WO2022143628A1 - 预防或治疗抗肿瘤剂相关疾病或病症的方法 - Google Patents

预防或治疗抗肿瘤剂相关疾病或病症的方法 Download PDF

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WO2022143628A1
WO2022143628A1 PCT/CN2021/141972 CN2021141972W WO2022143628A1 WO 2022143628 A1 WO2022143628 A1 WO 2022143628A1 CN 2021141972 W CN2021141972 W CN 2021141972W WO 2022143628 A1 WO2022143628 A1 WO 2022143628A1
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inhibitor
egfr
group
jak
jak inhibitor
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PCT/CN2021/141972
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English (en)
French (fr)
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李文晰
张诗宜
尤青
杨立楠
吴兆宇
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上海岸阔医药科技有限公司
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Priority to US18/259,716 priority Critical patent/US20240108633A1/en
Priority to CN202180087777.4A priority patent/CN116710141A/zh
Publication of WO2022143628A1 publication Critical patent/WO2022143628A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders

Definitions

  • the present application relates to the field of biomedicine, in particular to the use of a JAK inhibitor in the preparation of a medicament for preventing or treating a disease or condition related to an antitumor agent in a subject.
  • Chemotherapy, radiotherapy and surgery are the most commonly used methods in clinical treatment of tumors. Chemotherapy is not highly selective. While killing tumor cells, it will cause damage to normal cells and cause serious side effects. Compared with traditional anti-tumor regimens, targeted therapy targets specific targets on tumor cells (such as a specific gene mutation). Immunotherapy uses the body's immune system to attack tumor cells, but because it is not completely Distinguishing tumor cells from normal cells, or leading to abnormal activation of the immune system, can still cause side effects, such as myelosuppression, digestive toxicity, nephrotoxicity, or liver toxicity, which can adversely affect treatment efficacy, and serious adverse events can be life-threatening , the patient's survival time is shortened.
  • EGFR epidermal growth factor receptor
  • the present application provides the use of a JAK inhibitor in the preparation of a medicament for preventing or treating a disease or condition associated with an anti-tumor agent in a subject.
  • the present application provides the use of a pharmaceutical composition in the preparation of a medicament for preventing or treating a disease or condition associated with an antineoplastic agent in a subject, wherein the pharmaceutical composition comprises JAK inhibitors, and buffers.
  • the present application provides the use of a pharmaceutical composition in the preparation of a medicament for preventing or treating a disease or condition associated with an antineoplastic agent in a subject, wherein the pharmaceutical composition comprises JAK inhibitors, and excipients.
  • the JAK inhibitor comprises one or more selected from the group consisting of a JAK1 inhibitor, a JAK2 inhibitor, a JAK3 inhibitor, and a TYK-2 inhibitor.
  • the JAK inhibitor includes an inhibitor that reduces JAK expression, and/or an inhibitor that reduces JAK activity.
  • the JAK inhibitor acts directly on the JAK protein and/or the nucleic acid encoding the JAK protein.
  • the JAK inhibitor includes a small molecule JAK inhibitor, a protein macromolecule that specifically binds to JAK, RNAi that inhibits JAK protein expression, and/or an antisense oligonucleotide that inhibits JAK protein expression.
  • the small-molecule JAK inhibitor includes a small-molecule JAK inhibitor that binds reversibly to JAK, a small-molecule JAK inhibitor that irreversibly binds to JAK, and/or a small-molecule JAK inhibitor that specifically binds to mutant JAK agent.
  • the small molecule JAK inhibitor has less than or equal to 2000 Daltons, less than or equal to 1500 Daltons, less than or equal to 1200 Daltons, less than or equal to 1000 Daltons, less than or equal to 1000 Daltons 900 Daltons, less than or equal to 800 Daltons, less than or equal to 700 Daltons, less than or equal to 600 Daltons, less than or equal to 500 Daltons, less than or equal to 400 Daltons, less than or equal to 300 Daltons ton, less than or equal to 200 Daltons and/or less than or equal to 100 Daltons.
  • the JAK inhibitor includes Ruxolitinib, Tofacitinib, Oclacitinib, fedratinib, peficitinib, upadacitinib, barictinib, fligotinib, decernotinib, cerdulatinib, lestaurtinib, pacritinib, momelotinib , Gandotinib, Abrocitinib, Solcitinib, SHR-0203, itacitinib, PF-06651600, BMS-986165, abrocitinib, Ruxolitinib, Cucurbitacin I, CHZ868, TD-1473, zotiraciclib, alkotinib, jaktinib, AZD-4205, DTRMHS-07, KL130008, WXSH-0150, TQ05105, WXFL10203614, GLPG0634, C
  • the JAK inhibitor includes 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-36
  • the JAK inhibitor includes Peficitinib hydrobromide, Fedratinib hydrochloride, Tasocitinib citrate, Ruxolitinib phosphate, INCB-039110 adipate, Momelotinib dihydrochloride, Upadacitinib tartrate, Jaktinib dihydrochloride monohydrate, Ivarmacitinib sulfate, Zotiraciclib citrate.
  • the JAK inhibitor includes a compound containing at least one aromatic or heteroaromatic ring.
  • the JAK inhibitor comprises a compound of formula I or a pharmaceutically acceptable salt thereof:
  • R1, R2 and R3 are each independently selected from the group consisting of five- to six-membered aromatic rings, Five- to six-membered aromatic heterocycles, five- to six-membered cycloalkyl rings, five- to six-membered heterocycloalkyls, amino groups and amide groups, wherein the aromatic rings, aromatic heterocycles, cycloalkyl and/or or heterocycloalkyl is optionally substituted with substituents.
  • the X of Formula I is N, the Y is C, the Z is C, and the Q is C.
  • said X, Y, Z and Q of Formula I are all N.
  • the X of Formula I is N
  • the Y is N
  • the Z is C
  • the Q is C.
  • the X of Formula I is C
  • the Y is N
  • the Z is C
  • the Q is N.
  • the X of Formula I is C
  • the Y is C
  • the Z is N
  • the Q is C.
  • the R 1 and R 2 are each independently selected from hydrogen atoms benzene ring, C 1 -C 3 alkyl and Wherein, R 4 is selected from cyclopentyl, cyclobutanyl and azetidine, the substituent is piperidine, cyano, carbonyl, sulfonyl, the piperidine is further substituted by a substituent, and the sulfonyl is further is substituted by alkyl; the R 5 is C 1 -C 6 alkyl, and the alkyl is further substituted by cyano;
  • the benzene ring is optionally substituted by acyl, halogen, hydroxyl, C 1 -C 3 alkyl, and the acyl and alkyl are further optionally substituted by C 3 -C 5 cycloalkyl, C 3 -C 5 heterocycle Alkyl or C 1 -C 3 alkyl substituted, the cycloalkyl, heterocycloalkyl is further optionally substituted by C 1 -C 3 alkyl;
  • the R 10 and R 11 are each independently selected from a hydrogen atom, a C 1 -C 3 alkyl group, or a four- to ten-membered ring, and the ring is a monocyclic or bicyclic ring, and the ring is further modified by an amino group, a sulfonyl group , hydroxy, alkynyl, acyl or C 1 -C 3 alkyl substituted, or, the R 10 and R 11 form a ring.
  • the R 4 is wherein the R 6 is selected from -CF 3 , -CHF 2 , -CH 2 F and -CH 3 , and wherein the R 7 is selected from a hydrogen atom or a fluorine atom.
  • the R 4 is selected from cycloalkyl
  • the R 1 and R 2 are each independently selected from a hydrogen atom or a benzene ring optionally substituted with an acyl group, a halogen, a hydroxyl group, a C 1 -C 3 alkyl group, the The acyl group is further optionally substituted with an azetidinyl group, which is further optionally substituted with a methyl group.
  • the R 1 and R 2 are each independently selected from the group consisting of a hydrogen atom
  • the R 3 is selected from an amide group and a five- to ten-membered aromatic ring, which may be bicyclic and may be substituted with a cyclic or chain group.
  • the R 3 is an amide group optionally substituted with cyclobutyl or cyclopropyl.
  • the R is selected from any one of the following group:
  • the JAK inhibitor comprises any one or more of Compounds 1-1 to 1-15:
  • the JAK inhibitor comprises a compound of formula II:
  • Formula II wherein, the X and Y are each independently selected from C or N, and the R 12 , R 13 , R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, C 1 - C5 alkyl, halogen, alkoxy, amino, amido, sulfonamido, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl.
  • the X is C, and the Y is N.
  • the X is N, and the Y is C.
  • the JAK inhibitor comprises the structure shown in Formula II-a:
  • Ra 1 and Ra 2 contain any valence bond-allowed substituents
  • ring A is an aromatic ring or an aromatic heterocycle optionally substituted by Ra 3 and/or Ra 5
  • the Ra 3 and Ra 5 are each independently selected from: a hydrogen atom, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an alkoxy group, or a methyl group is included between the ring A and -NH-.
  • the Ra 1 is selected from the group consisting of: a hydrogen atom, an aryl group optionally substituted with a substituent, a heteroaryl group optionally substituted with a substituent, and a cycloalkane optionally substituted with a substituent group, heterocycloalkyl optionally substituted with substituents including hydrogen, halogen, alkyl, cyano, sulfonyl, amido.
  • the Ra 1 is selected from a four- to ten-membered aromatic ring group, a four- to ten-membered aromatic heterocyclic group, a four- to ten-membered cycloalkyl group, and a four- to ten-membered heterocycloalkyl group , the cyclic group is further substituted with an amide group, and the amide group is further substituted with a cyano group, a C 1 -C 6 alkyl group or a five- to six-membered heterocyclic group.
  • the Ra is selected from any one of the following group:
  • the Ra 2 is selected from the group consisting of: hydrogen, C 1 -C 3 alkyl, and halogen.
  • the Ra 2 is selected from the group consisting of: hydrogen, methyl and chlorine.
  • the Ring A ring is selected from a benzene ring or an imidazole ring, and the benzene ring or imidazole ring is optionally Member to six membered heteroaryl or halogen substituted, and the alkyl or ring is further substituted with hydroxy.
  • the Ra and Ra are each independently selected from the group consisting of a hydrogen atom, methyl, methoxy,
  • said R 12 , R 13 , R 14 are each independently selected from the group consisting of:
  • the JAK inhibitor comprises one or more of Compounds II-1 to II-7:
  • the JAK inhibitor comprises a junction compound of formula III:
  • R 15 and R 16 are each independently selected from hydrogen atoms, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted Substituted aryl and heteroaryl optionally substituted with substituents selected from the group consisting of: amido, alkyl, cycloalkyl, heterocycloalkyl, cyano, amino, hydroxy, and halo.
  • the R 15 or the R 16 is a four- to ten-membered heterocycloalkyl, and the heterocycloalkyl is optionally substituted with an amido group or a C 1 -C 6 alkyl group,
  • the amide group is further substituted with a C1 - C6 alkyl group which is further substituted with a halogen.
  • each of said R 15 or said R 16 is independently a hydrogen atom or wherein, the R 17 and R 18 are each independently a C 1 -C 6 alkyl group, and the alkyl group is substituted with halogen.
  • said R 15 and R 16 are each independently selected from hydrogen atoms and
  • the JAK inhibitor comprises Compound III-1:
  • the JAK inhibitor comprises the structure shown in formula IV:
  • R 19 and R 20 are each independently selected from a hydrogen atom, a nitro group, a four- to ten-membered cycloalkyl group, a four- to ten-membered heterocycloalkyl group, a four- to ten-membered aromatic group, and Four- to ten-membered heteroaryl, wherein said nitro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl is further optionally cyano, alkyl, cycloalkyl, heterocycloalkyl or Hydroxyl substitution.
  • the R 19 is nitro, which is optionally substituted with a substituted benzene ring.
  • the substituted benzene ring is substituted with piperidine, which is further optionally substituted with hydroxy.
  • the R 20 is piperidinyl, which is optionally substituted with C 1 -C 3 alkyl, which is further optionally substituted with cyano or hydroxy.
  • the R 20 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the JAK inhibitor comprises Compound IV-1:
  • the concentration of the JAK inhibitor in the medicament is 0.01%-10%.
  • the antineoplastic agent includes small molecule compounds, small molecule conjugates, proteins and/or polynucleotides.
  • the anti-tumor agent includes a targeted therapeutic agent and/or an immunotherapeutic agent.
  • the antineoplastic agent is a targeted therapeutic agent.
  • the targeted therapeutic agents include small molecule compounds and/or antibodies or antigen-binding fragments thereof.
  • the antibodies include monoclonal antibodies, multispecific antibodies, chimeric antibodies, humanized antibodies, fully human antibodies, and/or antibody drug conjugates.
  • the antigen-binding fragment comprises Fab, Fab', F(ab )2 , Fv fragment, F(ab') 2 , scFv, di-scFv and/or dAb.
  • the targeted therapeutic agent targets molecules within tumor cells, on the cell surface, and/or in the tumor microenvironment.
  • the targeted therapeutic agent targets protein and/or nucleic acid molecules of tumor cells.
  • the targeted therapeutic agent targets a tumor antigen.
  • the targeted therapeutic agent targets EGFR, ALK, MEK, VEGFR, FGFR, PDGFR, ABL, BTK, KIT, AKT, TORC, HER2, HER3, HER4, PI3K, CDK, JAK, ROS1 , RET, MET, KRAS, BRAF, BCRP, NTRK, RAS, MSI, PR/ER, BCR/ABL, HDAC, FAK, PYK2, CD20, PD-L1 and/or BRCA1/2, or mutants thereof.
  • the targeted therapeutic agent includes hormone therapy, signal transduction inhibitors, gene expression modulators, apoptosis inducers, angiogenesis inhibitors and/or toxin delivery molecules.
  • the targeted therapeutic agent is a tyrosine kinase inhibitor.
  • the targeted therapeutic agent is an EGFR inhibitor, MEK inhibitor, ALK inhibitor, BTK inhibitor, PI3K inhibitor, AKT inhibitor, VEGFR inhibitor, mTOR inhibitor, HDAC inhibitor, KIT inhibitors, FGFR inhibitors, FAK inhibitors, BCRP inhibitors, EGFR/cMET inhibitors and/or SRC inhibitors, and combinations thereof.
  • the targeted therapeutic agent is an EGFR inhibitor.
  • the targeted therapeutic agent is a VEGFR inhibitor.
  • the VEGFR inhibitor is selected from the group consisting of Sulfatinib, Anlotinib hydrochloride, Tivozanib, Lenvatinib, Apatinib, Intedanib, Ponatinib, Axitinib, Vandetanib, Pazopanib hydrochloride and/or Sorafenib.
  • the targeted therapeutic agent is an FGFR inhibitor.
  • the targeted therapeutic agent is an ALK inhibitor.
  • the targeted therapeutic agent is an mTOR inhibitor.
  • the mTOR inhibitor is selected from the group consisting of zotarolimus, sirolimus, everolimus and/or temsirolimus.
  • the targeted therapeutic agent is a BTK inhibitor.
  • the BTK inhibitor is selected from the group consisting of Orelabrutinib, Tirabrutinib hydrochloride, Zanubrutinib, Acalabrutinib, Ibrutinib, Dasatinib, Pirtobrutinib, Tolebrutinib, Rilzabrutinib, Fenebrutinib, and/or Evobrutinib.
  • the targeted therapeutic agent is a MEK inhibitor.
  • the MEK inhibitor is selected from the group consisting of Selumetinib sulfate, Binimetinib, Cobimetinib, Trametinib and/or GSK-1120212.
  • the targeted therapeutic agent is a PI3K inhibitor.
  • the PI3K inhibitor is selected from the group consisting of Umbralisib, Alpelisib, Duvelisib, Copanlisib hydrochloride, Idelalisib, Zandelisib, Buparlisib, Enzastaurin hydrochloride, Paxalisib, Leliolisib, Rigosertib, Dactolisib, Nortriptyline and/or Parsaclisib.
  • the targeted therapeutic agent is an AKT inhibitor.
  • the AKT inhibitor comprises Ipatasertib.
  • the targeted therapeutic agent is an EGFR/cMET inhibitor.
  • the targeted therapeutic agent is a BRAF inhibitor.
  • the BRAF inhibitor is selected from the group consisting of Tepotinib, Dabrafenib, Vemurafenib and/or encorafenib.
  • the targeted therapeutic agents include BRAF inhibitors and MEK inhibitors.
  • the targeted therapeutics include Dabrafenib and Trametinib.
  • the targeted therapeutic agent targeting CD20 is Rituximab.
  • the antineoplastic agent is an immunotherapeutic agent.
  • the immunotherapeutic agent is capable of altering an immune response in a subject.
  • the immunotherapeutic agent is capable of enhancing an immune response in a subject.
  • the immunotherapeutic agent is an immune checkpoint inhibitor, a modified immune cell and/or a vaccine.
  • the immunotherapeutic agent is an antibody.
  • the immunotherapeutic agent is a PD-1 inhibitor, a PD-L1 inhibitor and/or a CTLA-4 inhibitor.
  • the anti-tumor agent is selected from the group consisting of afatinib, dacomitinib, osimertinib, EAI045, gefitinib, almonertinib, pyrotinib, brigatinib, neratinib, olmutinib, bosutinib, icotinib, vandetanib, lapatinib, alflutinib, BPI-7711 , mobocertinib, dovitinib, zorifertinib, varlitinib, orelabrutinib, tirabrutinib, zanubrutinib, acalabrutinib, ibrutinib, dasatinib, pirtobrutinib, tolebrutinib, rilzabrutinib, fenebrutinib, evobrut
  • the disease or disorder comprises a skin disease or disorder and/or a subcutaneous tissue disease or disorder.
  • the skin disease or disorder comprises alopecia, body odor, bullous dermatitis, dry skin, eczema, erythema multiforme, erythroderma, lipoatrophy, hair color changes, abnormal hair texture, hirsutism, hyperhidrosis, hyperkeratosis, hypertrichosis, hypohidrosis, hyperlipidemia, nail changes, nail discoloration, loss of nails, raised nails, skin pain, hands and feet Syndrome, photosensitivity, pruritus, purpura, acneiform rash, maculopapular rash, scalp pain, skin atrophy, skin hyperpigmentation, skin hypopigmentation, skin induration, skin ulcers, Stevens -Johnson syndrome, subcutaneous emphysema, telangiectasia, toxic epidermal necrosis, rash and/or urticaria.
  • the disease or disorder includes a disease or disorder associated with the combination of two or more of the anti-neoplastic agents.
  • the disease or disorder includes a disease or disorder associated with the use of the antineoplastic agent in combination with one or more other therapies.
  • the disease or disorder comprises a disease or disorder associated with abnormal EGFR.
  • the disease or disorder comprises a rash associated with abnormal EGFR.
  • the rash associated with abnormal EGFR includes a rash associated with inhibition of EGFR.
  • the rash associated with an abnormal EGFR comprises an immune rash and/or a non-immune rash.
  • the rash associated with abnormal EGFR includes acne vulgaris associated with abnormal EGFR, acne rosacea associated with abnormal EGFR, pruritus rash associated with abnormal EGFR , Acne-like rash (acneiform rash) related to abnormal EGFR and cellulitis (cellulitis) related to abnormal EGFR, Lyme disease (Lyme disease) related to abnormal EGFR, allergic reaction (allergic reaction) related to abnormal EGFR, Hidradenitis suppurativa associated with EGFR abnormality, hives associated with EGFR abnormality, dermatitis associated with EGFR abnormality, cradle cap associated with EGFR abnormality, EGFR abnormality associated purpura, pityriasis rosea related to EGFR abnormality, erythema related to EGFR abnormality, shingles related to EGFR abnormality, bruise related to EGFR abnormality ) and/or EGFR abnormal related xanthelasma, EGFR abnormal,
  • the severity of the rash is grade 1 or above, grade 2 or above, grade 3 or above, or grade 4 or above according to NCI-CTCAE V5.0 , or Level 5.
  • the rash associated with inhibition of EGFR includes a rash associated with administration of an EGFR inhibitor.
  • the EGFR inhibitor includes a drug for the treatment of cancer.
  • the EGFR inhibitor acts directly on the EGFR protein and/or the nucleic acid encoding the EGFR protein.
  • the EGFR inhibitor includes a small molecule EGFR inhibitor, a protein macromolecule that specifically binds to EGFR, an RNAi that inhibits EGFR protein expression, and/or an antisense oligonucleotide that inhibits EGFR protein expression.
  • the small-molecule EGFR inhibitor includes a small-molecule EGFR inhibitor that binds reversibly to EGFR, a small-molecule EGFR inhibitor that irreversibly binds to EGFR, and/or a small-molecule EGFR inhibitor that specifically binds to mutant EGFR agent.
  • the EGFR inhibitor includes cetuximab, gefitinib, erlotinib, icotinib, Sapitinib, afatinib, lapatinib, vandetinib , neratinib, brigatinib, panitumumab, nexituzumab, nimotuzumab, Tesevatinib, alectinib, ciglitinib, rociletinib, canetinib, AZD3759, YZJ-0318 , naprotinib, Naquotinib, PF-06747775, SPH1188-11, Poziotinib, epitinib, Varlitinib, alflutinib, HM61713, CK-101, pyrotinib, lelotinib, HS-10296, AP32788 , Cimotinib, GMA204
  • the EGFR inhibitor is used in combination with one or more other therapies.
  • the subject includes a cancer patient.
  • the subject has been, is and/or will be administered the EGFR inhibitor.
  • the drug does not substantially affect the therapeutic effect of the EGFR inhibitor.
  • the medicament is formulated for topical administration.
  • the site of administration of the topical administration is not the site of occurrence of the cancer or the site of potential metastases of the cancer.
  • the medicament is formulated for topical administration.
  • the medicament is formulated for transdermal administration.
  • the medicament is administered in the form of creams, lotions, gels, ointments, salves, sprays, liposomal formulations, liniments and/or aerosols.
  • one or more other active ingredients are also included in the medicament.
  • the present application provides the use of the JAK inhibitor in the preparation of a medicament for preventing or treating an antitumor agent-related disease or condition.
  • the present application provides the use of the JAK inhibitor in the preparation of a medicament for preventing or treating skin rash.
  • the present application provides a method of preventing or treating a disease or disorder associated with an antineoplastic agent, comprising administering to a subject in need thereof the JAK inhibitor.
  • the present application provides a method of preventing or treating a rash associated with EGFR abnormalities, comprising administering the JAK inhibitor to a subject in need thereof.
  • the subject has been, is and/or will be administered an EGFR inhibitor.
  • the present application provides a method of preventing or treating an antineoplastic agent-related disease or disorder, comprising administering to a subject in need thereof the JAK inhibitor for the use described.
  • the present application provides a method of preventing or treating a rash comprising administering to a subject in need thereof the JAK inhibitor for the use described.
  • the application provides a pharmaceutical combination or kit comprising: 1) an anti-tumor agent; and 2) the JAK inhibitor.
  • the antineoplastic agent and the JAK inhibitor are not mixed with each other.
  • the antineoplastic agent and the JAK inhibitor are each independently present in separate containers.
  • the JAK inhibitor is formulated for topical administration.
  • the site of administration of the topical administration is not the site of occurrence of the cancer or the site of potential metastases of the cancer.
  • the JAK inhibitor is formulated for topical administration.
  • the JAK inhibitor is formulated for transdermal administration.
  • the JAK inhibitor is formulated as a cream, lotion, gel, ointment, salves, sprays, liposomal formulations, liniments and/or aerosols.
  • the JAK inhibitor of 2) is capable of preventing or treating a disease or disorder associated with administration of the antineoplastic agent of 1).
  • the JAK inhibitor in 2) does not substantially affect the therapeutic effect of the anti-tumor agent in 1).
  • the JAK inhibitor of 2) is administered before, concurrently with, or after administration of the anti-tumor agent of 1).
  • the application provides a pharmaceutical combination or kit comprising: 1) an EGFR inhibitor; and 2) the JAK inhibitor.
  • the EGFR inhibitor and the JAK inhibitor are not mixed with each other.
  • the EGFR inhibitor and the JAK inhibitor are each independently present in separate containers.
  • the JAK inhibitor is formulated for topical administration.
  • the site of administration of the topical administration is not the site of occurrence of the cancer or the site of potential metastases of the cancer.
  • the JAK inhibitor is formulated for topical administration.
  • the JAK inhibitor is formulated for transdermal administration.
  • the JAK inhibitor is formulated as a cream, lotion, gel, ointment, salves, sprays, liposomal formulations, liniments and/or aerosols.
  • the JAK inhibitor of 2) is capable of preventing or treating a disease or disorder associated with administration of the EGFR inhibitor of 1).
  • the JAK inhibitor of 2) does not substantially affect the therapeutic effect of the EGFR inhibitor of 1).
  • the JAK inhibitor of 2) is administered prior to, concurrently with, or subsequent to administration of the EGFR inhibitor of 1).
  • the application provides a method comprising the steps of: monitoring a disease or condition in a subject to which an antineoplastic agent is administered; In the case of a disease or condition associated with an antineoplastic agent, administering the JAK inhibitor in the use to the subject,
  • the method further comprises continued monitoring of the anti-neoplastic agent-related disease or condition, and optionally reducing or discontinuing the anti-neoplastic agent.
  • the severity of the disease or condition associated with the antineoplastic agent increases after the administration of the antineoplastic agent.
  • the antineoplastic agent does not comprise the JAK inhibitor.
  • the antineoplastic agent is administered to treat cancer.
  • the site of the rash is different from the site of the cancer.
  • the JAK inhibitor is administered topically to the subject.
  • the JAK inhibitor is administered locally to a site in the subject that is substantially free of cancer cells.
  • the JAK inhibitor is administered to a non-cancer site in the subject.
  • the application provides a method comprising the steps of: monitoring a rash in a subject administered an EGFR inhibitor; when the monitoring shows that the subject develops and administering the EGFR inhibitor In the event of an agent-related rash, administering to the subject the JAK inhibitor in the use,
  • the method further comprises continuing to monitor the rash, and optionally reducing or discontinuing the EGFR inhibitor.
  • the severity of the rash increases after the administration of the EGFR inhibitor.
  • the subject did not have the rash prior to the administration of the EGFR inhibitor.
  • the EGFR inhibitor does not comprise the JAK inhibitor.
  • the EGFR inhibitor is administered to treat cancer.
  • the site of the rash is different from the site of the cancer.
  • the JAK inhibitor is administered topically to the subject.
  • the JAK inhibitor is administered locally to a site in the subject that is substantially free of cancer cells.
  • the JAK inhibitor is administered to a non-cancer site in the subject.
  • Figure 1 Shown are photographs of the left, back and right sides of a rat model of rash caused by the EGFR inhibitors described herein.
  • FIG. 2 photographs showing the left side, back and right side of a typical rat in the control group and the JAK inhibitor group in Example 1 of the present application.
  • Fig. 3 shows the rash grade results of the control group and the JAK inhibitor group in Example 1 of the present application.
  • Fig. 4 shows the rash grade results of the control group and the JAK inhibitor group in Example 2 of the present application.
  • Fig. 5 photographs showing the left, back and right sides of a typical rat in the control group and the JAK inhibitor group in Example 3 of the present application.
  • Fig. 6 shows the results of the rash grade of the control group and the JAK inhibitor group in Example 3 of the present application.
  • Fig. 7 shows the rash grade results of the control group and the JAK inhibitor group in Example 4 of the present application.
  • Figure 8 shows the left side, back and right side photographs of typical rats in the other skin administration group and the JAK inhibitor group in Example 5 of the present application.
  • Figure 9 shows the results of the rash grade of the other skin medication groups and the JAK inhibitor group in Example 5 of the present application.
  • the present application provides the use of a JAK inhibitor in the preparation of a medicament for preventing or treating a disease or condition related to an antitumor agent in a subject.
  • the present application also provides the use of a pharmaceutical composition in the preparation of a medicament for preventing or treating a disease or condition related to an antineoplastic agent in a subject, wherein the pharmaceutical composition comprises JAK inhibitor, and buffer.
  • the present application also provides the use of a pharmaceutical composition in the preparation of a medicament for preventing or treating a disease or condition related to an antineoplastic agent in a subject, wherein the pharmaceutical composition comprises JAK inhibitors, and excipients.
  • the present application provides a method of preventing or treating a disease or disorder associated with an antineoplastic agent.
  • the disease or disorder associated with the antineoplastic agent includes side effects associated with the antineoplastic agent.
  • the disease or disorder associated with the antineoplastic agent may refer to the disease or disorder resulting from administration of one or more antineoplastic agents, and the disease or disorder developed or aggravated following administration of the antineoplastic agent.
  • the disease or disorder will develop after about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours after administration of the antineoplastic agent After hours, after about 7 hours, after about 8 hours, after about 9 hours, after about 10 hours, after about 11 hours, after about 12 hours, after about 1 day, after about 2 days, after about 4 days, after about 7 days, after about Appears or worsens after 2 weeks, after about 3 weeks, after about 1 month, after about 2 months, or more
  • the disease or disorder associated with the antineoplastic agent may include a skin disease or disorder.
  • the disease or disorder associated with the antineoplastic agent may include a subcutaneous tissue disease or disorder.
  • the disease or disorder associated with the antineoplastic agent may include alopecia, body odor, bullous dermatitis, dry skin, eczema, erythema multiforme, erythroderma, lipoatrophy, hair color changes, hair texture abnormalities, hirsutism, hyperhidrosis, hyperkeratosis, hypertrichosis, hypohidrosis, hyperlipidemia, nail changes, nail discoloration, loss of nails, raised nails, skin pain, hands and feet Syndrome, photosensitivity, pruritus, purpura, acneiform rash, maculopapular rash, scalp pain, skin atrophy, skin hyperpigmentation, skin hypopigmentation, skin induration, skin ulcers, Stevens -Johnson syndrome, subcutaneous emphysema, telangie
  • the disease or condition associated with the antineoplastic agent may be a skin rash.
  • the disease or disorder associated with an antineoplastic agent may include alopecia associated with an antineoplastic agent, body odor associated with an antineoplastic agent, bullous dermatitis associated with an antineoplastic agent, dry skin associated with an antineoplastic agent , eczema associated with antineoplastic agents, erythema multiforme associated with antineoplastic agents, erythroderma associated with antineoplastic agents, lipodystrophy associated with antineoplastic agents, hair color changes associated with antineoplastic agents, Hair texture abnormalities associated with antineoplastic agents, hirsutism associated with antineoplastic agents, hyperhidrosis associated with antineoplastic agents, hyperkeratosis associated with antineoplastic agents, and antineoplastic agents Hypertrichosis associated with antineoplastic agents, hypohidrosis associated with antineoplastic agents, lipid hypertrophy associated with antineoplastic agents, nail changes associated with antineoplastic agents, Nail loss associated with antineoplastic agents, Nail bulg
  • the disease or disorder associated with the antineoplastic agent may include a disorder or disorder associated with EGFR abnormalities.
  • the EGFR abnormality-related disease or disorder can include an EGFR abnormality-related rash.
  • the anti-tumor agent may include small molecule compounds, small molecule conjugates, proteins (eg, antibodies) and/or polynucleotides (eg, DNA or RNA).
  • the antineoplastic agent can be a targeted therapeutic agent.
  • the targeted therapeutic agent may comprise a small molecule compound.
  • the targeted therapeutic agent may comprise an antibody or antigen-binding fragment thereof.
  • the antibodies may include monoclonal antibodies, multispecific antibodies, chimeric antibodies, humanized antibodies, fully human antibodies, and/or antibody drug conjugates.
  • the antigen-binding fragment may comprise Fab, Fab', F(ab )2 , Fv fragment, F(ab') 2 , scFv, di-scFv and/or dAb.
  • the targeted therapeutic agent can target molecules inside tumor cells, on the cell surface, and/or in the tumor microenvironment.
  • the targeted therapeutic agent can target protein and/or nucleic acid molecules of tumor cells.
  • the targeted therapeutic agent can target a tumor antigen.
  • the targeted therapeutic agent can target EGFR, ALK, MEK, VEGFR, FGFR, PDGFR, ABL, BTK, KIT, AKT, TORC, HER2, HER3, HER4, PI3K, CDK, JAK, ROS1, RET, MET, KRAS, BRAF, BCRP, NTRK, RAS, MSI, PR/ER, BCR/ABL, HDAC, FAK, PYK2, CD20, PD-L1 and/or BRCA1/2, or mutants thereof.
  • the targeted therapeutic agent may include hormone therapy, signal transduction inhibitors, gene expression modulators, apoptosis inducers, angiogenesis inhibitors and/or toxin delivery molecules.
  • the targeted therapeutic agent can be a tyrosine kinase inhibitor.
  • the targeted therapeutic agent can be an EGFR inhibitor, MEK inhibitor, ALK inhibitor, BTK inhibitor, PI3K inhibitor, AKT inhibitor, VEGFR inhibitor, mTOR inhibitor, HDAC inhibitor, KIT inhibitor, FGFR inhibitors, FAK inhibitors, BCRP inhibitors, EGFR/cMET inhibitors and/or SRC inhibitors, and combinations thereof.
  • the targeted therapeutic agent can be an EGFR inhibitor.
  • the EGFR inhibitors include small-molecule EGFR inhibitors, protein macromolecules that specifically bind to EGFR, RNAi that inhibits EGFR protein expression, and/or antisense oligonucleotides that inhibit EGFR protein expression.
  • the small-molecule EGFR inhibitor includes a small-molecule EGFR inhibitor that binds reversibly to EGFR, a small-molecule EGFR inhibitor that irreversibly binds to EGFR, and/or a small-molecule EGFR inhibitor that specifically binds to mutant EGFR.
  • the EGFR inhibitors include cetuximab, gefitinib, erlotinib, icotinib, sapitinib, afatinib, lapatinib, vandetinib, neratinib , brigatinib, panitumumab, nexituzumab, nimotuzumab, Tesevatinib, alectinib, siritinib, rociletinib, canertinib, AZD3759, YZJ-0318, naprotinib , Naquotinib, PF-06747775, SPH1188-11, Poziotinib, epitinib, Varlitinib, alflutinib, HM61713, CK-101, pyrotinib, lelotinib, HS-10296, AP32788, simotinib , GMA204, Virlitin
  • the targeted therapeutic agent can be a VEGFR inhibitor.
  • the VEGFR inhibitor is selected from the group consisting of Sulfatinib, Anlotinib hydrochloride, Tivozanib, Lenvatinib, Apatinib, Intedanib, Ponatinib, Axitinib, Vandetanib, Pazopanib hydrochloride and/or Sorafenib.
  • the targeted therapeutic agent can be an FGFR inhibitor.
  • the targeted therapeutic agent can be an ALK inhibitor.
  • the targeted therapeutic agent can be an mTOR inhibitor.
  • the targeted therapeutic agent can be an mTORC inhibitor.
  • the targeted therapeutic agent can be an mTORC1 inhibitor.
  • the targeted therapeutic agent can be an mTORC2 inhibitor.
  • the mTOR inhibitor is selected from the group consisting of zotarolimus, sirolimus, everolimus and/or temsirolimus.
  • the targeted therapeutic agent can be a BTK inhibitor.
  • the BTK inhibitor is selected from the group consisting of Orelabrutinib, Tirabrutinib hydrochloride, Zanubrutinib, Acalabrutinib, Ibrutinib, Dasatinib, Pirtobrutinib, Tolebrutinib, Rilzabrutinib, Fenebrutinib and/or Evobrutinib.
  • the targeted therapeutic agent can be a MEK inhibitor.
  • the MEK inhibitor can be selected from the group consisting of Selumetinib sulfate, Binimetinib, Cobimetinib, Trametinib and/or GSK-1120212.
  • the targeted therapeutic agent can be a PI3K inhibitor.
  • the PI3K inhibitor can be selected from the group consisting of Umbralisib, Alpelisib, Duvelisib, Copanlisib hydrochloride, Idelalisib, Zandelisib, Buparlisib, Enzastaurin hydrochloride, Paxalisib, Leliolisib, Rigosertib, Dactolisib, Nortriptyline and/or Parsaclisib.
  • the targeted therapeutic agent can be an AKT inhibitor.
  • the AKT inhibitor can be Ipatasertib.
  • the targeted therapeutic agent can be an EGFR/cMET inhibitor.
  • the targeted therapeutic agent can be a BRAF inhibitor.
  • the BRAF inhibitor may be selected from the group consisting of Tepotinib, Dabrafenib, Vemurafenib and/or encorafenib.
  • the targeted therapeutic agents can include BRAF inhibitors and MEK inhibitors.
  • the targeted therapeutic agents can include Dabrafenib and Trametinib.
  • the therapeutic agent targeting CD20 can be Rituximab.
  • the targeted therapeutic agent can include an EGFR inhibitor.
  • the targeted therapeutic agent may not include an EGFR inhibitor.
  • the antineoplastic agent can be an immunotherapeutic agent.
  • the immunotherapeutic agent is capable of altering the immune response in a subject.
  • the immunotherapeutic agent is capable of enhancing an immune response in a subject.
  • the immunotherapeutic agent can be an immune checkpoint inhibitor, a modified immune cell, and/or a vaccine.
  • the immunotherapeutic agent can be an antibody.
  • the immunotherapeutic agent may be a PD-1 inhibitor, a PD-L1 inhibitor and/or a CTLA-4 inhibitor.
  • the immunotherapeutic agent may not include an EGFR inhibitor.
  • the anti-tumor agent may be selected from the group consisting of afatinib, dacomitinib, osimertinib, EAI045, gefitinib, almonertinib, pyrotinib, brigatinib, neratinib, olmutinib, bosutinib, icotinib, vandetanib, lapatinib, alflutinib, BPI-7711, mobocertinib, dovitinib , zorifertinib, varlitinib, orelabrutinib, tirabrutinib, zanubrutinib, acalabrutinib, ibrutinib, dasatinib, pirtobrutinib, tolebrutinib, rilzabrutinib, fenebrutinib, evobrutin
  • the disease or disorder associated with the anti-tumor agent may include a disease or disorder associated with the combined use of two or more of the anti-tumor agents.
  • the disease or disorder may include a disease or disorder associated with the use of the antineoplastic agent in combination with one or more other therapies.
  • the disease or disorder may include a disease or disorder associated with abnormal EGFR.
  • the disease or disorder may include a rash associated with abnormal EGFR.
  • the present application provides a method of preventing or treating a rash.
  • rash as used in this application generally refers to changes in the skin that affect the color, appearance or texture of the skin.
  • the rash can be limited to only one part of the body, or it can affect the entire skin.
  • the rash can also include hives.
  • the rash can be an immune rash and/or a non-immune rash.
  • the pathological manifestations of the rash may include marked changes in skin epidermal growth and/or differentiation, changes in terminal differentiation of keratinocytes, dense orthokeratology and epidermis seen in both affected and unaffected skin Parakeratosis, damage to sebaceous glands and/or follicular infundibulum, with or without signs of infection, impaired epidermal barrier, epidermal hypospadias, cytokine production, inflammatory cell infiltration (eg, neutrophils, lymphocytes), bacterial infection , telangiectasia, hyperpigmentation and/or inflammatory permeability of dense epithelium.
  • marked changes in skin epidermal growth and/or differentiation changes in terminal differentiation of keratinocytes, dense orthokeratology and epidermis seen in both affected and unaffected skin Parakeratosis, damage to sebaceous glands and/or follicular infundibulum, with or without signs of infection, impaired epidermal barrier, epidermal hypospadias
  • the clinical manifestations of the rash can be erythema, dry skin, itching, scaly plaques, tenderness, burning sensation, cracks, pustules, follicles, ulcers, abscesses, red bumps and/or purulent lesions.
  • the site of occurrence of the rash can be the epidermis, eg, including the seborrheic area of the skin.
  • the site of occurrence of the rash can include the scalp, face, neck, chest, upper back, extremities, lower back, abdomen, buttocks, periodontal area, abdomen, palms, soles, nails, and/or mucous membranes.
  • the rash may include acne vulgaris, papulopustular rash, acne rosacea, boil, acneiform rash, cellulitis ), Lyme disease, allergic reaction, hidradenitis suppurativa, hives, dermatitis, cradle cap, purpura, rosacea Pityriasis rosea, erythema, shingles, bruises and/or xanthelasma, melanoma, basal cell carcinoma, squamous cell Squamous cell carcinoma, Kaposi's sarcoma, erythema annulare centrifugum, folliculitis, follicular papules, xerosis, eczema xicca, and/or papillary pustules.
  • the severity of the rash can be graded according to the Terminology Criteria for Common Adverse Events (CTCAE) published by the National Cancer Institute, a standard classification and grading scale for adverse events in cancer treatment clinical trials and other oncology settings (NCI-CTCAE V5.0).
  • CTCCAE Terminology Criteria for Common Adverse Events
  • NCI-CTCAE V5.0 a standard classification and grading scale for adverse events in cancer treatment clinical trials and other oncology settings
  • the severity of the epithelial tissue disease may be grade 1 or above, grade 2 or above, grade 3 or above, grade 4 or above according to NCI-CTCAE V5.0 above, or level 5.
  • the present application provides a method of preventing or treating a rash associated with abnormal EGFR function.
  • EGFR generally refers to the Epidermal Growth Factor Receptor (Epidermal Growth Factor Receptor), also known as ErbB1 or HER1, which is a 170 kDa transmembrane glycoprotein encoded by the c-erbB1 proto-oncogene.
  • EGFR is a member of the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases (RTKs), which also includes HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4).
  • HER human epidermal growth factor receptor
  • RTKs receptor tyrosine kinases
  • EGFR signaling is initiated by ligand binding, followed by induction of conformational changes of the receptor with other ErbB family members, homodimerization or heterodimerization, and trans-autophosphorylation of the receptor, etc. (see, Ferguson et al., Annu Rev Biophys, 37:353-73, 2008), to initiate signal transduction cascades that ultimately affect a variety of cellular functions (eg, cell proliferation and survival).
  • Elevated expression of EGFR is known to be found in numerous cancers, such as glioma, breast cancer, ovarian cancer, and cervical cancer.
  • the rash associated with EGFR dysfunction includes a rash associated with inhibition of EGFR.
  • the term "EGFR inhibited” includes a decrease in EGFR activity, expression or amount caused by any cause (eg, caused by treatment or caused by the subject's own physical condition).
  • inhibition of EGFR generally refers to a reduction in the activity or amount of EGFR by at least 10%.
  • inhibition of EGFR generally refers to a reduction in the activity or amount of EGFR by at least 20%, 40%, 50%, 80%, 90%, 95%, or more.
  • the reduction is compared to a standard value in the same type of subject (eg, the same normal person or the same type of patient). In some embodiments, the reduction is compared to a value in the same subject over a period of time.
  • EGFR is inhibited due to administration of an EGFR inhibitor.
  • the term "EGFR inhibitor” generally refers to any EGFR inhibitor known in the art or discovered in the future, including any EGFR inhibitor that, when administered to a subject, results in a correlation with EGFR activity in the subject Any substance that inhibits the biological activity of EGFR (including inhibition of downstream biological effects resulting from the binding of any EGFR to its natural ligand).
  • EGFR inhibitors include any agent capable of blocking EGFR activity or any of its downstream biological effects in the treatment of cancer.
  • EGFR inhibitors can be identified or screened by methods well known in the art, eg, by detecting changes in EGFR expression levels following administration of a test compound.
  • the expression level of EGFR can be detected by methods known in the art, for example, immunohistochemical methods, PCR, RT-PCR, in situ hybridization, Southern blot, Western blot, Northern blot, spectrophotometry, and ELISA.
  • the EGFR inhibitor can be used to treat the subject for cancer.
  • cancer generally refers to any medical condition that is mediated by the growth, proliferation or metastasis of a tumor or malignant cell, and that causes both solid and non-solid tumors (eg, leukemia).
  • EGFR inhibitors can block the kinase activity of the EGFR receptor by directly binding to the intracellular domain of the EGFR receptor; or occupy the ligand binding site or a portion of the EGFR receptor, thereby rendering the EGFR receptor inaccessible to its natural ligand And lead to its biological activity being reduced or blocked; or by regulating the dimerization of EGFR polypeptide or regulating the interaction of EGFR polypeptide with other proteins, increasing the ubiquitination and endocytic degradation of EGFR, thereby reducing EGFR activity.
  • EGFR inhibitors may be non-specific inhibitors of EGFR, ie, such inhibitors inhibit other target proteins in addition to EGFR.
  • EGFR inhibitors act directly on the EGFR protein or the nucleic acid encoding the EGFR protein.
  • the EGFR inhibitor acts directly on the EGFR protein.
  • the term "acts directly on” when used to describe the inhibitor and the target protein, it usually means that the inhibitor and the target protein can be directly bound without the need of other molecules (including covalent binding and non-covalent binding). price binding).
  • an EGFR inhibitor can be a small molecule EGFR inhibitor, a protein macromolecule (eg, an antibody or antigen-binding fragment thereof) that specifically binds EGFR, or an RNAi or antisense oligonucleotide that inhibits EGFR protein expression.
  • an EGFR inhibitor can be a small molecule EGFR inhibitor or a protein macromolecule that specifically binds EGFR (eg, an antibody or antigen-binding fragment thereof).
  • nucleic acid generally refers to a polynucleotide molecule composed of monomeric nucleotides.
  • Nucleic acids include ribonucleic acid (RNA), deoxyribonucleic acid (DNA), single-stranded nucleic acid (ssDNA), double-stranded nucleic acid (dsDNA), small interfering ribonucleic acid (siRNA), and microRNA (miRNA).
  • polynucleotides include genes, gene fragments, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, ribozyme, cDNA, shRNA, single-stranded short or long RNA, Recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, control regions, isolated RNA of any sequence, nucleic acid probes and primers. Nucleic acids can be linear or circular.
  • RNAi generally refers to RNA interference technology, which is a process by which exogenous or endogenous double-stranded RNA molecules or small RNA molecules inhibit gene expression or translation by targeting mRNA and degrading it specifically.
  • oligonucleotide generally refers to an oligomer or polymer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) or any mimetic or structurally modified nucleic acid thereof.
  • RNA ribonucleic acid
  • DNA deoxyribonucleic acid
  • oligonucleotides composed of naturally-occurring nucleobases, sugars, and covalent internucleoside (backbone) linkages, as well as non-naturally-occurring oligonucleotides with similar functions.
  • antisense oligonucleotide generally refers to a single-stranded oligonucleotide having a nucleobase sequence that allows at least partial hybridization to a corresponding region or fragment of a target nucleic acid.
  • small molecule EGFR inhibitor may include small molecule EGFR inhibitors that reversibly bind to EGFR (eg, gefitinib, erlotinib, Sapitinib, and icotinib), those that irreversibly bind to EGFR Small molecule EGFR inhibitors (eg, afatinib, Dacomitinib, Lapatinib, eg GW572016 GlaxoSmithKline), vandetinib (Vandetanib, e.g.
  • ZACTIMATM ZD6474
  • lenvatinib canetinib, valitinib and neratinib
  • small molecule EGFR inhibition that specifically binds mutant EGFR agents (eg, osimertinib, toartinib, nositinib, omotinib, avitinib, and EAI045).
  • the protein macromolecule that specifically binds EGFR can be an antibody, antibody variant, fusion protein, derivative or fragment thereof directed against EGFR.
  • the protein macromolecule that specifically binds EGFR is an antibody or antigen-binding fragment thereof that specifically binds EGFR.
  • EGFR inhibitor specifically binds
  • EGFR inhibitor recognizes EGFR in a complex mixture with the binding constant of the inhibitor to EGFR that is not specific for other At least 2 times the binding constant of the binding protein.
  • the EGFR inhibitor can be used in combination with one or more other cancer treatments.
  • the other cancer therapy may be a method conventionally used in the art for the treatment of cancer, such as a cytotoxic anticancer agent, an immunotherapeutic anticancer agent, or a hormonal therapy anticancer agent.
  • drugs for cancer treatment can also be used in combination with radiation therapy or surgery.
  • an EGFR inhibitor and other anticancer agent are used in combination, they can be administered to the subject simultaneously, or administered separately at intervals.
  • the rash described herein may be a rash associated with abnormal EGFR function. In certain embodiments, the rash described herein can be a rash associated with EGFR inhibition. In certain embodiments, the rash described herein can be a rash associated with an EGFR inhibitor. In certain embodiments, the rash described herein can be a rash that occurs after administration of an EGFR inhibitor.
  • the rash associated with EGFR dysfunction may include acne vulgaris associated with EGFR dysfunction, papulopustular rash associated with EGFR dysfunction, and rosacea associated with EGFR dysfunction (acne rosacea), pruritus rash associated with EGFR dysfunction, acneiform rash associated with EGFR dysfunction, cellulitis associated with EGFR dysfunction, and EGFR dysfunction Lyme disease, allergic reaction associated with EGFR dysfunction, hidradenitis suppurativa associated with EGFR dysfunction, measles associated with EGFR dysfunction, EGFR dysfunction Dysfunction-related dermatitis, cradle cap related to EGFR dysfunction, purpura related to EGFR dysfunction, pityriasis rosea related to EGFR dysfunction, and EGFR dysfunction Abnormally related erythema, EGFR dysfunction related shingles, EGFR dysfunction related bruise and/or EGFR dysfunction related xanthelasma, EGFR dysfunction related Abnormally associated mel
  • the present application provides a method of preventing or treating a rash comprising administering a JAK inhibitor.
  • the term "JAK inhibitor” generally refers to the reduction of Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3) or non-receptor protein tyrosine kinases An agent for the expression of 2 (TYK-2) and/or the kinase activity of at least one of JAK1, JAK2, JAK3 and TYK-2.
  • the JAK inhibitor can reduce the expression of JAK1.
  • the JAK inhibitor can reduce the expression of JAK2.
  • the JAK inhibitor can reduce the expression of JAK3.
  • the JAK inhibitor can reduce the expression of TYK-2.
  • the JAK inhibitor can reduce the kinase activity of JAK1. In certain instances, the JAK inhibitor can reduce the kinase activity of JAK2. In certain instances, the JAK inhibitor can reduce the kinase activity of JAK3. In certain instances, the JAK inhibitor can reduce the kinase activity of TYK-2. In certain instances, the JAK inhibitor can reduce the kinase activity of JAK1, JAK2, JAK3 and TYK2. In certain instances, the JAK inhibitor can reduce the kinase activity of 2 or more (eg, 3 or 4) of JAK1, JAK2, JAK3, and TYK2.
  • the JAK inhibitor can reduce the kinase activity of a single JAK isoform (eg, JAK1, JAK2, JAK3, or TYK2). In certain instances, the JAK inhibitor can reduce the kinase activity of JAK1 and JAK2. In certain instances, the JAK inhibitor can reduce the kinase activity of JAK1 and JAK3. In certain instances, the JAK inhibitor can reduce the kinase activity of JAK2 and JAK3. In certain instances, the JAK inhibitor can reduce the kinase activity of JAK1, JAK2 and JAK3.
  • the JAK inhibitor may comprise an inhibitory nucleic acid.
  • the JAK inhibitor can include antisense nucleotides, ribozymes, small interfering RNAs, small hairpin RNAs, or microRNAs.
  • inhibitory nucleic acids that can reduce the expression of JAK1, JAK2, JAK3 or TYK2 mRNA in mammalian cells can be synthesized in vitro. These nucleotides can be constructed by chemical synthesis and enzymatic conjugation reactions using procedures known in the art, and can be modified.
  • the JAK inhibitor may include a protein macromolecule that specifically binds to JAK.
  • the protein macromolecule that specifically binds JAK can be an antibody, antibody variant, fusion protein, derivative or fragment thereof directed against JAK.
  • the protein macromolecule that specifically binds JAK is an antibody or antigen-binding fragment thereof that specifically binds JAK.
  • JAK inhibitor specifically binds
  • JAK inhibitor recognizes a JAK in a complex mixture with a binding constant to the JAK that it binds to other non-specific At least 2 times the binding constant of the binding protein.
  • the JAK inhibitors may include small molecule JAK inhibitors.
  • the small-molecule JAK inhibitors include small-molecule JAK inhibitors that reversibly bind to JAK, small-molecule JAK inhibitors that irreversibly bind to JAK, and/or small-molecule JAK inhibitors that specifically bind to mutant JAKs.
  • JAK inhibitors can include JAK1 and JAK2 inhibitors.
  • JAK1 and JAK2 inhibitors can include, for example, ruxolitinib (INCB018424), baricitinib (INCB028050 or LY3009104), AZD1480, filgotinib (GLPG0634 or G146034) and/or momelotinib (GS-0387 or CYT387).
  • the JAK inhibitor can include a JAK1 inhibitor.
  • JAK1 inhibitors can include, eg, GSK2586184, oclacitinib (PF03394197), upadacitinib, GLG0778, INCB039110, PF04965842, and/or SAR-20347.
  • the JAK inhibitor can include a JAK2 inhibitor.
  • the JAK2 inhibitor can include, for example, CEP-33779, fedratinib (TG101348, SAR302503), lestaurtinib (CEP-701), pacritinib (SB1518, BMS-911543, XL019, (LY-2784544), R723 and/or Z3.
  • the JAK inhibitor can include a JAK3 inhibitor.
  • the JAK3 inhibitor can include, for example, decernotinib (VX-509), R348, R256, INCB047986, INCB16562, NVP-BSK805, peficitinib (ASP015K or JNJ-54781532), tofacitinib ( tofacitinib) (CP-690,500), cucurbitacin I (JSI-124) and/or CHZ868.
  • the JAK inhibitor can include a TYK2 inhibitor.
  • the TYK2 inhibitor can include, for example, Ndi-031301, BMS-986165, SAR-20347, (4-methoxybenzene)malononitrile (tyrphostin A1) and/or triazopyridine (US 2013/ 0143915).
  • the JAK inhibitor can include a pan-JAK inhibitor.
  • pan-JAK inhibitor generally refers to an IC50 for wild-type human JAK1, wild-type human JAK2, and wild-type human JAK3 when using similar assay conditions (eg, the same assay conditions) for Each of the human JAK1, human JAK2, human JAK3 subtypes has an agent with an IC50 of about 500 nM to 4 ⁇ M (eg, about 500 nM to about 2 ⁇ M).
  • a pan-JAK inhibitor can be obtained when each IC50 value is tested under similar assay conditions (eg, the same assay as described in Kim et al., J. Med. Chem.
  • pan-JAK inhibitors can include, for example, tofacitinib (or CP-690550), cerdulatinib, pyridone 6 (P6), PF-06263276, JAK inhibitors 1 (CAS 457081-03-07) and/or baricitinib.
  • the JAK inhibitor can include a selective JAK1/JAK3 inhibitor.
  • selective JAK1/JAK3 inhibitor generally refers to when the IC50 is determined for each of wild-type human JAK1, wild-type human JAK2, and wild-type human JAK3 using similar experimental conditions (eg, the same assays such as the wild-type human JAK1, wild-type human JAK2, and wild-type human JAK3 assays described in Kim et al., J.Med.Chem.58(18):7596-5602, 2015), for wild-type human JAK1 and Wild-type JAK3 each has an agent that has an IC50 that is at least 5-fold lower (eg, at least 10-fold or at least 20-fold lower) than the IC50 of wild-type human JAK2.
  • the JAK inhibitor can include a selective JAK1 inhibitor.
  • selective JAK1 inhibitor generally refers to when measured using similar assay conditions (eg, the same assay, eg, Kim et al, J. Med. Chem. 58(18):7596-5602, 2015 Wild-type human JAK1, wild-type human JAK2, and wild-type human JAK3 assays described in ), have an IC50 for wild-type human JAK1 that is at least 10-fold lower than each of the IC50 for wild-type human JAK2 and the IC50 for wild-type human JAK3 (eg, at least 20-fold) IC50 of the reagent.
  • the JAK inhibitor can include a selective JAK2 inhibitor.
  • selective JAK2 inhibitor generally refers to when measured using similar assay conditions (eg, the same assay, eg, Kim et al, J. Med. Chem. 58(18):7596-5602, 2015 Wild-type human JAK1, wild-type human JAK2, and wild-type human JAK3 assays described in ), have an IC50 for wild-type human JAK2 that is at least 10-fold lower than each of the IC50 for wild-type human JAK1 and the IC50 for wild-type human JAK3 (eg, at least 20-fold) IC50 of the reagent.
  • the JAK inhibitor can have less than or equal to 2000 Daltons, less than or equal to 1500 Daltons, less than or equal to 1200 Daltons, less than or equal to 1000 Daltons, less than or equal to 900 Daltons Daltons, less than or equal to 800 Daltons, less than or equal to 700 Daltons, less than or equal to 600 Daltons, less than or equal to 500 Daltons, less than or equal to 400 Daltons, less than or equal to 300 Daltons, Molecular weight less than or equal to 200 Daltons and/or less than or equal to 100 Daltons.
  • the JAK inhibitors may include 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, CEP-33779, R
  • the JAK inhibitor can include Peficitinib hydrobromide, Fedratinib hydrochloride, Tasocitinib citrate, Ruxolitinib phosphate, INCB-039110 adipate, Momelotinib dihydrochloride, Upadacitinib tartrate, Jaktinib dihydrochloride monohydrate, Ivarmacitinib sulfate and/or Zotiraciclib citrate.
  • alkyl generally refers to a straight or branched chain saturated hydrocarbyl substituent (eg, a substituent obtained from a hydrocarbon by removal of a hydrogen) containing 1-20 carbon atoms; eg, 1-12 carbon atoms; in other embodiments, the number of carbon atoms is 1-10; in other embodiments, 1-6 carbon atoms, in other embodiments, 1-4 carbon atoms (such as 1 , 2, 3 or more carbon atoms).
  • substituents include, for example, methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl , isopentyl, hexyl, etc.
  • the number of carbon atoms in a hydrocarbyl substituent ie, alkyl, alkenyl, cycloalkyl, aryl, etc.
  • C a -C b where a is the smallest and b is the largest The number of carbon atoms in the substituent.
  • C1 - C6 alkyl refers to an alkyl substituent containing 1 to 6 carbon atoms, which may include straight or branched chain methyl, ethyl, propyl, butyl, pentyl and hexy.
  • cycloalkyl generally refers to a carbocyclic substituent obtained by removing hydrogen from a saturated carbocyclic molecule and having carbon atoms ranging from 3 to 14 carbon atoms. In some embodiments, a cycloalkyl substituent has 3-10 carbon atoms. Cycloalkyl groups may be monocyclic rings, which typically contain 4-7 ring atoms. Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cycloalkyl can also be 2-3 rings fused together, also referred to as "bicycloalkyl".
  • cycloalkyl also includes substituents fused to a C6 - C10 aromatic ring or a 5-10 membered heteroaromatic ring, wherein a group having such a fused cycloalkyl as a substituent The group is bound to a carbon atom of the cycloalkyl group.
  • a fused cycloalkyl group is substituted with one or more substituents, unless otherwise specified, the one or more substituents are each bonded to a carbon atom of the cycloalkyl.
  • the fused C6 - C10 aromatic ring or the 5-10 membered heteroaromatic ring may be optionally further substituted.
  • alkenyl generally refers to straight and branched chain aliphatic hydrocarbon groups containing at least one carbon-carbon double bond.
  • C 1 -C 6 alkenyl refers to alkenyl substituents containing 1 to 6 carbon atoms, which may include straight or branched chain vinyl, propenyl, butenyl, pentenyl and hexenyl.
  • alkynyl generally refers to straight and branched chain aliphatic hydrocarbon groups containing at least one carbon-carbon triple bond.
  • C 1 -C 6 alkynyl refers to alkynyl substituents containing 1 to 6 carbon atoms, which may include straight or branched chain ethynyl, propynyl, butynyl, pentynyl and hexynyl.
  • the term “deuterium” generally refers to a stable form isotope of hydrogen, also known as deuterium, with the element symbol typically D or 2 H. Its nucleus consists of a proton and a neutron.
  • the term “hydroxyl” generally refers to a group of formula -OH.
  • the term “amino” generally refers to a group of formula -NH2 .
  • the term “cyano” generally refers to a group of formula -CN.
  • the term “nitro” generally refers to the group remaining from the nitric acid molecule after removal of one of the hydroxyl groups.
  • halogen generally includes fluorine, chlorine, bromine and iodine.
  • hydrogen generally refers to a hydrogen substituent, possibly described as -H.
  • oxygen generally refers to an oxygen substituent, possibly described as -O-.
  • substituent can be: (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more substituents, then one or more hydrogens on that carbon (to the extent present) may be independently and/or together selected optional optional Substituent substitution. If a nitrogen of a substituent is described as being optionally substituted with one or more substituents, one or more hydrogens on that nitrogen (to the extent present) may each be substituted with an independently selected optional substituent.
  • An exemplary substituent can be described as -NR'R", wherein R' and R", taken together with the nitrogen atom to which they are attached, can form a heteroatom containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur. Heterocycle, wherein the heterocycloalkyl moiety may be optionally substituted. The heterocycle formed by R' and R" together with the nitrogen atom to which they are attached can be partially or fully saturated, or aromatic.
  • the term "formula I (or formula II, formula III)” can be referred to as “the compound of formula I (or formula II, formula III)", “the compound represented by formula I (or formula II, formula III)” ".
  • Such terms are also defined to include all forms of compounds of formula I (or formula II, formula III), including hydrates, solvates, isomers, crystalline and amorphous forms, isomorphs, polymorphs and metabolites thing.
  • a compound of formula I (or formula II, formula III), or a pharmaceutically acceptable salt thereof can exist in unsolvated and solvated forms.
  • the binding force of the solvent or water is strong, the complex has a well-defined stoichiometry, which is not affected by humidity.
  • solvent or water binding is weak, such as in channel solvates and hygroscopic compounds, the water/solvent content will depend on humidity and drying conditions, in which case non-stoichiometry is the norm.
  • Compounds of formula I (or formula II, formula III) may have asymmetric carbon atoms.
  • the carbon-carbon bonds of compounds of formula I (or formula II, formula III) can be represented by solid lines, solid wedges or dotted wedges.
  • the use of a solid line to depict a bond to an asymmetric carbon atom is meant to include all possible stereoisomers at that carbon atom (eg, specific enantiomers, racemic mixtures, etc.).
  • the compounds of the present application may contain more than one asymmetric carbon atom.
  • the use of solid lines to indicate bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers are to be included.
  • compounds of formula I may exist as enantiomers and diastereomers or as racemates and mixtures.
  • the compounds of the present application may exist in the form of clathrates or other complexes. Included within the scope of the invention are complexes, such as inclusion complexes, drug-host inclusion complexes, wherein the drug and host are present in stoichiometric or non-stoichiometric amounts, as opposed to the solvates described above. Also included are complexes of formula I (or formula II, formula III) containing two or more organic and/or inorganic components that may be stoichiometric or non-stoichiometric. The resulting complexes can be ionized, partially ionized or not.
  • Stereoisomers of formula I (or formula II, formula III) include cis and trans isomers, optical isomers such as R and S enantiomers, diastereomers, geometric isomers isomers, rotamers, conformers and tautomers, compounds of formula I (or formula II, formula III), including compounds exhibiting more than one type of isomerism; and mixtures thereof (e.g., external spinomers and diastereomeric pairs). Also included are acid or base addition salts in which the counterion is optically active, such as D-lactate or L-lysine, or racemates such as DL-tartrate or DL-arginine.
  • the first category is the above-mentioned racemic compounds (true racemates), in which a homogeneous form of crystals is produced containing equimolar amounts of the two enantiomers.
  • the second type is a racemic mixture or agglomerate, in which two forms of crystals are produced in equimolar amounts, each form containing a single enantiomer.
  • Compounds of formula I may exhibit tautomerism and structural isomerism.
  • compounds of Formula I may exist in several tautomeric forms, including enol and imine forms, and keto and enamine forms, as well as geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of compounds of formula I (or formula II, formula III).
  • Tautomers exist in solution as a mixture of tautomers. In solid form, usually one tautomer predominates. Even if one tautomer can be described, the present invention includes all tautomers of compounds of formula I (or formula II, formula III).
  • the present invention also includes isotopically-labeled compounds that are the same as described in Formula I (or Formula II, Formula III), but wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from that found in nature.
  • Isotopes to which compounds of formula I (or formula II, formula III) may be added include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as but not limited to: 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • isotopically-labeled compounds of formula I for example to which radioactive isotopes (such as3H and14C ) are added, are useful for drug and/or substrate tissue distribution due to their ease of preparation and detectability Determination. Heavier isotopes, such as 2 H, may offer certain therapeutic advantages due to their greater metabolic stability, eg, prolonged in vivo half-life or reduced dosage requirements.
  • Isotopically labeled compounds of Formula I (or Formula II, Formula III) can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • the compounds of the present application may be used in the form of salts derived from inorganic or organic acids. Certain compounds have advantages such as enhanced drug stability at different temperatures and humidity, or desired solubility in water/oil due to the physical properties of one or more salts. In some cases, salts of compounds can also be used as aids in the isolation, purification and/or resolution of compounds.
  • the JAK inhibitor comprises a compound represented by formula I or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 and R 3 can each be independently selected from the group consisting of five- to six-membered aromatic Rings, five- to six-membered aromatic heterocycles, five- to six-membered cycloalkyl rings, five- to six-membered heterocycloalkyls, amino groups and amide groups, wherein the aromatic rings, aromatic heterocycles, cycloalkyls and/or heterocycloalkyl are optionally substituted with substituents.
  • the X may be N
  • the Y may be C
  • the Z may be C
  • the Q may be C.
  • the X, Y, Z and Q may all be N.
  • the X may be N
  • the Y may be N
  • the Z may be C
  • the Q may be C.
  • the X may be C
  • the Y may be N
  • the Z may be C
  • the Q may be N.
  • the X may be C
  • the Y may be C
  • the Z may be N
  • the Q may be C.
  • R 1 and R 2 in the compound represented by the formula I may each independently be a hydrogen atom or
  • R 4 can be selected from cyclopentyl, cyclobutane and azetidine
  • the substituent is piperidine, cyano, carbonyl, sulfonyl
  • the piperidine can be further substituted by a substituent
  • the acyl group is further substituted with an alkyl group.
  • the R4 can be wherein the R6 may be selected from -CF 3 , -CHF 2 , -CH 2 F and -CH 3 . wherein said R7 may be selected from hydrogen atom or fluorine atom.
  • the R4 can be selected from cycloalkyl, cyclobutyl substituted with cyano, azetidinyl substituted with sulfonyl, and
  • the R4 can be selected from cycloalkyl
  • the R 5 can be -C-CN.
  • the JAK inhibitor can include the compound shown in formula I, wherein, the R1 and R2 can be independently selected from hydrogen atom,
  • the R1 and R2 can be independently selected from hydrogen atoms or benzene rings, and the benzene rings can be optionally substituted by acyl, halogen, hydroxyl, C1-C3 alkyl, and the acyl and alkyl Can be further optionally substituted by C3-C5 cycloalkyl, C3-C5 heterocycloalkyl or C1-C3 alkyl, and said cycloalkyl, heterocycloalkyl can be further optionally substituted by C1-C3 alkyl .
  • R1 and R2 can each be independently selected from a hydrogen atom or a benzene ring, which can be optionally substituted with an acyl group, a halogen, a hydroxyl group, a C1-C3 alkyl group, and the acyl group can be further optionally substituted with an azetidinyl group Alternatively, the azetidine group may be further optionally substituted with methyl.
  • R1 and R2 can each independently be selected from hydrogen atoms
  • the R1 and R2 may be independently selected from hydrogen atoms, C1-C3 alkyl groups and wherein the R10 and R11 may each independently be selected from a hydrogen atom, a C1-C3 alkyl group, or a four- to ten-membered ring, the ring may be optionally substituted with a substituent, and the ring may be a monocyclic or Bicyclic, the ring may be further substituted with amino, sulfonyl, hydroxy, alkynyl, acyl or C1-C3 alkyl.
  • the R10 and R11 may form a ring.
  • R1 and R2 can be independently selected from hydrogen atom, methyl,
  • the R1 can be and the R2 can be
  • the R1 can be and the R2 can be
  • the R1 may be a hydrogen atom
  • the R2 may be selected from
  • both the R1 and the R2 may be hydrogen atoms.
  • the JAK inhibitor may include a compound represented by formula I, wherein the R3 may be selected from an amide group and a five- to ten-membered aromatic ring (for example, a six-membered heteroaromatic ring or a nine-membered heteroaromatic ring) aromatic ring), which may be bicyclic and may be substituted with a cyclyl or chain radical group.
  • R3 may be selected from an amide group and a five- to ten-membered aromatic ring (for example, a six-membered heteroaromatic ring or a nine-membered heteroaromatic ring) aromatic ring), which may be bicyclic and may be substituted with a cyclyl or chain radical group.
  • the R3 can be an amide group, which can be optionally substituted with cyclobutyl or cyclopropyl, for example, the R3 can be
  • the R3 can be Wherein
  • the R6 can be Wherein
  • the R7 can be selected from -CF3, -CH2F, -CH2F and -CH3, and R8 can be selected from C1-C3 alkyl.
  • the R7 can be -CF3 and the R8 can be ethyl.
  • the R3 can be wherein, the R9 may be a six-membered heterocyclic ring or a six-membered aromatic ring, and the ring may be further substituted by a C1-C3 alkyl group.
  • the R9 can be selected from
  • the JAK inhibitor can include a compound represented by formula I, wherein the compound represented by formula I can include any one or more of compounds I-1 to I-15:
  • the JAK inhibitor may comprise a compound represented by formula II:
  • Said X and Y may each independently be selected from C or N, and said R12, R13, R14 may each independently comprise selected from the group consisting of hydrogen, protium, deuterium, tritium, C1-C5 alkyl, halogen, Alkoxy, amino, amido, sulfonamido, alkoxy, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl.
  • the X may be C, and the Y may be N; or the X may be N, and the Y may be C.
  • the JAK inhibitor may comprise a compound represented by formula II-a:
  • R a1 and R a2 may contain any valence bond-allowed substituents
  • ring A may be an aromatic ring or an aromatic heterocycle optionally substituted by R a3 and/or R a5
  • the R a3 and R a5 can be independently selected from: hydrogen atom, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, alkoxy group, or a methyl group is included between the ring A and -NH- .
  • the Ra1 may be selected from a four- to ten-membered aromatic ring group, a four- to ten-membered aromatic heterocyclic group, a four- to ten-membered cycloalkyl group, a four- to ten-membered heterocycloalkyl group, the ring group It may be further substituted with an amide group or a sulfonyl group, and the sulfonylamide group may be further substituted with a cyano group, a C1-C6 alkyl group, or a five- to six-membered heterocyclic group.
  • the rings may be monocyclic or bicyclic.
  • the Ra1 may be selected from a benzene ring, an eight-membered heterobicyclic ring, and a nine-membered heteroaromatic bicyclic ring, wherein the ring may be further substituted, the ring group may be further substituted with an amido group, and the amido group may be further Substituted by C1-C3 alkyl, cyclopropyl or five-membered heterocycle, said C1-C3 alkyl, cyclopropyl or five-membered heterocycle may be further substituted by cyano, fluoro, six-membered heterocycle.
  • the Ra1 may be an amino group substituted with a four- to ten-membered aromatic ring group.
  • the Ra1 can be an amino group substituted by a benzene ring or a five-membered heteroaromatic ring, the benzene ring can be further substituted by a sulfonyl group, and the five-membered heteroaromatic can be further substituted by a methyl group.
  • the Ra2 can be selected from: hydrogen, C1-C3 alkyl and halogen.
  • the Ra2 can be selected from: hydrogen, methyl and chlorine.
  • the ring A can be selected from a benzene ring or an imidazole ring, and the benzene ring or imidazole ring can be optionally replaced by a C1-C3 alkyl, A five- to six-membered heterocycloalkyl group, a five- to six-membered heteroaryl group, or a halogen-substituted alkyl group or ring may be further substituted with a hydroxyl group.
  • the Ra3 can be selected from methyl or methoxy, and the Ra5 is a hydrogen atom.
  • R 12 , R 13 , and R 14 are each independently selected from the following group:
  • the JAK inhibitor may comprise one or more of compounds II-1 to II-7:
  • the JAK inhibitor may comprise a junction compound represented by formula III:
  • R 15 and R 16 are each independently selected from a hydrogen atom, a cycloalkyl group optionally substituted with a substituent group, a heterocycloalkyl group optionally substituted with a substituent group, an aryl group optionally substituted with a substituent group and optionally substituted heteroaryl groups selected from the group consisting of: amido, alkyl, cycloalkyl, heterocycloalkyl, cyano, amino, hydroxy, and halogen.
  • the R15 or the R16 can be a four- to ten-membered heterocycloalkyl, and the heterocycloalkyl is optionally substituted with an amide group or a C1-C6 alkyl group, which can be further substituted with a C1 -C6 alkyl substituted, which may be further substituted by halogen.
  • the R15 or the R16 may be Wherein, the R17 and R18 are each independently a C1-C6 alkyl group, and the alkyl group may be substituted by halogen.
  • the R17 can be ethyl
  • the R18 can be ethyl substituted with fluorine
  • the R17 can be ethyl
  • the R18 can be -CH2-CF3.
  • one of the R15 or the R16 may be a hydrogen atom.
  • the JAK inhibitor can be compound III-1:
  • the JAK inhibitor may comprise a junction compound represented by formula IV: Formula IV, wherein, said R 19 and R 20 can be independently selected from hydrogen atom, nitro group, four- to ten-membered cycloalkyl, four- to ten-membered heterocycloalkyl, four- to ten-membered aromatic group and four- to ten-membered heteroaryl groups, wherein the nitro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl groups may be further replaced by cyano, alkyl, cycloalkyl, heterocycloalkyl or hydroxyl replace.
  • formula IV wherein, said R 19 and R 20 can be independently selected from hydrogen atom, nitro group, four- to ten-membered cycloalkyl, four- to ten-membered heterocycloalkyl, four- to ten-membered aromatic group and four- to ten-membered heteroaryl groups, wherein the nitro, cycloalkyl
  • the R19 may be a nitro group, and the nitro group may be substituted with a substituted benzene ring.
  • the benzene ring can be substituted with piperidine, and the piperidine can be further substituted with hydroxy.
  • the R 19 can be
  • the R 20 may be piperidinyl, which may be substituted with C1-C3 alkyl, which may be further substituted with cyano or hydroxy.
  • the R20 can be piperidinyl, the piperidinyl can be substituted by methyl, and the methyl can be further substituted by hydroxyl.
  • the R20 can be
  • the JAK inhibitor can be compound III-1:
  • the present application provides a method of preventing or treating a disease or disorder associated with an antineoplastic agent, the method comprising administering to a subject a JAK inhibitor as described above.
  • the present application provides a method of preventing or treating a rash associated with EGFR dysfunction, the method comprising administering to a subject a JAK inhibitor as described above.
  • the present application provides a method of preventing or treating a disease or disorder associated with an antineoplastic agent, the method comprising administering to a subject a JAK inhibitor as described above.
  • the present application provides a method of preventing or treating a rash associated with EGFR dysfunction, the method comprising administering to a subject a JAK inhibitor as described above.
  • prevention generally refers to preventing the onset, recurrence or spread of a disease or one or more symptoms thereof. "Prevention” is used interchangeably with “prophylactic treatment” in this application. In certain embodiments, “prevention” generally refers to providing a patient with a disease or disorder described herein, with or without other drugs described herein, prior to the onset of symptoms treatment with the mentioned drugs.
  • treating generally refers to eliminating or ameliorating a disease, or one or more symptoms associated with a disease.
  • treatment generally refers to the elimination or amelioration of the disease by administering one or more therapeutic agents to a patient suffering from the disease.
  • treatment may be the administration of a drug in the presence or absence of other therapeutic agents after the onset of symptoms of a particular disease.
  • subject generally refers to a human or non-human animal (including mammals) in need of diagnosis, prognosis, amelioration, prevention and/or treatment of a disease, particularly those in need of treatment or prevention with a JAK inhibitor subject.
  • the subject may include a cancer patient.
  • the cancer patient may have been, is and/or will be administered an antineoplastic agent.
  • the anti-tumor agent can be the anti-tumor agent described in this application.
  • the cancer patient may have been, is and/or will be administered an EGFR inhibitor.
  • the EGFR inhibitor can be the EGFR inhibitor described herein.
  • the subject can be a human or a non-human mammal.
  • Non-human mammals can include any mammalian species other than humans, such as livestock animals (eg, cattle, pigs, sheep, chickens, rabbits, or horses), or rodents (eg, rats and mice), or Primates (eg, gorillas and monkeys), or domestic animals (eg, dogs and cats).
  • the severity of a disease or disorder associated with the anti-neoplastic agent is alleviated in a subject. In some embodiments, following administration of a JAK inhibitor of the present application, the severity of the rash caused by the EGFR dysfunction in a subject is alleviated.
  • the remission can be judged according to the grading scale of NCI-CTCAE V5.0, eg, the severity of the epithelial tissue disease in the subject is reduced from grade 5 to grade 1 (eg, 5 Level 4 reduced to Level 4, Level 5 reduced to Level 3, Level 5 reduced to Level 2, Level 4 reduced to Level 3, Level 4 reduced to Level 2, Level 4 reduced to Level 1, Level 3 reduced to Level 2, Level 3 reduced to level 1 or level 2 reduced to level 1).
  • the remission can generally refer to a delay in the onset or development of the rash caused by the EGFR dysfunction in the subject.
  • administering to a subject in need thereof an effective amount of a JAK inhibitor described herein is capable of reducing the severity of the rash in the subject from grade 5 to grade 1 (eg, grade 5 to grade 4) , 5 to 3, 5 to 2, 4 to 3, 4 to 2, 4 to 1, 3 to 2, 3 to 1 or Level 2 is reduced to Level 1).
  • the JAK inhibitor in the methods of the present application can be a compound selected from the group consisting of:
  • It can be used to prevent or treat skin rashes associated with abnormal EGFR function.
  • the JAK inhibitors can be used to prevent or treat diseases or disorders associated with antineoplastic agents.
  • administration of an effective amount of one or more of Compound 1-1 to Compound 1-15 to a subject in need thereof is capable of reducing the severity of the rash in the subject from grade 5 to 1 level (e.g., level 5 reduced to level 4, level 5 reduced to level 3, level 5 reduced to level 2, level 4 reduced to level 3, level 4 reduced to level 2, level 4 reduced to level 1, level 3 reduced to level 2 Level 2, Level 3 reduced to Level 1 or Level 2 reduced to Level 1).
  • grade 5 to 1 level e.g., level 5 reduced to level 4, level 5 reduced to level 3, level 5 reduced to level 2, level 4 reduced to level 3, level 4 reduced to level 2, level 4 reduced to level 1, level 3 reduced to level 2 Level 2, Level 3 reduced to Level 1 or Level 2 reduced to Level 1).
  • the JAK inhibitor in the methods of the present application can be a compound selected from the group consisting of:
  • It can be used to prevent or treat skin rashes associated with abnormal EGFR function.
  • the above-described JAK inhibitors can be used to prevent or treat diseases or disorders associated with antineoplastic agents.
  • administration of an effective amount of one or more of Compound II-1 to Compound II-7 to a subject in need thereof is capable of reducing the severity of the rash in the subject from grade 5 to 1 level (e.g., level 5 reduced to level 4, level 5 reduced to level 3, level 5 reduced to level 2, level 4 reduced to level 3, level 4 reduced to level 2, level 4 reduced to level 1, level 3 reduced to level 2 Level 2, Level 3 reduced to Level 1 or Level 2 reduced to Level 1).
  • grade 5 to 1 level e.g., level 5 reduced to level 4, level 5 reduced to level 3, level 5 reduced to level 2, level 4 reduced to level 3, level 4 reduced to level 2, level 4 reduced to level 1, level 3 reduced to level 2 Level 2, Level 3 reduced to Level 1 or Level 2 reduced to Level 1).
  • the JAK inhibitor in the methods of the present application can be a compound It can be used to prevent or treat skin rashes associated with abnormal EGFR function.
  • the above-described JAK inhibitors can be used to prevent or treat diseases or disorders associated with antineoplastic agents.
  • administration of an effective amount of Compound III-1 to a subject in need thereof is capable of reducing the severity of the rash in the subject from grade 5 to grade 1 (eg, grade 5 to grade 4, 5 Level reduced to Level 3, Level 5 reduced to Level 2, Level 4 reduced to Level 3, Level 4 reduced to Level 2, Level 4 reduced to Level 1, Level 3 reduced to Level 2, Level 3 reduced to Level 1 or Level 2 down to level 1).
  • grade 5 to grade 1 eg, grade 5 to grade 4, 5 Level reduced to Level 3, Level 5 reduced to Level 2, Level 4 reduced to Level 3, Level 4 reduced to Level 2, Level 4 reduced to Level 1, Level 3 reduced to Level 2, Level 3 reduced to Level 1 or Level 2 down to level 1).
  • the JAK inhibitor in the methods of the present application can be a compound It can be used to prevent or treat skin rashes associated with abnormal EGFR function.
  • the above-described JAK inhibitors can be used to prevent or treat diseases or disorders associated with antineoplastic agents.
  • administration of an effective amount of Compound IV-1 to a subject in need thereof is capable of reducing the severity of the rash in the subject from grade 5 to grade 1 (eg, grade 5 to grade 4, 5 Level reduced to Level 3, Level 5 reduced to Level 2, Level 4 reduced to Level 3, Level 4 reduced to Level 2, Level 4 reduced to Level 1, Level 3 reduced to Level 2, Level 3 reduced to Level 1 or Level 2 down to level 1).
  • grade 5 to grade 1 eg, grade 5 to grade 4, 5 Level reduced to Level 3, Level 5 reduced to Level 2, Level 4 reduced to Level 3, Level 4 reduced to Level 2, Level 4 reduced to Level 1, Level 3 reduced to Level 2, Level 3 reduced to Level 1 or Level 2 down to level 1).
  • an effective amount generally refers to an amount of a drug that can alleviate or eliminate a disease or symptom in a subject, or prevent the occurrence of a disease or symptom prophylactically.
  • An effective amount can be that amount of a drug that alleviates to a certain extent one or more diseases or symptoms in a subject; can partially or fully restore one or more physiological or biochemical parameters associated with the cause of the disease or symptoms the amount of the drug to normal; and/or the amount of the drug that reduces the likelihood of the disease or symptoms.
  • the JAK inhibitors described herein can be administered by means of administration known in the art, such as injection administration (eg, subcutaneous, intraperitoneal, intraarticular, intraarterial, intrathecal, intrasternal, intrathecal, intralesional, intracranial, intramuscular, intradermal, and intravenous bolus or instillation) or non-injectable administration (eg, oral, nasal, sublingual, vaginal, rectal, or topical).
  • injection administration eg, subcutaneous, intraperitoneal, intraarticular, intraarterial, intrathecal, intrasternal, intrathecal, intralesional, intracranial, intramuscular, intradermal, and intravenous bolus or instillation
  • non-injectable administration eg, oral, nasal, sublingual, vaginal, rectal, or topical.
  • the JAK inhibitors of the present application can be administered in the form of pharmaceutical combinations or kits.
  • the JAK inhibitors may be formulated for transdermal administration.
  • the concentration of the JAK inhibitor provided herein can be from about 0.01% (w/w) to about 10% (w/w), for example, can be from about 0.01% (w/w) to about 9% % (w/w), about 0.01% (w/w) to about 8% (w/w), about 0.01% (w/w) to about 7% (w/w), about 0.01% (w/w) ) to about 6% (w/w), about 0.01% (w/w) to about 5% (w/w), about 0.01% (w/w) to about 4% (w/w), about 0.01% (w/w) to about 3% (w/w), about 0.01% (w/w) to about 2% (w/w), about 0.01% (w/w) to about 1% (w/w) , about 0.01% (w/w) to about 0.5% (w/w), about 0.01% (w/w) to about 0.1% (w/w), or about 0.01% (w/w)
  • the concentration of the JAK inhibitor provided herein can be about 0.02% (w/w) to about 0.05% (w/w), about 0.02% (w/w) to about 1% (w/w), about 0.02% (w/w) to about 2% (w/w), about 0.02% (w/w) to about 5% (w/w), about 0.02% (w/w) to about 0.75% (w/w) /w) or from about 0.02% (w/w) to about 1.5% (w/w).
  • the JAK inhibitors may be formulated for topical administration.
  • the site of administration of the topical administration may not be the site of occurrence of the cancer or the site of potential metastases of the cancer.
  • the administered moiety may not be the primary site of cancer.
  • the administered moiety may not be a metastatic site of cancer.
  • the metastatic site may include the site of cancer metastasis caused by lymphatic metastasis, vascular metastasis and/or implanted metastasis.
  • the metastatic site may include bone, brain, liver, stomach, and/or lung.
  • the administered portion may not be the recurrence site of the cancer.
  • the drug or the JAK inhibitor may be formulated for transdermal administration.
  • the drug or the JAK inhibitor may be formulated for topical administration.
  • the drug or the JAK inhibitor is formulated for topical skin administration.
  • the drug or the JAK inhibitor can be formulated as a cream, lotion, gel, ointment, salves, sprays, liposomal formulations, liniments and/or aerosols.
  • the drug or the JAK inhibitor prepared for transdermal administration may be a solution transdermal formulation (cream, gel, ointment, paste, etc.) or a suspension type Transdermal formulations (creams, gels, ointments, pastes, etc.).
  • the JAK inhibitors described herein can be co-administered with an EGFR inhibitor.
  • the JAK inhibitor can be administered before, concurrently with, or after the subject has received the EGFR inhibitor.
  • the JAK inhibitor can be administered separately from the EGFR inhibitor as part of a multiple dose regimen.
  • the JAK inhibitor can be administered concurrently with the EGFR inhibitor.
  • the JAK inhibitors may be part of a single dosage form that is combined with the presently disclosed EGFR inhibitors into a single composition.
  • the JAK inhibitors may be administered as separate doses at about the same time as the EGFR inhibitor.
  • the JAK inhibitor may be administered at intervals before or after administration of the EGFR inhibitor.
  • the interval 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 EGFR inhibitors described herein can be administered by the same route of administration as the JAK inhibitor or by a different route of administration.
  • a JAK inhibitor or a pharmaceutically acceptable salt thereof, can be administered as part of a drug or drug combination.
  • the medicament may include a JAK inhibitor or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.
  • the pharmaceutical combination or kit may comprise 1) an EGFR inhibitor; and 2) a JAK inhibitor or a pharmaceutically acceptable salt thereof.
  • the EGFR inhibitor and the JAK inhibitor or a pharmaceutically acceptable salt thereof may be immiscible with each other.
  • the EGFR inhibitor can be present in separate containers from the JAK inhibitor or a pharmaceutically acceptable salt thereof.
  • the EGFR inhibitor can be dispensed in one vial, and the JAK inhibitor or a pharmaceutically acceptable salt thereof can be dispensed in another vial.
  • the JAK inhibitor or a pharmaceutically acceptable salt thereof in 2) can prevent or treat diseases or conditions caused by the EGFR inhibitor in 1).
  • the JAK inhibitor or a pharmaceutically acceptable salt thereof in 2) does not substantially affect the therapeutic effect of the EGFR inhibitor in 1).
  • the "substantially no effect” may refer to the use of the JAK inhibitor in 2) of the pharmaceutical combination or kit or the treatment effect of the EGFR inhibitor alone, compared to the use of the EGFR inhibitor alone
  • the therapeutic effect of the pharmaceutically acceptable salt and the JAK inhibitor in 1) or the pharmaceutically acceptable salt thereof is comparable, or does not produce a significant disadvantage.
  • using the JAK inhibitor or the pharmacy thereof in 2) of the pharmaceutical combination or kit is compared with the therapeutic effect of using the JAK inhibitor or a pharmaceutically acceptable salt thereof alone.
  • the degree of tumor volume reduction caused by the acceptable salt above and the JAK inhibitor or a pharmaceutically acceptable salt thereof in 1) 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 about 0.1%, not less than about 0.01%, not less than about 0.001% or less.
  • the JAK inhibitor in 2) or a pharmaceutically acceptable salt thereof is used for administration before, at the same time or after the administration of the EGFR inhibitor in 1).
  • the application provides a method, the method comprises the following steps:
  • Example 1 Experiment to verify that JAK inhibitors prevent small molecule EGFR inhibitors from producing rashes in a rat animal model
  • a rat animal model was constructed.
  • the small-molecule EGFR inhibitor was administered to female SD rats by daily gavage for 6 weeks. After several days, a large area of rash appeared on the back of the rats (the photo is shown in Figure 1). There was no left-right difference in the site where the rash appeared, and the extent of the rash was similar on both sides. Similar to humans, rats developed rashes on the face and body after oral administration of small-molecule EGFR inhibitors. Both have exactly the same cause, and the symptoms are very similar. Therefore, the rat is a very good animal model for simulating the rash caused by EGFR inhibitors.
  • the rats were divided into 10 groups per group. On the day before the experiment, the back hair of the rat was gently removed with an electric shaver, and then the gavage test was performed.
  • the EGFR inhibitor was dissolved in sterile aqueous solution, diluted with PBS buffer solution, and the amount of each gavage was no more than 2 mL, and the dosage was shown in Table 1.
  • the experiment was divided into JAK inhibitor group and control group. After gavage, apply JAK inhibitor ointment (type and concentration as shown in Table 1) on the back (about 3cm*3cm) of the JAK inhibitor group; apply blank on the back (about 3cm*3cm) of the control group.
  • Matrix ointment (about 0.5 g); fix the rat with a fixation cylinder for about 4 hours after applying the medicine, release the rat after 4 hours, wipe off the residual drug on the application site with water, and put it back into the rat cage.
  • the gavage frequency of EGFR inhibitors is shown in Table 1, but JAK inhibitors and blank matrix ointment are applied only once a day. The gavage and smear tests were repeated every day until obvious rash appeared in the control group. At this time, the number of rats whose skin in the JAK inhibitor group remained normal or whose skin rash was significantly lighter than that in the control group was calculated as the number of rats with effectively inhibited rash.
  • Figure 2 shows photographs of the left, back and right sides of typical rats in the control group, the JAK inhibitor group in Table 1.
  • Figure 3 shows the rash grades of the JAK inhibitor group and the control group at the end of the experiment.
  • JAK inhibitor ointment can effectively prevent rashes caused by small molecule EGFR inhibitors.
  • Example 2 Experiment to verify that JAK inhibitors prevent rashes caused by monoclonal antibody-like EGFR inhibitors in rat animal models
  • the JAK inhibitor group applied JAK inhibitor ointment to the back of the rats (about 3cm*3cm) every day, and the control group applied blank matrix ointment (about 0.5g) to the back of the rats (about 3cm*3cm), Afterwards, the rats were fixed with a fixation cylinder for 4 hours. After 4 hours, the rats were released and the residual drug on the application site was wiped off with water, and then the rats were released back to the cage. The tail vein was injected twice a week, and the ointment was applied once a day until the control group developed a noticeable rash. After 10-14 days of drug application, the number of rats whose skin in the JAK inhibitor group remained normal or was significantly lighter than that in the control group was calculated as the number of rats with effectively inhibited rash.
  • Figure 4 shows the rash grades of the JAK inhibitor group and the control group (mAb-like EGFR inhibitor) at the end of the experiment.
  • JAK inhibitor ointment can effectively prevent rashes caused by monoclonal antibody EGFR inhibitors.
  • Example 3 Validation of JAK inhibitor treatment of small molecule EGFR inhibitor to produce rash in rat animal model
  • the rats were divided into 10 groups per group.
  • the back hair of the rat was gently removed with an electric shaver, and then the gavage test was performed.
  • the EGFR inhibitor was dissolved in sterile aqueous solution, diluted with PBS buffer solution, and the amount of each gavage did not exceed 2 mL, and the dosage was shown in Table 3.
  • the gavage was continued every day until the rats developed symptoms of rash, at which point the treatment experiment was started.
  • the experiment was divided into JAK inhibitor group and control group.
  • the EGFR inhibitor was continuously administered by gavage every day.
  • the JAK inhibitor ointment was applied to the back (about 3cm*3cm) of the rats in the JAK inhibitor group, and the back of the rats in the control group (about 3cm*3cm).
  • 3cm) Apply blank matrix ointment; fix the rat with a fixing cylinder for about 4 hours after applying the medicine, release the rat after 4 hours and wipe off the residual drug on the application site with water, and put it back into the rat cage.
  • the gavage frequency of EGFR inhibitor is shown in Table 3, but JAK inhibitor and blank ointment were applied only once a day.
  • the EGFR inhibitor was repeatedly administered by gavage every day, and the number of rats whose skin in the JAK inhibitor group returned to normal or whose skin rash was significantly lighter than that in the control group was calculated as the number of rats with effective rash treatment.
  • Figure 5 shows photographs of the left side, back and right side of typical rats in the control group, the JAK inhibitor group in Table 3.
  • Figure 6 shows the rash grades in the JAK inhibitor group and the control group at the end of the experiment.
  • JAK inhibitor ointment can effectively treat the rash caused by small molecule EGFR inhibitors.
  • Example 4 Experiment of JAK inhibitor treatment of monoclonal antibody EGFR inhibitor to produce skin rash on rat animal model
  • the rats were divided into 10 groups per group.
  • the day before the experiment the hair on the back of the rat was gently 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 were shown in Table 4; the rats were continuously administered for 1-2 weeks until skin rash appeared, and the treatment experiment was started at this time.
  • the experiment was divided into JAK inhibitor group and control group.
  • the monoclonal antibody EGFR inhibitor was continuously injected twice a week, and the JAK inhibitor ointment was applied to the back (about 3cm*3cm) of the rats in the JAK inhibitor group every day.
  • 3cm) Apply blank matrix ointment; fix the rat with a fixing cylinder for about 4 hours after applying the medicine, release the rat after 4 hours and wipe off the residual drug on the application site with water, and put it back into the rat cage.
  • the number of rats whose skin in the JAK inhibitor group remained normal or was significantly lighter than that in the control group was calculated as the number of rats with effectively inhibited rash.
  • Figure 7 shows the rash grades of the JAK inhibitor group and the control group (mAb-like EGFR inhibitor) at the end of the experiment.
  • Example 5 JAK inhibitor ointment was compared with other clinically available skin medicines in the experiment of preventing small molecule EGFR inhibitors from producing skin rashes.
  • the rats were divided into 10 groups per group.
  • the back hair of the rat was gently removed with an electric shaver, and then the gavage test was performed.
  • the EGFR inhibitor was dissolved in sterile aqueous solution, diluted with PBS buffer solution, and the amount of each gavage did not exceed 2 mL, and the dosage was shown in Table 5.
  • the experiment was divided into JAK inhibitor group and other skin medication group.
  • Figure 8 shows photographs of the left, back and right sides of typical rats in the other skin-administered groups, the JAK inhibitor group in Table 5.
  • Figure 9 shows the rash grades in the JAK inhibitor group and other skin drug groups at the end of the experiment.
  • JAK inhibitor ointment can effectively control the rash caused by EGFR inhibitors .
  • Example 6 Experiments to validate JAK inhibitors in the prevention of antineoplastic agent-related diseases or disorders in rat animal models
  • a rat animal model was constructed.
  • the antitumor agent was administered to female SD rats by daily gavage for 6 weeks, and after several days, a large area of skin rash appeared on the back of the rats. There was no left-right difference in the site where the rash appeared, and the extent of the rash was similar on both sides.
  • rats developed rashes on the face and body after oral antineoplastic agents. Both have exactly the same cause, and the symptoms are very similar. Therefore, rats are very good animal models for simulating skin rashes caused by antineoplastic agents.
  • the rats were divided into 10 groups per group.
  • the back hair of the rat was gently removed with an electric shaver, and then the gavage test was performed.
  • the anti-tumor agent was dissolved in the corresponding solution, diluted with PBS buffer solution, and the amount of each gavage was no more than 2 mL, and the dosage was shown in Table 6.
  • the experiment was divided into JAK inhibitor group and control group. After gavage, apply JAK inhibitor ointment (type and concentration as shown in Table 6) on the back (about 3cm*3cm) of the JAK inhibitor group; apply blank on the back (about 3cm*3cm) of the control group.
  • Matrix ointment (about 0.5 g); fix the rat with a fixation cylinder for about 4 hours after applying the medicine, release the rat after 4 hours, wipe off the residual drug on the application site with water, and put it back into the rat cage.
  • the gavage frequency of antineoplastic agents is shown in Table 6, but JAK inhibitor and blank matrix ointment were applied only once a day. The gavage and smear tests were repeated every day until obvious rash appeared in the control group. At this time, the number of rats with normal or significantly lighter skin rash in the JAK inhibitor group was calculated as the number of rats with effective rash inhibition.
  • Example 7 Experiments to validate JAK inhibitors in the treatment of antineoplastic agent-related diseases or disorders in rat animal models
  • the rats were divided into 10 groups per group.
  • the back hair of the rat was gently removed with an electric shaver, and then the gavage test was performed.
  • the antitumor agent was dissolved in the corresponding solution, diluted with PBS buffer solution, and the amount of each gavage was no more than 2 mL, and the dosage was shown in Table 7.
  • the gavage was continued every day until the rats developed symptoms of rash, at which point the treatment experiment was started.
  • the experiment was divided into JAK inhibitor group and control group. During the treatment experiment, the antitumor agent was continuously administered by gavage every day.
  • the JAK inhibitor ointment was applied to the back of the rats in the JAK inhibitor group (about 3cm*3cm), and the back of the rats in the control group (about 3cm*3cm) was smeared.
  • 3cm) Apply blank matrix ointment; fix the rat with a fixing cylinder for about 4 hours after applying the medicine, release the rat after 4 hours and wipe off the residual drug on the application site with water, and put it back into the rat cage.
  • the gavage frequency of antineoplastic agents is shown in Table 7, but JAK inhibitor and blank ointment were applied only once a day.
  • the antitumor agent was administered by gavage repeatedly every day, and the number of rats whose skin in the JAK inhibitor group returned to normal or whose rash was significantly lighter than that in the control group was calculated as the number of rats with effective rash treatment.
  • Example 8 Experiment to verify that JAK inhibitors prevent rash from monoclonal antibody inhibitors in rat animal model
  • mice After SD rats were acclimated for one week (about 200 g), the rats were divided into 10 groups per group. The day before the experiment, the hair on the back of the rat was gently removed with an electric shaver, and then the drug administration test was performed. The experiment was divided into JAK inhibitor group and control group. The monoclonal antibody inhibitor solution diluted with normal saline was injected into the tail vein twice a week, and the injection speed and time were shown in Table x.
  • the JAK inhibitor group applied JAK inhibitor ointment to the back of the rats (about 3cm*3cm) every day, and the control group applied blank matrix ointment (about 0.5g) to the back of the rats (about 3cm*3cm), Afterwards, the rats were fixed with a fixation cylinder for 4 hours. After 4 hours, the rats were released and the residual drug on the application site was wiped off with water, and then the rats were released back to the cage. The tail vein was injected twice a week, and the ointment was applied once a day until the control group developed a noticeable rash. After 10-14 days of drug application, the number of rats whose skin in the JAK inhibitor group remained normal or was significantly lighter than that in the control group was calculated as the number of rats with effectively inhibited rash.
  • the patient receiving targeted therapy is being treated with cetuximab, or other antibody-based anti-tumor agents; the patient receiving immunotherapy is being treated with CTLA-4 inhibitors (eg: Ipilimumab) and/or PD-1/PD-L1 inhibitor (eg: Pembrolizumab, Nivolumab, etc.) treatment.
  • CTLA-4 inhibitors eg: Ipilimumab
  • PD-1/PD-L1 inhibitor eg: Pembrolizumab, Nivolumab, etc.
  • the diagnostic criteria for rash refer to NCI-CTCAE v5.0 and ASCO guidelines, and rashes caused by targeted therapy and immunotherapy are classified as separate categories.
  • the experiment was divided into treatment group and control group.
  • the treatment group the rash was washed locally with water, and the affected area was smeared with JAK ointment three times a day in the morning, noon and evening; Apply blank base ointment to the affected area 3 times a day; 4 weeks is a course of treatment.
  • the efficacy evaluation methods are as follows:
  • the rash remission rate (clinical control + markedly effective + effective)/total number of cases in this group * 100% was calculated using the above-mentioned efficacy evaluation methods.
  • JAK ointment (tofacitinib ointment) was significantly less effective for patients receiving targeted therapy (Cetuximab, Panitumumab) and immunotherapy (CTLA-4 inhibitor, and/or PD-1/PD-L1 inhibition)
  • CTLA-4 inhibitor and/or PD-1/PD-L1 inhibition
  • the rash produced by the patients treated with the drug has a certain relieving effect.

Abstract

一种JAK抑制剂在制备药物中的用途，所述药物用于预防和/或治疗受试者中抗肿瘤剂相关的疾病或病症。还提供了包含所述JAK抑制剂的药物组合物和试剂盒。

Description

预防或治疗抗肿瘤剂相关疾病或病症的方法 技术领域
本申请涉及生物医药领域，具体的涉及一种JAK抑制剂在制备用于预防或者治疗受试者中与抗肿瘤剂相关的疾病或病症的药物中的用途。
背景技术
临床上***最常用的手段有化疗、放疗和手术等，化疗选择性不高，在杀伤肿瘤细胞的同时，对正常细胞会造成损害，副作用较大。相较于传统的抗肿瘤方案，靶向治疗针对的是肿瘤细胞上特定的靶点(例如某个特有的基因突变)，免疫治疗利用机体的免疫***攻击的肿瘤细胞，但由于也并不能完全区分肿瘤细胞和正常细胞，或导致免疫***的异常激活，仍会产生副作用，例如，骨髓抑制、消化***毒性、肾毒性或肝毒性，从而对治疗效果产生不利影响，严重的不良事件可能危及生命，患者生存期缩短。
表皮生长因子受体(EGFR)的突变或过表达已被发现与多种癌症相关，并且可以通过抑制EGFR疗法(例如，施用EGFR抑制剂)来治疗患有此类肿瘤的患者。然而，这类治疗会引起严重的副作用(特别是在皮肤，五官和胃肠道)。据报道，超过50％的接受EGFR抑制剂治疗的患者会产生皮肤副作用(例如，参见Heidary等人，Journal of the American Academy of Dermatology，58(4):545，2008)，例如，皮疹。抑制EGFR疗法的皮疹会导致停药或剂量减少，并且会损害患者的生活质量。
现有技术中尚没有成功的治疗方案来控制与抗肿瘤剂相关的副作用。因此，目前迫切需要能够成功控制该等副作用的治疗方案。
发明内容
一方面，本申请提供了一种JAK抑制剂在制备药物中的用途，所述药物用于预防或者治疗受试者中与抗肿瘤剂相关的疾病或病症。
另一方面，本申请提供了一种药物组合物在制备药物中的用途，所述药物用于预防或者治疗受试者中与抗肿瘤剂相关的疾病或病症，其中所述药物组合物包含JAK抑制剂，及缓冲液。
另一方面，本申请提供了一种药物组合物在制备药物中的用途，所述药物用于预防或者治疗受试者中与抗肿瘤剂相关的疾病或病症，其中所述药物组合物包含JAK抑制剂，及赋形 剂。
在某些实施方式中，所述JAK抑制剂包括选自下组的一种或多种：JAK1抑制剂、JAK2抑制剂、JAK3抑制剂和TYK-2抑制剂。
在某些实施方式中，所述JAK抑制剂包括减少JAK表达的抑制剂，和/或降低JAK活性的抑制剂。
在某些实施方式中，所述JAK抑制剂直接作用于JAK蛋白和/或编码JAK蛋白的核酸。
在某些实施方式中，所述JAK抑制剂包括小分子JAK抑制剂、特异性结合JAK的蛋白大分子、抑制JAK蛋白表达的RNAi和/或抑制JAK蛋白表达的反义寡核苷酸。
在某些实施方式中，所述小分子JAK抑制剂包括与JAK可逆结合的小分子JAK抑制剂、与JAK不可逆结合的小分子JAK抑制剂和/或特异性结合突变型JAK的小分子JAK抑制剂。
在某些实施方式中，所述小分子JAK抑制剂具备小于或等于2000道尔顿、小于或等于1500道尔顿、小于或等于1200道尔顿、小于或等于1000道尔顿、小于或等于900道尔顿、小于或等于800道尔顿、小于或等于700道尔顿、小于或等于600道尔顿、小于或等于500道尔顿、小于或等于400道尔顿、小于或等于300道尔顿、小于或等于200道尔顿和/或小于或等于100道尔顿的分子量。
在某些实施方式中，所述JAK抑制剂包括芦可替尼(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、Ruxolitinib、Cucurbitacin I、CHZ868、TD-1473、zotiraciclib、alkotinib、jaktinib、AZD-4205、DTRMHS-07、KL130008、WXSH-0150、TQ05105、WXFL10203614、GLPG0634、CEP-33779、R348、itacitinib、ritlecitinib和/或brepocitinib。
在某些实施方式中，所述JAK抑制剂包括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/或AC-1101。
在某些实施方式中，所述JAK抑制剂包括Peficitinib hydrobromide、Fedratinib hydrochloride、Tasocitinib citrate、Ruxolitinib phosphate、INCB-039110 adipate、Momelotinib dihydrochloride、Upadacitinib tartrate、Jaktinib dihydrochloride monohydrate、Ivarmacitinib sulfate、Zotiraciclib citrate。
在某些实施方式中，所述JAK抑制剂包括至少含有一个芳香环或芳香杂环的化合物。
在某些实施方式中，所述JAK抑制剂包含式I所示的化合物或其药学上可接受的盐：
Figure PCTCN2021141972-appb-000001
式I，其中，X为N或C，Y为N或C，Z为N或C，Q为N或C，R1、R2和R3各自独立地选自下组：五元至六元芳香环、五元至六元芳香杂环、五元至六元环烷基环、五元至六元杂环烷基、氨基和酰胺基，其中，所述芳香环、芳香杂环、环烷基和/或杂环烷基任选地被取代基取代。
在某些实施方式中，式I的所述X为N，所述Y为C，所述Z为C，且所述Q为C。
在某些实施方式中，式I的所述X、Y、Z和Q均为N。
在某些实施方式中，式I的所述X为N，所述Y为N，所述Z为C，且所述Q为C。
在某些实施方式中，式I的所述X为C，所述Y为N，所述Z为C，且所述Q为N。
在某些实施方式中，式I的所述X为C，所述Y为C，所述Z为N，且所述Q为C。
在某些实施方式中，所述R 1和R 2各自独立地选自氢原子
Figure PCTCN2021141972-appb-000002
苯环、C 1-C 3烷基和
Figure PCTCN2021141972-appb-000003
其中，R 4选自环戊烷基、环丁烷基和吖丁啶基，所述取代基为哌啶、氰基、羰基、磺酰基，所述哌啶进一步被取代基取代，所述磺酰基进一步被烷基取代；所述R 5为C 1-C 6烷基，所述烷基进一步被氰基取代；
所述苯环任选地被酰基、卤素、羟基、C 1-C 3烷基取代，所述酰基和烷基进一步任选地被C 3-C 5环烷基、C 3-C 5杂环烷基或C 1-C 3烷基取代，所述环烷基、杂环烷基进一步任选地被C 1-C 3烷基取代；
所述R 10和R 11各自独立地选自氢原子、C 1-C 3烷基、或四元至十元环，且所述环是单环或双环，所述环进一步被氨基、磺酰基、羟基、炔基、酰基或C 1-C 3烷基取代，或，所述R 10 和R 11形成环。
在某些实施方式中，所述R 4为
Figure PCTCN2021141972-appb-000004
其中所述R 6选自-CF 3、-CHF 2、-CH 2F和-CH 3，其中所述R 7选自氢原子或氟原子。
在某些实施方式中，所述R 4选自环烷基、
Figure PCTCN2021141972-appb-000005
在某些实施方式中，所述R 1和R 2各自独立地选自氢原子或苯环，所述苯环任选地被酰基、卤素、羟基、C 1-C 3烷基取代，所述酰基进一步任选地被吖丁啶基取代，所述吖丁啶基进一步任选地被甲基取代。
在某些实施方式中，所述R 1和R 2各自独立地选自下组：氢原子、
Figure PCTCN2021141972-appb-000006
Figure PCTCN2021141972-appb-000007
Figure PCTCN2021141972-appb-000008
在某些实施方式中，所述R 3选自酰胺基和五元至十元的芳香环，所述芳香环可以是二环，且可以被环基或链基基团取代。
在某些实施方式中，述R 3为酰胺基，所述酰胺基任选地被环丁基或环丙基取代。
在某些实施方式中，所述R 3选自下组中的任意一种：
Figure PCTCN2021141972-appb-000009
Figure PCTCN2021141972-appb-000010
根在某些实施方式中，JAK抑制剂包含化合物I-1至I-15中的任意一种或多种：
Figure PCTCN2021141972-appb-000011
在某些实施方式中，所述JAK抑制剂包含式II所示的化合物：
Figure PCTCN2021141972-appb-000012
式II，其中，所述X和Y各自独立地选自C或N，且所述R 12、R 13、R 14各自独立地包含选自下组：氢、氕、氘、氚、C 1-C 5的烷基、卤素、烷氧基、氨基、酰胺基、磺酰胺基、链烷基、环烷基、杂环烷基、烯基、炔基、芳香基和杂芳香基。
在某些实施方式中，在式II所示化合物中，所述X为C，且所述Y为N。
在某些实施方式中，在式II所示化合物中，所述X为N，且所述Y为C。
在某些实施方式中，所述JAK抑制剂包含式II-a所示的结构：
Figure PCTCN2021141972-appb-000013
式II-a，其中，所述Ra 1和Ra 2包含任意价键允许地取代基，环A为任选地被Ra 3和/或Ra 5取代的芳香环或芳香杂环，所述Ra 3和Ra 5各自独立地选自：氢原子、环烷基、杂环烷基、芳基、杂芳基、烷氧基，或者，所述环A与-NH-之间包含甲基。
在某些实施方式中，所述Ra 1选自：氢原子、任选地被取代基取代的芳基、任选地被取代基取代的杂芳基，任选地被取代基取代的环烷基、任选地被取代基取代的杂环烷基，所述取代基包括氢、卤素、烷基、氰基、磺酰基、酰胺基。
在某些实施方式中，所述Ra 1选自四元至十元芳香环基、四元至十元芳香杂环基、四元至十元环烷基、四元至十元杂环烷基，所述环基进一步被酰胺基取代，所述酰胺基进一步被氰基、C 1-C 6烷基或五元至六元杂环基取代。
在某些实施方式中，所述Ra 1选自下组中的任意一个：
Figure PCTCN2021141972-appb-000014
在某些实施方式中，所述Ra 2选自：氢、C 1-C 3烷基和卤素。
在某些实施方式中，所述Ra 2选自：氢、甲基和氯。
在某些实施方式中，所述环A环选自苯环或咪唑环，所述苯环或咪唑环任选地被C 1-C 3烷基、五元至六元杂环烷基、五元至六元杂芳香基或卤素取代，所述烷基或环进一步被羟基 取代。
在某些实施方式中，所述Ra 3和Ra 5各自独立地选自下组：氢原子、甲基、甲氧基、
Figure PCTCN2021141972-appb-000015
在某些实施方式中，所述R 12、R 13、R 14各自独立地选自下组：
Figure PCTCN2021141972-appb-000016
Figure PCTCN2021141972-appb-000017
在某些实施方式中，所述JAK抑制剂包含化合物II-1至II-7中的一种或多种：
Figure PCTCN2021141972-appb-000018
在某些实施方式中，所述JAK抑制剂包含式III所示的结化合物：
Figure PCTCN2021141972-appb-000019
式III，其中所述R 15和R 16各自独立地选自氢原子、任选地被取代基取代的环烷基、任选地被取代基取代的杂环烷基、任选地被取代基取代的芳基和任选地被取代基取代的杂芳基，所述取代基选自：酰胺基、烷基、环烷基、杂环烷基、氰基、氨基、羟基和卤素。
在某些实施方式中，所述R 15或所述R 16为四元至十元杂环烷基，且所述杂环烷基任选地被酰胺基或C 1-C 6烷基取代，所述酰胺基进一步被C 1-C 6烷基取代，所述烷基进一步被卤素取代。
在某些实施方式中，所述R 15或所述R 16各自独立地为氢原子或
Figure PCTCN2021141972-appb-000020
其中，所述R 17和R 18各自独立地为C 1-C 6烷基，且所述烷基被卤素取代。
在某些实施方式中，述R 15和R 16各自独立地选自氢原子和
Figure PCTCN2021141972-appb-000021
在某些实施方式中，所述JAK抑制剂包含化合物III-1：
Figure PCTCN2021141972-appb-000022
在某些实施方式中，所述JAK抑制剂包含式IV所示的结构：
Figure PCTCN2021141972-appb-000023
式IV，其中，所述R 19和R 20各自独立地选自氢原子、硝基、四元至十元环烷基、四元至十元杂环烷基、四元至十元芳香基和四元至十元杂芳香基，其中所述硝基、环烷基、杂环烷基、芳香基、杂芳香基进一步任选地被氰基、烷基、环烷基、杂环烷基或 羟基取代。
在某些实施方式中，所述R 19为硝基，所述硝基任选地被取代的苯环取代。
在某些实施方式中，所述被取代的苯环被哌啶取代，所述哌啶进一步任选地被羟基取代。
在某些实施方式中，所述R 20为哌啶基，所述哌啶基任选地被C 1-C 3烷基取代，所述烷基进一步任选地被氰基或羟基取代。
在某些实施方式中，所述R 20为
Figure PCTCN2021141972-appb-000024
在某些实施方式中，所述JAK抑制剂包含化合物IV-1：
Figure PCTCN2021141972-appb-000025
在某些实施方式中，所述药物中所述JAK抑制剂的浓度为0.01％-10％。
在某些实施方式中，所述抗肿瘤剂包括小分子化合物、小分子偶联物、蛋白质和/或多核苷酸。
在某些实施方式中，所述抗肿瘤剂包括靶向治疗剂和/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。
在某些实施方式中，所述靶向治疗剂包括小分子化合物和/或抗体或其抗原结合片段。
在某些实施方式中，所述抗体包括单克隆抗体、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。
在某些实施方式中，所述抗原结合片段包括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、细胞表面和/或肿瘤微环境中的分子。
在某些实施方式中，所述靶向治疗剂靶向肿瘤细胞的蛋白质和/或核酸分子。
在某些实施方式中，所述靶向治疗剂靶向肿瘤抗原。
在某些实施方式中，所述靶向治疗剂靶向EGFR、ALK、MEK、VEGFR、FGFR、PDGFR、ABL、BTK、KIT、AKT、TORC、HER2、HER3、HER4、PI3K、CDK、JAK、ROS1、RET、MET、KRAS、BRAF、BCRP、NTRK、RAS、MSI、PR/ER、BCR/ABL、HDAC、FAK、PYK2、 CD20、PD-L1和/或BRCA1/2，或它们的突变体。
在某些实施方式中，所述靶向治疗剂包括激素疗法、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激酶抑制剂。
在某些实施方式中，所述靶向治疗剂为EGFR抑制剂、MEK抑制剂、ALK抑制剂、BTK抑制剂、PI3K抑制剂、AKT抑制剂、VEGFR抑制剂、mTOR抑制剂、HDAC抑制剂、KIT抑制剂、FGFR抑制剂、FAK抑制剂、BCRP抑制剂、EGFR/cMET抑制剂和/或SRC抑制剂，以及它们的组合。
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VEGFR抑制剂。
在某些实施方式中，所述VEGFR抑制剂选自下组：Sulfatinib、Anlotinib hydrochloride、Tivozanib、Lenvatinib、Apatinib、Intedanib、Ponatinib、Axitinib、Vandetanib、Pazopanib hydrochloride和/或Sorafenib。
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ALK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mTOR抑制剂选自下组：zotarolimus、sirolimus、everolimus和/或temsirolimus。
在某些实施方式中，所述靶向治疗剂为BTK抑制剂。
在某些实施方式中，所述BTK抑制剂选自下组：Orelabrutinib、Tirabrutinib hydrochloride、Zanubrutinib、Acalabrutinib、Ibrutinib、Dasatinib、Pirtobrutinib、Tolebrutinib、Rilzabrutinib、Fenebrutinib和/或Evobrutinib。
在某些实施方式中，所述靶向治疗剂为MEK抑制剂。
在某些实施方式中，所述MEK抑制剂选自下组：Selumetinib sulfate、Binimetinib、Cobimetinib、Trametinib和/或GSK-1120212。
在某些实施方式中，所述靶向治疗剂为PI3K抑制剂。
在某些实施方式中，所述PI3K抑制剂选自下组：Umbralisib、Alpelisib、Duvelisib、Copanlisib hydrochloride、Idelalisib、Zandelisib、Buparlisib、Enzastaurin hydrochloride、Paxalisib、Leniolisib、Rigosertib、Dactolisib、Nortriptyline和/或Parsaclisib。
在某些实施方式中，所述靶向治疗剂为AKT抑制剂。
在某些实施方式中，所述AKT抑制剂包括Ipatasertib。
在某些实施方式中，所述靶向治疗剂为EGFR/cMET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BRAF抑制剂选自下组：Tepotinib、Dabrafenib、Vemurafenib和/或encorafenib。
在某些实施方式中，所述靶向治疗剂包括BRAF抑制剂和MEK抑制剂。
在某些实施方式中，所述靶向治疗剂包括Dabrafenib和Trametinib。
在某些实施方式中，所述靶向CD20的靶向治疗剂为Rituximab。
在某些实施方式中，所述抗肿瘤剂为免疫治疗剂。
在某些实施方式中，所述免疫治疗剂能够改变受试者体内的免疫应答。
在某些实施方式中，所述免疫治疗剂能够增强受试者体内的免疫应答。
在某些实施方式中，所述免疫治疗剂为免疫检查点抑制剂、经修饰的免疫细胞和/或疫苗。
在某些实施方式中，所述免疫治疗剂为抗体。
在某些实施方式中，所述免疫治疗剂为PD-1抑制剂、PD-L1抑制剂和/或CTLA-4抑制剂。
在某些实施方式中，所述抗肿瘤剂选自下组：afatinib、dacomitinib、osimertinib、EAI045、gefitinib、almonertinib、pyrotinib、brigatinib、neratinib、olmutinib、bosutinib、icotinib、vandetanib、lapatinib、alflutinib、BPI-7711、mobocertinib、dovitinib、zorifertinib、varlitinib、orelabrutinib、tirabrutinib、zanubrutinib、acalabrutinib、ibrutinib、dasatinib、pirtobrutinib、tolebrutinib、rilzabrutinib、fenebrutinib、evobrutinib、selumetinib、binimetinib、cobimetinib、trametinib、regorafenib、GSK-1120212、alpelisib、duvelisib、copanlisib、idelalisib、nortriptyline、inavolisib、dactolisib、apitolisib、parsaclisib、buparlisib、rigosertib、enzastaurin、paxalisib、leniolisib、ipatasertib、zotarolimus、sirolimus、everolimus、temsirolimus、sorafenib、apatinib、lenvatinib、sunitinib、cabozantinib、axitinib、nintedanib、brivanib、vatalanib、fruquintinib、dabrafenib、vemurafenib、encorafenib、pazopanib、crizotinib、panobinostat、erlotinib、rituximab、panitumumab、cetuximab、Ticilimumab、Erfonrilimab、BA-3071、MEDI-5752、defactinib、Zalifrelimab、Cadonilimab、BCD-217、ipilimumab、Tremelimumab、Quavonlimab、atezolizumab、durvalumab、Camrelizumab、Tislelizumab、Sintilimab、Toripalimab、pembrolizumab、nivolumab、Amivantamab、MCLA-129、EMB-01、LY3164530、Roche Glycart anti-EGFR/cMet、Genentech Anti-met/EGFR、Samsung Anti-EGFR/cMet、Merck serono Anti-cmet/egfr和GB263，以及它们的组合。
在某些实施方式中，所述疾病或病症包括皮肤疾病或病症和/或皮下组织疾病或病症。
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，所述疾病或病症包括由两种或两种以上所述抗肿瘤剂联用相关的疾病或病症。
在某些实施方式中，所述疾病或病症包括由所述抗肿瘤剂与一种或多种其他疗法联用相关的疾病或病症。
在某些实施方式中，所述疾病或病症包括与EGFR异常相关的疾病或病症。
在某些实施方式中，所述疾病或病症包括与EGFR异常相关的皮疹。
在某些实施方式中，与EGFR异常相关的皮疹包括与EGFR被抑制相关的皮疹。
在某些实施方式中，与EGFR异常相关的皮疹包括免疫性皮疹和/或非免疫性皮疹。
在某些实施方式中，与EGFR异常相关的皮疹包括与EGFR异常相关的寻常痤疮(acne vulgaris)、与EGFR异常相关的玫瑰痤疮(acne rosacea)、与EGFR异常相关的瘙痒性皮疹(pruritus rash)、与EGFR异常相关的痤疮样皮疹(acneiform rash)与EGFR异常相关的蜂窝织炎(cellulitis)、与EGFR异常相关的莱姆病(Lyme disease)、与EGFR异常相关的过敏反应(allergic reaction)、与EGFR异常相关的化脓性汗腺炎(hidradenitis suppurativa)、与EGFR异常相关的麻疹(hives)、与EGFR异常相关的皮炎(dermatitis)、与EGFR异常相关的乳痂(cradle cap)、与EGFR异常相关的紫癜(purpura)、与EGFR异常相关的玫瑰糠疹(pityriasis rosea)、与EGFR异常相关的红斑(erythema)、与EGFR异常相关的带状疱疹(shingles)、与EGFR异常相关的瘀伤(bruise)和/或与EGFR异常相关的黄瘤(xanthelasma)、与EGFR异常相关的黑色素瘤(melanoma)、与EGFR异常相关的基底细胞癌(basal cell carcinoma)、与EGFR异常相关的鳞状细胞癌(squamous cell carcinoma)、与EGFR异常相关的卡波西氏肉瘤(Kaposi's sarcoma)、与EGFR异常相关的环形红斑离心(erythema annulare centrifugum)。
在某些实施方式中，所述皮疹的严重程度为依据NCI-CTCAE V5.0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，与EGFR被抑制相关的皮疹包括与施用EGFR抑制剂相关的皮疹。
在某些实施方式中，所述EGFR抑制剂包括用于治疗癌症的药物。
在某些实施方式中，所述EGFR抑制剂直接作用于EGFR蛋白和/或编码EGFR蛋白的核酸。
在某些实施方式中，所述EGFR抑制剂包括小分子EGFR抑制剂、特异性结合EGFR的蛋白大分子、抑制EGFR蛋白表达的RNAi和/或抑制EGFR蛋白表达的反义寡核苷酸。
在某些实施方式中，所述小分子EGFR抑制剂包括与EGFR可逆结合的小分子EGFR抑制剂、与EGFR不可逆结合的小分子EGFR抑制剂和/或特异性结合突变型EGFR的小分子EGFR抑制剂。
在某些实施方式中，所述EGFR抑制剂包括西妥昔单抗、吉非替尼、厄洛替尼、埃克替尼、Sapitinib、阿法替尼、拉帕替尼、凡德替尼、来那替尼、brigatinib、帕尼单抗、耐昔妥珠单抗、尼妥珠单抗、Tesevatinib、艾力替尼、席栗替尼、Rociletinib、卡奈替尼、AZD3759、YZJ-0318、萘普替尼、Naquotinib、PF-06747775、SPH1188-11、Poziotinib、依吡替尼、Varlitinib、艾氟替尼、HM61713、CK-101、吡咯替尼、莱洛替尼、HS-10296、AP32788、西莫替尼、GMA204、Virlitinib、Yinlitinib、那扎替尼、诺司替尼、奥莫替尼、奥希替尼、达克替尼、艾维替尼、EAI045、Lazertinib、Alflutinib、Mobocertinib、Savolitinib、Almonertinib、Trastuzumab、Tepotinib、Irbinitinib、Cemiplimab、Pyrotinib、Dacomitinib、Neratinib、Olmutinib、Mereletinib、Bosutinib、Icotinib、Vandetanib、Lapatinib、Befotertinib、Poziotinib、Larotinib、BPI-7711、SKLB-1028、Famitinib、Dovitinib和/或Zorifertinib。
在某些实施方式中，所述EGFR抑制剂与一种或多种其他疗法联用。
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，所述受试者曾经、正在和/或将来被施用所述EGFR抑制剂。
在某些实施方式中，所述药物基本上不影响所述EGFR抑制剂的治疗效果。
在某些实施方式中，所述药物被制备为适用于局部给药。
在某些实施方式中，所述局部给药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，所述药物被制备为适用于外用给药。
在某些实施方式中，所述药物被制备为适用于透皮给药。
在某些实施方式中，所述药物的给药形式包含乳膏、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，所述药物中还包括一种或多种其他活性成分。
另一方面，本申请提供了所述的JAK抑制剂在制备药物中的用途，所述药物用于预防或者治疗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JAK抑制剂在制备药物中的用途，所述药物用于预防或者治疗皮疹。
另一方面，本申请提供了一种预防或治疗与抗肿瘤剂相关的疾病或病症的方法，包括向有需要的受试者施用所述的JAK抑制剂。
另一方面，本申请提供了一种预防或治疗与EGFR异常相关的皮疹的方法，包括向有需要的受试者施用所述的JAK抑制剂。
在某些实施方式中，所述受试者曾经、正在和/或将来被施用EGFR抑制剂。
另一方面，本申请提供了一种预防或治疗抗肿瘤剂相关的疾病或病症的方法，包括向有需要的受试者施用所述的用途中的所述JAK抑制剂。
另一方面，本申请提供了一种预防或治疗皮疹的方法，包括向有需要的受试者施用所述的用途中的所述JAK抑制剂。
另一方面，本申请提供了药物组合或试剂盒，其包含：1)抗肿瘤剂；以及2)所述JAK抑制剂。
在某些实施方式中，所述抗肿瘤剂与所述JAK抑制剂彼此不混合。
在某些实施方式中，所述抗肿瘤剂与所述JAK抑制剂各自独立地存在于单独的容器中。
在某些实施方式中，所述JAK抑制剂被制备为适用于局部给药。
在某些实施方式中，所述局部给药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JAK抑制剂被制备为适用于外用给药。
在某些实施方式中，所述JAK抑制剂被制备为适用于透皮给药。
在某些实施方式中，所述JAK抑制剂被制备为乳膏、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，2)中的所述JAK抑制剂能够预防或治疗与施用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)中的所述JAK抑制剂基本上不影响1)中的所述抗肿瘤剂的治疗效果。
在某些实施方式中，在施用1)的所述抗肿瘤剂之前、同时或者之后施用2)的所述JAK 抑制剂。
另一方面，本申请提供了药物组合或试剂盒，其包含：1)EGFR抑制剂；以及2)所述JAK抑制剂。
在某些实施方式中，所述EGFR抑制剂与所述JAK抑制剂彼此不混合。
在某些实施方式中，所述EGFR抑制剂与所述JAK抑制剂各自独立地存在于单独的容器中。
在某些实施方式中，所述JAK抑制剂被制备为适用于局部给药。
在某些实施方式中，所述局部给药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JAK抑制剂被制备为适用于外用给药。
在某些实施方式中，所述JAK抑制剂被制备为适用于透皮给药。
在某些实施方式中，所述JAK抑制剂被制备为乳膏、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，2)中的所述JAK抑制剂能够预防或治疗与施用1)中的所述EGFR抑制剂相关的疾病或病症。
在某些实施方式中，2)中的所述JAK抑制剂基本上不影响1)中的所述EGFR抑制剂的治疗效果。
在某些实施方式中，在施用1)的所述EGFR抑制剂之前、同时或者之后施用2)的所述JAK抑制剂。
另一方面，本申请提供了一种方法，所述方法包括下述步骤：监测被施用抗肿瘤剂的受试者的疾病或病症；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疾病或病症时，向所述受试者施用所述用途中的所述JAK抑制剂,
在某些实施方式中，所述方法还包括继续监控所述抗肿瘤剂相关的疾病或病症，以及任选地减少或停用所述抗肿瘤剂。
在某些实施方式中，所述抗肿瘤剂相关的疾病或病症的严重程度在所述施用抗肿瘤剂之后增加。
在某些实施方式中，所述抗肿瘤剂不包含所述JAK抑制剂。
在某些实施方式中，施用所述抗肿瘤剂来治疗癌症。
在某些实施方式中，所述皮疹的患处与癌症的患处不同。
在某些实施方式中，向所述受试者局部施用所述JAK抑制剂。
在某些实施方式中，向所述受试者中基本不含癌细胞的部位局部施用所述JAK抑制剂。
在某些实施方式中，向所述受试者中的非癌症部位施用所述JAK抑制剂。
另一方面，本申请提供了一种方法，所述方法包括下述步骤：监测被施用EGFR抑制剂的受试者的皮疹；当所述监测显示所述受试者出现与施用所述EGFR抑制剂相关的皮疹时，向所述受试者施用所述用途中的所述JAK抑制剂,
在某些实施方式中，所述方法还包括继续监控所述皮疹，以及任选地减少或停用所述EGFR抑制剂。
在某些实施方式中，所述皮疹的严重程度在所述施用EGFR抑制剂之后增加。
在某些实施方式中，在所述施用EGFR抑制剂之前，所述受试者未患有所述皮疹。
在某些实施方式中，所述EGFR抑制剂不包含所述JAK抑制剂。
在某些实施方式中，施用所述EGFR抑制剂来治疗癌症。
在某些实施方式中，所述皮疹的患处与癌症的患处不同。
在某些实施方式中，向所述受试者局部施用所述JAK抑制剂。
在某些实施方式中，向所述受试者中基本不含癌细胞的部位局部施用所述JAK抑制剂。
在某些实施方式中，向所述受试者中的非癌症部位施用所述JAK抑制剂。
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：显示的是本申请所述EGFR抑制剂导致皮疹的大鼠模型左侧、背部和右侧的照片。
图2：显示了本申请实施例1中的对照组、JAK抑制剂组中典型大鼠的左侧、背部和右侧的照片。
图3：显示了本申请实施例1中的对照组、JAK抑制剂组的皮疹等级结果。
图4：显示了本申请实施例2中的对照组、JAK抑制剂组的皮疹等级结果。
图5：显示了本申请实施例3中的对照组、JAK抑制剂组中典型大鼠的左侧、背部和右 侧的照片。
图6：显示了本申请实施例3中的对照组、JAK抑制剂组的皮疹等级结果。
图7：显示了本申请实施例4中的对照组、JAK抑制剂组的皮疹等级结果。
图8：显示了本申请实施例5中的其他皮肤用药组、JAK抑制剂组中典型大鼠的左侧、背部和右侧的照片。
图9：显示了本申请实施例5中的其他皮肤用药组、JAK抑制剂组的皮疹等级结果。
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。
发明详述
用途
本申请提供了一种JAK抑制剂在制备药物中的用途，所述药物用于预防或者治疗受试者中与抗肿瘤剂相关的疾病或病症。
另一方面，本申请还提供了一种药物组合物在制备药物中的用途，所述药物用于预防或者治疗受试者中与抗肿瘤剂相关的疾病或病症，其中所述药物组合物包含JAK抑制剂，及缓冲液。
另一方面，本申请还提供了一种药物组合物在制备药物中的用途，所述药物用于预防或者治疗受试者中与抗肿瘤剂相关的疾病或病症，其中所述药物组合物包含JAK抑制剂，及赋形剂。
抗肿瘤剂相关的疾病或病症
本申请提供了一种预防或治疗抗肿瘤剂相关的疾病或病症的方法。在某些实施方式中，所述抗肿瘤剂相关的疾病或病症包括抗肿瘤剂相关的副作用。例如，所述抗肿瘤剂相关的疾病或病症可以指所述疾病或病症由施用一种或多种抗肿瘤剂后引起，所述疾病或病症在施用所述抗肿瘤剂之后产生或加重。
在没有预防或治疗实施的情况下，所述疾病或病症会在所述抗肿瘤剂施用约1小时后、约2小时后、约3小时后、约4小时后、约5小时后、约6小时后、约7小时后、约8小时后、约9小时后、约10小时后、约11小时后、约12小时后、约1天后、约2天后、约4天后、约7天后、约2周后、约3周后、约1个月后、约2个月后或更久后出现或加重
例如，所述抗肿瘤剂相关的疾病或病症可以包括皮肤疾病或病症。例如，所述抗肿瘤剂 相关的疾病或病症可以包括皮下组织疾病或病症。例如，所述抗肿瘤剂相关的疾病或病症可以包括脱发症、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。
例如，所述抗肿瘤剂相关的疾病或病症可以是皮疹。
例如，所述抗肿瘤剂相关的疾病或病症可以包括与抗肿瘤剂相关的脱发症、与抗肿瘤剂相关的体臭、与抗肿瘤剂相关的大疱性皮炎、与抗肿瘤剂相关的皮肤干燥、与抗肿瘤剂相关的湿疹、与抗肿瘤剂相关的多形性红斑、与抗肿瘤剂相关的红皮病、与抗肿瘤剂相关的脂肪萎缩症、与抗肿瘤剂相关的发色改变、与抗肿瘤剂相关的毛发质地异常、与抗肿瘤剂相关的多毛症(hirsutism)、与抗肿瘤剂相关的多汗症(hyperhidrosis)、与抗肿瘤剂相关的角化过度症、与抗肿瘤剂相关的肥大症(hypertrichosis)、与抗肿瘤剂相关的少汗症(hypohidrosis)、与抗肿瘤剂相关的脂肥大、与抗肿瘤剂相关的指甲改变、与抗肿瘤剂相关的指甲变色、与抗肿瘤剂相关的指甲丢失、与抗肿瘤剂相关的指甲***、与抗肿瘤剂相关的皮肤疼痛、与抗肿瘤剂相关的手足综合征、与抗肿瘤剂相关的光敏感性、与抗肿瘤剂相关的瘙痒症、与抗肿瘤剂相关的紫癜、与抗肿瘤剂相关的痤疮样皮疹、与抗肿瘤剂相关的斑丘疹、与抗肿瘤剂相关的头皮疼痛、与抗肿瘤剂相关的皮肤萎缩、与抗肿瘤剂相关的皮肤色素沉着过多(skin hyperpigmentation)、与抗肿瘤剂相关的皮肤色素减退(skin hypopigmentation)、与抗肿瘤剂相关的皮肤硬结、与抗肿瘤剂相关的皮肤溃疡、与抗肿瘤剂相关的Stevens-Johnson综合征、与抗肿瘤剂相关的皮下气肿、与抗肿瘤剂相关的毛细血管扩张、与抗肿瘤剂相关的中毒性表皮坏死、与抗肿瘤剂相关的皮疹和/或荨麻疹。
例如，所述抗肿瘤剂相关的疾病或病症可以包括EGFR异常相关的疾病或病症。例如，所述EGFR异常相关的疾病或病症可以包括EGFR异常相关的皮疹。
在本申请中，所述抗肿瘤剂可以包括小分子化合物、小分子偶联物、蛋白质(例如抗体)和/或多核苷酸(例如DNA或RNA)。
例如，所述抗肿瘤剂可以为靶向治疗剂。
例如，所述靶向治疗剂可以包括小分子化合物。例如，所述靶向治疗剂可以包括抗体或 其抗原结合片段。例如，所述抗体可以包括单克隆抗体、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。例如，所述抗原结合片段可以包括Fab，Fab’，F(ab )2，Fv片段，F(ab’) 2，scFv，di-scFv和/或dAb。例如，所述靶向治疗剂可以靶向肿瘤细胞内部、细胞表面和/或肿瘤微环境中的分子。例如，所述靶向治疗剂可以靶向肿瘤细胞的蛋白质和/或核酸分子。例如，所述靶向治疗剂可以靶向肿瘤抗原。例如所述靶向治疗剂可以靶向EGFR、ALK、MEK、VEGFR、FGFR、PDGFR、ABL、BTK、KIT、AKT、TORC、HER2、HER3、HER4、PI3K、CDK、JAK、ROS1、RET、MET、KRAS、BRAF、BCRP、NTRK、RAS、MSI、PR/ER、BCR/ABL、HDAC、FAK、PYK2、CD20、PD-L1和/或BRCA1/2，或它们的突变体。
例如，所述靶向治疗剂可以包括激素疗法、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。
例如，所述靶向治疗剂可以为酪氨酸激酶抑制剂。例如，所述靶向治疗剂可以为EGFR抑制剂、MEK抑制剂、ALK抑制剂、BTK抑制剂、PI3K抑制剂、AKT抑制剂、VEGFR抑制剂、mTOR抑制剂、HDAC抑制剂、KIT抑制剂、FGFR抑制剂、FAK抑制剂、BCRP抑制剂、EGFR/cMET抑制剂和/或SRC抑制剂，以及它们的组合。
例如，所述靶向治疗剂可以为EGFR抑制剂。例如，所述EGFR抑制剂包括小分子EGFR抑制剂、特异性结合EGFR的蛋白大分子、抑制EGFR蛋白表达的RNAi和/或抑制EGFR蛋白表达的反义寡核苷酸。例如，所述小分子EGFR抑制剂包括与EGFR可逆结合的小分子EGFR抑制剂、与EGFR不可逆结合的小分子EGFR抑制剂和/或特异性结合突变型EGFR的小分子EGFR抑制剂。例如，所述EGFR抑制剂包括西妥昔单抗、吉非替尼、厄洛替尼、埃克替尼、Sapitinib、阿法替尼、拉帕替尼、凡德替尼、来那替尼、brigatinib、帕尼单抗、耐昔妥珠单抗、尼妥珠单抗、Tesevatinib、艾力替尼、席栗替尼、Rociletinib、卡奈替尼、AZD3759、YZJ-0318、萘普替尼、Naquotinib、PF-06747775、SPH1188-11、Poziotinib、依吡替尼、Varlitinib、艾氟替尼、HM61713、CK-101、吡咯替尼、莱洛替尼、HS-10296、AP32788、西莫替尼、GMA204、Virlitinib、Yinlitinib、那扎替尼、诺司替尼、奥莫替尼、奥希替尼、达克替尼、艾维替尼、EAI045、Lazertinib、Alflutinib、Mobocertinib、Savolitinib、Almonertinib、Trastuzumab、Tepotinib、Irbinitinib、Cemiplimab、Pyrotinib、Dacomitinib、Neratinib、Olmutinib、Mereletinib、Bosutinib、Icotinib、Vandetanib、Lapatinib、Befotertinib、Poziotinib、Larotinib、BPI-7711、SKLB-1028、Famitinib、Dovitinib和/或Zorifertinib。
例如，所述靶向治疗剂可以为VEGFR抑制剂。例如，所述VEGFR抑制剂选自下组：Sulfatinib、Anlotinib hydrochloride、Tivozanib、Lenvatinib、Apatinib、Intedanib、Ponatinib、 Axitinib、Vandetanib、Pazopanib hydrochloride和/或Sorafenib。
例如，所述靶向治疗剂可以为FGFR抑制剂。
例如，所述靶向治疗剂可以为ALK抑制剂。
例如，所述靶向治疗剂可以为mTOR抑制剂。例如，所述靶向治疗剂可以为mTORC抑制剂。例如，所述靶向治疗剂可以为mTORC1抑制剂。例如，所述靶向治疗剂可以为mTORC2抑制剂。例如，所述mTOR抑制剂选自下组：zotarolimus、sirolimus、everolimus和/或temsirolimus。
例如，所述靶向治疗剂可以为BTK抑制剂。例如，所述BTK抑制剂选自下组：Orelabrutinib、Tirabrutinib hydrochloride、Zanubrutinib、Acalabrutinib、Ibrutinib、Dasatinib、Pirtobrutinib、Tolebrutinib、Rilzabrutinib、Fenebrutinib和/或Evobrutinib。
例如，所述靶向治疗剂可以为MEK抑制剂。例如，所述MEK抑制剂可以选自下组：Selumetinib sulfate、Binimetinib、Cobimetinib、Trametinib和/或GSK-1120212。
例如，所述靶向治疗剂可以为PI3K抑制剂。例如，所述PI3K抑制剂可以选自下组：Umbralisib、Alpelisib、Duvelisib、Copanlisib hydrochloride、Idelalisib、Zandelisib、Buparlisib、Enzastaurin hydrochloride、Paxalisib、Leniolisib、Rigosertib、Dactolisib、Nortriptyline和/或Parsaclisib。
例如，所述靶向治疗剂可以为AKT抑制剂。例如，所述AKT抑制剂可以为Ipatasertib。
例如，所述靶向治疗剂可以为EGFR/cMET抑制剂。
例如，所述靶向治疗剂可以为BRAF抑制剂。例如，所述BRAF抑制剂可以选自下组：Tepotinib、Dabrafenib、Vemurafenib和/或encorafenib。
例如，所述靶向治疗剂可以包括BRAF抑制剂和MEK抑制剂。例如，所述靶向治疗剂可以包括Dabrafenib和Trametinib。
例如，所述靶向CD20的治疗剂可以为Rituximab。
例如，所述靶向治疗剂可以包括EGFR抑制剂。例如，所述靶向治疗剂可以不包括EGFR抑制剂。
例如，所述抗肿瘤剂可以为免疫治疗剂。例如，所述免疫治疗剂能够改变受试者体内的免疫应答。例如，所述免疫治疗剂能够增强受试者体内的免疫应答。例如，所述免疫治疗剂可以为免疫检查点抑制剂、经修饰的免疫细胞和/或疫苗。例如，所述免疫治疗剂可以为抗体。例如，所述免疫治疗剂可以为PD-1抑制剂、PD-L1抑制剂和/或CTLA-4抑制剂。
例如，所述免疫治疗剂可以不包括EGFR抑制剂。
例如，所述抗肿瘤剂可以选自下组：afatinib、dacomitinib、osimertinib、EAI045、gefitinib、 almonertinib、pyrotinib、brigatinib、neratinib、olmutinib、bosutinib、icotinib、vandetanib、lapatinib、alflutinib、BPI-7711、mobocertinib、dovitinib、zorifertinib、varlitinib、orelabrutinib、tirabrutinib、zanubrutinib、acalabrutinib、ibrutinib、dasatinib、pirtobrutinib、tolebrutinib、rilzabrutinib、fenebrutinib、evobrutinib、selumetinib、binimetinib、cobimetinib、trametinib、regorafenib、GSK-1120212、alpelisib、duvelisib、copanlisib、idelalisib、nortriptyline、inavolisib、dactolisib、apitolisib、parsaclisib、buparlisib、rigosertib、enzastaurin、paxalisib、leniolisib、ipatasertib、zotarolimus、sirolimus、everolimus、temsirolimus、sorafenib、apatinib、lenvatinib、sunitinib、cabozantinib、axitinib、nintedanib、brivanib、vatalanib、fruquintinib、dabrafenib、vemurafenib、encorafenib、pazopanib、crizotinib、panobinostat、erlotinib、rituximab、panitumumab、cetuximab、Ticilimumab、Erfonrilimab、BA-3071、MEDI-5752、defactinib、Zalifrelimab、Cadonilimab、BCD-217、ipilimumab、Tremelimumab、Quavonlimab、atezolizumab、durvalumab、Camrelizumab、Tislelizumab、Sintilimab、Toripalimab、pembrolizumab、nivolumab、Amivantamab、MCLA-129、EMB-01、LY3164530、Roche Glycart anti-EGFR/cMet、Genentech Anti-met/EGFR、Samsung Anti-EGFR/cMet、Merck serono Anti-cmet/egfr和GB263，以及它们的组合。
在本申请中，所述抗肿瘤剂相关的疾病或病症可以包括由两种或两种以上所述抗肿瘤剂联用相关的疾病或病症。在本申请中，所述疾病或病症可以包括由所述抗肿瘤剂与一种或多种其他疗法联用相关的疾病或病症。在本申请中，所述疾病或病症可以包括与EGFR异常相关的疾病或病症。在本申请中，所述疾病或病症可以包括与EGFR异常相关的皮疹。
皮疹
本申请提供了一种预防或治疗皮疹的方法。本申请中使用的术语“皮疹”通常是指会影响皮肤颜色、外观或纹理的皮肤变化。皮疹可以仅局限在在身体的一部分，或影响整个皮肤。皮疹还可以包括荨麻疹。所述皮疹可以是免疫性皮疹和/或非免疫性皮疹。
例如，所述皮疹的病理表现可包括皮肤表皮生长和/或分化的明显改变、角质细胞终末分化的改变在、受影响和未受影响的皮肤中都可以看到致密的角膜塑形和表皮角化不全、皮脂腺和/或毛囊漏斗的损伤、有或无感染迹象、表皮屏障受损、表皮角膜下裂、细胞因子产生、炎性细胞浸润(如中性粒细胞、淋巴细胞)、细菌感染、毛细血管扩张、色素沉着和/或致密的上皮发炎性通透性。
例如，所述皮疹的临床表现可以为红斑、皮肤干燥、瘙痒、鳞状的斑块、压痛、灼热感、裂痕、脓疱、滤泡、溃疡、脓肿、红色凸起和/或脓性病变。
例如，所述皮疹的发生部位可以为表皮，例如，包括皮肤的脂溢性区域。例如，所述皮 疹的发生部位可以包括头皮、面部、颈部、胸部、上背部、四肢、下背部、腹部、臀部、牙周区域、腹部、手掌、脚掌、指甲和/或粘膜。
在本申请中，所述皮疹可以包括寻常痤疮(acne vulgaris)、丘疹性皮疹(papulopustular rash)玫瑰痤疮(acne rosacea)、瘙痒性皮疹(boil)、痤疮样皮疹(acneiform rash)蜂窝织炎(cellulitis)、莱姆病(Lyme disease)、过敏反应(allergic reaction)、化脓性汗腺炎(hidradenitis suppurativa)、麻疹(hives)、皮炎(dermatitis)、乳痂(cradle cap)、紫癜(purpura)、玫瑰糠疹(pityriasis rosea)、红斑(erythema)、带状疱疹(shingles)、瘀伤(bruise)和/或黄瘤(xanthelasma)、黑色素瘤(melanoma)、基底细胞癌(basal cell carcinoma)、鳞状细胞癌(squamous cell carcinoma)、卡波西氏肉瘤(Kaposi's sarcoma)、环形红斑离心(erythema annulare centrifugum)、毛囊炎、滤泡性丘疹、干燥病、干燥性湿疹和/或***脓疱疹。
皮疹的严重程度分级可以根据美国国家癌症研究所发布的常见不良事件术语标准(CTCAE)进行划分，该标准是癌症治疗临床试验和其他肿瘤学设置中的不良事件的标准分类和严重度的分级标准(NCI-CTCAE V5.0)。在一些实施方式中，所述上皮组织疾病的严重程度可以为依据NCI-CTCAE V5.0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。
EGFR功能异常
一方面，本申请提供了一种预防或治疗EGFR功能异常相关的皮疹的方法。在本申请中，术语“EGFR”通常是指表皮生长因子受体(Epidermal Growth Factor Receptor)，也称为ErbB1或HER1，其是由c-erbB1原癌基因编码的170kDa的跨膜糖蛋白。EGFR是受体酪氨酸激酶(RTK)的人表皮生长因子受体(HER)家族的成员，该家族还包括HER2(ErbB2)、HER3(ErbB3)和HER4(ErbB4)。EGFR信号通过配体结合引发，随后通过诱导受体与其他ErbB家族成员的构象变化、同二聚化或异二聚化、以及受体的反式自磷酸化等(参见，Ferguson等人，Annu Rev Biophys，37：353-73，2008)，来启动信号转导级联，从而最终影响多种细胞功能(例如，细胞增殖和存活)。EGFR的表达或其激酶活性的增加与一系列人类癌症相关(参见，Mendelsohn等人，Oncogene 19：6550-6565，2000；GrUnwald等人，J Natl Cancer Inst 95：851-67，2003；Mendelsohn等人，Semin Oncol 33：369-85，2006)。已知在众多癌症，如脑胶质瘤、乳腺癌、卵巢癌、子***等中发现了EGFR的表达升高。
在某些情形中，所述EGFR功能异常相关的皮疹包括与EGFR被抑制相关的皮疹。本申请中，术语“EGFR被抑制”包括任何原因导致的(例如，由治疗引起的或者由受试者自身身体状况造成的)EGFR活性、表达或者数量的降低。在一些实施方式中，EGFR被抑制通常是指 EGFR的活性或者数量降低至少10％。在一些实施方式中，EGFR被抑制通常是指EGFR的活性或者数量降低至少20％、40％、50％、80％、90％、95％或更多。在一些实施方式中，所述的降低是与同类受试者(例如，同样的正常人或者同类型的患者)中的标准值相比较的。在一些实施方式中，所述的降低是与相同受试者一段时间之前的数值相比较的。
在某些情形中，EGFR被抑制是由于施用了EGFR抑制剂。本申请中，术语“EGFR抑制剂”通常是指本领域中已知的或将来发现的任何EGFR抑制剂，包括任何当其被施用至受试者时，导致了受试者中与EGFR活性相关的生物活性的抑制(包括任何EGFR与其天然配体结合产生的下游生物效应的抑制)的任何物质。在一些实施方式中，EGFR抑制剂包括在治疗癌症过程中任何能够阻断EGFR活性或其任何下游生物效应的试剂。
可以通过本领域公知的方法来确定或筛选EGFR抑制剂，例如通过检测施用受试化合物之后EGFR表达水平的变化。检测EGFR的表达水平可以通过本领域公知的方法，例如，免疫组织化学方法、PCR、RT-PCR、原位杂交、Southern blot，Western blot，Northern blot、分光光度法和ELISA等。
例如，所述EGFR抑制剂可以被用于对所述受试者进行癌症治疗。本申请中，术语“癌症”通常是指任何由肿瘤或恶性细胞生长、增殖或转移所介导，并引发实体瘤和非实体瘤(例如，白血病)的医学状况。
例如，EGFR抑制剂可以通过与EGFR受体细胞内结构域直接结合阻断其激酶活性；或者占据了EGFR受体的配体结合位点或其一部分，从而使得EGFR受体与其天然配体无法接近而导致其生物活性降低或被阻断；或者通过调节EGFR多肽的二聚化或调节EGFR多肽与其他蛋白的相互作用，增加EGFR的泛素化和内吞降解，从而降低EGFR活性。
例如，EGFR抑制剂可以是EGFR的非特异性抑制剂，即，该等抑制剂除了抑制EGFR之外，还抑制其它的靶蛋白。
例如，EGFR抑制剂直接作用于EGFR蛋白或者编码EGFR蛋白的核酸。在一些实施方式中，EGFR抑制剂直接作用于EGFR蛋白。在本申请中当使用术语“直接作用于”来形容抑制剂与靶蛋白时，通常是指抑制剂与靶蛋白之间能够直接的、不需要通过其它分子的结合(包括共价结合和非共价结合)。
例如，EGFR抑制剂可以是小分子EGFR抑制剂、特异性结合EGFR的蛋白大分子(例如，抗体或其抗原结合片段)或者抑制EGFR蛋白表达的RNAi或者反义寡核苷酸。例如，EGFR抑制剂可以是小分子EGFR抑制剂或特异性结合EGFR的蛋白大分子(例如，抗体或其抗原结合片段)。
本申请中，术语“核酸”通常是指由单体核苷酸组成的多核苷酸分子。核酸包括核糖核酸(RNA)、脱氧核糖核酸(DNA)、单链核酸(ssDNA)、双链核酸(dsDNA)、小干扰核糖核酸(siRNA)和微RNA(miRNA)。多核苷酸的其他非限制性实例包括基因，基因片段，外显子，内含子，信使RNA(mRNA)，转移RNA，核糖体RNA，核酶，cDNA，shRNA，单链短或长RNA，重组多核苷酸，支链多核苷酸，质粒，载体，任何序列的分离的DNA，对照区，任何序列的分离的RNA，核酸探针和引物。核酸可以是直链或环状的。
本申请中，术语“RNAi”通常是指RNA干扰技术，是外源或内源双链RNA分子或小分子RNA通过靶向mRNA并将其特异性降解而抑制基因的表达或翻译的过程。
本申请中，术语“寡核苷酸”通常是指核糖核酸(RNA)或脱氧核糖核酸(DNA)或其任何模拟物或结构修饰的核酸的低聚物或聚合物。该术语包括由天然存在的核碱基、糖和共价核苷(主链)间键组成的寡核苷酸，以及具有类似功能的非天然存在的寡核苷酸。
本申请中，术语“反义寡核苷酸”通常是指具有允许与靶核酸的对应区域或片段至少一部分地杂交的核碱基序列的单链寡核苷酸。
本申请中，术语“小分子EGFR抑制剂”可以包括与EGFR可逆结合的小分子EGFR抑制剂(例如，吉非替尼、厄洛替尼、Sapitinib和埃克替尼)，与EGFR不可逆结合的小分子EGFR抑制剂(例如，阿法替尼、Dacomitinib、拉帕替尼(Lapatinib，例如
Figure PCTCN2021141972-appb-000026
GW572016GlaxoSmithKline)、凡德替尼(Vandetanib，例如ZACTIMATM，ZD6474)、乐伐替尼、卡奈替尼、伐利替尼和来那替尼)和/或特异性结合突变型EGFR的小分子EGFR抑制剂(例如，奥希替尼、那扎替尼、诺司替尼、奥莫替尼、艾维替尼和EAI045)。
特异性结合EGFR的蛋白大分子可以是针对EGFR的抗体、抗体变体、融合蛋白、衍生物或其片段。在一些实施方式中，特异性结合EGFR的蛋白大分子是特异性结合EGFR的抗体或其抗原结合片段。
本申请中使用的术语“特异性结合”当用于形容EGFR抑制剂时通常是指：在复杂混合物中该EGFR抑制剂可识别EGFR，所述抑制剂与EGFR的结合常数为其与其他非特异性结合蛋白的结合常数的至少2倍。
在某些情形中，所述EGFR抑制剂可以与一种或多种其他癌症治疗法联用。所述其他癌症治疗法可以是本领域中常规用于治疗癌症的方法，例如细胞毒抗癌剂、免疫治疗抗癌剂或激素治疗抗癌剂。根据本申请，用于癌症治疗的药物也可以与放射治疗或手术组合使用。在一些实施方式中，在将EGFR抑制剂和其他抗癌剂组合使用的情况下，它们可以同时施用于受试者，或者以一定间隔分开施用。
EGFR功能异常相关的皮疹
本申请所述的皮疹可以是与EGFR功能异常相关的皮疹。在某些实施方式中，本申请所述的皮疹可以是与EGFR被抑制相关的皮疹。在某些实施方式中，本申请所述的皮疹可以是与EGFR抑制剂相关的皮疹。在某些实施方式中，本申请所述的皮疹可以是在施用EGFR抑制剂之后发生的皮疹。
在本申请中，所述与EGFR功能异常相关的皮疹可以包括与EGFR功能异常相关的寻常痤疮(acne vulgaris)、与EGFR功能异常相关的丘疹性皮疹(papulopustular rash)与EGFR功能异常相关的玫瑰痤疮(acne rosacea)、与EGFR功能异常相关的瘙痒性皮疹(pruritus rash)、与EGFR功能异常相关的痤疮样皮疹(acneiform rash)与EGFR功能异常相关的蜂窝织炎(cellulitis)、与EGFR功能异常相关的莱姆病(Lyme disease)、与EGFR功能异常相关的过敏反应(allergic reaction)、与EGFR功能异常相关的化脓性汗腺炎(hidradenitis suppurativa)、与EGFR功能异常相关的麻疹(hives)、与EGFR功能异常相关的皮炎(dermatitis)、与EGFR功能异常相关的乳痂(cradle cap)、与EGFR功能异常相关的紫癜(purpura)、与EGFR功能异常相关的玫瑰糠疹(pityriasis rosea)、与EGFR功能异常相关的红斑(erythema)、与EGFR功能异常相关的带状疱疹(shingles)、与EGFR功能异常相关的瘀伤(bruise)和/或与EGFR功能异常相关的黄瘤(xanthelasma)、与EGFR功能异常相关的黑色素瘤(melanoma)、与EGFR功能异常相关的基底细胞癌(basal cell carcinoma)、与EGFR功能异常相关的鳞状细胞癌(squamous cell carcinoma)、与EGFR功能异常相关的卡波西氏肉瘤(Kaposi's sarcoma)、与EGFR功能异常相关的环形红斑离心(erythema annulare centrifugum)、与EGFR功能异常相关的毛囊炎、与EGFR功能异常相关的滤泡性丘疹、与EGFR功能异常相关的干燥病、与EGFR功能异常相关的干燥性湿疹和/或与EGFR功能异常相关的***脓疱疹。
JAK抑制剂
本申请提供了一种预防或治疗皮疹的方法，所述方法包括施用JAK抑制剂。
在本申请中，术语“JAK抑制剂”通常是指减少詹纳斯激酶1(JAK1)、詹纳斯激酶2(JAK2)、詹纳斯激酶3(JAK3)或非受体蛋白酪氨酸激酶2(TYK-2)的表达和/或JAK1、JAK2、JAK3和TYK-2中的至少一种的激酶活性的试剂。在某些情形中，所述JAK抑制剂可以减少JAK1的表达。在某些情形中，所述JAK抑制剂可以减少JAK2的表达。在某些情形中，所述JAK抑制剂可以减少JAK3的表达。在某些情形中，所述JAK抑制剂可以减少TYK-2的表达。
在某些情形中，所述JAK抑制剂可以减少JAK1的激酶活性。在某些情形中，所述JAK 抑制剂可以减少JAK2的激酶活性。在某些情形中，所述JAK抑制剂可以减少JAK3的激酶活性。在某些情形中，所述JAK抑制剂可以减少TYK-2的激酶活性。在某些情形中，所述JAK抑制剂可以减少JAK1、JAK2、JAK3和TYK2的激酶活性。在某些情形中，所述JAK抑制剂可以减少JAK1、JAK2、JAK3和TYK2中的2种或2种以上(例如，3或4种)的激酶活性。在某些情形中，所述JAK抑制剂可以减少单个JAK亚型(例如，JAK1、JAK2、JAK3或TYK2)的激酶活性。在某些情形中，所述JAK抑制剂可以减少JAK1和JAK2的激酶活性。在某些情形中，所述JAK抑制剂可以减少JAK1和JAK3的激酶活性。在某些情形中，所述JAK抑制剂可以减少JAK2和JAK3的激酶活性。在某些情形中，所述JAK抑制剂可以减少JAK1、JAK2和JAK3的激酶活性。
在本申请中，所述JAK抑制剂可以包括抑制性核酸。在某些情形中，所述JAK抑制剂可以包括反义核苷酸、核糖酶、小干扰RNA、小发夹RNA或微小RNA。在本申请中，可以减少哺乳动物细胞中的JAK1、JAK2、JAK3或TYK2mRNA的表达的抑制性核酸可以在体外合成。这些核苷酸可以使用本领域已知的程序通过化学合成和酶结合反应来构建，并且可以是带有修饰的。
在本申请中，所述JAK抑制剂可以包括特异性结合JAK的蛋白大分子。特异性结合JAK的蛋白大分子可以是针对JAK的抗体、抗体变体、融合蛋白、衍生物或其片段。在一些实施方式中，特异性结合JAK的蛋白大分子是特异性结合JAK的抗体或其抗原结合片段。
本申请中使用的术语“特异性结合”当用于形容JAK抑制剂时通常是指：在复杂混合物中该JAK抑制剂可识别JAK，所述抑制剂与JAK的结合常数为其与其他非特异性结合蛋白的结合常数的至少2倍。
在本申请中，所述JAK抑制剂可以包括小分子JAK抑制剂。所述小分子JAK抑制剂包括与JAK可逆结合的小分子JAK抑制剂、与JAK不可逆结合的小分子JAK抑制剂和/或特异性结合突变型JAK的小分子JAK抑制剂。
在某些实施方式中，JAK抑制剂可以包括JAK1和JAK2抑制剂。例如，JAK1和JAK2抑制剂可以包括，例如，鲁索替尼(INCB018424)、baricitinib(INCB028050或LY3009104)、AZD1480、filgotinib(GLPG0634或G146034)和/或莫罗替尼(momelotinib)(GS-0387或CYT387)。
在某些实施方式中，JAK抑制剂可以包括JAK1抑制剂。例如,JAK1抑制剂可包括例如，GSK2586184、奥拉替尼(oclacitinib)(PF03394197)、乌帕替尼(upadacitinib)、GLG0778、INCB039110、PF04965842和/或SAR-20347。
在某些实施方式中，JAK抑制剂可以包括JAK2抑制剂。例如，所述JAK2抑制剂可以包括，例如，CEP-33779、fedratinib(TG101348,SAR302503)、来他替尼(lestaurtinib)(CEP-701)、帕瑞替尼(pacritinib)(SB1518、BMS-911543、XL019、(LY-2784544)、R723和/或Z3。
在某些实施方式中，JAK抑制剂可以包括JAK3抑制剂。例如所述JAK3抑制剂可以包括，例如，得克替尼(decernotinib)(VX-509)、R348、R256、INCB047986、INCB16562、NVP-BSK805、peficitinib(ASP015K或JNJ-54781532)、托法替尼(tofacitinib)(CP-690,500)、葫芦素I(JSI-124)和/或CHZ868。
在某些实施方式中，JAK抑制剂可以包括TYK2抑制剂。例如，所述TYK2抑制剂可包括，例如，Ndi-031301、BMS-986165、SAR-20347、(4-甲氧基苄烯)丙二腈(tyrphostin A1)和/或***吡啶(US 2013/0143915)。
在某些实施方式中，JAK抑制剂可以包括泛JAK抑制剂。在本申请中，术语“泛JAK抑制剂”通常是指当使用相似的试验条件(例如相同的试验条件)对野生型人类JAK1、野生型人类JAK2、和野生型人类JAK3测定IC 50时，对于人类JAK1、人类JAK2、人类JAK3亚型中的每一个具有约500nM至4μM(例如，约500nM至约2μM)的IC 50的试剂。例如，泛JAK抑制剂可以是当每个IC50值在相似的试验条件下试验(例如，相同的试验，例如Kim等,J.Med.Chem.58(18):7596-5602,2015中描述的野生型人类JAK1、野生型人类JAK2、和野生型人类JAK3试验)时，对于野生型人类JAK1、野生型人类JAK2、和野生型人类JAK3具有在彼此的±10％内的IC 50的试剂。
在某些实施方式中，泛JAK抑制剂可以包括，例如，托法替尼(tofacitinib或CP-690550)、赛度替尼(cerdulatinib)、吡啶酮6(P6)、PF-06263276、JAK抑制剂1(CAS 457081-03-07)和/或巴瑞替尼。
在某些实施方式中，JAK抑制剂可以包括选择性JAK1/JAK3抑制剂。在本申请中，术语“选择性JAK1/JAK3抑制剂”通常是指指当使用相似的试验条件对野生型人类JAK1、野生型人类JAK2和野生型人类JAK3的每一个测定IC50时(例如，相同的试验，例如Kim等,J.Med.Chem.58(18):7596-5602,2015中描述的野生型人类JAK1、野生型人类JAK2、和野生型人类JAK3试验)，对于野生型人类JAK1和野生型JAK3各自具有比野生型人类JAK2的IC50至少低5倍(例如至少10倍或至少20倍)的IC50的试剂。
在某些实施方式中，JAK抑制剂可以包括选择性JAK1抑制剂。在本申请中，“选择性JAK1抑制剂”通常是指当使用相似的试验条件测量时(例如，相同的试验，例如Kim等,J.Med.Chem.58(18):7596-5602,2015中描述的野生型人类JAK1、野生型人类JAK2、和野生 型人类JAK3试验)，对于野生型人类JAK1具有比对于野生型人类JAK2的IC50和对于野生型人类JAK3的IC50的每一个低至少10倍(例如，至少20倍)的IC50的试剂。
在某些实施方式中，JAK抑制剂可以包括选择性JAK2抑制剂。在本申请中，“选择性JAK2抑制剂”通常是指当使用相似的试验条件测量时(例如，相同的试验，例如Kim等,J.Med.Chem.58(18):7596-5602,2015中描述的野生型人类JAK1、野生型人类JAK2、和野生型人类JAK3试验)，对于野生型人类JAK2具有比对于野生型人类JAK1的IC50和对于野生型人类JAK3的IC50的每一个低至少10倍(例如，至少20倍)的IC50的试剂。
在本申请中，所述JAK抑制剂可以具备小于或等于2000道尔顿、小于或等于1500道尔顿、小于或等于1200道尔顿、小于或等于1000道尔顿、小于或等于900道尔顿、小于或等于800道尔顿、小于或等于700道尔顿、小于或等于600道尔顿、小于或等于500道尔顿、小于或等于400道尔顿、小于或等于300道尔顿、小于或等于200道尔顿和/或小于或等于100道尔顿的分子量。
在本申请中，所述JAK抑制剂可以包括芦可替尼(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、R348、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/或AC-1101。
在本申请中，所述JAK抑制剂可以包括Peficitinib hydrobromide、Fedratinib hydrochloride、Tasocitinib citrate、Ruxolitinib phosphate、INCB-039110 adipate、Momelotinib dihydrochloride、Upadacitinib tartrate、Jaktinib dihydrochloride monohydrate、Ivarmacitinib sulfate和/或Zotiraciclib citrate。
式I、式II和式III所示的化合物
在本申请中，术语“烷基”通常指包含1-20个碳原子的直链或支链饱和烃基取代基(例如，通过除去氢而从烃中获得的取代基)；例如1-12个碳原子；在另一些实施方案中，碳原子数为1-10；在另一些实施方案中，为1-6个碳原子，在另一些实施方案中，为1-4个碳原子(比如1，2，3或更多碳原子)。取代基的实例包括：例如，甲基、乙基、丙基(包括正丙基和异丙基)，丁基(包括正丁基，异丁基，仲丁基和叔丁基)，戊基，异戊基，己基等。在某些情况下，烃基取代基(即烷基，烯基，环烷基，芳基等)中的碳原子数用前缀“C a-C b”表示，其中a为最小，b为最大的取代基中的碳原子数。因此，例如，“C 1-C 6烷基”是指含有1至6个碳原子的烷基取代基，可包括直链或支链的甲基、乙基、丙基、丁基、戊基和己基。
在本申请中，术语“环烷基”通常指通过从饱和碳环分子中除去氢并具有3-14个碳原子的碳原子而获得的碳环取代基。在一些实施方案中，一个环烷基取代基具有3-10个碳原子。环烷基可以是单环，其通常包含4-7个环原子。环烷基包括环丙基、环丁基、环戊基和环己基。环烷基也可以是稠合在一起的2-3个环，也可以称为“双环烷基”。在本申请中，术语“环烷基”还包括稠合至C 6-C 10芳环或5-10元杂芳族环的取代基，其中具有这种稠合的环烷基作为取代基的基团结合至环烷基的碳原子上。当这种稠合的环烷基被一个或多个取代基取代时，除非另有说明，一个或多个取代基各自键合至环烷基的碳原子上。稠合的C 6-C 10芳环或5-10元杂芳环可任选被进一步取代。
在本申请中，术语“烯基”通常是指含有至少一个碳-碳双键的直链和支链脂肪族烃基。“C 1-C 6烯基”是指含有1至6个碳原子的烯基取代基，可包括直链或支链的乙烯基、丙烯基、丁烯基、戊烯基和己烯基。在本申请中，术语“炔基”通常是指含有至少一个碳-碳三键的直链和支链脂肪族烃基。“C 1-C 6炔基”是指含有1至6个碳原子的炔基取代基，可包括直链或支链的乙炔基、丙炔基、丁炔基、戊炔基和己炔基。
在本申请中，术语“氘”通常指氢的一种稳定形态同位素，又称重氢，元素符号一般为D或 2H。它的原子核由一个质子和一个中子组成。在本申请中，术语“羟基”通常指化学式为-OH的基团。在本申请中，术语“氨基”通常指化学式为-NH 2的基团。在本申请中，术语“氰基”通常指化学式为-CN的基团。在本申请中，术语“硝基”通常指硝酸分子中去掉一个羟基后剩下的基团。在本申请中，术语“卤素”通常包括氟、氯、溴和碘。在本申请中，术语“氢”通常指氢取代基，可能被描述为-H。在本申请中，术语“氧”通常指氧取代基，可能被描述为-O-。
在本申请中，术语“取代基”“自由基”和“基团”可以互换使用。
如果取代基被描述为是“任选地被取代”，则该取代基可以是：(1)未取代的或(2)取代 的。如果取代基的碳被描述为任选地被一个或多个取代基取代，则该碳上的一个或多个氢(就存在的程度而言)可以分别和/或一起被独立选择的任选取代基取代。如果取代基的氮被描述为任选地被一个或多个取代基取代，则该氮上的一个或多个氢(就存在的程度而言)可以各自被独立选择的任选取代基取代。一个示例性的取代基可以被描述为–NR’R”，其中R’和R”与它们所连接的氮原子一起可以形成包含1或2个独立地选自氧、氮和硫的杂原子的杂环，其中所述杂环烷基部分可以任选地被取代。由R’和R”与它们所连接的氮原子一起形成的杂环可以是部分或完全饱和的，或者是芳香族的。
在本申请中，术语“式I(或式II、式III)”可以称为“式I(或式II、式III)化合物”，“式I(或式II、式III)所示的化合物”。这样的术语也被定义为包括式I(或式II、式III)化合物的所有形式，包括水合物，溶剂合物，异构体，结晶和非结晶形式，同晶型，多晶型和代谢物。例如，式I(或式II、式III)化合物或其药学上可接受地盐，可以未溶剂化和溶剂化地形式存在。当溶剂或水的结合力较强时，配合物具有明确地化学计量，其不受湿度影响。但是，当溶剂或水的结合力较弱时，例如在通道溶剂化物和吸湿性化合物中，水/溶剂的含量将取决于湿度和干燥条件，在这种情况下，非化学计量是常态。
“式I(或式II、式III)化合物”可具有不对称碳原子。在本申请中，式I(或式II、式III)化合物的碳-碳键可用实线，实心楔形或点状楔形表示。使用实线描绘与不对称碳原子的键表示包括该碳原子上的所有可能的立体异构体(例如特定对映异构体，外消旋混合物等)。本申请的化合物可能包含一个以上的不对称碳原子。在这些化合物中，使用实线表示与不对称碳原子的键意在表明所有可能的立体异构体均应包括在内。例如，除非另有说明，否则意指式I(或式II、式III)化合物可以对映体和非对映体或作为外消旋体和混合物存在。表示使用实线描绘与式I(或式II、式III)化合物中一个或多个不对称碳原子的键，以及使用实心或虚线楔形描述与同一化合物中其他不对称碳原子的键表明存在非对映异构体的混合物。
本申请的化合物可以以包合物或其他配合物的形式存在。在本发明的范围内包括复合物，例如包合物，药物-宿主包合复合物，其中与上述溶剂化物相反，药物和主体以化学计量或非化学计量的量存在。还包括式I(或式II、式III)的配合物，其含有两种或更多种可以化学计量或非化学计量的有机和/或无机组分。所得的络合物可以被电离，部分被电离或未被电离。
式I(或式II、式III)的立体异构体包括顺式和反式异构体，光学异构体，例如R和S对映异构体，非对映异构体，几何异构体，旋转异构体，构象异构体和互变异构体，式I(或式II、式III)化合物，包括表现出一种以上类型异构性的化合物；及其混合物(例如外消旋体和非对映体对)。还包括其中抗衡离子具有旋光性的酸加成盐或碱加成盐，例如D-乳酸酯 或L-赖氨酸，或外消旋体，例如DL-酒石酸酯或DL-精氨酸。
当任何外消旋物结晶时，可能有两种不同类型的晶体。第一类是上述外消旋化合物(真正的外消旋体)，其中产生了一种均质形式的晶体，其中含有等摩尔量的两种对映异构体。第二类是外消旋混合物或团聚体，其中以等摩尔量产生两种形式的晶体，每种形式包含单个对映体。
式I(或式II、式III)化合物可以表现出互变异构现象和结构异构现象。例如，式I(或式II、式III)化合物可以几种互变异构形式存在，包括烯醇和亚胺形式，以及酮和烯胺形式，以及几何异构体及其混合物。所有这些互变异构形式都包括在式I(或式II、式III)化合物的范围内。互变异构体以互变异构体的混合物形式存在于溶液中。在固体形式中，通常一个互变异构体占主导。即使可以描述一个互变异构体，本发明也包括式I(或式II、式III)化合物的所有互变异构体。
本发明还包括同位素标记的化合物，其与式I(或式II、式III)中所述相同，但其一个或多个原子被具有不同于自然界已发现的原子质量或质量数的原子取代。可加入式I(或式II、式III)化合物的同位素包括氢，碳，氮，氧，磷，氟和氯的同位素，例如但不限于： 2H、 3H、 13C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。某些同位素标记的式I(或式II、式III)化合物，例如其中加入放射性同位素(如 3H和 14C)，由于其易于制备和可检测性，可用于药物和/或底物组织分布测定。较重的同位素如 2H，由于其较大的代谢稳定性，例如在体内半衰期延长或剂量要求降低，可以提供某些治疗上的优势。同位素标记的式I(或式II、式III)化合物通常可通过用同位素标记的试剂代替非同位素标记的试剂制备。
本申请的化合物可以以衍生自无机或有机酸的盐的形式使用。某些化合物由于具有一种或多种盐的物理性质，具有如在不同温度和湿度下增强的药物稳定性，或在水/油中的所需溶解度的优势。在某些情况下，化合物的盐也可以用作化合物的分离，纯化和/或解析的助剂。
在本申请中，对于化学式中的基团，其中的
Figure PCTCN2021141972-appb-000027
代表连接位点。
在本申请中，所述JAK抑制剂包含式I所示的化合物或其药学上可接受的盐：
Figure PCTCN2021141972-appb-000028
式I，其中，X可以为N或C，Y可以为N或C，Z可以为N或C，且R 1、R 2和R 3可以各自独立地选自下组：五元至六元芳香环、五元至六元芳香杂环、五元至六元环烷基环、五元至六元杂环烷基、氨基和酰胺基，其中，所述芳香环、芳香杂环、 环烷基和/或杂环烷基任选地被取代基取代。
在本申请中，所述式I所示的化合物中，所述X可以为N，所述Y可以为C，所述Z可以为C，且所述Q可以为C。
在本申请中，所述式I所示的化合物中，所述X、Y、Z和Q可以均为N。
在本申请中，所述式I所示的化合物中，所述X可以为N，所述Y可以为N，所述Z可以为C，且所述Q可以为C。
在本申请中，所述式I所示的化合物中，所述X可以为C，所述Y可以为N，所述Z可以为C，且所述Q可以为N。
在本申请中，所述式I所示的化合物中，所述X可以为C，所述Y可以为C，所述Z可以为N，且所述Q可以为C。
在本申请中，所述式I所示的化合物中的R 1和R 2可以各自独立地为氢原子或
Figure PCTCN2021141972-appb-000029
其中，R 4可以选自环戊烷基、环丁烷集和吖丁啶基，所述取代基为哌啶、氰基、羰基、磺酰基，所述哌啶可以进一步被取代基取代，所述磺酰基进一步被烷基取代。
例如，所述R4可以为
Figure PCTCN2021141972-appb-000030
其中所述R6可以选自-CF 3、-CHF 2、-CH 2F和-CH 3。其中所述R7可以选自氢原子或氟原子。
例如，所述R4可以选自环烷基、被氰基取代的环丁基、被磺酰基取代的吖丁啶基和
Figure PCTCN2021141972-appb-000031
例如，所述R4可以选自环烷基、
Figure PCTCN2021141972-appb-000032
在
Figure PCTCN2021141972-appb-000033
中，所述R 5可以为-C-CN。
在本申请中，所述JAK抑制剂可以包括式I所示的化合物，其中，所述R1和R2可以各自独立地选自氢原子、
Figure PCTCN2021141972-appb-000034
Figure PCTCN2021141972-appb-000035
在本申请中，所述R1和R2可以各自独立地选自氢原子或苯环，所述苯环可以任选地被酰基、卤素、羟基、C1-C3烷基取代，所述酰基和烷基可以进一步任选地被C3-C5环烷基、C3-C5杂环烷基或C1-C3烷基取代，所述环烷基、杂环烷基可以进一步任选地被C1-C3烷基取代。
例如，R1和R2可以各自独立地选自氢原子或苯环，所述苯环可以任选地被酰基、卤素、羟基、C1-C3烷基取代，所述酰基可以进一步任选地被吖丁啶基取代，所述吖丁啶基可以进一步任选地被甲基取代。
例如，R1和R2可以各自独立地选自氢原子、
Figure PCTCN2021141972-appb-000036
在本申请中，所述R1和R2可以各自独立地选自氢原子、C1-C3烷基和
Figure PCTCN2021141972-appb-000037
其 中所述R10和R11可以各自独立地选自氢原子、C1-C3烷基、或四元至十元环，所述环可以任选地被取代基取代，且所述环可以是单环或双环，所述环可以进一步被氨基、磺酰基、羟基、炔基、酰基或C1-C3烷基取代。
其中，所述R10和R11可以成环。
例如，所述R1和R2可以各自独立地选自氢原子、甲基、
Figure PCTCN2021141972-appb-000038
Figure PCTCN2021141972-appb-000039
在本申请中，所述R1可以是
Figure PCTCN2021141972-appb-000040
且所述R2可以是
Figure PCTCN2021141972-appb-000041
在本申请中，所述R1可以是
Figure PCTCN2021141972-appb-000042
且所述R2可以是
Figure PCTCN2021141972-appb-000043
在本申请中，所述R1可以是氢原子，且所述R2可以选自
Figure PCTCN2021141972-appb-000044
Figure PCTCN2021141972-appb-000045
Figure PCTCN2021141972-appb-000046
在本申请中，所述R1和所述R2可以均为氢原子。
在本申请中，所述JAK抑制剂可以包括式I所示的化合物，其中，所述R3可以选自酰胺基和五元至十元的芳香环(例如，六元杂芳香环或九元杂芳香环)，所述芳香环可以是二环，且可以被环基或链基基团取代。
例如，所述R3可以为酰胺基，所述酰胺基可以任选地被环丁基或环丙基取代，例如，所述R3可以为
Figure PCTCN2021141972-appb-000047
例如，所述R3可以为
Figure PCTCN2021141972-appb-000048
其中，所述R6可以为
Figure PCTCN2021141972-appb-000049
其中，所述R7可以选自-CF3、-CH2F、-CH2F和-CH3，且R8可以选自C1-C3烷基。例如，所述R7可以为-CF3，且所述R8可以为乙基。
又例如，所述R3可以为
Figure PCTCN2021141972-appb-000050
其中，所述R9可以为六元杂环或六元芳香环，所述环可以进一步被C1-C3烷基取代。例如，所述R9可以选自
Figure PCTCN2021141972-appb-000051
Figure PCTCN2021141972-appb-000052
在本申请中，所述JAK抑制剂可以包括式I所示的化合物，其中，所述式I所示的化合物可以包含化合物I-1至I-15中的任意一种或多种：
Figure PCTCN2021141972-appb-000053
在本申请中，所述JAK抑制剂可以包含式II所示的化合物：
Figure PCTCN2021141972-appb-000054
式II，其中，
所述X和Y可以各自独立地选自C或N，且所述R12、R13、R14可以各自独立地包含选自下组：氢、氕、氘、氚、C1-C5的烷基、卤素、烷氧基、氨基、酰胺基、磺酰胺基、链烷基、环烷基、杂环烷基、烯基、炔基、芳基和杂芳基。
例如，在式II所示的化合物中，所述X可以为C，且所述Y可以为N；或者所述X可以为N，且所述Y可以为C。
在本申请中，所述JAK抑制剂可以包含式II-a所示的化合物：
Figure PCTCN2021141972-appb-000055
式II-a，其中，所述R a1和R a2可以包含任意价键允许地取代基，环A可以为任选地被R a3和/或R a5取代的芳香环或芳香杂环，所述R a3和R a5可以各自独立地选自：氢原子、环烷基、杂环烷基、芳基、杂芳基、烷氧基，或者，所述环A与-NH-之间包含甲基。
例如，所述Ra1可以选自四元至十元芳香环基、四元至十元芳香杂环基、四元至十元环烷基、四元至十元杂环烷基，所述环基可以进一步被酰胺基或磺酰基取代，所述磺酰基酰胺 基可以进一步被氰基、C1-C6烷基或五元至六元杂环基取代。所述环可以是单环或双环。
例如，所述Ra1可以选自苯环、八元杂二环和九元杂芳香二环，其中所述环可以进一步被取代，所述环基可以进一步被酰胺基取代，所述酰胺基可以进一步被C1-C3烷基、环丙基或五元杂环取代，所述C1-C3烷基、环丙基或五元杂环取代可以进一步被氰基、氟、六元杂环基取代。
例如，所述Ra1可以为被四元至十元芳香环基取代的氨基。例如，所述Ra1可以为被苯环或五元杂芳香环取代的氨基，所述苯环可以进一步被磺酰基取代，所述五元杂芳香可以进一步被甲基取代。
例如，在所述式II-a所示的化合物中，所述Ra2可以选自：氢、C1-C3烷基和卤素。
例如，在所述式II-a所示的化合物中，所述Ra2可以选自：氢、甲基和氯。
在某些情形中，在所述式II-a所示的化合物中，所述环A可以选自苯环或咪唑环，所述苯环或咪唑环可以任选地被C1-C3烷基、五元至六元杂环烷基、五元至六元杂芳香基或卤素取代，所述烷基或环可以进一步被羟基取代。
在某些情形中，在所述式II-a所示的化合物中，所述Ra3可以选自
Figure PCTCN2021141972-appb-000056
Figure PCTCN2021141972-appb-000057
甲基或甲氧基，且所述Ra5为氢原子。
在本申请中，在所述式II所示的化合物中，所述R 12、R 13、R 14各自独立地选自下组：
Figure PCTCN2021141972-appb-000058
Figure PCTCN2021141972-appb-000059
在本申请中，所述JAK抑制剂可以包含化合物II-1至II-7中的一种或多种：
Figure PCTCN2021141972-appb-000060
在本申请中，所述JAK抑制剂可以包含式III所示的结化合物：
Figure PCTCN2021141972-appb-000061
其中所述R 15和R 16各自独立地选自氢原子、任选地被取代基取代的环烷基、任选地被取代基取代的杂环烷基、任选地被取代基取代的芳基和任选地被取代基取代的杂芳基，所述取代基选自：酰胺基、烷基、环烷基、杂环烷基、氰基、氨基、羟基和卤素。
例如，所述R15或所述R16可以为四元至十元杂环烷基，且所述杂环烷基任选地被酰胺基或C1-C6烷基取代，所述酰胺基可以进一步被C1-C6烷基取代，所述烷基可以进一步被卤素取代。例如，所述R15或所述R16可以为
Figure PCTCN2021141972-appb-000062
其中，所述R17和R18各自独立地为C1-C6烷基，且所述烷基可以被卤素取代。例如，所述R17可以为乙基，且所述R18可以为被氟取代的乙基，又例如，所述R17可以为乙基，且所述R18可以为-CH2-CF3。
例如，所述R15或所述R16中的一个可以为氢原子。
在本申请中，所述JAK抑制剂可以为化合物III-1：
Figure PCTCN2021141972-appb-000063
在本申请中，所述JAK抑制剂可以包含式IV所示的结化合物：
Figure PCTCN2021141972-appb-000064
式IV，其中，所述R 19和R 20可以各自独立地选自氢原子、硝基、四元至十元环烷基、四元至十元杂环烷基、四元至十元芳香基和四元至十元杂芳香基，其中所述硝基、环烷基、杂环烷基、芳香基、杂芳香基可以进一步被氰基、烷基、环烷基、杂环烷基或羟基取代。
例如，所述R19可以为硝基，所述硝基可以被取代的苯环取代。又例如，所述苯环可以被哌啶取代，所述哌啶可以进一步被羟基取代。例如，所述R 19可以为
Figure PCTCN2021141972-appb-000065
例如，所述R 20可以为哌啶基，所述哌啶基可以被C1-C3烷基取代，所述烷基可以进一步被氰基或羟基取代。又例如，所述述R20可以为哌啶基，所述哌啶基可以被甲基取代，所述甲基可以进一步被羟基取代。又例如，所述R20可以为
Figure PCTCN2021141972-appb-000066
在本申请中，所述JAK抑制剂可以为化合物III-1：
Figure PCTCN2021141972-appb-000067
方法
本申请提供了一种预防或治疗抗肿瘤剂相关的疾病或病症的方法，所述方法包括向受试者施用上文所述的JAK抑制剂。
本申请提供了一种预防或治疗EGFR功能异常相关的皮疹的方法，所述方法包括向受试者施用上文所述的JAK抑制剂。
本申请提供了一种预防或治疗抗肿瘤剂相关的疾病或病症的方法，所述方法包括向受试者施用上文所述的JAK抑制剂。
本申请提供了一种预防或治疗EGFR功能异常相关的皮疹的方法，所述方法包括向受试者施用上文所述的JAK抑制剂。
本申请中使用的术语“预防”通常是指预防疾病或其一种或多种症状的发作，复发或扩散。在本申请中“预防”可以与“预防性治疗”互换使用。在某些实施方案中，“预防”通常是指在症状发作之前，在有或没有本申请所述的其他药物的情况下，向患有本申请所述的疾病或病症的患者提供本申请所述的药物的治疗。
本申请中使用的术语“治疗”通常是指消除或改善疾病，或与疾病相关的一种或多种症状。在一些实施方式中，治疗通常是指通过向患有这种疾病的患者施用一种或多种治疗剂而使得疾病消除或缓解。在一些实施方式中，“治疗”可以是在特定疾病的症状发作后，在其他治疗剂存在或不存在的情况下施用药物。
本申请中使用的术语“受试者”通常是指需要诊断、预后、改善、预防和/或治疗疾病的人或非人动物(包括哺乳动物)，特别是需要JAK抑制剂治疗或预防的那些受试者。
在一些实施方式中，所述受试者可以包括癌症患者。
例如，所述癌症患者可以曾经、正在和/或将来被施用抗肿瘤剂。例如，所述抗肿瘤剂可以为本申请所述的抗肿瘤剂。
例如，所述癌症患者可以曾经、正在和/或将来被施用EGFR抑制剂。例如，所述EGFR抑制剂可以为本申请所述的EGFR抑制剂。
在一些实施方式中，所述受试者可以是人或非人哺乳动物。非人哺乳动物可以包括任何除人之外的哺乳动物物种，例如家畜动物(例如，牛、猪、羊、鸡、兔或马)，或啮齿类动物(例如，大鼠和小鼠)，或灵长类动物(例如，大猩猩和猴子)，或家养动物(例如，狗和猫)。
在一些实施方式中，在施用了本申请的JAK抑制剂后，受试者的所述抗肿瘤剂相关的疾病或病症的严重程度得到了缓解。在一些实施方式中，在施用了本申请的JAK抑制剂后，受试者的所述EGFR功能异常引起的皮疹的严重程度得到了缓解。在一些实施方式中，所述缓解可以是依据NCI-CTCAE V5.0的分级标准进行判断的，例如，所述受试者的上皮组织疾病的严重程度从5级降低至1级(例如，5级降低至4级、5级降低至3级、5级降低至2级，4级降低至3级、4级降低至2级、4级降低至1级、3级降低至2级、3级降低至1级或2级降低至1级)。在一些实施方式中，所述缓解通常可以指所述受试者的所述EGFR功能异常引起的皮疹的发作或发展被推迟。
在一些实施方案中，向需要受试者施用有效量的本申请所述的JAK抑制剂，能够使得受试者的皮疹的严重程度从5级降低至1级(例如，5级降低至4级、5级降低至3级、5级降低至2级，4级降低至3级、4级降低至2级、4级降低至1级、3级降低至2级、3级降低至1级或2级降低至1级)。
在一些实施方案中，在本申请的方法中的JAK抑制剂可以是选自下组的化合物：
Figure PCTCN2021141972-appb-000068
其可用于预防或者治疗的EGFR功能异常相关的皮疹。
在一些实施方式中，所述JAK抑制剂可以用于预防或者治疗抗肿瘤剂相关的疾病或病症。
在一些实施方案中，向需要其的受试者施用有效量的化合物I-1至化合物I-15中的一种或多种，能够使得受试者的皮疹的严重程度从5级降低至1级(例如，5级降低至4级、5级降低至3级、5级降低至2级，4级降低至3级、4级降低至2级、4级降低至1级、3级降低至2级、3级降低至1级或2级降低至1级)。
在一些实施方案中，在本申请的方法中的JAK抑制剂可以是选自下组的化合物：
Figure PCTCN2021141972-appb-000069
其可用于预防或者治疗的EGFR功能异常相关的皮疹。
在一些实施方案中，上述JAK抑制剂可以用于预防或者治疗抗肿瘤剂相关的疾病或病症。
在一些实施方案中，向需要其的受试者施用有效量的化合物II-1至化合物II-7中的一种或多种，能够使得受试者的皮疹的严重程度从5级降低至1级(例如，5级降低至4级、5级降低至3级、5级降低至2级，4级降低至3级、4级降低至2级、4级降低至1级、3级降低至2级、3级降低至1级或2级降低至1级)。
在一些实施方案中，在本申请的方法中的JAK抑制剂可以是化合物
Figure PCTCN2021141972-appb-000070
其可用于预防或者治疗的EGFR功能异常相关的皮疹。
在一些实施方案中，上述JAK抑制剂可以用于预防或者治疗抗肿瘤剂相关的疾病或病症。
在一些实施方案中，向需要其的受试者施用有效量的化合物III-1，能够使得受试者的皮疹的严重程度从5级降低至1级(例如，5级降低至4级、5级降低至3级、5级降低至2级，4级降低至3级、4级降低至2级、4级降低至1级、3级降低至2级、3级降低至1级或2级降低至1级)。
在一些实施方案中，在本申请的方法中的JAK抑制剂可以是化合物
Figure PCTCN2021141972-appb-000071
其可用于预防或者治疗的EGFR功能异常相关的皮疹。
在一些实施方案中，上述JAK抑制剂可以用于预防或者治疗抗肿瘤剂相关的疾病或病症。
在一些实施方案中，向需要其的受试者施用有效量的化合物IV-1，能够使得受试者的皮疹的严重程度从5级降低至1级(例如，5级降低至4级、5级降低至3级、5级降低至2级，4级降低至3级、4级降低至2级、4级降低至1级、3级降低至2级、3级降低至1级或2级降低至1级)。
本申请中使用的术语“有效量”通常是指可以缓解或者消除受试者的疾病或症状，或者可以预防性地抑制或防止疾病或症状发生的药物的量。有效量可以是将受试者的一种或多种疾病或症状缓解到一定程度的药物的量；可以将那些跟疾病或症状成因相关的一种或多种生理或生物化学参数部分或完全恢复到正常的药物的量；和/或可以降低疾病或症状发生的可能性的药物的量。
本申请所述的JAK抑制剂可以通过本领域已知的给药方式给药，例如注射给药(例如，皮下、腹腔、关节内、动脉内、鞘内、胸骨内、鞘内、病灶内、颅内、肌肉、皮内以及静脉推注或者滴注)或非注射给药(例如，口服、鼻腔、舌下、***、直肠或外用给药)。本申请的JAK抑制剂可以以药物组合或试剂盒的形式施用。
在本申请中，所述JAK抑制剂可以被制备为适用于透皮给药。
在一些实施方式中，本申请提供的JAK抑制剂的浓度可以为约0.01％(w/w)至约10％(w/w)，例如，可以为约0.01％(w/w)至约9％(w/w)、约0.01％(w/w)至约8％(w/w)、约0.01％(w/w)至约7％(w/w)、约0.01％(w/w)至约6％(w/w)、约0.01％(w/w)至约5％(w/w)、约0.01％(w/w)至约4％(w/w)、约0.01％(w/w)至约3％(w/w)、约0.01％(w/w)至约2％(w/w)、约0.01％(w/w)至约1％(w/w)、约0.01％(w/w)至约0.5％(w/w)、约0.01％(w/w)至约0.1％(w/w)或约0.01％(w/w)至约0.05％(w/w)。又例如，本申请提供的JAK抑制剂的浓度可以为约0.02％(w/w)至约0.05％(w/w)、约0.02％(w/w)至约1％(w/w)、约0.02％(w/w)至约2％(w/w)、约0.02％(w/w)至约5％(w/w)、约0.02％ (w/w)至约0.75％(w/w)或约0.02％(w/w)至约1.5％(w/w)。
在本申请中，所述JAK抑制剂可以被制备为适用于局部给药。
在一些实施方式中，所述局部给药的给药部位可以不为癌症的发生部位或癌症的潜在转移部位。例如，所述给药部分可以不为癌症的原发部位。又例如，所述给药部分可以不为癌症的转移部位。例如，所述转移部位可以包括淋巴转移、血管转移和/或种植性转移导致的癌症转移的发生部位。在一些实施方式中，所述转移部位可以包括骨、脑、肝、胃和/或肺。又例如，所述给药部分可以不为癌症的复发部位。
在本申请中，所述药物或所述JAK抑制剂可以被制备为适用于透皮给药。在本申请中，所述药物或所述JAK抑制剂可以被制备为适用于局部给药。在一些实施方式中，所述药物或所述JAK抑制剂被制备为用于局部皮肤施用。例如在本申请中，所述药物或所述JAK抑制剂可以被制备为乳膏、洗液、凝胶、软膏、油膏、喷剂、脂质体制剂、擦剂和/或气雾剂。例如本申请中，所述药物或所述JAK抑制剂被制备的透皮给药剂型，可以是溶液型透皮制剂(乳膏、凝胶、软膏、糊剂等)，也可以是混悬型透皮制剂(乳膏、凝胶、软膏、糊剂等)。
在一些实施方案中，本申请所述的JAK抑制剂可以与EGFR抑制剂共同施用。在一些实施方式中，所述JAK抑制剂可以在受试者接受了EGFR抑制剂之前、同时或者之后施用。在某些实施方案中，所述JAK抑制剂可以作为多剂量方案的一部分与EGFR抑制剂分别施用。在一些实施方案中，所述JAK抑制剂可以与EGFR抑制剂可以同时给药。在同时给药的实施方式中，这些JAK抑制剂可以是单一剂型的一部分，其与目前公开的EGFR抑制剂混合成为单一组合物。在另一些实施方案中，这些JAK抑制剂可以作为单独的剂量给予，与EGFR抑制剂大约同时施用。
在所述JAK抑制剂与EGFR抑制剂间隔给药的实施方式中，所述JAK抑制剂可以在施用EGFR抑制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。
在一些实施方案中，本申请所述的EGFR抑制剂可以与JAK抑制剂以相同的给药途径给药或者以不同的给药途径给药。
药物组合物和试剂盒
在一些实施方式中，JAK抑制剂或其药学上可接受的盐可以作为药物或药物组合的一部分而被施用。
在一些实施方式中，所述药物可包括JAK抑制剂或其药学上可接受的盐和一种或多种药 学上可接受的载体。
在一些实施方式中，所述药物组合或试剂盒可包含1)EGFR抑制剂；以及2)JAK抑制剂或其药学上可接受的盐。在一些实施方式中，所述EGFR抑制剂可以与所述JAK抑制剂或其药学上可接受的盐彼此不混合。例如，所述EGFR抑制剂可以与所述JAK抑制剂或其药学上可接受的盐各自独立地存在于单独的容器中。例如，所述EGFR抑制剂可以被分装在一个试剂瓶中，而所述JAK抑制剂或其药学上可接受的盐可以被分装在另一个试剂瓶中。
在本申请的所述药物组合或试剂盒中，2)中的所述JAK抑制剂或其药学上可接受的盐可以预防或治疗1)中的所述EGFR抑制剂引起的疾病或病症。
在本申请的所述药物组合或试剂盒中，2)中的所述JAK抑制剂或其药学上可接受的盐基本上不影响1)中的所述EGFR抑制剂的治疗效果。
在本申请中，所述“基本上不影响”可以指，与单独使用所述EGFR抑制剂的治疗效果相比，使用所述药物组合或试剂盒的2)中的所述JAK抑制剂或其药学上可接受的盐和1)中的所述JAK抑制剂或其药学上可接受的盐的治疗效果相当，或者不产生显著的劣势。例如，对任意的受试者，与单独使用JAK抑制剂或其药学上可接受的盐的治疗效果相比，使用所述药物组合或试剂盒的2)中的所述JAK抑制剂或其药学上可接受的盐和1)中的所述JAK抑制剂或其药学上可接受的盐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。
在本申请的所述药物组合或试剂盒中，2)中的所述JAK抑制剂或其药学上可接受的盐用于在施用1)中的所述EGFR抑制剂之前、同时或者之后施用。
另一方面，本申请提供了一种方法，所述方法包括下述步骤：
1)监测被施用EGFR抑制剂的受试者的皮疹；
2)当所述监测显示所述受试者出现与施用所述EGFR抑制剂相关的皮疹时，向所述受试者施用本申请JAK抑制剂或其药学上可接受的盐。
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融合蛋白、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
实施例1：在大鼠动物模型上验证JAK抑制剂预防小分子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抑制剂引起的皮疹的动物模型。
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1所示。实验分为JAK抑制剂组和对照组。灌胃后，对JAK抑制剂组大鼠的背部(约3cm*3cm)涂抹JAK抑制剂的药膏(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JAK抑制剂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JAK抑制剂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JAK抑制剂药膏的动物实验组合，以及相应的实验结果(其中，控制率栏的数值＝JAK抑制剂组皮疹轻于对照组的大鼠只数/JAK抑制剂组大鼠的总数量×100％)。
表1：实施例1的实验条件和实验结果
Figure PCTCN2021141972-appb-000072
Figure PCTCN2021141972-appb-000073
Figure PCTCN2021141972-appb-000074
图2显示了表1中对照组、JAK抑制剂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JAK抑制剂组和对照组的皮疹等级。
从表1和图2-3的结果可以看出：JAK抑制剂药膏能够有效地预防小分子EGFR抑制剂引起的皮疹。
实施例2：在大鼠动物模型上验证JAK抑制剂预防单抗类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JAK抑制剂组和对照组。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，JAK抑制剂组每天对大鼠背部(约3cm*3cm)涂JAK抑制剂软膏，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，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，JAK抑制剂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JAK抑制剂药膏的动物实验组合，以及相应的实验结果(其中，控制率栏的数值＝JAK抑制剂组皮疹轻于对照组的大鼠只数/JAK抑制剂组大鼠的总数量×100％)。
表2：实施例2的实验条件和实验结果
Figure PCTCN2021141972-appb-000075
图4显示了实验终点时JAK抑制剂组和对照组(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：JAK抑制剂药膏能够有效的预防单抗类EGFR抑制剂引起的皮疹。
实施例3：在大鼠动物模型上验证JAK抑制剂治疗小分子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JAK抑制剂组和对照组。治疗实验过程中，持续每日灌胃EGFR抑制剂，灌胃后，JAK抑制剂组对大鼠的背部(约3cm*3cm)涂抹JAK抑制剂的药膏，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JAK抑制剂和空白软膏每天只涂药一次。每日重复用EGFR抑制剂灌胃，将JAK抑制剂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JAK抑制剂药膏的动物实验组合，以及相应的实验结果(其中，控制率栏的数值＝JAK抑制剂组皮疹轻于对照组的大鼠只数/JAK抑制剂组大鼠的总数量×100％)。
表3：实施例3的实验条件和实验结果
Figure PCTCN2021141972-appb-000076
Figure PCTCN2021141972-appb-000077
Figure PCTCN2021141972-appb-000078
图5显示了表3中对照组、JAK抑制剂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JAK抑制剂组和对照组的皮疹等级。
从表3和图5-6中的结果可以看出：JAK抑制剂药膏能够有效的治疗小分子EGFR抑制剂引起的皮疹。
实施例4：在大鼠动物模型上JAK抑制剂治疗单抗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JAK抑制剂组和对照组。治疗实验过程中，持续注射单抗EGFR抑制剂一周2次，每日对JAK抑制剂组大鼠的背部(约3cm*3cm)涂抹JAK抑制剂的药膏，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8-10天后，JAK抑制剂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JAK抑制剂药膏的动物实验组合，以及相应的实验结果(其中，控制率栏的数值＝JAK抑制剂组皮疹轻于对照组的大鼠只数/JAK抑制剂组大鼠的总数量×100％)。
表4：实施例4的实验条件和实验结果
Figure PCTCN2021141972-appb-000079
图7显示了实验终点时JAK抑制剂组和对照组(单抗类EGFR抑制剂)的皮疹等级。
从表4和图7结果可以看出：JAK抑制剂药膏能够有效的治疗单抗类EGFR抑制剂引起的皮疹。
实施例5：在预防小分子EGFR抑制剂产生皮疹的实验中，JAK抑制剂软膏与临床上现有的其它皮肤用药对比。
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5所示。实验分为JAK抑制剂组和其他皮肤用药组。灌胃后，对JAK抑制剂组大鼠的背部(约3cm*3cm)涂抹JAK抑制剂软膏，其他皮肤用药组大鼠的背部(约3cm*3cm)分别涂抹临床上现有皮肤用药(实施例114-122)；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5所示，但临床上现有的其它皮肤用药和JAK抑制剂只涂药一次。每日重复用EGFR抑制剂灌胃，用药物涂抹背部，直到其他皮肤用药组出现明显的皮疹。统计JAK抑制剂组有多少大鼠的皮疹明显轻于其他皮肤用药组皮疹。
表5列出了JAK抑制剂软膏与临床上现有皮肤用药的动物实验组合，以及相应的实验结果(其中，相对缓解率栏的数值＝JAK抑制剂组皮疹轻于其他皮肤用药组的大鼠只数/JAK抑制剂组大鼠的总数量×100％)。
表5：实施例5的实验条件和实验结果
Figure PCTCN2021141972-appb-000080
图8显示了表5中其他皮肤用药组、JAK抑制剂组中典型大鼠的左侧、背部和右侧的照片。图9显示了实验终点时JAK抑制剂组和其他皮肤用药组的皮疹等级。
从表5中的结果可以看出：相比于临床上现有的皮肤用药(几乎对EGFR抑制剂所导致的皮疹没有治疗作用)，JAK抑制剂软膏能有效地控制EGFR抑制剂所导致的皮疹。
实施例6：在大鼠动物模型上验证JAK抑制剂预防抗肿瘤剂相关疾病或病症的实验
构建大鼠动物模型。通过每日灌胃的方式给予6周雌性SD大鼠抗肿瘤剂，若干天后，大鼠的背部大面积出现皮疹。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，大鼠在口服抗肿瘤剂之后面部、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抗肿瘤剂引起的皮疹的动物模型。
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。抗肿瘤剂溶解在相应的溶液中，用PBS缓冲溶液稀释，每次灌胃量不超过2mL，给药剂量如表6所示。实验分为JAK抑制剂组和对照组。灌胃后，对JAK抑制剂组大鼠的背部(约3cm*3cm)涂抹JAK抑制剂的药膏(种类和浓度如表6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。抗肿瘤剂的灌胃频率如表6所示，但JAK抑制剂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JAK抑制剂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6列出了各种抗肿瘤剂和JAK抑制剂药膏的动物实验组合，以及相应的实验结果(其中，控制率栏的数值＝JAK抑制剂组皮疹轻于对照组的大鼠只数/JAK抑制剂组大鼠的总数量×100％)。
表6实施例6的实验条件和实验结果
Figure PCTCN2021141972-appb-000081
Figure PCTCN2021141972-appb-000082
Figure PCTCN2021141972-appb-000083
Figure PCTCN2021141972-appb-000084
Figure PCTCN2021141972-appb-000085
Figure PCTCN2021141972-appb-000086
Figure PCTCN2021141972-appb-000087
Figure PCTCN2021141972-appb-000088
Figure PCTCN2021141972-appb-000089
Figure PCTCN2021141972-appb-000090
从表6的结果可以看出：JAK抑制剂药膏能够有效地预防小分子抗肿瘤剂引起的皮疹。
实施例7：在大鼠动物模型上验证JAK抑制剂治疗抗肿瘤剂相关疾病或病症的实验
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。抗肿瘤剂溶解在相应的溶液中，用PBS缓冲溶液稀释，每次灌胃量不超过2mL，给药剂量如表7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JAK抑制剂组和对照组。治疗实验过 程中，持续每日灌胃抗肿瘤剂，灌胃后，JAK抑制剂组对大鼠的背部(约3cm*3cm)涂抹JAK抑制剂的药膏，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。抗肿瘤剂的灌胃频率如表7所示，但JAK抑制剂和空白软膏每天只涂药一次。每日重复用抗肿瘤剂灌胃，将JAK抑制剂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7列出了各种抗肿瘤剂和JAK抑制剂药膏的动物实验组合，以及相应的实验结果(其中，控制率栏的数值＝JAK抑制剂组皮疹轻于对照组的大鼠只数/JAK抑制剂组大鼠的总数量×100％)。
表7实施例7的实验条件和实验结果
Figure PCTCN2021141972-appb-000091
Figure PCTCN2021141972-appb-000092
Figure PCTCN2021141972-appb-000093
从表7的结果可以看出：JAK抑制剂药膏能够有效地治疗小分子抗肿瘤剂引起的皮疹。
实施例8：在大鼠动物模型上验证JAK抑制剂预防单抗类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JAK抑制剂组和对照组。将用生理盐水稀释后的单抗抑制剂溶液每周尾静脉注射2次，注射速度及时间见表x。注射给药后，JAK抑制剂组每天对大鼠背部(约3cm*3cm)涂JAK抑制剂软膏，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，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，JAK抑制剂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8列出了各种单抗抑制剂和JAK抑制剂药膏的动物实验组合，以及相应的实验结果(其中，控制率栏的数值＝JAK抑制剂组皮疹轻于对照组的大鼠只数/JAK抑制剂组大鼠的总数量×100％)。
表8实施例8的实验条件和实验结果
Figure PCTCN2021141972-appb-000094
从表8的结果可以看出：JAK抑制剂药膏能够有效地预防单抗抑制剂引起的皮疹。
实施例9：JAK抑制剂对抗肿瘤剂产生皮疹的临床效果
测试的受试者来自于接受靶向疗法和/或免疫疗法并出现皮疹的患者。所述接受靶向疗法的患者正在进行西妥昔单抗(cetuximab)，或其他抗体类抗肿瘤剂治疗；所述接受免疫疗法的患者正在进行CTLA-4抑制剂(例如：Ipilimumab)和/或PD-1/PD-L1抑制剂(例如：Pembrolizumab,Nivolumab等)治疗。符合皮疹诊断标准，NCI-CTCAE v5.0评估1级以上者，症状持续1周以上。
皮疹诊断标准参考NCI-CTCAE v5.0和ASCO指南，将靶向治疗和免疫治疗导致的皮疹作为单独分类。
实验分为治疗组和对照组。在接受靶向疗法和免疫疗法过程中，治疗组：将皮疹局部用清水清洗干净，早中晚每日3次用JAK软膏涂抹患处；对照组：将皮疹局部用清水清洗干净，早中晚每日3次用空白基质软膏涂抹患处；4周为一个疗程。每周对患者电话随访；填写临床评估表：评估表由9个项目组成：既往治疗、含JAK或空白软膏的治疗、居家治疗、辅助治疗、伤口类型、病变评估(宽度和长度以厘米为单位)、病灶周围的皮肤、生活质量评估和是否暂停用药的评估。必要时进行皮肤活检，有病理学专家进行评估。
每周评估用药部位和非用药部位皮疹病变数量、区域大小及趋势变化，对疗效进行评价，疗效评价方法如下：
临床控制：疗程结束时，症状消失；
显著有效：疗程结束时，症状分级减少2级；
有效：疗程结束时，症状分级减少1级；
无效：达不到上述标准患者。
运用上述疗效评价方法计算皮疹缓解率(临床控制+显著有效+有效)/该组总例数*100％。
表9列出了抗肿瘤剂和软膏的不同组合，相对缓解率＝(临床控制+显著有效+有效)/该组总例数*100％。
表9：实施例9的实验条件和实验结果
Figure PCTCN2021141972-appb-000095
Figure PCTCN2021141972-appb-000096
从表9的结果可以看出：JAK软膏(托法替布油膏)对接受靶向疗法(Cetuximab、Panitumumab)和免疫疗法(CTLA-4抑制剂、和/或PD-1/PD-L1抑制剂)治疗的患者产生的皮疹具有一定的缓解作用。

Claims (161)

  1. JAK抑制剂在制备药物中的用途，所述药物用于预防或者治疗受试者中与抗肿瘤剂相关的疾病或病症。
  2. 根据权利要求1所述的用途，其中所述JAK抑制剂包括选自下组的一种或多种：JAK1抑制剂、JAK2抑制剂、JAK3抑制剂和TYK-2抑制剂。
  3. 根据权利要求1-2中任一项所述的用途，其中所述JAK抑制剂包括减少JAK表达的抑制剂，和/或降低JAK活性的抑制剂。
  4. 根据权利要求1-3中任一项所述的用途，其中所述JAK抑制剂直接作用于JAK蛋白和/或编码JAK蛋白的核酸。
  5. 根据权利要求1-4中任一项所述的用途，其中所述JAK抑制剂包括小分子JAK抑制剂、特异性结合JAK的蛋白大分子、抑制JAK蛋白表达的RNAi和/或抑制JAK蛋白表达的反义寡核苷酸。
  6. 根据权利要求5所述的用途，其中所述小分子JAK抑制剂包括与JAK可逆结合的小分子JAK抑制剂、与JAK不可逆结合的小分子JAK抑制剂和/或特异性结合突变型JAK的小分子JAK抑制剂。
  7. 根据权利要求5-6中任一项所述的用途，其中所述小分子JAK抑制剂具备小于或等于2000道尔顿、小于或等于1500道尔顿、小于或等于1200道尔顿、小于或等于1000道尔顿、小于或等于900道尔顿、小于或等于800道尔顿、小于或等于700道尔顿、小于或等于600道尔顿、小于或等于500道尔顿、小于或等于400道尔顿、小于或等于300道尔顿、小于或等于200道尔顿和/或小于或等于100道尔顿的分子量。
  8. 根据权利要求1-7中任一项所述的用途，其中所述JAK抑制剂包括芦可替尼(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/或AC-1101。
  9. 根据权利要求1-8中任一项所述的用途，其中所述JAK抑制剂包括至少含有一个芳香环或芳香杂环的化合物。
  10. 根据权利要求1-9中任一项所述的用途，其中所述JAK抑制剂包含式I所示的化合物或其药学上可接受的盐：
    Figure PCTCN2021141972-appb-100001
    其中，X为N或C，Y为N或C，Z为N或C，Q为N或C，R 1、R 2和R 3各自独立地选自下组：五元至六元芳香环、五元至六元芳香杂环、五元至六元环烷基环、五元至六元杂环烷基、氨基和酰胺基，其中，所述芳香环、芳香杂环、环烷基和/或杂环烷基任选地被取代基取代。
  11. 根据权利要求10所述的用途，其中所述X为N，所述Y为C，所述Z为C，且所述Q为C。
  12. 根据权利要求10所述的用途，其中所述X、Y、Z和Q均为N。
  13. 根据权利要求10所述的用途，其中所述X为N，所述Y为N，所述Z为C，且所述Q为C。
  14. 根据权利要求10所述的用途，其中所述X为C，所述Y为N，所述Z为C，且所述Q为N。
  15. 根据权利要求10所述的用途，其中所述X为C，所述Y为C，所述Z为N，且所述Q为C。
  16. 根据权利要求10-15中任一项所述的用途，其中所述R 1和R 2各自独立地选自氢原子
    Figure PCTCN2021141972-appb-100002
    苯环、C 1-C 3烷基和
    Figure PCTCN2021141972-appb-100003
    其中，R 4选自环戊烷基、环丁烷基和吖丁啶基，所述取代基选自哌啶、氰基、羰基和磺 酰基，所述哌啶进一步被取代基取代，所述磺酰基进一步被烷基取代；所述R 5为C 1-C 6烷基，所述烷基进一步被氰基取代；
    所述苯环任选地被酰基、卤素、羟基、C 1-C 3烷基取代，所述酰基和烷基进一步任选地被C 3-C 5环烷基、C 3-C 5杂环烷基或C 1-C 3烷基取代，所述环烷基、杂环烷基进一步任选地被C 1-C 3烷基取代；
    所述R 10和R 11各自独立地选自氢原子、C 1-C 3烷基、或四元至十元环，且所述环是单环或双环，所述环进一步被氨基、磺酰基、羟基、炔基、酰基或C 1-C 3烷基取代，或，所述R 10和R 11形成环。
  17. 根据权利要求16所述的用途，其中所述R 4为
    Figure PCTCN2021141972-appb-100004
    其中所述R 6选自-CF 3、-CHF 2、-CH 2F和-CH 3，其中所述R 7选自氢原子或氟原子。
  18. 根据权利要求16-17中任一项所述的用途，其中所述R 4选自环烷基、
    Figure PCTCN2021141972-appb-100005
    Figure PCTCN2021141972-appb-100006
  19. 根据权利要求10-18中任一项所述的用途，其中所述R 1和R 2各自独立地选自氢原子或苯环，所述苯环任选地被酰基、卤素、羟基、C 1-C 3烷基取代，所述酰基进一步任选地被吖丁啶基取代，所述吖丁啶基进一步任选地被甲基取代。
  20. 根据权利要求10-19中任一项所述的用途，其中所述R 1和R 2各自独立地选自下组：氢原子、
    Figure PCTCN2021141972-appb-100007
    Figure PCTCN2021141972-appb-100008
  21. 根据权利要求10-20中任一项所述的用途，其中所述R 3选自酰胺基和五元至十元的芳香环，所述芳香环可以是二环，且可以被环基或链基基团取代。
  22. 根据权利要求10-21中任一项所述的用途，其中所述R 3为酰胺基，所述酰胺基任选地被环丁基或环丙基取代。
  23. 根据权利要求10-22中任一项所述的用途，其中所述R 3选自下组中的任意一种：
    Figure PCTCN2021141972-appb-100009
  24. 根据权利要求1-23中任一项所述的用途，其中JAK抑制剂包含化合物I-1至I-15中的任意一种或多种：
    Figure PCTCN2021141972-appb-100010
  25. 根据权利要求1-9中任一项所述的用途，其中所述JAK抑制剂包含式II所示的化合物：
    Figure PCTCN2021141972-appb-100011
    其中，
    所述X和Y各自独立地选自C或N，且所述R 12、R 13、R 14各自独立地包含选自下组：氢、氕、氘、氚、C 1-C 5的烷基、卤素、烷氧基、氨基、酰胺基、磺酰胺基、链烷基、环烷基、杂环烷基、烯基、炔基、芳香基和杂芳香基。
  26. 根据权利要求25所述的用途，在式II所示化合物中，所述X为C，且所述Y为N。
  27. 根据权利要求25所述的用途，在式II所示化合物中，所述X为N，且所述Y为C。
  28. 根据权利要求25-27中任一项所述的用途，其中所述JAK抑制剂包含式II-a所示的结构：
    Figure PCTCN2021141972-appb-100012
    其中，所述R a1和R a2包含任意价键允许地取代基，环A为任选地被R a3和/或R a5取代的芳香环或芳香杂环，所述R a3和R a5各自独立地选自：氢原子、环烷基、杂环烷基、芳基、杂芳基、烷氧基，或者，所述环A与-NH-之间包含甲基。
  29. 根据权利要求28所述的用途，其中所述R a1选自：氢原子、任选地被取代基取代的芳基、 任选地被取代基取代的杂芳基，任选地被取代基取代的环烷基、任选地被取代基取代的杂环烷基，所述取代基包括氢、卤素、烷基、氰基、磺酰基、酰胺基。
  30. 根据权利要求28-29中任一项所述的用途，其中所述R a1选自四元至十元芳香环基、四元至十元芳香杂环基、四元至十元环烷基、四元至十元杂环烷基，所述环基进一步被酰胺基取代，所述酰胺基进一步被氰基、C 1-C 6烷基或五元至六元杂环基取代。
  31. 根据权利要求28-30中任一项所述的用途，其中所述R a1选自下组中的任意一个：
    Figure PCTCN2021141972-appb-100013
  32. 根据权利要求28-31中任一项所述的用途，其中所述R a2选自：氢、C1-C3烷基和卤素。
  33. 根据权利要求28-32中任一项所述的用途，其中所述R a2选自：氢、甲基和氯。
  34. 根据权利要求28-33中任一项所述的用途，其中所述环A环选自苯环或咪唑环，所述苯环或咪唑环任选地被C 1-C 3烷基、五元至六元杂环烷基、五元至六元杂芳香基或卤素取代，所述烷基或环进一步被羟基取代。
  35. 根据权利要求28-34中任一项所述的用途，其中所述R a3和R a5各自独立地选自下组：氢原子、甲基、甲氧基、
    Figure PCTCN2021141972-appb-100014
  36. 根据权利要求25-35中任一项所述的用途，其中所述R 12、R 13、R 14各自独立地选自下组：
    Figure PCTCN2021141972-appb-100015
    Figure PCTCN2021141972-appb-100016
  37. 根据权利要求25-36中任一项所述的用途，其中所述JAK抑制剂包含化合物II-1至II-7中的一种或多种：
    Figure PCTCN2021141972-appb-100017
  38. 根据权利要求1-9中任一项所述的用途，其中所述JAK抑制剂包含式III所示的结化合物：
    Figure PCTCN2021141972-appb-100018
    其中所述R 15和R 16各自独立地选自氢原子、任选地被取代基取代的环烷基、任选地被取代基取代的杂环烷基、任选地被取代基取代的芳基和任选地被取代基取代的杂芳基，所述取代基选自：酰胺基、烷基、环烷基、杂环烷基、氰基、氨基、羟基和卤素。
  39. 根据权利要求38所述的用途，其中所述R 15或所述R 16为四元至十元杂环烷基，且所述杂环烷基任选地被酰胺基或C 1-C 6烷基取代，所述酰胺基进一步被C 1-C 6烷基取代，所述烷基进一步被卤素取代。
  40. 根据权利要求38-39中任一项所述的用途，其中所述R 15或所述R 16各自独立地为氢原子或
    Figure PCTCN2021141972-appb-100019
    其中，所述R 17和R 18各自独立地为C 1-C 6烷基，且所述烷基被卤素取代。
  41. 根据权利要求38-40中任一项所述的用途，其中所述R 15和R 16各自独立地选自氢原子和
    Figure PCTCN2021141972-appb-100020
    代表连接位点。
  42. 根据权利要求38-41中任一项所述的用途，其中所述JAK抑制剂包含化合物III-1：
    Figure PCTCN2021141972-appb-100021
  43. 根据权利要求1-9中任一项所述的用途，其中所述JAK抑制剂包含式IV所示的结构：
    Figure PCTCN2021141972-appb-100022
    其中，所述R 19和R 20各自独立地选自氢原子、硝基、四元至十元环烷基、四元至十元杂环烷基、四元至十元芳香基和四元至十元杂芳香基，其中所述硝基、环烷基、杂环烷基、芳香基、杂芳香基进一步任选地被氰基、烷基、环烷基、杂环烷基或羟基取代。
  44. 根据权利要求43所述的用途，其中所述R 19为硝基，所述硝基任选地被取代的苯环取代。
  45. 根据权利要求44所述的用途，其中所述被取代的苯环被哌啶取代，所述哌啶进一步任选地被羟基取代。
  46. 根据权利要求43-46中任一项所述的用途，其中所述R 20为哌啶基，所述哌啶基任选地被C 1-C 3烷基取代，所述烷基进一步任选地被氰基或羟基取代。
  47. 根据权利要求43-47中任一项所述的用途，其中所述R 20为
    Figure PCTCN2021141972-appb-100023
  48. 根据权利要求43-48中任一项所述的用途，其中所述JAK抑制剂包含化合物IV-1：
    Figure PCTCN2021141972-appb-100024
  49. 根据权利要求1-48中任一项所述的用途，其中所述药物中所述JAK抑制剂的浓度为0.01％-10％。
  50. 根据权利要求1-49中任一项所述的用途，其中所述抗肿瘤剂包括小分子化合物、小分子偶联物、蛋白质和/或多核苷酸。
  51. 根据权利要求1-50中任一项所述的用途，其中所述抗肿瘤剂包括靶向治疗剂和/或免疫治疗剂。
  52. 根据权利要求1-51中任一项所述的用途，其中所述抗肿瘤剂为靶向治疗剂。
  53. 根据权利要求52所述的用途，其中所述靶向治疗剂包括小分子化合物和/或抗体或其抗原结合片段。
  54. 根据权利要求53所述的用途，其中所述抗体包括单克隆抗体、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。
  55. 根据权利要求53-54中任一项所述的用途，其中所述抗原结合片段包括Fab，Fab’，F(ab) 2，Fv片段，F(ab’) 2，scFv，di-scFv和/或dAb。
  56. 根据权利要求52-55中任一项所述的用途，其中所述靶向治疗剂靶向肿瘤细胞内部、细胞表面和/或肿瘤微环境中的分子。
  57. 根据权利要求52-56中任一项所述的用途，其中所述靶向治疗剂靶向肿瘤细胞的蛋白质和/或核酸分子。
  58. 根据权利要求52-57中任一项所述的用途，其中所述靶向治疗剂靶向肿瘤抗原。
  59. 根据权利要求52-58中任一项所述的用途，其中所述靶向治疗剂靶向EGFR、ALK、MEK、VEGFR、FGFR、PDGFR、ABL、BTK、KIT、AKT、TORC、HER2、HER3、HER4、PI3K、CDK、JAK、ROS1、RET、MET、KRAS、BRAF、BCRP、NTRK、RAS、MSI、PR/ER、BCR/ABL、HDAC、FAK、PYK2、CD20、PD-L1和/或BRCA1/2，或它们的突变体。
  60. 根据权利要求52-59中任一项所述的用途，其中所述靶向治疗剂包括激素疗法、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。
  61. 根据权利要求52--60中任一项所述的用途，其中所述靶向治疗剂为酪氨酸激酶抑制剂。
  62. 根据权利要求52-61中任一项所述的用途，其中所述靶向治疗剂为EGFR抑制剂、MEK抑制剂、ALK抑制剂、BTK抑制剂、PI3K抑制剂、AKT抑制剂、VEGFR抑制剂、mTOR抑制剂、HDAC抑制剂、KIT抑制剂、FGFR抑制剂、FAK抑制剂、BCRP抑制剂、EGFR/cMET抑制剂和/或SRC抑制剂，以及它们的组合。
  63. 根据权利要求52-62中任一项所述的用途，其中所述靶向治疗剂为EGFR抑制剂。
  64. 根据权利要求52-63中任一项所述的用途，其中所述靶向治疗剂为VEGFR抑制剂。
  65. 根据权利要求62-64中任一项所述的用途，其中所述VEGFR抑制剂选自下组：Sulfatinib、Anlotinib hydrochloride、Tivozanib、Lenvatinib、Apatinib、Intedanib、Ponatinib、Axitinib、Vandetanib、Pazopanib hydrochloride和/或Sorafenib。
  66. 根据权利要求52-65中任一项所述的用途，其中所述靶向治疗剂为FGFR抑制剂。
  67. 根据权利要求52-66中任一项所述的用途，其中所述靶向治疗剂为ALK抑制剂。
  68. 根据权利要求52-67中任一项所述的用途，其中所述靶向治疗剂为mTOR抑制剂。
  69. 根据权利要求62-68中任一项所述的用途，其中所述mTOR抑制剂选自下组：zotarolimus、sirolimus、everolimus和/或temsirolimus。
  70. 根据权利要求52-69中任一项所述的用途，其中所述靶向治疗剂为BTK抑制剂。
  71. 根据权利要求62-70中任一项所述的用途，其中所述BTK抑制剂选自下组：Orelabrutinib、Tirabrutinib hydrochloride、Zanubrutinib、Acalabrutinib、Ibrutinib、Dasatinib、Pirtobrutinib、Tolebrutinib、Rilzabrutinib、Fenebrutinib和/或Evobrutinib。
  72. 根据权利要求52-71中任一项所述的用途，其中所述靶向治疗剂为MEK抑制剂。
  73. 根据权利要求62-72中任一项所述的用途，其中所述MEK抑制剂选自下组：Selumetinib sulfate、Binimetinib、Cobimetinib、Trametinib和/或GSK-1120212。
  74. 根据权利要求52-73中任一项所述的用途，其中所述靶向治疗剂为PI3K抑制剂。
  75. 根据权利要求62-74中任一项所述的用途，其中所述PI3K抑制剂选自下组：Umbralisib、Alpelisib、Duvelisib、Copanlisib hydrochloride、Idelalisib、Zandelisib、Buparlisib、Enzastaurin hydrochloride、Paxalisib、Leniolisib、Rigosertib、Dactolisib、Nortriptyline和/或Parsaclisib。
  76. 根据权利要求52-75中任一项所述的用途，其中所述靶向治疗剂为AKT抑制剂。
  77. 根据权利要求62-76中任一项所述的用途，其中所述AKT抑制剂包括Ipatasertib。
  78. 根据权利要求52-77中任一项所述的用途，其中所述靶向治疗剂为EGFR/cMET抑制剂。
  79. 根据权利要求52-78中任一项所述的用途，其中所述靶向治疗剂为BRAF抑制剂。
  80. 根据权利要求62-79中任一项所述的用途，其中所述BRAF抑制剂选自下组：Tepotinib、Dabrafenib、Vemurafenib和/或encorafenib。
  81. 根据权利要求52-80中任一项所述的用途，其中所述靶向治疗剂包括BRAF抑制剂和MEK抑制剂。
  82. 根据权利要求52-81中任一项所述的用途，其中所述靶向治疗剂包括Dabrafenib和Trametinib。
  83. 根据权利要求59-82中任一项所述的用途，其中所述靶向CD20的靶向治疗剂为Rituximab。
  84. 根据权利要求1-83中任一项所述的用途，其中所述抗肿瘤剂为免疫治疗剂。
  85. 根据权利要求84所述的用途，其中所述免疫治疗剂能够改变受试者体内的免疫应答。
  86. 根据权利要求84-85中任一项所述的用途，其中所述免疫治疗剂能够增强受试者体内的免疫应答。
  87. 根据权利要求84-86中任一项所述的用途，其中所述免疫治疗剂为免疫检查点抑制剂、经修饰的免疫细胞和/或疫苗。
  88. 根据权利要求84-87中任一项所述的用途，其中所述免疫治疗剂为抗体。
  89. 根据权利要求84-88中任一项所述的用途，其中所述免疫治疗剂为PD-1抑制剂、PD-L1抑制剂和/或CTLA-4抑制剂。
  90. 根据权利要求1-89中任一项所述的用途，其中所述抗肿瘤剂选自下组：afatinib、dacomitinib、osimertinib、EAI045、gefitinib、almonertinib、pyrotinib、brigatinib、neratinib、olmutinib、bosutinib、icotinib、vandetanib、lapatinib、alflutinib、BPI-7711、mobocertinib、dovitinib、zorifertinib、varlitinib、orelabrutinib、tirabrutinib、zanubrutinib、acalabrutinib、ibrutinib、dasatinib、pirtobrutinib、tolebrutinib、rilzabrutinib、fenebrutinib、evobrutinib、selumetinib、binimetinib、cobimetinib、trametinib、regorafenib、GSK-1120212、alpelisib、duvelisib、copanlisib、idelalisib、nortriptyline、inavolisib、dactolisib、apitolisib、parsaclisib、buparlisib、rigosertib、enzastaurin、paxalisib、leniolisib、ipatasertib、zotarolimus、sirolimus、everolimus、temsirolimus、sorafenib、apatinib、lenvatinib、sunitinib、cabozantinib、axitinib、nintedanib、brivanib、vatalanib、fruquintinib、dabrafenib、vemurafenib、encorafenib、pazopanib、crizotinib、panobinostat、erlotinib、rituximab、panitumumab、cetuximab、Ticilimumab、Erfonrilimab、BA-3071、MEDI-5752、defactinib、Zalifrelimab、Cadonilimab、BCD-217、ipilimumab、Tremelimumab、Quavonlimab、atezolizumab、durvalumab、Camrelizumab、Tislelizumab、Sintilimab、Toripalimab、pembrolizumab、nivolumab、Amivantamab、MCLA- 129、EMB-01、LY3164530、Roche Glycart anti-EGFR/cMet、Genentech Anti-met/EGFR、Samsung Anti-EGFR/cMet、Merck serono Anti-cmet/egfr和GB263，以及它们的组合。
  91. 根据权利要求1-90中任一项所述的用途，其中所述疾病或病症包括皮肤疾病或病症和/或皮下组织疾病或病症。
  92. 根据权利要求91所述的用途，其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。
  93. 根据权利要求1-92中任一项所述的用途，其中所述疾病或病症包括由两种或两种以上所述抗肿瘤剂联用相关的疾病或病症。
  94. 根据权利要求1-93中任一项所述的用途，其中所述疾病或病症包括由所述抗肿瘤剂与一种或多种其他疗法联用相关的疾病或病症。
  95. 根据权利要求1-94中任一项所述的用途，其中所述疾病或病症包括与EGFR异常相关的疾病或病症。
  96. 根据权利要求1-95中任一项所述的用途，其中所述疾病或病症包括与EGFR异常相关的皮疹。
  97. 根据权利要求96所述的用途，其中与EGFR异常相关的皮疹包括与EGFR被抑制相关的皮疹。
  98. 根据权利要求96-97中任一项所述的用途，其中与EGFR异常相关的皮疹包括免疫性皮疹和/或非免疫性皮疹。
  99. 根据权利要求96-98中任一项所述的用途，其中与EGFR异常相关的皮疹包括与EGFR异常相关的寻常痤疮(acne vulgaris)、与EGFR异常相关的玫瑰痤疮(acne rosacea)、与EGFR异常相关的瘙痒性皮疹(pruritus rash)、与EGFR异常相关的痤疮样皮疹(acneiform rash)与EGFR异常相关的蜂窝织炎(cellulitis)、与EGFR异常相关的莱姆病(Lyme disease)、与EGFR异常相关的过敏反应(allergic reaction)、与EGFR异常相关的化脓性汗腺炎(hidradenitis suppurativa)、与EGFR异常相关的麻疹(hives)、与EGFR异常相关的皮炎 (dermatitis)、与EGFR异常相关的乳痂(cradle cap)、与EGFR异常相关的紫癜(purpura)、与EGFR异常相关的玫瑰糠疹(pityriasis rosea)、与EGFR异常相关的红斑(erythema)、与EGFR异常相关的带状疱疹(shingles)、与EGFR异常相关的瘀伤(bruise)和/或与EGFR异常相关的黄瘤(xanthelasma)、与EGFR异常相关的黑色素瘤(melanoma)、与EGFR异常相关的基底细胞癌(basal cell carcinoma)、与EGFR异常相关的鳞状细胞癌(squamous cell carcinoma)、与EGFR异常相关的卡波西氏肉瘤(Kaposi's sarcoma)、与EGFR异常相关的环形红斑离心(erythema annulare centrifugum)。
  100. 根据权利要求92-99中任一项所述的用途，其中所述皮疹的严重程度为依据NCI-CTCAEV5.0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。
  101. 根据权利要求97-100中任一项所述的用途，其中与EGFR被抑制相关的皮疹包括与施用EGFR抑制剂相关的皮疹。
  102. 根据权利要求62-101中任一项所述的用途，其中所述EGFR抑制剂包括用于治疗癌症的药物。
  103. 根据权利要求62-102中任一项所述的用途，其中所述EGFR抑制剂直接作用于EGFR蛋白和/或编码EGFR蛋白的核酸。
  104. 根据权利要求62-103中任一项所述的用途，其中所述EGFR抑制剂包括小分子EGFR抑制剂、特异性结合EGFR的蛋白大分子、抑制EGFR蛋白表达的RNAi和/或抑制EGFR蛋白表达的反义寡核苷酸。
  105. 根据权利要求104所述的用途，其中所述小分子EGFR抑制剂包括与EGFR可逆结合的小分子EGFR抑制剂、与EGFR不可逆结合的小分子EGFR抑制剂和/或特异性结合突变型EGFR的小分子EGFR抑制剂。
  106. 根据权利要求62-105中任一项所述的用途，其中所述EGFR抑制剂包括西妥昔单抗、吉非替尼、厄洛替尼、埃克替尼、Sapitinib、阿法替尼、拉帕替尼、凡德替尼、来那替尼、brigatinib、帕尼单抗、耐昔妥珠单抗、尼妥珠单抗、Tesevatinib、艾力替尼、席栗替尼、Rociletinib、卡奈替尼、AZD3759、YZJ-0318、萘普替尼、Naquotinib、PF-06747775、SPH1188-11、Poziotinib、依吡替尼、Varlitinib、艾氟替尼、HM61713、CK-101、吡咯替尼、莱洛替尼、HS-10296、AP32788、西莫替尼、GMA204、Virlitinib、Yinlitinib、那扎替尼、诺司替尼、奥莫替尼、奥希替尼、达克替尼、艾维替尼、EAI045、Lazertinib、Alflutinib、Mobocertinib、Savolitinib、Almonertinib、Trastuzumab、Tepotinib、Irbinitinib、Cemiplimab、Pyrotinib、 Dacomitinib、Neratinib、Olmutinib、Mereletinib、Bosutinib、Icotinib、Vandetanib、Lapatinib、Befotertinib、Poziotinib、Larotinib、BPI-7711、SKLB-1028、Famitinib、Dovitinib和/或Zorifertinib。
  107. 根据权利要求62-106中任一项所述的用途，其中所述EGFR抑制剂包括Alflutinib mesylate、Almonertinib mesilate、Trastuzumab deruxtecan、Tepotinib hydrochloride、Pyrotinib maleate、Mereletinib mesilate、Icotinib hydrochloride、Lapatinib ditosylate、Larotinib mesylate、Famitinib malate、Dovitinib lactate和/或Varlitinib tosylate。
  108. 根据权利要求62-107中任一项所述的用途，其中所述EGFR抑制剂与一种或多种其他疗法联用。
  109. 根据权利要求1-108中任一项所述的用途，其中所述受试者包括癌症患者。
  110. 根据权利要求62-109中任一项所述的用途，其中所述受试者曾经、正在和/或将来被施用所述EGFR抑制剂。
  111. 根据权利要求62-110中任一项所述的用途，其中所述药物基本上不影响所述EGFR抑制剂的治疗效果。
  112. 根据权利要求1-111中任一项所述的用途，其中所述药物被制备为适用于局部给药。
  113. 根据权利要求112所述的用途，其中所述局部给药的给药部位不为癌症的发生部位或癌症的潜在转移部位。
  114. 根据权利要求1-113中任一项所述的用途，其中所述药物被制备为适用于外用给药。
  115. 根据权利要求1-114中任一项所述的用途，其中所述药物被制备为适用于透皮给药。
  116. 根据权利要求1-115中任一项所述的用途，其中所述药物的给药形式包含乳膏、洗液、凝胶、软膏、油膏、喷剂、脂质体制剂、擦剂和/或气雾剂。
  117. 根据权利要求1-116中任一项所述的用途，其中所述药物中还包括一种或多种其他活性成分。
  118. 权利要求1-117中任一项所述的JAK抑制剂在制备药物中的用途，所述药物用于预防或者治疗皮疹。
  119. 一种预防或治疗与EGFR异常相关的皮疹的方法，包括向有需要的受试者施用权利要求1-118中任一项所述的JAK抑制剂。
  120. 根据权利要求119所述的方法，其中所述受试者曾经、正在和/或将来被施用EGFR抑制剂。
  121. 一种预防或治疗皮疹的方法，包括向有需要的受试者施用权利要求1-118中任一项所述的 用途中的所述JAK抑制剂。
  122. 药物组合或试剂盒，其包含：1)抗肿瘤剂；以及2)权利要求1-118中任一项所述的JAK抑制剂。
  123. 根据权利要求122所述的药物组合或试剂盒，其还包含缓冲液。
  124. 根据权利要求122-123中任一项所述的药物组合或试剂盒，其还包含赋形剂。
  125. 根据权利要求122-124任一项所述的药物组合或试剂盒，其中所述抗肿瘤剂与所述JAK抑制剂彼此不混合。
  126. 根据权利要求122-125任一项所述的药物组合或试剂盒，其中所述抗肿瘤剂与所述JAK抑制剂各自独立地存在于单独的容器中。
  127. 根据权利要求122-126任一项所述的药物组合或试剂盒，其中所述JAK抑制剂被制备为适用于局部给药。
  128. 根据权利要求127所述的药物组合或试剂盒，其中所述局部给药的给药部位不为癌症的发生部位或癌症的潜在转移部位。
  129. 根据权利要求122-128中任一项所述的药物组合或试剂盒，其中所述JAK抑制剂被制备为适用于外用给药。
  130. 根据权利要求122-129任一项所述的药物组合或试剂盒，其中所述JAK抑制剂被制备为适用于透皮给药。
  131. 根据权利要求122-130中任一项所述的药物组合或试剂盒，其中所述JAK抑制剂被制备为乳膏、洗液、凝胶、软膏、油膏、喷剂、脂质体制剂、擦剂和/或气雾剂。
  132. 根据权利要求122-131中任一项所述的药物组合或试剂盒，其中2)中的所述JAK抑制剂能够预防或治疗与施用1)中的所述抗肿瘤剂相关的疾病或病症。
  133. 根据权利要求122-132中任一项所述的药物组合或试剂盒，其中2)中的所述JAK抑制剂基本上不影响1)中的所述抗肿瘤剂的治疗效果。
  134. 根据权利要求122-133中任一项所述的药物组合或试剂盒，其中在施用1)的所述抗肿瘤剂之前、同时或者之后施用2)的所述JAK抑制剂。
  135. 药物组合或试剂盒，其包含：1)EGFR抑制剂；以及2)权利要求1-118中任一项所述的JAK抑制剂。
  136. 根据权利要求135所述的药物组合或试剂盒，其中所述EGFR抑制剂与所述JAK抑制剂彼此不混合。
  137. 根据权利要求135-136中任一项所述的药物组合或试剂盒，其中所述EGFR抑制剂与所 述JAK抑制剂各自独立地存在于单独的容器中。
  138. 根据权利要求135-137中任一项所述的药物组合或试剂盒，其中所述JAK抑制剂被制备为适用于局部给药。
  139. 根据权利要求138所述的药物组合或试剂盒，其中所述局部给药的给药部位不为癌症的发生部位或癌症的潜在转移部位。
  140. 根据权利要求135-139中任一项所述的药物组合或试剂盒，其中所述JAK抑制剂被制备为适用于外用给药。
  141. 根据权利要求135-140中任一项所述的药物组合或试剂盒，其中所述JAK抑制剂被制备为适用于透皮给药。
  142. 根据权利要求135-141中任一项所述的药物组合或试剂盒，其中所述JAK抑制剂被制备为乳膏、洗液、凝胶、软膏、油膏、喷剂、脂质体制剂、擦剂和/或气雾剂。
  143. 根据权利要求135-142中任一项所述的药物组合或试剂盒，其中2)中的所述JAK抑制剂能够预防或治疗与施用1)中的所述EGFR抑制剂相关的疾病或病症。
  144. 根据权利要求135-143中任一项所述的药物组合或试剂盒，其中2)中的所述JAK抑制剂基本上不影响1)中的所述EGFR抑制剂的治疗效果。
  145. 根据权利要求135-144中任一项所述的药物组合或试剂盒，其中在施用1)的所述EGFR抑制剂之前、同时或者之后施用2)的所述JAK抑制剂。
  146. 一种方法，所述方法包括下述步骤：
    1)监测被施用抗肿瘤剂的受试者的皮疹；
    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疾病或病症时，向所述受试者施用权利要求1-118中任一项所述的用途中的所述JAK抑制剂。
  147. 根据权利要求146所述的方法，其还包括继续监控所述疾病或病症，以及任选地减少或停用所述抗肿瘤剂。
  148. 根据权利要求146-147中任一项所述的方法，其中所述疾病或病症的严重程度在所述施用EGFR抑制剂之后增加。
  149. 根据权利要求146-148中任一项所述的方法，其中所述抗肿瘤剂不包含所述JAK抑制剂。
  150. 根据权利要求146-149中任一项所述的方法，其中向所述受试者局部施用所述JAK抑制剂。
  151. 根据权利要求146-150中任一项所述的方法，其中向所述受试者中的非癌症部位施用所述JAK抑制剂。
  152. 一种方法，所述方法包括下述步骤：
    1)监测被施用EGFR抑制剂的受试者的皮疹；
    2)当所述监测显示所述受试者出现与施用所述EGFR抑制剂相关的皮疹时，向所述受试者施用权利要求1-118中任一项所述的用途中的所述JAK抑制剂。
  153. 根据权利要求152所述的方法，其还包括继续监控所述皮疹，以及任选地减少或停用所述EGFR抑制剂。
  154. 根据权利要求152-153中任一项所述的方法，其中所述皮疹的严重程度在所述施用EGFR抑制剂之后增加。
  155. 根据权利要求152-154中任一项所述的方法，其中在所述施用EGFR抑制剂之前，所述受试者未患有所述皮疹。
  156. 根据权利要求152-155中任一项所述的方法，其中所述EGFR抑制剂不包含所述JAK抑制剂。
  157. 根据权利要求152-156中任一项所述的方法，其中施用所述EGFR抑制剂来治疗癌症。
  158. 根据权利要求152-157中任一项所述的方法，其中所述皮疹的患处与癌症的患处不同。
  159. 根据权利要求152-158中任一项所述的方法，其中向所述受试者局部施用所述JAK抑制剂。
  160. 根据权利要求152-159中任一项所述的方法，其中向所述受试者中基本不含癌细胞的部位局部施用所述JAK抑制剂。
  161. 根据权利要求152-160中任一项所述的方法，其中向所述受试者中的非癌症部位施用所述JAK抑制剂。
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