METHODS OF TREATMENT USING SUBSTITUTED DIAMINOPYRIMIDYL

COMPOUNDS

[0001] This application claims the benefit of priority to United States Provisional

Application Serial No. 62/180,311, filed June 16, 2015, United States Provisional Application Serial No. 62/193,407, filed July 16, 2015 and United States Provisional Application Serial No. 62/203,470, filed August 11, 2015, each of which is incorporated herein by reference in its entirety and for all purposes.

FIELD

[0002] Provided herein are uses of certain alkylheteroaryl-diaminopyrimidyl

compounds and compositions comprising an effective amount of such compounds, and methods for treating or preventing PKC-theta mediated disorders, comprising

administering an effective amount of such alkylheteroaryl-diaminopyrimidyl compounds to a subject in need thereof.

BACKGROUND

[0003] The connection between abnormal protein phosphorylation and the cause or consequence of diseases has been known for over 20 years. Accordingly, protein kinases have become a very important group of drug targets. {See Cohen, Nature, 1 :309-315

(2002), Gaestel et al. Curr.Med.Chem.14: 2214-223 (2007); Grimminger et al. Nat. Rev.

Drug Disc. 9(12):956-970 (2010)). Various protein kinase inhibitors have been used

clinically in the treatment of a wide variety of diseases, such as cancer and chronic

inflammatory diseases, including rheumatoid arthritis and psoriasis. {See Cohen, Eur. J.

Biochem., 268:5001-5010 (2001); Protein Kinase Inhibitors for the Treatment of Disease:

The Promise and the Problems, Handbook of Experimental Pharmacology, Springer Berlin Heidelberg, 167 (2005)).

[0004] The elucidation of the intricacy of protein kinase pathways and the

complexity of the relationship and interaction among and between the various protein

kinases and kinase pathways highlights the importance of developing pharmaceutical

agents capable of acting as protein kinase modulators, regulators or inhibitors that have beneficial activity on multiple kinases or multiple kinase pathways. Accordingly, there remains a need for new kinase modulators.

[0005] The protein kinase C (PKC) family is a group of serine/threonine kinases that is encompasses twelve related isoenzymes. The PKCs are expressed in a wide range of tissues and cell types. The PKC isozymes can be classified into three groups. Group I (classical PKCs) includes the Ca ²⁺ and DAG (diacylglycerol) dependent isozymes: PKC-a, PKC-βΙ, PKC-βΙΙ and PKC-γ. Group II (novel PKCs) includes the Ca ²⁺ independent isozymes: PKC-δ (or PKC-delta), PKC-ε, PKC-η (or PKC-eta) and PKC-Θ (or PKC-theta). Group III (atypical PKCs) includes the Ca ²⁺ and DAG independent isozymes: PKC-i, PKC-ζ and PKC-μ (protein kinase D). The PKC-theta isoform of protein kinase C is selectively expressed in T lymphocytes and plays an important role in the T cell antigen receptor (TCR)-triggered activation of mature T cells, and the subsequent release of cytokines such as IL-2 and T cell proliferation (Isakov and Altman, Annu. Rev. Immunol., 2002, 20, 761-94). It has been well established that T cells play an important role in regulating the immune response (Powrie and Coffman, Immunology Today, 1993, 14, 270) and the activation of T cells is often the initiating event in a variety of immunological disorders. Upon activation via the TCR, T cells produce cytokines, including IL-2, leading to cell proliferation, differentiation, and effector function. Clinical studies with inhibitors of IL-2 have shown that interference with T cell activation and proliferation effectively suppresses immune response in vivo (Waldmann, Immunology Today, 1993, 14, 264). Accordingly, agents that inhibit T lymphocyte activation and subsequent cytokine production are therapeutically useful for selectively suppressing the immune response in a patient in need of such immunosuppression and therefore are useful in treating

immunological disorders such as autoimmune and inflammatory diseases. PKC-theta activation has also been implicated in leukemia and thus inhibitors of PKC-theta may be useful for the treatment of leukemia (Villalba and Altman, Current Cancer Targets, 2002, 2, 125).

[0006] PKC-delta is closely related to PKC-theta, however, they exhibit different tissue expression patterns and serve unique cell functions. While PKC-theta is highly expressed in T-lymphocytes, K cells and to a lesser extent in skeletal muscle, PKC-delta is highly expressed in myeloid cells and B-lymphocytes (ExPasy database; PRKCT and PRKCD). PKC-delta is important for the regulation of B-cell tolerance so that mice lacking PKC-delta exhibit increased numbers of self-reactive B-cells, elevated IL-6, express auto-antibodies to nuclear antigens, and exhibit a lupus-like pathology

(Mecklenbrauker et al., Nature, 2002, 416, 860-865; Miyamoto et al., Nature, 2002, 416, 865-869). Furthermore, genetic examination of siblings with juvenile onset lupus identified a mutation in the PKC-delta (PRCKD) gene ( Belot et al.,

Arthritis&Rheumatism, 2013, 65, 2161-2165). For this reason, inhibition of PKC-delta may be detrimental in the treatment of autoimmune disease and there is rationale for avoiding chronic inhibition of this enzyme. Selective inhibition of PKC-delta for therapy has previously been clinically evaluated (delcasertib; Kai Pharmaceuticals) in the context of acute treatment of ischemia-reperfusion injury.

[0007] There remains a need to develop effective therapeutic agents for the majority of the diseases and disorders associated with activation of PKC-theta (Chaudhary and Kasaian, Curr Opin Investig Drugs 2006 7(5):432-437; Zhang, E.Y, Kong, K., and Altman, A., Adv Pharmacol 2013, Vol 66, 267-312; Chand, S., et. Al. Curr Pharmaceut Design 212, Vol 18(30):4725-4746). Accordingly, it would be beneficial to provide safe and effective compounds that are useful as selective inhibitors of PKC-theta and thus in the treatment of disorders and diseases associated with activation of PKC-theta. In particular there remains a need for effective therapeutic agents that are selective inhibitors of PKC-theta, without affecting other members of the PKC family, such as PKC-delta and/or PKC-eta.

[0008] Citation or identification of any reference in this section of the application is not to be construed as an admission that the reference is prior art to the present application.

SUMMARY

[0009] Provided herein are uses of Diaminopyrimidyl Compounds having the following formula (I):

or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, wherein L, X, R ¹ , and R ² are as defined herein.

[0010] In one aspect, provided herein are uses of Diaminopyrimidyl Compounds as described in the instant disclosure, such as, for example, a compound of formula (I). In some embodiments a Diaminopyrimidyl Compound is a compound from Table 1 or Table 2, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof.

[0011] In one aspect, provided herein are uses of pharmaceutical compositions comprising an effective amount of a Diaminopyrimidyl Compound, as described herein, and a pharmaceutically acceptable carrier, excipient or vehicle. In some embodiments the pharmaceutical composition is suitable for oral, parenteral, mucosal, transdermal or topical administration.

[0012] In one aspect, provided herein are uses of Diaminopyrimidyl Compounds for treating or preventing PKC-theta mediated disorders, such as allergic, inflammatory, or autoimmune T-cell mediated diseases, wherein the methods comprise administering to a subject in need thereof an effective amount of a Diaminopyrimidyl Compound as described herein. In another aspect, provided herein are uses of Diaminopyrimidyl Compounds for treating or preventing PKC-theta mediated disorders, such as ankylosing spondylitis, asthma (including refractory asthma and severe asthma), celiac disease, colitis (including ulcerative colitis), diabetes (including type I diabetes), dermatitis (including atopic dermatitis), Duchenne muscular dystrophy, graft-versus-host disease, inflammatory bowel disease (including Crohn's disease), insulin resistance, lupus (including systemic lupus erythematosus), multiple sclerosis (including relapsing remitting multiple sclerosis), myasthenia gravis, myositis (including polymyositis and dermatomyositis), organ transplant rejection, psoriasis (including plaque-type psoriasis, and psoriatic arthritis), rheumatoid arthritis, Sjogren syndrome, uveitis, or vitiligo, wherein the methods comprise administering to a subject in need thereof an effective amount of a Diaminopyrimidyl Compound as described herein.

[0013] In one aspect, provided herein are uses of Diaminopyrimidyl Compounds for inhibiting a kinase, for example PKC-theta, in a cell expressing said kinase, comprising contacting said cell with an effective amount of a Diaminopyrimidyl Compound, as described herein. In some embodiments, the Diaminopyrimidyl Compounds inhibit PKC-theta selectively over PKC-delta. In other such embodiments, the Diaminopyrimidyl Compounds inhibit PKC-theta selectively over PKC-delta and/or PKC-eta.

[0014] The present embodiments can be understood more fully by reference to the detailed description and examples, which are intended to exemplify non-limiting embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 depicts the PASI calculation questionnaire. PASI is a measure of psoriatic disease severity taking into account qualitative lesion characteristics (erythema, thickness, and scaling) and degree of skin surface area involvement on defined anatomical regions.

[0016] Figure 2 depicts the grading criteria for sPGA score.

[0017] Figure 3 depicts the DLQI questionnaire.

[0018] Figure 4 depicts the effect of a single dose of Compound 1 on ex vivo

T-cell activation marker CD69 (A) and IL-2 cytokine secretion (B) (pharmacodynamic markers) and their correlation with exposure (pharmacokinetic) of Compound 1. CD69 % inhibition values were calculated by comparing the mean flourescence intensity (MFI) of CD69 expression in Compound 1 treated group to that of vehicle, and subtracting the MFI value of non-stimulated cells. For IL-2, % inhibition values were calculated by comparing IL-2 levels of Compound 1 treated samples with that of the vehicle.

[0019] Figure 5 depicts Western blot measurement of the levels of phosphorylated and total protein quantities at the indicated times post stimulation with anti-CD3/anti- CD28 bound to beads at the indicated ratio of celkbead. Note: ns = no stimulation; CD3/28 = anti CD3 and anti CD28 coated beads; Actin = total beta actin protein, Bel 10 = total B- cell lymphoma/1 eukemia 10 protein; P-Erkl/2 = phosphorylated extracellular signal- regulated protein kinases 1 (upper band) and 2 (lower band); Erkl/2 = total Erk 1 (upper band) and Erk 2 protein (lower band); Cbl-b = total casitas b-lineage lymphoma-b protein; P-PKC0-538 = phosphorylated protein kinase C Θ at position threonine 538; IkBa = total I kappa B alpha protein.

[0020] Figure 6 depicts the effect of Compound 1 on Paw Clinical Score AUC

(Day 0 to Day 42). AUC = area under the curve; BID = twice daily; QD = once daily;

* p < 0.05; **** p< 0.0001. Note: Positive control was dexamethasone. Data shown as mean with error bars represents standard error of the mean. The percent inhibition was calculated compared to vehicle control.

[0021] Figure 7 depicts the effect of Compound 1 on serum levels of CTX- 1 (Day

42) in mouse CIA. CTX- 1 = collagen type 1 cross-linked C-telopeptide; BID = twice daily; * p < 0.05. Note: Positive control was dexamethasone. Bar line is the mean of the data points. The percent inhibition was calculated compared to vehicle control.

[0022] Figure 8 depicts the effect of Compound 1 on serum levels of CTX- II (Day

42) in mouse CIA. CTX- II = C-terminal crosslinked telopeptide type II collagen; BID = twice daily; * p < 0.05. Note: Positive control was dexamethasone. Bar line is the mean of the data points.

[0023] Figure 9 depicts the effect of Compound 1 doses at 10, 30, or 100 mg/kg

Twice Daily on Ear Thickness in the Dinitrochlorobenzene-induced Delayed-type

Hypersensitivity Model. BID = twice daily; Dex = dexamethasone; ** p < 0.01;

*** p < 0.001; **** p < 0.0001. Note: Data shown as mean with error bars represents standard error of the mean.

[0024] Figure 10 depicts the effect of Compound 1 Dose at 100 mg/kg Three

Times Daily on Ear Thickness in the Dinitrochlorobenzene-induced Delayed-type

Hypersensitivity Model. Dex = dexamethasone; TID = three times daily; * p < 0.05;

**** p < 0.0001. Note: Data shown as mean with error bars represents standard error of the mean.

[0025] Figure 11 depicts the effect of various doses of Compound 1 on murine popliteal lymph node (PLN) weight, when allogeneic spleen cells are injected into a mouse footpad. The numbers indicate % inhibition in PLN weight calculated by subtracting syngeneic PLN weight and comparing compound to vehicle treated group.

DETAILED DESCRIPTION DEFINITIONS

[0026] An "alkyl" group is a saturated, partially saturated, or unsaturated straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms, typically from 1 to 8 carbons or, in some embodiments, from 1 to 6, 1 to 4, or 2 to 6 or carbon atoms. Representative alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyl; while saturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl,

-4-methylpentyl, -2,3-dimethylbutyl and the like. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH ₃ ), -CH=C(CH ₃ ) ₂ , -C(CH ₃ )=CH ₂ , -C(CH ₃ )=CH(CH ₃ ), -C(CH ₂ CH ₃ )=CH ₂ , -C≡CH, -C≡C(CH ₃ ), -C≡C(CH ₂ CH ₃ ), -CH ₂ C≡CH, -CH ₂ C≡C(CH ₃ ) and -CH ₂ C≡C(CH ₂ CH ₃ ), among others. An alkyl group can be

substituted or unsubstituted. When the alkyl groups described herein are said to be

"substituted," they may be substituted with any substituent or substituents as those found in the exemplary compounds and embodiments disclosed herein, as well as halogen

(chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine;

aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone;

sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine;

alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide;

isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH) ₂ , or 0(alkyl)aminocarbonyl.

[0027] A "cycloalkyl" group is a saturated, or partially saturated cyclic alkyl group of from 3 to 10 carbon atoms having a single cyclic ring or multiple condensed or bridged rings which can be optionally substituted with from 1 to 3 alkyl groups. In some

embodiments, the cycloalkyl group has 3 to 8 ring members, whereas in other

embodiments the number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl,

2-methylcyclopentyl, 2-methylcyclooctyl, and the like, or multiple or bridged ring structures such as l-bicyclo[l . l . l]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl and the like. Examples of unsaturared cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, among others. A cycloalkyl group can be substituted or unsubstituted. Such substituted cycloalkyl groups include, by way of example, cyclohexanol and the like.

[0028] An "aryl" group is an aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). In some embodiments, aryl groups contain 6-14 carbons, and in others from 6 to 12 or even 6 to 10 carbon atoms in the ring portions of the groups. Particular aryls include phenyl, biphenyl, naphthyl and the like. An aryl group can be substituted or unsubstituted. The phrase "aryl groups" also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like).

[0029] A "heteroaryl" group is an aryl ring system having one to four heteroatoms as ring atoms in a heteroaromatic ring system, wherein the remainder of the atoms are carbon atoms. In some embodiments, heteroaryl groups contain 3 to 6 ring atoms, and in others from 6 to 9 or even 6 to 10 atoms in the ring portions of the groups. Suitable heteroatoms include oxygen, sulfur and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include but are not limited to, groups such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrolyl, pyridazinyl, pyrimidyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl

(e.g., indolyl-2-onyl or isoindolin-l-onyl), azaindolyl (pyrrolopyridyl or

lH-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (e.g., lH-benzo[d]imidazolyl), imidazopyridyl (e.g., azabenzimidazolyl or lH-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl (e.g., lH-benzo[d][l,2,3]triazolyl), benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl

(e.g., 3,4-dihydroisoquinolin-l(2H)-onyl), tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.

[0030] A "heterocyclyl" is an aromatic (also referred to as heteroaryl) or non- aromatic cycloalkyl in which one to four of the ring carbon atoms are independently replaced with a heteroatom from the group consisting of O, S and N. In some embodiments, heterocyclyl groups include 3 to 10 ring members, whereas other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members. Heterocyclyls can also be bonded to other groups at any ring atom (i.e., at any carbon atom or heteroatom of the heterocyclic ring). A heterocycloalkyl group can be substituted or unsubstituted. Heterocyclyl groups encompass unsaturated, partially saturated and saturated ring systems, such as, for example, imidazolyl, imidazolinyl and imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-dionyl) groups. The phrase heterocyclyl includes fused ring species, including those comprising fused aromatic and non-aromatic groups, such as, for example, 1-and 2-aminotetraline, benzotriazolyl (e.g., lH-benzo[d][l,2,3]triazolyl), benzimidazolyl (e.g., lH-benzo[d]imidazolyl), 2,3-dihydrobenzo[l,4]dioxinyl, and benzo[l,3]dioxolyl. The phrase also includes bridged polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Representative examples of a heterocyclyl group include, but are not limited to, aziridinyl, azetidinyl, azepanyl, oxetanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodithionyl, l,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, indolyl (e.g., indolyl-2-onyl or isoindolin-l-onyl), indolinyl, isoindolyl, isoindolinyl, azaindolyl (pyrrol opyridyl or lH-pyrrolo[2,3-b]pyridyl), indazolyl, indolizinyl, benzotriazolyl (e.g. lH-benzo[d][l,2,3]triazolyl), benzimidazolyl

(e.g., lH-benzo[d]imidazolyl or lH-benzo[d]imidazol-2(3H)-onyl), benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl (i.e., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, benzo[l,3]dioxolyl, pyrazol opyridyl (for example, lH-pyrazolo[3,4- b]pyridyl, lH-pyrazolo[4,3-b]pyridyl), imidazopyridyl (e.g., azabenzimidazolyl or lH-imidazo[4,5-b]pyridyl), triazol opyridyl, isoxazol opyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin-l(2H)-onyl), quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thianaphthalenyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl,

tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, tetrahydropyrimidin-2(lH)-one and tetrahydroquinolinyl groups. Representative non-aromatic heterocyclyl groups do not include fused ring species that comprise a fused aromatic group. Examples of

non-aromatic heterocyclyl groups include aziridinyl, azetidinyl, azepanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidyl, piperazinyl

(e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro- 2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dithianyl, l,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, or tetrahydropyrimidin-2(lH)-one. Representative substituted heterocyclyl groups may be mono- substituted or substituted more than once, such as, but not limited to, pyridyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents such as those listed below.

[0031] A "cycloalkylalkyl" group is a radical of the formula: -alkyl-cycloalkyl, wherein alkyl and cycloalkyl are as defined above. Substituted cycloalkylalkyl groups may be substituted at the alkyl, the cycloalkyl, or both the alkyl and the cycloalkyl portions of the group. Representative cycloalkylalkyl groups include but are not limited to methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl,

ethylcyclopropyl, ethylcyclobutyl, ethylcyclopentyl, ethylcyclohexyl, propylcyclopentyl, propylcyclohexyl and the like.

[0032] An "aralkyl" group is a radical of the formula: -alkyl-aryl, wherein alkyl and aryl are defined above. Substituted aralkyl groups may be substituted at the alkyl, the aryl, or both the alkyl and the aryl portions of the group. Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl.

[0033] An "heterocyclylalkyl" group is a radical of the formula: -alkyl- heterocyclyl, wherein alkyl and heterocyclyl are defined above. Substituted heterocyclylalkyl groups may be substituted at the alkyl, the heterocyclyl, or both the alkyl and the heterocyclyl portions of the group. Representative heterocylylalkyl groups include but are not limited to 4-ethyl-morpholinyl, 4-propylmorpholinyl, furan-2-yl methyl, furan-3-yl methyl, pyridin-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.

[0034] A "halogen" is fluorine, chlorine, bromine or iodine.

[0035] A "hydroxyalkyl" group is an alkyl group as described above substituted with one or more hydroxy groups.

[0036] An "alkoxy" group is -O-(alkyl), wherein alkyl is defined above.

[0037] An "alkoxyalkyl" group is -(alkyl)-O-(alkyl), wherein alkyl is defined above.

[0038] An "amino" group is a radical of the formula: - H ₂ .

[0039] An "alkylamino" group is a radical of the formula: -NH-alkyl or -N(alkyl) ₂ , wherein each alkyl is independently as defined above.

[0040] A "carboxy" group is a radical of the formula: -C(0)OH.

[0041] An "aminocarbonyl" group is a radical of the formula: -C(0)N(R ^# ) ₂ ,

-C(0) H(R ^# ) or -C(0) H ₂ , wherein each R ^# is independently a substituted or

unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclyl group as defined herein.

[0042] An "acylamino" group is a radical of the formula: - HC(0)( R ^# ) or

-N(alkyl)C(0)(R ^# ), wherein each alkyl and R ^# are independently as defined above.

[0043] A "sulfonylamino" group is a radical of the formula: - HS0 ₂ (R ^# ) or

-N(alkyl)S0 ₂ (R ^# ), wherein each alkyl and R ^# are defined above.

[0044] A "urea" group is a radical of the formula: -N(alkyl)C(0)N(R ^# ) ₂ ,

-N(alkyl)C(0) H(R ^# ), -N(alkyl)C(0) H ₂ , - HC(0)N(R ^# ) ₂ , - HC(0) H(R ^# ), or

- H(CO)NHR ^# , wherein each alkyl and R ^# are independently as defined above.

[0045] When the groups described herein, with the exception of alkyl group, are said to be "substituted," they may be substituted with any appropriate substituent or substituents. Illustrative examples of substituents are those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (=0); B(OH) ₂ , 0(alkyl)aminocarbonyl; cycloalkyl, which may be monocyclic or fused or non-fused poly cyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocyclyl, which may be monocyclic or fused or non-fused polycyclic

(e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl); monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidyl,

benzimidazolyl, benzothiophenyl, or benzofuranyl) aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclyl alkoxy.

[0046] As used herein, the term "Diaminopyrimidyl Compound" refers to compounds of formula (I). In one embodiment, a "Diaminopyrimidyl Compound" is a compound set forth in Tables 1, or 2. The term "Diaminopyrimidyl Compound" includes pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers of the compounds provided herein.

[0047] As used herein, the term "pharmaceutically acceptable salt(s)" refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base including an inorganic acid and base and an organic acid and base. Suitable pharmaceutically acceptable base addition salts of the compounds of formula (I) include, but are not limited to metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'-dibenzylethylenediamine,

chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl- glucamine) 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, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p- toluenesulfonic acid. Specific non-toxic acids include hydrochloric, hydrobromic, maleic, phosphoric, sulfuric, and methanesulfonic acids. Examples of specific salts thus include hydrochloride and mesylate salts. Others are well-known in the art, see for example, Remington 's Pharmaceutical Sciences, 18 ^th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19 ^th eds., Mack Publishing, Easton PA (1995).

[0048] As used herein and unless otherwise indicated, the term "stereoisomer" or

"stereomerically pure" means one stereoisomer of a Diaminopyrimidyl Compound that is substantially free of other stereoisomers of that compound. For example, a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical

stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. The Diaminopyrimidyl Compounds can have chiral centers and can occur as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms are included within the embodiments disclosed herein, including mixtures thereof.

[0049] The use of stereomerically pure forms of such Diaminopyrimidyl

Compounds, as well as the use of mixtures of those forms, are encompassed by the embodiments disclosed herein. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular Diaminopyrimidyl Compound may be used in methods and compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al, Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al, Tetrahedron 33 :2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).

[0050] It should also be noted the Diaminopyrimidyl Compounds can include

E and Z isomers, or a mixture thereof, and cis and trans isomers or a mixture thereof. In certain embodiments, the Diaminopyrimidyl Compounds are isolated as either the E or Z isomer. In other embodiments, the Diaminopyrimidyl Compounds are a mixture of the E and Z isomers.

[0051] "Tautomers" refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, in aqueous solution, pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:

[0052] As readily understood by one skilled in the art, a wide variety of functional groups and other stuctures may exhibit tautomerism and all tautomers of compounds of formula (I) are within the scope of the present invention.

[0053] It should also be noted the Diaminopyrimidyl Compounds can contain unnatural proportions of atomic isotopes at one or more of the atoms. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( ³ H), iodine-125 ( ¹²⁵ I), sulfur-35 ( ³⁵ S), or carbon-14 ( ¹⁴ C), or may be isotopically enriched, such as with deuterium ( ² H), carbon-13 ( ¹³ C), or nitrogen-15 ( ¹⁵ N). As used herein, an "isotopologue" is an isotopically enriched compound. The term "isotopically enriched" refers to an atom having an isotopic composition other than the natural isotopic

composition of that atom. "Isotopically enriched" may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. The term "isotopic composition" refers to the amount of each isotope present for a given atom. Radiolabeled and isotopically encriched compounds are useful as therapeutic agents, e.g., cancer and inflammation therapeutic agents, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the Diaminopyrimidyl Compounds as described herein, whether radioactive or not, are intended to be encompassed within the scope of the embodiments provided herein. In some embodiments, there are provided isotopologues of the

Diaminopyrimidyl Compounds, for example, the isotopologues are deuterium, carbon-13, or nitrogen-15 enriched Diaminopyrimidyl Compounds.

[0054] It is understood that, independently from the selection of substituents for each of L, X, R ¹ or R ² , stereomerical or isotopic composition, each Diaminopyrimidyl Compound referred to herein can be provided in the form of any of the pharmaceutically acceptable salts discussed herein. Equally, it is understood that the isotopic composition may vary independently from the stereomerical composition of each Diaminopyrimidyl Compound referred to herein. Further, the isotopic composition, while being restricted to those elements present in the respective Diaminopyrimidyl Compound or salt thereof, may otherwise vary independently from the selection of substituents for each of L, X, R ¹ or R ² or from the selection of the pharmaceutically acceptable salt of the respective

Diaminopyrimidyl Compound.

[0055] As used herein, "inhibit" and "inhibition" mean that a specified response of a designated activity (e.g., kinase or phosphorylation activity) is comparatively decreased in the presence of a Diaminopyrimidyl Compound. Inhibition of kinase activity, for example PKC-theta activity, can be determined by the biochemical assays described herein.

[0056] As used herein, "selective" or "selectively", means having an activity preference for a specific target, for example a kinase such as PKC-theta, over other targets, for example, a kinase such as PKC-delta and/or PKC-eta, which can be quantified based upon assays which demonstrate kinase activity, such biochemical assays disclosed herin. A Diaminopyrimidyl Compound's selectivity is determined from a comparison of its IC ₅₀ (or EC ₅₀ or ED ₅₀ if using an organism assay) at the relevant targets. For example, a

Diaminopyrimidyl Compound having an IC ₅₀ of 50 nM for PKC-delta and an IC ₅₀ of 10 nM for PKC-theta has a selectivity ratio for PKC-delta over PKC-theta of 5 : 1, or is 5-fold selective for PKC-theta over PKC-delta. In some embodiments, Diaminopyrimidyl Compounds are about 5-fold, about 10-fold, aboutl 5-fold, about 20-fold, about 50-fold, about 100-fold, about 150-fold, about 200-fold, about 250-fold, about 300-fold, or about 500-fold selective for PKC-theta over PKC-delta. In others, Diaminopyrimidyl Compounds are about 5-fold, about 10-fold, aboutl 5-fold, about 20-fold, about 50-fold, about 100-fold, about 150-fold, about 200-fold, about 250-fold, about 300-fold, or about 500-fold selective for PKC-theta over PKC-delta and PKC-eta.

[0057] The role of PKC-theta in disorders have been reported. For example,

PKC-theta mediated disorders include psoriasis (Skvara et al., J Clin Invest.

2008; 118(9):3151-3159), Duchenne muscular dystrophy (Madaro et al, PLoS One

2012;7(2):e31515), rheumatoid arthritis (Healy et al., J Immunol. 2006; 177(3): 1886-1893; Zanin-Zhorov et al., Science 2010; 328(5976):372-726), Type 2 diabetes and insulin resistance (Kim et al., J Clin Invest. 2004; 114(6):823-7), myasthenia gravis (Miles and Wagner, J Neurosci Res. 2003; 71(2): 188-195), multiple sclerosis (Salek-Ardakani et al., J Immunol. 2005; 175(11)7635-41), and colitis ((Zanin-Zhorov et al., Science 2010;

328(5976)372-726).

[0058] "Treating" as used herein, means an alleviation, in whole or in part, of a disorder, disease or condition, or one or more of the symptoms associated with a disorder, disease, or condition, or slowing or halting of further progression or worsening of those symptoms, or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself. In one embodiment, the disorder is a PKC-theta mediated disorder, such as, allergic, inflammatory, or autoimmune T-cell mediated diseases. In one embodiment, the disorder is a PKC-theta mediated disorder, such as, for example, ankylosing spondylitis, asthma (including refractory asthma and severe asthma), celiac disease, colitis (including ulcerative colitis), diabetes (including type I diabetes), dermatitis (including atopic dermatitis), Duchenne muscular dystrophy, graft-versus-host disease, inflammatory bowel disease (including Crohn's disease), insulin resistance, lupus (including systemic lupus erythematosus), multiple sclerosis (including relapsing remitting multiple sclerosis), myasthenia gravis, myositis (including polymyositis and dermatomyositis), organ transplant rejection, psoriasis (including plaque-type psoriasis, and psoriatic arthritis), rheumatoid arthritis, Sjogren syndrome, uveitis, or vitiligo. In some embodiments, "treating" means an alleviation, in whole or in part, of a disorder, disease or condition, or symptoms associated with a disorder, disease or condition, for example, a PKC-theta mediated disorder, such as, for example, ankylosing spondylitis, asthma (including refractory asthma and severe asthma), celiac disease, colitis (including ulcerative colitis), diabetes (including type I diabetes), dermatitis (including atopic dermatitis), Duchenne muscular dystrophy, graft-versus-host disease, inflammatory bowel disease (including Crohn's disease), insulin resistance, lupus (including systemic lupus erythematosus), multiple sclerosis (including relapsing remitting multiple sclerosis), myasthenia gravis, myositis (including polymyositis and dermatomyositis), organ transplant rejection, psoriasis (including plaque-type psoriasis, and psoriatic arthritis), rheumatoid arthritis, Sjogren syndrome, uveitis, or vitiligo, or a slowing, or halting of further progression or worsening of those symptoms. In another embodiment, "treating" means and alleviation, in whole or in part, of a disorder, disease or condition, or symptoms associated with a condition, treatable or preventable by inhibition of PKC-theta. In another embodiment, "treating" means and alleviation, in whole or in part, of a disorder, disease or condition, or symptoms associated with a condition, treatable or preventable by inhibition of PKC-theta selectively over PKC-delta. In yet another embodiment, "treating" means and alleviation, in whole or in part, of a disorder, disease or condition, or symptoms associated with a condition, treatable or preventable by inhibition of PKC-theta selectively over PKC-delta and/or PKC-eta.

[0059] "Preventing" as used herein, means a method of delaying and/or precluding the onset, recurrence or spread, in whole or in part, of a disorder, disease or condition; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject's risk of acquiring a disorder, disease, or condition. In one embodiment, the disorder is a PKC-theta mediated disorder, such as, allergic, inflammatory, or autoimmune T-cell mediated diseases. In one embodiment, the disorder is a PKC-theta mediated disorder, such as, for example, ankylosing spondylitis, asthma (including refractory asthma and severe asthma), celiac disease, colitis (including ulcerative colitis), diabetes (including type I diabetes), dermatitis (including atopic dermatitis), Duchenne muscular dystrophy, graft-versus-host disease, inflammatory bowel disease (including Crohn's disease), insulin resistance, lupus (including systemic lupus erythematosus), multiple sclerosis (including relapsing remitting multiple sclerosis), myasthenia gravis, myositis (including

polymyositis and dermatomyositis), organ transplant rejection, psoriasis (including plaque-type psoriasis, and psoriatic arthritis), rheumatoid arthritis, Sjogren syndrome, uveitis, or vitiligo, as described herein, or symptoms thereof.

[0060] The term "effective amount" in connection with a Diaminopyrimidyl

Compound means an amount capable of treating or preventing a disorder, disease or condition, or symptoms thereof, disclosed herein.

[0061] The term "subject" or "patient" includes an animal, including, but not limited to, an animal such a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig, in one embodiment a mammal, in another embodiment a human, in another embodiment a cell from any one of the foregoing animals. In one embodiment, a subject or patient is a non-human animal, in another embodiment a non-human mammal. In one embodiment, a subject or patient is a human having or at risk for having ankylosing spondylitis, asthma (including refractory asthma and severe asthma), celiac disease, colitis (including ulcerative colitis), diabetes (including type I diabetes), dermatitis (including atopic dermatitis), Duchenne muscular dystrophy, graft-versus-host disease, inflammatory bowel disease (including Crohn's disease), insulin resistance, lupus (including systemic lupus erythematosus), multiple sclerosis (including relapsing remitting multiple sclerosis), myasthenia gravis, myositis (including

polymyositis and dermatomyositis), organ transplant rejection, psoriasis (including plaque-type psoriasis, and psoriatic arthritis), rheumatoid arthritis, Sjogren syndrome, uveitis, or vitiligo, or a condition, treatable or preventable by inhibition of a kinse, for example PKC-theta, or a symptom thereof.

[0062] In certain embodiments, the treatment of psoriasis may be assessed by evaluation of Psoriasis Area Severity Index (PASI), Body Surface Area (BSA), Static Physicians Global Assessment (sPGA), and/or Dermatology Quality of Life Index (DLQI) before and after administration of a Diaminopyrimidyl Compound. PASI is a measure of psoriatic disease severity taking into account qualitative lesion characteristics (erythema, thickness, and scaling) and degree of skin surface area involvement on defined anatomical regions. The PASI is a validated instrument that has become standard in clinical trials for psoriasis. Psoriasis Area and Severity Index scores range from 0 to 72, with higher scores reflecting greater disease severity (Frederiksson, Dermatologica. 1978; 157:238-244). Erythema, thickness, and scaling are scored on a scale of 0 (none) to 4 (very severe) on 4 anatomic regions of the body: head, trunk, upper limbs, and lower limbs. Degree of involvement on each of the 4 anatomic regions is scored on a scale of 0 (no involvement) to 6 (90% to 100%) involvement). The total qualitative score (sum of erythema, thickness, and scaling scores) is multiplied by the degree of involvement for each anatomic region and then multiplied by a constant. These values for each anatomic region are summed to yield the PASI score. The PASI calculation is shown in Figure 1.

[0063] As used herein, a PASIIOO is defined as a 100% reduction from baseline in PASI at the end of study, a PASI75 is defined as a 75% reduction from baseline in PASI at end of treatment, and a PASI50 is defined as a 50% reduction from baseline in PASI at end of treatment. Treatment is assessed by the number of subjects that achieve PASI improvements (such as PASIIOO, PASI75, or PASI50). In some embodiments of the methods described herein, treatment with a Diaminopyrimidyl Compound results in 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of subjects achieving PASIIOO. In other embodiments, treatment with a Diaminopyrimidyl Compound results in 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of subjects achieving PASI75. In still other embodiments, treatment with a Diaminopyrimidyl Compound results in 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of subjects achieving PASI50.

[0064] Body surface area is a measurement of involved skin. The overall BSA affected by psoriasis is estimated based on the palm area of the subject's hand (entire palmar surface or "handprint"), which equates to approximately 1% of total body surface area. Treatment is evaluated by the change from baseline in BSA involvement. In some embodiments of the methods described herein, treatment with a Diaminopyrimidyl Compound results in subjects achieving a 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% reduction of BSA involvement.

[0065] The sPGA is the assessment by the Investigator of the overall disease severity at the time of evaluation. The sPGA is a 5-point scale ranging from 0 (clear) to 4 (severe), incorporating an assessment of the severity of the three primary signs of the disease: erythema, scaling and plaque elevation. When making the assessment of overall severity, the Investigator should factor in areas that have already been cleared (ie, have scores of 0) and not just evaluate remaining lesions for severity, ie, the severity of each sign is averaged across all areas of involvement, including cleared lesions. In the event of different severities across disease signs, the sign that is the predominant feature of the disease should be used to help determine the sPGA score. Treatment is evaluated by change from baseline in sPGA score. The grading criteria are shown in Figure 2.

[0066] In some embodiments of the methods described herein, treatment with a

Diaminopyrimidyl Compound results in an improvement over baseline score. In some embodiments, treatment with a Diaminopyrimidyl Compound results in 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of subjects achieving a reduction in sPGA score of at least 1. In some embodiments of the methods described herein, treatment with a Diaminopyrimidyl Compound results in 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of subjects achieving a

reduction in sPGA score of at least 2. In some embodiments of the methods described herein, treatment with a Diaminopyrimidyl Compound results in 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of subjects achieving a

reduction in sPGA score of at least 3. In some embodiments of the methods described herein, treatment with a Diaminopyrimidyl Compound results in 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of subjects achieving a

reduction in sPGA score of at least 4.

[0067] In some embodiments, treatment is assessed by assessment of the

Dermatology Quality of Life Index (DLQI) (Finlay, Clin Exp Dermatol. 1994; 19:210- 216). The instrument contains ten items dealing with the subject's skin. With the

exception of Item Number 7, the subject responds on a four-point scale, ranging from

"Very Much" to "Not at All." Item Number 7 is a multi-part item, the first part of which ascertains whether the subject's skin prevented them from working or studying (Yes or No), and if "No," then the subject is asked how much of a problem the skin has been at work or study over the past week, with response alternatives being "A lot," "A little," or "Not at all." The DLQI Total score has a possible range of 0 to 30, with 30 corresponding to the worst quality of life, and 0 corresponding to the best score. The developers suggest that the DLQI can be grouped into six subscales: symptoms and feelings; daily activities;

leisure; work/school; personal relationships; and treatment. Scores for four of the

subscales (symptoms and feelings, daily activities, leisure, and personal relationships) range from 0 to 6; scores for two of the subscales (work/school and treatment) range from 0 to 3. Higher scores correspond to poorer quality of life. The questionnaire questions are shown in Figure 3 (with one box for each question to be checked). Treatment is evaluated as change from baseline in DLQI score. In some embodiments of the methods described herein, treatment with a Diaminopyrimidyl Compound results in an improvement over baseline score. In some embodiments, treatment with a Diaminopyrimidyl Compound results in 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100%) of subjects achieving a reduction in DLQI score of at least 5. In some embodiments of the methods described herein, treatment with a Diaminopyrimidyl Compound results in 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of subjects achieving a reduction in DLQI score of at least 10. In some embodiments of the methods described herein, treatment with a Diaminopyrimidyl Compound results in 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of subjects achieving a reduction in DLQI score of at least 15. In some embodiments of the methods described herein, treatment with a Diaminopyrimidyl Compound results in 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of subjects achieving a reduction in DLQI score of at least 20. In some embodiments of the methods described herein, treatment with a Diaminopyrimidyl Compound results in 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of subjects achieving a reduction in DLQI score of at least 25. In some embodiments of the methods described herein, treatment with a Diaminopyrimidyl Compound results in 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of subjects achieving a reduction in DLQI score of at least 30.

DIAMINOPYRIMIDYL COMPOUNDS

(I) a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof,

wherein:

X is CN or CF ₃ ;

L is (Ci-4 alkyl);

R ¹ is substituted or unsubstituted heteroaryl; and

R ² is substituted or unsubstituted cycloalkyl.

[0069] In some embodiments of compounds of formula (I), X is CN. In others, X is CF ₃ .

[0070] In some embodiments of compounds of formula (I), L is CH ₂ . In another, L is

CH ₂ CH ₂ or CH ₂ CH ₂ CH ₂ . In still another, L is CH ₂ , CH ₂ CH ₂ or CH ₂ CH ₂ CH ₂ .

[0071] In some embodiments of compounds of formula (I), X is CN and L is CH ₂

(Ci alkyl). In others, X is CF ₃ and L is CH ₂ (Ci alkyl). In some embodiments of compounds of formula (I), X is CN and L is CH ₂ CH ₂ (C ₂ alkyl). In others, X is CF ₃ and L is CH ₂ CH ₂

(C ₂ alkyl). In some embodiments of compounds of formula (I), X is CN and L is CH ₂ CH ₂ CH ₂ (C ₃ alkyl). In others, X is CF ₃ and L is CH ₂ CH ₂ CH ₂ (C ₃ alkyl). In some embodiments of compounds of formula (I), X is CN and L is CH ₂ CH ₂ CH ₂ CH ₂ (C ₄ alkyl). In others, X is CF ₃ and L is CH ₂ CH ₂ CH ₂ CH ₂ (C ₄ alkyl).

[0072] In some embodiments of compounds of formula (I), X is CN, L is CH ₂ (Ci alkyl) and R ¹ is substituted heteroaryl. In others, X is CF ₃ , L is CH ₂ (Ci alkyl) and R ¹ is substituted heteroaryl. In some embodiments of compounds of formula (I), X is CN, L is CH ₂ CH ₂ (C ₂ alkyl) and R ¹ is substituted heteroaryl. In others, X is CF ₃ , L is CH ₂ CH ₂ (C ₂ alkyl) and R ¹ is substituted heteroaryl. In some embodiments of compounds of formula (I), X is CN, L is CH ₂ CH ₂ CH ₂ (C ₃ alkyl) and R ¹ is substituted heteroaryl. In others, X is CF ₃ , L is CH ₂ CH ₂ CH ₂ (C ₃ alkyl) and R ¹ is substituted heteroaryl. In some embodiments of compounds of formula (I), X is CN, L is CH ₂ CH ₂ CH ₂ CH ₂ (C ₄ alkyl) and R ¹ is substituted heteroaryl. In others, X is CF ₃ , L is CH ₂ CH ₂ CH ₂ CH ₂ (C ₄ alkyl) and R ¹ is substituted heteroaryl. In some embodiments of compounds of formula (I), X is CN, L is CH ₂ (Ci alkyl) and R ¹ is unsubstituted heteroaryl. In others, X is CF ₃ , L is CH ₂ (Ci alkyl) and R ¹ is unsubstituted heteroaryl. In some embodiments of compounds of formula (I), X is CN, L is CH ₂ CH ₂ (C ₂ alkyl) and R ¹ is unsubstituted heteroaryl. In others, X is CF ₃ , L is CH ₂ CH ₂ (C ₂ alkyl) and R ¹ is unsubstituted heteroaryl. In some embodiments of compounds of formula (I), X is CN, L is CH ₂ CH ₂ CH ₂ (C ₃ alkyl) and R ¹ is unsubstituted heteroaryl. In others, X is CF ₃ , L is CH ₂ CH ₂ CH ₂ (C ₃ alkyl) and R ¹ is unsubstituted heteroaryl. In some embodiments of compounds of formula (I), X is CN, L is CH ₂ CH ₂ CH ₂ CH ₂ (C ₄ alkyl) and R ¹ is unsubstituted heteroaryl. In others, X is CF ₃ , L is CH ₂ CH ₂ CH ₂ CH ₂

(C ₄ alkyl) and R ¹ is unsubstituted heteroaryl.

[0073] In some embodiments of compounds of formula (I), X is CN, L is CH ₂ (Ci alkyl),

R ¹ is substituted heteroaryl and R ² is substituted cycloalkyl. In others, X is CF ₃ , L is CH ₂ (Ci alkyl), R ¹ is substituted heteroaryl and R ² is substituted cycloalkyl. In some embodiments of compounds of formula (I), X is CN, L is CH ₂ CH ₂ (C ₂ alkyl), R ¹ is substituted heteroaryl and R ² is substituted cycloalkyl. In others, X is CF ₃ , L is CH ₂ CH ₂ (C ₂ alkyl), R ¹ is substituted heteroaryl and R ² is substituted cycloalkyl. In some embodiments of compounds of formula (I), X is CN, L is CH ₂ CH ₂ CH ₂ (C ₃ alkyl), R ¹ is substituted heteroaryl and R ² is substituted cycloalkyl. In others, X is CF ₃ , L is CH ₂ CH ₂ CH ₂ (C ₃ alkyl), R ¹ is substituted heteroaryl and R ² is substituted cycloalkyl. In some embodiments of compounds of formula (I), X is CN, L is CH ₂ CH ₂ CH ₂ CH ₂ (C ₄ alkyl), R ¹ is substituted heteroaryl and R ² is substituted cycloalkyl. In others, X is CF ₃ , L is CH ₂ CH ₂ CH ₂ CH ₂ (C ₄ alkyl), R ¹ is substituted heteroaryl and R ² is substituted cycloalkyl. In some embodiments of compounds of formula (I), X is CN, L is CH ₂ (Ci alkyl), R ¹ is unsubstituted heteroaryl and R ² is substituted cycloalkyl. In others, X is CF ₃ , L is CH ₂ (Ci alkyl), R ¹ is unsubstituted heteroaryl and R ² is substituted cycloalkyl. In some embodiments of compounds of formula (I), X is CN, L is CH ₂ CH ₂ (C ₂ alkyl), R ¹ is unsubstituted heteroaryl and R ² is substituted cycloalkyl. In others, X is CF ₃ , L is CH ₂ CH ₂ (C ₂ alkyl), R ¹ is unsubstituted heteroaryl and R ² is substituted cycloalkyl. In some embodiments of compounds of formula (I), X is CN, L is CH ₂ CH ₂ CH ₂ (C ₃ alkyl), R ¹ is unsubstituted heteroaryl and R ² is substituted cycloalkyl. In others, X is CF ₃ , L is CH ₂ CH ₂ CH ₂ (C ₃ alkyl), R ¹ is unsubstituted heteroaryl and R ² is substituted cycloalkyl. In some embodiments of compounds of formula (I), X is CN, L is CH ₂ CH ₂ CH ₂ (C ₄ alkyl), R ¹ is unsubstituted heteroaryl and R ² is substituted cycloalkyl. In others, X is CF ₃ , L is CH ₂ CH ₂ CH ₂ CH ₂ (C ₄ alkyl), R ¹ is unsubstituted heteroaryl and R ² is substituted cycloalkyl.

[0074] In some embodiments of compounds of formula (I), X is CN, L is CH ₂ (Ci alkyl),

R ¹ is substituted heteroaryl and R ² is unsubstituted cycloalkyl. In others, X is CF ₃ , L is CH ₂ (Ci alkyl), R ¹ is substituted heteroaryl and R ² is unsubstituted cycloalkyl. In some embodiments of compounds of formula (I), X is CN, L is CH ₂ CH ₂ (C ₂ alkyl), R ¹ is substituted heteroaryl and R ² is unsubstituted cycloalkyl. In others, X is CF ₃ , L is CH ₂ CH ₂ (C ₂ alkyl), R ¹ is substituted heteroaryl and R ² is unsubstituted cycloalkyl. In some embodiments of compounds of formula (I), X is CN, L is CH ₂ CH ₂ CH ₂ (C ₃ alkyl), R ¹ is substituted heteroaryl and R ² is unsubstituted cycloalkyl. In others, X is CF ₃ , L is CH ₂ CH ₂ CH ₂ (C ₃ alkyl), R ¹ is substituted heteroaryl and R ² is unsubstituted cycloalkyl. In some embodiments of compounds of formula (I), X is CN, L is CH ₂ CH ₂ CH ₂ CH ₂ (C ₄ alkyl), R ¹ is substituted heteroaryl and R ² is unsubstituted cycloalkyl. In others, X is CF ₃ , L is CH ₂ CH ₂ CH ₂ CH ₂ (C ₄ alkyl), R ¹ is substituted heteroaryl and R ² is unsubstituted cycloalkyl. In some embodiments of compounds of formula (I), X is CN, L is CH ₂ (Ci alkyl), R ¹ is unsubstituted heteroaryl and R ² is unsubstituted cycloalkyl. In others, X is CF ₃ , L is CH ₂ (C ₁ alkyl), R ¹ is unsubstituted heteroaryl and R ² is unsubstituted cycloalkyl. In some embodiments of compounds of formula (I), X is CN, L is CH ₂ CH ₂ (C ₂ alkyl), R ¹ is unsubstituted heteroaryl and R ² is unsubstituted cycloalkyl. In others, X is CF ₃ , L is CH ₂ CH ₂ (C ₂ alkyl), R ¹ is unsubstituted heteroaryl and R ² is unsubstituted cycloalkyl. In some embodiments of compounds of formula (I), X is CN, L is CH ₂ CH ₂ CH ₂ (C ₃ alkyl), R ¹ is unsubstituted heteroaryl and R ² is unsubstituted cycloalkyl. In others, X is CF ₃ , L is CH ₂ CH ₂ CH ₂ (C ₃ alkyl), R ¹ is unsubstituted heteroaryl and R ² is unsubstituted cycloalkyl. In some embodiments of compounds of formula (I), X is CN, L is CH ₂ CH ₂ CH ₂ CH ₂ (C ₄ alkyl), R ¹ is unsubstituted heteroaryl and R ² is unsubstituted cycloalkyl. In others, X is CF ₃ , L is

CH ₂ CH ₂ CH ₂ CH ₂ (C ₄ alkyl), R ¹ is unsubstituted heteroaryl and R ² is unsubstituted cycloalkyl.

[0075] In some embodiments of compounds of formula (I), R ¹ is a substituted or unsubstituted pyridyl, pyridyl-1 -oxide, or pyrimidyl. In some such embodiments, R ¹ is substituted with one or more substituents selected from halogen, -OR ³ , substituted or

unsubstituted C _1-4 alkyl, or substituted or unsubstituted aryl, wherein each R ³ is independently H, substituted or unsubstituted Ci _-6 alkyl, or substituted or unsubstituted aryl. In some

embodiments, R ¹ is substituted with one or more substituents selected from F, CI, Br, I, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, phenyl, naphthyl, -CH ₂ F, -CHF ₂ , -CF ₃ ,

-CHFCH ₃ , -CF ₂ CH ₃ , -C(CH ₃ ) ₂ F, -OCH ₃ , -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ F, -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , -OCH ₂ CH(CH ₃ )F, -OCH ₂ C(CH ₃ ) ₂ F, -OCH ₂ C(CH ₃ )F ₂ , -OCH ₂ CH ₂ CF ₃ , or -O-phenyl, wherein each phenyl is optionally substituted with halogen or substituted or unsubstituted C _1-4 alkyl. For example, R ¹ is substituted with one or more substituents selected from F, methyl, ethyl, isopropyl, phenyl, -CF ₃ , -CF ₂ CH ₃ , -C(CH ₃ ) ₂ F, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ F, -OCH ₂ CHF ₂ , -OCH ₂ C(CH ₃ )F ₂ , -OCH ₂ CH ₂ CF ₃ , or -O-phenyl, wherein each phenyl is optionally substituted with F or methyl.

[0076] In other embodiments, R ¹ is a substituted or unsubstituted pyrazinyl. In some embodiments, R ¹ is a substituted or unsubstituted pyridyl, pyridyl-l -oxide, pyrimidyl or pyrazinyl. In some such embodiments, R ¹ is substituted with one or more substituents selected from CI, or -OCH ₂ CF ₃ In other such embodiments, R ¹ is substituted with one or more substituents selected from F, CI, methyl, ethyl, isopropyl, phenyl, -CF ₃ , -CF ₂ CH ₃ , -C(CH ₃ ) ₂ F, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CF ₃ , -OCH ₂ CH ₂ F, -OCH ₂ CHF ₂ , -OCH ₂ C(CH ₃ )F ₂ , -OCH ₂ CH ₂ CF ₃ , or -O-phenyl, wherein each phenyl is optionally substituted with F or methyl.

[0077] m

wherein each R ^a is independently selected from halogen, -OR ³ , substituted or unsubstituted Ci _-4 alkyl, or substituted or unsubstituted aryl, wherein each R ³ is independently H, substituted or unsubstituted Ci _-6 alkyl, or substituted or unsubstituted aryl; and p is 0-3.

[0078] In some such embodiments, each R ^a is independently selected from F, CI, Br, I, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, phenyl, naphthyl, -CH ₂ F, -CHF ₂ , -CF ₃ , -CHFCH ₃ , -CF ₂ CH ₃ , -C(CH ₃ ) ₂ F, -OCH ₃ , -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ F, -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , -OCH ₂ CH(CH ₃ )F, -OCH ₂ C(CH ₃ ) ₂ F, -OCH ₂ C(CH ₃ )F ₂ , -OCH ₂ CH ₂ CF ₃ , or -O-phenyl, wherein each phenyl is optionally substituted with halogen or substituted or unsubstituted Ci _-4 alkyl; and p is 1-2. For example, each R ^a is independently selected from F, methyl, ethyl, isopropyl, phenyl, -CF ₃ , -CF ₂ CH ₃ , -C(CH ₃ ) ₂ F, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ F, -OCH ₂ CHF ₂ , -OCH ₂ C(CH ₃ )F ₂ , -OCH ₂ CH ₂ CF ₃ , or -O-phenyl, wherein each phenyl is optionally substituted with F or methyl and p is 1 or 2.

[0079] In some other embodiments of compounds of formula (I), each R ^a is

independently selected from CI, or -OCH ₂ CF ₃ . In some embodiments of compounds of formula (I), each R ^a is independently selected from F, CI, methyl, ethyl, isopropyl, phenyl, -CF ₃ , -CF ₂ CH ₃ , -C(CH ₃ ) ₂ F, -OCH ₃ , -OCH ₂ CH ₃ , OCH ₂ CF ₃ , -OCH ₂ CH ₂ F, -OCH ₂ CHF ₂ ,

-OCH ₂ C(CH ₃ )F ₂ , -OCH ₂ CH ₂ CF ₃ , or -O-phenyl, wherein each phenyl is optionally substituted with F or methyl and p is 1 or 2.

[0080] In some embodiments of com ounds of formula I R ¹ is selected from

wherein each R ^a is independently selected from halogen, -OR , substituted or unsubstituted C _1-4 alkyl, or substituted or unsubstituted aryl, wherein each R ³ is independently H, substituted or unsubstituted Ci _-6 alkyl, or substituted or unsubstituted aryl; and p is 0-3. For example, each R ^a is independently selected from F, methyl, ethyl, isopropyl, phenyl, -CF ₃ , -CF ₂ CH ₃ , -C(CH ₃ ) ₂ F, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ F, -OCH ₂ CHF ₂ , -OCH ₂ C(CH ₃ )F ₂ ,

-OCH ₂ CH ₂ CF ₃ , or -O-phenyl, wherein each phenyl is optionally substituted with F or methyl and p is 1 or 2. For example, each R ^a is independently selected from methyl, -CF ₃ , or -OCH ₂ CH ₃ .

[0081] In some embodiments of compounds of formula (I), R ¹ is a substituted or unsubstituted indolyl, indolinonyl, benzoxazolyl, pyrrol opyridyl, indazolyl, benzimidazolyl, dihydrobenzimidazolonyl, or quinolyl. In some such embodiments, R ¹ is substituted with one or more substituents selected from halogen, CN, -OR ³ , substituted or unsubstituted C _1-4 alkyl, or substituted or unsubstituted aryl, wherein each R ³ is independently H, substituted or

unsubstituted Ci _-6 alkyl, or substituted or unsubstituted aryl. In some such embodiments, R ¹ is substituted with one or more substituents selected from F, CI, CN, methyl, ethyl,

-CH ₂ S0 ₂ NHCH ₃ , -OH, -OCH ₃ , or OCF ₃ .

[0082] In some embodiments of compounds of formula (I), R ¹ is selected from

wherein each R ^c is independently selected from halogen, CN, -OR , substituted or unsubstituted C _1-4 alkyl, or substituted or unsubstituted aryl, wherein each R ³ is independently H, substituted or unsubstituted Ci _-6 alkyl, or substituted or unsubstituted aryl; R is H or C _1-4 alkyl; and r is 0-3. For example, each R ^c is independently selected from F, CI, CN, methyl, ethyl, -CH2SO2NHCH3, -OH, -OCH3, or -OCF3.

[0083] In some embodiments of compounds of formula (I), R ¹ is a substituted or unsubstituted furanyl, pyrrolyl, thiophenyl, oxazolyl, pyrazolyl, imidazolyl, oxadiazolyl, or triazolyl. In some such embodiments, R ¹ is substituted with one or more substituents selected from halogen, CN, -OR ³ , substituted or unsubstituted C _1-4 alkyl, or substituted or unsubstituted aryl, wherein each R ³ is independently H, substituted or unsubstituted Ci _-6 alkyl, or substituted or unsubstituted aryl. In some such embodiments, R ¹ is substituted with one or more substituents selected from CN, methyl, ethyl, -CF ₃ , or -CH ₂ OCH ₃ .

[0084] In some embodiments of compounds of formula (I), R ¹ is selected from

wherein each R ^d is independently selected from halogen, CN, -OR ³ , substituted or unsubstituted C _1-4 alkyl, or substituted or unsubstituted aryl, wherein each R ³ is independently H, substituted or unsubstituted Ci _-6 alkyl, or substituted or unsubstituted aryl; R is independently H, or Ci-4 alkyl; and s is 0-3. For example, each R ^d is independelty selected from CN, methyl, ethyl, -CF ₃ , or -CH ₂ OCH ₃ .

[0085] In some embodiments, R ¹ is a substituted or unsubstituted pyridyl,

pyridyl-1 -oxide, pyrimidyl, pyridazinyl, indolyl, indolinonyl, benzoxazolyl, pyrrol opyridyl, indazolyl, benzimidazolyl, dihydrobenzimidazolonyl, quinolyl, furanyl, pyrrolyl, thiophenyl, oxazolyl, pyrazolyl, imidazolyl, oxadiazolyl, or triazolyl. In some such embodiments, R ¹ is substituted with one or more substituents selected from halogen, CN, -OR ³ , substituted or unsubstituted C _1-4 alkyl, or substituted or unsubstituted aryl, wherein each R ³ is independently H, substituted or unsubstituted Ci _-6 alkyl, or substituted or unsubstituted aryl. In some such embodiments, R ¹ is substituted with one or more substituents selected from F, CI, CN, methyl, ethyl, isopropyl, phenyl, -CF ₃ , -CF ₂ CH ₃ , -C(CH ₃ ) ₂ F, -CH ₂ OCH ₃ , -CH ₂ S0 ₂ NHCH ₃ , -OH, -OCH ₃ , -OCF ₃ , -OCH ₂ CH ₃ , -OCH(CH ₃ ) ₂ , -OCH ₂ CF ₃ , -OCH ₂ CH ₂ F, -OCH ₂ CHF ₂ , -OCH ₂ C(CH ₃ )F ₂ , -OCH ₂ CH ₂ CF ₃ , or -O-phenyl, wherein each phenyl is optionally substituted with F or methyl.

[0086] In some embodiments of compounds of formula (I), R ² is substituted or unsubstituted C ₃ . ₁₂ cycloalkyl. For example, R ² is substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl. In some such embodiments, R ² is substituted with one or more substituents selected from C _1-4 alkyl, -OR ⁴ , or -C(=0)NR ₂ , wherein each R ⁴ is independently H or Ci _-6 alkyl, and each R is independently H or C _1-4 alkyl. In others, R ² is substituted with one or more substituents selected from methyl, ethyl, propyl, isopropyl, -CH ₂ OH, -CH(CH ₃ )OH, -C(CH ₃ ) ₂ OH, -OH, -OCH ₃ , -OCH ₂ CH ₃ , -C(=0) H ₂ , -C(=0)NHCH ₃ , or -C(=0)N(CH ₃ ) ₂ . For example, R ² is substituted with one or more substituents selected from methyl, -CH ₂ OH, -C(CH ₃ ) ₂ OH, -OH, -OCH ₃ , or -C(=0) HCH ₃ .

[0087] In some embodiments of com ounds of formula (I), R ² is selected from

wherein each R ^b is independenty selected from C _1-4 alkyl, -OR ⁴ , or -C(=0) R ₂ , wherein each R ⁴ is independently H or Ci _-6 alkyl, each R is independently H or C _1-4 alkyl, and q is 0-6.

[0088] In some such embodiments, each R ^b is independently selected from methyl, ethyl, propyl, isopropyl, -CH ₂ OH, -CH(CH ₃ )OH, -C(CH ₃ ) ₂ OH, -OH, -OCH ₃ , -OCH ₂ CH ₃ , -C(=0) H ₂ , -C(=0)NHCH ₃ , or -C(=0)N(CH ₃ ) ₂ , and q is 1-5. In others, each R ^b is independently selected from methyl, -CH ₂ OH, -C(CH ₃ ) ₂ OH, -OH, -OCH ₃ , or -C(=0)NHCH ₃ , and q is 1-5. In some such embodiments, each R ^b is independently selected from triazolyl, -C(=0) H ₂ , or

-C(=0)N(CH ₃ ) ₂ . In others, each R ^b is independently selected from methyl, triazolyl, -CH ₂ OH, -C(CH ₃ ) ₂ OH, -OH, -OCH ₃ , -C(=0) H ₂ , -C(=0) HCH ₃ , or -C(=0)N(CH ₃ ) ₂

[0089] In some embodiments of com ounds of formula (I), R ² is selected from

wherein each R ^b is independently selected from C _1-4 alkyl, -OR ⁴ , or -C(=0)NR ₂ , wherein each R ⁴ is independently H or Ci _-6 alkyl, each R is independently H or C _1-4 alkyl, and t is 0-5.

[0090] In some such embodiments, each R ^b is independently selected from methyl, ethyl, propyl, isopropyl, -CH ₂ OH, -CH(CH ₃ )OH, -C(CH ₃ ) ₂ OH, -OH, -OCH ₃ , -OCH ₂ CH ₃ , -C(=0) H ₂ , -C(=0)NHCH ₃ , or -C(=0)N(CH ₃ ) ₂ , and t is 0-4. In others, each R ^b is independently selected from methyl, -CH ₂ OH, -C(CH ₃ ) ₂ OH, -OH, -OCH ₃ , or -C(=0)NHCH ₃ , and t is 0-4.

[0091] In some other embodiments of com ounds of formula (I), R ² is selected from

wherein each R ^b is independently selected from C _1-4 alkyl, -OR ⁴ , or -C(=0)NR ₂ , wherein each R ⁴ is independently H or Ci _-6 alkyl, each R is independently H or C _1-4 alkyl, and t is 0-5.

[0092] In some such embodiments, each R ^b is independently selected from methyl, ethyl, propyl, isopropyl, -CH ₂ OH, -CH(CH ₃ )OH, -C(CH ₃ ) ₂ OH, -OH, -OCH ₃ , -OCH ₂ CH ₃ , -C(=0) H ₂ , -C(=0)NHCH ₃ , or -C(=0)N(CH ₃ ) ₂ , and t is 0-4. In others, each R ^b is independently selected from methyl, -CH ₂ OH, -C(CH ₃ ) ₂ OH, -OH, -OCH ₃ , or -C(=0)NHCH ₃ , and t is 0-4.

[0093] In other embodiments, each R ^b is independently selected from triazolyl, C _1-4 alkyl,

-OR ⁴ , -C(=0) R ₂ , wherein each R ⁴ is independently H or Ci _-6 alkyl, and each R is independently H or Ci-4 alkyl, and t is 0-5. For example, each R ^b is independently selected from triazolyl, -C(=0) H ₂ , or -C(=0)N(CH ₃ ) ₂ . In others, each R ^b is independently selected from methyl, triazolyl, -CH ₂ OH, -C(CH ₃ ) ₂ OH, -OH, -OCH ₃ , -C(=0) H ₂ , -C(=0) HCH ₃ , or -C(=0)N(CH ₃ ) ₂ .

[0094] In s ted from

wherein each R ^e is independently selected from C _1-4 alkyl, -OR ⁴ , or -C(=0) R ₂ , wherein each R ⁴ is independently H or Ci _-6 alkyl, each R is independently H or C _1-4 alkyl, and u is 0-4. For example, each R ^e is independently selected from methyl or -OH. [0095] In some such embodiments of R ² , R ¹ is selected from

wherein each R ^a is independently selected from halogen, -OR , substituted or unsubstituted C _1-4 alkyl, or substituted or unsubstituted aryl, wherein each R ³ is independently H, substituted or unsubstituted Ci _-6 alkyl, or substituted or unsubstituted aryl; and p is 0-3.

[0096] In other such embodiments of ² R ¹ is selected from

wherein each R ^a is independently selected from halogen, -OR , substituted or unsubstituted C _1-4 alkyl, or substituted or unsubstituted aryl, wherein each R ³ is independently H, substituted or unsubstituted Ci _-6 alkyl, or substituted or unsubstituted aryl; and p is 0-3.

[0097]

wherein each R ^c is independently selected from halogen, CN, -OR , substituted or unsubstituted C _1-4 alkyl, or substituted or unsubstituted aryl, wherein each R is independently H, substituted or unsubstituted Ci _-6 alkyl, or substituted or unsubstituted aryl; R is independently H or Ci-4 alkyl; and r is 0-3.

[0098] In yet other such embodiments of R ² , R ¹ is selected from

wherein each R ^d is independently selected from halogen, CN, -OR ³ , substituted or unsubstituted Ci _-4 alkyl, or substituted or unsubstituted aryl, wherein each R ³ is independently H, substituted or unsubstituted Ci _-6 alkyl, or substituted or unsubstituted aryl; R is independently H or Ci-4 alkyl; and s is 0-3.

[0099] Further embodiments provided herein include combinations of one or more of the particular embodiments set forth above.

[00100] Representative compounds of formula (I) are set forth in Table 1.

[00101] Table 1

Cmpd Cmpd Structure MS Act. Sel. No. (ESI) Level Level A- m/z

307 421.2 C G

308 421.2 C H

H OH

309 439.2 B G

310 439.2 B H

311 439.2 C G Cmpd Cmpd Structure MS Act. Sel. No. (ESI) Level Level A- m/z

312 439.2 C G

313 439.2 C F

314 439.2 C H

315 439.2 C G

316 439.2 D F

[00102] In other embodiments, the Diaminopyrimidyl Compound is selected from

Table 2.

[00103] Table 2

- Ill -

[00104] Note: Each of the compounds in Table 1 and Table 2 was tested in one or more of the biochemical assays and was found to have activity therein, with all of the compounds having an IC ₅₀ below 10 μΜ in the PKC-theta Assay, with some compounds having an IC ₅₀ below 100 nM (activity level D), some an IC ₅₀ between 100 nM and 800 nM (activity level C), some an IC ₅₀ between 800 nM and 2 μΜ (activity level B), and others having an IC ₅₀ between 2 μΜ and 10 μΜ (activity level A). The compounds were also found to have selectivity for PKC-theta over PKC-delta, which some compounds showing selectivity (Sel. Level = ratio of

IC50 PKC-delta/ICso PKC-theta) of > 100-fold (selectivity level E), some a selectivity of between 20- and 100-fold (selectivity level F), some a selectivity between 5- and 20-fold (selectivity level G) and others having a selectivity level of 5-fold or less (selectivity level H).

[00105] Diaminopyrimidyl Compounds set forth in Table 1 and Table 2 were tested in the

PKC assays described herein and were found to have activity as PKC-theta inhibitors. In one embodiment, the Diaminopyrimidyl Compound is a compound as described herein, wherein the compound at a concentration of 10 μΜ inhibits PKC-theta by at least about 50% or more. In one embodiment, the Diaminopyrimidyl Compound is a compound as described herein, wherein the compound at a concentration of 100 nM inhibits PKC-theta by at least about 50% or more. In some such embodiments, the Diaminopyrimidyl Compound is at least 5-fold selective for PKC-theta over PKC-delta. In some such embodiments, the Diaminopyrimidyl Compound is at least 20-fold selective for PKC-theta over PKC-delta. In some such embodiments, the

Diaminopyrimidyl Compound is at least 100-fold selective for PKC-theta over PKC-delta. In some such embodiments, the Diaminopyrimidyl Compound is more than 100-fold selective for PKC-theta over PKC-delta. In others, the Diaminopyrimidyl Compound is at least 20-fold selective for PKC-theta over PKC-delta and PKC-eta. In others, the Diaminopyrimidyl

Compound is at least 100- fold selective for PKC-theta over PKC-delta and PKC-eta.

[00106] It should be noted that if there is a discrepancy between a depicted structure and a name given that structure, the depicted structure is to be accorded more weight. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it.

METHODS FOR MAKING DIAMINOPYRIMIDYL COMPOUNDS

[00107] The Diaminopyrimidyl Compounds can be made using conventional

organic syntheses and commercially available starting materials. By way of example and not limitation, Diaminopyrimidyl Compounds of formula (I) can be prepared according to the methods described in U.S. Pat. App. No. 14/576, 197, filed on December 19, 2014, the disclosure of which is incorporated herein by reference in its entirety.

METHODS OF USE

[00108] The Diaminopyrimidyl Compounds have utility as pharmaceuticals to treat, prevent or improve conditions in animals or humans. Further, the Diaminopyrimidyl

Compounds are active against protein kinases, particularly PKC-theta. Accordingly, provided herein are many uses of the Diaminopyrimidyl Compounds, including the

treatment or prevention of those diseases set forth below. The methods provided herein comprise the administration of an effective amount of one or more Diaminopyrimidyl

Compound(s) to a subject in need thereof.

[00109] In one aspect provided herein are uses of the compounds in methods for treating or preventing a PKC-theta mediated disorder, such as, for example, ankylosing spondylitis, asthma (including refractory asthma and severe asthma), celiac disease, colitis (including ulcerative colitis), diabetes (including type I diabetes), dermatitis (including atopic dermatitis), Duchenne muscular dystrophy, graft-versus-host disease, inflammatory bowel disease (including Crohn's disease), insulin resistance, lupus (including systemic lupus erythematosus), multiple sclerosis (including relapsing remitting multiple sclerosis), myasthenia gravis, myositis (including polymyositis and dermatomyositis), organ

transplant rejection, psoriasis (including plaque-type psoriasis, and psoriatic arthritis), rheumatoid arthritis, Sjogren syndrome, uveitis, or vitiligo, comprising administering to a subject in need thereof an effective amount of a Diaminopyrimidyl Compound.

[00110] In another aspect provided herein are methods and compounds for use in methods for treating or preventing a PKC-theta mediated disorder, such as, for example, ankylosing spondylitis, asthma (including refractory asthma and severe asthma), celiac disease, colitis (including ulcerative colitis), diabetes (including type I diabetes), dermatitis (including atopic dermatitis), Duchenne muscular dystrophy, graft-versus-host disease, inflammatory bowel disease (including Crohn's disease), insulin resistance, lupus

(including systemic lupus erythematosus), multiple sclerosis (including relapsing remitting multiple sclerosis), myasthenia gravis, myositis (including polymyositis and

dermatomyositis), organ transplant rejection, psoriasis (including plaque-type psoriasis, and psoriatic arthritis), rheumatoid arthritis, Sjogren syndrome, uveitis, or vitiligo.

[00111] In one embodiment, the PKC-theta mediated disorder is an allergic, inflammatory, or autoimmune T-cell mediated disease.

[00112] In certain embodiments, provided herein are methods for achieving an

improvement in BSA in a patient having dermatitis (including atopic dermatitis), psoriasis (including plaque-type psoriasis and or psoriatic arthritis), comprising administering an effective amount of a Diaminopyrimidyl Compound to said patient. In some embodiments, the improvement is a 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% reduction of BSA involvement. In another embodiment, provided herein are methods for inducing a therapeutic response assessed by BSA in a patient having dermatitis (including atopic dermatitis), psoriasis (including plaque-type psoriasis, and psoriatic arthritis), comprising administering an effective amount of a Diaminopyrimidyl Compound to said patient. In some embodiments, the therapeutic response is a 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% reduction of BSA involvement. [00113] In certain embodiments, provided herein are methods for achieving an improvement in PASI in a patient having psoriasis (including plaque-type psoriasis and psoriatic arthritis), comprising administering an effective amount of a Diaminopyrimidyl Compound to said patient. In some embodiments, the improvement is the patient achieving PASI100. In another embodiment, the improvement is the patient achieving PASI75. In yet another embodiment, the improvement is the patient achieving PASI 50. In other embodiments, the improvement is 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100%) of patients achieving PASI100. In other embodiments, treatment with a

Diaminopyrimidyl Compound results in 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of patients achieving PASI75. In still other embodiments, treatment with a Diaminopyrimidyl Compound results in 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of patients achieving PASI50. In another embodiment, provided herein are methods for inducing a therapeutic response assessed by PASI in a patient having psoriasis (including plaque-type psoriasis and psoriatic arthritis), comprising administering an effective amount of a Diaminopyrimidyl Compound to said patient. In some embodiments, the therapeutic response is the patient achieving PASI100. In another

embodiment, the improvement is the patient achieving PASI75. In yet another embodiment, the improvement is the patient achieving PASI 50. In other embodiments, the improvement is 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of patients achieving PASI100. In other embodiments, treatment with a Diaminopyrimidyl Compound results in 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of patients achieving PASI75. In still other embodiments, treatment with a Diaminopyrimidyl Compound results in 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100%. of patients achieving PASI50.

[00114] In certain embodiments, provided herein are methods for achieving an improvement in sPGA in a patient having dermatitis (including atopic dermatitis), psoriasis (including plaque-type psoriasis and psoriatic arthritis), comprising administering an effective amount of a Diaminopyrimidyl Compound to said patient. In some embodiments, the improvement is the patient achieving a reduction in sPGA score of at least 1. In other embodiments, the improvement is the patient achieving a reduction in sPGA score of at least 2. In still other embodiments, the improvement is the patient achieving a reduction in sPGA score of at least 3. In yet other embodiments, the improvement is the patient achieving a reduction in sPGA score of at least 4. In other embodiments, the improvement is 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of patients achieving a reduction in sPGA score of at least 1. In some embodiments of the methods described herein, treatment with a Diaminopyrimidyl Compound results in 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of patients achieving a reduction in sPGA score of at least 2. In some embodiments of the methods described herein, treatment with a Diaminopyrimidyl Compound results in 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100%) of patients achieving a reduction in sPGA score of at least 3. In some embodiments of the methods described herein, treatment with a Diaminopyrimidyl Compound results in 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of patients achieving a reduction in sPGA score of at least 4. In another embodiment, provided herein are methods for inducing a therapeutic response assessed by sPGA in a patient having dermatitis (including atopic dermatitis), psoriasis (including plaque-type psoriasis and psoriatic arthritis), comprising administering an effective amount of a Diaminopyrimidyl Compound to said patient. In some embodiments, the therapeutic response is the patient achieving a reduction in sPGA score of at least 1. In other embodiments, the therapeutic response is the patient achieving a reduction in sPGA score of at least 2. In still other embodiments, the therapeutic response is the patient achieving a reduction in sPGA score of at least 3. In yet other embodiments, the therapeutic response is the patient achieving a reduction in sPGA score of at least 4. In other embodiments, the therapeutic response is 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of patients achieving a reduction in sPGA score of at least 1. In some embodiments of the methods described herein, treatment with a Diaminopyrimidyl Compound results in 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100%) of patients achieving a reduction in sPGA score of at least 2. In some embodiments of the methods described herein, treatment with a Diaminopyrimidyl Compound results in 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of patients achieving a reduction in sPGA score of at least 3. In some embodiments of the methods described herein, treatment with a Diaminopyrimidyl Compound results in 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of patients achieving a reduction in sPGA score of at least 4 [00115] In certain embodiments, provided herein are methods for achieving an improvement in DLQI in a patient having dermatitis (including atopic dermatitis), vitiligo, psoriasis (including plaque-type psoriasis and psoriatic arthritis), comprising administering an effective amount of a Diaminopyrimidyl Compound to said patient. In some embodiments, the improvement is a reduction in DLQI score of at least 5. In others, the improvement is a reduction in DLQI score of at least 10. In still others, the improvement is a reduction in DLQI score of at least 15. In others, the improvement is a reduction in DLQI score of at least 20. In yet others, the improvement is a reduction in DLQI score of at least 25. In still others, the improvement is a reduction in DLQI score of at least 30. In some embodiments, the improvement is 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of patients achieving a reduction in DLQI score of at least 5. In other embodiments, the improvement is 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of patients achieving a reduction in DLQI score of at least 10. In some embodiments, the improvement is 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of subjects achieving a reduction in DLQI score of at least 15. In some other embodiments, the improvement is 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of patients achieving a reduction in DLQI score of at least 20. In some embodiments, the improvement is 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100%) of patients achieving a reduction in DLQI score of at least 25. In some other embodiments, the improvement is 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of patients achieving a reduction in DLQI score of at least 30. In another embodiment, provided herein are methods for inducing a therapeutic response assessed by DLQI in a patient having dermatitis (including atopic dermatitis), vitiligo, psoriasis (including plaque-type psoriasis and psoriatic arthritis), comprising administering an effective amount of a Diaminopyrimidyl Compound to said patient. In some embodiments, the therapeutic response is a reduction in DLQI score of at least 5. In others, the therapeutic response is a reduction in DLQI score of at least 10. In still others, the therapeutic response is a reduction in DLQI score of at least 15. In others, the therapeutic response is a reduction in DLQI score of at least 20. In yet others, the therapeutic response is a reduction in DLQI score of at least 25. In still others, the therapeutic response is a reduction in DLQI score of at least 30. In some embodiments, the therapeutic response is 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%), 99% or 100% of patients achieving a reduction in DLQI score of at least 5. In other embodiments, the therapeutic response is 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of patients achieving a reduction in DLQI score of at least 10. In some embodiments, the therapeutic response is 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of subjects achieving a reduction in DLQI score of at least 15. In some other therapeutic response , the improvement is 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of patients achieving a reduction in DLQI score of at least 20. In some embodiments, the therapeutic response is 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100%) of patients achieving a reduction in DLQI score of at least 25. In some other embodiments, the therapeutic response is 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99% or 100% of patients achieving a reduction in DLQI score of at least 30.

[00116] In one aspect provided herein are methods and compounds for use in methods of inhibiting a kinase in a cell expressing said kinase in vivo, ex vivo or in vitro, comprising contacting said cell with an effective amount of a Diaminopyrimidyl

Compound. In one embodiment, the cell is in a patient. In one embodiment, the cell is not in a patient. In one embodiment, the kinase is PKC-theta. In some embodiments, the Diaminopyrimidyl Compound is selective for PKC-theta over PKC-delta. In others, the Diaminopyrimidyl Compound is selective for PKC-theta over PKC-delta and PKC-eta. Compound 1 referred to herein has the name 2-(((4-(2,2-difluoropropoxy)pyrimidin-5- yl)methyl)amino)-4-(((lR,4S)-4-hydroxy-3,3-dimethylcyclohexy l)amino)pyrimidine-5- carbonitrile (also referred to in Table 1 as Compound A39).

[00117] In some such embodiments, the Diaminopyrimidyl Compound is at least

5-fold selective for PKC-theta over PKC-delta. In some such embodiments, the

Diaminopyrimidyl Compound is at least 20-fold selective for PKC-theta over PKC-delta. In some such embodiments, the Diaminopyrimidyl Compound is at least 100-fold selective for PKC-theta over PKC-delta. In some such embodiments, the Diaminopyrimidyl Compound is more than 100-fold selective for PKC-theta over PKC-delta. In others, the Diaminopyrimidyl Compound is at least 20-fold selective for PKC-theta over PKC-delta and PKC-eta. In others, the Diaminopyrimidyl Compound is at least 100- fold selective for PKC-theta over PKC-delta and PKC-eta.

[001 18] For example, the Diaminopyrimidyl Compound is a compound from Table 1, or

Table 2. In one embodiment, the Diaminopyrimidyl Compound is Compound 1, also referred to in Table 1 as Compound A39.

[001 19] In one embodiment, provided herein are methods for modulating the levels of a disease marker in a subject having a PKC-theta mediated disorder, comprising administering an effective amount of a Diaminopyrimidyl Compound or a pharmaceutical composition provided herein, to said subject. In some such embodiments, the modulation of the disease marker is assessed in a biological sample of the subject, such as in circulating blood, skin biopsies, colon biopsies, synovial tissue, and/or urine. In such embodiments, the amount of disease marker modulation is assessed by comparison of the amount of disease marker before and after administration of the Diaminopyrimidyl Compound. In some embodiments, the modulation in disease marker is a reduction of about 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%), 95%), 99%), or about 100% compared to baseline levels. In some embodiments, the disease marker is mRNA or protein expression levels of one or more of ERKl, ERK2, IkBa and PKC0. In some such embodiments, the modulation is measured by measurement of the reduction of phosphorylation levels of one or more of ERKl, ERK2 and PKC0. In others, the modulation is measured by measurement of the reduction in mRNA or protein expression levels of one or more of ERKl, ERK2 and PKC0. In some embodiments, the disease marker is cell surface expression levels of one or more of CD25, CD69, CD71, CD95, and CD98. In some such embodiments, the modulation in the levels of disease marker is a reduction in cell surface expression levels of one or more of CD25, CD69, CD71, CD95, and CD98. In another embodiment, the disease marker is mRNA or protein expression of GRAIL. In some such embodiments, the modulation in the levels of disease marker is an increase in mRNA or protein expression levels of GRAIL. In some such embodiments, the modulation in mRNA or protein expression levels of GRAIL is an increase of about 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99%, or about 100%) compared to baseline levels. In some such embodiments, the modulation in the levels of disease marker is an increase in the mRNA or protein expression levels of FOXP3. In some such embodiments, the modulation in the levels of disease marker is an increase and/or sustained increase in the number of cells expressing the mRNA or protein FOXP3. In still another embodiment, the disease marker is protein or mRNA expression of one or more of IL-2, IFN-γ and IL-17. In some such embodiments, the modulation in the levels of disease marker is a reduction in protein or mRNA expression level of one or more of IL-2, IFN-γ and IL-17. In other embodiments, the disease marker is protein or mRNA expression of one or more of IL-2, IL-10, IL-17 A, IL-22, IL-12, and IFN-γ. In some such embodiments, the modulation in the levels of disease marker is a reduction in protein or mRNA expression levels of one or more of IL-2, IL-10, IL-17A, IL-22, IL-12, and IFN-γ. In yet another embodiment, the disease marker is protein or mRNA expression of one or more of IL-Ιβ, IL-2 , IL-22, IL-17F, and IL-17 A. In some such embodiments, the modulation in the levels of disease marker is a reduction in protein or mRNA expression levels of one or more of IL-Ιβ, IL-2 , IL-22, IL-17F, and IL-17A. In another embodiment, the disease marker is protein or mRNA expression of one or more of IFN-γ and IL-12. In some such embodiments, the modulation in the levels of disease marker is a reduction in protein or mRNA expression levels of one or more of IFN-γ and IL-12. In still another embodiment, the disease marker is protein or mRNA expression of one or more of IL-2, GM-CSF, IFN-γ, TNF-a, IL-12p70, IL-27, IL-5 or RANTES. In some such embodiments, the modulation in the levels of disease marker is a reduction in protein or mRNA expression level of one or more of IL-2, GM-CSF, IFN-γ, TNF-a, IL-12p70, IL-27, IL-5 or RANTES. In some embodiments, the disease marker is protein or mRNA expression of one or more of IL-2, IL-13, IL-9, IP- 10, IL-4, and Eotaxin. In some such embodiments, the modulation in the levels of disease marker is a reduction in protein or mRNA expression levels of one or more of IL-2, IL-13, IL-9, IP-10, IL-4, and Eotaxin. In still another embodiment, the disease marker is protein or mRNA expression of one or more of IL-2, IL-22, IL-23, monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-2 (MIP-2). In some such embodiments, the modulation in the levels of disease marker is a reduction in protein or mRNA expression levels of one or more of IL-2, IL-22, IL-23, monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-2 (MIP-2). In one embodiment, the disease marker is protein or mRNA expression of one or more of IL-2, IFN-γ, IL-12B, IL-17 A, IL-17F, IL-7, integrin beta 3 (ITGB3), matrix metalloproteinase-3 (MMP3), and E-Selectin. In some such embodiments, the modulation in the levels of disease marker is a reduction in protein or mRNA expression levels of one or more of of IL-2, IFN-γ, IL-12B, IL-17A, IL-17F, IL-7, integrin beta 3 (ITGB3), matrix metalloproteinase-3 (MMP3), and E-Selectin. In yet other embodiments, the disease marker is protein or mRNA expression of one or more of K16, ICAM-1 or HLA-DR. In some such embodiments, the modulation in the levels of disease marker is a reduction in protein or mRNA expression levels of one or more of K16, ICAM-1 or HLA-DR. In still other, the disease marker is protein or mRNA expression of one or more of tumor necrosis factor-alpha (TNF-a), IFN-γ, interferon beta (IFN-β), IL-2, IL-6, IL-8, IL-10, encoding p40 subunit of human interleukin-12 (IL12-p40), IL-17, IL-19, IL-20, encoding pl9 subunit of human interleukin-23 (IL-23-pl9), inducible nitric oxide synthase (iNOS), K16, MCP-1, STAT-1, MMP12, Granzyme B, MIP-3a, GM-CSF, IP-10, MX-1, VEGF, CD3, CD8, CD1 lc, and CD161. In some such embodiments, the modulation in the levels of disease marker is a reduction in protein or mRNA expression levels of one or more of tumor necrosis factor-alpha (TNF-a), IFN-γ, interferon beta (IFN-β), IL-2, IL-6, IL-8, IL-10, encoding p40 subunit of human interleukin-12 (IL12-p40), IL-17, IL-19, IL-20, encoding pl9 subunit of human interleukin-23 (IL-23-pl9), inducible nitric oxide synthase (iNOS), K16, MCP-1, STAT-1, MMP12, Granzyme B, MIP-3a, GM-CSF, IP-10, MX-1, VEGF, CD3, CD8, CD1 lc, and CD161. In some such embodiments, the PKC-theta mediated disorder is ankylosing spondylitis, asthma (including refractory asthma and severe asthma), celiac disease, colitis (including ulcerative colitis), diabetes (including type I diabetes), dermatitis (including atopic dermatitis), Duchenne muscular dystrophy, graft-versus-host disease, inflammatory bowel disease (including Crohn's disease), insulin resistance, lupus (including systemic lupus erythematosus), multiple sclerosis (including relapsing remitting multiple sclerosis), myasthenia gravis, myositis (including polymyositis and dermatomyositis), organ transplant rejection, psoriasis (including plaque-type psoriasis, and psoriatic arthritis), rheumatoid arthritis, Sjogren syndrome, uveitis, or vitiligo.

PHARMACEUTICAL COMPOSITIONS AND ROUTES OF ADMINISTRATION

[00120] The pharmaceutical compositions and unit dosage forms provided herein can be administered to a subject orally in the conventional form of preparations, such as capsules, microcapsules, tablets, granules, powder, troches, pills, solutions and emulsions.

[00121] In one embodiment, provided herein are pharmaceutical compositions or unit dosage forms comprising an effective amount of a Diaminopyrimidyl Compound and a pharmaceutically acceptable carrier or vehicle, wherein a pharmaceutically acceptable carrier or vehicle can comprise an excipient, diluent, or a mixture thereof.

[00122] In one embodiment, provided herein are capsules containing a

pharmaceutical composition or unit dosage form provided herein without an additional carrier or excipient.

[00123] The effective amount of a Diaminopyrimidyl Compound in the

pharmaceutical composition or unit dosage can be at a level that will exercise the desired effect; for example, about 0.005 mg/kg of a subject's body weight to about 50 mg/kg of a subject's body weight in unit dosage for both oral and parenteral administration.

[00124] In general, a Diaminopyrimidyl Compound can be administered one to four times a day in a dose of about 0.005 mg/kg of a subject's body weight to about 50 mg/kg of a subject's body weight in a subject, but the above dosage may be properly varied depending on the age, body weight and medical condition of the subject and the type of administration. In one embodiment, the dose is about 0.05 mg/kg of a subject's body weight to about 40 mg/kg of a subject's body weight, about 0.5 mg/kg of a subject's body weight to about 1.5 mg/kg of a subject's body weight, about 0.5 mg/kg of a subject's body weight to about 3 mg/kg of a subject's body weight, about 0.1 mg/kg of a subject's body weight to about 10 mg/kg of a subject's body weight, about 0.1 mg/kg of a subject's body weight to about 15 mg/kg of a subject's body weight, about 0.5 mg/kg of a subject's body weight to about 35 mg/kg of a subject's body weight, or about 1 mg/kg of a subject's body weight to about 50 mg/kg of a subject's body weight. In one embodiment, the dose is about 0.5 mg/kg of a subject's body weight to about 40 mg/kg of a subject's body weight or about 3 mg/kg of a subject's body weight to about 40 mg/kg of a subject's body weight. In one embodiment, one dose is given per day. In another embodiment, two doses are given per day. In some embodiments, the dose is administered as a single dose or in divided doses such as twice daily, thrice daily, four times daily, or every other day. In any given case, the amount of a Diaminopyrimidyl Compound administered will depend on such factors as the solubility of the active component, the formulation used and the route of administration.

[00125] In another embodiment, provided herein are methods for the treatment or prevention of a disease or disorder comprising the administration of about 0.375 mg/day to about 2500 mg/day, about 10 mg/day to about 2000 mg/day, about 25 mg/day to about 1800 mg/day, about 50 mg/day to about 1600 mg/day or about 60 mg/day to about 1600 mg/day of a Diaminopyrimidyl Compound to a subject in need thereof. In another embodiment, provided herein are methods for the treatment or prevention of a disease or disorder comprising the administration of about 60 mg/day to about 1600 mg/day or about 300 mg/day to about 1600 mg/day of a Diaminopyrimidyl Compound to a subject in need thereof.

[00126] In a particular embodiment, the methods disclosed herein comprise the administration of 60 mg/day, 120 mg/day, 300 mg/day, 400 mg/day, 600 mg/day, 800 mg/day, 1200 mg/day or 1600 mg/day of a Diaminopyrimidyl Compound to a subject in need thereof.

[00127] In another embodiment, provided herein are unit dosage formulations that comprise between about 1 mg and about 500 mg, about 5 mg and about 250 mg, about 5 mg and about 250 mg, about 10 mg and about 2500 mg, or about 10 mg and about 100 mg of a Diaminopyrimidyl Compound. In a particular embodiment, provided herein are unit dosage formulations comprising about 10 mg, 30 mg, or 100 mg of a

Diaminopyrimidyl Compound.

[00128] In another embodiment, provided herein are unit dosage formulations that comprise 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 60 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 1000 mg or 1400 mg of a Diaminopyrimidyl

Compound.

[00129] A pharmaceutical composition or unit dosage form provided herein can be administered orally for reasons of convenience. In one embodiment, when administered orally, a pharmaceutical composition or unit dosage form provided herein is administered with a meal and water. In another embodiment, the pharmaceutical composition or unit dosage form provided herein is dispersed in water or juice (e.g., apple juice or orange juice) and administered orally as a suspension. In another embodiment, the

pharmaceutical composition or unit dosage form is administered without a meal, or with a beverage such as milk, soda or juice (e.g., apple juice or orange juice). [00130] The pharmaceutical compositions or unit dosage forms provided herein can be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, troches, suppositories and suspensions and the like. The pharmaceutical compositions or unit dosage forms provided herein can be formulated to contain a daily dose, or a convenient fraction of a daily dose, in a dosage unit, which may be a single tablet or capsule or convenient volume of a liquid. In one embodiment, the solutions are prepared from water-soluble salts, such as the hydrochloride salt. In general, all of the compositions are prepared according to known methods in pharmaceutical chemistry. Capsules can be prepared by mixing a Diaminopyrimidyl Compound with a suitable carrier or diluent and filling the proper amount of the mixture in capsules. The usual carriers and diluents include, but are not limited to, inert powdered substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.

[00131] Tablets can be prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants and disintegrators as well as the compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like.

Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

[00132] A lubricant might be necessary in a tablet formulation to prevent the tablet and punches from sticking in the dye. The lubricant can be chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils. Tablet disintegrators are substances that swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins and gums. More particularly, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose, for example, can be used as well as sodium lauryl sulfate.

Tablets can be coated with sugar as a flavor and sealant, or with film-forming protecting agents to modify the dissolution properties of the tablet. The compositions can also be formulated as chewable tablets, for example, by using substances such as mannitol in the formulation. In one embodiment, the composition is administered via nasogastric tube.

[00133] The effect of a Diaminopyrimidyl Compound can be delayed or prolonged by proper formulation. For example, a slowly soluble pellet of the pharmaceutical composition or unit dosage form provided herein can be prepared and incorporated in a tablet or capsule, or as a slow-release implantable device. The technique also includes making pellets of several different dissolution rates and filling capsules with a mixture of the pellets. Tablets or capsules can be coated with a film that resists dissolution for a predictable period of time. Even the parenteral preparations can be made long-acting, by dissolving or suspending a Diaminopyrimidyl Compound in oily or emulsified vehicles that allow it to disperse slowly in the serum.

[00134] In one embodiment, the particle size of a Diaminopyrimidyl Compound in the pharmaceutical compositions provided herein is about 1-100 μπι, about 1-75 μπι, about 1-50 μπι or about 1-25 μπι. In another embodiment, the particle size of a

Diaminopyrimidyl Compound in the pharmaceutical compositions provided herein is about 100 μπι or less, about 75 μπι or less, about 50 μπι or less, or about 25 μπι or less. In another embodiment, the particle size of a Diaminopyrimidyl Compound in the

pharmaceutical compositions provided herein is about 1-25 μπι. In yet another

embodiment, the particle size of a Diaminopyrimidyl Compound in the pharmaceutical compositions provided herein is about 25 μπι or less. In another embodiment, the particle size of a Diaminopyrimidyl Compound in the pharmaceutical compositions provided herein is about 1-35 μπι. In yet another embodiment, the particle size of a

Diaminopyrimidyl Compound in the pharmaceutical compositions provided herein is about 35 μπι or less. In another embodiment, the particle size of a Diaminopyrimidyl Compound in the pharmaceutical compositions provided herein is about 1-50 μπι. In yet another embodiment, the particle size of a Diaminopyrimidyl Compound in the

pharmaceutical compositions provided herein is about 50 μπι or less. I. 10 MG FORMULATIONS

[00135] In one embodiment, provided herein is a pharmaceutical composition comprising a Diaminopyrimidyl Compound, and one or more pharmaceutically acceptable excipients or carriers.

[00136] In one embodiment, provided herein is a pharmaceutical composition comprising a Diaminopyrimidyl Compound and one or more pharmaceutically acceptable excipients and carriers selected from diluents, disintegrants, glidants and lubricants.

[00137] In certain embodiments, the diluents include, but are not limited to, mannitol (e.g.,

Pearlitol® SD200), and cellulose (e.g., microcrystalline cellulose, such as AVICEL®,

PHARMACEL®, NEOCEL®, CEOLUS®, for example, AVICEL® PH 102). In one

embodiment, the diluent is mannitol (e.g. Pearlitol®, Parteck®, Mannogen® EZ). In another embodiment, the diluent is Pearlitol® SD200. In yet another embodiment, the diluent is cellulose. In yet another embodiment, the diluent is microcrystalline cellulose. In yet another embodiment, the diluent is AVICEL® PH 102.

[00138] In certain embodiments, the disintegrants include, but are not limited to, carboxymethyl cellulose (e.g., croscarmellose sodium, for example, Ac-Di-Sol®, or DiSolcel®). In one embodiment, the disintegrant is carboxymethyl cellulose. In another embodiment, the disintegrant is croscarmellose sodium.

[00139] In certain embodiments, the glidants include, but are not limited to fumed silica

(e.g., silicon oxide, such as colloidal silicon dioxide, for example, Aerosil®, or Cabosil®). In one embodiment, the glidant is fumed silica. In another embodiment, the glidant is silicon oxide. In another embodiment, the glidant is colloidal silicon dioxide.

[00140] In certain embodiments, the lubricants include, but are not limited to, magnesium stearate. In one embodiment, the lubricant is magnesium stearate.

[00141] In certain embodiments, provided herein are pharmaceutical compositions comprising a Diaminopyrimidyl Compound and one or more pharmaceutically acceptable excipients or carriers, each independently selected from mannitol, cellulose, carboxymethyl cellulose, fumed silica and magnesium stearate.

[00142] In certain embodiments, provided herein are pharmaceutical compositions comprising a Diaminopyrimidyl Compound and one or more pharmaceutically acceptable excipients or carriers, each independently selected from mannitol, microcrystalline cellolose, croscarmellose sodium, silicon dioxide and magnesium stearate.

[00143] In certain embodiments, provided herein are pharmaceutical compositions comprising a Diaminopyrimidyl Compound and one or more pharmaceutically acceptable excipients or carriers, each independently selected from Pearlitol® SD200, AVICEL® PH 102, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate.

[00144] In one embodiment, provided herein is a pharmaceutical composition comprising a Diaminopyrimidyl Compound, a diluent(s)/binder(s), a disintegrant(s), a glidant(s) and a lubricant(s).

[00145] In one embodiment, provided herein is a pharmaceutical composition comprising a Diaminopyrimidyl Compound, mannitol and magnesium stearate.

[00146] In one embodiment, provided herein is a pharmaceutical composition comprising a Diaminopyrimidyl Compound, mannitol, cellulose and magnesium stearate.

[00147] In certain embodiments, provided herein are pharmaceutical compositions comprising a Diaminopyrimidyl Compound, mannitol, microcrystalline cellulose, carboxymethyl cellulose, fumed silica and magnesium stearate.

[00148] In certain embodiments, provided herein are pharmaceutical compositions comprising a Diaminopyrimidyl Compound, mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate.

[00149] In certain embodiments, provided herein are pharmaceutical compositions comprising a Diaminopyrimidyl Compound, Pearlitol® SD200, AVICEL® PH 102,

croscarmellose sodium, colloidal silicon dioxide and magnesium stearate.

[00150] In one embodiment, provided herein is a pharmaceutical composition comprising about 5-15% by weight of a Diaminopyrimidyl Compound, about 70-95%) by weight of diluent(s)/binder(s), about 1-10%> by weight of disintegrant(s), about 0.1-5% by weight of glidant(s), and about 0.1-5% by weight of lubricant(s).

[00151] In one embodiment, provided herein is a pharmaceutical composition comprising about 10.0%) by weight of a Diaminopyrimidyl Compound, about 84.75%) by weight of diluent(s)/binder(s), about 4.0% by weight of disintegrant(s), about 0.5% by weight of glidant(s), and about 0.75% by weight of lubricant(s). [00152] In one embodiment, provided herein is a pharmaceutical composition comprising about 5-15% by weight of a Diaminopyrimidyl Compound, about 55-75%) by weight of mannitol, about 10-30%) by weight of cellulose, about 1-10% by weight of carboxymethyl cellulose, about 0.1-5% by weight of fumed silica, and about 0.1-5% by weight of magnesium stearate.

[00153] In one embodiment, provided herein is a pharmaceutical composition comprising about 10.0%) by weight of a Diaminopyrimidyl Compound, about 64.75%) by weight of mannitol, about 20.0%) by weight of cellulose, about 4.0% by weight of carboxymethyl cellulose, about 0.5%) by weight of fumed silica, and about 0.75% by weight of magnesium stearate.

[00154] In one embodiment, provided herein is a pharmaceutical composition comprising about 5-15%) by weight of a Diaminopyrimidyl Compound, about 55-75%) by weight of mannitol, about 10-30%> by weight of microciystalline cellulose, about 1-10% by weight of carboxymethyl cellulose, about 0.1-5% by weight of silicon oxide, and about 0.1-5% by weight of magnesium stearate.

[00155] In one embodiment, provided herein is a pharmaceutical composition comprising about 10.0%) by weight of a Diaminopyrimidyl Compound, about 64.75%) by weight of mannitol, about 20.0%) by weight of microciystalline cellulose, about 4.0% by weight of carboxymethyl cellulose, about 0.5% by weight of silicon oxide, and about 0.75% by weight of magnesium stearate.

[00156] In one embodiment, provided herein is a pharmaceutical composition comprising about 5-15 %> by weight of a Diaminopyrimidyl Compound, about 10-30 %> by weight of Avicel® PH 102, about 55-75 % by weight of Pearlitol® SD 200, about 1-10 % by weight of sodium croscarmellose, about 0.1-5 %> by weight of colloidal silicon dioxide, and about 0.1-5 %> by weight of magnesium stearate.

[00157] In one embodiment, provided herein is a pharmaceutical composition comprising about 10.0 %> by weight of a Diaminopyrimidyl Compound, about 20.0 %> by weight of Avicel® PH 102, about 64.75 % by weight of Pearlitol® SD 200, about 4.0 % by weight of sodium croscarmellose, about 0.5 %> by weight of colloidal silicon dioxide, and about 0.75 %> by weight of magnesium stearate.

[00158] In certain embodiments, the weight of a pharmaceutical composition is about 80-

120 mg and comprises about 5-15 mg of a Diaminopyrimidyl Compound, about 70-95 mg diluent(s)/binder(s), about 2-8 mg disintegrant(s), about 0.1-1 mg glidant(s), and about 0.4-1.5 mg lubricant(s).

[00159] In certain embodiments, the weight of a pharmaceutical composition is about 100 mg and comprises about 10.0 mg of a Diaminopyrimidyl Compound, about 84.75 mg diluent(s)/binder(s), about 4.0 mg disintegrant(s), about 0.5 mg glidant(s), and about 0.75 mg lubricant(s).

[00160] In certain embodiments, the weight of a pharmaceutical composition is about 80-

120 mg and comprises about 5-15 mg of a Diaminopyrimidyl Compound, about 15-30 mg cellulose, about 50-80 mg mannitol, about 2-8 mg carboxymethyl cellulose, about 0.1-1 mg fumed silica, and about 0.4-1.5 mg magnesium stearate.

[00161] In certain embodiments, the weight of a pharmaceutical composition is about 100 mg and comprises about 10.0 mg of a Diaminopyrimidyl Compound, about 20.0 mg cellulose, about 64.75 mg mannitol, about 4.0 mg carboxymethyl cellulose, about 0.5 mg fumed silica, and about 0.75 mg magnesium stearate.

[00162] In certain embodiments, the weight of a pharmaceutical composition is about 80-

120 mg and comprises about 5-15 mg of a Diaminopyrimidyl Compound, about 15-30 mg microcrystalline cellulose, about 50-80 mg mannitol, about 2-8 mg carboxymethyl cellulose, about 0.1-1 mg silicon oxide, and about 0.4-1.5 mg magnesium stearate.

[00163] In certain embodiments, the weight of a pharmaceutical composition is about 100 mg and comprises about 10.0 mg of a Diaminopyrimidyl Compound, about 20.0 mg

microcrystalline cellulose, about 64.75 mg mannitol, about 4.0 mg carboxymethyl cellulose, about 0.5 mg silicon oxide, and about 0.75 mg magnesium stearate.

[00164] In certain embodiments, the weight of a pharmaceutical composition is about 80-

120 mg and comprises about 5-15 mg of a Diaminopyrimidyl Compound, about 15-30 mg Avicel® PH 102, about 50-80 mg Pearlitol® SD 200, about 2-8 mg sodium croscarmellose, about 0.1-1 mg colloidal silicon dioxide, and about 0.4-1.5 mg magnesium stearate.

[00165] In certain embodiments, the weight of a pharmaceutical composition is about 100 mg and comprises about 10.0 mg of a Diaminopyrimidyl Compound, about 20.0 mg Avicel® PH 102, about 64.75 mg Pearlitol® SD 200, about 4.0 mg sodium croscarmellose, about 0.5 mg colloidal silicon dioxide, and about 0.75 mg magnesium stearate. [00166] In certain embodiments, the pharmaceutical compositions and unit dosage forms provided herein are capsule dosage forms, including gelatin capsule dosage forms. In one embodiment, the unit dosage form is suitable for administration in a size 4 capsule.

[00167] In certain embodiments, the pharmaceutical compositions and unit dosage forms do not contain a surfactant (e.g., sodium lauryl sulfate). In certain embodiments, the

pharmaceutical compositions and unit dosage forms do not contain an acidifier or antioxidant (e.g., citric acid).

II. 30 MG FORMULATIONS

[00168] In one embodiment, provided herein is a pharmaceutical composition comprising a Diaminopyrimidyl Compound, and one or more pharmaceutically acceptable excipients or carriers.

[00169] In one embodiment, provided herein is a pharmaceutical composition comprising a Diaminopyrimidyl Compound and one or more pharmaceutically acceptable excipients and carriers selected from diluents, disintegrants, glidants and lubricants.

[00170] In certain embodiments, the diluents include, but are not limited to, mannitol (e.g.,

Pearlitol®, Parteck®, or Mannogen® EZ, for example, Pearlitol® SD200), and cellulose (e.g., microcrystalline cellulose, for example, Avicel®, Pharmacel®, Neocel®, or Ceolus®, such as AVICEL® PH 102). In one embodiment, the diluent is mannitol. In another embodiment, the diluent is Pearlitol® SD200. In yet another embodiment, the diluent is cellulose. In yet another embodiment, the diluent is microcrystalline cellulose. In yet another embodiment, the diluent is AVICEL® PH 102.

[00171] In certain embodiments, the disintegrants include, but are not limited to, carboxymethyl cellulose (e.g., croscarmellose sodium, for example Ac-Di-Sol®, or DiSolcel®). In one embodiment, the disintegrant is carboxymethyl cellulose. In another embodiment, the disintegrant is croscarmellose sodium.

[00172] In certain embodiments, the glidants include, but are not limited to fumed silica

(e.g., silicon oxide, such as colloidal silicon dioxide, for example, Aerosil®, or Cabosil®). In one embodiment, the glidant is fumed silica. In another embodiment, the glidant is silicon oxide. In another embodiment, the glidant is colloidal silicon dioxide. [00173] In certain embodiments, the lubricants include, but are not limited to, magnesium stearate. In one embodiment, the lubricant is magnesium stearate.

[00174] In certain embodiments, provided herein are pharmaceutical compositions comprising a Diaminopyrimidyl Compound and one or more pharmaceutically acceptable excipients or carriers, each independently selected from mannitol, cellulose, carboxymethyl cellulose, fumed silica and magnesium stearate.

[00175] In certain embodiments, provided herein are pharmaceutical compositions comprising a Diaminopyrimidyl Compound and one or more pharmaceutically acceptable excipients or carriers, each independently selected from mannitol, microcrystalline cellolose, croscarmellose sodium, silicon dioxide and magnesium stearate.

[00176] In certain embodiments, provided herein are pharmaceutical compositions comprising a Diaminopyrimidyl Compound and one or more pharmaceutically acceptable excipients or carriers, each independently selected from Pearlitol® SD200, AVICEL® PH 102, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate.

[00177] In one embodiment, provided herein is a pharmaceutical composition comprising a Diaminopyrimidyl Compound, a diluent(s)/binder(s), a disintegratnt(s), a glidant(s) and a lubricant(s).

[00178] In one embodiment, provided herein is a pharmaceutical composition comprising a Diaminopyrimidyl Compound, mannitol and magnesium stearate.

[00179] In one embodiment, provided herein is a pharmaceutical composition comprising a Diaminopyrimidyl Compound, mannitol, cellulose and magnesium stearate.

[00180] In certain embodiments, provided herein are pharmaceutical compositions comprising a Diaminopyrimidyl Compound, mannitol, microcrystalline cellulose, carboxymethyl cellulose, fumed silica and magnesium stearate.

[00181] In certain embodiments, provided herein are pharmaceutical compositions comprising a Diaminopyrimidyl Compound, mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate.

[00182] In certain embodiments, provided herein are pharmaceutical compositions comprising a Diaminopyrimidyl Compound, Pearlitol® SD200, AVICEL® PH 102,

croscarmellose sodium, colloidal silicon dioxide and magnesium stearate. [00183] In one embodiment, provided herein is a pharmaceutical composition comprising about 15-60 % by weight of a Diaminopyrimidyl Compound, about 50-70% by weight of diluent(s)/binder(s), about 2-8%> by weight of disintegrant(s), about 0.1-5% by weight of glidant(s), and about 0.1-5% by weight of lubricant(s).

[00184] In one embodiment, provided herein is a pharmaceutical composition comprising about 33.3%) by weight of a Diaminopyrimidyl Compound, about 61.4%> by weight of diluent(s)/binder(s), about 4.0% by weight of disintegrant(s), about 0.5% by weight of glidant(s), and about 0.75% by weight of lubricant(s).

[00185] In one embodiment, provided herein is a pharmaceutical composition comprising about 15-60 %> by weight of a Diaminopyrimidyl Compound, about 20-60%) by weight of mannitol, about 10-40%) by weight of cellulose, about 2-8% by weight of carboxymethyl cellulose, about 0.1-5% by weight of fumed silica, and about 0.1-5% by weight of magnesium stearate.

[00186] In one embodiment, provided herein is a pharmaceutical composition comprising about 33.3%) by weight of a Diaminopyrimidyl Compound, about 41.4% by weight of mannitol, about 20.0%) by weight of cellulose, about 4.0% by weight of carboxymethyl cellulose, about 0.5%) by weight of fumed silica, and about 0.75% by weight of magnesium stearate.

[00187] In one embodiment, provided herein is a pharmaceutical composition comprising about 15-60 %> by weight of a Diaminopyrimidyl Compound, about 20-60%) by weight of mannitol, about 10-40%> by weight of microciystalline cellulose, about 2-8% by weight of carboxymethyl cellulose, about 0.1-5% by weight of silicon oxide, and about 0.1-5% by weight of magnesium stearate.

[00188] In one embodiment, provided herein is a pharmaceutical composition comprising about 33.3%) by weight of a Diaminopyrimidyl Compound, about 41.4% by weight of mannitol, about 20.0%) by weight of microciystalline cellulose, about 4.0% by weight of carboxymethyl cellulose, about 0.5% by weight of silicon oxide, and about 0.75% by weight of magnesium stearate.

[00189] In one embodiment, provided herein is a pharmaceutical composition comprising about 15-60 %> by weight of a Diaminopyrimidyl Compound, about 10-40 %> by weight of Avicel® PH 102, about 20-60 % by weight of Pearlitol® SD 200, about 2-8 % by weight of sodium croscarmellose, about 0.1-5 % by weight of colloidal silicon dioxide, and about 0.1-5 % by weight of magnesium stearate.

[00190] In one embodiment, provided herein is a pharmaceutical composition comprising about 33.3 % by weight of a Diaminopyrimidyl Compound, about 20.0 % by weight of Avicel® PH 102, about 41.4 % by weight of Pearlitol® SD 200, about 4.0 % by weight of sodium croscarmellose, about 0.5 % by weight of colloidal silicon dioxide, and about 0.75 % by weight of magnesium stearate.

[00191] In certain embodiments, the weight of a pharmaceutical composition is about 70-

110 mg and comprises about 5-15 mg of a Diaminopyrimidyl Compound, about 45-65 mg diluent(s)/binder(s), about 1-10 mg disintegrant(s), about 0.1-2 mg glidant(s), and about 0.1-2 mg lubricant(s).

[00192] In certain embodiments, the weight of a pharmaceutical composition is about 90 mg and comprises about 30.0 mg of a Diaminopyrimidyl Compound, about 55.3 mg

diluent(s)/binder(s), about 3.6 mg disintegrant(s), about 0.5 mg glidant(s), and about 0.7 mg lubricant(s).

[00193] In certain embodiments, the weight of a pharmaceutical composition is about 70-

110 mg and comprises about 5-15 mg of a Diaminopyrimidyl Compound, about 10-40 mg cellulose, about 20-80 mg mannitol, about 1-10 mg carboxymethyl cellulose, about 0.1-2 mg fumed silica, and about 0.1-2 mg magnesium stearate.

[00194] In certain embodiments, the weight of a pharmaceutical composition is about 90 mg and comprises about 30.0 mg of a Diaminopyrimidyl Compound, about 18.0 mg cellulose, about 37.3 mg mannitol, about 3.6 mg carboxymethyl cellulose, about 0.5 mg fumed silica, and about 0.7 mg magnesium stearate.

[00195] In certain embodiments, the weight of a pharmaceutical composition is about 70-

110 mg and comprises about 5-15 mg of a Diaminopyrimidyl Compound, about 10-40 mg microcrystalline cellulose, about 20-80 mg mannitol, about 1-10 mg carboxymethyl cellulose, about 0.1-2 mg silicon oxide, and about 0.1-2 mg magnesium stearate.

[00196] In certain embodiments, the weight of a pharmaceutical composition is about 90 mg and comprises about 30.0 mg of a Diaminopyrimidyl Compound, about 18.0 mg

microcrystalline cellulose, about 37.3 mg mannitol, about 3.6 mg carboxymethyl cellulose, about 0.5 mg silicon oxide, and about 0.7 mg magnesium stearate. [00197] In certain embodiments, the weight of a pharmaceutical composition is about 70-

1 10 mg and comprises about 15-60 mg of a Diaminopyrimidyl Compound, about 10-40 mg Avicel® PH 102, about 20-80 mg Pearlitol® SD 200, about 1-10 mg sodium croscarmellose, about 0.1-2 mg colloidal silicon dioxide, and about 0.1 -2 mg magnesium stearate.

[00198] In certain embodiments, the weight of a pharmaceutical composition is about 90 mg and comprises about 30.0 mg of a Diaminopyrimidyl Compound, about 18.0 mg Avicel® PH 102, about 37.3 mg Pearlitol® SD 200, about 3.6 mg sodium croscarmellose, about 0.5 mg colloidal silicon dioxide, and about 0.7 mg magnesium stearate.

[00199] In certain embodiments, the pharmaceutical compositions and unit dosage forms provided herein are capsule dosage forms, including gelatin capsule dosage forms. In one embodiment, the unit dosage form is suitable for administration in a size 4 capsule.

[00200] In certain embodiments, the pharmaceutical compositions and unit dosage forms do not contain a surfactant (e.g., sodium lauryl sulfate). In certain embodiments, the

pharmaceutical compositions and unit dosage forms do not contain an acidifier or antioxidant (e.g., citric acid).

III. 100 MG FORMULATIONS

[00201] In one embodiment, provided herein is a pharmaceutical composition comprising a Diaminopyrimidyl Compound, and one or more pharmaceutically acceptable excipients or carriers.

[00202] In one embodiment, provided herein is a pharmaceutical composition comprising a Diaminopyrimidyl Compound and one or more pharmaceutically acceptable excipients and carriers selected from diluents, disintegrants, glidants and lubricants.

[00203] In certain embodiments, the diluents include, but are not limited to, mannitol (e.g.,

Pearlitol® SD200), and cellulose (e.g., microcrystalline cellulose, for example Avicel®,

Pharmacel®, Neocel®, or Ceolus®, such as AVICEL® PH 102). In one embodiment, the diluent is mannitol (e.g. Pearlitol®, Parteck®, or Mannogen® EZ). In another embodiment, the diluent is Pearlitol® SD200. In yet another embodiment, the diluent is cellulose. In yet another embodiment, the diluent is microcrystalline cellulose. In yet another embodiment, the diluent is AVICEL® PH 102. [00204] In certain embodiments, the disintegrants include, but are not limited to, carboxymethyl cellulose (e.g., croscarmellose sodium, for example, Ac-Di-Sol®, or DiSolcel®). In one embodiment, the disintegrant is carboxymethyl cellulose. In another embodiment, the disintegrant is croscarmellose sodium.

[00205] In certain embodiments, the glidants include, but are not limited to fumed silica

(e.g., silicon oxide, such as colloidal silicon dioxide, for example, Aerosil®, or Cabosil®). In one embodiment, the glidant is fumed silica. In another embodiment, the glidant is silicon oxide. In another embodiment, the glidant is colloidal silicon dioxide.

[00206] In certain embodiments, the lubricants include, but are not limited to, magnesium stearate. In one embodiment, the lubricant is magnesium stearate.

[00207] In certain embodiments, provided herein are pharmaceutical compositions comprising a Diaminopyrimidyl Compound and one or more pharmaceutically acceptable excipients or carriers, each independently selected from mannitol, cellulose, carboxymethyl cellulose, fumed silica and magnesium stearate.

[00208] In certain embodiments, provided herein are pharmaceutical compositions comprising a Diaminopyrimidyl Compound and one or more pharmaceutically acceptable excipients or carriers, each independently selected from mannitol, microcrystalline cellolose, croscarmellose sodium, silicon dioxide and magnesium stearate.

[00209] In certain embodiments, provided herein are pharmaceutical compositions comprising a Diaminopyrimidyl Compound and one or more pharmaceutically acceptable excipients or carriers, each independently selected from Pearlitol® SD200, AVICEL® PH 102, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate.

[00210] In one embodiment, provided herein is a pharmaceutical composition comprising a Diaminopyrimidyl Compound, a diluent(s)/binder(s), a disintegratnt(s), a glidant(s) and a lubricant(s).

[0021 1] In one embodiment, provided herein is a pharmaceutical composition comprising a Diaminopyrimidyl Compound, mannitol and magnesium stearate.

[00212] In one embodiment, provided herein is a pharmaceutical composition comprising a Diaminopyrimidyl Compound, mannitol, cellulose and magnesium stearate. [00213] In certain embodiments, provided herein are pharmaceutical compositions comprising a Diaminopyrimidyl Compound, mannitol, microcrystalline cellulose, carboxymethyl cellulose, fumed silica and magnesium stearate.

[00214] In certain embodiments, provided herein are pharmaceutical compositions comprising a Diaminopyrimidyl Compound, mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate.

[00215] In certain embodiments, provided herein are pharmaceutical compositions comprising a Diaminopyrimidyl Compound, Pearlitol® SD200, AVICEL® PH 102,

croscarmellose sodium, colloidal silicon dioxide and magnesium stearate.

[00216] In one embodiment, provided herein is a pharmaceutical composition comprising about 15-60 % by weight of a Diaminopyrimidyl Compound, about 50-70% by weight of diluent(s)/binder(s), about 2-8%> by weight of disintegrant(s), about 0.1-5% by weight of glidant(s), and about 0.1-5% by weight of lubricant(s).

[00217] In one embodiment, provided herein is a pharmaceutical composition comprising about 33.3%) by weight of a Diaminopyrimidyl Compound, about 61.4%> by weight of diluent(s)/binder(s), about 4.0% by weight of disintegrant(s), about 0.5% by weight of glidant(s), and about 0.75% by weight of lubricant(s).

[00218] In one embodiment, provided herein is a pharmaceutical composition comprising about 15-60 %> by weight of a Diaminopyrimidyl Compound, about 20-60%) by weight of mannitol, about 10-40%) by weight of cellulose, about 2-8% by weight of carboxymethyl cellulose, about 0.1-5% by weight of fumed silica, and about 0.1-5% by weight of magnesium stearate.

[00219] In one embodiment, provided herein is a pharmaceutical composition comprising about 33.3%) by weight of a Diaminopyrimidyl Compound, about 41.4% by weight of mannitol, about 20.0%) by weight of cellulose, about 4.0% by weight of carboxymethyl cellulose, about 0.5%) by weight of fumed silica, and about 0.75% by weight of magnesium stearate.

[00220] In one embodiment, provided herein is a pharmaceutical composition comprising about 15-60 %> by weight of a Diaminopyrimidyl Compound, about 20-60%) by weight of mannitol, about 10-40%) by weight of microcrystalline cellulose, about 2-8% by weight of carboxymethyl cellulose, about 0.1-5% by weight of silicon oxide, and about 0.1-5% by weight of magnesium stearate. [00221] In one embodiment, provided herein is a pharmaceutical composition comprising about 33.3% by weight of a Diaminopyrimidyl Compound, about 41.4% by weight of mannitol, about 20.0%) by weight of microciystalline cellulose, about 4.0% by weight of carboxymethyl cellulose, about 0.5% by weight of silicon oxide, and about 0.75% by weight of magnesium stearate.

[00222] In one embodiment, provided herein is a pharmaceutical composition comprising about 15-60 % by weight of a Diaminopyrimidyl Compound, about 10-40 % by weight of Avicel® PH 102, about 20-60 % by weight of Pearlitol® SD 200, about 2-8 % by weight of sodium croscarmellose, about 0.1-5 % by weight of colloidal silicon dioxide, and about 0.1-5 % by weight of magnesium stearate.

[00223] In one embodiment, provided herein is a pharmaceutical composition comprising about 33.3 % by weight of a Diaminopyrimidyl Compound, about 20.0 % by weight of Avicel® PH 102, about 41.4 % by weight of Pearlitol® SD 200, about 4.0 % by weight of sodium croscarmellose, about 0.5 % by weight of colloidal silicon dioxide, and about 0.75 % by weight of magnesium stearate.

[00224] In certain embodiments, the weight of a pharmaceutical composition is about 250-

350 mg and comprises about 5-15 mg of a Diaminopyrimidyl Compound, about 85-285 mg diluent(s)/binder(s), about 1-10 mg disintegrant(s), about 0.1-2 mg glidant(s), and about 0.1-2 mg lubricant(s).

[00225] In certain embodiments, the weight of a pharmaceutical composition is about 300 mg and comprises about 100.0 mg of a Diaminopyrimidyl Compound, about 184.4 mg diluent(s)/binder(s), about 12.0 mg disintegrant(s), about 1.5 mg glidant(s), and about 2.3 mg lubricant(s).

[00226] In certain embodiments, the weight of a pharmaceutical composition is about 250-

350 mg and comprises about 5-15 mg of a Diaminopyrimidyl Compound, about 10-40 mg cellulose, about 20-80 mg mannitol, about 1-10 mg carboxymethyl cellulose, about 0.1-2 mg fumed silica, and about 0.1-2 mg magnesium stearate.

[00227] In certain embodiments, the weight of a pharmaceutical composition is about 300 mg and comprises about 100.0 mg of a Diaminopyrimidyl Compound, about 60.0 mg cellulose, about 124.4 mg mannitol, about 12.0 mg carboxymethyl cellulose, about 1.5 mg fumed silica, and about 2.3 mg magnesium stearate. [00228] In certain embodiments, the weight of a pharmaceutical composition is about 250-

350 mg and comprises about 5-15 mg of a Diaminopyrimidyl Compound, about 10-40 mg microcrystalline cellulose, about 20-80 mg mannitol, about 1-10 mg carboxymethyl cellulose, about 0.1-2 mg silicon oxide, and about 0.1-2 mg magnesium stearate.

[00229] In certain embodiments, the weight of a pharmaceutical composition is about 300 mg and comprises about 100.0 mg of a Diaminopyrimidyl Compound, about 60.0 mg

microcrystalline cellulose, about 124.4 mg mannitol, about 12.0 mg carboxymethyl cellulose, about 1.5 mg silicon oxide, and about 2.3 mg magnesium stearate.

[00230] In certain embodiments, the weight of a pharmaceutical composition is about 250-

350 mg and comprises about 50-150 mg of a Diaminopyrimidyl Compound, about 30-90 mg Avicel® PH 102, about 50-250 mg Pearlitol® SD 200, about 6-18 mg sodium croscarmellose, about 0.5-3 mg colloidal silicon dioxide, and about 1-10 mg magnesium stearate.

[00231] In certain embodiments, the weight of a pharmaceutical composition is about 300 mg and comprises about 100.0 mg of a Diaminopyrimidyl Compound, about 60.0 mg Avicel® PH 102, about 124.4 mg Pearlitol® SD 200, about 12.0 mg sodium croscarmellose, about 1.5 mg colloidal silicon dioxide, and about 2.3 mg magnesium stearate.

[00232] In certain embodiments, the pharmaceutical compositions and unit dosage forms provided herein are capsule dosage forms, including gelatin capsule dosage forms. In one embodiment, the unit dosage form is suitable for administration in a size 0 capsule.

[00233] In certain embodiments, the pharmaceutical compositions and unit dosage forms do not contain a surfactant (e.g., sodium lauryl sulfate). In certain embodiments, the

pharmaceutical compositions and unit dosage forms do not contain an acidifier or antioxidant (e.g., citric acid).

EXAMPLES

[00234] The following Examples are presented by way of illustration, not limitation.

[00235] Abbreviations used here are listed in Table 3.

[00236] Table 3 : Abbreviations and Definition of Terms Abbreviation or specialist term Explanation

Ae Cumulative amount of drug excreted unchanged in urine during the collection period from predose (0-hour) to the end of collection

AE Adverse event

ANOVA Analysis of variance

AP-1 Activating Protein 1

AUC Area under the plasma concentration-time curve

AUCoo AUC from time zero extrapolated to infinity

AUC, AUC from time zero to tau (τ), where τ is the dosing interval

AUC ₂₄ AUC from time zero to 24 hours postdose

AUCoay 0-42 Area under the paw-swelling-time curve from Day 0 to Day

42

AUC _t AUC from time zero to the last quantifiable concentration

BID Twice daily

BMI Body mass index

BP Blood pressure

bpm Beats per minute

BSA Body surface area

Cbl-b Casitas b-lineage lymphoma-b protein

CI Confidence interval

CIA Collagen-induced arthritis

CIN Cervical intraepithelial neoplasia

CL/F Apparent total plasma clearance when dosed orally

CLr Renal clearance

Cmax Maximum observed plasma concentration

CV Cardiovascular

CVID Common variable immunodeficiency

CYP Cytochrome P450

DLQI Dermatology life quality index

DNCB 2,4- Dinitrochlorobenzene

DSM Diagnostic and statistical manual Abbreviation or specialist term Explanation

DTH Delayed-type hypersensitivity

ECG Electrocardiogram

ERK Extracellular signal-regulated kinase

ET Early termination

FCBP Female of childbearing potential

fe Cumulative percentage of the administered dose excreted unchanged in urine during the collection period from predose (0-hour) to the end of collection

FITC Fluorescein isothocyanate

FSH Follicle -stimulating hormone

GAPDH Glyceraldehyde-3 -phosphate dehydrogenase

GCP Good Clinical Practice

GI Gastrointestinal

GLP Good laboratory practice

GM-CSF Granulocyte macrophage colony stimulating factor

GRAIL Gene related to anergy in lymphocytes

HARP Human acidic ribosomal protein

HBsAg Hepatitis B surface antigen

HCV Ab Hepatitis C antibody

HDL High-density lipoprotein

HgB Hemoglobin

HIV Human immunodeficiency virus

HLA-DR Human leukocyte antigen-DR

IC ₅₀ Half maximal inhibitory concentration

ICAM-1 Intercellular adhesion molecule 1

ICF Informed consent form

ICH International Conference on Harmonisation

IFN-γ Interferon gamma

IgG Immunoglobulin G

IkBa I kappa B alpha

IL Interleukin Abbreviation or specialist term Explanation

iNOS Inducible nitric oxide synthase

IP Investigational product

ITGB3 Integrin beta 3

IU International units

IV Intravenous

K16 Keratin 16

m Michaelis-Menten constant

LDH Lactate dehydrogenase

LDL Low-density lipoprotein

MCP-1 Monocyte chemoattractant protein- 1

MIP-2 Macrophage inflammatory protein-2

MMP Matrix metalloproteinase

mRNA Messenger RNA

MTD Maximum tolerated dose

NF-KB Nuclear factor kappa B

NK Natural killer

NOAEL No-observed-adverse-effect level

PASI Psoriasis area and severity index

PBMCs Peripheral blood mononuclear cells

PK Pharmacokinetic(s)

PD Pharmacodynamics

PKC Protein kinase C

PKC0 Protein kinase C-theta

PKC5 Protein kinase C-delta

PLN Popliteal lymph node

PUVA Psoralen plus long-wave ultraviolet radiation

QD Once daily

QID Four times daily

RA Rheumatoid arthritis

SAD Single ascending dose

on the terminal phase

[00237] Compound 1 was developed to target allergic, inflammatory, and

autoimmune T cell mediated diseases, such as ankylosing spondylitis, asthma (including refractory asthma and severe asthma), celiac disease, colitis (including ulcerative colitis), diabetes (including type I diabetes), dermatitis (including atopic dermatitis), Duchenne muscular dystrophy, graft-versus-host disease, inflammatory bowel disease (including

Crohn's disease), insulin resistance, lupus (including systemic lupus erythematosus), multiple sclerosis (including relapsing remitting multiple sclerosis), myasthenia gravis, myositis (including polymyositis and dermatomyositis), organ transplant rejection,

psoriasis (including plaque-type psoriasis, and psoriatic arthritis), rheumatoid arthritis,

Sjogren syndrome, uveitis, or vitiligo, based on preclinical evidence. In T cells, PKC0 is the most abundantly expressed isoform of the PKC family. Protein kinase C-theta, when localized to the inner plasma cell membrane, couples signaling from the T cell receptor complex (TCR) and CD28 co-stimulation in the immunologic synapse. This coupling of the TCR and CD28 co-stimulatory molecule leads to activation of nuclear factor kappa B ( F-KB) and activating protein 1 (AP-1) transcription factors in effector T cells and subsequent gene expression that drives T cell activation and proliferation (Zhang, et al, Adv Pharmacol 2013;66:267-312). In regulatory T cells, PKC0 plays the opposite role, acting as a negative regulator of their suppressive activity (Zanin-Zhorov, et al, Science 2010;328(5976): 372-6). Based on the data presented, an inhibitor of PKC0 such as Compound 1 with effector T cell inhibitory activity in vitro and in vivo may represent a potential treatment for diseases in which T cells play a key role in the pathogenesis. There is also literature that indicates PKC0 is a crucial component in mediating fat-induced insulin resistance in skeletal muscle, suggesting that PKC0 is a potential therapeutic target for the treatment of type 2 diabetes (Kim, et al, J Clin Invest; 2004 Sep; l 14(6):823-7).

[00238] Several studies that define the activity of Compound 1 have been completed. In isolated enzyme systems, Compound 1 is a potent inhibitor of PKC0 (50% inhibitory concentration (IC ₅₀ ) = 9 ± 3 nM). Compound 1 was determined to be a selective compound, inhibiting only PKC0 by > 80% in 2 separate panels of 250 kinases or

456 kinases at a concentration of 3 μΜ.

[00239] Compound 1 was tested in several in vitro cellular assays designed to evaluate its effect on components of the PKC0 signaling pathway and on T cell activity. Compound 1 was shown to be an inhibitor of downstream markers of the PKC0 pathway in isolated human T cells following activation with anti-CD3/anti-CD28 antibodies.

Compound 1 also showed inhibitory activity on surface markers of T cell activation (CD25, CD69, CD71, CD95, and CD98) from both normal, disease (rheumatoid arthritis, psoriasis and atopic dermatitis) and T cell function in normal human peripheral blood mononuclear cells (PBMCs), human whole blood, and a mixed lymphocyte reaction (IC ₅₀ for inhibition of IL-2 production = 0.32, 1.4, and 0.29 μΜ for PBMCs, whole blood, and mixed lymphocyte reaction, respectively).

[00240] In vitro washout studies in human T cells demonstrated that once stimulated with anti-CD3/anti-CD28 antibodies in the presence of Compound 1, T cells remain unresponsive upon secondary stimulation, despite the absence of the inhibitor during the secondary stimulus, and upregulate protein levels of genes related to anergy in

lymphocytes (GRAIL; also known as RNF128), a marker of T cell anergy. In contrast, T cells preincubated with the inhibitor in the absence of concomitant T cell receptor stimulation were able to respond to stimulus after the washout period. Inhibition of these T cell functions, such as proliferation and upregulation of activation markers, persisted after drug withdrawal and re-stimulation of T cells, but only if the primary T cell activation event occurred in the presence of Compound 1. These results show that Compound 1 induced a functional unresponsiveness or "anergy-like" state in T cells during antigen recognition, suggesting a possible long-term therapeutic benefit in the treatment of T cell-mediated autoimmune and inflammatory diseases.

[00241] Several studies were conducted with Compound 1 to evaluate the effect on T cell function in vivo. In addition to inhibition of the primary endpoints such as paw clinical scores, lymph node size and ear swelling in models that recapitulate aspects of autoimmune and allergic inflammatory dieases such as arthritis and psoriasis, Compound 1 also inhibited similar cytokines in the Thl7, Thl and Th2 pathways across these models. These types of cytokines, including IFN-γ and IL-17, play a key role in the pathogenesis of diseases such as arthritis and psoriasis. The lowest efficacious dose level ranged from 10 mg/kg BID (area under the concentration-time curve was between 0.7 and 1.7 μΜ-hr) in the PLN model to 100 mg/kg BID in the mouse CIA model (total plasma exposure was estimated as area under the concentration-time curve from time 0 to 24 hours [AUC ₂ 4h] = 23.2 μΜ-hr [10420 ng hr/mL]).

[00242] Without being limited by theory, the potential for Compound 1 to induce

T cell anergy, as supported by the in vitro experiments, may explain the in vivo

pharmacological activities that were seen when Compound 1 exposure levels were low and/or above the cellular IC ₅₀ for only short periods of time. Taken together, the pharmacological results support the development of Compound 1 as an inhibitor of T cell function in T cell-mediated diseases.

[00243] Example 1: Compound 1 In Vitro Pharmacology - Intact Cultured

Cells

[00244] Protein Kinase C-theta Pathway Inhibition

[00245] Downstream signaling events that occur following activation of PKC0 include autophosphorylation of PKC0 on Threonine-538, phosphorylation and activation of mitogen-activated protein kinase pathways such as extracellular signal-regulated kinases I and II, and reduction of I kappa B alpha protein. Incubation with Compound 1 (10 μΜ) demonstrated inhibition of the PKC0 pathway in vitro, as measured by significant inhibition of autophosphorylation of PKC0 (32%, p < 0.05), phosphorylation of ERK1/2 (ranging from 15% to 72%, depending on the time point measured; p < 0.05), and a trend towards reduction of protein levels of I kappa B alpha protein components of the signaling pathway, in purified T cells following stimulation with anti-CD3/anti-CD28 antibodies.

[00246] Example 2: Compound 1 inhibits ex vivo T-cell responses

[00247] PK/PD in Mice

[00248] The effect of Compound 1 on T-cell activation was measured by ex vivo stimulation of peripheral blood T-cells after a single oral dose of Compound 1 given to C57/BL6 mice. Peripheral blood T-cells were activated ex vivo with anti-CD3 which leads to PKC-Θ activation via T-cell receptor. Single oral dose of 100 mg/kg Compound 1 inhibited ex-vivo peripheral blood T-cell responses as measured by IL-2 secretion from T-cells and CD69 expression on CD4+ T-cells, in an exposure dependent manner (see Figure 4).

[00249] Example 3: Effect of Compound 1 on Murine Models of Colitis, and Collagen-Induced Arthritis

[00250] Adoptive Transfer Model of Colitis in Mice

[00251] Adoptive transfer of CD4+CD62L+ T cells into CB-17 Prkdc ^scid mice resulted in the development of colitis, as evidenced by body weight loss and increased observation of soft and unformed stools (diarrhea) in the T cell-recipient mice, relative to non-transferred control mice. Compound 1, when dosed via the oral route at 10, 30, or 100 mg/kg once daily (QD), showed a trend towards a dose-dependent inhibition of the large bowel weightlength ratio and spleen weight that did not reach statistical

significance. No other effects were observed in this study. The lack of statistically significant effects in this model may be due to the high level of variability between animals in the control and drug-treated groups. The sensitivity of animals to oral gavage in this model represents a substantial limitation for increasing the dosing frequency. It should be noted that one of the positive controls, 5-aminosalicylic acid (5-ASA), also did not result in any significant effects on any of the endpoints measured, potentially due to the variability in the model. However, the other positive control, anti-p40

immunoglobulin G (IgG), did demonstrate statistically significant inhibition of disease endpoints. [00252] Effect of Compound 1 on Collagen-Induced Arthritis (CIA) in the Mouse

[00253] The effect of prophylactic treatment with Compound 1 on CIA in the mouse when dosed for 42 days at doses of 10, 30, or 100 mg/kg either QD or BID was evaluated. Injection of bovine collagen together with an adjuvant such as Freunds Complete Adjuvant induced an arthritis-like phenotype characterized by paw swelling and redness, inflammatory infiltrate into the paws, and bone damage.

[00254] Oral administration of Compound 1 showed a dose-dependent inhibition of paw swelling over the course of the study. In order to compare the QD versus

BID treatment groups, the statistical analysis was performed using a 2-way analysis of variance including all groups, followed by the Bonferroni multiple comparison test. When analyzed together, Compound 1 dosed at 100 mg/kg BID significantly inhibited paw swelling on Days 30 (p < 0.05), 32 (p < 0.01), 35 (p < 0.01), and 40 (p < 0.05) compared to the vehicle control (QD dosed). No statistical difference was observed between the

QD and BID dosing groups. A similar statistical significance was seen with the

100 mg/kg BID treatment group when the statistical analysis was performed independently on the QD and BID dose groups.

[00255] Inhibition of the area under the paw swelling-time curve from Day 0 to Day

42 (AUC _Day 0-42) (53% (p < 0.05)) was also seen with this dose of Compound 1 (Figure 5). No statistically significant inhibition of paw swelling was measured with the QD dose groups.

[00256] Significant inhibition of plasma IL-10 was observed at the terminal point of the study following treatment with Compound 1 at 10 (p < 0.05), 30 (p < 0.01), or

100 mg/kg (p < 0.05) QD. At a dose of 100 mg/kg QD, IL-17A was also significantly inhibited (p < 0.05). Trends towards inhibition of plasma IL-22, IL-12, and IFN-γ were also seen but no other significant effects were observed. The lack of a naive group prevents determination of induction of cytokine levels and therefore limits interpretation of the cytokine data to a comparison with the vehicle group alone.

[00257] Compared with the vehicle group, treatment with Compound 1 significantly inhibited IL-Ιβ messenger RNA (mRNA) expression in the joints at 10 or 30 mg/kg BID (56% (p < 0.05) and 67% (p < 0.05), respectively), or at 100 mg/kg both QD and BID (62%) (p < 0.01) and 68%> (p < 0.05), respectively. Treatment with Compound 1 at all dose levels significantly inhibited IL-22 (p < 0.05) and IL-17F (p < 0.05 at 10 and 100 mg/kg BID and p < 0.01 at all other dose levels) mRNA expression in the joints. Although it did not reach significance, a trend of IL-17A mRNA expression inhibition was observed in all treatment groups when compared with the vehicle. No other drug-related significant effects were observed; however, the lack of a naive group prevented determination of gene induction levels in the model, limiting interpretation of the data to comparison with the vehicle group.

[00258] Compared with vehicle group, treatment with Compound 1 reduced circulating levels of CTX-I (18.06 pg/ml ±1.15 versus vehicle 20.43±1.15 pg/ml; p<0.05) and CTX-II (14.34 pg/ml ±3.01 versus vehicle 20.70±2.29 pg/ml; p<0.05) at 100 mg/kg BID.

[00259] A significant inhibition on histological scoring was seen in the

30 (p < 0.01) and 100 mg/kg (p < 0.05) BID Compound 1 treatment groups.

[00260] The total plasma exposure (estimated as AUC ₂ 4h) at the lowest efficacious dose level for inhibition of paw swelling AUC (100 mg/kg BID) was 23.2 μΜ-hr

(10420 ng-hr/mL). See Figure 5.

[00261] Example 4: Effects of Compound 1 on Models of Delayed-type

Hypersensitivity

[00262] Similar cytokines were inhibited across two different models of delayed- type hypersensitivity including IFN-a and IL-12 indicative of inhibition of a Thl response. In one model this inhibition resulted in a reduction of ear swelling whereas in the second model of FITC-induced DTH ear swelling was not reduced.

[00263] Dinitrochlorobenzene-induced Delayed-type Hypersensitivity

[00264] Sensitization followed several days later with a DNCB challenge on the ears of mice induces a delayed-type hypersensitivity reaction that can be measured by an increase in ear thickness. Treatment starting on Day 0 with Compound 1 at doses of 10, 30, or 100 mg/kg BID or 100 mg/kg TID was active in reducing ear thickness significantly from Day 11 onwards, ranging from 53% to 87% inhibition (Figure 6 and Figure 7).

[00265] At the end of the study, the left ear was homogenized and the protein levels of cytokines were analyzed by a multiplex assay. Treatment with Compound 1 inhibited the protein levels of multiple cytokine levels in the tissue. Specifically, Compound 1 treatment significantly inhibited levels of GM-CSF, IFN-γ, TNF-a, IL-12p70, IL-27, IL-5, and regulated upon activation, normal T cell expressed and secreted (RANTES) compared to the vehicle control (Table 4). The relative expression of mRNA of several cytokines was also reduced but none of the reductions reached statistical significance.

Table 4: Effect of Compound 1 on Cytokine Protein Levels in the Ear in the

Dinitrochlorobenzene-induced Delayed-type Hypersensitivity Model

BID = twice daily; GM-CSF = granulocyte macrophage colony stimulating factor;

IFN-γ = interferon gamma; IL = interleukin; IP-10 = interferon gamma-induced protein 10; n = number of animals; RANTES = regulated upon activation, normal T cell expressed and secreted; SEM = standard error of the mean; TID = three times daily; TNF-a = tumor necrosis factor alpha. Note: The percent inhibition was calculated relative to vehicle control. The p-values were determined by comparison with the vehicle control using 1-way analysis of variance followed by Dunnett' s test.

[00266] Fluorescein Isothiocyanate-induced Delayed-type Hypersensitivity

[00267] Sensitization followed several days later with a challenge on the ears of mice with FITC induces a delayed-type hypersensitivity reaction that can be measured by an increase in ear thickness. Treatment starting on Day 0 with Compound 1 at doses of 10, 30, or 100 mg/kg BID or 100 mg/kg 3 times daily (TID) had no effect in reducing ear thickness. Treatment with Compound 1 BID significantly inhibited the protein levels of several cytokines in the ear when measured on the final day of the study (Table 5).

Compound 1 at 10, 30, and 100 mg/kg BID significantly inhibited the protein level of

IL-23, monocyte chemoattractant protein- 1 (MCP-1), and macrophage inflammatory

protein-2 (MIP-2) levels in the ear. Compound 1 at a dose of 10 and 100 mg/kg BID also significantly inhibited the protein levels of IL-22 in the ear.

Table 5. Effect of Compound 1 on Cytokine Protein Levels in the Ear in the Fluorescein Isothiocyanate-induced Delayed-type Hypersensitivity Model

Percent Inhibition of Cytokine Production

Dose

Cytokine p-value of Compound 1

Mean ± SEM n (Compared

With Vehicle Control)

MIP-2 10 mg/kg BID 48 ± 5.2 12 p < 0.01

30 mg/kg BID 46 ± 5.7 12 p < 0.01 100 mg/kg BID 50 ± 4.1 12 p < 0.01

100 mg/kg TID 61 ± 4.1 12 p < 0.0001

BID = twice daily; IL = interleukin; MCP-1 = monocyte chemoattractant protein 1; MIP-2 = macrophage inflammatory protein 2; n = number of animals; SEM = standard error of the mean; TID = 3 times daily.

[00268] Analysis of mRNA expression in the ear tissue on the last day of the study showed no significant effect of Compound 1 administered BID. Treatment with

Compound 1 administered at 100 mg/kg TID significantly inhibited the mRNA expression of the following cytokines: IFN-γ, IL-12B, IL-17A, IL-17F, IL-7, integrin beta 3

(ITGB3), matrix metalloproteinase-3 (MMP3), and E-Selectin.

[00269] Example 5: Effect of Compound 1 on Popliteal Lymph Node model of Graft vs Host Disease.

[00270] Injection of allogeneic spleen cells into a mouse host footpad mounts a

T-cell-dependent graft vs host disease response that manifests as an increase in the popliteal lymph node (PLN) size. The effect of Compound 1 at 3, 10, 30 given orally twice daily (BID) on PLN weight was tested in this model. Compound 1, when dosed at 10 mg/kg BID, significantly reduced PLN weight by 45% with no significant inhibition seen with Compound 1 when dosed at 3 mg/kg BID (as seen in Figure 8)

[00271] Example 6: Formulations of Compound 1

[00272] Table 6 provides three dosage formulations for 10 mg, 30 mg and 100 mg strength Compound 1 single dose unit in size #4 or #0 capsules that were prepared.

[00273] Table 6: Compound 1 Compositions of 10 mg, 30 mg and 100 mg strength

Capsules

Strength lOmg 30mg lOOmg Weight Weight Weight

% % %

Ingredients (mg) per (mg) per (mg) per

(w/w) (w/w) (w/w) capsule capsule capsule

Compound 1 10.0 10.0 30.0 33.3 100.0 33.3

Avicel PHI 02 20.0 20.0 18.0 20.0 60.0 20.0

Pearlitol SD200 64.75 64.75 37.3 41.4 124.4 41.4

Sodium

4.0 4.0 3.6 4.0 12.0 4.0

Croscarmellose

Colloidal Silicon

0.5 0.5 0.5 0.5 1.5 0.5 Dioxide

Magnesium Stearate 0.75 0.75 0.7 0.75 2.3 0.75

Total fill weight 100 mg 100 90 mg 100 300 mg 100

Capsule shell size #4 #4 #4 #4 #0 #0

Capsule weight 38 38 38 38 96 96

Gelatin/ API ratio: 3.80 3.80 1.27 1.27 0.96 0.96

[00274] Example 6: Clinical Protocol

[00275] Study Title - A Phase 1. Multicenter. Randomized. Double-blind.

Placebo-controlled. Single and Multiple Ascending Dose Study to Evaluate the Safety.

Tolerability. and Pharmacokinetics (PK) of Compound 1 in Healthy Subjects and Subjects with Moderate to Severe Plaque-type Psoriasis.

[00276] Objectives

[00277] Primary Objective

• To evaluate the safety and tolerability of single and multiple oral doses of

Compound 1 in healthy subjects and subjects with moderate to severe plaque-type psoriasis, respectively.

[00278] Secondary Objectives

• To evaluate the pharmacokinetics (PK) of Compound 1 following administration of single and multiple oral doses of Compound 1 in healthy subjects and subjects with moderate to severe plaque-type psoriasis, respectively. • To characterize the PK of Compound 1, under fasted and fed conditions, following administration of single oral doses of Compound 1 in healthy subjects.

• To assess the clinical efficacy of orally administered Compound 1 in subjects with moderate to severe plaque-type psoriasis.

• To assess the effect of Compound 1 on electrocardiogram (ECG) parameters in healthy subjects.

[00279] Study Design

[00280] This is a two-part study to be conducted at multiple study sites in the

United States (US). The Sponsor, study participants, Investigators, and any other clinical site staff directly involved in the conduct of the trial will be blinded to treatment

throughout the study. The study pharmacist and pharmacy staff at the clinical site(s) will have access to the randomization schedule in order to properly dispense Compound 1. The bioanalysis laboratory contracted to measure plasma concentrations of Compound 1 will also have access to the randomization schedule in order to properly identify samples.

[00281] Part 1

[00282] Part 1 is a randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and PK of Compound 1 following single oral doses in healthy subjects. Part 1 will also allow for characterization of the PK of Compound 1 under fasted and fed conditions by administering an additional single dose of Compound 1, under fed conditions, in a cohort of subjects that previously received a single dose of Compound 1 under fasted conditions (i.e., in the single ascending dose (SAD) portion of Part 1).

[00283] The SAD phase of Part 1 will employ an interleaved cohort (rotating panel) design in which dosing is alternated between three cohorts of subjects. Compound 1 will be administered at only one dose level at a time, and administration at the next dose level will not begin until the safety and tolerability of the preceding dose level have been evaluated and deemed acceptable by the Investigator and Sponsor's Medical Monitor.

There will be an interval of at least 7 days between dosing of successive SAD cohorts.

Once the SAD phase of Part 1 is completed, one of the cohorts will participate in an additional study period in Part 1 in which a single dose of Compound 1 will be

administered under fed conditions. Available safety data from the SAD phase will be used to guide selection of the dose to be administered under fed conditions (it is planned for the second highest dose that is tolerated by subjects in the SAD phase to be used).

[00284] Approximately 24 subjects will participate in Part 1. Each subject will be assigned to one of three planned cohorts (Cohorts 1 A, IB, and 1C), and each cohort will consist of eight subjects. For each of the planned dose levels in Part 1, six subjects will receive Compound 1 and two subjects will receive placebo according to the randomization schedule.

[00285] During the course of Part 1, each subject will participate in a screening phase, a baseline phase, a treatment phase (consisting of up to three study periods), and a follow-up visit. Subjects will be screened for eligibility. Subjects who have met all inclusion criteria and none of the exclusion criteria at screening will return to the clinical site on Day -1 of the first study period. During each study period, subjects will be domiciled at the clinical site from Day -1 to Day 2. In the SAD phase, all subjects will receive Investigational product (IP) twice - once during each of two study periods.

Investigational product (either Compound 1 or placebo) will be administered on Day 1 of each study period, under fasted conditions, according to the randomization schedule. Upon completion of the SAD phase, one of the cohorts (Cohort 1A, IB, or 1C) will participate in an additional study period in which a single dose of IP will be administered on Day 1 approximately 30 minutes after eating a high-fat, high-calorie meal. It is planned for the second highest dose that is tolerated by subjects in the SAD phase to be used, and each subject will receive the same dose of IP (either Compound 1 or placebo) that he or she received in the SAD phase. The dose of IP to be administered under fed conditions and the previous dose of IP administered under fasted conditions will be separated by an interval (ie, washout) of at least 21 days. Blood and urine samples will be collected at prespecified times for PK, clinical laboratory assessments and/or exploratory analyses. For certain dose levels in Part 1, subjects will also have blood samples collected at prespecified times for PD assessments. Safety will be monitored throughout the study. Subjects will be discharged from the clinical site on Day 2 of each study period upon satisfactory safety review and completion of the required study procedures. Each subject will then return to the clinical site for a follow-up visit within 6 to 8 days after the last dose in the last study period. In the event that a subject discontinues from the study, an early termination (ET) visit will be performed.

[00286] Following completion of each dose level in the SAD phase, safety data will be reviewed and PK data will be reviewed as needed, if available. The parameters to be reviewed prior to each dose escalation, along with specific dose escalation and stopping criteria will be provided. Individual subject stopping rules are not applicable to subjects receiving a single dose of IP.

[00287] Part 2

[00288] Part 2 is a randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and PK of Compound 1 following administration of multiple oral doses (28 days of dosing) in subjects with moderate to severe plaque type psoriasis. The chosen study design is an escalating dose in sequential groups.

[00289] Part 2 will not begin until safety data from at least the first three dose levels in Part 1 have been evaluated. Only doses that are safe and tolerated in Part 1 and predicted not to exceed Compound 1 steady state exposure at the NOAEL in male rats will be administered in Part 2.

[00290] Approximately 48 subjects will participate in Part 2. Each subject will be assigned to one of four planned cohorts (Cohorts 2A, 2B, 2C, and 2D). Each cohort will consist of 12 subjects; nine subjects will receive Compound 1 and three subjects will receive placebo daily for 28 days according to the randomization schedule.

[00291] During the course of Part 2, each subject will participate in a screening phase, a baseline phase, a treatment phase, and a follow-up visit. Subjects will be screened for eligibility. Subjects who have met all inclusion criteria and none of the exclusion criteria at screening will return to the clinical site on Day -1, and will be domiciled at the clinical site from Day -1 to at least Day 2. Based on logistics and at the discretion of the Investigator, subjects may then remain domiciled at the clinical site for the remainder of the treatment phase or return to the clinical site on an outpatient basis for scheduled study procedures (Note: at minimum, subjects will be domiciled at the clinical site from

Days 28 to 29). The first dose of IP (either Compound 1 or placebo) will be administered on Day 1 according to the randomization schedule. The same total daily dose will then be administered, either at the clinical site by site staff or self-administered on an outpatient basis, for the remainder of the planned treatment schedule. Blood samples will be collected at prespecified times for PK, PD, clinical laboratory assessments, and/or analyses. Urine samples will be collected at prespecified times for clinical laboratory assessments. Safety will be monitored throughout the study. When applicable, subjects will be discharged from the clinical site upon satisfactory safety review and completion of the required study procedures. Each subject will return to the study center for a follow-up visit within 6 to 8 days after the last dose. In the event that a subject discontinues from the study, an ET visit will be performed.

[00292] After each cohort has completed dosing, safety data will be reviewed and PK data will be reviewed as needed, if available.

[00293] The study will be conducted in compliance with International Conference on Harmonisation (ICH) Good Clinical Practices (GCPs).

[00294] Study Population

[00295] Approximately 72 adult male and/or female subjects from any race will be enrolled into the study across multiple study sites in the United States. Part 1 will consist of approximately 24 healthy subjects. Part 2 will consist of approximately 48 subjects with moderate to severe plaque-type psoriasis.

[00296] Length of Study

[00297] The estimated duration of the study, inclusive of Parts 1 and 2, from first-subject-first- visit to last-subject-last-visit, is approximately 12 months.

[00298] Part 1

[00299] The estimated duration of the clinical phase of Part 1, from

first-subject-first- visit to last-subject-last-visit, is approximately 4 months.

[00300] The estimated duration of each subject's participation in Part 1, from screening through the follow-up visit, is up to approximately 4 months depending on the cohort to which a subject is assigned.

[00301] Part 2

[00302] Part 2 will not begin until safety data from at least the first three dose levels in Part 1 have been evaluated.

[00303] The estimated duration of the clinical phase of Part 2, from screening through the follow-up visit, is approximately 2 months. [00304] End of Trial

[00305] The End of Trial is defined as either the date of the last visit of the last subject to complete the post-treatment follow-up, or the date of receipt of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, whichever is the later date.

[00306] Study Treatments

[00307] Part 1

[00308] Doses in Part 1 are planned to be administered orally as formulated capsules (or matching placebo) once daily (QD).

[00309] The following Compound 1 dose levels are planned for Part 1 as listed in Table 7.

[00310] Table 7

IP to be administered under fasted conditions unless otherwise specified. [00312] ^b One of the cohorts (Cohort 1 A, IB, or 1C) will participate in an additional study period in Part 1 in which a single dose of IP will be administered under fed conditions. It is planned for the second highest dose that is tolerated by subjects in the SAD phase to be used, and each subject will receive the same dose of IP (either

Compound 1 or placebo) that he or she received in the SAD phase.

[00313] If stopping criteria are met due to gastrointestinal (Gl)-related adverse events (AEs; specifically > Grade 2 nausea, vomiting, diarrhea, or abdominal pain), or if dose-limited absorption is observed, the same (or lower) total daily doses in Part 1 may be split and administered as a modified dose regimen (eg, BID, three times daily [TID], four times daily [QID], etc).

[00314] Planned dose levels in Part 1 may be modified, eliminated, and/or conducted in a non-interleaved fashion based on data obtained from prior cohorts in Part 1. Should a change to the planned dose escalation step(s) be required, the maximum dose escalation step in Part 1 will be < 3 -fold the previous dose level. If it is decided for a dose level to be conducted in a non-interleaving fashion, an additional [new] cohort of subjects may be used, with up to eight subjects in the cohort.

[00315] In Part 1, IP will be administered at only one dose level at a time, and administration at the next dose level will not begin until the safety and tolerability of the preceding dose level have been evaluated and deemed acceptable by the Investigator and Sponsor's Medical Monitor.

[00316] Part 2

[00317] The proposed dose regimen in Part 2 is formulated capsules (or matching placebo) BID for up to 28 days. The maximum dose administered in Part 2 will be capped such that the projected mean exposure (AUC ₂₄ at steady state; based on PK data from prior cohorts) should not exceed the AUC ₂₄ associated with the NOAEL in male rats.

[00318] The following Compound 1 dose levels are proposed for Part 2 as listed in Table 8. [00319] Table 8

[00320] ^a Only a morning dose will be administered on the final day of dosing (i.e.,

Day 28).

[00321] Proposed dose levels in Part 2 may be modified and/or eliminated based on data obtained from Part 1 and/or from prior cohorts in Part 2. Should a change to the proposed dose level be required, the maximum dose level step in Part 2 will be < 3-fold the previous dose level.

[00322] In Part 2, IP will be administered at only one dose level at a time, and administration at the next dose level will not begin until the safety and tolerability of the preceding dose level have been evaluated and deemed acceptable by the Investigator and Sponsor's Medical Monitor.

[00323] Overview of Key Efficacy Assessments

[00324] There are no planned efficacy assessments in Parts 1 and 2 since healthy subjects will be participating in this part. In Part 2, which includes subjects with moderate to severe plaque-type psoriasis, an assessment will be made at the end of dosing compared to baseline for body surface area (BSA) involvement, psoriasis area and severity index (PASI), static physicians global assessment (sPGA) score, and dermatology life quality index (DLQI) score.

[00325] Overview of Key Safety Assessments

[00326] Safety will be monitored throughout the study. Safety evaluations will include AE reporting, PEs, vital signs, 12-lead ECGs, clinical laboratory safety tests (including thyroid stimulating hormone [TSH], total cholesterol, triglycerides, high- density lipoprotein [HDL], and low-density lipoprotein [LDL] in addition to standard clinical chemistry, hematology, and urinalysis tests), review of concomitant

medications/procedures, finger sticks for real-time assessment of blood glucose levels, and pregnancy tests for female subjects of childbearing potential. All AEs will be monitored and recorded throughout the study from the time the informed consent form (ICF) is signed until study completion, and when made known to the Investigator within 28 days after the last dose of IP (and those SAEs made known to the Investigator at any time thereafter that are suspected of being related to IP). All concomitant medications and procedures will be reviewed and recorded from the time the subject signs the ICF

(including all medications used/procedures occurring < 28 days before screening) until study completion.

[00327] Overview of Key Pharmacokinetic (PK) Assessments

[00328] In both parts of the study, blood samples will be collected at prespecified times to determine levels of Compound 1 in plasma. In Part 1, urine samples will be collected at prespecified times.

[00329] The following PK parameters will be estimated for Compound 1, as appropriate:

• Maximum observed plasma concentration (Cmax)

• Time to C _max (T _max )

• Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC _∞ )

• Area under the plasma concentration-time curve from time zero to the last

quantifiable concentration (AUC _t )

• Area under the plasma concentration-time curve from time zero to 24 hours postd (AUC ₂₄ )

• Area under the plasma concentration-time curve from time zero to tau (τ), where τ the dosing interval (AUC _X )

• Terminal elimination half-life (ti _/2 ) • Apparent total plasma clearance when dosed orally (CL/F)

• Apparent total volume of distribution when dosed orally, based on the terminal phase

• Ratio of accumulation (RA) based on Day 1 and Day 7 (or Day 28) AUC _X

[00330] Compound 1 concentrations in urine samples collected in Part 1 may be further quantified using a validated method if exploratory analyses indicate that

Compound 1 is abundant in urine. The following PK parameters related to urine analyses may then be determined, as appropriate:

• Cumulative amount of Compound 1 excreted unchanged in urine during the

collection period from predose (0-hour) to the end of collection (Ae)

• Cumulative percentage of the administered dose excreted unchanged in urine during the collection period from predose (0-hour) to the end of collection (fe)

• Renal clearance (CL _r )

[00331] Overview of Key Pharmacodynamic (PD) Assessments

[00332] For select cohorts/dose levels in both parts of the study, blood samples will be collected at prespecified times to explore various PD biomarkers.

[00333] Skin biopsies will be taken and evaluated for structural features, cell

phenotype, and inflammatory protein expression. Normal skin (Day 1) and psoriatic plaque (Days 1 and 28) biopsy measures may include the following general assessments:

• Histopathology

- Epidermal thickness

• Immunohistochemistry

- Quantitation of T cells, T regulatory cells, natural killer (NK) cells, and dendritic cells in epidermis and dermis

- Qualitative keratin 16 (K16)

- Intracellular adhesion molecule 1 (ICAM-1)

- Human leukocyte antigen-DR (HLA-DR) • Reverse transcriptase - polymerase chain reaction for psoriasis-associated inflammatory biomarkers, such as tumor necrosis factor-alpha (TNF-a), IFN-γ, interferon beta (IFN-β), IL-2, IL-6, IL-8, IL-10, encoding p40 subunit of human interleukin-12 (IL12-p40), IL-17, IL-19, IL-20, encoding pl9 subunit of human interleukin-23 (IL-23-pl9), inducible nitric oxide synthase (iNOS), K16, MCP-1, STAT-1, MMP12, Granzyme B, MIP-3a, GM-CSF, IP-10, MX-1 and VEGF. All biomarkers will be normalized to constitutively expressed messenger ribonucleic acid (mRNA) proteins such as human acidic ribosomal protein (HARP) or glyceraldehyde- 3 -phosphate dehydrogenase (GAPDH).

[00334] Statistical Methods

[00335] Safety, PK, PD, and efficacy data will be summarized using descriptive statistics. The relationship between Compound 1 exposure and response variables (PD and clinical, as appropriate) will be explored graphically as appropriate

[00336] To characterize the PK of Compound 1 under fasted and fed conditions, an analysis of variance (ANOVA) model, with treatment as a fixed effect and subject as a random effect, will be performed on the natural log-transformed AUCs and Cma _X . The geometric means, percent ratios (fed/fasted) of the geometric means, and the 90% CIs for the ratios, will be presented. For Tma _X , a non-parametric analysis will be used to produce a median difference between treatments (fed-fasted).

[00337] Inclusion Criteria - Part 1 (Healthy Subjects)

[00338] Subjects must satisfy the following criteria to be enrolled in the study: (1) Female or male subject is > 18 and < 65 years of age at the time of signing the informed consent form (ICF). (2) Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted. (3) Subject is willing and able to adhere to the study visit schedule and other protocol requirements. (4) Subject is in good health as determined by a physical examination at screening. (5) Female subjects of

childbearing potential (FCBP) must: (a) Have two negative pregnancy tests as verified by the Investigator prior to the first dose of IP. She must agree to ongoing pregnancy testing during the course of the study, and prior to discharge from the clinical site. This applies even if the FCBP subject practices true abstinence from heterosexual contact, (b) Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with, effective contraception without interruption during the study (including dose

interruptions), and for at least 28 days after discontinuation of IP. The female subject's chosen form of contraception must be effective by the time the female subject is randomized into the study (for example, hormonal contraception should be initiated at least 28 days before randomization). (6) Female subjects NOT of childbearing potential must: (a) Have been surgically sterilized (hysterectomy or bilateral oophorectomy; proper documentation required) at least 6 months before screening, or be postmenopausal (defined as 24 consecutive months without menses before screening, with a

follicle-stimulating hormone [FSH] level of > 40 IU/L at screening). (7) Male subjects must: (a) Practice true abstinence (which must be reviewed on a monthly basis and source documented) or agree to use a condom during sexual contact with a pregnant female or FCBP while participating in the study, during dose interruptions and for at least 28 days after discontinuation of IP, even if he has undergone a successful vasectomy. (8) Subject has body mass index (BMI) > 18 and < 33 kg/m ² at screening. (9) Subject has platelet count, absolute neutrophil count, and absolute lymphocyte count above the lower limit of normal at screening. (10) Subject has liver function tests below the upper limit of normal at screening. (11) For all other clinical laboratory safety test parameters, the subject has results within normal limits or acceptable to the Investigator. (12) Subject is afebrile, with supine systolic blood pressure (BP) > 90 and < 140 mmHg, supine diastolic BP > 50 and < 90 mmHg, and pulse rate > 40 and < 110 bpm at screening. (13) Subject has a normal or clinically-acceptable 12-lead ECG at screening. In addition: (a) If male, subject has a QTcF value < 430 msec at screening, (b) If female, subject has a QTcF value < 450 msec at screening.

[00339] Inclusion Criteria - Part 2 (Subjects with Moderate to Severe Plaque-type Psoriasis)

[00340] Subjects must satisfy the following criteria to be enrolled in the study:

(1) Female or male subject is > 18 and < 70 years of age at the time of signing the ICF.

(2) Subject must understand and voluntarily sign an ICF prior to any study -related assessments/procedures being conducted. (3) Subject is willing and able to adhere to the study visit schedule and other protocol requirements. (4) Subject is generally healthy, with the exception of the underlying psoriasis, as determined by medical history review, physical examination, 12-lead ECG, clinical chemistry, hematology, and urinalysis at screening. (5) Subject has a clinical diagnosis of stable moderate to severe plaque-type psoriasis at least 6 months prior to screening, defined as: (a) PASI score > 12;

(b) BSA > 10%; and (c) sPGA score > 3. (6) FCBP must: (a) Have two negative pregnancy tests as verified by the Investigator prior to the first dose of IP. She must agree to ongoing pregnancy testing during the course of the study, and prior to discharge from the clinical site. This applies even if the FCBP subject practices true abstinence from heterosexual contact, (b) Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with, effective contraception without interruption during the study (including dose interruptions), and for at least 28 days after discontinuation of IP. The female subject's chosen form of contraception must be effective by the time the female subject is randomized into the study (for example, hormonal contraception should be initiated at least 28 days before randomization). (7) Female subjects NOT of childbearing potential must: (a) Have been surgically sterilized (hysterectomy or bilateral

oophorectomy; proper documentation required) at least 6 months before screening, or be postmenopausal (defined as 24 consecutive months without menses before screening, with a FSH level of > 40 IU/L at screening). (8) Male subjects must: (a) Practice true abstinence (which must be reviewed on a monthly basis and source documented) or agree to use a condom during sexual contact with a pregnant female or FCBP while participating in the study, during dose interruptions and for at least 28 days after discontinuation of IP, even if he has undergone a successful vasectomy. (9) Subject is a candidate for photo/systemic therapy. A subject is considered a candidate for photo/systemic therapy if, in the judgment of the Investigator, the subject requires any ultraviolet (UV) radiation or systemic therapy (eg, ultraviolet light B [UVB], psoralens and long-wave ultraviolet radiation [PUVA], methotrexate, cyclosporine, corticosteroids, oral retinoids, mycophenolate mofetil, thioguanine, hydroxyurea, sirolimus, tacrolimus, azathioprine, or approved biological agent) to control psoriasis, whether or not the subject has a history of receiving systemic therapy. (10) Subject has an antitetanus immunoglobulin (Ig) G titer > 0.15 IU/mL to ensure prior exposure of tetanus toxoid (Bingham, 2010, Arthritis Rheum., 62(l):64-74). [00341] Exclusion Criteria - Exclusion Criteria - Part 1 (Healthy Subjects)

[00342] The presence of any of the following will exclude a subject from

enrollment: (1) Subject has any significant and relevant medical condition (including but not limited to neurological, gastrointestinal (GI), renal, hepatic, CV, psychological, pulmonary, metabolic, endocrine, hematological, allergic disease, drug allergies, or other major disorders), laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study. (2) Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study. (3) Subject has any condition that confounds the ability to interpret data from the study. (4) Subject is pregnant or breastfeeding. (5) Subject was exposed to an investigational drug (new chemical entity) within 30 days preceding the first dose administration, or five half-lives of that investigational drug, if known

(whichever is longer). (60 Subject has used any prescribed systemic or topical medication (including but not limited to analgesics, anesthetics, etc) within 30 days prior to the first dose administration. (7) Subject has used any non-prescribed systemic or topical medication (including vitamin/mineral supplements, and herbal medicines) within 14 days prior to the first dose administration. (8) Subject has used CYP3A inducers and/or inhibitors (including St. John's wort) within 30 days prior to the first dose administration. The Indiana University "Cytochrome P450 Drug Interaction Table" should be utilized to determine inhibitors and/or inducers of CYP3 A

(http://medicine.iupui.edu/clinpharm/ddis/table.aspx). (9) Subject has any surgical or medical conditions possibly affecting drug absorption, distribution, metabolism and excretion, eg, bariatric procedure. Appendectomy and cholecystectomy are acceptable. (10) Subject donated blood or plasma within 8 weeks before the first dose administration to a blood bank or blood donation center. (11) Subject has a history of drug abuse (as defined by the current version of the Diagnostic and Statistical Manual [DSM]) within 2 years before the first dose administration, or positive drug screening test reflecting consumption of illicit drugs. (12) Subject has a history of alcohol abuse (as defined by the current version of the DSM) within 2 years before the first dose administration, or positive alcohol screen. (13) Subject is known to have serum hepatitis or known to be a carrier of hepatitis B surface antigen (HBsAg) or hepatitis C antibody (HCV Ab), or have a positive result to the test for human immunodeficiency virus (HIV) antibodies at screening.

(14) Subject smokes > 10 cigarettes per day, or the equivalent in other tobacco products

(self-reported). (15) Subject had systemic infection within 30 days prior to the first dose administration. (16) Subject has a previous history of autoimmune disease. (17) Subject is part of the clinical staff personnel or a family member of the clinical site staff.

[00343] Exclusion Criteria - Part 2 (Subjects with Moderate to Severe Plaque-type

Psoriasis)

[00344] The presence of any of the following will exclude a subject from enrollment: (1) Subject has any significant and relevant medical condition (including but not limited to neurological, GI, renal, hepatic, CV, psychological, pulmonary, metabolic, endocrine, hematological, allergic disease, drug allergies, or other major uncontrolled disease), laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study. (2) Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study. (3) Subject has any condition that confounds the ability to interpret data from the study. (4) Subject is pregnant or breastfeeding. (5) Subject has known active, current or history of recurrence of bacterial, viral, fungal, mycobacterial, or other infections (including but not limited to tuberculosis [TB] and atypical mycobacterial disease, and herpes zoster), HIV, or any major episode of infection requiring hospitalization or treatment with intravenous or oral antibiotics within 4 weeks prior to screening. (6) Subject completed treatment for mycobacterial infection (ie, TB) at least 3 years prior to screening but lacks documentation. (7) Subject has a positive QuantiFERON-Gold test or two successive indeterminate QuantiFERON-Gold tests at screening. Subjects with a history of TB who have undergone treatment (documented) may be eligible for study entry. (8) Subject has a history of incompletely treated Mycobacterium tuberculosis infection, as indicated by: (a) Subject's medical records documenting incomplete treatment for Mycobacterium tuberculosis, (b) Subject's self- reported history of incomplete treatment for Mycobacterium tuberculosis. (9) Subject has any clinically significant findings/abnormalities on chest X-ray at screening. (10 Subject is known to have serum hepatitis or known to be a carrier of HBsAg or HCV Ab, or have a positive result to the test for HIV antibodies at screening. (11) Subject has a history of positive congenital and acquired immunodeficiencies (eg, Common Variable Immunodeficiency [CVID]). (12) Subject has a history of solid tumors and hematologic malignancies. Note: Subjects with a history of squamous or basal cell carcinoma of the skin or cervical intraepithelial neoplasia (CIN) or in situ cervical carcinoma that has been excised and cured > 5 years from screening are eligible for study entry. (13) Subject has psoriasis flare within 4 weeks before screening, defined as a sudden intensification of psoriasis requiring prescribed medical intervention or a diagnosis of erythrodermic, guttate, or pustular psoriasis. (14) Subject has evidence of skin conditions that would interfere with evaluations related to the effect of IP on psoriasis. (15) Subject received topical therapy within 14 days prior to the first dose administration (including but not limited to topical corticosteroids, topical retinoids or vitamin D analog preparations, tacrolimus, pimecrolimus, or anthralin). Exceptions: low potency corticosteroids will be allowed as background therapy for treatment of the face, axillae and groin in accordance with the manufacturers' suggested usage during the course of the study. Subjects with scalp psoriasis will be permitted to use coal tar shampoo and/or salicylic acid scalp preparations on scalp lesions. Eucerin ^® cream (the standard emollient for this study) will also be permitted for body lesions only. Subjects must not use these treatments within 24 hours prior to each check-in. (16) Subject received systemic therapy for psoriasis within 4 weeks prior to the first dose administration (including but not limited to cyclosporine, corticosteroids, methotrexate, oral retinoids, mycophenolate mofetil, thioguanine, hydroxyurea, sirolimus, tacrolimus, azathioprine, fumaric acid esters, and apremilast). (17) Subject used phototherapy (eg, UVB, PUVA) within 4 weeks prior to the first dose administration. (18) Subject used adalimumab, etanercept, efalizumab or infliximab within 12 weeks prior to the first dose administration. (19) Subject used alefacept omalizumab, rituximab, ustekinumab, briakinumab, or other therapeutic antibody products within 24 weeks prior to the first dose administration. (20) Subject was exposed to an investigational drug (new chemical entity) within 30 days preceding the first dose administration, or five half-lives of that investigational drug, if known (whichever is longer). (21) Subject has a history of alcohol, drug or chemical abuse within 6 months prior to screening. (22) Subject had a major surgery within 8 weeks prior to screening and/or planned major surgery during the entire length of the study. (23) Subject has prolonged sun exposure or uses tanning booths or other UV light sources. (24) Subject received tetanus vaccination within 5 years prior to the first dose administration. (25) Subject self-reports a history of hypersensitivity to any component of TENIVAC® or any other tetanus or diphtheria toxoid-containing vaccine, including hypersensitivity to latex. (26) Subject self-reports any previous unacceptable adverse reaction, ie, extreme hypersensitivity or allergy, to Candida albicans antigen or to a similar product, immunization, or shellfish.

[00345] The embodiments disclosed herein are not to be limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of a few aspects of the disclosed embodiments and any embodiments that are functionally equivalent are encompassed by the present disclosure. Indeed, various modifications of the embodiments disclosed herein are in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

[00346] A number of references have been cited, the disclosures of which are incorporated herein by reference in their entirety.