Title of Invention	KINASE INHIBITORS
Abstract	The present invention relates to an extended release once daily pharmaceutical formulation comprising venlafaxine hydrochloride and pharmaceutically acceptable excipients. More particularly, the present invention relates to an extended release composition in the form of mini-tablets which are incorporated in hard gelatin capsules.

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FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION (See section 10, rule 13) "KINASE INHIBITORS" ELI LILLY AND COMPANY, Lilly Corporate Center, Indianapolis, IN 46285, United States of America; The following specification particularly describes the invention and the manner in which it is to be performed. WO 2005/075478 PCT/US2005/000025 2. KINASE INHIBITORS BACKGROUND OF THE INVENTION The p38 kinase is a mitogen-activated protein (MAP) kinase that belongs to the 5 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 a (TNF-a) and interleukin-ip 0L-lp*). These cytokines are implicated in the 10 pathology of a number of chronic inflammatory disorders (Lee, et aL, Ann. N.Y. Acad. Sci, «HS, 149-170 (1993); Mulkr-Ladner, Curr. Opin. Rheumatol.. 8,210-220 (19%)), cardiovascular and central nervous system disorders (Sahtnro, et ad., Current Medicinal Chemistry. 6, 807-823 (1999)), and autoimmune disorders (Pargellis, et aL, Nature Structural Biology. 9(41268-272 QOOZft. 15 A number of compounds within the pyridmylimidazole (W09621452, WO9725045, US5656644, US5686455, US5717100, W09712876, W09821957, W09847892, WO99903837, WO9901449, WO0061576, WO0172737) and pyrimidinyl-imidazole (WO9725048, WO9901452, WO9725046, W09932121, WO9901131, WO9901130, WO9901136, WO9807452, W09747618, W09856788, W09857996) 20 structural platforms have been identified as intabitors of p38 kinase or as cytokine inhibitors. Selective inhibitors of p38 kinase are known to suppress the expression of TNF-a and IL-lp* (McKenna, et al., J.Med.Chem.. 45(11), 2173-2184 (2002)). Antiinflammatory activity for compounds within the pyrirmdinylimidazole structural platform has been reported (Lantos, et aL, J. Med. Chem.. 27,72-75 (1984)), and a number of 2 5 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 3 0 treatment of conditions resulting from excessive cytokine production. WO 2005/075478 BRIEF SUMMARY OF THE INVENTION The present invention provides compounds of Formula I: where: R2 (i) R« (S) f»f) (v) f*»> (vH) X is N, or C-R1; R is C,-C7 alkyl, C3-C7 cyctoalkyi, (d-C7 alkyleneHC3-C7 cycloalkyl), -SOHCr 10 C7 alkyl), or -SQz-NR5*6; 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, Cj-C7 alkyl, C3-C7 cycloalkyl, or phenyl optionally substituted 15 with one or two substituents independently selected from halo and trifluoromethyl; R4 is hydrogen or C1-C7 alkyl; R5andR6 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 in a mammal 2 0 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. WO 2005/075478 ^ PCT/US2005/000025 The present invention also provides a method of suppressing the production of tumor necrosis factor a (TNF-a) in a mammal comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I or a pharmaceuticaUy acceptable salt thereof. 5 The present invention also provides a method of suppressing the production of interleukin-lp (IL-1P) 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 10 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 15 amount of a compound of Formula 1 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 20 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 2 5 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 pharmaceuticaUy acceptable salt thereof for use in the inhibition of p38 kinase in mammals. Furthermore, this invention provides a pharmaceutical composition adapted 30 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 WO 2005/075478 3 PCT/US2005/000025 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 5 pharmaceutically acceptable salt thereof for the manufacture of a medicament for the suppression of the production of tumor necrosis factor a (TNF-a). 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 a (TNF-a) in mammals. Furthermore, mis invention provides a pharmaceutical composition adapted 10 for the suppression of trie proota3k» of tumor necrosis factor a compound of Formula I c 15 of the production of tumor necrosis factor a (TNF-a). 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-ip (IL-iP). Additionally, this invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof for use in 20 the suppression of the production of interleukin-lp (JL-lp) in mammals. Furthermore, this invention provides a pharmaceutical composition adapted for the suppression of the production of interleukin-ip OL-ip) comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable exdpients, carriers, or diluents. The invention also provides 25 the use of a compound of Formula I for the manuf acture of a medicament for treating a disease or condition capable of being improved or prevented by suppression of the production of interleukin-lfi (ILr-iP). 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 3 0 treatment of conditions resulting from excessive cytokine production. Additionally, this invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof WO 2005/075478 ^ PCT/US20O5/0OO025 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 pharmaceurjcally acceptable salt thereof in combination with 5 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 10 pharmaceuticaUy acceptable sahmerr^ for the manufacture o treatment of a susceptible neoplasm. Additionally, mis invention provides a compound of Formula I or a pharmaceutically acceptable salt mereof tor use in me treatment of a susceptible neoplasm in mammals. Furthermore, this invention provides a pharmaceutical composition adapted f or the tieatment of a susceptible neoplasm comprising a compound 15 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, mis invention provides a compound of Formula I 20 or a pharmaceutically acceptable salt mereof 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. 2 5 This invention also provides the use of a compound of Formula I or a pharmaceutically acceptable salt mereof for the manufacture of a medicament for the treatment of rheumatoid arthritis. Additionally, mis 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 3 0 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. WO 2005/075478 PCT/US2005/000025 J DETAILED DESCRIPTION OF THE INVENTION The general chemical terms used in the formulae above have their usual meanings. 5 For example, the term "Cj-C7 alkyT includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-bntyl, pentyl, hexyl and beptyl moieties. The term "C1-C7 alkylene" includes methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butyiene, pentylene, hexylene and heptylene moieties. The term "C3-C7 cycloalkyl" includes cyclopropyl, cyclobutyl, cyciopentyl, cyclohexyl and cycloheptyl 10 moieties. The term "(Ci-C? a!kyleneHCrC7 cycloalkyl)" is taken to mean a C3-C7 cycloalkyl attached through a Ct-C7 alkylene linker. The term "halo" includes fhtoro, chloro, bromo, and iodo. The term "p-38 kinase" is taken to mean the p-38tt and/cv p-38$ kinase isoforms. The term "suppressing the production of TNF«(IL-lp,cvtokmeristakento 15 mean decreasing of excessive in vivo levels of TNF-ct, IL-1P> or another cytokine in a mammal to normal or sub-normal levels. This may be accranph^ed by inhibition of the m vivo release of TNF-ot, IL-lp\ or another cytokine by all cells, including macrophages; by down regulation, at die genomic level, of excessive m vivo levels of TNF-ot, IL-lp\ or another cytokine in a mammal to normal or sub-normal levels; by inhibition of the 20 synthesis of TNF-ot, IL-lp\ or another cytokine as a posttnimlationaleverit;orby adown regulation of TNF-ot, IH(J, or another cytokine at the translatkmal level. The term "Minimum Pffecrive Dose (MED)" is taken to mean the smallest dose mat produces an effect mat is statistically significantly different from the effect observed in a vehicle control group. 2 5 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 3 0 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. n WO 2005/075478 PCT/US2005/000025 10 The term "effective amounf' is taken to mean a dose of a compound of Formula 1 necessary to achieve die 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 chrornatographic 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: 111 Imidazole Tautomerl 3tMmklazole TautomerN 15 20 25 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 mterscience, New York, New York (1985), pages 66-70; and Allinger, Organic Chemistry. Second Edition, Worm Publishers, New York, New York, (1976), page 173) As such, the representation of a compound of Formula I, where variable T 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 lH-imidazole or a 3H-imidazole contemplates both tautomeric forms of the imidazole ring. Specifically, the name 5-[2-tert-butyl-5-(4-fluoro-r^nyl>lH-iinidazol^yl]-3K2,2-^^ ylamine contemplates the molecule in either the lH-imidazol-4-yl or 3H-imidazol-4-yl % WO 2005/075478 ^ PCT/US200S/000025 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 5 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 adds to form phannaceuticatty acceptable add addition salts. Preferred pharmaceutically acceptable salts are those formed with maleic acid, fumaric add, 10 sucdnic add, hydrochloric add, and rnethanesulfonic add. Especially preferred are di methanesurfonic add salts of the compounds of Formula L Certain classes of compounds of Formula I ate preferred inhibitors of p-38 kinase. The following paragraphs describe such preferred classes: a) Wis: Rf*—^/jf («) b) Wk R*—^ jf 15 (V) ; c)Xi$C-Rl; d)XisC-NH2; e) R2 is phenyl, 4-fluorophenyl, or 2,4-difluorophenyl; f) R2 is phenyl; 20 g) R2 is 4-fluorophenyl; h) R2 is 2,4-difluorophenyl; i) R4 is hydrogen; 9 WO 2005/075478 PCT/US2005/000025 j) W is 0) , X is C-R1, R2 is phenyl, 4-fluorophenyl, or 2,4- difluorophenyl, and R4 is hydrogen; k) W is (0 ,Xis C-NHz, R2 is phenyl, 4-fluorophenyl, or 2,4- difluorophenyi, and R4 is hydrogen; HX l)Wis (0 >XisC-R1,RisCi-C7alkyl>R2isphenyl>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 trifhioromethyl, and R4 is hydrogen; ■- R3- v ^ m)Wis (0 ,XisC-NH2>RisCi-C7allcyl,R2isphenyl,4- 10 fluorophenyl, or 2,4-difluorophenyi, 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 methanesulf onate salt. 15 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 V: 1° WO 2005/075478 PCTAJS2005/000025 r where: R' is 2,2-dimethylpropyl or 1,2,2-trimeihylpropyl; 5 R2 is phenyl, 4-fluorophenyl, or 2,4-difiuorophenyl; R3' is tert-butyL 2-chloro-6-fliiorophenyl, 2-fluoro^trifluoromethylphenyl, 2,6-dJchlorophenyL, or 2,6-diftuorophenyi; or a pharmaceurkally acceptable salt thereof. Mostpn&xredcoa^poundsofFoanular are those where: 10 1. R' is 2^-dimemyipropyl, Rr is 4-fluorophenyl, and R3' is 2-fluoro-6- trifmorometbylphenyl; 2. R* is 2>2^iimemvlpropvl> Rr is 4-fluorophenyl, and R3* is 2,6- dkhlorophenyl; 3. R' is 2^-dimemylpropyl, R2' is 4-fluorophenyl, and R3' is tert-butvi; 15 4. R'is2^-dimeulvhiK^^R2'isphenyl,andRyis2-chloio-^ fluorophenyl; 5. R' is 2,2-dimewylpropyl, R2' is 2,6-difluorophenyl, and R3' is tert- butyl; 6. R' is 1,2,2-rrimemylpropyl, R2' is 4-fluorophenyl, and R3' is tert-butyl; 20 and 7. R is 1,2,2-trimeAylpropyl, 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 2 5 especially preferred mat each of these compounds exist as the dimethanesulfonate salt. The compounds of Formula I are inhibitors of p38 kinase. Thus, the 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 (I WO 20.5/075478 PCT/US2005/0oeo25 ^ of Formula I. It is preferred diat tiae mammal to be treated by the administration of die compounds of Formula I is human. As inhibitors of p38 kinase, die compounds of the present invention are useful for suppressing me production of die pro-inflammatory cytokines tumor necrosis factor a 5 (TNF-a) and interieukin-ip (IL-l(l), and therefore for the treatment of disorders resulting from excessive cytokine production. Compounds of Formula I are djerefore believed to be useful in treating inflammatory disorders, including eczema, atopic dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, and toxic shock syndrome. Compounds of die present invention are also believed to be useful in die 10 treatment of cardiovascular disorders, such as aoite myocaindial infarction, chronic heart failure, adierosclerosis, viral myocarditis, cardiac allograft rejection, and sepsis-associated cardiac dysfunction. Furthermore, compounds of tibe present invention are also believed to be useful for die treatment of central nervous system disorders, such as meningococcal meningitis, Alzheimer's disease, Parkinson's disease, and multiple sclerosis. 15 Most solid tumors increase in mass dirough die 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 endostatm has been reported to result in antitumor activity (O'Reilly, et aL, Cell, 88,277-285 (1997)). The 2 6 selective p38 kinase inhibitor SB22025 has been shown to inhibit angiogenesis (J JR.. Jackson, et aL, J. Pharmacol. Exp. Therapeutics, 284,687 (1998)). Because angiogenesis is a critical component of die mass expansion of most solid tumors, die development of new p38 kinase inhibitors for die inhibition of tins process represents a promising approach for antitumor therapy. This approach to antitumor dierapy may lack die toxic 2 5 side effects or drug resistance-inducing properties of conventional chemodierapy (Judah Folkman, Endogenous Inhibitors of Angiogenesis, The Harvey Lectures, Series 92, pages 65-82, Wiley-Iiss Inc., (1998)). As inhibitors of p38 kinase, compounds of die present invention, therefore, are also useful in inhibiting growdi of susceptible neoplasms. Schultz, R. M. Potential ofp38 3 0 MAP kinase inhibitors in the treatment of cancer. La: E. Jucker (ed.), Progress in Drug Research. 60,59-92, (2003). A susceptible neoplasm is defined to be a neoplasm dtat depends upon p38 kinase for its survival, growdi, or metastasis. Susceptible neoplasms 12. WO 2005/075478 PCT/US2005/000025 ?* include tumors of the brain, genitourinary tract, lymphatic system, stomach, larynx, and hmg (U.S. Patent #5,717,100). Preferably, the term "susceptible neoplasms" as used in the present application includes human cancers including non-small cell lung carcinoma (A. Greenberg, et al., Am. J. Respir. Cell Mol. Biol.. 26, 558 (2002)), breast carcinoma (J. 5 Chen, et al., J. Biol. Chem., 276,47901 (2001); B. Salh, et al., mt J. Cancer. 98,148 (2002); and S. Xiong, et al., Cancer Res.. 61,1727 (2001)), gastric carcinoma (YD. 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 10 aL, Prostate. 55,128-139 (2003)), malignant melanoma (C. Denkert, et al., Clin. Exp. Metastasis. 19,79 (2002)), and multiple myeloma (Hideshima, et aL, Oncogene advance online publication, 1-11, (11 October 2004); and Hideshima, et ah, Blood, 101(2), 703 (2003)). Inhibition of angiogenesis by suppression of TNF-a has also been taught to be 15 useful in the inhibition or prevention of metastasis (U.S. Patent #6,414,150; U.S. Patent #6335336). Furthermore, suppression of TNF-a is indicated far 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 2 0 viral conditions such as influenza (K. Kujime, etal., J. Immunology.. 164, 3222-3228 (2000)), rhinovirus (S. Griego, et al.. J. Immunology. 165, 5211-5220 (2000)), and HTV (L. Shapiro, gjU 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 25 one of skill in the art that the individual steps in the following schemes may be varied to provide the compounds of Formula L 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 30 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. i^ WO 2005/075478 PCT/US2005/000025 Scheme I Etikctone (a) is reacted with ammonium acetate and an appropriate aldehyde in an appropriate sol vent, preferably acetic acid, to provide the corresponding nitropyridinyi- 5 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-snbstitnted-5^imidazol^yl)-2-aminopyridinyl-imidazole (la), with an appropriate orthoformate to provide the 3-substituted-5- The requisite diketones (a) may be prepared as described in the following scheme, where R and R2 are as previously defined. 14 WO 2005/075478 X PCT/U S2005/000025 Scheme II NHR NO. CT"~" 10 2,6-dichloronitropyridine (d) and an appropriate amine or amine derivative are heated together in an appropriate solvent to provide me corresponding 2-arnino-6-chloro-3-«itropyridine (eX which is men coupled with an appropriately substituted acetylene to provide the conesponding 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 tibe following Scheme where X, R, R1, and R2 are as previously defined. Scheme in NHR NO, NHR 15 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(dirriemyl-arnino)rnethane in a suitable solvent, typically dimethylformamide, to provide the enaminoketone (h). The enarninoketone is then treated with hydrazine in a suitable solvent, typically ethanol or methanol, to provide the phenylpyrazole (j). The \S WO 2005/075478 PCT/US2005/e00025 imidazo- or triazolopyridine moiety is prepared as previously described to provide the compounds of Formula Id. The compounds of Formula 1 where W is the [1,2,3]triazole (iv) may be prepared as described in the following Scheme where variables Y, R, and R are as previously defined. Scheme IV NHR *■ HN Oe) The acetylene (f) is reacted with a source of azide, typically sodium azide, in a 10 suitable solvent, such as drmethyoxyethane to provide the triazole(k). The imidazo-or triazolopyridine moiety is prepared as previously described to provide the compounds of Formula le. 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 15 previously defined and Y is O or S. lb WO 2005/075478 S*r PCT/US2005/0OO025 Scheme V Y x> 4s '^X (I) (n) N Br H2 (o) (P) The a-bromoketone Q) is reacted with an appropriate amide (m, Y=0) or thioamide (m, Y=S) in a suitable solvent to provide the corresponding oxazole or thiazole 5 (n). The oxazole (n, Y=€>) is then treated with bromine in a suitable solvent to provide the corresponding brominated heterocycle (o, Y=0). The thiazole (n, Y=S) is treated with n-butyllithhim and the resulting anion reacted wkh tributyhin 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 10 previously described to provide the compounds of Formula If. The requisite a-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, Modem Synthetic Reactions, W.A. Benjamin, Lac, Menlo Park, California (1972), pages 459-478) and Larock (R.C. Larock, Comprehensive 15 Organic Transformations. VCH Publishers, Inc., New York, New York (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 II WO 2005/075478 PCT/US2005/000025 following Scheme, where W is imidazole (i) or isoxazole (vi), and X and R are as previously defined. Scheme VI •"V^'1! (P) W N \ 0e) H 5 An appropriately substituted haloheteroaryl (q) is coupled with an appropriately substituted boronic acid (p) in the presence of a palladium catalyst, typically bis(triphenyh4Kisphine)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 10 Many of the compounds of u^ preseiit mvertkm arc 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 carboxync acids or amino acids under standard peptide coupling conditions. Furthermore, ester moieties may be reduced to the 15 corresponding alcohols or converted to amides under standard conditions. Alcohols may be activated and displaced by a number of nucleophiles to provide other compounds of the invention. Such leaving groups include but are not limited to halides, oxonhim ions, alkyl perchlorates, ammonioalkanesulfonate esters, aOcyl fluorosulfonates, nonaflates, tresylates, triflates, and sulfonic esters, preferably the mesylate or tosylate. Techniques 2 0 for the introduction of these groups are also well known to the skilled artisan; see, for example, March, Advanced Organic Chemistry. 5* Ed., John Wiley and Sons, New York, pg. 445-449 (2001). Additionally, the 2-amino moiety of the benzirnidazole nucleus may be diazotized and displaced to provide additional compounds of the invention under standard conditions. 2 5 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 men deprotected as necessary or desired. The skilled artisan will appreciate that the protecting groups may be removed at any convenient point in the 3 0 synthesis of the compounds of the present invention. Methods for introducing and X \V WO200S/075478 PCT/US2MMW625 >* 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, die order in which moieties are introduced is not critical. The 5 particular order of steps required to produce the compounds of Formula I is dependent upon die 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-diniemylfonnamide; DMSO = 10 dimethylsulfoxide; Et20 = diethyl ether, EtOAc = ethyl acetate; EtOH = ethanol; h = hour(s); MeOH = methanol; min = minute(s); MTBE = methyl tert-butyi ether, Pd(OAc>2 = palladium acetate; RT = room temperature; THF = tetrahydrofuran; VO(acac)2= vanadyl acetylacetonate. 15 Preparation 1 f6^2-tert-Butvl-5j)hepvl-31^^ dmiemyhYOpyl)amme (6-Crdoro-3-nitn>pvridir>-2-vlM2J2-dm>emvl-pitH>vl)am Add neopentylamine (18 mL, 150 mmol) to a suspension of 2,6-dichloro-3-2 0 nitropyridine (20 g, 103 mmol) and NagO) (185 g, 175 mmol) in EtOH (1.6 mL/mmol) at RT and stir overnight Concentrate and dilute the resultant slurry with water (100 mL) and slowly neutralize wim concentrated HC1 (approx. 40 mL) to pH = 7. Cool me suspension at 0 °C for 1 h and collect solid by vacuum filtration. Wash the solid with ice water (4 x 50 mL) and air dry overnight. Recrystallize the material from EtOAc and 2 5 hexanes to give the title compound as a yellow solid (21.23 g, 84%). MS (ES): m/z = 244 [M+H] (22-DimemvlpropvlH3-mtro^phenylefevnylpvridin-2-vl)ainine Dissolve (6-cUoro-3-nitropyrid1n-2-yl>(2,2-dirnemylpropyl)anm (7.3 g, 30.0 3 0 mmol), phenylacetylene (5.0 mL, 45 mmol) and triphenylphosphine (1.5 mmol, 0.39 g) in triethylamine (10 mL/g) in an oven-dried round bottom flask is flushed with nitrogen and evacuated three times. Add Pd(OAc)2 (0.10 g, 0.45 mmol) and the nitrogen 11 WO 2005/075478 PCT/US2005/000025 flush/evacuation cycle is repeated (3x). Heat at 70-80 °C with stirring under nitrogen for 1-3 h, then cool at RT for 2 h. Concentrate and partition between water (25 mL) and EtOAc (150 mL). Separate die organic layer and wash with water (4 x 25 mL), saturated aqueous NaCl (25 mL), dry with MgSQ*, filter, and concentrate. Purify me crude solid by 5 recrystallization from EtOAc /hexanes to give the title product as a bright orange solid (6.5 g, 21.2 mmol, 71%). MS (ES): m/z = 310 [M+H]; mp 90-92 °C. 1 -f 6-pvlaniirK>V5-nitropyr^ 1 J2-dione 10 Cool a mixture of (2^-dimemvh7ropvlH3-nitro-6-phenylemynylpyiridin-2- yl)ainine (3.11 g, 10 rnmolX NaHCOj (0.420 g, 5.0 mmol), MgS04 (2.40 g, 20 mmol) in acetone (85 mL), and water (25 mL) and cool to 0 °C. Add KMn04 (3.16 g, 20.0 mmol) to the cooled mixture, and stir the reaction mixture vigorously at 0 °C for about 1-2 h. Quench the mixture with NazSO) (5.67 g, 45 mmol). Remove ice bath and stir mixture at 15 RTfor2h- Filter me solid through a pad of filtering agent. Wash with water (2 x 50 mL) and EtOAc (50 mL). Separate me phases and extract the aqueous phase with EtOAc (3 x 50 mL). Wash the combined organic phases with saturated aqueous NaCl (25 mL), dry with MgSQ», filter and concentrate. Purify the crude (silica gel chromatography, eluting with 1:1 hexanes:CH2Cb) to give die title compound (1.586 g, 46%). 20 MS (ES): m/z = 342 [M+H]; mp 88-90 °C r6^(2-tert-Butvl-5-plienvl-3H-imidazol-4-vlV3-mtropvriQin-2-vll-(2^-dimemvlpropvI)amine Heat a mixture of l-[6-^,2-dmiemylpropylairuno>5-^rutropyridin-2-yl)-2- 25 phenylethane-l^-dione (1.0241 g, 3.0 mmol), trirnethylacetaldehyde (0.66 mL, 6.0 mmol), ammonium acetate (3.47 g, 45 mmol) in AcOH (5 mL/mmol) at 80 °C with monitoring by liquid cbioraatography—mass spectroscopy for the appearance of product. Cool the reaction mixture to 0 °C and neutralize to pH 7 with 5.0 N NaOH. Extract the neutralized aqueous phase with EtOAc (3 x 20 mL) and wash the combined organic 3 0 phases with 20 mL portions of saturated aqueous NaHCC«3 until no further neutralization is observed. Dry the organic phase with MgS04, filter, and concentrate. Triturate the orange crude solid with EtOAc to obtain the title compound (0.7578 g, 62%). £o WO 2005/075478 PCT/US2005/000025 MS (ES): m/z = 408 [M+H]; mp 224-226 °C. The compounds of Preparations 2-21 may be prepared essentially as described in Preparation 1. Prep. Compound MS(ES): m/z IM+BQ 2 {6^2-(2,6-I>ifhioiopbCTyl>5-pb^ nitropyridin-2-yl} ^2^-4firo£thyrpropyl)arnrne 464 3 {6-[2K2,6-Dkiuorophenyl>-5-phenyl-3H-imidazol-4-yl]-3-rritropyridiii-2-yl}-(2^-dimeAylrm>pyl)arrjine 496 4 {6-[2K2-CMoro^flur*opbOTyl>5-phen^ 3-nitropyridin-2-yl} -(2^-dimethylpropyl)arnirie 480 5 (2^-Dirnethylpn)pyl){6^[5-(4-fluorophenyl)-2-isopropyl-3 imidazol-4-yl]-3-introwrklii^2-ylarnine 412 6 Cyclopropyimethyl{6-[2 (2,6-difluocophenyl)-5-phenyl 3H iiriklazol-4-yl]-3-rntn)pyridin-2-ylainine ' 448 7 C^lopropyrmethyi{6-{2-(2>6-dki»loiophenyi>5-phenyl-3H^ irrudazol-4-yl]-3-nitiopyrid%i-2-ylanrine 480 8 (^lopropytaie*hyl{642-(2,6Hlifr^ fliK>rophenyl)-3H-iniklazol-4-yl}-3-n^ 466 9 Cyclopropyimeilryl{6^-(2>4lkftl^^ fltK>rophenyI)-3H-miklazol-4-yl)^^ 498 10 *"i i 1 .1. 11 f rr r A n x »\ r\ - % t~w~t 396 uydopjupyittieuiyi \ o^>^4-iiuui*|)ii*aiyi^-z-isopicopyi-JM-irrudazol-4-yl]-3-nitro|^ridin-2-ylafnine 11 r6^2-tert-Butvi-5-phc«vl-3IJHr^ yQcydopcopyhiiethylamme 392 12 482 (o-[Z^z>o-J^iuuoropi>cpyi^>^4HUuuroputaiyi/-jri->m yl]-3-iutropyridin-2-yl}-(2£-dra»^^ 13 {6-[2H^-Butyl-5^4-fliK)ropbxmyl)-3H-imidazol-4-yl]-3-mtropyridin-2-yl} cydoiwopyimetiiylairiine 410 14 [6^23-rritropyridin-2-ylK2,2-dimemylpiopyl)arnine 392 15 (2^-DiniethyrpropylH 6-[5-2-(2-fluorc>6-laffluoromethylphenyl)-3H-iinid^zol-4-yl]-3-riitropyridin-2-ylamine 532 16 (2,2-Dirnethyrpropyl>{6-[2-(2-fluoro-6-tcifluoromethylpb£nylV5-phenyl-3H-imidazol-4-yl]-3-nitropyridin-2-ylamine 514 17 {6-[2-(^lorKopyl-5^4-fluororAenyl>3H-irnidazol-4-yl]-3-nitropyridin-2-yl} ^2,2-diinemylpr0pyl)arnine 410 18 {6-[2-(2,6-Dichlorophenyl)-5^4-fto^ 4-yl]-3-nitropyrktin-2-ylM2£^irri^ 514 19 {6-[2-tert-Butyl-5-(4-fluorophenyl>3H-imidazol-4-yl]-3-nitropyridin-2-yl}- 20 f6^F2-tert-Butyl-53H-irnidazol-4-yl]-3- 444 £ WO 2005/075478 PCT/US2005/000025 nitropyridin-2-yl} ^2,2stonaemylpiopyl)airiirie 21 {6-[5-(2,4-I)ifliK)roiAeMylV2^2>6^ifhJororAenyl>3H-imida2»l-4-yl]-3-nirropyridin-2-yl} ^2,2-dirnemylpropyl)amine 500 Preparation 22 6-[2^2,6^rj>icrjJorophenyi)-5-phenyl-lH-ii^ diamine 5 Add sodium dithionite (2.58 g, 14.82 mmol) followed by 32% NH4OH (9 mL) to a solution of {6-[2^2,6^khlorophenyl>5-pheayl-l/J-irmdaz yljisobutylamine (1.43 g, 2.96 mmol) in 50 mL of 1:1 THF:water mixture. Stir the mixture at RT for 2 h. Dilute with EtOAc Wash the organic layer with saturated aqueous Nad and dry the organic phase over Na^SO^ Concentrate to yield the title 10 compound (1.32 g, 98%). Preparation 23 2-Isobutylarnirio-3-iuteo^[3^4-fluorcp yffryridine 15 2-Isobutylarnmo-3Hritoo-6^4-fhioro^ Add an aqueous suspension of HgO (0.55 g. 2_54 mmol) in 100 mL of 4% H2SO4 to a solution of 2-isobutylarnii»-3-mtro-6^4-fluo^ (3.99 g, 12.7 mmol) in 100 mL of MeOHL Stir at 95 °C for 17 h and cool to RT. Filter the mixture through a filtering agent and dissolve the precipitate with EtOAc (5 x 100 mL). 2 0 Concentrate and wash the residue with 10:2:1 hexane:diethyl etherMeOH (130 mL) to provide the title compound (2.60 g, 62%). MS(ES): m/z = 332 [M+H]. 2-Isobutylamirio-3-mtro^[3^4-fluorophenvl)pvrazol^vl1pvridme. 2 5 Add dimemylformamide dimethyl acetal (4.50 mL, 33.8 mmol) to a stirred solution of 2-isobutylamino-3Hritro-6-(4-fluoro^ (5.63 g, 16.1 mmol) in 15 mL of dry DMF. Heat the mixture at 80 °C for 6 h, cool to RT and concentrate. Dissolve the residue in 100 mL of EtOH, add 8.30 mL of hydrazine (80% in H2O), stir for 2 h and concentrate. Purify the residue (silica gel chromatography, eluting 3 0 with hexanes:EtOAc 1:1) to give the title compound (4.51 g, 75%). &2 WO 2005/075478 PCT/US200S/000025 J* MS(ES): m/z = 356[M+H). 2-IsooutvlamiiK>-3-mtro^f3^4-fluorophenviyi-m Treat a solution of 2-isobotylamiiK>-3-iiitro^[3^4-flooro0ienyl)pyrazol-4-5 yljpyridine (1.25 g, 3.52 mmol) in dry DMF (15 mL) with 95% NaH (0.36 g, 14.3 mmol) at 0 °C for 15 min. Add morphotinoethylchloride hydrochloride (0.983 g, 5.28 mmol) and slowly warm to RT. Add additional NaH (0.36 g, 14.3 mmol), after 1 h and stir the reaction mixture for 24 h. Quench with MeOH (1 mL) and dilute with water (30 mL). Extract with EtOAc (100 mL), dry with MgS04, and concentrate. Purify the residue 10 (sQica gel chromatography, eluting wim bexa (135 g, 81%). MS(ES): m^ = 469[M4H). Preparation 24 15 (2£-DhriemyrpropyiH3HUt^^ Add sodium azide (0.065 g) to a solution of 2^-dirnethyrpropyl-(2Haitro-5-p^nylemynylt*enyl)aimne (0.153 g)m of DMSO (2.5 mL). Heat at 80 °C for 2 h. Cool to RT. Add 10 mL of IN HC1 and extract with EtOAc (20 mL) and wash with saturated aqueous NaCl (2 x 10 mL). Dry the remaining organic phase over Na2S04 and 20 concentrate. Purify the residue (silica gel chromatography, elutmg with EtOAc:hexanes 1:2) to give the title compound as yellow solid (0.176 g, 100%). IvtS (ES): m/z = 353 [M+H]. Preparation 25 25 2-Ammo-5K2K>xo-2-phenylace^)imid^zo[4,5-b]pyridine-3-sulfonic acid dimethylamide KJ^-climemvl-NM6KMofO-3-pitropvridm-2-vl)suu^^ acid Stir a mixture of 2,6^dichloro-3-riitropyridine (1 g, 2.60 mmol) and N,N- dimeraylsulfamide (0.78 g, 3.12 mmol) in dry DMF (5 mL). Add lithium hydride (0.11 g, 6.76 mmol) and stir at RT overnight Add 10 mL of water and 3N HC1 until pH = 7. 3 0 Filter the yellow solid to provide the title compound (85%). VIS(ES): m/z = 279 [M+H]. o*3 WO 2005/075478 PCT/US2005/000025 X NJ^-*mriemvl-NM3-iiitro^phenvkafay acid Bubble nitrogen through a mixture of N J^-dirnethyl-NM6-cWoro-3-nitropyridin-2-yl)sulfonic acid (3.86 g, 13.7 mmol), phenylacetylene (2.3 mL, 20.67 mmol), 5 triphenylphosphine (0.09 g, 0.68 mmol) and copper (I) iodide (0.06 g, 0.34 mmol) in triemvlamine (30 mL) and THF (60 mL) for 3 min. Add bis(triphenylphosphine)palladium (II) chloride (0.24 g, 0.34 mmol) to the mixture and heat at 110 °C for 4 h. Biter through a pad of filtering agent and concentrate. Purify the residue (silica gel chromatography, eroting with 1:1 hexanes:EtOAc) to give die title 10 compound (80%). MS(ES): m* = 346r>Mfl. Ni*Hfanaemvl-N>-(3-anm?o-6-^^ acid Stir a mixture of N,N-*imiemyl-N,^nirro-6-plien^ 15 acid (0.09 g» 0.26 mmol) and tin chloride dihydrate (0.35 g, 136 mmol) in EtOAc (5 mL) andEtOH(2.5mL)at70°Cfor2h. Concentrate and purify me residue (silica gel chromatography, ehiting with 1:1 hexanes:EtOAc) to give the title compound (65%). MS (ES): m/z = 317 [M+H] 20 2-Anmio-5-phenvlemvnvlimidazof434>Tpvridine-3-sulfonk acid diethylamide Stir a mixture of N,N-^phenylem acid (0.20 g, 0.63 mmol), cyanogen bromide (0.07 g, 0.69 mmol) and lithium methoxide (0.04 g, 0.94 mmol) in 1,2 dichloroediane (20 mL) at 80 °C overnight. Concentrate and purify the residue (silica gel chromatography, eluting with 1:1 hexanesJBtOAc) to give the 2 5 title compound (45%). MS0ES): m/z = 342 [M+H). 2-Arm^o-5-(2^xo-2-plienvlacetvl)iniidazof4t5-bTpvridine-3-sulfonic acid dimemvlamide Add a solution of 2-anmio-5-phenylemynyh^dazo[4>5-b]pyridme-3-sttlfonic acid 3 0 dimethylamide (0.10 g, 0.31 mmol) in acetone (4 mL) over a mechanically stirred solution of NaHCOa (0.01 g, 0.15 mmol) and MgS04 (0.07 g, 0.62 mmol) in water (4 mL) at 0 °C. Add KMnQ4 (0.12 g, 0.748 mmol) and stir at 0 °C overnight. Add Na^Ch (0.13 g), and «5>V WO 2005/075478 PCI7US2005/000025 s&(^ stir for 1 h. Add EtOAc and wash with a saturated aqueous solution of NaCl, and concentrate to give the title compound as an orange solid which is used without further purification (68% yield). MS(ES): m/z = 372 [M+H]. 5 Preparation 26 Propane-2-sulfonic acid {3-arrmK)^[2-(2,6^ifluoropheayl)-5-phenyl-3H-imidazol- 4-yi]pyridin-2-yl} amide Propane-2-sulforuc acid (3-nitro^phenviemvnvlpvridin-2-yl)ainide 10 Add propane-2-sulfonic acid (5K;hloro-2-nitrophenyl)amide (10 g, 35.7mmol), phenylacetyiene (5.9 mL, 53.6mmol) and triphenylphosphine (0.46 g, 1.78 mmol) to a solution of triethylamine (25 mL, 178.5mmoi) in dry THF (25 mL) and flush the system with nitrogen. Aritf dkiutoobisOriphenylpbosp^ and copper (I) iodide (0.17 g,0.89mmol) to this stirring mixture. Heat the reaction to 15 reflux for 4 h. Cool to RT and concentrate to a slurry. Filter the erode material through a plug of silka gel using IfflAc as the dtatmgsorvenL Concentrate the filtrate and crystallize the title compound from EtOAc-hexanes (7.9 g, 64%). MS(ES): m& = 346[M+HL 20 Propane-2-sulfonic acid f3-mtro-6^2^xo-2-r^K«vlacx^l)pvridm-2-yl1arriide Heat a mixture of propane-2-sulfonic acid (3-nitro^phenylethynylpyridin-2-yl)amide (1.8 g, 5.26 mmol) and palladium (IT) chloride (0.93 g, 0.53mmol) in dry DMSO (20 mL) at 120 °C for 12 h under a nitrogen atmosphere. Cool to RT, concentrate to a slurry, and purify (silica gel chromatography, eluting with a gradient of 20:80 2 5 EtOAc:hexanes to 30:70 EtOAc-hexanes) to give the title compound (1.07 g, 54%). MS (ES): m/z - 346 [M+H]. »?r WO2WW07S47S PC17TC2005/M0025 X Prqpane-2-sulfcaric acid {6-r2^2,6-difliKMrDphenvlV5-phenyl-3H-imidazol-4-Yl1-3-nitropvridin-2-vl) amide Heat a mixture of propane-2-sulfonic acid [3-nitro-6-(2-oxo-2-phenylacetyl)pyridin-2-yi]amide(0.25g, 0.67mmol), 2,6-difluorobenzaldehyde (0.146 mL, 5 135mmol) and ammonium acetate (0.78 g, 10.05 mmol) in AcOH (5 mL) at 110 °C for 2h. Cool to RT and concentrate. Dilute with EtOAc (30 mL), extract successively with saturated NaHCQj and saturated aqueous NaCl. Dry die organic layer over NaS04, concentrate, and purify (silica gel chromatography, eluting wim 30:70 EtOAchexanes) to give the title compound (032 g, 95%). 10 MS (ES): mfz = 500 [M+HJ. Propane-2-sulfonk: acid (3-anrino^r2-^6-difluoiopnenviy^ 4-yll-pvridm-2-yl}amide Add 10% PuTC (0.033 g) to a stirring solution of propane-2-sulfornc acid {6-[2- 15 (2^6-difluc»rophenyl>5-phenyl-3H-miM^^ (Q33g, 0.66 mmol)inMeOH(lOmL). Add sodium borohydride (0.124 g. 33 mmol) in portions and with stirring under nitrogen for 15 min. F3terdie catalyst and concentrate. Dilute wim EtO Ac (20 mL) and extract successively wim saturated NaHCQj and saturated aqueous NaCl. Dry the organic layer over NajSO* and concentrate to give the title compound (0.3 20 g,98%). MS (ES): m/z = 470 [M+H]. Preparation 27 Propane-2-sulfonic acid {3-anunc*^[2^2,6^dhlorophenyl>5-phenyl-3H-imidaz»l-4-yl]- 2 5 pyridin-2-yl} amide Heat a mixture of propane-2-sulfonic acid {6-[2-(2,6-dichlorophenyl)-5-phenyl-3H-iinidW)l^yl]-3-mtropyridin-2-yl} amide (0.262 g, 0.49 mmol) and tin (H) chloride dihydrate (0.55 g, 2.46 mmol) in EtOH (10 mL) at 100 °C for 1 h. Cool to RT and concentrate to a slurry. Pour the reaction mixture into saturated NaHC03 (20 mL) and 3 0 add a filtering agent Filter and wash with EtO Ac. Separate the layers and extract successively with saturated NaHC03 and saturated aqueous NaCl. Dry the organic layer over Na2S04 and concentrate to give the title compound (0.21g, 85%). WO 2005/075478 PCT/US2OO5/OO0025 MS(ES): m^ = 504[M+HJ. Preparation 28 l-Ben2yl-2-methyl^bromo-5K2,4-difluorophenyl>lH-iiru 5 l-Benz^l-2-methyl-5-bromo-lH-iimdazole Add N-bromosuccmimide (7.85 g, 44 mmol) to a solution of l-benzyl-2-methyl-lH-imidazole (8.0 g, 46 mmol) in chloroform (200 mL) and stir for 6 h. Wash with saturated aqueous sodium hydrogen carbonate and saturated aqueous NaCl, dry over MgSO-t, and filter through a pad of silica gel. Concentrate filtrate and suspend the residue 10 in diethyl ether (600 mL),heat to reflux, and filter hot Concentrate ether filtrate to give the title compound as a tan solid (93 g). MS (ESy m/z = 252 [M+H]. 1 -Beaaz^-2-memvl-5^2»4-d 15 Heat a mixture of 14>erizyl-2-niemyl-5-bromo-lHhnidazole (4.71 g, 18.7 mmol), 2,4-diftuoTophenyl boronic acid (6.92 g, 43.8 mmol), bis(acetato)bis(tripb£nylpbospbine)-palladium(II) (1.4 g. 1.87S mmol), 2N Na^CO, (19 mL, 38 mmol), MeOH (19 mL) and l>2-dirrK^hoxyettane(120mL)torefhixfor 18h. Cool to RT. Add water andBtOAc and separate me layers. Dry organic layer over MgSC>4, filter, and concentrate. Purifythe 2 0 residue (silica gel chromatography, eluting with EtOAcrCEbCh mixtures) to give the desired compound (3.59 g). MS (ES): m/z = 285 [M+H]. Bromination 25 Stir a mixture of l^nzyl-2-rnemyl-5^2,4Hh^uorophenyl>lH-imidazole (3.58 g, 12.6 mmol) and N-bromosuocinimide (2.24 g, 12.6 mmol) in chloroform (100 mL) at RT for 18 h. Add the reaction mixture directly onto silica gel and elute with CH2Cl2:EtOAc mixtures to give title compound (3.41 g). MS(ES): w/2 = 364rM+Hl. 30 £1 WO 2005/075478 PCT/US2005/000025 Preparation 29 2-tert-Butyl-4-(4-fluorophenyl)oxazole Reflux a solution of commercially available 2-bromo-4'-fluoroacetophenpne (100.00 g, 460 mmol), 2^-dunemyl-propionamide (93.06 g, 20 mmol) in 1,4-dioxane 5 (600 mL) for 2 days. Filter precipitate, concentrate filtrate, and purify (silica gel chromatography, eluting with hexanes:EtOAc 60:1) to give the title compound (55 g, 55%). MS (ES): m/z = 220 [M+H]. 10 The compounds of Preparations 30-31 may be prepared essentially as described in Preparation 29. Prep. Compound MS(ES): m/z [M+H] 30 2 tert ButvM^2>4-difluorophenyl)oxazole 238 31 4~(4-Fhiorophenyl>2-isopropyk>xazDle 206 Preparation 32 2-tert-Bi)ty}~4-{4-fliiorophen^ 15 Dissolve 2-tert-but^-4^4-ftuorophenvlV>xazole (0.61 g, 2.77 mmol) in THF (15 ird>andaddteTt-butyllidmim(3.3mll.7M>at-780C. Stir the mixture for 45 min. Add trimethylstannanyl chloride (0.58 g, 2.90 mmol) and allow die temperature to reach RT. Stir for 2 h and add an ammonium chloride solution (200 itL, pH = 8 with ammonia) and concentrate. 20 *H NMR (CDC13) 5 7.46 (m. 2H)„ 6.95 (m, 2H), 1.32 (s, 9H), 0.24 (s, 9H). Preparation 33 4-(4-Fluorophenyl>2-methylthiazole Reflux a solution of 2-bromo-4'-fluoroacetophenone (10 g, 46 mmol) and 2 5 thioacetamide (6.9 g, 92 mmol) in 1,4-dioxane (60 mL) for 3h. Filter the precipitate and wash wUh EtOAc to give the title compound (6.5 g, 73%). MS (ES): m/z = 194 [M+H]. J8 WO 2005/075478 PCT/US2005/000025 ^&^ The compound of Preparation 34 may be prepared essentially as described in Preparation 33. Prep. Compound MS(ES): mfr [M+HJ 34 2-Memyl-4-phenylthiazole 176 5 Preparation 35 2-Arnino-5-bronx>irnidaz»[4^b]pyridine-3-sulfonic acid dimethylamide 2^6-Dibrorno-3-nitropYridine Heat at 50 "C a mixture of 2>6-diehloro-3-nitropyridine (9 g) and hydrobromic acid (90 mL) in AcOH (30%) overnight. Cool to RT and pour into water (600 mL). Filter the 10 solid to provide the title compound (87%). !H NMR (CDCb) 8 7.93 NJ^-Diir»ethvl-r^64>rorno-3-mtr^ acid Stir a mixture of 2,6-dibrori*o-3HMtropyridine (113g. 39.25 rmnol) and N, N-15 dimethylsulfarrude (0.006 g. 47.10 mrnol) in DMF (40 mL). Add lithium hydride (0.81 g, 102.05 mmol) and stir at RT overnight Add 100 mL of water and 3 N HC1 until pH = 7. Filter the yellow solid to provide the title compound (93%). 'H NMR (DMSO-dt) 510.25 (br s, 1H), 8.41(d, J= 839 Hz, 1H), 7.50 (d, J= 8.59 Hz, 1H),2.95(2,6H). 20 NJ^iimemvl-NM3-aimno-64>romo-pyri^ acid Heat a mixture of N^-4ime4hyl-N'-(6-bromo-3-nitropyridhv2-yl)sulfonic acid (11.6 g, 35.69 mmol) and tin chloride (40 g, 178 mmol) in EtOACEtOH 500:250 mL for 25 4 h. Concentrate and purify the residue (silica gel chromatography, eluting with 1:1 hexane:EtOAc). Triturate wim water to provide the tide compound (85%). MS (ES): m/z = 297 [M+H). 2-AmirK>-5-bromoimidazof43-bTpvridme-3-siilfonic acid dimethylamide 3 0 Stir a mixture of N^^inie&yl-N,-(3-ammo^bromopyridin-2-yl)sulfonic acid (0.40 g, 1.35 mmol), cyanogen bromide (0.08 g, 1.48 mmol) and lithium methoxide (0.08 Jl y»u ZUV3/U />* /» PCT/US2005/000025 g, 2.02 mmol) in 1,2-dichIoroethane (400 mL). Stir at 80 °C for 2 h. Concentrate and purify die residue (silica gel chromatography, eluting with 1:1 hexane:EtOAc) to give the title compound (82%). MS(ES): m/z = 322 [M+HJ. 5 Preparation 36 l-[2-amino-3^2,2-dimemyl-Fro^ phenyl)-emane-l ,2-dione 5-(2,4-difluoro-phenyiemvnyiy3-(2^-dini^ 10 ylamine Combine 5-b*omo-3-(2£- (30.00 g, 105.94 mmol), Et^N (60 mL), and Pd(OAc)z[P(Ph),l2 (3.97 g, 5.30 mmol) in toluene (150 mL) and heat me resulting mixture to-65^ under nitrogen. Add 1-ethynyl- 2,4-difluoro-benzene (21.95 g, 158.92 mmol) in toluene (30 mL) dropwise to tint above 15 mixture, and men heat the resulting reaction imxtiireat 80^ for 3 h. Cool the reaction to 25°C and quench wim saturated aqueous NHfQ (300 mL). Stir die resulting reaction mixture at room temperature for 20 minutes, ttten filter, washing die solid with H2O and drying under vacuum filtration for 30 minutes. Slurry ti»e solid in MTBE (200 mL), then filter and rinse with MTBE (50 mL). Dry die recovered solid under vacuum filtration to 2 0 provide 14.47 g of die title compound as a light-yellow solid. MS(ES+): m/z = 341 (M+l) Oxidation Treat a solution of 5-(^,4-difluoro-phenylethynyl>3-(2^-dimethyl-propyl)-3H-25 imidazo[4,5-b]pyridm-2-ylamine (14.47 g, 42.51 mmol) in acetone (350 mL) with a solution of MgS04 (10.23 g, 85.00 mmol) andNaHCO) (1.79 g, 21.30 mmol) in water (200 mL). Place the resulting reaction mixture in a H20 bath. Add celite (28.50 g), followed by KMnC>4 (14.11 g, 89.28 mmol) over 10 minutes, as the reaction exotherms to ~30°C. Stir at room temperature for 3 h, then quench wim 10 wt% of aqueous Na2S03 3 0 (150 mL). Stir for 30 minutes, tiien filter over a pad of celite, washing widi 10% MeOH/EtOAc (2 X 700 mL each). Separate die layers of die filtrate and extract the aqueous wim EtOAc (2 X 500 mL each). Wash the combined organics with H20 (500 3° WO 2003/075478 PCT/US2005/000025 mL) and saturated aqueous sodium chloride (500 mL), then dry over Na^SCV filter, and concentrate under reduced pressure to afford a solid. Wash the filter pad of celite with 10% MeOH/EtOAc and concentrate the filtrate under reduced pressure to obtain additional solid. Combine the solids and purify by column chromatography, eluting with 5 2% of 2N NH^MeOH in EtOAc, men 5% of 2N NWMeOH in EtOAc to give 13.08 g (82% yield) of the title compound as an orange-brown solid. MS(ES+): ro/z = 373 (M+l) Preparation 37 10 {6H£-tert-Butyl-5-(4-fluoro-pheny^^^ trimethyl-propyl)-amine l-[6-(l(R).2JZ-4rimt&ylprop'V^^ dione Dissolve [6-3-m^ 15 propylamine (2.73g, 8.00 mmol) in acetone (60 mL). Add water (20 mL), men NaHC03 (336 mg, 4 mmoL 0.5 eqtrivX and MgS04 (l-9g» 16 mmol, 2.0 equiv) and chill me reaction to about 3 °C. Add KM0O4 (23g, 16 mmol, 2.0 equiv) portionwise with vigramiig stirring whilf naintaimng the: tempftratmft hrfow 1 °C. Quench the reaction after 1 - 2h by adding water (20 mL) and NazSOs (4.5g, 36 mmol) and stirring the mixture at 2 0 ambient temperature for lh. Filter the suspension over Celite* with the aid of 600 mL ethyl acetate and about 300 mL water. Separate the layers and wash the organic layer four times with saturated aqueous NaHCOj and twice with saturated aqueous NaCL Dry the organic layer with NaaSO*, filter off the solids, and concentrate the supernatant under reduced pressure. Subject the residue to medium pressure silica gel chromatography 2 5 eluting with a 50 - 70% gradient of CH2CI2 in hexanes to give the desired compound as an orange oil (1.82g, 61% yield). MS(ES1): m/z = 374.1 (M+H)+. Ring Formation 30 Dissolve l-[6 fluorophenyl)emane-l,2-dione (747mg, 2.0 mmol) in glacial acetic acid (10 mL), add ammonium acetate (2.3g, 30 mmol, 15 equiv), and then add trimethylacetaldehyde (344 2 f WO 2005/075478 X POYUS2005/000025 mg, 4.0 mmol, 2 equiv). Heat die reaction mixture to 100 °C for lh and concentrate under reduced pressure. Partition die resulting solids between ethyl acetate and water. Wash the organic layer 5 times wim saturated aqueous NaHCOj, and twice with saturated aqueous NaCl. Dry tibe organic layer with NajSO^ filter, and concentrate under reduced pressure. Subject the residue to medium pressure silica gel chromatography eluting with an isocratic 10% ethyl acetate/hexanes system to give the title compound as an orange solid. (589 mg, 67% yield) MS(ESI): m/z = 440.2 (lrt+H)+ 10 The compounds of Preparations 38-40 may be prepared essentially as described in Preparation 37. Prept CoMpwd MS (ESI): m/z 38 {6-[2-(2,6^hfh»rophenyl>5K4-fliicw^ 4-yi]-3-rnta>^yrid1nr2-ylHlW>^-^^ 496.1 39 {6-[2-(2-fti»rc^-trifluoiorne^3H-mnoazol^yl}^niiro-pyrknri-2 ylH propyl)-arnirie 546.2 40 512L2 \ oH^K^-^:»**0!n>^>^uoiDplKi^>-->H^Uuw*>^)!neuyt^ •**** imidazol^yl]-3Hmtro-pyrk&>-2-ylH^propylamine Preparation 41 {6-[2-tert-Butyl-5-(4-fluoro-phei^ 15 dirnethyl-propyl>amine Dissolve 1 K4-fluon>-phenyi>2-[5-rritro^(2,2-dir^ yl]-ethane-l,2-dione (1.08g, 3.0 mmol) in glacial acetic acid, add ammonium acetate (3.47g, 45 mmol, 15 equiv), and then add trimethylacetaldehyde (517 mg, 6.0 mmol, 2 equiv). Heat the reaction mixture to 100 °C for lh and concentrate under reduced 20 pressure. Partition the resulting solids between ethyl acetate and water. AddNaHCCb until gas evolution ceases. Wash the organic layer 5 times with saturated aqueous NaHCOs and once with saturated aqueous NaCl. Dry the organic layer with Na2SC>4, filter, and concentrate under reduced pressure to give the title compound as a yellow-orange solid. (1.25g, 97% yield) 25 Exact MS: calc: m/z = 426.230 (M+H)+; found: m/z = 426.2313 (M+H)+. £2 WO 2005/075478 ^aS PCT/US2005/000025 EXAMPLE 1 5^2-tert-Butyi-5-phenyl-3H-ii^^ b]pyridm-2-ylamine methanesulfonate Stir a suspension of 6^2-tert-butyi-5-5)henvi-3H-imidazol ylH2^-dimemylpiropyl)arnine (0.20 g, 0.5 mmol) and 10% palladium on carbon (0.025 g) in EtOH (10 mL) under a balloon of hydrogen overnight. Filter the suspension through a filtering agent and wash with EtOH (2x5 mL). Concentrate the filtrate to about 5 mL, and treat at RT with cyanogen bromide (1.3 mmol). Quench with saturated aqueous sodium bicarbonate (2 mL) and stir for 15-60 min. Dilute the mixture with water (5 mL) and extract with CH2CI2 (2 x 10 mL). Wash the combined organic phases with saturated aqueous NaCl (5 mL), dry with MgSO*, filter, concentrate, and purify (silica gel chromatography, during with a step gradient beginning with 100% CH2CI2, to 5:95 ammoniated MeOHrCBbCh) to give the desired compound. The free base is isolated and men converted to the rnetnanesulfooate salt by treatment rf a MeOH-watersohmop with methanesulfonic acid followed by lyopfaflBatkm to grve the tide ooinpourid. MS (ES): m6 = 402 [M+HJ. The compounds of EXAMPLES 2-14 may be prepared essentially as described in EXAMPLE 1. EXAMPLE Compound MS(ES): 2 5-[2-(2,6-Difluorqpbeu^3^2^-^irnemylpropyl)-3H-irmda^4,5-b]pyridin-2-ylarnine methanesulfonate 459 3 5^2-tot-Biityl-5-phenyl-3H-imida2ol-4-yl)-3-cyclopn^ylmemyl-3H-irin^a2»[4,5-b]pvridin-2-ylamme methanesulfonate 387 4 5-(2<:yclorac> 5 3-(2>Dimemylpropyl>5-[5-(4-fluorophenyl)-2-(2-fluoro^trifluorc«nemyhAenyl)-3H-irnidazol-4-yl]-3H-imidazc^4^b]pyridin-2-ylamine methanesulfonate 527 6 3^2,2-Dimemylpropyi)-5-[2-(2-fluoro-6-trifiuororoe&ylT*enyr)-5-phen^ 3H-miidto2»[4\5^]pyridin-2-ylarmTie memanesulfonate 509 7 5-[2-C^lc^rci?yI-53H-iimdazol-4- 405 3J? WO 2005/075478 PCT/US2005/000025 J&? yl]-3^2>dime&yiprop^>3H-imidazo[4>5-b]pyridin-2-ylamine methanesulfonate 8 5-[2-(2,6-Difluoropbeayl>5-(4-fluorophenyl>3H-imidazoM-yl]-3^2^-diinemylpn>pyl)-3H-irrudazo[4>5-b)pyridm-2-ylamine rnethanesulfonate 477 9 5-[2-tert-Butyl-5^4-fli»jopbenyl)-3H-iiiiidazol-4-yl]-3-(2^nlirnemyh»opyl>3H-iniidazo[4>-b]pyridin-2-ylamine methanesulfonate 421 10 5-r2-tert-Butyl-5^4-fliK>rophenvlV3H-imida2ol-4-vl1-3-cyclopropylmethyl-3H-inn^azo[4>5-b]pyridin-2-ylamine methanesulfonate 405 11 5-[2-tert-Butyl-5K2,4-dirluorophenyl>3H-imidazol-4-yl]-3^2^^iroemyh7ropyl>3H-imid^zo[4,5-b)pyridin-2-ylamine methanesulfonate 439 12 R-M24ert-But^-5^4-flnarophenyl>3H-imidazol-4-yl]-3Kl^-triinelliylpiopyl>3H-iniid^zo(4^-bJpyrkhn-2-ylainme methanesulfonate 435 13 R-5-[2^2,6^Difli»oiopl»eiiyl>5K4-floonipb^yl)-3H-miklazol^yl)-3^1^^-ttimemylptopyl)-3H-imid^zo[4,^b]pyridin-2-ylamine methanesulfonate 491 14 R-5H^4-FhK*opl)enyI)-2K2-fluo^^phenyl>3H imidazol^yl] 3-(l^^ tnmethylpropyl>3H-mwlazo[4r54>)pyrkmv2-ylamme methanesulfonate 541 EXAMINE 15 3^ydopropyh»emyl-5-[2^6-dkiu«^^ 3H4midazo[4,5^]pyrklm-2-ylamine methanesulfonate Treat a suspension of (cydopropylmemyl{6-[2-5-(4-fluorophenyl>-3H-iniid^zol^yl]-3-nitiopyridin-2-yl} amine (0.250 g, 0.5 mmol) in EtOH (10 mL) with tin dichloride dihydrate (0.5641 g, 2.5 mmol) and heat at reflux for 2.5 h under nitrogen. Cool to RT and quench slowly with saturated aqueous NaHC03 (5 mL) and EtOAc (5 mL). Add filtering agent to the resulting suspension and dilute the mixture further with 5 mL each of aqueous NaHCC>3 and EtOAc. Filter the mixture through a pad of the filtering agent Wash the solid with 10 mL each of aqueous NaHC03 and EtOAc. Separate the layers and extract the aqueous phase with EtOAc (10 mL). Wash the combined organic phases with saturated aqueous NaCl (5 mL), dry with MgSO 31 WO 2005/075478 X PCT/US2005/000025 MgS04, fiher, concentrate, and purify (silica gel chromatography, eluting with a step gradient beginning with 100% CH2CI2 to 5:95 5% ammonia in MeOH:CH2Cl2 to give the desired compound. Isolate the free base and convert it to the methanesulfonate salt by treatment of a MeOH-water solution with methanesulfonic acid followed by lyophilization. MS (ES): m/z = 495.1 [M+HJ. The compounds of EXAMPLES 16-35 may be prepared essentially as described in EXAMPLE 15. EXAMPLE Conpound MS(ES): m/z [M+HJ) 16 3-Cyctopropylmrthyl-5-{^^ 461 tiuoiopDenyi^-jit^iwiciayci-^yij-jri-imwazoi^,^ bJpyndin-2-vlarnme methanesulfonate 17 5-{2-6-DkiilMOj*ienyl>5-3-(2£-dmiemylp^ 509 b)pyr niin-2-ylamnie rnethaucsulfutialc 18 5-£2-(2-Chloto-6-fluoroi)liei^ 4yl]-2K2^^rirriemyrc«opyl)-3H-im»dazc>l4> b]pvridin-2-ylamirie memanesulfonate 475 19 3 20 32-ylamine methanesulfonate 476 21 5-[5K2,4-Dffluorophenyl>2^2,6-difluoror>henyl>3H-mnd^zol-4-yl]-3-(2>2-dhT»e1hyh>rop^^ b]pyridin-2-ylarnine methanesulfonate 495 22 5-[3K4-RuororAenyl>l-rnethylpyrazol-4-yl]-3H-3-isobutyl-mrida2o[4^b]pyridm-2-ylarninemethanesulfonate 365 23 5-[5K4-Huorophenyl)-l-methylpyrazol-4-yl]-3H-3-isobutyl-irmd,a^4>5-b]pyriclin-2-ylarriinemethanesulfonate 365 24 5-[3-(4-Fluorophenyl)-l-morpholinoethylpyrazol-4-yl]-3H-3-isobutyl-hTnda2o[4,5-b]pyridm-2-ylairiinememanesulfonate 464 25 5-[3-(4-HuororAienyl)-pyrazol-4-yl]-3H-3-isobutyl-imidazo[4^b]pyridto-2-ylarnine di-methanesulfonate 351 26 3H-3-isobutyl-5-(3-phenyl-l-isopropylpyrazol-4-yl> mndaM[4^b]pyrid^-2-ylarnine di-methanesulfonate 375 27 3H-3-isobutyl-5-(3-phenyl- l-methylpyrazol-4-yl> 347 3r WO 2005/075478 ^ PCT/US2005/000025 mridazo[4,5-b]pyridm-2-ylamine di-medianesulfonate 28 3H-3-isobutyl-5-(3-phenyl-pyrazol-4-yl>-imidazo[4,5-b)pyridin-2-ylamine di-inethanesulfonate 333 29 5-[3-(2,4-Difluorophenyl)pvjra2X>l^^ inudazo[4,5-b]pyridin-2-ylanune di-methanesulfonate 369 30 5-[2^2,6^Diflu«rophenyl>5-phcfflyl-3H-irnidazol-4-yl]-3-isobutyl-3H-imida2^4^4)]pyridm-2-ylaininemethanesulfonate 445 31 5-[2^2,6-DkWorophenyl>5-phenyl-3H-imidazol-4-yl]-3K2^-^imethyh»opyl>3H-mrida^4,5-b]pyridm-2-ylamine rneftanesulfonate 491 32 S-P^^DkiuorophenylVS-phenyl-lH-imidazol^^ 3-isnhnty1-3t^imi«t»3^4^S4»]pyridm-2-ylamme 477 methanesulfonate 33 5-[2^2,6^I>iclu\Kophenyl>5^4-fhion>phenyl)-lH-imiHa7o|-4-Yl)-^-isfltmryi-^H-imid?»7o[ilJ *»-KJpyri ylamine methanesulfonate 34 5-[2K2,6^DiduVm)0ie^>5^ itniol-4-vl]-Vflwlmtyl-3H-ii^ 513 ylaikiitkc ihethaikcsulfonate 35 R 5-[2^2 Cl>k)TO^fh»oro|>henyl>5^4-fliK)rophenyl> 3H-imiAizol-4-yl)-3Kl^^-trmjeAvlpiopvl>3H-imklazo[4,5-b)pyridiD-2-vlamine nietharjesulfonate 507 EXAMPLE 36 5H£-iert-Butyl-5K4-fluoropiienyl^ 3Hhnidazo[4^-b]pyridine methanesulfonate Reduce and isolate {6-f2^ert-buryl-5-(4-fluoropheayl)-3H-iniida2ol-4-yl1-3-nitropyridin-2-yl}^2,2^irnethylpropyl)amine (0.43 g; 1.0 mmol) as in EXAMPLE 1. React the crude diamine with neat ttiethylorthoacetate at 120 °C overnight Concentrate and dilute with 15 mL IN HC1. Neutralize with saturated NaHCOj and extract with CH2CI2. Wash the organic layer with saturated NaCl, dry with NazSO^ concentrate, and purify (silica gel chromataography, eluting with EtOAc:CH2Cl2 50:50) to give the title compound as a tan solid (0.11 g; 53% yield). The free base product is converted to the methanesulfonate salt essentially as described in EXAMPLE 1. MS (ES): m/z = 420 [M+H]. The compounds of EXAMPLES 37-38 may be prepared essentially as described in EXAMPLE 36. 36 WO 2005/075478 PC17US2005/000025 EXAMPLE Compound MS(ES): Wz[M+H] 37 5^2]^-Butyl-5-j*enyl-3H-imidazol-4-yl)-3-(2,2-dimethyl-pK^yl)-2-nie&yl-3H-imidazo[4,5-b]pyridinemethanesulfonate 402 38 5-[2^25-pbenyl-3H-iinidazol-4-yl]-3^2^-diinetbylpropyl)-2-inethyl-3H-imidazo[4,5- 474 bjpyridine methanesulfonate EXAMPLE 39 H2^2,6-Difluorc^henyl>5-pDe^^ 3H-imidazo[4^-b]pyridine methanesulfcmate Reduce {6-[2^2,6-difluorophenyl>5-phenyJ-3H-imida2ol-4-yl]-3-nte vl}-(2^-dnriemyhxopyi)aniine essentially as described in EXAMPLE 16, and then react the diamine in toimethyjorthoacatate as described m EXAMPLE 36 to give the tree base as a tan solid (0.11 g; 49% yield). TTie methanesulfonate of the free base is formed essentially as described in EXAMPLE 1. MS (ES): m/z = 458 [M+H). The compounds of EXAMPLES 40-45 may be prepared essentially as described in EXAMPLE 39. EXAMPLE Compound MS(ES): m&[M+H] 40 5-[2K2,6-Difhiorophenyl)-5-(4-fluorophenyl)-3H-irrridazol^yl]-3^2^-dimemylpropyl>2-methyl-3H-inudazo[4,5-b]pyridine methanesulfonate 476 41 5-[2-(2,6-DichlcTODhenyl>-5-(4-fluorophenyl>3H-imidazol^yl)-3-(i2^imemylpi^yl)-2-rriethyl-3H-urjddazo[4,5-b]pyridine methanesulfonate 508 42 3-Cyclc^iopylinethyl-5-[25-phenyl-3H-iinidazol-4-yl]-2-methyl-3H-imidazo[4,5-b]pyridine methanesulfonate 442 43 3-Cydc^m>pylrnethyl-5-[2-(2,6-dichlorophenyl)-5-phenyl-3H-irnid^zol^yl]-2-methyl-3H-imidazo[4>5-b]pyridine methanesulfonate 474 44 5-(2-Cydc^ropyl-5-phenyl-3H-imidazol-4-yl)-3-(2,2-oimethylpropyl>2Haaethyl-3H-irJoidazo[4,5-b]pyridine methanesulfonate 386 45 5-[2-(2,6-DicWorophenyl>5-phenyl-3H-imidazol-4-yl]-3-h,2-dimethylpropyl>2-methyl-3H-imidazo[4,5- 490 37 WO 2005/075478 PCT/US2005/000025 I bjpyridine methaoesulfonate 10 EXAMPLE 46 5-[2^2-CMoro^fluorophenyl>5-phenyl-3H-i^ imidazo[4,5-b)pyridme methanesulfonate Reduce {6-[2-(2-chloro^flnorophenyl>5-phen^^ nitropYridin-2-yl}^2^-^limethyhicopYl)aniine essentially as described in EXAMPLE 15. React the diamine with refluxingneat triethylorthofonnate for 24 h and at RT for an additional 24 h. Purify and isolate the free base essentially as described in EXAMPLE 36 (0.11 g, 49% yield). Convert to the methanesulfonate essentially as described in EXAMPLE 1. MS(ES): m/fc = 460[M+HL The compounds of EXAMPLE 47-48 may be prepared essentially as described in EXAMPLE 46. 15 20 25 EXAMPLE CMapound MS(ES): j*£[M+H] 47 5^2^yclopiopyl-5-phemil-3H-hxdd^zol^yl)-3-(2^-dirriethvlptopvl)-3H-miJdazo(4r5-b]pyrkliijemethanesntfonate 372 48 5-[2^2,6-Difhicm)phenyl)-5^^3-isobutyl-3H-imidazo[4^-ft]pyridinemethanesulfonate 430 EXAMPLE 49 5-[3^4-Fluorophenyl)-l-isopropylpyrazol^yl]-3H-3-isobutylimidazo[4,5-b]pyri ylamine di-methanesulfonate Add sodium hydrosulfite (2.55 g, 14.6 mmol) to a solution of 2-isobutylarnmo-3-mtro-6-[3-(4-fraorophenyl>l-isor«opylpyrazol^yl]pyridine (0.50 g, 1.27 mmol) in 25 mL of 1:1 THF:H20, in the presence of NH4OH (8.70 mL, 32% in H20). Dilute with water (25 mL) after 2 h. Extract with EtOAc (100 mL), dry with MgSC>4, and concentrate. Dissolve the residue in 1:1 CHbCkEtOH (25 mL), add cyanogen bromide (0.16 g, 1.51 mmol), and stir for about 48 h. Concentrate and purify the residue (silica gel chromatography, eluting with EtOAcMeOH 16:1). Recrystallize from diethyl 38 WO 2005/075478 X etherhexanes to provide the free base (0.44 g„ 88%). Convert to the nc essentially as described in EXAMPLE 1 (58% yield). MS (ES): m/z = 393 [M+HJ. The compounds of EXAMPLE 50-62 may be prepared essenti EXAMPLE 49. EXAMPLE Compound 50 5-[2-iert-Buryl-5-rAienyl-lH-hnklazol-4-yl]-34sobuty 3H-imidazo{4^-b)pyridin-2-ylamine di-methanesulfonate 51 542-(2-FhxKO-6-chk>ropheayl>-5-^^4-yl)-3-isobutyl-3H-hiiidazol4>4>]py^^methanesulfonate 52 S-[?-C^lo|w^yl-S_phrTiy|-lH-iTO»'^'«'-4-yl]-3- isobwtyl-3H4midazo[4,5^)pyridi^^ merhanesnlfonate 53 5^2 54 5-[2^2-Fhwi©-6-dik>roi>beii^ iimdazol-^yl>-3-isobutyl-3H-imidazol4>54>)pyridi^ yiamine methanesulfonate 55 5-[2-isopropyl-5-pheayMH-iimd^ 3H-imida7o[4>5-b]pyrkm>-2-ylamine di-methanesulfonate 56 5-[2K2-Fhxm>-6-trnluonmiethylphenyl>5-(2>4-, difluoK>phenyl-lH-nTridazol-4-yl]-3-isobotyl-3H-imidazo[4,5-b]pyridin-2-ylamine methanesulfonate 57 5-r2-tert-BttWlV5^2.4-difluorophenvl-lH-irnidazol-^yl]-3-isobutyl-3H-imida2o[4,5-b]pyridm-2-ylaminemethanesulfonate 58 5-[2-lsopropyl)-5^2,4Hiifluorophenyl-lH-imidazol-^yl]-3-isobutyl-3H-imidazo[4,5-b]pyridm-2-ylammemethanesulfonate 59 5-[2 lH-irmd^z»l^yl]-3-isobutyl-3H-imidazo[4,5-b]pyridm-2-ylamine methanesulfonate 60 5-[2-Cyclopropyl-5 61 5-[2-Cyclopropyl-5-(4-fluorophenyl>lH-imidazol-4yl]-3-isobutyl-3H-inrida2»[4,54)]pyridm-2-ylarmnecmethanesulfonate 3") WO 2005/075478 j%£ PCT/US200S/00002S etherhexanes to provide the free base (0.44 g, 88%). Convert to the methanesulfonate essentially as described in EXAMPLE 1 (58% yield). MS (ES): m/z = 393 [M+H]. 5 The compounds of EXAMPLE 50-62 may be prepared essentially as described in EXAMPLE 49. EXAMPLE Compound MS(ES): m/z [M+H] 50 5-r2-tett-Bntyl-5-phenvl- lH-imklazol-4-yl]-3-isobutyl-3H-irmdazo{4^b]pyridin-2-ylamine di-memanesulfonate 389 51 5-[2-(2-FhMK>-6-chic«)pheiryl^^4-yl)-3-iscbutyl-3H-irmda2»(4^4>]pyridiii-2-ylaminemethanesulfonate 461 52 5-[2-Cyck>piopyl-5-pheayl-lH-r^^isobutyl-3H-iinidazo(4,5-b)r^din-2-ylainmememanesulfooate 373 53 5-[2^-HwM»^tiifluorom^ imida7iol^yIl-Visotatyl-3H-imKiUii7i'>(4 5-b]pyridm-?- 495 ylamine memanesulfooate 54 5-[2-(2-RtK*o-6 55 5-[2-isopKjpyl-5-pheavl-lItmiida^-4-vl)-3-isobutyl-3H-inikla20[4,54}]pyridin-2-vlamine di-meuianesulfonate 375 56 5-[2-(2-FhK»o-6^-triflucTOniethylphenyl> d^uoiophenyl-lH-hTridazol-4-yl)-3-isobutyl-3H-inudazo{4^b]pyridin-2-ylamine methanesulfonate 531 57 5-[2-tot-Butyl)-5-(2,4-dfflwmjphenyl-lH-imidaz»l-4-yl]-3-isobutyl-3H-imidazo{4^b]pyridiiF-2-ylaininemethanesulfonate 425 58 5-[2-Iscpropyl)-5-(2,4-difluoropbjenyl-lH-miklazol-4-yl]-3-isoWyl-3H-irmdazo{4^4)]r^rklhv2-ylanihiemedianesulfonate 411 59 5-[2-(2-Huc«>-6-cJUOTOphenyl)-5^2,4- 60 5-[2 61 5-[2 3^ WO 2005/07S478 J* PCT/US2005/00002S 62 5-[2-tert-Butyl-5^4-fluoix>phenyl>lH-unidazol-4-yl]-3-isobutyl-3H-imida2»[4,5-b]pyiii&-2-ylanime di-methanesulfonate 407 10 EXAMPLE 63 N' - {5-[2K2,6-Dffluorophenyl>5-phen^ b]pyridin-2-yl} -N,N-dimemylforinamidine Reflux N'-{5-[2,6Hlifluoiophenyl)-5-pfien^ imidazo[4,5^]pyridm-2-ylarnine prepared essentially as described in EXAMPLE 1 (0.10 g, 0.225 mmol), N, Nshme&ylfonnamide dimethyl aoetal (0.05 mL, 0.4 mmol) in toluene (1.5 mL) for 2 h. Cool to RT and concentrate. Purify (silica gel chromatography, ehiting with 1:1 CH2CI2 :acefonitrile) to give the title compound (0.11 g). MS(ES): m^ = 500[M+H]. The compound of EXAMPLE 64 may be prepared essentially as described in EXAMPLE 63. EXAMPLE Compomd MS(ES): m/j[M+H] 64 N*-{5^2K2,6-DkMcropbx»yI>5-plienyl-3H-inuda2ol-4-yl]-3-iscWyl-3H-imidazo[4>blpyridm-2-yl}-N^-dimemylformamidine 533 15 EXAMPLE65 r^-{5-[2^2,6-Dkiik>ropheiiyI>3-n^ imidazo[4,5-b]pvridm--2-yl} -N^-dimemylfoimamidme StkN'-{5-[2^2,6-dicWOTX)plierryl>5-phenyl-3H-i^ mMdazo(4^-b]pyridin-2-yl }-N,N-dimemylformamidine prepared essentially as described 20 in EXAMPLE 63 (0.10 g, 0.188 mmol), iodomethane (0.040 g, 0.282 mmol), and CS2CO3 (0.09 g, 0.28 mmol) in DMF (1.5 mL) at RT for about 24 h. Extract wim EtOAc and wash with water (3x), saturated aqueous NaCl, then dry over NajSO^ Filter and concentrate to give a mixture of methyl isomers. Purify (silica gel chromatography) eluting with 1.1:0.4 CH2Cl2:aeetomtrile:hexanes to give the title compound (0.02 g). 25 MS (ES): m/z = 548 [M+H]. MO WO 2005/075478 PCT/US2005/000025 EXAMPLE66 5-[2K2,6^Difluon^enyl)-3-methyl-5-phenyl-3H-imidazol-4-yl]-3-isobulyl-3H^ imid^o[4^-b]pyridin-2-ylamine HeatN'-{5-[2-(2,6^muorophenyl>3-inethyl-5-phenyl-3H-imidazol-»-yl]-3-5 isobutyl-3H-imidazo(4,5-b]pyridin-2-yl }-N^limethylformainidine (0.02 g, 0.04 mol) in 1:1 glacial acetic acidconcentrated Ha (0.6 mL) at 100 °C for 30 min. Cool to RT. Add CH2CI2 and water, neutralize with 5N NaOH to about pH = 7 with rapid stirring. Extract the aqueous phase 3x with CH2CI2, combine organic layers, wash with saturated aqueous NaCl and dry over NazSO^ Filter and concentrate to give the title compound (0.02 g). 10 MS02S): m/z = 459 [M+H] The compound of EXAMPLE 67 may be prepared essentially as described in EXAMPLE 66. EXAMPLE Compound MS(ES): 67 5-[2^2,6-L>ichk)topl»i^>3-inethyl-5-phenyl-3H-imiAwol^yll-^istihwlyl-^H-imidayx^, 5-bJpyridin-?- 493 ylamine 15 EXAMPLE 68 3^2>Dimeraylpropyiy5^5-phenvW^ yiamine methanesulfonate Suspend (2,2-Kiiinemyl-propYlH3Hritro^5-p^ yl)pyridin-2-yl]amine (0.180 g, 0.51 mmol), and 10% Pd/C (0.025 g) in EtOH (10 mL) 2 0 and stir at RT under a balloon containing hydrogen for 5 h. Filter the reaction mixture using a filtering agent and concentrate to approximately half the reaction volume. Use the diamine immediately without further isolation or purification (MS (ES): m/z 323 [M + H], and treat with cyanogen bromide (0.09 g) in EtOH (5 mL). Stir under nitrogen for 3.5 h, quench with saturated aqueous NaHCO3(2.0 mL), stir, dilute with CH2CI2 (5 mL) and 2 5 H20 (5 mL), and separate the phases. Extract the aqueous phase with CH2CI2 (2x5 mL), wash the combined organic phases with 5 mL each of H2O and saturated aqueous NaCl, and dry with MgSO*. Filter and concentrate. Purify the residue (silica gel chromataography, eluting with 4:96 2.0 N ammonia in MeOH:CH2Cl2) to give the free Ml WO 2005/075478 PCT/US2005/000025 JW base. Convert to the methanesulfonate salt by treatment of a MeOH-water solution with methanesulfonic acid followed by lyophilization to give the title compound (0.07 g, 39%). MS (ES): m/z = 348 [M+H]. The compounds of EXAMPLE 69-71 may be prepared essentially as described in EXAMPLE 68. EXAMPLE Compound MSfJES): w/ztM+HQ) 69 3-(2,2-DimeAyrpropyl>5-[5K4-fluorophenyl>3H-[1 ^3]triazol^yl]-3H-fanid^zo[4,5-b]pyridin-2-ylamine rnethanesulfbnate 364 70 3-C^c^Kopylrnethvl-S^5^4-fluorophenyl)-3H-[1^3]triaz»l^vl]-3H-iinid^2o{4>blpyridin-2-ylamine methanesulfonate 350 71 3-CyctopropvhwAyl-5-(5-phen^yl>3H-ra»ida^4^^1p5nridiD^2-ylaniinemethanesulfonate 332 EXAMPLE 72 5-[2-(2-Chloro^fluorophenyl>-5-p^ 10 [l;23]triazolo[4^-b]pyridinemethaiiesulfonate Add dropwise a solution of 6-[2^-cbJoro^fluorophenyl>5-prienyl-lH-imidazol-4-vl]-N2-isobutylpyridine-23-diamine (1.1 g, 2.52 mmol) in CHbCfe (9 mL) and 50% aqueous AcOH (9 mL) to a solution of sodium nitrite in water (0.1 mL) (0.184 g, 2.66 mmol). Stir the reaction mixture for 15 min, add additional CH2CI2 and wash the organic 15 layer with a saturated aqueous solution of NaCl, aqueous NaHC03 (5%), dry with MgSC>4, and concentrate. Purify the residue (silica gel chromatography, eluting with 4:1 to 1:2 hexane:EtOAc) to give the free base (70%). MS (ES): m/z = 447 [M+H]. Add 0.34 mL of a 1 M solution of methanesulfonic acid in CEbChMeOH 9:1 to a solution of the free base (0.15 g, 0.336 mmol) in 10 mL CH2Cl2:MeOH 9:1. Stir the solution 5 min, 2 0 concentrate, and triturate the white solid in diethyl ether. Filter the solid to provide the title compound (71 %). MS (ES): m/z = 447 [M+H]. 25 The compounds of EXAMPLE 73-75 may be prepared essentially as described in EXAMPLE 72. ^2 WO 2005/075478 PCT/US2005/000025 EXAMPLE Compound MS(ES): m/z [M+TO) 73 5-[2-(2,6-DicUoroi*enyl>5-^enyl-lH-iiiiidazol-4-yl]-3-isobutyl-3H-[l ^,3)tria2olo[4^-b]pyridine methanesulfonate 463 74 5-[2-(2,6-DichlorophenylV5-(2,4-difluoroi)henyl)-lH-imidazol-4-yl]-3-isobutyl-3H-[l^,3]triazolo[4,5-bjpyridine methanesulfonate 499 75 5-[2-tert-Butyl-5^4-fluorophenyl>lH-imida2ol-4-yl]-3-isobutyi-3H-[l ,23)triazolo[4,5-b]pyridme methanesulfonate 393 EXAMPLE 76 2-Ammo-5^2-tert-butyl-5-phenyl-3H-^^ acid dimethylairode methanesulfonate Heat a mixture of 2-affiuio-5^-oxo-2-pbenylacetyl)imid^^ sulfonic acid dimethylamide (0.07 g, 0.20 mmol), trimethylacetaldehyde (65 ul, 0.6 mmol) and ammonium acetate (0.23 g. 3 mmol) in AcOH (5 mL) at 90 °C for 4 h. Cool to RT. Dilute with a saturated aqueous NaHCC»3, and extract with EtOAc. Concentrate the organic phase and purify (silica gel chromatography, elurmg with 15:1 CHbCfcrMeOH) to give the free base (35%). MS (ES): m/z = 438 [M+Hj. Add 5.4 ul of a solution 1 M methanesulfonic acid in CH2Cl2:MeOH 95:5 to a solution of die free base (0.02 g, 0.054 mmol) in 5 mL CKbCbAfeOH 95:5. Stir the solution 5 min, concentrate, and triturate the white solid in diethyl ether. Filter the solid to give the title compound (71%). MS(ES): m/z = 440 [M+HJ. The compounds of EXAMPLE 77-79 may be prepared essentially as described in EXAMPLE 76. EXAMPLE Compound MS(ES): »i6[M+H]) 77 2-Amino-5-[(2-fluoro-6-chlorophenyl)-5-phenyl-3H-imidazol-4-yl)]miidazo[4,5-b]pyridine-3-sulfonic acid dimethylamide memanesulfonate 512 78 2-Ammo-5-[(2,6-dichlorophenyl)-5-phenyl-3H-imidazol-4-yl)]imidazo[43-b]pyridine-3-sulfonicacid dimethylamide methanesulfonate 528 79 2-Amino-5-(2-tert-butyl-5-(2,4-difluorophenyl)-3H- 476 MS WO 2005/075478 X PCT/LS2005/000025 imidazol^yl)inridaz^4,5-b]pyridine-3-sulfonic acid dimethyjamide methancsulfonate EXAMPLE 80 5-[2^2,6-Difluoroptenyl>5-phenyl-3fr imidazo[4,5-b)pyridin-2-ylamine rnethanesulfonate Stir a mixture of propane-2-sulfonic acid {3-amino-6-[2-(2>6-difluorophenyl>5-phenyl-3H-imidazol-4-yl]-pyridin-2-yl}amide (0.37 g, 0.79 mmol), cyanogen bromide (0.104 g, 0.99 mmol) and lithium methoxide (0.033 g, 0.87 mmol) in methylene chloride (10 mL) for 12 h at RT. Add saturated NaHCO, (10 mL) and stir for 1 h. Separate the layers and extract with saturated aqueous NaCl. Dry the organic layer over NaSQt, concentrate and purify (silica gel chromatography, eluting with a gradient of 40:60 EtOAChexanes to 80:20 EtOActhexaoes) to give me tree base (0.21 g, 54%). MS (ES): m/z = 495 [M+H]. Add methanesulfonic acid to a solution of the free base in 1 mL of a 5:1 mixture of methanol:methvlene chloride. Concentrate the solution and add diethyl ether. Filter the solid, and dry to give the title compound. MS(ES): m/fe = 495[M+H). The compounds of EXAMPLE 81-91 may be prepared essentially as described in EXAMPLE 80. EXAMPLE Compound MS(ES): m&(M+H) 81 3-Butyl-5-[2K2,6^ifluorophenyl>5-phemyl-3H-irmdazol-4-yl]-3H-imidazc»[4>4))pyridm-2-ylaminemethanesulfonate 445 82 3-Butyl-5-[2-(2-flviorophenyl>5-phenyl-3H-imidazol-4-yl]-3H-imidazo[4,5-b]pyrid^2-ylarnine, di-methanesulfonate 427 83 3-Butyl-5-[2-(2-chloro-6-fluorophenyl)-5-phenyl-3H-inndaTOl-4-yl]-3H-maidazo[4^-b]pyridin-2-ylaminemethanesulfonate 461 84 3-Butyl-5K2-tert-butyl-5-prienyl-3H-imidazol-4-yl)-3H-irjoklazo[4,5-b]pyridm-2-ylarrirne methanesulfonate 389 85 3-Butyl-5-[2^2-flvMKO^trifluoromethylphenyl>5-phenyl-3H-rrrndazol^ylJ-3H-iirriida2ot4,5-b]pyridm-2-ylarninemethanesulfonate 495 86 2-Amino-5-(5-(phenyl-2H-[l^,3]triazol-4-yl)uiiid^o[4^b]pyridine-3-sulfonic acid dimethylamide 385 t-fW WO 2005/075478 PCT/US2005/000025 87 5-[2-(2-Ruoro-6-trifluoromethylphenyl)-5-phenyl-3H-inu^azol^yl]-3-(pn^pane-2-sulfonyl)-3H-iinidazo[4,5-b]pyridii>-2-ylamine methanesulfonate 545 88 5^2-tert-Butyl-5-phenvl-3H-miida2ol-4-vI)-3-(propane-2-sulfooyl)-3H-iinidazo{4>5-blpyridin-2-ylaminememanesulfonate 439 89 5-[2K2,6^Di(Woiophenyl)-5-phenyl-3H-imidazol-4-yl)-3-(propane-2-sulfonyl)-3H-miid,a2^4,5-b]pyridm-2-ylaminememanesulfonate 529 90 5-[2^2-Chloro^fluoiopb«iyl)-5-phenyl-3H-iinidazol-4-yl]-3- 91 3-Butyl-5-[2-tart-but^-5^2,4-difluorophenyl>3H-imkla2ol^yl]-3H-raiidaz»[4^b]pyridm-2-ylaminememanesulfonate 425 EXAMPLE 92 M2-tert-Birtyl^4-fluojophcmyi)o^ ylamine Bubble with nitrogen a suspension of 2-tert-butyl^4-fluorophenyl)oxazole (0.145 g, 0.66 mmol), 5-broiiK>3-isobiityl~3H-imi&i^^ (0.355 g. 1.32 mmol), cesium carbonate (6.06 g, 18.6 mmol), palladium (II) acetate (0.201 g, 10%) and tiiphenylphospbiiie (0.14 g, 0.07 mmol) in DMF (1.5 mL). Heat the reaction at 100 "C overnight, cool to RT and partition between EtOAc and saturated aqueous NaCl. Wash the organic layer with saturated aqueous NaCl. Dry with NazSO^ filter, concentrate, and purify (silica gel chromatography, eluting with 2% of 2M ammonialMeOH in CH2CI2 to give the title compound (0.07 g, 34%). MS (ES): m/z = 408 [M+H]. The compounds of EXAMPLE 93-96 may be prepared essentially as described in EXAMPLE 92, with the free base converted to the methansulfonate essentially as described in EXAMPLE 1. EXAMPLE Compound MS(ES): m/z (M+H) 93 5-r2-tert-Btttvi-4-(2,4-difluorophenyl)oxazoI-5-yl]-3-isoburyl-3H-imidazo(4,5-b]pyridin-2-ylaminemethanesulfonate 426 94 5-[4-(4-Huorophenyl)-2-isopropyloxazol-5-yl]-3-isobutyl-3H-imid^zo[4i^]pvrklm-2-ylamine memanesulfonate 394 ^3 WO 2005/075478 *f PCT/US2005/000025 95 3-Isobutyl-5-(2-methyl-4-phenylthiazol-5-yl>3H-irnida2x>{4,5-b]pyridrn-2-ylarnine methanesulfonate 364 96 5-[4-(4-Huoroj^enyl)-2-iiiethyltbiazol-5-yl]-3-isobutyl-3H-imid'azo[4,5-b]pyridrn-2-ylanrine methanesulfonate 382 10 EXAMPLE 97 2-AmiiK>-5^2-tert4>utyl-5-(4-fluoro^ acid dimethylamide Dissolve 2-arruno-5-biomoimidazo{4^b]pyridine-3-sulfonic acid dimethylamide (0.05 g, 0,156 mmol) in toluene (3 ml) in a sealed tube. Add 2-tert-butyl-4-(4-fluorophenyl>5-trirnethylstannanyk)xazx^e (0.07 g, 0.17 mmol) and tetrakis(tripbenylphosphJne)palladium (0) (0.02 g, 0.015 mmol). Heat the mixture at 110 "C for 4 h. Concentrate and purify (silica gel chromatography, elutmg with 20:1 CHbCfeAleOH) to give the title compound. (14%). MS (ES): mfi = 459 [M+HJ. The compound in EXAMPLE 98 maybe prepared essentiaOy as described in EXAMPLE 97, with the free base converted to the methanesulfonate essentially as 15 described in EXAMPLE 1. EXAMPLE Compound MS(ES): iwfe(M+H) 98 2-Anm»-5^2-ispropyl-5^4-imorophenyl)oxa2ol-5-yl)imidazo[4>54>]pyridiiJe-3-sulfoiuc acid dimethylamide methanesulfonate 445 EXAMPLE 99 5-[2-(2,6-Dichlorc-phenyl)-5-(4-fluo^ propyl)-3H-imkiazo[4,5^]pyrknn-2-ylarinne methanesulfonate 20 Mix l-[2-aniino-3K2,2^imemyl-propyl)-3H-imid fraoro-phenyl)-ethane~l,2-dione (19.58 g, 55.24 mmol), 2,6-dichloro-benzaldehyde (15.47 g, 88.39 mmol) and NHUOAc (42.58 g, 552.41 mmol) in glacial acetic acid (200 mL) and stir at 85°C under nitrogen for 5 h. Concentrate the resulting reaction mixture under reduced pressure. Dissolve the residue in ethyl acetate (2,000 mL) and wash the resulting 2 5 solution with saturated aqueous sodium bicarbonate (2X1,000 mL each), water (1,000 mL), and saturated aqueous sodium chloride (1,000 mL). Dry the organics over MgSC^, lb WO20.5/.7547* PCT/US2W.MI0WB J" filter, and then concentrate under reduced pressure. Purify by column chromatography, etuting with ethyl acetate-hexanes (1:1), then ethyl acetate hexanes (2:1), then neat ethyl acetate, men 5% of 2N NH/MeOH in eulyl acetate to give 11.70 g (41.5% yield) of 5-[2-(2,6-dichloro-phenyl>5-(4-fluoro-ph^ 5 imidazo[4,5-b]pyridm-2-ylamine as an off-white solid. MS(ES+): m/z - 509 (M+l). Mix5-[2-(2,6-dkidoro-phenylV5-(4-fluoro-phenyl>lH-irmdazol^ dirncAyl-pTcyyl>3H-imida7.o[4^b]pyridm-2-ylarnine (11.20 g, 21.99 mmol) in methanol (150 mL), and then add a solution of methanesulfonic acid (2.11 g, 21.96 mmol) in methanol (10 mL) dropwise. Stir at room temperature for 20 minutes and then 10 concentrate under reduced pressure. Add ethyl acetate (150 mL), filter resulting slurry, and wash fiher cake with diethyl ether (200 mL). Dry the resulting solid in a drying oven at 80°C under house vacuum for 2 h to give 12.765 g (95% yield) of the title compound as a light-purple solid. 'H-NMR (400 MHz; CD3OD): 5 7.78-7.50 (m, 7H), 7.24-7.20 (m, 2H), 3.86 (s, 2H), 2.70 15 (s»3H)> 0.85 (s,9H) TOF-MS [ES+, M+H] Obs. m/z 509.1412, Calc. m/z 509.1423. EXAMPLE 100 3-(2£-Dimemyl-propyl>5-[5-(4-fluc^ 2 0 lH-irmd^zol-4-yl]-3H-iimn^zo{4^b]pyridm-2-ylarni^ methanesulfonate Mixl-[2-ammo-3-(2,2-dirnemyl-propyl^^ fluoro-phenyl)-ethane-l^-dione (18.32 g, 51.69 mmol) and 2-fluoro-6-trifluoromethyl-benzaldehyde (15.00 g, 78.08 mmol) and NH4OAC (39.84 g, 516.90 mmol) in glacial acetic acid (200 mL) and stir at 85°C under nitrogen for 4 h. Concentrate the resulting 25 reaction mixture under reduced pressure. Dissolve the residue in ethyl acetate (2,000 mL) and wash the resulting solution with saturated aqueous NaHCC>3 (2 X 1,000 mL each), water (1,000 mL), and saturated aqueous sodium chloride (1,000 mL). Dry the organics over MgSC>4, filter, and then concentrate under reduced pressure. Purify by column chromatography, eluting with neat ethyl acetate, then 2% of 2N ammonia/MeOH in ethyl 3 0 acetate, then 5% of 2N ammonia/MeOH in ethyl acetate to give 7.38 g 3-(2,2-dimethyl- T^pyiy5-[5-(4-fluoro-phenyl>2-(2-fluoro-6-^ 7 WO 2005/075478 PCT/US2005/0O0O25 3H-imidazo{475-b]pyridin-2-ylamine as an off-white solid. Purify the impure fractions by column chromatography, eluting with neat ethyl acetate, then 1% of 2N ammonia/MeOH in ethyl acetate, then 2% of 2N ammonia/MeOH in ethyl acetate, then 3% of 2N ammonia/MeOH in ethyl acetate) to give an additional 4.68 g of the desired compound. 5 MS(ES+): m£ = 527(M+l) Mix3-(2,2-dimethyl-propyi>5-[5-(4-f^^ phenyl>lH-inridazol^yl]-3H-imidazo[4,5-b]pyridm-2-ylarnine (11.56 g, 21.95 mmol) in methanol (150 mL), and then add a solution of methanesulfonic acid (2.11 g, 21.96 mmol) in MeOH (10 mL) dropwise. Allow Ihe resulting reaction mixture to stir at room 10 temperature for 20 minutes, then concentrate under reduced pressure. Slurry the residue in diethyl ether, filter, and wash with fresh diethyl ether. Dry the resulting solid in a drying oven at room temperature under house vacuum for 48 h to give 12.015 g (87.9% yield) of the title compound as a tight-purple solid. 1H-NMR(400 MHz; CD3OD): 87.84-7.60 (m, 7H), 7.24-7.20 (m, 2H), 3.86 (s, 2H), 2.70 15 (s,3H),0.85(s,9H) TOF-MS [ES+, M+H] Obs. m/z 527.1979, Calc m/z 527.1982. EXAMPLE 101 5-[2-tart-Butyl-5-(2,4-difliic40-p^ 20 irrud^zo[4^b]pyridin-2-ylanameniethanesulfonate Mix l-[2-ainino-3-(2,2-draKAyl-p^ difluoro-phenyl>ethane-l,2-dione (17.36 g, 46.62 mmol) and trimethylacetaldehyde (6.42 g, 74.53 mmol) and NRjOAc (35.93 g, 466.20 mmol) in glacial acetic acid (200 mL) and stir at 85°C under nitrogen for 4.5 h. Cool to room temperature overnight Heat the 25 reaction at 85°C for 5 h, then 100°C for 3 h, then cool to room temperature overnight. Concentrate the resulting reaction mixture under reduced pressure. Dissolve the residue in EtOAc (2 L) and wash the resulting solution with saturated NaHCCb (2X1 L), H20 (1 L), and saturated aqueous sodium chloride (1L). Dry the organics over Na2S04, filter, and then concentrate under reduced pressure. Purify by column chromatography, eluting 3 0 with neat EtOAc, then 1% of 2N ammonia/MeOH in EtOAc, then 2% of 2N ammonia/MeOH in EtOAc, then 3% of 2N ammonia/MeOH in EtOAc) to give 10.28 g of MS WO 2005/075478 PCT/US2WW06OO25 ^ H2^-butyl-5-(2,4-dffiuoro-pheMylHH-imid^ imklazo[4,5-b]pyridm-2-yiamine as an off-white solid. MS(ES+): m/z = 439 (M+l) Mix5-[2-ter^butyl-5-(2,4-difluoro^ 5 prc^viy3H-injidazc44^-b)pvridm-2-ylamine (11.55 g, 26.33 mmol) in MeOH (150 mL), and then add a solution of methanesuifonic acid (2.53 g, 26.33 mmol) in MeOH (10 mL) dropwise. Stir die resulting reaction mixture at room temperature for 20 minutes, then concentrate under reduced pressure. Slurry the residue in Et20, then filter and wash with fresh EtjO. Dry the resulting solid in a drying oven at room temperature under house 10 vacuum overnight, ttien at 80°C for 1.5 h. Dissolve the salt in MeOH and then treat with NaHCOj until basic. Extract me resulting solution with EtOAc, dry the combined orgamcs over ^SO*, filter, men concentrate under reduced pressure. Purify by column chromatography, eluting wim neat EtOAc, men l%of 2Naarnmonia/MeOHinEtOAc, men 2% of 2N ammonia/MeOH in EtOAc to give 9.38 g of 5-[2-tet-butyl-5-(2>4- 15 dffluoro-phenyl>lH-imi&BDl^yl^ vlamine. Mix 5-[2-tert4>utyl-5-(2,4-difluoio-pl^ propyl)-3H-inu 20 temperature for 30 minutes, men concentrate under reduced pressure. Slurry the residue in Et20, men filter and wash wim fresh BtjO. Dry the resulting solid in a drying oven at room temperature under house vacuum for 48 h to give 10.695 g (76% yield) of the title compound as a tan solid. 'H-NMR (400 MHz; CD3OD): 5 7.74-7.66 (m, 2H), 7.60-7.54 (m, 1H), 7.15-7.08 (m, 2 5 2H), 3.70 (s, 2H), 2.70 (s, 3H), 1.51 (s, 9H), 0.81 (s, 9H) TOF-MS [ES+, M+H]: Obs.: m/z = 439.2398; Calc: m/z = 439.2422 H WO 2005/075478 „„„., „ PCT/US2005/000025 ^ EXAMPLE 102 5-[2-tert-Butyl -5^(4-flwm)-phenyl>lH-inrida2»l^yl]-3^2^^memyl-propyl)-3H-inudazo[4,5-b}pyridin-2-ylamine methanesulfonate Stir a suspension of {6-[2-tet-Butyi-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-3-5 tritro-pyridin-2-yl}^2^-dimeniyh?n^yl>anrine (426 mg, 1.0 mmol) and 10% palladium on carbon (85 mg) in 100% ethanol under hydrogen from a balloon overnight. Filter the suspension through a 0.2 [im syringe filter and concentrate under reduced pressure. Dissolve the residue in 10% aqueous ethanol and treat at room temperature with cyanogen bromide (80 mg, 0.75 mmol, 13 equiv). When the reaction is complete, quench the 10 reaction wim saturated aqueous NaHCQj. Add ethyl acetate and water to dissolve all solids. Wash the organic layer once with saturated aqueous NaHCOj, once with saturated aqueous NaCL dry with NazSO^ filter, and concentrate under reduced pressure. Subject the residue to medium pressure sihca gel chromatography ehiting with 50% ethyl acetate/CHiCfe men with a gradient of 13-33% (2M ammonia m MeOHVCHzCb) to 15 provide 5-[2 tert-butyl 5- 3H-imidazo[43-bh>yridin-2-ylamine as a brown foam (156 mg, 74% yield). Treat a solution of 5-f2-tfrt4>utvl-5-3H-mikfcizo[43-b)pyrklin-2-ylanMne in methanol-water with methanesulfonic acid followed by lyophihzation to provide the title compound. 2 0 Exact MS calc: m/z = 421.2516 (M+H)+; found: m/z = 421.2523 (M+H)+. *H-NMR (DMSOds): 57.85 (d, 1H,7=7.9Hz), 7.85 (d, 1H, 7=7.9 Hz), 7.72 (d, 1H, 7=8.4 Hz), 7.62 (dd, 2H, 7=8.8,4.8 Hz), 7.27 (t, 2H, 7=8.8 Hz), 3.90 (s, 2H), 2.70 (s, 3H), 1.62 (s,9H), 0.89 (s,9H) 25 EXAMPLE 103 542-tert-Butyl-5-(4-fluoro-phenyiyiH-i^ iniid^zo[43-b]pyridin-2-ylamine fumarate Dissolve 126 mg (0.3 mmol) 5-r2-tert-butyl-5-(4-fluoro-i^envlVlH-imidazol-4- yl]-3-(2,2-dimemyl-propyi>3H-in^ in 1.0 ml 88% acetone*. 3 0 Add a solution of 70 mg fumaric acid in warm 88% acetone* incrementally with shaking. Add seed crystals and filter the resultant precipitate. Air dry to provide 145 mg (74%) of slight purple hair-like crystals. So WO 2005/075478 ^ PCT/U S2005/000025 ♦(remainder water by volume) EXAMPLE 104 Crystaffir«5-[2-tert-Butyl-5-(4-fl^^ 5 propyl)-3H-irnidazot4,5-b)pyridm-2-ylamine dimethanesulfonate Dissolve 126 mg (0.3 mmol) 5-f2-tert-botyl-5-(4-fluoro-phenvI)- lH-imidazol-4- yl]-3-(2^-3H-ir^^ in 2.0 ml acetone. Add 58 mg methanesulfonic acid incrementally. Add seed crystals and filter the resultant precipitate. Air dry to provide 114 mg (62%) of off-white irregular crystals. 10 m-p.>250°C EXAMPLE 105 Amorphous 5-r2-tert-But^-M44tocto-TAmviy propyl>3H-irnidazo{4^4>]pyridiDr2-ylami^ dimethariesulfonate 15 Dissolve 5{2-|ert-butyl-5K4-fluoio-pl^ propyl>3Il-irriid^zo(4^b]pyridm~2-ylamme dimethanesulf onate (300 mg) in S mL dekmized water. Filter solvitionthroiigh a 0.45 um filter m^ volumetric flask. Rapidly freeze solution on bottom and sides of flask. Freeze dry for 24 hours to provide amorphous 5-[2-fc^-butyl-5-(4-fnion>-phenylVlH-imidazol-4-yl]-3-(2,2-20 dimemyl-propyl)-3H~imidazo[4^b)^^ EXAMPLE 106 5-[2-t^-Butyl-5-(4-fluoro-prKmy^ imidazo[4^b]pyridm-2-ylamine succinate 2 5 Dissolve 126 mg (0.3 mmol) 5-f2-tert-butyl-5-(4-fluoro-phenvlVlH-irnidazol-4- yl]-3-(2^-dimethyl-propyl>3H-irnidazo[4>5-b]pyridm-2-ylamine in 2.0 mL 88% acetone*. Add a solution of 71 mg succinic acid in 1 mL warm 88% acetone* incrementally. Add seed crystals and filter the resultant precipitate. Air dry to provide 123 mg (63%) of very light purple crystals. 3 0 *(remainder water by volume) S) WOMKS075478 PCTAJS2005/00002S ^ EXAMPLE 107 5-[2-tert-Bvrtyl-5^4-fluoro-phenyi>lH-^^ imidazo[4,5-b]pyridin-2-ylamine dimaleate Dissolve 126 mg (0.3 mmol) 5-[2-tert-butyl-5-(4-fluoro-phenyl> lH-imida2ol-4-5 yi>3-(2^-dimethyl-propyl)-3H-imidazo{4>^b]pyridin-2-ylaini^ in 1.0 mL isopropanol. Add a solution of 69.6 mg maleic acid in 1 mL warm isopropanol incrementally. Add seed crystals and filter the resultant precipitate. Air dry to provide 120 mg (63%) of very light purple crystals. 10 EXAMPLE 108 5-[2-tert-Butyl-5K4-fhioio-phen^ imidazo{4>54>]pyridin-2-vlaniine hydrochloride Dissolve 126 mg (0.3 mmol) 5H2-te**utyl-5K4-fluoro-pheavl)-lH-miidaz»l^ yl]-3^2^-dirrie&yl-propyl>3H-iim in 2.0 mL acetone. Add 15 120ul.of5Nhydroduork:acklmcremenialry. FUter the resultam precipitate. Air dry to provide 140 rrig (93%) of very light pmk crystals. EXAMPLE 109 H2K2 2 0 imidazc^4>54>]pyridm-2-ylamine methanesulfonate Dissolve {6-[2^2^Wom^fluoro-phenyl)-5-phenyl-3H-imidazol^yl]-3-mtro-pyridm-2-yl}-(2^-^imemylpropyl>amine (240mg, 0.50 mmol) in 100% ethanol (10 mL) and add un(H) dicnloride dihydrate (564mg, 2.50 mmol, 5.0 equiv). Heat the reaction mixture until starting material is consumed. Cool the reaction solution to room 25 temperature, quench slowly with saturated aqueous NaHCC^. Add Celite® to the quenched reaction and filter the suspension on a Celite® pad with water and ethyl acetate washes. Separate the layers and wash the organic layer with saturated aqueous NaCl. Dry the organic layer with Na2SC>4, filter, and concentrate under reduced pressure. Add 10% aqueous ethanol and cyanogen bromide (106 mg, 1.00 mmol, 2.0 equiv) to the resulting 30 solid and stir overnight Quench the reaction with saturated aqueous NaHCCh (20 mL). Add ethyl acetate and water to dissolve all solids. Wash the organic layer three times with saturated aqueous NaCl, dry with Na^SC)^ filter, and concentrate under reduced 52 WO 2005/075478 &£ PCT/U S2005/000025 pressure. Subject the residue to medium pressure silica gel chromatography eluting with a gradient of 1.5-3% (2M ammonia in MeOHyCH2Cl2 to provide 5-[2-(2-Chloro-6-fluon)- pb^yl)-5-phenyl-3H-iniidazol^yl]-3-(2£-d^^ ylamine as a yellow-green solid (196 mg, 60% yield). 5 Treat a solution of 5-[2-(2-Chloro-6-fluoro-phenyiy5-phenyI-3H-i^^ 3-(2^-d^memylpropyl>3H-imk!azo[4>5-b]p^ in methanol-water with methanesulfonic acid followed by lyophilization to provide me title compound. MS(ESI): m/z = 475.2 (M+H)10 EXAMPLE 110 5-[2-^-Butyl-5-3H-ir^ imid^2o{4>*]pyridin-2-ylamine methanesurfonate Dissolve |6-f2-tert-buryl-5-(4-fluoro-p^ yl}-(l(R)^^tnmethyl-propyl)-amine (558mg, 1.27 mmol) in 100% ethanol (15 mL) and 15 add tmCD) dichloride dihydrate (1.4g, 63 mmoL 5 equiv). Heat me reaction mixture until starring material is consumed. Cc^rf the reaction solurkm to room temperature, quench slowly with saturated aqueous NaHCOj. Add Celite® and filter the suspension on a Celite® pad, washing with water and ethyl acetate. Separate the layers and wash the organic layer with saturated aqueous NaCl. Dry the organic layer with Na2SC>4, filter, and 20 concentrate under reduced pressure. Add 10% aqueous ethanol (13 mL) and cyanogen bromide (202 mg, 1.99 mmol, 1.5 equiv) to the residue and stir overnight Add another 1.5 equiv of cyanogen bromide, stir 3h, and quench with saturated aqueous NaHC03 (20 mL). Add ethyl acetate and water to dissolve all solids. Wash the organic layer three times with saturated aqueous NaCL dry with Na2SC>4, filter, and concentrate under 25 reduced pressure. Subject the residue to medium pressure silica gel chromatography eluting with a gradient of 1.5-4% (2M ammonia in MeOHyCH2Cl2 to provide 5-[2-tert-Butyl-5-(4-fluoro^henyl)-3H-imi6^zol^yl]-3-(l(R),2,2-trmiemyl-propyl>3H-imidazo[4,5-b]pyridin-2-ylamine as a tan glass (158 mg, 29% yield). Treat a solution of 5-r2-tert-butyl-5^4-fluoro-phenyl>3H-imidazol-4-yll-3- 3 0 (l(R),2^-trimemyl-propyl}-3H-iim in methanol-water with methanesulfonic acid followed by lyophilization to provide the title compound. MS(ESI): m/z= 435.2 (M+H)+ 53 WO 2005/075478 /* PCT/US2005/000025 EXAMPLE 111 5~[2^2,6-Dffluoro-phenyl>5K4-fluoro-ph^ propyl)-3H-irnidazo[4^b]pyridm-2-ylainine medianesulfonate 5 Dissolve {6-[2-(2,6-difluoro-phenyl>5-(4-imor^^ nitxo-pyridin-2-yl}^l(R)^^-traneu^yl-propyl>aiiffl»e (673mg, 1.4 mmol) in 100% etfaanol (15 mL) and add tin(II) dichloride dihydrate (15g, 6.8 mmol, 5 equiv). Heat tibe reaction mixture until starting material is consumed. Cool the reaction solution to room temperature, quench slowly wim saturated aqueous NaHCCb. Add Celite® to the 10 quenched reaction and filter ti»e suspension on a Celite® pad, washing with water and ethyl acetate. Separate the layers and wash the organic layer wim saturated aqueous Nad. Dry die organic layer wim NazSO*, filter, and concentrated under reduced pressure. Add 10% aqueous ethano! (14 mL) and cyanogen bromide (216 nog, 2.04 mmol, 1.5 equiv) to the residue and stir overnight Quench wim saturated aqueous NaHCOs (20 15 mL). Add ethyl acetate and water to dissolve all solids. Wash the organic layer is wim saturated aqueous NaCl, dry wim NagSCXi, filter, and concentrate under reduced pressure. Subject die residue to medium pressure silica gel chromatography eroting wim a gradient of 1.5-3% (2M ammonia in MeOHyCKfeCk to provide 5-[2-(2,6-diflttoro-phenyl>5-(4-fnM>ro-pbenyl>3H-imidarol-4-^^ 2 0 b]pyridm-2-ylamine as a tan glass (289 mg, 43% yield). Treat a solution of 5-[2K2,6-dffluoro-phenyl>5^4-fluoro-ph yl]-3Kl(R),2,2-trimemyl-propyi^ in methanol-water wim methanesulfonic acid followed by lyophilization to provide the title compound. MS(ESI): m/z = 491.2 (M+H)+ 25 EXAMPLE 112 5-r2-tert-butvl-5-(4-fluoro-phCTviyiH^^ imidaz»[4,5-b]pyridm-2-ylamine dimethanesulfonate 5-Bromo-3-(2.2-Klimemyl-propyiy3H-im^ 3 0 Stir a mixture of hypophosphorous acid 50 wt % aq. sol'n (0.555 g) and 5% Pt/C (2.5 g) in H20 (20 mL, 0.4 vol.) for 10 minutes. Add solid VO(acac)2 (0.420 g, 1.20 mmol) and stir the dark slurry for an additional 5 minutes. Charge tins slurry to a mixture s^ WO2005/07547S PCT«JS2005*N»25 ** of 2(2^ d1inethylpropylamiiK)>3-nitro^hTOmopyridine (50.00 g, 173.61 mmol) in toluene (500.00 mL) in a one liter autoclave at ambient temperature. Heat the autoclave to 75°C in the presence of Hi at 35 psi (2.38 atmospheres) with stirring at 100 rpm. After 3 hours filter the reaction mixture over a Hyflo Super Cel® pad and concentrate the filtrate 5 under reduced pressure to one half of the overall mass (273.0 g) of die solution. Stir the solution and add cyanogen bromide (18.4 g, 173.70 mmol) followed by MeOH (250 mL). After 18 h, heat to 40°C and concentrate under reduced pressure until 350 mL of solvent is collected via short path distillation. Dilute the resulting slurry with MTBE (350 mL, 7.0 vol.), cool to 0°C, and stir 1 h. Filter off solid, wash with MTBE (75 mL, 1.5 vol.), 10 and dry under reduced pressure at 40°C for 24 h to provide 48.06 g (76%) of the desired compound as a white solid. 'H-NMR (300 MHz, DMSOAs): 5 0.96 (9H, sX 3-91 (2H, s), 7.45 (1H, d, J = 8.1 Hz), 7.64 (UL d, J = 8.1 Hz), 8.73 (2H, bs). MS(ES-): mft = 282,0; (M-l)' 15 3-(2J24>iroemvl-prop^yM4-fl«^^ Add triemylamine (27.10 g, 267.80 mmol) to a mixture of 5-bromo-3-(2£- dmiemyl-propyl>3H-iiiridazo[4,54>]pyrk^ bromide (25.00 g, 68.67 mmol) in ethanol (25 mL) and toluene (75 mL). Heat to 70-75°C and men add Pd(OAc)2 20 (0.15 g, 0.69 mmol), triphenylphosphme (0.72 g, 2.75 mmol), and copper (I) iodide (0.13 g, 0.69 mmol). Add 2/3 of a solution of 4-fluorophenylacetylene (12.37 g, 103.00 mmol) in toluene (50 mL, 2.0 vol.) over 15 minutes. Add the remaining 4-fluoroacetyiene solution after 1 h. After 3b, add additional 4-fluorophenylacetylene (1.5 g, 12.86 mmol). After an additional hour, remove EtOH by distillation. Cool the reaction mixture to 25 Purification Step 3 0 Add methanol (1,200 mL) to combined lots of 3-(2,2-dimethyl-propyl)-5-(4- fluoro-phenylemynyl>3H-imidazo(4>5-b]pyridm-2-ylamine (37.30 g) and heat to reflux. Add activated charcoal (3.73 g, 10 wt %) and reflux for 1 h. Filter while slurry is hot, SS WO 2005/075478 PCT/US2005/000025 J& then add water (375 mL) to the filtrate with stirring at room temperature. Filter off solids, wash 2 x 100 mL water and dry under reduced pressure at 45-50°C to provide 30.0 g (80%) of tf»e desired compound. 'H-NMR (300 MHz, DMSO-de): 5 0.99 (9H, s), 3.91 (2H, s), 6.98 (2H, s), 7.25-7.32 5 (3H, m), 7.40 (1H, d, J = 7.8 Hz), 7.62-7.67 (2H, m). l-f2-Amino-3-(2^-dime^y]-propvlV3H-imidazor4.5-b1pyridm-5-ylV2-(4-fl^ ethane-1,2-dione Add MgS04(82.7 g, 687.05 mmol) and NaHC03 (14.4 g, 171.41 mmol) in 10 deionized water (1524 mL) over 5 minutes to a stirring solution of 3-(2^2-dimemyi- piopyl)-5-(4-fluoro-pb«jyledjynyl)-3H-inudazo[4^blpyridm 2-ylanu^ (110.76g, 343.57 mmol) in acetone (3665 mL). Add Hyflo Super Cel* (171. lg) followed by KMn04 (108.6 g, 687.21 mmol) Heat at 40^5X for 3 hours arriu^encoc)! to rocm temperature. Add saturated aqueous NazSOj (1,800 mL) followed by EtOAc (3,500 mL) and water 15 (3,500 mL). Filter through bed of Kryflo Super Cel* washing wim a mixture of 9% MeOH/EtOAc (2,860 mL). Separate layers of filtrate, back extract aqueous layer 2 x 2,750mLEtOAc. Combine organic extracts, wash 2 x 2380 mL saturated aqueous sodium chloride (4760 mL), and dry over Na2S04- Filter, then concentrate under reduced pressure to provide a daifc red-brown solid (185 g). Add acetone (650 mL), filter 20 suspension, wash collected solid 3x167 mLMTBE (501 mL), and dry under reduced pressure at 45°C to provide 106.79 g (88%) of me desired compound as a light yellow solid. 'H-NMR (500 MHz, DMSO-dtf): 5 0.72 (9H, s), 3.71 (2H, s), 7.47 (2H, dd, Ji = 7.5 Hz, h = 8.5 Hz), 7.56 (2H, bs), 7.65 (1H, d, 8.0 Hz), 7.97-7.99 (2H, m), 8.02 (1H, d, J = 8.0 25 Hz). MS(ES+): m/z = 355.4; (M+l)+ 5-f2-tert-Butvl-5-(4-fluorr>rAepviyiH^ irmdazof4.5-bTpyrid1n-2-vlamine 3 0 Heat a mixture of l-[2-aniino-3-(2^-dimemyl-propyl>3H-imidazo[4,5-b]pyridm- 5-yl]-2-(4-fluoro-phenyl)-ethane-l^-dione (25.33 g, 71.48 mmol), NH4OAC (82.3 g, 1.04 mol), and trimethyl-acetaldehyde (13.0 mL, 116 mmol), in MeOH (650 mL) to reflux 5% WO 2005/075478 zS PCT/US20O5/0O0O25 under nitrogen for 20 h Concentrate under reduced pressure. Dissolve residue in EtOAc (2,000 mL), deionized water (500 mL), and saturated aqueous NaHCOj (1000 mL). Separate die layers and wash organic layer with 1 L saturated aqueous NaHCOj (1000 mL), deionized water (500 mL), and saturated aqueous sodium chloride (500 mL), men 5 dry over NajSO^ Filter and concentrate under reduced pressure to provide 20.08 g of a dark solid/foam. Add MTBE (60 mL) and heat to reflux. Add hexane (290 mL) over 5 min. men cool slurry to room temperature. Stir 1.25 h, filter, wash collected solid wim hexane (80 mL), and dry under reduced pressure at 45°C overnight to provide 17.31 g (58%) of the desired compound as a light tan solid. 10 Purification Step Heat a mixture of combined lots of 5-[2-tert-Butyl-5-(4-fluoro-phenyl)-lH- irm MTBE (165 mL) to reflux. Add hexane (800 mL) and cool slurry to room temperature. 15 Filter solid, wash wim hexane (200 mL), and dry under reduced pressure at 45°C to provide 54.35 g (97%) of die desired compound as a light tan solid. 'H-NMR (300 MHz, CD3OD): 5 0.87 (9H, s), 1.45 (9H, s), 3.79 (2H, s), 7.05 (2H, dd. J, = 8.7 Hz, J2 = 9.0 Hz), 7.30 (1H, hsX 7.40-7.50 (3H, m). MS(ES+): mfz = 421.4 (M+l)* 20 M2-tert-Butvl-5-(4-fluoro-phenviyiH-tt^^ imidazof4.5-hlpyridin-2-ylamine dirnethanesulfonate Heat a solution of H2-tert-Butyl-5-(4-fluoro-phenyl>lH-imidazol-4-yl]-3-(2,2- dimemyl-propyl)-3H-iriudazo[4,5^^^ (10.0853 g, 23.98 mmol) in 25 MeOH (24 mL) to 40°C. Remove heat source and add methanesulfonic acid (3.14 mL, 47.91 mmol) in EtOAc (10 mL) dropwise over 3.5 ininutes. Stir for 1 h while cooling to room temperature. Add EtOAc (20 mL) and stir 5 minutes. Filter, wash solid with 2 x 50 mL EtOAc, and dry under reduced pressure at 45-50°C for 2.5 h to provide 12.62 g (86%) of the title compound as a white powder solid. 3 0 !H-NMR (500 MHz, CD3OD): 5 0.94 (9H, s), 1.65 (9H, s), 2.73 (6H, s), 3.91 (2H, s), 7.31-7.35 (2H, m), 7.63-7.67 (2H, m), 7.69 (1H, d, J = 8.5 Hz), 7.87 (1H, d, J = 8.5 Hz). MS(ES+): m/z = 421.5 (M+l)+ 51 WO 2005/075478 ^ PCT/US2005/000025 EXAMPLE 113 5-[2-tart-butyl-5-(4-fluoro-pb^y^ imidazo{4,5-b]pyridin-2-ylamine dimethanesulfonate 5 2-Amino-3-(2J2-dimemvl-prop^ blpyridin-1-ium rnetnanesulfpnate Heat a mixture of 3-(2^-dimethyl-rm>pyl>5-(4-flvioro-phenyletiiynyl>3H-imidazot4,5-b]pyridin-2-ylarnine (184.7 g, 0.573 mol), formic acid (923.0 mL), methanesulfonic acid (110.0 g, 1.14 mol), DMSO (224.0 g, 2.87 mol), and 48% HBr (9.7 10 g, 0.057 mol) at gentle reflux (105-107 °C)with a distillation device overnight. Distill out volatiles (550 mL) under reduced pressure. Cool to about 65 °C arid add water (1.2 L) containing Na^S^ (18.0 g, 0.114 mol) dropwise with rigorous stirring, maintaining the temperature at about 65 °C. Cool reaction mixture to ambient (about 3 hours), men in ice bath (about 30 minutes). Filter solid, rinse wim water (200 mLX and dry in vacuum oven 15 at about 50 °C to provide 217.0g (84%) or me desired compound. *H NMR(300 MHZ, DMSCMfe): 5 9.08 (s, 2H); 8.18 (d\ /=6.0 Hz, 2H); 7.92 -7.98 (m, 3H); 7.40 (t, J = 8.0 Hz, 2H); 3.67 (s, 2H); 2.40 (s, 2H); 0.66 (s, 9H). MSOES*): mk = 355.4 (M+l)+. 20 Ring Formation Heat a mixture of 2-airiino-3^2^-dimemyl-rTOpyl>5-[2-(4-fluorophenyl)-2^xo-acetyl]-3H-imidazo[4,5-b]pyridin-l-ium methanesulfonate (0.62 mol), ethanol (2.5 L), ammonium acetate (500.0 g, 6.2 mol), and trimethyl acetaldehyde (84.0 g, 0.93 mol) at about 70 °C overnight Evaporate the volatiles. Add ethyl acetate (4.0 L) and water (3.0 25 L) followed by 1.0 N NaOH (1.2 L) and stir for 20-30 minutes at room temperature. Separate die phases and extract the aqueous phase with ethyl acetate (2.0 L). Combine the ethyl acetate phases, wash twice with 10 volumes of saturated aqueous sodium chloride, treat wim Darco (30.0 g, 10% by weight). Filter tiirough a pad of Celite and concentrate the filtrate to about 1.0 L). Add ethanol (2.50 L) and heat to about 65 °C and 3 0 add methanesulfonic acid (150.0 g, 1.55 mol) in ethyl acetate (500 mL) in fast drops, maintaining the temperature at about 65 °C for 3 hours. Cool the reaction mixture to room temperature with stirring for 2 more hours. Filter the suspension, rinse the solid with 5& WO 2005/075478 PCT/IJS200S/000025 s&&- ethyl acetate (500 mL), and dry in vacuum oven at about 45 °C to provide 226.0 g of die title compound. 'H-NMR(300 MHZ, DMSO-de): 5 8.99 (s, 2H), 7.90 (d, 1H, J = 9.0 Hz); 7.86 (d, 1H, J = 9.0 Hz); 7.60 (dd, 2H, J = 9.0 Hz), 7.34 (dd, 2H, J = 9.0 Hz); 3.68 (s, 2H); 2.35 (s, 6H); 5 1.51 (s,9H); 0.71 (s,9H). MSCES*): m/z = 421.5 (M+l)EXAMPLE 114 General Procedure for tibe Preparation of Seed Crystals 10 A master plate is prepared with 250 uL of the free base of the subject compound in methanol (0.1 M) added to all welb set in a % well format. An array of acids is dispensed to each well in one and two molar equivalents. The solvents are evaporated from all 96 wells using a Genevac Series II evaporator leaving solid residue in the master plate. An array of solvents is dispensed to each one of these wells through a cap mat and 15 then heated to 55°C wim stirring and allowed to equilibrate for 60 - 90 rninutes at about 55°C. Each sample is then filtered hot and transferred to corresponding wells in an evaporation plate, a precipitation plate, and a cooling plate. The evaporation plate is prepared by transferring 200 uL of the filtrate from the master plate using 55°C heated syringes to die open well titer plate and is men allowed to evaporate to dryness over night 20 at room temperature and ambient humidity. The precipitation plate is prepared by adding 100 uL of tihe filtrate from tije master plate using 55°C heated syringes to capped 96 well titer plate where each well contains an anti-solvent of 200 pL of heptane or 2-propanol. After equilibrating for a period of nine hours at room temperature, me excess solution is wicked away using pre-cut Whatman filter paper. The cooling plate is prepared by 2 5 transferring 200 uL of the filtrate from me master plate to individual wells using 55°C heated syringes in a capped titer plate, and cooling exponentially from 55 to 10°C over a period of 8 hours. Photomicrographs are collected on the material at the bottom of each well in the 96 well plates using a Zeiss Axiovert 200M inverted incident-light microscope with a 2.5X objective. If the material is crystalline, it exhibits birefringence that is 3 0 displayed as white against a dark background. Amorphous solids appear dark or as opaque droplets or rings. si WO 2005/075478 -60- PCT/US2005/000025 Inhibition of p38 Kinase Standard Solution Preparations The kinase buffer solution is prepared by combining 2.5 mL 1 M Tris-HCl (pH 7.5), 0.1 mL 1 M dithiothreitol, 1.0 mL 1 M magnesium chloride, and 300 |0L 1% Triton 5 X-100 and diluting to 100 mL with water. 84 mL of this kinase buffer solution is combined with 16 mL DMSO to prepare the 16% DMSO solution. The 200 |iM ATP solution is prepared by adding 102.6 uX 10 mM aqueous ATP, 25 uL 33P-ATP, and 163.5 uL of 4 mM aqueous Epidermal Growth Factor Peptide 661- 681 (Biomol, Catalog #P-121) in 5 mL kinase buffer solution. 10 The p38 kinase enzyme solution is prepared by dissolving 9.5 jiL concentrated enzyme solution (250 ng p38 enzyme/uX kinase buffer solution) in 1536 uL kinase buffer solution. Sample Preparation 15 An 80 uM solution of each test compound and control compound are prepared by dissolving 2 |iL of a 10 mM stock solution of the respective compounds in dimethylsulfoxide in 248 |iL of the 16% DMSO solution in a Costar 96-well microtiter plate. The plate is placed onto the Tecan Genesis automated liquid handler for 1:3 serial dilutions. 20 Assay 10 uL of serially diluted compound is placed with a Beckman Multimek 96-well automated liquid handler to the assay plate. 20 ^iL of 200 |iM ATP solution is added with a Titertek Multidrop 8-channel liquid handler. 10 uL of p38 kinase enzyme solution is 2 5 transferred to the assay plate using the Multimek. The mixture is allowed to react for 40 min at 30 °C and then the reaction is stopped by adding 60 uL of freshly prepared 5% glacial AcOH with Multidrop. 80 uJL of this solution is transferred to an "MAPH" plate using the Multimek. The plates are allowed to set for 30 min at RT and then washed/aspirated on the Titertek MAP extractor with freshly prepared 0.5% glacial AcOH 3 0 (1 x 300 \xL, 2 x 200 |jL). The wells are blotted and 100 uL MicroScint-20 scintillation WO 2005/075478 -61- PCT/US2005/000025 fluid (Packard Bioscience) is added with the Multidrop. The plates are allowed to sit for 30 min and counted on a PE/Wallac Microbeta Trilux scintillation counter for P-isotope. All exemplified compounds were initially tested at 10 concentrations (20 \\M - 1 nM using 1:3 serial dilutions). Compounds with IC50 values less than 25 nM were re-5 tested at a starting concentration of 2 uM to 0.1 nM (1:3 serial dilutions). IC50 values were calculated (IDBS ActivityBase software) for each compound using non-linear regression. All exemplified compounds were tested essentially as described above and were found to inhibit the p38 kinase enzyme with an IC50 EXAMPLE ICso (nM) 6 7.2 9 4.6 11 2.3 12 3.6 13 3.3 18 3.6 19 3.2 Inhibition of TNF-ot in vitro Mouse Peritoneal Macrophages 15 1 mL thioglycolate broth (5.0 g yeast extract, 15.0 g casitone or trypticase, 5.0 g dextrose, 2.5 g sodium chloride, 0.75 g L-cystine, 0.5 g sodium thioglycolate, 1.0 mg resazurin, and 0.75 g agar in 1.0 L distilled water) is injected into the peritoneal cavity of Balb/C female mice. At day 4 or 5 post-injection the mice are sacrificed and then injected i.p. with 4 mL RPMI-1640 medium (BioWhittaker) and the peritoneal macrophages are 2 0 withdrawn by syringe. WO 2005/075478 -62- Cvtokine Production Mouse peritoneal microphages are counted with a hemocytometer and adjusted to 5 x 105 cells/well in 96-well plates in RPMI-1640 medium with 10% fetal bovine serum. 200 uL/well is plated in 96-well plates and the cells allowed to settle and adhere to the 5 bottom of the well for at least 3 h. The test compound or standard p38 kinase inhibitor is pre-treated using a series of 8 concentrations for 1 h at 37 °C (20 uL/well). The cells are treated with a mixture of 50 ng/mL lipopolysaccharide (LPS) and 10 U/mL interferon-Y for 18 h at 37 °C.(20 |iL/well). The conditioned media is harvested and assayed for TNF-oc production using the Luminex procedure. 10 TNF-0(/Luminex Detection Assay (Bio-Rad Bio-Plex Kit - Catalog #171-G1222n The lyophilized premixed TNF-a standard (1 standard tube/ two 96-well plates) is reconstituted with 50 (4L sterile water (500,000 pg/mL). The samples are vortexed for 5 seconds, incubated on ice for 30 min, and vortexed for 5 seconds before use. A set of 15 twelve 1.5 mL tubes are labeled with #l-thru #12 and then the amounts of cell media shown below added to the appropriate tubes (standard concentrations are as follows: 50,000; 25,000; 12,500; 6,250; 3,125; 1,562.5; 781.3; 390.6; 195.3; 97.7; 48.8; and 24.4 pg/mL). The premixed anti-cytokine conjugated beads are vortexed (25X) vigorously for 30 seconds. The anti-cytokine conjugated beads are diluted to a IX 2 0 concentration using IX Bio-Plex Assay Buffer. For every plate, 240 (XL of the pre-mixed beads is added to 5760 ^L of Bio-Plex Assay Buffer. A Millipore 96-well filter plate is blocked with 100 uX/well of blocking buffer. The blocking buffer is filtered through using a Millipore filtration system and then toweled dry. 2 washes are performed on the filter plate with 100 ul/well of Bio-Plex Assay Buffer and toweled dry. The IX anti- 2 5 cytokine conjugated beads are vortexed for 15 seconds and added 50 uL to each well. This is filtered through and toweled dry. 2 washes are performed on plates with 100 ul/well of Bio-Plex Wash Buffer. Again, it is filtered through and toweled dry. 50 |iL of sample or standard is added to each sample well. This is incubated for 60 seconds at RT on a shaker protected from light at setting 6 and then for 30 min at 3 0 setting 3 and then placed in the refrigerator overnight. 3 washes are performed with Bio- Plex Wash Buffer. Filter through and toweled dry. The cytokine detection antibody is WO 2005/075478 -63- PCT/US2005/000025 prepared (-10 min prior to use) for every plate and 60 |JL of the premixed cytokine detection antibody stock is added to 5940 uL of Bio-Plex Detection Antibody Diluent. 50 (iL of cytokine detection antibody is added and incubated for 60 seconds at RT on a shaker protected from light at setting 6 and then for 30 min at setting 3.3 washes are 5 performed with the Bio-Plex Wash Buffer. This is filtered through and toweled dry. Strept-PE (-10 minutes prior to use) is prepared for every plate and 60 uL to 5940 pL of Bio-Plex Assay Buffer added. 50 uX of Streptavidin-PE is added to each well and incubated for 60 seconds at RT on a shaker protected from light at setting 6 and then for 10 min at setting 3. 3 washes are performed with Bio-Plex Wash Buffer. This is filtered 10 through. The beads are re-suspended in 100 uX/well of Bio-Plex Assay Buffer. Standards and samples are read on a Luminex machine. These intensity readings are then converted to picogram/milliliter units based on a 12-point standard curve created in duplicate using a four-parameter logistic regression method (Bio-Plex Manager 2.0, Bio-Rad), and the IC50 calculated. 15 Representative members of the exemplified compounds were tested essentially as described above and suppressed TNF-a in vitro with an IC50 EXAMPLE IC50 (nM) 6 9 1.2 11 2.4 13 18 19 104 6.3 20 Inhibition of TNF-a in vivo Compounds are administered p.o. (100,30,10 and 3 mg/kg) to female Balb/c mice (5 mice/dose). After 2 h, lipopolysaccharide (LPS, E. coli serotype 0111:B4,5 WO 2005/075478 -64- PCT/US2005/000025 mg/kg) is administered i.v. in the tail vein of each mouse. One hour after LPS administration the mice are asphyxiated by CO2 inhalation and bled out via cardiac puncture. 5 TNF-ot/Luminex Detection Assay (Bio-Rad Bio-Plex Kit - Catalog #171-G12221) Reconstitute the lyophilized premixed TNF-a standard (1 standard tube/ two 96-well plates) with 50 \xL sterile water (500,000 pg/mL). Gently vortex for 5 seconds, incubate on ice for 30 min, and vortex for 5 seconds before use. Label a set of twelve 1.5 mL tubes with #l-thru #12 and then add the amounts of cell media shown below to 10 the appropriate tubes (standard concentrations are as follows: 50,000; 25,000; 12,500; 6,250; 3,125; 1,562.5; 781.3; 390.6; 195.3; 97.7; 48.8; and 24.4 pg/mL). Vortex the premixed anti-cytokine conjugated beads (25X) vigorously for 30 seconds. Dilute the anti-cytokine conjugated beads to a IX concentration using IX Bio-Plex Assay Buffer. For every plate, add 240 uL of the pre-mixed beads to 5760 |iL of Bio-Plex Assay Buffer. 15 Block a Millipore 96-well filter plate with 100 uL/well of blocking buffer. Filter through the blocking buffer using a Millipore filtration system. Towel dry. Perform 2 washes on the filter plate with 100 |il/well of Bio-Plex Assay Buffer and towel dry. Vortex the IX anti-cytokine conjugated beads for 15 seconds and add 50 |JL to each well. Filter through and towel dry. Perform 2 washes on plates with 100 ul/well of Bio-Plex Wash Buffer. 2 0 Filter thru and towel dry. Add 25 uL of serum sample and 25 ^L of diluent (Bio-Rad) or 50 (OL standard to each sample well. Incubate for 60 seconds at RT on a shaker protected from light at setting 6 and then for 30 min at setting 3 and then place in the refrigerator overnight. Perform 3 washes with Bio-Plex Wash Buffer. Filter through and towel dry. Prepare cytokine detection antibody (-10 min prior to use) for every plate, add 60 |JL of 25 the premixed cytokine detection antibody stock to 5940 \xL of Bio-Plex Detection Antibody Diluent. Add 50 uL of cytokine detection antibody and incubate for 60 seconds at RT on a shaker protected from light at setting 6 and then for 30 min at setting 3. Perform 3 washes with Bio-Plex Wash Buffer. Filter through and towel dry. Prepare strept-PE (~10 minutes prior to use) for every plate, add 60 |iL to 5940 \\L of Bio-Plex 3 0 Assay Buffer. Add 50 |iL of Streptavidin-PE to each well and incubate for 60 seconds at WO 2005/075478 -65- PCT/US2005/000025 RT on a shaker protected from light at setting 6 and then for 10 min at setting 3. Perform 3 washes with Bio-Plex Wash Buffer. Filter through. Re-suspend the beads in 100 uL/well of Bio-Plex Assay Buffer. Read standards and samples on Luminex machine. These intensity readings are then converted to picogram/milliliter units based on 5 a 12-point standard curve created in duplicate using a four-parameter logistic regression method (Bio-Plex Manager 2.0, Bio-Rad), and the IC50 calculated. Representative members of the exemplified compounds were tested essentially as described above and suppressed TNF-a in vivo with an IC50 Effect on Intra-articular LPS induced TNF-a Intra-articular injection of LPS into rat ankles induces the synthesis of TNF-a, which can be measured in synovial lavage fluid. High levels of TNF-a are detectable 15 within 2 hours. Since the joint is the site where arthritis develops, this model can rapidly determine whether an orally administered compound has an effect on an inflammatory response in the synovium. Six female Lewis rats (150-200 g) are place in each treatment group. The animals are given vehicle (1% NaCarboxymethylcellulose-0.25% Tween 80) or test compound 20 (1 mg/kg, 3mg/kg, lOmg/kg, and 30mg/kg) orally. One hour later, 10 (il LPS (10 pig) is administered intra-articularly into the right ankle of each rat, while the left ankle receives 10 uL of saline. After two hours, each ankle is lavaged with 100 uJL of saline. The lavage is collected and stored at -80 °C. 2 5 Group#l: Vehicle (l%NaCMC-0.25%Tween 80,1 mL, PO) Group#2: Test compound (1 mg/kg, 1 mL, PO) Group#3: Test compound (3 mg/kg, 1 mL, PO) Group#4: Test compound (10 mg/kg, 1 mL, PO) Group#5: Test compound (30 mg/kg, 1 mL, PO) WO 2005/075478 PCT/US2005/000025 -66- TNF-a is measured with a commercially available ELISA kit (R&D, RTA00). Treatment with the compound of EXAMPLE 104 produced a dose-dependent inhibition of TNF-a synthesis with TMED50 of 0.54 mg/kg. 5 B16F10 Melanoma Target (MAPKAP-K2 Phosphorylation) The B16F10 melanoma cell line is obtained from the American Type Culture Collection, Rockville, MD. The cells are cultured in RPMI-1640 medium supplemented with 10% fetal calf serum. The cells grown in vitro are harvested during their exponential growth phase by gentle trypsinization, washed twice in medium, and resuspended in 10 serum-free RPMI-1640 medium. The number of viable cells is determined using a hemocytometer and adjusted to 1 xl07/mL. Tumor cells are injected subcutaneously in normal C57B16 mice. Inoculum volume per mouse is 0.2 mL (2,000,000 cells). When the tumors reach 300-500 mg, the mice are used for target inhibition studies at either a fixed time (2.5 hours) after p.o. compound treatment or pharmacodynamic studies where 15 the tumors are collected at multiple time-points (e.g., 3, 6, 9,12,15, and 18 h) after p.o. compound treatment. Protein Extraction and Immuno-Blot Analysis 2 0 Tumors collected as described above are immediately snap-frozen in liquid nitrogen and stored at -80°C. Tumor tissues are homogenized on ice using a Daunce homogogenizer in an extraction buffer (25 mM Tris pH 7.5 containing the following protease inhibitors: 10 u,g/mL leupeptin, 10 u,g /mL soybean tryp-chymotrypsin inhibitor, 10 |ig/mL N-tosyl-L-phenylalanine chloromethyl ketone, 10 |ig/mL 2 5 aprotinin, Na-p-tosyl-L- arginine methyl ester, 7 mM benzamidine, 0.3 mM phenylmethylsulfonyl fluoride and two tablets of Roche complete protease inhibitor cocktail; following phosphatase inhibitors: 60 mM beta-glycerophosphate, 1 mM sodium vanadate, 10 mM sodium fluoride. 20 mM p-nitrophenyl phosphate, 1 uM okadaic acid, 1 uM microcystin, 2.5 mM sodium pyrophosphate; and 1 mM 3 0 dithiothreitol, 15 mM EDTA, 5 mM EGTA, 1% Triton X100 and 150 mM NaCl). Tissue lysates are cleared by centrifugation in a refrigerated microcentrifuge at 14,000 rpm and at 1 °C for 20 min. Supernatants are transferred to fresh microfuge tubes WO 2005/075478 -67- prechilled on ice and snap-freeze again in liquid nitrogen or dry ice. After quick thaw to about 80% completion in lukewarm water, the samples are placed on ice to complete thaw. The samples are centrifuged again at 14,000 rpm and at 1 °C for 15 min. The supernatant is transferred to fresh prechilled microfuge tubes and protein 5 concentrations are measured using Bio-Rad protein assay reagents using bovine serum albumin as protein standard. Protein extracts are equalized with the extraction buffer. An equal volume of 2X SDS sample buffer is added to the protein extracts and boiled in a waterbath for 5 min. 100 |ig of protein extract per sample is used for electrophoresis on 4-20% 10 gradient SDS-PAGE gel and transferred onto nitrocellulose (NC) membranes. NC membranes are blocked in 5% BSA in TBST (20 mM Tris pH = 7.5, 500 mM NaCl, . 0.05% Tween 20 and 0.02% sodium azide) for least 1 h. The membranes are then incubated in primary antibody at 1:1,000 with 5% BSA in TBST overnight on a shaker with 80 rpm at 4 °C. Membranes are washed 4 X, 10 min each, with TBST. 15 The membranes are then incubated for 40 min with secondary antibody HRP (horse radish peroxidase) conjugate at 1:10,000 dilution in 3% non-fat milk in TBST and washed again 4 times with TBST, 10 min each. The immuno-blots are then visualized by enhanced chemiluminescence (ECL, Amersham) as per manufacturer's instructions. All primary antibodies are purchased from Cell Signaling and secondary 2 0 antibody HRP conjugates are obtained from Amersham. Gels, membranes and apparatus used for electrophoresis and Western blotting are purchased from Invitrogen. Protein bands of interest are quantified from films using Kodak Image Station 1000. The compound of EXAMPLE 104 was tested essentially as described above 25 and exhibited a TMED50 = 3.59 mg/kg Rat Collagen Induced Arthritis Efficacy Model Female Lewis rats (=190 g, Charles River Labs) are immunized with Bovine type II collagen (2 mg/mL) emulsified with an equal volume of adjuvant (aluminum hydroxide). 3 0 were used. The rats are immunized with approximately 0.3 mg of the emulsion intrader- mally on the back near the base of the tail. All animals are re-immunized 7 days later according to the same protocol. The rats begin to develop arthritis (characterized by swell- WO 2005/075478 PCTAJS2005/000025 -68- ling and redness of one or both ankles) from 12 to 14 days after the first immunization. The rats are equally distributed into five treatment groups at the first signs of arthritis and treatment is initiated with each rat dosed bid for 14 days. Treatment groups: 5 Group 1 Vehicle (1% NaCarboxymethylcellulose+0.25% Tween 80) 1 mL, PO, Bid x 14 days Group 2 Test compound, 5 mg/kg, 1 mL, PO, Bid xl4 Group 3 Test compound, 15 mg/kg, 1 mL, PO, Bid xl4 Group 4 Test compound, 30 mg/kg, 1 mL, PO, Bid xl4 10 Group 5 Prednisolone 10 mg/kg, 1 mL, PO, qd xl4 Ankle diameter is measured with calipers 5 days a week and recorded. Data is expressed as the area under the curve (AUC) generated from the composite inflammation scores and statistical analysis performed. The compound of EXAMPLE 104 was tested essentially as 15 described above and exhibited a TMED50 =1.5 mg/kg (b.i.d.). Oral administration of the compounds of the present invention is preferred. However, oral administration is not the only route or even the only preferred route. For example, transdermal administration may be very desirable for patients who are forgetful or petulant about taking oral medicine, and the intravenous route may be preferred as a 2 0 matter of convenience or to avoid potential complications related to oral administration. Compounds of Formula I may also be administered by the percutaneous, intramuscular, intranasal or intrarectal route in particular circumstances. The route of administration may be varied in any way, limited by the physical properties of the drugs, the convenience of the patient and the caregiver, and other relevant circumstances (Remington's 2 5 Pharmaceutical Sciences. 18th Edition, Mack Publishing Co. (1990)). The pharmaceutical compositions are prepared in a manner well known in the pharmaceutical art. The carrier or excipient may be a solid, semi-solid, or liquid material that can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are well known in the art. The pharmaceutical composition may be adapted for 3 0 oral, inhalation, parenteral, or topical use and may be administered to the patient in the form of tablets, capsules, aerosols, inhalants, suppositories, solutions, suspensions, or the like. The compounds of the present invention may be administered orally, for example, with an inert diluent or capsules or compressed into tablets. For the purpose of oral WO 2005/075478 PCT/US2005/000025 -69- therapeutic administration, the compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. These preparations should contain at least 4% of the compound of the present invention, the active ingredient, but may be varied depending upon the particular 5 form and may conveniently be between 4% to about 70% of the weight of the unit. The amount of the compound present in compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations of the present invention may be determined by methods well known to the skilled artisan. The tablets, pills, capsules, troches, and the like may also contain one or more of 10 the following adjuvants: binders such as povidone, hydroxypropyl cellulose, microcrystalline cellulose, or gelatin; excipients or diluents such as: starch, lactose, microcrystalline cellulose or dicalcium phosphate, disintegrating agents such as: croscarmellose, crospovidone, sodium starch glycolate, corn starch and the like; lubricants such as: magnesium stearate, stearic acid, talc or hydrogenated vegetable oil; glidants 15 such as colloidal silicon dioxide; wetting agents such as: sodium lauryl sulfate and polysorbate 80; and sweetening agents such as: sucrose, aspartame or saccharin may be added or a flavoring agent such as: peppermint, methyl salicylate or orange flavoring. "When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil. Other dosage unit 2 0 forms may contain other various materials that modify the physical form of the dosage unit, for example, as coatings. Thus, tablets or pills may be coated with sugar, hydroxypropyl methyl cellulose, polymethacrylates, or other coating agents. Syrups may contain, in addition to the present compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in preparing these various 2 5 compositions should be pharmaceutical^ pure and non-toxic in the amounts used. The compounds of Formula I are generally effective over a wide dosage range. For example, dosages per day normally fall within the range of about 0.0001 to about 30 mg/kg of body weight. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses 3 0 may be employed without causing any harmful side effect, and therefore the above dosage range is not intended to limit the scope of the invention in any way. It will be understood that the amount of the compound actually administered will be determined WO 2005/075478 PCT/US2005/000025 -70- by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms. 5 WO 2005/075478 -71- PCT/US2005/000025 WE CLAM: 1. A compound of Formula I: where: N R4—N Wis: R N^R! (0 N r («) N (iii) / H—N N (iv) R' N^\R2 0-^R2 (v) (vi) (vii) XisN.orC-R1; R is C1-C7 alkyl, C3-C7 cycloalkyl, (C1-C7 alkylene)-(C3-C7 cycloalkyl), -S02-(Ci- C7 alkyl), or -S02-NR5R6; 10 R1 is hydrogen, amino, methyl, or -N=CH(NMe)2i 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; 15 R4 is hydrogen or C1-C7 alkyl; R5 and R6 are independently selected from the group consisting of C1-C7 alkyl; or a pharmaceutical^ acceptable salt thereof. WO 2005/075478 -72- PCT/XJS2005/000025 2. A compound of Formula I': r where: R' 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. 3. A compound of Formula I': r where: a) R' is 2,2-dimethylpropyl, R2' is 4-fluorophenyl, and R3' is 2-fluoro-6-trifluoromethylphenyl; b) R' is 2,2-dimethylpropyl, R2' is 4-fluorophenyl, and R3' is 2,6-dichlorophenyl; c) R' is 2,2-dimethylpropyl, R2' is 4-fluorophenyl, and R3' is tert-butyl; d) R' is 2,2-dimethylpropyl, R2' is phenyl, and R3' is 2-chloro-6-fluorophenyl; e) R' is 2,2-dimethylpropyl, R2' is 2,6-difluorophenyl, and R3' is tert-butyl; f) R' is 1,2,2-trimethylpropyl, R2' is 4-fluorophenyl, and R3' is tert-butyl; or WO 2005/075478 PCT/US2005/000025 -73- g) R is 1,2,2-trimethylpropyl, R2' is 4-fluorophenyl, and R3 is 2,6-difluorophenyl; or a pharmaceutically acceptable salt thereof. . 4. The compound 5-[2-tert-butyl-5-(4-fluoro-phenyl)-lH-imidazol-4-yl]-3-(2,2-duiiemyl-propyl)-3H-imidazo[4,5-b]pyridin-2-ylarnine, or a pharmaceutically acceptable salt thereof. 5. The compound 5-[2-tert-butyl-5-(4-fluoro-phenyl)-lH-imidazol-4-yl]-3-(2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridin-2-ylamine, or a fumarate, dimethanesulfonate, succinate, dimaleate, or dihydrochloride salt thereof. 6. The compound 5-[2-tert-butyl-5-(4-fluoro-phenyl)-lH-imidazol-4-yl]-3-(2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridin-2-ylamine dimethanesulfonate. 7. A pharmaceutical formulation comprising a compound of any of Claims 1-6 in combination with a pharmaceutically acceptable carrier, diluent or excipient. 8. The use of a compound of any of Claims 1-6 for the manufacture of a medicament for treating a disease or condition capable of being improved or prevented by inhibition of p-38 kinase. 9. The use of a compound of any of Claims 1-6 for the manufacture of a medicament for the treatment of susceptible neoplasms. 10. The use of Claim 9 where the susceptible neoplasm is multiple myeloma. 74 11. Method of inhibiting p-38 kinase 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 substantially described herewith foregoing description, examples and sequence listing Dated this 28th day of August 2006. Signature: GOUTAM BHATTACHARYYA OF K & S PARTNERS AGENT FOR THE APPLICANT(S) 75 ABSTRACT KINASE INHIBITORS The present invention provides compounds of Formula I, inhibiting p-38 kinase 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

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