Dose regimen for treatment with deuterated JAK inhibitor

Abstract

Disclosed is a method of treating a disease, disorder, or condition mediated, alone or in part, by a Janus-related kinase in a subject, which is beneficially treated by administering a JAK1 and / or JAK2 inhibitor. The method comprises administering to the subject an effective amount of Compound (I): or a pharmaceutically acceptable salt thereof. # imgabs0 #

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 338,320, filed May 4, 2022. The entire teachings of the above application are incorporated herein by reference. Background Art

[0003] Janus-associated kinases (JAKs) mediate signaling of certain cytokines and growth factors that are critical for hematopoiesis and immune function. JAK signaling involves recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, activation of STATs and subsequent localization of STATs to the nucleus, leading to regulation of gene expression.

[0004] Although certain JAK inhibitors, including ruxolitinib, baricitinib, and upadacitinib, have been approved for the treatment of JAK-associated disorders, including myelofibrosis, rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, and alopecia areata, there is a need for improved treatments of JAK-associated disorders. Summary of the invention

[0005] It has now been discovered that deuterated analogs of ruxolitinib (including compound (I), also known 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)propionitrile, or D8-ruxolitinib or CTP-543) can be used to treat diseases, disorders or conditions mediated solely or in part by Janus-associated kinases (JAKs, including JAK1 and / or JAK2). Compound (I) is represented by the following structural formula:

[0006]

[0007] In certain embodiments, compound (I) is administered as a pharmaceutically acceptable salt, such as a phosphate. Compound (I) can be administered at a dosage in the range of about 8 mg to about 32 mg per day (or based on a salt, such as an equal weight of a phosphate of compound (I)), in a single daily dose or in divided doses (e.g., twice a day). Based on these findings, disclosed herein is a novel therapy for a disease, disorder or condition mediated solely or in part by JAK in a mammalian subject, compound (I) or a pharmaceutically acceptable salt thereof. In other embodiments, disclosed herein is a novel therapy for a disease or condition mediated solely or in part by Janus-associated kinases (JAKs) in a mammalian subject, compound (I) or a pharmaceutically acceptable salt thereof.

[0008] In one aspect, a method for treating a disease or condition mediated solely or in part by a Janus-associated kinase (JAK) in a mammalian (e.g., human) subject is provided. The method comprises administering to the subject an effective amount of a compound represented by the following structural formula:

[0009] or a pharmaceutically acceptable salt thereof, wherein at least 95% of deuterium is incorporated at each position specifically designated as deuterium;

[0010] wherein (1) the compound, or a pharmaceutically acceptable salt thereof, is administered in an amount ranging from about 8 mg to about 32 mg per day for a first period of 8-24 weeks, followed by (2) the compound, or a pharmaceutically acceptable salt thereof, being administered for a second period of at least 8 weeks, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered in a daily amount that is 50 to 75% of the daily amount administered during the first period, such that the disease or condition is treated.

[0011] In certain embodiments, the disease or condition mediated solely or in part by a Janus-associated kinase (JAK) is not a hair loss disorder, such as alopecia areata. In certain embodiments, the disease or condition mediated solely or in part by a 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 or condition mediated solely or in part by JAK1 and / or JAK2 is not a hair loss disorder, such as alopecia areata.

[0012] In certain embodiments, the disease, condition or disorder mediated alone or in part by JAK is selected from a skin disease, such as a proliferative, autoimmune and / or inflammatory skin disorder, psoriasis, atopic dermatitis, scleroderma, rosacea, skin cancer, dermatitis, dermatitis herpetiformis, dermatomyositis, vitiligo, alopecia, contact dermatitis, xerosis, ichthyosis, hidradenitis suppurativa, urticaria, lichen planus, prurigo nodularis, vasculitis, cutaneous lupus erythematosus (CLE) and chronic idiopathic pruritus; a hyperproliferative disorder or cancer, including polycythemia vera, essential thrombocytopenia and myelofibrosis; a respiratory disease, such as asthma, chronic obstructive pulmonary disease, chronic lung allograft dysfunction, e.g., bronchiolitis obliterans syndrome, pulmonary fibrosis, Cystic fibrosis, rhinitis, bronchiolitis, byssinosis, pneumoconiosis, bronchiectasis, hypersensitivity pneumonitis, lung cancer, mesothelioma and sarcoidosis; gastrointestinal diseases, such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, retroperitoneal fibrosis, celiac disease and cancer; eye diseases, such as myasthenia gravis, Sjögren's syndrome, conjunctivitis, scleritis, uveitis, dry eye syndrome, keratitis, iritis; systemic indications, such as lupus, multiple sclerosis, rheumatoid arthritis, type I diabetes and diabetic complications, cancer, ankylosing spondylitis and psoriatic arthritis; and other autoimmune diseases and indications where immunosuppression is desired, for example to treat or prevent acute and / or chronic graft-versus-host disease (e.g., in organ transplantation).

[0013] In certain embodiments, the disease or condition mediated alone or in part by Janus-associated kinase (JAK) is not a hair loss disorder, such as alopecia areata. In certain embodiments, the disease or condition mediated alone or in part by Janus-associated kinase (JAK) is an autoimmune disease, a skin disorder, allograft rejection, graft-versus-host disease, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, type I diabetes, lupus, inflammatory bowel disease, Crohn's disease, myasthenia gravis, immunoglobulin nephropathy, myocarditis, autoimmune thyroid disorder, viral disease, Epstein Barr Virus (EBV), hepatitis B, hepatitis C, HIV, HTLV 1. Varicella-zoster virus (VZV), human papillomavirus (HPV), cancer, myeloproliferative disorders, inflammatory diseases, inflammatory diseases of the eye, iritis, uveitis, scleritis, conjunctivitis, inflammatory diseases of the respiratory tract, inflammatory diseases of the upper respiratory tract, inflammatory diseases of the lower respiratory tract, inflammatory myopathy, myocarditis, ischemia-reperfusion or disorders associated with ischemic events, anorexia or cachexia caused by or associated with cancer, fatigue caused by or associated with cancer, bone resorption disease or mast cell activation syndrome. In certain embodiments, the autoimmune disease is a bullous skin disorder; in certain embodiments, the bullous skin disorder is pemphigus vulgaris or bullous pemphigoid (BP). In certain embodiments, the skin disorder is skin sensitization, skin irritation, 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 myeloid 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, kidney 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. Additional examples of JAK-related diseases include allergic conditions such as asthma, food allergies, eczematous dermatitis, contact dermatitis, atopic dermatitis (atopic dermatitis) and rhinitis. Additional examples of JAK-associated diseases include viral diseases such as Epstein-Barr virus (EBV), hepatitis B, hepatitis C, HIV, HTLV 1, varicella-zoster virus (VZV), and human papillomavirus (HPV). Additional examples of JAK-associated diseases include diseases associated with cartilage turnover, such as gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, amyotrophic lateral sclerosis, Tietze syndrome, coastal arthropathy, endemic deforming osteoarthritis, Mseleni disease, Handigodu disease, degeneration caused by fibromyalgia, systemic lupus erythematosus, scleroderma, or ankylosing spondylitis. Additional examples of JAK-associated diseases include congenital cartilage malformations, including hereditary chondrolysis, chondrodysplasia and pseudochondrodysplasia (e.g., microtia, anotia, and metaphyseal chondrodysplasia. In certain embodiments, the disease or condition mediated solely or in part by a Janus-associated kinase (JAK) is not a hair loss disorder, such as alopecia areata.

[0014] In certain embodiments, during the first period, the compound or a pharmaceutically acceptable salt thereof is administered at about 12 mg / day, about 16 mg / day, about 24 mg / day, or about 32 mg per day.

[0015] In certain embodiments, during the second period, the compound or a pharmaceutically acceptable salt thereof is administered at about 6 mg / day, about 8 mg / day, about 12 mg / day, or about 16 mg per day.

[0016] 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, the compound or salt of about 24 mg / day is administered once a day, and the compound or salt of about 16 mg / day is administered once a day. In certain embodiments, the compound or salt of about 24 mg / day is administered twice a day at about 12 mg, and the compound or salt of about 16 mg / day is administered twice a day at about 8 mg.

[0017] In certain embodiments, in the first period, the compound or its pharmaceutically acceptable salt is administered at about 16 mg / day, and in the second period, the compound or its pharmaceutically acceptable salt is administered at about 8 mg / day. In certain embodiments, the compound or salt of about 16 mg / day is administered once a day, and the compound or salt of about 8 mg / day is administered once a day. In certain embodiments, the compound or salt of about 16 mg / day is administered twice a day at about 8 mg, and the compound or salt of about 8 mg / day is administered twice a day at about 4 mg.

[0018] In certain embodiments, the compound or a pharmaceutically acceptable salt thereof is administered orally.

[0019] In certain embodiments, the compound or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical formulation which is a tablet.

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

[0021] In certain embodiments, the compound or a pharmaceutically acceptable salt thereof is administered once daily during the second period. In certain embodiments, the compound or a pharmaceutically acceptable salt thereof is administered twice daily during the second period.

[0022] In certain embodiments, the first period is about 8-24 weeks. In certain embodiments, the first period is about 12 weeks. In certain embodiments, the first period is about 16 weeks. In certain embodiments, the first period is about 20 weeks. In certain embodiments, the first period is about 24 weeks. In certain embodiments, the second period is at least 12 weeks. In certain embodiments, the second period is at least 24 weeks.

[0023] In certain embodiments, the first period is about 8-12 weeks. In certain embodiments, the first period is about 8 weeks. In certain embodiments, the first period is about 12 weeks. In certain embodiments, the first period is at least 8 weeks. In certain embodiments, the second period is at least 8 weeks.

[0024] In certain embodiments, in compound (I), each position specifically designated as deuterium is incorporated with at least 97% deuterium.

[0025] In another aspect, a method for treating a disease or condition mediated solely or in part by a Janus-associated kinase (JAK) in a mammalian (e.g., human) subject is provided. The method comprises administering to the subject an effective amount of a compound represented by the following structural formula:

[0026] or a pharmaceutically acceptable salt thereof, wherein at least 95% of deuterium is incorporated at each position specifically designated as deuterium;

[0027] wherein (1) the compound, or a pharmaceutically acceptable salt thereof, is administered 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) the compound, or a pharmaceutically acceptable salt thereof, being administered for a second period of at least 8 weeks, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered in a daily amount that is 50 to 75% of the daily amount administered during the first period, such that the disease or condition is treated.

[0028] Another aspect of the present invention is a compound (I) or a pharmaceutically acceptable salt thereof (i.e., an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate salt), for treating a disease, disorder or condition mediated by a Janus-associated kinase (JAK), i.e., the disease, disorder or condition 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 can be administered in a dosage regimen disclosed herein. In certain embodiments, the disease, disorder or condition mediated solely or in part by a Janus-associated kinase (JAK) is not a hair loss disorder, such as alopecia areata. In certain embodiments, the disease, disorder or condition mediated solely or in part by a Janus-associated kinase (JAK) is a disease or condition mediated solely or in part by a Janus-associated kinase 1 (JAK1) and / or a 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 a hair loss disorder, such as alopecia areata. In certain embodiments, the disease, disorder or condition is an autoimmune skin disorder. In certain embodiments, the disease, disorder or condition is selected from psoriasis, atopic dermatitis, dermatomyositis, vitiligo, hidradenitis suppurativa, lichen planus, or prurigo nodularis.

[0029] Still another aspect of the present invention is a compound (I) or a pharmaceutically acceptable salt thereof (i.e., an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate) for the preparation of a medicament for treating a disorder, disease or condition, which 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 can 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 a hair loss disorder, 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 a hair loss disorder, such as alopecia areata.

[0030] Still another aspect provides a pharmaceutical composition for 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 pharmaceutically acceptable salt thereof (i.e., an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate); and a pharmaceutically acceptable carrier. In certain embodiments, (1) a pharmaceutical composition comprising 4-50 mg of compound (I) or a pharmaceutically acceptable salt thereof is 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 for a second period of at least 8 weeks, wherein the pharmaceutical composition is administered in an amount of 50 to 75% of the amount of compound (I) administered per day during the first period, so as to treat the disease or condition.

[0031] In any of the aspects and embodiments disclosed herein, in certain embodiments, the disease or condition mediated solely or in part by a Janus-associated kinase (JAK) is not a hair loss disorder, such as alopecia areata. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 Shown are the percentages of responders (patients with a ≥50% reduction in SALT score from baseline) at Week 24 in the Phase 2a trial, including the placebo, 4 mg BID, 8 mg BID, and 12 mg BID cohorts.

[0033] Figure 2 Shown are the percentages of responders (patients with a ≥50% reduction in SALT score from baseline) who were seen in the Phase 2a trial for the placebo, 4 mg BID, 8 mg BID, and 12 mg BID cohorts.

[0034] Figure 3 Shown are the percentages of responders (patients with a ≥75% reduction in SALT score from baseline) who were seen in the Phase 2a trial for the placebo, 4 mg BID, 8 mg BID, and 12 mg BID cohorts.

[0035] Figure 4 Shown are the percentages of responders (patients with a ≥90% reduction in SALT score from baseline) who were seen in the Phase 2a trial for the placebo, 4 mg BID, 8 mg BID, and 12 mg BID cohorts.

[0036] Figure 5 Improvements in patient SALT scores after 24 weeks in the Phase 2a trial are shown, including placebo, 4 mg BID, 8 mg BID, and 12 mg BID cohorts.

[0037] Figure 6 Relative changes in SALT scores at visits in the Phase 2a trial are shown, including the placebo, 4 mg BID, 8 mg BID, and 12 mg BID groups.

[0038] Figure 7 Shown is the design of a study in which 8 mg BID or 12 mg BID of Compound (I) (CTP-543) is administered in a first period, followed by a lower dose of Compound (I) or placebo in a second period.

[0039] Figure 8 Shown are patient enrollment and placement of subjects in the open-label extension (OLE) study of Compound (I) (CTP-543). DETAILED DESCRIPTION

[0040] definition

[0041] The term "treat" means to reduce, inhibit, attenuate, decrease, arrest or stabilize the development or progression of a disease (e.g., a disease or disorder described herein), reduce the severity of a disease, or improve symptoms associated with a disease. For example, treatment of a hair loss disorder includes regrowth of hair, prevention of further hair loss, or reduction in the rate of hair loss.

[0042] "Hair loss disorder" means any condition or disorder that causes hair loss in one or more parts of the body. Hair loss disorders include, but are not limited to, androgenic alopecia, alopecia areata, telogen effluvium, alopecia areata, alopecia totalis, and alopecia universalis.

[0043] The efficacy of the treatment of hair loss disorders such as alopecia can be measured in a variety of ways, some of which are known in the art. For example, "Alopecia Severity Tool", also referred to as SALT, is a validated evaluation scale developed by the National Alopecia Areata Foundation working committee to evaluate the degree of hair loss. See, for example, Isen EA, Hordinsky MK, Price VH et al. Alopecia areata investigational assessment guidelines-Part II. "Journal of the American Academy of Dermatology (J Am Acad Dermatol)" 2004:51:440-447 (incorporated herein by reference). The SALT score of the patient is calculated by measuring the hair loss percentage in each of the 4 areas of the scalp and summing up to obtain a composite score. The SALT score reduction reflects hair regrowth. For example, the SALT score of no hair on the scalp will be 100, and the SALT score of complete hair regrowth will be 0. In certain embodiments, the treatment methods as described herein can provide a SALT score improvement 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 as described herein can provide a SALT score improvement 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 as described herein can provide a SALT score improvement of at least 20% relative to baseline in a patient, or at least 30% relative to baseline in a patient, or at least 40% relative to baseline in a patient, or at least 50% relative to baseline in a patient, or at least 60% relative to baseline in a patient, or at least 70% relative to baseline in a patient, or at least 75% relative to baseline in a patient, or at least 80% relative to baseline in a patient, or at least 90% relative to baseline in a patient.

[0044] The term "a disease, disorder or condition mediated solely or in part by Janus-associated kinases (JAKs)" refers to a disease, disorder or condition treatable 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, but are not limited to, skin diseases, such as proliferative, autoimmune and / or inflammatory skin disorders, including psoriasis, atopic dermatitis, scleroderma, rosacea, skin cancer, dermatitis, dermatitis herpetiformis, dermatomyositis, vitiligo, alopecia, contact dermatitis, xerosis, 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; respiratory diseases, such as asthma, chronic obstructive pulmonary disease, chronic lung allograft dysfunction, e.g., bronchiolitis obliterans syndrome, pulmonary fibrosis, Cystic fibrosis, rhinitis, bronchiolitis, byssinosis, pneumoconiosis, bronchiectasis, hypersensitivity pneumonitis, lung cancer, mesothelioma and sarcoidosis; Gastrointestinal diseases, such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, retroperitoneal fibrosis, celiac disease and cancer; Eye diseases, such as myasthenia gravis, Sjögren's syndrome, conjunctivitis, scleritis, uveitis, dry eye syndrome, keratitis, iritis; Systemic indications, such as lupus, multiple sclerosis, rheumatoid arthritis, type I diabetes and diabetic complications, cancer, ankylosing spondylitis and psoriatic arthritis; And other autoimmune diseases and indications where immunosuppression is desired, for example, to treat or prevent acute and / or chronic graft-versus-host disease (e.g., in organ transplantation). In certain embodiments, the disease or condition mediated solely or in part by a Janus-associated kinase (JAK) is not a hair loss disorder, such as alopecia areata.

[0045] In certain embodiments, additional examples of diseases, conditions or disorders that may 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 disorders, allograft rejection, graft-versus-host disease, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, type I diabetes, lupus, inflammatory bowel disease, Crohn's disease, myasthenia gravis, immunoglobulin nephropathy, myocarditis, autoimmune thyroid disorders, viral diseases, Epstein-Barr virus (EBV), hepatitis B, hepatitis C, HIV, HTLV 1. Varicella-zoster virus (VZV), human papillomavirus (HPV), cancer, myeloproliferative disorders, inflammatory diseases, inflammatory diseases of the eye, iritis, uveitis, scleritis, conjunctivitis, inflammatory diseases of the respiratory tract, inflammatory diseases of the upper respiratory tract, inflammatory diseases of the lower respiratory tract, inflammatory myopathy, myocarditis, ischemia-reperfusion or disorders associated with ischemic events, anorexia or cachexia caused by or associated with cancer, fatigue caused by or associated with cancer, bone resorption disease or mast cell activation syndrome. In certain embodiments, the autoimmune disease is a bullous skin disorder; in certain embodiments, the bullous skin disorder is pemphigus vulgaris or bullous pemphigoid (BP). In certain embodiments, the skin disorder is skin sensitization, skin irritation, 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 myeloid 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, kidney cancer, liver cancer, breast cancer, lung cancer, thyroid cancer, Kaposi's sarcoma, Kallmann's disease, pancreatic cancer, a blood cancer, a lymphoma, a 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. Additional examples of JAK-related diseases include allergic conditions such as asthma, food allergies, eczematous dermatitis, contact dermatitis, atopic dermatitis (atopic dermatitis), and rhinitis. Additional examples of JAK-related diseases include viral diseases such as Epstein Barr virus (EBV), hepatitis B, hepatitis C, HIV, HTLV 1, varicella-zoster virus (VZV), and human papillomavirus (HPV). Additional examples of JAK-related diseases include diseases associated with cartilage turnover, e.g., gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, amyotrophic pain, Tietze syndrome, coastal arthropathy, local osteoarthritis deformans, Meseleni disease, Handigodu disease, degeneration caused by fibromyalgia, systemic lupus erythematosus, scleroderma, or ankylosing spondylitis. Additional examples of JAK-related diseases include congenital cartilage malformations, including hereditary chondrolysis, chondrodysplasia, and pseudochondrodysplasia (e.g., microtia, aphonia, and metaphyseal chondrodysplasia). In certain embodiments, the disease or condition mediated solely or in part by a Janus-associated kinase (JAK) is not a hair loss disorder, such as alopecia areata.

[0046] 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 apes), and the like.

[0047] As used herein, the term "about" means "approximately," i.e., within an acceptable error range for a particular value as determined by one of ordinary skill in the art. For example, "about" may mean a range of up to 10% higher or lower than a particular value, up to 5% higher or lower than a particular value, or up to 1% higher or lower than a particular value. In addition, when a particular value is a length of time in weeks, the term "about" may mean up to two weeks more or less, or one week more or less.

[0048] It will be appreciated that, depending on the source of the chemical materials used in the synthesis, some variation in natural isotopic abundance will occur in the synthetic compound. Therefore, the preparation of ruxolitinib will inherently contain a small amount of deuterated isotopologues. Despite this variation, the concentrations of naturally abundant stable hydrogen and carbon isotopes are small and insignificant 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., Comparative Biochemistry and Physiology A: Molecular and Integrated Physiology (Comp Biochem Physiol Mol Integr Physiol), 1998, 119: 725.

[0049] In compound (I), any atom not specifically designated as a particular isotope is intended to represent any stable isotope of the atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", the position is understood to have hydrogen according to its natural abundance isotopic composition. However, in certain embodiments stated therein, when a position is specifically designated as "H" or "hydrogen", 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 specifically stated, when a position is specifically designated as "H" or "hydrogen", the position incorporates ≤20% deuterium, ≤10% deuterium, ≤5% deuterium, ≤4% deuterium, ≤3% deuterium, ≤2% deuterium or ≤1% deuterium. Furthermore, unless otherwise indicated, when a position is specifically designated as "D" or "deuterium," the position is understood to have an abundance of deuterium at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% deuterium incorporated). The amount of deuterium incorporated at a given position can be measured by analytical methods known to those of ordinary skill in the art, such as by proton NMR.

[0050] As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a particular isotope.

[0051] In other embodiments, compound (I) has an isotopic enrichment factor of at least 3500 (52.5% deuterium incorporated at each designated deuterium position (or atom), at least 4000 (60% deuterium incorporated), at least 4500 (67.5% deuterium incorporated), at least 5000 (75% deuterium incorporated), at least 5500 (82.5% deuterium incorporated), at least 6000 (90% deuterium incorporated), at least 6333.3 (95% deuterium incorporated), at least 6466.7 (97% deuterium incorporated), at least 6600 (99% deuterium incorporated), or at least 6633.3 (99.5% deuterium incorporated) for each designated deuterium position (or atom).

[0052] In some embodiments, in the compounds of the present invention, each designated deuterium position (or atom) incorporates at least 52.5% of deuterium. In some embodiments, in the compounds of the present invention, each designated deuterium position incorporates at least 60% of deuterium. In some embodiments, in the compounds of the present invention, each designated deuterium position incorporates at least 67.5% of deuterium. In some embodiments, in the compounds of the present invention, each designated deuterium position incorporates at least 75% of deuterium. In some embodiments, in the compounds of the present invention, each designated deuterium position incorporates at least 80% of deuterium. In some embodiments, in the compounds of the present invention, each designated deuterium position incorporates at least 85% of deuterium. In some embodiments, in the compounds of the present invention, each designated deuterium position incorporates at least 90% of deuterium. In some embodiments, in the compounds of the present invention, each designated deuterium position incorporates at least 95% of deuterium. In some embodiments, in the compounds of the present invention, each designated deuterium position incorporates at least 97% of deuterium. In some embodiments, in the compounds of the invention, each designated deuterium position is incorporated with at least 98% deuterium. In some embodiments, in the compounds of the invention, each designated deuterium position is incorporated with at least 99% deuterium. In some embodiments, in the compounds of the invention, each designated deuterium position is incorporated with at least 99.5% deuterium.

[0053] The term "isotopologue" refers to a molecule in which the chemical structure differs from the structure shown for compound (I) only in its isotopic composition.

[0054] The term "compound" refers to a collection of molecules with the same chemical structure when referring to the compounds of the present invention, except that there may be isotopic changes between the constituent atoms of the molecules. Therefore, it will be apparent to those skilled in the art that, although compound (I) is represented by a specific chemical structure with deuterium atoms at eight specified positions, compound (I) will contain molecules with deuterium at each of the eight specified positions, and may also contain one or more isotopologues with hydrogen atoms in the specified deuterium positions in the structure. The relative amount of such isotopologues in compound (I) will depend on many factors, including the isotopic purity of the deuterated reagent used to prepare the compound and the efficiency of incorporating deuterium in the various synthesis steps used to prepare the compound. In certain embodiments, the relative amount of all such isotopologues will be less than 49.9% of the compound. In other embodiments, the relative amounts of all such isotopologues will be 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 compound.

[0055] The present invention also provides a salt of compound (I). The salt of the compound of the present invention is formed between an acidic group and a basic group (such as an amino functional group) of the compound or between a basic group and an acidic group (such as a carboxyl functional group) of the compound. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt, such as a phosphate.

[0056] As used herein, the term "pharmaceutically acceptable" refers to components that are suitable for use in contact with the tissues of humans and other mammals without excessive toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. "Pharmaceutically acceptable salt" means any non-toxic salt that is capable of providing, directly or indirectly, a compound of the present invention when administered to a recipient. "Pharmaceutically acceptable counterions" are ionic portions of salts that are non-toxic when released from the salt when administered to a recipient.

[0057] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid; and organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric 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, as well as related inorganic and organic acids. Thus, such pharmaceutically acceptable salts include sulfates, pyrophosphates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, caprates, heptanoates, propionates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, Pharmaceutically acceptable acid addition salts include butyrate, succinate ...

[0058] As used herein, the term "stable compound" refers to a compound that has a stability sufficient to allow its manufacture and maintains the integrity of the compound for a period of time sufficient to be useful for the purposes detailed herein (e.g., formulated into a therapeutic product to treat a disease or condition responsive to a therapeutic agent, an intermediate for producing a therapeutic compound, an isolable or storable intermediate compound).

[0059] "D" and "d" both refer to deuterium. "Stereoisomers" refers to both enantiomers and diastereomers. "Tert" and "t-" each refer to tris. "US" refers to the United States.

[0060] "Substituting with deuterium" means replacing one or more hydrogen atoms with a corresponding number of deuterium atoms.

[0061] It has been found that the administration of compound (I) or an equivalent amount of a pharmaceutically acceptable salt thereof can cause hair growth after the first administration period. According to the present invention, the amount of compound (I) or its salt to be administered to a patient or subject can then be reduced (after the first administration period) in a second treatment period while maintaining and / or extending (increasing) the hair growth achieved during the first period. In general, the amount of compound (I) or its salt administered in the second period is sufficient to maintain the hair growth achieved during the first period (e.g., as measured by the Severity of Hair Loss Tool (SALT) score), such as about 50 to 75% of the daily amount administered during the first period (e.g., if 16 mg / day of compound (I) or its salt is administered during the first period, 8 to 12 mg / day can be administered during the second period). In certain embodiments, the maintenance dose (the daily amount administered during the second period) is about 33.3% of the daily amount administered during the first period.

[0062] Treatment

[0063] In one aspect, the present invention provides a method of treating a hair loss disorder in a human subject, the method comprising administering to the subject a compound represented by the following structural formula:

[0064] or a pharmaceutically acceptable salt thereof; wherein at least 90% of deuterium is incorporated at each position specifically designated as deuterium; wherein (1) the compound or a pharmaceutically acceptable salt thereof is administered for a first period of time, wherein the compound or a pharmaceutically acceptable salt thereof is administered in an amount ranging from 8 mg to 32 mg per day, followed by (2) the compound or a pharmaceutically acceptable salt thereof is administered for a second period of time, wherein the compound or a pharmaceutically acceptable salt thereof is administered in an amount of 50 to 75% of the amount per day administered during the first period of time, such that the hair loss disorder is treated. In certain embodiments, the first period of time is about 8-24 weeks, e.g., 8 weeks, 12 weeks, 16 weeks, 20 weeks, or 24 weeks. In certain embodiments, the second period of time is at least 8 weeks, e.g., 8 weeks, 12 weeks, 16 weeks, 20 weeks, or 24 weeks (or longer).

[0065] In one aspect, the present invention provides a method of treating a hair loss disorder in a human subject, the method comprising administering to the subject a compound represented by the following structural formula:

[0066] or a pharmaceutically acceptable salt thereof; wherein at least 95% of deuterium is incorporated at each position specifically designated as deuterium;

[0067] wherein (1) the compound or a pharmaceutically acceptable salt thereof is administered for a first period of time, wherein the compound or a pharmaceutically acceptable salt thereof is administered in an amount ranging from 8 mg to 32 mg per day, followed by (2) the compound or a pharmaceutically acceptable salt thereof is administered for a second period of time, wherein the compound or a pharmaceutically acceptable salt thereof is administered in an amount per day that is 50 to 75% of the amount per day administered during the first period of time, such that the hair loss disorder is treated. In certain embodiments, the first period of time is about 8-24 weeks, e.g., 8 weeks, 12 weeks, 16 weeks, 20 weeks, or 24 weeks. In certain embodiments, the second period of time is at least 8 weeks, e.g., 8 weeks, 12 weeks, 16 weeks, 20 weeks, or 24 weeks (or longer).

[0068] In certain embodiments, the hair loss condition is treated when the change in the subject's SALT score at the end of the first period is ≥50% relative to the subject's pre-treatment baseline SALT score. In certain embodiments, the hair loss condition is treated when the subject's SALT score is less than or equal to 20 at the end of the second period. In certain embodiments, the hair loss condition is treated when the change in the subject's SALT score at the end of the first period is ≥50% relative to the subject's pre-treatment baseline SALT score and the subject's SALT score is less than or equal to 20 at the end of the second period.

[0069] In some embodiments, the length of the first period is sufficient to achieve a SALT score of less than or equal to 50, less than or equal to 40, less than or equal to 30, less than or equal to 20, less than or equal to 15, less than or equal to 10, less than or equal to 5, less than or equal to 1, or zero at the end of the first period. In some embodiments, the length of the first period is sufficient to achieve a SALT score of less than or equal to 20 at the end of the first period. In some embodiments, the length of the first period is sufficient to achieve a SALT score of less than or equal to 15 at the end of the first period. In some embodiments, the length of the first period is sufficient to achieve a SALT score of less than or equal to 10 at the end of the first period. In some embodiments, the length of the first period is sufficient to achieve a SALT score of less than or equal to 5 at the end of the first period. In some embodiments, the length of the first period is sufficient to achieve a SALT score of less than or equal to 1 at the end of the first period. In some embodiments, the length of the first period is sufficient to achieve a SALT score of zero at the end of the first period.

[0070] In certain embodiments, the hair loss disorder is alopecia areata.

[0071] In certain embodiments, during the first period, the compound or a pharmaceutically 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 per day. In certain embodiments, during the first period, the compound or a pharmaceutically acceptable salt thereof is administered at about 16 mg / day, about 24 mg / day, or about 32 mg / day.

[0072] In certain embodiments, in the second period, the compound or its pharmaceutically acceptable salt 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 per day. In certain embodiments, in the second period, the compound or its pharmaceutically acceptable salt is administered at about 8 mg / day, about 12 mg / day or about 16 mg / day. In certain embodiments, the maintenance dose (the amount per day administered during the second period) is about 33.3% of the amount per day administered during the first period. In certain embodiments, the maintenance dose is about 50% of the amount per day administered during the first period. In certain embodiments, the maintenance dose is about 66.7% of the amount per day administered during the first period. In certain embodiments, the maintenance dose is about 75% of the amount per day administered during the first period.

[0073] 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 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 as two doses of about 12 mg each (i.e., about 12 mg twice a day), and about 16 mg / day is administered as two doses of about 8 mg each (i.e., about 8 mg twice a day).

[0074] In certain embodiments, in the first period, the compound or a pharmaceutically acceptable salt thereof is administered at about 16 mg / day, and in the second period, the compound or a pharmaceutically acceptable salt thereof 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).

[0075] 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 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 as two doses of about 12 mg each (i.e., about 12 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).

[0076] In certain embodiments, the compound or a pharmaceutically acceptable salt thereof is administered orally.

[0077] In certain embodiments, the compound or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical formulation which is a tablet.

[0078] In certain embodiments, the compound or a pharmaceutically acceptable salt thereof is administered once a day (QD) during the first period of time. In certain embodiments, the compound or a pharmaceutically acceptable salt thereof is administered twice a day (BID) during the first period of time.

[0079] In certain embodiments, the compound or a pharmaceutically acceptable salt thereof is administered once a day (QD) during the second period. In certain embodiments, the compound or a pharmaceutically acceptable salt thereof is administered twice a day (BID) during the second period.

[0080] In certain embodiments, the first period is about 8-24 weeks. In certain embodiments, the first period is about 8-12 weeks. In certain embodiments, the first period is about 8 weeks. In certain embodiments, the first period is about 10 weeks. In certain embodiments, the first period is about 12 weeks. In certain embodiments, the first period is about 16 weeks. In certain embodiments, the first period is about 20 weeks. In certain embodiments, the first period is about 24 weeks.

[0081] In certain embodiments, the second period is at least 8 weeks. In certain embodiments, the second period is at least 12 weeks. In certain embodiments, the second period is at least 24 weeks.

[0082] In certain embodiments, in compound (I), each position specifically designated as deuterium is incorporated with at least 97% deuterium.

[0083] 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.

[0084] It should be understood that reference to a specified amount of Compound (I) or a pharmaceutically acceptable salt thereof includes both the stated amount of Compound (I) as the free base, and the amount of a pharmaceutically acceptable salt (e.g., phosphate) of Compound (I) that is equal (in moles) to the stated amount of Compound (I) as the free base (e.g., 10.5 mg of Compound (I) phosphate is equivalent to 8 mg of Compound (I) free base).

[0085] In certain embodiments, the amount of Compound (I) or a pharmaceutically acceptable salt thereof (i.e., an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate salt) administered in a method for treating a hair loss disorder (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).

[0086] In certain embodiments, the amount of Compound (I) or a pharmaceutically acceptable salt thereof (i.e., an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate salt) administered in the method for treating a hair loss disorder (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).

[0087] In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in the method for 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). In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof 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).

[0088] In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in the method for 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). In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is about 16 mg / day to about 32 mg / day, for example, 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).

[0089] In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in a method for treating alopecia (e.g., in a first period or a second period) is 10.6 mg / day of compound (I) phosphate, for example, administered once a day as a 10.6 mg dose, or twice a day as a 5.3 mg dose. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 21.1 mg / day of compound (I) phosphate, for example, administered once a day as a 21.1 mg dose, or twice a day as a 10.5 mg dose. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 31.6 mg / day of compound (I) phosphate, for example, administered once a day as a 31.6 mg dose, or twice a day as a 15.8 mg dose. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 42.2 mg / day of compound (I) phosphate, for example, administered once a day as a 42.2 mg dose, or twice a day as a 21.1 mg dose.

[0090] In certain embodiments, the amount of Compound (I) or a pharmaceutically acceptable salt thereof 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 daily. In a specific embodiment, Compound (I) is administered twice daily as a phosphate salt of Compound (I) at about 10.5 mg (e.g., 10.5 mg).

[0091] In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in a method for treating a hair loss disorder (e.g., in the first period or the second period) is about 8 mg (e.g., 8 mg) in a single dose once a day or in divided doses twice a day. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in a method for treating a hair loss disorder (e.g., in the first period or the second period) is about 12 mg (e.g., 12 mg) in a single dose once a day or in divided doses twice a day. In a specific embodiment, compound (I) is administered once a day in a single dose of about 15.8 mg (e.g., 15.8 mg) of the phosphate salt of compound (I), or administered twice a day in divided doses. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in a method for treating a hair loss disorder (e.g., in the first period or the second period) is about 16 mg (e.g., 16 mg) in a single dose once a day or in divided doses twice a day. In a specific embodiment, Compound (I) is administered once a day in a single dose of about 21.1 mg (e.g., 21.1 mg) of the phosphate salt of Compound (I), or twice a day in divided doses. In certain embodiments, the amount of Compound (I) or a pharmaceutically acceptable salt thereof administered in a method for treating alopecia (e.g., in a first period or a second period) is about 24 mg (e.g., 24 mg) in a single dose once a day or twice a day in divided doses. In certain embodiments, the amount of Compound (I) or a pharmaceutically acceptable salt thereof administered in a method for treating alopecia (e.g., in a first period) is about 32 mg (e.g., 32 mg) once a day or twice a day in divided doses.

[0092] In certain embodiments, the hair loss disorder 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 a phosphate) is orally administered at any dose described herein. In certain embodiments, compound (I) or a pharmaceutically acceptable salt thereof is orally administered at any dose described herein in the form of a pharmaceutical formulation, and the pharmaceutical formulation is a tablet.

[0093] In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered during the second period is about 50% of the daily amount administered during the first period. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered during the second period is about 66.7% of the daily amount administered during the first period. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered during the second period is about 75% of the daily amount administered during the first period.

[0094] Exemplary amounts of Compound (I) or a pharmaceutically acceptable salt thereof to be administered are shown in the following table:

[0095] First period Second period 8 mg / day 6 mg / day 8 mg / day 4 mg / day 12 mg / day 8 mg / day 12 mg / day 6 mg / day 16 mg / day 12 mg / day 16 mg / day 8 mg / day 24 mg / day 16 mg / day 24 mg / day 18 mg / day 24 mg / day 12 mg / day 32 mg / day 24 mg / day 32 mg / day 16 mg / day

[0096] In another aspect, the present invention provides a method of treating alopecia areata in a human subject in need thereof, the method comprising:

[0097] a) administering to the human subject an initial dose of a compound represented by the following structural formula during a first period of time:

[0098] or a pharmaceutically acceptable salt thereof,

[0099] wherein each position specifically designated as deuterium is incorporated with at least 95% deuterium,

[0100] wherein the length of the first period is sufficient to achieve a reduction in the SALT score of the patient, and

[0101] wherein the initial dose is about 8 to about 32 mg per day, followed by;

[0102] b) administering to the human subject a maintenance dose of the compound, or a pharmaceutically acceptable salt thereof, for a second period of time, wherein the maintenance dose is 50 to 75% of the initial dose, and wherein the maintenance dose is sufficient to maintain hair growth (e.g., a SALT score of less than or equal to 20).

[0103] In certain embodiments, the length of the first period is sufficient to achieve a decrease of at least 10% in the SALT score of the patient relative to baseline (e.g., a decrease from a SALT score of 100 before treatment to a SALT score of 90 after treatment). In other embodiments, the length of the first period is sufficient to achieve a decrease of at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, or at least 90% in the SALT score of the patient relative to baseline. In certain embodiments, the length of the first period is sufficient to achieve a decrease of at least 50% in the SALT score of the patient relative to baseline. In certain embodiments, the length of the first period is sufficient to achieve a decrease of at least 75% in the SALT score of the patient relative to baseline. In certain embodiments, the length of the first period is sufficient to achieve a decrease of at least 90% in the SALT score of the patient relative to baseline.

[0104] In some embodiments, the length of the first period is sufficient to achieve a SALT score of less than or equal to 50, less than or equal to 40, less than or equal to 30, less than or equal to 20, less than or equal to 15, less than or equal to 10, less than or equal to 5, less than or equal to 1, or zero at the end of the first period. In some embodiments, the length of the first period is sufficient to achieve a SALT score of less than or equal to 20 at the end of the first period. In some embodiments, the length of the first period is sufficient to achieve a SALT score of less than or equal to 15 at the end of the first period. In some embodiments, the length of the first period is sufficient to achieve a SALT score of less than or equal to 10 at the end of the first period. In some embodiments, the length of the first period is sufficient to achieve a SALT score of less than or equal to 5 at the end of the first period. In some embodiments, the length of the first period is sufficient to achieve a SALT score of less than or equal to 1 at the end of the first period. In some embodiments, the length of the first period is sufficient to achieve a SALT score of zero at the end of the first period.

[0105] 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.

[0106] In certain embodiments, the maintenance dose administered during the second period is sufficient to achieve a SALT score of less than or equal to 50, less than or equal to 40, less than or equal to 30, less than or equal to 20, less than or equal to 15, less than or equal to 10, less than or equal to 5, less than or equal to 1, or zero at the end of the second period. In certain embodiments, the maintenance dose administered during the second period is sufficient to achieve a SALT score of less than or equal to 20 at the end of the second period. In certain embodiments, the maintenance dose administered during the second period is sufficient to achieve a SALT score of less than or equal to 15 at the end of the second period. In certain embodiments, the maintenance dose administered during the second period is sufficient to achieve a SALT score of less than or equal to 10 at the end of the second period. In certain embodiments, the maintenance dose administered during the second period is sufficient to achieve a SALT score of less than or equal to 5 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 administered during the second period is sufficient to achieve an increase of <10 points or <5 points in the subject's SALT score at the end of the second period relative to the subject's SALT score at the end of the first period). In certain embodiments, the maintenance dose administered during the second period is sufficient to achieve an increase of <30% in the subject's SALT score at the end of the second period relative to the subject's SALT score at the end of the first period. In certain embodiments, the maintenance dose administered during the second period is sufficient to achieve an increase of <5 points and an increase of <30% in the subject's SALT score at the end of the second period relative 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 of <4 points, an increase of <3 points, an increase of <2 points, or an increase of <1 point in the subject's SALT score at the end of the second period relative 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 of <20%, an increase of <15%, an increase of <10%, or an increase of <5% in the subject's SALT score at the end of the second period relative to the subject's SALT score at the end of the first period.

[0107] In another aspect, the present invention provides a method of treating a hair loss disorder in a human subject, the method comprising administering to the subject a compound represented by the following structural formula:

[0108] or a pharmaceutically acceptable salt thereof, wherein at least 95% of deuterium is incorporated at each position specifically designated as deuterium; wherein the compound or a pharmaceutically acceptable salt thereof is first administered for an induction period to induce hair growth, and is subsequently administered for a second period to further treat a hair loss disorder, wherein the induction period is at least 8 weeks and no more than 24 weeks, the amount of the compound or a pharmaceutically acceptable salt thereof administered during the induction period is within the range of 16 mg per day and 32 mg per day, and after the induction period, the amount of the compound or a pharmaceutically acceptable salt thereof administered in the second period is reduced by 50 to 75% (e.g., 50, 66.7 or 75%).

[0109] In certain embodiments, the length of the first period is 8 to 24 weeks. In certain embodiments, the first period is about 12 weeks. In certain embodiments, the first period is about 16 weeks. In certain embodiments, the first period is about 20 weeks. In certain embodiments, the first period is about 24 weeks.

[0110] In certain embodiments, the second period is at least 12 weeks in length. In certain embodiments, the second period is at least 24 weeks.

[0111] Exemplary dosages for the first period and the second period are described above.

[0112] In certain embodiments, the reduction in the baseline SALT score of the patient in the first period is about 10% to about 50%. In certain embodiments, the reduction in the baseline SALT score is about 20% to about 50%. In certain embodiments, the reduction in the baseline SALT score of the patient in the first period is about 50%. In certain embodiments, the reduction in the baseline SALT score is about 30% to about 50%. In certain embodiments, the reduction in the baseline SALT score of the patient in the first period is at least 50%. In certain embodiments, the reduction in the baseline SALT score is about 50% to about 99%. In certain embodiments, the reduction in the baseline SALT score is about 50% to about 90%. In certain embodiments, the reduction in the baseline SALT score is about 50% to about 75%. In certain embodiments, the reduction in the baseline SALT score is about 75% to about 90%.

[0113] In certain embodiments, during the first period, the compound or a pharmaceutically acceptable salt thereof is administered at about 12 mg / day, about 16 mg / day, about 24 mg / day, or about 32 mg per day.

[0114] In certain embodiments, during the second period, the compound or a pharmaceutically acceptable salt thereof is administered at about 6 mg / day, about 8 mg / day, about 12 mg / day, or about 16 mg per day.

[0115] In certain embodiments, in the first period, the compound or a pharmaceutically acceptable salt thereof is administered at about 24 mg / day, and in the second period, the compound or a pharmaceutically acceptable salt thereof is administered at about 16 mg / day. In certain embodiments, the about 24 mg / day is administered once a day, and the about 16 mg / day is administered once a day. In certain embodiments, the about 24 mg / day is administered at about 12 mg twice a day (in divided doses), and the about 16 mg / day is administered at about 8 mg twice a day (in divided doses).

[0116] In certain embodiments, during the first period, the compound, or a pharmaceutically acceptable salt thereof, is administered at about 16 mg / day, and during the second period, the compound, or a pharmaceutically acceptable salt thereof, is administered at about 8 mg / day.

[0117] In certain embodiments, the compound or a pharmaceutically acceptable salt thereof is administered orally.

[0118] In certain embodiments, the compound or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical formulation that is a tablet. In certain embodiments, the compound or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical formulation that is a capsule.

[0119] In certain embodiments, the compound or a pharmaceutically acceptable salt thereof is administered once daily during the first period.

[0120] In certain embodiments, the compound or a pharmaceutically acceptable salt thereof is administered twice daily during the first period.

[0121] In certain embodiments, in compound (I), each position specifically designated as deuterium is incorporated with at least 97% deuterium.

[0122] In the method of the present invention, the first period and the second period can vary in length depending on factors such as the amount of hair growth induced in the first period (e.g., as determined by the SALT score measured before and after the first period) and the desired duration of treatment. The first period can be, for example, 8-24 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.

[0123] 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).

[0124] In another embodiment, the first period is at most 24 weeks, and the second period is at least 24 weeks (eg, 24 weeks).

[0125] In another aspect, the present invention provides a method for inducing hair growth in a subject. The method comprises administering to a mammalian subject an effective amount of a compound (I) or a pharmaceutically acceptable salt thereof (i.e., an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate), wherein at least 95% of deuterium is incorporated into each position specifically designated as deuterium; or a pharmaceutically acceptable salt thereof; wherein (1) the compound or a pharmaceutically acceptable salt thereof is administered in an amount ranging from about 8 mg to about 32 mg per day for a first period of 8-24 weeks, followed by (2) the compound or a pharmaceutically acceptable salt thereof is administered for a second period of at least 8 weeks, wherein the compound or a pharmaceutically acceptable salt thereof is administered in an amount of 50 to 75% (e.g., 50%, 66.7%, 75%) of the daily amount administered during the first period, so that hair growth is induced in the subject.

[0126] In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in the method for inducing hair growth is about 4 mg / day (such as 4 mg / day), about 8 mg / day (such as 8 mg / day), about 16 mg / day (such as 16 mg / day), about 24 mg / day (such as 24 mg / day), about 32 mg / day (such as 32 mg / day) or about 48 mg / day (such as 48 mg / day).

[0127] In certain embodiments, the amount of Compound (I) or a pharmaceutically acceptable salt thereof administered in the method for inducing hair growth is about 16 mg / day (such as 16 mg / day), about 24 mg / day (such as 24 mg / day) or about 32 mg / day (such as 32 mg / day).

[0128] In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof used in the method for inducing hair growth is about 8 mg / day (such as 8 mg / day), about 16 mg / day (such as 16 mg / day), about 24 mg / day (such as 24 mg / day) or about 32 mg / day (such as 32 mg / day). In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof used in the method for inducing hair growth is about 8 mg / day (such as 8 mg / day), about 12 mg / day (such as 12 mg / day), about 16 mg / day (such as 16 mg / day) or about 24 mg / day (such as 24 mg / day).

[0129] In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in the method for inducing hair growth is 10.6 mg / day of compound (I) phosphate, for example, once a day at a dose of 10.6 mg or twice a day at a dose of 5.3 mg. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 21.1 mg / day of compound (I) phosphate, for example, once a day at a dose of 21.1 mg or twice a day at a dose of 10.5 mg. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 31.6 mg / day of compound (I) phosphate, for example, once a day at a dose of 31.6 mg or twice a day at a dose of 15.8 mg. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 42.2 mg / day of compound (I) phosphate, for example, once a day at a dose of 42.2 mg or twice a day at a dose of 21.1 mg.

[0130] In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in the method for inducing hair growth (e.g., in the second period) is about 4 mg (e.g., 4 mg) twice a day. In a specific embodiment, compound (I) is administered twice a day as a phosphate salt of about 5.3 mg (e.g., 5.3 mg) of compound (I).

[0131] In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in the method for inducing hair growth (e.g., in the first or second period) is about 8 mg (e.g., 8 mg) twice a day. In a specific embodiment, compound (I) is administered twice a day as a phosphate salt of about 10.5 mg (e.g., 10.5 mg) of compound (I).

[0132] In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in the method for inducing hair growth (e.g., in the first or second period) is about 12 mg (e.g., 12 mg) twice a day. In a specific embodiment, compound (I) is administered twice a day as a phosphate salt of about 15.8 mg (e.g., 15.8 mg) of compound (I).

[0133] In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in the method for inducing hair growth (e.g., in the first period) is about 16 mg (e.g., 16 mg) twice a day. In a specific embodiment, compound (I) is administered twice a day as a phosphate salt of about 21.1 mg (e.g., 21.1 mg) of compound (I).

[0134] In certain embodiments, the subject suffers from a hair loss disorder; in other embodiments, the hair loss disorder 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 a pharmaceutically acceptable salt thereof (such as a phosphate salt) is orally administered at any of the aforementioned doses. Preferably, compound (I) or a pharmaceutically acceptable salt thereof is orally administered at any of the aforementioned doses in the form of a pharmaceutical formulation, which is a tablet or capsule.

[0135] Hair loss disorders include, but are not limited to, androgenetic alopecia, alopecia areata, telogen effluvium, alopecia totalis, and alopecia universalis.

[0136] In certain embodiments of any of the methods described herein, the condition is alopecia areata in a subject in need thereof, such as a mammal (e.g., a human). In certain embodiments, alopecia areata is moderate to severe alopecia areata (e.g., at least 30% hair loss of the scalp, at least 40% hair loss of the scalp, at least 50% hair loss of the scalp, or at least 75% hair loss of the scalp).

[0137] In another aspect, the present invention provides a method of treating a disease, disorder or condition mediated solely or in part by a Janus-associated kinase (JAK) (e.g., JAK1 and / or JAK2) in a human subject, the method comprising administering to the subject a compound represented by the following structural formula:

[0138] or a pharmaceutically acceptable salt thereof;

[0139] wherein at least 95% of deuterium is incorporated at each position specifically designated as deuterium;

[0140] wherein (1) the compound or a pharmaceutically acceptable salt thereof is administered in an amount ranging from about 8 mg to about 32 mg per day for a first period of 8-24 weeks, followed by (2) the compound or a pharmaceutically acceptable salt thereof is administered for a second period of at least 8 weeks, wherein the compound or a pharmaceutically acceptable salt thereof is administered in an amount of 50 to 75% of the amount administered during the first period, such that the disease, disorder or condition mediated solely or in part by JAK is treated.

[0141] In certain embodiments, the disease, condition or disorder is not a hair loss disorder.

[0142] In certain embodiments, in compound (I), each position specifically designated as deuterium is incorporated with at least 97% deuterium.

[0143] In certain embodiments, the disease, condition or disorder is selected from a skin disease, such as a proliferative, autoimmune and / or inflammatory skin disorder, psoriasis, atopic dermatitis, scleroderma, rosacea, skin cancer, dermatitis, dermatitis herpetiformis, dermatomyositis, vitiligo, contact dermatitis, xerosis, ichthyosis, hidradenitis suppurativa, urticaria, lichen planus, prurigo nodularis, vasculitis, cutaneous lupus erythematosus (CLE), and chronic idiopathic pruritus; a hyperproliferative disorder or cancer, including polycythemia vera, essential thrombocytopenia, and myelofibrosis; a respiratory disease, such as asthma, chronic obstructive pulmonary disease, chronic lung allograft dysfunction, e.g., bronchiolitis obliterans syndrome, pulmonary fibrosis, cystic fibrosis, fibrosis, rhinitis, bronchiolitis, byssinosis, pneumoconiosis, bronchiectasis, hypersensitivity pneumonitis, lung cancer, mesothelioma and sarcoidosis; gastrointestinal diseases, such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, retroperitoneal fibrosis, celiac disease and cancer; eye diseases, such as myasthenia gravis, Sjögren's syndrome, conjunctivitis, scleritis, uveitis, dry eye syndrome, keratitis, iritis; systemic indications, such as lupus, multiple sclerosis, rheumatoid arthritis, type I diabetes and diabetic complications, cancer, ankylosing spondylitis and psoriatic arthritis; and other autoimmune diseases and indications where immunosuppression is desired, for example to treat or prevent acute and / or chronic graft-versus-host disease (e.g., in organ transplantation).

[0144] In certain embodiments, during the first period, the compound or a pharmaceutically acceptable salt thereof is administered at about 16 mg / day, about 24 mg / day, or about 32 mg / day.

[0145] In certain embodiments, during the second period, the compound or a pharmaceutically acceptable salt thereof is administered at about 8 mg / day, about 12 mg / day, or about 16 mg / day.

[0146] In certain embodiments, during the first period, the compound, or a pharmaceutically acceptable salt thereof, is administered at about 24 mg / day, and during the second period, the compound, or a pharmaceutically acceptable salt thereof, is administered at about 16 mg / day.

[0147] In certain embodiments, said about 24 mg / day of said compound or salt thereof is administered once daily, and said about 16 mg / day is administered once daily.

[0148] In certain embodiments, said about 24 mg / day of said compound or salt thereof is administered at about 12 mg twice daily, and said about 16 mg / day of said compound or salt thereof is administered at about 8 mg twice daily.

[0149] In certain embodiments, during the first period, the compound, or a pharmaceutically acceptable salt thereof, is administered at about 16 mg / day, and during the second period, the compound, or a pharmaceutically acceptable salt thereof, is administered at about 8 mg / day.

[0150] In certain embodiments, the compound or a pharmaceutically acceptable salt thereof is administered once daily during the first period.

[0151] In certain embodiments, the compound or a pharmaceutically acceptable salt thereof is administered twice daily during the first period.

[0152] In certain embodiments, the first period of time is about 8-12 weeks.

[0153] In certain embodiments, the first period of time is about 24 weeks.

[0154] In certain embodiments, the second period is at least 12 weeks.

[0155] In certain embodiments, the second period is at least 24 weeks.

[0156] In certain embodiments, the disease, condition or disorder is not alopecia areata.

[0157] In certain embodiments, the compound or a pharmaceutically acceptable salt thereof is administered orally.

[0158] In certain embodiments, the compound or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical formulation which is a tablet.

[0159] In certain embodiments, the subject is a human. In one embodiment, the subject is a human of 6 years of age or older. In certain embodiments, compound (I) or a pharmaceutically acceptable salt thereof (such as a phosphate) is orally administered at any dose described herein. In certain embodiments, compound (I) or a pharmaceutically acceptable salt thereof is orally administered at any dose described herein in the form of a pharmaceutical formulation, which is a tablet.

[0160] In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered during the second period is about 50% of the daily amount administered during the first period. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered during the second period is about 66.7% of the daily amount administered during the first period. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered during the second period is about 75% of the daily amount administered during the first period.

[0161] Exemplary amounts of Compound (I) or a pharmaceutically acceptable salt thereof to be administered are shown in the following table:

[0162] First period Second period 8 mg / day 6 mg / day 8 mg / day 4 mg / day 12 mg / day 8 mg / day 12 mg / day 6 mg / day 16 mg / day 12 mg / day 16 mg / day 8 mg / day 24 mg / day 16 mg / day 24 mg / day 18 mg / day 24 mg / day 12 mg / day 32 mg / day 24 mg / day 32 mg / day 16 mg / day

[0163] In one embodiment of any aspect, the compound is administered orally once a day. In other embodiments of any aspect, the compound is administered orally twice a day.

[0164] As will be appreciated by those skilled in the art, the effective dose may also vary depending on the disease being treated, the severity of the disease, the route of administration, the sex, age and general health of the subject, excipient usage, the possibility of co-use with other therapeutic treatments (such as the use of other agents), and the judgment of the treating physician.

[0165] Administration of Compound (I) or a pharmaceutically acceptable salt thereof (such as a phosphate salt) can be continued for as long as necessary to treat the hair loss disorder, for example, for one week, two weeks, one month, two months, three months, four months, six months, one year, two years, five years, ten years or longer.

[0166] Administration of compound (I) or a pharmaceutically 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 a Janus-associated kinase (JAK), for example, for one week, two weeks, one month, two months, three months, four months, six months, one year, two years, five years, ten years or longer.

[0167] 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.

[0168] In certain embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered in combination with another therapeutic agent. Preferably, the other therapeutic agent is an agent that can be used to treat alopecia or autoimmune conditions, such as inhibitors of JAK1, JAK2 or JAK3 and / or STAT1. Such inhibitors include ruxolitinib, tofacitinib, baricitinib, filgotinib, etc. Other orally administered additional therapeutic agents include agents for treating alopecia areata, including, for example, oral corticosteroids. In certain embodiments, the other therapeutic agent is an agent that can be used to treat a disease, disorder or condition mediated solely or in part by Janus-associated kinases (JAKs), and the disease, disorder or condition is not alopecia.

[0169] For pharmaceutical compositions comprising additional therapeutic agents, an effective amount of the additional therapeutic agent is between about 20% and 100% of the dosage normally used in a monotherapy regimen using only the agent. Preferably, the effective amount is between about 70% and 100% of the normal monotherapy dosage. The normal monotherapy dosages of these additional therapeutic agents are well known in the art. See, e.g., Wells et al., eds., Pharmacotherapy Handbook, 2nd ed., Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, hardcover, 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.

[0170] Some of the additional therapeutic agents mentioned above may act synergistically with the compounds of the present invention. When this occurs, the effective dose of the additional therapeutic agent and / or compound (I) or its pharmaceutically acceptable salt will be allowed to be reduced relative to the dose required in the monotherapy. This has the advantages of minimizing the toxic and side effects of the additional therapeutic agent or compound (I) or its pharmaceutically acceptable salt, synergistically improving the efficacy, improving the ease of administration or use, and / or reducing the total cost of the compound preparation or formulation.

[0171] As used herein, the term "co-administered" means that an additional therapeutic agent can be administered together with compound (I) or a pharmaceutically acceptable salt thereof, as part of a single dosage form (such as a composition of the present invention, comprising a compound of the present invention and a second therapeutic agent as described above), or as a separate multiple dosage form. Alternatively, the additional agent can be administered before, in succession with, or after the administration of compound (I) or a pharmaceutically acceptable salt thereof. In such combination therapy treatments, both compound (I) or a pharmaceutically acceptable salt thereof and (the additional therapeutic agent) are administered by conventional methods. Administration of a composition of the present invention comprising compound (I) or a pharmaceutically acceptable salt thereof and an additional therapeutic agent to a subject does not exclude the separate administration of the same therapeutic agent, any other additional therapeutic agent, or compound (I) or a pharmaceutically acceptable salt thereof to the subject at another time during the course of treatment.

[0172] The effective amounts of these additional therapeutic agents are well known to those skilled in the art, and guidance for administration can be found in the patents and published patent applications cited herein, as well as Wells et al., eds., Handbook of Pharmacotherapy, 2nd ed., Appleton and Lange Publishers, Stamford, Connecticut (2000); PDR Pharmacopoeia - Tarascon Pocket Pharmacopoeia 2000, hardcover, Tarascon Publishing, Loma Linda, Calif. (2000); and other medical texts. However, it is well within the purview of the skilled artisan to determine the optimal effective amount range of the additional therapeutic agent.

[0173] In one embodiment of the invention, where an additional therapeutic agent is administered to a subject, the effective amount of compound (I) or a pharmaceutically acceptable salt thereof will be less than the effective amount where the additional therapeutic agent is not administered. In another embodiment, the effective amount of the additional therapeutic agent will be less than the effective amount where compound (I) or a pharmaceutically acceptable salt thereof 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.

[0174] In another aspect, the present invention provides the use of compound (I) or a pharmaceutically acceptable salt thereof (i.e., an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate salt) alone or together with one or more of the above-mentioned additional therapeutic agents in the manufacture of a medicament as a single composition or as a separate dosage form for treating or preventing the above-shown diseases, disorders or symptoms in a subject. Another aspect of the present invention is compound (I) or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease, disorder or symptom described herein in a subject.

[0175] Another aspect of the present invention is a pharmaceutical composition comprising a compound (I) or an equivalent amount of a pharmaceutically acceptable salt thereof in the 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), together with a pharmaceutically acceptable carrier or diluent. In certain embodiments, the amount of compound (I) or its pharmaceutically acceptable salt is about 4 mg, 8 mg, 16 mg, 24 mg, 32 mg, or 48 mg. In certain embodiments, the amount of compound (I) or its pharmaceutically acceptable salt is 4 mg, 8 mg, 12 mg, or 16 mg. In certain embodiments, the amount of compound (I) or its pharmaceutically acceptable salt is 5.3 mg of compound (I) phosphate. In certain embodiments, the amount of compound (I) or its pharmaceutically acceptable salt is 10.5 or 10.6 mg of compound (I) phosphate. In certain embodiments, the amount of compound (I) or its pharmaceutically acceptable salt is 15.8 mg of compound (I) phosphate. In certain embodiments, the amount of Compound (I) or a pharmaceutically acceptable salt thereof is 21.1 mg of Compound (I) phosphate salt. In certain embodiments, the pharmaceutical composition is a tablet or a capsule.

[0176] Another aspect of the present invention is a unit dosage form comprising a compound (I) or an equivalent amount of a pharmaceutically acceptable salt thereof in the 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), together with a pharmaceutically acceptable carrier or diluent. In certain embodiments, the amount of compound (I) or its pharmaceutically acceptable salt is about 4 mg, 8 mg, 16 mg, 24 mg, 32 mg, or 48 mg. In certain embodiments, the amount of compound (I) or its pharmaceutically acceptable salt is 4 mg, 8 mg, 12 mg, or 16 mg. In certain embodiments, the amount of compound (I) or its pharmaceutically acceptable salt is 5.3 mg of compound (I) phosphate. In certain embodiments, the amount of compound (I) or its pharmaceutically acceptable salt is 10.5 or 10.6 mg of compound (I) phosphate. In certain embodiments, the amount of compound (I) or its pharmaceutically acceptable salt is 15.8 mg of compound (I) phosphate. In certain embodiments, the amount of Compound (I) or a pharmaceutically acceptable salt thereof is 21.1 mg of Compound (I) phosphate salt. In certain embodiments, the unit dosage form is a tablet or a capsule.

[0177] In one embodiment, any atom not designated as deuterium is present in Compound (I) or a pharmaceutically acceptable salt thereof at its natural isotopic abundance.

[0178] The synthesis of compound (I) or a pharmaceutically acceptable salt thereof (such as a phosphate) can be easily achieved by the method described in U.S. Patent No. 9,249,149, PCT Patent Publication WO2017 / 192905 or PCT Patent Publication WO2020 / 163653, the teachings of which are incorporated herein by reference with appropriate modifications. Additional synthesis methods are described in PCT Patent Publication WO2022 / 036030, the teachings of which are incorporated herein by reference in their entirety. For example, U.S. Patent No. 9,249,149 describes the use of D9-intermediate 15 to produce D9-ruxolitinib products; using intermediate A

[0179]

[0180] Compound (I) is provided in the process described in U.S. Pat. No. 9,249,149. Alternatively, intermediate B

[0181]

[0182] Can be used instead of intermediate 14 of U.S. Pat. No. 9,249,149 to prepare compound (I); removal of the amino protecting group can be accomplished by alkaline cleavage (e.g., with sodium hydroxide). Phosphoric acid can be used to convert compound (I) (free base) to its phosphate. Another method for preparing ruxolitinib (i.e., non-deuterated compound (I)) is disclosed in U.S. Pat. No. 9,000,161 and can be used to prepare compound (I) with a suitable deuterated reagent.

[0183] Such methods can be carried out utilizing corresponding deuterated and optionally other isotope-containing reagents and / or intermediates to synthesize the compounds described herein, or by invoking standard synthetic protocols known in the art for introducing isotopic atoms into chemical structures.

[0184] The present invention also provides a pharmaceutical composition comprising an effective amount of compound (I) or a pharmaceutically acceptable salt thereof (i.e., an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate); and a pharmaceutically 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 pharmaceutically acceptable carrier, is used in a drug in an amount that is harmless to the recipient thereof. In certain embodiments, the pharmaceutical composition is provided as a unit dosage form.

[0185] The present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and 4 to 50 mg of a compound represented by the following structural formula:

[0186] or a pharmaceutically acceptable salt thereof (ie, an equivalent amount of a pharmaceutically 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.

[0187] Pharmaceutically acceptable carriers, adjuvants and vehicles that can 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 phosphates), 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 silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin.

[0188] If necessary, the solubility and bioavailability of the compounds of the present invention in pharmaceutical compositions can be enhanced by methods well known in the art. One method includes using lipid excipients in formulations. See "Oral Lipid-Based Formulations: Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs and the Pharmaceutical Sciences)", David J. Hauss, ed. Informa Healthcare, 2007; and "Role of Lipid Excipients in Modifying Oral and Parenteral Drug Delivery: Basic Principles and Biological Examples", Kishor M. Wasan, ed. Wiley-Interscience, 2006.

[0189] Another known method for improving bioavailability is the use of an amorphous form of a compound of the invention, optionally in combination with a poloxamer, such as LUTROL TM and PLURONIC TM(BASF Corporation), or block copolymers of ethylene oxide and propylene oxide are formulated together. See U.S. Patent 7,014,866; and U.S. Patent Publications 20060094744 and 20060079502.

[0190] The pharmaceutical compositions of the present invention include pharmaceutical compositions suitable for oral administration. Other formulations can be conveniently presented in unit dosage forms, such as tablets, sustained-release capsules, granules, and liposomes, and can be prepared by any method well known in the pharmaceutical field. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th edition 2000).

[0191] Such preparation methods include the step of bringing the molecule to be administered into association with ingredients such as carriers which constitute one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers, liposomes or finely divided solid carriers or both and then, if necessary, shaping the product.

[0192] In certain embodiments, the compound is administered orally. Compositions of the invention suitable for oral administration may be discrete units, such as capsules, sachets or tablets, each containing a predetermined amount of active ingredient; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; oil-in-water liquid emulsions; water-in-oil liquid emulsions; packaged in liposomes; or presented as boluses, etc. Soft gelatin capsules may be used to contain such suspensions, which may beneficially increase the rate of absorption of the compound. In a specific embodiment, the compound is administered orally as a tablet. In another specific embodiment, the compound is administered orally in a capsule.

[0193] In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are typically also added. For oral administration in the form of capsules, useful diluents include lactose and dry corn starch. When an aqueous suspension is administered orally, the active ingredient is combined with an emulsifier and a suspending agent. If necessary, certain sweeteners and / or flavoring agents and / or coloring agents may be added. In another embodiment, the composition is in the form of a tablet. In certain embodiments, exemplary formulations of tablets are disclosed in U.S. Patent No. 8,754,224, the teachings of which are incorporated herein by reference.

[0194] In a specific embodiment, the tablet formulation contains about 4 mg to about 50 mg of Compound (I) or an equivalent amount of a pharmaceutically acceptable salt thereof (such as a phosphate salt), and the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, and povidone. Wet granulation followed by compression provides a tablet comprising Compound (I) or a pharmaceutically acceptable salt thereof. For example, to prepare a 200 mg tablet containing the 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 (based on the total formulation weight) are mixed in a high shear granulator, and 8.5% w / w Kollidon 30 aqueous solution (containing Kollidon 30, i.e., polyvinyl pyrrolidone (povidone); 5 wt%) is added during mixing to form granules. The granules are tray dried in an oven at 60±10°C and ground using a Quadro Comil U5 grinder. The granules retained on the cis sieve were passed through a #20 mesh screen using a stainless steel scraper. The resulting ground granules were mixed with Avicel PH-200 microcrystalline cellulose (18.5 wt%), Aerosil 200 colloidal silicon dioxide (0.5 wt%) and Hyqual magnesium stearate (1 wt%) in a Turbula mixer to form the final blend. The final blend was compressed into 200 mg tablets using a Riva Piccola rotary press with a 0.451" x 0.229" D-type modified capsule mold. Each tablet contained 21.1 mg of compound (I) (equivalent to 16 mg of compound (I) free base).

[0195] In certain embodiments, the tablet contains about 10.5 mg or about 10.6 mg of the phosphate salt of Compound (I) (equivalent to 8 mg of the free base of Compound (I)).

[0196] In certain embodiments, the tablet comprises the following ingredients:

[0197] 4 mg tablet

[0198]

[0199] *Equivalent to 4 mg of compound (I) free base

[0200] In another specific embodiment, the tablet comprises the following ingredients:

[0201] 8 mg tablet

[0202]

[0203] *Equivalent to 8 mg of compound (I) free base

[0204] In an alternative specific embodiment, the tablet comprises the following ingredients:

[0205] 8 mg tablet

[0206]

[0207]

[0208] *Equivalent to 8 mg of compound (I) free base

[0209] In yet another specific embodiment, the tablet comprises the following ingredients:

[0210] 16 mg tablet

[0211]

[0212] *Equivalent to 16 mg of compound (I) free base

[0213] In another embodiment, the 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 exhibit favorable properties when administered with a compound having the same mechanism of action as ruxolitinib.

[0214] Preferably, the additional therapeutic agent is an agent useful for treating alopecia or autoimmune conditions, including inhibitors of JAK1, JAK2 or JAK3 and / or STAT1. Such inhibitors include ruxolitinib, tofacitinib, baricitinib, filgotinib, etc. Other additional therapeutic agents include oral corticosteroids.

[0215] In another embodiment, the present invention provides a single dosage form of compound (I) or a pharmaceutically acceptable salt thereof, and one or more of any of the above-mentioned additional therapeutic agents, wherein compound (I) or a pharmaceutically 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 single dosage forms are packaged together or otherwise attached to each other so that it is readily apparent that the single dosage forms are intended to be sold and administered together (within less than 24 hours of each other, either consecutively or simultaneously).

[0216] In the pharmaceutical composition of the present invention, compound (I) or a pharmaceutically acceptable salt thereof is present in an effective amount. As used herein, the term "effective amount" refers to an amount sufficient to treat a targeted disorder when administered in an appropriate dosage regimen.

[0217] The interrelationship of dosages for animals and humans (based on milligrams per square meter of body surface) is described in Freireich et al., Cancer Chemother. Rep, 1966, 50:219. Body surface area can be roughly determined based on the height and weight of the subject. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, NY, 1970, 537.

[0218] In one embodiment, the effective amount of compound (I) (as a free base, or as an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate) can range from about 8 mg to 32 mg per day (such as 8 mg to 32 mg per day), such as about 10 mg / day (such as 10 mg / day), about 20 mg / day (such as 20 mg / day) or about 30 mg / day (such as 30 mg / day). In certain embodiments, the amount is about 8 mg / day (such as 8 mg / day), about 12 mg / day (such as 12 mg / day), about 16 mg / day (such as 16 mg / day), about 24 mg / day (such as 24 mg / day) or about 32 mg / day (such as 32 mg / day). In one embodiment, a dosage of about 8 mg / day (such as 8 mg / day), about 16 mg / day (such as 16 mg / day), about 24 mg / day (such as 24 mg / day) or about 32 mg / day (such as 32 mg / day) is administered once a day. In a specific example, a dose of 16 mg / day is administered with two 8 mg tablets of compound (I) (as a free base, or as an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate) (i.e., as a single dose). In another specific example, a dose of 16 mg / day is administered with one 16 mg tablet of compound (I) (as a free base, or as an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate). In another embodiment, a dose of 8 mg / day, 16 mg / day, 24 mg / day or 32 mg / day is administered twice a day in divided doses (e.g., a dose of 16 mg / day is administered twice a day at 8 mg, or a dose of 24 mg / day is administered twice a day at 12 mg). In another embodiment, a dose of 8 mg / day, 16 mg / day, 24 mg / day or 32 mg / day is administered twice daily in divided doses (e.g., a dose of 32 mg / day is administered twice daily with 16 mg of Compound (I) (as free base, or as an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate salt) i.e., administered in separate doses. In a specific embodiment, a dose of 16 mg / day is administered twice daily with 8 mg of Compound (I) (as free base, or as an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate salt) i.e., administered in separate doses. It should be understood that references to the amount of Compound (I) or its pharmaceutically acceptable salt include the amount of the pharmaceutically acceptable salt (such as the phosphate salt) of Compound (I) equivalent to the amount of Compound (I) as free base (e.g., 10.5 mg of Compound (I) phosphate salt is equivalent to 8 mg of Compound (I) free base).

[0219] In certain embodiments, the effective amount of compound (I) or a pharmaceutically acceptable salt thereof is about 4 mg (such as 4 mg) twice a day. In a specific embodiment, the effective amount of compound (I) is administered twice a day with about 5.3 mg (such as 5.3 mg) of the phosphate salt of compound (I). In certain embodiments, the effective amount of compound (I) or a pharmaceutically acceptable salt thereof is about 8 mg (such as 8 mg) twice a day. In a specific embodiment, compound (I) is administered twice a day with about 10.5 mg (such as 10.5 mg) of the phosphate salt of compound (I).

[0220] In certain embodiments, the effective amount of compound (I) or a pharmaceutically acceptable salt thereof is about 12 mg (such as 12 mg) twice a day. In a specific embodiment, the effective amount of compound (I) is about 15.8 mg (such as 15.8 mg) of the phosphate salt of compound (I) twice a day. In certain embodiments, the effective amount of compound (I) or a pharmaceutically acceptable salt thereof is about 16 mg (such as 16 mg) twice a day. In a specific embodiment, the effective amount of compound (I) is about 21.1 mg (such as 21.1 mg) of the phosphate salt of compound (I) twice a day.

[0221] Examples

[0222] Example 1 - Human Study - Phase 2a

[0223] A Phase 2a trial was conducted to evaluate the safety and efficacy of compound (I) (CTP-543) in subjects with alopecia, with a preliminary efficacy analysis conducted at week 24. The Phase 2a trial was a double-blind, randomized, placebo-controlled trial to evaluate the safety and efficacy of compound (I) in adult patients with moderate to severe alopecia areata. Patients were sequentially randomized to receive one of three doses of compound (I) phosphate salt (e.g., 10.5 mg of compound (I) phosphate salt is equivalent to 8 mg of compound (I) free base). The doses of compound (I) were 4, 8 (i.e., approximately 10.5 mg of compound (I) phosphate salt) and 12 mg twice daily, and there was also a group of patients receiving placebo. The primary outcome measure was the Severity of Alopecia Tool (SALT) after 24 weeks of dosing.

[0224] The interim topline analysis for the 4 mg, 8 mg, and 12 mg cohorts is discussed below.The primary endpoint of the study was a 50% relative reduction in SALT between Week 24 and baseline.

[0225] The demographics of the subjects enrolled in the trial and receiving 4, 8 or 12 mg twice daily or placebo are shown in Table 1 below:

[0226] Table 1

[0227]

[0228] The baseline characteristics of the subjects are shown in Table 2 below:

[0229] Table 2

[0230]

[0231] The most common treatment-emergent adverse events (≥10%) by patient are shown in Table 3 below:

[0232] Table 3

[0233]

[0234] No serious adverse events were reported. In the primary analysis of the placebo, 4 mg, and 8 mg groups, there were only 3 grade 3 / 4 hematologic events that were evenly distributed between the placebo, 4 mg, and 8 mg groups.

[0235] In summary, the primary efficacy endpoint of the study was achieved. Compared with 8.6% of placebos (p<0.001), 58% of patients treated with 12mg BID (twice a day) of CTP-543 and 47% of patients treated with 8mg BID (twice a day) achieved a reduction of ≥50% in their overall SALT score. In addition, compared with 7% of placebos, 42% of patients treated with 12mg BID (p<0.001) of CTP-543 and 29% of patients treated with 8mg BID (p<0.05) achieved a reduction of ≥75% in their overall SALT score. In addition, compared with 2% of placebos, 36% of patients treated with 12mg BID (p<0.001) of CTP-543 and 16% of patients treated with 8mg BID (p<0.05) achieved a reduction of ≥90% in their overall SALT score. 21% of patients treated with 4 mg BID of CTP-543 achieved a ≥50% reduction in their overall SALT score compared to 8.6% of 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 starting at Week 12 for the 12 mg and 8 mg groups compared to placebo (p<0.05).

[0236] Treatment was generally well tolerated with no serious adverse events. The 4 mg BID dose failed to separate from placebo on all measures. At week 24, the end of the trial, the 8 mg BID dose and the 12 mg BID dose were significantly different from placebo on all SALT measures. The 12 mg BID dose was numerically better and generally produced a faster onset and greater effect than the 8 mg BID dose.

[0237] Example 2 - Open-label extension study

[0238] In the ongoing open-label extension study, subjects who were previously enrolled in the qualifying clinical study (including the study described in Example 1) and received 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 extension study (OLE) and continue to be treated with CTP-543 phosphate. A total of 152 subjects were enrolled in the OLE. In the OLE, subjects were treated with CTP-543 at a dose of 8 mg BID or 12 mg BID daily (see Figure 8 ). Dose adjustments were allowed at the discretion of the investigator. 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 was zero, i.e., complete hair regrowth before the reduction). Subsequently, the subject's dose was reduced to a daily dose of 8 mg BID of CTP-543 phosphate. After approximately 7 months in the OLE receiving a lower daily dose of 8 mg BID of CTP-543, the subject continued to substantially maintain hair regrowth, with a SALT score of 7.92.

[0239] Example 3-Phase 2 Persistence Study

[0240] A Phase 2 clinical trial was conducted as a two-part, double-blind, randomized, multicenter study to evaluate the regrowth of hair after treatment with compound (I) (CTP-543) in adult patients with moderate to severe alopecia areata and the subsequent persistence of the regrowth after reduction or withdrawal. Patients were between 18 and 65 years old and experienced alopecia-related episodes lasting at least 6 months and no more than 10 years. Patients who were not currently undergoing alopecia areata treatment or other treatments that may affect hair regrowth or immune response must have at least 50% hair loss, as measured by the Severity of Hair Loss Tool (SALT) at screening and baseline. Patients with up to approximately 75% complete or near-complete (SALT ≥ 95) hair loss were recruited.

[0241] The study is divided into 2 parts:

[0242] Part A: Period 1 (treatment period) and Period 2 (dose adjustment period)

[0243] Part B: Re-treatment Period

[0244] Part A: Period 1

[0245] Part A, Period 1 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) in phosphate form (e.g., 10.5 mg of Compound (I) phosphate is equivalent to 8 mg of Compound (I) free base) for 24 weeks. The dose is 8 mg of Compound (I) twice a day (BID) (i.e., approximately 10.5 mg of Compound (I) phosphate), or 12 mg of Compound (I) BID (i.e., approximately 15.8 mg of Compound (I) phosphate). Randomization is stratified by scalp alopecia, divided into one of the following two categories: 1) partial scalp alopecia (SALT ≥ 50 and < 95); 2) complete or near-complete scalp alopecia (SALT ≥ 95). Patients take the first dose of study medication in the clinic on Day 1 and are instructed to take the study medication approximately every 12 hours per day for the duration of Period 1. Other baseline evaluations in Part A, Period 1, include patient and clinician global impressions of disease severity (CGI-S and PGI-S), as well as patient-reported satisfaction outcomes (SPRO) and hair quality (QPRO). Blood samples for pharmacokinetic evaluations are collected regularly. Photos of the scalp are also taken to provide a visual record at the time of the SALT evaluation, and are performed at additional selected visits throughout the study. When all patients complete Week 24 of Part A, Period 1, a preliminary efficacy analysis is performed to determine the responders for each dose group. In some embodiments, at the end of treatment (EOT) of Part A, Period 1, patients with a change of <50% in SALT score relative to baseline are defined as non-responders and have the opportunity to continue treatment in an open-label extension study, or can complete treatment at Week 24 and return 4 weeks later for post-treatment safety follow-up.

[0246] In some embodiments, patients from each dose group with a ≥50% change from baseline in SALT score at Week 24 are defined as responders and enter Part A, Period 2.

[0247] In some embodiments, treatment success (responders) are defined as patients with a SALT score ≤ 20 at Week 24 in each dose group at the end of treatment (EOT) in Part A, Period 1. These responders enter Part A, Period 2 of the study. Patients with a SALT score > 20 are defined as non-responders and have the opportunity to continue treatment in the open-label extension study or complete treatment at Week 24 and return 4 weeks later for a post-treatment safety follow-up.

[0248] Part A, Period 1 (Treatment Period) lasted 24 weeks. Evaluations of treatment response using SALT to determine efficacy occurred at Weeks 4, 8, 12, 16, 20, and 24.

[0249] Part A: Period 2

[0250] In Part A, Period 2, patients were re-randomized to receive a lower dose of Compound (I) (4 mg BID for patients who previously received 8 mg BID, or 8 mg BID for patients who previously received 12 mg BID) or placebo. Patients in Part A, Period 2, stayed at the assigned dose for up to 24 weeks, or until they met the criteria for loss of regrowth maintenance (LOM). The criterion for LOM was a SALT score greater than 20. Any patient who met the LOM criteria at any evaluation time point during Part A, Period 2, entered Part B of the study and returned to their original Compound (I) treatment (8 mg BID or 12 mg BID) in Part A, Period 1. Patients who did not meet the LOM criteria at the end of Week 2 (i.e., patients with a SALT score of less than or equal to 20) had the opportunity to continue treatment in the open-label extension study at their original Part A, Period 1 dose, or could complete treatment at Week 24 and return 4 weeks later for a post-treatment safety follow-up. Figure 7 The study design is depicted in .

[0251] Part A Period 2 (Dose Modifications) lasts up to 24 weeks or until patients meet LOM criteria. Treatment response using SALT for efficacy assessments will be performed monthly until LOM criteria are met or the 24-week period is completed.

[0252] Part B

[0253] Any patient in Part A, Period 2, who meets the LOM criteria (SALT>20) enters Part B of the study and returns to their original 8 mg BID or 12 mg BID dose from Part A, Period 1. In some embodiments, patients maintain their designated dose for 24 weeks, regardless of whether they meet the criteria for regrowth recovery (ROR). In some embodiments, patients maintain their designated dose for 24 weeks or until they meet the criteria for regrowth recovery (ROR). In some embodiments, ROR is defined as a patient achieving a SALT score ≦ their original EOT SALT score at the end of Part A, Period 1. In some embodiments, ROR is defined as a patient achieving a SALT score ≤20. In some embodiments, any patient who meets the ROR criteria at any evaluation time point during Part B exits the study and is eligible for enrollment in an open-label extension study. The therapeutic response using SALT to evaluate efficacy will be performed monthly until the regrowth recovery (ROR) criteria are met or the 24-week period is completed. Patients who do not meet the ROR criteria have the opportunity to continue treatment in an open-label extension study, or can complete treatment at Week 24 and return 4 weeks later for a post-treatment safety follow-up.

[0254] In the absence of further description, it is believed that those of ordinary skill in the art can use the foregoing description and illustrative examples to prepare and utilize the compounds of the present invention and practice the claimed methods. It should be understood that the foregoing discussion and examples only present detailed descriptions of certain preferred embodiments. It is apparent to those of ordinary skill in the art that various modifications and equivalents may be made without departing from the spirit and scope of the present invention.

Claims

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

2. The method according to any one of claims 1, wherein in compound (I), at least 97% of deuterium is incorporated at each position specifically designated as deuterium.

3. The method of claim 1 or claim 2, wherein the disease, condition or disorder is selected from a skin disease, such as a proliferative, autoimmune and / or inflammatory skin disorder, psoriasis, atopic dermatitis, scleroderma, rosacea, skin cancer, dermatitis, dermatitis herpetiformis, dermatomyositis, vitiligo, alopecia, contact dermatitis, xerosis, ichthyosis, hidradenitis suppurativa, urticaria, lichen planus, prurigo nodularis, vasculitis, cutaneous lupus erythematosus (CLE) and chronic idiopathic pruritus; a hyperproliferative disorder or cancer, including polycythemia vera, essential thrombocytopenia and myelofibrosis; a respiratory disease, such as asthma, chronic obstructive pulmonary disease, chronic lung allograft dysfunction, e.g., bronchiolitis obliterans syndrome, pulmonary fibrosis; , cystic fibrosis, rhinitis, bronchiolitis, byssinosis, pneumoconiosis, bronchiectasis, hypersensitivity pneumonitis, lung cancer, mesothelioma and sarcoidosis; gastrointestinal diseases, such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, retroperitoneal fibrosis, celiac disease and cancer; eye diseases, such as myasthenia gravis, Sjögren's syndrome, conjunctivitis, scleritis, uveitis, dry eye syndrome, keratitis, iritis; systemic indications, such as lupus, multiple sclerosis, rheumatoid arthritis, type I diabetes and diabetic complications, cancer, ankylosing spondylitis and psoriatic arthritis; and other autoimmune diseases and indications where immunosuppression is desired, for example to treat or prevent acute and / or chronic graft-versus-host disease (e.g., in organ transplantation).

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

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

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

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

8. The method of claim 6, wherein the about 24 mg / day of the compound or salt thereof is administered at about 12 mg twice daily, and the about 16 mg / day of the compound or salt thereof is administered at about 8 mg twice daily.

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

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

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

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

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

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

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

18. The method of any one of claims 1 to 17, wherein the disease, condition or disorder is selected from a skin disease such as a proliferative, autoimmune and / or inflammatory skin disorder, psoriasis, atopic dermatitis, scleroderma, rosacea, skin cancer, dermatitis, dermatitis herpetiformis, dermatomyositis, vitiligo, contact dermatitis, xerosis, ichthyosis, hidradenitis suppurativa, urticaria, lichen planus, prurigo nodularis, vasculitis, cutaneous lupus erythematosus (CLE) and chronic idiopathic pruritus; a hyperproliferative disorder or cancer including polycythemia vera, essential thrombocytopenia and myelofibrosis; a respiratory disease such as asthma, chronic obstructive pulmonary disease, chronic lung allograft dysfunction, e.g., bronchiolitis obliterans syndrome The invention relates to the treatment of autoimmune diseases and conditions involving the use of the drug. The invention relates to autoimmune diseases and conditions involving the use of the drug. The invention relates to autoimmune diseases and conditions involving the use of the drug.

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

20. The method according to any one of claims 1 to 19, wherein the compound or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical formulation which is a tablet.

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