Cyclopropanamide-containing compounds and uses thereof

Abstract

This application relates to the field of medicinal chemistry, specifically to cyclopropanamide-containing compounds represented by formula (I) and their uses, which have great medical value and market potential for autoimmune diseases and myeloproliferative neoplasms. [Formula 1] TIFF2025501662000047.tif33170

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to a Chinese patent application filed on January 18, 2022, bearing application number 202210052435.5 and entitled "Cyclopropanamide-Containing Compounds and Their Uses," the entire contents of which are incorporated herein by reference. [Technical field]

[0002] This application relates to the field of medicinal chemistry, and in particular to cyclopropanamide-containing compounds and their uses. [Background technology]

[0003] Protein kinases are a family of enzymes that catalyze the phosphorylation of specific residues in proteins, and are broadly classified as tyrosine and serine / threonine kinases. Inappropriate kinase activity due to mutation, overexpression or inappropriate regulation, dysregulation or disregulation, and overproduction or underproduction of growth factors and cytokines are related to many diseases, including but not limited to cancer, cardiovascular disease, hypersensitivity reactions, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative diseases (e.g., Alzheimer's disease). Therefore, protein kinases have already become one of the important enzymes as target spots for therapeutic intervention.

[0004] The Janus kinase (JAK) family is a type of non-receptor protein tyrosine kinase that plays an important role in cytokine receptor signaling pathways through interactions with signal transducer and activator of transcription (STAT). STAT is a group of cytoplasmic proteins that can bind to target gene regulatory DNA. As downstream substrates of JAK, STAT is activated by tyrosine phosphorylation under the stimulation of external signals, and then enters the cell nucleus to regulate gene transcription.

[0005] The regulation of many aberrant immune responses, such as allergy, asthma, (xeno)transplant rejection, autoimmune diseases such as rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, and hematological malignancies such as myeloproliferative disorders, leukemias and lymphomas, are all linked to the JAK / STAT signaling pathway.

[0006] The Janus kinase (JAK) family includes four members: JAK1, JAK2, JAK3, and TYK2. JAK1, JAK2, and TYK2 are widely present in various tissues and cells, while JAK3 is mainly distributed in lymphocytes.

[0007] JAK1 can bind to IL-10, IL-19, IL-20, IL-22, IL-26, IL-28, IFN-а, IFN-γ, IL-6 of the gp130 family, and other receptors containing γc, etc. (Rodig S.J.,etal.Cell,1998,93:373-383). JAK1 is a novel target spot in the field of diseases such as immune-related diseases, inflammation, and cancer. JAK1 inhibitors can be used to treat / prevent autoimmune diseases inflammatory (Hornakova T.,etal.,Blood,2010,115:3287-3295), such as leukemia, lymphoma, melanoma, arthritis, psoriasis, lupus erythematosus, acquired immune deficiency syndrome (Hou S.,etal.,HμM.Genet.,2013,132:1049-1058), etc.

[0008] JAK2 plays an important role in the regulation of multiple receptor signals, including IL-3, IFN-γ, EPO, GH, etc. (Levy D.E., et al., Nat. Rev. Mol. Cell Biol., 2002, 3:651-662). JAK2 inhibitors have great medical value and market potential for the treatment of diseases such as myelofibrosis, solid tumors, and hematological tumors.

[0009] JAK3 regulates cell signaling by binding to the common gamma chain (γc) in the cytokine receptor complexes of IL-2, IL-4, IL-7, IL-9, IL-15, IL-21, etc. JAK3 inhibitors can block T cell activation and prevent transplant rejection after transplant surgery. In addition, JAK3 inhibitors can also regulate the functions of lymphocytes, macrophages, and mast cells. JAK3 inhibitors are expected to be used for the treatment or prevention of several diseases related to the functions of lymphocytes, macrophages, or mast cells.

[0010] Torfatinib is the first FDA approved novel oral JAK inhibitor, which acts on JAK1 and JAK3 and is used to treat rheumatoid arthritis (RA). However, while torfatinib relieves RA symptoms, it also causes some side effects, including the occurrence of certain infections, malignancies and lymphomas. Studies have found that the overall risk of infection and mortality from torfatinib is similar to that of treating RA with biologics. Given the pleiotropic effects of JAK on many regulatory pathways and immune processes, selective JAK inhibitors have already become an important direction of current research, since non-selective JAK inhibitors carry the risk of adverse reactions.

[0011] Filgotinib, a new generation JAK1 selective inhibitor developed by Galapagos, Belgium, reduces the risk of anemia or infection caused by tolfatinib. However, Filgotinib has relatively weak activity and its clinical dose is relatively high, while its IC50 for JAK1 is greater than 10 nM (Expert Opin. Investig. Drugs. 2016, 25, 1355).

[0012] Although a series of JAK inhibitors have been disclosed on the market, there is still a need to develop new compounds with better efficacy and JAK selectivity. Through continuous efforts, the present application has developed a compound having a structure represented by general formula (I), and found that the compound having such a structure shows excellent effects. Summary of the Invention [Problem to be solved by the invention]

[0013] The present application aims to provide a cyclopropanamide-containing compound. The cyclopropanamide-containing compound is selected from the group consisting of compounds represented by general formula (I), stereoisomers thereof, and pharma- ceutically acceptable salts thereof. The stereoisomers include enantiomers, diastereomers, meso compounds, racemates, and the like. [Means for solving the problem]

[0014] In order to achieve the above object, the present application employs the following technical solutions:

[0015] The present application provides a compound represented by general formula (I), a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof. [ka] During the ceremony, X is selected from -CH or N; Y is selected from hydrogen or halogen, n is 1 or 2; TIFF2025501662000003.tif22170, where m is an integer from 1 to 4; TIFF2025501662000004.tif48170R is selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, or a halogen; Z1, Z2 and Z3 are each independently selected from -C(R3R4)-, -S(O)2-, -S(O)-, -CH(S(O)2R')-, or -CH(S(O)2NR'R'')-; R1 and R2 are each independently selected from hydrogen, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, or a C3-C7 cycloalkyl group; R' and R'' are each independently selected from a substituted or unsubstituted C1-C6 alkyl group or a C3-C7 cycloalkyl group, and the substituted group is selected from the group consisting of halogen, a C1-C6 alkoxy group, a C1-C6 alkylthio group, a C3-C7 cycloalkyl group, a hydroxy group, an amino group, an NHC1-C6 alkyl group, and an N(C1-C6 alkyl group)2; R3 and R4 are each independently selected from hydrogen, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, or a C3-C7 cycloalkyl group.

[0016] Preferably, the above compound, its stereoisomer or its pharma- ceutically acceptable salt has a structure represented by general formula (II): [ka] During the ceremony, X is selected from -CH or N; Y is selected from hydrogen or halogen, n is 1 or 2; m is an integer from 1 to 4; TIFF2025501662000006.tif22170R is selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, or a halogen; Z1, Z2 and Z3 are each independently selected from -C(R3R4)-, -S(O)2-, -S(O)-, -CH(S(O)2R')-, or -CH(S(O)2NR'R'')-; and when Y is hydrogen, Z2 is not -S(O)2-; R' and R'' are each independently selected from a substituted or unsubstituted C1-C6 alkyl group or a C3-C7 cycloalkyl group, and the substituted group is selected from the group consisting of halogen, a C1-C6 alkoxy group, a C1-C6 alkylthio group, a C3-C7 cycloalkyl group, a hydroxy group, an amino group, an NHC1-C6 alkyl group, and an N(C1-C6 alkyl group)2; R3 and R4 are each independently selected from hydrogen, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, or a C3-C7 cycloalkyl group.

[0017] Preferably, the above compound, its stereoisomer or its pharma- ceutically acceptable salt has a structure represented by general formula (III). [ka] During the ceremony, X is selected from -CH or N; Y is selected from hydrogen or halogen, n is 1 or 2; TIFF2025501662000008.tif22170 R1 and R2 are each independently selected from hydrogen, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, or a C3-C7 cycloalkyl group; R' is selected from substituted or unsubstituted C1-C6 alkyl groups or C3-C7 cycloalkyl groups, and the substituted groups are selected from the group consisting of halogen, C1-C6 alkoxy groups, C1-C6 alkylthio groups, C3-C7 cycloalkyl groups, hydroxy groups, amino groups, NHC1-C6 alkyl groups, and N(C1-C6 alkyl groups)2.

[0018] Preferably, the above compound, its stereoisomer or its pharma- ceutically acceptable salt has a structure represented by general formula (IV). [ka] During the ceremony, X is selected from -CH or N; Y is selected from hydrogen or halogen, n is 1 or 2; m is an integer from 1 to 4; R is selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, or a halogen; Z1 is selected from -C(R3R4)-, -S(O)2-, -S(O)-, -CH(S(O)2R')-, or -CH(S(O)2NR'R'')-; R' and R'' are each independently selected from a substituted or unsubstituted C1-C6 alkyl group or a C3-C7 cycloalkyl group, and the substituted group is selected from the group consisting of halogen, a C1-C6 alkoxy group, a C1-C6 alkylthio group, a C3-C7 cycloalkyl group, a hydroxy group, an amino group, an NHC1-C6 alkyl group, and an N(C1-C6 alkyl group)2; R3 and R4 are each independently selected from hydrogen, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, or a C3-C7 cycloalkyl group.

[0019] Preferably, the above compound, its stereoisomer or its pharma- ceutically acceptable salt has a structure represented by general formula (V). [ka] During the ceremony, X is selected from -CH or N; Y is selected from hydrogen or halogen, n is 1 or 2; m is an integer from 1 to 4; R is selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, or a halogen; Z2 is selected from -C(R3R4)-, -S(O)2-, -S(O)-, -CH(S(O)2R')-, or -CH(S(O)2NR'R'')-, and when Y is hydrogen, Z2 is not -S(O)2-; R' and R'' are each independently selected from a substituted or unsubstituted C1-C6 alkyl group or a C3-C7 cycloalkyl group, and the substituted group is selected from the group consisting of halogen, a C1-C6 alkoxy group, a C1-C6 alkylthio group, a C3-C7 cycloalkyl group, a hydroxy group, an amino group, an NHC1-C6 alkyl group, and an N(C1-C6 alkyl group)2; R3 and R4 are each independently selected from hydrogen, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, or a C3-C7 cycloalkyl group.

[0020] Preferably, the above compound, its stereoisomer or its pharma- ceutically acceptable salt has a structure represented by general formula (VI): [ka] During the ceremony, X is selected from -CH or N; Y is selected from hydrogen or halogen, n is 1 or 2; m is an integer from 1 to 4; R is selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, or a halogen; Z3 is selected from -C(R3R4)-, -S(O)2-, -S(O)-, -CH(S(O)2R')-, or -CH(S(O)2NR'R'')-; R' and R'' are each independently selected from a substituted or unsubstituted C1-C6 alkyl group or a C3-C7 cycloalkyl group, and the substituted group is selected from the group consisting of halogen, a C1-C6 alkoxy group, a C1-C6 alkylthio group, a C3-C7 cycloalkyl group, a hydroxy group, an amino group, an NHC1-C6 alkyl group, and an N(C1-C6 alkyl group)2; R3 and R4 are each independently selected from hydrogen, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, or a C3-C7 cycloalkyl group.

[0021] Preferably, the above compound, its stereoisomer or its pharma- ceutically acceptable salt has a structure represented by general formula (VII). [ka] During the ceremony, X is selected from -CH or N; Y is selected from hydrogen or halogen, n is 1 or 2; R1 and R2 are each independently selected from hydrogen, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, or a C3-C7 cycloalkyl group.

[0022] Preferably, the above compound, its stereoisomer or its pharma- ceutically acceptable salt has a structure represented by general formula (VIII). [ka] During the ceremony, X is selected from -CH or N; Y is selected from hydrogen or halogen, n is 1 or 2; R' is selected from substituted or unsubstituted C1-C6 alkyl groups or C3-C7 cycloalkyl groups, and the substituted groups are selected from the group consisting of halogen, C1-C6 alkoxy groups, C1-C6 alkylthio groups, C3-C7 cycloalkyl groups, hydroxy groups, amino groups, NHC1-C6 alkyl groups, and N(C1-C6 alkyl groups)2.

[0023] Preferably, Y is selected from H or F.

[0024] Preferably, in the above general formula Selected from TIFF2025501662000014.tif15170.

[0025] Preferably, in the above general formula (IV), Z1 is selected from -CH(SO2R')-, where R' is selected from unsubstituted C1-C6 alkyl groups or C3-C7 cycloalkyl groups, and R is selected from hydrogen, methyl group, methoxy group or halogen.

[0026] Preferably, in the above general formula (V), when Y is hydrogen, Z2 is selected from -CR3R4-, or -CH(S(O)2R')-, further, where R3 and R4 are each independently selected from hydrogen, halogen, C1-C6 alkyl group, C1-C6 haloalkyl group, or C3-C7 cycloalkyl group, R' is selected from C1-C6 alkyl group, or C3-C7 cycloalkyl group, R is selected from hydrogen, methyl group, methoxy group, or halogen, and when Y is halogen, Z2 is selected from -SO2-, and R is selected from hydrogen, methyl group, methoxy group, or halogen.

[0027] Preferably, in the above general formula (VI), Z3 is selected from -SO2- or -S(O)-, and R is selected from hydrogen, a methyl group, a methoxy group or a halogen.

[0028] Preferably, in the above general formula (VII), R1 and R2 are each independently selected from hydrogen, fluorine, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a t-butyl group, an s-butyl group, an n-pentyl group, a trifluoromethyl group, a cyclopropyl group, or a cyclopentyl group.

[0029] Preferably, in the above general formula (VIII), R' is selected from a substituted or unsubstituted methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, s-butyl group, n-pentyl group, isopentyl group, cyclopropyl group, and cyclopentyl group, and the substituted group is selected from the group consisting of halogen, C1-C6 alkoxy group, C1-C6 alkylthio group, C3-C7 cycloalkyl group, hydroxy group, amino group, NHC1-C6 alkyl group, and N(C1-C6 alkyl group)2.

[0030] Furthermore, the present application further provides a compound represented by the following formula, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: TIFF2025501662000015.tif137170

[0031] Furthermore, the present application further provides a compound represented by the following formula, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: TIFF2025501662000016.tif202170

[0032] Additionally, the present application further provides a pharmaceutical composition comprising a therapeutically effective amount of the above compound, its stereoisomer or a pharma- ceutically acceptable salt component, and a pharma- ceutically acceptable carrier.

[0033] Furthermore, the present application further provides a use of the above-mentioned compound, its stereoisomer or a pharma- ceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the manufacture of a medicament for treating a disease associated with an abnormality in the JAK signaling pathway.

[0034] Preferably, the disease is an autoimmune disease.

[0035] More preferably, the autoimmune disease is selected from rheumatoid arthritis, ulcerative colitis, atopic dermatitis or systemic lupus erythematosus.

[0036] Preferably, the disease is a myeloproliferative neoplasm.

[0037] More preferably, the myeloproliferative neoplasm is selected from essential thrombocytosis, polycythemia vera, or primary myelofibrosis.

[0038] Furthermore, the present application further provides a method for treating a disease associated with an abnormality in the JAK signaling pathway, the method comprising administering to a subject in need thereof a therapeutically effective amount of the above-mentioned compound, its stereoisomer or a pharma- ceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition.

[0039] Preferably, the disease is an autoimmune disease.

[0040] More preferably, the autoimmune disease is selected from rheumatoid arthritis, ulcerative colitis, atopic dermatitis or systemic lupus erythematosus.

[0041] Preferably, the disease is a myeloproliferative neoplasm.

[0042] More preferably, the myeloproliferative neoplasm is selected from essential thrombocytosis, polycythemia vera, or primary myelofibrosis.

[0043] The "therapeutically effective amount" varies depending on the subject, target organ, symptoms, administration method, etc., and can be determined by a physician's judgment, taking into consideration the type of dosage form, administration method, age and weight of the patient, symptoms of the patient, etc. Effect of the Invention

[0044] 1) The compounds of the present application have good JAK1, JAK2 or JAK3 kinase inhibitory activity, and have clear selectivity against JAK1, JAK2 or JAK3 kinase.

[0045] 2) The compounds of the present application have obvious pharmacokinetic advantages, provide more options for the prevention and / or treatment of diseases associated with abnormalities in the JAK signaling pathway, and have good prospects for clinical application. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0046] In order to make the objectives, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application are described below in a clear and complete manner, but obviously, the described embodiments are only some of the embodiments of the present application, and not all of the embodiments. Based on the embodiments of the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0047] Unless otherwise stated to the contrary, terms used in the specification and claims have the following meanings:

[0048] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. Preferred are alkyl groups containing 1 to 10 carbon atoms, more preferred are alkyl groups containing 1 to 6 carbon atoms, most preferred are alkyl groups containing 1 to 4 carbon atoms, and most preferred is a methyl group.

[0049] Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, s-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, and 5-methylhexyl. , 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and the various branched chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, s-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like.The alkyl group may be substituted or unsubstituted, and when substituted, the substitution group may be at any available attachment point, and is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxyl, or carboxylate.

[0050] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon-substituted 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 7 carbon atoms, and is most preferably a cyclopropyl group or a cyclopentyl group. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentene, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene (cycloheptatrienyl), cyclooctyl, and the like, preferably a cyclopropyl group or a cyclopentyl group. Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups. A cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituted groups are one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkyl groups, amino groups, halogens, sulfhydryl groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocyclic alkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocyclic alkoxy groups, cycloalkylthio groups, heterocyclic alkylthio groups, oxo groups, amino groups, haloalkyl groups, hydroxyalkyl groups, carboxyl groups, or carboxylate groups.

[0051] The term "alkoxy group" refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), where the definitions of alkyl group and cycloalkyl group are as above. Non-limiting examples include methoxy group, ethoxy group, propoxy group, butoxy group, cyclopropoxy group, cyclobutoxy group, cyclopentyloxy group, cyclohexyloxy group, etc. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituted groups are one or more groups independently selected from alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylthio group, alkyl group, amino group, halogen, sulfhydryl group, hydroxy group, nitro group, cyano group, cycloalkyl group, heterocyclic alkyl group, aryl group, heteroaryl group, cycloalkoxy group, heterocyclic alkoxy group, cycloalkylthio group, heterocyclic alkylthio group, amino group, haloalkyl group, hydroxyalkyl group, carboxyl group, or carboxylate group.

[0052] A "haloalkyl group" refers to an alkyl group substituted with one or more halogens, where alkyl is defined above.

[0053] A "hydroxy group" refers to an --OH group.

[0054] "Hydroxyalkyl group" refers to an alkyl group substituted with a hydroxy group, where alkyl group is defined above.

[0055] "Halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine or iodine.

[0056] An "amino group" refers to -NH2.

[0057] A "cyano group" refers to -CN.

[0058] A "nitro group" refers to --NO.sub.2.

[0059] An "oxo group" refers to =O.

[0060] A "carboxyl group" refers to -C(O)OH.

[0061] The term "carboxylate group" refers to -C(O)O (alkyl group) or -C(O)O (cycloalkyl group), where the alkyl group and the cycloalkyl group are defined above.

[0062] "Optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "an optional heterocycloalkyl group substituted with an alkyl group" means that the alkyl group may be present, but is not required to be present, and the description includes situations where the heterocycloalkyl group is substituted with an alkyl group and situations where the heterocycloalkyl group is not substituted with an alkyl group.

[0063] "Substituted" means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are replaced independently by a corresponding number of substitution groups. Needless to say, substitution groups are only present in their possible chemical positions, and a person skilled in the art can determine possible or impossible substitutions (by experiment or theory) without much effort. For example, amino or hydroxy groups with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (e.g., alkene) bond.

[0064] The technical solution of the present application will be further described below with reference to specific examples. Unless otherwise specified, the instruments, consumables, reagents, etc. used in the following examples can be obtained through conventional commercial means, and the experimental methods not specified in the examples can be selected according to conventional methods and conditions or according to the product instructions.

[0065] Example 1: Synthesis of Compounds 1-11 TIFF2025501662000017.tif142170Synthetic route of the general formula compound (IX) to which compounds 1-11 belong Step 1: Diethyl cyanomethylphosphonate (177 mg, 1 mmol) was dissolved in dry tetrahydrofuran (10 mL), and sodium hydride (60 mg, 1.5 mmol) was added under ice bath. After stirring for 1 hour, the corresponding aldehyde (1 mmol) was added. The reaction was stirred at room temperature overnight. After the reaction was completed, the reaction was quenched by adding saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was used directly in the next step. Step 2: N-(5-(1H-pyrazol-4-yl)imidazole[1,2-a]pyridin-2-yl)cyclopropanecarboxamide (134 mg, 0.5 mmol), the residue from the previous step (0.6 mmol) and 1,8-diazabicyclo[5,4,0]undecene-7 (2 drops) were dissolved in acetonitrile and heated to 80 ° C. to react for 8 hours. After returning to room temperature, water (20 mL) was added to the reaction mixture, which was then concentrated to remove most of the acetonitrile, and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (dichloromethane:methanol = 100:0-100:5) to obtain the compound.

[0066] Example 2: Synthesis of Compound 1 Following the synthesis route of Example 1, cyclopentylformaldehyde (cyclopentanecarbaldehyde) was used in step 1 to obtain compound 1 (70 mg), with a yield of 36%. LCMS (ESI+): 389.42 (M+H). + .

[0067] Example 3: Synthesis of Compound 2 Following the synthesis route of Example 1, cyclopropylformaldehyde (cyclopropanecarboxaldehyde) was used in step 1 to obtain compound 2 (100 mg), with a yield of 56%. LCMS (ESI+): 361.42 (M+H). + .

[0068] Example 4: Synthesis of Compound 3 Following the synthetic route of Example 1, 2-cyclopropylacetaldehyde was used in step 1 to obtain compound 3 (73 mg), with a yield of 39%. LCMS (ESI+): 375.38 (M+H). + .

[0069] Example 5: Synthesis of Compound 4 Following the synthetic route of Example 1, propionaldehyde was used in step 1 to obtain compound 4 (80 mg), with a yield of 41%. LCMS (ESI+): 349.16 (M+H). + .

[0070] Example 6: Synthesis of Compound 5 Following the synthetic route of Example 1, butyraldehyde was used in step 1 to obtain compound 5 (79 mg), yield 43%. LCMS (ESI+): 363.20 (M+H). + .

[0071] Example 7: Synthesis of Compound 6 Following the synthetic route of Example 1, compound 6 (55 mg) was obtained using 2-methoxyacetaldehyde in step 1, with a yield of 30%. LCMS (ESI+): 365.06 (M+H). + .

[0072] Example 8: Synthesis of Compound 7 Following the synthetic route of Example 1, compound 7 (72 mg) was obtained using valeraldehyde in step 1, with a yield of 38%. LCMS (ESI+): 377.08 (M+H). + .

[0073] Example 9: Synthesis of Compound 8 Following the synthetic route of Example 1, compound 8 (87 mg) was obtained using 4-methylvaleraldehyde in step 1, with a yield of 46%. LCMS (ESI+): 377.12 (M+H). + .

[0074] Example 10: Synthesis of Compound 9 Following the synthetic route of Example 1, 3-methoxypropionaldehyde was used in step 1 to obtain compound 9 (80 mg), with a yield of 42%. LCMS (ESI+): 379.09 (M+H). + .

[0075] Example 11: Synthesis of Compound 10 Following the synthetic route of Example 1, compound 10 (105 mg) was obtained using 4,4,4-trifluorobutyraldehyde in step 1, with a yield of 50%. LCMS (ESI+): 417.16 (M+H). + .

[0076] Example 12: Synthesis of Compound 11 Except for using N-(5-(1H-pyrazol-4-yl)-[1,2,4]triazolyl[1,5-a]pyridin-2-yl)cyclopropanecarboxamide instead of N-(5-(1H-pyrazol-4-yl)imidazole[1,2-a]pyridin-2-yl)cyclopropanecarboxamide in step 2, the rest of the synthesis was carried out according to the synthesis route of example 1, and cyclopentylformaldehyde was used in step 1 to obtain compound 11 (79 mg), with a yield of 41%. LCMS (ESI+): 390.25 (M+H) + .

[0077] Example 13: Synthesis of Compounds 12, 13, and 14 TIFF2025501662000018.tif73170Synthetic route for compound (X) of the general formula to which compounds 12, 13, and 14 belong Step 1: Diethyl cyanomethylphosphonate (177 mg, 1 mmol) was dissolved in dry tetrahydrofuran (10 mL), and sodium hydride (60 mg, 1.5 mmol) was added under ice bath, and after stirring for 1 hour, cyclohexanone derivative (1 mmol) was added. The reaction was stirred overnight at room temperature. The mixture was quenched by adding saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was used directly in the next step. Step 2: N-(5-(1H-pyrazol-4-yl)imidazole[1,2-a]pyridin-2-yl)cyclopropanecarboxamide (135 mg, 0.5 mmol), the residue obtained in step 1 (0.6 mmol) and 1,8-diazabicyclo[5,4,0]undecene-7 (2 drops) were dissolved in acetonitrile and heated to 80 ° C. for 8 hours. After returning to room temperature, water (20 mL) was added to the reaction mixture, which was then concentrated to remove most of the acetonitrile, and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (dichloromethane:methanol = 100:0-100:5) to obtain a compound.

[0078] Example 14: Synthesis of Compound 12 Following the synthetic route of Example 13, compound 12 (74 mg) was obtained using 4,4-difluorocyclohexanone in step 1, with a yield of 35%. LCMS (ESI+): 425.02 (M+H). + .

[0079] Example 15: Synthesis of Compound 13 Following the synthetic route of Example 13, compound 13 (113 mg) was obtained using 4-trifluoromethylcyclohexanone in step 1, with a yield of 49%. LCMS (ESI+): 457.01 (M+H). + .

[0080] Example 16: Synthesis of Compound 14 Following the synthetic route of Example 13, compound 14 (99 mg) was obtained using cyclohexanone in step 1, with a yield of 50%. LCMS (ESI+): 389.08 (M+H). + .

[0081] Example 17: Synthesis of Compound 15 TIFF2025501662000019.tif34170 Step 1: (4-(Bromomethyl)phenyl)-boronic acid (215 mg, 1 mmol) and 3-(methylsulfone)azetidine (135 mg, 1 mmol) were dissolved in acetonitrile, then potassium carbonate (207 mg, 1 mmol) was added in batches and reacted at room temperature overnight. The reaction was filtered and the filtrate was concentrated. The resulting residue was used directly in the next step. Step 2: The residue obtained in the previous step (135 mg, 0.5 mmol), N-(5-bromoimidazo[1,2-a]pyridin-2-yl)cyclopropanecarboxamide (140 mg, 1 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36 mg, 0.1 mmol) and potassium carbonate (138 mg, 2 mmol) were dissolved in dioxane (10 mL) and water (10 mL), purged with nitrogen three times, and reacted for 8 hours with stirring at 110 ° C. After returning to room temperature, water (20 mL) was added to the reaction mixture, 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 resulting residue was purified by column chromatography (dichloromethane:methanol=100:0-100:5) to obtain compound 15 (119 mg), with a yield of 56%. LCMS (ESI+): 212.99 (M / 2+H). + .

[0082] Example 18: Synthesis of Compound 16 TIFF2025501662000020.tif36170 Step 1: (4-(Bromomethyl)phenyl)-boronic acid (108 mg, 0.5 mmol) and 4-(methylsulfone)piperidine (84 mg, 0.5 mmol) were dissolved in acetonitrile (5 mL), then potassium carbonate (138 mg, 1 mmol) was added in batches and reacted at room temperature overnight, the reaction was filtered, the filtrate was concentrated, and the resulting residue was used directly in the next step. Step 2: Step 1 The obtained residue was dissolved in dioxane (10 mL) and water (10 mL), and then N-(5-bromoimidazo[1,2-a]pyridin-2-yl)cyclopropanecarboxamide (140 mg, 0.5 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36 mg, 0.1 mmol) and potassium carbonate (138 mg, 2 mmol) were added, and the mixture was purged with nitrogen three times and reacted at 110 ° C for 8 hours with stirring. After returning to room temperature, water (20 mL) was added to the reaction mixture, extracted with ethyl acetate (10 mL × 3), the organic phase was combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (dichloromethane:methanol = 100:0-100:5) to obtain compound 16 (108 mg), and the yield was 48%. LCMS(ESI+):227.13(M / 2+H) + .

[0083] Example 19: Synthesis of Compound 17 TIFF2025501662000021.tif86170 Step 1: Tetrahydro-2H-thiopyran-4-ol-1,1-dioxide (150 mg, 1 mmol) and p-toluenesulfonyl chloride (215 mg, 1 mmol) were dissolved in pyridine (5 mL) and reacted at room temperature overnight. After concentration, the residue was purified by column chromatography (petroleum ether:ethyl acetate=100:0-50:50) to obtain the compound 1,1-dioxotetrahydro-2H-thiopyran-4-yl-4-benzenesulfonate methyl ester. Step 2: p-Hydroxybenzeneboronic acid (138 mg, 1 mmol), N-(5-bromoimidazo[1,2-a]pyridin-2-yl)cyclopropanecarboxamide (279 mg, 1 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73 mg, 0.1 mmol) and potassium carbonate (276 mg, 2 mmol) were dissolved in dioxane (10 mL) and water (10 mL), purged with nitrogen three times, and reacted with stirring at 100 ° C. for 8 hours. After returning to room temperature, water (20 mL) was added to the reaction mixture, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (dichloromethane:methanol=100:0-100:5) to obtain the compound N-(5-(4-hydroxyphenyl)imidazole[1,2-a]pyridin-2-yl)cyclopropanecarboxamide. Step 3: 1,1-Dioxotetrahydro-2H-thiopyran-4-yl-4-benzenesulfonic acid methyl ester (152 mg, 0.5 mmol) obtained in step 1, N-(5-(4-hydroxyphenyl)imidazole[1,2-a]pyridin-2-yl)cyclopropanecarboxamide (146 mg, 0.5 mmol) obtained in step 2, and potassium carbonate (138 mg, 1 mmol) were added to N,N-dimethylformamide (5 mL), heated to 80 ° C., and reacted for 5 hours. After returning to room temperature, water (20 mL) was added to the reaction mixture, extracted with ethyl acetate (10 mL × 3), the organic phase was combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (dichloromethane:methanol = 100:0-100:5) to obtain compound 17 (137 mg), and the yield was 62%. LCMS(ESI+):425.98(M+H) + .

[0084] Example 20: Synthesis of Compound 18 TIFF2025501662000022.tif77170 Following the synthetic route of Example 19, compound 18 (104 mg) was obtained in 50% yield by using 2-fluoro-4-hydroxyphenylboronic acid instead of p-hydroxybenzeneboronic acid in step 2. LCMS (ESI+): 443.98 (M+H) + .

[0085] Example 21: Synthesis of Compound 19 TIFF2025501662000023.tif44170 Following the synthetic route of Example 19, N-(5-bromo-[1,2,4]triazole[1,5-a]pyridin-2-yl)cyclopropanecarboxamide was used instead of N-(5-bromoimidazo[1,2-a]pyridin-2-yl)cyclopropanecarboxamide in step 2 to obtain compound 19 (58 mg), with a yield of 43%. LCMS (ESI+): 427.15 (M+H) + .

[0086] Example 22: Synthesis of Compound 20 TIFF2025501662000024.tif40170 Step 1: (2-Fluoro-4-formylphenyl)boronic acid (168 mg, 1 mmol), 4-(methylsulfone)piperidine (135 mg, 1 mmol) and one drop of acetic acid were added to methanol and stirred at room temperature for 2 hours, after which sodium cyanoborohydride (126 mg, 2 mmol) was added and stirring was continued overnight. The reaction was concentrated, followed by addition of water (20 mL) and extraction 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 resulting residue was used directly in the next step. Step 2: The residue from step 1 was directly dissolved in dioxane (10 mL) and water (10 mL), and then N-(5-bromoimidazo[1,2-a]pyridin-2-yl)cyclopropanecarboxamide (140 mg, 0.5 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36 mg, 0.05 mmol) and potassium carbonate (138 mg, 1 mmol) were added, and the mixture was purged with nitrogen three times and stirred at 100 °C for 8 hours. After returning to room temperature, water (20 mL) was added to the reaction mixture, extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (dichloromethane:methanol = 100:0-100:5) to obtain compound 20 (120 mg), with a yield of 51%. LCMS(ESI+):236.13(M / 2+H) + .

[0087] Example 23: Synthesis of Compound 21 TIFF2025501662000025.tif73170 Step 1: Tetrahydrothiopyran-4-ol (590 mg, 5 mmol) and p-toluenesulfonyl chloride (1.1 g, 6 mmol) were dissolved in pyridine (10 mL) and reacted at room temperature overnight. After concentration, the residue was purified by column chromatography (petroleum ether:ethyl acetate=100:0-50:50) to obtain the compound tetrahydro-2H-thiopyran-4-yl-4-benzenesulfonate methyl. Step 2: p-Hydroxybenzeneboronic acid (1.38 g, 10 mmol), N-(5-bromo-[1,2,4]triazole[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (2.81 g, 10 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (730 mg, 1 mmol) and potassium carbonate (2.76 g, 20 mmol) were dissolved in dioxane (20 mL) and water (20 mL), purged with nitrogen three times, and reacted for 8 hours with stirring at 110 ° C. After returning to room temperature, water (20 mL) was added to the reaction mixture, 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. The obtained residue was purified by column chromatography (dichloromethane:methanol=100:0-100:5) to obtain the compound N-(5-(4-hydroxyphenyl)-[1,2,4]triazole[1,5-a]pyridin-2-yl)cyclopropanecarboxamide. Step 3: Tetrahydro-2H-thiopyran-4-yl-4-benzenesulfonic acid methyl ester (272 mg, 1 mmol) obtained in step 1, N-(5-(4-hydroxyphenyl)-[1,2,4]triazole[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (294 mg, 1 mmol) obtained in step 2, and potassium carbonate (276 mg, 2 mmol) were added to N,N-dimethylformamide (5 mL), heated to 80 ° C., and reacted for 5 hours. After returning to room temperature, water (20 mL) was added to the reaction mixture, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (dichloromethane:methanol=100:0-100:5) to obtain the compound N-(5-(4-((1-tetrahydrothiopyran-4-yl)oxy)phenyl)-[1,2,4]triazole[1,5-a]pyridin-2-yl)cyclopropanecarboxamide. N-(5-(4-((1-tetrahydrothiopyran-4-yl)oxy)phenyl)-[1,2,4]triazole[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (197 mg, 1 mmol) was dissolved in methanol (5 mL), and N-bromosuccinimide (178 mg, 2 mmol) and potassium tert-butoxide (112 mg, 2 mmol) were added under ice bath, and the mixture was reacted at room temperature overnight. Saturated saline (20 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3), and the organic phase was combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (dichloromethane:methanol = 100:0-100:5) to obtain compound 21 (66 mg), and the yield was 32%. LCMS (ESI+): 411.03 (M+H) + .

[0088] Example 24: Synthesis of Compound 22 TIFF2025501662000026.tif61170 Step 1: t-Butyl (5-bromoimidazo[1,2-a]pyridin-2-yl)carbamate (311 mg, 1 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (5 mL) was added under ice bath, and the mixture was reacted at room temperature for 5 hours, and then concentrated. The obtained residue was used directly in the next step. Step 2: The residue from step 1 was dissolved in dichloromethane (10 mL), trans 2-fluorocyclopropane carboxylic acid (114 mg, 1.1 mmol) was added, and N,N-diisopropylethylamine (260 mg, 2 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (570 mg, 1.5 mmol) were added under ice bath, and the mixture was reacted at room temperature overnight. After the reaction was completed, water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (dichloromethane:methanol=100:0-100:5) to obtain the compound trans-N-(5-bromoimidazo[1,2-a]pyridin-2-yl)-2-fluorocyclopropanecarboxamide. Step 3: trans-N-(5-bromoimidazo[1,2-a]pyridin-2-yl)-2-fluorocyclopropanecarboxamide (149 mg, 0.5 mmol), 4-{[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}thiomorpholine-1,1-dione (175 mg, 0.5 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36 mg, 0.05 mmol) and potassium carbonate (138 mg, 1 mmol) were dissolved in dioxane (10 mL) and water (10 mL), and the mixture was purged with nitrogen three times and reacted at 110 ° C. for 8 hours with stirring. After returning to room temperature, water (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (dichloromethane:methanol = 100:0-100:5) to give compound 22 (124 mg), with a yield of 56%. LCMS (ESI+): 443.55 (M+H). + . Then, the obtained compound 22 is divided, and the division conditions are as follows: first, compound 22 is dissolved in dichloromethane (concentration 10mg / mL), then diluted with ethanol to 2.5mg / mL, and HPLC chiral column UniChiral CMD-5H (21.2mm I.Dx250mmL) is used, ethanol / diethylamine (100:1) is used as the mobile phase, the flow rate is 12mL / min, UV is 254nm, and the column temperature is 25℃, and after division, compound 22-1 and compound 22-2 are obtained, respectively. Retention times: compound 22-1 was 10.69 min (>99% ee) and compound 22-2 was 13.54 min (>99% ee).

[0089] Example 25: Synthesis of Compound 23 TIFF2025501662000027.tif67170 Following the synthetic route of Example 24, t-butyl (5-bromo-[1,2,4]triazole[1,5-a]pyridin-2-yl)carbamate was used instead of t-butyl (5-bromoimidazo[1,2-a]pyridin-2-yl)carbamate in step 1 to obtain compound 23 (100 mg), with a yield of 45%. LCMS (ESI+): 444.17 (M+H) + . Then, the obtained compound 23 was split, and the splitting conditions were as follows: Compound 23 was dissolved in ethanol (4mg / mL), and HPLC chiral column UniChiral CMD-5H (21.2mm I.Dx250mmL) was used, the mobile phase was ethanol, the flow rate was 12mL / min, UV was 254nm, and the column temperature was 25℃. After splitting, compound 23-1 and compound 23-2 were obtained, respectively. Retention time: Compound 23-1 was 11.58 min (>99% ee), and compound 23-2 was 16.47 min (>99% ee).

[0090] Example 26: Synthesis of Compounds 24 to 33 Using appropriate raw materials, compounds 24 to 33 were synthesized with reference to the synthetic routes such as those in Examples 24 and 25.

[0091] Specifically, the compound numbers, structures, synthesis methods and characteristic data are as follows: TIFF2025501662000028.tif245170TIFF2025501662000029.tif107170

[0092] Example 27: JAK1 / JAK2 / JAK3 kinase inhibitory activity test 1. Experimental consumables JAK1:Thermo Fisher PV4774 2059141D JAK2:Carna 08-045 14CBS-0374 H JAK3:Carna 08-046 19CBS-0798 B ATP(10mM):CST 9804 DTT: 100 mM MgCl2: 1M MnCl2: 1M HTRF Kinase-TK kit: cis-bio 62TK0PEC HTRF 96 well low volume plate (HTRF 96 well microplate): cis-bio 66PL96100

[0093] 2. Test Conditions JAK1:0.32ng / μL, ATP 4μM, substrate 1μM, time 4h JAK2:0.008ng / μL, ATP 4μM, substrate 1μM, time 2h JAK3: 0.1ng / μL, ATP 3μM, substrate 1μM, time 3h

[0094] 3.JAK1 kinase inhibitory activity test 3.1 Preparation of reagents 1) Preparation of 1x kinase buffer: 5x kinase buffer was diluted with sterile water to 1x kinase buffer, then 5mM MgCl2, 1mM MnCl2 and 1mM DTT were added. 2) Preparation of 5xJAK1: The concentration of JAK1 mother solution is 160 ng / μL, and the mother solution is prepared to 5x the final concentration, i.e., 1.6 ng / μL, and then diluted 100-fold. 3) Preparation of 5x ATP: 4 µM ATP was prepared at 5x, i.e. 20 µM, and directly diluted 500-fold from 10 mM ATP to obtain the required ATP concentration. 4) Preparation of 5x substrate: 5x of 1 μM, i.e. 5 μM, substrate concentration was 500 μM, diluted to 100x, i.e. 5 μM substrate. 5) Preparation of 2.5x target compound: The concentration of compound buffer is 10mM, and the treatment concentration starts from 10μM. First, prepare 100x buffer, i.e. 1mM, dilute from 10mM to 10x, then dilute to a total of 10 concentrations with a 1:3 gradient. Take 2μL of the diluted compound and add it to 78μL of 1x kinase buffer, which becomes 2.5x target compound. Add 2μL of dimethyl sulfoxide (DMSO) to the positive control group and blank control group. 6) Preparation of 1 μM Streptavidin-XL665: The concentration of Streptavidin-XL665 is 16.67 μM, which is diluted 16.67-fold using detection buffer. 7) Preparation of 1x TK-Antibody: The TK-Antibody stock solution is a 100x solution, which is diluted to 1x with detection buffer prior to use.

[0095] 3.2 Testing Methodology 1) To an HTRF 96-well microplate, add 4 μL of 2.5× the compound to be detected as above, then add 2 μL of 5× substrate to one side of the well, add 2 μL of 5× JAK1 to the other side of the well, and add 2 μL of 1× kinase buffer to the blank control group. 2) The plate was sealed with a sealing plate film, placed in a centrifuge, and centrifuged at 1000 rpm for 2 minutes. 3) 2 μL of 5×ATP was added per well, the wells were sealed with a sealing plate film, centrifuged at 1000 rpm for 1 minute, and the plate was placed in a 30° C. incubator and incubated for 4 hours. 4) After the incubation was completed, the above 1 μM Streptavidin-XL665 and 1×TK-Antibody were mixed at a 1:1 ratio, 10 μL was added per well, and the plate was centrifuged at 1000 rpm for 1 minute. 5) The plate was placed back into the incubator and incubated for another 1 hour. After incubation was completed, the HTRF665 / 620 signal was read on the multifunctional microplate reader.

[0096] 4.JAK2 kinase inhibitory activity test 4.1 Preparation of reagents 1) Preparation of 1x kinase buffer: 5x kinase buffer was diluted with sterile water to 1x kinase buffer, then 5mM MgCl2 and 1mM DTT were added. 2) Preparation of 5xJAK2: The concentration of the JAK2 mother solution was 166 ng / μL, and it was adjusted to 5x the final concentration, i.e., 0.04 ng / μL. The mother solution was first diluted to 1.66 ng / μL, and then diluted 41.5 times from 1.66 ng / μL to adjust it to 0.04 ng / μL. 3) Preparation of 5x ATP: 4 µM ATP was prepared to 5x, i.e., 20 µM, and directly diluted 500-fold from 10 mM ATP to obtain the required ATP concentration. 4) Preparation of 5x substrate: 5x of 1 μM, i.e. 5 μM, substrate concentration was 500 μM, diluted to 100x to give 5 μM substrate. 5) Preparation of 2.5x target compound: The concentration of compound buffer is 10mM, and the treatment concentration is started from 10μM. First, prepare 100x buffer, i.e., 1mM, dilute from 10mM to 10x, and then dilute to a total of 10 concentrations with a 1:3 gradient. Take 2μL of the diluted compound and add it to 78μL of 1x kinase buffer, which becomes 2.5x target compound. Add 2μL of dimethyl sulfoxide (DMSO) to the positive control group and blank control group. 6) Preparation of 1 μM Streptavidin-XL665: The concentration of Streptavidin-XL665 is 16.67 μM, which is diluted 16.67-fold using detection buffer. 7) Preparation of 1x TK-Antibody: The TK-Antibody stock solution is a 100x solution, which is diluted to 1x with detection buffer prior to use.

[0097] 4.2 Testing Methodology 1) To an HTRF 96-well microplate, add 4 μL of 2.5× the compound to be detected as above, then add 2 μL of 5× substrate to one side of the well, add 2 μL of 5× JAK2 to the other side of the well, and add 2 μL of 1× kinase buffer to the blank control group. 2) The plate was sealed with a sealing plate film, placed in a centrifuge, and centrifuged at 1000 rpm for 2 minutes. 3) 2 μL of 5×ATP was added per well, the wells were sealed with a sealing plate film, centrifuged at 1000 rpm for 1 minute, and the plate was placed in a 30° C. incubator and incubated for 2 hours. 4) After the incubation was completed, the above 1 μM Streptavidin-XL665 and 1×TK-Antibody were mixed at a 1:1 ratio, 10 μL was added per well, and the plate was centrifuged at 1000 rpm for 1 minute. 5) The plate was placed back into the incubator and incubated for another 1 hour. After incubation was completed, the HTRF665 / 620 signal was read on the multifunctional microplate reader.

[0098] 5.JAK3 kinase inhibitory activity test 5.1 Preparation of reagents 1) Preparation of 1x kinase buffer: 5x kinase buffer was diluted with sterile water to 1x kinase buffer, then 5mM MgCl2 and 1mM DTT were added. 2) Preparation of 5xJAK3: The concentration of JAK3 mother solution was 124 ng / μL and was adjusted to 5x the final concentration, i.e., 0.5 ng / μL, and the mother solution was diluted 248-fold to obtain the required JAK3 concentration. 3) Preparation of 5x ATP: 3 µM ATP was prepared to 5x, i.e., 15 µM, and diluted 666.67-fold from 10 mM ATP to obtain the required ATP concentration. 4) Preparation of 5x substrate: 5x of 1 μM or 5 μM, substrate concentration was 500 μM, diluted to 100x to give 5 μM substrate. 5) Preparation of 2.5x target compound: The concentration of compound buffer is 10mM, and the treatment concentration starts from 10μM. First, prepare 100x buffer, i.e. 1mM, dilute from 10mM to 10x, then dilute to a total of 10 concentrations with a 1:3 gradient. Take 2μL of the diluted compound and add it to 78μL of 1x kinase buffer, which becomes 2.5x target compound. Add 2μL of dimethyl sulfoxide (DMSO) to the positive control group and blank control group. 6) Preparation of 1 μM Streptavidin-XL665: The concentration of Streptavidin-XL665 is 16.67 μM, and it is diluted 16.67-fold with detection buffer before use. 7) Preparation of 1x TK-Antibody: The TK-Antibody stock solution is a 100x solution, which is diluted to 1x with detection buffer prior to use.

[0099] 5.2 Testing Methodology 1) To an HTRF 96-well microplate, add 4 μL of 2.5× the compound to be detected as above, then add 2 μL of 5× substrate to one side of the well, add 2 μL of 5× JAK3 to the other side of the well, and add 2 μL of 1× kinase buffer to the blank control group. 2) The plate was sealed with a sealing plate film, placed in a centrifuge, and centrifuged at 1000 rpm for 2 minutes. 3) 2 μL of 5×ATP was added per well, the wells were sealed with a sealing plate film, centrifuged at 1000 rpm for 1 minute, and the plate was placed in a 30° C. incubator and incubated for 3 hours. 4) After the incubation was completed, the above 1 μM Streptavidin-XL665 and 1×TK-Antibody were mixed at a 1:1 ratio, 10 μL was added per well, and the plate was centrifuged at 1000 rpm for 1 minute. 5) The plate was placed back into the incubator and incubated for another 1 hour. After incubation was completed, the HTRF665 / 620 signal was read on the multifunctional microplate reader.

[0100] 6. Calculation of Percent Inhibition and IC 50 Fitting Inhibition rate = (positive control group - compound to be detected) / (positive control group - blank control group) x 100% The median inhibitory concentration (IC) was calculated using GraphPad Prism6 according to the inhibition rate of the kinase at different concentrations of the target compound. 50 ) was fitted.

[0101] The inhibitory activity of the representative compounds of the present application and the known control drug Filgotinib against JAK1, JAK2 and JAK3 kinases was measured by the above tests, and the measured IC 50 The values ​​are as shown in Table 1.

[0102] [Table 1]

[0103] As can be seen from Table 1, compared with the known control drug (Filgotinib), the compounds of the present application have good JAK1, JAK2 or JAK3 kinase inhibitory activity, and the compounds of the present application have obvious selectivity against JAK1, JAK2 or JAK3 kinase.

[0104] Example 28: Pharmacokinetic testing 1. Experimental Animals Three healthy male C57 mice, aged 6–8 weeks, were purchased from Shanghai Sino-British Sippr / BKLab Animal Co., Ltd.

[0105] 2. Experimental Method Mice were fasted overnight before oral administration, and food supply was resumed 4 hours after administration, and water was allowed ad libitum. Mice were intragastrically administered 10 mg compound / kg body weight, and whole blood samples were collected using the mouse facial vein semi-continuous blood collection method. 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, and placed in a test tube containing the anticoagulant sodium heparin, placed on ice until centrifugation within 15 min, and centrifuged at 6800 g for 6 min in a centrifuge at 6-8 °C. Plasma was transferred to a labeled test tube appropriately within 1 hour of blood collection / centrifugation and stored frozen at approximately -80 °C.

[0106] 3. Chromatography and Mass Spectrometry Conditions The chromatography column is Luna (登録商標) The system is an Omega ACQUITY UPLC BEH C18 (2.1 × 50 mm, 1.7 μm), mobile phase A is HO-0.1% FA, mobile phase B is ACN-0.1% FA, the flow rate is 0.80 mL / min, the gradient elution procedure is 10% B at the start, 10% B at 0.6 min, 90% B at 1.0 min, 90% B at 1.11 min, 10% B at 1.40 min, the column temperature is 40 °C, and the injection volume is 2 μL. Mass spectrometry method: LC-MS / MS-19 (TQ5500) (SCIEX, USA), the ion source was an ESI source, the detection mode was positive ion detection, the scan mode was multiple reaction monitoring (MRM) mode, and m / z: 271.10 / 172.00 Da (tolbutamide, internal standard).

[0107] 4. Plasma Sample Preparation 10 μL of plasma sample was taken, 200 μL of internal standard working solution (tolbutamide, 100 ng / mL) was added, vortexed for 1 min, centrifuged at 18,000 g for 10 min, 200 μL of the supernatant was transferred to a 96-well microplate, and 1 μL of the supernatant was injected into LC-MS / MS analysis.

[0108] 5. Analyzing the Results Pharmacokinetic (PK) parameters were calculated using Phoenix WinNonlin 7.0 software, and AUC, C max , T max The pharmacokinetic parameters of the mouse oral drug, including T1 / 2, etc., were estimated, and the results of the pharmacokinetic parameters of the representative compound 15 of the present application and the known control drug filgotinib, taken orally in mice, are shown in Table 2.

[0109] [Table 2]

[0110] As can be seen from Table 2, compared to the known control drug (Filgotinib), the compound 15 of the present application at a unit dose has a higher systemic exposure (AUC), thus providing a clear pharmacokinetic advantage.

[0111] Although the preferred embodiments of the present application have been described in detail above, the present application is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solutions of the present application within the technical concept of the present application, and all such simple modifications fall within the scope of protection of the present application.

[0112] It should be noted that the specific technical features described in the above specific embodiments may be combined in any suitable manner as long as there is no contradiction, and in this application, various possible combination manners are not separately described in order to avoid unnecessary duplication.

[0113] Furthermore, various different embodiments of the present application may be arbitrarily combined, and should be considered as the contents disclosed in the present application in the same manner, unless contrary to the spirit of the present application. [Industrial Applicability]

[0114] The present application provides a cyclopropanamide-containing compound and its preparation and use. The cyclopropanamide-containing compound provided in the present application has good inhibitory activity and clear selectivity against JAK1, JAK2 or JAK3 kinase, and has good pharmacokinetic characteristics, and has great medical value and market potential for diseases associated with abnormalities in the JAK signaling pathway (such as autoimmune diseases and myeloproliferative neoplasms).

Claims

1. A compound represented by the general formula (I), a stereoisomer thereof or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 [In the formula, X is selected from -CH or N; Y is selected from hydrogen or halogen, n is 1 or 2; 【change】 Where: m is an integer from 1 to 4; 【change】 R is hydrogen, C １ ~C ６ Alkyl group, C １ ~C ６ is selected from an alkoxy group or a halogen; Z １ , Z ２ and Z ３ are each independently -C(R ３ R ４ ) -, -S(O) ２ -, -S(O)-, -CH(S(O) ２ R')- or -CH(S(O) ２ NR′R″)-; R １ and R ２ are each independently hydrogen, halogen, or C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group or C ３ ~C ７ cycloalkyl groups, R′ and R″ are each independently a substituted or unsubstituted C １ ~C ６ Alkyl group or C ３ ~C ７ cycloalkyl groups, the substitution groups being selected from halogen, C １ ~C ６ Alkoxy group, C １ ~C ６ Alkylthio group, C ３ ~C ７ Cycloalkyl group, hydroxy group, amino group, NHC １ ~C ６ Alkyl groups and N(C １ ~C ６ Alkyl group) ２ is selected from the group consisting of R ３ and R ４ are each independently hydrogen, halogen, or C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group or C ３ ~C ７ cycloalkyl groups.

2. 2. A compound represented by general formula (I) according to claim 1, having a structure represented by general formula (II), a stereoisomer thereof or a pharma- ceutically acceptable salt thereof. 【Chemistry 2】 [In the formula, X is selected from -CH or N; Y is selected from hydrogen or halogen, n is 1 or 2; m is an integer from 1 to 4; 【change】 R is hydrogen, C １ ~C ６ Alkyl group, C １ ~C ６ is selected from an alkoxy group or a halogen; Z １ , Z ２ and Z ３ are each independently -C(R ３ R ４ ) -, -S(O) ２ -, -S(O)-, -CH(S(O) ２ R')- or -CH(S(O) ２ NR′R″)—, and when Y is hydrogen, Z ２ Ha-S(O) ２ -But, R′ and R″ are each independently a substituted or unsubstituted C １ ~C ６ Alkyl group or C ３ ~C ７ cycloalkyl groups, the substitution groups being selected from halogen, C １ ~C ６ Alkoxy group, C １ ~C ６ Alkylthio group, C ３ ~C ７ Cycloalkyl group, hydroxy group, amino group, NHC １ ~C ６ Alkyl groups and N(C １ ~C ６ Alkyl group) ２ is selected from the group consisting of R ３ and R ４ are each independently hydrogen, halogen, or C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group or C ３ ~C ７ cycloalkyl groups.

3. 2. A compound represented by general formula (I) according to claim 1, having a structure represented by general formula (III), a stereoisomer thereof or a pharma- ceutically acceptable salt thereof. 【Chemistry 3】 [In the formula, X is selected from -CH or N; Y is selected from hydrogen or halogen, n is 1 or 2; 【change】 R １ and R ２ are each independently hydrogen, halogen, or C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group or C ３ ~C ７ cycloalkyl groups, R' is a substituted or unsubstituted C １ ~C ６ Alkyl group or C ３ ~C ７ cycloalkyl groups, the substitution groups being selected from halogen, C １ ~C ６ Alkoxy group, C １ ~C ６ Alkylthio group, C ３ ~C ７ Cycloalkyl group, hydroxy group, amino group, NHC １ ~C ６ Alkyl groups and N(C １ ~C ６ Alkyl group) ２ is selected from the group consisting of

4. 3. A compound represented by general formula (I) according to claim 2, having a structure represented by general formula (IV), a stereoisomer thereof or a pharma- ceutically acceptable salt thereof. 【Chemistry 4】 [In the formula, X is selected from -CH or N; Y is selected from hydrogen or halogen, n is 1 or 2; m is an integer from 1 to 4; R is hydrogen, C １ ~C ６ Alkyl group, C １ ~C ６ is selected from an alkoxy group or a halogen; Z １ is -C(R ３ R ４ ) -, -S(O) ２ -, -S(O)-, -CH(S(O) ２ R')- or -CH(S(O) ２ NR′R″)-; R′ and R″ are each independently a substituted or unsubstituted C １ ~C ６ Alkyl group or C ３ ~C ７ cycloalkyl groups, the substitution groups being selected from halogen, C １ ~C ６ Alkoxy group, C １ ~C ６ Alkylthio group, C ３ ~C ７ Cycloalkyl group, hydroxy group, amino group, NHC １ ~C ６ Alkyl groups and N(C １ ~C ６ Alkyl group) ２ is selected from the group consisting of R ３ and R ４ are each independently hydrogen, halogen, or C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group or C ３ ~C ７ cycloalkyl groups.

5. 3. A compound represented by formula (I) according to claim 2, having a structure represented by formula (V), a stereoisomer thereof or a pharma- ceutically acceptable salt thereof. 【Chemistry 5】 [In the formula, X is selected from -CH or N; Y is selected from hydrogen or halogen, n is 1 or 2; m is an integer from 1 to 4; R is hydrogen, C １ ~C ６ Alkyl group, C １ ~C ６ is selected from an alkoxy group or a halogen; Z ２ is -C(R ３ R ４ ) -, -S(O) ２ -, -S(O)-, -CH(S(O) ２ R')- or -CH(S(O) ２ NR′R″)—, and when Y is hydrogen, Z ２ Ha-S(O) ２ -But, R′ and R″ are each independently a substituted or unsubstituted C １ ~C ６ Alkyl group or C ３ ~C ７ cycloalkyl groups, the substitution groups being selected from halogen, C １ ~C ６ Alkoxy group, C １ ~C ６ Alkylthio group, C ３ ~C ７ Cycloalkyl group, hydroxy group, amino group, NHC １ ~C ６ Alkyl groups and N(C １ ~C ６ Alkyl group) ２ is selected from the group consisting of R ３ and R ４ are each independently hydrogen, halogen, or C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group or C ３ ~C ７ cycloalkyl groups.

6. 3. The compound represented by general formula (I) according to claim 2, having a structure represented by general formula (VI), a stereoisomer thereof or a pharma- ceutically acceptable salt thereof. 【Chemistry 6】 [In the formula, X is selected from -CH or N; Y is selected from hydrogen or halogen, n is 1 or 2; m is an integer from 1 to 4; R is hydrogen, C １ ~C ６ Alkyl group, C １ ~C ６ is selected from an alkoxy group or a halogen; Z ３ is -C(R ３ R ４ ) -, -S(O) ２ -, -S(O)-, -CH(S(O) ２ R')- or -CH(S(O) ２ NR′R″)-; R′ and R″ are each independently a substituted or unsubstituted C １ ~C ６ Alkyl group or C ３ ~C ７ cycloalkyl groups, the substitution groups being selected from halogen, C １ ~C ６ Alkoxy group, C １ ~C ６ Alkylthio group, C ３ ~C ７ Cycloalkyl group, hydroxy group, amino group, NHC １ ~C ６ Alkyl groups and N(C １ ~C ６ Alkyl group) ２ is selected from the group consisting of R ３ and R ４ are each independently hydrogen, halogen, or C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group or C ３ ~C ７ cycloalkyl groups.

7. 4. A compound represented by general formula (I) according to claim 3, having a structure represented by general formula (VII), a stereoisomer thereof or a pharma- ceutically acceptable salt thereof. 【Chemistry 7】 [In the formula, X is selected from -CH or N; Y is selected from hydrogen or halogen, n is 1 or 2; R １ and R ２ are each independently hydrogen, halogen, or C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group or C ３ ~C ７ cycloalkyl groups.

8. 4. A compound represented by general formula (I) according to claim 3, having a structure represented by general formula (VIII), a stereoisomer thereof or a pharma- ceutically acceptable salt thereof. 【Chemistry 8】 [In the formula, X is selected from -CH or N; Y is selected from hydrogen or halogen, n is 1 or 2; R' is a substituted or unsubstituted C １ ~C ６ Alkyl group or C ３ ~C ７ cycloalkyl groups, the substitution groups being selected from halogen, C １ ~C ６ Alkoxy group, C １ ~C ６ Alkylthio group, C ３ ~C ７ Cycloalkyl group, hydroxy group, amino group, NHC １ ~C ６ Alkyl groups and N(C １ ~C ６ Alkyl group) ２ is selected from the group consisting of

9. The compound represented by the general formula (I) according to any one of claims 1 to 8, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, wherein Y is selected from H or F.

10. In the general formula The compound represented by the general formula (I) according to any one of claims 1 to 8, its stereoisomer or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

11. In the general formula (IV), Z １ is -CH(SO ２ R' is selected from unsubstituted C １ ~C ６ Alkyl group or C ３ ~C ７ 5. The compound represented by the general formula (I) according to claim 4, its stereoisomer or its pharma- ceutically acceptable salt, wherein R is selected from the group consisting of hydrogen, methyl, methoxy or halogen.

12. In the general formula (V), when Y is hydrogen, Z ２ is -CR ３ R ４ - or -CH(S(O) ２ R')-, and further wherein R ３ and R ４ are each independently hydrogen, halogen, or C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group or C ３ ~C ７ cycloalkyl groups, R' is selected from C １ ~C ６ Alkyl group or C ３ ~C ７ R is selected from hydrogen, methyl, methoxy or halogen; when Y is halogen, Z ２ is -SO ２ -, and R is selected from hydrogen, a methyl group, a methoxy group, or a halogen atom, a compound represented by the general formula (I) according to claim 5, its stereoisomer, or a pharma- ceutically acceptable salt thereof.

13. In the general formula (VI), Z ３ is -SO ２ -, -S(O)-, or -S(O)-, and R is selected from hydrogen, a methyl group, a methoxy group, or a halogen. The compound represented by the general formula (I) according to claim 6, its stereoisomer, or a pharma- ceutically acceptable salt thereof.

14. In the general formula (VII), R １ and R ２ are each independently selected from hydrogen, fluorine, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a t-butyl group, an s-butyl group, an n-pentyl group, a trifluoromethyl group, a cyclopropyl group, or a cyclopentyl group.

15. In the general formula (VIII), R' is selected from the group consisting of substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, s-butyl, n-pentyl, isopentyl, cyclopropyl, and cyclopentyl groups, and the substituents are halogen, C １ ~C ６ Alkoxy group, C １ ~C ６ Alkylthio group, C ３ ~C ７ Cycloalkyl group, hydroxy group, amino group, NHC １ ~C ６ Alkyl groups and N(C １ ~C ６ Alkyl group) ２ The compound represented by the general formula (I) according to claim 8, its stereoisomer or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

16. A compound represented by the following formula, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

17. A compound represented by the following formula, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 17, a stereoisomer thereof or a pharma- ceutically acceptable salt component thereof, and a pharma- ceutically acceptable carrier.

19. Use of a compound according to any one of claims 1 to 17, its stereoisomer or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, in the manufacture of a medicament for treating a disease associated with an abnormality in the JAK signaling pathway.

20. the disease is an autoimmune disease, 20. The use according to claim 19, wherein the autoimmune disease is selected from rheumatoid arthritis, ulcerative colitis, atopic dermatitis or systemic lupus erythematosus.

21. The disease is a myeloproliferative neoplasm, The use according to claim 19, wherein the myeloproliferative neoplasm is selected from the diseases essential thrombocytosis, polycythemia vera or primary myelofibrosis.

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