KR20220002489A - Combination therapy comprising apremilast and a TYK2 inhibitor - Google Patents

Abstract

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

Description

Combination therapy comprising apremilast and a TYK2 inhibitor

Related applications

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

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 type of phosphodiesterase currently approved for the treatment of both moderate to severe plaque psoriasis and active psoriatic arthritis. 4 (PDE4) inhibitor. PDE4 inhibition by apremilast elevates cyclic adenosine monophosphate (cAMP) levels in immune cells. This in turn down-regulates the inflammatory response by reducing the expression of pro-inflammatory mediators such as TNF-α, IL-23, IL-17 and other inflammatory cytokines, and increases the production of anti-inflammatory mediators. Studies have shown that a 75% reduction in plaque psoriasis is achievable in some patients with as little as 4 months of treatment.

Tyrosine kinase 2 (Tyk2), an intracellular signaling enzyme, activates signaling and transcriptional activator (STAT)-dependent gene expression and functional responses of IL-12, IL-23, and type I and type III interferon receptors. make it Among other conditions, tyrosine kinase inhibitors (TKIs) have recently received attention as effective agents for treating psoriasis and related conditions. For example, the TKI inhibitor BMS-986165 has recently shown positive results in a phase 2 clinical trial in subjects with moderate to severe plaque psoriasis. Kim Papp, M.D., Phase 2 Trial of Selective Tyrosine Kinase 2 Inhibition in Psoriasis, The New England Journal of Medicine, Sept. 12, 2018].

Apremilast and Tyk2 inhibitor 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3) Combination of -yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165) synergistically synergizes proinflammatory cytokines expressed in a whole blood assay under conditions that stimulate Th17 cells. has been found to reduce For example, a more than 2-fold increase in inhibition of IL-17F expression was seen with the combination of 0.01 μM BMS-986165 and 1 μM apremilast compared to the use of each drug alone. See, for example, Table 5 in the Examples section. Similar results were observed with BMS-986165 at a concentration of 0.1 μM in combination with 1 μM apremilast. See, for example, Table 5. The combination of BMS-986165 with 1 μM apremilast also reduced cytokine expression for IL-17A and IL-22 by more than 2-fold compared to the use of each drug alone. See, for example, Table 5.

In addition, the combination of apremilast and BMS-986165 was found to induce complementary effects on certain pro-inflammatory cytokines. For example, BMS-986165 increased TNF-α and GM-CSF cytokines in a whole blood assay, whereas apremilast inhibited the production of these cytokines. See, for example, Table 5, where the % of control of 1 μM apremilast for TNF-α is 10.7 and the % of control of 0.01 μM BMS-986165 is 143.1. However, when administered in combination, apremilast corrected the defect in BMS-986165, producing a complementary effect of 13.5% inhibition of TNF-α. See, for example, Table 5. This trend was also confirmed in BMS-986165 at a concentration of 0.1 μM for the cytokine GM-CSF. See, for example, Table 5. These results indicate synergistic and complementary pharmacological effects of BMS-986165 and apremilast.

In addition to the whole blood assay, the combination of BMS-986165 and apremilast also elicits complementary effects on specific proinflammatory cytokines in LPS stimulated PBMCs. BMS-986165 increased IL-23, IL-12 and TNF-α, whereas apremilast inhibited the production of these cytokines. See, for example, Table 6 in the Examples section. These results also support the benefit of the combination of BMS-986165 and apremilast in the treatment of Th17 related diseases.

Accordingly, provided herein are methods of 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. Such diseases and disorders include, for example, inflammatory diseases such as psoriasis, psoriatic arthritis and ulcerative colitis.

Also provided herein are pharmaceutical compositions comprising an effective amount of apremilast or a pharmaceutically acceptable salt thereof and an effective amount of a Tyk2 inhibitor, such as BMS-986165.

1 is anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood - in TruCulture® tube assays. Interleukin-17a (IL-17a) cytokine production (percent control) by apremilast and BMS-986165 is shown.
2 shows anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood - Apremil in TrueCulture® tube assays. Interleukin-17A (IL-17A) cytokine production by last and BMS-986165 is shown.
3 shows anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood - Apremil in TrueCulture® tube assays. Interleukin-17F (IL-17F) cytokine production (percent control) by last and BMS-986165 is shown.
4 shows anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood - Apremil in TrueCulture® tube assays. Interleukin-17F (IL-17F) cytokine production by last and BMS-986165 is shown.
5 shows anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood - Apremil in TrueCulture® tube assays. Interleukin-22 (IL-22) cytokine production (percent control) by last and BMS-986165 is shown.
6 shows anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood - Apremil in TrueCulture® tube assays. Interleukin-22 (IL-22) cytokine production by LAST and BMS-986165 is shown.
7 shows anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood - Apremil in TrueCulture® tube assays. Tumor necrosis factor alpha (TNF-α) cytokine production (percent control) by last and BMS-986165 is shown.
8 shows anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood - Apremil in TrueCulture® tube assays. Tumor necrosis factor alpha (TNF-α) cytokine production by last and BMS-986165 is shown.
9 shows anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood - Apremil in TrueCulture® tube assays. Granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine production (percent control) by last and BMS-986165 are shown.
10 shows anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1β, IL-6 and IL-23 (Th17) stimulated whole blood - Apremil in TrueCulture® tube assays. Granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine production by last and BMS-986165 is shown.
11 shows interleukin-23 (IL-23) cytokine production by apremilast in lipopolysaccharide (LPS) stimulated peripheral blood mononuclear cells (PBMC).
12 shows interleukin-23 (IL-23) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs.
13 shows interleukin-12p40 (IL-12p40) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs.
14 shows interleukin-12p70 (IL-12p70) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs.
15 shows tumor necrosis factor alpha (TNF-α) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs.
16 shows interferon gamma (IFN-γ) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs.
17 shows monocyte chemoattractant protein-1 (MCP-1) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs.
Figure 18 shows the effect of fixed dose combination of apremilast and Tyk2i (BMS-986165) in IL-17A whole blood.
19 shows the effect of fixed dose combination of apremilast and Tyk2i (BMS-986165) in IL-17F whole blood.
Figure 20 shows the effect of fixed dose combination of apremilast and Tyk2i (BMS-986165) in IL-22 whole blood.
Figure 21 shows the effect of fixed dose combination of apremilast and Tyk2i (BMS-986165) in TNF-α whole blood.

In a first embodiment, the subject is administered an effective amount of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-di Cyclic nucleotide phospho comprising administering hydro-1,3-dioxo-1H-isoindol-4-yl]acetamide (apremilast) or a pharmaceutically acceptable salt thereof and an effective amount of a Tyk2 inhibitor Provided herein are methods of treating a disease or disorder responsive to inhibition of diesterase isoenzyme IV (PDE4).

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

In another alternative, as part of the first embodiment, an effective amount of N-[2-[ (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-4- Provided are generic]acetamide (apremilast) or a pharmaceutically acceptable salt thereof and an effective amount of a Tyk2 inhibitor.

1. Definition

N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H -Isoindol-4-yl]acetamide (apremilast) is disclosed in 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:

.

.

Apremilast has a chiral center designated as (S) in its chemical structure and name. As used herein, the designation designation means that apremilast is (S) at this position in an amount of at least 80%, 90%, 95%, 98%, 99% or 99.9% compared to the corresponding (R) enantiomer. It means that it is optically enriched as an enantiomer. Thus, when apremilast is referred to herein as stereomerically or enantiomerically pure in a specified amount, it is meant that the (S) enantiomer is enriched 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 at least 95% (S) enantiomer and up to 5% (R) enantiomer.

Unless otherwise indicated, administration as described herein includes administration of apremilast prior to, concurrently with, or subsequent to administration of a Tyk2 inhibitor described herein. Thus, simultaneous administration is not essential for therapeutic purposes. In one aspect, apremilast and a disclosed Tyk2 inhibitor are administered together. In another aspect, apremilast and a disclosed Tyk2 inhibitor are administered on the same day and at different times. In another aspect, apremilast and the disclosed Tyk2 inhibitor are administered at different times as separate tablets or capsules. In another aspect, apremilast and a disclosed Tyk2 inhibitor are administered in a fixed dose combination in the same tablet or capsule.

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

The term “subject” means an animal, such as a mammal, such as a human. The terms “subject” and “patient” may be used interchangeably herein.

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

The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier, adjuvant or vehicle that does not adversely affect the pharmacological activity of the compound with which it is formulated, and which is also safe for human use. 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 such as phosphate, 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 salt, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based materials (eg, microcrystalline cellulose, hydroxypropyl methylcellulose, lactose monohydrate, sodium lauryl sulfate, and croscarmellose sodium), polyethylene glycol, sodium carboxymethylcellulose, polyacrylic rates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycols, and wool fats.

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. Suitable pharmaceutically acceptable base addition salts for the compounds described herein are metallic salts prepared from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or lysine, N,N'-dibenzylethylenediamine, chloroprocaine. , choline, diethanolamine, ethylene diamine, meglumine (N-methylglucamine) and organic salts prepared from procaine. Suitable non-toxic acids include inorganic and organic acids such as acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, Glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methane sulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid and p-toluenesulfonic acid.

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

The term “amorphous” refers to a solid that exists in a non-crystalline state or form. An amorphous solid is a disordered arrangement of molecules and thus does not have any distinguishable crystal lattice or unit cells, and consequently no definable long-range rules. The solid state rule of a solid can be determined by standard techniques known in the art, for example, X-ray powder diffraction (XRPD) or differential scanning calorimetry (DSC). Amorphous solids can also be distinguished from crystalline solids by, for example, birefringence using polarized light microscopy.

The 2-theta values of the X-ray powder diffraction patterns for the crystalline forms described herein vary from instrument to instrument and also from batch variation and sample preparation due to factors such as temperature variation, sample displacement, and the presence or absence of internal standards. may vary slightly depending on Accordingly, unless otherwise defined, the XRPD patterns/assignments referred to herein are not to be construed as absolute and may vary by ±0.2 degrees. It is well known in the art that such variability will account for this factor without interfering with the unambiguous identification of the crystal morphology.

2. Tyk2 inhibitor

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

In a second embodiment, the disclosed Tyk2 inhibitor is disclosed in Xingrui He et al., Expert Opinion on Therapeutics Patents 2019, Vol. 29, No. 2, 137-149, the entire contents of which are incorporated herein by reference.

In a third embodiment, the disclosed Tyk2 inhibitors may be selected from those having the formula: or a pharmaceutically acceptable salt thereof:

wherein the variable is as described in WO 2015/032423, the entire contents of which are incorporated herein by reference. Exemplary compounds having the formula above as part of the third embodiment include, but are not limited to, those having the formula: or a pharmaceutically acceptable salt thereof:

.

.

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

In a fourth embodiment, the disclosed Tyk2 inhibitor may be selected from those having the formula: or a pharmaceutically acceptable salt thereof:

wherein the variable is as described in WO 2013/174895, the entire contents of which are incorporated herein by reference. Exemplary compounds having the formula above as part of the fourth embodiment include, but are not limited to, those having the formula: or a pharmaceutically acceptable salt thereof:

.

.

Other Tyk2 inhibitors include those of WO 2012/062704, the entire contents of which are incorporated herein by reference.

In a fifth embodiment, the disclosed Tyk2 inhibitor may be selected from those having the formula: or a pharmaceutically acceptable salt thereof:

wherein the variable is as described in WO 2012/062704, the entire contents of which are incorporated herein by reference.

In a sixth embodiment, the disclosed Tyk2 inhibitor may be selected from those having the formula: or a pharmaceutically acceptable salt thereof:

wherein the variable is as described in WO 2015/091584, the entire contents of which are incorporated herein by reference. Exemplary compounds having the above formula as part of the sixth embodiment include, but are not limited to, those having the formula: or a pharmaceutically acceptable salt thereof:

.

.

In a seventh embodiment, the disclosed Tyk2 inhibitor may be selected from those having the formula: or a pharmaceutically acceptable salt thereof:

wherein the variable is as described in WO 2016/027195, the entire contents of which are incorporated herein by reference. Exemplary compounds having the formula above as part of the seventh embodiment include, but are not limited to, those having the formula: or a pharmaceutically acceptable salt thereof:

.

.

In an eighth embodiment, the disclosed Tyk2 inhibitor may be selected from those having the formula: or a pharmaceutically acceptable salt thereof:

wherein the variable is as described in US 2017/0240552, the entire contents of which are incorporated herein by reference. Exemplary compounds having the formula above as part of the eighth embodiment include, but are not limited to, those having the formula: or a pharmaceutically acceptable salt thereof:

.

.

In a ninth embodiment, the disclosed Tyk2 inhibitor may be selected from those having the formula: or a pharmaceutically acceptable salt thereof:

wherein the variable is as described in WO 2015/016206, the entire contents of which are incorporated herein by reference.

In a tenth embodiment, the disclosed Tyk2 inhibitor may be selected from those having the formula: or a pharmaceutically acceptable salt thereof:

wherein the variable is as described in WO 2013/146963, the entire contents of which are incorporated herein by reference.

In an eleventh embodiment, the disclosed Tyk2 inhibitor may be selected from those having the formula: or a pharmaceutically acceptable salt thereof:

wherein the variable is as described in WO 2016/047678, the entire contents of which are incorporated herein by reference.

In a twelfth embodiment, the disclosed Tyk2 inhibitors are disclosed in US 2015/0299139; WO 2015/069310; US 9,505,748; WO 2018/0162889; US 2013/0178478; or those described in WO 2015/123453, the entire contents of each of which are incorporated herein by reference.

In a thirteenth embodiment, the disclosed Tyk2 inhibitor may be selected from those having the formula: or a pharmaceutically acceptable salt thereof:

wherein the variable is as described in WO 2015/131080 or WO 2016/138352, the entire contents of which are incorporated herein by reference.

In a fourteenth embodiment, the disclosed Tyk2 inhibitor may be selected from those having the formula: or a pharmaceutically acceptable salt thereof:

wherein the variable is as described in WO 2017/040757, the entire contents of which are incorporated herein by reference.

In a fifteenth embodiment, the disclosed Tyk2 inhibitor may be selected from those having the formula: or a pharmaceutically acceptable salt thereof:

wherein the variable is as described in WO 2015/131080, WO 2016/138352, and WO 2017/040757, the entire contents of which are incorporated herein by reference.

In a sixteenth embodiment, the disclosed Tyk2 inhibitor may be selected from those having the formula: or a pharmaceutically acceptable salt thereof:

wherein the variable is as described in WO 2018/071794, the entire contents of which are incorporated herein by reference.

In a seventeenth embodiment, the disclosed Tyk2 inhibitor may be selected from those having the formula: or a pharmaceutically acceptable salt thereof:

wherein the variable is as described in WO 2018/075937, the entire contents of which are incorporated herein by reference.

In an eighteenth embodiment, the disclosed Tyk2 inhibitor may be selected from those having the formula: or a pharmaceutically acceptable salt thereof:

wherein the variable is as described in US 2013/0178478, the entire contents of which are incorporated herein by reference.

In a nineteenth embodiment, the disclosed Tyk2 inhibitor may be selected from those having the formula: or a pharmaceutically acceptable salt thereof:

wherein the variable is as described in WO 2015/123453, the entire contents of which are incorporated herein by reference.

In a twentieth embodiment, the disclosed Tyk2 inhibitor may be selected from those having the formula: or a pharmaceutically acceptable salt thereof:

wherein the variable is as described in WO 2015/089143, the entire contents of which are incorporated herein by reference.

In a twenty-first embodiment, the disclosed Tyk2 inhibitor may be selected from those having the formula: or a pharmaceutically acceptable salt thereof:

wherein the variable is as described in WO 2015/089143, the entire contents of which are incorporated herein by reference.

In a twenty-second embodiment, the disclosed Tyk2 inhibitor may be selected from those having the formula: or a pharmaceutically acceptable salt thereof:

wherein the variable is as described in WO 2018/067432, the entire contents of which are incorporated herein by reference.

In a twenty-third embodiment, the disclosed Tyk2 inhibitor may be selected from those having the formula: or a pharmaceutically acceptable salt thereof:

wherein the variable is as described in WO 2018/093968, the entire contents of which are incorporated herein by reference.

In a twenty-fourth embodiment, the disclosed Tyk2 inhibitor may be selected from those having the formula: or a pharmaceutically acceptable salt thereof:

wherein the variable is as described in WO 2018/081488, the entire contents of which are incorporated herein by reference.

In a twenty-fifth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the formula: or a pharmaceutically acceptable salt thereof:

here

R ¹ _{is C 1-3} alkyl optionally substituted with 0-7 R ^{1a ;}

R ^1a at each occurrence is independently hydrogen, deuterium, F, Cl, Br, CF ₃ or CN;

R ² is C _1-6 alkyl or —(CH ₂ ) _r- 3-14 membered carbocycle, each group substituted ^{with 0-4 R 2a ;}

R ^2a at each occurrence 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 0-3 R ^a , C _1-6 haloalkyl , substituted with 0-3 R ^a of the C _2-6 alkenyl group substituted by, 0 to 3 of the R ^a C _2-6 alkynyl, 0-1 of R ^a is substituted by - (CH _{2) r} -3 -14 membered carbocycle, or -(CH ₂ ) _r -5- containing carbon atoms or 1-4 heteroatoms selected from N, O, and S(O) _p ^{and substituted with 0-2 R a} 7 membered heterocycle;

R ³ is C _3-10 cycloalkyl, C _6-10 aryl, or 5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group having 0-4 R ^3a is substituted;

R ^3a at each occurrence 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 _{, C 1-6} alkyl substituted with 0-3 R ^{a ,} substituted with 0-3 R ^a of the C _2-6 alkenyl, 0-3 R ^a of the C _2-6 alkynyl, C _1-6 haloalkyl, 0-3 of R ^a substituted by a substituted - ( CH ₂ ) _r -3-14 membered carbocycle, or -(CH containing carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) _p ^{, substituted with 0-3 R a .} ₂ ) _{r is a} -5-10 membered heterocycle;

or two R ^3a are taken together with the atoms to which they are attached to form a fused ring, wherein said ring is phenyl and 5- containing carbon atoms and 1-4 heteroatoms selected from N, S or O 7 membered heterocycle, wherein said fused ring is further substituted by ^{R a1 ;}

R ⁴ and R ⁵ are independently hydrogen, _{C 1-4} alkyl substituted with ^{0-1 R f} , (CH ₂ ) _r -phenyl substituted with 0-3 R ^d , or a carbon atom and N, O, _{and -(CH 2} )-5-7 membered heterocycle comprising 1-4 heteroatoms selected from S(O) _{p ;}

R ¹¹ at each occurrence is independently hydrogen, _{C 1-4} alkyl substituted with ^{0-3 R f} , CF _{3 , C 3-10} cycloalkyl substituted with 0-1 R ^f , 0-3 R ^d (CH) _r -phenyl substituted with or -(CH ₂ ) _r containing carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) _p ^{and substituted with 0-3 R d} -5-7 membered heterocycle;

R ^a and R ^a1 at each occurrence are independently hydrogen, F, Cl, Br, OCF ₃ , CF ₃ , CHF ₂ , CN, NO ₂ , -(CH ₂ ) _r OR ^b , -(CH ₂ ) _r SR ^b , -(CH ₂ ) _r C(O)R ^b , -(CH ₂ ) _r C(O)OR ^b , -(CH ₂ ) _r OC(O)R ^b , -(CH ₂ ) _r NR ¹¹ R ¹¹ , -(CH ₂ ) _r C(O)NR ¹¹ R ¹¹ , -(CH ₂ ) _r NR ^b C(O)R ^c , -(CH ₂ ) _r NR ^b C(O)OR ^c , -NR ^b C (O)NR ¹¹ R ¹¹ , -S(O) _p NR ¹¹ R ¹¹ , -NR ^b S(O) _p R ^c , -S(O)R ^c , -S(O) ₂ R ^c , 0-3 the C _1-6 alkyl substituted with one R ^f, C _1-6 haloalkyl, 0-3 of the R ^a C _2-6 alkenyl group substituted by, 0 to 3 of the R ^a C _2-6 alkynyl substituted with , -(CH ₂ ) _r -3-14 membered carbocycle, or containing carbon atoms and 1-4 heteroatoms selected from _{N, O, and S(O) p} and substituted with ^{0-3 R f} -(CH ₂ ) _{r is a} -5-7 membered heterocycle;

R ^b at each occurrence is independently hydrogen, _{C 1-6} alkyl substituted with ^{0-3 R d} , C _1-6 haloalkyl, _{C 3-6} cycloalkyl substituted with ^{0-2 R d} , or carbon —(CH ₂ ) _r- 5-7 membered heterocycle containing atoms and 1-4 heteroatoms selected from N, O, and S(O) _p ^{and substituted with 0-3 R f , or 0-3} (CH ₂ ) _r -phenyl substituted with R ^{d ;}

R ^c is substituted with 0-3 R ^f of the C _1-6 alkyl, 0-3 of the R ^f (CH _{2) r} -C _3-6 cycloalkyl, 0-3 of R ^f is substituted by substituted with ( CH ₂ ) is _r -phenyl; or

R ^d at each occurrence is independently hydrogen, F, Cl, Br, OCF ₃ , CF ₃ , CN, NO ₂ , -OR ^e , -(CH ₂ ) _r C(O)R ^c , -NR ^e R ^e , —NR ^e C(O)OR ^c , C _1-6 alkyl, or (CH ₂ ) _r -phenyl ^{substituted with 0-3 R f ;}

R ^e at each occurrence is independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, and (CH ₂ ) _r -phenyl ^{substituted with 0-3 R f ;}

R ^f is independently at each occurrence 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 S(O ) _{-(CH 2} ) _r -5-7 membered heteroaryl comprising 1-4 heteroatoms selected from _p;

p is 0, 1, or 2;

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

In a twenty-sixth embodiment, the disclosed Tyk2 inhibitor may be selected from those having the formula: or a pharmaceutically acceptable salt thereof:

here

R ¹ _{is C 1-3} alkyl optionally substituted with 0-7 R ^{1a ;}

R ^1a at each occurrence is independently hydrogen, deuterium, F, CI, Br, CF ₃ or CN;

R ² is R ^2a 0-4 of the C _1-6 alkyl, R 0-4 of the C _6-10 aryl substituted with a C _3-6 cycloalkyl, 0-4 of R ^2a is substituted by substituted by ^2a, N is a 5-14 membered heterocycle containing 1-4 heteroatoms selected from , O, and S and substituted with 0-4 R ^2a , NR ⁶ R ⁶ or OR ^{b ;}

R ^2a at each occurrence 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 0-3 R ^a , C _1-6 halo alkyl, -(CH ₂ ) _r -3-14 membered carbocycle substituted with 0-1 R ^a , or contains 1-4 heteroatoms selected from carbon atoms or N, O, and S(O) _{p and 0} -(CH ₂ ) _r -5-7 membered heterocycle substituted with two R ^{a ;}

or one R ^2a and another R ^{2a taken} together with the atoms to which they are attached form a fused 5-6 membered ring, wherein said fused ring may be substituted with ^{0-2 R a ;}

R ³ is —(CH ₂ ) _r- 3-14 membered carbocycle substituted with 0-5 R ^{3a ;}

R ^3a at each occurrence 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 0-3 R ^a , C _1-6 halo alkyl, -(CH ₂ ) _r -3-14 membered carbocycle substituted with 0-3 R ^a , or contains 1-4 heteroatoms selected from carbon atoms or N, O, and S(O) _{p and 0} -(CH ₂ ) _r -5-10 membered heterocycle substituted with -3 R ^{a ;}

or two R ^3a are taken together with the atoms to which they are attached to form a fused ring, wherein said ring is phenyl and 5- containing carbon atoms and 1-4 heteroatoms selected from N, S or O 7 membered heterocycle, wherein said fused ring may be further substituted by ^{R a ;}

R ⁴ and R ⁵ are independently hydrogen, _{C 1-4} alkyl substituted with ^{0-1 R f} , (CH ₂ ) _r -phenyl substituted with 0-3 R ^d , or a carbon atom and N, O, _{and -(CH 2} )-5-7 membered heterocycle comprising 1-4 heteroatoms selected from S(O) _{p ;}

R ⁶ and R ¹¹ at each occurrence are independently hydrogen, _{C 1-4} alkyl substituted with ^{0-3 R f} , CF _{3 , C 3-10} cycloalkyl substituted with 0-1 R ^f , 0-3 (CH) _r -phenyl substituted with R ^d , or —(CH ) containing carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) _p and substituted with ^{0-3 R d .} ₂ ) _{r is a} -5-7 membered heterocycle;

R ^a is at each occurrence hydrogen, F, Cl, Br, OCF ₃ , CF ₃ , CHF ₂ , CN, NO ₂ , -(CH ₂ ) _r OR ^b , -(CH ₂ ) _r SR ^b , -(CH _{2 )} ) _r C(O)R ^b , -(CH ₂ ) _r C(O)OR ^b , -(CH ₂ ) _r OC(O)R ^b , -(CH ₂ ) _r NR ¹¹ R ¹¹ , -(CH _{2 )} ) _r C(O)NR ¹¹ R ¹¹ , -(CH ₂ ) _r NR ^b C(O)R ^C , -(CH ₂ ) _r NR ^b C(O)OR ^C , -NR ^b C(O)NR ¹¹ R ¹¹ , -S(O) _p NR ¹¹ R ¹¹ , -NR ^b S(O) _p R ^C , -S(O)R ^C , -S(O) ₂ R ^C , replaced with 0-3 R ^{f .} C _1-6 alkyl, C _1-6 haloalkyl, —(CH ₂ ) _r -3-14 membered carbocycle, or carbon atoms and 1-4 hetero selected from N, O, and S(O) _p -(CH ₂ ) _r- 5-7 membered heterocycle containing atoms and ^{substituted with 0-3 R f ;}

R ^b is at each occurrence hydrogen, _{C 1-6} alkyl substituted with ^{0-3 R d} , C _1-6 halo alkyl, _{C 3-6} cycloalkyl substituted with ^{0-2 R d} , or carbon atoms and -(CH ₂ ) _r- 5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(O) _p ^{and substituted with 0-3 R f} , or 0-3 R (CH ₂ ) _r -phenyl ^{substituted with d;}

R ^C is substituted with 0-3 R ^f of the C _1-6 alkyl, 0-3 of the R ^f (CH _{2) r} -C _3-6 cycloalkyl, or 0-3 of R ^f is substituted by a substituted (CH ₂ ) _r -phenyl;

R ^d at each occurrence is independently hydrogen, F, Cl, Br, OCF ₃ , CF ₃ , CN, NO ₂ , OR ^e , -(CH ₂ ) _r C(O)R ^C , NR ^e R ^e , -NR ^e C(O)OR ^C , C _1-6 alkyl, or (CH ₂ ) _r -phenyl ^{substituted with 0-3 R f ;}

R ^e at each occurrence is independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, and (CH ₂ ) _r -phenyl ^{substituted with 0-3 R f ;}

R ^f is independently at each occurrence 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 S(O ) _{-(CH 2} ) _r -5-7 membered heteroaryl comprising 1-4 heteroatoms selected from _p;

p is 0, 1, or 2;

r is 0, 1, 2, 3, or 4.

In a twenty-seventh embodiment, the disclosed Tyk2 inhibitors may be selected from those having the formula: or a pharmaceutically acceptable salt thereof:

wherein the variable is as described in WO 2015/069310, the entire contents of which are incorporated herein by reference.

In a twenty-eighth embodiment, the disclosed Tyk2 inhibitor may be selected from those having the formula: or a pharmaceutically acceptable salt thereof:

here

Y is N or CR ⁶ ;

R ¹ is H, C _1-3 alkyl or C _3-6 cycloalkyl, each optionally substituted by ^{0-7 R 1a ;}

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

R ² is C _1-6 alkyl, —(CH ₂ ) _r- ^{3-14 membered carbocycle substituted with 0-1 R 2a} , or contains 1-4 heteroatoms selected from N, O, and S is a 5-14 membered heterocycle, each group ^{being substituted with 0-4 R 2a} (for clarity, R ² is intended to include a substituted methyl group, such as —C(O)R ^{2a );}

R ^2a at each occurrence 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 0-3 R ^a , C _1-6 haloalkyl, 0 _{C 2-6} alkenyl substituted with -3 R ^a _{, C 2-6} alkynyl substituted with 0-3 R ^a , —(CH ₂ ) _r -3-14 substituted with 0-1 R ^{a .} membered carbocycle, or —(CH ₂ ) _r- 5-7 membered containing carbon atoms or 1-4 heteroatoms selected from N, O, and S(O) _p ^{and substituted with 0-2 R a .} heterocycle;

R ³ is C _3-10 cycloalkyl, C _6-10 aryl, or 5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group having 0-4 R ^3a is substituted;

R ^3a at each occurrence 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 _{, C 1-6} alkyl substituted with 0-3 R ^{a ,} substituted with 0-3 R ^a of the C _2-6 alkenyl, 0-3 R ^a of the C _2-6 alkynyl, C _1-6 haloalkyl, 0-3 of R ^a substituted by a substituted - ( CH ₂ ) _r -3-14 membered carbocycle, or -(CH containing carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) _p ^{, substituted with 0-3 R a .} ₂ ) _{r is a} -5-10 membered heterocycle;

or two R ^3a are taken together with the atoms to which they are attached to form a fused ring, wherein the ring is phenyl and a carbon atom and 1-4 heteroatoms selected from _{N, O, and S(O) p} wherein each fused ring is substituted with ^{0-3 R a1 ;}

R ⁴ and R ⁵ are independently hydrogen, _{C 1-4} alkyl substituted with ^{0-1 R f} , (CH ₂ ) _r -phenyl substituted with 0-3 R ^d , or a carbon atom and N, O, _{and -(CH 2} )-5-7 membered heterocycle comprising 1-4 heteroatoms selected from 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;

R ¹¹ at each occurrence is independently hydrogen, _{C 1-4} alkyl substituted with ^{0-3 R f} , CF _{3 , C 3-10} cycloalkyl substituted with 0-1 R ^f , 0-3 R ^d (CH) _r -phenyl substituted with or -(CH ₂ ) _r containing carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) _p ^{and substituted with 0-3 R d} -5-7 membered heterocycle;

R ^a and R ^a1 at each occurrence are independently hydrogen, F, Cl, Br, OCF ₃ , CF ₃ , CHF ₂ , CN, NO ₂ , -(CH ₂ ) _r OR ^b , -(CH ₂ ) _r SR ^b , -(CH ₂ ) _r C(O)R ^b , -(CH ₂ ) _r C(O)OR ^b , -(CH ₂ ) _r OC(O)R ^b , -(CH ₂ ) _r NR ¹¹ R ¹¹ , -(CH ₂ ) _r C(O)NR ¹¹ R ¹¹ , -(CH ₂ ) _r NR ^b C(O)R ^c , -(CH ₂ ) _r NR ^b C(O)OR ^c , -NR ^b C (O)NR ¹¹ R ¹¹ , -S(O) _p NR"R", -NR ^b S(O) _p R ^c , -S(O)R ^c , -S(O) ₂ R ^c , 0-3 the C _1-6 alkyl substituted with one R ^f, C _1-6 haloalkyl, 0-3 of the R ^a C _2-6 alkenyl group substituted by, 0 to 3 of the R ^a C _2-6 alkynyl substituted with , -(CH ₂ ) _r -3-14 membered carbocycle, or containing carbon atoms and 1-4 heteroatoms selected from _{N, O, and S(O) p} and substituted with ^{0-3 R f} -(CH ₂ ) _{r is a} -5-7 membered heterocycle;

R ^b is hydrogen, _{C 1-6} alkyl substituted with ^{0-3 R d} , C _1-6 haloalkyl, _{C 3-6} cycloalkyl substituted with ^{0-2 R d} , or carbon atoms and N, O -(CH ₂ ) _r -5-7 membered heterocycle comprising 1-4 heteroatoms selected from , and S(O) _p ^{and substituted with 0-3 R f} , or substituted with ^{0-3 R d .} (CH ₂ ) _r -phenyl;

R ^c is substituted with 0-3 R ^f of the C _1-6 alkyl, 0-3 of the R ^f (CH _{2) r} -C _3-6 cycloalkyl, or 0-3 of R ^f is substituted by a substituted (CH ₂ ) _r -phenyl;

R ^d at each occurrence is independently hydrogen, F, Cl, Br, OCF ₃ , CF ₃ , CN, NO ₂ , -OR ^e , -(CH ₂ ) _r C(O)R ^c , -NR ^e R ^e , —NR ^e C(O)OR ^c , C _1-6 alkyl, or (CH ₂ ) _r -phenyl ^{substituted with 0-3 R f ;}

R ^e at each occurrence is independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl and (CH ₂ ) _r -phenyl ^{substituted with 0-3 R f ;}

R ^f is independently at each occurrence 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 S(O ) _{-(CH 2} ) _r -5-7 membered heterocycle comprising 1-4 heteroatoms selected from _p;

p is 0, 1, or 2;

r is 0, 1, 2, 3, or 4, wherein further definitions and specific compounds are as described in US 9,505,748 and WO 2018/0162889, the entire contents of each of which are incorporated herein by reference.

In a twenty-ninth embodiment, the disclosed Tyk2 inhibitor may be selected from those having the formula: or a pharmaceutically acceptable salt thereof:

here

이고;R ¹ is

ego;

이다.R ² is

to be.

In a thirtieth embodiment, the Tyk2 inhibitor described herein is 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2, 4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165) or a pharmaceutically acceptable salt thereof:

.

.

Specific dosages and treatment regimens for the disclosed Tyk2 inhibitors used in combination with apremilast will depend on age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the specific It will depend on a variety of factors, including the severity of the disease.

In a 31 embodiment, the effective amount of a disclosed Tyk2 inhibitor (eg, as in any one of the second to thirtieth embodiments) used in combination with apremilast is 0.001 to 50 mg/kg body weight/day. is the range For example, as part of the thirty-first embodiment, an effective amount of a disclosed Tyk2 inhibitor (eg, as in any one of the second-30 embodiments) used in combination with apremilast is about 0.1 mg/ from about 250 mg/day to about 250 mg/day, such as from about 0.2 mg/day to about 100 mg/day, from about 0.5 mg/day to about 50 mg/day, and from about 1.0 mg to about 24 mg/day.

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

In a 33 embodiment, the Tyk2 inhibitor described herein is BMS-986165 or a pharmaceutically acceptable salt thereof, and the effective amount of BMS-986165 or a pharmaceutically acceptable salt thereof is about 0.1 mg/day, about 0.5 mg/day, about 1.0 mg/day, about 2 mg/day, about 3 mg/day, about 4 mg/day, about 5 mg/day, about 6 mg/day, about 7 mg/day, about 8 mg/day, about 9 mg/day day, about 10 mg/day, about 11 mg/day or about 12 mg/day. Alternatively, as part of the thirty-third embodiment, the effective amount of BMS-986165 or a pharmaceutically acceptable salt thereof is about 2 mg/day, about 3 mg/day, about 4 mg/day, about 5 mg/day, about 6 mg/day, about 7 mg/day, about 8 mg/day, about 9 mg/day, about 10 mg/day, about 11 mg/day, or about 12 mg/day. In another alternative, as part of the thirty-third embodiment, the effective amount of BMS-986165 or a pharmaceutically acceptable salt thereof is about 6 mg/day. In another alternative, as part of the thirty-third embodiment, the effective concentration of BMS-986165 or a pharmaceutically acceptable salt thereof is from about 1 nM to about 1 μM (eg, from about 0.01 μM to about 0.1 μM).

3. Apremilast

As described 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%, wherein the Tyk2 inhibitor and related features are as described herein, e.g., examples 1-33 as in any one of the aspects. Alternatively, as part of a thirty-fourth embodiment, the stereoisomeric purity of apremilast in the methods and compositions described herein is greater than 95%, wherein the Tyk2 inhibitor and related features are as described herein, e.g. As in any one of embodiments 1 to 33. In another alternative, as part of the thirty-fourth embodiment, the stereoisomeric purity of apremilast in the methods and compositions described herein is greater than 97%, wherein the Tyk2 inhibitor and related features are as described herein, e.g. As in any one of the first to the 33rd embodiments. In another alternative, as part of the thirty-fourth embodiment, the stereoisomeric purity of apremilast in the methods and compositions described herein is greater than 98%, wherein the Tyk2 inhibitor and related features are as described herein, e.g. As in any one of the first to the 33rd embodiments. In another alternative, as part of the thirty-fourth embodiment, the stereoisomeric purity of apremilast in the methods and compositions described herein is greater than 99%, wherein the Tyk2 inhibitor and related features are as described herein, e.g. As in any one of the first to the 33rd embodiments. In another alternative, as part of the thirty-fourth embodiment, the stereoisomeric purity of apremilast in the methods and compositions described herein is greater than 99.5%, wherein the Tyk2 inhibitor and related features are as described herein, e.g. As in any one of the first to the 33rd embodiments. In another alternative, as part of the thirty-fourth embodiment, the stereoisomeric purity of apremilast in the methods and compositions described herein is greater than 99.9%, wherein the Tyk2 inhibitor and related features are as described herein, e.g. As in any one of the first to the 33rd embodiments.

Polymorphic forms of apremilast are included in the disclosed methods and compositions, including those described, for example, in US 9,018,243, the entire contents of which are incorporated herein by reference. In a thirty-fifth embodiment, apremilast in the disclosed methods and compositions is in a single crystalline form, wherein additional features and related features for apremilast as well as the Tyk2 inhibitor are as described herein, e.g. As in any one of embodiments 1 to 34.

In a 36 embodiment, apremilast in the disclosed methods and compositions is a single crystalline Form B characterized by an X-ray powder diffraction peak at a 2θ angle selected from 10.1°, 13.5°, 20.7° and 26.9°, wherein Additional features and related features for apremilast as well as Tyk2 inhibitors are as described herein, for example as in any one of the first to thirty-fourth embodiments. Alternatively, as part of a thirty-sixth embodiment, apremilast in the disclosed methods and compositions has an X at a 2θ angle selected from 10.1°, 13.5°, 15.7°, 18.1°, 20.7°, 24.7° and 26.9°. is a single crystalline Form B characterized by a line powder diffraction peak, wherein additional features and related features for apremilast as well as Tyk2 inhibitors are as described herein, e.g., any of embodiments 1-34 as in one In another alternative, as part of the thirty-sixth embodiment, the apremilast in the disclosed methods and compositions is 10.1°, 13.5°, 15.7°, 16.3°, 18.1°, 20.7°, 22.5°, 24.7°, 26.2° , a single crystalline Form B characterized by an X-ray powder diffraction peak at a 2θ angle selected from , 26.9° and 29.1°, wherein additional features and related features for apremilast as well as a Tyk2 inhibitor are as described herein and , for example as in any one of the first to thirty-fourth embodiments.

In a 37 embodiment, the apremilast in the disclosed methods and compositions is at least 90% single crystalline Form B, wherein the apremilast as well as additional features and related features for the Tyk2 inhibitor are as described herein, For example as in any one of the first to 36th embodiments. Alternatively, in the disclosed methods and compositions apremilast is at least 95% single crystalline Form B, wherein additional features and related features for apremilast as well as Tyk2 inhibitors are as described herein, e.g. As in any one of the first to 36th embodiments. In another alternative, in the disclosed methods and compositions the apremilast is at least 99% single crystalline Form B, wherein additional features and related features for apremilast as well as the Tyk2 inhibitor are as described herein, e.g. for example as in any one of the first to thirty-sixth embodiments.

The specific dosage and treatment regimen of apremilast or a pharmaceutically acceptable salt thereof to be used in combination with the disclosed Tyk2 inhibitor will depend on age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, judgment of the treating physician. , and the severity of the particular disease being treated.

For example, in a 38 embodiment, the effective amount of apremilast or a pharmaceutically acceptable salt thereof is from about 0.5 mg/day to about 1000 mg/day, from about 1 mg/day to about 1000 mg/day, about 5 mg from about 500 mg/day to about 500 mg/day, from about 10 mg/day to about 200 mg/day, from about 10 mg/day to about 100 mg/day, from about 40 mg/day to about 100 mg/day, about 20 mg/day to about 40 mg/day, about 0.1 mg/day to about 10 mg/day, about 0.5 mg/day to about 5 mg/day, about 1 mg/day to about 20 mg/day, and about 1 mg/day to about 10 mg/day, about 1 mg/day to about 100 mg/day, about 1 mg/day to about 80 mg/day, about 5 mg/day to about 70 mg/day, about 10 mg/day to about 60 mg/day, and in the range of from about 10 mg/day to about 40 mg/day, wherein additional features and related features for apremilast as well as Tyk2 inhibitors are as described herein, e.g., from 1 to As in any one of the 37th embodiment. Alternatively, as part of the thirty-eighth embodiment, the effective amount of apremilast or a pharmaceutically acceptable salt thereof ranges from about 10 mg to about 60 mg/day, wherein apremilast as well as additional for a Tyk2 inhibitor The features and related features of are as described herein, for example as in any one of the first to thirty-seventh embodiments. In another alternative, as part of the thirty-eighth embodiment, the effective amount of apremilast or a pharmaceutically acceptable salt thereof ranges from about 40 mg to about 100 mg/day, wherein for apremilast as well as for the Tyk2 inhibitor Additional features and related features are as described herein, for example as in any one of the first to thirty-seventh embodiments. In another alternative, as part of the thirty-eighth embodiment, the effective amount of apremilast or a pharmaceutically acceptable salt thereof ranges from about 40 mg to about 100 mg/day, wherein for apremilast as well as for the Tyk2 inhibitor Additional features and related features are as described herein, for example as in any one of the first to thirty-seventh embodiments. In another alternative, as part of the thirty-eighth embodiment, the effective amount of apremilast or a pharmaceutically acceptable salt thereof ranges from about 4 mg to about 10 mg/day, wherein for apremilast as well as a Tyk2 inhibitor Additional features and related features are as described herein, for example as in any one of the first to thirty-seventh embodiments. In another alternative, as part of the thirty-eighth embodiment, the effective amount of apremilast or a pharmaceutically acceptable salt thereof ranges from about 4 mg to about 10 mg/day, wherein for apremilast as well as a Tyk2 inhibitor Additional features and related features are as described herein, for example as in any one of the first to thirty-seventh embodiments. In another alternative, as part of the thirty-eighth embodiment, the effective amount of apremilast or a pharmaceutically acceptable salt thereof ranges from about 10 mg to about 40 mg/day, wherein for apremilast as well as for a Tyk2 inhibitor Additional features and related features are as described herein, for example as in any one of the first to thirty-seventh embodiments. In another alternative, as part of the 38th embodiment, the effective amount of apremilast or a pharmaceutically acceptable salt thereof is about 1 mg/day, about 2 mg/day, about 3 mg/day, about 4 mg/day, about 5 mg/day, about 10 mg/day, about 15 mg/day, about 20 mg/day, about 25 mg/day, about 30 mg/day, about 35 mg/day, about 40 mg/day, about 45 mg/day, about 50 mg/day, about 55 mg/day, or about 60 mg/day, wherein additional features and related features for apremilast as well as Tyk2 inhibitors are as described herein, e.g. for example as in any one of the first to thirty-seventh embodiments. In another alternative, as part of the thirty-eighth embodiment, the effective amount of apremilast or a pharmaceutically acceptable salt thereof is about 30 mg/day or about 60 mg/day, wherein for apremilast as well as for a Tyk2 inhibitor Additional features and related features are as described herein, for example as in any one of the first to thirty-seventh embodiments. In another alternative, as part of the thirty-eighth embodiment, apremilast is administered at a dose of about 30 mg once daily, wherein additional features and related features for apremilast as well as a Tyk2 inhibitor are described herein as described in, for example as in any one of the first to 37th embodiments. In another alternative, as part of the thirty-eighth embodiment, apremilast is administered at a dose of about 30 mg twice daily, wherein additional features and related features for apremilast as well as a Tyk2 inhibitor are described herein as described in, for example as in any one of the first to 37th embodiments. In another alternative, as part of the thirty-eighth embodiment, the effective amount of apremilast or a pharmaceutically acceptable salt thereof is about 10 mg/day or about 40 mg/day, wherein for apremilast as well as for a Tyk2 inhibitor Additional features and related features are as described herein, for example as in any one of the first to thirty-seventh embodiments. In another alternative, as part of the thirty-eighth embodiment, apremilast is administered at a dose of about 10 mg once or twice daily, wherein apremilast as well as additional features and associations for a Tyk2 inhibitor The features are as described herein, for example as in any one of the first to thirty-seventh embodiments. In another alternative, as part of the thirty-eighth embodiment, apremilast is administered at a dose of about 20 mg once or twice daily, wherein apremilast as well as additional features and associations for a Tyk2 inhibitor The features are as described herein, for example as in any one of the first to thirty-seventh embodiments. In another alternative, as part of the 38th embodiment, the effective concentration of apremilast is between about 100 nM and about 10 μM (eg, between about 0.1 μM and about 1 μM), wherein the apremilast as well as Additional features and related features for the Tyk2 inhibitor are as described herein, for example as in any one of the first to thirty-seventh embodiments.

In a 39 embodiment, apremilast is administered on the following titration schedule:

Day 1: About 10 mg in the morning;

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

Day 3: About 10 mg in the morning and 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: titrated to a dose of about 30 mg administered twice daily using about 30 mg twice daily, wherein additional features and related features for apremilast as well as Tyk2 inhibitors is as described herein, for example as in any one of the first to thirty-seventh embodiments. Alternatively, apremilast is administered on the following titration schedule:

Day 1: About 10 mg in the morning;

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

Day 3: About 10 mg in the morning and 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: titrated at a dosage of about 40 mg/day to about 100 mg/day using about 40 mg/day to about 100 mg/day, wherein for apremilast as well as for Tyk2 inhibitor Additional features and related features are as described herein, for example as in any one of the first to thirty-seventh embodiments. In another alternative, apremilast is administered on the following titration schedule:

Day 1: About 10 mg in the morning;

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

Day 3: About 10 mg in the morning and 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: titrated to a dose of about 20 mg administered twice daily using about 20 mg twice daily, wherein additional features and related features for apremilast as well as Tyk2 inhibitors is as described herein, for example as in any one of the first to thirty-seventh embodiments. In another alternative, apremilast is administered on the following titration schedule:

Day 1: About 1 mg in the morning;

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

Day 3: About 1 mg in the morning and about 2 mg in the evening;

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

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

Day 6 and thereafter: titrated to a dosage of about 4 mg/day to about 10 mg/day using about 4 mg/day to about 10 mg/day, wherein for apremilast as well as Tyk2 inhibitor Additional features and related features are as described herein, for example as in any one of the first to thirty-seventh embodiments. In another alternative, apremilast is administered on the following titration schedule:

Day 1: About 1 mg in the morning;

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

Day 3: About 10 mg in the morning and about 2 mg in the evening;

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

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

Day 6 and thereafter: titrated to a dose of about 3 mg administered twice daily using about 3 mg twice daily, wherein additional features and related features for apremilast as well as Tyk2 inhibitors is as described herein, for example as in any one of the first to thirty-seventh embodiments.

3. Composition and Administration

Also included is 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 for the disclosed pharmaceutical compositions include elements described above, for example as in any one of the first to thirty eighth embodiments.

apremilast, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount for use in treating a disease or disorder responsive to inhibition of PDE4; and a therapeutically effective amount of a Tyk2 inhibitor (eg, BMS-986165). Features for the disclosed pharmaceutical compositions include elements described above, for example as in any one of the first to thirty eighth embodiments.

apremilast and a Tyk2 inhibitor (eg, BMS-986165) alone or together in a fixed dose for administration as described above (eg, as in any one of the first to 38th embodiments) pharmaceutical compositions comprising and single unit dosage forms are included. Single unit dosage forms of the disclosed methods and compositions may be administered to a patient orally, mucosally (eg, nasal, sublingual, vaginal, buccal or rectal), parenterally (eg, subcutaneously, intravenously, bolus injection, intramuscularly or intraarterial), or for transdermal administration.

Examples of dosage forms include tablets; caplet; capsules, such as soft elastic gelatin capsules; Cache; Troki; lozenge; dispersion; suppositories; Ointment; compresses (poultices); paste; powder; dressing; cream; plaster; solution; patch; aerosols (eg, nasal sprays or inhalers); gel; liquid dosage forms suitable for oral or mucosal administration to a patient, such as suspensions (eg, aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (eg, crystalline or amorphous solids) that can be reconstituted to provide a liquid dosage form suitable for parenteral administration to a patient.

The composition, form and type of dosage form will typically depend upon its use. For example, a dosage form used for the acute treatment of inflammation or a related disorder may contain one or more of the active ingredients it contains in a greater amount than a dosage form used for the chronic treatment of the same disease. Similarly, a parenteral dosage form may contain one or more of the active ingredients it contains in lower amounts than an oral dosage form used to treat the same disease or disorder.

These and other methods by which the specific dosage forms encompassed by the present invention will be distinguished from one another will be readily apparent to those of ordinary skill in the art.

See, eg, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990)].

In a 39 embodiment, apremilast in the disclosed methods and compositions is administered parenterally, transdermally, mucosally, nasally, bucally, sublingually or orally, wherein apremilast as well as a Tyk2 inhibitor Further features and related features for the are as described herein, for example as in any one of the first to thirty eighth embodiments. Alternatively, as part of a thirty-ninth embodiment, apremilast in the disclosed methods and compositions is administered orally, wherein additional features and related features for apremilast as well as the Tyk2 inhibitor are as described herein. same, for example as in any one of the first to 38th embodiments.

In a fortieth embodiment, in the disclosed methods and compositions apremilast is administered orally in the form of a tablet or capsule, wherein additional features and related features for apremilast as well as the Tyk2 inhibitor are as described herein, For example as in any one of the first to 39th embodiments.

In a 41 embodiment, in the disclosed methods and compositions apremilast is formulated as an extended release form, wherein additional features and related features for apremilast as well as the Tyk2 inhibitor are as described herein, e.g. As in any one of the first to 39th embodiments.

In a forty-two embodiment, in the disclosed methods and compositions apremilast is formulated as an immediate release form, wherein additional features and related features for apremilast as well as the Tyk2 inhibitor are as described herein, e.g. As in any one of the first to 39th embodiments.

In a 43 embodiment, in the disclosed methods and compositions both apremilast and a Tyk2 inhibitor are administered as a once-daily formulation in a fixed dose combination, wherein additional features and relevance to apremilast as well as the Tyk2 inhibitor The features are as described herein, for example as in any one of the first to forty-two embodiments.

4. Conditions Treated by the Methods and Compositions Disclosed herein

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.

In one aspect, the disease or disorder responsive to inhibition of PDE4 is chronic obstructive pulmonary disease, asthma, chronic pulmonary inflammatory disease, hyperoxic alveolar injury, 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, erythema nodosum leprosy, Sjoegren's syndrome, inflammatory bowel disease, Crohn's Crohn's Disease, Behcet's Disease and ulcerative colitis.

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

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

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

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

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

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

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

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

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

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

In one aspect, the disease or disorder responsive to inhibition of PDE4 is a solid tumor, such as a sarcoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial. Sarcoma, synovoma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous adenocarcinoma, papillary carcinoma adenocarcinoma, papillary adenocarcinoma, cystic adenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminothelioma, embryonic carcinoma, Wilms' tumor, cervical cancer, Testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngoma, ependymoma, Kaposi's sarcoma, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma , melanoma, neuroblastoma and retinoblastoma.

Example

1. Substance

Table 1: Whole Blood Assay: Study Materials and Reagents.

Table 2: LPS stimulated PBMC assay: study materials and reagents

Table 3: Test articles for study

2. General method

Whole blood was provided after informed consent and donor de-identification through the Celgene Donor program. All volunteers were healthy and did not receive any medications for at least 72 hours prior to blood collection. Blood was collected in sodium heparin tubes. Assays started within 2 hours of blood collection.

Ex vivo stimulation of healthy donor human whole blood was performed under two different stimulation conditions. Condition Th0 was stimulation with TrueCulture® tubes containing anti-CD3/anti-CD28. Condition Th17 was stimulation with TrueCulture® tubes containing anti-CD3/anti-CD28 + IL-1β, IL-6 and IL-23. Whole blood was separated into 15 milliliter conical tubes and pretreated with DMSO, apremilast alone, BMS-986165 alone, or BMS-986165 in combination with apremilast. Final concentrations were 0.2% DMSO, 1 μM apremilast alone, 1 μM, 0.1 μM, 0.01 μM and 0.001 μM BMS-986165 alone and in combination with 1 μM apremilast. The blood was mixed well, and then incubated for 1 hour in a _{37° C./5% CO 2 incubator.}

Anti-CD3/anti-CD28 (200 ng/ml and 330 ng/ml final concentrations, respectively) TrueCulture® tubes were thawed on the bench top for 30 minutes and then labeled. The plunger was depressed and then removed. The TrueCulture® tubes were placed in the rack upright with the plunger side facing down in the rack and the tube-cap facing up. While blood was incubated with 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 IL-23. 1 ml of pretreated whole blood was placed in each tube using a sterile pyrogen-free pipette tip. The cap was replaced and the contents of the tube were inverted 3 times to mix. Tubes were immediately placed on a 37° C. heating block and incubated for 42 hours (tube-cap end). After 42 hours, the tube was removed from the heating block, the top was opened, 250 μl of the supernatant removed, and transferred to three 96-well polypropylene plates. Samples were immediately frozen at -80°C. The supernatant was then thawed at room temperature and tested purely for cytokine production by Luminex Multi-Plex MagPix technology (Millipore) or for IL-22 by ELISA (Abcam). . This was done according to the manufacturer's procedure.

Peripheral Blood Mononuclear Cell (PBMC) Isolation: Whole blood was provided after informed consent and donor de-identification through the Cellgene donor program. All volunteers were healthy and did not receive any medications for at least 72 hours prior to blood collection. Blood was collected in sodium heparin tubes and used within 2 hours of blood collection for PBMC isolation. Prior to PBMC isolation, whole blood was diluted 1:1 with a PBS solution containing 2% FBS (2% FBS-PBS). 13 ml of Ficoll-Park solution was loaded into a SepMate® tube and 25 ml of diluted blood was loaded on top of Ficoll-Park. After centrifugation at 1200 g for 15 minutes with braking for cell detachment, the isolated PBMCs were transferred to a new tube. PBMCs were washed with 2% FBS-PBS and centrifuged at 800 g for 10 minutes. 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.

For Examples 6-11, PBMCs from 9 healthy donors were isolated and LPS-in vitro for IL-23, IL-12p40, IL-12p70, TNF-α, IFN-γ and MCP-1 cytokine assays. stimulated. PBMCs were plated in 96 well plates at a density of 200,000 cells/well in 200 μl of RPMI growth medium containing 10% FBS, then treated with DMSO and compounds. Each well received an equal amount of DMSO, which was 0.3% v/v as a final concentration. Serial dilution treatments of the compounds were performed according to Table 4 given below. After 2 hours of compound treatment, 100 ng/ml of LPS as final concentration was used as stimulant. PBMCs were then incubated for 16 hours in a 37° C./5% CO _{2 incubator.}

Table 4: Compound treatment conditions for PBMC assay

After 16 h incubation, the supernatant was collected into new 96-well polypropylene plates and centrifuged at 4000 rpm for 10 min to remove cell debris. Cytokine production was measured by Luminex Bio-Plex Multiplex Immunoassay (Bio-Rad) according to the manufacturer's procedure. To ensure that supernatant levels were within the range of standard cytokines for the assay, samples were diluted 5-fold for the IL-12p40 and 27-plex assays and used pure for the IL-23 assay.

3. Data Analysis

Data processing for cytokine analysis was performed using a Milliplex Analyst (Millipore), and the raw data were exported in Excel format for cytokine analysis. Data from Excel were plotted using GraphPad Prism 7.0 (GraphPad Software, Inc., La Jolla, CA) and expressed as pg/ml or % of control. . Statistical analyzes were also performed using One Way Anova and Dunnett's Post Test.

Data processing for PBMC assay was performed using Bio-plex manager, and raw data were exported in Excel format for cytokine analysis. Data were plotted using GraphPad Prism 7.0 (GraphPad Software, Inc., La Jolla, CA) and expressed as % of DMSO control. Statistical analysis was performed using one-way ANOVA and Tukey's multiple comparisons test.

To evaluate the combined effect of apremilast and BMS-986165, data from the two independent treatments were analyzed by comparing the combination response to the theoretical additive response of the two agents. The expected additive effects of the two agents (A and B) were calculated using the fractional multiplication method: ( f u)A,B = ( f u)A x ( f u)B; where f u = fraction unaffected by treatment. Synergy of a combination is determined when the unaffected fraction observed in the combination is less than ( f u)A,B, whereas an additive effect is determined when the unaffected fraction observed in the combination is equal to ( f u)A,B case is decided A partially additive effect is indicated if the unaffected fraction observed in the combination is greater than ( f u)A,B.

Example 1

Interleukin 17A 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 cytokine production

Whole blood from four healthy donors was analyzed for IL-17A, IL-17F, IL-22, TNF-α and GM-CSF cytokine production in both Th0 and Th17 conditions. Blood was pre-treated with apremilast and Tyk2 inhibitor BMS-986165, both alone and in combination, using the TrueCulture® tube system. IL-17A results presented in Figure 1 represent % of control of IL-17A and all data are normalized to Th17 DMSO control. Apremilast inhibited 28% of IL-17A cytokine expression under Th0 condition, and had no effect under Th17 condition. BMS-986165 had a similar effect in both stimulation conditions and inhibited 10-25% of IL-17A expression at 0.001-1 μM. When apremilast was combined with BMS-986165 under Th0 conditions, synergy was observed with a 65% reduction in IL-17A with 1 μM BMS-986165. Under Th17 conditions, there was synergy with inhibition of IL-17A of 24%, 44% and 85%, respectively, by the combination of 1 μM apremilast and 0.01 μM, 0.1 μM and 1 μM BMS-986165. 2 shows picogram levels per milliliter of IL-17A. The level of IL-17A was increased by 387% in the Th17 stimulation condition compared to the 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. Combination of apremilast with 1 μM BMS-986165 further reduced IL-17A levels to 24 pg/mL in Th0 stimulation. Under Th17 conditions, stimulation control measured 532 pg/mL, and apremilast did not inhibit IL-17A levels. BMS-986165 reduced IL-17A levels to 519 pg/mL at 0.01 μM, 428 pg/mL at 0.1 μM and 383 pg/mL at 1 μM. Combination of 1 μM apremilast with BMS-986165 reduced IL-17A levels to 379 pg/mL at 0.01 μM, 328 pg/mL at 0.1 μM and 68 pg/mL at 1 μM BMS-986165.

Example 2

Interleukin 17F 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 cytokine production

IL-17F cytokine expression data are in Figures 3 and 4. Apremilast inhibited 69% of IL-17F production in Th0 conditions and 49% in Th17 conditions. BMS-986165 had a similar effect on IL-17F in both Th0 and Th17 stimulation. There was a dose response for IL-17F expression of 31% inhibition at the lowest concentration of 0.001 μM and 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 under Th0 conditions was partially additive, with inhibition ranging from 60% at 0.001 to 95% at 1 μM. Lower concentrations of BMS-986165 combined with apremilast under Th17 conditions showed synergy. Under Th17 stimulation conditions, apremilast in combination with 0.001 μM BMS-986165 inhibited IL-17F production by 68%, in combination with 0.01 μM inhibited IL-17F production by 70%, and in combination with 0.1 μM 94 % inhibition, 99% inhibition in combination with 1 μM. The level of IL-17F in the Th0 stimulation control was 1085 pg/mL and increased to 6524 pg/mL in the Th17 stimulation. Apremilast reduced IL-17F to 368 pg/mL in Th0 stimulation and 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 for all concentrations of BMS-986165 in both stimulation conditions when combined with apremilast.

Example 3

Interleukin 22 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 cytokine production

IL-22 cytokine expression data are in FIGS. 5 and 6 . Apremilast inhibited 85% of IL-22 cytokine expression under Th0 conditions and 41% under Th17 conditions. Under Th0 stimulation conditions, BMS-986165 inhibited IL-22 by 16% at 0.01 μM, 86% at 0.1 μM and 91% at 1 μM. Under Th17 stimulation conditions, BMS-986165 had no effect on IL-22 cytokine expression at 0.001 μM, but inhibited 17% at 0.01 μM, 60% at 0.1 μM and 70% at 1 μM. Under Th0 conditions, the combination exhibited -90% inhibition at all concentrations of BMS-986165, with similar effects to apremilast alone. The combination under Th17 conditions 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 IL-22 at 1085 pg/mL, 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 for all concentrations of BMS-986165 in both stimulation conditions when combined with apremilast.

Example 4

TNF- 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 α cytokine production

TNF-α cytokine expression data are presented in FIGS. 7 and 8 . Apremilast inhibited 90% of TNF-α levels 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. The highest concentration of 1 μM BMS-986165 inhibited TNF-α cytokine expression by 66%. A similar increase in TNF-α production was observed by BMS-986165 under Th17 conditions, with a 19% increase at 0.01 μM and a 77% increase at 0.1 μM. There was also inhibition (68%) of TNF-α by 1 μM BMS-986165 under Th17 stimulation conditions. The combination of 1 μM apremilast with BMS-986165 reduced the levels of TNF-α by 80-95% (Th0) and 93-96% (Th17), with effects similar to single agent apremilast. Both stimulation conditions had a similar effect on the level of TNF-α, 1380 pg/mL in the Th0 stimulated control group and 1436 pg/mL in the Th17 stimulated control group. Apremilast significantly inhibited TNF-α levels by decreasing the TNF-α level to 148 pg/mL in the Th0 condition and 91 pg/mL in the Th17 condition. The increase in TNF-α level by BMS-986165 was significant at 0.1 μM under Th17 condition. Inhibition of TNF-α levels by 1 μM BMS-986165 was significant in both stimulation conditions. The combination of apremilast and BMS-986165 significantly inhibited TNF-α levels for all concentrations in both stimulation conditions.

Example 5

Granulocytes 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- Macrophage colony-stimulating factor cytokine production

The granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine expression results are shown in FIGS. 9 and 10 . GM-CSF cytokine expression was reduced by 80% under Th0 condition and 66% under Th17 condition by apremilast. BMS-986165 increased GM-CSF cytokine expression in 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 in Th0 conditions. When apremilast (0.1 μM) was added to BMS-986165, there was a 60-80% inhibition of GM-CSF cytokine expression. Upon Th17 stimulation, BMS-986165 increased GM-CSF by 41% at 0.01 μM, 139% at 0.1 μM and 104% at 1 μM. When apremilast was added, there was a 40-73% inhibition of GM-CSF cytokine expression. The total pg/mL of GM-CSF in the Th0 and Th17 stimulation controls was 409 and 637, respectively. Apremilast significantly inhibited GM-CSF in 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 for all concentrations in both stimulation conditions.

Example 6

IL-23 production by apremilast and Tyk2i (BMS-986165) treatment in LPS-stimulated PBMCs

PBMCs from 9 healthy donors were analyzed for cytokine production in LPS stimulation conditions ( FIGS. 11-17 ). The results of Figures 11 and 12 showed the level of IL-23. 11 shows that apremilast reduced IL-23 production in LPS-stimulated PBMCs. IL-23 levels from DMSO treated LPS stimulated PBMCs were set at 100% (control) and cytokine levels were presented as normalized values (%) compared to control. In contrast to the reduction of IL-23 levels by apremilast, FIG. 12 showed that BMS-986165 induced IL-23 levels in LPS stimulated PBMCs. In the range of 0.2 μM - 2 μM, BMS-986165 induced a 20-fold increase in IL-23 compared to the DMSO group. The combination of apremilast and BMS-986165 could reduce the induction of IL-23 by BMS-986165. As the level of apremilast increases, there is a significant decrease in IL-23 levels. Statistical analysis using ANOVA and Turkish multiple comparisons was performed to compare each treatment with BMS-986165 alone. There is a significant decrease in IL-23 when BMS-986165 is combined with low levels of apremilast (at a concentration of 0.037 μM) (**** p <0.001). When combined with 1 μM apremilast, the induction of IL-23 was inhibited by 90%, reaching a level almost similar to that of apremilast alone. Therefore, the curves of combination treatment with 1 μM apremilast do not have significant differences compared to apremilast treatment alone.

Example 7

IL-12p40 production by apremilast and Tyk2i (BMS-986165) treatment in LPS-stimulated PBMCs

The results in FIG. 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, whereas BMS-986165 increased it. The combination of BMS-986165 and apremilast significantly reduced the induction of IL-12p40 by BMS-986165. In the case of 1 μM apremilast, the increased IL-12p40 induced by BMS-986165 was inhibited by 85%, reaching a level similar to that of apremilast alone. Statistical analysis using ANOVA and Turkish multiple comparisons was performed to compare each treatment with BMS-986165 alone. ****p < 0.001

Example 8

IL-12p70 production by apremilast and Tyk2i (BMS-986165) treatment in LPS-stimulated PBMCs

The results in FIG. 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, whereas BMS-986165 increased it. 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 Turkish multiple comparisons was performed to compare each treatment with BMS-986165 alone. ****p < 0.001

Example 9

TNF-α production by apremilast and Tyk2i (BMS-986165) treatment in LPS-stimulated PBMCs

The results in FIG. 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 reduced the level of TNF-α. Statistical analysis using ANOVA and Turkish multiple comparisons was performed to compare each treatment with BMS-986165 alone. ****p < 0.001

Example 10

IFN-γ production by apremilast and Tyk2i (BMS-986165) treatment in LPS-stimulated PBMCs

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 has a synergistic effect in reducing IFN-γ levels and significantly reduces IFN-γ levels compared to single compound treatment. Statistical analysis using ANOVA and Turkish multiple comparisons was performed to compare each treatment with BMS-986165 alone. ****p<0.001.

Example 11

MCP-1 production by apremilast and Tyk2i (BMS-986165) treatment in LPS-stimulated PBMCs

The results in FIG. 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 Turkish multiple comparisons was performed to compare each treatment with BMS-986165 alone. ****p<0.001.

data summary

Table 5 below provides a summary of the cytokine effects of apremilast and BMS-986165 on stimulated whole blood in an ex vivo TrueCulture® assay. Synergistic effects are bolded and complementary effects are underlined.

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

Table 5

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

PBMCs from 9 healthy donors were tested in LPS stimulated conditions in the presence or absence of 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 unchanged or decreased compared to the DMSO control. These results indicate that apremilast can inhibit the induction of these cytokines by BMS-986165. Both apremilast and BMS-986165 decreased IFN-γ and MCP-1 production, and the combination further reduced these two cytokines with a synergistic effect. BMS-986165 inhibits Th17 lineage cytokines, which provides a means for treating diseases in which Th17 cytokines are involved in pathogenesis. However, induction of some pro-inflammatory cytokines such as IL-23, IL-12 and TNF-α by BMS-986165 may be disadvantageous in disease treatment. The combined effect of apremilast and BMS-986165 in reducing IL-23, IL-12 and TNF-α was achieved by combining these two compounds in the treatment of inflammatory diseases such as psoriasis, psoriatic arthritis and ulcerative colitis. showed the benefits of doing

Table 6

Example 12

Apremilast and Tyk2i (BMS-986165) Fixed Dose Combination in Whole Blood

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

As shown in Figures 18-21, the 6 mg QD dose concentration of BMS-986165 did not maximally inhibit IL-17A, IL-17F or IL-22, but elevated TNF-alpha. See Figures 18-21. However, the addition of apremilast at dose concentrations of 10-30 mg BID compensated for this and prevented TNF-alpha elevation. See Figures 18-21. Even low concentrations of apremilast have been shown to be effective. For example, a 20 mg BID dose of apremilast compensated suboptimal inhibition of IL-17F, a 10 mg BID dose of apremilast compensated suboptimal inhibition of IL-22, and increase was prevented. These data indicate that inflammatory diseases induced by these cytokines by inhibiting IL-17 and IL-22 and reducing TNF-alpha production, such as psoriasis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, Crohn's disease, psoriasis and the synergistic use of BMS-986165 (eg 6 mg QD) and apremilast (eg 10-20 mg QD or BID) to treat Behcet's disease.

Claims (70)

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

here
R ¹ _{is C 1-3} alkyl optionally substituted with 0-7 R ^{1a ;}
R ^1a at each occurrence is independently hydrogen, deuterium, F, Cl, Br, CF ₃ or CN;
R ² is C _1-6 alkyl or —(CH ₂ ) _r- 3-14 membered carbocycle, each group substituted ^{with 0-4 R 2a ;}
R ^2a at each occurrence 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 0-3 R ^a , C _1-6 haloalkyl , substituted with 0-3 R ^a of the C _2-6 alkenyl group substituted by, 0 to 3 of the R ^a C _2-6 alkynyl, 0-1 of R ^a is substituted by - (CH _{2) r} -3 -14 membered carbocycle, or -(CH ₂ ) _r -5- containing carbon atoms or 1-4 heteroatoms selected from N, O, and S(O) _p ^{and substituted with 0-2 R a} 7 membered heterocycle;
R ³ is C _3-10 cycloalkyl, C _6-10 aryl, or 5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group having 0-4 R ^3a is substituted;
R ^3a at each occurrence 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 _{, C 1-6} alkyl substituted with 0-3 R ^{a ,} substituted with 0-3 R ^a of the C _2-6 alkenyl, 0-3 R ^a of the C _2-6 alkynyl, C _1-6 haloalkyl, 0-3 of R ^a substituted by a substituted - ( CH ₂ ) _r -3-14 membered carbocycle, or -(CH containing carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) _p ^{, substituted with 0-3 R a .} ₂ ) _{r is a} -5-10 membered heterocycle;
or two R ^3a are taken together with the atoms to which they are attached to form a fused ring, wherein said ring is phenyl and 5- containing carbon atoms and 1-4 heteroatoms selected from N, S or O 7 membered heterocycle, wherein said fused ring is further substituted by ^{R a1 ;}
R ⁴ and R ⁵ are independently hydrogen, _{C 1-4} alkyl substituted with ^{0-1 R f} , (CH ₂ ) _r -phenyl substituted with 0-3 R ^d , or a carbon atom and N, O, _{and -(CH 2} )-5-7 membered heterocycle comprising 1-4 heteroatoms selected from S(O) _{p ;}
R ¹¹ at each occurrence is independently hydrogen, _{C 1-4} alkyl substituted with ^{0-3 R f} , CF _{3 , C 3-10} cycloalkyl substituted with 0-1 R ^f , 0-3 R ^d (CH) _r -phenyl substituted with or -(CH ₂ ) _r containing carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) _p ^{and substituted with 0-3 R d} -5-7 membered heterocycle;
R ^a and R ^a1 at each occurrence are independently hydrogen, F, Cl, Br, OCF ₃ , CF ₃ , CHF ₂ , CN, NO ₂ , -(CH ₂ ) _r OR ^b , -(CH ₂ ) _r SR ^b , -(CH ₂ ) _r C(O)R ^b , -(CH ₂ ) _r C(O)OR ^b , -(CH ₂ ) _r OC(O)R ^b , -(CH ₂ ) _r NR ¹¹ R ¹¹ , -(CH ₂ ) _r C(O)NR ¹¹ R ¹¹ , -(CH ₂ ) _r NR ^b C(O)R ^c , -(CH ₂ ) _r NR ^b C(O)OR ^c , -NR ^b C (O)NR ¹¹ R ¹¹ , -S(O) _p NR ¹¹ R ¹¹ , -NR ^b S(O) _p R ^c , -S(O)R ^c , -S(O) ₂ R ^c , 0-3 the C _1-6 alkyl substituted with one R ^f, C _1-6 haloalkyl, 0-3 of the R ^a C _2-6 alkenyl group substituted by, 0 to 3 of the R ^a C _2-6 alkynyl substituted with , -(CH ₂ ) _r -3-14 membered carbocycle, or containing carbon atoms and 1-4 heteroatoms selected from _{N, O, and S(O) p} and substituted with ^{0-3 R f} -(CH ₂ ) _{r is a} -5-7 membered heterocycle;
R ^b at each occurrence is independently hydrogen, _{C 1-6} alkyl substituted with ^{0-3 R d} , C _1-6 haloalkyl, _{C 3-6} cycloalkyl substituted with ^{0-2 R d} , or carbon —(CH ₂ ) _r- 5-7 membered heterocycle containing atoms and 1-4 heteroatoms selected from N, O, and S(O) _p ^{and substituted with 0-3 R f , or 0-3} (CH ₂ ) _r -phenyl substituted with R ^{d ;}
R ^c is substituted with 0-3 R ^f of the C _1-6 alkyl, 0-3 of the R ^f (CH _{2) r} -C _3-6 cycloalkyl, 0-3 of R ^f is substituted by substituted with ( CH ₂ ) is _r -phenyl; or
R ^d at each occurrence is independently hydrogen, F, Cl, Br, OCF ₃ , CF ₃ , CN, NO ₂ , -OR ^e , -(CH ₂ ) _r C(O)R ^c , -NR ^e R ^e , —NR ^e C(O)OR ^c , C _1-6 alkyl, or (CH ₂ ) _r -phenyl ^{substituted with 0-3 R f ;}
R ^e at each occurrence is independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, and (CH ₂ ) _r -phenyl ^{substituted with 0-3 R f ;}
R ^f is independently at each occurrence 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 S(O ) _{-(CH 2} ) _r -5-7 membered heteroaryl comprising 1-4 heteroatoms selected from _p;
p is 0, 1, or 2;
r is 0, 1, 2, 3, or 4. The method of claim 1 , wherein the Tyk2 inhibitor is of the formula: or a pharmaceutically acceptable salt thereof:

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

here
Y is N or CR ⁶ ;
R ¹ is H, C _1-3 alkyl or C _3-6 cycloalkyl, each optionally substituted by ^{0-7 R 1a ;}
R ^1a at each occurrence is independently hydrogen, deuterium, F, Cl, Br or CN;
R ² is C _1-6 alkyl, —(CH ₂ ) _r- ^{3-14 membered carbocycle substituted with 0-1 R 2a} , or contains 1-4 heteroatoms selected from N, O, and S is a 5-14 membered heterocycle, each group ^{being substituted with 0-4 R 2a} (for clarity, R ² is intended to include a substituted methyl group, such as —C(O)R ^{2a );}
R ^2a at each occurrence 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 0-3 R ^a , C _1-6 haloalkyl, 0 _{C 2-6} alkenyl substituted with -3 R ^a _{, C 2-6} alkynyl substituted with 0-3 R ^a , —(CH ₂ ) _r -3-14 substituted with 0-1 R ^{a .} membered carbocycle, or —(CH ₂ ) _r- 5-7 membered containing carbon atoms or 1-4 heteroatoms selected from N, O, and S(O) _p ^{and substituted with 0-2 R a .} heterocycle;
R ³ is C _3-10 cycloalkyl, C _6-10 aryl, or 5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group having 0-4 R ^3a is substituted;
R ^3a at each occurrence 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 _{, C 1-6} alkyl substituted with 0-3 R ^{a ,} substituted with 0-3 R ^a of the C _2-6 alkenyl, 0-3 R ^a of the C _2-6 alkynyl, C _1-6 haloalkyl, 0-3 of R ^a substituted by a substituted - ( CH ₂ ) _r -3-14 membered carbocycle, or -(CH containing carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) _p ^{, substituted with 0-3 R a .} ₂ ) _{r is a} -5-10 membered heterocycle;
or two R ^3a are taken together with the atoms to which they are attached to form a fused ring, wherein the ring is phenyl and a carbon atom and 1-4 heteroatoms selected from _{N, O, and S(O) p} wherein each fused ring is substituted with ^{0-3 R a1 ;}
R ⁴ and R ⁵ are independently hydrogen, _{C 1-4} alkyl substituted with ^{0-1 R f} , (CH ₂ ) _r -phenyl substituted with 0-3 R ^d , or a carbon atom and N, O, _{and -(CH 2} )-5-7 membered heterocycle comprising 1-4 heteroatoms selected from 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;
R ¹¹ at each occurrence is independently hydrogen, _{C 1-4} alkyl substituted with ^{0-3 R f} , CF _{3 , C 3-10} cycloalkyl substituted with 0-1 R ^f , 0-3 R ^d (CH) _r -phenyl substituted with or -(CH ₂ ) _r containing carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) _p ^{and substituted with 0-3 R d} -5-7 membered heterocycle;
R ^a and R ^a1 at each occurrence are independently hydrogen, F, Cl, Br, OCF ₃ , CF ₃ , CHF ₂ , CN, NO ₂ , -(CH ₂ ) _r OR ^b , -(CH ₂ ) _r SR ^b , -(CH ₂ ) _r C(O)R ^b , -(CH ₂ ) _r C(O)OR ^b , -(CH ₂ ) _r OC(O)R ^b , -(CH ₂ ) _r NR ¹¹ R ¹¹ , -(CH ₂ ) _r C(O)NR ¹¹ R ¹¹ , -(CH ₂ ) _r NR ^b C(O)R ^c , -(CH ₂ ) _r NR ^b C(O)OR ^c , -NR ^b C (O)NR ¹¹ R ¹¹ , -S(O) _p NR"R", -NR ^b S(O) _p R ^c , -S(O)R ^c , -S(O) ₂ R ^c , 0-3 the C _1-6 alkyl substituted with one R ^f, C _1-6 haloalkyl, 0-3 of the R ^a C _2-6 alkenyl group substituted by, 0 to 3 of the R ^a C _2-6 alkynyl substituted with , -(CH ₂ ) _r -3-14 membered carbocycle, or containing carbon atoms and 1-4 heteroatoms selected from _{N, O, and S(O) p} and substituted with ^{0-3 R f} -(CH ₂ ) _{r is a} -5-7 membered heterocycle;
R ^b is hydrogen, _{C 1-6} alkyl substituted with ^{0-3 R d} , C _1-6 haloalkyl, _{C 3-6} cycloalkyl substituted with ^{0-2 R d} , or carbon atoms and N, O -(CH ₂ ) _r -5-7 membered heterocycle comprising 1-4 heteroatoms selected from , and S(O) _p ^{and substituted with 0-3 R f} , or substituted with ^{0-3 R d .} (CH ₂ ) _r -phenyl;
R ^c is substituted with 0-3 R ^f of the C _1-6 alkyl, 0-3 of the R ^f (CH _{2) r} -C _3-6 cycloalkyl, or 0-3 of R ^f is substituted by a substituted (CH ₂ ) _r -phenyl;
R ^d at each occurrence is independently hydrogen, F, Cl, Br, OCF ₃ , CF ₃ , CN, NO ₂ , -OR ^e , -(CH ₂ ) _r C(O)R ^c , -NR ^e R ^e , —NR ^e C(O)OR ^c , C _1-6 alkyl, or (CH ₂ ) _r -phenyl ^{substituted with 0-3 R f ;}
R ^e at each occurrence is independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl and (CH ₂ ) _r -phenyl ^{substituted with 0-3 R f ;}
R ^f is independently at each occurrence 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 S(O ) _{-(CH 2} ) _r -5-7 membered heterocycle comprising 1-4 heteroatoms selected from _p;
p is 0, 1, or 2;
r is 0, 1, 2, 3, or 4. 5. The method of claim 1 or 4, wherein the Tyk2 inhibitor is of the formula: or a pharmaceutically acceptable salt thereof:

. 6. The method of any one of claims 1-5, wherein the effective amount of the Tyk2 inhibitor or pharmaceutically acceptable salt ranges from about 0.1 mg/day to about 250 mg/day. 7. The method of any one of claims 1-6, wherein the effective amount of the Tyk2 inhibitor or pharmaceutically acceptable salt is from about 0.2 mg/day to about 100 mg/day, from about 0.5 mg/day to about 50 mg/day, and about 1.0 mg to about 24 mg/day. 8. The method of any one of claims 1-7, wherein the effective amount of the Tyk2 inhibitor or pharmaceutically acceptable salt is about 1 mg/day to about 15 mg/day, about 1 mg/day to about 14 mg/day, about 2 mg/day to about 14 mg/day, about 2 mg/day to about 12 mg/day, or about 3 mg/day to about 12 mg/day. 9. The method of any one of claims 1 to 8, wherein the effective amount of the Tyk2 inhibitor is about 2 mg/day, about 3 mg/day, about 4 mg/day, about 5 mg/day, about 6 mg/day, about 7 mg/day, about 8 mg/day, about 9 mg/day, about 10 mg/day, about 11 mg/day, or about 12 mg/day. 10. The method of any one of claims 1-9, wherein the effective amount of the Tyk2 inhibitor is about 6 mg/day. 11. The method of any one of claims 1 to 10, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2 wherein the ,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is greater than 95% stereomerically pure. 12. The method according to any one of claims 1 to 11, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2 wherein the ,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is greater than 99% stereomerically pure. 13. The method of any one of claims 1 to 12, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2 wherein the ,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is greater than 99.5% stereomerically pure. 14. The method of any one of claims 1 to 13, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2 wherein the ,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is greater than 99.9% stereomerically pure. 15. The method of any one of claims 1 to 14, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2 wherein the ,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is in a single crystalline form. 16. The method of any one of claims 1 to 15, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2 ,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is characterized by an X-ray powder diffraction peak at a 2θ angle selected from 10.1°, 13.5°, 20.7° and 26.9° single crystalline form B. 17. The method of any one of claims 1 to 16, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2 ,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide at a 2θ angle selected from 10.1°, 13.5°, 15.7°, 18.1°, 20.7°, 24.7° and 26.9° A method of single crystalline Form B characterized by an X-ray powder diffraction peak of 18. The method of any one of claims 1 to 17, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2 ,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is 10.1°, 13.5°, 15.7°, 16.3°, 18.1°, 20.7°, 22.5°, 24.7°, 26.2 A method which is a single crystalline Form B characterized by an X-ray powder diffraction peak at a 2θ angle selected from °, 26.9 ° and 29.1 °. 19. The method of any one of claims 1 to 18, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2 wherein the ,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is at least 90% single crystalline Form B. 20. The method of any one of claims 1 to 19, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2 wherein the ,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is at least 95% single crystalline Form B. 21. The method of any one of claims 1-20, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2 wherein the ,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is at least 99% single crystalline Form B. 21. The method of any one of claims 1-20, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2 An effective amount of ,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof is from about 0.5 mg to about 1000 mg/day, from about 1 mg to about 1000 mg per day, about 5 mg to about 500 mg/day, about 10 mg to about 200 mg/day, about 10 mg to about 100 mg/day, about 40 mg to about 100 mg/day, about 20 mg to about 40 mg per day, from about 0.1 mg to about 10 mg/day, from about 0.5 mg to about 5 mg/day, from about 1 mg to about 20 mg/day, and from about 1 mg to about 10 mg/day, from about 1 mg to about 100 mg/day, from about 1 mg to about 80 mg/day, from about 5 mg to about 70 mg/day and from about 10 mg to about 60 mg/day. 23. The method of any one of claims 1-22, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2 wherein the effective amount of ,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof ranges from about 10 mg to about 60 mg/day. 24. The method of any one of claims 1-23, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2 wherein the effective amount of ,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof ranges from about 10 mg to about 40 mg/day. 25. The method of any one of claims 1-24, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2 A method wherein the effective amount of ,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof is about 10 mg administered once or twice a day. 25. The method of any one of claims 1-24, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2 A method wherein the effective amount of ,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof is about 20 mg administered once or twice a day. 24. The method of any one of claims 1-23, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2 An effective amount of ,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof is about 10 mg/day, about 15 mg/day, about 20 mg/day , about 25 mg/day, about 30 mg/day, about 35 mg/day, about 40 mg/day, about 45 mg/day, about 50 mg/day, about 55 mg/day, or about 60 mg/day. 28. The method of any one of claims 1-23 and 27, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) wherein the effective amount of ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof is about 30 mg/day or about 60 mg/day. 29. The method of any one of claims 1-23, 27 and 28, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-( wherein the effective amount of methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is about 30 mg administered once daily. 29. The method of any one of claims 1-23, 27 and 28, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-( wherein the effective amount of methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is about 30 mg administered twice daily. 29. The method of any one of claims 1-23, 27 and 28, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-( Methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide was titrated with the following titration schedule:
Day 1: About 10 mg in the morning;
Day 2: about 10 mg in the morning and about 10 mg in the evening;
Day 3: About 10 mg in the morning and 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: About 30 mg twice daily
The method is titrated to a dosage of about 30 mg administered twice a day using 23. The method of any one of claims 1-22, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2 wherein the effective amount of ,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof ranges from about 40 mg to about 100 mg/day. 33. The method of any one of claims 1-22 or 32, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) Ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide was titrated with the following titration schedule:
Day 1: About 10 mg in the morning;
Day 2: about 10 mg in the morning and about 10 mg in the evening;
Day 3: About 10 mg in the morning and 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: About 40 mg/day to about 100 mg/day
is titrated at a dose of about 40 mg/day to about 100 mg/day using 23. The method of any one of claims 1-22, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2 A method wherein the effective amount of ,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide, or a pharmaceutically acceptable salt thereof, is about 20 mg administered twice daily. 35. The method of any one of claims 1-22 or 34, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) Ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide was titrated with the following titration schedule:
Day 1: About 10 mg in the morning;
Day 2: about 10 mg in the morning and about 10 mg in the evening;
Day 3: About 10 mg in the morning and 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: About 20 mg twice daily
The method of claim 1, wherein the titration is performed at a dose of about 20 mg administered twice a day using 23. The method of any one of claims 1-22, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2 wherein the effective amount of ,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof ranges from about 4 mg to about 10 mg/day. 37. The method of any one of claims 1-22 or 36, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) Ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide was titrated with the following titration schedule:
Day 1: About 1 mg in the morning;
Day 2: about 1 mg in the morning and about 1 mg in the evening;
Day 3: About 1 mg in the morning and about 2 mg in the evening;
Day 4: about 2 mg in the morning and about 2 mg in the evening;
Day 5: about 2 mg in the morning and about 3 mg in the evening; and
Day 6: About 4 mg/day to about 10 mg/day
is titrated at a dosage of about 4 mg/day to about 10 mg/day using 23. The method of any one of claims 1-22, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2 wherein the effective amount of ,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof is about 3 mg/day. 39. The method of any one of claims 1-22 or 38, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) Ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide was titrated with the following titration schedule:
Day 1: About 1 mg in the morning;
Day 2: about 1 mg in the morning and about 1 mg in the evening;
Day 3: About 10 mg in the morning and about 2 mg in the evening;
Day 4: about 2 mg in the morning and about 2 mg in the evening;
Day 5: about 2 mg in the morning and about 3 mg in the evening; and
Day 6: About 3 mg twice daily
The method is titrated to a dose of 3 mg administered twice a day using 40. The method of any one of claims 1-39, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2 wherein the ,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is formulated as part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier. 41. The method of any one of claims 1-40, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2 wherein the ,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is administered parenterally, transdermally, mucosally, nasally, bucally, sublingually or orally. . 42. The method of any one of claims 1-41, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2 ,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is administered orally. 43. The method of any one of claims 1-42, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2 The method wherein the ,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is administered orally in the form of a tablet or capsule. 44. The method of any one of claims 40 to 43, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2 wherein the ,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is formulated as an extended release form. 44. The method of any one of claims 40 to 43, wherein N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2 wherein the ,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide is formulated as an immediate release form. 46. The method of any one of claims 1-45, wherein the disease or disorder is selected from viral, genetic, inflammatory, allergic and autoimmune diseases. 47. The method of any one of claims 1-46, wherein the disease or disorder is chronic obstructive pulmonary disease, asthma, chronic pulmonary inflammatory disease, hyperoxic alveolar injury, 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, erythema nodosum leprosy, Sjoegren's syndrome, inflammatory bowel disease, Crohn's Disease, Behcet's Disease and ulcerative colitis. 48. The method of any one of claims 1-47, wherein the disease or disorder is selected from psoriasis, psoriatic arthritis, contact dermatitis, systemic lupus erythematosus, cutaneous lupus erythematosus and ulcerative colitis. 49. The method of any one of claims 1-48, wherein the disease or disorder is psoriasis. 50. The method of any one of claims 1-49, wherein the disease or disorder is plaque psoriasis. 51. The method of any one of claims 1-50, wherein the disease or disorder is moderate to severe plaque psoriasis. 52. The method of any one of claims 49-51, wherein the subject is a candidate for phototherapy or systemic therapy. 49. The method of any one of claims 1-48, wherein the disease or disorder is psoriatic arthritis. 22. A therapeutically effective amount of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) as defined in any one of claims 11 to 21 . )ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a Tyk2 inhibitor as defined in any one of claims 2-5. 55. The pharmaceutical composition of claim 54, wherein the Tyk2 inhibitor is of the formula: or a pharmaceutically acceptable salt thereof:

. 56. The method of claim 54 or 55, wherein about 1 mg/day to about 15 mg/day, about 1 mg/day to about 14 mg/day, about 2 mg/day to about 14 mg/day, about 2 mg/day A pharmaceutical composition formulated for administration of a Tyk inhibitor from about 12 mg/day to about 12 mg/day, or from about 3 mg/day to about 12 mg/day. 57. The method of any one of claims 54 to 56, wherein about 2 mg/day, about 3 mg/day, about 4 mg/day, about 5 mg/day, about 6 mg/day, about 7 mg/day, A pharmaceutical composition formulated for administration of about 8 mg/day, about 9 mg/day, about 10 mg/day, about 11 mg/day, or about 12 mg/day of a Tyk inhibitor. 58. The pharmaceutical composition of any one of claims 54-57, formulated for administration of about 6 mg/day of a Tyk inhibitor. 59. The method of any one of claims 54 to 58, wherein about 1 mg to about 1000 mg/day, about 5 mg to about 500 mg/day, about 10 mg to about 200 mg/day, about 10 mg to about 100 mg/day, about 40 mg to about 100 mg/day, about 20 mg to about 40 mg/day, about 0.1 mg to about 10 mg/day, about 0.5 mg to about 5 mg/day, about 1 mg to about 20 mg/day, and about 1 mg to about 10 mg/day, about 1 mg to about 100 mg/day, about 1 mg to about 80 mg/day, about 5 mg to about 70 mg/day, and about 10 mg to about 60 mg/day of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3 A pharmaceutical composition formulated for administration of -dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof. 60. The method of any one of claims 54 to 59, wherein from about 10 mg to about 60 mg/day of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2 A pharmaceutical composition formulated for administration of -(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof. 61. The method of any one of claims 54 to 60, wherein about 10 mg/day, about 15 mg/day, about 20 mg/day, about 25 mg/day, about 30 mg/day, about 35 mg/day, about 40 mg/day, about 45 mg/day, about 50 mg/day, about 55 mg/day, or about 60 mg/day of N-[2-[(1S)-1-(3-ethoxy-4) -Methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof A pharmaceutical composition formulated for 62. The method of any one of claims 54-61, wherein about 30 mg/day or about 60 mg/day of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl) A pharmaceutical composition formulated for administration of -2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof. . 63. The method of any one of claims 54 to 62, wherein about 30 mg N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-( A pharmaceutical composition formulated for administration of methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof. 62. The method of any one of claims 54-61, wherein about 30 mg of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-( A pharmaceutical composition formulated for administration of methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof. 61. The method of any one of claims 54 to 60, wherein from about 10 mg to about 40 mg/day of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2 A pharmaceutical composition formulated for administration of -(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof. 66. The method of any one of claims 54 to 60 and 65, wherein about 10 mg of N-[2-[(1S)-1-(3-ethoxy-4-me Formulated for administration of toxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof pharmaceutical composition. 66. The method of any one of claims 54 to 60 and 65, wherein about 20 mg of N-[2-[(1S)-1-(3-ethoxy-4-methyl) once or twice daily Formulated for administration of toxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or a pharmaceutically acceptable salt thereof pharmaceutical composition. 68. The pharmaceutical composition according to any one of claims 54 to 67, in the form of a tablet or capsule. 69. The pharmaceutical composition of any one of claims 54-68, formulated for extended release. 69. The pharmaceutical composition of any one of claims 54-68, formulated for immediate release.

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