CN116669765A

CN116669765A - Methods for preventing or treating EGFR dysfunction-related side effects

Info

Publication number: CN116669765A
Application number: CN202180087422.5A
Authority: CN
Inventors: 张诗宜; 李文晰; 尤青
Original assignee: Shanghai Ankao Pharmaceutical Technology Co ltd
Current assignee: Shanghai Ankao Pharmaceutical Technology Co ltd
Priority date: 2020-12-29
Filing date: 2021-12-28
Publication date: 2023-08-29
Also published as: CN112933095A; TW202241438A; WO2022143630A1; CN114081889A; CN114099514A

Abstract

Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention and/or treatment of side effects associated with EGFR dysfunction in a subject. Pharmaceutical compositions and kits comprising the compounds are also provided.

Description

Methods for preventing or treating EGFR dysfunction-related side effects

Technical Field

The application relates to the field of biological medicine, in particular to application of the medicine in preventing or treating side effects related to EGFR dysfunction in a subject.

Background

Mutations or overexpression of the Epidermal Growth Factor Receptor (EGFR) have been found to be associated with a variety of cancers, and patients suffering from such tumors can be treated by inhibiting EGFR therapies (e.g., administration of EGFR inhibitors). However, such treatments can cause serious side effects (especially in the skin, the five elements and the gastrointestinal tract). More than 50% of patients treated with EGFR inhibitors have been reported to develop skin side effects (see, e.g., headary et al, journal of the American Academy of Dermatology,58 (4): 545, 2008). Inhibition of various side effects of EGFR therapy can lead to withdrawal or dose reduction and can impair the quality of life of the patient.

There is no successful treatment regimen in the prior art to control the side effects caused by EGFR therapy inhibition. Thus, there is an urgent need for therapeutic regimens that can successfully control these side effects.

Disclosure of Invention

The present application provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention and/or treatment of side effects associated with EGFR dysfunction in a subject:formula I wherein ring A is optionally substituted or unsubstituted comprising _1-3 C of individual rings ₄ -C ₉ Cycloalkyl or heterocyclyl, R ₅ Selected from hydrogen atoms, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkylsulfonyl, C ₂ -C ₆ Alkenyl and C ₂ -C ₆ Alkynyl, wherein the alkyl, alkenyl, alkynyl is optionally substituted with deuterium, hydroxy, amino, halogen, cyano and/or nitro.

In certain embodiments, the ring a is a monocyclic C optionally substituted or unsubstituted ₄ -C ₇ Cycloalkyl or heterocyclyl.

In certain embodiments, the ring a is a monocyclic C ₄ -C ₇ Cycloalkyl, monocyclic C ₄ -C ₇ A nitrogen-containing heterocyclyl, said cycloalkyl or nitrogen-containing heterocyclyl optionally being substituted with one or more substituents.

In certain embodiments, the ring a isWherein the R is ₁ Selected from hydrogen atoms, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl and C ₂ -C ₆ Alkynyl, R ₂ Selected from hydrogen atoms, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkenyl, C ₁ -C ₆ Alkynyl, acyl and cyano, wherein the alkyl, alkenyl, alkynyl, acyl are optionally substituted with halogen, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkynyl, C ₂ -C ₆ Alkynyl and/or cyano substitution.

In certain embodiments, the R ₁ Selected from C ₁ -C ₆ Alkyl groups and hydrogen atoms.

In certain embodiments, the R ₁ Is methyl or hydrogen atom.

In certain embodiments, the R ₂ is-C (O) -R ₄ Wherein said R is ₄ Selected from C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl and cyano groups, the alkyl, alkenyl, alkynyl, cyano groups being further optionally substituted with C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl and cyano substitutions.

In certain embodiments, the R ₂ Selected from-C (O) -ch=ch ₂ and-C (O) -CH ₂ -CN。

In certain embodiments, the ring a isWherein the R is ₃ Selected from hydrogen atoms, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, acyl, amino and/or sulfonate groups, said C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, acyl, amino or sulfonic acid groups are further substituted by one or more C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, acyl, amino and/or sulfonate substituents.

In certain embodiments, the R ₃ Is thatWherein the R is ₆ Selected from C ₁ -C ₆ An alkyl group.

In certain embodiments, the R ₃ Is that

In some implementationsIn this way, the ring A is C optionally substituted or unsubstituted ₅ -C ₁₀ A bicycloalkyl or bicycloheteroalkyl group, optionally substituted with a substituent.

In certain embodiments, the ring a isWherein the R is ₈ is-C (O) R ₇ Or- (CH) ₂ )n-C(O)OR ₇ Wherein said R is ₇ Selected from hydrogen atoms, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₂ -C ₆ Alkenyl, 5-to 10-membered heteroaryl and amino, said C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₂ -C ₆ Alkenyl and 5-to 10-membered heteroaryl and amino are further optionally C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₂ -C ₆ Alkenyl and/or 5-to 10-membered heteroaryl substitutions.

In certain embodiments, the R ₈ is-C (O) R ₇ And said R ₇ Is thatWherein ring B is a 5-to 7-membered heteroaryl, optionally R ₉ Substitution, said R ₉ Selected from hydrogen atoms, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy and C ₂ -C ₆ Alkenyl groups.

In certain embodiments, the ring B is a 5 membered heteroaryl, optionally substituted with R ₉ Substitution, said R ₉ Selected from hydrogen atoms, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy and C ₂ -C ₆ Alkenyl groups.

In certain embodiments, the ring B isThe R is ₉ Is C ₁ -C ₆ An alkoxy group.

In certain embodiments, the R ₉ is-O-CH ₃ 。

In certain embodiments, the R ₅ Selected from hydrogen atoms and C ₁ -C ₆ An alkyl group.

In certain embodiments, the R ₅ Selected from the group consisting of hydrogen atoms and methyl groups.

In certain embodiments, the compound of formula I is selected from the group consisting of compounds I-a, I-b, I-c, and I-d:

in certain embodiments, the side effects associated with EGFR dysfunction include side effects associated with EGFR inhibition. In certain embodiments, the side effect is associated with administration of an EGFR inhibitor.

In certain embodiments, the side effect is directly caused by EGFR inhibition.

In certain embodiments, the side effect is caused by an EGFR inhibitor.

In certain embodiments, the side effects associated with EGFR inhibition include epithelial tissue disease associated with EGFR inhibition. In certain embodiments, the epithelial tissue disorder associated with EGFR inhibition is associated with administration of an EGFR inhibitor.

In certain embodiments, the epithelial tissue disorder comprises an epithelial cell disorder and/or an endothelial cell disorder.

In certain embodiments, the epithelial cells include skin epithelial cells, oral epithelial cells, gastric epithelial cells, and/or intestinal epithelial cells.

In certain embodiments, the side effects associated with EGFR dysfunction include rash. In certain embodiments, the rash comprises a rash associated with the administration of an EGFR inhibitor

In certain embodiments, the rash associated with EGFR dysfunction comprises an immune rash and/or a non-immune rash.

In certain embodiments, the rash includes acne vulgaris (acne vulgaris), papular rash (papulopustular rash), rosacea (acne rosacea), pruritic rash (pruritis rash), acneiform rash (acneiform rash) cellulitis (celulitis), lyme disease (Lyme disease), allergic reactions (allergic reaction), suppurative sweat gland (hidradenitis suppurativa), measles (hives), dermatitis (dermatides), scab (cradle cap), purpura (purura), pityriasis rosea (pityriasis), erythema (erythema), shingles (shingles), bruise (bruise) and/or xanthoma (xanthosmala), melanoma (melama), basal cell carcinoma (basal cell carcinoma), cell carcinoma (squamous cell carcinoma), kaposi's sarcoma, annular centrifugation (erythema annulare centrifugum), papyriasis, dry folliculitis, and eczema, and/or eczema.

In certain embodiments, the rash associated with EGFR dysfunction includes acne vulgaris (acne vulgaris) associated with EGFR dysfunction, papular rash associated with EGFR dysfunction (papulopustular rash), rosacea associated with EGFR dysfunction (acerosacea), pruritic rash associated with EGFR dysfunction (boil), acne-like rash associated with EGFR dysfunction (acneiform rash), cellulitis associated with EGFR dysfunction (celulitis), lyme disease associated with EGFR dysfunction (Lyme), allergic reaction associated with EGFR dysfunction (allergic reaction), hidradenitis suppurativa associated with EGFR dysfunction (hidradenitis suppurativa), measles associated with EGFR dysfunction (hives), dermatitis associated with EGFR dysfunction (dermatides), scab associated with EGFR dysfunction (craddle cap), purpura associated with EGFR dysfunction (puura), pityriasis associated with EGFR dysfunction (rash), erythema associated with EGFR dysfunction (EGFR), kappy, dysfunctional (Karpa) associated with EGFR dysfunction (leiocarcinoma), xanthoma associated with EGFR dysfunction (leia) and xanthoma associated with EGFR dysfunction (leiomy), xanthoma associated with EGFR dysfunction (dysfunctional sarcoma (35), xanthoma associated with EGFR dysfunction (dysfunctional), xanthoma (dysfunctional, xanthoma associated with EGFR (dysfunctional), and xanthoma associated with EGFR (dysfunctional, xanthoma) associated with EGFR dysfunction (dysfunctional, xanthoma) Annular erythema centrifugation associated with EGFR dysfunction (erythema annulare centrifugum), folliculitis associated with EGFR dysfunction, follicular papules associated with EGFR dysfunction, xerosis eczema associated with EGFR dysfunction and/or papulopus associated with EGFR dysfunction.

In certain embodiments, the side effects associated with EGFR dysfunction include mucosal injury diseases or disorders.

In certain embodiments, the mucosal injury disease or condition comprises dry mouth, oral mucositis, epistaxis, nasopharyngitis, cheilitis, oesophageal mucositis, gastrointestinal mucositis, gastric ulcers, rectal mucositis, diarrhea, vomiting, nausea, anaesthesia, constipation and/or abdominal pain.

In certain embodiments, the mucosal injury disease or disorder associated with EGFR dysfunction includes dry mouth associated with EGFR dysfunction, oral mucositis associated with EGFR dysfunction, epistaxis associated with EGFR dysfunction, nasopharyngitis associated with EGFR dysfunction, cheilitis associated with EGFR dysfunction, esophagitis associated with EGFR dysfunction, gastrointestinal mucositis associated with EGFR dysfunction, gastric ulcer associated with EGFR dysfunction, rectal mucositis associated with EGFR dysfunction, diarrhea associated with EGFR dysfunction, emesis associated with EGFR dysfunction, nausea associated with EGFR dysfunction, anorexia associated with EGFR dysfunction, constipation associated with EGFR dysfunction and/or abdominal pain associated with EGFR dysfunction.

In certain embodiments, the severity of the side effect is according to grade 1 or more, grade 2 or more, grade 3 or more, grade 4 or more, or grade 5 in NCI-CTCAE V5.0.

In certain embodiments, the side effects associated with EGFR inhibition include side effects associated with administration of EGFR inhibitors.

In certain embodiments, the EGFR inhibitor comprises a medicament for treating cancer.

In certain embodiments, the EGFR inhibitor acts directly on the EGFR protein and/or nucleic acid encoding the EGFR protein.

In certain embodiments, the EGFR inhibitor comprises a small molecule EGFR inhibitor, a protein macromolecule that specifically binds EGFR, RNAi that inhibits expression of EGFR protein, and/or an antisense oligonucleotide that inhibits expression of EGFR protein.

In certain embodiments, the small molecule EGFR inhibitor comprises a small molecule EGFR inhibitor that binds reversibly to EGFR, a small molecule EGFR inhibitor that binds irreversibly to EGFR, and/or a small molecule EGFR inhibitor that specifically binds mutant EGFR.

In certain embodiments, the EGFR inhibitor comprises cetuximab, gefitinib, erlotinib, icotinib, sapitinib, afatinib, lapatinib, vanadtinib, lenatinib, briatinib, panitumumab, cetuximab, nimuzumab, teseretinib, ai Liti, xi Li tinib, rociletinib, canetinib, AZD3759, YZJ-0318, naproxtinib, naquotinib, PF-06747775, SPH1188-11, pozitinib, ibrutinib, varlitinib, ai Fu tinib, HM61713, CK-101, pyrroltinib, rilotinib, HS-10296, AP32788, cimetinib, GMA204, virlitinib, yinlitinib, natatinib, nostinib, motinib, octtinib, dactinib, eyetinib and/or Ovatinib 5.

In certain embodiments, the EGFR inhibitor is used in combination with one or more other therapies.

In certain embodiments, the subject comprises a cancer patient.

In certain embodiments, the subject is administered the EGFR inhibitor once, currently and/or in the future.

In certain embodiments, the compounds of formula I are prepared for transdermal administration.

In certain embodiments, the concentration of the compound of formula I in the medicament is from about 0.0001% to about 50%.

In certain embodiments, the compounds of formula I are prepared for administration to the gastrointestinal tract.

In certain embodiments, the compounds of formula I are prepared for administration by injection.

In certain embodiments, the effective dose of the compound of formula I is from 0.001mg/kg body weight/day to 3000mg/kg body weight/day.

In certain embodiments, the effective dose of the compound of formula I is from 0.1mg/kg body weight/day to 150mg/kg body weight/day.

In certain embodiments, the drug does not substantially affect the therapeutic effect of the EGFR inhibitor.

In certain embodiments, one or more additional active ingredients are also included in the medicament.

In another aspect, the application provides the use of compounds I-a, I-b, I-c and/or I-d and pharmaceutically acceptable salts thereof for the manufacture of a medicament for the prevention and/or treatment of side effects associated with EGFR dysfunction in a subject,

in another aspect, the application provides a method of preventing or treating side effects associated with EGFR dysfunction, comprising administering to a subject in need thereof a compound of formula I according to the application, or a pharmaceutically acceptable salt thereof:formula I wherein ring A is optionally substituted or unsubstituted comprising _1-3 C of individual rings ₄ -C ₉ Cycloalkyl or heterocyclyl, R ₅ Selected from hydrogen atoms, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkylsulfonyl, C ₂ -C ₆ Alkenyl and C ₂ -C ₆ Alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with deuterium, hydroxy, amino, halogen, cyano and/or nitro.

In certain embodiments, the subject is administered an EGFR inhibitor once, currently and/or in the future.

In another aspect, the application provides a method of preventing or treating side effects associated with EGFR dysfunction comprising administering to a subject in need thereof, compounds I-a, I-b, I-c and/or I-d, or a pharmaceutically acceptable salt thereof.

In another aspect, the application provides a pharmaceutical combination or kit comprising: 1) An EGFR inhibitor; and 2) a compound of formula I as described herein:formula I wherein ring A is optionally substituted or unsubstituted comprising _1-3 C of individual rings ₄ -C ₉ Cycloalkyl or heterocyclyl, R ₅ Selected from hydrogen atoms, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkylsulfonyl, C ₂ -C ₆ Alkenyl and C ₂ -C ₆ Alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with deuterium, hydroxy, amino, halogen, cyano and/or nitro.

In certain embodiments, the EGFR inhibitor and the compound of formula I are not mixed with each other.

In certain embodiments, the EGFR inhibitor and the compound of formula I are each independently present in separate containers.

In certain embodiments, the compounds of formula I are formulated for gastrointestinal, injection and/or transdermal administration.

In certain embodiments, the concentration of the compound of formula I is from about 0.0001% to about 50%.

In certain embodiments, the compound of formula I in 2) is capable of preventing or treating a disease or disorder associated with administration of the EGFR inhibitor in 1).

In certain embodiments, the compound of formula I in 2) does not substantially affect the therapeutic effect of the EGFR inhibitor in 1).

In certain embodiments, the compound of formula I of 2) is administered before, simultaneously with, or after the EGFR inhibitor of 1).

In another aspect, the present application provides a method comprising the steps of:

1) Monitoring the side effects of a subject administered an EGFR inhibitor;

2) When the monitoring indicates that the subject has side effects associated with administration of the EGFR inhibitor, administering to the subject a compound of formula I:formula I wherein ring A is C4-C9 cycloalkyl or heterocyclyl containing 1-3 rings, optionally substituted or unsubstituted, and R5 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkylsulfonyl, C2-C6 alkenyl, and C2-C6 alkynyl, wherein the alkyl, alkenyl, alkynyl are optionally substituted with deuterium, hydroxy, amino, halogen, cyano, and/or nitro.

In certain embodiments, the method further comprises continuing to monitor the side effects, and optionally reducing or disabling the EGFR inhibitor.

In certain embodiments, the severity of the side effect increases after the administration of the EGFR inhibitor.

In certain embodiments, the subject does not have the side effect rash prior to the administration of the EGFR inhibitor.

In certain embodiments, the EGFR inhibitor does not comprise a compound represented by formula I.

In certain embodiments, the EGFR inhibitor is administered to treat cancer.

In certain embodiments, the affliction of the side effect is different from the affliction of the cancer.

Other aspects and advantages of the present application will become readily apparent to those skilled in the art from the following detailed description. Only exemplary embodiments of the present application are shown and described in the following detailed description. As those skilled in the art will recognize, the present disclosure enables one skilled in the art to make modifications to the disclosed embodiments without departing from the spirit and scope of the application as claimed. Accordingly, the drawings and descriptions of the present application are to be regarded as illustrative in nature and not as restrictive.

Drawings

The specific features of the application related to the application are shown in the appended claims. A better understanding of the features and advantages of the application in accordance with the present application will be obtained by reference to the exemplary embodiments and the accompanying drawings that are described in detail below. The drawings are briefly described as follows:

fig. 1: shown are photographs of the left, back and right sides of a rat model of the EGFR inhibitor of the present application that resulted in rash.

Fig. 2: photographs of the left, back and right sides of a control group, JAK inhibitor group, representative rats in examples 1-37 of the present application are shown.

Fig. 3: the rash grade results for the control group and JAK inhibitor group of examples 1-37 of the present application are shown.

Fig. 4: the rash grade results for the control group and JAK inhibitor group of examples 38-65 of the present application are shown.

Fig. 5: the rash grade of the control group (mab-like EGFR inhibitor), JAK inhibitor group, in examples 66-67 of the present application is shown.

Fig. 6: the rash grade of the control group (mab-like EGFR inhibitor), JAK inhibitor group, in example 68 of the present application is shown.

Fig. 7: photographs of the left, back and right sides of a control group, JAK inhibitor group, representative rats in examples 69-98 of the present application are shown.

Fig. 8: the rash grade results for the control group and JAK inhibitor group of examples 69-98 of the present application are shown.

Fig. 9: the rash grade results for the control group and JAK inhibitor group of examples 99-122 of the present application are shown.

Fig. 10: the rash grade of the control group (mab-like EGFR inhibitor), JAK inhibitor group, of examples 123-124 of the present application is shown.

Fig. 11: photographs of the left, back and right sides of typical rats of the other dermatological groups, JAK inhibitor groups, of examples 125-130 of the present application are shown.

Fig. 12: the rash grade results for the other skin drug groups, JAK inhibitor groups, of examples 125-130 of the present application are shown.

Fig. 13: different grades of photographs showing that the EGFR inhibitors of the present application cause diarrhea in rats are shown.

Fig. 14: diarrhea grade results for the control group, JAK inhibitor group, of examples 131-155 of the present application are shown.

Fig. 15: diarrhea grade results for the control group and JAK inhibitor group of examples 157-178 of the present application are shown.

Fig. 16: the diarrhea grade results of the other drug groups, the JAK inhibitor group, of examples 180-185 of the present application are shown

Fig. 17: photographs of the lips of typical rats from the control group, JAK inhibitor group, of examples 186-202 of the present application are shown.

Detailed Description

Further advantages and effects of the present application will become readily apparent to those skilled in the art from the present disclosure, by describing embodiments of the present application with specific examples.

Detailed Description

Epithelial tissue disease

In the present application, a method of preventing and/or treating epithelial tissue disease is provided.

The term "epithelial tissue" as used herein generally refers to cells comprising one or more layers covering the free and closed surfaces of the entire body, including skin, mucus, lumen, serum and glandular spaces. All epithelial layers contain two specific domains: a apical domain facing the mucosal (or luminal) space and an basolateral membrane facing the serosal (or submerged) space. Thus, an important function of epithelial tissue is to provide adequate barrier work to separate and control many physiological processes between these two spaces. Epithelial tissue may include epithelial cells and endothelial cells. The epithelial cells may include skin epithelial cells, oral epithelial cells, gastric epithelial cells, and/or intestinal epithelial cells.

The term "epithelial tissue disorder" as used herein generally refers to disorders caused by epithelial cells and/or endothelial cytopathy, and in some embodiments, may include a disorder or condition selected from the group consisting of: rash, acne, skin itching, hand and foot syndrome, hair loss, hair changes, erythema, skin exfoliation (Skin irritation), pustules, hirsutism, pigmentation (hyper-Skin), nail diseases (nail disorders), paronychia and cracks, dry Skin, hypersensitive reactions, mucositis, nasopharyngitis, epistaxis, xerostomia, cheilitis, canker sores and gastrointestinal mucosal lesions. For example, the epithelial tissue disorder may include diarrhea. For example, the epithelial tissue disorder may include rash. For example, the epithelial tissue disorder may include cheilitis.

Depending on the site of disease occurrence, epithelial tissue diseases can be classified as epithelial cell diseases and/or endothelial cell diseases. In some embodiments, epithelial cell disorders can be divided into skin epithelial cell disorders (e.g., rash, acne, rosacea, atopic dermatitis, contact dermatitis, seborrheic dermatitis, lupus, scleroderma, tian-cell sore, pigmentation, melasma, vitiligo, urticaria, tinea corporis, skin itching, alopecia, hair changes, erythema, paronychia and first fissure, skin dryness, hypersensitivity and psoriasis), oral epithelial cell disorders (e.g., pemphigus, herpes labialis, vesicular stomatitis, granulomatous cheilitis, oral ulcers, pemphigoid, sjogren's syndrome, behcet's syndrome, and oral sarcoidosis, etc.), gastric epithelial cell disorders (e.g., gastritis, enterogenesis, gastric perforation, gastric fistula, gastric ulcer, and gastrointestinal polyp), or small intestinal epithelial cell disorders (e.g., enteritis, endosis, intestinal perforation, intestinal ulcer, ulcerative colitis, and NSAIDs intestinal polyp).

The severity of epithelial tissue disease can be classified according to the common adverse event terminology standard (CTCAE) published by the national cancer institute, which is a standard classification and severity of adverse events in clinical trials for cancer treatment and other oncology settings (NCI-CTCAE V5.0). In some embodiments, the severity of the epithelial tissue disease may be according to grade 1 or more, grade 2 or more, grade 3 or more, grade 4 or more, or grade 5 in NCI-CTCAE V5.0.

In some embodiments, the endothelial cells may be vascular endothelial cells. In some embodiments, the endothelial cell disorder may be a vascular endothelial cell disorder. Vascular endothelial cell diseases may include, but are not limited to: degenerative vascular diseases (e.g., atherosclerosis, arteriosclerosis, and arteriole (e.g., transparent degenerative arteriole and proliferative arteriole)), inflammatory vascular diseases (e.g., infectious arteritis, syphilis arteritis, giant cell arteritis, thromboangiitis obliterans, and rheumatic arteritis), functional vascular diseases (e.g., raynaud's disease, cyanosis of hands and feet, and erythromelalgia), and congenital vascular diseases (e.g., congenital arteriovenous fistulae), and the like.

In the present application, the epithelial cell disease may be a skin epithelial cell disease. For example, the skin epithelial cell disorder may be a rash.

The present application provides a method for preventing or treating rash.

The term "rash" as used herein generally refers to skin changes that affect the color, appearance, or texture of skin. Rashes may be localized to only a portion of the body or affect the entire skin. Rash may also include urticaria. The rash may be an immune rash and/or a non-immune rash. The rash of the application may be a rash that occurs in a subject following administration of an EGFR inhibitor.

For example, the pathological manifestations of the rash may include a marked change in skin epidermal growth and/or differentiation, a change in keratinocyte terminal differentiation, dense corneal shaping and epidermal hypoparagonization, damage to sebaceous glands and/or hair follicle funnels, with or without signs of infection, impaired epidermal barrier, epidermal corneal laceration, cytokine production, inflammatory cell infiltration (e.g., neutrophils, lymphocytes), bacterial infection, telangiectasia, pigmentation, and/or dense epithelial inflammatory permeability, all seen in affected and unaffected skin.

For example, the clinical manifestations of the rash may be erythema, dry skin, itching, squamous plaque, tenderness, burning sensation, cracks, pustules, follicles, ulcers, abscesses, red bumps, and/or purulent lesions.

For example, the site of occurrence of the rash may be the epidermis, e.g., including the seborrheic area of the skin. For example, the site of occurrence of the rash may include scalp, face, neck, chest, upper back, limbs, lower back, abdomen, buttocks, periodontal area, abdomen, palm, sole, nails, and/or mucous membrane.

In the present application, the rash may include acne vulgaris (acne vulgaris), papular rash (papulopustular rash) rosacea (acne rosacea), pruritic rash (pruritis rash), acneiform rash (acneiform rash) cellulitis (celulitis), lyme disease (Lyme disease), allergic reaction (allergic reaction), suppurative sweat (hidradenitis suppurativa), measles (hives), dermatitis (dermatitis), scab (cradle cap), purpura (purura), pityriasis rosea (pityriasis rosea), erythema (eryshima), herpes zoster (bruise), bruise (bruise) and/or xanthoma (xantholabra), melanoma (melama), basal cell carcinoma (basal cell carcinoma), squamous cell carcinoma (squamous cell carcinoma), kaposi's sarcoma (kapo's), annular centrifugation (erythema annulare centrifugum), folliculitis, dry folliculitis, eczema, and/or eczema.

In the present application, a method of preventing and/or treating a mucosal injury disease or disorder is provided. For example, the mucosa may include oral mucosa, eyelid mucosa, nasal mucosa, urethral mucosa, gastric mucosa, digestive tract mucosa, rectal mucosa, esophageal mucosa, and/or vulvar mucosa. The mucosal injury disease or condition may include mucosal thinning, breakage, infection, ulceration or abscess.

In certain embodiments, the mucosal injury disease or condition comprises dry mouth, oral mucositis, epistaxis, nasopharyngitis, cheilitis, esophagitis, gastrointestinal mucositis, gastric ulcers, rectal mucositis, diarrhea, vomiting, nausea, anorexia, constipation, and/or abdominal pain. For example, the mucosal injury disease or condition may be cheilitis. For example, the mucosal injury disease or condition may be diarrhea.

In the present application, the term "lipitis" generally refers to inflammation of the mouth or lips, and the principal symptoms may include dry lips, desquamation, chapping, crusting, blisters, exudates, redness, ulcers and/or bleeding. The cheilitis according to the present application may be cheilitis that occurs in a subject after administration of an EGFR inhibitor.

In the present application, the term "diarrhea" generally refers to fluid-like, watery or relaxed peristalsis of the intestinal tract. Diarrhea may be a subject having more than three bowel movements per day or more than three bowel movements, or a number of bowel movements greater than the subject's normal number of bowel movements. The diarrhea of the application may be diarrhea that occurs in a subject following administration of an EGFR inhibitor.

For example, the cheilitis of a mucosal injury disease or disorder may include lip chapping, actinic cheilitis, angular cheilitis, eczematous cheilitis, infectious cheilitis, granulomatous cheilitis, drug-related cheilitis, exfoliative cheilitis, adenosis, and/or androstatic cheilitis.

EGFR dysfunction

In one aspect, the application provides a method of preventing or treating side effects associated with EGFR dysfunction. In the present application, the term "EGFR" generally refers to the epidermal growth factor receptor (Epidermal Growth Factor Receptor), also known as ErbB1 or HER1, which is a 170kDa transmembrane glycoprotein encoded by the c-erbB1 proto-oncogene. EGFR is a member of the human epidermal growth factor receptor (HER) family of Receptor Tyrosine Kinases (RTKs), which also includes HER2 (ErbB 2), HER3 (ErbB 3) and HER4 (ErbB 4). EGFR signaling initiates by ligand binding followed by initiation of a signaling cascade by induction of conformational changes, homodimerization or heterodimerization of the receptor with other ErbB family members, trans autophosphorylation of the receptor, etc. (see Ferguson et al, annu Rev Biophys,37:353-73, 2008), ultimately affecting a variety of cellular functions (e.g., cell proliferation and survival). EGFR expression or an increase in its kinase activity has been associated with a range of human cancers (see Mendelsohn et al, oncogene 19:6550-6565, 2000; grUnwald et al, J Natl Cancer Inst 95:851-67, 2003; mendelsohn et al, semin Oncol 33:369-85, 2006). Elevated expression of EGFR is known to be found in a number of cancers, such as brain glioma, breast cancer, ovarian cancer, cervical cancer, and the like.

In certain cases, the side effects associated with EGFR dysfunction include side effects associated with EGFR inhibition. In the present application, the term "EGFR inhibited" includes any reduction in EGFR activity, expression or number (e.g., caused by treatment or by the subject's own physical condition) for any reason. In some embodiments, inhibition of EGFR generally refers to a reduction in the activity or number of EGFR by at least 10%. In some embodiments, inhibition of EGFR generally refers to a decrease in the activity or number of EGFR of at least 20%, 40%, 50%, 80%, 90%, 95% or more. In some embodiments, the decrease is compared to a standard value in a subject of the same class (e.g., the same normal person or the same type of patient). In some embodiments, the decrease is compared to a value of the same subject over a period of time.

In certain cases, the side effects associated with EGFR dysfunction include side effects associated with administration of EGFR inhibitors. For the subject, the side effects may result after administration of an EGFR inhibitor. For subjects, the severity of the side effects may be exacerbated after administration of EGFR inhibitors.

In some cases, EGFR is inhibited as a result of administration of an EGFR inhibitor. In the present application, the term "EGFR inhibitor" generally refers to any EGFR inhibitor known in the art or discovered in the future, including any substance that, when administered to a subject, results in inhibition of biological activity associated with EGFR activity in the subject (including inhibition of downstream biological effects resulting from the binding of any EGFR to its natural ligand). In some embodiments, the EGFR inhibitor comprises any agent capable of blocking EGFR activity or any downstream biological effect thereof during the course of treating cancer.

EGFR inhibitors can be determined or screened by methods well known in the art, for example, by detecting changes in EGFR expression levels following administration of the test compound. The expression level of EGFR can be detected by methods well known in the art, such as immunohistochemical methods, PCR, RT-PCR, in situ hybridization, southern blot, western blot, northern blot, spectrophotometry, ELISA, and the like.

For example, the EGFR inhibitor may be used for cancer treatment of the subject. In the present application, the term "cancer" generally refers to any medical condition mediated by tumor or malignant cell growth, proliferation or metastasis, and that causes both solid and non-solid tumors (e.g., leukemia).

For example, EGFR inhibitors can block their kinase activity by binding directly to the intracellular domain of the EGFR receptor; or occupy a ligand binding site of the EGFR receptor or a portion thereof, thereby rendering the EGFR receptor inaccessible to its natural ligand, resulting in its reduced or blocked biological activity; or by modulating dimerization of EGFR polypeptides or modulating interactions of EGFR polypeptides with other proteins, increasing ubiquitination and endocytic degradation of EGFR, thereby reducing EGFR activity.

For example, EGFR inhibitors may be non-specific inhibitors of EGFR, i.e., inhibitors that inhibit other target proteins in addition to EGFR.

For example, an EGFR inhibitor acts directly on the EGFR protein or on a nucleic acid encoding the EGFR protein. In some embodiments, the EGFR inhibitor acts directly on the EGFR protein. The term "direct acting" when used herein to describe an inhibitor and a target protein generally refers to the ability of the inhibitor to bind directly to the target protein without the need for other molecules (including covalent and non-covalent binding).

For example, the EGFR inhibitor may be a small molecule EGFR inhibitor, a protein macromolecule (e.g., an antibody or antigen binding fragment thereof) that specifically binds EGFR, or an RNAi or antisense oligonucleotide that inhibits expression of EGFR protein. For example, the EGFR inhibitor may be a small molecule EGFR inhibitor or a protein macromolecule (e.g., an antibody or antigen binding fragment thereof) that specifically binds EGFR.

In the present application, the term "nucleic acid" generally refers to a polynucleotide molecule consisting of monomeric nucleotides. Nucleic acids include ribonucleic acid (RNA), deoxyribonucleic acid (DNA), single-stranded nucleic acid (ssDNA), double-stranded nucleic acid (dsDNA), small interfering ribonucleic acid (siRNA), and microrna (miRNA). Other non-limiting examples of polynucleotides include genes, gene fragments, exons, introns, messenger RNAs (mrnas), transfer RNAs, ribosomal RNAs, ribozymes, cdnas, shRNA, single-stranded short or long RNAs, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, control regions, isolated RNAs of any sequence, nucleic acid probes and primers. The nucleic acid may be linear or circular.

In the present application, the term "RNAi" refers generally to RNA interference technology, which is the process by which exogenous or endogenous double-stranded RNA molecules or small-molecule RNAs inhibit gene expression or translation by targeting the mRNA and specifically degrading it.

In the present application, the term "oligonucleotide" generally refers to an oligomer or polymer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) or any mimic or structure modified nucleic acid thereof. The term includes oligonucleotides consisting of naturally occurring nucleobases, sugars and covalent internucleoside (backbone) linkages, as well as non-naturally occurring oligonucleotides having similar functions.

In the present application, the term "antisense oligonucleotide" generally refers to a single stranded oligonucleotide having a nucleobase sequence that allows hybridization to at least a portion of a corresponding region or fragment of a target nucleic acid.

In the present application, the term "small molecule EGFR inhibitor" may include small molecule EGFR inhibitors that bind reversibly to EGFR (e.g., gefitinib, erlotinib, sapitinib, and icotinib), small molecule EGFR inhibitors that bind irreversibly to EGFR (e.g., afatinib, dacomitinib, lapatinib (Lapatinib, e.g.)GW572016 GlaxoSmithKline), vanditinib (vanretanib, e.g., zactimat, ZD 6474), lenvatinib, canetinib, valatinib, and lenatinib), and/or small molecule EGFR inhibitors that specifically bind to mutant EGFR (e.g., octyitinib, natatinib, nostinib, omutinib, alvitinib, and EAI 045).

The protein macromolecule that specifically binds EGFR may be an antibody, antibody variant, fusion protein, derivative or fragment thereof directed against EGFR. In some embodiments, the protein macromolecule that specifically binds EGFR is an antibody or antigen-binding fragment thereof that specifically binds EGFR.

The term "specific binding" as used in the present application when used in reference to an EGFR inhibitor generally refers to: the EGFR inhibitor recognizes EGFR in a complex mixture, and has a binding constant to EGFR that is at least 2 times greater than its binding constant to other non-specific binding proteins.

In certain cases, the EGFR inhibitor may be used in combination with one or more other cancer therapies. The other cancer treatment may be a method conventionally used in the art for treating cancer, such as a cytotoxic anticancer agent, an immunotherapeutic anticancer agent, or a hormone therapeutic anticancer agent. According to the present application, the drug for cancer treatment may also be used in combination with radiotherapy or surgery. In some embodiments, where EGFR inhibitors and other anti-cancer agents are used in combination, they may be administered to the subject simultaneously, or separately at intervals.

Side effects associated with EGFR dysfunction

In the present application, the side effects include epithelial tissue diseases associated with EGFR inhibition.

The term "epithelial tissue disease associated with EGFR inhibition" as used herein generally refers to a disease caused by epithelial cells and/or endothelial cytopathy (e.g., epithelial cells and/or endothelial cytopathy associated with EGFR inhibition or caused by administration of an EGFR inhibitor). In some embodiments, "epithelial tissue disease associated with EGFR inhibition" may include a disease or disorder selected from the group consisting of: rash associated with EGFR inhibition, acne associated with EGFR inhibition, itch of Skin associated with EGFR inhibition, hand and foot syndrome associated with EGFR inhibition, alopecia associated with EGFR inhibition, hair changes associated with EGFR inhibition, erythema associated with EGFR inhibition, skin sloughing associated with EGFR inhibition (Skin exfollication), blepharitis associated with EGFR inhibition, hirsutism associated with EGFR inhibition, pigmentation associated with EGFR inhibition (hyper-Skin), nail diseases associated with EGFR inhibition (nail disorders), paronychia and nail cracks associated with EGFR inhibition, skin dryness associated with EGFR inhibition, hypersensitivity associated with EGFR inhibition, mucositis associated with EGFR inhibition, nasopharyngitis associated with EGFR inhibition, nasal bleeding associated with EGFR inhibition, oral dryness associated with EGFR inhibition, cheilitis associated with EGFR inhibition, oral ulcer associated with EGFR inhibition and gastrointestinal tract injury associated with EGFR inhibition. The epithelial tissue disorder associated with EGFR dysfunction may refer to an epithelial tissue disorder associated with administration of an EGFR inhibitor. For example, the epithelial tissue disorder may include diarrhea associated with EGFR inhibition. The diarrhea associated with EGFR dysfunction may refer to diarrhea associated with administration of EGFR inhibitors. For example, the epithelial tissue disorder may include rash associated with EGFR inhibition. The rash associated with EGFR dysfunction may refer to a rash associated with administration of an EGFR inhibitor. For example, the epithelial tissue disorder may include lipitis associated with EGFR inhibition. The lipitis associated with EGFR dysfunction may refer to lipitis associated with administration of EGFR inhibitors.

Depending on the site of disease occurrence, epithelial tissue diseases can be classified as epithelial cell diseases and/or endothelial cell diseases. In some embodiments, the epithelial cell disorder can be classified as a skin epithelial cell disorder associated with EGFR inhibition (e.g., rash, acne, rosacea, atopic dermatitis, contact dermatitis, seborrheic dermatitis, lupus, scleroderma, tenascus, pigmentation, melasma, vitiligo, urticaria, tinea corporis, skin pruritus, alopecia, hair changes, erythema, paronychia and onychomycosis, xerosis cutis, hypersensitivity reactions, and psoriasis), an oral epithelial cell disorder associated with EGFR inhibition (e.g., pemphigus, herpes labialis, vesicular stomatitis, granulomatous cheilitis, oral ulcer, pemphigoid, sjogren's syndrome, behcet's syndrome, oral nodular disease, etc.), a gastric epithelial cell disorder associated with EGFR inhibition (e.g., gastritis, intestinal metaplasia, gastric perforation, gastric fistula, gastric ulcer, and polyp), or an intestinal epithelial cell disorder associated with EGFR inhibition (e.g., enteritis, crohn's disease, intestinal ulcer, aids).

The present application provides a method for preventing or treating rash.

In the present application, the rash associated with EGFR dysfunction may include acne vulgaris (acne vulgaris) associated with EGFR dysfunction, papular rash associated with EGFR dysfunction (papulopustular rash) rose acne (acne rosacea) associated with EGFR dysfunction, pruritic rash associated with EGFR dysfunction (pruritis rash), acne-like rash associated with EGFR dysfunction (acneiform rash) cellulitis associated with EGFR dysfunction (celulitis), lyme disease associated with EGFR dysfunction (Lyme disease), allergic reaction associated with EGFR dysfunction (allergic reaction), pyogenic sweat (hidradenitis suppurativa) associated with EGFR dysfunction, measles associated with EGFR dysfunction (hives), dermatitis associated with EGFR dysfunction (decetitis), scab associated with EGFR dysfunction (craddress), purpura associated with EGFR dysfunction (prura), rose rash associated with EGFR dysfunction (rosea), kava associated with EGFR dysfunction (type of rolling rash), EGFR (flange associated with EGFR dysfunction (flange), EGFR associated with EGFR dysfunction (flange), EGFR (flange) and flange (flange) associated with EGFR dysfunction (flange), or flange (flange) associated with EGFR dysfunction (flange) of EGFR dysfunction (flange), EGFR associated with EGFR dysfunction (flange), or flange-35, EGFR associated with EGFR dysfunction (flange), EGFR associated with EGFR dysfunction (flange), and EGFR dysfunction (flange) associated with EGFR dysfunction (flange), EGFR dysfunction) Annular erythema centrifugation associated with EGFR dysfunction (erythema annulare centrifugum), folliculitis associated with EGFR dysfunction, follicular papules associated with EGFR dysfunction, xerosis eczema associated with EGFR dysfunction and/or papulopus associated with EGFR dysfunction. The rash associated with EGFR dysfunction may refer to a rash associated with administration of an EGFR inhibitor.

In certain embodiments, the side effects associated with EGFR dysfunction include mucosal injury diseases or disorders. The side effects associated with EGFR dysfunction may include mucosal injury diseases or conditions associated with administration of EGFR inhibitors.

In certain embodiments, the mucosal injury disease or disorder comprises oral mucosa, gastric mucosa, small intestine mucosa, rectal mucosa, and/or nasal mucosa. In certain embodiments, the mucosal injury disease or condition comprises dry mouth, oral mucositis, epistaxis, nasopharyngitis, cheilitis, esophagitis, gastrointestinal mucositis, gastric ulcers, rectal mucositis, diarrhea, vomiting, nausea, anorexia, constipation, and/or abdominal pain. In certain embodiments, the mucosal injury disease or disorder comprises oral mucosa, gastric mucosa, and/or small intestine mucosa. For example, diarrhea or cheilitis.

Compounds of formula (I)

The present application provides a method for preventing or treating side effects comprising administering a compound of formula I:

formula I wherein ring A is C4-C9 cycloalkyl or heterocyclyl optionally substituted with substituents containing 1-3 rings, R ₅ Selected from hydrogen atoms, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkylsulfonyl, C ₂ -C ₆ Alkenyl and C ₂ -C ₆ Alkynyl, wherein the alkyl, alkenyl, alkynyl is optionally substituted with deuterium, hydroxy, amino, halogen, cyano and/or nitro.

In the present application, the term "alkyl" generally refers to a straight or branched chain saturated hydrocarbyl substituent comprising 1 to 20 carbon atoms (e.g., a substituent obtained from a hydrocarbon by removal of hydrogen); for example 1 to 12 carbon atoms; in other embodiments, the number of carbon atoms is from 1 to 10; in other embodiments, from 1 to 6 carbon atoms, and in other embodiments, from 1 to 4 carbon atoms (e.g., 1,2,3, or more carbon atoms). Examples of substituents include: for example, methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl, isopentyl, hexyl, and the like. In some cases, the number of carbon atoms in the hydrocarbyl substituent (i.e., alkyl, alkenyl, cycloalkyl, aryl, etc.) is prefixed with the prefix "C _a -C _b "means that where a is the smallest and b is the largest number of carbon atoms in the substituent. Thus, for example, "C ₁ -C ₆ Alkyl "refers to an alkyl substituent containing 1 to 6 carbon atoms and may include straight or branched chain methyl, ethyl, propyl, butyl, pentyl and hexyl.

In the present application, the term "cycloalkyl" generally refers to a carbocyclic substituent obtained by removing hydrogen from a saturated carbocyclic molecule and having from 3 to 14 carbon atoms. In some embodiments, one cycloalkyl substituent has 3 to 10 carbon atoms. Cycloalkyl groups may be monocyclic, which typically contain 4-7 ring atoms. Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cycloalkyl groups may also be 2-3 rings fused together, and may also be referred to as "bicycloalkyl". In the present application, the term "cycloalkyl" also includes fused to C ₆ -C ₁₀ Substituents of aromatic rings or 5-10 membered heteroaromatic rings, wherein a group having such a fused cycloalkyl group as a substituent is bonded to a carbon atom of the cycloalkyl group. When such fused cycloalkyl groups are substituted with one or more substituents, unless otherwise indicatedOne or more substituents are each bonded to a carbon atom of a cycloalkyl group. Condensed C ₆ -C ₁₀ The aromatic ring or the 5-to 10-membered heteroaromatic ring may optionally be further substituted.

In the present application, the term "alkenyl" generally refers to straight and branched chain aliphatic hydrocarbon groups containing at least one carbon-carbon double bond. "C ₁ -C ₆ Alkenyl "refers to alkenyl substituents containing 1 to 6 carbon atoms and may include straight or branched chain ethenyl, propenyl, butenyl, pentenyl and hexenyl. In the present application, the term "alkynyl" generally refers to straight and branched chain aliphatic hydrocarbon groups containing at least one carbon-carbon triple bond. "C ₁ -C ₆ Alkynyl "refers to alkynyl substituents containing 1 to 6 carbon atoms and may include straight or branched chain ethynyl, propynyl, butynyl, pentynyl and hexynyl.

In the present application, the term "deuterium" generally refers to a stable form isotope of hydrogen, also known as deuterium, with the element symbol generally being D or ² H. Its nucleus consists of one proton and one neutron. In the present application, the term "hydroxy" generally refers to a group of the formula-OH. In the present application, the term "amino" generally refers to a compound of the formula-NH ₂ Is a group of (2). In the present application, the term "cyano" generally refers to a group of formula-CN. In the present application, the term "nitro" generally refers to the group of nitric acid molecules that remains after removal of one hydroxyl group. In the present application, the term "halogen" generally includes fluorine, chlorine, bromine and iodine. In the present application, the term "hydrogen" generally refers to a hydrogen substituent, which may be described as-H. In the present application, the term "oxygen" generally refers to an oxygen substituent, which may be described as-O-.

In the present application, the terms "substituent", "radical" and "group" are used interchangeably.

If a substituent is described as "optionally substituted," the substituent may be: (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as optionally substituted with one or more substituents, one or more hydrogens on that carbon (to the extent present) may be substituted individually and/or together with an independently selected optional substituent. If a nitrogen of a substituent is described as optionally substituted with one or more substituents, one or more hydrogens on the nitrogen (to the extent present) may each be replaced with an independently selected optional substituent. An exemplary substituent may be described as-NR 'R ", wherein R' and R" together with the nitrogen atom to which they are attached may form a heterocyclic ring comprising 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein the heterocycloalkyl moiety may be optionally substituted. The heterocyclic ring formed by R' and R "together with the nitrogen atom to which they are attached may be partially or fully saturated or aromatic.

In the present application, the term "formula I" may be referred to as "compound of formula I", "compound of formula I". Such terms are also defined to include all forms of the compounds of formula I, including hydrates, solvates, isomers, crystalline and non-crystalline forms, isoforms, polymorphs and metabolites. For example, the compound of formula I, or a pharmaceutically acceptable salt thereof, may exist in unsolvated as well as solvated forms. When the binding force of the solvent or water is strong, the complex has a definite stoichiometry, which is not affected by humidity. However, when the binding force of the solvent or water is weak, such as in channel solvates and hygroscopic compounds, the water/solvent content will depend on the humidity and drying conditions, in which case the non-stoichiometry is normal.

The "compounds of formula I" may have asymmetric carbon atoms. In the present application, the carbon-carbon bond of the compound of formula I may be represented by a solid line, a solid wedge shape or a dotted wedge shape. The use of a solid line to depict bonds to asymmetric carbon atoms is meant to include all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) on that carbon atom. The compounds of the application may contain more than one asymmetric carbon atom. In these compounds, the use of solid lines to indicate bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers are to be included. For example, unless otherwise indicated, it is intended that the compounds of formula I may exist as enantiomers and diastereomers or as racemates and mixtures. Representing the use of solid lines depicting bonds to one or more asymmetric carbon atoms in a compound of formula I, and solid or dashed wedges depicting bonds to other asymmetric carbon atoms in the same compound, indicates the presence of a mixture of diastereomers.

The compounds of the present application may exist in the form of inclusion complexes or other complexes. Included within the scope of the application are complexes, such as clathrates, drug-host inclusion complexes, wherein, in contrast to the solvates described above, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of formula I which contain two or more organic and/or inorganic components which may be stoichiometric or non-stoichiometric. The resulting complex may be ionized, partially ionized or not.

Stereoisomers of formula I include cis and trans isomers, optical isomers, e.g., R and S enantiomers, diastereomers, geometric isomers, rotamers, conformational isomers and tautomers, compounds of formula I, including compounds exhibiting more than one type of isomerism; and mixtures thereof (e.g., racemates and diastereomeric pairs). Also included are acid or base addition salts in which the counterion has optical activity, such as D-lactate or L-lysine, or racemates, such as DL-tartrate or DL-arginine.

When any racemate is crystallized, there may be two different types of crystals. The first is the above-mentioned racemic compound (true racemate) in which crystals are produced in a homogeneous form, containing equimolar amounts of the two enantiomers. The second type is a racemic mixture or agglomerate in which crystals are produced in equimolar amounts in two forms, each form comprising a single enantiomer.

The compounds of formula I may exhibit tautomerism and structural isomerism. For example, the compounds of formula I may exist in several tautomeric forms, including the enol and imine forms, as well as the keto and enamine forms, as well as geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the compounds of formula I. Tautomers exist in solution as mixtures of tautomers. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present invention also includes all tautomers of the compounds of formula I.

The application also includes isotopically-labelled compounds, which are identical to those recited in formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number found in nature. Isotopes that can be added to compounds of formula I include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to: ² H、 ³ H、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁸ O、 ¹⁷ O、 ³¹ P、 ³² P、 ³⁵ S、 ¹⁸ f and F ³⁶ Cl. Certain isotopically-labeled compounds of formula I, for example, to which a radioisotope (e.g. ³ H and ¹⁴ c) Because of its ease of preparation and detectability, it is useful in drug and/or substrate tissue distribution assays. Heavier isotopes such as ² H may provide certain therapeutic advantages due to its greater metabolic stability, e.g., increased half-life in vivo or reduced dosage requirements. Isotopically-labeled compounds of formula I can generally be prepared by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent.

The compounds of the application may be used in the form of salts derived from inorganic or organic acids. Some compounds have advantages such as enhanced drug stability at different temperatures and humidities, or desired solubility in water/oil, due to the physical properties of one or more salts. In some cases, salts of the compounds may also be used as an aid in the isolation, purification and/or resolution of the compounds.

In some cases, the pharmaceutically acceptable salt of the compound of the application may be citrate. For example, the compound of the present application may be citrate of compound I-a.

In the present application, ring A in formula I may be any C containing 1 to 3 rings _4- C ₉ Cycloalkyl, or C of 1-3 rings _4- C ₉ Heterocyclic group of (C)The hetero atoms in the heterocycloalkyl group may be one or more nitrogen atoms, and the cycloalkyl or heterocyclyl group may be optionally substituted with substituents selected from the group consisting of hydrogen atoms, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl and C ₂ -C ₆ Alkynyl, acyl and cyano groups, wherein the aforementioned substituents may further optionally be substituted by halogen, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkynyl, C ₂ -C ₆ Alkynyl and/or cyano substitution.

For example, ring A in formula I may be a monocyclic C optionally substituted or unsubstituted ₄ -C ₇ Cycloalkyl or monocyclic C ₄ -C ₇ A heterocyclic group, the hetero atom in the heterocyclic group may be one or more nitrogen atoms, wherein the substituent may be selected from a hydrogen atom, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl and C ₂ -C ₆ Alkynyl, acyl and cyano groups, wherein the aforementioned substituents may further optionally be substituted by halogen, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkynyl, C ₂ -C ₆ Alkynyl and/or cyano substitution.

For example, the ring A in the formula I may be Wherein the R is ₁ Can be selected from hydrogen atom, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl and C ₂ -C ₆ Alkynyl, R ₂ Can be-C (O) -R ₄ Wherein said R is ₄ Can be selected from C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl and cyano groups, the alkyl, alkenyl, alkynyl, cyano groups being optionally substituted with one or more of the following groupsTo further optionally be C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl and cyano substitutions.

For example, the ring A in the formula I may beWherein the R is ₁ Can be selected from C ₁ -C ₆ Alkyl or hydrogen atoms, R ₂ Can be selected from-C (O) -CH=CH ₂ and-C (O) -CH ₂ -CN。

For example, the ring A in the formula I may beWherein the R is ₁ Can be methyl or hydrogen atom, R ₂ Can be selected from-C (O) -CH=CH ₂ and-C (O) -CH ₂ -CN。

For example, the ring A in the formula I may be

In the present application, ring A in formula I may beWherein the R is ₃ Can be selected from hydrogen atom, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, acyl, amino and/or sulphonic acid groups, and said C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, acyl, amino or sulfonic groups may be further substituted with one or moreC (C) ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, acyl, amino and/or sulfonate substituents.

For example, ring A in formula I may beWherein the R is ₃ May beWherein the R is ₆ Can be selected from C ₁ -C ₆ An alkyl group.

For example, ring A in formula I may be Wherein the R is ₃ May be

For example, ring A in formula I may be

In the present application, the ring A in formula I may be C optionally substituted or unsubstituted ₅ -C ₁₀ A bicycloalkyl or bicycloheteroalkyl group, optionally substituted with a substituent.

In the present application, the term "bicyclic" generally refers to a molecule having two connecting rings. The bicyclic compound may be carbocyclic (all ring atoms are carbon) or heterocyclic (ring atoms are composed of at least two elements), and both rings may be aliphatic or aromatic, or a combination of aliphatic and aromatic. The connection between the two rings of the two rings may comprise: two rings share only one atom, two rings share two adjacent atoms (two rings share one covalent bond, the so-called bridgehead atoms being directly connected), or two rings share three or more atoms and the two bridgehead atoms are separated by a bridge containing at least one atom.

In the present application, the ring a in formula I may be a bicyclic ring in which two rings share two adjacent atoms. In the present application, the ring a in formula I may be a heterocycle and the heteroatom may be a nitrogen atom.

For example, the ring A may beWherein the R is ₈ Can be-C (O) R ₇ Or- (CH 2) _n -C(O)OR ₇ Wherein said R is ₇ Can be selected from hydrogen atom, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₂ -C ₆ Alkenyl, 5-to 10-membered heteroaryl and amino, said C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₂ -C ₆ Alkenyl and 5-to 10-membered heteroaryl and amino groups may further optionally be C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₂ -C ₆ Alkenyl and/or 5-to 10-membered heteroaryl substitutions.

For example, the ring A may beWherein the R is ₈ Can be-C (O) R ₇ And said R ₇ May beWherein ring B may be a 5 to 7 membered heteroaryl, optionally substituted with R ₉ Substitution, said R ₉ Can be selected from hydrogen atom, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy and C ₂ -C ₆ Alkenyl groups.

For example, the ring A may beWherein the R is ₈ Can be-C (O) R ₇ And said R ₇ May beWherein ring B may be a 5 membered heteroaryl, optionally substituted with R ₉ Substitution, said R ₉ Selected from hydrogen atoms, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy and C ₂ -C ₆ Alkenyl groups. For example, the ring A may be

For example, the ring A may beWherein the R is ₈ Can be-C (O) R ₇ And said R ₇ May beWherein ring B may beThe R is ₉ Selected from hydrogen atoms, C ₁ -C ₆ An alkyl group.

For example, the ring A may be

In the present application, R in formula I ₅ Can be selected from hydrogen atom, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkylsulfonyl, C ₂ -C ₆ Alkenyl and C ₂ -C ₆ Alkynyl, wherein the alkyl, alkenyl, alkynyl may be optionally substituted with deuterium, hydroxy, amino, halogen, cyano and/or nitro. The alkylsulfonyl refers to a sulfonyl groupSubstituted alkyl.

For example, the R in formula I ₅ Can be selected from hydrogen atoms and C ₁ -C ₆ An alkyl group. For example, the R ₅ May be selected from the group consisting of a hydrogen atom and a methyl group.

In the present application, the compounds of formula I may be selected from the group consisting of compounds I-a, I-b, I-c and I-d:

Method

the present application provides a method of preventing or treating side effects associated with EGFR dysfunction comprising administering to a subject a compound of formula I described above.

The term "preventing" as used herein generally refers to preventing the onset, recurrence or spread of a disease or one or more symptoms thereof. "prevent" is used interchangeably with "prophylactic treatment" in the present application. In certain embodiments, "preventing" or "prevention" generally refers to providing a treatment of a medicament described herein to a patient suffering from a disease or condition described herein, with or without other medicaments described herein, prior to the onset of symptoms.

The term "treatment" as used herein generally refers to the elimination or amelioration of a disease, or one or more symptoms associated with a disease. In some embodiments, treating generally refers to the elimination or alleviation of a disease by administration of one or more therapeutic agents to a patient suffering from such a disease. In some embodiments, "treatment" may be administration of a drug in the presence or absence of other therapeutic agents after onset of symptoms of a particular disease.

The term "subject" as used herein generally refers to a human or non-human animal (including mammals) in need of diagnosis, prognosis, amelioration, prophylaxis and/or treatment of a disease, particularly those subjects in need of treatment or prophylaxis with a compound of formula I.

In some embodiments, the subject may comprise a cancer patient. For example, the cancer patient may have been, be, and/or be administered an EGFR inhibitor. For example, the EGFR inhibitor may be an EGFR inhibitor according to the present application.

In some embodiments, the subject may be a human or a non-human mammal. The non-human mammal may include any mammalian species other than humans, such as livestock animals (e.g., cattle, pigs, sheep, chickens, rabbits, or horses), or rodents (e.g., rats and mice), or primates (e.g., gorillas and monkeys), or domestic animals (e.g., dogs and cats).

In some embodiments, the severity of the side effects caused by the EGFR dysfunction in a subject is reduced after administration of the compound of formula I of the present application. In some embodiments, the alleviation may be judged according to the grading criteria of NCI-CTCAE V5.0, e.g., the severity of the subject's epithelial tissue disease decreases from grade 5 to grade 1 (e.g., grade 5 to grade 4, grade 5 to grade 3, grade 5 to grade 2, grade 4 to grade 3, grade 4 to grade 2, grade 4 to grade 1, grade 3 to grade 2, grade 3 to grade 1, or grade 2 to grade 1). In some embodiments, the alleviating may generally refer to the subject having delayed onset or progression of the side effects caused by the EGFR dysfunction.

In some embodiments, administration of an effective amount of a compound of formula I described herein to a subject in need thereof results in a decrease in severity of rash, diarrhea, or lipitis in the subject from grade 5 to grade 1 (e.g., grade 5 to grade 4, grade 5 to grade 3, grade 5 to grade 2, grade 4 to grade 3, grade 4 to grade 2, grade 4 to grade 1, grade 3 to grade 2, grade 3 to grade 1, or grade 2 to grade 1).

In some embodiments, the compound of formula I in the methods of the application may beAnd the side effects associated with EGFR dysfunction that are prevented or treated are rash, diarrhea, or cheilitis. In some embodiments, an effective amount is administered to a subject in need thereofThe severity of rash, diarrhea, or cheilitis in a subject can be reduced from grade 5 to grade 1 (e.g., grade 5 to grade 4, grade 5 to grade 3, grade 5 to grade 2, grade 4 to grade 3, grade 4 to grade 2, grade 4 to grade 1, grade 3 to grade 2, grade 3 to grade 1, or grade 2 to grade 1).

In some embodiments, the compound of formula I in the methods of the application may beAnd the side effects associated with EGFR dysfunction that are prevented or treated are rash, diarrhea or lips And (3) inflammation. In some embodiments, an effective amount is administered to a subject in need thereofThe severity of rash, diarrhea, or cheilitis in a subject can be reduced from grade 5 to grade 1 (e.g., grade 5 to grade 4, grade 5 to grade 3, grade 5 to grade 2, grade 4 to grade 3, grade 4 to grade 2, grade 4 to grade 1, grade 3 to grade 2, grade 3 to grade 1, or grade 2 to grade 1).

In some embodiments, the compound of formula I in the methods of the application may beAnd the side effects associated with EGFR dysfunction that are prevented or treated are rash, diarrhea, or cheilitis. In some embodiments, an effective amount is administered to a subject in need thereof The severity of rash, diarrhea, or cheilitis in a subject can be reduced from grade 5 to grade 1 (e.g., grade 5 to grade 4, grade 5 to grade 3, grade 5 to grade 2, grade 4 to grade 3, grade 4 to grade 2, grade 4 to grade 1, grade 3 to grade 2, grade 3 to grade 1, or grade 2 to grade 1).

The term "effective amount" as used herein generally refers to an amount of a drug that can alleviate or eliminate a disease or condition in a subject, or can prophylactically inhibit or prevent the occurrence of a disease or condition. An effective amount may be an amount of a drug that alleviates to some extent one or more diseases or symptoms in a subject; the amount of the drug that partially or completely restores to normal one or more physiological or biochemical parameters associated with the cause of the disease or condition; and/or the amount of drug that may reduce the likelihood of occurrence of a disease or symptom.

The compounds of formula I according to the present application may be administered by means known in the art, such as injection (e.g., subcutaneous, intraperitoneal, intra-articular, intra-arterial, intrathecal, intrasternal, intrathecal, intralesional, intracranial, intramuscular, intradermal, and intravenous bolus or infusion) or non-injection (e.g., oral, nasal, sublingual, vaginal, rectal or topical administration). The compounds of formula I of the present application may be administered in a pharmaceutical combination or kit.

In the present application, the compound represented by formula I may be prepared to be suitable for transdermal administration.

In some embodiments, the present application provides a concentration of a compound of formula I of about 0.0001% (w/w) to about 50% (w/w), e.g., 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 10% (w/w), about 0.0001% (w/w) to about 5% (w/w), about 0.0001% (w/w) to about 1% (w/w), about 0.0001% (w/w) to about 0.5% (w/w), about 0.0001% (w/w) to about 0.1% (w/w), about 0.05% (w/w) to about 0.0001% (w/w) to about 0.01% (w/w), about 0.0001% (w/w) to about 0.005% (w) or about 0.0001% (w/w) to about 0.005% (w/w).

For example, the present application provides a concentration of a compound of formula I of about 0.02% (w/w) to about 10% (w/w), e.g., about 0.002% (w/w) to about 0.2% (w/w), about 0.002% (w/w) to about 1% (w/w), about 0.002% (w/w) to about 2% (w/w), about 0.002% (w/w) to about 3% (w/w), about 0.002% (w/w) to about 1.5% (w/w), about 0.002% (w/w) to about 0.5% (w/w), about 0.002% (w/w) to about 5% (w/w), about 0.002% (w/w) to about 8% (w/w), about 0.02% (w/w) to about 5% (w/w), about 0.5% (w/w) to about 3% (w/w), about 1.5% (w/w) to about 5% (w/w) or about 0.002% (w/w) to about 5% (w/w).

In the present application, the compounds of formula I may be prepared to be suitable for topical administration.

In the present application, the drug or the JAK inhibitor may be prepared to be suitable for transdermal administration. In the present application, the drug or the JAK inhibitor may be prepared to be suitable for topical administration. In some embodiments, the medicament or the JAK inhibitor is prepared for topical skin application. For example, in the present application, the drug or the JAK inhibitor may be prepared as a cream, lotion, gel, ointment, salve, spray, liposome formulation, liniment and/or aerosol. In the present application, the transdermal administration may be performed in the form of a solution-type transdermal preparation (such as cream, gel, ointment, paste, etc.), or in the form of a suspension-type transdermal preparation (such as cream, gel, ointment, paste, etc.).

In some embodiments, the site of administration of the topical administration may not be the site of occurrence of the cancer or the site of potential metastasis of the cancer. For example, the administration moiety may not be a primary site of cancer. For another example, the administration moiety may not be a metastatic site of cancer. For example, the metastatic sites may include sites of occurrence of metastasis from cancer resulting from lymphatic metastasis, vascular metastasis, and/or vegetative metastasis. In some embodiments, the transfer site may include bone, brain, liver, stomach, and/or lung. For another example, the administration moiety may not be a site of recurrence of cancer.

In the present application, the compound represented by formula I may be prepared to be suitable for injection administration. In the present application, the compounds of formula I may also be prepared to be suitable for gastrointestinal administration.

In some embodiments, the present application provides that an effective dose of a compound of formula I may be administered between about 0.001mg/kg and about 3000mg/kg (e.g., about 0.01mg/kg to about 2000mg/kg, about 0.05mg/kg to about 1000mg/kg, about 0.01mg/kg to about 10mg/kg, about 0.02mg/kg to about 10mg/kg, about 0.05mg/kg to about 10mg/kg, about 0.1mg/kg to about 10mg/kg, about 0.15mg/kg to about 10mg/kg, about 0.2mg/kg to about 10mg/kg, about 0.25mg/kg to about 10mg/kg, about 0.3mg/kg to about 10mg/kg, about 0.35mg/kg to about 10mg/kg, about 0.4mg/kg to about 10mg/kg, about 0.45mg/kg to about 10mg/kg, about 0.5mg/kg to about 10mg/kg, about 0.55mg/kg to about 10mg/kg, about 0.6mg/kg to about 10mg/kg about 0.65mg/kg to about 10mg/kg, about 0.7mg/kg to about 10mg/kg, about 0.75mg/kg to about 10mg/kg, about 0.8mg/kg to about 10mg/kg, about 0.85mg/kg to about 10mg/kg, about 0.9mg/kg to about 10mg/kg, about 0.95mg/kg to about 10mg/kg, about 1mg/kg to about 10mg/kg, about 2mg/k to about 10mg/kg, about 5mg/k to about 10mg/kg, about 6mg/kg to about 10mg/kg, about 8mg/kg to about 10mg/kg, about 9mg/kg to about 10mg/kg, about 10mg/kg to about 50mg/kg, about 10mg/kg to about 100mg/kg, about 10mg/kg to about 500mg/kg, about 10mg/kg to about 1000mg/kg, about 10mg/kg to about 2000mg/kg or about 10mg/kg to about 3000 mg/kg).

In some embodiments, the present application provides that an effective dose of a compound of formula I may be administered between about 0.1mg/kg and about 150mg/kg (e.g., about 0.1mg/kg to about 120mg/kg, about 0.1mg/kg to about 100mg/kg, about 0.1mg/kg to about 5mg/kg, about 0.1mg/kg to about 10mg/kg, about 0.1mg/kg to about 15mg/kg, about 0.1mg/kg to about 20mg/kg, about 0.1mg/kg to about 50mg/kg, about 0.1mg/kg to about 30mg/kg, about 0.1mg/kg to about 60mg/kg, about 0.1mg/kg to about 75mg/kg, about 0.1mg/kg to about 100mg/kg, about 10mg/kg to about 120mg/kg, about 1mg/kg to about 100mg/kg, about 10mg/kg to about 5mg/kg, about 10mg/kg to about 10mg/kg, about 10mg to about 10 mg/kg).

In some embodiments, the compound of formula I is administered at a dose of about 5mg/kg or less. In some embodiments, the dosage administered is 1mg/kg or less, 0.5mg/kg or less, 0.1mg/kg or less, 0.05mg/kg or less, or 0.01mg/kg or less. A particular dose may be administered in multiple intervals, for example once a day, twice a day or more, once a week, once every two weeks, once every three weeks, once a month, or once every two or more months. For example, the specific dose may be once daily.

In some embodiments, the compounds of formula I described herein may be co-administered with an EGFR inhibitor. In some embodiments, the compound of formula I may be administered before, simultaneously with, or after the subject has received an EGFR inhibitor. In certain embodiments, the compound of formula I may be administered separately from the EGFR inhibitor as part of a multi-dose regimen. In some embodiments, the compound of formula I may be administered concurrently with the EGFR inhibitor. In simultaneous administration embodiments, the compounds of formula I may be part of a single dosage form that is admixed with the presently disclosed EGFR inhibitors as a single composition. In other embodiments, the compounds of formula I may be administered as separate doses, administered at about the same time as the EGFR inhibitor.

In embodiments where the compound of formula I is administered at intervals with an EGFR inhibitor, the compound of formula I may be administered at intervals either before or after administration of the EGFR inhibitor. 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 longer.

In some embodiments, the EGFR inhibitors of the present application may be administered by the same route of administration as the compounds of formula I or by a different route of administration.

Pharmaceutical compositions and kits

In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof may be administered as part of a medicament or pharmaceutical combination.

In some embodiments, the medicament may comprise a compound of formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

In some embodiments, the pharmaceutical combination or kit may comprise 1) an EGFR inhibitor; and 2) a compound of formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the EGFR inhibitor may be not mixed with the compound of formula I or a pharmaceutically acceptable salt thereof. For example, the EGFR inhibitor may be present in separate containers, each independently of the compound of formula I or a pharmaceutically acceptable salt thereof. For example, the EGFR inhibitor may be dispensed in one reagent bottle and the compound of formula I or a pharmaceutically acceptable salt thereof may be dispensed in another reagent bottle.

In the pharmaceutical combination or kit of the present application, the compound represented by formula I in 2) or a pharmaceutically acceptable salt thereof can prevent or treat a disease or disorder caused by the EGFR inhibitor in 1).

In the pharmaceutical combination or kit of the application, the compound of formula I in 2) or a pharmaceutically acceptable salt thereof does not substantially affect the therapeutic effect of the EGFR inhibitor in 1).

In the present application, the "substantially no influence" may mean that the compound represented by formula I or a pharmaceutically acceptable salt thereof in 2) and the compound represented by formula I or a pharmaceutically acceptable salt thereof in 1) are equivalent in therapeutic effect or do not generate significant disadvantages, compared to the therapeutic effect of the EGFR inhibitor alone. For example, the degree of tumor volume reduction caused by the compound of formula I or a pharmaceutically acceptable salt thereof in 2) and the compound of formula I or a pharmaceutically acceptable salt thereof in 1) using the pharmaceutical combination or kit is the same, or the degree of reduction is not less than about 5%, not less than about 4%, not less than about 3%, not less than about 2%, not less than about 1%, not less than about 0.5%, not less than about 0.1%, not less than about 0.01%, not less than about 0.001% or less, as compared to the therapeutic effect of the compound of formula I or a pharmaceutically acceptable salt thereof alone in any subject.

In the pharmaceutical combination or kit of the application, the compound of formula I in 2) or a pharmaceutically acceptable salt thereof is for administration prior to, simultaneously with or after administration of the EGFR inhibitor in 1).

1) Monitoring the side effects of rash in a subject administered an EGFR inhibitor;

2) Administering to the subject a compound of formula I of the application or a pharmaceutically acceptable salt thereof when the monitoring indicates that the subject has side effects of rash associated with the administration of the EGFR inhibitor.

Without intending to be limited by any theory, the following examples are meant to illustrate the compounds, methods of preparation, uses, and the like of the present application and are not intended to limit the scope of the application.

Examples

Examples 1 to 37: experiments to verify that local administration of JAK inhibitors prevents the development of rash with small molecule EGFR inhibitors on rat animal models

And constructing a rat animal model. Small molecule EGFR inhibitors were administered daily to 6 week female SD rats and after several days the back of the rats developed rash over a large area (photographs are shown in fig. 1). There was no difference between the side and side of the rash, and the rash was similar to the side. Similar in humans, rats develop rash on the face and body after oral administration of small molecule EGFR inhibitors. The etiology of both are identical, and the symptoms are very similar. Thus, rats are a very good animal model for simulating rash caused by EGFR inhibitors.

After one week (about 200 g) of feeding adaptation of SD rats, the rats were divided into 10 groups. The day prior to the experiment, the hair on the back of the rat was gently removed with an electric razor and then subjected to a gavage administration test. EGFR inhibitor was dissolved in sterile aqueous solution, diluted with PBS buffer, and administered at doses not exceeding 2mL per lavage, as shown in Table 1. The experiments were divided into JAK inhibitor groups and control groups. After gavage, the backs (about 3cm x 3 cm) of the JAK inhibitor group rats were applied with an ointment of JAK inhibitor (the types and concentrations are shown in table 1); the backs (about 3 cm. Times.3 cm) of rats in the control group were coated with a blank matrix ointment (about 0.5 g); after the application, the rats are fixed for about 4 hours by a fixing cylinder, the rats are discharged after 4 hours, residual medicines at the application part are wiped off by clean water, and the rats are put back into the squirrel cage. The gastric lavage frequency of EGFR inhibitors is shown in table 1, but JAK inhibitors and blank matrix ointments are only applied once a day. The lavage and smear test was repeated daily until the control developed a significant rash, at which time the number of rats whose skin remained normal or significantly lighter than the control was counted as the number of rats effective in inhibiting rash.

Table 1 lists animal experimental combinations of various small molecule EGFR inhibitors and JAK inhibitor ointments, and corresponding experimental results (where the number of control rate bars = number of JAK group rash lighter than control group/total number of JAK group rats x 100%).

Table 1: experimental conditions and experimental results of examples 1 to 37

Fig. 2 shows photographs of the left, back and right sides of a typical rat in the control group, JAK inhibitor group in table 1. Figure 3 shows rash grade for JAK inhibitor groups and control groups at the end of the experiment.

From the results in Table 1 and FIGS. 2-3, it can be seen that: JAK inhibitor ointments can effectively prevent rash caused by small molecule EGFR inhibitors.

Examples 38 to 65: experiments to verify JAK inhibitors in rat animal models to prevent rash from small molecule EGFR inhibitors

After one week (about 200 g) of feeding adaptation of SD rats, the rats were divided into 10 groups. The day before the experiment, the hair on the back of the rat was gently removed with an electric razor and then the dosing experiment was performed. EGFR inhibitor was dissolved in sterile aqueous solution, diluted with PBS buffer, and administered at doses not exceeding 2mL per lavage, as shown in Table 2. The experiments were divided into JAK inhibitor groups and control groups (solvent control group). JAK inhibitor group: gastric lavage/injection of JAK inhibitor and EGFR inhibitor, respectively (species and concentrations are shown in table 2); control group: the same solvents and EGFR inhibitors (species and concentrations are shown in table 2) as JAK inhibitors were gavaged/injected separately. The gavage frequency of EGFR inhibitors is shown in table 2, JAK inhibitors and solvent control groups were gavaged/injected twice daily. The lavage/injection experiment was repeated daily until the control developed a significant rash, at which time the number of rats whose skin remained normal or significantly lighter than the control was counted as the number of rats that were effective in inhibiting rash.

Table 2 lists animal experimental combinations of various small molecule EGFR inhibitors and JAK inhibitors, and corresponding experimental results (where the number of control rate bars = number of JAK group rash lighter than control group/total number of JAK group rats x 100%).

Table 2: experimental conditions and experimental results of examples 38 to 65

Figure 4 shows rash grade for JAK inhibitor groups and control groups at the end of the experiment.

From the results of table 2 and fig. 4, it can be seen that: JAK inhibitors are effective in preventing rash caused by small molecule EGFR inhibitors.

Examples 66 to 67: experiments to verify that topical administration of JAK inhibitors prevents the production of rash with monoclonal EGFR inhibitors in a rat animal model

After one week (about 200 g) of feeding adaptation of SD rats, the rats were divided into 10 groups. The day before the experiment, the hair on the back of the rat was gently removed with an electric razor and then the dosing experiment was performed. The experiments were divided into JAK inhibitor groups and control groups. EGFR mab solution diluted with physiological saline was injected 2 times per tail vein at the rate and time shown in table 3. After injection, the JAK inhibitor group was daily applied with JAK inhibitor ointment to the back of rats (about 3cm x 3 cm), the control group was applied with blank matrix ointment (about 0.5 g) to the back of rats (about 3cm x 3 cm), the rats were fixed with a fixation cylinder for 4 hours after application, the rats were discharged after 4 hours and the applied sites were wiped off with clear water for residual drug, and the rats were returned to their cages. The mab-like EGFR inhibitor, JAK inhibitor and blank ointment were administered 2 times per tail vein every day, until the control group developed a significant rash. The number of rats whose skin remained normal or significantly lighter than the control group rash after 10-14 days of statistical application was counted as the number of rats that were effective in inhibiting rash.

Table 3 lists animal experimental combinations of various mab EGFR inhibitors and JAK inhibitor ointments, and corresponding experimental results (where the number of control rate bars = number of JAK group rash lighter than control group/total number of JAK group rats x 100%).

Table 3: experimental conditions and experimental results for examples 66-67

Figure 5 shows rash grade for JAK inhibitor groups and control (mab-like EGFR inhibitor) at the end of the experiment.

As can be seen from the results of table 3 and fig. 5: JAK inhibitor ointment can effectively prevent rash caused by monoclonal EGFR inhibitors.

Example 68: experiments to verify JAK inhibitors in rat animal models to prevent the generation of rash with monoclonal EGFR inhibitors

After one week (about 200 g) of feeding adaptation of SD rats, the rats were divided into 10 groups. The day before the experiment, the hair on the back of the rat was gently removed with an electric razor and then the dosing experiment was performed. The experiments were divided into JAK inhibitor groups and control groups (solvent control group). EGFR mab solution diluted with physiological saline was injected 2 times per tail vein at the rate and time shown in table 4.JAK inhibitor group: gastric lavage JAK inhibitors (species and concentrations are shown in table 4); control group: the same solvents (species and concentrations are shown in table 4) as JAK inhibitors were infused separately. The mab-like EGFR inhibitor was injected 2 times per tail vein, JAK inhibitor and control were lavaged twice daily until the control developed a clear rash. The number of rats whose skin remained normal or significantly lighter than that of the control group after 10 days of statistical administration was counted as the number of rats effective in inhibiting rash.

Table 4 lists animal experimental combinations of various mab EGFR inhibitors and JAK inhibitors, and corresponding experimental results (where the number of control rate bars = number of JAK group rash lighter than control group/total number of JAK group rats x 100%).

Table 4: experimental conditions and experimental results of example 68

Figure 6 shows rash grade for JAK inhibitor groups and control (mab-like EGFR inhibitor) at the end of the experiment.

As can be seen from the results of table 4 and fig. 6: oral JAK inhibitors are effective in preventing rash caused by monoclonal EGFR inhibitors.

Examples 69 to 98: experiments to verify JAK inhibitors on rat animal models to treat skin rash with small molecule EGFR inhibitors

After one week (about 200 g) of feeding adaptation of SD rats, the rats were divided into 10 groups. The day prior to the experiment, the hair on the back of the rat was gently removed with an electric razor and then subjected to a gavage administration test. EGFR inhibitor was dissolved in sterile aqueous solution, diluted with PBS buffer, and administered at doses not exceeding 2mL per lavage, as shown in Table 5. The stomach infusion was continued daily until the rats developed symptoms of rash, at which point the treatment experiment was started. The experiments were divided into JAK inhibitor groups and control groups. During the treatment experiment, the EGFR inhibitor is infused continuously daily, after the stomach infusion, the back (about 3cm x 3 cm) of the rat is coated with the ointment of the JAK inhibitor by the JAK inhibitor group, and the back (about 3cm x 3 cm) of the rat in the control group is coated with the blank matrix ointment; after the application, the rats are fixed for about 4 hours by a fixing cylinder, the rats are discharged after 4 hours, residual medicines at the application part are wiped off by clean water, and the rats are put back into the squirrel cage. The gavage frequency of EGFR inhibitors is shown in table 5, but JAK inhibitors and blank ointments are only applied once a day. The EGFR inhibitor was re-used daily for lavage and the number of rats whose skin was restored to normal or significantly lighter than the control group rash at the end of the experiment was counted as the number of rats effectively treated for rash.

Table 5 lists animal experimental combinations of various small molecule EGFR inhibitors and JAK inhibitor ointments, and corresponding experimental results (where the number of control rate bars = number of JAK group rash lighter than control group/total number of JAK group rats x 100%).

Table 5: experimental conditions and experimental results for examples 69-98

Fig. 7 shows photographs of the left, back and right sides of a typical rat in the control group, JAK inhibitor group in table 5. Figure 8 shows rash grade for JAK inhibitor groups and control groups at the end of the experiment.

From the results in table 5 and fig. 8, it can be seen that: JAK inhibitor ointments can effectively treat rash caused by small molecule EGFR inhibitors.

Examples 99 to 122: experiments to verify JAK inhibitors on rat animal models to treat skin rash with small molecule EGFR inhibitors

After one week (about 200 g) of feeding adaptation of SD rats, the rats were divided into 10 groups. The day before the experiment, the hair on the back of the rat was gently removed with an electric razor and then the dosing experiment was performed. EGFR inhibitor was dissolved in sterile aqueous solution, diluted three times with PBS buffer, and administered at doses not exceeding 2mL per lavage, as shown in Table 6. The stomach infusion was continued daily until the rats developed symptoms of rash, at which point the treatment experiment was started. The experiments were divided into JAK inhibitor groups and control groups (solvent control group). JAK inhibitor group: gastric lavage/injection of JAK inhibitor and EGFR inhibitor, respectively (species and concentrations are shown in table 6); control group: the same solvents and EGFR inhibitors (species and concentrations are shown in table 6) as JAK inhibitors were gavaged/injected separately. The gavage frequency of EGFR inhibitors is shown in table 6, JAK inhibitors and blank solvent control groups were gavaged/injected 2 times daily. During the treatment experiment, the administration was repeated daily, and the number of rats whose skin of the JAK inhibitor group was recovered to be normal or significantly lighter than that of the control group at the end of the experiment was calculated as the number of rats effectively treated with the rash.

Table 6 lists animal experimental combinations of various small molecule EGFR inhibitors and JAK inhibitors, and corresponding experimental results (where the number of control rate bars = number of JAK group rash lighter than control group/total number of JAK group rats x 100%).

Table 6: experimental conditions and experimental results for examples 99-122

Figure 9 shows rash grade for JAK inhibitor groups and control groups at the end of the experiment.

From the results in table 6 and fig. 9, it can be seen that: JAK inhibitors are effective in treating rash caused by small molecule EGFR inhibitors.

Examples 123 to 124: experiment of local administration of JAK inhibitor on rat animal model for treating rash caused by monoclonal EGFR inhibitor

After one week (about 200 g) of feeding adaptation of SD rats, the rats were divided into 10 groups. The day before the experiment, the hair on the back of the rat was gently removed with an electric razor and then the dosing experiment was performed. The EGFR monoclonal antibody solution diluted by normal saline is injected for 2 times per week into tail vein, and the injection speed and time are shown in Table 7; the treatment experiment was started at the time of continuous administration for 1-2 weeks until the rats developed rash. The experiments were divided into JAK inhibitor groups and control groups. During the treatment experiment, the single antibody EGFR inhibitor is continuously injected for 2 times a week, the back (about 3cm x 3 cm) of the rat in the JAK inhibitor group is coated with the ointment of the JAK inhibitor every day, and the back (about 3cm x 3 cm) of the rat in the control group is coated with the blank matrix ointment; after the application, the rats are fixed for about 4 hours by a fixing cylinder, the rats are discharged after 4 hours, residual medicines at the application part are wiped off by clean water, and the rats are put back into the squirrel cage. The number of rats whose skin remained normal or significantly lighter than that of the control group after 10 days of statistical application was counted as the number of rats that effectively inhibited the rash.

Table 7 lists animal experimental combinations of mab EGFR inhibitors and JAK inhibitor ointments, and corresponding experimental results (where the number of control rate bars = number of JAK group rash lighter than control group/total number of JAK group rats x 100%).

Table 7: experimental conditions and experimental results for examples 123-124

Figure 10 shows rash grade for JAK inhibitor groups and control (mab-like EGFR inhibitor) at the end of the experiment.

As can be seen from the results in table 7 and fig. 10: JAK inhibitor ointment can effectively treat rash caused by monoclonal EGFR inhibitors.

Example 125: experiment of JAK inhibitor treatment of monoclonal EGFR inhibitor to produce rash on rat animal model

After one week (about 200 g) of feeding adaptation of SD rats, the rats were divided into 10 groups. The day before the experiment, the hair on the back of the rat was gently removed with an electric razor and then the dosing experiment was performed. The EGFR monoclonal antibody solution diluted by normal saline is injected for 2 times per week into tail vein, and the injection speed and time are shown in Table 8; the treatment experiment was started at the time of continuous administration for 1-2 weeks until the rats developed rash. The experiments were divided into JAK inhibitor groups and control groups (solvent control group). JAK inhibitor group: gastric lavage JAK inhibitors (species and concentrations are shown in table 8); control group: the same solvents (species and concentrations are shown in table 8) as JAK inhibitors were infused separately. In the treatment experiments, the administration of the mab EGFR inhibitor was continued 2 times a week, and JAK inhibitor and control groups were gavaged twice daily. After 10 days of gastric lavage, the number of rats whose skin remains normal or significantly lighter than that of the control group was counted as the number of rats that were effective in inhibiting rash.

Table 8 lists animal experimental combinations of mab EGFR inhibitors and JAK inhibitors, and corresponding experimental results (where the number of control rate bars = number of rats in JAK inhibitor group lighter than control group/total number of rats in JAK group x 100%).

Table 8: experimental conditions and experimental results of example 125

From the results in table 8, it can be seen that: oral JAK inhibitors are effective in treating rash caused by monoclonal EGFR inhibitors.

Implementation of the embodimentsExamples 126 to 130: JAK inhibitor ointments are compared to other skin medications currently available in the clinic in experiments to prevent the development of rash with small molecule EGFR inhibitors.

After one week (about 200 g) of rat feeding, the rats were divided into 10 groups. The day prior to the experiment, the hair on the back of the rat was gently removed with an electric razor and then subjected to a gavage administration test. EGFR inhibitor was dissolved in sterile aqueous solution, diluted with PBS buffer, and administered at doses not exceeding 2mL per lavage, as shown in Table 9. The experiments were divided into JAK inhibitor groups and other skin drug groups. After stomach lavage, JAK inhibitor ointment is applied to the backs (about 3cm×3 cm) of rats in the JAK inhibitor group, and clinically existing skin drugs are respectively applied to the backs (about 3cm×3 cm) of rats in the other skin drug group (examples 126 to 130); after the application, the rats are fixed for about 4 hours by a fixing cylinder, the rats are discharged after 4 hours, residual medicines at the application part are wiped off by clean water, and the rats are put back into the squirrel cage. The lavage frequency of EGFR inhibitors is shown in table 9, but other skin medications and JAK inhibitors currently available in clinic are administered only once. The EGFR inhibitor is repeatedly used for lavage every day, and the medicine is smeared on the back until other skin medicine groups have obvious rash. The number of rash in rats in the JAK group was counted to be significantly lighter than in other skin drug groups.

Table 9 lists animal experimental combinations of JAK inhibitor ointments with clinically existing skin medications, and corresponding experimental results (where the relative remission rate bar values = JAK group rash lighter than other skin medications/total number of rats in JAK group x 100%).

Table 9: experimental conditions and experimental results for examples 126-130

Fig. 11 shows photographs of the left, back and right sides of typical rats in the other skin drug groups, JAK inhibitor group, of table 9. Figure 12 shows rash grade for JAK inhibitor groups and control groups at the end of the experiment.

From the results in table 9, it can be seen that: JAK inhibitor ointments are effective in controlling rash caused by EGFR inhibitors compared to clinically existing skin medications (almost no therapeutic effect on rash caused by EGFR inhibitors).

Examples 131 to 155Experiment for verifying JAK inhibitor to prevent diarrhea caused by small molecule EGFR inhibitor on rat animal model

The animal model of the rat was constructed by administering the small molecule EGFR inhibitor shown in Table 10 to SD rats of 8-week female by daily gavage, and the rats showed diarrhea symptoms (diarrhea grade of the rats is shown in FIG. 13) after several days of administration, similarly to the human body. Thus, the rat EGFR inhibitor-induced diarrhea model is a very good model for mimicking human EGFR inhibitor-induced diarrhea.

After the rats (about 200 g) were housed and adapted for one week, they were grouped, and the experiment was divided into a control group and a JAK inhibitor group, 10 animals each, and a gastric administration test was performed. Various small molecule EGFR inhibitors were dissolved in sterile aqueous solutions, and the EGFR inhibitor drug solutions were fixed to the desired concentrations with PBS (about 3-fold dilution with PBS solution) prior to gavage, with no more than 2mL of drug per gavage, and the dosing amounts shown in table 9. The experiments were divided into JAK inhibitor groups and control groups (solvent control group). JAK inhibitor group: gastric lavage JAK inhibitors and EGFR inhibitors, respectively (species and concentrations are shown in table 10); control group: the same solvents and EGFR inhibitors (species and concentrations are shown in table 10) as JAK inhibitors were infused separately. The gavage frequency of EGFR inhibitors is shown in table 9, JAK inhibitors and blank solvent control groups were gavaged 2 times daily. The diarrhea grade of each group of rats was recorded daily, and the number of rats in the JAK inhibitor group at the end of the experiment was counted as significantly lighter diarrhea grade than the control group.

Table 10 lists animal experimental combinations of each EGFR inhibitor and JAK inhibitor, and the corresponding experimental results (where the relative remission rate column values = number of rats in the JAK inhibitor group diarrhea lighter than the control group/total number of rats in the JAK inhibitor group x 100%).

Table 10: experimental conditions and experimental results for examples 131-155

Figure 14 shows diarrhea grade for JAK inhibitor groups and control groups at the end of the experiment.

As can be seen from the results of table 10 and fig. 14: JAK inhibitors are effective in preventing diarrhea caused by EGFR inhibitors.

Example 156: experiment for verifying JAK inhibitor to prevent monoclonal EGFR inhibitor from producing diarrhea on rat animal model

After one week (about 200 g) of feeding adaptation of SD rats, the rats were divided into 10 groups. The experiments were divided into JAK inhibitor groups and control groups. The Cetuximab monoclonal antibody solution diluted by normal saline is injected for 2 times per week at the speed of 1.3ml/kg/min, the single injection time is not less than 15min, and the dosage is 100mg/kg. Following injection, the JAK inhibitor group was perfused daily with the JAK inhibitor and the control group was not treated with other than mab. The diarrhea grade of each group of rats was recorded daily. The number of rats with JAK inhibitor groups at the end of the experiment was counted as significantly lighter diarrhea grade than the control group.

Table 11 lists animal experimental combinations of mab EGFR inhibitor and JAK inhibitor, and corresponding experimental results (where the number of control rate bars = number of rats diarrhea grade lighter than control group/total number of rats of JAK inhibitor group x 100%).

Table 11: experimental conditions and experimental results of example 156

From the results in Table 11, it can be seen that: JAK inhibitors are effective in preventing diarrhea caused by monoclonal antibody-like EGFR inhibitors.

Examples 157 to 178: experiments to verify JAK inhibitors on rat animal models to treat diarrhea with small molecule EGFR inhibitors

After the rats (about 200 g) were housed and adapted for one week, they were grouped, and the experiment was divided into a control group and a JAK inhibitor group, 10 animals each, and a gastric administration test was performed. Various small molecule EGFR inhibitors were dissolved in sterile aqueous solutions, and the EGFR inhibitor drug solutions were fixed to the desired concentrations with PBS (about 3-fold dilution with PBS solution) prior to gavage, with no more than 2mL of drug per gavage, and the dosing amounts shown in table 12. The stomach infusion was continued daily until the rats developed symptoms of diarrhea, at which point the treatment experiment was started. The experiments were divided into JAK inhibitor groups and control groups (solvent control group). JAK inhibitor group: gastric lavage/injection of JAK inhibitor and EGFR inhibitor, respectively (species and concentrations are shown in table 12); control group: the same solvents and EGFR inhibitors (species and concentrations are shown in table 12) as JAK inhibitors were gavaged/injected separately. The gavage frequency of EGFR inhibitors is shown in table 12, JAK inhibitors and blank solvent control groups were gavaged/injected 2 times daily. During the course of the treatment experiments, dosing was repeated daily, the diarrhea grade of each group of rats was recorded daily, and statistics were made as to how many rats in the JAK inhibitor group had significantly lighter diarrhea grade than the control group at the end of the experiment.

Table 12 lists animal experimental combinations of various small molecule EGFR inhibitors and JAK inhibitors, and corresponding experimental results (where the number in the control rate column = number of rats with diarrhea lighter than the control group/total number of rats in the JAK group x 100%).

Table 12: experimental conditions and experimental results for examples 157-178

Figure 15 shows diarrhea grade for JAK inhibitor groups and control groups at the end of the experiment.

As can be seen from the results in table 12 and fig. 15: JAK inhibitors are effective in treating diarrhea caused by small molecule EGFR inhibitors.

Example 179: experiments to verify that JAK inhibitors treat monoclonal EGFR inhibitors to produce diarrhea in rat animal models

After one week (about 200 g) of feeding adaptation of SD rats, the rats were divided into 10 groups. The experiments were divided into JAK inhibitor groups and control groups. The EGFR monoclonal antibody solution diluted by normal saline is injected for 2 times per week into tail vein, and the injection speed and time are shown in table 13; the treatment experiment was started at the time of continuous administration for 1-2 weeks until diarrhea occurred in the rats. The experiments were divided into JAK inhibitor groups and control groups (solvent control group). JAK inhibitor group: gastric lavage JAK inhibitors (species and concentrations are shown in table 13); control group: the same solvents as JAK inhibitors (species and concentrations are shown in table 13) were infused separately. In the treatment experiments, the administration of the mab EGFR inhibitor was continued 2 times a week, and JAK inhibitor and control groups were gavaged twice daily. The diarrhea grade of each group of rats was recorded daily, and the number of rats in the JAK inhibitor group at the end of the experiment was counted as significantly lighter diarrhea grade than the control group.

Table 13 lists animal experimental combinations of mab EGFR inhibitor and JAK inhibitor, and corresponding experimental results (where the number of control rate bars = number of rats diarrhea grade lighter than control group/total number of rats of JAK inhibitor group x 100%).

Table 13: experimental conditions and experimental results of example 179

From the results in table 13, it can be seen that: JAK inhibitors are effective in preventing diarrhea caused by monoclonal antibody-like EGFR inhibitors.

Examples 180 to 185: in experiments to prevent diarrhea with small molecule EGFR inhibitors, JAK inhibitors are compared to other clinically available drugs.

After one week (about 200 g) of adaptation, rats were grouped and the experiments were divided into other drug groups and JAK inhibitor groups, 10 each, and dosing experiments were performed. Various small molecule EGFR inhibitors were dissolved in sterile aqueous solutions, and the EGFR inhibitor drug solutions were fixed to the desired concentrations with PBS (about 3-fold dilution with PBS solution) prior to gavage, with no more than 2mL of drug per gavage, and the dosing amounts shown in table 14. The experiments were divided into JAK inhibitor groups and other drug groups. JAK inhibitor group: gastric lavage JAK inhibitors and EGFR inhibitors, respectively (species and concentrations are shown in table 14); other drug groups: other drugs (examples 180-185) and EGFR inhibitors (species and concentrations shown in Table 14) were given separately. The frequency of gastric lavage of EGFR inhibitors is shown in table 14, JAK inhibitor groups were lavaged 2 times daily, and the frequency and mode of administration of other groups are shown in table 14. The diarrhea grade of each group of rats was recorded daily, and the number of rats in the JAK inhibitor group at the end of the experiment was counted as significantly lighter than the diarrhea grade of the other drug groups.

Table 14 lists animal experimental combinations of JAK inhibitor ointments with clinically existing medications, and corresponding experimental results (where the relative remission rate bar values = JAK group diarrhea lighter than other medication groups/total number of rats in JAK group x 100%).

Table 14: experimental conditions and experimental results for examples 180-185

Figure 16 shows diarrhea grade results for JAK inhibitor groups, other drug groups.

From the results in table 14 and fig. 16, it can be seen that: compared with other clinically available drugs (which have no good therapeutic effect on diarrhea caused by EGFR inhibitors), JAK inhibitors can effectively control diarrhea caused by EGFR inhibitors.

Examples 186 to 202Experiments to verify JAK inhibitors on rat animal models to prevent small molecule EGFR inhibitors from producing orocheilitis

An animal model of rat was constructed, and small molecule EGFR inhibitors shown in Table 15 were administered to SD rats of 8-week females by daily gavage, and after several days of administration, the rats developed oral and peripheral inflammation, ulceration, crusting, bleeding and other symptoms of cheilitis (FIG. 17).

After the rats (about 200 g) were housed and adapted for one week, they were grouped, and the experiment was divided into a control group and a JAK inhibitor group, 10 animals each, and a gastric administration test was performed. Various small molecule EGFR inhibitors were dissolved in sterile aqueous solutions, and the EGFR inhibitor drug solutions were fixed to the desired concentrations with PBS (about 3-fold dilution with PBS solution) prior to gavage, with no more than 2mL of drug per gavage, and the dosing amounts shown in table 15. The experiments were divided into JAK inhibitor groups and control groups (solvent control group). JAK inhibitor group: gastric lavage JAK inhibitors and EGFR inhibitors, respectively (species and concentrations are shown in table 15); control group: the same solvents and EGFR inhibitors (species and concentrations are shown in table 15) as JAK inhibitors were infused separately. The gavage frequency of EGFR inhibitors is shown in table 15, JAK inhibitors and blank solvent control groups were gavaged 2 times daily. The number of rats with JAK inhibitor group at the end of the experiment was counted as significantly lighter than the control group.

Table 15 lists animal experimental combinations of each EGFR inhibitor and JAK inhibitor, and the corresponding experimental results (where the relative remission rate bar values = JAK inhibitor group lipsitis lighter than the control group rats/total number of JAK inhibitor group rats x 100%).

Table 15: experimental conditions and experimental results for examples 186-202

Fig. 17 shows photographs of oral labitis of typical rats in JAK inhibitor groups and control groups.

As can be seen from the results of table 15 and fig. 17: JAK inhibitors are effective in preventing cheilitis caused by EGFR inhibitors.

Example 203: experiment for verifying JAK inhibitor to prevent monoclonal EGFR inhibitor from producing orocheilitis on rat animal model

After one week (about 200 g) of feeding adaptation of SD rats, the rats were divided into 10 groups. The experiments were divided into JAK inhibitor groups and control groups. The Cetuximab monoclonal antibody solution diluted by normal saline is injected for 2 times per week at the speed of 1.3ml/kg/min, the single injection time is not less than 15min, and the dosage is 100mg/kg. Following injection, the JAK inhibitor group was perfused daily with the JAK inhibitor and the control group was not treated with other than mab. The number of rats with JAK inhibitor group at the end of the experiment was counted as significantly lighter than the control group.

Table 16 lists animal experimental combinations of mab EGFR inhibitor and JAK inhibitor, and corresponding experimental results (where the number of control rate bars = number of rats with less cheilitis symptoms than control group/total number of rats with JAK inhibitor group x 100%).

Table 16: experimental conditions and experimental results of example 203

From the results in table 16, it can be seen that: JAK inhibitors are effective in preventing cheilitis caused by monoclonal EGFR inhibitors.

Examples 204 to 216: experiments to verify JAK inhibitors on rat animal models to treat small molecule EGFR inhibitors to produce orocheilitis

After the rats (about 200 g) were housed and adapted for one week, they were grouped, and the experiment was divided into a control group and a JAK inhibitor group, 10 animals each, and a gastric administration test was performed. Various small molecule EGFR inhibitors were dissolved in sterile aqueous solutions, and the EGFR inhibitor drug solutions were fixed to the desired concentrations with PBS (about 3-fold dilution with PBS solution) prior to gavage, with no more than 2mL of drug per gavage, and the dosing amounts shown in table 17. The gastric lavage was continued daily until the rats developed symptoms of cheilitis, at which point the treatment experiment was started. The experiments were divided into JAK inhibitor groups and control groups (solvent control group). JAK inhibitor group: gastric lavage JAK inhibitors and EGFR inhibitors, respectively (species and concentrations are shown in table 17); control group: the same solvents and EGFR inhibitors (species and concentrations are shown in table 17) as JAK inhibitors were infused separately. The gavage frequency of EGFR inhibitors is shown in table 17, JAK inhibitors and blank solvent control groups were gavaged 2 times daily. During the treatment experiment, the stomach is repeatedly irrigated every day, and the number of the oral cheilitis symptoms of the JAK inhibitor group at the end point of the experiment is counted to be obviously lighter than that of the control group.

Table 17 lists animal experimental combinations of various small molecule EGFR inhibitors and JAK inhibitors, and corresponding experimental results (where the number in the control rate column = JAK group oral labitis symptom is lighter than the number of rats in the control group/total number of rats in the JAK group x 100%).

Table 17: experimental conditions and experimental results for examples 204-216

From the results in Table 17, it can be seen that: JAK inhibitors are effective in the treatment of cheilitis caused by small molecule EGFR inhibitors.

Example 217: verification of JAK inhibitors treatment of monoclonal EGFR inhibitors to produce cheilitis in rat animal modelsExperiment

After one week (about 200 g) of feeding adaptation of SD rats, the rats were divided into 10 groups. The experiments were divided into JAK inhibitor groups and control groups. The EGFR monoclonal antibody solution diluted by normal saline is injected for 2 times per week into tail vein, and the injection speed and time are shown in a table 18; the treatment experiment was started at this time with continuous dosing for 1-2 weeks until the rats developed cheilitis. The experiments were divided into JAK inhibitor groups and control groups (solvent control group). JAK inhibitor group: gastric lavage JAK inhibitors (species and concentrations are shown in table 18); control group: the same solvents (species and concentrations are shown in table 18) as JAK inhibitors were infused separately. In the treatment experiment, the single anti-EGFR inhibitor is continuously injected for 2 times a week, the JAK inhibitor and the control group are infused twice a day, and the number of the oral cheilitis symptoms of rats in the JAK inhibitor group at the end point of the experiment is counted to be obviously lighter than that of the control group.

Table 18 lists animal experimental combinations of mab EGFR inhibitor and JAK inhibitor, and corresponding experimental results (where the number of control rate bars = number of rats with less cheilitis symptoms than control group/total number of rats with JAK inhibitor group x 100%).

Table 18: experimental conditions and experimental results of example 217

From the results in table 18, it can be seen that: JAK inhibitors are effective in the treatment of cheilitis caused by monoclonal EGFR inhibitors.

Claims

Use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing and/or treating side effects associated with EGFR dysfunction in a subject:

formula I wherein ring A is optionally substituted or unsubstitutedSubstituted C containing 1-3 rings _4- C ₉ Cycloalkyl or heterocyclyl, R ₅ Selected from hydrogen atoms, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkylsulfonyl, C ₂ -C ₆ Alkenyl and C ₂ -C ₆ Alkynyl, wherein the alkyl, alkenyl, alkynyl is optionally substituted with deuterium, hydroxy, amino, halogen, cyano and/or nitro.
The use according to claim 1, wherein the ring a is a monocyclic C optionally substituted or unsubstituted by a substituent ₄ -C ₇ Cycloalkyl or heterocyclyl.
The use according to any one of claims 1-2, wherein the ring a is a monocyclic C ₄ -C ₇ Cycloalkyl, monocyclic C ₄ -C ₇ A nitrogen-containing heterocyclyl, said cycloalkyl or nitrogen-containing heterocyclyl optionally being substituted with one or more substituents.
The use according to any one of claims 1-3, wherein the ring a isWherein the R is ₁ Selected from hydrogen atoms, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl and C ₂ -C ₆ Alkynyl, R ₂ Selected from hydrogen atoms, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkenyl, C ₁ -C ₆ Alkynyl, acyl and cyano, wherein the alkyl, alkenyl, alkynyl, acyl are optionally substituted with halogen, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkynyl, C ₂ -C ₆ Alkynyl and/or cyano substitution.
The use according to claim 4, wherein said R ₁ Selected from C ₁ -C ₆ Alkyl groups and hydrogen atoms.
The use according to any one of claims 4-5, wherein said R ₁ Is methyl or hydrogen atom.
The use according to any one of claims 4-6, wherein said R ₂ is-C (O) -R ₄ Wherein said R is ₄ Selected from C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl and cyano groups, the alkyl, alkenyl, alkynyl, cyano groups being further optionally substituted with C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl and cyano substitutions.
The use according to any one of claims 4-7, wherein said R ₂ Selected from-C (O) -ch=ch ₂ and-C (O) -CH ₂ -CN。
The use according to any one of claims 1-8, wherein the ring a is Wherein the R is ₃ Selected from hydrogen atoms, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, acyl, amino and/or sulfonate groups, said C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, acyl, amino or sulfonic acid groups are further substituted by one or more C ₁ -C ₆ Alkyl, C ₂ - C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, acyl, amino and/or sulfonate substituents.
The use according to claim 9, wherein said R ₃ Is thatWherein the R is ₆ Selected from C ₁ -C ₆ An alkyl group.
The use according to any one of claims 9-10, wherein said R ₃ Is that
The use according to any one of claims 1-11, wherein the ring a is C optionally substituted or unsubstituted with substituents ₅ -C ₁₀ A bicycloalkyl or bicycloheteroalkyl group, optionally substituted with a substituent.
The use according to any one of claims 1-12, wherein the ring a isWherein the R is ₈ is-C (O) R ₇ Or- (CH 2) _n -C(O)OR ₇ Wherein said R is ₇ Selected from hydrogen atoms, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₂ -C ₆ Alkenyl, 5-to 10-membered heteroaryl and amino, said C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₂ -C ₆ Alkenyl and 5-to 10-membered heteroaryl and amino are further optionally C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₂ -C ₆ Alkenyl and/or 5-to 10-membered heteroaryl substitutions.
The use according to claim 13, wherein said R ₈ is-C (O) R ₇ And said R ₇ Is thatWherein ring B is a 5-to 7-membered heteroaryl, optionally R ₉ Substitution, said R ₉ Selected from hydrogen atoms, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy and C ₂ -C ₆ Alkenyl groups.
The use of claim 14, wherein the ring B is a 5 membered heteroaryl, optionally substituted with R ₉ Substitution, said R ₉ Selected from hydrogen atoms, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy and C ₂ -C ₆ Alkenyl groups.
The use according to any one of claims 14-15, wherein the ring B isThe R is ₉ Is C ₁ -C ₆ An alkoxy group.
The use according to claim 16, wherein said R ₉ is-O-CH ₃ 。
The use of any one of claims 1-17, wherein the R ₅ Selected from hydrogen atoms and C ₁ -C ₆ An alkyl group.
The use of any one of claims 1-18, wherein the R ₅ Selected from the group consisting of hydrogen atoms and methyl groups.
The use according to any one of claims 1-19, wherein the compound of formula I is selected from compounds I-a, I-b, I-c and I-d:
the use of any one of claims 1-20, wherein the side effects associated with EGFR dysfunction comprise side effects associated with EGFR inhibition.
The use of any one of claims 1-21, wherein the side effect is directly caused by EGFR inhibition.
The use of any one of claims 1-22, wherein the side effect is caused by an EGFR inhibitor.
The use of any one of claims 1-23, wherein the side effects associated with EGFR inhibition comprise epithelial tissue disease associated with EGFR inhibition.
The use of claim 24, wherein the side effects associated with EGFR inhibition comprise epithelial tissue diseases associated with EGFR inhibition.
The use of claim 25, wherein the epithelial tissue disorder comprises an epithelial cell disorder and/or an endothelial cell disorder.
The use of claim 26, wherein the epithelial cells comprise skin epithelial cells, oral epithelial cells, gastric epithelial cells, and/or intestinal epithelial cells.
The use of any one of claims 1-27, wherein the side effect associated with EGFR dysfunction comprises rash.
The use of claim 28, wherein the rash comprises an immune rash and/or a non-immune rash.
The use of any one of claims 1-29, wherein the EGFR dysfunction-related rash comprises acne vulgaris (acid vculgaris), EGFR dysfunction-related papule rash (papulopustular rash), EGFR dysfunction-related rosacea (acid rosacea), EGFR dysfunction-related pruritic rash (pruritis rash), EGFR dysfunction-related acne-like rash (acneiform rash), EGFR dysfunction-related cellulitis (celulitis), EGFR dysfunction-related Lyme disease (Lyme disk), EGFR dysfunction-related allergic reaction (allergic reaction), EGFR dysfunction-related suppurative sweat gland (hidradenitis suppurativa), EGFR dysfunction-related measles (hives), EGFR dysfunction-related dermatitis (dermatitis), EGFR dysfunction-related scab (craddress cap), EGFR dysfunction-related purpura (prurus), EGFR dysfunction-related purpura (EGFR), EGFR dysfunction-related rosedowny-related roses (Kadskin), EGFR dysfunction-related leiomy (leiocarcinoma-related xanthoma), EGFR dysfunction-related xanthoma (leiomy), EGFR dysfunction-related xanthoma (leiocarcinoma-related dysfunctional), EGFR (leiomy) and EGFR (leiomy-related xanthoma) and EGFR (leiocarcinoma-related xanthoma) Annular erythema centrifugation associated with EGFR dysfunction (erythema annulare centrifugum), folliculitis associated with EGFR dysfunction, follicular papules associated with EGFR dysfunction, xerosis eczema associated with EGFR dysfunction and/or papulopus associated with EGFR dysfunction.
The use of any one of claims 1-30, wherein the side effect associated with EGFR dysfunction comprises a mucosal injury disease or disorder.
The use of claim 31, wherein the mucosal injury disease or disorder comprises dry mouth, oral mucositis, epistaxis, nasopharyngitis, cheilitis, oesophageal mucositis, gastrointestinal mucositis, gastric ulcers, rectal mucositis, diarrhea, vomiting, nausea, anorexia, constipation, abdominal pain.
The use of any one of claims 31-32, wherein the mucosal injury disease or disorder associated with EGFR dysfunction comprises dry mouth associated with EGFR dysfunction, oral mucositis associated with EGFR dysfunction, epistaxis associated with EGFR dysfunction, nasopharyngitis associated with EGFR dysfunction, cheilitis associated with EGFR dysfunction, esophagitis associated with EGFR dysfunction, gastrointestinal mucositis associated with EGFR dysfunction, gastric ulcer associated with EGFR dysfunction, rectal mucositis associated with EGFR dysfunction, diarrhea associated with EGFR dysfunction, emesis associated with EGFR dysfunction, nausea associated with EGFR dysfunction, anorexia associated with EGFR dysfunction, constipation associated with EGFR dysfunction, abdominal pain associated with EGFR dysfunction.
The use of any one of claims 1-33, wherein the severity of the side effect is according to grade 1 or more, grade 2 or more, grade 3 or more, grade 4 or more, or grade 5 in NCI-CTCAE V5.0.
The use of any one of claims 21-34, wherein the side effects associated with EGFR inhibition comprise side effects associated with administration of an EGFR inhibitor.
The use of claim 35, wherein the EGFR inhibitor comprises a medicament for treating cancer.
The use of any one of claims 35-36, wherein the EGFR inhibitor acts directly on the EGFR protein and/or nucleic acid encoding the EGFR protein.
The use of any one of claims 35-37, wherein the EGFR inhibitor comprises a small molecule EGFR inhibitor, a protein macromolecule that specifically binds EGFR, RNAi that inhibits expression of EGFR protein, and/or an antisense oligonucleotide that inhibits expression of EGFR protein.
The use of claim 38, wherein the small molecule EGFR inhibitor comprises a small molecule EGFR inhibitor that binds reversibly to EGFR, a small molecule EGFR inhibitor that binds irreversibly to EGFR, and/or a small molecule EGFR inhibitor that specifically binds mutant EGFR.
The use of any one of claims 35-39, wherein the EGFR inhibitor comprises cetuximab, gefitinib, erlotinib, icotinib, sapitinib, afatinib, lapatinib, vandetanib, lenatinib, brinatinib, panitumumab, valatinib, nituzumab, tesevatinib, ai Liti, xi Li tinib, rociletinib, canetinib, AZD3759, YZJ-0318, naptinib, naquotinib, PF-06747775, SPH 8-11, pozitinib, eptinib, varlitinib, ai Fu tinib, HM61713, CK-101, pyrroltinib, lairottinib, HS-10296, AP32788, simotinib, GMA204, virlitinib, yinlitinib, natatinib, nortinib, aotinib, dasatinib, eastinib, and/or eateri 045.
The use of any one of claims 35-40, wherein the EGFR inhibitor is used in combination with one or more other therapies.
The use of any one of claims 1-41, wherein the subject comprises a cancer patient.
The use of any one of claims 1-42, wherein the subject was, is being and/or is in the future administered the EGFR inhibitor.
The use according to any one of claims 1 to 43, wherein the compound of formula I is prepared for transdermal administration.
The use of any one of claims 1-44, wherein the concentration of the compound of formula I in the medicament is from about 0.0001% to about 50%.
The use of any one of claims 1-45, wherein the compound of formula I is prepared for administration to the gastrointestinal tract.
The use according to any one of claims 1 to 46, wherein the compound of formula I is prepared for administration by injection.
The use of any one of claims 1-47, wherein the effective dose of the compound of formula I is from 0.001mg/kg body weight/day to 3000mg/kg body weight/day.
The use of any one of claims 1-48, wherein the effective dose of the compound of formula I is from 0.1mg/kg body weight/day to 150mg/kg body weight/day.
The use of any one of claims 35-49, wherein the medicament does not substantially affect the therapeutic effect of the EGFR inhibitor.
The use according to any one of claims 1-50, wherein the medicament further comprises one or more additional active ingredients.
The use of compounds I-a, I-b, I-c and/or I-d and pharmaceutically acceptable salts thereof for the manufacture of a medicament for the prevention and/or treatment of side effects associated with EGFR dysfunction in a subject,
a method of preventing or treating side effects associated with EGFR dysfunction, comprising administering to a subject in need thereof a compound of formula I according to any one of claims 1-51, or a pharmaceutically acceptable salt thereof:

formula I wherein ring A is optionally substituted or unsubstituted comprising ₁ - ₃ C of individual rings ₄ -C ₉ Cycloalkyl or heterocyclyl, R ₅ Selected from hydrogen atoms, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkylsulfonyl, C ₂ -C ₆ Alkenyl groupsAnd C ₂ -C ₆ Alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with deuterium, hydroxy, amino, halogen, cyano and/or nitro.
The method of claim 53, wherein the subject was, is, and/or is in the future administered an EGFR inhibitor.
A method of preventing or treating side effects associated with EGFR dysfunction, comprising administering to a subject in need thereof compound I-a, I-b, I-c and/or I-d, or a pharmaceutically acceptable salt thereof.
A pharmaceutical combination or kit comprising: 1) An EGFR inhibitor; and 2) a compound of formula I as defined in any one of claims 1 to 51: Formula I wherein ring A is optionally substituted or unsubstituted comprising ₁ - ₃ C of individual rings ₄ -C ₉ Cycloalkyl or heterocyclyl, R ₅ Selected from hydrogen atoms, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkylsulfonyl, C ₂ -C ₆ Alkenyl and C ₂ -C ₆ Alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with deuterium, hydroxy, amino, halogen, cyano and/or nitro.
The pharmaceutical combination or kit of claim 56, wherein the EGFR inhibitor and the compound of formula I are not mixed with each other.
The pharmaceutical combination or kit of any one of claims 56-57, wherein the EGFR inhibitor and the compound of formula I are each independently present in separate containers.
The pharmaceutical combination or kit of any one of claims 56-58, wherein the compound of formula I is prepared for transdermal administration.
The pharmaceutical combination or kit of any one of claims 56-59, wherein the concentration of the compound of formula I is about 0.0001% to about 50%.
The pharmaceutical combination or kit of any one of claims 56-60, wherein the compound of formula I is prepared for administration to the gastrointestinal tract.
The pharmaceutical combination or kit of any one of claims 56-61, wherein the compound of formula I is prepared for administration by injection.
The pharmaceutical combination or kit of any one of claims 56-62, wherein the effective dose of the compound of formula I is 0.001mg/kg body weight/day to 3000mg/kg body weight/day.
The pharmaceutical combination or kit of any one of claims 56-63, wherein the effective dose of the compound of formula I is from 0.1mg/kg body weight/day to 150mg/kg body weight/day.
The pharmaceutical combination or kit of any one of claims 56-64, wherein the compound of formula I in 2) is capable of preventing or treating a disease or disorder associated with administration of the EGFR inhibitor in 1).
The pharmaceutical combination or kit of any one of claims 56-65, wherein the compound of formula I in 2) does not substantially affect the therapeutic effect of the EGFR inhibitor in 1).
The pharmaceutical combination or kit of any one of claims 56-66, wherein the compound of formula I of 2) is administered prior to, simultaneously with, or after administration of the EGFR inhibitor of 1).
A method, the method comprising the steps of:

1) Monitoring the side effects of a subject administered an EGFR inhibitor;

2) When the monitoring indicates that the subject is experiencing a side effect associated with administration of the EGFR inhibitor, administering to the subject a compound of formula I according to any one of claims 1-51, or a pharmaceutically acceptable salt thereof:

formula I wherein ring A is optionally substituted or unsubstituted comprising ₁ - ₃ C of individual rings ₄ -C ₉ Cycloalkyl or heterocyclyl, R ₅ Selected from hydrogen atoms, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkylsulfonyl, C ₂ -C ₆ Alkenyl and C ₂ -C ₆ Alkynyl, wherein the alkyl, alkenyl, alkynyl is optionally substituted with deuterium, hydroxy, amino, halogen, cyano and/or nitro.
The method of claim 68, further comprising continuing to monitor the side effects, and optionally reducing or disabling the EGFR inhibitor.
The method of any one of claims 68-69, wherein the severity of the side effect increases after the administration of an EGFR inhibitor.
The method of any one of claims 68-70, wherein the subject does not have the side effect prior to the administration of an EGFR inhibitor.
The method of any one of claims 68-71, wherein the EGFR inhibitor does not comprise a compound of formula I.
The method of any one of claims 68-72, wherein the EGFR inhibitor is administered for the treatment of cancer.
The method of any of claims 68-73, wherein the affected area of the side effect is different from the affected area of the cancer.