Dosing regimens for treatment with deuterated JAK inhibitors

Abstract

A method for treating a disease, disorder, or condition in a subject that is mediated solely or in part by Janus-related kinases, which is beneficially treated by administering a JAK1 inhibitor and / or a JAK2 inhibitor, is disclosed. The method includes administering a therapeutically effective amount of Compound (I), [Formula 1] TIFF2025515051000023.tif56150, or a pharma- ceutically acceptable salt thereof, to a subject.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 338,320, filed May 4, 2022, the entire teachings of which are incorporated herein by reference. [Background technology]

[0002] Janus-associated kinases (JAKs) mediate the signal transduction of numerous cytokines and growth factors important for hematopoiesis and immune function. JAK signaling involves recruitment of signal transducers and activators of transcription (STATs) to cytokine receptors, activation, and subsequent localization of STATs to the nucleus, leading to the regulation of gene expression.

[0003] Although certain JAK inhibitors, including ruxolitinib, baricitinib, and upadacitinib, are approved for the treatment of JAK-associated disorders including myelofibrosis, rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, and alopecia areata, improved treatments for JAK-associated disorders are needed. Summary of the Invention

[0004] It has been discovered that deuterated analogs of ruxolitinib (including compound (I), also referred to as (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(cyclopentyl-2,2,3,3,4,4,5,5-d8)propanenitrile, or D8-ruxolitinib, or CTP-543) are useful in the treatment of diseases, disorders or conditions mediated solely or in part by Janus-related kinases (JAKs), including JAK1 and / or JAK2. Compound (I) is represented by the following structural formula:

[0005] [ka]

[0006] In certain embodiments, compound (I) is administered as a pharma- ceutically acceptable salt, such as a phosphate salt. Compound (I) can be administered in a dose ranging from about 8 mg to about 32 mg per day (or the equivalent weight based on a salt, such as a phosphate salt, of compound (I)) as a single daily dose or in divided doses (e.g., twice daily). Based on these discoveries, novel therapeutic methods using compound (I) or a pharma- ceutically acceptable salt thereof for diseases, disorders or conditions mediated solely or in part by JAK in mammalian subjects are disclosed herein. In other embodiments, novel therapeutic methods using compound (I) or a pharma- ceutically acceptable salt thereof for treating diseases or conditions mediated solely or in part by Janus-associated kinases (JAK) in mammalian subjects are disclosed herein.

[0007] In one embodiment, a method is provided for treating a disease or condition mediated solely or in part by Janus-associated kinase (JAK) in a mammalian (e.g., human) subject, comprising administering to the subject a compound represented by the structural formula, or a pharma- ceutical acceptable salt thereof:

[0008] [ka]

[0009] each position specifically designated as deuterium has at least 95% deuterium incorporation; The compound or a pharma- ceutically acceptable salt thereof is administered (1) in an amount ranging from about 8 mg to about 32 mg per day for a first period of 8 to 24 weeks, followed by (2) a second period of at least 8 weeks, wherein the compound or a pharma- ceutically acceptable salt thereof is administered in an amount that is 50-75% of the daily amount administered during the first period, to treat a disease or condition.

[0010] In certain embodiments, the disease or condition mediated solely or partially by Janus-associated kinase (JAK) is not alopecia, such as alopecia areata.In certain embodiments, the disease or condition mediated solely or partially by Janus-associated kinase (JAK) is the disease or condition mediated solely or partially by Janus-associated kinase 1 (JAK1) and / or Janus-associated kinase 2 (JAK2).In certain embodiments, the disease or condition mediated solely or partially by JAK1 and / or JAK2 is not alopecia, such as alopecia areata.

[0011] In certain embodiments, the disease, disorder or condition mediated solely or in part by JAK includes skin diseases such as proliferative, autoimmune and / or inflammatory skin diseases, psoriasis, atopic dermatitis, scleroderma, rosacea, skin cancer, dermatitis, dermatitis herpetiformis, dermatomyositis, vitiligo, alopecia, contact dermatitis, xeroderma, ichthyosis, hidradenitis suppurativa, urticaria, lichen planus, prurigo nodularis, vasculitis, cutaneous lupus erythematosus (CLE), chronic idiopathic pruritus, hyperproliferative disorders or cancers including polycythemia vera, essential thrombocytopenia, myelofibrosis, asthma, chronic obstructive pulmonary disease, chronic transplant pulmonary failure (e.g., bronchiolitis obliterans syndrome), pulmonary fibrosis, cystic fibrosis, rhinitis, bronchiolitis, byssinosis, dust mites, and the like. and respiratory diseases such as lung, bronchiectasis, hypersensitivity pneumonitis, lung cancer, mesothelioma, sarcoidosis; digestive diseases such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, retroperitoneal fibrosis, celiac disease, cancer; ophthalmic diseases such as myasthenia gravis, Sjogren's syndrome, conjunctivitis, scleritis, uveitis, dry eye syndrome, keratitis, iritis; systemic conditions such as systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, type 1 diabetes and diabetic complications, cancer, ankylosing spondylitis, psoriatic arthritis, and other autoimmune diseases and conditions in which immunosuppression may be desirable, for example to treat or prevent acute and / or chronic graft-versus-host disease (e.g., graft-versus-host disease in organ transplantation).

[0012] In certain embodiments, the disease or condition mediated solely or in part by Janus-associated kinase (JAK) is not alopecia, such as alopecia areata. In certain embodiments, the disease or condition mediated solely or in part by Janus-associated kinase (JAK) is not an autoimmune disease, a skin disease, an allograft rejection, a graft-versus-host disease, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, type 1 diabetes, systemic lupus erythematosus, an inflammatory bowel disease, Crohn's disease, myasthenia gravis, immunoglobulin nephropathy, myocarditis, an autoimmune thyroid disorder, a viral disease, Epstein-Barr virus (EBV), hepatitis B, hepatitis C, HIV, , HTLV1, Varicella-Zoster Virus (VZV), Human Papilloma Virus (HPV), cancer, myeloproliferative disorders, inflammatory disorders, ocular inflammatory disorders, iritis, uveitis, scleritis, conjunctivitis, inflammatory disorders of the airways, inflammatory disorders of the upper airways, inflammatory disorders of the lower airways, inflammatory myopathy, myocarditis, disorders associated with ischemia-reperfusion or ischemic events, anorexia or cachexia resulting from or associated with cancer, fatigue resulting from or associated with cancer, bone resorption disorders, or mast cell activation syndrome. In certain embodiments, the autoimmune disease is a bullous skin disease, and in certain embodiments, the bullous skin disease is pemphigus vulgaris or bullous pemphigoid (BP). In certain embodiments, the skin disease is skin sensitization, skin irritation, skin rash, contact dermatitis, or allergic contact sensitization or psoriasis. In certain embodiments, the myeloproliferative disorder (MPD) is polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV-MF), post-essential thrombocythemia myelofibrosis (post-ET-MF), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), or systemic mast cell disease (SMCD); in certain embodiments, the disease is primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV-MF), post-essential thrombocythemia myelofibrosis (post-ET-MF), polycythemia vera (PV), or essential thrombocythemia (ET), or the disease is primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV-MF), or post-essential thrombocythemia myelofibrosis (post-ET-MF).In certain embodiments, the cancer is a solid tumor, myeloma, prostate cancer, renal cancer, liver cancer, breast cancer, lung cancer, thyroid cancer, Kaposi's sarcoma, Castleman's disease, pancreatic cancer, blood cancer, lymphoma, leukemia, multiple myeloma, skin cancer, cutaneous T-cell lymphoma, or cutaneous B-cell lymphoma. In certain embodiments, the bone resorption disease is osteoporosis, osteoarthritis, bone resorption associated with hormone imbalance, bone resorption associated with hormone therapy, bone resorption associated with autoimmune disease, or bone resorption associated with cancer. Further examples of JAK-associated diseases include allergic conditions such as asthma, food allergies, eczematous dermatitis, contact dermatitis, atopic dermatitis (atopic eczema), and rhinitis. Further examples of JAK-associated diseases include viral diseases such as Epstein-Barr virus (EBV), hepatitis B, hepatitis C, HIV, HTLV1, varicella-zoster virus (VZV), and human papillomavirus (HPV). Further examples of JAK-related diseases include cartilage turnover-related diseases, such as gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, painful dystrophy, Tietze's syndrome, costoarthritis, endemic osteoarthritis, Musereni's disease, Handigodu's disease, degeneration due to fibromyalgia, systemic lupus erythematosus, scleroderma, or ankylosing spondylitis. Further examples of JAK-related diseases include congenital chondrodysplasia, such as hereditary chondrolysis, chondrodysplasia, and pseudochondrodysplasia (e.g. microtia, anotia, and metaphyseal chondrodysplasia). In certain embodiments, the disease or condition mediated solely or partially by Janus-related kinase (JAK) is not alopecia, such as alopecia areata.

[0013] In certain embodiments, during the first period, the compound or a pharma- ceutically acceptable salt thereof is administered at about 12 mg / day, about 16 mg / day, about 24 mg / day, or about 32 mg / day.

[0014] In certain embodiments, during the second period, the compound or a pharma- ceutically acceptable salt thereof is administered at about 6 mg / day, about 8 mg / day, about 12 mg / day, or about 16 mg / day.

[0015] In certain embodiments, in the first period, the compound or its pharma- ceutically acceptable salt is administered at about 24 mg / day, and in the second period, the compound or its pharma- ceutically acceptable salt is administered at about 16 mg / day. In certain embodiments, about 24 mg / day of the compound or salt is administered once a day, and about 16 mg / day of the compound or salt is administered once a day. In certain embodiments, about 24 mg / day of the compound or salt is administered at about 12 mg twice a day, and about 16 mg / day of the compound or salt is administered at about 8 mg twice a day.

[0016] In certain embodiments, in the first period, the compound or its pharma- ceutically acceptable salt is administered at about 16 mg / day, and in the second period, the compound or its pharma- ceutically acceptable salt is administered at about 8 mg / day. In certain embodiments, about 16 mg / day of the compound or salt is administered once a day, and about 8 mg / day of the compound or salt is administered once a day. In certain embodiments, about 16 mg / day of the compound or salt is administered at about 8 mg twice a day, and about 8 mg / day of the compound or salt is administered at about 4 mg twice a day.

[0017] In certain embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered orally.

[0018] In certain embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered in a pharmaceutical formulation that is a tablet.

[0019] In certain embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered once daily during the first period of time. In certain embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered twice daily during the first period of time.

[0020] In certain embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered once daily during the second period of time. In certain embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered twice daily during the second period of time.

[0021] In certain embodiments, the first period of time is about 8-24 weeks. In certain embodiments, the first period of time is about 12 weeks. In certain embodiments, the first period of time is about 16 weeks. In certain embodiments, the first period of time is about 20 weeks. In certain embodiments, the first period of time is about 24 weeks. In certain embodiments, the second period of time is at least 12 weeks. In certain embodiments, the second period of time is at least 24 weeks.

[0022] In certain embodiments, the first period of time is about 8-12 weeks. In certain embodiments, the first period of time is about 8 weeks. In certain embodiments, the first period of time is about 12 weeks. In certain embodiments, the first period of time is at least 8 weeks. In certain embodiments, the second period of time is at least 8 weeks.

[0023] In certain embodiments, in Compound (I), each position specifically designated as deuterium has at least 97% deuterium incorporation.

[0024] In another aspect, there is provided a method of treating a disease or condition mediated solely or in part by Janus-associated kinase (JAK) in a mammalian (e.g., human) subject, the method comprising administering to the subject a compound represented by the structural formula, or a pharma- ceutical acceptable salt thereof:

[0025] [ka]

[0026] each position specifically designated as deuterium has at least 95% deuterium incorporation; The compound or a pharma- ceutically acceptable salt thereof is administered (1) in an amount ranging from about 4 mg to about 50 mg per day for a first period of 8 to 24 weeks, followed by (2) a second period of at least 8 weeks, wherein the compound or a pharma- ceutically acceptable salt thereof is administered in an amount that is 50 to 75% of the daily amount administered during the first period, to treat a disease or condition.

[0027] Another aspect of the present invention is compound (I) or a pharma- ceutically acceptable salt thereof (i.e., the equivalent of a pharma- ceutically acceptable salt, such as a phosphate salt) for use in the treatment of a disease, disorder, or condition mediated solely or in part by Janus-associated kinase (JAK), i.e., a disease, disorder, or condition that can be treated by a compound that modulates the activity of Janus-associated kinase 1 (JAK1) and / or Janus-associated kinase 2 (JAK2). The compound may be administered in a dosing regimen disclosed herein. In certain embodiments, the disease, disorder, or condition mediated solely or in part by Janus-associated kinase (JAK) is not alopecia, such as alopecia areata. In certain embodiments, the disease, disorder, or condition mediated solely or in part by Janus-associated kinase (JAK) is a disease or condition mediated solely or in part by Janus-associated kinase 1 (JAK1) and / or Janus-associated kinase 2 (JAK2). In certain embodiments, the disease, disorder or condition mediated solely or partially by JAK1 and / or JAK2 is not alopecia, such as alopecia areata.In certain embodiments, the disease, disorder or condition is an autoimmune skin disease.In certain embodiments, the disease, disorder or condition is selected from psoriasis, atopic dermatitis, dermatomyositis, vitiligo, nasopharyngitis, lichen planus, or prurigo nodularis.

[0028] Yet another aspect of the present invention is the use of compound (I) or a pharma- ceutically acceptable salt thereof (i.e., an equivalent amount of a pharma- ceutically acceptable salt, such as a phosphate salt) for the manufacture of a medicament for treating a disorder, disease, or condition that can be treated by a compound that modulates the activity of Janus-associated kinase 1 (JAK1) and / or Janus-associated kinase 2 (JAK2). The compound may be administered in a dosing regimen disclosed herein. In certain embodiments, the disease, disorder, or condition mediated solely or in part by Janus-associated kinase (JAK) is not alopecia, such as alopecia areata. In certain embodiments, the disease, disorder, or condition mediated solely or in part by Janus-associated kinase (JAK) is a disease or condition mediated solely or in part by Janus-associated kinase 1 (JAK1) and / or Janus-associated kinase 2 (JAK2). In certain embodiments, the disease, disorder, or condition mediated solely or in part by JAK1 and / or JAK2 is not alopecia, such as alopecia areata.

[0029] Yet another aspect provides a pharmaceutical composition for use in treating a disease, disorder, or condition mediated solely or in part by a Janus associated kinase (JAK) as described herein. In certain embodiments, the pharmaceutical composition comprises 4-50 mg of Compound (I) or a pharma- ceutically acceptable salt thereof (i.e., the equivalent amount of a pharma- ceutically acceptable salt, such as a phosphate salt), together with a pharma- ceutical acceptable carrier. In certain embodiments, a pharmaceutical composition comprising 4-50 mg of Compound (I) or a pharma- ceutical acceptable salt thereof is (1) administered to a human subject in an amount ranging from about 4 mg to about 50 mg per day for a first period of 8-24 weeks, followed by (2) administration of the pharmaceutical composition in a daily amount that is 50-75% of the amount of Compound (I) administered per day during the first period for a second period of at least 8 weeks, such that the disease or condition is treated.

[0030] In any of the aspects and embodiments disclosed herein, in certain embodiments, the disease or condition mediated solely or in part by Janus-associated kinases (JAKs) is not alopecia, such as alopecia areata. [Brief description of the drawings]

[0031] [Figure 1] Figure 1 shows the proportion of responders (patients with a ≥50% reduction in SALT score compared with baseline) at week 24 in the phase 2a study, which includes the placebo, 4 mg BID, 8 mg BID, and 12 mg BID cohorts. [Diagram 2] Figure 2 shows the proportion of responders by visit in the Phase 2a study (patients who achieved a ≥50% reduction in SALT score compared with baseline), which includes the placebo, 4 mg BID, 8 mg BID, and 12 mg BID cohorts. [Diagram 3] Figure 3 shows the proportion of responders by visit in the Phase 2a study (patients who achieved a ≥75% reduction in SALT score compared with baseline), which includes the placebo, 4 mg BID, 8 mg BID, and 12 mg BID cohorts. [Figure 4] Figure 4 shows the proportion of responders by visit in the Phase 2a study (patients who achieved a ≥90% reduction in SALT score compared to baseline), which includes the placebo, 4 mg BID, 8 mg BID, and 12 mg BID cohorts. [Diagram 5] Figure 5 shows the improvement in SALT scores for patients after 24 weeks of the Phase 2a study, which included the placebo, 4 mg BID, 8 mg BID, and 12 mg BID cohorts. [Figure 6] FIG. 6 shows the relative change in SALT scores by visit in the Phase 2a study, which includes the placebo, 4 mg BID, 8 mg BID, and 12 mg BID cohorts. [Figure 7]FIG. 7 shows the study design for administering 8 mg BID or 12 mg BID of Compound (I) (CTP-543) for a first period, followed by a lower dose of Compound (I) or placebo for a second period. [Figure 8] FIG. 8 shows patient entry and disposition of subjects in the open-label extension (OLE) study of Compound (I) (CTP-543). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0032] definition The term "treat" refers to reducing, inhibiting, attenuating, decreasing, arresting, or stabilizing the onset or progression of a disease (e.g., a disease or disorder detailed herein), reducing the severity of a disease, or improving symptoms associated with a disease. For example, treating alopecia includes regrowing hair, preventing further hair loss, or reducing the rate of hair loss.

[0033] "Alopecia" means any condition or disorder that results in the loss of hair in one or more areas of the body. Alopecia includes, but is not limited to, androgenetic alopecia, alopecia areata, telogen effluvium, alopecia areata, alopecia totalis, and alopecia universalis.

[0034] The effectiveness of the treatment of alopecia, such as alopecia areata, can be measured in various ways, some of which are known in the art.For example, the "severity of alopecia tool," known as SALT, is a validated rating scale developed by the National Alopecia Areata Foundation Working Group to assess the extent of hair loss.See, for example, Olsen EA, Hordinsky MK, Price VH, et al. Alopecia Areata Clinical Trial Evaluation Guidelines-Part II. J Am Acad Dermatol 2004:51:440-447, incorporated herein by reference.The SALT score is calculated for a patient by measuring the percentage of hair loss in each of the four scalp regions and summing them to achieve a composite value.Hair regrowth is reflected by a decrease in SALT score.For example, complete absence of hair on the scalp has a SALT score of 100, while complete hair regrowth is a SALT score of 0. In certain embodiments, the treatment methods described herein can provide an improvement in the SALT score of at least 10 points after treatment (e.g., from a SALT score of 100 before treatment to a SALT score of 90 after treatment). In further embodiments, the treatment methods described herein can result in an improvement in the SALT score of at least 20 points, 30 points, 40 points, 50 points, 60 points, 70 points, 80 points, 90 points, or 100 points. In certain embodiments, the treatment methods described herein can provide at least a 20% improvement from baseline in the patient's SALT score, or at least a 30% improvement from baseline in the patient's SALT score, or at least a 40% improvement from baseline in the patient's SALT score, or at least a 50% improvement from baseline in the patient's SALT score, or at least a 60% improvement from baseline in the patient's SALT score, or at least a 70% improvement from baseline in the patient's SALT score, or at least a 75% improvement from baseline in the patient's SALT score, or at least an 80% improvement from baseline in the patient's SALT score, or at least a 90% improvement from baseline in the patient's SALT score.

[0035] The term disease, disorder, or condition mediated solely or in part by Janus-associated kinase (JAK) refers to a disease, condition, or disorder that can be treated by a compound that modulates the activity of Janus-associated kinase 1 (JAK1) and / or Janus-associated kinase 2 (JAK2). Such diseases, conditions or disorders include skin diseases such as psoriasis, atopic dermatitis, scleroderma, rosacea, skin cancer, dermatitis, dermatitis herpetiformis, dermatomyositis, vitiligo, alopecia, contact dermatitis, xeroderma, ichthyosis, hidradenitis suppurativa, urticaria, lichen planus, prurigo nodularis, vasculitis, cutaneous lupus erythematosus (CLE), chronic idiopathic pruritus; hyperproliferative disorders or cancers including polycythemia vera, essential thrombocytopenia, myelofibrosis; asthma, chronic obstructive pulmonary disease, chronic transplant pulmonary failure (e.g., bronchiolitis obliterans syndrome), pulmonary fibrosis, cystic fibrosis, rhinitis, bronchiolitis, byssinosis, pneumoconiosis, bronchiectasis, hypersensitivity pneumonitis, lung cancer, These include, but are not limited to, respiratory diseases such as mesothelioma and sarcoidosis, digestive diseases such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, retroperitoneal fibrosis, celiac disease, and cancer, eye diseases such as myasthenia gravis, Sjogren's syndrome, conjunctivitis, scleritis, uveitis, dry eye syndrome, keratitis, and iritis, systemic conditions such as systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, type 1 diabetes and diabetic complications, cancer, ankylosing spondylitis, and psoriatic arthritis, and other autoimmune diseases and conditions in which immunosuppression may be desirable, for example, to treat or prevent acute and / or chronic graft-versus-host disease (e.g., graft-versus-host disease in organ transplantation). In certain embodiments, the disease or condition mediated solely or partially by Janus-associated kinase (JAK) is not alopecia, such as alopecia areata.

[0036] In certain embodiments, further examples of diseases, conditions, or disorders that can be treated by compounds that modulate the activity of Janus-associated kinase 1 (JAK1) and / or Janus-associated kinase 2 (JAK2) include autoimmune diseases, skin diseases, allograft rejection, graft-versus-host disease, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, type 1 diabetes, systemic lupus erythematosus, inflammatory bowel disease, Crohn's disease, myasthenia gravis, immunoglobulin nephropathy, myocarditis, autoimmune thyroid disorders, viral diseases, Epstein-Barr virus disease, and the like. In certain embodiments, the autoimmune disease is a bullous skin disease, and in certain embodiments, the bullous skin disease is pemphigus vulgaris or bullous pemphigoid (BP). In certain embodiments, the skin disease is skin sensitization, skin irritation, skin rash, contact dermatitis, or allergic contact sensitization or psoriasis. In certain embodiments, the myeloproliferative disorder (MPD) is polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV-MF), post-essential thrombocythemia myelofibrosis (post-ET-MF), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), or systemic mast cell disease (SMCD); in certain embodiments, the disease is primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV-MF), post-essential thrombocythemia myelofibrosis (post-ET-MF), polycythemia vera (PV), or essential thrombocythemia (ET), or the disease is primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV-MF), or post-essential thrombocythemia myelofibrosis (post-ET-MF).In certain embodiments, the cancer is a solid tumor, myeloma, prostate cancer, renal cancer, liver cancer, breast cancer, lung cancer, thyroid cancer, Kaposi's sarcoma, Castleman's disease, pancreatic cancer, blood cancer, lymphoma, leukemia, multiple myeloma, skin cancer, cutaneous T-cell lymphoma, or cutaneous B-cell lymphoma. In certain embodiments, the bone resorption disease is osteoporosis, osteoarthritis, bone resorption associated with hormone imbalance, bone resorption associated with hormone therapy, bone resorption associated with autoimmune disease, or bone resorption associated with cancer. Further examples of JAK-associated diseases include allergic conditions such as asthma, food allergies, eczematous dermatitis, contact dermatitis, atopic dermatitis (atopic eczema), and rhinitis. Further examples of JAK-associated diseases include viral diseases such as Epstein-Barr virus (EBV), hepatitis B, hepatitis C, HIV, HTLV1, varicella-zoster virus (VZV), and human papillomavirus (HPV). Further examples of JAK-related diseases include cartilage turnover-related diseases, such as gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, painful dystrophy, Tietze's syndrome, costoarthritis, endemic osteoarthritis, Musereni's disease, Handigodu's disease, degeneration due to fibromyalgia, systemic lupus erythematosus, scleroderma, or ankylosing spondylitis. Further examples of JAK-related diseases include congenital chondrodysplasia, such as hereditary chondrolysis, chondrodysplasia, and pseudochondrodysplasia (e.g. microtia, anotia, and metaphyseal chondrodysplasia). In certain embodiments, the disease or condition mediated solely or partially by Janus-related kinase (JAK) is not alopecia, such as alopecia areata.

[0037] As used herein, the term "subject" includes humans, as well as non-human mammals such as cats, dogs, sheep, cows, pigs, goats, non-human primates (including monkeys and hominins).

[0038] The term "about" as used herein means "approximately," i.e., within an acceptable error range of a particular value as determined by one of ordinary skill in the art. For example, "about" can mean up to a 10% range above or below a particular value, up to a 5% range above or below a particular value, or up to a 1% range above or below a particular value. Furthermore, when a particular value is a length of time of several weeks, the term "about" can mean up to about 2 weeks, or up to about 1 week.

[0039] It is recognized that, depending on the origin of the chemicals used in synthesis, some variation in natural isotopic abundance occurs in the synthesized compound.Therefore, preparations of ruxolitinib inherently contain a small amount of deuterated isotope substitution.Despite this variation, the concentration of naturally abundant stable hydrogen and carbon isotopes is small and immaterial compared to the degree of stable isotope substitution of the compounds of the present invention.See, for example, Wada, E et al., Seikagaku, 1994, 66:15; Gannes, LZ et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725.

[0040] In compound (I), any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", it is understood that the position has hydrogen at its natural abundance isotopic composition. However, when a position is specifically designated as "H" or "hydrogen", as described in certain embodiments, the position has at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% hydrogen. In some embodiments, when a position is specifically designated as "H" or "hydrogen", as described in detail, the position incorporates ≦20% deuterium, ≦10% deuterium, ≦5% deuterium, ≦4% deuterium, ≦3% deuterium, ≦2% deuterium, or ≦1% deuterium. Also, unless otherwise noted, when a position is specifically designated as "D" or "deuterium," the position is understood to have deuterium at least 3340 times the natural abundance of deuterium, or 0.015% (i.e., at least 50.1% deuterium incorporation). The amount of deuterium incorporation at a designated position may be measured by analytical methods known to those of skill in the art, for example, by proton NMR.

[0041] The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0042] In other embodiments, Compound (I) has an isotopic enrichment factor for each designated deuterium position (or atom) of at least 3500 (52.5% deuterium incorporation at each designated deuterium position), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0043] In some embodiments, in the compounds of the present invention, each designated deuterium position (or atom) has at least 52.5% deuterium incorporation. In some embodiments, in the compounds of the present invention, each designated deuterium position has at least 60% deuterium incorporation. In some embodiments, in the compounds of the present invention, each designated deuterium position has at least 67.5% deuterium incorporation. In some embodiments, in the compounds of the present invention, each designated deuterium position has at least 75% deuterium incorporation. In some embodiments, in the compounds of the present invention, each designated deuterium position has at least 80% deuterium incorporation. In some embodiments, in the compounds of the present invention, each designated deuterium position has at least 85% deuterium incorporation. In some embodiments, in the compounds of the present invention, each designated deuterium position has at least 90% deuterium incorporation. In some embodiments, in the compounds of the present invention, each designated deuterium position has at least 95% deuterium incorporation. In some embodiments, in the compounds of the present invention, each designated deuterium position has at least 97% deuterium incorporation. In some embodiments, in the compounds of the invention, each designated deuterium position has at least 98% deuterium incorporation. In some embodiments, in the compounds of the invention, each designated deuterium position has at least 99% deuterium incorporation. In some embodiments, in the compounds of the invention, each designated deuterium position has at least 99.5% deuterium incorporation.

[0044] The term "isotopomer" refers to a molecule whose chemical structure differs from the structure shown for Compound (I) only in its isotopic composition.

[0045] The term "compound" when referring to the compounds of the present invention refers to a collection of molecules with the same chemical structure, except that there may be isotopic variations among the constituent molecules of the molecule.Thus, while compound (I) is represented by a specific chemical structure with deuterium atoms at eight designated positions, it is clear to one skilled in the art that compound (I) contains molecules with deuterium at each of the eight designated positions, and may also contain isotopic substitutions with hydrogen atoms at one or more designated deuterium positions in the structure.The relative amount of such isotopic substitutions in compound (I) depends on several factors, including the isotopic purity of the deuteration reagent used to make the compound, and the efficiency of deuterium incorporation in the various synthetic steps used to prepare the compound.In certain embodiments, the relative amount of such isotopic substitutions as a whole is less than 49.9% of the compound. In other embodiments, the relative amount of such isotopic substitutions overall is less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compounds.

[0046] The present invention also provides salts of compound (I). The salts of the compounds of the present invention are formed between an acid group of the compound, such as an amino acid functional group, and a basic group, or a basic group of the compound, such as a carboxyl functional group, and an acid group. According to another embodiment, the compound is a pharma- ceutically acceptable acid addition salt, such as a phosphate salt.

[0047] As used herein, the term "pharmaceutically acceptable" refers to a composition that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt that is capable of providing, directly or indirectly, a compound of the invention upon administration to a recipient. A "pharmaceutically acceptable counterion" is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.

[0048] Acids commonly used to form pharma- ceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and organic acids such as paratoluenesulfonic acid, salicylic acid, tartaric acid, bitaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, and related inorganic and organic acids. Such pharma- ceutically acceptable salts therefore include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylic acid, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, , benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactic acid, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelic acid and other salts. In one embodiment, pharma- ceutically acceptable acid addition salts include those formed with mineral acids, such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids, such as maleic acid.

[0049] The term "stable compound," as used herein, refers to a compound that has sufficient stability to permit its manufacture and maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., formulation into a therapeutic product, an intermediate for use in the manufacture of a therapeutic compound, an isolatable or storable intermediate compound, treatment of a disease or condition responsive to a therapeutic agent).

[0050] "D" and "d" both refer to deuterium. "Stereoisomer" refers to both enantiomers and diastereomers. "Tert" and "t-" each refer to tertiary. "US" means the United States of America.

[0051] "Deuterium substituted" refers to the replacement of one or more hydrogen atoms with a corresponding number of deuterium atoms.

[0052] It has been found that administration of an equivalent amount of compound (I) or a pharma- ceutically acceptable salt thereof can result in hair growth after administration in a first period. According to the present invention, the amount of compound (I) or a salt thereof administered to the patient or subject can then (after the first administration period) be reduced in a second treatment period while maintaining and / or prolonging (increasing) the hair growth achieved in the first period. In general, the amount of compound (I) or a salt thereof administered in the second period is sufficient to maintain the hair growth achieved in the first period (e.g., as measured by the severity of alopecia tool (SALT) score), e.g., about 50-75% of the daily amount administered in the first period (e.g., if 16 mg / day of compound (I) or a salt thereof is administered in the first period, 8-12 mg / day can be administered in the second period). In certain embodiments, the maintenance dose (amount administered per day during the second period) is about 33.3% of the daily amount administered in the first period.

[0053] Treatment method In one embodiment, the present invention provides a method of treating alopecia in a human subject, the method comprising administering to a subject a compound represented by the structural formula:

[0054] [ka]

[0055] or a pharma- ceutically acceptable salt thereof, wherein each position specifically designated as deuterium has at least 90% deuterium incorporation, the compound or a pharma- ceutically acceptable salt thereof is administered (1) for a first period during which the compound or a pharma- ceutically acceptable salt thereof is administered in an amount ranging from 8 mg to 32 mg per day, followed by (2) for a second period during which the compound or a pharma- ceutically acceptable salt thereof is administered in a daily amount that is 50-75% of the daily amount administered during the first period, to treat alopecia. In certain embodiments, the first period is about 8-24 weeks, e.g., 8 weeks, 12 weeks, 16 weeks, 20 weeks, or 24 weeks. In certain embodiments, the second period is at least 8 weeks, e.g., 8 weeks, 12 weeks, 16 weeks, 20 weeks, or 24 weeks (or more).

[0056] In one embodiment, the present invention provides a method of treating alopecia in a human subject, the method comprising administering to a subject a compound represented by the following structural formula:

[0057] [ka]

[0058] or a pharma- ceutical acceptable salt thereof, wherein each position specifically designated as deuterium has at least 95% deuterium incorporation; The compound or a pharma- ceutically acceptable salt thereof is administered (1) for a first period during which the compound or a pharma- ceutically acceptable salt thereof is administered in an amount ranging from 8 mg to 32 mg per day, followed by (2) for a second period during which the compound or a pharma- ceutically acceptable salt thereof is administered in a daily amount that is 50 to 75% of the daily amount administered during the first period, to treat alopecia. In certain embodiments, the first period is about 8 to 24 weeks, such as 8 weeks, 12 weeks, 16 weeks, 20 weeks, or 24 weeks. In certain embodiments, the second period is at least 8 weeks, such as 8 weeks, 12 weeks, 16 weeks, 20 weeks, or 24 weeks (or more).

[0059] In certain embodiments, alopecia is treated when the SALT score of the subject at the end of the first period is changed by 50% or more compared to the baseline SALT score of the subject before treatment.In certain embodiments, alopecia is treated when the SALT score of the subject at the end of the second period is 20 or less.In certain embodiments, alopecia is treated when the SALT score of the subject at the end of the first period is changed by 50% or more compared to the baseline SALT score of the subject before treatment, and when the SALT score of the subject at the end of the second period is 20 or less.

[0060] In certain embodiments, the length of the first period of time is sufficient to achieve a SALT score of 50 or less, 40 or less, 30 or less, 20 or less, 15 or less, 10 or less, 5 or less, 1 or less, or zero at the end of the first period of time. In certain embodiments, the length of the first period of time is sufficient to achieve a SALT score of 20 or less at the end of the first period of time. In certain embodiments, the length of the first period of time is sufficient to achieve a SALT score of 15 or less at the end of the first period of time. In certain embodiments, the length of the first period of time is sufficient to achieve a SALT score of 10 or less at the end of the first period of time. In certain embodiments, the length of the first period of time is sufficient to achieve a SALT score of 5 or less at the end of the first period of time. In certain embodiments, the length of the first period of time is sufficient to achieve a SALT score of 1 or less at the end of the first period of time. In certain embodiments, the length of the first period of time is sufficient to achieve a SALT score of zero at the end of the first period of time.

[0061] In certain embodiments, the alopecia is alopecia areata.

[0062] In certain embodiments, during the first period, the compound or a pharma- ceutically acceptable salt thereof is administered at about 8 mg / day, about 12 mg / day, about 16 mg / day, about 24 mg / day, or about 32 mg / day. In certain embodiments, during the first period, the compound or a pharma- ceutically acceptable salt thereof is administered at about 16 mg / day, about 24 mg / day, or about 32 mg / day.

[0063] In certain embodiments, during the second period, the compound or a pharma- ceutically acceptable salt thereof is administered at about 6 mg / day, about 8 mg / day, about 12 mg / day, about 16 mg / day, about 18 mg / day, about 20 mg / day, or about 24 mg / day. In certain embodiments, during the second period, the compound or a pharma- ceutically acceptable salt thereof is administered at about 8 mg / day, about 12 mg / day, or about 16 mg / day. In certain embodiments, the maintenance dose (the amount administered per day during the second period) is about 33.3% of the amount administered per day during the first period. In certain embodiments, the maintenance dose is about 50% of the amount administered per day during the first period. In certain embodiments, the maintenance dose is about 66.7% of the amount administered per day during the first period. In certain embodiments, the maintenance dose is about 75% of the amount administered per day during the first period.

[0064] In certain embodiments, in the first period, the compound or its pharma- ceutically acceptable salt is administered at about 24 mg / day, and in the second period, the compound or its pharma- ceutically acceptable salt is administered at about 16 mg / day. In certain embodiments, about 24 mg / day is administered in a single dose (i.e., once a day), and about 16 mg / day is administered in a single dose (i.e., once a day). In certain embodiments, about 24 mg / day is administered in two doses of about 12 mg each (i.e., about 12 mg twice a day), and about 16 mg / day is administered in two doses of about 8 mg each (i.e., about 8 mg twice a day).

[0065] In certain embodiments, in the first period, the compound or its pharma- ceutically acceptable salt is administered at about 16 mg / day, and in the second period, the compound or its pharma- ceutically acceptable salt is administered at about 8 mg / day. In certain embodiments, about 16 mg / day is administered in a single dose (i.e., once a day), and about 8 mg / day is administered in a single dose (i.e., once a day). In certain embodiments, about 16 mg / day is administered as two doses of about 8 mg each (i.e., about 8 mg twice a day), and about 8 mg / day is administered as two doses of about 4 mg each (i.e., about 4 mg twice a day).

[0066] In certain embodiments, in the first period, the compound or its pharma- ceutically acceptable salt is administered at about 24 mg / day, and in the second period, the compound or its pharma- ceutically acceptable salt is administered at about 8 mg / day. In certain embodiments, about 24 mg / day is administered in a single dose (i.e., once a day), and about 8 mg / day is administered in a single dose (i.e., once a day). In certain embodiments, about 24 mg / day is administered in two doses of about 12 mg each (i.e., about 12 mg twice a day), and about 8 mg / day is administered in two doses of about 4 mg each (i.e., about 4 mg twice a day).

[0067] In certain embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered orally.

[0068] In certain embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered in a pharmaceutical formulation that is a tablet.

[0069] In certain embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered once daily (QD) during the first period of time. In certain embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered twice daily (BD) during the first period of time.

[0070] In certain embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered once daily (QD) during the second period. In certain embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered twice daily (BID) during the second period.

[0071] In certain embodiments, the first period of time is about 8-24 weeks. In certain embodiments, the first period of time is about 8-12 weeks. In certain embodiments, the first period of time is about 8 weeks. In certain embodiments, the first period of time is about 10 weeks. In certain embodiments, the first period of time is about 12 weeks. In certain embodiments, the first period of time is about 16 weeks. In certain embodiments, the first period of time is about 20 weeks. In certain embodiments, the first period of time is about 24 weeks.

[0072] In certain embodiments, the second period of time is at least 8 weeks. In certain embodiments, the second period of time is at least 12 weeks. In certain embodiments, the second period of time is at least 24 weeks.

[0073] In certain embodiments, in Compound (I), each position specifically designated as deuterium has at least 97% deuterium incorporation.

[0074] In certain embodiments, the daily amount administered in the second period is about 50% of the daily amount administered in the first period. In certain embodiments, the daily amount administered in the second period is about 66.7% of the daily amount administered in the first period. In certain embodiments, the daily amount administered in the second period is about 75% of the daily amount administered in the first period.

[0075] References to a specified amount of Compound (I) or a pharma- ceutically acceptable salt thereof include both the specified amount of Compound (I) as the free base, and the amount of a pharma- ceutically acceptable salt of Compound (I), such as a phosphate salt, which amount of salt is equivalent (in moles) to the specified amount of Compound (I) as the free base (e.g., 10.5 mg of Compound (I) phosphate salt is equivalent to 8 mg of Compound (I) free base).

[0076] In certain embodiments, the amount of Compound (I) or its pharma- ceutically acceptable salt (i.e., the equivalent amount of a pharma- ceutically acceptable salt, such as a phosphate salt) administered in the method of treating alopecia (e.g., in the first period or the second period) is about 4 mg / day (e.g., 4 mg / day), about 8 mg / day (e.g., 8 mg / day), about 16 mg / day (e.g., 16 mg / day), about 24 mg / day (e.g., 24 mg / day), or about 32 mg / day (e.g., 32 mg / day).

[0077] In certain embodiments, the amount of Compound (I) or a pharma- ceutically acceptable salt thereof (i.e., the equivalent amount of a pharma- ceutically acceptable salt, such as a phosphate salt) administered in the method of treating alopecia (e.g., in the first period or the second period) is about 8 mg / day (e.g., 8 mg / day), about 16 mg / day (e.g., 16 mg / day), about 24 mg / day (e.g., 24 mg / day), or about 32 mg / day (e.g., 32 mg / day).

[0078] In certain embodiments, the amount of compound (I) or its pharmaceutically acceptable salt administered in the method of treating alopecia (e.g., in the first period or the second period) is about 8mg / day (e.g., 8mg / day), about 16mg / day (e.g., 16mg / day), about 24mg / day (e.g., 24mg / day), or about 32mg / day (e.g., 32mg / day).In certain embodiments, the amount of compound (I) or its pharmaceutically acceptable salt is about 8mg / day (e.g., 8mg / day), about 12mg / day (e.g., 12mg / day), about 16mg / day (e.g., 16mg / day), or about 24mg / day (e.g., 24mg / day).

[0079] In certain embodiments, the amount of compound (I) or its pharmaceutically acceptable salt administered in the method of treating alopecia (e.g., in the first period or the second period) is about 8mg / day (e.g., 8mg / day), about 16mg / day (e.g., 16mg / day), about 24mg / day (e.g., 24mg / day), or about 32mg / day (e.g., 32mg / day).In certain embodiments, the amount of compound (I) or its pharmaceutically acceptable salt is about 16mg / day to about 32mg / day, for example about 16mg / day (e.g., 16mg / day), about 24mg / day (e.g., 24mg / day), or about 32mg / day (e.g., 32mg / day).

[0080] In certain embodiments, the amount of compound (I) or its pharmaceutically acceptable salt administered in the method of treating alopecia (e.g., in the first period or the second period) is 10.6mg / day of compound (I) phosphate, for example, administered as a daily dose of 10.6mg or as a daily dose of 5.3mg.In certain embodiments, the amount of compound (I) or its pharmaceutically acceptable salt is 21.1mg / day of compound (I) phosphate, for example, administered as a daily dose of 21.1mg or as a daily dose of 10.5mg.In certain embodiments, the amount of compound (I) or its pharmaceutically acceptable salt is 31.6mg / day of compound (I) phosphate, for example, administered as a daily dose of 31.6mg or as a daily dose of 15.8mg. In certain embodiments, the amount of Compound (I) or a pharma- ceutically acceptable salt thereof is 42.2 mg / day of Compound (I) phosphate, e.g., administered as a once daily dose of 42.2 mg or as a twice daily dose of 21.1 mg.

[0081] In certain embodiments, the amount of compound (I) or its pharma- ceutically acceptable salt administered in the method for treating alopecia (e.g., in the first period or the second period) is about 8 mg (e.g., 8 mg), twice a day.In a particular embodiment, compound (I) is administered as about 10.5 mg (e.g., 10.5 mg) of the phosphate salt of compound (I) twice a day.

[0082] In certain embodiments, the amount of compound (I) or its pharmaceutically acceptable salt administered in the method of treating alopecia (e.g., in the first period or the second period) is about 8mg (e.g., 8mg), for example, once a day as a single dose or twice a day as divided doses.In certain embodiments, the amount of compound (I) or its pharmaceutically acceptable salt administered in the method of treating alopecia (e.g., in the first period or the second period) is about 12mg (e.g., 12mg), for example, once a day as a single dose or twice a day as divided doses.In a particular embodiment, compound (I) is administered as about 15.8mg (e.g., 15.8mg) of the phosphate salt of compound (I), for example, once a day as a single dose or twice a day as divided doses. In certain embodiments, the amount of compound (I) or its pharmaceutically acceptable salt administered in the method of treating alopecia (e.g., in the first period or the second period) is about 16mg (e.g., 16mg) as a single dose once a day or in a divided dose twice a day.In a particular embodiment, compound (I) is administered as a single dose once a day or in a divided dose twice a day, about 21.1mg (e.g., 21.1mg) of the phosphate salt of compound (I).In certain embodiments, the amount of compound (I) or its pharmaceutically acceptable salt administered in the method of treating alopecia (e.g., in the first period or the second period) is about 24mg (e.g., 24mg) as a single dose once a day or in a divided dose twice a day. In certain embodiments, the amount of Compound (I) or a pharma- ceutically acceptable salt thereof administered in the method of treating alopecia (e.g., during the first period of time) is about 32 mg (e.g., 32 mg) in a single dose once daily or in divided doses twice daily.

[0083] In certain embodiments, the alopecia is alopecia areata. In certain embodiments, the subject is a human. In one embodiment, the subject is a human aged 6 years or older. In certain embodiments, compound (I) or a pharmaceutically acceptable salt thereof (such as phosphate salt) is orally administered in any of the doses described herein. In certain embodiments, compound (I) or a pharmaceutically acceptable salt thereof is orally administered in any of the doses described herein in a pharmaceutical formulation that is a tablet.

[0084] In certain embodiments, the amount of compound (I) or its pharma- ceutically acceptable salt administered in the second period is about 50% of the amount administered in the first period per day.In certain embodiments, the amount of compound (I) or its pharma- ceutically acceptable salt administered in the second period is about 66.7% of the amount administered in the first period per day.In certain embodiments, the amount of compound (I) or its pharma- ceutically acceptable salt administered in the second period is about 75% of the amount administered in the first period per day.

[0085] Exemplary amounts of Compound (I) or a pharma- ceutically acceptable salt thereof to be administered are shown in the table below.

[0086] [Table 1]

[0087] In another aspect, the present invention provides a method of treating alopecia areata in a human subject in need thereof, the method comprising: a) for a first period of time,

[0088] [ka]

[0089] or a pharma- ceutically acceptable salt thereof to a human subject, each position specifically designated as deuterium has at least 95% deuterium incorporation; the length of the first period is sufficient to achieve a reduction in the patient's SALT score, The initial dose is about 8 to about 32 mg per day, and then b) administering to the human subject a maintenance dose of the compound or a pharma- ceutically acceptable salt thereof for a second period of time, wherein the maintenance dose is 50%-75% of the initial dose, and wherein the maintenance dose is sufficient to maintain hair growth (e.g., a SALT score of 20 or less).

[0090] In certain embodiments, the length of the first period is sufficient to achieve at least a 10% reduction in the patient's SALT score relative to baseline (e.g., from a pre-treatment SALT score of 100 to a post-treatment SALT score of 90). In further embodiments, the length of the first period is sufficient to achieve at least a 20%, at least a 30%, at least a 40%, at least a 50%, at least a 60%, at least a 70%, at least a 75%, at least a 80%, or at least a 90% reduction in the patient's SALT score relative to baseline. In certain embodiments, the length of the first period is sufficient to achieve at least a 50% reduction in the patient's SALT score relative to baseline. In certain embodiments, the length of the first period is sufficient to achieve at least a 75% reduction in the patient's SALT score relative to baseline. In certain embodiments, the length of the first period is sufficient to achieve at least a 90% reduction in the patient's SALT score relative to baseline.

[0091] In certain embodiments, the length of the first period of time is sufficient to achieve a SALT score of 50 or less, 40 or less, 30 or less, 20 or less, 15 or less, 10 or less, 5 or less, 1 or less, or zero at the end of the first period of time. In certain embodiments, the length of the first period of time is sufficient to achieve a SALT score of 20 or less at the end of the first period of time. In certain embodiments, the length of the first period of time is sufficient to achieve a SALT score of 15 or less at the end of the first period of time. In certain embodiments, the length of the first period of time is sufficient to achieve a SALT score of 10 or less at the end of the first period of time. In certain embodiments, the length of the first period of time is sufficient to achieve a SALT score of 5 or less at the end of the first period of time. In certain embodiments, the length of the first period of time is sufficient to achieve a SALT score of 1 or less at the end of the first period of time. In certain embodiments, the length of the first period of time is sufficient to achieve a SALT score of zero at the end of the first period of time.

[0092] In certain embodiments, the maintenance dose is about 25% of the initial dose. In certain embodiments, the maintenance dose is about 33.3% of the initial dose. In certain embodiments, the maintenance dose is about 50% of the initial dose. In certain embodiments, the maintenance dose is about 66.7% of the initial dose. In certain embodiments, the maintenance dose is about 75% of the initial dose.

[0093] In certain embodiments, the maintenance dose given during the second period is sufficient to achieve a SALT score of 50 or less, 40 or less, 30 or less, 20 or less, 15 or less, 10 or less, 5 or less, 1 or less, or zero at the end of the second period. In certain embodiments, the maintenance dose given during the second period is sufficient to achieve a SALT score of 20 or less at the end of the second period. In certain embodiments, the maintenance dose given during the second period is sufficient to achieve a SALT score of 15 or less at the end of the second period. In certain embodiments, the maintenance dose given during the second period is sufficient to achieve a SALT score of 10 or less at the end of the second period. In certain embodiments, the maintenance dose given during the second period is sufficient to achieve a SALT score of 5 or less at the end of the second period. In certain embodiments, the maintenance dose is sufficient to maintain the SALT score achieved in the first period (e.g., in certain embodiments, the maintenance dose given during the second period is sufficient to achieve an increase in the subject's SALT score of <10 points or <5 points at the end of the second period compared to the subject's SALT score at the end of the first period). In certain embodiments, the maintenance dose given during the second period is sufficient to achieve an increase in the subject's SALT score of <30% at the end of the second period compared to the subject's SALT score at the end of the first period. In certain embodiments, the maintenance dose given during the second period is sufficient to achieve an increase in the subject's SALT score of <5 points and <30% at the end of the second period compared to the subject's SALT score at the end of the first period. In certain embodiments, the maintenance dose is sufficient to achieve an increase in the subject's SALT score of <4 points, <3 points, <2 points, or <1 point at the end of the second period compared to the subject's SALT score at the end of the first period. In certain embodiments, the maintenance dose is sufficient to achieve a <20% increase, <15% increase, <10% increase, or <5% increase in the subject's SALT score at the end of the second period compared to the subject's SALT score at the end of the first period.

[0094] In another aspect, the present invention provides a method of treating alopecia in a human subject, the method comprising administering to a subject a compound represented by the following structural formula:

[0095] [ka]

[0096] or a pharmaceutically acceptable salt thereof to a subject, wherein each position specifically designated as deuterium has at least 95% deuterium incorporation, the compound or pharmaceutically acceptable salt thereof is first administered during an induction period to initiate initial hair growth and then administered during a second period to further treat the hair disorder, the induction period being at least 8 weeks and not more than 24 weeks, the amount of the compound or pharmaceutically acceptable salt thereof administered during the induction period being in the range of 16 mg / day to 32 mg / day, and after the induction period, the amount of the compound or pharmaceutically acceptable salt thereof is reduced by 50-75% (e.g., 50, 66.7, or 75%) during the second period.

[0097] In certain embodiments, the length of the first period of time is at least 8-24 weeks. In certain embodiments, the first period of time is about 12 weeks. In certain embodiments, the first period of time is about 16 weeks. In certain embodiments, the first period of time is about 20 weeks. In certain embodiments, the first period of time is about 24 weeks.

[0098] In certain embodiments, the second period of time is at least 12 weeks long. In certain embodiments, the second period of time is at least 24 weeks long.

[0099] Exemplary doses for the first and second time periods are described above.

[0100] In certain embodiments, the reduction in the patient's baseline SALT score over the first period of time is between about 10% and about 50%. In certain embodiments, the reduction in the baseline SALT score is between about 20% and about 50%. In certain embodiments, the reduction in the patient's baseline SALT score over the first period of time is about 50%. In certain embodiments, the reduction in the baseline SALT score is between about 30% and about 50%. In certain embodiments, the reduction in the patient's baseline SALT score over the length of the first period of time is at least 50%. In certain embodiments, the reduction in the baseline SALT score is between about 50% and about 99%. In certain embodiments, the reduction in the baseline SALT score is between about 50% and about 90%. In certain embodiments, the reduction in the baseline SALT score is between about 50% and about 75%. In certain embodiments, the reduction in the baseline SALT score is between about 75% and about 90%.

[0101] In certain embodiments, during the first period, the compound or a pharma- ceutically acceptable salt thereof is administered at about 12 mg / day, about 16 mg / day, about 24 mg / day, or about 32 mg / day.

[0102] In certain embodiments, during the second period, the compound or a pharma- ceutically acceptable salt thereof is administered at about 6 mg / day, about 8 mg / day, about 12 mg / day, or about 16 mg / day.

[0103] In certain embodiments, in the first period, the compound or its pharmaceutically acceptable salt is administered at about 24 mg / day, and in the second period, the compound or its pharmaceutically acceptable salt is administered at about 16 mg / day. In certain embodiments, about 24 mg / day is administered once a day, and about 16 mg / day is administered once a day. In certain embodiments, about 24 mg / day is administered twice a day at about 12 mg (split dose), and about 16 mg / day is administered twice a day at about 8 mg (split dose).

[0104] In certain embodiments, during the first period, the compound or a pharma- ceutically acceptable salt thereof is administered at about 16 mg / day, and during the second period, the compound or a pharma- ceutically acceptable salt thereof is administered at about 8 mg / day.

[0105] In certain embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered orally.

[0106] In certain embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered in a pharmaceutical formulation that is a tablet.In certain embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered in a pharmaceutical formulation that is a capsule.

[0107] In certain embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered once daily during the first period of time.

[0108] In certain embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered twice daily during the first period.

[0109] In certain embodiments, in Compound (I), each position specifically designated as deuterium has at least 97% deuterium incorporation.

[0110] In the method of the present invention, the first and second periods can vary in length depending on factors such as the amount of hair growth induced in the first period (e.g., as determined by SALT scores measured before and after the first period) and the desired duration of treatment. The first period can be, for example, 8 to 24 weeks, such as 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, or 24 weeks. The second period can be, for example, 8 weeks, 16 weeks, 24 weeks, 52 weeks, 2 years, 5 years, 10 years, or 20 years.

[0111] In one embodiment, the first period is at least 24 weeks (eg, 24 weeks) and the second period is at least 24 weeks (eg, 24 weeks).

[0112] In another embodiment, the first period of time is up to 24 weeks and the second period of time is at least 24 weeks (eg, 24 weeks).

[0113] In another aspect, the present invention provides a method of inducing hair growth in a subject, the method comprising administering to a mammalian subject an effective amount of Compound (I) or a pharma- ceutically acceptable salt thereof (i.e., an equivalent amount of a pharma- ceutically acceptable salt, such as a phosphate salt), where each position specifically designated as deuterium has at least 95% deuterium incorporation, and where the compound or a pharma- ceutically acceptable salt thereof is administered in an amount ranging from 8 to 32 mg per day (1) for a first period of 8 to 24 weeks, followed by (2) a second period of at least 8 weeks, where the compound or a pharma- ceutically acceptable salt thereof is administered in a daily amount that is 50 to 75% (e.g., 50%, 66.7%, 75%) of the daily amount administered during the first period, to induce hair growth in the subject.

[0114] In certain embodiments, the amount of Compound (I) or a pharma- ceutically acceptable salt thereof administered in the method of inducing hair growth is about 4 mg / day (e.g., 4 mg / day), about 8 mg / day (e.g., 8 mg / day), about 16 mg / day (e.g., 16 mg / day), about 24 mg / day (e.g., 24 mg / day), about 32 mg / day (e.g., 32 mg / day), or about 48 mg / day (e.g., 48 mg / day).

[0115] In certain embodiments, the amount of Compound (I) or a pharma- ceutically acceptable salt thereof administered in the method of inducing hair growth is about 16 mg / day (e.g., 16 mg / day), about 24 mg / day (e.g., 24 mg / day), or about 32 mg / day (e.g., 32 mg / day).

[0116] In certain embodiments, the amount of Compound (I) or a pharma- ceutically acceptable salt thereof administered in a method for inducing hair growth is about 8 mg / day (e.g., 8 mg / day), about 16 mg / day (e.g., 16 mg / day), about 24 mg / day (e.g., 24 mg / day), or about 32 mg / day (e.g., 32 mg / day). In certain embodiments, the amount of Compound (I) or a pharma- ceutically acceptable salt thereof administered in a method for inducing hair growth is about 8 mg / day (e.g., 8 mg / day), about 12 mg / day (e.g., 12 mg / day), about 16 mg / day (e.g., 16 mg / day), or about 24 mg / day (e.g., 24 mg / day).

[0117] In certain embodiments, the amount of Compound (I) or its pharma- ceutically acceptable salt administered in the method of inducing hair growth is 10.6 mg / day of Compound (I) phosphate, for example, administered as a 10.6 mg once-a-day dose or as a 5.3 mg twice-a-day dose. In certain embodiments, the amount of Compound (I) or its pharma-ceutically acceptable salt is 21.1 mg / day of Compound (I) phosphate, for example, administered as a 21.1 mg once-a-day dose or as a 10.5 mg twice-a-day dose. In certain embodiments, the amount of Compound (I) or its pharma-ceutically acceptable salt is 31.6 mg / day of Compound (I) phosphate, for example, administered as a 31.6 mg once-a-day dose or as a 15.8 mg twice-a-day dose. In certain embodiments, the amount of Compound (I) or a pharma- ceutically acceptable salt thereof is 42.2 mg / day of Compound (I) phosphate, e.g., administered as a once daily dose of 42.2 mg or as a twice daily dose of 21.1 mg.

[0118] In certain embodiments, the amount of Compound (I) or a pharma- ceutically acceptable salt thereof administered in the method of inducing hair growth (during the second time period) is about 4 mg (e.g., 4 mg) twice daily. In one particular embodiment, Compound (I) is administered as about 5.3 mg (e.g., 5.3 mg) of the phosphate salt of Compound (I) twice daily.

[0119] In certain embodiments, the amount of Compound (I) or a pharma- ceutically acceptable salt thereof administered (in the first or second time period) in the method of inducing hair growth is about 8 mg (e.g., 8 mg) twice daily. In one particular embodiment, Compound (I) is administered as about 10.5 mg (e.g., 10.5 mg) of the phosphate salt of Compound (I) twice daily.

[0120] In certain embodiments, the amount of Compound (I) or a pharma- ceutically acceptable salt thereof administered (in the first or second time period) in the method of inducing hair growth is about 12 mg (e.g., 12 mg) twice daily. In one particular embodiment, Compound (I) is administered as about 15.8 mg (e.g., 15.8 mg) of the phosphate salt of Compound (I) twice daily.

[0121] In certain embodiments, the amount of Compound (I) or a pharma- ceutically acceptable salt thereof administered in a method for inducing hair growth (e.g., during a first period of time) is about 16 mg (e.g., 16 mg) twice daily. In one particular embodiment, Compound (I) is administered as about 21.1 mg (e.g., 21.1 mg) of the phosphate salt of Compound (I) twice daily.

[0122] In certain embodiments, the subject suffers from alopecia, and in further embodiments, the alopecia is alopecia areata. In certain embodiments, the subject is a human. In one embodiment, the subject is a human aged 6 years or older. Preferably, compound (I) or its pharmaceutically acceptable salt (such as phosphate salt) is orally administered in any of the doses described above. Preferably, compound (I) or its pharmaceutically acceptable salt is orally administered in any of the doses described herein in a pharmaceutical formulation that is a tablet or capsule.

[0123] Alopecia include, but are not limited to, androgenetic alopecia, alopecia areata, telogen effluvium, alopecia totalis, and alopecia universalis.

[0124] In one particular embodiment of any of the methods described herein, the pathology is alopecia areata in a subject, such as a mammalian (e.g., human) patient in need thereof.In certain embodiments, the alopecia areata is moderate to severe alopecia areata (e.g., hair loss of at least 30% or more of scalp, hair loss of at least 40% or more of scalp, hair loss of at least 50% or more of scalp, or hair loss of at least 75% or more of scalp).

[0125] In another aspect, the present invention provides a method of treating a disease, disorder, or condition mediated solely or in part by Janus-associated kinases (JAK) (e.g., JAK1 and / or JAK2) in a human subject, the method comprising administering to a subject a compound represented by the following structural formula:

[0126] [ka]

[0127] or a pharma- ceutically acceptable salt thereof to said subject; each position specifically designated as deuterium has at least 95% deuterium incorporation; The compound or a pharma- ceutically acceptable salt thereof is administered (1) in an amount ranging from about 8 mg to about 32 mg per day for a first period of 8 to 24 weeks, followed by (2) a second period of at least 8 weeks, where the compound or a pharma- ceutically acceptable salt thereof is administered in an amount that is 50-75% of the daily amount administered during the first period, to treat a disease, disorder, or condition mediated solely or in part by JAK.

[0128] In certain embodiments, the disease, condition, or disorder is not alopecia.

[0129] In certain embodiments, in Compound (I), each position specifically designated as deuterium has at least 97% deuterium incorporation.

[0130] In certain embodiments, the disease, condition or disorder is a skin disease, such as proliferative, autoimmune and / or inflammatory skin disease, psoriasis, atopic dermatitis, scleroderma, rosacea, skin cancer, dermatitis, dermatitis herpetiformis, dermatomyositis, vitiligo, contact dermatitis, xeroderma, ichthyosis, hidradenitis suppurativa, urticaria, lichen planus, prurigo nodularis, vasculitis, cutaneous lupus erythematosus (CLE), chronic idiopathic pruritus, hyperproliferative disorders or cancers, including polycythemia vera, essential thrombocytopenia, myelofibrosis, asthma, chronic obstructive pulmonary disease, chronic transplant pulmonary failure (e.g., bronchiolitis obliterans syndrome), pulmonary fibrosis, cystic fibrosis, rhinitis, bronchiolitis, byssinosis, pneumoconiosis, bronchiectasis, hypersensitivity lung, gastrointestinal diseases such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, retroperitoneal fibrosis, celiac disease, cancer; ophthalmic diseases such as myasthenia gravis, Sjogren's syndrome, conjunctivitis, scleritis, uveitis, dry eye syndrome, keratitis, iritis; systemic conditions such as systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, type 1 diabetes and diabetic complications, cancer, ankylosing spondylitis, psoriatic arthritis, and other autoimmune diseases and conditions in which immunosuppression may be desirable, for example to treat or prevent acute and / or chronic graft versus host disease (e.g. graft versus host disease in organ transplantation).

[0131] In certain embodiments, during the first period, the compound or a pharma- ceutically acceptable salt thereof is administered at about 16 mg / day, about 24 mg / day, or about 32 mg / day.

[0132] In certain embodiments, during the second period, the compound or a pharma- ceutically acceptable salt thereof is administered at about 8 mg / day, about 12 mg / day, or about 16 mg / day.

[0133] In certain embodiments, during the first period, the compound or a pharma- ceutically acceptable salt thereof is administered at about 24 mg / day, and during the second period, the compound or a pharma- ceutically acceptable salt thereof is administered at about 16 mg / day.

[0134] In certain embodiments, about 24 mg / day of the compound or a salt thereof is administered once per day and about 16 mg / day is administered once per day.

[0135] In certain embodiments, about 24 mg / day of the compound or salt thereof is administered in about 12 mg doses twice daily, and about 16 mg / day of the compound or salt thereof is administered in about 8 mg doses twice daily.

[0136] In certain embodiments, during the first period, the compound or a pharma- ceutically acceptable salt thereof is administered at about 16 mg / day, and during the second period, the compound or a pharma- ceutically acceptable salt thereof is administered at about 8 mg / day.

[0137] In certain embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered once daily during the first period of time.

[0138] In certain embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered twice daily during the first period.

[0139] In certain embodiments, the first period of time is about 8 to 12 weeks.

[0140] In certain embodiments, the first period of time is about 24 weeks.

[0141] In certain embodiments, the second period of time is at least 12 weeks.

[0142] In certain embodiments, the second period of time is at least 24 weeks.

[0143] In certain embodiments, the disease, condition, or disorder is not alopecia areata.

[0144] In certain embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered orally.

[0145] In certain embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered in a pharmaceutical formulation that is a tablet.

[0146] In certain embodiments, the subject is a human. In one embodiment, the subject is a human aged 6 years or older. In certain embodiments, Compound (I) or a pharmaceutically acceptable salt thereof (such as a phosphate salt) is orally administered in any of the doses described herein. In certain embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is orally administered in any of the doses described herein in a pharmaceutical formulation that is a tablet.

[0147] In certain embodiments, the amount of compound (I) or its pharma- ceutically acceptable salt administered in the second period is about 50% of the amount administered in the first period per day.In certain embodiments, the amount of compound (I) or its pharma- ceutically acceptable salt administered in the second period is about 66.7% of the amount administered in the first period per day.In certain embodiments, the amount of compound (I) or its pharma- ceutically acceptable salt administered in the second period is about 75% of the amount administered in the first period per day.

[0148] Exemplary amounts of Compound (I) or a pharma- ceutically acceptable salt thereof to be administered are shown in the table below.

[0149] [Table 2]

[0150] In one embodiment of any aspect, the compound is administered orally once daily. In another embodiment of any aspect, the compound is administered orally twice daily.

[0151] The effective dose will also vary, as recognized by those skilled in the art, depending on the condition being treated, the severity of the condition, the route of administration, the sex, age, and general health of the subject, the use of excipients, the possibility of co-administration with other therapies such as the use of other drugs, and the judgment of the treating physician.

[0152] Administration of Compound (I) or a pharma- ceutically acceptable salt thereof (such as a phosphate salt) can continue for as long as necessary to treat the alopecia, for example, for 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 1 year, 2 years, 5 years, 10 years, or more.

[0153] Administration of Compound (I) or a pharma- ceutically acceptable salt thereof (such as a phosphate salt) can be continued for as long as necessary to treat a disease, disorder or condition mediated solely or in part by Janus-associated kinases (JAKs), for example, for 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 1 year, 2 years, 5 years, 10 years, or more.

[0154] In certain embodiments, treatment continues for a period of at least 8 weeks, or at least 12 weeks, or at least 16 weeks, or at least 20 weeks, or at least 24 weeks, or at least 28 weeks, or at least 32 weeks, or at least 36 weeks, or at least 40 weeks, or at least 44 weeks, or at least 48 weeks, or at least 52 weeks.

[0155] In certain embodiments, compound (I) or its pharma- ceutically acceptable salt is administered in combination with an additional therapeutic agent.Preferably, the additional therapeutic agent is an agent useful for treating alopecia or autoimmune conditions, such as an inhibitor of JAK1, JAK2 or JAK3 and / or STAT1.Such inhibitors include ruxolitinib, tofacitinib, baricitinib, filgotinib, etc.Other orally administered additional therapeutic agents include agents used for treating alopecia areata, such as oral corticosteroids.In certain embodiments, the additional therapeutic agent is an agent useful for treating diseases, disorders, or conditions that are not alopecia, but are mediated solely or in part by Janus-associated kinase (JAK).

[0156] For pharmaceutical compositions that include an additional therapeutic agent, the effective amount of the additional therapeutic agent is about 20%-100% of the dose normally used in a monotherapy regimen using only that agent. Preferably, the effective amount is about 70%-100% of the normal monotherapy dose. The normal monotherapy doses of these additional therapeutic agents are well known in the art. See, for example, Wells et al., eds., Pharmacotherapy Handbook, 2nd ed., Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000); FDA-approved labeling information for ruxolitinib and tofacitinib; and clinical trial information for baricitinib and filgotinib. Each of which is incorporated herein by reference in its entirety.

[0157] Some of the above-mentioned additional therapeutic agents may act synergistically with the compounds of the present invention. When synergistic action occurs, the effective dose of the additional therapeutic agent and / or compound (I) or its pharmaceutically acceptable salt can be reduced from that required in monotherapy. This has the advantage of minimizing the toxic side effects of either the additional therapeutic agent or compound (I) or its pharmaceutically acceptable salt, synergistic improvement in efficacy, improved ease of administration or use, and / or reduced overall cost of preparation or formulation of the compound.

[0158] The term "concomitant" as used herein means that the additional therapeutic agent can be administered together with compound (I) or a pharma- ceutically acceptable salt thereof as part of a single dosage form (such as the composition of the present invention comprising the compound of the present invention and the second therapeutic agent described above) or as separate multiple dosage forms. Alternatively, the additional agent can be administered before, consecutively with, or after the administration of compound (I) or a pharma- ceutically acceptable salt thereof. In such combination therapy treatment, both compound (I) or a pharma- ceutically acceptable salt thereof and the additional therapeutic agent are administered by conventional methods. The administration of a composition of the present invention comprising both compound (I) or a pharma- ceutically acceptable salt thereof and an additional therapeutic agent to a subject does not preclude the separate administration of the same therapeutic agent, any other additional therapeutic agent, or compound (I) or a pharma- ceutically acceptable salt thereof to a subject at another time during the course of treatment.

[0159] Effective amounts of these additional therapeutic agents are well known to those of skill in the art, and guidance for administration can be found in the patents and published patent applications referenced herein, in Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000), PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), and other medical literature. However, determining optimal effective amount ranges for additional therapeutic agents is well within the purview of one of ordinary skill in the art.

[0160] In one embodiment of the present invention, when an additional therapeutic agent is administered to a subject, the effective amount of compound (I) or its pharma- ceutically acceptable salt is less than its effective amount when the additional therapeutic agent is not administered. In another embodiment, the effective amount of the additional therapeutic agent is less than its effective amount when the additional therapeutic agent is not administered. In this way, undesirable side effects associated with high doses of either agent can be minimized. Other potential advantages (including, but not limited to, improved dosing regimens and / or reduced drug costs) will be apparent to those skilled in the art.

[0161] In yet another aspect, the present invention provides the use of Compound (I) or a pharma- ceutically acceptable salt thereof (i.e., an equivalent amount of a pharma- ceutically acceptable salt, such as a phosphate salt), in the manufacture of a medicament, either alone or together with one or more of the additional therapeutic agents described above, in a single composition or in separate dosage forms, for the treatment or prophylaxis in a subject of the diseases, disorders or conditions described above. Another aspect of the present invention is Compound (I) or a pharma- ceutically acceptable salt thereof, for use in the treatment or prophylaxis in a subject of the diseases, disorders or conditions detailed herein.

[0162] Another aspect of the present invention is a range of about 4 mg to about 50 mg (e.g., about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, or about 50 mg) of Compound (I) or an equivalent amount of a pharma- ceutically acceptable salt thereof, together with a pharma- ceutically acceptable carrier or diluent. In certain embodiments, the amount of Compound (I) or a pharma- ceutically acceptable salt thereof is about 4 mg, 8 mg, 16 mg, 24 mg, 32 mg, or 48 mg. In certain embodiments, the amount of Compound (I) or a pharma- ceutically acceptable salt thereof is 4 mg, 8 mg, 12 mg, or 16 mg. In certain embodiments, the amount of Compound (I) or a pharma- ceutically acceptable salt thereof is 5.3 mg of Compound (I) phosphate. In certain embodiments, the amount of Compound (I) or a pharma- ceutically acceptable salt thereof is 10.5 or 10.6 mg of Compound (I) phosphate. In certain embodiments, the amount of Compound (I) or a pharma- ceutically acceptable salt thereof is 15.8 mg of Compound (I) phosphate. In certain embodiments, the amount of Compound (I) or a pharma- ceutically acceptable salt thereof is 21.1 mg of Compound (I) phosphate. In certain embodiments, the pharmaceutical composition is a tablet or capsule.

[0163] Another aspect of the present invention is a unit dosage form comprising about 4 mg to about 50 mg (e.g., about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, or about 50 mg) of Compound (I) or an equivalent amount of a pharma- ceutically acceptable salt thereof, together with a pharma- ceutically acceptable carrier or diluent. In certain embodiments, the amount of Compound (I) or a pharma- ceutically acceptable salt thereof is about 4 mg, 8 mg, 16 mg, 24 mg, 32 mg, or 48 mg. In certain embodiments, the amount of Compound (I) or a pharma- ceutically acceptable salt thereof is 4 mg, 8 mg, 12 mg, or 16 mg. In certain embodiments, the amount of Compound (I) or a pharma- ceutically acceptable salt thereof is 5.3 mg of Compound (I) phosphate. In certain embodiments, the amount of Compound (I) or a pharma- ceutically acceptable salt thereof is 10.5 or 10.6 mg of Compound (I) phosphate. In certain embodiments, the amount of Compound (I) or a pharma- ceutically acceptable salt thereof is 15.8 mg of Compound (I) phosphate. In certain embodiments, the amount of Compound (I) or a pharma- ceutically acceptable salt thereof is 21.1 mg of Compound (I) phosphate. In certain embodiments, the unit dosage form is a tablet or capsule.

[0164] In one embodiment, any atom not designated as deuterium is present in Compound (I) or a pharma- ceutically acceptable salt thereof at its natural isotopic abundance.

[0165] Synthesis of compound (I) or a pharma- ceutically acceptable salt thereof (such as a phosphate salt) can be readily accomplished by the methods described in U.S. Pat. No. 9,249,149, PCT Patent Publication No. WO2017 / 192905, or PCT Patent Publication No. WO2020 / 163653, the teachings of which are incorporated herein by reference with appropriate amendments. Additional synthetic methods are described in PCT Patent Publication No. WO2022 / 036030, the teachings of which are incorporated herein by reference in their entirety. For example, U.S. Pat. No. 9,249,149 describes the use of D9-intermediate 15 to prepare D9-ruxolitinib, and intermediate A TIFF2025515051000012.tif30152

[0166] The use of intermediate B in the process described in U.S. Pat. No. 9,249,149 provides compound (I).

[0167] [ka]

[0168] Compound (I) can be prepared by replacing intermediate 14 of U.S. Pat. No. 9,249,149, and removal of the amino protecting group can be achieved by basic cleavage (e.g., with sodium hydroxide). Compound (I) (free base) can be converted to its phosphate salt using phosphoric acid. Additional methods for preparing ruxolitinib (i.e., non-deuterated Compound (I)) are disclosed in U.S. Pat. No. 9,000,161, and can be used with the use of a suitable deuterated reagent to prepare Compound (I).

[0169] Such methods can be carried out utilizing the corresponding deuterated, and optionally other isotopically-containing reagents and / or intermediates to synthesize the compounds detailed herein, or can be carried out by invoking standard synthetic protocols known in the art for introducing isotopic atoms into a chemical structure.

[0170] The present invention also provides a pharmaceutical composition comprising an effective amount of Compound (I) or a pharma- ceutically acceptable salt thereof (i.e., the equivalent amount of a pharma- ceutically acceptable salt, such as a phosphate salt), and a pharma- ceutically acceptable carrier. The carrier is "acceptable" in the sense of being compatible with the other ingredients of the formulation, and, in the case of a pharma- ceutically acceptable carrier, is not harmful to the recipient thereof in the amounts used in the medicament. In certain embodiments, the pharmaceutical composition is provided as a unit dosage form.

[0171] The present invention provides a pharmaceutical composition comprising a pharma- ceutical product comprising a pharma- ceutical product and 4 to 50 mg of a compound represented by the following structural formula:

[0172] [ka]

[0173] or a pharma- ceutical acceptable salt thereof (i.e., an equivalent amount of a pharma- ceutical acceptable salt such as a phosphate salt).For example, the amount of Compound (I) is 4 mg, 8 mg, 12 mg, 16 mg, or 24 mg.

[0174] Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphoric acid, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, wool fat.

[0175] If necessary, the solubility and bioavailability of the compounds of the present invention in pharmaceutical compositions can be enhanced by methods known in the art. One method involves the use of lipid excipients in the formulation. See "Oral Lipid-Based Formulations:Enhancing the Bioavailability of Poorly Water-Soluble Drugs(Drugs and the Pharmaceutical Sciences)," edited by David J. Hauss, Informa Healthcare, 2007, and "Role of Lipid Excipients in Modifying Oral and Parenteral Drug Delivery:Basic Principles and Biological Examples," edited by Kishor M. Wasan, Wiley-Interscience, 2006.

[0176] Another known method of enhancing bioavailability is the use of amorphous forms of the compounds of the invention, optionally formulated with poloxamers such as LUTROL™ and PLURONIC™ (BASF Corporation), or block copolymers of ethylene oxide and propylene oxide. See U.S. Patent No. 7,014,866 and U.S. Patent Publications 20060094744 and 20060079502.

[0177] The pharmaceutical composition of the present invention includes those suitable for oral administration.Other formulations may be conveniently presented in unit dosage form, such as tablets, sustained release capsules, granules, and liposomes, and may be prepared by any method known in the art of pharmacy.See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th edition, 2000).

[0178] Such preparative methods include the step of bringing into association the molecule to be administered, such as the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0179] In certain embodiments, the compound is administered orally. The composition of the present invention suitable for oral administration may be presented as a discrete unit such as capsule, sachet, or tablet (each containing a predetermined amount of active ingredient), or as a powder or granule, or as a solution or suspension in aqueous or non-aqueous liquid, or as an oil-in-water liquid emulsion, or as a water-in-oil liquid emulsion, or loaded into liposomes, or as a bolus. Soft gelatin capsules may be useful for containing such suspensions, which may advantageously increase the absorption rate of the compound. In one particular embodiment, the compound is administered orally as a tablet. In another particular embodiment, the compound is administered orally in a capsule.

[0180] For oral tablets, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspension is administered orally, active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added. In another embodiment, the composition is in the form of a tablet. In a particular embodiment, an exemplary formulation for tablets is disclosed in U.S. Pat. No. 8,754,224, the teachings of which are incorporated herein by reference.

[0181] In a particular embodiment, the tablet formulation contains about 4 mg to about 50 mg of Compound (I) or its pharma- ceutically acceptable salt (such as phosphate salt), and equivalent amounts of inactive ingredients (colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, povidone). After wet granulation followed by compression, a tablet containing Compound (I) or its pharma- ceutically acceptable salt is provided. For example, to prepare a 200 mg tablet containing an equivalent of 16 mg of Compound (I), 10.6 wt% of Compound (I) phosphate salt and 64.44 wt% of Avicel PH-101 microcrystalline cellulose are mixed in a high shear granulator, and 8.5% w / w of Kollidon 30 solution (Kollidon 30, containing polyvinylpyrrolidone (povidone)) is added, and 5 wt% (based on the total weight of the formulation) is added with mixing to form granules. The granules are tray dried in an oven at 60±10° C. and milled using a Quadro Comil U5 mill. The granules retained on the comil screen are passed through a #20 mesh sieve using a stainless steel spatula. The resulting milled granules are mixed with Avicel PH-200 microcrystalline cellulose (18.5% by weight), Aerosil 200 colloidal silicon dioxide (0.5% by weight) and Hyqual magnesium stearate (1% by weight) in a Turbula mixer to form the final blend. The final blend is compressed into 200 mg tablets using a Riva Piccola rotary press with 0.451″×0.229″ D-type modified capsule shape tooling. Each tablet contains 21.1 mg of Compound (I) (equivalent to 16 mg of Compound (I) free base).

[0182] In one particular embodiment, the tablet contains about 10.5 mg or about 10.6 mg of the phosphate salt of Compound (I) (equivalent to 8 mg of Compound (I) free base).

[0183] In one particular embodiment, the tablet comprises the following ingredients:

[0184] [Table 3]

[0185] In another particular embodiment, the tablet comprises the following ingredients:

[0186] [Table 4]

[0187] In an alternative specific embodiment, the tablet comprises the following ingredients:

[0188] [Table 5]

[0189] In yet another particular embodiment, the tablet comprises the following ingredients:

[0190] [Table 6]

[0191] In another embodiment, the pharmaceutical composition of the present invention further comprises an additional therapeutic agent. The additional therapeutic agent may be selected from any compound or therapeutic agent known to have or exhibiting advantageous properties when administered together with a compound having the same mechanism of action as ruxolitinib.

[0192] Preferably, the additional therapeutic agent is an agent useful for treating alopecia or autoimmune conditions, such as the inhibitor of JAK1, JAK2 or JAK3 and / or STAT1.Such inhibitors include ruxolitinib, tofacitinib, baricitinib, filgotinib, etc.Other additional therapeutic agents include oral corticosteroids.

[0193] In another embodiment, the present invention provides separate dosage forms of Compound (I) or a pharma- ceutically acceptable salt thereof, and any one or more of the additional therapeutic agents described above, wherein Compound (I) or a pharma- ceutically acceptable salt thereof, and the additional therapeutic agent are associated with each other. As used herein, the term "associated with each other" means that the separate dosage forms are packaged together, or sold together, and are attached to each other in such a way that it is readily apparent that the separate dosage forms are intended to be administered (within less than 24 hours of each other, either sequentially or simultaneously).

[0194] In the pharmaceutical composition of the present invention, compound (I) or its pharma- ceutically acceptable salt is present in an effective amount. As used herein, the term "effective amount" refers to an amount that is sufficient to treat the target disorder when administered in a suitable dosing regimen.

[0195] The interrelationship of animal and human dosages (based on milligrams per square meter of body surface) is described in Freireich et al., Cancer Chemother. Rep, 1966, 50:219. Approximate body surface area can be determined from the subject's height and weight. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, NY, 1970, 537.

[0196] In one embodiment, an effective amount of Compound (I) (either as the free base or as an equivalent amount of a pharma- ceutically acceptable salt such as a phosphate salt) may range from about 8 mg to 32 mg per day (e.g., 8 mg to 32 mg per day), for example about 10 mg / day (e.g., 10 mg / day), for example about 20 mg / day (e.g., 20 mg / day), or about 30 mg / day (e.g., 30 mg / day). In certain embodiments, the effective amount is about 8 mg / day (e.g., 8 mg / day), about 12 mg / day (e.g., 12 mg / day), about 16 mg / day (e.g., 16 mg / day), about 24 mg / day (e.g., 24 mg / day), or about 32 mg / day (e.g., 32 mg / day). In one embodiment, a dose of about 8mg / day (e.g., 8mg / day), about 16mg / day (e.g., 16mg / day), about 24mg / day (e.g., 24mg / day), or about 32mg / day (e.g., 32mg / day) is administered once a day.In one particular example, a dose of 16mg / day is administered as two 8mg tablets of compound (I) (as free base or as an equivalent amount of pharma- ceutically acceptable salt, such as phosphate) and administered together (i.e., as a single dose).In another particular example, a dose of 16mg / day is administered as one 16mg tablet of compound (I) (as free base or as an equivalent amount of pharma-ceutically acceptable salt, such as phosphate). In another embodiment, the 8 mg / day, 16 mg / day, 24 mg / day, or 32 mg / day dose is administered twice daily in split doses (e.g., the 16 mg / day dose is administered twice daily as 8 mg / day, or the 24 mg / day dose is administered twice daily as 12 mg / day). In another embodiment, the 8 mg / day, 16 mg / day, 24 mg / day, or 32 mg / day dose is administered twice daily in split doses (e.g., the 32 mg / day dose is administered as 16 mg of Compound (I) (either as the free base or as the equivalent of a pharma- ceutically acceptable salt, such as a phosphate salt), i.e., twice daily in separate doses. In a particular embodiment, the 16 mg / day dose is administered as 8 mg of Compound (I) (either as the free base or as the equivalent of a pharma-ceutically acceptable salt, such as a phosphate salt), twice daily, i.e., in separate doses.References to the amount of Compound (I) or a pharma- ceutically acceptable salt thereof include the amount of a pharma- ceutically acceptable salt of Compound (I) (such as a phosphate salt) that is equivalent to a given amount of Compound (I) as the free base (e.g., 10.5 mg of Compound (I) phosphate salt is equivalent to 8 mg of Compound (I) free base).

[0197] In a particular embodiment, the effective amount of Compound (I) or a pharma- ceutically acceptable salt thereof is about 4 mg (e.g., 4 mg) twice a day. In a particular embodiment, the effective amount of Compound (I) is administered twice a day as about 5.3 mg (e.g., 5.3 mg) of the phosphate salt of Compound (I). In a particular embodiment, the effective amount of Compound (I) or a pharma- ceutically acceptable salt thereof is administered twice a day as about 8 mg (e.g., 8 mg). In a particular embodiment, Compound (I) is administered twice a day as about 10.5 mg (e.g., 10.5 mg) of the phosphate salt of Compound (I).

[0198] In a particular embodiment, the effective amount of Compound (I) or a pharma- ceutically acceptable salt thereof is about 12 mg (e.g., 12 mg) twice a day. In a particular embodiment, the effective amount of Compound (I) is about 15.8 mg (e.g., 15.8 mg) of Compound (I) phosphate salt twice a day. In a particular embodiment, the effective amount of Compound (I) or a pharma- ceutically acceptable salt thereof is about 16 mg (e.g., 16 mg) twice a day. In a particular embodiment, the effective amount of Compound (I) is about 21.1 mg (e.g., 21.1 mg) of Compound (I) phosphate salt twice a day. EXAMPLES

[0199] Example 1 - Human Trials - Phase 2a A Phase 2a study was conducted to evaluate the safety and efficacy of Compound (I) (CTP-543) in subjects with alopecia, with a primary efficacy analysis at 24 weeks. The Phase 2a study was a double-blind, randomized, placebo-controlled study to evaluate the safety and efficacy of Compound (I) in adult patients with moderate to severe alopecia areata. Patients were randomized sequentially to receive one of three doses of Compound I as the phosphate salt (e.g., 10.5 mg of Compound (I) phosphate is equivalent to 8 mg of Compound (I) free base). Compound (I) doses were 4, 8 (i.e., approximately 10.5 mg of Compound (I) phosphate), and 12 mg, twice daily, with a patient group receiving placebo. The primary outcome measure utilized the severity of alopecia tool (SALT) after 24 weeks of treatment.

[0200] Interim top-line analyses for the 4 mg, 8 mg, and 12 mg cohorts are described below. The primary endpoint of the study was a 50% relative reduction in SALT between week 24 and baseline.

[0201] The demographic characteristics of subjects enrolled in the study and receiving 4, 8, or 12 mg (bid) or placebo are shown in Table 1 below.

[0202] [Table 7]

[0203] The baseline characteristics of the subjects are shown in Table 2 below.

[0204] [Table 8]

[0205] The most common (≥10%) treatment-emergent adverse events in patients are shown in Table 3 below.

[0206] [Table 9]

[0207] No serious adverse events were reported. In a preliminary analysis of the placebo, 4 mg, and 8 mg groups, only three grade 3 / 4 hematologic events were reported, distributed evenly across the placebo, 4 mg, and 8 mg groups.

[0208] In conclusion, the primary efficacy endpoint of the study was met: 58% of patients treated with 12 mg BID CTP-543 and 47% of patients treated with 8 mg BID CTP-543 experienced a 50% or greater reduction in overall SALT score compared to 8.6% on placebo (p<0.001). Additionally, 42% of patients treated with 12 mg BID CTP-543 and 29% of patients treated with 8 mg BID CTP-543 experienced a 75% or greater reduction in overall SALT score compared to 7% on placebo (p<0.05). Additionally, 36% of patients treated with 12 mg BID CTP-543 (p<0.001) and 16% of patients treated with 8 mg BID CTP-543 (p<0.05) achieved a 90% or greater reduction in overall SALT score compared to 2% with placebo. 21% of patients treated with 4 mg BID CTP-543 achieved a 50% or greater reduction in overall SALT score compared to 8.6% with placebo (not significant). The 12 mg BID and 8 mg BID dose groups were significantly different from the 4 mg BID dose group (p<0.05). Significant changes in SALT scores were observed for the 12 mg and 8 mg cohorts starting at week 12 compared to placebo (p<0.05).

[0209] Treatment was generally well tolerated, with no serious adverse events. The 4 mg BID dose was inseparable from placebo on all measures. The 8 mg BID and 12 mg BID doses were significantly different from placebo on all SALT measures at the end of the study, week 24. The 12 mg BID dose was numerically superior to the 8 mg BID dose, generally resulting in a more rapid onset and greater effect.

[0210] Example 2 - Open-label long-term study In the ongoing open-label long-term administration study, subjects who had previously been enrolled in an eligible clinical trial (including the study described in Example 1) and received either a total daily dose of 16 mg of Compound (I) (CTP-543, phosphate), a total daily dose of 24 mg of CTP-543, or placebo and completed the 24-week treatment period were eligible to enroll in the open-label long-term administration study (OLE) and continue to receive treatment with CTP-543 phosphate. A total of 152 subjects were enrolled in the OLE. In the OLE, subjects received daily treatment with CTP-543 at a dose of 8 mg BID or 12 mg BID (see Figure 8). Dose adjustments were possible at the investigator's discretion. One subject enrolled in the OLE received a daily dose of 24 mg QD of CTP-543 for approximately 9 months (i.e., the 24-week study period and the first 3 months of the OLE) and experienced hair growth at that dose (SALT score of zero, i.e., complete hair regrowth prior to dose reduction). The subject was then reduced to a daily dose of 8 mg BID of CTP-543 phosphate. After approximately 7 months of the OLE with a lower dose of 8 mg BID of CTP-543 daily, the subject continued to substantially maintain hair regrowth with a SALT score of 7.92.

[0211] Example 3 - Phase 2 persistence study The Phase 2 clinical trial will be conducted as a two-part, double-blind, randomized, multicenter study to evaluate hair regrowth following treatment with Compound (I) (CTP-543) and the subsequent persistence of that regrowth following dose reduction or drug interruption in adult patients with moderate to severe alopecia areata. Patients will be 18-65 years of age and have experienced episodes of alopecia-related hair loss for at least 6 months but not more than 10 years. Patients who are not receiving alopecia areata or other treatments that may affect hair regrowth or immune response must have at least 50% hair loss as measured by the Severity of Alopecia Tool (SALT) at screening and baseline. Up to approximately 75% of patients with complete or near-complete (SALT ≥ 95) hair loss will be enrolled.

[0212] The exam is divided into two parts.

[0213] Part A: Period 1 (treatment period) and Period 2 (dose titration period) Part B: Retreatment Phase

[0214] Part A: First Period The first period of Part A is a double-blind treatment period in which approximately 200 or 300 patients are randomized to receive one of two doses of Compound (I) (CTP-543) as the phosphate salt (e.g., 10.5 mg of Compound (I) phosphate is equivalent to 8 mg of Compound (I) free base) for 24 weeks. The doses are either 8 mg Compound (I) twice daily (BID) (i.e., approximately 10.5 mg of Compound (I) phosphate), or 12 mg Compound (I) twice daily (i.e., approximately 15.8 mg of Compound (I) phosphate). Randomization is stratified by type of hair loss into one of two categories: 1) partial hair loss (SALT ≥ 50 and < 95), 2) complete or near complete hair loss (SALT ≥ 95). Patients will receive their first dose of study medication in the clinic on Day 1 and will be instructed to administer study medication approximately every 12 hours daily during Phase 1. Other baseline assessments for Phase 1 of Part A will include Patient and Clinician Global Impression of Disease Severity (CGI-S and PGI-S), and Patient Reported Outcome for Satisfaction (SPRO) and Patient Reported Outcome for Hair Quality (QPRO). Blood samples for pharmacokinetic assessments will be collected periodically. Scalp photographs will also be taken to provide a visual record at the time of SALT assessment and will be performed at additional elective visits throughout the study. The primary efficacy analysis to determine responders for each dose group will be performed when all patients have completed Week 24 from Phase 1 of Part A. In some embodiments, patients with a <50% change in SALT score from baseline at End of Treatment (EOT) of Phase 1 of Part A are defined as non-responders and have the opportunity to continue treatment in an open-label extension study or complete treatment at Week 24 and return in 4 weeks for Post-Treatment Safety Follow-up.

[0215] In some embodiments, patients from each dose group have a 50% or greater change from baseline in SALT score at Week 24, are defined as responders, and enter the second period of Part A.

[0216] In some embodiments, at the end of treatment (EOT) of Phase 1 of Part A, successful treatment (responders) are defined as patients from each dose group with a SALT score of 20 or less at Week 24. These responders enter Phase 2 of Part A of the study. Patients with a SALT score >20 are defined as non-responders and have the opportunity to continue treatment in an open-label extension study or complete treatment at Week 24 and return in 4 weeks for post-treatment safety follow-up.

[0217] The first period of Part A (treatment period) will last 24 weeks. Response to treatment will be assessed using SALT for efficacy at weeks 4, 8, 12, 16, 20, and 24.

[0218] Part A: Second Period In the second period of Part A, patients are re-randomized to receive either a lower dose of Compound (I) (4 mg BID for patients previously receiving 8 mg BID or 8 mg BID for patients previously receiving 12 mg BID), or placebo. Patients in the second period of Part A continue on their assigned dose for up to 24 weeks or until they meet the criteria for loss of maintenance of hair regrowth (LOM). The criterion for LOM is a SALT score of greater than 20. Any patient who meets the LOM criteria at any evaluation time during the second period of Part A will enter Part B of the study and return to their original Compound (I) treatment from the first period of Part A (8 mg BID or 12 mg BID). Patients who do not meet the LOM criteria at the end of the 24 weeks (i.e., patients with a SALT score of 20 or less) will have the opportunity to continue treatment in an open-label extension study at their original Part A first period dose or complete treatment at week 24 and return at 4 weeks for post-treatment safety follow-up. The study design is described in Figure 7.

[0219] Phase 2 of Part A (dose titration) will continue for up to 24 weeks or until patients meet LOM criteria. Evaluation of treatment response using SALT for efficacy will be performed monthly until LOM criteria are met or the 24-week period is completed.

[0220] Part B: Any patient in the second phase of Part A who meets the LOM criteria (SALT>20) will enter Part B of the study and return to the original 8 mg BID or 12 mg BID dose in the first phase of Part A. In some embodiments, patients will continue on the assigned dose for 24 weeks, regardless of whether they meet the criteria for Restoration of Regrowth (ROR). In some embodiments, patients will continue on the assigned dose for 24 weeks or until they meet the criteria for Restoration of Regrowth (ROR). In some embodiments, ROR is defined as the patient's achievement of a "SALT score ≦ original EOT SALT score" at the end of the first phase of Part A. In some embodiments, ROR is defined as the patient's achievement of a SALT score ≦ 20. In some embodiments, any patient who meets the ROR criteria at any evaluation time during Part B is eligible to exit the study and enroll in an open-label extension study. Evaluation of treatment response using SALT for efficacy will be performed monthly until the criteria for Restoration of Regrowth (ROR) are met or the 24-week period is completed. Patients who do not meet the ROR criteria will have the opportunity to continue treatment in an open-label extension study or can complete treatment at week 24 and return in 4 weeks for post-treatment safety follow-up.

[0221] Without further description, it is believed that one skilled in the art can use the above description and illustrative examples to make and utilize the compounds of the present invention and to practice the claimed methods. It should be understood that the above discussion and examples merely provide detailed descriptions of certain preferred embodiments. It will be apparent to those skilled in the art that various modifications and equivalents can be made without departing from the spirit and scope of the present invention.

Claims

1. 1. A method of treating a disease, disorder or condition mediated solely or in part by a Janus associated kinase (JAK) in a human subject, said method comprising administering to a subject a compound represented by the following structural formula: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof to said subject; each position specifically designated as deuterium has at least 95% deuterium incorporation; wherein the compound or a pharma- ceutically acceptable salt thereof is administered in an amount ranging from about 8 mg to about 32 mg per day for (1) a first period of 8 to 24 weeks, followed by (2) a second period of at least 8 weeks, wherein the compound or a pharma- ceutically acceptable salt thereof is administered in an amount of 50-75% of the daily amount administered during the first period, to treat the disease, disorder or condition mediated solely or in part by JAK.

2. 2. The method of claim 1, wherein in compound (I), each position specifically designated as deuterium has at least 97% deuterium incorporation.

3. The disease, condition or disorder may be a skin disease, such as proliferative, autoimmune and / or inflammatory skin disease, psoriasis, atopic dermatitis, scleroderma, rosacea, skin cancer, dermatitis, dermatitis herpetiformis, dermatomyositis, vitiligo, alopecia, contact dermatitis, xeroderma, ichthyosis, hidradenitis suppurativa, urticaria, lichen planus, prurigo nodularis, vasculitis, cutaneous lupus erythematosus (CLE), or chronic idiopathic pruritus; a hyperproliferative disorder or cancer, including polycythemia vera, essential thrombocytopenia, myelofibrosis; a disease, condition or disorder, such as asthma, chronic obstructive pulmonary disease, chronic transplant pulmonary failure (e.g., bronchiolitis obliterans syndrome), pulmonary fibrosis, cystic fibrosis, rhinitis, bronchiolitis, byssinosis, pneumoconiosis, bronchiectasis, hypersensitivity pneumonitis, lung cancer, mesothelioma, sarcoidosis, pulmonary fibrosis ...

3. The method of claim 1 or 2, wherein the immunosuppressant is selected from respiratory diseases such as idiopathies, digestive diseases such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, retroperitoneal fibrosis, celiac disease, cancer, eye diseases such as myasthenia gravis, Sjogren's syndrome, conjunctivitis, scleritis, uveitis, dry eye syndrome, keratitis, iritis, systemic conditions such as systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, type 1 diabetes and diabetic complications, cancer, ankylosing spondylitis, psoriatic arthritis, and other autoimmune diseases and conditions in which immunosuppression may be desirable, for example to treat or prevent acute and / or chronic graft-versus-host disease (e.g. graft-versus-host disease in organ transplantation).

4. 4. The method of any one of claims 1 to 3, wherein during the first period, the compound or a pharma- ceutically acceptable salt thereof is administered at about 16 mg / day, about 24 mg / day, or about 32 mg / day.

5. 5. The method of any one of claims 1 to 4, wherein during the second period, the compound or a pharma- ceutically acceptable salt thereof is administered at about 8 mg / day, about 12 mg / day, or about 16 mg / day.

6. 6. The method of any one of claims 1 to 5, wherein during the first period of time, the compound or a pharma- ceutically acceptable salt thereof is administered at about 24 mg / day, and during the second period of time, the compound or a pharma- ceutically acceptable salt thereof is administered at about 16 mg / day.

7. 7. The method of claim 6, wherein said about 24 mg / day of said compound or a salt thereof is administered once daily and said about 16 mg / day is administered once daily.

8. 7. The method of claim 6, wherein the about 24 mg / day of the compound or salt thereof is administered twice a day in an amount of about 12 mg, and the about 16 mg / day of the compound or salt thereof is administered twice a day in an amount of about 8 mg.

9. 6. The method of any one of claims 1 to 5, wherein during the first period of time, the compound or a pharma- ceutically acceptable salt thereof is administered at about 16 mg / day, and during the second period of time, the compound or a pharma- ceutically acceptable salt thereof is administered at about 8 mg / day.

10. 10. The method of any one of claims 1 to 6 or claim 9, wherein the compound or a pharma- ceutically acceptable salt thereof is administered once daily during the first period of time.

11. 10. The method of any one of claims 1 to 6 or claim 9, wherein the compound or a pharma- ceutically acceptable salt thereof is administered twice daily during the first period of time.

12. 12. The method of any one of claims 1 to 11, wherein the first period of time is about 8 to 12 weeks.

13. The method of any one of claims 1 to 11, wherein the first period of time is about 24 weeks.

14. The method of any one of claims 1 to 13, wherein the second period of time is at least 12 weeks.

15. The method of any one of claims 1 to 14, wherein the second period of time is at least 24 weeks.

16. The method of any one of claims 1 to 15, wherein the disease, condition, or disorder is not alopecia.

17. The method of any one of claims 1 to 16, wherein the disease, condition, or disorder is not alopecia areata.

18. The disease, condition or disorder may be selected from the group consisting of skin diseases, including proliferative, autoimmune and / or inflammatory skin diseases, psoriasis, atopic dermatitis, scleroderma, rosacea, skin cancer, dermatitis, dermatitis herpetiformis, dermatomyositis, vitiligo, contact dermatitis, xeroderma, ichthyosis, hidradenitis suppurativa, urticaria, lichen planus, prurigo nodularis, vasculitis, cutaneous lupus erythematosus (CLE), and chronic idiopathic pruritus; hyperproliferative disorders or cancers, including polycythemia vera, essential thrombocytopenia, and myelofibrosis; and asthma, chronic obstructive pulmonary disease, chronic transplant pulmonary failure (e.g., bronchiolitis obliterans syndrome), pulmonary fibrosis, cystic fibrosis, rhinitis, bronchiolitis, byssinosis, pneumoconiosis, bronchiectasis, hypersensitivity pneumonitis, lung cancer, mesothelioma, sarcoidosis, and the like.

18. The method of any one of claims 1 to 17, wherein the immune suppression is selected from respiratory diseases such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, retroperitoneal fibrosis, celiac disease, cancer, digestive diseases such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, retroperitoneal fibrosis, celiac disease, cancer, eye diseases such as myasthenia gravis, Sjogren's syndrome, conjunctivitis, scleritis, uveitis, dry eye syndrome, keratitis, iritis, systemic conditions such as systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, type 1 diabetes and diabetic complications, cancer, ankylosing spondylitis, psoriatic arthritis, and other autoimmune diseases and conditions in which immunosuppression may be desirable, for example to treat or prevent acute and / or chronic graft versus host disease (e.g. graft versus host disease in organ transplantation).

19. The method of any one of claims 1 to 18, wherein the compound, or a pharma- ceutically acceptable salt thereof, is administered orally.

20. The method of any one of claims 1 to 19, wherein the compound or a pharma- ceutically acceptable salt thereof is administered in a pharmaceutical formulation that is a tablet.

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