Jak1 pathway inhibitors for treatment of chronic lung allograft dysfunction

Abstract

To provide drugs for treating chronic lung allograft dysfunction, e.g., bronchiolitis obliterans syndrome.SOLUTION: A drug for treating chronic lung allograft dysfunction in a subject comprises 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

Technical Field

[0001] The present disclosure relates to JAK1 pathway inhibitors and their use in the treatment of chronic lung allograft dysfunction, such as bronchiolitis obliterans syndrome.

Background Art

[0002] Allogeneic lung transplantation is an effective treatment for various end-stage lung diseases such as COPD, ILD, and cystic fibrosis. In 2016, more than 4,000 lung transplants were performed worldwide, approximately 2,300 of which were in the United States (2018 OPTN / SRTR Registry). Although survival rates at 1 year and 3 years after transplantation have improved, there has been no improvement in long-term survival after transplantation, and the median overall survival is 6.1 years (Chambers, D. et al. JHLT, 2017, Vol. 36, No. 10). The leading cause of death due to lung transplantation at 1 year post-operation is chronic lung allograft dysfunction (CLAD); the most common subset of CLAD is bronchiolitis obliterans syndrome (BOS). BOS after lung transplantation is associated with approximately 50% of patients who survive for 5 years and is also the leading cause of death in patients who survive for 1 year after transplantation (Chambers, D. et al. JHLT, 2017, Vol. 36, No. 10). BOS after lung transplantation is characterized by alloreactive immune infiltration, which ultimately causes progressive bronchiolectasis, fibrosis, and finally organ failure (Boehler, A. et al. Eur. Respir. J. Vol 22., No. 6 1007-1018, 2003). Even with prophylactic treatment using immunosuppressive agents, no change has been observed in the rate of BOS after lung transplantation. Few clinical trials have been conducted on BOS after lung transplantation, and currently, there are no drugs approved by the FDA for either the prevention or treatment of BOS after lung transplantation. Therapeutic interventions studied for the treatment of BOS after lung transplantation include azithromycin, changes in immunosuppressive therapy, everolimus, montelukast, aerosolized cyclosporine, aerosolized tacrolimus, alemtuzumab, total lymphoid irradiation, photopheresis, and ultimately re-transplantation. Among these, the only reliable causal therapy for progressive BOS is lung re-transplantation for suitable candidates. The survival years after the second transplantation are 2.6 years, which is significantly shorter than the survival years after the first transplantation (Thomas, M. et al., Ann. Thorac. Surg. 2015;100:452-7).

[0003] Therefore, there is a long-felt need for the development of new therapeutic methods for the prevention and treatment of chronic lung allograft dysfunction, such as bronchiolitis obliterans syndrome. This application addresses this need, as well as other needs. SUMMARY OF THE INVENTION

[0004] Provided herein is a method for treating chronic lung allograft dysfunction (e.g., bronchiolitis obliterans syndrome) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0005] Provided herein is a JAK1 pathway inhibitor for the treatment of chronic lung allograft dysfunction (e.g., bronchiolitis obliterans syndrome) in a subject in need thereof.

[0006] Provided herein is the use of a JAK1 pathway inhibitor for the manufacture of a medicament for the treatment of chronic lung allograft dysfunction (e.g., bronchiolitis obliterans syndrome) in a subject in need thereof. DETAILED DESCRIPTION OF THE INVENTION

[0007] The present invention provides, inter alia, a method for treating chronic lung allograft dysfunction, such as bronchiolitis obliterans syndrome, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a JAK1 pathway inhibitor, such as a JAK1 / 2 inhibitor or a JAK1 inhibitor, or a pharmaceutically acceptable salt thereof.

[0008] The diagnosis of BOS after lung transplantation can be made clinically and also by FEV 1It can be defined by the persistent decline in lung function measured by it. To diagnose BOS after lung transplantation, technical problems such as acute rejection, infections, lung problems of single-lung recipients, excessive weight gain of recipients, anastomotic dysfunction, respiratory muscle dysfunction, effusion, or mismeasurement due to equipment failure, etc., and other causes leading to deterioration after transplantation can be excluded from the causes of graft dysfunction (Meyer, K. C., et al. Eur. Respir. J. 2014;44: 1479-1503).

[0009] The BOS classification scheme is an evaluation system used in BOS after lung transplantation and can be based on spirometry showing a persistent decline in FEV 1 to 80% or less of the baseline FEV 1 after lung transplantation. The baseline can be defined as the average of two best FEV 1 (or FEF 25-75% ) values obtained at intervals of more than 3 weeks after waiting for functional recovery and stabilization after lung transplantation. The latest revised version shown below describes a new classification item, grade 0p, which was added to ensure early diagnosis of BOS after lung transplantation (Meyer, K. C., et al. Eur. Respir. J. 2014;44: 1479-1503). Table 1 is cited from Meyer, K. C., et al. Eur. Respir. J. 2014;44: 1479-1503, and its entire content is incorporated herein by reference. FEV 1 : forced expiratory volume in 1 second; FEF 25-75% : forced expiratory volume at 25-75% of forced vital capacity.

Table 1

[0010] There is no standard or consensus treatment algorithm for BOS, and there are few high-quality randomized trials demonstrating clear benefit in BOS patients (Meyer, K. C., et al. Eur. Respir. J. 2014;44: 1479-1503).

[0011] The methods described herein utilize JAK1 pathway inhibitors, particularly JAK1 / 2 and JAK1 selective inhibitors. JAK1 plays a central role in numerous cytokine and growth factor signaling pathways and, when dysregulated, can contribute to or be involved in disease states. JAK1 is known to mediate, in concert with other JAKs, the signaling of numerous inflammatory cytokines associated with many inflammatory diseases.

[0012] Itacitinib is a selective JAK1 pathway inhibitor and is currently in clinical trials for the treatment of both acute and chronic GVHD following HSCT. Chronic GVHD affects every organ in the body, such as the skin, liver, and intestine. Chronic GVHD also affects the lungs and presents with nearly the same clinical symptoms as BOS after lung transplantation. The correlation between pulmonary cGVHD and BOS after lung transplantation was first reported in 1995, where clinical data and tissue were obtained from nine patients with both pulmonary cGVHD and BOS after lung transplantation. Both groups demonstrated similar signs and symptoms, such as progressive dyspnea and an irreversible obstructive pattern, as well as similar outcomes and histology, such as diffuse inflammation leading to bronchiolitis obliterans (Philit et al., Eur. Respir. J. 1995, 8:551-558).

[0013] Lung cGVHD begins during the transplantation process through the development of normal tissue injury leading to a tissue damage response characterized by cytokine, toll-like receptor agonist, neutrophil, platelet release, and vascular inflammation (Cooke et al, Biol. Blood Marrow Transplant 2017, 23:211-234). CD4 and CD8 cells, as well as Th17 cells, are recruited to the site, but due to thymic injury or dysfunction, negative selection of these cells is impaired, and autoreactive T cell clones persist. In addition, essential immunosuppressive therapies used in cGVHD, such as CNI, result in T reg cell depletion. Ultimately, the initial T cell response activates various innate and adaptive immune cells, such as T cells, B cells, and NK cells, as well as APCs to the site, leading to upregulation of the inflammatory cytokines TGFβ, PDGFα, TNFα, and IL17. Chronic inflammation and fibroblast recruitment end with collagen deposition and continued dysfunction, fibrosis of the target organ (Cooke et al, Biol. Blood Marrow Transplant 2017, 23:211-234).

[0014] Many of the same biological principles are specific to BOS after lung transplantation. The main difference is that in cGVHD, the immune response is abnormal, and the transplanted stem cells attack the host tissue, while in BOS after lung transplantation, the immune response is physiologically normal, but the patient's outcome still remains poor. The inciting event in the allo-reactive acute inflammatory phase in BOS after lung transplantation is clear, that is, the transplantation of an allogeneic lung graft; however, similar to cGVHD, patients with problems that cause tissue damage such as acute rejection reactions that occur after transplantation, CMV infection, and other tissue damage phenomena such as GERD and cold ischemia time are at high risk of developing BOS after lung transplantation (Meyer, K. C., et al. Eur. Respir. J. 2014;44: 1479-1503). The thymic dysfunction seen in cGVHD is not related to BOS after lung transplantation because alloreactive T cells are not negatively selected. However, importantly, the roles of the initial infiltration of CD4, CD8, and Th17 cells, and the subsequent recruitment of B cells, NK cells, and APCs are well recognized in BOS after lung transplantation even if all are physiologically appropriate (Boehler and Estenne, Eur. Respir. J. 2003, 22:1007-1018;Gupta et al., Am. J. Respir. Cell Mol. Biol. 2017, 56:708-715;Fukami et al., Am. J. Transplant, 2012, 12:867-876;Hodge et al, J. Heart Lung Transplant, 2012, 31:888-895, Leonard et al., Am. J. Respir. Crit. Care Med. 2000, 161:1349-1354). Similar to cGVHD, in maintenance immunosuppressive therapy, CNI is used to T regdepletion and suppression (Meyer, K. C., et al. Eur. Respir. J. 2014;44: 1479-1503). Finally, it has been confirmed that each of the known cytokines such as TGFβ, PDGFα, TNFα, and IL-17, and cell mediators of abnormal tissue repair are present in BOS after lung transplantation.

[0015] In addition, in a mouse model, whether the prophylactic and therapeutic doses of itacitinib are 60 mg / kg / day or 120 mg / kg / day, the GVHD score has improved, which indicates the clinical effect in an alloreactive mouse model. Ruxolitinib (JAK1 / 2 inhibitor), a JAK inhibitor, and itacitinib have demonstrated clinical effects in acute GVHD (aGVHD); in addition, ruxolitinib has shown clinical effects in chronic GVHD (cGVHD).

[0016] Notably, 4 out of 5 patients in a study using lung cGVHD showed an FEV 1 increase defined as more than 10% of FEV 1 response. In addition, in a study investigating the use of ruxolitinib in 5 pediatric patients (4 evaluable) with lung cGVHD, 2 responses were observed in 1 patient with a 9% increase in FEV 1 . 4 out of 5 patients were able to completely discontinue steroids, and the last patient was able to reduce the steroid requirement by more than 50% (Schoettler et al, Bone Marrow Transplantation, 2019, 54:1158-1160). In addition to ruxolitinib, itacitinib has shown significant clinical activity in patients with aGVHD. In a recent study, the safety and efficacy of 2 doses of itacitinib, used at 200 mg QD and 300 mg QD, are being evaluated in patients undergoing treatment for naive or steroid-refractory aGVHD.

[0017] Accordingly, the present specification provides a method for treating chronic lung allograft dysfunction in a subject, the method comprising administering to the subject a JAK1 pathway inhibitor (e.g., a JAK1 / 2 inhibitor, or a selective JAK1 inhibitor), or a pharmaceutically acceptable salt thereof.

[0018] In some embodiments, the chronic lung allograft dysfunction is bronchiolitis obliterans syndrome.

[0019] In some embodiments, the subject is a lung transplant recipient (e.g., a single lung transplant recipient, or a double lung transplant recipient).

[0020] In some embodiments, the subject is a double lung transplant recipient.

[0021] In some embodiments, the subject has bronchiolitis obliterans syndrome of grade 0, grade 0p, grade 1, grade 2, or grade 3 as defined by the International Society for Heart and Lung Transplantation (ISHLT) criteria.

[0022] In some embodiments, the subject has bronchiolitis obliterans syndrome of grade 0p, grade 1, grade 2, or grade 3 as defined by the International Society for Heart and Lung Transplantation (ISHLT) criteria.

[0023] In some embodiments, the subject has bronchiolitis obliterans syndrome of grade 1 or grade 2 as defined by the International Society for Heart and Lung Transplantation (ISHLT) criteria.

[0024] In some embodiments, the subject has a reduced FEV 1 of about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% or less of the post-transplant baseline FEV1 has these numerical values. Using these numerical values, a range such as from about 50% to about 75% can be defined.

[0025] In some embodiments, the subject has an FEF value that is 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% or more, but less than 100%. 25-75% has these numerical values. Using these numerical values, a range such as from about 60% to about 80% can be defined.

[0026] In some embodiments, the subject has grade 0 obstructive bronchiolitis syndrome, and grade 0 obstructive bronchiolitis syndrome is defined as a reduced FEV that is less than 100% but more than 90% of the baseline FEV after transplantation, and / or an FEF that is more than 75% of the baseline after transplantation. 1 and / or an FEF that is more than 75% of the baseline after transplantation. 1 and / or an FEF that is more than 75% of the baseline after transplantation. 25-75% is defined as.

[0027] In some embodiments, the subject has grade 0p obstructive bronchiolitis syndrome, and grade 0p obstructive bronchiolitis syndrome is defined as a reduced FEV that is from 81% to 90% of the baseline FEV after transplantation, and / or an FEF that is 75% or less of the baseline after transplantation. 1 is defined as a reduced FEV that is from 81% to 90% of the baseline FEV after transplantation, 1 and / or an FEF that is 75% or less of the baseline after transplantation. 25-75% is defined as.

[0028] In some embodiments, the subject has grade 1 obstructive bronchiolitis syndrome, and grade 1 obstructive bronchiolitis syndrome is defined as a reduced FEV that is from 66% to 80% of the baseline FEV after transplantation. 1 is defined as a reduced FEV that is from 66% to 80% of the baseline FEV after transplantation. 1 is defined as.

[0029] In some embodiments, the subject has grade 2 obstructive bronchiolitis syndrome, and grade 2 obstructive bronchiolitis syndrome is defined as a reduced FEV that is from 51% to 65% of the baseline FEV after transplantation. 1 is defined as a reduced FEV that is from 51% to 65% of the baseline FEV after transplantation. 1 is defined as.

[0030] In some embodiments, the subject has grade 3 obstructive bronchiolitis syndrome, and grade 3 obstructive bronchiolitis syndrome is defined as a reduced FEV 1 to 50% or less of the baseline FEV after transplantation. 1 is defined as.

[0031] In some embodiments, treatment of obstructive bronchiolitis syndrome includes increasing FEV 1 by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% or more about 4 weeks, 8 weeks, 12 weeks, 3 months, 4 months, 5 months, or 6 months after first administering a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0032] In some embodiments, treatment of obstructive bronchiolitis syndrome includes increasing FEV 1 by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% or more about 4 weeks, 8 weeks, 12 weeks, 3 months, 4 months, 5 months, or 6 months after first administering a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0033] In some embodiments, treatment of obstructive bronchiolitis syndrome includes increasing FEV 1 by about 10% or more about 12 weeks after first administering a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0034] In some embodiments, treatment of obstructive bronchiolitis syndrome includes increasing FEV 1 by about 10% or more 12 weeks after first administering a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0035] Also provided herein is a method of suppressing the risk of obstructive bronchiolitis syndrome in a subject, the method comprising administering to the subject a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0036] This specification also provides a method for suppressing the risk of lung re-transplantation in a subject, the method comprising administering to the subject a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0037] This specification also provides a method for improving FEV 1 in a subject suffering from bronchiolitis obliterans syndrome, the method comprising administering to the subject an effective amount of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0038] This specification also provides a method for improving the quality of life in a subject suffering from bronchiolitis obliterans syndrome, the method comprising administering to the subject an effective amount of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0039] This specification also provides a method for a subject to avoid death, avoid progressive bronchiectasis, avoid organ failure, avoid decline in lung function, promote recovery and stability after lung transplantation, reduce hospitalizations, reduce medical utilization, and / or reduce the risk of re-transplantation, and enhance other potential benefits provided herein, the method comprising administering to the subject an effective amount of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0040] In some embodiments, the subject satisfies one or more of the selection criteria described in Example 1 below. In some embodiments, the subject satisfies one, two, three, four, five, or six of the selection criteria described in Example 1 below. In some embodiments, the subject satisfies all of the selection criteria described in Example 1 below.

[0041] In some embodiments, the subject corresponds to four, three, two, one of the exclusion criteria described in Example 1 below, or does not correspond to any of the exclusion criteria described in Example 1 below. In some embodiments, the subject does not correspond to any of the exclusion criteria described in Example 1 below.

[0042] In some embodiments, the subject satisfies all the selection criteria and does not meet any of the exclusion criteria as described in Example 1 below.

[0043] This specification also provides a method for suppressing the risk of a subject being hospitalized, the method including administering to the subject an effective amount of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof, where the subject: (a) has received a diagnosis of bronchiolitis obliterans syndrome; (b) has received a lung transplant within 1 to 5 years prior to administration of the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof; and (c) does not show a decrease in FEV 1 not attributable to bronchiolitis obliterans syndrome.

[0044] In some embodiments, the present disclosure relates to a method for treating non-transplant-related bronchiolitis obliterans syndrome in a subject in need thereof, the method including administering to the subject a therapeutically effective amount of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof, such as a JAK1 / 2 inhibitor or a pharmaceutically acceptable salt thereof, or a JAK1 inhibitor or a pharmaceutically acceptable salt thereof.

[0045] The methods described herein utilize JAK1 pathway inhibitors, i.e., JAK1 / 2 inhibitors or JAK1-selective inhibitors (either of which can be in the form of a pharmaceutically acceptable salt).

[0046] I. JAK1 / 2 inhibitors: In some embodiments, the JAK1 / 2 inhibitor is baricitinib or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, the JAK1 / 2 inhibitor is ruxolitinib, or a pharmaceutically acceptable salt thereof (see, e.g., U.S. Patent No. 7,598,257, the entire disclosure of which is incorporated herein by reference). In some embodiments, the salt is ruxolitinib phosphate (see, e.g., U.S. Patent No. 8,722,693, the entire disclosure of which is incorporated herein by reference).

[0048] In some embodiments, the JAK1 / 2 inhibitor is ruxolitinib, or a pharmaceutically acceptable salt thereof, and one or more hydrogen atoms are replaced with deuterium atoms. In some embodiments, the JAK1 / 2 inhibitor is any of the compounds of U.S. Patent 9,249,149, the entire disclosure of which is incorporated herein by reference, or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK1 / 2 inhibitor is CTP-543 (Compound 111), or a pharmaceutically acceptable salt thereof.

[0049] In some embodiments, the JAK1 / 2 inhibitor is a compound of Formula I:

Chemical formula

[0050] In some embodiments, the JAK1 / 2 inhibitor is a compound of formula I selected from Compounds 100 to 130 described in the following table (in the table, R 6 , R 7 , and R 8 are each H), or a pharmaceutically acceptable salt thereof. In some embodiments, the inhibitor of JAK1 and / or JAK2 is a compound of formula I selected from Compounds 200 to 231 described in the following table (in the table, R 6 , R 7 , and R 8 are each D), or a pharmaceutically acceptable salt thereof.

Table 2-1

Table 2-2

[0051] In some embodiments, the JAK1 / 2 inhibitor is baricitinib in which one or more hydrogen atoms are substituted with deuterium atoms, or a pharmaceutically acceptable salt thereof. In some embodiments, the inhibitor of JAK1 and / or JAK2 is any of the compounds of US Patent 9,540,367 (the entire disclosure of which is incorporated herein by reference), or a pharmaceutically acceptable salt thereof.

[0052] II. JAK1 Selective Inhibitor In some embodiments, the JAK1 pathway inhibitor is selective for JAK1 over JAK2, JAK3, and TYK2 (i.e., a JAK1-selective inhibitor). Patients with obstructive bronchiolitis syndrome may benefit from selective JAK1 inhibition. A selective inhibitor of JAK1 is effective while avoiding the unnecessary and potentially undesirable effects of inhibiting other JAK kinases. Specifically, by avoiding JAK2 inhibition, the risk of cytopenia in BOS patients after lung transplantation treated with a selective JAK1 inhibitor such as Compound 1 can be suppressed.

[0053] For example, the compounds described herein, or pharmaceutically acceptable salts thereof, preferentially inhibit JAK1 over one or more of JAK2, JAK3, and TYK2. In some embodiments, the compound preferentially inhibits JAK1 over JAK2 (e.g., has a JAK2 / JAK1 IC 50 ratio > 1). In some embodiments, the compound or salt is about 10-fold more selective for JAK1 over JAK2. In some embodiments, the compound or salt is about 3-fold, about 5-fold, about 10-fold, about 15-fold, or about 20-fold more selective for JAK1 over JAK2 as measured and calculated by measuring IC 50 at 1 mM ATP (see, e.g., Example A).

[0054] In some embodiments, the JAK1 pathway inhibitor is a compound of Table 2, or a pharmaceutically acceptable salt thereof. The compounds of Table 2 are selective JAK1 inhibitors (i.e., JAK1 pathway inhibitors that are selective over JAK2, JAK3, and TYK2). The IC 50 values obtained by the method of Example A at 1 mM ATP are shown in Table 2.

Table 3-1

Table 3-2

Table 3-3

Table 3-4

Table 3-5

Table 3-6

Table 3-7

Table 3-8

[0055] In some embodiments, the JAK1 pathway inhibitor is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3[4-(7H-pyrrolo[2,3-d]pyrimidin)-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments, the JAK1 pathway inhibitor is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile adipate.

[0057] The synthesis and preparation of {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile and its adipate can be found, for example, in U.S. Patent Publication No. 2011 / 0224190, filed on March 9, 2011, U.S. Patent Publication No. 2013 / 0060026, filed on September 6, 2012, and U.S. Patent Publication No. 2014 / 0256941, filed on March 5, 2014, each of which is hereby incorporated by reference in its entirety.

[0058] In some embodiments, the JAK1 pathway inhibitor is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide, or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, the JAK1 pathway inhibitor is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide phosphate.

[0060] The synthesis and preparation of 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide and its phosphate can be found, for example, in U.S. Patent Publication No. 2014 / 0343030, filed on March 16, 2014, which is hereby incorporated by reference in its entirety.

[0061] In some embodiments, the JAK1 pathway inhibitor is ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile, or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, the JAK1 pathway inhibitor is ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile monohydrate.

[0063] The characterization of ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile, and its anhydrous and monohydrate forms, is described in U.S. Patent Publication No. 2014 / 0121198, filed Oct. 31, 2013, and U.S. Patent Publication No. 2015 / 0344497, filed Apr. 29, 2015, each of which is hereby incorporated by reference in its entirety.

[0064] In some embodiments, the compounds of Table 2 are prepared by the synthetic procedures described in U.S. Patent Publication No. 2011 / 0224190, filed Mar. 9, 2011; U.S. Patent Publication No. 2014 / 0343030, filed May 16, 2014; U.S. Patent Publication No. 2014 / 0121198, filed Oct. 31, 2013; U.S. Patent Publication No. 2010 / 0298334, filed May 21, 2010; U.S. Patent Publication No. 2011 / 0059951, filed Aug. 31, 2010; U.S. Patent Publication No. 2012 / 0149681, filed Nov. 18, 2011; U.S. Patent Publication No. 2012 / 0149682, filed Nov. 18, 2011; U.S. Patent Publication No. 2013 / 0018034, filed Jun. 19, 2012; U.S. Patent Publication No. 2013 / 0045963, filed Aug. 17, 2012; and U.S. Patent Application No. 2014 / 0005166, filed May 17, 2013, each of which is incorporated herein by reference in its entirety.

[0065] In some embodiments, the JAK1 pathway inhibitor is selected from the compounds of U.S. Patent Publication No. 2011 / 0224190, filed Mar. 9, 2011; U.S. Patent Publication No. 2014 / 0343030, filed May 16, 2014; U.S. Patent Publication No. 2014 / 0121198, filed Oct. 31, 2013; U.S. Patent Publication No. 2010 / 0298334, filed May 21, 2010; U.S. Patent Publication No. 2011 / 0059951, filed Aug. 31, 2010; U.S. Patent Publication No. 2012 / 0149681, filed Nov. 18, 2011; U.S. Patent Publication No. 2012 / 0149682, filed Nov. 18, 2011; U.S. Patent Publication No. 2013 / 0018034, filed Jun. 19, 2012; U.S. Patent Publication No. 2013 / 0045963, filed Aug. 17, 2012; and U.S. Patent Application No. 2014 / 0005166, filed May 17, 2013, or a pharmaceutically acceptable salt thereof, each of which is incorporated herein by reference in its entirety.

[0066] In some embodiments, the JAK1 pathway inhibitor is a compound of formula I

Chemical formula

[0067] In some embodiments, the compound of formula I is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or a pharmaceutically acceptable salt thereof.

[0068] In some embodiments, the compound of formula I is 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

[0069] In some embodiments, the compound of formula I is [3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile, or a pharmaceutically acceptable salt thereof.

[0070] In some embodiments, the JAK1 pathway inhibitor is a compound of formula II

Chemical formula

[0071] In some embodiments, the compound of formula II is 4-[3-(cyanomethyl)-3-(3’,5’-dimethyl-1H,1’H-4,4’-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide, or a pharmaceutically acceptable salt thereof.

[0072] In some embodiments, the JAK1 pathway inhibitor is a compound of formula III

Chemical formula

[0073] 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]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile, or a pharmaceutically acceptable salt thereof.

[0074] In some embodiments, the JAK1 pathway inhibitor is a compound labeled with an isotope, or a pharmaceutically acceptable salt thereof. A "compound labeled with an isotope" or "radiolabeled compound" is a compound of the present disclosure in which one or more atoms have been replaced with, or are being replaced with, atoms having an atomic mass or mass number different from the atomic mass or mass number generally found in nature (i.e., naturally occurring). Suitable radionuclides that can be incorporated into the compounds of the present disclosure include, 2 H (also denoted as D in place of deuterium),3 H (also denoted as T instead of 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 I are present, but not limited thereto. For example, one or more hydrogen atoms in the compounds of the present disclosure can be replaced with deuterium atoms, for example, replacing -CH 3 with -CD 3 .

[0075] One or more constituent atoms of the compounds described herein can be replaced with, or substituted with, isotopes of the atoms, in natural or unnatural abundances. In some embodiments, the compounds of the invention contain at least one deuterium atom. In some embodiments, the compounds of the invention contain two or more deuterium atoms. In some embodiments, the compounds of the invention contain 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 deuterium atoms. In some embodiments, all hydrogen atoms in the compound can be replaced with, or substituted with, deuterium atoms.

[0076] Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011)). Compounds labeled with isotopes can be used in various studies such as NMR spectroscopy, metabolic experiments, and / or assays.

[0077] Substitution with heavier isotopes, such as deuterium, can be preferred in some situations because of certain therapeutic advantages resulting from higher metabolic stability, e.g., extending the in vivo half-life or reducing the required dosage (see, e.g., A. Kerekes et. al. J. Med. Chem. 2011, 54, 201-210; R. Xu et. al., J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular, substitution at one or more metabolic sites can provide one or more therapeutic advantages.

[0078] Thus, in some embodiments, the JAK1 pathway inhibitor is a compound, i.e., the compound in which one or more hydrogen atoms are replaced with deuterium atoms, or a pharmaceutically acceptable salt thereof.

[0079] In some embodiments, a JAK1 pathway inhibitor, or a pharmaceutically acceptable salt thereof, is administered on a free base basis at a daily dose of about 50 mg to about 600 mg. Thus, in some embodiments, a selective JAK1 pathway inhibitor, or a pharmaceutically acceptable salt thereof, is administered on a free base basis at a daily dose of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg.

[0080] In some embodiments, a JAK1 pathway inhibitor, or a pharmaceutically acceptable salt thereof, is administered on a free base basis at a daily dose of about 50 mg.

[0081] In some embodiments, a JAK1 pathway inhibitor, or a pharmaceutically acceptable salt thereof, is administered on a free base basis at a daily dose of about 100 mg.

[0082] In some embodiments, a JAK1 pathway inhibitor, or a pharmaceutically acceptable salt thereof, is administered on a free base basis at a daily dose of about 200 mg.

[0083] In some embodiments, a JAK1 pathway inhibitor, or a pharmaceutically acceptable salt thereof, is administered on a free base basis at a daily dose of about 300 mg.

[0084] In some embodiments, a JAK1 pathway inhibitor, or a pharmaceutically acceptable salt thereof, is administered on a free base basis at a daily dose of about 400 mg.

[0085] In some embodiments, a JAK1 pathway inhibitor, or a pharmaceutically acceptable salt thereof, is administered on a free base basis at a daily dose of about 500 mg.

[0086] In some embodiments, a JAK1 pathway inhibitor, or a pharmaceutically acceptable salt thereof, is administered on a free base basis at a daily dose of about 600 mg.

[0087] In some embodiments, a JAK1 pathway inhibitor, or a pharmaceutically acceptable salt thereof, is administered once daily in an amount of about 50 mg on a free base basis.

[0088] In some embodiments, a JAK1 pathway inhibitor, or a pharmaceutically acceptable salt thereof, is administered once daily in an amount of about 100 mg on a free base basis.

[0089] In some embodiments, a JAK1 pathway inhibitor, or a pharmaceutically acceptable salt thereof, is administered once daily in an amount of about 200 mg on a free base basis.

[0090] In some embodiments, a JAK1 pathway inhibitor, or a pharmaceutically acceptable salt thereof, is administered once daily in an amount of about 300 mg on a free base basis.

[0091] In some embodiments, a JAK1 pathway inhibitor, or a pharmaceutically acceptable salt thereof, is administered once daily in an amount of about 400 mg on a free base basis.

[0092] In some embodiments, a JAK1 pathway inhibitor, or a pharmaceutically acceptable salt thereof, is administered once daily in an amount of about 500 mg on a free base basis.

[0093] In some embodiments, a JAK1 pathway inhibitor, or a pharmaceutically acceptable salt thereof, is administered once daily in an amount of about 600 mg on a free base basis.

[0094] In some embodiments, a JAK1 pathway inhibitor, or a pharmaceutically acceptable salt thereof, is administered as one or more sustained release formulations, each comprising a JAK1 pathway inhibitor, or a pharmaceutically acceptable salt thereof.

[0095] The present specification provides a method for treating obstructive bronchitis syndrome in a subject in need thereof, comprising administering to the subject a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof on a free base basis, in a daily dose of about 50 mg to about 600 mg, and administering the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof as one or more sustained-release formulations comprising the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0096] The present specification provides a method for treating obstructive bronchitis syndrome in a subject in need thereof, comprising administering to the subject a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof on a free base basis, in a daily dose of about 100 mg to about 600 mg, and administering the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof as one or more sustained-release formulations comprising the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0097] In some embodiments, the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered as one or more sustained-release formulations each comprising the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0098] The sustained-release formulation of {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or a pharmaceutically acceptable salt thereof (Table 2, Compound 1) can be found in U.S. Patent Publication No. 2015-0065484, filed on August 6, 2014, which application is hereby incorporated by reference in its entirety herein. See also Example B below.

[0099] The present specification provides a method for treating obstructive bronchitis syndrome in a subject in need thereof, comprising administering to the subject, on a free base basis, {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or a pharmaceutically acceptable salt thereof, in a daily dose of from about 100 mg to about 600 mg, and administering {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or a pharmaceutically acceptable salt thereof, as one or more sustained release formulations.

[0100] The embodiments described herein are intended to be in every suitable combination, such as when the embodiment is a multiple dependent claim (e.g., embodiments related to a selective JAK1 pathway inhibitor and its dosage, embodiments related to any salt form of the compounds disclosed herein, and embodiments related to compositions and / or administration can be combined in any combination). For reasons of simplicity only, not all possible combinations are described individually herein.

[0101] The compounds described herein can be asymmetric, for example, having one or more stereocenters. Unless otherwise specified, all stereoisomers such as enantiomers and diastereomers are contemplated. Compounds containing asymmetrically substituted carbon atoms can be isolated in optically active form or in racemic form. Methods for preparing optically active forms from optically inactive starting materials are known in the art, such as by resolution of a racemic mixture or by stereoselective synthesis. The compounds described herein can also exist in numerous geometric isomers such as olefins, C=N double bonds, etc., and all such stable isomers are contemplated in the present invention. The cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as mixtures of isomers or in separated isomeric forms.

[0102] In some embodiments, the compound has an (R)-configuration. In some embodiments, the compound has an (S)-configuration.

[0103] The resolution of a racemic mixture of a compound can be carried out by any of a number of methods known in the art. As an example of such a method, there is fractional recrystallization using a chiral resolution acid, which is an optically active salt-forming organic acid. Examples of resolving agents suitable for the fractional recrystallization method include various optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or D-form and L-form of various optically active camphorsulfonic acids such as β-camphorsulfonic acid. Other resolving agents suitable for the fractional crystallization method include stereochemically 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.

[0104] Also, the resolution of a racemic mixture can be carried out by elution with a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). One of ordinary skill in the art can determine a suitable elution solvent composition.

[0105] The compounds described in this specification also include tautomeric forms. Tautomeric forms result from the simultaneous transfer of a proton along with the exchange of adjacent double and single bonds. Among the tautomeric forms are prototropic tautomers, which are protonated states of isomers having the same empirical formula and total charge. Examples of prototropic tautomers include keto - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and cyclic forms in which a proton can occupy two or more positions in a heterocyclic system, such as 1H - imidazole and 3H - imidazole, 1H -, 2H -, and 4H - 1,2,4 - triazole, 1H - and 2H - isoindole, and 1H - and 2H - pyrazole. Tautomeric forms can exist in equilibrium or can be stereochemically fixed into one form by appropriate substitution.

[0106] The compounds described in this specification can also include compounds labeled with isotopes of the present disclosure. A "compound labeled with an isotope" or "radiolabeled" compound is a compound of the present disclosure in which one or more atoms have been replaced with, or are being replaced with, atoms having an atomic mass or mass number different from the atomic mass or mass number generally found in nature (i.e., naturally occurring). Suitable radionuclides that can be incorporated into the compounds of the present disclosure include 2 H (also denoted as D instead of deuterium), 3 H (also denoted as T instead of 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 131I is present, but not limited thereto. For example, one or more hydrogen atoms in the compounds of the present disclosure can be replaced with deuterium atoms (e.g., the C of formula (I), (II), or (III)) 1-6 alkyl group, or one or more hydrogen atoms of the compounds in Table 2 can be replaced with -CH 3 to replace -CD 3 and the like, and optionally, can be replaced with deuterium atoms).

[0107] As used herein, the term "compound" means to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures shown therein, unless the name refers to a specific stereoisomer. Compounds specified herein by name or structure in a particular tautomeric form are intended to include other tautomeric forms thereof, unless otherwise stated.

[0108] In some embodiments, the compounds described herein, or salts thereof, 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 separation can include, for example, a composition rich in the compounds described herein. Substantial separation can include a composition comprising at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 90 wt%, at least about 95 wt%, at least about 97 wt%, or at least about 99 wt% of the compounds described herein, or salts thereof. Methods for isolating compounds and their salts are conventional means in the art.

[0109] All compounds, and pharmaceutically acceptable salts thereof, can be recognized together with other substances such as water and solvents (e.g., hydrates and solvates), or can be isolated. In the solid state, the compounds and salts thereof described herein can occur in various forms, for example, in the form of solvates including hydrates. Since the compounds can be in any solid-state form such as polymorphs or solvates, unless otherwise specified, references to the compounds and salts thereof in this specification should be understood to include any solid-state form of the compounds.

[0110] As used herein, the phrase "pharmaceutically acceptable" refers to compounds, substances, compositions, and / or dosage forms that are suitable for use in contact with the tissues of humans and animals within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio, and without undue toxicity, irritation, allergic response, or other problems or complications.

[0111] The present invention also includes pharmaceutically acceptable salts of the compounds described herein. The term "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds, where the parent compound has been modified by converting an existing acidic or basic moiety into 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. Pharmaceutically acceptable salts of the present invention include, for example, non-toxic salts of the parent compound formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or free base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol, or butanol) or acetonitrile (MeCN) are preferred. A list of suitable salts is recognized in Remington’s Pharmaceutical Sciences, 17 th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19, and in Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). In some embodiments, the compounds described herein include N-oxide forms.

[0112] The terms "individual", "patient", or "subject" are used interchangeably and refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans.

[0113] The phrase "therapeutically effective amount" refers to the amount of an active compound or agent that induces a biological or drug response that a researcher, veterinarian, physician, or other clinician seeks in an organization, system, animal, individual, or human.

[0114] The terms "treating" or "treatment" refer to (1) inhibiting a disease, e.g., inhibiting a disease, condition, or disorder in an individual who is experiencing or exhibiting the disease state or overall symptoms of the disease, condition, or disorder (i.e., preventing further worsening of the disease state and / or overall symptoms); and (2) alleviating a disease, e.g., alleviating a disease, condition, or disorder in an individual who is experiencing or exhibiting the disease state or overall symptoms of the disease, condition, or disorder (i.e., causing the disease state and / or overall symptoms to improve), e.g., reducing the severity of the disease. In certain embodiments, "treating" or "treatment" includes preventing or suppressing the risk of developing a disease; e.g., preventing or reducing the risk of developing bronchiolitis obliterans syndrome in an individual who may be predisposed to bronchiolitis obliterans syndrome (e.g., after single or double lung transplantation) but who has not yet experienced or exhibited the disease state or symptoms of the disease.

[0115] The terms "e.g.", "such as", and the phrase "and without limitation" which is a grammatical equivalent thereof are understood to mean that the text following is illustrative, unless otherwise indicated.

[0116] As used herein, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0117] As used herein, the term "about" means "approximately" (e.g., ± about 10% of the indicated value).

[0118] Combination therapy The methods described herein can further comprise administering one or more additional therapeutic agents. These therapeutic agents include anti-inflammatory agents, steroids, immunosuppressive agents, or therapeutic antibodies.

[0119] Patients diagnosed with newly developed BOS after lung transplantation are evaluated to confirm that they are receiving optimal immunosuppression, such as by complying with the prescribed medications and taking the immunosuppressive agents used. In the case of patients taking cyclosporine, when switching from cyclosporine to tacrolimus, there is evidence indicating that the predicted loss of FEV 1 is suppressed (Sarahrudhi, K. et al. JTCS, April 2004, Vol. 127, No. 4). Once immunosuppressive therapy is optimized, there are few treatment options with proven efficacy. The options are as follows. ● Azithromycin: Azithromycin has shown improvement in lung function defined by a 10 or greater increase in FEV 1 in approximately 35 - 40% of patients in multiple studies. This response appears to correlate with the presence of neutrophilia in the BAL fluid (Vos, R. et al. JHLT, 2010, Vol. 29, No. 12). Patients who showed a response to azithromycin had improved overall survival compared to those who did not show a response. Additionally, in a randomized study of prophylactic azithromycin compared to placebo in BOS after lung transplantation, although there were fewer cases of BOS, no effect was observed on overall survival (Vos, R. et al. Eur. Respir. J. 2011, Vol. 37). 1 ● Extracorporeal photopheresis (ECP): ECP has demonstrated moderate activity in studies at numerous single institutions (the largest of which had 51 patients enrolled). In this study, 61% of patients maintained a pre - ECP baseline FEV of - 5 to + 5 over 6 months. ● Extracorporeal photopheresis (ECP): ECP has demonstrated moderate activity in studies at numerous single institutions (the largest of which had 51 patients enrolled). In this study, 61% of patients maintained a pre - ECP baseline FEV of - 5 to + 5 over 6 months. 1had a stable disease over a long period defined by (Benden, E. C. et al. 2008 Transplantation, Vol. 86, No 11). ● Montelukast: Thirty patients were randomized to montelukast versus placebo. Montelukast did not affect the decline in lung function across the cohort. However, in a post hoc analysis of patients with BOS grade 1, montelukast 1 and predicted FEV 1 both arrested the further decline in FEV 1 during the study period (Ruttens, D. et al. Montelukast for bronchiolitis obliterans syndrome after lung transplantation: A randomized controlled trial. PLOS One April 6th 2018).

[0120] Accordingly, in some embodiments, the methods provided herein comprise administering a JAK1 pathway inhibitor, or a pharmaceutically acceptable salt thereof, and cyclosporine, or a pharmaceutically acceptable salt thereof.

[0121] In some embodiments, the methods provided herein comprise administering a JAK1 pathway inhibitor, or a pharmaceutically acceptable salt thereof, and azithromycin, or a pharmaceutically acceptable salt thereof. In some embodiments, azithromycin is administered at a daily dose of about 500 mg for 1 - 2 days.

[0122] In some embodiments, the methods provided herein comprise administering a JAK1 pathway inhibitor, or a pharmaceutically acceptable salt thereof, and extracorporeal photopheresis.

[0123] In some embodiments, the methods provided herein include administering a JAK1 pathway inhibitor, or a pharmaceutically acceptable salt thereof, and montelukast, or a pharmaceutically acceptable salt thereof. In some embodiments, montelukast is administered at a daily dose of about 4 mg to about 10 mg (e.g., a daily dose of about 4 mg, about 5 mg, or about 10 mg).

[0124] In some embodiments, the methods provided herein include administering a JAK1 pathway inhibitor, or a pharmaceutically acceptable salt thereof, and tacrolimus, or a pharmaceutically acceptable salt thereof. In some embodiments, tacrolimus is administered at a daily dose of about 0.075 mg / kg / day to about 0.2 mg / kg / day.

[0125] In some embodiments, the methods provided herein include administering a JAK1 pathway inhibitor, or a pharmaceutically acceptable salt thereof, and mycophenolate mofetil, or a pharmaceutically acceptable salt thereof. In some embodiments, mycophenolate mofetil, or a pharmaceutically acceptable salt thereof, is administered at a daily dose of about 500 - 1500 mg, e.g., a daily dose of about 1440 mg.

[0126] In some embodiments, the methods provided herein include administering a JAK1 pathway inhibitor, or a pharmaceutically acceptable salt thereof, and alemtuzumab. In some embodiments, alemtuzumab is administered in a first treatment course and in a second treatment course 12 months after the first treatment course, the first treatment course comprising administering about 12 mg / day for 5 consecutive days, and the second treatment course comprising administering about 12 mg / day for 3 consecutive days.

[0127] In some embodiments, the methods provided herein include administering a JAK1 pathway inhibitor, or a pharmaceutically acceptable salt thereof, and methotrexate, or a pharmaceutically acceptable salt thereof. In some embodiments, methotrexate is administered at a weekly dose of about 7.5 mg to about 30 mg (e.g., about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, or about 30 mg).

[0128] In some embodiments, the methods provided herein include administering a JAK1 pathway inhibitor, or a pharmaceutically acceptable salt thereof, and a corticosteroid, or a pharmaceutically acceptable salt thereof.

[0129] In some embodiments, the methods provided herein include administering a JAK1 pathway inhibitor, or a pharmaceutically acceptable salt thereof, and everolimus, or a pharmaceutically acceptable salt thereof. In some embodiments, everolimus is administered at a daily dose of about 2.5 mg to about 20 mg (e.g., a daily dose of about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, or about 20 mg).

[0130] When administering multiple pharmaceuticals to a subject, they can be administered simultaneously, sequentially, or in combination (e.g., with three or more agents).

[0131] Composition The compounds can be administered in the form of pharmaceutical compositions. These compositions can be prepared by methods well known in the pharmaceutical art and can be administered by various routes depending on whether local or systemic treatment is desired and on the area to be treated. Administration can be local (including percutaneous, epithelial, ocular, and those for mucosal surfaces including intranasal, vaginal, and rectal delivery), transpulmonary (e.g., by inhalation or insufflation of powders or aerosols including those by nebulizer; into the trachea or intranasally), oral, or parenteral. Parenteral administration can be intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or by injection or infusion; or intracranial, e.g., into the subarachnoid space or the ventricles of the brain. Parenteral administration can be in the form of a single bolus dose or, for example, by continuous perfusion pump. Pharmaceutical compositions and formulations for local administration include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous bases, powder bases, or oily bases, thickeners, etc. can be essential or desirable.

[0132] A pharmaceutical composition can include, as an active ingredient, a compound or a pharmaceutically acceptable salt thereof in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the composition is suitable for local administration. In preparing the composition, the active ingredient is generally mixed with, diluted with, or enclosed within such a carrier in the form of, for example, capsules, sachets, papers, or other receptacles. When the excipient functions as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Accordingly, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or liquid medium), e.g., ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0133] When preparing the formulation, the active compound can be ground to provide an appropriate particle size before being combined with other ingredients. If the active compound is substantially insoluble, it can be ground to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, it can be ground to adjust the particle size, for example, to about 40 mesh to provide a substantially uniform distribution in the formulation.

[0134] The compound can be ground using known grinding procedures such as wet grinding to obtain an appropriate particle size for tablet formation and other formulation types. Subdivided (nanoparticle) preparations of the compounds of the present invention can be prepared by processes known in the art; see, for example, WO2002 / 000196.

[0135] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. In addition, the formulation can include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; and sweetening and flavoring agents. The compositions of the present invention can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient using procedures known in the art.

[0136] The components used to formulate the pharmaceutical composition are of high purity and substantially free of potentially harmful contaminants (e.g., at least National Food grade, generally at least analytical grade, and more generally at least pharmaceutical grade). Particularly when it is for human consumption, the composition is preferably manufactured or formulated in accordance with the Good Manufacturing Practice standards defined by the operating regulations of the U.S. Food and Drug Administration. For example, suitable formulations are sterile and / or substantially isotonic and / or fully comply with all the regulations of the Good Manufacturing Practice standards of the U.S. Food and Drug Administration.

[0137] The active compound is effective over a wide range of dosages and is generally administered in a therapeutically effective amount. However, it will be understood that the amount of the compound actually administered will usually be determined by the physician according to relevant circumstances such as the condition being treated, the selected route of administration, the compound actually administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.

[0138] The therapeutic dosage of the compounds of the present invention varies, for example, according to the particular use for which the treatment is being carried out, the method of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of the compounds of the present invention in the pharmaceutical composition varies according to several factors such as the dosage, chemical nature (e.g., hydrophobicity), and route of administration.

[0139] To prepare a solid composition such as a tablet, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preliminary preparation composition containing a homogeneous mixture of the compounds of the present invention. When these preliminary preparation compositions are referred to as homogeneous, the active ingredient is generally uniformly dispersed throughout the composition, whereby the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid preliminary preparation is then subdivided into unit dosage forms of the type described above containing, for example, from about 0.1 to about 1000 mg of the active ingredient of the present invention.

[0140] The tablets or pills of the present invention can be formulated by coating or other methods to provide a dosage form with the advantage of long-term action. For example, the tablets or pills can contain an inner administration component and an outer administration component, and the latter is in the form of an envelope covering the former. These two components can be separated by an enteric coating layer, which functions to resist degradation in the stomach, allowing the inner component to reach the duodenum intact or enabling delayed release. Various materials can be used for such an enteric coating layer or coating, and such materials include several polymeric acids, as well as mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0141] As liquid forms for taking in the compounds and compositions of the present invention by oral administration or injection, there are aqueous solutions, appropriately 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.

[0142] The amount of the compound or composition to be administered to a patient varies depending on the content of what is administered, the purpose of administration such as prevention or treatment, the patient's condition, the administration method, etc. In therapeutic use, the composition can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially prevent the symptoms of the disease and its complications. The effective dose is determined by the judgment of the attending physician based on factors such as the medical condition being treated, as well as the severity of the disease, the patient's age, weight, and general condition.

[0143] The composition to be administered to the patient can be in the form of the pharmaceutical composition described above. These compositions can be sterilized by conventional sterilization techniques or can be sterilization filtered. The aqueous solution can be packaged for use as is or can be lyophilized, and the lyophilized preparation is combined with a sterile aqueous carrier before administration. The pH of the compound preparation is generally between 3 and 11, more preferably between 5 and 9, and most preferably between 7 and 8. It will be understood that the use of the specific excipients, carriers, or stabilizers described above may result in the formation of pharmaceutical salts.

[0144] Kit This application also includes a useful pharmaceutical kit comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound or any of its embodiments. Such kits can further include one or more of the various components of conventional pharmaceutical kits, such as a container containing one or more pharmaceutically acceptable carriers, additional containers, etc., which will be apparent to those skilled in the art. Instructions indicating the amount of the components to be administered, guidelines for administration, and / or guidelines for mixing the components can also be included in the kit, either as an accompanying document or in the form of a label.

Examples

[0145] The present invention will be described in more detail according to specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention regardless of the method. Those skilled in the art can easily recognize various non-essential parameters that can be changed or modified to achieve essentially the same results.

[0146] Example A: In Vitro JAK Kinase Assay A JAK1 pathway inhibitor that can be used for the treatment of cytokine-related diseases or disorders is tested for its 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 (a.a. 837-1142), JAK2 (a.a. 828-1132) and JAK3 (a.a. 781-1124) with a His tag at the N-terminus are expressed in insect cells using baculovirus and purified. The catalytic activities of JAK1, JAK2 or JAK3 are assayed by measuring the phosphorylation of biotinylated peptides. Homogeneous time-resolved fluorescence The phosphorylated peptides were detected by the (HTRF) method. For each kinase in a 40 μL reaction containing the enzyme, ATP, and 500 nM peptide in 50 mM Tris (pH 7.8) buffer containing 100 mM NaCl, 5 mM DTT, and 0.1 mg / mL (0.01%) BSA, the IC 50 of the compound is measured. For 1 mM IC 50 measurements, the ATP concentration in the reaction is 1 mM. The reaction is carried out at room temperature for 1 hour and then stopped with 20 μL of assay buffer (Perkin Elmer, Boston, MA) containing 45 mM EDTA, 300 nM SA-APC, 6 nM Eu-Py20. Binding to the antibody labeled with Europium is carried out for 40 minutes and the HTRF signal is measured with a Fusion plate reader (Perkin Elmer, Boston, MA). The compounds described in Table 2 have been tested in this assay and have been shown to have the IC 50 values described in Table 2.

[0147] Example B: Preparation of a Sustained Release Formulation of Compound 1 A sustained-release tablet containing Compound 1 was prepared using excipients in the amounts shown in the following table. Protocol A was used for SR1 tablets, Protocol B was used for SR2 tablets, Protocol C was used for SR3 tablets and 25 mg SR tablets, and Protocol D was used for SR4 tablets. These procedures are disclosed in U.S. Patent Publication No. 2015 / 0065484 regarding sustained-release formulations of Compound 1.

[0148] Protocol A: Step 1. Sieve the adipate of Compound 1, microcrystalline cellulose, hypromellose (Methocel K100 LV and Methocel K4M), and lactose monohydrate individually. Step 2. Transfer the materials sieved in Step 1 to a suitable mixer and mix. Step 3. Transfer the mixture obtained in Step 2 to a suitable granulator and mix. Step 4. Add purified water while mixing. Step 5. Transfer the granules obtained in Step 4 to a suitable dryer and dry until the LOD is less than 3%. Step 6. Sieve the granules obtained in Step 5. Step 7. Mix the granules obtained in Step 6 with the sieved magnesium stearate using a suitable mixer. Step 8. Compress the final mixture obtained in Step 7 using a suitable rotary tablet press.

[0149] Protocol B: Step 1. Sieve the adipate of the compound of Formula I, microcrystalline cellulose, hypromellose and pregelatinized starch individually. Step 2. Transfer the materials sieved in Step 1 to a suitable mixer and mix. Step 3. Transfer the mixture obtained in Step 2 to a suitable granulator and mix. Step 4. Add purified water while mixing. Step 5. Transfer the granules obtained in Step 4 to a suitable dryer and dry until the LOD is less than 3%. Step 6. Sieve the granules obtained in Step 5. Step 7. Sieve polyox, butylated hydroxytoluene, and colloidal silicon dioxide individually. Step 8. Transfer the granules obtained in Step 6 and the materials obtained in Step 7 to an appropriate mixer and mix them. Step 9. Add sieved magnesium stearate to the materials obtained in Step 8 and continue mixing. Step 10. Compress the final mixture obtained in Step 9 using an appropriate rotary tableting machine.

[0150] Protocol C: Step 1. Sieve lactose monohydrate, the adipate salt of the compound of formula I, microcrystalline cellulose, and hypromellose individually through an appropriate sieve. Step 2. Transfer the materials sieved in Step 1 to an appropriate mixer and mix them. Step 3. Transfer the mixture obtained in Step 2 to an appropriate granulator and mix. Step 4. Add purified water while mixing. Step 5. Perform appropriate sieving on the wet granules to sieve them. Step 6. Transfer the granules obtained in Step 5 to an appropriate dryer and dry until the LOD is less than 3%. Step 7. Grind the granules obtained in Step 6. Step 8. Mix the granules obtained in Step 7 and the sieved magnesium stearate in an appropriate mixer. Step 9. Compress the final mixture obtained in Step 8 using an appropriate rotary tableting machine.

[0151] Protocol D: Step 1. Sieve pregelatinized starch, the adipate salt of the compound of formula I, hypromellose, and a portion of the required microcrystalline cellulose individually through an appropriate sieve. Step 2. Transfer the materials sieved in Step 1 to an appropriate mixer and mix them. Step 3. Transfer the mixture obtained in Step 2 to an appropriate granulator and mix. Step 4. Add purified water while mixing. Step 5. Screen the wet granules through an appropriate sieve. Step 6. Transfer the granules obtained in Step 5 to an appropriate dryer and dry until the LOD is less than 3%. Step 7. Grind the granules obtained in Step 6. Step 8. Screen the remainder of the microcrystalline cellulose and half of the sodium bicarbonate. Step 9. Transfer the ground granules obtained in Step 7 and the screened material obtained in Step 8 to an appropriate mixer and mix. Step 10. Screen the remainder of the sodium bicarbonate and mix it with the mixture obtained in Step 9. Step 11. Screen the magnesium stearate and mix it with the mixture obtained in Step 10. Step 12. Compress the final mixture obtained in Step 11 using an appropriate rotary tablet press.

Table 4

Table 5

Table 6

Table 7

Table 8

[0152] Example 1: Study on the safety and efficacy of Compound 1 in participants with bronchiolitis obliterans syndrome (BOS) after lung transplantation In this Phase 1 / 2 trial, the safety and efficacy of Compound 1 are evaluated in participants with BOS after lung transplantation.

Table 9

[0153] The first phase adopts a non-blind parallel cohort design with partial randomization to evaluate safety, tolerability, PK, and PD, and to conduct dose selection in the trial phase to determine the recommended phase 2 dose (RP2D) of Compound 1 in participants with BOS after lung transplantation. A total of 30 participants with grade 1 or 2 BOS are assigned to receive one of three dose levels of Compound 1 (n = 10 each); for further details regarding the dose levels of Compound 1, please refer to Table 5. Participants who do not concomitantly use azole agents at the start of treatment or who are taking low to moderate CYP3A4-inhibiting azoles (e.g., posaconazole or isoconazole) are randomized at dose level 1 or 2. Participants who are taking itraconazole or voriconazole at the start of treatment are given at dose level 3. When the first phase is completed, an interim futility analysis is performed to determine the ORR (overall response rate) of all participants treated for 12 weeks or more. If a response (defined as a ≥ 10% increase in FEV 1 compared to baseline and confirmed by two consecutive spirometry evaluations performed at intervals of at least one week) is observed at the dose level selected as the RP2D, the study proceeds to the second phase. The practice of spirometry evaluation is reported in the art; for example, see Miller, M.R. et al. Eur. Respir. J. 2005;26: 319-338.

[0154] In the second phase, a single-arm non-blind design is adopted to evaluate the efficacy of Compound 1 at the RP2D and to further characterize its safety. Treatment with Compound 1 continues until there is a progression of BOS (defined as a ≥ 10% decrease from baseline in FEV 1 and confirmed by two consecutive spirometry evaluations performed at intervals of at least three weeks), unacceptable toxicity, or withdrawal of consent.

[0155] Information regarding the investigational drug and administration is shown in Table 4 below.

Table 10

Table 11

[0156] Participants may reduce or modify the dose during the treatment process based on AE (adverse event), clinical evaluation, change in concomitant medications, and clinical laboratory evaluation.

[0157] Investigation target population The following can be incorporated as the selection criteria for this study: ● Males or females aged 18 years or older ● Institution-prescribed informed consent that determines participation in all studies and compliance with the participation procedures, and consent form (if appropriate) ● Bilateral lung transplantation performed within 1 to 5 years prior to screening ● Submission of post-transplant baseline FEV 1 (average of the two highest values measured at least 3 weeks apart, according to the ISHLT criteria) after functional recovery and stabilization after lung transplantation. ● Grade 1 or 2 BOS (according to the ISHLT 2002 criteria) diagnosed and confirmed within 1 year from screening ● Grade 1 BOS can be defined as a reduction in FEV 1 to 66 - 80% of the post-transplant baseline FEV 1 ● Grade 2 BOS can be defined as a reduction in FEV 1 to 51 - 65% of the post-transplant baseline FEV 1 ● Note: The BOS grade can be determined by the average of two measurements taken at least 3 weeks apart with the patient not using inhaled bronchodilators. ● Participants taking azithromycin can start treatment at least 3 months before screening and should take a stable dose (e.g., 250 mg / day, at least 3 times a week). ● Note: After administration of azithromycin to the participant, FEV 1Keep it stable or deteriorating. In addition, before starting treatment with Compound 1, perform two pulmonary function tests at least three weeks apart for evaluation. ● If the participant is being treated with corticosteroids, keep the dose stable for four weeks before screening. ● Have the desire to avoid pregnancy and give birth based on the specified criteria.

[0158] The following can be incorporated as exclusion criteria for this study: ● History of single lung transplantation, heart-lung transplantation, lung re-transplantation, or other solid organ transplantation. ● Participants who are EBV-negative at the time of transplantation and have EBV donor IgG-positive lungs ● BOS grade 3 or higher according to the ISHLT 2002 diagnostic criteria ● Decrease in FEV due to other causes (multiple possible), such as BOS, inflammatory complications of lung allografts, antibody-mediated rejection, infections, airway dysfunction, allograft compression, graft expansion disorder, vascular occlusion, recurrence of transplantation indications, organizing pneumonia, etc. 1 ● Using other systemic treatments for BOS, such as extracorporeal photopheresis, montelukast, and alemtuzumab (except azithromycin). ● There has been a change in immunosuppressive therapy within four weeks before screening. ● Untreated and / or symptomatic GERD. ● Serious co-existing diseases such as invasive fungal diseases, B. Cepacia, non-TB mycobacteria, or TB. ● History of diffuse alveolar hemorrhage (DAH) ● Current or previous treatment with Janus kinase (JAK) inhibitors. ● Participants with test values at the time of screening defined in Table 6.

Table 12

[0159] In addition to the invention described herein, various modifications of the present invention will be apparent to those skilled in the art from the above description. The appended claims are also intended to cover such modifications. All patents, patent applications, and publications, etc., each reference cited in this application are hereby incorporated by reference in their entirety into this specification.

Claims

1. 13. A method of treating chronic pulmonary allograft dysfunction in a subject, comprising administering to the subject a JAK1 pathway inhibitor, or a pharma- ceutically acceptable salt thereof.

2. 2. The method of claim 1, wherein the chronic pulmonary allograft dysfunction is bronchiolitis obliterans syndrome.

3. The method of claim 1 or 2, wherein the subject is a lung transplant recipient.

4. 3. The method of claim 1 or 2, wherein the subject is a bilateral lung transplant recipient.

5. 3. The method of claim 2, wherein the subject is suffering from bronchiolitis obliterans syndrome, grade 0p, grade 1, grade 2, or grade 3 as determined by the International Society for Heart and Lung Transplantation (ISHLT) criteria.

6. The treatment of bronchiolitis obliterans syndrome comprises reducing FEV12 weeks after the first administration of a JAK1 pathway inhibitor, or a pharmacologic acceptable salt thereof. １ 3. The method of claim 2, comprising increasing the

7. The method of any one of claims 1 to 6, wherein the JAK1 pathway inhibitor, or a pharma- ceutically acceptable salt thereof, is a JAK1 / 2 inhibitor, or a pharma- ceutically acceptable salt thereof.

8. 8. The method of claim 7, wherein the JAK1 / 2 inhibitor is ruxolitinib, or a pharma- ceutically acceptable salt thereof, or baricitinib, or a pharma- ceutically acceptable salt thereof.

9. The method of any one of claims 1 to 6, wherein the JAK1 pathway inhibitor, or a pharma- ceutically acceptable salt thereof, is selective for JAK1 over JAK2, JAK3, and Tyk2.

10. 10. The method of claim 9, wherein the JAK1 pathway inhibitor is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or a pharma- ceutically acceptable salt thereof.

11. 10. The method of claim 9, wherein the JAK1 pathway inhibitor is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile adipate.

12. 13. A method of reducing the risk of bronchiolitis obliterans syndrome in a subject, comprising administering to the subject a JAK1 pathway inhibitor, or a pharma- ceutically acceptable salt thereof.

13. 13. The method of claim 12, wherein the subject is a lung transplant recipient.

14. 13. The method of claim 12, wherein the subject is a bilateral lung transplant recipient.

15. The method of any one of claims 12 to 14, wherein the JAK1 pathway inhibitor, or a pharma- ceutically acceptable salt thereof, is a JAK1 / 2 inhibitor, or a pharma- ceutically acceptable salt thereof.

16. 16. The method of claim 15, wherein the JAK1 / 2 inhibitor is ruxolitinib, or a pharma- ceutically acceptable salt thereof, or baricitinib, or a pharma- ceutically acceptable salt thereof.

17. The method of any one of claims 12 to 14, wherein the JAK1 pathway inhibitor is selective for JAK1 over JAK2, JAK3, and Tyk2.

18. 18. The method of claim 17, wherein the JAK1 pathway inhibitor is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or a pharma- ceutically acceptable salt thereof.

19. 18. The method of claim 17, wherein the JAK1 pathway inhibitor is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile adipate.

20. 13. A method of reducing the risk of lung retransplantation in a subject, comprising administering to the subject a JAK1 pathway inhibitor, or a pharma- ceutically acceptable salt thereof.

21. A method for reducing a subject's risk of being hospitalized, comprising administering to the subject an effective amount of a JAK1 pathway inhibitor, or a pharmacologic acceptable salt thereof, wherein the subject (a) has been diagnosed with bronchiolitis obliterans syndrome; (b) has undergone a lung transplant within 1 to 5 years prior to administration of the JAK1 pathway inhibitor, or a pharmacologic acceptable salt thereof; and (c) has an FEV1 attributable to causes other than bronchiolitis obliterans syndrome. １ The method according to claim 1, wherein no decrease in

Images