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CN108948003B - Preparation and use of pyrazino[2,3-c]quinoline-2(1H)-ones as mTOR inhibitors - Google Patents

Preparation and use of pyrazino[2,3-c]quinoline-2(1H)-ones as mTOR inhibitors Download PDF

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CN108948003B
CN108948003B CN201710365965.4A CN201710365965A CN108948003B CN 108948003 B CN108948003 B CN 108948003B CN 201710365965 A CN201710365965 A CN 201710365965A CN 108948003 B CN108948003 B CN 108948003B
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cancer
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quinoline
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CN108948003A (en
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向荣
范艳
郭庆祥
李永涛
张超
黄志�
王鑫
刘艳华
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Nankai University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

Pyrazino [2,3-c ] as mTOR inhibitors]Quinoline-2 (1)H) Preparation and use of ketone compounds. The invention relates to a method for producing substituted pyrazino [2,3-c ]]Quinoline-2 (1)H) -ketone compounds (formula I) or pharmaceutically acceptable salts thereof, which are useful in the treatment of proliferative diseases (e.g. benign neoplasms, cancer, inflammatory diseases, autoimmune diseases, diabetic retinopathy) and metabolic diseases. Novel small molecules are provided that inhibit one or more of mTORC1, mTORC2, and PI 3K-related proteins.

Description

Preparation and application of pyrazino [2,3-c ] quinoline-2 (1H) -ketone compound as mTOR inhibitor
Technical Field
The present invention relates to novel pyrazino [2,3-c ]]Quinoline-2 (1)H) -ketones and pharmaceutical compositions thereof, in particular pyrazino [2,3-c as mTORC1 and mTORC2 inhibitors]Quinoline-2 (1)H) -ketones and pharmaceutical compositions thereof. The invention also relates to methods and uses of these compounds and compositions in the treatment of hyperproliferative disorders (e.g., benign neoplasms, cancer, inflammatory diseases, autoimmune diseases, diabetic retinopathy) and metabolic diseases.
Background
mTOR is a highly conserved serine/threonine kinase. It belongs to the phosphoinositide 3-kinase-related kinase protein family (PIKK), and is commonly expressed in eukaryotic cells. mTOR can be classified into two major groups according to its protein composition, mTOR complex 1 (mTORC1) and mTOR complex 2(mTORC2), which have different biological functions. Two subtypes of mTOR play an important role in cell regulation. mTORC1 affects cell proliferation by promoting translation, ribosome biosynthesis, and autophagy. In particular, mTORC1 regulates many anabolic pathways. The method comprises metabolic synthesis processes closely related to cell and tissue growth, such as protein synthesis, ribosome production, lipogenesis, nucleotide synthesis and the like. Meanwhile, mTORC1 inhibits key catabolic processes and autophagy by inhibiting its activation, lysosomal production and the production of organelles capable of autophagy. Since mTORC2 has no specific inhibitor, the regulatory mechanism for mTORC2 is not currently well understood.
The mTOR signaling pathway is closely related to cell growth and metabolism. Dysregulation of this signaling pathway can lead to human diseases such as cancer, diabetes, obesity, neurological diseases, and genetic diseases. In recent years, a great deal of research on mTOR has shown that its associated pathways play an important role in the development of tumorigenesis. mTOR signaling is now found to be dysregulated in most tumors, such as lung cancer, prostate cancer, breast cancer, leukemia, and the like. The dysregulation of mTOR includes mainly the following two: the first is the over-activation of the PI3K/Akt/mTOR pathway, which results in accelerated cell cycle, decreased apoptosis, and promotion of tumor cell migration. Secondly, loss of PTEN function results in the release of PI3K inhibition, which activates Akt/mTOR downstream of the PTEN, and ultimately results in cell survival. The mTOR pathway is valued by globally relevant laboratories and pharmaceutical companies and has been exploited as an important target for cancer as a large number of small molecule inhibitors.
In conclusion, mTOR, as an important signal transduction molecule, is located at the central site of the entire signaling pathway, and plays a crucial role in the expression of the functions and actions of the entire signaling pathway. Various human diseases such as cancer, diabetes, Alzheimer's disease, etc. are related to the dysregulation of mTOR signaling pathway. Small molecule inhibitors of mTOR may provide effective methods for treating these diseases. The invention designs a synthetic small molecule inhibitor targeting mTOR kinase based on the existing findings, and the series of compounds have the potential of treating various diseases.
Disclosure of Invention
The compounds of the present invention are mTORC1 and mTORC2 inhibitors and are useful in the treatment of diseases and disorders mediated by mTORC1 and mTORC2, such as cancer, including mantle cell lymphoma, liposarcoma, non-small cell lung cancer, melanoma, squamous cell esophageal cancer, and breast cancer, among others. The invention also relates to the use of a compound of the invention or a pharmaceutical composition comprising a compound of the invention for the treatment of disorders associated therewith.
The invention relates to novel pyrazino [2,3-c ] having formula (I)]Quinoline-2 (1)H) -ketone compounds and salts thereof, including pharmaceutically acceptable salts:
Figure 99301DEST_PATH_IMAGE001
wherein:
R1and R4Selected from hydrogen, hydroxy, alkoxy, alkyl, halogen, cyano, amino or optionally substituted group: 6-10 membered aryl; c7-15Aralkyl group; c6-15Heteroaralkyl radical, C1-12A heteroaliphatic group; c1-12An aliphatic group; c3-8A cycloalkyl group; a 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and a 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
R2selected from the group consisting of optionally substituted: 6-10 membered aryl; c7-15Aralkyl group; c6-15Heteroaralkyl radical, C1-12A heteroaliphatic group; c1-12An aliphatic group; c3-8A cycloalkyl group; a 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and a 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
R3selected from H, halogen, -CN or selected from the following optionally substituted groups: c1-12An acyl group; 6-10 membered aryl; c7-15Aralkyl group; c6-15A heteroaralkyl group; c1-12A heteroaliphatic group C1-12An aliphatic group; a 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and a 4-7 membered heterocyclic group having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
In the definitions of the above compounds, the terms used, whether used alone or in compound words, represent the following substituents:
halogen is fluorine, chlorine, bromine or iodine;
aliphatic groups include, but are not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties;
alkyl is a straight or branched chain alkyl of 1 to 10 carbon atoms;
cycloalkyl is a monocyclic or polycyclic hydrocarbon group of 3 to 8 carbon atoms. Such groups may be substituted with groups such as fluoro, chloro, bromo, iodo, hydroxy, keto, amino, alkyl, and dialkylamino;
heterocyclyl is cycloalkyl carrying at least one nitrogen atom selected from O, S, N or a substituent. Such groups may be substituted with groups such as fluoro, chloro, bromo, iodo, hydroxy, keto, amino, alkyl, and dialkylamino;
alkoxy is a straight or branched chain alkyl of 1 to 10 carbon atoms and linked through an oxygen atom;
acyl is an alkyl or aryl group having 1 to 10 carbon atoms attached through a carbonyl group;
heteroaryl represents one or more 5-, 6-or 7-membered aromatic ring systems containing at least one up to four heteroatoms selected from nitrogen, oxygen or sulfur;
aryl represents an aryl carbocyclic group having a single ring, multiple rings or multiple condensed rings, at least one of which is aromatic, which may be mono-, di-, tri-substituted with halogen, alkyl, alkoxy, alkylthio, trifluoromethyl, acyloxy, aryl, heteroaryl, and hydroxy.
Cancers include, but are not limited to, the following cancers: breast cancer, ovarian cancer, prostate cancer, cervical cancer, esophageal cancer, testicular cancer, stomach cancer, skin cancer, lung cancer, bone cancer, colon cancer, pancreatic cancer, thyroid cancer, biliary tract cancer, small intestine cancer, colon-rectal cancer, large intestine cancer, rectal cancer, cancer of the brain and central nervous system, neuroblastoma, large cell cancer, adenocarcinoma, adenoma, follicular carcinoma, epidermoid carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, kidney cancer, bone marrow disorders, lymphoid disorders, hodgkin's disease, hair cell carcinoma, and leukemia.
Preferably R1Is hydrogen, hydroxy, alkoxy, halogen, cyano;
most preferably, R1Is hydrogen.
Preferably, R4Is H, halogen;
most preferably, R4Are hydrogen and fluorine.
Preference is given toEarth, R2Is an optionally substituted group of: 6-10 membered aryl; c7-15Aralkyl group; c6-15Heteroaralkyl radical, C1-12A heteroaliphatic group; c1-12An aliphatic group; c3-8A cycloalkyl group; a 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and a 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
more preferably, R2Is that
Figure 203392DEST_PATH_IMAGE002
。
Preferably, R3Is H, halogen, -CN or a group selected from the following optionally substituted groups: c1-12An acyl group; 6-10 membered aryl; c7-15Aralkyl group; c6-15A heteroaralkyl group; c1-12A heteroaliphatic group C1-12An aliphatic group; a 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and a 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
more preferably, R3Is that
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
Figure 630754DEST_PATH_IMAGE032
、
Figure 629934DEST_PATH_IMAGE033
、
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、
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、
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、
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、
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、
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、
Figure 316634DEST_PATH_IMAGE040
、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
Figure 953523DEST_PATH_IMAGE055
、
Figure 390190DEST_PATH_IMAGE056
。
Most preferably, R3Is that
Figure 375463DEST_PATH_IMAGE003
、
Figure 622905DEST_PATH_IMAGE004
、
Figure 693629DEST_PATH_IMAGE057
、
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、
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、
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、
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、
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、
Figure 35935DEST_PATH_IMAGE058
、
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、
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、
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、
Figure 889490DEST_PATH_IMAGE049
、
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、
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、
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、
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、
Figure 896629DEST_PATH_IMAGE064
、
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、
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。
Preferably, R5Is from
Figure 711504DEST_PATH_IMAGE065
、
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、
Figure 228253DEST_PATH_IMAGE067
、
Figure 58675DEST_PATH_IMAGE068
、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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；
Most preferably, R5Is that
Figure 77108DEST_PATH_IMAGE065
、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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。
Preferably R6Is hydrogen, alkyl, alkoxy, trifluoromethyl, halogen;
most preferably selected from R6Is hydrogen.
Preferably, n, i, j, k are integers from 0 to 4, including 1 and 4;
most preferably, j =0, 1, 2, k =0, 1 when i = 0; j =0, 1, k =0, 1 when i = 1.
The invention provides a process for the preparation of a compound of formula (II),
wherein:
PG is selected from Boc, Cbz, PMB, Bn;
x is selected from Cl, Br and I;
R1、R3、R4、 R5、R6n, i, j, k are as defined for formula (II);
the method comprises the following steps:
Figure 189289DEST_PATH_IMAGE115
general formula compound (III) compound (IV) is dissolved in organic solvent at a molar ratio of 1:1, then organic base is added, the mixture is stirred for 6-12 hours at room temperature, water is added for dilution, then compound (V) is obtained by filtration, compound (VI) is obtained under the action of reducing agent, compound (VI) and compound (VII) at a molar ratio of 1:1.1 are dissolved in organic solvent at room temperature, the mixture is stirred for 1-10 hours at room temperature, then condensing agent and organic base are added, compound (VIII) is obtained by stirring for 5-10 hours at room temperature, compound (VIII) is deprotected under the action of reducing agent or strong acid to obtain compound (IX), compound (IX) and compound X are reacted at 0-100 ℃ under the action of organic base or inorganic base for 5-12 hours to obtain compound (XI), compound (XI) and compound (XII) at a molar ratio of 1:1.5 are dissolved in organic solvent, adding a palladium catalyst and organic base or inorganic base, and reacting at 70-100 ℃ for 8-12 hours to obtain a compound (II); the organic solvent is selected from dichloromethane, chloroform, benzene, toluene, ethyl acetate, N-hexane, cyclohexane, tetrahydrofuran, 1, 4-dioxane, N-dimethyl polyamide and dimethyl sulfoxide; the organic base is selected from triethylamine, N-diisopropylethylamine, pyridine, N-dimethylaniline and 1, 8-diazacyclo [5,4,0] undecene-7; the inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide; the reducing agent is selected from iron powder/ammonium chloride, iron powder/acetic acid, zinc powder/acetic acid, palladium carbon hydrogen and palladium carbon ammonium formate; the strong acid is selected from hydrochloric acid and trifluoroacetic acid; the catalyst is selected from palladium acetate, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium dichloride, tris (dibenzylideneacetone) dipalladium and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride.
Pyrazino [2,3-c ] of the invention]Quinoline-2 (1)H) The ketone compounds may be mixed with pharmaceutical carriers or excipients (e.g., pharmaceutically acceptable carriers and excipients) according to conventional pharmaceutical formulation techniques to form pharmaceutical formulations. The pyrazino [2,3-c ] can be reacted with]Quinoline-2 (1)H) The ketone compounds are incorporated as the active ingredient in any of the usual oral dosage forms, including tablets, capsules and liquid preparations (e.g., elixirs and suspensions), containing coloring agents, flavoring agents, stabilizers and taste-masking substances. For mixed oral dosage forms, the pyrazino [2,3-c ] s]Quinoline-2 (1)H) The ketone compounds as active ingredients can be mixed with various common tablet materials (e.g. starch, calcium carbonate, lactose, sucrose and dicalcium phosphate) to facilitate tableting and encapsulation. The pyrazino [2,3-c ] can be reacted with]Quinoline-2 (1)H) -ketones in a pharmaceutically acceptable sterile liquid carrier such as sterile water, sterile organic solvent or a mixture of bothDissolving or suspending. The liquid carrier may be a carrier suitable for injection, such as physiological saline, propylene glycol or aqueous polyethylene glycol solution. In other cases, it may also be prepared by dispersing the micronised active ingredient in an aqueous solution of starch or sodium carboxymethylcellulose or in a suitable oil, for example arachis oil. Liquid pharmaceutical formulations (referred to as sterile solutions or suspensions) can be used for intravenous, intramuscular, intraperitoneal or subcutaneous injection.
The present invention also provides a pharmaceutical composition comprising at least one pyrazino [2,3-c ] according to the present invention as an active ingredient]Quinoline-2 (1)H) -ketone compounds. In addition, the pharmaceutical composition may comprise one or more inorganic or organic, solid or liquid pharmaceutically acceptable carriers or excipients. The term "pharmaceutically acceptable" refers to additives or compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction (e.g., dizziness, etc.) when administered to an animal such as a mammal (e.g., a human). Pharmaceutical carriers and excipients may include, but are not limited to, diluents, such as lactose, glucose, mannose, and/or glycerol; a lubricant; polyethylene glycol; binders, such as magnesium aluminum silicate, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone; and, if desired, disintegrating agents, such as starch, agar, alginic acid or a salt thereof such as sodium alginate; and/or adsorbents, colorants, preservatives, stabilizers, flavorants and sweeteners.
The invention also provides pyrazino [2,3-c ] of the formula (II)]Quinoline-2 (1)H) -therapeutic reforming uses of ketone compounds.
The invention also provides pyrazino [2,3-c ] of the formula (II)]Quinoline-2 (1)H) -ketones as adjuvant cancer therapy.
Detailed Description
Various aspects and features of the disclosure are described further below.
Abbreviations used herein are generally well known to those skilled in the art or may be readily understood based on basic knowledge.
The starting materials employed in the preparation of the compounds of the invention are known, can be prepared according to known methods or are commercially available.
The invention also relates to novel intermediates and/or starting materials. The same or similar reaction conditions and novel intermediates as those mentioned in the examples are particularly preferred.
Both intermediates and final products can be worked up and/or purified according to conventional methods including pH adjustment, extraction, filtration, drying, concentration, chromatography, trituration, crystallization, and the like.
In addition, the compounds of the present invention may be prepared by various methods known in the art or variations of the methods described herein.
The following examples are intended to illustrate the invention and are not intended to limit the scope of the invention in any way.
Example 1: 2- (4- (9- (6-aminopyridin-3-yl) -8-fluoro-2-oxopyrazino [2, 3-c)]Quinoline-1 (2)H) Preparation of (E) -yl) piperidin-1-yl) acetonitrile
Figure 925033DEST_PATH_IMAGE116
Step 1.1: preparation of tert-butyl 4- ((6-bromo-7-fluoro-3-nitroquinolin-4-yl) amino) piperidine-1-carboxylate
Figure 13075DEST_PATH_IMAGE117
In a 250mL two-necked flask, -6-bromo-4-chloro-7-fluoro-3-nitroquinoline (20 g, 65.5 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (14.4 g, 72.0 mmol) are dissolved in 150 mL DMF to give a yellow solution. DIEA (22.5 mL) was added and stirred overnight at room temperature. Adding 1L of water, stirring for 0.5 hour, filtering, washing filter residues with water, washing with ethanol until the filtrate is colorless, and drying at 60 ℃ under reduced pressure to obtain 21g of yellow solid with a yield of 68.4%.1H NMR (400 MHz, Chloroform-d) δ 9.38 (d, J = 8.6 Hz, 1H), 9.34 (s, 1H), 8.36 (d, J = 7.0 Hz, 1H), 7.68 (d, J = 9.0 Hz, 1H), 4.29 – 4.16 (m, 1H), 4.06 (d, J = 13.5 Hz, 2H), 3.06 (t, J = 12.1 Hz, 2H), 2.22 – 2.09 (m, 2H), 1.80 – 1.65 (m, 2H), 1.46 (s, 9H)；13C NMR (101 MHz, CDCl3) δ 162.08, 159.53, 154.55, 151.71, 151.59, 148.98, 148.67, 131.34, 131.31, 127.46, 117.52, 116.06, 115.85, 108.93, 108.70, 80.35, 55.72, 33.58, 28.50.
Step 1.2: preparation of tert-butyl 4- ((3-amino-6-bromo-7-fluoroquinolin-4-yl) amino) piperidine-1-carboxylic acid tert-butyl ester
Figure 217791DEST_PATH_IMAGE118
In a 500mL two-necked flask was added tert-butyl 4- ((6-bromo-7-fluoro-3-nitroquinolin-4-yl) amino) piperidine-1-carboxylate (21g, 1eq) and iron powder (25g, 10 eq). After adding 250mL of glacial acetic acid, the mixture is warmed to 60 ℃ and stirred moderately for 5 hours. Filtering with hot diatomaceous earth, and concentrating the filtrate to obtain crude product. The crude silica gel was chromatographed to give 9.8 g of a white solid, 49.9% yield.1H NMR (400 MHz, Chloroform-d) δ 8.47 (s, 1H), 7.96 (d, J = 7.1, 1.3 Hz, 1H), 7.64 (d, J= 9.5, 1.3 Hz, 1H), 4.12 (s, 2H), 3.84 (s, 2H), 3.52 – 3.36 (m, 2H), 2.73 (t, J = 12.8 Hz, 2H), 1.89 (d, J = 12.5 Hz, 2H), 1.45 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 157.81, 155.35, 154.75, 144.87, 143.73, 143.62, 132.82, 132.52, 124.95, 123.07, 114.83, 114.62, 110.12, 109.89, 79.92, 53.27, 34.00, 28.55.
Step 1.3: 4- (9-bromo-8-fluoro-2-oxopyrazino [2, 3-c)]Quinoline-1 (2)H)Preparation of tert-butyl (E) -yl) piperidine-1-carboxylate
Figure 151112DEST_PATH_IMAGE119
After tert-butyl 4- ((3-amino-6-bromo-7-fluoroquinolin-4-yl) amino) piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.14 mmol) was added to a 100 mL two-necked flask, the flask was evacuated and filled with argonThree times. Glyoxylic acid monohydrate (115 mg, 1.25 mmol) and 40 mL of extra dry tetrahydrofuran were added under argon to give a yellow solution. After stirring at room temperature for 8 hours, HATU (475 mg, 1.25 mmol) and DIEA (391. mu.L, 2.28 mmol) were added under argon and stirring continued overnight. The reaction solution was concentrated and purified by silica gel column chromatography to obtain 435 mg of a white solid with a yield = 73%.1H NMR (400 MHz, Chloroform-d) δ 9.18 (s, 1H), 8.34 (d, J = 6.9 Hz, 1H), 8.26 (s, 1H), 7.93 (d, J = 8.9 Hz, 1H), 4.79 – 4.67 (m, 1H), 4.40 (d, J = 28.5 Hz, 2H), 3.08 (qd, J = 12.5, 4.4 Hz, 2H), 2.82 (s, 2H), 1.87 (d, J = 12.7 Hz, 2H), 1.51 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 160.64, 158.10, 157.41, 154.55, 153.24, 152.06, 149.84, 149.73, 136.39, 129.51, 127.54, 116.24, 116.03, 115.71, 115.69, 110.06, 109.82, 80.30, 63.46, 28.93, 28.54.
Step 1.4: 9-bromo-8-fluoro-1- (piperidin-4-yl) pyrazino [2,3-c]Quinoline-2 (1)H) Preparation of keto hydrochloride
Figure 819991DEST_PATH_IMAGE120
5g of 4- (9-bromo-8-fluoro-2-oxopyrazino [2, 3-c)]Quinoline-1 (2)H) -yl) piperidine-1-carboxylic acid tert-butyl ester was dissolved in 40 mL ethyl acetate and 10 mL methylene chloride, and 4 mL concentrated HCl was added and stirred at room temperature for 3 hours. And concentrating the reaction solution to obtain a crude product. (proceed directly to the next step)
Step 1.5: 2- (4- (9-bromo-8-fluoro-2-oxopyrazino [2, 3-c)]Quinoline-1 (2)H) Preparation of (E) -yl) piperidin-1-yl) acetonitrile
Figure 265885DEST_PATH_IMAGE121
In a 100 mL single-necked flask, 9-bromo-8-fluoro-1- (piperidin-4-yl) pyrazino [2,3-c]Quinoline-2 (1)H) -keto hydrochloride (1.1 g, 2.66 mmol) suspended in 40 mL DMF, DIEA (3.66mL, 21.27 mmol) added to give a pale pink solution, bromoacetonitrile (370.9 μ L, 5.32 mmol) added and stirredOvernight. The reaction solution was concentrated and purified by silica gel column chromatography to obtain 860 mg of a white solid, yield = 77.7%.1H NMR (400 MHz, DMSO-d 6) δ 8.83 (s, 1H), 8.46 (d, J = 4.9 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.87 (s, 1H), 3.76 (p, J = 7.0 Hz, 1H), 3.48 (s, 2H), 3.11 – 2.97 (m, 2H), 2.51 – 2.28 (m, 4H), 1.56 – 1.39 (m, 2H); 13C NMR (101 MHz, DMSO-d 6) δ 160.65, 159.98, 158.63, 150.01, 149.11, 147.34, 147.27, 131.26, 131.20, 128.19, 128.09, 117.63, 117.60, 117.02, 112.19, 112.03, 105.95, 105.79, 50.74, 50.50, 46.18, 28.89.
Step 1.6: 2- (4- (9- (6-aminopyridin-3-yl) -8-fluoro-2-oxopyrazino [2, 3-c)]Quinoline-1 (2)H) Preparation of (E) -yl) piperidin-1-yl) acetonitrile
Figure 754635DEST_PATH_IMAGE116
2- (4- (9-bromo-8-fluoro-2-oxopyrazino [2, 3-c)]Quinoline-1 (2)H) -yl) piperidin-1-yl) acetonitrile (1.2 g, 2.88mmol), (6-aminopyridin-3-yl) boronic acid (437.4 mg, 3.17 mmol), sodium carbonate (8.65 mL, 1M in H2O), bis (triphenylphosphine) palladium dichloride (203.36 mg, 0.29mmol) were suspended in 80 mL1, 4-dioxane and stirred at 85 ℃ overnight. The reaction solution was concentrated, and silica gel column chromatography was performed to obtain 925 mg of a white solid, yield = 74.7%.1H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.29 (s, 1H), 8.27 (s, 1H), 8.09 (d, J = 8.1 Hz, 1H), 8.00 (d, J = 11.5 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H), 6.62 (d, J= 8.6 Hz, 1H), 6.39 (s, 2H), 4.92 – 4.74 (m, 1H), 3.79 (s, 2H), 3.07 – 2.89 (m, 4H), 2.40 – 2.26 (m, 2H), 2.02 – 1.91 (m, 2H)；13C NMR (101 MHz, DMSO) δ 160.74, 158.22, 157.33, 153.64, 152.69, 151.76, 149.49, 149.36, 144.12, 137.45, 136.08, 127.55, 127.51, 127.19, 123.17, 123.00, 118.85, 115.09, 114.81, 114.61, 113.97, 59.93, 51.39, 43.99, 26.53。
Example 2: (R) -2- (3- (9- (6-aminopyridin-3-yl) -8-fluoro-2-oxopyrazineAnd [2,3-c ]]Quinoline-1 (2)H) Preparation of (E) -yl) piperidin-1-yl) acetonitrile
Figure 694909DEST_PATH_IMAGE122
Step 2.1: preparation of (R) -3- ((6-bromo-7-fluoro-3-nitroquinolin-4-yl) amino) piperidine-1-carboxylic acid tert-butyl ester
Figure 218294DEST_PATH_IMAGE123
See step 1.1, 82% yield.1H NMR (400 MHz, Chloroform-d) δ 9.51 (d, J = 8.7 Hz, 1H), 9.34 (s, 1H), 8.42 (d, J = 7.0 Hz, 1H), 7.68 (d, J = 9.0 Hz, 1H), 4.26 (tp, J = 7.0, 3.3 Hz, 1H), 3.80 (d, J = 13.4 Hz, 1H), 3.46 (q, J = 6.2 Hz, 3H), 2.18 – 2.08 (m, 1H), 1.93 – 1.78 (m, 2H), 1.71 – 1.60 (m, 1H), 1.43 (s, 9H)；13C NMR (101 MHz, CDCl3) δ 162.06, 159.50, 154.76, 151.66, 151.54, 149.03, 148.61, 131.25, 127.57, 117.63, 115.99, 115.77, 109.10, 108.86, 80.70, 53.72, 31.64, 28.39, 22.48.
Step 2.2: preparation of (R) -3- ((3-amino-6-bromo-7-fluoroquinolin-4-yl) amino) piperidine-1-carboxylic acid tert-butyl ester
Figure 382559DEST_PATH_IMAGE124
See step 1.2, yield 58%.1H NMR (400 MHz, Chloroform-d) δ 8.36 (s, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.52 (d, J = 9.5 Hz, 1H), 3.96 – 3.87 (m, 1H), 3.60 (d, 1H), 3.45 (t, 3H), 1.95 – 1.77 (m, 1H), 1.75 – 1.54 (m, 2H), 1.53 – 1.44 (m, 1H), 1.36 (s, 9H)；13C NMR (101 MHz, CDCl3) δ 157.50, 155.05, 144.84, 143.58, 143.47, 133.58, 131.78, 125.30, 122.28, 114.24, 114.03, 109.36, 109.12, 80.09, 53.49, 51.44, 31.68, 28.31, 22.92.
Step 2.3: (R) -3- (9-bromo-8-fluoro-2-oxopyrazino [2, 3-c)]Quinoline-1 (2)H) Preparation of tert-butyl (E) -yl) piperidine-1-carboxylate
Figure 772256DEST_PATH_IMAGE125
See step 1.3, yield 64%.1H NMR (400 MHz, Chloroform-d) δ 9.16 (s, 1H), 8.50 (s, 1H), 8.25 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H), 4.75 – 4.56 (m, 1H), 4.11 (t, J = 11.7 Hz, 2H), 3.71 (dq, J = 12.5, 6.5 Hz, 1H), 3.17 (dt, J = 12.0, 5.6 Hz, 1H), 3.04 – 2.77 (m, 2H), 2.01 – 1.83 (m, 2H), 1.44 (dd, J = 13.8, 6.6 Hz, 9H)；13C NMR (101 MHz, CDCl3) δ 160.81, 157.62, 154.84, 152.93, 151.83, 129.59, 127.65, 115.80, 80.54, 61.94, 55.94, 43.87, 28.53, 27.50, 18.70.
Step 2.4: (R) -9-bromo-8-fluoro-1- (piperidin-3-yl) pyrazino [2,3-c]Quinoline-2 (1)H) Preparation of keto hydrochloride
Figure 312959DEST_PATH_IMAGE126
Refer to step 1.4.
Step 2.5: (R) -2- (3- (9-bromo-8-fluoro-2-oxopyrazino [2, 3-c)]Quinoline-1 (2)H) Preparation of (E) -yl) piperidin-1-yl) acetonitrile
Figure 690850DEST_PATH_IMAGE127
See step 1.5, yield 80%.1H NMR (400 MHz, DMSO-d 6) δ 9.14 (s, 1H), 8.34 (d, J = 7.3 Hz, 1H), 8.31 (s, 1H), 8.09 (d, J = 9.5 Hz, 1H), 4.72 (t, J = 11.3 Hz, 1H), 3.82 (q, J = 17.2 Hz, 2H), 3.39 (t, J = 10.5 Hz, 1H), 3.16 (d, J = 10.6 Hz, 1H), 2.84 (d, J = 10.9 Hz, 1H), 2.72 – 2.55 (m, 1H), 2.24 (t, J = 11.5 Hz, 1H), 2.04 – 1.82 (m, 2H), 1.67 – 1.49 (m, 1H)；1H NMR (400 MHz, DMSO-d 6) δ 9.14 (s, 1H), 8.34 (d, J = 7.3 Hz, 1H), 8.31 (s, 1H), 8.09 (d, J = 9.5 Hz, 1H), 4.72 (t, J = 11.3 Hz, 1H), 3.82 (q, J = 17.2 Hz, 2H), 3.39 (t, J = 10.5 Hz, 1H), 3.16 (d, J = 10.6 Hz, 1H), 2.84 (d, J = 10.9 Hz, 1H), 2.72 – 2.55 (m, 1H), 2.24 (t, J = 11.5 Hz, 1H), 2.04 – 1.82 (m, 2H), 1.67 – 1.49 (m, 1H).
Step 2.6: (R) -2- (3- (9- (6-aminopyridin-3-yl) -8-fluoro-2-oxopyrazino [2, 3-c)]Quinoline-1 (2)H) Preparation of (E) -yl) piperidin-1-yl) acetonitrile
Figure 478547DEST_PATH_IMAGE122
Referring to step 1.6, yield = 68%.1H NMR (400 MHz, DMSO-d 6) δ 9.09 (s, 1H), 8.34 (s, 1H), 8.30 (s, 1H), 8.16 (d, J = 8.1 Hz, 1H), 8.00 (d, J = 11.7 Hz, 1H), 7.81 (d, J = 8.7 Hz, 1H), 6.62 (d, J = 8.7 Hz, 1H), 6.40 (s, 2H), 4.97 – 4.87 (m, 1H), 3.95 – 3.75 (m, 2H), 3.49 – 3.39 (m, 2H), 2.86 (d, J = 10.9 Hz, 1H), 2.68 – 2.56 (m, 1H), 2.25 (t, J = 11.5 Hz, 1H), 1.87 – 1.75 (m, 2H), 1.65 – 1.48 (m, 1H)；13C NMR (101 MHz, DMSO) δ 161.14, 159.72, 158.62, 157.25, 151.80, 151.38, 148.68, 148.55, 148.02, 147.99, 137.44, 137.42, 137.10, 127.07, 127.06, 126.44, 126.28, 125.60, 125.55, 118.08, 118.07, 115.67, 115.08, 115.07, 114.79, 114.57, 108.06, 61.32, 53.59, 51.33, 45.24, 25.65, 24.46。
Example 3: 2- (3- (9- (6-aminopyridin-3-yl) -2-oxopyrazino [2, 3-c)]Quinoline-1 (2)H) Preparation of (E) -yl) pyrrolidin-1-yl) acetonitrile
Figure 879572DEST_PATH_IMAGE128
Step 3.1: preparation of tert-butyl 3- ((6-bromo-3-nitroquinolin-4-yl) amino) pyrrolidine-1-carboxylate
Figure 410917DEST_PATH_IMAGE129
See step 1.1, 82% yield.1H NMR (400 MHz, Chloroform-d) δ 9.47 (dd, J = 41.3, 7.8 Hz, 1H), 9.19 (s, 1H), 8.20 (s, 1H), 7.74 (s, 2H), 4.84 – 4.66 (m, 1H), 3.78 (dd, J = 11.7, 5.7 Hz, 1H), 3.64 – 3.39 (m, 3H), 2.47 – 2.30 (m, 1H), 2.11 (dq, J = 12.0, 5.7 Hz, 1H), 1.40 (s, 9H)；13C NMR (101 MHz, CDCl3) δ 154.14, 148.97, 148.62, 147.26, 135.71, 132.08, 128.34, 126.97, 120.39, 119.52, 80.07, 57.72, 56.74, 52.93, 52.60, 43.85, 43.51, 33.79, 32.98, 28.35.
Step 3.2: preparation of tert-butyl 3- ((3-amino-6-bromoquinolin-4-yl) amino) pyrrolidine-1-carboxylate
Figure 908894DEST_PATH_IMAGE130
See step 1.2, yield 55%.1H NMR (400 MHz, Chloroform-d) δ 8.47 (s, 1H), 7.86 (s, 1H), 7.79 (d, J = 8.9 Hz, 1H), 7.47 (d, J = 8.9 Hz, 1H), 4.16 – 4.08 (m, 1H), 4.07 – 3.96 (m, 1H), 3.69 – 3.59 (m, 1H), 3.47 (td, J = 16.8, 8.2 Hz, 1H), 3.39 – 3.21 (m, 1H), 2.12 – 2.01 (m, 1H), 1.94 – 1.82 (m, 1H), 1.45 (d, J = 12.3 Hz, 9H)；13C NMR (101 MHz, CDCl3) δ 154.78, 143.79, 142.40, 133.68, 131.75, 131.70, 129.06, 126.26, 122.33, 120.79, 79.77, 55.66, 54.91, 52.14, 51.70, 44.37, 44.01, 32.55, 31.96, 28.59.
Step 3.3: 3- (9-bromo-2-oxopyrazino [2, 3-c)]Quinoline-1 (2)H) Preparation of (tert-butyl) -yl) pyrrolidine-1-carboxylic acid
Figure 352645DEST_PATH_IMAGE131
See step 1.3, 61% yield.1H NMR (400 MHz, DMSO-d 6) δ 9.10 (s, 1H), 8.32 (s, 1H), 8.28 (s, 1H), 8.05 (s, 1H), 8.00 (d, J = 8.9, 1.8 Hz, 1H), 5.62 – 5.52 (m, 1H), 3.83 – 3.68 (m, 3H), 3.49 (td, J = 9.1, 5.5 Hz, 1H), 2.65 – 2.54 (m, 1H), 2.48 – 2.36 (m, 1H), 1.42 (s, 9H)；13C NMR (101 MHz, DMSO) δ 156.79, 153.16, 152.10, 151.44, 146.96, 136.36, 133.33, 131.93, 127.16, 119.19, 118.92, 78.49, 60.79, 60.08, 48.92, 48.38, 45.89, 45.38, 38.25, 29.86, 28.62, 28.20.
Step 3.4: 9-bromo-1- (pyrrolidin-3-yl) pyrazino [2,3-c]Quinoline-2 (1)H) Preparation of keto hydrochloride
Figure 755813DEST_PATH_IMAGE132
Refer to step 1.4;
step 3.5: 2- (3- (9-bromo-2-oxopyrazino [2, 3-c)]Quinoline-1 (2)H) Preparation of (E) -yl) pyrrolidin-1-yl) acetonitrile
Figure 638319DEST_PATH_IMAGE133
See step 1.5, yield 70%.1H NMR (400 MHz, Chloroform-d) δ 9.18 (s, 1H), 8.34 (s, 1H), 8.32 (s, 1H), 8.09 (d, J = 8.9 Hz, 1H), 7.89 (d, J = 8.9, 1.9 Hz, 1H), 5.51 (tt, J = 13.3, 6.4 Hz, 1H), 3.75 (s, 2H), 3.46 (t, J = 8.2 Hz, 1H), 3.39 (q, J = 8.1 Hz, 1H), 3.20 (t, J = 8.6 Hz, 1H), 3.10 (td, J = 7.9, 3.2 Hz, 1H), 2.65 – 2.44 (m, 2H)；13C NMR (101 MHz, CDCl3) δ 157.04, 152.12, 152.04, 147.82, 136.12, 134.12, 132.70, 127.81, 126.38, 120.66, 118.96, 114.98, 61.33, 53.75, 52.55, 41.72, 30.13.
Step 3.6: 2- (3- (9- (6-aminopyridin-3-yl) -2-oxopyrazino [2, 3-c)]Quinoline-1 (2)H) Preparation of (E) -yl) pyrrolidin-1-yl) acetonitrile
Figure 928486DEST_PATH_IMAGE134
Referring to step 1.6, yield = 75.2%.1H NMR (400 MHz, DMSO-d 6) δ 9.05 (s, 1H), 8.39 (d, J = 2.5 Hz, 1H), 8.32 (s, 1H), 8.28 (s, 1H), 8.19 – 8.10 (m, 2H), 7.83 (dd, J = 8.6, 2.6 Hz, 1H), 6.62 (d, J = 8.6 Hz, 1H), 6.27 (s, 2H), 5.69 – 5.57 (m, 1H), 3.92 (d, J = 2.2 Hz, 2H), 3.40 – 3.35 (m, 1H), 3.22 (t, J = 8.5 Hz, 1H), 3.18 – 3.09 (m, 1H), 2.99 – 2.91 (m, 1H), 2.46 – 2.39 (m, 1H), 2.38 – 2.27 (m, 1H)；13C NMR (101 MHz, DMSO) δ 159.57, 156.93, 151.47, 150.33, 147.19, 146.45, 137.14, 135.79, 135.77, 130.57, 128.72, 127.28, 122.95, 120.23, 118.00, 116.19, 108.44, 60.74, 53.05, 51.66, 40.94, 29.18。
Some of the compounds of the present invention are shown in table 1:
TABLE 1
Figure 605455DEST_PATH_IMAGE135
Figure 230340DEST_PATH_IMAGE136
Figure 41170DEST_PATH_IMAGE137
Figure 185843DEST_PATH_IMAGE138
Figure 486244DEST_PATH_IMAGE139
Figure 349157DEST_PATH_IMAGE140
Figure 573465DEST_PATH_IMAGE141
Figure 87492DEST_PATH_IMAGE142
Figure 496477DEST_PATH_IMAGE143
Figure 768058DEST_PATH_IMAGE144
Biological assay
In vitro mTOR enzyme inhibitory Activity assay
The invention provides the inhibition efficacy and selectivity of partial compounds on mTOR and related proteins, and related in vitro Kinase experiments are determined by Kinase Profile services of Eurofins. Table 2 shows the mTOR inhibition of a portion of the compounds at a concentration of 1. mu.M.
TABLE 2
Figure 733740DEST_PATH_IMAGE145
The invention provides the antitumor activity of part of compounds.
Experimental method for antitumor activity
The cell culture concentration was 3X 103 cells/0.1 mL/well, 96-well plate. Adding the medicine after 24 hours of culture, and adding the medicine according to the medicine concentration. Control group (inoculated cells without drug) and blank well (inoculated cells with culture medium) were set simultaneously with 5% CO2Incubate at 37 ℃ for 72 hours. The cell number was determined by CCK-8 (Promega, Wis.) colorimetry using a Microplate reader (Promega, Wis.) as the instrument. TABLE 3 partial compound 1 against some tumor cellssemi-Inhibitory Concentration (IC) in vitro50）
TABLE 3
Figure 102273DEST_PATH_IMAGE146
It can be seen from table 2 that most of the compounds of the present invention have a good inhibitory effect on mTOR kinase. From Table 3, it can be seen that compound 1 has very good inhibitory effect on A549, H1299, H460, T47D and MCF7, but has weak inhibitory effect on MDA-MB-231, Skov3, K562 and other cell lines. Pyrazino [2,3-c ] of the invention]Quinoline-2 (1)H) The ketone compound has good anti-tumor activity and selectivity.

Claims (6)

1.式(Ⅱ)化合物或其可药用盐1. The compound of formula (II) or a pharmaceutically acceptable salt thereof
Figure FDA0003073541220000011
Figure FDA0003073541220000011
 其中：in: R1和R6选自氢；R 1 and R 6 are selected from hydrogen; R3是
Figure FDA0003073541220000012
Figure FDA0003073541220000013
 R3 is
Figure FDA0003073541220000012
Figure FDA0003073541220000013
 R4选自氢、氟；R 4 is selected from hydrogen, fluorine; R5是
Figure FDA0003073541220000014
Figure FDA0003073541220000015
 R5 is
Figure FDA0003073541220000014
Figure FDA0003073541220000015
 所述的式(II)化合物，i＝0时，其中：当j＝1时，k＝0或1，当j＝2时，k＝0；The compound of formula (II), when i=0, wherein: when j=1, k=0 or 1, and when j=2, k=0; i＝1时，j＝1，k＝0或1；When i=1, j=1, k=0 or 1; n为0到4的整数。n is an integer from 0 to 4. 2.一种制备如权利要求1所述的式(II)化合物的方法，2. A method of preparing a compound of formula (II) as claimed in claim 1, 其中：in: PG选自Boc、Cbz、PMB、Bn；PG is selected from Boc, Cbz, PMB, Bn; X选自Cl、Br、I；X is selected from Cl, Br, I; R1、R3、R4、R5、R6、n、i、j、k是如权利要求1中式(II)化合物所定义的；R 1 , R 3 , R 4 , R 5 , R 6 , n, i, j, k are as defined in claim 1 for compounds of formula (II); 所述方法包含以下步骤：The method includes the following steps:
Figure FDA0003073541220000021
Figure FDA0003073541220000021
 通式化合物(Ⅲ)和通式化合物(Ⅳ)以摩尔比1:1溶于有机溶剂中，然后加入有机碱，室温搅拌6-12小时，加入水稀释后过滤得化合物(Ⅴ)，化合物(Ⅴ)在还原剂的作用下得化合物(Ⅵ)，化合物(Ⅵ)与化合物(Ⅶ)摩尔比1:1.1溶于有机溶剂中室温搅拌1-10小时，然后加入缩合剂和有机碱，室温搅拌5-10小时得化合物(Ⅷ)，在还原剂或强酸的作用下化合物(Ⅷ)脱去保护基得化合物(Ⅸ)，化合物(Ⅸ)与化合物Ⅹ在有机碱或无机碱的作用下，0-100摄氏度，反应5-12小时得化合物(Ⅸ)，化合物(Ⅸ)与化合物(Ⅻ)摩尔比1:1.5溶于有机溶剂中，加入钯催化剂和有机碱或无机碱，70-100摄氏度反应8-12小时得化合物(II)；所述的有机溶剂选自二氯甲烷、氯仿、苯、甲苯、乙酸乙酯、正己烷、环己烷、四氢呋喃、1，4-二氧六环、N，N-二甲基集酰胺、二甲基亚砜；所述的有机碱选自三乙胺、N，N-二异丙基乙胺、吡啶、N，N-二甲基苯胺、1，8-二氮杂环[5，4，0]十一烯-7；无机碱选自氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠、碳酸氢钾；所述的还原剂选自铁粉/氯化铵、铁粉/醋酸、锌粉/醋酸、钯碳氢气、钯碳甲酸铵；所述强酸选自盐酸、三氟乙酸；所述催化剂选自醋酸钯、四(三苯基膦)钯、双(三苯基膦)二氯化钯、三(二亚苄基丙酮)二钯、[1，1'-双(二苯基膦基)二茂铁]二氯化钯。The general formula compound (III) and the general formula compound (IV) are dissolved in an organic solvent in a molar ratio of 1:1, then an organic base is added, stirred at room temperature for 6-12 hours, diluted with water, and filtered to obtain compound (V), compound ( Ⅴ) Under the action of a reducing agent, compound (VI) is obtained. The molar ratio of compound (VI) to compound (VII) is 1:1.1, dissolved in an organic solvent and stirred at room temperature for 1-10 hours, then a condensing agent and an organic base are added, and the mixture is stirred at room temperature 5-10 hours to obtain compound (VIII), under the action of reducing agent or strong acid, compound (VIII) removes the protective group to obtain compound (IX), compound (IX) and compound X under the action of organic base or inorganic base, 0 -100 degrees Celsius, react for 5-12 hours to obtain compound (IX), compound (IX) and compound (XII) in a molar ratio of 1:1.5, dissolve in organic solvent, add palladium catalyst and organic base or inorganic base, and react at 70-100 degrees Celsius Compound (II) is obtained in 8-12 hours; the organic solvent is selected from methylene chloride, chloroform, benzene, toluene, ethyl acetate, n-hexane, cyclohexane, tetrahydrofuran, 1,4-dioxane, N , N-dimethyl amide, dimethyl sulfoxide; the organic base is selected from triethylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, 1, 8-diazacyclo[5,4,0]undecene-7; the inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate; the The reducing agent is selected from iron powder/ammonium chloride, iron powder/acetic acid, zinc powder/acetic acid, palladium carbon hydrogen, palladium carbon ammonium formate; the strong acid is selected from hydrochloric acid, trifluoroacetic acid; the catalyst is selected from palladium acetate, Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene] Palladium dichloride. 3.一种药物组合物，其包含权利要求1所述的化合物或其可药用盐以及可药用的载体或赋形剂。3. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. 4.如权利要求1所述的化合物或权利要求3所述的药物组合物在制备治疗与mTOR激酶相关的疾病的药物中的用途，所述疾病为癌症，其包括给有需要的个体施用权利要求1所述的化合物或权利要求3所述的药物组合物。4. Use of the compound of claim 1 or the pharmaceutical composition of claim 3 in the manufacture of a medicament for the treatment of a disease associated with mTOR kinase, the disease being cancer, comprising administering the right to an individual in need thereof The compound of claim 1 or the pharmaceutical composition of claim 3. 5.如权利要求1所述化合物或其可药用盐在制备治疗癌症的药物中的用途，其包括向有需要的患者给予有效量的权利要求1所述的化合物或其可药用盐。5. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer, comprising administering an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof to a patient in need thereof. 6.根据权利要求4所述的用途，其特征在于，所述的癌症选自乳腺癌、卵巢癌、前列腺癌、子宫颈癌、食道癌、睾丸癌、胃癌、皮肤癌、肺癌、骨癌、结肠癌、胰腺癌、甲状腺癌、胆道癌、小肠癌、结肠-直肠癌、大肠癌、直肠癌、脑与中枢神经系统的癌症、神经母细胞瘤、大细胞癌、滤泡癌、表皮样癌、精原细胞瘤、黑色素瘤、肉瘤、膀胱癌、肝癌、肾癌、何杰金氏病、毛发细胞癌和白血病。6. purposes according to claim 4 is characterized in that, described cancer is selected from breast cancer, ovarian cancer, prostate cancer, cervix cancer, esophagus cancer, testicular cancer, stomach cancer, skin cancer, lung cancer, bone cancer, Colon cancer, pancreatic cancer, thyroid cancer, biliary tract cancer, small bowel cancer, colorectal cancer, colorectal cancer, rectal cancer, cancer of the brain and central nervous system, neuroblastoma, large cell carcinoma, follicular carcinoma, epidermoid carcinoma , seminoma, melanoma, sarcoma, bladder cancer, liver cancer, kidney cancer, Hodgkin's disease, hair cell carcinoma and leukemia.
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