WO2023155905A1 - 化合物及其用途 - Google Patents

化合物及其用途 Download PDF

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WO2023155905A1
WO2023155905A1 PCT/CN2023/077089 CN2023077089W WO2023155905A1 WO 2023155905 A1 WO2023155905 A1 WO 2023155905A1 CN 2023077089 W CN2023077089 W CN 2023077089W WO 2023155905 A1 WO2023155905 A1 WO 2023155905A1
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disease
substituted
cancer
syndrome
unsubstituted
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PCT/CN2023/077089
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English (en)
French (fr)
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刘世岚
曾文琴
李文晰
张诗宜
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上海岸阔医药科技有限公司
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Publication of WO2023155905A1 publication Critical patent/WO2023155905A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present application relates to the field of medicine, in particular to a prodrug of a JAK inhibitor and its medical use.
  • Janus kinase is an intracellular non-receptor tyrosine kinase that mediates the signaling and activation of various cytokines.
  • the JAK kinase family is divided into four subtypes: JAK1, JAK2, JAK3 and TYK2. Each subtype mediates different types of cytokine signaling pathways.
  • JAK-1, JAK-2 and TYK-2 are found in various tissue cells of the human body.
  • Expression, JAK-3 is mainly expressed in various hematopoietic tissue cells.
  • the common feature of cytokine receptors is that the receptor itself does not have kinase activity, but the intracellular segment of the receptor has a binding site for the tyrosine kinase JAK.
  • the receptor-coupled JAK When the cytokine receptor binds to its ligand, the receptor-coupled JAK is activated, and the receptor is phosphorylated, and the phosphorylated tyrosine site can bind to the STAT protein containing the SH2 domain, so that the STAT recruited to the receptor and phosphorylated by JAK, then phosphotyrosine mediates STAT dimerization, and the activated STAT dimer is transferred to the nucleus and activates the transcription of its target genes, thereby regulating the growth and activation of various cells , Differentiation and other functions.
  • the JAK/STAT signaling pathway mediates the signal transduction of most cytokines in cells, and plays a key role in biological processes such as immune regulation and immune cell proliferation.
  • the JAK/STAT signaling pathway has a wide range of functions and is involved in many important biological processes such as cell proliferation, differentiation, apoptosis, and immune regulation.
  • the JAK/STAT signaling pathway is closely related to tumor diseases such as myelofibrosis, polycythemia vera and essential thrombocythemia, and the mutation of JAK molecule itself It can also lead to neoplastic diseases such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), breast ductal carcinoma, and non-small cell lung cancer (NSCLC).
  • AML acute myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • NSCLC non-small cell lung cancer
  • JAK inhibitors currently on the market and under research mainly compete for the binding of the kinase domain to ADP, so there is generally a problem of low selectivity, even for selective inhibitors of a certain subtype of JAK. Target related side effects issues.
  • the application provides a compound of formula (I), its pharmaceutically acceptable salt, bioactive metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer,
  • G is a JAK inhibitor
  • R and R are each independently selected from: hydrogen, deuterium, tritium, optionally substituted alkyl, optionally substituted deuterated alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted haloalkoxy, halogen and optionally substituted cyclic; and n is 1-5.
  • said n is 2-4.
  • said n is 1.
  • said n is 2.
  • said n is 3.
  • said n is 4. In some embodiments, said n is 5.
  • each of R 1 and R is independently selected from: -(CH 2 ) n1 Ra, -(CH 2 ) n1 ORa, -(CH 2 ) n1 SRa, -(CH 2 ) n1 C (O)Ra, -(CH 2 ) n1 C(O)ORa, -(CH 2 ) n1 S(O) m1 Ra, -(CH 2 ) n1 NRaRb, -(CH 2 ) n1 C(O)NRaRb, -(CH 2 ) n1 NRaC(O)Rb and -(CH 2 ) n1 NRaS(O) m1 Rb; where:
  • the Ra and Rb may be the same or different, and are each independently selected from hydrogen, deuterium, tritium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, Nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl , haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more groups selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted Substituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or un
  • the Ra and Rb are connected to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally selected from one of the following groups
  • One or more groups are substituted: hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
  • n1 is 0-5, for example, said n1 can be 0, 1, 2, 3, 4 or 5;
  • n1 0, 1 or 2.
  • the R 1 is a polymer compound, for example, a polymer compound with multiple repeating units substances, for example, polymer compounds obtained by cross-linking.
  • the R is a polymer compound, eg, a polymer compound having multiple repeating units, eg, a polymer compound obtained by crosslinking.
  • the cyclic group is selected from the group consisting of: cycloalkyl, heterocyclyl, oxoheterocyclyl, thioheterocyclyl, aryl and heteroaryl.
  • the cycloalkyl, heterocyclyl, oxoheterocyclyl, thioheterocyclyl, aryl and heteroaryl are optionally selected from one or more groups of the following group Substitution: hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl , substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted hetero
  • the R 1 is hydrogen, optionally substituted alkyl or optionally substituted deuterated alkyl.
  • the R 1 is hydrogen, optionally substituted C 1 -C 6 alkyl or optionally substituted C 1 -C 6 deuterated alkyl.
  • the R 1 is hydrogen, optionally substituted methyl or optionally substituted deuterated methyl.
  • R is selected from: optionally substituted alkyl, optionally substituted deuterated alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, Optionally substituted aryl and optionally substituted heteroaryl.
  • the R is selected from: optionally substituted C 1 -C 20 alkyl, optionally substituted C 1 -C 20 deuterated alkyl, optionally substituted C 3 -C 20 cycloalkyl, optionally substituted C 1 -C 20 heterocycloalkyl, optionally substituted C 6 -C 20 aryl and optionally substituted C 1 -C 20 heteroaryl.
  • said n is 2.
  • said R is hydrogen, optionally substituted methyl or optionally substituted deuterated methyl, said n is 2, and said R is optionally substituted C -C 20 cycloalkyl or optionally substituted C 1 -C 20 heterocycloalkyl.
  • the G is a JAK inhibitor selected from the group consisting of Ruxolitinib, Tofacitinib, Oclacitinib, fedratinib, peficitinib, upadacitinib, barictinib, fligotinib, decernotinib, Cerdulatinib, lestaurtinib, pacritinib, momelotinib, Gandotinib, Abrocitinib, Solcitinib, SHR-0203, itacitinib, PF-06651600, BMS-986165, abrocitinib, Cucurbitacin I, CHZ868, TD-1473, zotiraciclib, alkotinib, jaktinib, AZD-4205, DTRMHS-07, KL130008, WXSH-0150, TQ05105, WXFL10203614, GLPG0634, C
  • said G is a JAK inhibitor selected from the group consisting of tofacitinib, ruxolitinib, baricitinib, pefetinib, pacotinib, delgocitinib, Pf-04965842, Upadatinib, Filgotinib, Itatinib, Federatinib, Decernotinib, SHR-0302, ASN-002, Cerdulatinib, BMS-986165, PF-06700841, INCB-52793 , ATI-502, PF-06651600, AZD-4205, deuterium-modified ruxolitinib analogs, ATI-501, R-348, NS-018, jacotinib hydrochloride and KL-130008.
  • JAK inhibitor selected from the group consisting of tofacitinib, ruxolitinib, baricitinib, pefetinib, pacotinib, delgocitini
  • the compound is selected from the group consisting of:
  • the present application provides methods for preparing the compounds described herein, pharmaceutically acceptable salts, biologically active metabolites, solvates, hydrates, prodrugs, racemates, enantiomers or stereoisomers thereof .
  • the present application provides a composition comprising the compound described in the present application, its pharmaceutically acceptable salt, bioactive metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomers.
  • the composition is a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
  • the compound in the composition its pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof
  • concentration is from about 0.001% w/w to about 40% w/w.
  • the composition is a formulation suitable for topical administration. In certain embodiments, the composition is an ointment.
  • the compound described in the application its pharmaceutically acceptable salt, bioactive metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer; or
  • the composition can be used for preventing, alleviating and/or treating a disease or condition associated with the administration of an antineoplastic agent in a subject.
  • the application provides the compound, its pharmaceutically acceptable salt, bioactive metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer; or the Use of the composition of the invention for preparing a medicament for preventing, alleviating and/or treating a disease or condition associated with the administration of an antineoplastic agent in a subject.
  • the compound described in the application its pharmaceutically acceptable salt, bioactive metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer; or The composition of can be used to prepare JAK inhibitor.
  • the present application provides a method for preventing, alleviating and/or treating diseases related to the administration of antineoplastic agents in subjects. or a method for a disorder comprising administering to a subject in need thereof a compound described herein, a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, para enantiomers or stereoisomers; or a composition as described herein.
  • the present application provides a method for preventing, treating and/or alleviating a JAK-mediated disease or condition in a subject in need thereof, the method comprising: administering to the subject an effective amount of A compound described in the present application, its pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer; or a composition described in the present application.
  • the effective amount may be a dose capable of effectively preventing, treating and/or alleviating the JAK-mediated disease or condition.
  • the method further comprises administering an additional therapeutic agent.
  • the additional therapeutic agent may be an agent effective in preventing, treating and/or alleviating a JAK-mediated disease or condition.
  • the additional therapeutic agent is selected from the group consisting of: Ruxolitinib, Tofacitinib, Oclacitinib, fedratinib, peficitinib, upadacitinib, barictinib, fligotinib, decernotinib, cerdulatinib, lestaurtinib, Pacritinib, momelotinib, Gandotinib, Abrocitinib, Solcitinib, SHR-0203, itacitinib, PF-06651600, BMS-986165, abrocitinib, Cucurbitacin I, CHZ868, TD-1473, zotiraciclib, alkotinib, jaktinib,
  • the present application provides a compound described herein, a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof, or Use of the composition described in the present application for preparing a medicament for preventing, treating and/or alleviating a JAK-mediated disease or condition in a subject in need.
  • Figure 1 shows a mouse rash model after administration of antineoplastic agents.
  • Figure 2 shows photographs of the left side, back and right side of typical rats in the control group and the drug-administered group.
  • Figure 3 shows the rash grades of the administration group and the control group at the end of the experiment.
  • Figure 4 shows the rash grades of the administration group and the control group at the end of the experiment.
  • Figure 5 shows photographs of the left side, back and right side of typical rats in the control group and the drug-administered group.
  • Figure 6 shows the rash grades of the administration group and the control group at the end of the experiment.
  • prodrug also becomes “prodrug”, and generally refers to an agent or compound that is converted into a parent drug or active drug molecule in vivo.
  • the "prodrug” may be a precursor of another pharmaceutically active molecule that, after administration to a subject, undergoes chemical or physiological processes such as solvolysis or enzymatic cleavage, or under physiological conditions, The other pharmaceutically active molecule is produced in vivo.
  • the term "optionally substituted alkyl” includes straight-chain or branched-chain alkyl groups without any substituents, and straight-chain or branched-chain alkyl groups containing one or more non-hydrogen substituents .
  • the alkyl group generally includes a saturated aliphatic hydrocarbon group having the specified number of carbon atoms, which may be branched or straight chain.
  • alkyl also refers to non-aromatic cycloalkyl groups.
  • the alkyl group can have 1-20 carbons (ie, C 1 -C 20 ).
  • C 1 -C 10 as in “C 1 -C 10 alkyl” is defined to include 1, 2, 3, 4, A group of 5, 6, 7, 8, 9 or 10 carbons.
  • cycloalkyl refers to a monocyclic saturated aliphatic hydrocarbon group having the indicated number of carbon atoms.
  • alkyl specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl etc., and cycloalkyl, including cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and the like.
  • biologically active metabolite generally refers to a compound (such as a compound of the present application) that is processed in vivo through metabolism in a human or animal body or cell, thereby producing a metabolite.
  • said "biologically active metabolite” may include derivatives of any formula that are produced in an individual upon administration of the parent compound. These derivatives can be produced from the parent compound by various biochemical transformations in the body of an individual such as oxidation, reduction, hydrolysis or conjugation, and include, for example, oxide and demethylated derivatives. Metabolism of compounds of the invention can be identified using routine techniques known in the art things. See, eg, Bertolini, G. et al., J. Med.
  • JAK inhibitor generally refers to Janus tyrosine kinase inhibitors, which refer to compounds that target, decrease or inhibit Janus tyrosine kinases, which may directly or indirectly target one or more JAK, the JAK can be inhibited at the level of transcription, translation and/or protein post-translational modification, the quantity or expression of the JAK can be inhibited, and the activity of the JAK can also be inhibited.
  • the term "pharmaceutically acceptable salt” generally refers to a salt that retains the biological effectiveness and properties of the free base or free acid, and is biologically or otherwise desirable.
  • the salt may be a salt with an inorganic acid or a salt with an organic acid.
  • the pharmaceutically acceptable salts can be prepared by adding an inorganic base or an organic base to the free acid.
  • a pharmaceutically acceptable compound, material, composition, and/or dosage form is one approved by a regulatory agency (such as the U.S. Food and Drug Administration, China Food and Drug Administration, or European Medicines Agency) or listed on a generally recognized Those in pharmacopoeias, such as the US Pharmacopoeia, the Chinese Pharmacopoeia or the European Pharmacopoeia, for animals, more particularly for humans.
  • a regulatory agency such as the U.S. Food and Drug Administration, China Food and Drug Administration, or European Medicines Agency
  • the application provides a compound of formula (I), and also provides a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomers,
  • G is a JAK inhibitor
  • R and R are each independently selected from the group consisting of: hydrogen, deuterium, tritium, optionally substituted alkyl, optionally substituted deuterated alkyl , optionally substituted haloalkyl, optionally substituted alkoxy , optionally substituted haloalkoxy, halogen, and optionally substituted cyclic; and n is 1, 2, 3, 4 or 5.
  • the present application provides methods for preparing the above-mentioned compounds of the present application, their pharmaceutically acceptable salts, biologically active metabolites, solvates, hydrates, prodrugs, racemates, enantiomers or stereoisomers .
  • the application provides a composition comprising the compound of the application, its pharmaceutically acceptable salt, bioactive metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereo isomer.
  • compositions of the present application are pharmaceutical compositions.
  • it may contain one or more pharmaceutically acceptable carriers.
  • the pharmaceutically acceptable carrier may be selected from the group consisting of fillers, binders, disintegrants, buffers, preservatives, lubricants, flavoring agents, thickeners, colorants and emulsifiers.
  • the pharmaceutical compositions or the compounds of the present application are formulated for topical administration.
  • the drug or the compound may be formulated for transdermal administration.
  • the medicament or the compound is formulated for topical skin application.
  • the medicament is formulated as a cream, lotion, gel, ointment, salves, spray, liposomal formulation, liniment and/or aerosol.
  • the drug or the compound may be formulated as an ointment.
  • the pharmaceutical composition or the compound is an oral formulation. In some embodiments, the pharmaceutical composition or the compound may be an injectable formulation. In some embodiments, the pharmaceutical composition or the compound may be for topical administration in the oral cavity.
  • the concentration of the compound, its pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer may be about 0.0001% to about 50%.
  • the concentration of the compound can be from about 0.0001% (w/w) to about 40% (w/w), for example, can be from about 0.0001% (w/w) to about 30% (w/w), about 0.0001% (w/w) to about 20% (w/w), about 0.0001% (w/w) to about 15% (w/w), about 0.0001% (w/w) to about 10% (w/ w), about 0.0001% (w/w) to about 9.5% (w/w), about 0.0001% (w/w) to about 9% (w/w), about 0.0001% (w/w) to about 8.5 % (w/w), about 0.0001% (w/w) to about 8% (w/w), about 0.0001% (w/w) to about 7.5% (w/w), about
  • the concentration of the compound may be from about 0.05% (w/w) to about 10% (w/w). In certain embodiments, the concentration of the compound is about 5% (w/w). In certain embodiments, the concentration of the compound is about 2.5% (w/w). In certain embodiments, the concentration of the compound is about 1% (w/w).
  • one or more other active ingredients may also be included in the composition.
  • the active ingredient may refer to a monomeric compound having medical utility or physiological activity.
  • said other active ingredients may be selected from the group consisting of anti-inflammatory agents, analgesics, local anesthetics, antibiotics, antihistamines, antiseptics, immunosuppressants and anti-hemorrhagic agents.
  • composition eg, pharmaceutical composition
  • the composition can be used for preventing, alleviating and/or treating a disease or condition associated with the administration of an antineoplastic agent in a subject.
  • compositions can be used for the preparation of medicaments (eg, packaged medicaments), which can be used to prevent, alleviate and/or treat diseases or conditions associated with the administration of antineoplastic agents in a subject.
  • composition e.g, a pharmaceutical composition
  • a composition e.g, a pharmaceutical composition
  • a composition e.g, a pharmaceutical composition
  • the present application also provides a method for preventing, alleviating and/or treating a disease or condition associated with the administration of an antitumor agent in a subject, the method comprising administering the present application to a subject in need
  • the present application provides a method for preventing, treating and/or alleviating a JAK-mediated disease or condition in a subject in need thereof, the method comprising: administering to the subject an effective amount of A compound described in the present application, its pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer; or a composition described in the present application.
  • the effective amount can be an effective amount capable of preventing, treating and/or alleviating the JAK-mediated disease or disease Dosage for symptoms.
  • the method further comprises administering an additional therapeutic agent.
  • the additional therapeutic agent may be an agent effective in preventing, treating and/or alleviating a JAK-mediated disease or condition.
  • the additional therapeutic agent is selected from the group consisting of: Ruxolitinib, Tofacitinib, Oclacitinib, fedratinib, peficitinib, upadacitinib, barictinib, fligotinib, decernotinib, cerdulatinib, lestaurtinib, Pacritinib, momelotinib, Gandotinib, Abrocitinib, Solcitinib, SHR-0203, itacitinib, PF-06651600, BMS-986165, abrocitinib, Cucurbitacin I, CHZ868, TD-1473, zotiraciclib, alkotinib, jaktinib,
  • the present application provides a compound described herein, a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof, or Use of the composition described in the present application for preparing a medicament for preventing, treating and/or alleviating a JAK-mediated disease or condition in a subject in need.
  • said R 1 can be hydrogen, optionally substituted alkyl or optionally substituted deuterated alkyl.
  • the R 1 can be hydrogen, optionally substituted C 1 -C 6 alkyl or optionally substituted C 1 -C 6 deuterated alkyl.
  • the R 1 can be hydrogen, optionally substituted C 1 -C 3 alkyl or optionally substituted C 1 -C 3 deuterated alkyl.
  • R is hydrogen, optionally substituted methyl or optionally substituted deuterated methyl.
  • the R 1 can be unsubstituted alkyl (eg, unsubstituted C 1 -C 6 alkyl, unsubstituted C 1 -C 3 alkyl, such as unsubstituted methyl).
  • the R 1 can also be substituted alkyl (eg, substituted C 1 -C 6 alkyl, substituted C 1 -C 3 alkyl, such as substituted methyl ).
  • R 1 When said R 1 is a substituted alkyl group, it may be substituted by any other group, for example, it may be substituted by one or more groups selected from the group consisting of hydrogen, alkyl, alkoxy, ring Alkyl, Hetero Cycloalkyl, aryl, heteroaryl, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, heterocycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxyl, halogen, carboxyl, amino, cyano and/or sulfonyl.
  • the R 1 is selected from: -(CH 2 ) n1 Ra, -(CH 2 ) n1 ORa, -(CH 2 ) n1 SRa, -(CH 2 ) n1 C(O)Ra, -(CH 2 ) n1 C(O)ORa, -(CH 2 ) n1 S(O) m1 Ra, -(CH 2 ) n1 NRaRb, -(CH 2 ) n1 C(O)NRaRb, -(CH 2 ) n1 NRaC(O)Rb and -(CH 2 ) n1 NRaS(O) m1 Rb; wherein: the Ra and Rb can be the same or different, and each independently selected from hydrogen, deuterium, tritium, alkyl, deuterated alkanes radical, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyan
  • the R 1 is a polymer compound, eg, a polymer compound having multiple repeating units, eg, a polymer compound obtained by crosslinking.
  • the R can be selected from: optionally substituted alkyl, optionally substituted deuterated alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl , optionally substituted aryl and optionally substituted heteroaryl.
  • said R can be selected from: optionally substituted C 1 -C 20 alkyl, optionally substituted C 1 -C 20 deuterated alkyl, optionally substituted C 3 -C 20 cycloalkyl , optionally substituted C 1 -C 20 heterocycloalkyl, optionally substituted C 6 -C 20 aryl and optionally substituted C 1 -C 20 heteroaryl.
  • said R can be selected from: optionally substituted C 1 -C 10 alkyl, optionally substituted C 1 -C 10 deuterated alkyl, optionally substituted C 3 -C 10 cycloalkyl , optionally substituted C 1 -C 10 heterocycloalkyl, optionally substituted C 6 -C 10 aryl and optionally substituted C 1 -C 10 heteroaryl.
  • the R can be unsubstituted alkyl, deuterated alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl.
  • said R is unsubstituted C 1 -C 20 alkyl, C 1 -C 20 deuterated alkyl, C 3 -C 20 cycloalkane radical, C 1 -C 20 heterocycloalkyl, C 6 -C 20 aryl or C 1 -C 20 heteroaryl.
  • said R is unsubstituted C 1 -C 10 alkyl, C 1 -C 10 deuterated alkyl, C 3 -C 10 cycloalkyl, C 1 -C 10 heterocycloalkane radical, C 6 -C 10 aryl or C 1 -C 10 heteroaryl.
  • the R can also be substituted alkyl, substituted deuterated alkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl or substituted The heteroaryl.
  • said R is substituted C 1 -C 20 alkyl, substituted C 1 -C 20 deuterated alkyl, substituted C 3 -C 20 cycloalkyl, substituted C 1 -C 20 heterocycloalkyl, substituted C 6 -C 20 aryl or substituted C 1 -C 20 heteroaryl.
  • said R is substituted C 1 -C 10 alkyl, substituted C 1 -C 10 deuterated alkyl, substituted C 3 -C 10 cycloalkyl, substituted C 1 -C 10 heterocycloalkyl, substituted C 6 -C 10 aryl or substituted C 1 -C 10 heteroaryl.
  • R When said R is substituted alkyl, substituted deuterated alkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl or substituted heteroaryl, it can be Substituted by any other group, for example it may be substituted by one or more groups selected from the group consisting of hydrogen, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, heterocycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxy, halogen, carboxy, amino, cyano and/or sulfonyl.
  • the R is selected from: -(CH 2 ) n1 Ra, -(CH 2 ) n1 ORa, -(CH 2 ) n1 SRa, -(CH 2 ) n1 C(O)Ra, - (CH 2 ) n1 C(O)ORa, -(CH 2 ) n1 S(O) m1 Ra, -(CH 2 ) n1 NRaRb, -(CH 2 ) n1 C(O)NRaRb, -(CH 2 ) n1 NRaC(O)Rb and -(CH 2 ) n1 NRaS(O) m1 Rb; wherein: the Ra and Rb can be the same or different, and each independently selected from hydrogen, deuterium, tritium, alkyl, deuterated alkyl , haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano,
  • the R is a polymer compound, eg, a polymer compound having multiple repeating units, eg, a polymer compound obtained by crosslinking.
  • the alkyl group may include: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl , isohexyl, methylpentyl, dimethylbutyl, heptyl, octyl, nonyl or decyl.
  • the substituted alkyl group may be substituted with a group selected from the group consisting of hydroxyl, halogen, ester, nitrile and carbonyl.
  • the ring group (for example, a saturated ring group, a partially saturated ring group, or an unsaturated ring group, with or without heteroatoms) can be a three-membered ring, a four-membered ring rings, five-membered rings, six-membered rings, bridged rings, and/or fused rings.
  • the substituted ring group e.g., cycloalkyl, heterocycloalkyl, aryl, or heteroaryl
  • R is optionally substituted heterocycloalkyl (for example, optionally substituted C 1 -C 20 heterocycloalkyl, such as optionally substituted C 1 -C 10 heterocycloalkyl), Or optionally substituted heteroaryl (eg, optionally substituted C 1 -C 20 heteroaryl, such as optionally substituted C 1 -C 10 heteroaryl), which may include a group selected from (for example, monovalent groups of the following heteroatoms): fluorine, oxygen, sulfur, and nitrogen.
  • heterocycloalkyl for example, optionally substituted C 1 -C 20 heterocycloalkyl, such as optionally substituted C 1 -C 10 heterocycloalkyl
  • heteroaryl eg, optionally substituted C 1 -C 20 heteroaryl, such as optionally substituted C 1 -C 10 heteroaryl
  • the heterocyclyl (eg, heterocycloalkyl or heteroaryl) can be an optionally substituted six-membered nitrogen-containing heterocycle.
  • the heterocyclic group (e.g., heterocycloalkyl or heteroaryl) may be selected from the group consisting of: furan, thiophene, pyrrole, thiazole, imidazole, pyridine, pyrazine, pyrimidine, pyridazine, indole , quinoline, pteridine and acridine.
  • the cyclic group is selected from the group consisting of: cycloalkyl, heterocyclyl, oxoheterocyclyl, thioheterocyclyl, aryl and heteroaryl.
  • the cycloalkyl, heterocyclyl, oxoheterocyclyl, thioheterocyclyl, aryl and heteroaryl are optionally selected from one or more groups of the following group Substitution: hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl , substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted hetero
  • the optionally substituted aryl is optionally substituted phenyl.
  • the aryl group eg, phenyl
  • the aryl group can be substituted with a group selected from the group consisting of hydroxyl, halo, ester, nitrile, and carbonyl.
  • said n is 1-5. In certain embodiments, said n is 2-4. In certain embodiments, said n is 1, 2 or 3. In some embodiments, said n is 1. In some embodiments, said n is 2. In some embodiments, said n is 3. In some embodiments, said n is 4. In some embodiments, said n is 5.
  • said R is hydrogen , optionally substituted methyl or optionally substituted deuterated methyl, said n is 2, and said R is optionally Substituted C 3 -C 20 cycloalkyl or optionally substituted C 1 -C 20 heterocycloalkyl.
  • said R is hydrogen , optionally substituted methyl or optionally substituted deuterated methyl, said n is 2, and said R is optionally Substituted C 3 -C 10 cycloalkyl or optionally substituted C 1 -C 10 heterocycloalkyl.
  • the G is a JAK inhibitor selected from the group consisting of Ruxolitinib, Tofacitinib, Oclacitinib, fedratinib, peficitinib, upadacitinib, barictinib , fligotinib, decernotinib, cerdulatinib, lestaurtinib, pacritinib, momelotinib, Gandotinib, Abrocitinib, Solcitinib, SHR-0203, itacitinib, PF-06651600, BMS-986165, abrocitinib, Cucurbitacin I, CHZ868, TD-1473, z otiraciclib, alkotinib, jaktinib , AZD-4205, DTRMHS-07, KL130008, WXSH-0150, TQ05105, WXFL10
  • JAK inhibitor selected from the group consisting
  • the G is a JAK inhibitor selected from the group consisting of Tofacitinib, Ruxolitinib, Baricitinib, Pe Peficitinib, Pacritinib, Delgocitinib, Pf-04965842, Upadacitinib, Filgotinib, Itatinib ( Itacitinib), Fedratinib, Decernotinib, SHR-0302, ASN-002, Cerdulatinib, BMS-986165, PF-06700841, INCB-52793, ATI-502, PF-06651600, AZD-4205, deuterium modification Ruxolitinib analogs, ATI-501, R-348, NS-018, jacotinib hydrochloride and KL-130008.
  • JAK inhibitor selected from the group consisting of Tofacitinib, Ruxolitinib, Baricitinib, Pe Peficitinib, Pacritinib, Delgo
  • said G may comprise (or have) a structure selected from the group consisting of:
  • the structure of Tofacitinib is
  • the compounds of the present application are selected from the group consisting of:
  • the anti-tumor agent may include small molecule compounds, small molecule conjugates, proteins and/or polynucleotides.
  • the antineoplastic agents may include chemotherapeutics, targeted therapeutics and/or immunotherapeutics.
  • the antineoplastic agent is a targeted therapeutic agent.
  • the targeted therapeutic agents may include small molecule compounds and/or antibodies or antigen-binding fragments thereof.
  • the antibodies may include monoclonal antibodies, multispecific antibodies, chimeric antibodies, humanized antibodies, fully human antibodies and/or antibody drug conjugates.
  • the antigen-binding fragments may include Fab, Fab', F(ab) 2 , Fv fragment, F(ab') 2 , scFv, di-scFv and/or dAb.
  • the targeted therapeutic agent targets molecules inside tumor cells, on the surface of tumor cells and/or in the tumor microenvironment.
  • the targeted therapeutics can target proteins and/or nucleic acid molecules.
  • the targeted therapeutic may target a tumor-associated antigen.
  • the targeted therapeutic agent targets one or more targets selected from the group consisting of VEGF, EGFR, EGFR1, EGFR2, EGFR3, EGFR4, HER2, HER3, HER4, VEGFR, VEGFR1, VEGFR2, VEGFR3, VEGFR4, PDGFR, PDGFR ⁇ , PDGFR ⁇ , KIT, c-Kit, Ret, Raf, Raf-1, Abl, FGFR, FGFR1, MET, c-MET, Tie2, Src, c-Src, AXL, Ret, BCR-ABL, CSF-1R, FGFR, FGFR1, FGFR2, FGFR3, FGFR4, mTOR, TORC, BRaf, MEK, MEK1, MEK2, ALK, ABL, CDK, JAK, PI3K, NTRK, MSI, HDAC, FAK, PYK2, and their mutants.
  • targets selected from the group consisting of VEGF, EGFR, EGFR
  • the targeted therapeutic agent may inhibit the activity of one or more targets selected from the group consisting of VEGF, EGFR, EGFR1, EGFR2, EGFR3, EGFR4, HER2, HER3, HER4, VEGFR, VEGFR1, VEGFR2, VEGFR3, VEGFR4 , PDGFR, PDGFR ⁇ , PDGFR ⁇ , KIT, c-Kit, Ret, Raf, Raf-1, Abl, FGFR, FGFR1, MET, c-MET, Tie2, Src, c-Src, AXL, Ret, BCR-ABL, CSF -1R, FGFR, FGFR1, FGFR2, FGFR3, FGFR4, mTOR, TORC, BRaf, MEK, MEK1, MEK2, ALK, ABL, CDK, JAK, PI3K, NTRK, MSI, HDAC, FAK, PYK2, and their mutants .
  • targets selected from the group consisting of VEGF
  • the targeted therapeutic agent can reduce the expression of one or more targets selected from the group consisting of VEGF, EGFR, EGFR1, EGFR2, EGFR3, EGFR4, HER2, HER3, HER4, VEGFR, VEGFR1, VEGFR2, VEGFR3, VEGFR4 , PDGFR, PDGFR ⁇ , PDGFR ⁇ , KIT, c-Kit, Ret, Raf, Raf-1, Abl, FGFR, FGFR1, MET, c-MET, Tie2, Src, c-Src, AXL, Ret, BCR-ABL, CSF -1R, FGFR, FGFR1, FGFR2, FGFR3, FGFR4, mTOR, TORC, BRaf, MEK, MEK1, MEK2, ALK, ABL, CDK, JAK, PI3K, NTRK, MSI, HDAC, FAK, PYK2, and their mutants .
  • targets selected from the group consisting of VEGF
  • the targeted therapeutic agents may include hormones, signal transduction inhibitors, gene expression regulators, apoptosis inducers, angiogenesis inhibitors and/or toxin delivery molecules.
  • the targeted therapeutic agent is a tyrosinase inhibitor.
  • the targeted therapeutic agent is a VEGFR inhibitor and/or a VEGF inhibitor.
  • the VEGFR inhibitor can inhibit VEGFR1, VEGFR2 and/or VEGFR3.
  • the targeted therapeutic agent is an EGFR inhibitor.
  • the targeted therapeutic agent is a BRAF inhibitor.
  • the targeted therapeutic agent is a PDGFR inhibitor.
  • the targeted therapeutic agent is a FGFR inhibitor.
  • the targeted therapeutic agent is an mTOR inhibitor.
  • the targeted therapeutic agent is a HER2 inhibitor.
  • the EGFR (e.g., Her2) inhibitor can be selected from the following compounds and pharmaceutically acceptable salts thereof: afatinib, ombrutinib, lapatinib , gefitinib and dacomitinib.
  • the VEGFR inhibitor and/or VEGF inhibitor can be selected from the following compounds and pharmaceutically acceptable salts thereof: ramucirumab, bevacizumab, and Rotinib, regorafenib, cabozantinib, lenvatinib, sorafenib, fruquintinib, famitinib, apatinib, axitinib, and nintedanib.
  • the BRAF inhibitor can be selected from the following compounds and their druggable With salt: vemurafenib, encorafenib, selumetinib and dabrafenib.
  • the PDGFR inhibitor may be selected from the following compounds and pharmaceutically acceptable salts thereof: sunitinib and nintedanib.
  • the FGFR inhibitor may be selected from the following compounds and pharmaceutically acceptable salts thereof: erdafitinib and infigratinib.
  • the mTOR inhibitor may be selected from the following compounds and pharmaceutically acceptable salts thereof: everolimus.
  • the targeted therapeutic agent described in this application can be selected from one or more of the following group: afatinib, dacomitinib, osimertinib, EAI045, gefitinib, amotinib , Pirotinib, Brigatinib, Neratinib, Omorutinib, Bosutinib, Icotinib, Vandetanib, Lapatinib, Aflutinib, BPI-7711, Mobotinib, dovitinib, zoritinib, vallitinib, abrutinib, rabrutinib, brutinib, ibrutinib, dasatinib, pirtobrutinib, tolebrutinib, rilzabrutinib, fenebrutinib, evobrutinib, selumetinib, tivozanib, dovitinib
  • the targeted therapeutic agent may be administered in combination with one or more other therapies.
  • the antineoplastic agent is a chemotherapeutic agent.
  • the chemotherapeutic agents may include pyrimidine nucleoside analogs and/or prodrugs thereof.
  • the chemotherapeutic agent includes one or more selected from the group consisting of capecitabine, cytarabine, docetaxel, doxorubicin, fluorouracil (5-FU), Floxuridine, Tegafur, Idarubicin, Paclitaxel, Epirubicin, Acelarin (NUC-1031), doxorubicin, folinic acid, cisplatin, paclitaxel, cyclophosphamide, vincristine, and 5-FU prodrugs.
  • the chemotherapeutic agent includes one or more selected from the group consisting of furanfluridine, 5'-deoxyfluridine, floxuridine, 2'-deoxyfluridine, fluridine Prodrug derivatives of glycosides, prodrug derivatives of 2'-deoxyfluorouridine, trifluoro-methyl-2'-deoxyuridine, 6-azauridine and 3-deazauridine.
  • the chemotherapeutic agents may be administered in combination with one or more other therapies.
  • the one or more other therapies comprise one or more other antineoplastic therapies (eg, antineoplastic agents) described herein.
  • the antineoplastic agents may include alkylating agents such as nitrogen mustard, nitrogen mustard N-oxide hydrochloride, chlorambucil, cyclophosphamide, ifosfamide, Thiotepa, isothiocyanate, busulfan, nimustine hydrochloride, mitogen bromide, melphalan, dacarbazine, ramustine, imofol sodium phosphate, ethylenetriamine, Carmustine, lomustine, streptozotocin, pipobroman, ethoglucid, carboplatin, cisplatin, miplatin, nedaplatin, tenetamide, Mustin, diclopyridine, flupisteine, prednipixitine, pumitepa, bendamustine hydrochloride (Ribomustin), temozolomide, diclofenac, trovafloxacin,
  • alkylating agents such as nitrogen mustard, nitrogen mustard N-
  • Tumor agents such as bevacizumab
  • VEGF inhibitors such as bevacizumab
  • PCT patent applications WO 2005/012359, WO 2005/044853, WO 98/45332, WO 96/30046, WO 94/10202 US patent US7,060,269, US6,582,959, US6,703,020, US6,054,297, US patent applications US2006/009360, US2005/0186208, US2003/0206899, US2003/0190317, US2003/0203409 and US2005/0112126 Those VEGF inhibitors.
  • the anti-tumor agent may be an immunotherapy anti-tumor agent, which may include, for example: bubinanil, crestin, etofuran, lentinan, ubenmetacin, interferon, leukocyte Interleukins, macrophage colony-stimulating factor, granulocyte colony-stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, small coryneform bacteria, everolimus, levamisole, polysaccharide K, procodazole and/or or immune checkpoint inhibitors (eg, CTLA4 inhibitors, TIM-3 inhibitors, PD-1 inhibitors (eg, Nivolumab, Pembrolizumab, Pidilizumab, AMP514 (Amplimmune), AMP-224, and other PD-1s disclosed in PCT patent applications WO2006/121168, WO2009/114335, WO2009/101611, US patent US 8609089, US patent applications US2010
  • the antineoplastic agent may comprise a hormone therapy antineoplastic agent.
  • a hormone therapy antineoplastic agent may include fusastatin, diethylstilbestrol, chloromycetes, medroxyprogesterone acetate, megestrol acetate, cyproterone acetate, cyproterone acetate, danazol, allylestradiol, progesterone Ketones, mepartricin, raloxifene or meloxifene, levofloxacin, antiestrogens (e.g., tamoxifen citrate, toremifene citrate, etc.), Birth control pills, prostacyclanes, testosterone lactones, aminosuccinimide, LH-RH agonists (for example, goserelin acetate, buserelin, leuprolide, etc.), droloxifene, Epiandrostanol, ethinylestradiol sulf
  • the disease or condition associated with the administration of the anti-tumor agent may be caused by the anti-tumor agent alone, or may be caused by multiple treatment regimens, but including the anti-tumor agent .
  • the disease or condition results from administration of the antineoplastic agent.
  • the disease or condition may appear or be exacerbated after administration of the antineoplastic agent.
  • said subject was free of said disease or condition prior to administration of said antineoplastic agent.
  • the disease or disorder can include an epithelial tissue disease or disorder.
  • the epithelial tissue disease or disorder may include a disease or disorder associated with endothelial cell pathology, and/or a disease or disorder associated with epithelial cell pathology.
  • the epithelial cells may include skin epithelial cells, oral epithelial cells, nasal epithelial cells, gastric epithelial cells and/or intestinal epithelial cells.
  • the endothelial cells comprise vascular endothelial cells.
  • Lesions of vascular endothelial cells may include endothelial dysfunction.
  • the vascular endothelial cell pathology can include degenerative vascular diseases (e.g., atherosclerosis, arteriosclerosis, and arteriosclerosis (e.g., hyaline degenerative arteriosclerosis and hyperplastic arteriosclerosis)), inflammatory Vascular disease (eg, infectious arteritis, syphilitic arteritis, giant cell arteritis, thromboangiitis obliterans, and rheumatic arteritis), functional vascular disease (eg, Raynaud's disease, cyanosis of the extremities, and erythematous extremities pain) and/or congenital vascular disease (eg, congenital arteriovenous fistula), etc.
  • degenerative vascular diseases e.g., atherosclerosis, arteriosclerosis, and arteriosclerosis
  • the epithelial cells may include skin epithelial cells, oral epithelial cells, nasal cavity epithelial cells, gastric epithelial cells and/or intestinal epithelial cells.
  • the epithelial cell lesion can include a skin epithelial cell lesion (e.g., rash, acne, rosacea, atopic dermatitis, contact dermatitis, seborrheic dermatitis, lupus, scleroderma, pecycosis, pigmentation, Melasma, vitiligo, urticaria, tinea corporis, pruritus, alopecia, hair changes, erythema, paronychia and cleft nails, dry skin, hypersensitivity, and psoriasis), oral epithelial lesions (eg, pemphigus, Cold sores, herpetic stomatitis, granulomatous cheilitis, oral ulcers, pemphigo
  • antitumor agents can cause damage to endothelial cells and endothelial tissues, thereby causing diseases or disorders in skin tissues, oral tissues, nasal cavity tissues and/or gastrointestinal tract tissues.
  • the course of disease usually begins with damage/lesions of endothelial cells and endothelial tissues, while epithelial cells also have pathological changes, and finally end with endothelial cell lesions associated with the administration of antineoplastic agents , and/or forms of epithelial cell lesions associated with the administration of antineoplastic agents manifest in the patient.
  • the disease or condition may include a disease or condition of the skin, a disease or condition of the five sense organs, and/or a disease or condition of the gastrointestinal tract.
  • the skin disease or condition comprises alopecia, body odor, bullous dermatitis, dry skin, eczema, erythema multiforme, erythroderma, lipoatrophy, altered hair color, abnormal hair texture, Hirsutism, hyperhidrosis, hyperkeratosis, hypertrichosis, hypohidrosis, fat hypertrophy, nail changes, nail discoloration, nail loss, nail bumps, skin pain, hands and feet Syndrome, photosensitivity, pruritus, purpura, acneiform rash, maculopapular rash, scalp pain, skin atrophy, skin hyperpigmentation, skin hypopigmentation, skin induration, skin ulceration, Stevens - Johnson's syndrome, subcutaneous emphysema, telangiectasia, toxic epidermal necrosis, rash and/or urticaria.
  • the skin disease or condition is hand-foot syndrome.
  • the present application relates to the use of the compound of the present application (for example, the compound of formula (I) of the present application) to prevent, relieve and/or treat the combination of the antineoplastic agent (for example, EGFR) in a subject.
  • Inhibitors associated diseases or conditions (e.g., rashes).
  • the severity of the skin disease or condition is NCI-CTCAE grade 1 or above, grade 2 or above, grade 3 or above, grade 4 or above , or level 5.
  • the subject comprises a cancer patient.
  • the skin disease or disorder is affected in a different location than the cancer.
  • the disease or condition associated with the administration of an anti-tumor agent may be statistically significantly different from the anti-tumor agent relevance.
  • the disease or condition associated with the administration of an antineoplastic agent may be caused by the antineoplastic agent.
  • the diseases or disorders associated with the administration of anti-tumor agents may include skin diseases or disorders, facial features diseases or disorders, and/or gastrointestinal tract diseases or disorders associated with the administration of anti-tumor agents.
  • the skin diseases or disorders, facial features diseases or disorders, and/or gastrointestinal diseases or disorders associated with the administration of anti-tumor agents may include Disease or condition of epithelial tissue.
  • the disease or condition associated with the administration of the anti-tumor agent may include side effects or adverse reactions caused by the administration of the anti-tumor agent.
  • the disease or disease associated with the administration of antitumor agents may be a new indication, which may be different from any other disease or disease in the past.
  • diagnosis, treatment and/or symptoms of the disease or condition associated with the administration of the antineoplastic agent are unique.
  • erythromycin ointment can treat rashes, but has no therapeutic effect on rashes associated with the administration of antineoplastic agents.
  • the disease or condition associated with the administration of an antineoplastic agent may include rash associated with the administration of an antineoplastic agent, hand-foot syndrome associated with the administration of an antineoplastic agent, pruritus associated with the administration of an antineoplastic agent, Erythema associated with administration of antineoplastic agents, dry skin associated with administration of antineoplastic agents, alopecia associated with administration of antineoplastic agents, paronychia associated with administration of antineoplastic agents, pigmentation disorders associated with administration of antineoplastic agents, Oral ulcers associated with administration of antitumor agents, dry mouth associated with administration of antitumor agents, epistaxis associated with administration of antitumor agents, nasopharyngitis associated with administration of antitumor agents, cheilitis associated with administration of antitumor agents, Esophageal mucositis associated with administration of antitumor agents, gastric mucositis associated with administration of antitumor agents, gastric ulcer associated with administration of antit
  • the disease or condition associated with the administration of an antineoplastic agent includes hand-foot syndrome associated with the administration of an antineoplastic agent.
  • the severity of the disease or condition associated with the administration of antineoplastic agents is grade 1 or above, grade 2 or above, grade 3 or above, grade 4 or above in NCI-CTCAE V5.0 , and/or Level 5.
  • the disease or condition may include rash, hand-foot syndrome, pruritus, erythema, dry skin, alopecia, paronychia, pigmentation disorders, oral ulcers, dry mouth, epistaxis, nasopharyngitis, lip inflammation, esophageal mucositis, gastric mucositis, gastric ulcer, diarrhea, vomiting, nausea, anorexia, constipation and/or abdominal pain.
  • the disease or condition includes hand-foot syndrome.
  • the disease or condition associated with antineoplastic agents cannot be treated or alleviated substantially by administering an agent selected from the group consisting of 1% sildenafil, urea cream, vaseline ointment, urea ointment , Brimonidine ointment, vitamin B6 ointment, nicotine ointment, dexamethasone ointment, hydrocortisone ointment, vitamin K1 ointment (0.1%), erythromycin ointment and triamcinolone acetonide ointment.
  • an agent selected from the group consisting of 1% sildenafil, urea cream, vaseline ointment, urea ointment , Brimonidine ointment, vitamin B6 ointment, nicotine ointment, dexamethasone ointment, hydrocortisone ointment, vitamin K1 ointment (0.1%), erythromycin
  • the severity of said disease or condition may increase after said administration of an antineoplastic agent.
  • the severity of the disease or condition can be increased by about 5% or more, about 10% or more, about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 35% or more % or more, about 40% or more, about 45% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, about 100% or more Above, about 200% or above or more.
  • the subject may not suffer from the disease or condition before the administration of the anti-tumor agent.
  • the term "the subject does not suffer from the disease or disorder” generally means that the subject has no past medical history related to the disease or disorder associated with the administration of the antineoplastic agent. For example, more than 1 day, more than 1 week, more than 1 month, more than 1 year, more than 10 years before the administration of the anti-tumor agent, or since the subject was born, he has not suffered from the anti-tumor agent described in the present application. Drug-related diseases or conditions.
  • the JAK-mediated disease or condition may be selected from: autoimmune disorder or autoimmune response, generalized activation of immune response, bacterial infection, viral infection, inflammation, chronic and/or acute inflammatory Disorder or condition, and/or autoinflammatory disorder, fibrotic disorder, metabolic disorder, neoplasm, or cardiovascular or cerebrovascular disorder, skin disorder, pruritus, hair loss disorder, cancer or malignancy, autoimmune connective tissue and autoimmune conditions; Still's disease, adult-onset Still's disease, Th17-associated inflammation, polychondritis (eg, relapsing polychondritis); myositis, polymyositis, autoimmune myositis , dermatomyositis, juvenile dermatomyositis; myasthenia gravis; arthritis (eg, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic-onset juvenile rheumatoid arthritis, osteoarthritis, infection arthritis, inflammatory arthritis
  • the present application provides a pharmaceutical combination, which comprises: 1) an antineoplastic agent; and 2) a compound of formula (I).
  • the antineoplastic agent and the compound of the present application eg, the compound of formula (I) of the present application
  • the antineoplastic agent and the compound of the present application eg, the compound of formula (I) of the present application
  • the compound of the present application eg, the compound of formula (I) of the present application
  • the compound of the present application (eg, the compound of formula (I) of the present application) is prepared as an ointment.
  • the concentration of the compound of the present application (eg, the compound of formula (I) of the present application) in the pharmaceutical combination is about 0.005% w/w to about 40% w/w. In certain embodiments, the concentration of the compound of the present application (eg, the compound of formula (I) of the present application) in the pharmaceutical combination is about 0.05% w/w to about 10% w/w.
  • the composition or compound does not substantially affect the therapeutic effect of the antineoplastic agent.
  • the "substantially does not affect” may refer to, compared with the therapeutic effect of using the antineoplastic agent alone, using the compound of the present application (for example, the compound of formula (I) of the present application) and the Therapeutic effects of the antineoplastic agents are comparable, or do not result in significant disadvantages.
  • the tumor caused by using the compound of the present application for example, the compound of formula (I) of the present application
  • the degree of volume reduction is the same, or the degree of reduction is not less than about 5%, not less than about 4%, not less than about 3%, not less than about 2%, not less than about 1%, not less than about 0.5%, not less than Less than about 0.1%, not less than about 0.01%, not less than about 0.001%, or less.
  • the site of administration of the drug is different from the site of administration of the antineoplastic agent. In some embodiments, the site of administration of the drug is not the site of occurrence of cancer or the site of potential metastasis of cancer.
  • the drug is administered differently than the antineoplastic agent.
  • the antineoplastic agent and the compound of the present application are not mixed with each other.
  • the antineoplastic agent and the compound of the application each exists independently in a separate container.
  • the drug combination may include 2 or more drugs packaged independently of each other, wherein at least one of the drugs contains the antineoplastic agent described in the application, and wherein at least one other drug contains the anti-tumor agent described in the application.
  • the compound of the present application in 2) can prevent, relieve and/or treat the compound described in 1) Diseases or conditions associated with antineoplastic agents.
  • the compound of the present application in 2) (eg, the compound of formula (I) of the present application) does not substantially affect the therapeutic effect of the antineoplastic agent in 1).
  • the compound of the present application (for example, the compound of formula (I) of the present application) administered 2) before, simultaneously or after the anti-tumor agent of 1) is administered .
  • the subject may include humans or non-human animals.
  • the non-human animal can be selected from the group consisting of monkeys, chickens, geese, cats, dogs, mice and rats.
  • non-human animals may also include any animal species other than humans, such as livestock animals, or rodents, or primates, or domestic animals, or poultry animals.
  • the human can be Caucasian, African, Asian, Semitic, or other ethnicity, or a hybrid of various ethnicities.
  • the human can be elderly, adult, adolescent, child or infant.
  • the effective amount in humans can be inferred from the effective amount in experimental animals.
  • Freireich et al. describe the correlation of doses in animals and humans (based on milligrams per square meter of body surface) (Freiheim et al., Cancer Chemother. Rep. 50, 219 (1966)).
  • Body surface area can be approximately determined from the patient's height and weight. See, eg, Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 537 (1970).
  • the antineoplastic agent may result from administering an antineoplastic agent to the subject.
  • the compound of the present application eg, the compound of formula (I) of the present application
  • the antineoplastic agent described in the application is administered simultaneously with the compound of the application (for example, the compound of the formula (I) of the application)
  • the compound of the application is relative to the total Dosage of about 0.0001-10% (e.g.
  • the compound of the application for example, the compound of the formula (I) of the application
  • the antineoplastic agent is administered at intervals before or after.
  • the interval time can be 1 minute, 2 minutes, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 18 hours Hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months or longer.
  • the present application also provides a method, which includes administering a compound of formula (I) to a subject, wherein the subject has been, is and/or will be administered an antineoplastic agent and suffers from or is susceptible to A disease or condition associated with a neoplastic agent.
  • the present application also provides a method for preventing or treating a disease or disorder, comprising administering a compound of formula (I) to a subject susceptible to or suffering from the disease or disorder, wherein the subject has been, Antineoplastic agents are being and/or will be administered in the future.
  • the subject may already suffer from a disease or disorder related to the administration of an anti-tumor agent, or the subject may have a higher probability of suffering from a disease or disorder related to the administration of an anti-tumor agent.
  • the present application also provides a method comprising the steps of: 1) monitoring one or more side effects of a subject administered an antineoplastic agent, such as skin tissue, facial features and/or gastrointestinal tract characteristics; 2) when When the monitoring shows that the subject has side effects related to the administration of the anti-tumor agent, such as skin diseases or disorders, facial features diseases or disorders and/or gastrointestinal diseases or disorders, the subject is administered the formula The compound of (I).
  • antineoplastic agent such as skin tissue, facial features and/or gastrointestinal tract characteristics
  • the method may also include continuing to monitor the skin disease or disorder, facial organ disease or disorder and/or gastrointestinal disease or disorder, and optionally reducing or stopping the antineoplastic agent.
  • the continuing monitoring can refer to about at least 1 day, at least 1 week, at least 10 days, at least 2 weeks, at least 3 weeks, at least 1 month, at least 3 months or longer after administration of the antineoplastic agent to monitor.
  • said reduction or discontinuation may be directed to administering said subject with a dose of said antineoplastic agent that is reduced by about at least 5%, at least 10% compared to the dose of said antineoplastic agent in step 1) of said method , at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%, or 100%.
  • the severity of the disease or condition associated with the administration of the anti-tumor agent may increase after the administration of the anti-tumor agent.
  • the severity can be an increase of at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or more many.
  • the subject may not suffer from the disease or condition before the administration of the anti-tumor agent.
  • the compound of the present application (eg, the compound of formula (I) of the present application) can be administered topically to the subject.
  • a compound of the present application eg, a compound of formula (I) of the present application
  • the compound of the present application for example, the compound of formula (I) of the present application
  • n-octanol layer samples (4 ⁇ L/well) into a 96-well plate containing n-octanol internal standard dilution solution (796 ⁇ L/well), and accurately measure a certain amount of buffer salt layer
  • Samples (30 ⁇ L/well) are placed in a 96-well plate containing buffer internal standard diluent solution (570 ⁇ L/well); the dilution factor of the sample can be adjusted accordingly according to the nature of the sample.
  • Sample analysis was performed using a triple quadrupole mass spectrometer. The processed sample solution was analyzed by the fast isocratic small column retention method, Concentration correction was carried out by dilution factor and internal standard, and the ratio of the corrected peak area was used to calculate the final result (LogD/LogP value).
  • the assay method comprises the steps of:
  • Rat animal model was constructed.
  • the small-molecule EGFR inhibitor was given to female SD rats for 6 weeks by daily gavage. After several days, a large area of rash appeared on the back of the rats (the photo is shown in Figure 1). There is no difference between left and right where the rash appeared, The rash appeared on both sides to a similar degree.
  • rats develop rashes on the face and body after oral administration of small molecule EGFR inhibitors. The etiology of the two is exactly the same, and the symptoms are also very similar. Therefore, the rat is a very good animal model for simulating the rash induced by EGFR inhibitors.
  • the rats were divided into groups of 10. The day before the experiment, the hair on the back of the rat was gently removed with an electric shaver, and then the drug was administered by gavage.
  • EGFR inhibitors were dissolved in sterile aqueous solution, diluted with PBS buffer solution, and the amount of each gavage was not more than 2mL, and the dosage was shown in Table 1. The experiment was divided into administration group and control group.
  • Figure 2 shows photographs of the left side, back and right side of typical rats in the control group and drug administration group in Table 1.
  • Figure 3 shows the rash grades of the administration group and the control group at the end of the experiment.
  • the rats were divided into groups of 10. The day before the experiment, the hair on the back of the rat was lightly removed with an electric shaver, and then the drug administration test was performed. The experiment is divided into the compound group of the present application and the control group.
  • the EGFR monoclonal antibody solution diluted with normal saline was injected into the tail vein twice a week, and the injection speed and time are shown in Table 2.
  • the compound group of the present application is coated with the compound ointment of the present application to the rat back (about 3cm*3cm) every day, and the matched group is coated with blank matrix ointment (about 0.5g) to the rat back (about 3cm*3cm),
  • the rats were fixed with a fixing cylinder for 4 hours, and after 4 hours, the rats were released and the residual drug at the application site was wiped off with clear water, and the rats were returned to their cages.
  • the monoclonal antibody EGFR inhibitor was injected twice a week into the tail vein, and the compound and blank ointment of the present application were applied once a day until obvious rash appeared in the control group. After 10-14 days of statistical application, the number of rats whose skin remained normal in the compound group of the present application or whose skin rash was significantly lighter than that of the control group was calculated as the number of rats that effectively inhibited the rash.
  • Figure 4 shows the rash grades of the compound group of the present application and the control group (monoclonal antibody EGFR inhibitor) at the end of the experiment.
  • the rats were divided into groups of 10. On the day before the experiment, the hair on the back of the rat was lightly removed with an electric shaver, and then the intragastric administration test was performed.
  • EGFR inhibitors were dissolved in sterile aqueous solution, diluted with PBS buffer solution, and the amount of each gavage was not more than 2mL, and the dosage was shown in Table 3. The gavage continued every day until the rats showed symptoms of skin rash, at which time the treatment experiment began. The experiment is divided into the compound group of the present application and the control group. During the treatment experiment, the EGFR inhibitors were continuously fed daily.
  • the compound group of the application applied the compound ointment of the application to the back (about 3cm*3cm) of the rats, and the backs of the rats of the control group (about 3cm*3cm) *3cm) Apply blank matrix ointment; fix the rat with a fixed cylinder for about 4 hours after application, release the rat after 4 hours, wipe off the residual drug at the application site with clean water, and put it back into the mouse cage.
  • the frequency of intragastric administration of EGFR inhibitors is shown in Table 3, but the compound of the present application and the blank ointment are only applied once a day. Repeat intragastric administration with EGFR inhibitors every day, and calculate the number of rats whose skin of the compound group of the present application returned to normal or obviously lighter than the rash of the control group at the end of the experiment as the number of rats that effectively treated the rash.
  • Figure 5 shows photos of the left side, back and right side of typical rats in the control group and the compound group of the present application in Table 3.
  • Figure 6 shows the rash grades of the compound group of the present application and the control group at the end of the experiment.
  • the rats were divided into groups of 10. The day before the experiment, rats were reared The hair was lightly removed with an electric shaver, and then the drug administration test was performed.
  • the EGFR monoclonal antibody solution diluted with normal saline was injected into the tail vein twice a week, and the injection speed and time are shown in Table 4; the administration was continued for 1-2 weeks until the rats developed a rash, at which time the treatment experiment began.
  • the experiment is divided into the compound group of the present application and the control group.
  • the monoclonal antibody EGFR inhibitor was continuously injected 2 times a week, and the compound ointment of the application was smeared on the back (about 3cm*3cm) of the compound group rats of the application every day, and the back (about 3cm*3cm) of the rats in the control group was smeared.
  • the number of rats whose skin in the compound group of the application remained normal or was obviously lighter than that of the control group with rash was calculated as the number of rats that effectively inhibited rash.
  • Fig. 7 shows the rash grades of the compound group of the present application and the control group (mab EGFR inhibitor) at the end of the experiment.
  • Mouse skin contact delayed-type hypersensitivity (DTH) response is considered to be an effective model for clinical contact dermatitis and other T-lymphocyte-mediated skin immune diseases, such as atopic dermatitis and psoriasis.
  • Murine DTH shares several features with these cutaneous immune disorders, including immune infiltration with increased inflammatory cytokines and hyperproliferation of keratinocytes.
  • mice were sensitized by topical administration of the antigen 2,4, dinitro-fluorobenzene (DNFB) on the shaved back of the mice.
  • DNFB dinitro-fluorobenzene
  • the ointment of the compound of the present application is applied topically to the animal's ears for treatment throughout the allergic and challenge periods (-1 day to day 7) or before challenge or throughout the challenge period (usually days 4 to 7).
  • the therapeutic effect is indicated by a reduction in ear swelling compared to the case of the blank ointment.
  • Compounds that caused a reduction of 20% or more were considered effective.
  • Table 5 lists the experimental results of the compounds of the present application on skin contact delayed hypersensitivity in mice.
  • the mouse ear tissue was taken for formalin fixation and paraffin embedding to prepare ear slices, and immunohistochemical analysis showed that the ointment of the compound of the present application can reduce the number of infiltrating cells in the tissue.

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Abstract

本申请涉及式(I)的化合物及其用途，还涉及用于制备所述化合物的方法。

Description

化合物及其用途 技术领域
本申请涉及医药领域，具体的涉及一种JAK抑制剂的前药，及其医药用途。
背景技术
Janus激酶(JAK)是一种胞内非受体酪氨酸激酶，介导各种细胞因子的信号传导和激活。JAK激酶家族分为JAK1、JAK2、JAK3和TYK2四个亚型，各亚型分别介导不同类型的细胞因子信号通路，JAK-1、JAK-2和TYK-2在人体各组织细胞中均有表达，JAK-3主要表达于各造血组织细胞中。细胞因子受体的共同特点是受体本身不具有激酶活性，但受体胞内段具有酪氨酸激酶JAK的结合位点。当细胞因子受体与其配体结合后，激活受体偶联的JAK，进而使受体被磷酸化，经磷酸化的酪氨酸位点可与含有SH2结构域的STAT蛋白结合，从而使STAT被募集到受体并通过JAK磷酸化，随后磷酸酪氨酸介导STAT二聚化，激活的STAT二聚体转移到细胞核内并激活其靶点基因转录，进而调控多种细胞的生长、活化、分化等多种功能。
JAK/STAT信号通路介导细胞内大多数细胞因子的信号传导，在免疫调节、免疫细胞增殖等生物学过程中起关键作用。JAK/STAT信号通路功能广泛，参与细胞的增殖、分化、凋亡以及免疫调节等许多重要的生物学过程，与多种炎症性疾病如类风湿性关节炎、皮炎、银屑病、炎症性肠病(溃疡性结肠炎及克罗恩病)等密切相关；同时JAK/STAT信号通路与肿瘤性疾病如骨髓纤维化、真性红细胞增多症及原发性血小板增多症密切相关，JAK分子自身的突变也会导致急性骨髓细胞性白血病(AML)、急性淋巴细胞性白血病(ALL)、乳腺导管癌及非小细胞肺癌(NSCLC)等肿瘤性疾病。
目前上市和在研的JAK抑制剂主要是竞争激酶结构域与ADP的结合而发挥作用，因此普遍存在选择性不高的问题，即使是对JAK某个亚型的选择性抑制剂同样存在严重的靶点相关副作用问题。
鉴于JAK抑制剂的良好疗效和多种靶点相关性严重副作用，开发一种安全性更高的JAK抑制剂药物成为目前急需解决的问题。此外，针对不同的临床需求，开发一种提高药物局部暴露量的前药成为提高安全性的良好策略。
发明内容
一方面，本申请提供了式(I)的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体，
其中：
G为JAK抑制剂，R1和R各自独立地选自：氢、氘、氚、任选被取代的烷基、任选被取代的氘代烷基、任选被取代的卤代烷基、任选被取代的烷氧基、任选被取代的卤代烷氧基、卤素和任选被取代的环基；且n为1-5。在某些实施方式中，所述n为2-4。在某些实施方式中，所述n为1。在某些实施方式中，所述n为2。在某些实施方式中，所述n为3。在某些实施方式中，所述n为4。在某些实施方式中，所述n为5。
在某些实施方式中，所述R1和R各自独立地选自：-(CH2)n1Ra、-(CH2)n1ORa、-(CH2)n1SRa、-(CH2)n1C(O)Ra、-(CH2)n1C(O)ORa、-(CH2)n1S(O)m1Ra、-(CH2)n1NRaRb、-(CH2)n1C(O)NRaRb、-(CH2)n1NRaC(O)Rb和-(CH2)n1NRaS(O)m1Rb；其中：
所述Ra和Rb可以相同或不同，且各自独立地选自氢、氘、氚、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氰基、硝基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自下组的一种或多种基团取代：氢、氘、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基；
或者，所述Ra和Rb连接形成环烷基、杂环基、芳基或杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选被选自下组的一种或多种基团取代：氢、氘、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基；
n1为0-5，例如，所述n1可以为0,1,2,3,4或5；且
m1为0，1或2。
在某些实施方式中，所述R1为高分子化合物，例如，具有多个重复单元的高分子化合 物，例如，通过交联获得的高分子化合物。
在某些实施方式中，所述R为高分子化合物，例如，具有多个重复单元的高分子化合物，例如，通过交联获得的高分子化合物。
在某些实施方式中，所述环基选自：环烷基、杂环基、氧代杂环基、硫代杂环基、芳基和杂芳基。在某些实施方式中，所述环烷基、杂环基、氧代杂环基、硫代杂环基、芳基和杂芳基任选被选自下组的一种或多种基团取代：氢、氘、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基。
在某些实施方式中，所述R1为氢，任选被取代的烷基或任选被取代的氘代烷基。
在某些实施方式中，所述R1为氢，任选被取代的C1-C6烷基或任选被取代的C1-C6氘代烷基。
在某些实施方式中，所述R1为氢，任选被取代的甲基或任选被取代的氘代甲基。
在某些实施方式中，所述R选自：任选被取代的烷基，任选被取代的氘代烷基，任选被取代的环烷基，任选被取代的杂环烷基，任选被取代的芳基和任选被取代的杂芳基。
在某些实施方式中，所述R选自：任选被取代的C1-C20烷基，任选被取代的C1-C20氘代烷基，任选被取代的C3-C20环烷基，任选被取代的C1-C20杂环烷基，任选被取代的C6-C20芳基和任选被取代的C1-C20杂芳基。
在某些实施方式中，所述n为2。
在某些实施方式中，所述R1为氢，任选被取代的甲基或任选被取代的氘代甲基，所述n为2，且所述R为任选被取代的C3-C20环烷基或任选被取代的C1-C20杂环烷基。
在某些实施方式中，所述G为选自下组的JAK抑制剂：芦可替尼(Ruxolitinib)、托法替尼(Tofacitinib)、Oclacitinib、fedratinib、peficitinib、upadacitinib、barictinib、fligotinib、decernotinib、cerdulatinib、lestaurtinib、pacritinib、momelotinib、Gandotinib、Abrocitinib、Solcitinib、SHR-0203、itacitinib、PF-06651600、BMS-986165、abrocitinib、、Cucurbitacin I、CHZ868、TD-1473、zotiraciclib、alkotinib、jaktinib、AZD-4205、DTRMHS-07、KL130008、WXSH-0150、TQ05105、WXFL10203614、GLPG0634、CEP-33779、R-348、itacitinib、ritlecitinib、brepocitinib、Tasocitinib、Deucravacitinib、INCB-039110、Izencitinib、Entrectinib、Ivarmacitinib、Deuruxolitinib、Adelatinib、NDI-034858、Nezulcitinib、ATI-01777、TD-8236、INCB-054707、Ropsacitinib、AGA-201、ATI50001、Gusacitinib、Cerdulatinib、Roniciclib、AT-9283、FMX-114、OST-122、TT-00420、 Repotrectinib、INCB-052793、CT-340、BMS-911543、Ilginatinib、BGB-23339、ICP-332、ESK-001、SYHX-1901、VTX-958、TLL-018、CEE-321、CJ-15314、TD-5202、ABBV-712、GLPG-3667、CPL-116、AZD-4604、TAS-8274、MAX-40279、TD-3504、KN-002、AZD-0449、R-548、AC-410、Spebrutinib、ONX-0805、AEG-41174、XL-019、CR-4、WP-1066、GDC-0214、INCB-047986、PF-06263276、R-333、AZD-1480、Tozasertib、CS-12192和AC-1101。
在某些实施方式中，所述G为选自下组的JAK抑制剂：托法替尼、鲁索替尼、巴瑞替尼、培非替尼、帕克替尼、德尔戈西替尼、Pf-04965842、乌帕达替尼、菲尔戈替尼、伊他替尼、费德拉替尼、Decernotinib、SHR-0302、ASN-002、Cerdulatinib、BMS-986165、PF-06700841、INCB-52793、ATI-502、PF-06651600、AZD-4205、氘修饰鲁索替尼类似物、ATI-501、R-348、NS-018、盐酸雅克替尼和KL-130008。
在某些实施方式中，所述化合物选自下组：
另一方面，本申请提供了制备本申请所述化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体的方法。
另一方面，本申请提供了一种组合物，其包含本申请所述的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体。
在某些实施方式中，所述组合物为药物组合物，且包含药学上可接受的载体。
在某些实施方式中，所述组合物中所述化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体的浓度为约0.001％w/w至约40％w/w。
在某些实施方式中，所述组合物为适用于局部施用的制剂。在某些实施方式中，所述组合物为为软膏剂。
另一方面，本申请所述的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体；或者本申请所述的组合物，可用于预防，缓解和/或治疗受试者中与施用抗肿瘤剂相关的疾病或病症。
另一方面，本申请提供了所述的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体；或者所述的组合物用于制备药物的用途，所述药物用于预防，缓解和/或治疗受试者中与施用抗肿瘤剂相关的疾病或病症。
另一方面，本申请所述的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体；或者本申请所述的组合物可用于制备JAK抑制剂。
另一方面，本申请提供了一种预防，缓解和/或治疗受试者中与施用抗肿瘤剂相关的疾病 或病症的方法，所述方法包括向有需要的受试者施用本申请所述的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体；或者本申请所述的组合物。
另一方面，本申请提供了一种在有需要的受试者中预防、治疗和/或缓解JAK介导的疾病或病症的方法，所述方法包括：向所述受试者施用有效量的本申请所述的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体；或者本申请所述的组合物。所述有效量可以为能够有效预防、治疗和/或缓解所述JAK介导的疾病或病症的剂量。
在某些实施方式中，所述方法还包括施用另外的治疗剂。所述另外的治疗剂可以为能够有效预防、治疗和/或缓解JAK介导的疾病或病症的试剂。在某些实施方式中，所述另外的治疗剂选自：芦可替尼(Ruxolitinib)、托法替尼(Tofacitinib)、Oclacitinib、fedratinib、peficitinib、upadacitinib、barictinib、fligotinib、decernotinib、cerdulatinib、lestaurtinib、pacritinib、momelotinib、Gandotinib、Abrocitinib、Solcitinib、SHR-0203、itacitinib、PF-06651600、BMS-986165、abrocitinib、、Cucurbitacin I、CHZ868、TD-1473、zotiraciclib、alkotinib、jaktinib、AZD-4205、DTRMHS-07、KL130008、WXSH-0150、TQ05105、WXFL10203614、GLPG0634、CEP-33779、R-348、itacitinib、ritlecitinib、brepocitinib、Tasocitinib、Deucravacitinib、INCB-039110、Izencitinib、Entrectinib、Ivarmacitinib、Deuruxolitinib、Adelatinib、NDI-034858、Nezulcitinib、ATI-01777、TD-8236、INCB-054707、Ropsacitinib、AGA-201、ATI50001、Gusacitinib、Cerdulatinib、Roniciclib、AT-9283、FMX-114、OST-122、TT-00420、Repotrectinib、INCB-052793、CT-340、BMS-911543、Ilginatinib、BGB-23339、ICP-332、ESK-001、SYHX-1901、VTX-958、TLL-018、CEE-321、CJ-15314、TD-5202、ABBV-712、GLPG-3667、CPL-116、AZD-4604、TAS-8274、MAX-40279、TD-3504、KN-002、AZD-0449、R-548、AC-410、Spebrutinib、ONX-0805、AEG-41174、XL-019、CR-4、WP-1066、GDC-0214、INCB-047986、PF-06263276、R-333、AZD-1480、Tozasertib、CS-12192和AC-1101。
另一方面，本申请提供了本申请所述的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体，或者本申请所述的组合物用于制备药物的用途，所述药物用于预防、治疗和/或缓解有需要的受试者中JAK介导的疾病或病症。
在某些实施方式中，所述JAK介导的疾病或病症选自：自身免疫紊乱或自身免疫应答、免疫应答的广泛激活、细菌感染、病毒感染、炎症、慢性和/或急性炎性紊乱或病况、和/或自身炎性紊乱、纤维化紊乱、代谢紊乱、赘生物、或者心血管紊乱或脑血管紊乱、皮肤紊乱、 瘙痒、毛发缺损紊乱、癌症或恶性肿瘤、自身免疫性***病和自身免疫病况；斯蒂尔病、成年起病型斯蒂尔病、Th17相关性炎症、多软骨炎(例如，复发性多软骨炎)；肌炎、多肌炎、自身免疫性肌炎、皮肌炎、幼年型皮肌炎；重症肌无力；关节炎(例如，类风湿性关节炎、幼年型类风湿性关节炎、全身起病型幼年类风湿性关节炎、骨关节炎、感染性关节炎、炎症性关节炎、炎性肠病相关性关节炎、特发性关节炎、幼年型特发性关节炎、全身型幼年特发性关节炎、银屑病性关节炎)、脊椎炎/脊椎关节炎/脊椎关节病(强硬性脊椎炎)、痛风、硬皮病(全身性硬皮病、幼年型硬皮病)、赖特综合征/反应性关节炎、莱姆病、狼疮/***性红斑狼疮(SLE)(红斑狼疮、儿童***性红斑狼疮、皮肤狼疮(亚急性皮肤狼疮、慢性皮肤狼疮/盘状狼疮、冻疮样红斑狼疮))、风湿性多肌痛、起止点炎、混合型***病、起止点病、心脏炎、心肌炎、血管生成紊乱、骨髓增生异常综合征、动脉粥样硬化、再狭窄(动脉粥样硬化性冠状动脉再狭窄)、急性冠状动脉综合征、心肌梗死、心脏移植物血管病变、移植性动脉病；血管炎(大血管血管炎、小血管血管炎、巨细胞动脉炎、结节性多动脉炎、血管炎综合征，所述血管炎综合征包含大动脉炎、韦格纳肉芽肿、白塞病)、干扰素基因刺激蛋白(STING)相关的婴儿期起病型血管病变(SAVI)；胃肠道紊乱、小肠结肠炎、结肠炎、炎性肠病(溃疡性结肠炎、克罗恩病)、肠易激综合征、肠炎综合征/痉挛性结肠、乳糜泻；急性胰腺炎和慢性胰腺炎；原发性胆汁性肝硬化、原发性硬化性胆管炎、黄疸、肝硬化(例如，原发性胆汁性肝硬化、或归因于脂肪性肝病(例如，酒精性脂肪变性和非酒精性脂肪变性)的肝硬化)；食管炎、胃炎、胃溃疡和十二指肠溃疡、腹膜炎；肾病、免疫介导的肾小球性肾病、自身免疫性肾病、膜性肾小球病、慢性进行性肾病、糖尿病性肾脏疾病/糖尿病性肾病、肾纤维化、肾缺血/再灌注损伤、HIV相关性肾病、输尿管梗阻性肾病、肾小球硬化症、蛋白尿、肾病综合征、多囊性肾脏疾病、常染色体显性多囊性肾脏疾病、肾病是免疫介导的肾病、自身免疫性肾病、慢性进行性肾病、糖尿病性肾病、肾纤维化、缺血性/再灌注损伤相关性肾病、HIV相关性肾病、输尿管梗阻性肾病、肾小球肾炎、慢性肾脏疾病(例如，糖尿病性肾病)、高血压诱导的肾病、肾小球硬化症、蛋白尿、肾病综合征、多囊性肾脏疾病、常染色体显性多囊性肾脏疾病、糖尿病性肾脏疾病、狼疮性肾炎；间质性膀胱炎；牙周炎、龈炎；肺部炎症、窦炎、肺炎、支气管炎、哮喘、支气管哮喘、变应性哮喘、非变应性哮喘、变应性支气管肺真菌病、阿斯匹林诱导的哮喘、成年起病型哮喘、固定气流阻塞型哮喘、运动诱导的哮喘、咳嗽变异性哮喘、工作相关性哮喘、夜间哮喘、哮喘并发肥胖症、嗜酸细胞性哮喘、激素抵抗型哮喘/重度哮喘、外源性哮喘、内源性哮喘/隐源性哮喘、丘-施综合征、细支气管炎、闭塞性细支气管炎、慢性阻塞性肺病(COPD)、间质性肺疾病(肺纤维化、特发性肺纤维化)、急性肺损伤、肺纤维化(例如，特发性肺纤维化 或囊性纤维化)、慢性阻塞性肺病、成人呼吸窘迫综合征、急性肺损伤、药物诱导的肺损伤；梅尼埃病；眼部紊乱，所述眼部紊乱包含(例如)眼部炎症、葡萄膜炎、干眼/干燥性角膜结膜炎、巩膜炎、巩膜外层炎、角膜炎/角膜病、脉络膜炎、视网膜血管炎、视神经炎、视网膜病变(糖尿病性视网膜病变、免疫介导的视网膜病变、黄斑变性、湿性黄斑变性、干性(老年性)黄斑变性)；肥大细胞增生病、缺铁性贫血、***、嗜酸细胞增多综合征(HES)、***性肥大细胞病(SMCD)、骨髓增生异常综合征、特发性血小板减少性紫癜；骨吸收疾病；神经退行性紊乱、神经紊乱/神经肌肉紊乱(例如)，多发性硬化、帕金森病、亨廷顿病、肌萎缩性侧索硬化(ALS)(家族性ALS、散发性ALS)、阿尔茨海默病、重症肌无力、兰-伊肌无力综合征(LEMS)、格林-巴利综合征、脑膜炎、脑炎、创伤性脑损伤；神经***损害、寄生虫妄想症、神经元过程和感觉知觉的调节异常、中风/神经元缺血、脊髓损伤、外周神经病变、触幻觉、脊髓损伤、精神疾病；感觉异常性疼痛(急性疼痛、慢性疼痛、神经性疼痛、或纤维肌痛)、神经刺激、外周神经病变；瘙痒/痒病(特应性瘙痒、干燥性瘙痒、与银屑病相关的瘙痒/银屑病性痒病/银屑病相关性痒病)、急性瘙痒、慢性瘙痒、特发性瘙痒、慢性特发性痒病、胆汁性痒病、肝胆相关性痒病、肾相关性痒病/肾痒病、***性痒病、胆汁郁积、妊娠期肝内胆汁郁积、慢性单纯性苔癣相关性瘙痒、淋巴瘤相关性痒病、白血病相关性痒病、结节性痒疹、特应性皮炎相关性痒病、特应性痒病/特应性瘙痒、大疱性痒病、肱桡肌瘙痒、神经原性痒病、神经性痒病、感觉异常性背痛、HIV相关性瘙痒性丘疹、精神性痒病、游泳者痒病、瘙痒或***性痒病、荨麻疹性痒病；皮肤病(例如)，皮肤病药物反应/药疹、干燥病/皮肤干燥、皮疹、皮肤致敏、皮肤刺激、晒斑、修面、体虱、头虱/虱病、阴虱、皮肤幼虫移行症、疥疮、寄生虫感染、昆虫感染、荨麻疹/荨麻疹、丘疹性荨麻疹、昆虫咬伤、昆虫刺伤、头皮屑、皮肤上的异物或装置、真菌感染、疱疹、水痘/水痘、嗜酸性毛囊炎、妊娠皮肤病/妊娠瘙痒性荨麻疹性丘疹及斑块病(PUPP)、炎性皮肤病、嗜中性皮肤病、组织细胞样嗜中性皮肤病、肠旁路综合征皮肤病、银屑病/寻常型银屑病、扁平苔藓、硬化性萎缩性苔藓、痤疮(寻常型痤疮、粉刺型痤疮、炎性痤疮、结节囊肿性痤疮、瘢痕性痤疮、颈项部疤痕疙瘩性痤疮)、特应症(变应性接触性致敏、变应性皮炎)、皮炎(特应性皮炎/湿疹、接触性皮炎、光照性皮炎、脂溢性皮炎、瘀滞性皮炎)、急性发热性嗜中性皮肤病(斯威特综合征)、慢性非典型中性粒细胞与脂肪代谢障碍性皮肤病和高温综合征(CANDLE综合征)、化脓性汗腺炎、荨麻疹、坏疽性脓皮病、脱发(眉毛脱落、鼻内毛发脱落、瘢痕性脱发(例如，疤痕性脱发、中央离心性疤痕性脱发、毛发扁平苔藓、前额纤维化性脱发、脱发性毛囊炎)、非瘢痕性脱发(斑秃(AA)(斑块型AA、全秃(AT)、普秃(AU)、蛇形斑秃、马蹄形斑秃))、雄激素源性/雄激素性脱发(AGA)/男性及女性型AGA)、静止期脱 发、头癣、稀毛症(单纯性遗传性稀毛症)、毛发扁平苔藓(前额纤维化性脱发)、点状掌跖角皮病、持久***性红斑(EED)、嗜中性外分泌性汗腺炎、栅栏状嗜中性肉芽肿性皮炎、嗜中性荨麻疹皮肤病、白癜风，所述白癜风包含节段型白癜风(单节段型白癜风、双节段型白癜风、多节段型白癜风)、非节段型白癜风(肢端型白癜风、面部型白癜风、或肢端面部型白癜风、面部中央型白癜风、粘膜型白癜风、碎纸样白癜风、三色白癜风、边缘性炎性白癜风、四色白癜风、蓝色白癜风、凯布内现象、寻常型白癜风、泛发型白癜风、普发型白癜风)、混合型白癜风/非节段型白癜风伴发节段型白癜风、局限型白癜风、孤立性粘膜型白癜风、或者伴有或不伴有白发(身体毛发受累)的白癜风；大疱性疾病、免疫性大疱性疾病(大疱性类天疱疮、疤痕性类天疱疮、寻常型天疱疮、线性IgA疾病)、妊娠性类天疱疮、着色性干皮病；纤维化和瘢痕形成的紊乱：纤维瘤、肝纤维化、肺纤维化、特发性肺纤维化、诸如硬皮病、纤维化增加、疤痕疙瘩、术后瘢痕的低度瘢痕形成；伤口愈合、手术瘢痕形成、辐射诱导的纤维化(例如，头颈部、胃肠道或肺部)、中枢神经***瘢痕形成、消化道或胃肠道纤维化、肾纤维化、肝脏纤维化或胆管纤维化、肝纤维化(例如，非酒精性脂肪性肝炎、丙型肝炎、或肝细胞癌)、心脏纤维化(例如，心内膜心肌纤维化或心房纤维化)、眼部瘢痕形成、纤维硬化、瘢痕生长、伤口或痂愈合、疤痕疙瘩、纵隔纤维化、骨髓纤维化、腹膜后纤维化/奥蒙德病、进行性大块纤维化、肾源性***性纤维化；斯耶格伦综合征、结节病、家族性地中海热、冷吡啉相关周期性综合征(默-韦综合征、家族性寒冷性自身炎性综合征/家族性寒冷性荨麻疹/TNF受体相关周期性综合征、新生儿起病多***炎性疾病)、氧过多诱导的炎症、再灌注损伤、术后创伤、组织损伤、高温综合征；糖尿病(I型糖尿病、II型糖尿病)/糖尿病、桥本甲状腺炎、格雷夫斯病、艾迪生病、卡斯尔门病、甲状旁腺功能亢进、绝经期、肥胖症、类固醇耐药性、葡萄糖耐受不良、代谢综合征、甲状腺疾病、垂体炎；***性免疫衰老；自身免疫性萎缩性胃炎、恶性贫血的自身免疫性萎缩性胃炎、自身免疫性脑脊髓炎、自身免疫性***、古德帕斯彻病、斯耶格伦综合征、自身免疫性血小板减少、交感性眼炎；自身免疫性疾病的继发血液学表现(例如，贫血)、自身免疫性溶血综合征(自身免疫性溶血性贫血)、自身免疫性肝炎和炎性肝炎、自身免疫性卵巢衰竭、自身免疫性血小板减少、硅酮植入相关的自身免疫性疾病、药物诱导的自身免疫、HIV相关的自身免疫性综合征、金属诱导的自身免疫、自身免疫性聋、自身免疫性甲状腺紊乱；过敏反应和***反应，所述过敏反应和***反应包含超敏反应，如I型超敏反应(例如，包含过敏症)、II型超敏反应(例如，古德帕斯彻病、自身免疫性溶血性贫血)、III型超敏反应疾病(例如，阿图斯反应、血清病)和IV型超敏反应(例如，接触性皮炎、同种异体移植排斥)；急性感染和慢性感染、脓毒症综合征(脓毒症、脓毒性休克、内毒素性休克、 外毒素诱导的中毒性休克、革兰氏阴性脓毒症、革兰氏阳性脓毒症、真菌性脓毒症、中毒性休克综合征)；急性感染和慢性感染、脓毒症综合征(脓毒症、脓毒性休克、内毒素性休克、外毒素诱导的中毒性休克、革兰氏阴性脓毒症、革兰氏阳性脓毒症、真菌性脓毒症、中毒性休克综合征)；排斥反应：移植物抗宿主反应/移植物抗宿主病、同种异体移植排斥(例如，急性同种异体移植排斥或慢性同种异体移植排斥)、早期移植排斥；恶性肿瘤、癌症、淋巴瘤、白血病、多发性骨髓瘤、实体瘤、畸胎瘤、转移性紊乱和骨紊乱、内部癌症、骨癌、口腔癌/咽癌、食管癌、喉癌、胃癌、肠癌、结肠癌、直肠癌、肺癌(例如，非小细胞肺癌或小细胞肺癌)、肝癌(肝脏癌)、胰腺癌、神经癌、脑癌(例如，神经胶质瘤、多形性成胶质细胞瘤、星形细胞瘤、神经母细胞瘤、和神经鞘瘤)、头颈癌、咽喉癌、卵巢癌、子宫癌、***癌、睾丸癌、膀胱癌、肾癌(肾脏癌)、乳腺癌、胆囊癌、***、甲状腺癌、***癌、眼癌(眼部恶性肿瘤)、和皮肤癌(黑素瘤、角化棘皮瘤)；以及纤维化癌症、纤维瘤、纤维腺瘤、纤维肉瘤、骨髓增生性紊乱、赘生物(造血组织赘生物、脊髓赘生物、淋巴组织赘生物(骨髓纤维化、原发性骨髓纤维化、真性红细胞增多、原发性血小板增多))、白血病(急性淋巴细胞白血病、急性髓细胞白血病和慢性髓细胞白血病、慢性淋巴细胞白血病、急性淋巴细胞性白血病、慢性粒-单核细胞型白血病(CMML)、或前髓细胞白血病)、多发性骨髓瘤及其他骨髓性恶性肿瘤(骨髓纤维化伴髓样化生(MMM)、原发性骨髓纤维化(PMF)、特发性骨髓纤维化(IMF))、淋巴瘤(霍奇金病、皮肤淋巴瘤(皮肤T细胞淋巴瘤、蕈样肉芽肿病))、淋巴瘤(例如，B细胞淋巴瘤、T细胞淋巴瘤、套细胞淋巴瘤、毛细胞淋巴瘤、伯基特淋巴瘤、肥大细胞瘤、霍奇金病、或非霍奇金病)；卡波西肉瘤、横纹肌肉瘤、***瘤、畸胎癌、骨肉瘤、甲状腺滤泡状癌；外源性阿片类物质或合成阿片类物质的增加的累积、感觉异常性背痛、强迫性障碍、与强迫性障碍相关的怀乡症、及其组合。
本领域技术人员能够从下文的详细描述中容易地洞察到本申请的其它方面和优势。下文的详细描述中仅显示和描述了本申请的示例性实施方式。如本领域技术人员将认识到的，本申请的内容使得本领域技术人员能够对所公开的具体实施方式进行改动而不脱离本申请所涉及发明的精神和范围。相应地，本申请的附图和说明书中的描述仅仅是示例性的，而非为限制性的。
附图说明
本申请所涉及的发明的具体特征如所附权利要求书所显示。通过参考下文中详细描述的示例性实施方式和附图能够更好地理解本申请所涉及发明的特点和优势。对附图简要说明如下：
图1显示的是使用抗肿瘤剂后的小鼠皮疹模型。
图2显示的是对照组、给药组中典型大鼠的左侧、背部和右侧的照片。
图3显示的是实验终点时给药组和对照组的皮疹等级。
图4显示的是实验终点时给药组和对照组的皮疹等级。
图5显示的是对照组、给药组中典型大鼠的左侧、背部和右侧的照片。
图6显示的是实验终点时给药组和对照组的皮疹等级。
图7显示的是实验终点时给药组和对照组的皮疹等级。
具体实施方式
以下由特定的具体实施例说明本申请发明的实施方式，熟悉此技术的人士可由本说明书所公开的内容容易地了解本申请发明的其他优点及效果。
术语定义
在本申请中，术语“前药”也成为“前体药物”，通常指在体内转化成母体药物或活性药物分子的药剂或化合物。例如，所述“前药”可以是另一药物活性分子的前体，其在施用给受试者后，通过诸如溶剂分解或酶促裂解之类的化学或生理过程，或者在生理条件下，体内产生该另一药物活性分子。
如本文所使用的，术语“任选被取代的烷基”包括不含任何取代基的直链或支链烷基，也包括含有一个或多个非氢取代基的直链或支链烷基。例如，所述烷基通常包括具有指定数量碳原子的饱和脂族烃基，可以是分支的或直链的。术语“烷基”还指非芳族环烷基。例如，所述烷基可具有1-20个碳(即，C1-C20)。例如，如“C1-C10烷基”中的C1-C10被定义为包括具有直链的、支链的或环状排列(即环烷基)的1、2、3、4、5、6、7、8、9或10个碳的基团。术语“环烷基”是指具有指定数量碳原子的单环饱和的脂族烃基。例如，“烷基”具体包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基、己基、庚基、辛基、壬基、癸基等等，以及环烷基，包括环丙基、甲基-环丙基、2,2-二甲基-环丁基、2-乙基-环戊基、环己基等等。
在本申请中，术语“生物活性代谢物”通常是指化合物(例如本申请的化合物)通过在人或动物体或细胞内进行代谢而被体内加工，从而产生代谢物。例如，所述“生物活性代谢物”可包括在施用母体化合物后在个体体内产生的任何结构式的衍生物。这些衍生物可以通过个体体内的各种生物化学转化例如氧化、还原、水解或结合由母体化合物产生，并且包括例如氧化物和去甲基衍生物。可以用现有技术中已知的常规技术鉴定本发明化合物的代谢 物。参见例如，Bertolini，G.等人，J.Med.Chem.40：2011-2016(1997)；Shan，D.等人，J.Pharm.Sci.86(7)：765-767；Bagshawe K.，Drug Dev.Res.34：220-230(1995)；Bodor，N.，Advances in Drug Res.13：224-331(1984)；Bundgaard，H.，Design of Prodrugs(Elsevier Press1985)；和Larsen，I.K.，Design and Application of Prodrugs，Drug Design and Development(Krogsgaard-Larsen等人，编辑，Harwood Academic Publishers，1991)。应当清楚的是，作为式(I)化合物或它们的互变异构体、前药和立体异构体以及它们中任何一种的可药用的盐、酯和前药的代谢物的化学化合物都包括在本申请中。
在本申请中，术语“JAK抑制剂”通常是指Janus酪氨酸激酶抑制剂，其涉及靶向、降低或抑制Janus酪氨酸激酶的化合物，其可以直接或间接靶向一种或多种JAK，可以在转录水平，翻译水平和/或蛋白的翻译后修饰水平抑制所述JAK，可以抑制所述JAK的数量或表达量，也可以抑制所述JAK的活性。
在本申请中，术语“可药用盐”通常是指，保留了游离碱或游离酸的生物有效性和性质的盐，而且在生物学上或在其他方面也是符合需要的。所述盐可以是与无机酸形成的盐，也可以是与有机酸形成的盐。此外，可通过向游离酸中加入无机碱或有机碱制得所述可药用盐。
本申请中，术语“药学上可接受的”通常是指在合理的医学判断范围内适宜用于与人和动物的组织接触而无过度的毒性、刺激、过敏反应或者其他问题或并发症，具有合理的收益/风险比的那些化合物、材料、组合物和/或剂型。在一些实施方式中，药学上可接受的化合物、材料、组合物和/或剂型指由管理机构批准(如美国食品药品管理局、中国食品药品管理局或欧洲药品局)或者列于普遍认可的药典中(如美国药典、中国药典或欧洲药典)的用于动物(更特别地用于人)的那些。
发明详述
一方面，本申请提供了一种式(I)的化合物，还提供了该化合物的可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体，
其中：
G为JAK抑制剂，
R1和R各自独立地选自：氢、氘、氚、任选被取代的烷基、任选被取代的氘代烷基、任选被取代的卤代烷基、任选被取代的烷氧基、任选被取代的卤代烷氧基、卤素和任选被取代的环基；且n为1,2,3,4或5。
另一方面，本申请提供了制备上述本申请的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体的方法。
另一方面，本申请提供了一种组合物，其包含本申请的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体。
在某些实施方式中，本申请的组合物是药物组合物。例如，其可包含一种或多种药学上可接受的载体。例如，所述药学上可接受的载体可以选自下组：填充剂、粘合剂、崩解剂、缓冲液、防腐剂、润滑剂、搅味剂、增稠剂、着色剂和乳化剂。
在某些实施方式中，所述药物组合物或本申请的所述化合物被制备为适用于局部给药。例如，所述药物或所述化合物可被制备为适用于透皮给药。在一些实施方式中，所述药物或所述化合物被制备为用于局部皮肤施用。在某些实施方式中，所述药物被制备为乳膏，洗液，凝胶，软膏，油膏，喷剂，脂质体制剂，擦剂和/或气雾剂。在某些实施方式中，所述药物或所述化合物可以被制备为软膏剂。
在一些实施方式中，所述药物组合物或所述化合物为口服制剂。在一些实施方式中，所述药物组合物或所述化合物可以为注射制剂。在一些实施方式中，所述药物组合物或所述化合物可以用于口腔局部施用。
在所述药物组合物中，所述化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体的浓度可以为约0.0001％至约50％。例如，所述化合物的浓度可以为约0.0001％(w/w)至约40％(w/w)，例如，可以在约0.0001％(w/w)至约30％(w/w)、约0.0001％(w/w)至约20％(w/w)、约0.0001％(w/w)至约15％(w/w)、约0.0001％(w/w)至约10％(w/w)、约0.0001％(w/w)至约9.5％(w/w)、约0.0001％(w/w)至约9％(w/w)、约0.0001％(w/w)至约8.5％(w/w)、约0.0001％(w/w)至约8％(w/w)、约0.0001％(w/w)至约7.5％(w/w)、约0.0001％(w/w)至约7％(w/w)、约0.0001％(w/w)至约6.5％(w/w)、约0.0001％(w/w)至约6％(w/w)、约0.0001％(w/w)至约5.5％(w/w)、约0.0001％(w/w)至约5％(w/w)、约0.0001％(w/w)至约4.5％(w/w)、约0.0001％(w/w)至约4％(w/w)、约0.0001％(w/w)至约3.5％(w/w)、约0.0001％(w/w)至约3％(w/w)、约0.0001％(w/w)至约2.5％(w/w)、约0.0001％(w/w)至约2％(w/w)、约0.0001％(w/w)至约1.5％(w/w)、约0.0001％(w/w)至约1％(w/w)、约0.0001％(w/w)至约0.5％(w/w)、约0.0001％(w/w)至约0.01％(w/w)或更小的范围内变动。在本申请的所述组合物中，所述化合物、其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体的浓度可以为约0.0001％(w/w)至约5％(w/w)、约0.0001％ (w/w)至约4％(w/w)、约0.0001％(w/w)至约3％(w/w)、约0.0001％(w/w)至约2.5％(w/w)、约0.0001％(w/w)至约2％(w/w)、约0.0001％(w/w)至约1.5％(w/w)、约0.0001％(w/w)至约1％(w/w)、约0.0001％(w/w)至约0.9％(w/w)、约0.0001％(w/w)至约0.8％(w/w)、约0.0001％(w/w)至约0.7％(w/w)、约0.0001％(w/w)至约0.6％(w/w)、约0.05％(w/w)至约0.5％(w/w)、约0.05％(w/w)至约0.4％(w/w)、约0.05％(w/w)至约0.3％(w/w)、约0.05％(w/w)至约0.2％(w/w)、约0.1％(w/w)至约0.2％(w/w)或更小的范围内变动。例如，所述化合物的浓度可以为约0.05％(w/w)至约10％(w/w)。在某些实施方式中，所述化合物的浓度为约5％(w/w)。在某些实施方式中，所述化合物的浓度为约2.5％(w/w)。在某些实施方式中，所述化合物的浓度为约1％(w/w)。
在本申请中，所述组合物中还可以包括一种或多种其他活性成分。例如，所述活性成分可以指具有医疗效用或者生理活性的单体化合物。例如，所述其他活性成分可以选自下组：抗炎剂、止痛剂、局部麻醉剂、抗生素、抗组胺剂、防腐剂、免疫抑制剂和抗出血剂。
另一方面，本申请所述的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体，或者本申请所述的组合物(例如，药物组合物)可用于预防，缓解和/或治疗受试者中与施用抗肿瘤剂相关的疾病或病症。
例如，本申请所述的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体，或者本申请所述的组合物(例如，药物组合物)可用于制备药物(例如，经包装的药物)，所述药物可用于预防，缓解和/或治疗受试者中与施用抗肿瘤剂相关的疾病或病症。
另一方面，本申请所述的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体，或者本申请所述的组合物(例如，药物组合物)可用于制备JAK抑制剂，或者包含JAK抑制剂的组合物(例如，药物组合物)。
另一方面，本申请还提供了一种预防，缓解和/或治疗受试者中与施用抗肿瘤剂相关的疾病或病症的方法，所述方法包括向有需要的受试者施用本申请所述的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体，或者本申请所述的组合物(例如，药物组合物)。
另一方面，本申请提供了一种在有需要的受试者中预防、治疗和/或缓解JAK介导的疾病或病症的方法，所述方法包括：向所述受试者施用有效量的本申请所述的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体；或者本申请所述的组合物。所述有效量可以为能够有效预防、治疗和/或缓解所述JAK介导的疾病或病 症的剂量。
在某些实施方式中，所述方法还包括施用另外的治疗剂。所述另外的治疗剂可以为能够有效预防、治疗和/或缓解JAK介导的疾病或病症的试剂。在某些实施方式中，所述另外的治疗剂选自：芦可替尼(Ruxolitinib)、托法替尼(Tofacitinib)、Oclacitinib、fedratinib、peficitinib、upadacitinib、barictinib、fligotinib、decernotinib、cerdulatinib、lestaurtinib、pacritinib、momelotinib、Gandotinib、Abrocitinib、Solcitinib、SHR-0203、itacitinib、PF-06651600、BMS-986165、abrocitinib、、Cucurbitacin I、CHZ868、TD-1473、zotiraciclib、alkotinib、jaktinib、AZD-4205、DTRMHS-07、KL130008、WXSH-0150、TQ05105、WXFL10203614、GLPG0634、CEP-33779、R-348、itacitinib、ritlecitinib、brepocitinib、Tasocitinib、Deucravacitinib、INCB-039110、Izencitinib、Entrectinib、Ivarmacitinib、Deuruxolitinib、Adelatinib、NDI-034858、Nezulcitinib、ATI-01777、TD-8236、INCB-054707、Ropsacitinib、AGA-201、ATI50001、Gusacitinib、Cerdulatinib、Roniciclib、AT-9283、FMX-114、OST-122、TT-00420、Repotrectinib、INCB-052793、CT-340、BMS-911543、Ilginatinib、BGB-23339、ICP-332、ESK-001、SYHX-1901、VTX-958、TLL-018、CEE-321、CJ-15314、TD-5202、ABBV-712、GLPG-3667、CPL-116、AZD-4604、TAS-8274、MAX-40279、TD-3504、KN-002、AZD-0449、R-548、AC-410、Spebrutinib、ONX-0805、AEG-41174、XL-019、CR-4、WP-1066、GDC-0214、INCB-047986、PF-06263276、R-333、AZD-1480、Tozasertib、CS-12192和AC-1101。
另一方面，本申请提供了本申请所述的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体，或者本申请所述的组合物用于制备药物的用途，所述药物用于预防、治疗和/或缓解有需要的受试者中JAK介导的疾病或病症。
化合物
在本申请的化合物中，所述R1可以为氢，任选被取代的烷基或任选被取代的氘代烷基。例如，所述R1可以为氢，任选被取代的C1-C6烷基或任选被取代的C1-C6氘代烷基。例如，所述R1可以为氢，任选被取代的C1-C3烷基或任选被取代的C1-C3氘代烷基。在某些实施方式中，R1为氢，任选被取代的甲基或任选被取代的氘代甲基。
例如，所述R1可以是不经取代的烷基(例如，不经取代的C1-C6烷基，不经取代的C1-C3烷基，如不经取代的甲基)。
在某些实施方式中，所述R1也可以为经取代的烷基(例如，经取代的C1-C6烷基，经取代的C1-C3烷基，如经取代的甲基)。当所述R1为经取代的烷基时，其可以被任意其他基团取代，例如其可以被选自下组的一种或多种基团取代：氢、烷基、烷氧基、环烷基、杂 环烷基、芳基、杂芳基、烷基羰基、烷氧基羰基、环烷基羰基、杂环烷基羰基、芳基羰基、杂芳基羰基、羟基、卤素、羧基、氨基、氰基和/或磺酰基。
在某些实施方式中，所述R1选自：-(CH2)n1Ra、-(CH2)n1ORa、-(CH2)n1SRa、-(CH2)n1C(O)Ra、-(CH2)n1C(O)ORa、-(CH2)n1S(O)m1Ra、-(CH2)n1NRaRb、-(CH2)n1C(O)NRaRb、-(CH2)n1NRaC(O)Rb和-(CH2)n1NRaS(O)m1Rb；其中：所述Ra和Rb可以相同或不同，且各自独立地选自氢、氘、氚、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氰基、硝基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自下组的一种或多种基团取代：氢、氘、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基；或者，所述Ra和Rb连接形成环烷基、杂环基、芳基或杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选被选自下组的一种或多种基团取代：氢、氘、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基；n1为0-5，例如，所述n1可以为0,1,2,3,4或5；且m1为0，1或2。
在某些实施方式中，所述R1为高分子化合物，例如，具有多个重复单元的高分子化合物，例如，通过交联获得的高分子化合物。
在本申请的化合物中，所述R可以选自：任选被取代的烷基，任选被取代的氘代烷基，任选被取代的环烷基，任选被取代的杂环烷基，任选被取代的芳基和任选被取代的杂芳基。
例如，所述R可以选自：任选被取代的C1-C20烷基，任选被取代的C1-C20氘代烷基，任选被取代的C3-C20环烷基，任选被取代的C1-C20杂环烷基，任选被取代的C6-C20芳基和任选被取代的C1-C20杂芳基。例如，所述R可以选自：任选被取代的C1-C10烷基，任选被取代的C1-C10氘代烷基，任选被取代的C3-C10环烷基，任选被取代的C1-C10杂环烷基，任选被取代的C6-C10芳基和任选被取代的C1-C10杂芳基。
例如，所述R可以是不经取代的烷基，氘代烷基，环烷基，杂环烷基，芳基或杂芳基。在某些实施方式中，所述R是不经取代的C1-C20烷基，C1-C20氘代烷基，C3-C20环烷 基，C1-C20杂环烷基，C6-C20芳基或C1-C20杂芳基。在某些实施方式中，所述R是不经取代的C1-C10烷基，C1-C10氘代烷基，C3-C10环烷基，C1-C10杂环烷基，C6-C10芳基或C1-C10杂芳基。
在某些实施方式中，所述R也可以是经取代的烷基，经取代的氘代烷基，经取代的环烷基，经取代的杂环烷基，经取代的芳基或经取代的杂芳基。在某些实施方式中，所述R是经取代的C1-C20烷基，经取代的C1-C20氘代烷基，经取代的C3-C20环烷基，经取代的C1-C20杂环烷基，经取代的C6-C20芳基或经取代的C1-C20杂芳基。在某些实施方式中，所述R是经取代的C1-C10烷基，经取代的C1-C10氘代烷基，经取代的C3-C10环烷基，经取代的C1-C10杂环烷基，经取代的C6-C10芳基或经取代的C1-C10杂芳基。当所述R为经取代的烷基，经取代的氘代烷基，经取代的环烷基，经取代的杂环烷基，经取代的芳基或经取代的杂芳基时，其可以被任意其他基团取代，例如其可以被选自下组的一种或多种基团取代：氢、烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、烷基羰基、烷氧基羰基、环烷基羰基、杂环烷基羰基、芳基羰基、杂芳基羰基、羟基、卤素、羧基、氨基、氰基和/或磺酰基。
在某些实施方式中，所述R选自：-(CH2)n1Ra、-(CH2)n1ORa、-(CH2)n1SRa、-(CH2)n1C(O)Ra、-(CH2)n1C(O)ORa、-(CH2)n1S(O)m1Ra、-(CH2)n1NRaRb、-(CH2)n1C(O)NRaRb、-(CH2)n1NRaC(O)Rb和-(CH2)n1NRaS(O)m1Rb；其中：所述Ra和Rb可以相同或不同，且各自独立地选自氢、氘、氚、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氰基、硝基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自下组的一种或多种基团取代：氢、氘、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基；或者，所述Ra和Rb连接形成环烷基、杂环基、芳基或杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选被选自下组的一种或多种基团取代：氢、氘、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基；n1为0-5，例如，所述n1可以为0,1,2,3,4或5；且m1为0，1或2。
在某些实施方式中，所述R为高分子化合物，例如，具有多个重复单元的高分子化合物，例如，通过交联获得的高分子化合物。
在本申请中，所述烷基可包括：甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、异戊烷基、叔戊烷基、己基、异己基、甲基戊基、二甲基丁基、庚基、辛基、壬基或癸基。所述被取代的烷基可被选自下组的基团取代：羟基、卤素、酯基、腈基和羰基。
在本申请的某些实施方式中，所述环基(例如，饱和的环基，部分饱和的环基，或不饱和的环基，含有或不含杂原子)可以为三元环、四元环、五元环、六元环，桥环，和/或稠环。在某些实施方式中，所述被取代的环基(例如，环烷基，杂环烷基，芳基或杂芳基)可被选自下组的基团取代：羟基、卤素、酯基、腈基和羰基。
当所述R为任选被取代的杂环烷基(例如，任选被取代的C1-C20杂环烷基，如任选被取代的C1-C10杂环烷基)时，或任选被取代的杂芳基(例如，任选被取代的C1-C20杂芳基，如任选被取代的C1-C10杂芳基)时，其可包括选自下组的杂原子(例如，下述杂原子的单价基团)：氟、氧、硫和氮。
在某些实施方式中，所述杂环基(例如，杂环烷基或杂芳基)可以为任选被取代的六元含氮杂环。在某些实施方式中，所述杂环基(例如，杂环烷基或杂芳基)可选自：呋喃、噻吩、吡咯、噻唑、咪唑、吡啶、吡嗪、嘧啶、哒嗪、吲哚、喹啉、蝶啶和吖啶。
在某些实施方式中，所述环基选自：环烷基、杂环基、氧代杂环基、硫代杂环基、芳基和杂芳基。在某些实施方式中，所述环烷基、杂环基、氧代杂环基、硫代杂环基、芳基和杂芳基任选被选自下组的一种或多种基团取代：氢、氘、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基。
在某些实施方式中，所述任选被取代的芳基为任选被取代的苯基。例如，所述芳基(例如，苯基)可以被选自下组的基团取代：羟基、卤素、酯基、腈基和羰基。
在某些实施方式中，所述n为1-5。在某些实施方式中，所述n为2-4。在某些实施方式中，所述n为1,2或3。在某些实施方式中，所述n为1。在某些实施方式中，所述n为2。在某些实施方式中，所述n为3。在某些实施方式中，所述n为4。在某些实施方式中，所述n为5。
在本申请的化合物的某些实施方式中，所述R1为氢，任选被取代的甲基或任选被取代的氘代甲基，所述n为2，且所述R为任选被取代的C3-C20环烷基或任选被取代的C1-C20杂环烷基。
在本申请的化合物的某些实施方式中，所述R1为氢，任选被取代的甲基或任选被取代的氘代甲基，所述n为2，且所述R为任选被取代的C3-C10环烷基或任选被取代的C1-C10杂环烷基。
在本申请的化合物的某些实施方式中，所述G为选自下组的JAK抑制剂：芦可替尼(Ruxolitinib)、托法替尼(Tofacitinib)、Oclacitinib、fedratinib、peficitinib、upadacitinib、barictinib、fligotinib、decernotinib、cerdulatinib、lestaurtinib、pacritinib、momelotinib、Gandotinib、Abrocitinib、Solcitinib、SHR-0203、itacitinib、PF-06651600、BMS-986165、abrocitinib、、Cucurbitacin I、CHZ868、TD-1473、zotiraciclib、alkotinib、jaktinib、AZD-4205、DTRMHS-07、KL130008、WXSH-0150、TQ05105、WXFL10203614、GLPG0634、CEP-33779、R-348、itacitinib、ritlecitinib、brepocitinib、Tasocitinib、Deucravacitinib、INCB-039110、Izencitinib、Entrectinib、Ivarmacitinib、Deuruxolitinib、Adelatinib、NDI-034858、Nezulcitinib、ATI-01777、TD-8236、INCB-054707、Ropsacitinib、AGA-201、ATI50001、Gusacitinib、Cerdulatinib、Roniciclib、AT-9283、FMX-114、OST-122、TT-00420、Repotrectinib、INCB-052793、CT-340、BMS-911543、Ilginatinib、BGB-23339、ICP-332、ESK-001、SYHX-1901、VTX-958、TLL-018、CEE-321、CJ-15314、TD-5202、ABBV-712、GLPG-3667、CPL-116、AZD-4604、TAS-8274、MAX-40279、TD-3504、KN-002、AZD-0449、R-548、AC-410、Spebrutinib、ONX-0805、AEG-41174、XL-019、CR-4、WP-1066、GDC-0214、INCB-047986、PF-06263276、R-333、AZD-1480、Tozasertib、CS-12192和AC-1101。
在本申请的化合物的某些实施方式中，所述G为选自下组的JAK抑制剂：托法替尼(Tofacitinib)，鲁索替尼(Ruxolitinib)，巴瑞替尼(Baricitinib)，培非替尼(Peficitinib)，帕克替尼(Pacritinib)，德尔戈西替尼(Delgocitinib)，Pf-04965842，乌帕达替尼(Upadacitinib)，菲尔戈替尼(Filgotinib)，伊他替尼(Itacitinib)，费德拉替尼(Fedratinib)，Decernotinib，SHR-0302，ASN-002，Cerdulatinib，BMS-986165，PF-06700841，INCB-52793，ATI-502，PF-06651600，AZD-4205，氘修饰鲁索替尼类似物，ATI-501，R-348，NS-018，盐酸雅克替尼和KL-130008。
例如，所述G可以包含(或具有)选自下组的结构：
例如，所述托法替尼(Tofacitinib)的结构为
在某些实施方式中，本申请的化合物选自下组：


抗肿瘤剂
根据本申请的任一方面，所述抗肿瘤剂可包括小分子化合物，小分子偶联物，蛋白质和/或多核苷酸。
例如，所述抗肿瘤剂可包括化疗剂，靶向治疗剂和/或免疫治疗剂。
在某些实施方式中，所述抗肿瘤剂为靶向治疗剂。所述靶向治疗剂可包括小分子化合物和/或抗体或其抗原结合片段。所述抗体可包括单克隆抗体，多特异性抗体，嵌合抗体，人源化抗体，全人源抗体和/或抗体药物偶联物。所述抗原结合片段可包括Fab，Fab’，F(ab)2，Fv片段，F(ab’)2，scFv，di-scFv和/或dAb。
在某些实施方式中，所述靶向治疗剂靶向肿瘤细胞内部，肿瘤细胞表面和/或肿瘤微环境中的分子。例如，所述靶向治疗剂可靶向蛋白质和/或核酸分子。例如，所述靶向治疗剂可靶向肿瘤相关抗原。
在某些实施方式中，所述靶向治疗剂靶向选自下组的一个或多个靶标：VEGF，EGFR，EGFR1，EGFR2，EGFR3，EGFR4，HER2，HER3，HER4，VEGFR，VEGFR1，VEGFR2，VEGFR3，VEGFR4，PDGFR，PDGFRα，PDGFRβ，KIT，c-Kit，Ret，Raf，Raf-1，Abl，FGFR， FGFR1，MET，c-MET，Tie2，Src，c-Src，AXL，Ret，BCR-ABL，CSF-1R，FGFR，FGFR1，FGFR2，FGFR3，FGFR4，mTOR，TORC，BRaf，MEK，MEK1，MEK2，ALK，ABL，CDK，JAK，PI3K，NTRK，MSI，HDAC，FAK，PYK2，以及它们的突变体。
例如，所述靶向治疗剂可抑制选自下组的一个或多个靶标的活性：VEGF，EGFR，EGFR1，EGFR2，EGFR3，EGFR4，HER2，HER3，HER4，VEGFR，VEGFR1，VEGFR2，VEGFR3，VEGFR4，PDGFR，PDGFRα，PDGFRβ，KIT，c-Kit，Ret，Raf，Raf-1，Abl，FGFR，FGFR1，MET，c-MET，Tie2，Src，c-Src，AXL，Ret，BCR-ABL，CSF-1R，FGFR，FGFR1，FGFR2，FGFR3，FGFR4，mTOR，TORC，BRaf，MEK，MEK1，MEK2，ALK，ABL，CDK，JAK，PI3K，NTRK，MSI，HDAC，FAK，PYK2，以及它们的突变体。
例如，所述靶向治疗剂可降低选自下组的一个或多个靶标的表达：VEGF，EGFR，EGFR1，EGFR2，EGFR3，EGFR4，HER2，HER3，HER4，VEGFR，VEGFR1，VEGFR2，VEGFR3，VEGFR4，PDGFR，PDGFRα，PDGFRβ，KIT，c-Kit，Ret，Raf，Raf-1，Abl，FGFR，FGFR1，MET，c-MET，Tie2，Src，c-Src，AXL，Ret，BCR-ABL，CSF-1R，FGFR，FGFR1，FGFR2，FGFR3，FGFR4，mTOR，TORC，BRaf，MEK，MEK1，MEK2，ALK，ABL，CDK，JAK，PI3K，NTRK，MSI，HDAC，FAK，PYK2，以及它们的突变体。
例如，所述靶向治疗剂可包括激素，信号转导抑制剂，基因表达调节剂，细胞凋亡诱导剂，血管生成抑制剂和/或毒素递送分子。
在某些实施方式中，所述靶向治疗剂为酪氨酸酶抑制剂。
在某些实施方式中，所述靶向治疗剂为VEGFR抑制剂和/或VEGF抑制剂。例如，所述VEGFR抑制剂可抑制VEGFR1、VEGFR2和/或VEGFR3。在某些实施方式中，所述靶向治疗剂为EGFR抑制剂。在某些实施方式中，所述靶向治疗剂为BRAF抑制剂。在某些实施方式中，所述靶向治疗剂为PDGFR抑制剂。在某些实施方式中，所述靶向治疗剂为FGFR抑制剂。在某些实施方式中，所述靶向治疗剂为mTOR抑制剂。在某些实施方式中，所述靶向治疗剂为HER2抑制剂。
例如，在本申请任一方面的实施方式中，所述EGFR(e.g.,Her2)抑制剂可选自下述化合物及其可药用盐：阿法替尼，奥木替尼，拉帕替尼，吉非替尼和达克替尼。
例如，在本申请任一方面的实施方式中，所述VEGFR抑制剂和/或VEGF抑制剂可选自下述化合物及其可药用盐：雷莫芦单抗，贝伐珠单抗，安罗替尼，瑞戈非尼，卡博替尼，乐伐替尼，索拉非尼，呋喹替尼，法米替尼，阿帕替尼，阿昔替尼和尼达尼布。
例如，在本申请任一方面的实施方式中，所述BRAF抑制剂可选自下述化合物及其可药 用盐：威罗非尼，恩科拉非尼，司美替尼和达拉非尼。
例如，在本申请任一方面的实施方式中，所述PDGFR抑制剂可选自下述化合物及其可药用盐：舒尼替尼和尼达尼布。
例如，在本申请任一方面的实施方式中，所述FGFR抑制剂可选自下述化合物及其可药用盐：厄达替尼和英菲格拉替尼。
例如，在本申请任一方面的实施方式中，所述mTOR抑制剂可选自下述化合物及其可药用盐：依维莫司。
例如，本申请所述的靶向治疗剂可选自下组中的一种或多种：阿法替尼，达克替尼，奥希替尼，EAI045，吉非替尼，阿莫替尼，吡罗替尼，布加替尼，来那替尼，奥木替尼，博舒替尼，埃克替尼，凡德他尼，拉帕替尼，阿氟替尼，BPI-7711，莫波替尼，多维替尼，佐立替尼，瓦利替尼，奥布替尼，拉布替尼，布鲁替尼依鲁替尼，达沙替尼，pirtobrutinib，tolebrutinib，rilzabrutinib，fenebrutinib，evobrutinib，司美替尼(selumetinib)，tivozanib，dovitinib,索凡替尼，binimetinib，cobimetinib，trametinib，瑞戈非尼(regorafenib)，GSK-1120212，alpelisib，duvelisib，copanlisib，idelalisib，去甲替林，inavolisib，dactolisib，apitolisib，parsaclisib，buparlisib，rigosertib，enzastaurin，paxalisib，leniolisib，ipatasertib，zotarolimus，sirolimus，依维莫司，temsirolimus，索拉非尼(sorafenib)，阿帕替尼(apatinib)，乐伐替尼(lenvatinib)，舒尼替尼(sunitinib)，卡博替尼(cabozantinib)，阿昔替尼(axitinib)，尼达尼布(nintedanib)，brivanib，vatalanib，呋喹替尼(fruquintinib)，达拉非尼(dabrafenib)，威罗非尼(vemurafenib)，恩科拉非尼(encorafenib)，pazopanib，crizotinib，panobinostat，erlotinib，rituximab，panitumumab，cetuximab，erfonrilimab，efactinib，cadonilimab，ramucirumab，bevacizumab，安罗替尼(anlotinib)，ponatinib，法米替尼(famitinib)，厄达替尼(erdafitinib)，AZD4547，英菲格拉替尼(infigratinib，在本申请中也称为英飞替尼)，BCD-217，amivantamab，MCLA-129，EMB-01，LY3164530，JNJ-61186372，抗EGFR及cMet双特异性抗体，GB263，它们的可药用盐以及它们的任意组合。其中，所述EGFR及cMet双特异性抗体可以如WO2010115551A1，WO2014081954A1，或WO2015016559A1所描述的。
根据本申请的任一方面，所述靶向治疗剂可与一种或多种其它疗法联合施用。
在某些实施方式中，所述抗肿瘤剂为化疗剂。例如，所述化疗剂可包括嘧啶核苷类似物和/或其前药。
在某些实施方式中，所述化疗剂包括选自下组中的一种或多种：卡培他滨、阿糖胞苷、多西他赛、阿霉素、氟尿嘧啶(5-FU)、氟尿苷、替加氟、伊达比星、紫杉醇、表柔比星、Acelarin (NUC-1031)、多柔比星、亚叶酸、顺铂、紫杉醇、环磷酰胺、长春新碱和5-FU药物前体。
在某些实施方式中，所述化疗剂包括选自下组中的一种或多种：喃氟啶、5’-脱氧氟尿苷、氟尿苷、2’-脱氧氟尿苷、氟尿苷的药物前体衍生物、2’-脱氧氟尿苷的药物前体衍生物、三氟-甲基-2’-脱氧尿苷、6-氮杂尿苷和3-脱氮杂尿苷。
例如，所述的化疗剂可与一种或多种其它疗法联合施用。在某些实施方式中，所述一种或多种其它疗法包括一种或多种其它本申请所述的抗肿瘤疗法(e.g.，抗肿瘤剂)。
例如，所述抗肿瘤剂(例如细胞毒抗癌剂)可以包括烷基化剂如氮芥、氮芥N-氧化物盐酸盐、苯丁酸氮芥、环磷酰胺、异环磷酰胺、噻替派、异硫氰酸酯、白消安、盐酸尼莫司汀、米托溴铵、美法仑、达卡巴嗪、雷莫司汀、丙米酚磷酸钠、亚乙基三胺、卡莫司汀、洛莫司汀、链脲佐菌素、哌泊溴烷(pipobroman)、依托格鲁(ethoglucid)、卡铂、顺铂、米铂、奈达铂、替奈特胺、奥莫司汀、二氯吡啶、氟匹司坦、泼尼匹昔汀、嘌嘧替派(pumitepa)、盐酸苯达莫司汀(Ribomustin)、替莫唑胺、双氯芬酸、曲伐沙星、津诺他汀、辛伐他汀、青霉烯素、半胱胺亚硝脲(cystemustine)和比折来新(bizelesin)；抗代谢药物如巯嘌呤、6-巯基嘌呤核糖苷、硫代肌苷、甲氨蝶呤、培美曲塞、恩替西汀、阿糖胞苷、奥沙利铂、盐酸替沙巴汀、5-FU及其衍生物(例如，氟尿嘧啶、替加氟、UFT、多西葫芦、卡莫氟、卡培他滨等)、氨基喋呤、奈唑硫胺、甲酰四氢叶酸钙、小叶菌、叶酸钙、左派芬酸钙、克拉屈滨、埃米特福尔、氟达拉滨、吉西他滨、羟基脲、喷司他丁、吡曲克辛(piritrexim)、碘尿苷、米托胍酮、噻唑呋喃、维马司他和苯达莫司汀；抗肿瘤抗生素如放线菌素D、放线菌素C、丝裂霉素C、色霉素A3、博来霉素盐酸盐、硫酸博莱霉素、盐酸西替霉素、盐酸柔比星、盐酸米托蒽醌和盐酸伊达比星；和/或，依托泊苷、依托泊甙磷酸盐、硫酸长春碱、硫酸长春新碱、替尼泊苷、紫杉醇、多西他赛和长春瑞滨等植物来源的细胞毒抗肿瘤剂物；VEGF抑制剂如贝伐珠单抗、以及在PCT专利申请WO 2005/012359、WO 2005/044853、WO 98/45332、WO 96/30046、WO 94/10202、美国专利US7,060,269、US6,582,959、US6,703,020、US6,054,297、美国专利申请US2006/009360、US2005/0186208、US2003/0206899、US2003/0190317、US2003/0203409和US2005/0112126中公开的那些VEGF抑制剂。
在某些实施方式中，所述抗肿瘤剂可以为免疫治疗抗肿瘤剂，其可以包括，例如：布比奈尼、克雷司汀、依托呋喃、香菇多糖、乌苯美辛、干扰素、白细胞介素、巨噬细胞集落刺激因子、粒细胞集落刺激因子、红细胞生成素、淋巴毒素、BCG疫苗、小棒状杆菌、依维莫司、左旋咪唑、多糖K、丙考达唑(procodazole)和/或免疫检查点抑制剂(例如，CTLA4抑制剂、TIM-3抑制剂、PD-1抑制剂(例如，Nivolumab(纳武单抗)、Pembrolizumab(派姆单抗)、 Pidilizumab、AMP514(Amplimmune)、AMP-224、以及在PCT专利申请WO2006/121168、WO2009/114335、WO2009/101611、美国专利US 8609089、美国专利申请US2010/028330、US2012/0114649中公开的其它PD-1抑制剂)、PD-L1抑制剂(例如，YW243.55.S70、MPDL3280A、MEDI-4736、MSB-0010718C、MDX-1105、以及在PCT专利申请WO2010/077634和美国专利US7,943,743中公开的其它PD-L1抑制剂))。
在某些实施方式中，所述抗肿瘤剂可以包括激素治疗抗肿瘤剂。例如，可以包括夫司他丁、己烯雌酚、氯代木香烯、醋酸甲羟孕酮、乙酸甲地孕酮、乙酸环丙孕酮、醋酸环丙孕酮、丹那唑、烯丙雌醇、孕酮、美帕曲星(mepartricin)、雷洛昔芬或美洛昔芬、左旋氧氟沙星、抗***(例如，他莫昔芬柠檬酸盐、托瑞米芬柠檬酸盐等)、避孕药、前列环烷烷、睾酮内酯、氨基丁二酰亚胺、LH-RH激动剂(例如，醋酸戈舍瑞林、布舍瑞林、亮丙瑞林等)、屈洛昔芬、表雄甾烷醇、炔雌醇磺酸酯、盐酸呋苯唑、阿那曲唑、来曲唑、依西美坦、伏罗唑、抗雄激素(例如，氟他胺、比卡鲁胺、尼鲁他胺等)、5α-还原酶抑制剂(例如，非那雄胺、爱普列特(Epristeride))、皮质类固醇(例如，***、***龙、倍他米松、曲安奈德等)和/或雄激素合成抑制剂(例如，阿比特龙等)。
与抗肿瘤剂相关的疾病或病症
根据本申请的任一方面，与施用所述抗肿瘤剂相关的疾病或病症可以是由所述抗肿瘤单独引起的，也可以是由多种治疗方案引起的，但是其中包括所述抗肿瘤剂。
在某些实施方式中，所述疾病或病症是由施用所述抗肿瘤剂引起的。例如，所述疾病或病症可在施用所述抗肿瘤剂之后出现或加重。
在某些实施方式中，在施用所述抗肿瘤剂之前，所述受试者未患有所述疾病或病症。
例如，所述疾病或病症可包括上皮组织疾病或病症。所述上皮组织疾病或病症可包括与内皮细胞病变相关的疾病或病症，和/或与上皮细胞病变相关的疾病或病症。例如，所述上皮细胞可包括皮肤上皮细胞，口腔上皮细胞，鼻腔上皮细胞，胃上皮细胞和/或肠上皮细胞。
在某些实施方式中，所述内皮细胞包括血管内皮细胞。血管内皮细胞的病变可包括内皮功能障碍。例如，所述血管内皮细胞病变可以包括退行性变性血管疾病(例如，动脉粥样硬化、动脉中层硬化以及小动脉硬化(例如，透明变性型小动脉硬化和增生型小动脉硬化))、炎症性血管疾病(例如，感染性动脉炎、梅毒性动脉炎、巨细胞性动脉炎、血栓闭塞性脉管炎以及风湿性动脉炎)、功能性血管疾病(例如，雷诺氏病、手足发绀以及红斑肢痛症)和/或先天性血管疾病(例如，先天性动静脉瘘)等。
在本申请中，所述上皮细胞可包括皮肤上皮细胞、口腔上皮细胞、鼻腔上皮细胞、胃上 皮细胞和/或肠上皮细胞。例如，所述上皮细胞病变可以包括皮肤上皮细胞病变(例如，皮疹、痤疮、酒糟鼻、异位性皮炎、接触性皮炎、脂溢性皮炎、狼疮、硬皮病、天胞疮、色素沉淀、黑斑病、白癜风、荨麻疹、体癣、皮肤瘙痒、脱发、毛发改变、红斑、甲沟炎及甲裂、皮肤干燥、超敏反应以及牛皮癣)、口腔上皮细胞病变(例如，天疱疮、唇疱疹、疱疹性口炎、肉芽肿性唇炎、口腔溃疡、类天疱疮、舍格林氏综合征、贝赫切特综合征以及口腔结节病等)、鼻腔上皮细胞病变(鼻衄、鼻窦炎、鼻疖以及鼻息肉等)、胃上皮细胞病变(例如，胃炎、肠化生、胃穿孔、胃瘘、胃溃疡以及胃肠道息肉)和/或小肠上皮细胞病变(例如，肠炎、克罗恩病、肠穿孔、肠瘘、肠溃疡、溃疡性结肠炎以及NSAIDs肠病)等。
本申请的发明人发现，抗肿瘤剂会导致内皮细胞、内皮组织受损，从而引起皮肤组织、口腔组织、鼻腔组织和/或胃肠道组织的疾病或病症。在这些疾病或病症的发生及发展过程中，通常从内皮细胞、内皮组织的受损/病变开始发展病程，而上皮细胞也会有病变表现，并最终以与施用抗肿瘤剂相关的内皮细胞病变，和/或与施用抗肿瘤剂相关的上皮细胞病变的形式表现于患者。
例如，所述疾病或病症可包括皮肤疾病或病症，五官疾病或病症和/或胃肠道疾病或病症。
在某些实施方式中，所述皮肤疾病或病症包括脱发症，体臭，大疱性皮炎，皮肤干燥，湿疹，多形性红斑，红皮病，脂肪萎缩症，发色改变，毛发质地异常，多毛症(hirsutism)，多汗症(hyperhidrosis)，角化过度症，肥大症(hypertrichosis)，少汗症(hypohidrosis)，脂肥大，指甲改变，指甲变色，指甲丢失，指甲***，皮肤疼痛，手足综合征，光敏感性，瘙痒症，紫癜，痤疮样皮疹，斑丘疹，头皮疼痛，皮肤萎缩，皮肤色素沉着过多(skin hyperpigmentation)，皮肤色素减退(skin hypopigmentation)，皮肤硬结，皮肤溃疡，Stevens-Johnson综合征，皮下气肿，毛细血管扩张，中毒性表皮坏死，皮疹和/或荨麻疹。
在某些实施方式中，所述皮肤疾病或病症为手足综合征。
在某些实施方式中，本申请涉及使用本申请的化合物(例如，本申请式(I)的化合物)来预防，缓解和/或治疗受试者中与施用所述抗肿瘤剂(例如，EGFR抑制剂)相关的疾病或病症(例如，皮疹)。
在某些实施方式中，所述皮肤疾病或病症的严重程度为依据NCI-CTCAE中的第1级或其以上，第2级或其以上，第3级或其以上，第4级或其以上，或者第5级。
在某些实施方式中，所述受试者包括癌症患者。在某些实施方式中，所述皮肤疾病或病症的患处与癌症的患处不同。
在本申请中，所述与施用抗肿瘤剂相关的疾病或病症可以与抗肿瘤剂存在统计学上显著 的相关性。在某些实施方式中，所述与施用抗肿瘤剂相关的疾病或病症可以是由抗肿瘤剂引起的。例如，所述与施用抗肿瘤剂相关的疾病或病症可包括与施用抗肿瘤剂相关的皮肤疾病或病症、五官疾病或病症和/或胃肠道疾病或病症。例如，所述与施用抗肿瘤剂相关的皮肤疾病或病症、五官疾病或病症和/或胃肠道疾病或病症可以包括所述皮肤组织、五官和/或胃肠道中与施用抗肿瘤剂相关的上皮组织疾病或病症。在某些实施方式中，所述与施用抗肿瘤剂相关的疾病或病症可包括因施用抗肿瘤剂而引起的副作用或不良反应。
在本申请中，所述与施用抗肿瘤剂相关的疾病或病症可以为一种新的适应症，其可以不同于以往的任意一种其他的疾病或病症。例如，所述与施用抗肿瘤剂相关的疾病或病症的诊断方式、治疗方式和/或症状均是独特的。例如，红霉素软膏可以治疗皮疹，但是对与施用抗肿瘤剂相关的皮疹没有治疗作用。
在某些实施方式中，所述与施用抗肿瘤剂相关的疾病或病症可以包括与施用抗肿瘤剂相关的皮疹、与施用抗肿瘤剂相关的手足综合征、与施用抗肿瘤剂相关的瘙痒、与施用抗肿瘤剂相关的红斑、与施用抗肿瘤剂相关的皮肤干燥、与施用抗肿瘤剂相关的脱发、与施用抗肿瘤剂相关的甲沟炎、与施用抗肿瘤剂相关的色素沉积紊乱、与施用抗肿瘤剂相关的口腔溃疡、与施用抗肿瘤剂相关的口干、与施用抗肿瘤剂相关的鼻衄、与施用抗肿瘤剂相关的鼻咽炎、与施用抗肿瘤剂相关的唇炎、与施用抗肿瘤剂相关的食管黏膜炎、与施用抗肿瘤剂相关的胃黏膜炎、与施用抗肿瘤剂相关的胃溃疡、与施用抗肿瘤剂相关的腹泻、与施用抗肿瘤剂相关的呕吐、与施用抗肿瘤剂相关的恶心、与施用抗肿瘤剂相关的厌食、与施用抗肿瘤剂相关的便秘，和/或，与施用抗肿瘤剂相关的腹痛。例如，所述与施用抗肿瘤剂相关的疾病或病症包括与施用抗肿瘤剂相关的手足综合征。例如，所述与施用抗肿瘤剂相关的疾病或病症的严重程度为依据NCI-CTCAE V5.0中的第1级或以上、第2级或以上、第3级或以上、第4级或以上，和/或第5级。
在某些实施方式中，所述疾病或病症可以包括皮疹、手足综合征、瘙痒、红斑、皮肤干燥、脱发、甲沟炎、色素沉积紊乱、口腔溃疡、口干、鼻衄、鼻咽炎、唇炎、食管黏膜炎、胃黏膜炎、胃溃疡、腹泻、呕吐、恶心、厌食、便秘和/或腹痛。例如，所述疾病或病症包括手足综合征。
在某些实施方式中，所述与抗肿瘤剂相关的疾病或病症基本上无法通过施用选自下组的药剂而被治疗或缓解：1％西地那非、尿素霜、凡士林软膏、尿素软膏、溴莫尼定软膏、维生素B6软膏、尼古丁软膏、***软膏、氢化可的松软膏、维生素K1软膏(0.1％)、红霉素软膏和曲安奈德软膏。
在本申请中，所述疾病或病症的严重程度可以在所述施用抗肿瘤剂之后增加。例如，所述疾病或病症的严重程度可以增加约5％或以上，约10％或以上，约15％或以上，约20％或以上，约25％或以上，约30％或以上，约35％或以上，约40％或以上，约45％或以上，约50％或以上，约60％或以上，约70％或以上，约80％或以上，约90％或以上，约100％或以上，约200％或以上或更多。
在本申请中，在所述施用抗肿瘤剂之前，所述受试者可以未患有所述疾病或病症。在本申请中，术语“所述受试者未患有所述疾病或病症”通常是指受试者没有涉及所述与施用抗肿瘤剂相关的疾病或病症的既往病史。例如，在所述施用抗肿瘤剂之前1天以上、1周以上、1个月以上、1年以上、10年以上或所述受试者出生以来，未患有本申请所述与施用抗肿瘤剂相关的疾病或病症。
JAK介导的疾病或病症
根据本申请的任一方面，所述JAK介导的疾病或病症可选自：自身免疫紊乱或自身免疫应答、免疫应答的广泛激活、细菌感染、病毒感染、炎症、慢性和/或急性炎性紊乱或病况、和/或自身炎性紊乱、纤维化紊乱、代谢紊乱、赘生物、或者心血管紊乱或脑血管紊乱、皮肤紊乱、瘙痒、毛发缺损紊乱、癌症或恶性肿瘤、自身免疫性***病和自身免疫病况；斯蒂尔病、成年起病型斯蒂尔病、Th17相关性炎症、多软骨炎(例如，复发性多软骨炎)；肌炎、多肌炎、自身免疫性肌炎、皮肌炎、幼年型皮肌炎；重症肌无力；关节炎(例如，类风湿性关节炎、幼年型类风湿性关节炎、全身起病型幼年类风湿性关节炎、骨关节炎、感染性关节炎、炎症性关节炎、炎性肠病相关性关节炎、特发性关节炎、幼年型特发性关节炎、全身型幼年特发性关节炎、银屑病性关节炎)、脊椎炎/脊椎关节炎/脊椎关节病(强硬性脊椎炎)、痛风、硬皮病(全身性硬皮病、幼年型硬皮病)、赖特综合征/反应性关节炎、莱姆病、狼疮/***性红斑狼疮(SLE)(红斑狼疮、儿童***性红斑狼疮、皮肤狼疮(亚急性皮肤狼疮、慢性皮肤狼疮/盘状狼疮、冻疮样红斑狼疮))、风湿性多肌痛、起止点炎、混合型***病、起止点病、心脏炎、心肌炎、血管生成紊乱、骨髓增生异常综合征、动脉粥样硬化、再狭窄(动脉粥样硬化性冠状动脉再狭窄)、急性冠状动脉综合征、心肌梗死、心脏移植物血管病变、移植性动脉病；血管炎(大血管血管炎、小血管血管炎、巨细胞动脉炎、结节性多动脉炎、血管炎综合征，所述血管炎综合征包含大动脉炎、韦格纳肉芽肿、白塞病)、干扰素基因刺激蛋白(STING)相关的婴儿期起病型血管病变(SAVI)；胃肠道紊乱、小肠结肠炎、结肠炎、炎性肠病(溃疡性结肠炎、克罗恩病)、肠易激综合征、肠炎综合征/痉挛性结肠、乳糜泻；急性胰腺炎和慢性胰腺炎；原发性胆汁性肝硬化、原发性硬化性胆管炎、黄疸、肝硬化(例如，原发性胆汁性肝硬化、或归 因于脂肪性肝病(例如，酒精性脂肪变性和非酒精性脂肪变性)的肝硬化)；食管炎、胃炎、胃溃疡和十二指肠溃疡、腹膜炎；肾病、免疫介导的肾小球性肾病、自身免疫性肾病、膜性肾小球病、慢性进行性肾病、糖尿病性肾脏疾病/糖尿病性肾病、肾纤维化、肾缺血/再灌注损伤、HIV相关性肾病、输尿管梗阻性肾病、肾小球硬化症、蛋白尿、肾病综合征、多囊性肾脏疾病、常染色体显性多囊性肾脏疾病、肾病是免疫介导的肾病、自身免疫性肾病、慢性进行性肾病、糖尿病性肾病、肾纤维化、缺血性/再灌注损伤相关性肾病、HIV相关性肾病、输尿管梗阻性肾病、肾小球肾炎、慢性肾脏疾病(例如，糖尿病性肾病)、高血压诱导的肾病、肾小球硬化症、蛋白尿、肾病综合征、多囊性肾脏疾病、常染色体显性多囊性肾脏疾病、糖尿病性肾脏疾病、狼疮性肾炎；间质性膀胱炎；牙周炎、龈炎；肺部炎症、窦炎、肺炎、支气管炎、哮喘、支气管哮喘、变应性哮喘、非变应性哮喘、变应性支气管肺真菌病、阿斯匹林诱导的哮喘、成年起病型哮喘、固定气流阻塞型哮喘、运动诱导的哮喘、咳嗽变异性哮喘、工作相关性哮喘、夜间哮喘、哮喘并发肥胖症、嗜酸细胞性哮喘、激素抵抗型哮喘/重度哮喘、外源性哮喘、内源性哮喘/隐源性哮喘、丘-施综合征、细支气管炎、闭塞性细支气管炎、慢性阻塞性肺病(COPD)、间质性肺疾病(肺纤维化、特发性肺纤维化)、急性肺损伤、肺纤维化(例如，特发性肺纤维化或囊性纤维化)、慢性阻塞性肺病、成人呼吸窘迫综合征、急性肺损伤、药物诱导的肺损伤；梅尼埃病；眼部紊乱，所述眼部紊乱包含(例如)眼部炎症、葡萄膜炎、干眼/干燥性角膜结膜炎、巩膜炎、巩膜外层炎、角膜炎/角膜病、脉络膜炎、视网膜血管炎、视神经炎、视网膜病变(糖尿病性视网膜病变、免疫介导的视网膜病变、黄斑变性、湿性黄斑变性、干性(老年性)黄斑变性)；肥大细胞增生病、缺铁性贫血、***、嗜酸细胞增多综合征(HES)、***性肥大细胞病(SMCD)、骨髓增生异常综合征、特发性血小板减少性紫癜；骨吸收疾病；神经退行性紊乱、神经紊乱/神经肌肉紊乱(例如)，多发性硬化、帕金森病、亨廷顿病、肌萎缩性侧索硬化(ALS)(家族性ALS、散发性ALS)、阿尔茨海默病、重症肌无力、兰-伊肌无力综合征(LEMS)、格林-巴利综合征、脑膜炎、脑炎、创伤性脑损伤；神经***损害、寄生虫妄想症、神经元过程和感觉知觉的调节异常、中风/神经元缺血、脊髓损伤、外周神经病变、触幻觉、脊髓损伤、精神疾病；感觉异常性疼痛(急性疼痛、慢性疼痛、神经性疼痛、或纤维肌痛)、神经刺激、外周神经病变；瘙痒/痒病(特应性瘙痒、干燥性瘙痒、与银屑病相关的瘙痒/银屑病性痒病/银屑病相关性痒病)、急性瘙痒、慢性瘙痒、特发性瘙痒、慢性特发性痒病、胆汁性痒病、肝胆相关性痒病、肾相关性痒病/肾痒病、***性痒病、胆汁郁积、妊娠期肝内胆汁郁积、慢性单纯性苔癣相关性瘙痒、淋巴瘤相关性痒病、白血病相关性痒病、结节性痒疹、特应性皮炎相关性痒病、特应性痒病/特应性瘙痒、大疱性痒病、肱桡肌瘙痒、神经原性痒病、 神经性痒病、感觉异常性背痛、HIV相关性瘙痒性丘疹、精神性痒病、游泳者痒病、瘙痒或***性痒病、荨麻疹性痒病；皮肤病(例如)，皮肤病药物反应/药疹、干燥病/皮肤干燥、皮疹、皮肤致敏、皮肤刺激、晒斑、修面、体虱、头虱/虱病、阴虱、皮肤幼虫移行症、疥疮、寄生虫感染、昆虫感染、荨麻疹/荨麻疹、丘疹性荨麻疹、昆虫咬伤、昆虫刺伤、头皮屑、皮肤上的异物或装置、真菌感染、疱疹、水痘/水痘、嗜酸性毛囊炎、妊娠皮肤病/妊娠瘙痒性荨麻疹性丘疹及斑块病(PUPP)、炎性皮肤病、嗜中性皮肤病、组织细胞样嗜中性皮肤病、肠旁路综合征皮肤病、银屑病/寻常型银屑病、扁平苔藓、硬化性萎缩性苔藓、痤疮(寻常型痤疮、粉刺型痤疮、炎性痤疮、结节囊肿性痤疮、瘢痕性痤疮、颈项部疤痕疙瘩性痤疮)、特应症(变应性接触性致敏、变应性皮炎)、皮炎(特应性皮炎/湿疹、接触性皮炎、光照性皮炎、脂溢性皮炎、瘀滞性皮炎)、急性发热性嗜中性皮肤病(斯威特综合征)、慢性非典型中性粒细胞与脂肪代谢障碍性皮肤病和高温综合征(CANDLE综合征)、化脓性汗腺炎、荨麻疹、坏疽性脓皮病、脱发(眉毛脱落、鼻内毛发脱落、瘢痕性脱发(例如，疤痕性脱发、中央离心性疤痕性脱发、毛发扁平苔藓、前额纤维化性脱发、脱发性毛囊炎)、非瘢痕性脱发(斑秃(AA)(斑块型AA、全秃(AT)、普秃(AU)、蛇形斑秃、马蹄形斑秃))、雄激素源性/雄激素性脱发(AGA)/男性及女性型AGA)、静止期脱发、头癣、稀毛症(单纯性遗传性稀毛症)、毛发扁平苔藓(前额纤维化性脱发)、点状掌跖角皮病、持久***性红斑(EED)、嗜中性外分泌性汗腺炎、栅栏状嗜中性肉芽肿性皮炎、嗜中性荨麻疹皮肤病、白癜风，所述白癜风包含节段型白癜风(单节段型白癜风、双节段型白癜风、多节段型白癜风)、非节段型白癜风(肢端型白癜风、面部型白癜风、或肢端面部型白癜风、面部中央型白癜风、粘膜型白癜风、碎纸样白癜风、三色白癜风、边缘性炎性白癜风、四色白癜风、蓝色白癜风、凯布内现象、寻常型白癜风、泛发型白癜风、普发型白癜风)、混合型白癜风/非节段型白癜风伴发节段型白癜风、局限型白癜风、孤立性粘膜型白癜风、或者伴有或不伴有白发(身体毛发受累)的白癜风；大疱性疾病、免疫性大疱性疾病(大疱性类天疱疮、疤痕性类天疱疮、寻常型天疱疮、线性IgA疾病)、妊娠性类天疱疮、着色性干皮病；纤维化和瘢痕形成的紊乱：纤维瘤、肝纤维化、肺纤维化、特发性肺纤维化、诸如硬皮病、纤维化增加、疤痕疙瘩、术后瘢痕的低度瘢痕形成；伤口愈合、手术瘢痕形成、辐射诱导的纤维化(例如，头颈部、胃肠道或肺部)、中枢神经***瘢痕形成、消化道或胃肠道纤维化、肾纤维化、肝脏纤维化或胆管纤维化、肝纤维化(例如，非酒精性脂肪性肝炎、丙型肝炎、或肝细胞癌)、心脏纤维化(例如，心内膜心肌纤维化或心房纤维化)、眼部瘢痕形成、纤维硬化、瘢痕生长、伤口或痂愈合、疤痕疙瘩、纵隔纤维化、骨髓纤维化、腹膜后纤维化/奥蒙德病、进行性大块纤维化、肾源性***性纤维化；斯耶格伦综合征、结节病、家族性地中 海热、冷吡啉相关周期性综合征(默-韦综合征、家族性寒冷性自身炎性综合征/家族性寒冷性荨麻疹/TNF受体相关周期性综合征、新生儿起病多***炎性疾病)、氧过多诱导的炎症、再灌注损伤、术后创伤、组织损伤、高温综合征；糖尿病(I型糖尿病、II型糖尿病)/糖尿病、桥本甲状腺炎、格雷夫斯病、艾迪生病、卡斯尔门病、甲状旁腺功能亢进、绝经期、肥胖症、类固醇耐药性、葡萄糖耐受不良、代谢综合征、甲状腺疾病、垂体炎；***性免疫衰老；自身免疫性萎缩性胃炎、恶性贫血的自身免疫性萎缩性胃炎、自身免疫性脑脊髓炎、自身免疫性***、古德帕斯彻病、斯耶格伦综合征、自身免疫性血小板减少、交感性眼炎；自身免疫性疾病的继发血液学表现(例如，贫血)、自身免疫性溶血综合征(自身免疫性溶血性贫血)、自身免疫性肝炎和炎性肝炎、自身免疫性卵巢衰竭、自身免疫性血小板减少、硅酮植入相关的自身免疫性疾病、药物诱导的自身免疫、HIV相关的自身免疫性综合征、金属诱导的自身免疫、自身免疫性聋、自身免疫性甲状腺紊乱；过敏反应和***反应，所述过敏反应和***反应包含超敏反应，如I型超敏反应(例如，包含过敏症)、II型超敏反应(例如，古德帕斯彻病、自身免疫性溶血性贫血)、III型超敏反应疾病(例如，阿图斯反应、血清病)和IV型超敏反应(例如，接触性皮炎、同种异体移植排斥)；急性感染和慢性感染、脓毒症综合征(脓毒症、脓毒性休克、内毒素性休克、外毒素诱导的中毒性休克、革兰氏阴性脓毒症、革兰氏阳性脓毒症、真菌性脓毒症、中毒性休克综合征)；急性感染和慢性感染、脓毒症综合征(脓毒症、脓毒性休克、内毒素性休克、外毒素诱导的中毒性休克、革兰氏阴性脓毒症、革兰氏阳性脓毒症、真菌性脓毒症、中毒性休克综合征)；排斥反应：移植物抗宿主反应/移植物抗宿主病、同种异体移植排斥(例如，急性同种异体移植排斥或慢性同种异体移植排斥)、早期移植排斥；恶性肿瘤、癌症、淋巴瘤、白血病、多发性骨髓瘤、实体瘤、畸胎瘤、转移性紊乱和骨紊乱、内部癌症、骨癌、口腔癌/咽癌、食管癌、喉癌、胃癌、肠癌、结肠癌、直肠癌、肺癌(例如，非小细胞肺癌或小细胞肺癌)、肝癌(肝脏癌)、胰腺癌、神经癌、脑癌(例如，神经胶质瘤、多形性成胶质细胞瘤、星形细胞瘤、神经母细胞瘤、和神经鞘瘤)、头颈癌、咽喉癌、卵巢癌、子宫癌、***癌、睾丸癌、膀胱癌、肾癌(肾脏癌)、乳腺癌、胆囊癌、***、甲状腺癌、***癌、眼癌(眼部恶性肿瘤)、和皮肤癌(黑素瘤、角化棘皮瘤)；以及纤维化癌症、纤维瘤、纤维腺瘤、纤维肉瘤、骨髓增生性紊乱、赘生物(造血组织赘生物、脊髓赘生物、淋巴组织赘生物(骨髓纤维化、原发性骨髓纤维化、真性红细胞增多、原发性血小板增多))、白血病(急性淋巴细胞白血病、急性髓细胞白血病和慢性髓细胞白血病、慢性淋巴细胞白血病、急性淋巴细胞性白血病、慢性粒-单核细胞型白血病(CMML)、或前髓细胞白血病)、多发性骨髓瘤及其他骨髓性恶性肿瘤(骨髓纤维化伴髓样化生(MMM)、原发性骨髓纤维化(PMF)、特发性骨髓纤维化(IMF))、 淋巴瘤(霍奇金病、皮肤淋巴瘤(皮肤T细胞淋巴瘤、蕈样肉芽肿病))、淋巴瘤(例如，B细胞淋巴瘤、T细胞淋巴瘤、套细胞淋巴瘤、毛细胞淋巴瘤、伯基特淋巴瘤、肥大细胞瘤、霍奇金病、或非霍奇金病)；卡波西肉瘤、横纹肌肉瘤、***瘤、畸胎癌、骨肉瘤、甲状腺滤泡状癌；外源性阿片类物质或合成阿片类物质的增加的累积、感觉异常性背痛、强迫性障碍、与强迫性障碍相关的怀乡症、及其组合。
药物组合及药物组合物
另一方面，本申请提供了一种药物组合，其包含：1)抗肿瘤剂；以及2)式(I)的化合物。在某些实施方式中，在所述药物组合中，所述抗肿瘤剂与本申请的化合物(例如，本申请式(I)的化合物)彼此不混合。在某些实施方式中，在所述药物组合中，所述抗肿瘤剂与本申请的化合物(例如，本申请式(I)的化合物)各自独立地存在于单独的容器中。在某些实施方式中，在所述药物组合中，本申请的化合物(例如，本申请式(I)的化合物)被制备为适用于透皮给药。在某些实施方式中，在所述药物组合中，本申请的化合物(例如，本申请式(I)的化合物)被制备为软膏剂。在某些实施方式中，在所述药物组合中，本申请的化合物(例如，本申请式(I)的化合物)的浓度为约0.005％w/w至约40％w/w。在某些实施方式中，在所述药物组合中，本申请的化合物(例如，本申请式(I)的化合物)的浓度为约0.05％w/w至约10％w/w。
根据本申请的任何方面，所述组合物或化合物基本上不影响所述抗肿瘤剂的治疗效果。
在本申请中，所述“基本上不影响”可以指，与单独使用所述抗肿瘤剂的治疗效果相比，使用本申请的化合物(例如，本申请式(I)的化合物)和所述抗肿瘤剂的治疗效果相当，或者不产生显著的劣势。例如，对任意的受试者，与单独使用所述抗肿瘤剂的治疗效果相比，使用本申请的化合物(例如，本申请式(I)的化合物)和所述抗肿瘤剂所导致的肿瘤体积减少的程度是相同的，或者，减少的程度不小于约5％、不小于约4％、不小于约3％、不小于约2％、不小于约1％、不小于约0.5％、不小于约0.1％、不小于约0.01％、不小于约0.001％或更小。
在某些实施方式中，所述药物的给药部位和所述抗肿瘤剂的给药部位不同。在某些实施方式中，所述药物的给药部位不为癌症的发生部位或癌症的潜在转移部位。
在某些实施方式中，所述药物的给药方式和所述抗肿瘤剂的给药方式不同。
在本申请的药物组合和/或试剂盒中，在某些实施方式中，所述抗肿瘤剂与本申请的化合物(例如，本申请式(I)的化合物)彼此不混合。
在某些实施方式中，所述抗肿瘤剂与本申请的化合物(例如，本申请式(I)的化合物) 各自独立地存在于单独的容器中。例如，所述药物组合中可以包括2种或更多种彼此独立包装的药物，其中至少一种所述药物包含本申请所述的抗肿瘤剂，且其中至少一种另外的药物包含本申请所述的式(I)的化合物。
在某些实施方式中，在所述药物组合中，其中2)中的本申请的化合物(例如，本申请式(I)的化合物)能够预防，缓解和/或治疗与1)中的所述抗肿瘤剂相关的疾病或病症。
在某些实施方式中，2)中的本申请的化合物(例如，本申请式(I)的化合物)基本上不影响1)中的所述抗肿瘤剂的治疗效果。
在某些实施方式中，在本申请的药物组合中，在施用1)的所述抗肿瘤剂之前、同时或者之后施用2)的本申请的化合物(例如，本申请式(I)的化合物)。
预防和/或治疗方法
在本申请中，所述受试者可以包括人或非人动物。例如，所述非人动物可以选自下组：猴、鸡、鹅、猫、狗、小鼠和大鼠。此外，非人动物也可以包括任何除人以外的动物物种，例如家畜动物，或啮齿类动物，或灵长类动物，或家养动物，或家禽动物。所述人可以是高加索人、非洲人、亚洲人、闪族人，或其他种族，或各种种族的杂合体。又例如，所述人可以是老年、成年、青少年、儿童或者婴儿。
可以根据在实验动物中的有效量推测在人类中的有效量。例如，Freireich等人描述了动物和人的剂量的相互关系(基于每平方米身体表面的毫克数)(Freireich et al.，Cancer Chemother.Rep.50，219(1966))。身体表面积可以从患者的身高和体重近似确定。参见例如Scientific Tables，Geigy Pharmaceuticals，Ardsley，N.Y.，537(1970)。
在本申请的所述方法中，所述抗肿瘤剂可以由向所述受试者施用抗肿瘤剂引起。
例如，可以在向所述受试者施用所述抗肿瘤剂之前、同时或者之后施用本申请的化合物(例如，本申请式(I)的化合物)。当本申请所述的抗肿瘤剂与本申请的化合物(例如，本申请式(I)的化合物)同时施用时，本申请的化合物(例如，本申请式(I)的化合物)以相对于总剂量约0.0001-10％(例如约0.005-10％、约0.01-10％、约0.05-10％、约0.1-10％、约0.2-10％、约0.3-10％、约0.4-10％、约0.5-10％、约0.6-10％、约0.7-10％、约0.8-10％、约0.9-10％、约0.95-10％、约1-10％、约2-10％、约3-10％、约5-10％、约6-10％、约8-10％或更小范围)的剂量水平施用。在本申请的化合物(例如，本申请式(I)的化合物)与所述抗肿瘤剂间隔给药的实施方式中，本申请的化合物(例如，本申请式(I)的化合物)可以在施用所述抗肿瘤剂之前或之后间隔给药。所述间隔的时间可以为1分钟、2分钟、5分钟、10分钟、20分钟、30分钟、45分钟、1小时、2小时、3小时、4小时、5小时、6小时、12小时、18 小时、1天、2天、3天、1周、2周、3周、1个月、2个月、3个月或更长。
本申请还提供一种方法，其包括向受试者施用式(I)的化合物，其中所述受试者曾经、正在和/或将来被施用抗肿瘤剂且患有或易患有与施用抗肿瘤剂相关的疾病或病症。
本申请还提供一种用于预防或治疗疾病或病症的方法，包括向易患有或患有所述疾病或病症的受试者施用式(I)的化合物，其中所述受试者曾经、正在和/或将来被施用抗肿瘤剂。
在本申请中，所述受试者可以已经患有与施用抗肿瘤剂相关的疾病或病症，或者，所述受试者可具备较大概率患有与施用抗肿瘤剂相关的疾病或病症。
本申请还提供一种方法，其包括下述步骤：1)监测被施用抗肿瘤剂的受试者的一种或多种副作用，例如皮肤组织、五官和/或胃肠道特征；2)当所述监测显示所述受试者出现与施用所述抗肿瘤剂相关的副作用，例如皮肤疾病或病症、五官疾病或病症和/或胃肠道疾病或病症时，向所述受试者施用式(I)的化合物。
在本申请中，所述方法还可包括继续监控所述皮肤疾病或病症、五官疾病或病症和/或胃肠道疾病或病症，以及任选地减少或停用所述抗肿瘤剂。例如，所述继续监控可以指在施用所述抗肿瘤剂之后约至少1天、至少1周、至少10天、至少2周、至少3周、至少1个月、至少3个月或更长时间进行监控。例如，所述减少或停用可以指向所述受试者施用所述抗肿瘤剂的剂量较所述方法步骤1)中所述抗肿瘤剂的剂量相比，减少约至少5％、至少10％、至少20％、至少30％、至少40％、至少50％、至少60％、至少70％、至少80％、至少90％、至少95％、至少99％或100％。
在本申请中，所述与施用抗肿瘤剂相关的疾病或病症的严重程度可以在所述施用抗肿瘤剂之后增加。例如，所述严重程度可以为增加至少5％、至少10％、至少20％、至少30％、至少40％、至少50％、至少60％、至少70％、至少80％、至少90％或更多。
在本申请中，在所述施用抗肿瘤剂之前，所述受试者可以未患有所述疾病或病症。
在本申请中，可以向所述受试者局部施用本申请的化合物(例如，本申请式(I)的化合物)。例如，可以向所述受试者中基本不含癌细胞的部位局部施用本申请的化合物(例如，本申请式(I)的化合物)。又例如，可以向所述受试者中的非癌症部位施用本申请的化合物(例如，本申请式(I)的化合物)。
不欲被任何理论所限，下文中的实施例仅仅是为了阐释本申请的化合物、制备方法和用途等，而不用于限制本申请发明的范围。
实施例
化合物的制备
化合物A1：2-(4-((3R，4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲基)氨基)-N-甲基-7H-吡咯[2,3-d]嘧啶-7-甲酰胺基)乙基3,3-二氟环丁烷-1-羧酸酯的合成
第一步
3,3-二氟环丁烷甲酰氯(1-2)
0℃下向3,3-二氟环丁基甲酸(3.0g,22.0mmol,1.0eq)，N,N-二甲基甲酰胺(161.1mg,2.2mmol,169.6uL,0.1eq)的二氯甲烷(20mL)中加入草酰氯(4.2g,33.1mmol,2.9mL,1.5eq)，室温搅拌2小时。减压蒸馏除去溶剂得到3,3-二氟环丁基甲酰氯粗产品(3.4g),不经纯化直接用于下一步。
第二步
2-[叔丁氧羰基(甲基)氨基]乙基3,3-二氟环丁烷甲酸酯(1-3)
向N-BOC-N-甲基氨基乙醇(2.5g,14.3mmol,1.0eq)和三乙胺(14.4g,142.7mmol,19.9mL,10.0eq)的二氯甲烷(20mL)中加入3,3-二氟环丁基甲酰氯(3.3g,21.4mmol,1.5eq)。25℃搅拌3小时。减压蒸馏除去溶剂得到2-[叔丁氧羰基(甲基)氨基]乙基3,3-二氟环丁烷甲酸酯 粗产物(4.0g)，不经纯化直接用于下一步。
第三步
2-(甲氨基)乙基-3,3-二氟环丁酯(1-4)
向2-[叔丁氧羰基(甲基)氨基]乙基3,3-二氟环丁烷甲酸酯(1.8g,6.1mmol,1.0eq)的二氯甲烷(9mL)溶液中加入三氟乙酸(4.6g,40.5mmol,3.0mL)。0℃下搅拌2小时，减压蒸馏后得到2-(甲氨基)乙基-3,3-二氟环丁酯黄色固体粗产物(1.1g),不经纯化直接用于下一步。
第四步
(4-硝基苯基)4-[(3R，4R)-1-(2-氰基乙酰基)-4-甲基-3-哌啶基]-甲基氨基]吡咯[2,3-d]嘧啶-7-羧酸盐(1-6)
向3-[(3R，4R)-4-甲基-3-[甲基(7H吡咯[2,3-d]嘧啶-4-基)氨基]-1-哌啶基]-3-氧代丙腈(10.0g,32.0mmol,1.0eq)的二氯甲烷(50mL)中加入三乙胺(6.5g,64.0mmol,8.9mL,2.0eq)和对硝基苯基氯甲酸酯(9.7g,48.0mmol,1.5eq)。20℃下搅拌反应4小时，过滤，滤液旋蒸后得到黄色油状物(4-硝基苯基)4-[(3R，4R)-1-(2-氰基乙酰基)-4-甲基-3-哌啶基]-甲基氨基]吡咯[2,3-d]嘧啶-7-羧酸盐粗产品(15.1g)，不经纯化直接用于下一步。
第五步
2-[[4-[[(3R，4R)-1-(2-氰基乙酰基)-4-甲基-3-哌啶基]-甲基氨基]吡咯[2,3-d]嘧啶-7-羰基]-甲基氨基]乙基3,3-二氟环丁酯(实施例A1)
向2-[叔丁氧羰基(甲基)氨基]乙基3,3-二氟环丁烷甲酸酯(2.7g,5.7mmol,1.0eq)和2-(甲氨基)乙基-3,3-二氟环丁酯(1.1g,5.7mmol,1.0eq)的二氯甲烷(20mL)溶液中加入三乙胺(2.9g,28.5mmol,3.9mL,5.0eq)，25℃搅拌6小时。减压蒸馏去除溶剂后经反相HPLC(column:Xtimate C18 150*40mm*10um；mobile phase:[water(FA)-ACN]；B％:25％-60％,10min)制备得到2-[[4-[[(3R，4R)-1-(2-氰基乙酰基)-4-甲基-3-哌啶基]-甲基氨基]吡咯[2,3-d]嘧啶-7-羰基]-甲基氨基]乙基3,3-二氟环丁酯(2.1g,3.9mmol,68％yield,98％purity)，白色固体。LC-MS:(M+H)+,532.3.1H NMR(400MHz,DMSO-d6):δ(ppm)8.26-8.16(m,1H),7.32(br s,1H),6.82(br s,1H),4.86(br d,J＝2.0Hz,1H),4.38(br s,1H),4.22-3.96(m,3H),3.86-3.62(m,3H),3.50-3.41(m,3H),3.34(br s,1H),3.28(s,3H),3.20-3.00(m,2H),2.97-2.51(m,5H),2.42-2.34(m,1H),1.96-1.68(m,1H),1.62-1.48(m,1H),1.02(d,J＝7.0Hz,3H)。
利用适当的反应物，按照本发明化合物的合成方法，参照化合物A1的操作步骤类似地合成下表中的其他化合物，并对这些化合物进行了表征。





此外，还测定了上述化合物的溶解度及log D数据。简要地，测定方法如下：
热力学溶解度检测
称量不少于2毫克的样品粉末于Whatman miniuniprep的小瓶中。如果要求测试在多个缓冲溶液中测试样品热力学溶解度，则每个测试都需要一个单独的小瓶；分别添加450μL缓冲液到每个Whatman miniuniprep小瓶中；加入缓冲液后，将Whatman miniuniprep带过滤的活塞盖装上并压至液面上方，使在震摇过程中过滤网与缓冲溶液液接触；涡旋摇动溶解度样品1分钟。并记录溶液现象；以600转每分钟的速度室温(约25℃)震摇24小时；按压Whatman Miniunipreps过滤瓶盖至底部，获得样品溶解度溶液的滤液，所有样品小瓶都应进行过滤前后不溶物质及其渗漏现象；缓冲液稀释100倍得到样品稀释液。
从低浓度到高浓度注入3个紫外标准液至HPLC中，然后注入待测化合物的稀释液和上清，待测样品一式两份；对紫外色谱峰进行积分。模拟标准曲线并计算样品的热力学溶解度。
检测热力学溶解度时，用pH＝6.5的PBS缓冲液，肉豆蔻酸异丙酯中的热力学稳定性用肉豆蔻酸异丙酯做溶媒。
LogD检测
将待测化合物(DMSO储备液10mM，2μL/孔)和QC(DMSO的10mM，2μL/孔)各两份从存储管转移至96孔cluster tube管中。在每个孔中加入缓冲液饱和的正辛醇(149μL/孔)和正辛醇饱和的磷酸缓冲液(149μL/孔)；将cluster tube管涡旋混合1分钟，采用摇板机以880rpm/min的转速震摇混合一小时，再用离心机以4000rpm/min的转速离心10分钟。除掉盖垫，精密量取一定量正辛醇层样品(4μL/孔)至一含正辛醇内标稀释液(796μL/孔)的96孔板中，精密量取一定量的缓冲盐层样品(30μL/孔)至一含缓冲液内标稀释液溶液中(570μL/孔)的的96孔板中；样品稀释倍数可以根据样品的性质不同相应调整。采用三重四极杆质谱仪进行样品分析。采用快速等度方法小柱子保留方法分析处理的样品溶液， 通过稀释倍数和内标进行浓度校正，校正后的峰面积之比用以计算的最终结果(LogD/LogP值)。
测定的结果如下表所示：
此外，还测定了上述化合物的血浆稳定性。简要地，所述测定方法包括如下步骤：
1)实验前将冰冻的混合血浆在37℃下水浴解冻，然后在4000rpm下离心5分钟除去血块；
2)在96孔反应板里每孔加入98μL空白血浆；
3)除了空白样品外，在每个孔中再加入2μL 100μM受试化合物工作液；
3)将反应板于37℃下孵育，并开始计时。孵育时间分别为0、10、30、60和120分钟，每个时间点两个复孔；
4)在相应时间点终止孵育，加入400μL含200ng/mL甲苯磺丁脲和200ng/mL拉贝洛尔乙腈溶液沉淀蛋白；
5)每块板振摇20分钟，然后在4000rpm下离心20分钟，取50μL上清液转移到另一块 96孔板中，每个样品加100μL纯水稀释；
6)采用LC-MS/MS法分析样品。
实验结果如下所示，从实验结果看，所选化合物在人血浆中均较容易代谢成目标化合物。
结果如下表所示：

在大鼠动物模型上验证本申请的化合物局部给药预防小分子EGFR抑制剂产生皮疹的实验
构建大鼠动物模型。通过每日灌胃的方式给予6周雌性SD大鼠小分子EGFR抑制剂，若干天后，大鼠的背部大面积出现皮疹(照片如图1所示)。出现皮疹的部位没有左右的差异， 两侧出现皮疹的程度相似。与在人体上类似，大鼠在口服小分子EGFR抑制剂之后面部、身上会产生皮疹。两者病因完全相同，而病症也非常相似。因此，大鼠是非常好的用于模拟EGFR抑制剂引起的皮疹动物模型。
SD大鼠饲养适应一周(约200g)后，将大鼠分成每组10只。实验前一天将大鼠后背的毛发用电动剃发刀轻轻除去，然后进行灌胃给药试验。EGFR抑制剂溶解在无菌水溶液中，用PBS缓冲溶液稀释，每次灌胃量不超过2mL，给药剂量如表1所示。实验分为给药组和对照组。灌胃后，对给药组大鼠的背部(约3cm*3cm)涂抹本申请的化合物软膏(种类和浓度如表1所示)；对照组大鼠的背部(约3cm*3cm)涂抹空白基质软膏(约0.5g)；涂药后用固定筒将大鼠固定约4小时，4小时后放出大鼠，并用清水擦去涂药部位残留药物，放回鼠笼。EGFR抑制剂的灌胃频率如表1所示，但本申请的化合物和空白基质软膏每天只涂药一次。每日重复灌胃和涂抹试验，直到对照组出现明显的皮疹，此时将给药组皮肤保持正常或明显轻于对照组皮疹的大鼠只数计算为有效抑制皮疹大鼠的只数。
表1列出了各种小分子EGFR抑制剂和本申请的化合物软膏的动物实验组合，以及相应的实验结果(其中，控制率栏的数值＝给药组皮疹轻于对照组的大鼠只数/给药组大鼠的总数量×100％)。
表1：实施例1-24的实验条件和实验结果



图2显示了表1中对照组、给药组中典型大鼠的左侧、背部和右侧的照片。图3显示了实验终点时给药组和对照组的皮疹等级。
从表1和图2-3的结果可以看出：本申请的化合物的药膏能够有效地预防小分子EGFR抑制剂引起的皮疹。
在大鼠动物模型上验证本申请的化合物的局部给药预防单抗类EGFR抑制剂产生皮疹的实验
SD大鼠饲养适应一周(约200g)后，将大鼠分成每组10只。实验前一天将大鼠的后背的毛发用电动剃发刀轻轻除去，然后进行给药试验。实验分为本申请的化合物组和对照组。将用生理盐水稀释后的EGFR单抗溶液每周尾静脉注射2次，注射速度及时间见表2。注射给药后，本申请的化合物组每天对大鼠背部(约3cm*3cm)涂本申请的化合物软膏，对照组对大鼠背部(约3cm*3cm)涂空白基质软膏(约0.5g)，涂药后用固定筒将大鼠固定4小时，4小时后放出大鼠并用清水擦去涂药部位残留药物，放鼠回笼。每周尾静脉注射2次单抗类EGFR抑制剂，本申请的化合物的和空白软膏每日涂抹一次，直到对照组出现明显的皮疹。统计涂药10-14天后，本申请的化合物组皮肤保持正常或明显轻于对照组皮疹的大鼠只数计算为有效抑制皮疹大鼠的只数。
表2列出了各种单抗类EGFR抑制剂和本申请的化合物软膏的动物实验组合，以及相应的实验结果(其中，控制率栏的数值＝本申请的化合物组皮疹轻于对照组的大鼠只数/本申请的化合物组大鼠的总数量×100％)。
表2：实施例25-34的实验条件和实验结果


图4显示了实验终点时本申请的化合物组和对照组(单抗类EGFR抑制剂)的皮疹等级。
从表2和图4的结果可以看出：本申请的化合物软膏能够有效的预防单抗类EGFR抑制剂引起的皮疹。
在大鼠动物模型上验证本申请的化合物的局部给药治疗小分子EGFR抑制剂产生皮疹的实验
SD大鼠饲养适应一周(约200g)后，将大鼠分成每组10只。实验前一天将大鼠的后背的毛发用电动剃发刀轻轻除去，然后进行灌胃给药试验。EGFR抑制剂溶解在无菌水溶液中，用PBS缓冲溶液稀释，每次灌胃量不超过2mL，给药剂量如表3所示。每天持续灌胃，直到大鼠出现皮疹的症状，此时开始进行治疗实验。实验分为本申请的化合物组和对照组。治疗实验过程中，持续每日灌胃EGFR抑制剂，灌胃后，本申请的化合物组对大鼠的背部(约3cm*3cm)涂抹本申请的化合物软膏，对照组大鼠的背部(约3cm*3cm)涂抹空白基质软膏；涂药后用固定筒将大鼠固定约4小时，4小时后放出大鼠并用清水擦去涂药部位残留药物，放回鼠笼。EGFR抑制剂的灌胃频率如表3所示，但本申请的化合物的和空白软膏每天只涂药一次。每日重复用EGFR抑制剂灌胃，将实验终点时本申请的化合物组皮肤恢复正常或明显轻于对照组皮疹的大鼠只数计算为有效治疗皮疹大鼠的只数。
表3列出了各种小分子EGFR抑制剂和本申请的化合物软膏的动物实验组合，以及相应的实验结果(其中，控制率栏的数值＝本申请的化合物组皮疹轻于对照组的大鼠只数/本申请 的化合物组大鼠的总数量×100％)。
表3：实施例35-58的实验条件和实验结果


图5显示了表3中对照组、本申请的化合物组中典型大鼠的左侧、背部和右侧的照片。图6显示了实验终点时本申请的化合物组和对照组的皮疹等级。
从表3和图6中的结果可以看出：本申请的化合物的药膏能够有效的治疗小分子EGFR抑制剂引起的皮疹。
在大鼠动物模型上验证本申请的化合物的局部给药治疗单抗类EGFR抑制剂产生皮疹的实验
SD大鼠饲养适应一周(约200g)后，将大鼠分成每组10只。实验前一天将大鼠的后背 的毛发用电动剃发刀轻轻除去，然后进行给药试验。生理盐水稀释后的EGFR单抗溶液每周尾静脉注射2次，注射速度及时间见表4；连续给药1-2周至大鼠出现皮疹，此时开始进行治疗实验。实验分为本申请的化合物组和对照组。治疗实验过程中，持续注射单抗EGFR抑制剂一周2次，每日对本申请的化合物组大鼠的背部(约3cm*3cm)涂抹本申请的化合物软膏，对照组大鼠的背部(约3cm*3cm)涂抹空白基质软膏；涂药后用固定筒将大鼠固定约4小时，4小时后放出大鼠并用清水擦去涂药部位残留药物，放回鼠笼。统计涂药10天后，本申请的化合物组皮肤保持正常或明显轻于对照组皮疹的大鼠只数计算为有效抑制皮疹大鼠的只数。
表4列出了单抗类EGFR抑制剂和本申请的化合物软膏的动物实验组合，以及相应的实验结果(其中，控制率栏的数值＝本申请的化合物组皮疹轻于对照组的大鼠只数/本申请的化合物组大鼠的总数量×100％)。
表4：实施例59-68的实验条件和实验结果


图7显示了实验终点时本申请的化合物的组和对照组(单抗类EGFR抑制剂)的皮疹等级。
从表4和图7结果可以看出：本申请的化合物的药膏能够有效的治疗单抗类EGFR抑制剂引起的皮疹。
本申请的化合物的局部给药在小鼠皮肤接触性迟发型超敏反应应答试验中的治疗效果
鼠皮肤接触性迟发型超敏反应(DTH)应答被认为是临床接触性皮炎及其他T-淋巴细胞介导的皮肤免疫疾病的有效模型，如特应性皮炎、银屑病等。鼠DTH与这些皮肤免疫疾病有多种共同特征，包括免疫浸润、伴有炎性细胞因子的增加和角化细胞的过度增值。
在0天和第1天，通过在小鼠剃毛的背部局部给予抗原2,4,二硝基-氟代苯(DNFB)使Balb/c小鼠致敏。在第5天，使用工程测微计测量耳朵的厚度。记录该测量并用作基线。然后通过局部给予动物的两只耳朵总共20μL DNFB(10μL给予内耳廓和10μL给予外耳廓)进行攻击，浓度为0.2％。攻击后24-72小时，再次测量耳朵。在整个过敏期和攻击期(-1天至第7天)或攻击前或整个攻击期(通常为第4天至第7天)局部施于动物耳朵本申请的化合物的软膏进行治疗。治疗效果通过与空白软膏的情况比较，耳朵肿胀的减少来表示。化合物引起20％或以上的减少被认为是有效的。
表5列出了本申请的化合物的治疗小鼠皮肤接触性迟发型超敏反应实验结果。

从表5结果可以看出：本申请的化合物的药膏能够有效的治疗小鼠皮肤接触性迟发型超敏反应。
取小鼠耳组织进行***固定和石蜡埋置制备耳切片，通过免疫组化分析显示，本申请的化合物的药膏可减少组织中浸润细胞的数量。

Claims (26)

  1. 式(I)的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体，
    其中：
    G为JAK抑制剂，
    R1和R各自独立地选自：氢、氘、氚、任选被取代的烷基、任选被取代的氘代烷基、任选被取代的卤代烷基、任选被取代的烷氧基、任选被取代的卤代烷氧基、卤素和任选被取代的环基；且
    n为1，2，3，4或5。
  2. 根据权利要求1所述的化合物，其中所述R1和R各自独立地选自：-(CH2)n1Ra、-(CH2)n1ORa、-(CH2)n1SRa、-(CH2)n1C(O)Ra、-(CH2)n1C(O)ORa、-(CH2)n1S(O)m1Ra、-(CH2)n1NRaRb、-(CH2)n1C(O)NRaRb、-(CH2)n1NRaC(O)Rb和-(CH2)n1NRaS(O)m1Rb；其中：
    所述Ra和Rb可以相同或不同，且各自独立地选自氢、氘、氚、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氰基、硝基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自下组的一种或多种基团取代：氢、氘、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基；
    或者，所述Ra和Rb连接形成环烷基、杂环基、芳基或杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选被选自下组的一种或多种基团取代：氢、氘、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基；
    n1为0,1,2,3,4或5；且
    m1为0，1或2。
  3. 根据权利要求1-2中任一项所述的化合物，其中所述环基选自：环烷基、杂环基、氧代杂环基、硫代杂环基、芳基和杂芳基，且所述环烷基、杂环基、氧代杂环基、硫代杂环 基、芳基和杂芳基任选被选自下组的一种或多种基团取代：氢、氘、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基。
  4. 根据权利要求1-3中任一项所述的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体，其中所述R1为氢，任选被取代的烷基或任选被取代的氘代烷基。
  5. 根据权利要求1-4中任一项所述的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体，其中所述R1为氢，任选被取代的C1-C6烷基或任选被取代的C1-C6氘代烷基。
  6. 根据权利要求1-5中任一项所述的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体，其中所述R1为氢，任选被取代的甲基或任选被取代的氘代甲基。
  7. 根据权利要求1-6中任一项所述的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体，其中所述R选自：任选被取代的烷基，任选被取代的氘代烷基，任选被取代的环烷基，任选被取代的杂环烷基，任选被取代的芳基和任选被取代的杂芳基。
  8. 根据权利要求1-7中任一项所述的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体，其中所述R选自：任选被取代的C1-C20烷基，任选被取代的C1-C20氘代烷基，任选被取代的C3-C20环烷基，任选被取代的C1-C20杂环烷基，任选被取代的C6-C20芳基和任选被取代的C1-C20杂芳基。
  9. 根据权利要求1-8中任一项所述的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体，其中所述n为2。
  10. 根据权利要求1-9中任一项所述的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体，其中：
    所述R1为氢，任选被取代的甲基或任选被取代的氘代甲基，
    所述n为2，且
    所述R为任选被取代的C3-C20环烷基或任选被取代的C1-C20杂环烷基。
  11. 根据权利要求1-10中任一项所述的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体，其中所述G为选自下组的JAK抑制 剂：芦可替尼、托法替尼、Oclacitinib、fedratinib、peficitinib、upadacitinib、barictinib、fligotinib、decernotinib、cerdulatinib、lestaurtinib、pacritinib、momelotinib、Gandotinib、Abrocitinib、Solcitinib、SHR-0203、itacitinib、PF-06651600、BMS-986165、abrocitinib、、Cucurbitacin I、CHZ868、TD-1473、zotiraciclib、alkotinib、jaktinib、AZD-4205、DTRMHS-07、KL130008、WXSH-0150、TQ05105、WXFL10203614、GLPG0634、CEP-33779、R-348、itacitinib、ritlecitinib、brepocitinib、Tasocitinib、Deucravacitinib、INCB-039110、Izencitinib、Entrectinib、Ivarmacitinib、Deuruxolitinib、Adelatinib、NDI-034858、Nezulcitinib、ATI-01777、TD-8236、INCB-054707、Ropsacitinib、AGA-201、ATI50001、Gusacitinib、Cerdulatinib、Roniciclib、AT-9283、FMX-114、OST-122、TT-00420、Repotrectinib、INCB-052793、CT-340、BMS-911543、Ilginatinib、BGB-23339、ICP-332、ESK-001、SYHX-1901、VTX-958、TLL-018、CEE-321、CJ-15314、TD-5202、ABBV-712、GLPG-3667、CPL-116、AZD-4604、TAS-8274、MAX-40279、TD-3504、KN-002、AZD-0449、R-548、AC-410、Spebrutinib、ONX-0805、AEG-41174、XL-019、CR-4、WP-1066、GDC-0214、INCB-047986、PF-06263276、R-333、AZD-1480、Tozasertib、CS-12192和AC-1101。
  12. 根据权利要求1-11中任一项所述的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体，其中所述G为选自下组的JAK抑制剂：托法替尼、鲁索替尼、巴瑞替尼、培非替尼、帕克替尼、德尔戈西替尼、Pf-04965842、乌帕达替尼、菲尔戈替尼、伊他替尼、费德拉替尼、Decernotinib、SHR-0302、ASN-002、Cerdulatinib、BMS-986165、PF-06700841、INCB-52793、ATI-502、PF-06651600、AZD-4205、氘修饰鲁索替尼类似物、ATI-501、R-348、NS-018、盐酸雅克替尼和KL-130008。
  13. 化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体，所述化合物选自下组：


  14. 制备权利要求1-13中任一项所述化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体的方法。
  15. 组合物，其包含权利要求1-13中任一项所述的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体。
  16. 根据权利要求15所述的组合物，其为药物组合物，且包含药学上可接受的载体。
  17. 根据权利要求15-16中任一项所述的组合物，其中所述化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体的浓度为约0.001％w/w至约40％w/w。
  18. 根据权利要求15-17中任一项所述的组合物，其为适用于局部施用的制剂。
  19. 根据权利要求15-18中任一项所述的组合物，其为软膏剂。
  20. 权利要求1-13中任一项所述的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体；或者权利要求15-19中任一项所述的组合物，其用于预防，缓解和/或治疗受试者中与施用抗肿瘤剂相关的疾病或病症。
  21. 权利要求1-13中任一项所述的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体；或者权利要求15-19中任一项所述的组合物用于制备药物的用途，所述药物用于预防，缓解和/或治疗受试者中与施用抗肿瘤剂相关的疾病或病症。
  22. 权利要求1-13中任一项所述的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体；或者权利要求15-19中任一项所述的组合物用于制备JAK抑制剂的用途。
  23. 一种预防，缓解和/或治疗受试者中与施用抗肿瘤剂相关的疾病或病症的方法，所述方法包括向有需要的受试者施用权利要求1-13中任一项所述的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体；或者权利要求15-19中任一项所述的组合物。
  24. 一种在有需要的受试者中预防、治疗和/或缓解JAK介导的疾病或病症的方法，所述方法包括：向所述受试者施用有效量的权利要求1-13中任一项所述的化合物，其可药用盐、生物活性代谢物、溶剂化物、水合物、前药、外消旋体、对映体或立体异构体；或者权利要求15-19中任一项所述的组合物。
  25. 根据权利要求24所述的方法，所述方法还包括施用另外的治疗剂。
  26. 根据权利要求24-25中任一项所述的方法，其中所述JAK介导的疾病或病症选自：自身免疫紊乱或自身免疫应答、免疫应答的广泛激活、细菌感染、病毒感染、炎症、慢性和/或急性炎性紊乱或病况、和/或自身炎性紊乱、纤维化紊乱、代谢紊乱、赘生物、或者心血管紊乱或脑血管紊乱、皮肤紊乱、瘙痒、毛发缺损紊乱、癌症或恶性肿瘤、自身免疫性***病和自身免疫病况；斯蒂尔病、成年起病型斯蒂尔病、Th17相关性炎症、多软骨炎(例如，复发性多软骨炎)；肌炎、多肌炎、自身免疫性肌炎、皮肌炎、幼年型皮肌炎；重症肌无力；关节炎(例如，类风湿性关节炎、幼年型类风湿性关节炎、全身起病型幼年类风湿性关节炎、骨关节炎、感染性关节炎、炎症性关节炎、炎性肠病相关性关节炎、特发性关节炎、幼年型特发性关节炎、全身型幼年特发性关节炎、银屑病性关节 炎)、脊椎炎/脊椎关节炎/脊椎关节病(强硬性脊椎炎)、痛风、硬皮病(全身性硬皮病、幼年型硬皮病)、赖特综合征/反应性关节炎、莱姆病、狼疮/***性红斑狼疮(SLE)(红斑狼疮、儿童***性红斑狼疮、皮肤狼疮(亚急性皮肤狼疮、慢性皮肤狼疮/盘状狼疮、冻疮样红斑狼疮))、风湿性多肌痛、起止点炎、混合型***病、起止点病、心脏炎、心肌炎、血管生成紊乱、骨髓增生异常综合征、动脉粥样硬化、再狭窄(动脉粥样硬化性冠状动脉再狭窄)、急性冠状动脉综合征、心肌梗死、心脏移植物血管病变、移植性动脉病；血管炎(大血管血管炎、小血管血管炎、巨细胞动脉炎、结节性多动脉炎、血管炎综合征，所述血管炎综合征包含大动脉炎、韦格纳肉芽肿、白塞病)、干扰素基因刺激蛋白(STING)相关的婴儿期起病型血管病变(SAVI)；胃肠道紊乱、小肠结肠炎、结肠炎、炎性肠病(溃疡性结肠炎、克罗恩病)、肠易激综合征、肠炎综合征/痉挛性结肠、乳糜泻；急性胰腺炎和慢性胰腺炎；原发性胆汁性肝硬化、原发性硬化性胆管炎、黄疸、肝硬化(例如，原发性胆汁性肝硬化、或归因于脂肪性肝病(例如，酒精性脂肪变性和非酒精性脂肪变性)的肝硬化)；食管炎、胃炎、胃溃疡和十二指肠溃疡、腹膜炎；肾病、免疫介导的肾小球性肾病、自身免疫性肾病、膜性肾小球病、慢性进行性肾病、糖尿病性肾脏疾病/糖尿病性肾病、肾纤维化、肾缺血/再灌注损伤、HIV相关性肾病、输尿管梗阻性肾病、肾小球硬化症、蛋白尿、肾病综合征、多囊性肾脏疾病、常染色体显性多囊性肾脏疾病、肾病是免疫介导的肾病、自身免疫性肾病、慢性进行性肾病、糖尿病性肾病、肾纤维化、缺血性/再灌注损伤相关性肾病、HIV相关性肾病、输尿管梗阻性肾病、肾小球肾炎、慢性肾脏疾病(例如，糖尿病性肾病)、高血压诱导的肾病、肾小球硬化症、蛋白尿、肾病综合征、多囊性肾脏疾病、常染色体显性多囊性肾脏疾病、糖尿病性肾脏疾病、狼疮性肾炎；间质性膀胱炎；牙周炎、龈炎；肺部炎症、窦炎、肺炎、支气管炎、哮喘、支气管哮喘、变应性哮喘、非变应性哮喘、变应性支气管肺真菌病、阿斯匹林诱导的哮喘、成年起病型哮喘、固定气流阻塞型哮喘、运动诱导的哮喘、咳嗽变异性哮喘、工作相关性哮喘、夜间哮喘、哮喘并发肥胖症、嗜酸细胞性哮喘、激素抵抗型哮喘/重度哮喘、外源性哮喘、内源性哮喘/隐源性哮喘、丘-施综合征、细支气管炎、闭塞性细支气管炎、慢性阻塞性肺病(COPD)、间质性肺疾病(肺纤维化、特发性肺纤维化)、急性肺损伤、肺纤维化(例如，特发性肺纤维化或囊性纤维化)、慢性阻塞性肺病、成人呼吸窘迫综合征、急性肺损伤、药物诱导的肺损伤；梅尼埃病；眼部紊乱，所述眼部紊乱包含(例如)眼部炎症、葡萄膜炎、干眼/干燥性角膜结膜炎、巩膜炎、巩膜外层炎、角膜炎/角膜病、脉络膜炎、视网膜血管炎、视神经炎、视网膜病变(糖尿病性视网膜病变、免疫 介导的视网膜病变、黄斑变性、湿性黄斑变性、干性(老年性)黄斑变性)；肥大细胞增生病、缺铁性贫血、***、嗜酸细胞增多综合征(HES)、***性肥大细胞病(SMCD)、骨髓增生异常综合征、特发性血小板减少性紫癜；骨吸收疾病；神经退行性紊乱、神经紊乱/神经肌肉紊乱(例如)，多发性硬化、帕金森病、亨廷顿病、肌萎缩性侧索硬化(ALS)(家族性ALS、散发性ALS)、阿尔茨海默病、重症肌无力、兰-伊肌无力综合征(LEMS)、格林-巴利综合征、脑膜炎、脑炎、创伤性脑损伤；神经***损害、寄生虫妄想症、神经元过程和感觉知觉的调节异常、中风/神经元缺血、脊髓损伤、外周神经病变、触幻觉、脊髓损伤、精神疾病；感觉异常性疼痛(急性疼痛、慢性疼痛、神经性疼痛、或纤维肌痛)、神经刺激、外周神经病变；瘙痒/痒病(特应性瘙痒、干燥性瘙痒、与银屑病相关的瘙痒/银屑病性痒病/银屑病相关性痒病)、急性瘙痒、慢性瘙痒、特发性瘙痒、慢性特发性痒病、胆汁性痒病、肝胆相关性痒病、肾相关性痒病/肾痒病、***性痒病、胆汁郁积、妊娠期肝内胆汁郁积、慢性单纯性苔癣相关性瘙痒、淋巴瘤相关性痒病、白血病相关性痒病、结节性痒疹、特应性皮炎相关性痒病、特应性痒病/特应性瘙痒、大疱性痒病、肱桡肌瘙痒、神经原性痒病、神经性痒病、感觉异常性背痛、HIV相关性瘙痒性丘疹、精神性痒病、游泳者痒病、瘙痒或***性痒病、荨麻疹性痒病；皮肤病(例如)，皮肤病药物反应/药疹、干燥病/皮肤干燥、皮疹、皮肤致敏、皮肤刺激、晒斑、修面、体虱、头虱/虱病、阴虱、皮肤幼虫移行症、疥疮、寄生虫感染、昆虫感染、荨麻疹/荨麻疹、丘疹性荨麻疹、昆虫咬伤、昆虫刺伤、头皮屑、皮肤上的异物或装置、真菌感染、疱疹、水痘/水痘、嗜酸性毛囊炎、妊娠皮肤病/妊娠瘙痒性荨麻疹性丘疹及斑块病(PUPP)、炎性皮肤病、嗜中性皮肤病、组织细胞样嗜中性皮肤病、肠旁路综合征皮肤病、银屑病/寻常型银屑病、扁平苔藓、硬化性萎缩性苔藓、痤疮(寻常型痤疮、粉刺型痤疮、炎性痤疮、结节囊肿性痤疮、瘢痕性痤疮、颈项部疤痕疙瘩性痤疮)、特应症(变应性接触性致敏、变应性皮炎)、皮炎(特应性皮炎/湿疹、接触性皮炎、光照性皮炎、脂溢性皮炎、瘀滞性皮炎)、急性发热性嗜中性皮肤病(斯威特综合征)、慢性非典型中性粒细胞与脂肪代谢障碍性皮肤病和高温综合征(CANDLE综合征)、化脓性汗腺炎、荨麻疹、坏疽性脓皮病、脱发(眉毛脱落、鼻内毛发脱落、瘢痕性脱发(例如，疤痕性脱发、中央离心性疤痕性脱发、毛发扁平苔藓、前额纤维化性脱发、脱发性毛囊炎)、非瘢痕性脱发(斑秃(AA)(斑块型AA、全秃(AT)、普秃(AU)、蛇形斑秃、马蹄形斑秃))、雄激素源性/雄激素性脱发(AGA)/男性及女性型AGA)、静止期脱发、头癣、稀毛症(单纯性遗传性稀毛症)、毛发扁平苔藓(前额纤维化性脱发)、点状掌跖角皮病、持久***性红斑(EED)、嗜 中性外分泌性汗腺炎、栅栏状嗜中性肉芽肿性皮炎、嗜中性荨麻疹皮肤病、白癜风，所述白癜风包含节段型白癜风(单节段型白癜风、双节段型白癜风、多节段型白癜风)、非节段型白癜风(肢端型白癜风、面部型白癜风、或肢端面部型白癜风、面部中央型白癜风、粘膜型白癜风、碎纸样白癜风、三色白癜风、边缘性炎性白癜风、四色白癜风、蓝色白癜风、凯布内现象、寻常型白癜风、泛发型白癜风、普发型白癜风)、混合型白癜风/非节段型白癜风伴发节段型白癜风、局限型白癜风、孤立性粘膜型白癜风、或者伴有或不伴有白发(身体毛发受累)的白癜风；大疱性疾病、免疫性大疱性疾病(大疱性类天疱疮、疤痕性类天疱疮、寻常型天疱疮、线性IgA疾病)、妊娠性类天疱疮、着色性干皮病；纤维化和瘢痕形成的紊乱：纤维瘤、肝纤维化、肺纤维化、特发性肺纤维化、诸如硬皮病、纤维化增加、疤痕疙瘩、术后瘢痕的低度瘢痕形成；伤口愈合、手术瘢痕形成、辐射诱导的纤维化(例如，头颈部、胃肠道或肺部)、中枢神经***瘢痕形成、消化道或胃肠道纤维化、肾纤维化、肝脏纤维化或胆管纤维化、肝纤维化(例如，非酒精性脂肪性肝炎、丙型肝炎、或肝细胞癌)、心脏纤维化(例如，心内膜心肌纤维化或心房纤维化)、眼部瘢痕形成、纤维硬化、瘢痕生长、伤口或痂愈合、疤痕疙瘩、纵隔纤维化、骨髓纤维化、腹膜后纤维化/奥蒙德病、进行性大块纤维化、肾源性***性纤维化；斯耶格伦综合征、结节病、家族性地中海热、冷吡啉相关周期性综合征(默-韦综合征、家族性寒冷性自身炎性综合征/家族性寒冷性荨麻疹/TNF受体相关周期性综合征、新生儿起病多***炎性疾病)、氧过多诱导的炎症、再灌注损伤、术后创伤、组织损伤、高温综合征；糖尿病(I型糖尿病、II型糖尿病)/糖尿病、桥本甲状腺炎、格雷夫斯病、艾迪生病、卡斯尔门病、甲状旁腺功能亢进、绝经期、肥胖症、类固醇耐药性、葡萄糖耐受不良、代谢综合征、甲状腺疾病、垂体炎；***性免疫衰老；自身免疫性萎缩性胃炎、恶性贫血的自身免疫性萎缩性胃炎、自身免疫性脑脊髓炎、自身免疫性***、古德帕斯彻病、斯耶格伦综合征、自身免疫性血小板减少、交感性眼炎；自身免疫性疾病的继发血液学表现(例如，贫血)、自身免疫性溶血综合征(自身免疫性溶血性贫血)、自身免疫性肝炎和炎性肝炎、自身免疫性卵巢衰竭、自身免疫性血小板减少、硅酮植入相关的自身免疫性疾病、药物诱导的自身免疫、HIV相关的自身免疫性综合征、金属诱导的自身免疫、自身免疫性聋、自身免疫性甲状腺紊乱；过敏反应和***反应，所述过敏反应和***反应包含超敏反应，如I型超敏反应(例如，包含过敏症)、II型超敏反应(例如，古德帕斯彻病、自身免疫性溶血性贫血)、III型超敏反应疾病(例如，阿图斯反应、血清病)和IV型超敏反应(例如，接触性皮炎、同种异体移植排斥)；急性感染和慢性感染、脓毒症 综合征(脓毒症、脓毒性休克、内毒素性休克、外毒素诱导的中毒性休克、革兰氏阴性脓毒症、革兰氏阳性脓毒症、真菌性脓毒症、中毒性休克综合征)；急性感染和慢性感染、脓毒症综合征(脓毒症、脓毒性休克、内毒素性休克、外毒素诱导的中毒性休克、革兰氏阴性脓毒症、革兰氏阳性脓毒症、真菌性脓毒症、中毒性休克综合征)；排斥反应：移植物抗宿主反应/移植物抗宿主病、同种异体移植排斥(例如，急性同种异体移植排斥或慢性同种异体移植排斥)、早期移植排斥；恶性肿瘤、癌症、淋巴瘤、白血病、多发性骨髓瘤、实体瘤、畸胎瘤、转移性紊乱和骨紊乱、内部癌症、骨癌、口腔癌/咽癌、食管癌、喉癌、胃癌、肠癌、结肠癌、直肠癌、肺癌(例如，非小细胞肺癌或小细胞肺癌)、肝癌(肝脏癌)、胰腺癌、神经癌、脑癌(例如，神经胶质瘤、多形性成胶质细胞瘤、星形细胞瘤、神经母细胞瘤、和神经鞘瘤)、头颈癌、咽喉癌、卵巢癌、子宫癌、***癌、睾丸癌、膀胱癌、肾癌(肾脏癌)、乳腺癌、胆囊癌、***、甲状腺癌、***癌、眼癌(眼部恶性肿瘤)、和皮肤癌(黑素瘤、角化棘皮瘤)；以及纤维化癌症、纤维瘤、纤维腺瘤、纤维肉瘤、骨髓增生性紊乱、赘生物(造血组织赘生物、脊髓赘生物、淋巴组织赘生物(骨髓纤维化、原发性骨髓纤维化、真性红细胞增多、原发性血小板增多))、白血病(急性淋巴细胞白血病、急性髓细胞白血病和慢性髓细胞白血病、慢性淋巴细胞白血病、急性淋巴细胞性白血病、慢性粒-单核细胞型白血病(CMML)、或前髓细胞白血病)、多发性骨髓瘤及其他骨髓性恶性肿瘤(骨髓纤维化伴髓样化生(MMM)、原发性骨髓纤维化(PMF)、特发性骨髓纤维化(IMF))、淋巴瘤(霍奇金病、皮肤淋巴瘤(皮肤T细胞淋巴瘤、蕈样肉芽肿病))、淋巴瘤(例如，B细胞淋巴瘤、T细胞淋巴瘤、套细胞淋巴瘤、毛细胞淋巴瘤、伯基特淋巴瘤、肥大细胞瘤、霍奇金病、或非霍奇金病)；卡波西肉瘤、横纹肌肉瘤、***瘤、畸胎癌、骨肉瘤、甲状腺滤泡状癌；外源性阿片类物质或合成阿片类物质的增加的累积、感觉异常性背痛、强迫性障碍、与强迫性障碍相关的怀乡症、及其组合。
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