CN114621232B - Preparation method and application of Syk and VEGFR2 double-target-point inhibitor - Google Patents
Preparation method and application of Syk and VEGFR2 double-target-point inhibitor Download PDFInfo
- Publication number
- CN114621232B CN114621232B CN202210338012.XA CN202210338012A CN114621232B CN 114621232 B CN114621232 B CN 114621232B CN 202210338012 A CN202210338012 A CN 202210338012A CN 114621232 B CN114621232 B CN 114621232B
- Authority
- CN
- China
- Prior art keywords
- compound
- group
- formula
- alkyl
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pain & Pain Management (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Neurology (AREA)
- Transplantation (AREA)
- Otolaryngology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Obesity (AREA)
- Urology & Nephrology (AREA)
- Ophthalmology & Optometry (AREA)
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 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 thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, which does not require preferential protection of the pyrazole boronic ester and which facilitates subsequent Suzuki to prepare Syk and VEGFR2 dual target inhibitors.
Description
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 immune receptors described in this application include typical immune receptors and immune receptor-like molecules. Typical immune receptors include B-cell and T-cell antigen receptors as well as a variety of immunoglobulin receptors (Fc receptors). Immune receptor-like molecules are structurally related to immune receptors or participate in similar signal transduction 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 key role in both leukocyte adhesion and activation of 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. anti-VEGF has been shown to inhibit the expression and activation of pro-inflammatory factors, thereby reducing ocular surface inflammation. VEGFR2 transduces the main signals of angiogenesis through its powerful tyrosine kinase activity. However, unlike other representative tyrosine kinase receptors, VEGFR2 does not use the Ras pathway as the major downstream signaling, but rather 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 are important targets for the treatment of diseases involving angiogenesis and inflammation.
Thus, inhibition of Syk and VEGFR-2 activity may be useful for 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 as dual target inhibitors of Syk and VEGFR2 and uses" of the present applicant discloses a dual target inhibitor against Syk and VEGFR2 and further discloses various methods for the preparation of such dual target inhibitors, including for example:
the preparation method comprises the following steps:
the preparation method 2 comprises the following steps:
in the Suzuki coupling reaction of the PCT International patent application, the palladium catalyst system used 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 a Boc or SEM group to prevent the complex with the catalyst; after the coupling reaction was complete, the protecting group Boc or SEM was removed under the corresponding conditions to give crude compounds 1-6. In this process, boc protected pyrazole boronic acid ester needs to be carried outAdditional column chromatography purification is carried out to prevent the residual by-product in the reaction of protecting group from influencing the activity of the catalytic system of Suzuki reaction; and removal of the protecting group also requires an additional step of a specific reaction.
Therefore, a method is sought that does not require preferential protection of pyrazole boronic esters and that allows for facile subsequent Suzuki reactions to prepare dual target inhibitors of Syk and VEGFR 2.
Disclosure of Invention
The invention aims to overcome the defects that the existing method for preparing the Syk and VEGFR2 double-target-point inhibitor needs to protect pyrazole borate serving as a reaction raw material so as to prevent the pyrazole borate from complexing with a catalyst and 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 successfully carry out the subsequent Suzuki reaction so as to prepare the Syk and VEGFR2 double-target-point 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, a geometric isomer, a tautomer or a mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof,
wherein, the first and the second end of the pipe are connected with each other,
R 1 and R 2 One of H and the other pyrazolyl;
R 3 and R 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 halo;
T 1 is CH or N;
D 1 selected from the group consisting of-O-, -C (R) 5 )(R 6 )-、-N(R 7 ) -and
group (i) of (ii);
R 5 and R 6 Each independently selected from the group consisting of H, F, cl, br, I, OH and C 1-3 Alkyl, said C 1-3 Alkyl is optionally substituted with 1, 2 or 3 halo; or, R 5 And R 6 Together with the carbon atom to which they are both attached form an oxetanyl group;
R 7 is H,
Or C 1-3 Alkyl radical, said C 1-3 Alkyl is optionally substituted with 1, 2 or 3 halo;
R 8 is H or-C (= O) -C 1-3 An alkyl group; and
n is 1 or 2; and is
Wherein the method comprises the steps of:
in the presence of a palladium catalytic system and Ad 2 Reaction conditions of nBuP (n-butyl bis (1-adamantyl) phosphine) a compound of formula (II):
wherein the content of the first and second substances,
R 9 and R 10 One is H and the other is halogen;
with a compound of formula (III):
reacting to obtain the compound of formula (I).
In the process of the invention, the Suzuki reaction employs an unprotected pyrazole boronic ester; to ensure the activity of the palladium catalytic system, ad with higher steric hindrance is selected 2 nBuP is a ligand; the unprotected pyrazole group has no influence on the activity of the palladium catalytic system, and the Suzuki reaction can be smoothly carried out;after unprotected pyrazole borate is adopted, a crude product of the compound shown in the formula (I) can be directly generated by a Suzuki reaction, and the reaction step of removing protective groups in the original process is omitted; column chromatography is not needed in the post-treatment because the process of protecting groups on pyrazole borate is omitted.
In addition, the starting compounds for the reactions of the present application (for example, the compounds of formula (II) or (III)) can be prepared in a variety of ways known to the person skilled in the art of organic synthesis, for example also by the methods disclosed in PCT international patent application WO2021169958A1 in the name of the present applicant. In addition, one skilled in the art can refer to the synthetic routes of specific compounds of the specific examples herein, 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 substrate is,
the compound of formula (II) can be prepared by the following reaction equation:
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:
wherein, the reaction condition a may be: etOAc (ethyl acetate), N-dimethylaniline, POCl 3 (phosphorus oxychloride); reaction conditions B may be: DIPEA (N, N-diisopropylethylamine), NMP (N-methylpyrrolidone), H 2 O。
In addition, in a preferred embodiment of the present invention,
the pyrazolyl group can be
In another preferred embodiment of the present invention,
the R is 3 And R 4 Can be respectively and independently selected from H, F, cl, br, I, OH and NH 2 CN, methyl and methoxy.
In another preferred embodiment of the present invention,
said R is 5 And R 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,
said R is 5 And R 6 May be formed together with the carbon atom to which they are commonly attached
In another preferred embodiment of the present invention,
said R is 7 Can be H,
Or a methyl group.
In a further preferred embodiment of the present invention,
the R is 8 Can be H or-C (= O) -CH 3 。
In a further preferred embodiment of the present invention,
In another preferred embodiment of the present invention,
In another preferred embodiment of the present invention,
the palladium catalytic system may comprise Pd 2 (dba) 3 (Tris (dibenzylideneacetone) dipalladium), TEA (triethylamine), bisoxazole (Dioxane, 1, 4-oxahexacyclic)/H 2 O and DMSO (dimethyl sulfoxide).
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. 1:0.5-0.6; and/or the compound of the formula (II) with the palladium catalyst in the palladium catalyst system and Ad 2 The weight ratio of nBuP may be 1:0.01-0.1:0.05-0.2 (e.g. 1.03-0.08.
In another preferred embodiment of the present invention,
the reaction can be carried out at a temperature of 60 to 100 ℃ (e.g., 65 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃ or 95 ℃, etc.), preferably 85 to 95 ℃ (e.g., 87 ℃, 90 ℃ or 92 ℃, etc.).
In a further preferred embodiment of the present invention,
the method may further comprise a purification step of the compound of formula (I). The purification step may employ various purification means commonly used 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 is increased.
For the sake of brevity, any isotopically labelled compound of formula (I), or optical isomers, geometric isomers, tautomers or mixtures of isomers thereof, or a pharmaceutically acceptable salt thereof, or prodrug thereof, or metabolite thereof, may also be encompassed by the "compound of formula (I)" or "compound of the present application" described hereinafter.
The term "optical isomer" means that, when a compound has one or more chiral centers, each chiral center may exist in R configuration or S configuration, and thus the respective isomers constituted are optical isomers. Optical isomers include all diastereoisomers, enantiomers, meso-isomers, racemic forms or mixtures thereof. For example, optical isomers can 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-isomer, trans-isomer, E-isomer and Z-isomer. The geometric isomers include cis-isomer, trans-isomer, E-isomer, Z-isomer or mixtures thereof.
The term "tautomer" refers to an isomer resulting from the rapid movement of an atom in a molecule between two positions. Those skilled in the art will understand that: tautomers can be mutually converted, and in a certain state, a state of equilibrium can be reached and coexisted.
Unless otherwise indicated, references herein to "a compound of formula (I)" or "a compound of the invention" also encompass isotopically-labelled compounds in which any atom of the compound is replaced by an isotopic atom thereof. The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by an atom having the same atomic number, but a different atomic mass or mass number than the atomic number usually found in nature.
Examples of isotopes suitable for inclusion in compounds of the invention include isotopes of hydrogen, such as 2 H (D) and 3 h (T), isotopes of carbon, such as 11 C、 13 C and 14 isotopes of C, chlorine, such as 35 Cl and 37 cl, isotopes of fluorine, such as 18 F, isotopes of iodine, such as 123 I and 125 isotopes of nitrogen, such as 13 N and 15 isotopes of N, oxygen, such as 15 O、 17 O and 18 o, and isotopes of sulfur, such as 35 S。
Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by using a suitable isotopically-labelled reagent in place of a non-labelled reagent previously used in a manner analogous to that described in the examples and preparations appended hereto.
The compounds of formula (I) may be present 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 be present in 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 which form non-toxic salts. Examples thereof include, but are not limited to: acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclohexylamine sulfonate, edisylate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, 2- (4-hydroxybenzyl) benzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, 2-isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthenate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, hexadecanoate, phosphate/hydrogenphosphate/dihydrogenphosphate, 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. Hemisalts of acids and bases, such as hemisulfate and hemicalcium salts, may also be formed. For an overview 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 present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, compounds of formula (I), whether present in solvated or unsolvated form, are intended to be encompassed within the scope of the present invention.
Certain compounds of the present invention may exist in different or amorphous forms, and regardless of the form, the compounds of formula (I) are included within the scope of the present invention.
For the avoidance of doubt, 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 a regulatory agency such as any national regulatory agency of CFDA (china), EMEA (europe), FDA (us) and the like, certified for use in mammals, preferably humans.
The "prodrug" refers to a derivative that 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 of which is catalyzed by the enzyme.
"metabolite" refers to 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 a group are independently replaced by a corresponding number of substituents.
As used herein, the term "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 it describes 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 group has 1 to 8, or 1 to 6, or 1 to 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 in its definition the term" C 1-6 Alkyl group "," C 1 -C 3 Alkyl "and" C 1 -C 4 Alkyl groups ". 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 substituted with a halogen atom). For example, the term "C 1-6 Haloalkyl "means C having one or more halogen substituents 1-6 Alkyl groups (up to perhaloalkyl, i.e., an alkyl group with each hydrogen atom replaced by a halogen atom). As another example, the term "C 1-4 Haloalkyl "refers to 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 substituted with a halogen atom); the term "C 1-3 Haloalkyl "means having one or more halogen substituentsC 1-3 An alkyl group (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is substituted 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 substituted with a halogen atom). As another example, the term "C" can 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.
As used herein, the recitation of numerical ranges by numbers of substituents, carbon atoms, and ring atoms is meant to denote the recitation of integers individually within the range, and such ranges are intended to serve as a shorthand method of referring to each other. For example: "1-4 substituents" means 1, 2,3 or 4 substituents; "3 to 8 ring atoms" means 3, 4, 5, 6, 7 or 8 ring atoms. Thus, any numerical range relating to the number of substituents, the number of carbon atoms, the number of ring atoms also encompasses any subrange thereof, 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-labelled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutically acceptable carrier.
Pharmaceutically acceptable carriers can be organic or inorganic inert carrier materials, for example, suitable carriers include water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petrolatum, mannitol, cellulose derivatives, sodium saccharin, glucose, sucrose, magnesium carbonate, saline, glycerol, ethanol, and the like. In addition, the pharmaceutical compositions 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 dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pill, suppository, pellicle, patch, aerosol, spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like. The pharmaceutical composition can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various microparticle drug delivery systems.
In some embodiments, the pharmaceutical composition is in a dosage form 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 also include: (a) Fillers or extenders (e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid); (b) Binders (e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic); (c) humectants (e.g., glycerin); (d) Disintegrants (e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain synthetic silicates, sodium carbonate); (e) solution retarders (e.g., paraffin wax); (f) absorption accelerators (e.g., quaternary ammonium compounds); (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 glycols, sodium lauryl sulfate) or mixtures thereof.
Formulations suitable for parenteral administration, for example, injections, 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 the sterile liquid carrier, for example water for injection, immediately prior to use. Examples of suitable diluents for reconstituting a pharmaceutical composition (e.g., prior to injection) include bacteriostatic water for injection, 5% aqueous dextrose, 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. Sprays can additionally contain conventional propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. The inhalant may contain excipients such as lactose, or aqueous solutions containing, for example, polyethylene oxide-9-lauryl ether, glycocholate and deoxycholate, or oily solutions to be administered in the form of nasal drops or sprays, or 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, administration mode, administration subject, etc.), and is, for example, 0.1 to 95% by weight, such as 1 to 95% by weight, 5 to 90% by weight, 10 to 80% by weight, etc.
In particular, the pharmaceutical composition of the present application may specifically comprise 0.01-10g (e.g. 0.05g, 0.1g, 0.5g, 1g or 5g etc.) of a compound 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 thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, for the manufacture of a medicament as a dual target inhibitor of Syk and VEGFR2 for the treatment or prevention of a disease or disorder mediated by Syk and VEGFR2 in a subject in need thereof. A compound of formula (I) or an isotopically-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or prodrug thereof, or metabolite thereof, can be used to treat or prevent a disease or disorder 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 could 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 "treatment" as used herein includes the treatment of a disease or condition in a mammal, particularly a human, and includes: (a) Inhibiting, i.e., arresting or delaying the progression of, an infection, disease, or disorder; (b) Relieving the infection, disease, or condition, i.e., causing regression of the disease or condition, and/or (c) curing the infection, disease, or condition.
The term "prevention" as used herein includes prophylactic treatment in mammals, particularly humans, in order to reduce the likelihood of an infection, disease or condition occurring. Patients receiving prophylactic therapy may be selected based on an increased risk of infection or having a disease or condition compared to the general population. "preventing" can include treating a subject who has not yet presented an infection or clinical condition, and preventing a second occurrence of the same or similar infection or clinical condition.
In some embodiments, the disease or condition mediated by Syk and VEGFR2 may be selected from allergic diseases, autoimmune diseases 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 present invention may be administered by oral, parenteral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ocular, pulmonary, respiratory, vaginal, rectal, intraperitoneal, intralesional, perilesional routes, and the like.
By "therapeutically effective amount" is meant an amount of a compound of the present application that, when administered alone or in combination, is effective to treat or prevent a disease or condition mediated by Syk and VEGFR 2.
The specific dosage administered will depend on the route of administration, the severity of the disease, the age and weight of the patient, and other factors normally considered by the attending physician in determining the individual regimen and dosage level that best suits a particular patient. For example, a daily dose of a compound of the present application may be specifically 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 can be determined by one skilled in the relevant art, for example, 1 time a day, 2 times a day, 1 time a day, 3 times a day, 1 time a day, 4 times a day, 1 time a day, 6 times a day, 1 time a day, 2 times a day, 1 day, 3 times a day, and the like.
It will be understood by those skilled in the art that the definitions and preferences described in one aspect of the application apply equally to the other aspect. It will be clear to a person skilled in the art that embodiments of the various aspects of the present application can be combined in various ways without departing from the subject-matter and the idea of the application, and that such combinations are also included within the scope of the application.
Detailed Description
The invention is further illustrated with reference to the following examples; these examples do not limit the scope of the invention. All reactants used in the examples were obtained commercially unless otherwise stated; instruments and equipment used in synthesis experiments and product analysis and detection are all conventional instruments and equipment commonly used in organic synthesis.
Examples
The synthetic route is as follows:
1) Preparation of Compounds 1-2
Ethyl acetate (39kg, 8.5-9.5 w/w), compound 1-1 (4.65kg, 1.00. + -. 0.01 w/w), N-dimethylaniline (4.30kg, 0.91-0.93 w/w) and ethyl acetate (19kg, 4.0-9.5 w/w) were added to the reaction vessel in this order, followed by adjusting the temperature to 15-25 ℃ and adding phosphorus oxychloride (18.0kg, 3.45-3.85 w/w). The temperature is adjusted to 40 to 50 ℃, then the temperature is increased to 75 to 85 ℃, and the mixture is stirred for 45 to 50 hours at the temperature. Sampling and detecting (the result shows that the ratio of the compound 1-1 to the compound 1-2 is less than or equal to 3 percent).
After the reaction is finished, the temperature is reduced to 5 to 15 ℃, methyl tert-butyl ether (59kg, 10.0 to 20.0 w/w) is added and stirred for 3 to 6 hours, and the supernatant (namely the residual compound 1-2) is detected after sampling and filtering. The reaction solution was filtered, and methyl t-butyl ether (32kg, 6.32 to 7.22 w/w) and ethyl acetate (39kg, 7.68 to 8.78 w/w) were added thereto for rinsing, and the solid was collected to obtain Compound 1-2 as a wet product.
Adding process water (47kg, 9.5-10.5 w/w), compound 1-2 wet product and process water (25kg, 4.5-5.5 w/w) into a reaction kettle in sequence, adjusting the temperature to 15-25 ℃, stirring for 2-6 h, centrifuging the reaction solution, and processing the process water (76kg, 16-140 kg) for rinsing. And (3) drying the wet product of the compound 1-2 at 45-55 ℃ for 16-36 h under reduced pressure, and sampling and detecting (the result shows that the moisture content is less than or equal to 0.5%, and the w/w ratio) to obtain 4.20kg of the compound 1-2.
2) Preparation of Compounds 1-4
N-methylpyrrolidone (20kg, 6.5-7.5 w/w), compound 1-2 (3.00kg, 0.99-1.01 w/w), 4- (4-morpholinyl) aniline (compound 1-3) (2.30kg, 0.75-0.77 w/w), N, N-diisopropylethylamine (4.2kg, 1.35-1.40 w/w) and N-methylpyrrolidone (9kg, 2.5-3.5 w/w) were sequentially added into the reaction kettle. Firstly heating to 60-70 ℃, then continuously heating to 95-105 ℃, stirring for 55-65 h, and then sampling and detecting (the result shows that the ratio of the compound 1-2 to the compound 1-4 is less than or equal to 2%).
After the reaction is finished, adding process water (33kg, 9-11 w/w) into the reaction kettle at 15-25 ℃, stirring for 2-6 h, sampling, filtering and detecting supernatant (namely detecting residual compounds 1-4). After the reaction solution is centrifuged, process water (12kg, 1.75-4.50 w/w) is added to leach the filter cake, and the solid is collected to obtain a wet product of the compound 1-4.
Adding isopropanol (18kg, 5.5-6.5 w/w), compound 1-4 wet product and isopropanol (6kg, 1.5-2.5 w/w) into a reaction kettle in turn, heating to 55-65 ℃, and stirring for 2-4 h. Cooling to 35-45 deg.c, centrifuging, adding isopropanol (7 kg,1.0-3.0 w/w) to drip filter cake. And (3) drying the wet product of the compound 1-4 at 45-55 ℃ under reduced pressure for 16-20 h, and sampling and detecting (namely detecting residual isopropanol and residual N-methylpyrrolidone) to obtain 3.70kg of the compound 1-4.
3) Preparation of Compounds 1-6
Dioxane (14kg, 5.5-6.5 w/w) and process water (5kg, 1.8-2.2 w/w) were added to the reaction kettle, the temperature was adjusted to 20-30 ℃, and the compounds 1-4 (2.65kg, 1.00. + -. 0.02 w/w) and 1H-pyrazole-4-boronic acid pinacol ester (compound 1-5) (1.42kg, 0.53-0.57 w/w) were added, and argon was bubbled for 0.5-1H. Then tris (dibenzylideneacetone) dipalladium (0.152kg, 0.05-0.06 w/w), n-butylbis (1-adamantyl) phosphine (0.234kg, 0.08-0.09 w/w), triethylamine (2.2 kg,0.82-0.84 w/w) and dioxane (9 kg,3.5-4.5 w/w) were added, and argon bubbled for 0.5-1 h. Heating to 85-95 deg.C, stirring under 0.3-0.5MPa, and sampling for detection (compound 1-4/compound 1-6 is not more than 2.0%). Adjusting the temperature to 15-25 ℃, stirring for 6-8 h, sampling, filtering and detecting supernatant (namely detecting residual compounds 1-6). The reaction solution was filtered, and a process water/dioxane (1, v/v) solution was added for rinsing, and the solid was collected to obtain a wet product of compound 1-6, which was sampled for detection (i.e., purity of compound 1-6 was detected).
Adding dimethyl sulfoxide (41kg, 13.0-16.0 w/w), compound 1-6 wet product and dimethyl sulfoxide (41kg, 13.0-16.0 w/w) into a reaction kettle in sequence, heating to 55-65 ℃, stirring to dissolve and clear, performing CUNO circulating decolorization, adding dimethyl sulfoxide (1691, 3.5-6.5 w/w) for rinsing, and sampling to detect the rinsing liquid (namely detecting the residual compound 1-6). Adding the compound 1-6 dimethyl sulfoxide solution and rinsing liquid into a reaction kettle, adjusting the temperature to 55-65 ℃, adding silicon mercaptan (0.9kg, 0.25-0.35 w/w), and stirring for 4-8 h. The feed solution was filtered and rinsed by adding dimethyl sulfoxide (7kg, 1.5-2.5 w/w). Collecting the filtrate to obtain a compound 1-6 dimethyl sulfoxide solution, and detecting the solid (namely detecting residual palladium) after sampling treatment.
Adding the compound 1-6 dimethyl sulfoxide solution into a reaction kettle, adjusting the temperature to 55-65 ℃, performing CUNO circular decolorization again, adding dimethyl sulfoxide (17kg, 3.5-6.5 w/w) for rinsing, and sampling to detect a rinsing solution (namely detecting residual compounds 1-6). Adding the compound 1-6 dimethyl sulfoxide solution and rinsing liquid into a reaction kettle, adjusting the temperature to 55-65 ℃, adding silicon mercaptan (0.9kg, 0.25-0.35 w/w), and stirring for 4-8 h. The feed solution was filtered and rinsed by adding dimethyl sulfoxide (7kg, 1.5-2.5 w/w). Collecting filtrate to obtain compound 1-6 dimethyl sulfoxide solution, sampling, and detecting solid (namely detecting residual palladium).
Adding the compound 1-6 dimethyl sulfoxide solution into a reaction kettle, adjusting the temperature to 20-30 ℃, adding ethyl acetate (94kg, 47-120 kg), continuously adjusting the temperature to 15-25 ℃, processing water (129kg, 65-130 kg), and stirring for 3-6 h. The feed was centrifuged and the filter cake washed by addition of dimethyl sulfoxide/process water (1, 2,v/v) (13kg, 3.0-5.0 w/w) and the solid collected to give compounds 1-6. Adding process water (26kg, 10.0-20.0 w/w), compound 1-6 wet product and process water (26kg, 10.0-20.0 w/w) into a reaction kettle in sequence, stirring for 3-6 h at 15-25 ℃, centrifuging, adding process water (29kg, 9-50 kg) to wash a filter cake, collecting a solid to obtain the compound 1-6 wet product, and sampling and detecting (namely detecting the purity of the compound 1-6, wherein the single impurity is less than or equal to 0.5 percent, residual palladium and residual N-acetyl-L-cysteine). The wet compound 1-6 is dried under reduced pressure at 45-55 ℃ for 16-36 h, and then sampling and detecting (namely residual dioxane, residual dimethyl sulfoxide and residual N-methyl pyrrolidone) are carried out, thus obtaining 1.44kg of crude compound 1-6.
4) Purification of Compounds 1-6
A dimethyl sulfoxide/ethyl acetate (7, 3 v/v) solution (29.3kg, 19.8-21.8 w/w), a crude compound 1-6 (1.40kg, 0.98-1.02 w/w) and a dimethyl sulfoxide/ethyl acetate (7, 3 v/v) solution (14.4 kg,12.1-15.8 kg) were added to a reaction kettle in this order, and the mixture was heated to 63-68 ℃ and stirred until the materials were clear. And (3) filtering the material liquid in the kettle, transferring the material liquid to another reaction kettle, adjusting the temperature to 63-68 ℃, stirring for 0.5-3 h, adding methanol (21.9kg, 14.2-15.7 w/w) and compound 1-6 seed crystals (0.027kg, 0.015-0.025 w/w), continuing stirring, and sampling and detecting (XRPD: is consistent with a reference substance (batch number: PS 08079-41-FP-P) atlas). Adding methanol (12.8 kg,10.0-13.0 kg) again, and continuously stirring at 63-68 ℃ until the crystal form is qualified. The temperature in the kettle is reduced to 23-28 ℃ within 7-9 h, the kettle is stirred for 10-16 h, and sampling detection is carried out (supernate: residual compound 1-6; solid: compound 1-6 purity is more than or equal to 98.0 percent; XRPD is consistent with a reference substance (batch number: PS 08079-41-FP-P) map). The feed solution in the kettle was filtered and rinsed with methanol (6.1kg, 4.2-7.3 kg).
Drying the obtained wet product at 45-55 ℃ under reduced pressure for 20-24 h, sampling and detecting (the result shows that the water content is less than or equal to 1.0 percent, the residual dimethylacetamide is less than 1090ppm, the residual ethanol is less than 5000ppm, and the residual ethyl acetate is less than 5000ppm;
residual methyl tert-butyl ether is less than 5000ppm; residual N-methyl pyrrolidone is less than 530ppm; residual isopropanol is less than 5000ppm; residual dioxane is less than 380ppm; residual dimethyl sulfoxide <5000ppm; residual methanol <3000 ppm). 1.17kg of pure compound 1-6 was obtained.
5) Milled powders of Compounds 1-6
Setting the pushing gas pressure to be 10.0bar, the grinding gas pressure to be 9.0bar and the feeding rate to be 5g/min, and adding the pure products of the compounds 1-6 into a grinding module through a feeding bin for grinding. After grinding, sampling and detecting (PSD D10, PSD 50, PSD 90, polarizing microscope; purity of compound 1-6 is more than or equal to 98.0%; XRPD: consistent with reference product (batch number: PS 08079-41-FP-P) atlas). 0.810kg of compound 1-6 bulk drug is finally obtained.
Claims (17)
1. A process for the preparation of a compound of formula (I) or an isotopically-labelled compound thereof, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof,
Wherein the content of the first and second substances,
R 1 and R 2 One of H and the other pyrazolyl;
R 3 and R 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 by 1, 2 or 3Halogen substitution;
T 1 is CH or N;
D 1 selected from the group consisting of-O-, -C (R) 5 )(R 6 )-、-N(R 7 ) -and
a group of (a);
R 5 and R 6 Each independently selected from the group consisting of H, F, cl, br, I, OH and C 1-3 Alkyl, said C 1-3 Alkyl is optionally substituted with 1, 2 or 3 halo; or, R 5 And R 6 Together with the carbon atom to which they are both attached form an oxetanyl group;
R 7 is H,
Or C 1-3 Alkyl radical, said C 1-3 Alkyl is optionally substituted with 1, 2 or 3 halo;
R 8 is H or-C (= O) -C 1-3 An alkyl group; and
n is 1 or 2; and is
Wherein the method comprises the steps of:
in the presence of a palladium catalytic system and Ad 2 Under the reaction condition of nBuP, wherein the palladium catalyst in the palladium catalytic system is Pd 2 (dba) 3 Reacting a compound of formula (II):
wherein the content of the first and second substances,
R 9 and R 10 One is H and the other is halogen;
with a compound of formula (III):
to obtain said compound of formula (I),
whereinThe pyrazolyl group is
Or
。
2. The method of claim 1, wherein R is 3 And R 4 Each independently selected from the group consisting of H, F, cl, br, I, OH, NH 2 CN, methyl and methoxy.
3. The method of claim 1, wherein R is 5 And R 6 Each independently selected from the group consisting of H, F, cl, br, I, OH and methyl.
4. The method of claim 1, wherein R 5 And R 6 Together with the carbon atom to which they are jointly attached form
。
5. The method of claim 1, wherein R 7 Is H,
Or a methyl group.
6. The method of claim 1, wherein R 8 Is H or-C (= O) -CH 3 。
7. The method of claim 1, wherein,
is selected from the group consisting of
、
、
、
、
And
a group of (a) a group of (b),
wherein R is 5 、R 6 、R 7 And R 8 As defined in any one of claims 1 to 6.
8. The method of claim 7, wherein the
Is selected from the group consisting of
、
、
、
、
、
、
、
And
group (d) of (a).
9. The method of any one of claims 1-8, wherein the palladium catalytic system comprises Pd 2 (dba) 3 TEA, dioxane/H 2 O and DMSO.
10. The method of any one of claims 1-8, 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 compound of the formula (II) with the palladium catalyst in the palladium catalyst system and Ad 2 The weight ratio of nBuP is 1:0.01-0.1:0.05-0.2.
11. The method of claim 10, wherein the weight ratio of the compound of formula (II) to the compound of formula (III) is 1:0.5-0.6.
12. The method of claim 10, wherein the compound of formula (II) is reacted with a palladium catalyst in the palladium catalytic system and Ad 2 The weight ratio of nBuP is 1:0.03-0.08:0.05-0.1.
13. The process according to any one of claims 1 to 8, wherein the reaction is carried out at a temperature of 60-100 ℃.
14. The process according to claim 13, wherein the reaction is carried out at a temperature of 85-95 ℃.
15. The method of any one of claims 1-8, wherein the method further comprises a purification step of the compound of formula (I).
16. The process of any one of claims 1-8, wherein the compound of formula (II) is prepared by the following reaction equation:
17. The process of claim 16, wherein the reaction conditions of step 1 comprise EtOAc, N-dimethylaniline and POCl 3 (ii) a And reaction conditions B of step 2 include DIPEA, NMP and H 2 O。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210338012.XA CN114621232B (en) | 2022-03-31 | 2022-03-31 | Preparation method and application of Syk and VEGFR2 double-target-point inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210338012.XA CN114621232B (en) | 2022-03-31 | 2022-03-31 | Preparation method and application of Syk and VEGFR2 double-target-point inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114621232A CN114621232A (en) | 2022-06-14 |
| CN114621232B true CN114621232B (en) | 2023-03-14 |
Family
ID=81905926
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210338012.XA Active CN114621232B (en) | 2022-03-31 | 2022-03-31 | Preparation method and application of Syk and VEGFR2 double-target-point inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114621232B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116589469A (en) | 2020-02-24 | 2023-08-15 | 苏州欧康维视生物科技有限公司 | 1H-pyrazole derivatives as Syk and VEGFR2 double-target inhibitors and application thereof |
| CN116554177B (en) * | 2023-04-24 | 2024-02-27 | 苏州欧康维视生物科技有限公司 | Salt form and crystal form of nitrogen-containing heterocyclic compound and application of salt form and crystal form |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1609105A (en) * | 2003-10-22 | 2005-04-27 | 中国人民解放军军事医学科学院毒物药物研究所 | 1-methylolimidazole [1,2-alpha] quinoxaline compound and its application |
| WO2010135571A1 (en) * | 2009-05-20 | 2010-11-25 | Cylene Pharmaceuticals, Inc. | Novel protein kinase modulators |
| CN102413831A (en) * | 2009-04-29 | 2012-04-11 | 拜耳医药股份有限公司 | Substituted imidazoquinoxalines |
| WO2021169958A1 (en) * | 2020-02-24 | 2021-09-02 | 苏州欧康维视生物科技有限公司 | 1h-pyrazole derivative and application thereof as dual target inhibitor of syk and vegfr2 |
-
2022
- 2022-03-31 CN CN202210338012.XA patent/CN114621232B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1609105A (en) * | 2003-10-22 | 2005-04-27 | 中国人民解放军军事医学科学院毒物药物研究所 | 1-methylolimidazole [1,2-alpha] quinoxaline compound and its application |
| CN102413831A (en) * | 2009-04-29 | 2012-04-11 | 拜耳医药股份有限公司 | Substituted imidazoquinoxalines |
| WO2010135571A1 (en) * | 2009-05-20 | 2010-11-25 | Cylene Pharmaceuticals, Inc. | Novel protein kinase modulators |
| WO2021169958A1 (en) * | 2020-02-24 | 2021-09-02 | 苏州欧康维视生物科技有限公司 | 1h-pyrazole derivative and application thereof as dual target inhibitor of syk and vegfr2 |
Non-Patent Citations (1)
| Title |
|---|
| Mesopolymer synthesis by ligand-modulated direct arylation polycondensation towards n-type and ambipolar conjugated systems;polycZhenjie Ni等;《Nature Chemistry》;20190128;第271-277页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114621232A (en) | 2022-06-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI815396B (en) | Triazine derivatives with virus proliferation inhibitory effect and pharmaceutical compositions containing the same | |
| CN114621232B (en) | Preparation method and application of Syk and VEGFR2 double-target-point inhibitor | |
| CN113121530B (en) | Pyridinopyrimidine derivatives as KRASG12C mutant protein inhibitors | |
| CA2925889C (en) | Hydrochloride salt form for ezh2 inhibition | |
| TW202204323A (en) | Substituted pyridazine compound | |
| CA3136745A1 (en) | Dosage forms and regimens for amino acid compounds | |
| KR102142796B1 (en) | Salts of pyridinylaminopyrimidine derivatives, methods for their preparation, and uses thereof | |
| CN113784963B (en) | Compounds useful as RET kinase inhibitors and uses thereof | |
| CN114591338B (en) | Preparation method and application of Syk and VEGFR2 double-target inhibitor | |
| NZ583148A (en) | Crystalline form of methyl ((1s)-1-(((2s)-2-(5-(4'-(2-((2s)-1-((2s)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1h-imidazol-5-yl)-4-biphenylyl)-1h-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate dihydrochloride salt | |
| WO2005061466A1 (en) | Novel phenylalanine derivative | |
| WO2023054292A1 (en) | Pharmaceutical composition containing triazine derivative | |
| KR102142797B1 (en) | Crystalline forms of mesylate salts of pyridinylaminopyrimidine derivatives, methods for their preparation, and uses thereof | |
| JP7261529B1 (en) | Method for producing triazine derivative having virus growth inhibitory action | |
| WO2023033098A1 (en) | Bicyclic nitrogen-containing heterocyclic derivative having virus growth inhibitory activity and pharmaceutical composition containing same | |
| TW201733992A (en) | Methods for preparing substituted 5,6-dihydro-6-phenylbenzo[F] isoquinolin-2-amine | |
| JPWO2007063821A1 (en) | Acid addition salts of optically active dihydropyridine derivatives | |
| JP2005529933A (en) | Xanthine phosphodiesterase V inhibitor polymorph | |
| WO2023095860A1 (en) | Covid-19 treatment medicine characterized by combining 3cl protease inhibitor and covid-19 treatment drug | |
| JP7236065B1 (en) | Pharmaceutical composition containing triazine derivative | |
| EP1237886B1 (en) | Meglumine salt of a specific quinolinecarboxylic acid compound active on nmda receptors | |
| CN115427407A (en) | Novel N-heterocyclic BET bromodomain inhibitor, preparation method and medical application thereof | |
| JP2008290988A (en) | Pharmaceutical comprising acid addition salt of optically active dihydropyridine derivative | |
| WO2023195530A1 (en) | Uracil derivative having viral growth inhibitory activity and pharmaceutical composition containing same | |
| KR20240082359A (en) | Pharmaceutical compositions containing triazine derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |