Compounds containing a geminal difluoro group, methods for producing the same, and uses

Abstract

This application provides a compound represented by formula (I), its chiral enantiomer or a pharmaceutically acceptable salt thereof and a method for producing the same, an intermediate for producing the compound represented by formula (I), its chiral enantiomer or a pharmaceutically acceptable salt thereof and a method for producing the same, a pharmaceutical composition containing the compound represented by formula (I), its chiral enantiomer or a pharmaceutically acceptable salt thereof, and a pharmaceutical use of the compound represented by formula (I), its chiral enantiomer or a pharmaceutically acceptable salt thereof or its pharmaceutical composition. The compound of this application has good JAK2 kinase inhibitory activity and high selectivity for JAK2 kinase. In addition, the compound of this application has obvious pharmacokinetic advantages, providing more options for the prevention and / or treatment of diseases related to abnormalities in the JAK signaling pathway, and having good prospects for clinical application. 【Chemical 1】 TIFF2025521655000030.tif45170(I)

Description

Cross-reference of related applications

[0001] This application claims priority to the Chinese patent application filed on 5 July 2022, application number 202210784219.X, with the title of the invention "Compounds Containing Geminal Difluoro Groups, Methods for Producing the Same and Uses," which is incorporated herein by reference in its entirety. [Technical Field]

[0002] This application relates to the field of medicinal chemistry, and more specifically to compounds containing a geminal difluoro group, methods for producing the same, and uses thereof. [Background technology]

[0003] Janus kinase (JAK) is a type of tyrosine kinase, and the JAK family includes four members: JAK1, JAK2, JAK3, and TYK2. JAKs all play important roles in the signaling processes of various cytokines.

[0004] Signal transducers and activators of transcription (STATs) are a series of cytoplasmic proteins that can bind to target gene regulatory regions in DNA. As a downstream substrate of JAKs, STATs are activated by tyrosine phosphorylation under external signaling stimulation, and then translocate to the nucleus to regulate gene transcription.

[0005] Many abnormal immune responses, including allergies, asthma, allograft rejection, autoimmune diseases such as rheumatoid arthritis and multiple sclerosis, myeloproliferative disorders, and hematological malignancies such as leukemia and lymphoma, are all related to abnormal regulation of the JAK / STAT signaling pathway.

[0006] JAK protein kinase inhibitors, particularly JAK3 protein kinase inhibitors, not only inhibit T cell activation and prevent transplant rejection after transplant surgery, but are also effective against autoimmune diseases (such as rheumatoid arthritis and multiple sclerosis). Furthermore, research has revealed that myeloproliferative neoplastic disorders (including essential thrombocythemia, polycythemia vera, and primary myelofibrosis) are related to abnormal activity due to mutations in JAK2 kinase. Therefore, developing JAK2 protein kinase inhibitors has significant medical value for the treatment of myeloproliferative neoplastic disorders and is expected to have a large market.

[0007] Ruxolitinib is a selective JAK1 / 2 kinase inhibitor that was approved by the US FDA on November 16, 2011, and is marketed under the brand name Jakafi. It is the first drug for the treatment of primary myelofibrosis (PMF) in the United States. However, it does not have high selectivity for JAK2 kinase, has a short half-life, and has low exposure levels.

[0008] Therefore, it is still necessary to develop new compounds that have high selectivity for JAK2 kinase and better pharmacokinetic properties. [Overview of the project] [Problems that the invention aims to solve]

[0009] An object of the present application is to provide a compound represented by formula (I), a chiral enantiomer thereof or a pharmaceutically acceptable salt thereof, and a method for producing the same; an intermediate for producing the compound represented by formula (I), a chiral enantiomer thereof or a pharmaceutically acceptable salt thereof, and a method for producing the same; a pharmaceutical composition comprising the compound represented by formula (I), a chiral enantiomer thereof or a pharmaceutically acceptable salt thereof; and a pharmaceutical use of the compound represented by formula (I), a chiral enantiomer thereof or a pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof. The compound of the present application has good JAK2 kinase inhibitory activity and high selectivity for JAK2 kinase. Furthermore, the compound of the present application has obvious pharmacokinetic advantages, provides more options for the prevention and / or treatment of diseases associated with abnormal JAK signaling pathway (in particular, autoimmune diseases, myeloproliferative neoplastic diseases, graft-versus-host disease), and has promising prospects for good clinical application. [Means for Solving the Problem]

[0010] In a first aspect, the present application provides a compound represented by formula (I), a chiral enantiomer thereof or a pharmaceutically acceptable salt thereof. [Chemical formula] (I) In formula (I), A is an alkyl group or a cycloalkyl group, with the proviso that said alkyl group or said cycloalkyl group is optionally substituted by fluorine, an alkyl group or a cycloalkylene group, and said alkyl group, said cycloalkyl group or said cycloalkylene group has at least one pair of geminal difluoro groups, X is H or (CH2) n with the proviso that n is 0, 1, 2, 3, 4 or 5, and when X is (CH2) n X is linked to A to form a C3~C7 cycloalkylene group, said cycloalkylene group is optionally substituted by fluorine or an alkyl group, and said cycloalkylene group or said alkyl group has at least one pair of geminal difluoro groups.

[0011] In a preferred embodiment, the present application provides a compound represented by formula (II), a chiral enantiomer thereof, or a pharmaceutically acceptable salt thereof.

Chemical Structure

[0012] As a preferred specific embodiment, in the above formula (II), Y1 is CR1, wherein R1 is a bond, Z is a bond or (CH2) m , wherein m is 1, 2 or 3, Y2 is an alkylene group, X is (CH2) n , wherein n is 0, 1, 2, 3, 4 or 5, and X is bonded to Y1 to form a C3~C7 cycloalkylene group, preferably a C6 cycloalkylene group.

[0013] As another preferred specific embodiment, in the above formula (II), Y1 is CR1, wherein R1 is F, Z is a bond or (CH2) m, wherein m is 1, 2 or 3, Y2 is an alkylene group, preferably a C1-C5 alkylene group, more preferably a C2-C3 alkylene group, X is H.

[0014] In another preferred specific embodiment, in the above formula (II), Y1 is CR1, wherein R1 is F, Z is a bond or (CH2) m , wherein m is 1, 2 or 3, Y2 is an alkylene group, X is (CH2) n , wherein n is 1, 2, 3, 4 or 5, and X is linked to Z to form a C3-C7 cycloalkylene group, preferably a C6 cycloalkylene group.

[0015] In another preferred specific embodiment, in the above formula (II), Y1 is CR1, wherein R1 is a bond, Z is a bond or (CH2) m , wherein m is 1, 2 or 3, Y2 is an alkylene group, and Y2 is linked to Y1 to form a C3-C7 cycloalkylene group, preferably a C4 or C6 cycloalkylene group, X is H.

[0016] In another preferred specific embodiment, in the above formula (II), Y1 is CR1, wherein R1 is F, Z is (CH2) m , wherein m is 1, 2 or 3, Y2 is an alkylene group, and Y2 is linked to Z to form a C3-C7 cycloalkylene group, preferably a C6 cycloalkylene group, X is H.

[0017] In another preferred specific embodiment, in the above formula (II), Y1 is CR1, however R1 is F. Z represents a bond or (CH2) m And, however, m is 1, 2, or 3, Y2 is an alkylene group or a cycloalkylene group, and is optionally substituted with an alkyl group, a cycloalkyl group, or a cycloalkylene group. X is H.

[0018] In preferred embodiments, the present application provides the following compounds, their chiral enantiomers, or pharmaceutically acceptable salts thereof. [ka]

[0019] In the second embodiment, the present application Step (1) involves a reaction in which compound III-1 and diethyl cyanomethylphosphonate undergo an olefination reaction in the presence of a base to produce compound III-2, Step (2) involves a Michael addition reaction between compound III-2 and compound III-3 under the presence of a base and heating to produce compound III, The present invention provides a method for producing the compound described in the first embodiment, its chiral enantiomer, or a pharmaceutically acceptable salt thereof, comprising the step (3) of compound III removing a protecting group in the presence of a base to produce compound I. [ka]

[0020] In a preferred embodiment, in step (1), the base is selected from one or more of sodium hydride, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, lithium bromide, lithium chloride, triethylamine, 4-dimethylaminopyridine, cesium carbonate, potassium carbonate, and sodium carbonate, and the solvent in step (1) is an aprotic solvent, preferably one or more of the solvent selected from tetrahydrofuran, dimethylformamide, and dimethyl sulfoxide. In step (2), the base is selected from one or more of 1,8-diazabicycloundec-7-ene (1,8-diazabicyclo[5.4.0]undec-7-ene), sodium tert-butoxide, potassium tert-butoxide, triethylamine, 4-dimethylaminopyridine, cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, and sodium phosphate; in step (2), the solvent is a protic or aprotic solvent, preferably one or more of acetonitrile, N-methylpyrrolidone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methanol, and ethanol; and in step (2), the heating temperature is 52-82°C. In step (3), the base is selected from one or more of sodium hydroxide, lithium hydroxide, and potassium hydroxide.

[0021] In a third embodiment, the present application provides an intermediate having a structure represented by general formula (III) for producing the compound described in the first embodiment, its chiral enantiomer, or a pharmaceutically acceptable salt thereof. [ka] (III) In formula (III), A is an alkyl group or a cycloalkyl group, wherein the alkyl group or cycloalkyl group is optionally substituted with a fluorine, alkyl group or cycloalkylene group, and the alkyl group, cycloalkyl group or cycloalkylene group has at least one pair of geminal difluoro groups. X is H or (CH2). n And so on, where n is 0, 1, 2, 3, 4 or 5, and X is (CH2) n In this case, X is linked to A to form a C3-C7 cycloalkylene group, the cycloalkylene group is optionally substituted with fluorine or an alkyl group, and the cycloalkylene group or the alkyl group has at least one pair of geminal difluoro groups.

[0022] In the fourth embodiment, Step (1) involves a reaction in which compound III-1 and diethyl cyanomethylphosphonate undergo an olefination reaction in the presence of a base to produce compound III-2, The present invention provides a method for producing the intermediate according to the third embodiment, comprising the step (2) of a Michael addition reaction between compound III-2 and compound III-3 under the presence of a base and heating to produce compound III. [ka]

[0023] In a preferred embodiment, in step (1), the base is selected from one or more of sodium hydride, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, lithium bromide, lithium chloride, triethylamine, 4-dimethylaminopyridine, cesium carbonate, potassium carbonate, and sodium carbonate, and the solvent in step (1) is an aprotic solvent, preferably one or more of the solvent selected from tetrahydrofuran, dimethylformamide, and dimethyl sulfoxide. In step (2), the base is selected from one or more of 1,8-diazabicycloundeca-7-ene, sodium tert-butoxide, potassium tert-butoxide, triethylamine, 4-dimethylaminopyridine, cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, and sodium phosphate; in step (2), the solvent is a protic or aprotic solvent, preferably selected from one or more of acetonitrile, N-methylpyrrolidone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methanol, and ethanol; and in step (2), the heating temperature is 52 to 82°C.

[0024] In a fifth embodiment, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of the compound described in the first embodiment, its chiral enantiomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, and / or excipient.

[0025] In a sixth embodiment, the present application provides uses for the compound described in the first embodiment, its chiral enantiomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in the fifth embodiment, in the manufacture of a drug for preventing and / or treating a disease associated with abnormalities in the JAK signaling pathway.

[0026] Preferably, the disease is an autoimmune disease, a myeloproliferative neoplastic disease, or a graft-versus-host disease.

[0027] More preferably, the autoimmune disease is selected from rheumatoid arthritis, ulcerative colitis, systemic lupus erythematosus, atopic dermatitis, or multiple sclerosis.

[0028] More preferably, the myeloproliferative neoplastic disorder is selected from essential thrombocythemia, myelofibrosis, or polycythemia vera.

[0029] More preferably, the graft-versus-host disease is selected from acute graft-versus-host disease or chronic graft-versus-host disease. [Effects of the Invention]

[0030] The beneficial effects are as follows: 1. The compound of this application has good JAK2 kinase inhibitory activity and high selectivity for JAK2 kinase. 2. The compound of this application has clear pharmacokinetic advantages, offers more options for the prevention and / or treatment of diseases associated with abnormalities in the JAK signaling pathway, and has good prospects for clinical application. [Modes for carrying out the invention]

[0031] The following describes the technical solutions in the embodiments of this application clearly and completely, in order to further clarify the purpose, technical solutions, and advantages of this application. Needless to say, the embodiments described are not all embodiments of this application, but only a selection of them. All other embodiments obtained by a person skilled in the art based on the embodiments of this application without performing inventive work fall within the scope of protection of this application.

[0032] Furthermore, in order to further illustrate the present application, the following specific embodiments contain many detailed descriptions of the details. It will be understood by those skilled in the art that the present application can still be implemented even without some of these detailed descriptions of the details. In some embodiments, detailed descriptions of raw materials, methods, etc., which are well known to those skilled in the art, have been omitted in order to highlight the spirit of the present application.

[0033] Unless otherwise explicitly stated, in the entire specification and claims, the terms “include,” “equip,” and “contain,” and their variations thereof, shall be understood to include the components described, but not to exclude other components.

[0034] Unless otherwise specified, terms used in the specification and claims shall have the following meanings:

[0035] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group containing 1 to 20 straight and branched carbon atoms. Preferably, it is an alkyl group containing 1 to 10 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, most preferably an alkyl group containing 1 to 4 carbon atoms, and best of all is a methyl group. Non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, and 5-methylhexyl group. Examples include 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2,3-dimethylhexyl group, 2,4-dimethylhexyl group, 2,5-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 2-methyl-2-ethylpentyl group, 2-methyl-3-ethylpentyl group, n-nonyl group, 2-methyl-2-ethylhexyl group, 2-methyl-3-ethylhexyl group, 2,2-diethylpentyl group, n-decyl group, 3,3-diethylhexyl group, 2,2-diethylhexyl group, and various branched isomers thereof.More preferably, it is a lower alkyl group containing 1 to 6 carbon atoms, and non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, and the like. The alkyl group may be substituted or unsubstituted, and if substituted, the substituent may be substituted at any available linking point, and the substituent is preferably one or more atomic groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, amino groups, haloalkyl groups, hydroxyalkyl groups, carboxyl groups, or carboxylate groups.

[0036] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 10 carbon atoms, and most preferably 3 to 6 carbon atoms, with the best being a cyclopropyl group or a cyclopentyl group. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclopentenyl group, cyclohexyl group, cyclohexenyl group, cyclohexadienyl group, cycloheptyl group, cycloheptatrienyl group, and cyclooctyl group, with cyclopropyl group and cyclopentyl group being preferred. Polycyclic cycloalkyl groups include spirocyclic, fused, and crosslinked cycloalkyl groups. The cycloalkyl group may be optionally substituted or unsubstituted. If substituted, the substituent is preferably one or more atomic groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, amino groups, haloalkyl groups, hydroxyalkyl groups, carboxyl groups, or carboxylate groups.

[0037] The term "alkylene group" refers to a divalent linear or branched alkane group consisting of carbon and hydrogen atoms, having no degree of unsaturation, and linked to one atomic group by one single bond and to another atomic group (or ring system) by another single bond. For example, as used herein, "C 1~5 An alkylene group refers to an alkylene group containing 1 to 5 carbon atoms. 2~3An alkylene group refers to an alkylene group containing 2 to 3 carbon atoms. Non-limiting examples include the methylene group (-CH2-), 1,2-ethylene group (-CH2CH2-), 1,3-propylene group (-CH2CH2CH2-), 1-methyl-1,2-ethylene group (-CH(CH3)CH2-), 1,4-butylene group (-CH2CH2CH2CH2-), 1-methyl-1,3-propylene group (-CH(CH3)CH2CH2-), 1,1-dimethyl-1,2-ethylene group (-C(CH3)2CH2-), and 1,2-dimethyl-1,2-ethylene group (-CH(CH3)CH(CH3)-).

[0038] The term "cycloalkylene group" refers to a divalent monocyclic or polycyclic (including bridging rings and spiro rings) non-aromatic cyclic hydrocarbon group consisting only of carbon and hydrogen atoms, having no degree of unsaturation, and linked to one atomic group by one single bond and to another atomic group by another single bond. For example, as used herein, "C 3~7 A "cycloalkylene group" refers to a cycloalkylene group containing 3 to 7 carbon atoms, a "C4 cycloalkylene group" refers to a cycloalkylene group containing 4 carbon atoms, and a "C6 cycloalkylene group" refers to a cycloalkylene group containing 6 carbon atoms. Non-limiting examples include cyclopropane-1,1-ylidene, cyclopropane-1,2-ylidene, cyclobutane-1,1-ylidene, cyclobutane-1,2-ylidene, and cyclobutane-1,3-ylidene.

[0039] The term "bond" refers to a chemical bond between two atoms or two parts (i.e., an atomic group, a fragment), in which case the atoms linked by the bond are considered part of a larger substructure.

[0040] The term "chiral enantiomer" refers to two chiral molecules that are mirror images of each other but cannot be superimposed.

[0041] The term "protecting group" refers to an atomic group used to block the reactivity of a functional group. Examples of protecting groups include, but are not limited to, the methylene pivalate group.

[0042] The terms "optional" or "optionally" mean that the event or environment described thereafter may be present but is not necessarily present, and the description includes both cases where the event or environment is present and where it is not. For example, "a heterocycloalkyl group optionally substituted with an alkyl group" means that an alkyl group may be present but is not necessarily present, and the description includes cases where the heterocycloalkyl group is substituted with an alkyl group and cases where the heterocycloalkyl group is not substituted with an alkyl group.

[0043] "Substituted" means that one or more hydrogen atoms in a group of atoms, preferably up to five, more preferably one to three, are independently substituted by a corresponding number of substituents. Needless to say, substituents only appear in the chemical positions where they can exist, and those skilled in the art can determine possible or impossible substitutions (theoretically or experimentally) with little effort. For example, an amino group or hydroxyl group with free hydrogen can become unstable when bonded to a carbon atom with an unsaturated (e.g., olefinic) bond.

[0044] Unless otherwise specified, the equipment, consumables, reagents, etc. used in the following examples can all be obtained through normal sales channels. Experimental methods for which specific conditions are not explicitly stated in the examples should be selected according to normal methods and conditions, or according to the product description.

[0045] (Preparation of the compound represented by formula (I) of this application and its intermediates) The intermediate of the compound represented by formula (I) of this application may be synthesized according to the following general synthetic route. [ka] Specifically, this includes the following steps (1) and (2). In step (1), compound III-1 and diethyl cyanomethylphosphonate undergo an olefination reaction in the presence of a base to produce compound III-2. Preferably, the base is selected from one or more of the following: sodium hydride, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, lithium bromide, lithium chloride, triethylamine, 4-dimethylaminopyridine, cesium carbonate, potassium carbonate, and sodium carbonate. Preferably, the solvent used is selected from one or more of the following: tetrahydrofuran, dimethylformamide, and dimethyl sulfoxide. In step (2), compound III-2 and compound III-3 undergo a Michael addition reaction under the presence of a base and heating to produce compound III. Preferably, the base is selected from one or more of 1,8-diazabicycloundec-7-ene, sodium tert-butoxide, potassium tert-butoxide, triethylamine, 4-dimethylaminopyridine, cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, and sodium phosphate; preferably, the solvent used is selected from one or more of acetonitrile, N-methylpyrrolidone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methanol, and ethanol; and the heating temperature for the heating conditions is 52 to 82°C.

[0046] The compound represented by formula (I) of this application may be synthesized according to the following general synthetic route. [ka] Specifically, this includes the following steps (1) to (3). In step (1), the method for producing compound III-2 is as described above. In step (2), the method for producing compound III is as described above. In step (3), compound III removes its protecting group in the presence of a base to produce compound I. Preferably, the base is selected from one or more of sodium hydroxide, lithium hydroxide, and potassium hydroxide.

[0047] The following describes some specific manufacturing examples of the compound of formula (I) of this application, as well as their JAK2 / JAK3 kinase inhibitory activity and pharmacokinetic studies.

[0048] Example 1: Synthesis of Compound 1 [ka] The specific steps were as follows: In step (1), diethyl cyanomethylphosphonate (1.95 g, 11 mmol) was dissolved in dry tetrahydrofuran (50 mL), sodium hydride (420 mg, 13 mmol) was added under ice bath, and after stirring for 1 hour, compound 1A (1.34 g, 10 mmol) was added. The reaction was allowed to proceed overnight at room temperature with stirring. Saturated ammonium chloride solution (20 mL) was added to the reaction system to quench it, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated saline solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue, which was compound 1B (LCMS(ESI+): 158.08(M+H)). + ) and this was used directly in the next step.

[0049] In step (2), compound 1C (1.35 g, 5 mmol), compound 1B (15 mmol) obtained in step (1), and 1,8-diazabicyclo[5.4.0]-7-undecene (5 mmol) were dissolved in acetonitrile (30 mL) and heated to 80°C and reacted for 5 days. After returning to room temperature, the mixture was concentrated to remove most of the acetonitrile, water (20 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 100:0 to 100:5) to obtain compound 1D (LCMS(ESI+):457.22(M+H)). + ) was obtained.

[0050] In step (3), compound 1D (912 mg, 2 mmol) obtained in step (2) was dissolved in methanol and water (5 / 5 mL), sodium hydroxide (160 mg, 4 mmol) was added, and the reaction was carried out at room temperature under TLC monitoring. Once the starting material was completely consumed, it was extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 100:0 to 100:5) to obtain compound 1. (LCMS(ESI+):343.15(M+H)) + ).

[0051] Example 2: Synthesis and Resolution of Compound 2 [ka] The specific steps were as follows: Step (1): Compound 2A (1.42 g, 10 mmol) is dissolved in dichloromethane (20 mL), silica gel powder (SiO2, 3 g) and pyridinium chlorochromate (3.24 g, 15 mmol) are added, the mixture is stirred overnight at room temperature, filtered through diatomaceous earth, concentrated, and then compound 2B (LCMS(ESI+): 141.05(M+H) + ) was obtained and used directly in the next step.

[0052] In step (2), diethyl cyanomethylphosphonate (1.95 g, 11 mmol) was dissolved in dry tetrahydrofuran (50 mL), sodium hydride (420 mg, 13 mmol) was added under ice bath, and after stirring for 1 hour, compound 2B (1.4 g, 10 mmol) was added. The reaction was allowed to proceed overnight at room temperature with stirring. Saturated ammonium chloride solution (20 mL) was added to the reaction system to quench it, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue, which was compound 2C (LCMS(ESI+):164.07(M+H)). + ) and this was used directly in the next step.

[0053] In step (3), compound 1C (1.35 g, 5 mmol), compound 2C (15 mmol) obtained in step (2), and 1,8-diazabicyclo[5.4.0]-7-undecene (5 mmol) were dissolved in acetonitrile (30 mL) and heated to 80°C and reacted for 5 days. After returning to room temperature, the mixture was concentrated to remove most of the acetonitrile, water (20 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 100:0 to 100:5) to obtain compound 2D (LCMS(ESI+):463.21(M+H)). + ) was obtained.

[0054] In step (4), compound 2D (924 mg, 2 mmol) obtained in step (3) was dissolved in methanol and water (5 / 5 mL), sodium hydroxide (160 mg, 4 mmol) was added, and the reaction was carried out at room temperature under TLC monitoring. Once the starting material was completely consumed, it was extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 100:0 to 100:5) to obtain compound 2. (LCMS(ESI+):349.14(M+H)) + ).

[0055] (Resolution of compound 2) The separation conditions were as follows: Compound 2 was dissolved in ethanol (concentration 6 mg / mL). A UniChiral CND-H (50 mm ID × 250 mm L) chiral chromatography column was used, with a mobile phase of n-hexane:ethanol = 80:20 (V:V), a flow rate of 120 mL / min, UV 254 nm, and a column temperature of 30°C. After separation, compound 2-1 and compound 2-2 were obtained.

[0056] The retention times were as follows: Compound 2-1 had a retention time of 8.493 minutes (above 98% ee), and Compound 2-2 had a retention time of 9.994 minutes (above 98% ee).

[0057] Example 3: Synthesis of Compound 3 [ka] Following the synthesis route of Example 1, compound 3 was obtained using 4-(trifluoromethyl)cyclohexane-1-one as the starting material. LCMS(ESI+):375.15(M+H) + .

[0058] Example 4: Synthesis of Compound 4 [ka] Following the synthesis route of Example 1, compound 4 was obtained using 4,4-difluorocyclohexanecarboxyaldehyde as the starting material. LCMS(ESI+):357.16(M+H) + .

[0059] Example 5: Synthesis of Compound 5 [ka] Following the synthesis route of Example 2, compound 5 was obtained using 4-(trifluoromethyl)cyclohexanemethanol as the starting material. LCMS(ESI+):389.17(M+H) + .

[0060] Example 6: Synthesis and resolution of compound 6 [ka] Following the synthesis route of Example 1, compound 6 was obtained using 4,4,4-trifluorobutyraldehyde as the starting material. LCMS(ESI+):335.12(M+H) + .

[0061] (Resolution of compound 6) [ka] 6-1 6-2 The separation conditions were as follows: Compound 6 was dissolved in n-hexane:ethanol = 80:20 (V:V) (concentration 10 mg / mL). A ChiralCel OD-H (0.46 cm ID × 25 cmL) was used as the chiral chromatography column, the mobile phase was n-hexane:ethanol = 80:20 (V:V), the flow rate was 1.0 mL / min, the UV was 254 nm, and the column temperature was 30°C.

[0062] The retention times were as follows: Compound 6-1 had a retention time of 9.295 minutes (above 98% ee), and Compound 6-2 had a retention time of 11.252 minutes (above 98% ee).

[0063] Example 7: Synthesis of Compound 7 [ka] Following the synthesis route of Example 2, compound 7 was obtained using (3,3-difluorocyclobutyl)methanol as the starting material. LCMS(ESI+):329.13(M+H) + .

[0064] Example 8: Synthesis of Compound 8 [ka] Following the synthesis route of Example 2, compound 8 was obtained using 3,3,3-trifluoro-2,2-dimethylpropan-1-ol as the starting material. LCMS(ESI+):349.14(M+H) + .

[0065] Example 9: Synthesis of Compound 9 [ka] Following the synthesis route of Example 2, compound 9 was obtained using 1-(trifluoromethyl)-1-cyclobutyl-1-methanol as the starting material. LCMS(ESI+):361.14(M+H) + .

[0066] Example 10: Synthesis of Compound 10 [ka] Following the synthesis route of Example 2, compound 10 was obtained using 4,4,5,5,5-pentafluoropentanol as the starting material. LCMS(ESI+):385.12(M+H) + .

[0067] Example 11: Other manufacturing examples Other specific examples of compound production were as follows: [Table 1]

[0068] Example 12: JAK2 / JAK3 kinase inhibitory activity test 1. Laboratory consumables JAK2:Carna 09-045 14CBS-0374 H JAK3:Carna 08-046 19CBS-0798 B ATP (10mM): CST 9804 DTT: 100mM MgCl2:1M TK substrate-biotin (biotin-labeled tyrosine kinase substrate, hereinafter referred to as substrate): Cisbio, #61TK0BLC* Streptavidin-XL665 (Streptavidin-labeled XL665): Cisbio, #610SAXLG* HTRF Kinase-TK kit (HTRF tyrosine kinase kit): Cisbio, #62TK0PEC TK-Antibody-Eu 3 -Cryptate (Europium-labeled tyrosine kinase antibody): Derived from Kit Cisbio, #62TK0PEC HTRF 96-well low volume plate (HTRF 96-well microplate): Cisbio, #66PL96001 Ruxolitinib: Provided by Chongqing Gongzhou Pharmaceutical Technology Co., Ltd., CAS number: 941678-49-5

[0069] 2. Test Conditions JAK2:0.008ng / μL, ATP 4μM, substrate 1μM, action time 2 hours JAK3:0.1ng / μL, ATP 3μM, substrate 1μM, action time 3 hours

[0070] 3. JAK2 kinase inhibitory activity test 3.1 Preparation of Reagents 1) Preparation of 1× kinase buffer. 5× kinase buffer was diluted with sterile water to make 1× kinase buffer, and then 5 mM MgCl2 and 1 mM DTT were added. 2) Preparation of 5×JAK2. The concentration of JAK2 was 166 ng / μL, and it was prepared to the final concentration of 5×, i.e., 0.04 ng / μL. First, it was diluted to 1.66 ng / μL, and then diluted 41.5 times from 1.66 ng / μL to prepare 0.04 ng / μL. 3) Preparation of 5× ATP. Starting with 4 μM ATP, it was prepared to 5×, i.e., 20 μM. The desired ATP concentration was obtained by directly diluting 10 mM ATP 500 times. 4) Preparation of 5× substrate. 5× of 1 μM is equivalent to 5 μM, and since the substrate concentration is 500 μM, diluting it by 100× yields a 5 μM substrate. 5) Preparation of the 2.5× test compound. The concentration of the test compound buffer was 10 mM, and the treatment concentration was 10 μM. First, a 100× buffer, i.e., 1 mM, was prepared by diluting 10 × from 10 mM. Next, a 1:3 gradient dilution was used to a total concentration of 10. 2 μL of the diluted test compound solution was taken and added to 78 μL of 1 × kinase buffer to obtain the 2.5× test compound. Furthermore, when 2 μL of DMSO was aspirated and added to 78 μL of 1× kinase buffer, the resulting solution was 2.5× DMSO. 6) Preparation of 1 μM Streptavidin-XL665. The concentration of Streptavidin-XL665 is 16.67 μM, and it is recommended to dilute it 16.67 times with the measurement buffer before use. 7) 1 × TK-Antibody-Eu 3 -Cryptate preparation. TK-Antibody-Eu 3 -The cryptate stock solution is a 100x solution; it should be diluted to 1x with the measurement buffer before use.

[0071] 3.2 Test Method 1) The test compound was used in the wells (T-compound). 4 μL of the above 2.5× test compound was added to an HTRF 96-well microplate, followed by 2 μL of 5× substrate added to one side of the well, and 2 μL of 5× JAK2 added to the other side of the well. The control well was a DMSO-containing well (T-enzyme) without the test compound. 4 μL of the above 2.5×DMSO was added to a 96-well HTRF microplate, followed by 2 μL of 5× substrate in one well and 2 μL of 5×JAK2 in the other well. A blank control (T-without enzyme) was used. 4 μL of the above 2.5× DMSO was added to a 96-well HTRF microplate, followed by 2 μL of 5× substrate in one well and 2 μL of 1× kinase buffer in the other well. 2) The plate was sealed with a sealing plate film and placed in a centrifuge, where it was centrifuged at 1000 rpm for 2 minutes. 3) Add 2 μL of 5× ATP to each well, seal with a sealing plate film, centrifuge at 1000 rpm for 1 minute, and incubate the plate in a 30°C incubator for 2 hours. 4) Once incubation is complete, the above Streptavidin-XL665 and 1×TK-Antibody-Eu 3 -Cryptate was mixed in a 1:1 ratio, 10 μL was added to each well, and the mixture was centrifuged at 1000 rpm for 1 minute. 5) The plate was returned to the incubator and incubated for another hour. After incubation was complete, the HTRF 620 / 665 signal was read using a multifunctional microplate reader.

[0072] 4. JAK3 kinase inhibitory activity test 4.1 Preparation of Reagents 1) Preparation of 1× kinase buffer. 5× kinase buffer was diluted with sterile water to make 1× kinase buffer, and then 5 mM MgCl2 and 1 mM DTT were added. 2) Preparation of 5×JAK3. The concentration of JAK3 was 124 ng / μL, and it was adjusted to the final concentration of 5×, i.e., 0.5 ng / μL, and then diluted 248 times to obtain the desired concentration. 3) The preparation involved 5× ATP. Starting with 3 μM ATP, it was prepared to 5×, i.e., 15 μM. A direct 666.67-fold dilution from 10 mM ATP resulted in the desired ATP concentration. 4) Preparation of 5× substrate. 5× of 1 μM is equivalent to 5 μM, and since the substrate concentration is 500 μM, diluting it by 100× yields a 5 μM substrate. 5) Preparation of the 2.5× test compound. The concentration of the test compound buffer was 10 mM, and the treatment concentration was 10 μM. First, a 100× buffer, i.e., 1 mM, was prepared by diluting 10 × from 10 mM. Next, a 1:3 gradient dilution was used to a total concentration of 10. 2 μL of the diluted test compound solution was taken and added to 78 μL of 1 × kinase buffer to obtain the 2.5× test compound. Furthermore, when 2 μL of DMSO was aspirated and added to 78 μL of 1× kinase buffer, the resulting solution was 2.5× DMSO. 6) Preparation of 1 μM Streptavidin-XL665. The concentration of Streptavidin-XL665 is 16.67 μM, and it is recommended to dilute it 16.67 times with the measurement buffer before use. 7) 1 × TK-Antibody-Eu 3 -Cryptate preparation. TK-Antibody-Eu 3 -The cryptate stock solution is a 100x solution; it should be diluted to 1x with the measurement buffer before use.

[0073] 4.2 Test Method 1) The test compound was used in the wells (T-compound). 4 μL of the above 2.5× test compound was added to an HTRF 96-well microplate, followed by 2 μL of 5× substrate added to one side of the well, and 2 μL of 5× JAK3 added to the other side of the well. The control well was a DMSO-containing well (T-enzyme) without the test compound. 4 μL of the above 2.5×DMSO was added to a 96-well HTRF microplate, followed by 2 μL of 5× substrate in one well and 2 μL of 5×JAK3 in the other well. A blank control (T-without enzyme) was used. 4 μL of the above 2.5× DMSO was added to a 96-well HTRF microplate, followed by 2 μL of 5× substrate in one well and 2 μL of 1× kinase buffer in the other well. 2) The plate was sealed with a sealing plate film and placed in a centrifuge, where it was centrifuged at 1000 rpm for 2 minutes. 3) Add 2 μL of 5× ATP to each well, seal with a sealing plate film, centrifuge at 1000 rpm for 1 minute, and incubate the plate in a 30°C incubator for 3 hours. 4) Once incubation is complete, the above Streptavidin-XL665 and 1×TK-Antibody-Eu 3 -Cryptate was mixed in a 1:1 ratio, 10 μL was added to each well, and the mixture was centrifuged at 1000 rpm for 1 minute. 5) The plate was returned to the incubator and incubated for another hour. After incubation was complete, the HTRF 620 / 665 signal was read using a multifunctional microplate reader.

[0074] 5. Calculation of inhibition rate and IC 50 fitting Inhibition rate = (T-enzyme-T-compound) / (T-enzyme-T-without enzyme) × 100% Based on the inhibition rates against kinases at different concentrations of the test compound, the half-percentage inhibitory concentration (IC) was fitted using GraphPad Prism 6. 50 ) was obtained.

[0075] The JAK2 and JAK3 kinase inhibitory activities of the representative compound of this application and the positive control drug ruxolitinib were measured in the above tests, and the measured IC50 was determined. 50 Refer to Table 2 below for the value.

[0076] [Table 2] As can be seen from Table 2, the compound of the present invention has good JAK2 kinase inhibitory activity, and its selectivity for JAK2 is equivalent to or better than that of the positive control drug ruxolitinib.

[0077] Example 13: Pharmacokinetic study 1. Laboratory animals I purchased three healthy male C57 mice, 6-8 weeks old, from Shanghai Sippe-Bk Lab Animal Co., Ltd.

[0078] 2. Experimental Method Mice were fasted overnight before oral administration, and feeding was resumed 4 hours after administration, with unrestricted water intake. The compound was administered intragastricly to mice at a dose of 10 mg / kg body weight, and whole blood samples were collected using a semi-continuous facial vein sampling method. Approximately 30 μL of blood was collected at 0.125 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration to the test animals. These samples were placed in test tubes containing the anticoagulant heparin sodium and kept on ice in preparation for centrifugation. Within 15 minutes, the samples were centrifuged at 6800 g for 6 minutes in a centrifuge at 6-8°C. Within 1 hour of blood collection and centrifugation, the plasma was transferred to appropriately labeled test tubes and stored frozen at approximately -80°C.

[0079] 3. Conditions for chromatography and mass spectrometry The chromatography column used was Luna® Omega ACQUITY UPLC BEH C18 (2.1 × 50 mm, 1.7 μm). Mobile phase A was H2O-0.1%FA and mobile phase B was ACN-0.1%FA, with a flow rate of 0.80 mL / min. The gradient elution program was: start, 10%B 0.6 min, 10%B 1.0 min, 90%B 1.11 min, 90%B 1.40 min, 10%B. The column temperature was 40°C, and the injection volume was 2 μL.

[0080] The mass spectrometry setup was as follows: an LC-MS / MS-19 (TQ5500) (SCIEX, USA) was used, the ion source was an ESI source, the measurement method was cationization measurement, the scan mode was multiple reaction monitoring (MRM) mode, and the m / z was 271.10 / 172.00 Da (tolbutamide, internal standard).

[0081] 4. Preparation of plasma samples A 10 μL plasma sample was obtained, 200 μL of internal standard working solution (tolbutamide, 100 ng / mL) was added, the mixture was vortexed for 1 minute, centrifuged at 18000 g for 10 minutes, 200 μL of supernatant was transferred to a 96-well microplate, and 1 μL of supernatant was taken and used for LC-MS / MS analysis.

[0082] 5.Result analysis Pharmacokinetic (PK) parameters were calculated using Phoenix WinNonlin 7.0. A non-compartmental model was used to calculate the mouse oral pharmacokinetic parameters (AUC, C). max , T max Estimate the T1 / 2 (etc.), and refer to Table 3 for the results of the mouse oral pharmacokinetic parameters of the representative compound of this application (those prepared in the above examples, of which compound 2 is a mixture of compound 2-1 and compound 2-2) and the positive control drug ruxolitinib. [Table 3] *In the table, "dn" refers to dose normalization.

[0083] As can be seen from Table 3, the compound of this application has a half-life (T1 / 2) and exposure amount (AUC) per unit dose. (0-∞) Since the dn) values ​​are all significantly higher than those of the positive control drug ruxolitinib, it has a clear pharmacokinetic advantage.

[0084] Finally, it should be stated that the above embodiments are not intended to limit the technical solutions of the present application, but merely to illustrate them. Although the present application has been described in detail with reference to the above embodiments, those skilled in the art will understand the following: It is still possible to amend the technical solutions described in each of the above embodiments, or to replace some of their technical features with equivalent ones. Such amendments or replacements will not cause the intent of the technical solutions to deviate from the intent and scope of the technical solutions in each of the embodiments of the present application. [Industrial applicability]

[0085] The compounds containing the geminal difluoro group represented by formula (I) provided herein have good JAK2 kinase inhibitory activity and high selectivity for JAK2 kinase. Furthermore, the compounds of this application also have clear pharmacokinetic advantages, offering many options for the prevention and / or treatment of diseases associated with abnormalities in the JAK signaling pathway, and are expected to be well-suited for clinical application.

Claims

1. A compound having the structure shown in formula (II), its chiral enantiomer, or a pharmaceutically acceptable salt thereof. 【Chemistry 2】 (II) (In formula (II), Y １ CR １ And, however, R １ is F, Z is a bond or (CH ２ ) ｍ And, however, m is 1, 2, or 3. Y ２ is an alkylene group or a cycloalkylene group, and the alkylene group or the cycloalkylene group is optionally substituted with fluorine, an alkyl group or a cycloalkylene group. X is H or (CH ２ ) ｎ n, provided that n is 0, 1, 2, 3, 4 or 5, and when X is (CH ２ ) ｎ X is bonded to Y １ or Z to form a C 6 cycloalkylene group, however, When Z is (CH₂)m and Y₂ is an alkylene group, Y₂ may combine with Z to form a C₆-C₆ cycloalkylene group. When Y2 is an alkylene group, Y2 may be linked to Y1 to form a C4-C6 cycloalkylene group. When Y2 is linked to Y1 to form a C4-C6 cycloalkylene group, or when X is linked to Y1 to form a C6 cycloalkylene group, R1 is a bond.

2. Y １ CR １ And, however, R １ This is a combination, Z is bonded or (CH ２ ) ｍ And, however, m is 1, 2, or 3, Y ２ This is an alkylene group, X is (CH ２ ) ｎ And, where n is 0, 1, 2, 3, 4 or 5, Furthermore, if X is Y １ Connect to C ６ Forms cycloalkylene groups A compound according to claim 1, its chiral enantiomer, or a pharmaceutically acceptable salt thereof, characterized in that it is a compound according to claim 1.

3. Y １ CR １ And, however, R １ F is, Z is bonded or (CH ２ ) ｍ And, however, m is 1, 2, or 3, Y ２ C １ ~C ５ It is an alkylene group, X is H A compound according to claim 1, its chiral enantiomer, or a pharmaceutically acceptable salt thereof, characterized in that...

4. Y １ CR １ And, however, R １ F is, Z is bonded or (CH ２ ) ｍ And, however, m is 1, 2, or 3, Y ２ C ２ ~C ３ It is an alkylene group, X is H A compound according to claim 1, its chiral enantiomer, or a pharmaceutically acceptable salt thereof, characterized in that...

5. Y １ CR １ And, however, R １ F is, Z is bonded or (CH ２ ) ｍ And, however, m is 1, 2, or 3, Y ２ This is an alkylene group, X is (CH ２ ) ｎ And, where n is 1, 2, 3, 4 or 5, Furthermore, X is connected to Z and C ６ Forms cycloalkylene groups A compound according to claim 1, its chiral enantiomer, or a pharmaceutically acceptable salt thereof, characterized in that...

6. Y １ CR １ And, however, R １ This is a combination, Z is bonded or (CH ２ ) ｍ And, however, m is 1, 2, or 3, Y ２ is an alkylene group, and Y ２ Y １ Connect to C ４ or C ６ Forming a cycloalkylene group, X is H A compound according to claim 1, its chiral enantiomer, or a pharmaceutically acceptable salt thereof, characterized in that...

7. Y １ CR １ And, however, R １ F is, Z is (CH ２ ) ｍ And, however, m is 1, 2, or 3, Y ２ is an alkylene group, and Y ２ When Z is combined with C ６ Forming a cycloalkylene group, X is H A compound according to claim 1, its chiral enantiomer, or a pharmaceutically acceptable salt thereof, characterized in that it is a compound according to claim 1.

8. Y １ CR １ And, however, R １ F is, Z is bonded or (CH ２ ) ｍ And, however, m is 1, 2, or 3, Y ２ However, it is an alkylene group or a cycloalkylene group, and is optionally substituted with an alkyl group or a cycloalkylene group. X is H A compound according to claim 1, its chiral enantiomer, or a pharmaceutically acceptable salt thereof, characterized in that...

9. The following compounds, their chiral enantiomers, or pharmaceutically acceptable salts thereof. 【Transformation 3】

10. Step (1) involves compound III-1 and diethyl cyanomethylphosphonate undergoing an olefination reaction in a solvent in the presence of a base to produce compound III-2, Step (2) involves compound III-2 and compound III-3 undergoing a Michael addition reaction in a solvent under the presence of a base and heating conditions to produce compound III, The process includes the step (3) in which compound III removes its protecting group in the presence of a base to produce compound I, A method for producing a compound according to any one of claims 1 to 9, its chiral enantiomer, or a pharmaceutically acceptable salt thereof. 【Chemistry 4】 (Here, A is, 【change】 And; furthermore, here, Y １ Z, Y ２ (wherein X is defined in any one of claims 1 to 9; and further, X is defined in any one of claims 1 to 9.)

11. In step (1), the base is selected from one or more of the following: sodium hydride, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, lithium bromide, lithium chloride, triethylamine, 4-dimethylaminopyridine, cesium carbonate, potassium carbonate, and sodium carbonate, and the solvent in step (1) is an aprotic solvent. In step (2), the base is selected from one or more of 1,8-diazabicycloundec-7-ene, sodium tert-butoxide, potassium tert-butoxide, triethylamine, 4-dimethylaminopyridine, cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, and sodium phosphate; in step (2), the solvent is a protic or aprotic solvent; and in step (2), the heating temperature is 52 to 82°C. In step (3), the base is selected from one or more of sodium hydroxide, lithium hydroxide, and potassium hydroxide. The manufacturing method according to claim 10, characterized in that

12. In step (1), the solvent is selected from one or more of tetrahydrofuran, dimethylformamide, and dimethyl sulfoxide. In step (2), the solvent is selected from one or more of the following: acetonitrile, N-methylpyrrolidone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methanol, and ethanol. The manufacturing method according to claim 11, characterized in that

13. An intermediate having a structure represented by general formula (III) for producing a compound according to any one of claims 1 to 9, a chiral enantiomer thereof, or a pharmaceutically acceptable salt thereof. 【Transformation 5】 (III) (In formula (III), A is, 【change】 And; furthermore, here, Y １ Z, Y ２ (wherein X is defined in any one of claims 1 to 9; and further, X is defined in any one of claims 1 to 9.)

14. Step (1) involves compound III-1 and diethyl cyanomethylphosphonate undergoing an olefination reaction in a solvent in the presence of a base to produce compound III-2, The process includes step (2) in which compound III-2 and compound III-3 undergo a Michael addition reaction in a solvent under the presence of a base and heating to produce compound III. A method for producing the intermediate according to claim 13. 【Transformation 6】

15. In step (1), the base is selected from one or more of the following: sodium hydride, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, lithium bromide, lithium chloride, triethylamine, 4-dimethylaminopyridine, cesium carbonate, potassium carbonate, and sodium carbonate, and the solvent in step (1) is an aprotic solvent. In step (2), the base is selected from one or more of the following: 1,8-diazabicycloundec-7-ene, sodium tert-butoxide, potassium tert-butoxide, triethylamine, 4-dimethylaminopyridine, cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, and sodium phosphate; the solvent in step (2) is a protic or aprotic solvent; and the heating temperature in step (2) is 52 to 82°C. The manufacturing method according to claim 14, characterized in that

16. In step (1), the solvent is selected from one or more of tetrahydrofuran, dimethylformamide, and dimethyl sulfoxide. In step (2), the solvent is selected from one or more of the following: acetonitrile, N-methylpyrrolidone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methanol, and ethanol. The manufacturing method according to claim 15, characterized in that

17. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 9, a chiral enantiomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

18. The carrier is an excipient. The pharmaceutical composition according to claim 17, characterized in that...

19. Use of a compound according to any one of claims 1 to 9, a chiral enantiomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17, in the manufacture of a drug for preventing and / or treating a disease associated with abnormalities in the JAK signaling pathway.

20. The disease is an autoimmune disease, a myeloproliferative neoplastic disease, or a graft-versus-host disease. The use according to claim 19, characterized in that

21. The autoimmune disease is selected from rheumatoid arthritis, ulcerative colitis, systemic lupus erythematosus, atopic dermatitis, or multiple sclerosis. Myeloproliferative neoplastic disorders are selected from essential thrombocythemia, myelofibrosis, or polycythemia vera. Graft-versus-host disease is selected from acute graft-versus-host disease or chronic graft-versus-host disease. The use according to claim 20, characterized by the features described herein.

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