JAK1 pathway inhibitors for the treatment of asthma

Abstract

This disclosure relates to JAK1 pathway inhibitors and their use in the treatment of asthma.

Description

[Technical Field]

[0001] This application claims the interests of U.S. Provisional Application No. 63 / 452,530, filed on 16 March 2023, which is incorporated herein by reference in its entirety.

[0002] This disclosure relates to JAK1 pathway inhibitors and their use in the treatment of asthma. [Background technology]

[0003] Asthma is a chronic inflammatory airway disease affecting all age groups and is characterized by airway hyperresponsiveness. Asthma is a condition in which the airways are narrowed and swollen. Symptoms associated with airway obstruction include chest tightness, wheezing, coughing, and difficulty breathing. Healthcare professionals may identify asthma as intermittent or persistent asthma. Intermittent asthma comes and goes, so individuals may feel normal between asthma episodes. Persistent asthma refers to individuals who are symptomatic most of the time. Asthma is one of the leading causes of global morbidity, with an estimated global prevalence of 262 million people in 2019, affecting 1-18% of the world's population. Estimated prevalence of asthma is highest among Black people (11.2%), followed by White people (7.6%), Hispanic people (6.8%), and non-Hispanic people (6.3%). A significant number of deaths are linked to asthma, with 455,000 deaths worldwide and approximately 4,000 deaths in the United States in 2019.

[0004] Many cases of asthma remain uncontrolled despite the use of medium to high doses of inhaled corticosteroids (ICS) in combination with a second controller medication, such as a long-acting beta-agonist (LABA). Some cases of asthma require systemic oral corticosteroids (OCS) as controller therapy for persistent symptom control. A systematic literature review found that the prevalence of uncontrolled asthma reported among patients with moderate to severe asthma, despite ICS-LABA therapy, varied widely between studies (12.9% - 100%) and, when limited to larger cohort studies, the prevalence of uncontrolled asthma ranged from 15.4% - 75.1%. Regardless of dose, long-term use of OCS therapy has been reported to increase the risk of comorbidities and complications and is associated with a substantial increase in healthcare resource utilization. Therefore, there is an unmet need for new therapies, particularly for patients with asthma that remains uncontrolled despite ICS-LABA treatment.

Brief Description of the Drawings

[0005] [Figure 1] Shows an overview of a Phase 2 randomized, double-blind, placebo-controlled dosing study of the efficacy and safety of Compound 1. [Figure 2] A - C show the effect of Compound 1 on IL-4, IL-5, and IL-13 cytokine levels in a whole blood assay. [Figure 3] A - C show the effect of Compound 1 on Th1 and Th17 / Th22 cytokine levels in a whole blood assay. [Figure 4] A - B show the effect of Compound 1 on CXCL10 chemokine and IL-6 cytokine levels in a whole blood assay. [Figure 5] A - B show the effect of Compound 1 on eosinophil and neutrophil activation marker CD69. [Figure 6] A - B show the effect of Compound 1 on the elasticity of the lung (H). [Figure 7]Figures A and B show the effect of compound 1 on airway resistance in the small airways and alveoli (G). [Overview of the project]

[0006] Provided herein is a method for treating asthma in a subject requiring treatment, comprising administering to the subject a therapeutically effective dose of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0007] Provided herein are JAK1 pathway inhibitors or pharmaceutically acceptable salts thereof for the treatment of asthma in subjects requiring treatment for asthma.

[0008] Provided herein is the use of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a drug for use in administering asthma treatment to a person requiring such treatment. In some embodiments, the asthma is noneosinophilic asthma and / or eosinophilic asthma.

[0009] In some embodiments, a method for treating asthma in a subject comprises administering to the subject a therapeutically effective dose of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof, wherein the asthma is noneosinophilic asthma.

[0010] In some embodiments, JAK1 pathway inhibitors or pharmaceutically acceptable salts thereof are more selective to JAK1 than to JAK2, JAK3, and Tyk2.

[0011] In some embodiments, JAK1 pathway inhibitors or pharmaceutically acceptable salts thereof are more selective to JAK1 than to JAK2.

[0012] In some embodiments, the JAK1 pathway inhibitor is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazole-1-yl)azetidine-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, the JAK1 pathway inhibitor is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipirazole-1-yl)azetidine-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamidophosphate.

[0014] In some embodiments, the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered at a daily dose of approximately 10 mg to approximately 80 mg on a free base basis.

[0015] In some embodiments, the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered orally.

[0016] In some embodiments, the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered orally via a tablet.

[0017] In some embodiments, the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 15 mg, about 45 mg, or about 75 mg based on free base.

[0018] In some embodiments, a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered in combination with further therapeutic agents.

[0019] In some embodiments, further therapeutic agents include Janus kinase inhibitors.

[0020] In some embodiments, the Janus kinase inhibitor is ruxolitinib or a pharmaceutically acceptable salt thereof.

[0021] In some embodiments, administration involves administering a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof together with at least one pharmaceutically acceptable carrier or excipient.

[0022] In some embodiments, the subjects have an increase in lung function of approximately 10% or more after administration, based on FEV1.

[0023] In some embodiments, the target is a reduction in the number of hospitalization events due to asthma, which is a reduction of approximately 30%, 60%, or 90% of the number of hospitalization events due to asthma.

[0024] In some embodiments, an inpatient treatment event includes hospitalization at an inpatient facility or medical facility for 24 hours or more.

[0025] In some embodiments, subjects have an increase in lung function of approximately 10% or more after administration, based on FVC.

[0026] In some embodiments, subjects exhibit an improvement in lung function of approximately 10% or more after administration, based on FeNO.

[0027] In some embodiments, the subjects have an increase in lung function of approximately 10% or more after administration, based on PEF test results. [Modes for carrying out the invention]

[0028] The present invention provides, in particular, a method for treating asthma in subjects requiring treatment, comprising administering to the subject a therapeutically effective dose of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a method for treating asthma in subjects, comprising administering to the subject a therapeutically effective dose of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, a method for treating asthma in a subject comprises administering to the subject a therapeutically effective dose of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the asthma is noneosinophilic asthma and / or eosinophilic asthma.

[0030] In some embodiments, a method for treating asthma in a subject comprises administering to the subject a therapeutically effective dose of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof, wherein the asthma is noneosinophilic asthma.

[0031] In some embodiments, a method for treating asthma in a subject comprises administering to the subject a therapeutically effective dose of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof, wherein the asthma is noneosinophilic asthma.

[0032] In some embodiments, a method for treating asthma in a subject comprises administering to the subject a therapeutically effective dose of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof, wherein the asthma is eosinophilic asthma and noneosinophilic asthma.

[0033] In some embodiments, JAK1 pathway inhibitors or pharmaceutically acceptable salts thereof are more selective to JAK1 than to JAK2, JAK3, and Tyk2.

[0034] In some embodiments, a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof inhibits JAK1 (50% inhibitory concentration = 9 nM), with approximately 52-fold superior selectivity for JAK1 compared to JAK2, and a selectivity range of approximately 45 to 1000-fold across all JAK family members (JAK2, JAK3, and TYK2).

[0035] In some embodiments, the JAK1 pathway inhibitor is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazole-1-yl)azetidine-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethylbenzamide (compound 1) or a pharmaceutically acceptable salt thereof.

[0036] In some embodiments, the JAK1 pathway inhibitor is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipirazole-1-yl)azetidine-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamidophosphate.

[0037] In some embodiments, the asthma is eosinophilic asthma.

[0038] In some embodiments, the asthma is noneosinophilic asthma.

[0039] In some embodiments, the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered at a daily dose of approximately 5 mg to approximately 95 mg on a free base basis.

[0040] In some embodiments, the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered at a daily dose of approximately 10 mg to approximately 80 mg on a free base basis.

[0041] In some embodiments, the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 15 mg, about 45 mg, or about 75 mg based on free base.

[0042] In some embodiments, the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered at a daily dose of approximately 45 mg or approximately 75 mg on a free base basis.

[0043] In some embodiments, the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered at a daily dose of approximately 45 mg on a free base basis.

[0044] In some embodiments, the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered at a daily dose of approximately 75 mg on a free base basis.

[0045] In some embodiments, the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered at a daily dose of approximately 30 mg on a free base basis.

[0046] In some embodiments, the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered at a daily dose of approximately 60 mg on a free base basis.

[0047] In some embodiments, a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered in combination with further therapeutic agents.

[0048] In some embodiments, further therapeutic agents include Janus kinase inhibitors.

[0049] In some embodiments, the Janus kinase inhibitor is ruxolitinib or a pharmaceutically acceptable salt thereof.

[0050] In some embodiments, administration involves administering a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof together with at least one pharmaceutically acceptable carrier or excipient.

[0051] Asthma is heterogeneous in both its response to treatment and the underlying pathophysiological pathways (endotypes) involved. Two endotypes are widely recognized: eosinophilic (type 2 - high or type 2) and non-eosinophilic (type 2 - low or non-type 2) asthma. In some embodiments, the asthma treated with the compounds and methods described is eosinophilic asthma. Eosinophilic endotype is characterized by peripheral blood eosinophilia and eosinophilic infiltration in the airways. Eosinophilic endotype is associated with the activation of cytokines derived from Th2 cells (e.g., IL-4, IL-5, and IL-13) that drive inflammatory processes. In some embodiments, the asthma treated with the compounds and methods described is non-eosinophilic asthma. In non-eosinophilic endotypes, eosinophilia is not typically observed, but these patients often exhibit airway neutrophilism and inflammation, which can be mediated via Th1 (IFN-γ, TNF, IL-1, and IL-6) and / or Th17 (IL-17A, IL-17E, IL-17F, and IL-22) responses.

[0052] Many asthma therapies, including most currently available biological agents (e.g., monoclonal antibodies against cytokines or cytokine receptors), target type 2 inflammation, which is effective against eosinophilic asthma rather than non-eosinophilic endotypes. Non-eosinophilic asthma tends to respond poorly to CS therapy, likely due to cytokine production by Th17 cells that are resistant to CS inhibition. Importantly, for both endotypes, cytokines and growth factors that signal via JAK-coupled receptors are involved in the disease mechanism. Therefore, targeting JAK may offer a novel approach to treating asthma of both endotypes.

[0053] In some embodiments, the effectiveness of the therapeutic methods disclosed herein can be established based on the rate of change from various baseline measurements using various indicators. For example, lung function may be measured to track effectiveness. Lung function may be measured based on forced expiratory volume in the first second (FEV1). FEV1, expressed as a percentage of predicted normality (PNV), can be calculated as follows: PNV FEV1% = (FEV1 measurement / FEV1PNV) × 100.

[0054] Lung function may be measured based on forced vital capacity (FVC). Lung function may be measured using vital capacity measurement. PNV is determined using the Global Lung Function Initiative equation. In some embodiments, a JAK1 inhibitor, e.g., Compound 1, and / or the use described herein results in an increase in lung function of about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95% in a subject, based on FEV1 and / or FVC.

[0055] In some embodiments, the efficacy of the compounds and / or methods described herein is determined by monitoring the subject using fractionated exhaled nitric oxide (FeNO). In some embodiments, a JAK1 inhibitor, e.g., Compound 1, and / or the method of use described herein results in an improvement of about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95% in standardized single-breath FeNO test results in the subject.

[0056] Typically, since vital capacity measurements can affect nitric oxide measurements, the FeNO test should be completed before vital capacity measurements. Typically, the post-baseline FeNO test should be performed within ±1.5 hours of the time the FeNO test was performed at D1 / BL. If a participant has had a respiratory infection within two weeks prior to the FeNO test, the FeNO test should not be performed until more than two weeks after the infection. Participants should be instructed not to eat or drink for one hour before the FeNO test.

[0057] In some embodiments, the efficacy of the compounds and / or methods described herein is determined by monitoring the subject using peak expiratory flow evaluation (PEF). This test can be performed by the subject at home. In some embodiments, a JAK1 inhibitor, e.g., Compound 1, and / or the method of use described herein results in an improvement of about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95% in the PEF test results in the subject.

[0058] In some embodiments, the efficacy of the compounds and / or methods described herein is determined by monitoring several hospitalization events. In some embodiments, a JAK1 inhibitor, e.g., Compound 1, and / or the method of use described herein results in a reduction of approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% of hospitalization events in the subject. In some embodiments, the efficacy of the compounds and / or methods described herein is determined by monitoring several hospitalization events. In some embodiments, a JAK1 inhibitor, e.g., Compound 1, and / or the method of use described herein results in a reduction of approximately 30%, 60%, or 90% of hospitalization events in the subject. In some embodiments, a JAK1 inhibitor, e.g., Compound 1, and / or the method of use described herein may result in a reduction of asthma-related hospitalization events (defined as hospitalization to an inpatient facility and / or evaluation and treatment at a medical facility for 24 hours or more).

[0059] Typically, electronic handheld spirometers (peak flow meters) are distributed to subjects during the acclimatization period. Typically, subjects undergo PEF testing in the morning upon waking (and before taking their morning asthma controller) and in the evening (and before taking their evening asthma controller, if applicable). Subjects should perform three consecutive peak flow operations in the same position for all tests, either while sitting or standing. The highest of the three values ​​is recorded in the eDiary. If possible, PEF testing should be performed at least 6 hours after the last administration of a short-acting beta-agonist or SABA rescue medication.

[0060] In some embodiments, the efficacy of the compounds and / or methods described herein is determined by monitoring patient-reported outcomes (PROs). This testing may be performed at home or in a clinic. In some embodiments, a JAK1 inhibitor, e.g., Compound 1, and / or the method of use described herein results in an improvement of about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95% in PRO test results in subjects.

[0061] PRO may include an Asthma Symptom Diary (ASD). The ASD is a standardized, validated tool consisting of 10 items: 5 in the morning and 5 in the evening. The morning items assess the severity of nocturnal symptoms related to wheezing, shortness of breath, cough, chest tightness, and frequency of nighttime awakenings. The evening items assess the severity of symptoms related to wheezing, shortness of breath, cough, chest tightness, and activity limitations after waking up. Each item can be scored using a 5-point categorical response scale ranging from 0 (no symptoms, no nighttime awakenings, or no activity limitations) to 4 (very severe symptoms, insomnia, or extreme activity limitations). The daily ASD score is the average response to all 10 questions and is calculated using data from the evening diary assessment and the subsequent morning diary assessment. If at least four of the 7-day ASD scores are available, the 7-day mean asthma symptom score is calculated without substitution.

[0062] PRO may include an Asthma Control Questionnaire-6 (ACQ-6). The ACQ-6 may include a standardized, validated questionnaire used to collect data on the adequacy of asthma control after treatment or changes in asthma control. The ACQ-6 may consist of six items that assess asthma symptoms (5 items) and rescue use of bronchodilators (BDs) (1 item) using a recall period of the past week. The asthma symptoms assessed are nighttime awakenings, symptoms upon waking, activity limitations, shortness of breath, and wheezing. For each of the six items, the questionnaire uses a 7-point categorical response scale ranging from 0 (e.g., no impairment) to 6 (e.g., maximum impairment). The wording of the responses associated with each number differs based on the question asked. The mean ACQ-6 score is the average response across all six items. In some embodiments, the ACQ-5 score is also calculated by omitting the ACQ-6 BD use question from the scoring algorithm.

[0063] PRO may include a standardized Quality of Life Questionnaire for Asthma (AQLQ(S)). The AQLQ(S) may include a standardized, validated tool used to collect data on functional problems that are troublesome for most adults with asthma. The AQLQ(S) consists of 32 items grouped into four domains: symptoms, activity limitations, emotional functioning, and environmental stimuli, and uses a recall period of the past two weeks. For each of the 32 items, there is an 8-point categorical response scale ranging from 7 (no impairment) to 1 (severe impairment). The overall score is the average response for all 32 questions, and the individual domain score is the average response for all items within that domain.

[0064] PRO may include the EuroQol Five-Dimensional Five-Level Scale (EQ-5D-5L). EQ-5D-5L may include a standardized tool for use as a measure of health outcomes. EQ-5D-5L provides data for use in economic models and analyses, including developing health utility or quality-adjusted life years. EQ-5D-5L consists of two sections: the EQ-5D Descriptive System and the EQ VAS, which asks participants about their health status on a given day. The Descriptive System includes five dimensions: mobility, self-care, usual activity, pain / discomfort, and anxiety / depression. Each dimension has five levels: no problem, minor problem, moderate problem, severe problem, and extreme problem. The EQ VAS records participants' self-reported health status on a vertical VAS (0-100), with anchors labeled "best health condition imaginable" and "worst health condition imaginable."

[0065] PRO may include the Work Productivity and Activity Impairment Questionnaire: Asthma (WPAI: Asthma). WPAI: Asthma is a standardized, validated tool that provides data on participants' work impairments due to asthma, based on self-reported productivity losses. WPAI: Asthma consists of six questions; the first is used to determine if the completer is currently employed, and the remaining five questions are used to assess the impact of asthma on work over the past seven days.

[0066] PRO may include the Patient's Overall Impression of Severity (PGI-S). The PGI-S provides data on the severity of asthma symptoms from the participant's perspective. The PGI-S is a single-item questionnaire for assessing disease severity. Participants rate the asthma symptoms they experienced at each study visit using a 5-point scale (none, mild, moderate, severe, very severe).

[0067] PRO may include the overall clinician and patient perception of change (CGI-C and PGI-C). The CGI-C and PGI-C tools provide data on the overall response to treatment from the perspective of the investigator and the participant, respectively. CGI-C (investigator-completed) and PGI-C (participant-completed) are single-item questionnaires regarding the degree of change in the participant's overall asthma status compared to the start of treatment. Both use a 7-point categorical response scale ranging from 1 (greatly improved) to 7 (greatly worsened).

[0068] PRO may include a nasal sinusitis outcome test (SNOT-22). Chronic rhinosinusitis is a common comorbidity in patients with severe asthma who may benefit from JAK inhibition. Therefore, the SNOT-22, a standardized and validated tool, is completed to collect data on the impact of chronic rhinosinusitis on the quality of life of participants and to measure outcomes after treatment with the compounds disclosed herein. The SNOT-22 consists of 22 items (each listed as a specific symptom) and uses a recall period of the past two weeks. For each of the 22 items, in addition to a 6-point categorical response scale from 0 (no problem) to 5 (very bad problem), there is an additional column where participants can mark up to five symptoms they consider to be the “most important items.” The total score is the sum of all items (ranging from 0 to 110), with higher scores indicating worse outcomes.

[0069] The methods described herein utilize JAK1 pathway inhibitors, particularly JAK1 selective inhibitors. JAK1 selective inhibitors are compounds that preferentially inhibit JAK1 activity over other Janus kinases. JAK1 plays a central role in several cytokine and growth factor signaling pathways that, in dysregulation, can lead to or contribute to disease states. In other autoimmune diseases and cancers, elevated systemic levels of inflammatory cytokines that activate JAK1 may also contribute to the disease and / or associated symptoms. Therefore, patients with autoimmune diseases such as asthma may benefit from JAK1 inhibition. Selective JAK1 inhibitors may be beneficial while avoiding unwanted and potentially undesirable effects caused by inhibiting other JAK kinases.

[0070] In some embodiments, a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is selective for JAK1 over JAK2, JAK3, and TYK2 (i.e., a JAK1 selective inhibitor). For example, the compounds described herein, or pharmaceutically acceptable salts thereof, selectively inhibit JAK1 over one or more of JAK2, JAK3, and TYK2. In some embodiments, the compounds preferentially inhibit JAK1 over JAK2 (e.g., JAK2 / JAK1 IC2). 50 (Having a ratio > 1). In some embodiments, the compound or salt is about 10 times more selective to JAK1 than to JAK2. In some embodiments, the compound or salt IC2 at 1 mM ATP. 50 When calculated by measuring, JAK2 is approximately 3 times, 5 times, 10 times, 15 times, or 20 times more selective than JAK1 (see, for example, Example A).

[0071] In some embodiments, the JAK1 pathway inhibitor is a compound from Table 1 or a pharmaceutically acceptable salt thereof. The compounds in Table 1 are selective JAK1 inhibitors (more selective than JAK2, JAK3, and TYK2). IC obtained by the method of Example A with 1 mM ATP 50 The values ​​are shown in Table 1.

[0072] The compounds in Table 1 are, for example, incorporated herein by reference in their entirety by U.S. Patent Publication No. 2011 / 0224190 filed on 9 March 2011, U.S. Patent Publication No. 2014 / 0343030 filed on 16 May 2014, U.S. Patent Publication No. 2014 / 0121198 filed on 31 October 2013, U.S. Patent Publication No. 2010 / 0298334 filed on 21 May 2010, and U.S. Patent Publication No. 2011 / 0059951 filed on 31 August 2010. The compounds are selected from U.S. Patent Publication No. 2012 / 0149681, filed November 18, 2011; U.S. Patent Publication No. 2012 / 0149682, filed November 18, 2011; U.S. Patent Publication No. 2013 / 0018034, filed June 19, 2012; U.S. Patent Publication No. 2013 / 0045963, filed August 17, 2012; and U.S. Patent Publication No. 2014 / 0005166, filed May 17, 2013; or pharmaceutically acceptable salts thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8]

[0073] In some embodiments, the JAK1 pathway inhibitor is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazole-1-yl)azetidine-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethylbenzamide (compound 1) or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK1 pathway inhibitor is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazole-1-yl)azetidine-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethylbenzamide phosphate. Compound 1 and its salts can be prepared, for example, by the procedure described in US9,382,231, filed May 16, 2014 (see, for example, Example 7), which is incorporated herein by reference in its entirety.

[0074] In some embodiments, the JAK1 pathway inhibitor is U.S. Patent Publication No. 2011 / 0224190 filed on March 9, 2011, U.S. Patent Publication No. 2014 / 0343030 filed on May 16, 2014, U.S. Patent Publication No. 2014 / 0121198 filed on October 31, 2013, U.S. Patent Publication No. 2010 / 0298334 filed on May 21, 2010, U.S. Patent Publication No. 2011 / 0059951 filed on August 31, 2010, 2011 A compound selected from U.S. Patent Publication No. 2012 / 0149681 filed November 18, 2011, U.S. Patent Publication No. 2012 / 0149682 filed November 18, 2011, U.S. Patent Publication No. 2013 / 0018034 filed June 19, 2012, U.S. Patent Publication No. 2013 / 0045963 filed August 17, 2012, and U.S. Patent Publication No. 2014 / 0005166 filed May 17, 2013, or a pharmaceutically acceptable salt thereof.

[0075] In some embodiments, the JAK1 pathway inhibitor is a compound of formula I. [ka] or a pharmaceutically acceptable salt thereof, in the formula, X is either N or CH. L is either C(=O) or C(=O)NH, A is R, each of which is selected independently by one or two factors. 1 The group is optionally substituted with phenyl, pyridinyl, or pyrimidinyl, Each R 1 These are independently fluoromethyl or trifluoromethyl.

[0076] In some embodiments, the compound of formula I is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidine-4-yl}-3[4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]azetidine-3-yl}acetonitrile, or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments, the compound of formula I is 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]azetidine-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, the compound of formula I is [3-[4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-1-(1-{[2-(trifluoromethyl)pyrimidine-4-yl]carbonyl}piperidine-4-yl)azetidine-3-yl]acetonitrile, or a pharmaceutically acceptable salt thereof.

[0079] In some embodiments, the JAK1 pathway inhibitor is expressed as formula II [ka] or a pharmaceutically acceptable salt thereof, in the formula, R 2 C 1-6Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, or C 3-6 Cycloalkyl-C 1-3 Alkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 3-6 Cycloalkyl-C 1-3 Alkyl is each optionally substituted with one, two, or three substituents independently selected from fluoro, -CF3, and methyl, R 3 is H or methyl, R 4 is H, F, or Cl, R 5 is H or F, R 6 is H or F, R 7 is H or F, R 8 is H or methyl, R 9 is H or methyl, R 10 is H or methyl, R 11 is H or methyl.

[0080] In some embodiments, the JAK1 pathway inhibitor is a compound of formula III

Chemical formula

[0081] In some embodiments, the compound of formula III is ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridine-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile, or a pharmaceutically acceptable salt thereof.

[0082] In some embodiments, the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 10 mg to about 80 mg based on free base. In some embodiments, the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 75 mg based on free base. In some embodiments, the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 45 mg based on free base. In some embodiments, the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 15 mg based on free base.

[0083] The term "approximately" means "about" (for example, approximately plus or minus 10% of the given value).

[0084] In some embodiments, a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered as one or more sustained-release dosage forms, each containing a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0085] In some embodiments, the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered orally.

[0086] The embodiments described herein are intended to be combined in any preferred combination, as if they were multiple dependent claims (for example, embodiments relating to selective JAK1 pathway inhibitors and their doses, embodiments relating to any salt form of the compounds disclosed herein, embodiments relating to individual types of cytokine-related diseases or disorders, and embodiments relating to compositions and / or administrations can be combined in any combination).

[0087] For the sake of brevity, not all possible combinations are listed individually in this specification.

[0088] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds containing asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically inert starting materials are known in the art, such as by the resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers, such as olefins and C=N double bonds, may also be present in the compounds described herein, and all such stable isomers are intended in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described, and these may be isolated as mixtures of isomers or as separate isomeric forms.

[0089] In some embodiments, the compound has an (R) configuration. In some embodiments, the compound has an (S) configuration.

[0090] The separation of racemic mixtures of compounds can be carried out by any of a number of methods known in the art. Exemplary methods include fractional crystallization using chiral splitting acids, which are optically active salt-forming organic acids. Suitable splitting agents for fractional crystallization are, for example, optically active acids such as D- and L-type tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids such as β-camphorsulfonic acid. Other suitable splitting agents for fractional crystallization include stereoisomerically pure forms of α-methylbenzylamine (e.g., S- and R-forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0091] The separation of racemic mixtures can also be carried out by elution using a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by those skilled in the art.

[0092] The compounds described herein also include tautomers. Tautomers arise from the exchange of a single bond with an adjacent double bond and simultaneous proton transfer. Tautomers include prototropic tautomers, which are protonated states of isomers having the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imoid acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions in the heterocyclic system, such as 1H- and 3H-imidazoles, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. Tautomers may be in equilibrium or may be sterically fixed into one form by appropriate substitution.

[0093] The compounds described herein may also include isotope-labeled compounds of this disclosure. An “isotope” or “radio-labeled” compound is a compound of this disclosure in which one or more atoms are replaced or substituted with atoms having an atomic mass or mass number different from those normally found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated into the compounds of this disclosure include: 2 H (also written as D for deuterium), 3 H (also written as T as tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, and 131 This includes, but is not limited to, formula (I), (II), or (III). For example, one or more hydrogen atoms in the compounds of this disclosure may be replaced by deuterium atoms (e.g., C of formula (I), (II), or (III)). 1-6 One or more hydrogen atoms in an alkyl group or in a compound of Table 1 may optionally be substituted with a deuterium atom, such as -CD3 which is substituted with -CH3. As used herein, the term “compound” includes all stereoisomers, geometric isomers, tautomers, and isotopes of the structure shown, unless the name indicates a specific stereoisomer. A compound herein identified by name or structure as a specific tautomer is intended to include other tautomers unless otherwise specified.

[0094] All compounds, and their pharmaceutically acceptable salts, can be found together with other substances such as water and solvents (e.g., hydrates and solvates), or they can be isolated.

[0095] In some embodiments, the compounds or salts thereof described herein are substantially isolated. "Substantially isolated" means that the compound is at least partially, or substantially, separated from the environment in which it was formed or detected. Partial isolation may include, for example, a composition in which the compounds described herein are concentrated. Substantial isolation may include a composition containing at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compounds or salts thereof described herein. Methods for isolating compounds and salts thereof are common in the art.

[0096] The term "pharmaceutically acceptable" is used herein to mean a compound, substance, composition, and / or dosage form that is suitable for use in contact with human and animal tissues within the bounds of appropriate medical judgment, and that provides a reasonable benefit-to-risk ratio without causing excessive toxicity, irritation, allergic reactions, or other problems or complications.

[0097] As used herein, the terms “ambient temperature,” “room temperature,” or “rt” are understood in the art and generally refer to a temperature, for example, the temperature of the room in which the reaction is carried out, for example, a reaction temperature close to a temperature of about 20°C to about 30°C.

[0098] The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, “pharmaceutically acceptable salt” refers to a derivative of a disclosed compound in which the parent compound has been modified by converting an existing acidic or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts of the present invention include, for example, conventional non-toxic salts of parent compounds formed from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acidic or base form of these compounds with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture thereof, and non-aqueous media such as ether, ethyl acetate, alcohol (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (ACN) are generally preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0099] As used herein, the terms “subject,” “individual,” or “patient” are interchangeable and refer to any animal, most preferably human, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates. In some embodiments, the “subject,” “individual,” or “patient” is the one requiring the treatment.

[0100] In some embodiments, the inhibitor is administered in a therapeutically effective dose. As used herein, the term “therapeutically effective dose” refers to the amount of an active compound or drug that elicits a desired biological or pharmacological response in a tissue, system, animal, individual, or human, as determined by a researcher, veterinarian, physician, or other clinician.

[0101] As used herein, the terms “to treat” or “to treat” mean one or more of the following: (1) inhibiting a disease, for example, inhibiting a disease, condition or disorder in an individual who is experiencing or exhibiting the pathology or overall symptoms of a disease, condition or disorder (i.e., halting the further progression of the pathology and / or overall symptoms); or (2) improving a disease, for example, improving a disease, condition or disorder in an individual who is experiencing or exhibiting the pathology or overall symptoms of a disease, condition or disorder, such as reducing the severity of the disease (i.e., improving the pathology and / or overall symptoms).

[0102] In some embodiments, JAK1 inhibitors can prevent asthma in individuals who may be predisposed to the disease. The term “prevent” means preventing the onset of the disease in patients who may be predisposed to the disease but have not yet experienced or displayed the pathology or symptoms of the disease.

[0103] Combination therapy The methods described herein may further include administering one or more additional therapeutic agents. These additional therapeutic agents may be administered to the patient simultaneously or sequentially. The additional therapeutic agents may be administered using a method different from that of compound 1 (e.g., topically).

[0104] In some embodiments, additional therapeutic agents are selected from other JAK inhibitors. These additional JAK inhibitors may include ATI-50002 (JAK1 / 3 selective), PF-06651600 (JAK3 selective), PF06700841 (JAK1 / TYK2 selective), upadacitinib, abrocitinib (JAK1 selective), celduratinib (JAK1 / SYK selective), and duklavacitinib (TYK2 selective).

[0105] In some embodiments, additional therapeutic agents are moderate to high doses of inhaled corticosteroids (ICS). ICS agents may include beclomethasone, budesonide, budesonide / formoterol combinations, fluticasone, fluticasone INH powder, fluticasone / salmeterol combinations, mometasone, and / or mometasone / formoterol combinations.

[0106] In some embodiments, additional therapeutic agents are long-acting bronchodilators (LABAs). LABAs may include salmeterol, formoterol, olodaterol, and / or theophylline. ICS and LABAs may be used in combination.

[0107] In some embodiments, additional therapeutic agents are systemic oral corticosteroids (OCS). OCS agents may include betamethasone, budesonide, deflazacort, dexamethasone, dexamethasone sodium phosphate, fludrocortisone acetate, hydrocortisone, methylprednisolone acetate, prednisolone, and / or prednisolone.

[0108] In some embodiments, additional therapeutic agents are short-acting beta-agonists (SABAs). Examples of SABAs include albuterol / salbutamol and / or revalbuterol.

[0109] In some embodiments, additional therapeutic agents include immunomodulators. Immunomodulators may include PDE4 inhibitors (e.g., apremilast (e.g., oral) or crisabolol (e.g., topical)). Immunomodulators may include anti-CD20 therapies (e.g., ofatumumab). Immunomodulators may include anti-CD19 therapies (e.g., tafacitamab). Immunomodulators may include anti-IL15 therapies (e.g., AMG714 monoclonal antibodies). Immunomodulators may include anti-IL36 therapies (e.g., imsidrimab and spesolimab). Immunomodulators may include anti-TNFα therapies (e.g., etanercept and infliximab). Immunomodulators may include anti-CD122 therapies.

[0110] In some embodiments, the immunomodulator is selected from apremilast, crisablol, afamelanotide, rituximab, ofatumumab, tafacitamab, minocycline, latanoprost, zinc, tofacitinib, AMG714 monoclonal antibody, imsidrimab, spesolimab cyclosporine, etanercept, infliximab, cyclophosphamide, cyclosporine, methotrexate, and sodium oxo-dihydro-acridinyl acetate (ODHAA).

[0111] In some embodiments, the additional therapeutic agent is a Janus kinase inhibitor. In some embodiments, the Janus kinase inhibitor is ruxolitinib or a pharmaceutically acceptable salt thereof.

[0112] In some embodiments, the additional therapeutic agent is an IL-6 antagonist or receptor antagonist. In some embodiments, the IL-6 receptor antagonist is tocilizumab.

[0113] Pharmaceutical preparations and dosage forms When used as a pharmaceutical, JAK1 pathway inhibitors or pharmaceutically acceptable salts thereof can be administered in the form of pharmaceutical compositions. These compositions can be prepared in forms well known in the pharmaceutical field and can be administered by various routes depending on whether topical or systemic treatment is desired, and depending on the area being treated. Administration may be topical (including percutaneous, epidermal, ophthalmic, and mucosal delivery, as well as intranasal, intravaginal, and rectal delivery), pulmonary (intratracheal or intranasal, for example, by inhalation or blowing of powder or aerosol, including by a nebulizer), oral, or parenteral. Parenteral administration may include intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion, or intracranial, for example, intrathecal or intraventricular administration. Parenteral administration may be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, foams, liquids, and powders. Conventional pharmaceutical carriers, aqueous bases, powder bases, or oily bases, thickeners, etc., may be essential or desirable.

[0114] Pharmaceutical compositions and formulations for this purpose may be administered orally. Oral administration may include the use of tablets. The composition may be administered orally in the form of a tablet with water.

[0115] In some embodiments, a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is used in the manufacture of the drug. The drug may be used to treat asthma in subjects requiring it. The drug may be used to treat eosinophilic asthma in subjects requiring it. The drug may be used to treat noneosinophilic asthma in subjects requiring it.

[0116] The present invention also comprises a pharmaceutical composition containing, as an active ingredient, a JAK1 pathway inhibitor as described herein or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the composition is suitable for topical administration. When preparing the composition, the active ingredient is typically mixed with an excipient, diluted by the excipient, or encapsulated in such a carrier in the form of, for example, a capsule, sachet, paper, or other container. If the excipient functions as a diluent, it may be a solid, semi-solid, or liquid material acting as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or in a liquid medium), for example, ointments, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaging powders containing up to 10% by weight of the active compound.

[0117] When preparing a formulation, the active compound may be ground to provide an appropriate particle size before being combined with other components. If the active compound is substantially insoluble, it may be ground to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size may be adjusted by grinding to provide a substantially uniform distribution in the formulation, for example, about 40 mesh.

[0118] JAK1 pathway inhibitors may be ground using known grinding procedures, such as wet grinding, to obtain particle sizes suitable for tablet formation and other formulation types. Micronized (nanoparticle) preparations of JAK1 selective inhibitors can be prepared by processes known in the art. See, for example, International Application WO2002 / 000196.

[0119] The composition can be formulated into unit dosage forms, each containing a set amount of the active ingredient in free or salt form. The term "unit dosage form" refers to a physically distinct unit suitable as a unit dose for human subjects and other mammals, each containing a predetermined amount of the active substance calculated to produce the desired therapeutic effect in relation to a suitable pharmaceutically acceptable excipient.

[0120] In the methods and uses of the present invention, similar dosages of the compounds described herein can be used.

[0121] Since active compounds can be effective across a wide range of doses, they are generally administered in pharmaceutically effective amounts. However, it should be understood that the actual amount of compound administered is usually determined by the physician, taking into account relevant circumstances including the symptoms being treated, the chosen route of administration, the compound actually administered, the individual patient's age, weight, and response, and the severity of the patient's symptoms.

[0122] To prepare solid compositions such as tablets, the main active ingredient is mixed with pharmaceutically acceptable excipients to form a solid pre-formulation composition containing a homogeneous mixture of the compounds of the present invention. When these pre-formulation compositions are referred to as homogeneous, the active ingredient is typically uniformly dispersed throughout the composition, thereby allowing the composition to be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. Furthermore, this solid pre-formulation composition can be divided into the above-described unit dosage forms, for example, containing about 0.1 to about 1000 mg of the active ingredient of the present invention.

[0123] The present invention provides a dosage form that offers the benefits of long-term action by coating or otherwise compounding tablets or pills. For example, a tablet or pill may contain internal and external dose components, the latter in the form of an envelope over the former. These two components can be separated by an enteric coating, which functions to resist disintegration in the stomach and allow its internal components to pass intact into the duodenum, or to delay the release of its internal components. A variety of substances, including numerous polymer acids, as well as mixtures of polymer acids with substances such as shellac, cetyl alcohol, and cellulose acetate, can be used as such enteric coatings or coatings.

[0124] Liquid forms in which the compounds and compositions of the present invention may be incorporated for oral or injectable administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0125] Compositions for inhalation or inhalation include liquids and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, compositions are administered via the mouth or nasal respiratory route for topical or systemic effects. Compositions may be sprayed using an inert gas. The sprayed solution may be inhaled directly from a spraying device, or the spraying device may be attached to a face mask, tent, or intermittent positive pressure (PPP) respiration device. Compositions in solution, suspension, or powder form may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0126] Topical formulations may contain one or more conventional carriers. In some embodiments, ointments may contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, etc. Carrier compositions for creams may be based on water combined with glycerol and one or more other components, for example, glycerin monostearate, PEG-glycerin monostearate, and cetyl stearyl alcohol. Gels may be formulated using isopropyl alcohol and water, preferably in combination with other components such as glycerol, hydroxyethylcellulose, etc.

[0127] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of administration (such as prevention or treatment), the patient's condition, and the method of administration. For therapeutic use, a composition may be administered to a patient already suffering from the disease in an amount sufficient to cure or at least partially prevent the symptoms and complications of the disease. The effective dose depends on the patient's judgment, based on the disease condition being treated, as well as factors such as the severity of the disease, the patient's age, weight, and general condition.

[0128] The compositions administered to patients may be in the form of the pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques or aseptically filtered. Aqueous solutions may be packaged for immediate use or lyophilized, and the lyophilized preparations may be combined with a sterile aqueous carrier before administration. The pH of the compound preparations will typically be 3 to 11, more preferably 5 to 9, and most preferably 7 to 8. It will be understood that the use of some of the aforementioned excipients, carriers, or stabilizers may result in the formation of pharmaceutical salts.

[0129] The therapeutic dose of the compounds of the present invention may vary, for example, depending on the specific therapeutic use, the method of administering the compound, the patient's health and symptoms, and the judgment of the prescribing physician. The ratio or concentration of the compounds described herein in a pharmaceutical composition may vary depending on many factors, including the dose, chemical properties (e.g., hydrophobicity), and route of administration. The dose may depend on variables such as the type and progression of the disease or disorder, the overall health status of the particular patient, the relative bioefficacy of the selected compound, the formulation of the excipients, and the route of administration. The effective dose can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0130] The compositions of the present invention may further include one or more additional pharmaceuticals, such as chemotherapeutic agents, steroids, anti-inflammatory compounds, or immunosuppressants, examples of which are provided herein.

[0131] kit The present invention also includes, for example, a pharmaceutical kit useful in the treatment and / or prevention of asthma, which includes one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound as described herein. As will be readily apparent to those skilled in the art, such a kit may further include, if desired, one or more conventional pharmaceutical kit components, such as containers containing one or more pharmaceutically acceptable carriers, additional containers, sprayers, etc. Instructions indicating the amount of components to be administered, guidelines for administration, and / or guidelines for mixing the components may also be included in the kit, either as inserts or labels. [Examples]

[0132] The present invention will be described in more detail by specific examples. The following examples are provided for illustrative purposes only and are not intended to limit the invention in any way. Those skilled in the art will readily recognize various non-essential parameters that can be changed or modified to produce essentially the same results. The compounds of the examples have been found to be JAK inhibitors by at least one assay described herein.

[0133] Example A: In vitro JAK kinase assay JAK1 pathway inhibitors that can be used to treat cytokine-related diseases or disorders will be tested for their inhibitory activity against JAK targets according to the following in vitro assay described in Park et al., Analytical Biochemistry 1999, 269, 94-104. The catalytic domains of human JAK1 (amino acids 837-1142), JAK2 (amino acids 828-1132), and JAK3 (amino acids 781-1124), which have an N-terminal His tag, were expressed in insect cells using baculovirus and purified. The catalytic activity of JAK1, JAK2, or JAK3 was assayed by measuring the phosphorylation of biotinylated peptides. Phosphorylated peptides were detected by homogeneous time-resolved fluorescence (HTRF). IC of the compounds... 50 The enzymes, ATP, and 500 nM peptides were measured for each kinase in a 40 microL reaction mixture containing 100 mM NaCl, 5 mM DTT, and 0.1 mg / mL (0.01%) BSA in Tris (pH 7.8) buffer. 50 For the measurement, the ATP concentration in the reactant was 1 mM. The reaction was carried out at room temperature for 1 hour, and then stopped with 20 μL of 45 mM EDTA, 300 nM SA-APC, and 6 nM Eu-Py20 in assay buffer (Perkin Elmer, Boston, MA). Binding to the europium-labeled antibody was allowed for 40 minutes, and the HTRF signal was measured on a Fusion plate reader (Perkin Elmer, Boston, MA). When the compounds listed in Table 1 were tested in this assay, the IC2011 compounds also found in Table 1 were observed. 50 It was shown that it has a value.

[0134] Example B: Proposal for Phase 2 study of compound 1 Research design Phase 2 studies may include double-blind, placebo-controlled, multicenter studies of compound 1 with stable background therapy using moderate to high-dose inhaled corticosteroids in combination with long-acting bronchodilators (ICS-LABAs). Figure 1 outlines a Phase 2 randomized, double-blind, placebo-controlled dose-finding study of the efficacy and safety of compound 1. The study enrolls participants (e.g., approximately 240) with a randomization ratio of 1:1:1:1. Participants may be stratified by eosinophil count at screening (≥150 cells / μL vs <150 cells / μL). In some embodiments, a JAK1 inhibitor, e.g., compound 1, and / or the use described herein is effective in treating subjects with eosinophil counts of 150 cells / μL or higher. In some embodiments, a JAK1 inhibitor, e.g., compound 1, and / or the use described herein is effective in treating subjects with eosinophil counts of less than 150 cells / μL. Participants may be stratified by prior treatment of asthma with biological agents (yes or no). Participants may be stratified to one of four treatment groups during a 24-week placebo-controlled (PC) period. ●ICS-LABA+Compound 1 75mg QD(n≒60) ●ICS-LABA+Compound 1 45mg QD(n≒60) ●ICS-LABA+Compound 1 15mg QD(n≒60) ●ICS-LABA + Placebo QD (n≒60).

[0135] In some embodiments, the study includes screening / acclimatization, up to 28 days for continuous treatment over 52 weeks (including PC and extension (EXT) periods), and 30 (+7) days for safety follow-up after the last dose of the investigational drug. Individuals are estimated to participate for approximately 14 months.

[0136] After completing a 24-week PC period, participants enter a 28-week EXT period. During the EXT period, participants initially randomized to Compound 1 (e.g., Compound 1) doses A, B, and C continue to take Compound 1 at the same dose. Participants initially randomized to placebo are equally assigned to take one of these three doses of Compound 1. Participants and investigators remain blinded to the Compound 1 dose and previous treatment assignments throughout the EXT period.

[0137] Participants will receive the investigational drug until the 52-week treatment period is completed, or until one of the criteria for discontinuing the study treatment is met. Participants will return for a safety follow-up visit approximately 30 days after their last dose of the investigational drug.

[0138] All participants may be required to be treated with a stable dose of moderate to high dose ICS-LABA during the study (i.e., during the screening / acclimatization, PC, and EXT periods, and until completion of safety follow-up visits [EOS]). In addition, participants may use rescue medication (SABA or SMART) to treat worsening asthma symptoms during the study.

[0139] Participants will undergo regular efficacy assessments throughout the study. Efficacy may be assessed by measuring vital capacity and evaluating asthma exacerbations. Fractionated exhaled nitric oxide may be used as a measure of airway inflammation. Participants may perform a PEF test twice daily at home. Questionnaires may be used to assess the impact of treatment on asthma symptoms and health-related quality of life.

[0140] Participants may complete the eDiary twice a day from the start of the adjustment period (visit 2) until the completion of the safety follow-up visit (EOS). The eDiary may provide data on the participant's asthma symptoms, nocturnal awakenings, and rescue medication use.

[0141] Serum samples may be collected for biomarker / translational analysis, and blood samples may be collected throughout the study for measurement of systemic concentrations of compound 1.

[0142] The primary efficacy analysis of the change from baseline in pre-BD FEV1 may be performed either after all participants have completed their 24-week visit or after discontinuation of the study. Treatment assignments will be open-blinded to the sponsor at the time of the primary analysis at 24 weeks, but double-blinding will be maintained throughout the study for both participants and site staff.

[0143] In some embodiments, the study endpoint includes the absolute change from baseline in pre-BD FEV1 (e.g., at week 24) with respect to the effect of compound 1 on lung function. The study endpoint includes the number of asthma exacerbations (defined as worsening of asthma) with respect to the effect of compound 1 on asthma exacerbations. In some embodiments, a JAK1 inhibitor, e.g., compound 1, and / or the use described herein may result in an improvement of about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95% in the study endpoint. In some embodiments, a JAK1 inhibitor, e.g., compound 1, and / or the use described herein may result in a reduction of about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95% in asthma exacerbations.

[0144] In some embodiments, the objective is to determine the safety of compound 1. In some embodiments, the study endpoints include the absolute and percentage changes from baseline in FeNO at each visit regarding the effect of compound 1 on airway inflammation. In some embodiments, the study endpoints include the changes from baseline in AQLQ(S) scores, EQ-5D-5L scores, and / or WPAI:Asthma scores at each visit regarding the effect of compound 1 on asthma-related and general health-related QoL. In some embodiments, the study endpoints include the changes from baseline in ACQ-6 scores, ACQ-5 scores, PGI-S scores, ASD scores, rescue medication (SABA or SMART) use, and / or home lung function regarding the effect of compound 1 on asthma symptoms and other asthma control metrics. In some embodiments, the study endpoints include CGI-C and / or PGI-C scores regarding the effect of compound 1 on the overall impression of asthma treatment. In some embodiments, the endpoint of the study includes a change from baseline in the SNOT-22 score regarding the effect of compound 1 on symptoms of chronic sinusitis / nasal polyposis in participants with a history of current / ongoing chronic sinusitis and / or bilateral nasal polyposis. In some embodiments, the endpoint of the study includes the expression of selected biomarkers in peripheral blood at baseline regarding the effect of compound 1 on exploring blood biomarkers in participants. In some embodiments, the endpoint of the study includes population PK parameters of compound 1, such as apparent clearance, apparent volume of distribution, apparent oral absorption rate constant, and absorption delay time, as well as the effect of compound 1 on determining systemic exposure, as deemed applicable. max,ss , C avg,ss , C tau,ss t max,ss , and t 1 / 2 This includes model-based post-hoc predictions of steady-state PK exposure, such as those mentioned above. In some embodiments, the study endpoints include population PK / PD analysis of selected clinical response endpoints regarding the effect of compound 1 to determine the PK / PD relationship of compound 1.

[0145] Participants may be eligible to participate in the study if they are male or female between 18 and 65 years of age. Participants may be eligible to participate in the study if they have physician-diagnosed asthma requiring treatment with moderate to high-dose ICS-LABA for at least 12 months prior to screening. Participants may be eligible to participate in this clinical trial if they have had recorded treatment with moderate-dose ICS (e.g., total daily dose of 250 μg or more of fluticasone dry powder equivalent) or high-dose ICS (e.g., total daily dose of 500 μg or more of fluticasone dry powder equivalent) and a stable daily dose of LABA for at least 3 months prior to screening. Participants may be eligible to participate in the study if they agree to use moderate to high-dose ICS-LABA at a stable dose from screening through the entire study period. Participants may be eligible to participate in the study if they have a pre-BD FEV1 < 80% predicted according to the median overread value at visit 2. Participants may be eligible to participate in the study if they have a recorded history of reversible post-BD with FEV1 ≥ 12% and FEV1 ≥ 200 mL within the 12 months prior to screening. Participants may be eligible to participate in the study if they have a recorded history of reversible post-BD with FEV1 ≥ 12% and FEV1 ≥ 200 mL according to the median overread value at visit 2. Participants may be eligible to participate in the study if they have had at least two recorded asthma exacerbations (e.g., requiring treatment for systemic CS, hospitalization, or emergency department visit) within the 12 months prior to screening, but not within the past 4 weeks prior to screening. Participants may be eligible to participate in the study if they have an ACQ-6 score of ≥ 1.5 at screening. Participants may be eligible to participate in the study if they consent to the use of contraception.

[0146] In some embodiments, a JAK1 inhibitor, e.g., Compound 1, and / or the method of use described herein may result in an improvement in the number of asthma exacerbations during the PC period.

[0147] In some embodiments, a JAK1 inhibitor, e.g., Compound 1, and / or the method of use described herein may result in a reduction of the use of systemic CS over consecutive days, such as 2, 3, 4, or 5 days. In some embodiments, a single depot-injectable dose of CS is considered equivalent to a 3-day systemic CS course.

[0148] In some embodiments, a JAK1 inhibitor, e.g., Compound 1, and / or the use described herein may result in a reduction of emergency department or emergency care visits due to asthma requiring the use of systemic CS (defined as evaluation and treatment of less than 24 hours in an emergency department or emergency care center). In some embodiments, a JAK1 inhibitor, e.g., Compound 1, and / or the use described herein may result in a reduction of hospitalization due to asthma (defined as admission to an inpatient facility and / or evaluation and treatment of 24 hours or more in a medical facility).

[0149] In some embodiments, criteria for participant exclusion from the study include experiencing one or more asthma exacerbations during screening / acclimatization. Participants may be excluded for being unable to use an acceptable inhaler technique or for being unable to perform PEF and vital capacity measurements. Participants may be excluded for being unable to receive or initiate a medical procedure or treatment used for asthma management within a specified period. Participants may be excluded for having undergone bronchial thermoplasty. Participants may be excluded for being a current smoker (e.g., tobacco, vaping products, e-cigarettes) or for having a smoking history of 10 pack years or more. Participants may be excluded for being pregnant (or considering pregnancy) or breastfeeding. Participants may be excluded for having one or more, two or more, or three or more specific current conditions or a history of other diseases, as follows: a) Clinically significant lung diseases other than asthma (e.g., active lung infections, chronic obstructive pulmonary disease, bronchiectasis, pulmonary fibrosis, cystic fibrosis, obesity-related poor ventilation syndrome, lung cancer, alpha-1 antitrypsin deficiency, primary ciliary dyskinesia, allergic bronchopulmonary aspergillosis / mycosis, Churg-Strauss syndrome, and hypereosinophilia syndrome), b) Thrombocytopenia, coagulation disorders, or platelet dysfunction, c) Venous and arterial thrombosis, deep vein thrombosis, pulmonary embolism, moderate to severe heart failure (NYHA class III or IV), cerebrovascular event, myocardial infarction, coronary artery stenting, or CABG surgery, d) Diagnosis of angina pectoris, peripheral artery disease, or other important cardiovascular diseases, including but not limited to uncontrolled arrhythmias such as atrial fibrillation, supraventricular tachycardia, ventricular tachycardia, and forms of carditis. e) Uncontrolled hypertension defined by a confirmed systolic blood pressure > 160 mm Hg or diastolic blood pressure > 100 mm Hg, f) Permanently bedridden or requiring assistance in a wheelchair, g) Organ transplant recipients requiring continued immunosuppression, h) Immunodeficiency (e.g., lymphoma, acquired immunodeficiency syndrome, Wiskott-Aldrich syndrome), i) Malignant tumor or a history of malignant tumor. Note: Participants must have cured non-metastatic basal cell or squamous cell carcinoma, superficial bladder cancer, prostatic carcinoma in situ, cervical carcinoma in situ, or other non-invasive malignancies or cancers that have been disease-free for less than one year after treatment with the intention of cure. j) Conditions that may interfere with drug absorption, including but not limited to short bowel syndrome. k) Chronic or recurrent infections including, but not limited to, chronic kidney infections, chronic chest infections (e.g., bronchiectasis), recurrent urinary tract infections (recurrent pyelonephritis or chronic non-remittive cystitis), fungal infections, previous prosthetic joint infections, or open, draining, or infected skin wounds or ulcers. l) Current or past history of disseminated herpes zoster or recurrent cutaneous herpes zoster (one or more episodes). m) Current or past history of disseminated herpes simplex. n) An active systemic infection or active infection that, based on the clinical assessment of the principal investigator, makes the participant an unsuitable candidate for the study. o) Any clinically significant medical condition (excluding asthma), or any other reason that the Principal Investigator determines would prevent the participant from participating in this study, make the participant an unsuitable candidate for administration of the investigational drug, or endanger the participant by participation in the study. p) Any clinically significant medical condition other than asthma that is not adequately controlled by appropriate treatment or that may interfere with the course, severity, or assessment of asthma, as determined by the principal investigator. q) Albinism.

[0150] Participants may be excluded for having an acute upper or lower respiratory tract infection requiring antibiotics or antiviral medication. Participants may be excluded for having a screening 12-lead ECG showing clinically significant abnormalities requiring treatment. Participants may be excluded for having undergone major trauma or major surgery (previous or planned). Participants may be excluded for having a history of clinically significant drug or alcohol abuse. Participants may be excluded for having a history of treatment failure with any topical or systemic JAK inhibitor for any inflammatory condition, including asthma. Participants may be excluded for having received treatment or investigational medication within a certain period of time in which they were dependent on treatment / medication. Participants may be excluded for having concurrent enrollment in another clinical study. Participants may be excluded for having abnormal laboratory values. Participants may be excluded for having evidence of infection with Mycobacterium tuberculosis (i.e., TB). Participants may be excluded for having active HIV or acquired immunodeficiency syndrome. Active HIV is defined as a positive result confirmed by an anti-HIV antibody test. Participants may be excluded if they have evidence of HBV or HCV infection or are at risk of reactivation. Participants may be excluded if they have a known hypersensitivity or severe reaction to compound 1 or its excipients and / or other products of the same class. Participants may be excluded if they have:

[0151] In some embodiments, the criteria for excluding participants from the study include having one or more, two or more, or three or more of the test values ​​in the screening defined in Table 2. [Table 2]

[0152] Example C: In vitro study of compound 1 In vitro studies were conducted to investigate the effects of compound 1 on eosinophil and neutrophil activation and cytokine production, which play a role in eosinophilic and non-eosinophilic (neutrophilic) asthma endotypes. Whole blood from healthy volunteers was stimulated with Dynabeads® human T activator CD3 / CD28 for a total of 19 hours at 37°C, either unstimulated, in the absence of compound 1 (0), or in the presence of compound 1 (0.3 μM, 1 μM). Whole blood was analyzed for the cell surface activation marker CD69, gated for eosinophils or neutrophils, by flow cytometry (n=12). Plasma was isolated from whole blood and analyzed for various cytokines using the MSD multiplatform (n=6). As shown in Figures 2–5, the presence of compound 1 resulted in a concentration-dependent reduction of cytokines, as well as a reduction in eosinophil and neutrophil activation. Compound 1 significantly inhibited eosinophil and neutrophil activation by approximately 40%. Compound 1 inhibits the production of Th2 / Th1 / Th17 cytokines and reduces the activation of eosinophils and neutrophils; therefore, Compound 1 provides an endotype-independent means for treating severe asthma.

[0153] Figures 2–4 show the effect of compound 1 on cytokine levels in whole blood assays. Plasma was isolated from whole blood samples and analyzed for Th2 cytokines (Figures 2A–C: IL-4, IL-5, and IL-13, respectively); Th1 / Th17 cytokines (Figures 3A–C: IFNγ, TNFα, and IL-22, respectively); and other inflammatory cytokines / chemokines (Figures 4A–B: CXCL10 and IL-6, respectively). Each symbol represents a different donor. Values ​​from individual donors are shown along with the mean values ​​for each treatment. Data were plotted in GraphPad PRISM v.9.3.1 and analyzed by paired t-tests (*: p<0.05, **: p<0.01, ***: p<0.001).

[0154] The donors are Donor 17■, Donor 19●, Donor 20▲, Donor 36▼, Donor 37◆, Donor 38 [ka] , Donor 39 [ka] , donor 40 [ka] , Donor 41□, Donor 42 [ka] This includes donors 43▽ and 50△. Figures 2A-C show that compound 1 reduced the levels of Th2 cytokines induced by T cell activation in a concentration-dependent manner. Figures 3A-C show that compound 1 reduced Th1 and Th17 / Th22 cytokines induced by T cell activation in a concentration-dependent manner. Figures 4A-B show that compound 1 reduced inflammatory cytokines / chemokines induced by T cell activation in a concentration-dependent manner.

[0155] Figures 5A-B. Effect of compound 1 on the eosinophil and neutrophil activation marker CD69 in whole blood assays. Each symbol represents a different donor. Values ​​from individual donors are shown along with the mean values ​​for each treatment. Data were plotted in GraphPad PRISM v.9.3.1 and analyzed by paired t-tests (*: p<0.05, **: p≦0.01, ***: p≦0.001). Figures 5A-B show that compound 1 significantly reduced the eosinophil and neutrophil activation marker CD69 by 40%. In summary, these data suggest that, unlike existing treatment options that exclusively target eosinophilic asthma, compound 1 is effective in treating both eosinophilic and non-eosinophilic (neutrophilic) asthma endotypes.

[0156] Example D: Effect of Compound 1 tested in a mouse model of severe asthma. In vivo studies were conducted to test compound 1 in two models of severe asthma. The first study included an experimental house dust mite (HDM)-induced severe asthma model that represented both Th2 / eosinophilic and Th1 / Th17 / neutrophilic asthma endotypes. The second study included an ovalbumin (OVA) model of acute asthma that more closely represented the Th2 / eosinophilic asthma endotype. For each model, 58 female BALB / c mice were randomly and prospectively assigned to six groups: one group of six, one group of twelve, and four groups of ten animals each (see Table 3). [Table 3]

[0157] HDM Model: On day 0, animals in groups 2–6 were sensitized by subcutaneous injection (SC) of 50 μg of HDM in an emulsion containing 150 μg of complete Freund's adjuvant (CFA) in 100 μL volume. On day 14, animals in groups 2–6 were challenged by intranasal infusion (IN) of 50 μg of HDM in 40 μL of saline. Group 1 served as the naive control group. On days 12, 13, 14, and 15, animals in groups 2–6 were administered according to Table 3. Due to administration errors, mice in group 3 did not survive. On day 16, animals underwent metacholine challenge using pulmonary dynamics measurements with a flexVent mechanical ventilator.

[0158] OVA Model: On days 0 and 7, animals in groups 2–6 were sensitized by intraperitoneal injection (IP) of 20 μg of OVA and 1.5 mg of Alum in 100 μL volume. On days 13, 14, and 15, animals in groups 2–6 were challenged by intranasal infusion (IN) of 20 μg of OVA in 50 μL of PBS. Group 1 served as the naive control group. On days 12, 13, 14, and 15, animals in groups 2–6 were administered according to Table 3. On day 16, animals underwent metacholine challenge using pulmonary dynamics measurements with a flexiVent mechanical ventilator.

[0159] In the HDM model, measurements of lung function after the metacholine challenge showed that diseased vehicle-treated animals had significantly higher lung contractility (Rrs), higher pressure for lung expansion (Ers), higher resistance in the small airways and alveoli (G), and higher lung elasticity (H) compared to naive animals. No significant differences were observed in airway measurements between groups, including positive controls, but many of these measurements showed a decrease, most notably in small airway and alveolar resistance (G) and lung elasticity (H) in response to compound 1, suggesting improvement in lung function with treatment with compound 1 in mouse models representing both Th2 / eosinophilic and Th1 / Th17 / neutrophilic asthma endotypes (Figures 6-7).

[0160] In the OVA model, measurements of lung function after the metacholine challenge showed that vehicle-treated animals with the disease had significantly higher lung contractility (Rrs), higher pressure to inflate the lungs (Ers), significantly higher resistance in the small airways and alveoli (G), and significantly higher lung elasticity (H) compared to naive animals. Compound 1 reversed the increase in resistance in the small airways and alveoli (G) and lung elasticity (H), suggesting improvement in lung function with treatment with compound 1 (Figures 6-7). Significant reductions in these parameters were observed at a dose of 10 mg / kg. These data suggest that compound 1 provides improvement in lung function in a mouse model representing Th2 / eosinophilic asthma.

[0161] Figures 6-7 show the effect of compound 1 on lung function. Lung elasticity (H) shown in Figures 6A-B and airway resistance in the small airways and alveoli (G) shown in Figures 7A-B were measured using a flexiVent mechanical ventilator after a challenge with 25 mg / mL of metacholine. Group numbers represent the following treatments: 1) naive, 2) diseased, vehicle-treated, 3) diseased, compound 1 (1 mg / kg), 4) diseased, compound 1 (10 mg / kg), 5) diseased, compound 1 (30 mg / kg), and 6) diseased, positive control. Data are presented as mean ± SEM (n=6-12 per group). Statistical significance between groups was determined by one-way ANOVA with Dunnett's multiple comparison study, which was used to compare all groups to the vehicle control group. (*: p<0.05, **: p≦0.01).

[0162] Data from the OVA model of acute asthma and the HDM model of severe asthma demonstrate the characteristics of both human eosinophilic and non-eosinophilic (neutrophilic) asthma endotypes, respectively, and show that compound 1, an orally bioavailable small molecule, is effective in reversing disease in both models based on improved lung function. In summary, these data demonstrate that, unlike existing therapies including biologics that exclusively target eosinophilic asthma, compound 1 is an orally bioavailable small molecule effective in treating both human eosinophilic and non-eosinophilic (neutrophilic) asthma endotypes.

[0163] In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. All references, including all patents, patent applications, and publications cited herein, are incorporated herein by reference in their entirety.

Claims

1. A method for treating asthma in a subject, comprising administering to the subject a therapeutically effective amount of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof, wherein the asthma is noneosinophilic asthma.

2. The method according to claim 1, wherein the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is more selective for JAK1 than for JAK2, JAK3, and Tyk2.

3. The method according to claim 1, wherein the JAK1 pathway inhibitor is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipirazole-1-yl)azetidine-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide or a pharmaceutically acceptable salt thereof.

4. The method according to claim 1, wherein the JAK1 pathway inhibitor is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipirazole-1-yl)azetidine-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide phosphate.

5. The method according to any one of claims 1 to 4, wherein the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 10 mg to about 80 mg on a free base basis.

6. The method according to any one of claims 1 to 4, wherein the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered orally.

7. The method according to any one of claims 1 to 6, wherein the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered orally via a tablet.

8. The method according to any one of claims 1 to 4, wherein the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 15 mg, about 45 mg, or about 75 mg on a free base basis.

9. The method according to any one of claims 1 to 8, wherein the JAK1 inhibitor or a pharmaceutically acceptable salt thereof is administered in combination with a further therapeutic agent.

10. The method according to claim 9, wherein the further therapeutic agent comprises a Janus kinase inhibitor.

11. The method according to claim 10, wherein the Janus kinase inhibitor comprises ruxolitinib or a pharmaceutically acceptable salt thereof.

12. The method according to any one of claims 1 to 11, wherein the administration comprises administering the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof together with at least one pharmaceutically acceptable carrier or excipient.

13. The aforementioned target is FEV １ The method according to claim 1, wherein, based on the above, there is an increase in lung function of about 10% or more after administration.

14. The method according to claim 1, wherein the subject has a reduction in the number of hospitalization events due to asthma, and the reduction is a reduction of about 30%, about 60%, or about 90% of the number of hospitalization events due to asthma.

15. The method according to claim 14, wherein the hospitalization treatment event includes hospitalization in an inpatient facility or medical facility for 24 hours or more.

16. The method according to claim 1, wherein the subject has an increase in lung function of about 10% or more after administration, based on FVC.

17. The method according to claim 1, wherein the subject has an improvement in lung function of about 10% or more after administration based on FeNO.

18. The method according to claim 1, wherein the subject has an increase in lung function of approximately 10% or more after administration, based on the results of a PEF test.

19. A method for treating asthma, including the administration of a JAK1 pathway inhibitor.

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