WO2013025628A1 - Janus kinase inhibitor compounds and methods - Google Patents

Abstract

The present invention relates to Janus kinase inhibitor compounds, prodrugs, and compositions thereof. Some embodiments include the use of such compounds and compositions for the treatment or prevention of skin and/or eye disorders. Claimed are prodrug compounds of Formula I, II, III: (Formula I, II, III) wherein: A is selected from the group consisting of phosphono, phosphonomethyl, phosphonooxymethyl, alkylaminocarbonyl, and acetyl; wherein the acetyl is optionally substituted with methyl, ethyl, propyl, isopropyl, amino, methylamino, dimethylamino, benzyl, pyrrolidinyl, hydroxylcarbonylmethyl, and hydroxylated tetrahydropyranyl; The other variables are as defined in the claims.

Description

JANUS KINASE INHIBITOR COMPOUNDS AND METHODS

RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional No 61/523,720 entitled "JANUS KINASE INHIBITOR COMPOUNDS AND METHODS" filed on August 15, 2011, which is expressly incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0002] This disclosure relates generally to compounds that act as Janus kinase inhibitors or prodrugs thereof and compositions containing such compounds. Some embodiments include the use of such compounds and compositions for the treatment or prevention of skin and/or eye disorders.

BACKGROUND

[0003] Immunosuppression is an important clinical approach in treating autoimmune disease and in preventing organ and tissue rejection. Clinically available immunosuppressants, including azathioprine, cyclosporine and tacrolimus often cause undesirable side effects including nephrotoxicity, hypertension, gastrointestinal disturbances and gum inflammation. Inhibitors of the tyrosine kinase Jak3 are known to be useful as immunosuppressants (see e.g., US patent 6,313,129).

[0004] The members of the Janus kinase (Jak) family of non-receptor intracellular tyrosine kinases are components of cytokine signal transduction. Four family members have been identified to date: Jakl, Jak2, Jak3 and Tyk2. The Jak family members play a key role in the intracellular signaling mediated through cytokine receptors. Upon binding of cytokines to their receptors, Jak family members are activated and phosphorylate the receptors, creating docking sites for other signaling molecules, in particular, members of the signal transducer and activator of transcription (STAT) family. While expression of Jakl, Jak2 and Tyk2 is relatively ubiquitous, Jak3 expression is temporally and spatially regulated. Jak3 is predominantly expressed in cells of hematopoietic lineage; it is constitutively expressed in natural killer (NK) cells and thymocytes and is inducible in T cells, B cells and myeloid cells. Jak3 is also is expressed in mast cells, and its enzymatic activity is enhanced by IgE receptor/FccRI cross- linking.

[0005] A specific, orally active Jak3 inhibitor, CP-690,550 (tofacitinib), has been shown to act as an effective immunosuppressant and prolong animal survival in a murine model of heart transplantation and a primate model of kidney transplantation (Changelian P.S., et al., 2003, "Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor." Science 302: 875-878), and to meet primary endpoints in phase III clinical trials in patients with moderate-to-severe rheumatoid arthritis (RA) (Pfizer Press Release Mar 4, 2011 Primary Endpoints Met In Second Phase 3 Clinical Trial of Tofacitinib (CP-690,550) In Patients with Active Rheumatoid Arthritis).

[0006] Many skin and eye diseases or conditions are associated with disorders in immune system. For example, psoriasis is a chronic autoimmune disease that appears on the skin and a T-cell-mediated disorder. In a phase I clinical trial, oral CP-690,550 showed early promise against psoriasis (Boy MG, et al., 2009 "Double-Blind, Placebo-Controlled, Dose-Escalation Study to Evaluate the Pharmacologic Effect of CP-690,550 in Patients with Psoriasis." J Inves Dermatol 129, 2299-2302). A topical Jak 3 inhibitor may offer better efficacy and safety for the treatment of psoriasis. Dry eyes are typically associated with autoimmune disorders such as Sjogren's syndrome, or sometimes may be a symptom of diseases such as rheumatoid arthritis or systemic lupus erythematosus (lupus). Uveitis is another eye condition related to inflammation of the middle layer of the eye. In an ophthalmic formulation, CP-690,550 demonstrated antiinflammatory activities in dry eye patients in a phase I/II study (Huang J-F, et al., 2011 Modulation of HLA-DR On Conjunctival Cells And Inflammatory Mediators In Tears In Dry Eye Patients By CP-690,550, A Selective Inhibitor of The JAK Family. Poster#: D957, ARVO2011, Fort Lauderdale, FL).

[0007] Jak3 has also been shown to play a role in mast cell-mediated allergic reactions and inflammatory diseases and serves as a target in indications such as asthma and anaphylaxis. Accordingly, there is a need for inhibitors of Jak3 that are useful for topical and ocular indications such as psoriasis, dry eyes, mast cell-mediated allergic reactions and inflammatory diseases and disorders.

SUMMARY OF THE INVENTION

[0008] The present disclosure relates generally to compounds that act as Janus kinase inhibitors or prodrugs thereof and compositions containing such compounds. Some embodiments include the use of such compounds and compositions for the treatment or prevention of skin and/or eye disorders. Some embodiments include inhibitors of Jak3 compounds or prodrugs thereof.

[0009] Some embodiments include a prodrug compound, having a structure selected from Formula I, II, III:

(Ill)

wherein:

R¹ is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, and CN;

R² is absent, or is selected from the group consisting of hydrogen, methyl, ethyl, cyanomethyl, 4-pyridinylmethyl, and 2-hydroxyethyl;

R³ is oxygen when R² is not absent;

R³ is selected from the group consisting of NH₂, NHCH , methyl, and 5- pyrimidinyl when R² is absent;

R⁴ and R⁵ are independently selected from hydrogen and fluorine; R⁶ is selected from hydrogen and morpholinylcarbonyl;

R⁷ and R⁸ are independently selected from hydrogen, fluorine, and methyl; or R⁷ and R⁸ together with the atoms to which they are attached form an optionally substituted 5- or 6-member-ring heterocycle;

R⁹ is selected from hydrogen and OH;

R¹⁰ is selected from 4-tetrahydropyranyl, 4-(8-fluoro)chromanyl, 3,4- dihydroxylcyclohexyl, 2,6-difluorobenzyl, and optionally substituted l-(4-hydroxy- 1 ,2,3 ,4-tetrahydro)naphthalenyl;

A is selected from the group consisting of phosphono, phosphonomethyl, phosphonooxymethyl, alkylaminocarbonyl, and acetyl; wherein the acetyl is optionally substituted with methyl, ethyl, propyl, isopropyl, amino, methylamino, dimethylamino, benzyl, pyrrolidinyl, hydroxylcarbonylmethyl, and hydroxylated tetrahydropyranyl;

D is selected from the group consisting of alkyloxy, phosphate, phosphonomethoxy, phosphonooxymethoxy, acetylamino, and acetyloxy; wherein the acetyl of the acetyloxy and acetylamino is optionally substituted with methyl, ethyl, propyl, isopropyl, amino, methylamino, dimethylamino, benzyl, pyrrolidinyl, hydroxylcarbonylmethyl, and hydroxylated tetrahydropyranyl;

X is selected from C and N;

the dashed line "— " is a bond or is absent; and

pharmaceutically acceptable salts thereof.

[0010] In some embodiments, R² is selected from the group consisting of hydrogen, methyl, ethyl, cyanomethyl, 4-pyridinylmethyl, and 2-hydroxyethyl.

[0011] In some embodiments, R¹ is selected from CN and fluorine.

[0012] In some embodiments, R¹ is selected from nitrogen, chlorine and methyl.

[0013] In some embodiments, R³ is selected from the group consisting of NH₂, NHCH₃, methyl, and 5-pyrimidinyl. In some embodiments, R¹ is CN.

[0014] In some embodiments, R¹ is chlorine; and R⁶ is selected from hydrogen and morpholinylcarbonyl.

[0015] In some embodiments, R¹ is CN; and R⁶ is selected from hydrogen and morpholinylcarbonyl. In some embodiments, R⁹ is hydrogen. In some embodiments, R⁷ and R⁸ are linked to form an optionally substituted 5- or 6-member-ring heterocycle.

[0016] In some embodiments, R¹ is CN; and R¹⁰ is selected from 4- tetrahydropyranyl, 4-(8-fluoro)chromanyl, 3,4-dihydroxylcyclohexyl, 2,6-difluorobenzyl, and optionally substituted 1 -(4-hydroxy- 1 ,2,3 ,4-tetrahydro)naphthalenyl.

-7-

pharmaceutically acceptable salts or prodrugs thereof.

[0018] More embodiments include a method of treating a skin or eye disorder related to an immune disorder responsive to Jak 3 inhibitor therapy, said method comprising administering parenterally to a subject in need thereof an effective amount of a compound described herein.

[0019] More embodiments include the use of a compound described herein for treating a skin or eye disorder related to an immune disorder responsive to Jak 3 inhibitor therapy comprising administering parenterally to a subject in need thereof an effective amount of the compound.

[0020] More embodiments include the use of a compound described herein in the manufacture of a medicament for the treatment of a disorder responsive to inhibition of Janus kinase 3.

[0021] More embodiments include the use of the compound described herein in the manufacture of a medicament for the treatment of a disorder selected from the group consisting of an autoimmune disease, an inflammatory disease, a mast cell mediated disease, a cancer, a hematological malignancy, and organ transplant rejection.

[0022] More embodiments include a method of treating a disorder selected from the group consisting of an autoimmune disease, an inflammatory disease, a mast cell mediated disease, a cancer, a hematological malignancy, and organ transplant rejection, said method comprising administering parenterally to a subject in need thereof an effective amount of a compound described herein. [0023] More embodiments include a method of treating a skin or eye disorder related to an immune disorder responsive to Jak 3 inhibitor therapy, said method comprising administering parenterally to a subject in need thereof an effective amount of a compound selected from the group consisting of:

harmaceutically acceptable salts or prodrugs thereof.

[0024] More embodiments include the use of a compound described herein in the manufacture of a medicament for the treatment of a disorder responsive to inhibition of Janus kinase 3.

[0025] More embodiments include the use of the compound described herein in the manufacture of a medicament for the treatment of a disorder selected from the group consisting of an autoimmune disease, an inflammatory disease, a mast cell mediated disease, a cancer, a hematological malignancy, and organ transplant rejection.

[0026] More embodiments include a method of treating a disorder selected from the group consisting of an autoimmune disease, an inflammatory disease, a mast cell mediated disease, a cancer, a hematological malignancy, and organ transplant rejection, said method comprising administering parenterally to a subject in need thereof an effective amount of a compound described herein.

DETAILED DESCRIPTION

[0027] The present invention relates to Janus kinase inhibitor compounds or prodrugs thereof and compositions thereof. Some embodiments include the use of such compounds and compositions for the treatment or prevention of skin and/or eye disorders.

[0028] Some embodiments include prodrug compounds having Formula I, II, and III:

I)

(HI)

wherein:

R¹ is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, and CN;

R² is absent, or is selected from the group consisting of hydrogen, methyl, ethyl, cyanomethyl, 4-pyridinylmethyl, and 2-hydroxyethyl;

R³ is oxygen when R² is not absent;

R³ is selected from the group consisting of NH₂, NHCH₃, methyl, and 5- pyrimidinyl when R² is absent;

R⁴ and R⁵ are independently selected from hydrogen and fluorine;

R⁶ is selected from hydrogen and morpholinylcarbonyl; R⁷ and R⁸ are independently selected from hydrogen, fluorine, and methyl; or R⁷ and R⁸ together with the atoms to which they are attached form an optionally substituted 5- or 6-member-ring heterocycle;

R⁹ is selected from hydrogen and OH;

R¹⁰ is selected from 4-tetrahydropyranyl, 4-(8-fluoro)chromanyl, 3,4- dihydroxylcyclohexyl, 2,6-difluorobenzyl, and optionally substituted l-(4-hydroxy- 1 ,2,3 ,4-tetrahydro)naphthalenyl;

A is selected from the group consisting of phosphono, phosphonomethyl, phosphonooxymethyl, alkylaminocarbonyl, and acetyl; wherein the acetyl is optionally substituted with methyl, ethyl, propyl, isopropyl, amino, methylamino, dimethylamino, benzyl, pyrrolidinyl, hydroxylcarbonylmethyl, and hydroxylated tetrahydropyranyl;

D is selected from the group consisting of alkyloxy, phosphate, phosphonomethoxy, phosphonooxymethoxy, acetylamino, and acetyloxy; wherein the acetyl of the acetyloxy and acetylamino is optionally substituted with methyl, ethyl, propyl, isopropyl, amino, methylamino, dimethylamino, benzyl, pyrrolidinyl, hydroxylcarbonylmethyl, and hydroxylated tetrahydropyranyl;

X is selected from C and N;

the dashed line "— " is a bond or is absent; and

pharmaceutically acceptable salts or prodrugs thereof.

[0029] In some embodiments, R² is selected from the group consisting of hydrogen, methyl, ethyl, cyanomethyl, 4-pyridinylmethyl, and 2-hydroxyethyl.

[0030] In some embodiments, R¹ is selected from CN and fluorine.

[0031] In some embodiments, R¹ is selected from chlorine and methyl.

[0032] In some embodiments, R³ is selected from the group consisting of NH₂, NHCH₃, methyl, and 5-pyrimidinyl. In some embodiments, R¹ is CN.

[0033] In some embodiments, R¹ is chlorine; and R⁶ is selected from hydrogen and morpholinylcarbonyl.

[0034] In some embodiments, R¹ is CN; and R⁶ is selected from hydrogen and morpholinylcarbonyl. In some embodiments, R⁹ is hydrogen. In some embodiments, R⁷ and R⁸ are linked to form an optionally substituted 5- or 6-member-ring heterocycle.

[0035] In some embodiments, R¹ is CN; and R¹⁰ is selected from 4- tetrahydropyranyl, 4-(8-fluoro)chromanyl, 3,4-dihydroxylcyclohexyl, 2,6-difluorobenzyl, and optionally substituted 1 -(4-hydroxy- 1 ,2,3 ,4-tetrahydro)naphthalenyl. , ιο

[0036] In some embodiments, R¹, R², R^?, R⁴, R⁵, R⁶, R^?, R⁸' ^{and R are selected} from the corresponding groups present in Examples 101-154.

[0037] Some embodiments include compounds having a structure selected from the followin :

-15-

pharmaceutically acceptable salts or prodrugs thereof.

[0038] Some embodiments include a method of treating a skin or eye disorder related to an immune disorder responsive to Jak 3 inhibitor therapy, said method comprising administering parenterally to a subject in need thereof an effective amount of a compound selected from:

1 -(7-Ethyl-9-(( 1 l,41)-4-hydroxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)-8-oxo-8,9-dihydro- 7H-purin-2-yl)-lH-benzo[(i]imidazole-6-carbonitrile;

1 -(9-(( 1 l,41)-4-Hydroxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)-8-oxo-7-(pyridin-4- ylmethyl)-8,9-dihydro-7H-purin-2-yl)-lH-benzo[(i]imidazole-6-carbonitrile;

1 -(9-(( 11,41)-5 ,7-Difiuoro-4-hydroxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)-7-methyl-8- oxo-8,9-dihydro-7H-purin-2-yl)-lH-benzo[(i]imidazole-6-carbonitrile;

9-(( 11,41)-5 ,7-Difluoro-4-hydroxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)-2-(6-fluoro- 1H- benzo[(i]imidazol-l-yl)-7-methyl-7H-purin-8(9H)-one;

9-(( 1 l,41)-7-Fluoro-4-hydroxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)-2-(6-fluoro- 1H- benzo[(i]imidazol-l-yl)-7-methyl-7H-purin-8(9H)-one;

9-(( 1 l,41)-7-Fluoro-4-hydroxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)-2-(6-chloro- 1H- benzo[(i]imidazol-l-yl)-7-methyl-7H-purin-8(9H)-one;

1 -(7-(Cyanomethyl)-9-(( 1 l,41)-5-fluoro-4-hydroxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)-8- oxo-8,9-dihydro-7H-purin-2-yl)-lH-benzo[(i]imidazole-6-carbonitrile;

l-(8-Oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)-lH- benzo[d]imidazole-6-carbonitrile; 2-(6-Fluoro-lH-benzo[ ]imidazol-l-yl)-9-(8-fluorochroman-4-yl)-7H-purin-8(9H)-one;

1- (9-(2,6-Difluorobenzyl)-8-oxo-8,9-dihydro-7H-purin-2-yl)-lH-benzo[(i]imidazole-6- carbonitrile;

9-(( 11,41)-5 ,7-Difluoro-4-hydroxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)-2-(6-fiuoro- 1 Η- benzo[d]imidazol-l-yl)-7H-purin-8(9H)-one;

9-(( 11,41)-5 ,7-Difluoro-4-hydroxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)-2-(6-cyano- 1 Η- benzo[d]imidazol-l-yl)-7H-purin-8(9H)-one;

2- (6-Chloro- lH-benzo[ Jimidazol- 1 -yl)-9-((l l,41)-7-fluoro-4-hydroxy- 1 ,2,3 ,4- tetrahydronaphthalen- 1 -yl)-7H-purin-8(9H)-one;

2-(6-Fluoro-lH-benzo[ ]imidazol-l-yl)-9-((ll,41)-7-fluoro-4-hydroxy-l,2,3,4- tetrahydronaphthalen- 1 -yl)-7H-purin-8(9H)-one;

1 -(9-(( 1 l,41)-4-Hydroxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)-8-(pyrimidin-5-yl)-9H- purin-2-yl)-lH-benzo[(i]imidazole-6-carbonitrile;

1 -(9-(( 1 l,41)-4-Hydroxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)-8-(methylamino)-9H-purin- 2-yl)-lH-benzo[d]imidazole-6-carbonitrile;

l-(9-(5,8-Difluorochroman-4-yl)-8-(pyrimidin-5-yl)-9H-purin-2-yl)-lH- benzo[d]imidazole-6-carbonitrile;

1 -(9-(6-Fluorochroman-4-yl)-7-methyl-8-oxo-8 ,9-dihydro-7H-purin-2-yl)- 1H- benzo[d]imidazole-6-carbonitrile;

l-(9-Chroman-4-yl-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)-lH-benzo[(i]imidazole- 6-carbonitrile;

1 -(9-(( 1 l,41)-4-Hydroxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)-8-methyl-9H-purin-2-yl)- lH-benzo[d]imidazole-6-carbonitrile; and

pharmaceutically acceptable salts or prodrugs thereof.

Definitions

[0039] Unless specific definitions are provided, the nomenclatures utilized in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those known in the art. Standard chemical symbols are used interchangeably with the full names represented by such symbols. Thus, for example, the terms "hydrogen" and "Η" are understood to have identical meaning. Standard techniques may be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques may be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques may be performed e.g., using kits according to manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures may be generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See e.g. , Sambrook et al. Molecular Cloning: A Laboratory Manual (2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989)), which is incorporated herein by reference in its entirety for any purpose.

[0040] The term "alkyl" refers to a branched or unbranched fully saturated acyclic aliphatic hydrocarbon group. An alkyl may be branched or straight chain. Alkyls may be substituted or unsubstituted. Alkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like, each of which may be optionally substituted.

[0041] In certain embodiments, an alkyl comprises 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as "1 to 20" refers to each integer in the given range; e.g., "1 to 20 carbon atoms" means that an alkyl group may comprise only 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the term "alkyl" also includes instances where no numerical range of carbon atoms is designated). An alkyl may be designated as "Ci-C₆ alkyl" or similar designations. By way of example only, "Ci- C₄ alkyl" indicates an alkyl having one, two, three, or four carbon atoms, e.g., the alkyl is selected from methyl, ethyl, propyl, z^'so-propyl, butyl, z^'so-butyl, sec-butyl, and tert- vXy\.

[0042] The term "alkoxy" used herein refers to straight or branched chain alkyl radical covalently bonded to the parent molecule through an— O— linkage. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, n-butoxy, sec-butoxy, t-butoxy and the like. An alkoxy may be designated as "Ci-C₆ alkoxy" or similar designations. By way of example only, "Ci-C₄ alkoxy" indicates an alkyl having one, two, three, or four carbon atoms, e.g., the alkoxy is selected from methoxy, ethoxy, propoxy, iso- propoxy, butoxy, zso-butoxy, sec-butoxy, and fert-butoxy.

[0043] The term "heterocycle" refers to a group comprising a covalently closed ring wherein at least one atom forming the ring is a heteroatom. Heterocyclic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Any number of those atoms may be heteroatoms (i.e., a heterocyclic ring may comprise one, two, three, four, five, six, seven, eight, nine, or more than nine heteroatoms). In heterocyclic rings comprising two or more heteroatoms, those two or more heteroatoms may be the same or different from one another. Heterocycles may be optionally substituted. Binding to a heterocycle can be at a heteroatom or via a carbon atom. For example, binding for benzo-fused derivatives, may be via a carbon of the benzenoid ring. Examples of heterocycles include, but are not limited to the following:

[0044] wherein D, E, F, and G independently represent a heteroatom. Each of D, E, F, and G may be the same or different from one another. Heterocycles may be aromatic heterocycles (i.e., heteroaryls) or non-aromatic heterocycles. In some embodiments, a non- aromatic heterocycle is a fully statured covalently closed ring (for example, piperidine, pyrrolidine, morpholine, piperazine, and the like).

[0045] The term "compound" is intended to include salts, solvates and inclusion complexes of that compound. The term "solvate" refers to a compound in the solid state, wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent for therapeutic administration is physiologically tolerable at the dosage administered. Examples of suitable solvents for therapeutic administration are ethanol and water. When water is the solvent, the solvate is referred to as a hydrate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. Inclusion complexes are described in Remington: The Science and Practice of Pharmacy 19th Ed. (1995) volume 1, page 176-177, which is incorporated herein by reference. The most commonly employed inclusion complexes are those with cyclodextrins, and all cyclodextrin complexes, natural and synthetic, are specifically encompassed within the claims.

[0046] The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. When the compounds of the present invention are basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic, and the like. When the compounds contain an acidic side chain, suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.

[0047] The term "preventing" as used herein refers to administering a medicament beforehand to forestall or obtund an attack. A person of ordinary skill in the art will recognize that the term "prevent" is not an absolute term, and can refer to the prophylactic administration of a drug to substantially diminish the likelihood or seriousness of a condition, and this is the sense intended herein.

[0048] The term "carrier" refers to a compound that facilitates the incorporation of another compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a commonly used carrier for improving incorporation of certain organic compounds into cells or tissues.

[0049] The term "pharmaceutical agent" refers to a chemical compound or composition capable of inducing a desired therapeutic effect in a patient. In certain embodiments, a pharmaceutical agent comprises an active agent, which is the agent that induces the desired therapeutic effect. In certain embodiments, a pharmaceutical agent comprises a prodrug. In certain embodiments, a pharmaceutical agent comprises inactive ingredients such as carriers, excipients, and the like.

[0050] The term "pharmaceutical composition" refers to a preparation of one or more of the compounds described herein, or physiologically acceptable salts or solvents thereof, with other chemical components such as physiologically suitable carriers and excipients.

[0051] The term "therapeutically effective amount" refers to an amount of a pharmaceutical agent sufficient to achieve a desired therapeutic effect.

[0052] The term "pharmaceutically acceptable" refers to a formulation of a compound that does not significantly abrogate the biological activity, a pharmacological activity and/or other properties of the compound when the formulated compound is administered to a patient. In certain embodiments, a pharmaceutically acceptable formulation does not cause significant irritation to a patient. [0053] The term "patient" includes human and other animal subjects.

[0054] The term "prodrug" refers to a compound which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield an active compound or a salt and/or solvate thereof. In some embodiments, a prodrug is a compound that is not pharmacologically active, e.g., does not have a JAK3-like activity. Prodrugs can optimize physical properties of the active parent compounds for topical and/or ocular applications. Examples of such optimizations include improved aqueous solubility, human skin permeability, transdermal efficiency, and related pharmacokinetics properties. Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see: Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Acamedic Press, 1985); A Textbook of Drug Design and Development, edited by Krosgaard-Larsen and H. Bundgaard, Chapter 5, "Design and Application of Prodrugs," by H. Bundgaard, pp. 113-191 (1991); and H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992), each of which is incorporated herein by reference.

[0055] Some of the compounds described herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present invention is meant to include all such possible isomers, as well as mixtures thereof, including racemic and optically pure forms. Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefmic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. The configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration; thus a carbon- carbon double bond depicted arbitrarily herein as trans may be Z, E or a mixture of the two in any proportion.

[0056] The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr J. Chem. Ed. 62, 114-120 (1985): solid and broken wedges are used to denote the absolute configuration of a chiral element; wavy lines indicate disavowal of any stereochemical implication which the bond it represents could generate; solid and broken bold lines are geometric descriptors indicating the relative configuration shown but denoting racemic character; and wedge outlines and dotted or broken lines denote enantiomerically pure compounds of indeterminate absolute configuration. For example, the graphic representation indicates either, or both, of the two trans enantiomers.

[0057] It will be recognized that the compounds of this invention can exist in radiolabeled form, i.e., the compounds may contain an unnatural ratio of one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Radioisotopes of hydrogen, carbon, phosphorous, fluorine, chlorine and iodine include ³H, ¹⁴C, ³⁵S, ¹⁸F, ³⁶C1 and ¹²⁵I, respectively. Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention. Tritiated, i.e. ³H, and carbon-14, i.e., ¹⁴C, radioisotopes are particularly preferred for their ease in preparation and detectability. Radiolabeled compounds of this invention can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples by substituting a readily available radiolabeled reagent for a non-radiolabeled reagent. Because of the high affinity for the JAK3 enzyme active site, radiolabeled compounds of the invention are useful for JAK3 assays.

Chemical Synthesis

[0058] Terms such as "protecting", "deprotecting" and "protected" functionalities in the context of processes that involve sequential treatment with a series of reagents are well understood by the skilled artisan. In such contexts, a protecting group can refer to a group which is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable. The protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or "deprotection" occurs after the completion of the reaction or reactions in which the functionality would interfere. Thus, when a sequence of reagents is specified, a skilled artisan can readily envision those groups that would be suitable as "protecting groups." Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis by T.W. Greene [John Wiley & Sons, New York, 1991], which is incorporated herein by reference in its entirety.

[0059] A comprehensive list of abbreviations utilized by organic chemists appears in the first issue of each volume of the Journal of Organic Chemistry. The list, which is typically presented in a table entitled "Standard List of Abbreviations", is incorporated herein by reference in its entirety. [0060] In general, compounds provided herein may be prepared by the methods illustrated in the general reaction schemes as, for example, described herein, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In such reactions, it is also possible to make use of known variants. For example, the starting materials for suitably substituted benzimidazole ring compounds are either commercially available, synthesized as described here, or may be obtained by the methods well known to the skilled artisan.

[0061] Some embodiments of the present invention also include pharmaceutical compositions comprising prodrugs of Jak-3 inhibitor compounds described herein.

[0062] Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations which, can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.

[0063] Compounds that inhibit Jak-3 or are prodrugs of Jak-3 inhibitors can be formulated as pharmaceutical compositions and administered to a mammalian subject, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., parenterally, by intravenous, intramuscular, topical, transdermal or subcutaneous routes.

[0064] For injection, the compounds described herein may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's or Ringer's solution or physiological saline buffer. For transmucosal and transdermal administration, penetrants appropriate to the barrier to be permeated may be used in the composition. Such penetrants, including for example DMSO or polyethylene glycol, are known in the art.

[0065] Pharmaceutical compositions for parenteral administration include aqueous solutions of the active ingredients in water-soluble form. Additionally, suspensions of the active compounds or their prodrugs may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds, to allow for the preparation of highly concentrated solutions.

[0066] Depending on the severity and responsiveness of the condition to be treated, dosing can also be a single administration of a slow release composition, with course of treatment lasting from several days to several weeks or until cure is effected or diminution of the disease state is achieved. The amount of a composition to be administered will, of course, be dependent on many factors including the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician. The compounds of the invention may be administered topically or via injection at a dose from 0.001 to 2500 mg/kg/day. The dose range for adult humans is generally from 0.005 mg/day to 10 g/day. Forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg. The precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity. Also, the route of administration may vary depending on the condition and its severity.

[0067] It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

[0068] The compositions may be presented in a packaging device or dispenser, which may contain one or more unit dosage forms containing the active ingredient. Examples of a packaging device include metal or plastic foil, such as a blister pack and a nebulizer for inhalation. The packaging device or dispenser may be accompanied by instructions for administration. Compositions comprising a compound of the present invention formulated in a compatible pharmaceutical carrier may also be placed in an appropriate container and labeled for treatment of an indicated condition.

S heme I

[0069] Scheme I describe the synthesis of the benzo[d]imidazole analogs. The synthetic sequence starts from nucleophillic reaction of phenylenediamine compound of structure 1 and 2-chloropyrimidine compound of structure 2 to afford a product of structure 3. The benzyl protection group of structure 3 is removed by treatment with trimethylsilane, and condensed to form the benzimidazole intermediate of structure 4. The thiocyanato group of structure 4 is then replaced with a functionalized amine of structure 5 to afford the coupling product of structure 6. The nitro group of structure 6 is fully reduced and condensed with adjacent amino group to form a fused 5-membered-ring heterocycle of structure 7 after further modification depending on the nature of R² an R³ functional groups.

Scheme II

[0070] Scheme II describe the synthesis of the pyrazolo[l,5-a]pyridine analogs. Compound of structure 8 is prepared according to a literature procedure (Anderson, et al., 1981., "1,3-Dipolar Addition of Pyridine N-Imine to Acetylenes and the Use of C-13 NMR in Several Structural Assignments." J Het Chem 18, 1149-1152), and then converted to a carboximidamide of structure 9. Condensation reaction of the carboximidamide and a compound of structure 10 generates the final compound of structure 11. Alternatively, chloroheterocycle compound of structure 12 is coupled with an acetylene derivative to provide an intermediate compound of structure 13. Cycloaddition reaction of the acetylene of structure 13 and compound 14 generates a final product of structure 15 when R' is not a nitro group. The nitro group (R' = N0₂) of structure 15 is fully reduced to provide a 1,2-diamine derivative that can be condensed to form compounds of structure 11. Compounds of structure 15 (R' = N0₂) also can be converted to different heterocycle compounds of structures 16 and 17. Scheme III

[0071] Scheme III describe the synthesis of the imidazo[l,2-a]pyridine analogs. Compounds of structure 18 are prepared according to the method described in scheme I, and brominated to give compounds of structure 19. Condensation reaction of the bromide of structure 19 with compounds of structure 20 affords the imidazo[l,2-a]pyridine analogs of structure 21.

Indications

[0072] Compounds and compositions described herein are useful in inhibiting the activity if Jak3 or in inhibiting Jak3 mediated activity, either directly or after metabolism in the case of prodrugs. Such compounds and compositions are useful as immunosuppressive agents for tissue and organ transplants, including bone marrow transplant and in the treatment of autoimmune and inflammatory diseases and of complications arising therefrom.

[0073] Hyperacute, acute and chronic organ transplant rejection may be treated. Hyperacute rejection occurs within minutes of transplantation. Acute rejection generally occurs within six to twelve months of the transplant. Hyperacute and acute rejections are typically reversible where treated with immunosuppressant agents. Chronic rejection, characterized by gradual loss of organ function, is an ongoing concern for transplant recipients because it can occur anytime after transplantation.

[0074] There are about 75 different autoimmune disorders known that may be classified into two types, organ-specific (directed mainly at one organ) and non-organ-specific (affecting multiple organs).

[0075] Examples of organ-specific autoimmune disorders are insulin-dependent diabetes (Type I) which affects the pancreas, Hashimoto's thyroiditis and Graves' disease which affect the thyroid gland, pernicious anemia which affects the stomach, Cushing's disease and Addison's disease which affect the adrenal glands, chronic active hepatitis which affects the liver; polycystic ovary syndrome (PCOS), celiac disease, psoriasis, inflammatory bowel disease (IBD) and ankylosing spondylitis.

[0076] Examples of non-organ-specific autoimmune disorders are rheumatoid arthritis, multiple sclerosis, systemic lupus and myasthenia gravis.

[0077] Type I diabetes ensues from the selective aggression of autoreactive T-cells against insulin secreting β cells of the islets of Langerhans. Targeting Jak3 in this disease is based on the observation that multiple cytokines that signal through the Jak pathway are known to participate in the T-cell mediated autoimmune destruction of β cells. Indeed, a Jak3 inhibitor, JANEX-1 was shown to prevent spontaneous autoimmune diabetes development in the NOD mouse model of type I diabetes.

[0078] Graft-versus-host disease (GVHD) is a donor T-cell initiated pathological condition that frequently follows allogeneic bone marrow transplantation (BMT). Substantial experimental and clinical research have demonstrated that donor T-cells are the principal mediators and effectors of GVHD. Jak3 plays a key role in the induction of GVHD and treatment with a Jak3 inhibitor, JANEX-1, was shown to attenuate the severity of GVHD (reviewed in Cetkovic-Cvrlje and Ucken, 2004).

[0079] Mast cells express Jak3 and Jak3 is a key regulator of the IgE mediated mast cell responses including the release of inflammatory mediators. Jak3 was shown to be a valid target in the treatment of mast cell mediated allergic reaction.

[0080] Allergic disorders associated with mast cell activation include Type I immediate hypersensitivity reactions such as allergic rhinitis (hay fever), allergic urticaria (hives), angioedema, allergic asthma and anaphylaxis, i.e., "anaphylatic shock." These disorders are treated or prevented by inhibition of Jak3 activity, for example, by administration of a Jak3 inhibitor or prodrug thereof according to the present invention.

[0081] The Jak3 inhibitors and prodrugs thereof described herein may be administered prophylactically, i.e., prior to onset of acute allergic reaction, or they may be administered after onset of the reaction, or at both times.

[0082] Inflammation of tissues and organs occurs in a wide range of disorders and diseases and in certain variations, results from activation of the cytokine family of receptors. Exemplary inflammatory disorders associated with activation of Jak3 include, in a non-limiting manner, skin inflammation due radiation exposure, asthma, allergic inflammation and chronic inflammation. [0083] The Jak3 inhibitors or prodrugs thereof described herein are also useful in treating certain malignancies, including skin cancer and hematological malignancy such as lymphomas and leukemias.

[0084] Compounds that inhibit Jak3 and their prodrugs are useful for topical and ocular indications for skin and eye diseases and disorders such as psoriasis, dry eyes, and mast cell-mediated allergic reactions.

[0085] The following examples will further describe the invention, and are used for the purposes of illustration only, and should not be considered as limiting the invention being disclosed.

EXAMPLES

Comparative Example 1 : 1 -(7-Ethyl-9-(( 1 l,41)-4-hydroxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)-8- oxo-8,9-dihydro-7H-purin-2-yl)-lH-benzo[dlimidazole-6-carbonitrile (Compound 101)

[0086] Compound 101 was disclosed in WO 2009/048474 as Example 37.

Comparative Example 2: l-(9-((ll,41)-4-Hydroxy- 1,2,3, 4-tetrahvdronaphthalen- l-yl)-8-oxo-7- (pyridin-4-ylmethyl)-8,9-dihydro-7H-purin-2-yl)-lH-benzo[(i imidazole-6-carbonitrile

(Compound 102)

[0087] Compound 102 was disclosed in WO 2009/048474 as Example 56. Comparative Example 3: l-(9-((ll,41)-5,7-Difluoro-4-hydroxy- 1,2,3, 4-tetrahydronaphthalen- 1 - yl)-7-methyl-8-oxo-8,9-dihvdro-7H-purin-2-yl)-lH-benzor(i1imidazole-6-carbonitrile

(Compound 103)

[0088] Compound 103 was disclosed in WO 2009/048474 as Example 50.

Comparative Example 4: 9-((ll,41)-5,7-Difluoro-4-hvdroxy-l,2,3,4-tetrahvdronaphthalen-l-yl)- 2-(6-fluoro-lH-benzo[(i imidazo -l-yl)-7-methyl-7H-purin-8(9H)-one (Compound 104)

[0089] Compound 104 was disclosed in WO 2009/048474 as Example 51.

Comparative Example 5: 9-((ll,41)-7-Fluoro-4-hydroxy- 1,2,3 , 4-tetrahydronaphthalen- l-yl)-2- (6-fluoro-lH-benzo[(i imidazol-l-yl)-7-methyl-7H-purin-8(9H)-one (Compound 105)

[0090] Compound 105 was disclosed in WO 2009/048474 as Example 46. Comparative Example 6: 9-((ll,41)-7-Fluoro-4-hydroxy- 1,2,3 , 4-tetrahydronaphthalen- l-yl)-2 - (6-chloro-lH-benzor(i1imidazol-l-yl)-7-methyl-7H-purin-8(9H)-one (Compound 106)

[0091] Compound 106 was disclosed in WO 2009/048474 as Example 47.

Example 7 : 1 -(7-(Cyanomethyl)-9-(( 11,41)-5 -fluoro-4-hydroxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)-8-oxo-8,9-dihvdro-7H-purin-2-yl)-lH-benzord1imidazole-6-carbonitrile (Compound 107)

[0092] Compound 107 was prepared by a standard procedure described in Scheme I and disclosed under Formula I of WO 2009/048474.

Comparative Example 8: l-(8-Oxo-9-(tetrahvdro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)- lH-benzo[ imidazole-6-carbonitrile Compound 108)

[0093] Compound 108 was disclosed in WO 2006/108103 as Example 21.

Comparative Example 9: 2-(6-Fluoro-lH-benzo[(i imidazol-l-yl)-9-(8-fluorochroman-4-yl)- 7H-purin-8(9H)-one (Compound 109)

F

[0094] Compound 109 was disclosed in WO 2006/108103 as Example 28.

Comparative Example 10: l-(9-(2,6-Difluorobenzyl)-8-oxo-8,9-dihvdro-7H-purin-2-yl)-lH- benzo[ imidazole-6-carbonitrile Compound 110)

[0095] Compound 110 was disclosed in WO 2006/108103 as Example 20.

Example 11 : 9-(Y 11,40-5 ,7-Difluoro-4-hydroxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)-2-(6-fluoro- lH-benzor(i1imidazol-l-yl)-7H-purin-8(9H)-one (Compound 111)

[0096] Compound 111 was prepared by a standard procedure described in Scheme I and disclosed under Formula I of WO 2006/108103.

Example 12 : 9-(( 11,41)-5 ,7-Difluoro-4-hydroxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)-2-(6-cyano- lH-benzo[dlimidazol-l-yl)-7H-purin-8(9H)-one (Compound 112)

[0097] Compound 112 was prepared by a standard procedure described in Scheme I and disclosed under Formula I of WO 2006/108103. Example 13: 2-(6-Chloro-lH-benzor^limidazol-l-vn-9-((ll4n-7-fluoro-4-hvdroxy-l,2,3,4- tetrahvdronaphthalen-l-yl)-7H-purin-8(9H)-one (Compound 113)

[0098] Compound 113 was prepared by a standard procedure described in Scheme I and disclosed under Formula I of WO 2006/108103.

Example 14 : 2-(6-Fluoro- 1 H-benzo [dlimidazol- 1 -yl)-9-(( 1 l,41)-7-fluoro-4-hydroxy- 1 ,2,3 ,4- tetrahvdronaphthalen- l-yl)-7H-purin-8(9H)-one (Compound 114)

[0099] Compound 114 was prepared by a standard procedure described in Scheme I and disclosed under Formula I of WO 2006/108103.

Example 15: 1 -(9-(( 1 l,41)-4-Hydroxy- 1,2,3 ,4-tetrahvdronaphthalen- 1 -yl)-8 -(pyrimidin-5 -yl)- 9H-purin-2-yl)-lH-benzo[(i imidazole-6-carbonitrile (Compound 115)

[0100] Compound 115 was prepared by a standard procedure described in Scheme I and disclosed under Formula I of WO 2008/043019. Example 16: 1 -(9-((l l,41)-4-Hydroxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)-8-(methylamino)-9H- purin-2-yl)-lH-benzor(i1imidazole-6-carbonitrile (Compound 116)

[0101] Compound 116 was prepared by a standard procedure described in Scheme I and disclosed under Formula I of WO 2008/043019.

Comparative Example 17: l-(9-(5,8-Difluorochroman-4-yl)-8-(pyrimidin-5-yl)-9H-purin-2-yl)- lH-benzor 1imidazole-6-carbonitrile (Compound 117)

[0102] Compound 117 was disclosed in WO 2008/043019 as Example 6.

Comparative Example 18: l-(9-(6-Fluorochroman-4-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin- 2-yl)-lH-benzo[(i imidazole-6-carbonitrile (Compound 118)

[0103] Compound 118 was disclosed in WO 2008/060301 as Example 42.

Comparative Example 19: l-(9-Chroman-4-yl-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)-lH- benzo[ imidazole-6-carbonitrile (Compound 119)

[0104] Compound 1 19 was disclosed in WO 2008/060301 as Example 44.

Comparative Example 20: l-(9-((ll,41)-4-Hydroxy- 1 ,2,3 , 4-tetrahydronaphthalen- l-yl)-8- methyl-9H-purin-2-yl)-lH-benzo[(i imidazole-6-carbonitrile (Compound 120)

[0105] Compound 120 was disclosed in WO 2008/043019 as Example 100.

Example 21 : 1 -(8-Amino-9-(( 1 l,41)-4-hydroxy- 1 ,2,3 ,4-tetrahvdronaphthalen- 1 -yl)-9H-purin-2- yl)-lH-benzo[ ]imidazole-6-carbonitrile (Compound 121)

[0106] Compound 121 was prepared by the standard procedure described in Scheme

I.

Example 22: 2-(6-Fluoroimidazori ,2-a1pyridin-3-yl)-9-((ll,41)-4-hydroxy-l , 2,3,4- tetrahydronaphthalen-l-yl)-7H-purin-8(9H)-one (Compound 122)

[0107] Compound 122 was prepared by the standard procedure described in Scheme Example 23 : 3-(9-(l -(Cyanomethyl)pyrrolidin-3-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2- yl)pyrazolori,5-a1pyridine-5-carbonitrile (Compound 123)

[0108] Compound 123 was prepared by the standard procedure described in Scheme

II.

Example 24: 3-(7-Methyl-8-oxo-9-(l-(2,2,2-trifluoroethvnpyrrolidin-3-vn-8.9-dihvdro-7H- purin-2-yl)pyrazolo[l,5-alpyridine-5-carbonitrile (Compound 124)

[0109] Compound 124 was prepared by the standard procedure described in Scheme

II.

Example 25 : 9-(( 1 l,41)-4-Hydroxy- 1,2,3 ,4-tetrahydronaphthalen- 1 -yl)-7-(2-hydroxyethyl)-2-(5 - methylpyrazolori ,5-a1pyridin-3-yl)-7H-purin-8(9H)-one (Compound 125)

[0110] Compound 125 was prepared by the standard procedure described in Scheme

II. Example 26: 9-(( 1 l,41)-4-Hydroxy- 1 ,2,3.4-tetrahvdronaphthalen- 1 -yl)-2-(5-methylpyrazolo[ 1 ,5- a1pyridin-3-yl)-7H-purin-8(9H)-one (Compound 126)

[0111] Compound 126 was prepared by the standard procedure described in Scheme

II.

Example 27: 2-(4-(2-(5-Chloropyrazolori.5-a1pyridin-3-vn-7-methyl-8-oxo-7H-purin-9(8H)- yl)piperidin-l-yl)acetonitrile (Com ound 127)

[0112] Compound 127 was prepared by the standard procedure described in Scheme

II.

Example 28: 2-(5-Chloropyrazolori,5-a1pyridin-3-yl)-9-((ll,3u,41)-3,4-dihvdroxycvclohexyl)- 7H-purin-8(9H)-one (Compound 128)

[0113] Compound 128 was prepared by the standard procedure described in Scheme II; Ή-NMR (400 MHz, DMSO- ₆) 1 1.43 (s, 1H), 8.87 (d, lH), 8.69 (s, 1H), 8.55 (s, 1H), 8.29 (s, 1H), 7.12 (d, 1H), 4.68 (m, 1H), 3.96 (bs, 1H), 3.73 (m, 1H), 2.69-2.45 (m, 2H), 1.90-1.74 (m, 4H). Example 29: 2-(5-Chloropyrazolo[l,5-alpyridin-3-yl)-9-((ll,3u,41)-3,4-dihydroxycyclohexyl)- 7-methyl-7H-purin-8(9H)-one (Compound 129)

[0114] Compound 129 was prepared by the standard procedure described in Scheme II; 1H-NMR (400 MHz, DMSO-<¾) 8.85 (d, 1H), 8.66 (s, 1H), 8.55 (s, 1H), 8.45 (s, 1H), 7.11 (d, 1H), 4.70 (m, 1H), 4.63 (d, 1H), 4.58 (d, 1H), 3.98 (m, 1H), 3.73 (m, 1H), 3.38 (s, 3H), 2.69- 2.35 (m, 2H), 1.90-1.65 (m, 4H).

Example 30: 3-(3-(4,4-Difluorocyclohexyl)-l-(2-(methylamino)ethyl)-2-oxo-2,3-dihydro-lH- imidazor4,5-&1pyridin-5-vDpyrazolo 1 ,5-a1pyridine-5-carbonitrile (Compound 130)

[0115] Compound 130 was prepared by the standard procedure described in Scheme

II.

Example 31 : 3-(3-((l ,4-tra^)-4-Hydroxycyclohexyl)-2-oxo- 1 -(2-oxo-2-(piperidin- 1 -yDethyl)- 2J-dihvdro-lH-imidazor4,5-&1pyridin-5-yl)pyrazolori,5-a1pyridine-5-carbonitrile (Compound 131)

[0116] Compound 131 was prepared by the standard procedure described in Scheme

II.

Example 32: 3-(3-((l l,41)-4-Hydroxy- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)- 1 -methyl-2-oxo-2,3- dihydro- lH-imidazor4,5-&1pyridin-5-yl)pyrazolor 1 ,5-a1pyridine-5-carbonitrile (Compound 132)

[0117] Compound 132 was prepared by the standard procedure described in Scheme II; 1H-NMR (400 MHz, CDC1₃) 8.44 (d, IH), 8.35 (s, IH), 8.10 (s, IH), 7.91 (d, IH), 7.40 (d, IH), 7.31 (t, IH), 7.24 (d, IH), 7.08 (t, IH), 6.89 (d, IH), 6.85 (d, IH), 5.97-5.89 (m, IH), 5.35- 5.29 (m, IH), 3.55 (s, 3H), 2.92 (d, IH), 2.77 (q, IH), 2.55-2.45 (m, IH), 2.32-2.23 (m, IH), 2.04 (q, IH).

Example 33 : 3-(3-((l ,4-trafts)-4-Hydroxycyclohexyl)-2-oxo- 1 -(2-(methylamino)ethyl)-2,3- dihydro- lH-imidazor4,5-&1pyridin-5-yl)pyrazolor 1 ,5-a1pyridine-5-carbonitrile (Compound 133)

[0118] Compound 133 was prepared by the standard procedure described in Scheme

II.

Example 34: 3-(3-((l,4-tra^)-4-Hydroxycyclohexyl)-2-oxo-l-(2-hydroxyethyl)-2,3-dihydro- lH-imidazor4,5-&1pyridin-5-yl)pyrazolori,5-a1pyridine-5-carbonitrile (Compound 134)

[0119] Compound 134 was prepared by the standard procedure described in Scheme

II.

Example 35: 3-(3-((l,4-tra/? )-4-Hvdroxycvclohexyl)-2-oxo-l-methyl-2,3-dihvdro-lH- imidazo[4,5-&lpyridin-5-yl)pyrazolo[ 1 ,5-alpyridine-5-carbonitrile (Compound 135)

[0120] Compound 135 was prepared by the standard procedure described in Scheme

II. Example 36: 1 -(4-(( 1 ,4-trafts)-4-HydiOxycyclohexyl)-3 -oxo-2-(piperazin- 1 -yl)-3 ,4- dihvdropyridor2,3-&1pyrazin-6-yl)- lH-benzof 1imidazole-6-carbonitrile (Compound 136)

[0121] Compound 136 was prepared by a modified procedure that is similar to the standard procedure described in Scheme I.

Example 37j 1 -(4-(( 1 ,4-tra )-4-Hvdroxycvclohexyl)-3-oxo-2-((2-(pyrrolidin- 1 - yl)ethyl)amino)-3^-dihydropyrido[23-&lpy

(Compound 137)

[0122] Compound 137 was prepared in a similar fashion as described as in Example

36.

Example 38j 3-(4-((l,4-tra^)-4-Hvdroxycvclohexyl)-3-oxo-2-((2-(pyrrolidin-l- yl)ethyl)amino)-3^-dihydropyrido[23-&1pyra

(Compound 138)

[0123] Compound 138 was prepared by the standard procedure described in Scheme

II. Example 39: 3-(4-((l,4-tra^)-4-Hydroxycyclohexyl)-2-piperazinyl-3-oxo-3,4- dihvdropyridor2,3-&1pyrazin-6-vDpyrazolor 1 ,5-a1pyridine-5-carbonitrile (Compound 139)

[0124] Compound 139 was prepared by the standard procedure described in Scheme II. To a mixture of compound 139a (Structure 12 of Scheme II, where X = C, R' = N0₂, R = 4- tert-butyldiphenylsilyloxycyclohexyl) (7.9 g; 15 mmol), Cul (74 mg; 0.39 mmol), and PdCl₂(PPh₃)₂ (0.55 g; 0.78 mmol) in anhydrous DMF (30 mL) under argon atmosphere were added triethylamine (9.3 mL) and TMS-acetylene (2.6 mL; 19 mmol). The mixture was heated to 40 °C for 3 h. The mixture was then cooled to room temperature, diluted with EtOAc (100 mL) and filtered through a pad of Celite. The solvents were removed in vacuo and the crude residue was purified by column chromatography (160 g Si0₂; elution with 9: 1 hexanes/Et₂0) to provide 5.8 g (66%) of the acetylated product as yellow solid. To a solution of the yellow solid in THF (40 mL) and MeOH (10 mL) was added K₂C0₃ (4.2 g; 31 mmol) and the resultant reaction mixture stirred for 20 min at which time TLC analysis indicated complete reaction. This was immediately diluted with EtOAc (200 mL) and washed with brine (1 X 100 mL). The organic phase was dried (Na₂S0₄), filtered and concentrated in vacuo to provide 2.0 g of compound 139b (Structure 13 of Scheme II, where where X = C, R' = N0₂, R = 4-tert- butyldiphenylsilyloxycyclohexyl); 1H NMR (400 MHz, CDC1₃) 8.34 (d, IH), 8.07 (br d, IH), 7.68 (m, 4H), 7.39 (m, 6 H), 6.74 (d, IH), 4.23 (m, IH), 3.28 (s, IH), 2.07 (m, 2H), 1.85 (m, 2H), 1.60 (m, 2H), 1.24 (m, 2H), 1.06 (s, 9H); LC/MS (ESI) m/z: 500.1 [M+H]⁺.

[0125] A 250 mL round bottom flask was charged with compound 140b (3.1 g; 6.3 mmol) and anhydrous acetonitrile (60 mL) and fitted with a drying tube. The resultant solution was cooled to 0 °C, the drying tube was removed and to this was added the 4-cyano-l- aminopyridinium mesitylsulfonate salt (2.4 g; 7.5 mmol) followed by dropwise addition of DBU (1.1 mL; 7.5 mmol). The drying tube was replaced and the reaction mixture was stirred at 0 °C for 5 minutes. The cooling bath was removed and the reaction mixture was stirred for an additional 2.5 h at ambient temperature. The reaction mixture was quenched with H₂0 (100 mL) and the resultant greenish brown solid was collected by filtration. The filter cake was washed with H₂0 (2 X 20 mL) and cold MeOH (2 X 20 mL) and air dried. This was further dried in vacuo to afford 3.3 g (85%) of compound 139c (Structure 15 of Scheme II, where X = C, R' = N0₂, R = 4-tert-butyldiphenylsilyloxycyclohexyl, R¹ = CN) as an olive green solid; 1H NMR (400 MHz , CDC1₃) 9.00 (dd, 1H), 8.62 (dd, 1H), 8.54 (s, 1H), 8.44 (d, 1H), 8.39 (br d, 1H), 7.72 (m, 4H), 7.40 (m, 6H), 7.10 (dd, 1H), 7.00 (d, 1H), 4.26 (m, 1H), 3.76 (m, 1H), 2.24 (m, 2H), 1.97 (m, 2H), 1.75 (m, 2H), 1.38 (m, 2H), 1.08 (s, 9H); LC/MS (ESI) m/z: 617.3 [M+H]⁺.

[0126] A mixture of compound 139c (1.5 g; 2.4 mmol) and 10% Pd/C (0.5 g) in EtOH (10 mL) and EtOAc (10 mL) was placed under 1 arm. of H₂ (balloon) and this was stirred vigorously for 4 h. The mixture was then filtered through a pad of Celite with EtOAc rinses and the solvent removed in vacuo (important: dry thoroughly under vacuum to ensure removal of all EtOH which will interfere in next step). The crude residue was then taken up in anhydrous THF (20 mL) and to this added Ι,Γ-oxalyldiimidazole (0.56 g; 2.9 mmol). The reaction mixture was stirred at room temperature under argon atmosphere for 40 min. The reaction flask was then fitted with a reflux condenser and the mixture heated to 60 °C with stirring under argon atmosphere for 16 h. The mixture was then cooled to room temperature and partitioned between EtOAc (3 X 100 mL) and 10% citric acid (aq) (100 mL). The combined organic phases were washed with brine (1 X 100 mL), dried (Na₂S0₄), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography (40 g Si0₂ column; elution with 2%> MeOH/DCM) to provide 1.0 g (66%) of compound 139d (3-(4-((l,4-tra/75)-4-((fert- butyldiphenylsilyl)oxy)-cyclohexyl)-2,3-dioxo-l,2,3,4-tetrahydropyrido[2,3-¾]pyrazin-6- yl)pyrazolo[l,5-a]pyridine-5-carbonitrile) as a solid; LC/MS (ESI) m/z: 641.0 [M+H]⁺.

[0127] To a mixture of compound 139d (0.20 g; 0.31 mmol) and triethylamine (0.17 mL; 1.2 mmol) in anhydrous DCM (3 mL) under argon atmosphere was added TsCl (83 mg; 0.44 mmol) and the reaction mixture stirred at room temperature for 3 h. To this was added t- butyl-l-piperazinecarboxylate (0.12 g; 0.62 mmol) and the resultant mixture stirred an additional 2 h at room temperature. The mixture was then diluted with EtOAc (30 mL) and this was washed with 10% citric acid (aq) (1 X 20 mL) and sat. NaHC0₃ (aq) (1 X 20 mL). The organic phase was dried (Na₂S0₄), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography (12 g Si0₂ column; elution with 2% MeOH/DCM) to afford 0.22 g (86%) of the intermediate as brownish-orange solid. The intermediate was treated with 80% TFA (aq) (1 mL) and the resultant mixture allowed to stand at room temperature for 1 h. The mixture was concentrated in vacuo and the crude residue taken up in MeOH (3 mL) and to this added 20 drops of cone. NH₄OH (aq). This was allowed to stand at room temperature for 0.5 h at which time HPLC analysis indicated the disappearance of an undesired by-product. This was then concentrated in vacuo and the crude residue was purified by preparative HPLC. The desired fractions were combined and concentrated in vacuo. The resultant TFA salt of compound 140 (i.e. mobile phase of prep. HPLC contains 0.1% TFA) was taken up in MeOH (~4 mL) and treated with 20 drops of 12% HCl in EtOH. This was concentrated in vacuo and the residue was again taken up in MeOH (~ 4 mL), treated with 20 drops of 12% HCl in EtOH and concentrated in vacuo. This procedure was finally repeated a third time in order to convert the TFA salt into an HCl salt providing 102 mg (75%) of compound 139 as a HCl salt yellow solid; 1H NMR (400 MHz, D₂0) 8.49 (d, 1H), 8.19 (s, 1H), 8.01 (d, 1H), 7.51 (d, 1H), 7.12 (d, 1H), 7.02 (dd, 1H), 4.99 (m, 1H), 4.03 (m, 4H), 3.67 (m, 1H), 3.47 (m, 4H), 2.37 (m, 2 H), 1.96 (m, 2H), 1.35-1.22 (m, 4H); LC/MS (ESI) m/z: All 2 [M+H]⁺.

Example 40: 3-(4-((l ,4-tra^)-4-Hvdroxycvclohexyl)-2-(4-methylpiperazin-l-yl)-3-oxo-3,4- dihydropyrido[2,3-¾lpyrazin-6-yl)pyrazolo[l ,5-alpyridine-5-carbonitrile (Compound 140)

[0128] Compound 140 was prepared by a similar fashion as described in Example 39 from the intermediate compound 139d and N-methylpiperazine.

Example 41 : 3-(2-((ll41V2,5-Diazabicvclor2.2.11heptan-2-vn-4-((l ,4-tra/? V4- hvdroxycvclohexyl)-3-oxo-3,4-dihvdropyridor2,3-&1pyrazin-6-yl)pyrazolori ,5-a1pyridine-5- carbonitrile (Compound 141)

[0129] Compound 141 was prepared by a similar fashion as described in Example 39 from the intermediate compound 139d and 2,5-diazabicyclo[2.2.1]heptane. Example 42: 3-(2-(l,4-Diazepan-l-yl)-4-((l,4-tra^)-4-hydroxycyclohexyl)-3-oxo-3,4- dihvdropyridor2,3-&1pyrazin-6-yl)pyrazolori,5-a1pyridine-5-carbonitrile (Compound 142)

[0130] Compound 142 was prepared by a similar fashion as described in Example 39 from the intermediate compound 139d and 1,4-diazepane.

Example 43: 3-(2-(3-Aminopyrrolidin-l-yl)-4-((l,4-tra^)-4-hydroxycyclohexyl)-3-oxo-3,4- dihvdropyridor2,3-&1pyrazin-6-yl)pyrazolori,5-a1pyridine-5-carbonitrile (Compound 143)

[0131] Compound 143 was prepared by a similar fashion as described in Example 39 from the intermediate compound 139d and 3-aminopyrrolidine.

Example 44j 3-(4-((l,4-tra^)-4-Hvdroxycvclohexyl)-2-(methyl(2-(pyrrolidin-l- yl)ethyl)amino)-3-oxo-3^-dihydropyrido[23-¾lpyrazin-6-yl)pyrazolo[l,5-alpyridine-5- carbonitrile (Compound 144)

[0132] Compound 144 was prepared by a similar fashion as described in Example 39 from the intermediate compound 139d and l-methylamino-2-pyrrolidinylethane. Example 45 : 3-(8-((l ,4-tra^)-4-Hydroxycyclohexyl)-6-oxo-5,6,7,8-tetrahydropteridin-2- yl)pyrazolori ,5-a1pyridine-5-carbonitrile (Compound 145)

[0133] Compound 145 was prepared by the standard procedure described in Scheme

II.

Example 46j 3-(8-((l ,4-tra^)-4-Hydroxycyclohexyl)-l-methyl-6-oxo-5, 6,7,8- tetrahvdropteridin-2-vDpyrazolo Γ 1 ,5 -alpyridine-5 -carbonitrile (Compound 146)

[0134] Compound 146 was prepared by the standard procedure described in Scheme

II.

Example 47: 2-(5-Chloropyrazolori ,5-a1pyridin-3-yl)-8-((l ,4-tra/? )-4-hvdroxycvclohexyl)-5- methyl-7,8-dihydropteridin-6(5H)-one (Compound 147)

[0135] Compound 147 was prepared by the standard procedure described in Scheme

II. Example 48: 2-(5-Chloropyrazolo[l ,5-alpyridin-3-yl)-8-((l ,4-tra )-4-hydroxycyclohexyl)-7,8- dihydropteridin-6(5H)-one (Compound 148)

[0136] Compound 148 was prepared by the standard procedure described in Scheme

II.

Example 49: 3-(4-(((l ,4-tra )-4-Hvdroxycvclohexyl)(methyl)amino)pyrimidin-2- yl)pyrazolo[l ,5-alpyridine-5-carbonitrile (Compound 149)

[0137] Compound 149 was prepared by the standard procedure described in Scheme

II.

Example 50: (l ,4-tra/? )-4-((2-(5-Chloropyrazolo[l ,5-alpyridin-3-yl)pyrimidin-4- yl)amino)cyclohexanol (Compound 150)

[0138] Compound 150 was prepared by the standard procedure described in Scheme

II. Example 51 : N-(2-(5-Chloropyrazolo[l,5-alpyridin-3-yl)pyrimidin-4-yl)-4,5,6 ,7-tetrahydro-lH- indazol-5 -amine (Compound 151)

[0139] Compound 151 was prepared by the standard procedure described in Scheme

II.

Example 5_2j (2-(5 -Chloropyrazolo Γ 1 ,5 -alpyridin-3 -yl)-6-((( 1 ,4-tra ^ -4- hydroxycyclohexyl)amino)pyrimidin-4-yl)(morpholino)methanone (Compound 152)

[0140] Compound 152 was prepared by a modified procedure that is as similar as the standard procedure described in Scheme II.

Example 53 : (1 A-trans)-4-((2-(5 -Chloropyrazolo Γ1 ,5 -alpyridin-3 -yl)-5-fluoropyrimidin-4- yl)amino)cyclohexanol (Compound 153)

[0141] Compound 153 was prepared by the standard procedure described in Scheme

II. Example 54: 3-(4-(((l^-tra^)-4-Hydroxycyclohexyl)amino)pyrimidin-2-yl)pyrazolo[l,5- alpyridine-5-carbonitrile (Compound 154)

[0142] Compound 154 was prepared by the standard procedure described in Scheme

II.

Jak3 kinase assay

[0143] Human Jak3 cDNA was amplified by PCR. A fragment encoding the catalytic domain of Jak3 (508 aa to 1124 aa) was ligated with GST at 5' end. This fused GST- Jak3 DNA fragment was cloned into the EcoRI site of the donor plasmid pFastBac 1 (Life Technologies #10359-016). The transformation, transposition, and transfection of insect cells (Sf9) were performed according to the manufacture's instructions. The cell lysate containing recombinant GST-Jak3 was used in the kinase assay. Anti-GST antibody (10 μg/ml, Sigma #G1417) was coated onto a 384-well plate at 4 °C overnight. Cell lysate containing GST-Jak3 (1 : 100 dilution) was added to the anti-GST coated plates, and GST-Jak3 was captured by immobilized anti-GST antibody. Testing compounds and substrate mix (50 mM HEPES, pH 7, 0.5 mM Na₃V0₄, 25 mM MgCl₂, 1 mM DTT, 0.005% BSA, 1 μΜ ATP, and 4.5 μg/ml biotinyl poly-Glu,Ala,Tyr) were added to the plate to initiate the reaction. After a 60-min incubation, the reaction was stopped by 4 mM EDTA, and phosphorylation of biotinyl poly-Glu,Ala,Tyr was detected using 17 μg/ml Cy5-streptavidin (Amersham, #PA92005) and 2.7 μg/ml Europium- conjugated anti-phosphotyrosine antibody (PerkinElmer #AD0069) using homogeneous time- resolved fluorescence (HTRF) technology.

Jak3 cellular assay

[0144] The mouse F7 pre-B lymphocyte cell line was used for the cellular Jak3 assay. Human IL-2RPc cDNA is stably expressed in F7 cells (Kawahara et al., 1995). F7 cells were maintained in RPMI 1640 medium supplemented with 10% fetal bovine serum plus IL-3. Cells (30,000 cells/well) in serum- free medium were seeded in 96-well plates for the cell proliferation assay. Testing compounds were added to cells, followed by the addition of IL-2 (final 20 ng/ml). After a 24 hr incubation, the number of viable cells was determined by the CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, #G7573) according to the manufacturer's instructions.

Aurora A kinase assay

[0145] Aurora A kinase assay was performed using a fluorescence polarization format. A 100 nM solution of fluorescein-labeled FAM PKAtide (Molecular Devices), the substrate for Aurora A (Upstate Biotechnology), was incubated with Aurora A (80 ng/ml) and 30 mM ATP at room temperature for 1 hour in the presence of an appropriate concentration of test inhibitor. The reaction was terminated by adding IMAP Progressive Binding Reagent mix according to the manufacturer's instructions (Molecular Devices). The polarization signal was detected using Aquest (Molecular Devices).

[0146] The results of testing of representative species in the Jak3 Kinase assay are shown in Table 1.

TABLE 1

ICso ICso ICso

Compound Compound Compound

(nM) (nM) (nM)

152 3.4 153 1.4 154 1.4

IL-2-induced IFN-y production in the mouse

[0147] Administration of IL-2 leads to an increase in serum IFN-γ in the mouse due to NK secretion of the cytokine (Thornton S, Kuhn KA, Finkelman FD and Hirsch R. NK cells secrete high levels of IFN-γ in response to in vivo administration of IL-2. Eur J Immunol 2001 31 :3355-3360). The experiment was carried out essentially according to the protocol in Thornton et al. and the test compounds were administered in order to determine the level of inhibition attained. In summary, female BALB/c mice were fasted for 12-18 hours before a study but had free access to water at all times. Test compounds were administered by oral gavage one hour before intraperitoneal injection of IL-2 and capture antibody. At termination of the studies, the mice were sacrificed by carbon dioxide inhalation, terminal blood samples were collected by cardiac puncture and serum was generated. Serum was stored frozen until it was assayed for IFN-γ, as described by the kit manufacturer (BD Pharmingen™, San Diego, CA). A reference compound, CP690550, exhibited an ED50 of 1.8 mg/kg on oral dose.

[0148] All references cited herein, including but not limited to published and unpublished applications, patents, and literature references, are incorporated herein by reference in their entirety and are hereby made a part of this specification. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material.

[0149] The term "comprising" as used herein is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.

[0150] All numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claims in any application claiming priority to the present application, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches. [0151] The above description discloses several methods and materials of the present invention. This invention is susceptible to modifications in the methods and materials, as well as alterations in the fabrication methods and equipment. Such modifications will become apparent to those skilled in the art from a consideration of this disclosure or practice of the invention disclosed herein. Consequently, it is not intended that this invention be limited to the specific embodiments disclosed herein, but that it cover all modifications and alternatives coming within the true scope and spirit of the invention.

Claims

WHAT IS CLAIMED IS:

1. A prodrug mpound, having a structure selected from Formula I, II, III:

(III)

wherein:

R¹ is selected from the group consisting of fluorine, chlorine, methyl, and CN; R² is absent, or is selected from the group consisting of hydrogen, methyl, ethyl, cyanomethyl, 4-pyridinylmethyl, and 2-hydroxyethyl;

R³ is oxygen when R² is not absent;

R³ is selected from the group consisting of NH₂, NHCH₃, methyl, and 5- pyrimidinyl when R² is absent;

R⁴ and R⁵ are independently selected from hydrogen and fluorine; R⁶ is selected from hydrogen and morpholinylcarbonyl;

R⁷ and R⁸ are independently selected from hydrogen, fluorine, and methyl; or R⁷ and R⁸ together with the atoms to which they are attached form an optionally substituted 5- or 6-member-ring heterocycle;

R⁹ is selected from hydrogen and OH;

R¹⁰ is selected from 4-tetrahydropyranyl, 4-(8-fluoro)chromanyl, 3,4- dihydroxylcyclohexyl, 2,6-difluorobenzyl, and optionally substituted l-(4-hydroxy- 1 ,2,3 ,4-tetrahydro)naphthalenyl;

A is selected from the group consisting of phosphono, phosphonomethyl, phosphonooxymethyl, alkylaminocarbonyl, and acetyl; wherein the acetyl is optionally substituted with methyl, ethyl, propyl, isopropyl, amino, methylamino, dimethylamino, benzyl, pyrrolidinyl, hydroxylcarbonylmethyl, and hydroxylated tetrahydropyranyl;

D is selected from the group consisting of alkyloxy, phosphate, phosphonomethoxy, phosphonooxymethoxy, acetylamino, and acetyloxy; wherein the acetyl of the acetyloxy and acetylamino is optionally substituted with methyl, ethyl, propyl, isopropyl, amino, methylamino, dimethylamino, benzyl, pyrrolidinyl, hydroxylcarbonylmethyl, and hydroxylated tetrahydropyranyl;

X is selected from C and N;

the dashed line "— " is a bond or is absent; and

pharmaceutically acceptable salts thereof.

2. The prodrug compound of claim 1, wherein R² is selected from the group consisting of hydrogen, methyl, ethyl, cyanomethyl, 4-pyridinylmethyl, and 2-hydroxyethyl.

3. The prodrug compound of claim 2, wherein R¹ is selected from CN and fluorine.

4. The prodrug compound of claim 2, wherein R¹ is selected from chlorine and methyl.

5. The prodrug compound of claim 1, wherein R³ is selected from the group consisting of NH₂, NHCH₃, methyl, and 5-pyrimidinyl.

6. The prodrug compound of claim 5, wherein R¹ is CN.

7. The prodrug compound of claim 1, wherein R¹ is chlorine; and R⁶ is selected from hydrogen and morpholinylcarbonyl.

8. The prodrug compound of claim 1, wherein R¹ is CN; and R⁶ is selected from hydrogen and morpholinylcarbonyl.

9. The prodrug compound of claim 8, wherein R⁹ is hydrogen.

10. The prodrug compound of claim 9, wherein R⁷ and R⁸ together with the atoms to which they are attached form an optionally substituted 5- or 6-member-ring heterocycle.

11. The prodrug compound of claim 1, wherein R¹ is CN; and R¹⁰ is selected from 4- tetrahydropyranyl, 4-(8-fluoro)chromanyl, 3,4-dihydroxylcyclohexyl, 2,6-difluorobenzyl, and optionally substituted 1 -(4-hydroxy- 1 ,2,3 ,4-tetrahydro)naphthalenyl.

12. A compound, selected from the group consisting of

-58-

pharmaceutically acceptable salts or prodrugs thereof.

13. A method of treating a skin or eye disorder related to an immune disorder responsive to Jak 3 inhibitor therapy, said method comprising administering parenterally to a subject in need thereof an effective amount of the compound of any one of claims 1 - 12.

14. Use of the compound of any one of claims 1 - 12 for treating a skin or eye disorder related to an immune disorder responsive to Jak 3 inhibitor therapy comprising administering parenterally to a subject in need thereof an effective amount of the compound.

15. Use of the compound of any one of claims 1 - 12 in the manufacture of a medicament for the treatment of a disorder responsive to inhibition of Janus kinase 3.

16. Use of the compound of any one of claims 1 - 12 in the manufacture of a medicament for the treatment of a disorder selected from the group consisting of an autoimmune disease, an inflammatory disease, a mast cell mediated disease, a cancer, a hematological malignancy, and organ transplant rejection.

17. A method of treating a disorder selected from the group consisting of an autoimmune disease, an inflammatory disease, a mast cell mediated disease, a cancer, a hematological malignancy, and organ transplant rejection, said method comprising administering parenterally to a subject in need thereof an effective amount of the compound of any one of claims 1 - 12.

18. A method of treating a skin or eye disorder related to an immune disorder responsive to Jak 3 inhibitor therapy, said method comprising administering parenterally to a

-60-

pharmaceutically acceptable salts or prodrugs thereof.

19. Use of the compound of claim 18 in the manufacture of a medicament for the treatment of a disorder responsive to inhibition of Janus kinase 3.

20. Use of the compound of claim 18 in the manufacture of a medicament for the treatment of a disorder selected from the group consisting of an autoimmune disease, an inflammatory disease, a mast cell mediated disease, a cancer, a hematological malignancy, and organ transplant rejection.

21. A method of treating a disorder selected from the group consisting of an autoimmune disease, an inflammatory disease, a mast cell mediated disease, a cancer, a hematological malignancy, and organ transplant rejection, said method comprising administering parenterally to a subject in need thereof an effective amount of the compound of claim 18.