CN110950890A - Substituted imidazo [4,5-c ] quinoline macrocycles as multi-target kinase inhibitors - Google Patents

Substituted imidazo [4,5-c ] quinoline macrocycles as multi-target kinase inhibitors Download PDF

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CN110950890A
CN110950890A CN201811144433.9A CN201811144433A CN110950890A CN 110950890 A CN110950890 A CN 110950890A CN 201811144433 A CN201811144433 A CN 201811144433A CN 110950890 A CN110950890 A CN 110950890A
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CN110950890B (en
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姚金锁
刘琦超
许新合
张凯
闵汪洋
王静晗
季业龄
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Centaurus Biopharma Co Ltd
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Abstract

The present invention is substituted imidazo [4,5-c ]]Quinoline macrocyclic compounds as multi-target kinase inhibitors, to compounds of formula (I) or pharmaceutically acceptable salts, solvates, polymorphs or isomers thereof, and their use in the manufacture of medicaments for the treatment of ALK-mediated diseases.

Description

Substituted imidazo [4,5-c ] quinoline macrocycles as multi-target kinase inhibitors
Technical Field
The present invention relates generally to novel imidazo [4,5-c ] quinoline macrocyclic derivatives having multiple kinase inhibitory activities, to processes for their preparation, to pharmaceutical compositions thereof, and to the use of such compounds and their pharmaceutical compositions for the treatment of diseases where inhibition of these kinases is beneficial, for example in the treatment of cancer.
Background
Cancer, i.e. malignant tumor, is a serious disease that threatens human health and lives, especially the incidence and mortality of cancer in recent years are on the rapid rise, and the cancer becomes the first killer of human health beyond cardiovascular diseases.
The proliferation, apoptosis, metastasis and the like of tumors are closely related to the abnormality of a certain link in a series of signal transduction pathways inside and outside cells. One important class of molecules in these signaling pathways is protein kinases. Abnormalities in protein kinase activity are not only directly associated with tumors, but are also a major cause of a range of other inflammatory or proliferative responses related human diseases, such as rheumatoid arthritis, cardiovascular and psychiatric diseases, asthma, psoriasis, and the like. At present, four hundred or more human diseases are known to be directly or indirectly associated with protein kinases, which makes protein kinases an important class of drug targets.
Previous studies have shown that Anaplastic Lymphoma Kinase (ALK) is a receptor tyrosine kinase that is a member of the insulin receptor superfamily. ALK is a transmembrane protein with a transmembrane domain at its central site, an extracellular domain at the N-terminus, and an intracellular tyrosine kinase domain at the C-terminus. ALK is normally expressed in isolated regions of the developing nervous system, ALK mRNA is expressed in the small intestine and low in brain, colon, prostate and testis; the lung was not detected; ALK protein is detected in the human retina. The ALK gene can be fused with various protein genes to express and generate an ALK protein; mutations, amplifications, and the like may also be generated. In 1997, the oncogenic ALK gene recombination on the short arm of chromosome 2 on the heterosis large cell lymphoma was first described, and then it was found in other malignancies including diffuse large B cell lymphoma and malignant histoglobulism, and in a variety of solid tumors including inflammatory myofibroblastoma, esophageal squamous cell carcinoma, neuroblastoma and non-small cell lung carcinoma (NSCLC).
The ALK gene is firstly reported in 2007 to encode and produce ALK by forming a fusion gene with the EML4 gene, so that the growth of lung cancer cells is promoted. The EML4-ALK fusion is caused by the short arm insertion of chromosome 2, and several types of mutations have been found to date. The EML4-ALK fusion gene has low positive rate of about 3-7% in common non-small cell lung cancer patients. The EML4-ALK fusion gene is mainly found in non-smoking lung adenocarcinoma and is mutually exclusive to EGFR mutation and KRAS mutation. A study reported in 2010 shows that the EML4-ALK fusion gene positive rate of Chinese lung adenocarcinoma patients is obviously higher than that of European and American patients and is 16.13% (10/62 cases); the positive rate of non-smoking lung adenocarcinoma is 19.23% (10/52 cases); in lung adenocarcinomas lacking EGFR and KRAS mutations, the mutation rate was as high as 42.8% (9/21 cases).
XALKORI (Crizotinib, PF-02341066) from Peezuel corporation of America (Pfizer) was approved by the United states Food and Drug Administration (FDA) to be marketed in 11 months of 2011, and was the first ALK inhibitor non-small cell lung cancer targeted drug to be marketed. The curative effect is remarkable, but similar to other targeted drugs, the drug resistance of patients can be generated after about 10 months of administration. The mechanisms of drug resistance generation are mainly: amplification and overexpression of target genes, change of signal paths and secondary mutation. Subsequently, Ceritinib, Alectonib and Brigatinib which are approved to be marketed successively have higher activity on wild-type and secondary mutant ALK kinase, but simultaneously have new mutations such as solvent front mutation G1202R and the like.
Tropomyosin-related receptor tyrosine kinases (TRKs) are important transmembrane proteins, which are high affinity ligands for neurotrophic factors and play important roles in higher-level functions such as neuronal cell survival, proliferation, differentiation, migration, apoptosis, and learning and memory. TRK, however, begins to clone in the extracellular region as an oncogene fused with the tropomyosin gene. Activation mutations caused by chromosomal rearrangements or mutations in NTRK1(TRKA) are found in both papillary and medullary thyroid carcinomas, non-small cell lung cancer. Because TRKs play an important role in signal pathways of pain sensation, survival and proliferation of tumor cells, TRK inhibitors can be applied to the treatment of pain and cancer. No TRK inhibitors are currently approved for marketing, and various projects are essentially in clinical or preclinical stages of research, such as Entrectinib, larotryptinib, and the like.
ROS1 kinase is a receptor tyrosine kinase, closely related to ALK/LTK and insulin receptor kinase familyAnd (4) correlating. Although the normal physiological function of ROS1 kinase is not fully studied, its abnormal expression and sustained production of different fusion protein forms that are activated are found in many cancers, such as glioblastoma, non-small cell lung carcinoma, cholangiocarcinoma, ovarian carcinoma, gastric adenocarcinoma, colorectal carcinoma, inflammatory myofibroblastoma, angiosarcoma, epithelioid angioendothelioma, etc. The FIG-ROS1 fusion protein was the first ROS1 fusion protein discovered in glioblastoma multiforme in 2003. ROS1 were found to fuse with a variety of proteins in lung cancer, including TMP3, SDC4, SLC34a2, CD74, EZR, and LRIG3, etc., suggesting that ROS1 kinase is an oncogenic factor in lung cancer. More and more ROS1 fusion proteins are then found in different cancers, such as KDELR2, CCDC6, MSN and the like, and nearly twenty. Clinical trials show that the ALK/MET/ROS1 multi-target inhibitor Crizotinib has obvious curative effect on cancer patients with abnormal ROS1 expression. Like other targeted drugs, patients also develop secondary mutations such as ROS1 after a period of time following drug administrationG2032RAnd resistance due to activation of the shunt signal. Taken together, ROS1 kinase is a reliable target for the treatment of many cancers with abnormal ROS1 protein kinase activity. At present, no inhibitor against ROS1 is approved for marketing, and all projects are basically in clinical or preclinical research stage, such as Crizotinib, Lorlatinib, TPX-0005 and the like.
Not only will multi-target inhibitors have broader indications, but inhibition of multiple signaling pathways is expected to reduce resistance due to activation of alternative signals.
The substituted quinolinone compound provided by the invention has very good multi-target inhibition activity, the activity of the quinolinone compound is equivalent to or better than that of a multi-target kinase inhibitor TPX-0005 entering phase I clinic, and the quinolinone compound has very good in vivo metabolism level, and is expected to become a more suitable multi-target inhibitor medicine.
Summary of The Invention
The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof,
Figure BSA0000171399150000021
wherein,
R1selected from H and F;
R2selected from H, -CF3and-C (OH) (CH)3)2；
Ar is selected from phenyl and pyridyl, which may be optionally substituted with 1-2 fluorines;
L1is selected from C1-3Alkylene and
Figure BSA0000171399150000031
said alkylene group being optionally substituted by C1-6Alkyl substitution of said
Figure BSA0000171399150000032
Optionally substituted with 1-2 fluorines;
L2is selected from C2-6Alkylene, which alkylene may optionally be substituted by 1-2C1-3Alkyl substitution;
according to some embodiments of the invention, the compound of formula (I) of the invention is:
Figure BSA0000171399150000033
or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof;
the compounds of formula (I) of the present invention are useful in the treatment of ALK-mediated diseases; in some embodiments, the ALK-mediated disease is non-small cell lung cancer, anaplastic large cell lymphoma, inflammatory myofibroblastoma, nasopharyngeal carcinoma, breast cancer, colorectal cancer, diffuse large B cell lymphoma, systemic histiocytosis, neuroblastoma, and the like, preferably ALK-positive non-small cell lung cancer;
yet another aspect of the present invention is directed to a pharmaceutical composition comprising a compound of formula (I) of the present invention, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, and a pharmaceutically acceptable carrier;
in another aspect, the present invention provides a method of treating an ALK-mediated disease, comprising administering to a subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or a composition thereof; in some embodiments, the ALK-mediated disease is non-small cell lung cancer, anaplastic large cell lymphoma, inflammatory myofibroblastoma, nasopharyngeal carcinoma, breast cancer, colorectal cancer, diffuse large B cell lymphoma, systemic histiocytosis, neuroblastoma, and the like, preferably ALK-positive non-small cell lung cancer;
in some embodiments of the invention, the subject to which the invention relates is a mammal, including a human.
In another aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, in the manufacture of a medicament for the treatment of an ALK-mediated disease; in some embodiments, the ALK-mediated disease is non-small cell lung cancer, anaplastic large cell lymphoma, inflammatory myofibroblastoma, nasopharyngeal carcinoma, breast cancer, colorectal cancer, diffuse large B cell lymphoma, systemic histiocytosis, neuroblastoma, and the like, preferably ALK-positive non-small cell lung cancer;
Detailed Description
Exemplary embodiments utilizing the principles of the present invention are set forth in the following detailed description of the invention. The features and advantages of the present invention may be better understood by reference to the following summary.
It should be understood that the scope of the various aspects of the invention is defined by the claims and that methods and structures within the scope of these claims and their equivalents are intended to be covered thereby.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are incorporated by reference in their entirety unless otherwise indicated.
It is to be understood that both the foregoing general description and the following detailed description are exemplary, explanatory and are not restrictive of any inventive subject matter. The use of the singular forms also includes the plural unless specifically stated otherwise. The use of "or", "or" means "and/or" unless stated otherwise. Furthermore, the term "comprising" as well as other forms, such as "includes," "including," and "containing," are not limiting.
Certain chemical terms
The terms "optional," "optional," or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" means "unsubstituted alkyl" or "substituted alkyl". And, optionally substituted groups may be unsubstituted (e.g.: CH)2CH3) Fully substituted (e.g.: -CF2CF3) Monosubstituted (e.g.: -CH2CH2F) Or any level between mono-and fully substituted (e.g.: -CH2CHF2、-CF2CH3、-CFHCHF2Etc.). It will be appreciated by those skilled in the art that any group containing one or more substituents will not incorporate any substitution or substitution pattern which is sterically impossible and/or cannot be synthesized.
Unless otherwise indicated, conventional methods within the skill of the art are employed, such as mass spectrometry, nuclear magnetism, high performance liquid chromatography, infrared and ultraviolet/visible spectroscopy, and pharmacological methods. Unless specific definitions are set forth, the nomenclature used herein in the analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry, as well as the laboratory procedures and techniques, are those known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the instructions of the kit from the manufacturer, or according to the methods known in the art or the instructions of the present invention. The techniques and methods described above can generally be practiced according to conventional methods well known in the art, as described in various general and more specific documents referred to and discussed in this specification. In the present specification, groups and substituents thereof may be selected by one skilled in the art to provide stable moieties and compounds.
When a substituent is described by a general formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the formula is written from right to left. For example, -CH2O-is equivalent to-OCH2-。
As used herein, the terms "group", "chemical group" or "chemical group" refer to a particular portion or functional group of a molecule. Chemical groups are often considered as chemical entities embedded in or attached to a molecule.
Some of the chemical groups named herein may be referred to by a shorthand notation for the total number of carbon atoms. E.g. C1-C6Alkyl describes an alkyl group, as defined below, having a total of 1 to 6 carbon atoms. The total number of carbon atoms indicated by shorthand notation does not include carbon atoms on possible substituents.
The term "alkyl" as used herein alone or as part of another component (e.g., monoalkylamino) refers to an optionally substituted straight or optionally substituted branched chain monovalent saturated hydrocarbon having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, 2-methylhexyl, 3 methylhexyl, n-octyl, n-nonyl, n-decyl, and the like.
The term "alkylene" as used herein, alone or in combination, refers to a divalent group derived from a monovalent alkyl group as defined above. Examples include, but are not limited to, methylene (-CH)2) Ethylene (-CH)2CH2) Propylene (-CH)2CH2CH2) And isopropylidene (-CH (CH)3)CH2) And the like.
The term "polymorph" or "polymorph" as used herein means that the compounds of the present invention have multiple lattice morphologies. Some of the compounds of the present invention may have more than one crystal form, and the present invention encompasses all polymorphic forms or mixtures thereof.
Intermediate compounds of the present invention and polymorphs thereof are also within the scope of the present invention.
Unless otherwise specified, the compounds of the present invention contain olefinic double bonds including E and Z isomers.
It is understood that the compounds of the present invention may contain asymmetric centers. These asymmetric centers may independently be in the R or S configuration. It will be apparent to those skilled in the art that some of the compounds of the present invention may also exhibit cis-trans isomerism. It is to be understood that the compounds of the present invention include their individual geometric and stereoisomers as well as mixtures thereof, including racemic mixtures. These isomers may be separated from their mixtures by carrying out or modifying known methods such as chromatographic techniques and recrystallization techniques, or they may be prepared separately from the appropriate isomers of their intermediates.
The term "pharmaceutically acceptable salts" as used herein includes both acid and base salts.
"pharmaceutically acceptable acid addition salts" refers to those salts formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or organic acids such as, but not limited to, acetic acid, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, capric acid, caproic acid, carbonic acid, cinnamic acid, citric acid, and the like, which retain the biological potency and properties of the free base of the compound, which are not biologically or otherwise undesirable. "pharmaceutically acceptable salt to be added to base" refers to those salts that retain the biological potency and properties of the free acid of the compound and are not biologically or otherwise undesirable. These salts are prepared by reacting the free acid with an inorganic or organic base. Salts formed by reaction with an inorganic base include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and manganese salts.
Salt-forming organic bases include, but are not limited to, primary, secondary, tertiary, cyclic amines, and the like, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purine, piperazine, piperidine, choline, caffeine, and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
Crystallization often produces solvates of the compounds of the present invention. The term "solvate" as used herein refers to a combination of one or more molecules of the compound of the present invention and one or more molecules of a solvent.
The solvent may be water, in which case the solvate is a hydrate. In addition, an organic solvent may be used. Thus, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. The compounds of the present invention may be true solvates, but in other cases, the compounds of the present invention may also retain water only by chance or a mixture of water and some other solvent. The compounds of the invention may be reacted in a solvent or precipitated or crystallized in a solvent. Solvates of the compounds of the invention are also included within the scope of the invention.
The term "pharmaceutical composition" as used herein refers to a formulation mixed with a compound of the present invention and a vehicle generally accepted in the art for delivering biologically active compounds to a mammal, such as a human. Such media comprise all pharmaceutically acceptable carriers.
As used herein, the term "acceptable" in reference to a formulation, composition or ingredient means that there is no lasting deleterious effect on the overall health of the subject being treated.
The term "pharmaceutically acceptable" as used herein refers to a substance (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological response or interacting in an adverse manner with any of the components contained in the composition.
"pharmaceutically acceptable carriers" include, but are not limited to, adjuvants, carriers, excipients, adjuvants, deodorants, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the relevant governmental authorities for use in humans and domestic animals.
Preparation of the Compounds of the invention
The present invention also provides a process for preparing a compound of the above formula, comprising the following synthetic scheme:
synthesis scheme 1:
Figure BSA0000171399150000061
compounds 1-3 can be synthesized according to scheme 1. The compound 1-1 and N- (hydroxyl) alkyl phthalimide are subjected to Mitusnobu reaction to obtain an intermediate 1-2, and the intermediate 1-2 is reacted with methylamine or hydrazine hydrate to remove a phthaloyl protecting group to obtain a compound 1-3.
Synthesis scheme 2:
Figure BSA0000171399150000062
compounds 2-3 can be synthesized according to scheme 2. The compound 2-1 and N- (hydroxyl) alkyl phthalimide are subjected to Mitusnobu reaction to obtain an intermediate 2-2, and the intermediate 2-2 is reacted with methylamine or hydrazine hydrate to remove a phthaloyl protecting group to obtain a compound 2-3.
Synthesis scheme 3:
Figure BSA0000171399150000071
products 3-6 can be synthesized using synthesis scheme 3. The free amine 1-3 and the intermediate 3-1 are subjected to nucleophilic substitution reaction to obtain an intermediate 3-2, and the intermediate 3-2 is subjected to reduction of nitro group by stannous chloride to obtain an intermediate 3-3. The intermediate 3-3 is cyclized by trimethyl orthoformate to obtain an intermediate 3-4. And removing the protecting group of the intermediate 3-4 by using acid to obtain an intermediate 3-5. The intermediate 3-5 is subjected to intramolecular Buchwald reaction under the catalysis of palladium to close the ring to obtain a product 3-6.
Synthesis scheme 4:
Figure BSA0000171399150000072
product 4-2 can be synthesized by synthesis scheme 4. And (3) closing the ring of the intermediate 3-3 by using trifluoroacetic acid and deprotecting to obtain an intermediate 4-1. The intermediate 4-1 is subjected to intramolecular Buchwald reaction under the catalysis of palladium to close the ring to obtain a product 4-2.
Synthesis scheme 5:
Figure BSA0000171399150000081
products 3-6 can be synthesized using synthesis scheme 3. Nucleophilic substitution reaction is carried out between the free amine 2-3 and the intermediate 3-1 to obtain an intermediate 5-1, and the intermediate 5-1 reduces the nitro group by stannous chloride to obtain an intermediate 5-2. The intermediate 5-2 is cyclized by trimethyl orthoformate to obtain an intermediate 5-3. And removing the protecting group of the intermediate 5-3 by using acid to obtain an intermediate 5-4. The intermediate 5-4 is subjected to intramolecular Buchwald reaction under the catalysis of palladium to close the ring to obtain a product 5-5.
Synthesis scheme 6:
Figure BSA0000171399150000082
the compound of formula 6-1 can be synthesized by synthetic scheme 6. The compound 3-6 is firstly extracted with lithium bis (trimethylsilyl) amide to remove protons, and then reacts with acetone to obtain the compound 6-1.
The above synthetic schemes are only examples of the preparation methods of some compounds of the present invention, and the skilled person can synthesize the compounds of the present invention by similar methods based on the above synthetic schemes according to the well-known techniques in the art.
The following specific examples are included to provide those skilled in the art with a clear understanding of the invention and are included to provide a further understanding of the invention. They should not be considered as limiting the scope of the invention but merely as being exemplary illustrations and representative of the invention. Those skilled in the art will understand that: there are other synthetic routes to the compounds of the present invention, and the following non-limiting examples are provided.
All operations involving easily oxidizable or hydrolyzable raw materials were carried out under nitrogen protection. Unless otherwise indicated, the starting materials used in the present invention were commercially available and used without further purification.
The column chromatography adopts silica gel (200-300 mesh) produced by Qingdao chemical industry Co. The thin layer chromatography was carried out using a precast slab (silica gel 60 PF) manufactured by Merck, Inc2540.25 mm). Chiral compound separation and determination of enantiomeric excess (ee) using Agilent LC 1200series (column: CHIRALPAK AD-H,
Figure BSA0000171399150000083
mm, 5 μm, 30 ℃). Nuclear magnetic resonance chromatography (NMR) was measured using a Varian VNMRS-400 nuclear magnetic resonance instrument; liquid chromatography/Mass Spectrometry (LC/MS) Using FINNIGAN Thermo LCQ Advantage MAX, Agilent LC 1200series (column: Waters symmetry C18,
Figure BSA0000171399150000084
mm, 5 μm, 35 ℃), using ESI (+) ion mode.
Experimental part
Intermediate 1:(R) -2- (1-aminoethyl) -4-fluorophenol
Figure BSA0000171399150000091
(R) -2- (1-aminoethyl) -4-fluorophenol was synthesized according to the procedure of example 2 in patent WO 2017015367.
Intermediate 2:(R) -1- (5-fluoro-2-hydroxyphenyl) ethylcarboxylic acid tert-butyl ester
Figure BSA0000171399150000092
Intermediate 1(7.76g) was dissolved in dichloromethane (100mL), triethylamine (15mL) was added, then cooled to 0 deg.C, di-tert-butyl dicarbonate (12.0g) was added, and the mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was washed with water and saturated brine, respectively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting crude product was chromatographed on silica gel (petroleum ether: ethyl acetate, 20: 1) to give 12.0g of tert-butyl (R) -1- (5-fluoro-2-hydroxyphenyl) ethylcarboxylate. MS m/z [ ESI ]: 256.17[ M +1 ]. .
Intermediate 3:(4R) -4- (tert-butyldimethylsilyloxy) -2- (5-fluoro-2-methoxyphenyl) pyrrolidine-1- Carboxylic acid tert-butyl ester
Figure BSA0000171399150000093
Tert-butyl (4R) -4- (tert-butyldimethylsilyloxy) -2- (5-fluoro-2-methoxyphenyl) pyrrolidine-1-carboxylate was synthesized according to the procedure of patent US8933084, page 17.
Intermediate 4:5- ((2R, 4S) -4-fluoro-2- (5-fluoro-2-hydroxyphenyl) pyrrolidin-1-yl) pyrazolo [1, 5-a] Pyrimidine-3-carboxylic acid ethyl ester
Figure BSA0000171399150000094
Step 1: (4R) -2- (5-fluoro-2-methoxyphenyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester
A tetrahydrofuran solution of tetrabutylammonium fluoride (1M, 100mL) was slowly added dropwise to a solution of intermediate 3(26.5g) in anhydrous tetrahydrofuran (300mL) at 0 deg.C, then warmed to room temperature and stirred for 2 hours. Concentration under reduced pressure, dissolution of the residue in ethyl acetate, washing with water, drying, concentration and chromatography of the crude product on silica gel (petroleum ether: ethyl acetate, 15: 1) to give 17.5g of product. MS m/z [ ESI ]: 312.16[ M +1 ].
Step 2: (3R) -5- (5-fluoro-2-hydroxyphenyl) pyrrolidin-3-ol
Tert-butyl (4R) -2- (5-fluoro-2-methoxyphenyl) -4-hydroxypyrrolidine-1-carboxylate (15.6g) was dissolved in anhydrous dichloromethane (300mL), cooled to 0 deg.C, and then a 1M solution of boron tribromide in dichloromethane (200mL) was slowly added dropwise, followed by warming to room temperature and stirring for 1 hour. Cooling to 0 ℃, dropwise adding methanol to quench reaction, washing an organic phase with saturated sodium bicarbonate water solution, water and saturated salt water respectively, drying the organic phase with anhydrous sodium sulfate, and concentrating the organic phase under reduced pressure to obtain a crude product which is directly used for the next reaction. MS m/z [ ESI ]: 198.10[ M +1 ].
And step 3: (4R) -2- (5-fluoro-2-hydroxyphenyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester
The crude product from step 2 was dissolved in dichloromethane (150mL), triethylamine (15mL) was added, then cooled to 0 deg.C, di-tert-butyl dicarbonate (10.9g) was added, and the mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was washed with water and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was chromatographed on silica gel (petroleum ether: ethyl acetate, 15: 1) to give 9.5g of a product. MS m/z [ ESI ]: 298.15[ M +1 ].
And 4, step 4: (2R, 4S) -4-fluoro-2- (5-fluoro-2-hydroxyphenyl) pyrrolidine-1-carboxylic acid tert-butyl ester
Tert-butyl (4R) -2- (5-fluoro-2-hydroxyphenyl) -4-hydroxypyrrolidine-1-carboxylate (5.94g) obtained in step 3 was dissolved in dry dichloromethane (100mL), cooled to-78 deg.C, and then a solution of diethylaminosulfur trifluoride (3.55g) in dichloromethane (22mL) was slowly added dropwise thereto, and stirred at-78 deg.C for 1 hour. The organic phase was washed with saturated aqueous sodium bicarbonate, water and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the mixture was chromatographed over silica gel (petroleum ether: ethyl acetate, 20: 1) to give 1.90g of the product. MS m/z [ ESI ]: 300.14[ M +1 ].
Intermediate 5:5-fluoro-3- ((2R, 4S) -4-fluoropyrrolidin-2-yl) -2-methoxypyridine
Figure BSA0000171399150000101
5-fluoro-3- ((2R, 4S) -4-fluoropyrrolidin-2-yl) -2-methoxypyridine was synthesized according to the procedure of example 11 in patent WO 2017087778.
Intermediate 5A: (2R, 4S) -4-fluoro-2- (5-fluoro-2-oxo-1, 2-dihydropyridin-3-yl) pyrrolidine-1-carboxylic acid tert-butyl ester
Figure BSA0000171399150000102
Step 1: 5-fluoro-3- ((2R, 4S) -4-fluoropyrrolidin-2-yl) pyridin-2 (1H) -one
Dissolving intermediate 5(2.15g) in dichloromethane (40mL), cooling to 0 deg.C, adding boron tribromide (7.53g) dropwise, heating to room temperature, stirring for 2 hours, pouring into 10% sodium carbonate solution, separating, and extracting the aqueous phase with dichloromethane. The organic phase and the extract are combined, washed with water, dried and concentrated, and the crude product is directly put into the next step. MS m/z [ ESI ]: 201.09[ M +1 ].
Step 2: (2R, 4S) -4-fluoro-2- (5-fluoro-2-oxo-1, 2-dihydropyridin-3-yl) pyrrolidine-1-carboxylic acid tert-butyl ester
The crude product from the above step was dissolved in dichloromethane (50mL), triethylamine (1mL) was added, then cooled to 0 deg.C, di-tert-butyl dicarbonate (2.18g) was added, and the mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was washed with water and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was chromatographed on silica gel (petroleum ether: ethyl acetate, 10: 1) to give 1.85g of the product. MS m/z [ ESI ]: 301.14[ M +1 ].
Intermediate 6:(R) -2- (1-aminoethyl) -4, 6-difluorophenol
Figure BSA0000171399150000111
(R) -2- (1-aminoethyl) -4, 6-difluorophenol was synthesized according to the procedure of example 2 of patent WO2017015367, replacing 5-fluoro-2-hydroxybenzaldehyde with 3, 5-difluoro-2-hydroxybenzaldehyde to give the desired product. MS m/z [ ESI ]: 174.08[ M +1 ].
Intermediate 6A:(R) -1- (3, 5-difluoro-2-hydroxyphenyl) ethylcarboxylic acid tert-butyl ester
Figure BSA0000171399150000112
The desired product was obtained by following the procedure for intermediate 2, substituting intermediate 1 for intermediate 6. MS m/z [ ESI ]: 274.13[ M +1 ].
Intermediate 7:6-bromo-4-chloro-3-nitroquinoline
Figure BSA0000171399150000113
6-bromo-4-chloro-3-nitroquinoline was synthesized according to the procedure of example 1 in patent WO 2015145369.
Intermediate 8:6-bromo-4-chloro-7-fluoro-3-nitroquinoline
Figure BSA0000171399150000114
6-bromo-4-chloro-7-fluoro-3-nitroquinoline was synthesized according to the procedure of intermediate 1.3 in patent WO 2015022664.
Intermediate 9:2- (4-hydroxybutyl) isoindoline-1, 3-dione
Figure BSA0000171399150000115
4-amino-1-butanol (8.9g) and phthalic anhydride (7.4g) were dissolved in toluene (200mL), refluxed overnight with a water separator, the solvent was spin-dried, and the crude product was chromatographed on silica gel (petroleum ether: ethyl acetate, 5: 1 to 3: 1) to give the desired product. MSm/z [ ESI ]: 220.10[ M +1 ].
Intermediate 10:(R) -1- (2- (4- (1, 3-dioxoisoindolin-2-yl) butoxy) -5-fluorophenyl) ethylammonium Benzoic acid tert-butyl ester
Figure BSA0000171399150000121
Step 1: (R) -1- (2- (4- (1, 3-dioxoisoindolin-2-yl) butoxy) -5-fluorophenyl) ethylcarbamic acid tert-butyl ester
A solution of diisopropyl azodicarboxylate (4.45g) in tetrahydrofuran (10mL) was added dropwise to a solution of triphenylphosphine (5.77g), intermediate 2(5.12g), and intermediate 9(4.62g) in tetrahydrofuran (200mL) at 0 ℃ under a nitrogen atmosphere, after 20 minutes. After stirring was continued for 0.5 hour while maintaining 0 ℃, the temperature was raised to room temperature and the mixture was stirred for 12 hours. The solvent was dried by rotation, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate, 4: 1) to obtain 7.30g of the desired product. MS m/z [ ESI ]: 457.22[ M +1 ].
Step 2: (R) -1- (2- (4-Aminobutoxy) -5-fluorophenyl) ethylcarbamic acid tert-butyl ester
The product from step 1 was dissolved in methanol (20mL), a methylamine alcohol solution (33 wt%, 30mL) was added, and the mixture was refluxed for 4 hours. The solvent was spun off and the residue was chromatographed on a silica gel column (dichloromethane: methanol, 10: 1, + 1% ammonia) to give 4.40g of the desired product. MS m/z [ ESI ]: 327.21[ M +1 ].
Intermediate 11:2- (4-hydroxypentyl) isoindoline-1, 3-dione
Figure BSA0000171399150000122
Step 1: 2- (4-oxopentyl) isoindoline-1, 3-dione
Sodium hydride (60%, 4.2g) was added in portions to a solution of phthalimide (14.7g) in tetrahydrofuran (200mL) at 0 ℃ and, after the addition was completed, stirring was continued for 0.5 hour while maintaining 0 ℃, 5-chloro-2-pentanone (12.1g) was added, the temperature was slowly raised to room temperature, and stirring was continued for 6 hours. The solvent was dried by rotation, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate, 5: 1) to obtain 19.0g of the desired product. MS m/z [ ESI ]]：232.10[M+1]。1H NMR(400MHz，CDCl3)：δ＝7.85(2H，m)，7.72(2H，m)，3.72(1H，t，J＝6.6Hz)，2.51(1H，t，J＝7.0Hz)，2.15(3H，s)，1.97(2H，m)。
Step 2: 2- (4-hydroxypentyl) isoindoline-1, 3-dione
The product obtained in step 1 was dissolved in isopropanol (200mL), and aluminum isopropoxide (40.8g) was added and refluxed for 4 hours. Spin-drying the solvent, adding 1M hydrochloric acid and ethyl acetate, separating, washing the organic phase with water, saturated sodium bicarbonate water solution and saturated sodium chloride water, drying over anhydrous sodium sulfate, concentrating, and separating by silica gel column chromatography (petroleum ether: ethyl acetate, 5: 1-3: 1) to obtain 11.5g of the desired product. MS m/z [ ESI ]: 234.12[ M +1 ].
Intermediates12：(R) -1- (2- (5-Aminopent-2-yloxy) -5-fluorophenyl) ethylcarbamic acid tert-butyl ester
Figure BSA0000171399150000123
Step 1: (R) -1- (2- (5- (1, 3-dioxoisoindolin-2-yl) pent-2-yloxy) -5-fluorophenyl) ethylcarbamic acid tert-butyl ester
Following the synthesis of step 1 in intermediate 10, intermediate 9 was replaced with intermediate 11 to give the desired product. MSm/z [ ESI ]: 471.23[ M +1 ].
Step 2: (R) -1- (2- (5-Aminopent-2-yloxy) -5-fluorophenyl) ethylcarbamic acid tert-butyl ester
Following the synthesis of step 2 in intermediate 10, the product of step 1 in intermediate 10 was replaced with the product of step 1 in intermediate 12 to give the desired product. MS m/z [ ESI ]: 341.23[ M +1 ].
Intermediate 13:2- (5-hydroxypentan-2-yl) isoindoline-1, 3-dione
Figure BSA0000171399150000131
The desired product was obtained according to the synthetic method of Journal of the American Chemical Society, volume 77, page 4819. MS m/z [ ESI ]: 234.12[ M +1 ].
Intermediate 14:(R) -1- (2-4-Aminopentyloxy) -5-fluorophenyl) ethylcarbamic acid tert-butyl ester
Figure BSA0000171399150000132
Step 1: (R) -1- (2- (4- (1, 3-dioxoisoindolin-2-yl) pentyloxy) -5-fluorophenyl) ethylcarbamic acid tert-butyl ester
Following the synthesis of step 1 in intermediate 10, intermediate 9 was replaced with intermediate 13 to give the desired product. MSm/z [ ESI ]: 471.23[ M +1 ].
Step 2: (R) -1- (2-4-Aminopentyloxy) -5-fluorophenyl) ethylcarbamic acid tert-butyl ester
Following the synthesis of step 2 in intermediate 10, the product of step 1 in intermediate 10 was replaced with the product of step 1 in intermediate 14 to give the desired product. MS m/z [ ESI ]: 341.23[ M +1 ].
Intermediate 15:(2R, 4S) -2- (2- (4-Aminobutoxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl Esters
Figure BSA0000171399150000133
Step 1: (2R, 4S) -2- (2- (4- (1, 3-dioxoisoindolin-2-yl) butoxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
Following the synthesis of step 1 in intermediate 10, intermediate 2 was replaced with intermediate 4 to give the desired product. MS m/z [ ESI ]: 501.22[ M +1 ].
Step 2: (2R, 4S) -2- (2- (4-Aminobutoxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
Following the synthesis of step 2 in intermediate 10, the product of step 1 in intermediate 10 was replaced with the product of step 1 in intermediate 15 to give the desired product. MS m/z [ ESI ]: 371.22[ M +1 ].
Intermediate 16:(2R, 4S) -2- (2- (5-Aminopent-2-yloxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylic acid Tert-butyl ester
Figure BSA0000171399150000141
Step 1: (2R, 4S) -2- (2- (5- (1, 3-dioxoisoindolin-2-yl) pent-2-yloxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
Following the synthesis of step 1 in intermediate 10, intermediate 2 was replaced with intermediate 4 and intermediate 9 was replaced with intermediate 11 to give the desired product. MS m/z [ ESI ]: 515.23[ M +1 ].
Step 2: (2R, 4S) -2- (2- (5-Aminopent-2-yloxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
Following the synthesis of step 2 in intermediate 10, the product of step 1 in intermediate 10 was replaced with the product of step 1 in intermediate 16 to give the desired product. MS m/z [ ESI ]: 385.23[ M +1 ].
Intermediate 17:(S) -2- (4-hydroxypentyl) isoindoline-1, 3-dione
Figure BSA0000171399150000142
Intermediate 11(10.36g), vinyl acetate (22.87g) and lipase (4.43g) were added to isopropyl ether (450mL), stirred at room temperature overnight, filtered through celite, and the filtrate was concentrated and subjected to silica gel column chromatography (petroleum ether: ethyl acetate, 8: 1 to 3: 1) to give (S) -2- (4-hydroxypentyl) isoindoline-1, 3-dione (5.0g), MS m/z [ ESI ]: 234.12[ M +1 ]; and (R) -5- (1, 3-dioxoisoindolin-2-yl) pent-2-ylacetate (6.0g), MS m/z [ ESI ]: 276.13[ M +1 ].
Intermediate 18:(R) -2- (4-hydroxypentyl) isoindoline-1, 3-dione
Figure BSA0000171399150000143
Anhydrous methanol (40mL) was cooled to 0 ℃, sodium metal (184mg) was added, stirred until sodium reaction was complete, (R) -5- (1, 3-dioxoisoindolin-2-yl) pent-2-yl acetate (2.0g) obtained in the preparation of intermediate 17 was added, warmed to room temperature, stirred until ester hydrolysis was complete, excess sodium methoxide was neutralized with 1M hydrochloric acid in an ice bath, concentrated and separated by silica gel column chromatography (petroleum ether: ethyl acetate, 5: 1 to 3: 1) to give the desired product. MS m/z [ ESI ]: 234.12[ M +1 ].
Intermediate 19:(2R, 4S) -2- (2- ((R) -5-Aminopentyl-2-yloxy) -5-fluorophenyl) -4-fluoropyrrolidine-1- Carboxylic acid tert-butyl ester
Figure BSA0000171399150000144
Step 1: (2R, 4S) -2- (2- ((R) -5- (1, 3-dioxoisoindolin-2-yl) pent-2-yloxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
Following the synthesis of step 1 in intermediate 10, intermediate 2 was replaced with intermediate 4 and intermediate 9 was replaced with intermediate 17 to give the desired product. MS m/z [ ESI ]: 515.23[ M +1 ].
Step 2: (2R, 4S) -2- (2- ((R) -5-Aminopent-2-yloxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
Following the synthesis of step 2 in intermediate 10, the product of step 1 in intermediate 10 was replaced with the product of step 1 in intermediate 19 to give the desired product. MS m/z [ ESI ]: 385.23[ M +1 ].
Intermediate 20:(2R, 4S) -2- (2- ((S) -5-Aminopentyl-2-yloxy) -5-fluorophenyl) -4-fluoropyrrolidine-1- Carboxylic acid tert-butyl ester
Figure BSA0000171399150000151
Step 1: (2R, 4S) -2- (2- ((S) -5- (1, 3-dioxoisoindolin-2-yl) pent-2-yloxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
Following the synthesis of step 1 in intermediate 10, intermediate 2 was replaced with intermediate 4 and intermediate 9 was replaced with intermediate 18 to give the desired product. MS m/z [ ESI ]: 515.23[ M +1 ].
Step 2: (2R, 4S) -2- (2- ((S) -5-Aminopent-2-yloxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
Following the synthesis of step 2 in intermediate 10, the product of step 1 in intermediate 10 was replaced with the product of step 1 in intermediate 20 to give the desired product. MS m/z [ ESI ]: 385.23[ M +1 ].
Intermediate 21:(2R, 4S) -2- (2- (4-aminobutoxy) -5-fluoropyridin-3-yl) -4-fluoropyrrolidine-1-carboxylic acid Tert-butyl ester
Figure BSA0000171399150000152
Step 1: (2R, 4S) -2- (2- (4- (1, 3-dioxoisoindolin-2-yl) butoxy) -5-fluoropyridin-3-yl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
Following the synthesis of step 1 in intermediate 10, intermediate 2 was replaced with intermediate 5A to give the desired product. MSm/z [ ESI ]: 502.22[ M +1 ].
Step 2: (2R, 4S) -2- (2- (4-Aminobutoxy) -5-fluoropyridin-3-yl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
Following the synthesis of step 2 in intermediate 10, the product of step 1 in intermediate 10 was replaced with the product of step 1 in intermediate 21 to give the desired product. MS m/z [ ESI ]: 372.21[ M +1 ].
Intermediate 22:(2R, 4S) -2- (2- ((S) -5-aminopentan-2-yloxy) -5-fluoropyridin-3-yl) -4-fluoropyrrole Alkane-1-carboxylic acid tert-butyl ester
Figure BSA0000171399150000161
Step 1: (2R, 4S) -2- (2- ((S) -5- (1, 3-dioxoisoindolin-2-yl) pent-2-yloxy) -5-fluoropyridin-3-yl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
Following the synthesis of step 1 in intermediate 10, intermediate 2 was replaced with intermediate 5A and intermediate 9 was replaced with intermediate 18 to give the desired product. MS m/z [ ESI ]: 516.23[ M +1 ].
Step 2: (2R, 4S) -2- (2- ((S) -5-Aminopent-2-yloxy) -5-fluoropyridin-3-yl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
Following the synthesis of step 2 in intermediate 10, the product of step 1 in intermediate 10 was replaced with the product of step 1 in intermediate 22 to give the desired product. MS m/z [ ESI ]: 386.23[ M +1 ].
Intermediate 23:(R) -1- (2- (4-Aminobutoxy) -3, 5-difluorophenyl) ethylcarbamic acid tert-butyl ester
Figure BSA0000171399150000162
Step 1: (R) -1- (2- (4- (1, 3-dioxoisoindolin-2-yl) butoxy) -3, 5-difluorophenyl) ethylcarbamic acid tert-butyl ester
Following the synthesis of step 1 in intermediate 10, intermediate 2 was replaced with intermediate 6A to give the desired product. MSm/z [ ESI ]: 475.21[ M +1 ].
Step 2: (R) -1- (2- (4-Aminobutoxy) -3, 5-difluorophenyl) ethylcarbamic acid tert-butyl ester
Following the synthesis of step 2 in intermediate 10, the product of step 1 in intermediate 10 was replaced with the product of step 1 in intermediate 23 to give the desired product. MS m/z [ ESI ]: 345.20[ M +1 ].
Example 1: 5 1(3R, 6R) -4-fluoro-3, 6-dimethyl-1H-5-oxa-2-aza-1 (8, 1) -imidazo [4,5- c]Quinolino-4 (1, 2) -benzocyclononanesAnd example 2: 5 1(3R, 6S) -4-fluoro-3, 6-dimethyl-1H-5-oxa-2-nitrogen Hetero-1 (8, 1) -imidazo [4,5-c]Quinolino-4 (1, 2) -benzocyclononanes
Figure BSA0000171399150000163
Step 1: (R) -1- (2- (5- (6-bromo-3-nitroquinolin-4-ylamino) pent-2-yloxy) -5-fluorophenyl) ethylcarbamic acid tert-butyl ester
Intermediate 7(288mg), intermediate 12(340mg) and potassium carbonate (414mg) were added to N, N-dimethylformamide (5mL), and the mixture was stirred at room temperature for 4 hours. Poured into water (50mL), extracted with ethyl acetate, the extracts washed with water, dried, concentrated and the crude product chromatographed on silica gel (dichloromethane: methanol, 30: 1) to give 350mg of product. MS m/z [ ESI ]: 591.16[ M +1 ].
Step 2: (R) -1- (2- (5- (3-amino-6-bromoquinolin-4-ylamino) pent-2-yloxy) -5-fluorophenyl) ethylcarbamic acid tert-butyl ester
The product from step 1 (342mg), sodium acetate (476mg), and stannous chloride dihydrate (1.30g) were added to ethanol (15mL) and refluxed under nitrogen for 1 hour. Poured into saturated aqueous sodium bicarbonate (50mL), filtered through celite, the filtrate extracted with ethyl acetate, the extracts washed with water, dried, concentrated, and the crude product chromatographed on silica gel (dichloromethane: methanol, 20: 1) to give 295mg of product. MS m/z [ ESI ]: 561.18[ M +1 ].
And step 3: (R) -1- (2- (5- (8-bromo-1H-imidazo [4,5-c ] quinolin-1-yl) pent-2-yloxy) -5-fluorophenyl) ethylcarbamic acid tert-butyl ester
The product obtained in step 2 (280mg) was dissolved in trimethyl orthoformate (10mL) and refluxed for 4 hours. The solvent was dried by spinning, and the crude product was separated by silica gel column chromatography (dichloromethane: methanol, 30: 1) to give 190mg of the product. MS m/z [ ESI ]: 571.17[ M +1 ].
And 4, step 4: (R) -1- (2- (5- (8-bromo-1H-imidazo [4,5-c ] quinolin-1-yl) pent-2-yloxy) -5-fluorophenyl) ethylamine
The product obtained in step 3 (190mg) was dissolved in methylene chloride (5mL), and a dioxane solution of hydrogen chloride (4M, 5mL) was added thereto, followed by stirring at room temperature for 3 hours. Poured into saturated aqueous sodium bicarbonate (50mL), extracted with ethyl acetate, the extracts dried, concentrated under reduced pressure, and the residue chromatographed on silica gel (dichloromethane: methanol, 20: 1, + 1% ammonia) to give 125mg of product. MSm/z [ ESI ]: 471.12[ M +1 ].
And 5: (3R, 6R) -45-fluoro-3, 6-dimethyl-11H-5-oxa-2-aza-1 (8, 1) -imidazo [4, 5-c)]Quinolinhetero-4 (1, 2) -benzocyclononanes and (3R, 6S) -45-fluoro-3, 6-dimethyl-11H-5-oxa-2-aza-1 (8, 1) -imidazo [4, 5-c)]Quinolino-4 (1, 2) -benzocyclononanes
The product obtained in step 4 (125mg), palladium acetate (20mg), 2- (dicyclohexylphosphine) -2' - (dimethylamine) biphenyl (71mg) and cesium carbonate (173mg) were added to dry toluene (20mL), and vacuum/nitrogen evacuation was repeated three times, and reflux was carried out overnight under nitrogen atmosphere. After cooling to room temperature, ethyl acetate (20mL) was added to the reaction mixture, which was washed with water and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on thin layer silica gel (dichloromethane: methanol, 25: 1, + 0.5% aqueous ammonia) to give (3R, 6R) -45-fluoro-3, 6-dimethyl-11H-5-oxa-2-aza-1 (8, 1) -imidazo [4, 5-c)]Quinolinohexy-4 (1, 2) -benzocyclononane (20 mg). MS m/z [ ESI ]]：391.20[M+1]。1H NMR(400MHz，CDCl3)：δ＝9.02(1H，s)，8.04(1H，d，J＝9.2Hz)，7.93(1H，s)，7.44(1H，d，J＝2.0Hz)，7.14(1H，dd，J＝9.2Hz，2.0Hz)，7.02(1H, dd, J ═ 9.2Hz, 2.4Hz), 6.89(1H, dd, J ═ 9.2Hz, 4.8Hz), 6.79-6.84(1H, m), 5.17(1H, q, J ═ 6.4Hz), 4.64-4.73(3H, m), 4.46-4.58(1H, brs), 1.68-2.29(4H, m), 1.57(3H, d, J ═ 6.8Hz), 1.50(3H, d, J ═ 6.4 Hz). Simultaneously obtain the product (3R, 6S) -45-fluoro-3, 6-dimethyl-11H-5-oxa-2-aza-1 (8, 1) -imidazo [4, 5-c)]Quinolinohexy-4 (1, 2) -benzocyclononane (18 mg). MS m/z [ ESI ]]：391.20[M+1]。1H NMR(400MHz，CDCl3)：δ＝9.01(1H，s)，8.03(1H，d，J＝8.4Hz)，7.89(1H，s)，7.22(1H，d，J＝9.2Hz)，7.06(1H，d，J＝9.2Hz)，7.02(1H，s)，6.80-6.89(2H，m)，5.15-5.22(1H，m)，4.52-4.65(2H，m)，4.18-4.38(2H，m)，2.77-2.90(1H，m)，2.10-2.21(1H，m)，1.97-2.09(1H，m)，1.85-1.96(1H，m)，1.53(3H，d，J＝6.4Hz)，1.50(3H，d，J＝6.0Hz)。
Example 3: 5 1(R) -4-fluoro-3-methyl-1H-5-oxa-2-aza-1 (8, 1) -imidazo [4,5-c]Quinoline hetero- 4(1, 2) -benzocyclononanes
Figure BSA0000171399150000181
Step 1: (R) -1- (2- (4- (6-bromo-3-nitroquinolin-4-ylamino) butoxy) -5-fluorophenyl) ethylcarbamic acid tert-butyl ester
Following the synthetic procedure of step 1 in example 1, intermediate 12 was replaced with intermediate 10 to give the product tert-butyl (R) -1- (2- (4- (6-bromo-3-nitroquinolin-4-ylamino) butoxy) -5-fluorophenyl) ethylcarbamate. MS m/z [ ESI ]: 577.15[ M +1 ].
Step 2: (R) -1- (2- (4- (3-amino-6-bromoquinolin-4-ylamino) butoxy) -5-fluorophenyl) ethylcarbamic acid tert-butyl ester
The procedure used for the synthesis of step 2 in example 1 was followed, replacing the product of step 1 in example 1 with the product of step 1 in example 3, to give the product tert-butyl (R) -1- (2- (4- (3-amino-6-bromoquinolin-4-ylamino) butoxy) -5-fluorophenyl) ethylcarbamate. MS m/z [ ESI ]: 547.17[ M +1 ].
And step 3: (R) -1- (2- (4- (8-bromo-1H-imidazo [4,5-c ] quinolin-1-yl) butoxy) -5-fluorophenyl) ethylcarbamic acid tert-butyl ester
The product of step 2 in example 1 was replaced with the product of step 2 in example 3 by the synthesis method of step 3 in example 1 to give the product tert-butyl (R) -1- (2- (4- (8-bromo-1H-imidazo [4,5-c ] quinolin-1-yl) butoxy) -5-fluorophenyl) ethylcarbamate. MS m/z [ ESI ]: 557.16[ M +1 ].
And 4, step 4: (R) -1- (2- (4- (8-bromo-1H-imidazo [4,5-c ] quinolin-1-yl) butoxy) -5-fluorophenyl) ethylamine
The product of step 3 in example 1 was replaced with the product of step 3 in example 3 by the synthetic method of step 4 in example 1 to give the product (R) -1- (2- (4- (8-bromo-1H-imidazo [4,5-c ] quinolin-1-yl) butoxy) -5-fluorophenyl) ethylamine. MS m/z [ ESI ]: 457.11[ M +1 ].
And 5: (R) -45-fluoro-3-methyl-11H-5-oxa-2-aza-1 (8, 1) -imidazo [4, 5-c)]Quinolino-4 (1, 2) -benzocyclononanes
Following the synthesis procedure of step 5 in example 1, the product of step 4 in example 1 was replaced with the product of step 4 in example 3 to give the product (R) -45-fluoro-3-methyl-11H-5-oxa-2-aza-1 (8, 1) -imidazo [4, 5-c)]Quinolino-4 (1, 2) -benzocyclononanes. MS m/z [ ESI ]]：377.18[M+1]。1H NMR(400MHz，CDCl3)：δ＝9.01(1H，s)，8.06(1H，d，J＝9.2Hz)，7.89(1H，s)，7.22(1H，dd，J＝9.2Hz，3.2Hz)，7.14(1H，d，J＝2.0Hz)，7.05(1H，dd，J＝9.2Hz，2.4Hz)，6.87-6.93(1H，m)，6.83(1H，dd，J＝9.2Hz，4.4Hz)，5.20-5.26(1H，m)，4.58(1H，d，J＝3.2Hz)，4.41-4.49(1H，m)，4.27-4.35(2H，m)，4.15-4.21(1H，m)，2.72-2.83(1H，m)，2.34-2.48(1H，m)，1.96-2.16(2H，m)，1.53(3H，d，J＝6.4Hz)。
Example 4: 5 1(3R, 9S) -4-fluoro-3, 9-dimethyl-1H-5-oxa-2-aza-1 (8, 1) -imidazo [4,5- c]Quinolino-4 (1, 2) -benzocyclononanesAnd example 5: 5 1(3R, 9R) -4-fluoro-3, 9-dimethyl-1H-5-oxa-2-nitrogen Hetero-1 (8, 1) -imidazo [4,5-c]Quinolino-4 (1, 2) -benzocyclononanes
Figure BSA0000171399150000191
Step 1: (R) -1- (2- (4- (6-bromo-3-nitroquinolin-4-ylamino) pentyloxy) -5-fluorophenyl) ethylcarbamic acid tert-butyl ester
Following the synthetic procedure of step 1 in example 1, intermediate 12 was replaced with intermediate 14 to give the product tert-butyl (R) -1- (2- (4- (6-bromo-3-nitroquinolin-4-ylamino) pentyloxy) -5-fluorophenyl) ethylcarbamate. MS m/z [ ESI ]: 591.16[ M +1 ].
Step 2: (R) -1- (2- (4- (3-amino-6-bromoquinolin-4-ylamino) pentyloxy) -5-fluorophenyl) ethylcarbamic acid tert-butyl ester
The procedure used in step 2 of example 1 was followed, replacing the product of step 1 of example 1 with the product of step 1 of example 4, to give the product tert-butyl (R) -1- (2- (4- (3-amino-6-bromoquinolin-4-ylamino) pentyloxy) -5-fluorophenyl) ethylcarbamate. MS m/z [ ESI ]: 561.19[ M +1 ].
And step 3: (R) -1- (2- (4- (8-bromo-1H-imidazo [4,5-c ] quinolin-1-yl) pentyloxy) -5-fluorophenyl) ethylcarbamic acid tert-butyl ester
The procedure used in step 3 of example 1 was followed to replace the product of step 2 of example 1 with the product of step 2 of example 4 to give the product tert-butyl (R) -1- (2- (4- (8-bromo-1H-imidazo [4,5-c ] quinolin-1-yl) pentyloxy) -5-fluorophenyl) ethylcarbamate. MS m/z [ ESI ]: 571.17[ M +1 ].
And 4, step 4: (R) -1- (2- (4- (8-bromo-1H-imidazo [4,5-c ] quinolin-1-yl) pentyloxy) -5-fluorophenyl) ethylamine
Following the synthesis procedure of step 4 in example 1, the product of step 3 in example 1 was replaced with the product of step 3 in example 4 to give the product (R) -1- (2- (4- (8-bromo-1H-imidazo [4,5-c ] quinolin-1-yl) pentyloxy) -5-fluorophenyl) ethylamine. MS m/z [ ESI ]: 471.12[ M +1 ].
And 5: (3R, 9S) -45-fluoro-3, 9-dimethyl-11H-5-oxa-2-aza-1 (8, 1)-imidazo [4,5-c]Quinolino-4 (1, 2) -benzocyclononanes and (3R, 9R) -45-fluoro-3, 9-dimethyl-11H-5-oxa-2-aza-1 (8, 1) -imidazo [4, 5-c)]Quinolino-4 (1, 2) -benzocyclononanes
Following the synthesis procedure of step 5 in example 1, the product of step 4 in example 1 was replaced with the product of step 4 in example 4 to give the product (3R, 9S) -45-fluoro-3, 9-dimethyl-11H-5-oxa-2-aza-1 (8, 1) -imidazo [4, 5-c)]Quinolino-4 (1, 2) -benzocyclononanes. MS m/z [ ESI ]]：391.20[M+1]。1H NMR(400MHz，DMSO-d6): δ 8.76(1H, s), 8.43(1H, s), 7.77(1H, d, J ═ 8.8Hz), 7.29-7.34(2H, m), 7.06(1H, dd, J ═ 9.2Hz, 2.4Hz), 6.86-6.94(2H, m), 6.81(1H, d, J ═ 10.0Hz), 5.30-5.40(1H, m), 5.16-5.28(1H, m), 4.25-4.34(1H, m), 4.14-4.22(1H, m), 2.14-2.26(1H, m), 1.96-2.08(1H, m), 1.82-1.90(1H, m), 1.79(1H, d, J ═ 6.4), 1.56.68 (1H, m), 1.6H, 6H, 1.68 (1H, 8Hz), 3.8H, 8 Hz). Simultaneously obtain (3R, 9R) -45-fluoro-3, 9-dimethyl-11H-5-oxa-2-aza-1 (8, 1) -imidazo [4, 5-c)]Quinolino-4 (1, 2) -benzocyclononanes. MS m/z [ ESI ]]：391.20[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝8.81(1H，s)，8.49(1H，s)，7.82(1H，d，J＝8.8Hz)，7.29(1H，dd，J＝9.2Hz，2.8Hz)，7.13(1H，dd，J＝8.8Hz，1.6Hz)，6.99-7.09(2H，m)，6.93-6.98(2H，m)，4.99-5.09(1H，m)，4.58-4.69(1H，m)，4.13-4.25(2H，m)，2.69-2.82(1H，m)，2.29-2.34(1H，m)，1.91-2.05(1H，m)，1.75-1.90(1H，m)，1.76(3H，d，J＝6.8Hz)，1.41(3H，d，J＝6.8Hz)。
Example 6: 7 5 1(R) -1, 4-difluoro-3-methyl-1H-5-oxa-2-aza-1 (8, 1) -imidazo [4,5-c]Quinoline derivatives Quinoline hetero-4 (1, 2) benzene heterocyclic nonane
Figure BSA0000171399150000201
Step 1: (R) -1- (2- (4- (6-bromo-7-fluoro-3-nitroquinolin-4-ylamino) butoxy) -5-fluorophenyl) ethylcarbamic acid tert-butyl ester
Following the synthetic procedure of step 1 in example 1, intermediate 7 was replaced with intermediate 8 and intermediate 12 was replaced with intermediate 10 to give the product tert-butyl (R) -1- (2- (4- (6-bromo-7-fluoro-3-nitroquinolin-4-ylamino) butoxy) -5-fluorophenyl) ethylcarbamate. MS m/z [ ESI ]: 595.14[ M +1 ].
Step 2: (R) -1- (2- (4- (3-amino-6-bromo-7-fluoroquinolin-4-ylamino) butoxy) -5-fluorophenyl) ethylcarbamic acid tert-butyl ester
The product of step 1 in example 1 was replaced with the product of step 1 in example 6 by the synthesis method of step 2 in example 1 to give the product tert-butyl (R) -1- (2- (4- (3-amino-6-bromo-7-fluoroquinolin-4-ylamino) butoxy) -5-fluorophenyl) ethylcarbamate. MS m/z [ ESI ]: 565.16[ M +1 ].
And step 3: (R) -1- (2- (4- (8-bromo-7-fluoro-1H-imidazo [4,5-c ] quinolin-1-yl) butoxy) -5-fluorophenyl) ethylcarbamic acid tert-butyl ester
The synthesis procedure of step 3 in example 1 was followed, replacing the product of step 2 in example 1 with the product of step 2 in example 6, to give the product tert-butyl (R) -1- (2- (4- (8-bromo-7-fluoro-1H-imidazo [4,5-c ] quinolin-1-yl) butoxy) -5-fluorophenyl) ethylcarbamate. MS m/z [ ESI ]: 575.15[ M +1 ].
And 4, step 4: (R) -1- (2- (4- (8-bromo-7-fluoro-1H-imidazo [4,5-c ] quinolin-1-yl) butoxy) -5-fluorophenyl) ethylamine
Following the synthesis procedure of step 4 in example 1, the product of step 3 in example 1 was replaced with the product of step 3 in example 6 to give the product (R) -1- (2- (4- (8-bromo-7-fluoro-1H-imidazo [4,5-c ] quinolin-1-yl) butoxy) -5-fluorophenyl) ethylamine. MS m/z [ ESI ]: 475.10[ M +1 ].
And 5: (R) -17，45-difluoro-3-methyl-11H-5-oxa-2-aza-1 (8, 1) -imidazo [4, 5-c)]Quinolino-4 (1, 2) benzocyclononanes
Following the synthesis procedure of step 5 in example 1, the product of step 4 in example 1 was replaced with the product of step 4 in example 6 to give the product (R) -17，45-difluoro-3-methyl-11H-5-oxa-2-aza-1 (8, 1) -imidazo [4, 5-c)]Quinolinhetero-4 (1, 2) benzenecyclononanes. MS m/z [ ESI ]]：395.17[M+1]。1H NMR(400MHz，CDCl3)：δ＝9.05(1H，s)，7.96(1H，s)，7.81(1H，d，J＝8.4Hz)，7.20-7.27(2H，m)，6.89-6.94(1H，m)，6.82-6.86(1H，m)，5.21-5.30(1H，m)，4.86(1H，s)，4.29-4.46(3H，m)，4.16-4.22(1H，m)，2.70-2.87(1H，m)，2.36-2.48(1H，m)，1.97-2.16(2H，m)，1.58(3H，d，J＝6.8Hz)。
Example 7: 3 5 1(R) -4, 4-difluoro-3-methyl-1H-5-oxa-2-aza-1 (8, 1) -imidazo [4,5-c]Quinoline derivatives Quinoline hetero-4 (1, 2) -benzene heterocyclic nonane
Figure BSA0000171399150000211
Step 1: (R) -1- (2- (4- (6-bromo-3-nitroquinolin-4-ylamino) butoxy) -3, 5-difluorophenyl) ethylcarbamic acid tert-butyl ester
Following the synthetic procedure of step 1 in example 1, intermediate 12 was replaced with intermediate 23 to give the product tert-butyl (R) -1- (2- (4- (6-bromo-3-nitroquinolin-4-ylamino) butoxy) -3, 5-difluorophenyl) ethylcarbamate. MS m/z [ ESI ]: 595.14[ M +1 ].
Step 2: (R) -1- (2- (4- (3-amino-6-bromoquinolin-4-ylamino) butoxy) -3, 5-difluorophenyl) ethylcarbamic acid tert-butyl ester
The product of step 1 in example 1 was replaced with the product of step 1 in example 7 by the synthesis method of step 2 in example 1 to give the product tert-butyl (R) -1- (2- (4- (3-amino-6-bromoquinolin-4-ylamino) butoxy) -3, 5-difluorophenyl) ethylcarbamate. MS m/z [ ESI ]: 565.16[ M +1 ].
And step 3: (R) -1- (2- (4- (8-bromo-1H-imidazo [4,5-c ] quinolin-1-yl) butoxy) -3, 5-difluorophenyl) ethylcarbamic acid tert-butyl ester
The product of step 2 in example 1 was replaced with the product of step 2 in example 7 by the synthesis method of step 3 in example 1 to give the product tert-butyl (R) -1- (2- (4- (8-bromo-1H-imidazo [4,5-c ] quinolin-1-yl) butoxy) -3, 5-difluorophenyl) ethylcarbamate. MS m/z [ ESI ]: 575.15[ M +1 ].
And 4, step 4: (R) -1- (2- (4- (8-bromo-1H-imidazo [4,5-c ] quinolin-1-yl) butoxy) -3, 5-difluorophenyl) ethylamine
The product of step 3 in example 1 was replaced with the product of step 3 in example 7 by the synthesis of step 4 in example 1 to give the product (R) -1- (2- (4- (8-bromo-1H-imidazo [4,5-c ] quinolin-1-yl) butoxy) -3, 5-difluorophenyl) ethylamine. MS m/z [ ESI ]: 475.10[ M +1 ].
And 5: (R) -43，45-difluoro-3-methyl-11H-5-oxa-2-aza-1 (8, 1) -imidazo [4, 5-c)]Quinolino-4 (1, 2) -benzocyclononanes
Following the synthesis procedure of step 5 in example 1, the product of step 4 in example 1 was replaced with the product of step 4 in example 7 to give the product (R) -43，45-difluoro-3-methyl-11H-5-oxa-2-aza-1 (8, 1) -imidazo [4, 5-c)]Quinolino-4 (1, 2) -benzocyclononanes. MS m/z [ ESI ]]：395.17[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝8.77(1H，s)，8.23(1H，s)，7.82(1H，d，J＝8.8Hz)，7.06-7.18(4H，m)，6.86(1H，d，J＝8.0Hz)，5.13-5.21(1H，m)，4.65(1H，d，J＝8.4Hz)，4.31-4.57(2H，m)，4.31(1H，t，J＝10.4Hz)，2.21-2.38(1H，m)，2.04-2.16(1H，m)，1.89-2.03(2H，m)，1.39(3H，d，J＝6.8Hz)。
Example 8: 5 2 1(R) -4-fluoro-3-methyl-1- (trifluoromethyl) -1H-5-oxa-2-aza-1 (8, 1) -imidazo [4，5-c]Quinolino-4 (1, 2) -benzocyclononanes
Figure BSA0000171399150000221
Step 1: (R) -1- (2- (4- (6-bromo-3-nitroquinolin-4-ylamino) butoxy) -5-fluorophenyl) ethylcarbamic acid tert-butyl ester
Following the synthetic procedure of step 1 in example 1, intermediate 12 was replaced with intermediate 10 to give the product tert-butyl (R) -1- (2- (4- (6-bromo-3-nitroquinolin-4-ylamino) butoxy) -5-fluorophenyl) ethylcarbamate. MS m/z [ ESI ]: 577.15[ M +1 ].
Step 2: (R) -1- (2- (4- (3-amino-6-bromoquinolin-4-ylamino) butoxy) -5-fluorophenyl) ethylcarbamic acid tert-butyl ester
The product of step 1 in example 1 was replaced with the product of step 1 in example 8 by the synthesis method of step 2 in example 1 to give the product tert-butyl (R) -1- (2- (4- (3-amino-6-bromoquinolin-4-ylamino) butoxy) -5-fluorophenyl) ethylcarbamate. MS m/z [ ESI ]: 547.17[ M +1 ].
And step 3: (R) -1- (2- (4- (8-bromo-2- (trifluoromethyl) -1H-imidazo [4,5-c ] quinolin-1-yl) butoxy) -5-fluorophenyl) ethylamine
The product obtained in step 2 (50mg) was dissolved in toluene (5mL), and trifluoroacetic acid (0.5mL) was added to the solution, followed by refluxing for 2.5 hours. Pouring into saturated sodium bicarbonate water solution (100mL), extracting with ethyl acetate, drying the extract, concentrating under reduced pressure, and separating the residue by thin layer silica gel chromatography (dichloromethane: methanol, 20: 1, + 1% ammonia) to obtain the product (R) -1- (2- (4- (8-bromo-2- (trifluoromethyl) -1H-imidazo [4, 5-c)]Quinolin-1-yl) butoxy) -5-fluorophenyl) ethylamine 36 mg. MS m/z [ ESI ]]：525.09[M+1]。1H NMR(400MHz，CDCl3)：δ＝9.35(1H，s)，8.29(1H，d，J＝2.0Hz)，8.16(1H，d，J＝9.2Hz)，7.81(1H，dd，J＝8.8Hz，2.0Hz)，7.24(1H，m)，6.92(1H，m)，6.84(1H，dd，J＝8.8Hz，4.4Hz)，6.27(2H，brs)，4.76(2H，m)，4.65(1H，q，J＝6.8Hz)，4.10(2H，m)，2.13-2.21(4H，m)，1.54(3H，d，J＝7.2Hz)。
And 4, step 4: (R) -45-fluoro-3-methyl-12- (trifluoromethyl) -11H-5-oxa-2-aza-1 (8, 1) -imidazo 14, 5-c]Quinolino-4 (1, 2) -benzocyclononanes
Following the synthesis procedure of step 5 in example 1, the product of step 4 in example 1 was replaced with the product of step 3 in example 8 to give the product (R) -45-fluoro-3-methyl-12- (trifluoromethyl) -11H-5-oxa-2-aza-1 (8, 1) -imidazo [4, 5-c)]Quinolino-4 (1, 2) -benzocyclononanes. MS m/z [ ESI ]]：445.17[M+1]。MS m/z[ESI]：443.20[M+1]。1H NMR(400MHz，CDCl3)：δ＝9.05(1H，s)，8.02(1H，d，J＝8.8Hz)，7.19-7.22(2H，m)，7.09(1H，dd，J＝9.2Hz，2.4Hz)，6.88-6.93(1H，m)，6.84(1H，dd，J＝8.8Hz，4.4Hz)，5.21-5.29(1H，m)，4.60-4.68(1H，brs)，4.41-4.58(2H，m)，4.31-4.35(1H，m)，4.12-4.18(1H，m)，2.74-2.86(1H，m)，2.38-2.48(1H，m)，1.99-2.17(2H，m)，1.54(3H，d，J＝6.0Hz)。
Example 9: 5 1(R) -2- (4-fluoro-3-methyl-1H-5-oxa-2-aza-1 (8, 1) -imidazo [4, 5-c)]Quinolines 2Hetero-4 (1, 2) -benzocyclononan-1-yl) propan-2-ol
Figure BSA0000171399150000231
The product of example 3 (113mg) was dissolved in dry tetrahydrofuran (3mL), a solution of lithium hexamethyldisilazide in tetrahydrofuran (1M, 0.66mL) was added dropwise at 0 ℃ under a nitrogen atmosphere, the solution was slowly warmed to room temperature and stirred for 1 hour after the addition, then cooled to 0 ℃, acetone (0.2mL) was added dropwise and stirred for 2 hours after the warming to room temperature, the reaction mixture was partitioned between water and ethyl acetate, the organic phase was washed with saturated brine, dried, concentrated, and chromatographed on thin layer silica gel (dichloromethane: methanol, 20: 1, + 0.5% aqueous ammonia) to obtain the product (R) -2- (4)5-fluoro-3-methyl-11H-5-oxa-2-aza-1 (8, 1) -imidazo [4, 5-c)]Quinolines hetero-4 (1, 2) -benzocyclononanes-12-yl) propan-2-ol 18 mg. MS m/z [ ESI ]]：435.22[M+1]。MS m/z[ESI]：366.12[M+1]。1H NMR(400MHz，CDCl3)：δ＝8.82(1H，s)，7.99(1H，d，J＝7.6Hz)，7.23-7.26(1H，m)，7.11(1H，s)，6.84-6.98(3H，m)，5.16-5.27(1H，m)，4.94-5.09(1H，m)，4.11-4.60(4H，m)，2.68-2.86(1H，m)，2.31-2.46(1H，m)，1.96-2.16(3H，m)，1.86(6H，m)，1.53(3H，d，J＝6.4Hz)。
Example 10: 2 4 4 5 1(2R, 2S) -2, 3-difluoro-1H-4-oxa-1 (8, 1) -imidazo [4, 5-c)]Quinolines hetero-2 (1, 2) -Pyrrolidina-3 (1, 2) -benzenesHeterocyclic octane
Figure BSA0000171399150000232
Step 1: (2R, 4S) -2- (2- (4- (6-bromo-3-nitroquinolin-4-ylamino) butoxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
Following the synthetic procedure of step 1 in example 1, intermediate 12 was replaced with intermediate 15 to give the product tert-butyl (2R, 4S) -2- (2- (4- (6-bromo-3-nitroquinolin-4-ylamino) butoxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylate. MS m/z [ ESI ]: 621.15[ M +1 ].
Step 2: (2R, 4S) -2- (2- (4- (3-amino-6-bromoquinolin-4-ylamino) butoxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
The product of step 1 in example 1 was replaced with the product of step 1 in example 10 by the synthesis method of step 2 in example 1 to give tert-butyl (2R, 4S) -2- (2- (4- (3-amino-6-bromoquinolin-4-ylamino) butoxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylate, which is a product. MS m/z [ ESI ]: 591.18[ M +1 ].
And step 3: (2R, 4S) -2- (2- (4- (8-bromo-1H-imidazo [4,5-c ] quinolin-1-yl) butoxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
The product of step 2 in example 1 was replaced with the product of step 2 in example 10 by the synthesis method of step 3 in example 1 to give the product tert-butyl (2R, 4S) -2- (2- (4- (8-bromo-1H-imidazo [4,5-c ] quinolin-1-yl) butoxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylate. MS m/z [ ESI ]: 601.16[ M +1 ].
And 4, step 4: 8-bromo-1- (4- (4-fluoro-2- ((2R, 4S) -4-fluoropyrrolidin-2-yl) phenoxy) butyl) -1H-imidazo [4,5-c ] quinoline
The product of step 3 in example 1 was replaced with the product of step 3 in example 10 according to the synthesis procedure of step 4 in example 1 to give the product 8-bromo-1- (4- (4-fluoro-2- ((2R, 4S) -4-fluoropyrrolidin-2-yl) phenoxy) butyl) -1H-imidazo [4,5-c ] quinoline. MS m/z [ ESI ]: 501.11[ M +1 ].
And 5: (22R，24S)-24，35-difluoro-11H-4-oxa-1 (8, 1) -imidazo [4,5-c]Quinolinaeza-2 (1, 2) -pyrrolidinaea-3 (1, 2) -phenylcyclooctanes
The product obtained in step 4 of example 1 was replaced with the product obtained in step 4 of example 10 by the synthesis method of step 5 of example 1 to obtain the product (2)2R，24S)-24，35-difluoro-11H-4-oxa-1 (8, 1) -imidazo [4,5-c]Quinolinaeza-2 (1, 2) -pyrrolidinaea-3 (1, 2) -phenylcyclooctane. MS m/z [ ESI ]]：421.19[M+1]。1H NMR(400MHz，CDCl3)：δ＝9.05(1H，s)，8.17(1H，d，J＝8.8Hz)，7.88(1H，s)，7.21(1H，dd，J＝9.2Hz，2.4Hz)，7.16(1H，d，J＝2.0Hz)，7.10(1H，dd，J＝8.8Hz，2.8Hz)，6.83-6.93(2H，m)，5.57(1H，d，J＝7.6Hz)，5.45(1H，d，J＝53.2Hz)，4.20-4.41(5H，m)，3.95-4.05(1H，m)，2.79-2.91(1H，m)，2.41-2.52(1H，m)，2.03-2.24(3H，m)。
Example 11: 2 4 4 5 1(2R, 2S) -2, 3-difluoro-1H-4-oxa-1 (8, 1) -imidazo [4, 5-c)]Quinolines hetero-3 (3, 2) -pyridina-2 (1, 2) -pyrrolidine heterocyclooctane
Figure BSA0000171399150000241
Step 1: (2R, 4S) -2- (2- (4- (6-bromo-3-nitroquinolin-4-ylamino) butoxy) -5-fluoropyridin-3-yl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
Following the synthetic procedure of step 1 in example 1, intermediate 12 was replaced with intermediate 21 to give the product tert-butyl (2R, 4S) -2- (2- (4- (6-bromo-3-nitroquinolin-4-ylamino) butoxy) -5-fluoropyridin-3-yl) -4-fluoropyrrolidine-1-carboxylate. MS m/z [ ESI ]: 622.15[ M +1 ].
Step 2: (2R, 4S) -2- (2- (4- (3-amino-6-bromoquinolin-4-ylamino) butoxy) -5-fluoropyridin-3-yl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
The product of step 1 in example 1 was replaced with the product of step 1 in example 11 by the synthesis method of step 2 in example 1 to give the product tert-butyl (2R, 4S) -2- (2- (4- (3-amino-6-bromoquinolin-4-ylamino) butoxy) -5-fluoropyridin-3-yl) -4-fluoropyrrolidine-1-carboxylate. MS m/z [ ESI ]: 592.18[ M +1 ].
And step 3: (2R, 4S) -2- (2- (4- (8-bromo-1H-imidazo [4,5-c ] quinolin-1-yl) butoxy) -5-fluoropyridin-3-yl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
The product of step 2 in example 1 was replaced with the product of step 2 in example 11 by the synthesis method of step 3 in example 1 to give the product tert-butyl (2R, 4S) -2- (2- (4- (8-bromo-1H-imidazo [4,5-c ] quinolin-1-yl) butoxy) -5-fluoropyridin-3-yl) -4-fluoropyrrolidine-1-carboxylate. MS m/z [ ESI ]: 602.16[ M +1 ].
And 4, step 4: 8-bromo-1- (4- (5-fluoro-3- ((2R, 4S) -4-fluoropyrrolidin-2-yl) pyridin-2-yloxy) butyl) -1H-imidazo [4,5-c ] quinoline
Following the synthesis procedure of step 4 in example 1, the product of step 3 in example 1 was replaced with the product of step 3 in example 11 to give the product 8-bromo-1- (4- (5-fluoro-3- ((2R, 4S) -4-fluoropyrrolidin-2-yl) pyridin-2-yloxy) butyl) -1H-imidazo [4,5-c ] quinoline. MS m/z [ ESI ]: 502.11[ M +1 ].
And 5: (22R，24S)-24，35-difluoro-11H-4-oxa-1 (8, 1) -imidazo [4,5-c]Quinolina-3 (3, 2) -pyridinza-2 (1, 2) -pyrrolidina heterocyclooctane
The product obtained in step 4 of example 1 was replaced with the product obtained in step 4 of example 11 by the synthesis method of step 5 of example 1 to obtain the product (2)2R，24S)-24，35-difluoro-11H-4-oxa-1 (8, 1) -imidazo [4,5-c]Quinolinaza-3 (3, 2) -pyridinza-2 (1, 2) -pyrrolidino heterocyclooctane. MS m/z [ ESI ]]：422.18[M+1]。1H NMR(400MHz，CDCl3)：δ＝9.07(1H，s)，8.21(1H，d，J＝8.8Hz)，7.90(1H，s)，7.88(1H，d，J＝3.2Hz)，7.47(1H，dd，J＝8.0Hz，2.8Hz)，7.20(1H，dd，J＝9.2Hz，2.4Hz)，7.08(1H，d，J＝2.4Hz)，5.40-5.63(2H，m)，5.06(1H，td，J＝12.0Hz，4.4Hz)，4.18-4.46(4H，m)，3.93-4.03(1H，m)，2.81-2.95(1H，m)，2.58-2.74(1H，m)，2.30-2.41(1H，m)，2.14-2.24(1H，m)，1.86-2.10(2H，m)。
Example 12: 2 4 4 5 1(2R, 2S) -2, 3-difluoro-5-methyl-1H-4-oxa-1 (8, 1) -imidazo [4, 5-c)]Quinoline derivatives LININO-2 (1, 2) -PYRROLIDINO-3 (1, 2) -PHENYLHEXANOOCTANES
Figure BSA0000171399150000251
Step 1: (2R, 4S) -2- (2- (5- (6-bromo-3-nitroquinolin-4-ylamino) pent-2-yloxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
Following the synthetic procedure of step 1 in example 1, intermediate 12 was replaced with intermediate 16 to give the product tert-butyl (2R, 4S) -2- (2- (5- (6-bromo-3-nitroquinolin-4-ylamino) pent-2-yloxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylate. MS m/z [ ESI ]: 635.17[ M +1 ].
Step 2: (2R, 4S) -2- (2- (5- (3-amino-6-bromoquinolin-4-ylamino) pent-2-yloxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
The product of step 1 in example 1 was replaced with the product of step 1 in example 12 by the synthetic method of step 2 in example 1 to give tert-butyl (2R, 4S) -2- (2- (5- (3-amino-6-bromoquinolin-4-ylamino) pent-2-yloxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylate, which is a product. MS m/z [ ESI ]: 605.20[ M +1 ].
And step 3: (2R, 4S) -2- (2- (5- (8-bromo-1H-imidazo [4,5-c ] quinolin-1-yl) pent-2-yloxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
The product of step 2 in example 1 was replaced with the product of step 2 in example 12 by the synthesis method of step 3 in example 1 to give the product tert-butyl (2R, 4S) -2- (2- (5- (8-bromo-1H-imidazo [4,5-c ] quinolin-1-yl) pent-2-yloxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylate. MS m/z [ ESI ]: 615.18[ M +1 ].
And 4, step 4: 8-bromo-1- (4- (4-fluoro-2- ((2R, 4S) -4-fluoropyrrolidin-2-yl) phenoxy) pentyl) -1H-imidazo [4,5-c ] quinoline
The product of step 3 in example 1 was replaced with the product of step 3 in example 12 by the synthesis of step 4 in example 1 to give the product 8-bromo-1- (4- (4-fluoro-2- ((2R, 4S) -4-fluoropyrrolidin-2-yl) phenoxy) pentyl) -1H-imidazo [4,5-c ] quinoline. MS m/z [ ESI ]: 515.13[ M +1 ].
And 5: (22R，24S)-24，35-difluoro-5-methyl-11H-4-oxa-1 (8, 1) -imidazo [4,5-c]Quinolinaeza-2 (1, 2) -pyrrolidinaea-3 (1, 2) -phenylcyclooctanes
The product obtained in step 4 of example 1 was replaced with the product obtained in step 4 of example 12 by the synthesis method of step 5 of example 1 to obtain the product (2)2R，24S)-24，35-difluoro-5-methyl-11H-4-oxa-1 (8, 1) -imidazo [4,5-c]Quinolinaeza-2 (1, 2) -pyrrolidinaea-3 (1, 2) -phenylcyclooctane. MS m/z [ ESI ]]：435.20[M+1]。1H NMR(400MHz，CDCl3)：δ＝9.07(1H，s)，7.96-8.15(2H，m)，7.18-7.20(1H，m)，7.05-7.08(1H，m)，6.76-6.99(3H，m)，5.40-5.51(2H，m)，4.82-4.86(1H，m)，4.51-4.61(0.5H，m)，4.22-4.36(2.5H，m)，3.93-4.02(1H，m)，2.80-2.95(1.5H，m)，2.40-2.58(0.5H，m)，1.88-2.28(2H，m)，1.65(1.5H，d，J＝6.0Hz)，1.52(1.5H，d，J＝6.0Hz)。
Example 13: 2 4 4 5 1(2R, 2S, 5R) -2, 3-difluoro-5-methyl-1H-4-oxa-1 (8, 1) -imidazo [4, 5-c)] Quinolinaeza-2 (1, 2) -pyrrolidinaea-3 (1, 2) -phenylcyclooctanes
Figure BSA0000171399150000261
Step 1: (2R, 4S) -2- (2- ((R) -5- (6-bromo-3-nitroquinolin-4-ylamino) pent-2-yloxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
Following the synthetic procedure of step 1 in example 1, intermediate 12 was replaced with intermediate 19 to give the product tert-butyl (2R, 4S) -2- (2- ((R) -5- (6-bromo-3-nitroquinolin-4-ylamino) pent-2-yloxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylate. MS m/z [ ESI ]: 635.17[ M +1 ].
Step 2: (2R, 4S) -2- (2- ((R) -5- (3-amino-6-bromoquinolin-4-ylamino) pent-2-yloxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
The product of step 1 in example 1 was replaced with the product of step 1 in example 13 by the synthesis method of step 2 in example 1 to give the product tert-butyl (2R, 4S) -2- (2- ((R) -5- (3-amino-6-bromoquinolin-4-ylamino) pent-2-yloxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylate. MS m/z [ ESI ]: 605.20[ M +1 ].
And step 3: (2R, 4S) -2- (2- ((R) -5- (8-bromo-1H-imidazo [4,5-c ] quinolin-1-yl) pent-2-yloxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
The product of step 2 in example 1 was replaced with the product of step 2 in example 13 by the synthesis method of step 3 in example 1 to give the product tert-butyl (2R, 4S) -2- (2- ((R) -5- (8-bromo-1H-imidazo [4,5-c ] quinolin-1-yl) pent-2-yloxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylate. MS m/z [ ESI ]: 615.18[ M +1 ].
And 4, step 4: 8-bromo-1- ((R) -4- (4-fluoro-2- ((2R, 4S) -4-fluoropyrrolidin-2-yl) phenoxy) pentyl) -1H-imidazo [4,5-c ] quinoline
The product of step 3 in example 1 was replaced with the product of step 3 in example 13 by the synthesis of step 4 in example 1 to give the product 8-bromo-1- ((R) -4- (4-fluoro-2- ((2R, 4S) -4-fluoropyrrolidin-2-yl) phenoxy) pentyl) -1H-imidazo [4,5-c ] quinoline. MS m/z [ ESI ]: 515.13[ M +1 ].
And 5: (22R，24S，5R)-24，35-difluoro-5-methyl-11H-4-oxa-1 (8, 1) -imidazo [4,5-c]Quinolinaeza-2 (1, 2) -pyrrolidinaea-3 (1, 2) -phenylcyclooctanes
The product obtained in step 4 of example 1 was replaced with the product obtained in step 4 of example 13 by the synthesis method of step 5 of example 1 to obtain the product (2)2R，24S，5R)-24，35-difluoro-5-methyl-11H-4-oxa-1 (8, 1) -imidazo [4,5-c]Quinolinohexa-2 (1, 2) -pyrrolidinoheza-3 (1)2) -benzocyclooctane. MS m/z [ ESI ]]：435.20[M+1]。1H NMR(400MHz，CDCl3)：δ＝9.19(1H，s)，8.23-8.45(2H，m)，7.21(1H，d，J＝9.2Hz)，7.16(1H，s)，6.90-6.94(2H，m)，6.78(1H，t，J＝6.8Hz)，5.38-5.50(2H，m)，4.69-4.88(2H，m)，4.19-4.45(2H，m)，3.97(1H，dd，J＝24.8Hz，12.4Hz)，2.82-2.91(1H，m)，2.40-2.50(1H，m)，1.90-2.20(4H，m)，1.64(3H，d，J＝6.8Hz)。
Example 14: 2 4 4 5 1(2R, 2S, 5S) -2, 3-difluoro-5-methyl-1H-4-oxa-1 (8, 1) -imidazo [4, 5-c)] Quinolinaeza-2 (1, 2) -pyrrolidinaea-3 (1, 2) -phenylcyclooctanes
Figure BSA0000171399150000271
Step 1: (2R, 4S) -2- (2- ((S) -5- (6-bromo-3-nitroquinolin-4-ylamino) pent-2-yloxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
Following the synthetic procedure of step 1 in example 1, intermediate 12 was replaced with intermediate 20 to give the product tert-butyl (2R, 4S) -2- (2- ((S) -5- (6-bromo-3-nitroquinolin-4-ylamino) pent-2-yloxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylate, MS m/z [ ESI ]: 635.17[ M +1 ].
Step 2: (2R, 4S) -2- (2- ((S) -5- (3-amino-6-bromoquinolin-4-ylamino) pent-2-yloxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
The product of step 1 in example 1 was replaced with the product of step 1 in example 14 by the synthesis method of step 2 in example 1 to give tert-butyl (2R, 4S) -2- (2- ((S) -5- (3-amino-6-bromoquinolin-4-ylamino) pent-2-yloxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylate, which is a product. MS m/z [ ESI ]: 605.20[ M +1 ].
And step 3: (2R, 4S) -2- (2- ((S) -5- (8-bromo-1H-imidazo [4,5-c ] quinolin-1-yl) pent-2-yloxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
The product of step 2 in example 1 was replaced with the product of step 2 in example 14 by the synthesis method of step 3 in example 1 to give the product tert-butyl (2R, 4S) -2- (2- ((S) -5- (8-bromo-1H-imidazo [4,5-c ] quinolin-1-yl) pent-2-yloxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylate. MS m/z [ ESI ]: 615.18[ M +1 ].
And 4, step 4: 8-bromo-1- ((S) -4- (4-fluoro-2- ((2R, 4S) -4-fluoropyrrolidin-2-yl) phenoxy) pentyl) -1H-imidazo [4,5-c ] quinoline
Following the synthesis of step 4 in example 1, the product of step 3 in example 1 was replaced with the product of step 3 in example 14 to give the product 8-bromo-1- ((S) -4- (4-fluoro-2- ((2R, 4S) -4-fluoropyrrolidin-2-yl) phenoxy) pentyl) -1H-imidazo [4,5-c ] quinoline, MS m/z [ ESI ]: 515.13[ M +1 ].
And 5: (22R，24S，5S)-24，35-difluoro-5-methyl-11H-4-oxa-1 (8, 1) -imidazo [4,5-c]Quinolinaeza-2 (1, 2) -pyrrolidinaea-3 (1, 2) -phenylcyclooctanes
The product obtained in step 4 of example 1 was replaced with the product obtained in step 4 of example 14 by the synthesis method of step 5 of example 1 to obtain the product (2)2R，24S，5S)-24，35-difluoro-5-methyl-11H-4-oxa-1 (8, 1) -imidazo [4,5-c]Quinolinaeza-2 (1, 2) -pyrrolidinaea-3 (1, 2) -phenylcyclooctane. MS m/z [ ESI ]]：435.20[M+1]。1H NMR(400MHz，CDCl3)：δ＝9.03(1H，s)，8.13(1H，d，J＝9.2Hz)，7.83(1H，s)，7.18(1H，dd，J＝9.2Hz，2.4Hz)，7.07-7.11(2H，m)，6.82-6.90(2H，m)，5.39-5.54(2H，m)，4.53-4.62(1H，m)，4.16-4.38(3H，m)，3.93-4.02(1H，m)，2.80-2.93(2H，m)，1.82-2.25(4H，m)，1.52(3H，d，J＝6.0Hz)。
Example 15: 2 4 7 4 5 1(2R, 2S) -1, 2, 3-trifluoro-1H-4-oxa-1 (8, 1) -imidazo [4, 5-c)]Quinoline hetero- 2(1, 2) -pyrrolidino-hetero-3 (1, 2) -phenylcyclooctanes
Figure BSA0000171399150000281
Step 1: (2R, 4S) -2- (2- (4- (6-bromo-7-fluoro-3-nitroquinolin-4-ylamino) butoxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
Following the synthetic procedure of step 1 in example 1, intermediate 7 was replaced with intermediate 8 and intermediate 12 was replaced with intermediate 15 to give the product tert-butyl (R) -1- (2- (4- (6-bromo-7-fluoro-3-nitroquinolin-4-ylamino) butoxy) -5-fluorophenyl) ethylcarbamate. MS m/z [ ESI ]: 639.15[ M +1 ].
Step 2: (2R, 4S) -2- (2- (4- (3-amino-6-bromo-7-fluoroquinolin-4-ylamino) butoxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
The product of step 1 in example 1 was replaced with the product of step 1 in example 15 by the synthesis method of step 2 in example 1 to give the product tert-butyl (R) -1- (2- (4- (3-amino-6-bromo-7-fluoroquinolin-4-ylamino) butoxy) -5-fluorophenyl) ethylcarbamate. MS m/z [ ESI ]: 609.17[ M +1 ].
And step 3: (2R, 4S) -2- (2- (4- (8-bromo-7-fluoro-1H-imidazo [4,5-c ] quinolin-1-yl) butoxy) -5-fluorophenyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
The product of step 2 in example 1 was replaced with the product of step 2 in example 15 by the synthesis method of step 3 in example 1 to give the product tert-butyl (R) -1- (2- (4- (8-bromo-7-fluoro-1H-imidazo [4,5-c ] quinolin-1-yl) butoxy) -5-fluorophenyl) ethylcarbamate. MS m/z [ ESI ]: 619.16[ M +1 ].
And 4, step 4: 8-bromo-7-fluoro-1- (4- (4-fluoro-2- ((2R, 4S) -4-fluoropyrrolidin-2-yl) phenoxy) butyl) -1H-imidazo [4,5-c ] quinoline
The product of step 3 in example 1 was replaced with the product of step 3 in example 15 according to the synthesis procedure of step 4 in example 1 to give the product 8-bromo-7-fluoro-1- (4- (4-fluoro-2- ((2R, 4S) -4-fluoropyrrolidin-2-yl) phenoxy) butyl) -1H-imidazo [4,5-c ] quinoline. MS m/z [ ESI ]: 518.10[ M +1 ].
And 5: (22R，24S)-17，24，35-trifluoro-11H-4-oxa-1 (8, 1) -imidazo [4,5-c]Quinolinaeza-2 (1, 2) -pyrrolidinaea-3 (1, 2) -phenylcyclooctanes
The product obtained in step 4 of example 1 was replaced with the product obtained in step 4 of example 15 by the synthesis method of step 5 of example 1 to obtain the product (2)2R，24S)-17，24，35-trifluoro-11H-4-oxa-1 (8, 1) -imidazo [4,5-c]Quinolinaeza-2 (1, 2) -pyrrolidinaea-3 (1, 2) -phenylcyclooctane. MS m/z [ ESI ]]：438.18[M+1]。1H NMR(400MHz，CDCl3)：δ＝9.08(1H，s)，7.87(1H，d，J＝6.0Hz)，7.85(1H，d，J＝8.0Hz)，7.37(1H，d，J＝8.8Hz)，7.25(1H，dd，J＝8.8Hz，3.2Hz)，6.88(1H，td，J＝7.2Hz，2.8Hz)，6.82(1H，dd，J＝9.2Hz，4.4Hz)，5.54-5.59(1H，m)，5.37(1H，d，J＝52.8Hz)，4.474.62(1H，m)，4.18-4.40(4H，m)，3.71-3.83(1H，m)，2.61-2.80(2H，m)，2.35-2.47(1H，m)，1.93-2.13(3H，m)。
Example 16: 2 4 7 4 5 1(2R, 2S, 5S) -1, 2, 3-trifluoro-5-methyl-1H-4-oxa-1 (8, 1) -imidazo [4 ], 5-c]quinolina-3 (3, 2) -pyridinza-2 (1, 2) -pyrrolidina heterocyclooctane
Figure BSA0000171399150000291
Step 1: (2R, 4S) -2- (2- ((S) -5- (6-bromo-7-fluoro-3-nitroquinolin-4-ylamino) pent-2-yloxy) -5-fluoropyridin-3-yl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
Following the synthetic procedure of step 1 in example 1, intermediate 7 was replaced with intermediate 8 and intermediate 12 was replaced with intermediate 22 to give the product tert-butyl (2R, 4S) -2- (2- ((S) -5- (6-bromo-7-fluoro-3-nitroquinolin-4-ylamino) pent-2-yloxy) -5-fluoropyridin-3-yl) -4-fluoropyrrolidine-1-carboxylate. MS m/z [ ESI ]: 654.16[ M +1 ].
Step 2: (2R, 4S) -2- (2- ((S) -5- (3-amino-6-bromo-7-fluoroquinolin-4-ylamino) pent-2-yloxy) -5-fluoropyridin-3-yl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
The product of step 1 in example 1 was replaced with the product of step 1 in example 16 by the synthesis method of step 2 in example 1 to give the product tert-butyl (2R, 4S) -2- (2- ((S) -5- (3-amino-6-bromo-7-fluoroquinolin-4-ylamino) pent-2-yloxy) -5-fluoropyridin-3-yl) -4-fluoropyrrolidine-1-carboxylate. MS m/z [ ESI ]: 624.18[ M +1 ].
And step 3: (2R, 4S) -2- (2- ((S) -5- (8-bromo-7-fluoro-1H-imidazo [4,5-c ] quinolin-1-yl) pent-2-yloxy) -5-fluoropyridin-3-yl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
The product of step 2 in example 1 was replaced with the product of step 2 in example 16 by the synthesis method of step 3 in example 1 to give the product tert-butyl (2R, 4S) -2- (2- ((S) -5- (8-bromo-7-fluoro-1H-imidazo [4,5-c ] quinolin-1-yl) pent-2-yloxy) -5-fluoropyridin-3-yl) -4-fluoropyrrolidine-1-carboxylate. MS m/z [ ESI ]: 634.17[ M +1 ].
And 4, step 4: 8-bromo-7-fluoro-1- ((S) -4- (5-fluoro-3- ((2R, 4S) -4-fluoropyrrolidin-2-yl) pyridin-2-yloxy) pentyl) -1H-imidazo [4,5-c ] quinoline
Following the synthesis procedure of step 4 in example 1, the product of step 3 in example 1 was replaced with the product of step 3 in example 16 to give the product 8-bromo-7-fluoro-1- ((S) -4- (5-fluoro-3- ((2R, 4S) -4-fluoropyrrolidin-2-yl) pyridin-2-yloxy) pentyl) -1H-imidazo [4,5-c ] quinoline. MS m/z [ ESI ]: 534.11[ M +1 ].
And 5: (22R，24S，5S)-17，24，35-trifluoro-5-methyl-11H-4-oxa-1 (8, 1) -imidazo [4,5-c]Quinolina-3 (3, 2) -pyridinza-2 (1, 2) -pyrrolidina heterocyclooctane
The product obtained in step 4 of example 1 was replaced with the product obtained in step 4 of example 16 by the synthesis method of step 5 of example 1 to obtain the product (2)2R，24S，5S)-17，24，35-trifluoro-5-methyl-11H-4-oxa-1 (8, 1) -imidazo [4,5-c]Quinolinaza-3 (3, 2) -pyridinza-2 (1, 2) -pyrrolidino heterocyclooctane. MS m/z [ ESI ]]：454.19[M+1]。1H NMR(400MHz，CDCl3)：δ＝9.26(1H，s)，8.50(1H，m)，8.10(1H，s)，7.87(1H，d，J＝3.2Hz)，7.51(1H，dd，J＝8.0Hz，3.2Hz)，7.12(1H，d，J＝8.8Hz)，5.30-5.48(3H，m)，4.35-4.61(2H，m)，4.12-4.21(1H，m)，3.75-3.85(1H，m)，2.61-2.90(2H，m)，1.92-2.26(4H，m)，1.50(3H，d，J＝5.6Hz)。
Example 17: 2 4 4 5 1(2R, 2S, 5S) -2, 3-difluoro-5-methyl-1H-4-oxa-1 (8, 1) -imidazo [4, 5-c)] Quinolina-3 (3, 2) -pyridinza-2 (1, 2) -pyrrolidina heterocyclooctane
Figure BSA0000171399150000301
Step 1: (2R, 4S) -2- (2- ((S) -5- (6-bromo-3-nitroquinolin-4-ylamino) pent-2-yloxy) -5-fluoropyridin-3-yl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
Following the synthetic procedure of step 1 in example 1, intermediate 12 was replaced with intermediate 22 to give the product tert-butyl (2R, 4S) -2- (2- ((S) -5- (6-bromo-3-nitroquinolin-4-ylamino) pent-2-yloxy) -5-fluoropyridin-3-yl) -4-fluoropyrrolidine-1-carboxylate. MS m/z [ ESI ]: 636.17[ M +1 ].
Step 2: (2R, 4S) -2- (2- ((S) -5- (3-amino-6-bromoquinolin-4-ylamino) pent-2-yloxy) -5-fluoropyridin-3-yl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
The product of step 1 in example 1 was replaced with the product of step 1 in example 17 by the synthesis method of step 2 in example 1 to give the product tert-butyl (2R, 4S) -2- (2- ((S) -5- (3-amino-6-bromoquinolin-4-ylamino) pent-2-yloxy) -5-fluoropyridin-3-yl) -4-fluoropyrrolidine-1-carboxylate. MS m/z [ ESI ]: 606.19[ M +1 ].
And step 3: (2R, 4S) -2- (2- ((S) -5- (8-bromo-1H-imidazo [4,5-c ] quinolin-1-yl) pent-2-yloxy) -5-fluoropyridin-3-yl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
The product of step 2 in example 1 was replaced with the product of step 2 in example 17 by the synthesis method of step 3 in example 1 to give the product tert-butyl (2R, 4S) -2- (2- ((S) -5- (8-bromo-fluoro-1H-imidazo [4,5-c ] quinolin-1-yl) pent-2-yloxy) -5-fluoropyridin-3-yl) -4-fluoropyrrolidine-1-carboxylate. MS m/z [ ESI ]: 616.18[ M +1 ].
And 4, step 4: 8-bromo-1- ((S) -4- (5-fluoro-3- ((2R, 4S) -4-fluoropyrrolidin-2-yl) pyridin-2-yloxy) pentyl) -1H-imidazo [4,5-c ] quinoline
Following the synthesis procedure of step 4 in example 1, the product of step 3 in example 1 was replaced with the product of step 3 in example 17 to give the product 8-bromo-1- ((S) -4- (5-fluoro-3- ((2R, 4S) -4-fluoropyrrolidin-2-yl) pyridin-2-yloxy) pentyl) -1H-imidazo [4,5-c ] quinoline. MS m/z [ ESI ]: 516.12[ M +1 ].
And 5: (22R，24S，5S)-24，35-difluoro-5-methyl-11H-4-oxa-1 (8, 1) -imidazo [4,5-c]Quinolina-3 (3, 2) -pyridinza-2 (1, 2) -pyrrolidina heterocyclooctane
The product obtained in step 4 of example 1 was replaced with the product obtained in step 4 of example 17 by the synthesis method of step 5 of example 1 to obtain product (2)2R，24S，5S)-24，35-difluoro-5-methyl-11H-4-oxa-1 (8, 1) -imidazo [4,5-c]Quinolinaza-3 (3, 2) -pyridinza-2 (1, 2) -pyrrolidino heterocyclooctane. MS m/z [ ESI ]]：436.20[M+1]。1H NMR(400MHz，CDCl3)：δ＝9.06(1H，s)，8.15(1H，d，J＝9.2Hz)，7.88(1H，d，J＝2.8Hz)，7.85(1H，s)，7.44(1H，dd，J＝8.0Hz，2.8Hz)，7.18(1H，dd，J＝9.2Hz，2.8Hz)，6.98(1H，d，J＝2.4Hz)，5.36-5.55(3H，m)，4.14-4.40(3H，m)，3.92-3.99(1H，m)，2.78-2.93(2H，m)，1.99-2.24(3H，m)，1.79-1.91(1H，m)，1.51(3H，d，J＝6.0Hz)。
WTDetermination of TRKA enzyme inhibitory Activity of Compounds
The following method was used to determine TRKA pair of the compounds of the inventionWTInhibitory Activity of enzymes, the inhibitory Activity employing IC50Expressed by this index, IC50I.e. the concentration of the compound at which the activity of the enzyme is inhibited by 50%.
Materials and methods:
materials:
a. white 384 well plates (Perkin Elmer, Cat. No: 607290/99);
b.EnVision Reader(PerkinElmer 2103-0010)；
c.1M HEPES buffer (Invitrogen, Cat. No.: 15630-080);
TK Peptide substrate (Cisbio. HTRF KinEASE-TK Kit, catalog # 62TK0PEB), 500. mu.M, stored at-20 ℃;
ATP (Sigma-Aldrich A7699), 10mM, stored at-20 ℃;
f.TRKAWT(self-prepared), 2. mu.M, storage at-80 ℃ C
TK antibody (Cisbio. HTRF KinEASE-TK Kit, catalog # 62TK0PEB), 400X, stored at-20 ℃;
Steptavidin-XL665(Cisbio. HTRF KinEASE-TK Kit, Cat. No. 62TK0PEB), 16.67. mu.M, stored at-20 ℃ C
Detection Buffer (Cisbio. HTRF KinEASE-TK Kit, catalog number: 62TK0PEB), 16.67. mu.M, stored at-20 ℃ C
j.1M MgCl2(Sigma, cat # 7786-30-3)
k.0.5M Na3VO4
l.10％BSA
m.1％Tween-20
n.1M DTT
o.DMSO
p.ddH2O
Test compound q: positive control Compound TPX-0005 and Compounds of the examples of the invention
The method comprises the following steps:
1. preparation of TRKAWTEnzyme reaction buffer: 50mM HEPES (pH 7.5), 0.1mM Na3VO4，0.001％Tween-20，5mM MgCl20.01% BSA and 1mM DTT, mixing uniformly and placing on ice for later use;
2. dissolving a compound to be detected to be 100 times of the final operating concentration by using DMSO, performing 5-time gradient dilution on a 96-well plate to obtain 8 concentrations, adding DMSO into a 9 th well to serve as a blank control, and then diluting by using an enzyme reaction buffer solution to obtain 25 times of the final working concentration for later use;
3. dilution of TRKA with enzyme reaction bufferWTTo 2 times of working concentration (final working concentration of 0.5nM), mixing and post-treatingPlacing on ice for later use;
4. preparing substrates ATP (the final working concentration is 40 mu M) and TKpeptide (the final working concentration is 1 mu M) with 4 times of working concentration by using an enzyme reaction buffer solution, uniformly mixing, and placing on ice for later use;
5. adding 2.5 μ L of the compound with 4 times of working concentration to be detected, 2.5 μ L of the substrate with 4 times of working concentration, and adding 2 times of TRKA with working concentrationWT5 mu L, and centrifuging and mixing uniformly;
6. sealing the 384-well plate with a sealing membrane, and incubating in an incubator (23 ℃) for 1 hour;
7. preparing TK Antibody (100-fold dilution) with 4-fold working concentration and Steptavidin-XL665 (125 nM final working concentration) with 4-fold working concentration by using Detection Buffer, adding 5 mu L of the prepared TK Antibody and the Steptavidin-XL665 to a 384-well plate respectively to terminate the reaction, and centrifuging and uniformly mixing;
8. sealing the 384-well plate with a sealing membrane, and incubating in an incubator (23 ℃) for 1 hour;
9. fluorescence values were read on Envision (320nm excitation, detecting 665nm and 620nm emission, ratio for enzyme activity).
10. The activity of the enzyme was measured at 9 concentrations for each compound, and the data was calculated using Prisim software to obtain the IC of the compound50The value is obtained.
G595RDetermination of TRKA enzyme inhibitory Activity of Compounds
The following method was used to determine TRKA pair of the compounds of the inventionG595RInhibitory Activity of enzymes, the inhibitory Activity employing IC50Expressed by this index, IC50I.e. the concentration of the compound at which the activity of the enzyme is inhibited by 50%.
Materials and methods:
materials: materials:
a. white 384 well plates (Perkin Elmer, Cat. No: 607290/99);
b.EnVision Reader(PerkinElmer 2103-0010)；
c.1M HEPES buffer (Invitrogen, Cat. No.: 15630-080);
TK Peptide substrate (Cisbio. HTRF KinEASE-TK Kit, catalog # 62TK0PEB), 500. mu.M, stored at-20 ℃;
SEB (Cisbio. HTRF KinEASE-TK Kit, catalog number: 62TK0PEB), 2.5. mu.M, stored at-20 ℃;
ATP (Sigma-Aldrich A7699), 10mM, stored at-20 ℃;
g.TRKAG595R(self-prepared), 2. mu.M, storage at-80 ℃ C
TK antibody (Cisbio. HTRF KinEASE-TK Kit, catalog # 62TK0PEB), 400X, stored at-20 ℃;
Steptavidin-XL665(Cisbio. HTRF KinEASE-TK Kit, Cat: 62TK0PEB), 16.67. mu.M, stored at-20 ℃ C
Detection Buffer (Cisbio. HTRF KinEASE-TK Kit, catalog number: 62TK0PEB), 16.67. mu.M, stored at-20 ℃ C
k.1M MgCl2(Sigma, cat # 7786-30-3)
l.0.5M Na3VO4
m.10％BSA
n.1％Tween-20
o.1M DTT
p.DMSO
q.ddH2O
r. test compound: the positive control compound TPX-0005 and the compounds of the examples of the invention were performed in the following order of operation:
1. preparation of TRKAG595REnzyme reaction buffer: 50mM HEPES (pH 7.5), 0.1mM Na3VO4，0.001％Tween-20，5mM MgCl20.01% BSA, 1mM DTT and 50nM SEB, mixing and placing on ice for standby;
2. dissolving a compound to be detected to be 100 times of the final operating concentration by using DMSO, performing 5-time gradient dilution on a 96-well plate to obtain 8 concentrations, adding DMSO into a 9 th well to serve as a blank control, and then diluting by using an enzyme reaction buffer solution to obtain 25 times of the final working concentration for later use;
3. dilution of TRKA with enzyme reaction bufferG595RThe concentration is 2 times of the working concentration (the final working concentration is 0.05nM), and the mixture is evenly mixed and then placed on ice for standby;
4. preparing substrates ATP (the final working concentration is 5 mu M) and TK peptide (the final working concentration is 1 mu M) with 4 times of working concentration by using an enzyme reaction buffer solution, uniformly mixing, and placing on ice for later use;
5. adding 2.5 μ L of the compound with 4 times of working concentration to be detected, 2.5 μ L of the substrate with 4 times of working concentration, and adding 2 times of TRKA with working concentrationG595R5 mu L, and centrifuging and mixing uniformly;
6. sealing the 384-well plate with a sealing membrane, and incubating in an incubator (23 ℃) for 2 hours;
7. preparing TK Antibody (100-fold dilution) with 4-fold working concentration and Steptavidin-XL665 (125 nM final working concentration) with 4-fold working concentration by using Detection Buffer, adding 5 mu L of the prepared TK Antibody and the Steptavidin-XL665 to a 384-well plate respectively to terminate the reaction, and centrifuging and uniformly mixing;
8. sealing the 384-well plate with a sealing membrane, and incubating in an incubator (23 ℃) for 1 hour;
9. fluorescence values were read on Envision (320nm excitation, detecting 665nm and 620nm emission, ratio for enzyme activity).
10. The activity of the enzyme was measured at 9 concentrations for each compound, and the data was calculated using Prisim software to obtain the IC of the compound50The value is obtained.
G2032RDetermination of Compound Activity for inhibition of ROS1 enzyme
The following method was used to determine the ROS1 pair of the compounds of the inventionG2032RInhibitory Activity of enzymes, the inhibitory Activity employing IC50Expressed by this index, IC50I.e. the concentration of the compound at which the activity of the enzyme is inhibited by 50%.
Materials and methods:
materials:
a. white 384 well plates (Perkin Elmer, Cat. No: 607290/99);
b.EnVision Reader(PerkinElmer 2103-0010)；
c.1M HEPES buffer (Invitrogen, Cat. No.: 15630-080);
TK Peptide substrate (Cisbio. HTRF KinEASE-TK Kit, catalog # 62TK0PEB), 500. mu.M, stored at-20 ℃;
SEB (Cisbio. HTRF KinEASE-TK Kit, catalog number: 62TK0PEB), 2.5. mu.M, stored at-20 ℃;
ATP (Sigma-Aldrich A7699), 10mM, stored at-20 ℃;
g.ROS1G2032R(self-prepared), 1.5M, storage at-80 ℃ C
TK antibody (Cisbio. HTRF KinEASE-TK Kit, catalog # 62TK0PEB), 400X, stored at-20 ℃;
Steptavidin-XL665(Cisbio. HTRF KinEASE-TK Kit, Cat: 62TK0PEB), 16.67. mu.M, stored at-20 ℃ C
Detection Buffer (Cisbio. HTRF KinEASE-TK Kit, catalog number: 62TK0PEB), 16.67. mu.M, stored at-20 ℃ C
k.1M MgCl2(Sigma, cat # 7786-30-3)
l.1M MnCl2(Sigma, cat # 7773-01-5)
m.0.5M Na3VO4
n.10％BSA
o.1％Tween-20
p.1M DTT
q.DMSO
r.ddH2O
s. test compound: the positive control compound TPX-0005 and the compounds of the examples of the invention were performed in the following order of operation:
1. preparation of ROS1G2032REnzyme reaction buffer: 50mM HEPES (pH 7.5), 0.1mM Na3VO4，0.001％Tween-20，5mM MgCl2，5mM MnCl20.01% BSA, 1mM DTT and 50nM SEB, mixing and placing on ice for standby;
2. dissolving a compound to be detected to be 100 times of the final operating concentration by using DMSO, performing 5-time gradient dilution on a 96-well plate to obtain 7 concentrations, adding DMSO into the 8 th well to serve as a blank control, and then diluting the blank control by using an enzyme reaction buffer solution to obtain a solution 25 times of the final working concentration for later use;
3. dilution of ROS1 with enzyme reaction bufferG2032RThe concentration is 2 times of the working concentration (the final working concentration is 0.1nM), and the mixture is evenly mixed and then placed on ice for standby;
4. preparing substrates ATP (the final working concentration is 0.2 mu M) and TKpeptide (the final working concentration is 1 mu M) with 4 times of working concentration by using an enzyme reaction buffer solution, uniformly mixing, and placing on ice for later use;
5. adding 2.5 μ L of the compound with 4 times of working concentration to be detected, 2.5 μ L of the substrate with 4 times of working concentration, and adding 2 times of ROS1 with working concentrationG2032R5 mu L, and centrifuging and mixing uniformly;
6. sealing the 384-well plate with a sealing membrane, and incubating in an incubator (23 ℃) for 1 hour;
7. preparing TK Antibody (100-fold dilution) with 4-fold working concentration and Steptavidin-XL665 (125 nM final working concentration) with 4-fold working concentration by using Detection Buffer, adding 5 mu L of the prepared TK Antibody and the Steptavidin-XL665 to a 384-well plate respectively to terminate the reaction, and centrifuging and uniformly mixing;
8. sealing the 384-well plate with a sealing membrane, and incubating in an incubator (23 ℃) for 1 hour;
9. fluorescence values were read on Envision (320nm excitation, detecting 665nm and 620nm emission, ratio for enzyme activity).
10. The activity of the enzyme was measured at 8 concentrations for each compound, and the data was calculated using Prisim software to obtain the IC of the compound50The value is obtained.
TABLE 1 reference and example Compounds inhibitory Activity on target kinases
Figure BSA0000171399150000341
Figure BSA0000171399150000351
The test data in table 1 show that the compounds provided by the invention have good inhibitory activity on a plurality of target kinases.

Claims (6)

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof,
Figure FSA0000171399140000011
wherein,
R1selected from H and F;
R2selected from H, -CF3and-C (OH) (CH)3)2；
Ar is selected from phenyl and pyridyl, which may be optionally substituted with 1-2 fluorines;
L1is selected from C1-3Alkylene and
Figure FSA0000171399140000012
said alkylene group being optionally substituted by C1-6Alkyl substitution of said
Figure FSA0000171399140000013
Optionally substituted with 1-2 fluorines;
L2is selected from C2-6Alkylene, which alkylene may optionally be substituted by 1-2C1-3Alkyl substitution.
2. A compound selected from:
Figure FSA0000171399140000014
Figure FSA0000171399140000021
or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof.
3. A pharmaceutical composition comprising a compound according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, and a pharmaceutically acceptable carrier.
4. Use of a compound according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, in the manufacture of a medicament for the treatment of an ALK-mediated disease.
5. The use of claim 4, wherein the ALK-mediated disease is non-small cell lung cancer, anaplastic large cell lymphoma, inflammatory myofibroblastoma, nasopharyngeal carcinoma, breast carcinoma, colorectal carcinoma, diffuse large B-cell lymphoma, systemic histiocytosis, and neuroblastoma.
6. The use of claim 4, wherein the ALK-mediated disease is an ALK-positive non-small cell lung cancer.
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