A. Title:

SELECTIVE KINASE INHIBITORS

B. Cross-Reference to Related Applications:

[0001] This application claims priority to U.S. Provisional Application No. 61/527,180, entitled, "Selective Kinase Inhibitors," filed August 25, 2011, which is incorporated herein by reference in its entirety.

C. Government Interests: Not applicable

D. Parties to a Joint Research Agreement: Not applicable

E. Incorporation by Reference of Material submitted on a Compact Disc: Not applicable F. Background: Not applicable

G. Summary of the Invention:

[0002] In some embodiments, the present invention relates to methods of modulating (for example inhibiting) activity of Janus Kinase-3 (JAK3) and/or treating JAK3 - associated diseases including, for example, inflammatory disorders and autoimmune disorders. In some embodiments, the present invention also relates to novel compounds and compositions thereof, methods of preparation of the same, as well as methods of use the same for inhibition of JAK3 and/or treatment of JAK3 -associated diseases.

[0003] Cytokines are the key regulators of immunity and inflammation. Antagonism of cytokine function has emerged as an effective strategy for immunosuppression (Steinman L. Science 305:212-216 (2004)). Cytokines that bind type-I receptors (such as interleukin-2, 3, 4, 5, 6, 7, and 9) and type-II receptors (such as INFa/β, IFNy, IL-10, 19, and 20) are important in immunoregulation and inflammation, and critical for lymphoid development, homeostasis, and differentiation (O'Shea JJ et al, Nat. Rev. Immunol. 2: 37-45 (2002); O'Shea JJ et al, Curr Opin Rheumatol.l7:305-11 (2005); O'Shea JJ et al Immunity. 28, 477-487 (2008)).

[0004] Signal transducers and activators of transcription (STAT) are pleiotropic transcription factors which mediate cytokine-stimulated gene expression in multiple cell populations (Levy DA, Cytokine Growth Factor Rev., 8:81 (1997)). All STAT proteins contain a DNA binding domain, a Src homology 2 (SH2) domain, and a transactivation domain necessary for transcriptional activation of target gene expression.

[0005] Janus kinases (JAK), including JAK1 (also known as Janus kinase- 1), JAK2 (also known as Janus kinase-2), JAK3 (also known as Janus kinase, leukocyte; JAKL; L- JAK; and Janus kinase-3), and TYK2 (also known as protein-tyrosine kinase 2), are cytoplasmic protein tyrosine kinases (PTKs) which play pivotal roles in initiation of cytokine -triggered signaling events by activating the cytoplasmic latent forms of STAT proteins via tyrosine phosphorylation on a specific tyrosine residue near the SH2 domain (Ihle JN et al, Trends Genet., 11 : 69 (1995); Darnell JE et al, Science, 265: 1415 (1994); Johnston JA et al, Nature, 370: 1513 (1994)).

[0006] Binding of the cytokines to the receptor brings JAKs together, resulting in JAK activation and autophosphorylation, with subsequent phosphorylation of tyrosine residues on the cytoplasmic portion of the receptor. The inactive STAT monomers are then recruited to the activated receptor complex via the interaction of the SH2 domains with phosphotyrosine docking sites. STATs are phosphorylated by the JAKs on a conserved tyrosine residue in the c-terminal domain to form STAT homodimers or heterodimers. STATs then dissociate from the receptor, dimerize, and translocate into the nucleus. In the nucleus, STATs bind to specific response elements and induce gene transcription (Benekli M, et al, 101, 2940-2954 (2003); Leonard WJ, Nature Medicine, 2: 968 (1996); Leonard WJ, Nature Medicine, 2: 968 (1996); Zhong Z et al, PNAS USA, 91 :4806 (1994); Darnell Jr. JE et al, Science, 264: 1415-1421 (1994); and Scott, MJ et al, Clin Diagn Lab Immunol 9: 1153- 1159 (2002)). The STATs control fundamental cellular processes, including survival, proliferation, and differentiation.

[0007] Different ligands employ specific JAK and STAT family members, thus utilization of this pathway mandates specificity in signaling cascades and contributes to a diverse array of cellular responses. Janus kinases, including JAK3, are abundantly expressed in primary leukemic cells from children with acute lymphoblastic leukemia (ALL), the most common form of childhood cancer, and recent studies have correlated STAT activation in ALL cells with signals regulating apoptosis (Demoulin JB, et al, Mol. Cell. Biol. 16 : 4710- 4716 (1996); Jurlander J., et al, Blood. 89: 4146-4152, (1997); Kaneko S, et al, Clin. Exp. Immun. 109: 185-193 (1997); and Nakamura N et al, J. Biol. Chem. 271 : 19483-19488 (1996)). JAK3 mutations with continue activities are also found to express in acute megakaryoblastic leukemia (AMKL) patients, which implies the JAK3 mutants as potential therapeutic targets (Walters DK et al Cancer Cell, 10, 65-75 (2006); Kiyoi H et al Leukemia, 21, 574-576 (2007)).

[0008] Among the four members of the JAK family, JAK1, JAK2, and TYK2 are ubiquitously expressed. JAK3 is predominantly expressed in hematopoietic cells, such as Natural Killer cells and thymocytes, platelets, mast cells, and inducible T and B cells. JAK3 plays an important role in normal lymphocyte development and functions, as evidenced by qualitative and quantitative deficiencies in the B-cell as well as T-cell compartments of the immune system of JAK3 -deficient mice (T. Nosaka et al, Science, 270:800 (1995): D. C. Thomas et al, Science, 270:794 (1995)); development of severe combined immunodeficiency in J AK3 -deficient patients and development of severe combined immunodeficiency in JAK3- deficient patients (Buckley RH et al, J Pediatr., 130: 379 (1997)). JAK3 binds exclusively to the IL-2 cytokine receptor gamma chain and is activated by IL-2, IL-4, IL-7, IL-9, and IL-15. JAK3 is critical for lymphocyte survival, differentiation, and function. In humans, mutations in JA 3 have been associated with severe combined immunodeficiency (SCID) (Macchi P et al, Nature. 377: 65-68 (1995), Notarangelo LD Immunol Rev 178:39-48 (2000)), a disorder that is fatal in infancy unless treated by therapies such as hematopoetic stem cell transplantation. JAK3 knockout mice are found to display defects in T, B, and NK cell development and function (Nosaka T et al, Science, 270:800-802 (1995): Thomas DC et al, Science, 270:794-797 (1995).; Suzuki K N et al Int Immunol 12: 123-132 (2000)).

[0009] JAK/STAT signaling has been implicated in the mediation of many abnormal immune responses such as allergies, asthma, autoimmune diseases such as transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis as well as in solid and hematologic malignancies such as leukemias and lymphomas. An inhibitor of JAK3 will block the JAK3/STAT signaling pathway, and could be useful for treating or preventing diseases mentioned hereinabove (Cetkovic-Cvrlje et al Current Pharmaceutical Design, 10, 1767-1784 (2004); Luo C et al, 2004, Drug Discovery Today, 268-275 (2004); Pesu M et al Immunol.Rev. 223: 132-42 (2008)).

[0010] Besides hematopoietic cells, JAK3 is also found to express in variety levels in endothelial cells and smooth muscle cells (Verbsky J et al, J. Biol. Chem. 271, 13976- 13980 (1996)), cancers cells other than leukemia and lymphoma as described hereinabove. For example, JAK3 is constitutively phosphorylated and activated in colon carcinoma cells (Lin Q eta al Am. J. Pathol. 167, 969-980 (2005)). Information regarding the physiologic functions of JAK3 in these non-lymphoid cell populations also spurred much interest in research (Thomas DC et al., Curr. Opin. Immunol., 9: 541 (1997); Ihle JN, Philos. Trans. R. Soc. Lond B Biol. Sci., 351 : 159-166 (1996); Verbsky JW et al. J Biol. Chem., 271 : 13976 (1996)).

[0011] Animal studies have suggested that JAK3 not only play a critical role in B- and T- lymphocyte maturation, but that JAK3 is constitutively required to maintain T-cell function. Modulation of immune activity through this novel mechanism can prove useful in the treatment of T-cell proliferative disorders such as transplant rejection (e.g. organ transplant rejection) (Borie DC et al, Trends Mol. Med. 10, 532-541 (2004); Borie DC et al, transplantation, 79, 791-801 (2005)) and autoimmune diseases (e.g. insulin-dependent diabetes) (Cetkovic-Cvrlje M. et al, Clinical immunology, 106, 213-225 (2003).

[0012] The role of JAK3 in mast cells has been described in knockout mice. Thus, IgE/antigen induced degranulation and mediator release were substantially reduced in mast cells generated from JAK3 deficient mice. JAK3 deficiency does not affect mast cell proliferation in vitro, and it has also been shown that IgE receptor levels and mediator contents are identical in JAK3-/- and JAK3 +/+ mast cells. Therefore, JAK3 appears essential for the complete response of IgE challenged mast cells. The role of JAK3 in mast cell activation has been well established in murine system, and it was suggested that mast cells plays an important role in Autosomal Recessive- Severe Combined Immunodeficiency (AR-SCID) patients and that targeting JAK3 provides the basis for new and effective treatment of mast cell mediated allergic reactions. See e.g. WO/2004/099205. JAK3 inhibitors can be used to treat (including prevent) mast cell mediated immediate hypersensitivity reactions. See R. Malaviya, et. al, "Targeting Janus kinase 3 in mast cells prevents immediate hypersensitivity reactions and anaphylaxis"; Journal of Biological Chemistry, Vol. 274, No. 38, Issue of September 17, pp. 27028-27038, 1999.

[0013] The JA 3/STAT pathways play pivotal roles in diseases such as autoimmune diseases (e.g. rheumatoid arthritis (RA), psoriasis, multiple sclerosis, type I diabetes and complication from diabetes, lupus, autoimmune thyroid disorder, ulcerative colitis, Crohn's disease), cancer, leukemia, lymphoma, inflammatory diseases or disorders (e.g. asthma, rhinitis, and atopic dermatitis), Alzheimer's disease, and organ transplant rejection. See e.g. WO 2001042246. Pharmacological targeting of JAK3 has been employed successfully to control (treat and/or prevent) transplant complications (e. g. rejection of donor organs by the host immune system such as allograft rejection) and complications associated with bone marrow transplantation such as development of graft versus host disease (GVHD). In addition to its involvement in signaling of cytokine receptors, JAK3 is also engaged in the CD40 signaling pathway of peripheral blood monocytes. During CD40-induced maturation of myeloid dendritic cells (DCs), JAK3 activity is induced, and increases in costimulatory molecule expression, IL-12 production, and potent allogeneic stimulatory capacity are observed. A rationally designed JAK3 inhibitor WHI-P-154 prevented these effects arresting the DCs at an immature level, suggesting that immunosuppressive therapies targeting the tyrosine kinase JAK3 may also affect the function of myeloid cells (Saemann MD et al, Am J Transplant 3: 1341-1349 (2003)). In the mouse model system, JAK3 was also shown to be an important molecular target for treatment of autoimmune insulin-dependent (type 1) diabetes mellitus. The rationally designed JAK3 inhibitor JANEX-1 exhibited potent immunomodulatory activity and delayed the onset of diabetes in the NOD mouse model of autoimmune type 1 diabetes (Cetkovic-Cvrlje M et al, Clin Immunol 106: 213-25 (2003)). Moreover, JAK3 can be one of the regulators of platelet function, and JAK3 inhibitors can prevent platelet aggregation, inhibit thrombus formation, and thus can be anti-thrombotic agents. See e.g. Tibbies, H. E. "Role of a JAK3 -dependent Biochemical Signaling Pathway in Platelet Activation and Aggregation" J. Biol. Chem., Vol. 276, Issue 21, 17815-17822, May 25, 2001; See also Cetkovic-Cvrlje, M. "Therapeutic Potential of Janus Kinase 3 (JAK3) Inhibitors" Current Pharmaceutical Design, Volume 10, Number 15, June 2004 , pp. 1767- 1784(18). Because of the importance of JAK3 inhibitors and the market for specific immunosuppressants, many pharmaceutical companies have established JAK3 drug development programs, including Pfizer, Vertex, Rigel, InCyte, and Pharmacopeia (Pesu et al. Immunological Reviews. 223, 132-142 (2008)). Pfizer has progressed CP-690550 (Changelian PS et al, Science, 302, 875-878 (2003)) into 19 clinical studies on ulcerative colitis; acute rejection in kidney transplantation; rheumatoid arthritis (RA); dry eye syndromes; Crohn's disease; and psoriasis. These clinical studies include Phase II clinical trials for RA and an expanded Phase I acute kidney transplant rejection trial. CP-690550 has therapeutic effects with both adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA) rat models (Milici et al. Arthritis Research & Therapy I OIR (2008)). A new analog of CP-690550, PF-956980, was found to have improved JAK3 specificity (Changelian et al, Blood 111 :2155-2157 (2008); WO 2001042246; US6,627,754; and US 7,432,370).

[0014] Pharmacopeia (Ligand Pharmaceuticals Inc.) developed a JAK3 inhibitor, PS020613, for RA, psoriasis, and other immunological conditions. PS020613 has an IC50 value of 3.4 nM for Jak3 kinase. It inhibits IL2-induced cell proliferation in mouse F7 cells with an IC50 value of 64 nM, and demonstrates 31 -fold cell selectivity over Jak2. When administered orally to BALB/c mice, PS020613 inhibits IL2 -induced IFNg production with an ED50 value of 3 mg/kg, is efficacious in an oxazolone-induced model of delayed hypersensitivity and demonstrates good oral bioavailability (116%) (Sills M et al, Fourteenth international conference, Poster A155 (2006)).

[0015] Rigel Pharmaceuticals Inc. is testing the compound R 48 (an inhibitor for Jak3 and Syk) for Psoriasis/RA and transplant rejection (Deuse T et al, Transplantation, 85,885-892 (2008); US7435814; and US 74352879). [0016] Vertex Pharmaceuticals Inc. is testing compound VX-509 (a JAK3 inhibitor) in Phase la clinical development for the potential treatment of multiple immune -mediated inflammatory diseases. See e.g. US 7122552.

[0017] Parker-Hughes Institute had developed a group of compounds, such as WHI- P131 and WPI-P154, as potent inhibitors for PDGFR and EGFR, and also capable to inhibit JAK3 with IC50s in low μΜ ranges. These compounds have been studied for their immunosuppression (Marzec M et al, Lab Invest 85 : 1544-1554 (2005); Papageorgiou AC et al. Trends Pharmacol Sci. 25: 558-562 (2004); Changelian PS et al, Blood 111(4):2155-2157 (2008)). It was also reported that WHI-P131, as a JAK3 inhibitor, increased survival in a transgenic mouse model of amyotrophic lateral sclerosis (ALS) and can be useful for treatment of ALS such as FALS (Trieu VN, et. al, Biochem Biophys Res Commu., 267, 22- 25 (2000)).

[0018] A J AK3 -selective inhibitor (selective over other Kinases such as JAK1, JAK2, and TYK2) would not interfere with (or interfere insignificantly with) the signaling pathways mediated/controlled by other members of Kinases such as JAK1, JAK2, and TYK2. However, one drawback of some of the current JAK3 inhibitors is that they also have activities toward other kinases such as JAK1 and JAK2, which also play critical roles to the signaling of many hematopoietic cytokine and growth factor receptors. For example, a binding assay performed by Ambit has revealed that CP-690550 had very similar Ki for JAK3 (Kd = 2.5 nM) and JAK2 (Kd = 5 nM) (Karaman MW et al, Nat. Biotech. 26, 127-132 (2008)), although one Pfizer's publication (Changelian PS et al, Science , 302, 875 - 878 (2003)) indicated that with ELISA assays, CP-690550 inhibited JAK3 with an IC50 value of 1.5 nM, which is 20 fold more selective than toward JAK2. However low selectivity (about 2.5 fold more selective to JAK3 over JAK1) of CP-690550 was also reported according to Pharmacopeia's internal test (2nd Protein Kinases in Drug Discovery Conference, 2007). JAK3-selective inhibitors, such as compounds in the present invention, are useful in treating (and/or preventing) rheumatoid arthritis (RA), psoriasis, organ transplant rejection, allergic or type I hypersensitivity reaction such as urticaria and eczema, conjunctivitis, rhinorrhea, rhinitis,, asthma and gastroenteritis, familial amyotrophic lateral sclerosis (FALS), lupus, multiple sclerosis, dry eye disease, Type I diabetes and complications from diabetes, cancer, asthma, rhinitis, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia, thrombus, and other autoimmune disease.

[0019] New or improved agents which specifically inhibit JAK3 are continually needed for developing new and more effective pharmaceuticals to treat, autoimmune diseases and inflammatory diseases, to name a few. The compounds, compositions and methods described herein are directed toward these needs and other ends.

H. Description of Drawings: Not applicable

I. Detailed Description:

[0020] The present invention provides, inter alia, methods of modulating an activity of JAK3, comprising contacting the JAK3 with a compound of Formula I:

or pharmaceutically acceptable salt of the same, wherein constituent members are provided below.

[0021] In some embodiments, the present invention further provides methods of inhibiting an activity of JAK3, comprising contacting the kinases with a compound of Formula I, or pharmaceutically acceptable salt of the same.

[0022] In some embodiments, the present invention further provides methods of treating one or more of the various JAK3 -associated conditions, diseases and disorders named herein by administering to a patient a therapeutically effective amount of a compound of Formula I, or pharmaceutically acceptable salt of the same.

[0023] In some embodiments, the present invention further provides compounds of Formula I, or pharmaceutically acceptable salts thereof, for use in therapy.

[0024] In some embodiments, the present invention further provides use of the compounds of Formula I, or pharmaceutically acceptable salts thereof, for the manufacture/preparation of a medicament for use in therapy.

[0025] Some embodiments provide a method of inhibiting an activity of JAK3 comprising contacting said JAK3 with a compound of Formula

or pharmaceutically acceptable salt thereof.

[0026] Some embodiments provide a method of treating a condition or disease or disorder in a patient comprising administering to said patient a therapeutically effective amount of a compound of Formula I:

wherein

R ¹ is hydrogen atom or lower alkyl;

R is optionally substituted aryl, optionally substituted cycloalkyl or optionally substituted heterocyclic group;

R ³ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same or different and each is hydrogen atom, halogen atom, hydroxyl group, amino, optionally substituted lower alkyl or optionally substituted lower alkoxy;

R ⁴ is independently W, or R ⁴ and R ³ jointly form a group of the formula

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or

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Or R ⁴ and R ⁵ jointly form a group of the formula Error! Objects cannot be created from editing field codes.

W is -(CH ₂ ) ₁ -(Y) _m -(CH ₂ ) _n -Z;

{wherein Y is -CR ⁹ R ⁹ > - (wherein R ⁹ and R ⁹ * are the same or different and each is hydrogen atom, hydroxyl group, lower alkyl, lower alkoxy, lower alkylthio, lower alkylamino, di(lower)alkylamino, or heterocyclic group), -NR ¹⁰ -

(wherein R ¹⁰ is hydrogen atom or lower alkyl) , -0-, -S-, -S0 ₂ -, -CONH-, -NHCO- , -SONH-, -NHSO-, -S0 ₂ NH-, -NHS0 ₂ - or -S0 ₃ -,

Z is hydrogen atom, halogen atom, hydroxyl group, optionally substituted lower alkoxy, lower alkanoyl, lower alkoxycarbonyl, -NR ^U R ¹² (wherein R ¹¹ and R 12 are the same or different and each is hydrogen atom or lower alkyl), optionally

substituted amidino, optionally substituted guanidino, carbamoyl, lower alkylaminocarbonyl, optionally substituted aryl, optionally substituted cycloalkyl

or optionally substituted heterocyclic group,

1 is 0 or an integer of 1 to 4, m is 0 or 1, and n is 0 or an integer of 1 to

4}, W is hydrogen atom or the same as or different from W and is - (CH ₂ ) _r (Y) _m - (CH ₂ ) _n -Z (wherein each symbol is as defined above); and

p, q and r are the same or different and each is 0 or an integer of 1 to 4, the above-mentioned symbol "*" means that the side marked with a * binds to the nitrogen atom of the indole ring.

[0027] A method of treating a condition or disease or disorder in a patient comprising administering to said patient a therapeutically effective amount of a compound of Formula :

or pharmaceutically acceptable salt thereof. [0028] Some embodiments provide such a method wherein the condition or disease or disorder is selected from rheumatoid arthritis (RA), psoriasis, organ transplant rejection, allergic or type I hypersensitivity reaction, urticaria, eczema, conjunctivitis, rhinorrhea, rhinitis, asthma, gastroenteritis, familial amyotrophic lateral sclerosis (FALS), lupus, multiple sclerosis, dry eye disease, Type I diabetes and complications from diabetes, cancer, asthma, rhinitis, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia, and thrombus.

[0029] In some embodiments, the present invention further provides novel compounds and novel pharmaceutical compositions comprising the same and at least one pharmaceutically acceptable carrier.

[0030] In some embodiments, the present invention further provides methods of use and preparation of the novel compounds and pharmaceutical compositions provided herein.

[0031] The present invention provides, inter alia, methods of modulating an activity of JAK3, comprising contacting the JAK3 with a compound of Formula I:

wherein

R ¹ is hydrogen atom or lower alkyl;

R is optionally substituted aryl, optionally substituted cycloalkyl or optionally substituted heterocyclic group;

R ³ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same or different and each is hydrogen atom, halogen atom, hydroxyl group, amino, optionally substituted lower alkyl or optionally substituted lower alkoxy;

R ⁴ is independently W, or R ⁴ and R ³ jointly form a group of the formula

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or

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Or R ⁴ and R ⁵ jointly form a group of the formula

Error! Objects cannot be created from editing field codes. W is -(CH ₂ ) ₁ -(Y) _m -(CH ₂ ) _n -Z;

{wherein Y is -CR ⁹ R ⁹ > - (wherein R ⁹ and R ⁹ * are the same or different and each is hydrogen atom, hydroxyl group, lower alkyl, lower alkoxy, lower alkylthio, lower alkylamino, di(lower)alkylamino, or heterocyclic group), -NR ¹⁰ - (wherein R ¹⁰ is hydrogen atom or lower alkyl) , -0-, -S-, -S0 ₂ -, -CONH-, -NHCO- , -SONH-, -NHSO-, -S0 ₂ NH-, -NHS0 ₂ - or -SO3-,

Z is hydrogen atom, halogen atom, hydroxyl group, optionally substituted lower alkoxy, lower alkanoyl, lower alkoxycarbonyl, -NR ^U R ¹² (wherein R ¹¹ and

R 12 are the same or different and each is hydrogen atom or lower alkyl), optionally substituted amidino, optionally substituted guanidino, carbamoyl, lower alkylaminocarbonyl, optionally substituted aryl, optionally substituted cycloalkyl

or optionally substituted heterocyclic group,

1 is 0 or an integer of 1 to 4, m is 0 or 1, and n is 0 or an integer of 1 to 4}, W is hydrogen atom or the same as or different from W and is - (CH ₂ ) _r (Y) _m - (CH ₂ ) _n -Z (wherein each symbol is as defined above); and

p, q and r are the same or different and each is 0 or an integer of 1 to 4, the above-mentioned symbol * means that the side marked with a * binds to the nitrogen atom of the indole ring,

or a pharmaceutically acceptable salt thereof.

[0032] The disubstituted maleimide compound of the formula [I] of (1) above

wherein R is hydrogen atom or Ci— C ₆ lower alkyl (wherein Ci— C ₆ means having 1 to 6 carbon atoms, hereinafter the same);

R is optionally substituted C ₆ — C ₁₈ aryl, optionally substituted C3— C ₈ cycloalkyl or optionally substituted heterocyclic group (wherein said heterocyclic group has 1 to 4 hetero atoms selected from oxygen atom, nitrogen atom and sulfur atom, wherein the number of atoms constituting the ring is 5 to 12); 3 5

R\ R ^J , R6, R7 and R8 are the same or different and each is hydrogen atom,

halogen atom, hydroxyl group, amino, optionally substituted Ci— C ₆ lower alkyl or optionally substituted Ci— C ₆ lower alkoxy;

R ⁴ is independently W, or R ⁴ and R ³ jointly form a group of the formula

W

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or

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or R ⁴ and R ⁵ jointly form a group of the formula

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Wis-(CH ₂ ) ₁ -(Y) _m -(CH ₂ ) _n -Z

wherein Y is -CR ⁹ R ^9* - [wherein R ⁹ and R ^9* are the same or different and each is hydrogen atom, hydroxyl group, Ci— C ₆ lower alkyl, Ci— C ₆ lower alkoxy, Ci— C ₆ lower alkylthio, Ci— C ₆ lower alkylamino, di(Ci— C ₆ lower)alkylamino or heterocyclic group (wherein said heterocyclic group has 1 to 4 hetero atoms selected from oxygen atom, nitrogen atom and sulfur atom, wherein the number of atoms constituting the ring is 5 to 12)], -NR ¹⁰ - (wherein R ¹⁰ is hydrogen atom or Ci-C ₆ lower alkyl), -0-, -S-, -S0 ₂ -, -CONH-, -NHCO-, - SONH-, -NHSO-, -S0 ₂ NH-, -NHS0 ₂ - or -S0 ₃ -,

Z is hydrogen atom, halogen atom, hydroxyl group, optionally substituted Ci— C lower alkoxy, Ci— C ₆ lower alkanoyl, Q— C ₆ lower alkoxycarbonyl,

-NR 1" 1R 1 ¹ 2 (wherein R 11 and R 1 ¹ 2 are the same or different and each is hydrogen atom or Ci— C ₆ lower alkyl), optionally substituted amidino, optionally substituted guanidino, carbamoyl, Ci— C ₆ lower alkylaminocarbonyl, optionally substituted C ₆ — C ₁₈ aryl, optionally substituted C ₃ — Cg cycloalkyl or optionally substituted heterocyclic group (said heterocyclic group is as defined above),

1 is 0 or an integer of 1 to 4, m is 0 or 1 , and n is 0 or an integer of 1 to 4;

W is hydrogen atom or the same as or different from W and is -(CH ₂ ) _r (Y) _m -(CH ₂ ) _n -Z (wherein each symbol is as defined above); and

p, q and r are the same or different and each is 0 or an integer of 1 to 4, the above-mentioned symbol "*" means that the side marked with a * binds to the nitrogen atom of the indole ring, or a pharmaceutically acceptable salt thereof.

[0033] The disubstituted maleimide compound of (2) above, wherein R is optionally substituted C ₆ — C ₁₈ aryl or optionally substituted C ₃ — C ₈ cycloalkyl;

R ³ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same or different and each is hydrogen atom, optionally substituted Ci— C ₆ lower alkyl or optionally substituted Ci— C ₆ lower alkoxy;

Y at W is -CR ⁹ R ^9* -, -NR ¹⁰ - (wherein R ⁹ , R ^9* and R ¹⁰ are as defined in (2)), -0-, -S- or -SO2-;

Z at W is hydrogen atom, hydroxyl group, optionally substituted Ci— C ₆

11 12 11 12 lower alkoxy, Ci— C ₆ lower alkanoyl, -NR R (wherein R and R are as defined in (2)), optionally substituted amidino or optionally substituted heterocyclic group; and

W is hydrogen atom, or a pharmaceutically acceptable salt thereof.

[0034] The disubstituted maleimide compound of (2) above, wherein R ¹ is hydrogen atom, and R is optionally substituted C ₆ — C ₁₈ aryl, or a pharmaceutically acceptable salt thereof.

[0035] The disubstituted maleimide compound of (4) above, wherein R ⁴ is independently W or R ⁴ and R ³ jointly form a group of the formula

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wherein W, p and q are as defined in (2), and W is hydrogen atom, or a pharmaceutically acceptable salt thereof.

[0036] The disubstituted maleimide compound of (5) above, wherein R ⁴ and R ³ jointly form a group of the formula

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wherein W, p and q are as defined in (2), and W is hydrogen atom, or a pharmaceutically acceptable salt thereof.

[0037] The disubstituted maleimide compound of (6) above, wherein R ⁵ , R ⁶ , R ⁷ and

R 8 are each hydrogen atom, and R 2 is phenyl, or a pharmaceutically acceptable salt thereof.

[0038] The disubstituted maleimide compound of (7) above, wherein Z at W is

11 12 11 12

hydroxyl group, -NR R (wherein R and R are as defined in (2)) or optionally substituted heterocyclic group, or a pharmaceutically acceptable salt thereof. [0039] The disubstituted maleimide compound of (1) above or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of

3-(lH-indol-3-yl)-4-[(3-methoxyphenyl)amino]- lH-pyrrole-2,5 -dione,

3-(lH-indol-3-yl)-4-(phenylamino)-lH-pyrrole-2,5-dione,

3-(cyclohexylamino)-4-(lH-indol-3-yl)-lH-pyrrole-2,5-dione, 3-( lH-indol-3-yl)-4-[(4- methylphenyl)amino]- lH-pyrrole-2,5-dione,

3-( lH-indol-3-yl)-4-[(3-methylphenyl)amino]- lH-pyrrole-2,5-dione,

3-[(3-chlorophenyl)amino]-4-(lH-indol-3-yl)-lH-pyrrole-2,5-d ione,

3-(lH-indol-3-yl)-4-[(4-meliioxy-2-methylphenyl)amino]-lH-py rrole-2,5-dione,

3-[(2,4-dimethoxyphenyl)amino]-4-( lH-indol-3-yl)- lH-pyrrole-2,5-dione,

3-[(2,4-difluorophenyl)amino]-4-(lH-indol-3-yl)-lH-pyrrole-2 ,5-dione,

3-[(3-bromophenyl)amino]-4-(lH-indol-3-yl)-lH-pyrrole-2,5-di one,

3-(lH-indol-3-yl)-4-[(2-methylphenyl)amino]-lH-pyrrole-2,5-d ione,

3-[(3-fluorophenyl)amino]-4-(lH-indol-3-yl)-lH-pyrrole-2,5-d ione,

3-(lH-mdol-3-yl)-4-[(3-trifluoromethylphenyl)amino]-lH-pyrro le-2,5-dione,

3-( 1 H-indol-3-yl)-4-(biphenyl-3-ylamino)-l H-pyrrole-2,5-dione,

3-(lH-indol-3-yl)-4-[(3-phenoxyphenyl)amino]-l H-pyrrole-2,5-dione,

3-( lH-indol-3-yl)-4-[(3-isopropylphenyl)amino]-l H-pyrrole-2,5-dione,

3-( lH-indol-3-yl)-4-(N-methyl-N-phenylamino)- 1 H-pyrrole-2,5-dione,

3-[ l-(3-hydroxypropyl)- lH-indol-3-yl]-4-(phenyl amino)- lH-pyrrole-2,5-dione,

3-[l-(3-hydroxypropyl)-lH-indol-3-yl]-4-[(3-methylphenyl) amino]-lH-pyrrole-2,5- dione,

3-[(3-cWorophenyl)amino]-4-[l-(3-hydroxypropyl)-lH-indol-3-y l]-lH-pyrrole-2,5- dione,

3-[ l-(2-hydroxyethyl)- lH-indol-3-yl]-4-(phenylarnino)- lH-pyrrole-2,5-dione, 3-[l-(4-hydroxybulyl)-lH-indol-3-yl]-4-(phenylarnino)-lH-pyr role-2,5-dione,

3-[(3,4-dichlorophenyl)amino]-4-[ l-(3-hydroxypropyl)- lH-indol-3-yl]- lH-pyrrole- 2,5-dione,

3-[ l-(2-acetoxyethyl)- lH-indol-3-yl]-4-(phenylamino)- lH-pyrrole-2,5-dione, 3-[l-(3-dimemylaminopropyl)-lH-indol-3-yl]-4-(phenylamino)-l H-pyrrole-2,5-dione, 3-[l-(2-dimethylaminoelhyl)-lH-indol-3-yl]-4-(phenylamino)-l H-pyrrole-2,5-dione, 3-[ l-(4-dimethylaminobutyl)- lH-indol-3-yl]-4-(phenylamino)- lH-pyrrole-2,5-dione, 3-[ l-(3-dimethylaminopropyl)- lH-indol-3-yl]-4-[(3-methylphenyl)amino]- 1H- pyrrole-2,5-dione, 3-[l-(3-dimet±iylaminopropyl)-lH-in^

2,5-dione,

3-[l-(3-diethylaminopropyl)-lH-indol-3-yl]-4-(phenylammo)-lH -pyrrole-2,5-dione, 3 - [1- {3 - [N-(2-dimethylaminoethyl)-N-met Jiylarnino]propyl} -lH-indol-3-yl]-4- (phenylamino)-lH-pyrrole-2,5-dione,

3-[ 1- {3-[N-ethyl-N-(2-methoxyethyl)amino]propyl} - lH-indol-3-yl]-4-

(phenylamino)-lH-pyrrole-2,5-dione,

3-[ 1- {2-[N-(2-dimethylaminoethyl)-N-methylamino]ethyl} - lH-indol-3-yl]-4 (phenylamino)-lH-pyrrole-2,5-dione,

3-[ 1- {3-(N-ben2yl-N-ethylamino)propyl} - lH-indol-3-yl]-4-(phenylamino)-pyrrole 2,5-dione,

3-[ 1- {3-[N-ethyl-N-(4-pyridylmethyl)amino]propyl} - lH-indol-3-yl]-4-

(phenylamino)-lH-pyrrole-2,5-dione,

3-[ l-(3-morpholinopropyl)- lH-indol-3-yl]-4-(phenylamino)- lH-pyrrole-2,5-dione, 3-[l-(3-piperidinopropyl)-lH-indol-3-yl]-4-(phenylamino)-lH- pyrrole-2,5-dione, 3-(phenylamino)-4-[ l-(3-thiomorpholinopropyl)- lH-indol-3-yl]- lH-pyrrole-2,5- dione,

3-(phenylamino)-4-[ l-(3-pyrrolidin-l -ylpropyl)-l H-indol-3-yl]-l H-pyrrole-2,5- dione,

3-[ l-(3-azacycloheptan-l-ylpropyl)- lH-indol-3-yl]-4-(phenylamino)- lH-pyrrole-2,5- dione,

3-[ l-{3-(2-carbamoylpyrrolidin- l-yl)propyl}- lH-indol-3-yl]-4-(phenylamino)- 1H lpyrrole-2,5-dione,

3-[ l-{3-(4-hydroxypiperidino)propyl}- lH-indol-3-yl]-4-(phenylamino)- lH-pyrrole 2,5-dione,

3-[l-{3-(4-methylpiperazin-l-yl)propyl}-lH-indol-3-yl]-4-(ph enylamino)-lH-pyrrole- 2,5-dione,

3-[(3-chlorophenyl)ainino]-4-[l-{4-(4-hydroxypiperidino)buty l}-lH-indol-3-yl]-lH- pyrrole-2,5-dione,

3-[ l-{5-(4-hydroxypiperidino)pentyl}- lH-indol-3-yl]-4-(phenylamino)- 1H -pyrrole 2,5-dione,

3-[ l-{4-(4-methylpiperazin- l-yl)butyl}- lH-indol-3-yl]-4-(phenylamino)- lH-pyrrole- 2,5-dione, 3-[ 1 -{3 - [3 -(tert-butylaminocarbonyl)-decahydro-(4aS, 8 aS)-isoquinolin-2 yl]propyl}- lH-indol-3-yl]-4-(phenylamino)- lH-pyrrole-2,5-dione,

3-(phenylamino)-4-[l-{3-(4-piperidinopiperidino)propyl}-l H-indol-3-yl]-lH-pyrrole- 2,5-dione,

3-[l- {3-[4-(2-hydroxyethyl)piperazin- l-yl]propyl} -1 H-indol-3-yl]-4-(phenylamino)- lH-pyrrole-2,5-dione,

3-[ l-{3-(4-carbamoylpiperidino)propyl}- lH-indol-3-yl]-4-(phenylamino)- 1H pyrrole-2,5-dione,

3-[l-{3-(4-dimethylaminopiperidino)propyl}-lH-mdol-3-yl]-4-( phenylamino)-lH- pyrrole-2,5-dione,

3-[l-{3-(phenylsulfonyl)propyl}-lH-indol-3-yl]-4-(phenylamin o)-lH-pyrrole-2,5- dione,

3-[ l-(3-imidazol-l -ylpropyl)- lH-indol-3-yl]-4-(phenyl amino)- lH-pyrrole-2,5-dione, 3-(phenylamino)-4-[l-(3-pyrazol-l-ylpropyl)-lH-indol-3-yl]-l H-pyiTole-2,5-dione, 3-(phenylamino)-4-[ l-{3-( 1,2,4-triazol- l-yl)propyl}- lH-indol-3-yl]-lH-pyrrole-2,5- dione,

3-[(3-cWorophenyl)amino]-4-[l-(3-imidazol-l-ylpropyl)-lH-ind ol-3-yl]-lH-pyrrole- 2,5-dione,

3-[(3-chlorophenyl)amino]-4-[ l-(4-imidazol- 1-ylbutyl)- lH-indol-3-yl]- lH-pyrrole- 2,5-dione,

3-[l-(5-imidazol-l-ylpentyl)-lH-indol-3-yl]-4-(phenylamino)- lH-pyrrole-2,5-dione,

3-[(3-cWorophenyl)amino]-4-[l-{3-(2-methylimidazol-l-yl)p ropyl}-lH-indol-3-yl]-lH- pyrrole-2,5-dione,

3-[l-(3-ainidmolhiopropyl)-lH-indol-3-yl]-4-(phenylamino)-lH -pyrrole-2,5-dione hydrobromide,

3-[ l-(2,3-dihydroxypropyl)- lH-indol-3-yl]-4-(phenylamino)- lH-pyrrole-2,5-dione, 3-[ l-{3-(hydroxymethyl)benzyl}- lH-indol-3-yl]-4-(phenylamino)- lH-pyrrole-2,5- dione,

3-[ l-(3-hydroxypropyl)-5-methoxy- lH-indol-3-yl]-4-(phenyl amino)- lH-pyrrole-2,5 dione,

3-[l-{2-(4-hydroxypiperidmo)ethyl}-lH-mdol-3-yl]-4-(phenylam ino)-lH-pyrrole-2,5- dione,

3-[ l-{3-(4-benzylpiperidino)propyl}- lH-indol-3-yl]-4-(phenylamino)- 1H -pyrrole- 2,5-dione, 3-[ l-{3-(4-pyrrolidinylpiperidino)propyl}- lH-indol-3-yl]-4-(phenylamino)- 1H- pyrrole-2,5-dione,

3 - [1- {3 - [4-(hydroxyme 1 ±iyl)piperidino]propyl} -lH-uidol-3 -yl] -4-(phenylamino)-lH- pyrrole-2,5-dione,

3-[ 1- {3-[4-(tert-butoxycarbonyl)piperidino]propyl} - lH-indol-3-yl]-4-(phenylamino)- lH-pyrrole-2,5-dione,

3-[2-methyl-l-(3-morpholinopropyl)-lH-indol-3-yl]-4-(phenyla mino)-lH-py^ dione,

3-[2 -methyl- l-(3-piperidinopropyl)- lH-indol-3-yl]-4-(phenyl amino)- lH-pyrrole-2,5- dione,

3-[ l-(3 -dimethyl aminopropyl)-2-methyl- lH-indol-3-yl]-4-(phenylamino)- 1H- pyrrole-2,5-dione,

3-[2-meiJiyl-l-(3-pym)Udin-l-ylpropyl)-lH-mdol-3-yl]-4-(phen ylamino)-lH-pyrrole- 2,5-dione,

3-[l-{3-(el ±iylmethylamino)propyl} -2-methyl-lH-indol-3 -yl] -4-(phenylainino)-lH- pyrrole-2,5-dione,

3-[ l-(3 -dimethyl aminopropyl)-5-methoxy- lH-indol-3-yl]-4-(phenylamino)- 1H- pyrrole-2,5-dione,

3-[(3-chlorophenyl)amino]-4-[ l-{3-(4-methyl-imidazol- l-yl)propyl}- lH-indol-3-yl]- lH-pyrrole-2,5-dione,

3-[(3-chlorophenyl)amino]-4-[ l-{3-(5-methyl-imidazol- l-yl)propyl}- lH-indol-3-yl]- lH-pyrrole-2,5-dione,

3-[(3-chlorophenyl)amino]-4-[ l-{3-(4-hydroxymethyl-imidazol- l-yl)propyl}- 1H- indol-3-yl]-lH-pyrrole-2,5-dioneand3-[(3-chlorophenyl)amino] -4-[l-{3-(5- hydroxymethyl-imidazol- l-yl)propyl}- lH-indol-3-yl]- lH-pyrrole-2,5-dione,

3-[l-{3-(2-methylimidazol-l-yl)propyl}-lH-indol-3-yl]-4-( phenylamino)-lH-pyrrole- 2,5-dione,

3-[l-(2-imidazol-l-ylethyl)-lH-indol-3-yl]-4-(phenylamino)-l H-pyrrole-2,5-dione,

3 -[l-{2-(2 -methyl -imidazol- l-yl)ethyl}- lH-indol-3-yl]-4-(phenylamino)- lH-pyrrole-

2,5-dione,

3-[(4-chlorophenyl)amino]-4-[ l-(3 -imidazol- 1-ylpropyl)- lH-indol-3-yl]- lH-pyrrole- 2,5-dione,

3-[ l-(3 -imidazol- 1-ylpropyl)- lH-indol-3-yl]-4-[(4-methoxyphenyl)amino]- 1H- pyrrole-2,5-dione, 3-[(4-bromophenyl)amino]-4-[l-(3-imidazol-l-ylpropyl)-lH-ind ol-3-yl]-lH-pyrrole- 2,5-dione,

3-[ l-(3-imidazol- 1-ylpropyl)- lH-indol-3-yl]-4-[(4-trifluoromethylphenyl)amino]-lH- pyrrole-2,5-dione,

3-[(4-fluorophenyl)amino]-4-[l-(3-imidazol- 1-ylpropyl)- lH-indol-3-yl]- lH-pyrrole- 2,5-dione,

3-[l-(3-imidazol-l-ylpropyl)-2-meiJiyl-M

2,5-dione,

3-((yclohexylamino)-4-[l-(3-imidazol- 1-ylpropyl)- lH-indol-3-yl]- lH-pyrrole-2,5- dione,

3-(cyclopentylamino)-4-[ l-(3-imidazol- 1-ylpropyl)- lH-indol-3-yl]- lH-pyrrole-2,5- dione,

3-(cycloheptylamino)-4-[ l-(3-imidazol- 1-ylpropyl)- lH-indol-3-yl]- lH-pyrrole-2,5- dione,

3-[l-(3-imidazol-l-ylpropyl)-5-metJioxy-lH-indol-3-yl]-4-(ph enylamino)-lH-pyrrole- 2,5-dione,

3-(phenylamino)-4-[ l-(3-piperidylmethyl)- lH-indol-3-yl]- lH-pyrrole-2,5-dione), 3-(phenylamino)-4-[ l-(4-piperidylmethyl)- lH-indol-3-yl]- lH-pyrrole-2,5-dione, 3-[l-{(l-met±iylpiperidm-3-yl)methyl}-lH-indol-3-yl]-4-(phe nylamino)-lH-py^ 2,5-dione,

3-[l-{(l-methylpiperidin-4-yl)memyl}-lH-indol-3-yl]-4-(pheny lamino)-lH-pyrrole- 2,5-dione,

3-[ l-{[ l-(2,3-dihydroxypropyl)piperidin-4-yl]methyl}- lH-indol-3-yl]-4- (phenylamino)-lH-pyrrole-2,5-dione,

3-[ l-{( l-carbamoylpiperidin-4-yl)methyl}- lH-indol-3-yl]-4-(phenylamino)- 1H- pyrrole-2,5-dione, and

3-[ l-{( l-amidinopiperidin-4-yl)methyl}- lH-indol-3-yl]-4-(phenyl amino)- 1H- pyrrole-2,5-dione hydrochloride.

[0040] The disubstituted maleimide compound of (1) above or a pharmaceutically acceptable salt thereof, which is selected from the group consisting



20

21

22

[0041] A pharmaceutical composition comprising the disubstituted maleimide compound of any of (1) to (10) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0042] At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term "Ci_6 alkyl" is specifically intended to individually disclose methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, and C ₆ alkyl. [0043] For compounds of the invention in which a variable appears more than once, each variable can be a different moiety selected from the Markush group defining the variable. For example, each of R ¹ , R ² , R ³ , R ⁴ , and R ⁵ can be a different moiety selected from the Markush group defining the variable. For another example, where a structure is described having two R groups that are simultaneously present on the same compound; the two R groups can represent different moieties selected from the Markush group defined for R.

[0044] It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0045] The term "n-membered" where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, pyridine is an example of a 6-membered heteroaryl ring and thiophene is an example of a 5-membered heteroaryl group.

[0046] As used herein, the term "alkyl" is meant to refer to a saturated hydrocarbon group which is straight-chained or branched. Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like. An alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms. The term "alkylene" refers to a divalent alkyl linking group. An example of alkylene is methylene (CH ₂ ).

[0047] As used herein, "alkenyl" refers to an alkyl group having one or more double carbon-carbon bonds. Example alkenyl groups include, but are not limited to, ethenyl, propenyl, cyclohexenyl, and the like. The term "alkenylenyl" refers to a divalent linking alkenyl group.

[0048] As used herein, "alkynyl" refers to an alkyl group having one or more triple carbon-carbon bonds. Example alkynyl groups include, but are not limited to, ethynyl, propynyl, and the like. The term "alkynylenyl" refers to a divalent linking alkynyl group.

[0049] As used herein, "haloalkyl" refers to an alkyl group having one or more halogen substituents. Example haloalkyl groups include, but are not limited to CF3, C ₂ F ₅ , CHF ₂ , CC1 ₃ , CHC1 ₂ , C ₂ C1 ₅ , CH ₂ CF ₃ , and the like. [0050] As used herein, "aryl" refers to monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 6 to about 20 carbon atoms. In some embodiments, aryl groups have from 6 to about 10 carbon atoms.

[0051] As used herein, "cycloalkyl" refers to non-aromatic cyclic hydrocarbons including cyclized alkyl, alkenyl, and alkynyl groups that contain up to 20 ring-forming carbon atoms. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems as well as spiro ring systems. A cycloalkyl group can contain from 3 to about 15, from 3 to about 10, from 3 to about 8, from 3 to about 6, from 4 to about 6, from 3 to about 5, or from 5 to about 6 ring-forming carbon atoms. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido. Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of pentane, pentene, hexane, and the like (e.g., 2,3-dihydro-lH-indene-l-yl, or lH-inden-2(3H)-one-l- yi).

[0052] As used herein, "heteroaryl" groups refer to an aromatic heterocycle having up to 20 ring-forming atoms and having at least one heteroatom ring member (ring-forming atom) such as sulfur, oxygen, or nitrogen. In some embodiments, the heteroaryl group has at least one or more heteroatom ring-forming atoms each independently selected from sulfur, oxygen, and nitrogen. Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Examples of heteroaryl groups include without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like. In some embodiments, the heteroaryl group has from 1 to about 20 carbon atoms, and in further embodiments from about 1 to about 5, from about 1 to about 4, from about 1 to about 3, from about 1 to about 2, carbon atoms as ring-forming atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. [0053] As used herein, "heterocycloalkyl" refers to non-aromatic heterocycles having up to 20 ring-forming atoms including cyclized alkyl, alkenyl, and alkynyl groups where one or more of the ring-forming carbon atoms is replaced by a heteroatom such as an O, N, or S atom. Heterocycloalkyl groups can be mono or polycyclic (e.g., both fused and spiro systems). Example "heterocycloalkyl" groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1 ,3-benzodioxole, benzo-l ,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, pyrrolidin-2-one-3-yl, and the like. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by oxo or sulfido. For example, a ring-forming S atom can be substituted by 1 or 2 oxo [i.e., form a S(O) or S(0) ₂ ]. For another example, a ring-forming C atom can be substituted by oxo (i.e., form carbonyl). Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example pyridinyl, thiophenyl, phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles such as indolene, isoindolene, isoindolin-l-one-3-yl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-yl, 5,6-dihydrothieno[2,3- c]pyridin-7(4H)-one-5-yl, and 3,4-dihydroisoquinolin-l(2H)-one-3yl groups. Ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can be optionally substituted by oxo or sulfido. In some embodiments, the heterocycloalkyl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heterocycloalkyl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring- forming atoms. In some embodiments, the heterocycloalkyl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds.

[0054] As used herein, "halo" or "halogen" includes fluoro, chloro, bromo, and iodo.

[0055] As used herein, "alkoxy" refers to an -O-alkyl group. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.

[0056] As used herein, "haloalkoxy" refers to an -O-haloalkyl group. An example haloalkoxy group is OCF ₃ .

[0057] As used herein, "arylalkyl" refers to a Ci_ ₆ alkyl substituted by aryl and "cycloalkylalkyl" refers to Ci_ ₆ alkyl substituted by cycloalkyl. [0058] As used herein, "heteroarylalkyl" refers to a Ci_ ₆ alkyl group substituted by a heteroaryl group, and "heterocycloalkylalkyl" refers to a Ci_ ₆ alkyl substituted by heterocycloalkyl.

[0059] As used herein, "amino" refers to NH ₂ .

[0060] As used herein, "alkylamino" refers to an amino group substituted by an alkyl group.

[0061] As used herein, "dialkylamino" refers to an amino group substituted by two alkyl groups.

[0062] As used here, C(O) refers to C(=0).

[0063] As used here, C(S) refers to C(=S).

[0064] As used here, S(O) refers to S(=0).

[0065] As used here, S(0) ₂ refers to S(=0) ₂ .

[0066] As used herein, the term "optionally substituted" means that substitution is optional and therefore includes both unsubstituted and substituted atoms and moieties. A "substituted" atom or moiety indicates that any hydrogen on the designated atom or moiety can be replaced with a selection from the indicated substituent group, provided that the normal valency of the designated atom or moiety is not exceeded, and that the substitution results in a stable compound. For example, if a methyl group (i.e., CH ₃ ) is optionally substituted, then up to 3 hydrogen atoms on the carbon atom can be replaced with substituent groups.

[0067] Some compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. Where a compound capable of stereoisomerism or geometric isomerism is designated in its structure or name without reference to specific R/S or cis/trans configurations, it is intended that all such isomers are contemplated. [0068] Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An example method includes fractional recrystallizaion using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as Π-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of Q-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N- methylephedrine, cyclohexylethylamine, 1 ,2-diaminocyclohexane, and the like.

[0069] Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.

[0070] Some compounds of the invention may also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H- pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

[0071] Some compounds of the invention further include hydrates and solvates, as well as anhydrous and non-solvated forms.

[0072] The term, "compound," as used herein is meant to include all stereoisomers, geometric iosomers, tautomers, and isotopes of the structures depicted.

[0073] All compounds and pharmaceutically acceptable salts thereof, can be prepared or present together with other substances such as water and solvents (e.g. hydrates and solvates) or can be isolated.

[0074] Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. [0075] In some embodiments, the compounds of the invention, or salts thereof, are substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which is formed or detected. Partial separation can include, for example, a composition enriched in the compound of the invention. Substantial separation can include compositions containing at least about 50%, at least about 60%>, at least about 70%>, at least about 80%>, at least about 90%>, at least about 95%), at least about 97%, or at least about 99% by weight of the compound of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.

[0076] In some embodiments, compounds of the invention are intended to include compounds with stable structures. As used herein, "stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0077] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0078] The expressions, "ambient temperature" and "room temperature," as used herein, are understood in the art, and refer generally to a temperature, e.g. a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 °C to about 30 °C.

[0079] In some embodiments, the present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile (ACN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0080] In some embodiments, the present invention also includes quaternary ammonium salts of the compounds described herein, where the compounds are primary amines, secondary amines, or tertiary amines. As used herein, "quaternary ammonium salts" refers to derivatives of the disclosed primary amine, secondary amine, or tertiary amine compounds wherein the parent amine compounds are modified by converting the amines to quaternary ammonium cations via alkylation (and the cations are balanced by anions such as CI ^" , CH ₃ COO ^" , or CF ₃ COO ^" ), for example methylation or ethylation.

SYNTHESIS

[0081] The compounds disclosed herein can be made in accordance with the methods disclosed in WO 00/06564 (and the corresponding English language version Canadian patent application no. 2,338,866), which is hereby incorporated by reference in its entirety.

METHODS

[0082] Certain compounds of the invention have an IC50 with respect to JAK3 less than about 1000 nM, 500 nM, 200 nM, 100 nM, 50 nM, 20 nM, 10 nM, 5 nM, 2 nM, or 1 nM. Accordingly, compounds of the invention can modulate activity of JAK3. The term "modulate" is meant to refer to an ability to increase or decrease the activity of JAK3. Accordingly, compounds of the invention can be used in methods of modulating a JAK3 by contacting the JAK3 with any one or more of the compounds or compositions described herein. In some embodiments, compounds of the present invention can act as inhibitors of JAK3. In further embodiments, the compounds of the invention can be used to modulate (e.g. inhibiting) activity of a JAK3 in an individual in need of modulation (e.g. inhibition) of the enzyme by administering a modulating (e.g. inhibiting) amount of a compound of the invention.

[0083] In some embodiments, the modulating (e.g. inhibiting) JAK3 is selective over other members of the JAK family [i.e., JAK1, JAK2, and TYK2]. In some embodiments, the compounds used in the invention show 25% or more of binding to JAK3 comparing to other members of the JAK family. In some embodiments, the IC50 of compounds of the invention with respect to JAKl, JAK2, or TYK2 is greater than 1 μΜ, 5 μΜ, 10 μΜ, 20 μΜ, 50 μΜ, 100 μΜ, or 200 μΜ. In some embodiments, the relative ratio of IC50 of the compounds of invention with respect to JAKl, JAK2, or TYK2 to that with respect to JAK3 is greater than about 5: 1, 10: 1, 20: 1, 50: 1, 100: 1, 200: 1, 500: 1, 1000: 1, 2000: 1, 5000: 1, or 10000: 1.

[0084] Another aspect of the present invention pertains to methods of treating a JAK3 -associated disease or disorder in an individual (e.g., patient) by administering to the individual a therapeutically effective amount or dose of a compound of the present invention or a pharmaceutical composition thereof. In some embodiments, the individual has been diagnosed to have a JAK3 -associated disease or disorder and is in need of treatment for the disease or disorder. A JAK3 -associated disease can include any disease, disorder, or condition that is directly or indirectly linked to expression or activity of the JAK3, including over expression and/or abnormal activity levels. A JAK3 -associated disease can also include any disease, disorder or condition that can be prevented, ameliorated, or cured by modulating J AK activity.

[0085] Examples of JAK3 -associated diseases include diseases involving the immune system including, for example, organ transplant rejection [e.g., allograft rejection and graft versus host disease (GVHD)]. Some other examples of JAK3 -associated diseases include a mast cell mediated immediate hypersensitivity reaction, platelet aggregation, and thrombus formation.

[0086] Further examples of JAK3 -associated diseases include autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, type I diabetes, lupus, psoriasis, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), ankylosing spondylitis, myasthenia gravis, immunoglobulin nephropathies, autoimmune thyroid disorders, and the like. In some embodiments, the autoimmune disease is an autoimmune bullous skin disorder such as pemphigus vulgaris (PV) or bullous pemphigoid (BP). In some embodiments, JAK-associated diseases include rheumatoid arthritis.

[0087] Further examples of JAK3 -associated diseases include allergic or type I hypersensitivity reaction such as urticaria and eczema, conjunctivitis, rhinorrhea, rhinitis,, asthma, gastroenteritis, familial amyotrophic lateral sclerosis, lupus, multiple sclerosis, Type I diabetes and complications from diabetes, cancer, asthma, rhinitis, atopic dermatitis, autoimmune thyroid disorders, Alzheimer's disease, leukemia, thrombus and other autoimmune disease. [0088] Further examples of JA 3 -associated diseases or conditions include skin disorders such as psoriasis (for example, psoriasis vulgaris), atopic dermatitis, alopecia areata, skin rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis). For example, certain substances including some pharmaceuticals when topically applied can cause skin sensitization. In some embodiments, co-administration or sequential administration of at least one JAK3 inhibitor of the invention together with the agent causing unwanted sensitization can be helpful in treating such unwanted sensitization or dermatitis. In some embodiments, the skin disorder is treated by topical administration of at least one JAK inhibitor of the invention.

[0089] The JAK3 antagonists/inhibitors described herein can be used to treat any of the JAK3 -associated diseases, disorders or conditions, or any combination thereof.

[0090] Treatment of the diseases/disorders herein includes treating one or more symptoms associated with the diseases/disorders. For example, symptoms of a JAK3- associated skin disorder (such as psoriasis, atopic dermatitis, skin rash, skin irritation, or skin sensitization) include itching (prutitus).

[0091] As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a JAK3 with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having a JAK3, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the JAK3.

[0092] As used herein, the term "individual" or "patient," used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.

[0093] As used herein, the phrase "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.

[0094] As used herein, the term "treating" or "treatment" refers to one or more of (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting/retarding the disease; for example, inhibiting/retarding a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder; and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease or completely eliminating/curing the disease. As used herein, treating a disease further includes treating one or more symptoms associated with the disease.

[0095] Combination Therapies

[0096] One or more additional pharmaceutical agents such as, for example, antiinflammatory agents, steroids, immunosuppressants, as well as another JAK3 and/or other kinase inhibitors, such as BTK kinase and JAK2 kinase such as, for example, those described in WO 99/65909, WO 00/00202, and/or WO/2004/099205, or other agents can be used in combination with the compounds of the present invention for treatment of JAK3 -associated diseases, disorders or conditions. The one or more additional pharmaceutical agents can be administered to a patient simultaneously or sequentially.

[0097] In some embodiments, one or more JAK3 inhibitors/antagonists of the invention can be used in combination with one or more other therapeutics used in the treatment of JAK3-mediated/associated conditions/diseases/disorders, and may improve the treatment response as compared to the response to the other therapeutics alone, without exacerbation of its toxic effects. Additive or synergistic effects are desirable outcomes of combining a JAK3 inhibitor/antagonist of the present invention with one or more additional agent. The additional agents can be combined with the present compounds in a single or continuous dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms. In some embodiments, one or more additional agents can be administered to a patient in combination with at least one JAK3 inhibitor/antagonist described herein where the additional agents are administered intermittently as opposed to continuously.

[0098] Pharmaceutical Formulations and Dosage Forms

[0099] When employed as pharmaceuticals, the compounds of the invention can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. Coated condoms, gloves and the like may also be useful.

[00100] This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of the invention above in combination with one or more pharmaceutically acceptable carriers (excipients). In making the compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[00101] In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.

[00102] The compounds of the invention may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types. Finely divided (nano particulate) preparations of the compounds of the invention can be prepared by processes known in the art, for example see International Patent Application No. WO 2002/000196.

[00103] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.

[00104] The compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 1000 mg (1 g), more usually about 100 to about 500 mg, of the active ingredient. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[00105] The active compound can be effective over a wide dosage range and can be generally administered in a pharmaceutically effective amount. For example, the dosage of the active compounds of the invention as employed for the treatment of a patient in need thereof (such as an adult human) may range from 0.1 to 3000 mg per day, depending on the route and frequency of administration. Such a dosage corresponds to 0.001 to 50 mg/kg per day. In some embodiments, the dosage of the active compounds of the invention as employed for the treatment of a patient in need thereof (such as an adult human) may range from 1 to 2000 mg per day, from 1 to 1000 mg per day, from 10 to 1000 mg per day, or from 10 to 500 mg per day. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[00106] For preparing solid compositions such as tablets, the principal active ingredient can be mixed with a pharmaceutical excipient to form a solid pre-formulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these pre-formulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid pre-formulation is then subdivided into unit dosage forms of the type described above containing from, for example, about 0.1 to about 1000 mg of the active ingredient of the present invention. [00107] The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[00108] The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[00109] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.

[00110] The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.

[00111] The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11 , more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.

[00112] The therapeutic dosage of the compounds of the present invention can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dose ranges are from about l Qg/kg to about 1 g/kg of body weight per day. In some embodiments, the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose- response curves derived from in vitro or animal model test systems.

[00113] The compositions of the invention can further include one or more additional pharmaceutical agents such as a chemotherapeutic, steroid, anti-inflammatory compound, or immunosuppressant, examples of which are listed hereinabove.

[00114] Labeled Compounds and Assay Methods

[00115] Another aspect of the present invention relates to labeled compounds of the invention (radio-labeled, fluorescent-labeled, etc.) that would be useful not only in radio- imaging but also in assays, both in vitro and in vivo, for localizing and quantitating the enzyme in tissue samples, including human, and for identifying ligands by inhibition binding of a labeled compound. Accordingly, the present invention includes enzyme assays that contain such labeled compounds.

[00116] In some embodiments, the present invention further includes isotopically- labeled compounds of the invention. An "isotopically" or "radio-labeled" compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 2H (also written as D for deuterium), 3H (also written as T for tritium), 11C, 13C, 14C, 13N, 15N, 150, 170, 180, 18F, 35S, 36C1, 82Br, 75Br, 76Br, 77Br, 1231, 1241, 1251 and 1311. The radionuclide that is incorporated in the radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro receptor labeling and competition assays, compounds that incorporate 3H, 14C, 82Br, 1251 , 1311, 35S or will generally be most useful. For radio-imaging applications 11C, 18F, 1251, 1231, 1241, 1311, 75Br, 76Br or 77Br will generally be most useful.

[00117] It is understood that a "radio-labeled compound" is a compound that has incorporated at least one radionuclide. In some embodiments the radionuclide is selected from 3H, 14C, 1251 , 35S and 82Br.

[00118] In some embodiments, the labeled compounds of the present invention contain a fluorescent label.

[00119] Synthetic methods for incorporating radio-isotopes and fluorescent labels into organic compounds are well known in the art.

[00120] A labeled compound of the invention (radio-labeled, fluorescent-labeled, etc.) can be used in a screening assay to identify/evaluate compounds. For example, a newly synthesized or identified compound (i.e., test compound) which is labeled can be evaluated for its ability to bind a JAK3 by monitoring its concentration variation when contacting with the JAK3, through tracking the labeling. For another example, a test compound (labeled) can be evaluated for its ability to reduce binding of another compound which is known to bind to JAK3 (i.e., standard compound). Accordingly, the ability of a test compound to compete with the standard compound for binding to the JAK3 directly correlates to its binding affinity. Conversely, in some other screening assays, the standard compound is labeled and test compounds are unlabeled. Accordingly, the concentration of the labeled standard compound is monitored in order to evaluate the competition between the standard compound and the test compound, and the relative binding affinity of the test compound is thus ascertained.

[00121] Kits

[00122] In some embodiments, the present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of JAK3 -associated diseases or disorders such as allergies, asthma, autoimmune diseases such as transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis as well as in solid and hematologic malignancies such as leukemias and lymphomas, and other diseases referred to herein which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.

[00123] Some embodiments of the invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of non-critical parameters which can be changed or modified to yield essentially the same results. In some instances where the compounds of the examples were isolated by preparative HPLC in the presence of trifluoroacetic acid (TFA) or other acid, the compound may have been obtained as the corresponding salt. Certain compounds of the Examples were found to be inhibitors of JAK3 according to one or more of the assays provided herein. In some embodiments, the IC50 value for the compound of invention with respect JAK3 is less than about 100, 80, 50, 20, 10, 8, 5, 2, or 1 μΜ. In some embodiments, the IC50 value for the compound of invention with respect to JAK3 is less than about 1000, 800, 500, 200, 100, 80, 50, 20, 10, 5, 2, or 1 nM. Certain compounds described in Tables 1 and in the Example section were tested for inhibitory activity of JAK3 targets according to assays such as those described herein or those known in the art (e.g., Ma H et al, Expert Opin. Drug Discov. 3, 607-621 (2008); Olive DM, Expert Rev Proteomics, 1, 327 -341 (2004)). For instance, Examples 1, 8, 9, and 16 were found to have IC50 values less than 1000 nM, 800 nM, 500 nM, 200 nM, or 100 nM with respect to JAK3. Examples 1, 8, 9, and 16 were found to be JAK3 selective: they have IC50 values greater than 10 μΜ, 15 μΜ, or 20 μΜ with respect to JAK1, JAK2, and/or TYK2. Some exemplary data of the compounds of the invention are shown in Table 1 in the experimental section.

[00124] EXAMPLE:

[00125] A known PKC beta inhibitor, CAS number of 257879-35-9,

has been found to exhibit good JAK3 selectivity.

Table 1 : inhibition activities towards JAKs family enzymes.

IC50 (nM) Example 1 Example 1

(53964) (53964)

JAK1 38.55 32.54

JAK2 358.7 408.1

JAK3 <1 .5 <1 .5

TYK2 293.20 272.60

PKCb <1 .5 <1 .5

[00126] Current Jak3 inhibitors are not selective. Some of the most advanced JAK3 inhibitors have 2 to 3 fold selectivity over JAK2. As shown above, the compound of Example 1 is over 400-fold more selective toward JAK3 over JAK2.

[00127] Example 1 has been tested in a T-cell line for cell based activity. This compound was active in cell based assay, but relatively weak compared to a known JAK inhibitor as expected, since JAK2 also participates STAT5 pathway (Fig. 1).

[00128] Western blot detection of phosphorylated stat5 in SZ-4 cells stimulated with IL2. SZ-4 cells were treated with compounds or DMSO control for 1.5 hr in RPMI supplemented with 0.5% fetal bovine serum. IL-2 was added to the cell cultures at 3ng/ml for 30 min. Immediately after stimulation, the cells were collected and lysed in RIP A buffer supplemented with Halt protease and phosphatase inhibitors. The cell lysates were analyzed in 7.5%SDS-PAGE, transferred to PVDF membrane and blotted with anti-stat5-pi (CST) antibody according to manufacturer's instruction. The known JAK inhibitor, CP, was used as positive control.

[00129] This compound and its analogues can be JAK inhibitors especially for immune related diseases that the JAK3 associated with.

[00130] Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in the present application is herein incorporated by reference in its entirety.