Compounds and their uses

Abstract

This application relates to compounds of formula (I) and their uses, and further to processes for the preparation of said compounds. TIFF2025505812000035.tif31170

Description

[Technical field]

[0001] This application relates to the field of medicine, specifically to prodrugs of JAK inhibitors and their pharmaceutical uses. [Background technology]

[0002] Janus kinases (JAKs) are intracellular non-receptor tyrosine kinases that mediate the signal transduction and activation of various cytokines. The JAK kinase family is divided into four isoforms, JAK1, JAK2, JAK3 and TYK2, and each isoform mediates a different type of cytokine signaling pathway. JAK-1, JAK-2 and TYK-2 are expressed in cells of various tissues in the human body, while JAK-3 is mainly expressed in cells of various hematopoietic tissues. A common feature of cytokine receptors is that the receptors themselves do not have kinase activity, but the intracellular segments of the receptors have a site that binds to the tyrosine kinase JAK. When cytokine receptors bind to their ligands, the receptor-bound JAKs are activated and phosphorylate the receptor. The phosphorylated tyrosine sites bind to SH2 domain-containing STAT proteins, which then recruit STATs to receptors and are phosphorylated by JAKs, leading to phosphotyrosine-mediated STAT dimerization. The activated STAT dimers translocate to the nucleus and activate the transcription of target genes, thereby controlling the proliferation, activation, differentiation, and other functions of various cells.

[0003] The JAK / STAT signaling pathway mediates the intracellular signaling of most cytokines and plays an important role in immune regulation, immune cell proliferation, and other biological processes. The JAK / STAT signaling pathway has a wide range of functions and is involved in many important biological processes, such as cell proliferation, differentiation, apoptosis, and immune regulation, and is closely related to various inflammatory diseases, such as rheumatoid arthritis, dermatitis, psoriasis, and inflammatory bowel disease (ulcerative colitis, Crohn's disease). At the same time, the JAK / STAT signaling pathway is closely related to oncological diseases, such as myelofibrosis, polycythemia vera, and primary thrombocythemia, and mutations in the JAK molecule itself can cause oncological diseases, such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), ductal carcinoma, and non-small cell lung cancer (NSCLC).

[0004] Currently available and investigational JAK inhibitors work primarily by competing with the kinase structural domain for ADP binding, and therefore generally lack selectivity, and even selective inhibitors of specific JAK isoforms suffer from serious target-related side effects.

[0005] Considering the good efficacy of JAK inhibitors and the severe side effects associated with their multi-targeting, the development of safer JAK inhibitors is an urgent task. Furthermore, for various clinical needs, developing prodrugs that enhance the local exposure of the drug is a good strategy to improve safety. Summary of the Invention

[0006] On the one hand, this application relates to compounds of formula (I), their medicamentous salts, biologically active metabolites, solvates, hydrates, prodrugs, racemates, enantiomers or stereoisomers,

[0007] [ka]

[0008] During the ceremony: G is a JAK inhibitor, R and R are each independently selected from hydrogen, deuterium, tritium, optionally substituted alkyl, optionally substituted deuterium alkyl, optionally substituted halo alkyl, optionally substituted alkoxy, optionally substituted halo alkoxy, halogen, and an optionally substituted ring group; and n is 1 to 5. In certain embodiments, said n is 2 to 4. In certain embodiments, said n is 1. In certain embodiments, said n is 2. In certain embodiments, said n is 3. In certain embodiments, said n is 4. In certain embodiments, said n is 5.

[0009] In certain embodiments, R and R are each independently -(CH) n1 Ra, -(CH2) n1 ORa, -(CH2) n1 SRa, -(CH2) n1 C(O)Ra, -(CH2) n1 C(O)ORa, -(CH2) n1 S(O) m1 Ra, -(CH2) n1 NRaRb, -(CH2) n1 C(O)NRaRb, -(CH2) n1 NRaC(O)Rb and -(CH2) n1 NRaS(O) m1 Rb; wherein R and R are the same or different and are each independently selected from hydrogen, deuterium, tritium, alkyl, deuteroalkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, deuteroalkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, and heteroaryl are optionally further substituted with one or more groups selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or, Ra and Rb are linked to form a cycloalkyl, heterocycle, aryl, or heteroaryl, wherein the cycloalkyl, heterocycle, aryl, and heteroaryl are optionally further substituted with one or more groups selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; n1 is 0 to 5, for example, n1 may be 0, 1, 2, 3, 4 or 5; and m1 is 0, 1 or 2.

[0010] In certain embodiments, R1 is a polymeric compound, for example a polymeric compound having multiple repeating units, such as a polymeric compound obtained by crosslinking.

[0011] In certain embodiments, R is a polymeric compound, for example a polymeric compound having multiple repeating units, including polymeric compounds obtained by crosslinking.

[0012] In certain embodiments, the ring group is selected from cycloalkyl, heterocycle, oxoheterocycle, thioheterocycle, aryl, and heteroaryl. In certain embodiments, the cycloalkyl, heterocycle, oxoheterocycle, thioheterocycle, aryl, and heteroaryl are optionally further substituted with one or more groups selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0013] In certain embodiments, R1 is hydrogen, optionally substituted alkyl, or optionally substituted deuteroalkyl.

[0014] In certain embodiments, R1 is hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 deuteroalkyl.

[0015] In certain embodiments, R1 is hydrogen, optionally substituted methyl, or optionally substituted deuteromethyl.

[0016] In certain embodiments, R is selected from optionally substituted alkyl, optionally substituted deuteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0017] In certain embodiments, R is an optionally substituted C-C 20 Alkyl, optionally substituted C-C 20 Deuterated alkyl, optionally substituted C3-C 20 Cycloalkyl, optionally substituted C-C 20 Heterocycloalkyl, optionally substituted C-C 20 Aryl and optionally substituted C-C 20 Heteroaryl is selected from the group consisting of aryl, hetero ...

[0018] In certain embodiments, n is 2.

[0019] In certain embodiments, R1 is hydrogen, optionally substituted methyl, or optionally substituted deuterated methyl, n is 2, and R is an optionally substituted C3-C 20 Cycloalkyl or optionally substituted C-C 20 It is a heterocycloalkyl.

[0020] In certain embodiments, G is: Ruxolitinib, Tofacitinib, Oclacitinib, Fedratinib, Peficitinib, Upadacitinib, Barictinib, Filgotinib, Decernotinib, Cerdulatinib, Lestaurtinib, Pacritinib, Momelotinib, Gandotinib, Abrocitinib. , Solcitinib, SHR-0203, Itacitinib, PF-06651600, BMS-986165, Abrocitinib, Cucurbitacin II), CHZ868, TD-1473, zotiraciclib, alkotinib, jaktinib, AZD-4205, DTRMHS-07, KL130008, WXSH-0150, TQ05105, WXFL10203614, GLPG0634, CEP-33779, R-348, itacitinib, ritlecitinib, brepocitinib, tasocitinib, duclavacitinib (D eucravacitinib, INCB-039110, Izencitinib, Entrectinib, Ivarmacitinib, Deuruxolitinib, Adelatinib, NDI-034858, Nezulcitinib, ATI-01777, TD-8236, INCB-054707, Ropsacitinib, AGA-201, ATI50001, Gusac 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, GL The JAK inhibitor is selected from the group consisting of PG-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 and AC-1101.

[0021] In certain embodiments, G is: Tofacitinib, Ruxolitinib, Baricitinib, Peficitinib, Pacritinib, Delgocitinib, Pf-04965842, Upadacitinib, Filgotinib, Itacitinib, Fedratinib, Decernotinib, SHR-0302, ASN-002, Cerdulatinib, BMS-986165, PF-06700841, INCB-52793, The JAK inhibitor is selected from the group consisting of ATI-502, PF-06651600, AZD-4205, deuterated ruxolitinib analogs, ATI-501, R-348, NS-018, jactinib hydrochloride, and KL-130008.

[0022] In certain embodiments, the compound is

[0023] [ka]

[0024] TIFF2025505812000004.tif230170

[0025] is selected from the group consisting of:

[0026] In the meantime, this application provides methods for the preparation of the compounds described herein, their medicamentous salts, biologically active metabolites, solvates, hydrates, prodrugs, racemates, enantiomers or stereoisomers.

[0027] In the meantime, this application provides compositions comprising the compounds described herein, their medicamentable salts, biologically active metabolites, solvates, hydrates, prodrugs, racemates, enantiomers or stereoisomers.

[0028] In certain embodiments, the composition is a pharmaceutical composition and includes a pharma- ceutically acceptable carrier.

[0029] In certain embodiments, the compound, its medicamentous salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer, or stereoisomer is present in the composition at a concentration of about 0.001% w / w to about 40% w / w.

[0030] In certain embodiments, the composition is in a formulation suitable for topical application, hi certain embodiments, the composition is an ointment.

[0031] Alternatively, a compound described in this application, its medicamentous salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer; or a composition described in this application may be used for the prevention, alleviation and / or treatment of an anti-tumor disease or condition in a subject in association with administration of the agent.

[0032] On the one hand, this application provides the use of said compound, its medicamentous salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer; or said composition for the preparation of a medicament, said medicament being used for the prevention, alleviation and / or treatment of a disease or condition in a subject associated with the administration of an anti-tumor agent.

[0033] Alternatively, the compounds described in this application, their medicamentable salts, biologically active metabolites, solvates, hydrates, prodrugs, racemates, enantiomers or stereoisomers; or the compositions described in this application may be used in the preparation of JAK inhibitors.

[0034] On the other hand, this application provides a method for use in the prevention, alleviation and / or treatment of a disease or condition in a subject associated with the administration of an anti-tumor agent, said method comprising administering to a subject in need thereof a compound described in this application, a medicament salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof; or a composition described in this application.

[0035] Meanwhile, this application provides a method of preventing, treating and / or alleviating a disease or condition caused by JAK in a subject in need thereof, said method comprising administering to said subject an effective amount of a compound described herein, a medicament salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof; or a composition described herein, said effective amount may be a dose effective to effectively prevent, treat and / or alleviate said disease or condition caused by JAK.

[0036] In certain embodiments, the method further comprises administering an additional therapeutic agent, which may be an agent that can effectively prevent, treat and / or ameliorate a disease or condition caused by JAK. In certain embodiments, the additional therapeutic agent is: Ruxolitinib, Tofacitinib, Oclacitinib, Fedratinib, Peficitinib, Upadacitinib, Barictinib, Filgotinib, Decernotinib, Cerdulatinib, Lestaurtinib, Pacritinib, Momeltinib, Gandotinib, Abrocitinib. , Solcitinib, SHR-0203, Itacitinib, PF-06651600, BMS-986165, Abrocitinib, Cucurbitacin II), CHZ868, TD-1473, zotiraciclib, alkotinib, jaktinib, AZD-4205, DTRMHS-07, KL130008, WXSH-0150, TQ05105, WXFL10203614, GLPG0634, CEP-33779, R-348, itacitinib, ritlecitinib, brepocitinib, tasocitinib, duclavacitinib (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 and AC-1101.

[0037] In the meantime, this application provides the use of a compound described herein, its medicamentable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer, or a composition described herein in the preparation of a medicament, said medicament being used for preventing, treating and / or ameliorating a disease or condition caused by JAK in a subject in need thereof.

[0038] In certain embodiments, the JAK-induced disease or condition is selected from the following: an autoimmune disease or response, widespread activation of an immune response, bacterial infection, viral infection, inflammation, chronic and / or acute inflammatory disease or condition, and / or autoinflammatory disease, fibrotic disease, metabolic disease, neoplasm, or cardiovascular or cerebrovascular disease, skin disorder, pruritus, hair loss disorder, cancer or malignancy, autoimmune connective tissue disease and autoimmune disease; Still's disease, adult-onset Still's disease, Th17-associated inflammation, polychondritis (such as relapsing polychondritis); myositis, polymyositis, autoimmune myositis, dermatomyositis, juvenile dermatomyositis; myasthenia gravis; arthritis (e.g., rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile rheumatoid arthritis, osteoarthritis, infectious arthritis, inflammatory arthritis, inflammatory bowel disease-related arthritis, idiopathic arthritis, juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, psoriatic arthritis), spondylitis / spondyloarthritis / spondyloarthropathy (ankylosing spondylitis), gout, scleroderma (systemic sclerosis, juvenile scleroderma), Reiter's syndrome / reactive arthritis, Lyme disease, lupus / systemic lupus erythematosus (SLE) (lupus erythematosus, pediatric SLE, cutaneous lupus (subacute cutaneous lupus, chronic cutaneous lupus / discoid lupus, chilblain-like lupus) Lupus erythematosus), polymyalgia rheumatica, enthesitis, mixed connective tissue disease, enthesopathy, carditis, myocarditis, angiogenic disorders, myelodysplastic syndromes, atherosclerosis, restenosis (coronary artery restenosis due to atherosclerosis), acute coronary syndromes, myocardial infarction, cardiac allograft vasculopathy, transplant arterial disease; vasculitis (large vessel vasculitis, small vessel vasculitis, giant cell arteritis, polyarteritis nodosa, vasculitis syndromes, The vasculitis syndromes include aortitis, Wegener's granulomatosis, Behcet's disease), STING-associated vasculitis in infancy (SAVI); gastrointestinal disorders, enteritis, colitis, inflammatory bowel disease (ulcerative colitis, Crohn's disease), irritable bowel syndrome, bowel syndrome / spastic colon, celiac disease; acute pancreatitis, chronic pancreatitis; primary biliary cirrhosis, primary sclerosing cholangitis, jaundice, cirrhosis (e.g., primary biliary cirrhosis, cirrhosis due to fatty liver disease (alcoholic steatosis, nonalcoholic steatosis)); esophagitis, gastritis, gastric and duodenal ulcers, peritonitis; nephropathy, immune-mediated glomerular nephropathy, autoimmune nephropathy, membranous glomerulopathy, chronic progressive nephropathy, diabetic kidney disease / diabetic nephropathy, renal fibrosis,Renal ischemia / reperfusion injury, HIV-associated nephropathy, ureteral obstructive nephropathy, glomerulosclerosis, proteinuria, nephrotic syndrome, polycystic kidney disease, autosomal dominant polycystic kidney disease, nephropathy is immune-mediated nephropathy, autoimmune nephropathy, chronic progressive nephropathy, diabetic nephropathy, renal fibrosis, ischemia / reperfusion injury-associated nephropathy, HIV-associated nephropathy, ureteral obstructive nephropathy, glomerulonephritis, chronic kidney disease (diabetic nephropathy, etc.), hypertensive nephropathy, glomerulosclerosis, proteinuria, nephrotic syndrome, polycystic kidney disease, autosomal dominant polycystic kidney disease, diabetic kidney disease, lupus nephritis; interstitial cystitis; periodontitis, gingivitis; lung inflammation, sinusitis, pneumonia, bronchitis, Asthma, bronchial asthma, allergic asthma, non-allergic asthma, allergic bronchopulmonary mycosis, aspirin-induced asthma, adult-onset asthma, asthma with fixed airflow obstruction, exercise-induced asthma, cough fluctuating asthma, work-related asthma, nocturnal asthma, asthma associated with obesity, eosinophilic asthma, hormone-resistant asthma / severe asthma, extrinsic asthma, intrinsic asthma / idiopathic asthma, Churg-Strauss syndrome, bronchiolitis, bronchiolitis obliterans, chronic obstructive pulmonary disease (COPD), interstitial lung disease (pulmonary fibrosis, idiopathic pulmonary fibrosis), acute lung injury, pulmonary fibrosis (idiopathic pulmonary fibrosis or cystic fibrosis, etc.), chronic obstructive pulmonary disease, Adult respiratory distress syndrome, acute lung injury, drug-induced lung injury; Meniere's disease; eye disorders, including, for example, eye inflammation, uveitis, dry eye / keratoconjunctivitis, scleritis, episcleritis, keratitis / corneal disease, choroiditis, retinal vasculitis, optic neuritis, retinopathies (diabetic retinopathy, immune-mediated retinopathy, macular degeneration, wet macular degeneration, dry (age-related) macular degeneration); mastocytosis, iron deficiency anemia, uremia, hypereosinophilic syndrome (HES), systemic mastocytosis (SMCD), myelodysplastic syndrome group, idiopathic thrombocytopenic purpura;bone resorption disorders;neurodegenerative disorders, neurological / neuromuscular disorders (e.g.), multiple sclerosis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS) (familial ALS, sporadic ALS), Alzheimer's disease, myasthenia gravis, Lambert-Eaton myasthenic syndrome (LEMS), Guillain-Barre syndrome, meningitis, encephalitis, traumatic brain injury;neuropathy, delusional parasitosis, abnormalities in neuronal processes and sensory regulation, stroke / neural ischemia, spinal cord injury, peripheral neuropathy, tactile hallucinations, spinal cord injury, psychiatric disorders;paresthesia pain (acute pain, chronic pain, neuropathic pain, fibromyalgia), nerve irritation, peripheral neuropathy;pruritus / itch (atopic pruritus,Dry pruritus, pruritus associated with psoriasis / psoriatic pruritus / psoriasis-related pruritus), acute pruritus, chronic pruritus, idiopathic pruritus, chronic idiopathic pruritus, biliary pruritus, hepatobiliary pruritus, nephrotic pruritus / nephrotic pruritus, uremic pruritus, cholestasis, intrahepatic cholestasis of pregnancy, chronic lichen simplex-related pruritus, Lymphoma-associated itch, leukemia-associated itch, prurigo nodularis, atopic dermatitis-associated itch, atopic itch / atopic pruritus, bullous itch, brachioradial pruritus, neurogenic itch, neurogenic itch, dorsal paresthesias, HIV-associated pruritic papule, psychogenic itch, swimmer's itch, pruritic or uremic itch, urticarial itch; skin disorders ( For example), skin drug reactions / drug eruptions, xerosis / dry skin, rash, skin sensitization, skin irritation, sunburn, razor rash, body lice, head lice / pediculosis, hairy lice, cutaneous larva migrans, scabies, parasitosis, insect infection, urticaria / hives, papular urticaria, insect bites, insect stings, dandruff, foreign body or device on the skin, fungal infection, herpes, chickenpox / Chickenpox, Eosinophilic folliculitis, Skin diseases of pregnancy / Pruritic urticarial papules and plaques of pregnancy (PUPP), Inflammatory dermatoses, Neutrophilic dermatoses, Histiocytic neutrophilic dermatoses, Intestinal bypass syndrome dermatoses, Psoriasis / Psoriasis vulgaris, Lichen planus, Lichen sclerosus atrophicus, Acne (Acne vulgaris, Acne acne, Inflammatory acne, Nodular cystic acne, Keloid acne, Keloid acne cervical), Atopic diseases (Allergic contact sensitization, Allergic dermatitis), Dermatitis (Atopic dermatitis / Eczema, Contact dermatitis, Photodermatitis, Seborrheic dermatitis, Stasis dermatitis), Acute febrile neutrophilic dermatoses (Sweet's syndrome), Chronic atypical neutrophilic lipodystrophy and Hyperthermia group (CANDLE syndrome), hidradenitis suppurativa, urticaria, pyoderma gangrenosum, alopecia (eyebrow alopecia, alopecia of the internasal hairs, cicatricial alopecia (e.g., cicatricial alopecia, central centrifugal cicatricial alopecia, lichen planus, frontal fibrosing alopecia, alopecia alopecia)), non-cicatricial alopecia (alopecia areata (AA) (patchy AA, alopecia totalis (AT), alopecia universalis (AU), serpiginous pattern alopecia, sisaihpo pattern alopecia areata)), androgenic / androgenic alopecia (AGA) / male and female pattern AGA), telogen effluvium, tinea capitis, hypotrichosis (hereditary hypotrichosis simplex), lichen planus pilaris (frontal fibrosing alopecia), punctate palmoplantar keratoderma,Erythema vulgaris persistently (EED), neutrophilic exudative secretory hidradenitis, columnar cell neutrophilic granulomatous dermatitis, neutrophilic urticarial dermatosis, vitiligo vulgaris including segmental vitiligo (unisegmental vitiligo, bisegmental vitiligo, multisegmental vitiligo vulgaris), non-segmental vitiligo (on the fingers, toes, face, or extremities) Vitiligo vulgaris (type vitiligo, midfacial vitiligo, vitiligo vulgaris, mucosal type vitiligo vulgaris, confetti type vitiligo, tricolor vitiligo, marginal inflammatory vitiligo, tetracolor vitiligo, blue vitiligo vulgaris, Koebner phenomenon, vitiligo vulgaris, generalized vitiligo vulgaris, generalized vitiligo vulgaris), mixed vitiligo vulgaris / segmental related vitiligo Segmental vitiligo, localized vitiligo, isolated mucosal vitiligo or vitiligo with or without leukoderma (including body hair); bullous diseases, immune bullous diseases (bullous pemphigoid, cicatricial pemphigoid, pemphigus vulgaris, linear IgA disease), gestational pemphigoid, xeroderma pigmentosum; fibrotic and scarring disorders: fibroids, liver fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, e.g., scleroderma, increasing fibrosis, keloids, low-grade scar formation due to postoperative scar formation; wound healing, surgical scars, radiation-induced fibrosis (e.g., head and neck, digestive system or lungs), CNS scars, digestive tract or system Fibrosis, renal fibrosis, liver or bile duct fibrosis, liver fibrosis (e.g., nonalcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma), cardiac fibrosis (e.g., endomyocardial fibrosis or atrial fibrosis), ophthalmic scarring, fibrosclerosis, scarring enhancement, trauma or scabies healing, keloids, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis / Ormond's disease, progressive massive fibrosis, nephrogenic systemic fibrosis; Sjogren's syndrome, sarcoidosis, familial Mediterranean fever, cryopyrin-associated periodic syndrome (Muckle-Wells syndrome, familial cold autoinflammatory syndrome / familial cold urticaria / TNF receptor-associated peritoneal fibrosis) inflammatory syndrome, neonatal onset multisystem inflammatory disease), hyperoxia-induced inflammation, reperfusion injury, postoperative trauma, tissue injury, hyperthermia syndrome; diabetes (type I diabetes, type II diabetes) / diabetes, Hashimoto's thyroiditis, Graves' disease, Addison's disease, Castleman's disease, hyperparathyroidism, menopause, obesity, steroid-resistance, impaired glucose tolerance, metabolic syndrome, thyroid disease, hypophysitis; systemic immune senescence; autoimmune atrophic gastritis, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, Sjogren's syndrome, autoimmune thrombocytopenia,Sympathetic ophthalmia; hematologic manifestations secondary to autoimmune disease (e.g., anemia), autoimmune hemolytic syndrome (autoimmune hemolytic anemia), autoimmune and inflammatory hepatitis, autoimmune ovarian failure, autoimmune thrombocytopenia, silicone implant-associated autoimmune disease, drug-induced autoimmune disease, HIV-associated autoimmune syndrome, metal-induced autoimmune disease, autoimmune hearing loss, autoimmune thyroid disorders; allergies and allergic reactions, including hypersensitivity reactions, e.g., type I hypersensitivity reactions (e.g., (including anaphylaxis), type II hypersensitivity reactions (e.g., Goodpasture's disease, autoimmune hemolytic anemia), type III hypersensitivity reactions (e.g., Arthus reaction, serum sickness), and type IV hypersensitivity reactions (e.g., contact dermatitis, allograft rejection); acute and chronic infections, septic syndromes (sepsis, septic shock, endotoxin shock, exotoxin-induced toxic shock, gram-negative sepsis, gram-positive sepsis, fungal sepsis, toxic shock syndrome) symptoms); acute and chronic infections, sepsis syndromes (sepsis, septic shock, endotoxin shock, exotoxin-induced toxic shock, gram-negative sepsis, gram-positive sepsis, fungal sepsis, toxic shock syndrome); rejection: graft-versus-host reaction / graft-versus-host disease, allograft rejection (e.g., acute allograft rejection or chronic allograft rejection), early transplant rejection; malignancies, cancer, lymphoma, leukemia, multiple myeloma, solid tumors, teratomas, Metastatic and bone disorders, internal cancers, cancers of the bone, mouth / pharynx, esophagus, larynx, stomach, intestines, colon, rectum, lungs (e.g., non-small cell lung cancer or small cell lung cancer), liver (hepatic), pancreas, nerves, brain (e.g., glioma, glioblastoma multiforme, astrocytoma, neuroblastoma, and schwannoma), head and neck, throat, ovaries, uterus, prostate, testes, bladder, kidney (renal), breast, gallbladder, cervix, thyroid, prostate, eyes (eye malignancies), and skin (melanoma, keratoacanthoma); and fibrous carcinoma, fibroma, fibroadenoma, fibrosarcoma, myeloproliferative disorders, neoplasms (hematopoietic, myeloid, lymphoid neoplasms (myelofibrosis, primary myelofibrosis, polycythemia vera, essential thrombocythemia)), leukemias (acute lymphocytic leukemia, acute and chronic myeloid leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, chronic myelomonocytic leukemia (CMML), or promyelocytic leukemia), multiple myeloma and other myeloid malignancies (myeloid metaplasia with myelofibrosis (MMM), primary myelofibrosis (PMF), especially myelofibrosis (IMF)); lymphoma (Hodgkin's disease, cutaneous lymphoma (cutaneous T-cell lymphoma, mycosis fungoides); lymphoma (e.g., B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, hairy cell lymphoma, Burkitt lymphoma, mast cell tumor, Hodgkin's disease or non-Hodgkin's disease); Kaposi's sarcoma, rhabdomyosarcoma, seminoma, teratocarcinoma, osteosarcoma, follicular thyroid carcinoma; increased exogenous or synthetic opioid accumulation, paresthesia back pain, obsessive-compulsive disorder, obsessive-compulsive disorder-related nostalgia, and combinations thereof.

[0039] Those skilled in the art can easily ascertain other aspects and advantages of this application from the following detailed description. In the following detailed description, only exemplary embodiments of this application are shown and described. As will be recognized by those skilled in the art, the contents of this application will enable those skilled in the art to make changes to the specific embodiments disclosed without departing from the spirit and scope of the invention to which this application pertains. Accordingly, the drawings and description of this application are merely illustrative and are not intended to be limiting. [Brief description of the drawings]

[0040] Specific features of the invention of this application are set forth in the accompanying patent claims. A better understanding of the features and advantages of the invention of this application can be obtained by reference to the exemplary embodiments and drawings described in detail below. A brief description of the accompanying drawings is provided below: Figure 1 shows a mouse model of rash following the use of an antitumor agent. FIG. 2 shows photographs of the left side, back, and right side of a typical rat from the control and treatment groups. Figure 3 shows the severity of the rash in the treatment and control groups at the end of the experiment. Figure 4 shows the severity of the rash in the treatment and control groups at the end of the experiment. FIG. 5 shows photographs of the left side, back, and right side of a typical rat from the control and treatment groups. Figure 6 shows the severity of the rash in the treatment and control groups at the end of the experiment. Figure 7 shows the severity of rash in the treatment and control groups at the end of the experiment.

[0041] Hereinafter, the embodiments of the present invention will be described with reference to specific examples. However, other advantages and effects of the present invention will be easily understood by those skilled in the art from the contents disclosed in this specification.

[0042] In this application, the term "prodrug" is also referred to as a "precursor drug" and generally refers to an agent or compound that is converted to a parent or active drug molecule in vivo. For example, the "prodrug" may be a precursor of another active drug molecule, which upon administration to a subject, generates the other active drug molecule in vivo by a chemical or physiological process, such as solvolysis or enzymatic cleavage, or under physiological conditions.

[0043] As used herein, the term "optionally substituted alkyl" includes straight or branched chain alkyls that have no substituents, and also includes straight or branched chain alkyls that have one or more non-hydrogen substituents. For example, the alkyl typically consists of a saturated aliphatic hydrocarbon having a specified number of carbon atoms and may be branched or straight chain. The term "alkyl" also refers to non-aromatic cycloalkyls. For example, the alkyl may be a cycloalkyl having 1 to 20 carbon atoms (i.e., C1 to C6). 20 For example, "C1-C 10 "Alkyl" C1-C 10is defined as a group of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbons having a straight, branched, or cyclic arrangement (i.e., cycloalkyl). The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon having the specified number of carbon atoms. For example, "alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like, and cycloalkyl includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and the like.

[0044] In this application, the term "biologically active metabolite" generally refers to a compound (e.g., a compound of this application) that is processed in vivo by metabolism in the human or animal body or cells to produce a metabolite. For example, the "biologically active metabolite" may include derivatives of any structural formula that are produced in an individual's body after administration of the parent compound. These derivatives can be generated from the parent compound by various biochemical transformations in an individual's body, such as oxidation, reduction, hydrolysis, conjugation, and include, for example, oxidized derivatives and demethylated derivatives. Metabolites of the compounds of the invention can be identified using conventional techniques known in the art. Examples include Bertolini, G. et al, J. Med. Chem. 40: 2011-2016 (1997); Shan, D. et al, J. Pharm. Sci. 86 (7): 765-767; Bagshawe K., Drug Dev. Res. 34: 220-230 (1995); Bodor, N., Advances in Drug Res. 13: 224-331 (1984); Bundgaard, H., Design of Prodrugs (Elsevier Press 1985); and Larsen, IK, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al, Harwood Academic Publishers, 1991). It will be apparent that included in this application are chemical compounds that are metabolites of compounds of formula (I) or their tautomers, prodrugs and stereoisomers, as well as pharma- ceutical salts, esters and prodrugs of any of them.

[0045] In this application, the term "JAK inhibitor" generally refers to a Janus tyrosine kinase inhibitor, which relates to a compound that targets, decreases or inhibits Janus tyrosine kinase, and may directly or indirectly target one or more JAKs, inhibit said JAKs at the transcriptional level, translational level and / or at the level of post-translational modification of proteins, inhibit the number or expression of said JAKs, or inhibit the activity of said JAKs.

[0046] In this application, the term "pharmaceutical salt" generally refers to a salt that retains the biological effectiveness and properties of the free base or free acid and is biologically or otherwise desirable. The salt may be a salt formed with an inorganic acid or an organic acid. Furthermore, the pharmaceutical salt may be prepared by adding an inorganic or organic base to the free acid.

[0047] The term "pharmacologically acceptable" in this application generally refers to compounds, materials, compositions and / or dosage forms that are suitable for use in contact with the tissues of humans and animals, within the scope of reasonable medical judgment, without undue toxicity, irritation, allergic response, or other problem or complication, and with a reasonable benefit / risk ratio. In some embodiments, pharmacologically acceptable compounds, materials, compositions and / or dosage forms refer to those approved by a regulatory agency (e.g., the U.S. Food and Drug Administration, the State Food and Drug Administration of the People's Republic of China, or the European Medicines Agency) or listed in a universally recognized pharmacopoeia (e.g., the United States Pharmacopoeia, the Chinese Pharmacopoeia, or the European Pharmacopoeia) intended for use in animals (more specifically, humans). Description of the Invention

[0048] On the one hand, this application provides a compound of formula (I), and also provides a pharmaceutical salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer of the compound,

[0049] [ka]

[0050] During the ceremony: G is a JAK inhibitor, R and R are each independently selected from hydrogen, deuterium, tritium, optionally substituted alkyl, optionally substituted deuterium alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted haloalkoxy, halogen, and ring optionally substituted groups; and n is 1, 2, 3, 4, or 5.

[0051] In the meantime, this application provides methods for the preparation of the aforementioned compounds described herein, their medicamentous salts, biologically active metabolites, solvates, hydrates, prodrugs, racemates, enantiomers or stereoisomers.

[0052] However, this application provides compositions comprising the compounds, their medicamentable salts, biologically active metabolites, solvates, hydrates, prodrugs, racemates, enantiomers or stereoisomers.

[0053] In certain embodiments, the composition of the present application is a pharmaceutical composition.For example, it may contain one or more pharma-ceutically acceptable carriers.For example, the pharma-ceutically acceptable carriers may be selected from the group consisting of fillers, binders, disintegrants, buffers, preservatives, lubricants, flavoring agents, thickeners, coloring agents, and emulsifiers.

[0054] In certain embodiments, the pharmaceutical composition or compound described in this application is formulated to be suitable for topical administration. For example, the drug or compound may be formulated to be suitable for transdermal administration. In some embodiments, the drug or compound is formulated to be suitable for topical administration. In certain embodiments, the drug is formulated as a cream, lotion, gel, ointment, salve, spray, liposomal formulation, liniment, and / or aerosol. In certain embodiments, the drug or compound may be formulated in an ointment.

[0055] In some embodiments, the pharmaceutical composition or the compound is an oral dosage formulation. In some embodiments, the pharmaceutical composition or the compound may be an injectable formulation. In some embodiments, the pharmaceutical composition or the compound may be an oral topical medication.

[0056] The compound, its medicamentous salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer, or stereoisomer may be present in the pharmaceutical composition at a concentration of about 0.0001% (w / w) to about 50% (w / w). For example, the concentration of the compound may be about 0.0001% (w / w) to about 40% (w / w), about 0.0001% (w / w) to about 30% (w / w), about 0.0001% (w / w) to about 20% (w / w), about 0.0001% (w / w) to about 15% (w / w), e.g., about 0.0001% (w / w) to about 10% (w / w), about 0.0001% (w / w) to about 9.5% (w / w). 0.0001%(w / w) to about 9%(w / w), 0.0001%(w / w) to about 8.5%(w / w), 0.0001%(w / w) to about 8%(w / w), 0.0001%(w / w) to about 7.5%(w / w), 0.0001%(w / w) to about 7%(w / w), 0.0001%(w / w) to about 6.5%(w / w), 0.0001%(w / w) to about 6% (w / w), about 0.0001% (w / w) to about 5.5% (w / w), about 0.0001% (w / w) to about 5% (w / w), about 0.0001% (w / w) to about 4.5% (w / w), about 0.0001% (w / w) to about 4% (w / w), about 0.0001% (w / w) to about 3.5% (w / w), about 0.0001% (w / w) to about 3% (w / w), about 0.00 The amount of the active ingredient may vary within the range of from about 0.01% (w / w) to about 2.5% (w / w), from about 0.0001% (w / w) to about 2% (w / w), from about 0.0001% (w / w) to about 1.5% (w / w), from about 0.0001% (w / w) to about 1% (w / w), from about 0.0001% (w / w) to about 0.5% (w / w), from about 0.0001% (w / w) to about 0.01% (w / w), or less.In the compositions of this application, the concentration of the compound, its medicamentous salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer, or stereoisomer is from about 0.0001% (w / w) to about 5% (w / w), from about 0.0001% (w / w) to about 4% (w / w), from about 0.0001% (w / w) to about 3% (w / w), from about 0.0001% (w / w) to about 2.5% (w / w), from about 0.0001% (w / w) to about 2% (w / w), from about 0.0001% (w / w) to about 1.5 ... % (w / w), from about 0.0001% (w / w) to about 0.9% (w / w), from about 0.0001% (w / w) to about 0.8% (w / w), from about 0.0001% (w / w) to about 0.7% (w / w), from about 0.0001% (w / w) to about 0.6% (w / w), from about 0.05% (w / w) to about 0.5% (w / w), from about 0.05% (w / w) to about 0.4% (w / w), from about 0.05% (w / w) to about 0.3% (w / w), from about 0.05% (w / w) to about 0.2% (w / w), from about 0.1% (w / w) to about 0.2% (w / w), or less. For example, the concentration of the compound may be about 0.05% (w / w) to about 10% (w / w). In certain embodiments, the concentration of the compound is about 5% (w / w). In certain embodiments, the concentration of the compound is about 2.5% (w / w). In certain embodiments, the concentration of the compound is about 1% (w / w).

[0057] In this application, one or more other active ingredients may also be included in the composition. For example, the active ingredient may refer to a monomeric compound having medical utility or physiological activity. For example, the other active ingredient may be selected from the following groups: anti-inflammatory agents, analgesics, local anesthetics, antibiotics, antihistamines, antiseptics, immunosuppressants, and antihemorrhagic agents.

[0058] Alternatively, the compounds described in this application, their medicamentous salts, biologically active metabolites, solvates, hydrates, prodrugs, racemates, enantiomers or stereoisomers, or compositions (e.g., pharmaceutical compositions) described in this application are used in the prevention, amelioration and / or treatment of a disease or condition in a subject associated with the administration of an anti-tumor agent.

[0059] For example, a compound described in this application, its medicamentable salts, biologically active metabolites, solvates, hydrates, prodrugs, racemates, enantiomers or stereoisomers, or a composition (e.g., pharmaceutical composition) described in this application may be used in the preparation of a medicament (e.g., a packaged pharmaceutical product), which may be used in the prevention, amelioration and / or treatment of a disease or condition in a subject associated with the administration of an anti-tumor agent.

[0060] Alternatively, a compound described in this application, its medicamentable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer, or a composition (e.g., a pharmaceutical composition) described in this application may be used in the preparation of a JAK inhibitor or a composition (e.g., a pharmaceutical composition) comprising a JAK inhibitor.

[0061] Meanwhile, this application further provides a method for use in the prevention, alleviation and / or treatment of a disease or condition in a subject associated with the administration of an anti-tumor agent, said method comprising administering to a subject in need thereof a compound described in this application, a medicament salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof; or a composition (e.g., a pharmaceutical composition) described in this application.

[0062] Meanwhile, this application provides a method of preventing, treating and / or alleviating a disease or condition caused by JAK in a subject in need thereof, said method comprising administering to said subject an effective amount of a compound described herein, a medicament salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof; or a composition described herein, said effective amount may be a dose effective to effectively prevent, treat and / or alleviate said disease or condition caused by JAK.

[0063] In certain embodiments, the method further comprises administering an additional therapeutic agent, which may be an agent that can effectively prevent, treat and / or ameliorate a disease or condition caused by JAK. In certain embodiments, the additional therapeutic agent is: Ruxolitinib, Tofacitinib, Oclacitinib, Fedratinib, Peficitinib, Upadacitinib, Barictinib, Filgotinib, Decernotinib, Cerdulatinib, Lestaurtinib, Pacritinib, Momeltinib, Gandotinib, Abrocitinib. , Solcitinib, SHR-0203, Itacitinib, PF-06651600, BMS-986165, Abrocitinib, Cucurbitacin II), CHZ868, TD-1473, zotiraciclib, alkotinib, jaktinib, AZD-4205, DTRMHS-07, KL130008, WXSH-0150, TQ05105, WXFL10203614, GLPG0634, CEP-33779, R-348, itacitinib, ritlecitinib, brepocitinib, tasocitinib, duclavacitinib (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 and AC-1101.

[0064] In the meantime, this application provides the use of a compound described herein, its medicamentable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer, or a composition described herein in the preparation of a medicament, said medicament being used for preventing, treating and / or ameliorating a disease or condition caused by JAK in a subject in need thereof.

[0065] compound In the compounds of the present application, R1 may be hydrogen, an optionally substituted alkyl, or an optionally substituted deuterium alkyl. For example, R1 may be hydrogen, an optionally substituted C1-C6 alkyl, or an optionally substituted C1-C6 deuterium alkyl. For example, R1 may be hydrogen, an optionally substituted C1-C3 alkyl, or an optionally substituted C1-C3 deuterium alkyl. In certain embodiments, R1 is hydrogen, an optionally substituted methyl, or an optionally substituted deuterium methyl.

[0066] For example, R1 may be an unsubstituted alkyl (eg, an unsubstituted C1-C6 alkyl, an unsubstituted C1-C3 alkyl, an unsubstituted methyl).

[0067] In certain embodiments, R1 may be a substituted alkyl (e.g., substituted C1-C6 alkyl, substituted C1-C3 alkyl, substituted methyl). When R1 is a substituted alkyl, it may be optionally substituted with other groups, including one or more groups selected from the following groups: hydrogen, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, heterocycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxy, halogen, carbonyl, amino, cyano, and / or sulfonyl.

[0068] In certain embodiments, R1 is -(CH2) n1 Ra, -(CH2) n1 ORa, -(CH2) n1 SRa, -(CH2) n1 C(O)Ra, -(CH2) n1 C(O)ORa, -(CH2) n1 S(O) m1 Ra, -(CH2) n1 NRaRb, -(CH2) n1 C(O)NRaRb, -(CH2) n1 NRaC(O)Rb and -(CH2) n1 NRaS(O) m1Rb; wherein R and Rb may be the same or different and are each independently selected from hydrogen, deuterium, tritium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl are optionally selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. or the Ra and Rb are linked to form a cycloalkyl, a heterocycle, an aryl, or a heteroaryl, wherein the cycloalkyl, the heterocycle, the aryl, and the heteroaryl are optionally further substituted with one or more groups selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; n1 is 0 to 5, for example, the n1 may be 0, 1, 2, 3, 4, or 5; and m1 is 0, 1, or 2.

[0069] In certain embodiments, R1 is a polymeric compound, for example a polymeric compound having multiple repeating units, such as a polymeric compound obtained by crosslinking.

[0070] In the compounds of the present application, R may be selected from optionally substituted alkyl, optionally substituted deuterated alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0071] For example, R is an optionally substituted C-C 20 Alkyl, optionally substituted C-C 20 Deuterated alkyl, optionally substituted C3-C 20 Cycloalkyl, optionally substituted C-C 20 Heterocycloalkyl, optionally substituted C-C 20 Aryl and optionally substituted C-C 20 For example, R may be selected from optionally substituted C-C 10 Alkyl, optionally substituted C-C 10 Deuterated alkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Heterocycloalkyl, optionally substituted C-C 10 Aryl and optionally substituted C-C 10 Heteroaryl may be selected from the group consisting of aryl, heteroaryl,

[0072] For example, R can be an unsubstituted alkyl, deuterated alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In certain embodiments, R can be an unsubstituted C-C 20 Alkyl, C1-C 20 Deuterated alkyl, C3-C 20 Cycloalkyl, C1-C 20 Heterocycloalkyl, C6-C 20 Aryl or C1-C 20 In certain embodiments, R is an unsubstituted C-C 10 Alkyl, C1-C 10 Deuterated alkyl, C3-C 10 Cycloalkyl, C1-C10 Heterocycloalkyl, C6-C 10 Aryl or C1-C 10 It is heteroaryl.

[0073] In certain embodiments, R may be a substituted alkyl, a substituted deuteroalkyl, a substituted cycloalkyl, a substituted heterocycloalkyl, a substituted aryl, or a substituted heteroaryl. 20 Alkyl, substituted C1-C 20 Deuterium alkyl, substituted C3-C 20 Cycloalkyl, Substituted C1-C 20 Heterocycloalkyl, Substituted C6-C 20 Aryl or substituted C1-C 20 In certain embodiments, R is a substituted C-C 10 Alkyl, substituted C1-C 10 Deuterium alkyl, substituted C3-C 10 Cycloalkyl, Substituted C1-C 10 Heterocycloalkyl, Substituted C6-C 10 Aryl or substituted C1-C 10 When R is substituted alkyl, substituted deuteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl or substituted heteroaryl, it can be optionally substituted with other groups, such as one or more groups selected from the following groups: hydrogen, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, heterocycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxy, halogen, carbonyl, amino, cyano and / or sulfonyl.

[0074] In certain embodiments, R is: -(CH2) n1 Ra, -(CH2) n1 ORa, -(CH2)n1 SRa、-(CH2) n1 C(O)Ra、-(CH2) n1 C(O)ORa、-(CH2) n1 S(O) m1 Ra、-(CH2) n1 NRaRb、-(CH2) n1 C(O)NRaRb、-(CH2) n1 NRaC(O)Rb &-(CH2) n1 NRaS(O) m1Rb; wherein R and Rb may be the same or different and are each independently selected from hydrogen, deuterium, tritium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl are optionally selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. or the Ra and Rb are linked to form a cycloalkyl, a heterocycle, an aryl, or a heteroaryl, wherein the cycloalkyl, the heterocycle, the aryl, and the heteroaryl are optionally further substituted with one or more groups selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; n1 is 0 to 5, for example, the n1 may be 0, 1, 2, 3, 4, or 5; and m1 is 0, 1, or 2.

[0075] In certain embodiments, R is a polymeric compound, for example a polymeric compound having multiple repeating units, including polymeric compounds obtained by crosslinking.

[0076] In this application, the alkyl may include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, methylpentyl, dimethylbutyl, heptyl, octyl, nonyl, or decyl. The substituted alkyl may be substituted with a group selected from the following group: hydroxy, halogen, ester, nitrile, and carbonyl.

[0077] In certain embodiments of the present application, the ring group (e.g., saturated, partially saturated, or unsaturated, with or without heteroatoms) may be a three-membered ring, a four-membered ring, a five-membered ring, a six-membered ring, a bridged ring, and / or a fused ring. In certain embodiments, the substituted ring group (e.g., cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) may be substituted with a group selected from the group consisting of hydroxy, halogen, ester, nitrile, and carbonyl.

[0078] The R is an optionally substituted heterocycloalkyl (e.g., an optionally substituted C-C 20 Heterocycloalkyl, e.g., optionally substituted C-C 10 heterocycloalkyl), or optionally substituted heteroaryl (e.g., optionally substituted C-C 20 Heteroaryl, e.g., optionally substituted C-C 10 When the aryl group is a heteroaryl (heteroaryl), it may contain a heteroatom (eg, a monovalent radical of a heteroatom) selected from the group consisting of fluorine, oxygen, sulfur, and nitrogen.

[0079] In certain embodiments, the heterocycle (e.g., heterocycloalkyl or heteroaryl) may be an optionally substituted six-membered nitrogen-containing heterocycle. In certain embodiments, the heterocycle (e.g., heterocycloalkyl or heteroaryl) may be selected from furan, thiophene, pyrrole, thiazole, imidazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, quinoline, pteridine, and acridine.

[0080] In certain embodiments, the ring group is selected from cycloalkyl, heterocycle, oxoheterocycle, thioheterocycle, aryl, and heteroaryl. In certain embodiments, the cycloalkyl, heterocycle, oxoheterocycle, thioheterocycle, aryl, and heteroaryl are optionally further substituted with one or more groups selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0081] In certain embodiments, the optionally substituted aryl is an optionally substituted phenyl, for example, the aryl (e.g., phenyl) may be substituted with a group selected from the following group: hydroxy, halogen, ester, nitrile, and carbonyl.

[0082] In certain embodiments, n is 1 to 5. In certain embodiments, n is 2 to 4. In certain embodiments, n is 1, 2 or 3. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5.

[0083] In certain embodiments of the compounds of the present application, R1 is hydrogen, optionally substituted methyl, or optionally substituted deuterated methyl, n is 2, and R is an optionally substituted C3-C 20 Cycloalkyl or optionally substituted C-C 20 It is a heterocycloalkyl.

[0084] In certain embodiments of the compounds of the present application, R1 is hydrogen, optionally substituted methyl, or optionally substituted deuterated methyl, n is 2, and R is an optionally substituted C3-C 10 Cycloalkyl or optionally substituted C-C 10 It is a heterocycloalkyl.

[0085] In certain embodiments of the compounds of the present application, G is: Ruxolitinib, Tofacitinib, Oclacitinib, Fedratinib, Peficitinib, Upadacitinib, Barictinib, Filgotinib, Decernotinib, Cerdulatinib, Lestaurtinib, Pacritinib, Momeltinib, Gandotinib, Abrocitinib. , Solcitinib, SHR-0203, Itacitinib, PF-06651600, BMS-986165, Abrocitinib, Cucurbitacin II), CHZ868, TD-1473, zotiraciclib, alkotinib, jaktinib, AZD-4205, DTRMHS-07, KL130008, WXSH-0150, TQ05105, WXFL10203614, GLPG0634, CEP-33779, R-348, itacitinib, ritlecitinib, brepocitinib, tasocitinib, duclavacitinib (D eucravacitinib, INCB-039110, Izencitinib, Entrectinib, Ivarmacitinib, Deuruxolitinib, Adelatinib, NDI-034858, Nezulcitinib, ATI-01777, TD-8236, INCB-054707, Ropsacitinib, AGA-201, ATI50001, Gusac 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, GL The JAK inhibitor is selected from the group consisting of PG-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 and AC-1101.

[0086] In certain embodiments of the compounds of the present application, G is selected from the group consisting of Tofacitinib, Ruxolitinib, Baricitinib, Peficitinib, Pacritinib, Delgocitinib, Pf-04965842, Upadacitinib, Filgotinib, Itacitinib, Fedratinib, Decernotinib, SHR-0302, ASN-002, Cerdulatinib, BMS-986165, PF-06700841, INCB-52793, The JAK inhibitor is selected from the group consisting of ATI-502, PF-06651600, AZD-4205, deuterated ruxolitinib analogs, ATI-501, R-348, NS-018, jactinib hydrochloride, and KL-130008.

[0087] For example, the G can consist of (or have) a structure selected from the following group:

[0088] [ka]

[0089] For example, the structure of Tofacitinib is

[0090] [ka]

[0091] It is.

[0092] In certain embodiments, the compound is selected from the following group:

[0093] [ka]

[0094] TIFF2025505812000009.tif237170

[0095] is selected from.

[0096] Antitumor Agents According to any aspect of this application, the antitumor agent may comprise a small molecule compound, a small molecule complex, a protein and / or a polynucleotide.

[0097] For example, the anti-tumor agent may include a chemotherapeutic agent, a targeted therapeutic agent, and / or an immunotherapeutic agent.

[0098] In certain embodiments, the anti-tumor agent is a targeted therapeutic agent. The targeted therapeutic agent may comprise a small molecule compound and / or an antibody or antigen-binding fragment thereof. The antibody may comprise a monoclonal antibody, a multispecific antibody, a chimeric antibody, a humanized antibody, a fully human antibody, and / or an antibody-drug conjugate. The antigen-binding fragment may comprise a Fab, Fab', F(ab)2, an Fv fragment, F(ab')2, scFv, di-scFv, and / or a dAb.

[0099] In certain embodiments, the targeted therapeutic agent targets a molecule within a tumor cell, on the surface of a tumor cell, and / or in the tumor microenvironment. For example, the targeted therapeutic agent may target a protein and / or a nucleic acid molecule. For example, the targeted therapeutic agent may target a tumor-associated antigen.

[0100] In certain embodiments, the targeted therapy targets one or more targets selected from the group consisting of the following and variants thereof: VEGF, EGFR, EGFR1, EGFR2, EGFR3, EGFR4, HER2, HER3, HER4, VEGFR, VEGFR1, VEGFR2, VEGFR3, VEGFR4, PDGFR, PDGFRα, PDGFRβ, KIT, c-Kit, Ret, Raf, Raf-1, Abl, FGFR, FGFR1, MET, c-MET, Tie2, Src, c-Src, AXL, Ret, BCR-ABL, CSF-1R, FGFR, FGFR1, FGFR2, FGFR3, FGFR4, mTOR, TORC, BRaf, MEK, MEK1, MEK2, ALK, ABL, CDK, JAK, PI3K, NTRK, MSI, HDAC, FAK, PYK2.

[0101] For example, the targeted therapeutic agent may inhibit the activity of one or more targets selected from the group consisting of the following and variants thereof: VEGF, EGFR, EGFR1, EGFR2, EGFR3, EGFR4, HER2, HER3, HER4, VEGFR, VEGFR1, VEGFR2, VEGFR3, VEGFR4, PDGFR, PDGFRα, PDGFRβ, KIT, c-Kit, Ret, Raf, Raf-1, Abl, FGFR, FGFR1, MET, c-MET, Tie2, Src, c-Src, AXL, Ret, BCR-ABL, CSF-1R, FGFR, FGFR1, FGFR2, FGFR3, FGFR4, mTOR, TORC, BRaf, MEK, MEK1, MEK2, ALK, ABL, CDK, JAK, PI3K, NTRK, MSI, HDAC, FAK, PYK2.

[0102] For example, the targeted therapy may reduce expression of one or more targets selected from the group consisting of the following and mutants thereof: VEGF, EGFR, EGFR1, EGFR2, EGFR3, EGFR4, HER2, HER3, HER4, VEGFR, VEGFR1, VEGFR2, VEGFR3, VEGFR4, PDGFR, PDGFRα, PDGFRβ, KIT, c-Kit, Ret, Raf, Raf-1, Abl, FGFR, FGFR1, MET, c-MET, Tie2, Src, c-Src, AXL, Ret, BCR-ABL, CSF-1R, FGFR, FGFR1, FGFR2, FGFR3, FGFR4, mTOR, TORC, BRaf, MEK, MEK1, MEK2, ALK, ABL, CDK, JAK, PI3K, NTRK, MSI, HDAC, FAK, PYK2.

[0103] For example, the targeted therapeutic agent may include a hormone, a signal transduction inhibitor, a gene expression regulator, an apoptosis inducer, an angiogenesis inhibitor, and / or a toxin delivery molecule.

[0104] In certain embodiments, the targeted therapeutic agent is a tyrosinase inhibitor.

[0105] In certain embodiments, the targeted therapeutic agent is a VEGFR inhibitor and / or a VEGF inhibitor. For example, the VEGFR inhibitor may inhibit VEGFR1, VEGFR2 and / or VEGFR3. In certain embodiments, the targeted therapeutic agent is an EGFR inhibitor. In certain embodiments, the targeted therapeutic agent is a BRAF inhibitor. In certain embodiments, the targeted therapeutic agent is a PDGFR inhibitor. In certain embodiments, the targeted therapeutic agent is an FGFR inhibitor. In certain embodiments, the targeted therapeutic agent is an mTOR inhibitor. In certain embodiments, the targeted therapeutic agent is a HER2 inhibitor.

[0106] For example, in an embodiment of any aspect of this application, the EGFR (e.g., Her2) inhibitor may be selected from the following compounds and their medicamentable salts: afatinib, olmutinib, lapatinib, gefitinib, and dacomitinib.

[0107] For example, in an embodiment of any aspect of this application, the VEGFR inhibitor and / or VEGF inhibitor may be selected from the following compounds and their medicamentable salts: ramucirumab, bevacizumab, anlotinib, regorafenib, cabozantinib, lenvatinib, sorafenib, fruquintinib, famitinib, apatinib, axitinib and nintedanib.

[0108] For example, in embodiments of any aspect of this application, the BRAF inhibitor may be selected from the following compounds and their medicamentable salts: vemurafenib, encorafenib, selumetinib, and dabrafenib.

[0109] For example, in an embodiment of any aspect of this application, the PDGFR inhibitor may be selected from the following compounds and pharma- ceutical salts thereof: sunitinib and nintedanib.

[0110] For example, in an embodiment of any aspect of this application, the FGFR inhibitor may be selected from the following compounds and medicamentable salts thereof: erdafitinib and infigratinib.

[0111] For example, in embodiments of any aspect of this application, the mTOR inhibitor may be selected from the following compounds and medicamentable salts thereof: everolimus.

[0112] For example, the targeted therapeutic agent described in this application may be one or more selected from the following group: afatinib, dacomitinib, osimertinib, EAI045, gefitinib, amuvatinib, pyrotinib, brigutinib, neratinib, olmutinib, bosutinib, icotinib, vandetanib, lapatinib, alfutinib, BPI-7711, mobocertinib, dovitinib, zolifertinib, varlitinib, olebrutinib, labrutinib,Brutinib, ibrutinib, dasatinib, pirtobrutinib, trebrutinib, rilzabrutinib, fenebrutinib, evobrutinib, selumetinib, tivozanib, dovitinib, surufatinib, binimetinib, cobimetinib, trametinib, regorafenib, GSK-1120212, alpelisib, duvelisib, copanlisib, idelalisib, nortriptyline, inavolisib, dak Trisib, apitolisib, parsaclisib, buparlisib, rigosertib, enzastaurin, paxalisib, leniolisib, ipatasertib, zotarolimus, sirolimus, everolimus, temsirolimus, sorafenib, apatinib, lenvatinib, sunitinib, cabozantinib, axitinib, nin Tedanib, brivanib, vatalanib, fruquintinib, dabrafenib, vemurafenib, encorafenib, pazopanib, crizotinib, panobinostat, erlotinib, rituximab, panitumumab, cetuximab, erfonrilimab, defactinib, cadnilimab, ramucirumab, bevacizumab , anlotinib, ponatinib, famitinib, erdafitinib, AZD4547, infigratinib, BCD-217, amivantamab, MCLA-129, EMB-01, LY3164530, JNJ-61186372, anti-EGFR and cMet bispecific antibodies, GB263, medicamentous salts thereof, and any combination thereof, wherein the EGFR and cMet bispecific antibodies may be as described in WO2010115551A1, WO2014081954A1, or WO2015016559A1.

[0113] According to any aspect of this application, the targeted therapeutic agent may be administered in combination with one or more other therapies.

[0114] In certain embodiments, the anti-tumor agent is a chemotherapeutic agent. For example, the chemotherapeutic agent may include a pyrimidine nucleoside analog and / or a prodrug thereof.

[0115] In certain embodiments, the chemotherapeutic agent comprises one or more selected from the group consisting of capecitabine, cytarabine, docetaxel, adriamycin, fluorouracil (5-FU), floxuridine, tegafur, idarubicin, paclitaxel, epirubicin, Acelarin (NUC-1031), doxorubicin, folinic acid, cisplatin, paclitaxel, cyclophosphamide, vincristine, and a prodrug of 5-FU.

[0116] In certain embodiments, the chemotherapeutic agent comprises one or more selected from the group consisting of tegafur, 5'-deoxy-5-fluorouridine, fluorouridine, 2'-deoxy-5-fluorouridine, prodrug derivatives of fluorouridine, prodrug derivatives of 2'-deoxy-5-fluorouridine, trifluoro-methyl-2'-deoxyuridine, 6-azauridine, and 3-deazauridine.

[0117] For example, the chemotherapeutic agent may be administered in combination with one or more other therapies, hi certain embodiments, the one or more other therapies include one or more other anti-tumor therapies (e.g., anti-tumor agents) described herein.

[0118] For example, the antitumor agent (such as a cytotoxic anticancer agent) may be nitrogen mustard, nitrogen mustard N-oxide hydrochloride, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, isothiocyanate, busulfan, nimustine hydrochloride, mitropium bromide, melphalan, dacarbazine, ranimustine, sodium triose phosphate, ethylenetriamine, carmustine, lomustine, streptozocin, pipobroman, etoglucid, carboplatin, cisplatin, miriplatin, nedaplatin, t Alkylating agents such as inidamine, omustine, dichloropyridine, fupisitan, prednimustine, pumitepa, bendamustine hydrochloride (Ribomustin), temozolomide, diclofenac, trovafloxacin, norstatine, simvastatin, penem, cystemustine and bizelesin; mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed, entectine, cytarabine, oxaliplatin, tisabatin antimetabolites such as hydrochloride, 5-FU and its derivatives (e.g., fluorouracil, tegafur, UFT, doxycycline, carmofur, capecitabine, etc.), aminopterin, nazothioamine, leucovorin calcium, lobule, calcium folinate, levofloxacin calcium, cladribine, emiteflu, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, piritrexim, iodouridine, mitoguazone, thiazolylfuran, vemalstat, and bendamustine; actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, cetimycin anticancer antibiotics such as daunorubicin hydrochloride, mitoxantrone hydrochloride and idarubicin hydrochloride; and / or plant-derived cytotoxic anticancer agents such as etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, teniposide, paclitaxel, docetaxel and vinorelbine;These may include VEGF inhibitors such as bevacizumab and those disclosed in PCT patent applications WO 2005 / 012359, WO 2005 / 044853, WO 98 / 45332, WO 96 / 30046, WO 94 / 10202, US patent applications US7,060,269, US6,582,959, US6,703,020, US6,054,297, US patent applications US2006 / 009360, US2005 / 0186208, US2003 / 0206899, US2003 / 0190317, US2003 / 0203409 and US2005 / 0112126;

[0119] In certain embodiments, the anti-tumor agent may be an immunotherapeutic anti-tumor agent, such as butanamide, Krestin, etofuran, lentinan, ubenimex, interferons, interleukins, macrophage colony-stimulating factor, granulocyte colony-stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, Corynebacterium minutisimum, everolimus, levamisole, krestin, procodazole, and / or immune checkpoint inhibitors (e.g., CTLA4 inhibitors, TIM-3 inhibitors, PD-1 inhibitors (e.g., Nivolumab, Pembrolizumab, Pidilizumab, AMP514 (Amplimmune), AMP-224, and PCT patent applications WO2006 / 121168, WO2009 / 114335, WO2009 / 101611, US and PD-1 inhibitors (e.g., YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C, MDX-1105, and other PD-L1 inhibitors disclosed in PCT patent application WO2010 / 077634 and U.S. patent application US7,943,743).

[0120] In certain embodiments, the antitumor agent may include a hormonal therapy antitumor agent, such as: fusitidine, diethylstilbestrol, chlorinated costen, medroxyprogesterone acetate, megestrol acetate, cyproterone acetate, danazol, allylestrenol, progesterone, mepartricin, raloxifene or centchroman, levofloxacin, antiestrogens (such as tamoxifen citrate, toremifene citrate), contraceptives, prostacyclin, testolactone, aminosuccinimide, LH-RH agonists (such as goserelin acetate, buserelin, leuprorelin), droloxifene, epiandrostanol, ethinyl estradiol, furamestrozole. hydrochloride, anastrozole, letrozole, exemestane, vorozole, antiandrogens (such as flutamide, bicalutamide, nilutamide), 5-alpha reductase inhibitors (e.g., finasteride, epristeride), corticosteroids (such as dexamethasone, prednisolone, betamethasone, triamcinolone acetonide) and / or androgen synthesis inhibitors (such as abiraterone).

[0121] Diseases or conditions associated with antitumor agents According to any aspect of this application, the disease or condition associated with administration of the anti-tumor agent may be caused by the anti-tumor agent alone or by a multiple treatment regimen that includes the anti-tumor agent.

[0122] In certain embodiments, the disease or condition is caused by administration of the anti-tumor agent, e.g., the disease or condition may appear or worsen following administration of the anti-tumor agent.

[0123] In certain embodiments, said subject is free of said disease or condition prior to administration of said anti-tumor agent.

[0124] For example, the disease or condition may include a disease or condition of an epithelial tissue. For example, the epithelial tissue disease or condition may include a disease or condition associated with an endothelial cell lesion and / or a disease or condition associated with an epithelial cell lesion. For example, the epithelial cells may include skin epithelial cells, oral epithelial cells, nasal epithelial cells, gastric epithelial cells, and / or intestinal epithelial cells.

[0125] In certain embodiments, the endothelial cells include vascular endothelial cells. Vascular endothelial lesions may include endothelial dysfunction. For example, the vascular endothelial cell lesions may include retrograde degenerative vascular disease (e.g., atherosclerosis, medial sclerosis, and small arteriosclerosis (e.g., hyaline small arteriosclerosis and proliferative small arteriosclerosis)), inflammatory vascular disease (e.g., infectious arteritis, syphilitic arteritis, giant cell arteritis, thromboangiitis obliterans, and rheumatoid arteritis), functional vascular disease (e.g., Raynaud's disease, acrocyanosis, and erythromelalgia), and / or congenital vascular disease (e.g., congenital arteriovenous fistula).

[0126] In this application, the epithelial cells may include skin epithelial cells, oral epithelial cells, nasal epithelial cells, gastric epithelial cells, and / or intestinal epithelial cells. Examples of the epithelial cell lesions include skin epithelial cell lesions (e.g., rash, acne, nasal rosacea, atopic dermatitis, contact dermatitis, seborrheic dermatitis, lupus, scleroderma, pemphigus, pigmentation, melanosis, vitiligo, urticaria, tinea corporis, pruritus, alopecia, hair loss, hair alteration, erythema, paronychia and cracked nails, xerosis, hypersensitivity reactions, and psoriasis), oral epithelial cell lesions (e.g., pemphigus, herpes labialis, herpetic stomatitis, granulomatous cheilitis, oral mucositis, pemphigoid, Sjögren's syndrome, Behcet's syndrome, and oral sarcoidosis), nasal epithelial cell lesions (such as nosebleeds, sinusitis, nasal furuncles, and nasal polyps), and gastric epithelial cell lesions (e.g., gastritis, small intestine, gastric perforation, gastric fistula, gastric ulcer, and gastrointestinal polyps) and / or small intestinal epithelial cell lesions (e.g., enteritis, Crohn's disease, intestinal perforation, intestinal fistula, intestinal ulcer, ulcerative colitis, and NSAID-induced gastrointestinal disorders).

[0127] The inventors of this application have found that antitumor agents can damage endothelial cells and endothelial tissues, causing diseases or conditions in skin tissues, oral tissues, nasal tissues, and / or gastrointestinal tissues. In the onset and progression of these diseases or conditions, the disease process usually begins with damage / lesions to the endothelium and endothelial tissues, and then lesions appear in the epithelium, and finally appear in patients in the form of endothelial cell lesions associated with administration of antitumor agents, and / or epithelial cell lesions associated with administration of antitumor agents.

[0128] For example, the disease or condition may include a skin disease or condition, a 5-systemic disease or condition, and / or a gastrointestinal disease or condition.

[0129] In certain embodiments, the skin disease or condition comprises alopecia, body odor, bullous dermatitis, xeroderma, eczema, erythema multiforme, erythroderma, subcutaneous lipoatrophy, changes in hair color, abnormal hair texture, hirsutism, hyperhidrosis, hyperkeratosis, hypertrichosis, hypohidrosis, lipohypertrophy, nail changes, nail discoloration, nail loss, nail ridges, skin pain, hand-foot syndrome, photosensitivity, pruritus, purpura, acneiform rash, papules, scalp pain, skin atrophy, skin hyperpigmentation, skin hypopigmentation, skin sclerosis, skin ulcers, Stevens-Johnson syndrome, subcutaneous emphysema, telangiectasia, toxic epidermal necrolysis, rash and / or hives.

[0130] In certain embodiments, the skin disease or condition is hand-foot syndrome.

[0131] In certain embodiments, this application relates to the use of the compounds of the present application (e.g., compounds of formula (I) of this application) for preventing, alleviating and / or treating a disease or condition (e.g., a rash) in a subject associated with administration of said anti-tumor agent (e.g., an EGFR inhibitor).

[0132] In certain embodiments, the severity of the skin disease or condition is grade 1 or greater, grade 2 or greater, grade 3 or greater, grade 4 or greater, or grade 5 based on NCI-CTCAE.

[0133] In certain embodiments, the subject comprises a cancer patient. In certain embodiments, the area affected by the skin disease or condition is different from the area affected by the cancer.

[0134] In this application, the disease or condition associated with administration of an anti-tumor agent may have a statistically significant correlation with the anti-tumor agent. In certain embodiments, the disease or condition associated with administration of an anti-tumor agent may be caused by the anti-tumor agent. For example, the disease or condition associated with administration of an anti-tumor agent may include a skin disease or condition, a five organ system disease or condition, and / or a gastrointestinal disease or condition associated with administration of an anti-tumor agent. For example, the skin disease or condition, a five organ system disease or condition, and / or a gastrointestinal disease or condition associated with administration of an anti-tumor agent may consist of the epithelial tissue disease or condition in the skin tissue, the five organs, and / or the gastrointestinal tract associated with administration of an anti-tumor agent. In certain embodiments, the disease or condition associated with administration of an anti-tumor agent may include a side effect or adverse reaction caused by administration of an anti-tumor agent.

[0135] In this application, the disease or condition associated with the administration of an antitumor agent may be a new indication, which may be different from any one of the previous other diseases or conditions. For example, the diagnostic method, therapeutic method, and / or symptoms of the disease or condition associated with the administration of an antitumor agent are unique to those described. For example, erythromycin ointment can treat rash, but has no therapeutic effect on rash associated with the administration of an antitumor agent.

[0136] In certain embodiments, the disease or condition associated with administration of an anti-tumor agent may comprise rash associated with administration of an anti-tumor agent, hand-foot syndrome associated with administration of an anti-tumor agent, pruritus associated with administration of an anti-tumor agent, erythema associated with administration of an anti-tumor agent, xerosis associated with administration of an anti-tumor agent, alopecia associated with administration of an anti-tumor agent, paronychia associated with administration of an anti-tumor agent, pigmentation disorder associated with administration of an anti-tumor agent, pigmentation disorder associated with administration of an anti-tumor agent, oral mucositis associated with administration of an anti-tumor agent, dry mouth associated with administration of an anti-tumor agent, nosebleeds associated with administration of an anti-tumor agent, nasopharyngitis associated with administration of an anti-tumor agent, cheilitis associated with administration of an anti-tumor agent, esophageal mucositis associated with administration of an anti-tumor agent, gastric mucositis associated with administration of an anti-tumor agent, gastric ulcer associated with administration of an anti-tumor agent, diarrhea associated with administration of an anti-tumor agent, vomiting associated with administration of an anti-tumor agent, nausea associated with administration of an anti-tumor agent, loss of appetite associated with administration of an anti-tumor agent, constipation associated with administration of an anti-tumor agent, and / or abdominal pain associated with administration of an anti-tumor agent. For example, the disease or condition associated with administration of an antitumor agent includes hand-foot syndrome associated with administration of an antitumor agent. For example, the severity of the disease or condition associated with administration of an antitumor agent is grade 1 or higher, grade 2 or higher, grade 3 or higher, grade 4 or higher, and / or grade 5 based on NCI-CTCAE V5.0.

[0137] In certain embodiments, the disease or condition may include rash, hand-foot syndrome, pruritus, erythema, xerosis, alopecia, perionychia, pigmentation disorders, oral mucositis, dry mouth, nosebleeds, nasopharyngitis, cheilitis, esophageal mucositis, gastric mucositis, gastric ulcers, diarrhea, vomiting, nausea, loss of appetite, constipation, and / or abdominal pain. For example, the disease or condition includes hand-foot syndrome.

[0138] In certain embodiments, the disease or condition associated with an anti-tumor agent cannot be substantially treated or alleviated by administration of a drug selected from the group consisting of sildenafil 1%, urea cream, petrolatum ointment, urea ointment, brimonidine ointment, vitamin B6 ointment, nicotine ointment, dexamethasone ointment, hydrocortisone ointment, vitamin K1 ointment (0.1%), erythromycin ointment, and triamcinolone acetonide ointment.

[0139] In this application, the severity of the disease or condition may be increased after administration of the anti-tumor agent. For example, the severity of the disease or condition may be increased by about 5% or more, about 10% or more, about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 35% or more, about 40% or more, about 45% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, about 100% or more, about 200% or more, or more.

[0140] In this application, the subject may not have the disease or condition before administration of the antitumor agent. In this application, the term "the subject does not have the disease or condition" generally means that the subject does not have a past medical history including the disease or condition associated with administration of the antitumor agent. For example, the subject has not had a disease or condition associated with administration of the antitumor agent described in this application for more than one day, more than one week, more than one month, more than one year, more than ten years, or since the birth of the subject.

[0141] JAK-related diseases or conditions According to any aspect of this application, the JAK-attributable disease or condition may be selected from the following: an autoimmune disease or response, widespread activation of an immune response, bacterial infection, viral infection, inflammation, chronic and / or acute inflammatory disease or condition, and / or autoinflammatory disease, fibrotic disease, metabolic disease, neoplasm, or cardiovascular or cerebrovascular disease, skin disorder, pruritus, hair loss disorder, cancer or malignant tumor, autoimmune connective tissue disease and autoimmune disease; Still's disease, adult-onset Still's disease, Th17-associated inflammation, polychondritis (such as relapsing polychondritis); myositis, polymyositis, autoimmune myositis, dermatomyositis, juvenile dermatomyositis; myasthenia gravis; arthritis (e.g., rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile rheumatoid arthritis, osteoarthritis, infectious arthritis, inflammatory arthritis, inflammatory Enteropathy-related arthritis, idiopathic arthritis, juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, psoriatic arthritis), spondylitis / spondyloarthritis / spondyloarthropathy (ankylosing spondylitis), gout, scleroderma (systemic sclerosis, juvenile scleroderma), Reiter's syndrome / reactive arthritis, Lyme disease, lupus / systemic lupus erythematosus (SLE) (lupus erythematosus, pediatric SLE, cutaneous lupus (subacute cutaneous lupus, chronic cutaneous lupus / discoid lupus, frostbite) Lupus erythematosus (buccal lupus erythematosus), polymyalgia rheumatica, enthesitis, mixed connective tissue disease, enthesopathy, carditis, myocarditis, angiogenesis disorders, myelodysplastic syndromes, atherosclerosis, restenosis (coronary artery restenosis due to atherosclerosis), acute coronary syndromes, myocardial infarction, cardiac allograft vasculopathy, transplant arterial disease; vasculitis (large vessel vasculitis, small vessel vasculitis, giant cell arteritis, polyarteritis nodosa, vasculitis syndromes, The vasculitis syndromes include aortitis, Wegener's granulomatosis, Behcet's disease), STING-associated vasculitis in infancy (SAVI); gastrointestinal disorders, enteritis, colitis, inflammatory bowel disease (ulcerative colitis, Crohn's disease), irritable bowel syndrome, bowel syndrome / spastic colon, celiac disease; acute pancreatitis, chronic pancreatitis; primary biliary cirrhosis, primary sclerosing cholangitis, jaundice, cirrhosis (e.g., primary biliary cirrhosis, cirrhosis due to fatty liver disease (alcoholic steatosis, nonalcoholic steatosis)); esophagitis, gastritis, gastric and duodenal ulcers, peritonitis; nephropathy, immune-mediated glomerular nephropathy, autoimmune nephropathy, membranous glomerulopathy, chronic progressive nephropathy, diabetic nephropathy / diabetic nephropathy,Renal fibrosis, renal ischemia / reperfusion injury, HIV-associated nephropathy, ureteral obstructive nephropathy, glomerulosclerosis, proteinuria, nephrotic syndrome, polycystic kidney disease, autosomal dominant polycystic kidney disease, nephropathy is immune-mediated nephropathy, autoimmune nephropathy, chronic progressive nephropathy, diabetic nephropathy, renal fibrosis, ischemia / reperfusion injury-associated nephropathy, HIV-associated nephropathy, ureteral obstructive nephropathy, glomerulonephritis, chronic kidney disease (diabetic nephropathy, etc.), hypertensive nephropathy, glomerulosclerosis, proteinuria, nephrotic syndrome, polycystic kidney disease, autosomal dominant polycystic kidney disease, diabetic kidney disease, lupus nephritis; interstitial cystitis; periodontitis, gingivitis; lung inflammation, sinusitis, pneumonia, bronchitis, Asthma, bronchial asthma, allergic asthma, non-allergic asthma, allergic bronchopulmonary mycosis, aspirin-induced asthma, adult-onset asthma, asthma with fixed airflow obstruction, exercise-induced asthma, cough fluctuating asthma, work-related asthma, nocturnal asthma, asthma associated with obesity, eosinophilic asthma, hormone-resistant asthma / severe asthma, extrinsic asthma, intrinsic asthma / idiopathic asthma, Churg-Strauss syndrome, bronchioles inflammation, bronchiolitis obliterans, chronic obstructive pulmonary disease (COPD), interstitial lung disease (pulmonary fibrosis, idiopathic pulmonary fibrosis), acute lung injury, pulmonary fibrosis (such as idiopathic pulmonary fibrosis or cystic fibrosis), chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute lung injury, drug-induced lung injury; Meniere's disease; eye disorders, such as (e.g.) eye inflammation, uveitis, dry eye / keratoconjunctivitis sicca, scleritis, episcleritis, keratitis / Corneal diseases, choroiditis, retinal vasculitis, optic neuritis, retinopathies (including diabetic retinopathy, immune-mediated retinopathy, macular degeneration, wet macular degeneration, dry (age-related) macular degeneration); mastocytosis, iron deficiency anemia, uremia, hypereosinophilic syndrome (HES), systemic mastocytosis (SMCD), myelodysplastic syndrome, idiopathic thrombocytopenic purpura; bone resorption disorders; neurodegenerative diseases, neurological / neuromuscular diseases (e.g. multiple sclerosis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS) (familial ALS, sporadic ALS), Alzheimer's disease, myasthenia gravis, Lambert-Eaton myasthenic syndrome (LEMS), Guillain-Barre syndrome, meningitis, encephalitis, traumatic brain injury; neuropathy, delusional parasitosis, abnormalities of neuronal processes and sensory control, stroke / neural ischemia, spinal cord injury, Peripheral neuropathy, tactile hallucinations, spinal cord injury, psychiatric disorders; paresthesia pain (acute pain, chronic pain, neuropathic pain, fibromyalgia), nerve stimulation,Peripheral neuropathy; pruritus / itch (atopic pruritus, dry pruritus, pruritus associated with psoriasis / psoriatic itch / psoriasis-associated itch), acute pruritus, chronic pruritus, idiopathic pruritus, chronic idiopathic itch, biliary itch, hepatobiliary itch, nephrotic itch / nephrotic itch, uremic itch, cholestasis, intrahepatic cholestasis of pregnancy, chronic lichen simplex-associated pruritus, Lymphoma-associated itch, leukemia-associated itch, prurigo nodularis, atopic dermatitis-associated itch, atopic itch / atopic pruritus, bullous itch, brachioradial pruritus, neurogenic itch, neurogenic itch, dorsal paresthesias, HIV-associated pruritic papule, psychogenic itch, swimmer's itch, pruritic or uremic itch, urticarial itch; skin disorders ( For example), skin drug reactions / drug eruptions, xerosis / dry skin, rash, skin sensitization, skin irritation, sunburn, razor rash, body lice, head lice / pediculosis, hairy lice, cutaneous larva migrans, scabies, parasitosis, insect infection, urticaria / hives, papular urticaria, insect bites, insect stings, dandruff, foreign body or device on the skin, fungal infection, herpes, chickenpox / Chickenpox, Eosinophilic folliculitis, Skin diseases of pregnancy / Pruritic urticarial papules and plaques of pregnancy (PUPP), Inflammatory dermatoses, Neutrophilic dermatoses, Histiocytic neutrophilic dermatoses, Intestinal bypass syndrome dermatoses, Psoriasis / Psoriasis vulgaris, Lichen planus, Lichen sclerosus atrophicus, Acne (Acne vulgaris, Acne acne, Inflammatory acne, Nodular cystic acne, Keloid acne, Keloid acne cervical), Atopic diseases (Allergic contact sensitization, Allergic dermatitis), Dermatitis (Atopic dermatitis / Eczema, Contact dermatitis, Photodermatitis, Seborrheic dermatitis, Stasis dermatitis), Acute febrile neutrophilic dermatoses (Sweet's syndrome), Chronic atypical neutrophil Cialis-lipodystrophy and hypertension syndrome (CANDLE syndrome), hidradenitis suppurativa, urticaria, pyoderma gangrenosum, alopecia (eyebrow alopecia, alopecia of the internasal hairs, cicatricial alopecia (e.g. cicatricial alopecia, central centrifugal cicatricial alopecia, lichen planus, frontal fibrosing alopecia, alopecia alopecia)), non-cicatricial alopecia (alopecia areata (AA) (patchy AA, alopecia totalis (AT), alopecia universalis (AU), serpentine pattern alopecia, sisaihpo pattern alopecia areata)), androgenic / androgenic alopecia (AGA) / male and female pattern AGA), telogen effluvium, tinea capitis, hypotrichosis (hereditary hypotrichosis simplex),Lichen squamosal (frontal desmoplastic alopecia), palmoplantar keratoderma punctate, erythema edema permanent (EED), neutrophilic secretory hidradenitis, columnar cell neutrophilic granulomatous dermatitis, neutrophilic urticarial dermatosis, vitiligo vulgaris including segmental vitiligo (unisegmental vitiligo, bisegmental vitiligo) vitiligo vulgaris (common vitiligo, multisegmental vitiligo vulgaris), non-segmented vitiligo (digital, facial, or extremity facial vitiligo, midface vitiligo, mucosal vitiligo, confetti-type vitiligo, tricolor vitiligo, marginal inflammatory vitiligo, tetracolor vitiligo, blue vitiligo vulgaris) , Koebner phenomenon, vitiligo vulgaris, generalized vitiligo vulgaris, generalized vitiligo vulgaris), mixed vitiligo vulgaris / segmental-associated non-segmental vitiligo vulgaris, localized vitiligo vulgaris, isolated mucosal vitiligo vulgaris or vitiligo vulgaris with or without leukoderma (including body hair); bullous diseases, immune bullous diseases (bullous pemphigoid, cicatricial pemphigoid, pemphigus vulgaris, linear IgA disease), pemphigoid of gestation, xeroderma pigmentosum; fibrotic and scarring disorders: fibroids, liver fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, e.g., scleroderma, increased fibrosis, keloids, post-operative scars low-grade scar formation due to scar formation; wound healing, surgical scars, radiation-induced fibrosis (e.g., head and neck, digestive system or lung), CNS scar, gastrointestinal or digestive tract fibrosis, renal fibrosis, liver or bile duct fibrosis, liver fibrosis (e.g., nonalcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma), cardiac fibrosis (e.g., endomyocardial fibrosis or atrial fibrosis), ophthalmic scar, fibrosclerosis, scar augmentation, trauma or scabies healing, keloids, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis / Ormond's disease, progressive massive fibrosis, nephrogenic systemic fibrosis Fibrosis; Sjogren's syndrome, sarcoidosis, familial Mediterranean fever, cryopyrin-associated periodic syndrome (Muckle-Wells syndrome, familial cold autoinflammatory syndrome / familial cold urticaria / TNF receptor-associated periodic syndrome, neonatal onset multisystem inflammatory disease), hyperoxia-induced inflammation, reperfusion injury, postoperative trauma, tissue injury, hyperthermia syndrome; diabetes (type I diabetes, type II diabetes) / diabetes, Hashimoto's thyroiditis, Graves' disease, Addison's disease, Castleman's disease, hyperparathyroidism, menopause, obesity, steroid-resistance, impaired glucose tolerance, Metabolic syndrome, thyroid disease, hypophysitis; systemic immune senescence; autoimmune atrophic gastritis, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, Sjögren's syndrome, autoimmune thrombocytopenia, sympathetic ophthalmia; secondary hematologic manifestations of autoimmune disease (e.g., anemia), autoimmune hemolytic syndrome (autoimmune hemolytic anemia), autoimmune and inflammatory hepatitis, autoimmune ovarian failure, autoimmune thrombocytopenia, silicone implant-associated autoimmune disease, drug-induced autoimmunity autoimmune diseases, HIV-associated autoimmune syndromes, metal-induced autoimmune diseases, autoimmune hearing loss, autoimmune thyroid disorders; allergies and allergic reactions, including hypersensitivity reactions, e.g., Type I hypersensitivity reactions (e.g., including anaphylaxis), Type II hypersensitivity reactions (e.g., Goodpasture's disease, autoimmune hemolytic anemia), Type III hypersensitivity reaction disorders (e.g., Arthus reaction, serum sickness), and Type IV hypersensitivity reactions (e.g., contact dermatitis, allograft rejection); acute and chronic infections, septic syndromes (sepsis, septic shock, endotoxic shock, synshock, exotoxin-induced toxic shock, gram-negative sepsis, gram-positive sepsis, fungal sepsis, toxic shock syndrome);acute and chronic infections, septic syndromes (sepsis, septic shock, endotoxin shock, exotoxin-induced toxic shock, gram-negative sepsis, gram-positive sepsis, fungal sepsis, toxic shock syndrome);rejection: graft-versus-host reaction / graft-versus-host disease, allograft rejection (e.g. acute allograft rejection or chronic allograft rejection), early transplant rejection;malignancy , cancer, lymphoma, leukemia, multiple myeloma, solid tumors, teratomas, metastatic and bone disorders, internal cancers, cancer of the bone, mouth / pharynx, esophagus, larynx, stomach, intestines, colon, rectum, lungs (e.g., non-small cell lung cancer or small cell lung cancer), liver (hepatic), pancreas, nerves, brain (e.g., glioma, glioblastoma multiforme, astrocytoma, neuroblastoma, and schwannoma), head and neck, throat, ovaries, uterus, prostate, testes, bladder, kidney (renal), breast, gallbladder, cervix, thyroid, prostate, eye (eye malignancies), and skin (melanoma, keratoacanthoma);and fibrous carcinoma, fibroma, fibroadenoma, fibrosarcoma, myeloproliferative disorders, neoplasms (hematopoietic neoplasms, myeloid neoplasms, lymphoid neoplasms (myelofibrosis, primary myelofibrosis, polycythemia vera, essential thrombocythemia)), leukemias (acute lymphocytic leukemia, acute and chronic myeloid leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, chronic myelomonocytic leukemia (CMML), or promyelocytic leukemia), multiple myeloma and other myeloid malignancies (myeloid metaplasia with myelofibrosis (MMM), primary myelofibrosis (PMF), idiopathic myelofibrosis (IDM), myelofibrosis (MMM), myelofibrosis (PMF), myelofibrosis (PMM ... myelofibrosis (IMF)), lymphoma (Hodgkin's disease, cutaneous lymphoma (cutaneous T-cell lymphoma, mycosis fungoides), lymphoma (e.g., B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, hairy cell lymphoma, Burkitt lymphoma, mast cell tumor, Hodgkin's disease or non-Hodgkin's disease); Kaposi's sarcoma, rhabdomyosarcoma, seminoma, teratocarcinoma, osteosarcoma, follicular thyroid carcinoma; increased exogenous or synthetic opioid accumulation, paresthesia back pain, obsessive-compulsive disorder, obsessive-compulsive disorder-related nostalgia, and combinations thereof.

[0142] Drug Combinations and Pharmaceutical Compositions Meanwhile, this application provides a pharmaceutical combination comprising: 1) an antitumor agent; and 2) a compound of formula (I). In certain embodiments, in the pharmaceutical combination, the antitumor agent and the compound of the present application (e.g., the compound of formula (I) of this application) are not mixed with each other. In certain embodiments, in the pharmaceutical combination, the antitumor agent and the compound of the present application (e.g., the compound of formula (I) of this application) are present in separate containers. In certain embodiments, in the pharmaceutical combination, the compound of the present application (e.g., the compound of formula (I) of this application) is prepared to be suitable for transdermal administration. In certain embodiments, in the pharmaceutical combination, the compound of the present application (e.g., the compound of formula (I) of this application) is prepared into an ointment. In certain embodiments, in the pharmaceutical combination, the compound of the present application (e.g., the compound of formula (I) of this application) has a concentration of about 0.005% w / w to about 40% w / w. In certain embodiments, the drug combination has a concentration of the compound of the present application (eg, the compound of Formula (I) of this application) of about 0.05% w / w to about 10% w / w.

[0143] According to any aspect of this application, the composition or compound does not substantially affect the therapeutic effect of the anti-tumor agent.

[0144] In this application, "does not substantially affect" may mean that the therapeutic effect of the compound of the present application (e.g., the compound of formula (I) of this application) and the antitumor agent is equivalent to the therapeutic effect of the antitumor agent alone, or that no significant disadvantage occurs. For example, for any subject, the degree of reduction in tumor volume by the use of the compound of the present application (e.g., the compound of formula (I) of this application) and the antitumor agent is the same as the therapeutic effect of the antitumor agent alone, or the degree of reduction is about 5% or more, about 4% or more, about 3% or more, about 2% or more, about 1% or more, about 0.5% or more, about 0.1% or more, about 0.01% or more, about 0.001% or more, or less.

[0145] In certain embodiments, the site of administration of the drug is different from the site of administration of the anti-tumor agent, hi certain embodiments, the site of administration of the drug is not the site of cancer initiation or the site of potential cancer metastasis.

[0146] In certain embodiments, the method of administration of the drug is different from the method of administration of the anti-tumor agent.

[0147] In the drug combinations and / or kits of the present application, in certain embodiments, the anti-tumor agent and the compound of the present application (eg, the compound of formula (I) of this application) are not mixed with each other.

[0148] In certain embodiments, the anti-tumor agent and the compound of the present application (e.g., the compound of formula (I) of this application) are in separate containers. For example, the drug combination may include two or more drugs packaged independently of each other, where at least one of the drugs comprises an anti-tumor agent as described in this application, and at least one additional drug comprises a compound of formula (I) as described in this application.

[0149] In certain embodiments, in the drug combination, 2) the compound of the present application (e.g., the compound of formula (I) of this application) can prevent, alleviate and / or treat a disease or condition associated with the anti-tumor agent of 1).

[0150] In certain embodiments, 2) the compound of the present application (eg, the compound of formula (I) of this application) does not substantially affect the therapeutic effect of the antitumor agent of 1).

[0151] In a specific embodiment, in the drug combination of the present application, 2) the compound of the present application (e.g., the compound of formula (I) of this application) is administered before, simultaneously with, or after administration of the anti-tumor agent of 1).

[0152] Preventive and / or therapeutic methods In the present application, the subject may consist of a human or a non-human animal. For example, the non-human animal may be selected from the following group: monkey, chicken, goose, cat, dog, mouse and rat. Furthermore, the non-human animal may include non-human animal species such as livestock, rodents, primates, domesticated animals, poultry, etc. The human may be Caucasian, African, Asian, Sumerian, or other races, or a mixture of different races. As another example, the human may be an elderly person, an adult, a teenager, a child, or an infant.

[0153] Effective doses in humans may be extrapolated from those in experimental animals. For example, Freireich et al. have described the correlation of dosage in animals and humans (based on milligrams per square meter of body surface). (Freireich et al., Cancer Chemother. Rep. 50, 219 (1966)). Body surface area can be estimated from the height and weight of the patient. See Scientific Tables, Geigy Pharmaceuticals, Ardsley, NY, 537 (1970).

[0154] In the methods of this application, the anti-tumor agent may be induced by administration of an anti-tumor agent to the subject.

[0155] For example, a compound of the present application (eg, a compound of formula (I) of this application) may be administered prior to, concurrently with, or following administration of the anti-tumor agent to the subject. When an antitumor agent described in the present application is co-administered with a compound of the present application (e.g., a compound of formula (I) of this application), the compound of the present application (e.g., a compound of formula (I) of this application) is administered at a dosage level of about 0.0001 to 10% (e.g., about 0.005 to 10%, about 0.01 to 10%, about 0.05 to 10%, about 0.1 to 10%, about 0.2 to 10%, about 0.3 to 10%, about 0.4 to 10%, about 0.5 to 10%, about 0.6 to 10%, about 0.7 to 10%, about 0.8 to 10%, about 0.9 to 10%, about 0.95 to 10%, about 1 to 10%, about 2 to 10%, about 3 to 10%, about 5 to 10%, about 6 to 10%, about 8 to 10%, or a smaller range) of the total administered amount. In embodiments in which the compound of the present application (e.g., a compound of formula (I) of this application) is administered at an interval from the anti-tumor agent, the compound of the present application (e.g., a compound of formula (I) of this application) may be administered at an interval before or after administration of the anti-tumor agent. The interval may 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, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, or more.

[0156] The present application also provides a method comprising administering a compound of formula (I) to a subject, wherein the subject has been administered, is being administered, and / or will be administered an anti-tumor agent, and is suffering from or susceptible to a disease or condition associated with administration of the anti-tumor agent.

[0157] The application also provides a method for preventing or treating a disease or condition comprising administering a compound of formula (I) to a subject susceptible to or suffering from said disease or condition, wherein said subject has been, is being, and / or is to be administered an anti-tumor agent.

[0158] In this application, the subject may already be suffering from a disease or condition associated with administration of an anti-tumor agent, or the subject may be more likely to suffer from a disease or condition associated with administration of an anti-tumor agent.

[0159] The present application provides a method comprising the steps of: 1) monitoring one or more side effects, such as skin tissue, organ system and / or gastrointestinal characteristics, in a subject to which an anti-tumor agent is administered; and 2) administering a compound of formula (I) to the subject if said monitoring reveals that the subject is experiencing a side effect, such as a skin disease or condition, organ system disease or condition, and / or gastrointestinal disease or condition, associated with administration of the anti-tumor agent.

[0160] In this application, the method may further include continuing to monitor the skin disease or condition, the 5 organ system disease or condition, and / or the gastrointestinal disease or condition, and optionally reducing or ceasing the anti-tumor agent. For example, the continued monitoring may refer to monitoring for at least one day, at least one week, at least ten days, at least two weeks, at least three weeks, at least one month, at least three months, or more after administration of the anti-tumor agent. For example, the reduction or ceasing may be a reduction of about 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 99% or more, or 100% in the dose of the anti-tumor agent administered to the subject, compared to the dose of the anti-tumor agent in step 1) of the method.

[0161] In this application, the severity of the disease or condition associated with administration of an anti-tumor agent may be increased after administration of the anti-tumor agent, for example, the severity may be increased by 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or more.

[0162] In this application, the subject need not be suffering from the disease or condition prior to administration of the anti-tumor agent.

[0163] In this application, the compound of the present application (e.g., the compound of formula (I) of this application) can be administered locally to the subject. For example, the compound of the present application (e.g., the compound of formula (I) of this application) can be administered locally to a site of the subject that is substantially free of cancer cells. Also, for example, the compound of the present application (e.g., the compound of formula (I) of this application) can be administered to a non-cancerous site of the subject.

[0164] Without wishing to be bound by any theory, the following examples are intended merely to elucidate the compounds, preparation methods, uses, etc. of the present application, and are not intended to limit the scope of the invention of this application. EXAMPLES

[0165] Preparation of compounds Synthesis of compound A1: 2-(4-((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-N-methyl-7H-pyrrole[2,3-d]pyrimidine-7-formamido)ethyl 3,3-difluorocyclobutane-1-carboxylate

[0166] [ka]

[0167] Step 1 3,3-Difluorocyclobutane formyl chloride (1-2) 3,3-Difluorocyclobutane formic acid (3.0 g, 22.0 mmol, 1.0 eq), N,N-dimethylformamide (161.1 mg, 2.2 mmol, 169.6 uL, 0.1 eq) in dichloromethane (20 mL) was added with oxalyl chloride (4.2 g, 33.1 mmol, 2.9 mL, 1.5 eq) and stirred at room temperature for 2 hours at 0° C. The solvent was removed by distillation under reduced pressure to give the crude product of 3,3-difluorocyclobutane formyl chloride (3.4 g), which was used directly in the next step without purification.

[0168] Step 2 2-[tert-Butoxycarbonyl(methyl)amino]ethyl 3,3-difluorocyclobutane formate (1-3) 3,3-Difluorocyclobutane formyl chloride (3.3 g, 21.4 mmol, 1.5 eq) was added to a solution of N-BOC-N-methylaminoethanol (2.5 g, 14.3 mmol, 1.0 eq) and triethylamine (14.4 g, 142.7 mmol, 19.9 mL, 10.0 eq) in dichloromethane (20 mL). The mixture was stirred at 25° C. for 3 h. The solvent was removed by distillation under reduced pressure to give crude 2-[tert-butoxycarbonyl(methyl)amino]ethyl 3,3-difluorocyclobutane formate (4.0 g), which was used directly in the next step without purification.

[0169] Step 3 2-(Methylamino)ethyl-3,3-difluorocyclobutyl ester (1-4) To a solution of 2-[tert-butoxycarbonyl(methyl)amino]ethyl 3,3-difluorocyclobutane formate (1.8 g, 6.1 mmol, 1.0 eq) in dichloromethane (9 mL) was added trifluoroacetic acid (4.6 g, 40.5 mmol, 3.0 mL). After stirring at 0°C for 2 h, distillation under reduced pressure afforded crude 2-(methylamino)ethyl-3,3-difluorocyclobutyl ester as a yellow solid (1.1 g), which was used directly in the next step without purification.

[0170] Step 4 (4-Nitrophenyl) 4-[(3R,4R)-1-(2-cyanoacetyl)-4-methyl-3-piperidine]-methylamino]pyrrole[2,3-d]pyrimidine-7-carboxylate (1-6) To a solution of 3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrole[2,3-d]pyrimidin-4-yl)amino]-1-piperidine]-3-oxopropionitrile (10.0 g, 32.0 mmol, 1.0 eq) in dichloromethane (50 mL) was added triethylamine (6.5 g, 64.0 mmol, 8.9 mL, 2.0 eq) and p-nitrophenyl chloroformate (9.7 g, 48.0 mmol, 1.5 eq). The reaction was stirred at 20° C. for 4 h, filtered, and the filtrate was rotary evaporated to give a yellow oily crude product of (4-nitrophenyl) 4-[(3R,4R)-1-(2-cyanoacetyl)-4-methyl-3-piperidine]-methylamino]pyrrole[2,3-d]pyrimidine-7-carboxylate (15.1 g), which was used directly in the next step without purification.

[0171] Step 5 2-[[4-[[(3R,4R)-1-(2-cyanoacetyl)-4-methyl-3-piperidine]-methylamino]pyrrole[2,3-d]pyrimidine-7-carbonyl]-methylamino]ethyl 3,3-difluorocyclobutyl ester (Example A1) To a solution of 2-[tert-butoxycarbonyl(methyl)amino]ethyl 3,3-difluorocyclobutane formate (2.7 g, 5.7 mmol, 1.0 eq) and 2-(methylamino)ethyl-3,3-difluorocyclobutyl ester (1.1 g, 5.7 mmol, 1.0 eq) in dichloromethane (20 mL), triethylamine (2.9 g, 28.5 mmol, 3.9 mL, 5.0 eq) was added and the mixture was stirred at 25° C. for 6 hours. After removing the solvent by distillation under reduced pressure, reverse phase HPLC (column: Xtimate C18 150*40 mm *10 um; mobile phase: [water(FA)-ACN]; B%: 25%-60%,10 min) preparation gave 2-[[4-[[(3R,4R)-1-(2-cyanoacetyl)-4-methyl-3-piperidine]-methylamino]pyrrole[2,3-d]pyrimidine-7-carbonyl]-methylamino]ethyl 3,3-difluorocyclobutyl ester (2.1 g, 3.9 mmol, 68% yield, 98% purity), a white solid. LC-MS: (M+H) + , 532.3. 1 H NMR(400 MHz, DMSO-d6): δ (ppm) 8.26-8.16 (m, 1H), 7.32 (br s, 1H), 6.82 (br s, 1H), 4.86 (br d, J = 2.0 Hz, 1H), 4.38 (br s, 1H), 4.22-3.96 (m, 3H), 3.86-3.62 (m, 3H), 3.50-3.41 (m, 3H), 3.34 (br s, 1H), 3.28 (s, 3H), 3.20-3.00 (m, 2H), 2.97-2.51 (m, 5H), 2.42-2.34 (m, 1H), 1.96-1.68 (m, 1H), 1.62-1.48 (m, 1H), 1.02 (d, J = 7.0 Hz, 3H).

[0172] Using the appropriate reactants and following the methods for synthesizing the compounds of the present invention with reference to the procedures for compound A1, the other compounds in the table below were similarly synthesized and characterized.

[0173] TIFF2025505812000011.tif230170

[0174] TIFF2025505812000012.tif229170

[0175] TIFF2025505812000013.tif245170

[0176] TIFF2025505812000014.tif234170

[0177] TIFF2025505812000015.tif229170

[0178] TIFF2025505812000016.tif64170

[0179] Additionally, the solubility and log D data of the above compounds were measured. Briefly, the measurement methods are as follows: Thermodynamic Solubility Test Weigh out at least 2 mg of sample powder into a Whatman miniuniprep vial. If the thermodynamic solubility of a sample in multiple buffers needs to be tested, one vial is needed for each test. Add 450 μL of buffer solution to the Whatman miniuniprep vial separately; After adding the buffer solution, put the Whatman miniuniprep filter piston cap on the top of the liquid surface so that the filter is in contact with the buffer solution during vortex shaking; Vortex the solubility sample for 1 minute, and record the solution phenomenon; Shake at 600 revolutions per minute at room temperature (about 25 °C) for 24 hours; Press the cap of the Whatman Miniunipreps filtration vial to the bottom to obtain the filtrate of the sample dissolution solution, all sample vials should be checked for insoluble material and leaks; Dilute the buffer solution 100 times to obtain the sample dilution solution.

[0180] Three UV standard solutions were injected into the HPLC from low to high concentration, followed by duplicate injections of dilutions of the test compound, supernatants, and test samples, and the UV peaks were integrated to simulate the standard curve and calculate the thermodynamic solubility of the samples.

[0181] PBS buffer pH=6.5 was used for the thermodynamic solubility test, and isopropyl myristate was used as the solvent for the thermodynamic stability test in isopropyl myristate.

[0182] LogD measurement Test compounds (DMSO stock solution 10 mM, 2 μL / well) and QCs (DMSO 10 mM, 2 μL / well) were transferred from storage tubes to 96-well cluster tubes in duplicate. Buffer-saturated n-octanol (149 μL / well) and n-octanol-saturated phosphate buffer (149 μL / well) were added to each well; the cluster tubes were mixed by vortexing for 1 min, shaken at 880 rpm / min on a plate shaker for 1 h, and then centrifuged at 4000 rpm / min for 10 min. The lid pad was removed, and a certain amount of octanol layer sample (4 μL / well) was measured on a 96-well plate containing octanol internal standard dilution solution (796 μL / well), and a certain amount of buffer salt layer sample (30 μL / well) was measured on a 96-well plate containing buffer internal standard dilution solution (570 μL / well). The dilution ratio of the sample can be adjusted appropriately depending on the properties of the sample. A triple quadrupole mass spectrometer was used to analyze the samples. The sample solutions were analyzed and processed using the rapid isocratic method and the small column retention method, and the concentrations were corrected using the dilution factor and internal standard. The final results (LogD / LogP values) were calculated using the ratio of the corrected peak areas.

[0183] The measured results are shown in the table below:

[0184] TIFF2025505812000017.tif149170

[0185] In addition, the stability of the above compounds in plasma was measured. Briefly, the method for measuring the stability of the above compounds in plasma comprises the following steps: 1) Frozen mixed plasma was thawed in a 37°C water bath before the experiment and centrifuged at 4000 rpm for 5 min to remove clots; 2) 98 μL of blank plasma was added per well to a 96-well reaction plate; 3) In addition to the blank sample, 2 μL of 100 μM test substance working solution was added to each well; 3) The reaction plate was incubated at 37°C and the time was recorded. The incubation times were 0, 10, 30, 60, and 120 minutes, with 2 replicate wells for each time point; 4) At the appropriate time point, the incubation was terminated and proteins were precipitated by adding 400 μL of an acetonitrile solution containing 200 ng / mL tolbutamide and 200 ng / mL labetalol; 5) Each plate was shaken for 20 min, then centrifuged at 4000 rpm for 20 min, 50 μL of the supernatant was transferred to another 96-well plate, and each sample was diluted with 100 μL of purified water; 6) Samples were analyzed by LC-MS / MS.

[0186] The experimental results, shown below, demonstrated that all of the selected compounds were susceptible to metabolism by the target compound in human plasma.

[0187] The results are shown in the table below:

[0188] TIFF2025505812000018.tif233170

[0189] TIFF2025505812000019.tif175170

[0190] Topical administration of the compound to verify the prevention of rash by small molecule EGFR inhibitors in a rat animal model A rat model was constructed. A small molecule EGFR inhibitor was orally administered to 6-week-old female SD rats every day, and after a few days, a rash appeared over a wide area of ​​the back (photo shown in Figure 1). There was no difference in the location of the rash, and the rash appeared equally on both sides. Similar to humans, rats developed a rash on the face and body after oral administration of a small molecule EGFR inhibitor. The cause of both is exactly the same, and the symptoms are very similar. Thus, rats are very suitable for mimicking an animal model of EGFR inhibitor-induced rash.

[0191] SD rats (approximately 200 g) were acclimated for one week and then divided into groups of 10 rats each. On the day before the experiment, the hair on the backs of the rats was gently removed with an electric razor, and an oral administration experiment was performed. The EGFR inhibitor was dissolved in a sterile aqueous solution, diluted with PBS buffer, and administered so that the oral dose did not exceed 2 mL per dose, as shown in Table 1. The experiment was divided into an administration group and a control group. After oral administration, an ointment of the present compound (type and concentration shown in Table 1) was applied to the backs (approximately 3 cm x 3 cm) of the rats in the drug administration group, and blank matrix ointment (approximately 0.5 g) was applied to the backs (approximately 3 cm x 3 cm) of the rats in the control group; after application, the rats were fixed in a fixed canister for approximately 4 hours, and after 4 hours, the rats were released, the drug remaining at the application site was wiped off with water, and the rats were returned to their cages. The number of oral administrations of the EGFR inhibitor is shown in Table 1, but the present compound and blank matrix ointment were administered only once a day. Oral administration and topical application experiments were repeated daily until obvious rashes appeared in the control group, at which point the number of rats in the treatment group whose skin was normal or whose condition was significantly less severe than that of the control group was counted as the number of rats in which the rash was effectively suppressed.

[0192] Table 1 shows animal experiments using various combinations of small molecule EGFR inhibitors and ointments of the present compound, and the corresponding experimental results (where the value in the control rate column = number of rats in the treatment group with milder rash than the control group / total number of rats in the treatment group × 100%).

[0193] TIFF2025505812000020.tif225170

[0194] TIFF2025505812000021.tif247170

[0195] TIFF2025505812000022.tif248170

[0196] TIFF2025505812000023.tif51170

[0197] Figure 2 shows photographs of the left side, back, and right side of typical rats in the control and treatment groups in Table 1. Figure 3 shows the severity of the rash in the treatment and control groups at the end of the experiment.

[0198] As can be seen from the results in Table 1 and Figures 2 to 3, the ointment of the compound of the present invention can effectively prevent rash caused by a small molecule EGFR inhibitor.

[0199] Topical administration of the compound of the present application to verify the prevention of rash by monoclonal antibody EGFR inhibitor in a rat animal model SD rats (approximately 200 g) were acclimated for one week and then divided into groups of 10 rats each. The day before the experiment, the rats were gently shaved with an electric razor to perform the administration experiment. The experiment was divided into a group that received the compound of the present application and a control group. An EGFR monoclonal antibody solution diluted with saline was injected into the tail vein twice a week, and the injection rate and injection time are shown in Table 2. After the injection, the compound of the present application group was applied to the rat's back (approximately 3 cm x 3 cm) every day, and the control group was applied with blank matrix ointment (approximately 0.5 g) to the rat's back (approximately 3 cm x 3 cm). After application, the rats were fixed in a fixed canister for approximately 4 hours, and after 4 hours, the rats were released, the drug remaining at the application site was wiped off with water, and the rats were returned to their cages. The monoclonal antibody EGFR inhibitor was injected into the tail vein twice a week, and the compound of the present application and blank ointment were applied once a day until a visible rash appeared in the control group. Ten to fourteen days after application, the number of rats in the compound group in which the skin was normal or showed a significant improvement compared to the control group was counted as the number of rats in which the rash was effectively suppressed.

[0200] Table 2 shows animal experiments using various combinations of each monoclonal antibody EGFR inhibitor and the ointment of the compound of the present application, and the corresponding experimental results (wherein the value in the control rate column = the number of rats in the compound of the present application group whose rash was milder than that in the control group / the total number of rats in the compound of the present application group × 100%).

[0201] TIFF2025505812000024.tif235170

[0202] TIFF2025505812000025.tif126170

[0203] FIG. 4 shows the grade of rash at the end of the experiment in the group administered the compound of the present invention and the control group (monoclonal antibody EGFR inhibitor).

[0204] As can be seen from the results in Table 2 and FIG. 4, the ointment of the compound of the present invention can effectively prevent the rash caused by the monoclonal antibody EGFR inhibitor.

[0205] Topical administration of the compound of the present application to test the treatment of rash with a small molecule EGFR inhibitor in a rat animal model SD rats (approximately 200 g) were acclimated for one week and then divided into groups of 10 rats each. On the day before the experiment, the hair on the backs of the rats was gently removed with an electric razor, and an oral administration experiment was performed. The EGFR inhibitor was dissolved in a sterile aqueous solution, diluted with PBS buffer, and administered so that the oral dose did not exceed 2 mL per dose, as shown in Table 3. Daily oral administration was continued until the rats showed signs of a rash, at which point the treatment experiment began. The experiment was performed with the rats divided into a compound group and a control group. During the treatment experiment period, the EGFR inhibitor was orally administered continuously every day, and after oral administration, the compound group was applied with an ointment of the compound of the present application on the rats' backs (approximately 3 cm x 3 cm), and the control group was applied with a blank matrix ointment on the rats' backs (approximately 3 cm x 3 cm); after application, the rats were fixed in a fixed canister for approximately 4 hours, and after 4 hours, the rats were released, and the drug remaining at the application site was wiped off with water and returned to the rat cage. The number of oral administrations of the EGFR inhibitor is shown in Table 3, but the compound of the present application and the blank ointment were administered only once a day. The EGFR inhibitor was administered orally every day, and the number of rats whose rash had returned to normal or significantly improved compared to the control group at the end of the experiment was counted as the number of rats whose rash had been effectively treated.

[0206] Table 3 shows animal experiments using various combinations of low molecular weight EGFR inhibitors and ointments of the compound of the present application, and the corresponding experimental results (wherein the value in the control rate column = the number of rats in the compound of the present application group whose rash was milder than that in the control group / the total number of rats in the compound of the present application group × 100%).

[0207] TIFF2025505812000026.tif230170

[0208] TIFF2025505812000027.tif242170

[0209] TIFF2025505812000028.tif215170

[0210] Figure 5 shows photographs of the left side, back, and right side of typical rats in the control group and the present compound group in Table 3. Figure 6 shows the degree of rash in the present compound group and the control group at the end of the experiment.

[0211] As can be seen from the results in Table 3 and Figure 6, the ointment of the compound of the present invention can effectively treat the rash caused by a small molecule EGFR inhibitor.

[0212] Topical administration of the compound of the present application to test the treatment of rash with monoclonal antibody EGFR inhibitor in a rat animal model SD rats (approximately 200 g) were acclimated for one week and then divided into groups of 10 rats each. The day before the experiment, the hair on the backs of the rats was gently removed with an electric razor, and the administration experiment was performed. EGFR monoclonal antibody solution diluted with saline was injected into the tail vein twice a week, and the injection rate and injection time are shown in Table 4. The administration was continued for 1 to 2 weeks until the rats developed a rash, at which point the treatment experiment was started. The experiment was performed with the rats divided into the present compound group and the control group. During the treatment experiment period, the monoclonal antibody EGFR inhibitor was continuously injected twice a week, the present compound group was applied with an ointment of the present compound on the rats' backs (approximately 3 cm x 3 cm) every day, and the control group was applied with a blank matrix ointment on the rats' backs (approximately 3 cm x 3 cm); after application, the rats were fixed in a fixed canister for approximately 4 hours, and after 4 hours the rats were released, the drug remaining at the application site was wiped off with water, and the rats were returned to their cages. Ten days after application, the number of rats in the compound group in which the skin was normal or in which the skin condition was significantly improved compared to the control group was counted as the number of rats in which the rash was effectively suppressed.

[0213] Table 4 shows animal experiments using various combinations of monoclonal antibody EGFR inhibitors and ointments of the compound of the present application, and the corresponding experimental results (wherein the value in the control rate column = the number of rats in the compound of the present application group whose rash was milder than that in the control group / the total number of rats in the compound of the present application group × 100%).

[0214] TIFF2025505812000029.tif236170

[0215] TIFF2025505812000030.tif204170

[0216] FIG. 7 shows the grade of rash at the end of the experiment in the group administered the compound of the present invention and the control group (monoclonal antibody EGFR inhibitor).

[0217] As can be seen from the results in Table 4 and Figure 7, the ointment of the compound of the present invention can effectively treat the rash caused by the monoclonal antibody EGFR inhibitor.

[0218] Therapeutic effect of topical administration of the compound in delayed-type hypersensitivity reaction experiments induced by skin contact in mice The mouse skin contact delayed-type hypersensitivity (DTH) response is considered a valid model of clinical contact dermatitis and other T-lymphocyte-mediated skin immunological diseases, such as atopic dermatitis and psoriasis. Mouse DTH shares several characteristics with these skin immunological diseases, such as immune infiltration accompanied by increased levels of inflammatory cytokines and hyperkeratinocyte transformation.

[0219] Balb / c mice were sensitized by topical application of the antigen 2,4-dinitrofluorobenzene (DNFB) to the shaved back of the mouse on days 0 and 1. On day 5, ear thickness was measured with a micrometer. This measurement was recorded and used as a baseline. The animals were then sensitized by topical application of 0.2% DNFB to both ears in a total of 20 μL (10 μL to the inner pinna and 10 μL to the outer pinna). Ear thickness was measured again 24 to 72 hours after sensitization. Animals were treated with topical application of an ointment of the compound to the ear during the hypersensitivity and sensitization phases (days -1 to 7), or prior to or during the sensitization period (usually days 4 to 7). Treatment was indicated by a reduction in ear swelling compared to that observed when a blank ointment was applied. Compounds that produce a reduction of 20% or more are considered effective.

[0220] Table 5 shows the experimental results of the compounds of the present invention for the treatment of delayed-type hypersensitivity reactions by skin contact in mice.

[0221] TIFF2025505812000031.tif119170

[0222] As can be seen from the results in Table 5, the ointment of the compound of the present invention is effective in treating delayed-type hypersensitivity reactions caused by skin contact in mice.

[0223] Mouse ear tissue was fixed in formalin, embedded in paraffin, and cut into sections for immunohistochemical analysis, which showed that the application of the compound of the present invention reduced the number of infiltrating cells in the tissue.

Claims

1. A compound of formula (I), its medicamentous salts, biologically active metabolites, solvates, hydrates, prodrugs, racemates, enantiomers or stereoisomers, 【Chemistry 1】 During the ceremony: G is a JAK inhibitor; R 1 and R are each independently selected from hydrogen, deuterium, tritium, optionally substituted alkyl, optionally substituted deuterium alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted haloalkoxy, halogen, and optionally substituted ring groups; and n is 1, 2, 3, 4 or 5.

2. R 1 and R are each independently -(CH 2 ) n1 Ra, -(CH 2 ) n 1ORa, -(CH 2 ) n1 SRa, -(CH 2 ) n1 C(O)Ra, -(CH 2 ) n1 C(O)ORa, -(CH 2 ) n1 S(O) m1 Ra, -(CH 2 ) n1 NRaRb, -(CH 2 ) n1 C(O)NRaRb, -(CH 2 ) n1 NRaC(O)Rb and -(CH 2 ) n1 NRaS(O) m1 Rb; The Ra and Rb may be the same or different and are each independently selected from hydrogen, deuterium, tritium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl are optionally further substituted with one or more groups selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; Alternatively, Ra and Rb are linked to form a cycloalkyl, heterocycle, aryl, or heteroaryl, wherein the cycloalkyl, heterocycle, aryl, and heteroaryl are optionally further substituted with one or more groups selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; n1 is 0, 1, 2, 3, 4 or 5; and m1 is 0, 1 or 2.

3. 3. The compound of any one of claims 1 to 2, wherein the ring group is selected from cycloalkyl, heterocycle, oxoheterocycle, thioheterocycle, aryl, and heteroaryl, and the cycloalkyl, heterocycle, oxoheterocycle, thioheterocycle, aryl, and heteroaryl are optionally further substituted with one or more groups selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

4. A compound according to any one of claims 1 to 3, or a medicamentous salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer, or stereoisomer thereof, wherein R １ is hydrogen, optionally substituted alkyl, or optionally substituted deuteroalkyl.

5. A compound according to any one of claims 1 to 4, or a medicamentous salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer, or stereoisomer thereof, wherein R １ is hydrogen, optionally substituted C １ -C ６ Alkyl, or optionally substituted C １ -C ６ It is a deuterated alkyl.

6. A compound according to any one of claims 1 to 5, or a medicamentous salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer, or stereoisomer thereof, wherein R １ is hydrogen, optionally substituted methyl, or optionally substituted deuteromethyl.

7. The compound of any one of claims 1 to 6, or a medicamentable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer, or stereoisomer thereof, wherein R is selected from optionally substituted alkyl, optionally substituted deuterated alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.

8. 8. The compound of any one of claims 1 to 7, its medicamentous salts, biologically active metabolites, solvates, hydrates, prodrugs, racemates, enantiomers, or stereoisomers, wherein R is an optionally substituted C １ -C ２０ Alkyl, optionally substituted C １ -C ２０ Deuterated alkyl, optionally substituted C ３ -C ２０ Cycloalkyl, optionally substituted C １ -C ２０ Heterocycloalkyl, optionally substituted C ６ -C ２０ Aryl and optionally substituted C １ -C ２０ Heteroaryl is selected from the group consisting of aryl, hetero ...

9. A compound according to any one of claims 1 to 8, or a medicamentable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof, wherein said n is 2.

10. 10. A compound according to any one of claims 1 to 9, or a medicamentous salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof, wherein: The R １ is hydrogen, optionally substituted methyl, or optionally substituted deuterated methyl; The n is 2, and The R is an optionally substituted C ３ -C ２０ Cycloalkyl, or optionally substituted C １ -C ２０ It is a heterocycloalkyl.

11. The compound of any one of claims 1 to 10, or a medicamentous salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof, wherein G is ruxolitinib, tofacitinib, oclacitinib, fedratinib, peficitinib, upadacitinib, barictinib, filgotinib, decernotinib, cerdulatinib, lestaurtinib, pacritinib, momelotinib, gandotinib, abrocitinib. , Solcitinib, SHR-0203, Itacitinib, PF-06651600, BMS-986165, Abrocitinib, Cucurbitacin II), CHZ868, TD-1473, zotiraciclib, alkotinib, jaktinib, AZD-4205, DTRMHS-07, KL130008, WXSH-0150, TQ05105, WXFL10203614, GLPG0634, CEP-33779, R-348, itacitinib, ritlecitinib, brepocitinib, tasocitinib, deuclavacitinib, eucravacitinib, INCB-039110, Izencitinib, Entrectinib, Ivarmacitinib, Deuruxolitinib, Adelatinib, NDI-034858, Nezulcitinib, ATI-01777, TD-8236, INCB-054707, Ropsacitinib, AGA-201, ATI50001, Gusac 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, GL The JAK inhibitor is selected from the group consisting of PG-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 and AC-1101.

12. The compound according to any one of claims 1 to 11, or a medicamentous salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof, wherein G is selected from the group consisting of tofacitinib, ruxolitinib, baricitinib, peficitinib, pacritinib, delgocitinib, Pf-04965842, upadacitinib, filgonitib, itacitinib, fedratinib, decernotinib (De and a JAK inhibitor selected from the group consisting of cernotinib, SHR-0302, ASN-002, cerdulatinib, BMS-986165, PF-06700841, INCB-52793, ATI-502, PF-06651600, AZD-4205, deuterated ruxolitinib analogs, ATI-501, R-348, NS-018, jactinib hydrochloride, and KL-130008.

13. A compound, its medicamentous salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer, wherein said compound is 【Chemistry 2】 【change】 is selected from.

14. A process for the preparation of a compound according to any one of claims 1 to 13, its medicamentous salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer.

15. A composition comprising a compound according to any one of claims 1 to 13, its medicamentous salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer.

16. The composition of claim 15 which is a pharmaceutical composition and comprises a pharma- ceutically acceptable carrier.

17. 17. The composition of any one of claims 15 to 16, wherein the compound, its medicamentous salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer, or stereoisomer is present in a concentration of about 0.001% w / w to about 40% w / w.

18. The composition according to any one of claims 15 to 17, which is a formulation suitable for topical application.

19. The composition according to any one of claims 15 to 18, which is an ointment.

20. A compound according to any one of claims 1 to 13, or a medicamentous salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof; or a composition according to any one of claims 15 to 19 for use in the prevention, alleviation and / or treatment of an anti-tumor disease or condition in a subject associated with administration of the agent.

21. Use of a compound according to any one of claims 1 to 13, its medicamentous salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer; or a composition according to any one of claims 15 to 19 for the preparation of a medicament, said medicament being used for the prevention, alleviation and / or treatment of a disease or condition in a subject associated with the administration of an antitumor agent.

22. A compound according to any one of claims 1 to 13, or a medicamentous salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof; or use of a composition according to any one of claims 15 to 19 for the preparation of a JAK inhibitor.

23. A method for use in the prevention, alleviation and / or treatment of a disease or condition in a subject associated with the administration of an anti-tumor agent, said method comprising administering to a subject in need thereof a compound according to any one of claims 1 to 13, a medicamentous salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof; or a composition according to any one of claims 15 to 19.

24. A method for preventing, alleviating and / or treating a disease or condition caused by JAK in a subject in need thereof, said method comprising administering to said subject an effective amount of a compound according to any one of claims 1 to 13, a medicamentous salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof; or a composition according to any one of claims 15 to 19.

25. 25. The method of claim 24, further comprising administering an additional therapeutic agent.

26. 26. The method of any one of claims 24-25, wherein the JAK-induced disease or condition is selected from the following: autoimmune disease or response, widespread activation of an immune response, bacterial infection, viral infection, inflammation, chronic and / or acute inflammatory disease or condition, and / or autoinflammatory disease, fibrotic disease, metabolic disease, neoplasm, or cardiovascular or cerebrovascular disease, skin disorder, pruritus, hair loss disorder, cancer or malignancy, autoimmune connective tissue disease and autoimmune disease; Still's disease, adult-onset Still's disease, Th17-associated inflammation, polychondritis (such as relapsing polychondritis); myositis, polymyositis, autoimmune myositis, dermatomyositis, juvenile dermatomyositis; myasthenia gravis; arthritis (e.g. rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile rheumatoid arthritis, osteoarthritis, infectious arthritis, inflammatory arthritis). , Inflammatory Bowel Disease-Associated Arthritis, Idiopathic Arthritis, Juvenile Idiopathic Arthritis, Systemic Juvenile Idiopathic Arthritis, Psoriatic Arthritis), Spondylitis / Spondyloarthritis / Spondyloarthropathy (Ankylosing Spondylitis), Gout, Scleroderma (Systemic Sclerosis, Juvenile Scleroderma), Reiter's Syndrome / Reactive Arthritis, Lyme Disease, Lupus / Systemic Lupus Erythematosus (SLE) (Lupus Erythematosus, Pediatric SLE, Cutaneous Lupus (Subacute Cutaneous Lupus, Chronic Cutaneous Lupus / Discoid Lupus) , Chilblain-like lupus erythematosus), polymyalgia rheumatica, enthesitis, mixed connective tissue disease, enthesopathy, carditis, myocarditis, angiogenic disorders, myelodysplastic syndromes, atherosclerosis, restenosis (coronary artery restenosis due to atherosclerosis), acute coronary syndromes, myocardial infarction, cardiac allograft vasculopathy, transplant arterial disease; vasculitis (large vessel vasculitis, small vessel vasculitis, giant cell arteritis, polyarteritis nodosa, vasculitis syndromes, The vasculitis syndromes include aortitis, Wegener's granulomatosis, Behcet's disease), STING-associated vasculitis in infancy (SAVI); gastrointestinal disorders, enteritis, colitis, inflammatory bowel disease (ulcerative colitis, Crohn's disease), irritable bowel syndrome, bowel syndrome / spastic colon, celiac disease; acute pancreatitis, chronic pancreatitis; primary biliary cirrhosis, primary sclerosing cholangitis, jaundice, cirrhosis (e.g., primary biliary cirrhosis, cirrhosis due to fatty liver disease (alcoholic steatosis, nonalcoholic steatosis)); esophagitis, gastritis, gastric and duodenal ulcers, peritonitis; nephropathy, immune-mediated glomerular nephropathy, autoimmune nephropathy, membranous glomerulopathy, chronic progressive nephropathy,Diabetic kidney disease / diabetic nephropathy, renal fibrosis, renal ischemia / reperfusion injury, HIV-associated nephropathy, ureteral obstructive nephropathy, glomerulosclerosis, proteinuria, nephrotic syndrome, polycystic kidney disease, autosomal dominant polycystic kidney disease, nephropathy means immune-mediated nephropathy, autoimmune nephropathy, chronic progressive nephropathy, diabetic nephropathy, renal fibrosis, ischemia / reperfusion injury-associated nephropathy, HIV-associated nephropathy, ureteral obstructive nephropathy, glomerulonephritis, chronic kidney disease (diabetic nephropathy, etc.), hypertensive nephropathy, glomerulosclerosis, proteinuria, nephrotic syndrome, polycystic kidney disease, autosomal dominant polycystic kidney disease, diabetic kidney disease, lupus nephritis; interstitial cystitis; periodontitis, gingivitis; lung inflammation, sinusitis, pneumonia, bronchitis, Asthma, bronchial asthma, allergic asthma, non-allergic asthma, allergic bronchopulmonary mycosis, aspirin-induced asthma, adult-onset asthma, asthma with fixed airflow obstruction, exercise-induced asthma, cough fluctuating asthma, work-related asthma, nocturnal asthma, asthma associated with obesity, eosinophilic asthma, hormone-resistant asthma / severe asthma, extrinsic asthma, intrinsic asthma / idiopathic asthma, Churg-Strauss syndrome, bronchiolitis, bronchiolitis obliterans, chronic obstructive pulmonary disease (COPD), interstitial lung disease (pulmonary fibrosis, idiopathic pulmonary fibrosis), acute lung injury, pulmonary fibrosis (idiopathic pulmonary fibrosis or cystic fibrosis, etc.), chronic obstructive pulmonary disease, Adult respiratory distress syndrome, acute lung injury, drug-induced lung injury; Meniere's disease; eye disorders, including (for example) eye inflammation, uveitis, dry eye / dry keratoconjunctivitis, scleritis, episcleritis, keratitis / corneal disease, choroiditis, retinal vasculitis, optic neuritis, retinopathies (diabetic retinopathy, immune-mediated retinopathy, macular degeneration, wet macular degeneration, dry (age-related) macular degeneration); mastocytosis, iron deficiency anemia, uremia, hypereosinophilic syndrome (HES), systemic mastocytosis (SMCD), myelodysplastic syndrome group, idiopathic thrombocytopenic purpura; bone resorption disorders; neurodegenerative disorders, neurological / neuromuscular disorders (examples), multiple sclerosis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS) (familial ALS, sporadic ALS), Alzheimer's disease, myasthenia gravis, Lambert-Eaton myasthenic syndrome (LEMS), Guillain-Barre syndrome, meningitis, encephalitis, traumatic brain injury; neuropathy, delusional parasitosis, abnormalities in neuronal processes and sensory regulation, stroke / neural ischemia, spinal cord injury, peripheral neuropathy, tactile hallucinations, spinal cord injury, psychiatric disorders; paresthesia pain (acute pain, chronic pain, neuropathic pain, fibromyalgia), nerve stimulation,Peripheral neuropathy; pruritus / itch (atopic pruritus, dry pruritus, pruritus associated with psoriasis / psoriatic itch / psoriasis-associated itch), acute pruritus, chronic pruritus, idiopathic pruritus, chronic idiopathic itch, biliary itch, hepatobiliary itch, nephrotic itch / nephrotic itch, uremic itch, cholestasis, intrahepatic cholestasis of pregnancy, chronic lichen simplex-associated pruritus, Lymphoma-associated itch, leukemia-associated itch, prurigo nodularis, atopic dermatitis-associated itch, atopic itch / atopic pruritus, bullous itch, brachioradial pruritus, neurogenic itch, neurogenic itch, dorsal paresthesias, HIV-associated pruritic papule, psychogenic itch, swimmer's itch, pruritic or uremic itch, urticarial itch; skin disorders ( For example, cutaneous drug reactions / drug eruptions, xerosis / dry skin, rash, skin sensitization, skin irritation, sunburn, razor rash, body lice, head lice / pediculosis, hairy lice, cutaneous larva migrans, scabies, parasitosis, insect infection, urticaria / hives, papular urticaria, insect bites, insect stings, dandruff, foreign body or device on the skin, fungal infection, herpes, chickenpox / Chickenpox, Eosinophilic folliculitis, Skin diseases of pregnancy / Pruritic urticarial papules and plaques of pregnancy (PUPP), Inflammatory dermatoses, Neutrophilic dermatoses, Histiocytic neutrophilic dermatoses, Intestinal bypass syndrome dermatoses, Psoriasis / Psoriasis vulgaris, Lichen planus, Lichen sclerosus atrophicus, Acne (Acne vulgaris, Acne acne, Inflammatory acne, Nodular cystic acne, Keloid acne, Keloid acne cervicalis), Atopic diseases (Allergic contact sensitization, Allergic dermatitis), Dermatitis (Atopic dermatitis / Eczema, Contact dermatitis, Photodermatitis, Seborrheic dermatitis, Stasis dermatitis), Acute febrile neutrophilic dermatoses (Sweet syndrome), Chronic atypical neutrophil CANDLE syndrome, hidradenitis suppurativa, urticaria, pyoderma gangrenosum, alopecia (eyebrow alopecia, alopecia of the internasal hairs, cicatricial alopecia (e.g., cicatricial alopecia, central centrifugal cicatricial alopecia, lichen planus, frontal fibrosing alopecia, alopecia alopecia)), non-cicatricial alopecia (alopecia areata (AA) (patchy AA, alopecia totalis (AT), alopecia universalis (AU), serpentine pattern alopecia, sisaihpo pattern alopecia areata)), androgenic / androgenic alopecia (AGA) / male and female pattern AGA), telogen effluvium, tinea capitis, hypotrichosis (hereditary hypotrichosis simplex),Lichen planopilaris (frontal fibrosing alopecia), palmoplantar keratoderma punctate, erythema exfoliatus (EED), neutrophilic secretion hidradenitis, columnar cell neutrophils Vitiligo vulgaris, including granulomatous dermatitis, neutrophilic urticarial dermatosis, and segmental vitiligo (unisegmental vitiligo, bisegmental vitiligo, multisegmental vitiligo) vitiligo vulgaris), nonsegmental vitiligo (digital, facial, or extremity facial vitiligo, midface vitiligo, mucosal vitiligo, confetti-type vitiligo, tricolor vitiligo, marginal inflammatory vitiligo, tetracolor vitiligo, blue vitiligo vulgaris, Koebner phenomenon, vitiligo vulgaris, generalized vitiligo vitiligo, generalized vitiligo), mixed vitiligo / segmental associated non-segmental vitiligo, localized vitiligo, isolated mucosal vitiligo or vitiligo with or without leukoderma (including body hair); bullous diseases, immune bullous diseases (bullous pemphigoid, cicatricial pemphigoid, pemphigus vulgaris, linear IgA disease), gestational pemphigoid, xeroderma pigmentosum; fibrotic and scarring disorders: fibroids, liver fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, e.g., scleroderma, increasing fibrosis, keloids, low-grade scarring due to postoperative scarring; wound healing, surgical scars, radiation-induced fibrosis (e.g., head and neck, gastrointestinal or pulmonary), CNS scarring, gastrointestinal or digestive tract fibrosis, renal fibrosis, liver or bile duct fibrosis, liver fibrosis (e.g., nonalcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma), cardiac fibrosis (e.g., endomyocardial fibrosis or atrial fibrosis), ophthalmic scarring, fibrosclerosis, scarring enhancement, trauma or scabies healing, keloids, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis / Ormond's disease, progressive massive fibrosis, nephrogenic systemic fibrosis; Sjogren's syndrome, sarcoidosis, familial Mediterranean fever, cryopyrin-associated periodic syndrome (Muckle-Wells syndrome, familial cold-induced autoinflammatory syndrome / familial cold urticaria / TNF receptor-associated periodic syndrome, neonatal onset multisystem inflammatory disease), hyperoxia-induced inflammation, reperfusion injury, postoperative trauma, tissue injury, hyperthermia syndrome; diabetes (type I diabetes, type II diabetes) / diabetes, Hashimoto's thyroiditis, Graves' disease, Addison's disease, Castleman's disease, hyperparathyroidism, menopause, obesity, steroid resistance, impaired glucose tolerance, metabolic syndrome, thyroid disease, hypophysitis; systemic immune aging; autoimmune atrophic gastritis, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis,Goodpasture's disease, Sjogren's syndrome, autoimmune thrombocytopenia, sympathetic ophthalmia; secondary hematologic manifestations of autoimmune disease (e.g., anemia), autoimmune hemolytic syndrome (autoimmune hemolytic anemia), autoimmune and inflammatory hepatitis, autoimmune ovarian failure, autoimmune thrombocytopenia, silicone implant-associated autoimmune disease, drug-induced autoimmune disease, HIV-associated autoimmune syndrome, metal-induced autoimmune disease, autoimmune hearing loss, autoimmune thyroid disorders; allergies and allergic reactions, including hypersensitivity reactions, e.g., Type I hypersensitivity reactions (including, e.g., anaphylaxis), Type II hypersensitivity reactions (e.g., Goodpasture's disease, autoimmune hemolytic anemia), Type III hypersensitivity reaction disorders (e.g., Arthus reaction, serum sickness), and Type IV hypersensitivity reactions (e.g., contact dermatitis, allograft rejection); Acute and chronic infections, septic syndromes (sepsis, septic shock, endotoxin shock, exotoxin-induced toxic shock, gram-negative sepsis, gram-positive sepsis, fungal sepsis, toxic shock syndrome);acute and chronic infections, septic syndromes (sepsis, septic shock, endotoxin shock, exotoxin-induced toxic shock, gram-negative sepsis, gram-positive sepsis, fungal sepsis, toxic shock syndrome);rejection: graft-versus-host reaction / graft-versus-host disease, allograft rejection (e.g. acute allograft rejection) or chronic allograft rejection), early transplant rejection; malignant tumors, carcinoma, lymphoma, leukemia, multiple myeloma, solid tumors, teratomas, metastatic and bone disorders, internal cancers, cancer of the bone, mouth / pharynx, esophagus, larynx, stomach, intestine, colon, rectum, lung (e.g., non-small cell lung cancer or small cell lung cancer), liver (hepatic), pancreas, nerve, brain (e.g., glioma, glioblastoma multiforme, astrocytoma, neuroblastoma, and schwannoma), head and neck, throat, ovary, uterus, prostate, testis, bladder, kidney (renal), breast, gallbladder, cervix, thyroid, prostate, eye (ocular malignancies) ), and skin (melanoma, keratoacanthoma); and fibrous carcinoma, fibroma, fibroadenoma, fibrosarcoma, myeloproliferative disorders, neoplasms (hematopoietic neoplasms, myeloid neoplasms, lymphoid neoplasms (myelofibrosis, primary myelofibrosis, polycythemia vera, essential thrombocythemia)), leukemias (acute lymphocytic leukemia, acute and chronic myelogenous leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, chronic myelomonocytic leukemia (CMML), or promyelocytic leukemia), multiple myeloma and other myeloid malignancies (myeloid metaplasia with myelofibrosis (MMM), primary bone marrow fibrosis (PBMC), primary osteoporosis (BAC), primary osteoporosis (OS), primary osteoporosis (OS), primary osteoporosis (OA ... myelofibrosis (PMF), idiopathic myelofibrosis (IMF)), lymphoma (Hodgkin's disease, cutaneous lymphoma (cutaneous T-cell lymphoma, mycosis fungoides)), lymphoma (e.g., B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, hairy cell lymphoma, Burkitt's lymphoma, mast cell tumor, Hodgkin's disease or non-Hodgkin's disease); Kaposi's sarcoma, rhabdomyosarcoma, seminoma, teratocarcinoma, osteosarcoma, follicular thyroid carcinoma; increased exogenous or synthetic opioid accumulation, paresthesia back pain, obsessive-compulsive disorder, obsessive-compulsive disorder-related nostalgia, and combinations thereof.

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