CN111187257B - RET receptor tyrosine kinase inhibitors - Google Patents
RET receptor tyrosine kinase inhibitors Download PDFInfo
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- CN111187257B CN111187257B CN202010097637.2A CN202010097637A CN111187257B CN 111187257 B CN111187257 B CN 111187257B CN 202010097637 A CN202010097637 A CN 202010097637A CN 111187257 B CN111187257 B CN 111187257B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Abstract
The present invention discloses novel compounds as inhibitors of transfection Rearrangement (RET) kinases, pharmaceutical compositions containing them, methods for their preparation and uses thereof.
Description
Technical Field
The present invention relates to novel compounds which are inhibitors of the Transfection Rearrangement (RET) kinase, methods for their preparation and their use, alone or in combination, in therapy for the treatment of the normalization of gastrointestinal sensitivity, motility and/or secretion, and/or abdominal conditions or diseases, and/or the following diseases associated with RET dysfunction or in which modulation of RET activity may be of therapeutic benefit.
Background
The transfection Rearrangement (RET) is a nerve growth factor receptor tyrosine kinase which is activated upon binding to one of the four neurotrophic factors (glial cell line-derived neurotrophic factor, neurturin, artemin and persephin) in combination with the co-receptor neurotrophic factor (GDNF) family receptors alpha-1, 2, 3 and 4, respectively (Plaza-Menacho, I., et al, Trends Genet.,2006, 22: 627-. RET is known to play an important role in the development and survival of cutaneous and intestinal afferent pain receptors. RET kinase knockout mice lack enteric neurons and have other nervous system abnormalities indicating the need for functional RET kinase protein products during Development (Taraviras, S.et al, Development,1999,126: 2785-. Furthermore, studies of patient populations with Hirschspung disease characterized by colonic obstruction due to lack of normal colonic weakening (enervation) have a higher proportion of familial and sporadic functional RET mutation loss (Butler Tjaden N., et al., Transl. Res.,2013,162: 1-15).
Similarly, abnormal RET kinase activity is associated with multiple endocrine tumors (MEN 2A and 2B), Familial Medullary Thyroid Carcinoma (FMTC), Papillary Thyroid Carcinoma (PTC), and Hirschsprung disease (HSCR) (Borello, m., et al, Expert opin. MEN 2A is a cancer syndrome caused by dimerization via disulfide bonds due to mutations in the extracellular cysteine-rich domain of RET, which leads to constitutive activation of tyrosine kinase activity (Wells Jr, S., et al., J.Clin.Endocrinol.Metab.,2013,98: 3149-. Individuals with this mutation may develop Medullary Thyroid Carcinoma (MTC), parathyroid hyperplasia, and pheochromocytoma. MEN 2B is due to the Met918Thr mutation on RET, which alters the specificity of tyrosine kinases. MEN 2B is similar to MEN 2A, but lacks parathyroid hyperplasia, and also causes development of many mucosal ganglia of the lips, tongue, and intestinal tract. Chromosomal rearrangements linking the promoter to the NH2 terminal domain or to genes unrelated to the COOH-terminus of RET kinase to form a constitutively active chimeric form of the receptor (RET/PTC) are considered tumor initiating events in the PTC (Viglietto, G.et. al., Oncogene,1995, 11: 1207-1210). PTC covers about 80% of all thyroid cancers. These data suggest that inhibition of RET may be an attractive therapeutic strategy for the treatment of pain associated with IBS and other gastrointestinal disorders, as well as for the treatment of cancers with constitutive RET kinase activity.
Disclosure of Invention
The invention provides a RET inhibitor
In particular, the method comprises the following steps of,
in one aspect, the invention provides a compound having a structure according to formula I or a salt thereof:
wherein R is1Is alkyl or heteroalkyl;
each R2Independently a hydroxy-substituted alkyl, a halogen-substituted alkyl, a cycloalkylalkoxy, a heterocyclylalkoxy;
n is 1 or 2.
In some embodiments, R1Is C1-6Alkyl or C1-6A heteroalkyl group.
In some embodiments, each R2Independently is hydroxy-substituted C1-6Alkyl, halogen substituted C1-6Alkyl, 4-6 membered cycloalkyl C1-6Alkoxy or4-6 membered heterocyclyl C1-6An alkoxy group.
In some embodiments of the present invention, the,
R1is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, isopentyl or dimethylaminoethyl;
R2is hydroxymethyl, 2-hydroxyethyl, 1-fluoroethyl, trifluoromethyl, oxetanylethoxy, oxetanylpropoxy, azetidinylethoxy, azetidinylpropoxy, oxolanylethoxy, oxolanylpropyloxy, aziridinylethoxy or aziridinylpropoxy.
In some embodiments, the compounds of the present invention have a structure as shown in formula II or a salt of a structure as shown in formula II:
in some embodiments, the compounds of the present invention have one of the following structures:
in another aspect, the method provides a pharmaceutical composition comprising a compound of the invention, and an excipient.
In another aspect, the invention provides the use of a compound of the invention or a composition of the invention in the manufacture of a medicament for the treatment, prevention or alleviation of cancer selected from the group consisting of non-small cell lung cancer, hepatocellular cancer, colorectal cancer, medullary thyroid cancer, follicular thyroid cancer, undifferentiated thyroid cancer, papillary thyroid cancer, brain tumor, peritoneal cavity cancer, solid tumor, head and neck cancer, glioma, neuroblastoma, breast cancer, fallopian tube cancer, ovarian cancer, prostate cancer.
Another aspect of the invention relates to methods for the preparation, isolation and purification of compounds encompassed by formula (I) or (II).
The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below.
Definitions and general terms
Unless otherwise indicated, the terms used in the specification and claims have the following definitions. Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
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 this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.
The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to articles of one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.
The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects, e.g., also primates (e.g., humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.
Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.
Unless otherwise indicated, the structural formulae depicted herein include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomers): such as the R, S configuration containing an asymmetric center, the (Z), (E) isomers of the double bond, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers, or geometric isomers (or conformers) thereof are within the scope of the present invention.
The salts mentioned in the present invention are pharmaceutically acceptable salts, wherein "pharmaceutically acceptable salts" are well known in the art, such as: berge et al, describe the description of the descriptive pharmaceutical acceptable salts in detail in J. Pharmacol Sci,1997,66, 1-19. Examples of pharmaceutically acceptable, non-limiting salts include inorganic acid salts formed by reaction with amino groups, such as hydrochloride, hydrobromide, phosphate, metaphosphate, sulfate, sulfite, nitrate, perchlorate, and organic acid salts, such as carboxylate, sulfonate, sulfinate, thiocarboxylate, and the like.
The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.
Hair brushAny formulae given are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H，3H，11C，13C，14C，15N，17O，18O，18F，31P，32P，35S，36Cl and125I。
the term "alkyl" as used herein denotes a saturated straight or branched chain monovalent hydrocarbon radical of 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, wherein the alkyl radical may be independently and optionally substituted with one or more substituents as described herein. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)3) Ethyl (Et, -CH)2CH3) N-propyl (n-Pr, -CH)2CH2CH3) Isopropyl (i-Pr, -CH (CH)3)2) N-butyl (n-Bu, -CH)2CH2CH2CH3) Isobutyl (i-Bu, -CH)2CH(CH3)2) Sec-butyl (s-Bu, -CH (CH)3)CH2CH3) Tert-butyl (t-Bu, -C (CH)3)3) N-pentyl (-CH)2CH2CH2CH2CH3) 2-pentyl (-CH (CH)3)CH2CH2CH3) 3-pentyl (-CH (CH)2CH3)2) 2-methyl-2-butyl (-C (CH)3)2CH2CH3) 3-methyl-2-butyl (-CH (CH)3)CH(CH3)2) 3-methyl-1-butyl (-CH)2CH2CH(CH3)2) 2-methyl-1-butyl (-CH)2CH(CH3)CH2CH3) N-hexyl (-CH)2CH2CH2CH2CH2CH3) 2-hexyl (-CH (CH)3)CH2CH2CH2CH3) 3-hexyl (-CH (CH)2CH3)(CH2CH2CH3) 2-methyl-2-pentyl (-C (CH))3)2CH2CH2CH3) 3-methyl-2-pentyl (-CH (CH)3)CH(CH3)CH2CH3) 4-methyl-2-pentyl (-CH (CH)3)CH2CH(CH3)2) 3-methyl-3-pentyl (-C (CH)3)(CH2CH3)2) 2-methyl-3-pentyl (-CH (CH)2CH3)CH(CH3)2) 2, 3-dimethyl-2-butyl (-C (CH)3)2CH(CH3)2) 3, 3-dimethyl-2-butyl (-CH (CH)3)C(CH3)3)N-heptyl, n-octyl, and the like. The term "alkyl" and its prefix "alkane" as used herein, both include straight and branched saturated carbon chains. The term "alkylene" is used herein to denote a saturated divalent hydrocarbon radical resulting from the elimination of two hydrogen atoms from a straight or branched chain saturated hydrocarbon, examples of which include, but are not limited to, methylene, ethylidene, and the like.
The term "heteroalkyl" as used herein means that 1 or more carbons in the alkyl group described herein are replaced with a heteroatom.
The term "alkoxy" as used herein means an alkyl group as described herein attached to the rest of the molecule through an oxygen atom.
The term "cycloalkyl" as used herein refers to a cyclic saturated hydrocarbon group. Suitable cycloalkyl groups may be substituted or unsubstituted monocyclic, bicyclic or tricyclic saturated hydrocarbon groups having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
The term "heterocyclyl" as used herein refers to a saturated cyclic hydrocarbon group containing a heteroatom.
The term "halogen" refers to F, Cl, Br or I.
The "hydroxy-substituted" and "halogen-substituted" in the present invention respectively represent that the following groups are substituted with hydroxy or halogen, and the number of substitution may be one or more.
The term "heteroatom" means one or more O, S, N, P and Si atoms, including any oxidation state form of N, S and P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, e.g., N (e.g., N in 3, 4-dihydro-2H-pyrrolyl), NH (e.g., NH in pyrrolidinyl) or NR (e.g., NR in N-substituted pyrrolidinyl).
When a group is described as "each.. independently" it is meant that when the group is plural, the plural groups may be the same or different and are independent of each other, such as "each R2Independently "means that there are a plurality of R2When each R is2Are independent of each other, can be the same or different, and do not affect each other.
The combination of terms described herein, such as cycloalkylalkoxy, heterocyclylalkoxy, and the like, wherein cycloalkyl, alkoxy, heterocyclyl have the definitions described herein.
General synthetic procedure
In general, the compounds of the invention may be prepared by the methods described herein. The following reaction schemes and examples serve to further illustrate the context of the invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.
The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin HaoLiyu Chemicals Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaseiki chemical plant.
The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N-dimethylacetamide and N, N-dimethylformamide were used by being dried beforehand over anhydrous sodium sulfate.
The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.
The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants. Nuclear magnetic resonance spectroscopy with CDC13、d6-DMSO、CD3OD or d6Acetone as solvent (reported in ppm) with TMS (0ppm) or chloroform (7.25ppm) as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets), and dt (doublet of triplets). Coupling constants are expressed in hertz (Hz).
Low resolution Mass Spectral (MS) data were measured by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315B DAD detector were applied for analysis, and an ESI source was applied to the LC-MS spectrometer.
Low resolution Mass Spectral (MS) data were determined by Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was used for the LC-MS spectrometer.
Both spectrometers were equipped with an Agilent Zorbax SB-C18 column, 2.1X 30mm, 5 μm. The injection volume is determined by the sample concentration; the flow rate is 0.6 mL/min; peaks of HPLC were recorded by UV-Vis wavelength at 210nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase a) and 0.1% formic acid in ultrapure water (phase B). Gradient elution conditions are shown in table 1:
TABLE 1
| Time (min) | A(CH3CN，0.1％HCOOH) | B(H2O，0.1％HCOOH) |
| 0-3 | 5-100 | 95-0 |
| 3-6 | 100 | 0 |
| 6-6.1 | 100-5 | 0-95 |
| 6.1-8 | 5 | 95 |
The process conditions for HPLC preparation are as follows:
(1) taking a proper amount of a mixture of diastereoisomers containing the compound (II), and dissolving the mixture by using a mobile phase;
(2) setting the flow rate, detection wavelength and column temperature of the mobile phase;
(3) injecting a proper amount of the sample solution obtained in the step (1) into a high performance liquid chromatograph, recording a chromatogram, and completing separation and analysis of isomers;
a chromatographic column: a normal phase chiral chromatographic column with silica gel containing polysaccharide derivatives on the surface as a stationary phase; more specifically, the column used was either cellosolve AD-H (10 x 250nm, 5um) or cellosolve AD (20 x 250nm, 5 um).
Mobile phase: a mixture of two or more of methanol, ethanol, isopropanol, acetonitrile, n-hexane, n-pentane, isohexane, n-heptane, diethylamine, triethylamine, trifluoroacetic acid and glacial acetic acid; more specifically, the volume ratio of n-hexane, n-pentane, isohexane and n-heptane in the mixture of the mobile phase is 10-20%, the volume ratio of methanol, ethanol, isopropanol and acetonitrile is 20-95%, the volume ratio of diethylamine, triethylamine, trifluoroacetic acid and glacial acetic acid is 0-2%, and the total amount of the components in the mobile phase is 100%; more specifically, the volume ratio of n-hexane in the mixture of the mobile phase is 15-20%, the volume ratio of isopropanol is 80-90%, the volume ratio of diethylamine and triethylamine is 0.5-1%, and the total amount of all the components in the mobile phase is 100%.
Detection wavelength: 280 nm-320 nm;
flow rate: 0.5-10 mL/min; more specifically 2-5 mL/min;
column temperature: 10 to 35 ℃.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
And (3) synthesis of an intermediate:
step A1:
adding 5% sodium hydroxide (100mL) and a raw material 1 (2-trifluoromethylphenol, CAS: 444-30-4, 0.03mol) into a reaction bottle, stirring until the sodium hydroxide and the raw material are dissolved, sequentially adding the raw material 2(0.15mol) and tetrabutylammonium bromide (0.6g), heating to 80 ℃ for reaction, monitoring the reaction process by TLC, cooling to room temperature after the reaction is finished, extracting chloroform (50mL X3), washing the extracted chloroform phase with water and drying with anhydrous sodium sulfate, and concentrating the dried chloroform solution under reduced pressure to obtain a brownish yellow sticky substance. And (5) detecting and identifying by LC-MS.
Step A2:
iodine (3mmol) and H5IO6(1.5mmol) is added into a reaction bottle, tetrahydrofuran (100mL) is added for dissolving, then the intermediate L (3mmol) obtained in the previous step is added, the temperature is raised to 50 ℃, then stirring is carried out, the reaction progress is monitored by TLC, after the reaction is finished, the temperature is cooled to room temperature, and the mixture is purified by a silica gel chromatographic column after being concentrated. And (5) detecting and identifying by LC-MS.
The reaction results for different starting materials 2 were as follows:
example 1: synthesis of N-ethyl-6-oxo-8- (2-oxo-4- ((4- (3- (pyrrolidin-1-yl) propoxy) -3- (trifluoromethyl) phenyl) amino) piperidin-1-yl) -6H-benzo [ c ] chromene-3-carboxamide
Step 1) 8-fluoro-6H-benzo [ c ] chromen-6-one
2-bromo-5-fluoro-benzaldehyde (1mmol), 2-hydroxyphenylboronic acid (1mmol), K2CO3(1mmol.),and PPh3(0.25mmol) and Pd (OAc)2(5 mol%) was charged into a reaction flask, 3mL of DMF was added under nitrogen, the mixture was stirred at 90 ℃ under nitrogen, the progress of the reaction was checked by TLC, after completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (20mL) and extracted with ethyl acetate (20mL X3), the ethyl acetate phase was collected and dried over anhydrous sodium sulfate, and purified and isolated by silica gel chromatography after concentration (yield: 79%). LC-MS: [ M + H ]]+＝215.06.
Step 2) 8-fluoro-3-iodo-6H-benzo [ c ] chromen-6-one
Iodine (3mmol) and H5IO6(1.5mmol) was added to a reaction flask, tetrahydrofuran (100mL) was added to dissolve, and 8-fluoro-6H-benzo [ c ] was added]Chromen-6-one (3mmol), warmed to 50 ℃ and then stirred, followed by monitoring the progress of the reaction by TLC, cooled to room temperature after completion of the reaction, concentrated and purified by silica gel chromatography (50.1% yield). LC-MS: [ M + H ]]+＝340.95。
Step 3) 8-fluoro-6-oxo-6H-benzo [ c ] chromene-3-carboxylic acid
Under the protection of nitrogen, 8-fluoro-3-iodo-6H-benzo [ c ] is reacted]To a mixture of chromen-6-one (1.0mmol), palladium acetate (3 mol%), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (3 mol%) and dicyclohexylcarbodiimide (2.0mmol) were added formic acid (7.0mmol), triethylamine (2.0mmol) and N, N-dimethylformamide (2 mL). Stirring the obtained mixed reactant at 80 ℃ for reaction, monitoring the reaction process by TLC, adding water into the reaction solution after the reaction is finished, adjusting the pH to 9, back-extracting the reaction mixed solution by dichloromethane for 3 times,discarding the back extraction solution, adjusting pH of the water phase to 2-3 with dilute hydrochloric acid, and extracting with ethyl acetate for 3 times. The extract was collected, dried over anhydrous sodium sulfate and concentrated to be used directly for the next reaction (yield: 88%). LC-MS: [ M + H ]]+＝259.05。
Step 4) N-ethyl-8-fluoro-6-oxo-6H-benzo [ c ] chromene-3-carboxamide
Under the protection of nitrogen, 8-fluoro-6-oxo-6H-benzo [ c ] at 0 DEG C]To a solution of chromene-3-carboxylic acid (1.0mmol) in tetrahydrofuran (2mL) was added N, N-dimethylformamide (1mL) followed by oxalyl chloride (2 mmol). After the addition, the temperature was naturally raised to room temperature, and the reaction was stirred at room temperature for 30 minutes. Ethylamine (2mmol) was added to the reaction mixture, and the reaction was continued for 2 hours with stirring. After the reaction, the reaction solution was poured into an ice-water mixture, the pH was adjusted to 2 to 3, the reaction mixture was back-extracted with dichloromethane 3 times, the back-extract was discarded, and the aqueous phase was extracted with dichloromethane 3 times, the pH was adjusted to 9. The extract was collected, dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by means of a silica gel column chromatography (yield: 69%). LC-MS: [ M + H ]]+＝286.08
Step 5)8- (4-amino-2-oxopiperidin-1-yl) -N-ethyl-6-oxo-6H-benzo [ c ] chromene-3-carboxamide
4-Aminopiperidin-2-one (2.0mmol) and potassium tert-butoxide (3.0mmol) in N, N-dimethylformamide were stirred at 0 ℃ for 1 hour, after which N-ethyl-8-fluoro-6-oxo-6H-benzo [ c ] was added]Chromene-3-carboxamide (1.0 mmol). The resulting mixture was heated to 90 ℃ for 6 hours. After completion of the reaction, it was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate 3 times. The extract was collected, dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by means of a silica gel column chromatography (yield: 59.8%). LC-MS: [ M + H ]]+＝380.17。
Step 6) N-ethyl-6-oxo-8- (2-oxo-4- ((4- (3- (pyrrolidin-1-yl) propoxy) -3- (trifluoromethyl) phenyl) amino) piperidin-1-yl) -6H-benzo [ c ] chromene-3-carboxamide
To a mixture of (S) -7- (4-amino-2-oxopiperidin-1-yl) -N-methyldibenzo [ b, d ] furan-3-carboxamide (1.0mmol), 1- (3- (4-iodo-2- (trifluoromethyl) phenoxy) propyl) pyrrolidine (I2, 1.5mmol) and copper acetylacetonate (1 mol%) was added glycerol (10mL) under nitrogen, followed by potassium hydroxide (4 mmol). The final mixture was reacted at 80 ℃ and the reaction was checked by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, and dichloromethane was added to the reaction mixture, followed by washing with water 3 times. The organic phase was dried over anhydrous sodium sulfate and then separated by column chromatography on silica gel (yield: 82%).
1HNMR(400MHz,CDCl3)δ8.10-7.90(m,5H),7.85(d,1H),7.65(d,1H),6.85-6.71(m,3H),4.11(t,2H),4.01(s,1H),3.52-3.20(m,4H),2.81-2.75(dd,1H),2.68-2.55(m,8H),1.92-1.75(m,8H),1.19-0.98(t,3H)；
LC-MS:[M+H]+＝651.28。
Examples 2-6 were synthesized using the synthetic intermediates I1, I3, I4, I5, with reference to the synthesis of example 1, with the following results:
biological analysis
The cytoplasmic domain of human RET kinase was expressed as an N-terminal GST-fusion protein using a baculovirus expression system. GST-RET was purified using glutathione agarose chromatography. Increasing concentrations of RET kinase inhibitor as monomer in 384-well templates were used in a total volume of 10 μ L. 100nL of various concentrations of RET inhibitor were added to 384-well plates.mu.L/well of a2 Xenzyme cocktail (50mM HEPES (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid); 1mM CHAPS (3- [ (3-cholamidopropyl) dimethylamino)]-1-propanesulfonic acid salt); 0.1mg/mL BSA (bovine serum albumin); 1mM DTT (dithiothreitol); 0.2nM RET kinase) were added to the 384 well plates and incubated at 23 ℃ for 30 minutes. Add 5. mu.L/well of 2 Xsubstrate mix (50mM HEPES; 1mM CHAPS; 0.1mg/mL BSA; 20. mu.M adenosine triphosphate; 20mM MgCl)2And 1mM biotinylated peptide substrate) and incubated at 23 ℃ for 1 hour. 10 μ L/well of 2X stop/assay mix (50mM HEPES; 0.1% BSA; 800mM potassium fluoride; 50mM EDTA (ethylenediaminetetraacetic acid; 200X dilution of europium cryptate-labeled anti-phosphotyrosine antibody; 62.5nM streptavidin-XL 665) were incubated at 23 ℃ for hours and read on a Homogenis Time-Resolved Fluorescence reader. IC50 was fitted to a sigmoidal dose-response curve using GraphPad Prism.
Example compounds of the invention were tested in the RET assay described above. Data for specific examples tested in the enzymatic assay for human RET kinase are listed in table 2 below.
TABLE 2
| Numbering | IC50nM |
| Example 1 | 21 |
| Example 2 | 18 |
| Example 3 | 65 |
| Example 4 | 78 |
| Example 5 | 33 |
| Example 6 | 195 |
| Example 7 | 155 |
The compound provided by the invention has good RET kinase inhibition activity. Useful for treating, preventing, reducing the normalization of gastrointestinal sensitivity, motility, and/or secretion, and/or abdominal conditions or diseases, and/or diseases associated with RET dysfunction or in which modulation of RET activity may be of therapeutic benefit.
In the description herein, reference to the description of the terms "one embodiment," "some embodiments," "other embodiments," "an example," "a specific example" or "some examples" or the like means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that those skilled in the art can make changes, modifications, substitutions and alterations to the above embodiments without departing from the principle and spirit of the present invention, the scope of which is defined by the appended claims and their equivalents.
Claims (3)
1. A compound or salt thereof having one of the following structures
2. A pharmaceutical composition comprising a compound of claim 1 and an adjuvant.
3. Use of a compound of claim 1 or a composition of claim 2 in the manufacture of a medicament for treating, preventing, alleviating cancer selected from the group consisting of non-small cell lung cancer, hepatocellular carcinoma, medullary thyroid carcinoma, follicular thyroid carcinoma, undifferentiated thyroid carcinoma, papillary thyroid carcinoma, brain tumor, peritoneal cavity cancer, head and neck cancer, glioma, neuroblastoma, breast cancer, fallopian tube cancer, ovarian cancer, prostate cancer.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012112791A1 (en) * | 2011-02-16 | 2012-08-23 | Paloma Pharmaceuticals, Inc. | Radiation countermeasure agents |
| CN107250110A (en) * | 2014-09-10 | 2017-10-13 | 葛兰素史克知识产权发展有限公司 | The noval chemical compound of (RET) inhibitor is reset as transfection |
| CN108440404A (en) * | 2018-05-08 | 2018-08-24 | 西安凯伦生物科技有限公司 | Antitumor drug and its preparation method and application with multiple kinase inhibitory activity |
| CN108840862A (en) * | 2018-05-30 | 2018-11-20 | 淮安培元基因科技有限公司 | A kind of quinazolinone ester derivant and the biomedical uses as DAPK gene methylation inhibitor |
| CN109096264A (en) * | 2018-08-28 | 2018-12-28 | 山东理工职业学院 | RET inhibitor and preparation method thereof, composition and purposes |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012112791A1 (en) * | 2011-02-16 | 2012-08-23 | Paloma Pharmaceuticals, Inc. | Radiation countermeasure agents |
| CN107250110A (en) * | 2014-09-10 | 2017-10-13 | 葛兰素史克知识产权发展有限公司 | The noval chemical compound of (RET) inhibitor is reset as transfection |
| CN108440404A (en) * | 2018-05-08 | 2018-08-24 | 西安凯伦生物科技有限公司 | Antitumor drug and its preparation method and application with multiple kinase inhibitory activity |
| CN108840862A (en) * | 2018-05-30 | 2018-11-20 | 淮安培元基因科技有限公司 | A kind of quinazolinone ester derivant and the biomedical uses as DAPK gene methylation inhibitor |
| CN109096264A (en) * | 2018-08-28 | 2018-12-28 | 山东理工职业学院 | RET inhibitor and preparation method thereof, composition and purposes |
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