CN116178433A - Salts of AXL kinase inhibitors, methods of preparation and use thereof - Google Patents

Salts of AXL kinase inhibitors, methods of preparation and use thereof Download PDF

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CN116178433A
CN116178433A CN202111422552.8A CN202111422552A CN116178433A CN 116178433 A CN116178433 A CN 116178433A CN 202111422552 A CN202111422552 A CN 202111422552A CN 116178433 A CN116178433 A CN 116178433A
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compound
acid salts
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ray powder
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张林林
马昌友
吴有智
裴俊杰
吴舰
徐丹
朱春霞
田舟山
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Nanjing Chia Tai Tianqing Pharmaceutical Co Ltd
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Abstract

The invention provides a salt of a compound of formula I, a crystal form of the salt, a preparation method and application thereof. Wherein the salt is selected from the group consisting of methanesulfonate, benzenesulfonate, oxalate, fumarate, citrate, hippurate, hydrochloride, hydrobromide, sulfate or phosphate.
Figure DDA0003377019880000011

Description

Salts of AXL kinase inhibitors, methods of preparation and use thereof
Technical Field
The invention belongs to the technical field of medicines, and relates to an AXL kinase inhibitor, in particular to a salt of the AXL inhibitor, a preparation method and medical application thereof.
Background
Receptor Tyrosine Kinases (RTKs) are multi-domain transmembrane proteins that act as sensors for extracellular ligands. Ligand receptor binding induces receptor dimerization and activation of its intracellular kinase domain, which in turn leads to recruitment, phosphorylation and activation of multiple downstream signaling cascades (Robinson, D.R. et al, oncogene,19:5548-5557,2000). To date, 58 RTKs have been identified in the human genome that can regulate a variety of cellular processes including cell survival, growth, differentiation, proliferation, adhesion, and motility (Segaliny, a.i., et al, j. Bone Oncol,4:1-12,2015).
AXL (also known as UFO, ARK and Tyro 7) belongs to the TAM family of receptor tyrosine kinases, members of which also include Mer and Tyro3. Of these, AXL and Tyro3 have the most similar gene structure, while AXL and Mer have the most similar tyrosine kinase domain amino acid sequence. Like other Receptor Tyrosine Kinases (RTKs), the TAM family of structures comprises an extracellular domain, a transmembrane domain, and a conserved intracellular kinase domain. The extracellular domain of AXL has a unique structure that juxtaposizes immunoglobulin and fibronectin type III repeat units and reminds humans of the structure of a neutrophil adhesion molecule. TAM family members have 1 common ligand, growth inhibitory specific protein 6 (Gas 6), which binds to all TAM receptor tyrosine kinases. AXL binding to Gas6 results in receptor dimerization and AXL autophosphorylation, which activate downstream multiple signal transduction pathways and are involved in multiple processes of tumorigenesis (Linger, R.M et al, ther. Targets,14 (10), 1073-1090, 2010; rescigno, J. Et al, oncogene,6 (10), 1909-1913, 1991).
AXL is widely expressed in normal tissues of the human body, such as monocytes, macrophages, platelets, endothelial cells, cerebellum, heart, skeletal muscle, liver, kidney, etc., where myocardial and skeletal muscle expression is highest, bone marrow cd34+ cells and stromal cells are also highly expressed, and normal lymphoid tissues are very low in expression (Wu YM, robinson DR, kung HJ, cancer Res,64 (20), 7311-7320,2004;hung BI, etc., DNA Cell Biol, 22 (8), 533-540, 2003). In many cancer cell studies, it was found that there is overexpression or ectopic expression of the AXL gene in hematopoietic, mesenchymal and endothelial cells. The phenomenon of AXL kinase overexpression is particularly pronounced in various leukemias and most solid tumors. Inhibition of AXL receptor tyrosine kinase can reduce pro-survival signals of tumor cells, block invasion ability of tumor, and increase sensitivity of targeted drug treatment and chemotherapy. Finding potent AXL inhibitors is therefore an important direction in the development of current tumor-targeted drugs.
Disclosure of Invention
In one aspect, the invention provides a pharmaceutically acceptable salt of a compound of formula I selected from the group consisting of organic acid salts selected from one of methanesulfonate, benzenesulfonate, oxalate, fumarate, citrate and hippurate, or inorganic acid salts selected from one of hydrochloride, hydrobromide, sulfate or phosphate, the compound of formula I having the structure:
Figure BDA0003377019860000011
in some embodiments, the organic acid salt is selected from mesylate salts.
In some embodiments, the mesylate salt is a hydrate of the mesylate salt.
In some embodiments, the mesylate salt is the dihydrate of the mesylate salt.
In some embodiments, the molar ratio of the compound of formula I to the organic acid of the organic acid salt is 1:1.
in some embodiments, the mineral acid salt of the compound of formula I is present in a molar ratio to the mineral acid of 1:1 or 1:2.
in some embodiments, the molar ratio of the compound of formula I to hydrogen chloride in the hydrochloride salt is 1:1 or 1:2.
in some embodiments, the molar ratio of the compound of formula I to hydrogen chloride in the hydrochloride salt is 1:2.
in some embodiments, the sulfate salt of the compound of formula I has a molar ratio to sulfuric acid of 1:1.
in some embodiments, the hydrobromide salt has a molar ratio of the compound of formula I to hydrobromic acid of 1:1.
in some embodiments, the phosphate salt has a molar ratio of compound of formula I to phosphoric acid of 1:1.
it will be understood that the salts of the present invention are obtained by salifying a compound of formula I with the corresponding acid, in which reaction the compound of formula I is converted into a cation which is combined with the acid radical of the corresponding acid to form the salt; . The molar ratio of the compound of formula I to the acid according to the invention is therefore to be understood as meaning the molar ratio of the cation of the compound of formula I in the salt to the acid radical of the corresponding acid.
In some exemplary embodiments, the present invention provides mesylate salts of compounds of formula I, wherein the molar ratio of the compound of formula I to the methanesulfonic acid is 1:1, or the molar ratio of the cation of the compound of formula I to the acid radical of methanesulfonic acid is 1:1.
in another aspect, the invention provides a crystalline form of a pharmaceutically acceptable salt of a compound of formula I, selected from the group consisting of an organic acid salt selected from the group consisting of methanesulfonate, benzenesulfonate, oxalate, fumarate, citrate and hippurate, or an inorganic acid salt selected from the group consisting of hydrochloride, hydrobromide, sulfate or phosphate.
In some embodiments, the present invention provides crystalline forms of the mesylate salt of the compound of formula I.
In some embodiments, the present invention provides crystalline forms of the mesylate salt of the compound of formula I, having an X-ray powder diffraction pattern as shown in figure 1.
In some embodiments, the present invention provides crystalline forms of the monohydrochloride salt of the compound of formula I.
In some embodiments, the present invention provides crystalline forms of the monohydrochloride salt of a compound of formula I having an X-ray powder diffraction pattern as shown in fig. 4.
In some embodiments, the present invention provides crystalline forms of the dihydrochloride salt of the compound of formula I.
In some embodiments, the present invention provides crystalline forms of the dihydrochloride salt of the compound of formula I, with an X-ray powder diffraction pattern as shown in fig. 5.
In some embodiments, the present invention provides crystalline forms of the phosphate salt of the compound of formula I.
In some embodiments, the present invention provides crystalline forms of the phosphate salt of the compound of formula I, whose X-ray powder diffraction pattern is shown in fig. 6.
In some embodiments, the present invention provides crystalline forms of the hippurate of the compound of formula I.
In some embodiments, the present invention provides crystalline forms of the hippurate of the compound of formula I, the X-ray powder diffraction pattern of which is shown in fig. 7.
In some embodiments, the present invention provides for the amorphous form of the sulfate salt of the compound of formula I.
In some embodiments, the present invention provides crystalline forms of the hydrobromide salt of the compound of formula I.
In some embodiments, the present invention provides crystalline forms of the hydrobromide salt of the compound of formula I, having an X-ray powder diffraction pattern as shown in fig. 9.
In some embodiments, the present invention provides crystalline forms of the benzenesulfonate salt of the compound of formula I.
In some embodiments, the present invention provides crystalline forms of the benzenesulfonate salt of the compound of formula I having an X-ray powder diffraction pattern as shown in fig. 10.
In some embodiments, the invention provides crystalline forms of oxalates of compounds of formula I.
In some embodiments, the invention provides crystalline forms of the oxalate salt of the compound of formula I having an X-ray powder diffraction pattern as shown in figure 11.
In some embodiments, the present invention provides crystalline forms of the fumarate salt of the compound of formula I.
In some embodiments, the present invention provides crystalline forms of the fumarate salt of a compound of formula I, having an X-ray powder diffraction pattern as shown in fig. 12.
In some embodiments, the present invention provides crystalline forms of the citrate salt of the compound of formula I.
In some embodiments, the present invention provides crystalline forms of the citrate salt of the compound of formula I having an X-ray powder diffraction pattern as shown in figure 13.
In another aspect, the present invention provides a crystalline form a of a compound of formula I having an X-ray powder diffraction pattern with diffraction peaks at 7.6 ° ± 0.2 °, 10.2 ° ± 0.2 °, 17.6 ° ± 0.2 °, 20.3 ° ± 0.2 ° and 20.9 ° ± 0.2 ° 2Θ.
Further, the crystal form a has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 4.1°±0.2°, 7.6°±0.2°, 10.2°±0.2°, 12.6°±0.2°, 13.0°±0.2°, 17.6°±0.2°, 19.7°±0.2°, 20.3°±0.2°, 20.9°±0.2° and 22.2°±0.2°.
Further, the crystal form a has an X-ray powder diffraction pattern having diffraction peaks at 2θ of 4.1 ° ± 0.2 °, 5.6 ° ± 0.2 °, 7.6 ° ± 0.2 °, 10.2 ° ± 0.2 °, 10.9 ° ± 0.2 °, 12.6 ° ± 0.2 °, 13.0 ° ± 0.2 °, 15.2 ° ± 0.2 °, 17.6 ° ± 0.2 °, 19.7 ° ± 0.2 °, 20.3 ° ± 0.2 °, 20.9 ° ± 0.2 °, 22.2 ° ± 0.2 °, 23.2 ° ± 0.2 °, 24.6 ° ± 0.2 °, 27.0 ° ± 0.2 °, 28.8 ° ± 0.2 °, 37.0 ° ± 0.2 ° and 37.7 ° ± 0.2 °.
In some embodiments, the crystal form a, whose X-ray powder diffraction pattern 2 theta is detailed in the following table:
TABLE 1X-ray powder diffraction pattern data for form A
Figure BDA0003377019860000021
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Figure BDA0003377019860000031
In some embodiments, the X-ray powder diffraction of form a expressed in terms of 2θ has a profile as shown in fig. 14.
In another aspect, the invention provides pharmaceutically acceptable salts of the compounds of formula I and processes for the preparation of the crystalline forms of the salts, comprising the step of salifying a compound of formula I with a corresponding acid.
In some embodiments, the solvent of the reaction is selected from the group consisting of a mixed solvent of an alcoholic solvent and an alkane solvent, a mixed solvent of a ketone solvent and an alkane solvent, a mixed solvent of an ester solvent and an alkane solvent, a mixed solvent of a nitrile-water solvent and an alkane solvent, a mixed solvent of an alkylbenzene solvent and an alkane solvent, and a mixed solvent of a halogenated hydrocarbon solvent and an alkane solvent.
In some embodiments, the alcoholic solvent is selected from methanol, ethanol, or isopropanol; the ketone solvent is selected from acetone or butanone; preferably acetone; the ester solvent is selected from ethyl acetate or butyl acetate; ethyl acetate is preferred; the nitrile-water solvent is selected from nitrile-water mixed solution, and the alkane solvent is selected from n-heptane.
In another aspect, the invention also provides pharmaceutical compositions comprising pharmaceutically acceptable salts of the compounds of formula I.
In some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.
In some embodiments, the pharmaceutical composition is a solid pharmaceutical formulation suitable for oral administration, preferably a tablet or capsule.
In another aspect, the invention also provides pharmaceutical compositions comprising crystalline forms of the pharmaceutically acceptable salts of the compounds of formula I.
In some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.
In some embodiments, the pharmaceutical composition is a solid pharmaceutical formulation suitable for oral administration, preferably a tablet or capsule.
In another aspect, the invention also provides a pharmaceutically acceptable salt of a compound of formula I, or a pharmaceutical composition thereof, for use as a medicament.
In another aspect, the invention also provides a crystalline form of a pharmaceutically acceptable salt of a compound of formula I, or a pharmaceutical composition thereof, for use as a medicament.
In another aspect, the invention also provides a method for preventing and/or treating AXL kinase mediated diseases or conditions comprising administering to a subject in need thereof a salt of the compound of formula I of the invention or a pharmaceutical composition thereof.
In another aspect, the invention also provides a method for preventing and/or treating AXL kinase mediated diseases or conditions comprising administering to a subject in need thereof a crystalline form of a salt of the compound of formula I of the invention or a pharmaceutical composition thereof.
In another aspect, the present invention also provides a salt of the compound of formula I of the present invention or a pharmaceutical composition thereof for use in the prevention and/or treatment of AXL kinase mediated diseases or conditions.
In another aspect, the invention also provides crystalline forms of salts of the compounds of formula I of the invention or pharmaceutical compositions thereof for use in the prevention and/or treatment of AXL kinase mediated diseases or conditions.
In some embodiments, the AXL kinase mediated disease or condition is cancer.
In some typical embodiments, the cancer is a disease associated with hematological and solid tumors.
Correlation definition
Unless specifically indicated, the following terms used in the specification and claims have the following meanings:
pharmaceutically acceptable salts of the invention also include their hydrated forms.
The term "pharmaceutically acceptable carrier" refers to those carriers which have no significant irritating effects on the body and which do not impair the biological activity and properties of the active compound. Including but not limited to any diluents, disintegrants, binders, glidants, wetting agents permitted by the national food and drug administration to be useful in humans or animals.
The term "fumaric acid" refers to fumaric acid having the structure:
Figure BDA0003377019860000041
the term "alcoholic solvent" refers to a material derived from substitution of one or more hydroxyl groups (OH) for one or more hydrogen atoms on a C1-C6 alkane, which C1-C6 alkane refers to a straight or branched chain alkane containing 1-6 carbon atoms, specific examples of alcoholic solvents include, but are not limited to: methanol, ethanol, isopropanol or n-propanol.
The term "alkane solvent" refers to a straight or branched or cyclic alkane containing 5 to 7 carbon atoms, specific examples include, but are not limited to, n-hexane, cyclohexane, n-heptane.
The term "ester solvent" refers to a chain compound having an ester group-COOR and having 3 to 10 carbon atoms, wherein R is a C1-C6 alkyl group, and said C1-C6 alkyl group refers to a straight or branched alkane having 1 to 6 carbon atoms, and specific examples of the ester solvent include, but are not limited to, methyl acetate, ethyl acetate, propyl acetate.
The term "halogenated hydrocarbon solvent" refers to a substance derived from substitution of one or more halogen atoms for one or more hydrogen atoms on a C1-C6 alkane, the C1-C6 alkane being a straight or branched chain alkane containing 1-6 carbon atoms, the halogen atoms being fluorine, chlorine, bromine, iodine, specific examples of halogenated hydrocarbon solvents including but not limited to methylene chloride or chloroform.
The term "ketone solvent" refers to a chain or cyclic compound containing carbonyl-CO-and having 3 to 10 carbon atoms, and specific examples include, but are not limited to, acetone, butanone, or cyclohexanone.
The term "benzene-based solvent" refers to a solvent containing phenyl groups, and specific examples include toluene, xylene, cumene or chlorobenzene.
The term "equivalent" refers to the equivalent amount of other starting materials required in terms of equivalent relationship of chemical reactions, with 1 equivalent of base material used in each step.
The X-ray powder diffraction pattern is obtained by using Cu-K alpha radiation measurement.
In X-ray powder diffraction spectra (XRPD), diffraction patterns derived from crystalline compounds are often characteristic for specific crystals, where the relative intensities of the bands (especially at low angles) may vary due to the dominant orientation effects resulting from differences in crystallization conditions, particle size and other measurement conditions. Thus, the relative intensities of the diffraction peaks are not characteristic for the crystals aimed at. It is determined whether or not the relative positions of peaks, rather than their relative intensities, are concurrent with the known crystalline phases. Furthermore, there may be slight errors in the position of the peaks for any given crystal, as is also well known in the crystallographic arts. For example, the position of the peak may be shifted due to a change in temperature at the time of analyzing the sample, a sample shift, calibration of the instrument, or the like, and a measurement error of the 2θ value may be about ±0.2°. Therefore, this error should be taken into account when determining each crystalline structure. The peak position is typically represented in the XRPD pattern by a2θ angle or a crystal plane distance d, with a simple scaling relationship between the two: d=λ/2sin θ, where d represents the crystal face distance, λ represents the wavelength of the incident X-ray, and θ is the diffraction angle. For isomorphous crystals of the same compound, the peak positions of the XRPD spectra have similarities overall, and the relative intensity errors may be large. It should also be noted that in the identification of mixtures, the loss of part of the diffraction lines may be caused by content reduction, etc., and that, in this case, it is not necessary to rely on all bands observed in the high purity sample, even one band may be characteristic for a given crystallization.
Differential Scanning Calorimetry (DSC) determines the transition temperature when a crystal absorbs or releases heat due to its crystal structure changing or the crystal melting. For the isoforms of the same compound, the thermal transition temperature and melting point errors are typically within about 5 ℃, usually within about 3 ℃ in successive assays. When a compound is described as having a given DSC peak or melting point, it is referred to that DSC peak or melting point ± 5 ℃. DSC provides an auxiliary method to distinguish between different crystal forms. Different crystal morphologies can be identified based on their different transition temperature characteristics. It should be noted that the DSC peak or melting point of the mixture may fluctuate over a larger range. Furthermore, since decomposition is accompanied during melting of the substance, the melting temperature is related to the rate of temperature rise.
Thermogravimetric analysis (TGA) refers to a thermal analysis technique that measures the relationship between the mass and temperature change of a sample under test at a programmed temperature. When the measured substance sublimates or evaporates in the heating process, the measured substance is decomposed into gas or loses crystal water, and the measured substance is caused to change in quantity. At this time, the thermogravimetric curve is not a straight line but is reduced. By analyzing the thermal weight curve, the temperature at which the measured substance changes can be known, and the amount of the lost substance can be calculated according to the lost weight.
The term "as shown in … …" when referring to, for example, an XRPD pattern, DSC pattern or TGA pattern includes patterns which are not necessarily the same as those depicted herein, but which fall within the limits of experimental error when considered by one of skill in the art.
The abbreviations of the invention have the following meanings, unless otherwise specified:
M：mol/L
mM：mmol/L
nM：nmol/L
boc
1 H NMR: nuclear magnetic resonance hydrogen spectrum
MS (esi+): mass spectrometry
DMSO-d 6 Deuterated dimethyl sulfoxide
CDCl 3: Deuterated chloroform
DTT: dithiothreitol
SEB: supplemented Enzymatic Buffer (enzyme-supplementing buffer)
IMDM (Iscove's Modified Dulbecco's Medium) modified Dulbecco's (name) Medium.
Room temperature: 25 ℃.
Drawings
In order to more clearly illustrate the embodiments of the present invention and the technical solutions of the prior art, the following description will briefly explain the embodiments and the drawings needed in the prior art, and it is obvious that the drawings in the following description are only some embodiments of the present invention and that other drawings can be obtained according to these drawings by a person skilled in the art.
FIG. 1 is an X-ray powder diffraction (XRPD) spectrum of the mesylate salt of compound I;
FIG. 2 is a Differential Scanning Calorimeter (DSC) diagram of the mesylate salt of the compound of formula I;
FIG. 3 Thermogravimetric (TGA) diagram of mesylate of compound of formula I;
FIG. 4 shows an X-ray powder diffraction (XRPD) pattern for a monohydrochloride salt of a compound of formula I;
FIG. 5 shows an X-ray powder diffraction (XRPD) pattern for the dihydrochloride of the compound of formula I;
FIG. 6 shows an X-ray powder diffraction (XRPD) pattern for a phosphate of a compound of formula I;
FIG. 7 shows an X-ray powder diffraction (XRPD) pattern of the hippurate of the compound of formula I;
FIG. 8 shows an X-ray powder diffraction (XRPD) pattern for a sulfate salt of a compound of formula I;
FIG. 9 shows an X-ray powder diffraction (XRPD) pattern of the hydrobromide salt of the compound of formula I;
FIG. 10 shows an X-ray powder diffraction (XRPD) pattern for the benzenesulfonate salt of compound of formula I;
FIG. 11 shows an X-ray powder diffraction (XRPD) pattern of the oxalate salt of the compound of formula I;
FIG. 12 shows an X-ray powder diffraction (XRPD) pattern of the fumarate salt of the compound of formula I;
FIG. 13 shows an X-ray powder diffraction (XRPD) pattern for the citrate salt of the compound of formula I;
figure 14 shows an X-ray powder diffraction (XRPD) pattern of form a of the compound of formula I.
Detailed Description
The invention is described in more detail below by means of examples. However, these specific descriptions are only for illustrating the technical scheme of the present invention, and do not limit the present invention in any way.
The test conditions of each instrument are as follows:
(1) X-ray powder diffractometer (X-ray Powder Diffraction, XRPD)
Instrument model: bruker D2 Phaser 2 nd
Figure BDA0003377019860000051
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Figure BDA0003377019860000061
(2) Thermogravimetric analyzer (thermal gravimetric, TGA)
Instrument model: TA Instruments TGA25 and 25
Sweep gas: nitrogen gas
Rate of temperature rise: 10 ℃/min
Heating range: room temperature-300 DEG C
The method comprises the following steps: the sample was placed in an aluminum pan, and then the aluminum pan was placed in a platinum pan, and the opening was warmed up from room temperature to a set temperature at a rate of 10 ℃/min in a nitrogen atmosphere.
(3) Differential scanning calorimeter (Differential Scanning Calorimeter DSC)
Instrument model: TA Instruments DSC25 and 25
Sweep gas: nitrogen gas
Rate of temperature rise: 10 ℃/min
Heating range: 20-300 DEG C
The method comprises the following steps: the sample was placed in an aluminum pan and after capping, heated from 20 ℃ to a set temperature at a rate of 10 ℃/min in a nitrogen atmosphere.
(4) Dynamic moisture adsorption (DVS)
Instrument model: surface Measurement System (SMS) -DVS Intrinsic
The specific instrument setting parameters are as follows:
Figure BDA0003377019860000062
example 1 preparation of (S) - (2- ((5-chloro-2- ((7- (pyrrolidin-1-yl) -6,7,8, 9-tetrahydro-5H-benzo [7] rota-n-2-yl ] amino) pyrimidin-4-yl) amino) -5- (methoxymethyl) phenyl) dimethylphosphine oxide
Figure BDA0003377019860000071
a) 2-iodo-4- (methoxymethyl) aniline
To a solution of dichloromethane (261 mL)/water (135 mL) was added 4- (methoxymethyl) aniline (9 g), iodine (16.65 g) and sodium bicarbonate (16.53 g), and the mixture was stirred at 22℃for 16h. The reaction solution was quenched with saturated sodium thiosulfate (10 ml) at room temperature. The resulting mixture was extracted with dichloromethane (3×100 mL), followed by washing the combined organic layers with saturated aqueous sodium chloride (1×100 mL), and the organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1 v/v) to give the title product (16 g). MS (ESI+): 264.0 (M+H).
b) 2-amino-5- (methoxymethyl) phenyl) dimethylphosphine oxide
To a stirred solution of 2-iodo-4- (methoxymethyl) aniline (16 g,60.82mmol,1.00 eq.), potassium phosphate (14.20 g), palladium acetate (0.68 g) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (1.76 g) was added dimethyl phosphine oxide (5.22 g) under nitrogen atmosphere (224 mL), and the mixture was stirred at 120℃for 2 hours. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with N, N-dimethylformamide (3X 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1 v/v) to give the title product (12.9 g). MS (ESI+): 214.1 (M+H).
c) (2- ((2, 5-dichloropyrimidin-4-yl) amino) -5- (methoxymethyl) phenyl) dimethylphosphine oxide
To N, N-dimethylformamide (22 mL) was added (2- ((2, 5-dichloropyrimidin-4-yl) amino) -5- (methoxymethyl) phenyl) dimethylphosphine oxide (1.10 g), 2,4, 5-trichloropyrimidine (1.23 g) and N, N-diisopropylethylamine (2.00 g) at room temperature, and the mixture was stirred for 3h. The resulting mixture was diluted with dichloromethane (30 mL). The reaction was quenched by the addition of water (10 ml) at 0deg.C. The resulting mixture was extracted with dichloromethane (3 x50 ml). The combined organic layers were washed with saturated sodium chloride (1×50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1 v/v) to give the title product (1.28 g).
MS(ESI+):360.0(M+H).
d) (S) - (2- ((5-chloro-2- ((7- (pyrrolidinyl-1-yl) -6,7,8, 9-tetrahydro-5H-benzo [7] cyclohen-2-yl ] amino) pyrimidin-4-yl) amino) -5- (methoxymethyl) phenyl) dimethylphosphine oxide
To isopropyl alcohol (2 mL) were added (2- ((2, 5-dichloropyrimidin-4-yl) amino) -5- (methoxymethyl) phenyl) dimethylphosphine oxide (50.00 mg) and (S) -7- (pyrrolidin-1-yl) -6,7,8, 9-tetrahydro-5H-benzo [7] cyclo-en-2-amine (31.98 mg), followed by the addition of a 1, 4-dioxane solution of hydrogen chloride (10 drops, 4M) and microwave irradiation at 130 ℃ for 3.5 hours. The mixture was then cooled to room temperature and concentrated under reduced pressure. The crude product was purified by reverse phase high performance liquid chromatography (column YMC Actus Triart C, 30 x 150mm, particle size 5 μm, mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60mL/min, gradient: 20% B to 50% B,8min, wavelength: 220nm, retention time: 6.83min, column temperature: 25 ℃) to give the title product (20.2 mg).
1 H NMR(400MHz,DMSO-d 6 ,ppm)：δ11.07(s,1H),9.26(s,1H),8.52(d,J＝4.6Hz,1H),8.17(s,1H), 7.53(dd,J＝14.0,2.0Hz,1H),7.44(q,J＝3.1Hz,2H),7.26(dd,J＝8.1,2.3Hz,1H),6.97(d,J＝8.1Hz,1H), 4.42(s,2H),3.31(s,3H),3.01–2.75(m,2H),2.55(s,5H),2.50(s,2H),1.84(s,2H),1.81(s,3H),1.77(s,3H), 1.70(q,J＝3.6,3.2Hz,4H),1.54(s,2H).MS(ESI+):554.2(M+H).
Example 2 Activity assay
The related compounds prepared in example 1 underwent related enzyme activities, cells, in vivo related activities
The specific structure of positive drug 1 (BGB 324) used in the activity test is as follows:
Figure BDA0003377019860000081
the positive drug 2 (TP 0903) has the following specific structure:
Figure BDA0003377019860000082
all of the above compounds were purchased from Shanghai Cheng Biotech Co.
(1) AXL kinase inhibitory Activity
1. Experimental procedure
a) AXL enzyme (Carna, 08-107) configuration and addition: with 1 Xenzyme buffer (200. Mu.L of Enzymatic buffer kinase X, 10. Mu.L of 500mM MgCl) 2 mu.L of 100mM DTT, 6.26. Mu.L of 2500nM SEB, and 773.75. Mu.L of H are added 2 O, 1ml of 1 Xenzyme buffer was prepared. ) AXL enzyme 33.33ng/uL was diluted to 0.027 ng/. Mu.L (1.67×, final control.=0.016 ng/uL) and 6. Mu.L of 1.67-fold final concentration enzyme solution was added to each of the compound well and positive control well using a BioTek (MultiFlo FX) automatic liquid separator; 6. Mu.L of 1 Xenzymatic buffer was added to the negative control wells.
b) Compound preparation and addition: the compounds prepared in the examples and positive drugs were diluted from 10mM to 100. Mu.M using DMSO and titrated with a compound titrator (Tecan, D300 e) which automatically sprays the required concentration per well at 1. Mu.M, 1/2log gradient dilution for a total of 8 concentrations. Centrifugation at 2500rpm for 30s and incubation at room temperature for 15min.
c) ATP, substrate preparation and addition: ATP (Sigma, A7699) was diluted with 1 Xenzyme buffer from 10mM to 75. Mu.M (5X) at a final concentration of 15. Mu.M; substrate TK Substrate 3-biotin (Cisbio, 61TK0 BLC) was diluted from 500. Mu.M to 5. Mu.M (5X) with 1 Xenzyme buffer, at a final concentration of 1. Mu.M; ATP was mixed with substrate in equal volumes and added to each well using a BioTek automatic dipstick 4. Mu.L; centrifuge at 2500rpm for 30s, react at 25℃for 45min.
d) Preparing and adding a detection reagent: strepitavidin-XL 665 (Cisbio, 610 SAXLG) was diluted from 16.67. Mu.M to 250nM (4X) with HTRF KinEASE detection buffer (Cisbio) to a final concentration of 62.5nM; TK anti-Cryptate (Cisbio) was diluted from 100X to 5X with HTRF KinEASE detection buffer (cisbio) to a final concentration of 1X; XL665 was mixed with an equal volume of anti-body and 10. Mu.L was added to each well using a BioTek automatic dispenser, centrifuged at 2500rpm for 30s and reacted at 25℃for 1 hour. After the reaction is finished, the detection is carried out by using a multifunctional plate reader HTRF.
2. Data analysis
response-Variable slope fit of the response curve using GraphPad Prism 5 software log (inhibitor) vs. IC for AXL kinase inhibition by the compound 50 Values.
The inhibition rate calculation formula is as follows:
Figure RE-GDA0003456834460000013
conversion% _sample: is a conversion reading of the sample;
convertion% _min: representing conversion readings without enzyme wells;
convesion% _max: representing conversion readings without compound inhibition wells.
3. The experimental results are detailed in the following table
TABLE 2 Compounds AXL inhibitory Activity IC 50 Data
Figure BDA0003377019860000091
(2) Detection of inhibition of cell proliferation by Compounds
1. Experimental procedure
MV-4-11 (human myelomonocytic leukemia cell line, medium: IMDM+10% fetal bovine serum) was purchased from Nanjac, bai Biotechnology Co., ltd, placed at 37℃and 5% CO 2 Is cultured in an incubator of (a). Cells in the logarithmic growth phase were plated in 96-well plates at cell densities of 8000 cells/well, 6000 cells/well, 2000 cells/well and 3000 cells/well, respectively, and a blank group was simultaneously set.
The test compound and the positive drug were dissolved in dimethyl sulfoxide to prepare a 10mM stock solution, which was stored in a-80℃refrigerator for a long period of time. After 24h of cell plating, a working solution with a concentration of 200 times (maximum concentration of 200 or 2000. Mu.M, 3 times gradient, total 10 concentrations) was obtained by diluting 10mM of the compound stock solution with dimethyl sulfoxide, 3. Mu.L of each concentration was added to 197. Mu.L of complete medium, the working solution with a concentration of 3 times was obtained by dilution, and 50. Mu.L was then obtainedL was added to 100. Mu.L of the cell culture broth (final concentration of dimethyl sulfoxide 0.5%, v/v), and two duplicate wells were set for each concentration. After 72h of dosing, 50. Mu.l of each well was added
Figure BDA0003377019860000092
(from Promega), fluorescence signals were measured on Envision (PerkinElmer) according to the protocol described in the specification, and a response-Variable slope fitted dose-response curve was used to obtain IC for inhibition of cell proliferation by the compound using GraphPad Prism 5 software log (inhibitor) vs. response-Variable slope 50 Values. The inhibition rate calculation formula:
Figure BDA0003377019860000093
wherein:
test object signal value: cell + medium + compound group fluorescence signal mean;
blank group signal value: medium group (containing 0.5% dmso) fluorescence signal mean;
negative control signal values: cell + media group (containing 0.5% dmso) fluorescence signal mean.
2. Experimental results
IC of antiproliferative Activity of Compound MV4-11 cells of example 1 50 (MV 4-11, nM) 6.97.
(3) MV4-11 in vivo efficacy of the Compound
The inhibition effect of the compound and the positive medicine on the in-vivo growth of human acute monocytic leukemia cell MV-4-11 nude mice transplanted tumor model tumor is tested.
1. Construction of mouse model
Collecting MV-4-11 cells in logarithmic growth phase, and adjusting cell concentration to 7.0X10 after cell count and re-suspension 7 cells/mL; is injected into the anterior right armpit of nude mice subcutaneously, and each animal is inoculated with 200. Mu.L (14×10) 6 Cell/tumor), and establishing MV-4-11 graft tumor model. The volume of the tumor to be 100-300 mm 3 Tumor-bearing mice with good health conditions and similar tumor volumes are selected.
2. Configuration of the Compounds
The compound and the positive medicine are mixed uniformly by vortex oscillation with proper solvent, ultrasound is used to dissolve the compound completely, then proper amount of citric acid buffer solution is added slowly, the vortex oscillation is carried out, and the concentration is 0.1, 0.5 and 1 mg.mL -1 Is a formulation for administration.
Solvent control group: PEG400& citrate buffer (20:80, v:v).
3. Grouping and administration of animals
The modeled mice were randomly grouped (n=6), and the relevant compounds and positive drugs were given starting on the day of grouping, after 21 days or in the solvent control group tumor volumes reached 2000mm 3 Ending the experiment (based on the first reaching index), and the administration volume is 10 mL/kg -1 . The compounds and positive drugs were administered by gavage, once daily. Tumor volumes were calculated by measuring tumor diameters and animal weights 2 times per week after the start of the experiment.
4. Data analysis
The Tumor Volume (TV) calculation formula is: tumor volume (mm) 3 )＝l×w 2 /2，
Wherein l represents the tumor major diameter (mm); w represents the tumor minor diameter (mm).
The Relative Tumor Volume (RTV) was calculated as: rtv=tv t /TV initial
Wherein, TV initial Tumor volume measured for group dosing; TV set t Tumor volume at each measurement during dosing.
The calculation formula of the tumor growth inhibition rate TGI (%) is as follows: tgi=100% × [1- (TV) t(T) －TV initial(T) )/(TV t(C) －TV initial(C) )]
Wherein, TV t(T) Tumor volume per measurement of treatment group; TV set initial(T) Tumor volume for treatment group at the time of group dosing; TV set t(C) Tumor volume per measurement of the solvent control group is indicated; TV set initial(C) Tumor volumes of the solvent control group at the time of group administration are shown.
The calculation formula of the relative tumor proliferation rate (% T/C) is as follows: % T/c=100% × (RTV T /RTV C )
Wherein RTV T Representing treatment group RTV; RTV (real time kinematic) C Solvent control RTV is shown.
Experimental data were calculated and related statistical processing was performed using Microsoft Office Excel 2007 software.
5. The experimental results are detailed in the following table:
in vivo efficacy of the compounds of Table 3
Figure BDA0003377019860000101
Remarks: the experimental data in the table are the end of the experiment (the end of the experiment is defined as the tumor volume of the solvent control group reaching 2000mm after 21 days) 3 And (3) ending the experiment (based on the first reaching index)), and obtaining relevant data.
(4) ICR mouse pharmacokinetic study of Compounds
1. Gastric lavage prescription configuration of compounds
Each compound was formulated with DMSO as a 10mg/mL stock solution.
Preparing a mixed solvent: tween 80:PEG400:Water=1:9:90 (v/v/v)
And (3) accurately sucking 450 mu l of compound DMSO stock solution with the concentration of 10mg/mL into a glass bottle, adding DMSO and mixed solvent with proper volumes, wherein the ratio of solvent in the final preparation is DMSO to mixed solvent (v/v) =10:90, and carrying out vortex (or ultrasonic) to uniformly disperse to obtain 4.5mL of administration test solution with the concentration of 1 mg/mL.
2. Test protocol
Male 6-10 week old ICR mice (mouse source: vetolihua laboratory animal technologies Co., ltd.) were taken, 6 mice per group, fasted overnight, and fed 4 hours after dosing. On the day of the experiment, mice were given respective 10 mg.kg by gavage -1 Compound test solution. After administration, the mice are subjected to EDTA-K treatment at 0, 5min, 15min, 30min, 1h, 2h, 4h, 8h, and 24h, and blood is collected from the eye socket by about 100 μl 2 In the anticoagulant tube. Centrifuging whole blood sample at 1500-1600 g for 10min, and storing the separated plasma in-40- -20deg.C refrigerator for biological sampleAnd (5) analyzing. The LC-MS/MS method is used for measuring the blood concentration.
3. Data analysis and results
Pharmacokinetic parameters were calculated using the non-compartmental model in Pharsight Phoenix 7.0.7.0, with specific results given in the following table.
Table 4: mouse pharmacokinetic results of Compounds
Compounds of formula (I) Cmax(ng/mL) Tmax(h) AUC 0-24 (ng.h/mL) T1/2(h)
Example 1 324 2.17 1300 1.35
Positive medicine 2 (TP-0903) 26.8 0.25 52.2 1.20
EXAMPLE 3 preparation of salts and crystalline forms of the Compound of formula I
About 50mg of the free base, i.e. the compound of formula 1, and 1.05 equivalents of the acid (hydrochloric acid with the molar ratio of acid to free base set at 2.10) are taken separately, 1mL of solvent is added and stirred at room temperature for 2 days. The resulting supernatant was attempted to crystallize by stirring at 5 ℃ and slow volatilizing, and the solids were isolated by centrifugation, dried by air blow or under reduced pressure at 40 ℃ for 2-5 hours for XRPD characterization.
TABLE 5 results of salt formation of the compounds of formula I
Figure BDA0003377019860000111
/>
Figure BDA0003377019860000121
Figures 4-13 are X-ray powder diffraction (XRPD) patterns of hydrochloride, dihydrochloride, phosphate, hippurate, sulfate, hydrobromide, benzenesulfonate, oxalate, fumarate, and citrate, respectively.
EXAMPLE 4 preparation of methanesulfonate salt
To a 20-mL glass vial was added (S) - (2- ((5-chloro-2- ((7- (pyrrolidin-1-yl) -6,7,8, 9-tetrahydro-5H-benzo [7] rota-en-2-yl) amino)) pyrimidin-4-yl) amino) -5- (methoxymethyl) phenyl-dimethylphosphine oxide (50 mg), toluene (1 mL), and methanesulfonic acid (10 mg) successively, and the reaction was stirred at room temperature for 2 hours to give the (S) - (2- ((5-chloro-2- ((7- (pyrrolidin-1-yl) -6,7,8, 9-tetrahydro-5H-benzo [7] rota-en-2-yl) amino)) pyrimidin-4-yl) amino) -5- (methoxymethyl) phenyl-dimethylphosphine oxide methanesulfonate crystalline form in the form of a suspension.
EXAMPLE 5 preparation of methanesulfonate salt
To a 20-mL glass vial was added (S) - (2- ((5-chloro-2- ((7- (pyrrolidin-1-yl) -6,7,8, 9-tetrahydro-5H-benzo [7] rota-en-2-yl) amino)) pyrimidin-4-yl) amino) -5- (methoxymethyl) phenyl dimethylphosphine oxide (1 g), ethyl acetate (20 mL), and methanesulfonic acid (172.8 mg), and after stirring at room temperature for 10 minutes, the methanesulfonic acid salt crystal form prepared in example 4 was added as seed (5 mg) and stirred for 30 minutes. To a glass vial, ethyl acetate (20 mL), acetone (10 mL) and form A seed crystals (10 mg) were added sequentially, followed by stirring and crystallization for 20 minutes. Suction filtration and drying of the wet cake under vacuum at 40 ℃ for 20 hours afforded (S) - (2- ((5-chloro-2- ((7- (pyrrolidin-1-yl) -6,7,8, 9-tetrahydro-5H-benzo [7] chromen-2-yl) amino)) pyrimidin-4-yl) amino) -5- (methoxymethyl) phenyl dimethylphosphine mesylate as a pale yellow solid powder form.
1 H NMR(400MHz,DMSO-d6):11.11(s,1H)；9.46(br,1H)；9.36(s,1H)；8.58-8.50(m,1H)；8.19(s,1H)； 7.60-7.43,(m,3H)；7.37(dd,J＝8.2,2.2Hz,1H)；7.04(d,J＝8.2Hz,1H)；4.44(s,2H)；3.53-3.46(m,3H)；3.33(s, 3H)；3.15(s,2H)；2.82-2.62(m,4H)；2.32-2.29(m,5H)；1.99(s,2H)；1.89-1.75(m,8H)；1.40(q,J＝12.3Hz,2H).
The XRD pattern is shown in figure 1, the DSC pattern is shown in figure 2, and the TGA pattern is shown in figure 3.
EXAMPLE 6 preparation of form A of the Compound of formula I
200mg of S) - (2- ((5-chloro-2- ((7- (pyrrolidin-1-yl) -6,7,8, 9-tetrahydro-5H-benzo [7] chromen-2-yl ] amino) pyrimidin-4-yl) amino) -5- (methoxymethyl) phenyl-dimethylphosphine oxide prepared according to the method of example 1 and 2mL of purified water were sequentially added to a 3mL glass bottle, after magnetically stirring at room temperature for 6 hours, the sample was centrifuged, the wet sample was dried at 40℃under reduced pressure for 21 hours to give 176mg of form A, the yield was 88.0%, and XRD patterns were shown in FIG. 14, and X-ray powder diffraction pattern data were shown in Table 6.
TABLE 6X-ray powder diffraction pattern data for free base form A
Figure BDA0003377019860000131
Figure BDA0003377019860000141
/>

Claims (10)

1. A pharmaceutically acceptable salt of a compound of formula I selected from the group consisting of organic acid salts selected from one of methanesulfonic acid salts, benzenesulfonic acid salts, oxalic acid salts, fumaric acid salts, citric acid salts, and hippuric acid salts, or inorganic acid salts selected from one of hydrochloric acid salts, hydrobromic acid salts, sulfuric acid salts, or phosphoric acid salts, the compound of formula I having the structure:
Figure FDA0003377019850000011
2. the salt according to claim 1, wherein the organic acid is selected from methanesulfonic acid.
3. The mesylate salt of a compound of formula I according to claim 2, which is in the form of a hydrate, in particular dihydrate.
4. The salt of the compound of formula I according to claim 1, the molar ratio of the compound of formula I to the organic acid of the organic acid salt being 1:1.
5. the salt of the compound of formula I according to claim 1, wherein the molar ratio of the compound of formula I to the mineral acid in the mineral acid salt is 1:1 or 1:2, further the molar ratio of the compound of formula I to hydrogen chloride in the hydrochloride is 1:1 or 1:2.
6. a crystalline form of a pharmaceutically acceptable salt of a compound of formula I, said salt being selected from the group consisting of organic acid salts selected from the group consisting of methanesulfonic acid salts, benzenesulfonic acid salts, oxalic acid salts, fumaric acid salts, citric acid salts and hippuric acid salts, or inorganic acid salts selected from the group consisting of hydrochloric acid salts, hydrobromic acid salts, sulfuric acid salts or phosphoric acid salts.
7. The crystalline form of a salt of a compound of formula I according to claim 6, which salt is a mesylate salt, further having an X-ray powder diffraction pattern as shown in figure 1.
8. A crystalline form of a compound of formula I having an X-ray powder diffraction pattern with diffraction peaks at 7.6 ° ± 0.2 °, 10.2 ° ± 0.2 °, 17.6 ° ± 0.2 °, 20.3 ° ± 0.2 ° and 20.9 ° ± 0.2 ° in 2Θ; further X-ray powder diffraction patterns have diffraction peaks at 2θ of 4.1°±0.2°, 7.6°±0.2°, 10.2°±0.2°, 12.6°±0.2°, 13.0°±0.2°, 17.6°±0.2°, 19.7°±0.2°, 20.3°±0.2°, 20.9°±0.2° and 22.2°±0.2°; further, the X-ray powder diffraction pattern thereof has diffraction peaks at 4.1 ° ± 0.2 °, 5.6 ° ± 0.2 °, 7.6 ° ± 0.2 °, 10.2 ° ± 0.2 °, 10.9 ° ± 0.2 °, 12.6 ° ± 0.2 °, 13.0 ° ± 0.2 °, 15.2 ° ± 0.2 °, 17.6 ° ± 0.2 °, 19.7 ° ± 0.2 °, 20.3 ° ± 0.2 °, 20.9 ° ± 0.2 °, 22.2 ° ± 0.2 °, 23.2 ° ± 0.2 °, 24.6 ° ± 0.2 °, 27.0 ° ± 0.2 °, 28.8 ° ± 0.2 °, 37.0 ° ± 0.2 ° and 37.7 ° ± 0.2 °, and the further X-ray powder diffraction pattern expressed in terms of 2θ angle has the pattern as shown in fig. 14.
9. A process for the preparation of pharmaceutically acceptable salts and crystalline forms of the salts of the compounds of formula I, comprising the step of salifying the compounds of formula I with the corresponding acids.
10. A pharmaceutical composition of a pharmaceutically acceptable salt of a compound of formula I.
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