Combination therapy comprising apremilast and TYK2 inhibitor

Abstract

The present invention provides methods of treating diseases and disorders responsive to inhibition of PDE4 comprising administering to a subject apremilast and a Tyk2 inhibitor. The present invention also provides a pharmaceutical composition comprising apremilast and a Tyk2 inhibitor.

Description

[0001] This application is a divisional application of the Chinese invention patent application with an application date of April 30, 2020, application number 202080046457.X, and invention name “Combination therapy comprising Apremilast and TYK2 inhibitor”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to International Application No. PCT / US2019 / 029772, filed on April 30, 2019, the entire contents of which are hereby incorporated by reference. Background Art

[0004] by Commercially available N-[2-[(1S)1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide (apremilast), is a phosphodiesterase type 4 (PDE4) inhibitor currently approved for the treatment of both moderate to severe plaque psoriasis and active psoriatic arthritis. Inhibition of PDE4 by apremilast increases cyclic adenosine monophosphate (cAMP) levels in immune cells. This in turn downregulates the inflammatory response by reducing the expression of pro-inflammatory mediators such as TNF-α, IL-23, IL-17, and other inflammatory cytokines, and increasing the production of anti-inflammatory mediators. Studies have shown that a 75% reduction in plaque psoriasis can be achieved in some patients in as little as just over 4 months of treatment.

[0005] Tyrosine kinase 2 (Tyk2), an intracellular signaling enzyme, activates signal transducers and activators of transcription (STAT)-dependent IL-12, IL-23 gene expression and functional responses as well as type I and type III interferon receptors. Among other conditions, tyrosine kinase inhibitors (TKIs) have recently gained attention as effective agents for the treatment of psoriasis and related conditions. For example, the TKI inhibitor BMS-986165 recently showed positive results in a Phase II clinical trial of subjects with moderate to severe plaque psoriasis. See Kim Papp, MD, Phase 2 Trial of Selective Tyrosine Kinase 2 Inhibition in Psoriasis, The New England Journal of Medicine, Sept. 12, 2018. Summary of the invention

[0006] It has been found that the combination of Apremilast and the Tyk2 inhibitor 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165) synergistically reduces proinflammatory cytokines expressed in a whole blood assay under conditions that stimulate Th17 cells. For example, the combination of 0.01 μM BMS-986165 and 1 μM Apremilast resulted in greater than a 2-fold increase in inhibition of IL-17F expression when compared to each drug alone. See, e.g., Table 5 in the Examples section. Similar results were observed at 0.1 μM concentrations of BMS-986165 and 1 μM Apremilast. See, e.g., Table 5. The combination of BMS-986165 and 1 μM apremilast also reduced cytokine expression of IL-17A and IL-22 by 2-fold or more compared to each drug alone. See, e.g., Table 5.

[0007] It was also found that the combination of Apremilast and BMS-986165 caused a complementary effect on certain proinflammatory cytokines. For example, BMS-986165 increased TNF-α and GM-CSF cytokines in whole blood assays, while Apremilast inhibited the production of these cytokines. See, for example, Table 5, where the % of the control for TNF-α, 1 μM Apremilast was 10.7, and the % of the control for 0.01 μM BMS-986165 was 143.1. However, when administered in combination, Apremilast corrected the defect of BMS-986165 to produce a complementary effect of 13.5% inhibition of TNF-α. See, for example, Table 5. At a concentration of 0.1 μM BMS-986165, this trend was also established for the cytokine GM-CSF. See, for example, Table 5. These results illustrate the synergistic and complementary pharmacological effects of BMS-986165 and Apremilast.

[0008] In addition to whole blood assays, the combination of BMS-986165 and Apremilast can also cause complementary effects on certain proinflammatory cytokines in LPS-stimulated peripheral blood mononuclear cells (PBMCs). BMS-986165 increases IL-23, IL-12, and TNF-α, while Apremilast inhibits the production of these cytokines. See, for example, Table 6 in the Examples section. These results further support the advantages of combining BMS-986165 and Apremilast in the treatment of Th17-related diseases.

[0009] Therefore, provided herein is a method for treating a disease or disorder responsive to the inhibition of PDE4 in a subject using an effective amount of Apremilast or a pharmaceutically acceptable salt thereof and an effective amount of a Tyk2 inhibitor such as BMS-986165. Such diseases and disorders include, for example, inflammatory diseases such as psoriasis, psoriatic arthritis, and ulcerative colitis.

[0010] Also provided herein is a pharmaceutical composition comprising an effective amount of Apremilast, or a pharmaceutically acceptable salt thereof, and an effective amount of a Tyk2 inhibitor such as BMS-986165. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 Whole blood stimulated with anti-CD3 / anti-CD28 (Th0) or anti-CD3 / anti-CD28, IL-1β, IL-6 and IL-23 (Th17) is shown. Interleukin-17a (IL-17a) cytokine production by Apremilast and BMS-986165 in the tube assay (percent of control).

[0012] Figure 2 Whole blood stimulated with anti-CD3 / anti-CD28 (Th0) or anti-CD3 / anti-CD28, IL-1β, IL-6 and IL-23 (Th17) is shown. Interleukin-17A (IL-17A) cytokine production by apremilast and BMS-986165 in a tube assay.

[0013] Figure 3 Whole blood stimulated with anti-CD3 / anti-CD28 (Th0) or anti-CD3 / anti-CD28, IL-1β, IL-6 and IL-23 (Th17) is shown. Interleukin-17F (IL-17F) cytokine production by Apremilast and BMS-986165 in the tube assay (percent of control).

[0014] Figure 4 Whole blood stimulated with anti-CD3 / anti-CD28 (Th0) or anti-CD3 / anti-CD28, IL-1β, IL-6 and IL-23 (Th17) is shown. Interleukin-17F (IL-17F) cytokine production by apremilast and BMS-986165 in a tube assay.

[0015] Figure 5 Whole blood stimulated with anti-CD3 / anti-CD28 (Th0) or anti-CD3 / anti-CD28, IL-1β, IL-6 and IL-23 (Th17) is shown. Interleukin-22 (IL-22) cytokine production by Apremilast and BMS-986165 in the tube assay (percent of control).

[0016] Figure 6Whole blood stimulated with anti-CD3 / anti-CD28 (Th0) or anti-CD3 / anti-CD28, IL-1β, IL-6 and IL-23 (Th17) is shown. Interleukin-22 (IL-22) cytokine production by apremilast and BMS-986165 in a tube assay.

[0017] Figure 7 Whole blood stimulated with anti-CD3 / anti-CD28 (Th0) or anti-CD3 / anti-CD28, IL-1β, IL-6 and IL-23 (Th17) is shown. Tumor necrosis factor alpha (TNF-α) cytokine production by apremilast and BMS-986165 in the tube assay (percent of control).

[0018] Figure 8 Whole blood stimulated with anti-CD3 / anti-CD28 (Th0) or anti-CD3 / anti-CD28, IL-1β, IL-6 and IL-23 (Th17) is shown. Tumor necrosis factor alpha (TNF-α) cytokine production by apremilast and BMS-986165 in a tube assay.

[0019] Fig. 9 Whole blood stimulated with anti-CD3 / anti-CD28 (Th0) or anti-CD3 / anti-CD28, IL-1β, IL-6 and IL-23 (Th17) is shown. Granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine production by apremilast and BMS-986165 in the tube assay (percent of control).

[0020] Fig.10 Whole blood stimulated with anti-CD3 / anti-CD28 (Th0) or anti-CD3 / anti-CD28, IL-1β, IL-6 and IL-23 (Th17) is shown. Granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine production by apremilast and BMS-986165 in a tube assay.

[0021] Fig.11 Interleukin-23 (IL-23) cytokine production by Apremilast in lipopolysaccharide (LPS) stimulated peripheral blood mononuclear cells (PBMCs) is shown.

[0022] Fig.12 Shown is interleukin-23 (IL-23) cytokine production by Apremilast and Tyk2i (BMS-986165) in LPS-stimulated PBMCs.

[0023] Fig.13 Shown is interleukin-12p40 (IL-12p40) cytokine production by Apremilast and Tyk2i (BMS-986165) in LPS-stimulated PBMCs.

[0024] Fig.14 Shown is interleukin-12p70 (IL-12p70) cytokine production by Apremilast and Tyk2i (BMS-986165) in LPS-stimulated PBMCs.

[0025] Fig.15 Shown is the tumor necrosis factor alpha (TNF-α) cytokine production by Apremilast and Tyk2i (BMS-986165) in LPS-stimulated PBMCs.

[0026] Fig.16 Shown is interferon gamma (IFN-γ) cytokine production by Apremilast and Tyk2i (BMS-986165) in LPS-stimulated PBMCs.

[0027] Fig.17 Shown is the monocyte chemoattractant protein-1 (MCP-1) cytokine production by Apremilast and Tyk2i (BMS-986165) in LPS-stimulated PBMCs.

[0028] Fig.18 Shown is the fixed dose combination effect of Apremilast and Tyk2i (BMS-986165) in IL-17A whole blood.

[0029] Fig.19 Shown is the fixed dose combination effect of Apremilast and Tyk2i (BMS-986165) in IL-17F whole blood.

[0030] Fig. 20 Shown is the fixed dose combination effect of Apremilast and Tyk2i (BMS-986165) in IL-22 whole blood.

[0031] Fig.21 Shown is the fixed dose combination effect of Apremilast and Tyk2i (BMS-986165) in TNF-α whole blood. DETAILED DESCRIPTION

[0032] In a first embodiment, provided herein is a method for treating a disease or disorder responsive to inhibition of cyclic nucleotide phosphodiesterase isozyme IV (PDE4), the method comprising administering to a subject an effective amount of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide (Apremilast), or a pharmaceutically acceptable salt thereof, and an effective amount of a Tyk2 inhibitor.

[0033] Alternatively, as part of a first embodiment, there is provided the use of an effective amount of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide (Apremilast), or a pharmaceutically acceptable salt thereof, and an effective amount of a Tyk2 inhibitor in the preparation of a medicament for treating a disease or disorder responsive to inhibition of cyclic nucleotide phosphodiesterase isozyme IV (PDE4).

[0034] In another alternative, as part of the first embodiment, an effective amount of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide (Apremilast), or a pharmaceutically acceptable salt thereof, and an effective amount of a Tyk2 inhibitor are provided for treating a disease or disorder responsive to said inhibition of cyclic nucleotide phosphodiesterase isozyme IV (PDE4).

[0035] 1. Definition

[0036] N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide (Apremilast) is disclosed in U.S. Patent No. 6,962,940, the contents of which are incorporated herein by reference, and refers to a compound having the following chemical structure:

[0037]

[0038] Apremilast has a chiral center designated as (S) in the chemical structure and name. As used herein, the designated name means that Apremilast is optically enriched as the (S) enantiomer at the position with respect to the corresponding (R) enantiomer at least 80%, 90%, 95%, 98%, 99% or 99.9%. Therefore, when Apremilast is referred to as a stereoisomer or enantiomer-pure under a designated amount in this article, it means that (S) enantiomer is enriched with this amount. For example, at least 95% stereoisomer-pure N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl] acetamide means that the compound contains more than or equal to 95% of the (S) enantiomer and 5% or less of the (R) enantiomer.

[0039] Unless otherwise stated, administration as described herein includes administration of Apremilast before, simultaneously or after administration of the Tyk2 inhibitor described herein. Therefore, simultaneous administration is not necessary for therapeutic purposes. In one aspect, Apremilast and the disclosed Tyk2 inhibitor are administered together. On the other hand, Apremilast and the disclosed Tyk2 inhibitor are administered at different times of the same day. On the other hand, Apremilast and the disclosed Tyk2 inhibitor are administered as separate tablets or capsules at different times. On the other hand, Apremilast and the disclosed Tyk2 inhibitor are administered in a fixed dose combination in the same tablet or capsule.

[0040] The terms "treatment," "treat," and "treating" refer to reversing, alleviating, or inhibiting the progression of a disease or disorder responsive to inhibition of PDE4 as described herein, or one or more symptoms thereof.

[0041] The term "subject" refers to an animal, such as a mammal, and, for example, a human. The terms "subject" and "patient" can be used interchangeably.

[0042] The term "effective amount" or "therapeutically effective amount" refers to the amount of a compound described herein that will elicit a biological or medical response in a subject, for example, a dosage of 0.001-100 mg / kg body weight / day.

[0043] The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier, adjuvant or medium that does not adversely affect the pharmacological activity of the compound formulated therewith, and is also safe for human use. Pharmaceutically acceptable carriers, adjuvants or medium that can be used in the compositions of the present disclosure include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, magnesium stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based materials (e.g., microcrystalline cellulose, hydroxypropyl methylcellulose, lactose monohydrate, sodium lauryl sulfate and cross-linked sodium carboxymethylcellulose), polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[0044] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts of the compounds described herein include, but are not limited to, metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, vinylsulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid.

[0045] "Crystalline" refers to a solid form of a compound in which there is a long-range order of atoms in the positions of the atoms. The crystalline nature of the solid can be confirmed, for example, by examining an X-ray powder diffraction pattern. "Single crystalline form" means that the compound, i.e., N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide, exists as a single crystal or multiple crystals, each of which has the same crystalline form (e.g., Form B). When the crystalline form is defined as a specific single crystalline form of a compound as a specific percentage, the remainder consists of an amorphous form and / or a crystalline form different from the specified one or more specific forms. In one aspect, for example, the disclosed crystalline form is at least 80% by weight single crystalline form, at least 90% by weight single crystalline form, at least 95% by weight single crystalline form, or at least 99% by weight single crystalline form. The weight percent of a particular crystalline form is determined by dividing the weight of the particular crystalline form by the total weight of the particular crystalline form, plus the weight of other crystalline forms present plus the weight of the amorphous form present, times 100%.

[0046] The term "amorphous" refers to a solid that exists in a non-crystalline state or form. An amorphous solid is a disordered arrangement of molecules and thus has no distinguishable lattice or unit cell, and therefore has no definable long-range order. The solid-state order of a solid can be determined by standard techniques known in the art, such as by X-ray powder diffraction (XRPD) or differential scanning calorimetry (DSC). Amorphous solids can also be distinguished from crystalline solids, such as by birefringence using a polarized light microscope.

[0047] The 2-θ values ​​of the X-ray powder diffraction patterns of the crystalline forms described herein may vary slightly from instrument to instrument and also depend on variations in sample preparation and batch-to-batch variations due to factors such as temperature variations, sample displacement, and the presence or absence of an internal standard. Therefore, unless otherwise defined, the XRPD patterns / assignments described herein should not be interpreted as absolute and may vary by ±0.2 degrees. It is well known in the art that such variability will account for the above factors without hindering the unambiguous identification of the crystalline form.

[0048] 2.Tyk2 inhibitors

[0049] Tyk2 inhibitors used in the disclosed methods and compositions include compounds that block the action of tyrosine kinase 2, a non-receptor tyrosine-protein kinase encoded by the Tyk2 gene.

[0050] In a second embodiment, the disclosed Tyk2 inhibitors include but are not limited to those described in Xingrui He et al., Expert Opinion on Therapeutics Patents 2019, Vol. 29, No. 2, 137-149, the entire contents of which are incorporated herein by reference.

[0051] In a third embodiment, the disclosed Tyk2 inhibitors may be selected from those having the following formula:

[0052]

[0053] or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO2015 / 032423, the entire contents of which are incorporated herein by reference. Exemplary compounds of this formula as part of the third embodiment include, but are not limited to, those having the following formula:

[0054]

[0055] or a pharmaceutically acceptable salt thereof. Other Tyk2 inhibitors as part of the third embodiment include those in WO2008 / 139161 and WO2010 / 055304, the entire contents of each of which are incorporated herein by reference.

[0056] In a fourth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the following formula:

[0057]

[0058] or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO2013 / 174895, the entire contents of which are incorporated herein by reference. Exemplary compounds of this formula as part of the fourth embodiment include, but are not limited to, those having the following formula:

[0059]

[0060] or a pharmaceutically acceptable salt thereof. Other Tyk2 inhibitors include those in WO2012 / 062704, the entire contents of which are incorporated herein by reference.

[0061] In a fifth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the following formula:

[0062]

[0063] or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO2012 / 062704, the entire contents of which are incorporated herein by reference.

[0064] In a sixth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the following formula:

[0065]

[0066] or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO2015 / 091584, the entire contents of which are incorporated herein by reference. Exemplary compounds of this formula as part of the sixth embodiment include, but are not limited to, those having the following formula:

[0067]

[0068] or a pharmaceutically acceptable salt thereof.

[0069] In a seventh embodiment, the disclosed Tyk2 inhibitors may be selected from those having the following formula:

[0070]

[0071] or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO2016 / 027195, the entire contents of which are incorporated herein by reference. Exemplary compounds of this formula as part of the seventh embodiment include, but are not limited to, those having the following formula:

[0072]

[0073] or a pharmaceutically acceptable salt thereof.

[0074] In an eighth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the following formula:

[0075]

[0076] or a pharmaceutically acceptable salt thereof, wherein the variables are as described in US2017 / 0240552, the entire contents of which are incorporated herein by reference. Exemplary compounds of this formula as part of the eighth embodiment include, but are not limited to, those having the following formula:

[0077]

[0078] or a pharmaceutically acceptable salt thereof.

[0079] In a ninth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the following formula:

[0080]

[0081] or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO2015 / 016206, the entire contents of which are incorporated herein by reference.

[0082] In a tenth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the following formula:

[0083]

[0084] or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO2013 / 146963, the entire contents of which are incorporated herein by reference.

[0085] In an eleventh embodiment, the disclosed Tyk2 inhibitors may be selected from those having the following formula:

[0086]

[0087] or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO2016 / 047678, the entire contents of which are incorporated herein by reference.

[0088] In a twelfth embodiment, the disclosed Tyk2 inhibitor may be selected from those described in US2015 / 0299139; WO2015 / 069310; US 9505748; WO 2018 / 0162889; US2013 / 0178478; or WO2015 / 123453, the entire contents of each of which are incorporated herein by reference.

[0089] In a thirteenth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the following formula:

[0090]

[0091] or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO2015 / 131080 or WO2016 / 138352, the entire contents of which are incorporated herein by reference.

[0092] In a fourteenth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the following formula:

[0093]

[0094] or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO2017 / 040757, the entire contents of which are incorporated herein by reference.

[0095] In a fifteenth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the following formula:

[0096]

[0097] or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO2015 / 131080, WO2016 / 138352 and WO2017 / 040757, the entire contents of which are incorporated herein by reference.

[0098] In a sixteenth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the following formula:

[0099]

[0100] or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO2018 / 071794, the entire contents of which are incorporated herein by reference.

[0101] In a seventeenth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the following formula:

[0102]

[0103] or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO2018 / 075937, the entire contents of which are incorporated herein by reference.

[0104] In an eighteenth embodiment, the disclosed Tyk2 inhibitor may be selected from those having the following formula:

[0105]

[0106] or a pharmaceutically acceptable salt thereof, wherein the variables are as described in US 2013 / 0178478, the entire contents of which are incorporated herein by reference.

[0107] In a nineteenth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the following formula:

[0108]

[0109] or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO2015 / 123453, the entire contents of which are incorporated herein by reference.

[0110] In the twentieth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the following formula:

[0111]

[0112] or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO2015 / 089143, the entire contents of which are incorporated herein by reference.

[0113] In a twenty-first embodiment, the disclosed Tyk2 inhibitor may be selected from those having the following formula:

[0114]

[0115] or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO2015 / 089143, the entire contents of which are incorporated herein by reference.

[0116] In a twenty-second embodiment, the disclosed Tyk2 inhibitors may be selected from those having the following formula:

[0117]

[0118] or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO2018 / 067432, the entire contents of which are incorporated herein by reference.

[0119] In the twenty-third embodiment, the disclosed Tyk2 inhibitor can be selected from those having the following formula:

[0120]

[0121] or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO2018 / 093968, the entire contents of which are incorporated herein by reference.

[0122] In a twenty-fourth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the following formula:

[0123]

[0124] or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO2018 / 081488, the entire contents of which are incorporated herein by reference.

[0125] In a twenty-fifth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the following formula:

[0126]

[0127] or a pharmaceutically acceptable salt thereof, wherein

[0128] R 1 is optionally replaced by 0-7 R 1a Substituted C1-3 alkyl;

[0129] R 1a is independently at each occurrence hydrogen, deuterium, F, Cl, Br, CF3 or CN;

[0130] R 2 It is C 1-6 Alkyl or -(CH2) r -3-14 membered carbon ring, each group is composed of 0-4 R 2a replace;

[0131] R 2a is independently at each occurrence hydrogen, =O, halogen, OCF3, CN, NO2, -(CH2) r OR b 、-(CH2) r SR b 、-(CH2) r C(O)R b 、-(CH2) r C(O)OR b 、-(CH2) r OC(O)R b 、-(CH2) r NR 11 R 11 、-(CH2) r C(O)NR 11 R 11 、-(CH2) r NR b C(O)R c 、-(CH2) r NR b C(O)OR c 、-NR b C(O)NR 11 R 11 、-S(O) p NR 11 R 11 、-NR b S(O) p R c 、-S(O) p R c , 0-3 R a Substituted C 1-6 Alkyl, C 1-6 Halogenated alkyl, 0-3 R a Substituted C 2-6 Alkenyl, 0-3 R a Substituted C 2-6 Alkynyl, 0-1 R aSubstituted -(CH2) r -3-14 membered carbon ring or 0-2 R a The substituted one contains carbon atoms or 1 to 4 atoms selected from N, O and S(O) p Heteroatom -(CH2) r -5-7 membered heterocyclic ring;

[0132] R 3 It is C 3-10 Cycloalkyl, C 6-10 Aryl or a 5-10 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S, each of which is surrounded by 0-4 R 3a replace;

[0133] R 3a is independently at each occurrence hydrogen, =O, halogen, OCF3, CF3, CHF2, CN, NO2, -(CH2) r OR b 、-(CH2) r SR b 、-(CH2) r C(O)R b 、-(CH2) r C(O)OR b 、-(CH2) r OC(O)R b 、-(CH2) r NR 11 R 11 、-(CH2) r C(O)NR 11 R 11 、-(CH2) r NR b C(O)R c 、-(CH2) r NR b C(O)OR c 、-NR b C(O)NR 11 R 11 、-S(O) p NR 11 R 11 、-NR b S(O) p R c 、-S(O) p R c , 0-3 R a Substituted C 1-6 Alkyl, 0-3 R a Substituted C 2-6 Alkenyl, 0-3 R a Substituted C2-6 Alkynyl, C 1-6 Halogenated alkyl, 0-3 R a Substituted -(CH2) r -3-14 membered carbon ring or 0-3 R a The substituted one contains carbon atoms and 1 to 4 atoms selected from N, O and S(O) p Heteroatom -(CH2) r -5-10 membered heterocyclic ring;

[0134] or two R 3a Together with the atoms to which they are attached, they form a fused ring, wherein the ring is selected from phenyl and a 5-7 membered heterocyclic ring comprising carbon atoms and 1-4 heteroatoms selected from N, S or O, and the fused ring is further R a1 replace;

[0135] R 4 and R 5 are independently hydrogen, 0-1 R f Substituted C 1-4 Alkyl, 0-3 R d Substituted (CH2) r -phenyl, or -(CH2)-5-7 membered heterocyclic ring containing carbon atoms and 1-4 heteroatoms selected from N, O and S(O)p;

[0136] R 11 is independently hydrogen at each occurrence, surrounded by 0-3 R f Substituted C 1-4 Alkyl, CF3, 0-1 R f Substituted C 3-10 Cycloalkyl, 0-3 R d Substituted (CH) r -phenyl, or 0-3 R d The substituted one contains carbon atoms and 1 to 4 atoms selected from N, O and S(O) p Heteroatom -(CH2) r -5-7 membered heterocyclic ring;

[0137] R a and R a1 is independently at each occurrence hydrogen, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, -(CH2) r OR b 、-(CH2) r SR b 、-(CH2) r C(O)R b 、-(CH2) r C(O)OR b、-(CH2) r OC(O)R b 、-(CH2) r NR 11 R 11 、-(CH2) r C(O)NR 11 R 11 、-(CH2) r NR b C(O)R c 、-(CH2) r NR b C(O)OR c 、-NR b C(O)NR 11 R 11 、-S(O) p NR 11 R 11 、-NR b S(O) p R c 、-S(O)R c 、-S(O)2R c , 0-3 R f Substituted C 1-6 Alkyl, C 1-6 Halogenated alkyl, 0-3 R a Substituted C 2-6 Alkenyl, 0-3 R a Substituted C 2-6 Alkynyl, 0-3 R f Substituted -(CH2) r -3-14 membered carbon ring or 0-3 R f The substituted one contains carbon atoms and 1 to 4 atoms selected from N, O and S(O) p Heteroatom -(CH2) r -5-7 membered heterocyclic ring;

[0138] R b is independently hydrogen at each occurrence, surrounded by 0-3 R d Substituted C 1-6 Alkyl, C 1-6 Halogenated alkyl, 0-2 R d Substituted C 3-6 Cycloalkyl, or 0-3 R f The substituted one contains carbon atoms and 1 to 4 atoms selected from N, O and S(O) p Heteroatom -(CH2) r -5-7 membered heterocyclic ring or 0-3 R d Substituted (CH2) r -phenyl;

[0139] R c Is 0-3 R f Substituted C 1-6 Alkyl, 0-3 R f Substituted (CH2) r -C 3-6 Cycloalkyl, 0-3 R f Substituted (CH2) r -phenyl; or

[0140] R d is independently at each occurrence hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -OR e 、-(CH2) r C(O)R c 、-NR e R e 、-NR e C(O)OR c , 0-3 R f Substituted C 1-6 Alkyl, 0-3 R f Substituted C 1-6 Alkyl, or 0-3 R f Substituted (CH2) r -phenyl;

[0141] R e independently selected at each occurrence from hydrogen, 0-3 R f Substituted C 1-6 Alkyl, 0-3 R f Substituted C 3-6 Cycloalkyl and 0-3 R f Substituted (CH2) r -phenyl;

[0142] R f is independently at each occurrence hydrogen, halogen, CN, NH2, OH, C 3-6 Cycloalkyl, CF3, O(C 1-6 alkyl), or containing carbon atoms and 1 to 4 selected from N, O and S(O) p Heteroatom -(CH2) r -5-7 membered heteroaryl;

[0143] p is 0, 1, or 2; and

[0144] r is 0, 1, 2, 3 or 4, wherein further definitions and specific compounds can be found, for example, in US 2015 / 0299139, the entire contents of which are incorporated herein by reference.

[0145] In a twenty-sixth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the following formula:

[0146]

[0147] or a pharmaceutically acceptable salt thereof, wherein

[0148] R 1 is optionally replaced by 0-7 R 1a Substituted C 1-3 alkyl

[0149] R 1a is independently at each occurrence hydrogen, deuterium, F, Cl, Br, CF3 or CN;

[0150] R 2 Is 0-4 R 2a Substituted C 1-6 Alkyl, 0-4 R 2a Substituted C 3-6 Cycloalkyl, 0-4 R 2a Substituted C 6-10 Aryl, 0-4 R 2a NR 6 R 6 OR b a substituted 5-14 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S;

[0151] R 2a is independently at each occurrence hydrogen, =O, halogen, OCF3, CN, NO2, -(CH2) r OR b 、-(CH2) r SR b 、-(CH2) r C(O)R b 、-(CH2) r C(O)OR b 、-(CH2) r OC(O)R b 、(CH2) r NR 11 R 11 、-(CH2) r C(O)NR 11 R 11 、-(CH2) r NR b C(O)R C 、-(CH2) r NR b C(O)OR C 、-NRb C(O)NR 11 R 11 、-S(O) p NR 11 R 11 、-NR b S(O) p R C 、-S(O) p R C , 0-3 R a Substituted C 1-6 Alkyl, C 1-6 Halogenated alkyl, 0-1 R a Substituted -(CH2) r -3-14 membered carbon ring or 0-2 R a The substituted one contains carbon atoms or 1 to 4 atoms selected from N, O and S(O) p Heteroatom -(CH2) r -5-7 membered heterocyclic ring;

[0152] or an R 2a and another R 2a , together with the atoms to which they are attached, to form a fused 5-6 membered ring, wherein the fused ring may be substituted by 0-2 R a replace;

[0153] R 3 Is 0-5 R 3a Substituted -(CH2) r -3-14 membered carbon ring;

[0154] R 3a is independently at each occurrence hydrogen, =O, halogen, OCF3, CN, NO2, -(CH2) r OR b 、-(CH2) r SR b 、-(CH2) r C(O)R b 、-(CH2) r C(O)OR b 、-(CH2) r OC(O)R b 、(CH2) r NR 11 R 11 、-(CH2) r C(O)NR 11 R 11 、-(CH2) r NR b C(O)R C 、-(CH2)r NR b C(O)OR C 、-NR b C(O)NR 11 R 11 、-S(O) p NR 11 R 11 、-NR b S(O) p R C 、-S(O) p R C , 0-3 R a Substituted C 1-6 Alkyl, C 1-6 Halogenated alkyl, 0-3 R a Substituted -(CH2) r -3-14 membered carbon ring or 0-3 R a The substituted one contains carbon atoms or 1 to 4 atoms selected from N, O and S(O) p Heteroatom -(CH2) r -5-10 membered heterocyclic ring;

[0155] or two R 3a The fused ring is combined with the atoms to which they are attached to form a fused ring, wherein the ring is selected from phenyl and a 5-7 membered heterocyclic ring containing carbon atoms and 1-4 heteroatoms selected from N, S or O, and the fused ring may be further substituted by R a replace;

[0156] R 4 and R 5 are independently hydrogen, 0-1 R f Substituted C 1-4 Alkyl, 0-3 R d Substituted (CH2) r -phenyl, or containing 5 carbon atoms and 1 to 4 selected from N, O and S(O) p -(CH2)-5-7 membered heterocyclic ring containing a heteroatom;

[0157] R 6 and R 11 is independently hydrogen at each occurrence, surrounded by 0-3 R f Substituted C 1-4 Alkyl, CF3, 0-1 R f Substituted C 3-10 Cycloalkyl, 0-3 R d Substituted (CH) r -phenyl, or 0-3 R d The substituted one contains carbon atoms and 1 to 4 atoms selected from N, O and S(O) pHeteroatom -(CH2) r -5-7 membered heterocyclic ring;

[0158] R a At each occurrence, it is hydrogen, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, -(CH2) r OR b 、-(CH2) r SR b 、-(CH2) r C(O)R b 、-(CH2) r C(O)OR b 、-(CH2) r OC(O)R b 、-(CH2) r NR 11 R 11 、-(CH2) r C(O)NR 11 R 11 、-(CH2) r NR b C(O)R C 、-(CH2) r NR b C(O)OR C 、-NR b C(O)NR 11 R 11 、-S(O) p NR 11 R 11 、-NR b S(O) p R C 、-S(O)R C 、-S(O)2R C , 0-3 R f Substituted C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) r -3-14 membered carbon ring, or 0-3 R f The substituted one contains carbon atoms and 1 to 4 atoms selected from N, O and S(O) p Heteroatom -(CH2) r -5-715 membered heterocycle;

[0159] R b In each occurrence it is hydrogen, surrounded by 0-3 R d Substituted C 1-6 Alkyl, C 1-6 Halogenated alkyl, 0-2 R d Substituted C3-6 Cycloalkyl, or 0-3 R f The substituted one contains carbon atoms and 1 to 4 atoms selected from N, O and S(O) p Heteroatom -(CH2) r -5-7 membered heterocyclic ring, or 0-3 R d Substituted (CH2) r -phenyl;

[0160] R C Is 0-3 R f Substituted C 1-6 Alkyl, 0-3 R f Substituted (CH2) r -C 3-6 Cycloalkyl or 0-3 R f Substituted (CH2) r -phenyl;

[0161] R d Each occurrence is independently hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, OR e 、-(CH2) r C(O)R C NR e R e 、-NR e C(O)OR C , C 1-6 Alkyl or 0-3 R f Substituted (CH2) r -phenyl;

[0162] R e independently selected at each occurrence from hydrogen, 0-3 R f Substituted C 1-6 Alkyl, 0-3 R f Substituted C 3-6 Cycloalkyl and 0-3 R f Substituted (CH2) r -phenyl;

[0163] R f is independently at each occurrence hydrogen, halogen, CN, NH2, OH, C 3-6 Cycloalkyl, CF3, O(C 1-6 Alkyl) or containing carbon atoms and 1-4 selected from N, O or S (O) p Heteroatom -(CH2) r -5-7 membered heteroaryl;

[0164] p is 0, 1, or 2; and

[0165] r is 0, 1, 2, 3 or 4.

[0166] In the twenty-seventh embodiment, the disclosed Tyk2 inhibitors may be selected from those having the following formula:

[0167]

[0168] or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO2015 / 069310, the entire contents of which are incorporated herein by reference.

[0169] In a twenty-eighth embodiment, the disclosed Tyk2 inhibitor may be selected from those having the following formula:

[0170]

[0171] or a pharmaceutically acceptable salt thereof, wherein

[0172] Y is N or CR6;

[0173] R 1 It is H, C 1-3 Alkyl or C 3-6 Cycloalkyl, each optionally substituted with 0-7 R 1a replace;

[0174] R 1a is independently at each occurrence hydrogen, deuterium, F, Cl, Br or CN;

[0175] R 2 It is C 1-6 Alkyl, 0-1 R 2a Substituted -(CH2) r -3-14 membered carbocyclic ring or 5-14 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S, each of which is surrounded by 0-4 R 2a Replace (for clarity, R 2 It is intended to include substituted methyl radicals, such as -C(O)R 2a );

[0176] R 2a is independently at each occurrence hydrogen, =O, halogen, OCF3, CN, NO2, -(CH2) r OR b 、-(CH2) r SR b 、-(CH2) r C(O)R b 、-(CH2) r C(O)OR b 、-(CH2) r OC(O)Rb , -CH2) r NR 11 R 11 、-(CH2) r C(O)NR 11 R 11 、-(CH2) r NR b C(O)R c 、-(CH2) r NR b C(O)OR c 、-NR b C(O)NR 11 R 11 、-S(O) p NR 11 R 11 、-NR b S(O) p R c 、-S(O) p R c , 0-3 R a Substituted C 1-6 Alkyl, C 1-6 Halogenated alkyl, 0-3 R a Substituted C 2-6 Alkenyl, 0-3 R a Substituted C 2-6 Alkynyl, 0-1 R a Substituted -(CH2) r -3-14 membered carbon ring or 0-2 R a The substituted one contains carbon atoms or 1 to 4 atoms selected from N, O and S(O) p Heteroatom -(CH2) r -5-7 membered heterocyclic ring;

[0177] R 3 It is C 3-10 Cycloalkyl, C 6-10 Aryl or a 5-10 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S, each of which is surrounded by 0-4 R 3a replace;

[0178] R 3a Each occurrence is independently hydrogen, =O, halogen, OCF3, CF3, CHF2, CN, NO2, -(CH2) r OR b 、-(CH2) r SR b 、-(CH2) r C(O)R b 、-(CH2)r C(O)OR b 、-(CH2) r OC(O)R b 、-(CH2) r NR 11 R 11 、-(CH2) r C(O)NR 11 R 11 、-(CH2) r NR b C(O)R c 、-(CH2) r NR b C(O)OR c 、-NR b C(O)NR 11 R 11 、-S(O) p NR 11 R 11 、-NR b S(O) p R c 、-S(O) p R c , 0-3 R a Substituted C 1-6 Alkyl, 0-3 R a Substituted C 2-6 Alkenyl, 0-3 R a Substituted C 2-6 Alkynyl, C 1-6 Halogenated alkyl, 0-3 R a Substituted -(CH2) r -3-14 membered carbon ring or 0-3 R a The substituted carbon atoms and 1 to 4 atoms selected from N, O and S (O )p Heteroatom -(CH2) r -5-10 membered heterocyclic ring;

[0179] or two R 3a , together with the atoms to which they are attached, to form a fused ring, wherein the ring is selected from phenyl and contains carbon atoms and 1-4 atoms selected from N, O and S(O) p A heterocyclic ring containing a heteroatom, each fused ring being 0-3 R a1 replace;

[0180] R 4 and R 5 are independently hydrogen, 0-1 R f Substituted C 1-4 Alkyl, 0-3 R dSubstituted (CH2) r -phenyl or -(CH2)-5-7 membered heterocyclic ring containing carbon atoms and 1-4 heteroatoms selected from N, O and S(O)p;

[0181] R 6 For hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, OC 1-4 Halogenated alkyl, OC 1-4 Alkyl, CN, NO2 or OH;

[0182] R 11 Each occurrence is independently hydrogen, surrounded by 0-3 R f Substituted C 1-4 Alkyl, CF3, 0-1 R f Substituted C 3-10 Cycloalkyl, 0-3 R d Substituted (CH) r -phenyl or 0-3 R d The substituted one contains carbon atoms and 1 to 4 atoms selected from N, O or S(O) p Heteroatom -(CH2) r -5-7 membered heterocyclic ring;

[0183] R a and R a1 Each occurrence is independently hydrogen, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, -(CH2) r OR b 、-(CH2) r SR b 、-(CH2) r C(O)R b 、-(CH2) r C(O)OR b 、-(CH2) r OC(O)R b 、-(CH2) r NR 11 R 11 、-(CH2) r C(O)NR 11 R 11 、-(CH2) r NR b C(O)R c 、-(CH2) r NR b C(O)OR c 、-NR b C(O)NR 11 R 11、-S(O) p NR "R", -NR b S(O) p R c 、-S(O)R c 、-S(O)2R c , 0-3 R f Substituted C 1-6 Alkyl, C 1-6 Halogenated alkyl, 0-3 R a Substituted C 2-6 Alkenyl, 0-3 R a Substituted C 2-6 Alkynyl, 0-3 R f Substituted -(CH2) r -3-14 membered carbon ring or 0-3 R f The substituted one contains carbon atoms and 1 to 4 atoms selected from N, O and S(O) p Heteroatom -(CH2) r -5-7 membered heterocyclic ring;

[0184] R b Is hydrogen, with 0-3 R d Substituted C 1-6 Alkyl, C 1-6 Halogenated alkyl, 0-2 R d Substituted C 3-6 Cycloalkyl, or 0-3 R f The substituted one contains carbon atoms and 1 to 4 atoms selected from N, O and S(O) p Heteroatom -(CH2) r -5-7 membered heterocyclic ring or 0-3 R d Substituted (CH2) r -phenyl;

[0185] R c Is 0-3 R f Substituted C 1-6 Alkyl, 0-3 R f Substituted (CH2) r -C 3-6 Cycloalkyl or 0-3 R f Substituted (CH2) r -phenyl;

[0186] R d Each occurrence is independently hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -OR e 、-(CH2) r C(O)R c 、-NR e Re 、-NR e C(O)OR c , 0-3 R f Substituted C 1-6 Alkyl or 0-3 R f Substituted (CH2) r -phenyl;

[0187] R e Each occurrence is independently selected from hydrogen, 0-3 R f Substituted C 1-6 Alkyl, 0-3 R f Substituted C 3-6 Cycloalkyl and 0-3 R f Substituted (CH2) r -phenyl;

[0188] R f Each occurrence is independently hydrogen, halogen, CN, NH2, OH, C 3-6 Cycloalkyl, CF3, O(C 1-6 alkyl) or containing carbon atoms and 1-4 selected from N, O and S(O) p Heteroatom -(CH2) r -5-7 membered heterocyclic ring;

[0189] p is 0, 1, or 2; and

[0190] r is 0, 1, 2, 3 or 4, wherein further definitions and specific compounds are as described in US9505748 and WO2018 / 0162889, the entire contents of each of which are incorporated herein by reference.

[0191] In the twenty-ninth embodiment, the disclosed Tyk2 inhibitor can be selected from those having the following formula:

[0192]

[0193] or a pharmaceutically acceptable salt thereof, wherein:

[0194] R 1 yes and

[0195] R 2 yes

[0196] In the thirtieth embodiment, the Tyk2 inhibitor described herein is 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165), which has the following chemical structure:

[0197]

[0198] or a pharmaceutically acceptable salt thereof.

[0199] The specific dosage and treatment regimen of the disclosed Tyk2 inhibitors used in combination with Apremilast will depend on a variety of factors, including age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated.

[0200] In the thirty-first embodiment, the effective amount of the disclosed Tyk2 inhibitor used in combination with Apremilast (e.g., as in any one of the second to 30th embodiments) ranges from 0.001 to 50 mg / kg body weight / day. For example, as part of the thirty-first embodiment, the effective amount of the disclosed Tyk2 inhibitor used in combination with Apremilast (e.g., as in any one of the second to 30th embodiments) ranges from about 0.1 mg / day to about 250 mg / day, for example, about 0.2 mg / day to about 100 mg / day, about 0.5 mg / day to about 50 mg / day, and about 1.0 mg to about 24 mg / day.

[0201] In the thirty-second embodiment, the Tyk2 inhibitor described herein is BMS-986165, or a pharmaceutically acceptable salt thereof, and the effective amount of BMS-986165 or a pharmaceutically acceptable salt thereof ranges from about 0.1 mg / day to about 250 mg / day, about 0.1 mg / day to about 100 mg / day, about 0.1 mg / day to about 50 mg / day, about 0.1 mg / day to about 25 mg / day, 0.1 mg / day to about 15 mg / day, about 0.1 mg / day to about 10 mg / day, about 0.5 mg / day to about 15 mg / day, about 0.5 mg / day to about 10 mg / day, about 0.1 mg / day to about 5 mg / day, about 0.5 mg / day to about 5 mg / day, about 1 mg / day to about 25 mg / day, about 2 mg / day to about 14 mg / day, about 2 mg / day to about 12 mg / day, or about 3 mg / day to about 12 mg / day. Alternatively, as part of the thirty-second embodiment, the effective amount of BMS-986165 or a pharmaceutically acceptable salt thereof ranges from about 1 mg / day to about 15 mg / day, from about 1 mg / day to about 14 mg / day, from about 2 mg / day to about 14 mg / day, from about 2 mg / day to about 12 mg / day, or from about 3 mg / day to about 12 mg / day.

[0202] In the thirty-third embodiment, the Tyk2 inhibitor described herein is BMS-986165 or a pharmaceutically acceptable salt thereof, and the effective amount of BMS-986165 or a pharmaceutically acceptable salt thereof is about 0.1 mg / day, about 0.5 mg / day, about 1.0 mg / day, about 2 mg / day, about 3 mg / day, about 4 mg / day, about 5 mg / day, about 6 mg / day, about 7 mg / day, about 8 mg / day, about 9 mg / day, about 10 mg / day, about 11 mg / day, or about 12 mg / day. Alternatively, as part of the thirty-third embodiment, the effective amount of BMS-986165 or a pharmaceutically acceptable salt thereof is about 2 mg / day, about 3 mg / day, about 4 mg / day, about 5 mg / day, about 6 mg / day, about 7 mg / day, about 8 mg / day, about 9 mg / day, about 10 mg / day, about 11 mg / day, or about 12 mg / day. In another alternative, as part of the thirty-third embodiment, the effective amount of BMS-986165 or a pharmaceutically acceptable salt thereof is about 6 mg / day. In another alternative, as part of the thirty-third embodiment, the effective concentration of BMS-986165 or a pharmaceutically acceptable salt thereof is about 1 nM to about 1 μM (e.g., about 0.01 μM to about 0.1 μM).

[0203] 3. Apremilast

[0204] As described above, Apremilast is optically enriched as the (S) enantiomer. In the thirty-fourth embodiment, the stereoisomeric purity of Apremilast in the methods and compositions described herein is greater than 90%, wherein the Tyk2 inhibitor and related features are as described herein, for example, as described in any one of the first to thirty-third embodiments. Or, as part of the thirty-fourth embodiment, the stereoisomeric purity of Apremilast in the methods and compositions described herein is greater than 95%, wherein the Tyk2 inhibitor and related features are as described herein, for example, as described in any one of the first to thirty-third embodiments. In another alternative, as part of the thirty-fourth embodiment, the stereoisomeric purity of Apremilast in the methods and compositions described herein is greater than 97%, wherein the Tyk2 inhibitor and related features are as described herein, for example, as described in any one of the first to thirty-third embodiments. In another alternative, as part of the thirty-fourth embodiment, the stereoisomeric purity of Apremilast in the methods and compositions described herein is greater than 98%, wherein the Tyk2 inhibitor and related features are as described herein, for example, as described in any one of the first to thirty-third embodiments. In another alternative, as part of the thirty-fourth embodiment, the stereoisomeric purity of Apremilast in the methods and compositions described herein is greater than 99%, wherein the Tyk2 inhibitor and related features are as described herein, for example, as described in any one of the first to thirty-third embodiments. In another alternative, as part of the thirty-fourth embodiment, the stereoisomeric purity of Apremilast in the methods and compositions described herein is greater than 99.5%, wherein the Tyk2 inhibitor and related features are as described herein, for example, as described in any one of the first to thirty-third embodiments. In another alternative, as part of the thirty-fourth embodiment, the stereoisomeric purity of Apremilast in the methods and compositions described herein is greater than 99.9%, wherein the Tyk2 inhibitor and related features are as described herein, for example, as described in any one of the first to thirty-third embodiments.

[0205] Polymorphic forms of Apremilast are included in the disclosed methods and compositions, and include, for example, those described in US9018243, the entire contents of which are incorporated herein by reference. In the thirty-fifth embodiment, the Apremilast in the disclosed methods and compositions is in single crystalline form, wherein the other features and related features of Apremilast and the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-fourth embodiments.

[0206] In the thirty-sixth embodiment, the Apremilast in the disclosed methods and compositions is a single crystalline Form B characterized by an X-ray powder diffraction peak at a 2θ angle selected from 10.1°, 13.5°, 20.7° and 26.9°, wherein the other characteristics and related characteristics of Apremilast and the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-fourth embodiments. Alternatively, as part of the thirty-sixth embodiment, the Apremilast in the disclosed methods and compositions is a single crystalline Form B characterized by an X-ray powder diffraction peak at a 2θ angle selected from 10.1°, 13.5°, 15.7°, 18.1°, 20.7°, 24.7° and 26.9°, wherein the other characteristics and related characteristics of Apremilast and the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-fourth embodiments. In another alternative, as part of the thirty-sixth embodiment, the Apremilast in the disclosed methods and compositions is in single crystalline Form B, characterized by an X-ray powder diffraction peak at a 2θ angle selected from 10.1°, 13.5°, 15.7°, 16.3°, 18.1°, 20.7°, 22.5°, 24.7°, 26.2°, 26.9° and 29.1°, wherein the other characteristics and related characteristics of Apremilast and the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-fourth embodiments.

[0207] In the thirty-seventh embodiment, the Apremilast in the disclosed methods and compositions is at least 90% of the single crystalline Form B, wherein the other features and related features of Apremilast and the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-sixth embodiments. Alternatively, the Apremilast in the disclosed methods and compositions is at least 95% of the single crystalline Form B, wherein the other features and related features of Apremilast and the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-sixth embodiments. In another alternative, the Apremilast in the disclosed methods and compositions is at least 99% of the single crystalline Form B, wherein the other features and related features of Apremilast and the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-sixth embodiments.

[0208] The specific dosage and treatment regimen of Apremilast or a pharmaceutically acceptable salt thereof used in combination with the disclosed Tyk2 inhibitors will depend on a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated.

[0209] For example, in the thirty-eighth embodiment, the effective amount of Apremilast or a pharmaceutically acceptable salt thereof ranges from about 0.5 mg to about 1000 mg / day, about 1 mg to about 1000 mg / day, about 5 mg to about 500 mg / day, about 10 mg to about 200 mg / day, about 10 mg to about 100 mg / day, about 40 mg to about 100 mg / day, about 20 mg to about 40 mg / day, about 0.1 mg to about 10 mg / day, about 0.5 mg to about 5 mg / day, about 1 mg to about 20 mg / day and about 1 mg to about 10 mg / day, about 1 mg to about 100 mg / day, about 1 mg to about 80 mg / day, about 5 mg to about 70 mg / day, about 10 mg to about 60 mg / day and about 10 mg to about 40 mg / day, wherein the other features and related features of Apremilast and the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-seventh embodiments. Alternatively, as part of the thirty-eighth embodiment, the effective amount of Apremilast or its pharmaceutically acceptable salt ranges from about 10 mg to about 60 mg / day, wherein the other features and related features of Apremilast and the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-seventh embodiments. In another alternative, as part of the thirty-eighth embodiment, the effective amount of Apremilast or its pharmaceutically acceptable salt ranges from about 40 mg to about 100 mg / day, wherein the other features and related features of Apremilast and the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-seventh embodiments. In another alternative, as part of the thirty-eighth embodiment, the effective amount of Apremilast or its pharmaceutically acceptable salt ranges from about 40 mg to about 100 mg / day, wherein the other features and related features of Apremilast and the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-seventh embodiments. In another alternative, as part of the thirty-eighth embodiment, the effective amount of Apremilast or a pharmaceutically acceptable salt thereof ranges from about 4 mg to about 10 mg / day, wherein the other features and related features of Apremilast and the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-seventh embodiments. In another alternative, as part of the thirty-eighth embodiment, the effective amount of Apremilast or a pharmaceutically acceptable salt thereof ranges from about 4 mg to about 10 mg / day, wherein the other features and related features of Apremilast and the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-seventh embodiments.In another alternative, as part of the thirty-eighth embodiment, the effective amount of Apremilast or its pharmaceutically acceptable salt ranges from about 10 mg to about 40 mg / day, wherein the other features and related features of Apremilast and the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-seventh embodiments. In another alternative, as part of the thirty-eighth embodiment, the effective amount of Apremilast or its pharmaceutically acceptable salt is about 1 mg / day, about 2 mg / day, about 3 mg / day, about 4 mg / day, about 5 mg / day, about 10 mg / day, about 15 mg / day, about 20 mg / day, about 25 mg / day, about 30 mg / day, about 35 mg / day, about 40 mg / day, about 45 mg / day, about 50 mg / day, about 55 mg / day or about 60 mg / day, wherein the other features and related features of Apremilast and the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-seventh embodiments. In another alternative, as part of the thirty-eighth embodiment, the effective amount of Apremilast or its pharmaceutically acceptable salt is about 30 mg / day or about 60 mg / day, wherein Apremilast and other features and related features of the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-seventh embodiments. In another alternative, as part of the thirty-eighth embodiment, Apremilast is administered at a dose of about 30 mg, once a day, wherein Apremilast and other features and related features of the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-seventh embodiments. In another alternative, as part of the thirty-eighth embodiment, Apremilast is administered at a dose of about 30 mg, twice a day, wherein Apremilast and other features and related features of the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-seventh embodiments. In another alternative, as part of the thirty-eighth embodiment, the effective amount of Apremilast or its pharmaceutically acceptable salt is about 10 mg / day or about 40 mg / day, wherein the other features and related features of Apremilast and the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-seventh embodiments. In another alternative, as part of the thirty-eighth embodiment, Apremilast is administered at a dose of about 10 mg, once or twice a day, wherein the other features and related features of Apremilast and the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-seventh embodiments. In another alternative, as part of the thirty-eighth embodiment, Apremilast is administered at a dose of about 20 mg, once or twice a day, wherein the other features and related features of Apremilast and the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-seventh embodiments.In another alternative, as part of the thirty-eighth embodiment, the effective concentration of Apremilast is about 100 nM to about 10 μM (e.g., from about 0.1 μM to about 1 μM), wherein the other features and related features of Apremilast and the Tyk2 inhibitor are as described herein, as described in any one of the first to thirty-seventh embodiments.

[0210] In a thirty-ninth embodiment, Apremilast is titrated to a dose of about 30 mg, administered twice daily, using the following titration regimen:

[0211] Day 1: about 10 mg in the morning;

[0212] Day 2: about 10 mg in the morning and about 10 mg in the evening;

[0213] Day 3: about 10 mg in the morning and 20 mg in the evening;

[0214] Day 4: about 20 mg in the morning and about 20 mg in the evening;

[0215] Day 5: about 20 mg in the morning and about 30 mg in the evening; and

[0216] Day 6 and thereafter: about 30 mg, twice daily, wherein the other features and related features of Apremilast and the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-seventh embodiments. Alternatively, Apremilast is titrated to a dose between about 40 mg / day and about 100 mg / day using the following titration scheme:

[0217] Day 1: about 10 mg in the morning;

[0218] Day 2: about 10 mg in the morning and about 10 mg in the evening;

[0219] Day 3: about 10 mg in the morning and 20 mg in the evening;

[0220] Day 4: about 20 mg in the morning and about 20 mg in the evening;

[0221] Day 5: about 20 mg in the morning and about 30 mg in the evening; and

[0222] Day 6 and thereafter: between about 40 mg / day and about 100 mg / day, wherein the other features and related features of Apremilast and the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-seventh embodiments. In another alternative, Apremilast is titrated to a dose of about 20 mg using the following titration regimen, administered twice a day:

[0223] Day 1: about 10 mg in the morning;

[0224] Day 2: about 10 mg in the morning and about 10 mg in the evening;

[0225] Day 3: about 10 mg in the morning and 20 mg in the evening;

[0226] Day 4: about 20 mg in the morning and about 20 mg in the evening;

[0227] Day 5: about 20 mg in the morning and about 30 mg in the evening; and

[0228] Day 6 and thereafter: about 20 mg, twice daily, wherein the other features and related features of Apremilast and the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-seventh embodiments. In yet another alternative, Apremilast is titrated to a dose between about 4 mg / day and about 10 mg / day using the following titration regimen:

[0229] Day 1: about 1 mg in the morning;

[0230] Day 2: about 1 mg in the morning and about 1 mg in the evening;

[0231] Day 3: about 1 mg in the morning and about 2 mg in the evening;

[0232] Day 4: about 2 mg in the morning and about 2 mg in the evening;

[0233] Day 5: about 2 mg in the morning and about 3 mg in the evening; and

[0234] Day 6 and thereafter: between about 4 mg / day and about 10 mg / day, wherein the other features and related features of Apremilast and the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-seventh embodiments. In yet another alternative, Apremilast is titrated to a dose of about 3 mg using the following titration regimen, administered twice daily:

[0235] Day 1: about 1 mg in the morning;

[0236] Day 2: about 1 mg in the morning and about 1 mg in the evening;

[0237] Day 3: about 10 mg in the morning and about 2 mg in the evening;

[0238] Day 4: about 2 mg in the morning and about 2 mg in the evening;

[0239] Day 5: about 2 mg in the morning and about 3 mg in the evening; and

[0240] Day 6 and thereafter: about 3 mg, twice daily, wherein other features and related features of Apremilast and the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-seventh embodiments.

[0241] 3. Composition and Administration

[0242] Also provided herein is a pharmaceutical composition comprising a therapeutically effective amount of Apremilast or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a Tyk2 inhibitor (e.g., BMS-986165). The features of the disclosed pharmaceutical composition include the above elements, for example, the elements described in any one of the first to thirty-eighth embodiments.

[0243] Also provided is a pharmaceutical composition comprising a therapeutically effective amount of Apremilast or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a Tyk2 inhibitor (e.g., BMS-986165) for treating a disease or disorder responsive to inhibition of PDE4. The features of the disclosed pharmaceutical composition include the above elements, e.g., the elements described in any one of the first to thirty-eighth embodiments.

[0244] Pharmaceutical compositions and single unit dosage forms, comprising Apremilast and a Tyk2 inhibitor (e.g., BMS-986165) for administration alone or together in a fixed dose as described above (e.g., as in any one of the first to thirty-eighth embodiments). The single unit dosage forms of the disclosed methods and compositions are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, oral or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular or intraarterial) or transdermal administration to a patient. Examples of dosage forms include, but are not limited to, tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; lozenges; lozenges; dispersions; suppositories; ointments; poultices; pastes; powders; dressings; creams; plasters; solutions; sheets; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or transmucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.

[0245] The composition, shape and type of the dosage form will generally vary depending on its use. For example, a dosage form for acute treatment of inflammation or related disorders may contain a larger amount of one or more active ingredients than a dosage form for chronic treatment of the same disease. Similarly, a parenteral dosage form may contain a smaller amount of one or more active ingredients contained therein than an oral dosage form for treating the same disease. These and other ways in which the specific dosage forms encompassed by the present invention differ from each other will be apparent to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).

[0246] In the thirty-ninth embodiment, the Apremilast in the disclosed methods and compositions is administered parenterally, dermally, mucosally, nasally, buccally, sublingually or orally, wherein the other features and related features of Apremilast and the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-eighth embodiments. Alternatively, as part of the thirty-ninth embodiment, the Apremilast in the disclosed methods and compositions is administered orally, wherein the other features and related features of Apremilast and the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-eighth embodiments.

[0247] In the 40th embodiment, Apremilast in the disclosed methods and compositions is administered orally in the form of tablets or capsules, wherein other features and related features of Apremilast and the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-ninth embodiments.

[0248] In the forty-first embodiment, the Apremilast in the disclosed methods and compositions is formulated in a sustained release form, wherein the other features and related features of Apremilast and the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-ninth embodiments.

[0249] In the forty-second embodiment, the Apremilast in the disclosed methods and compositions is formulated as an immediate release form, wherein the other features and related features of Apremilast and the Tyk2 inhibitor are as described herein, for example, as described in any one of the first to thirty-ninth embodiments.

[0250] In the forty-third embodiment, both the Apremilast and the Tyk2 inhibitor in the disclosed methods and compositions are administered in a fixed dose combination in a once-daily formulation, wherein the other features and related features of Apremilast and the Tyk2 inhibitor are as described herein, e.g., as described in any one of the first to forty-second embodiments.

[0251] 4. Conditions Treated by the Methods and Compositions Disclosed herein

[0252] Diseases or disorders responsive to PDE4 inhibition using the methods and compositions disclosed herein include, for example, viral, genetic, inflammatory, allergic, and autoimmune disorders.

[0253] In one aspect, the disease or disorder responsive to inhibition of PDE4 is selected from chronic obstructive pulmonary disease, asthma, chronic pulmonary inflammatory disease, hyperoxic alveolar damage, inflammatory skin diseases, psoriasis, psoriatic arthritis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, atopic dermatitis, rheumatoid spondylitis, depression, osteoarthritis, contact dermatitis, ankylosing spondylitis, lupus, lupus nephritis, cutaneous lupus erythematosus, systemic lupus erythematosus, erythema nodosum leprosum, Sjögren's syndrome, inflammatory bowel disease, Crohn's disease, Behcet's disease and ulcerative colitis.

[0254] In one aspect, the disease or disorder responsive to PDE4 inhibition is selected from psoriasis, psoriatic arthritis, contact dermatitis, systemic lupus erythematosus, cutaneous lupus erythematosus, and ulcerative colitis.

[0255] In one aspect, the disease or disorder responsive to inhibition of PDE4 is psoriasis. In another aspect, the disease or disorder responsive to inhibition of PDE4 is psoriasis, and the subject being treated is a candidate for phototherapy or systemic therapy.

[0256] In one aspect, the disease or disorder responsive to inhibition of PDE4 is plaque psoriasis. In another aspect, the disease or disorder responsive to inhibition of PDE4 is plaque psoriasis and the subject being treated is a candidate for phototherapy or systemic therapy.

[0257] In one aspect, the disease or disorder responsive to inhibition of PDE4 is moderate to severe plaque psoriasis. In another aspect, the disease or disorder responsive to inhibition of PDE4 is severe plaque psoriasis, and the subject being treated is a candidate for phototherapy or systemic therapy.

[0258] In one aspect, the disease or disorder responsive to inhibition of PDE4 is psoriatic arthritis.

[0259] In one aspect, the disease or disorder responsive to inhibition of PDE4 is active psoriatic arthritis.

[0260] In one aspect, the disease or disorder responsive to inhibition of PDE4 is a cardiac disease, such as congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acute viral myocarditis, cardiac allograft rejection, and myocardial infarction.

[0261] In one aspect, the disease or condition responsive to inhibition of PDE4 is HIV, hepatitis, adult respiratory distress syndrome, bone resorption disease, cystic fibrosis, septic shock, sepsis, endotoxic shock, hemodynamic shock, sepsis syndrome, ischemia-reperfusion injury, meningitis, fibrotic disease, cachexia, transplant rejection, osteoporosis, multiple sclerosis and radiation injury.

[0262] In one aspect, the disease or disorder responsive to inhibition of PDE4 is cancer of the head, thyroid, neck, eye, skin, mouth, throat, esophagus, chest, bone, blood, bone marrow, lung, colon, sigmoid colon, rectum, stomach, prostate, breast, ovary, kidney, liver, pancreas, brain, intestine, heart, adrenal gland, subcutaneous tissue, lymph node, heart, and combinations thereof.

[0263] In one aspect, the disease or disorder responsive to inhibition of PDE4 is multiple myeloma, malignant melanoma, malignant glioma, acute lymphocytic leukemia, acute lymphocytic B-cell leukemia, acute lymphocytic T-cell leukemia, acute myeloid leukemia, acute promyelocytic leukemia, acute monocytic leukemia, acute erythroleukemia, acute megakaryocytic leukemia, acute myelomonocytic leukemia, acute non-lymphocytic leukemia, acute undifferentiated leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, multiple myeloma and acute lymphocytic leukemia, myeloid leukemia, lymphocytic leukemia and myeloid leukemia.

[0264] In one aspect, the disease or disorder responsive to inhibition of PDE4 is a solid tumor, such as a sarcoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovial sarcoma, mesothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, nipple cancer, carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatocellular carcinoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumors, lung cancer, small cell lung cancer, bladder cancer, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, Kaposi's sarcoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma and retinoblastoma.

[0265] Example

[0266] 1. Materials

[0267] Table 1: Whole blood assay: study materials and reagents.

[0268]

[0269] Table 2: LPS-stimulated PBMC assay: study materials and reagents

[0270]

[0271] Table 3: Test articles used in the study

[0272]

[0273] 2. General Methods

[0274] Whole blood was received through the Celgene donor program after informed consent and donor de-identification. All volunteers were healthy and had not taken any medications for at least 72 hours before blood draw. Blood was collected in sodium heparin tubes. The assay was started within 2 hours of the blood draw.

[0275] Ex vivo stimulation of healthy donor human whole blood was performed under two different stimulation conditions. Condition Th0 was performed with a 1:1 ratio containing anti-CD3 / anti-CD28. Conditional Th17 was stimulated with anti-CD3 / anti-CD28 plus IL-1β, IL-6, and IL-23 Tube stimulation. Whole blood was separated into 15 ml conical tubes and pretreated with DMSO, apremilast alone, BMS-986165 alone, or a combination of BMS-986165 and apremilast. The final concentrations were 0.2% DMSO, 1 μM apremilast alone, 1 μM, 0.1 μM, 0.01 μM, and 0.001 μM BMS-986165 alone and in combination with 1 μM apremilast. The blood was mixed thoroughly and then incubated in a 37°C / 5% CO2 incubator for 1 hour.

[0276] Anti-CD3 / anti-CD28 (final concentrations of 200 ng / ml and 330 ng / ml, respectively) The tubes were thawed on the benchtop for 30 minutes and then labeled. The plunger was pressed and snapped off. The tube is placed in an upright support so that one side of the plunger points downward in the support and the tube cap points upward. When the blood is incubated with the compound, human recombinant IL-6, IL-1β and IL-23 are added to all Th17 tubes at the following concentrations: 120ng IL-6, 120ng IL-1b and 150ng IL-23. 1ml of pretreated whole blood is placed in each tube using a sterile pyrogen-free pipette tip. Replace the cap and mix the contents of the tube by inverting 3 times. The tube is immediately placed in a 37°C heating block and incubated for 42 hours (tube cap end). After these 42 hours, the tube is removed from the heating block, the top is unscrewed, and 250 μl of supernatant is taken out and transferred to three 96-well polypropylene plates. The sample is immediately frozen at -80°C. The supernatant is then thawed at room temperature, and the production of pure cytokines is detected by Luminex Multi-Plex MagPix technology (Millipore) or IL-22 is detected by ELISA (Abcam). Follow the manufacturer's procedures accordingly.

[0277] Peripheral blood single cell (PBMC) isolation: Whole blood was received through the Celgene donor program after informed consent and donor de-identification. All volunteers were healthy and had not taken any medications for at least 72 hours before blood draw. Blood was collected in sodium heparin tubes and used for PBMC isolation within 2 hours of blood draw. Before PBMC isolation, whole blood was diluted 1:1 with PBS solution containing 2% FBS (2% FBS-PBS). 13 ml of lymphocyte separation solution was placed in the tube and load 25ml of the diluted blood on top of the lymphocyte separation solution. Centrifuge at 1200g for 15 minutes and turn on the brake for cell separation, then transfer the isolated PBMC to a new tube. Wash the PBMC with 2% FBS-PBS and centrifuge at 800g for 10 minutes. Resuspend the pellet in 2% FBS-PBS and filter through a 40μm cell strainer to obtain a single cell suspension. Use 3ml RBC lysis buffer to eliminate red blood cells in the isolated population. The isolated PBMCs are washed with 2% FBS-PBS and resuspended in RPMI growth medium containing 10% FBS and antibiotics.

[0278] For Examples 6-11, PBMCs from 9 healthy donors were isolated and subjected to ex vivo LPS-stimulation for IL-23, IL-12p40, IL-12p70, TNF-α, IFN-γ and MCP-1 cytokine analysis. PBMCs were seeded in 96-well plates at a density of 200,000 cells per well in 200 μl RPMI growth medium containing 10% FBS, followed by DMSO and compound treatment. Each well received the same amount of DMSO, which was at a final concentration of 0.3% v / v. Serial dilutions of compound treatment were performed as shown below according to Table 4. After 2 hours of compound treatment, LPS at a final concentration of 100 ng / ml was used as a stimulus. The PBMCs were then incubated in a 37°C / 5% CO2 incubator for 16 hours.

[0279] Table 4: Compound treatment conditions used for PBMC assay

[0280]

[0281] After 16 hours of incubation, the supernatant was collected into a new 96-well polypropylene plate and centrifuged at 4000 rpm for 10 minutes to remove cell debris. Cytokine production was measured by Luminex Bio-Plex multiple immunoassay (Bio-Rad) according to the manufacturer's procedure. In order to ensure that the supernatant level is within the range of the standard cytokines for determination, the sample was diluted 5 times for IL-12p40 and 27-plex determinations, and pure samples were used for IL-23 determinations.

[0282] 3. Data Analysis

[0283] Milliplex Analyst (Millipore) was used to process the data of cytokine analysis, and the raw data were exported to Excel templates for cytokine analysis. GraphPad Prism 7.0 (GraphPad Software, Inc., Lajolla, CA) was used to draw the data from the templates and expressed as pg / ml or % of control. One-way Anova and Dunnett's post-test were also used for statistical analysis.

[0284] Bio-plex manager was used to process the data of PBMC assays, and raw data were exported to Excel templates for cytokine analysis. GraphPad Prism 7.0 (GraphPad Software, Inc., La Jolla, CA) was used to plot data and expressed as % of DMSO control. Statistical analysis was performed using one-way ANOVA and Tukey's multiple comparison test.

[0285] To evaluate the combined effect of apremilast and BMS-986165, data from two independent treatments were analyzed by comparing the combined response of the two agents to the theoretical additive response. The expected additive effect of the two agents (A and B) was calculated using the fractional product method: (fu)A,B = (fu)A × (fu)B; where fu = fraction unaffected by treatment. Synergy of the combination was determined when the observed unaffected fraction in the combination was less than (fu)A,B, while additive effect was determined when the observed unaffected fraction in the combination was equal to (fu)A,B. Partial additive effect was indicated when the observed unaffected fraction in the combination was greater than (fu)A,B.

[0286] Example 1

[0287] Interleukin 17A cytokine production by apremilast and BMS-986165 in whole blood stimulated with anti-CD3 / anti-CD28 (Th0) or anti-CD3 / anti-CD28, IL-1β, IL-6, and IL-23 (Th17)

[0288] Whole blood from four healthy donors was analyzed for IL-17A, IL-17F, IL-22, TNF-α, and GM-CSF cytokine production under both Th0 and Th17 conditions. The blood was pretreated with both Apremilast and the Tyk2 inhibitor BMS-986165, alone and in combination, using a tube system. Figure 1 The IL-17A results in the table show IL-17A% of the control, and all data are normalized to the Th17 DMSO control. Apremilast inhibited IL-17A cytokine expression by 28% under Th0 conditions and had no effect under Th17 conditions. BMS-986165 had similar effects under both stimulation conditions and inhibited IL-17A expression by 10-25% at 0.001-1 μM. Under Th0 conditions, when Apremilast was combined with BMS-986165, a synergistic effect with 1 μM BMS-986165 was observed, with a 65% reduction in IL-17A. Under Th17 conditions, there was a synergistic effect in the combination of 1 μM Apremilast and 0.01 μM, 0.1 μM, and 1 μM MBS-986165, with inhibition of IL-17A of 24%, 44%, and 85%, respectively. Figure 2Picograms per milliliter of IL-17A levels are shown. IL-17A levels increased 387% in Th17 stimulation conditions compared to Th0 stimulation. Apremilast reduced IL-17A levels from 138pg / mL to 93pg / mL in Th0 conditions. BMS-986165 reduced IL-17A levels to 97pg / mL at 1μM. Under Th0 stimulation, the combination of Apremilast with 1μM BMS-986165 further reduced IL-17A levels to 24pg / mL. Under Th17 conditions, the stimulation control measured 532pg / mL, and Apremilast did not inhibit IL-17A levels. BMS-986165 reduced IL-17A levels to 519 pg / mL at 0.01 μM, 428 pg / mL at 0.1 μM, and 383 pg / mL at 1 μM. The combination of 1 μM apremilast and BMS-986165 reduced IL-17A levels to 379 pg / mL at 0.01 μM BMS-986165, 328 pg / mL at 0.1 μM BMS-986165, and 68 pg / mL at 1 μM BMS-986165.

[0289] Example 2

[0290] Interleukin 17F cytokine production by apremilast and BMS-986165 in whole blood stimulated with anti-CD3 / anti-CD28 (Th0) or anti-CD3 / anti-CD28, IL-1β, IL-6, and IL-23 (Th17)

[0291] IL-17F cytokine expression data in Figure 3 and Figure 4Apremilast inhibited 69% of IL-17F production under Th0 conditions and 49% of IL-17F production under Th17 conditions. BMS-986165 has similar effects on IL-17F under both Th0 and Th17 stimulations. There was a 31% inhibition at the lowest concentration of 0.001 μM, and a dose response of 34% inhibition of IL-17F expression at 0.01 μM, 70% inhibition of IL-17F expression at 0.1 μM, and 95% inhibition of IL-17F expression at 1 μM (Th17 results). Under Th0 conditions, the combination of 1 μM Apremilast and BMS-986165 was partially cumulative, with an inhibition range from 60% at 0.001 μM to 95% at 1 μM. Under Th17 conditions, lower concentrations of BMS-986165 combined with Apremilast showed synergistic effects. Under Th17 stimulation conditions, Apremilast inhibited IL-17F production by 68% in combination with BMS-986165 at 0.001 μM, 70% in combination with BMS-986165 at 0.01 μM, 94% in combination with BMS-986165 at 0.1 μM, and 99% in combination with BMS-986165 at 1 μM. The level of IL-17F was 1085 pg / mL in the Th0 stimulation control and increased to 6524 pg / mL in Th17 stimulation. Apremilast reduced IL-17F to 368 pg / mL in Th0 stimulation and to 3643 pg / mL in Th17 stimulation. In both stimulation conditions, BMS-986165 significantly reduced IL-17F at 0.1 and 1 μM. There was significant inhibition of IL-17F at all concentrations of BMS-986165 when combined with apremilast and under both stimulation conditions.

[0292] Example 3

[0293] Interleukin 22 cytokine production by apremilast and BMS-986165 in whole blood stimulated with anti-CD3 / anti-CD28 (Th0) or anti-CD3 / anti-CD28, IL-1β, IL-6, and IL-23 (Th17)

[0294] IL-22 cytokine expression data in Figure 5 and Figure 6Apremilast inhibited IL-22 cytokine expression by 85% under Th0 conditions and 41% under Th17 conditions. Under Th0 stimulation conditions, BMS-986165 inhibited IL-22 by 16% at 0.01 μM, 86% at 0.1 μM, and 91% at 1 μM. Under Th17 stimulation conditions, BMS-986165 had no effect on IL-22 cytokine expression at 0.001 μM, but inhibited IL-22 cytokine expression by 17% at 0.01 μM, 60% at 0.1 μM, and 70% at 1 μM. Under Th0 conditions, the combination had a similar effect to Apremilast alone, with an inhibition of ~90% at all concentrations of BMS-98616. This combination under Th17 conditions is a synergist, suppressing 60% IL-22 cytokine expression at 0.01μM concentration, and 90% IL-22 cytokine expression at 0.1μM concentration. The Th0 stimulation control has 1085pg / mL of IL-22 and the Th17 control is 6524pg / mL. Apremilast significantly reduces IL-22 levels to 368pg / mL under Th0 conditions and significantly reduces to 3643pg / mL under Th17 conditions. BMS-986165 significantly reduces IL-22 cytokine expression in two stimulation conditions at 0.1μM and 1μM. When combined with Apremilast and under two stimulation conditions, IL-22 is significantly suppressed at all concentrations of BMS-986165.

[0295] Example 4

[0296] TNF-α cytokine production by apremilast and BMS-986165 in whole blood stimulated with anti-CD3 / anti-CD28 (Th0) or anti-CD3 / anti-CD28, IL-1β, IL-6, and IL-23 (Th17)

[0297] TNF-α cytokine expression data are located at Figure 7 and Figure 8Apremilast inhibited TNF-α levels by 90% in Th0 conditions and 94% in Th17 conditions. In Th0 stimulation, BMS-986165 increased TNF-α expression by 21% at 0.001 μM, 43% at 0.01 μM, and 61% at 0.1 μM. BMS-986165 at the highest concentration of 1 μM inhibited TNF-α cytokine expression by 66%. Under Th17 conditions, similar increases in TNF-α production were observed with BMS-986165, with an increase of 19% at 0.01 μM and 77% at 0.1 μM. Under Th17 stimulation conditions, TNF-α was also inhibited (68%) with 1 μM BMS-986165. The combination of 1 μM Apremilast and BMS-986165 reduces TNF-α levels of 80-95% (Th0) and 93-96% (Th17), similar to the effect of single agent Apremilast. Two stimulation conditions have similar effects on TNF-α levels, with the Th0 stimulation control being 1380pg / mL, and the Th17 stimulation control being 1436pg / mL. Apremilast significantly inhibits TNF-α by reducing levels to 148pg / mL in Th0 conditions and to 91pg / mL in Th17 conditions. The increase in TNF-α levels by BMS-986165 at 0.1μM in Th17 conditions is significant. Under two stimulation conditions, the inhibition of TNF-α levels using 1μM BMS-986165 is significant. At all concentrations and under two stimulation conditions, the combination of Apremilast and BMS-986165 significantly inhibits TNF-α levels.

[0298] Example 5

[0299] Granulocyte-macrophage colony-stimulating factor cytokine production by apremilast and BMS-986165 in whole blood stimulated with anti-CD3 / anti-CD28 (Th0) or anti-CD3 / anti-CD28, IL-1, IL-6, and IL-23 (Th17)

[0300] Granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine expression results in Fig. 9 and Fig.10Apremilast reduced GM-CSF cytokine expression by 80% under Th0 conditions and by 66% under Th17 conditions. BMS-986165 increased GM-CSF cytokine expression under both conditions. In Th0 conditions, BMS-986165 increased GM-CSF by 19% at 0.001 μM, 36% at 0.01 μM, 110% at 0.1 μM, and 31% at 1 μM. When Apremilast (0.1 μM) was added to BMS-986165, there was a 60-80% inhibition of GM-CSF cytokine expression. In Th17 stimulation, BMS-986165 increased GM-CSF by 41% at 0.01 μM, 139% at 0.1 μM, and 104% at 1 μM. When Apremilast was added, there was a 40-73% inhibition of GM-CSF cytokine expression. The total pg / mL of GM-CSF in the Th0 and Th17 stimulation controls were 409 and 637, respectively. Apremilast significantly inhibited GM-CSF under both stimulation conditions. The increase in GM-CSF by BMS-986165 at 0.1 μM (both Th0 and Th17) and 1 μM (Th17) was significant. The combination of Apremilast and BMS-986165 significantly reduced GM-CSF cytokine levels at all concentrations and under both stimulation conditions.

[0301] Example 6

[0302] IL-23 production in LPS-stimulated PBMCs treated with apremilast and Tyk2i (BMS-986165)

[0303] PBMCs from 9 healthy donors were analyzed for cytokine production under LPS stimulation conditions ( Figures 11 to 17 ). Fig.11 and Fig.12 The results in Figure 2 show the levels of IL-23. Fig.11 Apremilast was shown to reduce IL-23 production in LPS-stimulated PBMCs. IL-23 levels from DMSO-treated LPS-stimulated PBMCs were set to 100% (control), and cytokine levels are shown as normalized values ​​(%) compared to control. In contrast to the reduction of IL-23 levels by Apremilast, Fig.12BMS-986165 is shown to induce IL-23 levels in LPS-stimulated PBMCs. In the range of 0.2 μM-2 μM, BMS-986165 induces IL-23 by 20 times compared to the DMSO group. The combination of Apremilast and BMS-986165 is able to reduce the induction of IL-23 by BMS-986165. As the level of Apremilast increases, the level of IL-23 decreases significantly. Statistical analysis was performed using ANOVA and Turkey's multiple comparisons to compare each treatment with BMS-986165 alone. When BMS-986165 was combined with a low level of Apremilast at a concentration of 0.037 μM, IL-23 was significantly reduced (****p<0.001). When combined with 1 μM Apremilast, the induction of IL-23 was inhibited by 90%, and almost reached a level similar to that of Apremilast alone. Therefore, there was no significant difference in the curve of the combined treatment with 1 μM Apremilast compared to the treatment with Apremilast alone.

[0304] Example 7

[0305] IL-12p40 production in LPS-stimulated PBMCs treated with apremilast and Tyk2i (BMS-986165)

[0306] Fig.13 The results in show the normalized levels of IL-12p40 compared to the DMSO treated LPS stimulated PBMC group. Apremilast reduced IL-12p40 in a dose-dependent manner, while BMS-986165 increased IL-12p40. The combination of BMS-986165 with Apremilast significantly reduced the induction of IL-12p40 by BMS-986165. With 1 μM Apremilast, the increased IL-12p40 induced by BMS-986165 was 85% inhibited and almost reached a level similar to that of Apremilast alone. Statistical analysis was performed using ANOVA and Turkey's multiple comparisons to compare each treatment with BMS-986165 alone. ****p<0.001.

[0307] Example 8

[0308] IL-12p70 production in LPS-stimulated PBMCs treated with apremilast and Tyk2i (BMS-986165)

[0309] Fig.14The results in show the normalized levels of IL-12p70 compared to the DMSO treated LPS stimulated PBMC group. Apremilast reduced IL-12p70 in a dose-dependent manner, while BMS-986165 increased IL-12p70. The combination of BMS-986165 with Apremilast significantly reduced the induction of IL-12p70 by BMS-986165. In the combined treatment, both 0.3 μM and 1 μM significantly reduced the levels of IL-12p70 induced by BMS-986165, and there was no significant difference compared to Apremilast alone. Statistical analysis was performed using ANOVA and Turkey's multiple comparisons to compare each treatment with BMS-986165 alone. ****p<0.001.

[0310] Example 9

[0311] TNF-α production in LPS-stimulated PBMCs treated with apremilast and Tyk2i (BMS-986165)

[0312] Fig.15 Results in show normalized levels of TNF-α compared to the DMSO treated LPS stimulated PBMC group. Apremilast reduced TNF-α levels in a dose dependent manner, however, BMS-986165 induced a 1.2-1.5 fold increase in TNF-α. The combination of BMS-986165 and Apremilast significantly reduced the levels of TNF-α. Statistical analysis was performed using ANOVA and Turkey's multiple comparisons to compare each treatment with BMS-986165 alone. ****p<0.001.

[0313] Example 10

[0314] IFN-γ production in LPS-stimulated PBMCs treated with apremilast and Tyk2i (BMS-986165)

[0315] Fig.16 The results in show the normalized levels of IFN-γ compared to the PBMC group stimulated by LPS treated with DMSO. Both Apremilast alone and BMS-986165 alone reduce IFN-γ in a dose-dependent manner. The combination of BMS-986165 and Apremilast has a synergistic effect in reducing IFN-γ levels, which significantly reduces IFN-γ levels compared to single compound treatment. Statistical analysis was performed using ANOVA and Turkey's multiple comparisons to compare each treatment with BMS-986165 alone. ****p<0.001.

[0316] Embodiment 11

[0317] MCP-1 production in LPS-stimulated PBMCs treated with apremilast and Tyk2i (BMS-986165)

[0318] Fig.17 The results in show the normalized levels of MCP-1 compared to the PBMC group stimulated by LPS treated with DMSO. Both Apremilast and BMS-986165 alone reduce MCP-1 in a dose-dependent manner. The combination of BMS-986165 and Apremilast has a synergistic effect in reducing MCP-1 levels. ANOVA and Turkey's multiple comparison statistical analysis are used to compare each treatment with BMS-986165 alone. ****p<0.001.

[0319] Data Summary

[0320] The following Table 5 provides the Summary of cytokine effects of Apremilast and BMS-986165 on stimulated whole blood in the assay. Synergistic effects are shown in bold and complementary effects are underlined.

[0321] Whole blood from four healthy donors was tested in the TruCulture assay for 48 hours with the Tyk2 inhibitor BMS-986165 + / - Apremilast in Th0 (anti-CD3 / anti-CD28) or Th17 (anti-CD3 / anti-CD28 + IL-1β, IL-6, and IL-23) conditions. BMS-986165 inhibited IL-17A, IL-17F, and IL-22 cytokine expression under Th0 and Th17 conditions. Under Th17 conditions, these cytokines were further reduced when combined with Apremilast, with synergistic effects on IL-17A, IL-17F, and IL-22. BMS-986165 increased the production of TNF-α and GM-CSF, while Apremilast inhibited the production of these cytokines. When BMS-986165 is combined with Apremilast, there are complementary effects on TNF-α and GM-CSF cytokine expression, with Apremilast correcting the deficiency of BMS-986165. These combined actions provide methods for treating diseases or disorders that respond to inhibition of PDE4, such as for treating inflammatory diseases (e.g., psoriasis, psoriatic arthritis, and ulcerative colitis).

[0322] Table 5

[0323]

[0324]

[0325] Table 6 below provides a summary of the cytokine effects of Apremilast and BMS-986165 on LPS-stimulated PBMCs. Red arrows indicate induction, and green arrows indicate reduction in cytokine production.

[0326] PBMC from 9 healthy donors were tested in the condition of LPS stimulation with or without BMS-986165 or Apremilast or a combination of the two. Individual BMS-986165 treatment induces IL-23, IL-12p40, IL-12p70 and TNF-α, while individual Apremilast treatment reduces these cytokines. When BMS-986165 was combined with Apremilast, these cytokines did not change or decrease compared with the DMSO control group. These results show that Apremilast can inhibit the induction of these cytokines by BMS-986165. Both Apremilast and BMS-986165 reduce IFN-γ and MCP-1 production, and the combination of the two further reduces these two cytokines with synergistic effect. BMS-986165 inhibits Th17 lineage cytokines, which provides a method for treating a disease in which Th17 cytokines are involved in pathogenesis. However, the induction of some pro-inflammatory cytokines such as IL-23, IL-12 and TNF-α by BMS-986165 may be a disadvantage in disease treatment. The combined effects of Apremilast and BMS-986165, where IL-23, IL-12 and TNF-α were reduced, show the advantages of combining these two compounds in the treatment of inflammatory diseases such as psoriasis, psoriatic arthritis and ulcerative colitis.

[0327] Table 6

[0328]

[0329] Example 12

[0330] Fixed-dose combination of apremilast and Tyk2i (BMS-986165) in whole blood

[0331] Apremilast and BMS-986165 were tested in whole blood for IL-17A, IL-17F, IL-22, and TNF-α at the following fixed doses: 2 mg BID BMS-986165, 6 mg QD BMS-986165, 6 mg BID BMS-986165, 10 mg BID apremilast, 20 mg BID apremilast, and 30 mg BID apremilast. These concentrations were derived from observed mean plasma concentrations or extrapolated from clinical pharmacokinetic data.

[0332] like Figure 18-21As shown, BMS-986165 at the 6 mg QD dose concentration did not maximally inhibit IL-17A, IL-17F, or IL-22, and it elevated TNF-α. Figure 18-21 However, the addition of apremilast at dose concentrations of 10 to 30 mg BID compensated for this and prevented the TNF-α elevation. Figure 18-21 . Even low concentrations of apremilast were shown to have an effect. For example, apremilast at a 20 mg BID dose compensated for suboptimal inhibition of IL-17F, and apremilast at a 10 mg BID dose compensated for suboptimal inhibition of IL-22 and prevented increases in TNF-α. The data support the synergistic use of BMS-986165 (e.g., at 6 mg QD) and apremilast (e.g., 10-20 mg QD or BID) to inhibit IL-17 and IL-22 and reduce TNF-α production for the treatment of inflammatory diseases driven by these cytokines such as psoriasis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, Crohn's disease, hidradenitis suppurativa, and Behcet's disease.

Claims

1. A method for treating a disease or disorder responsive to inhibition of phosphodiesterase type 4 (PDE4) in a subject, comprising administering to the subject a therapeutically effective amount of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide, or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a tyrosine kinase 2 (Tyk2) inhibitor or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the Tyk2 inhibitor has the following formula: or a pharmaceutically acceptable salt thereof, wherein R 1 It is optional to be 0-7 R 1a Substituted C 1-3 alkyl; R 1a is independently at each occurrence hydrogen, deuterium, F, Cl, Br, CF3 or CN; R 2 It is C 1-6 Alkyl or -(CH2) r -3-14 membered carbon ring, each group is composed of 0-4 R 2a replace; R 2a is independently at each occurrence hydrogen, =O, halogen, OCF3, CN, NO2, -(CH2) r OR b 、-(CH2) r SR b 、-(CH2) r C(O)R b 、-(CH2) r C(O)OR b 、-(CH2) r OC(O)R b 、-(CH2) r NR 11 R 11 、-(CH2) r C(O)NR 11 R 11 、-(CH2) r NR b C(O)R c 、-(CH2) r NR b C(O)OR c 、-NR b C(O)NR 11 R 11 、-S(O) p NR 11 R 11 、-NR b S(O) p R c 、-S(O) p R c , 0-3 R a Substituted C 1-6 Alkyl, C 1-6 Halogenated alkyl, 0-3 R a Substituted C 2-6 Alkenyl, 0-3 R a Substituted C 2-6 Alkynyl, 0-1 R a Substituted -(CH2) r -3-14 membered carbon ring or 0-2 R a The substituted one contains carbon atoms or 1 to 4 atoms selected from N, O and S(O) p Heteroatom -(CH2) r -5-7 membered heterocyclic ring; R 3 It is C 3-10 Cycloalkyl, C 6-10 Aryl or a 5-10 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S, each of which is surrounded by 0-4 R 3a replace; R 3a is independently at each occurrence hydrogen, =O, halogen, OCF3, CF3, CHF2, CN, NO2, -(CH2) r OR b 、-(CH2) r SR b 、-(CH2) r C(O)R b 、-(CH2) r C(O)OR b 、-(CH2) r OC(O)R b 、-(CH2) r NR 11 R 11 、-(CH2) r C(O)NR 11 R 11 、-(CH2) r NR b C(O)R c 、-(CH2) r NR b C(O)OR c 、-NR b C(O)NR 11 R 11 、-S(O) p NR 11 R 11 、-NR b S(O) p R c 、-S(O) p R c , 0-3 R a Substituted C 1-6 Alkyl, 0-3 R a Substituted C 2-6 Alkenyl, 0-3 R a Substituted C 2-6 Alkynyl, C 1-6 Halogenated alkyl, 0-3 R a Substituted -(CH2) r -3-14 membered carbon ring or 0-3 R a The substituted carbon atoms and 1 to 4 atoms selected from N, O and S(O) p Heteroatom -(CH2) r -5-10 membered heterocyclic ring; or two R 3a , together with the atoms to which they are attached, to form a fused ring, wherein the ring is selected from phenyl and a 5-7 membered heterocyclic ring comprising carbon atoms and 1-4 heteroatoms selected from N, S or O, the fused ring being further R a1 replace; R 4 and R 5 are independently hydrogen, 0-1 R f Substituted C 1-4 Alkyl, 0-3 R d Substituted (CH2) r -phenyl, or -(CH2)-5-7 membered heterocyclic ring containing carbon atoms and 1-4 heteroatoms selected from N, O and S(O)p; R 11 is independently hydrogen at each occurrence, 0-3 R f Substituted C 1-4 Alkyl, CF3, 0-1 R f Substituted C 3-10 Cycloalkyl, 0-3 R d Substituted (CH) r -phenyl, or 0-3 R d The substituted one contains carbon atoms and 1 to 4 atoms selected from N, O and S(O) p Heteroatom -(CH2) r -5-7 membered heterocyclic ring; R a and R a1 is independently at each occurrence hydrogen, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, -(CH2) r OR b 、-(CH2) r SR b 、-(CH2) r C(O)R b 、-(CH2) r C(O)OR b 、-(CH2) r OC(O)R b 、-(CH2) r NR 11 R 11 、-(CH2) r C(O)NR 11 R 11 、-(CH2) r NR b C(O)R c 、-(CH2) r NR b C(O)OR c 、-NR b C(O)NR 11 R 11 、-S(O) p NR 11 R 11 、-NR b S(O) p R c 、-S(O)R c 、-S(O)2R c , 0-3 R f Substituted C 1-6 Alkyl, C 1-6 Halogenated alkyl, 0-3 R a Substituted C 2-6 Alkenyl, 0-3 R a Substituted C 2-6 Alkynyl, 0-3 R f Substituted -(CH2) r -3-14 membered carbon ring or 0-3 R f The substituted one contains carbon atoms and 1 to 4 atoms selected from N, O and S(O) p Heteroatom -(CH2) r -5-7 membered heterocyclic ring; R b is independently hydrogen at each occurrence, 0-3 R d Substituted C 1-6 Alkyl, C 1-6 Halogenated alkyl, 0-2 R d Substituted C 3-6 Cycloalkyl, or 0-3 R f The substituted one contains carbon atoms and 1 to 4 atoms selected from N, O and S(O) p Heteroatom -(CH2) r -5-7 membered heterocyclic ring or 0-3 R d Substituted (CH2) r -phenyl; R c Is 0-3 R f Substituted C 1-6 Alkyl, 0-3 R f Substituted (CH2) r -C 3-6 Cycloalkyl, 0-3 R f Substituted (CH2) r -phenyl; or R d is independently at each occurrence hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -OR e 、-(CH2) r C(O)R c 、-NR e R e 、-NR e C(O)OR c , C 1-6 Alkyl, or 0-3 R f Substituted (CH2) r -phenyl; R e is independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, and 0-3 R f Substituted (CH2) r -phenyl; R f is independently at each occurrence hydrogen, halogen, CN, NH2, OH, C 3-6 Cycloalkyl, CF3, O(C 1-6 alkyl), or containing carbon atoms and 1 to 4 selected from N, O and S(O) p Heteroatom -(CH2) r -5-7 membered heteroaryl; p is 0, 1, or 2; and r is 0, 1, 2, 3 or 4.

3. The method of claim 1, wherein the Tyk2 inhibitor has the following formula: or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally replaced by 0-7 R 1a Substituted C 1-3 alkyl R 1a is independently at each occurrence hydrogen, deuterium, F, Cl, Br, CF3 or CN; R 2 Is 0-4 R 2a Substituted C 1-6 Alkyl, 0-4 R 2a Substituted C 3-6 Cycloalkyl, 0-4 R 2a Substituted C 6-10 Aryl, 0-4 R 2a NR 6 R 6 OR b a substituted 5-14 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S; R 2a is independently at each occurrence hydrogen, =O, halogen, OCF3, CN, NO2, -(CH2) r OR b 、-(CH2) r SR b 、-(CH2) r C(O)R b 、-(CH2) r C(O)OR b 、-(CH2) r OC(O)R b 、(CH2) r NR 11 R 11 、-(CH2) r C(O)NR 11 R 11 、-(CH2) r NR b C(O)R C 、-(CH2) r NR b C(O)OR C 、-NR b C(O)NR 11 R 11 、-S(O) p NR 11 R 11 、-NR b S(O) p R C 、-S(O) p R C , 0-3 R a Substituted C 1-6 Alkyl, C 1-6 Halogenated alkyl, 0-1 R a Substituted -(CH2) r -3-14 membered carbon ring or 0-2 R a The substituted one contains carbon atoms or 1 to 4 atoms selected from N, O and S(O) p Heteroatom -(CH2) r -5-7 membered heterocyclic ring; or an R 2a and another R 2a , together with the atoms to which they are attached, to form a fused 5-6 membered ring, wherein the fused ring may be substituted by 0-2 R a replace; R 3 Is 0-5 R 3a Substituted -(CH2) r -3-14 membered carbon ring; R 3a is independently at each occurrence hydrogen, =O, halogen, OCF3, CN, NO2, -(CH2) r OR b 、-(CH2) r SR b 、-(CH2) r C(O)R b 、-(CH2) r C(O)OR b 、-(CH2) r OC(O)R b 、(CH2) r NR 11 R 11 、-(CH2) r C(O)NR 11 R 11 、-(CH2) r NR b C(O)R C 、-(CH2) r NR b C(O)OR C 、-NR b C(O)NR 11 R 11 、-S(O) p NR 11 R 11 、-NR b S(O) p R C 、-S(O) p R C , 0-3 R a Substituted C 1-6 Alkyl, C 1-6 Halogenated alkyl, 0-3 R a Substituted -(CH2) r -3-14 membered carbon ring or 0-3 R a The substituted one contains carbon atoms or 1 to 4 atoms selected from N, O and S(O) p Heteroatom -(CH2) r -5-10 membered heterocyclic ring; or two R 3a , together with the atoms to which they are attached, to form a fused ring, wherein the ring is selected from phenyl and a 5-7 membered heterocyclic ring containing carbon atoms and 1-4 heteroatoms selected from N, S or O, and the fused ring may be further R a replace; R 4 and R 5 are independently hydrogen, 0-1 R f Substituted C 1-4 Alkyl, 0-3 R d Substituted (CH2) r -phenyl, or containing 5 carbon atoms and 1 to 4 selected from N, O and S(O) p Heteroatom -(CH2) r -5-7 membered heterocyclic ring; R 6 and R 11 is independently hydrogen at each occurrence, 0-3 R f Substituted C 1-4 Alkyl, CF3, 0-1 R f Substituted C 3-10 Cycloalkyl, 0-3 R d Substituted (CH) r -phenyl, or 0-3 R d The substituted one contains carbon atoms and 1 to 4 atoms selected from N, O and S(O) p Heteroatom -(CH2) r -5-7 membered heterocyclic ring; R a At each occurrence, it is hydrogen, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, -(CH2) r OR b 、-(CH2) r SR b 、-(CH2) r C(O)R b 、-(CH2) r C(O)OR b 、-(CH2) r OC(O)R b 、-(CH2) r NR 11 R 11 、-(CH2) r C(O)NR 11 R 11 、-(CH2) r NR b C(O)R C 、-(CH2) r NR b C(O)OR C 、-NR b C(O)NR 11 R 11 、-S(O) p NR 11 R 11 、-NR b S(O) p R C 、-S(O)R C 、-S(O)2R C , 0-3 R f Substituted C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) r -3-14 membered carbon ring, or 0-3 R f The substituted one contains carbon atoms and 1 to 4 atoms selected from N, O and S(O) p Heteroatom -(CH2) r -5-715 membered heterocycle; R b In each occurrence, it is hydrogen, surrounded by 0-3 R d Substituted C 1-6 Alkyl, C 1-6 Halogenated alkyl, 0-2 R d Substituted C 3-6 Cycloalkyl, or 0-3 R f The substituted one contains carbon atoms and 1 to 4 atoms selected from N, O and S(O) p Heteroatom -(CH2) r -5-7 membered heterocyclic ring, or 0-3 R d Substituted (CH2) r -phenyl; R C Is 0-3 R f Substituted C 1-6 Alkyl, 0-3 R f Substituted (CH2) r -C 3-6 Cycloalkyl or 0-3 R f Substituted (CH2) r -phenyl; R d Each occurrence is independently hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, OR e 、-(CH2) r C(O)R C NR e R e 、-NR e C(O)OR C , 0-3 R f Substituted C 1-6 Alkyl or 0-3 R f Substituted (CH2) r -phenyl; R e independently selected at each occurrence from hydrogen, 0-3 R f Substituted C 1-6 Alkyl, 0-3 R f Substituted C 3-6 Cycloalkyl and 0-3 R f Substituted (CH2) r -phenyl; R f independently at each occurrence is hydrogen, halogen, CN, NH2, OH, C 3-6 Cycloalkyl, CF3, O(C 1-6 Alkyl) or containing carbon atoms and 1-4 selected from N, O or S (O) p Heteroatom -(CH2) r -5-7 membered heteroaryl; p is 0, 1, or 2; and r is 0, 1, 2, 3 or 4.

4. The method of claim 1, wherein the Tyk2 inhibitor has the formula: or a pharmaceutically acceptable salt thereof, wherein Y is N or CR6; R 1 It is H, C 1-3 Alkyl or C 3-6 Cycloalkyl, each optionally substituted with 0-7 R 1a replace; R 1a is independently at each occurrence hydrogen, deuterium, F, Cl, Br or CN; R 2 It is C 1-6 Alkyl, 0-1 R 2a Substituted -(CH2) r - a 3- to 14-membered carbocyclic ring or a 5- to 14-membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S, each of which is surrounded by 0-4 R 2a Replace (for clarity, R 2 It is intended to include substituted methyl groups, such as -C(O)R 2a ); R 2a is independently at each occurrence hydrogen, =O, halogen, OCF3, CN, NO2, -(CH2) r OR b 、-(CH2) r SR b 、-(CH2) r C(O)R b 、-(CH2) r C(O)OR b 、-(CH2) r OC(O)R b , -CH2) r NR 11 R 11 、-(CH2) r C(O)NR 11 R 11 、-(CH2) r NR b C(O)R c 、-(CH2) r NR b C(O)OR c 、-NR b C(O)NR 11 R 11 、-S(O) p NR 11 R 11 、-NR b S(O) p R c 、-S(O) p R c , 0-3 R a Substituted C 1-6 Alkyl, C 1-6 Halogenated alkyl, 0-3 R a Substituted C 2-6 Alkenyl, 0-3 R a Substituted C 2-6 Alkynyl, 0-1 R a Substituted -(CH2) r -3-14 membered carbon ring or 0-2 R a The substituted one contains carbon atoms or 1 to 4 atoms selected from N, O and S(O) p Heteroatom -(CH2) r -5-7 membered heterocyclic ring; R 3 It is C 3-10 Cycloalkyl, C 6-10 Aryl or a 5-10 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S, each of which is surrounded by 0-4 R 3a replace; R 3a Each occurrence is independently hydrogen, =O, halogen, OCF3, CF3, CHF2, CN, NO2, -(CH2) r OR b 、-(CH2) r SR b 、-(CH2) r C(O)R b 、-(CH2) r C(O)OR b 、-(CH2) r OC(O)R b 、-(CH2) r NR 11 R 11 、-(CH2) r C(O)NR 11 R 11 、-(CH2) r NR b C(O)R c 、-(CH2) r NR b C(O)OR c 、-NR b C(O)NR 11 R 11 、-S(O) p NR 11 R 11 、-NR b S(O) p R c 、-S(O) p R c , 0-3 R a Substituted C 1-6 Alkyl, 0-3 R a Substituted C 2-6 Alkenyl, 0-3 R a Substituted C 2-6 Alkynyl, C 1-6 Halogenated alkyl, 0-3 R a Substituted -(CH2) r -3-14 membered carbon ring or 0-3 R a The substituted carbon atoms and 1 to 4 atoms selected from N, O and S (O )p Heteroatom -(CH2) r -5-10 membered heterocyclic ring; or two R 3a , together with the atoms to which they are attached, to form a fused ring, wherein the ring is selected from phenyl and contains carbon atoms and 1-4 atoms selected from N, O and S(O) p A heterocyclic ring containing a heteroatom, each fused ring being 0-3 R a1 replace; R 4 and R 5 are independently hydrogen, 0-1 R f Substituted C 1-4 Alkyl, 0-3 R d Substituted (CH2) r -phenyl or containing carbon atoms and 1-4 selected from N, O or S(O) p -(CH2)-5-7 membered heterocyclic ring containing a heteroatom; R 6 is hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, OC 1-4 Halogenated alkyl, OC 1-4 Alkyl, CN, NO2 or OH; R 11 Each occurrence is independently hydrogen, surrounded by 0-3 R f Substituted C 1-4 Alkyl, CF3, 0-1 R f Substituted C 3-10 Cycloalkyl, 0-3 R d Substituted (CH) r -phenyl or 0-3 R d The substituted one contains carbon atoms and 1 to 4 atoms selected from N, O or S(O) p Heteroatom -(CH2) r -5-7 membered heterocyclic ring; R a and R a1 Each occurrence is independently hydrogen, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, -(CH2) r OR b 、-(CH2) r SR b 、-(CH2) r C(O)R b 、-(CH2) r C(O)OR b 、-(CH2) r OC(O)R b 、-(CH2) r NR 11 R 11 、-(CH2) r C(O)NR 11 R 11 、-(CH2) r NR b C(O)R c 、-(CH2) r NR b C(O)OR c 、-NR b C(O)NR 11 R 11 、-S(O) p NR"R", -NR b S(O) p R c 、-S(O)R c 、-S(O)2R c , 0-3 R f Substituted C 1-6 Alkyl, C 1-6 Halogenated alkyl, 0-3 R a Substituted C 2-6 Alkenyl, 0-3 R a Substituted C 2-6 Alkynyl, 0-3 R f Substituted -(CH2) r -3-14 membered carbon ring or 0-3 R f The substituted one contains carbon atoms and 1 to 4 atoms selected from N, O and S(O) p Heteroatom -(CH2) r -5-7 membered heterocyclic ring; R b Is hydrogen, with 0-3 R d Substituted C 1-6 Alkyl, C 1-6 Halogenated alkyl, 0-2 R d Substituted C 3-6 Cycloalkyl, or 0-3 R f The substituted one contains carbon atoms and 1 to 4 atoms selected from N, O and S(O) p Heteroatom -(CH2) r -5-7 membered heterocyclic ring or 0-3 R d Substituted (CH2) r -phenyl; R c Is 0-3 R f Substituted C 1-6 Alkyl, 0-3 R f Substituted (CH2) r -C 3-6 Cycloalkyl or 0-3 R f Substituted (CH2) r -phenyl; R d Each occurrence is independently hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -OR e 、-(CH2) r C(O)R c 、-NR e R e 、-NR e C(O)OR c , 0-3 R f Substituted C 1-6 Alkyl or 0-3 R f Substituted (CH2) r -phenyl; R e Each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and 0-3 R f Substituted (CH2) r -phenyl; R f Each occurrence is independently hydrogen, halogen, CN, NH2, OH, C 3-6 Cycloalkyl, CF3, O(C 1-6 Alkyl) or containing carbon atoms and 1-4 selected from N, O and S(O) p Heteroatom -(CH2) r -5-7 membered heterocyclic ring; p is 0, 1, or 2; and r is 0, 1, 2, 3 or 4.

5. The method of claim 1 or 4, wherein the Tyk2 inhibitor has the following formula: or a pharmaceutically acceptable salt thereof.

6. The method of any one of claims 1 to 5, wherein the effective amount of the Tyk2 inhibitor or the pharmaceutically acceptable salt ranges from about 0.1 mg / day to about 250 mg / day.

7. The method of any one of claims 1 to 6, wherein the effective amount of the Tyk2 inhibitor or the pharmaceutically acceptable salt ranges from about 0.2 mg / day to about 100 mg / day, about 0.5 mg / day to about 50 mg / day, and about 1.0 mg to about 24 mg / day.

8. The method of any one of claims 1 to 7, wherein the effective amount of the Tyk2 inhibitor or the pharmaceutically acceptable salt ranges from about 1 mg / day to about 15 mg / day, about 1 mg / day to about 14 mg / day, about 2 mg / day to about 14 mg / day, about 2 mg / day to about 12 mg / day, or about 3 mg / day to about 12 mg / day.

9. The method of any one of claims 1 to 8, wherein the effective amount of the Tyk2 inhibitor is about 2 mg / day, about 3 mg / day, about 4 mg / day, about 5 mg / day, about 6 mg / day, about 7 mg / day, about 8 mg / day, about 9 mg / day, about 10 mg / day, about 11 mg / day or about 12 mg / day.

10. The method of any one of claims 1 to 9, wherein the effective amount of the Tyk2 inhibitor is about 6 mg / day.

11. The method of any one of claims 1 to 10, wherein the N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is greater than 95% stereoisomerically pure.

12. The method of any one of claims 1 to 11, wherein the N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is greater than 99% stereoisomerically pure.

13. The method of any one of claims 1 to 12, wherein the N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is greater than 99.5% stereoisomerically pure.

14. The method of any one of claims 1 to 13, wherein the N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is greater than 99.9% stereoisomerically pure.

15. The method of any one of claims 1 to 14, wherein the N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is in single crystalline form.

16. The method of any one of claims 1 to 15, wherein the N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is a single crystalline Form B characterized by an X-ray powder diffraction peak at 2θ angles selected from 10.1°, 13.5°, 20.7° and 26.9°.

17. The method of any one of claims 1 to 16, wherein the N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is a single crystalline Form B characterized by an X-ray powder diffraction peak at 2θ angles selected from 10.1°, 13.5°, 15.7°, 18.1°, 20.7°, 24.7° and 26.9°.

18. The method of any one of claims 1 to 17, wherein the N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is a single crystalline Form B characterized by an X-ray powder diffraction peak at 2θ angles selected from 10.1°, 13.5°, 15.7°, 16.3°, 18.1°, 20.7°, 22.5°, 24.7°, 26.2°, 26.9° and 29.1°.

19. The method of any one of claims 1 to 18, wherein the N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is at least 90% single crystalline Form B.

20. The method of any one of claims 1 to 19, wherein the N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is at least 95% single crystalline Form B.

21. The method of any one of claims 1 to 20, wherein the N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is at least 99% single crystalline Form B.

22. The method of any one of claims 1 to 20, wherein the effective amount of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof ranges from about 0.5 mg / day to about 1000 mg / day, from about 1 mg / day to about 1000 mg / day, from about 5 mg / day to about 500 mg / day, from about 10 mg / day to about 200 mg / day. / day, about 10 mg / day to about 100 mg / day, about 40 mg / day to about 100 mg / day, about 20 mg / day to about 40 mg / day, about 0.1 mg / day to about 10 mg / day, about 0.5 mg / day to about 5 mg / day, about 1 mg / day to about 20 mg / day, and about 1 mg / day to about 10 mg / day, about 1 mg / day to about 100 mg / day, about 1 mg / day to about 80 mg / day, about 5 mg / day to about 70 mg / day, and about 10 mg / day to about 60 mg / day.

23. The method of any one of claims 1 to 22, wherein the effective amount of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof ranges from about 10 mg / day to about 60 mg / day.

24. The method of any one of claims 1 to 23, wherein the effective amount of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof ranges from about 10 mg / day to about 40 mg / day.

25. The method of any one of claims 1 to 24, wherein the effective amount of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof is about 10 mg, administered once or twice a day.

26. The method of any one of claims 1 to 24, wherein the effective amount of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof is about 20 mg, administered once or twice a day.

27. The method of any one of claims 1 to 23, wherein the effective amount of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof is about 10 mg / day, about 15 mg / day, about 20 mg / day, about 25 mg / day, about 30 mg / day, about 35 mg / day, about 40 mg / day, about 45 mg / day, about 50 mg / day, about 55 mg / day or about 60 mg / day.

28. The method of any one of claims 1 to 23 and 27, wherein the effective amount of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof is about 30 mg / day or about 60 mg / day.

29. The method of any one of claims 1 to 23, 27 and 28, wherein the effective amount of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is about 30 mg, administered once a day.

30. The method of any one of claims 1 to 23, 27 and 28, wherein the effective amount of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is about 30 mg, administered twice daily.

31. The method of any one of claims 1 to 23, 27 and 28, wherein the N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is titrated to a dose of about 30 mg, administered twice daily, using the following titration regimen: Day 1: about 10 mg in the morning; Day 2: about 10 mg in the morning and about 10 mg in the evening; Day 3: about 10 mg in the morning and 20 mg in the evening; Day 4: about 20 mg in the morning and about 20 mg in the evening; Day 5: about 20 mg in the morning and about 30 mg in the evening; and Day 6 and thereafter: about 30 mg, twice a day.

32. The method of any one of claims 1 to 22, wherein the effective amount of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof ranges from about 40 mg / day to about 100 mg / day.

33. The method of any one of claims 1 to 22 and 32, wherein the N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is titrated to a dose between about 40 mg / day and about 100 mg / day using the following titration protocol: Day 1: about 10 mg in the morning; Day 2: about 10 mg in the morning and about 10 mg in the evening; Day 3: about 10 mg in the morning and 20 mg in the evening; Day 4: about 20 mg in the morning and about 20 mg in the evening; Day 5: about 20 mg in the morning and about 30 mg in the evening; and Day 6 and thereafter: between about 40 mg / day to about 100 mg / day.

34. The method of any one of claims 1 to 22, wherein the effective amount of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof is about 20 mg, administered twice a day.

35. The method of any one of claims 1 to 22 and 34, wherein the N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is titrated to a dose of about 20 mg, administered twice daily, using the following titration regimen: Day 1: about 10 mg in the morning; Day 2: about 10 mg in the morning and about 10 mg in the evening; Day 3: about 10 mg in the morning and 20 mg in the evening; Day 4: about 20 mg in the morning and about 20 mg in the evening; Day 5: about 20 mg in the morning and about 30 mg in the evening; and Day 6 and thereafter: about 20 mg, twice a day.

36. The method of any one of claims 1 to 22, wherein the effective amount of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof ranges from about 4 mg / day to about 10 mg / day.

37. The method of any one of claims 1 to 22 and 36, wherein the N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is titrated to a dose between about 4 mg / day and about 10 mg / day using the following titration protocol: Day 1: About 1 mg in the morning; Day 2: about 1 mg in the morning and about 1 mg in the evening; Day 3: about 1 mg in the morning and about 2 mg in the evening; Day 4: about 2 mg in the morning and about 2 mg in the evening; Day 5: about 2 mg in the morning and about 3 mg in the evening; and Day 6 and thereafter: between about 4 mg / day to about 10 mg / day.

38. The method of any one of claims 1 to 22, wherein the effective amount of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof is about 3 mg / day.

39. The method of any one of claims 1 to 22 and 38, wherein the N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is titrated to a dose of 3 mg, administered twice daily, using the following titration regimen: Day 1: About 1 mg in the morning; Day 2: about 1 mg in the morning and about 1 mg in the evening; Day 3: about 10 mg in the morning and about 2 mg in the evening; Day 4: about 2 mg in the morning and about 2 mg in the evening; Day 5: about 2 mg in the morning and about 3 mg in the evening; and Day 6 and thereafter: about 3 mg, twice a day.

40. The method of any one of claims 1 to 39, wherein the N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is formulated as part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

41. The method of any one of claims 1 to 40, wherein the N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is administered parenterally, transdermally, mucosally, nasally, buccally, sublingually or orally.

42. The method of any one of claims 1 to 41, wherein the N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is administered orally.

43. The method of any one of claims 1 to 42, wherein the N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is administered orally in the form of a tablet or capsule.

44. The method of any one of claims 40 to 43, wherein the N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is formulated for sustained release.

45. The method of any one of claims 40 to 43, wherein the N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is formulated for immediate release.

46. ​​The method of any one of claims 1 to 45, wherein the disease or disorder is selected from viral, genetic, inflammatory, allergic, and autoimmune diseases.

47. The method of any one of claims 1 to 46, wherein the disease or disorder is selected from chronic obstructive pulmonary disease, asthma, chronic pulmonary inflammatory disease, hyperoxic alveolar damage, inflammatory skin diseases, psoriasis, psoriatic arthritis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, atopic dermatitis, rheumatoid spondylitis, depression, osteoarthritis, contact dermatitis, ankylosing spondylitis, lupus, lupus nephritis, cutaneous lupus erythematosus, systemic lupus erythematosus, erythema nodosum leprosum, Sjögren's syndrome, inflammatory bowel disease, Crohn's disease, Behcet's disease, and ulcerative colitis.

48. The method of any one of claims 1 to 47, wherein the disease or disorder is selected from psoriasis, psoriatic arthritis, contact dermatitis, systemic lupus erythematosus, cutaneous lupus erythematosus, and ulcerative colitis.

49. The method of any one of claims 1 to 48, wherein the disease or disorder is psoriasis.

50. The method of any one of claims 1 to 49, wherein the disease or disorder is plaque psoriasis.

51. The method of any one of claims 1 to 50, wherein the disease or disorder is severe plaque psoriasis.

52. The method of any one of claims 49 to 51, wherein the subject is a candidate for phototherapy or systemic therapy.

53. The method of any one of claims 1 to 48, wherein the disease or disorder is psoriatic arthritis.

54. A pharmaceutical composition comprising a therapeutically effective amount of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide as defined in any one of claims 11 to 21, or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a Tyk2 inhibitor as defined in any one of claims 2 to 5.

55. The pharmaceutical composition of claim 54, wherein the Tyk2 inhibitor has the formula: or a pharmaceutically acceptable salt thereof.

56. The pharmaceutical composition of claim 54 or 55, wherein the composition is formulated for administration of about 1 mg / day to about 15 mg / day, about 1 mg / day to about 14 mg / day, about 2 mg / day to about 14 mg / day, about 2 mg / day to about 12 mg / day, or about 3 mg / day to about 12 mg / day of the Tyk inhibitor.

57. A pharmaceutical composition as described in any one of claims 54 to 56, wherein the composition is formulated for administration of about 2 mg / day, about 3 mg / day, about 4 mg / day, about 5 mg / day, about 6 mg / day, about 7 mg / day, about 8 mg / day, about 9 mg / day, about 10 mg / day, about 11 mg / day, or about 12 mg / day of the Tyk inhibitor.

58. The pharmaceutical composition of any one of claims 54 to 57, wherein the composition is formulated for administration of about 6 mg / day of the Tyk inhibitor.

59. A pharmaceutical composition as described in any one of claims 54 to 58, wherein the composition is formulated for administration of about 1 mg / day to about 1000 mg / day, about 5 mg / day to about 500 mg / day, about 10 mg / day to about 200 mg / day, about 10 mg / day to about 100 mg / day, about 40 mg / day to about 100 mg / day, about 20 mg / day to about 40 mg / day, about 0.1 mg / day to about 10 mg / day, about 0.5 mg / day to about 5 mg / day, about 1 mg / day to about 20 mg / day, and about 1 mg / day to about 10 mg / day, about 1 mg / day to about 100 mg / day, about 1 mg / day to about 80 mg / day, about 5 mg / day to about 70 mg / day, and about 10 mg / day to about 60 mg / day of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof.

60. A pharmaceutical composition as described in any one of claims 54 to 59, wherein the composition is formulated for administration of about 10 mg / day to about 60 mg / day of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof.

61. A pharmaceutical composition as described in any one of claims 54 to 60, wherein the composition is formulated for administration of about 10 mg / day, about 15 mg / day, about 20 mg / day, about 25 mg / day, about 30 mg / day, about 35 mg / day, about 40 mg / day, about 45 mg / day, about 50 mg / day, about 55 mg / day or about 60 mg / day of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof.

62. A pharmaceutical composition as described in any one of claims 54 to 61, wherein the composition is formulated for administration of about 30 mg / day or about 60 mg / day of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof.

63. A pharmaceutical composition as described in any one of claims 54 to 62, wherein the composition is formulated for once daily administration of about 30 mg of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof.

64. A pharmaceutical composition as described in any one of claims 54 to 61, wherein the composition is formulated for administration of about 30 mg of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof twice daily.

65. A pharmaceutical composition as described in any one of claims 54 to 60, wherein the composition is formulated for administration of about 10 mg / day to about 40 mg / day of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof.

66. A pharmaceutical composition as described in any one of claims 54 to 60 and 65, wherein the composition is formulated for administration of about 10 mg of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof once or twice daily.

67. A pharmaceutical composition as described in any one of claims 54 to 60 and 65, wherein the composition is formulated for administration of about 20 mg of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof once or twice daily.

68. A pharmaceutical composition as described in any one of claims 54 to 67, wherein the pharmaceutical composition is in tablet or capsule form.

69. The pharmaceutical composition of any one of claims 54 to 68, wherein the pharmaceutical composition is formulated for sustained release.

70. The pharmaceutical composition of any one of claims 54 to 68, wherein the pharmaceutical composition is formulated for immediate release.

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