Urticaria treatment using JAK inhibitors

Abstract

The present application provides a method of treating urticaria in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a JAK1 inhibiting compound or a pharmaceutically acceptable salt thereof.

Description

[0001] Priority declaration

[0002] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 395,613, filed on August 5, 2022, which is incorporated herein by reference in its entirety. Technical Field

[0003] The present application provides a method for treating urticaria using a compound that modulates the activity of Janus kinase (JAK) 1. Background Art

[0004] Protein kinases (PKs) regulate a variety of biological processes, including cell growth, survival, differentiation, organ formation, morphogenesis, angiogenesis, tissue repair and regeneration. Protein kinases also play a special role in a host of human diseases, including cancer. Cytokines (low molecular weight polypeptides or glycoproteins) regulate many pathways involved in the host's inflammatory response to sepsis. Cytokines affect cell differentiation, proliferation and activation, and can regulate pro-inflammatory and anti-inflammatory responses so that the host responds appropriately to pathogens. The signaling of many cytokines involves the Janus kinase family of protein tyrosine kinases (JAKs) and signal transducers and activators of transcription (STATs). There are 4 known mammalian JAKs: JAK1 (Janus kinase-1), JAK2, JAK3 (also known as leukocyte Janus kinase; JAKL; and L-JAK) and TYK2 (protein-tyrosine kinase 2).

[0005] Cytokine-stimulated immune and inflammatory responses contribute to the pathogenesis of disease: pathologies such as severe combined immunodeficiency (SCID) are caused by suppression of the immune system, while overactive or inappropriate immune / inflammatory responses contribute to the pathology of autoimmune diseases (e.g., asthma, systemic lupus erythematosus, thyroiditis, myocarditis) and diseases such as scleroderma and osteoarthritis (Ortmann, RA, T. Cheng et al. (2000) Arthritis Res 2(1):16-32).

[0006] Defects in JAK expression are associated with many disease states. For example, Jak1- / - mice are stunted at birth, unable to suckle, and die in the perinatal period (Rodig, SJ, MA Meraz et al. (1998) Cell 93(3): 373-83). Jak2- / - mouse embryos suffer from anemia and die at about 12.5 days after mating due to lack of clear erythropoiesis.

[0007] It is believed that the JAK / STAT pathway and all four JAKs in particular play a role in the pathogenesis of asthmatic reactions, chronic obstructive pulmonary disease, bronchitis, and other related inflammatory diseases of the lower respiratory tract. A variety of cytokines that signal via JAKs are associated with inflammatory diseases / disorders of the upper respiratory tract (such as those affecting the nose and sinuses, e.g., rhinitis and sinusitis, whether or not they are classic allergic reactions). The JAK / STAT pathway is also associated with inflammatory diseases / disorders of the eye and chronic allergic reactions.

[0008] JAK / STAT in cancer can be activated by cytokine stimulation (e.g., IL-6 or GM-CSF) or by reducing endogenous inhibitors of JAK signaling such as SOCS (suppressors of cytokine signaling) or PIAS (protein inhibitors of activated STAT) (Boudny, V. and Kovarik, J., Neoplasm. 49:349-355, 2002). STAT signaling and activation of other pathways downstream of JAK (e.g., Akt) are associated with poor prognosis in many cancer types (Bowman, T. et al., Oncogene 19:2474-2488, 2000). Elevated levels of circulating cytokines that signal via JAK / STAT play a causal role in cachexia and / or chronic fatigue. Therefore, JAK inhibition may benefit cancer patients for reasons beyond potential anti-tumor activity.

[0009] JAK2 tyrosine kinase may benefit patients with myeloproliferative disorders: for example, polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM) (Levin et al., Cancer Cell, Vol. 7, 2005: 387-397). Inhibition of JAK2V617F kinase reduces the proliferation of hematopoietic cells, indicating that JAK2 is a potential target for pharmacological inhibition in patients with PV, ET and MMM.

[0010] JAK inhibition may benefit patients with skin immune disorders such as psoriasis and skin allergies. It is believed that the maintenance of psoriasis depends on a number of inflammatory cytokines (JCI, 113: 1664-1675) in addition to various chemokines and growth factors, many of which signal via JAKs (Adv Pharmacol. 2000; 47: 113-74).

[0011] Urticaria is a heterogeneous group of diseases characterized by pruritic wheals and / or angioedema. Chronic spontaneous urticaria (formerly chronic idiopathic urticaria) is generally defined as the presence of wheals (wheals), angioedema, or both for more than 6 weeks without an identifiable cause. The overall global prevalence of CSU is approximately 1% and can result in a high disease burden. Affected patients can experience an unpredictable disease course and duration and have symptoms that occur in a spontaneous and recurrent manner and persist for years. In addition, severe itching and the sudden onset of unpredictable wheals and angioedema can affect sleep and the patient's sense of well-being.

[0012] The treatment of CSU remains challenging, with non-sedating second-generation H1 antihistamines being the first-line therapy with up to 4 times the recommended daily dose as needed. Although second-generation H1 antihistamines are effective in alleviating symptoms in some patients, approximately 50% of individuals do not respond adequately to high doses of second-generation antihistamines. As a second-line treatment option, a combination of Omalizumab (an anti-IgE monoclonal antibody, administered subcutaneously) and second-generation H1 antihistamine treatment is recommended, with only approximately 35% of patients achieving a complete response after 12 weeks. For those patients who still have symptoms despite insufficient disease control, cyclosporin is recommended as a third-line treatment option in combination with a second-generation H1 antihistamine, but it is not licensed for urticaria and has a high incidence of adverse effects, limiting its use in many patients with CSU. Therefore, there is a need for other second- and third-line treatment options that can be administered orally and may provide improved efficacy and side effect profiles for the management of CSU.

[0013] Therefore, there is a continuing need for new or improved agents that inhibit kinases such as JAKs in order to develop new and more effective drugs aimed at enhancing or inhibiting immune and inflammatory pathways, such as for the treatment of urticaria. The present application is directed to these and other needs. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 Depicted is a graphic representation of Compound 1-mediated pharmacological inhibition of lesional skin genes using the JAK1 inhibitor Compound 1.

[0015] Figure 2 An overview of the Phase 2 randomized, double-blind, placebo-controlled, dose-ranging study of the efficacy and safety of Compound 1 is described. Summary of the invention

[0016] The present application provides a method for treating urticaria in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound that inhibits JAK1 or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments, the compound or salt is selective for JAK1 over JAK2, JAK3, and TYK2.

[0018] In some embodiments, the compound is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the salt is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile adipate.

[0020] In some embodiments, the compound is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide (Compound 1) or a pharmaceutically acceptable salt thereof.

[0021] In some embodiments, the salt is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide phosphate.

[0022] In some embodiments, the compound or salt is administered at a dose of 15, 30, 45, or 75 mg as the free base.

[0023] In some embodiments, the compound is ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile or a pharmaceutically acceptable salt thereof.

[0024] In some embodiments, the compound is ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile monohydrate.

[0025] In some embodiments, the method further comprises administering another therapeutic agent (eg, an antibiotic, a retinoid, a corticosteroid, an anti-TNF-α agent, or an immunosuppressant).

[0026] In some embodiments, the method further comprises administering an additional therapeutic agent, wherein the additional therapeutic agent is an antihistamine, and wherein the antihistamine is a second generation H1 antihistamine.

[0027] In some embodiments, administration of the compound or salt is topical. In some embodiments, administration of the compound or salt is oral.

[0028] In some embodiments, the methods improve the number and / or size of redness by about 10% to about 90%.

[0029] In some embodiments, the methods improve the amount and / or size of redness by about 10%, 20%, 30%, 40%, or 50%.

[0030] In some embodiments, the method improves the severity of wheal by about 10% to about 90% (eg, based on HSS7 (7-day wheal severity score)).

[0031] In some embodiments, the methods improve the severity of wheal by about 10%, 20%, 30%, 40%, or 50% (eg, based on HSS7).

[0032] In some embodiments, the method improves the severity of angioedema by about 10% to about 90% (eg, based on AAS7 (Angioedema Activity Score over 7 days)).

[0033] In some embodiments, the methods improve the severity of angioedema by about 10%, 20%, 30%, 40%, or 50% (eg, based on AAS7).

[0034] In some embodiments, the method results in an improvement from baseline in the Itch Severity Score (ISS) or the 7-day Weekly Itch Severity Score (ISS7) by about 10% to about 90%.

[0035] In some embodiments, the method improves ISS or ISS7 by about 10%, 20%, 30%, 40%, or 50% relative to baseline.

[0036] In some embodiments, the method results in an improvement in the Urticaria Activity Score (UAS) or the Urticaria Activity Score within 7 days (UAS7) from about 10% to about 90% relative to baseline.

[0037] In some embodiments, the method improves UAS or UAS7 by about 10%, 20%, 30%, 40%, or 50% relative to a baseline.

[0038] In some embodiments, the method results in an improvement in the weekly Urticaria Control Test (UCT) from about 10% to about 90% relative to baseline.

[0039] In some embodiments, the method results in an improvement in the weekly Urticaria Control Test (UCT) by about 10%, 20%, 30%, 40%, or 50% from baseline.

[0040] In some embodiments, the methods result in an improvement in quality of life and / or other patient reported outcomes (PROs) of about 10% to about 90%.

[0041] In some embodiments, the methods improve quality of life and / or other PROs by about 10%, 20%, 30%, 40%, or 50%.

[0042] The present application also provides a compound that inhibits JAK1 or a pharmaceutically acceptable salt thereof, which is used to treat urticaria with or without angioedema and various types of urticaria (including cholinergic urticaria, cold-induced urticaria (CINDU), skin scratch disease / artificial urticaria (urticaria factitism), heat urticaria, delayed pressure urticaria, solar urticaria, contact urticaria and aquagenic urticaria).

[0043] The present application also provides a compound that inhibits JAK1 or a pharmaceutically acceptable salt thereof, which is used for treating urticaria.

[0044] The present application further provides the use of a compound that inhibits JAK1 or a pharmaceutically acceptable salt thereof for preparing a medicament for treating urticaria. DETAILED DESCRIPTION

[0045] The present application particularly provides a method for treating urticaria in a patient in need thereof, the method comprising administering a therapeutically effective amount of a compound that inhibits JAK1 or a pharmaceutically acceptable salt thereof.

[0046] The methods described herein utilize compounds or salts that are JAK1 inhibitors. In some embodiments, the compound is:

[0047] {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[0048] 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide;

[0049] [3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile;

[0050] 4-[3-(Cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide;

[0051] ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile;

[0052] 3-[1-(6-chloropyridin-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propionitrile;

[0053] 3-(1-[1,3]oxazolo[5,4-b]pyridin-2-ylpyrrolidin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propionitrile;

[0054] 4-[(4-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperazin-1-yl)carbonyl]-3-fluorobenzonitrile;

[0055] 4-[(4-{3-cyano-2-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]propyl}piperazin-1-yl)carbonyl]-3-fluorobenzonitrile;

[0056] [trans-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-(4-{[2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)cyclobutyl]acetonitrile;

[0057] {trans-3-(4-{[4-[(3-hydroxyazetidin-1-yl)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

[0058] {trans-3-(4-{[4-{[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

[0059] {trans-3-(4-{[4-{[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

[0060] 4-(4-{3-[(dimethylamino)methyl]-5-fluorophenoxy}piperidin-1-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

[0061] 5-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropylpyrazine-2-carboxamide;

[0062] 4-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide;

[0063] 5-{3-(Cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropylpyrazine-2-carboxamide;

[0064] {1-(cis-4-{[6-(2-hydroxyethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[0065] {1-(cis-4-{[4-[(ethylamino)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[0066] {1-(cis-4-{[4-(1-hydroxy-1-methylethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[0067] {1-(cis-4-{[4-{[(3R)-3-hydroxypyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[0068] {1-(cis-4-{[4-{[(3S)-3-hydroxypyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[0069] {trans-3-(4-{[4-({[(1S)-2-hydroxy-1-methylethyl]amino}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

[0070] {trans-3-(4-{[4-({[(2R)-2-hydroxypropyl]amino}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

[0071] {trans-3-(4-{[4-({[(2S)-2-hydroxypropyl]amino}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

[0072] {trans-3-(4-{[4-(2-hydroxyethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

[0073] or a pharmaceutically acceptable salt of any one of the foregoing.

[0074] In some embodiments, the compound or salt is a JAK1 inhibitor. In some embodiments, the compound or salt has a higher selectivity for JAK1 than JAK2, JAK3 and TYK2. For example, some compounds described herein or pharmaceutically acceptable salts thereof preferentially inhibit JAK1, rather than one or more of JAK2, JAK3 and TYK2. JAK1 plays a major role in many cytokine and growth factor signaling pathways that can cause or contribute to disease states when disordered. For example, IL-6 levels in rheumatoid arthritis are increased, which is considered to have a deleterious effect in this disease (Fonesca et al., Autoimmunity Reviews, 8: 538-42, 2009). Because IL-6 transmits signals at least in part via JAK1, IL-6 can be indirectly regulated via JAK1 inhibition, thereby producing potential clinical benefits (Guschin et al., Embo J 14: 1421, 1995; Smolen et al., Lancet 371: 987, 2008). In addition, in some cancers, JAK1 mutates, causing constitutive undesirable tumor cell growth and survival (Mullighan, Proc Natl Acad Sci USA. 106: 9414-8, 2009; Flex, J Exp Med. 205: 751-8, 2008). In other autoimmune diseases and cancers, elevated systemic levels of inflammatory cytokines that activate JAK1 may also contribute to the disease and / or associated symptoms. Therefore, patients with such diseases may benefit from JAK1 inhibition. Selective JAK1 inhibitors may be effective while avoiding the unnecessary and potentially undesirable effects of inhibiting other JAK kinases.

[0075] Urticaria (also more commonly known as wheals) is characterized by severe skin inflammation. Urticaria may be characterized by redness and swelling that varies in size and shape. Urticaria may be characterized by itching that may be severe. Urticaria may be characterized by angioedema (swelling and pain on the lips, eyelids and / or inside the throat). The examples presented herein support the hypothesis that inflammation is primarily driven by JAK / STAT-mediated pathways. Therefore, patients with urticaria may benefit from JAK1 inhibition. Selective JAK1 inhibitors may be effective while avoiding the unnecessary and potentially undesirable effects of inhibiting other JAK kinases.

[0076] Urticaria is an autoimmune disease driven by mast cells, presenting with chronic pruritus and characterized by spontaneous and recurrent appearance of wheals, angioedema or both for more than 6 consecutive weeks. There is no known initial cause of urticaria. Urticaria lesions show strong T cell infiltration. IL-6 expression in urticaria lesions is upregulated. The expression of IL-33, IL-25 and TSLP (from epithelial cells) triggers mast cells (MC). Autoimmune Ab (IgE or IgG) activates MC. Activated MC secretes vasoactive mediators, cytokines and chemokines that promote immune infiltration. Elevated serum levels of Th1, Th2 and Th17 related cytokines) are associated with the severity of urticaria. JAK1 / 2 inhibition eliminates cytokine signaling from IL-6 and Th1 / Th2 / Th22 related cytokines. JAK1 / 2 inhibition can regulate MC activation, including degranulation and cytokine production. JAK1 / 2 inhibition interferes with itch signaling on skin nerve endings (ie, TSLP, IL31, IL13 receptor signaling). JAK1 / 2 inhibition reduces chemokine secretion, resulting in less cellular infiltration (ie, CXCL10).

[0077] The total prevalence of urticaria is about 0.7% of the world's population. Specifically, the prevalence is about 0.7% in North America, about 0.5% in Europe, about 1.5% in Latin America, and about 1.4% in Asia. Urticaria usually occurs between the ages of 20 and 40. The prevalence of urticaria in women is usually twice that of men and 70% of patients are Caucasians.

[0078] Typical current treatments include standard or high-dose 2nd generation antihistamines (1st and 2nd lines), but about 50% of patients show insufficient response to high-dose antihistamines. The only approved drug is omalizumab (anti-IgE, 3rd line, add-on therapy), but about 35% of patients achieve a complete response to omalizumab. Omalizumab is a humanized anti-IgE monoclonal antibody that binds and captures circulating IgE, thereby preventing IgE from interacting with receptors on mast cells and basophils, thereby interrupting the allergic cascade. Omalizumab can cause problems in patients with, for example, low IgE levels that high doses of anti-IgE cannot bind. Therefore, blocking other pathways with JAK1 inhibitors that reduce, for example, IgE, Il-4, Il-13, and TSLP will produce greater efficacy in a wider range of patients (especially patients who cannot obtain satisfactory treatment using antihistamines such as omalizumab). In some embodiments, JAK1 inhibitors are used to treat CSU patients who are inadequately controlled with second generation H1 antihistamines.

[0079] In some embodiments, urticaria includes subtypes spontaneous urticaria and physical urticaria. In some embodiments, spontaneous urticaria includes acute urticaria and chronic urticaria (including but not limited to chronic persistent urticaria and chronic recurrent urticaria). In some embodiments, physical urticaria includes skin scratch urticaria, delayed pressure urticaria, cold contact urticaria, hot contact urticaria, solar urticaria and vibration urticaria / angioedema. In some embodiments, urticaria includes subtypes called special urticaria types, including cholinergic urticaria, adrenergic urticaria, contact urticaria (allergic or pseudoallergic) and water-induced urticaria. Examples of diseases associated with urticaria in history include urticaria pigmentosa (mastocytosis), urticarial vasculitis and familial cold urticaria.

[0080] The target population included patients with chronic spontaneous urticaria (CSU), defined as the presence of recurrent urticaria (wheals or hives), angioedema, or both for more than 6 weeks or longer, with symptoms occurring at least three to four times per week, with no known triggers, and no response to 4-fold daily doses of second-generation antihistamines.

[0081] In Europe, chronic spontaneous urticaria (CSU) is defined as the presence of recurrent urticaria (wheals or urticaria), angioedema, or both for more than 6 weeks or longer, with symptoms occurring at least three to four times per week, with no known trigger and with inadequate response, contraindication, or intolerance to previous biologic therapy.

[0082] In some embodiments, use is for chronic spontaneous urticaria (CSU) in adults and adolescents 12 years of age and older who remain symptomatic after treatment with an H1 antihistamine. Doses may include 15 mg, 30 mg, 45 mg, and / or 75 mg. Doses may include 15 or 30 mg of a JAK1 inhibitor. Doses may include 15 mg of a JAK1 inhibitor. Doses may include 30 mg of a JAK1 inhibitor.

[0083] In some embodiments, an endpoint (e.g., primary) may include a change from baseline in weekly pruritus severity scores (except in certain countries / regions (e.g., EU and EU reference countries) [e.g., time frame: baseline to week 24]. For example, a change from baseline in weekly pruritus severity scores (ISS7) at week 24 may include at least 25% or at least 30% (adjusted for PBO). For example, a change from baseline in weekly urticaria activity scores (UAS7, a composite score of patient-reported pruritus and wheals) at week 24 may include at least 25% or at least 30% (adjusted for PBO).

[0084] In some embodiments, the change from baseline in UAS7 is defined as the 7-day sum of the individual daily recorded scores for HSS and ISS, for example at week 12.

[0085] In some embodiments, the methods improve the severity of wheal by about 10% to about 90% (eg, based on the HSS or HSS7 (7-day wheal severity score)).

[0086] In some embodiments, the methods improve the severity of wheal by about 10%, 20%, 30%, 40%, or 50% (eg, based on HSS or HSS7).

[0087] In some embodiments, the method improves the severity of angioedema by about 10% to about 90% (e.g., based on AAS or AAS7 (angioedema activity score within 7 days)). In some embodiments, the method improves the severity of angioedema by about 10%, 20%, 30%, 40% or 50% (e.g., based on AAS or AAS7). The AAS records whether the participant has experienced an episode of swelling within the previous 24 hours. If the participant answers yes, other questions are asked, including time of event, physical discomfort, impact on daily activities, appearance, and overall severity. If the participant has entered at least 5 daily AAS scores within 7 days before the study visit, the AAS7 score is calculated as the sum of the available AAS scores divided by the number of days with AAS scores multiplied by 7. In some embodiments, an endpoint (e.g., secondary) may include a change of at least 25% or at least 30% relative to baseline in a weekly urticaria activity score (UAS or UAS7) at, for example, week 12 and, for example, week 24 (e.g., PBO adjustment is performed at week 24). The change from baseline in ISS7 (EU) may include at least 25% or at least 30% (e.g., PBO adjustment at Week 24). UAS is a composite score of a numeric severity intensity scale (0 = none to 3 = strong / severe) of a) the number of wheals (i.e., HSS) and b) the intensity of itching (i.e., ISS) in the past 24 hours. UAS7 is the 7-day sum of daily UAS. UAS7 (range 0 to 42) is equal to ISS7 (range 0 to 21) plus HSS7 (range 0 to 21). If the participant has entered at least 5 daily UAS scores within the 7 days prior to the study visit, the UAS7 score is calculated as the sum of the available UAS scores divided by the number of days with UAS scores multiplied by 7. If more than 2 daily UAS scores are missing in the previous 7 days, the UAS7 score is missing for this week.

[0088] In some embodiments, the method makes weekly urticaria control test (UCT) relative baseline improvement about 10% to about 90%. UCT is a way to measure urticaria disease activity. An example scale of UCT is 0-16, where 0 equals the most severe activity and 16 equals no disease activity. In some embodiments, a UCT score of less than 12 identifies a subject with poor control of chronic urticaria, and a score greater than or equal to 12 identifies a subject with good symptom control. In some embodiments, a 3-point improvement is a minimal response, and an improvement greater than or equal to 6 points is a significant response.

[0089] In some embodiments, the method results in an improvement in the weekly Urticaria Control Test (UCT) by about 10%, 20%, 30%, 40%, or 50% from baseline.

[0090] In some embodiments, the method improves quality of life and / or other patient-reported outcomes (PROs) by about 10% to about 90%. In some embodiments, the method improves quality of life and / or other PROs by about 10%, 20%, 30%, 40%, or 50%. In some embodiments, the efficacy of the treatment methods disclosed herein can be established based on patient-reported outcomes (PROs). In some embodiments, the efficacy of the treatment methods disclosed herein can be established based on the Dermatology Life Quality Index (DLQI). In some embodiments, Compound 1 and / or methods of use described herein improve the participant's DLQI response relative to baseline. The DLQI is a validated questionnaire (e.g., 10-questions) that measures the extent to which skin problems have affected participants in the previous 7 days. Participants will answer the questionnaire with the following: (1) very much, (2) a lot, (3) a little, or (4) not at all. The questionnaire can be analyzed under the following 6 headings: symptoms and feelings; daily activities; leisure; work and school; personal relationships; and treatment.

[0091] In some embodiments, the method improves the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) by about 10% to about 90%. In some embodiments, the method improves the CU-Q2oL by about 10%, 20%, 30%, 40% or 50%. In some embodiments, the efficacy of the treatment methods disclosed herein can be established based on the CU-Q2oL. Participants will complete the CU-Q2oL validation questionnaire at the study visit. The CU-Q2oL can be a 23-item, CSU-specific, health-related quality of life questionnaire. Participants rate their CSU symptoms and the impact of their CSU on various aspects of their lives in the previous 14 days. Total scores for the following areas can also be calculated: itching, swelling, impact on life activities, sleep problems, limitations, and appearance.

[0092] In some embodiments, the method improves the angioedema quality of life questionnaire (AE-QoL) by about 10% to about 90%. In some embodiments, the method improves the AE-QoL by about 10%, 20%, 30%, 40% or 50%. Participants will complete the AE-QoL validation questionnaire at the study visit. AE-QoL is a validated tool used as a measure of quality of life impairment caused by angioedema. AE-QoL consists of 17 questions covering the following 4 areas: function, fatigue / mood, fear / shame and food. Participants will answer the frequency of each item affected by swelling episodes in the past 4 weeks.

[0093] In some embodiments, the method improves the Work Productivity and Activity Index-Chronic Urticaria (WPAI-CU) by about 10% to about 90%. In some embodiments, the method improves the WPAI-CU by about 10%, 20%, 30%, 40% or 50%. Participants will complete the WPAI-CU questionnaire at the time of the study visit. The WPAI-CU questionnaire is a 6-item, validated tool designed to measure the impairment in paid and unpaid work. It measures absence and attendance during the past 7 days and unpaid activity impairment caused by health problems. The minimum clinically important difference is defined as half the STD of the total population baseline score. Absence, attendance and overall work impairment will be evaluated only for employed participants.

[0094] In some embodiments, the method improves the EuroQol 5-dimensional 5-level scale (EQ-5D-5L) by about 10% to about 90%. In some embodiments, the method improves the EQ-5D-5L by about 10%, 20%, 30%, 40% or 50%. Participants will complete the EQ-5D-5L questionnaire. EQ-5D-5L is a standardized tool used as a measure of health outcomes. EQ-5D-5L will provide data for economic models and analyses (including the development of health utility or quality-adjusted life expectancy). EQ-5D-5L consists of the following 2 parts: the EQ-5D description system and the EQ VAS, which asks participants about their health status on the day. The description system includes the following 5 dimensions: mobility, self-care, daily activities, pain / discomfort and anxiety / depression. Each dimension has the following 5 levels: no problem, mild problem, moderate problem, severe problem and extreme problem. The EQ VAS records the participant's self-rated health status on a vertical VAS (0 to 100) with anchor points labeled "Best Health Imaginable" and "Worst Health Imaginable."

[0095] In some embodiments, the method improves the Patient Global Impression of Change (PGI-C) by about 10% to about 90%. In some embodiments, the method improves the PGI-C by about 10%, 20%, 30%, 40% or 50%. The PGI-C questionnaire will be completed according to the schedule. The PGI-C tool will provide data on the overall treatment response from the participant's perspective. The PGI-C is a single-item questionnaire about the degree of change in the participant's overall CSU status compared to the start of treatment, using a 7-point categorical response scale ranging from 1 (greatly improved) to 7 (very bad).

[0096] In some embodiments, the method improves the Patient Global Severity Impression (PGI-S) by about 10% to about 90%. In some embodiments, the method improves the PGI-S by about 10%, 20%, 30%, 40% or 50%. Participants will complete the PGI-S questionnaire. The PGI-S will provide data on the severity of CSU symptoms from the perspective of the participant. The PGI-S is a single-item questionnaire used to assess disease severity. Participants will use a 5-point scale (none, mild, moderate, severe, very severe) to rate the CSU symptoms they experience at each study visit.

[0097] In some embodiments, the compound or salt preferentially inhibits JAK1 over JAK2 (e.g., JAK2 / JAK1 IC 50 Ratio>1). In some embodiments, the compound or salt is about 10-fold selective for JAK1 over JAK2. In some embodiments, the compound or salt is about 3-fold, about 5-fold, about 10-fold, about 15-fold, or about 20-fold selective for JAK1 over JAK2, as measured by IC at 1 mM ATP. 50 Calculated (see Example A).

[0098] In some embodiments, the JAK1 inhibitor is a compound of Table 1 or a pharmaceutically acceptable salt thereof. The compounds in Table 1 are selective JAK1 inhibitors (selective over JAK2, JAK3 and TYK2). Table 1 shows the IC values ​​obtained by the method of Example A at 1 mM ATP. 50 value.

[0099] Table 1

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109] + means <10 nM (for analytical conditions, see Example A)

[0110] ++ means ≤100 nM (for analytical conditions, see Example A)

[0111] +++ means ≤300 nM (see Example A for analytical conditions)

[0112] a Data for enantiomer 1

[0113] b Data for Enantiomer 2

[0114] In some embodiments, the JAK1 inhibitor is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile or a pharmaceutically acceptable salt thereof.

[0115] In some embodiments, the JAK1 inhibitor is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile adipate.

[0116] The synthesis and preparation of {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile and its adipate salt can be found, for example, in U.S. Patent Publication No. 2011 / 0224190 filed on March 9, 2011, U.S. Patent Publication No. 2013 / 0060026 filed on September 6, 2012, and U.S. Patent Publication No. 2014 / 0256941 filed on March 5, 2014, each of which is incorporated herein by reference in its entirety.

[0117] In some embodiments, the JAK1 inhibitor is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide or a pharmaceutically acceptable salt thereof.

[0118] In some embodiments, the JAK1 inhibitor is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide phosphate.

[0119] In some embodiments, the JAK1 inhibitor is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide hydrochloride.

[0120] In some embodiments, the JAK1 inhibitor is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide hydrobromide.

[0121] In some embodiments, the JAK1 inhibitor is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide sulfate.

[0122] The synthesis and preparation of 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide and its phosphate salt can be found in, for example, U.S. Patent Publication No. US2014 / 0343030, filed on May 16, 2014, which is incorporated herein by reference in its entirety.

[0123] In some embodiments, the JAK1 inhibitor is ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile or a pharmaceutically acceptable salt thereof.

[0124] In some embodiments, the JAK1 inhibitor is ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile monohydrate.

[0125] The synthesis of ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile and the characterization of its anhydrous and monohydrate forms are described in U.S. Patent Publication No. 2014 / 0121198, filed on October 31, 2013, and U.S. Patent Publication No. 2015 / 0344497, filed on April 29, 2015, each of which is incorporated herein by reference in its entirety.

[0126] In some embodiments, the compounds of Table 1 are prepared by the synthetic procedures described in the following cases: U.S. Patent Publication No. 2011 / 0224190 filed on March 9, 2011, U.S. Patent Publication No. 2014 / 0343030 filed on May 16, 2014, U.S. Patent Publication No. 2014 / 0121198 filed on October 31, 2013, U.S. Patent Publication No. 2010 / 0298334 filed on May 21, 2010, U.S. Patent Publication No. 2011 / 0 059951, U.S. Patent Publication No. 2012 / 0149681, filed on November 18, 2011, U.S. Patent Publication No. 2012 / 0149682, filed on November 18, 2011, U.S. Patent Publication No. 2013 / 0018034, filed on June 19, 2012, U.S. Patent Publication No. 2013 / 0045963, filed on August 17, 2012, and U.S. Patent Publication No. 2014 / 0005166, filed on May 17, 2013, each of which is incorporated herein by reference in its entirety.

[0127] In some embodiments, the JAK1 inhibitor is selected from the compounds or pharmaceutically acceptable salts thereof of the following cases: U.S. Patent Publication No. 2011 / 0224190 filed on March 9, 2011, U.S. Patent Publication No. 2014 / 0343030 filed on May 16, 2014, U.S. Patent Publication No. 2014 / 0121198 filed on October 31, 2013, U.S. Patent Publication No. 2010 / 0298334 filed on May 21, 2010, U.S. Patent Publication No. 2011 / 0343030 filed on May 16, 2014, 0059951, U.S. Patent Publication No. 2012 / 0149681, filed on November 18, 2011, U.S. Patent Publication No. 2012 / 0149682, filed on November 18, 2011, U.S. Patent Publication No. 2013 / 0018034, filed on June 19, 2012, U.S. Patent Publication No. 2013 / 0045963, filed on August 17, 2012, and U.S. Patent Publication No. 2014 / 0005166, filed on May 17, 2013, each of which is incorporated herein by reference in its entirety.

[0128] In some embodiments, the JAK1 inhibitor is a compound of Formula I:

[0129]

[0130] or a pharmaceutically acceptable salt thereof, wherein:

[0131] X is N or CH;

[0132] L is C(═O) or C(═O)NH;

[0133] A is phenyl, pyridinyl or pyrimidinyl, each of which is optionally substituted with 1 or 2 independently selected R 1 group substitution; and

[0134] Each R 1 is independently fluoro or trifluoromethyl.

[0135] In some embodiments, the compound of Formula I is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile or a pharmaceutically acceptable salt thereof.

[0136] In some embodiments, the compound of Formula I is 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide or a pharmaceutically acceptable salt thereof.

[0137] In some embodiments, the compound of Formula I is [3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile or a pharmaceutically acceptable salt thereof.

[0138] In some embodiments, the JAK1 inhibitor is a compound of Formula II:

[0139]

[0140] or a pharmaceutically acceptable salt thereof, wherein:

[0141] R 2 It is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or C 3-6 Cycloalkyl-C 1-3 Alkyl, wherein the C 1-6 Alkyl, the C 3-6 Cycloalkyl and the C 3-6 Cycloalkyl-C 1-3 The alkyl groups are each optionally substituted with 1, 2 or 3 substituents independently selected from fluorine, -CF3 and methyl;

[0142] R 3 is H or methyl;

[0143] R 4 is H, F or Cl;

[0144] R 5 is H or F;

[0145] R 6 is H or F;

[0146] R 7 is H or F;

[0147] R 8 is H or methyl;

[0148] R 9 is H or methyl;

[0149] R 10 is H or methyl; and

[0150] R 11 It is H or methyl.

[0151] In some embodiments, the compound of Formula II is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide or a pharmaceutically acceptable salt thereof.

[0152] In some embodiments, the JAK1 inhibitor is a compound of Formula III:

[0153]

[0154] or a pharmaceutically acceptable salt thereof, wherein:

[0155] Cy 4 is a tetrahydro-2H-pyran ring, which is optionally substituted by 1 or 2 independently selected from CN, OH, F, Cl, C 1-3 Alkyl, C 1-3 Haloalkyl, CN-C 1-3 Alkyl, HO-C 1-3 Alkyl, amino, C 1-3 Alkylamino and di(C 1-3 alkyl)amino group, wherein the C 1-3 The alkyl group and the di(C 1-3 alkyl)amino is optionally substituted by 1, 2 or 3 independently selected from F, Cl, C 1-3 Alkylaminosulfonyl and C 1-3 The substituent of the alkylsulfonyl group is substituted; and

[0156] R 12 It is -CH2-OH, -CH(CH3)-OH or -CH2-NHSO2CH3.

[0157] In some embodiments, the compound of Formula III is ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile or a pharmaceutically acceptable salt thereof.

[0158] In some embodiments, the JAK1 inhibitor may be an isotopically labeled compound or a pharmaceutically acceptable salt thereof. An "isotopically" or "radiolabeled" compound is a compound of the present disclosure in which one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated into the compounds of the present disclosure include, but are not limited to 2 H (also written as D, deuterium), 3 H (also written as T, tritium), 11 C.13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 18 F. 35 S. 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I. 124 I. 125 I and 131 I. For example, one or more hydrogen atoms in the compounds of the present disclosure may be replaced by a deuterium atom, such as replacing -CH3 with -CD3).

[0159] One or more constituent atoms of the compounds described herein may be replaced or substituted by natural or non-natural abundance atomic isotopes. In some embodiments, the compound includes at least one deuterium atom. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1-2, 1-3, 1-4, 1-5 or 1-6 deuterium atoms. In some embodiments, all hydrogen atoms in the compound may be replaced or substituted by deuterium atoms.

[0160] Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry, Alan F. Thomas (New York, NY, Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange, Jens Atzrodt, Volker Derdau, Thorsten Fey, and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling, James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds are useful in a variety of studies, such as NMR spectroscopy, metabolic experiments and / or analysis.

[0161] Substitution with heavier isotopes (e.g., deuterium) may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some cases. (See, for example, A. Kerekes et al., J. Med. Chem. 2011, 54, 201-210; R. Xu et al., J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular, substitution at one or more metabolic sites may provide one or more therapeutic advantages.

[0162] Thus, in some embodiments, the JAK1 inhibitor is a compound or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen atoms in the compound are replaced with a deuterium atom.

[0163] As used herein, the phrase "optionally substituted" means unsubstituted or substituted. As used herein, the term "substituted" means that a hydrogen atom is removed and replaced by a substituent. It is understood that substitution at a given atom is limited by valence.

[0164] As used herein, the term “C n-m "Alkyl" (alone or in combination with other terms) refers to a saturated hydrocarbon radical having n to m carbon atoms, which may be straight chain or branched. In some embodiments, the alkyl group contains 1 to 6 or 1 to 3 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methyl-1-butyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like.

[0165] As used herein, the term "alkylene" (used alone or in combination with other terms) refers to a divalent alkyl linking group that can be branched or straight, wherein two substituents can be attached to any position of the alkylene linking group. Examples of alkylene include, but are not limited to, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, and the like.

[0166] As used herein, the term "HO-C 1-3 "-Alkyl" refers to a radical of the formula -alkylene-OH wherein the alkylene has 1 to 3 carbon atoms.

[0167] As used herein, the term "CN-C 1-3 "Alkyl" refers to a C 1-3 alkyl.

[0168] As used herein, the term "amino" refers to a group of formula -NH2.

[0169] As used herein, the term " 1-3"-alkyl)amino" refers to a radical of the formula -N(alkyl)2, wherein the two alkyl radicals each independently have 1 to 3 carbon atoms.

[0170] As used herein, the term “C 1-3 "Alkylamino" refers to a radical of the formula -NH(alkyl) wherein the alkyl radical has 1 to 3 carbon atoms.

[0171] As used herein, the term " 1-3 "alkyl)aminosulfonyl" refers to a radical of the formula -S(O)2N(alkyl)2 wherein each alkyl radical independently has 1 to 3 carbon atoms.

[0172] As used herein, the term “C 1-3 "Alkylsulfonyl" refers to a radical of the formula -S(O)2-alkyl wherein the alkyl radical has 1 to 3 carbon atoms.

[0173] As used herein, "halo" or "halogen" (alone or in combination with other terms) includes fluoro, chloro, bromo, and iodo. In some embodiments, halo is fluoro or chloro.

[0174] As used herein, the term “C n-m "Haloalkyl" (alone or in combination with other terms) means a C-1-alkyl radical having up to {2(nm)+1} halogen atoms which may be the same or different n-m In some embodiments, the halogen atom is a fluorine atom. In some embodiments, the alkyl group has 1-6 or 1-3 carbon atoms. Example haloalkyl groups include CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5, etc. In some embodiments, the haloalkyl group is a fluoroalkyl group.

[0175] As used herein, the term “C 1-3 "Fluoroalkyl" refers to a C 1-3 alkyl.

[0176] As used herein, the term “C 3-6 "Cycloalkyl" (used alone or in combination with other terms) refers to a non-aromatic monocyclic hydrocarbon moiety having 3-6 carbon atoms, which may optionally contain one or more alkenylene groups as part of the ring structure. One or more ring-forming carbon atoms of the cycloalkyl group may be oxidized to form a carbonyl linkage. Exemplary C 3-6 Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, etc. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0177] As used herein, the term “C 3-6 Cycloalkyl-C 1-3 "Alkyl" refers to a group of the formula -C 1-3Alkylene-C 3-6 Cycloalkyl groups.

[0178] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers (such as enantiomers and diastereomers) are contemplated. Compounds containing asymmetrically substituted carbon atoms may be separated in optically active or racemic forms. Methods for preparing optically active forms from optically inert starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, etc. may also be present in the compounds described herein, and the present application contemplates all such stable isomers. The cis and trans geometric isomers of the compounds of the present application are described and they may be separated into mixtures of isomers or separate isomeric forms. In some embodiments, the compound has an (R)-configuration. In some embodiments, the compound has an (S)-configuration.

[0179] The racemic mixture of compound can be resolved by any of many methods known in the art. An exemplary method includes using chiral resolution acid to carry out fractional recrystallization, and the chiral resolution acid is a kind of optically active salified organic acid. Suitable resolving agent for fractional recrystallization method is for example optically active acid, such as tartaric acid D and L form, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acid (such as β-camphorsulfonic acid). Other resolving agents suitable for fractional crystallization method include stereoisomerically pure form (such as S and R form or diastereoisomerically pure form) of α-methylbenzylamine, 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane etc.

[0180] The racemic mixture can also be resolved by eluting on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by those skilled in the art.

[0181] The compounds described herein include tautomeric forms. Tautomeric forms are produced by the exchange of a single bond with an adjacent double bond and the concomitant migration of a proton. Tautomeric forms include proton-transfer tautomers, which are isomeric protonation states with the same empirical formula and total charge. Example proton-transfer tautomers include keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs; and cyclic forms in which protons can occupy two or more positions of a heterocyclic system, such as 1H- and 3H-imidazoles, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. Tautomeric forms can be in equilibrium or spatially locked into one form due to appropriate substitution. For example, it should be recognized that the following pyrazole rings can form the following two tautomers:

[0182]

[0183] The claims are intended to cover both tautomers.

[0184] All compounds and pharmaceutically acceptable salts thereof may be obtained together with other substances (such as water and solvents) (eg, hydrates and solvates) or may be isolated.

[0185] In some embodiments, the compounds described herein or their salts are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially isolated from the environment in which the compound is formed or detected. Partial separation may include, for example, a composition rich in the compounds described herein. Substantially separating may include a composition containing at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compounds described herein or their salts. The method for separating compounds and their salts is a conventional method in the art.

[0186] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit / risk ratio.

[0187] As used herein, the expressions "ambient temperature," "room temperature," and "rt" are understood in the art and generally refer to a temperature (e.g., reaction temperature) that is about the temperature of the room in which the reaction is carried out, e.g., a temperature of about 20°C to about 30°C.

[0188] The present application also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, wherein the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (such as amines), alkaline or organic salts of acidic residues (such as carboxylic acids), and the like. The pharmaceutically acceptable salts of the present application include, for example, conventional non-toxic salts of the parent compound formed by non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present application can be synthesized by conventional chemical methods from a parent compound containing a basic or acidic moiety. Typically, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or in a mixture of the two; typically, non-aqueous media are preferred, such as ether, ethyl acetate, alcohol (e.g., methanol, ethanol, isopropanol or butanol) or acetonitrile (ACN). Lists of suitable salts may be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0189] As used herein, the term "contacting" refers to mixing the indicated parts in an in vitro system or an in vivo system. For example, "contacting" a JAK with a compound of the present invention includes administering a compound of the present application to an individual or patient (e.g., a human) having a JAK, and, for example, introducing a compound of the present invention into a sample containing cells or purified preparations containing a JAK.

[0190] As used herein, the terms "subject", "individual" or "patient" are used interchangeably and refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates and most preferably humans. In some embodiments, a "subject", "individual" or "patient" is in need of such treatment.

[0191] In some embodiments, the inhibitor is administered in a therapeutically effective amount. As used herein, the phrase "therapeutically effective amount" refers to the amount of an active compound or agent that induces a biological or medical response that a researcher, veterinarian, medical doctor or other clinician is seeking in a tissue, system, animal, individual or human.

[0192] As used herein, the terms "treating" or "treatment" refer to one or more of the following: (1) inhibiting a disease; e.g., inhibiting a disease, illness, or condition in an individual who is experiencing or exhibiting the pathology or symptoms of a disease, disorder, or condition (i.e., preventing further development of the pathology or symptoms); (2) ameliorating a disease; e.g., ameliorating a disease, illness, or condition in an individual who is experiencing or exhibiting the pathology or symptoms of a disease, disorder, or condition (i.e., reversing the pathology or symptoms), such as reducing the severity of the disease; or (3) preventing a disease, disorder, or condition in an individual who may be susceptible to a disease, disorder, or condition but does not yet experience or exhibit the pathology or symptoms of the disease. In some embodiments, treating refers to inhibiting or ameliorating a disease. In some embodiments, treatment is preventing a disease.

[0193] Combination therapy

[0194] The methods described herein may further comprise administering one or more additional therapeutic agents. The one or more additional therapeutic agents may be administered to the patient simultaneously or sequentially.

[0195] In some embodiments, another therapeutic agent includes antibiotics, antivirals, antifungals, anesthetics, anti-inflammatory agents (including steroidal and non-steroidal anti-inflammatory agents), and anti-allergic agents. Examples of suitable agents include aminoglycosides such as amikacin, gentamycin, tobramycin, streptomycin, netilmycin, and kanamycin; fluoroquinolones such as ciprofloxacin, norfloxacin, ofloxacin, trovafloxacin, lomefloxacin, levofloxacin, and enoxacin; naphthyridines; sulfonamides; polymyxins; chloramphenicol; neomycin; paramomycin; colistimethate; bacitracin; vancomycin. vancomycin; tetracycline; rifampin and its derivatives ("rifampicins"); cycloserine; beta-lactam; cephalosporin; amphotericin; fluconazole; flucytosine; natamycin; miconazole; ketoconazole; diclofenac; flurbiprofen; ketorolac; suprofen; cromolyn; lodoxamide; levocabastin; naphazoline; antazoline; pheniramine; or an azalide antibiotic.

[0196] In some embodiments, the additional therapeutic agent comprises an antihistamine. The antihistamine is a second generation H1 antihistamine.

[0197] In some embodiments, another therapeutic agent is an antibiotic. In some embodiments, the antibiotic is clindamycin, doxycycline, minocycline, trimethoprim-sulfamethoxazole, erythromycin, metronidazole, rifampicin, moxifloxacin, dapsone or a combination thereof. In some embodiments, the antibiotic is a combination of clindamycin, doxycycline, minocycline, trimethoprim-sulfamethoxazole or erythromycin and metronidazole. In some embodiments, the antibiotic is a combination of rifampicin, moxifloxacin and metronidazole. In some embodiments, the antibiotic is a combination of moxifloxacin and rifampicin.

[0198] In some embodiments, the other therapeutic agent is a retinoid. In some embodiments, the retinoid is etretinate, acitretin, or isotretinoin.

[0199] In some embodiments, the other therapeutic agent is a steroid. In some embodiments, the other therapeutic agent is a corticosteroid. In some embodiments, the steroid is such as triamcinolone, dexamethasone, fluocinolone, cortisone, prednisone, prednisolone, or flumetholone.

[0200] In some embodiments, the other therapeutic agent is an anti-TNF-α agent. In some embodiments, the anti-TNF-α agent is an anti-TNF-α antibody. In some embodiments, the anti-TNF-α agent is infliximab or etanercept or adalimumab.

[0201] In some embodiments, the other therapeutic agent is an immunosuppressant. In some embodiments, the immunosuppressant is methotrexate or cyclosporin A. In some embodiments, the immunosuppressant is mycophenolate mofetil or mycophenolate sodium.

[0202] In some embodiments, the additional therapeutic agent is finasteride, metformin, adapalene, or azelaic acid.

[0203] In some embodiments, the method further comprises administering another therapeutic agent selected from an IMiD, an anti-IL-6 agent, a hypomethylating agent, and a biological response modifier (BRM).

[0204] Typically, BRMs are substances made from living organisms used to treat disease, which may occur naturally in the body or may be made in the laboratory. Examples of BRMs include IL-2, interferon, various types of colony stimulating factors (CSF, GM-CSF, G-CSF), monoclonal antibodies (such as abciximab, etanercept, infliximab, omalizumab, rituximab, trastuzumab), and high-dose ascorbate.

[0205] In some embodiments, the hypomethylating agent is a DNA methyltransferase inhibitor. In some embodiments, the DNA methyltransferase inhibitor is selected from 5-azacytidine and decitabine.

[0206] Typically, IMiDs are used as immunomodulators. In some embodiments, IMiDs are selected from thalidomide, lenalidomide, pomalidomide, CC-11006, and CC-10015.

[0207] In some embodiments, the method further comprises administering another therapeutic agent selected from anti-thymocyte globulin, recombinant human granulocyte colony stimulating factor (G CSF), granulocyte-monocyte CSF (GM-CSF), erythropoiesis stimulating agent (ESA), and cyclosporine.

[0208] In some embodiments, the method further includes applying another JAK inhibitor to the patient. In some embodiments, another JAK inhibitor is ruxolitinib, barcitinib, tofacitinib, oclacitinib, filgotinib, gandotinib, lestaurtinib, momelotinib, PF-04965842, upadacitinib, peficitinib, fedratinib, cucurbitacin I or CHZ868. Other JAK inhibitors may include ATI-50002 (JAK1 / 3 selectivity). Other JAK inhibitors may include PF-06651600 (JAK3 selectivity). Other JAK inhibitors may include PF06700841 (JAK1 / TYK2 selectivity). Additional JAK inhibitors may include TYK2 selective inhibitors.

[0209] In some embodiments, another therapeutic agent is selected from antioxidants. Antioxidants can be selected from pseudocatalase, vitamin E, vitamin C, ubiquinone, lipoic acid, P olypodium leucotomos, catalase / superoxide dismutase combination and Ginkgo biloba. In some embodiments, antioxidants can be further used in combination with phototherapy. Antioxidants are used during or before phototherapy to counteract the oxidative stress caused by UV radiation itself, thereby increasing the effectiveness of phototherapy.

[0210] In some embodiments, the additional therapeutic agent comprises an antihistamine.

[0211] In some embodiments, the additional therapeutic agent is selected from topical corticosteroids, immunomodulators, calcineurin inhibitors, and light therapy. In some embodiments, the additional therapy is systemic steroids.

[0212] One or more additional agents (such as anti-inflammatory agents, immunosuppressants, and PI3Kδ, mTor, Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors, such as those described in WO 2006 / 056399, which is incorporated herein by reference in its entirety) or other agents may be combined with the compounds described herein for the treatment of JAK-related diseases, disorders or conditions. The one or more additional agents may be administered to the patient simultaneously or sequentially.

[0213] Exemplary Bcr-Abl inhibitors include compounds of the genera and species disclosed in US Pat. No. 5,521,184, WO 04 / 005281, and US No. 60 / 578,491, and pharmaceutically acceptable salts thereof, all of which are incorporated herein by reference in their entirety.

[0214] Exemplary suitable Flt-3 inhibitors include compounds disclosed in WO 03 / 037347, WO 03 / 099771, and WO 04 / 046120, and pharmaceutically acceptable salts thereof, each of which is incorporated herein by reference in its entirety.

[0215] Exemplary suitable RAF inhibitors include compounds disclosed in WO 00 / 09495 and WO 05 / 028444, and pharmaceutically acceptable salts thereof, each of which is incorporated herein by reference in its entirety.

[0216] Exemplary suitable FAK inhibitors include compounds disclosed in WO 04 / 080980, WO 04 / 056786, WO 03 / 024967, WO 01 / 064655, WO 00 / 053595 and WO 01 / 014402, and pharmaceutically acceptable salts thereof, all of which are incorporated herein by reference in their entirety.

[0217] In some embodiments, one or more compounds of the invention may be used in combination with one or more other kinase inhibitors, including imatinib, particularly for treating patients who are resistant to imatinib or other kinase inhibitors.

[0218] In some embodiments, the additional therapeutic agent is fluocinolone acetonide or rimexolone (AL-2178, Vexol, Alcon).

[0219] In some embodiments, the additional therapeutic agent is cyclosporine

[0220] In some embodiments, the additional therapeutic agent is selected from Dehydrex TM(Holles Labs), Civamide (Opko), sodium hyaluronate (Vismed, Lantibio / TRB Chem edia), cyclosporine (ST-603, Sirion Therapeutics), ARG101 (T) (testosterone, Argentis), AGR1012 (P) (Argentis), ecabet sodium (Sen ju-Ista), gefarnate (Santen), 15-(S)-hydroxyeicosatetraenoic acid (15(S)-HETE), cevimeline, doxycycline (ALTY-0501, Alacrity), minocycline, iDestrin TM(NP50301, Nascent Pharmaceuticals), cyclosporin A (Nova22007, Novagali), oxytetracycline (Duramycin, MOLI1901, Lantibio), CF101 (2S, 3S, 4R, 5R)-3, 4-dihydroxy-5-[6-[(3-iodophenyl) methylamino] purin-9-yl]-N-methyl-oxacyclopentane-2-carboxamide, Can-Fite Biopharm a), voclosporin (LX212 or LX214, Lux Biosciences), A RG103 (Agentis), RX-10045 (synthetic resolvin analog, Resolvyx), DYN15 (Dyanmis Therapeutics), rivoglitazone (DE011, Daiichi Sanko), TB4 (RegeneRx), OPH-01 (Ophtalmis Monaco), PCS101 (Pericor Science), REV1-31 (Evolutec), Lacritin (Senju), rebamipide (Otsuka-Novartis), OT-551 (Othera), PAI-2 (University of Pennsylvania and Temple University), pilocarpine, tacrolimus, pimecrolimus (AMS981, Novartis), loteprednoletabonate, rituximab, diquafosol tetrasodium (INS365, Inspire), KLS-0611 (Kissei Pharmaceuticals), dehydroepiandrosterone, anakinra ( kinra), efalizumab, mycophenolate sodium, etanercept Hydroxychloroquine, NGX267 (Torrey Pines Therapeutics), actemra, gemcitabine, oxaliplatin, L-asparaginase, or thalidomide.

[0221] In some embodiments, another therapeutic agent is an anti-angiogenic agent, a cholinergic agonist, a TRP-1 receptor modulator, a calcium channel blocker, a mucin secretagogue, a MUC1 stimulator, a calcineurin inhibitor, a corticosteroid, a P2Y2 receptor agonist, a muscarinic receptor agonist, an mTOR inhibitor, another JAK inhibitor, a Bcr-Abl kinase inhibitor, a Flt-3 kinase inhibitor, a RAF kinase inhibitor, and a FAK kinase inhibitor, such as those described in WO2006 / 056399 (which is incorporated herein by reference in its entirety). In some embodiments, another therapeutic agent is a tetracycline derivative (e.g., minocycline or doxycycline). In some embodiments, another therapeutic agent binds to FKBP12.

[0222] In some embodiments, the additional therapeutic agent is an alkylating agent or a DNA cross-linking agent; an antimetabolite / demethylating agent (e.g., 5-fluorouracil, capecitabine, or azacitidine); an anti-hormonal therapy (e.g., a hormone receptor antagonist, a SERM, or an aromatase inhibitor); a mitotic inhibitor (e.g., vincristine or paclitaxel); a topoisomerase (I or II) inhibitor (e.g., mitoxantrone and irinotecan); notecan); apoptosis inducers (e.g. ABT-737); nucleic acid therapies (e.g. antisense or RNAi); nuclear receptor ligands (e.g. agonists and / or antagonists: all-trans retinoic acid or bexarotene); epigenetic targeting agents such as histone deacetylase inhibitors (e.g. vorinostat), hypomethylating agents (e.g. decitabine); protein stability modulators such as Hsp90 inhibitors, ubiquitin and / or ubiquitin-like conjugating or deconjugating molecules; or EGFR inhibitors (erlotinib).

[0223] Drug preparations and dosage forms

[0224] When used as a medicament, the compounds of the present invention can be administered in the form of a pharmaceutical composition. These compositions can be prepared in a well-known manner in the pharmaceutical field and can be administered by various routes, depending on whether local or systemic treatment is desired and the area to be treated. Administration can be surface (including transdermal, epidermal, ocular and applied to mucous membranes, including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or blowing of powder or aerosol, including by a nebulizer; intratracheal or intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial (e.g., intrathecal or intraventricular) administration. Parenteral administration may be in the form of a single bolus dose, or may be performed, for example, by a continuous infusion pump. Pharmaceutical compositions and preparations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners, etc. may be necessary or desired.

[0225] In some embodiments, the administering is topical. In some embodiments, the administering is topical to the skin.

[0226] In some embodiments, administration is oral.

[0227] The present invention also includes pharmaceutical compositions containing (as active ingredients) a compound of the present invention or a pharmaceutically acceptable salt thereof and a combination of one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the composition is suitable for topical administration. When preparing the composition of the present invention, the active ingredient is usually mixed with an excipient, diluted by the excipient or enclosed in such a carrier in the form of, for example, a capsule, a sachet, paper or other container. When the excipient is used as a diluent, it can be a solid, semisolid or liquid material, which is used as a medium, carrier or medium for the active ingredient. Therefore, the composition can be in the form of tablets, pills, powders, lozenges, sachets, pills, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments (containing, for example, up to 10% by weight of active compounds), soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

[0228] When preparing a formulation, the active compound may be ground to provide an appropriate particle size before combining with other ingredients. If the active compound is substantially insoluble, it may be ground to a particle size of less than 200 mesh. If the active compound is substantially soluble in water, the particle size may be adjusted by grinding to provide a substantially uniform distribution (e.g., about 40 mesh) in the formulation.

[0229] The compounds of the invention may be ground using known grinding procedures (such as wet grinding) to obtain particle sizes suitable for tablet forms and other formulation types. Finely divided (nanoparticulate) preparations of the compounds of the invention may be prepared by processes known in the art, for example, see International Application No. WO 2002 / 000196.

[0230] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup and methylcellulose. The formulation may additionally include: lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl hydroxybenzoate and propyl hydroxybenzoate; sweeteners; and flavoring agents. The compositions of the present invention can be formulated using procedures known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a patient.

[0231] In some embodiments, the pharmaceutical composition comprises silicified microcrystalline cellulose (SMCC) and at least one compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the silicified microcrystalline cellulose comprises about 98% microcrystalline cellulose and about 2% silicon dioxide (w / w).

[0232] In some embodiments, the composition is a sustained release composition comprising at least one compound described herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. In some embodiments, the composition comprises at least one compound described herein or a pharmaceutically acceptable salt thereof and at least one component selected from microcrystalline cellulose, lactose monohydrate, hydroxypropyl methylcellulose and polyethylene oxide. In some embodiments, the composition comprises at least one compound described herein or a pharmaceutically acceptable salt thereof and microcrystalline cellulose, lactose monohydrate and hydroxypropyl methylcellulose. In some embodiments, the composition comprises at least one compound described herein or a pharmaceutically acceptable salt thereof and microcrystalline cellulose, lactose monohydrate and polyethylene oxide. In some embodiments, the composition further comprises magnesium stearate or silicon dioxide. In some embodiments, microcrystalline cellulose is Avicel PH102 TM In some embodiments, lactose monohydrate is Fast-flo 316 TM In some embodiments, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208K4M (e.g., Methocel K4 M Premier TM ) and / or hydroxypropyl methylcellulose 2208K100LV (e.g. Methocel K00LV TMIn some embodiments, the polyethylene oxide is polyethylene oxide WSR1105 (e.g., Polyox WSR 1105 TM ).

[0233] In some embodiments, a wet granulation process is used to produce the composition.In some embodiments, a dry granulation process is used to produce the composition.

[0234] The composition can be formulated into a unit dosage form, each dose containing about 1 mg to about 1,000 mg, about 1 mg to about 100 mg, 1 mg to about 50 mg, and about 1 mg to 10 mg of active ingredient. Preferably, the dose is about 1 mg to about 50 mg or about 1 mg to about 10 mg of active ingredient. In some embodiments, each dose contains about 10 mg of active ingredient. In some embodiments, each dose contains about 50 mg of active ingredient. In some embodiments, each dose contains about 25 mg of active ingredient. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect and a suitable pharmaceutical excipient.

[0235] In some embodiments, the composition comprises about 1 mg to about 1,000 mg, about 1 mg to about 100 mg, 1 mg to about 50 mg, and about 1 mg to 10 mg of active ingredient. Preferably, the composition comprises about 1 mg to about 50 mg or about 1 mg to about 10 mg of active ingredient. One of ordinary skill in the art will appreciate that this is embodied as a compound or composition containing about 1 mg to about 10 mg, about 1 mg to about 20 mg, about 1 mg to about 25 mg, about 1 mg to about 50 mg of active ingredient.

[0236] In some embodiments, the dose of the compound or its pharmaceutically acceptable salt is about 10-90 mg based on the free base. In some embodiments, the dose of the compound or its pharmaceutically acceptable salt is about 15-75 mg based on the free base. In some embodiments, the dose of the compound or its pharmaceutically acceptable salt is 15, 30, 45 or 75 mg based on the free base. In some embodiments, the dose is 15, 30, 45 or 75 mg of compound 4 of Table 1 or its pharmaceutically acceptable salt based on the free base. In some embodiments, the dose of the compound or its pharmaceutically acceptable salt is 15 mg based on the free base. In some embodiments, the dose of the compound or its pharmaceutically acceptable salt is 30 mg based on the free base. In some embodiments, the dose of the compound or its pharmaceutically acceptable salt is 45 mg based on the free base. In some embodiments, the dose of the compound or its pharmaceutically acceptable salt is 75 mg based on the free base.

[0237] The active compound is effective within a wide dosage range and is generally administered in a pharmaceutically effective amount. However, it should be understood that the actual amount of the compound administered will generally be determined by a physician based on relevant circumstances including the condition to be treated, the selected route of administration, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0238] The active compounds described herein (such as JAK1 inhibitors) may have long half-lives. Once steady state is reached (e.g., after 24 hours of dosing), the long half-life of JAK inhibitors provides good peak and trough levels of availability. Unlike JAK inhibitors, for example, omalizumab is typically administered at a higher dose than the study level (600 mg per month) for more refractory patients.

[0239] In order to prepare solid compositions (such as tablets), the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the compound of the present application. When these preformulation compositions are referred to as homogeneous, the active ingredient is generally evenly dispersed throughout the composition, so that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the above-mentioned type containing, for example, about 0.1 mg to about 1000 mg of the active ingredient of the present application.

[0240] The tablet or pill of the present application can be coated or otherwise compounded to provide a dosage form with a prolonged effect advantage. For example, the tablet or pill can include an inner dosage component and an outer dosage component, the latter being a coated form of the former. The two components can be separated by an enteric layer, which is used to resist the decomposition in the stomach and allow the inner component to enter the duodenum intact or delay release. Such enteric layers or coatings can use a variety of materials, including a large amount of polymeric acids and mixtures of polymeric acids with materials such as shellac, hexadecanol and cellulose acetate.

[0241] Liquid forms in which the compounds and compositions of the present application may be incorporated for oral or injection administration include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions and emulsions flavored with edible oils (such as cottonseed oil, sesame oil, coconut oil or peanut oil), as well as elixirs and similar pharmaceutical vehicles.

[0242] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered by oral or nasal respiratory route to obtain local or systemic effects. The composition may be atomized by the use of an inert gas. The atomized solution may be breathed directly from the atomizing device or the atomizing device may be connected to a mask, curtain, or intermittent positive pressure breathing machine. The solution, suspension, or powder composition may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0243] Topical preparations may contain one or more conventional carriers. In some embodiments, ointments may contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white vaseline, etc. The carrier composition of a cream may be based on a combination of water with glycerol and one or more other components (e.g., glyceryl monostearate, PEG-glyceryl monostearate, and cetearyl alcohol). Gels may be formulated using isopropyl alcohol and water in combination with other components (such as glycerol, hydroxyethyl cellulose, etc.). In some embodiments, topical preparations contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5wt% of the compounds of the present invention. Topical preparations may be suitably packaged in, for example, a 100g tube, which may optionally be provided with instructions for treating selected indications (e.g., psoriasis or other skin disorders).

[0244] The amount of the compound or composition administered to a patient will vary depending on the drug being administered, the purpose of the administration (such as prevention or therapy), the patient's condition, the mode of administration, etc. In therapeutic applications, the composition can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will depend on the disease condition being treated and the judgment of the attending clinician based on factors such as the severity of the disease, the patient's age, weight, and general condition.

[0245] The composition administered to the patient may be in the form of the above-mentioned pharmaceutical composition. These compositions can be sterilized by conventional sterilization techniques, or can be aseptically filtered. The aqueous solution can be packaged for use as is, or it can be lyophilized, and the lyophilized preparation is combined with a sterile aqueous carrier before administration. The pH of the compound preparation is generally between 3 and 11, more preferably 5 to 9 and most preferably 7 to 8. It should be understood that the use of some of the aforementioned excipients, carriers or stabilizers will form a pharmaceutical salt.

[0246] The therapeutic dose of the compound of the present application may vary according to factors such as the following: the specific use for treatment, the mode of administering the compound, the health and physical condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of the compound of the present invention in the pharmaceutical composition may vary depending on factors including dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. For example, the compound of the present invention may be provided for parenteral administration in a physiologically buffered aqueous solution containing about 0.1 to about 10% w / v of the compound. Some typical dosage ranges are about 1 μg / kg body weight / day to about 1 g / kg body weight / day. In some embodiments, the dosage range is about 0.01 mg / kg body weight / day to about 100 mg / kg body weight / day. The dosage may depend on variables such as the type and degree of progression of the disease or condition, the overall health status of a particular patient, the relative biological efficacy of the selected compound, the formulation of the excipient, and its route of administration. The effective dose can be obtained by extrapolation of a dose-response curve obtained from an in vitro or animal model test system.

[0247] The compositions of the invention may also include one or more additional pharmaceutical agents, examples of which are listed above.

[0248] Reagent test kit

[0249] The application also includes a drug kit that can be used, for example, to treat and / or prevent cytokine-related diseases or conditions (such as CRS), including one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound described herein. As should be apparent to those skilled in the art, such kits may also include one or more of various conventional drug kit components (such as containers with one or more pharmaceutically acceptable carriers, additional containers, etc.) if necessary. The kit may also include instructions (in the form of inserts or labels) indicating the amount of components to be administered, administration guidelines, and / or component mixing guidelines.

[0250] Example

[0251] The present invention will be described in more detail by specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any way. Those skilled in the art will readily recognize various non-critical parameters that may be changed or modified to produce substantially the same result.

[0252] Example A: In vitro JAK kinase assay

[0253] According to the following in vitro analysis described in Park et al., Analytical Biochemistry 1999, 269, 94-104, the inhibitory activity of JAK1 inhibitors that can be used to treat cytokine-related diseases or disorders on JAK targets was tested. The catalytic domains with N-terminal His tags in human JAK1 (aa837-1142), JAK2 (aa828-1132) and JAK3 (aa781-1124) were expressed in insect cells using baculovirus and purified. The catalytic activity of JAK1, JAK2 or JAK3 was analyzed by measuring the phosphorylation of biotinylated peptides. Phosphorylated peptides were detected by homogeneous time-resolved fluorescence (HTRF). The IC of the compound for each kinase was measured in a 40 μL reaction containing enzyme, ATP and 500 nM peptide in 50 mM Tris (pH 7.8) buffer containing 100 mM NaCl, 5 mM DTT and 0.1 mg / mL (0.01%) BSA. 50 For 1mM IC 50 For measurement, the ATP concentration in the reaction was 1 mM. The reaction was carried out at room temperature for 1 hour and then stopped with 20 μL 45 mM EDTA, 300 nM SA-APC, 6 nM Eu-Py20 in an assay buffer (PerkinElmer, Boston, MA). The binding with the europium labeled antibody occurred for 40 minutes and the HTRF signal was measured on a Fusion plate reader (Perkin Elmer, Boston, MA). The compounds in Table 1 were tested in this analysis and the compounds were shown to have IC values ​​in Table 1. 50 value.

[0254] Embodiment B:

[0255] Upregulation of JAK-STAT pathway

[0256] RNA was isolated from paraffin-embedded (FFPE) skin biopsy sheets fixed by formalin from active disease, untreated urticaria patients. RNA was processed using nCounter autoimmune analysis code set (770 genes) or neuropathology analysis code set (770 genes) (Nanostring, USA) according to the manufacturer's scheme. After 18h hybridization, samples were run on nCounter SPRINT analyzer (Nanostring, USA). Data were analyzed using nSolver 4.0Advanced analysis software (Nanostring, USA). P value was adjusted using Benjamini-Ye kutieli false discovery rate method.

[0257] Pharmacological inhibition of JAK1-mediated regulation in PN pathophysiology

[0258] Full-thickness skin biopsy pieces were obtained from patients with untreated active disease and untreated urticaria. Single 4mm puncture biopsy pieces were obtained from the same lesions of each patient and were divided into two pieces longitudinally. The biopsy pieces were cultured in KBM culture medium + CaCl2 for 8 days and updated every 2-3 days. Compounds or DMSO (control) were added to the cell culture medium. The conditioned supernatant collected before the culture medium was updated was stored at -80 ° C until subsequent analysis. On the 8th day, culture was terminated and tissue RNA was isolated for subsequent analysis. According to the manufacturer's scheme, RNA was processed using nCounter autoimmune analysis code set (770 genes) or neuropathology analysis code set (770 genes) (Nanostring, USA). After 18h hybridization, samples were run on nCounter SPRINT analyzer (Nanostring, USA). Data were analyzed using nSolver 4.0Advanced analysis software (Nanostring, USA). P value was adjusted using Benjamini-Yekutieli false discovery rate method.

[0259] Example C:

[0260] Upregulation of JAK-STAT pathway

[0261] Signature pathway analysis was performed on publicly available data from two published studies to help determine gene expression profiles in CSU: Gimenez-Arnau et al. (https: / / pubmed.ncbi.nlm.nih.gov / 28407332 / ) and Patel et al. (https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC4541630 / ), both of which are incorporated by reference. After analyzing these data for signature pathways, 22 pre-defined pathways were identified as upregulated in the skin of CSU patients, including a signature inflammatory response pathway, a signature interferon gamma response pathway, and a signature IL6 J AK STAT3 signaling pathway.

[0262] Pharmacological inhibition of JAK1 in the pathophysiology of CSU

[0263] Full-thickness skin biopsy sheets were obtained from active disease, untreated urticaria patients. Single 4mm puncture biopsy sheets were obtained from the same lesions of each patient and were divided into two sheets longitudinally. With or without compound (i.e., compound 1) or DMSO (control), biopsy sheets were cultured in KBM culture medium + CaCl2 for 24 hours. After 24 hours, tissue RNA was isolated for subsequent analysis. RNA extracts were quantified using Qubit fluorometer (Invitrogen) and quality was evaluated by TapeStation automated electrophoresis (Agilent Technologies). Total RNA (250ng) processed by amplification grade DNase I (Invitrogen) was enriched for non-ribosomal RNA using NEBNext rRNA depletion kit v2 (New England BioLabs). The manufacturing scheme (Section 2) of the library preparation of the RNA of complete or partial degradation was followed, and library preparation was performed using NEBNext Ultra II directional RNA library preparation kit (Illumina, New England BioLabs). For comparability, all samples used the same scheme. RNA-seq libraries were pooled and double-end sequencing was performed on NextSeq 2000 (Illumina), with an average sequencing depth of 200M reads. FASTQ files were processed with the Nextflow RNASeq pipeline (v.22.10.1). Differentially expressed genes (DEGs) were identified by normalizing gene counts with the DESeq2 package in R (v.4.1.1) and applying a log2 fold change cutoff of 1.5. The effects of JAK1 inhibition using compound 1 on the DEGs identified in the previous analysis were further evaluated. In addition to the above-mentioned pathway analysis, individual differentially expressed genes (DEGs) in the Gimenez-Arnau and Patel studies were also compared to identify the unique CSU gene signatures shared by the two studies. Differential expression analysis was performed between lesional skin versus non-lesional skin, lesional skin versus healthy skin, and non-lesional skin versus healthy skin. Non-lesional versus healthy comparisons did not produce any differentially expressed genes in either study. Based on this analysis, seven genes were found to contribute to the disease (CCL2, S100A8, SELE, PTX3, MT2A, NNMT, TNFAIP6), of which four were associated with diseased skin (CCL2, S100A8, SELE, and PTX3). Finally, the effects of JAK inhibition on cultured CSU skin involving these four genes were examined. All four genes, CCL2, S100A8, SELE, and PTX3, showed altered expression in the presence of JAK1 inhibition. Figure 1As can be seen in Figure 2, PTX3 expression in CSU skin was significantly reduced after 24 hours of treatment with JAK1 inhibition ex vivo. These results indicate the effectiveness of JAK1 inhibitors (particularly Compound 1) in treating CSU.

[0264] Embodiment D:

[0265] Phase 2 study

[0266] A phase 2 randomized, double-blind, placebo-controlled, dose-ranging study of the efficacy and safety of the JAK inhibitor compound 1 (4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide or a pharmaceutically acceptable salt thereof) in the treatment of patients with CSU (chronic spontaneous urticaria) is described. Figure 2 An overview of a Phase 2 randomized, double-blind, placebo-controlled, dose-ranging study of the efficacy and safety of Compound 1 is described. This study is a Phase 2, double-blind, placebo-controlled, multicenter study of Compound 1 with a second generation H1 antihistamine for stable SOC in participants with CSU. The study will include a maximum of 28 days of screening, 36 weeks of continuous treatment (including PC and EXT phases), and 60 (± 7) days of follow-up after the last dose of study drug. It is estimated that individuals will participate for approximately 11 months.

[0267] In some embodiments, the dosage will be administered orally via tablets. The dosage should be 15 mg, 45 mg or 75 mg of compound 1. The dosage can be administered in the form of 1 or more 15 mg tablets. Unless otherwise indicated by the site staff, compound 1 or matching placebo will be taken orally QD with water at approximately the same time every day. The study drug may be taken with or without food. Note: During the visit, the dose should be administered at the study site. Participants should stop self-administration on those visits. All participants should need to maintain a stable dose of a second-generation H1 antihistamine as background therapy (SOC) and cannot change throughout the study.

[0268] The Screening Period may include 28 days. The Study Period may include 12 weeks. The EXT Period may include 24 weeks.

[0269] Inclusion criteria for study participants included having CSU refractory to treatment with second-generation H1 antihistamines, as defined by one or more of the following:

[0270] a. Persistent (nearly daily) pruritus and urticaria for >6 weeks at any time prior to Screening, despite current use of a second generation H1 antihistamine consistent with the SOC during this time period.

[0271] b. UAS7 ≥ 16 within 7 days prior to randomization (Day 1). - NOTE: Participants must have at least 5 non-missing UAS daily scores within 7 days prior to Day 1 to calculate UAS7.

[0272] c. Participants must have been taking a stable dose of a second generation H1 antihistamine (consistent with SOC therapy for CSU) for at least 3 consecutive days starting prior to the Screening Visit until Day 1, and must agree to maintain a stable dose of a second generation H1 antihistamine throughout the study and have its use documented.

[0273] Inclusion criteria for study participants included willingness to use contraception. The study could include men and women aged 18 to 65 years who had CSU for at least 3 months.

[0274] In some embodiments, criteria for excluding participants from the study include any of the following: treatment with an anti-IgE biologic (e.g., omalizumab) within 8 weeks prior to screening; chronic urticaria with a clear primary or sole trigger (chronic induced urticaria), including artificial urticaria (symptomatic dermatographism), cold-, heat-, solar-, pressure-, delayed pressure-, aquagenic-, cholinergic-, or contact urticaria; other skin or systemic diseases with symptoms of urticaria or angioedema; other skin or systemic diseases associated with chronic pruritus (e.g., AD, bullous pemphigoid, dermatitis herpetiformis, senile pruritus, or psoriasis); or women are pregnant or considering pregnancy or are breastfeeding. In some embodiments, criteria for excluding participants from the study include any of the following concurrent conditions: thrombocytopenia, coagulopathy, or platelet dysfunction; venous and arterial thrombosis, deep vein thrombosis, pulmonary embolism, stroke, moderate to severe heart failure (NYHA class III or IV), cerebrovascular accident, MI, coronary artery stenting, or CABG surgery; diagnosis of other serious cardiovascular disease, including but not limited to angina, peripheral arterial disease, or uncontrolled arrhythmias (such as atrial fibrillation, supraventricular tachycardia, ventricular tachycardia, and various forms of carditis); uncontrolled hypertension, as defined as confirmed systolic blood pressure >160 mm Hg or diastolic blood pressure >100 mm Hg; participants are chronically bedridden or require wheelchair assistance; organ transplant recipients require continuous immunosuppression; any malignancy or history of malignancy, except appropriately treated or resected non-metastatic basal cell or squamous cell skin cancer or in situ cervical cancer; conditions that may interfere with drug absorption, including but not limited to short bowel syndrome; chronic or recurrent infectious disease, including but not limited to chronic kidney infection, chronic chest infection (e.g., bronchiectasis), recurrent urinary tract infection (recurrent pyelonephritis or chronic persistent cystitis), fungal infection, previous infection of a prosthetic joint at any time, or open, draining, or infected skin wounds or ulcers; current or past herpes zoster, either disseminated or recurrent (more than one episode) dermatomal herpes zoster; current or Past history of pervasive herpes simplex; active systemic infection or any active infection that, based on the investigator's clinical evaluation, makes the participant an unsuitable candidate for the study; any other active skin disease or condition (e.g., bacterial, fungal, or viral infection) that could interfere with the course, severity, or evaluation of CSU; any clinically significant medical condition (other than CSU) or any other reason determined by the investigator that would interfere with the participant's participation in the study or would make the participant an unsuitable candidate for receiving the study drug or would place the participant at risk by participating in the study; any clinically significant medical condition other than CSU that, as determined by the investigator, cannot be adequately controlled with appropriate treatment or that could interfere with the course, severity, or evaluation of CSU; or albinism.

[0275] In some embodiments, the criteria for excluding participants from the study include screening 12-lead ECGs showing clinically significant abnormalities requiring treatment (e.g., acute MI, severe tachyarrhythmias, or bradyarrhythmias) or indications of severe underlying heart disease (e.g., cardiomyopathy, major congenital heart disease, low voltage in all leads, Wolff-Parkinson-White syndrome) or criteria related to abnormal Q wave intervals (QT) / Fridericia-corrected Q wave intervals (QTcF). In some embodiments, the criteria for excluding participants from the study include severe trauma or major surgery within 30 days prior to the screening visit (according to the evaluation of the researcher). In some embodiments, the criteria for excluding participants from the study include drug or alcohol abuse; use of any systemic or surface JAK inhibitors to treat failure; receiving medical treatment or study drugs within a predetermined time period before starting the trial; or being recruited in another clinical study at the same time. At the screening visit, any laboratory abnormality is defined in Table 2.

[0276] Table 2

[0277]

[0278]

[0279] In some embodiments, the criteria for excluding participants from the study include any of the following: evidence of Mycobacterium tuberculosis infection; active HIV or acquired immunodeficiency syndrome; evidence of HBV or HCV infection or risk of reactivation; known allergic or severe reaction to Compound 1 or an excipient of Compound 1; or any condition, laboratory result, or screening evaluation result that, in the judgment of the investigator and sponsor (or designer), would interfere with full study participation.

[0280] In some embodiments, the efficacy of the treatment methods disclosed herein can be established based on the change from baseline in UAS7, defined as the 7-day sum of the individual daily recorded scores of HSS and ISS at Week 12. The efficacy of the treatment methods disclosed herein can be established based on the proportion of participants who achieve UAS7≤6 (controlled disease) at Week 12; the time to first achievement of UAS7≤6 (controlled disease) during the PC period; or the proportion of participants with UAS7=0 at Week 12.

[0281] The efficacy of the treatment methods disclosed herein can be established based on a reduction in wheal severity. Urticaria severity can be assessed based on the following: weekly change from baseline in HSS7 at each visit until Week 36; the proportion of participants with HSS7=0 at Week 12; or the time to first achieving an HSS7 MID (≥5 points) improvement from baseline until Week 36.

[0282] The efficacy of the treatment methods disclosed herein can be established based on a reduction in itch severity. Pruritus severity can be assessed based on the following: change from baseline in ISS7 per week at each visit until Week 36; proportion of participants with ISS7=0 at Week 12; or time to first achieving an ISS7 MID (≥5 points) improvement from baseline until Week 36.

[0283] The efficacy of the treatment methods disclosed herein can be established based on a reduction in the severity of angioedema. Angioedema severity can be assessed based on the following: weekly change from baseline in AAS7 at each visit until Week 36; the proportion of participants with AAS7=0 at Week 12; or the time to first achieving an AAS7 MID (≥5 points) improvement from baseline until Week 36.

[0284] The efficacy of the treatment methods disclosed herein can be established based on disease control. Disease control can be assessed based on the following: change from baseline in UCT7 at each visit until week 36; time to first improvement from baseline in UAS7 ≥ 9.5 points until week 36; proportion of participants requiring treatment of CSU with corticosteroids from baseline until week 36; proportion of participants requiring rescue treatment of CSU with another second generation H1 antihistamine from baseline until week 36; or time to first rescue therapy from baseline until week 36.

[0285] The efficacy of the treatment methods disclosed herein can be established based on quality of life and other PROs. Quality of life can be assessed based on the following: change from baseline in DLQI score at a designated visit through Week 36; change from baseline in CU-Q2oL score at a designated visit through Week 36; change from baseline in WPAI-CU score at a designated visit through Week 36; change from baseline in AE-QoL score at a designated visit through Week 36; change from baseline in EQ-5D-5L score at a designated visit through Week 36; proportion of participants achieving a ≥4-point reduction in DLQI score through Week 36; proportion of participants with a DLQI score of 0 or 1 at Week 12; change from baseline in PGI-C at a designated visit through Week 36; or change from baseline in PGI-S at a designated visit through Week 36.

[0286] The efficacy of the treatment methods disclosed herein can be established based on the maintenance of response during the EXT phase. Maintenance of response during the EXT phase can be assessed based on the proportion of participants who achieve UAS7≤6 at Week 12 and maintain or improve their response at each visit until Week 36 or EOT2; or the proportion of participants who achieve UAS7=0 at Week 12 and maintain their response at each visit until Week 36 or EOT2.

[0287] The efficacy of the treatment methods disclosed herein can be established based on the persistence of response during the post-treatment follow-up period. The persistence of response during the post-treatment follow-up period can be assessed based on the following: the change from baseline in HSS7 per week during the post-treatment follow-up period (EOT2 to EOS); the change from baseline in ISS7 per week during the post-treatment follow-up period (EOT2 to EOS); the change from baseline in AAS7 per week during the post-treatment follow-up period (EOT2 to EOS); the proportion of participants who used rescue medication during the post-treatment follow-up period (EOT2 to EOS); or the time of using rescue medication during the post-treatment follow-up period (EOT2 to EOS).

[0288] The efficacy of the treatment methods disclosed herein can be established by characterizing PK and determining systemic exposure. PK can be characterized and systemic exposure can be determined based on the following: plasma concentration of Compound 1 at a specified time point; or model-predicted PK exposure at steady state, such as peak concentration, trough concentration, and mean concentration, as well as time to peak value and terminal elimination half-life.

[0289] The efficacy of the treatment methods disclosed herein can be established based on participant heterogeneity and the effects of Compound 1 on blood biomarkers. Participant heterogeneity and the effects of Compound 1 on blood biomarkers can be assessed based on: the expression level of the biomarker in peripheral blood before and / or after Compound 1 treatment; or the change in biomarker expression in peripheral blood from baseline after Compound 1 treatment.

[0290] Statistical analysis

[0291] In some embodiments, a primary analysis will be performed in the full analysis set (FAS). A mixed model of repeated measures (MMRM) will be used to evaluate the mean change of UAS7 scores from baseline per week at week 12, including all available data from the placebo-controlled (PC) phase until the 12th week at the post-baseline visit. Participants with at least 1 post-baseline value in the baseline and PC phase will be included in the analysis. MMRM will include the change from baseline to week 12 (as a response variable), as well as the fixed effects of the covariates of the treatment group, randomization stratification factors (previous use of anti-IgE biologics [yes or no]), visits, treatment visit interactions, and baseline values ​​and baseline value visit interactions. An unstructured covariance matrix will be assumed for intra-participant errors. If the model using an unstructured variance covariance does not converge, a composite symmetric covariance matrix will be used. The Kenward-Roger method will be used to estimate degrees of freedom. Missing data will not be entered. The least squares mean estimate for each treatment group and the associated covariance matrix obtained from the MMRM will be provided and further used in the generalized MCP-mod framework.

[0292] In some embodiments, in the MCP stage, contrast test statistics and multiple adjusted p-values ​​for the contrast tests will be provided for each predetermined candidate model. If at least one model in the set of 6 predetermined candidate models is identified as statistically significant in the α=0.025 level one-sided trend test, a dose-response relationship will be declared. Once a significant dose-response is established, the Akaike Information Criterion will be used to select the best model.

[0293] In some embodiments, in the Mod stage, the selected model will be used to obtain dose-response curves and 95% CIs.

[0294] In some embodiments, a secondary efficacy analysis will be performed in the FAS as a primary analysis. The odds ratio and corresponding 95% CI for the proportion of participants with UAS7≤6 at Week 12 in each Compound 1 group and placebo group will be estimated using logistic regression with treatment and stratification factors (prior use of anti-IgE biologics [yes or no]). All participants who do not achieve UAS7≤6 in the PC period and all participants with missing post-baseline values ​​will be defined as non-responders for non-responder imputation analysis.

[0295] Logistic regression was used to estimate the odds ratio and corresponding 95% CI for the proportion of participants with UAS7=0 at Week 12 in each Compound 1 group and placebo group using treatment and stratification factors (prior use of anti-IgE biologics [yes or no]). All participants who did not achieve UAS7=0 during the PC period and all participants with missing post-baseline values ​​will be defined as non-responders for non-responder imputation analysis.

[0296] The time to first achievement of UAS7≤6 during the PC period will be defined as the time from the date of randomization until the earliest date of achievement of UAS7≤6 during the PC period. Participants who do not achieve UAS7≤6 during the PC period will be censored at the time of the last available UAS7 measurement. The summary of the time to first achievement of UAS7≤6 during the PC period will be evaluated using the Kaplan-Meier method, and the estimated Kaplan-Meier curves will be presented graphically.

[0297] All other secondary efficacy variables will be summarized using descriptive statistics. For categorical measures, the summary statistics will include the number and percentage of participants in each category. For continuous measures, the summary statistics will include the number of observations, mean, median, STD, minimum, and maximum. If applicable, summary statistics for continuous measures will be provided for baseline, actual measurements at each visit, and change and percentage change from baseline at each visit.

[0298] In some embodiments, safety analysis will be performed for the safety population. Adverse events will be coded by the MedDRA dictionary, and TEAEs (i.e., AEs first reported after the first dose of study drug and up to 60 days after the last dose of study drug or exacerbation of pre-existing events) will be tabulated according to priority and system organ class for all events, related events, and Grade 3 or higher events.

[0299] In some embodiments, if applicable, descriptive statistics are used to summarize all exploratory efficacy variables. For categorical measurements, the summary statistics will include the number and percentage of participants in each category. For continuous measurements, the summary statistics will include the number of observations, mean, median, STD, minimum and maximum values. If applicable, the summary statistics of continuous measurements will be provided for baseline, actual measurements at each visit, and changes and percentage changes relative to baseline at each visit.

[0300] In some embodiments, pharmacokinetic analysis will be performed on the PK evaluable population. The plasma concentration data of compound 1 will be analyzed by population PK modeling. Such data can be combined with data from other studies in the clinical development program to develop or refine a population PK model, wherein the population of healthy participants, participants with moderate to severe asthma, and / or participants with other diseases will be assessed and included in the model (if significant as a covariate). This model can be used to assess the effects of intrinsic and extrinsic covariates on the PK of compound 1 and measure individual plasma exposure (such as steady-state peak concentrations, trough concentrations, and / or time-averaged concentrations). Population PK analysis will be reported separately.

[0301] In some embodiments, the exposure-response analysis framework will be used to explore the relationship between compound 1PK exposure and clinical response (efficacy and safety) when it is considered appropriate. For dichotomous endpoints, a generalized linear or nonlinear model using a binomial link function is used. For continuous endpoints, linear or nonlinear regression is used. When supported by data, random effects for inter-individual variability will be considered. Clinical responses (such as primary and secondary efficacy reactions) and TEAEs with an incidence rate of >10% will be analyzed. Exposure-response analysis will be reported separately.

[0302] In addition to those described herein, it will be apparent to those skilled in the art that various modifications of the present invention will be apparent from the foregoing description. Such modifications are also intended to be within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications and publications) is incorporated herein by reference in its entirety.

Claims

1. A method for treating urticaria in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound that inhibits JAK1 or a pharmaceutically acceptable salt thereof, wherein the compound is: {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide; [3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; 4-[3-(Cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide; ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile; 3-[1-(6-chloropyridin-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propionitrile; 3-(1-[1,3]oxazolo[5,4-b]pyridin-2-ylpyrrolidin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propionitrile; 4-[(4-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperazin-1-yl)carbonyl]-3-fluorobenzonitrile; 4-[(4-{3-cyano-2-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]propyl}piperazin-1-yl)carbonyl]-3-fluorobenzonitrile; [trans-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-(4-{[2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)cyclobutyl]acetonitrile; {trans-3-(4-{[4-[(3-hydroxyazetidin-1-yl)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile; {trans-3-(4-{[4-{[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile; {trans-3-(4-{[4-{[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile; 4-(4-{3-[(dimethylamino)methyl]-5-fluorophenoxy}piperidin-1-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile; 5-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropylpyrazine-2-carboxamide; 4-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide; 5-{3-(Cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropylpyrazine-2-carboxamide; {1-(cis-4-{[6-(2-hydroxyethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(cis-4-{[4-[(ethylamino)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(cis-4-{[4-(1-hydroxy-1-methylethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(cis-4-{[4-{[(3R)-3-hydroxypyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(cis-4-{[4-{[(3S)-3-hydroxypyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {trans-3-(4-{[4-({[(1S)-2-hydroxy-1-methylethyl]amino}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile; {trans-3-(4-{[4-({[(2R)-2-hydroxypropyl]amino}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile; {trans-3-(4-{[4-({[(2S)-2-hydroxypropyl]amino}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile; {trans-3-(4-{[4-(2-hydroxyethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile; or a pharmaceutically acceptable salt of any one of the foregoing.

2. The method of claim 1, wherein the compound or salt is selective for JAK1 over JAK2, JAK3 and TYK2.

3. The method of any one of claims 1-2, wherein the compound is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile or a pharmaceutically acceptable salt thereof.

4. The method of any one of claims 1-2, wherein the salt is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile adipate.

5. The method of any one of claims 1-2, wherein the compound is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide or a pharmaceutically acceptable salt thereof.

6. The method of any one of claims 1-2, wherein the salt is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide phosphate.

7. The method of any one of claims 1-2, wherein the compound is ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile or a pharmaceutically acceptable salt thereof.

8. The method of any one of claims 1-2, wherein the compound is ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile monohydrate.

9. The method of any one of claims 1-8, wherein the compound or salt is administered at a dose of 15, 30, 45 or 75 mg calculated as the free base.

10. The method of any one of claims 1-8, wherein the compound or salt is administered at a dose of 15, 45 or 75 mg as free base.

11. The method of any one of claims 1-8, wherein the compound or salt is administered at a dose of 15 mg or 45 mg as the free base.

12. The method of any one of claims 1-11, further comprising administering another therapeutic agent.

13. The method of claim 12, wherein the additional therapeutic agent is an antihistamine.

14. The method of claim 13, wherein the antihistamine is a second generation H1 antihistamine.

15. The method of claim 12, wherein the additional therapeutic agent is an antibiotic, a retinoid, a corticosteroid, an anti-TNF-a agent, or an immunosuppressant.

16. The method of claim 15, wherein the antibiotic is clindamycin, doxycycline, minocycline, cotrimoxazole, erythromycin, metronidazole, rifampicin, moxifloxacin, dapsone, or a combination thereof.

17. The method of claim 15, wherein the retinoid is acitretin, acitretin or isotretinoin.

18. The method of claim 15, wherein the corticosteroid is triamcinolone acetonide, dexamethasone, fluocinolone, cortisone, prednisone, prednisolone, or fluorometholone.

19. The method of claim 15, wherein the anti-TNF-α agent is infliximab, etanercept, or adalimumab.

20. The method of claim 15, wherein the immunosuppressant is methotrexate, cyclosporin A, mycophenolate mofetil, or mycophenolate sodium.

21. The method of claim 15, wherein the additional therapeutic agent is finasteride, metformin, adapalene, or azelaic acid.

22. The method of any one of claims 1-21, wherein said administration of said compound or salt is topical.

23. The method of any one of claims 1-21, wherein said administration of said compound or salt is oral.

24. The method of any one of claims 1-23, wherein the method improves the number and / or size of redness by about 10% to about 90%.

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