JP7453251B2 - Combination therapy including apremilast and TYK2 inhibitor - Google Patents

Description

Related applications
[0001] This application claims priority to International Application No. PCT/US2019/029772, filed April 30, 2019, which is incorporated herein by reference in its entirety.

[0002] 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) inhibitor. PDE4 inhibition by apremilast increases cyclic adenosine monophosphate (cAMP) levels in immune cells. This in turn downregulates the inflammatory response by reducing the expression of pro-inflammatory mediators such as TNF-α, IL-23, IL-17, and other pro-inflammatory cytokines, and of anti-inflammatory mediators. Increase production. Studies have shown that a 75% reduction in plaque psoriasis can be achieved in some patients with as little as four months of treatment.

[0003] Tyrosine kinase 2 (Tyk2), an intracellular signaling enzyme, regulates signal transducing transcription factor (STAT)-dependent gene expression and IL-12, IL-23, and type I and type III interferon receptors. activates functional responses. Tyrosine kinase inhibitors (TKIs) have gained attention in recent years as effective agents to treat psoriasis and related conditions, among other conditions. The TKI inhibitor BMS-986165, for example, recently showed promising results in a phase 2 clinical trial in subjects with moderate to severe plaque psoriasis. The New England Journal of Medicine, September 12, 2018, Kim Papp, M. D. , Phase 2 Trial of Selective Tyrosine Kinase 2 Inhibition in Psoriasis.

[0004] Apremilast and Tyk2 inhibitor 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)- Here, the combination with N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165) was shown to synergistically reduce pro-inflammatory cytokines expressed under conditions that stimulate Th17 cells in whole blood assays. discovered. For example, using the combination of 0.01 μM BMS-986165 and 1 μM apremilast, there was a more 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 with BMS-986165 at a concentration of 0.1 μM along with 1 μM apremilast. See, eg, 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 the value of each drug alone. See, eg, Table 5.

[0005] 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 the 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, thereby producing a complementary effect of 13.5% inhibition on TNF-α. See, eg, Table 5. This trend was also observed for BMS-986165 at a concentration of 0.1 μM and for the cytokine GM-CSF. See, eg, Table 5. These results demonstrate synergistic and complementary pharmacological actions of BMS-986165 and apremilast.

[0006] In addition to whole blood assays, the combination of BMS-986165 and apremilast induces complementary effects on certain pro-inflammatory cytokines in LPS-stimulated PBMCs as well. BMS-986165 increased IL-23, IL-12 and TNF-α, while apremilast inhibited the production of these cytokines. See, for example, Table 6 in the Examples paragraph. These results further support the benefits of combining BMS-986165 and apremilast in the treatment of Th17-related diseases.

[0007] 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.

[0008] 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.

[0009] Anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood - apremilast and BMS in TruCulture® tube assays Figure 2 illustrates interleukin-17a (IL-17a) cytokine production (percentage of control) by -986165. [0010] Anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood - apremilast and BMS in TruCulture® tube assays FIG. 3 illustrates interleukin-17A (IL-17A) cytokine production by -986165. [0011] Anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood - apremilast and BMS in TruCulture® tube assays Figure 2 illustrates interleukin-17F (IL-17F) cytokine production (percentage of control) by -986165. [0012] Anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood - apremilast and BMS in TruCulture® tube assays FIG. 3 illustrates interleukin-17F (IL-17F) cytokine production by -986165. [0013] Anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood - apremilast and BMS in TruCulture® tube assays Figure 2 illustrates interleukin-22 (IL-22) cytokine production (percentage of control) by -986165. [0014] Anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood - apremilast and BMS in TruCulture® tube assays FIG. 3 illustrates interleukin-22 (IL-22) cytokine production by -986165. [0015] Anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood - apremilast and BMS in TruCulture® tube assays FIG. 3 illustrates tumor necrosis factor alpha (TNF-α) cytokine production (percentage of control) by -986165. [0016] Anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood - apremilast and BMS in TruCulture® tube assays FIG. 3 illustrates tumor necrosis factor alpha (TNF-α) cytokine production by -986165. [0017] Anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood - apremilast and BMS in TruCulture® tube assays Figure 2 illustrates granulocyte macrophage colony stimulating factor (GM-CSF) cytokine production (percentage of control) by -986165. [0018] Anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood - apremilast and BMS in TruCulture® tube assays -986165 illustrates granulocyte macrophage colony stimulating factor (GM-CSF) cytokine production. [0019] FIG. 2 illustrates interleukin-23 (IL-23) cytokine production by apremilast in lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs). [0020] FIG. 2 illustrates interleukin-23 (IL-23) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS-stimulated PBMC. [0021] FIG. 3 illustrates interleukin-12p40 (IL-12p40) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS-stimulated PBMCs. [0022] FIG. 3 illustrates interleukin-12p70 (IL-12p70) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS-stimulated PBMCs. [0023] FIG. 3 illustrates tumor necrosis factor alpha (TNF-α) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS-stimulated PBMCs. [0024] FIG. 3 illustrates interferon gamma (IFN-γ) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS-stimulated PBMC. [0025] Figure 2 illustrates monocyte chemoattractant protein-1 (MCP-1) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS-stimulated PBMCs. [0026] FIG. 3 illustrates the combined effect of a fixed dose of apremilast and Tyk2i (BMS-986165) in IL-17A whole blood. [0027] FIG. 3 illustrates the combined effect of a fixed dose of apremilast and Tyk2i (BMS-986165) in IL-17F whole blood. [0028] Figure 2 illustrates the combined effect of a fixed dose of apremilast and Tyk2i (BMS-986165) on IL-22 whole blood. [0029] FIG. 3 illustrates the combined effect of a fixed dose of apremilast and Tyk2i (BMS-986165) on TNF-α whole blood.

[0030] 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), which method comprises administering 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.

[0031] 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.

[0032] 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
[0033]N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-iso Indol-4-yl]acetamide (apremilast) is disclosed in US Pat. No. 6,962,940, the contents of which are incorporated herein by reference, and refers to a compound having the following chemical structure.

[0034] Apremilast has a chiral center designated as (S) in its chemical structure and name. As used herein, this designation means that apremilast is at least 80%, 90%, 95%, 98%, 99%, or It means that it is optically enriched by an amount of 99.9%. Thus, when apremilast is referred to herein as stereomerically or enantiomerically pure in a specified amount, it means that it is enriched in the (S) enantiomer in that amount. For example, at least 95% stereomerically pure N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro -1,3-dioxo-1H-isoindol-4-yl]acetamide means that the compound contains 95% or more of the (S) enantiomer and 5% or less of the (R) enantiomer.

[0035] Unless otherwise indicated, administration as described herein includes administering apremilast before, concurrently with, or after administration of a Tyk2 inhibitor as described herein. Therefore, simultaneous administration is not necessarily 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 the present disclosure are administered at different times on the same day. In another aspect, apremilast and a Tyk2 inhibitor of the present disclosure are administered as separate tablets or capsules at different times. In another aspect, apremilast and a Tyk2 inhibitor of the present disclosure are administered in a fixed-dose combination in the same tablet or capsule.

[0036] The terms "treatment," "treating," and "treating" refer to the progression of, or one or more symptoms of, a disease or disorder that is responsive to inhibition of PDE4, as described herein. Refers to improving, alleviating, or inhibiting.

[0037] The term "subject" refers to animals such as mammals, humans, and the like. The terms "subject" and "patient" may be used interchangeably.
[0038] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein that elicits a biological or medical response in a subject, e.g., 0.001 to 100 mg/ The dosage is between kg of body weight/day.

[0039] The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier, adjuvant, which does not adversely affect the pharmacological activity of the compound with which it is formulated and is safe for human use. , or refer 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, For example 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, cellulosic materials (e.g., microcrystalline cellulose, hydroxypropylmethylcellulose, lactose monohydrate, sodium lauryl sulfate, and croscarmellose sodium), polyethylene glycol, sodium carboxymethylcellulose, Includes, but is not limited to, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycols and wool fats.

[0040] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids and bases and organic acids and bases. Pharmaceutically acceptable base addition salts suitable for the compounds described herein include metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or lysine, N,N'- Organic salts made from dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine include, but are not limited to. 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, mucilage 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.

[0041] "Crystalline" refers to the solid state of a compound in which there is a long range of atomic order in the positions of the atoms. The crystallinity of a solid can be confirmed, for example, by examination of the X-ray powder diffraction pattern. "Single crystal form" refers to the referenced compound, namely N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3 -dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is present as a single crystal or multiple crystals, each crystal having the same crystal form (eg crystal form B). If a crystalline form is defined as one particular single crystal form of a defined percentage of a compound, the remainder is from amorphous and/or crystalline forms other than the defined one or more particular forms. Become. In one aspect, for example, a crystalline form of the disclosure is 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 total weight of the particular crystal plus the weight of any other crystalline forms present plus the weight of any amorphous form present. It is determined by dividing and multiplying by 100%.

[0042] The term "amorphous" refers to a solid that exists in a non-crystalline state or form. An amorphous solid is a disordered arrangement of molecules and therefore has no discernible crystal lattice or unit crystal and consequently no definable long-range order. The solid state of an ordered solid can be determined by standard techniques known in the art, such as by X-ray powder diffraction (XRPD), or differential scanning calorimetry (DSC). Amorphous solids can also be distinguished from crystalline solids by birefringence using, for example, polarized light microscopy.

[0043] The 2-theta values of the X-ray powder diffraction patterns for the crystal forms described herein vary from instrument to instrument and due to factors such as temperature changes, sample displacement, and the presence or absence of internal standards. May vary slightly due to variations in sample preparation and batch-to-batch variations. Therefore, unless otherwise defined, XRPD patterns/assignments cited herein are not to be construed as absolute and may vary by ±0.2 degrees. It is known in the art that this variability accounts for the above elements without preventing unambiguous identification of the crystalline form.
2. Tyk2 inhibitor
[0044] Tyk2 inhibitors used 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.

[0045] In a second embodiment, the Tyk2 inhibitors of the present disclosure include those described by Xingrui He et al., Expert Opinion on Therapeutics Patents 2019, Vol. 29, No. 2, pp. 137-149, the entire contents of which are incorporated herein by reference.

[0046] In a third embodiment, the Tyk2 inhibitors of the present disclosure have the formula:

[0047] or a pharmaceutically acceptable salt thereof, the variables of which are as described in WO 2015/032423, herein incorporated by reference in its entirety. Exemplary compounds having this formula include, as part of the third embodiment, the formula:

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

[0048] In a fourth embodiment, the Tyk2 inhibitors of the present disclosure have the formula:

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

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

[0049] In a fifth embodiment, the Tyk2 inhibitors of the present disclosure have the formula:

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

[0050] In a sixth embodiment, the Tyk2 inhibitors of the present disclosure have the formula

or a pharmaceutically acceptable salt thereof, the variables of which are as described in WO 2015/091584, herein incorporated 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.
[0051] In a seventh embodiment, the Tyk2 inhibitors of the present disclosure have the formula:

or a pharmaceutically acceptable salt thereof, the variables of which are as described in WO 2016/027195, herein incorporated 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.
[0052] In an eighth embodiment, the Tyk2 inhibitors of the present disclosure have the formula:

or a pharmaceutically acceptable salt thereof, the variables of which are as described in US2017/0240552, herein incorporated 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.
[0053] In a ninth embodiment, the Tyk2 inhibitors of the present disclosure have the formula:

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

[0054] In a tenth embodiment, the Tyk2 inhibitors of the present disclosure have the formula:

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

[0055] In an eleventh embodiment, a 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, herein incorporated by reference in its entirety.

[0056] In a twelfth embodiment, the Tyk2 inhibitors of the present disclosure are described in US2015/0299139, WO 2015/069310, US9,505,748, WO 2018/0162889, US2013/0178478, or WO 2015/123453. , each of which is incorporated herein by reference in its entirety.

[0057] In a thirteenth embodiment, a 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 or WO 2016/138352, the entire contents of which are incorporated herein by reference. .

[0058] In a fourteenth embodiment, a 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, herein incorporated by reference in its entirety.

[0059] In a fifteenth embodiment, a 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 entire contents of which are herein incorporated by reference. Incorporated by reference into this document.

[0060] In a sixteenth embodiment, a 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, herein incorporated by reference in its entirety.

[0061] In a seventeenth embodiment, a Tyk2 inhibitor of the present disclosure has the formula:

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

[0062] In an eighteenth embodiment, a 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, herein incorporated by reference in its entirety.

[0063] In a nineteenth embodiment, a 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, herein incorporated by reference in its entirety.

[0064] In a twentieth embodiment, a Tyk2 inhibitor of the present disclosure has the formula:

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

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

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

[0066] In a twenty-second embodiment, the Tyk2 inhibitors of the present disclosure have the formula:

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

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

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

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

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

[0069] In a twenty-fifth embodiment, a Tyk2 inhibitor of the present disclosure has the formula:

[In the formula,
R ¹ is C _1-3 alkyl optionally substituted with 0 to 7 R ^1a ;
R ^1a is independently at each occurrence hydrogen, deuterium, F, Cl, Br, CF ₃ or CN;
R ² is C _1-6 alkyl or -(CH ₂ ) _r -3- to 14-membered carbocycle, each group substituted with 0-4 R ^2a ;
Each occurrence of R ^2a is independently 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 to 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 , C _2-6 alkynyl substituted with 0-1 R ^a -(CH ₂ ) _r -3- to 14-membered carbocycle, or 1 to 4 carbon atoms selected from N, O, and S(O) _p substituted with 0 to 2 R ^a -(CH ₂ ) _r -5- to 7-membered heterocycle containing a heteroatom;
R ³ is C _3-10 cycloalkyl, C _6-10 aryl, or a 5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, and each group is substituted with 0 to 4 R ^3a ;
Each occurrence of R ^3a is independently 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 to 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 carbocycle substituted with R ^a of -(CH 2 ) ^{r -} selected from carbon atoms and N, O, and S(O) _p substituted with 0 to 3 R a -(CH ₂ ) _r -5- to 10-membered heterocycle containing 1 to 4 heteroatoms;
or two R ^3a , together with the atoms to which they are attached, together form a fused ring, said ring containing phenyl and 1 to 4 hetero atoms selected from carbon atoms and N, S or O. selected from 5- to 7-membered heterocycles comprising atoms, said fused ring being further substituted by R ^a1 ;
R ⁴ and R ⁵ are independently hydrogen, C _1-4 alkyl substituted with 0 to 1 R ^f , (CH ₂ ) _r -phenyl substituted with 0 to 3 R ^d , or -( _CH2 )-5- to 7-membered heterocycle containing carbon atoms and 1 to 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 to 3 R ^f , CF ₃ , C _3-10 cyclo substituted with 0 to 1 R ^f alkyl, (CH) _r -phenyl substituted with 0 to 3 R ^d , or selected from carbon atoms and N, O, and S(O) _p substituted with 0 to 3 R ^d -(CH ₂ ) _r -5- to 7-membered heterocycle containing 1 to 4 heteroatoms;
R ^a and R ^a1 each independently represent 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 selected from carbon atoms and N, O, and S(O) _p substituted with C _2-6 alkynyl, -(CH ₂ ) _r -3- to 14-membered carbocycle, or 0 to 3 R ^f -(CH ₂ ) _r -5- to 7-membered heterocycle containing 1 to 4 heteroatoms;
Each occurrence of R ^b is independently hydrogen, C _1-6 alkyl substituted with 0 to 3 R ^d , C _1-6 haloalkyl, C ₃ substituted with 0 to 2 R ^d _- (CH ₂ ) r containing carbon atoms and 1 to 4 heteroatoms selected from N, O, and S(O) _p substituted with ~6 cycloalkyl or 0 to 3 _R ^f - a 5- to 7-membered heterocycle or (CH ₂ ) _r -phenyl substituted with 0 to 3 R ^d ;
R ^c is C _1-6 alkyl substituted with 0 to 3 R ^f , (CH ₂ ) _r -C _3-6 cycloalkyl substituted with 0 to 3 R ^f , (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 substituted with 0 to 3 R ^f ( CH ₂ ) _r -phenyl;
R ^e is independently selected at each occurrence from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, and (CH ₂ ) _r -phenyl substituted with 0 to 3 R ^f ;
Each independent occurrence of R ^f represents hydrogen, halo, CN, NH ₂ , OH, C _3-6 cycloalkyl, CF ₃ , O (C _1-6 alkyl), or _a carbon atom as well as N, O, and -(CH ₂ ) _r -5- to 7-membered heteroaryl containing 1 to 4 heteroatoms selected from S(O) _p ;
p is 0, 1, or 2;
r is 0, 1, 2, 3, or 4]
or pharmaceutically acceptable salts thereof; additional definitions and specific compounds may be found, for example, in US2015/0299139, the entire contents of which are incorporated herein by reference. Incorporated by.

[0070] In a twenty-sixth embodiment, a Tyk2 inhibitor of the present disclosure has the formula:

[In the formula,
R ¹ is C _1-3 alkyl optionally substituted with 0 to 7 R ^1a and 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 It is a heterocycle;
Each occurrence of R ^2a is independently 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 to 3 R ^a , C _1-6 haloalkyl, -(CH ₂ ) _r -3- to 14-membered carbocycle substituted with 0-1 R ^a , or a carbon atom or N, O, substituted with 0-2 R ^a , and -(CH ₂ ) _r -5- to 7-membered heterocycle containing 1 to 4 heteroatoms selected from S(O) _p ;
or one R ^2a and another R ^2a together with the atoms to which they are attached form a fused 5- to 6-membered ring, said fused ring being substituted with 0 to 2 R ^a You can leave it there;
R ³ is -(CH ₂ ) _r -3- to 14-membered carbocycle substituted with 0 to 5 R ^3a ;
Each occurrence of R ^3a is independently 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 to 3 R ^a , C _1-6 haloalkyl, -(CH ₂ ) _r -3- to 14-membered carbocycle substituted with 0-3 R ^a , or a carbon atom or N, O, substituted with 0-3 R ^a , and -(CH ₂ ) _r -5- to 10-membered heterocycle containing 1 to 4 heteroatoms selected from S(O) _p ;
or two R ^3a , together with the atoms to which they are attached, together form a fused ring, said ring containing phenyl and 1 to 4 hetero atoms selected from carbon atoms and N, S or O. selected from 5- to 7-membered heterocycles containing atoms, said fused ring being optionally further substituted by R ^a ;
R ⁴ and R ⁵ are independently hydrogen, C _1-4 alkyl substituted with 0 to 1 R ^f , (CH ₂ ) _r -phenyl substituted with 0 to 3 R ^d , or -( _CH2 )-5- to 7-membered heterocycle containing 5 carbon atoms and 1 to 4 heteroatoms selected from N, O, and S(O) _p ;
R ⁶ and R ¹¹ each independently represent hydrogen, C _1-4 alkyl substituted with 0 to 3 R ^f , CF ₃ , C ₃ substituted with 0 to 1 R ^f _~10 cycloalkyl, (CH) _r -phenyl substituted with 0 to 3 R ^d , or from carbon atoms and N, O, and S(O) _p substituted with 0 to 3 R ^d -(CH ₂ ) _r -5- to 7-membered heterocycle containing 1 to 4 selected heteroatoms;
Each time R ^a appears, 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 to 3 R ^f , C _1-6 haloalkyl, -(CH ₂ ) _r -3- to 14-membered carbocycle , or containing carbon atoms and 1 to 4 heteroatoms selected from N, O, and S(O) _p , substituted with 0 to 3 R ^f -(CH ₂ ) _r -5 to 7 is a membered heterocycle;
Each occurrence of R ^b represents hydrogen, C _1-6 alkyl substituted with 0 to 3 R ^d , C _1-6 haloalkyl, C _3-6 cyclo substituted with 0 to 2 R ^d -(CH ₂ ) _r -5~ containing carbon atoms and 1 to 4 heteroatoms selected from N, O, and S(O) _p substituted with alkyl or 0 to 3 R ^f a 7-membered heterocycle, or (CH ₂ ) _r -phenyl substituted with 0 to 3 R ^d ;
R ^C is C _{1-6 alkyl substituted with 0 to 3} R ^f , (CH ₂ ) _r -C 3-6 cycloalkyl substituted with 0 to 3 R ^f , or C _1-6 alkyl substituted with 0 to 3 R f (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 _, ( ^CH ₂ ) _r -phenyl;
R ^e is independently selected at each occurrence from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl and (CH ₂ ) _r -phenyl substituted with 0 to 3 R ^f ;
R ^f 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 to 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.

[0071] In a twenty-seventh embodiment, a Tyk2 inhibitor of the present disclosure has the formula:

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

[0072] In a twenty-eighth embodiment, a Tyk2 inhibitor of the present disclosure has the formula:

[In the formula,
Y is N or CR ₆ ;
R ¹ is H, C _1-3 alkyl or C _3-6 cycloalkyl, each optionally substituted with 0 to 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 members selected from N, O, and S; a 5- to 14-membered heterocycle containing heteroatoms, each group substituted with 0 to 4 R ^2a (for clarity, R ² is a substituted group such as -C(O)R ^2a) . (intended to include methyl groups);
Each occurrence of R ^2a is independently 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 to 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 , C _2-6 alkynyl substituted with 0-1 R ^a -(CH ₂ ) _r -3- to 14-membered carbocycle, or 1 to 4 carbon atoms selected from N, O, and S(O) _p substituted with 0 to 2 R ^a -(CH ₂ ) _r -5- to 7-membered heterocycle containing a heteroatom;
R ³ is C _3-10 cycloalkyl, C _6-10 aryl, or a 5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, and each group is substituted with 0 to 4 R ^3a ;
Each occurrence of R ^3a is independently 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 to 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 carbocycle substituted with R ^a of -(CH 2 ) ^{r -} selected from carbon atoms and N, O, and S(O) _p substituted with 0 to 3 R a -(CH ₂ ) _r -5- to 10-membered heterocycle containing 1 to 4 heteroatoms;
or two R ^3a , together with the atoms to which they are attached, together form a fused ring, said ring being phenyl and carbon atoms and 1 selected from N, O, and S(O) _p selected from heterocycles containing ~4 heteroatoms, each fused ring being substituted with 0 to 3 R ^a1 ;
R ⁴ and R ⁵ are independently hydrogen, C _1-4 alkyl substituted with 0 to 1 R ^f , (CH ₂ ) _r -phenyl substituted with 0 to 3 R ^d , or -( _CH2 )-5- to 7-membered heterocycle containing carbon atoms and 1 to 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 to 3 R ^f , CF ₃ , C _3-10 cyclo substituted with 0 to 1 R ^f alkyl, (CH) _r -phenyl substituted with 0 to 3 R ^d , or selected from carbon atoms and N, O, and S(O) _p substituted with 0 to 3 R ^d -(CH ₂ ) _r -5- to 7-membered heterocycle containing 1 to 4 heteroatoms;
R ^a and R ^a1 each independently represent 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 selected from carbon atoms and N, O, and S(O) _p substituted with C _2-6 alkynyl, -(CH ₂ ) _r -3- to 14-membered carbocycle, or 0 to 3 R ^f -(CH ₂ ) _r -5- to 7-membered heterocycle containing 1 to 4 heteroatoms;
R ^b is hydrogen, C _1-6 alkyl substituted with 0 to 3 R ^d , C _1-6 haloalkyl, C _3-6 cycloalkyl substituted with 0 to 2 R ^d , or 0 to -(CH ₂ ) _r -5- to 7-membered heterocycle containing carbon atoms and 1 to 4 heteroatoms selected from N, O, and S(O) _p , substituted with 3 R ^{f or} (CH ₂ ) _r -phenyl substituted with 0 to 3 R ^d ;
R ^c is C _{1-6 alkyl substituted with 0 to 3} R ^f , (CH ₂ ) _r -C 3-6 cycloalkyl substituted with 0 to 3 R ^f , or C _1-6 alkyl substituted with 0 to 3 R f (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 to 3 R ^f ;
R ^e is independently selected at each occurrence from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, and (CH ₂ ) _r -phenyl substituted with 0 to 3 R ^f ;
R ^f 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 heterocycle containing 1 to 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 respective full contents of which is incorporated herein by reference.

[0073] In a twenty-ninth embodiment, a Tyk2 inhibitor of the present disclosure has the formula:

[In the formula:
^R1 is

And;
^R2 is

]
or a pharmaceutically acceptable salt thereof.
[0074] In a thirtieth embodiment, the Tyk2 inhibitors described herein have the following chemical structure:

6-(cyclopropanecarboxamide)-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.

[0075] The particular dosage and treatment regimen for the Tyk2 inhibitors of the present disclosure used in combination with apremilast depend on age, weight, general health, gender, diet, time of administration, rate of excretion, drug It depends on a variety of factors including the combination, the judgment of the treating physician, and the severity of the particular disease being treated.

[0076] In a thirty-first embodiment, the effective amount of a Tyk2 inhibitor of the present disclosure (eg, in any one of the second to thirty embodiments) used in combination with apremilast is from 0.001 to The range is 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 (e.g., in any one of the second to thirty 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/day to about 24 mg/day. .

[0077] In a thirty-second embodiment, the Tyk2 inhibitor described herein is BMS-986165, or a pharmaceutically acceptable salt thereof; The effective amount of 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. /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 the thirty-second embodiment, the effective amount of BMS-986165, or a pharmaceutically acceptable salt thereof, is about 1 mg/day to about 15 mg/day, about 1 mg/day to about 14 mg/day, The range is 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.

[0078] In a thirty-third embodiment, the Tyk2 inhibitor described herein is BMS-986165, or a pharmaceutically acceptable salt thereof; The effective amount of is about 0.1 mg/day, about 0.5 mg/day, about 1.0 mg/day, about 2 mg/day, about 3 mg/day, about 4 mg/day, about 5 mg/day, about 6 mg/day. , about 7 mg/day, about 8 mg/day, about 9 mg/day, about 10 mg/day, about 11 mg/day, or about 12 mg/day. Alternatively, as part of the thirty-third embodiment, the effective amount of BMS-986165, or a pharmaceutically acceptable salt thereof, is about 2 mg/day, about 3 mg/day, about 4 mg/day, about 5 mg/day, about 6 mg/day, about 7 mg/day, about 8 mg/day, about 9 mg/day, about 10 mg/day, about 11 mg/day, or about 12 mg/day. As part of another alternative thirty-third embodiment, the effective amount of BMS-986165, or a pharmaceutically acceptable salt thereof, is about 6 mg/day. As part of another alternative thirty-third embodiment, the effective concentration of BMS-986165, or a pharmaceutically acceptable salt thereof, is about 1 nM to about 1 μM (e.g., about 0.01 μM to about 0.1 μM). It is.
3. Apremi last
[0079] As mentioned 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 present in the methods and compositions described herein, e.g. As described herein in any one of the forms. Alternatively, as part of a thirty-fourth embodiment, the stereoisomeric purity of the apremilast in the methods and compositions described herein is greater than 95%, and the Tyk2 inhibitor and related features are, e.g. As described herein as in any one of the thirty-third embodiments from . 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 to 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 to 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 to 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 include: For example, as described herein as in any one of the first to 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 include: For example, as described herein as in any one of the first to thirty-third embodiments.

[0080] 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, herein incorporated by reference in its entirety. In a thirty-fifth embodiment, the apremilast in the methods and compositions of the present disclosure is in single-crystalline form, and the additional features and related features regarding the Tyk2 inhibitor as well as apremilast are as described in, e.g., the first to thirty-fourth embodiments. As described herein as in any one of:

[0081] In a thirty-sixth embodiment, the apremilast in the methods and compositions of the present disclosure is Single crystal form B characterized by powder diffraction peaks, additional features and related features for the Tyk2 inhibitor as well as apremilast, e.g. as in any one of the first to thirty-fourth embodiments. As stated in the specification. Alternatively, as part of the thirty-sixth embodiment, apremilast in the methods and compositions of the present disclosure comprises: 10.1°, 13.5°, 15.7°, 18.1°, 20.7°, 24. 7°, and a single crystalline form B characterized by X-ray powder diffraction peaks at 2θ angles selected from 26.9°, additional and related features for Tyk2 inhibitors as well as apremilast are, for example As described herein as in any one of the first to thirty-fourth embodiments. As part of another alternative thirty-sixth embodiment, the apremilast in the methods and compositions of the present disclosure comprises: 10.1°, 13.5°, 15.7°, 16.3°, 18.1°, Single crystal form B characterized by X-ray powder diffraction peaks at 2θ angles selected from 20.7°, 22.5°, 24.7°, 26.2°, 26.9°, and 29.1° and the additional features and related features for Tyk2 inhibitors as well as apremilast are as described herein, eg, as in any one of the first to thirty-fourth embodiments.

[0082] 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 the additional and related features for Tyk2 inhibitors as well as apremilast include, for example: As described herein as in any one of the first to thirty-sixth embodiments. Alternatively, the apremilast in the methods and compositions of the present disclosure is at least 95% single-crystalline Form B, and the additional features and related features for apremilast as well as Tyk2 inhibitors, such as those of embodiments 1 through 36 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 the additional features and related features for the Tyk2 inhibitor as well as apremilast are, e.g. As described herein in any one of the embodiments.

[0083] The particular dosage and treatment regimen of apremilast, or a pharmaceutically acceptable salt thereof, used in combination with the Tyk2 inhibitors of the present disclosure will depend on age, weight, general health, gender, diet, will depend on a variety of factors, including time of administration, rate of excretion, drug combination, judgment of the treating physician, and severity of the particular disease being treated.

[0084] 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. ~500mg, approximately 10mg to approximately 200mg per day, approximately 10mg to approximately 100mg per day, approximately 40mg to approximately 100mg per day, approximately 20mg to approximately 40mg per day, approximately 0.1mg to approximately 10mg per day, approximately 0 per day .5 mg to about 5 mg, about 1 mg to about 20 mg per day, and about 1 mg to about 10 mg per day, 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, about . 10 mg to about 60 mg, and from about 10 mg to about 40 mg per day, additional features and related features for Tyk2 inhibitors as well as apremilast, such as in any one of the first to thirty-seventh embodiments. As described herein. Alternatively, as part of the 38th embodiment, the effective amount of apremilast, or a pharmaceutically acceptable salt thereof, ranges from about 10 mg to about 60 mg per day, with additional dosages for apremilast as well as for Tyk2 inhibitors. The features and related features are as described herein, eg, in any one of the first to 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, with the addition of apremilast as well as a Tyk2 inhibitor. and related features are as described herein, such as in any one of the first to 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 and about 100 mg per day, and like apremilast, the Tyk2 inhibitor Additional features and related features are as described herein, such as in any one of the first to 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, with the addition of apremilast as well as a Tyk2 inhibitor. and related features are as described herein, such as in any one of the first to thirty-seventh embodiments. As part of another alternative 38th 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, the Tyk2 inhibitor Additional features and related features are as described herein, such as in any one of the first to 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 10 mg to about 40 mg per day, with the addition of apremilast as well as a Tyk2 inhibitor. and related features are as described herein, such as in any one of the first to 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, about 55 mg per day, or about 60 mg per day, and additional features and related features regarding Tyk2 inhibitors as well as apremilast are described herein, such as in any one of the first to 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, with the addition of apremilast as well as a Tyk2 inhibitor. and related features are as described herein, such as in any one of the first to thirty-seventh embodiments. As part of another alternative thirty-eighth embodiment, apremilast is administered once daily at a dose of about 30 mg, and the additional features and related features for the Tyk2 inhibitor 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 a day, and the additional features and related features for the Tyk2 inhibitor 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 amount of apremilast, or a pharmaceutically acceptable salt thereof, is about 10 mg per day or about 40 mg per day, with the addition for apremilast as well as a Tyk2 inhibitor. and related features are as described herein, such as in any one of the first to thirty-seventh embodiments. As part of another alternative thirty-eighth embodiment, apremilast is administered once or twice daily at a dose of about 10 mg, and the additional and related features for apremilast as well as Tyk2 inhibitors include, for example: As described herein as in any one of the first to thirty-seventh embodiments. As part of another alternative thirty-eighth embodiment, apremilast is administered once or twice daily at a dose of about 20 mg, and the additional and related features for apremilast as well as Tyk2 inhibitors include, for example: As described herein as in any one of the first to thirty-seventh embodiments. As part of another alternative thirty-eighth embodiment, the effective concentration of apremilast is about 100 nM to about 10 μM (e.g., about 0.1 μM to about 1 μM), with additional features for apremilast as well as Tyk2 inhibitors. and related features as described herein, such as in any one of the first to thirty-seventh embodiments.

[0085] 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: Morning, approximately 10mg;
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 thereafter: about 30 mg twice a day.
Additional features and related features for Tyk2 inhibitors as well as apremilast are as described herein, eg, in any one of the first to thirty-seventh embodiments. Alternatively, apremilast is titrated to a dosage between about 40 mg/day and about 100 mg/day using the following titration schedule:
Day 1: Morning, approximately 10mg;
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 thereafter: between about 40 mg/day and about 100 mg/day.
Additional features and related features for Tyk2 inhibitors as well as apremilast are as described herein, eg, in any one of the first to thirty-seventh embodiments. In another alternative, apremilast is titrated to a dosage of approximately 20 mg administered twice daily using the following titration schedule:
Day 1: Morning, approximately 10mg;
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 thereafter: about 20 mg twice a day.
Additional features and related features for Tyk2 inhibitors as well as apremilast are as described herein, eg, in any one of the first to thirty-seventh embodiments. In yet another alternative, apremilast is titrated to a dosage between about 4 mg/day and about 10 mg/day using the following titration schedule:
Day 1: Morning, approximately 1mg;
Day 2: About 1 mg in the morning and about 1 mg in the evening;
3rd day: about 1 mg in the morning and about 2 mg in the evening;
Day 4: about 2 mg in the morning and about 2 mg in the evening;
Day 5: about 2 mg in the morning and about 3 mg in the evening; and Day 6 and thereafter: between about 4 mg/day and about 10 mg/day.
Additional features and related features for Tyk2 inhibitors as well as apremilast are as described herein, eg, in any one of the first to 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: Morning, approximately 1mg;
Day 2: About 1 mg in the morning and about 1 mg in the evening;
Day 3: About 10 mg in the morning and about 2 mg in the evening;
Day 4: about 2 mg in the morning and about 2 mg in the evening;
Day 5: about 2 mg in the morning and about 3 mg in the evening; and Day 6 and thereafter: about 3 mg twice a day.
Additional features and related features for Tyk2 inhibitors as well as apremilast are as described herein, eg, in any one of the first to thirty-seventh embodiments.
3. Composition and administration
[0086] 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 to thirty-eighth embodiments.

[0087] 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 -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 to thirty-eighth embodiments.

[0088] For administration as described above (e.g., as in any one of the first to thirty-eighth embodiments) comprising apremilast and a Tyk2 inhibitor (e.g., BMS-986165) alone or together in a fixed dose. Includes pharmaceutical compositions and single unit dosage forms. Single unit dosage forms of the methods and compositions of the present disclosure can be administered to a patient orally, mucosally (e.g., nasally, sublingually, intravaginally, buccal, or rectally), parenterally (e.g., subcutaneously, intravenously, Suitable for administration by bolus injection, intramuscular or intraarterial), or transdermal. Examples of dosage forms include tablets, caplets, capsules such as soft elastic gelatin capsules, cachets, lozenges, 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 a patient, including emulsions or water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; These include, but are not limited to, sterile solids (eg, crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to patients.

[0089] 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 a greater amount of one or more active ingredients than a dosage form used for chronic treatment of the same disease. Similarly, parenteral dosage forms may contain lower amounts of one or more active ingredients than oral dosage forms used to treat the same disease or disorder. These and other ways in which the particular dosage forms encompassed by this invention vary will be readily apparent to those skilled in the art.
For example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing, Easton Pa. (1990).

[0090] In a thirty-ninth embodiment, apremilast in the methods and compositions of the present disclosure is administered parenterally, transdermally, mucosally, nasally, bucally, sublingually, or orally, and like apremilast, Tyk2 Additional features and related features for the inhibitor are as described herein, eg, in any one of the first to thirty-eighth embodiments. Alternatively, as part of the thirty-ninth embodiment, the apremilast in the methods and compositions of the present disclosure is administered orally, and the additional features and related features for Tyk2 inhibitors as well as apremilast, e.g. As described herein as in any one of the thirty-eighth embodiments from .

[0091] In a fortieth embodiment, the apremilast in the methods and compositions of the present disclosure is administered orally in the form of a tablet or capsule, and the additional and related features for Tyk2 inhibitors as well as apremilast are , e.g., as described herein as in any one of the first to thirty-ninth embodiments.

[0092] 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 and related features for the Tyk2 inhibitor as well as the apremilast, e.g. As described herein as in any one of embodiments 1 to 39.

[0093] In a forty-second embodiment, the apremilast in the methods and compositions of the present disclosure is formulated as an immediate release form, and the additional and related features for apremilast as well as Tyk2 inhibitors, e.g. As described herein as in any one of embodiments 1 to 39.

[0094] In a forty-third embodiment, both the 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, and the apremilast as well as the Tyk2 inhibitor are administered as a once-daily formulation. Additional features and related features are, for example, as described herein as in any one of the first to forty-second embodiments.
4. Conditions treated by the methods and compositions disclosed herein
[0095] Diseases or disorders responsive to inhibition of PDE4 using the methods and compositions disclosed herein include, for example, viral, genetic, inflammatory, allergic, and autoimmune conditions. included.

[0096] 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, whole body selected from lupus erythematosus, lupus vulgaris, Sjögren's syndrome, inflammatory bowel disease, Crohn's disease, Behcet's disease, and ulcerative colitis.

[0097] In one embodiment, 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.

[0098] In one embodiment, the disease or disorder responsive to inhibition of PDE4 is psoriasis. In another aspect, the disease or disorder responsive to inhibition of PDE4 is psoriasis and the subject being treated is a candidate for phototherapy or systemic therapy.

[0099] In one embodiment, the disease or disorder responsive to inhibition of PDE4 is plaque psoriasis. In another aspect, the disease or disorder responsive to inhibition of PDE4 is plaque psoriasis and the subject being treated is a candidate for phototherapy or systemic therapy.

[00100] In one embodiment, the disease or disorder responsive to inhibition of PDE4 is moderate to severe plaque psoriasis. In another aspect, the disease or disorder responsive to inhibition of PDE4 is severe plaque psoriasis and the subject being treated is a candidate for phototherapy or systemic therapy.

[00101] In one embodiment, the disease or disorder responsive to inhibition of PDE4 is psoriatic arthritis.
[00102] In one embodiment, the disease or disorder responsive to inhibition of PDE4 is active psoriatic arthritis.

[00103] In one embodiment, the diseases or disorders responsive to inhibition of PDE4 include congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acute viral myocarditis, cardiac allograft rejection, and myocardial Heart disease such as infarction.

[00104] In one embodiment, 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, These are sepsis syndrome, post-ischemic reperfusion injury, meningitis, fibrotic disease, cachexia, graft rejection, osteoporosis, multiple sclerosis, and radiation injury.

[00105] In one aspect, the disease or disorder responsive to inhibition of PDE4 includes the head, thyroid, neck, eye, skin, mouth, pharynx, esophagus, cheat, bone, blood, bone marrow, lung, colon. cancers of the sigmoid colon, rectum, stomach, prostate, breast, ovary, kidney, liver, pancreas, brain, intestines, heart, adrenal glands, subcutaneous tissue, lymph nodes, heart, and combinations thereof.

[00106] In one embodiment, 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, lymphoid leukemia, and myeloid leukemia.

[00107] In one aspect, the disease or disorder responsive to inhibition of PDE4 is sarcoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma. , lymphangioendotheliosarcoma, synoviomas, mesothelioma, Ewing tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma , basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic lung cancer, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, spermatozoa. Epithelioma, embryonal carcinoma, Wilms tumor, cervical cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, Solid tumors such as Kaposi's sarcoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, and retinoblastoma.

1. material

2. General method
[00108] Whole blood was obtained after informed consent and donor deidentification through the Celgene donor program. All volunteers were healthy and had not received any medication for at least 72 hours prior to blood collection. Blood was collected into sodium heparin tubes. Assays were started within 2 hours of blood collection.

[00109] 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 IL-1β, IL-6 and IL-23 in addition to TruCulture® tubes containing anti-CD3/anti-CD28. 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 of BMS-986165 alone, 0.1 μM, 0.01 μM and 0.001 μM, and in combination with 1 μM apremilast. The blood was mixed well and then incubated for 1 hour in an incubator at 37°C/5% _CO2 .

[00110] Anti-CD3/anti-CD28 (final concentrations of 200 ng/mL and 330 ng/mL, respectively) TruCulture® tubes were thawed on the benchtop for 30 minutes and then labeled. I pressed the plunger, then snapped it off and removed it. The TruCulture® tubes were placed upright in the rack with the plunger side facing down and the tube cap facing up. During 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 the tube three times. The tubes were immediately placed in a 37°C heat shield and incubated for 42 hours (tube cap end). After 42 hours, the tubes were removed from the heat shield, the tops were spun open, 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 for IL-22 by ELISA (Abcam). Manufacturer's instructions were followed accordingly.

[00111] 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 had not received 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 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. Centrifugation was performed at 1200 g for 15 min with braking for cell separation, after which the isolated PBMCs were transferred to a new tube. PBMCs were washed with 2% FBS-PBS and centrifuged at 800 g for 10 min. The pellet 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.

[00112] 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. For this purpose, ex vivo LPS stimulation was performed. PBMC 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 shown below. Two hours after compound treatment, LPS was used as the stimulant at a final concentration of 100 ng/mL. PBMCs were then incubated for 16 hours in an incubator at 37°C/5% _CO2 .

[00113] 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 Luminex Bio-Plex Multiplex Immunoassay (Bio-Rad) according to the manufacturer's procedures. To ensure supernatant levels were within the standard cytokine range for the assays, samples were diluted 5-fold for the IL-12p40 and 27-plex assays and used directly for the IL-23 assays. .
3. data analysis
[00114] 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 the templates were plotted using GraphPad Prism 7.0 (GraphPad Software, Inc., 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.

[00115] For PBMC assays, data processing was performed using 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, Inc., La Jolla, Calif.) and expressed as % of DMSO control. Statistical analysis was performed using one-way ANOVA and Tukey's multiple comparison test.

[00116] To evaluate the combination effect of apremilast and BMS-986165, data from two independent treatments were analyzed by comparing the response of the combination to the theoretical additive response of the two drugs. did. The expected additive effect of two drugs (A and B) was calculated using the fractional product method: (fu)A,B = (fu)A x (fu)B; Medium, fu = fraction unaffected by treatment. If the observed combination-insensitive fraction is less than (fu)A,B, the synergistic effect of the combination is determined, while if the observed combination-insensitive fraction is equal to (fu)A,B, then the effect is determined. If the observed combination-insensitive fraction is greater than (fu)A,B, a partially 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.
[00117] 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 TruCulture® tubing system. The IL-17A results in Figure 1 represent % of IL-17A control; all data are normalized to Th17DMSO control. Apremilast inhibited 28% of IL-17A cytokine expression under Th0 conditions and had no effect under Th17 conditions. BMS-986165 produced similar effects under both stimulation conditions, inhibiting 10-25% of IL-17A expression at 0.001-1 μM. When apremilast was combined with BMS-986165, synergy was seen with a 65% reduction in IL-17A using 1 μM BMS-986165 under Th0 conditions. Under Th17 conditions, there was a synergistic effect in the combination of 1 μM apremilast with 0.01 μM, 0.1 μM and 1 μM BMS-986165 with inhibition of IL-17A by 24%, 44% and 85%, respectively. Ta. Figure 2 shows the levels of IL-17A in picograms per milliliter. Levels of IL-17A were increased by 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 with Th0 stimulation. Under Th17 conditions, the stimulation control was measured at 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, 428 pg/mL at 0.1 μM, and 383 pg/mL at 1 μM. The combination of 1 μM apremilast and BMS-986165 reduced IL-17A levels to 379 pg/mL at 0.01 μM of BMS-986165, to 328 pg/mL at 0.1 μM, and to 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.
[00118] IL-17F cytokine expression data are in Figures 3 and 4. Apremilast inhibited 69% of IL-17F production under Th0 conditions and 49% under Th17 conditions. BMS-986165 produced similar effects on IL-17F with both Th0 and Th17 stimulation. There was a 31% inhibition of IL-17F expression at the lowest concentration of 0.001 μM, 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 under Th0 conditions with inhibition ranging from 60% at 0.001 μM to 95% at 1 μM. Under Th17 conditions, lower concentrations of BMS-986165 in combination with apremilast showed synergism. Apremilast inhibited IL-17F by 68% in combination with 0.001 μM BMS-986165, 70% at 0.01 μM, 94% at 0.1 μM, and 1 μM under Th17 stimulating conditions. 99% of IL-17F production was inhibited. IL-17F levels in Th0 stimulated controls were 1085 pg/mL and increased to 6524 pg/mL upon Th17 stimulation. 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.
[00119] IL-22 cytokine expression data are in Figures 5 and 6. Apremilast inhibited 85% of IL-22 cytokine expression under Th0 conditions and 41% under Th17 conditions. Under Th0 stimulating conditions, BMS-986165 inhibited IL-22 by 16% at 0.01 μM, 86% at 0.1 μM, and 91% at 1 μM. Under Th17 stimulating 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 similar effects 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. The Th0 stimulated control had 1085 pg/mL of IL-22 and the Th17 control had 6524 pg/mL. Apremilast significantly reduced IL-22 levels to 368 pg/mL in Th0 conditions and 3643 pg/mL in Th17 conditions. BMS-986165 significantly reduced IL-22 cytokine expression at 0.1 μM and 1 μM in 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.
[00120] TNF-α cytokine expression data are in FIGS. 7 and 8. Apremilast inhibited TNF-α levels by 90% in Th0 conditions and 94% in Th17 conditions. In Th0 stimulation, BMS-986165 increased TNF-α expression by 21% at 0.001 μM, 43% at 0.01 μM, and 61% at 0.1 μM. 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%) using 1 μM BMS-986165 under Th17 stimulating conditions. The combination of 1 μM apremilast and BMS-986165 reduced TNF-α levels by 80-95% (Th0) and 93-96% (Th17), similar in efficacy to single agent apremilast. Both stimulation conditions had similar effects on the levels of TNF-α, with a Th0 stimulation control of 1380 pg/mL, and a Th17 stimulation 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 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.
[00121] Granulocyte macrophage colony stimulating factor (GM-CSF) cytokine expression results are in FIGS. 9 and 10. 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 by 19% at 0.001 μM, 36% at 0.01 μM, 110% at 0.1 μM, and 31% at 1 μM under Th0 conditions. When apremilast (0.1 μM) was added to BMS-986165, there was a 60-80% inhibition of GM-CSF cytokine expression. In Th17 stimulation, BMS-986165 increased GM-CSF by 41% at 0.01 μM, 139% at 0.1 μM, and 104% at 1 μM. 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 upon apremilast and Tyk2i (BMS-986165) treatment
[00122] PBMC from nine healthy donors were analyzed for cytokine production under 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 PBMCs 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. As the levels of apremilast are increased, there is a significant reduction in IL-23 levels. Statistical analysis using ANOVA and Turkey's multiple comparisons was performed to compare each treatment with BMS-986165 alone. When BMS-986165 is combined with a low level of apremilast at a concentration of 0.037 μM, there is a significant reduction in IL-23 (***p<0.001). When combined with 1 μM apremilast, the induction of IL-23 was inhibited by 90%, almost reaching levels similar to apremilast alone. Therefore, the curves for co-treatment with 1 μM apremilast were not significantly different compared to apremilast treatment alone.

Example 7
IL-12p40 production in LPS-stimulated PBMCs upon apremilast and Tyk2i (BMS-986165) treatment
[00123] The results in Figure 13 showed normalized levels of IL-12p40 compared to the DMSO-treated LPS-stimulated PBMC group. Apremilast decreased IL-12p40 in a dose-dependent manner, 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%, almost reaching levels 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 upon apremilast and Tyk2i (BMS-986165) treatment
[00124] The results in Figure 14 showed normalized levels of IL-12p70 compared to the DMSO-treated LPS-stimulated PBMC group. Apremilast decreased IL-12p70 in a dose-dependent manner, 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 treatment, 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 upon apremilast and Tyk2i (BMS-986165) treatment
[00125] The results in Figure 15 showed normalized levels of TNF-α compared to the DMSO-treated LPS-stimulated PBMC group. Apremilast decreased TNF-α levels in a dose-dependent manner, whereas BMS-986165 induced a 1.2-1.5-fold increase in TNF-α. The combination of BMS-986165 and apremilast significantly decreased the levels of TNF-α. 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 upon apremilast and Tyk2i (BMS-986165) treatment
[00126] The results in FIG. 16 showed normalized levels of IFN-γ compared to the DMSO-treated LPS-stimulated PBMC group. Both apremilast alone and BMS-986165 alone reduced IFN-γ in a dose-dependent manner. The combination of BMS-986165 and apremilast had a synergistic effect in reducing IFN-γ levels and significantly reduced 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 upon apremilast and Tyk2i (BMS-986165) treatment
[00127] 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 reduced MCP-1 in a dose-dependent manner. The combination of BMS-986165 and apremilast has 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 summary
[00128] 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 and complementary effects are underlined.

[00129] Whole blood from four healthy donors was tested in a True-culture assay in Th0 (anti-CD3/anti-CD28) or Th17 (anti-CD3/anti-CD28 + IL-1β, IL-6 and IL-23) conditions. , 48 hours, using 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 the 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 to treat diseases or disorders that respond to inhibition of PDE4, such as the treatment of inflammatory diseases such as psoriasis, psoriatic arthritis, and ulcerative colitis.

[00130] Table 6 below provides a summary of the cytokine effects of apremilast and BMS-986165 on LPS-stimulated PBMCs. Red arrows represent induction of cytokine production and green arrows represent decreased cytokine production.

[00131] PBMC from nine healthy donors were tested in LPS-stimulated conditions with or without BMS-986165 or apremilast or a combination of both. Treatment with BMS-986165 alone induced IL-23, IL-12p40, IL-12p70 and TNF-α, whereas treatment with apremilast alone decreased 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 the production of IFN-γ and MCP-1, and the combination of both further reduced these two cytokines with a synergistic effect. BMS-986165 inhibits Th17 lineage cytokines, which provides a means to treat diseases in which Th17 cytokines are implicated in pathogenesis. However, the induction of some pro-inflammatory cytokines such as IL-23, IL-12 and TNF-α by BMS-986165 may be a drawback in disease treatment. The combined effect of apremilast and BMS-986165, with reduced IL-23, IL-12 and TNF-α, suggests that the combination of these two compounds in the treatment of inflammatory diseases such as psoriasis, psoriatic arthritis, and ulcerative colitis. demonstrated the advantages of

Example 12
Fixed dose combination of apremilast and Tyk2i (BMS-986165) in whole blood
[00132] Apremilast and BMS-986165 were tested in whole blood for IL-17A, IL-17F, IL-22, and TNF-α at the following fixed dosages: 2 mg twice daily (BID); BMS-986165, 6 mg once daily (QD) BMS-986165, 6 mg BID BMS-986165, 10 mg BID apremilast, 20 mg BID apremilast, and 30 mg BID apremilast. These concentrations were derived from mean plasma concentrations observed or estimated from clinical PK data.

[00133] As seen in Figures 18-21, the 6 mg QD dose concentration of BMS-986165 did not maximally inhibit IL-17A, IL-17F, or IL-22, and did not inhibit TNF-α. rose. See Figures 18-21. However, addition of apremilast at BID dose concentrations of 10-30 mg compensated for this and prevented the rise in TNF-α. See Figures 18-21. Even low concentrations of apremilast were shown to be effective. For example, a 20 mg BID dose of apremilast compensated for suboptimal inhibition of IL-17F, and a 10 mg BID dose of apremilast compensated for suboptimal inhibition of IL-22 and prevented the increase in TNF-α. This data shows that inhibiting IL-17 and IL-22 and reducing TNF-α production can be used to treat psoriasis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and Crohn's disease, which are enhanced by these cytokines. , supports the synergistic use of BMS-986165 (e.g., 6 mg QD) and apremilast (e.g., 10-20 mg QD or BID) for the treatment of inflammatory diseases such as hidradenitis suppurativa, and Behcet's disease. .

Claims (19)

A combination for treating a disease or disorder responsive to inhibition of phosphodiesterase 4 (PDE4) in a subject, the combination comprising: a therapeutically effective amount of N-[2-[(1S)-1-(3-ethoxy-4-methoxy); phenyl)-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 formula:
tyrosine kinase 2 (Tyk2) inhibitor or a pharmaceutically acceptable salt thereof,
Here, the N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-iso [indol-4-yl]acetamide or a pharmaceutically acceptable salt thereof, and said Tyk2 inhibitor or said pharmaceutically acceptable salt thereof are administered as separate formulations or in the same formulation. The above combination. 2. The combination of claim 1 , wherein the effective amount of the Tyk2 inhibitor, or pharmaceutically acceptable salt thereof, ranges from about 0.1 mg/day to about 250 mg/day. 3. The combination of claim 1 or 2 , wherein the effective amount of the Tyk2 inhibitor, or pharmaceutically acceptable salt thereof, ranges from about 2 mg/day to about 14 mg/day. 4. A combination according to any one of claims 1 to 3 , wherein the effective amount of the Tyk2 inhibitor is about 4 mg/day, about 6 mg/day, or about 12 mg/day. Said N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole- 5. A combination according to any one of claims 1 to 4 , wherein the 4-yl]acetamide is more than 95% stereomerically pure. N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-4 6. The combination according to any one of claims 1 to 5 , wherein the effective amount of the pharmaceutically acceptable salt thereof ranges from about 0.5 mg to about 1000 mg per day. N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-4 7. The combination according to any one of claims 1 to 6 , wherein the effective amount of the 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, is about 20 mg per day, about 40 mg per day, or about 60 mg per day. A combination of. N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-4 8. The combination according to any one of claims 1 to 7 , wherein the effective amount of 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 8. A combination according to any one of claims 1 to 7 , wherein the effective amount of -yl]acetamide is administered once a day at about 30 mg. N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-4 8. A combination according to any one of claims 1 to 7 , wherein the effective amount of [-yl]acetamide is administered at about 30 mg twice a day. Said N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole- 12. A combination according to any one of claims 1 to 11 , wherein the 4-yl]acetamide is formulated as part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier. Said N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole- 13. A combination according to any one of claims 1 to 12 , wherein the 4-yl]acetamide is administered orally. Said N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole- 14. A combination according to any one of claims 1 to 13 , wherein the 4-yl]acetamide is administered orally in the form of a tablet or capsule. 15. A combination according to any one of claims 1 to 14 , wherein the disease or disorder is selected from viral, genetic, inflammatory, allergic and autoimmune diseases. The disease or disorder is chronic obstructive pulmonary disease, asthma, chronic pulmonary inflammatory disease, hyperoxia 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, Sjogren's syndrome, inflammatory 16. A combination according to any one of claims 1 to 15 , selected from intestinal diseases, Crohn's disease, Behcet's disease and ulcerative colitis. 17. A combination according to any one of claims 1 to 16 , wherein the disease or disorder is selected from psoriasis and psoriatic arthritis. 18. A combination according to any one of claims 1 to 17 , wherein the disease or disorder is plaque psoriasis, or moderate to severe plaque psoriasis. A pharmaceutical composition for treating a disease or disorder responsive to inhibition of phosphodiesterase 4 (PDE4) in a subject, the composition comprising: a therapeutically effective amount of N-[2-[(1S)-1-(3-ethoxy-4); -methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide, or a pharmaceutically acceptable salt thereof; and therapeutically effective quantity, expression
or a pharmaceutically acceptable salt thereof.