereof

R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₈ 、R ₉ Selected from: h, R ₆ 、R ₇ Independently of each other selected from：-OCH ₃ ；

X is selected from NH;

y is selected from CN;

R ₁₁₁ selected from H, CF ₃ 、F、Cl、Br、I、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ An alkoxy group.

5. A compound according to claim 3, wherein said compound is of formula IA2, and pharmaceutically acceptable salts thereof

X is selected from NH;

y is selected from CN;

R ₁₁₂ selected from H, CF ₃ 、F、Cl、Br、I、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ An alkoxy group.

6. A compound according to claim 3, wherein said compound is of formula IA3, and pharmaceutically acceptable salts thereof

X is selected from NH;

y is selected from CN;

R ₁₁₃ selected from H, CF ₃ 、F、Cl、Br、I、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ An alkoxy group.

7. A compound according to claim 3, wherein said compound is of formula IA4, and pharmaceutically acceptable salts thereof

X is selected from NH;

y is selected from CN;

R ₁₁₄ selected from H, CF ₃ 、F、Cl、Br、I、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ An alkoxy group.

8. A compound according to claim 3, wherein said compound is of formula IA5, and pharmaceutically acceptable salts thereof

X is selected from NH;

y is selected from CN;

R ₁₁₅ selected from H, CF ₃ 、F、Cl、Br、I、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ An alkoxy group.

9. A compound according to claim 3, wherein said compound is of formula IA6, and pharmaceutically acceptable salts thereof

X is selected from NH;

y is selected from CN;

R ₁₁₆ selected from H, CF ₃ 、F、Cl、Br、I、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ An alkoxy group.

10. A compound according to claim 3, wherein said compound is of formula IA7, and pharmaceutically acceptable salts thereof

X is selected from NH;

y is selected from CN;

R ₁₁₇ selected from H, CF ₃ 、F、Cl、Br、I、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ An alkoxy group;

r' is H, C ₁ -C ₄ Straight or branched chain alkyl.

11. A compound according to claim 3, wherein said compound is of formula IA8, and pharmaceutically acceptable salts thereof

X is selected from NH;

y is selected from CN;

R ₁₁₈ selected from H, CF ₃ 、F、Cl、Br、I、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ An alkoxy group.

12. A compound according to claim 3, wherein said compound is of formula IA9, and pharmaceutically acceptable salts thereof

X is selected from NH;

y is selected from CN;

R ₁₁₉ selected from H, CF ₃ 、F、Cl、Br、I、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ An alkoxy group.

13. A compound according to claim 3, wherein said compound is of formula IA10, and pharmaceutically acceptable salts thereof

R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₈ 、R ₉ Selected from the group consisting of: h, R ₆ 、R ₇ Independently of each other selected from: -OCH ₃ ；

X is selected from NH;

y is selected from CN;

R ₁₁₁₀ selected from H, CF ₃ 、F、Cl、Br、I、C ₁ -C ₄ Straight-chain or branched alkyl, C ₁ -C ₄ An alkoxy group.

14. A compound according to any one of claims 1-2, wherein said compound is of formula IA11, and pharmaceutically acceptable salts thereof

X is selected from NH;

y is selected from CN;

R ₁₁₁₁ is selected from C ₁ -C ₆ Linear or branched alkyl groups of (a).

15. A compound according to any one of claims 1-2, wherein said compound is of formula IB, and pharmaceutically acceptable salts thereof

Y is selected from CN;

R ₁₂ represents one or more substituents independently selected from H.

16. A compound according to any one of claims 1-2, wherein: the compound is selected from

17. A pharmaceutical composition comprising a compound of any one of claims 1 to 16, and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

18. A pharmaceutical composition according to claim 17, wherein the carrier comprises one or more carriers selected from the group consisting of: diluents, binders, wetting agents, disintegrants, lubricants and glidants.

19. A pharmaceutical composition according to any one of claims 17 to 18, further comprising an additional active ingredient which can be administered in combination with the compound and pharmaceutically acceptable salts thereof.

20. The use of a compound according to any one of the preceding claims 1 to 16, and pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment of a disease selected from: leukemia, melanoma, gastric cancer, lung cancer, breast cancer, renal cancer, liver cancer, oral epidermoid carcinoma, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, and colon cancer.