CN115260156A - Compounds as JAK2 inhibitors and uses thereof - Google Patents

Compounds as JAK2 inhibitors and uses thereof Download PDF

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CN115260156A
CN115260156A CN202110474822.3A CN202110474822A CN115260156A CN 115260156 A CN115260156 A CN 115260156A CN 202110474822 A CN202110474822 A CN 202110474822A CN 115260156 A CN115260156 A CN 115260156A
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李洪林
赵振江
刁妍妍
朱丽丽
刘丹丹
葛欢
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East China University of Science and Technology
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Abstract

The invention relates to a compound serving as a JAK2 inhibitor and application thereof. In particular, the invention relates to a compound shown in the formula I and application of the compound in treating JAK2 mediated related diseases and preparing drugs for treating JAK2 mediated related diseases.

Description

Compounds as JAK2 inhibitors and uses 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
Janus kinase (JAK) is an unresponsive tyrosine protein kinase, a relatively large protein of the tyrosine kinase family (120-130 kDa). The JAK family has four members: JAK1, JAK2, TYK2 and JAK3. The first three are widely expressed in vivo, whereas JAK3 is expressed only in myeloid and lymphoid lineage cells. All members of the JAK family contain 7 homologous domains of different lengths, with the tyrosine kinase domain JH1 and the pseudokinase domain JH2 located in the carboxy-terminal portion. The pseudokinase domain JH2 modulates kinase domain activity and produces inhibition. Domains JH3-JH4 are similar in structure to SH2 domains. The JH4-JH7 domain is located at the amino terminus of the kinase and is important for binding of the JAKs kinase to cytokine receptors on the cell surface and for maintaining receptor expression.
JAK kinases play a pivotal role in the signaling of many cytokine receptors, primarily through the JAK-STAT signaling pathway to regulate the signaling process. JAK-STAT refers to the JAK kinase-cell signaling and transcriptional activator pathway that operates downstream of over 50 cytokines and growth factors, and is considered an important communication node of the immune system. The JAK-STAS signaling process generally involves, first, the binding of cytokines to specific receptors on the cell membrane, inducing receptor-JAK complex dimerization, and the activation of JAK kinases. Activated JAKs then phosphorylate tyrosine residues in the cytoplasmic domain of cytokine receptors to 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 gene expression by binding to specific DNA.
JAKs play a key role in both innate and adaptive immunity as well as hematopoiesis, making them attractive targets for many therapeutic indications. Therefore, JAKs have been attracting attention as targets of new drugs since their discovery in the early 1990 s. A variety of chemical entities now exist in the clinic, covering a variety of indications, including myeloproliferative diseases and a variety of inflammatory diseases.
JAK2 signaling has a key role in the pathogenesis of myeloproliferative diseases, with a point mutation in the JAK2 pseudokinase domain V617F found in about 90% of patients with polycythemia vera, and about 50% of patients with primary myelofibrosis and primary thrombocythemia. This mutation results in continuous cytokine-independent activation of JAK2 and activates downstream signaling pathways. 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 JAK2 pseudokinase domain, 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 the field, and JAK2 inhibitors have good application prospects in inflammation, autoimmune diseases, myelofibrosis and various hematologic malignancies.
So far, most of JAK small-molecule inhibitors on the market are pan-inhibitors, and lack of sufficient selectivity on JAK family members leads to possible adverse reactions in the clinical application process. For example, JAK2 inhibitors, which inhibit JAK3 simultaneously, can lead to immunodeficiency. Therefore, the research and development of a new structure with high selectivity on JAK2 have important clinical significance and application value.
Disclosure of Invention
The invention aims to design and synthesize a JAK2 inhibitor which is efficient, high in selectivity, low in toxicity and good in safety.
In a first aspect of the invention, there is provided a compound of formula I, or a stereoisomer or an optical isomer, a pharmaceutically acceptable salt, a prodrug or a solvate thereof,
Figure BDA0003047001850000021
in the formula (I), the compound is shown in the specification,
R1selected from the group consisting of: hydrogen, halogen, C1-C10Alkyl, halo C1-C10Alkyl radical, C1-C10Alkoxy, halo C1-C10Alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted 5-or 6-membered nitrogen-containing heterocycle; wherein said substitution means that one or more hydrogen atoms on the above groups are substituted by a group selected from the group consisting of: c1-C10Alkyl, 5-to 7-membered ring containing one or two heteroatoms selected from nitrogen or oxygen or sulfur, haloC1-C10Alkyl, hydroxy, cyano, substituted or unsubstituted (C)1-C10Alkyl-a 5-to 7-membered ring containing one or two heteroatoms selected from nitrogen or oxygen or sulfur), or substituted or unsubstituted (C)1-C10Alkoxy-a 5-7 membered ring containing one or two heteroatoms selected from nitrogen or oxygen or sulfur);
R2selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted pyrimidine, substituted or unsubstituted C5-C7Cycloalkyl, substituted or unsubstituted indole, substituted or unsubstituted benzimidazole; the substitution means that one or more hydrogen atoms on the above groups are substituted by a group selected from the group consisting of: hydrogen, halogen, cyano, amido (C (O) NH)2)、C1-C3Alkyl, halo C1-C3Alkyl radical, C1-C3Alkoxy, halo C1-C3An alkoxy group;
R3selected from the group consisting of: hydrogen, halogen, C1-C10Alkyl, halo C1-C10Alkyl, hydroxy, C1-C10An alkoxy group;
R4selected from the group consisting of: hydrogen, C1-C10Straight or branched alkyl, C1-C10An acyl group;
x is selected from the group consisting of: CH (CH)2、O、NH、S、SO、SO2；
Unless otherwise specified, the substitution refers to the substitution of one or more hydrogen atoms on the group with a substituent selected from the group consisting of: halogen, C1-C10An alkyl group.
In another preferred embodiment, theR of (A) to (B)1Selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted 5-or 6-membered nitrogen-containing heterocycle; wherein said substitution means that one or more hydrogen atoms on the above groups are substituted by a group selected from the group consisting of: c1-C4Alkyl, 5-to 7-membered ring containing one or two heteroatoms selected from nitrogen or oxygen or sulfur, substituted or unsubstituted (C)1-C4Alkyl-a 5-to 7-membered ring containing one or two heteroatoms selected from nitrogen or oxygen or sulfur), or substituted or unsubstituted (C)1-C4Alkoxy-a 5-to 7-membered ring containing one or two heteroatoms selected from nitrogen or oxygen or sulfur).
In another preferred embodiment, the compound is of formula II:
Figure BDA0003047001850000031
in the formula
R1、R2、R4Is defined as in claim 1.
In another preferred embodiment, the 5-or 6-membered nitrogen-containing heterocycle is selected from the group consisting of: pyrrole, pyrazole, pyridine, imidazole, thiazole.
In another preferred embodiment, the compound is of formula III:
Figure BDA0003047001850000032
in the formula (I), the compound is shown in the specification,
ring A is selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-or 6-membered nitrogen-containing heterocycle;
R5selected from the group consisting of: - (CH)2)p- (5-to 7-membered ring containing one or two heteroatoms selected from nitrogen or oxygen or sulfur), -O (CH)2)p- (5-to 7-membered rings containing one or two heteroatoms selected from nitrogen or oxygen or sulphur); wherein p is 0, 1 or 2.
In another preferred embodiment, R is5Selected from the group consisting of:
Figure BDA0003047001850000033
wherein x is 1, 2 or 3.
In another preferred embodiment, the a ring is selected from the group consisting of: phenyl, pyrrole, pyrazole, pyridine, imidazole, thiazole and triazole.
In another preferred embodiment, the compound is selected from the group consisting of:
Figure BDA0003047001850000041
Figure BDA0003047001850000051
in a second aspect of the present invention, there is provided a pharmaceutical composition comprising a compound according to the first aspect of the present invention, 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 third aspect of the present invention, there is provided a use of a compound according to the first aspect of the present invention or a stereoisomer or an optical isomer thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, for the preparation of a medicament for the prevention or treatment of a JAK 2-mediated disease; and/or for the preparation of a JAK2 inhibitor.
In another preferred embodiment, 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, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, pediatric solid tumors, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, cancer of the renal pelvis, tumors of the Central Nervous System (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brain stem glioma, pituitary adenoma, kaposi's sarcoma, epidermoid 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, type b and type c), herpes viruses, 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, dermatitis bud yeast.
In another preferred embodiment, the present invention provides a JAK2 inhibitor comprising a compound according to the first aspect of the present invention, or a stereoisomer or an optical isomer thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, or a pharmaceutical composition according to the second aspect of the present invention.
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 inventor finds the effective application of the aminopyrimidine structure in JAK inhibitors through extensive and intensive research, finally finds a series of compounds capable of selectively inhibiting JAK2 kinase, and provides a brand-new material basis for the development of immune inflammation and antitumor drugs. On the basis of this, the inventors have completed the present invention.
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, "JAK2" 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 having 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 long, more preferably 1 to 4 carbon atoms long. 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-C3An 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 substituted" 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 the group consisting of: halogen, C1-4Aldehyde group, C1-6Straight or branched 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, ethoxycarbonyl, 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 BDA0003047001850000071
in the formula I, R1、R2、R3、R4And X is as 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 specified group are replaced with a specified 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 substituents in the above general formula and combinations of some of the substituents shown in the general formula 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 formed by a compound of the present invention and an acid or base, which 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 conformers): e.g., R, S configuration containing asymmetric centers, (Z), (E) isomers of double bonds, etc..) and, thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers or geometric isomers (or conformers) thereof are intended to be 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 shifts) include interconversion by proton shifts, such as 1H-indazoles and 2H-indazoles. Valence tautomers include interconversion by some recombination of bonding electrons.
As used herein, the term "solvate" refers to a compound of the present invention coordinated to solvent molecules to form a complex 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. <xnotran> ( , , ), , , ( , ), , ( , , , ), ( , , , </xnotran>Sorbitol, etc.), emulsifiers (e.g.
Figure BDA0003047001850000081
) 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, hydroxymethyl cellulose, 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 used 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 using pharmaceutical compositions, a safe and effective amount of a compound of the present invention is administered to a mammal (e.g., a human) in need of treatment at a dosage that is pharmaceutically considered to be effective, typically 1 to 2000mg, preferably 20 to 500mg per day for a human of 60kg body weight. Of course, the particular dosage will also take into account such factors as the route of administration, the health of the patient, and the like, which are 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.
Scheme 1:
Figure BDA0003047001850000101
areagents and conditions: (a) NaBH4,MeOH,0℃,3h,97％；(b)HNO3,H2SO4,0℃,4h,62％；(c)DIAD,PPh3,THF,r.t.,6h,90％；(d)Fe,AcOH,EtOH,78℃,2.5h,67％；(e)Aryl borate,PdCl2(dppf),Cs2CO3,MePh,H2O,80℃,5h,60％；(f)Alkyl iodide,NaH,DMF,0℃,8h,43％；(g)TFA,DCM,r.t.,1h,51％；(h)4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane),AcOK,PdCl2(dppf),dioxide,100℃,8h,80％；(i)Aryl halide,Cs2CO3,PdCl2(dppf),Dimethoxyethane,80℃,12h,31.85％.
Scheme 2:
Figure BDA0003047001850000111
areagents and conditions: (a) Cs2CO3,MeCN,78℃,10h；(b)PdCl2(dppf),Cs2CO3,MePh,H2O,80℃,5h,44.45％.
Scheme 3:
Figure BDA0003047001850000112
areagents and conditions: (a) 4N HCl, reflux,4h,58.34 percent; (b) DIAD, PPh3,THF,r.t.,6h,90％；(c)(Boc)2O,DMAP,CH2Cl2,r.t.,1h,82.7％；(d)PdCl2(dppf),Cs2CO3,MePh,H2O,80℃,5h,60％；(e)TFA,DCM,r.t.,1h,51％.
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 JAK2 inhibition.
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 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 X-1
1) Synthesis of 1- (2-chloro-5-fluorophenyl) ethanol
Figure BDA0003047001850000121
2-chloro-5-fluoroacetophenone (10g, 0.0579mol) was dissolved in MeOH (30 mL) and NaBH was added slowly in an ice bath4(0.45g, 0.011895mol), reaction at room temperature for about 3h, and monitoring the progress of the reaction by TLC. After the reaction is completed, methanol and CH are spin-dried2Cl2Extraction, organic phase combination, anhydrous sodium sulfate drying, spin drying to obtain colorless oily liquid 1- (2-chloro-5-fluorophenyl) ethanol 9.8g (97%).
1H-NMR(400MHz,CDCl3)δ7.36–7.30(dd,1H),7.30–7.26(dd,1H),6.99–6.85(m,1H),5.29–5.19(m,1H),2.08(d,J＝3.5Hz,1H),1.47(d,J＝6.4Hz,3H).
2) Synthesis of 3-hydroxy-5-bromo-2-nitropyridine
Figure BDA0003047001850000122
3-hydroxy-5-bromopyridine (5.00g, 0.0287mmol) was dissolved in concentrated H2SO4(30 mL), stirred for about 20min in ice bath, and 65% concentrated HNO was added dropwise3(2.8mL, 0.0402mmol), after completion of the addition, the mixture was de-iced and reacted at room temperature for about 4 hours. After the reaction, the reaction solution was slowly poured into ice water, stirred continuously, a large amount of white floc was precipitated, filtered, the filter cake was washed with ice water to remove the acid, and dried to obtain 3.96g (62%) of yellow solid 3-hydroxy-5-bromo-2-nitropyridine.
1H-NMR(400MHz,CDCl3)δ10.27(s,1H),8.23(s,1H),7.84(s,1H).LC-MS(m/z):216.90/218.95(M+H)+.
3) Synthesis of 5-bromo-3- (1- (2-chloro-5-fluorophenyl) ethoxy) -2-nitropyridine
Figure BDA0003047001850000131
3-hydroxy-5-bromo-2-nitropyridine (3.76g, 0.01717mol), 1- (2-chloro-5-fluorophenyl) ethanol (3 g, 0.01718mmol) and PPh3(5.4g, 0.02059mol) is called a reaction flask, N2Replacement, anhydrous THF was added and DIAD (4.17g, 0.02062mol) was added dropwise over an ice bath. Then the mixture is moved to room temperature for reaction for about 6h. After the reaction, EA extraction, organic phase combination, anhydrous sodium sulfate drying, and concentration. The product was isolated by silica gel column chromatography (PE: EA =30 1) to give 5.8g (90%) of 5-bromo-3- (1- (2-chloro-5-fluorophenyl) ethoxy) -2-nitropyridine as a white solid.
1H-NMR(400MHz,CDCl3)δ8.09(d,J＝1.7Hz,1H),7.43–7.35(m,2H),7.24(dd,J＝8.9,3.0Hz,1H),7.00(ddd,J＝8.8,7.6,3.0Hz,1H),5.78(q,J＝6.2Hz,1H),1.68(d,J＝6.3Hz,3H).
4) Synthesis of 5-bromo-3- (1- (2-chloro-5-fluorophenyl) ethoxy) -2-aminopyridine
Figure BDA0003047001850000132
5-bromo-3- (1- (2-chloro-5-fluorophenyl) ethoxy) -2-nitropyridine (5.80g, 0.0154mol), fe powder (2.16g, 0.03868mol) was dissolved in a mixed solution (40 mL) of ethanol and acetic acid =1, and reacted at 78 ℃ for about 2.5h. After the reaction is completed, the solvent is removed by spin-drying, and CH is added2Cl2Dissolving, adjusting pH to 7-8 with NaOH saturated water solution, filtering with diatomaceous earth, and filtering with CH2Cl2Extraction and washing with saturated aqueous NaCl solution. The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The product was isolated by silica gel column chromatography (PE: EA =10: 1) to give 5-bromo-3- (1- (2-chloro-5-fluorophenyl) ethoxy) -2-aminopyridine as a white solid 3.56g (67%).
1H-NMR(400MHz,CDCl3)δ7.68(d,J＝1.7Hz,1H),7.37(dd,J＝8.8,5.0Hz,1H),7.09(dd,J＝9.1,3.0Hz,1H),6.97(ddd,J＝8.8,7.7,3.0Hz,1H),6.70(d,J＝1.7Hz,1H),5.59(q,J＝6.3Hz,1H),4.77(s,2H),1.65(d,J＝6.4Hz,3H).
5) Synthesis of Compound X-1
Figure BDA0003047001850000141
5-bromo-3- (1- (2-chloro-5-fluorophenyl) ethoxy) -2-aminopyridine (100mg, 0.29mmol), 1-methyl-4-boronic acid ester pyrazole (73mg, 0.35mmol), and cesium carbonate (108mg, 1.02mmol) were placed in a 50mL three-necked flask, 18mL MePh and H were added2Mixed solution of O (MePh: H)2O = 4). Under the protection of nitrogen, a palladium catalyst (20mg, 0.03mmol) was added, and the mixture was heated to 80 ℃ and stirred under reflux. The reaction was followed by TLC and after 20 hours the reaction was complete, the reaction was spun off and purified by silica gel column chromatography (DCM: meOH = 100) to give the product as a yellow solid 28mg (27.83%), m.p.: 210.2-211.1 ℃.
1H-NMR(400MHz,CDCl3):δ7.65(s,1H),7.43(s,1H),7.32(s,1H),7.30(dd,J＝8.8Hz,J＝4.8Hz,1H),7.08(dd,J＝9.2Hz,J＝3.2Hz,1H),6.88(td,J＝8.2Hz,J＝3.2Hz,1H),6.67(s,1H),5.64(q,J＝6.1Hz,1H),5.02(s,2H),3.83(s,3H),1.61(d,J＝6.4Hz,3H).13C-NMR(151MHz,CDCl3):δ162.9,161.3,148.3,141.3,140.3,136.2,132.7,131.1,126.2,119.7,119.2,116.8,116.5,113.7,72.9,39.1,22.5.HRMS(ESI)(m/z):[M+H]+calcd for C17H17ClFN4O,347.0997；found,347.1073.
EXAMPLE 2 preparation of Compound X-2
Figure BDA0003047001850000142
The product was 22mg (21.01%) of a white solid, melting point: 213.1-213.9 ℃.
1H-NMR(400MHz,CDCl3):δ7.40(s,1H),7.37(s,1H),7.27(dd,J＝8.8Hz,J＝4.8Hz,1H),7.05(dd,J＝8.8Hz,J＝2.8Hz,1H),6.87(td,J＝8.0Hz,J＝3.2Hz,1H),5.56(q,J＝6.2Hz,1H),1.99(s,6H),1.61(d,J＝6.4Hz,3H).13C-NMR(151MHz,CDCl3):δ162.9,161.2,148.3,141.9,139.5,138.49,131.1,126.1,119.7,119.3,116.3,115.1,113.6,113.4,72.7,22.5,11.2.HRMS(ESI)(m/z):[M+H]+calcd for C18H19ClFN4O,361.1153；found,361.1230.
EXAMPLE 3 preparation of Compound X-3
Figure BDA0003047001850000151
Product as white solid 47mg (16.16%), melting point: 207.9-208.5 ℃.
1H-NMR(400MHz,DMSO-d6):δ12.69(s,1H),7.95(s,1H),7.68(d,J＝1.2Hz,1H),7.53(dd,J＝8.8Hz,J＝5.2Hz,1H),7.20(s,1H),7.18(td,J＝8.4Hz,J＝3.2Hz,1H),6.46(s,1H),6.10(s,3H),6.00(s,1H),5.78(q,J＝6.2Hz,1H),1.62(d,J＝6.0Hz,3H).13C-NMR(151MHz,DMSO):δ162.7,161.1,142.7,139.2,136.4,131.7,131.6,126.6,117.2,117.0,115.0,114.5,114.4,101.0,72.0,22.3.HRMS(ESI)(m/z):[M+H]+calcd for C16H15ClFN4O,333.0840；found,333.0916.
EXAMPLE 4 preparation of Compound X-4
Figure BDA0003047001850000152
The product was a white solid 101mg (33.56%), m.p.: 203.6-204.2 ℃.
1H-NMR(400MHz,DMSO-d6):δ12.52(s,1H),7.58(s,1H),7.53(dd,J＝8.8Hz,J＝5.2Hz,1H),7.47(dd,J＝9.6Hz,J＝3.2Hz,1H),7.19(td,J＝8.0Hz,J＝3.2Hz,1H),6.74(d,J＝1.6Hz,1H),5.85(s,1H),5.76(q,J＝6.1Hz,1H),2.11(s,3H),1.62(d,J＝6.4Hz,3H).13C-NMR(161MHz,DMSO-d6):δ162.7,161.1,149.9,142.8,142.7,139.0,137.3,131.7,126.6,118.6,117.2,117.0,114.5,114.3,71.9,40.0,22.5.HRMS(ESI)(m/z):[M+H]+calcd for C17H17ClFN4O,347.0997；found,347.1076.
EXAMPLE 5 preparation of Compound X-5
Figure BDA0003047001850000153
The product was 20mg (10.36%) of a yellow solid, melting point: 208.9-209.6 ℃.
1H-NMR(400MHz,CDCl3):δ7.90(s,1H),7.59(s,2H),7.29(dd,J＝8.8Hz,J＝5.0Hz,1H),7.10(d,J＝3.0Hz,1H),7.04(s,1H),6.88(ddd,J＝8.7Hz,J＝7.7Hz,J＝3.0Hz,1H),6.33(t,J＝2.1Hz,1H),5.68(q,J＝6.3Hz,1H),4.87(s,2H),1.62(d,J＝6.3Hz,3H).13C-NMR(151MHz,CDCl3):δ162.81,161.17,148.87,141.24,140.83,131.23,127.02,126.41,116.61,116.45,113.56,113.40,111.51,107.27,73.11,22.27.HRMS(ESI)(m/z):[M+H]+calcd for C16H15ClFN4O,333.0840；found,333.1108.
EXAMPLE 6 preparation of Compound L-1
1) Synthesis of tert-butyl 4- (4- (6-amino-5- (1- (2-chloro-5-fluorophenyl) ethoxy) pyridin-3-yl) -1H-pyrazole) -1-yl) piperidine-1-carboxylate
Figure BDA0003047001850000161
The product was 1.52g (51%) as a yellow solid.
1H-NMR(400MHz,CDCl3)δ7.76(d,J＝1.6Hz,1H),7.53(s,1H),7.45(s,1H),7.36(dd,J＝8.8,5.0Hz,1H),7.15(dd,J＝9.1,3.0Hz,1H),6.99–6.88(m,1H),6.73(d,J＝1.5Hz,1H),5.69(q,J＝6.2Hz,1H),4.73(s,2H),4.33–4.16(m,3H),2.88(t,J＝12.9Hz,2H),2.11(d,J＝10.2Hz,2H),1.91(qd,J＝12.2,4.2Hz,2H),1.67(d,J＝6.4Hz,3H),1.47(s,9H).
2) Synthesis of tert-butyl 4- (4- (6-methylamino-5- (1- (2-chloro-5-fluorophenyl) ethoxy) pyridin-3-yl) -1H-pyrazole) -1-yl) piperidine-1-carboxylate
Figure BDA0003047001850000162
The starting material (100mg, 0.1938mmol) and 60% NaH (12.40mg, 0.5167mmol) were added to a three-necked flask, N2After displacement, anhydrous DMF (4 mL) was added and stirred for 30min, methyl iodide (33.03mg, 0.2327 mmol) was added and the reaction was carried out at room temperature for about 8h, and the progress of the reaction was monitored by TLC. After the reaction is finished, pouring the reaction liquid into ice water, and adding saturated NH4Aqueous Cl solution, EA extraction, and organic phase, dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (PE: EA = 3) gave 44.17mg (43%) of a yellow solid.
1H-NMR(400MHz,DMSO)δ7.99(s,1H),7.82(d,J＝1.3Hz,1H),7.61(s,1H),7.56–7.49(m,2H),7.19(td,J＝8.5,3.1Hz,1H),6.97(d,J＝1.1Hz,1H),6.26(d,J＝4.8Hz,1H),5.82(q,J＝5.9Hz,1H),4.32(dd,J＝13.3,9.5Hz,1H),4.11–3.96(m,3H),2.87(d,J＝4.7Hz,3H),2.04–1.94(m,3H),1.82–1.72(m,2H),1.59(d,J＝6.2Hz,3H),1.41(s,9H).
3) Synthesis of Compound L-1
Figure BDA0003047001850000171
The starting material (200mg, 0.3773mmol) was dissolved in DCM (4 mL), TFA (1 mL) was added dropwise, and the reaction was carried out at room temperature for about 1h. After the reaction was complete, saturated NaHCO was used3Adjusting the pH value of the aqueous solution to 7-8, extracting by DCM, and washing by brine. After combining the organic phases, dried over anhydrous sodium sulfate, the product was purified by silica gel column chromatography (DCM: meOH = 20.
1H-NMR(400MHz,DMSO)δ7.94(s,1H),7.82(s,1H),7.58(s,1H),7.52(dd,J＝8.7,5.4Hz,2H),7.18(td,J＝8.5,3.0Hz,1H),6.96(s,1H),6.25(d,J＝4.6Hz,1H),5.82(q,J＝12.1,5.8Hz,1H),4.22–4.05(m,1H),3.02(d,J＝12.2Hz,2H),2.86(d,J＝4.6Hz,3H),2.57(t,J＝11.7Hz,2H),1.92(d,J＝10.8Hz,2H),1.81–1.68(m,2H),1.59(d,J＝6.2Hz,3H).13C NMR(151MHz,DMSO)δ161.05,149.89,142.64,139.70,135.70,135.09,131.66,126.71,123.86,119.64,117.22,116.64,114.70,114.43,71.84,59.66,45.60,34.11,28.33,22.19.
EXAMPLE 7 preparation of Compound L-2
Figure BDA0003047001850000172
The same preparation as that of compound L-1 was used, and the product was 20mg (51%) of a yellow solid.
1H-NMR(400MHz,DMSO)δ7.93(s,1H),7.80(s,1H),7.57(s,1H),7.57–7.48(m,2H),7.18(td,J＝8.5,3.1Hz,1H),6.98(s,1H),6.18(t,J＝5.6Hz,1H),5.82(q,J＝5.8Hz,1H),4.20–4.09(m,1H),3.42–3.38(m,2H),3.01(d,J＝12.2Hz,2H),2.60–2.53(m,2H),1.91(d,J＝11.3Hz,2H),1.74(dd,J＝20.2,11.4Hz,2H),1.61(d,J＝6.2Hz,3H),1.15(t,J＝7.0Hz,3H).13C-NMR(151MHz,DMSO)δ161.04,149.20,142.64,139.53,135.80,135.06,131.65,126.76,123.82,119.62,117.23,116.66,114.91,114.76,72.07,59.66,45.60,35.52,34.12,22.22,15.58.
EXAMPLE 8 preparation of Compound L-3
Figure BDA0003047001850000173
The same preparation as that of Compound L-1 was used, yielding 84mg (51%) of a pale yellow solid.
1H-NMR(400MHz,DMSO)δ9.81(s,1H),8.19(s,2H),7.74(s,1H),7.67(dd,J＝9.7,2.8Hz,1H),7.55(dd,J＝8.8,5.1Hz,1H),7.23(s,1H),7.22–7.13(m,1H),5.81(q,J＝6.2Hz,1H),4.24–4.12(m,1H),3.02(d,J＝12.4Hz,2H),2.57(t,J＝11.7Hz,2H),2.10(s,3H),1.94(d,J＝10.9Hz,2H),1.83–1.68(m,2H),1.56(d,J＝6.1Hz,3H).13C NMR(151MHz,DMSO)δ162.71,161.09,142.37,140.15,136.52,136.03,131.68,127.63,126.41,125.64,118.09,117.93,117.24,115.07,114.91,72.47,59.86,45.53,34.02,23.57,22.24.
EXAMPLE 9 preparation of Compound L-4
Figure BDA0003047001850000181
The same preparation as that of Compound L-1 was carried out to give 64.89mg (30%) of a yellow solid.
EXAMPLE 10 preparation of Compound X-6
1) Synthesis of 3- (1- (5-fluoro-2-chlorophenyl) ethoxy) -2-aminopyridine-5-boronic acid ester
Figure BDA0003047001850000182
5-bromo-3- (1- (2-chloro-5-fluorophenyl) ethoxy) -2-aminopyridine (150mg, 0.436 mmol), pinacol diboron (216mg, 0.851mmol), potassium acetate (129mg, 1.316 mmol) were charged into a 50mL single-neck flask, and 15mL of anhydrous 1, 4-dioxane was added to dissolve it sufficiently. Under nitrogen, a palladium catalyst (31.8mg, 0.043mmol) was added, and the mixture was stirred at 100 ℃ under reflux. The reaction was followed by TLC and ended after 8 hours. And (3) removing 1, 4-dioxane from the reaction solution, adding DCM to dissolve the system in a large amount, carrying out suction filtration on the obtained product by using kieselguhr, and concentrating the filtrate to obtain a black crude product which is directly put into the next step.
2) Synthesis of Compound X-6
Figure BDA0003047001850000183
2-bromothiazole (173mg, 0.504mmol), 3- (1- (5-fluoro-2-chlorophenyl) ethoxy) -2-aminopyridine-5-boronic acid ester (192mg, 0.756 mmol), cesium carbonate (246 mg,0.756 mmol) were placed in a 50mL three-necked flask, and 12mL of a mixed solution of ethylene glycol dimethyl ether and water (ethylene glycol dimethyl ether: water = 3) was added and the mixture was completely dissolved. Nitrogen was bubbled through to remove oxygen, palladium catalyst (20mg, 0.030mmol) was added, reflux stirring was performed at 80 ℃, the reaction was followed by TLC, and after 12 hours, the reaction was completed, the solvent was removed by rotary evaporation, and the reaction solution was purified by silica gel column chromatography (DCM: meOH = 100. The product was 54mg as a brown solid in 31.85% yield, m.p.: 205.7-206.4 ℃.
1H-NMR(400MHz,CDCl3):δ8.12(d,J＝1.8Hz,1H),7.69(d,J＝3.3Hz,1H),7.31(dd,J＝8.8Hz,J＝5.0Hz,1H),7.23(d,J＝1.7Hz,1H),7.15(d,J＝3.3Hz,1H),7.08(dd,J＝9.0Hz,J＝3.0Hz,1H),6.92-6.85(m,1H),5.73(q,J＝5.9Hz,1H),5.39(s,2H),1.63(d,J＝6.3Hz,3H).13C-NMR(151MHz,CDCl3):δ165.8,162.8,161.2,151.2,143.4,141.3,139.7,137.3,131.2,126.5,120.9,117.6,115.6,113.4,73.0,22.3.HRMS(ESI)(m/z):[M+H]+calcd for C16H14ClFN3OS,350.0452；found,350.0531.
EXAMPLE 11 preparation of Compound X-7
Figure BDA0003047001850000191
By the same preparation method as that of the compound X-6, the product was 40mg (35.40%) of a yellow solid, melting point: 209.6-210.2 ℃.
1H-NMR(400MHz,CDCl3):δ7.94(s,1H),7.33(s,1H),7.26(dd,J＝8.8Hz,J＝5.0Hz,1H),7.11(d,J＝3.0Hz,1H),7.05(d,J＝1.4Hz,1H),6.85(ddd,J＝8.7Hz,J＝7.7Hz,J＝3.1Hz,2H),5.68(q,J＝6.3Hz,1H),4.85(s,2H),3.60(s,3H),1.59(d,J＝6.3Hz,3H).13C-NMR(151MHz,CDCl3):δ162.8,161.2,148.2,140.9,138.3,131.2,129.0,126.4,116.8,116.7,116.6,115.6,113.7,113.6,73.4,33.7,22.2.HRMS(ESI)(m/z):[M+H]+calcd for C17H17ClFN4O,347.0997；found,347.1076.
EXAMPLE 12 preparation of Compound X-8
Figure BDA0003047001850000192
Using the same preparation method as compound X-6, the product was 46mg (31.57%) of a light brown solid, melting point: 213.5-214.2 ℃.
1H-NMR(400MHz,CDCl3):δ7.97(d,J＝1.4Hz,1H),7.53(s,1H),7.30(dd,J＝8.8Hz,J＝5.0Hz,1H),7.09(dd,J＝9.1Hz,J＝3.0Hz,1H),7.00(d,J＝1.5Hz,1H),6.90-6.84(m,1H),5.69(q,J＝6.3Hz,1H),4.98(s,2H),4.11(s,3H),1.62(d,J＝6.3Hz,3H).13C-NMR(151MHz,CDCl3):δ162.8,161.2,150.1,145.5,141.5,139.9,136.2,131.1,130.1,126.2,116.5,115.6,113.6,72.8,41.7,22.4.HRMS(ESI)(m/z):[M+H]+calcd for C16H16ClFN5O,348.0949；found,348.1028.
EXAMPLE 13 preparation of Compound X-9
Figure BDA0003047001850000201
By the same preparation method as that of the compound X-6, the product was 40mg (35.40%) of a dark brown solid, melting point: 215.3-215.9 ℃.
1H-NMR(600MHz,DMSO-d6):δ11.67(s,1H),7.92(s,1H),7.49(ddd,J＝13.7Hz,J＝9.0Hz,J＝2.1Hz,3H),7.34(s,1H),7.27(d,J＝5.0Hz,1H),7.19-7.14(m,1H),6.21(t,J＝6.6Hz,1H),6.03(s,2H),5.72(q,J＝6.0Hz,1H),1.58(d,J＝6.3Hz,3H).13C-NMR(151MHz,DMSO-d6):δ162.7,161.7,161.0,151.1,142.8,139.0,136.7,133.9,131.6,128.0,126.6,121.6,118.0,117.1,114.4,105.9,71.9,22.3.HRMS(ESI)(m/z):[M+H]+calcd for C18H16ClFN3O2,360.0837；found,360.0916.
EXAMPLE 14 preparation of Compound X-10
Figure BDA0003047001850000202
By the same preparation method as that of the compound X-6, the product was 38mg (32.19%) of a black solid, melting point: 219.2-219.9 ℃.
1H-NMR(400MHz,DMSO-d6):δ7.94(s,1H),7.63(dd,J＝6.7Hz,J＝1.9Hz,1H),7.55(dd,J＝9.6Hz,J＝3.1Hz,1H),7.49(dd,J＝8.9Hz,J＝5.1Hz,1H),7.45(dd,J＝7.0Hz,J＝2.0Hz,1H),7.32(d,J＝1.6Hz,1H),7.17(td,J＝8.5Hz,J＝3.1Hz,1H),6.24(t,J＝6.8Hz,1H),6.12(s,2H),5.75(q,J＝6.1Hz,1H),3.45(s,3H),1.58(d,J＝6.3Hz,3H).13C-NMR(151MHz,DMSO-d6):δ162.6,161.3,150.7,142.5,138.7,138.4,136.3,131.7,127.0,126.6,121.7,118.5,117.1,117.0,114.6,105.9,72.1,38.0,22.1.HRMS(ESI)(m/z):[M+H]+calcd for C19H18ClFN3O2,374.0993；found,374.1073.
EXAMPLE 15 preparation of Compound X-11
Figure BDA0003047001850000211
By the same preparation method as that of the compound X-6, the product was 68mg (40.58%) of a yellow solid, melting point: 217.3-218.1 deg.C.
1H-NMR(400MHz,CDCl3):δ7.81(s,1H),7.69(d,J＝7.7Hz,1H),7.57(td,J＝7.7Hz,J＝1.3Hz,1H),7.35(dt,J＝8.8Hz,J＝6.4Hz,3H),7.17(dd,J＝9.1Hz,J＝3.0Hz,1H),6.98-6.90(m,2H),5.72(q,J＝6.3Hz,1H),5.03(s,2H),1.69(d,J＝6.3Hz,3H).13C-NMR(151MHz,CDCl3):δ162.86,161.22,150.23,142.22,141.40,139.46,138.30,133.91,132.91,131.22,129.56,127.36,126.30,124.25,118.01,116.47,113.39,111.01,73.17,22.39.HRMS(ESI)(m/z):[M+H]+calcd for C20H16ClFN3O,367.0888；found,367.0923.
EXAMPLE 16 preparation of Compound X-15
Figure BDA0003047001850000212
By the same preparation method as that of the compound X-6, the product was 35.97mg (17.68%) of a yellow solid, melting point: 227.9-228.5 ℃.
1H-NMR(400MHz,CDCl3):δ8.18(d,J＝2.3Hz,1H),7.79(d,J＝1.7Hz,1H),7.48(dd,J＝8.8Hz,J＝2.5Hz,1H),7.35(dd,J＝8.8Hz,J＝5.0Hz,1H),7.15(dd,J＝9.1Hz,J＝3.0Hz,1H),6.97-6.90(m,1H),6.77(d,J＝1.6Hz,1H),6.65(d,J＝8.8Hz,1H),5.70(q,J＝6.2Hz,1H),4.82(s,2H),3.55-3.49(m,4H),3.03-2.95(m,4H),1.67(d,J＝6.3Hz,3H).13C-NMR(151MHz,CDCl3):δ162.84,161.20,158.56,149.04,145.33,139.96,136.49,135.43,131.12,126.21,124.73,123.75,116.46,115.94,113.64,107.00,72.65,46.12,45.65,22.53.HRMS(ESI)(m/z):[M+H]+calcd for C22H24ClFN5O,428.1575；found,428.1654.
EXAMPLE 17 preparation of Compound L-5
Figure BDA0003047001850000221
4-pyrazole boronic acid pinacol ester (100.00mg, 0.5154mmol), N-chloroethyl pyrrolidine hydrochloride (175.30mg, 1.0307mmol) and Cs2CO3(503.77mg, 1.5462mmol) was added to the reaction flask, dissolved by adding acetonitrile (4 mL), and allowed to warm to 78 deg.C for about 10h. The reaction solution was then extracted three times with EA, washed with brine, the organic phases were combined and dried over anhydrous sodium sulfate, the solvent was dried by spinning, and the reaction was carried out in the next step without purification.
The crude product from the previous step was transferred to a reaction flask and 5-bromo-3- (1- (2-chloro-5-fluorophenyl) ethoxy) -2-aminopyridine (178.12mg, 0.5154mmol), pdCl2(dppf) (37.71mg, 0.05154mmol) and Cs2CO3(587.75mg, 1.8039mmol) was placed in a 50mL three-necked flask, 5mL of a mixed solution of toluene and water (toluene: water =4: 1) was added, and the mixture was heated to 80 ℃ under nitrogen atmosphere and stirred under reflux for about 5 hours. TLC to monitor the progress of the reaction, after the reaction is finished, the reaction solution is dried by spinning, EA is extracted, and silica gel column Chromatography (CH)2Cl2MeOH = 40) to yield 98.50mg (44.45%) of a light brown solid.
1H-NMR(400MHz,DMSO)δ7.91(s,1H),7.73(s,1H),7.59(s,1H),7.56(d,J＝7.9Hz,1H),7.50(dd,J＝8.5,5.1Hz,1H),7.18(t,J＝6.9Hz,1H),6.99(s,1H),5.87(s,2H),5.81(q,J＝6.0Hz,1H),4.16(t,J＝6.1Hz,2H),2.79(t,J＝6.1Hz,2H),2.44(s,4H),1.65(s,4H),1.59(d,J＝5.9Hz,3H).13C-NMR(151MHz,DMSO)δ162.68,161.06,150.31,142.68,139.24,136.01,135.42,131.59,126.36,119.76,117.80,117.05,115.71,114.63,71.89,55.80,53.95,51.16,23.60,22.28.LC-MS(m/z):430.20/431.20/432.20(M+H)+.
EXAMPLE 18 preparation of Compound L-6
Figure BDA0003047001850000222
The same preparation as that of compound L-5 was used, and the product was 45.05mg (45.00%) of a light brown solid.
1H-NMR(400MHz,DMSO)δ7.88(s,1H),7.73(s,1H),7.59(s,1H),7.55(dd,J＝9.5,2.4Hz,1H),7.52–7.46(m,1H),7.22–7.12(m,1H),6.98(s,1H),5.88(s,2H),5.82(q,1H),4.15(t,J＝6.3Hz,2H),2.62(t,J＝6.4Hz,2H),2.34(m,4H),1.59(d,J＝6.0Hz,3H),1.52–1.40(m,4H),1.40–1.31(m,2H).13C-NMR(151MHz,DMSO)δ162.68,161.06,150.31,142.72,139.25,135.99,135.42,131.59,126.38,119.74,117.82,117.18,115.65,114.74,71.90,58.65,54.43,49.63,26.05,24.42,22.29.LC-MS(m/z):444.20/445.15/446.20(M+H)+.
EXAMPLE 19 preparation of Compound L-7
Figure BDA0003047001850000231
The same preparation as that of compound L-5 was used, and the product was 65.25mg (44.50%) as a light brown solid.
1H-NMR(400MHz,DMSO)δ7.91(s,1H),7.73(s,1H),7.60(s,1H),7.55(dd,J＝9.6,2.9Hz,1H),7.50(dd,J＝8.8,5.1Hz,1H),7.18(td,J＝8.4,3.0Hz,1H),6.98(s,1H),5.88(s,2H),5.81(q,J＝6.0Hz,1H),4.18(t,J＝6.4Hz,2H),3.58–3.50(m,4H),2.68(t,J＝6.4Hz,2H),2.39(s,4H),1.60(d,J＝6.2Hz,3H).13C-NMR(151MHz,DMSO)δ162.68,161.06,150.34,142.72,139.24,136.03,135.49,131.54,126.45,119.78,117.78,117.20,115.69,114.61,71.90,66.64,58.23,53.61,49.18,40.40,40.26,40.12,39.98,39.84,39.71,39.57,22.29.LC-MS(m/z):446.20/447.20/448.20(M+H)+.
EXAMPLE 20 preparation of Compound L-8
Figure BDA0003047001850000232
The same preparation as that of compound L-5 was used, and the product was 28.07mg (51.56%) of a pale yellow solid.
1H-NMR(400MHz,DMSO)δ12.84(s,1H),8.08(s,1H),7.80(s,1H),7.72(s,1H),7.65–7.55(m,1H),7.48(s,2H),7.17(s,2H),5.95–5.79(m,3H),4.23–4.04(m,1H),3.03(d,J＝11.9Hz,2H),2.58(t,J＝11.9Hz,2H),1.95(d,J＝11.6Hz,2H),1.85–1.73(m,2H),1.69(d,J＝6.2Hz,3H).13C-NMR(151MHz,DMSO)δ158.54,158.34,154.96,150.47,139.46,136.15,135.26,124.13,119.66,118.20,116.77,71.10,59.61,45.54,34.05,20.75.LC-MS(m/z):404.20(M+H)+.
EXAMPLE 21 preparation of Compound L-9
Figure BDA0003047001850000233
The same preparation as that of compound L-5 was used, and the product was 67.07mg (48.50%) of a pale yellow solid.
1H-NMR(400MHz,DMSO)δ8.63(s,1H),8.44(d,J＝1.0Hz,1H),8.20(s,2H),7.74(d,J＝8.3Hz,1H),7.51–7.41(m,1H),7.31–7.21(m,1H),6.55(q,J＝6.1Hz,1H),4.49–4.36(m,1H),4.14–3.98(m,3H),2.08(d,J＝11.8Hz,2H),1.98(s,1H),1.91(d,J＝6.3Hz,3H),1.87–1.72(m,2H),1.53(s,9H),1.42(s,9H).
EXAMPLE 22 preparation of Compound X-12
Figure BDA0003047001850000241
The same preparation as that of compound L-5 was carried out, and the product was 66mg (34.38%) of a brown oily liquid. Melting point: 221.8-222.7 ℃.
1H-NMR(400MHz,DMSO-d6):δ8.28(d,J＝2.9Hz,1H),8.16(d,J＝1.5Hz,1H),7.68(d,J＝8.8Hz,1H),7.56-7.53(m,1H),7.53-7.49(m,1H),7.47(d,J＝1.5Hz,1H),7.42(dd,J＝8.8Hz,J＝2.9Hz,1H),7.17(td,J＝8.5Hz,J＝3.1Hz,1H),6.19(s,2H),5.83(q,J＝6.1Hz,1H),4.28(t,J＝5.2Hz,2H),3.16(s,2H),2.89(s,4H),1.80(s,4H),1.60(d,J＝6.3Hz,3H).13C-NMR(151MHz,CDCl3):δ162.8,161.2,152.9,150.1,148.8,141.9,139.8,137.6,137.4,131.1,126.4,125.8,122.2,119.7,116.4,116.1,72.6,65.7,54.6,54.4,23.4,22.3.HRMS(EI)(m/z):[M]+calcd for C24H26ClFN4O2,456.1728；found,456.1729.
EXAMPLE 23 preparation of Compound X-13
Figure BDA0003047001850000242
The same preparation as that of compound L-5 was used, and the product was 58mg (25.29%) of a brown oily liquid. Melting point: 228.5-229.7 ℃.
1H-NMR(400MHz,CDCl3):δ8.41(d,J＝5.7Hz,1H),8.23(s,1H),7.38(d,J＝1.7Hz,1H),7.37-7.34(m,1H),7.17(dd,J＝9.1Hz,J＝3.0Hz,1H),6.99(d,J＝2.3Hz,1H),6.96-6.90(m,1H),6.69(dd,J＝5.7Hz,J＝2.3Hz,1H),5.82(q,J＝6.2Hz,1H),5.04(s,2H),4.41(t,J＝5.2Hz,2H),3.25(t,J＝5.1Hz,2H),3.05(s,4H),2.03-1.99(m,4H),1.68(d,J＝6.3Hz,3H).13C-NMR(151MHz,CDCl3):δ165.23,162.91,161.27,157.22,151.04,150.85,141.96,139.75,138.26,131.18,126.54,126.09,116.48,113.81,108.27,105.90,72.72,66.13,54.79,54.55,23.56,22.41.HRMS(ESI)(m/z):[M+H]+calcd for C24H27ClFN4O2,457.1728；found,457.1806.
EXAMPLE 24 preparation of Compound X-14
Figure BDA0003047001850000251
The same preparation as that of compound L-5 was carried out, and the product was 58mg (21.62%) as a brown oily liquid. Melting point: 224.4-225.1 ℃.
1H-NMR(400MHz,CDCl3):δ7.68(d,J＝1.8Hz,1H),7.38(dd,J＝8.8Hz,J＝4.9Hz,1H),7.36-7.32(m,2H),7.16(dd,J＝9.1Hz,J＝3.0Hz,1H),6.97(ddd,J＝10.8Hz,J＝6.8Hz,J＝2.4Hz,1H),6.67(d,J＝1.7Hz,1H),6.58(d,J＝10.2Hz,1H),5.70(q,J＝6.2Hz,1H),4.83(s,2H),4.12(t,J＝6.4Hz,2H),2.90(t,J＝6.7Hz,2H),2.66(s,4H),1.81(s,4H),1.68(d,J＝6.4Hz,3H).13C-NMR(151MHz,CDCl3):δ162.89,161.68,161.25,149.36,141.62,139.89,138.91,136.11,134.50,131.11,126.24,122.97,120.93,116.66,115.58,113.77,72.67,54.28,48.72,29.70,23.65,22.50.HRMS(ESI)(m/z):[M+H]+calcd for C24H27ClFN4O2,457.1728；found,457.1806.
EXAMPLE 25 preparation of Compound X-16
Figure BDA0003047001850000252
The same preparation as that of compound L-5 was used, and the product was 48mg (24.49%) of a brown oily liquid. Melting point: 225.6-226.3 ℃.
1H-NMR(400MHz,CDCl3):δ8.28(d,J＝2.8Hz,1H),8.12(d,J＝1.3Hz,1H),7.48(d,J＝1.5Hz,1H),7.43-7.29(m,6H),7.21(dd,J＝8.7Hz,J＝2.9Hz,1H),5.49(q,J＝6.3Hz,1H),5.01(s,2H),4.33(t,J＝5.2Hz,2H),3.19(t,J＝5.1Hz,2H),2.99(s,4H),1.96(s,4H).13C-NMR(151MHz,CDCl3):δ148.26,145.85,143.98,137.38,135.73,132.72,131.98,124.01,123.13,120.88,117.44,114.96,111.71,72.59,72.37,72.16,71.67,61.19,49.87,49.71,19.19,18.62.HRMS(ESI)(m/z):[M+H]+calcd for C24H29N4O2,404.2212；found,405.2292.
EXAMPLE 26 preparation of Compound X-17
Figure BDA0003047001850000253
The same preparation as that of compound L-5 was used, and the product was 35.97mg (17.68%) of a yellow solid. Melting point: 219.2-219.9 ℃.
1H-NMR(400MHz,CDCl3):δ7.78(s,1H),7.68(s,1H),7.61(t,J＝8.6Hz,2H),7.50(t,J＝3.8Hz,2H),7.47(s,1H),6.78(s,1H),5.39(q,J＝6.4Hz,1H),4.78(s,2H),4.23(tt,J＝11.4Hz,J＝3.9Hz,1H),3.29(d,J＝12.7Hz,2H),2.86-2.76(m,2H),2.18(d,J＝11.4Hz,2H),1.96(qd,J＝12.1Hz,J＝3.9Hz,2H),1.69(d,J＝6.4Hz,3H).13C-NMR(101MHz,CDCl3):δ149.05,143.81,139.96,136.33,135.84,131.71,129.88,129.82,129.06,122.89,119.80,119.34,118.51,116.64,113.07,75.58,59.26,45.22,33.26,24.09.HRMS(ESI)(m/z):[M+H]+calcd for C22H25N6O,389.2012；found,389.2091.
EXAMPLE 26 preparation of Compound X-18
Figure BDA0003047001850000261
The same preparation as that of compound L-5 was used, and the product was 33mg (19.41%) of a yellow solid. Melting point: 223.2-223.8 ℃.
1H-NMR(400MHz,CDCl3):δ7.97(s,1H),7.80(s,1H),7.74(d,J＝7.6Hz,1H),7.60(d,J＝11.7Hz,3H),7.42(t,J＝7.6Hz,1H),7.06(s,1H),5.59(dd,J＝12.1Hz,J＝5.8Hz,1H),4.35(td,J＝10.7Hz,J＝5.2Hz,1H),3.35(d,J＝13.0Hz,2H),2.96(dd,J＝17.3Hz,J＝7.3Hz,2H),2.16(d,J＝12.8Hz,2H),2.06(d,J＝11.8Hz,2H),1.67(d,J＝6.3Hz,3H).13C-NMR(151MHz,CDCl3):δ170.70,149.84,143.02,140.49,135.60,134.06,133.07,128.94,128.66,126.71,125.09,124.32,119.93,118.45,116.75,75.89,57.02,48.46,43.54,30.50,22.80.HRMS(ESI)(m/z):[M+H]+calcd for C22H27N6O2,407.2117；found,407.2194.
Experimental example 8 JAK2 inhibitor molecular level Activity test
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 fluorophores coumarin and fluorescein. Based on fluorescence energy resonance transfer (FRET) method, JAK2 catalyzes ATP to react to cause two fluorophores to approach, a donor (coumarin) is excited at 400nM, part of the energy is released, the emission wavelength is 445nM, and the other part of the energy is transferred to fluoroscein, the emission wavelength is 520nM. Different compounds inhibit JAK2 to different degrees, resulting in different degrees of phosphorylation of the substrate, so that the inhibition rate of different compounds can be calculated by measuring 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 1h; 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. Fedratinib is used as a positive control in the experimental process, and at least three parallels are set in each experiment.
TABLE 1 Activity of Compounds on JAK2 in vitro enzyme assays
Figure BDA0003047001850000271
Figure BDA0003047001850000272
Figure BDA0003047001850000281
Figure BDA0003047001850000291
The results show that the compounds of the present invention have good JAK2 inhibitory activity.
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. The half inhibition rate of the compounds on cell proliferation of SET2, HEL and BaF3_ JAK 2V 617F was measured by CCK-8 method.
The experimental method comprises the following steps:
culturing the cells using RPIM medium containing 10% FBS, adding 100. Mu.L per well, inoculating 3500 cells to a 96-well plate, placing at 37 deg.C, 5%2Culturing 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.
Note: HEL, SET-2, baF3 u JAK2 V617F cells were all purchased from ATCC (American type culture collection), Z' -LYTETM kinase assay platform from Invitrogen, HTRF KinEASETM-TK from Cisbio, cell Counting Kit-8 from Byunyun.
Figure BDA0003047001850000292
Figure BDA0003047001850000301
The results show that the compounds of the present invention have good SET2, HEL and BaF3_ JAK 2V 617F cell proliferation inhibitory activities.
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 (10)

1. A compound shown as the following formula I, or a stereoisomer or an optical isomer, a pharmaceutically acceptable salt, a prodrug or a solvate thereof,
Figure FDA0003047001840000011
in the formula (I), the compound is shown in the specification,
R1selected from the group consisting of: hydrogen, halogen, C1-C10Alkyl, halo C1-C10Alkyl radical, C1-C10Alkoxy, halo C1-C10Alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted 5 or 6 membered nitrogen containing heterocycle; wherein said substitution means that one or more hydrogen atoms on the above groups are substituted by a group selected from the group consisting of: c1-C10Alkyl, 5-to 7-membered ring containing one or two heteroatoms selected from nitrogen or oxygen or sulfur, halogeno C1-C10Alkyl, hydroxy, cyano, substituted or unsubstituted (C)1-C10Alkyl-5-to 7-membered rings containing one or two heteroatoms selected from nitrogen or oxygen or sulfur), or substituted or unsubstituted (C)1-C10Alkoxy-a 5-7 membered ring containing one or two heteroatoms selected from nitrogen or oxygen or sulfur);
R2selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted pyrimidine, substituted or unsubstituted C5-C7Cycloalkyl, substituted or unsubstituted indole, substituted or unsubstituted benzimidazole; the substitution means that one or more hydrogen atoms on the above groups are substituted by a group selected from the group consisting of: hydrogen, halogen, cyano, amido (C (O) NH)2)、C1-C3Alkyl, halo C1-C3Alkyl radical, C1-C3Alkoxy, halo C1-C3An alkoxy group;
R3selected from the group consisting of: hydrogen, halogen, C1-C10Alkyl, halo C1-C10Alkyl, hydroxy, C1-C10An alkoxy group;
R4selected from the group consisting of: hydrogen, C1-C10Straight or branched alkyl, C1-C10An acyl group;
x is selected from the group consisting of: CH (CH)2、O、NH、S、SO、SO2；
Unless otherwise specified, the substitution refers to the substitution of one or more hydrogen atoms on the group with a substituent selected from the group consisting of: halogen, C1-C10An alkyl group.
2. The compound of claim 1, or a stereoisomer or optical isomer thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein R is1Selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted 5-or 6-membered nitrogen-containing heterocycle; wherein said substitution means that one or more hydrogen atoms on the above groups are substituted by a group selected from the group consisting of: c1-C4Alkyl, a 5-to 7-membered ring containing one or two heteroatoms selected from nitrogen or oxygen or sulfur, substituted or unsubstituted (C)1-C4Alkyl-a 5-to 7-membered ring containing one or two heteroatoms selected from nitrogen or oxygen or sulfur), or substituted or unsubstituted (C)1-C4Alkoxy-a 5-to 7-membered ring containing one or two heteroatoms selected from nitrogen or oxygen or sulfur).
3. The compound of claim 1, or a stereoisomer or optical isomer thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the compound is according to formula II:
Figure FDA0003047001840000021
in the formula
R1、R2、R4Is as defined in claim 1.
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 compound is according to formula III:
Figure FDA0003047001840000022
in the formula (I), the compound is shown in the specification,
ring A is selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-or 6-membered nitrogen-containing heterocycle;
R5selected from the group consisting of: - (CH)2)p- (5-to 7-membered ring containing one or two hetero atoms selected from nitrogen or oxygen or sulfur), -O (CH)2)p- (5-to 7-membered rings containing one or two heteroatoms selected from nitrogen or oxygen or sulphur); wherein p is 0, 1 or 2.
5. The compound of claim 4, or a stereoisomer or optical isomer thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein R is5Selected from the group consisting of:
Figure FDA0003047001840000023
wherein x is 1, 2 or 3.
6. The compound of claim 4, or a stereoisomer or optical isomer thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein ring a is selected from the group consisting of: phenyl, pyrrole, pyrazole, pyridine, imidazole, thiazole and triazole.
7. The compound of claim 1, 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 FDA0003047001840000031
Figure FDA0003047001840000041
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 7, 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, endometrial cancer, cervical cancer, vaginal cancer, vulval cancer, hodgkin's disease, non-hodgkin's lymphoma, esophageal cancer, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, pediatric solid tumors, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, central Nervous System (CNS) tumors, primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brain stem glioma, pituitary adenoma, 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, type b and type c), herpes viruses, 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.
CN202110474822.3A 2021-04-29 2021-04-29 Compounds as JAK2 inhibitors and uses thereof Pending CN115260156A (en)

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