CN108948003A - Pyrazine as mTOR inhibitors simultaneously [2,3-c] quinoline -2(1H) -one class compound preparation and purposes - Google Patents

Pyrazine as mTOR inhibitors simultaneously [2,3-c] quinoline -2(1H) -one class compound preparation and purposes Download PDF

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CN108948003A
CN108948003A CN201710365965.4A CN201710365965A CN108948003A CN 108948003 A CN108948003 A CN 108948003A CN 201710365965 A CN201710365965 A CN 201710365965A CN 108948003 A CN108948003 A CN 108948003A
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cancer
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alkyl
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CN108948003B (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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    • 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
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Abstract

Pyrazine as mTOR inhibitors simultaneously [2,3-c] quinoline -2(1H) -one class compound preparation and purposes.Substituted pyrazine simultaneously [2,3-c] quinoline -2(1 is prepared the present invention relates to a kind ofH) -one class compound (Formulas I) or its pharmaceutically acceptable method at salt, the compound is suitable for treatment proliferative disease (such as benign neoplasm, cancer, inflammatory diseases, autoimmune disease, diabetic retinopathy) and metabolic disease.It provides and inhibits one of mTORC1, mTORC2 and PI3K GAP-associated protein GAP or one or more of novel small molecule.

Description

Pyrazine as mTOR inhibitors simultaneously [2,3-c] quinoline -2(1H) -one class compound Preparation and purposes
Technical field
The present invention relates to new pyrazine simultaneously [2,3-c] quinoline -2(1H) -one and its pharmaceutical composition, particularly conduct The pyrazine of mTORC1 and mTORC2 inhibitor simultaneously [2,3-c] quinoline -2(1H) -one and its pharmaceutical composition.The invention further relates to this A little compounds and composition are in treatment hyperproliferative disorders (such as benign neoplasm, cancer, inflammatory diseases, autoimmunity Disease, diabetic retinopathy) and metabolic disease method and purposes.
Background technique
MTOR is highly conserved serine/threonine kinase.It belongs to phosphoinositide 3-kinase associated kinase albumen man Race (phosphoinositide 3-kinase-related kinase family, PIKK), generally expresses in eukaryocyte In.Two major classes, i.e. mTOR complex 1 (mTORC1) and mTOR complex 2 can be divided into according to the different mTOR that protein forms (mTORC2), they have different biological functions.Two hypotypes of mTOR play an important role in cell adjusting.mTORC1 Cell Proliferation is influenced by promoting translation, ribosomes biosynthesis and autophagy.Specifically, mTORC1 has regulated and controled many conjunctions At metabolic pathway.It is synthesized including protein, ribosomal production, fat generation and the synthesis of nucleotide etc. and cell and group Knit the metabolism synthesis process of growth substantial connection.MTORC1 is by inhibiting itself activation simultaneously, the generation of lysosome and can send out The generation for the organelle bitten is born to inhibit crucial catabolic process and autophagy.Since mTORC2 inhibits without specificity Agent is at present not very clear the regulatory mechanism of mTORC2.
MTOR signal path and cell are grown and metabolism has close relationship.The dysregulation of the signal path will lead to Human diseases such as cancer, diabetes, obesity, neurological disease and genetic disease.In recent years, largely show about mTOR correlative study Its related pathways plays key player in tumor development.Have now been found that mTOR signal path in most of tumours such as lung All dysregulation in cancer, prostate cancer, breast cancer, leukaemia etc..Abnormal adjust of mTOR mainly includes following two: being first The excessive activation of PI3K/Akt/mTOR access, so as to cause cell cycle acceleration, Apoptosis is reduced, and promotes tumour thin The migration of born of the same parents.The missing of followed by PTEN function causes the inhibiting effect of PI3K to release, to have activated Akt/ downstream MTOR eventually leads to the survival of cell.MTOR access is paid attention to by the relevant laboratory in the whole world and drugmaker, and by conduct The important target spot of anticancer has carried out the exploitation of a large amount of micromolecular inhibitor.
In short, signal transducers mTOR important as one kind, positioned at the center site of entire signal path, to entire The expression of signal path function and effect is played the role of vital.The a variety of disorders such as cancers of the mankind, diabetes, alzheimer ' It writes from memory, all has relationship with the imbalance of mTOR signal path.The micromolecular inhibitor of mTOR can provide effective method to treat these Disease.The present invention be it has been found that on the basis of, design synthesis targeting mTOR kinases micromolecular inhibitor, the seriation Closing object has the potentiality for treating a variety of diseases.
Summary of the invention
The compound of the present invention is mTORC1 and mTORC2 inhibitor, can be used for treating by mTORC1 and mTORC2 mediation Disease and disorder, such as cancer including lymphoma mantle cell, sarcolipoma, non-small cell lung cancer, melanoma, squamous cell food Pipe cancer and breast cancer etc..Pharmaceutical composition the invention further relates to the compound of the present invention is used or comprising the compound of the present invention is come Treat associated disorder.
The present invention relates to the new pyrazine with formula (I) simultaneously [2,3-c] quinoline -2(1H) -one compound and its salt including Officinal salt:
Wherein:
R1And R4Selected from hydrogen, hydroxyl, alkoxy, alkyl, halogen, cyano, amino or any following group that replaces: 6-10 member virtue Base；C7-15Aralkyl；C6-15Heteroarylalkyl; C1-12Miscellaneous fatty group；C1-12Fatty group；C3-8Naphthenic base；Solely with 1-4 Heteroatomic 5-10 unit's heteroaryl on the spot selected from the group being made of nitrogen, oxygen and sulphur；With with 1-2 independently selected from by The heteroatomic 4-7 circle heterocyclic ring base of the group of nitrogen, oxygen and sulphur composition；
R2Selected from any substituted following group: 6-10 member aryl；C7-15Aralkyl；C6-15Heteroarylalkyl; C1-12Miscellaneous aliphatic Base；C1-12Fatty group；C3-8Naphthenic base；With 1-4 independently selected from the heteroatomic of the group being made of nitrogen, oxygen and sulphur 5-10 unit's heteroaryl；With with 1-2 heteroatomic 4-7 circle heterocyclic rings independently selected from the group being made of nitrogen, oxygen and sulphur Base；
R3Selected from H, halogen ,-CN or selected from any substituted following group group: C1-12Acyl group；6-10 member aryl；C7-15Aralkyl Base；C6-15Heteroarylalkyl；C1-12Miscellaneous fatty group; C1-12Fatty group；With 1-4 independently selected from by nitrogen, oxygen and sulphur group At group heteroatomic 5-10 unit's heteroaryl；With with 1-2 independently selected from the group being made of nitrogen, oxygen and sulphur Heteroatomic 4-7 circle heterocyclic ring base.
In the definition of above compound, no matter term used exclusive use is also used in compound word, representative takes as follows Dai Ji:
Halogen is fluorine, chlorine, bromine or iodine；
Fatty group includes but is not limited to alkyl, alkenyl, alkynyl, naphthenic base, cycloalkenyl and cycloalkynyl radical part；
Alkyl is the linear or branched alkyl group of 1 to 10 carbon atom；
Naphthenic base is the monocycle or multi-ring alkyl of 3 to 8 carbon atoms.This kind of group can by such as fluorine, chlorine, bromine, iodine, hydroxyl, The groups such as ketone group, amino, alkyl and dialkyl amido replace；
Heterocycle is to carry at least one naphthenic base for being selected from O, S, N or substituted nitrogen-atoms.This kind of group can by such as fluorine, The groups such as chlorine, bromine, iodine, hydroxyl, ketone group, amino, alkyl and dialkyl amido replace；
Alkoxy is 1 to 10 carbon atom and passes through the linear or branched alkyl group of oxygen atom connection；
Acyl group is the alkyl or aryl with 1 to 10 carbon atom connected by carbonyl；
The aromatic ring system of heteroaryl basis representation one or more 5-, 6- or 7- member, at least containing one at most containing there are four be selected from The hetero atom of nitrogen, oxygen or sulphur；
Aryl indicates aryl carbon ring group, has single ring, multiple rings or multiple condensed ring, and wherein at least one is aromatics, it Can by halogen, alkyl, alkoxy, alkylthio group, trifluoromethyl, acyloxy, aryl, heteroaryl and hydroxyl it is mono-, two-, three- Replace.
Cancer includes but is not limited to following cancer: breast cancer, oophoroma, prostate cancer, cervix cancer, cancer of the esophagus, testis It is cancer, gastric cancer, cutaneum carcinoma, lung cancer, osteocarcinoma, colon cancer, cancer of pancreas, thyroid cancer, cancer of bile ducts, carcinoma of small intestine, colon-rectum, big Intestinal cancer, the carcinoma of the rectum, brain and the cancer of central nervous system, neuroblastoma, large cell carcinoma, gland cancer, adenoma, follicular carcinoma, table Dermoid cancer, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, kidney, bone marrow disorder, lymph obstacle, He Jiejinshi Disease, hair cell cancer and leukaemia.
Preferably R1It is hydrogen, hydroxyl, alkoxy, halogen, cyano；
Most preferably, R1It is hydrogen.
Preferably, R4It is H, halogen；
Most preferably, R4It is hydrogen and fluorine.
Preferably, R2It is any substituted following group: 6-10 member aryl；C7-15Aralkyl；C6-15Heteroarylalkyl; C1-12 Miscellaneous fatty group；C1-12Fatty group；C3-8Naphthenic base；With 1-4 independently selected from the group being made of nitrogen, oxygen and sulphur Heteroatomic 5-10 unit's heteroaryl；With with 1-2 heteroatomic 4-7 independently selected from the group being made of nitrogen, oxygen and sulphur Circle heterocyclic ring base；
It is highly preferred that R2It is。
Preferably, R3It is H, halogen ,-CN or selected from any substituted following group group: C1-12Acyl group；6-10 member aryl； C7-15Aralkyl；C6-15Heteroarylalkyl；C1-12Miscellaneous fatty group; C1-12Fatty group；With 1-4 independently selected from by nitrogen, The heteroatomic 5-10 unit's heteroaryl of the group of oxygen and sulphur composition；With with 1-2 independently selected from being made of nitrogen, oxygen and sulphur Group heteroatomic 4-7 circle heterocyclic ring base；
It is highly preferred that R3It is、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、。
Most preferably, R3It is、、、、、、、、、、、、、、、、、、、、。
Preferably, R5It is certainly、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、 、；
Most preferably, R5It is、、、、、、、、、、、、。
Preferably R6It is hydrogen, alkyl, alkoxy, trifluoromethyl, halogen；
Most preferably from R6It is hydrogen.
Preferably, the integer that n, i, j, k are 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 as i=1.
The present invention provides a kind of method for preparing formula (II) compound,
Wherein:
PG is selected from Boc, Cbz, PMB, Bn;
X is selected from Cl, Br, I;
R1 、R3 、R4、 R5 、R6, n, i, j, k be as defined in formula (II);
The method comprises the steps of:
General formula compound (III) general formula compound (IV) molar ratio 1:1 is dissolved in organic solvent, organic base is then added, room temperature is stirred It mixes 6-12 hours, filters to obtain compound (V) after water dilution is added, compound (V) obtains compound under the action of reducing agent (VI), compound (VI) and compound (VII) molar ratio 1:1.1, which are dissolved in organic solvent, is stirred at room temperature 1-10 hours, is then added Condensing agent and organic base are stirred at room temperature 5-10 hours to obtain compound (VIII), compound (VIII) under the action of reducing agent or strong acid It sloughs protecting group to obtain compound (Ⅸ), under the action of organic base or inorganic base, 0-100 is Celsius for compound (Ⅸ) and compound Ⅹ Degree obtains compound (Ⅺ) in reaction 5-12 hours, and compound (Ⅺ) and compound (Ⅻ) molar ratio 1:1.5 are dissolved in organic solvent, Palladium catalyst and organic base or inorganic base is added, 70-100 degrees Celsius obtains compound (II) in reaction 8-12 hours；Described is organic Solvent is selected from methylene chloride, chloroform, benzene, toluene, ethyl acetate, n-hexane, hexamethylene, tetrahydrofuran, 1,4- dioxane, N, N- diformazan basis set amide, dimethyl sulfoxide；The organic base is selected from triethylamine, N, N- diisopropylethylamine, pyridine, N, N- bis- Methylaniline, 1,8- diazacyclo [5,4,0] hendecene -7；Inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, carbonic acid Potassium, cesium carbonate, sodium bicarbonate, saleratus, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide；The reducing agent is selected from iron powder/chlorine Change ammonium, 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；It is described to urge Agent be selected from palladium acetate, tetrakis triphenylphosphine palladium, bis- (triphenylphosphine) palladium chlorides, tris(dibenzylideneacetone) dipalladium, [1, Bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride.
Pyrazine of the present invention simultaneously [2,3-c] quinoline -2(1H) -one class compound can according to conventional medicine prepare skill Art and pharmaceutical carrier or excipient (such as pharmaceutically acceptable carrier and excipient) are mixed to form pharmaceutical preparation.Can by institute State pyrazine simultaneously [2,3-c] quinoline -2(1H) -one class compound is blended in any commonly employed peroral dosage form as active constituent, institute Stating peroral dosage form includes tablet, capsule and liquid preparation (such as elixir and suspension), wherein comprising colorant, corrigent, The substance of stabilizer and taste masking.For mixing peroral dosage form, the pyrazine simultaneously [2,3-c] quinoline -2(1H) -one class Compound can be with various conventional tablet materials (such as starch, calcium carbonate, lactose, sucrose and Dicalcium Phosphate) as active constituent Mixing is to help tabletting and is packed into capsule.It can be by the pyrazine simultaneously [2,3-c] quinoline -2(1H) -one class compound is pharmaceutically It dissolves or is suspended in the mixture of acceptable sterile liquid carrier such as sterile water, sterile organic solvent or both.Liquid Carrier can be the carrier of suitable injection, such as physiological saline, propylene glycol or Aqueous Solutions of Polyethylene Glycol.In other situations Under, can also the active constituent of micronization be dispersed in the aqueous solution of starch or sodium carboxymethylcellulose or is dispersed in and is appropriate It is made in oily (such as peanut oil).Liquid pharmaceutical formulation (referring to sterile solution or suspension) can be used for intravenous injection, muscle Injection, intraperitoneal injection or subcutaneous injection.
The present invention also provides a kind of pharmaceutical composition, which includes at least one sheet as active constituent Invent the pyrazine simultaneously [2,3-c] quinoline -2(1H) -one class compound.In addition to this, described pharmaceutical composition can also include The pharmaceutically acceptable carrier or excipient of one or more inorganic or organic, solid or liquid.Term " can pharmaceutically connect Receive " refer to physiologically tolerable when being administered to animal such as mammal (such as mankind) and will not usually generate allergy Or the additive or composition of similar adverse reaction (such as dizziness etc.).Pharmaceutical carrier and excipient can include but is not limited to Diluent, such as lactose, glucose, mannose and/or glycerol；Lubricant；Polyethylene glycol；Adhesive, such as aluminum magnesium silicate, shallow lake Powder, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone；Also, if necessary, further include Disintegrating agent, such as starch, agar, alginic acid or its salt such as sodium alginate；And/or adsorbent, colorant, preservative, stabilizer, Corrigent and sweetener.
The present invention also provides the pyrazine of above-mentioned formula (II) simultaneously [2,3-c] quinoline -2(1H) -one class compound treatment again Whole purposes.
The present invention also provides the pyrazine of above-mentioned formula (II) simultaneously [2,3-c] quinoline -2(1H) -one class compound conduct auxiliary Treatment of cancer purposes.
Specific embodiment
It is further described to various aspects of the present invention with feature below.
Abbreviation used herein is usually well-known to those skilled in the art, or can be easy according to rudimentary knowledge In understanding.
The starting material employed in the preparation of the compounds of this invention be it is known, can be prepared according to known method Or it is commercially available.
The invention further relates to new intermediate and/or starting materials.It is particularly preferably identical as those of being mentioned in embodiment Or similar reaction condition and new intermediate.
Intermediate and final product can be post-processed according to conventional methods and/or be purified, and the conventional method includes Adjust pH, extraction, filtering, drying, concentration, chromatography, grinding, crystallization etc..
In addition, the compounds of this invention can also pass through the accommodation of various methods known in the art or methods described herein It is prepared by method.
The following example is only used for illustrating the present invention, and does not limit in any way the scope of the present invention.
Embodiment 1:2- (4- (9- (6- aminopyridine -3- base) fluoro- 2- Oxopyrazine of -8- simultaneously [2,3-c] quinoline -1 (2H)-yl) piperidin-1-yl) acetonitrile preparation
The fluoro- 3- nitroquinoline -4- base of the bromo- 7- of step 1.1:4-((6-) amino) piperidines -1- carboxylic acid tert-butyl ester preparation
In 250mL two-mouth bottle, by the fluoro- 3- nitroquinoline of the chloro- 7- of the bromo- 4- of -6- (20g, 65.5 mmol) and 4- amino piperidine - 1- carboxylic acid tert-butyl ester (14.4g, 72.0 mmol), which is dissolved in 150 mL DMF, obtains yellow solution.DIEA(22.5mL is added) rear chamber Temperature is stirred overnight.Be added 1L water continue stirring 0.5 hour after filter, filter residue is washed respectively, and ethyl alcohol is washed till that filtrate is colourless, and 60 take the photograph Family name's degree is dried under reduced pressure to obtain 21 g yellow solids, yield 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: the preparation of tert-butyl 4- ((the bromo- 7- fluorine quinolyl-4 of 3- amino -6-) amino) piperidines -1- t-butyl formate
The fluoro- 3- nitroquinoline -4- base of the bromo- 7- of 4-((6- is added in 500mL two-mouth bottle) amino) piperidines -1- carboxylic acid tert-butyl ester (21g, 1eq) and iron powder (25g, 10eq).60 minds are warming up to after addition 250mL glacial acetic acid to be slightly agitated for 5 hours.Diatom while hot Soil filtering, filtrate are concentrated to give crude product.Crude product silica gel, which is wished, chromatographs to obtain 9.8 g white solids, yield 49.9%.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- (the fluoro- 2- Oxopyrazine of the bromo- 8- of 9- simultaneously [2,3-c] quinoline -1 (2H)Base) piperidines -1- t-butyl formate Preparation
Tert-butyl 4- ((the bromo- 7- fluorine quinolyl-4 of 3- amino -6-) amino) piperidines -1- formic acid is added in 100 mL bottle with two necks Applying argon gas is vacuumized three times after the tert-butyl ester (500 mg, 1.14 mmol).Argon gas protection is lower to be added glyoxalic acid monohydrate (115 Mg, 1.25 mmol) and the super dry tetrahydrofuran of 40 mL obtain yellow solution.It was stirred at room temperature 8 as a child, argon gas protection is lower to be added Continue to be stirred overnight after HATU (475 mg, 1.25 mmol) and DIEA (391 μ L, 2.28 mmol).Reaction solution is concentrated, Silica gel column chromatography purifying, obtains 435 mg white solids, 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.
The bromo- 8- of step 1.4:9- fluoro- 1- (piperidin-4-yl) pyrazine simultaneously [2,3-c] quinoline -2 (1H) -one hydrochloride preparation
By the 4- of 5 g (the fluoro- 2- Oxopyrazine of the bromo- 8- of 9- simultaneously [2,3-c] quinoline -1 (2H)-yl) piperidines -1- t-butyl formate is molten In the ethyl acetate of 40 mL and the methylene chloride of 10 mL, the concentrated hydrochloric acid that 4 mL are added is stirred at room temperature 3 hours.Reaction solution is dense Contract to obtain crude product.(directly carrying out in next step)
Step 1.5:2- (4- (the fluoro- 2- Oxopyrazine of the bromo- 8- of 9- simultaneously [2,3-c] quinoline -1 (2H)-yl) piperidin-1-yl) acetonitrile Preparation
In 100 mL single port bottles, by the bromo- 8- of 9- fluoro- 1- (piperidin-4-yl) pyrazine simultaneously [2,3-c] quinoline -2 (1H) -one hydrochloric acid Salt (1.1 g, 2.66 mmol) is suspended in the DMF of 40 mL, and DIEA (3.66mL, 21.27 mmol) are added and obtain lightpink Solution is stirred overnight after bromoacetonitrile (370.9 μ L, 5.32 mmol) is added.Reaction solution is concentrated, silica gel column chromatography purifying obtains 860 mg white solids, 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- aminopyridine -3- base) fluoro- 2- Oxopyrazine of -8- simultaneously [2,3-c] quinoline -1 (2H)-yl) Piperidin-1-yl) acetonitrile preparation
By 2- (4- (the fluoro- 2- Oxopyrazine of the bromo- 8- of 9- simultaneously [2,3-c] quinoline -1 (2H)-yl) piperidin-1-yl) acetonitrile (1.2 g, 2.88mmol), (6- aminopyridine -3- base) boric acid (437.4 mg, 3.17 mmol), sodium carbonate (8.65 mL, 1M in H2O), two (triphenylphosphine) palladium chlorides (203.36 mg, 0.29mmol) are suspended in 80 mL1, in 4- dioxane, heating It is stirred overnight to 85 degrees Celsius.Reaction solution is concentrated, silica gel column chromatography obtains 925 mg white solids, 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。
Embodiment 2:(R) -2- (3- (9- (6- aminopyridine -3- base) fluoro- 2- Oxopyrazine of -8- simultaneously [2,3-c] quinoline -1 (2H)-yl) piperidin-1-yl) acetonitrile preparation
Step 2.1:(R) -3- ((the fluoro- 3- nitroquinoline -4- base of the bromo- 7- of 6-) amino) piperidines -1- t-butyl formate preparation
Referring to step 1.1, yield 82%.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:(R) -3- ((the bromo- 7- fluorine quinolyl-4 of 3- amino -6-) amino) piperidines -1- t-butyl formate preparation
Referring to 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- (the fluoro- 2- Oxopyrazine of the bromo- 8- of 9- simultaneously [2,3-c] quinoline -1 (2H)-yl) piperidines -1- formic acid uncle The preparation of butyl ester
Referring to 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) the fluoro- 1- of the bromo- 8- of -9- (piperidines -3- base) pyrazine simultaneously [2,3-c] quinoline -2 (1H) -one hydrochloride preparation
Referring to step 1.4.
Step 2.5:(R) -2- (3- (the fluoro- 2- Oxopyrazine of the bromo- 8- of 9- simultaneously [2,3-c] quinoline -1 (2H)-yl) piperidines -1- Base) acetonitrile preparation
Referring to 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- aminopyridine -3- base) fluoro- 2- Oxopyrazine of -8- simultaneously [2,3-c] quinoline -1 (2H)- Base) piperidin-1-yl) acetonitrile preparation
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。
Embodiment 3:2- (3- (9- (6- aminopyridine -3- base) -2- Oxopyrazine simultaneously [2,3-c] quinoline -1 (2H) - Base) pyrrolidin-1-yl) acetonitrile preparation
The preparation of step 3.1:3- ((the bromo- 3- nitroquinoline -4- base of 6-) amino) pyrrolidines -1- carboxylic acid tert-butyl ester
Referring to step 1.1, yield 82%.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.
The preparation of step 3.2:3- ((3- amino -6- bromoquinoline -4- base) amino) pyrrolidines -1- carboxylic acid tert-butyl ester
Referring to 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- (the bromo- 2- Oxopyrazine of 9- simultaneously [2,3-c] quinoline -1 (2H)-yl) pyrrolidines -1- t-butyl formate system It is standby
Referring to step 1.3, yield 61%.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) pyrazine simultaneously [2,3-c] quinoline -2 (1H) -one hydrochloride preparation
Referring to step 1.4；
Step 3.5:2- (3- (the bromo- 2- Oxopyrazine of 9- simultaneously [2,3-c] quinoline -1 (2H)-yl) pyrrolidin-1-yl) acetonitrile system It is standby
Referring to 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- aminopyridine -3- base) -2- Oxopyrazine simultaneously [2,3-c] quinoline -1 (2H)-yl) pyrroles Alkane -1- base) acetonitrile preparation
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。
Part of compounds of the invention is as shown in table 1:
Table 1
Biological characteristis
External mTOR enzyme inhibition activity measurement
The present invention provides part of compounds to the inhibition effect and selectivity of mTOR and GAP-associated protein GAP, the outer kinase assay of dependent body It is measured by Eurofins company Kinase Profiler services.Table 2 is mTOR of the part of compounds under 1 μM of concentration Inhibiting rate.
Table 2
The present invention provides the anti-tumor activities of part of compounds.
Anti-tumor activity experimental method
Cell culture concentration is 3 × 103 The hole cells/0.1 mL/, 96 orifice plates.It is small that drug culture 24 is added after culture 24 hours When after drug, drug concentration is added.Control group (not dosing only inoculating cell) and blank well are arranged simultaneously, and (non-inoculating cell only adds Culture medium), 5 % CO2, 37 DEG C of incubators are incubated for 72 hours.Use CCK-8 (Promega, WI) colorimetric method for determining cell Number is Microplate reader (Promega, WI) using instrument.Table 3 is part of compounds 1 to some tumour cells External 503nhibiting concentration (IC50)
Table 3
The majority of compounds in the present invention has good inhibiting effect to mTOR kinases as can be seen from Table 2.It can be with from table 3 Find out compound 1 to A549, H1299, H460, T47D, MCF7 have extraordinary inhibiting effect, and to MDA-MB-231, The inhibiting effect of the cell lines such as Skov3, K562 is weaker.Therefore pyrazine of the invention simultaneously [2,3-c] quinoline -2(1H) -one class chemical combination Object has good anti-tumor activity and selectivity.

Claims (12)

  1. Formula 1. (I) compound or pharmaceutically acceptable salt thereof
    Wherein:
    R1And R4Selected from hydrogen, hydroxyl, alkoxy, alkyl, halogen, cyano, amino or any following group that replaces: 6-10 member virtue Base；C7-15Aralkyl；C6-15Heteroarylalkyl; C1-12Miscellaneous fatty group；C1-12Fatty group；C3-8Naphthenic base；Solely with 1-4 Heteroatomic 5-10 unit's heteroaryl on the spot selected from the group being made of nitrogen, oxygen and sulphur；With with 1-2 independently selected from by The heteroatomic 4-7 circle heterocyclic ring base of the group of nitrogen, oxygen and sulphur composition；
    R2Selected from any substituted following group: 6-10 member aryl；C7-15Aralkyl；C6-15Heteroarylalkyl; C1-12Miscellaneous aliphatic Base；C1-12Fatty group；C3-8Naphthenic base；With 1-4 independently selected from the heteroatomic of the group being made of nitrogen, oxygen and sulphur 5-10 unit's heteroaryl；With with 1-2 heteroatomic 4-7 circle heterocyclic rings independently selected from the group being made of nitrogen, oxygen and sulphur Base；
    R3Selected from H, halogen ,-CN or selected from any substituted following group group: C1-12Acyl group；6-10 member aryl；C7-15Aralkyl Base；C6-15Heteroarylalkyl；C1-12Miscellaneous fatty group; C1-12Fatty group；With 1-4 independently selected from by nitrogen, oxygen and sulphur group At group heteroatomic 5-10 unit's heteroaryl；With with 1-2 independently selected from the group being made of nitrogen, oxygen and sulphur Heteroatomic 4-7 circle heterocyclic ring base；
    In the definition of above compound, no matter term used exclusive use is also used in compound word, following substituent group is represented:
    Halogen is fluorine, chlorine, bromine or iodine;
    Fatty group includes but is not limited to alkyl, alkenyl, alkynyl, naphthenic base, cycloalkenyl and cycloalkynyl radical part;
    Alkyl is the linear or branched alkyl group of 1 to 10 carbon atom;
    Naphthenic base is the monocycle or multi-ring alkyl of 3 to 8 carbon atoms.This kind of group can by such as fluorine, chlorine, bromine, iodine, hydroxyl, The groups such as ketone group, amino, alkyl and dialkyl amido replace;
    Heterocycle is to carry at least one naphthenic base for being selected from O, S, N or substituted nitrogen-atoms.This kind of group can by such as fluorine, The groups such as chlorine, bromine, iodine, hydroxyl, ketone group, amino, alkyl and dialkyl amido replace;
    Alkoxy is 1 to 10 carbon atom and passes through the linear or branched alkyl group of oxygen atom connection;
    Acyl group is the alkyl or aryl with 1 to 10 carbon atom connected by carbonyl;
    The aromatic ring system of heteroaryl basis representation one or more 5-, 6- or 7- member, at least containing one at most containing there are four be selected from The hetero atom of nitrogen, oxygen or sulphur;
    Aryl indicates aryl carbon ring group, has single ring, multiple rings or multiple condensed ring, and wherein at least one is aromatics, it Can by halogen, alkyl, alkoxy, alkylthio group, trifluoromethyl, acyloxy, aryl, heteroaryl and hydroxyl it is mono-, two-, three- Replace.
  2. 2. compound described in claim 1, has a structure that
    Wherein:
    R1It is hydrogen；
    R3It is as defined in formula (I);
    N, the integer that i, j, k are 0 to 4, including 1 and 4;
    R4It is hydrogen, fluorine;
    R5It is selected from、、、、、、、、、、、、、、、、、、、、、、、、、、 、、、、、、、、、、、、 、;
    R6Selected from hydrogen, alkyl, alkoxy, trifluoromethyl, halogen.
  3. 3. according to claim 1 or the compound of claim 2, wherein R6It is hydrogen.
  4. 4. according to the compound of claim 1 or claim 2, wherein R5It is、、、、、、、、、、、、。
  5. 5. according to claim 1 or the compound of claim 2, wherein R3It is selected from、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、。
  6. 6. compound according to claim 5, R3It is、、、、、、、、、、、、、、、、、、、、、。
  7. 7. compound according to claim 2, wherein j=0,1,2, k=0,1 when i=0；J=0,1, k=0,1 as i=1.
  8. 8. a kind of method for preparing formula (II) compound,
    Wherein:
    PG is selected from Boc, Cbz, PMB, Bn;
    X is selected from Cl, Br, I;
    R1 、R3 、R4、 R5 、R6, n, i, j, k be as defined in formula (II);
    The method comprises the steps of:
    General formula compound (III) general formula compound (IV) molar ratio 1:1 is dissolved in organic solvent, and organic base, room temperature is then added Stirring 6-12 hours filters to obtain compound (V) after water dilution is added, and compound (V) obtains compound under the action of reducing agent (VI), compound (VI) and compound (VII) molar ratio 1:1.1, which are dissolved in organic solvent, is stirred at room temperature 1-10 hours, is then added Condensing agent and organic base are stirred at room temperature 5-10 hours to obtain compound (VIII), compound (VIII) under the action of reducing agent or strong acid It sloughs protecting group to obtain compound (Ⅸ), under the action of organic base or inorganic base, 0-100 is Celsius for compound (Ⅸ) and compound Ⅹ Degree obtains compound (Ⅺ) in reaction 5-12 hours, and compound (Ⅺ) and compound (Ⅻ) molar ratio 1:1.5 are dissolved in organic solvent, Palladium catalyst and organic base or inorganic base is added, 70-100 degrees Celsius obtains compound (II) in reaction 8-12 hours；Described is organic Solvent is selected from methylene chloride, chloroform, benzene, toluene, ethyl acetate, n-hexane, hexamethylene, tetrahydrofuran, 1,4- dioxane, N, N- diformazan basis set amide, dimethyl sulfoxide；The organic base is selected from triethylamine, N, N- diisopropylethylamine, pyridine, N, N- bis- Methylaniline, 1,8- diazacyclo [5,4,0] hendecene -7；Inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, carbonic acid Potassium, cesium carbonate, sodium bicarbonate, saleratus, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide；The reducing agent is selected from iron powder/chlorine Change ammonium, 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；It is described to urge Agent be selected from palladium acetate, tetrakis triphenylphosphine palladium, bis- (triphenylphosphine) palladium chlorides, tris(dibenzylideneacetone) dipalladium, [1, Bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride.
  9. 9. the method for treating disease relevant to mTORC1 and mTORC2 inhibiting effect, obstacle or syndrome, such as cancer, the side Method includes to needing its individual the application compound of -2 any one or its prodrug or comprising formula (I) according to claim 1 The pharmaceutical composition of compound or its prodrug and pharmaceutically acceptable excipient.
  10. 10. pharmaceutical composition, the compound or pharmaceutically acceptable salt thereof comprising any one of the claims and comprising pharmaceutical Carrier or excipient.
  11. 11. the method for the treatment of cancer in the patient for needing its treatment, this method includes that a effective amount of the claims are any The compound or pharmaceutically acceptable salt thereof of item.
  12. 12. any cancer is selected from breast cancer, oophoroma, prostate cancer, cervix cancer, cancer of the esophagus, testis in right 9 It is cancer, gastric cancer, cutaneum carcinoma, lung cancer, osteocarcinoma, colon cancer, cancer of pancreas, thyroid cancer, cancer of bile ducts, carcinoma of small intestine, colon-rectum, big Intestinal cancer, the carcinoma of the rectum, brain and the cancer of central nervous system, neuroblastoma, large cell carcinoma, gland cancer, adenoma, follicular carcinoma, table Dermoid cancer, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, kidney, bone marrow disorder, lymph obstacle, He Jiejinshi Disease, hair cell cancer and leukaemia.
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