ZA200600466B

ZA200600466B - Inhibitors of Akt activity

Info

Publication number: ZA200600466B
Application number: ZA200600466A
Authority: ZA
Inventors: Dirk A Heerding; David H Drewry; Safonov Igor; Tammy J Clark; Leber Jack Dale; Yamashita Dennis Shinji
Original assignee: Smithkline Beecham Corp
Priority date: 2003-07-29
Filing date: 2006-01-17
Publication date: 2007-05-30
Also published as: CN1859912A

Description

INLHIBITORS OF Akt ACTIVITY

FIELD OF THE INVENTION

This invention relates to novel 1H-imidazo[4,5-c]pyridin-2-y! compounds, the use of such compounds as inhibitors of protein kinase B (hereinafter PKB/Akt, PKEB or Akt) activity and in the treatment of cancer and arthritis.

BACKGROUND OF THE INVENTION

The present invention rexlates to 1H-imidazo[4,5-c]pyridin-2-yl containing compounds that are inhibitors Of the activity of one or more of the isoforms of the serine/threonine kinase, Akt (allso known as protein kinase B). The present invention also relates to pharm aceutical compositions comprising such compoundess and methods of using the instaant compounds in the treatment of cancer and arthritis (Liu et al. Current Opin. Pharmacology 3:317-22 (2003).

Apoptosis (programmed cell death) plays essential roles in embryonic development and pathogenesis of various diseases, such as degenerative neuroma diseases, cardiovascular disezses and cancer. Recent work has led to the identification of various pro- ard anti-apoptotic gene products that are involved in the regulation or execution of programmed cell death. Expression of anti-apoptottic genes, such as Bcl2 or Bcl-x;, inhibits apoptotic cell death induced by various stimuli. On the other hand, expression of pro-apoptotic genes, such as Bax or Bad, leads to programmed cell death (Adams et al. Science, 281:1322-1326 (1998).

The execution of programmed cell death is mediated by caspase -1 related proteinases, including caspasse-3, caspase- 7, caspase-8 and caspase-9 etc (Thomberry et al. Science, 2681:1312-1316 (1998).

The phosphatidylinositol 3-OH kinase (PI13K)/Akt/PKB pathway appears important for regulating cell swivival/cell death (Kulik et al. Mol.Cell.Biol. 17:1595— 1606 (1997); Franke et al, Cel, 88:435-437 (1997); Kauffmann-Zeh et al. Natures 385:544-548 (1997) Hemmings Science, 275:628-630 (1997); Dudek et al.,

Science, 275:661-665 (1997p). Survival factors, such as platelet derived growth factor (PDGF), nerve growth factor (NGF) and insulin-like growth factor-1 (IGF-I, promote cell survival under various conditions by inducing the activity of PI3K (Kulik et al. 1997, Hemmings 1997). Activated PI3K leads to the production of phosphatidylinositol (3,4,5)-tr-iphosphate (Ptdins (3,4,5)-P3), which in turn binds to, and promotes the activation «f, the serine/ threonine kinase Akt, which contains a pleckstrin homology (PH)-do main (Franke et al Cell, 81:727-736 (1995); Hemmi ngs

Science, 277:534 (1997); Downward, Curr. Opin. Cell Biol. 10:262-267 (1998),

Alessi et al., EMBO J. 15: 6541-6551 (1996). Specific inhibitors of PI3K or dominant negative AkVPKB mutants abolish survival-promoting activities of these growth factors or cytokines. it has been previously disclosed that inhibitors of PI3K (LY294002 or wortmannin) blocked the activation of Akt/PKB by upstream kina=ses.

In addition, introduction of constitutively active P13K or Akt/PKB mutants promostes cell survival under conditions in whaich cells normally undergo apoptotic cell death (Kulik et al. 1997, Dudek et al. 1927).

Analysis of Akt levels in hu man tumors showed that Akt2 is overexpresssed in a significant number of ovarian «J. Q. Cheung et al. Proc. Natl. Acad. Sci. U-S.A. 89:9267-9271(1992)) and pancreatic cancers (J. Q. Cheung et al. Proc. Natl. cad.

Sci. U.S.A. 93:3636-3641 (1996))- Similarly, Akt3 was found to be overexpresssed in breast and prostate cancer cell lines (Nakatani et al. J. Biol. Chem. 274:21528- 21532 (1999). It was demonstrated that Akt-2 was over-expressed in 12% of ovarian carcinomas and that amplification of Akt was especially frequent in 508% of undifferentiated tumors, suggestieon that Akt may also be associated with tumeor aggressiveness (Bellacosa, et al., Int. J. Cancer, 64, pp. 280-285, 1995).

Increased Akt1 kinase activity ha-s been reported in breast, ovarian and prostate - cancers (Sun et al. Am. J. Pathof. 159: 431-7 (2001)).

The tumor suppressor PT EN, a protein and lipid phosphatase that specifically removes the 3' phosphate of Ptdins(3,4,5)-P3, is a negative regul ator of the PI3K/Akt pathway (Li et al. Science 275:1943-1947 (1997), Stambolic et al. Cell 95:29-39 (1998), Sun et al. Proc. Nati. Acad. Sci. U.S.A. 96:6199-6204 (1999).

Germline mutations of PTEN are= responsible for human cancer syndromes s=uch as

Cowden disease (Liaw et al. Nature Genetics 16:64-67 (1997)). PTEN is deleted in a large percentage of human turmors and tumor cell lines without functional PTEN show elevated levels of activatecd Akt (Li et al. supra, Guldberg et al. Cancer

Research 57:3660-3663 (1997), Risinger et al. Cancer Research 57:4736-4'a 38 (1997).

These observations demonstrate that the PI3K/Akt pathway plays important roles for regulating cell survival or apoptosis in tumorigenesis.

Three members of the AckV/PKB subfamily of second-messenger regulated serinefthreonine protein kinasess have been identified and termed Akt1/ PKEBSa,

Akt2/PKBB, and Akt3/PKBY resgpectively. The isoforms are homologous, particularly in regions encoding the catalytic domains. Akt/PKBs are activated by phosphorylation events occurrirg in response to PI3K signaling. PI3K phosphorylates membrane inossitol phospholipids, generating the second messengers phosphatidyl- inos itol 3,4,5-trisphosphate and phosphatidylinossitol 3,4-

bisphosphate, which have been shown to bind to the PH domain of AKUPKB. The current mode! of Akt/PIKB activation proposes recruitment of the enzyme to the : membrane by 3'-phosphhorylated phosphoinositides, where phosphorylation of the’ regulatory sites of Akt/FPKB by the upstream kinases occurs (B.A. Hemmings,

Science 275:628-630 (1997), BA. Hemmings, Science 276:534 (1997); J.

Downward, Science 27 9:673-674 (1998).

Phosphorylation of Akt1/PKBa occurs on two regulatory sites, Thr'™ in the catalytic domain activation loop-and on Ser” near the carboxy terminus (D.R.

Alessi et al. EMBO J. 15:6541-6551 (1996) and R. Meier et al. J. Biol. Chem. : 272:30491-30497 (1997). Equivalent regulatory phosphorylation sites occur in

Akt2/PKBp and Akt3/PPKBy. The upstream kinase, which phosphorylates Akt/PKB at the activation loop site has been cloned and termed 3 '-phosphoinositide dependent protein kinase 1 (PDK1). PDK1 phosphorylates not only Akt/PKB, but also p70 ribosomal S6 kinase, p9ORSK, serum and glucocorticoid-regulated kinase (SGK), and protein kirsase C. The upstream kinase phosphorylating the regulatory site of Akt/PKB near the carboxy terminus has not been identified yet, but recent reports imply a role for the integrin-linked kinase (ILK-1), a serine/threonine protein kinase, or autophosphuorylation.

Inhibition of Alt activation and activity can be achieved by inhibiting PI13K with inhibitors such ass LY294002 and wortmannin. However, PI3K inhibition has the potential to indiscriminately affect not just all three Akt isozymes but also other

PH domain-containing signaling molecules that are dependent on Pdtins(3,4,5)-

P3, such as the Tec family of tyrosine kinases. Furthermore, it has been disclosed that Akt can be activated by growth signals that are independent of PI3K.

Alternatively, Akt activity can be inhibited by blocking the activity of the upstream kinase PDKK1. The compound UCN-01 is a reported inhibitor of PDK1.

Biochem. J. 375(2):256 (2003). Again, inhibition of PDK1 would result in inhibition of multiple protein kin ases whose activities depend on PDK1, such as atypical PKC isoforms, SGK, and S56 kinases (Williams et al. Curr. Biol. 10:439-448 (2000). : 30 Small molecule inhibitors of Akt are useful in the treatment of tumors, especially those with activated Akt (e.g. PTEN null tumors and tumors with ras mutations). PTEN is a critical negative regulator of Akt and its function is lost in many cancers, including breast and prostate carcinomas, glioblastomas, and several cancer syndromes including Bannayan-Zonana syndrome (Maehama, T. et al. Annual Review of Biochemistry, 70: 247 (2001)), Cowden disease (Parsons, R;

Simpson, L. Methodss in Molecular Biology (Totowa, NJ, United States), 222 (Tumor-

Suppressor Genes, Volume 1): 147 (2003)), and Lhermitte-Duclos disease

(Backman, S. et al. Curresnt Opinion in Neurobiology, 12(5). 516 (2002). AKi3 is up-regulated in estrogen veceptor-deficient breast cancers and androgen- independent prostate carcer cell lines and Akt2 is over-expressed in pancreatic and ovarian carcinomas. Akt1is amplified in gastric cancers (Staal, Proc. Natl. 5s Acad. Sci. USA 84: 50347 (1987) and upregulated in breast cancers (Stal et al.

Breast Cancer Res. 5: R37-R44 (2003)). Therefore a small molecule Akt imhibitor is expected to be useful For the treatment of these types of cancer as well as other types of cancer. Akt inhi bitors are also useful in combination with further chemotherapeutic agents. :

It is an object of the instant invention to provide novel compounds €hat are inhibitors of Akt/PKB.

It is also an object of the present invention to provide pharmaceutical compositions that comprise a pharmaceutical carrier and compounds useful in the methods of the invention. it is also an object of the present invention to provide a method for treating cancer that comprises a dministering such inhibitors of Akt/PKB activity. it is also an object of the present invention to provide a method for treating arthritis that comprises administering such inhibitors of Akt/PKB activity.

SUMMARY OF THE INVENTION

This invention reslates to novel compounds of Formula (1): ’ R4 —

NN

R1 R7

M wherein:

Het is selected from the group consisting of:

H SJ * * *

Lor LEG

O~N , N ~~ , NH, N ,» HN N° N™ "NH, .

NH, Ne oy ( yd of

YH (J. HNN ONT ONe, ed HNN

R1 is selected from hydrogen, alkyl, alkyl substituted with one or more substituents s«elected from the group consisting of: hydroxy, alkoxy, amino, N-acylamino, cyclopropyl and halogen, cycloalkyl, cycloalkyl substituted with one or more substituents selected from the group consisting of: hydroxy, alkoxy, amino, N-acylamino and halogen, cycloalkyl corutaining from 1 to 4 heteroatoms, cycloalkyl containing from 1 to 4 heteroatoms substituted with one or more substituents selected from the grou p consisting of: hydroxy, alkoxy, amino, N-acylamino and halogen, C4_Cq2aryland C4.Cq2aryl substituted with one or more substituents selected from the group consisting of: hydroxy, alkoxy, amino, N-acy lamino and halogen;

R4 is selected “from hydrogen, halogen, alkyl, substituted alkyl, cycloalkyl, cwecloalkyl containing from 1 to 4 heteroatoms and a cyclic or polycyclic aromatic ring containing from 3 to 16 carbon atoms and optionally cortaining one or more heteroatoms, provided that when the number of carbon atoms is 3 the aromatic ring contains at least two : 20 heteroatoms and when the number of carbon atoms is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: alkyl, substituted © alkyl, alkoxy, acetamide, cyano, nitrile, urea, substituted urea, aryl, substituted cycloalkyl, substituted aryl, aryloxy, oxo, hydroxy, alkoxy, cycloalkyl, acyloxy, amino, N-acylamino, nitro, halogen, :C(O)OR2, -

C(O)NRSRS , -5(0)2NRORE, -8(0),R2 and protected -OH, where nis 0-2,

R2 is selected from hydrogen, alkyl, cycloalkyl, C4-Cq2aryl, substituted alkyl, substituted cycloalkyl and substituted C4.C1zanyl, and

R5 andi R6 are independently hydrogen, cycloalkyl, C4.C42anyl, substiteuted cycloalkyl, substituted Cq.Cqoanl, alkyl or alkyl substituted with ore or more substituents selected from the group consisting of: alkoxy , acyloxy, aryloxy, amino, N-acylamino, oxo, fmydroxy, -C(O)OR2, -

S(0)IR2, -C(O)NRZR3, -S(0)oNR2R3, nitro, cyano , cycloalkyl, substituted cycloalkyl, halogen, aryl, substituted ary® and protected OH, or RS and RE taken together with the nitrogen to winich they are attached representa 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen, wheere the ring is optionally subtituted with one or more substituents =selected from amino, methyw/lamino and dimethylamino, where R2 and R3 are independently hydrogen, alkyl, cycloalkyl,

C1.Cq2anyl, substituted alkyl, substituted cycloalkyl and substituted C1.Cq2aryl, and nis 0-2; and

R is selected from hydrogen, -C(O)NROR10, -(CH)RNRER10, -

SONRIR10, -(CHR)HORS, -0-(CH2)mNROR10® and -N- (CH2)MNRER10, whesenis 0-2, mis 1-8, where the carbon chain formed by mis optionally substituted, ’

R8 iss alkyl, cycloalkyl, cycloalkyl containing from 1 to 4 heteroatoms, and aryl, each of which is optionally substituted with one or more substituents selected from the group consisting od: alkoxy, acyloxy, aryloxy, amino, amino substituted with one or meore substituents selected fron the group consisting of: hydroxy, alkoxy anck amino, N-acylamino, oxo , hydroxy, -C(O)OR2, -S(O)nR2, -C(O)NRZRS, -S(0)oNR2R3, nitro, guamnadine, substituted guanadine, cyano, cycloa Tkyl, cycloalkyl containing frorm 1 to 4 heteroatoms, substituted cycloalkyl containing from 1 to 4 : heteroatoms, substituted cycloalkyl, halogen, ary~1, substituted aryl and protected —OH, where R2 and R3 are independently hydro gen, alkyl, cycloalkyl,

C4.Cqoaryl, substituted alkyl, substituted cycloalkyl and substituted C4.Cq2aryl, and nis 0-2,

RY and R10 are independently hydrogen, cycloalkyl, cycloalkyl cortaining from 1 to 4 heteroatoms, C4.Cq2aryl, substituted cycloalkyl, substituted C4-Cq2aryl, alkyl or alkyl substitute=d with one or more sullbstituents selected from the group consisting -of: alkoxy, acyloxy,

aryloxy, amino, N-acylamino, oxo, hydroxy, methylamino, dimethylaamino, hydroxyalkyl, -C(O)OR2, -S(0)R2, -C(O)NR2R3, -5(0)2NR2R3, -

NRZR3, nitro, cyano, cycloalkyl, cycloalkyl containing from 1to 4 heteroatoms, substituted cycloalkyl, halogen, aryl, substituted aryl and protected —OH, or RS and R10 taken together with the nitrogen to which they are attached represent a 510 6 member saturated ring containing up to one otheer heteroatom selected from oxygen and nitrogen, where the ring is optionally subtituted with one or more substituents selected from aamino, methylamino and dimethylamino, where R2 and R3 are independently hydrogen, alkyl, cycloalkyl, : - C4-Cq2amyl, substituted alkyl, substituted cycloalkyl and substituted C1.Cq2aryl, and nis 0-2; except 4-[1-Ethyl-7-(piperidin-4-yloxy)-1 H-imidazo[4,5-c]pyridin-2-yl]- furazan-3-ylamine and/o=r pharmaceutically acceptable salts, hydrates, solvates and pro-drugss thereof.

This invention relates to a method of treating cancer, which compri ses admimistering to a subject in need thereof an effective amount of an Akt/PIKB inhibi ting compound of Formula (1). ~~

This invention relates to a method of treating arthritis, which comprises admi nistering to a subject in need thereof an effective amount of an Akt/P~KB inhibiting compound of Formula (1).

The present invention also relates to the discovery that the composunds of

Formula (I) are active as inhibitors of Ak/PKB.

In a further aspect of the invention there is provided novel processses and noves! intermediates useful in preparing the presently invented AkUPKB imahibiting com pounds.

Included in the present invention are pharmaceutical compositions that comprise a pharmaceutical carrier and compounds useful in the methods of the invention.

Also included in the present invention are methods of co-administering the presently invented AkV/PKB inhibiting compounds with further active ingredients.

DETAILED DESCRIPTION OF THE INVENTION

S This invention relates to conmipounds of Formula (1) as described above.

The presently invented compounds of Formula (1) inhibit Akt/PKB activity. "In particular, the compounds disclossed herein inhibit each of the three Akt/PKB isoforms.

Included among the presently invented compounds of Formula (I) are those 1.0 having Formula (lI):

NH, R4 ~~

NON

R1 R7 an wherein:

R1 is selected from hydrogen, alkyl, alkyl substituted with one or more substituents selected frorn the group consisting of: hydroxy, alkoxy, amino, N-acylamino, cyclopropyl and halogen, cycloalkyl, cycloalkyl substituted with one or more substituents selected from the group consisting of: hydroxy, ak koxy, amino, N-acylamino and halogen, cycloalkyl containing frorm 1 to 4 heteroatoms, cycloalkyl containing fraem 1 to 4 heteroatoms substituted with one or more substituents selected from the group consisting of: hydroxy, alkoxy, amino, N-acylamino and halogen, C4.Cqzary! and C1.Cq2ary! substituted with one or more substituents selected frosm the group consisting of: hydroxy, alkoxy, amino, N-acylamino andl halogen;

R4% is selected from hydrogen, halogen, alkyl, substituted alkyl, cycloalkyl, cycloalkyl cosntaining from 1 to 4 heteroatoms and a cyclic or polycyclic aromatic ring containing from 3 to 16 carbon atoms and optionally containing onee or more heteroatoms, provided that when the number of carbon atoms is 3 the aromatic ring contains at least two heteroatoms and when <the number of carbon atoms is 4 the aromatic ring contains at least one hesteroatom, and optionally substituted with one or more substituents selected from the group consisting of: alkyl, substit_iated alkyl, alkoxy, acetamide, cyano, nitrile, urea, substituted urea, aryl, substituted cycloalkyl, substituted aryl, aryloxy, oxo, hydroxy, alkoxy, cycloal kyl, acyloxy, amino, N-acylamino, nitro, halogen, C(O)ORZ, -

C(O)NBRSRS, -S(O)NR3RE, -5(0)pR2 and protected -OH, where nis 0-2,

R2 is selected from hydrogen, alkyl, cycloalkyl, C4-Cq2aryl, substituted alkyl, substituted cycloalkyl and substituted C1.C42aryl, and

R5 an«d RO are independently hydrogen, cycloalkyl, C4-Cq2amyl, substituted cycloalkyl, substituted C1.Cq2anyl, alkyl or alkyl substituted with o-ne or more substituents selected from the group consisting of= alkoxwy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, -C(0)O RZ, -

S(0)~R2, -C(OINR2R3, -S(0)oNR2R3, nitro, cyano, cycloalkyl, subst ituted cycloalkyl, halogen, aryl, substituted aryl and protected —OH, or R5 and RO taken together with the nitrogen to which they are attaached repre=sent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen, where the ring is optio nally subtituted with one or more substituents selected from amino, methaylamino and dimethylamino, } where R2 and R3 are independently hydrogen, alkyl, cycloalkyl,

C1-Cq2aryl, substituted. alkyl, substituted cycloalkyl and substituted C1.C{2aryl, and nis 0-2; and

R7 is selected from hydrogen, _C(O)NROR10, -(CH2)nNRER10, -

SO=NRIR10, ~(CH2)NORE, -0-(CH2)NRER10 and -N- (CH 2)mNRSR10, : whezre nis 0-2, miss 1-8, where the carbon chain formed by m is optionally substituted,

R8 dis alkyl, cycloalkyl, cycloalkyl containing from 1 to 4 heteroatoms, andi aryl, each of which is optionally substituted with one or more submstituents selected from the group consisting of: alkoxy, acylox-y, arylloxy, amino, amino substituted with one or more substituents selected frorn the group consisting of: hydroxy, alkoxy and amino, N-acyl amino, oxe, hydroxy, -C(0)OR2, -S(O)nR2, -C(O)NR2R3, -S(0)2NR2R3, nitro, guaanadine, substituted guanadine, cyano, cycloalkyl, cycloalkyl c=ontaining fromm 1 to 4 heteroatoms, substituted cycloalkyl containing from 1 tod heteroatoms, substituted cycloalkyl, halogen, aryl, substituted army! and protected —OH,

WO ~2005/011700 PCT/US2004/024340 where R2 and R3 are independently hydrogen, alkyl, cycloalkyl,

C1-Cq2anyl, substituted alkyl, substituted cycloalkyl and substituted C4.C42aryl, and n= is 0-2,

RY and R10 are independently hyclrogen, cycloalkyl, cycloalkyl containing from 1 to 4 heteroatoms, C4-Cqzamnyl, substituted cycloalkyl, substituted C1.Cq2aryl, alkyl or aWkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, methylamino, dimethylamino, hydroxyalkyl, -C(O)ORZ, S(0)R2, -C(O)NR2R3, -S(0)2NR2R3, -

NR2R3, nitro, cyano, cycloalkyl, cycloalkyl containing from 1 to 4 heteroatoms, substituted cycloalkyl, halogen, aryl, substituted aryl and protected —~OH, } or R9 and R10 taken together witi the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygerm and nitrogen, where the ring is optionally subtituted with one or nore substituents selected from amino, methylamino and dimethylamino, where R2 and R3 are indep-endently hydrogen, alkyl, cycloalkyl,

C1.Cq2aryl, substituted allyl, substituted cycloalkyl and substituted C4.Cqoaryl, ancinis 0-2; except 4{1 -Ethyl-7-(piperidin-4-ylo xy)-1 H-imidazo[4,5-clpyridin-2-yi]- furazan-3-ylamine and/or pharmaceutically acceptable salts, hydrates, solvates and pro-drugs thereoT.

Included among the presently invented compounds of Formula (I) are those having Formula (IH):

NH, R4 eee

ON MNT

Ri R7 qu wherein:

R1 is selected from alkyl, alkyl ssubstituted with one or more substituents selected from the group consisting of: hydroxy, alkoxy, amino, N- acylamino, cyclopropyl and haleogen, cycloalkyl, cycloalkyl substituted with one or more substituents selected from the group consisting of: hydroxy, alkoxy, amino, N-acylamino and halogen, cycloalicyl containing from 1 to 3 heteroatoms, cycloalkyl containing from 1 to 3 eteroatoms substituted with one or more substituents selected from the group consisting of: hydroxy, alkoxy, amino, N-acylamino and halogen, C4.

Cqparyl and Cq.C42aryl substituted with one or more subsstituents selected from the group consisting of: hydroxy, alkoxy, amino, N- acylamino and halogen;

R4 is selected from hydrogen, halogen, alkyl, substituted alkyl, cycloalkyl, cycloalkyl! containing from 1 to 3 heteroatoms and a cyclic or polycyclic aromatic ring containing from 3 to 16 carbon atoms and optionally containing one or more heteroatoms, provided that when the number of carbon atoms is 3 the aromatic ring contains at least two heteroatoms and when the number of carbon atoms is 4 the aromatic ring contains at least one heteroatom, and optionally substitutezd with one or more substituents selected from the group consisting of: alkyl, substituted alkyl, alkoxy, acetamide, cyano, nitrile, urea, substituted Lirea, aryl, substituted cycloalkyl, substituted aryl, aryloxy, oxo, hydroxy, alkoxy, cycloalkyl, acyloxy, amino, N-acylamino, nitro, halogen, —C(O)OR2, -

C(O)NRSRS, -5(0)2NRER8, -S(0)nR? and protected -OH, where nis 0-2,

R2 is selected from hydrogen, alkyl, cycloalkyl, C1.C1—2amyl, substituted alkyl, substituted cycloalkyl and substituted C4.Cq2aryl. and

R5 and RO are independently hydrogen, cycloalkyl, C4.-Cq2aryl, substituted cycloalkyl, substituted C1-Cq2aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, -C(O)ORZ, -

S(O)pR2, -C(OINRZR3, -5(0)2NR2R3, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, aryl, substituted ary! anc protected —OH, or RS and R6 taken together with the nitrogen to which &hey are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen, where t he ring is optionally subtituted with one or more substituents selected from amino, methylamino and dimethylamino,

where R2 and R3 are independently hydrogen, alkyl, cycloalkyl,

C4-.Cq2anyl, substituted alkyl, substituted cycloalkyl and substituted C4_Cq2aryl, and nis 0-2; and

R7 is selected from -C(OINROR10, «(CH2)NROR10, —S0oNROR10, - (€CHp) ORS, -0-CH2)mNROR10 and N-(CH2)mNRER10, where nis 0-2, mis 1-6, where the carbon chain formed by m is optaonally substituted,

R8is alkyl, piperidine, imidazolidine, phenyl, piperazine, piperidyl and pyrrolidinyl, each of which is optionally substituted with one or more : substituents selected from the group consisting of: all<oxy, acyloxy, aryloxy, amino, amino substituted with one or more substituents selected

From the group consisting of: hydroxy, alkoxy and amiino, N-acylamino, ©x0, hydroxy, -C(O)OR2, -S(0)nR?2, _C(O)NR2R3, -S (0)2NR2R3, nitro, «guanadine, substituted guanadine, cyano, cycloalkyl, cycloalkyl containing “rom 1 to 3 heteroatoms, substituted cycloalkyl containing from 1t03 heteroatoms, substituted cycloalkyl, halogen, aryl, su bstituted aryl and : ~ protected —OH,

Co where R2 and R3 are independently hydrogen. alkyl, cycloalkyl, : 20 C4.Cqoaryl, substituted alkyl, substituted cycloalkyl and substituted C{.C42aryl, and nis 0-2,

R9 and R10 are independently hydrogen, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms, C1.Cqoaryl, substituted cycloalkyl, substituted C4.C42aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of. a 1koxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, methylarmino, dimethylamino, hydroxyalkyl, -C(O)OR2, -S(O)nR?, -C(O)NR2R3, -S(0)2NR2RS3, -

NR2R3, nitro, cyano, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms, substituted cycloalkyl, halogen, aryl, seabstituted aryl and protected —OH, or RO and R10 taken together with the nitrogen to w hich they are attached represent a 5 to 6 member saturated ring containingg up to one other heteroatom selected from oxygen and nitrogen, whesre the ring is optionally subtituted with one or more substituents selected from amino, methylamino and dimethylamino,

\where R2 and R3 are independently hydrogen, alkyl, cycloalkyl, &1.C12ani, substituted alkyl, substituted cycloalkyl and =substituted C1.C42aryl, and nis 0-2; except eexcept 4-{1-Ethy}-7-(piperidin-4-yloxy)-1 H-imidazo[4,5—clpyridin-2-yi}- furazzan-3-ylamine } and/or pharmamceutically acceptable salts, hydrates, solvates and pros-drugs thereof. includead among the presently invented compounds of Formu la (1) are those having Formula (IV):

NH, R4

O-N NF

RI R7 (y) wherein:

R1 is selected from hydrogen, alkyl, alkyl substituted with sone or more substituents selected from the group consisting of: hydroxzy, alkoxy, amirno, N-acylamino, cyclopropyl and halogen, cycloalkyl, cycloalkyl subsstituted with one or more substituents selected from th e group conssisting of: hydroxy, alkoxy, amino, N-acylamino and hamlogen, cycloalkyl containing from 1 to 3 heteroatoms, cycloalkyl containing from 1 to: 3 heteroatoms substituted with one or more substitue-nts selected : froran the group consisting of: hydroxy, alkoxy, amino, N-accylamino and halogen, Cq1.Cqparyl and C4.Ci2amyl substituted with orme or more subestituents selected from the group consisting of: hydroxy, alkoxy, amino, N-acylamino and halogen;

R4 is selected from hydrogen, halogen, alkyl, substituted alkyl, cyc=loalkyl, cycloalkyl containing from 1 to 3 heteroatoms and a cyclic or pol=ycyclic aromatic ring containing from 3 to 16 carbon atoms and optzionally containing one or more heteroatoms, provided that when the nurnber of carbon atoms is 3 the aromatic ring contains amt least two het-eroatoms and when the number of carbon atoms is 4 —the aromatic ring corains at least one heteroatom, and optionally substituted with one or mawre substituents selected from the group consisting of: alkyl, substituted alkcyl, aryl, substituted cycloalkyl, substituted aryl, aryloxy~, oxo, hydroxy,

alkoxy, cycloalkyl, acyloxy, amino, N-acylamiro, nitro, cyano, halogen, -

C(O)OR2, -C(O)NRSRS, .S(O)oNRSRE, -S(CO)nR?2 and protected -OH, where n is 0-2,

R2 is selected from hydrogen, alkyl, cycloa liyl, G1-C4 oaryl, substituted alkyl, substituted cycloalkyl and substituted C1.C12aryl, and

RS and RS are independently hydrogen, cycloalkyl, C4.Cq2amyl, substituted cycloalkyl, substituted C4.C12arVl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylaminc, oxo, hydroxy, -C(O)ORZ, -

S(0)pR2, -C(O)NRZR3, -S(0)NR2R3, nitroe, cyano, cycloalkyl, substituted cycloalkyl, halogen, aryl, substituted ary! and protected =0OH, or RS and RO taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen, where the ring is optionally subtituted with one or more substatuents selected from amino, methylamino and dimethylamino, where R2 and R3 are independently Fydrogen, alkyl, cycloalkyl,

C1.Cqoaryl, substituted alkyl, substituted cycloalkyl and substituted C4.C12aryl, and nis 0-2; and

RY is hydrogen; an-dior pharmaceutically acceptable salts, hydrates, solvates and pro-drugs thereof.

Included among the presently invented compounds of Formula (Il) are those in “which:

R1 is selected from: alkyl, alkyl substituted “with one or more substituents selected from the group consisting of. hydroxy, alkoxy, amino, N- acylamino, cyclopropyl and halogen, cycloalkyl containing from 1 to 3 heteroatoms and C4.Cq2aryl;

R4 is selected from hydrogen, halogen, allyl, substituted alkyl, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms, C1.Cqoanyt and C4.Cq2aryl substituted with one or m ore substituents selected from the group consisting of: alkyl, substituted alkyl, aryloxy, hydroxy, alkoxy, acyloxy, amino, N-acylamino, nitro, cyano and halogen; and

RT is selected from hydrogen, -C(O)NROFR'10 and -(CH2)nORS, where nis 0-2;

R8is alkyl, piperidine, imidazolidine, p iperidyl and pyrrolidinyl, each of which is optionally substituted with one oF more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, hydroxy, nitro, cyano, cycloalkyl, haloger and C4-Cq2aryl,

RY and R10 are independently hydroge n, cycloalkyl, cycloalkyl containing from 1 to 3'heteroatoms, C4 _Cqoaryi, substituted cycloalkyl, substituted C4.Cq2aryl, alkyl or alkyl saubstituted with one or more substituents selected from the group comnsisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, methylamino, dimethylamino, hydroxyalkyl, -NR2R3, nitro, cyano, cycloalkyl, halogen, aryl and substituted aryl, or R9 and R10 taken together with the mitrogen to which they are attached represent a 5 to 6 member saturated rigng containing up to one other heteroatom selected from oxygen and mitrogen, where the ring is : optionally subtituted with one or more substituents selected from amino, methylamino and dimethylamino, where R2 and R3 are independertly hydrogen, alkyl, cycloalkyl, : C4-Cq2aryl, substituted alkyl, substituted cycloalkyl and substituted C4.Cq2aryl; except 4-{1-Ethyl-7-(piperidin-4-yloxy)-1 I-imidazo[4,5-c]pyridin-2-yll- furazan-3-ylamine and/or pharmaceutically acceptable salts, hydrates, solvates and pro-drugs thereof.

Included among the presently invented scompounds of Formula (tl) are those in which:

R1 is selected from: alkyl, alkyl substit_uted with one or more substituents selected from the group consisting of= hydroxy, alkoxy, amino, N- acylamino, cyclopropyl and halogen, cycloalkyl containing from1to3 heteroatoms and C4.Cq2aryl;

R4 is selected from hydrogen, halogem, alkyl, substituted alkyl, cycloalkyl, cycloalkyl containing fromm 1 to 3 heteroatoms, C1.C4oaryl and C4.Cqoaryl substituted with one or more substituents selected from the group consisting of: alkyl, Substituted alkyl, aryloxy, hydroxy, alkoxy, acyloxy, amino, N-acylamino, mitro, cyano and halogen; and

R7 is selected from -C(OINROR0 and «CH2)nORS, where nis 0-2;

R8is alkyl, piperidine, imidaazolidine, piperidyl and pyrrolidinyl, each of which is optionally substitutecd with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, hydroxy, nitro, cyano, cycloal kyl, halogen and C4-C42anl,

RO and R10 are independently hydrogen, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms, C4.Cqoanyl, substituted cycloalkyl, substituted C4.Cq2aryl, ‘alkyl or alkyl substituted with one or more substituents selected from tine group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylaminos, oxo, hydroxy, methylamino, dimethylamino, hydroxyalkyl, -NR2R3, nitro, cyano, cycloalkyl, halogen, aryl and substituted aryl, or R9 and R10 taken together with the nitrogen to which they are attached representa 5to 6 member saturated ring containing up to one other : 20 heteroatom selected from oxygen and nitrogen, where the ring is optionally subtituted with ore or more substituents selected from amino, methylamino and dimethylaamino, where R2 and R3 are independently hydrogen, alkyl, cycloalkyl,

C4.Cq2anyl, substituted alkyl, substituted cycloalkyl and substituted C4-Cq2aryi; except 4-1 -Ethyl-7-(piperidir-4-yloxy)-1 H-imidazo[4,5-c]pyridin-2-yl}- furazan-3-ylamine and/or pharmaceutically acceptable: salts, hydrates, solvates and pro-drugs thereof.

Included among the presently invented compounds of Formula (IV) are those in which:

R1 is selected from: alkyl, alkyl substituted with one or more substituents selected from the group cansisting of: hydroxy, alkoxy, amino, N- acylamino, cyclopropyl ard halogen, cycloalkyl containing from 1t03 heteroatoms and C4-Cq2aryl;

FR4 is selected from hydrogen, halogen, allyl, substituted alkyl, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms, C1.Cq2anyl and C4.Cqoaryl substituted with one or more substituents selected from the group consisting of: alkyl, substituted =alky), aryloxy, hydroxy, alkoxy, acyloxy, amino, N-acylamino, nitro, cyanos and halogen; and

R’ is hydrogen; and/or pharmaceutically acceptable salts, hydratess, solvates and pro-drugs thereeof. included among the presently invented cormpounds of Formula (1) are those in whicsh: "15 R1 is selected from: alkyl, alkyl substitutead with one or more substituent=s selected from the group consisting of: hydroxy, alkoxy, amino, N- acylamino, cyclopropyl and halogen, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms and C4.Cq2aryi; . : 20 R4 is selected from hydrogen, halogen, alkyl, substituted alkyl, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms, C4.Cq2amyl and C4.Cqoaryl substituted with one om more substituents selected from the group consisting of: alkyl, substitutexd alkyl, alkoxy, acetamide, cya.no, nitrile, urea, substituted urea, aryloxy, inydroxy, alkoxy, acyloxy, amino , N- acylamino, nitro and halogen; and

R7 is selected from, -C(ONRER10, -(CH)pNROR10, -(CH2)nORS, —O- (CH2)mNROR 10 and -N-(CH2)mNROR10, where nis 0-2; mis 1-8, where the carbon chain forrned by m is optionally substituted,

R8is alkyl, piperidine, imidazolidine, phenyl, piperazine, piperidyl and pyrrolidinyl, each of which is optionally substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, amino substituted witth one or more substituents selected from the group consisting of: hydroxy, alkoxy and amino, N-acylamizno, hydroxy, nitro, guanadine, substitutes guanadine, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms,

substituted cycloalkyl containing from 1 to 3 heteroatoms, halogen, Cq-

C42aryl and substituted Cqg-Cq2any},

RI and R10 are independently hydrogen, cycloalkyl, cycloalkyl containing from 1to 3 hetesroatoms, C4.Cq2amy, substituted cycloalkyl, substituted C4.C12aryl, akkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamimno, oxo, hydroxy, methylamino, dimethylamino, hydroxyalkyl, -NR2R3, nitro, cyano, cycloalkyl, halogen, aryl and substituted aryl, or R9 and R10 taken togesther with the nitrogen to which they are attached representa 5to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen, where the ring is optionally subtituted with ©ne or more substituents selected from amino, methylamino and dimethyslamino, where R2 and R3 are independently hydrogen, alkyl, cycloalkyl,

C1.Cqzaryl, substituted alkyl, substituted cycloalkyl and substituted C4.Cq2anh; : except 4-[1 -Ethyl-7-(pipericlin-4-yloxy)-1 H-imidazo[4,5-c}pyridin-2-yl]- furazan-3-ylamine 20 . : and/or pharmaceutically acceptable salts, hydrates, solvates and pro-drugs thereof.

Included among the presemtly invented compounds of Formula (lif) are those in which:

R1 is selected from: alkyl. alkyl substituted with one or more substituents selected from the group consisting of: hydroxy, alkoxy, amino, N- acylamino, cyclopropyl and halogen, cycloalkyl, cycloalkyl containing : from 1 to 3 heteroatoms and C4.Cq2aryl;

R4 is selected from hydrogen, halogen, alkyl, substituted alkyl, cycloalkyl, cycloalkyl coentaining from 1 to 3 heteroatoms, C1.Cqoaryl and C4.Cq2aryl substitwted with one or more substituents selected from the group consisting of: alkyl, substituted alkyl, alkoxy, acetamide, cyano, nitrile, urea, substituted urea, aryloxy, hydroxy, alkoxy, acyloxy, amino, N- acylamino, nitro, and halogen; and

R7 is selected frorn ~(CH2)ROR8, -O-CH)mNRIR10 and -N- (CH2)mNRER1O, where nis 0-2; mis 1-6, where the carbon chain formed by mis optionally substituted,

R8 is alkyl, piperidine, imidazolidine, phenyl, piperazine, pip=eridyl and : pymolidinyl, each of which is optionally substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, amino substituted with one or mare substituermts selected from the group consisting of: hydroxy, alkoxy and amino, N-a cylamino, hydroxy, nitro, guanadine, substituted guanadine, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyl containing from 1 to 3 heteroamtoms, substituted cycloalkyl containing from 1 to 3 heteroatoms, halosgen, Cq-

C1qoaryl and su bstituted C4-C42aryl,

RY and R10 are independently hydrogen, cycloalkyl, cycloalkyl containing fron 1 to 3 heteroatoms, C4-C1oanyl, substituted cycloalkyl, substituted C4_C12aryl, alkyl or alkyl substituted with one or rmore substituents sezlected from the group consisting of: alkoxy, acy=loxy, . aryloxy, amino , N-acylamino, oxo, hydroxy, methylamine, dimeathylamino, hydroxyalkyl, -INR2R3, nitro, cyano, cycloalkyl, halogen, aryl amnd substituted aryl, or RY and R10 taken together with the nitrogen to which they =are attached represent a 5 £0 6 member saturated ring containing up to one other heteroatom sezlected from oxygen and nitrogen, where the ring is optionally subtituted with one or more substituents selected freom amino, : methylamino and dimethylamino, . where R2 and R3 are Independently hydrogen, alkyl, cycloalkyl,

C4.C12any, substituted alkyl, substituted cycloalkyl aned substituted C1.Cq2aryl; except 4-[1-Ethw-7-(piperidin-4-yloxy)-1 H-imidazo[4,5-c]pyridin—2-yl]- furazan-3-ylarmine and/or pharmaceutically acceptable salts, hydrates, solvates and pro-clirugs thereof.

R1 is selected from: alkyl, alkyl substituted with one or more substituents selected from the group consisting of: hydroxy, alkoxy, amino, N- acylamino, cyclopropyl and halogen, cylcoalkyl, cycloalkyl containing ~ from 1 to 3 heteroatoms and C4.Cq2aryl,

R4 is selected from hydrogen, halogen, alkyl, substituted alkyl, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms, Cq.Cq2aryl and C4.C42aryl substituted with ane or more substituents selected from the group consisting of: alkyl, substituted alkyl, alkoxy, acetamide, cyano, nitrile, urea, substituted urea, aryloxy, hydroxy, alkoxy, acyloxy, amino, N- acylamino, nitro, yano and halogen; and

R7 is hydrogen; and/or pharmaceutically acceptable salts, hydrates, solvates and pro-drugs thereof.

Included among th e presently invented compounds of Formula (1) are those + in which:

R1 is selected from: alkyl, alkyl substituted with one or more substituents selected from the group consisting of: hydroxy, alkoxy, amino, N- acylamino, cyciospropyl and halogen, cycloalkyl, cycloalkyl containing from 1 to 3 hetewoatoms and C4.Cq2anyl;

R4 is selected frorn alkyl, alkyl substituted with one or more substituents selected from the group consisting of: hydroxy, methoxy, ethoxy, amino,

N-acylamino, cyclopropyl and halogen, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms and C4.Cq2aryl; and

R7 is selected from -(CH2)nNROR10, -(CH2)nORS, -O-(CH2)mNRER10 and -N-(CH2)maNROR10, : where nis 0-2; mis 1-6, where the carbon chain formed by m is optionally substituted,

R8is alkyl, piperidine, piperidyl and pyrrolidinyl, each of which is optionally substituted with one or more substituents selected from the group consisting of: methoxy, ethoxy, acyloxy, aryloxy, amino, amino substituted withe one or more substituents selected from the group consisting of: hydroxy, alkoxy and amino, N—acylamino, hydroxy, nitro, cauanadine, substituted guanadine, cyano, cyecloalkyl, substituted cycloalkyl, cycloalkyl containing from 1 to 3 hmeteroatoms, substituted : : cycloalkyl containing from 1 to 3 heteroatomss, halogen, C4-C12aryl and substituted C4-Cq2amyl,

KRY and R10 are independently hydrogen, c=ycloalkyl, cycloalkyl «containing from 1 to 3 heteroatoms, C1-Ci=2anh, substituted cycloalkyl, substituted C41.Cq2aryl, alkyl or alkyl subst™ituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, rmethylamino, dimethylamino, hydroxyalkyl, nitro, cyano, cycloalkyl, halogen, aryl and substituted aryl; e xcept 4-[1-Ethyl-7-(piperidin-4-yloxy)-1 H-imicdazo[4,5-c]pyridin-2-yl]- {furazan-3-ylamine and/or p harmaceutically acceptable salts, hydrates, =solvates and pro-drugs thereof. ncluded among the presently invented compounds of Formula (111) are those in which: :

IR! is selected from: alkyl, alkyl substituted with one or more substituents selected from the group consisting of: hydroxy, alkoxy, amino, N- acylamino, cyclopropyl and halogen, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms and C4.Cq2aryl;

RY is selected from alkyl, alkyl substituted ~with one or more substituents selected from the group consisting of: hydliroxy, methoxy, ethoxy, amino, cyclopropyl and halogen, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms and C4.Cq2aryl;, and

R7 is selected from ~(CH2)nNROR10, -(CH2)nORS, -0-(CH2)NROR10 and -N-(CH2)mNROR10, , where nis 0-2; mis 1-8, where the carbon chain formed by m is optionally substituted,

R8 is alkyl, piperidine, piperidyl and pytrrolidinyl, each of which is optionally substituted with one or more substituents selected from the ’ group consisting of: alkoxy, acyloxy, aryloxy, amino, amino substituted with one or more substituents selected fr-om the group consisting of:

hydroxy, alkoxy and amino, hydroxy, nitro, guanadiline, substituted guanadine, cyano, cycloalkyl, substituted cycloalkyld, cycloalkyl containing from 1 to 3 heteroatoms, substituted cycloalkyl containing from1to 3 heteroatoms, halogen, C4-C42ayl and substituted C4-Cq2aryl,

RO and R10 are independently hydrogen, cycloali=yl, cycloalkyl containing from 1 to 3 heteroatoms, C4-Cq2amyl, ~substituted cycloalkyl, substituted C1.Cq2aryl, alkyl or alkyl! substituted with one or more substituents selected from the group consisting of = alkoxy, aryloxy, amino, oxo, hydroxy, methylamino, dimethylamino, hydroxyalkyl, nitro, cyano, cycloalkyl, halogen, C4-C42aryl and substituted C=4-Cq2aryl; except 4-[1 -Ethyl-7-(piperidin-4-yloxy)-1 H-imidazo[4é,5-c]pyridin-2-yl}- furazan-3-ylamine anci/or pharmaceutically acceptable salts, hydrates, solvates and pro-drugs thereof.

R1 is selected from: alkyl, alkyl substituted with osne or more substituents selected from the group consisting of: hydroxy, alkoxy, amino, N- acylamino, cyclopropyl and halogen, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms and C1.C1q2aryl;

R4 is selected from alkyl, alkyl substituted with osne or more substituents selected from the group consisting of: hydroxy, methoxy, ethoxy, amino, cyclopropyl and halogen, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms and C4.Cqaryl; and

Included among the presently invented compounds of Formula (1) are those i.n which:

R1 is selected from alkyl, alkyl substituted with one or more substituents selected from the group consisting of: hydroxy, alkoxy, amino, N-

Va 0 2005/011700 PCT/US2004/0243480) acylamino, cyclopropyl! and halogsen, cycloalkyl, cycloalkyl substituted with one or more substituents sellected from the group consisting of: hydroxy, alkoxy, amino, N-acylarmino and halogen, cycloalkyl containing from 1 to 3 heteroatoms, cycloalkyl containing from 1 to 3 heteroatoms 5s substituted with one or more substituents selected from the group consisting of: hydroxy, alkoxy, asmino, N-acylamino and halogen, Cq-

Coaryl and C4.Cq2anyl substituted with one or more substituents selected from the group consisti ng of: hydroxy, alkoxy, amino, N- acylamino and halogen;

R4 is selected from hydrogen, h alogen, alkyl, substituted alkyl, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms and a cyclic om polycyclic aromatic ring contain ing from 3 to 16 carbon atoms and optionally containing one or masre heteroatoms, provided that when the number of carbon atoms is 3 trae aromatic ring contains at least two heteroatoms and when the nurmnber of carbon atoms is 4 the aromatic rirg contains at least one heteroatosm, and optionally substituted with one or more substituents selected fromm the group consisting of: alkyl, substituteed alkyl, alkoxy, acetamide, cyano, nitrile, urea, substituted urea, any, substituted cycloalkyl, substituted aryl, aryloxy, oxo, hydroxy, alkoxy, cycloalkyl, acyloxy, amino, N-aacylamino, nitro, halogen, -C(O)OR2, -

C(O)NRSRE, -S(0)oNRSRE ard -S(0)nR?, ' where n is 0-2,

R2 is selected from hydrogerms, alkyl, cycloalkyl, C1-Cq2aryl, substitLated alkyl, substituted cycloalkyl amd substituted C4.C12aryl, and

RS and RE are independently hydrogen, cycloalkyl, C4-Cq2amyi, substituted cycloalkyl, substituted C4.Cqoaryl, alkyl or alkyl substitutead with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amirwo, N-acylamino, oxo, hydroxy, -C(O)ORZ=, -

S(O)nR2, -C(O)NR2R3, -S(O»),NR2R3, nitro, cyano, cycloalkyl, substituted cycloalkyl, haloge=n, aryl and substituted aryl, or R5 and RO taken together with the nitrogen to which they are attached represent a 5 to 6 member saaturated ring containing up to one other heteroatom selected from oxygen and nitrogen, where thering is’ optionally subtituted with one= or more substituents selected from amiro, methylamino and dimethylanciino,

where R2 and R3 are indeperdently hydrogen, alkyl, cycloalkyl, : C4-.Cq2anl, substituted alkyl, substituted cycloalkyl and substituted C4.Cq2aryl, and nis 0-2; and

RT is selected from -(CH2)nORS, —e0-(CHg)NROR10 and -N- (CHo)mNROR10, where nis 0-2, mis 1-6, where the carbon chain formed by m is optionally substituted,

R8 is alkyl substituted with one or~ more substituents selected from the group consisting of: alkoxy, acyloycy, aryloxy, amino, amino substituted with one or more substituents selected from the group consisting of: hydroxy, alkoxy and amino, N-aczylamino, oxo, hydroxy, -C(O)ORZ2, -

S(0)nR2, -C(O)NRZR3, -S(O)oNFR2R3, nitro, guanadine, substituted guanadine, cyano, cycloalkyl, cycloalkyl containing from 1to 3 heteroatoms, substituted cycloalkyl, substituted cycloalkyl containing from : 1 to 3 heteroatoms, halogen, aryl and substituted aryl, cycloalkyl and cycloalkyl containing from 1 to 3 heteroatoms, each of said cycloalkyl and = - “cycloalkyl containing from 1 to 3 eteroatoms is optionally substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylarmnino, oxo, hydroxy, -C(O)OR2, -S(O)nR2, : -C(O)NR2R3, -S(0)2NR2R3, nitro, cyano, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms, substitusted cycloalkyl, halogen, aryl and substituted aryl, where R2 and R3 are independently hydrogen, alkyl, cycloalkyl,

C1.Cq2aryl, substituted allyl, substituted cycloalkyl and substituted C4.Cq2aryl, and nis 0-2,

RY and R10 are independently Hydrogen, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatorms, C4-Cqoaryl, substituted cycloalkyl, substituted C4.C42aryl, alkylor alkyl substituted with one or more substituents selected from the gwroup consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxeo, hydroxy, methylamino, dimethylamino, hydroxyalkyl, -C(O)OR2, -S(O)n#R2, -C(O)NRZR3, -S(0)2NR2R3, -

NR2R3, nitro, cyano, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms, substituted cycloalkyl, halogen, aryl and substituted aryl, where R2 and R3 are independently hydrogen, alkyl, cycloalkyl,

C4.Cqzaryl, substituted all kyl, substituted cycloalkyl and substituted C4.C42aryl, armd nis 0-2; i, J except 4-1 -Ethyl-7-(piperidin-4-=yloxy)-1 H-imidazo[4,5-c]pyridin-2-yl}- furazan-3-ylamine ' and/or pharmaceutically acceptable sal ts, hydrates, solvates and pro-drugs therecf.

Included among the presently irwvented compounds of Formula (Il) are thosse in which: :

Ris selected from alkyl, alkysl substituted with one or more substituents selected from the group conssisting of: hydroxy, alkoxy, amino, N- acylamino, cyclopropyl and halogen, cycloalkyl, cycloalkyl substituted with one or more substituents selected from the group consisting of: hydroxy, alkoxy, amino, N-accylamino and halogen, cycloalkyl containingg from 1 to 3 heteroatoms, cyscloalkyl containing from 1to 3 heteroatoms= substituted with one or more= substituents selected from the group consisting of: hydroxy, alkoxy, amino, N-acylamino and halogen, C1.

Cqoaryl and C1.C4oaryl sullstituted with one or more substituents selected from the group con sisting of: hydroxy, alkoxy, amino, N- : acylamino and halogen;

R4% is selected from hydrogery, halogen, alkyl, substituted alkyl, cycloalkyl, cycloalkyl contai ning from 1 to 3 heteroatoms and a cyclic or polycyclic aromatic ring containing from 3 to 16 carbon atoms and optionally containing one or more heteroatoms, provided that when the= number of carbon atoms is 3 the aromatic ring contains at least two heteroatoms and when the number of carbon atoms is 4 the aromatic wing contains at least one heteroatom, and optionally substituted with one Or more substituents selected from the group consisting of: alkyl, substit_ted alkyl, alkoxy, acetamide, cy=ano, nitrile, urea, substituted urea, aryl, . substituted cycloalkyt, substituted aryl, aryloxy, oxo, hydroxy, alkoxy, cycloalkyl, acyloxy, amino, N-acylamino, nitro, halogen, -C(O)ORZ, -

C(O)NR5RS, -S(0)oNRSRS and -S(0)RZ, where nis 0-2,

R2 is selected from hydrogen, alkyl, cycloalkyl, C1-Cq saryl, substituted alkyl, substituted cycloalkyl and substituted C4.Cq2aryl, and

FR5 and RB are independently hydrogen, cycloalkyl, C4.C-12anl, ssubstituted cycloalkyl, substituted C4.Cq2aryl, alkyl or alkyl substituted with one or more substituents selected from the group cons=sisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy”, .C(O)OR2, -

SS(0)R2, -C(O)NR2R3, -S(0)oNR2R3, nitro, cyano, cycloalkyl, ssubstituted cycloalkyl, halogen, aryl and substituted aryl, : «or RS and RO taken together with the nitrogen to which they are attached representa 5to 6 member saturated ring containing up to» one other heteroatom selected from oxygen and nitrogen, where the ring is optionally subtituted with one or more substituents selected from amino, methylamino and dimethylamino, where R2 and R3 are independently hydrogen, alkyl, cycloalkyl,

C4.Cqoanyl, substituted alkyl, substituted cycloalkyl and substituted C1.Cq2aryl, and nis 0-2; and

FR7 is selected from -(CH2)nORS, -0-(CHp)mNROR10 anc -N- (CH2)mNRER10, : : where nis 0-2, : mis 1-6, where the carbon chain formed by m is option=ally substituted, :

R8 is alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, amino substituted with one or more substituents selected from the group consisting of: ’ hydroxy, alkoxy and amino, N-acyiamino, oxo, hydroxy. -C(O)OR2, -

S(O)nR2, _C(O)NR2R3, -S(0)oNR2R3, nitro, guanadine=, substituted guanadine, cyano, cycloalkyl, cycloalkyl containing from 1to3 heteroatoms, substituted cycloalkyl, substituted cycloalkyl containing from 1 to 3 heteroatoms, halogen, aryl and substituted aryl, cycloalkyl and cycloalkyl containing from 1 to 3 heteroatoms, each of s-aid cycloalkyl and cycloalkyl containing from 1to 3 heteroatoms is optiona lly substituted with one or more substituents selected from the group consissting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, -C( O)OR2, -S(O)R2, _C(O)NR2R3, -8(0)2NR2R3, nitro, cyano, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms, substituted cycloalkyl, haloger, aryl and substituted aryl, where R2 and R3 are independently hydrogen, alkyl, cycloalkyl,

C4.Cqoaryl, substituted alkyl, substituted cycloakkyl and substituted C4.C42aryl, and nis 0-2,

WY 0 2005/611700 PCT/US2004/024340

RO and R10 are independently hydrogen, cwcloalkyl, cycloalkyl containing from 1 to 3 heteroatoms, C4-Ci2-anl, substituted cycloalkyl, substituted C1_C42aryl, alkyl or alky! substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, rnethylamino, dimethylamino, hydroxyalkyl, -C(O)OR2, -S(O)nR2, -C(O)NFR2R3, -S(0)2NR2RS3, -

NR2R3, nitro, cyano, cycloalkyl, cycloalkyl c-ontaining from1to3 heteroatoms, substituted cycloalkyl, haloger, aryl and substituted aryl, where R2 and R3 are independently Fydrogen, alkyl, cycloalkyl,

C1.Cqoaryl, substituted alkyl, substit uted cycloalkyl and substituted C4.Cq2aryl, and nis 0-2; except 4-{1 -Ethyl-7-(piperidin-4-yloxy)-1 H-imisdiazo[4,5-clpyridin-2-yll- furazan-3-ylamine and/or pharmaceutically acceptable salts, hydrates, solvates and pro-drugs thereof.

Included among the presently invented compounds of Formula (1) are those in which: Co

R1 is selected from alkyl, alky! substituted wnith one or more substituents selected from the group consisting of: hydwoxy, alkoxy, amino, N- acylamino, cyclopropyl and halogen, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms and C4 .Cqoanyl;

R4 is selected from hydrogen, halogen, al kyl, substituted alkyl, cycloalkyl, cycloalkyl containing from 1to 3 heteroatoms, C4.Cq2aryl : and C4.Cqoaryl substituted with one or nore substituents selected from the group consisting of: alkyl, substituted -alkyl, alkoxy, acetamide, cyano, nitrile, urea, substituted urea, aryloxy, hyc3roxy, alkoxy, acyloxy, amino, N- acylamino, nitro and halogen; and

R7 is selected from ~(CH2)nOR8, -O-(CH2)mNRERS and -N- (CH2)mNRERS, where nis 0-2, . mis 1-6, where the carbon chain formed by m is optionally substituted,

R8 is alkyl substituted with one or more substituents selected from the group consisting of: cycloalkyl, cycloalkyl. containing from 1 to 3 heeteroatoms, substituted cycloalkyl, substituted c=ycloalkyl containing from 1 to 3 heteroatoms, aryl and substituted arvl,

R9is hydrogen, cycloalkyl, cycloalkyl containing from 1t03

Mmeteroatoms, C4.C42amyl, substituted cycloalky }, substituted C1.

CSqoaryl, alkyl or alkyl substituted with one or m ore substituents selected from the group consisting of: alkoxy, acyloxy, ary/loxy, amino, N- acylamino, oxo, hydroxy, methylamino, dimethyl=amino, hydroxyalkyl, -

C(O)ORZ, -S(O)nR2, -C(O)NRZR3, -S(0)NR2ER3, -NR2R3, nitro, cyano, cycloalkyl, cycloalkyl containing from 1 to 3 hete=roatoms, substituted «cycloalkyl, halogen, aryl and substituted aryl, where RZ and R3 are independently hydreogen, alkyl, cycloalkyl,

C4.Cqoamyl, substituted alkyl, substituted cycloalkyl and substituted C4_Cq2aryl, and nis 0-2; and/or prarmaceutically acceptable salts, hydrates, solvates and pro-drugs thereof. ‘Included among the presently invented compoun ds of Formula (11) are those in which: oo r= is selected from alkyl, alkyl substituted with one or more substituents selected from the group consisting of: hydroxy, alkoxy, amino, N- acylamino, cyclopropyl and halogen, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms and C{.C1 saryl; 4 is selected from hydrogen, halogen, alkyl, substituted alkyl, ) cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms, C4.Cq22ryl and C4.Cqzaryl substituted with one or more substituents selected from the group consisting of: alkyl, substituted alkyl , alkoxy, acetamide, cyano, nitrile, urea, substituted urea, aryloxy, hydroxy, alkoxy, acyloxy, amino, N- acylamino, nitro and halogen; and a7 is selected from <CH2)nORS, -O-(CH2)mMNIRBR? and -N- (CH2)mNRERS, where nis 0-2, . mis 1-8, where the carbon chain formed by m is optionally substituted,

R8 is alkyl substituted with one or more substituents selected from the group consisting of: cycloalkyl, cycloalkyl containing from 1to 3 heteroatoms, substituted cycloalkyl, substituted cycloalkyl containing from 1 to 3 heteroatoms, ary! and substituted amaryl,

ROis hydrogen, cycloalkyl, cycloalkyl containing from 1to3 heteroatoms, C1.Cq2aryl, substituted cycloalkyl, substituted C4.

Cqoaryl, alkyl or alkyl substituted with ome or more substituents selected from the group consisting of: alkoxy, acyL oxy, aryloxy, amino, N- acylamino, oxo, hydroxy, methylamino, d imethylamino, hydroxyalkyl, -

C(O)ORZ, -S(O)nR2, -C(O)NR2R3, -S(C3)NR2R3, -NR2RS3, nitro, cyano, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms, substituted cycloalkyl, halogen, aryl and substituted aryl, where R2 and R3 are independent ly hydrogen, alkyl, cycloalkyl,

C1.Cq2oaryl, substituted alkyl, substituted cycloalkyl and substituted C4.Cq2aryl, and nis O-2; and/or pharmaceutically acceptable salts, hydrates, solvates and pro-drugs thereof.

Included among the presently invented compounds of Formula (1) are those : in which: -.

R1 is selected from alkyl, alky! substituted with one or more substituents selected from the group consisting of: Ehydroxy, alkoxy, amino, N- acylamino, cyclopropyl and halogen, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms and C1.Cq2aaryl;

R4 is selected from hydrogen, halogen , alkyl, substituted alkyl, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms, C1.Cqyzanyi and C4.Cq2aryl substituted with one ©r more substituents selected from the group consisting of: alkyl, substituted alkyl, alkoxy, acetamide, cyano, nitrile, urea, substituted urea, aryloxy, hydroxy, alkoxy, acyloxy, amino, N- acylamino, nitro and halogen; and

RT is selected from ~(CHo)nORS, -O-( CH2)mNRERI and -N- (CH2)mNRSRS, where nis 0-2, mis 1-8, where the carbon chain formed by m is optionally substituted, to -29-

R8is alkyl substituted with one or more substituents selected from the group consisting of. piperidine, substituted piperidine, phenyl and, substituted phenyl,

RO is hydrogen, cycloalkyl, cycloalkyl containing from 1t0 3 heteroatoms, C4.Cq2aryl, substituted cycloalkyl, substituted C1.

Cqoaryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N- acylamino, 0X0, hydroxy, methy amino, dimethylamino, hydroxyalkyl, nitro, cyano, cycloalkyl, cycloalkyl cortaining from 1 to 3 heteroatoms, halogen and aryl; and/or pharmaceutically acceptable salts, hydrates, solvates and pro-drugs thereof¥.

Included among the presently inwented compounds of Formula (I) are those in which: : R1 is selected from alkyl, alkyl substituted with one or more substituents ’ selected from the group consisting of. hydroxy, alkoxy, amino, N- acylamino, cyclopropyl and halogen, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms and €1.Cq2aryl;

R4 is selected from hydrogen, halogen, alkyl, substituted alkyl, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms, C4.Cqoanyl and C4.Cq2aryl substituted with one or more substituents selected fronm the group consisting of: alkyl, substituted alkyl, alkoxy, acetamide, cyan+o, nitrile, urea, substituted urea, aryloxy, hydroxy, alkoxy, acyloxy, amino, IN- acylamino, nitro and halogens and

R7 is selected from -(CHp)nOIRS, -O-(CH2)NRBRI and -N- (CH2)MNRER®, where nis 0-2, mis 1-8, where the carbon chain formed by m is optionally substitutecd, : ‘R8 is alkyl substituted with one or more: substituents selected from the= group consisting of: piperidine, substituted piperidine, phenyl and, substituted phenyl, oo

RO is hydrogen, cycloalkyl, cycloalkyl containing from 1t0 3 heteroatoms, C1-Cq2ary!, substituted cycloalkyl, substituted C1-

Cq2paryl, alkyl or alkyl substituted “with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N- acylamino, oxo, hydroxy, methylamino, dimethylamino, hydroxyalkyl, nitro, cyano, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms, halogen and aryl; and/or pharmaceutically acceptable salts, h-ydrates, solvates and pro-drugs thereof.

Included among the novel compoun ds useful in the present invention are: 4-(4-Phenyl-1-piperidin-4-yl-1 H-imidliazo[4,5-clpyridin-2-yl)-furazan-3- ylamine; 4-14-(3-Chloro-phenyl)-1 -piperidin-4--yl-1 H-imidazo-{4,5-c]pyridin-2- yljfurazan-3-ylamine; 4-1 -(3-Amino-2,2-dimethylpropyi)-=1-(3-chlorophenyl)-1 H-imidazo[4,5- clpyridin-2-yl]-furazan-3-ylamine; 4-[1 ~(cyclopropylmethyl)-4-(2-methyylphenyl)-1 H-Imidazo[4,5-c]pyridin-2-yl}- 1,2,5-oxadiazol-3-amine; . 4-[4-(2-chlorophenyl)-1-(cycloprop/imethyl)-1 H-imidazol[4,5-clpyridin-2-y}- 1,2,5-oxadiazol-3-amine; 4-[1 -(3-Amino-2,2-dimethylpropyl)—4-phenyi-1 H-imidazo[4,5-c]pyridinyi-2-yll- furazan-3-ylamine; 4-[4-(3-chlorophenyi)-1 -(cyclopropyimethyl)-1 H-imidazol4,5-clpyridin-2-yi]- 1,2,5-oxadiazol-3-amine; 4-{4-chloro-1 ~(cyclopropylmethyl)-—1 H-imidazo[4,5-c]pyridin-2-yl}-1 ,2,5- oxadiazol-3-amine,; 4-{1-(cyclopropyimethyl)-4-(3-furaryl)-1 H-imidazo[4,5-c]pyridin-2-yi}-1 .2,5- oxadiazol-3-amine; 41 -(5-aminopentyl)-4-phenyl-1 H—imidazo[4,5-c]pyridin-2-yl}-1,2,5- oxadiazol-3-amine, 4-1 -(6-aminohexyl)-4-phenyl-1 H-&midazol[4,5-c]pyridin-2-yij-1 ,2,5-oxadiazol- 3-amine; 4-1 ~(5-aminopentyl)-4-(3-chloroplhenyl)-1 H-imidazo[4,5-c]pyridin-2-y1]-1 ,2,5- oxadiazol-3-amine; 41 -(8-aminohexyl)-4-(3-chloroptenyl)-1 H-imidazol4,5-clpyridin-2-yl}-1,2,5- oxadiazol-3-amine;

4-[1-(3-Amino-2,2-dimethyl propyl)-4-(3-methoxyphenyl)-1 H-imidazo[4,5- clpyridinyl-2-yl]-furazan-3-ylamine; 4-1 -(5-aminopentyl)-4-(3-thienyl)-1 H-imidazol4,5-c]pyridin-2-yl}-1 .2,5- oxadiazol-3-amine; 41 -(B-aminchexyl)-4-(3-thieryl)-1 H-imidazo[4,5-c]pyridin-2-yi}-1 .2,5- oxadiazol-3-amine; 4-[4-phenyi-1 -(3-piperidinyimethyl)-1 H-i midazo[4,5-clpyridin-2-yiI-1 2,5 oxadiazol-3-amine; 4-[4-(3-chlorophenyl)-1 -(3-piperidinylmethyl)-1 H-imidazo[4,5-clpyridin-2-y{}- 1,2,5-oxadiazol-3-amine; 4-[4-(4-chlorophenyl)-1 -(3-piperidinylmethyl)-1 H-imidazo[4,5-clpyridin-2-yi}- 1,2,56-oxadiazol-3-amine; 41 -(3-aminopropyl)-4-(2-thienyl)-1 H-imidazo[4,5-clpyridin-2-yi]-1,2,5- oxadiazol-3-amine; : 4-[1-(3-aminopropyl)-4~(1 -piperidinyl)-1 H-imidazo[4,5-cpyridin-2-yi}-1,2,5- oxadiazol-3-amine; 1-[2-(4-Aminofurazan-3-yl)-1 -ethyl-4-phenyl-1 -H-imidazo[4,5-c]pyridin-7-yl}- = 1-(3-aminopyrrolidin-1-yl)methanone; 2 1-[2-(4-Aminofurazan-3-yi)-1 -ethyl-4-thiophen-3-yl-1 -H-imidazo[4,5- - c]pyridin-7-yl}-1 -(3-aminopyrrolidin--1 -yl)methanone; 1-{2-(4-Aminofurazan-3-yl)-1 -ethyl-4-pyridin-yi-1 -H-imidazo[4,5-c]pyridin-7- yl]-1-(3-aminopyrrolidin-1 -yl)ymethanone, 1-[2-(4-Aminofurazan-3-yl)-1 -ethyl-4-pyridin-3-yl-1 -H-imidazo[4,5-c]pyridin- 7-yl}-1-(3-aminopyrrolidin-1-yl)meth anone, 1-[2-(4-Aminofurazan-3-y1)-1 -ethyl-4-furan-3-yl-1 -H-imidazo[4,5-c]pyridin-7- yl}-1-(3-aminopyrrolidin-1-yl)methanone; 1-{2-(4-Amino-furazan-3-yl)-4-chloro-1 -ethyl-1 -H-imidazo[4,5-c]pyridin-7-yi}- 1-(3-amino-pyrrolidin-1 -yl)-methanone; 1-{2-(4-Amino-furazan-3-yl) -4-(1H-pyrrol-2-yl))-1-ethy-1 -H-imidazo{4,5- c)pyridin-7-yl}-1 -(3-amino-pyrrolidin-1-yl}-methanons; 1-{2-(4-Amino-furazan-3-yl)-1 -ethyl-4-(2-methoxyphenyl)-1 H-imidazo[4,5- clpyridin-7-yl]-1 -(3-amino-pyrrolidin-1 -yl)-methanone; 1-[2~(4-Amino-furazan-3-yl) -1 -ethyl-4-(3-chloro-phenyl)-1 H-imidazo[4,5- clpyridin-7-yl}-1 -(3-amino-pyrrolidin-1-yl)-methanone;

1-{2-(4-Amino-furazan-3-y)-1 -ethyl-4-furan-2-yl-1 H-@midazo{4,5-clpyridin-7- yl]-1—~(3-amino-pyrrolidin-1 -yl)-methanone; 2-(4-Amino-furazan-3-yl)-1 -ethyl-4-phenyl-1 H-imida==o[4,5-c]pyridine-7- carbeoxylic acid [1 ~(4-chioro-benzyl)-2-hydroxy-ethyll-amide= 2-(4-Amino-furazan-3-yi)-1 —ethyl-4-(3-chloro-phenylD-1 H-imidazo[4.5- c)py-ridine-7-carboxylic acid [1-(4-chloro-benzyl)-2-hydroxy—ethyll-amide; 2-(4-Amino-furazan-3-yl)-1 —ethyl-4-(2,3-dichloro-phe=nyl)-1 H-imidazof4,5- clpywridine-7-carboxylic acid [1-(4-chloro-benzyl)-2-hydroxy—ethyll-amide; 2-(4-Amino-furazan-3-yl)-1 -ethyl-4-(2-chloro-phenyl)-1 H-imidazo[4,5- c)pwridine-7-carboxylic acid [1 -(4-chloro-benzyl)-2-hydroxy—ethyl}-amide; 2-(4-Amino-furazan-3-yi)-1 _ethyl-4-(2-hydroxy-phery)-1H-imidazo{4,5- clpwyridine-7-carboxylic acid [1 -{4-chioro-benzyl)-2-hydroxy-—ethyll-amide; 2-(4-Amino-furazan-3-yl)-4-(3-chloro-phenyl)-1 -ethTyl-1 H-imidazo{4,5- clp=yridine-7-carboxylic acid pyrrolidin-3-ylamide; 2-(4-Amino-furazan-3-yl)-4-phenyl-1 -gthyl-1 H-imid=azol4, 5-c]pyridine-7- carboxylic acid pyrrolidin-3-ylamide; 2-(4-Amino-furazan-3-yl)-4-(5-chloro-thiophen-2-yl:)-1 -ethyl-1 H-imidazo}4,5- c]p=yridine-7-carboxylic acid pyrrolidin-3-ylamide; 2-(4-Amino-furazan-3-yl)-4-(2-amino-phenyl)-1 -ethnyl-1H-imidazo(4,5- c]pwyridine-7-carboxylic acid pyrrolidin-3-ylamide; 2-(4-Amino-furazan-3-yl)-4-(3-amino-phenyl)-1 -ethyl-1H-imidazo[4,5- cl yridine-7-carboxylic acid pyrrolidin-3-ylamide; - 2-(4-Amino-furazan-3-yl)-4-(3-bromo-pheny})-1-etliyl-1H-imidazol4,5- clpoyridine-7-carboxylic acid pyrrolidin-3-ylamide; 2-(4-Amino-furazan-3-yl)-4-(1-haphthalenyl)-1-eth yk1H-imidazo[4,5- c]Pyridine-7-carboxylic acid pyrrolidin-3-ylamide; 2-(4-Amino-furazan-3-yl)-4-(thiophen-2-yl)-1-ethyl -1H-imidazo[4.5- c)poyridine-7-carboxylic acid pyrrolidin-3-ylamide; . 9-(4-Amino-furazan-3-yl)-4-(3,4-methylenedioxyptneny))-1-ethyl-1 H- immidazo[4,5-c]pyridine-7-carboxylic acid pyrrolidin-3-ylam .ide; 2-(4-Amino-furazan-3-yl)}-4-(3,5-dichloro-phenyl)-=1 -ethyl-1H-imidazo}4,5- clgoyridine-7-carboxylic acid pyrrolidin-3-ylamide; 4-{7-[(3-amino-1-pyrrolidinyl)carbonyl}-4-(3-chlorosphenyl)-1- (cyclopropylmethyl)-1 H-imidazol[4,5-clpyridin-2-yl}-1 ,2,5-coxadiazol-3-amine; 4-[7-[(3-amino-1 -pyrrolidinyl)carbonyl}-4-(4-biphemnylyl)-1 -ethyl-1H- invidazo[4,5-c]pyridin-2-yl}-1 ,2,5-oxadiazol-3-amine;

4-[7-{C 3-amino-1 _pyrrolidinyl)carbonyl]-4-(2,4-dllichioropheny!)-1 -ethyl-1H- imidazol[4,5-c=]pyridin-2-yl]-1 2,5-oxadiazol-3-amine; 4-[7-{«(3-amino-1 -pyrrolidiny)carbonyl}-1 -ethyl—4-(phenylethynyl)-1 H- imidazo[4,5-c=]pyridin-2-yi}-1 2,5-oxadiazol-3-amine; 2-{2-C4-amino-1 2 5-oxadiazol-3-yl)-7-{(3-amirmo-1 -pyrrolidinyl)carbonyl}-1- ethyl-1H-imici azol4,5-clpyridin-4-yi}phenol; 4-[7-E(3-amino-1 _pyrrolidinylicarbonyl}-4-(2-chalorophenyl)-1 -ethyl-1H- imidazo[4,5- cpyridin-2-yi}-1 ,2,5-oxadiazol-3-amine; (2-{2 -(4-amino-1 2,5-oxadiazol-3-yl)-7-{(3-am fino-1-pyrrolidinyl)carbonyl}-1 - ethyl-1H-imi dazo[4,5-clpyridin-4-yl}phenyl)methanol; 2-{2—(4-amino-1 '2,5-oxadiazol-3-yl)-7-[(3-amimnc-1-pyrrolidinyl)carbonyl]-1 - ethyl-1 H-imiidazo[4, 5-c]pyridin-4-yi}-4-chlorophenol, 4-(1 —ethyl-7-{[3-(methylamino)-1 -pyrrolidinyljcarbonyl}-4-phenyl-1 H- imidazo[4,5—c]pyridin-2-yl)-1 ,2,5-oxadiazol-3-amine; 47—[(3-amino-1 -pyrrolidinyl)carbonyl}-1 -ethy=l-4-(4-methylphenyl)-1 H- imidazo[4,5=-c}pyridin-2-yl}-1 ,2,5-oxadiazol-3-amine; . 4-[7—[(3-amino-1 -pyrrolidinyl)carbonyl}-4-(2,5 .—dichlorophenyl)-1-ethyl-1H- imidazo[4,5e-c]pyridin-2-yl--1 2,6-oxadiazol-3-amine; : . 4-[7"-{(3-amino-1-pyrrolidinyl)carbonyf}-4-(1 -enzothien-2-yl)-1-ethyl-1H- imidazo[4,5-c]pyridin-2-yi}-1,2 5-oxadiazol-3-amine; . 4-[1 —ethyl-4-phenyl-7-(4-piperidinyloxy)-1 H-immidazo[4,5-c]pyridin-2-yl]-1 2,5 oxadiazol-33-amine; : : : 4-{#-{(3-amino-1 -pyrrolidinyl)carbonyi]-1 -eth-yl-4-[4-(methyloxy)phenyi}-1 H- imidazo[4, S-c]pyridin-2-yi}-1 ,2,5-oxadiazol-3-amineg 4-{2-(4-amino-1 2,5-oxadiazol-3-yl)-7-[(3-anino-1 -pyrrolidinyl)carbonyl}-1- ethyi-1 H-irmnidazo4,5-c]pyridin-4-yl}phenol; 4-[oF {(3-amino-1 -pyrrolidinyl)carbonyl}-4-(4-echlorophenyl)-1 -ethyl-1H- imidazo[4,25-c]pyridin-2-yl}-1 ,2,5-oxadiazol-3-amine ; 4-[«AA~(3-chlorophenyt)-1 -ethyl-7~(4-piperidinywloxy)-1 H-imidazo[4,5-c]pyridin-2- yil-1,2,5-o0=xadiazol-3-amine; : 2-(~4-amino-1 2 5-oxadiazol-3-yl)}4-(3-chlorophenyl)-1 -(cyclopropyimethyl)-

N-{2-{(phe= nylmethyl)amino]ethyi}-1 H-imidazo[4,5-c=]pyridine-7-carboxamide; 3-{{2-(4-amino-1 ,2,5-oxadiazol-3-yl)-7-{(3-armino-1 -pyrrolidinyl)carbonyl]-1- ethyl-1 H-immidazof4,5-cpyridin-4-yl}phenol;

4-{2-(4-amino-1 2 5-oxadiazol-3-yi)-7-{(3-amino-1-pyrolidinyf)carbonyl}-1- ethyl-1 H-imidazol4,5-c]pyridin—4-yiYoenzonitrile; 1 -{2-(4-Amino-furazan-3-yl)-4-phenyl-1 -piperidin-dyl-1-H-imidazo[4,5- c)pyridin-7-yi}-1 -(3-amino-pyrrolidin-1 -yl)}-methanone; 4-(4-(3-chlorophenyl)-1 -ethyl-7<{[3-(methylamino)-1 -pyrrolidinyljcarbonyl}- 1H-imidazol4,5-clpyridin-2-yh)—1.2 ,5-oxadiazol-3-amine; 4-(4~(2,5-dichlorophermyl)-1 -ethyl-7-{[3-(methylamino)-1- pyrrolidinyljcarbonyl}-1H-imid 2az0[4,5-c]pyridin-2-yl)-1 ,2,5-oxadiazol-3-amine; 4-[4-(2,5-dichloropheryl)-1 -ethyl-7-(4-piperidinyloxy)-1 H-imidazo[4,5- c]pyridin-2-yl]-1 ,2,5-oxadiazo 1-3-amine; 2-(4-amino-1 2, 5-oxacliazol-3-y1)-4-(3-chlorophenyl)-1 -(cyclopropylmethyl)-

N-[3-(dimethylamino)propyl}- 1 H-imidazol4,5-c]pyridine-7-carboxamide; 4-[7-[(3-amino-1 -pyrrolidinyf)carbonyl}-1 -ethyl-4-(1H-pyrrol-2-yl)-1H- imidazo[4,5-c]pyridin-2-yi}-1, 2 5-oxadiazol-3-amine; 4-[7-{(3-amino-1 -pyrrolidinyl)carbonyl]-4-(4-bromopheny!)-1 ~ethyl-1H- imidazo[4,5-c]pyridin-2-yi]-1 2 5-oxadiazol-3-amine; 4-[7{(3-amino-1 -pyrrolidinyl)carbonyl}-4-phenyl-1 -(4-piperidinyl)-1H- imidazo[4,5-c]pyridin-2-yl}-1 ,2.5-oxadiazol-3-amine; : : 4-{7-[(4-aminobuty)oxy]-1 -ethyl-4-phenyl-1 H-imidazo[4,5-c]pyridin-2-yl}- 1,2,5-oxadiazol-3-amine; } 4-{1 -ethyl-4-phenyl-Z-{(4-piperidinyimethyl)oxy]-1 H-imidazo[4,5-c]pyridin-2- yl}-1,2,5-oxadiazol-3-amine ; 4-{4-(3-chloropheny 1)-1 -ethy!-7-[(4-piperidinylmethyloxy]-1 H-imidazo[4,5- clpyridin-2-yl}-1,2,5-oxadia=ol-3-amine; 4-[7-[(4-aminobutyl) oxy]-4-(3-chlorophenyl)-1 -ethyl-1H-imidazo[4,5- clpyridin-2-yl}-1 ,2,5-oxadia=zol-3-amine; 4-{7-{(2-aminoethyDoxy}-1 -ethyl-4-phenyl-1 H-imidazo[4,5~c]pyridin-2-yl}- 1,2,5-oxadiazol-3-amine; 4{1 -ethyl-4-phenyl—7-{(3-pyrrolidinylmethyl)oxy]-1 H-imidazo[4,5-c]pyridin-2- yi}-1,2,5-oxadiazol-3-amines; 4-{7-{(3-aminoprop-yljoxy}-1 -ethyl-4-phenyl-1 H-imidazo[4,5-c]pyridin-2-yl}- 1,2,5-oxadiazol-3-amine; 4-(741(28)-2-amino>-3-phenylpropylloxy}-1-ethyl-4-phenyh-1 H-imidazo[4,5- c]pyridin-2-yl)-1 ,2,5-oxadiaazol-3-amine; 4-1 -ethyl-4-phenyl-7-(3-piperidinyloxy)-1 H-imidazo[4,5-c)pyridin-2-yl}-1,2,5- oxadiazol-3-amine;

2-(4-amino-1,2,5-oxadiazo (-3-yi)-1 -ethyl-N-methyl-N-(1 -methyl-4- piperidinyl)-4-phenyl-1 H-imidazol4,5-c]pyridine-7-carboxamide;

N-{[2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1 -ethyl-4-phenyl-1 H-imidazo[4,5- clpyridin-7-ylJmethyl}-N.1 -dimethyl-4-piperidinamine; 4-(1 _ethyl-4-phenyl-7-{[2-(4-pipesridinyDethyljoxy}-1 H-imidazo[4,5-clpyridin-2- yh)-1 ,2,5-oxadiazol-3-amine; 4-{1 -(4-aminobutyl)-7-[(3-amino-1 -pyrrolidinyl)carbonyi}-4-phenyh-1 H- imidazo[4,5-clpyridin-2-yi}-1,2, 5-oxadiaazol-3-amine; 4-(7 {[(2R)-2-amino-3-phenylpr-opyljoxy}-1 -ethyl-4-phenyl-1 H-imidazo[4,5- clpyridin-2-y1)-1,2,6-oxadiazol-3-amine; 4-{1 -(4-aminobutyl)-7-{(3-amin«©-1 -pyrrolidinyl)carbonyl}-4-phenyl-1 H- imidazo[4,5-clpyridin-2-yi}-1 ,2,5-oxadi azol-3-amine; 4-(1 _(4-aminobutyl)-7-{[3-(metlhylamino)-1-pymolidinyljcarbonyl}-4-phenyi- 1H-imidazo[4,5-c)pyridin-2-yl)-1 ,2,5-oxadiazol-3-amine; 4-{1-ethyl-7-{(4-methyl-1-piper-aziny)methyl}-4-phenyl-1 H-imidazo[4,5- - ¢]pyridin-2-yl}-1 ,2,5-oxadiazol-3-amin €; : : 4-(1 _ethyl-7-{3-(methylamino)-1-pyrrolidinyljmethyl}4-pheny}-1 H- : - imidazo[4,5-c]pyridin-2-yl)-1 ,2,5-oxadliazol-3-amine; Cc (3-amino-2,2-dimethylpropyl){_[2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethy-4- phenyH-1 H-imidazo[4,5-c]pyridin-7-yl] methyl}amine; 4-(7-4{[3-(dimethylamino)-1 -py rrolidinylimethyl}-1 -ethyl-4-phenyl-1H- imidazo[4,5-c]pyridin-2-yl)-1 ,2,5-oxacliazol-3-amine; : 4-1 -ethyl-7-{[2-(methylamince)ethylloxy}-4-phenyl-1 H-imidazo[4,5~c]pyridin— 2-yl)-1,2,5-oxadiazol-3-amine; 4{1-ethyl-4-phenyl-7-({2-{(phaenyimethyl)amincjethyl}oxy)-1 H-imidazo{4,5- c]pyridin-2-yl]-1 ,2,5-oxadiazol-3-amime; 4-1 -ethyl-4-phenyl-7-[(3-pipesridinyimethyl)oxy}-1 H-imidazo[4,5-c]pyridin-2— yi ,2,5-oxadiazol-3-amine; . 4-{7-[(5-aminopentyl)oxy]-1 -othyl-4-phenyl-1 H-imidazo[4,5-c]pyridin-2-yi}- 1,2,5-oxadiazol-3-amine; 4-(7-{[3-(dimethylamino)-2,2 -dimethylpropylloxy}-1 -ethyl-4-phenyl-1H- imidazo[4,5-c)pyridin-2-yl)-1,2, 5-oxadiazol-3-amine; 1-(4-aminobutyl)-2-(4-aminos-1 2,5-oxadiazol-3-yl)-4-phenyl-N-{2- [(phenyimethyl)aminolethyi}-1 H-imicdazoj4,5-c]pyridine-7-carboxamide; 2-(4-amino-1,2,5-oxadiazol-3-yl)-1-(1 -methylethyl)-4-phenyl-N-3-pyrrolidin=yl- 1H-imidazo[4,5-c}pyridine-7-carbox amide;

4-{74[3-(methylamino)-1-pyrrolidinyllcarbonye{}-1-(1-methylethyl)-4-phenyl . {H-imidazo[4,5-c]pyridin-2-yl}-1 2,5-oxadiazol-3-amiline; 4-(7-{[(3S)-3-amino-1 -pyrrolidinyljmethyl}-1 -esthyl-4-phenyl-1 H-imidazo[4,5- clpyridin-2-y)-1,2, 5-oxadiazol-3-amine; 4-[1 -ethyl-7-(hexahydro-1 H-1,4-diazepin-1 -ywimethyl)-4-phenyl-1 H- imidazo[4,5-clpyridin-2-yl]-1 ,2,5-oxadiazol-3-aminez 4-{1-ethyl-4-phenyl-7-(1 -piperazinyimethyl)- 1 H-imidazo[4,5-clpyridin-2-yi]- 1,2,5-oxadiazol-3-amine; 4-(7-{[2-(dimethylamino)ethyljoxy}-1 -ethy|-48-phenyl-1 H-imidazo[4,5- c]pyridin-2-yi)-1 ,2,5-oxadiazol-3-amine; 4-(1 _ethyl-4-phenyl-7-{{(2S)-2-pyrrolidinylm wethylloxy}-1 H-imidazo[4,5- c]pyridin-2-yi)-1 ,2,5-oxadiazol-3-amine; 4-(1 _ethyl-4-phenyl-7-{[(2R)-2-pyrrolidinyimmethyljoxy}-1 H-imidazo[4,5- c]pyridin-2-yi)-1 ,2,5-oxadiazol-3-amine; 2-(4-amino-1 2,6-oxadiazol-3-yl)-N-(3-amiropropyl)-1-(1 -methylethyl)-4- phenyl-1 H-imidazo[4,5-clpyridine-7-carboxamide; : 2-(4-amino-1,2, 5-oxadiazol-3-yl)-1 -(1-metinylethyl)-4-phenyl-N-2-propen-1 - yl-1H-imidazof4,5-c]pyridine-7-carboxamide; . 2-(4-amino-1 2,5-oxadiazol-3-yl)-1-ethyl-N —{3-(4-morpholinyl)propyi}-4- phenyl-1 H-imidazo[4,5-c]pyridine-7-carboxamide; : 2-(4-amino-1,2,5-oxadiazol-3-yI)-1 -ethyl-NE-[2-(1 H-imidazol-4-yl)ethyl]-4- phenyl-1 H-imidazo[4,5-c}pyridine-7-carboxamide 5 : 2-(4-amino-1 ,2,5-oxadiazol-3-yi)-1 -ethyl-N1-{3-(4-methyl-1- : piperazinyl)propyll-4-phenyl-1 H-imidazo[4,5-c]pymridine-7-carboxamide; 4-[7-[(3-aminopropyfoxy]-4-(2-chloropheryi)-1 -ethyl-1H-imidazo[4,5- clpyridin-2-yl}-1 ,2,5-oxadiazol-3-amine; 4-[7-{(3-aminopropyloxy]-4-(3-chioropheryl)-1-ethyl-1 H-imidazo[4,5- cJpyridin-2-yi}-1 ,2,5-oxadiazol-3-amine; 4-[7-{(3-aminopropyl)oxy]-4-(4-chiorophemnyl)-1 -ethyl-1H-imidazo{4,5- 30» clpyridin-2-yl}-1,2,5-oxadiazol-3-amine; 4-{7-](3-aminopropyl)oxyl-4-[5-chloro-2-(mmethyloxy)phenyl]-1 -ethyl-1H- imidazo[4,5-c]pyridin-2-yl}-1 2, 5-oxadiazol-3-am@ine;

N-(1-{[2-(4-amino-1 ,2,5-oxadiazol-3-y1)-1 -ethyl-4-phenyl-1H-imidazof4,5- clpyridin-7-yljcarbonyl}-3-pyrrolidinyl)-N-methyla _cetamide; 2-(4-amino-1 2 5-oxadiazol-3-yl)-N-[3-(di: methylamino)propyl}-1-ethyi-4- phenyl-1 H-imidazo[4,5-c]pyridine-7-carboxamide=;

2-{2-(4-amino-1 2,5-oxadiazol-3-w)-7-{(3-aminopropyloxy]-1 -ethyl-1H- imidazo{4,5-clpyridin-4-yl}-4-chlorophencl; 4-{7-{(3-aminopropyl)oxy]-1 -ethyk-4-(2-pyridinyl)-1 H-imidazo[4,5-c]pyridin-2- yl}-1,2,5-oxadiazol-3-amine; 4-(7-{13-{dimethylamino)propyljoxy}-1-ethyl-4-phenyl-1H-imidazol4,5- c]pyridin-2-yl)-1 2 5-oxadiazol-3-amine; 4-(1 ethyl-74{[3-(4-morpholinyl)p Topylloxy}-4-phenyl-1 H-imidazo[4,5- clpyridin-2-yi)-1 ,2,5-oxadiazol-3-amine; , 2-(4-amino-1 ,2,5-oxadiazol-3-ylp-1 —cyclopentyl-4-phenyl-N-3-pyrrolidinyl-1 H- imidazo[4,5-clpyridine-7-carboxamide; 4-{7-[(3-amino-1 -pyrrolidinyl)car-bonyl}-1 -cyclopentyl-4-pheny-1 H- imidazo[4,5-clpyridin-2-yl}-1 ,2,5-oxadia zol-3-amine; 4-(1 -cyclopentyl-7-{[3-(methylarmino)-1 -pyrrolidinyljcarbonyl}-4-phenyl-1 H- imidazo[4,5-clpyridin-2-yi)-1 ,2,5-oxadiaazol-3-amine; 15 . 4(1 —ethy}-7-{[3-(methylamino)p-ropyljoxy}-4-phenyl-1 H-imidazo{4,5-c]pyridin- 2-yl}-1,2,5-oxadiazol-3-amine; 4{1 ~ethyl-7-[(3-hydrazinopropyT)oxy]-4-phenyl-1 H-imidazo[4,5-c]pyridin-2- yi}-1,2,5-oxadiazol-3-amine; . oo 2-{(3-{[2-(4-amino-1,2,5-oxadia. zol-3-y!)-1-ethyl-4-phenyl-1 H-imidazo[4,5- c]pyridin-7-ylloxy}propyl)aminolethano-}; _ ’ 4-(1 —ethyl-74{[3-(hydroxyaminoJpropyljoxy}-4-phenyl-1 H-imidazo[4,5- : clpyridin-2-yl)-1 ,2,5-oxadiazol-3-amine; } (3R)-1{[2-(4-amino-1 ,2,5-oxac3iazol-3-yl)-1 -ethyl-4-phenyl-1H-imidazo[4,5- clpyridin-7-ylJcarbonyl}-3-pyrrolidinol; 2-(4-amino-1 2,5-oxadiazol-3-wl)-N-{3-(diethylamino)propyll-1 -ethyl-4- phenyl-1 H-imidazo[4,5-c]pyridine-7-carboxamide; 2-(4-amino-1,2,5-oxadiazol-3-wl)-1 -ethyl-N-[3-(2-methy!-1 -piperidinyl)propyll- 4-phenyl-1 H-imidazo[4,5-c]pyridine-7—carboxamide; 4-(1-methyl-7-{[3-(methylamin«)-1 -pyrrolidinyl]carbonyt}-4-phenyl-1 H- imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxad ¥azol-3-amine; 4-{7-[(3-amino-1 -pyrrolidinyl)czarbonyl}-1 -methyl-4-phenyl-1H-imidazo[4,5- c]pyridin-2-yi}-1 ,2,5-oxadiazol-3-amin €; 4-(1-butyl-7-{[3-(methylamino)»-1 -pyrrolidinyljcarbonyl}-4-phenyl-1 H- imidazo[4,5-c]pyridin-2-yl)-1 ,2,5-oxadliazol-3-amine; 4-{7-[(3-amino-1 -pyrrolidinyl)c=arbonyl]-1 -butyl-4-phenyl-1H-imidazo[4,5- c]pyridin-2-yl}-1,2,5-oxadiazol-3-amirme;

4-[7-[(3-amino-1 -pyrrolidinyl)carbonyl]-1 -(4-fluorophenyl)-4-phenyk-1 H- imidazol(4,5-cJpyridin-2-yl}- 2, 5-oxadiazol-3-amine;

N-(2-aminoethyl)-2- (4-amino-1 ,2,5-oxadiazol-3-yl)-1 -(4-fluorophenyl)-4- phenyl-1 H-imidazo[4,5-c]pwridine-7-carboxamide; 4-{1 -(4-aminophenyy!)-7-[(3-amino-1 —pyrrolidinyl)carbonyl]-4-phenyl-1 H- imidazo[4,5-c}pyridin-2-yi}—1 2,5-oxadiazol-3-amine; 1-{[2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1 -ethyl-4-phenyl-1 H-imidazo[4,5- cJpyridin-7-yljoxy}-3-(4-mo rpholinyl)-2-propanaf;

N-[2-(4-amino-1 ,2,55-oxadiazol-3-y!)-1 -ethyi-4-pheny!-1 H-imidazo[4,5- clpyridin-7-yl}-4-piperidine carboxamide; 4-[7-{[3-(dimethyla mino)-1 -pyrrolidinyijcarbonyi}-4-phenyl-1 -(2,2,2- trifluoroethyl)-1 H-imidazo[[4,5-c]pyridin-2-yl}-1 2 5-oxadiazol-3-amine; 4-1 —ethyl-7-{[2-(4—morpholinyl)ethyljoxy}-4-phenyl-1 H-imidazo[4,5-clpyri din- 2-yh-1 ,2,5-oxadiazol-3-annine; 4-(1 -ethyl-4-phenyi-7-{[3-(1 -piperidinyhpropyfjoxy}-1 H-imidazo[4,5-c]pyriidin- 2-yh-1 ,2,5-oxadiazol-3-armine trifluoroacetate; 2-(4-amino-1 ,2,5-©xadiazol-3-yl)-1 -ethyl-N-[2-(1 -methyl-2-pyrrolidinyl)etihyl}- oo 4-phenyl-1 H-imidazo[4,5—c]pyridine-7-carboxamide; ) : 1-(1-{[2-(4-amino—1 2,5-oxadiazol-3-yi)-1 -ethyl-4-phenyl-1 H-imidazo[4,5 - clpyridin-7-yllcarbonyl}-4—piperidiny)-1,3-dihydro-2H-benzimidazol-2-one; 1-{[2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1 -ethyl-4-phenyl-1 H-imidazol4,5- c]pyridin-7-yllcarbonyl}-3—piperidinecarboxamide; (2-aminoethyl)(2-{[2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1 -ethyl-4-phenyl-1H4- imidazo[4,5-c]pyridin-7-y" ljoxy}ethyl)amine; 4-(1-ethyl-4-pheruwyl-7-{[2-(1 -piperazinyl)ethylloxy}-1 H-imidazo[4,5-c]pyr-idin- 2-yi)-1 ,2,5-oxadiazol-3-a mine; 4-(7-{[2-(4-acetyl -1-piperazinyl)ethyljoxy}-1 -ethyl-4-phenyl-1H-imidazo[-4,5- clpyridin-2-yl)-1 ,2,5-oxacliazof-3-amine trifluoroacetate; 4-(1-ethyl-7-{[3-(=4-methyl-1 -piperazinyl) propyljoxy}-4-phenyl-1H- imidazo[4,5-clpyridin-2-wi)-1 ,2,5-oxadiazol-3-amine; : 4-(1-ethyl-4-pheryl-7-{3-(1 -piperazinyf)propylloxy}-1 H-imidazof4,5-c]p=yridin- 2-yh)-1 ,2,5-oxadiazol-3-amine; 4-(1 _ethyl-4-phemyl-7-{[2-(1-piperidinylethyiloxy}-1 H-imidazo[4,5-c]pyr-idin-2- yl)-1,2,5-oxadiazol-3-anmine trifluoroacetate; (3[2-(4-amino-—1 ,2,5-oxadiazol-3-yl)-1 -ethyl-4-phenyl-1H-imidazo[4,5— clpyridin-7-ylloxy}propyB)[2-(dimethylamino)ethyljmethylamine;

3-{(3-{[2- (4-amino-1 ,2,5-oxadiazol-3-yl)-1 -ethyl-4-phenyi-1 H-imiciazo[4,5- c]pyridin-7-ylJoxsy}propyl)amino}-1 ,2-propanediol;

N-(3-amiino-2-hydroxypropyl)-2-(4-amino-1 2,5-oxadiazol-3-y!)- 8 -ethyl-4- phenyi-1 H-imideazof4,5-c]pyridine-7-carboxamide;

N-(2-am ino-3-hydroxypropyl)-2-(4-amino-1 2,5-oxadiazol-3-yl)-1 -ethyl-4- phenyi-1 H-imidaazo[4,5-c]pyridine-7-carboxamide; ‘

N-(3-{2—(4-amino-1 2 5-oxadiazol-3-yl)-7-{(3-aminopropyloxyl-1 -athyl-1H- imidazo[4,5-clpeyridin-4-ylipheny)-N'-phenylurea; 3-{[2-(4—~amino-1 ,2,5-oxadiazol-3-yl)-1 -ethyl-4-phenyl-1H-imida=0[4.5- clpyridin-7-yljoxy}-1-propanc; (4-{[2-(=-amino-1 2,5-oxadiazol-3-yl)-1 -ethyl-4-phenyl-1 H-imidazo[4.5- clpyridin-7-yl]c arbony!}-2-piperazinyl)methanol; 4-1 -ethy-7-({3-[(methyloxy)methyll-1 -piperazinyl}carbonyl)-4-wphenyl-1 H- imidazo[4,5-c]goyridin-2-yi}-1 ,2,5-oxadiazol-3-amine; 4-7 B-({[2.4-bis(methyloxy)phenyllmethyljamino)propylloxy}—1-ethyl-4- phenyl-1 H-imi«dazo[4,5-clpyridin-2-yl)-1 ,2,5-oxadiazol-3-amine; : (2S)-2—](3~{[2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1 -ethyl-4-phenyl—1H- imidazol4,5-cRpyridin-7-ylloxy}propyl)amino}-4-methyl-1 -pentanol; diethyl 1-[2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1 -ethyl-7-hydroxy—=4-phenyl-1 H- : imidazof4,5-cJpyridin-6-yl]-1,2-hydrazinedicarboxylate; and 4-(2-(«4-amino-1 ,2,5-oxadiazol-3-yl)-1 -ethyl-7{[3-({2-4- (methyloxy)pEnenyljethyltamino)propyiloxy}-1 H-imidazo[4,5-c]pyridin—4-yl)-2-methyl- 3-butyn-2-ol; and/or pharmaceutically acceptable salts, hydrates, solvates and preo-drugs thereof.

Compounds of Formula (1) are included in the pharmaceutical compositions of the invention and used in the methods of the invention. The comapound 4-[1-

Ethyl-7-(pipe=ridin-4-yloxy)-1 H-imidazo[4,5-clpyridin-2-yl]-furazan-3-wlamine is also included in tine methods of the invention.

By thme term "protected hydroxy" or “protected -OH" as used herein, is meant the alcoholics or carboxylic-OH groups which can be protected by conventional blocking gro=ups in the art such as described in "Protective Groups In Organic

Synthesis" by Theodora W. Greene, Wiley-Interscience, 1981, Nevv York.

Compoundss containing protected hydroxy groups may also be use¥ul as intermediates in the preparation of the pharmaceutically activee compounds of the invention.

By the term "aryl" as used herein, unless otherwise defined, is meant a cyclic or p-olycyclic aromatic ring containing from 1 to 14 carbeon atoms and optionally containing from one to five heteroatoms, provided that when the number of carbon atoms is 1 the aromatic ring contains at least four theteroatoms, when the number of carbon atoms is 2 the aromatic ring contains at le-ast three heteroatoms, when the number of carbons is 3 the aromatic ring contains at least two heteroatcams and when the number of carbon atoms is 4 thes aromatic ring contains at least osne heteroatom.

By the term "C4-Cq2aryl" as used herein, unless otherwise defined, is meant pienyl, naphthalene, 3,4-methylenedioxyphenyl, pyridine, biphenyl, . quinoline, pyrimidine, quinazoline, thiophene, furan, pyrrole, pyrazole, imidazole, indole, imdene, pyrazine, 1,3-dihydro-2H-benzimidazol, ben=zothiohpene and tetrazole=.

T he term "substituted" as used herein, unless otherwise defined, is meant that the subject chemical moiety has one or more substitue=nts selected from the . group consisting of: -CO2R20, aryl, -C(O)NHS(0)2R20, -NBHS(0)2R20, hydroxy alky!, alkoxy, -C(O)NR21 R22, acyloxy, alkyl, amince, methylamino, nitrile, : acetamiide, urea, alkylurea, benzoate, sulfonamide, benzozateurea, alkoxya lkylamide, alkoxyC4-Cq2aryl, triphenylalkyl, cyclohexyl, C4q-

CqoaryBalkylurea, C4 -C42aryl, haloC1-Cq aryl, dimethylarmino, N-acylamino, hydroxy, -(CH2)gC(O)OR?3, -8(0)R23, nitro, tetrazole, cyano, oxo, halogen and trifluorosmethyl, where g is 0-6, R23 is hydrogen or alkyl, R220 is selected form hydrogen, C1-Caalkyl, aryl and trifluoromethyl, and R21 amd R22 are independently selecte-d form hydrogen, C4-C4alkyl, aryl and trifluorometinyl, and n is 0-2.

By the term "alkoxy" as used herein is meant -Oallkyi where alkyl is as described herein including -OCH3 and -OC(CH3)2CH3.

The term "cycloalkyl™ as used herein unless othenwise defined, is meant a nonarcmatic, unsaturated or saturated, cyclic or polycyclic C3-C42-

Examples of cycloalkyl and substituted cycloalkyl substituents as used herein include: cyclohexyl, 4-hydroxy-cyclohexyl, 2-ethylecyciohexyl, propyl 4- metho xycyclohexyl, 4-methoxycyclohexyl, 4-carboxycyciohexyl, cyclopropyl and cyclopentyl.

The term "cycloalkyl containing from 1 to 4 heteroatoms” and the term "eyclo alkyl containing from 1to 3 heteroatoms" as used Enerein unless otherwise

W= 0 2005/011700 PCT/US2004/024340 defined, is meant a nonaromatic, unsaturated or satura ted, cyclic or polycyclic ring containing from 1 to 12 carbons and containing from ore to four heteroatoms or from one to three heteroatoms (respectively), provided that when the number of carbon atoms is 1 the aromatic ring contains at least four heteroatoms (applicable only where "cycloalkyl containing from 1 to 4 heteroatosms" is indicated), when the number of carbon atoms is 2 the aromatic ring contain-s at least three heteroatoms, when the number of carbon atoms is 3 the nonaromatiiic ring contains at least two heteroatoms and when the number of carbon atoms iss 4 the nonaromatic ring contains at least one heteroatom.

Examples of cycloalkyl containing from 1 to 4 Feteroatoms, cycloalkyl containing from 1 to 3 heteroatoms, substituted cycloalkyl containing from 1to 4 heteroatoms and substituted cycloalkyl containing fromm 1 to 3 heteroatoms as used herein include: piperidyl, piperidine, pyrrolidine, 3-metchylaminopyrrolidine, piperazinly, tetrazole, hexahydrodiazepine and morpholine.

By the term "acyloxy" as used herein is meant -OC(O)alky! where alkyl is as described herein. Examples of acyloxy substituents aas used herein include: - . OC(O)CHa, -OC(Q)CH(CH3)2 and -OC(O)(CH2)3CHl3.

By the term "N-acylamino" as used herein is rneant -N(H)C(O)alkyl, where : . alkyl is as described herein. Examples of N-acylamimo substituents as used herein - : 200 include: -N(H)C(O)CH3, -N(H)C(O)CH(CH3)2 and -BN(H)C(O)(CH2)3CHa.

By the term "aryloxy" as used herein is mean t -Oaryl where aryl is phenyl, - naphthyl, 3,4-methylenedioxyphenyl, pyridyl or biphe=nyl optionally substituted with one or more substituents selected from the group consisting of: alkyl, hydroxyatkyl, alkoxy, trifuloromethyl, acyloxy, amino, N-acylamino., hydroxy, ~(CH2)gC(O)ORZ5, - $(0),R25, nitro, cyano, halogen and protected -OH , where g Is 0-6, R25 is hydrogen or alkyl, and n is 0-2. Examples of aryloxyy substituents as used herein include: phenoxy, 4-fluorophenyloxy and biphenyloxCy. :

By the term "heteroatom" as used herein is rmeant oxygen, nitrogen or sulfur.

By the term "halogen" as used herein is meaant a substituent selected from bromide, iodide, chloride and fluoride.

By the term "alkyl" and derivatives thereof a nd in all carbon chains as used ' herein, including alkyl chains defined by the term “_ (CHo)p", “~(CH2)m" and the like, is meant a linear or branched, saturated or unsaturated hydrocarbon chain, and =35 unless otherwise defined, the carbon chain will contain from 1 to 12 carbon atoms.

Examples of alkyl and substituted alkyl substituents as used herein include: -CH3, -

CH2-CHag, -CHy-CHp-CHl3, -CH(CHa3)2, “CHy-CH2-C(CH3)3, -CHp—CF3, -C=C-

C(CHa3)3, -C=EC-CH2-OH , cyclopropylmethyl, -CHo-C(CH3)2-CHa-IIH2, -C=C-

CgHs. -C=C-C(CH3)2-OH, _CHo-CH(OH)-CH(OH)-CH(OH)-CH(O)-CHz-OH, piperidinylmethyl, methoxxyphenylethyl, -C(CH3)3, -(CH2)3-CHg, -C-Hp-CH(CH3)2, -CH(CHg)-CH2-CH3, -ChH=CHy, and -C=C-CH3.

By the term "treating" and derivatives thereof as used hereim, is meant prophylatic and therapeutic therapy.

All publications, i ncluding but not limited to patents and pateent applications, cited in this specificatior are herein incorporated by reference as tihough fully set forth,

As used herein, “the term "effective amount” and derivativess thereof means that amount of a drug o ¥ pharmaceutical agent that will glicit the bllological or medical response of a tissue, system, animal or human that is bei ng sought, for instance, by a research er or clinician. Furthermore, the term “themrapeutically effective amount” and clerivatives thereof means any amount which, as compared to a corresponding sub. ject who has not received such amount, re=suits in improved treatment, healing, prewention, or amelioration of a disease, disorder, or side effect, . or a decrease in the rate of advancement of a disease or disordemr. The term also includes within its scopse amounts effective to enhance normal phaysiological : : : 20 function. ;

Compounds of Formula (i) are included in the pharmaceuwntical compositions _ of the invention and ussed in the methods of the invention. Where2 a -COOH or -OH group is present, pharsmaceutically acceptable esters can be employed, for example methyl, ethyl, pivaloyloxymethyl, and the like for -COOH, and acetate maleate and the like for -OH, and those esters known in the art For modifying solubility or hydrolysis characteristics, for use as sustained relea_se or prodrug formulations.

The novel compounds of Formulas |, Il, Ili and IV are pre=pared as shown in

Schemes 1 to 13 belosw, or by analogous methods, wherein the Het and R substituents are as dexfined in Formulas |, iI, Ill and IV respectivesly and provided that the 'Het' and 'R' ssubstituents do not include any such substituents that render inoperative the processses of Schemes 1 to 13. All of the startin g materials are commercially availabke or are readily made from commercially amvailable starting materials by those of skill in the art.

Scheme 1

NO. . NO. cl Cl H, x NO, a N = 2 b N Ns 2 ed NTS Ny elg ES yoy or = “opt Ae LA -—_’ W-0

Br Br Br ) Br 3 1 2 3 4 5 1 BocN h NSN ASN ik SPs 1 85 m —_ |! J N-O — 00 0 — I 3 NT i

Br % oH / sok 6 7 8

Ph BocNI Ph HN

D we SYS

Cr J NO n x / 0 lo] 3 Le] h socte. J SJ 9 10 . ~ «a) Br, NaOAc; (b) Et.NH, EtOH: (c) SnCl, HCI; (d) ethyl ~cyanoacetate, 190 °C; . (e) NaNO, HCI; (f) NH.OH; (g) EtaN, dioxane; (h) (Boc):O=, DMAP, pyridine; (i) n-

BuLi, THF; (j) B(OMe)s; (k) H;O2, NaOH; (I) 1,1-dimethylet=hyl 4-hydroxy-1- ) piperidinecarboxylate, DEAD, polymer bound PPha, CH,CHl; (m) PhB(OH)., _

Pd(PPhs)s, 2N Na,COs, EtOH/toluene; (n) TFA, CHCl.

Compounds of Formula (I) can be prepared in a maanner analogous to those shown in Scheme 1. Bromination of 3-nitro-4-ethoxy pyriciine (1-Scheme 1) using : bromine buffered in sodium acetate gives 3-bromo-4-(eth~yloxy)-5-nitropyridine (2-

Scheme 1). Other alternative methods exist and are known to those skilled in the art for carrying out this transformation. A compilation of t hese methods can be : found in standard organic synthesis texts such as Larock , "Comprehensive Organic

Transformations,” VCH, N.Y.(1989). The ethoxy group iss then displaced by a primary amine such as ethyl amine in a polar solvent suc -h as ethanol to give compounds such as 3-Scheme 1. In the case liquid amires, the reaction can be carried out in the absence of solvent. The reduction of tie nitro group with concomitant introduction of the chloro group is achieved using tin (li) chloride according to the method described by Kelley et al. J. Mead. Chem. 1995, 38(20), 4131-34. The corresponding 5-bromo-2-chloro diaminopoyridine is condensed with an appropriate acid or ester such as ethyl cyanoacetate. Continued heating affects a cyclodehydraation reaction to give imidazopyridines su ch as 4-Scheme 1.

Reaction with NaNO in concentrated HCI following by mreaction with hydroxylamine gives a bis-ox@ime that cyclodehydrates in the presence of an appropriate base such as triethylamire to give an aminofurazan such as 5-Sctheme 1. The amino group is protected by reacting with di-t-butyldicarbonate to give the corresponding t-butyl carbamate, 6—~Scheme 1. Many different protecting groups are available to one skilled in the art and can be used here as long as they do not interfere with the processes listed herein. The hydroxy! group is introdusced by generating an aryl anion by halosgen-metal exchange using a suitable basse such as n-butyl lithium, reacting the anion with an appropriate boron electrophuile such as trimethyl borate and oxidizing the resulting aryl boronate with an approspriate oxidizing agent such as hydrogen peroxide in aqueous base to give imidazcoopyridinols such as 7-Scheme 1. Etherificattion of the imidazopyridinol is carried out with an appropriate alcohol such as 1,1-climethylethyl 4-hydroxy-1-piperidinecarboOxylate using the methods described by Mitsunobu, Synthesis 1981, 1 to give eters such as 8-Scheme 1.

Subsequent reaction with an aryl boronic acid such ass phenyl boronic acid in the presence of a catalyst, preferably tetrakistriphenylphoesphino palladium and a base such as sodium carbonate or triethylamine in a suitabsle solvent mixture such as toluene and ethanol gives the corresponding aryl compound such as 9-Scheme 1.

Removal of ®the protecting groups is achieved using a_ protic or Lewis acid such as trifluoroacetic acid in a polar solvent such as methylemne chloride giving compounds : of Formula C1) such as 10-Scheme 1.

Scheme 2

Cl Bo | ol HN oH ) oH v BocNBH._~_0 > © 7-Scheme 1 1 2

Ph HN : Ph Hl,

BooNH._~__-0 > HN _~© ) 3 4 (a) TFA, CHIC; (b) 1,1-dimethylethyl (3-bromoprop=yljcarbamate, Cs,CO3, DMF; (c) PhB(OH),, Pd(PPhs)s, 2N Na;COs, dioxane; (d) TFA, CHCl.

Alternatively, compounds of Formula (I) can be prepared starting with an intearmediate such as 7-Scheme 1. Removal of the protecting groups using a protic or MLewis acid such as trifluoroacetic acid in a polar solwent such as methylene chi. oride gives an imidazopyridinol such as 1-Scheme =2. The phenolic -OH is depporotonated using a mild base such as Cs,CO; and t hen alkylated with an ap propriate electrophile such as 1,1-dimethylethyl (3-romepropyl)carbamate ina po-lar solvent such as DMF to give the corresponding ether such as 2-Scheme 2.

Stabsequent reaction with an aryl boronic acid such ass phenyl boronic acid in the preesence of a catalyst, preferably tetrakistriphenylpho: sphino palladium and a base sumch as sodium carbonate or triethylamine in a suitab’le solvent such as dioxane givves the corresponding aryl compound such as 3-Sclheme 2. Removal of the protecting groups is achieved using a protic or Lewis acid such as trifluoroacetic acid in a polar solvent such as methylene chloride giving compounds of Formula (1) stich as 4-Scheme 2. ’ Scheme 3 : :

BooNH Ph BocN Ph HN Ph : © OM ) OH ) OH J Bra ~0 ) ) 7-Scheme 1 1 ’ 2 3 .

Ph HN

Cr d 2 N-©

No~_o h wold 4 (Ca) PhB(OH), Pd(PPha)s, 2N Na,CO;, dioxane; (b) WFA, CH2CI2; (c) cdibromopropane, Cs2CO3, DMF; (d) 4-(2-aminoethyvl)benzenesulfonamide, DMSO, 5 °C.

Alternatively, compounds of Formula (1) can be prepared starting from an Wntermediate such as 7-Scheme 1. Reaction with ar aryl boronic acid such as gohenyl boronic acid in the presence of a catalyst, pr-eferably tetrakistriphenylphosphino palladium and a base suech as sodium carbonate or triethylamine in a suitable solvent such as dioxane gives the corresponding ary!

compound such as 1-Scheme 3. Removal of the protecting groups using a protic or Lewis acid such as trifluoroacetic acidin a polar solvent such as methylene chloride gives an imidazopyridinol suche as 2-Scheme 3. The phenolic -OHis deprotonated using a mild base such as Cs,CO; and then alkylated with an appropriate electrophile such as dibrormopropane in a polar solvent such as DMF to give the corresponding ether such as 3-Scheme 3. Heating with an appropriate nucleophile such as 4-(2-aminoethyl)benzenesulfonamide in polar solvent such as dimethyl sulfoxide gives compounds of Formula (1) such as 4-Scheme 3.

Scheme 4 1 BocNH Ph BoeN Ph a: LI os NO 8 We Cy we

Zz N-O N N NL)

Br ) | (J (J (J hoe foo N 8-Scheme 1 1 2 3 (a) Pdy(dba)s, xantphos, 1 ,A-dimethy lethy! 1 -piperazinecarboxylate; (b) PhB(OH)a,

Pd(PPhy)s, 2N Na,COs, toluene/EtOH; (c) TFA, CHCl. : n

Alternatively, compounds of Formula (1) can be prepared starting from intermediate 6-Scheme 1. Reaction. with an amine such as 1,1-dimethylethyl 1- piperazinecarboxylate in the presence of a catalyst, preferably Pdz(dba)s following the method of Buchwald ef al. J. Orgy. Chem. 2003, 68(25), 9563-73 gives the corresponding compound such as 4 -Scheme 4. Reaction with an aryl boronic acid such as pheny! boronic acid in the presence of a catalyst, preferably tetrakistriphenylphosphino palladiurn and a base such as sodium carbonate or triethylamine in a suitable solvent rraixture such as toluene and EtOH gives the corresponding aryl compound such as 2-Scheme 4. Removal of the protecting groups is achieved using a protic ow Lewis acid such as trifluoroacetic acid in a polar solvent such as methylene chaloride giving compounds of Formula (1) such as 3-Scheme 4.

Scheme 5 1 Bo

C' BocNH Cl BocN | A \ oon

PES: _ab pas N_=© oe Wo 4»

N- Z N_ N-O

Br 3 COM socH— ° 6-Scheme 1 1 2 a cl

BocN HN

N— " woe wr 3 4 (a) n-BuLi, THF, -100 = C; (b) CO. (c) 1,1-dimethylethyl 3-pyrrolidinylcarbamate,

EDCI, HOAt, NMM; (d) (3-chlorophenyl)boronic acid, Pd(PPhs)s, 2N Na,COs; toluene; (8) TFA, CHCl. , Alternatively, compounds of Formula (I) can prepared starting from . intermediate 6-Schem e 1. Selective halogen metal exchange of the bromine using a suitable base such as n-Buliin a suitable solvent such as THF at low _ temperatures generates the aryl anion which is guenched with CO. to give the .. corresponding carboxylic acid such as 1-Scheme 5. The acid is activated with a suitable reagent such as EDC! in the presence of a base such as N-methyl : morpholine and is cordensed with a suitable amine such as 1,1-dimethylethyl 3- pymolidinylcarbamate to give the corresponding amide such as 3-Scheme 5. Other alternative methods exist and are known to those skilled in the art for carrying out this transformation. A compilation of these methods can be found in standard organic synthesis texts such as Larock, "Comprehensive Organic

Transformations,” VCH, N.Y.(1989). Reaction with an aryl boronic acid such as (33- chiorophenyl)boronic: acid in the presence of a catalyst, preferably tetrakistriphenylphos phino palladium and a base such as sodium carbonate or triethylamine in a suitable solvent such as toluene gives compounds such as 3-

Scheme 5. Removal of the protecting groups is achieved using a protic or Lewis acid such as trifluorcacetic acid in a polar solvent such as methylene chloride giving compounds off Formula (1) such as 4-Scheme 5. _48 -

Scheme 6 cl ! Ph Ph Ph H

Cr . oc b Se) . CC . x oN

Aa LANm Nw Aw — om

COLE BOC A BoC AL eo,c A BOC A 1 2 3 4 =

Ph Ph HN Ph Hy

EOC pu Et0,C ju HOC )—~ 6 7 8 i

Ph Ph

LAW NO LAN NO a ca 8 10 (a) i-PrNHy; (b) PhB(OH)., Pd(PPha)s, Na,COs, toluene; (c) H,, 10% Pd/C, 1 atm,

EtOH; (d) cyanoacetic acid, EDCI, DMF; (e) AcOH, reflux; (f) NaNO,, HCI; (9)

NH,OH; (h) Et,N, dio>cane; (i) 6N NaOH, MeOH; (i) 1,1-dimethylethyl 3- : pyrrolidinylcarbamate., EDCI, HOAt, NMM, DMF; (K). TFA, CHCl. :

Alternatively , compounds of Formula (I) can be prepared in a manner _ analogous to that shown in Scheme 6. Ethyl 4 6-dichloro-5-nitro-3- : pyridinecarboxylate , prepared according to Sanchez et al. J.Heterocycl.Chem _ 1993, 30(4), 855-860, is reacted with an appropriate primary amine such as isopropyl amine to give a secondary amine such as 2-Scheme 6. Reaction wilth an aryl boronic acid such as phenylboronic acid in the presence of a catalyst, preferably tetrakistriphenylphosphino palladium and a base such as sodium carbonate or triethylamine in a suitable solvent such as toluene gives the corresponding aryl compound such as 3-Scheme 6. The nitro group is reduc-ed using hydrogen gas at a suitable pressure such as 1 atmosphere in the presence of a suitable catalyst such as 10% Pd on carbon in a suitable solvent such as EXOH to give the corresponding diaminopyridine such as 4-Scheme 6. Other alternative methods exist and are known to those skilled in the art for carrying out this transformation. A compilation of these methods can be found in standard oreganic synthesis texts such as Larock, "Comprehensive Organic Transformations,” “WCH,

N.Y.(1989). The pyridyldiamine is condensed with cyanoacetic acid that has been activated by a suitable reagent such as EDCI in a polar solvent such as DMF. _49 -

Heating the resulting amide such as 5-Scheme 6 in an acidic solveant such as acetic acid affects- a cyclodehydration reaction to give the corresponding imidazopyridine such as 6-Scheme 6. Reaction with NaNO, in concentrated HC! following by reaction with hydroxylamine gives a bis-oxime that cyclodehydrate=s in the presence ofan appropriate base such as triethylamine to give an aminofura=zan such as 7-

Scheme 6. Saponification. of the ester using a base such as 6N N220H in a suitable polar solve-nt such as MeOH gives the corresponding acid such ass 8-Scheme 6.

The acid iss activated by suitable reagents such as EDCI and HOAXT in the presence of a suitabfe base such as N-methyl morpholine in a polar solvent such as DMF and conde-nsed with an appropriate amine such as 1,1-dimethylefhyl 3- pyrrolidiny@carbamate to give the corresponding amide such as 9—Scheme 6. The protecting groups are removed using a protic or Lewis acid such as trifluoroacetic acid in a peoiar solvent such as methylene chloride to give compounds of Formula : (1) such ass 10-Scheme 6.

Scheme 7

Ph

NO NO NSO

CEI) (a ec 7 Pa 7 NH Bog N

Et0,C : } NTO : x HOC A CN 3-Scheme @&6 1 2

Ph ’ AN =N

NTO }

A= . 4

NH ~r-N

Pr } N

Boc, H \ I~

A = NTO

MEY o ) ~) 3 . 5

Ph :

NN Ns

Sea

NO =

A= 8

(a) 6M NaOH, EtOH; (b) 1,1-dimethylethyl methyl(3-pyrrolidinyl)esarbamate, EDC,

HOA, Et:N, CH.Cl2; (c) Ha, 10% PD/C, MeOH; (d) nicotinoyl chloride, EtsN,

CHC, (e) TFA; (f) furan carboxylic acid, EDC, HOAT, DMF; (cB) 1 H-imidazole-4- carbaldehyde, EtOH/Toluene, reflux.

Alternatively, compounds of Formula (I) can be prepare«d starting with intermediate 3-Scheme 6. Saponification of the ester using a boase such as 6N

NaOH in a suitable polar solvent such as EtOH gives the corresponding acid such as 1~Scheme 7. The acid is activated by suitable reagents such as EDC and

HOANT in the presence of a suitable base such as Et;N in a pol ar solvent such as

CHZ2CI2 and condensed with an appropriate amine such as 1, -dimethylethyl metihyl(3-pyrrolidinyl)carbamate to give the corresponding ami«de such as 2-

Scheme 7. The nitro group is reduced using hydrogen gas at a suitable pressure such as 1 atmosphere in the presence of a suitable catalyst sich as 10% Pd on carloon in a suitable solvent such as MeOH to give the corresponding diarminopyridine such as 3-Scheme 7. The pyridyldiamine is condensed with a suitable acid chloride such as nicotinoyl chloride in the presermce of a suitable base such as Et:N in a suitable solvent such as CH.Cl,. The resulting amide is heated in the presence of a Lewis or protic acid such as TFA to affect aa cyclodehydration with concomitant removal of the protecting groups to give cormnpounds of Formula : (1) such as 4-Scheme 7. Altematively, a suitable diaminopyridkine such as 3- . Sckheme 7 is condensed with a suitable acid such as furan ca rboxylic acid that has been activated by a suitable reagents such as EDC and HOAWT in a polar solvent such as DMF. The resulting amide is heated in the presence= of a Lewis or protic acikdsuch as TFA to affect a cyclodehydration to give compounds of Formula (1) such as 5-Scheme 7. Alternatively, the pyridyldiamine is heaated with a suitable aldehyde such as 1H-imidazole~4-carbaldehyde in an suitable solvent system such as EtOH/toluene to give compounds of Formula (1) such as &-Scheme 7.

Scheme 8

Ph Ph K Ph Ph = NH, a NT b rN c NT N, 4 NCbz > — 7=0 ——~ No yO —e ha

EC A E0,C pS Et0,C j= BOC 4Scheme 8 1 2 3

Ph Ph

NOSE Noe SN de (LC i. Saas ony 07 Seals 4 5 (a) triphosgene, toluene; (b) POCl,, HCI, (c) phenylrmethyl 4-(trimethylstannanyl)- 1H-pyrazole-1-carboxylate, Pd(PPhs)s, THF, reflux; (d) BN NaOH, EtOH; (e) phenyimethyl 3-pyrrolidinylcarbamate, EDC, HOAT,, EtsN, DMF; (f) Hz, 10% Pd/C,

EtOH

Alternatively, compounds of Formula (1) care be prepared from intermediate ° 4-Scheme 6. The imidazopyridinone such as 1-Scheme 8 is prepared by condensing a diaminopyridine sucha s 4-Scheme 6 with a suitable reagent such as : triphosgene. Treatment with a halogenating reage=nt such as POCI; gives the corresponding halo-imidazopyridine such as 2-Schweme 8. Reaction with an aryl : boronic acid or aryl stannane such as phenyimethy/| 4-(trimethylstannanyl)-1H- pyrazole-1-carboxylate in the presence of a catalyst, preferably tetrakistriphenylphosphino palladium in a suitable solvent such as THF gives the corresponding aryl compound such as 3-Scheme 8. Saponification of the ester using a base such as 6N NaOH in a suitable polar solvent such as EtOH gives the corresponding acid. The acid is activated by suitaable reagents such as EDC and

HOAT in the presence of a suitable base such as EN in a polar solvent such as

DMF and condensed with an appropriate amine swch as phenylmethyl 3- pyrrolidinylcarbamate to give the corresponding a mide such as 4-Scheme 8. The protecting groups are removed under hydrogenolxysis conditions using a catalyst such as 10% Pd/C in a suitable solvent such a EtOH to give compounds of Formula (1) such as 5-Scheme 8.

! Scheme 9

Ph Ph a NH, b aA SANC: c NT NO, ph NO —— or ANNO, g Leo = LA

COEt - EOC 1 2 3 C4

Ph Ph 4 Oo . oC — 1 —_—

Z cl Z “NH

Et0,C EOC A 4.Scheme 6 (a) methoxylamine, EtaN, potassium t-butoxide; (b) diethyl 5 [(ethyloxy)methylidene]propanedioate; (c) diphe=nyl ether, heat; (d) POCls; (€) iPrNH,.

Alternatively, an intermediate like 4-Sch-eme 6 can be prepared in a manner ’ _ analogous to those shown in Scheme 9. A suitable nitro-enamine such as 2- :

Scheme 9 is prepared by condensing a suitable nitroalkene such as 1-Scheme 9 with methoxylamine in the presence of a suitabsle base such as potassium t- i butoxide and Et;N. A 1,4-addition to diethyl [(e=thyloxy)methylidene]propanedioate : gives the corresponding enamine such as 3-Scheme 9. Heating ina suitable : solvent such as diphenyl ether gives a substitumted pyridine such as 4-Scheme 9.

Treatment with a chlorination agent such as PEC; gives the corresponding pyridyl chloride such as 5-Scheme 9. Treatment with an appropriate primary amine such as i-propyl amine gives an intermediate such as 4-Scheme 6 which can be used to prepare compounds of Formula (1.

Scheme 10

Ph HN Ph Hy Ph H,

CO . Pade > Sedu

A “°o \~ NOC TT =

HOC j= BocNH ju BooNH._~_ Mego" 8-Scheme 6 1 2

Ph HN

N= 2S CO

HN ~NH ~~ 3 (a) DPPA, EtsN, tBuOH; (b) 1,1-dimethylethyl (3-bromopropyf)carbamate, Cs;C=0;,

DMF; (c) TFA, CHCl.

Alternatively, compounds of Formula (1) can be prepared from intermed iate 8-Scheme 6. Treatment of the acid with diphenylphosphoryl azide in a suitable= solvent such as t-butanol affects a Curtius rearrangement to give a protected ammine such as 1-Scheme 10. Other alternative methods exist and are known to those= ’ skilled in the art for carrying out this transformation. A compilation of these methods can be found in standard organic synthesis texts such as Hassner amid : Stumer, "Organic Syntheses Based On Name Reactions and Unnamed React®ons," "Pergamon, N.Y. (1994). Deprotenation with a mild base such as Cs,CO; in a suitable solvent such as DMF followed by alkylation with a suitable alkyl halide such as 1,1-dimethylethyl (3-bromopropyl)carbamate gives the corresponding protescted amine such as 2-Scheme 10. The protecting groups are removed using a prottic or

Lewis acid such as trifluoroacetic acid in a polar solvent such as methylene chloride to give compounds of Formula (1) such as 3-Scheme 10.

Scheme 11

N

Lore PIL SE OEE os oF

N N N

1 2 3 4 5

HN | om : N HNBoc ot CLs eo. C5 Ch CL SEER

Br ) Br ) OH / 6 7 8 5. ok

Cr LI CX { - i i» poYy wi WJ : : 9 10 : 5 (a) EtNH; (b) Bra, NaOAc, AcOH: (c) Fe powder, AcOH; (d) ethyl cyanoacetate, . 190 °C; (e) NaNO; (f) NHOH; (9) di-t-butyldiccarbonate, DMAP, pyridine; hi-n- . Bulli, ii - B(OMe)s; (i) H202, NaOH; (j) 1,1-dimeathylethyl 4-hydroxy-1- : piperidinecarboxylate, polymer-bound PhaP, DEAD, CH,Clz; (k) TFA, CH,Cla.

Alternatively, compounds of Formula (I) can bse prepared in a manner analogous to that shown in Scheme 11. A suitably substitusted pyridine such as 1-Scheme 11is reacted with a suitable primary amine such ass ethyl amine to give the corresponding aminopyridine such as 2-Sche=me 11. Bromination of the aminopyridine using bromine buffered in sodi um acetate gives the corresponding bromopyridine such as 3-Scheme 11. Reducstion of the nitro group can be accomplished using iron powder in acetic aciad to give the corresponding diaminopyridine such as 4-Scheme 11. ‘Othe=r alternative methods exist and are known to those skilled in the art for carrying out the previous two transformations.

A compilation of these methods can be found in standard organic synthesis texts such as Larock, "Comprehensive Organic Transformations,” VCH, N.Y.(1989).

Condensation with ethyl cyanoacetate followed by cyclodehydration upon continued ) heating gives the corresponding imidazopyricline such as 5-Scheme 11. Reaction with NaNO, in concentrated HCI following by» reaction with hydroxylamine gives a bis-oxime that cyclodehydrates with continued heating to give an aminofurazan such as 6-Scheme 11. The amino group is protecsted by reacting with di-- butylcicarbonate to give the corresponding t-butyla carbamate, 7-Scheme 11. Many different protecting groups are available to one sisilled in the art and can be used here as long as they do not interfere with the procsesses listed herein. The hydroxyl grout ls introduced by generating an aryl anion bey halogen-metal exchange using a suitaable base such as n-butyl lithium, reacting the anion with an appropriate boron elec®rophile such as trimethyl borate and oxidizirmg the resulting ary! boronate with an appropriate oxidizing agent such as hydroger peroxide in agueous base to give : imid_azopyridinols such as 8-Scheme 11. EtherifTication of the imidazopyridinol is carried out with an appropriate alcohol such as ‘Hl ,1-dimethylethyl 4-hydroxy-1- pipearidinecarboxylate using the methods descritoed by Mitsunobu, Synthesis 1981, 1 toe give ethers such as 9-Scheme 11. Removal of the protecting groups is ach _ieved using a protic or Lewis acid such as trifluoroacetic acid in a polar solvent such as methylene chloride giving compounds of Formula (1) such as 10-Scheme 11.

Scheme 12 o

NNO a NS NO, b Cor c Cr _X — XL ANP bl —= FTN. CoN

OMe N NPth wen EN

NIP

- 2 3 4

Ph Ph HN : Ph H, = CO le, Ory LE. Cp

I. pu NH, 5 6 7 (am) 1-amino-3-phthalimidopropane, Et,N, EtOH; (b) SnCl,, HC; (c) ethyl cyyanoacetate; (d) PhB(OH),, Pd(PPhs)s, 2N NE 2,CO,, toluene; (¢) NaNO, HCI; (H

NEH,OH; (g) EtsN, dioxane; (h) hydrazine, THF. Adlternatively, compouns of Formula (1) can be= prepared in a manner analogous to ti~0se shown in Scheme 12. A suitably substi tuted pyridine such as 1-Scheme 12 iss reacted with a suitable primary amine such as 1-amino-3-phthalimidopropane to give the corresponding aminopyridine such ass 2-Scheme 11. Reduction of the nitro group with concomitant introduction of the chloro group is achiieved using tin (Il) chloride. Condensation with ethyl cyanoacetate followed by cyyclodehydration upon continued heating gives the corresponding imidazopyridine su .ch as 4-Scheme 12.

Reactior with an aryl boronic acid such as phenylboronic acid in the presence of a catalyst. preferably tetrakistriphenyliphosphino palladium and sa base such as sodium carbonate or triethylamine in a suitable solvent such xs toluene gives the cotresp onding aryl compound such as 5-Scheme 12. Reaction with NaNO; in concentrated HCI following by reaction with hydroxylamine gi*ves a bis-oxime that cyclode=hydrates with continued heating to give an aminofura=zan such as 6-Scheme 12. Re=moval of the protecting group is achieved using hydramzine in a suitable solvent= such as THF giving compounds of Formula (I) such &s 7-Scheme 12.

Scheme 13

OH oH

Cl H

Sus: a | HNP L yoo

BoeNH_~_0 ZN N-© N N

BocNH._~_O HN 2-Scheme 2 1 2 (a) 2-mmethyl-3-butyn-2-ol, Pd(PPhs)s, iPr;NH, dioxane, 100 °C; (b) 30%

TFAICCH;Cle.

Alternatively, compounds of Formula (1) can be prepoared in a manner ° analosgous to that shown in Scheme 13. Treatment of an asppropriate aryl halide such as 2-Scheme 2 with an appropriate catalyst such as : tetral<istriphenylphosphine palladium and a terminal alkynes in the presence of a suitable base such as di-isopropylamine in an appropriate ssolvent such as dioxane givess the corresponding aryl alkyne such as 1-Scheme 13_ Removal of the prote=cting groups is achieved using a protic or Lewis acid euch as trifluoroacetic acid in a polar solvent such as methylene chloride giving csompounds of Formula )] suctm as 2-Scheme 13.

In preparing the presently invented compounds of Formula (I), the following novesl intermediates are prepared.

WE 2005/011700 PCT/US2004/024340 4-(7-Bromo-4-chloro-1-ethyl-1 H-imidlazo[4,5-clpyridin-2-yi)-1 ,2,5-oxadiazol- 3-amine, is an intermediate that can be pregpared as described in Example 18 (e). 2-(4-Amino-1 ,2,5-oxadiazol-3-y)-1 -rnethyl-4-phenyl-1 H-imidazof4,5- clpyridine-7-carboxylic acid, is an intermedi ate that can be prepared as described in Example 98 (g).

In preparing the presently invented compounds of Formula (1), the following novel intermediate is prepared.

Ethyl 4-chloro-5-nitro-6-phenyl-3-pyridinecarboxylate, is an intermediate that can be prepared as described in Example 88 (d).

The invention also relates to a process for preparing a compound of

Formula (1), and/or pharmaceutically accepptable salts, hydrates, solvates and pro- drugs thereof, which comprises converting ethyl 4-chloro-5-nitro-B-phenyl-3- pyridinecarboxylate into a compound of Fomula (1), and thereafter optionally preparing a pharmaceutically acceptable salt, hydrate, solvate or pro-drug thereof.

The invention also relates to a proecess for preparing a compound of

Formula (If), and/or pharmaceutically acceptable salts, hydrates, solvates and pro- drugs thereof, which comprises converting 4-(7-Bromo-4-chioro-1-ethyk-1H- imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazo }-3-amine into a compound of Formula (11), and thereafter optionally preparing a pharmaceutically acceptable salt, hydrate, solvate or pro-drug thereof.

The invention also relates to a process for preparing a compound of

Formula (H), and/or pharmaceutically acceptable salts, hydrates, solvates and pro- drugs thereof, which comprises convertirmg 2-(4-Amino-1 ,2,5-oxadiazol-3-yl)-1- methyl-4-phenyl-1H-imidazo[4,5-clpyridire-7-carboxylic acid into a compound of

Formula (11), and thereafter optionally preparing 2 pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.

By the term "co-administering" ard derivatives thereof as used herein is meant either simultaneous administratiomn or any manner of separate sequential administration of an AKT Inhibiting compeound, as described herein, and a further active ingredient or ingredients, known te be useful in the treatment of cancer, including chemotherapy and radiation treatment, or to be useful in the treatment of arthritis. The term further active ingredient or ingredients, as used herein, includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patiemt in need of treatment for cancer or © arthritis. Preferably, if the administratior is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not - matter if the compounds are administereed in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.

Typically, any anti-neoplastic agent that has activity versus a susceptible= tumor being treated may be co-administered in the treatment of cancer in the present invention. Examples of such agents can be found in Cancer Principles and

Practice f Oncology by V.T. Devita and S. Hellman (editors), 8" edition (Februawry 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill im the art would be abl e to discem which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved.

Typical anti-neoplasstic agents useful in the present invention include, but are net limited to, anti-micretubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards.. oxazaphosphoriness, alkylsuifonates, nitrosoureas, and triazenes; antibiotic agesnts such as anthracycli ns, actinomycins and bleomygcins; topoisomerase Il inhibitors such as epipodophwllotoxins; antimetabolites such as purine and pyrimidine analogues and anti folate compounds; topoisomerase | inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; non-rece=ptor tyrosine kinase angiogenesis inhibitors; immunotherap eutic agents; proapoptotic agents; and cell cycle signaling inhibitors. .

Examples of a further active ingredient or ingredients for use in combirmation . or co-administered with the presently invented AKT Inhibiting compounds are : chemotherapeutic agents.

Anti-microtubule or anti-mitotic agents are phase specific agents actives against the microtubules of tumor cells during M or the mitosis phase of the ce=ll - cycle. Examples of anti-microtubule agents include, but are not limited to, diterpenoids and v inca alkaloids.

Diterpenoids, which are derived from natural sources, are phase specific anti -cancer agents that operate at the G,/M phases of the cell cycle. it is beli eved that the diterpenoiads stabilize the B-tubulin subunit of the microtubules, by binading with this protein. Disassembly of the protein appears then to be inhibited with mitosis being arrested and cell death following. Examples of diterpenoids incl ude, but are not limited to, paclitaxel and its analog docetaxel.

Paclitaxel, 5B,20-epoxy-1,20.,4,76, 108.1 3a-hexa-hydroxytax-11-en-9-one 4,10-dlacetate 2-bmenzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine=; is a natural diterpene product isolated from the Pacific yew tree Taxus brevifolia a nd is commercially available as an injectable solution TAXOL®. It is a member of the taxane family of tesrpenes. It was first isolated in 1971 by Waniet al. J. Am.

Chem, Soc. 93:2325. 1971), who characterized its structure by chermical and X-ray crystallogragohic methods. One mechanism for its activity relates to paclitaxel's capacity to find tubulin, thereby inhibiting cancer cell growth. Schiff et al., Proc.

Natl, Acad, Sci. USA, 77:1561-1 565 (1980); Schiff et al., Nature, 277:665-667 (1979); Kurwar, J. Biol, Chem, 256: 10435-10441 (1981). Fora review of synthesis and anticarcer adtivity of some paclitaxel derivatives see: D. G. |. Kingston et al.,

Studies in Organic Chemistry vol. 26, entitled “New trends in Natural Products

Chemistry 1986", Attaur-Rahman, PW. Le Quesne, Eds. (Elsevier, Amsterdam, 1986) pp 2 19-235.

Paclitaxel has been approved for clinical use in the treatmert of refractory ovarian camcer in the United States (Markman et al., Yale Journal of Biology and

Medicine, ©4:583, 1991; McGuire et al., Ann. Intem, Med. 141:273 ,1989) and for the treatm ent of breast cancer (Holmes et al., J. Nat. Cancer Inst., 83:1797,1991.)

It is a potential candidate for treatment of neoplasms in the skin (E.inzig et. al.,

Proc. Am. Soc. Clin. Oncol, 20:46) and head and neck carcinomas (Forastire et. al., Sem. ©ncol., 20:56, 1990). The compound also shows potential for the treatment of polycystic kidney disease (Woo et. al., Nature, 368:750. 1994), lung - cancer arad malaria. Treatment of patients with paclitaxel results im bone marrow Co : suppression (multiple cell lineages, Ignoff, R.J. et. al, Cancer Che motherapy

Pocket G uide, 1998) related to the duration of dosing above a threxshold ' . concentration (50nM) (Keams, C.M. et. al., Seminars in Oncology”, 3(6) p.16-23, : 1995). :

D ocetaxel, (2R,3S)- N-carboxy-3-phenylisoserine,N-tert-buatyl ester, 13-ester with 5p-20-epoxy-1 20,,4,7B,10B,13a-hexahydroxytax-11-en-8-one 4-acetate 2- benzoate, trihydrate; is commercially available as an injectable solution as . TAXOTERE®. Docetaxel is indicated for the treatment of breast «cancer. Docetaxel is a semiisynthetic derivative of paclitaxel g.v., prepared using a raatural precursor, 10-deacestyl-baccatin ili, extracted from the needle of the European Yew tree. The dose lim iting toxicity of docetaxel is neutropenia. inca alkaloids are phase specific anti-neoplastic agents derived from the periwinkle plant. Vinca alkaloids act at the M phase (mitosis) of &the cell cycle by - : binding specifically to tubulin. Consequently, the bound tubulin rnolecule is unable to polynerize into microtubules. Mitosis is believed to be arrestezd in metaphase with cell death following. Examples of vinca alkaloids include, brut are not limited to, vinblastine, vincristine, and vinorelbine.

Winblastine, vincaleukoblastine sulfate, is commercially available as

VELBAKN® as an injectable solution. Although, it has possible imdication as a

WO» 2005/011700 PCT/US2004/024340 <econd line therapy of various solid tumors, it is primariky indicated in the treatment

Of testicular cancer and various lymphomas including H odgkin’s Disease; and 1 ymphocytic and histiocytic lymphomas. Myelosuppresssion is the dose limiting side effect of vinblastine.

Vincristine, vincaleukoblastine, 22.0x0-, sulfate, is commercially available as =ONCOVIN® as an injectable solution. Vincristine is inclicated for the treatment of acute leukemias and has also found use in treatment resgimens for Hodgkin's and non-Hodgkin's malignant lymphomas. Alopecia and neaurologic effects are the most common side effect of vincristine and to a lesser extent myelosupression and gastrointestinal mucositis effects occur. vinorelbine, 3',4'-didehydro -4’-deoxy-C'-norvin caleukoblastine [R-(R*,R*)- 2,3-dihydroxybutanedioate (1:2)(salt)], commercially awailable as an injectable solution of vinorelbine tartrate (NAVELBINE®), is a se misynthetic vinca alkaloid.

Vinorelbine is indicated as a single agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of various solid tumors, particularly non-small cell lung, advanced breast, and hormone refractory prostate cancers. Myelosuppression is the most comrmon dose limiting side effect - of vinorelbine. LC

Platinum coordination complexes are non-phasse specific anti-cancer - - agents, which are interactive with DNA. The platinums complexes enter tumor cells, undergo, aquation and form intra- and interstrand crosslinks with DNA causing adverse biological effects to the tumor. Examples of platinum coordination complexes include, but are not limited to, cisplatin and carboplatin.

Cisplatin, cis-diamminedichloroplatinum, is commmercially available as

PLATINOL® as an injectable solution. Cisplatin is primarily indicated in the treatment of metastatic testicular and ovarian cancer and advanced bladder cancer. The primary dose limiting side effects of cissplatin are nephrotoxicity, which may be controlled by hydration and diuresis, ard ototoxicity.

Carboplatin, platinum, diammine [1,1-cyclobuttane-dicarboxylate(2-)-0,07, is commercially available as PARAPLATIN® as an injectable solution. Carboplatin is primarily indicated in the first and second line treatme=nt of advanced ovarian carcinoma. Bone marrow suppression is the dose limiting toxicity of carboplatin.

Alkylating agents are non-phase anti-cancer specific agents and strong electrophiles. Typically, alkylating agents form covaleant linkages, by alkylation, to

DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups. Such alkylation disrupts nucleic acid function leading to cell death. Exampless of alkylating agents include,

} but are not limited to, nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates such as busulfan ; nitrosoureas such as carmustine; and triazenes such as dacarbazine.

Cyclophosphamide, 2-{bis(2-chloroethylyaminojtetrahydro-2H-1 ,3,2- oxazaphosphorine 2-oxide monohydrate, is commezrcially available as an injectable solution or tablets as CYTOXAN®. Cyclophospharmide is indicated as a single agent or in combination with other chemotherapeutic agents, in the treatment of malignant lymphomas, multiple myeloma, and leulcemias. Alopecia, nausea, vomiting and leukopenia are the most common dosse limiting side effects of cyclophosphamide.

Melphalan, 4-{bis(2-chloroethyl)amino}-L-plnenylalanine, is commercially available as an injectable solution or tablets as AL KERAN®. Melphalan is indicated for the palliative treatment of multiple myeloma and non-resectable epithelial carcinoma of the ovary. Bone marrow sauppression is the most common : 15 dose limiting side effect of melphalan.

Chlorambucil, 4-fbis(2-chioroethyl)amino}beenzenebutanoic acid, is : commercially available as LEUKERAN® tablets. ‘Chlorambucil is indicated for the palliative treatment of chronic lymphatic leukemia , and malignant lymphomas such as lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease. Bone : ; 20 marrow suppression is the most common dose limiting side effect of chlorambucil.

Busuifan, 1,4-butanediol dimethanesulfonzate, is commercially available as

MYLERAN® TABLETS. Busulfanis indicated for the palliative treatment of chronic myelogenous leukemia. Bone marrow suppression is the most common dose limiting side effects of busulfan.

Carmustine, 1,3-[bis(2-chloroethyi)-1-nitrosourea, is commercially available as single vials of lyophilized material as BICNU® . Carmustine is indicated forthe palliative treatment as a single agent or in combimation with other agents for brain tumors, multiple myeloma, Hodgkin's disease, amd non-Hodgkin's lymphomas.

Delayed myelosuppression is the most common dose limiting side effects of . cammustine.

Dacarbazine, 5-(3,3-dimethyl-1-triazeno)—imidazole-4-carboxamide, is commercially available as single vials of material as DTIC-Dome®. Dacarbazine is indicated for the treatment of metastatic malignaant melanoma and in combination with other agents for the second line treatment of Hodgkin's Disease. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dacarbazine.

Antibiotic anti-neoplastics are non-phase specific agents, which bind or intercalate with DNA. Typically, such action results in stable DNA complexes or strand breakage, which disrupts ordinary function of the nucleic acids leading to cell death. Examples of antibiotic anti-neoplastic agents include, but are not limited to, actinomycins such as dactinomycin, anthrocyclins such as daunorubicin and doxorubicin; and bleomycins.

Dactinomycin, also know as Actinomycin D, is commercially available in injectable form as COSMEGEN®. Dactinomycin is indicated for the treatment of

Wilm’s tumor and rhabdomyosarcoma. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dactinomycin.

Daunorubicin, (8S-cis-)-8-acetyl—10-{(3-amino-2,3,6-trideoxy-o-LAyxo- hexopyranosyl)oxyl-7,8,9,1 O-tetrahydro-6,8,11 -trihydroxy-1-methoxy-5,12 naphthacenedione hydrochloride, is cormmercially available as a liposomal injectable form as DAUNOXOME® or as an injectable as CERUBIDINE®.

Daunorubicin is indicated for remission induction in the treatment of acute nonlymphocytic leukemia and advance d HIV associated Kaposi's sarcoma.

Myelosuppression is the most commons dose limiting side effect of daunorubicin.

Doxorubicin, (8S, 108)-1 0-[(3-aamino-2,3,6-trideoxy-a-L-lyxo- Ny hexopyranosyl)oxy]-8-glycoloyl, 7,8,9,1 0-tetrahydro-6,8,11-trihydroxy-1 ~-methoxy- 5,12 naphthacenedione hydrochloride, is commercially available as an injectable oo . . form as RUBEX® or ADRIAMYCIN RDF®. Doxorubicin is primarily indicated for “ the treatment of acute lymphoblastic leukemia and acute myeloblastic leukemia, but is also a useful component in the treatment of some solid tumors and lymphomas. Myelosuppression is the wnost common dose limiting side effect of doxorubicin.

Bleomycin, a mixture of cytotoxic glycopeptide antibiotics isolated from a - strain of Streptomyces verticillus, is commercially available as BLENOXANE®.

Bleomycin is indicated as a palliative treatment, as a single agent or in combination with other agents, of squamous cell carcinoma, lymphomas, and testicular ‘ 30 carcinomas. Pulmonary and cutaneous toxicities are the most common dose limiting side effects of bleomycin.

Topoisomerase lI inhibitors include, but are not limited to, epipodophyllotoxins.

Epipodophyliotoxins are phase specific anti-neoplastic agents derived from the mandrake plant. Epipodophyllotoxins typically affect cells in the S and G; phases of the cell cycle by forming a ternary complex with topoisomerase Il and

DNA causing DNA strand breaks. The strand breaks accumulate and cell death follows. Examples of epipodophyliotoxins irmclude, but are not limited to, etoposide and teniposide.

Etoposide, 4'-demethyl-epipodophyiBotoxin o[4,6-0-(R }-ethylidene-f-D- glucopyranoside], is commercially available as an injectable solution or capsules as VePESID® and is commonly known as VP--16. Etoposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of testicular and non-small cell lung cancers. Myelosuppression is the most common © side effect of etoposide. The incidence of leucopenia tends to be more severe than thrombocytopenia.

Teniposide, 4-demethyl-epipodophaylliotoxin 9[4,6-0-(R )-thenylidene-B-D- glucopyranoside], is commercially available as an injectable solution as VUMON® and is commonly known as VM-26. Tenip oside Is indicated as a single agent or in combination with other chemotherapy age=nts in the treatment of acute leukemia in children. Myelosuppression is the most common dose limiting side effect of teniposide. Teniposide can induce both le ucopenia and thrombocytopenia. .

Antimetabolite neoplastic agents amare phase specific anti-neoplastic agents that act at S phase (DNA synthesis) of thea cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA : : synthesis. Consequently, S phase does mot proceed and cell death follows.

Examples of antimetabolite anti-neoplastiic agents include, but are not limited to, : : fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine. : 5-fluorouracil, 5-fluoro-2,4- (1H,3WH) pyrimidinedione, is commercially available as fluorouracil. Administration of s-fluorouracil leads to inhibition of thymidylate synthesis and is also incorporated into both RNA and DNA. The result typically is cell death. 5-fluorouracil is in dicated as a single agent or in combination with other chemotherapy agents in the treatment of carcinomas of the breast, colon, rectum, stomach and pancreas. BViyelosuppression and mucositis are dose limiting side effects of 5-fluorouracil. Ot her fluoropyrimidine analogs include 5- fluoro deoxyuridine (floxuridine) and 5-fi uorodeoxyuridine monophosphate.

Cytarabine, 4-amino-1 -B-D-arabinofuranosyl-2 (1 H)-pyrimidinone, is commercially available as CYTOSAR-U ® and is commonly known as Ara-C. Itis believed that cytarabine exhibits cell phase specificity at S-phase by inhibiting DNA chain elongation by terminal incorporati on of cytarabine into the growing DNA chain. Cytarabine is indicated as a single agent or in combination with other chemotherapy agents in the treatment «of acute leukemia. Other cytidine analogs include 5-azacytidine and 2' ,2'-difluorodeoxycytidine o( gemcitabine). Cytarabine induces leucop enia, thrombocytopenia, and mucositi=s.

Mercaptopurine, 1,7-dihydro-6H-purine-6-thiosne monohydrate, is commercially amvailable as PURINETHOL®. Mercaptopurine exhibits cell phase specificity at S—phase by inhibiting DNA synthesis by an as of yet unspecified mechanism. Neflercaptopurine is indicated as a single= agent or in combination with other chemoth.erapy agents in the treatment of acutea leukemia. Myelosuppression and gastrointe=stinal mucositis are expected side effexcts of mercaptopurine at high doses. A useful mercaptopurine analog is azathiopr-ine.

Thiogumanine, 2-amino-1 ,7-dihydro-8H-purine=-8-thione, is commercially available as T_ABLOID®. Thioguanine exhibits cell gohase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism. Thioguanine is indicated as am single agent or in combination with ofther chemotherapy agents in the treatment of acute leukemia. Myelosuppression, inecluding leucopenia, thrombocytopmenia, and anemia, is the most commoen dose limiting side effect of thioguanine amdministration. However, gastrointestimal side effects occur and can be dose limiti ng. Other purine analogs include pen—tostatin, erythrohydros=ynonyladenine, fludarabine phosphatee, and cladribine. :

Gemcsitabine, 2'-deoxy-2', 2'-difluorocytidine2 monohydrochloride (B-isomer), : . 20 is commercially available as GEMZAR®. Gemcitabine exhibits cell phase : specificity at S-phase and by blocking progression of cells through the G1/S : boundary. Gemcitabine is indicated in combinatior with cisplatin in the treatment of locally advarmced non-small cell lung cancer and aleone in the treatment of locally , advanced pamncreatic cancer. Myelosuppression, imncluding leucopenia, thrombocytospenia, and anemia, is the most commeon dose limiting side effect of ' gemcitabine administration.

Meth otrexate, N-[4[[(2.4-diamino-8-pteridin Yi) methylJmethylamino] benzoyi]-

L-glutamic a cid, is commercially available as methmotrexate sodium. Methotrexate exhibits cell phase effects specifically at S-phase Boy inhibiting DNA synthesis, repair and/or replication through the inhibition of d yhydrofolic acid reductase which is required feor synthesis of purine nucleotides andu thymidylate. Methotrexate is indicated as a single agent or in combination with other chemotherapy agents in the treatment off choriocarcinoma, meningeal leukemi=a, non-Hodgkin's lymphoma, and carcinomas of the breast, head, neck, ovary and boladder. Myelosuppression (leucopenia. thrombocytopenia, and anemia) and mucositis are expected side effect of methotrexate administration.

Campstothecins, including, camptothecin and camptothecin derivatives are available or uander development as Topoisomerase | inhibitors. Canmaptothecins cytotoxic acti=vity is believed to be related to its Topoisomerase | inhaibitory activity.

Examples of camptothecins include, but are not limited to irinotecar, topotecan, and the variosus optical forms of 7-(4-methylpiperazino-methylene)-~1 0,11- ethylenediox-y-20-camptothecin described below.

Irinoteecan HCI, (45)-4,1 1-diethyl-4-hydroxy-9-{(4-piperidinopiperidino) carbonyloxyl-1 H-pyranol[3’.4',6,7]indolizino[1 ,2-bjquinoline-3,14(4H.,1 2H)-dione hydrochloridee, is commercially available as the injectable solution CCAMPTOSAR®.

Irinot-ecan is a derivative of camptothecin which binds, aloneg with its active metabolite SSN-38, to the topoisomerase | — DNA complex. It is belii eved that cytotoxicity ©ccurs as a result of irreparable double strand breaks caused by interaction cof the topoisomerase | : DNA : irintecan or SN-38 terna ry complex with replication e=nzymes. lrinotecan is indicated for treatment of metasstatic cancer of the colon or rectum. The dose limiting side effects of irinotecan H=Cl are myelosuppreession, including neutropenia, and Gl effects, including diarrhea.

Topootecan HCI, (S)-1 0-{(dimethylamino)methyll-4-ethyl-4,E3-dihydroxy-1 H- pyrano[3’,4’ 6,7}indolizino[1,2-blquinoline-3,14-(4H,12H)-dione mcanohydrochloride, is commercsially available as the injectable solution HYCAMTIN®. Topotecan is a derivative o f camptothecin which binds to the topoisomerase | — DBNA complex and : prevents re*igation of singles strand breaks caused by Topoisome=rase | in response to torsional strain of the DNA molecule. Topotecan is irdicated for : second line= treatment of metastatic carcinoma of the ovary and srmall cell lung cancer. Thae dose limiting side effect of topotecan HCl is myelosuppression, primarily nesutropenia.

Also of interest, is the camptothecin derivative of formula A following, currently urder development, including the racemic mixture (R,S) form aswell as the R and SS enantiomers: ( NMe

No

COC

0 NT \ A lo]

Me © © known by the chemical name 47-(4-methylpiperazino—methylene)-1 0,11- ethylenexdioxy-20(R,S)-camptothecin (racemic mixtur—e) or =7-(4-methylpiperazino- methyle=ne)-10,1 1-sthylenedioxy-20(R)-camptothecirn (R enantiomer) or “7-(4- methylpiperazino-methylene)-1 01 1-ethylenedioxy-2@(S)-camptothecin (S § enantio-mer). Such compound as well as related cormpounds are described, includirg methods of making, in U.S. Patent Nos. 6,7063,923; 5,342,947; 5,569,235; 5,491,237 and pending U.S. patent Application No. #08/977,217 filed November 24, 1997.

Hormones and hormonal analogues are use=ful compounds for treating cancer-sin which there is a relationship between the hormone(s) and growth and/or lack of growth of the cancer. Examples of hormones and hormonal analogues useful in cancer treatment include, but are not limited to, adrenocorticosteroids such &as prednisone and prednisolone which are us.-eful in the treatment of maligrant lymphoma and acute leukemia in childre=n; aminoglutethimide and other aromatase inhibitors such as anastrozole, letrazole=, vorazole, and exemestane usefull in the treatment of adrenocortical carcinoma and hormone dependent breast carcirmoma containing estrogen receptors; progestr-ins such as megestrol acetate . usefu 1in the treatment of hormone dependent breast cancer and endometrial carcimoma; estrogens, androgens, and anti-androggens such as flutamide, . 20 niluta mide, bicalutamide, cyproterone acetate and 5o-reductases such as : finasteride and dutasteride, useful in the treatment of prostatic carcinoma and oo benign prostatic hypertrophy; anti-estrogens such as tamoxifen, toremifene, raloxsfene, droloxifene, iodoxyfene, as well as sel ective estrogen receptor modulators (SERMS) such those described in U.S. Patent Nos. 5,681,835, 5,877,219, and 6,207,716, useful in the treatments of hormone dependent breast carci noma and other susceptible cancers; and go-nadotropin-releasing hormone (GnRH) and analogues thereof which stimulate tihe release of leutinizing hormone (LH) and/or follicle stimulating hormone (FSH) for— the treatment prostatic carcinoma, for instance, LHRH agonists and antaagagonists such as goserelin acetate and luprolide.

Signal transduction pathway inhibitors ares those inhibitors, which block or inhiloit a chemical process which evokes an intracellular change. As used herein this change is cell proliferation or differentiation. Signal tranduction inhibitors useful in thse present invention include inhibitors of rece ptor tyrosine kinases, non-receptor tyro-sine kinases, SH2/SH3domain blockers, seri-ne/threonine kinases, phosphotidyl inossitol-3 kinases, myo-inositol signaling, and Raas oncogenes.

Several protein tyrosine kinases catalyse the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth. Such protein tyrosine kinases can be broadly classified as receptor or non-receptor } kinases.

Receptor tyrosine kinases are transmembrane proteins having an extracellular ligand binding domain, a transmembrane domain, and a tyrosine kinase domain. Receptor tyrosine kinases are involved in the regulation of cell growth and are generally termed growth factor receptors. inappropriate or uncontrolled activation of many of these kinases, i.e. aberrant kinase growth faactor receptor activity, for example by over-expression or mutation, has been shown to result in uncontrolled cell growth. Accordingly, the aberrant activity of such kirmases has been linke=d to malignant tissue growth. Consequently, inhibitors of such kinases could provide cancer treatment methods. Growth factor receptors inczlude, for example, e=pidermal growth factor receptor (EGF), platelet derived growth factor receptor (PDGF), erbB2, erbB4, vascular endothelial growth factor receptor (VEGF), tyrosine kinase with immunoglobulin-like and epidermal growth factor homology dormains (TIE-2), insulin growth factor ~1 (IGF) receptor, macrophage : . colony stimulating factor (cfims), BTK, ckit, cmet, fibroblast growth factor (FCW) : . ‘receptors, Tri< receptors (T rkA, TrkB, and TrkC), ephrin (eph) receptors, and the : 20 - RET protoonecogene. Several inhibitors of growth receptors are under development : . and include li gand antagonists, antibodies, tyrosine kinase inhibitors and ant@-sense oligonucleoticles. Growth factor receptors and agents that inhibit growth factor ‘receptor function are described, for instance, in Kath, John C., Exp. Opin. Ther.

Patents (200) 10(6):803-818; Shawver et al DDT Vol 2, No. 2 February 1997, and

Lofts, F. J. et al, “Growth factor receptors as targets”, New Molecular Targets for

Cancer Chemmotherapy, ed. Workman, Paul and Kerr, David, CRC press 1994,

London.

Tyrosine kinases, which are not growth factor receptor kinases are teermed non-receptosr tyrosine kinases. Non-receptor tyrosine kinases useful in the goresent invention, wrhich are targets or potential targets of anti-cancer drugs, include2 cSrc,

Lek, Fyn, Yess, Jak, cAbl, FAK (Focal adhesion kinase), Brutons tyrosine kirase, and Ber-AbN. Such non-receptor kinases and agents which inhibit non-rece ptor tyrosine kin ase function are described in Sinh, S. and Corey, S.J., (1999) J-ournal of

Hematothewrapy and Stem Cell Research 8 (5): 465 — 80; and Bolen, J.B., BBrugge,

J.S., (19977) Annual review of immunology. 15: 371-404.

SH=2/SH3 domain blockers are agents that disrupt SH2 or SH3 domain binding in aa variety of enzymes or adaptor proteins including, P13-K p85 sumbunit,

Src family kinases, adaptor molecules (Shc, Crk, Nek, Grb2) and Ras-GAP.

SH2/SH3 domains as targets for anti-cancer drugs are discusssed in Smithgall, T.E. (1995), Journal of Pharmacological and Toxicological Method s. 34(3) 125-32.

Inhibitors of Serine/Threonine Kinases including MAP kinase cascade blockers which include blockers of Raf Kinases (rafk), Mitogemn or Extracellular

Regulated Kinase (MEKs), and Extracellular Regulated Kinases (ERKs); and

Protein Kinase C family member blockers including blockers of PKCs (alpha, beta, gamm a, epsilon, mu, lambda, iota, zeta). IkB kinase family (1 KKa, IKKb), PKB family kinases, akt kinase family members, and TGF beta resceptor kinases. Such

Serine/Threonine kinases and inhibitors thereof are describe=d in Yamamoto, T.,

Taya, S., Kaibuchi, K., (1 999), Journal of Biochemistry. 126 5) 799-803; Brodt, P,

Samani, A., and Navab, R. (2000), . Biochemical Pharmacology, 60. 1 101-1107;

Massague, J., Weis-Garcia, F. (1996) Cancer Surveys. 27:.<41-64; Philip, P.A., and

Harris, A.L. (1995), Cancer Treatment and Research. 78: 3—27, Lackey, K. et al

Bioorganic and Medicinal Chemistry Letters, (10), 2000, 2233-226; U.S. Patent No. - 6,2688,391; and Martinez-lacaci, L., et al, Int. J. Cancer (200-0), 88(1), 44-52,

Inhibitors of Phosphotidy! inositol-3 Kinase family members including : blockers of PI3-kinase, ATM, DNA-PK, and Ku are also useful in the present Co invention. Such kinases are discussed in Abraham, R.T. (1996), Current Opinion in

Immunology. 8 (3) 412-8; Canman, C.E., Lim, D.S. (1998), Oncogene 17 (25) : : 3301 -3308; Jackson, S.P. (1997), Intemational Journal of Biochemistry and Cell

Biology. 29 (7):935-8; and Zhong, H. et al, Cancer res, (2000) 60(6), 1641-1548. :

Also useful in the present invention are Myo-inositol signaling inhibitors such as phospholipase C blockers and Myoinositol analogues. Such signal inhibitors are described in Powis, G., and Kozikowski A., (1994) New Mo-lecular Targets for

Cancer Chemotherapy ed., Paul Workman and David Kerr , CRC press 1994,

London.

Another group of signal transduction pathway inhibitors are inhibitors of Ras

Oncogene. Such inhibitors include inhibitors of farnesyltra. nsferase, geranyl- geranyl transferase, and CAAX proteases as well as anti-ssense oligonucleotides, ribozymes and immunotherapy. Such inhibitors have beer shown to block ras activation in cells containing wild type mutant ras , thereby acting as antiyproliferation agents. Ras oncogene inhibition is discusssed in Scharovsky, O.G.,

Rozados, V.R., Gervasoni, S.I. Matar, P. (2000), Journal of Biomedical Science. 7(4) 292-8; Ashby, M.N. (1998), Current Opinion in Lipidoliogy. 9 (2) 99 — 102; and

Bio©Chim. Biophys. Acta, (19899) 1423(3):19-30.

As mentioned above, antibedy antagonists to receptor kinase ligand binding may also serve as signal transduction inhibitors. This group of signaal transduction pathway inhibitors includes the use of humanized antibodies to the extracellular ligand binding domair of receptor tyrosine kinases. For exampl-e 5s Imclone C225 EGFR specific antitoody (see Green, M.C. et al, Monoclonal Aantibody

Therapy for Solid Tumors, Cancer” Treat. Rev., (2000), 26(4), 269-286); Her~ceptin ® erbB2 antibody (see Tyrosine Klinase Signalling in Breast cancer.erbB Family

Receptor Tyrosine Kniases, Breast cancer Res., 2000, 2(3), 176-183); and 2CB

VEGFR2 specific antibody (see Bmrekken, R.A. et al, Selective Inhibition of WEGFR2

Activity by a monoclonal Anti-VEGSF antibody blocks tumor growth in mice, Cancer

Res. (2000) 80, 5117-5124).

Non-receptor kinase angicgenesis inhibitors may also find use in thes present invention. Inhibitors of argiogenesis related VEGFR and TIE2 are discussed above in regard to sigrmal transduction inhibitors (both receptors are receptor tyrosine kinases). Angiosgenesis in general is linked to erbB2/EGFR signaling since inhibitors of erbB= and EGFR have been shown to inhibit angiogenesis, primarily VEGF exppression. Thus, the combination of an erbB2/EGFR inhibitor with an inhibitor of angiogenesis makes sense. Accomrdingly, non-receptor tyrosine kinase inhiloitors may be used in combination with thea :

EGFR/erbB2 inhibitors of the present invention. For example, anti-VEGF o : antibodies, which do not recognizze VEGFR (the receptor tyrosine kinase), Bout bind © to the ligand; small molecule inhibitors of integrin (alpha, betas) that will inhibit : angiogenesis; endostatin and anggiostatin (non-RTK) may also prove useful in combination with the disclosed er-b family inhibitors. (See Bruns CJ et al (22000),

Cancer Res., 60: 2926-2935; Sc=hreiber AB, Winkler ME, and Derynck R. «1986),

Science, 232: 1250-1253; Yen Let al. (2000), Oncogene 19: 3460-3469)

Agents used in immunoterapeutic regimens may also be useful in combination with the compoundss of formula (1). There are a number of immunologic strategies to generate an immune response against erbB2 or~ EGFR.

These strategies are generally ina the realm of tumor vaccinations. The effiecacy of immunologic approaches may bes greatly enhanced through combined inhiflbition of erbB2/EGFR signaling pathways using a small molecule inhibitor. Discussion of the immunologic/tumor vaccine approach against erbB2/EGFR are found in Reeilly RT et al. (2000), Cancer Res. 60: 3560-3576: and Chen Y, Hu D, Eling DJ, Robbins

J, and Kipps TJ. (1998), Cancer Res. 58: 1965-1971.

Agents used in proapoptotic regimens (e.9., bcl-2 antisense i oligonucleotides) may also be ussed in the combination of the present invertion.

Members oof the Bel-2 family of proteins block apoptosis. Upregulation of bcl-2 has therefore beeen linked to chemoresistance. Studies have sshown that the epidermal growth fac®or (EGF) stimulates anti-apoptotic members off the bel-2 family (i.e., mcl- 1). Therefore, strategies designed to downregulate the expression of bcl-2 in tumors hawe demonstrated clinical benefit and are now im Phase 1/1 trials, namely

Genta's G-3139 bcl-2 antisense oligonucleotide. Such proapoptotic strategies using the antisemsa oligonucleotide strategy for bel-2 are discusssed in Water JS etal. (2000), J. Clin. Oncol. 18: 1812-1823; and Kitada S et al_ (1994), Antisense Res.

Dev. 4: 7 1-79. : 10 Cell cycle signalling inhibitors inhibit molecules involved in the control of the cell cycle A family of protein kinases called cyclin deperndent kinases (CDKs) and their interaction with a family of proteins termed cyclins controls progression through tlhe eukaryotic cell cycle. The coordinate activation and inactivation of different ecyclin/CDK complexes is necessary for normal progression through the cell cycle-. Several inhibitors of cell cycle signalling are winder development. For instance, examples of cyclin dependent kinases, including CDK2, CDK4, and CDK6 and inhibitors for the same are described in, for instancee, Rosania et al, Exp. Opin. . : “Ther. Pa-tents (2000) 10(2):215-230. E

I one embodiment, the cancer treatment method of the claimed invention : 20 includes the co-administration a compound of formula 1 and/or a pharmaceutically “acceptalbole salt, hydrate, solvate or pro-drug thereof an d at least one anti- : * neoplastzic agent, such as one selected from the group consisting of anti- microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, —topoisomerase lI inhibitors, antimetabolites, topooisomerase | inhibitors, hormone=s and hormonal analogues, signal transduction pathway inhibitors, non- receptom tyrosine kinase angiogenesis inhibitors, immu notherapeutic agents, proapoptotic agents, and cell cycle signaling inhibitors

Eecause the pharmaceutically active compounads of the present invention are acti=ve as AKT inhibitors they exhibit therapeutic utility in treating cancer and arthritis .

Suitably, the present invention relates to a met_hod for treating or lessening the sev erity of a cancer selected from brain (gliomas), glioblastomas, Bannayan-

Zonanaa syndrome, Cowden disease, Lhermitte-Ducloss disease, breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, panecreatic, prostate, sarcoma and thyroid.

Suitably, the present invention relate sto a method for treating or lessening the severity of a cancer selected from ovarian, pancreatic and prostate.

Isolation and Purification of His-tagged AKT 1 (2a 136-480)

Insect cells expressing His-tagged AKT1 (aa 136-480) were fysed in 25 mM

HEPES, 100 mM NaCl, 20 mM imidazole; PH 7.5 using a polytron (5 mLs lysis buffer/g cells). Cell debris was removed bys centrifuging at 28,000 x g for 30 minutes. The supematant was filtered thro» ugh a 4.5-micron filter then loaded onto a nickel-chelating column pre-equilibrated with lysis puffer. The column was washed with 5 column volumes (CV) of lysis buffer then with 5 CV of 20% buffer B, where buffer B is 25 mM HEPES, 100 mM NaCl, 300 mM imidazole; pH 7.5. His- tagged AKT1 (aa 136-480) was eluted with a 20-100% linear gradient of buffer B over 10 CV. His-tagged AKT1 (136-480) eluting fractions were pooled and diluted 3-fold with buffer C, where buffer C is 25 rmM HEPES, pH 7.5. The sample was then chromatographed over a Q-Sepharosse HP column pre-equilibrated with buffeer

C. The column was washed with 56 CV of buffer C then step eluted with 5 CV 10%D, 5 CV 20% D, 5 CV 30% D, 5CV 50% D and 5 CV of 100% D; where buffer

D is 25 mM HEPES, 1000 mM NaCl; pH 7.5. His-tagged AKT1 (aa 136-480) containing fractions were pooled and concentrated in a 10-kDa molecular weight . cutoff concentrator. His-tagged AKT1 (aaa 136-480) was chromatographed over & R : Superdex 75 gel filtration column pre-equ ilibrated with 25 mM HEPES, 200 mM:

NaCl, 1 mM DTT; pH 7.5. His-tagged AK_T1 (aa 136-480) fractions were examin ed using SDS-PAGE and mass spec. The protein was pooled, concentrated and frozen at —80C.

His-tagged AKT2 (aa 138-481) ard His-tagged AKT3 (aa 135-479) were isolated and purified in a similar fashion.

AKT Enzyme Assay

Compounds of the present invention were tested for AKT 1, 2, and 3 pro tein serine kinase inhibitory activity in substrate phosphorylation assays. This assay* examines the ability of small molecule organic compounds to inhibit the serine phosphorylation of a peptide substrate. The substrate phosphorylation assays ase the catalytic domains of AKT 1, 2, or 3. AKT 1, 2 and 3 are also commercially available from Upstate USA, Inc. The method measures the ability of the isolated enzyme to catalyze the transfer of the gmamma-phosphate from ATP onto the se=rine residue of a biotinylated synthetic: peptide SEQ. ID NO: 1 (Biotin-ahx-

ARKRERAYSFGHHA-amide). Substrate phosphorylation was detected by the following procedure:

Assays were performed in 384well U-bottom white plates. 10 nM activated

AKT enzyme was incubated for 4.0 minutes at room temperature in an assay volume of 20ul containing 50MM MOPS, pH 7.5, 20mM MgCi2, 4uM ATP, 8uM peptide, 0.04 uCi [g->3P) ATPAwel, 1 mM CHAPS, 2 mM DTT, and ful of test compound in 100% DMSO. The reaction was stopped by the addition of 50 ul SPA bead mix (Dulbecco's PBS without Mg?" and Ca? 0.1% Triton X-100, 5mM EDTA, 50uM ATP, 2.5mg/ml Streptavidin-coated SPA beads.) The plate was sealed, the beads were allowed to settle ovemight, and then the plate was counted in a

Packard Topcount Microplate Scintillation Counter (Packard Instrument Co,

Meriden, CT).

The data for dose responses were plotted as % Control calculated with the data reduction formula 100*(U1 -C2)/(C1-C2) versus concentration of compound where U is the unknown value, 1 is the average control value obtained for DMSO, and C2 is the average control value obtained for 0.1M EDTA. Data are fitted to the : curve described by: y = ((Vmax* x) / (K + x)) where Vmax is the upper asymptote and K is the IC50. ’ : : : 20 -

The compound of Example 236 [(S)-3-{3-[2-(4-Amino-furazan-3-yl)-4-(3- chloro-phenyl)-1-ethyl-1 H-imidazo[4,5-c]pyridin-7-ylamino]-propylamino}-propane- 1,2-diol} demonstrated an IC50 (uM) activity of: 0.0689, delta-PH AKT 1; 0.038, delta-

PH AKT2; and 0.032, delta-PH AKT3 in the above assay.

The pharmaceutically active compounds within the scope of this invention are useful as AKT inhibitors in mammals, particularly humans, in need thereof.

The present invention therefore provides a method of treating cancer, arthritis and other conditions requiring AKT inhibition, which comprises administering an effective compound of Formula (1) or a pharmaceutically acceptable salt, hydrate, solvate or pro-drug thereof. The compounds of Formula (1) also provide for a method of treating the above indicated disease states because of their demonstrated ability to act as Akt inhibitors. The drug may be administered to a patient in need thereof by any conventional route of administration, including, but not limited to, intravenous, intramuscular, oral, subcutaneous, intradermal, and parenteral.

The pharmaceutically active compounds of the pres-ent invention are incorporated imsto convenient dosage forms such as capsulezs, tablets, or injectable preparations. Solid or liquid pharmaceutical carriers are ermployed. Solid carriers include, starch , lactose, calcium sulfate dihydrate, terra alb=a, sucrose, talc, gelatin, agar, pectin, a cacia, magnesium stearate, and stearic acid ;. Liquid carriers include syrup, peanut oil, olive oil, saline, and water. Similarly, the= carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alosne or with a wax. The amount of solid carriexr varies widely but, preferably, wik | be from about 25 mg to about 1 g per dosasge unit. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous of nonaqueous Biquid suspension. :

The pharmaceutical preparations are made followiing conventional techniques off a pharmaceutical chemist involving mixing, granulating, and ~ 15 compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, &s appropriate, to give the desired oral or pawrenteral products.

Dosess of the presently invented pharmaceutically active compounds in a pharmaceutiecal dosage unit as described above will be am efficacious, nontoxic quantity prefeerably selected from the range of 0.001 - 1080 mg/kg of active compound, preferably 0.001 - 50 mg/kg. When treating =a human patient in need of an Akt inhibitor, the selected dose is administered preferably from 1-6 times daily, . orally or parenterally. Preferred forms of parenteral administration include topically, rectally, tran sdermally, by injection and continuously by irnfusion. Oral dosage units for human a dministration preferably contain from 0.05 to= 3500 mg of active compound. Oral administration, which uses lower dosages is preferred. Parenteral administration, at high dosages, however, also can be ussed when safe and convenient for the patient.

Optimal dosages to be administered may be reaadily determined by those skilled in the art, and will vary with the particular Akt inhi bitor in use, the strength of the preparation, the mode of administration, and the adwsancement of the disease condition. Additional factors depending on the particular patient being treated will result in a meed to adjust dosages, including patient age=, weight, diet, and time of administration.

The method of this invention of inducing Akt inhibitory activity in mammals, including heuimans, comprises administering to a subject in need of such activity an effective Al<t inhibiting amount of a pharmaceutically ac=tive compound of the present inv-ention.

WO “2005/011700 PCT/US2004/024340

The invention also provides for the use of a compound of Formula (1) in the manufacture of a medicament for use as an Akt inhibitor.

The invention also provides for the use of a compound of Formula (I) in the renanufacture of a medicament for use in therapy.

The invention also provides for the use of a compeound of Formula (1) in the rnanufacture of a medicament for use in treating cancer. n

The invention also provides for the use of a compeound of Formula (1) in the rnanufacture of a medicament for use in treating arthritis.

The invention also provides for a pharmaceutical - composition for use as an «Akt inhibitor which comprises a compound of Formula () anda pharmaceutically =acceptable carrier.

The invention also provides for a pharmaceutical composition for use in the - treatment of cancer which comprises a compound of Formula (1) and a pharmaceutically acceptable carrier.

The invention also provides for a pharmaceutical composition for use in treating arthritis which comprises a compound of Formula (I) and a : pharmaceutically acceptable carrier. ’

No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the prese=nt invention. . 20 In addition, the pharmaceutically active compounds of the present invention can be co-administered with further active ingredients, ssuch as other compounds ' . known to treat cancer or arthritis, or compounds Known to have utility when used in combination with an Akt inhibitor.

Without further elaboration, it is believed that onme skilled in the art can, using the preceding description, utilize the present invention to its fullest extent.

The following Examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in =any way.

Experimental Details

The compounds of Examples 1 to 265 are readily made according to - Schemes 1 to 13 or by analogous methods.

Example 1

Preparation of 4-(4-Phenyi-1 -piperidin-4-yl-1H-imidazo [4.5-clpyridin-2-yh-furazan-3- ylamine trifluoroacetate

WE 2005/011700 PCT/US2004/024340 a) (1-Benzyl-piperidin-4-yl)-(3-nitro-pyridin-4-yl)-armine

A mixture of 4-methoxy-3-nitropyridine 4.349, 281 mmol), 4-amino-1- benzypiperidine (6.01 g, 30.9 mmol), and NaOAc (2.318, 28.1 mmol) in absolute ethanol (20 mL) was stirred at reflux for 54 h. Thea reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was dissolved in

CH.Cl, (100 mL) and washed with water (2 x 30 rml). The organic layer was dried over anhydrous MgSO, and concentrated in vacuo to provide the product (8.78 g) as a dark yellow solid. 1H NMR (400 MHz, CDClg) § 9.21 (s, 1H), 8.26 (dd, J = 6.0, 0.4 Hz, 1 H), 8.20 (broad d, J=T7.1Hz, 1 H)a 7.34-7.25 (complex m, 5H), 6.70 (d, J = 6.0 Hz, 1 H), 3.62-3.53 (m, 1 H), 3.55 (s, 2H), 2.89-2.79 (m, 2 H), 2.30-2.20 (m, 2 H), 2.10-2.00 (m, 2 H), 1.76-1.65 (m, 2 H). b) NA-(1-Benzyl-piperidin-4-yl)-2-chloro-pyridin-38,4-diamine

To a stirred solution of the compound of “Example 1(a) (3.00 g, 9.60 mmol) in conc. HCI at 90 “C was added tin (1) chloride (9.09 g, 48.0 mmol) portionwise over 10-15 min, at which time the resultant mixture was stirred at 90 °C for . additional 30 min. The reaction was cooled to ammbient temperature, and the : precipitated product (HCI salt thereof) was colle=cted via filtration. The free base was isolated upon treatment of the hydrochlorid e salt with excess 2.5 N NaOH, followed by an exhaustive extraction with CH,CHl,, drying of the combined organic - extracts over anhydrous MgSO,, and solvent ewwaporation. Additional product can be obtained upon treatment of the HCI filtrate with 50% NaOH solution, followed by removal of the tin salts via filtration, and extraction of the filtrate with CH2Clo. A total of 3.00 g of the product was obtained as am yellow foamy solid. MS (ES+) m/z 317.2 [M+H]*. c)[1-(1 -Benzyl-piperidin-4-yl)-4-chloro-1 H-imid=azo[4,5-c]pyridin-2-yi}-acetonitrile

A mixture of the compound of Example 1(b) (2.10 g, 6.63 mmol) and ethyl cyanoacetate (5 mL, 46.4 mmol) was heated a—t 180 °c for 2.5 h. Purification of the crude reaction mixture by flash chromatographay (silica gel, 50:1-35:1-20:1

CH,Cl/MeOH gradient) provided the product ( 1.44 g) as a deep yellow foamy solid.

MS (ES+) m/z 366.2 [M+H]*. dn -(1-Benzyl-piperidin-4-yl)-4-phenyl-1 H-imiedlazo]4,5-c]pyridin-2-yl}-acetonitrile

A solution of the compound of Example 1(c) (185 mg, 0.506 mmol), phenylboronic acid (92 mg, 0.758 mmol), and Pd(PPh;).Cl; (35 mg, 0.0506 mmol)

in toluene (5 EL) at ambient temperature was treated with a 2 M solution of sodium carbonate, amd the resultant dark biphasic mixture was heated at reflux for =3 h.

The reaction “was cooled to ambient temperature, concentrated in vacuo, ard purified by flash chromatogrphy (silica gel, 30:11 0:1 CH,Cl/MeOH gradieant) to give the prodRuct (177 mg) as a yellow crystalline solid. MS (ES+) m/z 408.22 [M+HI*. e) [1-(1 -Ben=zy--piperidin-4-yl)-4-phenyl-1 H-imidazol4,5-c}pyridin-2-yl}-furaz=an-3- ylamine

Toa solution of the compound of Example 1(d) (165 mg, 0.405 mnmol) in

MeOH (4 mi) and 2 NHC! (1.5 mL, 3.00 mmol) was added sodium nitrite (66 mg, 0.810 mmol.) portionwise. The reaction mixture was stirred at ambient temperature for 1.5 h, at which time the pH of the solution was adjusted to 12 with 50 wt. %

NaOH aqueous solution. The resultant dark mixture was then treated with hydroxylamine (50 wt. % solution in water, 1.1 mL, 17.95 mmol) and stirred at 80 °C for 15 h— After allowing the reaction to cool to RT, the resulting yellow precipitate “was isolated by filtration, washed with cold MeOH and dried umnder high vacuum to give pure product (85 mg). - MS (ES+) m/z 452.2 [M+H]*. : f) 4-(4-Phe=nyl-1 -piperidin-4-yl-1 H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-yl=amine : : . trifluoroacestate oo

A ssolution of the compound of Example 1(e) (33 mg, 0.073 mmol ) in dry

CH.Cl, (2.25 mL) at RT was treated with 1-chioroethyl chioroformate (24 mil, 0.219 mmol). THe resultant mixture was heated at reflux for 1 h, then cooled te RT and concentrated in vacuo. The residue was then heated at reflux in MeOH for 1 h.

The produmct was isolated by preparative HPLC (Zorbax C18 column, 7 rmicron particle si=ze, 250 mm x 21.2 mm i.d.; 20-90% acetonitrile/water (0.1 % WFA); 20 mU/min; LIV detection at 2564 nm; Ry =4.3 min) to afford the product (27 mg) as a 20 white solicl. MS (ES+) m/z 362.2 [M+H]*.

Example 2

Preparatieon of 4-[4-(3-Chloro-phenyl)-1 -piperidin-4-yi-1 H-imidazo[4.5-cRpyridin-2-yl}- furazan-3-ylamine hydrochloride

The title compound was prepared by substituting 3-chlorophenywlboronic acid for phen! boronic acid in Example 1(d) and the proceeding as describe=d for

Examples 1(e) through 1(f) and triturating with 4N HCl/dioxane. MS (ES+) m/z 306.0 [M+H]*.

Example 3 a) N'-(3-Nitropyridin-4-yl)-2,2-dimethyl-1 ,3-propanediamine

A soliation of 4-methoxy-3-nitropyridine (5.00 g, 32.4 mmol) and 2,2- dimethyl-1,3—propanediamine (16.2 g, 161 mmol) in DMF (100 ranL) was heated at - 100°C for 5 Th. The solvent was removed under reduced pressure to give 7.30 g of the desired compound. 'H NMR (400 MHz, CDCls) 59.20 (s, 28H), 8.10 (br, 1H), 8.20 (d, 1H), 6.70 (d, 1H), 3.25 (d, 2H), 2.60 (s, 2H), 1.25 (br, ZH), 0.95 (s, 6H). : b) 2-[3-(3-N itropyridin-4-ylamino)-2,2-dimethyipropyil-isoindole-~1,3-dione .

A solution of the compound of Example 3(a) (7.30 g, 322.4 mmol) and : phthalic anh ydride (4.80 g, 32.4 mmol) in glacial acetic acid (160 mL) was heated ; overnight at 120 °C. After 16 h, the solution was allowed to co of to RT and the : : 20 solventwas removed in vacuo. The residue was partitioned bestween EtOAc (650 : mL) and 5% NaHCO, (100 mL). The organic layer was washe=d with brine (50 mL) and dried ower Na,SO,. The solvent was removed in vacuo to give 10.5 g of the desired conmpound. MS (ES) m/z 355.2 [M+HJ". ©) 2-[3-(3-Amino-2-chloropyridin-4-ylamino)-2,2-dimethylpropw/il-isoindole-1,3-dione

A suspension of the compound of Example 3(b) (10.5 «g, 29.6 mmol) in conc. HCI ( 220 mL) was heated to 70 °C and tin (Il) chloride cliihydrate (35.3 g, 157 mmol) adde=d portionwise. The solution was heated for 30 mir at 90 °C, allowed to cool and th en filtered. The collected solid was partitioned between EtOAc (760 mL) and 0.5N NJaOH (200 mL). This mixture was filtered and the filter cake slurried with 1.0N NaOH (75 mL). The sluny was extracted with EtOAc (2 x 250 mL) and the combined =organic layers were washed with brine (70 mL), drieed over Na,SO, and concentrated in vacuo to give 5.41 g of the desired compound. MS (ES) m/z 359.2 [M+H]". 35 . d) 4-Chlor-o-1-[3-(1,3-dioxo-1 3-dihydroisoindol-2-yl)-2,2-dimeethylpropy]-1 H- imidazo[4, 5-c]pyridin-2-yl]-acetonitrile

A mixture of the compound of Example 3(c) (5.40 g, 150 mmof) and ethyl cyanoacetate (15- mL) was heated at 190 °C. After 6 h, the cooled crude reaction mixture was subjeected to flash chromatography (silica gel, Et20 to 50%

Et,O/CH.Cl,) to ive 1.70 g of the desired compound. MS (ES) miz 408.0 [M+H]" . e) 4-Chloro~1-[3=-(1 ,3-dioxo-1 3-dihydroisoindol-2-yl)-2,2-dimethylpropyl}-1 H- imidazo[4,5-c]py-ridin-2-yl-hydroxyiminoacetonitrile

Sodium mitrite (0.15 g, 2.20 mmol) was added to a stirred suspension of the compound of E>xample 3(d) (0.45 g, 1.10 mmol)in a mixture of MeOH (10 mL) amd 2N HCI (4.4 mL). After 18 h, the product was isolated by filtration to give 0.41 g ©f the desired conmipound. MS (ES) m/z 437.0 [M+H]". f) 4-Chloro-1-[33-(1,3-dioxo-1 3-dihydroisoindol-2-yl)-2,2-dimethyipropy}-1 H- imidazol4,5-c]peyridin-2-yll-N-hydroxy-2-hydroxyiminoacetamidine

A solutieon of the compound of Example 3(e) (0.40 g, 0.92 mmol), Et:N (1.4 mL) and 50% aqueous hydroxylamine (0.25 mL) in THF (20 mL) was heated in a sealed flask at 90 °C. After 1 h, the reaction was allowed to cool to RT and was partitioned betwveen EtOAc (125 mL) and water (50 mL). The organic layer was washed with water (50 mL), brine (40 mL) and dried over Na,SO;. The solvent was removed in vaecuo to give 0.42 g of the desired compound. MS (ES) m/z 470.2 :

MH" oo +) 2-{3-[2-(4-M\minofurazan-3-yf}-4-chioro-1 H-imidazo[4,5-c]pyridin-1 -yi}-2,2- dimethylpropy-i}-isoindole-1,3-dione

A solution of the compound of Example 3(f) (0.42 g, 0.91 mmol) in a mixture of dioxane (14% mL) and Et;N (1.4 mL) was heated to 150 °C in a sealed flask. After 1 h, the reaction was allowed to cool to RT and the solvent was removed in va clo.

Flash chromaatography (silica gel, 3% MeOH/CH,Cl,) gave 0.32 g of the desirexd compound. NAS (ES) m/z 452.2 [M+H]". h) N~{3-[2-(4--Aminofurazan-3-yl)-4-(3-chlorophenyl)-1H-imidazo{4,5-clpyridin—~1-yi} 2,2-dimethylporopyl}-phthalamic acid

A stirmred mixture of toluene (5 mi), EtOH (5 mL), 3-chlorophenyl-boromic acid (0.045 gg, 0.29 mmol) and the compound of Example 3(g) (0.10 g, 0.22 mmol) was treated with 1.0 M Na,COs (0.6 mL) followed by (PhsP)4Pd (0.025g, 0.022 mmol). After 5 h at reflux, the solvent was removed in vacuo and the residue= was dissolved in “water (5 mL). The solution was adjusted to pH 5 with 0.2 N HCI and the resulting suspension was extracted with EtOAc (3 x 75 mL). The combinecd extracts were dried over Na,SO, and the solvent was removed in vacuo.

Purification of the by preparative HPLC (10 to 50% acetonitrile/water, 01% TF A over 10 min., 50 x 20 mm. 1.D. “YMC Combi-Prep ODS-A) gave 0.068 9 of the desired compound. MS (ES) 546.2 [(M+H]". i) 4-[1-(3-Amino-2,2-dimethylp ropyl)-4-(3-chlorophenyl)-1 H-imidazo[4,5-c]pyriedin-2- yl}furazan-3-ylamine trifluoroacetate

A solution of the compound of Example 3(h) (0.055 g, 0.083 mmol) in =a mixture of EtOH (7 mL) and hydrazine hydrate (3 mL) was heated at reflux forr 20 h.

The solvent was removed in vacuo and the residue subjected to preparative HPLC (10 to 50% acetonitrile/water, 0.1% TFA over 10 min., 50 x 20 mm. 1.D. YMC

Combi-Prep ODS-A) to give 0.020 g of the title compound. MS (ES) m/z 398..2

M+H]". :

Example 4

Preparation of 4-11-(3-amino-2 2-dimethylpropyl)-4-phenyl-1H-imidazold,5- : clpyridinyl-2-yi}-furazan-3-ylarmine trifluoroacetate "

The title compound was prepared in an analogous manner to Example 3 by substituting phenyl boronic acid for 3-chiorophenyl-boronic acid in step (h). IVS (ES) m/z 364.2 [M+H]".

Example 5

Preparation of 4-1-(5-aminopentyl)-4-phenyl-1H-imidazol4.5-clpyridin-2-yl -1.2.5- oxadiazol-3-amine triflucroacetate

The title compound was prepared in an analogous manner to Example 3 by substituting 1,5-diaminopentaane for 2,2-dimethyl-1,3-propanediamine in stepo (a) and phenyl boronic acid for 3-chlorophenyl-boronic acid in step (h). MS (ESS) m/z 364.0 [M+H]".

Example 6

Preparation of 4-[1 -(6-aminohexyl)-4-phenyl-1 H-imidazo[4,5=--clpyridin-2-y}-1 2.5 oxacliazol-3-amine trifluoroacetate . The title compound was prepared in an analogous manner to Example 3 by substituting 1,6-diaminohexane for 2,2-dimethyl-1,3-propan ediamine in step (a) and phe nyl boronic acid for 3-chlorophenyl-boronic acid in step (h). MS (ES) m/z 378.0 [M+H]".

Example 7

Preeparation of 4-[1-(5-aminopentyl)-4-(3-chloro henvi)-1H—imidazo[4,5-clpyridin-2- yi]-—1.2.5-oxadiazol-3-amine trifiuoroacetate

The title compound was prepared in an analogous mmanner to Example 3 by substituting 1,5-diaminopentane for 2,2-dimethyl-1,3-propaanediamine in step (a).

MSS (ES) m/z 398.0 [M+H]". : Example 8

Presparation of 4-]1-(6-aminohexyl)-4-(3-chiorophenyl)-1 H- imidazo[4.5-clpyridin-2- yl}—1.2,5-oxadiazol-3-amine trifluoroacetate :

The title compound was prepared in an analogous manner to Example 3 by - substituting 1,6-diaminohexane for 2,2-dimethyl-1,3-propaanediamine in step (a).

MSS (ES) miz 412.0 [M+H]".

Example 8 .

Preparation of 4-[1-(3-amino-2.2-dimethylpropyl)-4-(3-mefthoxypheny()-1 H- immidazo[4.5-clpyridinyl-2-yl J-furazan-3-ylamine trifluoroace=tate

The title compound was prepared in an analogouss manner to Example 3 by substituting 3-methoxypheny! boronic acid for 3-chlorophe=nyl-boronic acid in step (h ). MS (ES) m/z 394.2 M+H]".

Example 10

1,2,5-oxadiazol-3-armine trifluoroacetate

The title cormpound was prepared in an analogous manneer to Example 3 by substituting 1,5-diamminopentane for 2,2-dimethyl-1 ,3-propanedizamine in step (a) and 3-thienylboroniic acid for 3-chlorophenyi-boronic acid in step (h). MS (ES) m/z 370.0 [M+H]".

Example 11

Preparation of 4-{ 8 -(6-aminohexyl)-4-(3-thienyl)-1H-imidazol4.58-cloyridin-2-vil 1,2.5-oxadiazol-3- amine trifluoroacetate

The title compound was prepared in an analogous mananer to Example 3 by substituting 1,6-di.aminohexane for 2,2-dimethyl-1,3-propanedi-amine in step (a) and 3-thienylboronic aacid for 3-chlorophenyl-boronic acid in step (ha). MS (ES) m/z 384.0 [M+H]".

Example 12 : : Preparation of 4-%4-chloro-1 ~(cyclopropylmethyl)-1 H-imidazo[4k,5-c]pyridin-2-yl}- : 1,2,5-oxadiazol-3-amine : : a) N-(Cyclopropywimethyi)-3-nitro-4-pyridinamine 4-methoxy-3-nitropyridine (10.0 g, 64 mmol), cyclopro-pylmethyl amine (4.56 g, 64 mmol), anc EtOH (7 mL) were combined in a sealed tute and heated to 85 °C with vigourou s shaking for 48 h. The mixture was concentitrated in vacuo to afford the desiread compound as a solid (12.0 g). MS(ES+) m/z 194 [M+H]". b) 2-Chloro-N*-(_cyclopropylmethyl)-3,4-pyridinediamine

A solutiosn of the compound of Example 12(a) (12.09 , 62 mmol) in EtOH (136 mL) was cooled to 0 oC. Conc. HCI (136 mL) was adde=d and the mixture was stirred at 0 °C for 15 min. Tin (Il) chloride dihydrate (42.2 g, 188 mmol) was added and stirring wass continued at 0 °C for 3 h. The reaction was quenched by adjusting to pH 8 with 1VB NaOH. The mixture was extracted with EtO®Ac (200 mL x 3) and : the combined e=xtracts were washed with brine (300 mL), dri-ed over Na,SO;, and concentrated ir vacuo to afford the desired compound (3.988 g). MS(ES+) m/z 198 [M+H]".

c) [4~Chloro-1-(cyclopropylmethyl)-1 H-imidazo[4,5-c]pyridin-2-yl]=acetonitrile

The compound of Example 12(b) (3.98 g, 20 mmol), ethy~Icyanoacetate (10 mL, 94 mmol), and N,N-dimethylacetamide (10 mL) were combired ina sealed tube= and heated to 150 °C for 3 h. The mixture was cooled to R_T and concentrated in veacuo. Flash chromatography (silica gel, MeOH/CHCIs gradient) yielded the desired compound (3.83 g). MS(ES+) m/z 247 [M+H]". d) (=2E)-[4-Chloro-1 -(cyclopropyimethyl)-1 H-imidazo[4,5-c]pyridir-2- yi(Mydroxyimino)ethanenitrile

Sodium nitrite (2.11 g, 31 mmol) was added to a solutior of the compound of Example 12(c) (3.83 g, 16 mmol) in MeOH (110 mL) and 2M HCI (50 mL). The mixcture was stirred at RT for 1.5 h and then cooled to 0 °C. Thee resulting pre cipitate was collected via filtration, rinsed with cold water aned dried to afford the dessired compound as a yellow solid (2.4 g). MS(ES+) m/z 276 M+H]". €) =4-{4-Chloro-1 -(cyclopropylmethyl)-1 H-imidazo[4,5-c]pyridin-2-yl]-1 ,2,5-oxadiazol- 3-aamine

The compound of Example 12(d) (24 g, 8.7 mmol), THRF (58 mL), Et:N (4.7 mL), and 50% aqueous hydroxylamine (1.56 mL) were combineed in a sealed tube aned heated to 100 °C for 48 h. The mixture was then cooled to RT and comncentrated in vacuo. Flash chromatography (silica gel, MeCBH/CHCls gradient) yieelded the title compound (1.6 g). MS(ES+) m/z 291 [M+H]".

Example 13

Preparation of 4-[4-(3-chlorophenyl)-1 -(cyclopropylmethyh-1 H—imidazo[4.5- clpoyridin-2-yll-1,2,5-oxadiazol-3-amine

A mixture of toluene (8.4 mL) and 2M Na,COs (1.0 mL) was deoxygenated by purging with nitrogen. The compound of Example 12(e) (1€00 mg, 0.31 mmol), 3- chlorophenyl boronic acid (81 mg, 0.52 mmol), and diechlorobis(triphenylphosphine)paliadium(ll) (24 mg, 0.035 mranol) were added and the mixture was heated to 100 °C for 16 h. After cooling to RW, the reaction was concentrated in vacuo. Flash chromatography (silica gel, MeCOH/CHCI, gradient) gaave the title compound (66 mg). MS(ES+) mle 367 [M+H]".

Example 14

Preparation of 4-]1= (cyclopropylmethyl)-4-(2-methyiphenyl)-1H-imidazzol4.5- clpyridin-2-yil-1 .2.5—~oxadiazol-3-amine

The title cornpound was prepared in an analogous manner to Example 13 by substituting 2-m ethylphenylboronic acid for 3~chlorophenylboronic acid.

MS(ES+) m/z 347.€ [M+HT".

Example 15

Preparation of 4-[4-(2-chlorophenyl)-1-(cyclopro, methyl)-1H-imida==o[4.5- clpyridin-2-yl}-1 ,2.55 oxadiazol-3-amine

The title compound was prepared in an analogous manner to Example 13 by substituting 2-chiorophenylboronic acid for 3-chlorophenylboronic acid.

MS(ES+) m/z 367.0 [M+H]". : ' Example 16 : . 20

Preparation of 4-[ 1-{cyclopropyimethyl)-4-(3-furanyl)-1 H-imidazo}4,55-c]pyridin-2-yil- : 1,2,5-oxadiazol-3-~amine

The title compound was prepared in an analogous manner &o Example 13 by substituting 3—furanylboronic acid for 3-chlorophenyl boronic acied. MS(ES+) m/z 323.0 (M+H]".

Example 17

Preparation of 4—[1-ethyl-7-(piperidin-4-yloxy)-1 H-imidazo[4.5-clpyridin-2-yll- furazan-3-ylamire trifluoroacetate a) Ethyl (3-nitropyridin-4-yl)amine

A solution consisting of 4-methoxy-3-nitropyridine (15.0 g, 97.3 mrol)with ethyl amine (46.5 mL of 70% aqueous solution, 584 mmol) in ethanol (30 mL) was stirred at 85 °C in a sealed flask for 2 h. Removal of all volatiles ir vacuo afforded the title compound (16.2 g, 99 %). MS: (M+H)" = m/z 168.

b) Ethyl (3-bromo-5—nitropyridin-4-yl)amine

A mixture cosnsisting of ethyl (3-nitropyridin-4-yl)amine (4 1.76 g, 70 mmol) in acetic acid (140 mL.) with sodium acetate (28.7 g, 350 mmol) and bromine (13.44 g, 84 mmol) was stireadin a sealed flask at 100 OC for 18 h. Most of the solvert was removed in vacuo a&nd the residue partitioned between CH2Cl2 and water a nd the aqueous layer basi-Tied with NaHCO3. The organic extract was washed with. water then brine, dried (N122S04) and all volatiles removed in vacuo. The residue was chromatographed on silica gel eluted with ethyl acetate: hexane (2:8) to afford the title compound (10 .4g, 60%). MS: (M+H)" = m/z 246. c) 5-Bromo-N4-ethayl-pyridine-3,4-diamine

A mixture of ethyl (3-bromo-5-nitropyridin-4-yl)amine (7.0 g, 28.4 m mol) in acetic acid (100 mal) with iron powder (<50 micron, 9.51 g, 170 mmol) wass stirred at 75 OC for 1 h. The reaction mixture was cooled then diluted with EtOAc: CHCl (1:4) and filtered through celite. The filtrate was concentrated in vacuo them chromatographed on silica gel eluted with ethyl acetate: methanol (96:4) to afford the title compound (5.68 g, 92.7%). MS: (M+H)" = m/z 216. _ d) (7-Bromo-1-ethyl-1 H-imidazo[4,5-c]pyridin-2-yl)-acetonitrile :

A solution of 5-Bromo-N4-ethyl-pyridine-3,4-diamine (5.88 g, 26.3 mmol)in : ethyl cyanoaceta€e (5.6 mL, 52.6 mmol) was stirred at 190 °C for 1 h. The product crystallized on co-oling and addition of EtOAc (50 mL). The solid was collected, washed with EtOAc then dried to afford the title compound (4.15 g, 59%). MS: (M+H)" = m/z 265. e) 4-(7-Bromo-1—ethyl-1H-imidazo[4,5-c Jpyridin-2-yl)-[1 ,2,5)oxadiazolidin~—3-ylamine

To a solution of (7-bromo-1-ethyh-1 H-imidazo[4,5-c]pyridin-2-yl)-amcetonitrile (3.2 g, 12.1 mmol) in methanol (40 mL) was added in portions sodium nit_rite (1.67 g, 24.2 mmol). T he resulting mixture was stirred 2 h then adjusted to pH 12 with 50% aqueous NaOH. To this was added 50% aqueous NHO0H (33 mL) =and the mixture was stirred at 90 °C for 2 h. The solid which formed on cooling w.ras collected by filtraation to afford the title compound (2.50 g, 67%). MS: (M+H)" = m/z © 3089. ' f) [4-(7-Bromo-1 -ethyi-1 H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-yi}-carbarmic acid tert-butyl ester

A solution consisting of 4-(7-bromo-1-ethyl-1 H-imidazo[4,5-¢ Jpyridin-2-yl)— [1,2.5]oxadiazolidin-3-ylamine (2.14 g, 6.95 mmol) in methylene chloride (10 mL) and pyridine (20 mL) with di-t-butyl dicarbonate (2.27 g, 10.43 mmol) and DMAP (0.85 g, €.95 mmol) was stirred at 90 OC in a sealed tube for 2.5 h. Additional di- t- butyl dicarbonate (2.27 g, 10.43 mmol) was added and stirring at 90 °C continue=d . for 18 h. The product muixture was partitioned between EtOAc and water, the layers separated and the orgaanic extract washed with water then brine, dried (NasS0O4) and all volitiles removed in vacuo. The residue was chromatographed on silica 20% EtOAc in hexane to afford the title compound as an off-white solid 1.60 g, 58.4%) MS: (M+H)" = rm/z 409. q) [4-(1-Ethyl-7- hydroxy-1 H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-yl]-carbamic acid tert-butyl ester

To a solution oF [4-(7-bromo-1 —ethyl-1H-imidazo[4,5-clpyridin-2-yi)-furazan- 3-yl]-carbamic acid tert-butyl ester (205 mg, 0.5 mmol) in THF (4 mL) stirred at 78 oC under Np was added n-BuLi (0.6 mL of 256M solution in hexane, 1.25 mmosl).

This was stirred at —78 °C for 20 min then trimethyl borate (168 uL, 1.5 mmol) with

THF (1 mL) was adde=d. Stirring was continued for 1.5 h while the reaction mixture was allowed to warm to room temperature. To the resulting mixture was addecl a i 20 solution consisting of 30% H202 (1.1 mL) in 3N NaOH (0.35 mL) and stirring : continued at room termperature for 30 min. The reaction mixture was diluted with

EtOAc then washed with 1N NaOH (3X). The combined aqueous extract was acidified with 6N HC! and the product extracted into EtOAc. The organic extract k was dried (NapSO4) and all volitiles removed in vacuo to afford the product ass an : orange solid (144 mgs, 83%). MS: (M+H)" = m/z 347. h) 4-[2-(4-tert-Butoxyrcarbonylamino-furazan-3-yl)-1-ethyl-1H -imidazo[4,5-c ]pyridin-7-yloxyl-pipe=ridine-1-carboxylic acid tert-butyl ester

To a stirred mnixture of triphenyl phosphine polystyrene (2.4 g, 1.2 mmol/g, 2.88 mmol) in CHC 13 (25 mL) was added 4-hydroxypiperidine-1 -carboxylic amcid tert-butyl ester (1.15 g, 5.76 mmol) followed by diethyl azodicarboxylate (0.45 mL, 2.88 mmol). After 10 min at room temperature the mixture was cooled to 0 °C and a solution of [4-(1-ethyl-7- hydroxy-1 H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-y-1}- carbamic acid tert-butyl ester (200 mg, 0.58 mmol) in CHaCl2 (15 mL) was a dded.

This was stirred 1.5 hat 0 OC then filtered. the resin was washed with CHoCR and the combined orgarmic extract washed with 1 N NaOH soln then water, dried (NapS04) and all volitiles removed. The residue was purified by preparative HPLC

(eluted with CH3CN / H20 /0.1% TFA) to afford the title compound as an off white solid (131 mg, 43%). MS: (M+H)" = m/z 530. i) 4-[1-Ethyl-7-(piperidin-4-yloxy)-1 H-imidazo[4,5-clpyridin-2-yl]-furazan-3-ylamine trifluoroacetate

A solution of 4-[2-(4-tert-butoxycarkbonylamino-furazan-3-yi)-1 -ethyl-1H - imidazo[4,5-c Jpyridin-7-yloxy}-piperidine-1 -carboxylic acid tert-butyl ester (130 mg, 0.25 mmol) in CHaCla (1.5 mL) with TFA (0.75 mL) was stirred at room temperature for 40 min. Removal of all volatiles followed by purification by preparative HPLC (eluted with CH3CN / HO) afforded the title compound (80 mg, 97%). MS: (M+H)" = m/z 330.

Example 18

Preparation of 1-2- 4-Amino-furazan-3-y1)-1-ethyi-4-(3-chioro-pheny-1H- imidazol4,5-clpyridin-7-yll-1-(3-amino-py rrolidin-1-yl}-methanone trifluoroacetate . a) 5-Bromo-2-chioro-N4-ethyl-pyridine-3,,4-diamine

To a solution of ethyl (3-bromo-5-nitropyridin-4-yl)amine (22.0 g, 89.4 mmol) in concentrated HCI (250 mL) was added in portions tinll) chloride dihydrate (60.5 ‘g, 270 mmol). The mixture was stirred 1 h at room temperature then poured into ices : (300 g). EtOAc (500 mL) was added and the mixture made basic with NaOH. The layers were separated and the organic extract washed with water then brine, dried (NapSO4) and all volatiles removed. The residue was purified by chromatography on silica eluted with 25% EtOAc, 76% hexanes to afford the title compound (17.8 g , 80%). MS (ES+) m/z 250(M+H)*. b) N-(5-Bromo-2-chloro-4-ethylamino-pyridin-3-yl)-cyanoacetamide

To a solution of 5-bromo-2-chloro-N4-ethyl-pyridine-3,4-diamine (1 7.79, 70.9 mmol)in DMF (100 mL) stirred at O oC was added cyanoacstic acid (9.06 g, 106 mmol), N-methyl morpholine (39 mL, 350 mmol) and EDCI (20.3 g, 106 mmol).

The cooling bath was removed and stirring continued 3h. EtOAc (300 mL) was added and the resulting mixture was washed with water then brine. crystalization from EtOAc / hexanes afforded the title compound (225g. quantative). MS (ES+) m/z 317(M+H)*. ¢) (7-Bromo-4-chioro-1-ethyl-1 H-imida=zo[4,5-c]pyridin-2-yl)-acetonitrile

A solution of N-(5-bromo-2-chloro-4-ethylamino-pyridin-3-y1}- cy anoacetamide (35.6 g, 112 mmol) in acetic acid (300 mL) was s*tirred at 90 oC for 11. All volatiles were removed to afford the title compound used assis in the next st ep (29.5 9). MS (ES+) m/z 299(M+H)*. dD) (7-Bromo-4-chioro-1-ethyk1 H-imidazo[4,5-c]pyridin-2-yl)-hydro=xyimino- a cetonitrile

To a mixture of (7-bromo-4-chloro-1 -ethyl-1 H-imidazo[4,5—c]pyridin-2-yi)- acetonitrile (29.5 g, 98 mmol) in2N HCI (400 mL) was added portion wise, at room temperature, over 20 min sodium nitrite (14.0 g, 203 mmol)s. After stirring an additional 30 min the precipitated product was filtered, washed with water and dried to afford the title compound used as is in the next step (32 g, quaant.). MS (ES+) rn/z 328(M+H)*. : «)4-(7-Bromo-4-chloro-1 -ethyl-1 H-imidazo[4,5-c]pyridin-2-yl)-1 ,2 5-oxadiazol-3- © amine ) A solution of (7-bromo-4-chloro-1 -ethyl-1 H-imidazo[4,5-c=]pyridin-2-yl)- hydroxyimino-acetonitrile (98 mmol crude from previous step) in. THF (250 mL) with

TEA (40'mL) and 50% hydroxyl amine in water (16 mL) was stirred in a sealed flask at 90 OC for 1.5 h. The solution was cooled to room temperature then partitioned ’ “between EtOAc and water. The organic extract was washed wit_h brine, dried and : all volatiles removed. the residue was dissolved in dioxane (200 mL) with TEA (35 " mL) and stirred in a sealed flask at 150 OC for 1.5 h. The solvemnt was removed in vacuo and the residue crystallized from methylene chloride to amfford the title compound (17.3 g, 51% for three steps). MS (ES+) m/z 343(M—+H)*. f) 1,1-Dimethylethy! [4~(7-bromo-4-chioro-1-ethyi-1 H-imidazol4 . ,5-c]pyridin-2-y1)- 1,2,5-oxadiazol-3-ylJcarbamate

A solution consisting of 4-(7-bromo-4-chloro-1-ethyi-1 HA¥-imidazo[4,5- cjpyridin-2-yl)-1 2,5-oxadiazol-3-amine (8.5 g, 24.7 mmol) in 1. 2-dichloroethane (140 mL) and pyridine (70 mL) with di-t-butyl dicarbonate (21.54 g, 98.8 mmol) and

DMAP (3.01 g, 24.7 mmol) was stired at 85°Cina sealed flamsk for 1 h. The - product mixture was partitioned between EtOAc and 1N HCI, the layers separated and the organic extract washed with 1N HCI then brine, dried e(Na2S04) and all volatiles removed in vacuo. The residue was triturated with EROACc to afford the title compound as beige solid (5.06 g), MS (ES+) m/z 443(M+B)*. The mother liquor was evaporated to dryness and treated with 2% trifluorc>acetic acid in dichloromethane (100mL) for 20 h. The rexaction mixture was neutralized with saturated sodium bicarbonate, then washeed with brine, dried (NapSO4) and all volatiles removed in vacuo The residue was chromatagraphed on silica (20%

EtOAc in hexane) to afford the title compound (2.450). MS (ES+) m/z 443(M+H)*. =< The combined weight of the title compound was 8.55g (78%). g) 4-Chloro-2-{4-({{(1 1-dimethylethyl)oxy*Icarbonyl}amino)-1 ,2,5-oxadiazol-3-yl}-1- ethyl-1 H-imidazo[4,5-c]pyridine-7-carboxylic acid

To a solution of [4-(7-bromo-4-chmioro-1-ethyl-1 H-imidazo[4,5-c]pyridin-2- 20 yl)furazan-3-yljcarbamic acid tert-butyl ester (1.0 9, 2.25 mmol) in dry THF stirred at 78 ©C under Np was added n-butyl i&thium (2.7 mL of 2.5 M solution in hexane=s, 6.75 mmol) rapidly dropwise. This was sstired 1 min then CO» was bubbled throucgh the solution for 30 min while the temperature was maintained at —-78 C. The mixture was allowed to warm to room te=mperature then partitioned between EtOAc and 1 N HCI. The organic extract was weashed with water then brine and dried (Na2S0y). The organic solution was pamssed through a silica plug then all volatile s were removed in vacuo to afford the title compound (620 mg, 67%). MS: (M+H)" = : m/z 409. : _ h) (4{7-11-(3-tert _Butoxycarbonylaminepyrolidin-1-yl)methanoy(}-4-chioro-1 -eth=yl- : 1H -imidazo[4,5-a]pyridin-2-yl{furazan-3-yl)carbamic acid tert-butyl ester :

A mixture consisting of 4-chloroe-2-{4-({[(1,1- : dimethylethyl)oxylcarbonyl}amino)-1,2, 5-oxadiazol-3-yl]-1-ethyl-1H-imidazo[4,5- clpyridine-7-carboxylic acid (410 mg, 1 mmol), Pyrrolidin-3-yl-carbamic acid tert - butyl ester (327 mg, 2 mmol), HOAT (272 mg, 2 mmol), EDCI (383 mg, 2 mmol® and N-methyl morpholine (2 mL) in DAF (4 mL) was stirred at room temperature for 20 h. The mixture was partitioned betvween EtOAc and 1 N HCI. The organic extcract was washed with water then brine, dried (Na2S04) and all volitiles removed in vacuo. Chromatography on silica (eluted with75% EtOAc, 25% hexanes) affordeed the title compound (375 mg, 81%). MS: (M+H)' = m/z 577. i) {4-[7-(3-tert-Butoxycarbonylaminopywrrolidin-1 -yimethy})-4-(3-chlorophenyl)-1- ethyl-1 H-imidazo[4,5-c]pyridin-2-yllfur-azan-3-yl}carbamic acid tert-butyl ester

A mixture consisting of (4-{7-[~1-(3-tert -Butoxycarbonylaminopyrrolidin-4 - yl)methanoyl]-4-chloro-1-ethyl-1H -im jdazol4,5-a}pyridin-2-yl}furazan-3-yl)carb=amic acid tert-butyl ester (100 mg, 0.17 mryol), 3-chlorophenylboronic acid (63 mg, ©.34 mmol) and tetrakis(triphenyiphosphin e)palladium(0) (25 mg) in toluene (2.3 mL)

with E-tOH (0.25 mL) and 2 M aqueous NapCO3 solution (0.30 mL) was -stirred at 90 OC. ‘for 18 h in a sealed tube. The organic solution was separated ana chromatographed on silica (eluted with 60% EtOAc, 40% hexanes) to afford the title compound (130 mg, 86%). MS: (M+H)" = m/z 653. . j) 1{2-(4-Amino-furazan-3-yl)-1 -ethyle4-(3-chlorophenyl)-1 H-imidazo[4,5-clpyridin- 7-yl}-1 -(3-amino-pyrrolidin-1-yl)-methanone trifluoroacetate

A solution of {4-[7-((S)-3-tert-butoxycarbonylaminopyrrolidin-1 -yBmethyl)-4- (3-chelorophenyl)-1 -ethyi-1 H-imidazol4,5-clpyridin-2-yilfurazan-3-yl}carbeamic acid tert-butyl ester (130 mg, 0.2 mmol) in CHoCla (2 mL) with TFA (1 mL) was sstirred at room temperature for 1h. All volatiles were removed and the residues purified by

HPLC (acetonitrile water gradient 0.1% TFA) to afford the title compou nd (61 mg, 68%). MS: (M+H)" = m/z 453.

Example 19

Preparation of 1-[2-(4-Aminofurazan-3-yl)-1 -ethyl4-phenyl-1 -H-imidaz_[4,5- clpyeridin-7-yil-1-(3-aminopyrrolidin-1-y)methanone hydrochloride

The title compound was prepared in an analogous manner to E=xample 18

B by ssubstituting phenyl boronic acid for 3-chlorophenylboronic acid in s-tep (7) and Co

Bh tritumrating with 4N HCl/dioxane. MS(ES+) m/z 419.0 [M+H]". .

Example 20

Pre=paration of 1-[2-(4-Aminofurazan-3-yl)-1-ethyl-4-thiophen-3-yi-1 -Hi-imidazoj4.5- clpyridin-7-yll-1 -(3-aminopyrolidin-1-yl)methanone hydrochloride

The title compound was prepared in an analogous manner to Example 18 by substituting 3-thienylboronic acid for 3-chlorophenylboronic acid ir step (i) and tritwrating with 4N HCl/dioxane. MS(ES+) m/z 425.0 (M+H]".

Example 21 :

Preparation of 1-12-(4-Aminofurazan-3-y))-1-ethyl-4-pyridin-yl-1-H-im idazo[4.5- clpvridin-7-yil-1 -(3-aminopyrrolidin-1-ylmethanone :

The title compound was prepared in an analogous manner to Example ~18 by substituting 4-pyridylboronic acid for 3-chiorophenylboronic acid in step (iD.

MS(ES+) m/z 420.0 [M+H]".

Example 22

Preparation of 1-2-(4-Aminof urazan-3-yl)-1-eth \-4-pyridin-3-yl-1-H-imidazo[4, 5- clovridin-7-vil-1-(3-aminopyrreolidin-1-yimethanone

The title compound was prepared in an analogous manner to Example 18 by substituting 3-pyridylbororic acid for 3-chlorophenylboronic acid in step (i).

MS(ES+) m/z 420.0 [M+HT".

Example 23

Preparation of 1-[2-(4-Aminofurazan-3- 1-ethyl-4-furan-3-yl-1-H-imidazo[4,5- clpyridin-7-yl}-1-(3-aminopyrvolidin-1 -yl)methanone "The title compound vwas prepared in an analogous manner to Example= 18 by substituting 3-furanylboronic acid for 3-chlorophenylboronic acid in step (i=. _ MS(ES+) m/z 409.0 [M+H]".

Example 24 :

Preparation of 1-[2-(4-Amin©-furazan-3-yh-4-chloro-1 -ethyl-1-H-imidazo[4,5- clpyridin-7-yli-1 -(3-amino-pwrrolidin-1-yl)-methanone trifiuoroacetate

The title compound was prepared in an analogous manner to Example 18 except omitting step (i). MS(ES+) m/z 409.0 [M+H]".

Example 25

Preparation of 1-[2-(4-Amirso-furazan-3-yl)-4-(1 H-pyrrol-2-yl))-1-ethyl-1-H- imidazo[4.5-clpyridin-7-y!}-1 -(3-amino-pyrrolidin-1-yl}-methanone trifluoroacestate

The title compound was prepared in an analogous manner to Example 18 by substituting 2-pyrroleborronic acid for 3-chlorophenylboronic acid in step Ci).

MS(ES+) m/z 408.0 [M+H]™. 40 Example 26

Preparation of 1-] 2-(4-Amino-furazan-3-yl)-1 -ethyl-4-(2-methoxyphermyi)-1 H- imidazol4.5-clpyridin-7-yi}-1-(3-amino-pyrrolidin-1-yl methanone trifl®ioroacetate

The title compound was prepared in an analogous manner to Example 18 by substituting 2-methoxyphenylboronic acid for 3-chlorophenylbororic acid in step (). MS(ES+) m/z 449.0 [M+H]".

Example 27 .

Preparation of 1-[2-(4-Amino-furazan-3-yl)-1 -ethyl-4-furan-2-yl-1H-inmidazo[4.5- clpyridin-7-yil-1-(3-amino-pyrrolidin-1 -yl)-methanone trifluoroacetate

The title compound was prepared in an analogous manner to Example 18 by substituting 2-furanylboronic acid for 3-chlorophenylboronic acid in step (i).

MS(ES+) m/z 409.0 [M+H]". : Example 28 20° Preparation of 2-(4-Amino-furazan-3-yl)-1-ethyl-4-phenyl-1 H-imidazeo[4,5-clpyridine- 7-carboxylic acid [1-(4-chloro-benzyl)-2-hydroxy-ethyll-amide

The title compound was prepared in an analogous manner to Example 18 : by substituting 2-amino-3-(4-chlorophenyl)-1-propanol for pyrrolidin—3-yl-carbamic acid tert -butyl ester in step (h) and phenylboronic acid for 3-chloropehenylboronic acid in step (i). MS(ES+) m/z 518.0 [M+H]". : Example 29

Preparation of 2-(4-Amino-furazan-3-yi)-1-ethyl-4-(3-chloro-phenyl)—1 H-imidazo[4.5- clpyridine-7-carboxylic acid [1-(4-chloro-benzyh)-2-hydroxy-ethyll-anide

The title compound was prepared in an analogous manner teo Example 18 by substituting 2-amino-3-(4-chlorophenyl)-1-propanol for pyrrolidin—3-yl-carbamic acid tert -butyl ester in step (h). MS(ES+) m/z 552.0 [M+H]".

Example 30

Preparation of 2-(4-Amiro-furazan-3-yl)-1-ethyl-4~(2,3-dichloro-phenyl)-1 H- imidazo[4 5-clpyridine-7 ~carboxylic acid [1-(4-chloro-benzyl)-2-hydroxy-ethyl l-amide trifluoroacetate

The title compouand was prepared in an analogous manner to Example 18. by substituting 2-amino—3-(4-chlorophenyl)-1-propanol for pyrrolidin-3-yl-car bamic acid tert -butyl ester in sstep (h) and 2,3-dichlorophenylboronic acid for 3- chlorophenylboronic acid in step (i). MS(ES+) m/z 588.0 (M+H]".

Example 31

Preparation of 2-(4-Am ino-furazan-3-yl)-1-ethyi-4- 2.chloro-phenyl)-1H-imiciazo[4,5- clpvridine-7-carboxylic acid [1-(4-chloro-benzyl -2-hydroxy-ethyll-amide trifluoroacetate

The title compound was prepared in an analogous manner to Example 18 by substituting 2-amino-3-(4-chlorophenyl)-1-propanol for pyrrolidin-3-yl-caarbamic . acid tert -butyl ester in step (h) and 2-chiorophenylboronic acid for 3- chlorophenylboronic acid in step (i). MS(ES+) m/z 552.0 (M+H]".

Example 32 . Preparation of 2-(4-Annino-furazan-3-yl)-1 -ethyl-4-(2-hydroxy-phenyi}-1 H- imidazo[4.5-clpyridine—7-carboxylic acid [1-(4-chioro-benzyl)-2-hydroxy-etiavil-amide trifluoroacétate

The title compound was prepared in an analogous manner to Exarmple 18 by substituting 2-amire o-3-(4-chlorophenyl)-1-propanol for pyrrolidin-3-yl-caarbamic acid tert -butyl ester ir step (h) and 2-hydroxyphenylboronic acid for 3- chlorophenylboronic acid in step (i). MS(ES+) m/z 534.0 [M+H]". . , Example 33

Preparation of 2-(4-Armino-furazan-3-yl)-4-(3-chloro-phenyl)-1 -ethyl-1H-inmidazo[4.5- clpyridine-7-carboxyliec acid pyrrolidin-3-ylamide trifluoroacetate

The title compound was prepared in an analogous manner to Exammple 18 by substituting 1,1-dirnethylethyl 3-amino-1-pyrrolidinecarboxylate for pyrxolidin-3- yl-carbamic acid tert —butyl ester in step (h). MS(ES+) miz 453.0 [M+H]".

Example 34

Preparation of 2-(4-Amino-furazan-3- he nyl-1-ethyk-1 H-imidazo[4.5-clpyridine-

S 7-carboxylic acid pyrrolidin-3-ylamide trifluoro=acetate

The title compound was prepared in ar analogous manner to Example 18 by substituting 1,1-dimethylethyl 3-amino-1-pysrrolidinecarboxylate for pyrrolidin-3- yl-carbamic acid tert -butyl ester in step (h) ard phenylboronic acid for 3- chiorophenylboronic acid in step (i). MS(ES+D m/z 419.0 [MH].

Example 35

Preparation of 2-{4-Amino-furazan-3-yl)-4-(5- chloro-thiophen-2-yl}-1-ethyl-1H- imidazo[4,5-clpyridine-7-carboxylic acid rramlidin-3-viamide trifluoroacetate

The title compound was prepared in aan analogous manner to Example 18 by substituting 1,1-dimethylethyl 3-amino-1 -pmyrrolidinecarboxylate for pyrrolidin-3- yl-carbamic acid tert -butyl ester instep (h) a nd 5-chloro-2-thienylboronic acid for 3- : . 20 chlorophenylboronic acid in step (i). MS(ES-®) m/z 459.0 MeH]Y. =»

Example= 36 . h Preparation of 2-(4-Amino-furazan-3-y)-4-(2—amino-phenyl)-1-ethyl-1H-imidazol4.5- clpyridine-7-carboxylic acid pyrrolidin-3-ylam ide trifluoroacetate

The title compound was prepared in aan analogous manner to Example 18 by substituting 1,1-dimethylethyl 3-amino-1-pymolidinecarboxylate for pyrrolidin-3- ° yl-carbamic acid tert -butyl ester in step (h) &and 2-aminophenylboronic acid for 3- chlorophenylboronic acid in step (i). MS(ES—+) miz 434.0 [M+H]'.

Examples 37

Preparation of 2-(4-Amino-furazan-3-y)-4-(3-amino-phenyl)-1 -ethyl-1H-imidazo[4,5~ clpyridine-7-carboxvlic acid pyrrolidin-3-ylanide trifluoroacetate

The title compound was prepared in an analogous manner to Example 18 by substituting 1,1-dimethylethyl 3-amino-1—pyrrolidinecarboxylate for pyrrolidin-3-

yl-carbamic acid tert -butyl esster in step (h) and 3-aminophenylboronic aecid for 3- chiorophenylboronic acid in sstep (i). MS(ES+) m/z 434.0 [M+H]".

Example 38 } Preparation of 2-(4-Amino-fumrazan-3-yl)-4-(3-bromo-phenyl)-1 -ethyl-1H- imidazo[4.5-c]pyridine-7-carkooxylic acid pyrrolidin-3- amide trifluoroa tate

The title compound vevas prepared in an analogous manner to Exxample 18 by substituting 1,1-dimethylesthyl 3-amino-1 -pyrrolidinecarboxylate for pwymolidin-3- yl-carbamic acid tert -butyl easter in step (h) and 3-bromophenylboronic =acid for 3- chlorophenylboronic acid in step (i). MS(ES+) m/z 497.0 [M+H]".

Example 39

Preparation of 2-(4-Amino-f urazan-3-yi)-4-(1-naphthalenyl)-1-ethyl-1 H-nimidazo[4.5- clpyridine-7-carboxylic acid pyrrolidin-3-ylamide trifluoroacetate . : The title compound -was prepared in an analogous manner to E_xample 18 by substituting 1,1-dimethyllethyl 3-amino-1-pyrrolidinecarboxylate for poyrrolidin-3- yl-carbamic acid tert -butyl eester in step (h) and 1-napthylboronic acid #or 3- chiorophenylboronic acid im step (i). MS(ES+) m/z 469.0 [M+H]". a : Example 40

Preparation of 2-(4-Amino-=furazan-3-yl)-4-(thiophen-2-yl)-1 -ethyl-1H-irmidazof4.5- clpyridine-7-carboxylic acic3 pyrrolidin-3-ylamide trifluoroacetate

The title compound was prepared in an analogous manner to E=xample 18 by substituting 1,1-dimethywlethyl 3-amino-1-pyrrolidinecarboxylate for goyrrolidin-3- yl-carbamic acid tert -butyl ester in step (h) and 2-thienylboronic acid for 3- chiorophenylboronic acid im step (i). MS(ES+) m/z 425.0 [M+H]".

Example 41

Preparation of 2-(4-Amino—furazan-3-yl )-4-(3.4-methylenedioxyphenyl)-1 ~ethyl-1H- imidazo[4,5-clpyridine-7-caarboxylic acid pyrrolidin-3-ylamide trifluoroascetate

The title compound was prepared in an analogous nmanner to Example 18 by substituting 1,1-dimethylethyl 3-amino-1 -pyrrolidinecarbosXxylate for pyrrolidin-3- yl-carbamic acid tert -butyl ester in step (h) and 1 ,3-benzodiioxol-5-ylboronic acid for 3-chlorophenylboronic acid in step (1). MS(ES+) m/z 463.0 [M+H]'

Example 42

Preparation of 2-(4-Amino-furazan-3-yi}-4~(3.5-dichloro- heanyl)-1-ethyl-1H- imidazol4.5-clpyridine-7-carboxylic acid pyrrolidin-3- lamid e trifluoroacetate

The title compound was prepared in an analogous manner to Example 18 by substituting 1,1-dimethylethyl 3-amino-1-pyrrolidinecaritooxylate for pyrrolidin-3- yl-carbamic acid tert -butyl ester in step (h) and 3 5-dichlomrophenylboronic acid for 3-chlorophenylboronic acid in step (i). MS(ES+) m/z 487.0 [M+H]

Example 43

Preparation of 4-{7-{(3-amino-1 -pyrrolidinyl)carbonyll-4-(4 -biphenyly)-1-ethyl-1H- . imidazol4,5-clpyridin-2-vi}-1 .2.5-oxadiazol-3-amine trifluowroacetate ‘ : a The title compound was prepared in an analogous manner to Example 18 by substituting 4-biphenylboronic acid for 3-chlorophenyliooronic acid in step ().

MS(ES+) m/z 495.0 [M+H]". 25. Example 44

Preparation of 4-[7-[(3-amino-1 -pyrrolidinyl)carbonyll-4-(=3-chlorophenyh-1- (cyclopropylmethyl)-1 H-imidazo[4 5-c]pyridin-2-y[l-1 .2.5--«0xadiazol-3-amine trifluoroacetate

The title compound was prepared in an analogous manner to Example 18 by substituting 3-bromo-N-(cyclopropylmethyi)-5-nitro-4—pyridinamine for ethyl (3- bromo-5-nitropyridin-4-yl)amine in step (a). MS(ES+) mm/z 479.2 [M+H]".

Example 45

Preparation of 4-[7-[(3-amino-1 _pymolicinyllcarbonyll-4—(2 4-dichiorophenyl)-1 -ethyl- 1H-imidazo[4,5-c]pyridin-2-yi]-1,2 5-oxadiazol-3-amine R’trifluoroacetate

The title compound was prepared in an analogous manner to Example 188 by substituting 2,4-dichlorophen ylboronic acid for 3-chlorophenyiboronic acid in step (i). MS(ES+) m/iz407.0[M +H].

Example 46

Preparation of 2-{2-(4-amino-1. 22 5-oxadiazol-3-yl)-7- 3-amino-1- olidiny)carbonyll-1-ethyl-1H-imidazo{4.5-clpyridin-4- phenol triflucroacetatee

The title compound wass prepared in an analogous manner to Example 1 8 ’ by substituting 2-hydroxypheny-iboronic acid for 3-chlorophenylboronic acid in st-ep (i). MS(ES+) m/z 435.0 [M+H]".

Example 47 :

Preparation of 4-[7-[(3-amino-"1 -pyrrolidiny))carbonyl]-4- 2-chiorophenyl)-1-ethyB-1H- imidazo[4 5-clpyridin-2-yl]-1 2,5-oxadiazol-3-amine trifluoroacetate

The title compound was prepared in an analogous manner to Example —18 by substituting 2-chlorophenyllboronic acid for 3-chlorophenylboronic acid in step (i). :

MS(ES+) m/z 453.0 [M+H]". :

Example 48

Preparation of (2-{2-(4-amino—1.2,5-oxadiazol-3-yl)-7-{(3-amino-1- pyrrolidinyl)carbonyl]-1-ethyl-1 H-imidazo[4,5-clpyridin-4-yfiphenymethanol trifluoroacetate

The title compound waas prepared in an analogous manner to Example 18 by substituting 2-(hydroxymet hyl)phenylboronic acid for 3-chlorophenylboronice acid in step (i). MS(ES+) m/z 449_0 [M+H]".

Example 49

Preparation of 4-(1-ethyl-7-{[3-(methylamino)-1 -pyrrolidinyllcarbonyl}-4-phenytd-1H- imidazof4,5-clpyridin-2-yl)-1,2,5-oxadiazol-3-amine trifluoroacetate

The title compound was prepared in an analogous manner to Example 18 by substituting 1,1-dimethyletthyl methyl(3-pyrrolidinyl)carbamate for pyrrolidins-3-yl-

cartoamic acid tert -butyl ester in step (h) and phenylb=oronic acid for 3- chiorophenylboronic acid in step (i). MS(ES+) m/z 4383.0 (M+H]".

Example 50

Preaparation of 4-[7-1(3-amino-1-pyrrolidinyl)carbonyl}—1-ethyl-4-(4-methylphenyl)- 1H—~imidazo[4,5-c]pyridin-2-yil-1 2.5-oxadiazol-3-amire trifiuoroacetate

The title compound was prepared in an analosgous manner to Example 18 by substituting 4-methylphenylboronic acid for 3-chicaarophenylboronic acid in step (i). MS(ES+) m/z 433.0 [MH].

Example 51

Preparation of 4-[7-(3-amino-1-pyrrolidinyl) carbonyl )-4-(2,5-dichlorophenyl)-1-ethmyl- 1H{-imidazol4.5-clpyridin-2-yl}-1 2 5-oxadiazol-3-ami_ne trifluoroacetate

The title compound was prepared in an analeogous manner to Example 188 by substituting 2,5-dichiorophenylboronic acid for 3—chlorophenyiboronic acid in st-ep (i). MS(ES+) m/z 487.0 M+H]".

Example 52

P_reparation of 4-[7-[(3-amino-1 -pyrrolidinylcarbony=i}-4-(1-benzothien-2-yi)-1 -eth-yl- 1BH-imidazo[4.5-clpyridin-2-yil-1,2,5-oxadiazol-3-ammine trifluoroacetate

The title compound was prepared in an analogous manner to Example 18 by substituting 1-benzothien-2-ylboronic acid for 3-achlorophenylboronic acid in sitep (iD. MS(ES+) m/z 475.0 [M+H]".

Example 53

Preparation of 4-{7-{(3-amino-1-pyrrolidinyl\carbon=y(}-1 -ethyl-4-[4- {mmethyloxy)phenyl}-1 H-imidazo[4,5-c]pyridin-2-y}-H ,2,5-oxadiazol-3-amine twifluoroacetate

The title compound was prepared in an analogous manner to Example 1 8 oy substituting 4-methoxyphenylboronic acid for 3—chlorophenylboronic acid in step ( 7). MS(ES+) m/z 449.0 [M+H]". :

Example 54

Preparation of 4-{7-[(3-amino-1 -pymrrolidinyl carbonyl J-4-(4-chlorophenyl )-1-ethyl-"TH- 5S imidazo[4 5-clpyridin-2-y(}-1 2,5-0xzadiazol-3-amine triflucroacetate

The title compound was preepared in an analogous manner to Example 188 by substituting 4-chlorophenylboronic acid for 3-chlorophenylboronic acid in step ().

MS(ES+) m/z 453.0 [M+H]".

Example 55

Preparation of 2-(4-amino-1.2.5-cexadiazol-3-yl}-4-(3-chiorophenyl)-1- (cyclopropyimethyl)-N-{2-] (phenyBmethyaminolethyl}-1 H-imidazol4.5-clpyridine=-7- carboxamide trifluoroacetate

The title compound was prepared in an analogous manner to Example —18 by substituting 3-bromo-N-(cyclopropylmethyl)-5-nitro-4-pyridinamine for ethyl &3- . bromo-5-nitropyridin-4-yl)amine En step (a) and 1,1-dimethylethyl (2- aminoethyl)(phenylmethyl)carbammate for pyrrolidin-3-yl-carbamic acid tert -butyy ester in step (h). MS(ES+) m/z 5543.4 [M+H]". : Example 56

Preparation of 3-{2-(4-amino-1 2 5-oxadiazol-3-yI)-7-[(3-amino-1- pyrrolidinyl)carbonyll-1-ethyl-1 H -imidazol4,5-clpyridin-4-yi}phenol trifluoroacet :ate

The title compound was prepared in an analogous manner to Example= 18 by substituting 3-hydroxyphenyL boronic acid for 3-chlorophenylboronic acid in step (i). MS(ES+) m/z 435.0 [M+H]" .

Example 57

Preparation of 4-{2-(4-amino-1 =2.5-oxadiazol-3-y)-7-] (3-amino-1- pyrolidinycarbonyll-1-ethyl-1Ht-imidazof4,5-clpyridin-4-yibenzonitrile triflucroacetate

The title compound was prepared irs an analogous manner to Example 18 by substituting 4-cyanophenylboronic acid €or 3-chlorophenylboronic acid in step Qi).

MS(ES+) m/z 444.0 [M+H]".

Example 58 :

Preparation of 1-j2-(4-Amino-furazan-3-yi)—4-phenyl-1-piperidin-4yt-1-H- imidazof4.5-clpyridin-7-yl }-1-{3-amino-pyrrolidin-1-yl)-methanone

The title compound was prepared ir an analogous manner to Example 18 by substituting 1,1-dimethylethyl 4-[(3-brorno-5-nitro-4-pyridinyl)amino}-1- piperidinecarboxylate for ethyl (3-bromo-5—nitropyridin-4-y)amine in step (a) and phenylboronic acid for 3-chlorophenylboromic acid in step (i). MS(ES+) m/z 474.0

M+H]".

Example 59

Preparation of 4-(4-(3-chlorophenyl)-1-ethyk7-{[3-( methylamino)-1- pyrrolidinyllcarbonyl}-1 H-imidazo[4,5-clpyridin-2-yi)-1 ,2.5-oxadiazol-3-amine . trifluoroacetate : -

The title compound was prepared §n an analogous manner to Example 18 - : by substituting 1,1-dimethylsthyl methyl(3—pyrrolidinyl)carbamate for pyrrolidin-3—yi- : carbamic acid tert -butyl ester in step (h). MS(ES+) m/z 467.0 {M+H]".

Example 60

Preparation of 4-(4-(2,5-dichlorophenyl)-1 —ethyl-7-{[3-(methylamino)-1- pyrrolidinylicarbony(}-1 H-imidazo[4,5-clpyrridin-2-yl)-1,2.5-oxadiazol-3-amine trifluoroacetate

The title compound was prepared in an analogous manner to Example 1 8 by substituting 1,1-dimethylethyl methyl(3—pyrrolidinyl)carbamate for pyrrolidin-3—yl- . carbamic acid tert -butyl ester in step (h) and 2,5-dichlorophenylboronic acid for 3- chlorophenylboronic acid in step (i). MS(EES+) m/z 501.0 [M+H]".

Exam ple 61

Preparation of 2-(4-amino-1 2.5 oxadiazol-3-yl)-4-(3-chlorophenyl)-1- (cylopropyimethyl-N-[3-(dimetrytaminopropyll-1 H-imidazo[4.5-clpyridine-7- carboxamide trifluoroacetate

The title compound was prepared in an analogous manner to Example 18 by substituting 3-bromo-N-(cyclopropylmethyl)-5-nitro-4-pyridinamine for ethyl (3- bromo-5-nitropyridin-4-yl)amine in step (a) and N,N-dimethyl-1,3-propanediamine for pyrrolidin-3-yl-carbamic acid tert -butyl ester in step (h). MS(ES+) m/z 496.4 [M+H]".

Example 62

Preparation of 4-[7-{(3-amino—1-pyrrolidiny)carbon {1-1-ethyl-4-(1H-pyrrol-2-yh-1H- imidazo[4.5-clpyridin-2-yI}-1 2 5-oxadiazol-3-amine trifluoroacetate

The title compound was prepared in an analogous manner to Example 18 by substituting 1H-pyrrol-2-yiboronic acid for 3~chlorophenylboronic acid in step OR

MS(ES+) m/z 408.0 {M+H]".

Example 63 : * Preparation of 4-[7-[(3-amino-1-pyrrolidinylcarbonyil-4-(4-bromophenyl)-1 -ethyl- . 1H-imidazo[4,5-c]pyridin-2-y11-1 .2 5-oxadiazol-3-amine trifluoroacetate

The title compound was prepared in an analogous manner to Example 18 by substituting 4-bromophenylboronic acid for 3-chlorophenyliboronic acid in step (i). MS(ES+) m/z497.0 [M+ HJ.

Example 64

Preparation of 4-{7-[(3-amino-1 -pyrrolidinyl)carbonyl}-4-phenyl-1 -(4-piperidinyl)-1H- i imidazo[4.5-clpyridin-2-yi}-1 .2.5-oxadiazol-3-amine

The title compound wvas prepared in an analogous manner to Example 18 by substituting 1,1-dimethylethyl 4-[(3-bromo-5-nitro-4-pyridinyl)amino]-1- piperidinecarboxylate for ethyl (3-bromo-5-nitropyridin-4-yl)amine in step (a) and phenylboronic acid for 3-chlorophenylboronic acid in step (i). MS(ES+) m/z 474.0 [M+HJ".

Example 65

Preparation of 4-{2-(4-amino-1,2.5-oxadiazol-3-y!}-7-[(3—~amino-1- olidinvl) carbonyl]-1-ethyl-1H-imidazo[4.5-clpyridin-4-—yliphenol trifluoroacetate

To a stirred solution of the compound of Examp le 53 (140 mg, 0.21 mmol) in methylerme chloride (10 mL) at -78 OC was added dropwise boron tribromide (2.1 mL of 1 M ssolution in methylene chloride, 2.1 mmol). Tine reaction mixture was evaporated three times from methanol. Purification by Foreparative reverse phase

HPLC (ace tonitrile/water gradient with 0.1%TFA) afforcled the title compound (51 mg, 56%). MS: (M+H)" = m/z 435.

Example 66

Preparation of 2{2-(4-amino-1 2 5-oxadiazol-3-y}-7-{(3-amino-1- pyrrolidinyd Yearbonyl]-1-ethyl-1 H-imidazol4,5-clpyridin-=4-yl}-4-chlorophenol trifluoroacetate

The title compound was prepared in an analogeous fashion to the preparatiom of the compound of Example 65 by substituting the compound of

Example £53 with 4-{7-[(3-amino-1 -pyrrolidinyl)carbonyHl]-4-[5-chloro-2- (methyloxyy)phenyl}-1-ethyl-1 H-imidazo[4,5-c]pyridin-2—yl}-1 ,2,5-oxadiazol-3-amine. :

MS: (M+H )* = m/z 469. + Example 67

Preparati on of 4-[7-[(3-amino-1-pyrrofidinyl)carbomnyi]-1-(1-methylethyi)}-4- phenyl-1/-imidazo{4,5-clpyridin-2-y{]-1.2,5-0xadi=azol-3-amine trifluoroaacetate a) 6-Chlor-o-4-isopropylamino-5-nitro-nicotinic acid ety! ester

Tow a solution of 4,6-dichloro-5-nitro-nicotinic a cid ethyl ester (1.305 g, 4.92 mmol) in clichioromethane (30 mL) at 0 °C was addedB isopropylamine (0.755 mL, 5.41 mmol). The mixture was then stirred at ambient temperature for 0.5 h, at which timee it was concentrated in vacuo to provide thea product as an orange solid (1.397 g, 99% yield). MS (ES+) m/z 288.2 (M+H)*.

b) 4-Isopropylamino-5-nitro-6-phenyl-nicotinic acid ethyl ester

A solution of the compound of Example 67(a) (708 mg, 2.46 mmol), phenylboronic acid (600 mg, 4.92 mmol), and dichlorobis(triphenylphosphine)palladium(ll) (173 mg , 0.246 mmol) in dioxane (23 mL) was treated with sodium carbonate (2 M aqueoums solution, 3.94mL, 7.88 mmol). The resultant biphasic mixture was vigorousBy stirred in a sealed tube at 100 °C for 3.5 h. The mixture was cooled to ambient temperature, concentrated, and purified on silica ge! (50:1 — 30:1 dichloromethaane/methanol) to give the desired product as a light brown oil (739 mg, 91% yiseid). MS (ES+) m/z 330.2 (M+H)*. ¢) 5-Amino-4-isopropylamino-6-phenyl-nicotinic acid ethyl ester :

A mixture of the compound of Example 67(bD (735 mg, 2.23 mmol) and palladium on carbon (10 wt. %, 20 mg} in absolute ethanol (20 mL) was stirred at ambient temperature under hydrogen gas (1 atm) for 16 h, at which time the flask was flushed with argon. The catalyst was filtered of=f on a pad of celite, and the filtrate was concentrated in vacuo to afford the prod .uct as a dark yellow oil (639 mg, 96% yield). MS (ES+) m/z 300.2 (M+H)*. 20+ d) 5-(2-Cyano-ethanoylamino)-4-isopropylaminoc-8-pohenyl-nicatinic acid ethyl ester

A solution of the compound of the Example 67(c) (635 mg, 2.12 mmol), cyanoacetic acid (451 mg, 5.30 mmol), 4-methyimosrpholine (1.17 mL, 1.06 mmol) in dimethylformamide (10 mL) was treated with 1-(3-~dimethylaminopropyl)-3- ethyicarbodiimide hydrochloride (1.016 g, 5.30 mmeol), and the resultant mixture 25s was stirred under argon at 45 °C for 3 hours. The wreaction was then diluted with water (30 mL) and extracted with ethy) acetate (3 x 50 mL). The combined organic extracts were sequentially washed with saturated asqueous sodium bicarbonate solution (1 x 25 mL), water (1 x 25 mL), brine (1 x 550 mL), and then dried over magnesium sulfate and concentrated in vacuo to fuamish the product (723 mg, 93% yield) as a pale brown oil. MS (ES+) m/z 367.4 (M—+H)*. e) 2-Cyanomethyl-1-isopropyl-4-phenyl-1 H-imidazoo[4,5-c]pyridine-7-carboxylic acid ethyl ester

A mixture of the compound of the Example 67(d) (723 mg, 1.97 mmol) and 355 acetic acid (15 mL) was stirred in a sealed tube at 100 °C for 1 h. Concentration in vacuo, followed by silica gel chromatography provi ded the product (500 mg, 73% yield) as an ivory solid. MS (ES+) m/z 349.2 (M+HD™.

f) 2-(1-Cyano-1-hydroxyimino-methyl)- -isopropyl-4-phenyl-1H-imidazof4,5- clpyridine-7-carboxylic acid ethyl ester

To a solution of the compound «of the Example 67(e) (630 mg, 1.52 mmol) in acetic acid (11 mL) and water (1.5 mL)» was added sodium nitrite (210 mg, 3.04 mmol), portionwise over 2 min. The re=action was stirred at ambient temperatur-e for 16 h, at which time it was concentrated in vacuo. The residue was dissolved in dichloromethane (100 mL) and washecd with saturated aqueous sodium bicarbosnate solution (1 x 20 mL) and water (1 x20 mL). Drying over anhydrous magnesium sulfate, followed by concentration in v&acuo, gave the product (574 mg, 100% yield) as a pale yellow solid. MS (ES+) m/z 3378.4 (M+H)*. g) Ethyl 2-(4-amino-1,2,5-oxadiazol-3-7yl)-1 -(1-methylethyl)-4-phenyi-1H- imidazo[4,5-c]pyridine-7-carboxylate

A mixture of the compound of he Example 67(f) (574 mg, 1.52 mmol), triethylamine (2 mL, 14.3 mmol), and Enydroxylamine (50 wt. % solution in watesr, : 0.120 mL, 1.96 mmol) in dioxane (30 wml) was heated in a sealed tube at 110 =C for 6 h. The mixture was cooled to ambient temperature, concentrated in vacuo, 2nd purified on silica gel (50:1 — 30:1 dich loromethane/methanol) to afford the prosduct - 20 = (445 mg, 74% yield) a as pale yellow ssolid. MS (ES+) m/z 393.4 (M+H)*. cn h) 2-(4-Amino-1,2,5-oxadiazol-3-yl)-1—(1-methylethyl)-4-phenyl-1 H-imidazo[4,5— : clpyridine-7-carboxylic acid

To a solution of the compoundll of the Example 67(g) (440 mg, 1.12 mmol) in 4:1 methanolitetrahydrofuran was adcied 6 N aqueous sodium hydroxide solution (2.75 mL, 16.5 mmol). The mixture wwas vigorously stirred at ambient temperature for 3 hours, at which time it was conceentrated in vacuo and diluted with water «20 mL). The pH was adjusted to 7 by adlidition of 6 N hydrochloric acid (2.75 mL)_, and _ the aqueous phase was extracted wit™h ethyl acetate (3 x25 mL). The combineed organic extracts were washed with brine (1 x 15 mL), dried over magnesium s:ulfate and concentrated in vacuo to fumish —the product (380 mg, 93% yield) as a pal.e yellow solid. MS (ES+) m/z 365.2 (M+-H)*. i) 1,1-Dimethylethyl (1-{[2-(4-amino-1 ,25-oxadiazol-3-yl)-1-(1-methylethyl)-4- phenyl-1H-imidazo[4,5-clpyridin-7-yljcsarbonyl}-3-pyrralidinyl)carbamate

To a solution of the compound of the Example 67(h) (64 mg, 0.176 mnanol), pyrrolidin-3-yl-carbamic acid tert-buty-1 ester (66 mg, 0.352 mmol), 4-

methylmorpholin € (0.1 mL, 0.909 mmol), 1-hydroxy-7-azabenzotriazole (48 mag, 0.352 mmol) in Aimethylformamide (3 mL) was added 1-(3-dimethylaminopwropyl)-3- ethylcarbodiimid-e hydrochloride (68 mg, 0.352 mmol). The resultant mixture was stirred under argon at 45 °C for 2.5 h, at which time it was diluted with ethyl acetate (30 mL) and wasshed with water (3 x 10 mL). The organic phase was wash ed with brine (1 x 10 mL_.), dried over magnesium sulfate, and concentrated. Purification on - silica gel (20:1 —> 10:1 dichloromethane/methanol) provided the product (8:5 mg, 91% yield) as a pale yeliow oil that solidified upon standing. MS (ES+) m/z 533.6

M+H)*. : j) 4-{7-[(3-Amine>-1-pyrrolidinyl)carbonyl]-1 -(1-methylethyl)-4-phenyl-1 H-im@dazo[4,5- clpyridin-2-yiJ-1 ,2,5-oxadiazol-3-amine

A solution of the compound of the Example 67(i) (85 mg, 0.160 mmol) in dichloromethame 3 mL was treated with trifluoroacetic acid (0.6 mL, 7.79 nenmol).

The reaction waas stirred at ambient temperature for 1.5 h, at which time it was diluted with tolLaene (5 mL) and concentrated in vacuo to give the product (96 mg, 91% yield) as 2a pale tan solid. MS (ES+) m/z 433.6 (M+H)*. . : Example 68 :

E Preparation of 2-(4-amino-1,2,5-0xadiazol-3-yl)-1 -ethyl-N-methyl-N-(1-me=thyl-4- oo piperidinyl)-4-pmhenyl-1H-imidazo[4, 5-clpyridine-7-carboxamide triflucroactitetate

The title compound was prepared in an analogous manner to Exammple 67 by substituting ethylamine for isopropylamine in step (a) and N, 1-dimethy1-3- pyrrolidinamine for pyrrolidin-3-yl-carbamic acid tert-butyl ester in step (i)... MS(ES+) m/z 461.0 [M+ HJ". 20 Example 69

Preparation of” 4-{1-(4-aminobuty)-7-[(3-amino-1-pyrrolidinyl)carbonyl}-4- phenyl-1H- imidazo[4,5-c] pyridin-2-yi}-1,2,5-oxadiazol-3-amine trifluoroactetate

The titEe compound was prepared in an analogous manner to Example 67 by substituting 1,1-dimethylethyl (4-aminobuty!)carbamate for isopropylammine in step (a). MS(RES+) m/z 462.0 [M+H]".

Example 70

Preparation of 4-(1-(4-aminoloutyl)-7-{[3-(methylamino)-1-pyrrolidinyilcarbonyl}—4- henvl-1H-imidazo[4 5-clpyridin-2-yl)-1,2,5-oxadiazol-3-amine frifluoroactetate=

The title compound wras prepared in an analogous manner to Example- 67 by substituting 1,1-dimethylezthyl (4-aminobutyl)carbamate for isopropylamine in step (a) and 1,1-dimethylethyl methyl(3-pyrrolidinyl)carbamate for pyrrolidin-3—yl- carbamic acid tert-butyl estesr in step (). MS(ES+) m/z 476.0 [M+H]".

Example 71

Preparation of 1-(4-aminobuityl)-2-(4-amino-1,2,5-oxadiazol-3- -4-phenyi-N- {2- henvimethvaminolethyl}-1H-imidazol4.5-clpyridine-7-carboxamide trifiuoroactetate

The title compound was prepared in an analogous manner to Example 67 by substituting 1,1-dimethy lethyl (4-aminobutyl)carbamate for isopropylamine in step (a) and 1,1-dimethylethyl (2-aminoethyl)(phenylmethyl)carbamate for pyrrolidin-3-yl-carbamic acid tert-butyl ester in step (i). MS(ES+) m/z 526.0 EM+H].

Example 72

Preparation of 2-(4-amino—1.2,6-oxadiazol-3-y-1-(1-methylethyl)-4-phenyl-M-3- pyrrolidinyl-1 H-imidazol4,5-¢clpyridine-7-carboxamide trifluoroactetate :

The title compound was prepared in an analogous manner to Exampole 67 by substituting 1,1-dimethylethyl 3-amino-1-pyrrolidinecarboxylate for pyrroliidin-3- yl-carbamic acid tert-butyl ester in step (i). MS(ES+) m/z 433.4 [M+H]".

Example 73

Preparation of 4-{7-{I3-(msethylamino)-1 -pyrrolidinvilcarbonyl}-1-(1-methylet=hyi)4- phenyl-1H-imidazo[4,5-c]poyridin-2-yll-1 2 .5-oxadiazol-3-amine trifluoroacte®ate

The title compourad was prepared in an analogous manner to Example 67 by substituting 1,1-dimethylethyl methyl(3-pyrrolidinyl)carbamate for pyrrolidin-3-yl- carbamic acid tert-butyl ester in step (i). MS(ES+) miz 447.6 [M+H]".

Example 74 reparation of 2-(4-amino-1,2,5-oxadiazol-3-yl)-N—(3-aminopropyl}-1- 1- methylethyl)-4-phenyl-1H-imidazo[4,5-clpyridine-7~-carboxamide trifluoroactetate

The title compound was prepared in an ars alogous manner to Example 67 by substituting 1,1-dimethylethyl (4-aminobutyl)caarbamate for isopropylamine in step (a) and ethanolamine for pyrrolidin-3-yl-carbaamic acid tert-butyl ester in step (i). MS(ES+) m/z421.2 [M+H]".

Example 75

Preparation of 2-(4-amino-1,2.5-oxadiazol-3-yl)-1 —(1-methylethyl)-4-phenyl-N-2- propen-1-yl-1H-imidazo[4,5-clpyridine-7-carboxarmide

The title compound was prepared in an aralogous manner to Example 67 by substituting allyl amine for pyrrolidin-3-yl-carb=amic acid tert-butyl ester in step (f) © and omitting step (j). MS(ES+) m/z 404.4 [M+H]™".

Example 76

Preparation of 2-(4-amino-1,2,5-oxadiazol-3-yl}-1 -ethyl-N-[3-(4-morpholinyl)propyll- : 4-phenyl-1H-imidazo[4,5-c]pyridine-7-carboxamicie hydrochloride

Co The title compound was prepared in an amnalogous manner to Example 67 by substituting ethylamine for isopropylamine in Step (a), 3-(4-morpholinyl}-1- propanamine for pyrrolidin-3-yl-carbamic acid tert-butyl ester in step (i) and 4N

HCl/dioxane for trifluoroacetic acid and CHCl, ira step (j). MS(ES+) m/z 477.0 [MH

Example 77

Preparation of 2-(4-amino-1,2, 5-oxadiazol-3-yl)-M -ethyl-N-[2-(1H-imidazol-4- ylethyl]-4-phenyl-1H-imidazo[4.5-clpyridine-7-camrboxamide hydrochloride

The title compound was prepared in an a nalogous manner to Example 67 by substituting ethylamine for isopropylamine in step (a), 2-(1H-imidazol-4- yl)ethanamine for pyrrolidin-3-yl-carbamic acid tesrt-butyl ester in step ()) and 4N

HCl/dioxane for trifluoroacetic acid and CH,Cl, ir step (j). MS(ES+) m/z 444.0 [M+H]".

Example 78

Preparation of 2-(4-amino-1 2 5-0xadiazol-3-yl)-1-ethyl-N-{3-(4-methy}-1- iperazinyl)propyll-4-phenyl-1H-immidazo[4,5-clpyridine-7-carboxamide ftrifluoroacetate

The title compound was prepared in an analogous manner to Example= 67 by substituting ethylamine for isopsropylamine in step (a) and 3-(4-methyl-1- piperazinyl)-1-propanamine for py rrolidin-3-yl-carbamic acid tert-butyl ester in step (i). MS(ES+) m/z 490.0 [M+H]".

Example 79

Preparation of N-(1-{[2-(4-amino-"12 5-oxadiazol-3-yl)-1-ethyi-4-phenyl-1H- imidazo[4, 5-clpyridin-7-yllcarbony~1}-3-pyrrolidinyl)-N-methylacstamide trfluoroacetate

The title compound was prepared in an analogous manner to Example 67 by substituting ethylamine for isopropylamine in step (a) and N-methyi-N-3- : pymolidinylacetamide for pyrrolidir-3-yl-carbamic acid tert-butyl ester in step ( 1). :

MS(ES+) m/z 475.0 [M+H]".

Example 80

Preparation of 2-(4-amino-1 ,2,5-osxadiazol-3-yi)-N-[3-(dimethylamino)propy!- - ethyl-4-phenyl-1H-imidazo[4,5-cloyridine-7-carboxamide hydrochloride

The title compound was prepared in an analogous manner to Example 67 by substituting ethylamine for isopropylamine in step (a), N,N-dimethyl-1,3- propanediamine for pyrrolidin-3-yll-carbamic acid tert-butyl ester in step (i) and 4N

HCl/dioxane for trifluoroacetic acid and CHCl; in step (j). MS(ES+) m/z 435.60 [M+H]". .

Example 81

Preparation of 2-(4-amino-1 ,2 5-omxadiazol-3-yl)-1-cyclopentyi-4-phenyi-N-3- pyrrolidinyl-1H-imidazo[4,5-clpyriciine-7-carboxamide trifluoroacetate

WYO 2005/011700 PCT/US2004/024340

The title compound was prepared in an analogous manner to Example 67 by substituting cyclopentylamine for isopropylamine ir step (a) and 1,1- dimethylethyl 3-amino-1-pyrrolidinecarboxylate for pyrrolidin-3-yl-carbamic acid tert- butyl ester in step (i). MS(ES+) m/z 459.2 [M+H]".

Example 82 :

Preparation of {(3-amino-1-pymolidinyl)carbonyl]—1-cyclopentyl-4-phenyl-1H- imidazo[4,5-clpyridin-2-yl}-1.2, 5-oxadiazol-3-amine trifluoroacetate

The title compound was prepared in an analogous manner to Example 67 by substituting cyclopentylamine for isopropylamine ir step (a). MS(ES+) m/z 459.4 [M+H]".

Example 83

Preparation of 4-(1-cyclopentyl-7-{[3-(methylamino)-1 -pyrrolidinyllcarbonyl}-4- ~ phenyl-1H-imidazo[4.5-clpyridin-2-yl)}-1,2,5-oxadiazol—-3-amine triflucroacetate

The title compound was prepared in an analogous manner to Example 67 : by substituting cyclopentylamine for isopropylamine im step (a) and 1,1- v dimethylethyl methyl(3-pyrrolidinyl)carbamate for pyrr-olidin-3-yl-carbamic acid tert- : butyl ester in step (i). MS(ES+) m/z473.4 [M+H]".

Example 84

Preparation of (3R)-1-{[2-(4-amino-1,2.5-oxadiazol-3—yl)-1-ethyl-4-phenyl-1H- imidazo[4.5-clpyridin-7-ylcarbonyl}-3-pyrrolidinol hyd rochloride

The title compound was prepared in an analosgous manner to Example 67 by substituting ethylamine for isopropylamine in step (a), (3R)-3-pyrrolidinol for pyrrolidin-3-yi-carbamic acid tert-butyl ester in step (i) and 4N HCl/dioxane for trifluoroacetic acid and CHCl; in step (j). MS(ES+) m/z 420.0 [M+H]".

Example 85

Preparation of Preparation of 2-(4-amino-1,2,5-oxadizazol-3-yl}-N-[3- (diethylamino)propyll-1-ethyl-4-phenyl-1H-imidazo[4, &-clpyridine-7-carboxamide frifluoroacetate

The title compound was prepared in an analogous manner to Example 67 by substituting ethylamine for isopropylamine in step (a) and N,N-diethyl-1,3- propanediamine for pyrrolidin-3-yl-carbamic acid tert-butyl ester in step (i).

MS(ES+) m/z 463.0 [M+H]".

Example 86

Preparation of 2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-N-[3-(2-methyl-1- piperidinyl)propyil-4-phenyl-1 H-imidazo[4,5-c]pyridiine-7-carboxamide hydrochloride

The title compound was prepared in an analogous manner to Example 67 by substituting ethylamine for isopropylamine in steep (a), 3-(2-methyl-1 -piperidinyl)- 1-propanamine for pyrrolidin-3-yl-carbamic acid tesrt-butyl ester in step (iy and 4N

HCl/dioxane for trifluoroacetic acid and CHCl, in sstep (j). MS(ES+) m/z 489.0 [M+H]".

Example 87

Preparation of 4-[7-[(3-amino-1 -pyrrolidinyl)carbormyll-1-(4-flucrophenyl)-4-phenyt- 1H-imidazol4,5-c]pyridin-2-yil-1.2,5-oxadiazol-3-armine trifluoroacstate

The title compound was prepared in an analogous manner to Example 67 by substituting 4-fluoroaniline for isopropylamine ir step (a). MS(ES+) m/z 485.0

M+H]".

Example 88 "Preparation of N-(2-aminoethyl)-2-(4-amino-1,2,.5—oxadiazol-3-y)-1-{4- fluorophenyl)-4-phenyl-1H-imidazo[4,5-c]pyridine~'7 -carboxamide trifluoroacetate

The title compound was prepared in an analogous manner to Example 67 by substituting 4-filuoroaniline for isopropylamine ie step (a) and 1,1-dimethylethyi (2-aminoethyl)carbamate for pyrrolidin-3-yl-carbanmnic acid tert-butyl ester in step (i).

MS(ES+) m/z 459.0 [M+H]".

Example 89

Preparation of 4-{1-(4-aminophenyl)-7-[(3-amino—1-pyrrolidinylycarbonyll-4-phenyl- 1H-imidazol4,5-clpyridin-2-yl}-1.2 5-oxadiazol-3-amine trifluoroacetate

The title compound was prepared in an amalogous manner to Example 67 by substituting 1,1-dimethylethyl (4-aminophenyl) carbamate for isopropylamine in step (a). MS(ES+) m/z 482.0 [M+H]".

Example 90

Preparation of 4-[7-{[3-(dimethylamino)-1-pyrroliclinyllcarbonyl henyl-1-(2,2.2- trifluoroethyl)-1H-imidazo[4.5-clpyridin-2-yil-1,2, S-oxadiazol-3-amine trifluoroacetate

The title compound was prepared in an analogous manner to Example 67 by substituting 2,2,2-trifluoroethylamine for isopr-opylamine in step (a) and N,N- : dimethyl-3-pyrrolidinamine for pyrrolidin-3-yl-carbamic acid feri-butyl ester in step (i). MS(ES+) m/z 501.0 [M+H]'. oo Example 91 : o Preparation of 2-(4-amino-1,2,5-oxadiazol-3-yl)- 1-ethyl-N-[2-(1-methyl-2- : pyrrolidinyllethyll-4-phenyl-1H-imidazo[4,5-clpyrridine-7-carboxamide : trifluoroacetate :

The title compound was prepared in an analogous manner to Example 67 by substituting ethylamine for isopropylamine in step (a) and 2-(1-methy}-2- pyrrolidinyl)ethanamine for pyrrolidin-3-yl-carbarmic acid tert-butyl ester in step (i).

MS(ES+) m/z 461.0 [M+H]".

Example 922

Preparation of 1-(1-{[2-(4-amino-1,2,5-oxadiazo»]-3-yi)-1-ethyl-4-phenyl-1H- imidazo[4,5-clpyridin-7-yllcarbonyl}-4-piperidiny 1)-1,3-dihydro-2H-benzimidazol-2- one trifluoroacetate

The title compound was prepared in an analogous manner to Example 67 by substituting ethylamine for isopropylamine ire step (a) and 1-(4-piperidinyl}-1,3- dihydro-2H-benzimidazol-2-one for pyrrolidin-3~yl-carbamic acid tert-butyl ester in step (i). MS(ES+) m/z 550.0 [M+H]".

Example 93

Preparation of 1-{[2-(4-amino-1,2.5-oxadiazol-3-yl)-1-ethyl-4-phenyl-1H- imidazol4.5-clpyridin-7-yllcarbonyl}-3-piperidinecarboxamide hydrochioride

The title compound was prepared in an analogous manner to Example 67 by substituting ethylamine for isopropy/lamine in step (a), 3-piperidinecarboxamide for pyrrolidin-3-yl-carbamic acid tert-butyl ester in step (i) and 4N HCl/dioxane for trifluoroacetic acid and CHCl, in step (j). MS(ES+) m/z 461.0 [M+H]".

Example 94

Preparation of N-{(3-amino-2-hydroxypropyl)-2-(4-amino-1 .2.5-oxadiazol-3-y)-1- ethyl-4-phenyl-1H-imidazo[4.5-clpyrid iine-7-carboxamide trifluoroacetate

The title compound was prepared in an analogous manner to Example 67 ‘ by substituting ethylamine for isopropylamine in step (a) and 1,1-dimethylethyl 5- (aminomethyl)-2,2-dimethyi-1 .3-oxazolidine-3-carboxylate for pyrrolidin-3-yi- : 20 . carbamic acid teri-butyl ester in step i). MS(ES+) m/z 423.0 [M+H]". .

Example 95

Preparation of N-(2-amino-3-hydroxygoropyl)-2-(4-amino-1 ,2,5-oxadjazol-3-yl}-1- ethyl4-phenyl-1H-imidazo[4,5-clpyridline-7-carboxamide hydrochloride

The title compound was prepared in an analogous manner to Example 67 by substituting ethylamine for isopropylamine in step (a), 1,1-dimethylethyl 4- (aminomethyi)-2,2-dimethyl-1,3-oxaz ©lidine-3-carboxylate for pyrrolidin-3-yi- carbamic acid tert-butyl ester in step (i) and 4N HCl/dioxane for trifluoroacetic acid and CH,Cl, in step (j). MS(ES+) m/z 423.0 [M+H]".

Example 96 :

Preparation of (4-{[2-(4-amino-1 2,5-oxadiazol-3-yl)-1-ethyl-4-phenyl-1H- imidazof4,5-clpyridin-7-yticarbonyl}-2=-piperazinylimethanol hydrochloride

The title compound was prepared in an analogous manner to Example 67 by substituting ethylamine for isopropylamine in step (a), 2-

[(methylo>y)methyllpiperazine for pyrrolidin-3-wl-carbamic acid tert-butyl ester in . step (i) anmd 3M BCls in MeOH for trifluoroacetiec acid and CH,Cl, in step (j).

MS(ES+) m/z 449.0 [M+H]". ) 5 : Example S7

Preparaticon of 4-{1-ethyl-7-({3-[(methyloxy)me=thyi]-1-piperazinylicarbonyl)-4- phenyl-1H4-imidazo[4.5-clpyridin-2-yl]-1,2,5-ox=adiazol-3-amine hydrochloride

The title compound was prepared in ar analogous manner to Example 67 by substit-uting ethylamine for isopropylamine in step (a), 2- [(methyloy)methyilpiperazine for pyrrolidin-3—yl-carbamic acid tert-butyl ester in step (i) ard 4N HCl/dioxane for trifluoroacetic acid and CH.Cl, in step (i). MS(ES+) m/z 463.0 [M+H]'.

Example 98

Preparati-on of 4-(1-methyl-7-{[3-(methylaminc)-1-pyrrolidinyllcarbonyl}-4-phenyl- " 1H-imida==0[4,5-clpyridin-2-yl)-1,2,5-oxadiazol—3-amine hydrochloride : a) (2)-2-Mlitro-1-phenylethenamine .

Tr-iethylamine (8.4mL, .06mol) was added to a solution of methoxylamine-

HCI (5.2gm, .0625mol) in dimethylformamide (1 00mL) at 0°C in a ice bath. B- Nitrostyreane (7.50g, 0.05 mol) was added anc stirred at 0°C for 15min then at RT for 5min. Remove the precipate by filtration amnd wash the solid with a small amount oef DMF. Place the combined filtrate imnto an addition funnel and add dropwise over 30min to potassium t-butoxide(C16.8g, 0.15mol) in DMF (150 mL) at 0°C. Rermove the bath and stir at RT for 30m in. Quench reaction with sat NH4Cl (50 mL). Reaction volume reduced in 1/2 in vwacuo and extracted with CHCl.

Wash wit-h water, brine, dry Na,SO,, filter andl concentrate in vacuo to give the desired nmaterial as a yellow solid (7.6 g, 93%). MS(ES)" m/e 165 [M+H]". b) Diethyl} {{(2-nitro-1-phenylethyl)amino]jmeth ylidene}propanedioate

Diiethy! malonate (17 mL, 0.09 mol) waas added to the compound of Example 98(a) in triethylamine (30 mL) in a pressure beottle. The reaction was placed into ame . oil bath a~t 120°C and held for 1hr. Remove fr-om heat and concentrate in vacuo.

Dissolve ~the residue in hot CH,Cl, (50 mL) armd add 8% ethyl acetate/hexane (200 mL). Allow to cool to RT and then place in arm ice bath for 1h. Collect precipitate and wash with cold 8% ethyl actate/ hexane. Dry under vacuum and to give the desired material as a yellow solid (7.7 g, 80%). MS(ES)" m/e 335 M+H]". c) Ethyl 4-hydroxy-5-nitro-6-phenyl-3-pyr-idinecarboxylate

The compound of Example 98(b) in diphenyl ether (70mL) was heated to 260°C for 20 min. with stirring. After cooling to RT, dilute with hexane (70 mL) and collect the resulting precipitate. Rinse with hexane and dry the precipitate under vaccum to give the desired produxt as amn off-white solid (7.60 g, 81 %). MS(ES)" mile 289 [M+H]". d) Ethyl 4-chloro-5-nitro-6-phenyi-3-pyriciinecarboxylate

The compound of Example 98(c) and POCl (7 mL) was heated in a pressure bottle for 1h at 115 °C. The vomlatiles were removed in vacuo after allowing the reaction to cool to RT. Disssolve the residue in CH CI. and fitter ) through a plug of silica gel, flushing with additional CH,Cl2 (800 mL). The solvent was removed in vacuo to give the desire=d product as an oll that solidified on standing (3.10 g, 96%). MS(ES)" m/e 307 [M+H]". e) Ethyl 4-(methylamino)-5-nitro-6-phenywi-3-pyridinecarboxylate :

To the compound of Example 98.(d) and Et;N (0.75 mL, 3.60 mmol) in ethanol (30 mL) was added a solution of MeNH; in THF (1.80 mi, 2.0 M, 3.60 : mmol). After stirring at RT for 16 h, the =solvent was removed in vacuo. The : residue was dissolved in EtOAc and pas sed through a plug of silica gel eluting with 5% EtOAc/hexane. The solvent was renmoved to give the desired product as a solid (0.88 g, 98%). MS(ES)" m/e 302 [M+H]' f) Ethyl 5-amino-4-(methylamino)-6-phermyl-3-pyridinecarboxylate

To a solution of the compound of Example 98(e) in EtOH (30 mL) was added 10% Pd/C (0.1 9). The reaction v=essel was fitted with a H; filled balloon and heated to 45°C for 18h. The reaction weas allowed to cool to RT and the H, was vented. Celite and additional CH.Cl, wemre added to the mixture. The solid material was removed by filtration. The solids we=re washed with 5% MeOH/CH;Cl,. The solvent was removed from the combined filtrate to give the desired product as a yellow solid (0.81 g, 100%). MS(ES)" m/e 272 [M+H]". g) 2-(4-Amino-1,2,5-oxadiazol-3-yl)-1-me=thyl-4-phenyl-1H-imidazo[4,5-c]pyridine-7- carboxylic acid

This compound was prepared in a manner analogous to the preparation of the ecompound of Example 67(h), except substitmuting the compound of Example 98(f)) for the compound of Example 67(g). MS (EES+) m/z 337(M+H)*. 5h) 1 ,1-Dimethylethyl (1{[2-(4-amino-1,2,5-oxad iazol-3-yl)-1-methyl-4-phenyl-1H- imidlazol4,5-c]pyridin-7-yllcarbonyl}-3-pyrrolidinmyl)methylcarbamate

This compound was prepared in a manrmer analogous to the preparation of the compound of Example 67(j), except substitiiting methyl-pyrrolidin-3-yl-carbamic acid dimethyi-ethyl ester for pyrrolidin-3-yl-carbaamic acid tert-butyl ester. MS (ES+) m/z 519 (M+H)*. i) 4—(1-Methyl-7-{[3-(methylamino)-1 -pyrrolidinyB]carbonyl}-4-phenyl-1H-imidazo[4,5- clpywridin-2-yl)-1,2,5-oxadiazol-3-amine hydrochsloride

The title compound was prepared in a rananner analogous to the preparation of the compound of Example 67(j), except substituting the compound of Example 98(Mh) for the compound of Example 67(j) and substituting 4N HCl/dioxane for triflLaoroacetic acid in CH,Cl,. MS (ES+) m/z 489 (M+H)*. : Example 959 :

Pre paration of 4-{7-{(3-amino-1-pyrrolidinyl)carfibonyl ]-1-methyl-4-phenyl-1H- imicdazol4,5-clpyridin-2-yl}-1,2,5-oxadiazol-3-armnine hydrochloride

The title compound was prepared in an analogous manner to Example 98 by substituting 1,1-dimethylethyl! 3-pyrrolidinylc -arbamate for 1,1-dimethylethyl mefhyl(3-pyrrolidinyl)carbamate in step (h). MS (ES+) m/z 405.0 [M+H]".

Example 100 * Pre=paration of 4-(1-butyl-7-{I3-(methylamino)-1: -pyrrolidinyllcarbonyl}-4-phenyi-1H- imicdazo[4.5-clpyridin-2-yl)-1.2, 5-oxadiazol-3-armine hydrochloride

The title compound was prepared in an analogous manner to Example 98 by substituting butylamine for methylamine in sstep (8). MS(ES+) m/z 461.0 M+H]". . 35

Example 101

Pre=paration of 4-{7-[(3-amino-1-pyrrolidiny)car—bonyl]-1-butyl-4-phenyl-1H- imicdazo[4, 5-clpyridin-2-yl}-1,2 5-oxadiazol-3-armine hydrochloride .

The title compound was prepared in an analocgous manner to Example 98 by substituting butylamine for methylamine in step (e) and 1,1-dimethylethy! 3- pyrrolidinylcarbamate for 1,1-dimethylethyl methyl(3-pymolidinyl)carbamate in step

S (h). MS(ES+) m/z 447.0 [M+H]".

Example 102

Preparation of N-[2-(4-amino-1,2,5-oxadiazol-3-y)-1--ethyl-4-phenyi-1H-imidazo[4.5- 16 clpyridin-7-yl}~4-piperidinecarboxamide trifluoroaceta-te a) Ethyl 2~(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-4-plenyl-1 H-imidazo[4,5- c]pyridine-7-carboxylate

This compound was prepared in a manner aralogous to the preparation of 1 5 the compound of Example 67(a) through 67(g), exce=pt substituting ethylamine for isopropylamine. MS (ES+) m/z 379(M+H)*. b) Ethyl 2-[4~({{(1,1-dimethylethyl)oxy]carbonyl}amin: 0)-1,2,5-oxadiazol-3-yl}-1-ethyl- 4-phenyl-1H-imidazo[4,5-c]pyridine-7-carboxylate

A solution consisting of the compound of Example 102(a) (24.7 mmol) in 1,2-dichloroethane (140 mL) and pyridine (70 mL) weith di--butyl dicarbonate (21.54 . ’ g, 98.8 mmol) and DMAP (3.01 g, 24.7 mmol) was sstired at 85 OC in a sealed flask . for 1 h. The product mixture was partitioned betwee n EtOAc and 1N HCI, the layers separated and the organic extract washed with 1N HCl then brine, dried (NazSO4) and all volatiles removed in vacuo. The residue wass triturated with EtOAc to afford the desired compound as beige solid. MS (ES+) maz 479(M+H)*. ¢) 2-{4-({[(1,1-Dimethylethyl)oxy]carbonyl}amino)-1,: 2 5-oxadiazol-3-yl}-1-ethyl-4- phenyl-1H-imidazo[4,5-c]pyridine-7-carboxylic acid 330 This compound was prepared in a manner &analogous to the preparation of : the compound of Example 67(h), except substitutineg the compound of Example 102(b) for the compound of Example 67(g). MS (E-S+) m/z 451 (M+H)*, d) 1,1-Dimethylethy! [4-(7-amino-1-ethyl-4-phenyl-1. H-imidazo[4,5-c]pyridin-2-yi)- . 35 1,2,5-oxadiazol-3-ylJcarbamate -

To a suspension of the compound of 102(cX (0.14 g, 0.30 mmol) in toluene(5 mL).at RT was added Et;N (63 ul, 0.45 rrmimol) followed by dipheny!phosphoryl azide(&5 uL, 0.30 mmol). The mixture was stirred at RT for 15 min and then at reflux for ‘& h. Water (0.5 mL) was added and the soluttion was heated to reflux for 24 h. After allowing the reaction to cool to RT, the solvent was in vacuo. The residue wass diluted with CH,Cl, (10 mL), washed with H=O (2x 5 mL) and brine (5 mL). Fla=sh chromatography (2-5% CH;OH/CHCl., silica gel) gave 0.07 g (55%) of the desired compound. MS (ES+) m/z 422(M+H)t. e) Phenylmethyl 4-[({2-[4-C{[(1,1-dimethylethyl)oxy]carbonyl}amino)-1,2 .. S-oxadiazol- 3-yi]-1-ethyl4-phenyl-1H-immidazo[4,5-c]pyridin-7-yl}amino)carbonyl}-1- piperidinecarboxylate

A solution of the compound of 102(d) (0.14 g, 0.33 mmol) in TH F (3 mL), pyridine(0.1 mL) and phers yimethyl 4-(chlorocarbonyl)-1-piperidinecarboxylate(0.14 gd, 0.50 mmol) was stirred aat 60 °C for 1h. After cooling to RT, the solveent was removed in vacuo. Flash eshromatography (2% CH;OH/CH,Cl,, silica g=el) gave 0.11 g (50%) of the desire=d compound. MS (ES+) m/z 667(M+H)™. f) N-[2-(4-Amino-1,2,5-oxaadiazol-3-yl)-1-ethyl-4-phenyl-1H-imidazo[4,5—c]pyridin-7- yll-4-piperidinecarboxamidle trifluoroacetate

To a solution of 10=2(e) (0.05 g, 0.075 mmol) in CHCl, (8 mL) at-5°C was : added BBry (1 mL, 1.0 M im CH,Cl,, 1 mmol). The reaction mixture was stirred at "© 0°C for 1h and then RT fosr 1h. The mixture was diluted with MeOH (5 mL) and the solvent was evaporate din vacuo. The residue was subjected to rewerse g phase preparative HPLC (=acetonitrile water gradient + 0.1% TFA) to giwe the 0.018 g (33%) of the title compound. MS (ES+) m/z 433(M+H)*. :

Example 103

Preparation of N-[2-(4-ami&no-1.2,5-oxadiazol-3-yl}-4-phenyl-1H-imidazo[4,5- clpyridin-7-yl]-N'-3-pyrrolidiinylurea trifluoroacetate a) 1,1-Dimethylethyl 3-{[({=2-14-({I(1,1-dimethylethyl)oxy]carbonyl}amino-1,2,5- oxadiazol-3-yl]-4-phenyl-1#-imidazo[4,5-c]pyridin-7-yl}Jamino)carbonylj=amino}-1- pyrrolidinecarboxylate

DPPA (53 uL) was added dropwise to a mixture of the compourd of

Example 102(c) (100 mg, €0.20 mmol) and Et;N (37 ul) in toluene (2 mL) at RT.

After 30 min. at RT, the reaction was heated at 80 °C for 30 min and th en cooled to

RT. 1,1-Dimethylethyl 3-a minoc-1-pyrrolidinecarboxylate (62 mg) was a- dded to the resulting yellow precipitate and mixture was stirred at RT overnight, heated to 90 °C for 3 hr and cooled to RT. The reaction mixture was diluted with CH.Cl,, washed with 10% aq. tartaric acid, saturated NaHCO,, brine and dried over NasSO;.

Removal of the solvent followed by the purification of the residue by flash chromatography (5% MeOH/CH,Cl,, silica gel) gave 133 mg of the desired material as a light yellow solid. : b) N-2-(4-Amino-1,2,5-oxadiazol-3-yl)4-phenyl-1 H-imidaazo[4,5-c]pyridin-7-yl}-N'-3- pyrrolidinylurea :

A solution of the compound of Example 103(a) ard TFA (0.5 mL) in CH.Cl, was stirred at RT for 1 hr. The solvent was removed in vwacuo and the residue was azeotroped from toluene. The title compound was isolated by reverse phase HPLC (H,O/CHsCN/0.1%TFA) to give 40 mg of the title compound as a light brown. MS (ES+) m/z434 4 (M+H)".

Example 104

Preparation of 3-amino-N-[2-(4-amino-1,2.5-oxadiazol-3—yl)-4-phenv-1H- : imidazo[4.5-clpyridin-7-yi}-1-pyrrolidinecarboxamide triflumoroacetate .

The title compound was prepared in a manner analogouss to the preparation of the : compound of Example 103 except substituting 1,1-dimet hylethyl 3- pyrrolidinylcarbamate for 1,1-dimethylethyl 3-amino-1-pyrrolidinecarboxylate. MS (ES+) m/z 434.2 (M+H)". .

Example 105

Preparation of 4-{1-ethyl-7-[(4-methyl-1-piperazinyhmeth vil-4-phenyl-1H- imidazo[4,5-clpyridin-2-yl}-1.2.5-oxadiazol-3-amine trfluo_roacetate a) [2-(4-Amino-1,2,5-oxadiazol-3-yl)-1-ethyl-4-phenyl-1 H~imidazo[4,5-c]pyridin-7- yllmethanol :

To the solution of the compound of Example 67(c3) (0.50 g, 1.32 mmol) in

THF (10 mL) in an ice bath was added dropwise a solution of LAH (2.64 mL, 1M in

THF, 2.64 mmol). After stirring for 15 min., the reaction “was quenched by sequential dropwise addition of water (100 ul), 15% NaCOH (100 uL) and water (300 uL). The resulting suspension was stirred for 5 min. and then filtered. The filtrate was concentrated in vacuo to give the desired product (0.42 g, 93%). MS (ES+) m/z 337 (M+H)*. b) 4-[7-(Chloromethyl)-1-ethyl-4-phenyl-1 H-imidlazo[4,5-c]pyridin-2-yi]-1,2,5- oxadiazol-3-amine

The compound of Example 105(a) in CHCl, (30 mL) and SOC. (13.4 mmol) was stirred at room temperature for 2h. DMF (0.5 mL) was added and the reaction was stirred for 1h. A solution of 6N HCI was added and the reaction was stirred for 0.5h. The desired material was isola ted by filtration to give 0.72 g of the desired compound as a solid. MS (ES+) m/z 355 (M+H)*. c) 4-{1-Ethyl-7-[(4-methyl-1-piperazinyl)methyl]—4-phenyl-1 H-imidazo[4,5-c]pyridin- 2-yl}-1,2,5-oxadiazol-3-amine trfluoroacetate

A solution of the compound of Example 105(b) (50 mg, 0.13 mmol) and 1- methylpiperizine (0.52 mmol) in CHCl, (5mL) wvas stirred at RT for 18 h. The reaction mixture was diluted with CH.Cl, (15mL-), washed with water, brine, and dried over Na,SO,. The solvent was removed in vacuo. The title compound was isolated as a solid (29 mg) by preparative revewse phase HPLC (acetonitrile water gradient + 0.1% TFA). MS (ES+) m/z 419 (M+ H)*.

Example 106 : oo

B Preparation of N-{[2-(4-amino-1,2,5-oxadiazol-=3-y})-1-ethyl-4-phenyl-1H- imidazo[4,5-clpyridin-7-ylimethyl}-N, 1-dimethyl—4-piperidinamine

The title compound was prepared in an analogous manner to Example 105 by substituting N, 1-dimethyl-4-piperidinamine f or 1-methylpiperazine in step (c) and omitting the preparative reverse phase HPLC purification. MS(ES+) m/z 447.0

M+H]".

Example 107

Preparation of 4-(1-ethyl-7-{[3-(methylamino)- 1 -pyrrolidiny(imethyl}-4-phenyl-1H- imidazo[4, 5-clpyridin-2-y)-1,2.5-oxadiazol-3-armine trfluoroacetate

The title compound was prepared in an analogous manner to Example 105 by substituting 1,1-dimethylethyl methyl(3-pyrreolidinyl)carbamate for 1- methylpiperazine in step (¢). MS(ES+) m/z 419.0 [M+H]".

Example 108

Prepsaration of (3-amino-2,2-dimethylpropyl{[2-(4-am ino-1,2,5-oxadiazol-3-yi)-1- ethyl-4-phenyl-1H-imidazo[4.5-clpyridin-7-ylimethyl}a-mine trfluoroacetate

The title compound was prepared in an analoggous manner to Example 105 by substituting 2,2-dimethyl-1,3-propanediamine for ‘Hi -methylpiperazine in step (c)..

MS(E=S+) m/z 421.0 [M+H]".

Example 109

Preparation of 4-(7-{[3-(dimethylamino)-1-pyrrolidinyl Jmethyl}-1-ethyl-4-phenyl-1H- imidaazol4, 5-c]pyridin-2-y))-1,2 5-oxadiazol-3-amine trfluoroacetate

The title compound was prepared in an analosgous manner to Example 105 by saubstituting N,N-dimethyl-3-pyrrolidinamine for 1-rmethylpiperazine in step (c).

MS(EES+) m/z 433.0 [M+H]". "Example 110 imidaazo[4,5-clpyridin-2-y)-1,2,5-oxadiazol-3-amine

The title compound was prepared in an analosgous manner to Example 105 by swubstituting (3R)-3-pyrrolidinamine for 1-methylpipaerazine in step (c) and omitiiting the reverse phase preparative HPLC purificaation. MS(ES+) m/z 405.0 [M+H[".

Example 111

Prepearation of 4-[1-ethyl-7-(hexahydro-1H-1,4-diazepin-1-yimethyl)}-4-phenyl-1H- imid=azo[4,5-clpyridin-2-yl1-1.2 5-oxadiazol-3-amine

The title compound was prepared in an analosgous manner to Example 105 by stbstituting hexahydro-1H-1,4-diazepine for 1-metthylpiperazine in step (c) and omit&ing the reverse phase preparative HPLC purification. MS(ES+) m/z 419.0 [M+HT. : 40 Example 112

Preparation of 4-[1-ethyl-4-phenyl-7-(1~piperazinyimethyl)-1H-imidazo[4,5-clpyridin- 2-yll-1,2.5-oxadiazol-3-amine

The title compound was prepared in an analogous manner to Example 105 by substituting piperazine for 1-methylpiperazine in step (c) and omitting the reverse phase preparative HPLC purification. MS(ES+) m/z 405.0 [MH].

Example 113

Preparation of [2-(4-amino-1,2.5-oxadi azol-3-yl)-4-(3-chlorophenyl)-1-ethyl-1H- imidazo[4.5-clpyridin-7-yllmethanol hydrochloride a) Ethyl 2-(4-amino-1 ,2,5-oxadiazol-3-wl)-4-(3-chlorophenyl)-1-ethyl-1H- imidazo[4,5-c]pyridine-7-carboxylate

The desired compound was prepared in an analogous manner to Example 67(g) by substituting ethylamine for isopropylamine in step (a) and 3- chlorophenylboronic acid for phenylbo onic acid in step (b). b) [2-(4-amino-1,2,5-oxadiazol-3-yl)-4— (3-chlorophenyl)-1-ethyl-1H-imidazo[4,5- " c]pyridin-7-yllmethanol hydrochloride a

The title compound was prepared in an analogous manner to the compound of Example 105(a) substituting the cormpound of Example 113(a) for the compound of Example 87(9) and triturating the purified product from 3n HCl. MS(ES+) m/z 371.0 [M+H]".

Example 114

Preparation 4-{1-ethyl-4-phenyl-7-[(3-piperidinylmethyhoxy]-1 H-imidazo[4.5- clpyridin-2-yl}-1.2,5-oxadiazol-3-amine trifluoroacetate a) Ethyl (3-nitropyridin-4-yi)amine ‘

A solution consisting of 4-ethoxy-3-nitropyridine (15.0 g, 97.3 mmol) and

EtNH, (46.5 mL, 70% ag. solution, 58<4 mmol) in EtOH (30 mL) was stirred at 85 °C in a pressure vessel for 2 h. Removal of all volatiles in vacuo afforded the title compound (16.2 g, 99 %). MS (ES+) m/z 168(M+H)*. } b) Ethyl (3-bromo-5-nitropyridin-4-yl)asmine

A mixture of ethyl (3-nitropyridin-4-yl)amine (11.8 g, 70.0 mmol), ac=etic acid ’ (140 mL), sodium acetate (28.7 g, 0.35 mol) and bromine (13.4 g, 84.0 mmol) was stirred in a pressure vessel at ‘100 ©C for 18 h. The solvent was removed Fn vacuo and the residue partitioned between CH,Cl, and water. The aqueous laye r was made basic (pH ~ 8) with NaHCO; and further extracted with CH.Cl. The combined organic extracts were washed with water, brine and dried (NaxS«Qy).

The solvent was removed in vacuo. and the residue subjected to flash chromatography (20% EtOAc/hexanes, silica gel) to give 10.4 g (60%) of the desired compound. MS (ES+) m/z 246(M+H)*. c) 5-Bromo-2-chioro-N4-ethyl-pyridine-3,4-diamine

To a solution of ethyl (3-bromo-5-nitropyridin-4-yl)amine (22.0 g, 89.4 mmol) in conc HCI (250 mL) was added in portions tin(ll) chloride dihydrate (60.5 g@, 270 mmol). The mixture was stirred at RT for 1h and then poured onto ice (300~ g).

EtOAc (500 mL) was added ard the mixture made basic (pH~10) with solic NaOH.

The aqueous layer was extracted with EtOAC and the combined organic lamyers were washed with water, brine and dried (Na2SOg4). The solvent was removed in vacuo. and the residue subjected to flash chromatography (25% EtOAc/hexanes, : silica gel) to give 17.8 g (80%) of the desired compound. MS (ES+) m/z 250(M+H)*. d) N~(5-Bromo-2-chloro-4-ethylamino-pyridin-3-yl)-cyanoacetamide

To a solution of 5-brom o-2-chloro-N4-ethyl-pyridine-3,4-diamine (17.7 g, 70.9 mmol)in DMF (100 mL) at 0 °C was added cyanoacetic acid (9.06 g, 106 mmol), N-methyl morpholine (39 mL, 350 mmol) and EDCI (20.3 g, 106 mrmol).

The cooling bath was removed and stirring continued 3h. The reaction wass diluted with EtOAc (300 mL) and washed with water and brine. The solvent was removed in vacuo to give a solid. Recrystalization from EtOAc/hexanes afforded the= desired compound (22.5 g). MS (ES+) m/z 317(M+H)*. e) (7-Bromo-4-chloro-1-ethyl-1H-imidazo[4,5-c]pyridin-2-y!)-acetonitrile

A solution of N-(5-brom ©-2-chloro-4-ethylamino-pyridin-3-yl)- cyanoacetamide (35.6 g, 112 nmol) in acetic acid (300 mL) was stirred at £0 °C for 1h. The solvent was removed in vacuo to give the desired compound (29.5 g).

This was used without further purification. MS (ES+) m/z 299(M+H)*,

f) (7-Bromo-4-chioro—~1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-hydroxyimino- acetonitrile : :

To a mixture of (7-bromo-4-chloro-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)- acetonitrile (29.5 g, ©8 mmol) in 2 N HCI (400 mL) at RT was added portion wise over 20 min sodium nitrite (14.0 g, 203 mmol). After stirring for an additional 30 min the resulting precipitate isolated by filtration, washed with water and dried to afford the desired compound (32 g). This was used without further purification. MS (ES+) m/z 328(M+H)*. g) 4-(7-Bromo-4-chloro-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yi)-1 ,2,5-oxadiazol-3- amine , Asolution of the compound of Example 114(f) (98 mmol crude from previous step), EtsN (40 mL) and 50% aq hydroxyl amine (16 mL) in THF (250 mL) heated to 90 °C in a sealed pressure vessel for 1.5h. After cooling to RT, the reaction was poured into water and extracted with EtOAC. The combined organic extracts were wash ed with brine and dried (Na2S04). The solvent was removed in vacuo. The crude bris-oxime was dissolved in dioxane (200 mL) and EtsN (35 mL) and heated to 150 *Cin a sealed pressure vessel for 1.5h. After allowing the reaction to cool to RT, the solvent was removed in vacuo to give a solid.

Recrystalization frorn CH,Cl, afforded the desired compound (17.3 g). MS (ES+) m/z 343(M+H)*. h) 1,1-Dimethylethy 1 [4-(7-bromo-4-chloro-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)- 1,2,5-oxadiazol-3-yl Jcarbamate

A solution of the compound of Example 114(g) (8.50 g, 24.7 mmol), pyridine (70 mL), di-t-butyl d icarbonate (21.5 g, 98.8 mmol) and DMAP (3.01 g, 24.7 mmol) in 1,2-dichloroetharee (140 mL) was stirred at 85 °C in a sealed flask for 1 h. The product mixture was partitioned between EtOAc and 1N HCI. The layers were separated and the organic extract washed with 1N HCI, brine and dried (Na2S04).

The solvent was rermoved in vacuo and the resulting solid triturated with EtOAc to afford the desired compound as beige solid (5.06 g). The mother liquor was evaporated to dryness and treated with 2% trifluoroacetic acid in CHCl, (100mL) for 20 h. The reaction mixture was neutralized with sat NaHCOs, washed with brine and dried (Na2SO4). The solvent was removed in vacuo and the residue was subjected to flash chromatagraphy (20% EtOAc/hexane, silica gel) to afford an additional crop of thee desired compound (2.45g). The combined yield of the desired compound was 8.55g (78%). MS (ES+) m/z 443(M+H)*.

i) “R,1-Dimethylethyl {4-(4-chloro-1-ethyl-7-hyedroxy-1 H-imidazo[4,5-c]pyridin-2-yl)- 1,22 ,5-oxadiazol-3-yl]Jcarbamate

To a solution of the compound of Exzample 114(h) (2.00 g, 4.51 mmol) in 5S THF (60 mL), at -100 °C was added n-BuLi €4.50 mL, 2.5 M in hexane, 11.3 mmol) dreopwise. After five minutes, a solution of B (OMe)3 (1.50 mL, 13.5 mmol) in THF (2 mL) was added. After 10 min., the cooling bath was removed. After 1.5 h, 3M

N=OH (3 mL) and 30% w/w Ho02 (9 mL) wesre added to the reaction. After an aciditioal 1h, the reaction was quenched by adding EtOAc and washing sequentially wiith 1N HCI, HO and brine and then dryings over NagSO4. The solvent was re-moved in vacuo and the residue triturated with EtOAc to afford the desired compound (1.45 g). MS (ES+) m/z 381(M+IH)*. i) 1,1-Dimethylethy! [4-(1-ethyl-7-hydroxy-4- pheny}-1H-imidazo[4,5-c]pyridin-2-y1)- 151, 2 ,5-oxadiazol-3-yljcarbamate

The compound of Example 114() (1 .40 g, 3.67 mmol), phenylboronic acid (©.90 g, 7.34 mmol) and Pd(PPha), (0.24 g) were added to 1,4-dioxane( 40 mL) ard 2BM Na,COs (4.04 mL, 8.1 mmol). The reaction vessel was purged with nitrogen, sealed and heated to 90 °C for 18 h. After allowing the reaction to cool to RT, the= - 20 solids were removed by filtration. The filtrate was concentrated in vacuo and the residue subjected to flash chromatography (75% EtOAc/hexanes, silica gel) to gives the desired compound (1.16 g). MS (ES+) m/z 423(M+H)*.

KD 4-{1-Ethyl-4-phenyl-7-[(4-piperidinyimethyl)oxy]-1 H-imidazo[4,5-c]pyridin-2-yl}- 1 ,25-oxadiazol-3-amine

To a suspension of polymer-bound BPPh; (0.96 g, 1.2 mmol/g loading, 1.15 rmmol) in CH,Cl, (10 mL), was added 1,1-d methylethy| 4-(hydroxymethyt)-1- p iperidinecarboxylate (0.50 g, 2.30 mmol) and DEAD (0.18 mL, 1.15 mmol) d ropwise. After 30 min, the suspension wass cooled to 0 °C. A solution of the c-ompound of Example 114(j) (0.10 g, 0.23 mmol) in CH.Cl; (5 mL) was added.

After 1h at 0 °C, solids were removed by filtration and exhzaustively washed with

CH.Cl,. The combined filtrates were conceentrated in vacuo and the resulting residue subjected to flash chromatography (35% EtOAc/hexane, silica gel) to give tie desired title compound as a di-t-butylcaarbamate. MS (ES+) m/z 620(M+H)*.

The di-t-butyl carbamate obtained aabove was dissolved in TFA(2 mL) and

CHCl, (2 mL). After 2h, the solvent was reemoved in vacuo and the residue subjected to preparative reverse phase HPL-C (CH;CN/water gradient, 0.1%TFA) to give 34 mg of the title compound as a white solid. MS (ES+) m/z 420(M+H)*.

Example- 115

Preparation of 4-{7-[(4-amincbutyl)oxy}-1-etnhyl-4-phenyl-1H-imidazo-[4,5-clpyridin- 2-y}-1.2.5-oxadiazol-3-amine trifluoroacetatee

The title compound was prepared in an analogous manner to Example 114 by substituting 1,1-dimethylethyl (4-hydroxyBoutyl)carbamate for 1,1-dimethylethyl 4- (hydroxymethyl)-1-piperidinecarboxylate in Step (k). MS(ES+) m/z 384.0 M+H]

Examples 116

Preparation of 4-{4-(3-chlorophenyl})-1-ethyl—7- iperidinylmethyloxyl-1H- imidazo-[4 5-clpyridin-2-yi}-1,2, 5-oxadiazol-=3-amine trifluoroacetate

The title compound was prepared in an analogous manner to Example 114 by substituting 3-chlorophenyiboronic acid feor phenylborenic acid in step ().

MS(ES+) m/z 454.0 M+H]" :

Examples 117 : iE

Preparation of 4-[7-[(4-aminobutyl)oxy]-4-{3—chlorophenyl)-1-ethyl-1 H-imidazo-[4.5- .- clpyridin-2-yi}-1,2,5-oxadiazol-3-amine triflucroacetate

The title compound was prepared in an analogous manner to Example 114 by substituting 3-chlorophenylboronic acid feor phenylboronic acid in step (j) and 1,1-dimethylethyl (4-hydroxybutyl)carbamate= for 1,1-dimethylethyl 4- (hydroxymethyl)-1-piperidinecarboxylate in step (k). MS(ES+) m/z 428.0 [M+H]"

Example= 118

Preparation of 4-{ 7-[(2-aminoethyl)oxyl-1 -etlhyl-4-phenyl-1H-imidazo-[4,5-c]pyridin- 2-yl}-1,2 5-oxadiazol-3-amine trifluoroacetat-e

The title compound was prepared in an analogous manner to Example 114 by substituting 1,1-dimethylethy! (4-hydroxyeathyl)carbamate for 1,1-dimethylethy! 4- (hydroxymethyl)-1-piperidinecarboxylate in sstep (k). MS(ES+) m/z 366.0 [M+H]" 40

Example: 119

Preparation of 44{1-ethyl-4-phenyl-7-[(3—pyrrolidinylmethylloxyl-1H-imidazo-[4.5- clpyridin-2-yl}-1,2,5-oxadiazol-3-amine t rifluoroacetate

The title compound was prepare«d in an analogous manner to Example 114 by substituting 1,1-dimethylethyl 3-(hydr-oxymethyl)-1-pyrrolidinecarboxylate fomr 1,1- dimethylethy! 4-(nydroxymethyl)-1-piperiidinecarboxylate in step (K). MS(ES+) miz 406.0 [M+H]" a0 Exarmple 120

Preparation of 4-{7-[(3-aminopropyl)oxy}-1-ethyl-4-phenyl-1H-imidazo[4,5-c]pymridin- 2-y1}-1.2,5-oxadiazol-3-amine trifluoroaczetate a5 The title compound was prepare din an analogous manner to Example 114 by substituting 1,1-dimethylethyl (4-hydroxypropyl)carbamate for 1 ,1-dimethylemsthyl 4-(hydroxymethyl)-1-piperidinecarboxyl=ate in step (k). MS(ES+) m/z 380.0 [M-=-H]"

Exarnple 121

Preparation of 4-(7-{[(2S)-2-amino-3-phe=enylpropylloxy}-1-ethyl-4-phenyl-1H- imidazo-[4,5-clpyridin-2-yl)-1,2,5-oxadia zol-3-amine trifluorcacetate

The title compound was prepare-din an analogous manner to Example 114 by substituting 1,1-dimethylethyl [(1S)-2—hydroxy-1-(phenyimethyl)ethyllcarbanate for 1,1-dimethylethyl 4-(hydroxymethyl)—1-piperidinecarboxylate in step (k).

MS(ES+) m/z 456.0 [M+H]" .

Exarmple 122

Preparation of 4-[1-ethyl-4-phenyl-7-(3-piperidinyloxy)-1H-imidazo-[4,5-clpyridimn-2- yil-1.2 5-oxadiazol-3-amine trifluoroacet=ate

The title compound was prepared in an analogous manner to Example 114 335 by substituting 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate for 1,1- dimethylethy! 4-(hydroxymethyl)-1 -piperidinecarboxylate in step (kK). MS(ES+) mn/z 408.0 [M+H]"

Exarmple 123 a0

P reparation of 4-(1-ethyl-4-phenyi-7-{[2-(4-piperidinyhethylloxy}-1_H-imidazo-[4.5- chpyridin-2-yl)-1,2,5-oxadiazol-3-amine trifluoroacetate

The title compound was prepared in an analogous manne-r to Example 114 bry substituting 1,1-dimethylethyl 4-(2-hydroxyethyl)-1 -piperidinecaarboxylate for 1,1- d imethylethyl 4-(hydroxymethyl)-1-piperidinecarboxylate in step (Ex). MS(ES+) m/z 4 34.0 [M+H]'

Example 124

Pereparation of 4-(7-{[(2R)-2-amino-3-phenylpropyljoxy}-1-ethyl-4—phen -1H- " irnidazo-[4.5-clpyridin-2-yl)-1,2,5-oxadiazol-3-amine trifluoroacet=ate

The title compound was prepared in an analogous manner to Example 114 bey substituting 1,1-dimethylethyl [(1R)-2-hydroxy-1-(phenyimethy~l)ethylJcarbamate feor 1,1-dimethylethyl 4-(hydroxymethyl)-1-piperidinecarboxylate imn step x).

NAS(ES+) miz 456.0 [M+H]"

Example 125

Ce Preparation of 4-(1-ethyl-7-{[2-(methylamino)ethylloxy}-4-phenyl—1H-imidazo-[4,5- - c]pyridin-2-y)-1,2,5-oxadiazol-3-amine trifluoroacetate : ~The title compound was prepared in an analogous manner to Example 114 boy substituting 1,1-dimethylethyl (2-hydroxyethy)methylcarbama-te for 1,1- ddimethylethyl 4-(hydroxymethyl)-1-piperidinecarboxylate in step Ck). MS(ES+) miz 3380.0 [M+H]"

Example 126

Preparation of 4-1-ethyl-4-phenyl-7-({2-{(phenylmethyl)aminoletBhyiloxy)-1H- - immidazo-[4,5-c]pyridin-2-yl}-1,2,5-oxadiazol-3-amine trifluoroacet=ate

The title compound was prepared in an analogous manne=r to Example 114 boy substituting 1,1-dimethylethyl (2-hydroxyethyl)(phenylmethyl)carbamate for 1,1- ddimethylethyl 4-(hydroxymethyl)-1-piperidinecarboxylate in step Ck). MS(ES+) m/z £356.0 [M+H]"

Example 127 40

Preparation of 4-{1-ethyl-4-phenyl-7-[(3-piperidinylmesthyl)oxy}-1H-imidazo-[4,5-

Clpyridin-2-yi}-1,2 5-oxadiazol-3-amine trifluoroacetate

The title compound was prepared in an analogous manner to Example 114

Koy substituting 1,1-dimethylethyl 3-(hydroxymethyl)-1-piperidinecarboxylate for 1,1- «dimethylethyl 4-(hydroxymethyl)-1-piperidinecarboxyelate in step (k). MS(ES+) m/z «420.0 [M+H]"

Example 128

Preparation of 5-aminopentyl)oxy}-1-ethyl-4-p-henyl-1H-imidazo-[4,5-clpyridin- 2-yl}-1,2 5-oxadiazol-3-amine trifluoroacetate

The title compound was prepared in an anal ogous manner to Example 114 by substituting 1,1-dimethylethy} (5-hydroxypentyl)c arbamate for 1,1-dimethylethyl 4-(hydroxymethyl)-1-piperidinecarboxylate in step (I<). MS(ES+) m/z 408.0 [M+H]"

Example 129

Preparation of 4-(7-{[3-(dimethylamino)-2,2-dimethyslpropylloxy}-1 -ethyl-4-phenyl- : 1H-imidazo[4,5-clpyridin-2-y})-1,2,5-oxadiazol-3-amaine trifluoroacetate

The title compound was prepared in an analogous manner to Example 114 by substituting 1,1-dimethylethyi (3-hydroxy-2,2-dinmethylpropyl)carbamate for 1,1- - dimethylethyl 4-(hydroxymethyl)-1-piperidinecarboxcylate in step (k). MS(ES+) m/z 436.0 [M+H]"

Example 130

Preparation of 4-(7-{[2-(dimethylamino)ethyiloxy}-1 —ethyi-4-phenyl-1H-imidazo-[4,5- clpyridin-2-y1)-1,2 5-oxadiazol-3-amine trifluoroacettate

The title compound was prepared in an anaalogous manner to Example 114 by substituting 2-(dimethylamino)ethanot for 1,1-dirnethylethyl 4-(hydroxymethyl)-1- piperidinecarboxylate in step (k). MS(ES+) m/z 39-4.0 [M+H]"

Example 131

Preparation of 4-(1-ethyl-4-phenyl-7-{{(2S)-2-pyrroflidinyimethy{loxv}-1H-imidazo- 40 [4.5-c]pyridin-2-y)-1,2 5-oxadiazol-3-amine trifluorcacetate

The title compound was prepared in an analogous manner to Example 114 bay substituting 1,1-dimethylethyl (2S)-2-(hydroxymethyl )-1-pyrrolidinecarboxylate feor 1,1-dimethylethyl 4-(hydroxymethyl)-1-piperidinecarfooxylate in step (k).

MAS(ES+) m/z 406.0 [M+H]"

Example 132 : Freparation of 4-(1-ethyl-4-phenyl-7-{[(2R)-2-pyrrolidinywsimethylloxy}-1H-imidazo- [-4.5-c]pyridin-2-y})-1,2 5-oxadiazol-3-amine trifluorcace tate

The title compound was prepared in an analogous manner to Example 114 by substituting 1,1-dimethylethyl (2R)-2-(hydroxymethy 1)-1 -pyrrolidinecarboxylate for 1,1-dimethylethyl 4-(hydroxymethyl)-1-piperidinecar-boxylate in step (k).

MAS(ES+) m/z 406.0 [M+H]"

Example 133 : reparation of 4-7-{(3-aminopropylioxyl-4-(2-chloropheenyl)-1-ethyl-1H-imidazoj4,5- ) cclpyridin-2-yll-1,2.5-oxadiazol-3-amine trifluoroacetate ) : }

The title compound was prepared in an analogous manner to Example 114 k : Boy substituting 2-chlorophenylboronic acid for phenylboronic acid in step (j) and ~1,1-dimethylethyl (3-hydroxypropyl)carbamate for 1,1-cdimethylethyl 4- : no &hydroxymethyl)-1-piperidinecarboxylate in step (k). M S(ES+) m/z 414.0 M+H]"

Example 134

EPreparation of 4-[7-[(3-aminopropyl)oxy}-4-(3-chloropheenyl)-1-ethyl-1H-imidazo[4.5- «clpyridin-2-yll-1.2.5-oxadiazol-3-amine trifluoroacetate

The title compound was prepared in an analogous manner to Example 114 by substituting 3-chlorophenylboronic acid for phenylbcoronic acid in step (j) and ~1,1-dimethylethyl (3-hydroxypropyl)carbamate for 1,1-climethylethy! 4- «(hydroxymethyl)-1-piperidinecarboxylate in step (k). WLS(ES+) m/z 414.0 [M+H]"

Example 135

Preparation of 4-[7-[(3-aminopropyloxyl-4-(4-chloroph enyl)-1-ethyl-1H-imidazo[4.5- 40 «|pyridin-2-yi]-1,2 S5-oxadiazol-3-amine trifluoroacetate

The title compound was prepared in an analogous manner to Example 114 by substituting 4-chlorophenylborory ic acid for phenylboronic acid in step (j) and 1.1-dimethylethyl (3-hydroxypropyl)carbamate for 1,1-dimethylethy! 4- (hydroxymethyl)-1-piperidinecarboxylate in step (k). MS(ES+) m/z 414.0 [M+H]"

Example 136

Preparation of 4-{7-{(3-aminopropyl)oxy]-4-[5-chioro-2-(methyloxy)phenyll-1-ethyl- 1H-imidazo[4,5-clpyridin-2-yl}-1.2, 5—oxadiazol-3-amine trifluoroacetate

The title compound was prepared in an analogous manner to Example 114 by substituting 5-chloro-2-methoxypehenylboronic acid for phenylboronic acid in step (i) and 1,1-dimethylethyl (3-hydroxy propyl)carbamate for 1,1-dimethylethyl 4- (hydroxymethyl)-1-piperidinecarboxylate in step (k). MS(ES+) m/z 444.0 [M+H]"

Example 137

Preparation of 2-{2-(4-amino-1 2 5-oxadiazol-3-yl )-7-I(3-aminopropvi)oxy}-1-ethy]- 1H-imidazo[4,5-clpyridin-4-yl}-4-chlorophenol trifluoroacetate : The title compound was prepared in an analogous manner to Example 114 : - by substituting 5-chioro-2-methoxypehenylboronic acid for phenylboronic acid in step. (i); 1,1-dimethylethy! (3-hydroxypropyl)carbamate for 1,1-dimethylethy! 4- : (hydroxymethyl)-1-piperidinecarboxwlate and BCl,/MeOH for trifluoroacetic ’ acid/CH.Cl, in step (k). MS(ES+) mn/z 430.0 [M+H]"

Example 138

Preparation of 4-[7-[(3-aminopropyl»oxy]-1-ethyl-4-(2-pyridinyl)-1H-imidazo[4.5- clpyridin-2-yll-1,2 5-oxadiazol-3-ami ne trifluoroacetate

The title compound was prepared in an analogous manner to Example 114 by substituting 2-pyridineboronic aci d for phenylboronic acid in step (j) and 1,1- dimethylethy! (3-hydroxypropyl)carbamate for 1,1-dimethylethyl 4-(hydroxymethyl)- 1-piperidinecarboxylate in step (k). MS(ES+) m/z 381.0 [M+H]

Example 139

Preparation of 4-(7-{[3-(dimethylamino)prospviloxy}-1-ethyl-4-phenyl-1H- imidazo[4,5-clpyridin-2-yl)-1,2 6-oxadiazol—3-amine trifluoroacetate

The title compound was prepared i 1 an analogous manner to Example 1-14 by substituting 3-(dimethylamino)-1-proparol for 1,1-dimethylethyl 4- (hydroxymethyl)-1-piperidinecarboxylate irm step (k). MS(ES+) m/z 408.0 [M+H]

Exampele 140

Preparation of 4-(1-ethyl-7-{I3-(4-morpholi_nyhpropvijo: henyl-1H-imidazo[4 ,5- clpyridin-2-yl)-1,2, 5-oxadiazol-3-amine trifF uoroacetate

The title compound was prepared i n an analogous manner to Example 1-14 by substituting 3-(4-morpholinyl)-1-propan <ol for 1,1-dimethylethyl 4- (hydroxymethyi)-1-piperidinecarboxylate ir step (k). MS(ES+) m/z 450.0 [M+H]"

Exampele 141

Preparation of 4-(1-ethyl-7-{[3-(methylamiso)propylloxy}-4-phenyl-1H-imidazo[4, £- clpyridin-2-vi}-1.2,5-oxadiazol-3-amine triff uoroacetate : . The title compound was prepared i n an analogous manner to Example 1-14 : : by substituting 1, 1-dimethylethyl (3-hydrox<ypropyl)methylcarbamate for 1,1-

Ce dimethylethyl 4-(hydroxymethyl)-1-piperidimnecarboxylate in step (k). MS(ES+) m_/z 394.0 [M+H]"

Example 142

Preparation of 4-{1-ethyl-7-[(3-hydrazinopr-opyl)oxyl-4-phenyl-1H-imidazo(4.5- clpyridin-2-yl}-1.2,5-oxadiazol-3-amine trifl uoroacetate

The title compound was prepared im an analogous manner to Example 1-14 by substituting 1, 1-dimethylethyl 1-(2-hydreoxyethyl)hydrazinecarboxylate for 1,1- dimethylethyl 4-(hydroxymethyl)-1-piperidirecarboxylate in step (k). MS(ES+) mJ/z 3S 395.0 [M+H]

Examp le 143

Preparation of 2-[(3-{[2~(4-amino-1,2,5-ox=adiazol-3-yl)-1-ethyl-4-phenyl-1H- 40 imidazol4,5-clpyridin-7-ylloxy}propyl)aminclethanol triflucroacetate

The title compound was prepared in an analogous manner to Example 114 by substituting 1,1-dimethylethyl (3-hydroxyprospyl)[2-(tetrahydro-2H-pyran-2- - yloxy)ethyljcarbamate for 1,1-dimethylethyl 4-(hhydroxymethyl)-1- piperidinecarboxylate in step (k). MS(ES+) m/=z 424.0 [M+H]"

Example 114 : ' Preparation of 4-(1-ethyl-7-{[3-(hydroxyamino)gpropyllo: henyl-1H-imidazol4,5- -

A0 clpyridin-2-yl)-1,2 5-oxadiazol-3-amine trifluorceacetate

The title compound was prepared in an. analogous manner to Example 114 by substituting 1,1-dimethylethyl hydroxy(3-hyciroxypropyl)carbamate for 1,1- dimethylethyl 4-(hydroxymethyl)-1-piperidinecaarboxylate in step (k). MS(ES+) m/z

A5 396.0 M+H]

Example 1=15 E

Preparation of N-(3-{2-(4-amino-1 2 5-oxadiazek3-yl)-7-{(3-am inopropyhoxy}-1- sthyl-1H-imidazof4.5-clpyridin-4-yi}phenyD-N'-pohenvlurea trifluoroacetate : Co : The title compound was prepared in ane analogous manner to Example 114 : : by substituting (3-{[(phenylamino)carbonyllami no}phenyl)boronic acid for : : phenylboronic acid in step (j) and 1,1-dimethyleethyl (3-hydroxypropyl)carbamate for : 1,1-dimethylethyl 4-(hydroxymethyl)-1-piperidimecarboxylate in step (k). MS(ES+) m/z 514.0 [M+H]"

Example 116 =(0 Preparation of 3-{[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-4-phenyi-1H- imidazo[4.5-c]pyridin-7-ylJoxy}-1-propanol! triflu-oroacetate

The title compound was prepared in an analogous manner to Example 114 by substituting 3-(tetrahydro-2H-pyran-2-yloxy)-1-propanol for 1,1-dimethylethyl 4-

E5 (hydroxymethyl)-1-piperidinecarboxylate in step (k). MS(ES+) m/z 381.0 [M+H]"

Example 147

Preparation of 4-{7- (4-amino-2-methylbutyljox=y}-1 -ethyl-4-phenyl-1H-imidazo[4.5- 4-0 _clpyridin-2-vl}-1,2 5-oxadiazol-3-amine trifluoro acetate

The title compound was prepared in an analogous manner to Example 1%4 by substituting 1,1-dimethylethyl (4—hydroxy-3-methylbutyl)carbamate for 1,1- dimethylethyl 4-(hydroxymethyl)-1-piperidinecarboxylate in step (k). MS(ES+) m#/z 408.0 [M+H]"

Example 148

Preparation of 4-(1-ethyl-4-phenyl-7-{{2-(2-piperidinyl)ethylloxy}-1H-imidazo[4,5- clpyridin-2-yl)-1,2 5-oxadiazol-3-ameine trifluoroacetate

The title compound was prepared in an analogous manner to Example 1-14 by substituting 1,1-dimethylethyl 2-{2-hydroxyethyl)-1-piperidinecarboxylate for 1 ,1- dimethylethyl 4-(hydroxymethyl)-1-piperidinecarboxylate in step (k). MS(ES+) m_/z 434.0 [M+H]"

Example 149

Preparation of N-(4-{[2-(4-amino-1, 2,5-oxadiazol-3-yl)-1-ethyl-4-phenyi-1H- _ 20 ° imidazo[4,5-cipyridin-7-yiloxy}butyl}benzenesulfonamide : The title compound was pre pared in an analogous manner to Example 1-14 by substituting N-(4-hydroxybutyl)benzenesulfonamide for 1,1-dimethylethyl 4- (hydroxymethyl)-1-piperidinecarboxylate in step (k) and omitting the treatment wilith trifluoroacetic acid/CH,Cl, and reverse phase HPLC. MS(ES+) m/z 534.0 [M+HP"

Example 150

Preparation of N-(4-{[2-(4-amino-1, 2.5-oxadiazol-3-yl}-1-ethyl-4-phenyl-1H- imidazo[4, 5-c]pyridin-7-ylloxy}butyl) methanesulfonamide

The title compound was pre pared in an analogous manner to Example 1-14 by substituting N-(4-hydroxybutyl)rethanesulfonamide for 1,1-dimethylethyl 4- (hydroxymethyl)-1-piperidinecarboxylate in step (k) and omitting the treatment with trifluoroacetic acid/CH.Cl, and reverse phase HPLC. MS(ES+) m/z 472.0 [M+H]} *

Example 151 }

Preparation of 1-{[2-(4-amino-1,2 5—oxadiazol-3-yl)-1-ethyl-4-phenyl-1H- 40 imidazo[4,5-c]pyridin-7-vijoxy}-3-(4—-morpholinyl)-2-propanol trifluoroacetate a) 2-(4-Amino-1,2,5-oxadia=ol-3-yl)-1-ethyl-4-phenyl-1H-imidazoi4,5-c]pyridin-7-ol

The compound of Example 114(j) (50 mg, 0.12 mmol) was stirred in 30%

TFA/CH.CI, for 1h. The so lvent was removed in vacuo and the residue was azeotroped from toluene to give the desired compound. MS(ES+) m/z 323 (M+H)". © b) 4-{1-Ethyl-7-[(2-oxiranylrmethyl)oxy}-<4-phenyl-1 H-imidazo{4,5-c]pyridin-2-yl}- 1,2,5-oxadiazol-3-amine

A mixture of the cormpound of Example 151(a) (39 mg, 0.12 mmol), Cs.CO; (195 mg, 0.60 mmol) and bromoepihydrin (22 ul, 0.25 mmol) in DMF (1 mL) was stirred at RT for 18h. The reaction mixture was diluted with EtOAc, washed with water and dried. The solvernt was removed in vacuo to give the desired compound (40 mg). MS(ES+) m/z 379 (M+H)". c) 1-{[2-(4-Amino-1,2,5-oxa diazol-3-yl)-1-ethyl-4-phenyl-1H-imidazo[4,5-c)pyridin-7- ylloxy}-3-(4-morpholinyl)-2- propanol trifluoroacetate

A solution of the cornpound of Example 151(b) (40 mg, 0.11 mmol) and morpholine (0.6 mmol) in EtOH (1 mL) was heated at 80 OC for 15 min. The a solvent was removed in vacuo and the resulting residue subjected to preparative oo reverse phase HPLC (acetonitrile water gradient + 0.1% TFA) to give the title compound (25 mg). MS(ES+) m/z 466 (M+H)".

Example 152

Preparation of 4-(1-ethyl-7—{[2-(4-morpholinyl)ethylloxy}-4-phenyl-1H-imidazof4.5- clpyridin-2-vi)-1,2 5-oxadiazol-3-amine trifluoroacetate a) 4{7-{(2-Bromoethyl)oxy]~1-ethyl-4-phenyi-1 H-imidazo[4,5-c]pyridin-2-yl}-1,2,5- oxadiazol-3-amine

A mixture of the connipound of Example 151(a) (64 mg, 0.20 mmol), Cs,CO, (195 mg, 0.60 mmol) and 1,2-dibromoethane (69 ul, 0.80 mmol) in DMF (1 mL) was stirred at RT for 18h. The reaction mixture was diluted with EtOAc, washed with water and dried. The solvent was removed in vacuo to give the desired compound. MS(ES+) m/z «430 (M+H)".

b) 4-o(1-Ethyl-7-{{2-(4-morpholinyl)ethyl]oxy}-4-i=henyl-1 H-imidazo[4,5-c]pyridin-2- yl)-1,.2,5-oxadiazol-3-amine trifluoroacetate

A solution of the compound of Example - -152(a) (0.20 mmol) and morpholine (1.0 ammo) in THF (2 mL) was heated at 60 OC= for 20h. The solvent was removed in va.cuo and the resulting residue subjected to- preparative reverse phase HPLC (acetonitrile water gradient + 0.1% TFA) to give= the title compound. MS(ES+) m/z 436 «(M+H)".

Example 153

Prer>aration of 4-(1-ethyi-4-phenyl-7-{{3-(1-piperidinyl)propyllo 1H-imidazo[4,5- clpymridin-2-yl)-1.2 5-oxadiazol-3-amine trifiluorcoacetate

The title compound was prepared in ars analogous manner to Example 152 by smubstituting 1,3-dibromopropane for 1,2-dib=romoethane in step (a) and : pipe ridine for morpholine in step (b). MS (ES+) m/z 448.0 (M+H]

Example 1554

Preparation of (2-aminoethyl)(2-{]2-(4-amino-1 .2.5-oxadiazol-3-yl)-1-ethyl-4-phenyl- 1H-i_midazo[4,5-c]pyridin-7-yljoxy}ethyDamine frifluoroacetate :

The title compound was prepared in arm analogous manner to Example 152 by s ubstituting 1,2-diaminoethane for morpholine in step (b). MS (ES+) m/z 409.0 [M+EH[]

Example 1=55

Preparation of 4-(1-ethyl-4-phenyl-7-{[2-(1-pipwerazinyllethylloxy}-1 H-imidazo[4.5- clpy ridin-2-yi)-1.2,5-oxadiazol-3-amine trifluorcacetate

The title compound was prepared in ar analogous manner to Example 152 by s ubstituting piperazine for morpholine in steep (b). MS (ES+) m/z 435.0 (M+H]

Example 1:56

Preparation of 4-(7-{[2-(4-acetyl-1-piperazinyl) ethyfoxy}-1-ethyl-4-phenyl-1H- imid_azo[4,5-clpyridin-2-yl)-1,2,5-oxadiazol-3-atmine trifluoroacetate

The title compound was prepared in an analogous manner to Example 152 by substituting 1-acetylpiperazine for morphmoline in step (b). MS (ES+) m/z 477.0 [M+H]"

Examples 157

Preparation of 4-(1-ethyl-7-{[3-(4-methyl-1-poiperazinyl)propyllo henyl-1H- imidazol4.5-clpyridin-2-y1)-1,2 5-oxadiazol-S3-amine trifluoroacetate

The title compound was prepared ins an analogous manner to Example 152 by substituting 1,3-dibromopropane for 1,2—dibromoethane in step (a) and 1- methylpiperazine for morpholine in step (b)- MS (ES+) miz 463.0 [M+H]

Examples 158

Preparation of 4-(1-ethyl-4-phenyl-7-{[3-(1-gpiperazinyl)propylloxy}-1 H-imidazo[4.5- clpyridin-2-y1)-1,2,5-oxadiazol-3-amine trifiiaoroacetate

The title compound was prepared ire an analogous manner to Example 152 by substituting 1,3-dibromopropane for 1,2—dibromoethane in step (a) and piperazine for morpholine in step (b). MS ( ES+) m/z 449.0 [M+H]

Examplee 159

Preparation of 4-(1-ethyl-4-phenyl-7-{[2-(1-mpiperidiny)ethylloxy}-1 H-imidazo[45- -- clpyridin-2-yl)-1,2,5-oxadiazol-3-amine triflaoroacetate

The titie compound was prepared irm an analogous manner to Example 152 by substituting piperidine for morpholine in step (b). M$ (ES+) m/z 434.0 [M+H]"

Example 160

Preparation of (3-{[2-(4-amino-1 ,2.5-oxadiamz0l-3-yl)-1-ethyi-4-phenyl-1H- imidazo[4 5-clpyridin-7-ylloxy}propyl)[2-(dinmethylamino)ethylimethylamine trifluoroacetate

The title compound was prepared irs an analogous manner to Example 152 by substituting 1,3-dibromopropane for 1,2—dibromosthane in step (a) and N,N,N'- trimethyl-1,2-ethanediamine for morpholine= in step (b). MS (ES+) m/z 465.0 40 [MH]

Example 161

Preparation of 3-[(3-{[2-(4-amino-1.2,5-0x adiazol-3-yl)-1-ethyl-4-phenyl-1 H- imidazo[4 5-c]pyridin-7-ylloxy}propyhamirmo}-1 .2-propanediol trifluoroacetate

The title compound was prepared in an analogous manner to Example 152 by substituting 1,3-dibromopropane for 1, =2-dibromoethane in step (a) and 3-amiro- 1,2-propanediol for morpholine in step (b)s. MS (ES+) m/z 454.0 [M+H]

Examppole 162 :

Preparation of 4-(7-4{[3-({[2.4-bis(methyloxcy)phenyllmethyllamino)propyljoxy}-1- ethyl-4-pheny!-1H-imidazo{4.5-clpyridin-2=-yl)-1 ,2,5-oxadiazol-3-amine {triflucroacetate

The title compound was prepared in an analogous manner to Example 1552 by substituting 1,3-dibromopropane for 1 2 2-dibromoethane in step (a) and 1-{2,4-- } bis(methyloxy)phenyljmethanamine for nrmorpholine in step (b). MS (ES+) m/z 530.0 [M+H]' :

Exammple 163

Preparation of (28)-2-[(3-{[2-(4-amino-1 2 .5-oxadiazol-3-yl)-1-ethyl-4-phenyl-1H— imidazo[4,5-clpyridin-7-ylloxy}propyhamimnol-4-methyl-1 -pentanol triflucroacetate

The title compound was prepared in an analogous manner to Example 1 62 by substituting 1,3-dibromopropane for 1 ,2-dibromoethane in step (a) and (2R)-22- amino-4-methyl-1-pentanol for morpholine in step (b). MS (ES+) m/z 480.0 [M+ H]

Example 164

Preparation of 4-{1 -ethyl-4-phenyi-7-[3-(=2-pyridin-4-yl-ethylamino)-propoxy-1 H- imidazo[4,5-c]pyridin-2-yll-furazan-3-ylaraine trifluoroacetate

The title compound was preparecd in an analogous manner to Example 1 52 by substituting 1,3-dibromopropane for 1 ,2-dibromoethane in step (a) and 2-(4- pyridinyl)ethanamine for morpholine in stzep (b). MS (ES+) m/z 485.6 [M+H]" 40 Example 165 : -1.37-

Preparation of 4-(2-{3-[2-(4-amino-furazan-3-yl)-1-ethyl-4-phenyl-1 H-imidazol4,5- clpyricdRin-7-yloxyl-propylamino}-ethyl -benzenesulfonamide trifluoro acetate

The title compound was prepared in an analogous manner to Example 152 by substituting 1,3-dibromopropane for 1,2-dibromoethane in step (a) and 4-(2- amino-ethyl)benzenesulfonamide for morpholine in step (b). MS (EES+) m/z 563.4 [M+H]™

Example 166

Prepa ration of 4-(1-ethyl-7-{3-[2-(1-methyl-1 H-pyrrol-2-yl)-ethylam inol-propoxy}-4- henv-1-1H-imidazol4,5-clpyridin-2-yl)-furazan-3-ylamine trifluoroacetate

The title compound was prepared in an analogous manner— to Example 152 - by sulbostituting 1,3-dibromopropane for 1,2-dibromoethane in step (a) and 2-(1- methywl-1H-pyrrol-2-yl)ethanamine for morpholine in step (b). MS EES+) m/z 487.6

Example 167

Prepaaration of 4-(7-{3-[2-(4-amino-phenyl)-ethylamino]-propoxy}-1 -ethyl-4-phenvyl- 1H-immidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine trifluoroacetate oo

The title compound was prepared in an analogous manner to Example 152 by sukostituting 1,3-dibromopropane for 1,2-dibromoethane in step (a) and 4-(2- amincethylaniline for morpholine in step (b). MS (ES+) m/z 489.65 [M+H]

Example 168

Prepaaration of 4-(1-ethyl-7-{3-[2-(1H-imidazo-4-yl}-ethylamino ]-propoxy}-4-phenyl- 1H-inmidazo[4.5-c]pyridin-2-yl)-furazan-3-ylamine trifiuoroacetate

The title compound was prepared in an analogous manner to Example 152 by suBostituting 1,3-dibromopropane for 1,2-dibromoethane in step- (a) and 2-(1H- imida=zol-4-yl)ethanamine for morpholine in step (b). MS (ES+) maz474.4 [M+H]

Example 169

WJ 0 2005/011700 PCT/US2004/024340

Preparation of 4-{1-éthyl-7-{3-(3-imidazol-1-yl-propylamino)-pro -4-phenyl-1H- imidazo[4.5-c]pyridin-2-yi}-furazan-3-ylamine triflucroacetate

The title compound was prepared in an analogous manner to Example 152 by substituting 1,3-dibromopropane for 1,2-dibrora oethane in step (a) and 2-(1H- imidazol-1-yl)ethanamine for morpholine in step (b). MS (ES+) m/z488.4 [M+H]

Example 170

Preparation of 4-(2-{3-[2-(4-amino-furazan-3-y!)-1—ethyl-4-phenyl-1 H-imidazo[4.5- clpyridin-7-yloxyl-propylamino}-ethyl)-phenol triflucroacetate

The title compound was prepared in an analogous manner to Example 152 by substituting 1,3-dibromopropane for 1,2-dibronoethane in step (a) and 4-(2- aminoethyl)phenol for morpholine in step (b). MS (ES+) m/z 500.4 [M+H]"

Example 171

Preparation of 2-{3-[2-(4-amino-furazan-3-yf}-1 -ethhyl-4-phenyl-1H-imidazo[4.5- clpyridin-7-vioxy}-propylamino}-1-phenyl-ethanol tmifluoroacetate : The title compound was prepared in an an alogous manner to Example 152 by substituting 1,3-dibromopropane for 1,2-dibroncethane in step (a) and 2-amino- 1-phenylethanol for morpholine in step (b). MS (EES+) m/z 500.4 [M+H]"

Example 172

Preparation of 4-{1-ethyl-7-[3-(3-morpholin-4-yl-propylamino)-propoxyl-4-phenyl- 1H-imidazol4,5-clpyridin-2-yl}-furazan-3-ylamine trifluoroacetate

The title compound was prepared in an analogous manner to Example 152 by substituting 1,3-dibromopropane for 1,2-dibronmcethane in step (a) and 3-(4- morpholinyl)-1-propanamine for morpholine in stego (b). MS (ES+) m/z 507.4 [M+H]"

Example 173

Preparation of 4-(1-ethyl-7-{3-[2-(5-methoxy-1 H-irmdol-3-yl)-ethylamino}-propoxy}-4- phenyl-1H-imidazo[4.5-clpyridin-2-yl)-furazan-3-ylamine trifluoroacetate 40

WO~ 2005/011700 PCT/US2004/024340

The title compound was prepared in an analogous manner to Example 152

Boy substituting 1,3-dibromopropane for 1,2-dibromoefhane in step (a) and 2-[5- ~(methyloxy)-1H-indol-3-yi]ethanamine for morpholine in step (b). MS (ES+) m/z =553.6 [M+H]"

Example 174

Preparation of 4-{2-{(3-{[2-(4-amino-1 2 5-oxadiazol-=3-yl)-4-(3-chlorophenyl)-1- ethyl-1H-imidazo[4,5-clpyridin-7-ylloxy}propyhamino] ethyllbenzenesulfonamide trifluoroacetate a) 2-(4-Amino-1,2,5-oxadiazol-3-yi)-1 -ethyl-4-(3-chlomrophenyl)-1H-imidazo[4,5- clpyridin-7-ol

The desired compound was prepared in an asmnalogous manner to the compound of Example 151(a) substituting 1,1-dimetylethyl {4-[4-(3-chlorophenyl)- 7-hydroxy-1H-imidazo[4,5-c]pyridin-2-yi]-1 ,2,5-oxadi=azol-3-yl}carbamate for the compound of Example 114(). : : b) 4-{7-[(3-Bromopropyl)oxy]-4-(3-chiorophenyl)-1 H-Emidazo[4,5-c]pyridin-2-yi}- 1,2,5-oxadiazol-3-amine oo

The desired compound was prepared in a manner analogous to that of © Example 152(a) substituting the compound of Exam: ple 174(a) for the compound of

Example 151(a) and 1,3-dibromopropane for 1,2-dibsromoethane. : ¢) 4-{2-[(3{[2-(4-amino-1,2,5-oxadiazol-3-y)-4-(3-cha lorophenyl)-1-ethyl-1H- imidazo[4,5-c]pyridin-7-yiJoxy}propyl)aminojethyl}bemnzenesuifonamide trifluoroacetate

The title compound was prepared in an analogous manner to Example 152(b) substituting the compound of Example 174(be) for the compound of Example 152(a) and 4-(2-aminoethyl)benzenesulfonamide for- morpholine. MS (ES+) m/z 597.4 [M+H]'

Example 175

Preparation of 4-{4-(3-chlorophenyl)-1-ethyl-7-[(3-{[2-(1H-imidazo}-4- yl)ethyllamino}propyi)oxyl-1H-imidazo[4,5-clpyridin-22-yl}-1.2.5-oxadiazol-3-amine trifluoroacetate .

The title compound wa s prepared in an analogous manner to Example 174 by substituting 2-(1H-imidazol—4-yl)ethanamine for 4-(2- aminoethyl)benzenesulfonami de in step (c). MS (ES+) m/z 508.4 [M+H]"

Example 176

Preparation of (S)-3-{3-[2-(4-aamino-furazan-3-yl)-ethyl-4-phenyl-1H-imidazo[4,5- clpyridin-7-yloxyl-propylamino}-propane-1,2-diol trifluoroacetate

The title compound was prepared in an analogous manner to Example 152 by substituting 1,3-dibromopropane for 1,2-dibromoethane in step (a) and (28)-3- amino-1,2-propanediol for mosrpholine in step (b). MS (ES+) m/z 454 4 (M+H]'

Example 177 ’

Preparation of 4-(7-[(3-](3-amninophenyl)methyllamino}propyloxy]-1 -ethyl-4-phenyl- 1H-imidazo[4,5-c]pyridin-2-yl}-1,2,5-oxadiazol-3-amine trifluoroacetate

The title compound was prepared in an analogous manner to Example 152 by substituting 1,3-dibromopropane for 1,2-dibromoethane in step (a) and 3- (aminomethyl)aniline for morpholine in step (b). MS (ES+) m/z 485.6 [M+H]"

Example 178 : :

Preparation of 4-{1-ethyl-7-[(3-{[(5-methyl-2-pyrazinyl)methyilamino}propyloxy}-4- phenyl-1H-imidazo[4.5-c]pyridlin-2-yl}-1,2 5-oxadiazol-3-amine trifluoroacetate

The title compound was prepared in an analogous manner to Example 152 by substituting 1,3-dibromopropane for 1,2-dibromoethane in step (a) and 1-(5- methyl-2-pyrazinyl)methanarine for morpholine in step (b). MS (ES+) m/z 486.6 [M+H]"

Example 179

Preparation of 5-{[(3-{[2-{4-armino-1,2 5-oxadiazol-3-yl)-4-(3-chlorophenyl)-1-ethyl- 1H-imidazol4,5-clpyridin-7-yIT oxy}propyhaminolmethyl}-2-methyl-4-pyrimidinamine trifluoroacetate

The title compound was prepared in an analogous manner to Exampele 174 by substituting 1-(2-methyI-5-pyrimidinyl)methanamine for 4-(2- aminoethyl)benzenesulfonamide in step (c). MS (ES+) m/z 535.4 [M+H]"

Example 180

Preparation of 3- 2.(4-amino-1.2.5-oxadiazol-3-yl)-4-(3-chlorophenyl)-1—ethyl- _ 1H-imidazo[4.5-clpyridin-7-yiloxy}propyl)amino}l-1 ,2-propanediol trifluoroace tate

The title compound was prepared in an analogous manner to Example 174 by substituting 3-amino-1 ,2-propanediol for 4-(2-aminoethyl)benzenesulfonaamide in step (c). MS (ES+) m/z 488.4 [M+H]"

Example 181

Preparation of 4-4{2-[(3-{[2-(4-amino-1 .2.5-0xadiazol-3-yl)-1 -ethyi-4-(1H-pyrrol-2-yl)- 1 H-imidazo[4.5-clpyridin-7-ylloxy}propyllaminolethyl}phenol trifluoroacetate . a) 2-(4-Amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-4-(1H-pyrrol-2-yl)-1 H-imidazol4, 5- : 20 c]pyridin-7-ol oo

The desired compound was prepared in an analogous manner to the compound of Example 151(a) substituting 1 ,1-dimethylethyl {4-{1-ethyl-7-hyrdroxy- 4-(1H-pyrrol-2-yl)-1H-imidazo{4,5-c]pyridin-2-yl}-1 ,2,5-oxadiazol-3-yljcarbarmnate for : the compound of Example 114(j). b) 4-[7-[(3-Bromopropyl)oxy]-1-ethyl-4-(1H-pyrrol-2-yl)-1 H-imidazo[4,5-c]pyridin-2- yil-1,2,5-oxadiazol-3-amine

The desired compound was prepared in a manner analogous to that of

Example 152(a) substituting the compound of Example 181(a) for the compound of

Example 151(a) and 1,3-dibromopropane for 1,2-dibromoethane. ¢) 4{2-[(3-{[2-(4-Amino-1,2,5-oxadiazol-3-yl)-1-ethyl-4-(1 H-pyrrol-2-yl)-1H- imidazo[4,5-c]pyridin-7-ylJoxy}propyl)amino]ethyl}phencl trifluoroacetetate

The title compound was prepared in an analogous manner to Example 152(b) substituting the compound of Example 181(b) for the compound of EExample 152(a) and 4-(2-aminoethyl)pheno! for morpholine. MS (ES+) m/z 489.4 [MA+H]"

Example 182

Preparation of 4-[7-[(3 [2-(4-aminophenyl)ethyllamino}propyloxyl-1 -ethyl-4-(1H- pyrrol-2-yl)-1H-imidazo[ 4.5-clpyridin-2-y(]-1 2 5-oxadiazol-3-amine triffuoroacetate

The title compound was prepared in an analogous manner to Example 181 by substituting 4-(2-ami noethyl)aniline for 4-(2-aminoethyl)phenol in step (c). MS (ES+) m/z 488.2 (M+H]™ : Example 183

Preparation of 4-{[(3-{[2-(4-amino-1 2 5-oxadiazol-3-yl)-4-(3-chiorophenyl)-1-ethyl- 1H-imidazo[4,5-clpyridi n-7-ylloxylpropyl)aminolmethyllbenzenesulfonamide trifluoroacetate .

The title compound was prepared in an analogous manner to Example 174 by substituting 4-(aminomethyl)benzenesuifonamide for 4-(2- aminoethyl)benzenesulifenamide in step (c). MS (ES+) m/z 583.4 [M+H]"

Example 184

Preparation of 1 2. 4-amino-1.2.5-oxadiazol-3-y!)-4-(3-chlorophenyl)-1-ethyl- g -1H-imidazo[4,5-c]pyrid in-7-ylloxy}propyl)amino}-1 -deoxy-D-glucitol frifluoroacetate .

The title compound was prepared in an analogous manner to Example 174 by substituting 1-amino-1-deoxy-D-iditol for 4-(2-aminoethyl)benzenesulfonamide in step (c). MS (ES+) m/= 578.6 [M+H]"

Example 185

Preparation of 4-{2-[(3—{[2-(4-amino-1,2.5-oxadiazol-3-y})-1-ethyl-4-(1 H-pyrrol-2-yl}- 1H-imidazo[4,5-clpyrid in-7-ylloxy}propyl)aminolethyilbenzenesulfonamide trifluoroacetate

The title compound was prepared in an analogous manner to Example 181 by substituting 4-(2-aminoethyl)benzenesulfonamide for 4-(2-aminoethyl)phenol in step (c). MS (ES+) m/z 552.4 [M+H]'

Example 186

Preparation of 3-{[2-(4-amino-1,2 5-oxadiazol-3-yl)—~1-ethyl-4-(1 H-pyrrol-2-yh-1H- imidazeol4,5-clpyridin-7-ylloxy}propyl 4-(aminometh-yibenzoate triflucroacetate

The title compound was prepared in an anaalogous manner to Example 181 by substituting 4-(aminomethyl)benzoic acid for 4-C 2-aminosthyl)phenol in step (c). : MS (ESS+) m/z 503.4 [M+H]"

Example 187 Prepamation of 1-{[2-(4-amino-1,2,5-oxadiazol-3-yi»-1-ethyl-4-phenyl-1 H- imidaz=ol4,5-clpyridin-7-ylloxy}-3-{[(3-aminophenylemethyllamino}-2-propanol trifluor-oacetate

The title compound was prepared in an analogous manner to Example 151 by sukostituting 4-(aminomethyl)aniline for morphoBine in step (c). MS (ES+) m/z 501.4 [M+H]

Example 188

Preparation of 4-{I(3{[2-(4-amino-1.2,5-oxadiazol—3-yl)-1 -ethyl-4-phenyl-1H- : imida=zo[4,5-clpyridin-7-yiloxy}-2-hydroxypropyharminolmethyllbenzenesulfonamide - trifluoeroacetate

The title compound was prepared in an armalogous manner to Example 151 by suabstituting 4-(aminomethyl)benzenesulfonam ide for morpholine in step (c). MS (ES+D m/z 565.4 [M+H]"

Example 189

Prepaaration of 4-{(1R)-2-[(3-{[2-(4-amino-1 ,2,5-0y<adiazol-3-yl)-1-sthyl-4-phenyl-1H- imidzmzo[4,5-clpyridin-7-ylloxy}oropyl}aminol-1-hyedroxyethyl}-1 2-benzenediol triflucroacetate :

The title compound was prepared in an aralogous manner to Example 152 by substituting 1,3-dibromopropane for 1,2-dibrormoethane in step (a) and 4-[(1R)- 2-ammino-1-hydroxyethyl]-1,2-benzenediol for mor-pholine in step (b). MS (ES+) m/z 532.4 [M+H]" :

Example 190

Preparation of 4-{(1R)-2-](3-{[2-(4-amino-1 2 5-oxadiazol-3—yl)-1-ethyl-4-phenyi-1 H- imidazo[4,5-c]pyridin-7-yljoxy}-2-hydroxypropyllamino}-1 -hwrdroxyethyl}-1,2- benzenedio| trifiuoroacetate

The title compound was prepared in an analogous rmanner to Example 151 by substituting 4-[(1R)-2-amino-1 -hydroxyethyl}-1,2-benzerediol for morpholine in step (c). MS (ES+) m/z 548.4 [M+H]

Example 191

Preparation of N 2-(4-amino-1,2 5-oxadiazol-3-yl Henyl-1H-imidazof4,5- clpyridin-7-ylloxy}butyl)-1,4-benzenediamine trifluoroaceta-te

The title compound was prepared in an analogous manner to Example 152 : by substituting 1,4-dibromobutane for 1,2-dibromoethane in step (a) and 1,4- : benzenediamine for morpholine in step (b). MS (ES+) m/== 484.4 [M+H]"

Example 192 . 20

Preparation of 3- 2-(4-amino-1,2.5-oxadiazol-3-yl)-1-ethyl-4-phenyl-1H- : imidazo[4 5-clpyridin-7-ylloxy}butyllamino}-1 2-propanedioc| trifluoroacetate

The title compound was prepared in an analogouss manner to Example 152 by substituting 1,4-dibromobutane for 1,2-dibromoethane in step (a) and 3-amino- 1,2-propanediol for morpholine in step (b). MS (ES+) m/= 468.0 [M+H]"

Example 193

Preparation of 4-11-ethyl-4-phenyl-7-({4-{(3-pyridinyimeth-yhaminolbutyloxy)-1 H- imidazo[4,5-clpyridin-2-yil-1,2.5-oxadiazoi-3-amine trifluceroacetate

The title compound was prepared In an analogou=s manner to Example 152 by substituting 1,4-dibromobutane for 1,2-dibromoethane in step (a) and 1-(3- : 35 pyridinyl)methanamine for morpholine in step (b). MS (ES+) m/z 485.2 [M+H]"

Example 194

Prepa ration of 4-{2-[(4-{[2-(4-amino-1 2. 5-oxadiazol-3-yN—1 -ethyl-4-phenyi-1H- imidazzo[4,5-clpyridin-7-ylloxy}butyaminolethyllbenzenessufonamide trifluoroacetate

The title compound was prepared in an analogouss manner to Example 152 by sulbstituting 1,4-dibromobutane for 1,2-dibromoethane in step (a) and 4-(2- aminoethyl)benzenesutfonamide for morpholine in step (Ib). MS (ES+) m/z 577.2

M+HT

Example 195

Prepaaration of 4-{1-ethyl-4-phenyl-7- 2-(4-pyridinyleathyllamino}butyl)oxy]-1H- imidzazo[4.5-clpyridin-2-yl}-1,2.5-oxadiazol-3-amine triflucroacetate

The title compound was prepared in an analogoiLis manner to Example 152 by substituting 1,4-dibromobutane for 1,2-dibromoethanee in step (a) and 2-(4- pyrid inyl)ethanamine for morpholine in step (b). MS (ES+) m/z 499.2 M+H]"

Example 196 :

Preparation of 4-[1-ethyl-4-phenyl-7-({4-[(4-pyridinyimethyl)aminojbutyloxy)-1 H- imidaxzo[4,5-clpyridin-2-yi]-1 .2,5-oxadiazol-3-amine triflu oroacetate

The title compound was prepared in an analogows manner to Example 152 : by substituting 1,4-dibromobutane for 1,2-dibromoetharae in step (a) and 1-(3- pyriclinyl)methanamine for morpholine in step (b). MS (EES+) m/z 485.2 [M+H]"

Example 197

Preparation of 4-{1-ethyl-4-pheny!-7-[(4-{12-(2-pyridinyi) ethyllamino}butyl)oxy}-1H- imid azo[4.5-clpyridin-2-yl}-1,2 5-oxadiazol-3-amine trifltoroacetate

The title compound was prepared in an analogous manner to Example 152 by substituting 1,4-dibromobutane for 1,2-dibromoethare in step (a) and 2-(2- pyriciinyl)ethanamine for morpholine in step (b). MS (E=S+) m/z 499.4 [M+H]"

Example 198

Preparation of 4-{1-ethyl-7- 5-methyl-2-pyrazinylimeth+yllamino}butyl)oxy]-4- phenyi-1H-imidazo[4.5-clpyridin-2-yl}-1 2 5-oxadiazol-3-amiline trifluoroacetate

The title compound was prepared in an analogous rmanner to Example 152 by substituting 1,4-dibromobutane for 1,2-dibromoethane ir step (a) and 1-(5- methyl-2-pyrazinyl)methanamine for morpholine in step (b)— MS (ES+) m/z 500.2

M+H]"

Example 199

Preparation of 4-{1-ethyl-7-[(4-{[2-(1 H-imidazol-2-yl)ethyllamminolbutyloxy}-4- envl-1H-imidazo[4,5-clpyridin-2-y}-1,2,5-oxadiazol-3-amsine trifluoroacetate : The title compound was prepared in an analogous enanner to Example 152 by substituting 1,4-dibromobutane for 1,2-dibromoethane ie step (a) and 2-(1H- imidazol-2-yl)ethanamine for morpholine in step (b). MS (E=S+) m/z 488.2 [M+H]

Example 200

Preparation of 4-{](4-{[2-(4-amino-1 ,2 5-oxadiazol-3-yl)-1-esthyl-4-phenyl-1H- : imidazo[4,5-clpyridin-7-ylloxy}butylaminolmethyilbenzene=sulfonamide : . trifluoroacetate

The title compound was prepared in an analogous smanner to Example 152 by substituting 1,4-dibromobutane for 1,2-dibromoethane im step (a) and 4- (aminomethyl)benzenesulfonamide for morpholine in step «(b). MS (ES+) m/z 563.2

MH]

Example 201

Preparation of N-(4-{[2-(4-amino-1 .2.5-oxadiazol-3-yl)-1-etfhyi-4-phenyl-1H- : imidazo[4.5-clpyridin-7-vi loxy}butvl)-N'-2-pyrimidinyl-1.2-etBhanediamine tifluoroacetate

The title compound was prepared in an analogous wmanner to Example 152 by substituting 1,4-dibromobutane for 1,2-dibromoethane imn step (a) and N-(2- pyrimidine)ethylenediamine for morpholine in step (b). MSs (ES+) m/z 515.6 [M+HT"

Example 202 _147-

WO) 2005/011700 PCT/US2004/024340

Preparation of 4-{[2-(4-amino-1 2 5-oxadiazol-3—yl)-1-ethyl-4-phényl-1 H- imidazo[4.5-clpyridin-7-ylloxy}butyl 4-(aminome®hyhbenzoate trifluoroacetate

The title compound was prepared in an &nalogous manner to Example 152 by substituting 1,4-dibromobutane for 1,2-dibrormoethane in step (a) and 4- ’ (aminomethyl)benzoic acid for morpholine in steep (b). MS (ES+) m/z 528.2 [M+H]

Example 20-3

Preparation of 4-{2-{(4-{[2-(4-amino-1.2. 5-oxadiliazol-3-yi)-1-ethyl-4-phenyl-1H- imidazo[4. 5-clpyridin-7-ylloxy}b aminolethyl }-1,2-benzenediol trifluoroacetate

The title compound was prepared in an analogous manner to Example 152 by substituting 1,4-dibromobutane for 1,2-dibro-moethane in step (a) and 4-(2- aminoethy!)-1,2-benzenediol for morpholine in step (b). MS (ES+) m/z 530.2 :

M+H]

Example 204 : :

Preparation of 4-{7-](4-{12-(4-chlorophenvl)ethywilaminolbutyhoxyl-1 -ethyl-4-phenyl- 1H-imidazo[4.5-clpyridin-2-y(}-1 .2,5-oxadiazol-Z3-amine trifluoroacetate

The title compound was prepared in an analogous manner to Example 152 by substituting 1,4-dibromcbutane for 1,2-dibromoethane in step (a) and 2-(4- chlorophenyl)ethanamine for morpholine in ste p (b). MS (ES+) m/z 532.4 [M+H]"

Example 205

Preparation of 4-{2-[(4-{12~(4-amino-1 2.5-oxacliazol-3-yl)-1-ethyl-4-phenyl-1 H- imidazol4,5-clpyridin-7-ylloxylbutyhaminolethy=1}-2-fluorophenol trifluoroacetate

The title compound was prepared in ans analogous manner to Example 152 by substituting 1,4-dibromobutane for 1,2-dibromoethane in step (a) and 4~(2- aminoethyl)-2-flucrophenol for morpholine in sitep (b). MS (ES+) m/z 532.2 M+H]"

Example 206

Preparation of 4-{7-[(4-{[2-(4-fluorophenyl)ethylJamino}butyloxy}-1 -ethyl-4-phenyl- 1H-imidaszo[4,5-clpyridin-2-yl}-1,2 5-oxadiazol-3-amine triflL_toroacetate

T he title compound was prepared in an analogous mmanner to Example 152 by substituting 1,4-dibromobutane for 1,2-dibromoethane imn step (a) and 2-(4- fluorophe2nyl)ethanamine for morpholine in step (b). MS (E=S+) m/z 516.4 (M+H]

Example 207

Preparation of methyl 4-{|(4-{[2-(4-amino-1 2 5-oxadiazol-=3-yl)-1-ethyl-4-phenyl-1H- imidazo[=4 5-clpyridin-7-ylloxy}butyllaminolmethyllbenzoate trifluoroacetate

T he title compound was prepared in an analogous manner to Example 152 by substituting 1,4-dibromobutane for 1,2-dibromoethane iin step (a) and methyl 4- (aminommethyl)benzoate for morpholine in step (b). MS (ESS+) miz 542.2 [M+H]' : Example 208

Preparattion of 4-(74[4-( [4-(dimethylaminolphenylimethyl}-amino)butylloxy }-1-ethyl- 4-pheny 1-1H-imidazo[4.5-clpyridin-2-yi)-1 .2.5-oxadiazol-3-zamine trifluoroacetate

Whe title compound was prepared in an analogous manner to Example 152 by substituting 1,4-dibromobutane for 1,2-dibromoethane instep (a) and 4- (aminonethyl)-N,N-dimethylaniline for morpholine in step (b). MS (ES+) m/z 527.4 [M+H]

Example 209 .

Preparation of N-(4-{[2-(4-amino-1 .2.5-oxadiazol-3-yl)-1-e -thyl-4-phenyl-1H- imidazolf4.5-clpyridin-7-vlloxy}butyl)guanidine trifluoroacetiate ~1 H-Pyrazole-1-carboximidamide hydrochloride (198 mg, 0.13 mmol) was added tao a solution of the compound of Example 115 (50 mg, 0.13 mmol) and diisopro pylamine (81 uL, 0.52 mmol) in DMF (1.5 mL). AfTter 18h, the solvent was removeed in vacuo and the residue subjected to preparative reverse phase HPLC (YMC C=ombiscreen ODS-A 50x20mm, 20mL/min, gradiert, A:acetonitrile- 0.1%TF-A, B:water-01% TFA, 10-65% A during 7min, UV «detection at 214) to afford the title compound (35 mg). MS(ES)" m/z 436.0 [M+H]".

Example 210

Preparation of 4-{1-ethyl-7-[(1 -met hyl-4-piperidinyoxy]-4-phenyl-1 H-imidazol4,5- clpyridin-2-yl}-1.2,5-oxadiazol-3-armine trifluoroacetate 4-Chloro-1-methylpiperidine hydrochloride (31 mg, 0.18 mmol) was added to a solution of the compound of Example 151(a) (50 mg, 0.15 mmol), Cs,CO, (0.16 g, 0.48 mmol) and Nal (3 mg) in DMF (2 mL). After heating in a microwave reactor at 155 °C for 30 min., the reaction was diluted with sat. NH,CI and extracted

EtOAc. The combined organic extracts were washed with brine, dried with sodium sulfate, and the solvent removed 7.1 vacuo. The resulting residue was subjected to preparative HPLC (YMC Combiscxeen ODS-A 50x20mm, 20mL/min, gradient,

Aacetonitrile-0.1%TFA, B:water-0.1% TFA, 10-50% A during 7min, UV detection at 214) to afford the tite compound C14 mg). MS(ES)' m/z 420.0 [M+H]".

Example 211

Preparation of 4-{[(4-{2-(4-amino—1,2,5-oxadiazcl-3-yl)-1-ethyl-4-phenyl-1H- imidazol4,5-clpyridin-7-ylloxy}butwl)aminolmethyllbenzoic acid trifiuoroacetate

A solution of the compourad of Example 207 (0.036 g., 0.065 mmol) ina mixture of methanol (10 mL.) and 1M NaOH (2 mL.) was stirred at ambient temperature for 16 h. The solverat was removed in vacuo and the residue suspended in a mixture of water C10 mL.) and trifluoroacetic acid (0.5 mL). Solve=nt was removed in vacuo and the re sidue subjected to preparative HPLC (YMC

Combiscreen ODS-A 50x20mm, 20mL/min, gradient, A:acetonitrile-0.1%TFA,

B:water-0.1% TFA, 10-80% A during 12min, UV detection at 255) to give the title compound (0.027 g). MS (ES+) rmiz 528.2 (M+H)*.

Example 212

Preparation of 4-[7-[(3-aminopropyl)oxy]-1 -ethyl-4-(2-pyrimidinyl)-1H-imidazo[4,5- clpyridin-2-yil-1,2,5-oxadiazol-3-aamine trifluoroacetate

A mixture of 1,1-dimethylesthyl [3-({4-chloro-2-[4~({[(1,1- dimethylethyl)oxy]carbonyl}amincg)-1 ,2,5-oxadiazol-3-yl]-1-ethyl-1H-imidazo[4,5-

clpyridin-7-yi}oxy)propyllcarkbamate (150 mg, 0.28 mmol), pyrimidin-2-y! tribsutyl tin (0.22 g, 0.56 mmol) and PdCPh3P)2Cla (20 mg) in dioxane (5 mL) was stirreed in a sealed tube at 110 OC for 8M. Additional Pd(Ph3P)2Cl2 (20 mg) was added and the temperature increased to 150 OC. After 18h, the reaction mixture was filterexd and the solvent was removed in vacuo. The residue was treated with 30% TFA/CH.Cl> for 30 min. The solvent was removed in vacuo and the residue azeotropedl from toluene. The crude product was subjected to preparative HPLC to give the= title compound (23 mg). MS (ES+) m/z 382.0 M+H)*.

Example 213

Preparation of 4-/1-ethyl-4-pohenyi-7-(1-piperazinyl)-1H-imidazol4,5-cloyridi n-2-yl}- 1.2,5-oxadiazol-3-amine trifJuoroacetate a) 1,1-Dimethylethyl 4-{4-chloro-2-[4-({I(1,1-dimethylethyl)oxy]carbonyljam ino)- 1,2,5-oxadiazol-3-yl]-1-ethy +1 H-imidazo[4,5-c]pyridin-7-yi}-1 -piperazinecar-boxylate

Xantphos (10.9 mg, 0.019 mmol) and Pd.dbas (5.7 mg, 0.006 mmol) were combined in toluene (3 mL, N; purged) and stirred at RT for 20 min. The - compound of Example 18(f) (0.14 g, 0.31 mmol), N-Boc piperazine (52 mgm) and t- :

BuONa (75 mg) were added and the resulting mixture was stirred at 100 °€C overnight. After allowing to cool to RT, the reaction was diluted with EtOA« and sequentially washed with saat. NH,Cl, sat. Na,CO;, brine and then dried oveer

Na,SO.. The solvent was removed in vacuo and the residue subjected to flash chromatography (3:1 hexame/EtOAG, silica gel) to give 53 mg of the desire=d compound as a light yellow solid. b) 1,1-Dimethylethyl 4-{2-[®-({[(1 ,1-dimethylethyl)oxy]carbonyl}amino)-1,2,%5- oxadiazol-3-yl]-1-ethyl-4-phaenyl-1 H-imidazo[4, 5-c]pyridin-7-yl}-1- piperazinecarboxylate

A mixture of the cormpound of Example 213(a) (53 mg, 0.097 mmo n. phenyiboronic acid (23.7 m.g), Pd(PhsP)s (11.2 mg) and 2N Na,CO; (0.21 aml) in 1,4-dioxane (0.9 mL) was sstimed at 100 °C for 1h. The reaction mixture was filtered . through celite and the filter cake was rinsed with EtOAc. The combined filtrates were concentrated in vacuo and the residue was subjected to flash chromatography (3:1 hexarme/EtOAc, silica gel) to give 43 mg of the desiread compound as a white solid.

c) 4-[1-Ethyl-4-phenyl-7-(1-piperazinyl)-1 H-imidazo[4,5-c]pyridin-2-yl]-1,2,5- oxadiazol—~3-amine trifluoroacetate

A solution of the compound of Example 213(b) and TFA (0.5 mL)» in CH.Cl> was stirresd at RT for 1h. The solvent was removed in vacuo and the res idue azeotrope-d from toluene. Preparative reverse phase HPLC (H.O/CH3ECN/0.1%TFA) gave the title compound as a light brown solid. BVS (ES+) m/z 391.2 (M+H)".

Example 214

Preparation of 4-[7-l(4-aminobutylloxy}-1-ethyl-4-(phenylethynyl)-1H-Imiciazol4.5- clpyridin-2-yi}-1,2,5-oxadiazol-3-aminetrifiuoroacetate a) Bis(1,1—dimethylethyi) {4-[7-({[(1 ,1-dimethylethyl)oxy]carbonyl}oxy)-1-ethyl-4- (phenyletraynyl)-1H-imidazof4,5-c]pyridin-2-yl}-1 ,2,5-oxadiazol-3- ylyimidodicarbonate

Pheenylacetylene (0.30mL, 2.70 mmol) and diisopropylamine (0.30mL, 2.10 - mmol) were added to a solution of the compound of Example 114(j) (88 rng, 0.15" mmol) ancl Pd(PPhs)s (50 mg, 0.043 mmol) in dioxane (3 mL). The react ion vessel was sealed and heated to 110 °C for 2h. After cooling to RT, the solvent was : removed ir vacuo and the residue was subjected to flash chromatographwy (silica : - "gel, 5% to 20% EtOActhexane) to afford the desired compound (60 mg). MS(ES)" m/z 647.0 [M+H]". b)2-(4-Ameino-1 2,5-oxadiazol-3-yl)-1-ethyi-4-(phenylethynyl)-1H-imidazol[4.5- cJpyridin-7—ol

Triffluoracetic acid (0.40 mL) was added to a solution of the compound of

Example 2-13(a) (54 mg, 0.08 mmol) in CH;Clz (1 mL). After 1h, the solveant was removed ira vacuo to give the desired compound (70 mg). This was used without further purification. MS(ES)" m/z 347.0.[M+H]". c) 1,1-Dimesthylethyl (4-{[2-(4-amino-1 ,2 5-oxadiazol-3-yl)-1-ethyl-4-(phenyylethynyl)- 1 H-imidazoe[4,5-clpyridin-7-ylloxy}butyl)carbamate 1,1- dimethylethy! (4-iodobutyl)carbamate (62 mg, 0.21 mmol) was added to the compound of Example 213(b) (73 mg, 0.12 mmol) and Cs.CO; (0.20 Og, 0.6 mmol) in DEMF (2 mL). The reaction vessel was sealed and heated to 65°&C for 40min. After cooling to RT, the reaction was diluted with sat. NH,Cl and e=xtracted with EROAGc. The combined extracts were washed with brine and dried over Na,SO..

The solvent was removed in vacuo and the residue was sus bjected to flash chrom atography (silica gel, 3% to 8% MeOH/CH.CL,) to afford the desired compound (25 mg). MS(ES)* miz 518.0 [M+H]". d) 4-[7 -[(4-Aminobutyl)oxyl-1 -ethyl-4-(phenylethynyl)-1 H-innidazo[4,5-c]pyridin-2-yl}- 1,2,5-oxadiazol-3-amine trifluoroacetate " Trifluoracetic acid (0.4 mL) was added to a solutior of the compound of

Example 213(c) (25 mg, 0.048 mmol) in CHCl. (2 mL). After 1h, the solvent was removed in vacuo and the residue was subjected to reverse phase HPLC (YMC

Combiiscreen ODS-A 50x20mm, 20mL/min, gradient, Acac etonitrile-0.1%TFA,

B:water-0.1% TFA, 10-65% A during 7min, UV detection at 214) to afford the title compound (21 mg). MS(ES)* m/z 418.0 [M+H]".

Example 215

Preparation of 4-[7-{(4-aminobutyl)oxy}-2-(4-amino-1 2 5-orxadiazol-3-yl)-1-ethyl-1H- imidazo}4,5-c]pyridin-4-yi}-2-methyl-3-butyn-2-ol trifluoroacetate

The title compound was prepared in an analogous manner to Example 214 "by substituting 2-methyl-3-butyn-2-ol for phenylacetylene im step (a). MS(ES+) m/z : 400.0 [M+H]"

Example 216

Preparation of 4-[7-[(4-aminobutyNoxyl-4-(cyclopropylethyryi)-1-ethyl-1 H- imidazof4,5-clpyridin-2-yil-1,2 5-oxadiazol-3-amine trifluoroacetate ’

The title compound was prepared in an analogous smanner to Example 214 by substituting ethynylcyclopropane for phenylacetylene in step (a). MS(ES+) m/z 382.0 [M+H]'

Example 217

Preparation of 4-[7-[(3-amino-1-pyrrolidinyl)carbonyll-1-eth yl-4-(phenylethynyl)-1H- imidaz©[4,5-c]pyridin-2-yl]-1,2.5-oxadiazol-3-amine trifluorcacetate a) 4-{7-11 ~(3-tert-Butoxycarbonylamino-pyrrolidin-1 -yi)-methanoyl]- #8 -ethyh-4- phenylethynyl-1 H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-yl)-carbamic acid tert-butyl ester

A mixture of the compound of Example 18(h) (100 mg, 0.17 mmol), ethynylbenzene (42 mg, 0.41 mmol), bis(benzonitrile)palladium(il) c=hloride (12 mg, 0.03 mmol), copper(}) iodide (3.9 mg, 0.02 mmol), tri-tert-butylphosgohine and diisopropyl amine (0.17 mL, 0.85 mmol) in dioxane (2 mL) was stirred at 80 OC for 1 8h in a sealed tube. Additional ethynylbenzene (42 mg, 41 mmol) was added and stirring at 80 °C continued for 4h. The solvent was removed in vacmuo and the residue was subjected to fiash chromatography (70% EtOAc/hexan es, silica gel) to afford the desired compound (60 mg). MS(ES+) m/z 643.0 (M+H)' — b») 1-{2-(4-Amino-furazan-3-yl)-1 -ethyl-4-phenylethynyl-1 H-imidazo[=4 5-]pyridin-7- y’1}-1-(3-amino-pyrrolidin-1-yl)-methanone trifluoroacetate

A solution of the compound of Example 217(a) (27 mg) in C=HxCl2 (2 mL) with TFA (1 mL) was sstirred at room temperature for 1h. All volatiles were removed and the residue purified by reverse phase HPLC (acetonitrile water gradient 0.1% TFA) to afford the title compound (27 mg). MS (ES+) m/z 443.0 : (M+H)*

Example 218

Preparation of 3-{3- 2-(4-Amino-furazan-3-yi)-1 -ethyl-4-(1H-pyrrol-=2-yl)-1H- . ismidazo[4,5-clpyridin-7-yloxyl-propylamino}-propane-1 2-diol trifluor-oacetate

The title compound was prepared in an analogous manner fo Example 181 by substituting 3-amino-1,2-propanediol for 4-(2-aminoethyl)phenol’ in step (c). MS ( ES+) m/z 443.2 [M+H]"

Example 219

Preparation of 2-{3-[2-(4-Amino-furazan-3-yl)-1 -ethyl-4-(1H-pyrrol-2-yl)-1H- ismidazo(4,5-clpyridin-7-yloxyl-propylamino}-1 -phenyl-ethanol trifluo_roacetate

The title compound was prepared in an analogous manner 0 Example 181 by substituting 2-amino-1-phenylethanol for 4-(2-aminoethyl)pheno 1 in step (c). MS (ES+) m/z 489.4 [M+H]"

Example 220

Preparation of 4-[7-[3-(5-Amminomethyl-tetrazol-1-yl)-propoxy}-1-ethyl-4-( 1H-pyrrol- 2-yh)-1 H-imidazo[4 5-clpyrid#n-2-yll-furazan-3-ylamine 1

The title compound wvas prepared in an analogous manner to Ex-ample 181 by substituting 1-(1 H-tetrazol-5-yl)methanamine for 4-(2-aminoethyl)phe=nol in step (c) and omitting the preparaative reverse phase HPLC. MS (ES+) m/z 4551.2 (M+H]"

Example 221

Preparation of 4-((R)-2-{3-]2-(4-Amino-furazan-3-yl)-1-ethyl-4-(1H-pyrreal-2-yi)-1H- imidazol4.5-clpyridin-7-yloxcyl-propylamino}-1-hydroxy-eth nzene-1 ,2-diol trifluoroacetate

The title compound was prepared in an analogous manner to Example 181 by substituting 4-[(1R)-2-arnino-1 -hydroxyethyi]-1 ,2-benzenediol for 4-(22- aminoethyl)phenoal in step €c). MS (ES+) m/z 521.4 [M+H]" ,

Example 222

Preparation of 4-{2-(4-amiro-1 2 5-oxadiazol-3-yl)-7-[(3-aminopropyljoxy}-1-ethyi- : 1H-imidazo[4.5-clpyridin-4—yl }-2-methyl-3-butyn-2-ol trifluoroacetate

The title compoundll was prepared in an analogous manner to Example 214 by substituting 2-methyl-3—butyn-2-ol for phenylacetylene in step (a) amd 1,1- dimethylethyt (3-iodopropyrl)carbamate for 1,1 -dimethylethyl (4-iodobutcyl)carbamate in step (c). MS(ES+) m/z 386.0

Example 223 :

Preparation of 4-{2-(4-amiino-1.2, 5-oxadiazol-3-yi)-1-ethyl-7-{(4- piperidinylmethyhoxyl-1 H—imidazo[4,5-clpyridin-4-yl}-2-methyl-3-butyn—2-ol trifluoroacetate

The title compound was prepared in an analogous manner to Example 214 by substituting 2-methyl-3--butyn-2-ol for phenylacetylene in step (a) and 1,1- dimethylethy! 4-(iodomethayi)-1-piperidinecarboxylate for 1,1-dimethyle=thyl (4- iodobutyl)carbamate in step (c). MS(ES+) m/z 426.0

Example 224

Preparation of 3-{2-(4-amino-1,2,5-oxadiazol-3-yl)-7-[(3-amminopro Noxyl-1-ethyl- 1H-imidazo[4,5-clpyridin-4-yi}-2-propyn-1-ol trifluoroacetates

The title compound was prepared in an analogous smanner to Example 214 by substituting propargyl alcohol for phenylacetylene in steep (a) and 1,1- dimethylethyl (3-iodopropyl)carbamate for 1,1-dimethylethyy!l (4-iodobutyl)carbamate in step (c). MS(ES+) m/z 358.0

Example 225

Preparation of 4-[7-{(3-aminopropyl)oxyl-4-(3-amino-1 -pro_pyn-1-yl)-1-ethyl-1H- imidazof4.5-c]pyridin-2-yl}-1 ,2.5-oxadiazol-3-amine trifluoreoacetate

The title compound was prepared in an analogous manner to Example 214 by substituting 1,1-dimethylethyl 2-propyn-1-ylcarbamate for phenylacetylene in step (a) and 1,1-dimethylethyl (3-iodopropyl)carbamate for 1,1-dimethylethy! (4- iodobutyl)carbamate in step (C). MS(ES+) m/z 357.0 [M+EH]"

Example 226

Preparation of 4-{7-[(3-aminopropvoxy}-4-(cyclopropylettynyi)-1-ethyi-1 H- imidazo[4,5-c]pyridin-2-yi}-1.2,5-oxadiazol-3-amine trifluomroacetate

The title compound was prepared in an analogous manner to Example 214 : by substituting ethynyicyclopropane for phenylacetylene i nstep (a) and 1,1- dimethylethyl (3-iodopropyl)carbamate for 1,1-dimethyletEny! (4-iodobutyl)carbamate in step (c). MS(ES+) m/z 368.0 [M+H]'

Example 227

Preparation of 4{2-(4-amino-1 2 5-oxadiazol-3-y)-7-[(3-=aminopropyloxyl-1-ethyl- 1H-imidazo[4.5-clpyridin-4-yl}-3-butyn-1-ol trifluoroacetat e ’

The title compound was prepared in an analogouss manner to Example 214 by substituting 3-butyn-1-ol for phenylacetylene in step (=a) and 1,1-dimethyiethyl (3-

iodopropyl)cartaamate for 1,1-dimethylethyl (4-iodobutyl)carbaamate in step (c).

MS(ES+) m/z 372.0 [M+H]

Example 228

Preparation of 4-{7-{(3-aminopropylloxy]-1 -ethyl-4-[3-(methyleoxy)-1-propyn-1 -yi}- 1H-imidazof4, S-clpyridin-2-yl}-1,2 6-oxadiazol-3-amine trifluowoacetate

The title compound was prepared in an analogous manner to Example 214 by substituting methyl 2-propyn-1-yl ether for phenylacetylen ein step (a) and 1,1- dimethylethyl {3-iodopropyl)carbamate for 1,1-dimethylethyl &4-iodobutyl)carbamate in step (c). MSS(ES+) m/z 372.0 [M+H]'

Example 229

Preparation off 4-{2-(4-amino-1,2,5-oxadiazol-3-yl}-7 3-amimopropyloxyl-1-ethyl- 1H-imidazo(4 .. 5-clpyridin-4-y}-3-butyn-2-ol trifluoroacetate

The title compound was prepared in an analogous nmanner to Example 214 : 20 by substituting 3-butyn-2-ol for phenylacetylene in step (a) and 1,1-dimethylethyl (3- : iodopropyl)camrbamate for 1,1-dimethylethyl (4-iodobutyl)carlbbamate in step (c).

MS(ES+) m/z 372.0 [M+H]

Example 230

Preparation of (25)-3-[(3-{[2-(4-amino-1 2.5-oxadiazol-3-yI)—1-(3,3-dimethylbutyl)-4- phenyl-1 H-inmidazo[4.5-clpyridin-7-yllamino}propyl)aminol-8 ,2-propanediol trifluoroacetamte a) Ethyl 6-ch loro-4-[(3,3-dimethylbutyl)amino]-5-nitro-3-pyridinecarboxylate

To a solution of 4,6-dichloro-5-nitro-nicotinic acid ethyl ester (1.00 g, 3.77 mmol) in CH Cl» (10 mL) at 0 °C was added Et:N (0.58 mL, 4.15 mmol) and (3,3- dimethylbuty~)amine (0.56 mL, 4.15 mmol). After 30 min at RT, the reaction was diluted with CSH,Cl,, washed with water and dried over MgS 0a. The solvent was removed in vacuo to provide the desired compound as a yeellow solid (1 259). MS (ES+) m/z 3330.2 (M+H)*. b) Ethyl 4-{(3,3-dimethylbutyl)amino]-5-nitro-6-phenyl-3-py ridinecarboxylate

A solution of the compound of Example 230(=a) (1.25 9, 3.79 mmol), phenylboronic acid (0.92 g, 7.58 mmol), dichlorobis(triphenylphosphine)palladium(ll) (0.27 g, 0.38 mmol) and 2M Na,CO3 (8.06 mL, 12.1 mmol) in toluene (30 mL) was heated at 110 °C in a sealed tube for -5 3.5h. The reaction was allowed to cool to RT and th e solvent was removed in vacuo. Flash chromatorgaphy (50:1 to 30:1 CH.Cl,/"MeOH, silica gel) gave the desired compound as a thick yellow syrup that solidi—fied upon standing (1.36 g).

MS (ES+) m/z 372.2 (M+H)*. cc) Ethyl 5-amino-4-{(3,3-dimethylbutyl)amino]-6-phemnyl-3-pyridinecarpoxylate

A mixture of the compound of Example 230(lb) (1.36 g, 3.67 mmol) and 10%Pd/C (0.21 g) in absolute EtOH (70 ml) was stitrred overnight at 40 °C under hydrogen gas (1 atm). The hydrogen was vented ard the catalyst was removed by filtration through a pad of celite. The filter cake was: washed with additional CHCl.

The solvent was removed from the combined filtrate= in vacuo to afford the desired ‘compound as a pale yellow oil that solidified upon standing (1.11 9). MS (ES+) miz 342.4 (M+H)*. ‘d) Ethyl 5-[(cyanoacetyl)amino}-4-[(3,3-dimethylbuty=l)amino]-6-pheny-3- - 20 pyridinecarboxylate

A solution of the compound of Example 230¢c) (1.109, 3.22 mmol), cyanoacetic acid (0.82 g, 9.66 mmol), 4-methylmorpoholine (2.12 mL, 19.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.85 g, 9.66 , . mmol) in dry DMF (20 mL) was stirred overnight at FRT. The reaction was diluted with EtOAc and washed with water, sat NaHCO,, waater, brine and then dried overMgSO,. The solvent was removed in vacuo to #umish the desired compound as a pale yellow solid (1.31 g). MS (ES+) m/z 409.4% (M+H)*. Co e) Ethyl 2-(cyanomethyl)-1-(3,3-dimethylbutyl)-4-phe=nyl-1 H-imidazo[4,5-c]pyridine- 3=®0 7-carboxylate

A mixture of the compound of Example 230(-d) (1.31 g, 3.21 mmol) and acetic acid (30 mL) was stirred in a sealed tube at 1 00 °C for 1.5h. The solvent was removed in vacuo and the residue subjected to flash chromatography (50:1 to 30:1 CH,Cl,/MeOH, silica gel) to give the desired ccompound as a pale grey solid

R/S (1.24 g). MS (ES+) m/z 391.2 (M+H)*.

f) Ethyl 2-[(E)-cyano(hydroxyimino)methyi}-1-(3,3-dimethylbutyl)-4-phenyl-1 H- imidazo[4,5-c]pyridine-7-carboxylate

To a solution of the compound of Example 230(e) (1.24 g, 3.18 mmol) in glacial acetic acid (25 mL) and water (2 mL) was added NaNO, (0.438 g, 6.36 mmol) portionwise over 5 min. After 3h at RT, the solvent was removed in vacuo.

The residue was dissolved in CH;Cl,, washed with water, brine (50 mL)and dried over MgSO,. The solvent was removed in vacuo to give the desired compound as a tan solid (1.33 g). MS (ES+) m/z 420.4 (M+H)*. g) Ethyl 2-(4-amino-1,2,5-oxadiazol-3-y8)-1 -(3,3-dimethylbutyl)-4-phenyl-1H- imidazo[4,5-c]pyridine-7-carboxylate

A mixture of the compound of Example 230(f) (1.33 g, 3.17 mmol), EtsN (4 mL, 28.7 mmol), and hydroxylamine (50 wt. % solution in water, 0.25 mL, 3.80 mmol) in dioxane (60 mL) was heated overnight in a sealed tube at 110 °C. The mixture was allowed to cool to RT and the solvent was removed in vacuo. Flash chromatography (30:1 CH.Cl./MeOH, s iica gel) gave the desired compound as a pale yellow solid (1.13 g). MS (ES+) mdz 435.4 (M+H)*. © h) 2-(4-Amino-1,2,5-oxadiazol-3-yl)-1 -(3,3-dimethylbutyl)-4-phenyi-1 H-imidazo[4,5- c]pyridine-7-carboxylic acid

To a solution of the compound of Example 203(g) (1.12 g, 2.58 mmol) in 2:1

MeOH/THF (45 mL) was added 6N NaOH (6.40 mL, 38.4 mmol). After stirring vigorously at RT for 1.5h, the solvent was removed in vacuo. The residue was dissolved in water and the pH was adjusted to 7 8N HCI. The aqueous phase was extracted with EtOAc and the combined organic extracts were washed with brine, dried over MgSO; and the solvent was removed in vacuo to furnish the desired compound as a pale yellow solid (1.05 @). MS (ES+) m/z 407.4 (M+H)*. i) 1,1-Dimethylethyl [2-(4-amino-1 ,2 5-oexadiazol-3-yl)-1-(3,3-dimethylbutyl)-4- phenyk1H-imidazo[4,5-c]pyridin-7-yljca rbamate

To a stirred suspension of the compound of Example 230(h) (100 mg, 0.25 mmol) in dry t-BuOH (2 mL) under argon at RT was added activated 4 A molecular sieves, Et;N (41 uL, 0.29 mmol) and diphenylphosphoryl azide (60 ul., 0.28 mmol).

The mixture was stirred at RT for 1.5h and then at 100 °C for 16h. The solvent was removed in vacuo and the residue subjected to flash chromatography (30:1

CH.Cl,/MeOH, silica gel) to give the de sired compound as a pale yellow solid (104 mg). MS (ES+) m/z 478.4 (M+H)*.

j) 1, 1-Dimethylethyt [2-(4-amino-1,2,5-oxadiazol-3-yl)e -1-(3,3-dimethylbutyl)-4- phe nyl-1H-imidazo[4,5-clpyridin-7-yi}(3-bromopropyl carbamate

Cs,CO; (60 mg, 0.183 mmol) and 1,3-dibrom opropane (30 uL, 0.293 mmol) werve added to a solution of the compound of Examp le 230(j) (35 mg, 73 umal) in dry DMF (2 mL) at 30 °C. After 2h at 30 °C, the reacztion was diluted with EtOAc (20 mL) and washed with water, brine and dried ovemr MgSO,. The solvent was removed in vacuo and the residue subjected to flash chromatography (50:1 to 30:1

CH=Cl./MeOH, silica gel) gave the desired compouned as a yellow solid (35 mg).

MS (ES+)m/iz5984 (M+H)*. kK) 2-(4-Amino-1 2,5-oxadiazol-3-yl)-N-(3-bromopropwyl)-1 -(3,3-dimethyibutyl)-4- phenyl-1H-imidazo[4,5-c]pyridin-7-amine

To a solution of the compound of Example 2=30() (35 mg, 58.5 umol) in

CH._xCl, (3 mL) was added trifluoroacetic acid (0.5 mill). After 3h at RT, the solvent : was removed in vacuo to afford the desired compou nd as a yellow solid (36 mg). © MSs (ES+) miz 498.4 (M+H)*.

I) (225)-3-[(34{[2-(4-Amino-1 2 5-oxadiazol-3-yl)-1-(3,=3-dimethylbutyl)-4-phenyl-1 H- imiediazo[4,5-c]pyridin-7-yllamino}propyl)amino}-1 ,2-poropanediol trifluoroacetate

To a solution of the compound of Example 2:30(k) (36 mg, 58.5 umol} in :

DMSO (2 mL) was added (2S)-3-amino-1 ,2-propane=diol (27 mg, 0.296 mmol), and } the- resultant mixture was heated at 90 °C for 0.5h. Purification on preparative

HP ‘LC (Zorbax ® SB-C18, 21.2 mm i.d. x 25 cm, 20 mL/min, gradient, A: water- ot © trifluoroacetic acid, B: acetonitrile-0.1% trifluor—oacetic acid, 10-90% acetonitrile during 12 min, UV detection at 255 nm) —fumished the title compound as a y-ellow solid (28 mg). MS (ES+) m/z 509.4 (M+H)™,

Example 231

Pre=paration of N1-[2-(4-Amino-furazan-3-yi)-1 -cyclo-pentyl-4-phenyl-1 H- imiedazol4.,5-c]pyridin-7-yll-propane-1.3-diamine trflLn oroacetate

The title compound was prepared in an analeogous manner to Example 230 by - substituting cyclopentylamine for 3,3-dimethyl-1 -Boutanamine in step (a) and ammonia in MeOH for (2S)-3-amino-1,2-propanedioe! in step (I). MS(ES+) m/z 419.6 (M+H)".

Example 232

Preparation of N-{3-Amino-benzyl)-N'-[2- 4-amiryo-furazan-3-yl)-1-cyclopen

Fenyl-1H-imidazo{4,5-¢ ridin-7-vil-propane-1_,3-diamine trfluoroacetate

The title compound was prepared in an analogous manner to Example 230 by substituting cyclopentylamine for 3,3-dimethwyl-1-butanamine in step (a) and 3- (emminomethylaniline for (25)-3-amino-1 ,2-prop=anediol in step (I). MS(ES+) m/z 5224.4 (M+H)".

Example 2353 :

P= reparation of (S)-34{3-[2-(4-Amino-furazan-3-wi)-1-cyclopen -4-phenyl-1H- irnidazo[4,5-clpyridin-7-ylamino]-propylamino ropane-1,2-diol trfluoroacetate

The title compound was prepared in an analogous manner to Example 230 tay substituting cyclopentylamine for 3,3-dimetinyl-1-butanamine in step (a).

NAS(ES+) m/z 493.4 (M+H)".

Example 2234

Preparation of N-[2-(4-amino-1 2,5-oxadiazol-Z3-yl)-4-(3-chlorophenyl)-1-ethyl-1H- oo i midazof4,5-clpyridin-7-yl}-1.3-p ropanediamine trfluoroacetate : a)Ethyl 6-chloro-4-(ethylamino)-5-nitro-3-pyriciinecarboxylate

Following the procedure of Example 2330(a), except substituting ethylamine

For (3,3-dimethylbutyl)amine, the desired comgpound was prepared. MS (ES+) m/z 274.4 (M+H)*.

Wb) Ethyl 5-amino-6-chloro-4-(ethylamino)-3-py~ridinecarboxylate

A solution of the compound of Exampl e 234(a) (5.00 g, 18.3 mmol) in conc

HCI (25 mL) at 90 °C was treated portionwise with SnCl, (16.6 g, 87.7 mmol). After 30 min at 90 °C, the reaction was cooled to 0 °C and neutralized to pH ~7 with 50%

NaOH. The mixture was diluted with CHCl, {200 mL) and filtered through a pad of celite. The organic layer was separated, was: hed with brine, dried over MgSO..

The solvent was removed in vacuo to give the= desired product as a tan solid (3.32 q). MS (ES+) miz 244.2 (M+H)*.

c) Ethyl 6-chloro-5-{(cyanoacetyl)amino]-4-(ethwlamine)-3-pyridinecarboxylate

Following the procedure of Example 23Q(d), except substituting the compound of Example 234(b) for the compoun-d of Example 230(c), the desired compound was prepared. MS (ES+) m/z 311.2 (M+H)*. d) Ethyl 4-(3-chlorophenyl)-2-(cyanomethyl)-1-~sethyl-1H-imidazo[4,5-clpyridine-7- carboxylate

Following the procedure of Example 230(b), except substituting the compound of Example 234(c) for the compourd of Example 230(a) and substituting 3-chlorophenyliboronic acid for phenylboronic acid, the desired compound was prepared. MS (ES+) m/z 369.4 (M+H)*. e) Ethyl 4-(3-chlorophenyl)-2-{(E)-cyano(hydroxyimino)methyl}-1 -athyl-1H- imidazo[4,5~-c]pyridine-7-carboxylate

Following the procedure of Example 2330(f), except substituting the compound of Example 234(d) for the compou nd of Example 230(e), the desired compound was prepared. MS (ES+) m/z 398 .4 (M+H)*. f) Ethyl 2-{(4-amino-1 ,2,5-oxadiazol-3-yl)-4-(3—chlorophenyi)-1 -ethyl-1H-imidazo[4,5- c]pyridine-7-carboxylate . Following the procedure of Example 2230(g), except substituting the : compound of Example 234(e) for the compound of Example 230(f), the desired compound was prepared. MS (ES+) m/z 413.4 (M+H)*. . g) 2-(4-Amino-1,2,5-oxadiazol-3-yl)4-(3-chlo rophenyl)-1-ethyl-1H-imidazo[4,5- clpyridine-7-carboxylic acid

Following the procedure of Example =230(h), except substituting the compound of Example 234(f) for the compouand of Example 230(g), the desired compound was prepared. MS (ES+) m/z 385.2 (M+H)*. h) 1,1-Dimethylethyl [2-(4-amino-1 ,2,5-oxadizazol-3-yl)-4-(3-chlorophenyl)-1-ethyl- 1H-imidazo[4,5-c]pyridin-7-ylJcarbamate :

Following the procedure of Example =230(i), except substituting the compound of Example 234(g) for the compo und of Example 230(h), the desired compound was prepared (75%). MS (ES+) am/z 456.4 (M+H)*.

i) 1,1-Dimethylethy! [2-(4-amino-1 ,2,5-oxadiazol—3-yl)-4-(3-chlorophenyl)-1 -ethyl- 1H-imidazo[4,5-c]pyridin-7-yl][3-({[(1.1- dimethylethyl)oxylcarbonyl}amino)propyljcarbarinate

Following the procedure of Example 2303(j), except substituting the compound of Example 234(h) for the compound of Example 230(i) and subsituting 1,1-dimethylethyl (3-bromopropyl)carbamate fowr 1,3-dibromopropane, the desired compound was prepared. MS (ES+) m/z 613.4 (M+H)*. j) N-[2-(4-amino-1 ,2,5-oxadiazol-3-yl)-4-(3-chlomrophenyl)-1 -ethyl-1H-imidazo[4,5- ¢]pyridin-7-yil-1,3-propanediamine trifluoroacet=ate

Following the procedure of Example 23€D(k), except substituting the compound of Example 234(j) for the compound of Example 230(j), the title compound was prepared. MS (ES+) m/z 413.4 (M+H)*.

Example 235

Preparation of N-(3-amino-benzyl)-N'{2- 4-am ino-furazan-3-yl)-4-(3-chloro-phenyl)- : 1-ethyl-1 H-imidazo[4,5-clpyridin-7-yii-propane—1 ,3-diamine trifluoroacetate a) 1,1-Dimethylethyl [2-(4-amino-1 ,2,5-oxadiaz=ol-3-yl)-4-(3-chlorophenyl)-1-ethyl- . 1 H-imidazo[4,5-c]pyridin-7-yl)(3-bromopropyl)carbamate

The desired compound was prepared i han analogous manner to the compound of Example 230(j) except substitutimng the compound of Example 234(h) for the compound of Example 230(i). b) N-(3-Amino-benzyl)-N'*-[2-(4-amino-furazan—3-yl)-4-(3-chloro-phenyl)-1 -ethyl-1H- imidazo[4,5-c]pyridin-7-yl}-propane-1,3-diamirme trifluoroacetate

The title compound was prepared in ar analogous manner to steps (k) and (1) for the compound of Example 230 except substituting the compound of Example 235(a) for the compound of Example 230(j) in step (k) and 3-(aminomethyl)aniline for (2S)-3-amino-1,2-propanediol in step (1). MAS(ES+) m/z 518.4 [MH].

Example 236

Preparation of (S)-3-{3-2-(4-amino-furazan-3 -yl)-4-(3-chloro-phenyl)-1-ethyi-1H- imidazo[4,5-clpyridin-7-ylamino}-propylaminog-propane-1 ,2-diol trifluoroacetate a) 1,1-Dimethylethyl [2-(4-amino~-1 2.5-oxadiazol-3-yl)-4-(3-chlorophenyl)-1 -e=thyl- 1H-imidazo[4,5-c]pyridin-7-yl}(3-boromopropyl)carbamate

The desired compound was prepared in an analogous manner to the compound of Example 230() except substituting the compound of Example 234) for the compound of Example 230(). b) N-(3-Amino-benzyl)-N'{2-(4-amino-furazan-3-yl)-4-(3-chloro-phenyl)-1 -ethyl-1H- imidazo[4,5-c]pyridin-7-yl}-propane-1,3-diamine trifluoroacetate

The title compound was prepared in an analogous manner to steps ( Kk) and ()) for the compound of Example 230 except substituting the compound of Example 236(a) for the compound of Exa mple 230(j) in step (k). MS(ES+) m/z 487.4 [M+H]". oo Example 237

B

Preparation of 14{[2-(4-amino-1,2 5-oxadiazol-3-yl)-1-cyclopen henyl-1 H- imidazol4.5-clpyridin-7-yllamino}-3-{[(3-aminophenylimethyllaminc}-2-propaanl : - trfluoroacetate : :

The title compound was prepared in an analogous manner to Example 230 by substituting cyclopentylamine for 3,3-dimethyl-1-butanamine in step (a), : epichlorohydrin for 1,3-dibromo propane in step (i) and 3-(aminomethyl)anilime for (2S)-3-amino-1,2-propanediol ir step (1). MS(ES+) m/z 540.4 MH)".

Example 238 . 4-{[(E)-1(3{[2-(4-amino-1,2.5-0xadiazol-3-y)-1 -ethyl-4-phenyl-1H-imidazo[4- ,5-clpyridin-7- yiloxy}oropyhamino}(imino)methyllaminolbenzenesulfonamide trifluoroacetaate a) Methyl N-[4-(aminosulfonyl)phenyllimidothiocarbamate hydroiodide

A mixture of methyl iodide (0.43 g, 3.00 mmol), 4-thioureidobenzene=sulfonamide (0.33 g, 1.44 mmol) in acetone (40 mL). was stirred 16h at ambient temperzature. The solvent was removed in vacuo and the residue triturated with ether to give tthe desired compound (0.51g). MS (ES+) m/z 246.1 (M+H)*. b) 2-(4-Amino-1,2,5-oxadiazol-3-yl)-1 -ethyl-4-phenyl-1H-imidazo[4,5-c]pyricdin-7-ol

A mixture of the compound of Example 114(i) (0.60 g, 2.14 mmol), phenysiboronic acid (0.54 g, 4.40 mmol), 2.0 M Na,CO;s (2.6 mL, 5.00 mmol) and Pd(PPhs), (0.304, 0.26 mmol) in dioxane (25 mL) was stired 16h at 90 °C ina sealed flask. The mixture was cooled, filtered aand the filtrate concentrated in vacuo to give the crude product. Flash chromatography” (50:1, then 30:1, CH.Cl.:MeOH, silica gel) gave the desired cormpound (0.43 g). MS (ESS+) m/z 323.2 (M+H)*. c) 1,1-Dimethyle=thy! (3-{[2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-4-phenyl-1 H-innidazo[4,5- clpyridin-7-ylloxw}propyl)carbamate

A mixture of the compound of Example 238(b) (0.21 g, 0.65 mmol), 1,1- dimethylethyl (3—bromopropyl)carbamate (0.46 g, 1.96 mmol) and Cs,COs (0.64 g, 1.96 mmol) in DMF (~16 mL) was stirred 16h at ambient temperature. The solvent weas removed in vacuo and the residue partitioned between EtOAc and water. The organic layser was washed with water and brine, dried (Na,SO,) and the solvent was removed in vacuo to give the crude product. Trituration from hexane (10 mL) gave the desired compound (0.25 g). MS (ES+) m/z 480.2 (M+H)*. d) 4-{7-[(3-Amirmopropy!)oxy]-1-ethyl-4-phenyi-1 H-imidazof4,5-clpyridin-2-yi}-1 2,5 oxadiazol-3-amiine

The compound of Example 238(c) (0.18 g, 0.37 mmol) was dissolved in a mixture of CHCl, (10 mel) and trifluoroacetic acid (2 mL). After 1h, the solvent was renoved in vacuo and the residue partitioned between EtOAc and 0.5 M NaOH. The orgaric layer was washed with brine, dried (Na.SO4) and the solvent was removed in vacuo t © give the desired compouand (0.12 g). MS (ES+) m/z 380.2 (M+H)*. e) 4-{[(E)-[(3-{[2-(4-Amino-1,2,5-oxadiazol-3-yl)-1 -ethyl-4-phenyl-1H-imidazo[4,5-c]pyridin- 7-ylJoxy}propyl)@mino}(imino)methyl}aminc}benzenesulfonamide trifluoroacetate

A mixtur-e of the compound of Example 238(a) (32 mg, 0.09 mmol), the «compound of Example 238 (d) (30 mg, 0.08 mmol), DBU (18 mg, 0.1 18 mmol) and acetonitrile (2 mL) was stirred overnight at 80 °C in a sealed tube. The solvent was removed in vaacuo and the residue purified by preparative reverse phase HPLC (YMC CombiPrep ODSS-A, 20 mm i.d. x 50 mm, 20 mL/min, gradient, A: water-0.1% trifluoroacetic acid, B: acetoniitrile-0.1% trifluoroacetic a«cid, 10-90% acetonitrile over 8 min, UV detection at 214 nm) to give the title compound (24 rmg). MS (ES+) m/z 577.2 (M+H)*,

Example 239

Preparation of 4-{[(E)- 2.(4-amino-1.2,5-oxadia=zol-3-yl)-1-ethyl-4-(1H 0l-2- yl)-1H—imidazo[4 5-c]pyridin-7-

No ropyllaminol(iminoymethyilamino}benzeneswutfonamide trifluoroacetate

The title compound was prepared in an anal ogous manner to Example 238 by substituting 2-pyrroleboronic acid for phenylboroimic acid in step (b). MS(ES+) m/z 56-64 [M+H]'.

Example 240

Preparation of N-(3-{[2-(4-amino-1,2 5-oxadiazol-3- {)-1-ethyl-4-phenyt-1H- imidaze(4,5-clpyridin-7-yllo: roovh)-N'-(4-nitrophe_nyliguanidine trifluoroacetate

The title compound was prepared in an anal=ogous manner to Example 238 by substituting N-(4-hydroxyphenyl)thiourea for 4-th ioureidobenzenesulfonamide in step (a). MS(ES+) m/z 543.2 [M+H]".

Example 241

Preparation of N-(3-{[2-(4-amino-1 2.5-oxadiazol-3-w/)-1-ethyl-4-phenyl-1 H- imidazo[4.5-clpyridin-7-ylloxy}propyl)-N'-(4-hydroxy henylguanidine : trifluoroacetate

The title compound was prepared in an analcogous manner to Example 238 by subsstituting N-(4-nitrophenyi)thiourea for 4-thiour-eidobenzenesulfonamide in step (a). MS(ES+) m/z 514.4 [M+H]".

Example 242

Preparation of N-(3-{2-(4-amino-1.2,5-oxadiazol-3-yl )-7-[(3-aminopropyloxy]-1- - ethyl-1 F—-imidazo}4,5-clpyridin-4-yiipheny})-N'-(4-chicrophenylurea trifluoroacetate a) [3-({{ (4-Chlorophenyl)amino]carbonyl}amino)phen yijooronic acid ~4-chlorophenyl isocyanate (0.52 g, 3.50 mmaol) was added to (3- aminophenyl)boronic acid (0.48 g, 3.50 mmol) in THIF (25 mL) at 0 °C. After Smin, the reacstion was allowed to warm to RT. After 4h, half of the solvent was removed in vacuo and reaction was poured into water (50 mL)s. The precipitate was collected by filtration and washed with water and Et,0. The solid waas dried under waccum for 2h at 40 °C to afford the desired compound (0.80 g). MIS(ES)’ m/e 2290.0 [M+H]".

Ib) 1,1-Dimethylethyl [3-({2-(4-amino-1 ,2,5-oxadiazol-3-yl)-4-[3~({[(4— echlorophenyl)aminojcarbonyl}amino)phenyl}-1-ethyl-1 H-imidazo[4,5-clpyridin-7- -yljoxy)propyllcarbamate

To 1,1-dimethylethyl [3-({4-chloro-2-{4-({{(1,1- dimethylethyl)oxy]carbonyi}amino)-1 ,2,5-oxadiazol-3-yl]-1-ethyl-1 H—imidazo[4,5- clpyridin-7-yl}oxy)propyllcarbamate (85 mg, 0.20 mmol) and the cosmpound of

Example 242(a) (0.12 g, 0.40 mmol) in dioxane (3 mL) was added Pd(PPhs), (25 mg, 0.02 mmol) and 2M Na,COs (0.3 mL). The reaction vessel wa s purged with argon then sealed and heated at 95 °C for 16h. The solvent was reemoved in vacuo and the residue was subjected to flash chromatography (0.5% to 2% - 15 MeOH/CH,Cl,, silica gel) to afford the desired compound as a solic} (0.12 g).

MS(ES)* m/e 649.0 [M+H]". <) N-(3-{2-(4-Amino-1,2,5-0xadiazol-3-yl)-7-[(3-aminopropyl)oxy}-1 ~ethyl-1H- : imidazo[4,5-c]pyridin-4-yl}phenyl)-N-(4-chlorophenyljurea trifluoro=axcetate : - 20 Trifluoroacetic acid (1 mL) was added to a solution of the c=ompound of : Example 242(b) (0.12 g, 0.20 mmol) in CH,Cl2 (3 mL). After 2h at RT, the solvent was removed in vacuo and the residue subjected to reverse phase HPLC (YMC

Combiscreen ODS-A 57x30mm, 25 mL/min, gradient, A:acetonitrile-0.1%TFA,

B:water-0.1% TFA, 8-75% A during 10min, UV detection at 214) to afford the title compound (80 mg). MS(ES)* m/e 548.0 [M+H]".

Example 243

Preparation of N~{3-{2-(4-amino-1 2 5-oxadiazol-3-yl)-7-[(3-aminoporopyloxy}-1- ethyl-1H-imidazo[4 5-clpyridin-4-yliphenyl)-N'-methylurea trifluoro=acetate

The title compound was prepared in an analogous manner fo Example 242 by substituting methylisocyanate for 4-chlorophenylisocyanate in step (a).

MS(ES+) m/z 452.0 [M+HJ". :

Example 244

Preparation of N-(3-{2—(4-amino-1 2 5-oxadiazol-3-y!)-7-{(3-aminopropyldoxy]-1- ethvl-1H-imidazo[4.5-clpyridin-4-yliphenyl)-N'-(phenylmethyilurea trifluomroacetate

The title compound was prepared in an analogous manner to Exzample 242 by substituting benzylisocyanate for 4-chlorophenylisocyanate in step (aa).

MS(ES+) m/z 528.0 [NAH].

Example 245

Preparation of N-(3-{2-(4-amino-1.2.5-oxadiazol-3- 1)-1-ethyl-7-[(4- piperidinyimethyl)oxy} -1 H-imidazo[4,5-c]pyridin-4-yi}ohenyl)-N'-ethylure a

The title compsound was prepared in an analogous manner to Example 242 by substituting ethylis-ocyanate for 4-chlorophenylisocyanate in step (a) and 1,1- dimethylethyl 4~({{2-(<1-amino-1 ,2,5-oxadiazol-3-yl)-4-chloro-1-ethyl-1 H—imidazo[4,5- clpyridin-7-ylJoxy}methyl)-1 -piperidinecarboxylate for 1 ,1-dimethylethy! [3-({4- chloro-2-J4-({[(1 ,1-dinnethylethyl)oxylcarbonyl}amino)-1 ,2,5-oxadiazol-38-yl]-1-ethyl- . 1H-imidazo[4,5-c]pyriidin-7-yfjoxy)propyljcarbamate in step (b). MS(ES+) m/z 506.0 [M+H]". h

Example 246

Preparation of N-(3-{ 2-(4-amino-1 2 5-oxadiazol-3-yl)-7-[(3-aminoprop=wl)oxy]-1- ethyl-1 H-imidazol4,5—clpyridin-4-yi}phenyl)-N'-ethylurea trifluoroacetatee

The title comppound was prepared in an analogous manner to EExample 242 by substituting ethylissocyanate for 4-chlorophenylisocyanate in step (am). MS(ES+) m/z 466.0 [M+H]".

Example 247

Preparation of N-(3-§2-(4-amino-1 2.5-oxadiazol-3-yl)-7-{(3-aminopropylioxyl-1 - ethyl-1 H-imidazo[4,5-c]pyridin-4-yliphenyl)-N'-(1-methylethyDurea trifimioroacetate

The title com pound was prepared in an analogous manner to EExample 242 by substituting isopropylisocyanate for 4-chlorophenylisocyanate in steep (a).

MS(ES+) m/z 480.0 [M+H]".

Example 248

Preparation of NJ-(3-{2-(4-amino-1 2.5-oxadiazol-3-yl)-7-{(3-aminopropyl)omxy}-1- ethyl-1H-imidazeo[4,5-clpyridin-4-yl }phenyl)-N'-[3-(trifluoromethyl)phenyllumrea trfiuoroacetate

The title compound was prepared in an analogous manner to Exa mple 242 by substituting S3-(trifluoromethyl)phenylisocyanate for 4-chlorophenylisocsyanate in step (a). MS(ESS+) m/z 582.0 [M+H]".

Example 249

Preparation of M\L(3-{2-(4-amino-1.2 5-oxadiazo}-3-yl)-7-[(3-aminopropyeoxy}-1- ethyl-1H-imidaz=ol4,5-clpyridin-4-yi ‘phenyl )-N"-j4-(triflucromethyliphenyi luirea triflucroacetate

The title= compound was prepared in an analogous manner to Example 242 : by substituting 4-(trifluoromethyl)phenylisocyanate for 4-chlorophenylisoscyanate in step (a). MS(EES+) m/z 582.0 [M+H]".

Example 250

Preparation of N-(3-{2-(4-amino-1,2,5-oxadiazol-3-y}-7- 3-aminopropylBoxyl-1- ethyl-1H-imida=zo[4 5-clpyridin-4-yl \phenyl)-N'-[3-(methyloxy)phenyt Juream trifluoroacetatea

The title compound was prepared in an analogous manner to Exzample 242 by substituting 3-(methoxy)phenylisocyanate for 4-chlorophenylisocyanaate in step (a). MS(ES+) m/z 544.0 [M+H]".

Example 251

Preparation of” N-(3-{2-(4-amino-1,2,5-oxadiazol-3-yl)-7-[(3-aminopropy)oxy}-1- ethyl-1 H-imidamzo[4,5~c]pyridin-4-yliphenyl)-N'-{4-(methyloxy)phenyllure=a

The title compound was prepared in an analogous manner to Example 2-42 by substituting 4-(methoxy)phenylisocyanate for 4-chlorophenylisocyanate in step (a). MS(ES+) m/z 544.0 [M+HT".

Example 252

Preparation of N-(3-{2-(4-amino-1,2,5-oxadiazel-3-yl)-1-ethyl-7- 4- : iveridinvimethvoxyl-1H-imidazo[4.5-clpyridirm-4-yliphenyh-N'-(phen imethyliumrea trifiuoroacetate

The title compound was prepared in arm analogous manner to Example 242 by substituting benzylisocyanate for 4-chlorophenylisocyanate in step (a) and 1, 1- dimethylethyl 4-({{2-(4-amino-1 ,2,5-oxadiazol-33-yl)-4-chloro-1-ethyl-1 H-imidazo[l[4,5- c]pyridin-7-ylJoxy}methyl)-1-piperidinecarboxyl=ate for 1,1-dimethylethyl [3-({4- chloro-2-[4-({[(1.1 -dimethylethyl)oxy]carbonyl}=amino)-1 ,2,5-oxadiazol-3-yl}-1-etiwyl- 1H-imidazo[4,5-c]pyridin-7-yl}oxy)propyllcarba mate in step (b). MS(ES+) m/z 5268.0 (M+HT". :

Example 2-53

Preparation of N-(3-{2-(4-amino-1 2, 5-oxadiaz=ol-3-y))-1-ethyl-7-{(4- piperidinylmethyloxy}-1 H-imidazo[4,5-c]pyridir-4-yl}phenyl)-N'-(3-chlorophenyl urea trifluoroacetate

The title compound was prepared in ar analogous manner to Example =242 by substituting 3-chlorophenylisocyanate for 4—chlorophenylisocyanate in step (Ca) and 1,1-dimethylethyl 4-({[2-(4-amino-1 ,2,5-oxzadiazol-3-yl)-4-chioro-1-ethyl-1H— imidazol4,5-c]pyridin-7-yljoxy}methyl)-1 -piperiediinecarboxylate for 1,1-dimethyle=thyl [3-({4-chloro-2-[4-({{(1 ,1-dimethylethyl)oxy}caribonyl}jamino)-1 ,2,5-oxadiazol-3-y -1]-1- ethyl-1H-imidazo[4,5-c]pyridin-7-yl}oxy)propyll ‘carbamate in step (b). MS(ES+) m/z 588.0 [M+H]".

Example 2-54

Preparation of N-(3-{2~(4-amino-1,2,5-oxadiaz=ol-3-yl)-1-ethyl-7-{(4- piperidinylmethyl)oxy}-1 H-imidazo[4.5-c]pyridir-4-yliphenyl)}-N'3- (methyloxy)phenyllurea trifluoroacetate

The title compound was prepared in an analogous manner to Exasmple 242 by substituting 3-methoxyphenylisocyanate for 4-chlorophenylisocyanate in step (a) and 1,1-dimet hylethy! 4-({[2-(4-amino-1 2 5-oxadiazol-3-yl)-4-chioro-1-ethmyl-1 H- imidazo[4,5-cL pyridin-7-yijoxy}methyl)-1 -piperidinecarboxylate for 1 ,1-dimeethylethyl [3-({4-chloro-2-]4-({I(1.1 -dimethylethyt)oxy]carbonyljamino)-1 ,2,5-oxadiaz-ol-3-yl}-1- ethyl-1 H-imidaazo[4,5-c}pyridin-7-yl}oxy)propyllcarbamate in step (b). MSEES+) m/z 584.0 [M+H]".

Example 255

Preparation off N-(3-{2-(4-amino-1,2,5-oxadiazol-3-yl)-7-[(3-aminopro Noxyl-1- ethyl-1H-imid=azo[4 5-c]pyridin-4-yliphenyl)-N'-[2-(methyio henyllurea trifluoroacetat-e :

The title compound was prepared in an analogous manner to Exa mple 242 by substituting 2-(methoxy)phenylisocyanate for 4-chlorophenylisocyanatee in step (2). MS(ES+) m/z 544.0 [M+H]". :

Example 256 . Preparation off N-(3{2-(4-amino-1,2,5-oxadiazol-3-y)-7-{(3-aminopropyNoxy}-1- ethyl-1H-imid=azo[4,5-c]pyridin-4-yliohenyl)-N'-(2.3-dihvdro-1 H-inden-5-yl) .urea triflucroacetat-e

The titlle compound was prepared in an analogous manner to Example 242 by substitutingy 5-isocyanato-2,3-dihydro-1H-indene for 4-chlorophenylisoecyanate in step (a). MS(RES+) m/z 554.0 [M+H]'.

Example 257

Preparation of= N-(3-{2-(4-amino-1 .2.5-oxadiazol-3-yl)-7-](3-aminopropyl)osxyl-1- ethyl-1 H-imid=azo[4 5-c]pyridin-4-yllphenyl)-N'-(2-chlorophenyl)urea trifluomroacetate

The title compound was prepared in an analogous manner to Exammple 242 by substitutingg 2-chlorophenylisocyanate for 4-chiorophenylisocyanate in =step (a).

MS(ES+) m/z 548.0 [M+H]".

Example 258

Preparation of N-(3-{2—(4-amino-1.2,5-oxadiazol-3-yl)-7-[(3-aminopropyi)o -1- ethyl-1H-imidazo]4,5-c]pyridin-4-yiiphenyl)-N'-(3-chlorophenyjurea trifluoreoacetate

The title compound was prepared in an analogous manner to Exarmnple 242 by substituting 3-chlorophenylisocyanate for 4-chlorophenylisocyanate in sstep (a).

MS(ES+) m/z 548.0 [MX +HI". :

Example 259

Preparation of N-(3-{2~ 4-amino-1.2,5-oxadiazol-3-yl)-7-[(3-aminopropyo><y}-1- ethyl-1H-imidazol4.5-c Jpyridin-4-yiiphenyl)-N'-{(4-cyanophenyljurea trifluorcyacetate

The title compo und was prepared in an analogous manner to Exanple 242 by substituting 4-cyanosphenylisocyanate for 4-chlorophenylisocyanate in s-tep (a).

MS(ES+) m/z 540.0 [M-+H]".

Example 260

Preparation of N-(3-{2-q4-amino-1 2 5-oxadiazol-3-yl)-7-[(3-aminopropylioxxyl-1- ethyl-1H-imidazo[4.5-c} pyridin-4-yl}phenyl)-N'-(3-cyanophenyl)urea trifluorco acetate

The title compomund was prepared in an analogous manner to Examaple 242 by substituting 3-cyano gohenylisocyanate for 4-chlorophenylisocyanate in s&ep (a).

MS(ES+) m/z 539.0 [M—+H]".

Example 261 }

Preparation of N-(3-{2-( 4-amino-1,2,5-oxadiazol-3-y})-7-{(3-aminopropyhox=y}-1- ' ethyl-1H-imidazo[4.5-c]povridin-4-yiiphenyl)-N'-cyclohexylurea trifluoroacetafte

The title compound was prepared in an analogous manner to Exam ple 242 by substituting cyclohexcylisocyanate for 4-chlorophenylisocyanate in step (2).

MS(ES+) m/z 520.0 [M+H]".

Example 262

Preparation of N-(3-{2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyi-7-[(~4- piperisdinylmethyi)oxy]-1 H-imidazo[4, 5-clpyridin-4-yi}phenyl)aceta mide trifluo roacetate

The title compound was prepared in an analogous manner to Example 242 by su bestituting acetyl chloride for 4-chlorophenylisocyanate in step (a) and 1,1- dimethylethy! 4-({{2-(4-amino-1 ,2,5-oxadiazol-3-yl)-4-chloro-1-ethayi-1 H-imidazo[4,5- c]pyri din-7-ylloxylmethy!)-1 -piperidinecarboxylate for 1,1-dimethy=lethyl [3-({4- chlore-2-{4-({[(1 ,1-dimethylethyl)oxy]carbonyl}amino)-1 ,2,5-oxadi azol-3-yl]-1-ethyl- 1H-imidazol4,5-clpyridin-7-yi}oxy)propyljcarbamate in step (b). MIS(ES+) m/z 477.0

M+HRY.

Example 263

Prep=aration of ethyl 3-({I(3-{2-(4-amino-1 2 5-oxadiazol-3-y)-7-f( 3- aminsopropyloxy}-1-ethyi-1 H-imidazo[4,5-c]pyridin-4- yl}phsenyl)aminolcarbonyilamino)benzoate trifluoroacetate

The title compound was prepared in an analogous mannesr to Example 242 by substituting ethyl 4-isocyanatobenzoate for 4-chlorophenyliso cyanate in step (a). :

MS(ESS+) m/z 586.0 [M+H]".

Example 264 : Prep=aration of N-(3-{2-(4-amino-1,2.5-oxadiazol-3-y))-7-{(3-amin=opropyloxy}-1- ethyl—1H-imidazol4,5-clpyridin-4-yl}phenyh-3-(methyloxy)propanzamide triflucroacetate

The title compound was prepared in an analogous manneer to Example 242 by substituting 3-(methyloxy)propanoy! chloride for 4-chlorophermylisocyanate in step (a). MS(ES+) m/z 481.0 [M+H]".

Example 265

Preparation of 4-(2-(4-amino-1 .2.5-oxadiazol-3-yl)-1-ethyl-7-{[3-({2-[4- 3-butyn-2-ol. (a) 2-(4-Amino-1 2, 5-oxadiazol-3-yl)-4-chloro-1-ethyl-1 H-imidazo[4,5-c]pyridin-7—ol

A solution of the compound of Example 114(g) (2.0, 5.8 mmol) in THF (270 mL) was cooled to -100 °C under an atmosphere of nitrogen. n-Butyl lithiurm (7.2 mL, 18 mmol, 2.5 M in hexanes) at -78 °C was added over 4 minutes using a syringe pump. After an additional 3 min at -100 °C trimethyl borate (2.1 mL, 19 mmol) was added. The cooling bath was removed and the mixture was allowed to warm to RT. After 3h, a solution of 30% aqueous hydrogen peroxide (13 mL) in 3M

NaOH (4.3 mL) was added. After an additional 45 min, the reaction was quencimied by partitioning between EtOAc and 1N HCI. The aqueous layer was extracted with additional EtAOc and the com bined organic extracts were washed with water, br-ine, and dried over Na;SO,. The solvent was removed in vacuo and the residue was triturated with 3% MeOH/CH,C, to give the desired material as a pale yellow so lid (0.96 g). MS (ES+) m/z 281.0 [M+H]*. (b) 4-(2-(4-Amino-1,2,5-oxadiazol-3-yl)-1 -ethyl-7-{[3-({2-{4- a 20 (methyloxy)phenyljethyl}amino)propyljoxy}-1 H-imidazo[4,5-c]pyridin-4-yi)}-2-metinyl- : 3-butyn-2-ol :

Anhydrous Cs,COs (1-4 g, 4.2 mmol) was added to a solution of the compound of Example 265(a)y (1.0 g, 3.6 mmol) in DMF (40 mL) at RT. After 5 min., 1,3-dibromopropane (2.9 g, 14 mmol) was added and the mixture was heaated to 60 °C for 3.5 h. The mixture was cooled to RT, filtered through celite and and the filter cake rinsed with EtA©Oc. The combined filtrate was concentrated to a brown residue, which was dis solved in DMF (40 mL). Et3N (1.9 mL, 14 mmol) =nd 2-[4-(methyloxy)phenyllethanamine (1.9 mL, 13 mmol) were added and the mixture was heated to 60 °C. After 30 min., the reaction was cooled to RT and quenched by partitioning between EtOAc and water. The aqueous layer was extracted witkh additional EtOAc, and the cormbined extracts were washed with water and brine=, dried over MgSO. The solvent was removed in vacuo to give a brown solid.

Trituration with Et;O gave the title compound as a pale yellow solid (1.4 g). MS (ES+) m/z 472.0 [M+H]*.

Exam ple 266 - Capsule Composition

An oral dosage forrm for administering the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table |, below.

Table

INGREDIENTS AMOUNTS

4-(4-Phenyl-1-piperidin-4-wi-1 H-imidazo[4,5-c]pyridin-2-yl)- 25mg furazan-3-ylamine

Lactose 55 mg

Talc 16 mg

Magnesium Stearate 4mg

Examples 267 - Injectable Parenteral Composition

An injectable form for administering the present invention is produced by stirring 1.5% by weight of 1-{2-(4-Aminofurazan-3-yl)-1-ethyl-4-phenyi-1 -H- imidazo[4,5-clpyridin-7-ylf-1-(3-aminopyrrolidin-1-y)methanone in 10% by volume : propylene glycol in water.

Example 268 - Tablet Composition

The sucrose, calcium sulfate dihydrate and an Akt inhibitor as shown in

Table Il below, are mixed and granulated in the proportions shown with a 10% gelatin solution. The wet granules are screened, dried, mixed with the starch, talc and stearic acid;, screene=d and compressed into a tablet.

Table il

INGREDIENTS AMOUNTS

2-(4-amino-~1 ,2,5-oxadiazwol-3-yl)-4-(3-chlorophenyi)-1- 20 mg (cyclopropylmethyl)-N-[3-(dimethylamino)propyi]-1 H- imidazol4,5-c]pyridine-7-carboxamide calcium sulfate dihydrate 30 mg sucrose 4 mg starch 2mg talc . 1mg stearic acid 0.5 mg

While the preferred embodiments of the invention are illustrated by the above, it is to be understood that the invention is not limited to the precise instructions herein disclosed and that the right to all modifications coming within the scope of the following claims is reserved. i

Claims

What is claimed i s:

1. A compound of Formula (1): R4 ee NF ) R1 R7 ® wherein: ’ Het is selected from the group consisting of: H Po . . . oy, 8 NH, ~~ “N” . HN NT NTONK, NH, No” Ne” N+ CN a NC. HNTONT 0 ONTONH, 8nd NTN R1 is selected from hydrogen, alkyl, alkyl substituted with one or more - substituents selected from the group consisting of. hydroxy, alkoxy, amiro, N-acylamino, cyclopropyl and halogen, cycloalkyl, cycloalkyl subsstituted with one or more substituents selected from the grasup consisting of: hydroxy, alkoxy, amino, N-acylamino and halogemn,

. cycloalkyl containing from 1 to 4 heteroatoms, cycloalkyl contaxining from 1to 4 heteroatoms substituted with one or more substituents s elected fron the group consisting of: hydroxy, alkoxy, amino, N-acylanmmino and halogen, C4.Cqoaryland C4.Cqzaryl substituted with one or more submsiituents selected from the group consisting of: hydroxy, alkoxy, amino, N-acylamino and halogen; R4 iss selected from hydrogen, halogen, alkyl, substituted alkyl, cycloalkyl, cycloalkyl containing from 1 to 4 heteroatoms and a cyclic or polycyclic aromatic ring containing from =3 to 16 carbon atoms and optionally containing one or more hetero atoms, provided that when the number of carbon atoms is 3 the aromat_ic ring contains at least two heteroatoms and when the number of carbon atoms is 4 the aromatic riMg contains at least one heteroatom, and ogptionally substituted with one or more substituents selected from the gro up consisting of: alkyl, substitutead alkyl, alkoxy, acetamide, cyano, nitrile, Lirea, substituted urea, aryl, : substituted cycloalkyl, substituted aryl, &xryloxy, oxo, hydroxy, alkoxy, cycloalkyl, acyloxy, amino, N-acylamino , nitro, halogen, -C(O)OR2, - C(O)NRSRS, -S(0)2NR5R6, -S(0),R2 zand protected -OH, where n is 0-2, , R2 is selected from hydrogen, alkyl, csycloalkyl, C1.Cq2aryl, substituted alkyl, substituted cycloalkyl and substi-tuted C4.Cq2aryl, and RS and R6 are independently hydroger, cycloalkyl, C1.Cq2amyi, substituted cycloalkyl, substituted C1.C12aryl, alkyl or alkyl substitute=d with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acyl&amino, oxo, hydroxy, -C(O)ORZ2, - S(0)pR2, -C(OINR2R3, -S(0)o,NR2R3 , nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, aryl, sumbstituted aryl and protected —OH, or RS and RS taken together with the rmitrogen to which they are attached represent a 5 to 6 member saturated ri ng containing up to one other . heteroatom selected from oxygen and nitrogen, where the ring is optionally subtituted with one or more sSsubstituents selected from amino, methylamino and dimethylamino, where R2 and R3 are independemntly hydrogen, alkyl, cycloalkyl ,

C1.Cq2oaryl, substituted alkyl, substituted cycloalkyl and substituted C4.C42aryl, and nis 0-2; and RT is selected from hydrogen, -C(O)NFRSR10, -(CH2),NROR10, - SOoNRIR10 | -(CH)nOR8, -O-(CH2)MNROR10 and -N- (CH2)mNRER10, where nis 0-2, mis 1-8, where the carbon chain forrmed by m is optionally substitute=d, R8is alkyl, cycloalkyl, cycloalkyl cormtaining from 1 to 4 heteroatoms, and aryl, each of which is optionally sLsbstituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, amino substituted witch one or more substituents sele cted from the group consisting of: hydroxy, alkoxy and amino, N-acylamino, oxo, hydroxy... -C(0)OR2, -S(0)nR2, -C(O)NR2RS3, -S(0)2NR2R3, nitro, guanadine, s ubstituted guanadine, cyano, cycloalkyl, cycloalkyl containing. from 1 to 4 heeteroatoms, substituted cycloalkyl containing from 1t04 heteroatoms. substituted cycloalkyl, halogen, aryl, substituted aryl and protected ~OPH, where IR2 and R3 are independently hydrogen, alkyl, cycloalkyl,

C1.Cqaryl, substituted alkyl, substituted cycloalkyl and substituited C4.Cq2anyl, and nis 0-2, RO and R10 are independently hydrogen, cycloalkyl, cycloalkyl containing from 1 to 4 heteroatoms, C4.Cqoamyl, substituted cycloalkyl, substituted C4.Cq2aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amimno, N-acylamino, oxo, hydroxy, methylamino, dimethylamino, hydroxyalkyl , -C(O)OR2, -S(O)nR2, -C(O)NR2R3, -S(0)2NR2R3, - NR2R3, nitro, cyano, cycloalkyl, cycloalkyl containing from 1 to 4 heteroatoms, substituted cycloalkyl, halogen, aryl, substituted aryl and . : protected —OH, . or R9 and R=10 taken together with the nitrogen to which they are attache=d . 20 represent a 5to 6 member saturated ring containing up to one other . heteroatom selected from oxygen and nitrogen, where the ring is iE optionally subtituted with one or more substituents selected from amino, : : : methylamine and dimethylamino, where R2 and R3 are independently hydrogen, alkyl, cycloalkyl, ,

C4.C4 zaryl, substituted aikyl, substituted cycloalkyl and substituted C4.Cq2aryl, and nis 0-2; except 4-[1-E-thyl-7-(piperidin-4-yloxy)-1 H-imidazo[4,5-c]pyridin-2-yi}- furazan-3-yllamine.

2. A pharmaceutically acceptable salt, hydrate, solvate or pro- drug of a compound of Formula (1), as described in claim 1.

3. A compound of Claim 1 represented by the following Formumia (i):

NH, R4 pS ON NT R1 R7 (In wherein: , R1 is selecied from hydrogen, alkyl, alkyl substituted with one or more substituents selected from the grou p consisting of: hydroxy, alkoxy, amino, N-acylamino, cyclopropyl ard halogen, cycloalkyl, cycloalkyl substituted with one or more substituents selected from the group consisting of: hydroxy, alkoxy, amiro, N-acylamino and halogen, cycloalkyl containing from 1 to 4 heateroatoms, cycloalkyl containing from 1 to 4 heteroatoms substituted witha one or more substituents selected from the group consisting of: hydramxy, alkoxy, amino, N-acylamino and halogen, C4.Cqoaryl and C1.Cqi2-aryl substituted with one or more substituents selected from the group consisting of: hydroxy, alkoxy, amino, N-acylamino and halogen;

R4 is selected from hydrogen, halo gen, alkyl, substituted alkyl, . : cycloalkyl, cycloalkyl containing freom 1to 4 heteroatoms and a cyclic or polycyclic aromatic ring containing from 3 to 16 carbon atoms and optionally containing one or more Fneteroatoms, provided that when the number of carbon atoms is 3 the amromatic ring contains at least two heteroatoms and when the numbe=r of carbon atoms is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from tine group consisting of: alkyl, substituted alkyl, alkoxy, acetamide, cyano, nitrile, urea, substituted urea, aryl, substituted cycloalkyl, substituted aryl, aryloxy, oxo, hydroxy, alkoxy, cycloalkyl, acyloxy, amino, N-acylaamino, nitro, halogen, -C(O)OR?, - C(O)NR5SRS, -S(0)oNR5RS, -S(0)R2 and protected -OH, where nis 0-2, R2 is selected from hydrogen, al kyl, cycloalkyl, C1 .Cqoaryl, substituted alkyl, substituted cycloalkyl and substituted C1.C42aryl, and RS and RB are independently hycirogen, cycloalkyl, C1.C12aryi, substituted cycloalkyl, substituted C4_Cqzaryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, NE -acylamino, oxo, hydroxy, -C(O)OR?, -

S(0)R2, -C(O)NR2R3, -S(0)oNR2R3, nitro, cwano, cycloalkyl, substituted cycloalkyl, halogen, aryl, substituted aryl and protected ~OH, or R5 and RS taken together with the nitrogen t-o which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen , where the ring is optionally subtituted with one or more substituents selected from amino, methylamino and dimethylamino, where R2 and R3 are independently hyd rogen, alkyl, cycloalkyl,

C4.C12aryl, substituted alkyl, substitute=d cycloalkyl and substituted C4.Cq2aryl, and nis 0-2; an R7 is selected from hydrogen, -C(ONROR10, ~(CH2)NROR10, - SOoNROR10, ~(CH2)nOR8, -O-(CH2)mNROR10 and -N- (CH) NRER10, where nis 0-2, : mis 1-6, where the carbon chain formed by Em is optionally substituted, RBis alkyl, cycloalkyl, cycloalkyl containing from 1 to 4 heteroatoms, and aryl, each of which is optionally substitutead with one or more substituents selected from the group consistirg of: alkoxy, acyloxy,

20 .aryloxy, amino, amino substituted with one or more substituents selected

. from the group consisting of: hydroxy, alkoxy and amino, N-acylamino, oxo, hydroxy, -C(O)OR2, -S{O)nR2, -C(O)NRR2R3, -S(0)2NR2R3, nitro, guanadine, substituted guanadine, cyano, cycloalkyl, cycloalkyl containing from 1 to 4 heteroatoms, substituted cycloalicyl containing from 1 to 4

25 . heteroatoms, substituted cycloalkyl, halogen,. aryl, substituted aryl and protected ~OH, : where R2 and R3 are independently hydrogen, alkyl, cycloalkyl,

C4.Cq2aryl, substituted alkyl, substitu-ted cycloalkyl and substituted C4.Cq2aryl, and nis 0-2, RY and R10 are independently hydrogen, c-ycloalkyl, cycloalkyl containing from 1 to 4 heteroatoms, C4.Cqmaryl, substituted cycloalkyl, substituted C4.Cqparyl, alkyl or alkyl substituted with one or more substituents selected from the group consist ing of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, rmethylamino, dimethylamino, hydroxyalkyl, -C(O)OR2, -S(0)nR2, -C(O)NFR2R3, -S(0)2NR2RS3, - NR2R3, nitro, cyano, cycloalkyl, cycloalkyl ceontaining from 1 to 4 heteroatoms, substituted cycloalkyl, haloge n, aryl, substituted aryl and protected —OH, or R9 and R10 taken together with the nitrcagen to which they are attached represent a 5 to 8 member saturated ring czontaining up to one other heteroatom selected from oxygen and nitrogen, where the ring is optionally subtituted with one or more substituents selected from amino, methylamino and dimethylamino, where R2 and R3 are independently hydrogen, alkyl, cycloalkyl, : C1.Cqoaryl, substituted alkyl, substituted cycloalkyl and substituted C4.Cq42aryl, and nis 0-22; except 4-[1-Ethyl-7-(piperidin-4-yloxy)-1 H-inmidazol4,5-c}pyridin-2-yl]- furazan-3-ylamine.

4. A pharmaceutically acceptabole salt, hydrate, solvate or pro- driag of a compound of Formula (11), as described im claim 3.

5. A compound of Claim 1 repr-esented by the following Formula (BY:

20 . NH, Ré ON NN Ri RT ny whherein: R1 is selected from alkyl, alkyl substitute=d with one or more substituents selected from the group consisting of: h=ydroxy, alkoxy, amino, N- acylamino, cyclopropyl and halogen, cy-cloakyl, cycloalkyl substituted with one or more substituents selected #rom the group consisting of: hydroxy, alkoxy, amino, N-acylamino arad halogen, cycloalkyl containing from 1 to 3 heteroatoms, cycloalkyl cortaining from 1 to 3 heteroatoms substituted with one or more substituen-ts selected from the group consisting of: hydroxy, alkoxy, amino, N3-acylamino and halogen, C4. Cqoaryl and C4.Cq2aryl substituted wi-th one or more substituents selected from the group consisting of: "hydroxy, alkoxy, amino, N- acylamino and halogen;

R4 is selected from hydrogen, halogen, albicyl, substituted alkyl, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms and a cyclic or polycyclic aromatic ring containing from 3 -to 16 carbon atoms and optionally containing one or more heteroatoms, provided that when the number of carbon atoms is 3 the aromatic= ring contains at least two heteroatoms and when the number of carfioon atoms is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of. alkyl, substituted 190 alkyl, alkoxy, acetamide, cyano, nitrile, urea, substituted urea, aryl, substituted cycloalkyl, substituted aryl, arwyloxy, oxo, hydroxy, alkoxy, cycloalkyl, acyloxy, amino, N-acylamino, mnitro, halogen, -C(O)OR2, - C(O)NRSRB, -8(0)2NR5RS, -5(0)R2 ard protected -OH, ' ] where nis 0-2, L5 R2 is selected from hydrogen, alkyl, cycloalkyl, C4.Cq2aryl, substituted alkyl, ‘substituted cycloalkyl and substituted C4.Cq2aryl, and R5 and RS are independently hydrogen, cycloalkyl, C4 .Cqoaryl, substituted cycloalkyl, substituted C4.Cqgoanyl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylarmino, oxo, hydroxy, -C(O)ORZ, - S(0)nR2, -C(O)NR2ZR3, -8(0);NR2R3, mitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, aryl, subsstituted aryl and protected —~OH, or RS and R6 taken together with the nitmrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other "heteroatom selected from oxygen and nitrogen, where the ring is optionally subtituted with one or more sumbstituents selected from amino, methylamino and dimethylamino, where R2 and R3 are independent’ly hydrogen, alkyl, cycloalkyl,

C4.C2aryl, substituted alkyl, sutostituted cycloalkyl and . substituted C4.C12aryl, and n is 08-2; and R7 is selected from -C(O)NROR10, -(CH-2)oNRSR10, -SOoNRER10, - (CH)nORS, -O-(CH2)MNROR10 and —N-(CH2)mNRER10, where nis 0-2, mis 1-8, where the carbon chain forme=d by m is optionally substituted, R8is alkyl, piperidine, imidazolidine, gohenyl, piperazine, piperidyl and pyrrolidinyl, each of which is optionally substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, amino substituted with one or more substituents selected from the group consisting of: hydroxy, alkoxy and amino, N-acylamino, oxo, hydroxy, -C(O)OR2, -S(0)nR2, -C(O)NR2RS3, -S(0)2NR2R3, nitro, guanadine, substituted guaradine, cyano, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms, suabstituted cycloalkyl containing from 1to3 heteroatoms, substituted cycloalkyl, halogen, aryl, substituted aryl and protected —OH, where R2 and R3 are independently hydrogen, alkyl, cycloalkyl, i C1.Cqoaryl, substituted alkyl, substituted cycloalkyl and substituted C4.Cqoaryl, and nis 0-2, RY and R10 are independently hydrogen, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms, C4.C42aryl, substituted cycloalkyl, substituted C4.C4oaryl, alkyl or alkyl substituted with one or more

15 . substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamiro, oxo, hydroxy, methylamino, dimethylamino, hydroxyalkyl, -C(O)OR2, -S(0)nR?, -C(O)NR2R3, -S(0)oNR2RS3, - : o NR2R3, nitro, cyano, cycloalkyl, cycloalkyl containing from 1to 3 : heteroatoms, substituted cycloalkyl, halogen, aryl, substituted aryl and protected —OH, or R9 and R10 taken together with the nitrogen to which they are attached

= . represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen, where the ring is optionally subtituted with one or more substituents selected from amino, methylamino and dimethyl#amino, where R2 and R3 are independently hydrogen, alkyl, cycloalkyl,

C4.Cqoaryl, substituted alkyl, substituted cycloalkyl and substituted C4.Cq2aryl, and nis 0-2; except 4-[1-Ethyl-7-(piperidin-4-yloxy)-1H-imidazo[4,5-clpyridin-2-yi}- furazan-3-ylamine.

6. A pharmaceutically acceptable salt, hydrate, solvate or pro- drug of a compound of Formula (IIE), as described in claim 5.

7. A compound represented by Formula (lI), as defined in claim 3, wherein:

R1 is selected from: alkyl, alkyl substituted with one or more substituents selected from the group consisting of: hydroxy, alkoxy, amino, N- acylamino, cycl-opropyl and halogen, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms and C1.Cqoaryl;

R4 is selected from hydrogen, halogen, alkyl, substituted alkyl, cycloalkyl, cycBoalkyl containing from 1 to 3 heteroatoms, C4.Cq2anyi and C4_Cq2arylsubstituted with one or more substituents selected fro-m the group cons isting of: alkyl, substituted alkyl, alkoxy, acetamide, cyamo, nitrile, urea, su bstituted urea, aryloxy, hydroxy, alkoxy, acyloxy, amino, N- acylamino, nitro and halogen; and R7 is selected from, -C(ONROR10, -(CH2),NROR10, -(CH2),ORS, -O- : (CH2)mNROR 10 and -N~CH2)mNRER10, where nis 0-2; mis 1-8, whe=re the carbon chain formed by m is optionally substitute=d, R8is alkyl, piperidine, imidazolidine, phenyl, piperazine, piperidyl 2nd pyrrolidinyl, each of which is optionally substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, amino substituted with one or more substituents sele-cted . from the group consisting of: hydroxy, alkoxy and amino, N-acylamirmo, : hydroxy, nitro, guanadine, substituted guanadine, cyano, cycloalkyl, substituted cy«cloalkyl, cycloalkyl containing from 1 to 3 heteroatoms, substituted cycloalkyl containing from 1 to 3 heteroatoms, halogen, C-1-

C12aryl and s ubstituted C1-C42anyl,

R9 and R10 are independently hydrogen, cycloalkyl, cycloalkyl containing fromm 1 to 3 heteroatoms, C4-Cq2aryl, substituted cycloall<yl, substituted C-1.Cq2aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy,

aryloxy, amino, N-acylamino, oxo, hydroxy, methylamino, dimethylam ino, hydroxyalkyl, -NRZ2R3, nitro, cyano, cycloalkyl, halogen, aryl and substituted aryl, or R9 and R1O taken together with the nitrogen to which they are attached representa 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen, where the ring is optionally substituted with one or more substituents selected from amimno, methylamino and dimethylamino,

where R2 and R3 are independently hydrogen, alkyl, cycloalkyl,

C1.Cq2aryl, substituted alkyl, substituted cycloalkyl and substituted C4_C12aryl; except 4-[1-Ethyl-7 -(piperidin-4-yloxy)-1 H-imidazo[4,5-c]pyridin-2-yl]- furazan-3-ylamine.

8. A pharmaceutically acceptable salt, hydrate, solvate or pro- drug of a compound of Formula (il), as described in claim 7.

9. A compound represented by Formula (ly, as defined in clainn 5, wherein: R1 is selected frorm: alkyl, alkyl substituted with one or more substituents selected from thee group consisting of: hydroxy, alkoxy, amino, N- acylamino, cyclopropyl and halogen, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms and C4.Cq2aryl; R4is selected from hydrogen, halogen, alkyl, substituted alkyl, cycloalkyl, cycloalkyl containing from 1to 3 heteroatoms, C4.Cq2aryl and C4.C4oary! substituted with one or more substituents selected from : the group consisting of: alkyl, substituted alkyl, alkoxy, acetamide, cyano , : : nitrile, urea, substituted urea; aryloxy, hydroxy, alkoxy, acyloxy, amino, N - - acylamino, nitro, and halogen; and R7 is selected from -(CH2)nORB, -O-(CH2)mNROR10 and N- (CHIMNRSR1O, where nis 0-2; mis 1-6, where the carbon chain formed by m is optionally substituted, R8 is alkyl, piperidine, imidazolidine, phenyl, piperazine, piperidyl ancl pyrrolidinyl, each of which is optionally substituted with one or more substituents se lected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, amino substituted with one or more substituents selectexd from the group consisting of: hydroxy, alkoxy and amino, N-acylamino, hydroxy, nitro, guanadine, substituted guanadine, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms, substituted cycloalkyl containing from 1 to 3 heteroatoms, halogen, C4~ Cq2aryl and substituted C41-C42aryl,

RY and R10 are independently hydrogen, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms, C1.Cq2ary}, substituted cycloalkyl, substituted C4.C42aryl, alkyl or alkyl substituted with one or more substituents seleacted from the group consisting of: alkoxy, acyloxy, S aryloxy, amino, PN-acylamino, oxo, hydroxy, methylamino, dimethylarmino, hydroxyalkyl, -NBRZR3, nitro, cyano, cycloalkyl, halogen, ary! and substituted aryl, or R9 and R10 t=aken together with the nitrogen to which they are attached represent a 5to 6 member saturated ring containing up to one othe r heteroatom selected from oxygen and nitrogen, where the ring is optionally subtitauted with one or more substituents selected from armnino, methylamino armd dimethylamino, where R2 and R3 are independently hydrogen, alkyl, cycloa lkyl,

C4.Cq2arwi, substituted alkyl, substituted cycloalkyl and substituted C1.Cq2aryl; except 4-[1-Ethyl—7-(piperidin-4-yloxy)-1 H-imidazo[4,5-c]pyridin-2-yl}- furazan-3-ylamine. : 10. A gpharmaceutically acceptable salt, hydrate, solvate or pro- drug of a compound of Formula (II), as described in claim 9. : a 11. A «compound represented by Formula (1), as defined in claim 1, wherein: R1 is selected from alkyl, alkyl substituted with one or more substituents selected from tthe group consisting of: hydroxy, alkoxy, amino, N- acylamino, cyclopropyl and halogen, cycloalkyl, cycloalkyl substituted with one or mo re substituents selected from the group consisting of: hydroxy, alkoxy, amino, N-acylamino and halogen, cycloalkyl containing from 1 to 3 heteroatoms, cycloalkyl containing from 1 to 3 heteroatoms substituted with one or more substituents selected from the group consisting of: kaydroxy, alkoxy, amino, N-acylamino and halogen, Cy. Cqzaryland C=4.Cqparyl substituted with one or more substituents selected from the group consisting of: hydroxy, alkoxy, amino, N- acylamino and halogen;

R4 is selected from hydrogen, halogen, alkyl, substituted alkyl, cycloalky), cycloalkyl containing from 1 to 3 heteroatoms and a cyclic or polycycli c aromatic ring containing from 3 to 16 carbon atoms and optionally containing one or more heteroatoms, provided that when th.e number of carbon atoms is 3 the aromatic ring contains at least two heteroatzoms and when the number of carbon atoms is 4 the aromatics ring contains at least one heteroatom, and optionally substituted with one or more suabstituents selected from the group consisting of: alkyl, substituted alkyl, alkoxy, acetamide, cyano, nitrile, urea, substituted urea, aryl,

10 . substitu ted cycloalkyl, substituted aryl, aryloxy, oxo, hydroxy, alkoxy, cycloali<yi, acyloxy, amino, N-acylamino, nitro, halogen, -C(O)ORZ, - C(O)NFR5RB, -5(0)2NR5R8 and -S(0)nR2, where Nis 0-2, : R2 is selected from hydrogen, alkyl, cycloalkyl, C4.Cq2aryl, subs#tituted alkyl, substituted cycloalkyl and substituted C4.C1q2aryl, and R5 andl R6 are independently hydrogen, cycloalkyl, C1-C12anyl, - substituted cycloalkyl, substituted C1.C42aryl, alkyl or alkyl substituted with orme or more substituents selected from the group consisting of: alkoxy. acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, -C(O)OIR?, - S(0)nR2, -C(O)NR2R3, -5(0)oNR2R3, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, aryl and substituted aryl, : or RS and RO taken together with the nitrogen to which they are attached : represent a 5 to 6 member saturated ring containing up to one other hetero atom selected from oxygen and nitrogen, where the ring is optionally subtituted with one or more substituents selected from anmnino, methyllamino and dimethylamino, wvhere R2 and R3 are independently hydrogen, alkyl, cycloa kyl,

C1.Cqoaryl, substituted alkyl, substituted cycloalkyl and substituted C1.C42aryl, and nis 0-2; and R7 is sezlected from -(CH2)nOR8, -O-(CH2)NR®R10 and -N- (CH2) mNRER1O, where= nis 0-2, mis —1-6, where the carbon chain formed by m is optionally substiEuted, R8is alkyl substituted with one or more substituents selected fromm the group» consisting of: alkoxy, acyloxy, aryloxy, amino, amino substi—tuted ) with osne or more substituents selected from the group consisting osf:

hydroxy, alkoxy and amino, N-acylamino, oxo, Ehydroxy, -C(O)OR2, - S(0)nR2, -C(O)NR2R3, -S(0)2NRZR3, nitro, gur anadine, substituted guanadine, cyano, cycloalkyl, cycloalky! containi ng from 1 to 3 heteroatoms, substituted cycloalkyl, substituted cycloalkyl containing from 1 to 3 heteroatoms, halogen, aryl and substitute d aryl, cycloalkyl and cycloalkyl containing from 1 to 3 heteroatoms, each of said cycloalkyl and cycloalkyl containing from 1 to 3 heteroatoms is optionally substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, -C(O)OR2, -S(0)nR2, -C(O)NR2R3, -S(0)2NR2R3, nitro, cyano, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms, substituted cycloalkyl, halogen, aryl and substituted aryl, where R2 and R3 are independently hydrogen, alkyl, cycloalkyl,

C1.Cqoaryl, substituted alkyl, substituted cycloalkyl and substituted C4.Cq2aryl, and nis 0-2, RY and R10 are hydrogen, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms, C4.Cq2aryl, substituted cycloali<y, substituted C4. : Cqoaryl, alkyl or alky! substituted with one or emore substituents selected from the group consisting of: alkoxy, acyloxy, aaryloxy, amino, N- acylamino, oxo, hydroxy, methylamine, dimethyslamino, hydroxyalkyl, - C(O)OR2, -8(0);R2, -C(O)NR2R3, -S(0)2NR=R3, -NR2R3, nitro, cyano, : cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms, substituted cycloalkyl, halogen, aryl and substituted aryl, where R2 and R3 are independently hyd rogen, alkyl, cycloalkyl,

C4.Cqoaryl, substituted alkyl, substitute d cycloalkyl and substituted C4.Cq2aryl, and n is 0-2; except 4-[1-Ethyl-7-(piperidin-4-yloxy)-1 H-imidazo[4,5-c]pyridin-2-yl]- furazan-3-ylamine.

12. A pharmaceutically acceptable samlt, hydrate, solvate or pro- drug of a compound of Formula (I), as described in clairm 11.

13. A compound represented by Forrmula (11), as defined in claim 3, wherein: R1is selected from alkyl, alkyl substituted with one or more substituents selected from the group consisting of: hydroxy~, alkoxy, amino, N-

acylamino, cyclopropyl and halogen, cycloalkyl, cycloalkyl substituted with one or more substituents selected from the group consisting of: hydroxy, alkoxy, amino, N-acylamino and halogen, cycloalkwyl containing from 1 to 3 heteroatoms, cycloalkyl containing from 1 to 3 h eteroatoms substituted with one or more substituents selected from the group consisting of: hydroxy, alkoxy, amino, N-acylamino and halo-gen, C4.

Cqoaryl and C{.Cq2aryl substituted with one or more substituents selected from the group consisting of: hydroxy, alkoxy, amiro, N-

acylamino and halogen;

R4 is selected from hydrogen, halogen, alkyl, substituted alkyl, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms arid a cyclic or polycyclic aromatic ring containing from 3 to 16 carbon atorms and optionally containing one or more heteroatoms, provided th at when the number of carbon atoms is 3 the aromatic ring contains at heast two heteroatoms and when the number of carbon atoms is 4 th<e aromatic ring contains at least one heteroatom, and optionally substituted with one or : : more substituents selected from the group consisting of: al kyl, substituted alkyl, alkoxy, acetamide, cyano, nitrile, urea, substituted ur-ea, aryl, substituted cycloalkyl, substituted aryl, aryloxy, oxo, hydroxy, alkoxy, cycloalkyl, acyloxy, amino, N-acylamino, nitro, halogen, C (O)OR2, - C(O)NRSRS, -S(0)o2NR5R6 and -S(0)nR?, where nis 0-2, R2 is selected from hydrogen, alkyl, cycloalkyl, C4.Cq2@m, substituted alkyl, substituted cycloalkyl and substituted C1.C12aryl, &and RS and RS are independently hydrogen, cycloalkyl, C1.C12amyl,

_ substituted cycloalkyl, substituted C4.Cqoaryl, alkyl or altkyl substituted with one or more substituents selected from the group corsisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, -C(O)ORZ, -

S(O)yR2, -C(O)NR2R3, -8(0)2NRZR3, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, aryl and substituted aryl, or RS and RE taken together with the nitrogen to which theey are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen, where thea ring is optionally subtituted with one or more substituents selected from amino,

methylamino and dimethylamino,

where R2 and R3 are indespendently hydrogen, alkyl, cycloalkyl, : C4.Cq2aryl, substituted alkyl, substituted cycloalkyl and substituted C4.C12aryl, and n is 0-2; and Ss R7 is selected from -(CH2)nORS, -O-(CH2)mNROR10 and -N- (CH2)mNRER10, where nis 0-2, mis 1-6, where the carbon chain formed by m is optionally substitutecd, R8 is alkyl substituted with one or more substituents selected from the= group consisting of: alkoxy, acyloxy, aryloxy, amino, amino substituteed with one or more substituents selected from the group consisting of: hydroxy, alkoxy and amino, Nl-acylamino, oxo, hydroxy, -C(O)ORZ, - S(0)nR2, -C(O)NR2R3, -S(0)2NR2R3, nitro, guanadine, substituted guanadine, cyano, cycloalkyl, «cycloalkyl containing from 1 to 3 heteroatoms, substituted cycloalkyl, substituted cycloalkyl containing from 1 to 3 heteroatoms, halogen, aryl and substituted aryl, cycloalkyl and cycloalkyl containing from 1 tos 3 heteroatoms, each of said cycloalkyl and - ; . cycloalkyl containing from 1 tos 3 heteroatoms is optionally substituted wwith one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acyslamino, oxo, hydroxy, -C(O)OR2, -S(0)R2, : -C(O)NR2R3, -S(0)oNR2R3, nitro, cyano, cycloalkyl, cycloalkyl contai-ning from 1 to 3 heteroatoms, subsstituted cycloalkyl, halogen, aryl and substituted aryl, where R2 and R3 are inclependently hydrogen, alkyl, cycloalkyl, C1-Cqoaryl, substituted alkyl, substituted cycloalky! and substituted C4.Cq2aryl, and nis 0-2, RY and R10 are hydrogen, cycloalkyl, cycloalkyl containing from 1 tc 3 heteroatoms, C1.C42aryl, stibstituted cycloalkyl, substituted C4. Cqoaryl, alkyl or alkyl substit-uted with one or more substituents selected from the group consisting of: @alkoxy, acyloxy, aryloxy, amino, N- acylamino, oxo, hydroxy, metiaylamino, dimethytamino, hydroxyalkyl, - C(O)OR2, -S(0)R2, -C(O)NFR2R3, -S(0)2NR2R3, -NR2R3, nitro, cyzano, cycloalkyl, cycloalkyl containirg from 1 to 3 heteroatoms, substituted cycloalkyl, halogen, aryl and substituted aryl, where R2 and R3 are independently hydrogen, alkyl, cycloalky~l, C1-Cq2aryl, substituted alkyl, substituted cycloalkyl and substituted C1.Cqoaryl, and nis 0-2;

except 4-{1-Ethyl-7-(piperidin-4-yloxy)-1 H-imidazo[4,5-c]pyridin-2-yi]- furazan-3-ylamine. 14, A pharmaceutically acceptable salt, hywdrate, solvate or pro- drug of a compound of Formula (I), as described in claim 13.

15. A compound represented by Formula (1), as defined in claim 1, wherein: R1 is selected from alkyl, alkyl substituted with one or more substituents selected from the group consisting of: hydroxy, alk oxy, amino, N- acylamino, cyclopropyl and halogen, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms and C4.Cq2aryl; : 15 R4 is selected from hydrogen, halogen, alkyl, sub-stituted alkyl, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms, C4.Cq2aryl and C4.Cq2aryl substituted with one or more subsstituents selected from SE : the group consisting of: alkyl, substituted alkyl, allkzoxy, acetamide, cyano, nitrile, urea, substituted urea, -aryloxy, hydroxy, all<oxy, acyloxy, amino, N- acylamino, nitro and halogen; and : : : R7 is selected from ~(CH2)nOR8, -O-(CH2)mNRBR® and -N- : (CH2)mNRERS, where nis 0-2, : mis 1-8, where the carbon chain formed by m iss optionally substituted, R8 is alkyl substituted with one or more substitue=nts selected from the group consisting of: cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms, substituted cycloalkyl, substituted cycloalkyl containing from 1 to 3 heteroatoms, aryl and substituted aryl, : RO is hydrogen, cycloalkyl, cycloalkyl containing from1to3 heteroatoms, C4.C12aryl, substituted cycloalkyl , substituted C4. Cqoaryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, arylloxy, amino, N- acylamino, oxo, hydroxy, methylamino, dimethyla_mino, hydroxyalkyl, - C(O)OR2, -5(0)yR2, -C(O)NR2R3, -S(0)2NRZR.3, -NR2R3, nitro, cyano, cycloalkyl, cycloalkyl containing from 1 to 3 hetereoatoms, substituted cycloalkyl, halogen, aryl and substituted aryl,

where RZ and R3 are independently hydrosgen, alkyl, cycloalkyl,

C4.Cq2anyl, substituted alkyl, substituted cycloalkyl and substituted C4_Cqoaryl, and nis 0-2.

16. A pharmaceutically acceptable salt, hydrate, solvate or pro- drug of a cosmpound of Formula (1), as described in claim 15.

17. A compound represented by Formula (if), as defined in claim 3, wherein: : "R1 fis selected from alkyl, alkyl substituted with One or more substituents selected from the group consisting of: hydroxy, alkoxy, amino, N- aczylamino, cyclopropyl and halogen, cycloalkyl , cycloalkyl containing freom 1 to 3 heteroatoms and C4.Cq2aryl; R4 is selected from hydrogen, halogen, alkyl, substituted alkyl, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms, C4.Cqzaryl and C1.Cqaary! substituted with one or more Substituents selected from } the group consisting of: alkyl, substituted alkyl, alkoxy, acetamide, cyano, rwitrile, urea, substituted urea, aryloxy, hydroxy. alkoxy, acyloxy, amino, N- . amcylamino, nitro and halogen; and R7 is selected from ~(CH2),OR8, -O-(CH2)mN R8R® and -N- © (CCH2)mNRERS, where nis 0-2, : rnis 1-6, where the carbon chain formed by rmis optionally substituted, Ex8 is alkyl substituted with one or more substituents selected from the yroup consisting of: cycloalkyl, cycloalkyl cont aining from 110 3 Bheteroatoms, substituted cycloalkyl, substitute=d cycloalkyl containing from “1 to 3 heteroatoms, aryl and substituted aryl, RI is hydrogen, cycloalkyl, cycloalkyl contai ning from 1to 3 “heteroatoms, C4.Cq2aryl, substituted cycloalkyl, substituted C4. C1oaryl, alkyi or alkyl substituted with one omr more substituents selected —from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N- acylamino, oxo, hydroxy, methylamino, dimet@hylamino, hydroxyalkyl, - C(O)OR2, -S(0)nR2, -C(O)NR2R3, -8(0)2NFR?R?3, -NR2ZR3, nitro, cyano,

VW0 2005/011700 PCT/US2004/024340 cycloalkyl, cycloalkyl containing from 1 to 3 heateroatoms, substituted cycloalkyl, halogen, aryl and substituted aryl, where RZ and R3 are independently hy=drogen, alkyl, cycloalkyl, C4-Cq2aryl, substituted alkyl, substitufited cycloalkyl and substituted C4.C42aryl, and nis 0-2.

18. A pharmaceutically acceptable salt, hydrate, solvate or pro- drug of a compound of Formula (It), as described in claim 17.

19. A compound represented by Formula (1), as defined in claim 1, wherein: R1 is selected from alkyl, alkyl substituted wilith one or more substituents selected from the group consisting of: hydrasxy, alkoxy, amino, N- acylamino, cyclopropyl and halogen, cycloamlkyl, cycloalkyl containing from 1 to 3 heteroatoms and C4.Cq2aryl; R4 is selected from hydrogen, halogen, alkwyl, substituted alkyl, : cycloalkyl, cycloalkyl containing from 1 to 3B heteroatoms, C4.Cqoaryl 20m and Cq.Cq2aryl substituted with one or momre substituents selected from the group consisting of: alkyl, substituted akikyl, alkoxy, acetamide, cyano, nitrile, urea, substituted urea, aryloxy, hydroxy, alkoxy, acyloxy, amino, N- acylamino, nitro and halogen; and R7 is selected from -(CH2)nOR8, -O-(CH2) mNRBR9 and -N- (CH2)mNRERS, : where nis 0-2, , mis 1-6, where the carbon chain formed by m is optionally substituted, R8 is alkyl substituted with one or more siubstituents selected from the group consisting of: piperidine, substitute d piperidine, phenyl and, substituted phenyl, : : RY is hydrogen, cycloalkyl, cycloalkyl comntaining from 1t03 heteroatoms, C{.Cqoaryl, substituted cycloalkyl, substituted C1. Cq2aryl, alkyl or alkyl substituted with onee or more substituents selected from the group consisting of: alkoxy, acyloexy, aryloxy, amino, N- acylamino, oxo, hydroxy, methylamino, dirmethylamino, hydroxyalkyl, nitro,

cyano, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms, halogen and aryl.

20. A pharmaceutically acceptable salt, hydrate, solvate or pro- drug of a compound of Formula (I), as described in claim 19.

21. A compound represe nted by Formula (ll), as defined in claim 3, wherein: R1 is selected from alkyl, alkyl sub»stituted with one or more substituents selected from the group consisting of: hydroxy, atkoxy, amino, N- acylamino, cyclopropyl and halogen, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms and C4.<Cq22aryl; R4 is selected from hydrogen, halogen, alkyl, substituted alkyl, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms, C1.C4oaryl and C4.Cqaaryl substituted with one or more substituents selected from the group consisting of: alkyl, substituted alkyl, alkoxy, acetamide, cyano,

". _ nitrile, urea, substituted urea, arylloxy, hydroxy, alkoxy, acyloxy, amino, N- acylamino, nitro and halogen; and : R7 is selected from -(CH2),OR8, -O-(CH2)y,NR8R9 and -N- (CH2)mNRERS, whera nis 0-2, mis 1-6, where the carbon chain formed by m is optionally substituted, R8 is alkyl substituted with one or more substituents selected from the group consisting of: piperidine, substituted piperidine, phenyl and, substituted phenyl, RO is hydrogen, cycloalkyl, cycBoalkyl containing from 1 to 3 heteroatoms, C4.Cqparyl, substituted cycloalkyl, substituted Cq. C1oaryl, alkyl or alkyl substitute d with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N- acylamino, oxo, hydroxy, methylaamino, dimethylamino, hydroxyalkyl, nitro, cyano, cycloalkyl, cycloalkyl containing from 1 to 3 heteroatoms, halogen and aryl.

22. A pharmaceutically acceptable salt, hydrate, solvate or pro- drug of a compound of Formula (il), as described in claim 21 ~

23. A compound of claim 1 selected from: 4-(4-PHnenyl-1-piperidin-4-yl-1 H-imidazo[4,5-c]pyridin- 2-yl)-furazan-3- ylamine; 4-[4-(3a-Chloro-phenyl)-1-piperidin-4-yl-1 H-imidazo-[4 .. 5-c]pyridin-2- yljfurazan-3-yBlamine; 41 ~(38-Amino-2,2-dimethylpropyl)-4-(3-chlorophenyl)- -1H-imidazo[4,5- c]pyridin-2-yl}—furazan-3-ylamine; 4-1 ~(c=yclopropylmethyl)-4-(2-methylphenyl)-1 H-imid=azo[4,5-c]pyridin-2-yi}- 1,2,5-oxadiaz-ol-3-amine; 4-[4-(2-chlorophenyl)-1-(cyclopropyimethyl)-1 H-imidamzo[4,5-c]pyridin-2-yl}- 1,2,5-oxadiaz:ol-3-amine; : 4-[1-(33-Amino-2,2-dimethylpropyl)-4-phenyl-1 H-imidzazo[4,5-c]pyridinyl-2-yl}- furazan-3-ylammine; : 4-14-(S3-chlorophenyl)-1-(cyclopropyimethyl)-1 H-imideazo[4,5-clpyridin-2-yi}- . 1,2,5-oxadiaz=ol-3-amine; : 4-[4-clhloro-1-(cyclopropylmethyl)-1 H-imidazo[4,5-c]poyridin-2-yl}-1,2,5- oxadiazol-3-ammine; ; 4-[1-(czyclopropylmethyl)-4-(3-furanyl)-1 H-imidazo[4,55-c]pyridin-2-yl}-1,2,5- oxadiazol-3-ammine, 4-[1-(=5-aminopentyl)-4-phenyi-1 H-imidazo[4,5-c]pyriclin-2-yl}-1,2,5- oxadiazol-3-aamine; : 4-[1-(eB-aminohexyl)-4-phenyi-1 H-imidazo[4,5-clpyridin-2-yi]-1,2,5-oxadiazol- 3-amine; 4-[1-(25-aminopentyl)-4-(3-chlorophenyl)-1 H-imidazo[_4,5-c]pyridin-2-yi}-1,2,5- oxadiazol-3-=zamine; 4-[1-(e6-aminohexyl)-4-(3-chlorophenyl)-1 H-imidazo[<%,5-c]pyridin-2-yi}-1,2,5- . oxadiazol-3-=amine; 4-1 -(=3-Amino-2,2-dimethylpropyl)-4-(3-methoxyphemyl)-1H-imidazo[4,5- clpyridinyl-2-=yl]-furazan-3-ylamine; 4-[1-(=5-aminopentyl)}-4-(3-thienyl)-1 H-imidazo[4,5-c]gpyridin-2-yl}-1,2,5- oxadiazol-3-=2amine; 4-[1-(~6-aminchexyl)-4-(3-thienyl)-1 H-imidazo[4,5-c]peyridin-2-yl}-1,2,5- oxadiazol-3-eamine;

4-{4-phenyl-1-(3-piperidinylmethn yI)-1 H-imidazol4,5-c}pyridin-2-yi}-1,2,5- oxadiazol-3-amine; 4-[4-(3-chiorophenyl)-1-(3-piperEdinyimethyl)-1 H-imidazo[4,5-c]pyridin-2-yi]- 1,2,5-oxadiazol-3-amine; 4-[4-(4-chlorophenyl)-1 -(3-piper-idinyimethyl)-1 H-imidazo[4,5-c]pyridin-2-yl]- 1,2,5-oxadiazol-3-amine; . 4-[1-(3-aminopropyl)-4-(2-thienys1)-1 H-imidazo[4,5-c}pyridin-2-yl}-1,2,5- oxadiazol-3-amine; 4-[1-(3-aminopropyl)-4-(1-piperidinyl}-1 H-imidazo[4,5-c]pyridin-2-yl}-1,2,5- oxadiazol-3-amine; 1-[2-(4-Aminofurazan-3-yl)-1-et hyl-4-phenyl-1-H-imidazo[4, 5-c]pyridin-7-yl}- 1-(3-aminopyrrolidin-1-yl)methanone; 1 {[2-(4-Aminofurazan-3-yl)-1 -ethyl-4-thiophen-3-yl-1-H-imidazo[4,5- clpyridin-7-yl}-1-(3-aminopyrrolidin-1 -yB)methanone; 1-[2-(4-Aminofurazan-3-yl)-1 -ethyl-4-pyridin-yi-1 -H-imidazol[4,5-c]pyridin-7- yll-1-(3-aminopyrrolidin-1-yl)methanon«e; : : 1-[2-(4-Aminofurazan-3-yl)-1 -e&hyl-4-pyridin-3-yi-1-H-imidazo[4,5-c]pyridin- 7-yl]-1-(3-aminopyrrolidin-1-y)methancone; 1-[2-(4-Aminofurazan-3-yi)-1 -ethyl-4-furan-3-yl-1-H-imidazo[4,5-c]pyridin-7- yl]-1-(3-aminopyrralidin-1-yl)methanon €; : 1-[2-(4-Amino-furazan-3-yl)-4-chloro-1-ethyl-1 -H-imidazo[4,5-c]pyridin-7-yl]- 1-(3-amino-pyrrolidin-1-yl)-methanone 3 : 1-[2-(4-Amino-furazan-3-yl)-4-( 1H-pyrrol-2-yl))-1-ethyl-1 -H-imidazo[4,5- clpyridin-7-yi]-1-(3-amino-pyrrolidin-1-wl)}-methanone; 1-[2-(4-Amino-furazan-3-yl)-1 -eathyl-4-(2-methoxyphenyl)-1H-imidazo[4,5- clpyridin-7-yl}-1-(3-amino-pyrrolidin-1-wli}-methanone; 1-[2-(4-Amino-furazan-3-yl)-1 -exthyl4-(3-chloro-phenyl)-1H-imidazo[4,5- c]pyridin-7-yi]-1-(3-amino-pyrrolidin-1-syi)}-methanone; 1-[2-(4-Amino-furazan-3-yl)-1-ethyl-4-furan-2-yl-1 H-imidazo[4,5-c]pyridin-7- yi]-1-(3-amino-pyrrolidin-1-yl)-methancne; 2-(4-Amino-furazan-3-yl)-1-eth-yl-4-phenyl-1 H-imidazo[4,5-c]pyridine-7- carboxylic acid [1-(4-chloro-benzyl)-2-Thydroxy-ethyl}-amide; 2-(4-Amino-furazan-3-yl)-1-eth yl-4-(3-chloro-phenyl)-1H-imidazo[4,5- c]pyridine-7-carboxylic acid [1-(4-chlor-o-benzyl)-2-hydroxy-ethyl}-amide; C-197-

2-(4-Amino-furazan-3-yl)-1-ethyrl-4-(2,3-dichloro-phenyl)-1 H-imidazo[4,5- c]pyridine-7-carboxylic acid [1 -(4-chloro>-benzyl)-2-hydroxy-ethyll-amide; 2-(4-Amino-furazan-3-yl)-1 -ethyi-4-(2-chloro-phenyl)-1H-imidazo[4,5- c)pyridine-7-carboxylic acid [1 -(4-chlora-benzyl)-2-hydroxy-ethyl]-amide; 2-(4-Amino-furazan-3-yl)-1 -ethy1-4-(2-hydroxy-phenyl)-1H-imidazo[4,5- c)pyridine-7-carboxylic acid [1 ~(4-chlore@>-benzyl)-2-hydroxy-ethyil-amide; 2-(4-Amino-furazan-3-yl)-4-(3-chioro-phenyl)-1 -ethyl-1H-imidazo[4,5- : c]pyridine-7-carboxylic acid pyrrolidin-3-ylamide; 2-(4-Amino-furazan-3-yl)-4-phe=nyl-1-ethyl-1 H-imidazo[4,5-c}pyridine-7- carboxylic acid pyrrolidin-3-ylamide; 2-(4-Amino-furazan-3-yl)-4-(5-chioro-thiophen-2-yl)-1 -ethyl-1H-imidazo[4,5- c]pyridine-7-carboxylic acid pyrrolidin-3-ylamide; 2-(4-Amino-furazan-3-yl)-4-(2-&amino-phenyl)-1 -ethyl-1H-imidazo[4,5- c]pyridine-7-carboxylic acid pyrrolidin-3-ylamide; 2-(4-Amino-furazan-3-yl)-4-(3-amino-phenyl)-1 -ethyl-1H-imidazo{4,5- clpyridine-7-carboxylic acid pyrrolidin-=3-ylamide; 2-(4-Amino-furazan-3-yl)-4-(3-loromo-phenyl)-1-ethyi-1 H-imidazo[4,5- c]pyridine-7-carboxylic acid pyrrolidin- 3-ylamide; 2-(4-Amino-furazan-3-yi)-4-(1 -maphthalenyl)-1-ethyl-1H-imidazof4,5- c]pyridine-7-carboxylic acid pyrrolidin—3-ylamide; 4 2-(4-Amino-furazan-3-yl)-4-(thTophen-2-yl)-1 -ethyl-1H-imidazo[4,5- c]pyridine-7-carboxylic acid pyrrolidin—3-ylamide; oe 2-(4-Amino-furazan-3-yl)-4-(3,<4-methylenedioxyphenyl)-1 -ethyl-1H- imidazo[4,5-c]pyridine-7-carboxylic acid pyrrolidin-3-ylamide; 2-(4-Amino-furazan-3-yl)-4-(3, 5.dichloro-phenyl)-1-ethyl-1H-imidazo[4,5- c]pyridine-7-carboxylic acid pyrrolidin—3-ylamide; 4-[7-[(3-amino-1 -pyrrolidinyl)caarbonyl]-4-(3-chlorophenyi)-1 - (cyclopropyimethyl)-1 H-imidazo([4,5-cJpyridin-2-yl}-1 ,2,5-oxadiazol-3-amine; 4-[7-{(3-amino-1 -pyrrolidinyl)caarbonyi]-4-(4-biphenylyi)-1 -ethyl-1H- imidazo[4,5-c]pyridin-2-yi]-1,2,5-oxad¥azol-3-amine; 4-[7-[(3-amino-1 -pyrrolidinyl)caarbonyl]-4-(2,4-dichlorophenyi)-1 -ethyl-1H- imidazo[4,5-c]pyridin-2-yl]-1,2,5-oxad iazol-3-amine; 4-[7-{(3-amino-1-pyrrolidinyl)czarbonyl}-1 -ethyl-4-(phenylethynyl)-1H- imidazo([4,5-c]pyridin-2-yi]-1,2,5-oxad jazol-3-amine; 2-{2-(4-amino-1,2,5-oxadiazol -3-yl)-7-[(3-amino-1 -pyrrolidinyl)carbonyl]-1- ethyl-1H-imidazo[4,5-c]pyridin-4-yl}preenol; .

4[7-[C3-amino-1 -pyrrolidinyl)carbonyl}-4-(2-chlor-ophenyl)-1 -ethyl-1H- imidazo[4,5-c=]pyridin-2-yl]-1,2,5-oxadiazol-3-amine; (2-{2-&(4-amino-1 2 5-oxadiazol-3-yl)-7-[(3-amino—~1-pyrrolidinyf)carbonyi}-1 - ethyl-1H-imid azo[4,5-clpyridin-4-yl}phenyl)methanol; S 2-{2-(=4-amino-1 2 5-oxadiazol-3-yl)-7-[(3-amino-- 1-pyrrolidinyl)carbonyi}-1- ethyl-1H-imidll azo[4,5-clpyridin-4-y}-4-chlorophenol; 4-(1-eathyl-7-{[3-(methylamino)-1 -pyrrolidinyljcarioonyi}-4-phenyl-1H- : imidazo[4,5-c=]pyridin-2-yl)-1,2,5-oxadiazol-3-amine; 4-[7-[#(3-amino-1-pyrrolidinyl)carbonyl}-1 -ethyl-4—(4-methylphenyl)-1H- imidazo[4,5-c)pyridin-2-yi}-1,2,5-oxadiazol-3-amine; 4-[7-{=(3-amino-1-pyrrolidinyl)carbonyl]-4-(2,5-dic=hlorophenyi)-1 -ethyl-1H- imidazo[4,5-c]pyridin-2-yi}-1 ,2,5-oxadiazol-3-amine; 4-[7- (3-amino-1-pyrrolidinyl)carbonyl]-4-(1 -ben=othien-2-yl)-1-ethyl-1H- imidazo[4,5-c=)pyridin-2-yi]-1 ,2,5-oxadiazol-3-amine; 4-[1-ethyl-4-phenyl-7-(4-piperidinyloxy)-1 H-imidaazo[4,5-c]pyridin-2-yi}-1,2,5- oxadiazol-3-=amine; 4-{7-[_(3-amino-1-pyrrolidinyl)carbonyl}-1 -ethyl-4—[4-(methyloxy)phenyl]-1H- imidazo[4,5-ac)pyridin-2-yl}-1,2,5-oxadiazol-3-amine; g : 4-{2-&4-amino-1 ,2,5-oxadiazol-3-yl)-7-[(3-amino—1 -pyrrolidinyl)carbonyi}-1- ethyl-1H-imicdazo[4,5-c]pyridin-4-yl}phenol; : 4-[7-[(3-amino-1 -pyrrolidinyl)carbonyl]-4-(4-chlo-rophenyi)-1 -ethyl-1H- imidazo[4,5-ac]pyridin-2-yl]-1,2,5-oxadiazol-3-amine; 4-[4-¢3-chlorophenyl)-1 -ethyl-7-(4-piperidinyloxyw)-1H-imidazo[4, 5-c]pyridin-2- yl}-1,2,5-oxa-diazol-3-amine; 2-(4-=amino-1 2 5-oxadiazol-3-yl)-4-(3-chlorophe=nyl)-1-(cyclopropyimethyl)- N-{2-[(pheny=Imethyl)amino]ethyl}-1 H-imidazo[4,5-c]pyriidine-7-carboxamide; 3-{2-(4-amino-1 ,2,5-oxadiazol-3-yl)-7-[(3-amino-1- pyrmolidinyl)csarbonyl}-1-ethyl-1 H-imidazo[4,5-c]pyridin-<3-yi}phenol; 4-{2-e(4-amino-1,2,5-oxadiazol-3-yl)-7-[(3-amino=-1 -pyrrolidinyl)carbonyl]-1- ethyl-1H-imicdazo[4, 5-c]pyridin-4-yl}benzonitrile; 1-[2-&(4-Amino-furazan-3-yl)-4-phenyl-1-piperidir-4yl-1 ~H-imidazo[4,5- clpyridin-7-y: 11-1-(3-amino-pyrmrolidin-1-yl}-methanone; 4-(4-o(3-chlorophenyl)-1-ethyl-7-{{3-(methylamin ©)-1 -pyrrolidinyfjcarbonyl}- 1H-imidazo[=4 5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-amine: ;

4-(4-(2,5-dichlorophenyl)-1-ethyl-7-{[3-(methylamino)-1 - pyrrolidinyljcarbonyl}-1 H-imidazo[4,5-c]pyrickin-2-yi)-1 ,2,5-oxadiazol-3-amine; 4-14-(2,5-dichlorophenyl)-1-ethyl-7-(<-piperidinyloxy)-1 H-imidazo[4,5- clpyridin-2-yl]-1,2,5-oxadiazol-3-amine, 2-(4-amino-1 2 5-oxadiazol-3-y1)-4-(3-chlorophenyl)-1 -(cyclopropylmethayl)- N-[3-(dimethylamino)propyl]-1 H-imidazo[4,5-c]pyridine-7-carboxamide; 4-[7-{(3-amino-1-pyrrolidinyl)carbonysl}-1 -ethyl-4-(1H-pyrrol-2-yl)-1H- imidazo[4,5-c)pyridin-2-yl}-1 ,2,5-oxadiazol-3B-amine; 4-[7-[(3-amino-1 -pyrrolidinyl)carbonywil4-(4-bromophenyl)-1 -ethyl-1H- imidazo[4,5-c]pyridin-2-yi}-1 ,2,5-oxadiazol-3-amine; 4-[7-[(3-amino-1 -pyrrolidinyl)carbonyy/i}-4-phenyl-1 -(4-piperidinyl)-1H- imidazo[4,5-c]pyridin-2-yi]-1,2,5-oxadiazol-3-amine; : 4-{7-{(4-aminobutyl)oxy]-1-ethyl-4-pEnenyl-1 H-imidazo[4,5-c]pyridin-2-yi_}- 1,2,5-oxadiazol-3-amine; 4-{1 -ethyl-4-phenyl-7-{(4-piperidinylrnethyloxy]-1 H-imidazo[4,5-c]pyrid@in-2- yi}-1,2,5-oxadiazol-3-amine; 4-{4-(3-chlorophenyl)-1 -ethyl-7-{(4-psiperidinylmethyl)oxy}-1 H-imidazo[4-.5- : clpyridin-2-yl}-1,2,5-oxadiazol-3-amine; 4-[7-{(4-aminobutyl)oxy]-4-(3-chlorogohenyl)-1 -ethyl-1H-imidazo[4,5- : clpyridin-2-yl}-1,2,5-oxadiazol-3-amine; : 4-{7-{(2-aminoethyl)oxy}-1-ethyl-4-piheny!-1 H-imidazo[4,5-c]pyridin-2-yl.} 1 :2,5-oxadiazol-3-amine; 4-{1-ethyl-4-phenyi-7-{(3-pyrrolidinyBimethyl)oxy]-1 H-imidazo[4,5-clpyriclin-2- yl}1,2,5-oxadiazol-3-amine; 4-{7-[(3-aminopropyl)oxy]-1-ethyl-4—phenyl-1 H-imidazo[4,5-c]pyridin-2-yi}- 1,2,5-oxadiazol-3-amine; 4-(7-{[(2S)-2-amino-3-phenylpropyl] oxy}-1-ethyl-4-phenyl-1 H-imidazo[<},5- clpyridin-2-yl)-1,2,5-oxadiazol-3-amine; 4-{1-ethyl-4-phenyl-7-(3-piperidinylomxy)-1 H-imidazo[4,5-c]pyridin-2-yi}-3,2,5- oxadiazol-3-amine; : 2-(4-amino-1,2,5-oxadiazol-3-yl)-1 -e2thyl-N-methyl-N-(1-methyl-4- piperidinyl)-4-phenyl-1 H-imidazo[4,5-c]pyriciine-7-carboxamide; N-{[2-(4-amino-1,2,5-0xadiazol-3-yIp-1-ethyl-4-phenyi-1 H-imidazo[4,5- clpyridin-7-ylimethyl}-N,1-dimethyl-4-pipericiinamine; 4-(1-ethyl-4-phenyl-7-{[2-(4-piperidiryl)ethyljoxy}-1 H-imidazo[4,5-c]pyridin-2- yh-1,2,5-oxadiazol-3-amine;

4-{1-(4-aminobutyl)-7-{(3-amino-1 -pyrroltidinyl)carbonyl]-4-phenyl-1H- imidazo[4, 5-c]pyridin-2-yl}-1,2,5-oxadiazol-3-anine; 4-(7-{[(2R)-2-amino-3-phenylpropylloxy}-1 -ethyl-4-phenyl-1H-imidazo[4,5- c]pyridin-2-yl)-1,2,5-oxadiazol-3-amine; 4-1 ~(4-aminobutyl)-7-{(3-amino-1 -pyrro Yidinyl)carbonyl}-4-phenyl-1H- imidazo[4,5-c]pyridin-2-yi}-1,2,5-oxadiazoi-3-armnine; 4-(1 ~(4-aminobutyl)-7-{[3-(methylamino)-1 -pyrrolidinyljcarbonyi}-4-phenyl- 1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-amine; 4-{1-ethyl-7-{(4-methyl-1 -piperazinyl)me=thyl}-4-phenyl-1 H-imidazo[4,5- clpyridin-2-yl}-1,2,5-oxadiazol-3-amine; 4-(1-ethyl-7-{[3-(methylamino)-1 -pyrroliciinyljmethyl}-4-phenyi-1 H- imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-armine; (3-amino-2,2-dimethylpropyl){[2-(4-amiro-1 2, 5-oxadiazol-3-yf)-1-ethyl-4- phenyl-1 H-imidazo[4,5-c]pyridin-7-ylimethyl}anine; 4-(7-{[3-(dimethylamino)-1-pyrrolidinylJrmethyi}-1 -ethyl-4-phenyl-1H- imidazo|4,5-c]pyridin-2-yl)-1 ,2,5-oxadiazol-3-armine; 4-(1 -ethyl-7-{[2-(methylamino)ethylJoxy 3-4-phenyl-1 H-imidazo[4,5-c]pyridin- . -2-yl)-1,2,5-oxadiazol-3-amine; : 4-[1 ethyl-4-pheny!l-7-({2-[(phenylimethy=l)aminclethyjoxy)-1 H-imidazo[4,5- clpyridin-2-yl]-1,2,5-oxadiazol-3-amine; : 4-{1-ethyl-4-phenyl-7-[(3-piperidinyimet hyl)oxy]-1 H-imidazo[4,5-c]pyridin-2- - yi}-1,2,5-oxadiazol-3-amine; Co 4-{7-{(5-aminopentyl)oxy]-1-ethyl-4-phe=nyi-1 H-imidazo[4,5-c]pyridin-2-yl}- : 1,2,5-oxadiazol-3-amine; 4~(7-{[3~(dimethylamino)-2,2-dimethylpr-opyljoxy}-1 -ethyl-4-phenyl-1H- imidazo[4,5-c]pyridin-2-yl)-1,2,5-0xadiazol-3-ar nine; 1-(4-aminobutyl)-2-(4-amino-1 ,2,5-oxacliazol-3-yl)-4-phenyl-N-{2- [(phenyimethyl)aminojethyl}-1H-imidazo[4 ,5-c]gpyridine-7-carboxamide; : 2-(4-amino-1,2,5-oxadiazol-3-yl)-1-(1 -methylethyl)-4-phenyl-N-3-pyrrolidinyl- 1H-imidazo[4,5-clpyridine-7-carboxamide; 4-[7-{[3-(methylamino)-1-pyrrolidinyllca rbonyl}-1-(1 -methylethyl)-4-phenyl- 1H-imidazo[4,5-clpyridin-2-yi}-1,2,5-oxadiazol-=3-amine; 4-(7{[(3S)-3-amino-1-pyrrolidinyljmethwyl}-1 -ethyl-4-phenyl-1 H-imidazo[4,5- c]pyridin-2-yi)-1,2,5-oxadiazol-3-amine; 4-[1-ethyl-7-(hexahydro-1H-1,4-diazepi n-1-yimethyl)-4-phenyl-1H- imidazo[4,5-c]pyridin-2-yl]-1,2,5-oxadiazol-3-armine;

4-[1-ethyl-4-phenyl-7-(1 -piperazinyimethmyi)-1 H-imidazo[4,5-c]pyridin-2-yi}- 1,2,5-oxadiazol-3-amine; 4-(7{[2-(dimethylamino)ethyloxy}-1 -eth y+4-phenyl-1H-imidazof4,5- clpyridin-2-yl)-1,2 5-oxadiazol-3-amine; 4-(1 -ethyl-4-phenyl-7-{[(2S)-2-pyrrolidinw ImethylJoxy}-1 H-imidazo[4,5- c]pyridin-2-yl)-1,2,5-oxadiazol-3-amine; 4-(1 -ethyl-4-phenyl-7-{[(2R)-2-pyrrolidinsylmethyljoxy}-1 H-imidazol4,5- clpyridin-2-yl)-1,2,5-oxadiazol-3-amine; 2-(4-amino-1 ,2,5-oxadiazol-3-yl)-N-(3-amminopropyl)-1 -(1-methylethyl)-4- phenyl-1H-imidazo[4,5-c]pyridine-7-carboxamicie; 2-(4-amino-1,2,5-oxadiazol-3-yl)-1-(1-m ethylethyl)-4-phenyl-N-2-propen-1- y-1 H-imidazo[4,5-c]pyridine-7-carboxamide; 2-(4-amino-1 2,5-oxadiazol-3-yl)-1-ethy B-N-{3-(4-morpholinyl)propyi]-4- phenyl-1 H-imidazo[4,5-c]pyridine-7-carboxamicle; 2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethy B-N-[2-(1 H-imidazol-4-yl)ethyl}-4- phenyl-1 H-imidazo[4,5-c]pyridine-7-carboxamicle; 2-(4-amino-1,2,5-oxadiazol-3-yl)-1 -ethy B-N-[3-(4-methyl-1- piperazinyl)propyi}-4-phenyl-1 H-imidazo[4,5-c]poyridine-7-carboxamide; : 4-[7-[(3-aminopropyl)oxy]-4-(2-chlorophaenyi)-1 -ethyl-1H-imidazo[4,5- : cjpyridin-2-yl]-1,2,5-oxadiazol-3-amine; 4-{7-{(3-aminopropyl)oxy}-4-(3-chiorophaenyl)-1-ethyl-1 H-imidazo[4,5- c]pyridin-2-yl}-1,2,5-oxadiazol-3-amine; : : 4-[7-{(3-aminopropyl)oxy]-4-(4-chlorophmenyl)-1 -ethyl-1H-imidazof4,5- clpyridin-2-yl]-1,2,5-oxadiazol-3-amine; 4-{7-{(3-aminopropyl)oxy}-4-{5-chloro-2—(methyloxy)phenyl]-1 -ethyl-1H- imidazo[4,5-c]pyridin-2-yl}-1,2,5-oxadiazol-3-armine; N-(1-{[2-(4-amino-1,2,5-oxadiazol-3-yt)—1 -ethyl-4-phenyl-1H-imidazo{4,5- cpyridin-7-yllcarbonyl}-3-pyrrolidinyl)-N-methyl acetamide; 2-(4-amino-1 ,2,5-oxadiazol-3-yl)-N-[3-(climethylamino)propyl]-1 -sthyl-4- phenyl-1H-imidazo[4,5-c]pyridine-7-carboxamicle; 2-{2-(4-amino-1 ,2,5-oxadiazol-3-yl)-7-[(<3-aminopropyl)oxy}-1-ethyl-1H- imidazo[4,5-c]pyridin-4-yl}-4-chlorophenol; 4-[7-[(3-aminopropylyoxy}-1-ethyl-4-(2-pyridinyl)-1 H-imidazo[4,5-c]pyridin-2— - yl}-1,2,5-oxadiazol-3-amine; 4-(7-{[3-(dimethylamino)propyljoxy}-1-e thyl-4-phenyl-1H-imidazo[4,5- clpyridin-2-yl)-1,2,6-oxadiazol-3-amine;

4-(1 -ethyi-7-{[3-(4-morpholinyl)propyljoxy 3-4-phenyl-1 H-imidazo[4,5- clpyridin-2-yl)-1 ,2,5-oxadiazol-3-amine; 2-(4-amino-1,2,5-oxadiazol-3-yl)-1 -cyclopeentyl-4-phenyl-N-3-pyrrolidinyl-1 H- imidazoj4,5-c]pyridine-7-carboxamide; 4-{7-[(3-amino-1 -pyrrolidinyl)carbonyfl-1 -cyclopentyl-4-phenyl-1H- imidazo[4,5-c]pyridin-2-y1}-1,2,5-oxadlazol-3-ami ne; 4-1 -cyclopentyl-7-{[3-(methylamino)-1 -pwyrolidinyfjcarbonyl}-4-phenyi-1 H- imidazol[4,5-c]pyridin-2-yl)-1 ,2,5-oxadiazol-3-amiine; 4-(1 -ethyl-7-{[3-(methylamino)propylloxy&-4-phenyl-1 H-imidazo[4,5-c]pyridin- 2-yl)-1,2,5-oxadiazol-3-amine; 4-{1-ethyl-7-[(3-hydrazinopropyl)oxy}-4-p henyl-1H-imidazo[4,5-c]pyridin-2- yi}-1,2,5-oxadiazol-3-amine; 2-{(3{[2-(4-amino-1 ,2,5-oxadiazo!-3-yl)- -ethyl-4-phenyl-1H-imidazo[4,5- clpyridin-T-yljoxy}propyl)amino]ethanol; 4-(1 -ethyl-7-{[3-(hydroxyamino)propyljosxcy}4-phenyl-1 H-imidazo[4,5- cJpyridin-2-yi)-1 ,2,5-oxadiazol-3-amine; (3R)-1-{[2-(4-amino-1,2,5-oxadiazol-3-y1)-1 -ethyl-4-phenyl-1H-imidazo[4,5- : clpyridin-7-yilcarbonyl}-3-pyrrolidinol; : : Co 2-(4-amino-1,2,5-oxadiazol-3-yl)-N-[3-(d Jethylamino)propyl}-1-ethyl-4- : 20 phenyl-1H-imidazo[4,5-c]pyridine-7-carboxamid e; i. 2-(4-amino-1 2,5-oxadiazol-3-yl)-1-ethyl—N-[3-(2-methy}-1-piperidinyl)propyl]- 4-phenyi-1 H-imidazo[4,5-c]pyridine-7-carboxarrside; . 4-(1-methyl-7-{[3-(methylamino)-1-pyrro lidiny!]carbony(}-4-phenyl-1H- : . imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-armine; 4-{7-{(3-amino-1-pyrrolidinyl)carbonyl}-1 —methyl-4-phenyl-1H-imidazo[4,5- c]pyridin-2-yl}-1,2,5-oxadiazol-3-amine; 4-(1-butyl-7<{[3-(methylamino)-1 -pyrroliciinyljcarbonyi}-4-phenyl-1H- imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-amine; : 4-{7-[(3-amino-1-pyrrolidinyl)carbonyl}-1 -butyl-4-phenyl-1H-imidazo[4,5- c]pyridin-2-yl}-1,2,5-oxadiazol-3-amine; 4-[7-](3-amino-1-pyrrolidinyl)carbonyl]-1 -(4-fluoropheny!)-4-phenyl-1H- imidazo[4,5-c]pyridin-2-yl}-1,2,5-oxadiazol-3-anmine; N-(2-aminoethyl)-2-(4-amino-1,2,5-oxacdiazol-3-yl)-1 -(4-fluorophenyl)-4- phenyl-1H-imidazo[4,5-c]pyridine-7-carboxamicie; 4-{1 -(4-aminophenyl)-7-[(3-amino-1-pyr=rolidinyl)carbonyl]-4-phenyl-1 H- imidazo[4,5-c]pyridin-2-yl}-1,2,5-oxadiazol-3-armine;

1-{[2-(4-amino-1,2,5-oxadiazol-3-yl)-1 -ethyl-4-phenyl-1 H-imidazo[4,5- cpyridin-7-ylloxy}-3-(4-morpholinyl)~2-propanol; N-[2-(4-amino-1,2,5-oxadiaz ol-3-y)-1 -ethyl-4-phenyl-1 H-imidazo[4,5- clpyridin-7-yi}-4-piperidinecarboxanside; 4-[7-{[3-(dimethylamino)-1 -pymolidinyl]carbonyl}-4-phenyl-1 -(2,2,2- trifluoroethyl)-1H-imidazo[4,5-c]pyridin-2-yl}-1 ,2,5-oxadiazol-3-amine; 4-(1-ethyl-7-{[2-(4-morpholiryl)ethylloxy}-4-phenyl-1 H-imidazo[4,5-c]pyridlin- 2-yl)-1,2,5-oxadiazol-3-amine; 4-(1-ethyl-4-phenyl-7-{[3-(1 —piperidinyl)propylloxy}-1 H-imidazo[4,5-c]pyricin- 2-yl)-1,2,5-oxadiazol-3-amine triflucroacetate; 2-(4-amino-1,2,5-oxadiazol-3-y)-1 -ethyl-N-[2-(1 -methyi-2-pyrrolidinyl)ethzyi}- 4-phenyl-1 H-imidazo[4,5-c]pyridine~7-carboxamide; 1-(1{[2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1 -ethyl-4-phenyl-1 H-imidazo[4,5- c]pyridin-7-yllcarbonyl}-4-piperidinyl)-1 ,3-dihydro-2H-benzimidazol-2-one; : 1-{[2-(4-amino-1 ,2,5-oxadiaazol-3-yl)-1 -ethyl-4-phenyl-1H-imidazo[4,5- cJpyridin-7-yljcarbonyi}-3-piperidinexcarboxamide; (2-aminoethyl)(2-{[2-(4-ami no-1,2,5-oxadiazol-3-yl)-1 -ethyl-4-phenyl-1H— imidazo[4,5-c]pyridin-7-yljoxy}ethyB)amine; 4-(1-ethyl-4-phenyl-7-{[2-(1 -piperazinyl)ethyljoxy}-1 H-imidazo[4,5-c]pyriciin- ‘ 2-yl)-1,2,5-oxadiazol-3-amine; 4-(7-{[2~(4-acetyl-1 -piperazinyl)ethyljoxy}-1 -ethyl-4-phenyl-1H-imidazo[4-,5- c]pyridin-2-yl)-1,2,5-oxadiazol-3-arnine trifluoroacetate; : 4-(1-ethyl-7-{[3-(4-methyl-1 -piperazinyl)propylloxy}-4-phenyl-1 H- imidazo[4,5-c]pyridin-2-yl)-1 ,2,5-oxcadiazol-3-amine; 4-(1-ethyl-4-phenyl-7-{[3-(1 -piperaziny!)propylloxy}-1 H-imidazo[4,5-clpy ridin- 2-yl)-1 ,2,5-oxadiazol-3-amine; 4-(1-ethyl-4-phenyl-7-{[2-(1 -piperidinyl)ethylJoxy}-1 H-imidazo[4,5-c]pyricdin-2- yl)-1,2,5-oxadiazol-3-amine trifluoroacetate; (3-{{2-(4-amino-1,2,5-oxadliazol-3-yl)-1 -ethyl-4-phenyl-1H-imidazo[4,5- clpyridin-7-ylloxy}propyl)[2-(dimet hytamino)ethyllmethylamine; 3-(34{[2-(4-amino-1 ,2,5-0xadiazol-3-y1)-1 -ethyl-4-phenyl-1H-imidazo[4,%5- cJpyridin-7-ylJoxy}propyl)amino]-1 L2-propanediol; N-(3-amino-2-hydroxypropyl)-2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-4-~ phenyl-1 H-imidazo[4,5-c]pyridine—7-carboxamide; N-(2-amino-3-hydroxypropyl)-2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-&3- phenyl-1 H-imidazo[4,5-c]pyridine—7-carboxamide;

. v N-(3-{2-(4-amino-1,2,5-oxad&azo!-3-yi)-7-{(3-aminopropyl)oxy}- 1-ethyl-1H- imidazo[4,5-c]pyridin-4-yl}phenyl)-N*-phenylurea; 3-{[2-(4-amino-1,2,5-oxadiazol-3-yl}- 1 -ethyl-4-phenyl- 1H-imidazo[4,5- clpyridin-7-yljoxy)-1-propanot; (4{[2-(4-amino-1,2,5-oxadia=2ol-3-yi}-1-ethyl-4-phenyl- 1 H-imidazo[4,5- clpyridin-7-yi]carbonyi}-2-piperaziny®)methanol; 4-[1-ethyl-7-({3-[(methyloxy)rmethyl]-1-piperazinyl}carbonyt)}-4-phenyl-1H- imidazo{4,5-c]pyridin-2-yl}-1,2,5-oxadiazol-3-amine; 4-(7{[3-({[2.4-bis(methyloxy} phenyljmethy(}amino)propyijoxy}-1-ethyl-4- phenyl-1H-imidazo[4,5-c]pyridin-2-yt )-1,2,5-oxadiazol-3-amine; (28)-2-[(3-{[2-(4-amino-1,2,5—~0xadiazol-3-yl}- 1-ethyl-4-phenyl-1H- imidazo[4,5-c]pyridin-7-yljoxy}propyt Yamino}-4-methyl-1-pentanol; diethyl 1-[2-(4-amino-1,2,5-0xadiazol-3-yl)-1-ethyl-7-hydroxy-4-phenyl-1H- imidazo(4,5-c]pyridin-6-yl}-1,2-hydra zinedicarboxylate; and 4-(2-(4-amino-1,2,5-oxadiazol-3-y)-1-ethyt-7-{[3-({2-[4- (methyloxy)phenyilethyljJamino prop wlloxy}- 1 H-imidazo{4 ,5-c]pyridin-4-yi}-2-methyl- 3-butyn-2-ol.

24. A pharmaceutically acceptable salt, hydrate, solvate or pro- drug of a compound of claim 23.

25. A pharmaceutical composition comprising a compound according to claim 1, and/or a pharmaceutically acceptable salt, hydrate, solvate or pro-drug thereof and a pharmaceuticzally acceptable carrier.

26. A process for preparing a pharmaceutical composition containing a pharmaceutically accep-table carrier or diluent and an effective amount of a compound of Formula (lI) as des:cribed in claim 1 and/or a pharmaceutically acceptable salt, hydrate, solvate or pro-drug thereof, which process comprises bringing the compound of Formula (lI ) and/or a pharmaceutically acceptable salt, hydrate, solvate or pro-drug thereof i-nto association with a pharmaceutically acceptable carrier or diluent.

27. Use of a compound of Formula |, as described in claim 1 3F AVIENDED SHE and/or a pharmaceutically acceptable salt, hydrate, solvate or pro-drug there=of, in the manufacture of a medicament for treating or lessening the severity of a disease or condition selected from cancer and arthritis in a mammal.

28. The use of claim 27 wherein the mammal is a human.

29. Use of a compound of Formula Il, as described in claim 3 and/or a pharmaceutically acceptable salt, hydrate, solvate or pro-drug thereof in the manufacture of a medicament for treating or lessening the severity of a disease= or condition selected from cancer and arthritis in a mammal.

30. The use of claim 29 wherein the mammal is a human.

31. The use according to claim 27 wherein said cancer is seBected from brain (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowden dissease, Lhermitte-Duclos disease, breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma and thyroid.

32. The use according to claim 29 wherein said cancer is selected from brain (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma and thyroid.

33. Use of a compound of Formula I, as described in claim 1 and/or a pharmaceutically acceptable salt, hydrate, solvate or pro-drug thereof inthe manufacture of a medicament for inhibiting Akt activity in a mammal.

34. The use of claim 33 wherein the mammal is a human.

35. Use of a pharmaceutical combination comprising a) a compound of Formula (1), as described in claim 1 and/or a pharmaceutically acceptable salt, hydrate, solvate or pro-drug thereof; and b) at least one anti-neoplastic agent in the manufacture of &a medicament for treating cancer in a mammal in need thereof. Fa UNDIES SET

36. The use of claim 35, wherein the atc least one anti-neoplastic agent is selected from the group consisting essentially of .anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase It , antimetabolites, topoisomerase | inhibitors, hormones and hormonal analogues, signal transduction pathway inhibito - rs; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agentss; proapoptotic agents; and «cell cycle signaling inhibitors.

37. The use of claim 35, wherein the alt least one antineoplastic agent is an anti-microtubule agent selected from diterpeneoids and vinca alkaloids.

38. The use of claim 35, wherein the ag least one antineoplastic agent is a diterpenoid.

39. The use of claim 35, wherein the ai least one antineoplastic agent is a vinca alkaloid.

40. The use of claim 35, wherein the at least one antineoplastic agent is a platinum coordination complex.

41. The use of claim 35, wherein the af least one antineoplastic agent is paclitaxel, carboplatin, or vinorelbine.

42. The use of claim 35, wherein the att least one antineoplastic agent is paclitaxel.

43. The use of claim 35, wherein the att least one antineoplastic agent is carboplatin.

44. The use of claim 35, wherein the ait least one antineoplastic agent is vinorelbine. 207 -206- SArahED © Fe

45. The use of claim 35, wherein the at least one antineoplatic agent is a signal transduction pathway inhi bitor.

46. The use of claim 45, wherein the signal transduction pathway inhibitor is an inhibitor of a growth factor receptor kinase selected from the group consisting of VEGFR2, TIE2, PDGFR, BTK, IGFR-1, TrkA, TrkB, TrkC, and cfms.

47. The use of claim 45, wherein the signal transduction pathway inhibitor is an inhibitor of a serine/threonine kinase selected from the group consisting of rafk, akt, and PKC-zeta.

48.. The use of claim 45, wherein the signal transduction pathway inhibitor is an inhibitor of a serine/threonine kinase selected from the src family of kinases.

49. The use of claim 48, wherein the signal transduction pathway inhibitor is an inhibitor of c-src.

50. The use of claim 45, wherein the signal transduction pathway inhibitor is an inhibitor of Ras oncogene se lected from inhibitors of farnesyl transferase and geranylgeranyl transferase.

51. The use of claim 45, wherein the signal transduction pathway inhibitor is an inhibitor of a serine/threonine kinase selected from the group consisting of PI3K.

52. The use of claim 35, wherein the at least one antineoplastic agent is a cell cycle signaling inhibitor.

53. The use of claim 52, wherein the cell cycle signaling inhibitor is selected from inhibitors of the group CDIK2, CDK4, and CDK6.

54. A pharmaceutical combination as claimed in claim 35 for use in therapy. uh SNEED See

55. A compound selected from: 4-(7-Bromo-4-chloro-1-ethyl-1 H-imidazo[4,5-c]pyridir-2-yl)-1,2,5- oxadiazol-3-amine; 2-(4-Amino-1,2,5-oxadiazol-3-yl)-1-methyl-4-phenyl- 1 H-imidazo[4,5- clpyridine-7- carboxylic acid; and Ethyl 4-chloro-5-nitro-6-phenyl-3-pyridinecarboxylate=.

56. A process for preparing a compound of Formuaula (I), and/or pharmaceuti cally acceptable salts, hydrates, solvates and pro-drugss thereof, which comprises converting ethyl 4-chloro-5-nitro-6-phenyl-3-pyridinecarbOxytate into a compound o f Formula (1), and thereafter optionally preparing a pharmmaceutically acceptable ssalt, hydrate, solvate or pro-drug thereof.

57. A process for preparing a compound of Formula (Il), and/or pharmaceuti-cally acceptable salts, hydrates, solvates and pro-drugss thereof, which comprises converting 4-(7-Bromo-4-chioro-1-cthyl-1H-imidazo[4,5-c*]pyridin-2-yl)- 1,2,5-oxadia=zol-3-amine into a compound of Formula (ll), and thereafter optionally preparing a pharmaceutically acceptable salt, hydrate, solvate or prco-drug thereof.

58. A process for preparing a compound of Formula (ll), and/or pharmaceuti«cally acceptable salts, hydrates, solvates and pro-drugs- thereof, which comprises converting 2-(4-Amino-1,2,5-oxadiazol-3-yl)-1-methyl-4-p henyl-1H- imidazo[4,5- «Clpyridine-7-carboxylic acid into a compound of Formula (il), and thereafter optionally preparing a pharmaceutically acceptable salt, h=ydrate, solvate or pro-drug thereof.

59. Use of 4-[1-Ethyl-7-(piperidin-4-yloxy)-1H-imicdazo[4,5- clpyridin-2-yl ]-furazan-3-ylamine and/or a pharmaceutically acceptalole salt, hydrate, solvate or preo-drug thereof in the manufacture of a medicament for tireating or lessening the severity of a disease or condition selected from cancew and arthritis.

60. A compound of Formula I, as described in clam 1 and/or a pharmaceutically acceptable salt, hydrate, solvate or pro-drug thereof for use in treating or le=ssening the severity of a disease or condition selected f rom cancer and arthritis in a rnammal. Lod AMENDED Si

61. The compound of claim 60 wherein the mammal is a human.

62. A compound of Formula Il, as described in claim 3 and/or a pharmaceutically acceptable salt, hydrate, solvate or pero-drug thereof for use in treating or lessening the severity of a disease or condition selected from cancer and arthritis in a mammal.

63. The compound of claim 62 wherein the mammal is a human.

64. The compound according to clam 60 wherein said cancer is selected from brain (gliomas), glioblastomas, Bannaya_n-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma and thyroid.

65. The compound according to claf m 62 wherein said cancer is selected from brain (gliomas), glioblastomas, Bannaya n-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma and thyroid.

66. A compound of Formula |, as de scribed in claim 1 and/or a pharmaceutically acceptable salt, hydrate, solvate or p ro-drug thereof for use in inhibiting Akt activity in a mammal.

67. The compound of claim 66 wher ein the mammal is a human.

68. A pharmaceutical combination ceomprising a) a compound of Formula (1), as d escribed in claim 1 and/or a pharmacedtically acceptable salt, hydrate, solvate or p ro-drug thereof; and b) at least one anti-neoplastic agert for use in treating cancer.

69. The combination of claim 68, whaerein the at least one anti- neoplastic agent is selected from the group consisting essentially of anti-microtubule agents, platinum coordination complexes, alkylating aggents, antibiotic agents, topoisomerase Hl , antimetabolites, topoisomerase | inhibitors, hormones and LAINIE SLT hormonal analogues, signal transsduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; irmmunotherapeutic agents; proapoptotic agents; and cell cycle signaling inhibitors.

70. The combination of claim 68, wherein the at least one anti- neoplastic agent is an anti-micro®ubule agent selected from diterpenoids and vinca alkaloids.

71. The combination of claim 68, wherein the at least one anti- neoplastic agent is a diterpenoid

72. The combination of claim 68, wherein the at least one anti- neoplastic agent is a vinca alkalosid.

73. The combi nation of claim 68, wherein the at least one anti- neoplastic agent is a platinum co ordination complex.

74. The combi nation of claim 68, wherein the at least one anti- neoplastic agent is paclitaxel, carboplatin, or vinorelbine.

75. The combi nation of claim 68, wherein the at least one anti- neoplastic agent is paclitaxel.

76. The combi nation of claim 68, wherein the at least one anti- neoplastic agent is carboplatin.

77. The combi nation of claim 68, wherein the at least one anti- neoplastic agent is vinorelbine.

78. The combi nation of claim 68, wherein the at least one anti- neoplastic agent is a signal transaduction pathway inhibitor.

79. The combi nation of claim 78, wherein the signal transduction pathway inhibitor is an inhibitor off a growth factor receptor kinase selected from the group consisting of VEGFR2, TIEE2, PDGFR, BTK, IGFR-1, TrkA, TrkB, TrkC, and c-

fms. AVTINDED SHE

80. The combination of claim 78, wherein tlhe signal transduction pathway inhibitor is an inhibitor of a serine/threonine kinase seelected from the group consisting of rafk, akt and PKC-zeta.

81. The combination of claim 78, wherein the signal transduction pathway inhibitor is an inhibitor of a serine/threonine kinase selected from the src family of kinases.

82. The combination of claim 81, wherein tke signal transduction pathway inhibitor is an inhibitor of c-src.

83. The combination of claim 78, wherein tie signal transduction pathway inhibitor is an inhibitor of Ras oncogene selected frorm inhibitors of farnesyl transfera se and geranylgerany! transferase.

84. The combination of claim 78, wherein tine signal transduction pathway inhibitor is an inhibitor of serine/theonine kinase selected from the group consisting of PI3K.

85. The combination of claim 68, wherein the at least one anti- neoplastic agent is a cell cycle signaling inhibitor.

86. The combination of claim 85, wherein the cell cycle signaling inhibitor is selected from inhibitors of the group CDK2, CDK4, and CDK®6.

87. Use of 4-[1-Ethyl-7-(piperidin-4-yloxy)-1 H-imidazo[4,5- cJpyridin- 2-yl}-furazan-3-ylamine and/or a pharmaceutically acceptable salt, hydrate, solvate or pro-drug thereof in the manufacture of a medicamert for treating or lessening the severity of a disease or condition selected from ccancer and arthritis.

88. A compound of any one of claim 1, 60, 6&2 and 66, substantially as herein described and exemplified.

89. A pharmaceutically acceptable salt, hydrate, solvate or pro- drug of amy one of claims 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24, substantially as herein described and exemplified. 23 CLONED 8

90. Use of any of claims 27, 229, 33, 35, 59 and 87, substantially as herein described and exemplified.

91. A process of any one of claims 26, 56, 57 and 58, substantially as herein described and exemplifiead.

92. A pharmaceutical composition of claim 25, substantially as herein described and exemplified.

93. A pharmaceutical combination of claim 68, substantially as herein described and exemplified. BP SOTNIED SH