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WO2020223431A1 - Combination therapies comprising apremilast and tyk2 inhibitors - Google Patents

Combination therapies comprising apremilast and tyk2 inhibitors Download PDF

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Publication number
WO2020223431A1
WO2020223431A1 PCT/US2020/030608 US2020030608W WO2020223431A1 WO 2020223431 A1 WO2020223431 A1 WO 2020223431A1 US 2020030608 W US2020030608 W US 2020030608W WO 2020223431 A1 WO2020223431 A1 WO 2020223431A1
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WO
WIPO (PCT)
Prior art keywords
day
substituted
per day
dioxo
methylsulfonyl
Prior art date
Application number
PCT/US2020/030608
Other languages
French (fr)
Inventor
Peter Henry SCHAFER
Robert PLENGE
Mary Adams
Lisa BEEBE
Gilles BUCHWALTER
Tiffany CARR
Te-Chen TZENG
Original Assignee
Celgene Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to CN202080046457.XA priority Critical patent/CN114206333A/en
Priority to SG11202112018YA priority patent/SG11202112018YA/en
Priority to CN202411627841.5A priority patent/CN119454692A/en
Priority to KR1020217038512A priority patent/KR20220002489A/en
Priority to AU2020266143A priority patent/AU2020266143A1/en
Priority to JP2021564471A priority patent/JP7453251B2/en
Priority to MX2021013318A priority patent/MX2021013318A/en
Priority to CA3138686A priority patent/CA3138686A1/en
Priority to BR112021021826A priority patent/BR112021021826A8/en
Priority to EP20725978.9A priority patent/EP3962476A1/en
Application filed by Celgene Corporation filed Critical Celgene Corporation
Publication of WO2020223431A1 publication Critical patent/WO2020223431A1/en
Priority to IL287670A priority patent/IL287670A/en
Priority to CONC2021/0015622A priority patent/CO2021015622A2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • BMS-986165 elicit complementary effects against certain pro-inflammatory cytokines.
  • BMS-986165 for example, increased TNF-a and GM-CSF cytokine in whole blood assay, while apremilast inhibited the production of these cytokines. See e.g., Table 5 where the % control for 1 mM apremilast was 10.7 and the % control for 0.01 mM BMS-986165 was 143.1 against TNF-oc.
  • apremilast corrected the deficiency of BMS- 986165 thereby producing a complementary effect of 13.5% inhibition against TNF-oc.
  • BMS-986165 In addition to whole blood assay, the combination of BMS-986165 and apremilast elicit complementary effects against certain pro-inflammatory cytokines in LPS stimulated PBMCs as well. BMS-986165 increased IL-23, IL-12 and TNF-oc, while apremilast inhibited the production of these cytokines. See e.g., Table 6 in the Exemplification section. These results further support the advantage of combining BMS-986165 and apremilast in treatment of Thl7 related diseases.
  • diseases or disorders responsive to the inhibition of PDE4 in a subject using an effective amount of apremilast, or a pharmaceutically acceptable salt thereof, and an effective amount of a Tyk2 inhibitor such as BMS-986165.
  • diseases and disorders include e.g., inflammatory diseases such as psoriasis, psoriatic arthritis, and ulcerative colitis.
  • 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.
  • FIG. 1 illustrates interleukin- 17a (IL-17a) cytokine production (percent of control) by apremilast and BMS-986165 in anti-CD3/anti-CD28 (ThO) or anti-CD3/anti-CD28, IL-Ib, IL-6 and IL-23 (Thl7) stimulated whole blood - TruCulture® tube assay.
  • IL-17a interleukin- 17a
  • ThO anti-CD3/anti-CD28
  • Thl-7 anti-CD3/anti-CD28
  • IL-6 and IL-23 Thl-7
  • IL-17A interleukin- 17 A
  • ThO anti-CD3/anti-CD28
  • Thl7 anti-CD3/anti-CD28
  • Thl7 stimulated whole blood - TruCulture® tube assay.
  • FIG. 3 illustrates interleukin- 17F (IL-17F) cytokine production (percent of control) by apremilast and BMS-986165 in anti-CD3/anti-CD28 (ThO) or anti-CD3/anti-CD28, IL-Ib, IL-6 and IL-23 (Thl7) stimulated whole blood - TruCulture® tube assay.
  • IL-17F interleukin- 17F
  • FIG. 4 illustrates interleukin- 17F (IL-17F) cytokine production by apremilast and BMS-986165 in anti-CD3/anti-CD28 (ThO) or anti-CD3/anti-CD28, IL-Ib, IL-6 and IL-23 (Thl7) stimulated whole blood - TruCulture® tube assay.
  • IL-17F interleukin- 17F
  • FIG. 5 illustrates interleukin- 22 (IL-22) cytokine production (percent of control) by apremilast and BMS-986165 in anti-CD3/anti-CD28 (ThO) or anti-CD3/anti-CD28, IL-Ib, IL-6 and IL-23 (Thl7) stimulated whole blood - TruCulture® tube assay.
  • FIG. 6 illustrates interleukin- 22 (IL-22) cytokine production by apremilast and BMS-986165 in anti-CD3/anti-CD28 (ThO) or anti-CD3/anti-CD28, IL-Ib, IL-6 and IL-23 (Thl7) stimulated whole blood - TruCulture® tube assay.
  • IL-22 interleukin- 22
  • FIG. 7 illustrates tumor necrosis factor alpha (TNF-a) cytokine production (percent of control) by apremilast and BMS-986165 in anti-CD3/anti-CD28 (ThO) or anti-CD3/anti- CD28, IL-Ib, IL-6 and IL-23 (Thl7) stimulated whole blood - TruCulture® tube assay.
  • TNF-a tumor necrosis factor alpha
  • FIG. 8 illustrates tumor necrosis factor alpha (TNF-a) cytokine production by apremilast and BMS-986165 in anti-CD3/anti-CD28 (ThO) or anti-CD3/anti-CD28, IL-Ib, IL-6 and IL-23 (Thl7) stimulated whole blood - TruCulture® tube assay.
  • TNF-a tumor necrosis factor alpha
  • FIG. 9 illustrates granulocyte-macrophage colony- stimulating factor (GM-CSF) cytokine production (percent of control) by apremilast and BMS-986165 in anti-CD3/anti- CD28 (ThO) or anti-CD3/anti-CD28, IL-Ib, IL-6 and IL-23 (Thl7) stimulated whole blood - TruCulture® tube assay.
  • GM-CSF granulocyte-macrophage colony- stimulating factor
  • FIG. 10 illustrates granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine production by apremilast and BMS-986165 in anti-CD3/anti-CD28 (ThO) or anti- CD3/anti-CD28, IL-Ib, IL-6 and IL-23 (Thl7) stimulated whole blood - TruCulture® tube assay.
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • FIG. 11 illustrates interleukin-23 (IL-23) cytokine production by apremilast in Lipopolysaccharide (IPS) stimulated peripheral blood mononuclear cells (PBMCs).
  • IPS Lipopolysaccharide
  • PBMCs peripheral blood mononuclear cells
  • FIG. 12 illustrates interleukin-23 (IL-23) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs.
  • FIG. 13 illustrates interleukin- 12p40 (IL-12p40) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs.
  • FIG. 14 illustrates interleukin- 12p70 (IL-12p70) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs.
  • IL-12p70 interleukin- 12p70
  • Tyk2i BMS-986165
  • FIG. 15 illustrates tumor necrosis factor alpha (TNF-a) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs.
  • TNF-a tumor necrosis factor alpha
  • FIG. 16 illustrates interferon gamma (IFN-g) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs.
  • IFN-g interferon gamma
  • FIG. 17 illustrates monocyte chemoattractant protein- 1 (MCP-1) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs.
  • FIG. 18 illustrates fixed dose combination effects of apremilast and Tyk2i (BMS- 986165) in IL-17A whole blood.
  • FIG. 19 illustrates fixed dose combination effects of apremilast and Tyk2i (BMS- 986165) in IL-17F whole blood.
  • FIG. 20 illustrates fixed dose combination effects of apremilast and Tyk2i (BMS- 986165) in IL-22 whole blood.
  • FIG. 21 illustrates fixed dose combination effects of apremilast and Tyk2i (BMS- 986165) in TNF-a whole blood.
  • a disease or disorder responsive to the inhibition of cyclic nucleotide phosphodiesterase isoenzyme IV comprising administering to a subject an effective amount of N-[2-[(lS)-l-(3-ethoxy- 4-metho xyphenyl)-2-(methylsulfonyl)ethyl]-2, 3-dihydro- 1,3-dioxo- lH-isoindo 1-4- yl] acetamide (apremilast), or a pharmaceutically acceptable salt thereof, and an effective amount of a Tyk2 inhibitor.
  • PDE4 cyclic nucleotide phosphodiesterase isoenzyme IV
  • PDE4 phosphodiesterase isoenzyme IV
  • PDE4 cyclic nucleotide phosphodiesterase isoenzyme IV
  • Apremilast has a chiral center designated as (S) in the chemical structure and name.
  • this designation means that apremilast is optically enriched as the (S) enantiomer at this position in an amount of at least 80%, 90%, 95%, 98%, 99%, or 99.9% relative to the corresponding (R) enantiomer.
  • apremilast is referred to herein as being stereomerically or enantiomerically pure at a specified amount, it means that the (S) enantiomer is enriched in that amount.
  • N-[2-[(lS)-l-(3-ethoxy-4- methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide that is at least 95% stereomerically pure means that the compound contains greater than or equal to 95% of the (S) enantiomer and 5% or less of the (R) enantiomer.
  • apremilast and a disclosed Tyk2 inhibitor are administered together.
  • apremilast and a disclosed Tyk2 inhibitor are administered at different times on the same day.
  • apremilast and a disclosed Tyk2 inhibitor are administered at different times as separate tablets or capsules.
  • apremilast and a disclosed Tyk2 inhibitor are administered in a fixed dose combination in the same tablet or capsule.
  • the term“subject” means an animal, such as a mammal, and such as a human.
  • the terms“subject” and“patient” may be used interchangeably.
  • 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 of a subject e.g., a dosage of between 0.001 - 100 mg/kg body weight/day.
  • 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.
  • compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, magnesium stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances (e.g., microcrystalline cellulose, hydroxypropyl methylcellulose, lactose monohydrate, sodium lauryl sulfate, and crosscarmellose sodium), polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,
  • Suitable pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases.
  • Suitable pharmaceutically acceptable base addition salts for the compounds described herein include, but are not limited to include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylene diamine, meglumine (N-methylglucamine) and procaine.
  • Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methane sulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid.
  • inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulf
  • Crystall refers to a solid form of a compound wherein there exists long-range atomic order in the positions of the atoms. The crystalline nature of a solid can be confirmed, for example, by examination of the X-ray powder diffraction pattern.
  • A“single crystalline form” means that the recited compound, i.e., N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide, is present as a single crystal or a plurality of crystals in which each crystal has the same crystal form (e.g., crystalline Form B).
  • the crystal form is defined as a specified percentage of one particular single crystalline form of the compound, the remainder is made up of amorphous form and/or crystalline forms other than the one or more particular forms that are specified.
  • a disclosed crystalline form is at least 80% a single crystalline form, at least 90% a single crystalline form, at least 95% a single crystalline form, or at least 99% a single crystalline form by weight. Percent by weight of a particular crystal form is determined by the weight of the particular crystal form divided by the sum weight of the particular crystal, plus the weight of the other crystal forms present plus the weight of amorphous form present multiplied by 100%.
  • amorphous refers to a solid that is present in a non-crystalline state or form.
  • Amorphous solids are disordered arrangements of molecules and therefore possess no distinguishable crystal lattice or unit cell and consequently have no definable long range ordering.
  • Solid state ordering of solids may be determined by standard techniques known in the art, e.g., by X-ray powder diffraction (XRPD) or differential scanning calorimetry (DSC).
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • Amorphous solids can also be differentiated from crystalline solids e.g., by birefringence using polarized light microscopy.
  • the 2-theta values of the X-ray powder diffraction patterns for the crystalline forms described herein may vary slightly from one instrument to another and also depending on variations in sample preparation and batch to batch variation due to factors such as
  • Tyk2 inhibitors used in the disclosed methods and compositions include compounds which block the action of tyrosine kinase 2, a non-receptor tyrosine-protein kinase encoded by the Tyk2 gene.
  • the disclosed Tyk2 inhibitors include, but are not limited to, those described in Xingrui He et al., Expert Opinion on Therapeutics Patents 2019, Vol. 29, No. 2, 137-149, the entire contents of which are incorporated herein by reference.
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • Exemplary compounds having this formula as part of the third embodiment include, but are not limited to, those having the formula:
  • Tyk2 inhibitors as part of the third embodiment include those in WO 2008/139161, and WO 2010/055304, the entire contents of each of which are incorporated herein by reference.
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • Tyk2 inhibitors include those in WO 2012/062704, the entire contents of which are incorporated herein by reference.
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formulae:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • R is C 3-10 cycloalkyl, C 6-10 aryl, or a 5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-4 R 3a ;
  • R 3a together with the atoms to which they are attached, combine to form a fused ring wherein said ring is selected from phenyl and a 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, S or O said fused ring further substituted by R al ;
  • R 4 and R 5 are independently hydrogen, C 1.4 alkyl substituted with 0-1 R f , (CH 2 - phenyl substituted with 0-3 R d , or a -(CH 2 )-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(0) p ;
  • R d at each occurrence is independently hydrogen, F, Cl, Br, OCF 3 , CF 3 , CN, NO 2 , - OR e , -(CH 2 ) r C(0)R c , -NR e R e , -NR e C(0)OR c , C 1 _ 6 alkyl, or (CH 2 ) r -phenyl substituted with 0-3
  • R independently at each occurrence is hydrogen, halo, CN, N3 ⁇ 4, OH, C3-6cycloalkyl, CF3, O( C 1-6 alkyl), or a— (CH 2 ) r -5-7 membered heteroaryl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(0) p ;
  • R 5 is C 1-3 alkyl optionally substituted by 0-7 R 1 a
  • R 1a at each occurrence is independently hydrogen, deuterium, F, CI, Br, CF3 or CN;
  • R 3 is -(CH 2 ) r -3-14 membered carbocycle substituted 0-5 R 3a ;
  • R 3a or two R 3a , together with the atoms to which they are attached, combine to form a fused ring wherein said ring is selected from phenyl and a 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, S or O, 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 ,
  • 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 , (CH) r -phenyl substituted with 0-3 R d , or -(CH 2 ) r -5-7 membered heterocycle comprising carbon atoms and 1-4
  • heteroatoms selected from N, O, and S(O) p substituted with 0-3 R d ;
  • R a at each occurrence is hydrogen, F, Cl, Br, OCF 3 , CF 3 , CHF 2 , CN, NO 2 ,
  • R c is C 1-6 alkyl substituted with 0-3 R f , (CH 2 ) r- C 3 _ 6 cycloalkyl substituted with 0-3 R f or (CH 2 ) r -phenyl substituted with 0-3 R f ;
  • R d at each occurrence is independently hydrogen, F, Cl, Br, OCF3, 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,
  • R independently at each occurrence is hydrogen, halo, CN, N3 ⁇ 4, OH,
  • p 0, 1, or 2;
  • r 0, 1,2,3, or 4.
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • Y is N or CR 6 ;
  • 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 a 5-14 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-4 R 2a (for the sake of clarity, R 2 is intended to include substituted methyl groups such as -C(O)R 2a );
  • R 3a or two R 3a , together with the atoms to which they are attached, combine to form a fused ring wherein said ring is selected from phenyl and a heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p , each fused ring substituted with 0- 3 R a1 ;
  • R 4 and R 5 are independently hydrogen, C 1-4 alkyl substituted with 0-1 R f , (CH 2 ) r- phenyl substituted with 0-3 R d or a -(CH 2 )-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and 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 , (CH)r-phenyl substituted with 0-3 R d or -(CH 2 )r- 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-3 R d ;
  • 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 , -
  • 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 -(CH 2 ) r -5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-3 R f or (CH 2 ) r -phenyl substituted with 0-3 R d ;
  • R c is C1-6 alkyl substituted with 0-3 R f , (CH2)r-C3-6 cycloalkyl substituted with 0-3 R f or (CH 2 ) r -phenyl substituted with 0-3 R f ;
  • 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 f independently at each occurrence is hydrogen, halo, CN, NH 2 , OH, C 3-6 cycloalkyl, CF 3 , O(C 1-6 alkyl) or a -(CH 2 ) r -5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p ;
  • p 0, 1, or 2;
  • r is 0, 1, 2, 3, or 4, wherein additional definitions and specific compounds are as described in US 9,505,748 and WO 2018/0162889, the entire contents of each of which are incorporated herein by reference.
  • the disclosed Tyk2 inhibitors may be selected from those having the formulae:
  • the Tyk2 inhibitor described herein is 6- (cyclopropanecarboxamido)-4-((2-methoxy-3-(l-methyl-lH-l,2,4-triazol-3- yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165), having the following chemical structure:
  • the specific dosage and treatment regimen for a disclosed Tyk2 inhibitor to be used in combination with apremilast will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated.
  • the effective amount of a disclosed Tyk2 inhibitor (e.g., as in any one of the second to thirtieth embodiment) to be used in combination with apremilast ranges from 0.001 to 50 mg/kg body weight/day.
  • the effective amount of a disclosed Tyk2 inhibitor (e.g., as in any one of the second to thirtieth embodiment) to be used in combination with apremilast ranges from about 0.1 mg/day to about 250 mg/day, e.g., from about 0.2 mg/day to about 100 mg./day, about 0.5 mg/ day to about 50 mg/day, and about 1.0 mg to about 24 mg/day.
  • the Tyk2 inhibitor described herein is BMS-986165, or a pharmaceutically acceptable salt thereof, and the effective amount of BMS-986165, or a pharmaceutically acceptable salt thereof, ranges from about 0.1 mg/day to about 250 mg/day, about 0.1 mg/day to about 100 mg/day, about 0.1 mg/day to about 50 mg/day, about 0.1 mg/day to about 25 mg/day 0.1 mg/day to about 15 mg/day, about 0.1 mg/day to about 10 mg/day, about 0.5 mg/day to about 15 mg/day, about 0.5 mg/day to about 10 mg/day, about 0.1 mg/day to about 5 mg/day, about 0.5 mg/day to about 5 mg/day, about 1 mg/day to about 25 mg/day, about 2 mg/day to about 14 mg/day, about 2 mg/day to about 12 mg/day, or about 3 mg/day to about 12 mg/day.
  • the effective amount of BMS-986165, or a pharmaceutically acceptable salt thereof ranges from about 1 mg/day to about 15 mg/day, about 1 mg/day to about 14 mg/day, about 2 mg/day to about 14 mg/day, about 2 mg/day to about 12 mg/day, or about 3 mg/day to about 12 mg/day.
  • the Tyk2 inhibitor described herein is BMS-986165, or a pharmaceutically acceptable salt thereof, and the effective amount of BMS-986165, or a pharmaceutically acceptable salt thereof, is about 0.1 mg/day, about 0.5 mg/day, about 1.0 mg/day, about 2 mg/day, about 3 mg/day, about 4 mg/day, about 5 mg/day, about 6 mg/day, about 7 mg/day, about 8 mg/day, about 9 mg/day, about 10 mg/day, about 11 mg/day, or about 12 mg/day.
  • 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.
  • the effective amount of BMS-986165, or a pharmaceutically acceptable salt thereof is about 6 mg/day.
  • the effective concentration of BMS-986165, or a pharmaceutically acceptable salt thereof is about 1 nM to about 1 mM (e.g., from about 0.01 mM to about 0.1 mM).
  • apremilast is optically enriched as the (S) enantiomer.
  • compositions described herein is greater than 90%, wherein the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-third embodiments.
  • the stereomeric 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 the first to thirty- third embodiments.
  • the stereo meric 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 thirty- third embodiments.
  • the stereo meric 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 thirty-third embodiments.
  • the stereomeric 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 thirty-third embodiments.
  • the stereomeric 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 thirty-third embodiments.
  • the stereomeric 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 thirty-third embodiments.
  • apremilast Polymorphic forms of apremilast are included in the disclosed methods and compositions and include e.g., those described in US 9,018,243, the entire contents of which are incorporated herein by reference.
  • apremilast in the disclosed methods and compositions is a single crystalline form, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-fourth embodiments.
  • apremilast in the disclosed methods and compositions is a single crystalline Form B characterized by X-ray powder diffraction peaks at 2Q angles selected from 10.1°, 13.5°, 20.7°, and 26.9°, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- fourth embodiments.
  • apremilast in the disclosed methods and compositions is a single crystalline Form B characterized by X-ray powder diffraction peaks at 2Q angles selected from 10.1°, 13.5°, 15.7°, 18.1°, 20.7°, 24.7°, and 26.9°, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-fourth embodiments.
  • apremilast in the disclosed methods and compositions is a single crystalline Form B characterized by X-ray powder diffraction peaks at 2Q angles selected from 10.1°, 13.5°, 15.7°, 16.3°, 18.1°, 20.7°, 22.5°, 24.7°, 26.2°, 26.9°, and 29.1°, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-fourth embodiments.
  • apremilast in the disclosed methods and compositions is at least 90% single crystalline Form B, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- sixth embodiments.
  • apremilast in the disclosed methods and compositions is at least 95% single crystalline Form B, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-sixth embodiments.
  • apremilast in the disclosed methods and compositions is at least 99% single crystalline Form B, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., 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 a disclosed Tyk2 inhibitor will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated.
  • the effective amount of apremilast, or the pharmaceutically acceptable salt thereof ranges from about 0.5 mg to about 1000 mg per day, about 1 mg to about 1000 mg per day, about 5 mg to about 500 mg per day, about 10 mg to about 200 mg per day, about 10 mg to about 100 mg per day, about 40 mg to about 100 mg per day, about 20 mg to about 40 mg per day, about 0.1 mg to about 10 mg per day, about 0.5 mg to about 5 mg per day, about 1 mg to about 20 mg per day, and about 1 mg to about 10 mg per day, about 1 mg to about 100 mg per day, about 1 mg to about 80 mg per day, about 5 mg to about 70 mg per day, about 10 mg to about 60 mg per day, and about 10 mg to about 40 mg per day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments.
  • the effective amount of apremilast, or the pharmaceutically acceptable salt thereof ranges from about 10 mg to about 60 mg per day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments.
  • the effective amount of apremilast, or the pharmaceutically acceptable salt thereof ranges from about 40 mg to about 100 mg per day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments.
  • the effective amount of apremilast, or the pharmaceutically acceptable salt thereof ranges from between about 40 mg to between about 100 mg per day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments.
  • the effective amount of apremilast, or the pharmaceutically acceptable salt thereof ranges from about 4 mg to about 10 mg per day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments.
  • the effective amount of apremilast, or the pharmaceutically acceptable salt thereof ranges from between about 4 mg to between about 10 mg per day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments.
  • the effective amount of apremilast, or the pharmaceutically acceptable salt thereof ranges from about 10 mg to about 40 mg per day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments.
  • the effective amount of apremilast, or the pharmaceutically acceptable salt thereof is about 1 mg per day, about 2 mg per day, about 3 mg per day, about 4 mg per day, about 5 mg per day, about 10 mg per day, about 15 mg per day, about 20 mg per day, about 25 mg per day, about 30 mg per day, about 35 mg per day, about 40 mg per day, about 45 mg per day, about 50 mg per day, about 55 mg per day, or about 60 mg per day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments.
  • the effective amount of apremilast, or the pharmaceutically acceptable salt thereof is about 30 mg per day or about 60 mg per day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments.
  • apremilast is administered at a dose of about 30 mg once daily, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments.
  • apremilast is administered at a dose of about 30 mg twice daily, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments.
  • the effective amount of apremilast, or the pharmaceutically acceptable salt thereof is about 10 mg per day or about 40 mg per day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments.
  • apremilast is administered at a dose of about 10 mg once or twice daily, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments.
  • apremilast is administered at a dose of about 20 mg once or twice daily, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments.
  • the effective concentration of apremilast is about 100 nM to about 10 mM (e.g., from about 0.1 mM to about 1 mM), wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments.
  • apremilast is titrated to a dosage of about 30 mg administered twice daily using the following titration schedule:
  • Day 2 about 10 mg in morning and about 10 mg in evening;
  • Day 3 about 10 mg in morning and about 20 mg in evening;
  • Day 4 about 20 mg in morning and about 20 mg in evening;
  • Day 5 about 20 mg in morning and about 30 mg in evening;
  • apremilast is titrated to a dosage of between about 40 mg/day to between about 100 mg/day using the following titration schedule:
  • Day 2 about 10 mg in morning and about 10 mg in evening;
  • Day 3 about 10 mg in morning and about 20 mg in evening;
  • Day 4 about 20 mg in morning and about 20 mg in evening
  • Day 5 about 20 mg in morning and about 30 mg in evening
  • apremilast is titrated to a dosage of about 20 mg administered twice daily using the following titration schedule:
  • Day 2 about 10 mg in morning and about 10 mg in evening;
  • Day 3 about 10 mg in morning and about 20 mg in evening;
  • Day 4 about 20 mg in morning and about 20 mg in evening;
  • Day 5 about 20 mg in morning and about 30 mg in evening;
  • apremilast is titrated to a dosage of between about 4 mg/day to between about 10 mg/day using the following titration schedule:
  • Day 2 about 1 mg in morning and about 1 mg in evening;
  • Day 3 about 1 mg in morning and about 2 mg in evening;
  • Day 4 about 2 mg in morning and about 2 mg in evening;
  • Day 5 about 2 mg in morning and about 3 mg in evening;
  • apremilast is titrated to a dosage of about 3 mg administered twice daily using the following titration schedule:
  • Day 2 about 1 mg in morning and about 1 mg in evening;
  • Day 3 about 10 mg in morning and about 2 mg in evening;
  • Day 4 about 2 mg in morning and about 2 mg in evening;
  • Day 5 about 2 mg in morning and about 3 mg in evening;
  • compositions comprising a therapeutically effective amount of apremilast, or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a Tyk2 inhibitor (e.g., BMS-986165).
  • a Tk2 inhibitor e.g., BMS-986165.
  • compositions comprising a therapeutically effective amount of apremilast, or a pharmaceutically acceptable thereof; and a
  • a Tyk2 inhibitor e.g., BMS-986165
  • a Tyk2 inhibitor for use in treating a disease or disorder responsive to the inhibition of PDE4.
  • a Tyk2 inhibitor e.g., BMS-986165
  • compositions and single unit dosage forms comprising apremilast and a Tyk2 inhibitor (e.g., BMS-986165) alone or together in a fixed dose for administration as described above (e.g., as in any one of the first to thirty-eighth embodiments) is included.
  • Single unit dosage forms of the disclosed methods and compositions are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,
  • dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non- aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suit able for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids)
  • composition, shape, and type of dosage forms of the will typically vary depending on their use.
  • inflammation or a related disorder may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the chronic treatment of the same disease.
  • a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease or disorder.
  • apremilast in the disclosed methods and compositions is administered parenterally, transdermally, mucosally, nasally, buccally, sublingually, or orally, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-eighth embodiments.
  • additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-eighth embodiments.
  • apremilast in the disclosed methods and compositions is administered orally in the form of a tablet or a capsule, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- ninth embodiments.
  • apremilast in the disclosed methods and compositions is formulated as an extended release form, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- ninth embodiments.
  • compositions is formulated as an immediate release form, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- ninth embodiments.
  • both the apremilast and the Tyk2 inhibitor in the disclosed methods and compositions are administered in fixed dosage combination as a once a day formulation, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to forty-second embodiments.
  • Diseases or disorders that are responsive to the inhibition of PDE4 using the methods and compositions disclosed herein include e.g., viral, genetic, inflammatory, allergic, and autoimmune conditions.
  • the disease or disorder responsive to the inhibition of PDE4 is selected from chronic obstructive pulmonary disease, asthma, chronic pulmonary embolism, and the like.
  • 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 erythrematosus, erythema nodosum leprosum, Sjogren’s syndrome, inflammatory bowel disease, Crohn’s Disease, Behcet’s Disease, and ulcerative colitis.
  • the disease or disorder responsive to the inhibition of PDE4 is selected from psoriasis, psoriatic arthritis, contact dermatitis, systemic lupus erythrematosus, cutaneous lupus erythematosus, and ulcerative colitis.
  • the disease or disorder responsive to the inhibition of PDE4 is psoriasis. In another aspect, the disease or disorder responsive to the inhibition of PDE4 is psoriasis and the subject being treated is a candidate for phototherapy or systematic therapy.
  • the disease or disorder responsive to the inhibition of PDE4 is plaque psoriasis.
  • the disease or disorder responsive to the inhibition of PDE4 is plaque psoriasis and the subject being treated is a candidate for phototherapy or systematic therapy.
  • the disease or disorder responsive to the inhibition of PDE4 is moderate to severe plaque psoriasis. In another aspect, the disease or disorder responsive to the inhibition of PDE4 is severe plaque psoriasis and the subject being treated is a candidate for phototherapy or systematic therapy.
  • the disease or disorder responsive to the inhibition of PDE4 is psoriatic arthritis.
  • the disease or disorder responsive to the inhibition of PDE4 is active psoriatic arthritis.
  • the disease or disorder responsive to the inhibition of PDE4 is heart disease, such as congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acute viral myocarditis, cardiac allograft rejection, and myocardial infarction.
  • heart disease such as congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acute viral myocarditis, cardiac allograft rejection, and myocardial infarction.
  • the disease or disorder responsive to the inhibition of PDE4 is HIV, hepatitis, adult respiratory distress syndrome, bone-resorption diseases, cystic fibrosis, septic shock, sepsis, endotoxic shock, hemodynamic shock, sepsis syndrome, post ischemic reperfusion injury, meningitis, fibrotic disease, cachexia, graft rejection, osteoporosis, multiple sclerosis, and radiation damage.
  • the disease or disorder responsive to the inhibition of PDE4 is cancer of the head, thyroid, neck, eye, skin, mouth, throat, esophagus, cheat, bone, blood, bone marrow, lung, colon, sigmoid, rectum, stomach, prostate, breast, ovaries, kidney, liver, pancreas, brain, intestine, heart, adrenal, subcutaneous tissue, lymph nodes, heart, and combinations thereof.
  • the disease or disorder responsive to the inhibition of PDE4 is multiple myeloma, malignant melanoma, malignant glioma, acute lymphoblastic leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute
  • myeloblastic leukemia acute promyelocytic leukemia, acute monoblastic leukemia, acute erythroleukemic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocyctic leukemia, acute undifferentiated leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, hairy cell leukemia, multiple myeloma and acute, lymphoblastic leukemia, myelogenous leukemia, lymphocytic leukemia, and myelocytic leukemia.
  • the disease or disorder responsive to the inhibition of PDE4 is a solid tumor, such as sarcoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangio sarcoma, lymphangioendotheliosarcoma, syn-ovioma, 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 gland carcinoma, papillary car-cinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma,
  • sarcoma such
  • Table 1 Whole blood assay: Study Materials and Reagents.
  • Condition Thl7 was a stimulation with TruCulture® tubes containing anti-CD3/anti-CD28 plus IL-Ib, IL-6 and IL-23.
  • Whole blood was separated into 15 milliliter conical tubes and pre-treated with DMSO, apremilast alone, BMS-986165 alone or BMS-986165 combined with apremilast. Final concentrations were 0.2% DMSO, 1 mM for apremilast alone, 1 mM, 0.1 mM, 0.01 mM and 0.001 mM BMS- 986165 alone and in combination with 1 mM apremilast. Blood was mixed well and then incubated in a 37°C/5%C0 2 incubator for 1 hour.
  • Pellets were resuspended in 2%FBS-PBS and filtered through a 40mm cell strainer to obtain single-cell suspension. 3ml of RBC lysis buffer were used to eliminate red blood cells in the isolated population. Isolated PBMCs were washed with 2%FBS-PBS and were resuspended in RPMI growth medium containing 10%FBS and antibiotics.
  • PBMCs from 9 healthy donors were isolated and LPS- stimulated ex- vivo for IL-23, IL-12p40, IL-12p70, TNF-a , IFN-g and MCP-1 cytokine analysis.
  • PBMCs were plated in 96 well plate at a density of 200,000 cells per well in 200 m ⁇ of RPMI growth medium containing 10%FBS followed by treatment with DMSO and compounds. Each well received the same amount of DMSO, which is 0.3% v/v as final concentration.
  • Series dilutions of compound treatment was performed according to Table 4 shown below. After two hours of compound treatment, LPS 100 ng/ml as final concentration was used as the stimulator.
  • PBMCs were then incubated in a 37°C/5%C0 2 incubator for 16 hours.
  • IL-17A Whole blood from 4 healthy donors were analyzed for IL-17A, IL-17F, IL-22, TNF-a and GM-CSF cytokine production in both ThO and Thl7 conditions.
  • the blood was pre-treated with apremilast and Tyk2 inhibitor BMS-986165 both alone and in combination using the TruCulture® Tube System.
  • the IL-17A results located in FIG. 1 show the IL- 17A% of control and all data is normalized to the Thl7 DMSO control. Apremilast inhibited 28% of IL-17A cytokine expression under ThO conditions and had no effect in Thl7 conditions.
  • BMS-986165 had a similar effect under both stimulation conditions and inhibited 10-25% of IL-17A expression at 0.001-1 mM.
  • BMS- 986165 had a similar effect under both stimulation conditions and inhibited 10-25% of IL-17A expression at 0.001-1 mM.
  • FIG. 2 shows the picograms per milliliter levels of IL-17A.
  • Levels of IL-17A increased in the Thl7 stimulation conditions by 387% compared to the ThO stimulation.
  • ThO conditions apremilast reduced IL-17A levels from 138 pg/mL to
  • BMS-986165 at 1 mM reduced IL-17A levels to 97 pg/mL.
  • the combination of apremilast with 1 mM BMS-986165 further reduced IL-17A levels to 24pg/mL with the ThO stimulation.
  • the 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 mM, 428 pg/mL at 0.1 mM and 383 pg/mL at 1 mM.
  • IL-17F cytokine expression data is in FIG. 3 and FIG. 4. Apremilast inhibited 69% of IL-17F production under ThO conditions and 49% under Thl7 conditions. BMS- 986165 had a similar effect on IL-17F with both the ThO and Thl7 stimulation. There was 31% inhibition at the lowest concentration of 0.001 mM and a dose response with 34% inhibition at 0.01 mM, 70% inhibition at 0.1 mM and 95% inhibition of IL-17F expression at 1 mM (Thl7 results). The combination of 1 mM apremilast with BMS-986165 under ThO conditions was partially additive with inhibition ranging from 60% at 0.001 to 95% at 1 mM.
  • IL-22 cytokine expression data is in FIG. 5 and FIG. 6. Apremilast inhibited
  • BMS-986165 inhibited 16% of IL-22 at 0.01 mM, 86% at 0.1 mM and 91% at 1 mM.
  • BMS-986165 had no effect on IL-22 cytokine expression at 0.001 mM but inhibited 17% at 0.01 mM, 60% at 0.1 mM and 70% at 1 mM. Under ThO conditions the combination had similar effects to apremilast alone with -90% inhibition at all concentrations of BMS-986165.
  • Thl7 The combination under Thl7 conditions was synergist at 0.01 mM with 60% inhibition and at 0.1 mM with 90% inhibition of IL-22 cytokine expression.
  • the ThO stimulation control had 1085 pg/mL of IL-22 and the Thl7 control was 6524 pg/mL.
  • Apremilast significantly lowered IL-22 levels to 368 pg/mL in the ThO conditions and 3643 pg/mL in the Thl7 conditions.
  • BMS-986165 significantly lowered IL-22 cytokine expression in both stimulation conditions at 0.1 mM and 1 mM.
  • TNF-a cytokine expression data is located in FIG. 7 and FIG. 8. Apremilast inhibited 90% of TNF-a levels in ThO conditions and 94% in Thl7 conditions.
  • BMS-986165 increased TNF-a expression by 21% at 0.001 mM, 43% at 0.01 mM and 61% at 0.1 mM.
  • BMS-986165 inhibited 66% of TNF-a cytokine expression.
  • TNF-a (68%) with 1 mM BMS-986165 under Thl7 stimulation conditions.
  • Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) cytokine expression results are in FIG. 9 and FIG. 10.
  • GM-CSF cytokine expression was reduced 80% by apremilast under ThO conditions and by 66% under Thl7 conditions.
  • BMS-986165 increased GM-CSF cytokine expression under both conditions.
  • BMS-986165 increased GM- CSF by 19% at 0.001 mM, 36% at 0.01 mM, 110% at 0.1 mM and 31% at 1 mM in the ThO conditions.
  • apremilast 0.1 mM
  • BMS-986165 increased GM- CSF by 41% at 0.01 mM, 139% at 0.1 mM and 104% at 1 mM. When apremilast was added there was 40-73% inhibition of GM-CSF cytokine expression.
  • Total pg/mL of GM-CSF in the ThO and Thl7 stimulation controls were 409 and 637 respectively.
  • the increase of GM-CSF by BMS-986165 was significant at 0.1 mM (both ThO and Thl7) and 1 mM (Thl7).
  • the combination of apremilast and BMS-986165 significantly reduced GM-CSF cytokine levels at all concentrations and under both stimulation conditions.
  • FIG. 11 showed that Apremilast decreased IL-23 production in LPS stimulated PBMCs.
  • IL-23 level from DMSO treated LPS stimulated PBMCs was set as 100% (control), cytokine levels were shown as normalized value in % compared to control.
  • FIG. 12 showed that BMS-986165 induces IL-23 level in LPS stimulated PBMCs.
  • BMS-986165 induced a 20 fold increases of IL-23 compared to DMSO group.
  • the combination of apremilast with BMS- 986165 was able to decrease the induction of IL-23 by BMS-986165. With increased level of apremilast, there is significant reduction of IL-23 level.
  • Statistical analysis using ANOVA and Turkey’s multiple comparisons were performed to compare each treatment with BMS- 986165 alone. There is significant reduction of IL-23 when combining BMS-986165 with low level of apremilast, which is at the concentration of 0.037mM (**** p ⁇ 0.001).
  • Results in FIG. 13 showed the normalized level of IL-12p40 compared to DMSO treated LPS stimulated PBMCs group.
  • Apremilast decreased IL-12p40 in a dose dependent manner, whereas BMS-986165 increased it.
  • the combination of BMS-986165 with apremilast significantly decreased the induction of IL-12p40 by BMS-986165.
  • With lmM apremilast the increased IL-12p40 induced by BMS-986165 was 85% inhibited, and almost reached a similar level as Apremilast alone.
  • Statistical analysis using ANOVA and Turkey’s multiple comparisons were performed to compare each treatment with BMS- 986165 alone. **** p ⁇ 0.001
  • Results in FIG. 14 showed the normalized level of IL-12p70 compared to DMSO treated LPS stimulated PBMCs group. Apremilast decreased IL-12p70 in a dose dependent manner, whereas BMS-986165 increased it. The combination of BMS-986165 with apremilast significantly decreased the induction of IL-12p70 by BMS-986165. In combination treatment, both 0.3 mM and 1 mM significantly reduced IL-12p70 level induced by BMS-986165 and have no significant difference compared to apremilast alone. Statistical analysis using ANOVA and Turkey’s multiple comparisons were performed to compare each treatment with BMS-986165 alone. **** p ⁇ 0.001
  • Results in FIG. 15 showed the normalized level of TNF-oc compared to DMSO treated LPS stimulated PBMCs group. Apremilast decreased TNF- a level in a dose dependent manner, however, BMS-986165 induced 1.2-1.5 fold increase of TNF-oc. The combination of BMS-986165 and apremilast significantly decreased the level of TNF-oc. Statistical analysis using ANOVA and Turkey’s multiple comparisons were performed to compare each treatment with BMS-986165 alone. **** p ⁇ 0.001
  • Results in FIG. 16 showed the normalized level of IFN-g compared to DMSO treated LPS stimulated PBMCs group. Both apremilast alone and BMS-986165 alone decreased IFN-g in a dose dependent manner. The combination of BMS-986165 and apremilast has synergistic effect in reducing IFN-g level which significantly decreased IFN- g level compared to single compound treatment. Statistical analysis using ANOVA and Turkey’s multiple comparisons were performed to compare each treatment with BMS- 986165 alone. **** p ⁇ 0.001 Example 11
  • Results in FIG. 17 showed the normalized level of MCP-1 compared to DMSO treated LPS stimulated PBMCs group. Both apremilast alone and BMS-986165 alone decreased MCP-1 in a dose dependent manner. The combination of BMS-986165 and
  • Table 5 provides a summary of the cytokine effects of apremilast and BMS-986165 on stimulated whole blood in the Ex-Vivo TruCulture® Assay. Synergistic effects are shown in bold and complementary effects are underlined.
  • BMS-986165 increased TNF-a and GM-CSF production, while apremilast inhibited production of these cytokines.
  • BMS-986165 was combined with apremilast there was a complementary effect on TNF-a and GM-CSF cytokine expression, with apremilast correcting the defect of BMS-986165.
  • These combined effect provide means for treating diseases or disorders responsive to the inhibition of PDE4 such as for the treatment inflammatory diseases (e.g., psoriasis, psoriatic arthritis, and ulcerative colitis).
  • Table 6 below provides a summary of the cytokine effects of apremilast and BMS-986165 on LPS stimulated PBMCs. Red arrows indicate induction and green arrows indicate decrease of the production of cytokines.
  • PBMCs from 9 healthy donors were tested in LPS stimulated condition with or without BMS-986165 or apremilast or the combination of both.
  • BMS-986165 treatment alone induced IL-23, IL-12p40, IL-12p70 and TNF-a, whereas apremilast treatment alone decreased these cytokines.
  • BMS-986165 was combined with apremilast these cytokines were either unchanged or reduced compared to DMSO control group.
  • BMS-986165 Both apremilast and BMS-986165 reduced IFN-g and MCP-1 production, and the combination of both further reduced these two cytokines with a synergistic effect.
  • BMS-986165 inhibits Thl7 lineage cytokines, which provide a means for treating diseases where Thl7 cytokines are implicated in the pathogenesis.
  • the induction of some proinflammatory cytokines, such as IL-23, IL-12 and TNF-a, by BMS-986165 could be a disadvantage in disease treatment.
  • Apremilast and BMS-986165 were tested in IL-17A, IL-17F, IL-22, and TNF- oc whole blood at the following fixed dosages: 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 average plasma concentrations observed or extrapolated from clinical PK data.
  • FIGs. 18-21 the 6 mg QD dose concentration of BMS-986165 did not maximally inhibit IL-17A, IL-17F, or IL-22, and it elevated TNF-alpha. See FIGs. 18-21.
  • Even low concentrations of apremilast where shown to be effective.
  • the 20 mg BID dose of apremilast compensated for the suboptimal inhibition of IL-17F
  • the 10 mg BID dose of apremilast compensated for the suboptimal inhibition of IL-22 and to prevent the increase of TNF-alpha.
  • BMS-986165 e.g., at 6 mg QD
  • apremilast e.g., 10-20 mg QD or BID
  • psoriasis psoriatic arthritis
  • ankylosing spondylitis e.g., ankylosing spondylitis
  • ulcerative colitis e.g., Crohn’
  • hidradenitis suppurativa e.g., Behcet’s disease.

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Abstract

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

Description

COMBINATION THERAPIES COMPRISING APREMILAST AND TYK2
INHIBITORS
RELATED APPLICATIONS
[0001] This application claims priority to International Application No.
PCT/US2019/029772, filed April 30, 2019, the entire contents of which are incorporated herein by reference.
BACKGROUND
[0002] N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro- l,3-dioxo-lH-isoindol-4-yl] acetamide (apremilast), marketed as Otezla®, is a
phosphodiesterase type 4 (PDE4) inhibitor currently approved for treating both moderate to severe plaque psoriasis and active psoriatic arthritis. PDE4 inhibition by apremilast elevates cyclic adenosine monophosphate (cAMP) levels in immune cells. This in turn down-regulates inflammatory responses by reducing the expression of pro-inflammatory mediators such as TNF-a, 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 in as little as just over 4 months of treatment.
[0003] Tyrosine kinase 2 (Tyk2), an intracellular signaling enzyme, activates signal transducer and activator of transcription (STAT)-dependent gene expression and functional responses of IL-12, IL-23, and type I and III interferon receptors. Amongst other conditions, tyrosine kinase inhibitors (TKIs) have recently gained attention as effective agents for treating psoriasis and related conditions. The TKI inhibitor BMS-986165, for example, recently showed positive results in phase 2 clinical trials in subjects with moderate to severe plaque psoriasis. See Kim Papp, M.D., Phase 2 Trial of Selective Tyrosine Kinase 2
Inhibition in Psoriasis, The New England Journal of Medicine, Sept. 12, 2018.
SUMMARY
[0004] It has now been found that the combination of apremilast and the Tyk2 inhibitor 6- (cyclopropanecarboxamido)-4-((2-methoxy-3-(l-methyl-lH-l,2,4-triazol-3- yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165) synergistically reduces pro-inflammatory cytokines expressed in a whole blood assay under conditions that stimulate Thl7 cells. For example, there was over a 2-fold increase in the inhibition of IL- 17F expression using the combination of 0.01 mM BMS-986165 and 1 mM apremilast when compared to the use of each drug alone. See e.g., Table 5 in the Exemplification section. Similar results were seen at 0.1 mM concentrations of BMS-986165 with 1 mM apremilast. See e.g., Table 5. The combination of BMS-986165 with 1 mM apremilast also reduced cytokine expression for IL-17A and IL-22 at values of 2-fold or greater over the use of each drug alone. See e.g., Table 5.
[0005] It was also found that the combination of apremilast and BMS-986165 elicit complementary effects against certain pro-inflammatory cytokines. BMS-986165, for example, increased TNF-a and GM-CSF cytokine in whole blood assay, while apremilast inhibited the production of these cytokines. See e.g., Table 5 where the % control for 1 mM apremilast was 10.7 and the % control for 0.01 mM BMS-986165 was 143.1 against TNF-oc. When administered in combination, however, apremilast corrected the deficiency of BMS- 986165 thereby producing a complementary effect of 13.5% inhibition against TNF-oc. See e.g., Table 5. This trend was also established at 0.1 mM concentrations of BMS-986165 and against cytokine GM-CSF. See e.g., Table 5. These results illustrate the synergistic and complementary pharmacological effects of BMS-986165 and apremilast.
[0006] In addition to whole blood assay, the combination of BMS-986165 and apremilast elicit complementary effects against certain pro-inflammatory cytokines in LPS stimulated PBMCs as well. BMS-986165 increased IL-23, IL-12 and TNF-oc, while apremilast inhibited the production of these cytokines. See e.g., Table 6 in the Exemplification section. These results further support the advantage of combining BMS-986165 and apremilast in treatment of Thl7 related diseases.
[0007] Provided herein, therefore are methods of treating diseases or disorders responsive to the inhibition of PDE4 in a subject using an effective amount of apremilast, or a pharmaceutically acceptable salt thereof, and an effective amount of a Tyk2 inhibitor such as BMS-986165. Such diseases and disorders include e.g., inflammatory diseases such as psoriasis, psoriatic arthritis, and ulcerative colitis.
[0008] 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.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 illustrates interleukin- 17a (IL-17a) cytokine production (percent of control) by apremilast and BMS-986165 in anti-CD3/anti-CD28 (ThO) or anti-CD3/anti-CD28, IL-Ib, IL-6 and IL-23 (Thl7) stimulated whole blood - TruCulture® tube assay. [0010] FIG. 2 illustrates interleukin- 17 A (IL-17A) cytokine production by apremilast and BMS-986165 in anti-CD3/anti-CD28 (ThO) or anti-CD3/anti-CD28, IL-Ib, IL-6 and IL-23 (Thl7) stimulated whole blood - TruCulture® tube assay.
[0011] FIG. 3 illustrates interleukin- 17F (IL-17F) cytokine production (percent of control) by apremilast and BMS-986165 in anti-CD3/anti-CD28 (ThO) or anti-CD3/anti-CD28, IL-Ib, IL-6 and IL-23 (Thl7) stimulated whole blood - TruCulture® tube assay.
[0012] FIG. 4 illustrates interleukin- 17F (IL-17F) cytokine production by apremilast and BMS-986165 in anti-CD3/anti-CD28 (ThO) or anti-CD3/anti-CD28, IL-Ib, IL-6 and IL-23 (Thl7) stimulated whole blood - TruCulture® tube assay.
[0013] FIG. 5 illustrates interleukin- 22 (IL-22) cytokine production (percent of control) by apremilast and BMS-986165 in anti-CD3/anti-CD28 (ThO) or anti-CD3/anti-CD28, IL-Ib, IL-6 and IL-23 (Thl7) stimulated whole blood - TruCulture® tube assay.
[0014] FIG. 6 illustrates interleukin- 22 (IL-22) cytokine production by apremilast and BMS-986165 in anti-CD3/anti-CD28 (ThO) or anti-CD3/anti-CD28, IL-Ib, IL-6 and IL-23 (Thl7) stimulated whole blood - TruCulture® tube assay.
[0015] FIG. 7 illustrates tumor necrosis factor alpha (TNF-a) cytokine production (percent of control) by apremilast and BMS-986165 in anti-CD3/anti-CD28 (ThO) or anti-CD3/anti- CD28, IL-Ib, IL-6 and IL-23 (Thl7) stimulated whole blood - TruCulture® tube assay.
[0016] FIG. 8 illustrates tumor necrosis factor alpha (TNF-a) cytokine production by apremilast and BMS-986165 in anti-CD3/anti-CD28 (ThO) or anti-CD3/anti-CD28, IL-Ib, IL-6 and IL-23 (Thl7) stimulated whole blood - TruCulture® tube assay.
[0017] FIG. 9 illustrates granulocyte-macrophage colony- stimulating factor (GM-CSF) cytokine production (percent of control) by apremilast and BMS-986165 in anti-CD3/anti- CD28 (ThO) or anti-CD3/anti-CD28, IL-Ib, IL-6 and IL-23 (Thl7) stimulated whole blood - TruCulture® tube assay.
[0018] FIG. 10 illustrates granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine production by apremilast and BMS-986165 in anti-CD3/anti-CD28 (ThO) or anti- CD3/anti-CD28, IL-Ib, IL-6 and IL-23 (Thl7) stimulated whole blood - TruCulture® tube assay.
[0019] FIG. 11 illustrates interleukin-23 (IL-23) cytokine production by apremilast in Lipopolysaccharide (IPS) stimulated peripheral blood mononuclear cells (PBMCs).
[0020] FIG. 12 illustrates interleukin-23 (IL-23) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs. [0021] FIG. 13 illustrates interleukin- 12p40 (IL-12p40) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs.
[0022] FIG. 14 illustrates interleukin- 12p70 (IL-12p70) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs.
[0023] FIG. 15 illustrates tumor necrosis factor alpha (TNF-a) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs.
[0024] FIG. 16 illustrates interferon gamma (IFN-g) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs.
[0025] FIG. 17 illustrates monocyte chemoattractant protein- 1 (MCP-1) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs.
[0026] FIG. 18 illustrates fixed dose combination effects of apremilast and Tyk2i (BMS- 986165) in IL-17A whole blood.
[0027] FIG. 19 illustrates fixed dose combination effects of apremilast and Tyk2i (BMS- 986165) in IL-17F whole blood.
[0028] FIG. 20 illustrates fixed dose combination effects of apremilast and Tyk2i (BMS- 986165) in IL-22 whole blood.
[0029] FIG. 21 illustrates fixed dose combination effects of apremilast and Tyk2i (BMS- 986165) in TNF-a whole blood.
DETAILED DESCRIPTION
[0030] In a first embodiment, provided herein are methods for treating a disease or disorder responsive to the inhibition of cyclic nucleotide phosphodiesterase isoenzyme IV (PDE4), the method comprising administering to a subject an effective amount of N-[2-[(lS)-l-(3-ethoxy- 4-metho xyphenyl)-2-(methylsulfonyl)ethyl]-2, 3-dihydro- 1,3-dioxo- lH-isoindo 1-4- yl] acetamide (apremilast), or a pharmaceutically acceptable salt thereof, and an effective amount of a Tyk2 inhibitor.
[0031] Alternatively, as part of a first embodiment, provided is the use of an effective amount of N-[2-[( IS)- l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2, 3-dihydro- 1,3-dioxo- lH-isoindol-4-yl] acetamide (apremilast), or a pharmaceutically acceptable salt thereof, and an effective amount of a Tyk2 inhibitor, in the manufacture of a medicament for treating a disease or disorder responsive to the inhibition of cyclic nucleotide
phosphodiesterase isoenzyme IV (PDE4).
[0032] In another alternative, as a part of a first embodiment, provided is an effective amount of N-[2-[( IS)- l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2, 3-dihydro- l,3-dioxo-lH-isoindol-4-yl] acetamide (apremilast), or a pharmaceutically acceptable salt thereof, and an effective amount of a Tyk2 inhibitor, for use in treating a disease or disorder responsive to the inhibition of cyclic nucleotide phosphodiesterase isoenzyme IV (PDE4).
1. Definitions
[0033] N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2, 3-dihydro- l,3-dioxo-lH-isoindol-4-yl] acetamide (apremilast) is disclosed in U.S. Patent No. 6,962,940, the contents of which are incorporated herein by reference, and refers to the compound having the following chemical structure:
Figure imgf000006_0001
[0034] Apremilast has a chiral center designated as (S) in the chemical structure and name. As used herein, this designation means that apremilast is optically enriched as the (S) enantiomer at this position in an amount of at least 80%, 90%, 95%, 98%, 99%, or 99.9% relative to the corresponding (R) enantiomer. Thus, when apremilast is referred to herein as being stereomerically or enantiomerically pure at a specified amount, it means that the (S) enantiomer is enriched in that amount. For example, N-[2-[(lS)-l-(3-ethoxy-4- methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide that is at least 95% stereomerically pure means that the compound contains greater than or equal to 95% of the (S) enantiomer and 5% or less of the (R) enantiomer.
[0035] Unless otherwise indicated, the administrations described herein include
administering apremilast prior to, concurrently with, or after administration of the Tyk2 inhibitor described herein. Thus, simultaneous administration is not necessary 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 at different times on the same day. In another aspect, apremilast and a 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. [0036] The terms“treatment,”“treat,” and“treating” refer to reversing, alleviating, or inhibiting the progress of a disease or disorder responsive to the inhibition of PDE4, or one or more symptoms thereof, as described herein.
[0037] The term“subject” means an animal, such as a mammal, and such as a human. The terms“subject” and“patient” may be used interchangeably.
[0038] The term“effective amount” or“therapeutically effective amount” refers to an amount of a compound described herein that will elicit a biological or medical response of a subject e.g., a dosage of between 0.001 - 100 mg/kg body weight/day.
[0039] 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 this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, magnesium stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances (e.g., microcrystalline cellulose, hydroxypropyl methylcellulose, lactose monohydrate, sodium lauryl sulfate, and crosscarmellose sodium), polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
[0040] The term“pharmaceutically acceptable salts” refer to salts prepared from
pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts for the compounds described herein include, but are not limited to include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylene diamine, meglumine (N-methylglucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methane sulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid.
[0041] “Crystalline” refers to a solid form of a compound wherein there exists long-range atomic order in the positions of the atoms. The crystalline nature of a solid can be confirmed, for example, by examination of the X-ray powder diffraction pattern. A“single crystalline form” means that the recited compound, i.e., N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide, is present as a single crystal or a plurality of crystals in which each crystal has the same crystal form (e.g., crystalline Form B). When the crystal form is defined as a specified percentage of one particular single crystalline form of the compound, the remainder is made up of amorphous form and/or crystalline forms other than the one or more particular forms that are specified.
In one aspect, e.g., a disclosed crystalline form is at least 80% a single crystalline form, at least 90% a single crystalline form, at least 95% a single crystalline form, or at least 99% a single crystalline form by weight. Percent by weight of a particular crystal form is determined by the weight of the particular crystal form divided by the sum weight of the particular crystal, plus the weight of the other crystal forms present plus the weight of amorphous form present multiplied by 100%.
[0042] The term“amorphous” refers to a solid that is present in a non-crystalline state or form. Amorphous solids are disordered arrangements of molecules and therefore possess no distinguishable crystal lattice or unit cell and consequently have no definable long range ordering. Solid state ordering of solids may be determined by standard techniques known in the art, e.g., by X-ray powder diffraction (XRPD) or differential scanning calorimetry (DSC). Amorphous solids can also be differentiated from crystalline solids e.g., by birefringence using polarized light microscopy.
[0043] The 2-theta values of the X-ray powder diffraction patterns for the crystalline forms described herein may vary slightly from one instrument to another and also depending on variations in sample preparation and batch to batch variation due to factors such as
temperature variation, sample displacement, and the presence or absence of an internal standard. Therefore, unless otherwise defined, the XRPD patterns / assignments recited herein are not to be construed as absolute and can vary ± 0.2 degrees. It is well known in the art that this variability will account for the above factors without hindering the unequivocal identification of a crystal form. 2. Tyk2 Inhibitors
[0044] Tyk2 inhibitors used in the disclosed methods and compositions include compounds which block the action of tyrosine kinase 2, a non-receptor tyrosine-protein kinase encoded by the Tyk2 gene.
[0045] In a second embodiment, the disclosed Tyk2 inhibitors include, but are not limited to, those described in Xingrui He et al., Expert Opinion on Therapeutics Patents 2019, Vol. 29, No. 2, 137-149, the entire contents of which are incorporated herein by reference.
[0046] In a third embodiment, the disclosed Tyk2 inhibitors may be selected from those having the formula:
Figure imgf000009_0001
[0047] or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO 2015/032423, the entire contents of which are incorporated herein by reference.
Exemplary compounds having this formula as part of the third embodiment include, but are not limited to, those having the formula:
Figure imgf000009_0002
or a pharmaceutically acceptable salt thereof. Other Tyk2 inhibitors as part of the third embodiment include those in WO 2008/139161, and WO 2010/055304, the entire contents of each of which are incorporated herein by reference. [0048] In a fourth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the formula:
Figure imgf000010_0001
or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO 2013/174895, the entire contents of which are incorporated herein by reference. Exemplary compounds having this formula as part of the fourth embodiment include, but are not limited to, those having the formula:
Figure imgf000010_0002
or a pharmaceutically acceptable salt thereof. Other Tyk2 inhibitors include those in WO 2012/062704, the entire contents of which are incorporated herein by reference.
[0049] In a fifth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the formula:
Figure imgf000010_0003
or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO 2012/062704, the entire contents of which are incorporated herein by reference.
[0050] In a sixth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the formulae:
Figure imgf000010_0004
or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO 2015/091584, the entire contents of which are incorporated herein by reference. Exemplary compounds having this formula as part of the sixth embodiment include, but are not limited to, those having the formula:
Figure imgf000011_0001
or a pharmaceutically acceptable salt thereof.
[0051] In a seventh embodiment, the disclosed Tyk2 inhibitors may be selected from those having the formula:
Figure imgf000011_0002
or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO 2016/027195, the entire contents of which are incorporated herein by reference. Exemplary compounds having this formula as part of the seventh embodiment include, but are not limited to, those having the formula:
Figure imgf000011_0003
or a pharmaceutically acceptable salt thereof.
[0052] In an eighth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the formula:
Figure imgf000012_0001
or a pharmaceutically acceptable salt thereof, wherein the variables are as described in US 2017/0240552, the entire contents of which are incorporated herein by reference. Exemplary compounds having this formula as part of the eighth embodiment include, but are not limited to, those having the formula:
Figure imgf000012_0002
or a pharmaceutically acceptable salt thereof.
[0053] In a ninth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the formula:
Figure imgf000012_0003
or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO 2015/016206, the entire contents of which are incorporated herein by reference.
[0054] In a tenth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the formula:
Figure imgf000012_0004
or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO 2013/146963, the entire contents of which are incorporated herein by reference.
[0055] In an eleventh embodiment, the disclosed Tyk2 inhibitors may be selected from those having the formula:
Figure imgf000013_0001
or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO 2016/047678, the entire contents of which are incorporated herein by reference.
[0056] In a twelfth embodiment, the disclosed Tyk2 inhibitors may be selected from those described in US 2015/0299139; WO 2015/069310; US 9,505,748; WO 2018/0162889; US 2013/0178478; or WO 2015/123453, the entire contents of each of which are incorporated herein by reference.
[0057] In a thirteenth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the formula:
Figure imgf000013_0002
or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO 2015/131080 or WO 2016/138352, the entire contents of which are incorporated herein by reference.
[0058] In a fourteenth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the formula:
Figure imgf000013_0003
or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO 2017/040757, the entire contents of which are incorporated herein by reference. [0059] In a fifteenth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the formula:
Figure imgf000014_0001
or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO 2015/131080, WO 2016/138352, and WO 2017/040757, the entire contents of which are incorporated herein by reference.
[0060] In a sixteenth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the formula:
Figure imgf000014_0002
or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO 2018/071794, the entire contents of which are incorporated herein by reference.
[0061] In a seventeenth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the formula:
Figure imgf000014_0003
or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO 2018/075937, the entire contents of which are incorporated herein by reference.
[0062] In an eighteenth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the formula:
Figure imgf000014_0004
or a pharmaceutically acceptable salt thereof, wherein the variables are as described in US 2013/0178478, the entire contents of which are incorporated herein by reference. [0063] In a nineteenth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the formula:
Figure imgf000015_0001
or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO 2015/123453, the entire contents of which are incorporated herein by reference.
[0064] In a twentieth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the formula:
Figure imgf000015_0002
or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO 2015/089143, the entire contents of which are incorporated herein by reference.
[0065] In a twenty-first embodiment, the disclosed Tyk2 inhibitors may be selected from those having the formula:
Figure imgf000015_0003
or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO 2015/089143, the entire contents of which are incorporated herein by reference.
[0066] In a twenty- second embodiment, the disclosed Tyk2 inhibitors may be selected from those having the formula:
Figure imgf000015_0004
or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO 2018/067432, the entire contents of which are incorporated herein by reference.
[0067] In a twenty-third embodiment, the disclosed Tyk2 inhibitors may be selected from those having the formula:
Figure imgf000016_0001
or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO 2018/093968, the entire contents of which are incorporated herein by reference.
[0068] In a twenty- fourth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the formula:
Figure imgf000016_0002
or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO 2018/081488, the entire contents of which are incorporated herein by reference.
[0069] In a twenty-fifth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the formula:
Figure imgf000016_0003
or a pharmaceutically acceptable salt thereof, wherein
R1 is C1-3alkyl optionally substituted by 0-7 R1a;
R1aat each occurrence is independently hydrogen, deuterium, F, Cl, Br, CF3 or CN;
R is C1_6alkyl or-(CH2)r-3-14 membered carbocycle, each group substituted with 0-4
R2a;
R2aat each occurrence is independently hydrogen, =0, halo, OCF3, CN, NO2, - (CH2)rORb, -(CH2)rSRb, -(CH2)rC(0)Rb, -(CH2)rC(0)ORb, -(CH2)rOC(0)Rb, -(CH2)rNR11 , -(CH2)rC(0)NR11R1 -(CH2)rNRbC(0)Rc, -(CH2)rNRbC(0)ORc, -NRbC(0)NR11R
S(0)pNR1 1R11, -NRbS(0)pRc, -S(0)pRc, C1-6 alkyl substituted with 0-3 Ra, C1_6 halo alkyl, C2. 6 alkenyl substituted with 0-3 Ra, C2-6 alkynyl substituted with 0-3 Ra, -(CH2)r-3-14 membered carbocycle substituted with 0-1 Raor a -(CH2)r-5-7 membered heterocycle comprising carbon atoms or 1-4 heteroatoms selected from N, O, and S(0)p substituted with 0-2 Ra;
R is C3-10 cycloalkyl, C6-10aryl, or a 5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-4 R3a;
R3aat each occurrence is independently hydrogen, =0, halo, OCF3, CF3, CHF2, CN, NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(0)Rb, -(CH2)rC(0)ORb, -(CH2)rOC(0)Rb, - (CH2)rNR1R11, -(CH2)rC(0)NR11 , -(CH2)rNRbC(0)Rc, -(CH2)rNRbC(0)ORc, - NRbC(0)NR11R11, -S(0)pNR1 1R11, -NRbS(0)pRc, -S(0)pRc, c1-6 alkyl substituted with 0-3 Ra, C2-6 alkenyl substituted with 0-3 Ra, C2-6 alkynyl substituted with 0-3 Ra, C 1-6 halo alkyl, - (CH2)r-3-14 membered carbocycle substituted with 0-3 Raor a -(CH2)r-5- 10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and
S(0)p substituted with 0-3 Ra;
or two R3a, together with the atoms to which they are attached, combine to form a fused ring wherein said ring is selected from phenyl and a 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, S or O said fused ring further substituted by Ral;
R4 and R5 are independently hydrogen, C1.4 alkyl substituted with 0-1 Rf, (CH2 - phenyl substituted with 0-3 Rd, or a -(CH2)-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(0)p;
R 1 1 at each occurrence is independently hydrogen, C1.4 alkyl substituted with 0-3 R f , CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd, or - (CH2)r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(0)p substituted with 0-3 Rd;
Raand Ra1 at each occurrence are independently hydrogen, F, C1, Br, OCF3, CF3,
CHF2, CN, NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(0)Rb, -(CH2)rC(O)ORb, -(CH2)rOC(O)Rb, -(CH2)rNR R11, -(CH2)rC(O)NR11R11, -(CH2)rNRbC(O)Rc, -(CH2)rNRbC(0)ORc, - NRbC(0)NR11R -S(0)pNR11R11, -NRbS(0)pRc, -S(0)Rc, -S(0)2Rc, C1-6 alkyl substituted with 0-3 Rf, C 1-6 halo alkyl, C2-6 alkenyl substituted with 0-3 Ra, C2-6 alkynyl substituted with 0-3 Ra, -(CH2)r-3-14 membered carbocycle or -(CH2)r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(0)p substituted with 0-3 Rf;
Rb at each occurrence is independently hydrogen, C1-6 alkyl substituted with 0-3 Rd,
C 1-6 halo alkyl, C3.6 eye lo alkyl substituted with 0-2 Rd, or -(CH2)r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(0)p substituted with 0-3 Rfor (CH2)r-phenyl substituted with 0-3 Rd;
Rc is Ci-6 alkyl substituted with 0-3 Rf, (CH2)r-C3_6 cycloalkyl substituted with 0-3 Rf, (CH2)r-phenyl substituted with 0-3 Rf; or
Rd at each occurrence is independently hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, - ORe, -(CH2)rC(0)Rc, -NReRe, -NReC(0)ORc, C1 _6 alkyl, or (CH2)r-phenyl substituted with 0-3
Re at each occurrence is independently selected from hydrogen, Ci.6 alkyl, C3.
6 cycloalkyl, and (CH2)r-phenyl substituted with 0-3 Rf;
R independently at each occurrence is hydrogen, halo, CN, N¾, OH, C3-6cycloalkyl, CF3, O( C1-6alkyl), or a— (CH2)r-5-7 membered heteroaryl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(0)p;
p is 0, 1, or 2; and
r is 0, 1, 2, 3, or 4, wherein additional definitions and specific compounds can be found e.g., in US 2015/0299139, the entire contents of which are incorporated herein by reference.
[0070] In a twenty-sixth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the formula:
Figure imgf000018_0001
or a pharmaceutically acceptable salt thereof, wherein
R5 is C 1-3alkyl optionally substituted by 0-7 R1 a
R1a at each occurrence is independently hydrogen, deuterium, F, CI, Br, CF3 or CN;
R2 is Ci-6 alkyl substituted with 0-4 R2a, C3.6 cycloalkyl substituted with 0-4 R2a, C6- 10 aryl substituted with 0-4 R2a, a 5-14 membered heterocycle containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-4 R2a, NR6R6 or ORb;
R2a at each occurrence is independently hydrogen, =0, halo, OCF3, CN, NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(0)Rb, -(CH2)rC(0)ORb, -(CH2)rOC(0)Rb,
(CH2)rNR1R11, -(CH2)rC(0)NRR , -(CH2)rNRbC(0)Rc, -(CH2)rNRbC(0)ORc,
-NRbC(O)NR11R11, -S(O)pNR1R11, -NRbS(0)pRc, -S(0)pRc, C1-6 alkyl substituted with 0-3 Ra, C1-6 halo alkyl, -(CH2)r-3-14 membered carbocycle substituted with 0-1 Ra or a-(CH2)r-5-7 membered heterocycle comprising carbon atoms or 1-4 heteroatoms selected from N, O, and S(O)p substituted with 0-2 Ra;
or one R2a and another R2a, together with the atoms to which they are attached, combine to form a fused 5-6 membered ring wherein said fused ring may be substituted with 0-2 Ra;
R3 is -(CH2)r-3-14 membered carbocycle substituted 0-5 R3a;
R3a at each occurrence is independently hydrogen, =O, halo, OCF3, CN, NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(O)Rb, -(CH2)rC(O)ORb, -(CH2)rOC(O)Rb,
(CH2)rNR11R11, -(CH2)rC(O)NR11R11, -(CH2)rNRbC(O)RC, -(CH2)rNRbC(O)ORC,
-NRbC(O)NR11R11, -S(O)pNR11R11, -NRbS(O)pRC, -S(O)pRC, C1-6 alkyl substituted with 0-3 Ra, C1-6 halo alkyl, -(CH2)r-3-14 membered carbocycle substituted with 0-3 Ra or a-(CH2)r-5-10 membered heterocycle comprising carbon atoms or 1-4 heteroatoms selected from N, O, and S(O)p substituted with 0-3 Ra;
or two R3a, together with the atoms to which they are attached, combine to form a fused ring wherein said ring is selected from phenyl and a 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, S or O, said fused ring may be further substituted by Ra;
R4 and R5 are independently hydrogen, C 1-4 alkyl substituted with 0-1 Rf,
(CH2)r-phenyl substituted with 0-3 Rd, or a -(CH2)-5-7 membered heterocycle comprising 5 carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p;
R6 and R11 at each occurrence are independently hydrogen, C 1-4 alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd, or -(CH2)r-5-7 membered heterocycle comprising carbon atoms and 1-4
heteroatoms selected from N, O, and S(O)p substituted with 0-3 Rd;
Ra at each occurrence is hydrogen, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2,
-(CH2)rORb, -(CH2)rSRb, -(CH2)rC(O)Rb, -(CH2)rC(O)ORb, -(CH2)rOC(O)Rb,
-(CH2)rNR11R11, -(CH2)rC(O)NR11R11, -(CH2)rNRbC(O)RC, -(CH2)rNRbC(O)ORC,
-NRbC(O)NR11R11, -S(O)pNR11R11, -NRbS(O)pRC, -S(O)RC, -S(O)2RC, C1-6alkyl
substituted with 0-3 Rf, Cl-6haloalkyl, -(CH2)r-3-14 membered carbocycle, or -(CH2)r-5-7 15 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p substituted with 0-3 Rf;
Rb at each occurrence is hydrogen, C1-6 alkyl substituted with 0-3 Rd,
C1-6 halo alkyl, C3-6 cycloalkyl substituted with 0-2 Rd, or -(CH2)r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(0)p substituted with 0-3 Rf, or (CH2)r-phenyl substituted with 0-3 Rd;
Rc is C1-6 alkyl substituted with 0-3 Rf, (CH2)r-C3_6 cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf;
Rd at each occurrence is independently hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, ORe, -(CH2)rC(O)Rc, NReRe, -NReC(O)ORc, C1-6 alkyl or (CH2)r-phenyl substituted with 0-3 Rf;
Re at each occurrence is independently selected from hydrogen, C1-6 alkyl,
C3-6 cycloalkyl and ( CH2)r- phenyl substituted with 0-3 Rf;
R independently at each occurrence is hydrogen, halo, CN, N¾, OH,
C3-6 cycloalkyl, CF3, 0( C1-6alkyl) or a -(CH2)r-5-7 membered heteroaryl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(0)p;
p is 0, 1, or 2; and
r is 0, 1,2,3, or 4.
[0071] In a twenty- seventh embodiment, the disclosed Tyk2 inhibitors may be selected from those having the formula:
Figure imgf000020_0001
or a pharmaceutically acceptable salt thereof, wherein the variables are as described in WO 2015/069310, the entire contents of which are incorporated herein by reference.
[0072] In a twenty-eighth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the formula:
Figure imgf000020_0002
or a pharmaceutically acceptable salt thereof, wherein
Y is N or CR6;
R1 is H, Ci-3alkyl or C3_6cycloalkyl, each optionally substituted by 0-7 R1a;
R1aat each occurrence is independently hydrogen, deuterium, F, Cl, Br or CN; R2 is C1-6alkyl, -(CH2)r-3-14 membered carbocycle substituted with 0-1 R2a or a 5-14 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-4 R2a (for the sake of clarity, R2 is intended to include substituted methyl groups such as -C(O)R2a);
R2a at each occurrence is independently hydrogen, =O, halo, OCF3, CN, NO2, - (CH2)rORb, -(CH2)rSRb, -(CH2)rC(O)Rb, -(CH2)rC(O)ORb, -(CH2)rOC(O)Rb, CH2)rNR11R11, - (CH2)rC(O)NR11R11, -(CH2)rNRbC(O)Rc, -(CH2)rNRbC(O)ORc, -NRbC(O)NR11R11, - S(O)pNR11R11, -NRbS(O)pRc, -S(O)pRc, C1-6 alkyl substituted with 0-3 Ra, C1-6 haloalkyl, C2- 6 alkenyl substituted with 0-3 Ra, C2-6 alkynyl substituted with 0-3 Ra, -(CH2)r-3-14 membered carbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle comprising carbon atoms or 1-4 heteroatoms selected from N, O, and S(O)p substituted with 0-2 Ra;
R3 is C3-10 cycloalkyl, C6-10 aryl or a 5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-4 R3a;
R3a at each occurrence is independently hydrogen, =O, halo, OCF3, CF3, CHF2, CN, NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(O)Rb, -(CH2)rC(O)ORb, -(CH2)rOC(O)Rb, - (CH2)rNR11R11, -(CH2)rC(O)NR11R11, -(CH2)rNRbC(O)Rc, -(CH2)rNRbC(O)ORc, - NRbC(O)NR11R11, -S(O)pNR11R11, -NRbS(O)pRc, -S(O)pRc, C1-6 alkyl substituted with 0-3 Ra, C2-6 alkenyl substituted with 0-3 Ra, C2-6 alkynyl substituted with 0-3 Ra, C1-6 haloalkyl, - (CH2)r-3-14 membered carbocycle substituted with 0-3 Ra or a -(CH2)r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and
S(O)p substituted with 0-3 Ra;
or two R3a, together with the atoms to which they are attached, combine to form a fused ring wherein said ring is selected from phenyl and a heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p, each fused ring substituted with 0- 3 Ra1;
R4 and R5 are independently hydrogen, C1-4 alkyl substituted with 0-1 Rf, (CH2)r- phenyl substituted with 0-3 Rd or a -(CH2)-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p;
R6 is hydrogen, halo, C1-4alkyl, C1-4haloalkyl, OC1-4haloalkyl, OC1-4alkyl, CN, NO2 or OH;
R11 at each occurrence is independently hydrogen, C1-4 alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd or -(CH2)r- 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p substituted with 0-3 Rd; Ra and Ra1 at each occurrence are independently hydrogen, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(O)Rb, -(CH2)rC(O)ORb, -(CH2)rOC(O)Rb, -(CH2)rNR11R11, -(CH2)rC(O)NR11R11, -(CH2)rNRbC(O)Rc, -(CH2)rNRbC(O)ORc, - NRbC(O)NR11R11, -S(O)pNR“R”, -NRbS(O)pRc, -S(O)Rc, -S(O)2Rc, C1-6 alkyl substituted with 0-3 Rf, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, C2-6 alkynyl substituted with 0-3 Ra, -(CH2)r-3-14 membered carbocycle or -(CH2)r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p substituted with 0-3 Rf;
Rb is hydrogen, C1-6 alkyl substituted with 0-3 Rd, C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 Rd, or -(CH2)r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rd;
Rc is C1-6 alkyl substituted with 0-3 Rf, (CH2)r-C3-6 cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf;
Rd at each occurrence is independently hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, - ORe, -(CH2)rC(O)Rc, -NReRe, -NReC(O)ORc, C1-6 alkyl or (CH2)r-phenyl substituted with 0-3 Rf;
Re at each occurrence is independently selected from hydrogen, C1-6 alkyl, C3- 6cycloalkyl and (CH2)r-phenyl substituted with 0-3 Rf;
Rf independently at each occurrence is hydrogen, halo, CN, NH2, OH, C3-6 cycloalkyl, CF3, O(C1-6alkyl) or a -(CH2)r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p;
p is 0, 1, or 2; and
r is 0, 1, 2, 3, or 4, wherein additional definitions and specific compounds are as described in US 9,505,748 and WO 2018/0162889, the entire contents of each of which are incorporated herein by reference.
[0073] In a twenty-ninth embodiment, the disclosed Tyk2 inhibitors may be selected from those having the formulae:
Figure imgf000022_0001
;
or a pharmaceutically acceptable salt thereof, wherein:
Figure imgf000023_0001
[0074] In a thirtieth embodiment, the Tyk2 inhibitor described herein is 6- (cyclopropanecarboxamido)-4-((2-methoxy-3-(l-methyl-lH-l,2,4-triazol-3- yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165), having the following chemical structure:
Figure imgf000023_0002
or a pharmaceutically acceptable salt thereof.
[0075] The specific dosage and treatment regimen for a disclosed Tyk2 inhibitor to be used in combination with apremilast will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated.
[0076] In a thirty-first embodiment, the effective amount of a disclosed Tyk2 inhibitor (e.g., as in any one of the second to thirtieth embodiment) to be used in combination with apremilast ranges from 0.001 to 50 mg/kg body weight/day. For example, as part of a thirty- first embodiment, the effective amount of a disclosed Tyk2 inhibitor (e.g., as in any one of the second to thirtieth embodiment) to be used in combination with apremilast ranges from about 0.1 mg/day to about 250 mg/day, e.g., from about 0.2 mg/day to about 100 mg./day, about 0.5 mg/ day to about 50 mg/day, and about 1.0 mg to about 24 mg/day.
[0077] 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, ranges from about 0.1 mg/day to about 250 mg/day, about 0.1 mg/day to about 100 mg/day, about 0.1 mg/day to about 50 mg/day, about 0.1 mg/day to about 25 mg/day 0.1 mg/day to about 15 mg/day, about 0.1 mg/day to about 10 mg/day, about 0.5 mg/day to about 15 mg/day, about 0.5 mg/day to about 10 mg/day, about 0.1 mg/day to about 5 mg/day, about 0.5 mg/day to about 5 mg/day, about 1 mg/day to about 25 mg/day, about 2 mg/day to about 14 mg/day, about 2 mg/day to about 12 mg/day, or about 3 mg/day to about 12 mg/day. Alternatively, as part of a thirty-second embodiment, the effective amount of BMS-986165, or a pharmaceutically acceptable salt thereof ranges from about 1 mg/day to about 15 mg/day, 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.
[0078] In a thirty-third embodiment, the Tyk2 inhibitor described herein is BMS-986165, or a pharmaceutically acceptable salt thereof, and the effective amount of BMS-986165, or a pharmaceutically acceptable salt thereof, is about 0.1 mg/day, about 0.5 mg/day, about 1.0 mg/day, about 2 mg/day, about 3 mg/day, about 4 mg/day, about 5 mg/day, about 6 mg/day, about 7 mg/day, about 8 mg/day, about 9 mg/day, about 10 mg/day, about 11 mg/day, or about 12 mg/day. Alternatively, as part of a thirty-third embodiment, the effective amount of BMS-986165, or a pharmaceutically acceptable salt thereof, is about 2 mg/day, about 3 mg/day, about 4 mg/day, about 5 mg/day, about 6 mg/day, about 7 mg/day, about 8 mg/day, about 9 mg/day, about 10 mg/day, about 11 mg/day, or about 12 mg/day. In another alternative, as part of a 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 a thirty-third embodiment, the effective concentration of BMS-986165, or a pharmaceutically acceptable salt thereof, is about 1 nM to about 1 mM (e.g., from about 0.01 mM to about 0.1 mM).
3. Apremilast
[0079] As described above, apremilast is optically enriched as the (S) enantiomer. In a thirty-fourth embodiment, the stereomeric 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., as in any one of the first to thirty-third embodiments. Alternatively, as part of a thirty-fourth embodiment, the stereomeric 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 the first to thirty- third embodiments. In another alternative, as part of a thirty-fourth embodiment, the stereo meric 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 thirty- third embodiments. In another alternative, as part of a thirty- fourth embodiment, the stereo meric 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 thirty-third embodiments. In another alternative, as part of a thirty- fourth embodiment, the stereomeric 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 thirty-third embodiments. In another alternative, as part of a thirty-fourth embodiment, the stereomeric 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 thirty-third embodiments. In another alternative, as part of a thirty-fourth embodiment, the stereomeric 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 thirty-third embodiments.
[0080] Polymorphic forms of apremilast are included in the disclosed methods and compositions and include e.g., those described 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 a single crystalline form, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-fourth embodiments.
[0081] In a thirty-sixth embodiment, apremilast in the disclosed methods and compositions is a single crystalline Form B characterized by X-ray powder diffraction peaks at 2Q angles selected from 10.1°, 13.5°, 20.7°, and 26.9°, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., 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 is a single crystalline Form B characterized by X-ray powder diffraction peaks at 2Q angles selected from 10.1°, 13.5°, 15.7°, 18.1°, 20.7°, 24.7°, and 26.9°, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-fourth embodiments. In another alternative, as part of a thirty-sixth embodiment, apremilast in the disclosed methods and compositions is a single crystalline Form B characterized by X-ray powder diffraction peaks at 2Q angles selected from 10.1°, 13.5°, 15.7°, 16.3°, 18.1°, 20.7°, 22.5°, 24.7°, 26.2°, 26.9°, and 29.1°, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-fourth embodiments.
[0082] In a thirty- seventh embodiment, apremilast in the disclosed methods and compositions is at least 90% single crystalline Form B, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- sixth embodiments. Alternatively, apremilast in the disclosed methods and compositions is at least 95% single crystalline Form B, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-sixth embodiments. In another alternative, apremilast in the disclosed methods and compositions is at least 99% single crystalline Form B, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-sixth embodiments.
[0083] The specific dosage and treatment regimen of apremilast, or a pharmaceutically acceptable salt thereof, to be used in combination with a disclosed Tyk2 inhibitor will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated.
[0084] For example, in a thirty-eighth embodiment, the effective amount of apremilast, or the pharmaceutically acceptable salt thereof, ranges from about 0.5 mg to about 1000 mg per day, about 1 mg to about 1000 mg per day, about 5 mg to about 500 mg per day, about 10 mg to about 200 mg per day, about 10 mg to about 100 mg per day, about 40 mg to about 100 mg per day, about 20 mg to about 40 mg per day, about 0.1 mg to about 10 mg per day, about 0.5 mg to about 5 mg per day, about 1 mg to about 20 mg per day, and about 1 mg to about 10 mg per day, about 1 mg to about 100 mg per day, about 1 mg to about 80 mg per day, about 5 mg to about 70 mg per day, about 10 mg to about 60 mg per day, and about 10 mg to about 40 mg per day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments. Alternatively, as part of a thirty-eighth embodiment, the effective amount of apremilast, or the pharmaceutically acceptable salt thereof, ranges from about 10 mg to about 60 mg per day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments. In another alternative, as part of a thirty-eighth embodiment, the effective amount of apremilast, or the pharmaceutically acceptable salt thereof, ranges from about 40 mg to about 100 mg per day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments. In another alternative, as part of a thirty-eighth embodiment, the effective amount of apremilast, or the pharmaceutically acceptable salt thereof, ranges from between about 40 mg to between about 100 mg per day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments. In another alternative, as part of a thirty- eighth embodiment, the effective amount of apremilast, or the pharmaceutically acceptable salt thereof, ranges from about 4 mg to about 10 mg per day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments. In another alternative, as part of a thirty- eighth embodiment, the effective amount of apremilast, or the pharmaceutically acceptable salt thereof, ranges from between about 4 mg to between about 10 mg per day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments. In another alternative, as part of a thirty-eighth embodiment, the effective amount of apremilast, or the pharmaceutically acceptable salt thereof, ranges from about 10 mg to about 40 mg per day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments. In another alternative, as part of a thirty-eighth embodiment, the effective amount of apremilast, or the pharmaceutically acceptable salt thereof, is about 1 mg per day, about 2 mg per day, about 3 mg per day, about 4 mg per day, about 5 mg per day, about 10 mg per day, about 15 mg per day, about 20 mg per day, about 25 mg per day, about 30 mg per day, about 35 mg per day, about 40 mg per day, about 45 mg per day, about 50 mg per day, about 55 mg per day, or about 60 mg per day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments. In another alternative, as part of a thirty-eighth embodiment, the effective amount of apremilast, or the pharmaceutically acceptable salt thereof, is about 30 mg per day or about 60 mg per day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments. In another alternative, as part of a thirty-eighth embodiment, apremilast is administered at a dose of about 30 mg once daily, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments. In another alternative, as part of a thirty-eighth embodiment, apremilast is administered at a dose of about 30 mg twice daily, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments. In another alternative, as part of a thirty-eighth embodiment, the effective amount of apremilast, or the pharmaceutically acceptable salt thereof, is about 10 mg per day or about 40 mg per day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments. In another alternative, as part of a thirty-eighth embodiment, apremilast is administered at a dose of about 10 mg once or twice daily, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments. In another alternative, as part of a thirty-eighth embodiment, apremilast is administered at a dose of about 20 mg once or twice daily, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments. In another alternative, as part of a thirty-eighth embodiment, the effective concentration of apremilast is about 100 nM to about 10 mM (e.g., from about 0.1 mM to about 1 mM), wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments.
[0085] In a thirty-ninth embodiment, apremilast is titrated to a dosage of about 30 mg administered twice daily using the following titration schedule:
Day 1: about 10 mg in morning;
Day 2: about 10 mg in morning and about 10 mg in evening;
Day 3: about 10 mg in morning and about 20 mg in evening;
Day 4: about 20 mg in morning and about 20 mg in evening;
Day 5: about 20 mg in morning and about 30 mg in evening; and
Day 6 and thereafter: about 30 mg twice daily, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments. Alternatively, apremilast is titrated to a dosage of between about 40 mg/day to between about 100 mg/day using the following titration schedule:
Day 1: about 10 mg in morning;
Day 2: about 10 mg in morning and about 10 mg in evening;
Day 3: about 10 mg in morning and about 20 mg in evening;
Day 4: about 20 mg in morning and about 20 mg in evening; Day 5: about 20 mg in morning and about 30 mg in evening; and
Day 6 and thereafter: between about 40 mg/day to between about 100 mg/day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments. In another alternative, apremilast is titrated to a dosage of about 20 mg administered twice daily using the following titration schedule:
Day 1: about 10 mg in morning;
Day 2: about 10 mg in morning and about 10 mg in evening;
Day 3: about 10 mg in morning and about 20 mg in evening;
Day 4: about 20 mg in morning and about 20 mg in evening;
Day 5: about 20 mg in morning and about 30 mg in evening; and
Day 6 and thereafter: about 20 mg twice daily, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments. In yet another alternative, apremilast is titrated to a dosage of between about 4 mg/day to between about 10 mg/day using the following titration schedule:
Day 1: about 1 mg in morning;
Day 2: about 1 mg in morning and about 1 mg in evening;
Day 3: about 1 mg in morning and about 2 mg in evening;
Day 4: about 2 mg in morning and about 2 mg in evening;
Day 5: about 2 mg in morning and about 3 mg in evening; and
Day 6 and thereafter: between about 4 mg/day to between about 10 mg/day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments. In yet another alternative, apremilast is titrated to a dosage of about 3 mg administered twice daily using the following titration schedule:
Day 1: about 1 mg in morning;
Day 2: about 1 mg in morning and about 1 mg in evening;
Day 3: about 10 mg in morning and about 2 mg in evening;
Day 4: about 2 mg in morning and about 2 mg in evening;
Day 5: about 2 mg in morning and about 3 mg in evening; and
Day 6 and thereafter: about 3 mg twice daily, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments. 3. Compositions and Administration
[0086] Also provided herein are pharmaceutical compositions comprising a therapeutically effective amount of apremilast, or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a Tyk2 inhibitor (e.g., BMS-986165). Features for the disclosed pharmaceutical compositions include elements described above e.g., as in any one of the first to thirty-eighth embodiments.
[0087] Further provided are pharmaceutical compositions comprising a therapeutically effective amount of apremilast, or a pharmaceutically acceptable thereof; and a
therapeutically effective amount of a Tyk2 inhibitor (e.g., BMS-986165), for use in treating a disease or disorder responsive to the inhibition of PDE4. Features for the disclosed pharmaceutical compositions include elements described above e.g., as in any one of the first to thirty-eighth embodiments.
[0088] Pharmaceutical compositions and single unit dosage forms comprising apremilast and a Tyk2 inhibitor (e.g., BMS-986165) alone or together in a fixed dose for administration as described above (e.g., as in any one of the first to thirty-eighth embodiments) is included. Single unit dosage forms of the disclosed methods and compositions are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,
Subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), or transdermal administration to a patient. Examples of dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non- aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suit able for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.
[0089] The composition, shape, and type of dosage forms of the will typically vary depending on their use. For example, a dosage form used in the acute treatment of
inflammation or a related disorder may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the chronic treatment of the same disease. Similarly, a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease or disorder. These and other ways in which specific dosage forms encompassed by this invention will vary from one another will be readily apparent to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).
[0090] In a thirty-ninth embodiment, apremilast in the disclosed methods and compositions is administered parenterally, transdermally, mucosally, nasally, buccally, sublingually, or orally, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., 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 for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-eighth embodiments.
[0091] In a fortieth embodiment, apremilast in the disclosed methods and compositions is administered orally in the form of a tablet or a capsule, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- ninth embodiments.
[0092] In a forty-first embodiment, apremilast in the disclosed methods and compositions is formulated as an extended release form, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- ninth embodiments.
[0093] In a forty- second embodiment, apremilast in the disclosed methods and
compositions is formulated as an immediate release form, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- ninth embodiments.
[0094] In a forty- third embodiment, both the apremilast and the Tyk2 inhibitor in the disclosed methods and compositions are administered in fixed dosage combination as a once a day formulation, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to forty-second embodiments.
4. Conditions Treated by the Methods and Compositions Disclosed Herein
[0095] Diseases or disorders that are responsive to the inhibition of PDE4 using the methods and compositions disclosed herein include e.g., viral, genetic, inflammatory, allergic, and autoimmune conditions. [0096] In one aspect, the disease or disorder responsive to the inhibition of PDE4 is selected from 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 erythrematosus, erythema nodosum leprosum, Sjogren’s syndrome, inflammatory bowel disease, Crohn’s Disease, Behcet’s Disease, and ulcerative colitis.
[0097] In one aspect, the disease or disorder responsive to the inhibition of PDE4 is selected from psoriasis, psoriatic arthritis, contact dermatitis, systemic lupus erythrematosus, cutaneous lupus erythematosus, and ulcerative colitis.
[0098] In one aspect, the disease or disorder responsive to the inhibition of PDE4 is psoriasis. In another aspect, the disease or disorder responsive to the inhibition of PDE4 is psoriasis and the subject being treated is a candidate for phototherapy or systematic therapy.
[0099] In one aspect, the disease or disorder responsive to the inhibition of PDE4 is plaque psoriasis. In another aspect, the disease or disorder responsive to the inhibition of PDE4 is plaque psoriasis and the subject being treated is a candidate for phototherapy or systematic therapy.
[00100] In one aspect, the disease or disorder responsive to the inhibition of PDE4 is moderate to severe plaque psoriasis. In another aspect, the disease or disorder responsive to the inhibition of PDE4 is severe plaque psoriasis and the subject being treated is a candidate for phototherapy or systematic therapy.
[00101] In one aspect, the disease or disorder responsive to the inhibition of PDE4 is psoriatic arthritis.
[00102] In one aspect, the disease or disorder responsive to the inhibition of PDE4 is active psoriatic arthritis.
[00103] In one aspect, the disease or disorder responsive to the inhibition of PDE4 is heart disease, such as congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acute viral myocarditis, cardiac allograft rejection, and myocardial infarction.
[00104] In one aspect, the disease or disorder responsive to the inhibition of PDE4 is HIV, hepatitis, adult respiratory distress syndrome, bone-resorption diseases, cystic fibrosis, septic shock, sepsis, endotoxic shock, hemodynamic shock, sepsis syndrome, post ischemic reperfusion injury, meningitis, fibrotic disease, cachexia, graft rejection, osteoporosis, multiple sclerosis, and radiation damage.
[00105] In one aspect, the disease or disorder responsive to the inhibition of PDE4 is cancer of the head, thyroid, neck, eye, skin, mouth, throat, esophagus, cheat, bone, blood, bone marrow, lung, colon, sigmoid, rectum, stomach, prostate, breast, ovaries, kidney, liver, pancreas, brain, intestine, heart, adrenal, subcutaneous tissue, lymph nodes, heart, and combinations thereof.
[00106] In one aspect, the disease or disorder responsive to the inhibition of PDE4 is multiple myeloma, malignant melanoma, malignant glioma, acute lymphoblastic leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute
myeloblastic leukemia, acute promyelocytic leukemia, acute monoblastic leukemia, acute erythroleukemic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocyctic leukemia, acute undifferentiated leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, hairy cell leukemia, multiple myeloma and acute, lymphoblastic leukemia, myelogenous leukemia, lymphocytic leukemia, and myelocytic leukemia.
[00107] In one aspect, the disease or disorder responsive to the inhibition of PDE4 is a solid tumor, such as sarcoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangio sarcoma, lymphangioendotheliosarcoma, syn-ovioma, 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 gland carcinoma, papillary car-cinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarci-noma, seminoma, embryonal carcinoma, Wilms’ tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, Kaposi’s sarcoma, pinealoma, hemangioblas-toma, acoustic neuroma, oligodendroglioma, menangioma, melanoma, neuroblastoma, and retinoblastoma. EXEMPLIFICATION
1. Materials
Table 1: Whole blood assay: Study Materials and Reagents.
Figure imgf000034_0001
Table 2: LPS stimulated PBMCs assay: Study Materials and Reagents
Figure imgf000034_0002
Table 3: Test Articles for Studies
Figure imgf000034_0003
2. General Methods
[00108] Whole blood was received through the Celgene Donor program after informed consent and donor deidentification. All volunteers were healthy and were not on any medications for at least 72 hours prior to the blood draw. Blood was collected in sodium heparin tubes. The assay was started within 2 hours of the blood draw.
[00109] An ex- vivo stimulation of healthy donor human whole blood was performed under two different stimulation conditions. Condition ThO was a stimulation with
TruCulture® tubes containing anti-CD3/anti-CD28. Condition Thl7 was a stimulation with TruCulture® tubes containing anti-CD3/anti-CD28 plus IL-Ib, IL-6 and IL-23. Whole blood was separated into 15 milliliter conical tubes and pre-treated with DMSO, apremilast alone, BMS-986165 alone or BMS-986165 combined with apremilast. Final concentrations were 0.2% DMSO, 1 mM for apremilast alone, 1 mM, 0.1 mM, 0.01 mM and 0.001 mM BMS- 986165 alone and in combination with 1 mM apremilast. Blood was mixed well and then incubated in a 37°C/5%C02 incubator for 1 hour.
[00110] The anti-CD3/anti-CD28 (200 ng/ml and 330 ng/ml final concentrations respectively) TruCulture® tubes were thawed on the bench top for 30 minutes and then labeled. Plungers were pressed and then broken off. TruCulture® tubes were placed in a rack standing upright such that the plunger side is pointing down in the rack and the tube-cap is pointing up. While blood was incubating with compound Human recombinant IL-6, IL-Ib and IL-23 were added to all Thl7 tubes in the following concentrations: 120 ng IL-6, 120 ng IL-lb and 150 ng IL-23. One ml of the pre-treated whole blood was placed in each tube, using sterile pyrogen-free pipette tips. The cap was replaced and the contents of the tube were mixed by inverting 3 times. The tubes were immediately placed in a 37°C heat block and incubated for 42 hours (tube-cap end). After the 42 hours the tubes were removed from the heat block, tops were unscrewed and 250 mΐ of the supernatant was removed and transferred into three 96-well polypropylene plates. Samples were immediately frozen at -80°C. The supernatants were then thawed at room temperature and tested neat for cytokine production by Luminex Multi-Plex MagPix technology (Millipore) or IL-22 by ELISA (Abeam). The manufacturer’s procedures were followed accordingly.
[00111] Peripheral blood mononuclear cells (PBMCs) isolation: Whole blood was received through the Celgene Donor program after informed consent and donor
deidentification. All volunteers were healthy and were not on any medications for at least 72 hours prior to the blood draw. Blood was collected in Sodium Heparin tubes and were used within 2 hours of the blood draw for PBMCs isolation. Before PBMCs isolation, whole blood was diluted 1:1 with PBS solution containing 2%FBS (2%FBS-PBS). 13ml of Ficoll-Paque solution was loaded in the SemMate® tube and 25ml of diluted blood was loaded on top of the Ficoll-Paque. Centrifugation at 1200g for 15 minutes with the brake on for cell separation, after which isolated PBMCs were transferred into a new tube. PBMCs were washed with 2%FBS-PBS and centrifuged at 800g 10 minutes. Pellets were resuspended in 2%FBS-PBS and filtered through a 40mm cell strainer to obtain single-cell suspension. 3ml of RBC lysis buffer were used to eliminate red blood cells in the isolated population. Isolated PBMCs were washed with 2%FBS-PBS and were resuspended in RPMI growth medium containing 10%FBS and antibiotics.
[00112] For Example 6-11, PBMCs from 9 healthy donors were isolated and LPS- stimulated ex- vivo for IL-23, IL-12p40, IL-12p70, TNF-a , IFN-g and MCP-1 cytokine analysis. PBMCs were plated in 96 well plate at a density of 200,000 cells per well in 200 mΐ of RPMI growth medium containing 10%FBS followed by treatment with DMSO and compounds. Each well received the same amount of DMSO, which is 0.3% v/v as final concentration. Series dilutions of compound treatment was performed according to Table 4 shown below. After two hours of compound treatment, LPS 100 ng/ml as final concentration was used as the stimulator. PBMCs were then incubated in a 37°C/5%C02 incubator for 16 hours.
Table 4: Compound treatment conditions for PBMC assays
Figure imgf000036_0001
Figure imgf000037_0001
[00113] After 16 hours incubation, supernatants were collected into new 96- well polypropylene plates and centrifuged at 4000 rpm for 10 minutes to get rid of cell debris. Cytokine production was measured by Luminex Bio-Plex Multiplex Immunoassay (Bio-Rad) according to the manufacturer’s procedures. To ensure that supernatant level was within the range of the standard cytokine for the assay, samples were diluted 5 fold for IL-12p40 and 27-plex assays, and used neat for IL-23 assay.
3. Data Analysis
[00114] Data processing for the cytokine analysis was done using Milliplex Analyst (Millipore), and raw data was exported to Excel template for the cytokine analysis. Data from the template was plotted using GraphPad Prism 7.0 (GraphPad Software, Inc., La Jolla, CA) and expressed as pg/ml or % of control. Statistical analysis was also performed using One Way Anova and Dunnett’s Post Test.
[00115] Data processing for PBMCs assays was done using Bio-plex manager, and raw data was exported to Excel template for the cytokine analysis. Data was 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.
[00116] To evaluate the combinatory effect of apremilast and BMS-986165, data from the two independent treatments were analyzed by comparing the combinatory response against the theoretical additive response of the two agents. The expected additive effect of two agents (A and B) was calculated using the fractional product method: (/u)A,B = (/u)A x (/u)B; where /u = fraction unaffected by treatment. A synergism of a combination is determined when the observed fraction unaffected in combination is less than (/u)A,B, whereas an additive effect is determined when the observed fraction unaffected in
combination equals (/u)A,B. A partially additive effect is indicated when the observed fraction unaffected in combination is greater than (/u)A,B. Example 1
Interleukin 17A Cytokine Production by Apremilast and BMS-986165 in anti-CD3/anti- CD28 (ThO) or anti-CD3/anti-CD28, IL-Ib, IL-6 and IL-23 (Thl7) Stimulated Whole
Blood
[00117] Whole blood from 4 healthy donors were analyzed for IL-17A, IL-17F, IL-22, TNF-a and GM-CSF cytokine production in both ThO and Thl7 conditions. The blood was pre-treated with apremilast and Tyk2 inhibitor BMS-986165 both alone and in combination using the TruCulture® Tube System. The IL-17A results located in FIG. 1 show the IL- 17A% of control and all data is normalized to the Thl7 DMSO control. Apremilast inhibited 28% of IL-17A cytokine expression under ThO conditions and had no effect in Thl7 conditions. BMS-986165 had a similar effect under both stimulation conditions and inhibited 10-25% of IL-17A expression at 0.001-1 mM. When apremilast was combined with BMS- 986165 under ThO conditions there was synergy seen with 1 mM BMS-986165 with a 65% reduction in IL-17A. Under Thl7 conditions there was synergy with the combination of 1 mM apremilast and 0.01 mM, 0.1 mM and 1 mM BMS-986165 with inhibition of 24%, 44% and 85% of IL-17A respectively. FIG. 2 shows the picograms per milliliter levels of IL-17A. Levels of IL-17A increased in the Thl7 stimulation conditions by 387% compared to the ThO stimulation. In ThO conditions apremilast reduced IL-17A levels from 138 pg/mL to
93 pg/mL. BMS-986165, at 1 mM reduced IL-17A levels to 97 pg/mL. The combination of apremilast with 1 mM BMS-986165 further reduced IL-17A levels to 24pg/mL with the ThO stimulation. Under Thl7 conditions the 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 mM, 428 pg/mL at 0.1 mM and 383 pg/mL at 1 mM. The combination of 1 mM apremilast with BMS-986165 reduced IL-17A levels to 379 pg/mL at 0.01 mM, 328 pg/mL at 0.1 mM and 68 pg/mL at 1 mM BMS-986165.
Example 2
Interleukin 17F Cytokine Production by Apremilast and BMS-986165 in anti-CD3/anti- CD28 (ThO) or anti-CD3/anti-CD28, IL-Ib, IL-6 and IL-23 (Thl7) Stimulated Whole
Blood
[00118] IL-17F cytokine expression data is in FIG. 3 and FIG. 4. Apremilast inhibited 69% of IL-17F production under ThO conditions and 49% under Thl7 conditions. BMS- 986165 had a similar effect on IL-17F with both the ThO and Thl7 stimulation. There was 31% inhibition at the lowest concentration of 0.001 mM and a dose response with 34% inhibition at 0.01 mM, 70% inhibition at 0.1 mM and 95% inhibition of IL-17F expression at 1 mM (Thl7 results). The combination of 1 mM apremilast with BMS-986165 under ThO conditions was partially additive with inhibition ranging from 60% at 0.001 to 95% at 1 mM. Under Thl7 conditions lower concentrations of BMS-986165 combined with apremilast showed synergy. Apremilast combined with BMS-986165 at 0.001 mM inhibited 68% of IL- 17F, 0.01 mM inhibited 70%, 0.1 mM inhibited 94% and 1 mM inhibited 99% of IL-17F production under Thl7 stimulation conditions. Levels of IL-17F in the ThO stimulation control were 1085 pg/mL and increased to 6524 pg/mL in the Thl7 stimulation. Apremilast reduced IL-17F to 368 pg/mL in the ThO stimulation and to 3643 pg/mL in the Thl7 stimulation. BMS-986165 significantly reduced IL-17F at 0.1 and 1 mM in both stimulation conditions. There was significant inhibition of IL-17F at all concentrations of BMS-986165 when combined with apremilast and under both stimulation conditions.
Example 3
Interleukin 22 Cytokine Production by Apremilast and BMS-986165 in anti-CD3/anti- CD28 (ThO) or anti-CD3/anti-CD28, IL-Ib, IL-6 and IL-23 (Thl7) Stimulated Whole
Blood
[00119] IL-22 cytokine expression data is in FIG. 5 and FIG. 6. Apremilast inhibited
85% of IL-22 cytokine expression under ThO conditions and 41% under Thl7 conditions. Under ThO stimulation condition BMS-986165 inhibited 16% of IL-22 at 0.01 mM, 86% at 0.1 mM and 91% at 1 mM. Under Thl7 stimulation conditions BMS-986165 had no effect on IL-22 cytokine expression at 0.001 mM but inhibited 17% at 0.01 mM, 60% at 0.1 mM and 70% at 1 mM. Under ThO conditions the combination had similar effects to apremilast alone with -90% inhibition at all concentrations of BMS-986165. The combination under Thl7 conditions was synergist at 0.01 mM with 60% inhibition and at 0.1 mM with 90% inhibition of IL-22 cytokine expression. The ThO stimulation control had 1085 pg/mL of IL-22 and the Thl7 control was 6524 pg/mL. Apremilast significantly lowered IL-22 levels to 368 pg/mL in the ThO conditions and 3643 pg/mL in the Thl7 conditions. BMS-986165 significantly lowered IL-22 cytokine expression in both stimulation conditions at 0.1 mM and 1 mM. There was significant inhibition of IL-22 at all concentrations of BMS-986165 when combined with apremilast and under both stimulation conditions. Example 4
TNF-a Cytokine Production by Apremilast and BMS-986165 in anti-CD3/anti-CD28 (ThO) or anti- CD3/anti- CD28, IL-Ib, IL-6 and IL-23 (Thl7) Stimulated Whole Blood
[00120] TNF-a cytokine expression data is located in FIG. 7 and FIG. 8. Apremilast inhibited 90% of TNF-a levels in ThO conditions and 94% in Thl7 conditions. In the ThO stimulation BMS-986165 increased TNF-a expression by 21% at 0.001 mM, 43% at 0.01 mM and 61% at 0.1 mM. At the highest concentration of 1 mM BMS-986165 inhibited 66% of TNF-a cytokine expression. There was a similar increase in TNF-a production seen with BMS-986165 under Thl7 conditions with a 19% increase at 0.01 mM and a 77% increase at 0.1 mM. There was also inhibition of TNF-a (68%) with 1 mM BMS-986165 under Thl7 stimulation conditions. The combination of 1 mM apremilast with BMS-986165 reduced levels of TNF-a by 80-95% (ThO) and 93-96% (Thl7), a similar effect to single agent apremilast. Both stimulation conditions had a similar effect on levels of TNF-a with the ThO stimulation control of 1380 pg/mL and the Thl7 stimulation control of 1436 pg/mL.
Apremilast significantly inhibited TNF-a by reducing levels to 148 pg/mL in ThO conditions and 91 pg/mL in Thl7 conditions. The increase in TNF-a levels by BMS-986165 was significant in Thl7 conditions at 0.1 mM. The inhibition of TNF-a levels with 1 mM BMS- 986165 was significant under both stimulation conditions. The combination of apremilast with BMS-986165 significantly inhibited TNF-a levels with all concentrations and in both stimulation conditions.
Example 5
Granulocyte-Macrophage Colony-Stimulating Factor Cytokine Production by Apremilast and BMS-986165 in anti-CD3/anti-CD28 (ThO) or anti-CD3/anti-CD28, IL- 1b, IL-6 and IL-23 (Thl7) Stimulated Whole Blood
[00121] Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) cytokine expression results are in FIG. 9 and FIG. 10. GM-CSF cytokine expression was reduced 80% by apremilast under ThO conditions and by 66% under Thl7 conditions. BMS-986165 increased GM-CSF cytokine expression under both conditions. BMS-986165 increased GM- CSF by 19% at 0.001 mM, 36% at 0.01 mM, 110% at 0.1 mM and 31% at 1 mM in the ThO conditions. When apremilast (0.1 mM) was added to BMS-986165 there was inhibition 60- 80% of GM-CSF cytokine expression. In the Thl7 stimulation BMS-986165 increased GM- CSF by 41% at 0.01 mM, 139% at 0.1 mM and 104% at 1 mM. When apremilast was added there was 40-73% inhibition of GM-CSF cytokine expression. Total pg/mL of GM-CSF in the ThO and Thl7 stimulation controls were 409 and 637 respectively. Apremilast significantly inhibited GM-CSF under both stimulation conditions. The increase of GM-CSF by BMS-986165 was significant at 0.1 mM (both ThO and Thl7) and 1 mM (Thl7). The combination of apremilast and BMS-986165 significantly reduced GM-CSF cytokine levels at all concentrations and under both stimulation conditions.
Example 6
IL-23 production in LPS Stimulated PBMCs with Apremilast and Tyk2i (BMS-986165)
Treatment
[00122] PBMCs from 9 healthy donors were analyzed for cytokine production in LPS stimulation condition (FIG. 11 to FIG. 17). Results in FIG. 11 and FIG. 12 showed the level of IL-23. FIG. 11 showed that Apremilast decreased IL-23 production in LPS stimulated PBMCs. IL-23 level from DMSO treated LPS stimulated PBMCs was set as 100% (control), cytokine levels were shown as normalized value in % compared to control. In contrast to decreasing IL-23 level by Apremilast, FIG. 12 showed that BMS-986165 induces IL-23 level in LPS stimulated PBMCs. At the range of 0.2 mM - 2 mM, BMS-986165 induced a 20 fold increases of IL-23 compared to DMSO group. The combination of apremilast with BMS- 986165 was able to decrease the induction of IL-23 by BMS-986165. With increased level of apremilast, there is significant reduction of IL-23 level. Statistical analysis using ANOVA and Turkey’s multiple comparisons were performed to compare each treatment with BMS- 986165 alone. There is significant reduction of IL-23 when combining BMS-986165 with low level of apremilast, which is at the concentration of 0.037mM (**** p<0.001). When combined with 1 mM apremilast, the induction of IL-23 was 90% inhibited, and almost reached a similar level as apremilast alone. Thus, the curve of combination treatment with 1 mM apremilast has no significant difference compared to apremilast treatment alone.
Example 7
IL-12p40 Production in LPS Stimulated PBMCs with Apremilast and Tyk2i (BMS-
986165) Treatment
[00123] Results in FIG. 13 showed the normalized level of IL-12p40 compared to DMSO treated LPS stimulated PBMCs group. Apremilast decreased IL-12p40 in a dose dependent manner, whereas BMS-986165 increased it. The combination of BMS-986165 with apremilast significantly decreased the induction of IL-12p40 by BMS-986165. With lmM apremilast, the increased IL-12p40 induced by BMS-986165 was 85% inhibited, and almost reached a similar level as Apremilast alone. Statistical analysis using ANOVA and Turkey’s multiple comparisons were performed to compare each treatment with BMS- 986165 alone. **** p<0.001
Example 8
IL-12p70 Production in LPS Stimulated PBMCs with Apremilast and Tyk2i (BMS-
986165) Treatment
[00124] Results in FIG. 14 showed the normalized level of IL-12p70 compared to DMSO treated LPS stimulated PBMCs group. Apremilast decreased IL-12p70 in a dose dependent manner, whereas BMS-986165 increased it. The combination of BMS-986165 with apremilast significantly decreased the induction of IL-12p70 by BMS-986165. In combination treatment, both 0.3 mM and 1 mM significantly reduced IL-12p70 level induced by BMS-986165 and have no significant difference compared to apremilast alone. Statistical analysis using ANOVA and Turkey’s multiple comparisons were performed to compare each treatment with BMS-986165 alone. **** p<0.001
Example 9
TNF-a Production in LPS Stimulated PBMCs with Apremilast and Tyk2i (BMS-
986165) Treatment
[00125] Results in FIG. 15 showed the normalized level of TNF-oc compared to DMSO treated LPS stimulated PBMCs group. Apremilast decreased TNF- a level in a dose dependent manner, however, BMS-986165 induced 1.2-1.5 fold increase of TNF-oc. The combination of BMS-986165 and apremilast significantly decreased the level of TNF-oc. Statistical analysis using ANOVA and Turkey’s multiple comparisons were performed to compare each treatment with BMS-986165 alone. **** p<0.001
Example 10
IFN-g Production in LPS Stimulated PBMCs with Apremilast and Tyk2i (BMS-986165)
Treatment
[00126] Results in FIG. 16 showed the normalized level of IFN-g compared to DMSO treated LPS stimulated PBMCs group. Both apremilast alone and BMS-986165 alone decreased IFN-g in a dose dependent manner. The combination of BMS-986165 and apremilast has synergistic effect in reducing IFN-g level which significantly decreased IFN- g level compared to single compound treatment. Statistical analysis using ANOVA and Turkey’s multiple comparisons were performed to compare each treatment with BMS- 986165 alone. **** p<0.001 Example 11
MCP-1 Production in LPS Stimulated PBMCs with Apremilast and Tyk2i (BMS-
986165) Treatment
[00127] Results in FIG. 17 showed the normalized level of MCP-1 compared to DMSO treated LPS stimulated PBMCs group. Both apremilast alone and BMS-986165 alone decreased MCP-1 in a dose dependent manner. The combination of BMS-986165 and
Apremilast has synergistic effect in reducing MCP-1 level. Statistical analysis using ANOVA and Turkey’s multiple comparisons were performed to compare each treatment with BMS- 986165 alone. **** p<0.001.
Data Summary
[00128] Table 5 below provides a summary of the cytokine effects of apremilast and BMS-986165 on stimulated whole blood in the Ex-Vivo TruCulture® Assay. Synergistic effects are shown in bold and complementary effects are underlined.
[00129] Four healthy donors’ whole blood was tested in the Tru-culture assay in ThO (anti-CD3/anti-CD28) or Thl7 (anti-CD3/anti-CD28 + IL-Ib, IL-6 and IL-23) conditions for 48 hours with the Tyk2 inhibitor BMS-986165 +/- apremilast. BMS-986165 inhibited IL-17A, IL-17F, and IL-22 cytokine expression under ThO and Thl7 conditions. When combined with apremilast these cytokines were further reduced with a synergistic effect on IL-17A, IL-17F and IL-22 under Thl7 conditions. BMS-986165 increased TNF-a and GM-CSF production, while apremilast inhibited production of these cytokines. When BMS-986165 was combined with apremilast there was a complementary effect on TNF-a and GM-CSF cytokine expression, with apremilast correcting the defect of BMS-986165. These combined effect provide means for treating diseases or disorders responsive to the inhibition of PDE4 such as for the treatment inflammatory diseases (e.g., psoriasis, psoriatic arthritis, and ulcerative colitis).
Table 5
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000044_0002
Figure imgf000045_0001
[00130] Table 6 below provides a summary of the cytokine effects of apremilast and BMS-986165 on LPS stimulated PBMCs. Red arrows indicate induction and green arrows indicate decrease of the production of cytokines.
[00131] PBMCs from 9 healthy donors were tested in LPS stimulated condition with or without BMS-986165 or apremilast or the combination of both. BMS-986165 treatment alone induced IL-23, IL-12p40, IL-12p70 and TNF-a, whereas apremilast treatment alone decreased these cytokines. When BMS-986165 was combined with apremilast, these cytokines were either unchanged or reduced compared to DMSO control group. These results indicate that apremilast could inhibit the induction of these cytokines by BMS-986165. Both apremilast and BMS-986165 reduced IFN-g and MCP-1 production, and the combination of both further reduced these two cytokines with a synergistic effect. BMS-986165 inhibits Thl7 lineage cytokines, which provide a means for treating diseases where Thl7 cytokines are implicated in the pathogenesis. However, the induction of some proinflammatory cytokines, such as IL-23, IL-12 and TNF-a, by BMS-986165 could be a disadvantage in disease treatment. The combined effects of apremilast and BMS-986165 in which IL-23, IL- 12 and TNF-a were decreased showed an advantage of combining these two compounds in treating inflammatory diseases such as psoriasis, psoriatic arthritis, and ulcerative colitis.
Table 6
Figure imgf000045_0002
Example 12
Apremilast and Tyk2i (BMS-986165) Fixed Dose Combinations in Whole Blood
[00132] Apremilast and BMS-986165 were tested in IL-17A, IL-17F, IL-22, and TNF- oc whole blood at the following fixed dosages: 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 average plasma concentrations observed or extrapolated from clinical PK data.
[00133] As shown by FIGs. 18-21, the 6 mg QD dose concentration of BMS-986165 did not maximally inhibit IL-17A, IL-17F, or IL-22, and it elevated TNF-alpha. See FIGs. 18-21. The addition of apremilast, however, at the 10 to 30 mg BID dose concentrations compensated for this, and prevented the TNF-alpha elevation. See FIGs. 18-21. Even low concentrations of apremilast where shown to be effective. For example, the 20 mg BID dose of apremilast compensated for the suboptimal inhibition of IL-17F, and the 10 mg BID dose of apremilast compensated for the suboptimal inhibition of IL-22, and to prevent the increase of TNF-alpha. This data supports the synergistic use of BMS-986165 (e.g., at 6 mg QD) and apremilast (e.g., 10-20 mg QD or BID) to inhibit IL-17 and IL-22, and reduce TNF-alpha production for the treatment of inflammatory diseases driven by these cyotkines such as psoriasis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, Crohn’s disease, hidradenitis suppurativa, and Behcet’s disease.

Claims

Claims
1. A method of treating a disease or disorder responsive to the inhibition of
phosphodiesterase type 4 (PDE4) in a subject, comprising administering to the subject a therapeutically effective amount of N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide, or a
pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a tyrosine kinase 2 (Tyk2) inhibitor or a pharmaceutically acceptable salt thereof.
2. The method of Claim 1, wherein the Tyk2 inhibitor is of the formula:
Figure imgf000047_0001
or a pharmaceutically acceptable salt thereof, wherein
R1 is Ci-3alkyl optionally substituted by 0-7 R1a;
R1a at each occurrence is independently hydrogen, deuterium, F, Cl, Br, CF3 or CN;
R is Ci_6alkyl or-(CH2)r-3-14 membered carbocycle, each group substituted with 0-4
R2a;
-(CH2)rC(0)NRR , -(CH2)rNRbC(0)Rc, -(CH2)rNRbC(0)0Rc, -NRbC(0)NR R , - S(0)pNRR , -NRbS(0)pRc, -S(0)pRc, Ci_6 alkyl substituted with 0-3 Ra, Ci_6 halo alkyl, C2.
6 alkenyl substituted with 0-3 Ra, C2_6 alkynyl substituted with 0-3 Ra, -(CH2)r-3-14 membered carbocycle substituted with 0-1 Raor a -(CH2)r-5-7 membered heterocycle comprising carbon atoms or 1-4 heteroatoms selected from N, O, and S(0)p substituted with 0-2 Ra;
R is C3-10 cycloalkyl, C6-10 aryl, or a 5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-4 R3a;
R3a at each occurrence is independently hydrogen, =0, halo, OCF3, CF3, CHF2, CN, N02, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(0)Rb, -(CH2)rC(0)ORb, -(CH2)rOC(0)Rb, - (CH2)rNRR , -(CH2)rC(0)NRR , -(CH2)rNRbC(0)Rc, -(CH2)rNRbC(0)ORc, - NRbC(0)NR R , -S(O)pNRR , -NRbS(0)pRc, -S(0)pRc, C1_6 alkyl substituted with 0-3 Ra, C2-6 alkenyl substituted with 0-3 Ra, C2.6 alkynyl substituted with 0-3 Ra, C1-6 halo alkyl, - (CH2)r-3-14 membered carbocycle substituted with 0-3 Ra or a -(CH2)r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and
S(O)p substituted with 0-3 Ra;
or two R3a, together with the atoms to which they are attached, combine to form a fused ring wherein said ring is selected from phenyl and a 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, S or O said fused ring further substituted by Ra1;
R4 and R5 are independently hydrogen, C1-4 alkyl substituted with 0-1 Rf, (CH2)r- phenyl substituted with 0-3 Rd, or a -(CH2)-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p;
R11 at each occurrence is independently hydrogen, C1-4 alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd, or - (CH2)r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p substituted with 0-3 Rd;
Ra and Ra1 at each occurrence are independently hydrogen, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(O)Rb, -(CH2)rC(O)ORb, -(CH2)rOC(O)Rb, -(CH2)rNR11R11, -(CH2)rC(O)NR11R11, -(CH2)rNRbC(O)Rc, -(CH2)rNRbC(O)ORc, - NRbC(O)NR11R11, -S(O)pNR11R11, -NRbS(O)pRc, -S(O)Rc, -S(O)2Rc, C1-6 alkyl substituted with 0-3 Rf, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, C2-6 alkynyl substituted with 0-3 Ra, -(CH2)r-3-14 membered carbocycle or -(CH2)r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p substituted with 0-3 Rf;
Rb at each occurrence is independently hydrogen, C1-6 alkyl substituted with 0-3 Rd, C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 Rd, or -(CH2)r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rd;
Rc is C1-6 alkyl substituted with 0-3 Rf, (CH2)r-C3-6 cycloalkyl substituted with 0-3 Rf, (CH2)r-phenyl substituted with 0-3 Rf; or
Rd at each occurrence is independently hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, - ORe, -(CH2)rC(O)Rc, -NReRe, -NReC(O)ORc, C1-6 alkyl, or (CH2)r-phenyl substituted with 0-3 Rf;
Re at each occurrence is independently selected from hydrogen, C1-6 alkyl, C3- 6 cycloalkyl, and (CH2)r-phenyl substituted with 0-3 Rf; Rf independently at each occurrence is hydrogen, halo, CN, NH2, OH, C3-6cycloalkyl, CF3, O(C1-6alkyl), or a—(CH2)r-5-7 membered heteroaryl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p;
p is 0, 1, or 2; and
r is 0, 1, 2, 3, or 4 3. The method of Claim 1, wherein the Tyk2 inhibitor is of the formula:
Figure imgf000049_0001
or a pharmaceutically acceptable salt thereof, wherein
R1 is C 1-3alkyl optionally substituted by 0-7 R1a
R1a at each occurrence is independently hydrogen, deuterium, F, CI, Br, CF3 or CN; R2 is C1-6 alkyl substituted with 0-4 R2a, C3-6 cycloalkyl substituted with 0-4 R2a, C6-10 aryl substituted with 0-4 R2a, a 5-14 membered heterocycle containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-4 R2a, NR6R6 or ORb;
R2a at each occurrence is independently hydrogen, =O, halo, OCF3, CN, NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(O)Rb, -(CH2)rC(O)ORb, -(CH2)rOC(O)Rb,
(CH2)rNR11R11, -(CH2)rC(O)NR11R11, -(CH2)rNRbC(O)RC, -(CH2)rNRbC(O)ORC,
-NRbC(O)NR11R11, -S(O)pNR11R11, -NRbS(O)pRC, -S(O)pRC, C1-6 alkyl substituted with 0-3 Ra, C1-6 halo alkyl, -(CH2)r-3-14 membered carbocycle substituted with 0-1 Ra or a-(CH2)r-5-7 membered heterocycle comprising carbon atoms or 1-4 heteroatoms selected from N, O, and S(O)p substituted with 0-2 Ra;
or one R2a and another R2a, together with the atoms to which they are attached, combine to form a fused 5-6 membered ring wherein said fused ring may be substituted with 0-2 Ra;
R3 is -(CH2)r-3-14 membered carbocycle substituted 0-5 R3a;
R3a at each occurrence is independently hydrogen, =O, halo, OCF3, CN, NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(O)Rb, -(CH2)rC(O)ORb, -(CH2)rOC(O)Rb,
(CH 1
2)rNR11R1 , -(CH2)rC(O)NR11R11, -(CH2)rNRbC(O)RC, -(CH2)rNRbC(O)ORC,
-NRbC(O)NR11R11, -S(O)pNR11R11, -NRbS(O)pRC, -S(O)pRC, C1-6 alkyl substituted with 0-3 Ra, C1-6 halo alkyl, -(CH2)r-3-14 membered carbocycle substituted with 0-3 Ra or a-(CH2)r-5- 10 membered heterocycle comprising carbon atoms or 1-4 heteroatoms selected from N, O, and S(0)p substituted with 0-3 Ra;
or two R3a, together with the atoms to which they are attached, combine to form a fused ring wherein said ring is selected from phenyl and a 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, S or O, said fused ring may be further substituted by Ra;
R4 and R5 are independently hydrogen, C 1.4 alkyl substituted with 0-1 Rf,
(CH2)r-phenyl substituted with 0-3 Rd, or a -(CH2)-5-7 membered heterocycle comprising 5 carbon atoms and 1-4 heteroatoms selected from N, O, and S(0)p;
R6 and R1 1 at each occurrence are independently hydrogen, C 1.4 alkyl substituted with 0-3 R f , CF3, C3-10 cycloalkyl substituted with 0-1 R f , (CH)r-phenyl substituted with 0-3 Rd, or -(CH2)r-5-7 membered heterocycle comprising carbon atoms and 1-4
heteroatoms selected from N, O, and S(0)p substituted with 0-3 Rd;
Ra at each occurrence is hydrogen, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2,
-(CH2)rORb, -(CH2)rSRb, -(CH2)rC(0)Rb, -(CH2)rC(0)ORb, -(CH2)rOC(0)Rb,
-(CH2)rNR1R11, -(CH2)rC(0)NR1 1R11, -(CH2)rNRbC(0)Rc, -(CH2)rNRbC(0)ORc,
-NRbC(0)NR R1 1, -S(0)pNR1 1R11, -NRbS(0)pRc, -S(0)Rc, -S(0)2RC, Ci.6alkyl
substituted with 0-3 R , Ci_6halo alkyl, -(CH2)r-3-14 membered carbocycle, or -(CH2)r-5-7 15 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(0)p substituted with 0-3 Rf;
Rb at each occurrence is hydrogen, C1-6 alkyl substituted with 0-3 Rd,
Ci-6 halo alkyl, C3.6 cycloalkyl substituted with 0-2 Rd, or -(CH2)r-5-7 membered
heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(0)p substituted with 0-3 Rf, or (CH2)r-phenyl substituted with 0-3 Rd;
Rc is C1-6 alkyl substituted with 0-3 Rf, (CH2)r-C3-6 cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf;
Rd at each occurrence is independently hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, ORe, -(CH2)rC(0)Rc, NReRe, -NReC(0)ORc, C1-6 alkyl or (CH2)r-phenyl substituted with 0-3 Rf;
Re at each occurrence is independently selected from hydrogen, C1-6 alkyl,
C3-6 cycloalkyl and (CH2)r-phenyl substituted with 0-3 Rf;
R independently at each occurrence is hydrogen, halo, CN, N¾, OH,
C3-6 cycloalkyl, CF3, 0(C1-6alkyl) or a -(CH2)r-5-7 membered heteroaryl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p; p is 0, 1, or 2; and
r is 0,1,2,
3, or 4.
4. The method of Claim 1, wherein the Tyk2 inhibitor is of the formula:
Figure imgf000051_0001
or a pharmaceutically acceptable salt thereof, wherein
Y is N or CR6;
R1 is H, C1-3alkyl or C3-6cycloalkyl, each optionally substituted by 0-7 R1a;
R1a at each occurrence is independently hydrogen, deuterium, F, Cl, Br or CN;
R2 is C1-6alkyl, -(CH2)r-3-14 membered carbocycle substituted with 0-1 R2a or a 5-14 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-4 R2a (for the sake of clarity, R2 is intended to include substituted methyl groups such as -C(O)R2a);
R2a at each occurrence is independently hydrogen, =O, halo, OCF3, CN, NO2, - (CH2)rORb, -(CH2)rSRb, -(CH2)rC(O)Rb, -(CH2)rC(O)ORb, -(CH2)rOC(O)Rb, CH2)rNR11R11, - (CH2)rC(O)NR11R11, -(CH2)rNRbC(O)Rc, -(CH2)rNRbC(O)ORc, -NRbC(O)NR11R11, - S(O)pNR11R11, -NRbS(O)pRc, -S(O)pRc, C1-6 alkyl substituted with 0-3 Ra, C1-6 haloalkyl, C2- 6 alkenyl substituted with 0-3 Ra, C2-6 alkynyl substituted with 0-3 Ra, -(CH2)r-3-14 membered carbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle comprising carbon atoms or 1-4 heteroatoms selected from N, O, and S(O)p substituted with 0-2 Ra;
R3 is C3-10 cycloalkyl, C6-10 aryl or a 5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-4 R3a;
R3a at each occurrence is independently hydrogen, =O, halo, OCF3, CF3, CHF2, CN, NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(O)Rb, -(CH2)rC(O)ORb, -(CH2)rOC(O)Rb, - (CH2)rNR11R11, -(CH2)rC(O)NR11R11, -(CH2)rNRbC(O)Rc, -(CH2)rNRbC(O)ORc, - NRbC(O)NR11R11, -S(O)pNR11R11, -NRbS(O)pRc, -S(O)pRc, C1-6 alkyl substituted with 0-3 Ra, C2-6 alkenyl substituted with 0-3 Ra, C2-6 alkynyl substituted with 0-3 Ra, C1-6 haloalkyl, - (CH2)r-3-14 membered carbocycle substituted with 0-3 Ra or a -(CH2)r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and
S(O)p substituted with 0-3 Ra; or two R3a, together with the atoms to which they are attached, combine to form a fused ring wherein said ring is selected from phenyl and a heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p, each fused ring substituted with 0- 3 Ra1;
R4 and R5 are independently hydrogen, C1-4 alkyl substituted with 0-1 Rf, (CH2)r- phenyl substituted with 0-3 Rd or a -(CH2)-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p;
R6 is hydrogen, halo, C1-4alkyl, C1-4haloalkyl, OC1-4haloalkyl, OC1-4alkyl, CN, NO2 or OH;
R11 at each occurrence is independently hydrogen, C1-4 alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-3 Rd or -(CH2)r- 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p substituted with 0-3 Rd;
Ra and Ra1 at each occurrence are independently hydrogen, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(O)Rb, -(CH2)rC(O)ORb, -(CH2)rOC(O)Rb, -(CH2)rNR11R11, -(CH2)rC(O)NR11R11, -(CH2)rNRbC(O)Rc, -(CH2)rNRbC(O)ORc, - NRbC(O)NR11R11, -S(O)pNR“R”, -NRbS(O)pRc, -S(O)Rc, -S(O)2Rc, C1-6 alkyl substituted with 0-3 Rf, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, C2-6 alkynyl substituted with 0-3 Ra, -(CH2)r-3-14 membered carbocycle or -(CH2)r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p substituted with 0-3 Rf;
Rb is hydrogen, C1-6 alkyl substituted with 0-3 Rd, C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 Rd, or -(CH2)r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rd;
Rc is C1-6 alkyl substituted with 0-3 Rf, (CH2)r-C3-6 cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf;
Rd at each occurrence is independently hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, - ORe, -(CH2)rC(O)Rc, -NReRe, -NReC(O)ORc, C1-6 alkyl or (CH2)r-phenyl substituted with 0-3 Rf;
Re at each occurrence is independently selected from hydrogen, C1-6 alkyl, C3- 6cycloalkyl and (CH2)r-phenyl substituted with 0-3 Rf;
Rf independently at each occurrence is hydrogen, halo, CN, NH2, OH, C3-6 cycloalkyl, CF3, O(C1-6alkyl) or a -(CH2)r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p; p is 0, 1, or 2; and
r is 0, 1, 2, 3, or 4.
5. The method of Claim 1 or 4, wherein the Tyk2 inhibitor is of the formula:
Figure imgf000053_0001
or a pharmaceutically acceptable salt thereof.
6. The method of any one of Claims 1 to 5, wherein the effective amount of the Tyk2 inhibitor, or the pharmaceutically acceptable salt ranges from about 0.1 mg/day to about 250 mg/day.
7. The method of any one of Claims 1 to 6, wherein the effective amount of the Tyk2 inhibitor, or the pharmaceutically acceptable salt ranges from about 0.2 mg/day to about 100 mg./day, about 0.5 mg/ day to about 50 mg/day, and about 1.0 mg to about 24 mg/day.
8. The method of any one of Claims 1 to 7, wherein the effective amount of the Tyk2 inhibitor, or the pharmaceutically acceptable salt ranges from about 1 mg/day to about 15 mg/day, about 1 mg/day to about 14 mg/day, about 2 mg/day to about 14 mg/day, about 2 mg/day to about 12 mg/day, or about 3 mg/day to about 12 mg/day.
9. The method of any one of Claims 1 to 8, wherein the effective amount of the Tyk2 inhibitor is about 2 mg/day, about 3 mg/day, about 4 mg/day, about 5 mg/day, about 6 mg/day, about 7 mg/day, about 8 mg/day, about 9 mg/day, about 10 mg/day, about 11 mg/day, or about 12 mg/day.
10. The method of any one of Claims 1 to 9, wherein the effective amount of the Tyk2 inhibitor is about 6 mg/day.
11. The method of any one of Claims 1 to 10, wherein the N-[2-[(lS)-l-(3-ethoxy-4- methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide is greater than 95% stereo merically pure.
12. The method of any one of Claims 1 to 11, wherein the N-[2-[(lS)-l-(3-ethoxy-4- methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide is greater than 99% stereomerically pure.
13. The method of any one of Claims 1 to 12, wherein the N-[2-[(lS)-l-(3-ethoxy-4- methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide is greater than 99.5% stereomerically pure.
14. The method of any one of Claims 1 to 13, wherein the N-[2-[(lS)-l-(3-ethoxy-4- methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide is greater than 99.9% stereomerically pure.
15. The method of any one of Claims 1 to 14, wherein the N-[2-[(lS)-l-(3-ethoxy-4- methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide is a single crystalline form.
16. The method of any one of Claims 1 to 15, wherein the N-[2-[(lS)-l-(3-ethoxy-4- methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide is a single crystalline Form B characterized by X-ray powder diffraction peaks at 2Q angles selected from 10.1°, 13.5°, 20.7°, and 26.9°.
17. The method of any one of Claims 1 to 16, wherein the N-[2-[(lS)-l-(3-ethoxy-4- methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide is a single crystalline Form B characterized by X-ray powder diffraction peaks at 2Q angles selected from 10.1°, 13.5°, 15.7°, 18.1°, 20.7°, 24.7°, and 26.9°.
18. The method of any one of Claims 1 to 17, wherein the N-[2-[(lS)-l-(3-ethoxy-4- methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide is a single crystalline Form B characterized by X-ray powder diffraction peaks at 2Q angles selected from 10.1°, 13.5°, 15.7°, 16.3°, 18.1°, 20.7°, 22.5°, 24.7°, 26.2°, 26.9°, and 29.1°.
19. The method of any one of Claims 1 to 18, wherein the N-[2-[(lS)-l-(3-ethoxy-4- methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide is at least 90% single crystalline Form B.
20. The method of any one of Claims 1 to 19, wherein the N-[2-[(lS)-l-(3-ethoxy-4- methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide is at least 95% single crystalline Form B.
21. The method of any one of Claims 1 to 20, wherein the N-[2-[(lS)-l-(3-ethoxy-4- methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide is at least 99% single crystalline Form B.
22. The method of any one of Claims 1 to 20, wherein the effective amount of N-[2-[(lS)- l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol- 4-yl] acetamide, or the pharmaceutically acceptable salt thereof, ranges from about 0.5 mg to about 1000 mg per day, about 1 mg to about 1000 mg per day, about 5 mg to about 500 mg per day, about 10 mg to about 200 mg per day, about 10 mg to about 100 mg per day, about 40 mg to about 100 mg per day, about 20 mg to about 40 mg per day, about 0.1 mg to about 10 mg per day, about 0.5 mg to about 5 mg per day, about 1 mg to about 20 mg per day, and about 1 mg to about 10 mg per day, about 1 mg to about 100 mg per day, about 1 mg to about 80 mg per day, about 5 mg to about 70 mg per day, and about 10 mg to about 60 mg per day.
23. The method of any one of Claims 1 to 22, wherein the effective amount of N-[2-[(lS)- l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol- 4-yl] acetamide, or the pharmaceutically acceptable salt thereof, ranges from about 10 mg to about 60 mg per day.
24. The method of any one of Claims 1 to 23, wherein the effective amount of N-[2-[(lS)- l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol- 4-yl] acetamide, or the pharmaceutically acceptable salt thereof, ranges from about 10 mg to about 40 mg per day.
25. The method of any one of Claims 1 to 24, wherein the effective amount of N-[2-[(lS)- l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol- 4-yl] acetamide, or the pharmaceutically acceptable salt thereof, is about 10 mg administered once or twice a day.
26. The method of any one of Claims 1 to 24, wherein the effective amount of N-[2-[(lS)- l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol- 4-yl] acetamide, or the pharmaceutically acceptable salt thereof, is about 20 mg administered once or twice a day.
27. The method of any one of Claims 1 to 23, wherein the effective amount of N-[2-[(lS)- l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol- 4-yl] acetamide, or the pharmaceutically acceptable salt thereof, is about 10 mg per day, about 15 mg per day, about 20 mg per day, about 25 mg per day, about 30 mg per day, about 35 mg per day, about 40 mg per day, about 45 mg per day, about 50 mg per day, about 55 mg per day, or about 60 mg per day.
28. The method of any one of Claims 1 to 23 and 27, wherein the effective amount of N- [2-[( IS)- l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2, 3-dihydro- 1,3-dioxo-lH- isoindol-4-yl] acetamide, or the pharmaceutically acceptable salt thereof, is about 30 mg per day or about 60 mg per day.
29. The method of any one of Claims 1 to 23, 27, and 28, wherein the effective amount of N-[2-[( IS)- l-(3-etho xy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2, 3-dihydro- 1,3-dioxo- lH-isoindol-4-yl]acetamide is about 30 mg administered once daily.
30. The method of any one of Claims 1 to 23, 27, and 28, wherein the effective amount of N-[2-[( IS)- l-(3-etho xy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2, 3-dihydro- 1,3-dioxo- lH-isoindol-4-yl]acetamide is about 30 mg administered twice daily.
31. The method of any one of Claims 1 to 23, 27, and 28, wherein the N-[2-[(lS)-l-(3- etho xy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2, 3-dihydro- 1,3-dioxo- lH-isoindo 1-4- yl]acetamide is titrated to a dosage of about 30 mg administered twice daily using the following titration schedule:
Day 1: about 10 mg in morning;
Day 2: about 10 mg in morning and about 10 mg in evening;
Day 3: about 10 mg in morning and about 20 mg in evening;
Day 4: about 20 mg in morning and about 20 mg in evening;
Day 5: about 20 mg in morning and about 30 mg in evening; and
Day 6 and thereafter: about 30 mg twice daily.
32. The method of any one of Claims 1 to 22, wherein the effective amount of N-[2-[(lS)- l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro- 1,3-dioxo- lH-isoindol- 4-yl] acetamide, or the pharmaceutically acceptable salt thereof, ranges from about 40 mg to about 100 mg per day.
33. The method of any one of Claims 1 to 22 and 32, wherein the N-[2-[(lS)-l-(3-ethoxy- 4-metho xyphenyl)-2-(methylsulfonyl)ethyl]-2, 3-dihydro- 1,3-dioxo- lH-isoindo 1-4- yl] acetamide is titrated to a dosage of between about 40 mg/day to between about 100 mg/day using the following titration schedule:
Day 1: about 10 mg in morning;
Day 2: about 10 mg in morning and about 10 mg in evening;
Day 3: about 10 mg in morning and about 20 mg in evening;
Day 4: about 20 mg in morning and about 20 mg in evening;
Day 5: about 20 mg in morning and about 30 mg in evening; and
Day 6 and thereafter: between about 40 mg/day to between about 100 mg/day.
34. The method of any one of Claims 1 to 22, wherein the effective amount of N-[2-[(lS)- l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2, 3-dihydro- 1,3-dioxo- lH-isoindol- 4-yl] acetamide, or the pharmaceutically acceptable salt thereof, is about 20 mg administered twice daily.
35. The method of any one of Claims 1 to 22 and 34, wherein the N-[2-[(lS)-l-(3-ethoxy- 4-metho xyphenyl)-2-(methylsulfonyl)ethyl]-2, 3-dihydro- 1,3-dioxo- lH-isoindo 1-4- yl] acetamide is titrated to a dosage of about 20 mg administered twice daily using the following titration schedule:
Day 1: about 10 mg in morning;
Day 2: about 10 mg in morning and about 10 mg in evening;
Day 3: about 10 mg in morning and about 20 mg in evening;
Day 4: about 20 mg in morning and about 20 mg in evening;
Day 5: about 20 mg in morning and about 30 mg in evening; and
Day 6 and thereafter: about 20 mg twice daily.
36. The method of any one of Claims 1 to 22, wherein the effective amount of N-[2-[(lS)- l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2, 3-dihydro- 1,3-dioxo- lH-isoindol- 4-yl] acetamide, or the pharmaceutically acceptable salt thereof, ranges from about 4 mg to between about 10 mg per day.
37. The method of any one of Claims 1 to 22 and 36, wherein the N-[2-[(lS)-l-(3-ethoxy- 4-metho xyphenyl)-2-(methylsulfonyl)ethyl]-2, 3-dihydro- 1,3-dioxo- lH-isoindo 1-4- yl] acetamide is titrated to a dosage of between about 4 mg/day to between about 10 mg/day using the following titration schedule:
Day 1: about 1 mg in morning;
Day 2: about 1 mg in morning and about 1 mg in evening;
Day 3: about 1 mg in morning and about 2 mg in evening;
Day 4: about 2 mg in morning and about 2 mg in evening;
Day 5: about 2 mg in morning and about 3 mg in evening; and
Day 6 and thereafter: between about 4 mg/day to between about 10 mg/day.
38. The method of any one of Claims 1 to 22, wherein the effective amount of N-[2-[(lS)- l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2, 3-dihydro- 1,3-dioxo- lH-isoindol- 4-yl] acetamide, or the pharmaceutically acceptable salt thereof, is about 3 mg/day.
39. The method of any one of Claims 1 to 22 and 38, wherein the N-[2-[(lS)-l-(3- etho xy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2, 3-dihydro- 1,3-dioxo- lH-isoindo 1-4- yl]acetamide is titrated to a dosage of 3 mg administered twice daily using the following titration schedule:
Day 1: about 1 mg in morning;
Day 2: about 1 mg in morning and about 1 mg in evening;
Day 3: about 10 mg in morning and about 2 mg in evening;
Day 4: about 2 mg in morning and about 2 mg in evening;
Day 5: about 2 mg in morning and about 3 mg in evening; and
Day 6 and thereafter: about 3 mg twice daily.
40. The method of any one of Claims 1 to 39, wherein the N-[2-[(lS)-l-(3-ethoxy-4- metho xyphenyl)-2-(methylsulfonyl)ethyl]-2, 3-dihydro- 1,3-dioxo- lH-isoindol-4-yl]acetamide is formulated as part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
41. The method of any one of Claims 1 to 40, wherein the N-[2-[(lS)-l-(3-ethoxy-4- methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide is administered parenterally, transdermally, mucosally, nasally, buccally, sublingually, or orally.
42. The method of any one of Claims 1 to 41, wherein the N-[2-[(lS)-l-(3-ethoxy-4- methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide is administered orally.
43. The method of any one of Claims 1 to 42, wherein the N-[2-[(lS)-l-(3-ethoxy-4- methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide is administered orally in the form of a tablet or a capsule.
44. The method of any one of Claims 40 to 43, wherein the N-[2-[(lS)-l-(3-ethoxy-4- methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide is formulated as an extended release form.
45. The method of any one of Claims 40 to 43, wherein the N-[2-[(lS)-l-(3-ethoxy-4- methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide is formulated as an immediate release form.
46. The method of any one of Claims 1 to 45, wherein the disease or disorder is selected from a viral, genetic, inflammatory, allergic, and autoimmune disease.
47. The method of any one of Claims 1 to 46, wherein the disease or disorder is selected from chronic obstructive pulmonary disease, asthma, chronic pulmonary inflammatory disease, hyperoxic alveolar 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 erythrematosus, erythema nodosum leprosum, Sjogren’s syndrome, inflammatory bowel disease, Crohn’s Disease, Behcet’s Disease, and ulcerative colitis.
48. The method of any one of Claims 1 to 47, wherein the disease or disorder is selected from psoriasis, psoriatic arthritis, contact dermatitis, systemic lupus erythrematosus, cutaneous lupus erythematosus, and ulcerative colitis.
49. The method of any one of Claims 1 to 48, wherein the disease or disorder is psoriasis.
50. The method of any one of Claims 1 to 49, wherein the disease or disorder is plaque psoriasis.
51. The method of any one of Claims 1 to 50, wherein the disease or disorder is moderate to severe plaque psoriasis.
52. The method of any one of Claims 49 to 51, wherein the subject is a candidate for phototherapy or systematic therapy.
53. The method of any one of Claims 1 to 48, wherein the disease or disorder is psoriatic arthritis.
54. A pharmaceutical composition comprising a therapeutically effective amount of N-[2- [( IS)- l-(3-etho xy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2, 3-dihydro- 1,3-dioxo-lH- isoindol-4-yl] acetamide, or a pharmaceutically acceptable thereof, as defined in any one of Claims 11 to 21; and a therapeutically effective amount of a Tyk2 inhibitor as defined in any one of Claims 2 to 5.
55. The pharmaceutical composition of Claim 54, wherein the Tyk2 inhibitor is of the formula:
Figure imgf000060_0001
or a pharmaceutically acceptable salt thereof.
56. The pharmaceutical composition of Claims 54 or 55, wherein the composition is formulated for administration of from about 1 mg/day to about 15 mg/day, about 1 mg/day to about 14 mg/day, about 2 mg/day to about 14 mg/day, about 2 mg/day to about 12 mg/day, or about 3 mg/day to about 12 mg/day, of the Tyk inhbitor.
57. The pharmaceutical composition of any one of Claims 54 to 56, wherein the composition is formulated for administration of about 2 mg/day, about 3 mg/day, about 4 mg/day, about 5 mg/day, about 6 mg/day, about 7 mg/day, about 8 mg/day, about 9 mg/day, about 10 mg/day, about 11 mg/day, or about 12 mg/day of the Tyk inhibitor.
58. The pharmaceutical composition of any one of Claims 54 to 57, wherein the composition is formulated for administration of about 6 mg/day of the Tyk inhibitor.
59. The pharmaceutical composition of any one of Claims 54 to 58, wherein the composition is formulated for administration of from about 1 mg to about 1000 mg per day, about 5 mg to about 500 mg per day, about 10 mg to about 200 mg per day, about 10 mg to about 100 mg per day, about 40 mg to about 100 mg per day, about 20 mg to about 40 mg per day, about 0.1 mg to about 10 mg per day, about 0.5 mg to about 5 mg per day, about 1 mg to about 20 mg per day, and about 1 mg to about 10 mg per day, about 1 mg to about 100 mg per day, about 1 mg to about 80 mg per day, about 5 mg to about 70 mg per day, and about 10 mg to about 60 mg per day of N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)ethyl]-2, 3-dihydro- 1,3-dioxo- lH-isoindol-4-yl]acetamide, or the
pharmaceutically acceptable salt thereof.
60. The pharmaceutical composition of any one of Claims 54 to 59, wherein the composition is formulated for administration of from about 10 mg to about 60 mg per day of N-[2-[( IS)- l-(3-etho xy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2, 3-dihydro- 1,3-dioxo- lH-isoindol-4-yl]acetamide, or the pharmaceutically acceptable salt thereof.
61. The pharmaceutical composition of any one of Claims 54 to 60, wherein the composition is formulated for administration of about 10 mg per day, about 15 mg per day, about 20 mg per day, about 25 mg per day, about 30 mg per day, about 35 mg per day, about 40 mg per day, about 45 mg per day, about 50 mg per day, about 55 mg per day, or about 60 mg per day of N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3- dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide, or the pharmaceutically acceptable salt thereof.
62. The pharmaceutical composition of any one of Claims 54 to 61, wherein the composition is formulated for administration of about 30 mg per day or about 60 mg per day of N-[2-[( IS)- l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2, 3-dihydro- 1,3- dioxo- lH-isoindol-4-yl]acetamide, or the pharmaceutically acceptable salt thereof.
63. The pharmaceutical composition of any one of Claims 54 to 62, wherein the composition is formulated for administration of about 30 mg once daily of N-[2-[(lS)-l-(3- etho xy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2, 3-dihydro- 1,3-dioxo- lH-isoindo 1-4- yl] acetamide, or the pharmaceutically acceptable salt thereof.
64. The pharmaceutical composition of any one of Claims 54 to 61, wherein the composition is formulated for administration of about 30 mg twice daily of N-[2-[(lS)-l-(3- etho xy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2, 3-dihydro- 1,3-dioxo- lH-isoindo 1-4- yl] acetamide, or the pharmaceutically acceptable salt thereof.
65. The pharmaceutical composition of any one of Claims 54 to 60, wherein the composition is formulated for administration of from about 10 mg to about 40 mg per day of N-[2-[( IS)- l-(3-etho xy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2, 3-dihydro- 1,3-dioxo- lH-isoindol-4-yl]acetamide, or the pharmaceutically acceptable salt thereof.
66. The pharmaceutical composition of any one of Claims 54 to 60 and 65, wherein the composition is formulated for administration of from about 10 mg once or twice daily of N- [2-[( IS)- l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2, 3-dihydro- 1,3-dioxo- 1H- isoindol-4-yl] acetamide, or the pharmaceutically acceptable salt thereof.
67. The pharmaceutical composition of any one of Claims 54 to 60 and 65, wherein the composition is formulated for administration of from about 20 mg once or twice daily of N- [2-[( IS)- l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2, 3-dihydro- 1,3-dioxo- 1H- isoindol-4-yl] acetamide, or the pharmaceutically acceptable salt thereof.
68. The pharmaceutical composition of any one of Claims 54 to 67, wherein the pharmaceutical composition is in the form of a tablet or a capsule.
69. The pharmaceutical composition of any one of Claims 54 to 68, wherein the pharmaceutical composition is formulated for extended release.
70. The pharmaceutical composition of any one of Claims 54 to 68, wherein the pharmaceutical composition is formulated for immediate release.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11613548B2 (en) 2021-02-19 2023-03-28 Sudo Biosciences Limited Substituted pyridines, pyridazines, pyrimidines, and 1,2,4-triazines as TYK2 inhibitors
WO2023076161A1 (en) 2021-10-25 2023-05-04 Kymera Therapeutics, Inc. Tyk2 degraders and uses thereof
US12084458B2 (en) 2021-02-19 2024-09-10 Sudo Biosciences Limited Substituted pyridines, pyridazines, and pyrimidines as TYK2 inhibitors

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020222773A1 (en) * 2019-04-30 2020-11-05 Celgene Corporation Combination therapies comprising apremilast and tyk2 inhibitors
WO2023049241A1 (en) * 2021-09-23 2023-03-30 Bristol-Myers Squibb Company Methods of treating hair-loss disorders with tyk2 inhibitors

Citations (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6962940B2 (en) 2002-03-20 2005-11-08 Celgene Corporation (+)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione: methods of using and compositions thereof
WO2008139161A1 (en) 2007-05-10 2008-11-20 Sareum Limited Oxazole tyrosine kinase inhibitors
WO2010055304A2 (en) 2008-11-13 2010-05-20 Sareum Limited Pharmaceutical compounds
WO2012062704A1 (en) 2010-11-09 2012-05-18 Cellzome Limited Pyridine compounds and aza analogues thereof as tyk2 inhibitors
US20130178478A1 (en) 2012-01-10 2013-07-11 Hoffman-La Roche Inc. Pyridazine amide compounds
WO2013146963A1 (en) 2012-03-28 2013-10-03 武田薬品工業株式会社 Heterocyclic compound
WO2013174895A1 (en) 2012-05-24 2013-11-28 Cellzome Limited Heterocyclyl pyrimidine analogues as tyk2 inhibitors
WO2015016206A1 (en) 2013-07-30 2015-02-05 武田薬品工業株式会社 Heterocyclic compound
WO2015032423A1 (en) 2013-09-03 2015-03-12 Sareum Limited Pharmaceutical compounds
US9018243B2 (en) 2002-03-20 2015-04-28 Celgene Corporation Solid forms comprising (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, compositions thereof, and uses thereof
WO2015069310A1 (en) 2013-11-07 2015-05-14 Bristol-Myers Squibb Company Alkyl-amide-substituted pyridyl compounds useful as modulators of il-12, il-23 and/or ifnalpha responses
WO2015089143A1 (en) 2013-12-10 2015-06-18 Bristol-Myers Squibb Company Imidazopyridazine compounds useful as modulators of il-12, il-23 and/or ifn alpha responses
WO2015091584A1 (en) 2013-12-18 2015-06-25 F. Hoffmann-La Roche Ag Thiazolopyridine compounds, compositions and their use as tyk2 kinase inhibitors
WO2015123453A1 (en) 2014-02-14 2015-08-20 Portola Pharmaceuticals, Inc. Pyridazine compounds as jak inhibitors
WO2015131080A1 (en) 2014-02-28 2015-09-03 Nimbus Lakshmi, Inc. Tyk2 inhibitors and uses thereof
US20150299139A1 (en) 2012-11-08 2015-10-22 Bristol-Myers Squibb Company Alkyl amide-substituted pyrimidine compounds useful in the modulation of il-12, il-23 and/or ifn alpha
US20160045475A1 (en) * 2014-08-15 2016-02-18 Celgene Corporation Methods for the treatment of diseases ameliorated by pde4 inhibition using dosage titration of apremilast
WO2016027195A1 (en) 2014-08-21 2016-02-25 Pfizer Inc. Aminopyrimidinyl compounds as jak inhibitors
WO2016047678A1 (en) 2014-09-25 2016-03-31 武田薬品工業株式会社 Heterocyclic compound
WO2016138352A1 (en) 2015-02-27 2016-09-01 Nimbus Lakshmi, Inc. Tyk2 inhibitors and uses thereof
US9505748B2 (en) 2012-11-08 2016-11-29 Bristol-Myers Squibb Company Amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23 and/or IFNα responses
WO2017040757A1 (en) 2015-09-02 2017-03-09 Nimbus Lakshmi, Inc. Tyk2 inhibitors and uses thereof
US20170240552A1 (en) 2016-02-24 2017-08-24 Pfizer Inc. Pyrazolo[1,5-a]pyrazin-4-yl derivatives
WO2018067432A1 (en) 2016-10-07 2018-04-12 Bristol-Myers Squibb Company Imidazopyridazine compounds useful as modulators of il-12, il-23 and/or ifn alpha responses
WO2018071794A1 (en) 2016-10-14 2018-04-19 Nimbus Lakshmi, Inc. Tyk2 inhibitors and uses thereof
WO2018075937A1 (en) 2016-10-21 2018-04-26 Nimbus Lakshmi, Inc. Tyk2 inhibitors and uses thereof
WO2018081488A1 (en) 2016-10-28 2018-05-03 Bristol-Myers Squibb Company Heterobicyclic compounds useful as modulators of il-12, il-23 and/or ifn alpha responses
WO2018093968A1 (en) 2016-11-17 2018-05-24 Bristol-Myers Squibb Company Imidazopyridazine modulators of il-12, il-23 and/or ifn-alpha
US20180258086A1 (en) * 2017-03-08 2018-09-13 Nimbus Lakshmi, Inc. Tyk2 inhibitors, uses, and methods for production thereof
WO2018162889A1 (en) 2017-03-06 2018-09-13 Jet Physics Limited Collapsible frame and linear shaped charge

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW201040162A (en) * 2009-05-06 2010-11-16 Portola Pharm Inc Inhibitors of JAK
AU2012249536B2 (en) * 2011-04-28 2016-09-22 Amgen (Europe) GmbH Methods and compositions using PDE4 inhibitors for the treatment and management of autoimmune and inflammatory diseases
MX373934B (en) * 2011-12-27 2025-03-05 Celgene Corp Formulations of (+)-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-4-acetyl aminoisoindoline-1,3-dione
WO2014151180A1 (en) * 2013-03-14 2014-09-25 Celgene Corporation Treatment of psoriatic arthritis using apremilast
US10300042B2 (en) * 2014-06-23 2019-05-28 Celgene Corporation Apremilast for the treatment of a liver disease or a liver function abnormality
WO2020222773A1 (en) * 2019-04-30 2020-11-05 Celgene Corporation Combination therapies comprising apremilast and tyk2 inhibitors

Patent Citations (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6962940B2 (en) 2002-03-20 2005-11-08 Celgene Corporation (+)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione: methods of using and compositions thereof
US9018243B2 (en) 2002-03-20 2015-04-28 Celgene Corporation Solid forms comprising (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, compositions thereof, and uses thereof
WO2008139161A1 (en) 2007-05-10 2008-11-20 Sareum Limited Oxazole tyrosine kinase inhibitors
WO2010055304A2 (en) 2008-11-13 2010-05-20 Sareum Limited Pharmaceutical compounds
WO2012062704A1 (en) 2010-11-09 2012-05-18 Cellzome Limited Pyridine compounds and aza analogues thereof as tyk2 inhibitors
US20130178478A1 (en) 2012-01-10 2013-07-11 Hoffman-La Roche Inc. Pyridazine amide compounds
WO2013146963A1 (en) 2012-03-28 2013-10-03 武田薬品工業株式会社 Heterocyclic compound
WO2013174895A1 (en) 2012-05-24 2013-11-28 Cellzome Limited Heterocyclyl pyrimidine analogues as tyk2 inhibitors
US9505748B2 (en) 2012-11-08 2016-11-29 Bristol-Myers Squibb Company Amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23 and/or IFNα responses
US20150299139A1 (en) 2012-11-08 2015-10-22 Bristol-Myers Squibb Company Alkyl amide-substituted pyrimidine compounds useful in the modulation of il-12, il-23 and/or ifn alpha
WO2015016206A1 (en) 2013-07-30 2015-02-05 武田薬品工業株式会社 Heterocyclic compound
WO2015032423A1 (en) 2013-09-03 2015-03-12 Sareum Limited Pharmaceutical compounds
WO2015069310A1 (en) 2013-11-07 2015-05-14 Bristol-Myers Squibb Company Alkyl-amide-substituted pyridyl compounds useful as modulators of il-12, il-23 and/or ifnalpha responses
WO2015089143A1 (en) 2013-12-10 2015-06-18 Bristol-Myers Squibb Company Imidazopyridazine compounds useful as modulators of il-12, il-23 and/or ifn alpha responses
WO2015091584A1 (en) 2013-12-18 2015-06-25 F. Hoffmann-La Roche Ag Thiazolopyridine compounds, compositions and their use as tyk2 kinase inhibitors
WO2015123453A1 (en) 2014-02-14 2015-08-20 Portola Pharmaceuticals, Inc. Pyridazine compounds as jak inhibitors
WO2015131080A1 (en) 2014-02-28 2015-09-03 Nimbus Lakshmi, Inc. Tyk2 inhibitors and uses thereof
US20160045475A1 (en) * 2014-08-15 2016-02-18 Celgene Corporation Methods for the treatment of diseases ameliorated by pde4 inhibition using dosage titration of apremilast
WO2016027195A1 (en) 2014-08-21 2016-02-25 Pfizer Inc. Aminopyrimidinyl compounds as jak inhibitors
WO2016047678A1 (en) 2014-09-25 2016-03-31 武田薬品工業株式会社 Heterocyclic compound
WO2016138352A1 (en) 2015-02-27 2016-09-01 Nimbus Lakshmi, Inc. Tyk2 inhibitors and uses thereof
WO2017040757A1 (en) 2015-09-02 2017-03-09 Nimbus Lakshmi, Inc. Tyk2 inhibitors and uses thereof
US20170240552A1 (en) 2016-02-24 2017-08-24 Pfizer Inc. Pyrazolo[1,5-a]pyrazin-4-yl derivatives
WO2018067432A1 (en) 2016-10-07 2018-04-12 Bristol-Myers Squibb Company Imidazopyridazine compounds useful as modulators of il-12, il-23 and/or ifn alpha responses
WO2018071794A1 (en) 2016-10-14 2018-04-19 Nimbus Lakshmi, Inc. Tyk2 inhibitors and uses thereof
WO2018075937A1 (en) 2016-10-21 2018-04-26 Nimbus Lakshmi, Inc. Tyk2 inhibitors and uses thereof
WO2018081488A1 (en) 2016-10-28 2018-05-03 Bristol-Myers Squibb Company Heterobicyclic compounds useful as modulators of il-12, il-23 and/or ifn alpha responses
WO2018093968A1 (en) 2016-11-17 2018-05-24 Bristol-Myers Squibb Company Imidazopyridazine modulators of il-12, il-23 and/or ifn-alpha
WO2018162889A1 (en) 2017-03-06 2018-09-13 Jet Physics Limited Collapsible frame and linear shaped charge
US20180258086A1 (en) * 2017-03-08 2018-09-13 Nimbus Lakshmi, Inc. Tyk2 inhibitors, uses, and methods for production thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", 1990, MACK PUBLISHING
KIM PAPP, M.D.: "Phase 2 Trial of Selective Tyrosine Kinase 2 Inhibition in Psoriasis", THE NEW ENGLAND JOURNAL OF MEDICINE, 12 September 2018 (2018-09-12)
See also references of EP3962476A1
XINGRUI HE ET AL., EXPERT OPINION ON THERAPEUTICS PATENTS, vol. 29, no. 2, 2019, pages 137 - 149

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11613548B2 (en) 2021-02-19 2023-03-28 Sudo Biosciences Limited Substituted pyridines, pyridazines, pyrimidines, and 1,2,4-triazines as TYK2 inhibitors
US12084458B2 (en) 2021-02-19 2024-09-10 Sudo Biosciences Limited Substituted pyridines, pyridazines, and pyrimidines as TYK2 inhibitors
US12103937B2 (en) 2021-02-19 2024-10-01 Sudo Biosciences Limited Substituted pyridines and pyridazines as TYK2 inhibitors
US12122785B2 (en) 2021-02-19 2024-10-22 Sudo Biosciences Limited Substituted pyridines, pyridazines, pyrimidines, and 1,2,4-triazines as TYK2 inhibitors
WO2023076161A1 (en) 2021-10-25 2023-05-04 Kymera Therapeutics, Inc. Tyk2 degraders and uses thereof

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