JP2022537877A - Combination therapy including apremilast and a TYK2 inhibitor - Google Patents

Abstract

Provided herein are methods of treating diseases or disorders responsive to inhibition of PDE4, comprising administering apremilast and a Tyk2 inhibitor to a subject. Also provided herein are pharmaceutical compositions comprising apremilast and a Tyk2 inhibitor.

Description

[0001] N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro, sold as Otezla® -1,3-dioxo-1H-isoindol-4-yl]acetamide (apremilast) is a phosphodiesterase 4 (phosphodiesterase 4) currently approved to treat both moderate to severe plaque psoriasis and active psoriatic arthritis. PDE4) inhibitors. PDE4 inhibition by apremilast increases cyclic adenosine monophosphate (cAMP) levels in immune cells. This in turn down-regulates the inflammatory response by reducing the expression of pro-inflammatory mediators such as TNF-α, IL-23, IL-17, and other pro-inflammatory cytokines. Increase production. Studies have shown that a 75% reduction in plaque psoriasis can be achieved in some patients with as little as 4 months of treatment.

[0002] Tyrosine kinase 2 (Tyk2), an intracellular signaling enzyme, regulates signal transducer transcription factor (STAT)-dependent gene expression and IL-12, IL-23, and type I and III interferon receptors. activates the functional response of Tyrosine kinase inhibitors (TKIs), among other conditions, have recently attracted attention as effective agents for treating psoriasis and related conditions. The TKI inhibitor BMS-986165, for example, recently showed promising results in Phase 2 clinical trials in subjects with moderate to severe plaque psoriasis. The New England Journal of Medicine, Sept. 12, 2018, Kim Papp, M. D. , Phase 2 Trial of Selective Tyrosine Kinase 2 Initiative in Psoriasis.

[0003] Apremilast and the Tyk2 inhibitor 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)- Combination with N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165) synergistically reduced pro-inflammatory cytokines expressed under conditions stimulating Th17 cells in a whole blood assay here. was spotted. For example, using a combination of 0.01 μM BMS-986165 and 1 μM apremilast resulted in a greater than 2-fold increase in inhibition of IL-17F expression when compared to the use of each drug alone. See, for example, Table 5 in the Examples section. Similar results were seen at a concentration of 0.1 μM BMS-986165 with 1 μM apremilast. See, for example, Table 5. The combination of BMS-986165 and 1 μM apremilast also reduced cytokine expression for IL-17A and IL-22 by more than twice that of each drug used alone. See, for example, Table 5.

[0004] It has also been found that the combination of apremilast and BMS-986165 induces complementary effects on certain pro-inflammatory cytokines. BMS-986165, for example, increased TNF-α and GM-CSF cytokines in whole blood assays, while apremilast inhibited production of these cytokines. For example, see Table 5 where the % control for 1 μM apremilast for TNF-α was 10.7 and the % control for 0.01 μM BMS-986165 was 143.1. However, when administered in combination, apremilast corrected the defect of BMS-986165, resulting in a complementary effect of 13.5% inhibition on TNF-α. See, for example, Table 5. This trend was also observed at a concentration of 0.1 μM BMS-986165 and for the cytokine GM-CSF. See, for example, Table 5. These results indicate a synergistic and complementary pharmacological action of BMS-986165 and apremilast.

[0005] In addition to the whole blood assay, the combination of BMS-986165 and apremilast induces complementary effects on certain pro-inflammatory cytokines in LPS-stimulated PBMC as well. BMS-986165 increased IL-23, IL-12 and TNF-α, while apremilast inhibited production of these cytokines. See, for example, Table 6 in the Examples section. These results further support the benefit of combining BMS-986165 with apremilast in the treatment of Th17-related diseases.

[0006] Thus, treating a disease or disorder responsive to 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 A method is provided herein. Such diseases and disorders include, for example, inflammatory diseases such as psoriasis, psoriatic arthritis, and ulcerative colitis.

[0007] 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.

[0008] Apremilast and BMS in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood-TruCulture® tube assays FIG. 4 illustrates interleukin-17a (IL-17a) cytokine production (percentage of control) by -986165. [0009] Apremilast and BMS in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood-TruCulture® tube assays FIG. 4 illustrates interleukin-17A (IL-17A) cytokine production by -986165. [0010] Apremilast and BMS in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood-TruCulture® tube assays FIG. 4 illustrates interleukin-17F (IL-17F) cytokine production (percentage of control) by -986165. [0011] Apremilast and BMS in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood-TruCulture® tube assays FIG. 4 illustrates interleukin-17F (IL-17F) cytokine production by -986165. [0012] Apremilast and BMS in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood-TruCulture® tube assays FIG. 4 illustrates interleukin-22 (IL-22) cytokine production (percentage of control) by -986165. [0013] Apremilast and BMS in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood-TruCulture® tube assays FIG. 4 illustrates interleukin-22 (IL-22) cytokine production by -986165. [0014] Apremilast and BMS in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood-TruCulture® tube assays FIG. 4 illustrates tumor necrosis factor alpha (TNF-α) cytokine production (percentage of control) by -986165. [0015] Apremilast and BMS in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood-TruCulture® tube assays FIG. 4 illustrates tumor necrosis factor alpha (TNF-α) cytokine production by -986165. [0016] Apremilast and BMS in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood-TruCulture® tube assays FIG. 4 illustrates granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine production (percentage of control) by -986165. [0017] Apremilast and BMS in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood-TruCulture® tube assays FIG. 4 illustrates granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine production by -986165. [0018] Figure 1 illustrates interleukin-23 (IL-23) cytokine production by apremilast in lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs). [0019] Figure 1 illustrates interleukin-23 (IL-23) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS-stimulated PBMCs. [0020] Figure 1 illustrates interleukin-12p40 (IL-12p40) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS-stimulated PBMCs. [0021] Figure 1 illustrates interleukin-12p70 (IL-12p70) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS-stimulated PBMCs. [0022] Figure 1 illustrates tumor necrosis factor alpha (TNF-α) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS-stimulated PBMCs. [0023] Figure 1 illustrates interferon-gamma (IFN-γ) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS-stimulated PBMCs. [0024] Figure 1 illustrates monocyte chemoattractant protein-1 (MCP-1) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS-stimulated PBMCs.

[0025] In a first embodiment, provided herein is a method of treating a disease or disorder responsive to inhibition of cyclic nucleotide phosphodiesterase isoenzyme IV (PDE4), the method comprising 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 to the subject.

[0026] Alternatively, 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.

[0027] As part of another alternative 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.
1. definition
[0028] N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-iso Indol-4-yl]acetamide (apremilast) refers to a compound disclosed in US Pat. No. 6,962,940, the contents of which are incorporated herein by reference, having the following chemical structure.

[0029] Apremilast has a chiral center designated as (S) in its chemical structure and name. As used herein, this designation means that apremilast, as the (S) enantiomer at this position, is at least 80%, 90%, 95%, 98%, 99% relative to the corresponding (R) enantiomer, or It means optically enriched in an amount of 99.9%. Thus, when apremilast is referred to herein as being stereoisomerically or enantiomerically pure in a given amount, it is meant to be enriched in the (S) enantiomer in that amount. For example, N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro that is at least 95% stereoisomerically pure. -1,3-dioxo-1H-isoindol-4-yl]acetamide means that the compound contains 95% or more (S) enantiomer and 5% or less (R) enantiomer.

[0030] Unless otherwise indicated, administration as described herein includes administration of apremilast prior to, concurrently with, or after administration of a Tyk2 inhibitor as described herein. Therefore, co-administration is not necessary for therapeutic purposes. In one aspect, apremilast and a Tyk2 inhibitor of the present disclosure are administered together. In another aspect, apremilast and a Tyk2 inhibitor of this disclosure are administered at different times on the same day. In another aspect, apremilast and a Tyk2 inhibitor of this disclosure are administered as separate tablets or capsules at different times. In another aspect, apremilast and a Tyk2 inhibitor of this disclosure are administered in a fixed dose combination in the same tablet or capsule.

[0031] The terms "treatment," "treat," and "treating" refer to the progression of a disease or disorder, or one or more symptoms thereof, responsive to inhibition of PDE4, as described herein. Refers to ameliorating, alleviating, or inhibiting.

[0032] The term "subject" means animals such as mammals, and humans and the like. The terms "subject" and "patient" may be used interchangeably.
[0033] The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound described herein that elicits a biological or medical response in a subject, e.g. Dosage in kg of body weight/day.

[0034] The term "pharmaceutically acceptable carrier" refers to non-toxic carriers, adjuvants, which do not adversely affect the pharmacological activity of compounds with which they are formulated and which are safe for human use. , or refers to the vehicle. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the present disclosure include ion exchangers, alumina, aluminum stearate, magnesium stearate, lecithin, serum proteins such as human serum albumin, buffer substances, 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 silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosics (e.g., microcrystalline cellulose, hydroxypropyl methylcellulose, lactose monohydrate, sodium lauryl sulfate, and croscarmellose sodium), polyethylene glycol, sodium carboxymethylcellulose, Including, but not limited to, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycols and wool grease.

[0035] The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts for the compounds described herein include metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or lysine, N,N'- Including, but not limited to, organic salts made from dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Suitable non-toxic acids include inorganic and organic acids such as acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic 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.

[0036] "Crystalline" refers to a solid state of a compound in which there is long-range atomic order in the positions of the atoms. Crystallinity of a solid can be confirmed, for example, by examination of an X-ray powder diffraction pattern. "Single crystalline form" refers to the cited compound namely 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 crystal having the same crystal form (eg, crystal form B). Where a crystalline form is defined as one specific single crystalline form of a specified percentage of a compound, the remainder is composed of amorphous and/or crystalline forms other than the specified one or more specific forms. Become. In one aspect, for example, the crystalline forms of the present disclosure are at least 80% single crystalline form, at least 90% single crystalline form, at least 95% single crystalline form, or at least 99% single crystalline form by weight. The weight percentage of a particular crystalline form is the weight of the particular crystalline form plus the weight of the other crystalline forms present plus the weight of the amorphous form present. is determined by dividing and multiplying by 100%.

[0037] The term "amorphous" refers to a solid that exists in a non-crystalline state or form. Amorphous solids are disordered arrangements of molecules, thus having no discernible crystal lattice or unit crystal and consequently no definable long-range order. Solid state ordering solids can be determined by standard techniques known in the art, such as X-ray powder diffraction (XRPD), or differential scanning calorimetry (DSC). Amorphous solids can also be distinguished from crystalline solids by birefringence, for example using polarized light microscopy.

[0038] The 2-theta values of the X-ray powder diffraction patterns for the crystalline forms described herein are instrument to instrument and due to factors such as temperature change, sample displacement, and the presence or absence of an internal standard. May vary slightly due to variations in sample preparation and batch-to-batch variations. Therefore, unless otherwise defined, XRPD patterns/assignments quoted herein should not be construed as absolute and may vary ±0.2 degrees. It is known in the art that this variability accounts for the above elements without precluding unambiguous identification of crystal forms.
2. Tyk2 inhibitor
[0039] Tyk2 inhibitors for use in the methods and compositions of the present disclosure include compounds that block the action of tyrosine kinase 2, a non-receptor tyrosine protein kinase encoded by the Tyk2 gene.

[0040] In a second embodiment, the Tyk2 inhibitors of the present disclosure include those described in Xingrui He et al., Expert Opinion on Therapeutics Patents 2019, Vol. 29, No. 2, pages 137-149, the entirety of which is incorporated herein by reference.

[0041] In a third embodiment, the Tyk2 inhibitor of the present disclosure has the formula:

[0042], or a pharmaceutically acceptable salt thereof, the variables of which are as described in WO 2015/032423, which is incorporated herein by reference in its entirety. Exemplary compounds having this formula include, as part of a third embodiment, the formula:

or a pharmaceutically acceptable salt thereof. Other Tyk2 inhibitors include those in WO 2008/139161 and WO 2010/055304 as part of the third embodiment, each of which is incorporated herein by reference in its entirety.

[0043] In a fourth embodiment, the Tyk2 inhibitor of the present disclosure has the formula:

or a pharmaceutically acceptable salt thereof, the variables of which are as described in WO 2013/174895, which is incorporated herein by reference in its entirety. Exemplary compounds having this formula include, as part of a fourth embodiment, the formula:

or a pharmaceutically acceptable salt thereof. Other Tyk2 inhibitors include those of WO 2012/062704, which is incorporated herein by reference in its entirety.

[0044] In a fifth embodiment, the Tyk2 inhibitor of the present disclosure has the formula:

or a pharmaceutically acceptable salt thereof, the variables of which are as described in WO 2012/062704, which is incorporated herein by reference in its entirety.

[0045] In a sixth embodiment, the Tyk2 inhibitor of the present disclosure has the formula

or a pharmaceutically acceptable salt thereof, the variables of which are as described in WO 2015/091584, which is incorporated herein by reference in its entirety. Exemplary compounds having this formula include, as part of the sixth embodiment, the formula:

or a pharmaceutically acceptable salt thereof.
[0046] In a seventh embodiment, the Tyk2 inhibitor of the present disclosure has the formula:

or a pharmaceutically acceptable salt thereof, the variables of which are as described in WO 2016/027195, which is incorporated herein by reference in its entirety. Exemplary compounds having this formula include, as part of the seventh embodiment, the formula:

or a pharmaceutically acceptable salt thereof.
[0047] In an eighth embodiment, the Tyk2 inhibitor of the present disclosure has the formula:

or a pharmaceutically acceptable salt thereof, the variables of which are as described in US2017/0240552, which is incorporated herein by reference in its entirety. Exemplary compounds having this formula include, as part of the eighth embodiment, the formula:

or a pharmaceutically acceptable salt thereof.
[0048] In a ninth embodiment, the Tyk2 inhibitor of the present disclosure has the formula:

or a pharmaceutically acceptable salt thereof, the variables of which are as described in WO 2015/016206, which is incorporated herein by reference in its entirety.

[0049] In a tenth embodiment, the Tyk2 inhibitor of the present disclosure has the formula:

or a pharmaceutically acceptable salt thereof, the variables of which are as described in WO 2013/146963, which is incorporated herein by reference in its entirety.

[0050] In an eleventh embodiment, the Tyk2 inhibitor of the present disclosure has the formula:

or a pharmaceutically acceptable salt thereof, the variables of which are as described in WO 2016/047678, which is incorporated herein by reference in its entirety.

[0051] In a twelfth embodiment, the Tyk2 inhibitors of this disclosure are described in US2015/0299139, WO 2015/069310, US9,505,748, WO 2018/0162889, US2013/0178478, or WO 2015/123453. , the entire contents of each of which are incorporated herein by reference.

[0052] In a thirteenth embodiment, the Tyk2 inhibitor of this disclosure has the formula:

or a pharmaceutically acceptable salt thereof, the variables of which are as described in WO 2015/131080 or WO 2016/138352, the entire contents of which are incorporated herein by reference. .

[0053] In a fourteenth embodiment, the Tyk2 inhibitor of the present disclosure has the formula:

or a pharmaceutically acceptable salt thereof, the variables of which are as described in WO 2017/040757, which is incorporated herein by reference in its entirety.

[0054] In a fifteenth embodiment, the Tyk2 inhibitor of the present disclosure has the formula:

or a pharmaceutically acceptable salt thereof, the variables of which are as described in WO 2015/131080, WO 2016/138352, and WO 2017/040757, the entirety of which is herein incorporated by reference into the book.

[0055] In a sixteenth embodiment, the Tyk2 inhibitor of the present disclosure has the formula:

or a pharmaceutically acceptable salt thereof, the variables of which are as described in WO 2018/071794, which is incorporated herein by reference in its entirety.

[0056] In a seventeenth embodiment, the Tyk2 inhibitor of this disclosure has the formula:

or a pharmaceutically acceptable salt thereof, the variables of which are as described in WO 2018/075937, which is incorporated herein by reference in its entirety.

[0057] In an eighteenth embodiment, the Tyk2 inhibitor of the present disclosure has the formula:

or a pharmaceutically acceptable salt thereof, the variables of which are as described in US2013/0178478, which is incorporated herein by reference in its entirety.

[0058] In a nineteenth embodiment, the Tyk2 inhibitor of the present disclosure has the formula:

or a pharmaceutically acceptable salt thereof, the variables of which are as described in WO 2015/123453, which is incorporated herein by reference in its entirety.

[0059] In a twentieth embodiment, the Tyk2 inhibitor of this disclosure has the formula:

or a pharmaceutically acceptable salt thereof, the variables of which are as described in WO 2015/089143, which is incorporated herein by reference in its entirety.

[0060] In a twenty-first embodiment, the Tyk2 inhibitor of this disclosure has the formula:

or a pharmaceutically acceptable salt thereof, the variables of which are as described in WO 2015/089143, which is incorporated herein by reference in its entirety.

[0061] In a twenty-second embodiment, the Tyk2 inhibitor of this disclosure has the formula:

or a pharmaceutically acceptable salt thereof, the variables of which are as described in WO 2018/067432, which is incorporated herein by reference in its entirety.

[0062] In a twenty-third embodiment, the Tyk2 inhibitor of this disclosure has the formula:

or a pharmaceutically acceptable salt thereof, the variables of which are as described in WO 2018/093968, which is incorporated herein by reference in its entirety.

[0063] In a twenty-fourth embodiment, the Tyk2 inhibitor of this disclosure has the formula:

or a pharmaceutically acceptable salt thereof, the variables of which are as described in WO 2018/081488, which is incorporated herein by reference in its entirety.

[0064] In a twenty-fifth embodiment, the Tyk2 inhibitor of this disclosure has the formula:

[In the formula,
R ¹ is C _1-3 alkyl optionally substituted with 0-7 R ^1a ;
R ^1a is independently at each occurrence hydrogen, deuterium, F, Cl, Br, _CF3 or CN;
R ² is C _1-6 alkyl or —(CH ₂ ) _r —3-14 membered carbocyclic ring, each group substituted with 0-4 R ^2a ;
R ^2a independently at each occurrence hydrogen, =O, halo, OCF ₃ , CN, NO ₂ , —(CH ₂ ) _r OR ^b , —(CH ₂ ) _r SR ^b , —(CH ₂ ) _r C(O)R ^b , —(CH ₂ ) _r C(O)OR ^b , —(CH ₂ ) _r OC(O)R ^b , —(CH ₂ ) _r NR ¹¹ R ¹¹ , —(CH ₂ ) _r C(O)NR ¹¹ R ¹¹ , —(CH ₂ ) _r NR ^b C(O)R ^c , —(CH ₂ ) _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 , C _1-6 alkyl substituted with 0-3 R ^a , C _1-6 haloalkyl, C _2-6 alkenyl substituted with 0-3 R ^a , C _2-6 alkynyl substituted with ^0-3 R ^a , —(CH ₂ ) _r —3- to 14-membered carbocyclic ring, or 1-4 carbon atoms or 1-4 selected from N, O, and S(O) _p substituted with 0-2 R ^a —(CH ₂ ) _r —a 5- to 7-membered heterocyclic ring containing a heteroatom;
R ³ 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 group being substituted with 0-4 R ^3a ;
R ^3a is independently at each occurrence hydrogen, ═O, halo, OCF ₃ , CF ₃ , CHF ₂ , CN, NO ₂ , —(CH ₂ ) _r OR ^b , —(CH ₂ ) _r SR ^b , —(CH ₂ ) _r C(O)R ^b , —(CH ₂ ) _r C(O)OR ^b , —(CH ₂ ) _r OC(O)R ^b , —(CH ₂ ) _r NR ¹¹ R ¹¹ , —(CH ₂ ) _r C(O)NR ¹¹ R ¹¹ , —(CH ₂ ) _r NR ^b C(O)R ^c , —(CH ₂ ) _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 , substituted with 0-3 R ^a C _1-6 alkyl, C _2-6 alkenyl substituted with 0-3 R ^a , C _2-6 alkynyl substituted with 0-3 R ^a , C _1-6 haloalkyl, 0-3 —(CH ₂ ) _r —3- to 14-membered carbocyclic ring substituted with R ^a of or selected from carbon atoms and N, O, and S(O) _p substituted with 0-3 R ^a —(CH ₂ ) _r —a 5- to 10-membered heterocyclic ring containing 1 to 4 heteroatoms;
or two R ^3a , taken together with the atoms to which they are attached, together form a fused ring, said ring comprising a phenyl and a carbon atom and 1-4 heteroatoms selected from N, S or O; a 5- to 7-membered heterocyclic ring containing atoms, said fused ring further substituted with R ^a1 ;
R ⁴ and R ⁵ are independently hydrogen, C _1-4 alkyl substituted with 0-1 R ^f , (CH ₂ ) _r -phenyl substituted with 0-3 R ^d , or —(CH ₂ )—5- to 7-membered heterocyclic ring containing carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) _p ;
Each occurrence of R ¹¹ is independently hydrogen, C _1-4 alkyl substituted with 0-3 R ^f , CF ₃ , C _3-10 cyclo substituted with 0-1 R ^f alkyl, (CH) _r -phenyl substituted with 0-3 R ^d , or carbon atom and N, O, and S(O) 2 _p substituted with 0-3 R ^d —(CH ₂ ) _r —5- to 7-membered heterocyclic ring containing 1-4 heteroatoms;
Each occurrence of R ^a and R ^a1 is independently hydrogen, F, Cl, Br, OCF ₃ , CF ₃ , CHF ₂ , CN, NO ₂ , —(CH ₂ ) _r OR ^b , —(CH ₂ ) _r SR ^b , —(CH ₂ ) _r C(O)R ^b , —(CH ₂ ) _r C(O)OR ^b , —(CH ₂ ) _r OC(O)R ^b , —(CH ₂ ) _r NR ¹¹ R ¹¹ , —(CH ₂ ) _r C(O)NR ¹¹ R ¹¹ , —(CH ₂ ) _r NR ^b C(O)R ^c , —(CH ₂ ) _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) ₂ R ^c , C _1-6 alkyl substituted with 0-3 R ^f , C _1-6 haloalkyl, C _2-6 alkenyl substituted with 0-3 R ^a , substituted with 0-3 R ^a C _2-6 alkynyl, —(CH ₂ ) _r —3-14 membered carbocycle, or carbon atoms and N, O, and S(O) _p substituted with 0-3 R ^f —(CH ₂ ) _r —a 5- to 7-membered heterocyclic ring containing 1 to 4 heteroatoms;
Each occurrence of R ^b is independently hydrogen, C _1-6 alkyl substituted with 0-3 R ^d , C _1-6 haloalkyl, C ₃ substituted with 0-2 R ^d _- (CH ₂ ) _r containing carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) _p substituted with ∼6 cycloalkyl, or 0-3 R ^f - 5- to 7-membered heterocycle or (CH ₂ ) _r -phenyl substituted with 0-3 R ^d ;
R ^c is C _1-6 alkyl substituted with 0-3 R ^f , (CH ₂ ) _r —C _3-6 cycloalkyl substituted with 0-3 R ^f , 0-3 (CH ₂ ) _r -phenyl substituted with R ^f ; or R ^d is independently at each occurrence hydrogen, F, Cl, Br, OCF ₃ , CF ₃ , CN, NO ₂ , -OR ^e , —(CH ₂ ) _r C(O)R ^c , —NR ^{e Re , —NR e C} (O)OR ^c , C _1-6 alkyl, or substituted with 0-3 R ^f ( CH ₂ ) _r -phenyl;
each occurrence of R ^e is independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, and (CH ₂ ) _r -phenyl substituted with 0-3 R ^f ;
each occurrence of R ^f independently is hydrogen, halo, CN, NH ₂ , OH, C _3-6 cycloalkyl, CF ₃ , O(C _{1-6 alkyl} ), or a carbon atom and N, O, —(CH ₂ ) _r —5- to 7-membered heteroaryl containing 1-4 heteroatoms selected from and S(O) _p ;
p is 0, 1, or 2;
r is 0, 1, 2, 3, or 4]
or a pharmaceutically acceptable salt thereof, and additional definitions and specific compounds can be found, for example, in US2015/0299139, which is incorporated herein in its entirety. incorporated by

[0065] In a twenty-sixth embodiment, the Tyk2 inhibitor of this disclosure has the formula:

[In the formula,
R ¹ is C _1-3 alkyl optionally substituted with 0-7 R ^1a where each occurrence of R ^1a is independently hydrogen, deuterium, F, Cl, Br, CF ₃ or CN;
R ² is C _1-6 alkyl substituted with ^{0-4 R 2a ,} C _3-6 cycloalkyl substituted with 0-4 R ^2a , substituted with 0-4 R 2a 5-14 membered containing 1-4 heteroatoms selected from C _6-10 aryl, N, O, and S and substituted with 0-4 R ^2a , NR ⁶ R ⁶ or OR ^b is a heterocycle;
R ^2a independently at each occurrence hydrogen, =O, halo, OCF ₃ , CN, NO ₂ , —(CH ₂ ) _r OR ^b , —(CH ₂ ) _r SR ^b , —(CH ₂ ) _r C(O)R ^b , —(CH ₂ ) _r C(O)OR ^b , —(CH ₂ ) _r OC(O)R ^b , (CH ₂ ) _r NR ¹¹ R ¹¹ , —(CH ₂ ) _r C(O)NR ¹¹ R ¹¹ , —(CH ₂ ) _r NR ^b C(O)R ^C , —(CH ₂ ) _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 , C _1-6 alkyl substituted with 0-3 R ^a , C _1-6 haloalkyl, —(CH ₂ ) _r —3- to 14-membered carbocyclic ring substituted with 0-1 R ^a , or a carbon atom or N, O, substituted with 0-2 R ^a —(CH ₂ ) _r —5- to 7-membered heterocyclic ring containing 1-4 heteroatoms selected from and S(O) _p ;
or one R ^2a and another R ^2a , taken together with the atoms to which they are attached, together form a fused 5-6 membered ring, said fused ring substituted with 0-2 R ^a may be;
R ³ is —(CH ₂ ) _r —3-14 membered carbocyclic ring substituted with 0-5 R ^3a ;
R ^3a independently at each occurrence hydrogen, ═O, halo, OCF ₃ , CN, NO ₂ , —(CH ₂ ) _r OR ^b , —(CH ₂ ) _r SR ^b , —(CH ₂ ) _r C(O)R ^b , —(CH ₂ ) _r C(O)OR ^b , —(CH ₂ ) _r OC(O)R ^b , (CH ₂ ) _r NR ¹¹ R ¹¹ , —(CH ₂ ) _r C(O)NR ¹¹ R ¹¹ , —(CH ₂ ) _r NR ^b C(O)R ^C , —(CH ₂ ) _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 , C _1-6 alkyl substituted with 0-3 R ^a , C _1-6 haloalkyl, —(CH ₂ ) _r —3- to 14-membered carbocyclic ring substituted with 0-3 R ^a , or a carbon atom or N, O, substituted with 0-3 R ^a and S(O) _p —(CH ₂ ) _r —5- to 10-membered heterocyclic ring containing 1-4 heteroatoms selected from;
or two R ^3a , taken together with the atoms to which they are attached, together form a fused ring, said ring comprising a phenyl and a carbon atom and 1-4 heteroatoms selected from N, S or O; a 5- to 7-membered heterocyclic ring containing atoms, said fused ring optionally further substituted by R ^a ;
R ⁴ and R ⁵ are independently hydrogen, C _1-4 alkyl substituted with 0-1 R ^f , (CH ₂ ) _r -phenyl substituted with 0-3 R ^d , or —(CH ₂ )—5- to 7-membered heterocyclic ring containing 5 carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) _p ;
each occurrence of R ⁶ and R ¹¹ is independently hydrogen, C _1-4 alkyl substituted with 0-3 R ^f , CF ₃ , C ₃ substituted with 0-1 R ^f _from ∼10 cycloalkyl, (CH) _r -phenyl substituted with 0-3 R ^d , or carbon atoms and N, O, and S(O) 2 _p substituted with 0-3 R ^d —(CH ₂ ) _r —5- to 7-membered heterocyclic ring containing 1-4 selected heteroatoms;
R ^a is, at each occurrence, hydrogen, F, Cl, Br, OCF ₃ , CF ₃ , CHF ₂ , CN, NO ₂ ,
—(CH ₂ ) _r OR ^b , —(CH ₂ ) _r SR ^b , —(CH ₂ ) _r C(O)R ^b , —(CH ₂ ) _r C(O)OR ^b , —(CH ₂ ) _r OC(O)R ^b , —(CH ₂ ) _r NR ¹¹ R ¹¹ , —(CH ₂ ) _r C(O) NR ¹¹ R ¹¹ , —(CH ₂ ) _r NR ^b C(O)R ^C , —( CH ₂ ) _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) ₂ R ^C , C _1-6 alkyl substituted with 0-3 R ^f , C _1-6 haloalkyl, —(CH ₂ ) _r —3-14 membered carbocyclic ring , or —(CH ₂ ) _r —5-7 containing carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) _p substituted with 0-3 R ^f is a membered heterocycle;
R ^b at each occurrence is hydrogen, C _1-6 alkyl substituted with 0-3 R ^d , C _1-6 haloalkyl, C _3-6 cyclo substituted with 0-2 R ^d alkyl, or —(CH ₂ ) _r —5~ containing carbon atoms and 1 to 4 heteroatoms selected from N, O, and S(O) _p substituted with 0 to 3 R ^f a 7-membered heterocyclic ring, or (CH ₂ ) _r -phenyl substituted with 0-3 R ^d ;
R ^C is C _1-6 alkyl substituted with 0-3 R ^f , (CH ₂ ) _r —C _3-6 cycloalkyl substituted with 0-3 R ^f or 0-3 (CH ₂ ) _r -phenyl substituted with R ^f ;
R ^d is independently at each occurrence hydrogen, F, Cl, Br, OCF ₃ , CF ₃ , CN, NO ₂ ,
OR ^e , —(CH ₂ ) _r C(O)R ^C , NR ^{e Re} , ^{—NR e} C(O)OR ^C , C _1-6 alkyl or (CH ₂ ) is _r -phenyl;
each occurrence of R ^e is independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl and (CH ₂ ) _r -phenyl substituted with 0-3 R ^f ;
each occurrence of R ^f independently is hydrogen, halo, CN, NH ₂ , OH, C _3-6 cycloalkyl, CF ₃ , O(C _1-6 alkyl) or a carbon atom and N, O, and -(CH ₂ ) _r -5- to 7-membered heteroaryl containing 1-4 heteroatoms selected from S(O) _p ;
p is 0, 1, or 2;
r is 0, 1, 2, 3, or 4]
or a pharmaceutically acceptable salt thereof.

[0066] In a twenty-seventh embodiment, the Tyk2 inhibitor of this disclosure has the formula:

or a pharmaceutically acceptable salt thereof, the variables of which are as described in WO 2015/069310, which is incorporated herein by reference in its entirety.

[0067] In a twenty-eighth embodiment, the Tyk2 inhibitor of this disclosure has the formula:

[In the formula,
Y is N or _CR6 ;
R ¹ is H, C _1-3 alkyl or C _3-6 cycloalkyl, each optionally substituted with 0-7 R ^1a ;
R ^1a is independently at each occurrence hydrogen, deuterium, F, Cl, Br or CN;
R ² is C _1-6 alkyl, —(CH ₂ ) _r —substituted with 0-1 R ^2a —3-14 membered carbocyclic ring or 1-4 selected from N, O and S 5- to 14-membered heterocyclic rings containing heteroatoms, each group substituted with 0-4 R ^2a (for clarity, R ² is substituted such as —C(O)R ^2a are intended to include methyl groups that have been defined);
R ^2a independently at each occurrence hydrogen, =O, halo, OCF ₃ , CN, NO ₂ , —(CH ₂ ) _r OR ^b , —(CH ₂ ) _r SR ^b , —(CH ₂ ) _r C(O)R ^b , —(CH ₂ ) _r C(O)OR ^b , —(CH ₂ ) _r OC(O)R ^b , —(CH ₂ ) _r NR ¹¹ R ¹¹ , —(CH ₂ ) _r C(O)NR ¹¹ R ¹¹ , —(CH ₂ ) _r NR ^b C(O)R ^c , —(CH ₂ ) _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 , C _1-6 alkyl substituted with 0-3 R ^a , C _1-6 haloalkyl, C _2-6 alkenyl substituted with 0-3 R ^a , C _2-6 alkynyl substituted with ^0-3 R ^a , —(CH ₂ ) _r —3- to 14-membered carbocyclic ring, or 1-4 carbon atoms or 1-4 selected from N, O, and S(O) _p substituted with 0-2 R ^a —(CH ₂ ) _r —a 5- to 7-membered heterocyclic ring containing a heteroatom;
R ³ 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 group being substituted with 0-4 R ^3a ;
R ^3a is independently at each occurrence hydrogen, ═O, halo, OCF ₃ , CF ₃ , CHF ₂ , CN, NO ₂ , —(CH ₂ ) _r OR ^b , —(CH ₂ ) _r SR ^b , —(CH ₂ ) _r C(O)R ^b , —(CH ₂ ) _r C(O)OR ^b , —(CH ₂ ) _r OC(O)R ^b , —(CH ₂ ) _r NR ¹¹ R ¹¹ , —(CH ₂ ) _r C(O)NR ¹¹ R ¹¹ , —(CH ₂ ) _r NR ^b C(O)R ^c , —(CH ₂ ) _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 , substituted with 0-3 R ^a C _1-6 alkyl, C _2-6 alkenyl substituted with 0-3 R ^a , C _2-6 alkynyl substituted with 0-3 R ^a , C _1-6 haloalkyl, 0-3 —(CH ₂ ) _r —3- to 14-membered carbocyclic ring substituted with R ^a of or selected from carbon atoms and N, O, and S(O) _p substituted with 0-3 R ^a —(CH ₂ ) _r —a 5- to 10-membered heterocyclic ring containing 1 to 4 heteroatoms;
or two R ^3a , together with the atoms to which they are attached, form a fused ring, said rings being selected from phenyl and carbon atoms and N, O, and S(O) _p 1 heterocycles containing up to 4 heteroatoms, each fused ring substituted with 0-3 R ^a1 ;
R ⁴ and R ⁵ are independently hydrogen, C _1-4 alkyl substituted with 0-1 R ^f , (CH ₂ ) _r -phenyl substituted with 0-3 R ^d , or —(CH ₂ )—5- to 7-membered heterocyclic ring containing carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) _p ;
R ⁶ is hydrogen, halo, C _1-4 alkyl, C _1-4 haloalkyl, OC _1-4 haloalkyl, OC _1-4 alkyl, CN, NO ₂ or OH;
Each occurrence of R ¹¹ is independently hydrogen, C _1-4 alkyl substituted with 0-3 R ^f , CF ₃ , C _3-10 cyclo substituted with 0-1 R ^f alkyl, (CH) _r -phenyl substituted with 0-3 R ^d , or carbon atom and N, O, and S(O) 2 _p substituted with 0-3 R ^d —(CH ₂ ) _r —5- to 7-membered heterocyclic ring containing 1-4 heteroatoms;
Each occurrence of R ^a and R ^a1 is independently hydrogen, F, Cl, Br, OCF ₃ , CF ₃ , CHF ₂ , CN, NO ₂ , —(CH ₂ ) _r OR ^b , —(CH ₂ ) _r SR ^b , —(CH ₂ ) _r C(O)R ^b , —(CH ₂ ) _r C(O)OR ^b , —(CH ₂ ) _r OC(O)R ^b , —(CH ₂ ) _r NR ¹¹ R ¹¹ , —(CH ₂ ) _r C(O)NR ¹¹ R ¹¹ , —(CH ₂ ) _r NR ^b C(O)R ^c , —(CH ₂ ) _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) ₂ R ^c , C _1-6 alkyl substituted with 0-3 R ^f , C _1-6 haloalkyl, C _2-6 alkenyl substituted with 0-3 R ^a , substituted with 0-3 R ^a C _2-6 alkynyl, —(CH ₂ ) _r —3-14 membered carbocycle, or carbon atoms and N, O, and S(O) _p substituted with 0-3 R ^f —(CH ₂ ) _r —a 5- to 7-membered heterocyclic ring containing 1 to 4 heteroatoms;
R ^b is hydrogen, C _1-6 alkyl substituted with 0-3 R ^d , C _1-6 haloalkyl, C _3-6 cycloalkyl substituted with 0-2 R ^d , or 0- —(CH ₂ ) _r —5- to 7-membered heterocyclic ring containing carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) _p , substituted with 3 R ^f or (CH ₂ ) _r -phenyl substituted with 0-3 R ^d ;
R ^c is C _1-6 alkyl substituted with 0-3 R ^f , (CH ₂ ) _r —C _3-6 cycloalkyl substituted with 0-3 R ^f or 0-3 (CH ₂ ) _r -phenyl substituted with R ^f ;
R ^d is independently at each occurrence hydrogen, F, Cl, Br, OCF ₃ , CF ₃ , CN, NO ₂ , —OR ^e , —(CH ₂ ) _r C(O)R ^c , —NR ^e R ^e , —NR ^e C(O)OR ^c , C _1-6 alkyl, or (CH ₂ ) _r -phenyl substituted with 0-3 R ^f ;
each occurrence of R ^e is independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, and (CH ₂ ) _r -phenyl substituted with 0-3 R ^f ;
Each occurrence of R ^f independently is hydrogen, halo, CN, NH ₂ , OH, C _3-6 cycloalkyl, CF ₃ , O(C _1-6 alkyl) or a carbon atom and N, O, and -(CH ₂ ) _r -5- to 7-membered heterocyclic ring containing 1-4 heteroatoms selected from S(O) _p ;
p is 0, 1, or 2;
r is 0, 1, 2, 3, or 4]
or a pharmaceutically acceptable salt thereof; additional definitions and specific compounds are as described in US 9,505,748 and WO 2018/0162889, the entire contents of each of which are is incorporated herein by reference.

[0068] In a twenty-ninth embodiment, the Tyk2 inhibitor of this disclosure has the formula:

[In the formula:
^R1 is

is;
^R2 is

is]
or a pharmaceutically acceptable salt thereof.
[0069] In a thirtieth embodiment, the Tyk2 inhibitors described herein have the following chemical structure:

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), or a pharmaceutically acceptable salt thereof.

[0070] Specific dosages and treatment regimens for Tyk2 inhibitors of the present disclosure used in combination with apremilast include age, weight, general health, sex, diet, time of administration, excretion rate, drug The combination will depend on a variety of factors, including the judgment of the treating physician and the severity of the particular disease being treated.

[0071] In a thirty-first embodiment, an effective amount of a Tyk2 inhibitor of this disclosure (eg, in any one of the second through thirtieth embodiments) used in combination with apremilast is from 0.001 to It ranges from 50 mg/kg of body weight/day. For example, as part of the thirty-first embodiment, an effective amount of a Tyk2 inhibitor of the present disclosure (eg, in any one of the second-thirtieth embodiments) used in combination with apremilast is about 0 .1 mg/day to about 250 mg/day, such as 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. .

[0072] In a thirty-second embodiment, the Tyk2 inhibitor described herein is BMS-986165, or a pharmaceutically acceptable salt thereof, BMS-986165, or a pharmaceutically acceptable salt thereof is 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 in the range of about 3 mg/day to about 12 mg/day. Alternatively, as part of a thirty-second embodiment, the effective amount of BMS-986165, or a pharmaceutically acceptable salt thereof, is from about 1 mg/day to about 15 mg/day, from about 1 mg/day to about 14 mg/day, It ranges 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.

[0073] In a thirty-third embodiment, the Tyk2 inhibitor described herein is BMS-986165, or a pharmaceutically acceptable salt thereof, 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 a 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. As part of another alternative thirty-third embodiment, the effective concentration of BMS-986165, or a pharmaceutically acceptable salt thereof, is from about 1 nM to about 1 μM (eg, from about 0.01 μM to about 0.1 μM). is.
3. Apremilast
[0074] As noted above, apremilast is optically enriched as the (S) enantiomer. In a thirty-fourth embodiment, the stereoisomeric purity of apremilast in the methods and compositions described herein is greater than 90%, and the Tyk2 inhibitor and related features are, for example, As described herein as in any one of the forms. Alternatively, as part of a thirty-fourth embodiment, the stereoisomeric purity of apremilast in the methods and compositions described herein is greater than 95% and the Tyk2 inhibitor and related features are, for example, the first and as described herein as in any one of embodiments 1 through 33. As part of another alternative thirty-fourth embodiment, the stereoisomeric purity of apremilast in the methods and compositions described herein is greater than 97%, and the Tyk2 inhibitor and related features include, for example, As described herein as in any one of the first through thirty-third embodiments. As part of another alternative thirty-fourth embodiment, the stereoisomeric purity of apremilast in the methods and compositions described herein is greater than 98%, and the Tyk2 inhibitor and related features include, for example, As described herein as in any one of the first through thirty-third embodiments. As part of another alternative thirty-fourth embodiment, the stereoisomeric purity of apremilast in the methods and compositions described herein is greater than 99%, and the Tyk2 inhibitor and related features include, for example, As described herein as in any one of the first through thirty-third embodiments. As part of another alternative thirty-fourth embodiment, the stereoisomeric purity of apremilast in the methods and compositions described herein is greater than 99.5%, and the Tyk2 inhibitor and related features are For example, as described herein as in any one of the first through thirty-third embodiments. As part of another alternative thirty-fourth embodiment, the stereoisomeric purity of apremilast in the methods and compositions described herein is greater than 99.9%, and the Tyk2 inhibitor and related features are For example, as described herein as in any one of the first through thirty-third embodiments.

[0075] Polymorphic forms of apremilast are included in the methods and compositions of the present disclosure, including, for example, those described in US 9,018,243, which is incorporated herein by reference in its entirety. In a thirty-fifth embodiment, the apremilast in the methods and compositions of the present disclosure is in single crystal form, and additional features and related features relating to Tyk2 inhibitors as well as apremilast are described, for example, in the first through thirty-fourth embodiments. as described herein as in any one of

[0076] In a thirty-sixth embodiment, the apremilast in the methods and compositions of the present disclosure is X-ray at a 2-theta angle selected from 10.1°, 13.5°, 20.7°, and 26.9°. Additional and related features relating to single crystal Form B, a Tyk2 inhibitor similar to apremilast, characterized by a powder diffraction peak, for example, the present invention as in any one of the first to thirty-fourth embodiments. As described in the specification. Alternatively, as part of the thirty-sixth embodiment, apremilast in the methods and compositions of the present disclosure is Single crystalline Form B characterized by X-ray powder diffraction peaks at 2-theta angles selected from 7° and 26.9°; As described herein as in any one of the first through thirty-fourth embodiments. As part of another alternative thirty-sixth embodiment, the apremilast in the methods and compositions of the present disclosure is Single crystal Form B characterized by X-ray powder diffraction peaks at 2-theta angles selected from 20.7°, 22.5°, 24.7°, 26.2°, 26.9°, and 29.1° and additional and related features for Tyk2 inhibitors as well as apremilast are as described herein, eg, as in any one of the first through thirty-fourth embodiments.

[0077] In a thirty-seventh embodiment, the apremilast in the methods and compositions of the present disclosure is at least 90% single crystalline Form B, and additional and related features for the Tyk2 inhibitor as well as apremilast include, for example: As described herein as in any one of the first through thirty-sixth embodiments. Alternatively, the apremilast in the methods and compositions of the present disclosure is at least 95% single crystalline Form B, and additional features and related features for Tyk2 inhibitors as well as apremilast are, for example, As described herein as in any one. In another alternative, the apremilast in the methods and compositions of the present disclosure is at least 99% single crystalline Form B, and additional and related features for Tyk2 inhibitors as well as apremilast are, for example, As described herein as in any one of the embodiments.

[0078] Specific dosages and treatment regimens of apremilast, or a pharmaceutically acceptable salt thereof, to be used in combination with the Tyk2 inhibitors of the present disclosure are based on age, weight, general health, gender, diet, , time of administration, excretion rate, drug combination, judgment of the treating physician, and severity of the particular disease being treated.

[0079] For example, in the thirty-eighth embodiment, the effective amount of apremilast, or a pharmaceutically acceptable salt thereof, is about 0.5 mg to about 1000 mg per day, about 1 mg to about 1000 mg per day, about 5 mg per day to about 500 mg, about 10 mg to about 200 mg per day, about 10 mg to about 100 mg per day, about 40 mg to about 100 mg per day, about 20 mg to about 40 mg per day, about 0.1 mg to about 10 mg per day, about 0 mg per day .5 mg to about 5 mg, from about 1 mg to about 20 mg per day, and from about 1 mg to about 10 mg per day, from about 1 mg to about 100 mg per day, from about 1 mg to about 80 mg per day, from about 5 mg to about 70 mg per day, and from about 1 mg to about 10 mg per day Additional and related features for Tyk2 inhibitors as well as apremilast are described herein, such as in any one of the first through thirty-seventh embodiments. as it is. Alternatively, as part of a thirty-eighth embodiment, the effective amount of apremilast, or a pharmaceutically acceptable salt thereof, ranges from about 10 mg to about 60 mg per day; The features and related features are as described herein, eg, in any one of the first through thirty-seventh embodiments. As part of another alternative thirty-eighth embodiment, the effective amount of apremilast, or a pharmaceutically acceptable salt thereof, ranges from about 40 mg to about 100 mg per day; Typical features and related features are as described herein, eg, in any one of the first through thirty-seventh embodiments. As part of another alternative thirty-eighth embodiment, the effective amount of apremilast, or a pharmaceutically acceptable salt thereof, ranges between about 40 mg to about 100 mg per day and, like apremilast, is a Tyk2 inhibitor. Additional features and related features for are as described herein, such as in any one of the first through thirty-seventh embodiments. As part of another alternative thirty-eighth embodiment, the effective amount of apremilast, or a pharmaceutically acceptable salt thereof, ranges from about 4 mg to about 10 mg per day; Typical features and related features are as described herein, eg, in any one of the first through thirty-seventh embodiments. As part of another alternative thirty-eighth embodiment, the effective amount of apremilast, or a pharmaceutically acceptable salt thereof, ranges between about 4 mg to about 10 mg per day and, like apremilast, is a Tyk2 inhibitor. Additional features and related features for are as described herein, such as in any one of the first through thirty-seventh embodiments. As part of another alternative thirty-eighth embodiment, the effective amount of apremilast, or a pharmaceutically acceptable salt thereof, is about 1 mg per day, about 2 mg per day, about 3 mg per day, about 4 mg per day, about 5 mg per day, about 10 mg per day, about 15 mg per day, about 20 mg per day, about 25 mg per day, about 30 mg per day, about 35 mg per day, about 40 mg per day, about 45 mg per day, about 50 mg per day; Additional features and related features for Tyk2 inhibitors as well as apremilast are described herein, for example as in any one of the first through thirty-seventh embodiments. as described in As part of another alternative thirty-eighth embodiment, the effective amount of apremilast, or a pharmaceutically acceptable salt thereof, is about 30 mg per day or about 60 mg per day; Typical features and related features are as described herein, eg, in any one of the first through thirty-seventh embodiments. As part of another alternative thirty-eighth embodiment, apremilast is administered at a dose of about 30 mg once daily, additional features and related features for Tyk2 inhibitors as well as apremilast are e.g. As described herein as in any one of the thirty-seventh embodiments. As part of another alternative thirty-eighth embodiment, apremilast is administered at a dose of about 30 mg twice daily, and additional and related features for Tyk2 inhibitors as well as apremilast are e.g. As described herein as in any one of the thirty-seventh embodiments. As part of another alternative thirty-eighth embodiment, the effective concentration of apremilast is from about 100 nM to about 10 μM (eg, from about 0.1 μM to about 1 μM); and related features are as described herein, eg, in any one of the first through thirty-seventh embodiments.

[0080] In a thirty-ninth embodiment, apremilast is titrated to a dosage of about 30 mg administered twice daily using the following titration schedule:
Day 1: approximately 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 about 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 beyond: about 30 mg twice a day;
Additional and related features for Tyk2 inhibitors as well as apremilast are as described herein, eg, in any one of the first through thirty-seventh embodiments. Alternatively, apremilast is titrated at a dosage between about 40 mg/day to about 100 mg/day using the following titration schedule:
Day 1: approximately 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 about 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 beyond: between about 40 mg/day and about 100 mg/day;
Additional and related features for Tyk2 inhibitors as well as apremilast are as described herein, eg, in any one of the first through thirty-seventh embodiments. In another alternative, apremilast is titrated to a dosage of about 20 mg twice daily using the following titration schedule:
Day 1: approximately 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 about 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 beyond: about 20 mg twice daily.
Additional and related features for Tyk2 inhibitors as well as apremilast are as described herein, eg, in any one of the first through thirty-seventh embodiments. In yet another alternative, apremilast is titrated at a dosage between about 4 mg/day and about 10 mg/day using the following titration schedule:
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 beyond: between about 4 mg/day and about 10 mg/day;
Additional and related features for Tyk2 inhibitors as well as apremilast are as described herein, eg, in any one of the first through thirty-seventh embodiments. In yet another alternative, apremilast is titrated to a dosage of about 3 mg administered twice daily using the following titration schedule:
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 beyond: about 3 mg twice daily.
Additional and related features for Tyk2 inhibitors as well as apremilast are as described herein, eg, in any one of the first through thirty-seventh embodiments.
3. Composition and administration
[0081] 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 (eg, BMS-986165). Features of the pharmaceutical compositions of the present disclosure include, for example, the elements described above as in any one of the first through thirty-eighth embodiments.

[0082] Additionally, a therapeutically effective amount of apremilast, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a Tyk2 inhibitor (e.g., BMS) for use in treating a disease or disorder responsive to inhibition of PDE4 -986165) is provided. Features of the pharmaceutical compositions of the present disclosure include, for example, the elements described above as in any one of the first through thirty-eighth embodiments.

[0083] For administration as described above (eg, as in any one of the first to thirty-eighth embodiments) comprising apremilast and a Tyk2 inhibitor (eg, BMS-986165) alone or together in a fixed dose. Pharmaceutical compositions and single unit dosage forms are included. A single unit dosage form of the methods and compositions of the present disclosure can be administered to a patient orally, mucosally (eg, nasally, sublingually, intravaginally, buccally, or intrarectally), parenterally (eg, subcutaneously, intravenously, bolus injection, intramuscular, or intraarterial), or transdermal administration. Examples of dosage forms include tablets, caplets, capsules such as soft elastic gelatin capsules, cachets, troches, lozenges, dispersions, suppositories, ointments, poultices, pastes, and powders. , dressings, creams, plasters, solutions, patches, aerosols (e.g. nasal sprays or inhalers), gels, suspensions (e.g. aqueous or non-aqueous liquid suspensions, oil-in-water liquid dosage forms suitable for oral or mucosal administration to patients, liquid dosage forms suitable for parenteral administration to patients, including emulsions, or water-in-oil liquid emulsions), solutions, and elixirs. Sterile solids (eg, crystalline or amorphous solids) that can be reconstituted to provide a liquid dosage form suitable for parenteral administration to the body include, but are not limited to.

[0084] The composition, shape, and type of dosage form desired will typically vary depending on its use. For example, a dosage form used for acute treatment of inflammation or related disorders may contain greater amounts of one or more active ingredients than a dosage form used for chronic treatment of the same disease. Similarly, a parenteral dosage form may contain lower amounts of one or more active ingredients than an oral dosage form used to treat the same disease or disorder contains. These and other ways in which specific dosage forms encompassed by this invention will vary will be readily apparent to those skilled in the art.
See, eg, Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing, Easton Pa. (1990).

[0085] In a thirty-ninth embodiment, the apremilast in the methods and compositions of this disclosure is administered parenterally, transdermally, mucosally, nasally, buccal site, sublingually, or orally and is administered Tyk2 as apremilast. Additional and related features for inhibitors are as described herein, eg, in any one of the first through thirty-eighth embodiments. Alternatively, as part of the thirty-ninth embodiment, the apremilast in the methods and compositions of this disclosure is administered orally, and additional and related features for Tyk2 inhibitors like apremilast are provided, for example, in the first and as described herein as in any one of embodiments from the thirty-eighth embodiment.

[0086] In a fortieth embodiment, the apremilast in the methods and compositions of this disclosure is administered orally in tablet or capsule form, and like apremilast, additional and related features for Tyk2 inhibitors are , eg, as described herein as in any one of the first through thirty-ninth embodiments.

[0087] In a forty-first embodiment, the apremilast in the methods and compositions of the present disclosure is formulated as an extended release form, and additional features and related features for Tyk2 inhibitors as well as apremilast are, for example, As described herein as in any one of embodiments 1 through 39.

[0088] In a forty-second embodiment, the apremilast in the methods and compositions of the present disclosure is formulated as an immediate release form, and additional features and related features related to Tyk2 inhibitors as well as apremilast are, for example, As described herein as in any one of embodiments 1 through 39.

[0089] In a forty-third embodiment, both apremilast and the Tyk2 inhibitor in the methods and compositions of the present disclosure are administered as a once-daily formulation in a fixed-dosage combination; Additional features and related features are as described herein, eg, in any one of the first through forty-second embodiments.
4. Conditions Treated by the Methods and Compositions Disclosed herein
[0090] Diseases or disorders that respond to inhibition of PDE4 using the methods and compositions disclosed herein include, for example, viral, genetic, inflammatory, allergic, and autoimmune conditions. included.

[0091] In one aspect, the disease or disorder responsive to inhibition of PDE4 is chronic obstructive pulmonary disease, asthma, chronic pulmonary inflammatory disease, hyperoxic alveolar damage, inflammatory skin disease, 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, lupus vulgaris, Sjögren's syndrome, inflammatory bowel disease, Crohn's disease, Behcet's disease, and ulcerative colitis.

[0092] In one aspect, the disease or disorder responsive to inhibition of PDE4 is selected from psoriasis, psoriatic arthritis, contact dermatitis, systemic lupus erythematosus, cutaneous lupus erythematosus, and ulcerative colitis.

[0093] 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 to be treated is a candidate for phototherapy or systemic therapy.

[0094] In one aspect, the disease or disorder responsive to inhibition of PDE4 is psoriasis vulgaris. In another aspect, the disease or disorder responsive to inhibition of PDE4 is psoriasis vulgaris and the subject to be treated is a candidate for phototherapy or systemic therapy.

[0095] 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 psoriasis vulgaris and the subject to be treated is a candidate for phototherapy or systemic therapy.

[0096] In one aspect, the disease or disorder responsive to inhibition of PDE4 is psoriatic arthritis.
[0097] In one aspect, the disease or disorder responsive to inhibition of PDE4 is active psoriatic arthritis.

[0098] In one aspect, the disease or disorder responsive to inhibition of PDE4 is congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acute viral myocarditis, cardiac allograft rejection, and myocardial Cardiac disease such as infarction.

[0099] In one aspect, the disease or disorder responsive to inhibition of PDE4 is HIV, hepatitis, adult respiratory distress syndrome, bone resorption disease, cystic fibrosis, septic shock, sepsis, endotoxic shock, hemodynamic shock, Septic syndrome, postischemic reperfusion injury, meningitis, fibrotic disease, cachexia, graft rejection, osteoporosis, multiple sclerosis, and radiation injury.

[00100] In one aspect, the disease or disorder responsive to inhibition of PDE4 is head, thyroid, neck, eye, skin, mouth, pharynx, esophagus, cheat, 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.

[00101] In one aspect, the disease or disorder responsive to inhibition of PDE4 is multiple myeloma, malignant melanoma, malignant glioma, acute lymphoblastic leukemia, B-cell acute lymphoblastic leukemia, T cellular acute lymphoblastic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute monoblastic leukemia, acute erythroleukemic leukemia, acute megakaryoblastic leukemia, acute bone marrow Monocytic leukemia, acute nonlymphocytic leukemia, acute undifferentiated leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, multiple myeloma and acute, lymphoblastic leukemia, myeloid leukemia, lymphocytic leukemia, and myeloid leukemia.

[00102] In one aspect, the disease or disorder responsive to inhibition of PDE4 is sarcoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma , lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma , basal cell carcinoma, adenocarcinoma, sweat adenocarcinoma, sebaceous adenocarcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic lung cancer, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, spermatozoa Epithelioma, embryonic carcinoma, Wilms tumor, cervical cancer, testicular tumor, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, Solid tumors such as Kaposi's sarcoma, pineocytoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, and retinoblastoma.

1. material

2. General method
[00103] Whole blood was obtained after informed consent and donor deidentification through the Celgene donor program. All volunteers were healthy and free of any medication for at least 72 hours prior to blood collection. Blood was collected in sodium heparin tubes. Assays were initiated within 2 hours of blood collection.

[00104] Ex vivo stimulation of human whole blood from healthy donors was performed under two different stimulation conditions. Condition Th0 was stimulation with TruCulture® tubes containing anti-CD3/anti-CD28. Condition Th17 was stimulation with TruCulture® tubes containing anti-CD3/anti-CD28 plus IL-1β, IL-6 and IL-23. Whole blood was separated into 15 milliliter conical tubes and pretreated with DMSO, apremilast alone, BMS-986165 alone, or BMS-986165 in combination with apremilast. Final concentrations were 0.2% DMSO, 1 μM for 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 well and then incubated for 1 hour in a 37°C/5% CO ₂ incubator.

[00105] Anti-CD3/anti-CD28 (200 ng/mL and 330 ng/mL final concentrations, respectively) TruCulture® tubes were thawed for 30 minutes on the benchtop and then labeled. The plunger was pressed and then snapped off. The TruCulture® tubes were placed upright in the rack with the plunger side facing down and the tube caps facing up in the rack. During the blood incubation, the compounds human recombinant IL-6, IL-1β and IL-23 were added to all Th17 tubes at the following concentrations: 120 ng IL-6, 120 ng IL-1b and 150 ng. of IL-23. 1 ml of pretreated whole blood was placed into each tube using a sterile, pyrogen-free pipette tip. The contents of the tube were mixed by replacing the cap and inverting it upside down three times. Tubes were immediately placed in a 37° C. heat breaker and incubated for 42 hours (tube cap ends). After 42 hours, the tubes were removed from the heat breaker, the tops were unscrewed and 250 μl of supernatant was removed and transferred to three 96-well polypropylene plates. Samples were immediately frozen at -80°C. Supernatants were then thawed at room temperature and tested directly for cytokine production by Luminex Multi-Plex MagPix technology (Millipore) or by ELISA (Abcam) for IL-22. The manufacturer's procedures were followed as appropriate.

[00106] Peripheral blood mononuclear cell (PBMC) isolation: Whole blood was obtained after informed consent and donor anonymization through the Celgene donor program. All volunteers were healthy and free of any medication for at least 72 hours prior to blood collection. Blood was collected into sodium heparin tubes and used for PBMC isolation within 2 hours of blood collection. Before PBMC isolation, whole blood was diluted 1:1 with a PBS solution containing 2% FBS (2% FBS-PBS). 13 ml of Ficoll-Paque solution was placed in a SepMate® tube and 25 ml of diluted blood was placed on top of the Ficoll-Paque. After centrifugation at 1200 g for 15 minutes with braking for cell separation, the isolated PBMCs were transferred to a new tube. PBMC were washed with 2% FBS-PBS and centrifuged at 800g for 10 minutes. The sediment was resuspended in 2% FBS-PBS and filtered through a 40 μM cell strainer to obtain a single cell suspension. Red blood cells in the isolated population were removed using 3 ml of RBC lysis buffer. Isolated PBMCs were washed with 2% FBS-PBS and resuspended in RPMI growth medium containing 10% FBS and antibiotics.

[00107] For Examples 6-11, PBMC were isolated from nine healthy donors and analyzed for IL-23, IL-12p40, IL-12p70, TNF-α, IFN-γ and MCP-1 cytokines. LPS stimulation was performed ex vivo for PBMCs were plated in 96-well plates at a density of 200,000 cells per well in 200 μl of RPMI growth medium containing 10% FBS, followed by treatment with DMSO and compounds. Each well received the same amount of DMSO with a final concentration of 0.3% v/v. Serial dilutions of compound treatments were performed according to Table 4 below. Two hours after compound treatment, LPS at a final concentration of 100 ng/mL was used as a stimulant. PBMC were then incubated for 16 hours in a 37°C/5% CO ₂ incubator.

[00108] After 16 hours of incubation, supernatants were collected into new 96-well polypropylene plates and centrifuged at 4000 rpm for 10 minutes to remove cell debris. Cytokine production was measured by the Luminex Bio-Plex Multiplex Immunoassay (Bio-Rad) according to the manufacturer's protocol. Samples were diluted 5-fold for IL-12p40 and 27-plex assays and used directly for IL-23 assays to ensure that supernatant levels were within the normal cytokine range for the assays. .
3. data analysis
[00109] For cytokine analysis, data processing was performed using Milliplex Analyst (Millipore) and raw data was exported to an excel template for cytokine analysis. Data from templates were plotted using GraphPad Prism 7.0 (GraphPad Software, La Jolla, Calif.) and expressed as pg/mL or % of control. Statistical analysis was also performed using one-way ANOVA and Dunnett's post-test.

[00110] For the PBMC assay, data processing was performed using the Bio-plex manager and raw data was exported to an excel template for cytokine analysis. Data were plotted using GraphPad Prism 7.0 (GraphPad Software, La Jolla, Calif.) and expressed as % of DMSO control. Statistical analysis was performed using one-way ANOVA and Tukey's multiple comparison test.

[00111] To assess the combined effect of apremilast and BMS-986165, data from two independent treatments were analyzed by comparing the combination response to the theoretical additive response of the two agents. did. The expected additive effects of the two drugs (A and B) were calculated using the fractional product method: (fu)A,B = (fu)A x (fu)B; Medium, fu=fraction unaffected by treatment. Synergy of the combination is determined if the observed proportion of combination insensitivity is less than (fu) A,B, whereas additive if the observed proportion of combination indifference is equal to (fu) A,B effect is determined. If the observed combination insensitivity is greater than (fu)A,B, a partial additive effect is indicated.

Example 1
Interleukin 17A cytokine production by apremilast and BMS-986165 in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood
[00112] Whole blood from four healthy donors was analyzed for cytokine production of IL-17A, IL-17F, IL-22, TNF-α and GM-CSF in both Th0 and Th17 conditions. Blood was pretreated with apremilast and the Tyk2 inhibitor BMS-986165 both alone and in combination using the TruCulture® tubing system. The IL-17A results in FIG. 1 show % of control for IL-17A and all data are normalized to the Th17DMSO control. Apremilast inhibited IL-17A cytokine expression by 28% under Th0 conditions and had no effect under Th17 conditions. BMS-986165 produced similar effects under both stimulation conditions, inhibiting IL-17A expression by 10-25% at 0.001-1 μM. When apremilast was combined with BMS-986165, synergy was seen with 65% reduction in IL-17A with 1 μM BMS-986165 under Th0 conditions. Under Th17 conditions, there was synergy with 24%, 44% and 85% inhibition of IL-17A in combination with 1 μM apremilast and 0.01 μM, 0.1 μM and 1 μM BMS-986165, respectively. rice field. FIG. 2 shows levels of IL-17A in picograms per milliliter. Levels of IL-17A increased 387% in Th17 stimulation conditions compared to Th0 stimulation. In Th0 conditions, apremilast reduced IL-17A levels from 138 pg/mL to 93 pg/mL. BMS-986165 reduced IL-17A levels to 97 pg/mL at 1 μM. The combination of apremilast and 1 μM BMS-986165 further reduced IL-17A levels to 24 pg/mL upon Th0 stimulation. Under Th17 conditions, the stimulated control measured 532 pg/mL and apremilast did not inhibit IL-17A levels. BMS-986165 reduced IL-17A levels to 519 pg/mL at 0.01 μM, to 428 pg/mL at 0.1 μM, and to 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, 328 pg/mL at 0.1 μM, and 68 pg/mL at 1 μM of BMS-986165.

Example 2
Interleukin 17F cytokine production by apremilast and BMS-986165 in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood
[00113] IL-17F cytokine expression data are in FIGS. Apremilast inhibited IL-17F production by 69% under Th0 conditions and by 49% under Th17 conditions. BMS-986165 produced similar effects on IL-17F with both Th0 and Th17 stimulation. There was 31% inhibition of IL-17F expression at the lowest concentration of 0.001 μM, and a dose response with 34% inhibition at 0.01 μM, 70% inhibition at 0.1 μM, and 95% inhibition at 1 μM (Th17 results ). The combination of 1 μM apremilast and BMS-986165 was partially additive with inhibition ranging from 60% at 0.001 μM to 95% at 1 μM under Th0 conditions. Under Th17 conditions, lower concentrations of BMS-986165 in combination with apremilast showed synergy. Apremilast inhibited IL-17F by 68% in combination with BMS-986165 at 0.001 μM, 70% at 0.01 μM, 94% at 0.1 μM, 94% at 0.1 μM, 1 μM 99% of IL-17F production was inhibited at . IL-17F levels in Th0-stimulated controls were 1085 pg/mL and increased to 6524 pg/mL in Th17-stimulated controls. Apremilast reduced IL-17F to 368 pg/mL in Th0 stimulation and to 3643 pg/mL in Th17 stimulation. BMS-986165 significantly reduced IL-17F at 0.1 and 1 μM in both stimulation conditions. There was significant inhibition of IL-17F at all concentrations of BMS-986165 under both stimulation conditions when combined with apremilast.

Example 3
Interleukin-22 cytokine production by apremilast and BMS-986165 in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood
[00114] IL-22 cytokine expression data are in FIGS. Apremilast 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 17% at 0.01 μM, 60% at 0.1 μM, and 70% at 1 μM. Under Th0 conditions, the combination produced an effect similar to apremilast alone, with approximately 90% inhibition at all concentrations of BMS-986165. Under Th17 conditions, the combination was synergistic with 60% inhibition of IL-22 cytokine expression at 0.01 μM and 90% inhibition at 0.1 μM. Th0-stimulated controls had 1085 pg/mL IL-22 and Th17 controls had 6524 pg/mL. Apremilast significantly reduced IL-22 levels to 368 pg/mL in Th0 conditions and to 3643 pg/mL in Th17 conditions. BMS-986165 significantly reduced IL-22 cytokine expression at 0.1 μM and 1 μM under both stimulation conditions. There was significant inhibition of IL-22 at all concentrations of BMS-986165 under both stimulation conditions when combined with apremilast.

Example 4
TNF-α cytokine production by apremilast and BMS-986165 in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood
[00115] TNF-α cytokine expression data are in FIGS. Apremilast inhibited TNF-α levels by 90% in Th0 conditions and by 94% in Th17 conditions. Upon 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. At the highest concentration of 1 μM, BMS-986165 inhibited TNF-α cytokine expression by 66%. Under Th17 conditions, a similar increase in TNF-α production was seen with BMS-986165 with a 19% increase at 0.01 μM and a 77% increase at 0.1 μM. There was also inhibition of TNF-α (68%) with 1 μM BMS-986165 under Th17 stimulation conditions. The combination of 1 μM apremilast and BMS-986165 reduced TNF-α levels by 80-95% (Th0) and 93-96% (Th17), an effect similar to single agent apremilast. Both stimulation conditions had similar effects on TNF-α levels with a Th0-stimulated control of 1380 pg/mL and a Th17-stimulated control of 1436 pg/mL. Apremilast significantly inhibited TNF-α by reducing levels to 148 pg/mL in Th0 conditions and 91 pg/mL in Th17 conditions. The increase in TNF-α levels by BMS-986165 was significant at 0.1 μM in Th17 conditions. Inhibition of TNF-α levels with 1 μM BMS-986165 was significant under both stimulation conditions. The combination of apremilast and BMS-986165 significantly inhibited TNF-α levels at all concentrations and under both stimulation conditions.

Example 5
Granulocyte-macrophage colony-stimulating factor cytokine production by apremilast and BMS-986165 in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood
[00116] Granulocyte macrophage colony stimulating factor (GM-CSF) cytokine expression results are in FIGS. GM-CSF cytokine expression was reduced by apremilast by 80% under Th0 conditions and 66% under Th17 conditions. BMS-986165 increased GM-CSF cytokine expression under both conditions. BMS-986165 increased GM-CSF in Th0 conditions 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 60-80% inhibition of GM-CSF cytokine expression. Upon Th17 stimulation, BMS-986165 increased GM-CSF by 41% at 0.01 μM, 139% at 0.1 μM, and 104% at 1 μM. There was a 40-73% inhibition of GM-CSF cytokine expression when apremilast was added. Total pg/mL of GM-CSF in Th0 and Th17 stimulated controls were 409 and 637, respectively. Apremilast significantly inhibited GM-CSF under both stimulation conditions. The increase in GM-CSF by BMS-986165 was significant at 0.1 μM (both Th0 and Th17) and 1 μM (Th17). The combination of apremilast and BMS-986165 significantly reduced GM-CSF cytokine levels at all concentrations and under both stimulation conditions.

Example 6
IL-23 production in LPS-stimulated PBMCs with apremilast and Tyk2i (BMS-986165) treatment
[00117] PBMC from nine healthy donors were analyzed for cytokine production in LPS-stimulated conditions (Figures 11-17). The results in Figures 11 and 12 showed the levels of IL-23. Figure 11 showed that apremilast reduced IL-23 production in LPS-stimulated PBMCs. IL-23 levels from DMSO-treated LPS-stimulated PBMC were set as 100% (control) and cytokine levels were expressed as normalized values in % compared to control. In contrast to the decrease in IL-23 levels by apremilast, Figure 12 showed that BMS-986165 induced IL-23 levels in LPS-stimulated PBMCs. In the range of 0.2 μM to 2 μM, BMS-986165 induced a 20-fold increase in IL-23 compared to the DMSO group. The combination of apremilast and BMS-986165 was able to reduce the induction of IL-23 by BMS-986165. There is a significant reduction in IL-23 levels with increasing levels of apremilast. Statistical analysis using ANOVA and Turkey's multiple comparisons was performed to compare each treatment with BMS-986165 alone. There is a significant reduction in IL-23 when BMS-986165 is combined with low levels of apremilast at a concentration of 0.037 μM (***p<0.001). When combined with 1 μM apremilast, induction of IL-23 was inhibited by 90%, reaching levels almost similar to apremilast alone. Thus, the curves for combined treatment with 1 μM apremilast were not significantly different compared to apremilast treatment alone.

Example 7
IL-12p40 production in LPS-stimulated PBMCs with apremilast and Tyk2i (BMS-986165) treatment
[00118] The results in Figure 13 showed normalized levels of IL-12p40 compared to the DMSO-treated LPS-stimulated PBMC group. Apremilast dose-dependently decreased IL-12p40, while BMS-986165 increased IL-12p40. The combination of BMS-986165 and apremilast significantly reduced the induction of IL-12p40 by BMS-986165. With 1 μM apremilast, the increase in IL-12p40 induced by BMS-986165 was inhibited by 85%, reaching levels almost similar to apremilast alone. Statistical analysis using ANOVA and Turkey's multiple comparisons was performed to compare each treatment with BMS-986165 alone. ***p<0.001
Example 8
IL-12p70 production in LPS-stimulated PBMCs with apremilast and Tyk2i (BMS-986165) treatment
[00119] The results in Figure 14 showed normalized levels of IL-12p70 compared to the DMSO-treated LPS-stimulated PBMC group. Apremilast dose-dependently decreased IL-12p70, while BMS-986165 increased IL-12p70. The combination of BMS-986165 and apremilast significantly reduced the induction of IL-12p70 by BMS-986165. In combination treatments, both 0.3 μM and 1 μM significantly reduced IL-12p70 levels induced by BMS-986165 with no significant difference compared to apremilast alone. Statistical analysis using ANOVA and Turkey's multiple comparisons was performed to compare each treatment with BMS-986165 alone. ***p<0.001
Example 9
TNF-α production in LPS-stimulated PBMCs with apremilast and Tyk2i (BMS-986165) treatment
[00120] The results in Figure 15 showed normalized levels of TNF-α compared to the DMSO-treated LPS-stimulated PBMC group. Apremilast dose-dependently decreased TNF-α levels, whereas BMS-986165 induced a 1.2-1.5 fold increase in TNF-α. The combination of BMS-986165 and apremilast significantly reduced TNF-α levels. Statistical analysis using ANOVA and Turkey's multiple comparisons was performed to compare each treatment with BMS-986165 alone. ***p<0.001
Example 10
IFN-γ production in LPS-stimulated PBMCs with apremilast and Tyk2i (BMS-986165) treatment
[00121] The results in Figure 16 showed normalized levels of IFN-γ compared to the DMSO-treated LPS-stimulated PBMC group. Both apremilast alone and BMS-986165 alone dose-dependently decreased IFN-γ. The combination of BMS-986165 and apremilast had a synergistic effect in reducing IFN-γ levels, significantly reducing IFN-γ levels compared to single compound treatment. Statistical analysis using ANOVA and Turkey's multiple comparisons was performed to compare each treatment with BMS-986165 alone. ***p<0.001.
Example 11
MCP-1 production in LPS-stimulated PBMCs with apremilast and Tyk2i (BMS-986165) treatment
[00122] The results in Figure 17 showed normalized levels of MCP-1 compared to the DMSO-treated LPS-stimulated PBMC group. Both apremilast alone and BMS-986165 alone dose-dependently decreased MCP-1. The combination of BMS-986165 and apremilast produces a synergistic effect in reducing MCP-1 levels. Statistical analysis using ANOVA and Turkey's multiple comparisons was performed to compare each treatment with BMS-986165 alone. ***p<0.001.
data summarization
[00123] Table 5 below provides a summary of the cytokine effects of apremilast and BMS-986165 on stimulated whole blood in the Ex-Vivo TruCulture® assay. Synergistic effects are shown in bold, complementary effects are underlined.

[00124] Whole blood from 4 healthy donors was tested in the Tru-culture assay in Th0 (anti-CD3/anti-CD28) or Th17 (anti-CD3/anti-CD28 plus IL-1β, IL-6 and IL-23) conditions. , 48 hours, with the Tyk2 inhibitor BMS-986165 +/- apremilast. BMS-986165 inhibited IL-17A, IL-17F, and IL-22 cytokine expression under Th0 and Th17 conditions. When combined with apremilast, these cytokines were further reduced under Th17 conditions with a synergistic effect on IL-17A, IL-17F and IL-22. BMS-986165 increased TNF-α and GM-CSF production, while apremilast inhibited production of these cytokines. When BMS-986165 was combined with apremilast, apremilast corrected the defect of BMS-986165 and had complementary effects on TNF-α and GM-CSF cytokine expression. These combined effects provide a means of treating diseases or disorders that respond to inhibition of PDE4, such as treating inflammatory diseases (eg, psoriasis, psoriatic arthritis, and ulcerative colitis).

[00125] Table 6 below provides a summary of the cytokine effects of apremilast and BMS-986165 on LPS-stimulated PBMCs. Up arrows represent induction of cytokine production and down arrows represent decrease in cytokine production.

[00126] PBMC from 9 healthy donors were tested with or without BMS-986165 or apremilast or a combination of both in the LPS-stimulated condition. BMS-986165 treatment alone induced IL-23, IL-12p40, IL-12p70 and TNF-α, while apremilast treatment alone reduced these cytokines. When BMS-986165 was combined with apremilast, these cytokines were either unchanged or reduced compared to the DMSO control group. These results indicate that apremilast was able to inhibit the induction of these cytokines by BMS-986165. Both apremilast and BMS-986165 reduced IFN-γ and MCP-1 production, and the combination of both further reduced these two cytokines with a synergistic effect. BMS-986165 inhibits Th17 lineage cytokines, providing a means of treating diseases in which Th17 cytokines are implicated in pathogenesis. However, induction of some pro-inflammatory cytokines such as IL-23, IL-12 and TNF-α by BMS-986165 may be a drawback in disease treatment. The combined effect of apremilast and BMS-986165 in reducing IL-23, IL-12 and TNF-α supports the combination of these two compounds in the treatment of inflammatory diseases such as psoriasis, psoriatic arthritis, and ulcerative colitis. showed the advantage of

Claims (62)

A method of treating a disease or disorder responsive to inhibition of phosphodiesterase 4 (PDE4) in a subject 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, or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of tyrosine kinase 2 A method comprising administering a (Tyk2) inhibitor or a pharmaceutically acceptable salt thereof to said subject. The Tyk2 inhibitor has the formula:

[In the formula,
R ¹ is C _1-3 alkyl optionally substituted with 0-7 R ^1a ;
R ^1a is independently at each occurrence hydrogen, deuterium, F, Cl, Br, _CF3 or CN;
R ² is C _1-6 alkyl or —(CH ₂ ) _r —3-14 membered carbocyclic ring, each group substituted with 0-4 R ^2a ;
R ^2a independently at each occurrence hydrogen, =O, halo, OCF ₃ , CN, NO ₂ , —(CH ₂ ) _r OR ^b , —(CH ₂ ) _r SR ^b , —(CH ₂ ) _r C(O)R ^b , —(CH ₂ ) _r C(O)OR ^b , —(CH ₂ ) _r OC(O)R ^b , —(CH ₂ ) _r NR ¹¹ R ¹¹ , —(CH ₂ ) _r C(O)NR ¹¹ R ¹¹ , —(CH ₂ ) _r NR ^b C(O)R ^c , —(CH ₂ ) _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 , C _1-6 alkyl substituted with 0-3 R ^a , C _1-6 haloalkyl, C _2-6 alkenyl substituted with 0-3 R ^a , C _2-6 alkynyl substituted with ^0-3 R ^a , —(CH ₂ ) _r —3- to 14-membered carbocyclic ring, or 1-4 carbon atoms or 1-4 selected from N, O, and S(O) _p substituted with 0-2 R ^a —(CH ₂ ) _r —a 5- to 7-membered heterocyclic ring containing a heteroatom;
R ³ 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 group being substituted with 0-4 R ^3a ;
R ^3a is independently at each occurrence hydrogen, ═O, halo, OCF ₃ , CF ₃ , CHF ₂ , CN, NO ₂ , —(CH ₂ ) _r OR ^b , —(CH ₂ ) _r SR ^b , —(CH ₂ ) _r C(O)R ^b , —(CH ₂ ) _r C(O)OR ^b , —(CH ₂ ) _r OC(O)R ^b , —(CH ₂ ) _r NR ¹¹ R ¹¹ , —(CH ₂ ) _r C(O)NR ¹¹ R ¹¹ , —(CH ₂ ) _r NR ^b C(O)R ^c , —(CH ₂ ) _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 , substituted with 0-3 R ^a C _1-6 alkyl, C _2-6 alkenyl substituted with 0-3 R ^a , C _2-6 alkynyl substituted with 0-3 R ^a , C _1-6 haloalkyl, 0-3 —(CH ₂ ) _r —3- to 14-membered carbocyclic ring substituted with R ^a of or selected from carbon atoms and N, O, and S(O) _p substituted with 0-3 R ^a —(CH ₂ ) _r —a 5- to 10-membered heterocyclic ring containing 1 to 4 heteroatoms;
or two R ^3a , taken together with the atoms to which they are attached, together form a fused ring, said ring comprising a phenyl and a carbon atom and 1-4 heteroatoms selected from N, S or O; a 5- to 7-membered heterocyclic ring containing atoms, said fused ring further substituted with R ^a1 ;
R ⁴ and R ⁵ are independently hydrogen, C _1-4 alkyl substituted with 0-1 R ^f , (CH ₂ ) _r -phenyl substituted with 0-3 R ^d , or —(CH ₂ )—5- to 7-membered heterocyclic ring containing carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) _p ;
Each occurrence of R ¹¹ is independently hydrogen, C _1-4 alkyl substituted with 0-3 R ^f , CF ₃ , C _3-10 cyclo substituted with 0-1 R ^f alkyl, (CH) _r -phenyl substituted with 0-3 R ^d , or carbon atom and N, O, and S(O) 2 _p substituted with 0-3 R ^d —(CH ₂ ) _r —5- to 7-membered heterocyclic ring containing 1-4 heteroatoms;
Each occurrence of R ^a and R ^a1 is independently hydrogen, F, Cl, Br, OCF ₃ , CF ₃ , CHF ₂ , CN, NO ₂ , —(CH ₂ ) _r OR ^b , —(CH ₂ ) _r SR ^b , —(CH ₂ ) _r C(O)R ^b , —(CH ₂ ) _r C(O)OR ^b , —(CH ₂ ) _r OC(O)R ^b , —(CH ₂ ) _r NR ¹¹ R ¹¹ , —(CH ₂ ) _r C(O)NR ¹¹ R ¹¹ , —(CH ₂ ) _r NR ^b C(O)R ^c , —(CH ₂ ) _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) ₂ R ^c , C _1-6 alkyl substituted with 0-3 R ^f , C _1-6 haloalkyl, C _2-6 alkenyl substituted with 0-3 R ^a , substituted with 0-3 R ^a C _2-6 alkynyl, —(CH ₂ ) _r —3-14 membered carbocycle, or carbon atoms and N, O, and S(O) _p substituted with 0-3 R ^f —(CH ₂ ) _r —a 5- to 7-membered heterocyclic ring containing 1 to 4 heteroatoms;
Each occurrence of R ^b is independently hydrogen, C _1-6 alkyl substituted with 0-3 R ^d , C _1-6 haloalkyl, C ₃ substituted with 0-2 R ^d _- (CH ₂ ) _r containing carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) _p substituted with ∼6 cycloalkyl, or 0-3 R ^f - 5- to 7-membered heterocycle or (CH ₂ ) _r -phenyl substituted with 0-3 R ^d ;
R ^c is C _1-6 alkyl substituted with 0-3 R ^f , (CH ₂ ) _r —C _3-6 cycloalkyl substituted with 0-3 R ^f , 0-3 is (CH ₂ ) _r -phenyl substituted with R ^f ; or
R ^d is independently at each occurrence hydrogen, F, Cl, Br, OCF ₃ , CF ₃ , CN, NO ₂ , —OR ^e , —(CH ₂ ) _r C(O)R ^c , —NR ^e R ^e , —NR ^e C(O)OR ^c , C _1-6 alkyl, or (CH ₂ ) _r -phenyl substituted with 0-3 R ^f ;
each occurrence of R ^e is independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, and (CH ₂ ) _r -phenyl substituted with 0-3 R ^f ;
each occurrence of R ^f independently is hydrogen, halo, CN, NH ₂ , OH, C _3-6 cycloalkyl, CF ₃ , O(C _{1-6 alkyl} ), or a carbon atom and N, O, —(CH ₂ ) _r —5- to 7-membered heteroaryl containing 1-4 heteroatoms selected from and S(O) _p ;
p is 0, 1, or 2;
r is 0, 1, 2, 3, or 4]
or a pharmaceutically acceptable salt thereof. The Tyk2 inhibitor has the formula:

[In the formula,
R ¹ is C _1-3 alkyl optionally substituted with 0-7 R ^1a where each occurrence of R ^1a is independently hydrogen, deuterium, F, Cl, Br, CF ₃ or CN;
R ² is C _1-6 alkyl substituted with ^{0-4 R 2a ,} C _3-6 cycloalkyl substituted with 0-4 R ^2a , substituted with 0-4 R 2a 5-14 membered containing 1-4 heteroatoms selected from C _6-10 aryl, N, O, and S and substituted with 0-4 R ^2a , NR ⁶ R ⁶ or OR ^b is a heterocycle;
R ^2a independently at each occurrence hydrogen, =O, halo, OCF ₃ , CN, NO ₂ , —(CH ₂ ) _r OR ^b , —(CH ₂ ) _r SR ^b , —(CH ₂ ) _r C(O)R ^b , —(CH ₂ ) _r C(O)OR ^b , —(CH ₂ ) _r OC(O)R ^b , (CH ₂ ) _r NR ¹¹ R ¹¹ , —(CH ₂ ) _r C(O)NR ¹¹ R ¹¹ , —(CH ₂ ) _r NR ^b C(O)R ^C , —(CH ₂ ) _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 , C _1-6 alkyl substituted with 0-3 R ^a , C _1-6 haloalkyl, —(CH ₂ ) _r —3- to 14-membered carbocyclic ring substituted with 0-1 R ^a , or a carbon atom or N, O, substituted with 0-2 R ^a —(CH ₂ ) _r —5- to 7-membered heterocyclic ring containing 1-4 heteroatoms selected from and S(O) _p ;
or one R ^2a and another R ^2a , taken together with the atoms to which they are attached, together form a fused 5-6 membered ring, said fused ring substituted with 0-2 R ^a may be;
R ³ is —(CH ₂ ) _r —3-14 membered carbocyclic ring substituted with 0-5 R ^3a ;
R ^3a independently at each occurrence hydrogen, ═O, halo, OCF ₃ , CN, NO ₂ , —(CH ₂ ) _r OR ^b , —(CH ₂ ) _r SR ^b , —(CH ₂ ) _r C(O)R ^b , —(CH ₂ ) _r C(O)OR ^b , —(CH ₂ ) _r OC(O)R ^b , (CH ₂ ) _r NR ¹¹ R ¹¹ , —(CH ₂ ) _r C(O)NR ¹¹ R ¹¹ , —(CH ₂ ) _r NR ^b C(O)R ^C , —(CH ₂ ) _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 , C _1-6 alkyl substituted with 0-3 R ^a , C _1-6 haloalkyl, —(CH ₂ ) _r —3- to 14-membered carbocyclic ring substituted with 0-3 R ^a , or a carbon atom or N, O, substituted with 0-3 R ^a and S(O) _p —(CH ₂ ) _r —5- to 10-membered heterocyclic ring containing 1-4 heteroatoms selected from;
or two R ^3a , taken together with the atoms to which they are attached, together form a fused ring, said ring comprising a phenyl and a carbon atom and 1-4 heteroatoms selected from N, S or O; a 5- to 7-membered heterocyclic ring containing atoms, said fused ring optionally further substituted by R ^a ;
R ⁴ and R ⁵ are independently hydrogen, C _1-4 alkyl substituted with 0-1 R ^f , (CH ₂ ) _r -phenyl substituted with 0-3 R ^d , or —(CH ₂ )—5- to 7-membered heterocyclic ring containing 5 carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) _p ;
each occurrence of R ⁶ and R ¹¹ is independently hydrogen, C _1-4 alkyl substituted with 0-3 R ^f , CF ₃ , C ₃ substituted with 0-1 R ^f _from ∼10 cycloalkyl, (CH) _r -phenyl substituted with 0-3 R ^d , or carbon atoms and N, O, and S(O) 2 _p substituted with 0-3 R ^d —(CH ₂ ) _r —5- to 7-membered heterocyclic ring containing 1-4 selected heteroatoms;
R ^a is, at each occurrence, hydrogen, F, Cl, Br, OCF ₃ , CF ₃ , CHF ₂ , CN, NO ₂ , —(CH ₂ ) _r OR ^b , —(CH ₂ ) _r SR ^b , — (CH ₂ ) _r C(O)R ^b , —(CH ₂ ) _r C(O)OR ^b , —(CH ₂ ) _r OC(O)R ^b , —(CH ₂ ) _r NR ¹¹ R ¹¹ , — (CH ₂ ) _r C(O)NR ¹¹ R ¹¹ , —(CH ₂ ) _r NR ^b C(O)R ^C , —(CH ₂ ) _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) ₂ R ^C , 0 to 3 C _1-6 alkyl substituted with R ^f , C _1-6 haloalkyl, —(CH ₂ ) _r —3-14 membered carbocyclic ring, or a carbon atom and N substituted with 0-3 R ^f , —(CH ₂ ) _r —5- to 7-membered heterocyclic ring containing 1-4 heteroatoms selected from O, and S(O) _p ;
R ^b at each occurrence is hydrogen, C _1-6 alkyl substituted with 0-3 R ^d , C _1-6 haloalkyl, C _3-6 cyclo substituted with 0-2 R ^d alkyl, or —(CH ₂ ) _r —5~ containing carbon atoms and 1 to 4 heteroatoms selected from N, O, and S(O) _p substituted with 0 to 3 R ^f a 7-membered heterocyclic ring, or (CH ₂ ) _r -phenyl substituted with 0-3 R ^d ;
R ^C is C _1-6 alkyl substituted with 0-3 R ^f , (CH ₂ ) _r —C _3-6 cycloalkyl substituted with 0-3 R ^f or 0-3 (CH ₂ ) _r -phenyl substituted with R ^f ;
Each occurrence of R ^d is independently hydrogen, F, Cl, Br, OCF ₃ , CF ₃ , CN, NO ₂ , OR ^e , —(CH ₂ ) _r C(O)R ^C , NR ^e R ^e , —NR ^e C(O)OR ^C , C _1-6 alkyl or (CH ₂ ) _r -phenyl substituted with 0-3 R ^f ;
each occurrence of R ^e is independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl and (CH ₂ ) _r -phenyl substituted with 0-3 R ^f ;
each occurrence of R ^f independently is hydrogen, halo, CN, NH ₂ , OH, C _3-6 cycloalkyl, CF ₃ , O(C _1-6 alkyl) or a carbon atom and N, O, and -(CH ₂ ) _r -5- to 7-membered heteroaryl containing 1-4 heteroatoms selected from S(O) _p ;
p is 0, 1, or 2;
r is 0, 1, 2, 3, or 4]
or a pharmaceutically acceptable salt thereof. The Tyk2 inhibitor has the formula:

[In the formula,
Y is N or _CR6 ;
R ¹ is H, C _1-3 alkyl or C _3-6 cycloalkyl, each optionally substituted with 0-7 R ^1a ;
R ^1a is independently at each occurrence hydrogen, deuterium, F, Cl, Br or CN;
R ² is C _1-6 alkyl, —(CH ₂ ) _r —3- to 14-membered carbocyclic ring substituted with 0-1 R ^2a , or 1-4 selected from N, O, and S and each group is substituted with 0-4 R ^2a (for clarity R ² can be -C(O)R ^2a such as intended to include substituted methyl groups);
R ^2a independently at each occurrence hydrogen, =O, halo, OCF ₃ , CN, NO ₂ , —(CH ₂ ) _r OR ^b , —(CH ₂ ) _r SR ^b , —(CH ₂ ) _r C(O)R ^b , —(CH ₂ ) _r C(O)OR ^b , —(CH ₂ ) _r OC(O)R ^b , —(CH ₂ ) _r NR ¹¹ R ¹¹ , —(CH ₂ ) _r C(O)NR ¹¹ R ¹¹ , —(CH ₂ ) _r NR ^b C(O)R ^c , —(CH ₂ ) _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 , C _1-6 alkyl substituted with 0-3 R ^a , C _1-6 haloalkyl, C _2-6 alkenyl substituted with 0-3 R ^a , C _2-6 alkynyl substituted with ^0-3 R ^a , —(CH ₂ ) _r —3- to 14-membered carbocyclic ring, or 1-4 carbon atoms or 1-4 selected from N, O, and S(O) _p substituted with 0-2 R ^a —(CH ₂ ) _r —a 5- to 7-membered heterocyclic ring containing a heteroatom;
R ³ 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 group being substituted with 0-4 R ^3a ;
R ^3a is independently at each occurrence hydrogen, ═O, halo, OCF ₃ , CF ₃ , CHF ₂ , CN, NO ₂ , —(CH ₂ ) _r OR ^b , —(CH ₂ ) _r SR ^b , —(CH ₂ ) _r C(O)R ^b , —(CH ₂ ) _r C(O)OR ^b , —(CH ₂ ) _r OC(O)R ^b , —(CH ₂ ) _r NR ¹¹ R ¹¹ , —(CH ₂ ) _r C(O)NR ¹¹ R ¹¹ , —(CH ₂ ) _r NR ^b C(O)R ^c , —(CH ₂ ) _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 , substituted with 0-3 R ^a C _1-6 alkyl, C _2-6 alkenyl substituted with 0-3 R ^a , C _2-6 alkynyl substituted with 0-3 R ^a , C _1-6 haloalkyl, 0-3 —(CH ₂ ) _r —3- to 14-membered carbocyclic ring substituted with R ^a of or selected from carbon atoms and N, O, and S(O) _p substituted with 0-3 R ^a —(CH ₂ ) _r —a 5- to 10-membered heterocyclic ring containing 1 to 4 heteroatoms;
or two R ^3a , together with the atoms to which they are attached, form a fused ring, said rings being selected from phenyl and carbon atoms and N, O, and S(O) _p 1 heterocycles containing up to 4 heteroatoms, each fused ring substituted with 0-3 R ^a1 ;
R ⁴ and R ⁵ are independently hydrogen, C _1-4 alkyl substituted with 0-1 R ^f , (CH ₂ ) _r -phenyl substituted with 0-3 R ^d , or —(CH ₂ )—5- to 7-membered heterocyclic ring containing carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) _p ;
R ⁶ is hydrogen, halo, C _1-4 alkyl, C _1-4 haloalkyl, OC _1-4 haloalkyl, OC _1-4 alkyl, CN, NO ₂ or OH;
Each occurrence of R ¹¹ is independently hydrogen, C _1-4 alkyl substituted with 0-3 R ^f , CF ₃ , C _3-10 cyclo substituted with 0-1 R ^f alkyl, (CH) _r -phenyl substituted with 0-3 R ^d , or carbon atom and N, O, and S(O) 2 _p substituted with 0-3 R ^d —(CH ₂ ) _r —5- to 7-membered heterocyclic ring containing 1-4 heteroatoms;
Each occurrence of R ^a and R ^a1 is independently hydrogen, F, Cl, Br, OCF ₃ , CF ₃ , CHF ₂ , CN, NO ₂ , —(CH ₂ ) _r OR ^b , —(CH ₂ ) _r SR ^b , —(CH ₂ ) _r C(O)R ^b , —(CH ₂ ) _r C(O)OR ^b , —(CH ₂ ) _r OC(O)R ^b , —(CH ₂ ) _r NR ¹¹ R ¹¹ , —(CH ₂ ) _r C(O)NR ¹¹ R ¹¹ , —(CH ₂ ) _r NR ^b C(O)R ^c , —(CH ₂ ) _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) ₂ R ^c , C _1-6 alkyl substituted with 0-3 R ^f , C _1-6 haloalkyl, C _2-6 alkenyl substituted with 0-3 R ^a , substituted with 0-3 R ^a C _2-6 alkynyl, —(CH ₂ ) _r —3-14 membered carbocycle, or carbon atoms and N, O, and S(O) _p substituted with 0-3 R ^f —(CH ₂ ) _r —a 5- to 7-membered heterocyclic ring containing 1 to 4 heteroatoms;
R ^b is hydrogen, C _1-6 alkyl substituted with 0-3 R ^d , C _1-6 haloalkyl, C _3-6 cycloalkyl substituted with 0-2 R ^d , or 0- —(CH ₂ ) _r —5- to 7-membered heterocyclic ring containing carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) _p , substituted with 3 R ^f or (CH ₂ ) _r -phenyl substituted with 0-3 R ^d ;
R ^c is C _1-6 alkyl substituted with 0-3 R ^f , (CH ₂ ) _r —C _3-6 cycloalkyl substituted with 0-3 R ^f or 0-3 (CH ₂ ) _r -phenyl substituted with R ^f ;
R ^d is independently at each occurrence hydrogen, F, Cl, Br, OCF ₃ , CF ₃ , CN, NO ₂ , —OR ^e , —(CH ₂ ) _r C(O)R ^c , —NR ^e R ^e , —NR ^e C(O)OR ^c , C _1-6 alkyl, or (CH ₂ ) _r -phenyl substituted with 0-3 R ^f ;
each occurrence of R ^e is independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, and (CH ₂ ) _r -phenyl substituted with 0-3 R ^f ;
each occurrence of R ^f independently is hydrogen, halo, CN, NH ₂ , OH, C _3-6 cycloalkyl, CF ₃ , O(C _1-6 alkyl) or a carbon atom and N, O, and -(CH ₂ ) _r -5- to 7-membered heterocyclic ring containing 1-4 heteroatoms selected from S(O) _p ;
p is 0, 1, or 2;
r is 0, 1, 2, 3, or 4]
or a pharmaceutically acceptable salt thereof. The Tyk2 inhibitor has the formula:

or a pharmaceutically acceptable salt thereof. 6. The method of any one of claims 1-5, wherein the effective amount of the Tyk2 inhibitor, or the pharmaceutically acceptable salt thereof, ranges from about 0.1 mg/day to about 250 mg/day. . The effective amount of the Tyk2 inhibitor, or the pharmaceutically acceptable salt thereof, is 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/day to about 1.0 mg/day. 7. The method of any one of claims 1-6, in the range of about 24 mg/day. an effective amount of the Tyk2 inhibitor, or the pharmaceutically acceptable salt thereof, is 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; 8. The method of any one of claims 1-7, which ranges from about 2 mg/day to about 12 mg/day, or from about 3 mg/day to about 12 mg/day. 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 9. The method of any one of claims 1-8, which is 10 mg/day, about 11 mg/day, or about 12 mg/day. The N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole- 10. A process according to any one of claims 1 to 9, wherein the 4-yl]acetamide is greater than 95% stereoisomerically pure. The N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole- 11. A process according to any one of claims 1 to 10, wherein the 4-yl]acetamide is more than 99% stereoisomerically pure. The N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole- 12. A process according to any one of claims 1 to 11, wherein the 4-yl]acetamide is greater than 99.5% stereoisomerically pure. The N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole- 13. The method of any one of claims 1 to 12, wherein the 4-yl]acetamide is greater than 99.9% stereoisomerically pure. The N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole- 14. The method of any one of claims 1-13, wherein the 4-yl]acetamide is in single crystal form. The N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole- 4-yl]acetamide is single crystal form B characterized by X-ray powder diffraction peaks at 2-theta angles selected from 10.1°, 13.5°, 20.7°, and 26.9°. 15. A method according to any one of claims 1-14. The N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole- 4-yl]acetamide is X at a 2θ angle selected from 10.1°, 13.5°, 15.7°, 18.1°, 20.7°, 24.7°, and 26.9° 16. The method of any one of claims 1-15, wherein the single crystal form B is characterized by a line powder diffraction peak. The N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole- 4-yl]acetamide at 10.1°, 13.5°, 15.7°, 16.3°, 18.1°, 20.7°, 22.5°, 24.7°, 26.2 17. A method according to any one of claims 1 to 16, which is single crystalline Form B characterized by X-ray powder diffraction peaks at 2-theta angles selected from °, 26.9 ° and 29.1 °. The N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole- 18. The method of any one of claims 1 to 17, wherein the 4-yl]acetamide is at least 90% single crystalline Form B. The N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole- 19. The method of any one of claims 1 to 18, wherein the 4-yl]acetamide is at least 95% single crystalline Form B. The N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole- 20. The method of any one of claims 1 to 19, wherein the 4-yl]acetamide is at least 99% single crystalline Form B. N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-4 -yl]acetamide, or said pharmaceutically acceptable salt thereof, in an effective amount of about 0.5 mg to about 1000 mg per day, about 1 mg to about 1000 mg per day, about 5 mg to about 500 mg per day, about 10 mg per day. to about 200 mg, about 10 mg to about 100 mg per day, about 40 mg to about 100 mg per day, about 20 mg to about 40 mg per day, about 0.1 mg to about 10 mg per day, about 0.5 mg to about 5 mg per day about 1 mg to about 20 mg; 21. A method according to any one of claims 1 to 20. N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-4 -yl]acetamide, or said pharmaceutically acceptable salt thereof, ranges from about 10 mg to about 60 mg per day. N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-4 -yl]acetamide, or the pharmaceutically acceptable salt thereof, in an effective amount of about 10 mg per day, about 15 mg per day, about 20 mg per day, about 25 mg per day, about 30 mg per day, about 35 mg per day; 23. The method of any one of claims 1-22, which is about 40 mg per day, about 45 mg per day, about 50 mg per day, about 55 mg per day, or about 60 mg per day. N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-4 -yl]acetamide, or the pharmaceutically acceptable salt thereof, is about 30 mg per day or about 60 mg per day. N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-4 -yl]acetamide is administered at about 30 mg once daily. N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-4 -yl]acetamide is administered at about 30 mg twice daily. The N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole- 4-yl]acetamide is titrated to a dosage of approximately 30 mg administered twice daily using the following titration schedule:
Day 1: approximately 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 about 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 beyond: about 30 mg twice a day;
25. The method of any one of claims 1-24. N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-4 -yl]acetamide, or said pharmaceutically acceptable salt thereof, ranges from about 40 mg to about 100 mg per day. The N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole- 4-yl]acetamide is titrated at a dosage between about 40 mg/day to about 100 mg/day using the following titration schedule:
Day 1: approximately 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 about 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 beyond: between about 40 mg/day and about 100 mg/day;
29. The method of any one of claims 1-21 and 28. N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-4 -yl]acetamide, or said pharmaceutically acceptable salt thereof, is administered at about 20 mg twice daily. The N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole- 4-yl]acetamide is titrated to a dosage of approximately 20 mg administered twice daily using the following titration schedule:
Day 1: approximately 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 about 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 beyond: about 20 mg twice daily.
31. The method of any one of claims 1-21 and 30. N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-4 -yl]acetamide, or said pharmaceutically acceptable salt thereof, ranges between about 4 mg and about 10 mg per day. The N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole- 4-yl]acetamide is titrated at a dosage between about 4 mg/day to about 10 mg/day using the following titration schedule:
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 beyond: between about 4 mg/day and about 10 mg/day;
33. The method of any one of claims 1-21 and 32. N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-4 -yl]acetamide, or said pharmaceutically acceptable salt thereof, is an effective amount of about 3 mg/day. The N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole- 4-yl]acetamide is titrated to a dosage of approximately 3 mg administered twice daily using the following titration schedule:
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 beyond: about 3 mg twice daily.
35. The method of any one of claims 1-21 and 34. The N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole- 36. The method of any one of claims 1-35, wherein the 4-yl]acetamide is formulated as part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier. The N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole- 37. The method of any one of claims 1-36, wherein the 4-yl]acetamide is administered parenterally, transdermally, mucosally, nasally, buccal site, sublingually, or orally. The N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole- 38. The method of any one of claims 1-37, wherein the 4-yl]acetamide is administered orally. The N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole- 39. The method of any one of claims 1-38, wherein the 4-yl]acetamide is administered orally in tablet or capsule form. The N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole- 40. The method of any one of claims 36-39, wherein the 4-yl]acetamide is formulated as an extended release form. The N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole- 40. The method of any one of claims 36-39, wherein the 4-yl]acetamide is formulated as an immediate release form. 42. The method of any one of claims 1-41, wherein said disease or disorder is selected from viral, genetic, inflammatory, allergic and autoimmune diseases. said disease or disorder is chronic obstructive pulmonary disease, asthma, chronic pulmonary inflammatory disease, hyperoxic alveolar damage, inflammatory skin disease, 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, lupus vulgaris, Sjögren's syndrome, inflammatory 43. The method of any one of claims 1-42, selected from enteropathy, Crohn's disease, Behcet's disease, and ulcerative colitis. 44. The method of any one of claims 1-43, wherein the disease or disorder is selected from psoriasis, psoriatic arthritis, contact dermatitis, systemic lupus erythematosus, cutaneous lupus erythematosus, and ulcerative colitis. 45. The method of any one of claims 1-44, wherein the disease or disorder is psoriasis. 46. The method of any one of claims 1-45, wherein the disease or disorder is psoriasis vulgaris. 47. The method of any one of claims 1-46, wherein the disease or disorder is moderate to severe plaque psoriasis. 48. The method of any one of claims 45-47, wherein the subject is a candidate for phototherapy or systematic therapy. 45. The method of any one of claims 1-44, wherein the disease or disorder is psoriatic arthritis. N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- according to any one of claims 10 to 20 in a therapeutically effective amount 2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide, or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of any one of claims 2 to 5. A pharmaceutical composition comprising a Tyk2 inhibitor as described. The Tyk2 inhibitor has the formula:

or a pharmaceutically acceptable salt thereof. 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 of the Tyk inhibitor 52. The pharmaceutical composition of claim 50 or 51, formulated for administration of to about 12 mg/day. Tyk inhibitor 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, 53. The pharmaceutical composition of any one of claims 50-52, formulated for administration of about 11 mg/day, or about 12 mg/day. N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-4 -yl]acetamide, or said pharmaceutically acceptable salt thereof, from about 1 mg to about 1000 mg per day, from about 5 mg to about 500 mg per day, from about 10 mg to about 200 mg per day, from about 10 mg to about 100 mg per day, 1 about 40 mg to about 100 mg per day, about 20 mg to about 40 mg per day, about 0.1 mg to about 10 mg per day, about 0.5 mg to about 5 mg per day, about 1 mg to about 20 mg per day, and about 1 mg to about 1 mg per day 10 mg, about 1 mg to about 100 mg per day, about 1 mg to about 80 mg per day, about 5 mg to about 70 mg per day, and about 10 mg to about 60 mg per day. A pharmaceutical composition according to any one of claims. N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-4 -yl]acetamide, or said pharmaceutically acceptable salt thereof, formulated for administration of from about 10 mg to about 60 mg per day. . N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-4 -yl]acetamide, or the pharmaceutically acceptable salt thereof, about 10 mg per day, about 15 mg per day, about 20 mg per day, about 25 mg per day, about 30 mg per day, about 35 mg per day, about 35 mg per day, about 56. The pharmaceutical composition of any one of claims 50-55, formulated for administration of 40 mg, about 45 mg per day, about 50 mg per day, about 55 mg per day, or about 60 mg per day. N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-4 -yl]acetamide, or said pharmaceutically acceptable salt thereof, formulated for administration of about 30 mg per day or about 60 mg per day. Composition. N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-4 -yl]acetamide, or said pharmaceutically acceptable salt thereof, formulated for administration of about 30 mg once daily. . N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-4 -yl]acetamide, or said pharmaceutically acceptable salt thereof, formulated for administration of about 30 mg twice daily. . 58. A pharmaceutical composition according to any one of claims 50 to 57 in the form of tablets or capsules. 59. The pharmaceutical composition of any one of claims 50-58, formulated for extended release. 59. The pharmaceutical composition of any one of claims 50-58, formulated for immediate release.

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