Compound Containing Geminal Difluoro Group, Method for Producing the Same, and Use Thereof

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 to related applications

[0001] This application claims the priority of a Chinese patent application filed on July 5, 2022, with application number 202210784219.X and invention title "Compounds Containing Geminal Difluoro Groups, Their Preparation Methods and Uses", and incorporates it herein by reference in its entirety.

Technical Field

[0002] This application relates to the field of pharmaceutical chemistry, specifically to compounds containing geminal difluoro groups, their preparation methods and uses.

Background Art

[0003] Janus kinase (JAK) is a type of tyrosine kinase, and the JAK family includes four members: JAK1, JAK2, JAK3, and TYK2. JAK plays an important role in the signal transduction processes of various cytokines.

[0004] Signal Transducer and Activator of Transcription (STAT) is a series of cytoplasmic proteins that can bind to the DNA of the target gene regulatory region. As a downstream substrate of JAK, STAT is activated by tyrosine phosphorylation under the stimulation of external signals, and then translocates to the nucleus to regulate gene transcription.

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

[0006] JAK protein kinase inhibitors, particularly JAK3 protein kinase inhibitors, not only prevent the activation of T cells and prevent transplant rejection after transplantation surgery, but also are effective against autoimmune diseases (such as rheumatoid arthritis and multiple sclerosis). In addition, myeloproliferative neoplastic diseases (including essential thrombocythemia, polycythemia vera, and primary myelofibrosis) have been found by research to be related to abnormal activation due to mutations in JAK2 kinase. Therefore, the development of JAK2 protein kinase inhibitors has great medical value and a large market is expected for the treatment of myeloproliferative neoplastic diseases.

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

[0008] Therefore, there is still a need to develop new compounds that have high selectivity for JAK2 kinase and better pharmacokinetic properties.

Summary of the Invention

Problems to be Solved by the Invention

[0009] The object of the present application is to provide 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 the present application has good JAK2 kinase inhibitory activity and high selectivity for JAK2 kinase. In addition, the compound of the present application has obvious pharmacokinetic advantages and provides more options for the prevention and / or treatment of diseases related to abnormalities in the JAK signaling pathway (especially autoimmune diseases, myeloproliferative neoplastic diseases, graft-versus-host disease), and has good prospects for clinical application.

Means for Solving the Problems

[0010] In a first aspect, the present application provides a compound represented by formula (I), its chiral enantiomer or a pharmaceutically acceptable salt thereof.

Chemical formula

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

Chemical formula

[0012] As a preferred specific embodiment, in the above formula (II), Y1 is CR1, provided that 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 linked 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, provided that R1 is F, Z is a bond or (CH2) mwherein 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, provided that R1 is F, Z is a bond or (CH2) m wherein m is 1, 2 or 3, Y2 is an alkylene group or a cycloalkylene group, optionally substituted by an alkyl group, a cycloalkyl group or a cycloalkylene group, X is H.

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

Chemical formula

[0019] In a second aspect, the present application Step (1) 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) in which compound III-2 and compound III-3 undergo a Michael addition reaction under the conditions of the presence of a base and heating to produce compound III, Step (3) in which compound III removes a protecting group in the presence of a base to produce compound I, and provides a method for producing the compound, its chiral enantiomer or pharmaceutically acceptable salt thereof according to the above first aspect.

Chemical formula

[0020] In a preferred embodiment, in step (1), the base is selected from any 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; in step (1), the solvent is an aprotic solvent, preferably, the solvent is selected from any one or more of tetrahydrofuran, dimethylformamide, and dimethyl sulfoxide. In step (2), the base is selected from any 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, the solvent is selected from any one or more of acetonitrile, N-methylpyrrolidone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methanol, and ethanol; in step (2), the heating temperature of the heating condition is 52 to 82 °C. In step (3), the base is selected from any one or more of sodium hydroxide, lithium hydroxide, and potassium hydroxide.

[0021] In a third aspect, the present application provides an intermediate having a structure represented by general formula (III) for producing the compound described in the first aspect above, its chiral enantiomer, or a pharmaceutically acceptable salt thereof. [Chemical formula] (III) In formula (III), A is an alkyl group or a cycloalkyl group, provided that the alkyl group or the cycloalkyl group is optionally substituted by fluorine, an alkyl group or a cycloalkylene group, and the alkyl group, the cycloalkyl group or the cycloalkylene group has at least one pair of geminal difluoro groups. X is H or (CH2) n wherein 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, the cycloalkylene group is optionally substituted by fluorine or an alkyl group, and the cycloalkylene group or the alkyl group has at least one pair of geminal difluoro groups.

[0022] In a fourth aspect, the present application Step (1) 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) in which compound III-2 and compound III-3 undergo a Michael addition reaction under the conditions of the presence of a base and heating to produce compound III, and a method for producing the intermediate according to the third aspect described above is provided. [Chemical formula]

[0023] In a preferred embodiment, in step (1), the base is selected from any 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 in step (1), the solvent is an aprotic solvent, preferably, the solvent is selected from any one or more of tetrahydrofuran, dimethylformamide and dimethyl sulfoxide. In step (2), the base is selected from any 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. Preferably, the solvent is selected from any one or more of acetonitrile, N-methylpyrrolidone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methanol and ethanol. In step (2), the heating temperature of the heating condition is 52 to 82 °C.

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

[0025] In a sixth aspect, the present application provides the use of the compound according to the first aspect above, its chiral enantiomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to the fifth aspect above, in the manufacture of a drug for preventing and / or treating a disease associated with an abnormality in the JAK signaling pathway.

[0026] Preferably, the disease is an autoimmune disease, a myeloproliferative neoplastic disease or 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 disease 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.

Advantages of the Invention

[0030] The beneficial effects are as follows. 1. The compound of the present application has good JAK2 kinase inhibitory activity and high selectivity for JAK2 kinase. 2. The compound of the present application has obvious pharmacokinetic advantages, provides more options for the prevention and / or treatment of diseases related to abnormalities in the JAK signaling pathway, and has good prospects for clinical application.

Mode for Carrying Out the Invention

[0031] Hereinafter, in order to make the objectives, technical solutions and advantages of the present application clearer, the technical solutions in the embodiments of the present application will be clearly and completely described. Needless to say, the described embodiments are only some embodiments of the present application, not all embodiments. Other embodiments obtained by those skilled in the art based on the embodiments of the present application without inventive work all belong to the protection scope of the present application.

[0032] In addition, for further explanation of the present application, there are many specific descriptions of details in the following specific embodiments. It will be understood by those skilled in the art that the present application can still be implemented even without some of these specific descriptions of details. In some embodiments, in order to highlight the gist of the present application, details of raw materials, methods, etc. well-known to those skilled in the art are not described in detail.

[0033] Unless otherwise clearly defined, throughout the specification and the claims, the terms "comprising", "including", "containing" and their variants are understood to include the recited components, but do not exclude other components.

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

[0035] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group containing a straight-chain and branched-chain atomic group of 1 to 20 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 most preferably 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, 5-methylhexyl group, 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-chain isomers thereof, etc.More preferably, it is a lower alkyl group containing 1 to 6 carbon atoms. 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, etc. The alkyl group may be substituted or unsubstituted. When it is substituted, the substituent may substitute at any available linking point, and the substituent is preferably one or more atomic groups independently selected from an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an alkylamino group, a halogen, a mercapto group, a hydroxy group, a nitro group, a cyano group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a cycloalkoxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, an oxo group, an amino group, a haloalkyl group, a hydroxyalkyl group, a carboxy group or a carboxylate group.

[0036] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon atomic 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, and the best ones are cyclopropyl group or 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, cyclooctyl group, etc., and preferably, cyclopropyl group and cyclopentyl group. Polycyclic cycloalkyl groups include spirocyclic, fused-ring and bridged-ring cycloalkyl groups. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more atomic groups independently selected from alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylthio group, alkylamino group, halogen, mercapto group, hydroxy group, nitro group, cyano group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, cycloalkoxy group, heterocycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, oxo group, amino group, haloalkyl group, hydroxyalkyl group, carboxy group or carboxylate group.

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

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

[0039] The term "bond" refers to a chemical bond between two atoms or two moieties (i.e., atomic groups, fragments), 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 and 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 term "optional" or "optionally" means that the event or circumstance described subsequently may or may not be present, and the description includes both cases where the event or circumstance is present and where it is not. For example, "a heterocycloalkyl atomic group optionally substituted by an alkyl group" means that the alkyl group may or may not be present, and the description includes the case where the heterocycloalkyl atomic group is substituted by an alkyl group and the case where the heterocycloalkyl atomic group is not substituted by an alkyl group.

[0043] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in an atomic group are independently replaced by an appropriate number of substituents. Needless to say, substituents only appear at the chemical positions where they can exist, and those skilled in the art can determine (theoretically or experimentally) possible or impossible substitutions without much effort. For example, an amino group or a hydroxy group having free hydrogen may become unstable when bonded to a carbon atom having an unsaturated (e.g., olefinic) bond.

[0044] Unless otherwise specified, all equipment, consumables, reagents, etc. used in the following examples can be obtained through normal sales routes, and experimental methods not specifically specified in the examples are selected according to normal methods and conditions or according to the product instructions.

[0045] (Preparation of the compound represented by formula (I) of the present application and its intermediates) The intermediates of the compound represented by formula (I) of the present application may be synthesized according to the following general synthetic routes.

Chemical formula

[0046] The compound represented by formula (I) of the present application may be synthesized according to the following general synthetic route.

Chemical formula

[0047] Hereinafter, some specific production examples of the compound of formula (I) of the present application, as well as its JAK2 / JAK3 kinase inhibitory activity test and pharmacokinetic test will be described.

[0048] Example 1: Synthesis of Compound 1 [Chemical formula] 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 an ice bath, and after stirring for 1 hour, Compound 1A (1.34 g, 10 mmol) was added. The reaction was allowed to proceed overnight with stirring at room temperature. A saturated ammonium chloride solution (20 mL) was added to the reaction system to quench it, and it was extracted with ethyl acetate (20 mL × 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 a residue, which was Compound 1B (LCMS(ESI+): 158.08(M+H) + ) and this was used directly in the next step.

[0049] 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), heated to 80 °C, and reacted for 5 days. After returning to room temperature, it was concentrated to remove most of the acetonitrile, water (20 mL) was added, extracted with ethyl acetate (10 mL × 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 1D (LCMS(ESI+): 457.22 (M+H) + ) was obtained.

[0050] 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, reacted at room temperature, monitored by TLC, and when the raw materials were completely consumed, extracted with ethyl acetate (10 mL × 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

Chemical formula

[0052] 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 an ice bath, and after stirring for 1 hour, compound 2B (1.4 g, 10 mmol) was added. The reaction was allowed to proceed overnight with stirring at room temperature. A 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 × 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 a residue, which was compound 2C (LCMS(ESI+): 164.07(M+H) + ). This was used directly in the next step.

[0053] Step (3): Compound 1C (1.35 g, 5 mmol), compound 2C obtained in step (2) (15 mmol), and 1,8-diazabicyclo[5.4.0]-7-undecene (5 mmol) were dissolved in acetonitrile (30 mL), heated to 80 °C, and reacted for 5 days. After returning to room temperature, it was concentrated to remove most of the acetonitrile, water (20 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 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) + ).

[0054] Step (4): Dissolve the compound 2D (924 mg, 2 mmol) obtained in step (3) in methanol and water (5 / 5 mL), add sodium hydroxide (160 mg, 4 mmol), react at room temperature, monitor by TLC. When the raw materials are completely consumed, extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (dichloromethane:methanol = 100:0 - 100:5) to obtain compound 2. (LCMS(ESI+): 349.14(M+H) + )。

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

[0056] The retention times were as follows. Compound 2-1 was 8.493 minutes (exceeding 98% ee), and compound 2-2 was 9.994 minutes (exceeding 98% ee).

[0057] Example 3: Synthesis of compound 3

Chemical formula

[0058] Example 4: Synthesis of compound 4

Chemical formula

[0059] Example 5: Synthesis of Compound 5 [Chemical formula] According to the synthetic route of Example 2, using 4-(trifluoromethyl)cyclohexanemethanol as the starting material for synthesis, Compound 5 was obtained. LCMS(ESI+): 389.17(M+H) + .

[0060] Example 6: Synthesis and Resolution of Compound 6 [Chemical formula] According to the synthetic route of Example 1, using 4,4,4-trifluorobutanaldehyde (4,4,4-TRIFLUOROBUTYRALDEHYDE) as the starting material for synthesis, Compound 6 was obtained. LCMS(ESI+): 335.12(M+H) + .

[0061] (Resolution of Compound 6) [Chemical formula] 6-1 6-2 The resolution conditions were as follows. Compound 6 was dissolved in n-hexane:ethanol = 80:20 (V:V) (concentration 10 mg / mL). ChiralCel OD-H (0.46 cm I.D × 25 cm L) 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, UV was 254 nm, and the column temperature was 30 °C.

[0062] The retention times were as follows. Compound 6-1 was 9.295 minutes (exceeding 98% ee), and Compound 6-2 was 11.252 minutes (exceeding 98% ee).

[0063] Example 7: Synthesis of Compound 7

Chemical Structure

[0064] Example 8: Synthesis of Compound 8

Chemical Structure

[0065] Example 9: Synthesis of Compound 9

Chemical Structure

[0066] Example 10: Synthesis of Compound 10

Chemical Structure

[0067] Example 11: Other Preparation Examples The preparation examples of other specific compounds were as follows.

Table 1

[0068] Example 12: JAK2 / JAK3 Kinase Inhibition Activity Test 1. Consumables for Experiment JAK2: Carna 09-045 14CBS-0374 H JAK3: Carna 08-046 19CBS-0798 B ATP (10 mM): CST 9804 DTT: 100 mM MgCl2: 1 M 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 Medical Technology Co., Ltd., CAS No.: 941678-49-5

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

[0070] 3. JAK2 Kinase Inhibition Activity Test 3.1 Preparation of Reagents 1) Preparation of 1× kinase buffer. The 5× kinase buffer was diluted with sterile water to 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 adjusted to 5× of the final concentration, i.e., 0.04 ng / μL. First, it was diluted to 1.66 ng / μL, and then further diluted 41.5-fold from 1.66 ng / μL to prepare 0.04 ng / μL. 3) Preparation of 5× ATP. It was 4 μM ATP, and it was adjusted to 5× of it, i.e., 20 μM. Diluting directly 500-fold from 10 mM ATP resulted in the predetermined ATP concentration. 4) Preparation of 5× substrate. It was 5× of 1 μM, i.e., 5 μM. Since the substrate concentration was 500 μM, diluting 100-fold resulted in 5 μM substrate. 5) Preparation of 2.5× test compound. The concentration of the test compound buffer was 10 mM, and the treatment concentration was from 10 μM. First, it was diluted 10-fold from 10 mM to prepare 100× buffer, i.e., 1 mM, and then diluted in a 1:3 gradient to a total of 10 concentrations. Taking 2 μL from the diluted test compound solution and adding it to 78 μL of 1× kinase buffer resulted in 2.5× test compound. Also, sucking out 2 μL of DMSO and adding it to 78 μL of 1× kinase buffer resulted in 2.5× DMSO. 6) Preparation of 1 μM Streptavidin-XL665. The concentration of Streptavidin-XL665 was 16.67 μM, and it may be diluted 16.67-fold with the measurement buffer during use. 7) 1× TK-Antibody-Eu 3 -Cryptate preparation. The TK-Antibody-Eu 3 -Cryptate stock solution was a 100× solution, and it may be diluted to 1× with the measurement buffer during use.

[0071] 3.2 Test method 1) Test compound-treated well (T-compound). In a HTRF 96-well microplate, 4 μL of the above 2.5× test compound was added, followed by adding 2 μL of 5× substrate to one side of the well and 2 μL of 5× JAK2 to the other side of the well. It was a DMSO control well (T-enzyme) without the test compound. 4 μL of the above 2.5× DMSO was added to an HTRF 96-well microplate, followed by adding 2 μL of 5× substrate to one side of the well and 2 μL of 5× JAK2 to the other side of the well. It was a blank control (T-without enzyme) without enzyme. 4 μL of the above 2.5× DMSO was added to an HTRF 96-well microplate, followed by adding 2 μL of 5× substrate to one side of the well and 2 μL of 1× kinase buffer to the other side of the well. 2) The plate was sealed with a seal plate film, placed in a centrifuge, and centrifuged at 1000 rpm for 2 minutes. 3) 2 μL of 5× ATP was added to each well, sealed with a seal plate film, centrifuged at 1000 rpm for 1 minute, and the plate was placed in an incubator at 30 °C and incubated for 2 hours. 4) When the incubation was completed, the above Streptavidin-XL665 and 1× TK-Antibody-Eu 3 -Cryptate were mixed at a ratio of 1:1, 10 μL was added to each well, and centrifuged at 1000 rpm for 1 minute. 5) The plate was returned to the incubator and incubated for an additional 1 hour. After the incubation was completed, the HTRF 620 / 665 signal was read in a multifunctional microplate reader.

[0072] 4. JAK3 Kinase Inhibition Activity Test 4.1 Preparation of Reagents 1) It was the preparation of 1× kinase buffer. 5× kinase buffer was diluted with sterile water to 1× kinase buffer, and then 5 mM MgCl2 and 1 mM DTT were added. 2) It was the preparation of 5× JAK3. The concentration of JAK3 was 124 ng / μL, adjusted to 5× of the final concentration, i.e., 0.5 ng / μL, and diluted 248-fold to reach the predetermined concentration. 3) Preparation of 5×ATP. It was 3 μM ATP, and it was adjusted to 5×, i.e., 15 μM. Diluting directly 666.67-fold from 10 mM ATP resulted in the predetermined ATP concentration. 4) Preparation of 5× substrate. It was 1 μM of 5×, i.e., 5 μM. Since the substrate concentration was 500 μM, diluting 100-fold resulted in 5 μM substrate. 5) Preparation of 2.5× test compound. The concentration of the test compound buffer was 10 mM, and the treatment concentration was from 10 μM. First, it was diluted 10-fold from 10 mM to prepare 100× buffer, i.e., 1 mM, and then, by serial dilution with a 1:3 gradient, a total of 10 concentrations were obtained. Taking 2 μL from the diluted test compound solution and adding it to 78 μL of 1× kinase buffer resulted in 2.5× test compound. Also, sucking out 2 μL of DMSO and adding it to 78 μL of 1× kinase buffer resulted in 2.5× DMSO. 6) Preparation of 1 μM Streptavidin-XL665. The concentration of Streptavidin-XL665 was 16.67 μM, and it may be diluted 16.67-fold with the measurement buffer during use. 7) 1×TK-Antibody-Eu 3 -Cryptate preparation. The TK-Antibody-Eu 3 -Cryptate stock solution was a 100× solution, and it may be diluted to 1× with the measurement buffer during use.

[0073] 4.2 Test method 1) Test compound-treated wells (T-compound). In a HTRF 96-well microplate, 4 μL of the above 2.5× test compound was added, followed by adding 2 μL of 5× substrate to one side of the well and 2 μL of 5× JAK3 to the other side of the well. DMSO control wells without test compound (T-enzyme). In a HTRF 96-well microplate, 4 μL of the above 2.5× DMSO was added, followed by adding 2 μL of 5× substrate to one side of the well and 2 μL of 5× JAK3 to the other side of the well. It was a blank control without enzyme (T-without enzyme). To the HTRF 96-well microplate, 4 μL of the above 2.5× DMSO was added, followed by adding 2 μL of 5× substrate to one side of the well and 2 μL of 1× kinase buffer to the other side of the well. 2) Seal the plate with a sealing plate film, place it in a centrifuge, and centrifuge 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 place the plate in an incubator at 30 °C for 3 hours for incubation. 4) When the incubation is completed, mix the above Streptavidin-XL665 and 1× TK-Antibody-Eu 3 -Cryptate at a ratio of 1:1, add 10 μL to each well, and centrifuge at 1000 rpm for 1 minute. 5) Return the plate to the incubator and continue to incubate for 1 hour. After the incubation is completed, read the HTRF 620 / 665 signal in 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 of the test compound against the kinase at different concentrations, fit with GraphPad Prism 6 to obtain the half-maximal inhibitory concentration (IC 50 )

[0075] The JAK2 and JAK3 kinase inhibitory activities of the representative compounds of this application and the positive control drug ruxolitinib were measured in the above tests, and the measured IC 50 values are shown in Table 2 below.

[0076]

Table 2

[0077] Example 13: Pharmacokinetic Test 1. Experimental Animals Three healthy male C57 mice, 6 - 8 weeks old, were purchased from Shanghai Sippe-Bk Lab Animal Co., Ltd.

[0078] 2. Experimental Method Before oral administration, the mice were fasted overnight, and feeding was resumed 4 hours after administration. They were allowed to drink water without restriction. The compound was administered intragastrically to the mice at a dose of 10 mg / kg body weight, and whole blood samples were collected using the method of semi - continuous blood sampling from the facial vein of the mice. Approximately 30 μL of blood was collected at 0.125 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after administration to the test animals, placed in test tubes containing the anticoagulant sodium heparin, and kept on ice in preparation for centrifugation. Within 15 minutes, centrifugation was performed at 6800 g for 6 minutes in a centrifuge at 6 - 8°C. Within 1 hour after 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 was Luna (registered trademark) Omega ACQUITY UPLC BEH C18 (2.1×50 mm, 1.7 μm). Mobile phase A was H2O - 0.1% FA, mobile phase B was ACN - 0.1% FA, and the flow rate was 0.80 mL / min. The gradient elution program was: start, 10% B for 0.6 min, 10% B for 1.0 min, 90% B for 1.11 min, 90% B for 1.40 min, 10% B. The column temperature was 40°C, and the injection volume was 2 μL.

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

[0081] 4. Preparation of plasma samples 10 μL of plasma sample was obtained, 200 μL of internal standard working solution (tolbutamide, 100 ng / mL) was added, vortexed for 1 minute, centrifuged at 18,000 g for 10 minutes, 200 μL of the supernatant was transferred to a 96-well microplate, and 1 μL of the supernatant was taken for LC-MS / MS analysis.

[0082] 5. Result analysis Pharmacokinetic (PK) parameters were calculated using Phoenix WinNonlin 7.0. By the non-compartmental model, mouse oral pharmacokinetic parameters (AUC, C max , T max , T1 / 2, etc.) were estimated. For the representative compounds of the present application (produced in the above examples, among which Compound 2 is a mixture of Compound 2-1 and Compound 2-2) and the mouse oral pharmacokinetic parameter results of the positive control drug, nilotinib, refer to Table 3.

Table 3

[0083] As can be seen from Table 3, the compounds of the present application have obvious pharmacokinetic advantages because both the half-life (T1 / 2) and the exposure at the unit dose (AUC (0-∞) d.n.) are significantly higher than those of the positive control drug, nilotinib.

[0084] Finally, it should be explicitly stated that the above embodiments are not intended to limit the technical solutions of this application, but merely to explain them. Although this 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 correct the technical solutions described in each of the above embodiments or make equivalent substitutions for some of their technical features. By these corrections or substitutions, the gist of the targeted technical solutions will not deviate from the gist and scope of the technical solutions of each embodiment of this application.

Industrial Applicability

[0085] The compound containing a geminal difluoro group represented by formula (I) provided by this application has good JAK2 kinase inhibitory activity and high selectivity for JAK2 kinase. In addition, the compound of this application also 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.

Claims

1. A compound represented by formula (I), its chiral enantiomer, or a pharmaceutically acceptable salt thereof. 【Chemical 1】 (I) (In formula (I), A is an alkyl group or a cycloalkyl group, provided that the alkyl group or the cycloalkyl group is optionally substituted by fluorine, an alkyl group, or a cycloalkylene group, and the alkyl group, the cycloalkyl group, or the cycloalkylene group has at least one pair of geminal difluoro groups. X is H or (CH ２ ) ｎ , provided that n is 0, 1, 2, 3, 4 or 5, and when X is (CH ２ ) ｎ , X is linked to A to form a C ３ -C ７ cycloalkylene group, the cycloalkylene group is optionally substituted by a fluorine or an alkyl group, and the cycloalkylene group or the alkyl group has at least one pair of geminal difluoro groups.).

2. The compound according to claim 1, its chiral enantiomer, or a pharmaceutically acceptable salt thereof, characterized by having the structure represented by formula (II). 【Chemical 2】 (II) (In formula (II), Y １ is CR １ wherein, however, R １ is bond, H or F, Z is a bond or (CH ２ ) ｍ where 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 by fluorine, an alkyl group or a cycloalkylene group, or Y ２ is Z or Y １ is linked to C ３ -C ７ to form a cycloalkylene group, X is H or (CH ２ ) ｎ , provided that n is 0, 1, 2, 3, 4 or 5, and when X is (CH ２ ) ｎ , X is linked to Y １ , Z or Y ２ to form a C ３ -C ７ cycloalkylene group. )

3. Y １ is CR １ wherein, provided that R １ is a bond Z is bonded or (CH ２ ) ｍ where m is 1, 2 or 3, provided that Y ２ is an alkylene group, X is (CH ２ ) ｎ where n is 0, 1, 2, 3, 4 or 5, and X is Y １ is linked to C ３ ~C ７ to form a cycloalkylene group, preferably C ６ forms a cycloalkylene group The compound according to claim 2, its chiral enantiomer, or a pharmaceutically acceptable salt thereof, characterized by...

4. Y １ is CR １ wherein, however, R １ is F Z is bonded or (CH ２ ) ｍ wherein, however, m is 1, 2 or 3, Y ２ is an alkylene group, preferably a C １ -C ５ alkylene group, more preferably a C ２ -C ３ alkylene group, X is H The compound according to claim 2, its chiral enantiomer, or a pharmaceutically acceptable salt thereof, characterized by...

5. Y １ is CR １ wherein, however, R １ is F, Z is bonded or (CH ２ ) ｍ wherein, however, m is 1, 2 or 3, Y ２ is an alkylene group, X is (CH ２ ) ｎ wherein n is 1, 2, 3, 4 or 5, and X is linked to Z to form C ３ ~C ７ forms a cycloalkylene group, preferably C ６ forms a cycloalkylene group The compound according to claim 2, its chiral enantiomer, or a pharmaceutically acceptable salt thereof, characterized by...

6. Y １ is CR １ wherein, provided that R １ is a bond Z is bonded or (CH ２ ) ｍ wherein m is 1, 2 or 3, Y ２ is an alkylene group, and Y ２ is Y １ is linked to C ３ to C ７ to form a cycloalkylene group, preferably C ４ or C ６ to form a cycloalkylene group, X is H The compound according to claim 2, its chiral enantiomer, or a pharmaceutically acceptable salt thereof, characterized by...

7. Y １ is CR １ wherein, provided that R １ is F Z is (CH ２ ) ｍ wherein, m is 1, 2 or 3, Y ２ is an alkylene group, and Y ２ is linked to Z to form a C ３ -C ７ cycloalkylene group, preferably forming a C ６ cycloalkylene group, X is H The compound according to claim 2, its chiral enantiomer, or a pharmaceutically acceptable salt thereof, characterized by...

8. Y １ is CR １ wherein, however, R １ is F Z is bonded or (CH ２ ) ｍ wherein, m is 1, 2 or 3, Y ２ is an alkylene group or a cycloalkylene group, optionally substituted by an alkyl group, a cycloalkyl group or a cycloalkylene group, X is H The compound according to claim 2, its chiral enantiomer, or a pharmaceutically acceptable salt thereof, characterized by...

9. The following compound, its chiral enantiomer, or a pharmaceutically acceptable salt thereof. [Chemical Formula 3]

10. Step (1) 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) in which compound III-2 and compound III-3 undergo a Michael addition reaction under the conditions of the presence of a base and heating to produce compound III; Step (3) in which compound III is deprotected in the presence of a base to produce compound I, A method for producing the compound according to any one of claims 1 to 9, its chiral enantiomer, or a pharmaceutically acceptable salt thereof. 【Chemical Formula 4】

11. In step (1), the base is selected from any 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. In step (1), the solvent is an aprotic solvent. Preferably, the solvent is selected from any one or more of tetrahydrofuran, dimethylformamide, and dimethyl sulfoxide. In step (2), the base is selected from any 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. Preferably, the solvent is selected from any one or more of acetonitrile, N-methylpyrrolidone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methanol, and ethanol. In step (2), the heating temperature of the heating condition is 52 to 82 °C. In step (3), the base is selected from any one or more of sodium hydroxide, lithium hydroxide, and potassium hydroxide. The production method according to claim 10, characterized in that.

12. An intermediate having a structure represented by general formula (III) for producing the compound according to any one of claims 1 to 9, its chiral enantiomer, or a pharmaceutically acceptable salt thereof. 【Chemical Formula 5】 (III) (In formula (III), A is an alkyl group or a cycloalkyl group, provided that the alkyl group or the cycloalkyl group is optionally substituted by fluorine, an alkyl group, or a cycloalkylene group, and the alkyl group, the cycloalkyl group, or the cycloalkylene group has at least one pair of geminal difluoride groups. X is H or (CH ２ ) ｎ , provided that n is 0, 1, 2, 3, 4 or 5, and when X is (CH ２ ) ｎ , X is linked to A to form a C ３ -C ７ cycloalkylene group, the cycloalkylene group is optionally substituted by a fluorine or alkyl group, and the cycloalkylene group or the alkyl group has at least one pair of geminal difluoro groups.).

13. Step (1) 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) in which compound III-2 and compound III-3 undergo a Michael addition reaction under the conditions of the presence of a base and heating to produce compound III. The method for producing the intermediate according to claim 12. 【Chemical Formula 6】

14. In step (1), the base is selected from any 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; in step (1), the solvent is an aprotic solvent, preferably the solvent is selected from any one or more of tetrahydrofuran, dimethylformamide and dimethyl sulfoxide. In step (2), the base is selected from any 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, preferably the solvent is selected from any one or more of acetonitrile, N-methylpyrrolidone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methanol and ethanol; the heating temperature of the heating condition in step (2) is 52-82 °C. The production method according to claim 13, characterized in that.

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

16. Use of the compound according to any one of claims 1 to 9, its chiral enantiomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 15, in the manufacture of a drug for preventing and / or treating a disease associated with an abnormality in the JAK signaling pathway, preferably, the disease is an autoimmune disease, a myeloproliferative neoplastic disease or graft-versus-host disease, more preferably, the autoimmune disease is selected from rheumatoid arthritis, ulcerative colitis, systemic lupus erythematosus, atopic dermatitis or multiple sclerosis, more preferably, the myeloproliferative neoplastic disease is selected from essential thrombocythemia, myelofibrosis or polycythemia vera. More preferably, the use is such that the graft-versus-host disease is selected from acute graft-versus-host disease or chronic graft-versus-host disease.

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