CN114591338B - Preparation method and application of Syk and VEGFR2 double-target inhibitor - Google Patents

Preparation method and application of Syk and VEGFR2 double-target inhibitor Download PDF

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CN114591338B
CN114591338B CN202210343193.5A CN202210343193A CN114591338B CN 114591338 B CN114591338 B CN 114591338B CN 202210343193 A CN202210343193 A CN 202210343193A CN 114591338 B CN114591338 B CN 114591338B
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刘晔
钱文远
王宏健
谭亮
陈曙辉
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Abstract

The application relates to a preparation method and application of a Syk and VEGFR2 double-target inhibitor. In particular, the present application relates to a process for preparing a compound of formula (I) or an isotopically-labelled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, which does not require preferential protection of pyrazole borates and which is capable of proceeding smoothly with the subsequent Suzuki reaction for the preparation of Syk and VEGFR2 dual target inhibitors.

Description

Preparation method and application of Syk and VEGFR2 double-target inhibitor
Technical Field
The application belongs to the field of medicine synthesis, and particularly relates to a preparation method and application of a spleen tyrosine kinase (Syk) and vascular endothelial growth factor 2 (VEGFR 2) double-target inhibitor.
Background
Syk is a non-receptor tyrosine kinase that plays an important role in immunoreceptor-mediated and integrin-mediated signal transduction in a variety of cell types, including B cells, macrophages, monocytes, mast cells, eosinophils, basophils, neutrophils, dendritic cells, T cells, natural killer cells, platelets and osteoclasts. The immunoreceptors described in this application include typical immunoreceptors and immunoreceptor-like molecules. Typical immunoreceptors include B-cell and T-cell antigen receptors and a variety of immunoglobulin receptors (Fc receptors). Immunoreceptor-like molecules are structurally related to immunoreceptors or participate in similar signaling pathways, and are primarily involved in non-adaptive immune functions (including neutrophil activation, natural killer cell recognition, and osteoclast activity). Integrins are cell surface receptors that play a critical role in leukocyte adhesion and activation of both innate and acquired immunity.
VEGFR2, also known as KDR or Flk-1, is identified as a receptor for VEGF and VEGFC, an early marker of endothelial cell progenitors, whose expression is restricted to endothelial cells in vivo. VEGFR2 has been shown to be the primary signal transducer for angiogenesis and the development of pathological conditions such as cancer and diabetic retinopathy. Studies have shown that anti-VEGF can exert an inhibitory effect on the expression and activation of pro-inflammatory factors, thereby reducing ocular surface inflammation. VEGFR2 transduces the primary signal of angiogenesis through its potent tyrosine kinase activity. However, unlike other representative tyrosine kinase receptors, VEGFR2 does not use the Ras pathway as the primary downstream signaling, but uses the phospholipase C protein kinase C pathway to express Mitogen Activated Protein (MAP) kinase activation and DNA synthesis. Therefore, inhibition of VEGFR2 activity and its downstream signaling is an important target for the treatment of diseases involving angiogenesis, inflammation, etc.
Thus, inhibition of Syk and VEGFR-2 activity is useful in the treatment of allergic, autoimmune and inflammatory diseases including, but not limited to, dry eye and allergic conjunctivitis, retinal inflammatory diseases, age-related macular degeneration (AMD), proliferative Diabetic Retinopathy (PDR) and retinopathy of prematurity (ROP), cancer, rheumatoid arthritis, glomerulonephritis, multiple vasculitis, idiopathic Thrombocytopenic Purpura (ITP), myasthenia gravis, allergic rhinitis, chronic Obstructive Pulmonary Disease (COPD), adult respiratory distress syndrome (ARD), asthma, and the like.
PCT international patent application WO2021169958A1, entitled "1H-pyrazole derivatives and uses as dual-target inhibitors of Syk and VEGFR 2", discloses a dual-target inhibitor for Syk and VEGFR2, and further discloses various methods of preparing such dual-target inhibitors, including, for example:
the preparation method 1 comprises the following steps:
Figure BDA0003575639270000021
the preparation method 2 comprises the following steps:
Figure BDA0003575639270000022
in the Suzuki coupling reaction of the PCT International patent application, the palladium catalyst system adopted is Pd (dppf) Cl 2 A catalytic system that is a precursor; in order to ensure the reactivity of the palladium catalyst system in the Suzuki reaction, the pyrazole borate needs to be protected by adopting a Boc or SEM group to prevent complexation with the catalyst; after the coupling reaction is completed, the protecting group Boc or SEM is removed under the corresponding conditions to give crude compounds 1-6. In this process, the Boc-protected pyrazole boronates require additional column chromatography purification to prevent the byproduct residues in the reaction of the upper protecting group from affecting the catalytic system activity of the Suzuki reaction.
Thus, a method is being sought that does not require preferential protection of pyrazole borates and that can successfully proceed with subsequent Suzuki reactions to produce Syk and VEGFR2 dual-target inhibitors.
Disclosure of Invention
The invention aims to overcome the defect that the existing method for preparing the Syk and VEGFR2 double-target inhibitor needs to protect pyrazole borate serving as a reaction raw material to prevent complexation with a catalyst and also needs an additional specific step to remove a protecting group, and provides a method which does not need to protect the pyrazole borate preferentially and can smoothly carry out subsequent Suzuki reaction to prepare the Syk and VEGFR2 double-target inhibitor.
In a first aspect, the present application provides a process for the preparation of a compound of formula (I) or an isotopically-labelled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof,
Figure BDA0003575639270000031
wherein,,
R 1 and R is 2 One of which is H and the other of which is pyrazolyl;
R 3 and R is 4 Each independently selected from the group consisting of H, F, cl, br, I, OH, NH 2 、CN、C 1-3 Alkyl and C 1-3 Alkoxy group, said C 1-3 Alkyl and C 1-3 Alkoxy is optionally substituted with 1, 2 or 3 halogens;
T 1 CH or N;
D 1 selected from the group consisting of-O-, -C (R) 5 )(R 6 )-、-N(R 7 ) -sum of
Figure BDA0003575639270000041
A group of;
R 5 and R is 6 Each independently selected from the group consisting of H, F, cl, br, I, OH and C 1-3 Alkyl group, said C 1-3 Alkyl is optionally substituted with 1, 2 or 3 halogens; alternatively, R 5 And R is 6 Together with the carbon atoms to which they are attached form an oxetanyl group;
R 7 is H,
Figure BDA0003575639270000042
Or C 1-3 Alkyl, said C 1-3 Alkyl is optionally substituted with 1, 2 or 3 halogens;
R 8 is H or-C (=O) -C 1-3 An alkyl group; and
n is 1 or 2; and is also provided with
Wherein the method comprises the steps of:
reacting a compound of formula (II):
Figure BDA0003575639270000043
wherein,,
R 9 and R is 10 One of which is H and the other is halogen;
with a compound of formula (III):
Figure BDA0003575639270000044
the reaction is carried out,
and after the reaction is finished, adding a deprotection agent into a reaction system to remove a protected SEM group so as to obtain the compound of the formula (I).
In the method, unprotected pyrazole borate is adopted in the Suzuki reaction, and SEM-Cl is selected as a ligand; unprotected pyrazole groups have no influence on the activity of the palladium catalytic system, and the Suzuki reaction can be smoothly carried out; the unprotected pyrazole borate is used for Suzuki reaction, and then a deprotection agent is directly added into a reaction system to directly generate a crude product of the compound shown in the formula (I), namely, the synthesis is completed in one reaction system without transfer.
In addition, the reactant compounds of the present application (e.g., compounds of formula (II) or (III)) may be prepared in a variety of ways known to those skilled in the art of organic synthesis, for example, as described in PCT international patent application WO2021169958A1 by the applicant. In addition, those skilled in the art can refer to the synthetic routes of the specific compounds of the specific examples of the present application, and appropriately adjust the reaction raw materials and reaction conditions to obtain synthetic methods of other compounds.
In one embodiment of the present invention,
the compound of formula (II) can be prepared by the following reaction equation:
Figure BDA0003575639270000051
wherein R is 3 、R 4 、R 9 、R 10 、T 1 、D 1 N is as defined above.
More specifically, for example, in a preferred embodiment of the present invention, the compound of formula (II) may be prepared by the following reaction equation, but is not limited thereto:
Figure BDA0003575639270000052
wherein, the reaction condition A can be: etOAc (ethyl acetate), N-dimethylaniline, POCl 3 (phosphorus oxychloride); the reaction conditions B may be: DIPEA (N, N-diisopropylethylamine), DMSO (dimethyl sulfoxide).
In addition, in a preferred embodiment of the present invention,
the pyrazolyl can be
Figure BDA0003575639270000053
In another preferred embodiment of the present invention,
the R is 3 And R is 4 Can be each independently selected from H, F, cl, br, I, OH, NH 2 CN, methyl and methoxy.
In another preferred embodiment of the present invention,
the R is 5 And R is 6 May each be independently selected from the group consisting of H, F, cl, br, I, OH and methyl.
In another preferred embodiment of the present invention,
the R is 5 And R is 6 Can be formed together with the carbon atoms to which they are commonly attached
Figure BDA0003575639270000061
In another preferred embodiment of the present invention,
the R is 7 Can be H,
Figure BDA0003575639270000062
Or methyl.
In another preferred embodiment of the present invention,
the R is 8 Can be H or-C (=O) -CH 3 。
In another preferred embodiment of the present invention,
Figure BDA0003575639270000063
can be selected from the group consisting of
Figure BDA0003575639270000064
Figure BDA0003575639270000065
Wherein R is a group consisting of 5 、R 6 、R 7 And R is 8 As defined above.
In another preferred embodiment of the present invention,
Figure BDA0003575639270000066
can be selected from the group consisting of
Figure BDA0003575639270000067
Figure BDA0003575639270000068
A group of groups.
In another preferred embodiment of the present invention,
the palladium catalyst system may comprise Pd (dppf) Cl 2 ([ 1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride, K 2 CO 3 (Potassium carbonate), DIPEA (N, N-diisopropylbenzene)Phenylethylamine), 2-methyltetrahydrofuran and H 2 O。
In another preferred embodiment of the present invention,
the deprotection agent may comprise a solution of ethylenediamine and tetrabutylammonium fluoride (TBAF) in tetrahydrofuran.
In another preferred embodiment of the present invention,
the weight ratio of the compound of formula (II) to the compound of formula (III) may be 1:0.3-0.8 (e.g., 1:0.4, 1:0.45, 1:0.5, 1:0.53, 1:0.57, 1:0.6, or 1:0.7, etc.), preferably 1:0.5-0.6; and/or the weight ratio of the compound of formula (II) to the palladium catalyst in the palladium catalytic system may be 1:0.05-0.2 (e.g., 1:0.07, 1:0.08, 1:0.09, 1:0.1, 1:0.12, 1:0.15, 1:0.18, etc.), preferably 1:0.08-0.15.
In another preferred embodiment of the present invention,
the reaction may be carried out at a temperature of 60-100 ℃ (e.g., 65 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃, or 95 ℃, etc.), preferably 85-95 ℃ (e.g., 87 ℃, 90 ℃, or 92 ℃, etc.).
In another preferred embodiment of the present invention,
the method may further comprise a purification step of the compound of formula (I). The purification step may use various purification means common in the art, and may include, for example, rinsing, distillation, filtration, centrifugation, recrystallization, and the like, as long as the concentration of the compound of formula (I) in the product can be increased.
For the sake of brevity, the "compound of formula (I)" or "compound of the present application" described hereinafter may also encompass any isotopically-labeled compound of the compound of formula (I), or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof.
The term "optical isomer" means that when a compound has one or more chiral centers, each chiral center may exist in either the R configuration or the S configuration, and thus the various isomers constituted are optical isomers. Optical isomers include all diastereoisomers, enantiomers, meso, racemates or mixtures thereof. For example, the optical isomers may be separated by chiral chromatography columns or by chiral synthesis.
The term "geometric isomer" means that when a double bond is present in a compound, the compound may exist as cis, trans, E and Z isomers. Geometric isomers include cis, trans, E, Z, or mixtures thereof.
The term "tautomer" refers to an isomer that results from the rapid movement of an atom in a molecule at two positions. Those skilled in the art will appreciate that: tautomers can be transformed into each other, and in a certain state, an equilibrium state may be reached and coexist.
Unless otherwise indicated, references herein to "a compound of formula (I)" or "a compound of the invention" also encompass isotopically-labeled compounds in which any one of the atoms of the compound is replaced by an isotopic atom thereof. The present invention includes all pharmaceutically acceptable isotopically-labeled compounds of formula (I) wherein one or more atoms are replaced by an atom having the same atomic number as, but a different atomic mass or mass number than, an atom typically found in nature.
Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H (D) and 3 isotopes of H (T), carbon, such as 11 C、 13 C and C 14 Isotopes of C, chlorine, such as 35 Cl and Cl 37 Isotopes of Cl, fluorine, such as 18 Isotopes of F, iodine, such as 123 I and 125 isotopes of I, nitrogen, such as 13 N and 15 isotopes of N, oxygen, such as 15 O、 17 O and 18 isotopes of O, and sulfur, such as 35 S。
Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously used in a manner analogous to those described in the examples and preparations attached herein.
The compounds of formula (I) may exist in the form of pharmaceutically acceptable salts, for example, acid addition salts and/or base addition salts of the compounds of formula (I). As used herein, unless otherwise indicated, "pharmaceutically acceptable salts" include acid addition salts or base addition salts that may occur within the compounds of formula (I).
Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include, but are not limited to: acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclohexylamine sulfonate, ethanedisulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, 2- (4-hydroxybenzyl) benzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, 2-isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, napthalate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, glucarate, stearate, salicylate, tannate, tartrate, tosylate and trifluoroacetate. Suitable base addition salts are formed from bases which form non-toxic salts. Examples include, but are not limited to: aluminum, arginine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine and zinc salts. Semi-salts of acids and bases, such as hemisulfate and hemicalcium salts, may also be formed. For a review of suitable salts, see Handbook of Pharmaceutical Salts:Properties, selection and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds described herein are known to those skilled in the art.
Certain compounds of the invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the compounds of formula (I), whether in solvated form or unsolvated form, are encompassed within the scope of the present invention.
Certain compounds of the present invention may exist in different crystalline or amorphous forms, and, regardless of the form in which they exist, the compounds of formula (I) are included within the scope of the present invention.
To avoid ambiguity, definitions are given below for terms used herein. Unless otherwise indicated, the terms used herein have the following meanings.
The term "pharmaceutically acceptable" means that the corresponding compound, carrier or molecule is suitable for administration to a human. Preferably, the term refers to use with mammals, preferably humans, as certified by regulatory authorities such as any national regulatory agency of CFDA (china), EMEA (europe), FDA (united states), etc.
"prodrug" means a derivative which is converted into the compound of the present invention by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, for example, by oxidation, reduction, hydrolysis or the like each carried out under the catalysis of an enzyme.
"metabolite" means all molecules derived from any of the compounds of the invention in a cell or organism, preferably a human.
As used herein, the term "substituted" means that one or more (preferably 1 to 5, more preferably 1 to 3) hydrogen atoms in the group are independently replaced by a corresponding number of substituents.
As used herein, the term "each independently" means that when the number of substituents exceeds one, the substituents may be the same or different.
As used herein, the term "optional" or "optionally" means that the event described may or may not occur. For example, a group "optionally substituted" means: the group may be unsubstituted or substituted.
As used herein, the term "alkyl" refers to saturated aliphatic hydrocarbons, including straight and branched chains. In some embodiments, the alkyl groups have 1 to 8, or 1 to 6,Or 1-3 carbon atoms. For example, the term "C 1-8 Alkyl "refers to a straight or branched chain radical having 1 to 8 carbon atoms. The term "C 1-8 Alkyl "includes the term" C "in its definition 1-6 Alkyl "," C 1 -C 3 Alkyl "and" C 1 -C 4 An alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, (R) -2-methylbutyl, (S) -2-methylbutyl, 3-methylbutyl, 2, 3-dimethylpropyl, 2, 3-dimethylbutyl, hexyl, and the like. The alkyl group may be optionally substituted with one or more (e.g., 1 to 5) suitable substituents.
As used herein, the term "haloalkyl" refers to an alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is replaced with a halogen atom). For example, the term "C 1-6 Haloalkyl "means C having one or more halogen substituents 1-6 An alkyl group (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is replaced with a halogen atom). As another example, the term "C 1-4 Haloalkyl "means C having one or more halogen substituents 1-4 An alkyl group (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is replaced with a halogen atom); the term "C 1-3 Haloalkyl "means C having one or more halogen substituents 1-3 An alkyl group (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is replaced with a halogen atom); and the term "C 1-2 Haloalkyl "means C having one or more halogen substituents 1-2 An alkyl group (i.e., methyl or ethyl) (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is replaced with a halogen atom). As another example, the term "C 1 Haloalkyl "refers to a methyl group having 1, 2 or 3 halogen substituents. Examples of haloalkyl groups include: CF (compact flash) 3 、C 2 F 5 、CHF 2 、CH 2 F、CH 2 CF 3 、CH 2 Cl, and the like.
In this context, a range of numbers relating to the number of substituents, the number of carbon atoms, and the number of ring atoms represents a list of all integers within the range, and the range is merely a simplified representation. For example: "1-4 substituents" means 1, 2,3 or 4 substituents; "3-8 ring atoms" means 3, 4, 5, 6, 7 or 8 ring atoms. Accordingly, a range of numbers relating to the number of substituents, the number of carbon atoms, the number of ring atoms also encompasses any one of its subranges, and each subrange is also considered disclosed herein.
In a second aspect, the present application provides a pharmaceutical composition comprising a compound of formula (I) or an isotopically-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutically acceptable carrier.
The pharmaceutically acceptable carrier may be an organic or inorganic inert carrier material, for example, suitable carriers include water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, mannitol, cellulose derivatives, sodium saccharin, glucose, sucrose, magnesium carbonate, saline, glycerol, ethanol, and the like. In addition, the pharmaceutical composition may contain other pharmaceutical additives such as flavoring agents, preservatives, stabilizers, emulsifiers, buffers, diluents, binders, wetting agents, disintegrants, lubricants, glidants and the like.
The dosage form of the pharmaceutical composition of the present application may be a liquid dosage form, a solid dosage form or a semi-solid dosage form. The liquid preparation can be solution (including true solution and colloid solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including injection solution, powder injection and transfusion), eye drop, nasal drop, lotion, liniment, etc.; the solid dosage forms can be tablets (including common tablets, enteric coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, enteric coated capsules), granules, powders, pills, suppositories, films, patches, aerosols, sprays and the like; the semisolid dosage form may be an ointment, gel, paste, or the like. The pharmaceutical composition of the present application can be formulated as a general formulation, as well as a sustained release formulation, a controlled release formulation, a targeted formulation, and various microparticle delivery systems.
In some embodiments, the dosage form of the pharmaceutical composition is selected from the group consisting of tablets, granules, powders, syrups, inhalants and injections.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert excipient (or carrier) (e.g., sodium citrate or dicalcium phosphate), which may further include: (a) Fillers or admixtures (e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid); (b) Binders (e.g., carboxymethyl cellulose, alginates, gels, polyvinyl pyrrolidone, sucrose, and gum arabic); (c) humectants (e.g., glycerol); (d) Disintegrants (e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain synthetic silicates, sodium carbonate); (e) a solution retarder (e.g., paraffin); (f) an absorption enhancer (e.g., a quaternary ammonium compound); (g) Wetting agents (e.g., cetyl alcohol and glycerol monostearate); (h) Adsorbents (e.g., kaolin and bentonite) and (i) lubricants (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate) or mixtures thereof.
Formulations suitable for parenteral administration, such as injection, may include aqueous and non-aqueous isotonic sterile solutions suitable for injection, and aqueous and non-aqueous sterile suspensions. The parenteral formulations provided herein are optionally contained in unit-dose or multi-dose sealed containers (e.g., ampoules) and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier (e.g., water for injection) immediately prior to use. Examples of suitable diluents for reconstitution of the pharmaceutical composition (e.g., prior to injection) include bacteriostatic water for injection, 5% dextrose in water, phosphate buffered saline, ringer's solution, saline, sterile water, deionized water, and combinations thereof.
Sprays can contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. The spray may additionally contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane. The inhalants may comprise excipients such as lactose, or aqueous solutions comprising, for example, polyethylene oxide-9-lauryl ether, glycocholate and deoxycholate, or oily solutions for administration as nasal drops or sprays, or as gels.
The content of the compound of the present application in the pharmaceutical composition thereof may be adjusted according to actual needs (e.g., dosage form, mode of administration, administration subject, etc.), for example, 0.1 to 95% by weight, for example, 1 to 95% by weight, 5 to 90% by weight, 10 to 80% by weight, etc.
In particular, 0.01 to 10g (e.g., 0.05g, 0.1g, 0.5g, 1g, 5g, etc.) of a compound of the present application may be specifically included in a pharmaceutical composition of the present application.
In a third aspect, the present application provides the use of a compound of formula (I) or an isotopically-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, in the manufacture of a medicament for treating or preventing a disease or condition mediated by Syk and VEGFR2 in a subject in need thereof as a dual-target inhibitor of Syk and VEGFR 2. The compounds of formula (I) or isotopically-labeled compounds thereof, or optical isomers, geometric isomers, tautomers or mixtures of isomers thereof, or pharmaceutically acceptable salts thereof, or prodrugs thereof, or metabolites thereof, may be used for treating or preventing diseases or disorders mediated by Syk and VEGFR2 in a subject in need thereof.
The term "subject" as used herein refers to any human or non-human organism that can potentially benefit from treatment with a compound of formula (I). Exemplary subjects include humans or mammals of any age. Preferably, the subject is a human.
The term "treating" as used herein includes treating a disease or condition in a mammal, particularly a human, and includes: (a) Inhibiting an infection, disease or condition, i.e., inhibiting or delaying the progression of an infection, disease or condition; (b) Remit an infection, disease or condition, i.e., cause regression of the disease or condition, and/or (c) cure of the infection, disease or condition.
The term "prophylaxis" as used herein includes prophylactic treatment in mammals, particularly humans, to reduce the likelihood of an infection, disease or condition occurring. Patients receiving prophylactic therapy may be selected based on the increased risk of infection or suffering from a disease or disorder as compared to the general population. "preventing" may include treating a subject who has not yet presented with an infection or clinical condition, and preventing a second occurrence of the same or a similar infection or clinical condition.
In some embodiments, the disease or disorder mediated by Syk and VEGFR2 may be selected from allergic, autoimmune and inflammatory diseases, such as dry eye and allergic conjunctivitis, retinal inflammatory diseases, age-related macular degeneration (AMD), proliferative Diabetic Retinopathy (PDR) and retinopathy of prematurity (ROP), rheumatoid arthritis, glomerulonephritis, multiple vasculitis, idiopathic Thrombocytopenic Purpura (ITP), myasthenia gravis, allergic rhinitis, chronic Obstructive Pulmonary Disease (COPD), adult respiratory distress syndrome (ARD), and asthma. In other embodiments, the disease or disorder is cancer.
In some embodiments, the compounds of the invention may be administered by oral, parenteral, intravenous, intramuscular, subcutaneous, nasal, oral mucosal, ocular, pulmonary, respiratory, vaginal, rectal, intraperitoneal, intralesional, perilesional, and the like routes.
By "therapeutically effective amount" is meant an amount of a compound of the present application that, when administered alone or in combination, treats or prevents a disease or disorder mediated by Syk and VEGFR 2.
The particular dosage administered will depend on the route of administration, the severity of the disease, the age and weight of the patient, and other factors typically considered by the attending physician in determining the individual regimen and dosage level best suited for a particular patient. For example, the daily dose of a compound of the present application may be, in particular, 0.001-150mg/kg body weight (e.g., 0.1mg/kg body weight, 1mg/kg body weight, 10mg/kg body weight, 100mg/kg body weight, etc.).
The specific frequency of administration may be determined by one of skill in the relevant art, for example, 1 day 1, 2 days 1, 3 days 1, 4 days 1, 5 days 1, 6 days 1,1 day 2, 1 day 3, etc.
Those skilled in the art will appreciate that the definitions and preferences described in one aspect of the present application apply equally to other aspects. It will be apparent to those skilled in the art that the embodiments of the various aspects of the present application may be combined in various ways without departing from the subject matter and concepts of the application, and such combinations are also included within the scope of the application.
Detailed Description
The invention is further illustrated by the following examples; but these examples do not limit the scope of the invention. All reactants used in each example were obtained commercially unless otherwise stated; the instruments and equipment used in the synthesis experiments and the product analysis and detection are all conventional instruments and equipment commonly used in organic synthesis.
Examples
The synthetic route is as follows:
Figure BDA0003575639270000141
1) Preparation of Compounds 2-3
The raw materials and the amounts of the raw materials in step 1 are shown in Table 1 below.
TABLE 1
Figure BDA0003575639270000142
To a 50L reactor, 11.0L dimethyl sulfoxide was added, stirring was started at 150rpm, and the temperature was shown to be an internal temperature of 20 ℃. 833.0g of Compound 2-2, 1510.0g of N, N-diisopropylethylamine and 1100.0g of Compound 2-1 were added in this order. Setting the external temperature to be 100 ℃ and stirring for 24 hours at the internal temperature of 95-100 ℃.
The reaction was checked by HPLC, which showed less than 3% of compound 2-1 remaining. The heating was turned off and the reaction solution was cooled to 20 to 25 ℃. The reaction solution was slowly poured into 30.0L of stirred water. The internal temperature is controlled to be 10-15 ℃, and the stirring is carried out for 0.5 hour, and the rotating speed is 100rpm. And (3) maintaining the internal temperature at 10-15 ℃, carrying out vacuum filtration, collecting a filter cake, putting the filter cake into a reaction kettle again, and adding 15.0L of isopropanol into the kettle. Setting the external temperature at 85 ℃ and stirring for 1 hour at the internal temperature of 80-85 ℃. And (3) carrying out reduced pressure suction filtration under the condition of keeping the internal temperature at 80-85 ℃, and washing the filter cake with 4.0L of isopropanol. The filter cake is collected and placed in a vacuum drying oven, and vacuum drying is carried out for 12 hours under the conditions of 50-55 ℃ and minus 0.1Mpa, thus 1300.0g of compound 2-3 is obtained, and the yield is 79.0%.
2) Preparation of Compounds 2-5
The raw materials and the amounts of the raw materials in step 2 are shown in Table 2 below.
TABLE 2
Figure BDA0003575639270000151
8.0L of 2-methyltetrahydrofuran is added into a 50L reaction kettle, stirring is started, the rotating speed is 150rpm, and the external temperature is set to be 5-10 ℃. 1070.0g of Compound 2-4, 764.0g of potassium carbonate and 711.7g of N, N-diisopropylethylamine were added in this order. 1200.0g of 2-chloromethoxyethyl trimethylsilicon is added dropwise by a constant pressure dropping funnel at an internal temperature of 5-10 ℃, and the mixture is stirred for 3 hours under the condition that the internal temperature is controlled to be 15-20 ℃ after the completion of the dropwise addition.
The reaction solution is taken for HPLC detection, and the spectrogram shows that the residual content of the compound 2-4 is less than 1.0 percent. The reaction vessel was continuously charged with 7.2L2-methyltetrahydrofuran, 3.8L of water, 1900.0g of Compound 2-3, 1376.0g of Potassium carbonate and 164.0g of Pd (dppf) Cl 2 . Nitrogen was introduced into the reaction vessel to displace for 20 minutes, and the external temperature was set at 85 ℃. Stirring at 80-85 deg.c for 16 hr. Sampling HPLC detects that the compound 2-3 has been completely converted, cooling to an internal temperature of 15-20 ℃, and slowly adding 10.0L of water and 40.0L of n-heptane into the reaction kettle under stirring. Stirring at 15-20 deg.C for 20 min, vacuum filtering, vacuum drying the filter cake in vacuum drying oven at 50-55 deg.C and-0.1 MPa for 20 hr2800.0g of crude compound 2-5 were obtained.
28.0L2-methyltetrahydrofuran was added to a 50L reaction vessel, and 2800.0g of crude compound 2-3 was added with stirring. Heating is started, the external temperature is set to be 75-80 ℃, after stirring for 1 hour, the crude compound 2-3 is completely dissolved, then 820.0g CPL type active carbon is added, and stirring is carried out for 16 hours at the internal temperature of 75-80 ℃. Filtering the mixture at the temperature of 70-80 ℃ through a diatomite layer with the thickness of 2-4 cm while the mixture is hot, and collecting filtrate.
The collected filtrate was poured back into the reaction vessel again, and 560.0g of CPL activated carbon was continuously added. Stirring for 16 hours at the internal temperature of 75-80 ℃. Filtering through a diatomite layer with the thickness of 2-4 cm at the temperature of 70-80 ℃ while the diatomite layer is hot, collecting filtrate, concentrating under reduced pressure at the temperature of 40-45 ℃ and the pressure of minus 0.1MPa until the total volume of the filtrate is about 15 liters, pouring the filtrate back into a reaction kettle again, adding 30.0L of n-heptane in batches, stirring for 1 hour at the temperature of 15-20 ℃, decompressing and filtering to obtain a filter cake, and vacuum drying (40-50 ℃ and the pressure of minus 0.1 MPa) the filter cake for 20 hours to constant weight to obtain 1650.0g of compound 2-3, wherein the yield is 68.0%.
3) Preparation of Compounds 2-6
The raw materials and the amounts of the raw materials in step 3 are shown in Table 3 below.
TABLE 3 Table 3
Figure BDA0003575639270000161
To a 50L reactor was added 20.0L of 1mol/L TBAF tetrahydrofuran solution, and stirring was started at 150rpm. 2000.0g of Compound 2-3 and 222.0g of ethylenediamine were added in this order. Stirring for 16 hours at the internal temperature of 65-72 ℃.
Taking the reaction liquid for HPLC detection, wherein the spectrogram shows that the residual content of the compound 2-3 is less than 1%, and 16.0L tetrahydrofuran is added into a reaction kettle under the condition that the temperature is kept between 50 and 55 ℃, the internal temperature is controlled between 39 and 42 ℃ and stirred for 2 hours, and then the stirring is continued for 2 hours at 15 to 20 ℃. Vacuum filtering, pouring the filter cake back into the kettle again, adding 25.0L of water and 12.5L of ethanol, and stirring for 16 hours at the internal temperature of 65-70 ℃. Vacuum heat filtering at 65-70 deg.c, collecting filter cake, vacuum drying at 50-55 deg.c and-0.1 MPa for 12 hr to constant weight to obtain 1270.3g compound 2-6 crude product with yield of 84.0%.
4) Purification of Compounds 2-6
The raw materials and the amounts of the raw materials in step 4 are shown in Table 4 below.
TABLE 4 Table 4
Figure BDA0003575639270000171
To a 50L reactor was added 15.0L ethanol and 25.0L deionized water, and 1200.0g crude compound 2-6 was added in portions. The external temperature is set to be 72 ℃, and the stirring is carried out for 48 hours at the internal temperature of 65-72 ℃.
Maintaining the internal temperature at 65-72 ℃, filtering while the mixture is hot under reduced pressure, collecting a filter cake, pouring the filter cake back into the reaction kettle again, and adding 40.0L of deionized water into the kettle. The internal temperature is controlled to be 65-75 ℃ and stirred for 16 hours. Vacuum filtering at 65-75deg.C, vacuum drying (40-50deg.C, -0.1 MPa) for 20 hr to constant weight to obtain 1140.0g compound 2-6 with yield of 95.0%.

Claims (19)

1. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof,
Figure FDA0004164580590000011
wherein,,
R 1 and R is 2 One of which is H and the other of which is pyrazolyl;
R 3 and R is 4 Each independently selected from the group consisting of H, F, cl, br, I, OH, NH 2 、CN、C 1-3 Alkyl and C 1-3 Alkoxy group, said C 1-3 Alkyl and C 1-3 Alkoxy is optionally substituted with 1, 2 or 3 halogens;
T 1 CH or N;
D 1 selected from the group consisting of-O-, -C (R) 5 )(R 6 )-、-N(R 7 ) -sum of
Figure FDA0004164580590000012
A group of;
R 5 and R is 6 Each independently selected from the group consisting of H, F, cl, br, I, OH and C 1-3 Alkyl group, said C 1-3 Alkyl is optionally substituted with 1, 2 or 3 halogens; alternatively, R 5 And R is 6 Together with the carbon atoms to which they are attached form an oxetanyl group;
R 7 is H,
Figure FDA0004164580590000013
Or C 1-3 Alkyl, said C 1-3 Alkyl is optionally substituted with 1, 2 or 3 halogens;
R 8 is H or-C (=O) -C 1-3 An alkyl group; and
n is 1 or 2; and is also provided with
Wherein the method comprises the steps of:
under the reaction condition of existence of palladium catalytic system and SEM-Cl, wherein the palladium catalytic system comprises 2-methyltetrahydrofuran and H 2 O, reacting a compound of formula (II):
Figure FDA0004164580590000014
wherein,,
R 9 and R is 10 One of which is H and the other is halogen;
with a compound of formula (III):
Figure FDA0004164580590000021
the reaction is carried out,
and after the reaction is finished, adding a deprotection agent into a reaction system to remove a protected SEM group so as to obtain the compound of the formula (I).
2. The method of claim 1, wherein the pyrazolyl is
Figure FDA0004164580590000022
3. The method of claim 1, wherein the R 3 And R is 4 Each independently selected from the group consisting of H, F, cl, br, I, OH, NH 2 CN, methyl and methoxy.
4. The method of claim 1, wherein the R 5 And R is 6 Each independently selected from the group consisting of H, F, cl, br, I, OH and methyl.
5. The method of claim 1, wherein the R 5 And R is 6 Together with the carbon atoms to which they are commonly attached form
Figure FDA0004164580590000023
6. The method of claim 1, wherein the R 7 Is H,
Figure FDA0004164580590000024
Or methyl.
7. The method of claim 1, wherein the R 8 Is H or-C (=O) -CH 3 。
8. The method of claim 1, wherein,
Figure FDA0004164580590000025
selected from->
Figure FDA0004164580590000026
Figure FDA0004164580590000027
A group of which is composed of,
wherein R is 5 、R 6 、R 7 And R is 8 As defined in claim 1.
9. The method of claim 8, wherein the
Figure FDA0004164580590000028
Selected from->
Figure FDA0004164580590000029
Figure FDA0004164580590000031
Figure FDA0004164580590000032
A group of groups.
10. The process of any one of claims 1-9, wherein the palladium catalytic system further comprises Pd (dppf) Cl 2 、K 2 CO 3 And DIPEA.
11. The method of any of claims 1-9, wherein the deprotection agent comprises a solution of ethylenediamine and tetrabutylammonium fluoride in tetrahydrofuran.
12. The method of any one of claims 1-9, wherein the weight ratio of the compound of formula (II) to the compound of formula (III) is 1:0.3-0.8; and/or the weight ratio of the compound of formula (II) to the palladium catalyst in the palladium catalytic system is 1:0.05-0.2.
13. The method of claim 12, wherein the weight ratio of the compound of formula (II) to the compound of formula (III) is 1:0.5-0.6.
14. The process of claim 12, wherein the weight ratio of the compound of formula (II) to the palladium catalyst in the palladium catalytic system is 1:0.08-0.15.
15. The process according to any one of claims 1-9, wherein the reaction is carried out at a temperature of 60-100 ℃.
16. The method of claim 15, wherein the reaction is performed at a temperature of 85-95 ℃.
17. The process according to any one of claims 1-9, wherein the process further comprises a step of purifying the compound of formula (I).
18. The process according to any one of claims 1 to 9, wherein the compound of formula (II) is prepared by the following reaction equation:
Figure FDA0004164580590000033
wherein R is 3 、R 4 、R 9 、R 10 、T 1 、D 1 N is as defined in any one of claims 1 to 9.
19. The process of claim 18, wherein the reaction conditions of step 1 comprise EtOAc, N-dimethylaniline and POCl 3 The method comprises the steps of carrying out a first treatment on the surface of the And reaction conditions B of step 2 include DIPEA and DMSO.
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