WO2014074471A1

WO2014074471A1 - Methods for treating inflammatory diseases and pharmaceutical combinations useful therefor

Info

Publication number: WO2014074471A1
Application number: PCT/US2013/068387
Authority: WO
Inventors: Lori Kell TAYLOR; Kathryn Lea Sewell; Thomas Carl HOOCK
Original assignee: Vertex Pharmaceuticals Incorporated
Priority date: 2012-11-06
Filing date: 2013-11-05
Publication date: 2014-05-15

Abstract

The present invention provides a method of treating psoriasis comprising the administration of a compound of Formula I or a compound of Formula I and a co-therapy, and administrations of pharmaceutical compositions comprising a compound of Formula (I).

Description

METHODS FOR TREATING INFLAMMATORY DISEASES AND

PHARMACEUTICAL COMBINATIONS USEFUL THEREFOR

CROSS REFERENCE TO RELATED APPLICATION

[0001] The present U.S. patent application claims the benefit of U.S. Application Serial No. 61/722,859, filed on November 6, 2012. This application is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to pharmaceutical compositions and methods for treating psoriasis with a compound of Formula I or a combination of a compound of Formula I and a co-therapy.

BACKGROUND

[0003] The Janus kinases (JAK) are a family of tyrosine kinases consisting of JAK1, JAK2, JAK3, and TYK2. The JAKs play a critical role in cytokine signaling. The down-stream substrates of the JAK family of kinases include the signal transducer and activator of transcription (STAT) proteins. JAK/STAT signaling has been implicated in the mediation of many abnormal immune responses such as psoriasis. Moreover, JAK kinases represent an established therapeutic target for this disease. For example, JAK kinases are an established therapeutic target for treating psoriasis. Stump K. L., et al., Arthritis Res. Ther. (201 1) 13:R68; Fridman J.S., et al., J Immunol. (2010) 184:5298-5307; West K., Curr. Op. Investig. Drugs (2009) 10:491-504; Kremer J. M. et al., Arthritis Rheumatism (2009) 60(7):1895- 1905; Xiong, W. et al., Ther Adv Musculoskelet Dis. (201 1) 3(5): 255-266; Panes, J. et al. 19^th Ann. Eur. Gastroenterology Week (Oct 22-26, 2011) Stockholm, SE, PI 456; and Drugs in R & D "Tofacitinib" (2010) 10(4):271-84.

[0004] Compounds described as kinase inhibitors, particularly the JAK family kinases, are disclosed in WO 2005/095400 and WO 2007/084557. Also disclosed in these publications are processes and intermediates for preparing these compounds. There remains, however, a need for stable bioavailable pharmaceutical compositions useful for treating patients suffering from abnormal immune responses such as psoriasis and methods of administering the same.

SUMMARY OF THE INVENTION

[0005] In general, the invention relates to pharmaceutical compositions and methods for treating or lessening the severity of psoriasis with a compound of Formula I or a combination of a compound of Formula I and a co-therapy. [0006] One aspect of the present invention provides a method for treating or lessening the severity of psoriasis comprising administering to a patient in need thereof a compound of Formula I

I

or a pharmaceutically acceptable salt thereof, wherein:

X¹ is N or CR⁴;

R² is H or halo;

R is H or halo;

R⁴ is H or halo;

R" is H or an unsubstituted Ci.₂ aliphatic;

R is an unsubstituted C^ aliphatic;

R⁹ is an unsubstituted C aliphatic;

R⁷ is a Ci_-3 aliphatic optionally substituted with up to 3 occurrences of F; and

R¹⁴ is H or unsubstituted Ci_-2 alkyl.

[0007] In some embodiments, R² is H or F.

[0008] In some embodiments, R³ is H or CI.

[0009] In some embodiments, each of R⁸ and R⁹ is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl. For example, each of R and R is independently selected from methyl or ethyl.

[0010] In some embodiments, R¹⁴ is H or methyl.

[0011] In some embodiments, R⁷ is an unsubstituted C₁.3 aliphatic.

[0012] In other embodiments, R is a Ci_-3 aliphatic substituted with 1 -3 occurrences of F.

[0013] In some embodiments, R is a group selected from -CH₂CH₃, -CH₂CF₃,

-CH₂CH₂CH₃, or -CHCH₃CH₃.

[0014] And, in some embodiments, the compound of Formula I is a compound selected from Table 1 . [0015] In some embodiments, the compound of Formula I is administered at least once per day.

[0016] In some embodiments, the compound of Formula I is administered from 1 to 4 times per day.

[0017] In some embodiments, the compound of Formula I is orally administered to the patient in need thereof.

[0018] In some embodiments, at least about 25 mg (e.g., at least about 50 mg) of the compound of Formula I is administered to the patient once per day. For example, at least about 100 mg of the compound of Formula I is administered to the patient once per day. In other examples, at least about 150 mg of the compound of Formula I is administered to the patient once per day. And, in some examples, at least about 200 mg of the compound of Formula I is administered to the patient once per day.

[0019] In some embodiments, at least about 20 mg (at least about 25 mg, at least about 50 mg, or at least about 100 mg) of the compound of Formula I is administered to the patient twice per day.

[0020] Some embodiments further comprise administering to the patient a co-therapy. Co- therapies that are useful in the methods of the present invention may be administered concurrently with the compound of Formula I or sequentially. For example, some embodiments further comprise administering to the patient a phototherapy (e.g., psoralen and ultraviolet A [PUVA] light therapy).

[0021] Some embodiments further comprise administering to the patient an additional agent selected from a corticosteroid, cyclosporine, methotrexate, an oral retinoid, mycophenolate mofetil, thioguanine, hydroxyurea, sirolimus, azathioprine, 6-mercaptopurine, or any combination thereof.

[0022] Some embodiments further comprise administering a chemotherapy agent to the patient. And, in some instances, the chemotherapy agent comprises methotrexate, azathioprine (e.g., Imuran), 6-mercaptopurine, cyclosporine, cyclophosphamide (e.g., Cytoxan), or any combination thereof.

[0023] In some embodiments, the chemotherapy agent comprises an injectable formulation or an oral formulation. And, in some instances, the patient is administered from about 5 mg to about 100 mg of the chemotherapy agent per month.

[0024] Another aspect of the present invention provides a method for treating or lessening the severity of psoriasis comprising administering to a patient in need thereof a

pharmaceutical composition comprising a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

X¹ is N or CR⁴;

R² is H or halo;

R³ is H or halo;

R⁴ is H or halo;

R" is H or an unsubstituted Ci_-2 aliphatic;

R⁸ is an unsubstituted CM aliphatic;

R⁹ is an unsubstituted C aliphatic;

R¹⁴ is H or unsubstituted Ci_-2 alkyl.

[0025] Some embodiments further comprise administering to the patient a chemotherapy agent.

[0026] In some embodiments, the chemotherapy agent comprises methotrexate, azathioprine (e.g., Imuran), 6-mercaptopurine, cyclosporine, cyclophosphamide (e.g., Cytoxan), or any combination thereof.

[0027] In some embodiments, the chemotherapy agent comprises an injectable formulation or an oral formulation.

[0028] In some embodiments, the patient is administered from about 5 mg to about 100 mg of the chemotherapy agent per month.

[0029] In some embodiments, for the compound of Formula I, R is H or F.

[0030] In some embodiments, R³ is H or CI.

[0031] In some embodiments, each of R and R is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl. For example, each of R and R is

independently selected from methyl or ethyl.

[0032] In some embodiments, R¹⁴ is H or methyl.

[0033] In some embodiments, R⁷ is an unsubstituted Ci_-3 aliphatic. [0034] In some embodiments, R is a Ci_-3 aliphatic substituted with 1-3 occurrences of F.

[0035] In some embodiments, R⁷ is a group selected from -CH2CH3, -CH₂CF₃,

-CH₂CH₂CH₃, or -CHCH₃CH₃.

[0036] In some embodiments, the compound of Formula I is a compound selected from

Table 1.

[0037] In some embodiments, the pharmaceutical composition further comprises a topical cream.

[0038] In some embodiments, the pharmaceutical composition further comprises a tablet.

[0039] In some embodiments, the tablet further comprises a diluent, a binder, a glidant, a disintegrant, a surfactant, a lubricant, or any combination thereof.

[0040] Some embodiments further comprise administering the tablet at least once per day (e.g., 1, 2, 3, or 4 times per day).

[0041] In some embodiments, the tablet comprises at least about 10 mg of the compound of Formula I. For example, the tablet comprises from about 15 mg to about 100 mg of the compound of Formula I.

[0042] In some embodiments, the tablet is administered at least twice per day.

[0043] In some embodiments, the tablet comprises at least about 10 mg of the compound of Formula I. For example, the tablet comprises from about 15 mg to about 100 mg of the compound of Formula I.

[0044] Some embodiments further comprise administering once per day at least one tablet

(e.g., from 1 tablet to 6 tablets) comprising the pharmaceutical composition.

[0045] Some embodiments further comprise administering twice per day at least one tablet

(e.g., from 1 tablet to 6 tablets) comprising the pharmaceutical composition.

[0046] In some embodiments, each tablet further comprises from about 5 mg to about 100 mg of the compound of Formula I.

[0047] Another aspect of the present invention provides a method for treating or lessening the severity of psoriasis comprising administering to a patient in need thereof a compound of Formula I

I

or a pharmaceutically acceptable salt thereof, wherein: X is N or CR⁴;

is H or halo;

R

R' is H or an unsubstituted Ci_-2 aliphatic;

8

R' is an unsubstituted C aliphatic;

is an unsubstituted C_1-4 aliphatic;

R⁷ is a C]-3 aliphatic optionally substituted with up to 3 occurrences of F; and

R¹⁴ is H or unsubstituted Ci_-2 alkyl,

or a pharmaceutically acceptable salt thereof wherein:

at least about 25 mg of the compound of Formula I is administered to the patient at least once per day.

[0048] Some embodiments further comprise administering to the patient from about 25 mg to about 250 mg of the compound of formula I once per day or twice per day.

[0049] Some embodiments further comprise administering to the patient from about 100 mg to about 200 mg of the compound of formula I once per day or twice per day.

[0050] Some embodiments further comprise administering to the patient a chemotherapy agent.

[0051] In some embodiments, for the compound of Formula I, R is H or F.

[0052] In some embodiments, R is H or CI.

[0053] In some embodiments, each of R and R is independently selected from methyl, ft Q

ethyl, propyl, iso-propyl, butyl, or tert-butyl. For example, each of R and R is

independently selected from methyl or ethyl.

[0054] In some embodiments, R¹⁴ is H or methyl.

[0055] In some embodiments, R is an unsubstituted Ci-3 aliphatic.

[0056] In some embodiments, R is a Ci_-3 aliphatic substituted with 1-3 occurrences of F.

[0057] In some embodiments, R is a group selected from -CH₂CH3, -CH₂CF₃,

-CH₂CH₂CH₃, or -CHCH₃CH₃.

[0058] In some embodiments, the compound of Formula I is a compound selected from

Table 1.

[0059] Some embodiments further comprise administering to the patient a co-therapy. Co- therapies that are useful in the methods of the present invention may be administered concurrently with the compound of Formula I or sequentially. For example, some embodiments further comprise administering to the patient a phototherapy (e.g., psoralen and ultraviolet A [PUVA] light therapy).

[0060] Some embodiments further comprise administering to the patient an additional agent selected from a corticosteroid, cyclosporine, methotrexate, an oral retinoid, mycophenolate mofetil, thioguanine, hydroxyurea, sirolimus, azathioprine, or any combination thereof.

[0061] Some embodiments further comprise administering a chemotherapy agent to the patient. And, in some instances, the chemotherapy agent comprises methotrexate, azathioprine (e.g., Imuran), 6-mercaptopurine, cyclosporine, cyclophosphamide (e.g., Cytoxan), or any combination thereof.

[0062] In some embodiments, the chemotherapy agent comprises an injectable formulation or an oral formulation. And, in some instances, the patient is administered from about 5 mg to about 100 mg of the chemotherapy agent per month.

BRIEF DESCRIPTION OF THE DRAWINGS

[0063] The following figures are provided by way of example and are not intended to limit the scope of the claimed invention.

[0064] Fig. 1 is a bar graph showing ear disc weight for test groups described in Example 8 for the prophylactic regimen.

[0065] Fig. 2 is a bar graph showing ear disc weight for test groups described in Example 8 for the therapeutic regimen.

[0066] Fig. 3 is a bar graph showing ear disc weight for test groups described in Example 8 that were dosed throughout the course of the experiment.

[0067] Fig. 4 is a bar graph showing ear disc weight for test groups described in Example 8 that were dosed only during the sensitization phase.

DETAILED DESCRIPTION

[0068] The present invention provides methods of treating or lessening the severity of psoriasis comprising the administration of a compound of Formula I.

[0069] I. DEFINITIONS

[0070] As used herein, the term "active pharmaceutical ingredient" or "API" refers to a biologically active compound. An exemplary API include a protein kinase inhibitor (e.g., a JAK inhibitor) such as a compound of Formula I:

I

or a pharmaceutically acceptable salt thereof, wherein:

X¹ is N or CR⁴;

R² is H or halo;

R³ is H or halo;

R⁴ is H or halo;

R" is H or an unsubstituted C_1-2 aliphatic;

R⁸ is an unsubstituted C aliphatic;

R⁹ is an unsubstituted aliphatic;

R⁷ is a Cj-3 aliphatic optionally substituted with up to 3 occurrences of F; and

R¹⁴ is H or unsubstituted Ci_-2 alkyl.

[0071] As used herein, a "protein kinase inhibitor" refers to a compound that exhibits biological activity characterized by blocking the action of one or more protein kinases.

[0072] As used herein, an "excipient" is an inactive ingredient in a pharmaceutical composition. Examples of excipients include fillers or diluents, wetting agents (e.g., surfactants), binders, glidants, lubricants, disintegrants, or the like.

[0073] As used herein, a "disintegrant" is an excipient that hydrates a pharmaceutical composition and aids in tablet dispersion. Examples of disintegrants include sodium croscarmellose and/or sodium starch glycolate.

[0074] As used herein, a "diluent" or "filler" is an excipient that adds bulkiness to a pharmaceutical composition. Examples of fillers include lactose, sorbitol, celluloses, calcium phosphates, starches, sugars (e.g., mannitol, sucrose, or the like) or any combination thereof.

[0075] As used herein, a "wetting agent" or a "surfactant" is an excipient that imparts pharmaceutical compositions with enhanced solubility and/or wetability. Examples of wetting agents include sodium lauryl sulfate (SLS), sodium stearyl fumarate (SSF), polyoxyethylene 20 sorbitan mono-oleate (e.g., Tween™), or any combination thereof. [0076] As used herein, a "binder" is an excipient that imparts a pharmaceutical composition with enhanced cohesion or tensile strength (e.g., hardness). Examples of binders include dibasic calcium phosphate, sucrose, corn (maize) starch, microcrystalline cellulose, and modified cellulose (e.g., hydroxymethyl cellulose).

[0077] As used herein, a "glidant" is an excipient that imparts a pharmaceutical

compositions with enhanced flow properties. Examples of glidants include colloidal silica and/or talc.

[0078] As used herein, a "colorant" is an excipient that imparts a pharmaceutical composition with a desired color. Examples of colorants include commercially available pigments such as FD&C Blue # 1 Aluminum Lake, FD&C Blue #2, other FD&C Blue colors, titanium dioxide, iron oxide, and/or combinations thereof.

[0079] As used herein, a "lubricant" is an excipient that is added to pharmaceutical compositions that are pressed into tablets. The lubricant aids in compaction of granules into tablets and ejection of a tablet of a pharmaceutical composition from a die press. Examples of lubricants include magnesium stearate, stearic acid (stearin), hydrogenated oil, sodium stearyl fumarate, or any combination thereof.

[0080] As used herein, "friability" refers to the property of a tablet to remain intact and withhold its form despite an external force of pressure. Friability can be quantified using the mathematical expression presented in equation 1 :

[ψ - ψ )

%friabiliy = 100 x ^ ( 1 ) wherein Wo is the original weight of the tablet and W/is the final weight of the tablet after it is put through the friabilator.

[0081] Friability is measured using a standard USP testing apparatus that tumbles experimental tablets for 100 revolutions. Some tablets of the present invention have a friability of less than about 1% (e.g., less than about 0.75%, less than about 0.50%, or less than about 0.30%).

[0082] As used herein, the term "psoriasis" refers to conditions including psoriasis vulgaris, plaque-type psoriasis, guttate psoriasis, pustular psoriasis, inverse psoriasis, erythrodermic psoriasis, nail psoriasis, psoriasis of the scalp, and any combinations thereof.

[0083] II. METHODS OF TREATMENT

[0084] One aspect of the present invention provides a method for treating or lessening the severity of psoriasis comprising administering to a patient in need thereof a compound of Formula I

I

or a pharmaceutically acceptable salt thereof, wherein:

X¹ is N or CR⁴;

R² is H or halo;

R³ is H or halo;

R⁴ is H or halo;

R is

R" is H or an unsubstituted Ci_-2 aliphatic;

R⁸ is an unsubstituted C_1-4 aliphatic;

R⁹ is an unsubstituted C aliphatic;

R⁷ is a Ci-3 aliphatic optionally substituted with up to 3 occurrences of F; and

R¹⁴ is H or unsubstituted Ci_-2 alkyl.

[0085] In some embodiments, R² is H or F.

[0086] In some embodiments, R³ is H or CI.

[0087] In some embodiments, each of R⁸ and R⁹ is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl. For instance, each of R and R is independently selected from methyl or ethyl.

[0088] In some embodiments, R¹⁴ is H or methyl.

[0089] In some embodiments, R⁷ is an unsubstituted Ci_-3 aliphatic.

[0090] In some embodiments, R⁷ is a Ci_-3 aliphatic substituted with 1-3 occurrences of F.

[0091] In some embodiments, R⁷ is a group selected from -CH₂CH₃, -CH₂CF₃, -

CH₂CH₂CH₃, or -CHCH₃CH₃.

[0092] In some embodiments, the compound of Formula I is selected from Table 1 : Table 1:

[0093] In some embodiments, the compound of Formula I is administered at least once per day (e.g., q.d. or b.i.d. administration). In other embodiments, the compound of Formula I is administered at least twice per day (e.g., b.i.d. administration).

[0094] In some embodiments, the compound of Formula I is orally administered to the patient.

[0095] In some embodiments, at least about 20 mg (e.g., at least about 25 mg, at least about 50 mg, at least about 75 mg, at least about 100 mg, at least about 150 mg, at least about 200 mg, or at least about 250 mg) of the compound of Formula I is administered to the patient once per day. For example, at least about 100 mg of the compound of Formula I is administered to the patient once per day. In other examples, at least about 200 mg of the compound of Formula I is administered to the patient once per day.

[0096] In other embodiments, at least about 20 mg (e.g., at least about 25 mg, at least about 50 mg, at least about 75 mg, at least about 100 mg, at least about 150 mg, at least about 200 mg, or at least about 250 mg) of the compound of Formula I is administered to the patient twice per day.

[0097] In some embodiments, the patient in need thereof suffers from plaque-type psoriasis. For example, the patient suffers from plaque-type psoriasis for an extended period of time (e.g., 10 weeks or more, 20 weeks or more, or 24 weeks or more). In some embodiments, the patient in need thereof has a BSA >10% involved with psoriasis vulgaris and PASI score >8 OR BSA >5% involved with psoriasis vulgaris and PASI score >10. And, in some embodiments, the patient in need thereof has an sPGA score of >3. [0098] Some embodiments further comprise the administration of one or more additional therapies, i.e., co-therapies, to the patient. Optional co-therapies include anti-infiammatories, steroids, chemotherapies, phototherapy, or the like, or any combination thereof.

[0099] Some embodiments further comprise administering to the patient a phototherapy (e.g., psoralen and ultraviolet A [PUVA] light therapy).

[0100] Some embodiments further comprise administering to the patient an additional agent selected from a corticosteroid (e.g., desoximetasone, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, mometasone, triamcinolone, or any combination thereof), a cyclosporine, methotrexate, an oral retinoid, a mycophenolate mofetil, a thioguanine, a hydroxyurea, sirolimus, an azathioprine, or any combination thereof.

[0101] Co-therapies may be administered concurrently with the compound of Formula I, or sequentially.

[0102] Some embodiments further comprise administering to the patient a chemotherapy agent.

[0103] In some embodiments, the chemotherapy agent comprises methotrexate, azathioprine (e.g., Imuran), 6-mercaptopurine, cyclosporine, cyclophosphamide (e.g., Cytoxan), or any combination thereof. And, in some instances, the chemotherapy agent comprises an injectable formulation or an oral formulation. For example, the chemotherapy agent comprises an injectable formulation or an oral formulation of methotrexate.

[0104] In other embodiments, the patient is administered from about 5 mg to about 100 mg of the chemotherapy agent (e.g., methotrexate) per month. The chemotherapy agent may be administered once per month or more than once per month (e.g., twice per month, three times per month, or four times per month).

[0105] Another aspect of the present invention provides a method for treating or lessening the severity of psoriasis comprising administering to a patient in need thereof a

pharmaceutical composition comprising a compound of Formula I

I

pharmaceutically acceptable salt thereof, wherein:

X¹ is N or CR⁴;

R is H or halo; R³ is H or halo;

R⁴ is H or halo;

R" is H or an unsubstituted Ci_-2 aliphatic;

R⁸ is an unsubstituted C aliphatic;

R⁹ is an unsubstituted C aliphatic;

R¹⁴ is H or unsubstituted Ci_-2 alkyl.

[0106] In some embodiments, R² is H or F.

[0107] In some embodiments, R³ is H or CI.

_Q Q

[0108] In some embodiments, each of R and R is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl. For example, each of R⁸ and R⁹ is

independently selected from methyl or ethyl.

[0109] In some embodiments, R¹⁴ is H or methyl.

[0110] In some embodiments, R⁷ is an unsubstituted C1.3 aliphatic.

[0111] In some embodiments, R⁷ is a Ci_-3 aliphatic substituted with 1-3 occurrences of F.

[0112] In some embodiments, R⁷ is a group selected from -CH₂CH3, -CH₂CF₃,

-CH₂CH₂CH₃, or -CHCH₃CH₃.

[0113] In some embodiments, the compound of Formula I is a compound selected from Table 1.

[0114] In some embodiments, the pharmaceutical composition further comprises a topical cream.

[0115] In some embodiments, the pharmaceutical composition further comprises a tablet. And, in some of these embodiments, the tablet further comprises a diluent, a binder, a glidant, a disintegrant, a surfactant, a lubricant, or any combination thereof.

[0116] In some embodiments, the tablet is administered at least once per day (e.g., q.d. or b.i.d. administration).

[0117] In some embodiments, the tablet comprises at least about 10 mg (e.g., at least about 15 mg, at least about 20 mg, at least about 25mg, at least about 50 mg, at least about 75 mg, at least about 100 mg, at least about 150 mg, at least about 175 mg, at least about 200 mg, at least about 250 mg,) of the compound of Formula I. [0118] In some embodiments, the tablet comprises from about 5 mg to about 150 mg (e.g., from about 10 mg to about 100 mg, 20 mg to about 75 mg, or from about 25 mg to about 50 mg) of the compound of Formula I.

[0119] Some embodiments further comprise administering once per day at least one tablet (e.g., 1-6 tablets) comprising the pharmaceutical composition. For example, some embodiments further comprise administering once per day at least one table comprising from about 5 mg to about 150 mg (e.g., from about 10 mg to about 100 mg, 20 mg to about 75 mg, or from about 25 mg to about 50 mg) of the compound of Formula I.

[0120] Some embodiments further comprise administering twice per day at least one tablet comprising the pharmaceutical composition. For example, some embodiments further comprise administering twice per day at least one table comprising from about 5 mg to about 150 mg (e.g., from about 10 mg to about 100 mg, 20 mg to about 75 mg, or from about 25 mg to about 50 mg) of the compound of Formula I.

[0121] In several embodiments, the pharmaceutical composition comprises:

a. a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

X¹ is N or CR⁴;

R² is H or halo;

R is H or halo;

R⁴ is H or halo;

R" is H or an unsubstituted Ci_-2 aliphatic;

o

R is an unsubstituted C aliphatic;

R⁹ is an unsubstituted C aliphatic

R¹⁴ is H or unsubstituted Ci_-2 alkyl; b. a diluent;

c. a disintegrant;

d. a wetting agent;

e. a binder;

f. a glidant; and

g. a lubricant.

[0122] In some embodiments, X¹ is N, CH, or CF.

[0123] In some embodiments, R" is H or methyl.

[0124] In some embodiments, R is H or F.

[0125] In some embodiments, R⁸ is an unsubstituted C aliphatic, for example a straight or branched unsubstituted C aliphatic.

[0126] In some embodiments, R⁹ is an unsubstituted C_1- aliphatic, for example a straight or branched unsubstituted C aliphatic.

[0127] In some embodiments, each of R⁸ and R⁹ is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl, each of which is unsubstituted. For example, each of R⁸ and R⁹ is independently selected from methyl or ethyl.

[0128] In some embodiments, R¹⁴ is H or methyl.

7 7

[0129] In some embodiments, R is an unsubstituted Ci_-3 aliphatic. For example, R is a straight or branched unsubstituted Ci_-3 aliphatic.

[0130] In some embodiments, R⁷ is a Cj_-3 aliphatic substituted with 1-3 occurrences of F.

[0131] In some embodiments, R⁷ is a group selected from -CH₂CH₃, -CH₂CF₃,

-CH₂CH₂CH₃, or -CHCH₃CH₃.

[0132] In some embodiments, the pharmaceutical composition comprises from about 20 mg to about 250 mg (e.g., from about 25 mg to about 200 mg, from about 50 mg to about 175 mg, or from about 75 mg to about 150 mg) of a compound of Formula I.

[0133] In some embodiments, the pharmaceutical composition comprises about 25 mg of a compound of Formula I.

[0134] In some embodiments, the pharmaceutical composition comprises about 50 mg of a compound of Formula I.

[0135] In some embodiments, the pharmaceutical composition comprises about 75 mg of a compound of Formula I.

[0136] In some embodiments, the pharmaceutical composition comprises about 100 mg of a compound of Formula I.

[0137] In some embodiments, the pharmaceutical composition comprises about 150 mg of a r nnrmnH of Formula I. [0138] In some embodiments, the pharmaceutical composition comprises about 200 mg of a compound of Formula I.

[0139] In some embodiments, the pharmaceutical composition comprises from about 20 mg to about 200 mg (e.g., from about 25 mg to about 100 mg) of a compound selected from Table 1.

[0140] In some embodiments, the pharmaceutical composition comprises about 25 mg of a compound selected from Table 1.

[0141] In some embodiments, the pharmaceutical composition comprises about 50 mg of a compound selected from Table 1.

[0142] In some embodiments, the pharmaceutical composition comprises about 75 mg of a compound selected from Table 1.

[0143] In some embodiments, the pharmaceutical composition comprises about 100 mg of a compound selected from Table 1.

[0144] In some embodiments, the pharmaceutical composition comprises about 150 mg of a compound selected from Table 1.

[0145] Some embodiments further comprise the administration of one or more additional therapies to the patient.

[0146] Some embodiments further comprise administering to the patient a phototherapy (e.g., psoralen and ultraviolet A [PUVA] light therapy).

[0147] Some embodiments further comprise administering to the patient an additional agent selected from corticosteroids, cyclosporine, methotrexate, oral retinoids, mycophenolate mofetil, thioguanine, hydroxyurea, sirolimus, azathioprine, or any combination thereof.

[0148] Some embodiments further comprise administering to the patient a chemotherapy agent.

[0149] In some embodiments, the chemotherapy agent comprises methotrexate, azathioprine (e.g., Imuran), 6-mercaptopurine, cyclosporine, cyclophosphamide (e.g., Cytoxan), or any combination thereof. And, in some instances, the chemotherapy agent comprises an injectable formulation or an oral formulation. For example, the chemotherapy agent comprises an injectable formulation or an oral formulation of methotrexate.

[0150] In other embodiments, the patient is administered from about 5 mg to about 100 mg of the chemotherapy agent (e.g., methotrexate) per month. The chemotherapy agent may be administered once per month or more than once per month (e.g., twice per month, three times per month, or four times per month).

[0151] Another aspect of the present invention provides a method of treating or reducing the oMorl r r,f psoriasis comprising administering to a patient once daily or twice daily a pharmaceutical composition comprising a compound of Formula I, wherein the pharmaceutical composition is as described herein.

[0152] Some embodiments further comprise the administration of one or more additional therapies to the patient.

[0153] Some embodiments further comprise administering to the patient a phototherapy (e.g., psoralen and ultraviolet A [PUVA] light therapy).

[0154] Some embodiments further comprise administering to the patient an additional agent selected from corticosteroids, cyclosporine, methotrexate, oral retinoids, mycophenolate mofetil, thioguanine, hydroxyurea, sirolimus, azathioprine, or any combination thereof.

[0155] Some embodiments further comprise administering to the patient a chemotherapy agent.

[0156] In some embodiments, the chemotherapy agent comprises methotrexate, azathioprine (e.g., Imuran), 6-mercaptopurine, cyclosporine, cyclophosphamide (e.g., Cytoxan), or any combination thereof. And, in some instances, the chemotherapy agent comprises an injectable formulation or an oral formulation. For example, the chemotherapy agent comprises an injectable formulation or an oral formulation of methotrexate.

[0157] In other embodiments, the patient is administered from about 5 mg to about 100 mg of the chemotherapy agent (e.g., methotrexate) per month. The chemotherapy agent may be administered once per month or more than once per month (e.g., twice per month, three times per month, or four times per month).

[0158] In some embodiments, the pharmaceutical composition comprising a JAK inhibitor API (e.g., a compound of Formula I) and optionally other excipients (e.g., a diluent, a disintegrant, a wetting agent, a binder, a glidant, a colorant, a lubricant, or any combination thereof).

[0159] In some embodiments, the pharmaceutical composition comprises:

a. a compound of Formula I, as described above;

b. a diluent;

c. a disintegrant;

d. a surfactant;

e. a binder;

f. a glidant; and

g. a lubricant.

[0160] In other embodiments, the pharmaceutical composition comprises about 25 mg of a compound of Formula I, a diluent, a disintegrant, a surfactant, a binder, a glidant, and a [0161] In other embodiments, the pharmaceutical composition comprises about 50 mg of a compound of Formula I, a diluent, a disintegrant, a surfactant, a binder, a glidant, and a lubricant.

[0162] In other embodiments, the pharmaceutical compositions of the present invention also comprise one or more excipients such as diluents, disintegrants, surfactants, binders, glidants, lubricants, colorants, or fragrances, such as any of those described below.

[0163] In some embodiments, the pharmaceutical composition can comprise tablets and the tablets can be coated with a colorant and optionally labeled with a logo, other image and/or text using a suitable ink. In still other embodiments, the pharmaceutical composition can be made into tablets and the tablets can be coated with a colorant, waxed, and optionally labeled with a logo, other image and/or text using a suitable ink. Suitable colorants and inks are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the chemical stability, the physical stability, the hardness, or the biological activity of the pharmaceutical composition. The suitable colorants and inks can be any color and are water based or solvent based. In some embodiments, tablets made from the pharmaceutical composition are coated with a colorant and then labeled with a logo, other image, and/or text using a suitable ink. For example, tablets comprising a

pharmaceutical composition as described herein can be coated with about 3 wt% (e.g., less than about 6 wt% or less than about 4 wt%) of film coating comprising a colorant. The colored tablets can be labeled with a logo and text indicating the strength of the active ingredient in the tablet using a suitable ink. The colored tablets can be labeled with a logo and text indicating the strength and/or mass of the active ingredient in the tablet using a black ink (e.g., Opacode® WB, commercially available from Colorcon, Inc. of West Point, PA.).

In another embodiment, tablets made from the pharmaceutical composition are coated with a colorant, waxed, and then labeled with a logo, other image, and/or text using a suitable ink.

The colored tablets can be waxed with Carnauba wax powder weighed out in the amount of about 0.01 % w/w of the starting tablet core weight. The waxed tablets can be labeled with a logo and text indicating the strength of the active ingredient in the tablet using a suitable ink.

[0164] In some embodiments, the pharmaceutical composition comprises from about 5 wt% to about 50 wt% of a compound of Formula I, by weight of the composition; from about

25 wt% to about 50 wt% of a diluent; from about 1 wt% to about 10 wt% of a disintegrant; from about 2 wt% to about 0.3 wt% of a wetting agent (e.g., surfactant); from about 5 wt% to about 50 wt% of a binder; from about 2 wt% to about 0.05 wt% of a glidant; and from about

2 wt% to about 0.1 wt% of a lubricant. Or, the pharmaceutical composition comprises from

" —+ it ^«vt% to about 50 wt% of a compound of Formula I; from about 25 wt% to about 50 wt% of a diluent; from about 1 wt% to about 10 wt% of a disintegrant; from about 2 wt% to about 0.3 wt% of a wetting agent (e.g., surfactant); from about 5 wt% to about 50 wt% of a binder; from about 2 wt% to about 0.05 wt% of a glidant; and from about 2 wt% to about 0.1 wt% of a lubricant.

[0165] In some embodiments, the pharmaceutical composition comprises from about 30 wt% to about 50 wt% of a compound of Formula I; from about 35 wt% to about 55 wt% of microcrystalline cellulose by weight of the composition; from about 35 wt% to about 55 wt% of lactose by weight of the composition; from about 1 wt% to about 5 wt% of sodium croscarmellose by weight of the composition; from about 0.5 wt% to about 1.5 wt% of SLS by weight of the composition; from about 0.5 wt% to about 1.5 wt% of colloidal silicon dioxide by weight of the composition; and from about 0.5 wt% to about 1.0 wt% of magnesium stearate by weight of the composition.

[0166] Or, the pharmaceutical composition of the present invention comprises about 20 wt% of a compound of Formula I, about 37 wt% of microcrystalline cellulose by weight of the composition, about 37 wt% of lactose by weight of the composition, about 3 wt% of sodium croscarmellose by weight of the composition, about 1 wt% of SLS by weight of the composition, about 1 wt% of colloidal silicon dioxide by weight of the composition, and about 0.75 wt% of magnesium stearate by weight of the composition.

[0167] In some embodiments, the pharmaceutical composition of the present invention comprises about 10 wt% of a compound of Formula I; about 42 wt% of microcrystalline cellulose by weight of the composition; about 42 wt% of lactose by weight of the

composition; about 3 wt% of sodium croscarmellose by weight of the composition; about 1 wt% of SLS by weight of the composition; about 1 wt% of colloidal silicon dioxide by weight of the composition; and about 0.75 wt% of magnesium stearate by weight of the composition.

[0168] In some embodiments, the pharmaceutical composition consists of a tablet that comprises a protein kinase inhibitor API (e.g., a compound of Formula I) and other excipients

(e.g., a filler, a disintegrant, a surfactant, a binder, a glidant, a colorant, a lubricant, or any combination thereof), each of which is described above and in the Examples below, wherein the tablet has a hardness of about 5 Kp or greater. In one example, the pharmaceutical composition consists of a tablet that comprises a JA inhibitor API (e.g., a compound of

Formula I) and other excipients (e.g., a filler, a disintegrant, a surfactant, a binder, a glidant, a colorant, a lubricant, or any combination thereof), each of which is described above and in the Examples below, wherein the tablet has a hardness of about 5 Kp or greater (e.g., about

5.5 Kp or greater, about 6 Kp or greater, or about 7 Kp or greater). [0169] In some embodiments, the pharmaceutical composition comprises a compound of Formula I; a diluent; a disintegrant; a wetting agent; a binder; a glidant; and a lubricant.

[0170] In some embodiments, the diluent is lactose, sorbitol, cellulose, calcium phosphate, starch, sugar, or any combination thereof.

[0171] In some embodiments, the diluent is lactose and has a concentration of about 10 wt% or greater by weight of the composition.

[0172] In some embodiments, the disintegrant is sodium croscarmellose, sodium starch glycolate, or a combination thereof. For example the disintegrant is sodium croscarmellose and has a concentration of about 10 wt% or less by weight of the composition.

[0173] In some embodiments, the wetting agent is sodium lauryl sulfate, sodium stearyl fumarate, polyoxyethylene 20 sorbitan mono-oleate, or any combination thereof. For example, the wetting agent is sodium lauryl sulfate and has a concentration of about 10 wt% or less by weight of the composition.

[0174] In some embodiments, the binder is microcrystalline cellulose, dibasic calcium phosphate, sucrose, corn starch, modified cellulose, or any combination thereof. For example, the binder is microcrystalline cellulose and has a concentration of about 1 wt% or greater by weight of the composition.

[0175] In some embodiments, the glidant is colloidal silicon dioxide, talc, or a combination thereof. For example, the glidant is colloidal silicon dioxide and has a concentration of 2 wt% or less by weight of the composition.

[0176] In some embodiments, the lubricant is magnesium stearate, stearic acid,

hydrogenated oil, sodium stearyl fumarate, or any combination thereof. For example, the lubricant is magnesium stearate and has a concentration of less than about 2 wt% by weight of the composition.

[0177] In some embodiments, the pharmaceutical composition further comprises a colorant.

[0178] In some embodiments, the pharmaceutical composition comprises a tablet having a hardness of about 5 Kp.or greater (e.g., about 5.5 Kp or greater, about 6 Kp or greater, or about 7 Kp or greater).

[0179] In some embodiments, the tablet has a dissolution of about 50% or greater in about

30 minutes. For example, the pharmaceutical composition consists of a tablet that comprises a compound of Formula I, a diluent, a disintegrant, a surfactant, a binder, a glidant, and a lubricant, wherein the tablet has a dissolution of about 50% or greater in about 30 minutes.

[0180] Note that dissolution can be measured with a standard USP Type II apparatus that employs a dissolution media of 0.6% sodium lauryl sulfate dissolved in 900 mL of DI water, Q⁺ about 50-75 rpm at a temperature of about 37 °C. A single experimental tablet is tested in each test vessel of the apparatus. Dissolution can also be measured with a standard USP Type II apparatus that employs a dissolution media of 0.7% sodium lauryl sulfate dissolved in 900 mL of 50 mM sodium phosphate buffer (pH 6.8), stirring at about 65 rpm at a temperature of about 37 °C. A single experimental tablet is tested in each test vessel of the apparatus. Dissolution can also be measured with a standard USP Type II apparatus that employs a dissolution media of 0.5% sodium lauryl sulfate dissolved in 900 mL of 50 mM sodium phosphate buffer (pH 6.8), stirring at about 65 rpm at a temperature of about 37 °C, wherein a single experimental tablet is tested in each test vessel of the apparatus.

[0181] In some embodiments, the pharmaceutical composition comprises a compound of Formula I, a binder, a glidant, a surfactant, a lubricant, a disintegrant, and a filler, wherein each of these ingredients comprises a powder (e.g., provided as particles having a mean diameter, measured by light scattering, of about 250 μηι or less (e.g., about 150 μπι or less, about 100 μπι or less, about 50 μηι or less, about 45 μπι or less, about 40 μηι or less, or about 35 μηι or less)). For instance, the pharmaceutical composition comprises a compound of Formula I, wherein the compound of Formula I comprises a powder having a mean diameter of about 250 μηι or less (e.g., about 1 0 μηι or less, about 100 μηι or less, about 50 μπι or less, about 45 μπι or less, about 40 μπι or less, or about 35 μηι or less). In other instances, the pharmaceutical composition comprises one or more excipients selected from a binder, a glidant, a surfactant, a lubricant, a disintegrant, and a filler, wherein the excipient comprises a powder having a mean particle diameter of about 250 μηι or less (e.g., about 150 μπι or less, about 100 μηι or less, about 50 μηι or less, about 45 μηι or less, about 40 μ^ηι or less, or about 35 μπι or less)).

[0182] In some embodiments, the pharmaceutical composition comprises a tablet, a capsule, or a suspension.

[0183] In some embodiments, the pharmaceutical composition comprises:

a. about 20 wt% of a compound of Formula I by weight of the composition; b. about 37 wt% of microcrystalline cellulose by weight of the composition; c. about 37 wt% of lactose by weight of the composition;

d. about 3 wt% of sodium croscarmellose by weight of the composition; e. about 1 wt% of SLS by weight of the composition;

f. about 1 wt% of colloidal silicon dioxide by weight of the composition; and

g. about 0.75 wt% of magnesium stearate by weight of the composition.

[0184] In some embodiments, the pharmaceutical composition comprises:

a. about 10 wt% of a compound of Formula I by weight of the composition; b. about 47 wt% of microcrystalline cellulose by weight of the composition; c. about 47 wt% of lactose by weight of the composition;

f. about 1 wt% of colloidal silicon dioxide by weight of the composition; and

about 0.75 wt% of magnesium stearate by weight of the composition.

[0185] Another aspect of the present invention provides a method for treating or lessening the severity of psoriasis comprising administering to a patient in need thereof a compound of Formula I

I

or a pharmaceutically acceptable salt thereof, wherein:

X¹ is N or CR⁴;

R² is H or halo;

R³ is H or halo;

R⁴ is H or halo;

R" is H or an unsubstituted Ci_-2 aliphatic;

R is an unsubstituted C aliphatic;

R⁹ is an unsubstituted C aliphatic

R¹⁴ is H or unsubstituted Ci_-2 alkyl,

wherein at least about 25 mg of the compound of Formula I is administered to the patient at least once per day.

[0186] Some embodiments further comprise administering the compound of Formula I from 1 to 4 times per day.

[0187] In some embodiments, from about 20 mg to about 250 mg (e.g., from about 25 mg to about 200 mg, from about 50 mg to about 175 mg, or from about 75 mg to about 150 mg) of the compound of formula I is administered to the patient at least once per day (e.g., from 1 to 4 times per day).

[0188] In some embodiments, about 25 mg of the compound of formula I is administered to the patient once per day.

[0189] In some embodiments, about 50 mg of the compound of formula I is administered to the patient once per day.

[0190] In some embodiments, about 75 mg of the compound of formula I is administered to the patient once per day.

[0191] In some embodiments, about 100 mg of the compound of formula I is administered to the patient once per day.

[0192] In other embodiments, about 150 mg of the compound of formula I is administered to the patient once per day.

[0193] In other embodiments, about 200 mg of the compound of formula I is administered to the patient once per day.

[0194] In other embodiments, about 250 mg of the compound of formula I is administered to the patient once per day.

[0195] And, in some embodiments, from about 20 mg to about 250 mg (e.g., from about 25 mg to about 200 mg, from about 50 mg to about 175 mg, or from about 75 mg to about 150 mg) of the compound of formula I is administered to the patient twice per day.

[0196] Some embodiments further comprise administering to the patient a chemotherapy agent. And, in some embodiments, the chemotherapy agent is selected from methotrexate, azathioprine (e.g., Imuran), cyclophosphamide (e.g., Cytoxan), or any combination thereof.

[0197] In some embodiments, R² is H or F.

[0198] In some embodiments, each of R⁸ and R⁹ is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl. For example, each of R and R is

independently selected from methyl or ethyl.

[0199] In some embodiments, R¹⁴ is H or methyl.

[0200] In some embodiments, R⁷ is an unsubstituted Ci_-3 aliphatic.

[0201] In some embodiments, R⁷ is a Ci_-3 aliphatic substituted with 1-3 occurrences of F.

[0202] In some embodiments, R⁷ is a group selected from -CH₂CH₃, -CH₂CF₃,

-CH₂CH₂CH₃, or -CHCH₃CH₃.

[0203] In some embodiments, the compound of Formula I is a compound selected from Table 1.

[0204] In some embodiments, the compound of Formula I is administered to the patient in fm f an oral tablet. In some examples, the tablet comprises 50 mg of the compound of Formula I (e.g., Tablet 1, described below). In embodiments wherein 100 mg of the compound of Formula I is administered, either once per day (q.d.) or twice per day (b.i.d.), the administration may further include the oral administration of two 50 mg tablets (e.g., 2><Tablet 1) once per day or twice per day depending on the dosage regime. In embodiments wherein 150 mg of the compound of Formula I is administered, either once per day (q.d.) or twice per day (b.i.d.), the administration may further include the oral administration of three of the 50 mg tablets (e.g., 3 Tablet 1) once per day or twice per day depending on the dosage regime. And, in embodiments wherein 200 mg of the compound of Formula I is

administered, either once per day (q.d.) or twice per day (b.i.d.), the administration may further include the oral administration of four 50 mg tablets (e.g., 4*Tablet 1) once per day or twice per day depending on the dosage regime.

[0205] Another aspect of the present invention provides a method of treating or reducing the severity of psoriasis comprising administering to a patient 2-((2-(lH-pyrrolo[2,3-b]pyridin-3- yl)pyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide (compound no. 1) or a pharmaceutical composition comprising this compound.

[0206] In some embodiments, compound no. 1 is administered at least once per day (e.g., q.d. or b.i.d. administration). In other embodiments, compound no. 1 is administered at least twice per day (e.g., b.i.d. administration).

[0207] In some embodiments, compound no. 1 is orally administered to the patient (e.g., in the form of a tablet such as any of the tablets described above).

[0208] In some embodiments, at least about 20 mg (e.g., at least about 25 mg, at least about 50 mg, at least about 75 mg, at least about 100 mg, at least about 150 mg, at least about 200 mg, or at least about 250 mg) of compound no. 1 is administered to the patient once per day. For example, at least about 100 mg of compound no. 1 is administered to the patient once per day. In other examples, at least about 200 mg of compound no. 1 is administered to the patient once per day.

[0209] In other embodiments, at least about 20 mg (e.g., at least about 25 mg, at least about

50 mg, at least about 75 mg, at least about 100 mg, at least about 150 mg, at least about 200 mg, or at least about 250 mg) of compound no. 1 is administered to the patient twice per day.

[0210] In some embodiments, the patient in need thereof suffers from plaque-type psoriasis.

For example, the patient suffers from plaque-type psoriasis for an extended period of time

(e.g., 10 weeks or more, 20 weeks or more, or 24 weeks or more). In some embodiments, the patient in need thereof has a BSA >10% involved with psoriasis vulgaris and PASI score >8

OR BSA >5% involved with psoriasis vulgaris and PASI score >10. And, in some ⁱ» .Kr.Hirr._ents, the patient in need thereof has an sPGA score of >3. [0211] Some embodiments further comprise the administration of one or more additional therapies, i.e., co-therapies, to the patient. Optional co-therapies include anti-infiammatories, steroids, chemotherapies, phototherapy, or the like, or any combination thereof.

[0212] Some embodiments further comprise administering to the patient a phototherapy (e.g., psoralen and ultraviolet A [PUVA] light therapy).

[0213] Some embodiments further comprise administering to the patient an additional agent selected from a corticosteroid (e.g., desoximetasone, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, mometasone, triamcinolone, or any combination thereof), a cyclosporine, methotrexate, an oral retinoid, a mycophenolate mofetil, a thioguanine, a hydroxyurea, sirolimus, an azathioprine, or any combination thereof.

[0214] Co-therapies may be administered concurrently with compound no. 1, or

sequentially.

[0215] Some embodiments further comprise administering to the patient a chemotherapy agent.

[0216] In some embodiments, the chemotherapy agent comprises methotrexate, azathioprine (e.g., Imuran), 6-mercaptopurine, cyclosporine, cyclophosphamide (e.g., Cytoxan), or any combination thereof. And, in some instances, the chemotherapy agent comprises an injectable formulation or an oral formulation. For example, the chemotherapy agent comprises an injectable formulation or an oral formulation of methotrexate.

[0217] In other embodiments, the patient is administered from about 5 mg to about 100 mg of the chemotherapy agent (e.g., methotrexate) per month. The chemotherapy agent may be administered once per month or more than once per month (e.g., twice per month, three times per month, or four times per month).

[0218] III. ADMINISTRATIONS

[0219] In another aspect, the invention also provides a method of treating or lessening the severity of psoriasis in a patient in need thereof comprising administering to said patient one of the compositions as defined herein.

[0220] Some embodiments further comprise the administration of one or more additional therapies to the patient.

[0221] Some embodiments further comprise administering to the patient a phototherapy (e.g., psoralen and ultraviolet A [PUVA] light therapy).

[0222] Some embodiments further comprise administering to the patient an additional agent selected from corticosteroids, cyclosporine, methotrexate, oral retinoids, mycophenolate mofetil, thioguanine, hydroxyurea, sirolimus, azathioprine, or any combination thereof. [0223] Some embodiments further comprise administering to the patient a chemotherapy agent.

[0224] In some embodiments, the chemotherapy agent comprises methotrexate, azathioprine (e.g., Imuran), 6-mercaptopurine, cyclosporine, cyclophosphamide (e.g., Cytoxan), or any combination thereof. And, in some instances, the chemotherapy agent comprises an injectable formulation or an oral formulation. For example, the chemotherapy agent comprises an injectable formulation or an oral formulation of methotrexate.

[0225] In other embodiments, the patient is administered from about 5 mg to about 100 mg of the chemotherapy agent (e.g., methotrexate) per month. The chemotherapy agent may be administered once per month or more than once per month (e.g., twice per month, three times per month, or four times per month).

[0226] Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient at least once per day the composition comprising about 20 mg or greater (e.g., about 25 mg) of a compound of Formula I.

[0227] Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient at least once per day the composition comprising about 45 mg or greater (e.g., about 50 mg) of a compound of Formula I.

[0228] Another aspect of the present invention provides a method of administering a pharmaceutical composition comprising orally administering to a patient at least once per day at least one tablet comprising a pharmaceutical composition comprising:

a. a compound of Formula I;

b. a diluent;

c. a binder;

d. a glidant;

e. a disintegrant;

f. a surfactant; and

g. a lubricant.

[0229] In several embodiments, the tablet comprising the pharmaceutical composition comprising a compound of Formula I, the diluent, the binder, the glidant, the disintegrant, the surfactant, and the lubricant is orally administered to the patient once per day or twice per day (e.g., about every 12 hours). In other embodiments, the tablet comprising the

pharmaceutical composition comprising a compound of Formula I, the diluent, the binder, the glidant, the disintegrant, the surfactant, and the lubricant is orally administered to the patient twice per day.

[0230] In some embodiments, the tablet comprises about 25 mg or greater of a compound of Formula I.

[0231] In some instances, the tablet comprises about 25 mg of a compound of Formula I. In other instances, the tablet comprises about 50 mg of a compound of Formula I.

[0232] Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient at least once per day the composition comprising about 20 mg or greater of a compound of Formula I.

[0233] Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient at least once per day the composition comprising about 25 mg of a compound of Formula I.

[0234] Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient at least once per day the composition comprising about 50 mg of a compound of Formula I.

[0235] Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient twice per day the

composition comprising a compound of Formula I.

[0236] Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient twice per day the

composition comprising about 25 mg of a compound of Formula I.

[0237] Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient twice per day the

composition comprising about 50 mg of a compound of Formula I.

[0238] Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient twice per day the

composition comprising about 100 mg of a compound of Formula I.

[0239] Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient twice per day the

composition comprising about 150 mg of a compound of Formula I.

[0240] Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient a pharmaceutical

composition once every 12 hours. The composition comprises about 25 mg or greater of a compound of Formula I. [0241] Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient once every 12 hours, about 50 mg or greater of a compound of Formula I.

[0242] Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient once every 12 hours, about 100 mg or greater of a compound of Formula I.

[0243] Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient once every 12 hours, about 150 mg or greater of a compound of Formula I.

[0244] In still other aspects of the present invention, a pharmaceutical composition as described herein is orally administered to a patient once every 24 hours.

[0245] Another aspect of the present invention provides a method of administering a pharmaceutical composition comprising orally administering to a patient at least once per day at least one tablet comprising a pharmaceutical composition comprising a compound of Formula I, a diluent, a binder, a glidant, a disintegrant, a surfactant, and a lubricant, each of which is described above and in the Examples below, wherein the composition comprises about 25 mg or greater (e.g., at least 35 mg, at least 40 mg, or at least 45 mg) of a compound of Formula I.

[0246] In some embodiments, the present invention provides a method of administering a pharmaceutical composition comprising orally administering to a patient at least one tablet comprising:

a. about 25 mg of a compound of Formula I;

b. a diluent;

c. a disintegrant;

d. a wetting agent;

e. a binder;

f. a glidant; and

g- a lubricant.

[0247] In some embodiments, the present invention provides a method of administering a pharmaceutical composition comprising orally administering to a patient at least one tablet comprising:

a. about 50 mg of a compound of Formula I; b. a diluent;

c. a disintegrant;

d. a surfactant; e. a binder;

f. a glidant; and

g. a lubricant.

[0248] In some embodiments, the present invention provides for a method of orally administering the pharmaceutical composition described herein once a day. In other embodiments, the present invention provides for a method of orally administering the pharmaceutical composition described herein twice a day.

[0249] Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient at least once per day at least one tablet comprising about 25 mg or greater of a compound of Formula I, a diluent, a binder, a glidant, a disintegrant, a surfactant, and a lubricant. In some embodiments, the tablet is orally administered to the patient once per day. In other embodiments, the administration comprises orally administering to a patient twice per day at least one tablet comprising about 25 mg or greater of a compound of Formula I, a diluent, a binder, a glidant, a disintegrant, a surfactant, and a lubricant. Some tablets useful in this method comprise about 50 mg of a compound of Formula I. In another method, the administration includes orally administering to a patient twice per day at least one tablet comprising about 50 mg or greater of a compound of Formula I, a diluent, a binder, a glidant, a disintegrant, a surfactant, and a lubricant.

[0250] In one embodiment, the method of administering a pharmaceutical composition includes orally administering to a patient at least once per day at least one tablet comprising a pharmaceutical composition containing from about 20 mg to about 55 mg of a compound of

Formula I; and a diluent, a binder, a glidant, a disintegrant, a surfactant, and a lubricant.

[0251] In another embodiment, the method of administering a pharmaceutical composition includes orally administering to a patient once per day at least one tablet comprising a pharmaceutical composition containing a compound of Formula I, a filler, a binder, a glidant, a disintegrant, a surfactant, and a lubricant, each of which is described above and in the

Examples below, wherein the compound of Formula I is present in an amount of about 25 mg or greater (e.g., about 35 mg or greater, about 40 mg or greater, about 45 mg or greater, about

75 mg or greater, about 100 mg or greater, about 150 mg or greater, or about 250 mg or greater). In another example, the method of administering a pharmaceutical composition includes orally administering to a patient once per day a plurality of tablets (e.g., two tablets, three tablets, four or five tablets), wherein each tablet comprises a pharmaceutical

composition comprising a compound of Formula I, a filler, a binder, a glidant, a disintegrant, o ο,,,-ίΌ^αη^ and a lubricant, wherein the compound of Formula I is present in an amount of about 25 mg or greater (e.g., about 35 mg or greater, about 40 mg or greater, about 45 mg or greater, about 75 mg or greater, about 150 mg or greater, or about 250 mg or greater).

[0252] In another embodiment, the method of administering a pharmaceutical composition includes orally administering to a patient twice per day at least one tablet comprising a pharmaceutical composition containing a compound of Formula I, a filler, a binder, a glidant, a disintegrant, a surfactant, and a lubricant, each of which is described above and in the Examples below, wherein the compound of Formula I is present in an amount of about 25 mg or greater (e.g., about 35 mg or greater, about 40 mg or greater, about 45 mg or greater, about 50 mg or greater, about 75 mg or greater, about 150 mg or greater, or about 250 mg or greater). In another example, the method of administering a pharmaceutical composition includes orally administering to a patient twice per day a plurality of tablets (e.g., two tablets, three tablets, four tablets or five tablets), wherein each tablet comprises a pharmaceutical composition comprising a compound of Formula I, a filler, a binder, a glidant, a disintegrant, a surfactant, and a lubricant, wherein the compound of Formula I is present in an amount of about 20 mg or greater (e.g., about 25 mg or greater, about 30 mg or greater, about 35 mg or greater, about 45 mg or greater, about 75 mg or greater, about 150 mg or greater, or about 250 mg or greater) per tablet. In embodiments wherein a plurality of tablets are administered, each of the tablets may comprise about the same amount of a compound of Formula I or at least two of the tablets may comprise different amounts of the compound of Formula I.

[0253] It will also be appreciated that the compound and pharmaceutically acceptable compositions of the present invention can be employed in combination therapies, that is, the compound and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated".

[0254] In one embodiment, the additional agent is selected from a mucolytic agent, bronchodialator, an anti-biotic, an anti-infective agent, an anti-inflammatory agent, a protein kinase inhibitor other than a compound of Formula I, or a nutritional agent (e.g., nutraceutical or vitamin).

[0255] In another embodiment, the additional agent is an anti-inflammatory agent, i.e., an agent that can reduce the inflammation in the lungs. Exemplary such agents useful herein include ibuprofen, docosahexanoic acid (DHA), sildenafil, inhaled glutathione, pioglitazone, hydroxychloroquine, or simavastatin.

[0256] In another embodiment, the additional agent is a nutritional agent. Exemplary agents include vitamin a, vitamin b, vitamin c, vitamin e, pancrelipase (pancreating enzyme replacement), including Pancrease®, Pancreacarb®, Ultrase®, or Creon®, Liprotomase® (formerly Trizytek®), Aquadeks®, or glutathione inhalation. In one embodiment, the additional nutritional agent is pancrelipase.

[0257] IV. EXAMPLES

[0258] In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.

[0259] Example 1: Analytical Methods Used

[0260] (A) HPLC on C18 column. Mobile phase was acetonitrile/water/TFA (60:40:0.1). Flow rate was 1.0 mL/min. Detection at wavelength of 230 nm. Run time was 25-26 minutes.

[0261] (B) HPLC on C18 column. Mobile phase was acetonitrile/water/TFA (90: 10:0.1). Flow rate was 1.0 mL/min. Detection at wavelength of 230 nm.

[0262] (C) HPLC on a Waters XBridge Phenyl column, 4.6 x 150 mm, 3.5 μπι. Mobile phase A was water/1 M ammonium formate, pH 4.0 (99: 1). Mobile phase B was

acetonitrile/water/ 1M ammonium formate, pH 4.0 (90:9:1). Gradient 5 % to 90 % B in 15 minutes. Total run time 22 minutes. Flow rate 1.5 mL/min. Detection at UV, 245 nm.

T = 25 °C.

[0263] (D) HPLC on a Waters XBridge Phenyl column, 4.6 x 150 mm, 3.5 μπι. Mobile phase A was water/1 M ammonium formate, pH 4.0 (99: 1). Mobile phase B was

acetonitrile/water/ 1M ammonium formate, pH 4.0 (90:9: 1). Gradient 15% to 90 % B in 15 minutes. Total run time 22 minutes. Flow rate 1.5 mL/min. Detection at UV, 220 nm.

T = 35 °C.

[0264] Example 2: Preparation of Compounds of Formula I [0265] General Synthetic Scheme

[0266] The Boc-protected amino acid starting material (1) undergoes amidation in the presence of an activating agent, a coupling reagent, and the acid salt of the amine HNR⁷R¹⁷ to generate the Boc-protected amide intermediate (2). The amide intermediate (2) is

deprotected under acidic conditions and reacted with the halogenated heteroaryl (3) to generate the aminoheteroaryl intermediate (4). Boronated azaindole (5) is coupled with the aminoheteroaryl intermediate (4) under cross-coupling condition to generate the compound of Formula I.

[0267] Example 3: Synthesis of 2-(2-(lH-pyrrolo[2,3-b]pyridin-3-yI)pyriinidin-4- ylamino)-2-methyI-N-(2,2,2-trifluoroethyl)butanamide

[0268] 3-bromo-l H-pyrrolo[2, 3-b]pyridine:

[0269] Commercially available 7-Azaindole (6.9 kg, 58.4 moles) was added to a 200L glass-lined reactor containing 52.6 kg DMF. A solution of Br₂ in DMF (9.7 kg Br₂ in 14.7 kg DMF) was added drop wise to maintain the mixture temperature of about 0-10 °C. After the addition was complete, the temperature was maintained at about 0-10 °C. The completeness of the reaction was measured by HPLC (method A) with sample aliquots after 30 minutes. The reaction was considered complete when the 7-azaindole was less than 3% (after about 2 hours and 40 minutes). Typical retention time for 3-bromo-lH-pyrrolo[2,3-b]pyridine was 3.228 minutes.

[0270] The reaction was quenched with 10% aqueous solution of NaHS0₃ (17.5 kg) while maintaining the temperature below 15 °C. A saturated aqueous solution of NaHC0₃ (61.6 kg) below 25 °C was added to adjust the pH to about 7 to 8. After neutralization, the mixture was transferred into a 50L vacuum filter and filtered. The resultant cake was washed with water (18 kg) and then petroleum ether (12 kg). The cake was dried in a tray dryer at about 50-60 °C until the water content detected by KF (Karl Fisher reaction) was less than 0.8%. A yellow solid resulted (10.3 kg, 99.1% purity as measured by HPLC (method A), 89.6% yield of 3-bromo-lH-pyrrolo[2,3-b]pyridine).

[0271] 3-bromo-l-tosyl-lH-pyrrolo[2, 3-bJpyridine:

[0272] 3-bromo-lH-pyrrolo[2,3-b]pyridine (10.7 kg, 54.3 moles) was added to 94.3 kg of THF in a 200L glass-lined reactor. The solid was dissolved completely by stirring. After the mixture was cooled to about 10-15 °C, NaH (3.4 kg, 85 moles) was added in portions (about 200-250 g each portion) every 3 to 5 minutes while venting any ¾ gas released by the reaction. After the addition of NaH, the mixture was stirred for one hour while maintaining the temperature of about 10-20 °C. 4-methylbenzenesulfonylchloride (12.4 kg, 65.0 moles) was added at a rate of 0.5 kg/10 minutes at about 10-20 °C. After the addition was complete, the temperature was maintained at about 10-20 °C. The completeness of the reaction was measured by HPLC (method A) with sample aliquots after 30 minutes. The reaction was considered complete when the peak area of 3-bromo-lH-pyrrolo[2,3-b]pyridine was less than 1% (after about 1.5 hours). Typical retention time for 3-bromo-l-tosyl-lH-pyrrolo[2,3- b]pyridine was 20.2 minutes.

[0273] The reaction was quenched with water (10.7 kg) while maintaining the temperature below 20 °C. Dichloromethane (41.3 kg) was added to the mixture. Then 3% HC1 acid

(42.8 kg) was added into the mixture while maintaining the temperature below 25 °C. After the addition, the phases were allowed to separate for 0.5 hour. The aqueous phase was extracted twice with dichloromethane. During each extraction, the mixture was stirred for 15 minutes and then held for 15 minutes. All the organic phases were combined. The combined organic phases were washed with 3% HC1 acid (33.4 kg) and water (40 kg). During each wash, the mixture was stirred for 15 minutes and then held for 30 minutes.

[0274] The mixture was transferred into a 50L vacuum filter and filtered through silica gel

(3 kg). The cake was washed with dichloromethane (35 kg) twice. The filtrate and washings were combined. The organic phase was concentrated below 40 °C under vacuum of a

m_an -0.085 MPa until 10L mixture remained. Petroleum ether (9 kg) was added into the residue. The mixture was stirred until it was homogeneous. The slurry was transferred into a 50L vacuum filter and filtered. The cake was washed with petroleum ether (9 kg). A light brown solid resulted (17 kg, 99.7% purity as measured by HPLC analysis (method A), 94% yield of 3-bromo-l-tosyl-lH-pyrrolo[2,3-b]pyridine).

[0275] l-tosyl-lH-pyrrolo[2, 3-b ]pyridin-3-ylboronic acid:

[0276] THF (28.5 kg) and 3-bromo-l-tosyl-lH-pyrrolo[2,3-b]pyridine (4 kg) were added to a 72L flask. The mixture was stirred until the solid dissolved completely. Triisopropyl borate (3.2 kg) was added and the mixture was cooled to below -80 °C. n-BuLi (4.65 kg) was added drop wise at a rate of about 0.6-0.9 kg/hour maintaining the temperature of about -80 to -90 °C. After the addition, the temperature was maintained at about -80 to -90 °C. The completeness of the reaction was measured by HPLC (method A) with sample aliquots after 30 minutes. The reaction was considered complete when the peak area of 3-bromo-l-tosyl- lH-pyrrolo[2,3-b]pyridine was less than 4%. Typical retention time for 1-tosyl-lH- pyrrolo[2,3-b]pyridin-3-ylboronic acid was 4.6 minutes. Extra triisopropyl borate and n-BuLi was added to lower the peak area of 3-bromo-l-tosyl-lH-pyrrolo[2,3-b]pyridine.

[0277] Water (2 kg) was slowly added to the mixture to quench the reaction. The mixture temperature returned to about 15-25 °C. The mixture was transferred to a 50L reactor to be concentrated below 40 °C under vacuum of a pressure less than -0.08 MPa until no THF distilled out. The residue was dissolved into water (25 kg) and 10% aqueous NaOH solution (26 kg). The mixture was stirred until the solid dissolved completely. The mixture was transferred into a vacuum filter and filtered. The filtrate was extracted twice with MTBE (21 kg each) at about 20-30 °C. During each extraction, the mixture was stirred 15 minutes and held 15 minutes. HC1 acid (28L) was added into the aqueous phase to adjust the pH to between 3 and 4 while maintaining the temperature of about 10-20 °C. The mixture was stirred at about 10-15 °C for 1 hour. The mixture was transferred into a centrifuge and filtered. The resultant cake after filtering was washed with water (5 kg) and petroleum ether (5 kg). The cake was dried at 35-45 °C until the LOD (loss on drying) was less than 3%. An off-white solid resulted (2.5 kg and 98.8% purity as measured by HPLC analysis (method A), 69.4% yield of l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-ylboronic acid).

[0278] 3-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-l-tosyl-lH-pyrrolo[2, 3-b Jpyridine:

[0279] Dichloromethane (165.6 kg) and pinacolate alcohol (3.54 kg) was added to a 200L glass-lined reactor. The mixture was stirred until the solid dissolved completely. Then, l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-ylboronic acid (8.65 kg) was added in portions (2 kg every 5 minutes) while maintaining the temperature of about 20-30 °C. After the addition, ^t -rature was maintained at about 20-30 °C while stirring. The completeness of the reaction was measured by HPLC (method B) with sample aliquots every 60 minutes. The reaction was considered complete when the peak area of 3 l-tosyl-lH-pyrrolo[2,3-b]pyridin- 3-ylboronic acid was less than 1%. Typical retention time for 3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridine) was 6.4 minutes.

[0280] The mixture was filtered through silica gel (3 kg). The cake was rinsed twice with dichloromethane (15 kg each rinse). The filtrate was combined with the washing liquids, and then concentrated below 30 °C under vacuum at a pressure less than -0.08 MPa until no fraction distilled out. Solvent was continued to be removed by vacuum for 2 hours.

Isopropanol (17.2 kg) was added to the residue. The mixture was heated to reflux at about 80-85 °C. The mixture refluxed for 30 minutes until the solid dissolved completely. The mixture was cooled below 35 °C, and then to about 0-10 °C. The mixture crystallized at 0-10 °C for 2 hours and then filtered. After filtration, the resultant cake was dried at about 35-45 °C until the water content detected by KF (Karl Fisher reaction) was less than 0.5% and the LOD (loss on drying) was less than 0.5%. An off-white solid resulted (8.8 kg and 99.7% purity as measured by HPLC analysis (method B), 81.5% yield of

3-(4,4,5,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 -tosyl- 1 H-pyrrolo[2,3-b]pyridine).

[0281] (R)-2-methyl-2-(2-(l-tosyl-lH^yrrolo[2 -b]pyridin-3-yl)pyrimidin-4- ylamino)butanoic acid:

[0282] Tripotassium phosphate (K₃P0₄) (7.20 kg, 3 equiv.) was mixed with three volumes of water (9.0 kg). The mixture was agitated for at least 20 minutes, cooled to a temperature of < 30 °C and added to acetonitrile (16.8 g, 7 volumes) into a 120 L reactor. The resultant mixture was agitated. 3.0 kg (11.3 moles, 1.0 equiv.) of (R)-2-(2-chloropyrimidin-4- ylamino)-2-methylbutanoic acid hydrochloride were added to the reaction mixture in the reactor while maintaining a temperature <30 °C. The mixture was agitated for at least 20 minutes. 5.16 kg (13.0 moles, 1.15 equiv.) of 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridine were then added to the reactor. The reaction mixture was agitated and de-gassed with N₂ sparging for at least 30 minutes. The mixture was heated to 65 ± 5 °C.

[0283] In a separate vessel, 0.075 kg (0.03 equiv.) of palladium(II) acetate was mixed with

4.80 kg (2 volumes) of de-gassed acetonitrile (CH₃CN). This mixture was agitated until homogenous. 0.267 kg (1.02 moles, 0.09 equiv.) of triphenylphosphine (PPh₃) was added and the resultant mixture was agitated for at least 30 minutes at 20 ± 5 °C. The palladium(II) acetate/PPh3/ CH₃CN mixture was then added to the reactor above while maintaining the nitrogen purge. The reactor contents were heated to 75 ± 5 °C for at least 17 hours under r>itr-_{nn n} ^urge. After 5 hours the conversion was shown to be about 86% complete as measured by HPLC analysis (method C) of a 1.0 mL aliquot. Typical retention times are 6.2 minutes for (R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid hydrochloride and 10.6 minutes for (R)-2-methyl-2-(2-(l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4- ylamino)butanoic acid. Additional catalyst and 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridine (900 g, 2.26 moles, 0.2 equiv.) were then added to the reaction mixture and the mixture was stirred. After an additional 12 hours, the reaction was shown to be 99.7% complete as measured by HPLC analysis (method C) of a 1.0 mL aliquot. The additional catalyst added above was prepared by dissolving 37.5 g palladium(II) acetate in 1 volume of acetonitrile (which was de-gassed for 20 minutes), and then adding 133.5 g of triphenylphosphine.

[0284] (R)-2-(2-(lH-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-m

acid:

[0285] A solution of 4N aqueous KOH, which was previously prepared with 6.0 kg of KOH in 27.0 kg of water at a rate to control the temperature rise, was added to the reactor above and the reaction was heated to 75 ± 5 °C for at least 5 hours while agitating the mixture. An aliquot of about 1.0 mL was removed from the reaction mixture and analyzed by HPLC (method C) to show 98.6% R)-2-(2-(lH-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2- methylbutanoic acid and 1.4% (R)-2-methyl-2-(2-(l-tosyl-lH-pyrrolo[2,3-b]pyridin-3- yl)pyrimidin-4-ylamino)butanoic acid. Typical retention times are 10.6 minutes for (R)-2- methyl-2-(2-(l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)butanoic acid and 5.5 minutes for (R)-2-(2-(lH-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2- methylbutanoic acid.

[0286] 15.0 kg (5 volumes) of water was added to the reactor. The reaction mixture was cooled to 35 ± 5 °C. Isopropyl acetate (7.8 g, 3 volumes) was added, and the reaction mixture was agitated for at least 5 minutes. The reaction mixture was filtered through a 4-cm pad of celite in an 18-inch Nutsche filter. The reactor was rinsed with 9.0 kg of water and the water was then used to rinse the celite pad. The aqueous and organic phases were separated.

0.9 kg of Darco G-60 activated carbon (30% w/w) was added to the aqueous phase in a

120-liter reactor. The pH of the mixture was adjusted to less than 1.0 with concentrated HC1 solution at 25 ± 10 °C and held for at least 4 hours. If necessary, the pH was readjusted with

6N NaOH. The mixture was then filtered through a Nutshce filter, which was equipped with a filter cloth, and the solids were rinsed with 6.0 kg (2 volumes) of IN HC1. The filter cake was maintained under positive pressure of nitrogen for at least 30 minutes. The HC1 filtrate was agitated and heated to 25 ± 5 °C. 0.9 kg of Darco G-60 activated carbon was added to tho ΗΠ filtrate and the mixture was stirred for at least 4 hours. The mixture was then filtered through a Nutshce filter, which was equipped with a filter cloth, and the solids were washed with 6.0 kg (2 volumes) of IN HC1. The second filter cake was maintained under positive pressure of nitrogen for at least 30 minutes. The HC1 filtrate was again agitated and heated, charcoal was added and filtering step was repeated with a Nutshce filter, which was equipped with a 0.45 um in-line filter between the Nutsche filter and the receiver flask, to yield a third filter cake and a final filtrate. The solids were washed with 6.0 kg of IN HC1. The third filter cake was maintained under positive pressure of nitrogen for at least 30 minutes.

[0287] The pH of the final filtrate was adjusted to between 4.5 and 5.0 using 6N NaOH while the temperature was maintained between 25 ± 5 °C. If necessary, the pH was readjusted using IN HC1. The final filtrate was then cooled to 5 ± 5 °C and agitated for at least 2 hours. The mixture was filtered was filtered with a Nutshce filter, which was equipped with a filter cloth. The solids were rinsed with 6.0 kg (2 volumes) of water. The final filter cake was maintained under positive pressure of nitrogen for at least 30 minutes.

[0288] The wet solids (i.e., filter cakes) were dried in a drying oven at < 60 °C under vacuum, with a nitrogen purge, over 5 days to yield 3.561 kg of (R)-2-(2-(lH-pyrrolo[2,3- b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoic acid (yield of 102%).

[0289] 2-(2-(lH-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methy

trifluoroethyl)butanamide

[0290] Diisopropylethylamine (DIEA) (3.61 kg, 28.1 moles, 2.5 equiv.) was added to

(R)-2-(2-(lH-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoic acid

(3.5 kg, 11.24 moles, 1.0 equiv.) in 7 volumes (32.6 kg) of dichloromethane (CH₂C1₂ or

DCM) while keeping the temperature at < 30 °C. Water (0.103 kg) was added to make

5.5 ± 0.5% total water content for the reaction system, and the mixture was stirred at < 30 °C for at least 30 minutes. The reaction mixture was cooled to 0 ± 5 °C. Propylphosphonic anhydride solution (17.9 kg, 28.1 moles, 2.5 equiv.) was added to the mixture while maintaining the temperature below 20 °C. The mixture was agitated for at least an hour keeping the temperature at 20 ± 5 °C, then 2,2,2-trifluoroethylamine (1.68 kg, 16.86moles,

1.5 equiv.) was added while maintaining the temperature below 20 °C. The reaction mixture was warmed to 25 ± 5 °C and agitated for 5 hours while holding the temperature. A 1.OmL aliquot was removed and the reaction was determined to be 100% complete. Water (17.5 kg,

5 volumes) was added to the reaction mixture, and the resultant mixture was agitated for at least 30 minutes while maintaining the temperature below 30 °C.

[0291] The mixture was concentrated under vacuum with a rotary evaporator at a temperature < 45 °C. Isopropylacetate (1.55 kg, 0.5 volumes) was added to the concentrated anⁱi^pn c solution, and the pH of the solution was adjusted to 7.5-8.0 using 6N NaOH solution at < 35 °C. The mixture was cooled to 10 ± 5 °C and stirred at for at least one hour. If necessary, 6N HC1 was added to readjust the pH of mixture to 7.5-8.0. The resultant slurry was filtered and washed with water (10.5 kg, 3 volumes). The filter cake was maintained under positive pressure of nitrogen for at least 30 minutes. The wet cake was dissolved in methanol (44.7 kg, 12 volumes) by agitation, and the solution was treated with PL-BnSH MP- Resin (BNSHMP) polymer resin (0.235 kg of 5 % wt of resin) at 25 ± 5 °C. After agitating at 25 ± 5 °C for at least 12 hours, the mixture was filtered. The solids were washed with methanol (2.77 kg, 1 volume). The filtrate was concentrated under vacuum in a rotary evaporator at a temperature < 50 °C. The filtrate was not concentrated to dryness. The concentrated filtrate was allowed to sit at room temperature for about 2.5 days. The mixture was then stirred until homogeneous and heated to 40 °C, followed by slow addition of preheated water (56.1 kg at 45 °C) while maintaining a temperature of 45 ± 5 °C. After the mixture was spun for 1 hour, the remaining methanol was concentrated further, but not concentrated to dryness. The resultant mixture was cooled down to at least 5 ± 5 °C and agitated for at least 2 hours. The product was filtered, and the solids were washed with water (10.5 kg, 3 volumes). The filter cake was maintained under positive pressure of nitrogen for at least 30 minutes. The isolated product was dried to a constant weight under vacuum in a drying oven at a temperature of < 70 °C with a nitrogen purge to yield 2-(2-(lH-pyrrolo[2,3- b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide (4.182 kg, white powder, 0.18% water content, 98.6% AUC using HPLC (method D)). Typical retention times are 4.4 minutes for (R)-2-(2-(lH-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4- ylamino)-2-methylbutanoic acid and 6.2 minutes for 2-(2-(lH-pyrrolo[2,3-b]pyridin-3- yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide.

[0292] Then general scheme, provided in Example 2 and the experimental description provided in Example 3 were used to generate the compounds in Table 1.

[0293] Example 4: JAK3 Inhibition Assay

[0294] Compounds were screened for their ability to inhibit JAK3 using the assay shown below. Reactions were carried out in a kinase buffer containing 100 mM HEPES (pH 7.4), 1 mM DTT, 10 mM MgCl₂, 25 mM NaCl, and 0.01% BSA. Substrate concentrations in the assay were 5 μΜ ATP (200 uCi^mole ATP) and 1 μΜ poly(Glu)₄Tyr. Reactions were carried out at 25°C and 1 nM JAK3.

[0295] To each well of a 96 well polycarbonate plate was added 1.5 μΐ of a compound of Formula I along with 50 μΐ of kinase buffer containing 2 μΜ poly(Glu)₄Tyr and 10 μΜ ATP. This was then mixed and 50 μΐ of kinase buffer containing 2 nM JAK3 enzyme was added to start the reaction. After 15 minutes at room temperature (25 °C), the reaction was stopped with 50 μΐ of 20% trichloroacetic acid (TCA) that also contained 0.4 mM ATP. The entire contents of each well were then transferred to a 96 well glass fiber filter plate using a TomTek Cell Harvester. After washing, 60 μΐ of scintillation fluid was added and P incorporation detected on a Perkin Elmer TopCount.

[0296] Example 5: JAK2 Inhibition Assay

[0297] The assays were as described above in Example 4 except that JAK-2 enzyme, at a concentration of 5 nm, was used, the final poly(Glu)₄Tyr concentration was 15 μΜ, and final ATP concentration was 12 μΜ.

[0298] The data generated from these assays is provided in Table 2, below:

Table 2: Inhibition data for selected compounds of Formula I.

[0299] Example 6: JAK3 Cellular Inhibition Assay

[0300] HT-2 clone A5E cells (ATCC Cat. # CRL- 1841 ) were grown and maintained at 37 °C in a humidified incubator in cell culture medium (RPMI 1640 supplemented with 2 mM L-glutamine adjusted to contain 1.5 g/L sodium bicarbonate, 4.5 g/L glucose, 10 mM HEPES, 1.0 mM sodium pyruvate, 0.05 mM 2-mercaptoethanol, 10% fetal bovine serum, and 10% by volume rat T-STIM factor [Fisher Scientific Cat # CB401 15] with Con A). On the day of the experiment, HT-2 cells were washed, resuspended at a density of 5 x 10⁶ cells per ml in fresh cell culture medium without T-STIM and incubated for 4 hours without T-STIM. After four hours, 50 μΐ (0.25 x 10⁶ cells) of the resuspended cells were added to each well of a 96 well plate. Serial dilutions of compounds were made in DMSO and then added to RPMI. 100 μΐ of the diluted compounds were added to each well and the plates were incubated for 1 hour at 37°C. 50 μΐ of recombinant murine interleukin-2 (rmIL-2) at 40ng/ml (R & D systems Inc. Cat # 402-ML) was added and the plates were incubated for 15 minutes at 37°C.

[0301] The plates were then centrifuged for 5 minutes at 1000 rpm, the supernatant was aspirated and 50 μΐ of 3.7% formaldehyde in phosphate buffered saline (PBS) was added per well. The plates were incubated for 5 minutes at room temperature on a plate shaker. The plates were again centrifuged at 1000 rpm for 5 minutes. The supernatant was aspirated, 50 μΐ of 90% methanol was added to each well, and the plate was incubated on ice for 30 minutes. The supernatant was aspirated and the plate washed with PBS. 25 μΐ per well of 1 : 10 diluted Phospho STAT-5 (Y694) PE conjugated antibody (PS-5 PE antibody; Becton- Dickinson Cat. # 61256) was added to the plates and the plates were incubated for 45 minutes at room temperature on a plate shaker. 100 μΐ PBS was added and the plates were centrifuged. The supernatant was aspirated and the cells resuspended in 100 μΐ PBS. The plate was then read on a 96 well FACS reader (Guava PCA-96).

[0302] Compounds of the invention were found to inhibit JAK3 in this cellular assay.

[0303] Example 7: JAK2 Cellular Inhibition Assay

[0304] TF-1 cells (ATCC Cat. # CRL-2003) were grown and maintained at 37°C in a humidified incubator in cell culture medium (RPMI 1640 supplemented with 2 mM

L-glutamine adjusted to contain 1.5 g/L sodium bicarbonate, 4.5 g/L glucose, 10 mM

HEPES, 1.0 mM sodium pyruvate, 10% fetal bovine serum and recombinant human granulocyte-macrophage colony stimulating factor [rhGMCSF, R&D Systems Inc. Cat.

# 215-GM]). On the day of the experiment, TF-1 cells were washed, resuspended at a density of 5 x 10⁶ cells per ml in fresh cell culture medium without rhGMCSF and incubated for 4 krmrc «πΐ¾_ον rhGMCSF. After four hours, 50 μΐ (0.25 x 10⁶ cells) of the resuspended cells were added to each well of a 96 well plate. Serial dilutions of compounds were made in DMSO and then added to RPMI. 100 μΐ of the diluted compounds were added to each well and the plates were incubated for 1 hour at 37 °C. 50 μΐ of rhGMCSF at lOng/ml was added and the plates were incubated for 15 minutes at 37 °C. The plates were then processed for FACS analysis as detailed above in Example 6.

[0305] Compounds of the invention were found to inhibit JAK2 in this cellular assay.

[0306] Example 8: Administration of Compound No. 1 to Mouse Model for Psoriasis

[0307] 6-7 week-old male CD-I mice were topically sensitized and challenged with 5% and 1% oxazolone on shaved abdomen and ears, respectively. Vehicle, compound no. 1 (10, 25, and 50 mg/kg), and prednisolone (PRED, 5 mg/kg) (dosing volume: 10 ml/kg) were administered via oral gavage. Doses were given twice, 12 hours apart, starting at the time of or 24 hours after the challenge for the prophylactic or therapeutic dosing regimen,

respectively. Doses were also given twice daily throughout the course of experiment or only during the sensitization phase. Mice were euthanized 24 hours after the challenge except for the therapeutic dosing regimen in which mice were euthanized 48 hours after the challenge phase. Ear edema of each mouse was quantified by determining the net weight increase of matched 9-mm ear discs collected from the oxazolone- (right) and solvent-treated (left) ears. PRED served as a reference positive control.

[0308] The data from this experiment is illustrated in Figures 1-4.

[0309] Dosing vehicle was prepared by dissolving 10 g D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) per 100 mL water to yield a 10% TPGS solution. Compound no. 1 dosing material was prepared by dissolving the compound in 10% TPGS to yield the 10, 25 and 50 mg/kg dosages at a dosing volume of 10 mL/kg. Prednisolone (PRED, Sigma, St. Louis, MO) was also dissolved in 10% TPGS to yield a 5 mg/kg dosage at a dosing volume of 10 mL/kg.

[0310] Naive male CD-I mice (Charles River Laboratories, Wilmington, MA) at 6 to 7 weeks of age (28 to 32 g body weight) were randomized and immunized topically on the shaved abdomen with 150 μΕ-3ΐΐςυοΐ3 of a 5% (w/v) solution of oxazolone (Sigma, St. Louis,

MO) in a solvent composed of 1 part of absolute ethanol and 3 part of acetone (v:v). Three days after the sensitization, the mice were challenged with 10 of a 1% (w/v) solution of oxazolone on both sides of the right ears. Both sides of the left ears were treated with the same volume of the ethanol: acetone solvent. For the prophylactic regimen, compound no. 1,

PRED, and vehicle were orally dosed twice, 12 hours apart, starting at the time of challenge.

For the therapeutic regimen, compound no. 1, PRED, and vehicle were dosed twice, 12 hours a , ctartjng _at 24 hours after the challenge. For dosing throughout the course of experiment, compound no. 1, PRED, and vehicle were dosed twice daily (b.i.d.), 12 hours apart, for a total of 4 days. For dosing during the sensitization phase, compound no. 1, PRED, and vehicle were dosed b.i.d., 12 hours apart, for 3 days during the sensitization. Mice were euthanized 24 hours after the challenge except for the therapeutic regimen where mice were euthanized 48 hours after the challenge. After euthanization, 9-mm (diameter) size ear discs were created from both right and left ears of all the mice. Ear discs were weighed

individually. Statistical analysis was done using Prism software version 4.0a (GraphPad Software, Inc., San Diego, CA).

[0311] In the prophylactic regimen, compound no. 1 inhibited ear edema. In the therapeutic regimen, compound no. 1 also inhibited ear edema. When mice were dosed throughout the course of experiment, compound no. 1 inhibited ear edema at each dosage tested.

[0312] Example 9: Manufacture of Tablets

[0313] A formulation is provided in Table 3 for Exemplary Tablet 1 comprising 50 mg of API, i.e., a compound of Formula I.

Table 3: Exemplary Tablet 1

Amt. Per

Ingredient wt%

Tablet (mg)

Compound of Formula I 50.00 20

Binder (Avicel PH 102) 92.8125 37.125

Diluent (Lactose Monohydrate, NF (Fast-Flo 316) 92.8125 37.125

Disintegrant (AcDiSol) 7.5 3

Glidant (CaBoSil) 2.5 1

Wetting Agent (Sodium Lauryl Sulfate, NF) 2.5 1

Lubricant (Magnesium Stearate) 1.875 0.75

Total 250 100

1 A formulation is provided in Table 4 for Exemplary Tablet 2 comprising 25 mg

.e., a compound of Formula I.

Table 4: Exemplary Tablet 2.

Amt. Per

Ingredient wt %

Tablet (mg)

Compound of Formula I 25.00 10

Binder (Avicel PH 102) 105.31 42.125

Diluent (Lactose Monohydrate, NF (Fast-Flo 316) 105.31 42.125

Disintegrant (AcDiSol) 7.5 3

Glidant (CaBoSil) 2.5 1

Wetting Agent (Sodium Lauryl Sulfate, NF) 2.5 1

Lubricant (Magnesium Stearate) 1.875 0.75

Total 250 100 [0315] Example 10: Exemplary Tablet 1 (Formulated to have 50 mg of a Compound of Formula I)

[0316] A batch of 250 mg total weight tablets can be formulated to have approximately 50 mg of compound of Formula I per tablet using the amounts of ingredients recited in Table 3, above.

[0317] Sieve the compound of Formula I, microcrystalline cellulose (FMC MCC Avicel® PHI 02, commercially available from FMC BioPolymer Corporation of Philadelphia, PA), lactose (Foremost FastFlo® Lactose #316 commercially available from Foremost Farms USA of Baraboo, WI), sodium croscarmellose (FMC Ac-Di-Sol®, commercially available from FMC BioPolymer Corporation of Philadelphia, PA), sodium lauryl sulfate (commercially available from Stepan Company of Northfield, II), and colloidal silicon dioxide (Cabot Cab- O-Sil® M-5P Fumed Silicon Dioxide, commercially available from Cabot Corporation of Alpharetta, GA) through a 20 mesh screen to remove lumps.

[0318] Add these sieved ingredients to a 16 quart V-blender and blend for about 20 minutes in a V-blender at 10-12 rpm.

[0319] Sieve magnesium stearate (commercially available from Mallinckrodt, Inc.) through a 20 mesh screen to remove lumps, and add to the blended mixture. Blend the second mixture containing the newly added magnesium stearate for another 4 minutes at a speed of about 10 to 24 rpm.

[0320] Once the final blend has been completed, transfer the mixture to a tablet press (e.g., a Piccola B-Tooling, 10 Station rotary tablet press (half tooled)) for compression into 250 mg tables having approximately 50 mg of a compound of Formula I.

[0321] Example 11: Exemplary Tablet 2 (Formulated to have 25 mg of a Compound of Formula I)

[0322] A batch of 250 mg total weight tablets can be formulated to have approximately 25 mg of a compound of Formula I per tablet using the amounts of ingredients recited in Table B, above.

[0323] Sieve the compound of Formula I, microcrystalline cellulose (FMC MCC Avicel® PHI 02, commercially available from FMC BioPolymer Corporation of Philadelphia, PA), lactose (Foremost FastFlo® Lactose #316 commercially available from Foremost Farms USA of Baraboo, WI), sodium croscarmellose (FMC Ac-Di-Sol®, commercially available from FMC BioPolymer Corporation of Philadelphia, PA), sodium lauryl sulfate (commercially available from Stepan Company of Northfield, II.), and colloidal silicon dioxide (Cabot Cab- O-Sil® M-5P Fumed Silicon Dioxide, commercially available from Cabot Corporation of Alpharetta, GA) through a 20 mesh screen to remove lumps.

[0324] Add these sieved ingredients to a 16 quart V-blender and blend for about 20 minutes in a V-blender at 10-12 rpm.

[0325] Sieve magnesium stearate (commercially available from Mallinckrodt, Inc.) through a 20 mesh screen to remove lumps, and add to the blended mixture. Blend the second mixture containing the newly added magnesium stearate for another 4 minutes at a speed of about 10 to 24 rpm.

[0326] Once the final blend has been completed, transfer the mixture to a tablet press (e.g., a Piccola B-Tooling, 10 Station rotary tablet press (half tooled)) for compression into 250 mg tables having approximately 25 mg of the compound of Formula I.

[0327] Example 12: Exemplary Capsule (Formulated to have 25 mg of the compound of Formula I)

[0328] Add 25 mg of a compound of Formula I to one half of a 2-piece gelatin capsule, and cap the filled half of the gelatin capsule with the second half of the 2-piece capsule.

[0329] Example 13: Exemplary Capsule (Formulated to have 50 mg of a Compound of Formula I)

[0330] Add 50 mg of a compound of Formula I to one half of a 2-piece gelatin capsule, and cap the filled half of the gelatin capsule with the second half of the 2 piece capsule.

[0331] Example 14: Exemplary Capsule (Formulated to have 75 mg of a compound of Formula I)

[0332] Add 75 mg of the compound of Formula I to one half of a 2-piece gelatin capsule, and cap the filled half of the gelatin capsule with the second half of the 2 piece capsule.

[0333] Example 15: Administration of Pharmaceutical Formulations

[0334] Example 15 A Exemplary Administration A

[0335] Human patients are orally administered a pharmaceutical formulation comprising a compound of Formula I according to Table 5:

Table 5: Exemplary administration of pharmaceutical formulations of the present invention.

Frequency of Dosage of API

dosing

200 mg (e.g., 4 ^χ Tablet 1 or 8

q.d.

Tablet 2)

q.d. 250 mg (e.g., 5 x Tablet 1)

q.d. 300 mg (e.g., 6 x Tablet 1)

[0336] The pharmaceutical formulations may be administered to subjects anytime during the day, and in some administrations, the pharmaceutical formulation is given at

approximately the same time (within a 1-hour window) on each dosing occasion.

[0337] Furthermore, the tablets (e.g., Tablet 1 and/or Tablet 2) may be administered with or without a fluid (e.g., water or other beverage). Also, human patients being administered the tablet(s) may fast for a period of time prior to or after the administration.

[0338] In several instances, the administration of the tablet(s) may last for a period of about

12 weeks.

[0339] Example 15B: Exemplary Administration B

[0340] Human patients are orally administered a pharmaceutical formulation comprising a compound of Formula I according to Table 6:

Table 6: Exemplary administration of pharmaceutical formulations of the present invention.

[0341] The pharmaceutical formulations may be administered to subjects in the morning, e.g., between 5:00 AM and 12:00 PM, and evening, e.g., between 5:00 PM and 12:00 AM, and in some administrations, the pharmaceutical formulation is given at approximately the same time (within a 1 -hour window) on each dosing occasion.

[0342] Furthermore, the tablet(s) (e.g., Tablet 1 and/or Tablet 2) may be administered with or without a fluid (e.g., water or other beverage). Also, human patients being administered the tablet may fast for a period of time prior to or after the administration.

[0343] In several instances, the administration of the tablet(s) lasts for a period of about 12 weeks.

[0344] Example 16: Administration of Pharmaceutical Formulations

[03451 Example 16 A: Exemplary Administration A [0346] Human patients are orally administered a pharmaceutical formulation comprising a compound of Formula I according to Table 7:

Table 7: Exemplary administration of pharmaceutical formulations of the present invention.

[0347] When frequency of dosing is twice a day, the pharmaceutical formulations may be administered to subjects in the morning, e.g., between 6:00 AM and 12:00 PM, and evening, e.g., between 5:00 PM and 11 :00 PM, and in some administrations, the pharmaceutical formulation is given at approximately the same time (within a 1-hour window) on each dosing occasion. In instances where the frequency dosing is once per day, the pharmaceutical formulation may be given anytime during the day, and in some administrations, the pharmaceutical formulation is given at approximately the same time (within a 1-hour window) on each dosing occasion.

[0348] Furthermore, the tablets (e.g., Tablet 1 and/or Tablet 2) may be administered with or without a fluid (e.g., water or other beverage). Also, human patients being administered the tablet(s) may fast for a period of time prior to or after the administration.

[0349] In several instances, the administration of the tablet(s) may last for a period of about 12 weeks.

[0350] Example 16B: Exemplary Administration B

[0351] Human patients are orally administered a pharmaceutical formulation comprising a compound of Formula I according to Table 8:

Table 8: Exemplary administration of pharmaceutical formulations of the present invention.

[0352] The pharmaceutical formulations may be administered to subjects anytime during the 24 hr. interval, and in some administrations, the pharmaceutical formulation is given at approximately the same time (within a 1-hour window) on each dosing occasion.

[0353] Furthermore, the tablet(s) (e.g., Tablet 1 and/or Tablet 2) may be administered with or without a fluid (e.g., water or other beverage). Also, human patients being administered the tablet may fast for a period of time prior to or after the administration.

[0354] In several instances, the administration of the tablet(s) lasts for a period of about 12 weeks.

[0355] Example 17: Administration of Pharmaceutical Formulations

[0356] Example 17 A: Exemplary Administration A

[0357] Human patients are orally administered a pharmaceutical formulation comprising a compound of Formula I according to Table 9:

Table 9: Exemplary administration of pharmaceutical formulations of the present invention.

[0358] The pharmaceutical formulations may be administered to subjects in the morning, e.g., between 6:00 AM and 12:00 PM, and evening, e.g., between 5:00 PM and 1 1 :00 PM, and in some administrations, the pharmaceutical formulation is given at approximately the same time (within a 1 -hour window) on each dosing occasion.

[0359] Furthermore, the tablets (e.g., Tablet 1) may be administered with or without a fluid (e.g., water or other beverage). Also, human patients being administered the tablet(s) may fast for a period of time prior to or after the administration.

[0360] In several instances, the administration of the tablet(s) may last for a period of about 12 weeks.

[0361] Some embodiments further comprise administering to the patient a co-therapy. Co- therapies that are useful in the methods of the present invention may be administered concurrently with the compound of Formula I or sequentially. For example, some embodiments further comprise administering to the patient a phototherapy (e.g., psoralen and ultraviolet A [PUVA] light therapy).

[0362] Some embodiments further comprise administering to the patient an additional agent selected from a corticosteroid, cyclosporine, methotrexate, an oral retinoid, mycophenolate mofetil, thioguanine, hydroxyurea, sirolimus, azathioprine, or any combination thereof.

[0363] Some embodiments further comprise administering a chemotherapy agent to the patient. And, in some instances, the chemotherapy agent comprises methotrexate, azathioprine (e.g., Imuran), 6-mercaptopurine, cyclosporine, cyclophosphamide (e.g., Cytoxan), or any combination thereof.

[0364] In some embodiments, the chemotherapy agent comprises an injectable formulation or an oral formulation. And, in some instances, the patient is administered from about 5 mg to about 100 mg of the chemotherapy agent per month.

OTHER EMBODIMENTS

[0365] All publications and patents referred to in this disclosure are incorporated herein by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Should the meaning of the terms in any of the patents or publications incorporated by reference conflict with the meaning of the terms used in this disclosure, the meaning of the terms in this disclosure are intended to be controlling. Furthermore, the foregoing discussion discloses and describes merely exemplary embodiments of the present invention. One skilled in the art will readily recognize from such discussion and from the accompanying drawings and claims, that various changes, modifications and variations can be made therein without departing from the spirit and scope of the invention as defined in the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method for treating or lessening the severity of psoriasis comprising administering to a patient in need thereof a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

X¹ is N or CR⁴

R² is H or halo;

R³ is H or halo

R⁴ is H or halo

R" is H or an unsubstituted Ci_-2 aliphatic;

R⁸ is an unsubstituted C1 -4 aliphatic;

R⁹ is an unsubstituted C 1- aliphatic;

R⁷ is a C 1-3 aliphatic optionally substituted with up to 3 occurrences of F; and R¹⁴ is H or unsubstituted C_1-2 alkyl.

The method of claim 1, wherein R is H or F.

3. The method of either of claims 1 or 2, wherein R³ is H or CI.

4. The method of any one of claims 1 -3, wherein each of R and R is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl.

5. The method of claim 4, wherein each of R⁸ and R⁹ is independently selected from methyl or ethyl.

6. The method of any one of claims 1-5, wherein R¹⁴ is H or methyl.

7. The method of any one of claims 1-6, wherein R⁷ is an unsubstituted Ci_-3 aliphatic.

8. The method of any one of claims 1-6, wherein R⁷ is a Ci_-3 aliphatic substituted with 1- 3 occurrences of F.

9. The method of any one of claims 1-6, wherein R⁷ is a group selected from -CH₂CH₃, -CH₂CF₃, -CH₂CH₂CH₃, or -CHCH₃CH₃.

10. The method of claim 1, wherein the compound of Formula I is selected from Table 1.

1 1. The method of any one of claims 1-10, wherein the compound of Formula I is administered at least once per day.

12. The method of any one of claims 1-1 1 , wherein the compound of Formula I is administered from 1 to 4 times per day.

13. The method of any one of claims 1-12, wherein the compound of Formula I is orally administered to the patient in need thereof.

14. The method of any one of claims 1-13, wherein at least about 50 mg of the compound of Formula I is administered to the patient once per day.

15. The method of any one of claims 1-14, wherein at least about 100 mg of the compound of Formula I is administered to the patient once per day.

16. The method of any one of claims 1-15, wherein at least about 150 mg of the compound of Formula I is administered to the patient once per day.

17. The method of any one of claims 1-16, wherein at least about 200 mg of the compound of Formula I is administered to the patient once per day.

18. The method of any one of claims 1-13, wherein at least about 20 mg of the compound of Formula I is administered to the patient twice per day.

19. The method of any one of claims 1-13 or 18, wherein at least about 50 mg of the compound of Formula I is administered to the patient twice per day.

20. The method of any one of claims 1-13, 18, or 19, wherein at least about 100 mg of the compound of Formula I is administered to the patient twice per day.

21. The method of any one of claims 1-20, further comprising administering a co-therapy to the patient, wherein the co-therapy is selected from a phototherapy agent, methotrexate, a corticosteroid, a cyclosporine, an oral retinoid, a mycophenolate mofetil, a thioguanine, a hydroxyurea, a sirolimus, an azathioprine, or any combination thereof.

22. The method of claim 21, further comprising administering an injectable formulation or an oral formulation of methotrexate.

23. The method of either of claims 21 or 22, wherein the patient is administered from about 5 mg to about 100 mg of methotrexate per month.

24. A method for treating or lessening the severity of psoriasis comprising administering to a patient in need thereof a pharmaceutical composition comprising a compound of Formula I

I

or a pharmaceutically acceptable salt thereof, wherein:

X¹ is N or CR⁴;

R² is H or halo;

R³ is H or halo;

R⁴ is H or halo;

R" is H or an unsubstituted Ci_-2 aliphatic; R is an unsubstituted C aliphatic;

R⁹ is an unsubstituted C aliphatic;

R is a C[-3 aliphatic optionally substituted with up to 3 occurrences of F; and R¹⁴ is H or unsubstituted Ci_-2 alkyl.

25. The method of claim 24, wherein R² is H or F.

26. The method of either of claims 24 or 25, wherein R is H or CI.

27. The method of any one of claims 24-26, wherein each of R and R is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl.

28. The method of claims 27, wherein each of R⁸ and R⁹ is independently selected from methyl or ethyl.

29. The method of any one of claims 24-28, wherein R¹⁴ is H or methyl.

30. The method of any one of claims 24-29, wherein R⁷ is an unsubstituted Ci_-3 aliphatic.

31. The method of any one of claims 24-29, wherein R⁷ is a Ci_-3 aliphatic substituted with 1-3 occurrences of F.

32. The method of any one of claims 24-29, wherein R⁷ is a group selected from

-CH₂CH₃, -CH₂CF₃, -CH₂CH₂CH₃, or -CHCH₃CH₃.

33. The method of any one of claims 24-32, wherein the compound of Formula I is selected from Table 1.

34. The method of any one of claims 24-33, wherein the pharmaceutical composition further comprises a tablet.

35. The method of claim 34, wherein the tablet further comprises a diluent, a binder, a glidant, a disintegrant, a surfactant, a lubricant, or any combination thereof.

36. The method of either of claims 34 or 35, further comprising administering the tablet at least once per day.

37. The method of claim 36, wherein the tablet comprises at least about 10 mg of the compound of Formula I.

38. The method of claim 37, wherein the tablet comprises from about 15 mg to about 100 mg of the compound of Formula I.

39. The method of either of claims 34 or 35, wherein the tablet is administered at least twice per day.

40. The method of claim 39, wherein the tablet comprises at least about 10 mg of the compound of Formula I.

41. The method of claim 40, wherein the tablet comprises from about 15 mg to about 100 mg of the compound of Formula I.

42. The method of either of claims 34 or 35, further comprising administering once per day at least one tablet comprising the pharmaceutical composition.

43. The method of either of claims 34 or 35, further comprising administering twice per day at least one tablet comprising the pharmaceutical composition.

44. The method of either of claims 42 or 43, wherein each tablet further comprises from about 5 mg to about 100 mg of the compound of Formula I.

45. The method of any one of claims 24-44, further comprising administering a co- therapy to the patient, wherein the co-therapy is selected from a phototherapy agent, methotrexate, a corticosteroid, a cyclosporine, an oral retinoid, a mycophenolate mofetil, a thioguanine, a hydroxyurea, a sirolimus, an azathioprine, or any combination thereof.

46. The method of claim 45, further comprising administering an injectable formulation or an oral formulation of methotrexate.

47. The method of either of claims 44 or 45, wherein the patient is administered from about 5 mg to about 100 mg of methotrexate per month.

48. A method for treating or lessening the severity of psoriasis comprising administering to a patient in need thereof a co

I

or a pharmaceutically acceptable salt thereof, wherein:

X¹ is N or CR⁴;

R² is H or halo;

R³ is H or halo;

R⁴ is H or halo;

R" is H or an unsubstituted Ci.₂ aliphatic;

R⁸ is an unsubstituted C aliphatic;

R⁹ is an unsubstituted C aliphatic;

R⁷ is a C]_-3 aliphatic optionally substituted with up to 3 occurrences of F; and

R¹⁴ is H or unsubstituted Cj_-2 alkyl,

or a pharmaceutically acceptable salt thereof wherein:

49. The method of claim 48, wherein from about 25 mg to about 250 mg of the compound of formula I is administered to the patient once per day or twice per day.

50. The method of claim 49, wherein from about 100 mg to about 200 mg of the compound of formula I is administered to the patient once per day or twice per day.

51. The method of any one of claims 48-50, wherein R is H or F.

52. The method of any one of claims 48-51 , wherein R³ is H or CI.

53. The method of any one of claims 48-52, wherein each of R⁸ and R⁹ is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl. Q

54. The method of claim 53, wherein each of R and R is independently selected from methyl or ethyl.

55. The method of any one of claims 48-54, wherein R¹⁴ is H or methyl.

56. The method of any one of claims 48-55, wherein R is an unsubstituted C 1.3 aliphatic.

57. The method of any one of claims 48-55, wherein R is a Ci_-3 aliphatic substituted with 1-3 occurrences of F.

58. The method of any one of claims 48-55, wherein R⁷ is a group selected from

-C¾CH₃, -CH₂CF₃, -CH₂CH₂CH₃, or -CHCH₃CH₃.

59. The method of any one of claims 48-58, wherein the compound of Formula I is selected from Table 1.

60. The method of any one of claims 48-59, further comprising administering a co- therapy to the patient, wherein the co-therapy is selected from a phototherapy agent, methotrexate, a corticosteroid, a cyclosporine, an oral retinoid, a mycophenolate mofetil, a thioguanine, a hydroxyurea, a sirolimus, an azathioprine, or any combination thereof.

61. The method of claim 60, further comprising administering an injectable formulation or an oral formulation of methotrexate.

62. The method of either of claims 60 or 61 , wherein the patient is administered from about 5 mg to about 100 mg of methotrexate per month.