Kinase inhibitors   

BACKGROUND OF THE INVENTION

The p38 kinase is a mitogen-activated protein (MAP) kinase that belongs to the serine/threonine kinase superfamily. This kinase is activated by extracellular stresses such as heat, UV light, and osmotic stress, as well as by inflammatory stimuli such as lipopolysaccharide. When activated, p38 kinase phosphorylates intracellular protein substrates that regulate the biosynthesis of the pro-inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β). These cytokines are implicated in the pathology of a number of chronic inflammatory disorders (Lee, et al., Ann. N.Y. Acad. Sci., 696, 149-170 (1993); Muller-Ladner, Curr. Opin. Rheumatol., 8, 210-220 (1996)), cardiovascular and central nervous system disorders (Salituro, et al., Current Medicinal Chemistry, 6, 807-823 (1999)), and autoimmune disorders (Pargellis, et al, Nature Structural Biology, 9(4), 268-272 (2002)).

A number of compounds within the pyridinylimidazole (WO9621452, WO9725045, U.S. Pat. No. 5,656,644, U.S. Pat. No. 5,686,455, U.S. Pat. No. 5,717,100, WO9712876, WO9821957, WO9847892, WO99903837, WO9901449, W00061576, WO0172737) and pyrimidinylimidazole (WO9725048, WO9901452, WO9725046, WO9932121, WO9901131, WO9901130, WO9901136, WO9807452, WO9747618, WO9856788, WO9857996) structural platforms have been identified as inhibitors of p38 kinase or as cytokine inhibitors. Selective inhibitors of p38 kinase are known to suppress the expression of TNF-α and IL-1β (McKenna, et al., J. Med. Chem., 45(11), 2173-2184 (2002)). Anti-inflammatory activity for compounds within the pyrimidinylimidazole structural platform has been reported (Lantos, et al., J. Med. Chem., 27, 72-75 (1984)), and a number of inhibitors of p38 kinase are under active investigation for the treatment of a variety of disorders (Boehm and Adams, Exp. Opin. Ther. Patents, 10(1), 25-37 (2000)). There remains a need for treatment in this field for compounds that are cytokine suppressive drugs, i.e., compounds that are capable of inhibiting p38 kinase.

The present invention provides new inhibitors of p38 kinase useful for the treatment of conditions resulting from excessive cytolkine production.

SUMMARY

The present invention provides compounds of Formula I:

where: W is:

X is N, or C-R1; R is C1-C7 alkyl, C3-C7 cycloalkyl, (C1-C7 alkylene)-(C3-C7 cycloalkyl), —SO2—(C1-C7 alkyl), or —SO2—NR5R6; R1 is hydrogen, amino, methyl, or —N=CH(NMe)2; R2 is phenyl optionally substituted with one or two substituents independently selected from halo; R3 is hydrogen, C1-C7 alkyl, C3-C7 cycloalkyl, or phenyl optionally substituted with one or two substituents independently selected from halo and trifluoromethyl; R4 is hydrogen or C1-C7 alkyl; R5 and R6 are independently selected from the group consisting of C1-C7 alkyl; or a pharmaceutically acceptable salt thereof.

The present invention provides a method of inhibiting p-38 kinase ill a mammal comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

The present invention also provides a method of suppressing the production of tumor necrosis factor α (TNF-α) in a mammal comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

The present invention also provides a method of suppressing the production of interleukin-1 β (IL-1 β) in a mammal comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

The present invention further provides a method of treating conditions resulting from excessive cytokine production in a mammal comprising administering to a mammal in need of such treatment a cytokine-suppressing amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

The present invention also provides a method of treating a susceptible neoplasm in a mammal comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

The present invention also provides a method of inhibiting metastasis in a mammal comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

The present invention also provides a method of treating rheumatoid arthritis in a mammal comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

The present invention also provides a pharmaceutical formulation comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, diluent or excipient.

This invention also provides the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the inhibition of p38 kinase. Additionally, this invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof for use in the inhibition of p38 kinase in mammals. Furthermore, this invention provides a pharmaceutical composition adapted for the inhibition of p38 kinase comprising a compound of Formula I or a pharmaceutically acceptable salt thereof in combination with one or more pharmaceutically acceptable excipients, carriers, or diluents thereof. The invention also provides the use of a compound of Formula I for the manufacture of a medicament for treating a disease or condition capable of being improved or prevented by inhibition of p-38 kinase.

This invention also provides the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the suppression of the production of tumor necrosis factor α (TNF-α. Additionally, this invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof for use in the suppression of the production of tumor necrosis factor α (TNF-α) in mammals. Furthermore, this invention provides a pharmaceutical composition adapted for the suppression of the production of tumor necrosis factor α (TNF-α) comprising a compound of Formula I or a pharmaceutically acceptable salt thereof in combination with one or more pharmaceutically acceptable excipients, carriers, or diluents. The invention also provides the use of a compound of Formula I for the manufacture of a medicament for treating a disease or condition capable of being improved or prevented by suppression of the production of tumor necrosis factor α (TNF-α).

This invention also provides the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the suppression of the production of interleukin-1 β(IL-1 β). Additionally, this invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof for use in the suppression of the production of interleukin-1 β (IL-1 β) in mammals. Furthermore, this invention provides a pharmaceutical composition adapted for the suppression of the production of interleukin-1 β (IL-1 β) comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable excipients, carriers, or diluents. The invention also provides the use of a compound of Formula I for the manufacture of a medicament for treating a disease or condition capable of being improved or prevented by suppression of the production of interleukin-1 β (IL-1 β).

This invention also provides the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of conditions resulting from excessive cytokine production. Additionally, this invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of conditions resulting from excessive cytokine production in mammals. Furthermore, this invention provides a pharmaceutical composition adapted for the treatment of conditions resulting from excessive cytokine production comprising a compound of Formula I or a pharmaceutically acceptable salt thereof in combination with one or more pharmaceutically acceptable excipients, carriers, or diluents. The invention also provides the use of a compound of Formula I for the manufacture of a medicament for treating a disease or condition capable of being improved or prevented by suppression of excessive cytokine production.

This invention also provides the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a susceptible neoplasm. Additionally, this invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of a susceptible neoplasm in mammals. Furthermore, this invention provides a pharmaceutical composition adapted for the treatment of a susceptible neoplasm comprising a compound of Formula I or a pharmaceutically acceptable salt thereof in combination with one or more pharmaceutically acceptable excipients, carriers, or diluents.

This invention also provides the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the inhibition of metastasis. Additionally, this invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof for use in the inhibition of metastasis in mammals. Furthermore, this invention provides a pharmaceutical composition adapted for the inhibition of metastasis comprising a compound of Formula I or a pharmaceutically acceptable salt thereof in combination with one or more pharmaceutically acceptable excipients, carriers, or diluents.

This invention also provides the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of rheumatoid arthritis. Additionally, this invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of rheumatoid arthritis in mammals. Furthermore, this invention provides a pharmaceutical composition adapted for the treatment of rheumatoid arthritis comprising a compound of Formula I or a pharmaceutically acceptable salt thereof in combination with one or more pharmaceutically acceptable excipients, carriers, or diluents.

DETAILED DESCRIPTION

The general chemical terms used in the formulae above have their usual meanings. For example, the term “C1-C7 alkyl” includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and heptyl moieties. The term “C1-C7 alkylene” includes methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, pentylene, hexylene and heptylene moieties. The term “C3-C7 cycloalkyl” includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl moieties. The term “(C1-C7 alkylene)-(C3-C7 cycloalkyl)” is taken to mean a C3-C7 cycloalkyl attached through a C1-C7 alkylene linker. The term “halo” includes fluoro, chloro, bromo, and iodo.

The term “p-38 kinase” is taken to mean the p-38 α and/or p-38 β kinase isoforms.

The term “suppressing the production of TNF-α (IL-1 β, cytokine)” is taken to mean decreasing of excessive in vivo levels of TNF-α, IL-1 β, or another cytokine in a mammal to normal or sub-normal levels. This may be accomplished by inhibition of the in vivo release of TNF-α, IL-1 β, or another cytokine by all cells, including macrophages; by down regulation, at the genomic level, of excessive in vivo levels of TNF-α, IL-1 β, or another cytokine in a mammal to normal or sub-normal levels; by inhibition of the synthesis of TNF-α, IL-1 β, or another cytokine as a posttranslational event; or by a down regulation of TNF-α, IL-1 β, or another cytokine at the translational level.

The term “Minimum Effective Dose (MED)” is taken to mean the smallest dose that produces an effect that is statistically significantly different from the effect observed in a vehicle control group.

The term “Threshold Effective Dose (TED)” is taken to mean the dose required to achieve a specified threshold of activity. For example, the TED50 is the dose required to achieve a response of 50%.

The term “Threshold Minimum Effective Dose (TMED)” is taken to mean the lowest dose that guarantees a statistically significant effect that also achieves a specified threshold level of activity. For example, the TMED50 is the lowest dose that achieves a 50% response and is certain to be statistically significantly different from a vehicle control group.

The term “effective amount” is taken to mean a dose of a compound of Formula I necessary to achieve the desired pharmacological effect.

The skilled artisan will appreciate that certain compounds of Formula I contain at least one chiral center. The present invention contemplates all individual enantiomers or diastereomers, as well as mixtures of the enantiomers and diastereomers of said compounds including racemates. It is preferred that compounds of Formula I containing at least one chiral center exist as single enantiomers or diastereomers. The single enantiomers or diastereomers may be prepared beginning with chiral reagents or by stereoselective or stereospecific synthetic techniques. Alternatively, the single enantiomers or diastereomers may be isolated from mixtures by standard chiral chromatographic or crystallization techniques.

The skilled artisan will also appreciate that when variable “W” is imidazole (i), and R4 is hydrogen, the imidazole ring exists in the following two tautomeric forms:

Although Tautomers I and II are structurally distinct, the skilled artisan will appreciate that they exist in equilibrium and are easily and rapidly interconvertible under ordinary conditions. (See: March, Advanced Organic Chemistry, Third Edition, Wiley interscience, New York, New York (1985), pages 66-70; and Allinger, Organic Chemistry, Second Edition, Worth Publishers, New York, New York, (1976), page 173) As such, the representation of a compound of Formula I, where variable “W” is imidazole (i) and R4 is hydrogen, in one tautomeric form contemplates both tautomeric forms of the imidazole ring. Likewise, the naming of a compound of Formula I where “W” is imidazole (i) and R4 is hydrogen as either a 1H-imidazole or a 3H-imidazole contemplates both tautomeric forms of the imidazole ring. Specifically, the name 5-[2-tert-butyl-5-(4-fluoro-phenyl)-1H-imidazol-4-yl]-3 -(2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridin-2-ylamine contemplates the molecule in either the 1H-imidazol-4-yl or 3H-imidazol-4-yl form. Similarly, when variable “W” is triazole (iv), the triazole moiety exists in three tautomeric forms, and the representation or naming of one tautomeric form contemplates all three tautomeric forms of the triazole ring.

It will be understood by the skilled reader that compounds of the present invention are capable of forming salts. In all cases, the pharmaceutically acceptable salts of all of the compounds are included in the names of them. The compounds of the present invention are amines, and accordingly react with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Preferred pharmaceutically acceptable salts are those formed with maleic acid, fumaric acid, succinic acid, hydrochloric acid, and methanesulfonic acid. Especially preferred are di-methanesulfonic acid salts of the compounds of Formula I.

Certain classes of compounds of Formula I are preferred inhibitors of p-38 kinase. The following paragraphs describe such preferred classes: a) W is:

b) W is:

c) X is C-R1; d) X is C-NH2; e) R2 is phenyl, 4-fluorophenyl, or 2,4-difluorophenyl; f) R2 is phenyl; g) R2 is 4-fluorophenyl; h) R2 is 2,4-difluorophenyl; i) R4 is hydrogen; j) W is

X is C-R1, R2 is phenyl, 4-fluorophenyl, or 2,4-difluorophenyl, and R4 is hydrogen; k) W is

X is C-NH2, R2 is phenyl, 4-fluorophenyl, or 2,4-difluorophenyl, and R4 is hydrogen; l) W is

X is C-R1, R is C1-C7 alkyl, R2 is phenyl, 4-fluorophenyl, or 2,4-difluorophenyl, R3 is C1-C7 alkyl or phenyl optionally substituted with one or two substituents independently selected from halo and trifluoromethyl, and R4 is hydrogen; m) W is

X is C-NH2, R is C1-C7 alkyl, R2 is phenyl, 4-fluorophenyl, or 2,4-difluorophenyl, R3 is C1-C7 alkyl or phenyl optionally substituted with one or two substituents independently selected from halo, and R4 is hydrogen; n) The compound of Formula I is a free base. o) The compound of Formula I is a salt. p) The compound of Formula I is a methanesulfonate salt. q) The compound of Formula I is a di-methanesulfonate salt.

Preferred embodiments of the present invention include all combinations of paragraphs a)-q).

An especially preferred subgenus of compounds within the scope of Formula I are compounds of Formula I′:

where: R1 is 2,2-dimethylpropyl or 1,2,2-trimethylpropyl; R2′ is phenyl, 4-fluorophenyl, or 2,4-difluorophenyl; R3′ is tert-butyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-trifluoromethylphenyl, 2,6-dichlorophenyl, or 2,6-difluorophenyl; or a pharmaceutically acceptable salt thereof.

Most preferred compounds of Formula I′ are those where: 1. R′ is 2,2-dimethylpropyl R2′ is 4-fluorophenyl, and R3′ is 2-fluoro-6-trifluoromethylphenyl; 2. R′ is 2,2-dimethylpropyl, R2′ is 4-fluorophenyl, and R3′ is 2,6-dichlorophenyl; 3. R′ is 2,2-dimethylpropyl, R2′ is 4-fluorophenyl, and R3′ is tert-butyl; 4. R′ is 2,2-dimethylpropyl, R2′ is phenyl, and R3′ is 2-chloro-6-fluorophenyl; 5. R′ is 2,2-dimethylpropyl, R2′ is 2,6-difluorophenyl, and R3′ is tert-butyl; 6. R′ is 1,2,2-trimethylpropyl, R2′ is 4-fluorophenyl, and R3′ is tert-butyl; and 7. R′ is 1,2,2-trimethylpropyl, R2′ is 4-fluorophenyl, and R3′ is 2,6-difluorophenyl.

It is also preferred that each of these compounds exist as the methanesulfonate, succinate, fumarate, dimaleate, dihydrochloride, or dimethanesulfonate salt. It is especially preferred that each of these compounds exist as the dimethanesulfonate salt.

The compounds of Formula I are inhibitors of p38 kinase. Thus, die present invention also provides a method of inhibiting p38 kinase in a mammal that comprises administering to a mammal in need of said treatment an effective amount of a compound of Formula I. It is preferred that the mammal to be treated by the administration of the compounds Formula I is human.

As inhibitors of p38 kinase, the compounds of the present invention are useful for suppressing the production of the pro-inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin-1 β (IL-1 β), and therefore for the treatment of disorders resulting from excessive cytokine production. Compounds of Formula I are therefore believed to be useful in treating inflammatory disorders, including eczema, atopic dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, and toxic shock syndrome. Compounds of the present invention are also believed to be useful in the treatment of cardiovascular disorders, such as acute myocardial infarction, chronic heart failure, atherosclerosis, viral myocarditis, cardiac allograft rejection, and sepsis-associated cardiac dysfunction. Furthermore, compounds of the present invention are also believed to be useful for the treatment of central nervous system disorders, such as meningococcal meningitis, Alzheimer\'s disease, Parkinson\'s disease, and multiple sclerosis.

Most solid tumors increase in mass through the proliferation of malignant cells and stromal cells, including endothelial cells. In order for a tumor to grow larger than 2-3 millimeters in diameter, it must form a vasculature, a process known as angiogenesis.

Suppression of tumor-induced angiogenesis by angiostatin and endostatin has been reported to result in antitumor activity (O\'Reilly, et al., Cell, 88, 277-285 (1997)). The selective p38 kinase inhibitor SB22025 has been shown to inhibit angiogenesis (J. R. Jackson, et al., J. Pharmacol. Exp. Therapeutics, 284, 687 (1998)). Because angiogenesis is a critical component of the mass expansion of most solid tumors, the development of new p38 kinase inhibitors for the inhibition of this process represents a promising approach for antitumor therapy. This approach to antitumor therapy may lack the toxic side effects or drug resistance-inducing properties of conventional chemotherapy (Judalh Folkman, Endogenious Inhibitors of Angiogelesis, The Harvey Lectures, Series 92, pages 65-82, Wiley-Liss AIc., (1998)).

As inhibitors of p38 kinase, compounds of the present invention, therefore, are also useful in inhibiting growth of susceptible neoplasms. Schultz, R. M. Potential of p38 MAP kinase inhibitors in the the treatment of cancer. In: E. Jucker (ed.), Progress in Drug Research, 60, 59-92, (2003). A susceptible neoplasm is defined to be a neoplasm that depends upon p38 kinase for its survival, growth, or metastasis. Susceptible neoplasms include tumors of the brain, genitourinary tract, lymphatic system, stomach, larynx, and lung (U.S. Pat. No. 5,717,100). Preferably, the term “susceptible neoplasms” as used in the present application includes human cancers including non-small cell lung carcinoma (A. Greenbero, et al., Am. J. Respir. Cell Mol. Biol., 26, 558 (2002)), breast carcinoma (J. Chen, et al., J. Biol. Chem., 276, 47901 (2001); B. Salh, et al., Int. J. Cancer, 98, 148 (2002); and S. Xiono, et al., Cancer Res., 61, 1727 (2001)), gastric carcinoma (Y. D. Jung, et al., Proc. Am. Assoc. Cancer Res., 43, 9 (2002)), colorectal carcinomas (S. Xiong, et al., Cancer Res., 61, 1727 (2001)), prostate carcinomas (J-I Park, et al., Oncogene, 22, 4314-4332 (2003); L. Chen, et al., Cancer Lett., 215, 239-247 (2004); and A. R. Uzgara, et al., Prostate, 55, 128-139 (2003)), malignant melanoma (C. Denkert, et al., Clin. Exp. Metastasis, 19, 79 (2002)), and multiple myeloma (Hideshima, et al., Oncozene advance online publication, 1-11, (Oct. 11, 2004); and flideshima, et al., Blood, 101(2), 703 (2003)).

Inhibition of angiogeniesis by suppression of TNF-α has also been taught to be useful in the inhibition or prevention of metastasis (U.S. Pat. No. 6,414,150; U.S. Pat. No. 6,335,336). Furthermore, suppression of TNF-α is indicated for the treatment and prevention of cachexia, a wasting syndrome experienced by about half of all cancer patients (T. Yoneda, et al., J. Clin. Invest., 87, 977 (1991)).

Furthermore, inhibition of p38 kinase may be effective in the treatment of certain viral conditions such as influenza (K. Kujime, et al., J. Immunology., 164, 3222-3228 (2000)), rhinovirus (S. Griego, et al., J. Immunology, 165, 5211-5220 (2000)), and HIV (L. Shapiro, et al., Proc. Natl. Acad. Sci. USA, 95, 7422-7426, (1998)).

The compounds of the present invention may be prepared by a variety of procedures, some of which are illustrated in the Schemes below. It will be recognized by one of skill in the art that the individual steps in the following schemes may be varied to provide the compounds of Formula I. The particular order of steps required to produce the compounds of Formula I is dependent upon the particular compound being synthesized, the starting compound, and the relative lability of the substituted moieties. Some substituents have been eliminated in the following schemes for the sake of clarity and are not intended to limit the teaching of the schemes in any way.

Compounds of Formula I where W is the imidazole (i) may be prepared as illustrated in the following scheme where R, R1, R2, and R3 are as previously defined.

Diketone (a) is reacted with ammonium acetate and an appropriate aldehyde in an appropriate solvent, preferably acetic acid, to provide the corresponding nitropyridinyl-imidazole (b). The nitro moiety is reduced under standard hydrogenation or chemical conditions to provide the corresponding diamine (c). This diamine is then either reacted with cyanogen bromide to provide the 3-substituted-5-(imidazol-4-yl)-2-aminopyridinyl-imidazole (Ia), with an appropriate orthofoimate to provide the 3-substituted-5-(imidazol-4-yl)pyridinylimidazole (Ib), or with an appropriate nitrite to provide the 3-substituted-5-(imidazol-4-yl)pyridinyltriazole (Ic).

The requisite diketones (a) may be prepared as described in the following scheme, where R and R2 are as previously defined.

2,6-dichloronitropyridine (d) and an appropriate amine or amine derivative are heated together in an appropriate solvent to provide the corresponding 2-amino-6-chloro-3-nitropyridine (e), which is then coupled with an appropriately substituted acetylene to provide the corresponding 1,2-disubstituted acetylene (f). This acetylene is oxidized to provide the target diketone (a).

Compounds of Formula I where W is pyrazole (ii) or (iii) are prepared as described in the following Scheme where X, R, R , and R2 are as previously defined.

Acetylene (f) is treated with mercuric oxide in aqueous sulfuric acid to provide the ketone (g). This ketone is treated with dimethylformamide dimethylacetal or tris(dimethyl-amino)methane in a suitable solvent, typically dimethylformamide, to provide the enaminoketone (h). The enaminoketone is then treated with hydrazine in a suitable solvent, typically ethanol or methanol, to provide the phenylpyrazole (j). The imidazo- or triazolopyridine moiety is prepared as previously described to provide the compounds of Formula Id.

The compounds of Formula I where W is the [1,2,3]triazole (iv) may be prepared as described in the following Scheme where variables Y, R, and R2 are as previously defined.

The acetylene (f) is reacted with a source of azide, typically sodium azide, in a suitable solvent, such as dimethyoxyethane to provide the triazole (k). The imidazo- or triazolopyridine moiety is prepared as previously described to provide the compounds of Formula Ie.

The compounds of Formula I where W is the thiazole (v) or oxazole (vii) may be prepared as described in the following Scheme where variables X, R, R2, and R3 are as previously defined and Y is O or S.

The α-bromoketone (I) is reacted with an appropriate amide (m, Y=O) or thioamide (m, Y=S) in a suitable solvent to provide the corresponding oxazole or thiazole (n). The oxazole (n, Y=O) is then treated with bromine in a suitable solvent to provide the corresponding brominated heterocycle (o, Y=O). The thiazole (n, Y=S) is treated with n-butyllithium and the resulting anion reacted with tributyltin chloride to provide the corresponding tin derivative (o, Y=S). The appropriately substituted heterocycle (o) is reacted with an appropriate boronic acid (p) in the presence of a suitable catalyst as previously described to provide the compounds of Formula If.

The requisite α-bromoketones are either commercially available or may be prepared by standard conditions from the corresponding carbonyl compound, for example, as described by House (H. O. House, Modern Synthetic Reactions, W. A. Benjamin, Inc., Menlo Park, Calif. (1972), pages 459-478) and Larock (R. C. Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, N.Y. (1989), pages 369-471, 755). The requisite amides and thioamides are either commercially available or may be prepared by standard methods well known to the skilled artisan.

Additional compounds of Formula I where W is imidazole (i) or isoxazole (vi) may be prepared under standard palladium coupling conditions as described in the following Scheme, where W′ is imidazole (i) or isoxazole (vi), and X and R are as previously defined.

An appropriately substituted haloheteroaryl (q) is coupled with an appropriately substituted boronic acid (p) in the presence of a palladium catalyst, typically bis(triphenylphosphine)palladium(II) chloride, in a suitable solvent to provide the desired compound of Formula Ie. The requisite starting materials are either commercially available or may be prepared by methods well known to one of ordinary skill in the art.

Many of the compounds of the present invention are not only useful as inhibitors of p38 kinase, but are also useful intermediates for the preparation of additional compounds of the present invention. For example, primary and secondary amines may be acylated, alkylated or coupled with carboxylic acids or amino acids under standard peptide coupling conditions. Furthermore, ester moieties may be reduced to the corresponding alcohols or converted to amides under standard conditions. Alcohols may be activated and displaced by a number of nucleophilcs to provide other compounds of the invention. Such leaving groups include but are not limited to halides, oxonium ions, alkyl perchlorates, ammonioalkanesulfonate esters, alkyl fluorosulfonates, nonaflates, tresylates, triflates, and sulfonic esters, preferably the mesylate or tosylate. Techniques for the introduction of these groups are also well known to the skilled artisan; see, for example, March, Advanced Organic Chemistry, 5th Ed., John Wiley and Sons, New York, pg. 445-449 (2001). Additionally, the 2-amino moiety of the benzimidazole nucleus may be diazotized and displaced to provide additional compounds of the invention under standard conditions.

The skilled artisan will also appreciate that not all of the substituents in the compounds of Formula I will tolerate certain reaction conditions employed to synthesize the compounds. These moieties may be introduced at a convenient point in the synthesis, or may be protected and then deprotected as necessary or desired. The skilled artisan will appreciate that the protecting groups may be removed at any convenient point in the synthesis of the compounds of the present invention. Methods for introducing and removing nitrogen and oxygen protecting groups are well known in the art; see, for example, Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons, New York, Chapter 7 (1999). Furthermore, the skilled artisan will appreciate that in many circumstances, the order in which moieties are introduced is not critical. The particular order of steps required to produce the compounds of Formula I is dependent upon the particular compound being synthesized, the starting compound, and the relative lability of the substituted moieties.

The abbreviations, symbols and terms used in the examples and assays have the following meanings: AcOH=acetic acid; DMF=N,N-dimethylformamide; DMSO dimethylsulfoxide; Et2O=diethyl ether; EtOAc=ethyl acetate; EtOH=ethanol; h=hour(s); MeOH=methanol; min=minute(s); MTBE=methyl tert-butyl ether; Pd(OAc)2 =palladium acetate; RT =room temperature; THF=tetrahydrofuran; VO(acac)2=vanadyl acetylacetonate.

[6-(2-tert-Butyl-5-phenyl-3H-imidazol-4-yl)-3-nitropyridin-2-yl]-(2,2-dimethylpropyl)amine

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