CN112321604A - Macrocyclic JAK2 inhibitor and application thereof - Google Patents

Macrocyclic JAK2 inhibitor and application thereof Download PDF

Info

Publication number
CN112321604A
CN112321604A CN201910717773.4A CN201910717773A CN112321604A CN 112321604 A CN112321604 A CN 112321604A CN 201910717773 A CN201910717773 A CN 201910717773A CN 112321604 A CN112321604 A CN 112321604A
Authority
CN
China
Prior art keywords
group
carcinoma
substituted
unsubstituted
compound
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.)
Pending
Application number
CN201910717773.4A
Other languages
Chinese (zh)
Inventor
李洪林
赵振江
朱丽丽
王艳玲
葛欢
贺欢
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
East China University of Science and Technology
Original Assignee
East China University of Science and Technology
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by East China University of Science and Technology filed Critical East China University of Science and Technology
Priority to CN201910717773.4A priority Critical patent/CN112321604A/en
Publication of CN112321604A publication Critical patent/CN112321604A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • 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
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • A61P7/06—Antianaemics
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention relates to a macrocyclic JAK2 inhibitor and application thereof. Specifically, the invention relates to a compound shown in the formula I and application of the compound in treating related diseases mediated by JAK2 and preparing a medicament for treating the related diseases mediated by JAK 2.

Description

Macrocyclic JAK2 inhibitor and application thereof
Technical Field
The present invention relates to the field of pharmaceutical chemistry; in particular, the present invention relates to novel JAK2 inhibitors and uses thereof.
Background
JAK kinases (Janus Kinase) are the first non-receptor tyrosine kinases discovered in the early 90 s of the 20 th century and play an important role in the signal transduction process mediated by various cytokine receptors. JAKs, together with downstream Signal Transducers and Activator of Transcription (STAT), are involved in a number of important physiological functions such as innate immunity, inflammation, and hematopoietic function. Dysregulation of this signaling pathway is associated with the pathogenesis of immune diseases and cancer. Therefore, JAKs are attractive targets for the treatment of a variety of diseases.
Signaling of the JAK/STAT pathway begins with the binding of a ligand (e.g., a growth factor, interferon, or interleukin) to a specific transmembrane receptor. A variety of receptors are involved in the activation of the JAK-STAT pathway, with cytokine receptors probably being the most common family of transmembrane receptors associated with JAK activation.
More than 50 cytokines, growth factors and hormones act upstream of the JAK/STAT pathway, mediating multiple physiological functions. Binding of cytokines to specific receptors on cell membranes induces dimerization of receptor-JAK complexes, and JAK kinases are activated. Tyrosine residues in the cytoplasmic domain of the activated JAK phosphorylated cytokine receptor provide docking sites for STATs. Specific STATs bind to cytokine receptors through their SH2 domain and are phosphorylated on tyrosine residues by JAKs, resulting in the formation of homo-or heterodimers via SH 2-phosphate interactions. Dimeric STATs are then transferred from the cytoplasm to the nucleus, where they regulate the expression of genes by binding to specific DNA.
It was found that point mutations in JAK2 pseudo kinase domain V617F were identified in greater than 90% of polycythemia vera patients and in about 50% of patients with primary myelofibrosis and primary thrombocythemia. This mutation was also found in Ph negative chronic myelogenous leukemia, chronic myelogenous monocytic leukemia, the pathogenesis of megakaryocytic acute myelogenous leukemia, and juvenile myelogenous monocytic leukemia (10-20%). Other mutations in the pseudo kinase domain of JAK2, including the point mutation of Arg683, have been detected in approximately 20% of down syndrome-associated acute lymphocytic and acute myeloid leukemias. Therefore, JAK2 has become a hot target in this field.
To date, four JAK inhibitors have entered the market, but they all belong to pan JAK inhibitors, showing varying degrees of selectivity for JAK1, JAK2, JAK3 and TYK 2. Among JAK inhibitors, lack of selectivity for JAK2 can lead to several side effects, particularly an increased risk of infection. Therefore, the research and development of the small molecule inhibitor targeting JAK2 kinase have important clinical significance and application prospect.
Disclosure of Invention
The invention aims to provide a JAK inhibitor with a brand-new structure, and the JAK inhibitor has a selective inhibition effect on JAK2, so that the JAK inhibitor has clinical significance and an application prospect.
In a first aspect, the present invention provides a compound of formula I or a stereoisomer or an optical isomer, a pharmaceutically acceptable salt, a prodrug or a solvate thereof,
Figure BDA0002156053160000021
in the formula
R1Selected from substituted or unsubstituted 5-or 6-membered nitrogen-containing heterocycles;
R2selected from the group consisting of: hydrogen, substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C1-C10An acyl group;
R3selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted C1-C10Alkyl (e.g. halo C)1-C10Alkyl), hydroxy, substituted or unsubstituted C1-C10An alkoxy group;
R4selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted C1-C10Alkyl, hydroxy, substituted or unsubstituted C1-C10An alkoxy group;
X1selected from the group consisting of: CH (CH)2、O、NH、S、SO、SO2；
X2Is absent or selected from the group consisting of: CH (CH)2、O、NH、S、SO、SO2(ii) a And
X3selected from the group consisting of: CH (CH)2、O、NH、S、SO、SO2。
In a specific embodiment, R1Selected from the group consisting of:
Figure BDA0002156053160000022
wherein R or R' is selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted C1-C10Alkyl (e.g. halo C)1-C10Alkyl), hydroxy, substituted or unsubstituted C1-C10Alkoxy (e.g. halo C)1-C10Alkoxy groups).
In a specific embodiment, the compound is of formula II:
Figure BDA0002156053160000031
in the formula
R1And X1、X2Is as defined in claim 1 or 2.
In a specific embodiment, the 5-or 6-membered nitrogen-containing heterocycle is selected from the group consisting of:
Figure BDA0002156053160000032
in particular embodiments, the compound is selected from the group consisting of:
Figure BDA0002156053160000033
in a specific embodiment, R1Selected from the group consisting of:
Figure BDA0002156053160000034
r is selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted C1-C10Alkyl, hydroxy, substituted or unsubstituted C1-C10An alkoxy group;
R2selected from the group consisting of: hydrogen, substituted or unsubstituted C1-C10An alkyl group;
R3selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted C1-C10Alkyl, hydroxy, substituted or unsubstituted C1-C10An alkoxy group;
R4selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted C1-C10Alkyl, hydroxy, substituted or unsubstituted C1-C10An alkoxy group;
X1selected from the group consisting of: CH (CH)2、O、NH、S；
X2Selected from the group consisting of: CH (CH)2O, NH, S; and
X3selected from the group consisting of: CH (CH)2、O、NH、S。
In particular embodiments, the compound is selected from the group consisting of:
Figure BDA0002156053160000041
in a second aspect, the present invention provides a pharmaceutical composition comprising a compound of the first aspect, or a stereoisomer or an optical isomer thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, and a pharmaceutically acceptable carrier or excipient.
In a fourth aspect, the present invention provides the use of a compound of the first aspect, or a stereoisomer or optical isomer thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, for the manufacture of a medicament for the prevention or treatment of a JAK 2-mediated disease; and/or for the preparation of a JAK2 inhibitor.
In particular embodiments, the JAK 2-mediated disease is myelodysplastic syndrome (MDS), eosinophilia, a tumor, an inflammatory disease, or an infection caused by a bacterium, virus, or fungus;
preferably, the tumor is selected from the group consisting of: myeloproliferative carcinoma (MPN), melanoma, lung cancer, kidney cancer, ovarian cancer, prostate cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, rectal cancer, anal cancer, stomach cancer, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, hodgkin's disease, non-hodgkin's lymphoma, carcinoma of the esophagus, carcinoma of the small intestine, carcinoma of the endocrine system, carcinoma of the thyroid gland, carcinoma of the parathyroid gland, carcinoma of the adrenal gland, sarcoma of soft tissue, carcinoma of the urethra, carcinoma of the penis, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, pediatric solid tumors, lymphocytic lymphoma, carcinoma of the bladder, carcinoma of the kidney or ureter, carcinoma of the renal pelvis, tumors of the Central Nervous System (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, Pituitary adenomas, kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma; and/or
The inflammatory disease is selected from the group consisting of: rheumatoid arthritis, ankylosing spondylitis, autoimmune hemolytic anemia, arthritis, myasthenia gravis, systemic lupus erythematosus, pernicious anemia, polymyositis; and/or
The virus is selected from the group consisting of: hepatitis viruses (type a, b and c), herpesviruses, influenza viruses, adenoviruses, coronaviruses, measles viruses, dengue viruses, polio viruses, rabies viruses; and/or
The bacteria are selected from the group consisting of: chlamydia, rickettsia, mycobacteria, staphylococci, pneumococci, cholera, tetanus; and/or
The fungus is selected from the group consisting of: candida, aspergillus, dermatitides.
In a fifth aspect, the present invention provides a JAK2 inhibitor comprising a compound of the first aspect, or a stereoisomer or an optical isomer thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, or a pharmaceutical composition of the second aspect.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventors have conducted extensive and intensive studies and unexpectedly found a series of 11-to 13-membered macrocycles having entirely novel structures. The compound can selectively inhibit JAK2 kinase, thereby becoming a small molecular lead compound for researching JAK2 inhibitor and further providing a brand new material basis for the development of immune inflammation and antitumor drugs. The present invention has been completed based on this finding.
Definition of terms
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed invention belongs. For the purpose of understanding the present invention, the following definitions will be made for terms related to the present invention, but the scope of the present invention is not limited to these specific definitions.
As used herein, "JAK 2" refers to Janus kinase 2, an intracytoplasmic non-receptor type soluble protein tyrosine kinase. JAK-STAT is a Janus kinase-cell signal transduction and transcriptional activator pathway, and is a hot spot in the current cytokine research field.
Herein, "alkyl" refers to a straight or branched chain saturated group consisting of carbon atoms and hydrogen atoms. For example, "C1-C10Alkyl "refers to a saturated branched or straight chain alkyl group with a carbon chain length of 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms. Examples of alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, heptyl, pentyl, and the like.
Herein, "alkoxy" refers to an oxy group substituted with an alkyl group. In a particular embodiment, alkoxy as used herein is an alkoxy group of 1 to 10 carbon atoms in length, more preferably 1 to 4 carbon atoms in length. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and the like. In further embodiments, the alkoxy group may be a substituted alkoxy group, for example, a halogen substituted alkoxy group. In particular embodiments, halogen substituted C is preferred1-3An alkoxy group.
"heterocyclyl" or "heterocycle" as used herein includes, but is not limited to, 5-or 6-membered heterocyclic groups containing 1-3 heteroatoms selected from O, S or N, including, but not limited to, furyl, thienyl, pyrrolyl, pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, piperidinyl, morpholinyl, isoindolyl and the like.
Herein, "halogen" refers to fluorine, chlorine, bromine and iodine. In a preferred embodiment, the halogen is chlorine or fluorine.
As used herein, "halo" refers to fluoro, chloro, bromo, and iodo.
As used herein, "substituted or unsubstituted" or "optionally substitutedBy "means that the substituent modified by the term may be optionally substituted with 1 to 5 (e.g., 1,2, 3, 4, or 5) substituents selected from: halogen, C1-4Aldehyde group, C1-6Straight or branched chain alkyl, halogen substituted C1-6Straight or branched chain alkyl (e.g. trifluoromethyl), C1-6Alkoxy, halogen substituted C1-6Alkoxy (e.g. trifluoromethoxy), cyano, nitro, amino, hydroxy, hydroxymethyl, carboxy, ethoxyformyl, -N (CH)3) And C1-4An acyl group.
Active ingredient
As used herein, "compound of the invention" refers to a compound of formula (I), and also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compound of formula (I),
Figure BDA0002156053160000061
in the formula I, R1、R2、R3、R4、X1、X2And X3As described above.
Based on the teachings of the present invention and the general knowledge in the art, one skilled in the art will appreciate that various groups in the compounds of the present invention can be further substituted to provide derivatives that have the same or similar activity as the specifically disclosed compounds of the present invention. Each group in the compounds of the present invention may be substituted with various substituents which are conventional in the art, as long as such substitution does not violate the rules of chemical synthesis or the rules of valency.
The term "substituted" as used herein means that one or more hydrogen atoms on a particular group are replaced with a particular substituent. The specific substituents may be those described above in correspondence with the description, or may be specific substituents appearing in each example or substituents conventional in the art. Therefore, in the present invention, the substituents in the general formula may also each independently be the corresponding group in the specific compounds in the examples; that is, the present invention includes both combinations of the respective substituents in the above general formulae and combinations of partial substituents shown in the general formulae with other specific substituents appearing in the examples. Preparing compounds having such combinations of substituents and testing the resulting compounds for activity is readily accomplished by those skilled in the art based on routine skill in the art.
The term "pharmaceutically acceptable salt" as used herein refers to a salt of a compound of the present invention with an acid or base that is suitable for use as a pharmaceutical. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is that formed by reacting a compound of the present invention with an acid. Suitable acids for forming the salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, phenylmethanesulfonic acid, benzenesulfonic acid, etc.; and acidic amino acids such as aspartic acid and glutamic acid.
Unless otherwise specified, the structural formulae depicted herein are intended to include all isomeric forms (e.g., enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, R, S configuration containing an asymmetric center, (Z), (E) isomers of double bonds, and the like. Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers or geometric isomers (or conformers) thereof are within the scope of the present invention.
As used herein, the term "tautomer" means that structural isomers having different energies may exceed the low energy barrier and thus be converted to each other. For example, proton tautomers (i.e., proton transmutations) include interconversion by proton shift, such as 1H-indazoles and 2H-indazoles. Valence tautomers include interconversion by recombination of some of the bonding electrons.
As used herein, the term "solvate" refers to a complex of a compound of the present invention coordinated to solvent molecules in a specified ratio.
As used herein, the term "hydrate" refers to a complex formed by the coordination of a compound of the present invention with water.
Pharmaceutical compositions and methods of administration
Since the compound of the present invention has an excellent inhibitory activity against JAK kinases, the compound of the present invention and various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the prevention and/or treatment (stabilization, alleviation or cure) of JAK kinase-associated diseases.
The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention in combination with a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 10-200mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like
Figure BDA0002156053160000081
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous).
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When administered in combination, the pharmaceutical composition further comprises one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds. One or more of the other pharmaceutically acceptable compounds may be administered simultaneously, separately or sequentially with a compound of the invention.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 20 to 500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
Preparation method
The compounds of the present invention may be prepared according to conventional routes or methods, or may be obtained according to the methods or routes described herein. Such as route 1 or route 2.
Scheme 1:
Figure BDA0002156053160000101
synthetic route of 11-membered macrocyclea
aReagents and conditions: (a) methyl magnesium bromides ol, THF,0 ℃ to r.t.,1.5h, 90.1%; (b) h2SO4,HNO3,0℃ to r.t.,overnight,80.2％；(c)PPh3,DIAD,THF,0℃ to r.t.,overnight,79.9％；(d)NBS,BPO,DCE,88℃,overnight,58.7％；(e)Cs2CO3,DMF,r.t.,overnight,32-43％；(f)Fe,HOAc:EtOH＝1:1,70℃,1h,70-75％；(g)CataCXium A,Pd(OAc)2,B2pin2,CsF,MeOH,H2O,100℃,12h,3.7-8.2％.
Scheme 2:
Figure BDA0002156053160000111
synthetic route to 13-membered macrocyclesa
Reagents and conditions: (a) pyridine, (Boc)2O,85℃,4h,53.6％；(b)DMF,Cs2CO3,80℃,4h,36.2％；(c)DCM,TFA,r.t.,2h,78.6％；(d)MeCN,K2CO3,r.t.,overnight,30.7-50.6％；(e)DMF,Cs2CO3,Pd2(dba)3,Xantphos,90℃,5h,24.9-40.3％；(f)10％Pd/C,H2,r.t.,2h,30.2-60.4％.
The main advantages of the invention are:
1. the compound has a novel structure and an excellent JAK kinase inhibitor effect;
2. the compounds of the invention are more selective for JAK 2.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight. The test materials and reagents used in the following examples are commercially available without specific reference.
Herein, "reflux" means reflux.
EXAMPLE 1 preparation of Compound WYL-1
1) Synthesis of 1- (5-fluoro-2-methylphenyl) -1-ethanol
Figure BDA0002156053160000121
3.0M methyl magnesium bromide in ethyl ether (13.3mL,0.04mol) was added dropwise to a solution of 5-fluoro-2-methylbenzaldehyde (5.00g, 0.036mol) in anhydrous THF under ice-bath conditions, the ice-bath was removed after the addition was complete, the reaction was allowed to proceed at room temperature for 1.5h, and the progress of the reaction was monitored by TLC. After the reaction is finished, saturated NH is used4The reaction was quenched with aqueous Cl. The reaction solution was extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give 5.03g (90.13%) of a colorless oily liquid.
1H NMR(400MHz,CDCl3)δ7.15(dd,J＝10.2Hz,2.8Hz,1H),6.99(dd,J＝8.3Hz,5.8Hz,1H),6.78-6.75(m,1H),5.03-4.95(m,1H),2.20(s,3H),1.84(s,1H),1.35(d,J＝6.4Hz,3H).GC-MS(EI):m/z:154.1.
2) Synthesis of 5-bromo-2-nitropyridin-3-ol
Figure BDA0002156053160000122
Concentrated nitric acid (3.90g) was added dropwise to a concentrated sulfuric acid solution of 2-nitropyridin-3-ol (5.00g, 0.029mol) under ice bath conditions, after the addition was complete, the ice bath was removed, the reaction was allowed to proceed overnight at room temperature, and the progress of the reaction was monitored by TLC. After the reaction was complete, the reaction solution was poured into ice water with stirring, and a large amount of white solid was precipitated. Filtration, cake dissolution in DCM, pH adjustment to neutral with NaOH, extraction three times with DCM, organic phase combination and evaporation under reduced pressure gave 5.30g (80.2%) of a pale yellow solid.
1H NMR(400MHz,CDCl3):δ10.28(s,1H),8.24(d,J＝2.0Hz,1H),7.84(d,J＝2.0Hz,1H).GC-MS(EI):m/z:217.1.
3) Synthesis of 5-bromo-3- (1- (2- (methyl) -5-fluorophenyl) ethoxy) -2-nitropyridine
Figure BDA0002156053160000123
DIAD (4.72g, 0.023mol) was added dropwise under ice-bath conditions to a solution of 1- (5-fluoro-2-methylphenyl) -1-ethanol (3.00g, 0.019mol), 5-bromo-2-nitropyridin-3-ol (4.26g, 0.019mol) and triphenylphosphine (6.12g, 0.023mol) in anhydrous THF. After the addition was completed, the reaction mixture was transferred to room temperature for overnight reaction, and the progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and then passed through a silica gel column (PE: EA ═ 20:1), whereby 5.52g (79.9%) of a white solid was obtained.
1H NMR(400MHz,CDCl3)δ8.00(d,J＝1.8Hz,1H),7.15(d,J＝1.8Hz,1H),7.10(dd,J＝8.4Hz,5.6Hz,1H),7.05(dd,J＝9.6Hz,2.7Hz,1H),6.88-6.83(m,1H),5.44(q,J＝6.2Hz,1H),2.31(s,3H),1.59(d,J＝6.4Hz,3H).LC-MS(ESI):m/z:355.0/357.0(M+H)+.
4) Synthesis of 5-bromo-3- (1- (2- (bromomethyl) -5-fluorophenyl) ethoxy) -2-nitropyridine
Figure BDA0002156053160000131
NBS (0.43g,2.4mol), BPO (0.05g,2mol) were added to a solution of 5-bromo-3- (1- (2- (methyl) -5-fluorophenyl) ethoxy) -2-nitropyridine (0.78g,2.2mmol) in DCE, the temperature was raised to 90 ℃ for reaction overnight, and the progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was extracted with DCM, and the organic phase was dried over anhydrous sodium sulfate and passed through a silica gel column (PE: EA ═ 15:1) to obtain 0.56g (58.7%) of a white solid.
1H NMR(400MHz,CDCl3)δ8.02(d,J＝1.4Hz,1H),7.71(d,J＝1.5Hz,1H),7.31(dd,J＝8.5Hz,5.4Hz,1H),7.15(dd,J＝9.4Hz,2.5Hz,1H),6.97-6.92(m,1H),5.69(q,J＝6.1Hz,1H),4.50(s,2H),1.67(d,J＝6.4Hz,3H).LC-MS(ESI):m/z:432.9/434.9/436.9(M+H)+.
5) Synthesis of 4-bromo-3- ((2- (1- ((5-bromo-2-nitro-pyridin-3-yl) oxy) ethyl) -4-fluorobenzyl) amino) -1-methyl-1H-pyrazole-5-carbonitrile
Figure BDA0002156053160000132
To a solution of 3-amino-4-bromo-1-methyl-1H-pyrazole-5-carbonitrile (0.46g,2.4mmol) in MeCN was added K2CO3(0.48g,3.6mmol), stirred at room temperature for 5min, added to the reaction solution 5-bromo-3- (1- (2- (methyl) -5-fluorophenyl) ethoxy) -2-nitropyridine (1.00g,2.4mmol), stirred at 90 ℃ overnight, and monitored by TLC for progress. After completion of the reaction, the reaction mixture was extracted with DCM, and the organic phase was dried over anhydrous sodium sulfate and passed through a silica gel column (PE: EA ═ 5:1) to obtain 0.41g (32.1%) of a pale yellow solid.
1H NMR(400MHz,DMSO-d6)δ8.27(d,J＝1.7Hz,1H),8.15(d,J＝1.7Hz,1H),7.45(dd,J＝8.4Hz,6.0Hz,1H),7.17-7.13(m,2H),6.36(t,J＝5.9Hz,1H),6.21(q,J＝6.2Hz,1H),4.49-4.31(m,2H),3.77(s,3H),1.60(d,J＝6.2Hz,3H).LC-MS(ESI):m/z:552.1/554.1/556.1(M+H)+.
6) Synthesis of 3- ((2- (1- ((2-amino-5-bromopyridin-3-yl) oxy) ethyl) -4-fluorobenzyl) amino) -4-bromo-1-methyl-1H-pyrazole-5-carbonitrile
Figure BDA0002156053160000141
4-bromo-3- ((2- (1- ((5-bromo-2-nitro-pyridin-3-yl) oxy) ethyl) -4-fluorobenzyl) amino) -1-methyl-1H-pyrazole-5-carbonitrile (0.20g, 0.38mmol) was dissolved in acetic acid: to a mixed solvent of ethanol 1:1, reduced iron powder (0.05g, 0.95mmol) was added to the solution, reacted at 70 ℃ for 2 hours, and the progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was extracted with EA, and the organic phase was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, and then passed through a silica gel column (PE: EA ═ 3:1) to obtain 0.25g (70.21%) of a pale yellow solid.
1H NMR(400MHz,DMSO-d6)δ7.53(d,J＝2.0Hz,1H),7.42(dd,J＝8.5Hz,6.0Hz,1H),7.33(dd,J＝10.3Hz,2.8Hz,1H),7.09-7.04(m,1H),7.00(d,J＝1.9Hz,1H),6.38(t,J＝6.0Hz,1H),6.15(s,2H),5.88(q,J＝6.0Hz,1H),4.50-4.31(m,2H),3.79(s,3H),1.57(d,J＝6.2Hz,3H).LC-MS(ESI):m/z:522.1/524.1/526.1(M+H)+.
7) Synthesis of 7-amino-12-fluoro-2, 10-dimethyl-2, 10,15, 16-tetrahydro-4, 8- (methylene-bridged) benzo [ k ] pyrazolo [4,3-g ] [1] oxa [4,9] diazacyclotridecane-3-carbonitrile (WYL-1)
Figure BDA0002156053160000142
3- ((2- (1- ((2-amino-5-bromopyridin-3-yl) oxy) ethyl) -4-fluorobenzyl) amino) -4-bromo-1-methyl-1H-pyrazole-5-carbonitrile (0.53g, 1mmol), B2Pin2(1.27g,5mmol), CsF (0.76g, 5mmol) in MeOH H2Heating to 65 ℃ in a solvent with O10: 1 under the protection of nitrogen, and adding Pd (OAc) into the reaction liquid2(0.05g, 0.2mmol), CataCxiUMA (0.08g, 0.2mmol) in toluene, 100 ℃ overnight, TLC to monitor the progress of the reaction. After completion of the reaction, the reaction mixture was extracted with DCM and passed through a silica gel column (DCM: MeOH: 40:1) to give 35mg (8.25%) of a pale yellow solid.
mp:194.5-196.0℃.1H NMR(400MHz,DMSO-d6)δ7.62(d,J＝1.7Hz,1H),7.32-7.23(m,3H),6.92-6.87(m,1H),6.45(dd,J＝8.7Hz,4.8Hz,1H),5.85(s,2H),5.75(dd,J＝6.3Hz,2.0Hz,1H),4.63(dd,J＝16.7Hz,4.9Hz,1H),3.96(dd,J＝16.6Hz,8.9Hz,1H),3.75(s,3H),1.62(d,J＝6.2Hz,3H).13C NMR(101MHz,DMSO-d6)δ162.43,160.03,155.27,152.13,140.31,140.12,139.34,138.76,130.99,128.28,115.47,113.57,112.39,111.80,111.60,74.74,45.07,38.20,21.40.HRMS(ESI):(m/z):(M+H)+calcd for C19H18FN6O,365.1526；found 365.1527.HPLC purity:97.5％,retention time＝12.07min.
EXAMPLE 2 preparation of Compound WYL-2
Figure BDA0002156053160000151
WYL-2 was synthesized as WYL-1 to give 23mg (3.76%) of a pale red solid.
mp:249.8-251.5℃.1H NMR(400MHz,CDCl3)δ7.46(d,J＝1.6Hz,1H),7.40(d,J＝1.8Hz,1H),7.33(dd,J＝8.7Hz,5.9Hz,1H),7.17(dd,J＝13.1,4.6Hz,2H),6.94-6.89(m,1H),5.36-5.30(m,1H),4.74(s,2H),4.37(d,J＝15.7Hz,1H),4.07(d,J＝15.6Hz,1H),3.67(s,3H),1.67(d,J＝6.5Hz,3H).13C NMR(101MHz,DMSO-d6)δ162.44,160.03,155.17,150.39,140.39,138.82,131.82,128.20,128.00,117.89,115.37,112.39,107.38,75.15,49.07,45.30,38.43,21.90.HRMS(ESI):(m/z):(M+H)+calcd for C18H19FN5O,340.1574；found 3340.1575.HPLC purity:96.7％,retention time＝13.15min.
EXAMPLE 3 preparation of Compound WYL-3
1) Synthesis of tert-butyl (4-hydroxypyrimidin-2-yl) carbamate
Figure BDA0002156053160000152
2-Aminopyrimidin-4-ol (1.00g,0.01mmol) was dissolved in 20mL of pyridine, and the reaction mixture was added dropwise (Boc) at 65 ℃2O (2.94g,0.014mol), after the addition was completed, the temperature was raised to 85 ℃ to react for 4 hours, and the progress of the reaction was monitored by TLC. After completion of the reaction, EA was used to extract the reaction mixture, and the organic phase was washed with acid water and passed through a silica gel column to obtain 1.06g (53.65%) of a white solid.
1H NMR(400MHz,DMSO-d6)δ11.28(s,2H),7.70(d,J＝6.8Hz,1H),5.93(d,J＝6.8Hz,1H),1.48(s,9H).LC-MS(ESI):m/z:212.1(M+H)+.
2) Synthesis of 4- ((2- (1- ((5-bromo-2-nitro-pyridin-3-yl) oxy) ethyl) -4-fluorobenzyl) oxy) pyrimidin-2-amine
Figure BDA0002156053160000161
Reacting 5-bromo-3- (1- (2- (bromomethyl) -5-fluorophenyl)) Ethoxy) -2-nitropyridine (0.11g, 0.25mmol), (4-hydroxypyrimidin-2-yl) carbamic acid tert-butyl ester (0.05g, 0.25mmol), Cs2CO3(0.08g, 0.25mmol) was dissolved in 5mL DMF and reacted at 80 ℃ for 4h, and the progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was extracted with EA, and the extract was passed through a silica gel column to obtain 0.04g (30.1%) of a white solid. LC-MS (ESI) M/z 564.1/566.1(M + H)+The product was dissolved in DCM and TFA 4:1 solution and reacted at rt for 2h, and the progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was extracted with EA, and the extract was applied to a silica gel column to obtain 0.65g (78.64%) of a white solid.
1H NMR(400MHz,DMSO-d6)δ8.49(d,J＝1.6Hz,1H),8.33(d,J＝1.7Hz,1H),7.36(d,J＝7.5Hz,1H),7.31(dd,J＝10.0Hz,2.7Hz,1H),7.24-7.22(m,1H),6.99(s,2H),6.81(dd,J＝8.6Hz,5.6Hz,1H),6.10(q,J＝6.1Hz,1H),5.64(d,J＝7.5Hz,1H),5.21-5.07(m,2H),1.57(d,J＝6.2Hz,3H).LC-MS(ESI):m/z:464.1/465.1(M+H)+.
3)65-fluoro-5-methyl-36Synthesis of (E) -nitro-4, 8-dioxan-2-aza-1 (2,4) -pyrimidine-3 (3,5) -pyridine-6 (1,2) -benzocyclooctane (15a)
Figure BDA0002156053160000162
4- ((2- (1- ((5-bromo-2-nitro-pyridin-3-yl) oxy) ethyl) -4-fluorobenzyl) oxy) pyrimidin-2-amine (0.52g,1.13mmol), Cs2CO3(1.10g,3.39mmol)、Xantphos(0.13g,0.23mmol)、Pd2(dba)3(0.16g,0.17mmol) in anhydrous DMF, N2The reaction was carried out for 6h at 90 ℃ under protection and the progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was extracted with DCM, and the organic phase was dried over anhydrous sodium sulfate and passed through a silica gel column (PE: EA ═ 1:1) to obtain 0.12g (27.7%) of a yellow solid.
1H NMR(400MHz,DMSO-d6)δ10.63(s,1H),9.77(d,J＝2.0Hz,1H),8.37(d,J＝5.7Hz,1H),7.81(d,J＝2.0Hz,1H),7.43-7.39(m,1H),7.16(dd,J＝10.1Hz,2.7Hz,1H),7.12-7.07(m,1H),6.67(d,J＝5.7Hz,1H),6.25(d,J＝5.5Hz,1H),6.20(d,J＝14.3Hz,1H),5.26(d,J＝14.1Hz,1H),1.64(d,J＝6.2Hz,3H).LC-MS(ESI):m/z:384.3(M+H)+.
4)65-fluoro-5-methyl-4, 8-dioxa-2-aza-1 (2,4) -pyrimidine-3 (3,5) -pyridine-6 (1,2) -benzocyclooctaalkane-36Synthesis of the amine (WYL-3)
Figure BDA0002156053160000171
Will 65-fluoro-5-methyl-36-nitro-4, 8-dioxa-2-aza-1 (2,4) -pyrimidine-3 (3,5) -pyridine-6 (1,2) -benzocyclooctane (0.10g,0.26mmol) with 10% Pd/C in MeOH EA 1:1 mixed solvent in H2The reaction was carried out for 3h at room temperature in an atmosphere and the progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was extracted with DCM, and the organic phase was dried over anhydrous sodium sulfate and passed through a silica gel column (PE: EA ═ 1:4) to obtain 0.06g (69.4%) of a brown solid.
mp:>300℃.1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.91(d,J＝2.1Hz,1H),8.15(d,J＝5.7Hz,1H),7.32-7.26(m,3H),8.98-7.03(m,1H),6.35(d,J＝5.7Hz,1H),6.13(d,J＝14.2Hz,1H),5.98(q,J＝6.2Hz,1H),5.36(s,2H),5.08(d,J＝14.0Hz,1H),1.59(d,J＝6.2Hz,3H).13C NMR(101MHz,DMSO-d6)δ167.77,160.06,159.86,145.93,143.84,138.66,132.98,128.76,127.94,115.93,115.57,115.36,112.44,112.23,98.08,71.18,63.89,24.15.HRMS(ESI):(m/z):(M+H)+calcd for C18H17FN5O2,354.1366；found 354.1367.HPLC purity:97.8％,retention time＝15.63min.
EXAMPLE 4 preparation of Compound WYL-4
Figure BDA0002156053160000172
WYL-4 was synthesized as synthesized from WYL-3 to give a pale purple solid 0.55g (60.3%).
mp:>300℃.1H NMR(400MHz,DMSO-d6)δ9.45(d,J＝2.1Hz,1H),8.44(s,1H),7.41(dd,J＝8.7Hz,6.1Hz,1H),7.35(t,J＝5.4Hz,1H),7.19-7.11(m,3H),6.99-6.94(m,1H),5.90(d,J＝7.9Hz,2H),5.76(d,J＝7.8Hz,1H),5.09-4.97(m,3H),3.92(dd,J＝15.9Hz,5.9Hz,1H),1.58(d,J＝6.2Hz,3H).13C NMR(101MHz,DMSO-d6)δ162.87,160.47,156.52,155.31,143.98,143.91,138.95,138.34,136.32,131.82,128.58,125.54,114.91,113.97,111.55,97.07,96.64,70.28,24.24.HRMS(ESI):(m/z):(M+H)+calcd for C19H19FN5O,352.1574；found 352.1573.HPLC purity:98.1％,retention time＝16.04min.
EXAMPLE 5 preparation of Compound WYL-5
Figure BDA0002156053160000173
WYL-5 was synthesized as WYL-3 to give 0.41g (59.1%) of a pale gray solid.
mp:289.8-291.6℃.1H NMR(400MHz,DMSO-d6)δ9.12(d,J＝2.1Hz,1H),8.82(s,1H),7.42(t,J＝7.9Hz,1H),7.33(dd,J＝8.7Hz,5.9Hz,1H),7.26(dd,J＝10.4Hz,2.8Hz,1H),7.16(d,J＝2.1Hz,1H),7.01-6.98(m,1H),6.20(dd,J＝10.7Hz,7.8Hz,2H),6.03(s,1H),5.93(d,J＝4.8Hz,1H),5.23(s,2H),4.97(d,J＝14.3Hz,1H),1.59(d,J＝6.2Hz,3H).13C NMR(101MHz,DMSO-d6)δ162.56,162.03,157.91,156.43,145.71,144.82,140.69,139.87,138.16,133.71,129.55,127.06,116.15,114.26,113.05,99.49,97.52,79.35,21.06.HRMS(ESI):(m/z):(M+H)+calcd for C19H18FN4O2,353.1414；found 353.1413.HPLC purity:98.6％,retention time＝16.49min.
EXAMPLE 6 preparation of Compound WYL-6
Figure BDA0002156053160000181
WYL-6 was synthesized as WYL-3 to give 0.56g (60.4%) of a pale gray solid.
mp:182.9-183.6℃.1H NMR(400MHz,DMSO-d6)δ7.67(d,J＝2.0Hz,1H),7.60(s,1H),7.49-7.40(m,2H),7.09(d,J＝2.1Hz,1H),7.03-6.98(m,1H),6.78(t,J＝7.9Hz,1H),6.39(s,1H),6.19(d,J＝6.0Hz,1H),6.14-6.03(m,2H),5.97(dd,J＝7.8Hz,1.7Hz,1H),5.45(s,2H),4.45(dd,J＝15.9Hz,1.9Hz,1H),4.02(d,J＝14.2Hz,1H),1.54(d,J＝6.1Hz,3H).13C NMR(151MHz,DMSO-d6)δ162.45,160.85,151.37,147.00,145.98,144.44,144.40,139.55,135.87,135.85,130.69,130.40,130.35,130.12,129.64,118.70,115.24,112.24,105.77,105.38,98.38,74.20,46.16,24.75.HRMS(ESI):(m/z):(M+H)+calcd for C20H20FN4O,351.1621；found 351.1620.HPLC purity:98.3％,retention time＝18.21min.
EXAMPLE 7 preparation of Compound WYL-7
Figure BDA0002156053160000182
WYL-7 was synthesized by the method of WYL-3 synthesis to give 0.18g (35.7%) of a pale yellow solid.
mp:298.9-299.3℃.1H NMR(400MHz,DMSO-d6)δ9.41(d,J＝2.0Hz,1H),9.23(s,1H),7.79(dd,J＝8.7Hz,5.6Hz,2H),7.42(dd,J＝8.6Hz,6.1Hz,1H),7.19(dd,J＝9.4Hz,2.3Hz,2H),7.02-6.97(m,1H),5.94(d,J＝5.6Hz,1H),5.87(d,J＝5.8Hz,1H),5.23(d,J＝78.7Hz,2H),4.94(dd,J＝16.0Hz,4.6Hz,1H),3.96(dd,J＝15.9Hz,6.2Hz,1H),1.58(d,J＝6.2Hz,3H).13C NMR(151MHz,DMSO-d6)δ161.35,160.91,160.38,156.84,145.39,144.05,138.71,135.77,129.67,128.74,126.76,115.77,115.04,111.70,96.55,70.83,46.15,24.33.HRMS(ESI):(m/z):(M+H)+calcd for C18H18FN6O,353.1526；found 353.1527.HPLC purity:99.5％,retention time＝15.07min.
Experimental example 8 molecular level Activity test of JAK2 inhibitor
The experimental principle is as follows:
JAK2 catalyzes the transfer of a phosphate group of Adenosine Triphosphate (ATP) to a polypeptide substrate labeled with two fluorescent groups, coumarin and fluorescein. Based on fluorescence energy resonance transfer (FRET) method, JAK2 catalyzes ATP to react resulting in the proximity of two fluorophores, and donor (coumarin) is excited at 400nM, part of energy is released, emission wavelength is 445nM, and the other part of energy is transferred to fluoroscein, emission wavelength is 520 nM. The inhibition of JAK2 by different compounds varies in extent, resulting in varying degrees of phosphorylation of the substrate, and thus the inhibition rates of different compounds were calculated by determining the ratio of the percentage of phosphorylation of the enzyme-catalyzed substrate.
The experimental method comprises the following steps:
adding 2.5. mu.L of test compound, 5. mu.L of kinase/peptide substrate mixture, 2.5. mu.L of ATP solution into a 384-well plate, shaking 10. mu.L of reaction system for 30s, mixing uniformly, and incubating at room temperature for 1 h; adding 5 mu L of proteolytic enzyme, oscillating a 15 mu L reaction system for 30s, mixing uniformly, and incubating for 1h at room temperature; adding 5 mu L of stopping reagent, oscillating the reaction system with the total volume of 20 mu L for 30s, mixing uniformly, and detecting a fluorescent signal by using a microplate reader, wherein the excitation wavelength is 400nm, and the emission wavelengths are 445nm and 520nm respectively. The inhibition of the compounds at 7 concentration gradients was determined and the IC of each compound was calculated by Origin 8.0 fitting of the curve50The value is obtained. Positive control is carried out in the experimental process to confirm the feasibility of the reaction system, and each experiment is carried out in three parallels. The experimental process adopts Ruxolitinib as a positive control, and at least three parallels are arranged in each experiment.
TABLE 1 Activity of Compounds on JAK2 in vitro enzyme assays
Figure BDA0002156053160000191
Figure BDA0002156053160000192
Figure BDA0002156053160000201
CCK-8 cell proliferation detection principle:
WST-8 (chemical name: 2- (2-Methoxy-4-nitrophenyl) -3- (4-nitrophenyl) -5- (2, 4-disulfonic acid phenyl) -2H-tetrazole monosodium salt), which is reduced by a dehydrogenase in the cell to a yellow Formazan product (Formazan dye) with high water solubility under the action of the electron carrier 1-Methoxy-5-methylphenazinium dimethyl sulfate (1-Methoxy PMS). The amount of formazan produced was proportional to the number of living cells. Cell viability can therefore be calculated indirectly by measuring the light absorption at 450 nm. Half inhibition rate of the compound on H3122, SET2 and HEL cell proliferation is determined by CCK-8 method.
The experimental method comprises the following steps:
cells were cultured in RPIM medium containing 10% FBS, 100. mu.L of each well was added, 3500 cells were inoculated into a 96-well plate and the plate was incubated at 37 ℃ under 5% CO2Culturing in an incubator for 24h, adding medicines with different concentration gradients respectively when the cell confluency reaches 50-70%, continuously incubating for 72h, adding 10 μ L of CCK-8 into each hole, shaking and uniformly mixing, incubating at 37 ℃ for 2h, and finally measuring the light absorption value of each hole under the wavelength of 450 nm. Finally, calculating IC by origin software50The value is obtained.
ALK kinase IC50The test principle is as follows:
the HTRF method labels a biotin on the polypeptide substrate, which is capable of specifically binding to XL 665-labeled streptavidin. When the kinase adds a phosphate group to the polypeptide substrate in the first step, the Eu-labeled specific phosphorylated antibody can be recognized and bound to the substrate. Thus, in the second detection step, a complex can be formed in which XL 665-labeled streptavidin, phosphorylated polypeptide substrate and Eu-labeled phosphorylated antibody are bound. Since the distance between XL665 and Eu is short, FRET can be formed. On the other hand, Eu has a relatively long fluorescence half-life period, and can be applied to time-resolved fluorescence detection.
The experimental method comprises the following steps:
adding 4 μ L of test compound, 2 μ L of kinase, 2 μ L of biotin-labeled substrate, 2 μ L of ATP, 10 μ L of reaction system, shaking for 30s, mixing, and incubating at room temperature for 1 h; adding 5 mu L of Eu-labeled phosphorylation site specific antibody and 5 mu L of XL 665-labeled streptavidin, oscillating the reaction system for 30s, mixing uniformly, incubating at room temperature for 1h, and detecting a fluorescence signal by using an enzyme-labeling instrument. The inhibition of compounds at 8 concentration gradients was determined and the IC50 values for each compound were calculated by Origin 8.0 fitting curves. Positive control is carried out in the experimental process to confirm the feasibility of the reaction system, and each experiment is carried out in three parallels.
Note: HEL, SET-2, H3122 cells were purchased from ATCC (American type culture collection), Z' -LYTETM kinase assay platform from Invitrogen, HTRF KinEASETM-TK from Cisbio, and Cell Counting Kit-8 from Byssunday.
Figure BDA0002156053160000211
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (11)

1. A compound shown in formula I, or a stereoisomer or an optical isomer, a pharmaceutically acceptable salt, a prodrug or a solvate thereof,
Figure FDA0002156053150000011
in the formula
R1Selected from substituted or unsubstituted 5-or 6-membered nitrogen-containing heterocycles;
R2selected from the group consisting of: hydrogen, substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C1-C10An acyl group;
R3selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted C1-C10Alkyl (e.g. halo C)1-C10Alkyl), hydroxy, substituted or unsubstituted C1-C10An alkoxy group;
R4selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted C1-C10Alkyl, hydroxy, substituted or unsubstituted C1-C10An alkoxy group;
X1selected from the group consisting of: CH (CH)2、O、NH、S、SO、SO2；
X2Is absent or selected from the group consisting of: CH (CH)2、O、NH、S、SO、SO2(ii) a And
X3selected from the group consisting of: CH (CH)2、O、NH、S、SO、SO2。
2. The compound of claim 1, or a stereoisomer or optical isomer thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein R1Selected from the group consisting of:
Figure FDA0002156053150000012
wherein R or R' is selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted C1-C10Alkyl (e.g. halo C)1-C10Alkyl), hydroxy, substituted or unsubstituted C1-C10Alkoxy (e.g. halo C)1-C10Alkoxy groups).
3. The compound of claim 1 or 2, or a stereoisomer or an optical isomer thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the compound is of formula II:
Figure FDA0002156053150000021
in the formula
R1And X1、X2Is as defined in claim 1 or 2.
4. The compound of claim 1 or 2, or a stereoisomer or optical isomer thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the 5-or 6-membered nitrogen-containing heterocycle is selected from the group consisting of:
Figure FDA0002156053150000022
5. the compound of claim 1 or 2, or a stereoisomer or optical isomer thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the compound is selected from the group consisting of:
Figure FDA0002156053150000023
6. the compound of claim 2, or a stereoisomer or optical isomer thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein R1Selected from the group consisting of:
Figure FDA0002156053150000024
r is selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted C1-C10Alkyl, hydroxy, substituted or unsubstituted C1-C10An alkoxy group;
R2selected from the group consisting of: hydrogen, substituted or unsubstituted C1-C10An alkyl group;
R3selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted C1-C10Alkyl, hydroxy, substituted or unsubstituted C1-C10An alkoxy group;
R4selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted C1-C10Alkyl, hydroxy, substituted or unsubstituted C1-C10An alkoxy group;
X1selected from the group consisting of: CH (CH)2、O、NH、S；
X2Selected from the group consisting of: CH (CH)2O, NH, S; and
X3selected from the group consisting of: CH (CH)2、O、NH、S。
7. The compound of claim 6, or a stereoisomer or optical isomer thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the compound is selected from the group consisting of:
Figure FDA0002156053150000031
8. a pharmaceutical composition comprising a compound of any one of claims 1-7, or a stereoisomer or an optical isomer thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, and a pharmaceutically acceptable carrier or excipient.
9. Use of a compound of any one of claims 1-7, or a stereoisomer or optical isomer thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, for the manufacture of a medicament for the prevention or treatment of a JAK 2-mediated disease; and/or for the preparation of a JAK2 inhibitor.
10. The use according to claim 9, wherein the JAK 2-mediated disease is myelodysplastic syndrome (MDS), eosinophilia, tumor, inflammatory disease, or infection by bacteria, viruses, or fungi;
preferably, the tumor is selected from the group consisting of: myeloproliferative carcinoma (MPN), melanoma, lung cancer, kidney cancer, ovarian cancer, prostate cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, rectal cancer, anal cancer, stomach cancer, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, hodgkin's disease, non-hodgkin's lymphoma, carcinoma of the esophagus, carcinoma of the small intestine, carcinoma of the endocrine system, carcinoma of the thyroid gland, carcinoma of the parathyroid gland, carcinoma of the adrenal gland, sarcoma of soft tissue, carcinoma of the urethra, carcinoma of the penis, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, pediatric solid tumors, lymphocytic lymphoma, carcinoma of the bladder, carcinoma of the kidney or ureter, carcinoma of the renal pelvis, tumors of the Central Nervous System (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, Pituitary adenomas, kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma; and/or
The inflammatory disease is selected from the group consisting of: rheumatoid arthritis, ankylosing spondylitis, autoimmune hemolytic anemia, arthritis, myasthenia gravis, systemic lupus erythematosus, pernicious anemia, polymyositis; and/or
The virus is selected from the group consisting of: hepatitis viruses (type a, b and c), herpesviruses, influenza viruses, adenoviruses, coronaviruses, measles viruses, dengue viruses, polio viruses, rabies viruses; and/or
The bacteria are selected from the group consisting of: chlamydia, rickettsia, mycobacteria, staphylococci, pneumococci, cholera, tetanus; and/or
The fungus is selected from the group consisting of: candida, aspergillus, dermatitides.
11. A JAK2 inhibitor comprising a compound of any one of claims 1 to 7, or a stereoisomer or an optical isomer thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, or a pharmaceutical composition of claim 8.
CN201910717773.4A 2019-08-05 2019-08-05 Macrocyclic JAK2 inhibitor and application thereof Pending CN112321604A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201910717773.4A CN112321604A (en) 2019-08-05 2019-08-05 Macrocyclic JAK2 inhibitor and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201910717773.4A CN112321604A (en) 2019-08-05 2019-08-05 Macrocyclic JAK2 inhibitor and application thereof

Publications (1)

Publication Number Publication Date
CN112321604A true CN112321604A (en) 2021-02-05

Family

ID=74319432

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201910717773.4A Pending CN112321604A (en) 2019-08-05 2019-08-05 Macrocyclic JAK2 inhibitor and application thereof

Country Status (1)

Country Link
CN (1) CN112321604A (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022213980A1 (en) * 2021-04-07 2022-10-13 上海齐鲁制药研究中心有限公司 Tyk2 inhibitor and use thereof
US11542278B1 (en) 2020-05-05 2023-01-03 Nuvalent, Inc. Heteroaromatic macrocyclic ether chemotherapeutic agents
US11667649B2 (en) 2020-05-05 2023-06-06 Nuvalent, Inc. Heteroaromatic macrocyclic ether chemotherapeutic agents

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101360751A (en) * 2005-11-16 2009-02-04 S*Bio私人有限公司 Oxygen linked pyrimidine derivatives
CN102617599A (en) * 2012-04-10 2012-08-01 江苏先声药物研究有限公司 Macrocyclic compound and application thereof
CN104169286A (en) * 2012-03-06 2014-11-26 辉瑞大药厂 Macrocyclic derivatives for the treatment of proliferative diseases
CU20140107A7 (en) * 2013-01-31 2014-12-26 Pfizer MACROCYCLIC DERIVATIVES FOR THE TREATMENT OF DISEASES
WO2014207606A1 (en) * 2013-06-28 2014-12-31 Pfizer Inc. Solid forms of a macrocyclic kinase inhibitor
CN104513253A (en) * 2013-10-01 2015-04-15 南京波尔泰药业科技有限公司 Macrocyclic compounds for the treatment of proliferative diseases
MA37291A2 (en) * 2012-03-06 2016-10-31 Pfizer Inc ( Etat De Delaware) Macrocyclic derivatives for the treatment of proliferative diseases
CN106459084A (en) * 2014-04-11 2017-02-22 拜耳医药股份有限公司 Novel macrocyclic compounds
CN107207528A (en) * 2014-08-20 2017-09-26 苏州韬略生物科技有限公司 Big ring and its application method are substituted as kinase inhibitor
CN108290903A (en) * 2015-09-29 2018-07-17 拜耳医药股份有限公司 New big ring sulphonyl diimine compounds
WO2018137679A1 (en) * 2017-01-25 2018-08-02 Teligene Ltd Process for the Preparation of (10R) -7- (2-aminoacetyl) amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15, 16, 17-tetrahydro-2H-8, 4- (metheno) pyrazolo [4, 3-h] [2, 5, 11] -benzoxadiazacyclotetradecine-3-carbonitrile
CN108368129A (en) * 2015-10-08 2018-08-03 拜耳医药股份有限公司 New modification macrocyclic compound
WO2019073347A1 (en) * 2017-10-10 2019-04-18 Pfizer Inc. Crystalline form of lorlatinib free base hydrate

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101365703A (en) * 2005-11-16 2009-02-11 S*Bio私人有限公司 Heteroalkyl linked pyrimidine derivatives
CN101360751A (en) * 2005-11-16 2009-02-04 S*Bio私人有限公司 Oxygen linked pyrimidine derivatives
MA37291A2 (en) * 2012-03-06 2016-10-31 Pfizer Inc ( Etat De Delaware) Macrocyclic derivatives for the treatment of proliferative diseases
CN104169286A (en) * 2012-03-06 2014-11-26 辉瑞大药厂 Macrocyclic derivatives for the treatment of proliferative diseases
CN102617599A (en) * 2012-04-10 2012-08-01 江苏先声药物研究有限公司 Macrocyclic compound and application thereof
CU20140107A7 (en) * 2013-01-31 2014-12-26 Pfizer MACROCYCLIC DERIVATIVES FOR THE TREATMENT OF DISEASES
WO2014207606A1 (en) * 2013-06-28 2014-12-31 Pfizer Inc. Solid forms of a macrocyclic kinase inhibitor
CN104513253A (en) * 2013-10-01 2015-04-15 南京波尔泰药业科技有限公司 Macrocyclic compounds for the treatment of proliferative diseases
CN106459084A (en) * 2014-04-11 2017-02-22 拜耳医药股份有限公司 Novel macrocyclic compounds
CN107207528A (en) * 2014-08-20 2017-09-26 苏州韬略生物科技有限公司 Big ring and its application method are substituted as kinase inhibitor
CN108290903A (en) * 2015-09-29 2018-07-17 拜耳医药股份有限公司 New big ring sulphonyl diimine compounds
CN108368129A (en) * 2015-10-08 2018-08-03 拜耳医药股份有限公司 New modification macrocyclic compound
WO2018137679A1 (en) * 2017-01-25 2018-08-02 Teligene Ltd Process for the Preparation of (10R) -7- (2-aminoacetyl) amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15, 16, 17-tetrahydro-2H-8, 4- (metheno) pyrazolo [4, 3-h] [2, 5, 11] -benzoxadiazacyclotetradecine-3-carbonitrile
WO2019073347A1 (en) * 2017-10-10 2019-04-18 Pfizer Inc. Crystalline form of lorlatinib free base hydrate

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11542278B1 (en) 2020-05-05 2023-01-03 Nuvalent, Inc. Heteroaromatic macrocyclic ether chemotherapeutic agents
US11667649B2 (en) 2020-05-05 2023-06-06 Nuvalent, Inc. Heteroaromatic macrocyclic ether chemotherapeutic agents
WO2022213980A1 (en) * 2021-04-07 2022-10-13 上海齐鲁制药研究中心有限公司 Tyk2 inhibitor and use thereof
CN116888125A (en) * 2021-04-07 2023-10-13 上海齐鲁制药研究中心有限公司 TYK2 inhibitor and application thereof
CN116888125B (en) * 2021-04-07 2024-04-12 上海齐鲁制药研究中心有限公司 TYK2 inhibitor and application thereof

Similar Documents

Publication Publication Date Title
WO2018121228A1 (en) Compound having axl inhibitory activity, preparation method therefor and use thereof
CN105315285B (en) 2,4 2 substitution 7H pyrrolo-es [2,3 d] pyrimidine derivatives, its preparation method and purposes pharmaceutically
JP6606278B2 (en) 2-Arylaminopyridine, pyrimidine or triazine derivatives and their production and use
JP6465996B2 (en) 3-Acetylenyl-pyrazole-pyrimidine derivative, process for its preparation and its use
CN112119070B (en) Selective JAK2 inhibitors and uses thereof
CN112724145A (en) Pyrazine derivatives for inhibiting SHP2 activity
WO2006050946A1 (en) 1,4 substituted pyrazolopyrimidines as kinase inhibitors
CN110582483A (en) Compound containing o-amino heteroaromatic ring alkynyl and preparation method and application thereof
TWI753918B (en) Crystallization of Pyrrolopyrimidine Compounds as JAK Inhibitors
WO2001083456A1 (en) Condensed heteroaryl derivatives
CN106187915A (en) There is inhibitor of ALK Yu EGFR double activity and its preparation method and application
CN112321604A (en) Macrocyclic JAK2 inhibitor and application thereof
CN112979679B (en) Fluoroheterocyclic derivative having macrocyclic structure and use thereof
AU2017295628A1 (en) Heterocyclic compound used as FGFR inhibitor
CN112574216B (en) Compound, preparation method thereof and application thereof in preparing anti-cancer drugs
CN105732615A (en) CDK kinase inhibitor
CN109721600A (en) A kind of nitrogenous fused ring compound and its preparation method and application
WO2020005935A1 (en) Glucose uptake inhibitors
CN112638897A (en) EGFR kinase inhibitor and preparation method and application thereof
TW200529825A (en) Diazaindole-dicarbonyl-piperazinyl antiviral agents
WO2020221209A1 (en) Cd73 inhibitor, preparation method therefor and application thereof
CN111138417B (en) Triazole modified 5-fluoro-2, 4-pyrimidinediamine compound and application thereof
CN110357892B (en) Tetrahydropyrimidino [1,2-a ] indole derivative and synthesis method and application thereof
CN115260202A (en) Cyclic compounds as JAK2 inhibitors and uses thereof
CN112279863A (en) Conjugate of Hsp90 inhibitor and camptothecin derivative as well as preparation method and application thereof

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