New use

Abstract

The present disclosure relates to a new use, and mainly relates to the use of an FAK inhibitor, such as IN10018, in the preparation of a drug for treating or preventing interstitial pneumonia, a method for treating or preventing interstitial pneumonia by means of administering a therapeutically effective amount of the FAK inhibitor, such as IN10018, and a pharmaceutical combination product, kit and pharmaceutical composition containing the FAK inhibitor, such as IN 10018, for treating or preventing interstitial pneumonia.

Description

New use

[0001] This application claims priority to Chinese Patent Application No. 202411062164.7 filed on August 2, 2024 and Chinese Patent Application No. 202510870004.3 filed on June 25, 2025, the disclosures of which are incorporated herein in their entirety by this reference as part of this application. TECHNICAL FIELD

[0002] The present disclosure belongs to the field of pharmaceutical chemistry. Specifically, the present disclosure relates to the use of IN10018 in the manufacture of a medicament for treating or preventing interstitial pneumonia. BACKGROUND

[0003] Interstitial lung disease is a complex lung disease involving the lung interstitium. It includes idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, sarcoidosis, and connective tissue disease-associated interstitial lung disease, etc. In clinical practice, the main manifestation is dyspnea (shortness of breath), followed by cough, mostly persistent dry cough. The fibrotic changes in the lungs of patients with interstitial pneumonia are irreversible, and the treatment used in clinical practice is to alleviate the inflammatory response and prevent or reduce the progression of pulmonary fibrosis, thereby improving the quality of life of patients and prolonging survival. During treatment, known pathogenic or inducing factors should be avoided first. For example, caused by the use of antibody drug conjugates (ADCs), which need to be discontinued in clinical practice. If interstitial pneumonia is not treated in time, it may endanger life. Antibody drug conjugates have achieved great results in clinical application, but some toxic side effects have also appeared. Since the first approval of trastuzumab emtansine conjugate in 2013, antibody drug conjugates (ADCs) targeting human epidermal growth factor receptor 2 (ERBB2) have become a key treatment strategy for ERBB2 (HER2) positive advanced breast cancer. Another Anti-ERBB2 ADC drug trastuzumab deruxtecan (DS-8201) was also listed in 2022, but in the trials of Trastuzumab emtansine, trastuzumab deruxtecan and trastuzumab duocarmazine, deaths related to lung injury (especially interstitial lung injury) have been reported, with varying incidence rates. Once the patient has related lung injury, the drug needs to be discontinued immediately, and then treated with glucocorticoids. For tumor patients, discontinuation means that they cannot receive effective treatment, and treatment with glucocorticoids can also cause various side effects, such as osteoporosis, immune system destruction, hyperglycemia, etc. Therefore, there is an urgent need to solve the above problems in clinical practice. SUMMARY

[0004] In one aspect, the present disclosure provides use of a FAK inhibitor in the manufacture of a medicament for treating or preventing interstitial pneumonia.

[0005] In one aspect, the present disclosure provides a pharmaceutical combination of a FAK inhibitor and another therapeutic agent or agents for treating or preventing interstitial pneumonia.

[0006] In one aspect, the present disclosure provides a method of treating or preventing interstitial pneumonia, comprising administering to a subject in need thereof a therapeutically effective amount of a FAK inhibitor.

[0007] In one aspect, the present disclosure provides a pharmaceutical composition for treating or preventing interstitial pneumonia, comprising: a FAK inhibitor, and optionally one or more pharmaceutically acceptable carriers.

[0008] In one aspect, the present disclosure provides a kit for treating or preventing interstitial pneumonia, comprising: a FAK inhibitor, and optionally instructions for use.

[0009] In some embodiments, for the use, the pharmaceutical combination, the method, the kit or the pharmaceutical composition, wherein the interstitial pneumonia is caused by an antibody drug conjugate.

[0010] In some embodiments, for the use, the pharmaceutical combination, the method, the kit or the pharmaceutical composition, wherein the antibody drug conjugate is an antibody drug conjugate of HER2.

[0011] In some embodiments, for the use, the pharmaceutical combination, the method, the kit or the pharmaceutical composition, wherein the antibody drug conjugate of HER2 is ado-trastuzumab emtansine, deruxtezumab (DS-8201), trastuzumab duocarmazine, MRG-002, Disitamab Vedotin, DB-1303, SHR-A1811 (trastuzumab rezetecan), JSKN-003, anvatabart opadotin, KL-A166, LCB-14, BL-M07D1 or DP-303c.

[0012] In some embodiments, for the use, the pharmaceutical combination, the method, the kit or the pharmaceutical composition, wherein the antibody drug conjugate of HER2 is deruxtezumab (DS-8201).

[0013] In some embodiments, for the stated use, pharmaceutical combination product, method, kit, or pharmaceutical composition, the therapeutic agent is a hormone.

[0014] In some embodiments, for the stated use, pharmaceutical combination product, method, kit, or pharmaceutical composition, the antibody-drug conjugate is an antibody-drug conjugate for HER2, preferably, the antibody-drug conjugate for HER2 is trastuzumab.

[0015] In some embodiments, for the stated use, pharmaceutical combination product, method, kit, or pharmaceutical composition, the hormone is methylprednisolone, dexamethasone, dexamethasone sodium phosphate, hydrocortisone, prednisolone acetate, triamcinolone acetate, betamethasone / budesonide combination, fluticasone, beclomethasone, mometasone gluconate, fluticasone propionate, triamcinolone, clobetasol propionate, prednisolone, cortisone, dexamethasone acetate, fluocinolone acetonide, or halometasone; preferably, the hormone is betamethasone combination.

[0016] In some embodiments, for the stated use, pharmaceutical combination product, method, kit, or pharmaceutical composition, the dose of said hormone is from 0.1 mg to 60 mg, preferably from 1 mg to 10 mg.

[0017] In some embodiments, for the stated use, pharmaceutical combination product, method, kit, or pharmaceutical composition, the hormone is administered intramuscularly every 2-4 weeks at a dose of 1 mg to 10 mg.

[0018] In some embodiments, for the stated uses, pharmaceutical combination products, methods, kits, or pharmaceutical compositions, the hormone is betamethasone bismuth subsalicylate, administered intramuscularly every 2-4 weeks at a dose of 1 mg to 10 mg. Attached Figure Description

[0019] To more clearly illustrate the technical solutions of the embodiments of this disclosure, the accompanying drawings of the embodiments will be briefly described below. Obviously, the drawings described below only relate to some embodiments of this disclosure and are not intended to limit this disclosure.

[0020] Figure 1 shows the serum IL-6 in animals in Example 1.

[0021] Figure 2 shows the animal serum SP-A in Example 1.

[0022] Figure 3 shows the animal serum KL-6 in Example 1.

[0023] Figure 4 shows the bronchoalveolar lavage fluid IL-6 from Example 1.

[0024] Figure 5 shows the bronchoalveolar lavage fluid SP-A from Example 1.

[0025] Figure 6 shows the bronchoalveolar lavage fluid KL-6 from Example 1.

[0026] Figure 7 shows the bronchoalveolar lavage fluid HSP-47 from Example 1.

[0027] Figure 8 shows the TNF-α in the bronchoalveolar lavage fluid of the animal in Example 1.

[0028] Figure 9 shows the bronchoalveolar lavage fluid (WBC) from animals in Example 1.

[0029] Figure 10 shows the HE staining results of the blank control group in Example 1 (HE, 10X), with no obvious abnormalities observed.

[0030] Figure 11 shows the HE staining results of the model control group in Example 1 (HE, 10X). Large areas of consolidation were observed in the lungs, containing multifocal lymphocyte infiltration (arrows). Focal infiltration of foamy cells was also visible (star-shaped symbol), and cholesterol crystals were visible (sword-shaped blank areas indicated by thick arrows). Inflammatory exudate was visible in the bronchi.

[0031] Figure 12 shows the HE staining results of group IN10018 in Example 1 (HE, 10X), with no obvious abnormalities observed.

[0032] Figure 13 shows the weight change curves of the animals in Example 2. The data points represent the average weight within the group, and the error bars represent the standard error (SEM).

[0033] Figure 14 shows the inspiratory time variation curves of lung function in animals in Example 2. The data points represent the mean Ti value within the group, and the error bars represent the standard error (SEM).

[0034] Figure 15 shows the change curve of lung function minute ventilation in animals in Example 2. The data points represent the mean MV value within the group, and the error bar represents the standard error (SEM).

[0035] Figure 16 shows the respiratory rate variation curves of lung function in animals in Example 2. The data points represent the mean f value within the group, and the error bars represent the standard error (SEM).

[0036] Figure 17 shows the serum biochemical levels of the animals in Example 2, including IL-6, SP-A, KL-6, and HSP-47 data for each group of mice on the last day of the experiment. The error bars represent standard errors (SEM).

[0037] Figure 18 shows the biochemical detection levels of the lavage fluid in animals in Example 2. The data of IL-6, SP-A, KL-6, and HSP-47 in mice in each group on the last day of the experiment are shown. The error bars represent standard errors (SEM).

[0038] Figures 19A and 19B show the HE staining results of the blank control group D004 in Example 2 (Figure 19A: 10X, Figure 19B: 20X).

[0039] Figures 20A and 20B show the HE staining results of the blank control group D005 in Example 2 (Figure 20A: 10X, Figure 20B: 20X).

[0040] Figures 21A and 21B show the HE staining results of the blank control group D006 in Example 2 (Figure 21A: 10X, Figure 21B: 20X).

[0041] Figures 22A and 22B show the HE staining results of the model control group D010 in Example 2 (Figure 22A: 10X, Figure 22B: 20X).

[0042] Figures 23A and 23B show the HE staining results of the model control group D011 in Example 2 (Figure 23A: 10X, Figure 23B: 20X).

[0043] Figures 24A and 24B show the HE staining results of the model control group D012 in Example 2 (Figure 24A: 10X, Figure 24B: 20X).

[0044] Figures 25A and 25B show the HE staining results of the positive control group D016 in Example 2 (Figure 25A: 10X, Figure 25B: 20X).

[0045] Figures 26A and 26B show the HE staining results of the positive control group D017 in Example 2 (Figure 26A: 10X, Figure 26B: 20X).

[0046] Figures 27A and 27B show the HE staining results of the positive control group D018 in Example 2 (Figure 27A: 10X, Figure 27B: 20X).

[0047] Figures 28A and 28B show the HE staining results of D022 in the Enhertu+Betamethasone+INX0011 group in Example 2 (Figure 28A: 10X, Figure 28B: 20X).

[0048] Figures 29A and 29B show the HE staining results of D023 in the Enhertu+Betamethasone+INX0011 group in Example 2 (Figure 29A: 10X, Figure 29B: 20X).

[0049] Figures 30A and 30B show the HE staining results of D024 in the Enhertu+Betamethasone+INX0011 group in Example 2 (Figure 30A: 10X, Figure 30B: 20X).

[0050] Figure 31 shows the Western Blot results of the FAK signaling pathway in RAW264.7 cells after 72 hours of DXD treatment in Example 3.

[0051] Figure 32 shows the Western Blot results of the FAK signaling pathway after 72 hours of Enhertu treatment on a co-culture of RAW264.7 and HCC827 cells in Example 3. Detailed Implementation

[0052] To make the objectives, technical solutions, and advantages of the embodiments of this disclosure clearer, the technical solutions of the embodiments of this disclosure will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of this disclosure. All other embodiments obtained by those skilled in the art based on the described embodiments of this disclosure without creative effort are within the scope of protection of this disclosure.

[0053] This disclosure may be implemented in other specific forms without departing from its essential attributes. It should be understood that, without conflict, any and all embodiments of this disclosure may be combined with technical features of any or more other embodiments to obtain further embodiments. This disclosure includes such further embodiments obtained through combination.

[0054] All publications and patents mentioned in this disclosure are incorporated herein by reference in their entirety. In the event of any conflict between the use or terminology used in any publications and patents incorporated by reference and the use or terminology used in this disclosure, the use and terminology of this disclosure shall prevail.

[0055] The chapter titles used in this article are for organizational purposes only and should not be construed as limiting the subject matter.

[0056] Unless otherwise specified, all technical and scientific terms used herein have their usual meaning in the field to which the claimed subject matter pertains. Where multiple definitions exist for a term, the definition herein shall prevail.

[0057] The following terms and symbols used in this disclosure have the meanings described below, unless otherwise specified in the context.

[0058] Except as indicated in the working embodiments or otherwise, all figures for quantitative properties such as dosage set forth in the specification and claims should be understood to be modified in all cases by the term "about". It should also be understood that any range of figures enumerated in this disclosure is intended to include all subranges within that range and any combination of the endpoints of that range or subranges. In this disclosure, the term "about" should have the meaning of within 10%, preferably within 5%, of the specified value or range.

[0059] As used herein, the words “comprising,” “containing,” or “including” mean that the element preceding the word encompasses the elements listed following the word and their equivalents, without excluding elements not described. The terms “containing” or “comprising (including)” as used herein can be open-ended, semi-closed, or closed-ended. In other words, the terms also include “consistently composed of” or “composed of”.

[0060] FAK inhibitors, potent inhibitors of the FAK protein tyrosine kinase, are suitable for therapeutic use in mammals, particularly humans, as antiproliferative agents (e.g., anticancer agents), antitumor agents (e.g., effective against solid tumors), and antiangiogenic agents (e.g., stopping or preventing angiogenesis). The compounds described herein, such as FAK inhibitors, can be used for the prevention and treatment of the diseases or conditions described herein (e.g., cancer). The compounds described herein, such as FAK inhibitors, can be used for the prevention and treatment of non-hematologic malignancies, various human hyperproliferative diseases, such as the following malignant and benign tumors: liver, kidney, bladder, breast, stomach, ovary, colorectal cancer, prostate cancer, pancreatic cancer, lung cancer, vulvar cancer, thyroid cancer, liver cancer, sarcoma, glioblastoma, head and neck cancer, and other proliferative diseases such as benign skin hyperplasia (e.g., psoriasis) and benign prostatic hyperplasia (e.g., BPH), as well as the prevention and treatment of diseases such as mesothelioma.

[0061] The CAS number of IN10018 is 1227948-82-4. The structure of IN10018 is shown in formula (I):

[0062] Defactinib, having the following structure, is also known as VS-6063 (e.g., VS-6063 free base) or PF-04554878. VS-6063 and related compounds are also disclosed, for example, in U.S. Patent No. 7,928,109, the contents of which are incorporated herein by reference. In some embodiments, VS-6063 may form a pharmaceutically acceptable salt (e.g., hydrochloride).

[0063] Defactinib has several deuterated compounds, such as deuterated compound 1 (CAS No. 2384121-03-1) and deuterated compound 2 (CAS No. 2384120-99-2).

[0064] AMP945, having the following structure, is described in WO2012110773 for synthesis and characterization. In some embodiments, AMP945 can form pharmaceutically acceptable salts (e.g., tartrates).

[0065] The CAS NO of APG-2449 is 2196186-84-0.

[0066] Conteltinib, also known as CT-707, has a CAS NO of 1384860-29-0.

[0067] The term "antibody-drug conjugate" (ADC) used in this article refers to a small molecule drug with biological activity linked to a monoclonal antibody via a chemical chain, with the monoclonal antibody acting as a carrier to target and deliver the small molecule drug to target cells.

[0068] The term "HER2 antibody-drug conjugate" as used in this article refers to targeted antibody-drug conjugates used to treat HER2-positive patients.

[0069] As used in this article, "drug combination" or "drug combination product" can refer to a fixed combination of drugs in the form of a single dosage unit (e.g., all active pharmaceutical ingredients are present in one dosage form) or a set of pills for combined administration, or it can refer to a combination of a drug and instructions for use that indicate that the drug can be used in combination with one or more other drugs.

[0070] As used in this article, "combination therapy," "combination treatment," or "combination drugs" refers to the use of one drug in combination with one or more other drugs to treat a disease. This includes both combinations of one drug with one or more other drugs and combinations of one drug with instructions that indicate that the drug can be used in combination with one or more other drugs.

[0071] The term “application” or “administration” when applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids refers to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with the subject, cells, tissues, organs, or biological fluid.

[0072] "Simultaneous or sequential administration" in this disclosure refers to the simultaneous or sequential administration of two or more drugs within a single dosing cycle (e.g., within 4 weeks, 3 weeks, 2 weeks, 1 week, or 24 hours). The methods of drug administration (e.g., oral, intravenous, intramuscular, or subcutaneous administration) may be the same or different, and the dosing frequencies / cycles of the two or more drugs may be the same or different. When the treatment method, product, or use of this disclosure involves two drugs, the two drugs may be administered simultaneously or separately at certain time intervals.

[0073] As used herein, the term "treatment" means the administration of one or more pharmaceutical substances to a person suffering from or having symptoms of a disease in order to cure, alleviate, reduce, alter, treat, improve, enhance, or influence the disease or its symptoms.

[0074] As used herein, the terms "subject" or "object" refer to both mammals and non-mammals. Mammals include any member of the mammalian class, including but not limited to: humans; non-human primates such as chimpanzees and other ape and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs; livestock such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs; and so on. Examples of non-mammals include, but are not limited to, birds. The term "object" is not limited to a specific age or sex. In some embodiments, the object is a human.

[0075] As used herein, the term "pharmaceutical composition" means that it must be chemically and / or toxicologically compatible with other components, including the formulation, and / or compatible with the subject receiving treatment therefrom. The term "therapeuticly effective amount" as used herein refers to an amount generally sufficient to produce a beneficial therapeutic effect on the subject. The therapeutically effective amount of this disclosure can be determined by conventional methods (e.g., modeling, dose-escalation studies, or clinical trials) in conjunction with conventional influencing factors (e.g., route of administration, pharmacokinetics of the compound, severity and duration of disease, subject's medical history, subject's health status, subject's response to the drug, etc.).

[0076] The term “inhibition” as used in this article refers to a reduction in the baseline activity of a biological activity or process.

[0077] The term "reagent kit" as used in this article refers to a box used to hold chemical reagents for detecting chemical components, drug residues, virus types, etc.

[0078] The compounds in the kit may be contained in separate containers. Optionally, two or more compounds may be contained in the same container. For example, the kit may include a first container, a second container, and a packaging insert, wherein the first container contains at least one dose of a FAK inhibitor, the second container contains at least one dose of an antibody-drug conjugate, and the packaging insert contains instructions for use for treating interstitial pneumonia in the recipient. The first and second containers may contain the same or different shapes (e.g., vials, syringes, and bottles) and / or materials (e.g., plastic or glass). The kit may also include other materials that may facilitate drug administration, such as diluents, filters, IV bags and tubing, needles, and syringes.

[0079] The precise amount of FAK inhibitors and other therapeutic agents (e.g., hormones, preferably glucocorticoids, such as methylprednisolone, dexamethasone, dexamethasone sodium phosphate, hydrocortisone, prednisolone acetate, triamcinolone acetate, betamethasone acetonide, budesonide, fluticasone, beclomethasone, mometasone gluconate, fluticasone propionate, triamcinolone, clobetasol propionate, prednisolone, cortisone, dexamethasone acetate, fluocinolone acetonide, or halometasone) administered to the subject will depend on various factors, such as the given drug or compound, the drug formulation, the route of administration, the type of disease, the condition, the identity of the subject or host being treated, etc., but can still be routinely determined by those skilled in the art. For example, determining the effective amount also depends on the degree, severity, and type of cell proliferation. Those skilled in the art will be able to determine the appropriate dosage based on these and other factors.

[0080] IN10018 and other therapeutic agents may be administered via appropriate methods such as oral, intravenous, intramuscular, or subcutaneous administration. In some embodiments, the other therapeutic agents are hormones. In some specific embodiments, the hormones are glucocorticoids, such as methylprednisolone, dexamethasone, dexamethasone sodium phosphate, hydrocortisone, prednisolone acetate, triamcinolone acetate, betamethasone acetonide, budesonide, fluticasone, beclomethasone, mometasone disulfide, fluticasone propionate, triamcinolone acetonide, clobetasol propionate, prednisolone, cortisone, dexamethasone acetate, fluocinolone acetonide, or halometasone. In some embodiments, the hormones are administered by intramuscular injection.

[0081] For example, when administered orally, the drug can be taken orally with a pharmaceutically acceptable carrier such as an excipient, an inert diluent, or an absorbable edible carrier. These can be encapsulated in hard or soft-shell gelatin capsules, compressed into tablets, or mixed directly with the patient's food. For example, the drug can be combined with one or more excipients and used in the form of ingestible tablets, oral tablets, lozenges, capsules, elixirs, suspensions, syrups, or rice paper capsules. Tablets, lozenges, pills, capsules, etc., may further include: binders such as astragalus gum, gum arabic, corn starch, or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, alginate, etc.; lubricants such as magnesium stearate; or sweeteners such as sucrose, fructose, lactose, or aspartame; or flavoring agents.

[0082] For example, when administering drugs intravenously or intraperitoneally by infusion or injection, the solution of the drug can be prepared in water, optionally mixed with a non-toxic surfactant.

[0083] Exemplary drug dosage forms for injection or infusion include: sterile aqueous solutions, dispersions, or sterile powders containing an active ingredient suitable for ad hoc preparation of sterile injectable or infusion solutions or dispersions. In any case, the final dosage form should be sterile, flowable, and stable under both manufacturing and storage conditions.

[0084] Sterile injectable solutions can be prepared by incorporating the required amount of the drug with the various other desired components described above into a suitable solvent, followed by filtration and sterilization. For sterile powders used to prepare sterile injectable solutions, preferred preparation methods include vacuum drying and freeze-drying techniques, which can produce a powder containing the active ingredient plus any other desired components present after previous sterile filtration.

[0085] The amount of IN10018 required for treatment can vary not only with the specific reagent chosen, but also with the route of administration, the nature of the disease being treated, and the patient's age and condition, and can ultimately be determined by the attending physician or clinician. However, generally, the dosage can range from about 0.1 to about 200 mg per day, for example: 0.1 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg, preferably 50 mg, 75 mg, 100 mg, or within any two of the aforementioned values, for example 0.1-25 mg, 0.1-50 mg, 0.1-75 mg, 0.1-100 mg, 0.1-125 mg, 0.1-150 mg, 0.1-200 mg, 25-50 mg. mg, 25-75mg, 25-100mg, 25-125mg, 25-150mg, 25-200mg, 50-75mg, 50-100mg, 50-125mg, 50-150mg, 50-200mg, 75 -100mg, 75-125mg, 75-150mg, 75-200mg, 100-125mg, 100-150mg, 100-200mg, 125-150mg, 125-200mg, 150-200mg. In some embodiments, the packaged dosage (unit dose) of IN10018 can be in the range of about 25 mg to about 200 mg, such as 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg, preferably 25 mg, 50 mg, or in the range between any two of the foregoing values, such as 25-50 mg, 25-75 mg, 25-100 mg, 25-125 mg, 25- 150mg, 25-200mg, 50-75mg, 50-100mg, 50-125mg, 50-150mg, 50-200mg, 75-100mg, 75-125mg, 75-150mg, 75-200mg, 100-125mg, 100-150mg, 100-200mg, 125-150mg, 125-200mg, 150-200mg.

[0086] In some embodiments, the dosage of other therapeutic agents (e.g., hormones, preferably glucocorticoids, such as methylprednisolone, dexamethasone, dexamethasone sodium phosphate, hydrocortisone, prednisolone acetate, triamcinolone acetate, betamethasone acetonide, budesonide, fluticasone, beclomethasone, mometasone disulfide, fluticasone propionate, triamcinolone acetonide, clobetasol propionate, prednisolone, cortisone, dexamethasone acetate, fluocinolone acetonide, or halometasone) is from 0.1 mg to 60 mg, preferably from 1 mg to 10 mg. In some specific embodiments, the dose is 1 mg; in other specific embodiments, the dose is 2 mg; in other specific embodiments, the dose is 3 mg; in other specific embodiments, the dose is 4 mg; in other specific embodiments, the dose is 5 mg; in other specific embodiments, the dose is 6 mg; in other specific embodiments, the dose is 7 mg; in other specific embodiments, the dose is 8 mg; in other specific embodiments, the dose is 9 mg; and in other specific embodiments, the dose is 10 mg.

[0087] In some embodiments, other therapeutic agents (e.g., hormones, preferably glucocorticoids, such as methylprednisolone, dexamethasone, dexamethasone sodium phosphate, hydrocortisone, prednisolone acetate, triamcinolone acetate, betamethasone acetonide, budesonide, fluticasone, beclomethasone, mometasone acetate, fluticasone propionate, triamcinolone, clobetasol propionate, prednisolone, cortisone, dexamethasone acetate, fluocinolone acetonide, or halometasone) are administered intramuscularly at the above doses every 2-4 weeks. In some specific embodiments, other therapeutic agents are administered intramuscularly at the above doses every 2 weeks. In other specific embodiments, other therapeutic agents are administered intramuscularly at the above doses every 3 weeks. In other specific embodiments, other therapeutic agents are administered intramuscularly at the above doses every 4 weeks.

[0088] This disclosure also includes the following implementation schemes.

[0089] 1. Use of FAK inhibitors in the preparation of medicaments for the treatment or prevention of interstitial pneumonia.

[0090] 2. Use of FAK inhibitors and one or more other therapeutic agents in the preparation of medicaments for the treatment or prevention of interstitial pneumonia.

[0091] 3. In the use described in Implementation Scheme 1 or 2, the FAK inhibitor is IN10018, Defactinib, AMP945, APG-2449, Conteltinib, a deuterated compound of IN10018, a deuterated compound of Defactinib, a deuterated compound of AMP945, a deuterated compound of APG-2449, a deuterated compound of Conteltinib, or a pharmaceutically acceptable salt thereof.

[0092] The structure of IN10018 is shown in formula (I):

[0093] 4. The use described in Implementation Scheme 3, wherein the FAK inhibitor is IN10018, or a pharmaceutically acceptable salt thereof, wherein the structure of IN10018 is as shown in Formula (I):

[0094] 5. The use described in embodiment 4, wherein the unit dose of IN10018 is about 25 mg to about 200 mg.

[0095] 6. The use described in Implementation Scheme 4, wherein the unit dose of IN10018 is 25-50 mg, 25-75 mg, 25-100 mg, 25-125 mg, 25-150 mg, 25-200 mg, 50-75 mg, 50-100 mg, 50-125 mg, 50-150 mg, 50-200 mg, 75-100 mg, 75-125 mg, 75-150 mg, 75-200 mg, 100-125 mg, 100-150 mg, 100-200 mg, 125-150 mg, 125-200 mg, or 150-200 mg.

[0096] 7. The use described in Implementation Scheme 4, wherein the unit dose of IN10018 is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg or 200 mg.

[0097] 8. The use described in Implementation Scheme 4, wherein the unit dose of IN10018 is 25 mg or 50 mg.

[0098] 9. The use described in embodiment 4, wherein the dose of IN10018 is about 0.1 to about 200 mg per day.

[0099] 10. The use described in embodiment 4, wherein the dose of IN10018 is 0.1 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg or 200 mg per day.

[0100] 11. The use described in Implementation Scheme 4, wherein the dosage of IN10018 is 0.1-25 mg, 0.1-50 mg, 0.1-75 mg, 0.1-100 mg, 0.1-125 mg, 0.1-150 mg, 0.1-200 mg, 25-50 mg, 25-75 mg, 25-100 mg, 25-125 mg, 25-150 mg, 25-2 00mg, 50-75mg, 50-100mg, 50-125mg, 50-150mg, 50-200mg, 75-100mg, 75-125mg, 75-150mg, 75-200mg, 100-125mg, 100-150mg, 100-200mg, 125-150mg, 125-200mg or 150-200mg.

[0101] 12. The use described in embodiment 4, wherein the dose of IN10018 is 50 mg, 75 mg or 100 mg per day.

[0102] 13. The use according to any one of embodiments 4-12, wherein the IN10018 is administered orally, intravenously, intramuscularly or subcutaneously, preferably wherein the IN10018 is administered orally.

[0103] 14. A method for treating or preventing interstitial pneumonia, comprising administering a therapeutically effective amount of a FAK inhibitor to a subject in need.

[0104] 15. The method of embodiment 14, wherein the FAK inhibitor is IN10018, Defactinib, AMP945, APG-2449, Conteltinib, a deuterated compound of IN10018, a deuterated compound of Defactinib, a deuterated compound of AMP945, a deuterated compound of APG-2449, a deuterated compound of Conteltinib, or a pharmaceutically acceptable salt thereof.

[0105] The structure of IN10018 is shown in formula (I):

[0106] 16. The method of embodiment 14 or 15, wherein the FAK inhibitor is IN10018, or a pharmaceutically acceptable salt thereof.

[0107] 17. The method of embodiment 16, wherein the unit dose of IN10018 is about 25 mg to about 200 mg.

[0108] 18. The method of embodiment 16, wherein the unit dose of IN10018 is 25-50 mg, 25-75 mg, 25-100 mg, 25-125 mg, 25-150 mg, 25-200 mg, 50-75 mg, 50-100 mg, 50-125 mg, 50-150 mg, 50-200 mg, 75-100 mg, 75-125 mg, 75-150 mg, 75-200 mg, 100-125 mg, 100-150 mg, 100-200 mg, 125-150 mg, 125-200 mg, or 150-200 mg.

[0109] 19. The method of embodiment 16, wherein the unit dose of IN10018 is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg or 200 mg.

[0110] 20. The method of embodiment 16, wherein the unit dose of IN10018 is 25 mg or 50 mg.

[0111] 21. The method of embodiment 16, wherein the dose of IN10018 is about 0.1 to about 200 mg per day.

[0112] 22. The method of embodiment 16, wherein the dose of IN10018 is 0.1 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg or 200 mg per day.

[0113] 23. The method of embodiment 16, wherein the dosage of IN10018 is 0.1-25 mg, 0.1-50 mg, 0.1-75 mg, 0.1-100 mg, 0.1-125 mg, 0.1-150 mg, 0.1-200 mg, 25-50 mg, 25-75 mg, 25-100 mg, 25-125 mg, 25-150 mg, 25- 200mg, 50-75mg, 50-100mg, 50-125mg, 50-150mg, 50-200mg, 75-100mg, 75-125mg, 75-150mg, 75-200mg, 100-125mg, 100-150mg, 100-200mg, 125-150mg, 125-200mg or 150-200mg.

[0114] 24. The method of embodiment 16, wherein the dose of IN10018 is 50 mg, 75 mg or 100 mg per day.

[0115] 25. The method of any one of embodiments 16-24, wherein the IN10018 is administered orally, intravenously, intramuscularly or subcutaneously, preferably wherein the IN10018 is administered orally.

[0116] 26. The method according to any one of embodiments 14-25, wherein the method further comprises administering one or more additional therapeutic agents to the subject in need, optionally, a FAK inhibitor, such as IN10018, simultaneously or sequentially with the other one or more therapeutic agents.

[0117] 27. A pharmaceutical composition for the treatment or prevention of interstitial pneumonia, comprising: a therapeutically effective amount of a FAK inhibitor.

[0118] 28. The pharmaceutical composition for treating or preventing interstitial pneumonia according to embodiment 27, wherein the FAK inhibitor is IN10018, Defactinib, AMP945, APG-2449, Conteltinib, a deuterated compound of IN10018, a deuterated compound of Defactinib, a deuterated compound of AMP945, a deuterated compound of APG-2449, a deuterated compound of Conteltinib, or a pharmaceutically acceptable salt thereof, wherein the structure of IN10018 is shown in formula (I):

[0119] 29. The pharmaceutical composition for treating or preventing interstitial pneumonia as described in Embodiment 28, wherein the FAK inhibitor is IN10018, or a pharmaceutically acceptable salt thereof.

[0120] 30. The pharmaceutical composition for treating or preventing interstitial pneumonia as described in embodiment 29, wherein the unit dose of IN10018 is from about 25 mg to about 200 mg.

[0121] 31. The pharmaceutical composition for treating or preventing interstitial pneumonia as described in Embodiment 29, wherein the unit dose of IN10018 is 25-50 mg, 25-75 mg, 25-100 mg, 25-125 mg, 25-150 mg, 25-200 mg, 50-75 mg, 50-100 mg, 50-125 mg, 50-150 mg, 50-200 mg, 75-100 mg, 75-125 mg, 75-150 mg, 75-200 mg, 100-125 mg, 100-150 mg, 100-200 mg, 125-150 mg, 125-200 mg, or 150-200 mg.

[0122] 32. The pharmaceutical composition for treating or preventing interstitial pneumonia as described in embodiment 29, wherein the unit dose of IN10018 is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg or 200 mg.

[0123] 33. The pharmaceutical composition for treating or preventing interstitial pneumonia as described in embodiment 29, wherein the unit dose of IN10018 is 25 mg or 50 mg.

[0124] 34. The pharmaceutical composition for treating or preventing interstitial pneumonia according to any one of embodiments 27-33, further comprising one or more additional therapeutic agents.

[0125] 35. A kit for the treatment or prevention of interstitial pneumonia, comprising: a therapeutically effective amount of a FAK inhibitor and optionally, instructions for use.

[0126] 36. The kit for treating or preventing interstitial pneumonia as described in Implementation Scheme 35, wherein the FAK inhibitor is IN10018, Defactinib, AMP945, APG-2449, Conteltinib, a deuterated compound of IN10018, a deuterated compound of Defactinib, a deuterated compound of AMP945, a deuterated compound of APG-2449, a deuterated compound of Conteltinib, or a pharmaceutically acceptable salt thereof, wherein the structure of IN10018 is shown in Formula (I):

[0127] 37. The kit for treating or preventing interstitial pneumonia as described in Implementation Scheme 36, wherein the FAK inhibitor is IN10018, or a pharmaceutically acceptable salt thereof.

[0128] 38. The kit for treating or preventing interstitial pneumonia as described in embodiment 37, wherein the unit dose of IN10018 is about 25 mg to about 200 mg.

[0129] 39. The kit for treating or preventing interstitial pneumonia as described in Implementation Scheme 37, wherein the unit dose of IN10018 is 25-50 mg, 25-75 mg, 25-100 mg, 25-125 mg, 25-150 mg, 25-200 mg, 50-75 mg, 50-100 mg, 50-125 mg, 50-150 mg, 50-200 mg, 75-100 mg, 75-125 mg, 75-150 mg, 75-200 mg, 100-125 mg, 100-150 mg, 100-200 mg, 125-150 mg, 125-200 mg, or 150-200 mg.

[0130] 40. The kit for treating or preventing interstitial pneumonia as described in Implementation Scheme 37, wherein the unit dose of IN10018 is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg or 200 mg.

[0131] 41. The kit for treating or preventing interstitial pneumonia as described in Implementation Scheme 37, wherein the unit dose of IN10018 is 25 mg or 50 mg.

[0132] 42. The kit for treating or preventing interstitial pneumonia according to any one of embodiments 35-41, further comprising one or more additional therapeutic agents.

[0133] 43. A combination product of a therapeutically effective amount of a FAK inhibitor and one or more other therapeutic agents for the treatment or prevention of interstitial pneumonia.

[0134] 44. The pharmaceutical combination product of embodiment 43, wherein the FAK inhibitor is IN10018, Defactinib, AMP945, APG-2449, Conteltinib, a deuterated compound of IN10018, a deuterated compound of Defactinib, a deuterated compound of AMP945, a deuterated compound of APG-2449, a deuterated compound of Conteltinib, or a pharmaceutically acceptable salt thereof, wherein the structure of IN10018 is shown in formula (I):

[0135] 45. The pharmaceutical combination product of embodiment 44, wherein the FAK inhibitor is IN10018, or a pharmaceutically acceptable salt thereof.

[0136] 46. ​​The pharmaceutical combination product of embodiment 45, wherein the unit dose of IN10018 is about 25 mg to about 200 mg.

[0137] 47. The pharmaceutical combination product of embodiment 45, wherein the unit dose of IN10018 is 25-50 mg, 25-75 mg, 25-100 mg, 25-125 mg, 25-150 mg, 25-200 mg, 50-75 mg, 50-100 mg, 50-125 mg, 50-150 mg, 50-200 mg, 75-100 mg, 75-125 mg, 75-150 mg, 75-200 mg, 100-125 mg, 100-150 mg, 100-200 mg, 125-150 mg, 125-200 mg, or 150-200 mg.

[0138] 48. The pharmaceutical combination product of embodiment 45, wherein the unit dose of IN10018 is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg or 200 mg.

[0139] 49. The pharmaceutical combination product of embodiment 45, wherein the unit dose of IN10018 is 25 mg or 50 mg.

[0140] 50. Uses, pharmaceutical combination products, methods, kits, or pharmaceutical compositions as described in any one of embodiments 2-13, 26, 34, 42, or 43-49, wherein the therapeutic agent is a hormone.

[0141] 51. Uses, pharmaceutical combination products, methods, kits, or pharmaceutical compositions as described in any one of embodiments 2-13, 26, 34, 42, or 43-49, wherein the therapeutic agent is an antibody-drug conjugate.

[0142] 52. The use, pharmaceutical combination product, method, kit, or pharmaceutical composition as described in any one of embodiments 1-51, wherein the interstitial pneumonia is caused by an antibody-drug conjugate.

[0143] 53. Uses, pharmaceutical combination products, methods, kits, or pharmaceutical compositions as described in embodiments 51 or 52, wherein the antibody-drug conjugate is an antibody-drug conjugate of HER2.

[0144] 54. The use, pharmaceutical combination product, method, kit, or pharmaceutical composition as described in embodiment 53, wherein the antibody-drug conjugate for HER2 is selected from trastuzumab-metazine conjugate (ado-trastuzumab-metazine), detrastuzumab (DS-8201), trastuzumab duocarmazine, MRG-002, disitamab-vedotin, DB-1303, SHR-A1811 (trastuzumab rezetecan), JSKN-003, anvatabart opadotin, KL-A166, LCB-14, BL-M07D1, or DP-303c.

[0145] 55. Uses, pharmaceutical combination products, methods, kits, or pharmaceutical compositions as described in embodiment 54, wherein the antibody-drug conjugate of HER2 is trastuzumab (DS-8201).

[0146] 56. The use, pharmaceutical combination product, method, kit, or pharmaceutical composition as described in any one of embodiments 50 or 52-55, wherein the hormone is a glucocorticoid, especially methylprednisolone, dexamethasone, dexamethasone sodium phosphate, hydrocortisone, prednisolone acetate, triamcinolone acetate, betamethasone valerate, budesonide, fluticasone, beclomethasone, mometasone disulfide, fluticasone propionate, triamcinolone valerate, clobetasol propionate, prednisolone, cortisone, dexamethasone acetate, fluocinolone acetonide, or halometasone, preferably, the hormone is betamethasone valerate.

[0147] 57. The use, pharmaceutical combination product, method, kit, or pharmaceutical composition as described in any one of embodiments 50 or 52-56, wherein the dose of said hormone is from 0.1 mg to 60 mg, preferably from 1 mg to 10 mg.

[0148] 58. The use, pharmaceutical combination product, method, kit, or pharmaceutical composition as described in any one of claims 50 or 52-56, wherein the hormone is administered intramuscularly every 2-4 weeks at a dose of 1 mg to 10 mg.

[0149] 59. The use, pharmaceutical combination product, method, kit, or pharmaceutical composition as described in any one of claims 50 or 52-56, wherein the hormone is betamethasone acetonide, administered intramuscularly every 2-4 weeks at a dose of 1 mg to 10 mg.

[0150] 60. Use of IN10018 and betamethasone granules in the preparation of a medicament for the treatment or prevention of interstitial pneumonia, wherein the structure of said IN10018 is as shown in formula (I):

[0151] The interstitial pneumonia is caused by an antibody-drug conjugate, preferably trastuzumab.

[0152] 61. A method for treating or preventing interstitial pneumonia, the method comprising administering to a subject in need a therapeutically effective amount of IN10018 and betamethasone bismuth subsalicylate, wherein the structure of IN10018 is as shown in formula (I):

[0153] The interstitial pneumonia is caused by an antibody-drug conjugate, preferably trastuzumab.

[0154] 62. A pharmaceutical composition for the treatment or prevention of interstitial pneumonia, comprising: IN10018 and betamethasone trimethoate, and optionally comprising one or more pharmaceutically acceptable carriers, wherein the structure of said IN10018 is as shown in formula (I):

[0155] The interstitial pneumonia is caused by an antibody-drug conjugate, preferably trastuzumab.

[0156] 63. A kit for the treatment or prevention of interstitial pneumonia, comprising: IN10018 and betamethasone acetonide, and optionally instructions for use, wherein the structure of IN10018 is as shown in formula (I):

[0157] The interstitial pneumonia is caused by an antibody-drug conjugate, preferably trastuzumab.

[0158] 64. A pharmaceutical combination product of IN10018 and betamethasone, used for the treatment or prevention of interstitial pneumonia, wherein the structure of IN10018 is as shown in formula (I):

[0159] The interstitial pneumonia is caused by an antibody-drug conjugate, preferably trastuzumab.

[0160] 65. The use or method described in embodiment 60 or 61, wherein the dose of IN10018 is about 0.1 to about 200 mg per day, preferably, wherein the dose of IN10018 is 0.1 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg or 200 mg per day, preferably, wherein the dose of IN10018 is 0.1-25 mg, 0.1-50 mg, 0.1-75 mg, 0.1-100 mg, 0.1-125 mg, 0.1-150 mg, 0.1-200 mg, 25-50 mg, 25-70 mg per day. 5 mg, 25-100 mg, 25-125 mg, 25-150 mg, 25-200 mg, 50-75 mg, 50-100 mg, 50-125 mg, 50-150 mg, 50-200 mg, 75-100 mg, 75-125 mg, 75-150 mg, 75-200 mg, 100-125 mg, 100-150 mg, 100-200 mg, 125-150 mg, 125-200 mg or 150-200 mg, more preferably, wherein the dose of IN10018 is 50 mg, 75 mg or 100 mg per day.

[0161] 66. The pharmaceutical combination product, kit, or pharmaceutical composition according to any one of embodiments 62-64, wherein the unit dose of IN10018 is from about 25 mg to about 200 mg, preferably, wherein the unit dose of IN10018 is 25-50 mg, 25-75 mg, 25-100 mg, 25-125 mg, 25-150 mg, 25-200 mg, 50-75 mg, 50-100 mg, 50-125 mg, 50-150 mg, 50-200 mg, 75 mg, etc. -100mg, 75-125mg, 75-150mg, 75-200mg, 100-125mg, 100-150mg, 100-200mg, 125-150mg, 125-200mg or 150-200mg, preferably, wherein the unit dose of IN10018 is 25mg, 50mg, 75mg, 100mg, 125mg, 150mg or 200mg, more preferably, wherein the unit dose of IN10018 is 25mg or 50mg.

[0162] 67. The use, pharmaceutical combination product, method, kit or pharmaceutical composition of any one of embodiments 60-64, wherein the compound betamethasone is administered intramuscularly once every 2-4 weeks at a dose of 1 mg to 10 mg.

[0163] Undefined technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0164] Example

[0165] The following embodiments are provided to further illustrate this disclosure. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of this disclosure.

[0166] Unless otherwise specified, the experimental methods described in the following examples can be performed under the standard conditions for such reactions or under the conditions recommended by the manufacturer.

[0167] Unless otherwise specified, all experimental materials and reagents used in the following examples are available from commercially available sources.

[0168] Example 1: Efficacy study of IN10018 in inhibiting ADC-induced interstitial pneumonia in mice

[0169] Experimental animals: Animal and strain Specific pathogen free (SPF)-level HER-2 humanized mice Quantity and sex 24, female Body weight of animals upon entry 18 g ± 2 g Body weight of animals at the first drug administration 20 g ± 2 g Animal identification Cage cards and ear tags Animal source Jiangsu GICC Biopharma Co., Ltd. License number SCXK(Su)2023-0009

[0170] After purchasing the experimental animals, they were isolated and adaptively raised in the quarantine isolation room. The animal diet, clinical observation, etc. were all normal. After one week, the isolation feeding was terminated, and the animals were identified by cage cards marked with ear tags, sex, and groups. They were raised in the SPF-level barrier area. The temperature of the breeding room was 20.0 - 26.0 °C, the humidity was 40 - 60%, and the day-night light-dark alternation time was 12 h / 12 h. The bedding was sterile wood shavings bedding, with 3 animals in each cage, and the animals were identified by cage cards marked with animal numbers and sex. Except in cases where fasting was required, sterilized mouse maintenance feed was continuously supplied every day, without limit, and freely ingested. During the quarantine and experiment processes, water meeting the national hygienic standards for urban domestic drinking water was continuously supplied, and the animals freely ingested it. There were no pollutants in the feed and drinking water at levels that would interfere with the research results.

[0171] According to the body weight on the experimental day, the animals were randomly divided into a blank control group, a model control group, and an IN10018 group, with 6 animals in each group. Except for the blank control group, animals in other groups were intravenously injected with trastuzumab deruxtecan (DS-8201) for injection at 40 mg / kg, 0.1 ml / 10 g, twice a week, on Monday and Thursday respectively. After injection, the animals were closely observed. The injection was continuously carried out for 6 weeks. Animals in the blank control group were injected with an equal volume of normal saline via the tail vein. Meanwhile, the animals in each group were administered drugs as shown in Table 1:

[0172] Table 1:

[0173] Drug administration method and cycle for the IN10018 group: Oral administration (po), once a day, for 6 weeks.

[0174] Reagent sources are shown in Table 2:

[0175] Table 2:

[0176] Measurement indicators:

[0177] 1. Body weight monitoring: On the day of purchasing the animals, before animal grouping, and twice a week after grouping.

[0178] 2. Lung Function Testing: The testing method involved using the EMKA whole body plethysmography (WBP) system software in a quiet environment, and calibrating the system using a 10ml syringe. After calibration, mice were placed in four channels. Once the mice were familiar with their surroundings and calmed down, measurements were taken to determine their overall lung function over a 15-minute period. This method was used in this experiment, with lung function testing performed on mice before modeling and every two weeks thereafter.

[0179] 3. Blood and tissue samples were collected 4 hours after the last administration:

[0180] Blood serum was separated and aliquoted for testing of IL-6, SP-A, KL-6, and HSP-47.

[0181] Three mice underwent bronchoalveolar lavage of their entire lungs, and samples were taken for white blood cells, IL-6, TNF-α, SP-A, KL-6, and HSP-47.

[0182] White blood cells (WBC): In interstitial pneumonia, a large number of white blood cells reach the alveoli under the influence of pulmonary inflammation, chemokines, and immune cell activation, resulting in an increase in alveolar white blood cells. In this experiment, a Mindray five-part differential hematology analyzer was used for detection.

[0183] IL-6: During the pathogenesis of interstitial pneumonia, the inflammatory response is activated, and IL-6 levels increase significantly. High levels of IL-6 may induce fibroblast activation and proliferation, further exacerbating interstitial pneumonia. In this experiment, the mouse IL-6 ELISA kit (LOT: Jun2024) provided by Shanghai Enzyme-Link Biotechnology Co., Ltd. was used for detection.

[0184] TNF-α: An inflammatory cytokine, TNF-α levels typically rise during the inflammatory response of interstitial pneumonia. It promotes the infiltration of inflammatory cells such as neutrophils and macrophages into lung tissue, enhancing the inflammatory response and leading to lung tissue damage. TNF-α is involved in the process of pulmonary fibrosis. It can activate fibroblasts, promoting the synthesis and deposition of extracellular matrix, leading to interstitial fibrosis, a key pathological feature of interstitial pneumonia. In this experiment, the mouse TNF-α ELISA kit (LOT: Jun2024) provided by Shanghai Enzyme-Linked Biotechnology Co., Ltd. was used for detection.

[0185] SP-A is a protein synthesized and secreted by type II alveolar epithelial cells, playing a crucial role in maintaining alveolar surfactant homeostasis and lung immune defense. In this experiment, the mouse SP-A ELISA kit (LOT: Jun2024) provided by Shanghai Enzyme-Linked Biotechnology Co., Ltd. was used for detection.

[0186] KL-6 is a mucoid glycoprotein. In patients with interstitial pneumonia, damage and stimulation of alveolar and bronchial epithelial cells lead to increased expression of KL-6, resulting in elevated serum levels. In this experiment, the mouse KL-6 ELISA kit (LOT: Jun2024) provided by Shanghai Enzyme-Link Biotechnology Co., Ltd. was used for detection.

[0187] HSP-47 plays a crucial role in collagen synthesis, and interstitial pneumonia is often accompanied by pulmonary interstitial fibrosis, during which excessive collagen deposition occurs. In the pathogenesis of interstitial pneumonia, lung tissue damage and inflammation induce increased HSP-47 expression, thereby promoting collagen synthesis and deposition, and exacerbating pulmonary interstitial fibrosis. In this experiment, the mouse HSP-47 ELISA kit (LOT: Jun2024) provided by Shanghai Enzyme-Linked Biotechnology Co., Ltd. was used for detection.

[0188] Lung tissue samples were taken from three mice, placed in 10% formalin, and stained with hematoxylin and eosin (HE).

[0189] Statistical analysis

[0190] For quantitative data: ① First, use Bartlett's test to test data uniformity. If the data are uniform (p ≥ 0.05), then perform an analysis of variance (ANOVA) test (F-test). If the Bartlett's test result is significant (p < 0.05), then perform a Kruskal-Wallis test. ② If the ANOVA result is significant (p < 0.05), then further perform a multiple comparison test using the Dunett parametric test. If the ANOVA result is not significant (p ≥ 0.05), then the statistical analysis is complete. ③ If the Kruskal-Wallis test result is significant (p < 0.05), then further perform a multiple comparison test using the Dunett nonparametric test. If the Kruskal-Wallis test result is not significant, then the statistical analysis is complete.

[0191] Experimental results

[0192] Lung function test

[0193] Lung function was assessed on day 0 (D(0)), day 15 (D(15)), day 29 (D(29)), and day 43 (D(43)). At D(15), D(29), and D(43), the lung function of the model control group was significantly weaker than that of the other groups (p < 0.05, p < 0.01, p < 0.001).

[0194] Inhalation time

[0195] Inspiratory time, no significant differences were observed among the groups in D(0). In the D(15) test, the model control group showed a significantly prolonged inspiratory time compared to the blank control group (p < 0.05) and a significantly prolonged inspiratory time compared to the IN10018 group (p < 0.01). There was no significant difference between the IN10018 group and the blank control group. In the D(29) test, the model control group showed a significantly prolonged inspiratory time compared to the blank control group (p < 0.05) and a significantly prolonged inspiratory time compared to the IN10018 group (p < 0.01). There was no significant difference between the IN10018 group and the blank control group. In the D(43) test, the model control group showed a significantly prolonged inspiratory time compared to the blank control group (p < 0.01) and a significantly prolonged inspiratory time compared to the IN10018 group (p < 0.01). There was no significant difference between the IN10018 group and the blank control group. See Table 3.

[0196] Table 3: Inspiratory Time (msec) Note: * indicates p < 0.05 compared to the model control; ** indicates p < 0.01 compared to the model control; *** indicates p < 0.001 compared to the model control.

[0197] Exhalation time

[0198] Expiratory time: No significant differences were observed among the groups in D(0). In D(15), the model control group showed prolonged expiratory time compared to the blank control group, but no significant difference was observed; compared to the IN10018 group, expiratory time was also prolonged, but no significant difference was observed. In D29, the model control group showed significantly prolonged expiratory time compared to the blank control group (p < 0.05); compared to the IN10018 group, expiratory time was also prolonged, but no significant difference was observed. In D(43), the model control group showed significantly prolonged expiratory time compared to the blank control group (p < 0.05); compared to the IN10018 group, expiratory time was also significantly prolonged (p < 0.05). There was no significant difference between the IN10018 group and the blank control group. See Table 4.

[0199] Table 4: Expiratory Time (msec) Note: * indicates p < 0.05 compared to the model control; ** indicates p < 0.01 compared to the model control; *** indicates p < 0.001 compared to the model control.

[0200] minute ventilation

[0201] Minute ventilation (MVO) showed no significant difference among the groups in D(0). In D(15), the model control group showed a decrease in MVO compared to the blank control group, but no statistical difference was observed; compared to the IN10018 group, the MVO was significantly decreased (p < 0.01). There was no significant difference between the IN10018 group and the blank control group. In D(29), the model control group showed a significant decrease in MVO compared to the blank control group (p < 0.05); compared to the IN10018 group, the MVO was significantly decreased (p < 0.05). There was no significant difference between the IN10018 group and the blank control group. In D(43), the model control group showed a significant decrease in MVO compared to the blank control group (p < 0.05); compared to the IN10018 group, the MVO was significantly decreased (p < 0.01). There was no significant difference between the IN10018 group and the blank control group. See Table 5.

[0202] Table 5: Minute ventilation (ml) Note: * indicates p < 0.05 compared to the model control; ** indicates p < 0.01 compared to the model control; *** indicates p < 0.001 compared to the model control.

[0203] respiratory rate

[0204] Respiratory rate: No significant differences were observed among the groups in D(0). In tests D(15) and D(29), the model control group showed a significantly lower respiratory rate compared to the blank control group (p < 0.05) and compared to the IN10018 group (p < 0.05). There was no significant difference between the IN10018 group and the blank control group. In test D43, the model control group showed a significantly lower respiratory rate compared to the blank control group (p < 0.01) and compared to the IN10018 group (p < 0.01). There was no significant difference between the IN10018 group and the blank control group. See Table 6.

[0205] Table 6: Respiratory Rate (bpm) Note: * indicates p < 0.05 compared to the model control; ** indicates p < 0.01 compared to the model control; *** indicates p < 0.001 compared to the model control.

[0206] Expiratory flow rate corresponding to 50% of exhaled air volume

[0207] The expiratory flow rate corresponding to 50% exhalation volume showed no significant difference among the groups in D(0). In the D(15) test, the model control group showed a significantly lower expiratory flow rate compared to the blank control group (p < 0.05) and compared to the IN10018 group (p < 0.05). In the D(29) test, the model control group showed a significantly lower expiratory flow rate compared to the blank control group (p < 0.05) and compared to the IN10018 group (p < 0.01). There was no significant difference between the IN10018 group and the blank control group. In the D(43) test, the model control group showed a significantly lower expiratory flow rate compared to the blank control group (p < 0.05) and compared to the IN10018 group (p < 0.01). There was no significant difference between the IN10018 group and the blank control group. See Table 7.

[0208] Table 7: Expiratory flow rate (ml / s) corresponding to 50% of exhaled air volume Note: * indicates p < 0.05 compared to the model control; ** indicates p < 0.01 compared to the model control; *** indicates p < 0.001 compared to the model control.

[0209] Biochemical detection of serum and bronchoalveolar lavage fluid

[0210] At the end of the experiment, blood was collected from each group of animals to separate serum, and the levels of IL-6, SP-A, KL-6, and HSP-47 were measured. All indicators in the model control group were significantly higher than those in the other groups (p < 0.001). Three mice from each group underwent bronchoalveolar lavage to measure white blood cell count, IL-6, TNF-α, SP-A, KL-6, and HSP-47. The IN10018 group showed significantly higher levels than the model control group (p < 0.001). The levels of IL-6, TNF-α, SP-A, KL-6, and HSP-47 in the model control group were also significantly higher than those in the other groups (p < 0.001).

[0211] Serum detection of interleukin-6 (IL-6)

[0212] Model control group: Compared with the blank control group, it was significantly increased (p < 0.001); compared with the IN10018 group, it was significantly increased (p < 0.001). There was no significant difference between the IN10018 group and the blank control group. See Figure 1.

[0213] Serum detection of human surfactant protein A (SP-A)

[0214] Model control group: Compared with the blank control group, it was significantly increased (p < 0.001); compared with the IN10018 group, it was significantly increased (p < 0.001). There was no significant difference between the IN10018 group and the blank control group. See Figure 2.

[0215] Serum detection of salivary glycoprotein antigen (KL-6)

[0216] Model control group: Compared with the blank control group, it was significantly increased (p<0.001); compared with the IN10018 group, it was significantly increased (p<0.001). There was no significant difference between the IN10018 group and the blank control group. See Figure 3.

[0217] Detection of interleukin-6 (IL-6) in bronchoalveolar lavage fluid

[0218] Model control group: Compared with the blank control group, it was significantly increased (p<0.001); compared with the IN10018 group, it was significantly increased (p<0.001). There was no significant difference between the IN10018 group and the blank control group. See Figure 4.

[0219] Detection of human surfactant protein A (SP-A) in bronchoalveolar lavage fluid

[0220] Model control group: Compared with the blank control group, it was significantly increased (p < 0.001); compared with the IN10018 group, it was significantly increased (p < 0.001). There was no significant difference between the IN10018 group and the blank control group. See Figure 5.

[0221] Detection of salivary glycan antigen (KL-6) in bronchoalveolar lavage fluid

[0222] Model control group: Compared with the blank control group, it was significantly increased (p < 0.001); compared with the IN10018 group, it was significantly increased (p < 0.001). There was no significant difference between the IN10018 group and the blank control group. See Figure 6.

[0223] Detection of heat shock protein (HSP-47) in bronchoalveolar lavage fluid

[0224] Model control group: Compared with the blank control group, the level was significantly increased (p < 0.001); compared with the IN10018 group, the level was significantly increased (p < 0.001). There was no significant difference between the IN10018 group and the blank control group. See Figure 7.

[0225] Detection of tumor necrosis factor-α (TNF-α) in bronchoalveolar lavage fluid

[0226] Model control group: Compared with the blank control group, the level was significantly increased (p < 0.001); compared with the IN10018 group, the level was significantly increased (p < 0.001). There was no significant difference between the IN10018 group and the blank control group. See Figure 8.

[0227] White blood cell (WBC) detection in bronchoalveolar lavage fluid

[0228] Model control group: Compared with the blank control group, it was significantly increased (p < 0.001); compared with the IN10018 group, it was significantly increased (p < 0.001). There was no significant difference between the IN10018 group and the blank control group. See Figure 9.

[0229] Pathological examination

[0230] The submitted samples included lung tissue, which was fixed in 10% formaldehyde. After good fixation, the samples were trimmed, dehydrated, embedded, sectioned, stained, and mounted in strict accordance with the SOP procedure for pathological laboratory testing of Beijing Yaoxuan Technology Co., Ltd. Finally, the samples that passed the microscopic examination were examined.

[0231] Browse and observe the slides under a microscope, examining the tissue sections in detail at different magnifications. Describe the basic pathological changes in the slides in text, and reflect the differences between the slides. Image typical lesion sites and mark them with arrows in a Word document.

[0232] The specific groupings are shown in Table 8:

[0233] Table 8: Animal Grouping Table

[0234] Inspection results

[0235] We graded the pathological condition of lung tissue, and the grading criteria are shown in Table 9.

[0236] Table 9: Pathological grading criteria for the efficacy study of IN10018 against DS-8201-induced interstitial pneumonia in mice.

[0237] Under HE staining and microscopic observation, the following can be observed:

[0238] Blank control group: After excluding the influence of the background, no obvious abnormalities were found in the lung tissue of E76, E77 and E78 mice.

[0239] Model control group: E82: large area of ​​consolidation in the lungs, containing multifocal lymphocyte infiltration, with focal foam cell infiltration in some areas, and inflammatory exudate in the bronchi; E83: focal infiltration of local inflammatory cells, inflammatory exudate in the alveoli, and focal foam cell infiltration in some areas; E84: focal infiltration of local inflammatory cells, and inflammatory exudate in the small bronchioles.

[0240] IN10018 group: E85 and E86 showed focal infiltration of local inflammatory cells; E87 showed basically normal lung tissue.

[0241] The pathological grading of each mouse is as follows:

[0242] Table 10: Pathological grading results of the efficacy study of IN10018 against ADC-induced interstitial pneumonia in mice.

[0243] Under the conditions of this experiment, compared with the blank control group, the model control group showed obvious pathological changes of lung inflammation, including multifocal lymphocytic infiltration, focal foam cell infiltration, and inflammatory exudate in the bronchi. Compared with the model control group, the inflammatory lesions in the lung tissue of the animals in the IN10018 group were significantly improved and protected, and the improvement was significant, indicating that IN10018 has a good therapeutic effect on interstitial pneumonia caused by DS-8201. See Figures 10-12 for details.

[0244] Example 2: The therapeutic effect of IN10018 combined with betamethasone on interstitial pneumonia induced by trastuzumab (Enhertu, DS-8201) in mice.

[0245] Unless otherwise specified, refer to Example 1.

[0246] The supplier of compound betamethasone injection is Organon Group, batch number / product number 0001650623. The solvent is physiological saline. The storage conditions are 4℃ and sealed. The specification is 1mL: betamethasone dipropionate (calculated as betamethasone) 5mg and betamethasone sodium phosphate (calculated as betamethasone) 2mg.

[0247] Animals were divided into a blank control group and a model group based on their weight on the day of the experiment. The blank control group consisted of 6 animals, and the model group consisted of 18 animals. Animals in the model group received intravenous injections of Enhertu 40 mg / kg (0.1 mL / 10 g) twice a week, on Tuesdays and Fridays. The animals were closely monitored after injection, and the injections continued for 6 weeks. Animals in the blank control group received an equal volume of saline via the tail vein. Two weeks after modeling, the animals in the model group were further divided into a model control group, an investigational drug group, and a positive control group based on IL-6, SP-A, body weight, and lung function indicators. Intervention (QD, 5 weeks) then began. Grouping information is shown in Table 11.

[0248] Table 11: Note: 1. N: Number of mice in each group; 2. Except for the blank control, all other groups received intravenous (IV) trastuzumab (Enhertu) 40 mg / kg, 0.1 mL / 10 g, twice a week, on Tuesdays and Fridays respectively. 3. Mice were given Enhertu starting from day 0, and after 2 weeks, they were randomly divided into Enhertu + saline group, Enhertu + Betamethasone group, and Enhertu + INX0011 + Betamethasone group, and were given the drug continuously for 5 weeks.

[0249] Experimental results:

[0250] The changes in the animal's body weight are shown in Figure 13.

[0251] Lung function test:

[0252] Lung function was assessed on day 0 (D(0)), day 14 (D(14)), day 28 (D(28)), day 42 (D(42)), and day 49 (D(49)). At D(14), D(28), D(42), and D(49), the lung function of the model animals was significantly weakened, inferior to that of the blank control group (p < 0.05). At D(28), D(42), and D(49), both the test drug group and the positive control group showed significant improvement (p < 0.05, p < 0.01, p < 0.001). See Tables 12 to 14 and Figures 14 to 16 for details.

[0253] Table 12: Inspiratory Time (msec) Note: * indicates p < 0.05 compared to the model control; ** indicates p < 0.01 compared to the model control; *** indicates p < 0.001 compared to the model control.

[0254] Table 13: Minute ventilation (mL) Note: * indicates p < 0.05 compared to the model control; ** indicates p < 0.01 compared to the model control; *** indicates p < 0.001 compared to the model control.

[0255] Table 14: Respiratory Rate (bpm) Note: * indicates p < 0.05 compared to the model control; ** indicates p < 0.01 compared to the model control; *** indicates p < 0.001 compared to the model control.

[0256] Biochemical detection of serum and bronchoalveolar lavage fluid

[0257] At the end of the experiment, blood was collected from each group of animals to separate serum, and IL-6, SP-A, KL-6, and HSP-47 levels were measured. All indicators in the model control group were significantly higher than those in the other groups (p < 0.001), while there were no significant differences among the other groups. Three mice from each group underwent bronchoalveolar lavage to measure albumin, leukocytes, IL-6, TNF-α, SP-A, KL-6, and HSP-47. Except for albumin, which showed no significant difference among the groups, all other indicators in the model control group were significantly higher than those in the other groups (p < 0.001). (Figures 17 and 18)

[0258] Pathological examination

[0259] HER-2 humanized mouse lungs were used in this experiment. The lungs were divided into a blank control group, a model control group, a positive control group, and a compound betamethasone injection + IN10018 group. Three lungs were used in each group and HE staining was performed.

[0260] The specific groupings are shown in Table 15.

[0261] Table 15:

[0262] We classify the pathological condition of lung tissue as follows (see Table 16).

[0263] Table 16:

[0264] As can be seen under a microscope (see Figures 19-30 for details):

[0265] Blank control group: After excluding the influence of the background, no obvious abnormalities were found in the lung tissue of D004, D005 and D006 mice.

[0266] Model control group: D010 Lung tissue structure destruction, alveolar structure disorder; thickened alveolar septa, inflammatory cell infiltration, erythrocytes visible in the alveolar cavity, and congestion of alveolar wall vessels. D011 Local inflammatory changes in lung tissue, thickened alveolar septa, infiltration of inflammatory cells such as neutrophils and lymphocytes, and congestion of alveolar wall vessels. D012 Lung tissue structure destruction, widespread hemorrhage in the alveolar cavity, inflammatory cell infiltration, congestion of alveolar wall vessels, and thickened alveolar septa.

[0267] Positive drug group: D016 Lung tissue structural lesions, thickening of alveolar septa, inflammatory cell infiltration, and alveolar wall vascular congestion. D017 Lung tissue structural destruction, alveolar wall vascular congestion, thickening of alveolar septa, focal consolidation, fibrosis, and inflammatory cell infiltration. D018 Mild congestion of bronchioles and alveolar wall vessels in lung tissue, with no obvious necrosis or other abnormalities observed.

[0268] Treatment group: D022: Lung tissue showed clear and intact bronchiolar and alveolar structures, with slight congestion of alveolar wall vessels and no obvious histopathological changes. D023: Lung tissue showed clear and intact bronchiolar and alveolar structures, with slight congestion of alveolar wall vessels and a small amount of inflammatory cell infiltration, and no obvious histopathological changes. D024: Lung tissue showed clear and intact bronchiolar and alveolar structures, with slight congestion of alveolar wall vessels and no obvious histopathological changes.

[0269] The pathological grades of each mouse are shown in Table 17 below.

[0270] Table 17:

[0271] Under the conditions of this experiment, compared with the blank control group, the model control group showed obvious pathological changes of lung inflammation, including destruction of lung tissue structure, disordered alveolar structure, thickening of alveolar septa, infiltration of inflammatory cells such as neutrophils and lymphocytes, and congestion of alveolar wall vessels. Compared with the model control group, both the positive control group and the compound betamethasone injection + IN10018 group showed some improvement and protection in lung tissue inflammation, but the improvement effect in the positive control group was weaker, while the compound betamethasone injection combined with IN10018 showed good therapeutic effect on interstitial pneumonia caused by ADC.

[0272] In summary, the combined administration of compound betamethasone injection and IN10018 showed superior therapeutic effects on ADC-induced interstitial pneumonia compared to the positive control group.

[0273] Example 3: DXD and Enhertu induce p-FAK expression in RAW264.7 macrophage cells

[0274] Grouping information is shown in Tables 19 and 20.

[0275] Table 19: DXD Experiment Grouping Scheme

[0276] Table 20: Enhertu Experiment Grouping Scheme

[0277] Information on the compounds to be tested is shown in Table 21.

[0278] Table 21:

[0279] The main reagent information for the experiment is shown in Table 22.

[0280] Table 22:

[0281] This invention reveals that ADC drugs using DXD as a warhead are internalized by alveolar macrophages, leading to the release of DXD and subsequent macrophage activation. This activation is accompanied by activation of the FAK target. FAK activation induces alveolar macrophages to release more cytokines, resulting in an interstitial pneumonia phenotype. This may be the main reason why targeting FAK can treat ADC-induced interstitial pneumonia.

[0282] HCC827 cells (from Shanghai Cell Bank, catalog number: THu153) and RAW264.7 cells (from Wuhan Pronosei Life Sciences Co., Ltd., catalog number: CL-0190) were maintained and passaged. Cells were cultured in vitro in monolayers. HCC827 cells were cultured in 1640 medium with 10% FBS, and RAW264.7 cells were cultured in DMEM medium with 10% FBS. Cells were incubated at 37°C in a 5% CO2 incubator. HCC827 cells were routinely digested and passaged with trypsin two to three times per week. RAW264.7 cells were collected by gently pipetting them off the culture vessel. When the cells were in the exponential growth phase and adhered to the culture vessel to a confluence of 80%-90%, the cells were harvested and plated.

[0283] RAW264.7 cells were gently pipetted off and collected for counting. Based on the counting results, the cells were diluted with DMEM + 10% FBS to a concentration of 125,000 cells per mL. The cells were then seeded into six-well cell culture plates, with 2 mL of cell suspension per well (250,000 cells). After seeding, the cells were incubated at 37°C in a 5% CO2 incubator.

[0284] A cell co-culture system was established. Based on the RAW264.7 cell count, the cells were diluted with DMEM + 10% FBS to a concentration of 133,000 cells / mL. The cells were then seeded into the lower layer of a 12-well Transwell cell culture plate, with 1.5 mL of cell suspension (200,000 cells) per well. After seeding, the cells were incubated at 37°C in a 5% CO2 incubator. Four hours after RAW264.7 cells adhered, their condition was observed under a microscope. HCC827 cells were digested with trypsin, harvested, and counted. Based on the count, the cells were diluted with 1640 + 10% FBS to a concentration of 400,000 cells / mL. The cells were then seeded into the upper layer of a 12-well Transwell cell culture plate, with 0.5 mL of cell suspension (200,000 cells) per well. After seeding, the cells were incubated at 37°C in a 5% CO2 incubator.

[0285] Eighteen hours after plating, the test compound was added to different wells. The test compound was prepared and dispensed uniformly beforehand, dissolved in DMSO or DPBS, and dispensed in 50 μL / vial. The vials were stored at -20℃ in the dark. One of the vials was taken out for this experiment for drug addition and detection.

[0286] Cells were lysed using RIPA buffer containing 1% protease / phosphatase inhibitors, and proteins were quantified. Proteins in the lysate were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and then transferred to a nitrocellulose membrane. The membrane was blocked with 5% skim milk powder and incubated with antibody, followed by washing with Tris buffered saline (TBS-T) containing 0.1% Tween-20. Primary antibody was incubated overnight at 4°C, and secondary antibody was incubated for 1 hour at room temperature. The nitrocellulose membrane was placed on an imager, ECL working solution was added evenly, and exposure was initiated.

[0287] This study investigated the expression of p-FAK in RAW264.7 macrophages induced by DXD and Enhertu in RAW264.7 cells.

[0288] Seventy-two hours after drug administration, the results of Western blot analysis are shown in Figures 31 and 32. Compared with the control group, both DXD and Enhertu alone significantly upregulated p-FAK expression, indicating that the payload can induce p-FAK expression in macrophages.

[0289] All references cited in this disclosure are incorporated herein by reference in their entirety, as if each reference were listed separately. It should be understood that, upon reading this disclosure, those skilled in the art can make various alterations or modifications to this disclosure, and these equivalent forms also fall within the scope defined by the appended claims.

[0290] All references mentioned in this invention are incorporated herein by reference in their entirety, as if each reference were listed separately. It should be understood that, after reading this disclosure, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. Use of a FAK inhibitor in the manufacture of a medicament for the treatment or prevention of interstitial pneumonitis.

2. Use of a FAK inhibitor and another therapeutic agent or agents in the manufacture of a medicament for the treatment or prevention of interstitial pneumonitis.

3. A method of treating or preventing interstitial pneumonitis, the method comprising administering to a subject in need thereof a therapeutically effective amount of a FAK inhibitor.

4. The use of claim 1 or 2 or the method of claim 3, wherein the FAK inhibitor is IN10018, Defactinib, AMP945, APG-2449, Conteltinib, a deuterated compound of IN10018, a deuterated compound of Defactinib, a deuterated compound of AMP945, a deuterated compound of APG-2449, a deuterated compound of Conteltinib, or a pharmaceutically acceptable salt thereof. wherein the structure of the IN10018 is shown as formula (I):

5. The use or method of claim 4, wherein the FAK inhibitor is IN10018, or a pharmaceutically acceptable salt thereof.

6. The use or method of claim 5, wherein the unit dose of IN10018 is about 25 mg to about 200 mg, preferably wherein the unit dose of IN10018 is 25-50 mg, 25-75 mg, 25-100 mg, 25-125 mg, 25-150 mg, 25-200 mg, 50-75 mg, 50-100 mg, 50-125 mg, 50-150 mg, 50-200 mg, 75-100 mg, 75-125 mg, 75-150 mg, 75-200 mg, 100-125 mg, 100-150 mg, 100-200 mg, 125-150 mg, 125-200 mg, or 150-200 mg, preferably wherein the unit dose of IN10018 is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, or 200 mg, more preferably wherein the unit dose of IN10018 is 25 mg or 50 mg.

7. The use or method of claim 5, wherein the dose of IN 10018 is about 0.1 to about 200 mg per day, preferably wherein the dose of IN 10018 is 0.1 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, or 200 mg per day, preferably wherein the dose of IN 10018 is 0.1-25 mg, 0.1-50 mg, 0.1-75 mg, 0.1-100 mg, 0.1-125 mg, 0.1-150 mg, 0.1-200 mg, 25-50 mg, 25-75 mg, 25-100 mg, 25-125 mg, 25-150 mg, 25-200 mg, 50-75 mg, 50-100 mg, 50-125 mg, 50-150 mg, 50-200 mg, 75-100 mg, 75-125 mg, 75-150 mg, 75-200 mg, 100-125 mg, 100-150 mg, 100-200 mg, 125-150 mg, 125-200 mg, or 150-200 mg per day, more preferably wherein the dose of IN 10018 is 50 mg, 75 mg, or 100 mg per day.

8. The use or method of any one of claims 5-7, wherein the IN 10018 is administered orally, intravenously, intramuscularly, or subcutaneously, preferably wherein the IN 10018 is administered orally.

9. The method of any one of claims 3-8, wherein the method further comprises administering to the subject in need thereof one or more additional therapeutic agents, optionally wherein the FAK inhibitor is administered simultaneously or sequentially with the one or more additional therapeutic agents.

10. A pharmaceutical composition for treating or preventing interstitial pneumonitis, comprising: a FAK inhibitor, and optionally one or more pharmaceutically acceptable carriers.

11. The pharmaceutical composition for treating or preventing interstitial pneumonitis of claim 10, wherein the FAK inhibitor is IN 10018, Defactinib, AMP945, APG-2449, Conteltinib, a deuterated compound of IN 10018, a deuterated compound of Defactinib, a deuterated compound of AMP945, a deuterated compound of APG-2449, a deuterated compound of Conteltinib, or a pharmaceutically acceptable salt thereof, preferably IN 10018 or a pharmaceutically acceptable salt thereof.

12. The pharmaceutical composition for treating or preventing interstitial pneumonitis of claim 10 or 11, further comprising one or more additional therapeutic agents.

13. A kit for treating or preventing interstitial pneumonitis, comprising: a FAK inhibitor, and optionally instructions for use.

14. The kit for the treatment or prevention of interstitial pneumonitis according to claim 13, wherein the FAK inhibitor is IN10018, Defactinib, AMP945, APG-2449, Conteltinib, a deuterated compound of IN10018, a deuterated compound of Defactinib, a deuterated compound of AMP945, a deuterated compound of APG-2449, a deuterated compound of Conteltinib, or a pharmaceutically acceptable salt thereof, preferably IN10018 or a pharmaceutically acceptable salt thereof.

15. The kit for the treatment or prevention of interstitial pneumonitis according to claim 13 or 14, further comprising one or more additional therapeutic agents.

16. A pharmaceutical combination of a FAK inhibitor and one or more additional therapeutic agents for the treatment or prevention of interstitial pneumonitis.

17. The pharmaceutical combination according to claim 16, wherein the FAK inhibitor is IN10018, Defactinib, AMP945, APG-2449, Conteltinib, a deuterated compound of IN10018, a deuterated compound of Defactinib, a deuterated compound of AMP945, a deuterated compound of APG-2449, a deuterated compound of Conteltinib, or a pharmaceutically acceptable salt thereof, preferably IN10018 or a pharmaceutically acceptable salt thereof.

18. The pharmaceutical combination, kit or pharmaceutical composition of any one of claims 11, 12, 14, 15 or 17, wherein the unit dose of IN10018 is from about 25 mg to about 200 mg, preferably wherein the unit dose of IN10018 is 25-50 mg, 25-75 mg, 25-100 mg, 25-125 mg, 25-150 mg, 25-200 mg, 50-75 mg, 50-100 mg, 50-125 mg, 50-150 mg, 50-200 mg, 75-100 mg, 75-125 mg, 75-150 mg, 75-200 mg, 100-125 mg, 100-150 mg, 100-200 mg, 125-150 mg, 125-200 mg or 150-200 mg, preferably wherein the unit dose of IN10018 is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg or 200 mg, more preferably wherein the unit dose of IN10018 is 25 mg or 50 mg.

19. The use, pharmaceutical combination, method, kit or pharmaceutical composition of any one of claims 2, 4-9, 12, 15-18, wherein the therapeutic agent is an antibody drug conjugate or a hormone.

20. The use, pharmaceutical combination, method, kit or pharmaceutical composition of any one of claims 1-19, wherein the interstitial pneumonitis is caused by an antibody drug conjugate.

21. The use, pharmaceutical combination, method, kit or pharmaceutical composition of claim 19 or 20, wherein the antibody drug conjugate is an antibody drug conjugate of HER2.

22. The use, pharmaceutical combination, method, kit or pharmaceutical composition of claim 21, wherein the antibody drug conjugate of HER2 is selected from ado-trastuzumab emtansine, deruxteumab (DS-8201), trastuzumab duocarmazine, MRG-002, Disitamab Vedotin, DB-1303, SHR-A1811 (trastuzumab rezetecan), JSKN-003, anvatabart opadotin, KL-A166, LCB-14, BL-M07D1 or DP-303c.

23. The use, pharmaceutical combination, method, kit or pharmaceutical composition of claim 22, wherein the antibody drug conjugate of HER2 is deruxteumab (DS-8201).

24. The use, pharmaceutical combination, method, kit or pharmaceutical composition of any one of claims 19-23, wherein the hormone is a glucocorticoid, preferably the hormone is methylprednisolone, dexamethasone, dexamethasone sodium phosphate, hydrocortisone, prednisone acetate, triamcinolone acetonide, betamethasone, budesonide, fluticasone, beclomethasone, mometasone furoate, fluticasone propionate, triamcinolone acetonide, clobetasol propionate, prednisolone, cortisone, dexamethasone acetate, fluocinolone, or halometasone. Preferably, the hormone is betamethasone.

25. The use, pharmaceutical combination, method, kit or pharmaceutical composition of any one of claims 19-24, wherein the dose of the hormone is 0.1 mg to 60 mg, preferably 1 mg to 10 mg.

26. The use, pharmaceutical combination, method, kit or pharmaceutical composition of any one of claims 19-25, wherein the hormone is administered intramuscularly at a dose of 1 mg to 10 mg once every 2-4 weeks.

27. The use, pharmaceutical combination, method, kit or pharmaceutical composition of claim 26, wherein the hormone is betamethasone administered intramuscularly at a dose of 1 mg to 10 mg once every 2-4 weeks.

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