ZA200700315B - Pyrrolo-pyridine kinase modulators - Google Patents

Description

PYRROLO-PYRIDINE KINASE MODULATORS

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims the benefit of US. Provisional Patent Applicatio=n No. 60/591,8883, filed July 27, 2004, U.S. Provisional Patent Application No. 60/591,887, filed

July 27, 20804, and U.S. Provisional Patent Application No. 60/683,510, filed Mays 19, 2005, each of whmich is incorporated herein by reference in its entirety for all purposes.

BACKGROUND OF THE INVENTION

[0002] Mammalian protein kinases are important regulators of cellular functiorns. Because dysfunctio -ns in protein kinase activity have been associated with several diseasess and disorders, —protein kinases are targets for drug development.

[0003] The tyrosine kinase receptor, FMS-like tyrosine kinase 3 (FLT3), is implicated in cancers, ircluding leukemia, such as acute myeloid leukemia (AML), acute lympmhoblastic leukemia (ALL), and myelodysplasia. About ome-quarter to one-third of AML p-atients have

FLT3 mutations that lead to constitutive activation of the kinase and downstreanm signaling pathways. Although in normal humans, FLT3 is expressed mainly by normal myeloid and lymphoid progenitor cells, FLT3 is expressed ir the leukemic cells of 70-80% ofS patients with AMI_ and ALL. Inhibitors that target FLT 3 have been reported to be toxic sto leukemic cells expreessing mutated and/or constitutively-active FLT3. Thus, there is a neecd to develop potent FL=T3 inhibitors that may be used to treat diseases and disorders such as leukemia.

[0004] ~The Abelson non-receptor tyrosine kinase (c-Abli) is involved in signal transduction, via phosphorylation of its substrate proteins. Ir the cell, c-Abl shuttles between “the cytoplasnm and nucleus, and its activity is norm ally tightly regulated through a m_imber of diverse m_echanisms. Abl has been implicated in the control of growth-factor an_d integrin signaling. cell cycle, cell differentiation and neurogenesis, apoptosis, cell adhesion, cytoskeletal structure, and response to DNA damage and oxidative stress.

[0005] ~The c-Abl protein contains approximately 1150 amino-acid residues, o-rganized into a N-termi_nal cap region, an SH3 and an SH2 domain, a tyrosine kinase domain, anuclear localizatieon sequence, a DNA-binding domain, and an actin-binding domain. [0006) Chronic myelogenous leukemia (CML) is associated with the Philadelgphia chromosomal translocation, between chromosomes 9 and 22. This translocatior generates an aberrant ¥usion between the ber gene and the gene encoding c-Abl. The resultarat Ber-Abl fusion preotein has constitutively active tyrosine-kinase activity. The elevated ki. nase activity is reported to be the primary causative factor of CML, and is responsible for ce=lular transformatiosn, loss of growth-factor dependence, and cell proliferation.

[0007] The= 2-phenylaminopyrimidine compoun d imatinib (also referred to ass STI-571,

CGP 57148, «or Gleevec) has been identified as a sspecific and potent inhibitor o-fBcr-Abl, as well as two omther tyrosine kinases, c-kit and plateKet-derived growth factor receptor. Imatinib blocks the tymosine-kinase activity of these proteirs. Imatinib has been reportecd to be an effective therapeutic agent for the treatment of all stages of CML. However, thme majority of patients with advanced-stage or blast crisis CML suffer a relapse despite contirmued imatinib therapy, due to the development of resistance to the drug. Frequently, the molecular basis for this resistance is the emergence of imatinib-resistaant variants of the kinase doomain of Ber-

Abl. The most commonly observed underlying azxmino-acid substitutions include Glu255Lys,

Thr3151le, T yr293Phe, and Met351Thr.

[0008] MET was first identified as a transforming DNA rearrangement (TPR_-MET) in a human osteo=sarcoma cell line that had been treatesd with N-methyl-N'-nitro-nitr—osoguanidine (Cooper et al_. 1984). The MET receptor tyrosine kinase (also known as hepatocyte growth factor recepteor, HGFR, MET or c-Met) and its ligand hepatocyte growth factor— ("HGF") have numerous biological activities including the stimulation of proliferation, surviv-al, differentiatiosn and morphogenesis, branching tub-ulogenesis, cell motility and i nvasive growth. Patlologically, MET has been implicated in the growth, invasion and metastasis of many differe nt forms of cancer including kidney «<ancer, lung cancer, ovarian c=ancer, liver cancer and bareast cancer. Somatic, activating mutations in MET have been fou nd in human carcinoma m_etastases and in sporadic cancers such as papillary renal cell carcimioma. The evidence is g=rowing that MET is one of the long-sought oncogenes controlling progression to metastasis ard therefore a very interesting target. In addition to cancer there is evidence that

MET inhibit®on may have value in the treatment Of various indications includirag: Listeria invasion, Os®eolysis associated with multiple myeloma, Malaria infection, diabwetic retinopathies._, psoriasis, and arthritis. :

[0009] The tyrosine kinase RON is the receptor= for the macrophage stimulating protein and belongs to th_e MET family of receptor tyrosine kinases. Like MET, RON is inmplicated in growth, invassion and metastasis of several different forms of cancer including ggastric cancer and bladder cancer.

[0010] The Aurora family of serine/theronine kinases is essentiaml for mitotic progressiorm.

Express®on and activity of the Arurora kinases are tightly regulatead during the cell cycle. _A variety Of proteins having roles in cell division have been identified as Aurora kinase substratess. Based on the known function of the Aurora kinases, imnmhibition of their activity~ is believed to disrupt the cell cycle and block proliferation and there—fore tumor cell viability —

Harringston et al., Nature Medicine, advanced publication online (22004).

[0011] 3-Phosphoinositide-dependent kinase 1 (PDK1) is a Ser/” Thr protein kinase that can phosphorylate and activate a number of kinases in the AGC kinasee super family, including

Akt/PKIB, protein kinase C (PKC), PE C-related kinases (PRK 1 ard PRK2), p70 ribobsonrmal

S6-kinasse (S6K1), and serum and glucocorticoid-regulated kinase= (SGK). The first identified

PDK 1 substrate is the proto-oncogene Akt. Numerous studies hawwe found a high level of activate-d Akt in a large percentage (30-60%) of common tumor ty./pes, including melanoma and breast, lung, gastric, prostate, hematological and ovarian canc=ers. The PDK1/Akt signalin_g pathway thus represents an attractive target for the deve_lopment of small molecule inhibito—xs that may be useful in the treatment of cancer. Feldman et al., JBC Papers in Press.

Publishezd on March 16, 2005 as Manuscript M501367200.

[0012] Because kinases have been implicated in numerous dise=ases and conditions, sucka as cancer, —there is a need to develop news and potent protein kinase modulators that can be used for treatment. The present invention Fulfills these and other needss in the art. Although certain porotein kinases are specifically named herein, the present ®nvention is not limited to modulators of these kinases, and, includes, within its scope, modumlators of related protein kinases,. and modulators of homologous proteins.

BRIEF SUMMARY OF THE INVENTI-ON

[0013] It has been discovered that, surprisingly, pyrrolo-pyridinme compounds of the pressent inventicon may be used to modulate kimase activity and to treat dis eases mediated by kinas e activity These novel pyrrolo-pyridine kinase modulators are described in detail below. In additiorn, inhibitory activities of selected compounds are disclosed herein. "[0014] In one aspect, the present inwention provides a pyrrolo-peyridine kinase modulatomr (also referred to herein as a "compourad of the present invention") having the formula:

V0 2006/015123 PC T/US2005/026792

Ny —NH () ®

[0015] In Formula (I), L' and L? are independently a bond, -S(O)x-, -O-, -NH-, substituted or wunsubstituted C;-Cs alkylene, or substituted or unsubstituted 2 to 5 membered het eroalkylene. The symbol n represents an integer from 0 to 2. [0OM16] A! and A? are independently substituted or unsubstituted cycloall<yl, substituted or unssubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unssubstituted heteroaryl.

[0017] In another aspect, the present iravention provides methods of moculating protein kirase activity using the pyrrolo-pyridine kinase modulators of the present= invention. The method includes contacting said kinase with a pyrrolo-pyridine kinase moaedulator of the present invention.

[0018] In another aspect, the present iravention provides methods of treating a disease mediated by kinase activity (kinase-med iated disease or disorder) in a subJject (e.g. mammals, suech as humans) in need of such treatment. The method includes administering to the subject an effective amount of a pyrrolo-pyridin e kinase modulator of the present invention.

[06019] In another aspect, the present invention provides a pharmaceutic=al composition including a pyrrolo-pyridine kinase modulator in admixture with a pharmaceutically aceceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS

Fisgure 1 shows the wild-type ABL numbering according to ABL exon Ia.

DETAILED DESCRIPTION OF THE INVENTION Definitions

[02020] Abbreviations used herein hav € their conventional meaning withmin the chemical and biwlogical arts. [0 021] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identicaTl substituents that would result from writing the structure from right to left, e.g., -CH,0- is equivalent to -OCH;-.

[O022] The term "alkyl," bey itself or as part of another substituent, means, unlesss otherwise stated, a straight (i.e. unbran_ched) or branched chain, or cyc=lic hydrocarbon radi-cal, or combination thereof, which may be fully saturated, mono- or polyunsaturated amd can include d i- and multivalent radicals, having the number of carbon atoms designated (i.e. Ci-Cio means one to ten carbons). Examples of saturated hydrocarbon radicals include, but are not 11 mited to, groups such as m_ethyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec- butyl, cyclohexyl, (cyclohexzylymethyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alky_1 group is one

Im aving one or more double bonds or triple bonds. Exampless of unsaturated alky~1 groups imclude, but are not limited fo, vinyl, 2-propenyl, crotyl, 2-i sopentenyl, 2-(butad ienyl), 2,4- prentadienyl, 3-(1,4-pentadie=nyl), ethynyl, 1- and 3-propyny~1, 3-butynyl, and the= higher

Imomologs and isomers. Alk=yl groups which are limited to Eaydrocarbon groups =are termed '* homoalkyl". [ 0023] The term "alkylene" by itself or as part of another substituent means a divalent radical derived from an alky~], as exemplified, but not limiteed, by -CH,CH;CH,=CH-, - CH,CH=CHCHj,-, —CH,;C=CCH;-, -CH,CH,CH(CH,CH,«CH;)CH,-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferre=d in the present invention. A "Mower alkyl" or "loweer alkylene" is aa shorter chain alkyl or alky~lene group, generally having ei_ght or fewer carbon aatoms. [ 0024] The term "heteroallkyl," by itself or in combinatiomn with another term, means, unless otherwise stated, a stable straight or branched chain, or cyc lic hydrocarbon radiecal, or combinations thereof, consi sting of at least one carbon atorms and at least one hesteroatom selected from the group con_sisting of O, N, P, Si and S, ancl wherein the nitroge=n, phosphorus, and sulfur ators may optionally be oxidized and the nitrogen heter—oatom may

Optionally be quaternized. The heteroatom(s) O, N, P and SS and Si may be plac=ed at any interior position of the heter-oalkyl group or at the position zat which alkyl group is attached to tthe remainder of the molecumle. Examples include, but are rot limited to, -CH,-&CH,-O-CHs, — CH,-CH,;-NH-CH3, -CH,-CH,-N(CH3)-CHj, -CH,-S-CH,>—CHj, -CH,-CHa,-S(@0)-CHs, - CH,-CH;-S(0),-CHj, -CH==CH-0-CHj, -Si(CHa)3, -CH,-C_H=N-OCHj3, -CH=«~CH-N(CH3)-

CH;, O-CHs, -O-CH,-CHj;, and —CN. Up to two or three hesteroatoms may be ceonsecutive, such as, for example, -CH,-_NH-OCHj; and —-CH,-O-Si(CH=);. Similarly, the te—m reheteroalkylene" by itself om as part of another substituent rmeans a divalent radi_cal derived rom heteroalkyl, as exemplified, but not limited by, -CH,-=CH,-S-CH,-CH,- an_d ~CH;-S-

CH,-CH=-NH-CH,-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxo, alkyleredioxo, alkyleneamino, alkyl _enediamino, and the like). Still further, for alkylene and hetero alkylene linking groups, no omrientation of the linking g-roup is implied by the direction in which the formula of the linking group is written.

For example, the formula -C(O)OR'- represemuts both ~C(O)OR'- and -R'OCZ(0)-. As described above, heteroalkyl groups, as used herein, include those groups tknat are attached to the rema-inder of the molecule through a heter oatom, such as -C(O)R', -C(O®)NR, -NRR, -

OR’, -SR=’, and/or -SO;R'. Where "heteroalkyl" is recited, followed by recitations of specific heteroall<yl groups, such as -NR'R’ or the like , it will be understood that the= terms heteroalkyl and -NR_'R" are not redundant or mutually exclusive. Rather, the specific heeteroalkyl groups are recite=d to add clarity. Thus, the term "heteroalkyl" should not be interp—reted herein as excluding specific heteroalkyl groups, such ass -NRR" or the like.

[0025] The terms "cycloalkyl" and "heterocycloalkyl”, by themselves or Sin combination with oth er terms, represent, unless otherwise stated, cyclic versions of "alk=y1" and "heteroalkyl", respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalk—yl include, but are not limited to, cyc lopentyl, cyclohexyl, 1-cyclolexenyl, 3- cyclohex<enyl, cycloheptyl, and the like. Exaxmples of heterocycloalkyl include, but are not limited to, 1 —(1,2,5,6-tetrahydropyridyl), 1-priperidinyl, 2-piperidinyl, 3-pi—peridinyl, 4- morphoMinyl, 3-morpholinyl, tetrahydrofuran—2-yl, tetrahydrofuran-3-yl, tetorahydrothien-2-yl, tetrahyd-rothien-3-yl, 1 —piperazinyl, 2-pipera zinyl, and the like. The termss "cycloalkylene" and "het=erocycloalkylene" refer to the divalerat derivatives of cycloalkyl an _d heterocy~cloalkyl, respectively.

[0026] The terms "halo" or "halogen," by themselves or as part of anothe=r substituent, mean, umnless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms sumch as "haloalkyl," are meant to inclucle monohaloalkyl and polyhalloalkyl. For examples, the term "halo(C;-Cq)alkyl" is mear to include, but not be limitec3 to, trifluorosmethyl, 2,2,2-triflucroethyl, 4-chlorosbutyl, 3-bromopropyl, and thes like.

[0027] The term "aryl" means, unless otherwise stated, a polyunsaturatecd, aromatic, hydrocazrbon substituent which can be a singl. e ring or multiple rings (prefe-rably from 1 to 3 rings) which are fused together or linked covalently. The term "heteroaryl*™ refers to aryl groups (Cor rings) that contain from one to four heteroatoms (in each separa~te ring in the case of multipole rings) selected from N, O, ancl S, wherein the nitrogen an sulfur atoms are optional ly oxidized, and the nitrogen atorm(s) are optionally quaternizeed. A heteroaryl group can be amtached to the remainder of the molecule through a carbon or “heteroatom. Non- limiting examples of aryl and heteroaryl groups include phenyl, 1-nap>hthyl, 2-naphthyl, 4- biphenyR, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrol=yl, 3-pyrazolyl, 2-imidazolyl , 4-imidazolyl, pyraziny~l, 2-oxazolyl, 4-oxazolyl, 2-phermyl-4-oxazolyl, 5-oxazolyl, 3 -isoxazolyl, 4- isoxazol_yl, 5-isoxazolyl, 2-thiazolyl, 4-th_iazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3- thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2 -pyrimidyl, 4-pyrimidyl, 5-bmenzothiazolyl, purinyl, 2-benzirmidazolyl, 5-indolyl, 1-isoquinolsyl, 5-isoquinolyl, 2-quinoxal=inyl, 5-quinoxalinyl, 3- quinolyl, and 6-quinolyl. Substituents fo-r each of above noted aryl ard heteroaryl ring systems are selected from the group of acceptable substituents described below. The terms “arylene=" and "heteroarylene” refer to thes divalent radicals of aryl ani heteroaryl, respecti—vely.

[0028] For brevity, the term "aryl" whesn used in combination with other terms (e.g., aryloxo_, arylthioxo, arylalkyl) includes both aryl and heteroaryl rings as defined above.

Thus, the term "arylalkyl" is meant to include those radicals in whichm an aryl group is attachecd to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl anc the like) including those al kyl groups in which a carbon ato-m (e.g., a methylene group) —has been replaced by, for examples, an oxygen atom (e.g., phenoxy methyl, 2-pyridyloxymethyl , 3-(1- naphthy~loxy)propyl, and the like). However, the term "haloaryl," as used herein is meant to cover omly aryls substituted with one or amore halogens.

[0029] Where a heteroalkyl, heterocyc loalkyl, or heteroaryl includess a specific number of members (e.g. "3 to 7 membered"), the tesrm "member" referrers to a carbon or heteroatom.

[0030] The term "oxo" as used herein mmeans an oxygen that is dou ble bonded to a carbon atom.

[0031] Each of above terms (e.g., "alkyl," "heteroalkyl," "cycloalkyl, and "heteroacycloalkyl”, "aryl," "heteroaryl" as well as their divalent radical derivatives) are meamt to inclu_de both substituted and unsubstituted forms of the indicated radical. Preferred substitiments for each type of radical are provided below.

[0032] Substituents for alkyl, heteroallkyl, cycloalkyl, heterocycloamlkyl monovalent and divalen-t derivative radicals (including thmose groups often referred to as alkylene, alkenyl, heteroa lkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can “be one or more of a variety of groups selected from, but not Mimited to: -OR', =O, =NR', =N-«OR’, -NR'R", -SR’, -halogen, -SiRR2'"R", -OC(O)R’, -C(O)R’ , -CO;R',-C(O)NR'R", -O C(O)NR'R", -NR"C(O)R', -NR'-C(CO)NR"R™, -NR"C(O)OR' , -NR-C(NR'R")=NR", -S(O)R/, -S(O):R’, -S(0):NRR", -NRRSO;R', -CN and -NO; in_ a number ranging from zero to (2m'+1), where m' is the total snumber of carbon atoms i_n such radical. R', R", R™ and IR" each preferably independently refer to hydrogen, substit_ited or unsubstituted heteroalky~], substituted or unsubstituted cyclosalkyl, substituted or unsumbstituted heterocycloalkyl, substit-uted or unsubstituted aryl (e.g., ary substituted with 1-3 halogens), substituted or unsubstitumted alkyl, alkoxy or thioalkoxy growips, or arylalkyl groups. “When a compound of the invention includes more than one R group , for example, each of the=R groups is independently selected as are each R', R", R" and R"" groups when more tEnan one of these groups is preserat. When R' and R" are attached to —the same nitrogen atom, they can be combined with the ni trogen atom to form a 4-, 5-, 6-, or “7-membered ring. For ex_ample, -NR'R" is meant to incliade, but not be limited to, 1-pyrroliclinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art vill understand that the tezxm "alkyl" is meant to inclumde groups including carbon atoms Hound to groups other tha—n hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH>CE~3) and acyl (e.g., -C(O)C_H;, -C(0)CF3, -C(O)CH,OCCHs, and the like).

[0033] Similar to the substituents described for alkyl radi cals above, exemplary su” bstituents for ary] and heteroaryl groups ( as well as their divalent derivatives) are varied and a-re selected from, for example: halogen, -OR', -NR'R", -SR', -Iaalogen, -SiRR"R", -OCCO)R, -

C(O)R!, -CO2R!, -C(O)INR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"™, -NR"C(O)OR', -NR-C(INR'R"R")=NR"", -NR-C(NR'R")=I=R", -S(O)R, -S(O)R, -S(0);NR'R", -NRSO,R, -CN and -NO;, -R', -N3, -CH(Ph),, fluoro(C;-Cs)alkoxo, and + fluoro(C;-Ca)alkyl, in a number ranging from zero to the to-tal number of open valeneces on aromatic ring system; axad where R', R", R" and R"" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substitut-ed or unsubstituted heteroalkyl, substituted or unsubstitiated cycloalkyl, substituted or unsulostituted heterocycloalkyl , substituted or unsubstittated aryl and substituted or unsubsti tuted heteroaryl. When am compound of the invent-ion includes more than one R group, for example, each of thee R. groups is independently~ selected as are each R', R", R™ andl R"" groups when more t_ han one of these groups is presemat.

[0034] Two of the substituents on adjacent ators of aryl or heteroaryl ring may optionally form a ring of thee formula -T-C(O)-(CRR"),-U-, wherein T and U are indeperadently -NR-, -

O-, -CRR'- or a ssingle bond, and q is an integer off from 0 to 3. Alternatively. two of the substituents on adjacent atoms of aryl or heteroar=yl ring may optionally be replaced with a substituent of thes formula -A-(CH;),-B-, wherein A and B are independently —CRR'-, -O-, -

NR-, -S-, -S(0)- , -S(0);-, -S(0):NR'- or a single bond, and r is an integer of #rom 1 to 4. One of the single borwds of the new ring so formed ma=y optionally be replaced with a double bond.

Alternatively, two of the substituents on adjacent atoms of aryl or heteroaryl -Tmg may optionally be replaced with a substituent of the fosrmula -(CRR")-X"-(C"R"")a—, where s and d are independent] y integers of from 0 to 3, and X' is —O-, -NR-, -S-, -S(0)-, -S(0O)-, or -

S(0);NR'-. The substituents R, R', R" and R" are= preferably independently selected from hydrogen, substi tuted or unsubstituted alkyl, subs=tituted or unsubstituted cycloalkyl, substituted or urmsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or urmsubstituted heteroaryl.

[0035] As used herein, the term "heteroatom" owr "ring heteroatom" is mearat to include oxygen (O), nitreogen (N), sulfur (8), phosphorus (P), and silicon (Si).

[0036] An "aminoalkyl" as used herein refers tc an amino group covalently bound to an alkylene linker. The amino group is -NR'R", whesrein R' and R" are typically selected from hydrogen, substi tuted or unsubstituted alkyl, subsstituted or unsubstituted heteroalkyl, substituted or urmsubstituted cycloalkyl, substitute=d or unsubstituted heterocyecloalkyl, substituted or urmsubstituted aryl, or substituted or— unsubstituted heteroaryl.

[0037] A "sub stituent group," as used herein, means a group selected from the following moieties:

[0038] (A) -COH, -NH,, -SH, -CN, -CF3, -NO- _, 0x0, halogen, unsubstitute-d alkyl, unsubstituted heteroalkyl, unsubst—ituted cycloalkyl, unsubstittated h eterocycloalkyl, unsubstituted ar=yl, unsubstituted heteroaryl, and

[0039] (B) aJkyl, heteroalkyl, cycloalkyl, hetesrocycloalkyl, aryl, and hetesroaryl, substituted with at least one substi tuent selected from:

[0040] 9) oxo, -OH, -NH,, -SH, -CN, -CF3, -NO,, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, wmsubstituted cycloalkyl, urmsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and

[0041] (il) alkyl, heteroalkyl, cycloalkyl, heterocycloal kyl, aryl, and heteroaaryl, substituted with at least one substituent selescted from:

[0042] (a) oxo, —OH, -NH,, -SH, -CN, -CF3, -NFO;, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unswmubstituted cycloalkyl , unsubstituted heterocycloalkyl, unsumbstituted aryl, - unsubstituted heteroaryl, and

[0043] (b) alkyl, heteroalkyl, cycloalkyl, heteromcycloalkyl, aryl, or heteroaryl, substituted with at least one substituent select ed from oxo, -OH, -NH,, -SH, -CN, -CZF,, -NO,, halogen, unsubstituted alkyl, unsubstituted hesteroalkyl, unsubstitu ted cycloalkyl, unsubstituted heterocycleoalkyl, unsubstituted aryl, and unsubstituted heteroaryl.

[0044] A "size-limited substituent" or " size-limited substituent mgroup,” as used herein means a group selected from all of the substituents described abov—e for a "substituent g_roup,” wherein each substituted or unsubstituted alkyl is a substituted or vansubstituted C,-C,p alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unssubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalky~1 is a substituted or unsubstituted C4-Cs cycloalkyl, and each substituted or unsubstituted heterocycloalkyl dsa substituted or unsubstituted 4 to 8 membered heterocycloalkyl.

[0045] A "lower substituent” or *' lower substituent group,” as u_sed herein means a gzroup selected from all of the substituents described above for a "substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted CC;-Cjg alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubsti_tuted 2 to 8 membered “heteroalkyl, each substituted or unsubstituted cycloalkyl is a substi tuted or unsubstitute d Cs- <C; cycloalkyl, and each substituted or unsubstituted heterocycloallsyl is a substituted or- —unsubstituted 5 to 7 membered heterocycloalkyl.

J0046] The compounds of the present invention may exist as salt=s. The present invermtion ancludes such salts. Examples of applicable salt forms include hyd_rochlorides,

Thydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumar ates, ®artrates (eg (+)-tartrates, (-)-tartrates or mixtures thereof includingz racemic mixtures, ssuccinates, benzoates and salts with. amino acids such as glutamic &acid. These salts ma=y be porepared by methods known to those skilled in art. Also included zare base addition salt-s such as sod jum, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. \Vhen compounds of the present invention contain relatively basic “functionalities, acid addition salts can be obtained by contacting the neutral form of such cormpounds with a sufficient amount of the desired acid, either neat or in a suitable inert soLvent. Examples of accepiable acid addition salts include those derived from inorganic acids like hydrochloric, hydro®bromic, nitric, carbonic, monoh ydrogencarbonic, phosphoric, monohhydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydro sensulfuric, hydricdic, or phosphorous acids and the like, as well as the salts derived. organic acids like acetic , propionic, isobutyric, maleic, xnalonic, benzoic, succinic, suberic, fumaric, lactic, mandeelic, phthalic, benzenesulfonic, y-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. _Also included are salts of amino acids such as arginate and the likes, and salts of organic acids like glucuronic or galactunoric acids and the like. Certain specific compounds of the presemnt invention contain both basic and acidic functionalities that allow the compounds to be convesrted into either base or acid addition salts.

[0047] The neutral forms of the cormpounds are preferably regeneratesd by contacting the salt w==ith a base or acid and isolating the parent compound in the converational manner. The paren_t form of the compound differs from the various salt forms in certain physical prope=tties, such as solubility in polar solvents.

[00488] Certain compounds of the present invention can exist in unsol-vated forms as well as solvated forms, including hydrated forms. In general, the solvated formas are equivalent to unsol vated forms and are encompassed within the scope of the present nvention. Certain compeounds of the present invention ray exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and axe intended to be within the scope of the present invention.

[004] Certain compounds of the present invention possess asymmetwric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautommers, geometric isomers, stereoisometric forms that may be definesd, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encor=npassed within the scope of the present invention. The compounds of the present invermtion do not include those which. are known in art to be too unstabl « to synthesize and/or isolatze. The present invention is meant to include compounds in racemic and optically pure formss. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or c=hiral reagents, or resolved using conventional techniques. "When the compounds described herrein contain olefinic bonds or «other centers of geometric asymmetry, and unless specified oth erwise, it is intended that the compounds include both E an_d Z geometric isomers.

[0050] The term "tautomer," as used herein, refers to one of two or meore structural isomers which exist Ln equilibrium and which are readily converted from one isomeric form to another.

[0051] It will be apparent to one skilled iin the art that certain compounds of this invention may exist in tautomeric forms, all such taumtomeric forms of the compoumnds being within the scope of the invention.

[0052] Un less otherwise stated, structures depicted herein are also meant to include all stereochemiccal forms of the structure; i.e., the R and S configurations foor each asymmetric center. Theresfore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of she present compounds are within the scope of the inventiom.

[0053] Un_less otherwise stated, structuress depicted herein are also meant to include compounds which differ only in the preserace of one or more isotopically enriched atoms. For example, commpounds having the present sg&ructures except for the replacement of a hydrogen by a deuterivm or tritium, or the replacement of a carbon by >C- or 4C-enriched carbon are within the scope of this invention.

[0054] Th-e compounds of the present in vention may also contain unraatural proportions of atomic isoto pes at one or more of atoms that constitute such compound s. For example, the compounds may be radiolabeled with radi «active isotopes, such as for example tritium CH), jodine-125 CPI) or carbon-14 (**C). Alli sotopic variations of the comgpounds of the present invention, w=hether radioactive or not, are «encompassed within the scop e of the present invention.

[0055] Th_eterm "pharmaceutically acceptable salts" is meant to inchuade salts of active compounds ~which are prepared with relati_vely nontoxic acids or bases, depending on the particular sumbstituent moieties found on thue compounds described herein. When compounds of the presertinvention contain relatively acidic functionalities, base acldition salts can be obtained by contacting the neutral form off such compounds with a suffJcient amount of the desired bases, either neat or in a suitable in_ert solvent. Examples of pharmaceutically acceptable base addition salts inc -lude sodium, potassium, calcium, ammonium, organic armino, or magnesium salt, or a si_mmilar salt. When compounds of tke present invention cOntain relatively basic functionalities, acid addition salts can be obtained by contacting thee neutral form of such compounds with a sufficient amount of the de sired acid, either neat or= in a suitable inert solvent. Example=s of pharmaceutically acceptable =acid addition salts incluade th_ose derived from inorganic acicls like hydrochloric, hydrobromic, nitric, carbonic, m_onohydrogencarbonic, phosphoric, monohydrogenphosphoric, di‘hydrogenphosphoric, stalfuric, monohydrogensulfuric, “hydriodic, or phosphorous acids amd the like, as well as thae samlts derived from relatively nont-oxic organic acids like acetic, propionic, isobutyric, maleic, me alonic, benzoic, succinic, suber—ic, fumaric, lactic, mandelic, phth alic, benzenesulfonic, p— tomlylsulfonic, citric, tartaric, metinanesulfonic, and the like. Also iracluded are salts of amirao acids such as arginate and the like, and salts of organic acids like g-lucuronic or galactunorimc acids and the like (see, for example, Berge er al., "Pharmaceutical Salts", Journal of

Pharmaceutical Science, 1977, 6-6, 1-19). Certain specific compouands of the present imavention contain both basic and acidic functionalities that allow tlae compounds to be converted into either base or acidll addition salts. [0®056] In addition to salt formss, the present invention provides ceompounds, which are in_ a prodrug form. Prodrugs of the compounds described herein are those compounds that readily urdergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the presemat in_vention by chemical or biochermical methods in an ex vivo enviroonment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed mn a traansdermal patch reservoir with a suitable enzyme or chemical rea gent. [0®057] The terms "a," "an," or ™'a(n)", when used in reference to a group of substituents he=rein, mean at least one. For ex ample, where a compound is substituted with "an" alkyl omr aryl, the compound is optionally substituted with at least one alkyl and/or at least one aryl.

Moreover, where a moiety is subsstituted with an R substituent, the group may be referred t o ass "R-substituted." Where a moieety is R-substituted, the moiety is substituted with at least ore R substituent and each R sub-stituent is optionally different. [0w058] Description of compourads of the present invention are limited by principles of chemical bonding known to those= skilled in the art. Accordingly, wvhere a group may be sux bstituted by one or more of a nwumber of substituents, such substi #utions are selected so ass to comply wi th principles of chemical bonding and to give compounds winich are not inherently umstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqu-eous, neutral, and several l<nown physiolo gical conditions. For example, a heterocycloalkyl or- heteroaryl is attached to tine remainder of the molecule via. a ring heteroatom in compliance vavith principles of chemical bonding known to those skilled in the art thereby avoiding inherertly unstable compounds.

[0059] The terms "treating" or "treatment" in_ reference to a particular disease includes prevention ofthe disease.

[0060] The symbol ~~ denotes the point of emttachment of a moiety to tlhe remainder of the molecule.

Pyrrolo-Pyr-idine Kinase Modulators

[0061] In One aspect, the present invention pwrovides a pyrrolo-pyridine kinase modulator (also referred to herein as a "compound of the goresent invention") having the formula:

N_—NH

Of:

D-

[0062] In ¥ormula (I), L' and L? are independently a bond, -S(O),-, -O—, -NH-, substituted or unsubstittated C,-Cs alkylene, or substituted or unsubstituted 2 to 5 memmbered heteroalkyleme. The symbol n represents an integer from 0 to 2.

[0063] A' and A? are independently substituted or unsubstituted cycloalkyl, substituted or unsubstituted] heterocycloalkyl, substituted or vansubstituted aryl, or substmtuted or unsubstitutec heteroaryl.

[0064] In some embodiments, L! and L? are sndependently a bond, -S(O)-, -O-, -NH-, unsubstitutecl C;-Cs alkylene, or unsubstituted _2 to 5 membered heteroalk—ylene. In other embodiment s L! and/or I? is a bond.

[0065] A' and A? may independently be substituted or unsubstituted ar=yl, or substituted or unsubstitutec] heteroaryl. A! and A? may also independently be substitute=d or unsubstituted aryl, or 6-membered substituted or unsubstitute=d heteroaryl.

[0066] In some embodiments, A’ is a substituted or unsubstituted aryl (e.g. a 6-nmembered substituted or unsubstituted aryl such as phenyl) or 6-membe=red substituted or unsubstituted heteroaryl. A' may also be substituted phenyl or 6-membere=d substituted heteroaryl. In some embodiments, A! is substituted or unsubstituted pheny~1, substituted or unsub- stituted pyridinyl, substituted or unsubstituted pyrimidinyl, substituteed or unsubstituted benzodioxolyl, substituted or unsubstituted benzodioxanyl, substituted or unsubstistuted benzimidazolyl, or substituted or unsubstituted indolyl.

[0067] A’ may be a substituted aryl or substituted heteroaryl. In some embodimu ents, Ais a substituted phenyl, substituted thiopenyl, substituted pyrid—inyl, substituted pyrro_1yl, substituted triazolyl, substituted pyrimidinyl, substituted pyr—azinyl, or substituted ®midazolyl.

[0068] In some embodim ents, A' and A? are independentl—y selected from substistuted or unsubstituted phenyl, substituted or unsubstituted hydantoin yl, substituted or unsubstituted dioxolanyl, substituted or umsubstituted benzodioxolyl, substituted or unsubstituted dioxanyl, substituted or unsubstituted. trioxanyl, substituted or unsubst=ituted tetrahydrothien=s1, substituted or unsubstituted. tetrahydrofuranyl, substituted or— unsubstituted tetrahydrothiophenyl, substituted or unsubstituted tetrahydrcopyranyl, substituted o—r unsubstituted tetrahydrothiopyranyl, substituted or unsubstit-uted pyrrolidinyl, substituted or unsubstituted morpholino, substituted or unsubstituted piper-idinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted pyraz olyl, substituted or unssubstituted furanyl, substituted or unsubstituted imidazolyl, substituted =or unsubstituted isoxa=zoly], substituted or unsubstituted. oxadiazolyl, substituted or unsulbstituted oxazolyl, sub=stituted or unsubstituted pyridyl, substituted or unsubstituted pyrazyl, s ubstituted or unsubstit-uted pyrimidyl, substituted or urasubstituted pyridazinyl, substitut=ed or unsubstituted thmazolyl, substituted or unsubstituted isothioazolyl, substituted or unsmubstituted triazolyl, substituted or unsubstituted thienyl, substituted or unsubstituted triazinyl, ssubstituted or unsubsti tuted thiadiazolyl, or substituted ©r unsubstituted tetrazolyl.

[0069] In some embodiments, A! is substituted with at lea=st one R'* group, wher—ein each

R" group is optionally different. Each R'® may be independently selected from hamlogen, -OR’, -NR’R’, -C(Z)R®, -SCO)wR’, -CN, -NO,, -CF3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsulostituted cycloalkyl, stubstituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aaryl, or substituted or unsubstituted heteroaryl. Ira some embodiments, at least twos R'® groups are combi_ned to form a substituted or unsubsti tuted ring with the atoms to whic-h they are attached. As us-ed herein, the term "substituted or unsubstituted ring" refers to a s=ubstituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, subst-ituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl. In other embocliments, R'? is independen tly halogen (e.g. fluorine or chlorine), -NR°R’, OR’, or substituteca or unsubstituted alkyl.

[0070] In some embodiments, A? is substituted with at least mone R?’ group and/or one RR! group, wherein each R? group is optionally different. R' and esach R*° may be independently selected from halogen, -OR®, -NR’R’, -C(Z)R?, -S(0)wR’, -CNT, -NO,, -CF3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, sumbstituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, subst-ituted or unsubstituted ary-1, or substituted or unsubstituted heteroaryl. In some embodiments, at least two R% groups or— an :

R¥ and R! group are combined to form a substituted or unsubsstituted ring with the atomss to which they are attached. In some embodiments, R? is indepermdently halogen, -NR°R’, -<OR?, or substituted or unsubstituted alkyl.

[0071] Z represents Z is N(R™), S, or O, and w represents an: integer from Oto 2. R® iss hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstit=uted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstitutecd heteroaryl. In some embodiments, R? is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. R*> may also be hydrogen, or substi—tuted or unsubstituted C,-C; alkyl. In some embodiments, R? is hydro gen or unsubstituted C,-Cs alkyl.

[0072] R®is independently hydrogen, -CFj, substituted or unsubstituted alkyl, substitut=ed or unsubstituted heteroalkyl, substituted or unsubstituted cyclozalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary], or substituted or unsubstituted heteroaryl.

[0073] R®and R’ are independently hydrogen, -C(O)R'®, -S(CO),R"., substituted or ~~ unsubstituted alkyl, substituted or unsubstituted heteroalkyl, sulbstituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substi_tuted or unsubstituted aryl , or substituted or unsubstituted heteroaryl.

[0074] R'®and R" are independently hydrogen, -NR!2R'?, su_bstituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or un_substituted cycloalkyl,

substituted or unsub stituted heterocycloalkyl, substituated or unsubstituted aryl, or substituted or unsubstituted hetesroaryl.

[0075] R' and R! 3 are independently hydrogen, subostituted or unsubstituted alkyl, substituted or unsubmstituted heteroalkyl, substituted o-r unsubstituted cycloalkyl, substituted or unsubstituted heteroscycloalkyl, substituted or unsubstituted aryl, or substituted. or unsubstituted hetercmaryl.

[0076] R®is independently hydrogen, NRMR!, -OR!S, substituted or unsubzstituted alkyl, substituted or unsub>stituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterccycloalkyl, substituted or unsubs tituted aryl, or substituted or unsubstituted heteroaryl.

[0077] R'* R'S, and R'S are independently hydrogen, substituted or unsubsti_ tuted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalky=1, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substitute or unsubstituted heteroaryl.

[0078] In some erubodiments, R' and R” are independently substituted or Lansubstituted alkyl, substituted or unsubstituted heteroalkyl, or are combined with the nitrogmen to which they are attached to form substituted or unsubstituted piperidinyl, or substitute=d or unsubstituted piper=azinyl, substituted or unsubstituted pyrrolidinyl, or substittmted or unsubstituted morpholino. In some embodiments, R 14 and/or R' are substituted with a group having the formula -(CH2)-NR?'R*2. The symbol t represents an integer from 0 to 10. In some embodiments , t represents an integer from Oto 6. R?! and R* are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heter—oalkyl, substituted or unsulostituted cycloalkyl, substituted ox unsubstituted heterocycRoalkyl, substituted or unsubstituted aryl, or substituted or un substituted heteroaryl. Inm some embodiments, R?' ennd R? are optionally combined wvith the nitrogen to whicha they are attached to form a substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted 5-memmbered heteroaryl.

[0079] In some emmbodiments, R*!' and R? are com bined with the nitrogen tc which they are attached to form a ssubstituted or unsubstituted piperaazinyl. In other embodim ents, R*' and

R?# are independently hydrogen, substituted or unsubostituted alkyl, or substitu _ted or unsubstituted aminoalkyl.

[0080] R® is imdependently hydrogen, substituted or unsubstituted alkyl, subsstituted or unsubstituted heteroalkyl, substituted or unsubstitu-ted cycloalkyl, substituted oer unsubstituted heterocycloalkyll, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein if w is 2, then R® may optionally be -NR'"_R'%,

[0081] R! and R'® are independently hydrogen, substituted or unsubstituted alkyl, substituted or urasubstituted heteroalkyl, substitute or unsubstituted cycloalky 1, substituted or unsubstituted he=terocycloalkyl, substituted or unsubstituted aryl, or substituteds or unsubstituted he=teroaryl.

[0082] In som e embodiments, R® and R”, R'? anciR'?, R™ and R'®, and/or R™" and R'*® are, independently, -may be joined with the nitrogen to which they are attached to #orm substituted or urasubstituted heterocycloalkyl, or svabstituted or unsubstituted S—membered heteroaryl.

[0083] In somme embodiments, R', R%, RS, R7, R®_ R®, R™*, R', RZ, RP, RY, TR, RS, R”,

R"® RY R® RZ! R* and/or R2 are independently selected from hydrogen, su. bstituted or unsubstituted C—-Cyg alkyl, substituted or unsubstituted 2 to 20 membered hete=roalkyl, substituted or ursubstituted C;-Cg cycloalkyl, subsstituted or unsubstituted 3 to 8 membered heterocycloalky1, substituted or unsubstituted aryl, or substituted or unsubstitu_ted heteroaryl.

In other embodi ments, R, R®, RS, R7, R®, R?, R!?, R'!, R'2 R1® R™, R'* RS, m7, REE R",

R®, R?!, R® and/or R? are independently selected from hydrogen, substituted or unsubstituted C4 -Cyg alkyl, substituted or unsubstitcuted 2 to 20 membered hete=roalkyl, substituted or urasubstituted Cs-Cg cycloalkyl, subsstituted or unsubstituted 3 to 6 membered heterocycloalky~1, substituted or unsubstituted aryl, or substituted or unsubstitu_ted heteroaryl.

[0084] Wheres R), RS, RS, RR}, R%, RY, R!,, R®? RR" RY R'S R' R'-2RY R® RZ,

RZ and/or R? i=s a ring or are joined together to form a ring (e.g. cycloalkyl, heterocycloalky~1, aryl, or heteroaryl), the ring may~ be independently selected #rom substituted or unsubstituted phenyl, substituted or unsubstituted hydantoinyl, substituted cor unsubstituted dioxolanyl, substituted or unsubstituted benzodiox-olyl, substituted or unsubsti—tuted dioxanyl, substituted or urisubstituted trioxanyl, substituted cor unsubstituted tetrahydrotinienyl, substituted or urnsubstituted tetrahydrofuranyl, sub stituted or unsubstituted tetrahydrothiopkaenyl, substituted or unsubstituted —tetrahydropyranyl, substituteed or unsubstituted te-trahydrothiopyranyl, substituted or- unsubstituted pyrrolidinyl, substituted or unsubstituted m_orpholino, substituted or unsubstitwited piperidinyl, substituted or

WC) 2006/015123 PCT/US2005/026792 unsubstituted piperazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted furan=yl, substituted or unsubstituted imidazolyl, substituted or urasubstituted isoxazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstitwuted oxazolyl, substituted or unsubmstituted pyridyl, substituted or unsubstituted pyrazyl, subst ituted or unsubstituted pyrimmidyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted thiazolyl, substi tuted or unsubstituted isothioazolyl, substituted or unsubstmtuted triazolyl, substituted or unsubstituted thienyl, substituted or unsubstituted triazinyl, substituted or unsubstituted thiadi” azolyl, or substituted or unsubstituted tetrazolyl. One of skill will recognize that the normazal rules of valency apply. Therefore, where two groups are= joined together with a nitrogen to which they are attached to form a ring, the ring will t=ypically be a substituted ox unsubostituted heterocycloalkyl or S membered heteroaryl.

[00855] One of skill in the art will immediately recognize that t=he compounds of the present inven. tion may include more than one rR’, RS, rR, RE RS, RO, R!®, RZ, RY, RY, RY, RIS RY,

R'® R= R¥® Rr? R? and/or R® group. Where more than one R_5 RS R’ R® R’ R!® R!!,

RZ, RE RY RP, RY RY, R® RS, R%, R?, R® and/or R® group is present, each R’, R®, RR’,

RE, R_%, RI R!! RZ R13, RM, RIS, RIS, RY, R'E RY, R®, R%, R=2 and/or R® group is optiomnally different.

[008] In some embodiments, A is substituted with a halogens, -OR®, or unsubstituted C ;-

Cio alkyl. In some embodiments, A is substituted with at least aone OR’. In some related embosdiments, R is independently hydrogen, substituted or unsumbstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted hetercocycloalkyl, substituted or unsubstituted aryl, or substitute or unsubstituted heteroar=yl.

In other related embodiments, R® is hydrogen or unsubstituted C=1-Cy; alkyl (e.g. A' is subst tuted with -O-CH3).

[0087] In some embodiments, A? is substituted with at least orzie -C(Z)R® group. In some relate=d embodiments, Z is O and R3is -NR"“R!’. In some relatesd embodiments, R' and R_1° are inmdependently hydrogen, substituted or unsubstituted alkyl, ssubstituted or unsubstituted hetercoalkyl, or are joined together to form a substituted or unsubmstituted heterocycloalkyl or 5-memmbered heteroaryl (e.g. piperidinyl or piperazinyl). In som e embodiments, R'* and/ox

R'S amre substituted with a group having the formula -(CH)-NR='R*. The symbol t, R*! ard

R?* ame as described above.

[00888] In some embodiments, A." has the formula:

RR

ANE

9 (R™), a.

[0089] In Formula (I), x is an integer from 1 to 5.

[0090] As describesd above, each RY is independently halogen, -OR’, -NR°R’, -&C(Z)R, -S(O)wR’, -CN, -NO =, -CF3, substituted or unsubstitutesd alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, sutostituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or smubstituted or unsubstituted heteroaryl.

In some embodiments, two R' groups are optionally combined to form a substitufited or unsubstituted ring wath the carbons to which they are asttached. R® RS, R”, R® ana R® are as defined above in the discussion of Formula (I).

[0091] In some emabodiments, R'? is attached at positzion 1 and/or position 2. Am RY attached at position 1 may be combined with an R'® att. ached at position 2 to form a substituted or unsubstituted ring (fused to A!). In somes embodiments, an RY attached at position 2 is combined with an RY attached at position 3 to form a substituted or unsubstituted ring (fused to A'). Examples of rings for-med by the combination of two RY groups are discussed. above. In some embodiments, thes ring formed is a substituted or unsubstituted heteroccycloalkyl or substituted or unsubs- tituted heteroaryl.

[0092] In some embodiments, x is 1 and R" is attachmed at position 2. In other embodiments, x is 1 and R' is attached at position 1. ~Alternatively, x is an intege=r from 2 to and at least one R! ® is attached at position 1. In other- embodiments, x is an integzer from 2 to 5 and at least one R'? is attached at position 2.

[0093] Examples of R® RS and R’ groups are discussed above. In some embod iments, if

R'is -OR>, or -NRSR’, then R’, R%, and R’ are indeperadently hydrogen, substituted or unsubstituted alkyl, Or substituted or unsubstituted hete=roaryl. In other embodime=nts, R>, R®, and R” are hydrogen or substituted or unsubstituted C;—C;s alkyl. In other embodirments, R®,

RS, and R’ are hydro gen or unsubstituted C,-Cs alkyl.

[0094] In some emrxbodiments, A! has the formula:

A? : (2)

R! (I.

[0095] In Formula (II), X' is -C(R?)=, -CaRA)RY)-, -N=, -N(R*-, -S -,0r-O-. Thus, Ais substitutesd or unsubstituted cycloalkyl, substituted or unsubstituted het=erocycloalkyl, substitutesd or unsubstituted aryl, or substituted or unsubstituted substituted heteroaryl. In

Formula (III), where A” is unsubstituted, A! has no further substituentss other than R' (and : hydrogern). In Formula (IIT), where A? is substituted, A' is substituted with substituents in addition to R' (e.g. with one or more R? groups).

[0096] In some embodiments, A? is substi tuted or unsubstituted pheryl, substituted or unsubstituted thiopenyl, substituted or unsubstituted pyridinyl, substittated or unsubstituted pyrrolyl, substituted or unsubstituted triazol yl, substituted or unsubstituted pyrimidinyl, substitut ed or unsubstituted pyrazinyl, or substituted or unsubstituted i-midazolyl.

[0097] R'is halogen, -OR>, -NR°R’, -C(Z2)R8, -S(0)R®, -CN, -NO,_, -CF;, substituted or unsubstituted alkyl, substituted or unsubstitwited heteroalkyl, substitute=d or unsubstituted cycloalk yl, substituted or unsubstituted hetesrocycloalkyl, substituted o-r unsubstituted aryl, o—x substituted or unsubstituted heteroaryl.

[0098] RZ and R® are independently hydrogen, halogen, -OR’, -NRIR', -C(Z)R?, -S(0).R”™, -CN, -N«O,, -CF3, substituted or unsubstituted alkyl, substituted or uns—ubstituted heteroalkyl. substitut-ed or unsubstituted cycloalkyl, substituted or unsubstituted he=terocycloalkyl, substituted or unsubstituted aryl, or substitu ted or unsubstituted heterowaryl.

[0099] R*is hydrogen, -C(O)R®, -S(O),R *!, substituted or unsubstitiated alkyl, substituted or unsubsstituted heteroalkyl, substituted or winsubstituted cycloalkyl, smibstituted or unsubsti tuted heterocycloalkyl, substituted «or unsubstituted aryl, or substituted or unsubsti tuted heteroaryl.

[0100] R% RS, R’, R%, RR, Z, and w axe as described above in thee discussion of Formula (OD.

[0101] Thus, in some embodiments, the c-ompound of the present invention has the formula=

H oe

A? pv;

R! IV).

HPCT/US2005/026792

[0102] In Formu.la(IV), R, A? and X! are as described above in Form—ula (UI) and 12, L} and A' are as described in Formulae (I) and (I). Th us, in some embodinments, A! is a 6- membered substituted or unsubstituted aryl or 6-mermbered substituted or— unsubstituted heteroaryl.

[0103] In some e-mbodiments, A? has the formula: ( 7, 2

R1 W).

[0104] In Formul a (IV), yis an integer from 0 to 4 . R! is as described ambove in Formula (I). R* is as described above in the discussion of Formula (I).

[0105] As descritoed above, each R® is independermtly halogen, -OR®, -NJR°R’, -C(Z)R®, -S(O)WR®, -CN, -NO,, -CFj3, substituted or unsubstitum ted alkyl, substituted or unsubstituted heteroalkyl, substitizrted or unsubstituted cycloalkyl, ssubstituted or unsubst—ituted heterocycloalkyl, sumbstituted or unsubstituted aryl, or- substituted or unsub stituted heteroaryl.

In some embodimerats, two R?® groups are combined to form a substituted or unsubstituted ring with the carbon=s to which they are attached. In other embodiments, o-ne R* and R! are combined to form a substituted or unsubstituted ring =with the carbons to which they are attached.

[0106] Examples ©fR5, RS and R7 groups are discumssed above. In some embodiments, if

R? is -OR’® , Or -NR®R/, then R®, RS, and R” are indepe=ndently hydrogen, siabstituted or unsubstituted alkyl, cor substituted or unsubstituted he®eroaryl. In other emMbodiments, R®, RS, and R’ are hydrogen or substituted or unsubstituted C 2-Cs alkyl. In other embodiments, RS,

RS, and R are hydro_gen or unsubstituted C;-Cs alkyl.

[0107] As also des-cribed above, R®, R®, and R” may independently be hyedrogen, or substituted or unsubstituted alkyl. R%, R®, and R” may also independently bee hydrogen, or substituted or unsubstituted Ci-Cy alkyl. R®, R®, and IR’ may also be indep endently hydrogen, or unsubstituted C;-Cyy alkyl.

[0108] In some embodiments, y is 1 and R? is attacked at position 3'. In other embodiments, y is 2, and R? is attached at position 3' &and position 4'. In other embodiments, an R?® attached at possition 3' is combined with an R*® sattached at position 4™ to form a

PCT/US2005/026792 substituted or unsubstituted ring. In other embodiments, an R?° attached a—t position 3' is combined. with R' to form a substituted or unsubstituted ring.

[0109] Xn other embodiments, A? has thes formula: (r=)

Nl 2

R! VD.

[0110] In Formula (VD), y is an integer from 0 to 3. R' is as described =above in Formula 1n. R2"C is as described above in the discussion of Formula (I). In some= embodiments, one

R® and "R' are optionally combined to form a substituted or umsubstitutec ring with the carbons to which they are attached. In other embodiments, two R? grou-ps are optionally combine=d to form a substituted or unsubstituted ring with the carbons to which they are attached. {0111] Insome embodiments, y is 1 ard R® is attached at position 3'. In other embodiments, an R? attached at position 3' is combined with R' to forma substituted or unsubstituted ring.

[0112] Insome embodiments of the compounds of Formulae (I)-(VD>- L' andlor Lisa bond.

[0113] Insome embodiments of the compounds of Formulae (D-(VD -» R'is CDR. The symbol Z may simply be O. R® may be NR“RY. R" and RY are as d_escribed above. In some related embodiments, y is 0. Thu s,R" and RY may independentBy be substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or are combined with the nitroge=n to which they are attached to Form substituted or unsubstituteca piperidiny}, or substituted or unsubstituted piperazinyX, substituted or unsubstituted pyorrolidinyl, or substituted or unsubstituted morpholino. R" and R" may also be combined with the nitrogen to whitch they are attached to form a substituted or unsubstituted piperiidinyl, or substituted or unsub stituted piperazinyl. R'* and R'S may also be combined with the= nitrogen to which they are attached to form a piperazinyl substituted with a substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl. [0114:] R' and/or R'S may be substituted with a substituent having t=he formula -(CH2)r

NR2'™R?. For example, where R™ and R'S are combined to form a hetterocycloalkyl (€.g-

p iperazinyl or piperidinyl), the heterocycloalky! may be substit-uted with a -(CH,)-NIR?'R*.

T he symbol t, R?! and R?? are ass described above. [O115] In some embodiments, A! has the formula of Formula (IT) and A? has the formula of

F~omula (III), (V) or (VI). In sosme related embodiments, L! arad/or L? is a bond. [O116] In some embodiments «of the compounds of Formulae (V) and/or (VD, R® Sis -CCZ)R®, Z is O, and R® is -NR'3R'®. R'* and R! are combined to form a substituted or unsubstituted heterocycloalkyl, or heteroaryl with the carbon to which R! is attached. and the nitrogen to which R' is attached. [O117] In other embodiments, of the compounds of Formulaes (V) and/or (VI), R! is -CC(Z)R%, Z is O, and R® is -NR"®R'®. R' and R¥ are combined to form a substituted or umnsubstituted heterocycloalkyl, or heteroaryl with the carbon toe which R? is attached and the nmtrogen to which R'? is attached. [O118] Insome embodiments, R’, R®, and R’ are independently hydrogen, substitu—ted or umsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstity_ited cxwcloalkyl, substituted or unsubsstituted heterocycloalkyl, substi tuted or unsubstituted aryl, or stabstituted or unsubstituted hetemroaryl. R® and R” may be joine=d with nitrogen to whmich they ar—e attached to form substituted or unsubstituted heterocycloalk=yl, or substituted or ursubstituted 5-membered heteroaryl. In other embodiments, IR*, RS, and R’ are in_dependently hydrogen, or substituted or unsubstituted alkyl. IR’, R® and R’ may al=so in-dependently be hydrogen, or stabstituted or unsubstituted C;-Cy alkyl. In other embodiments, R®, RS, and R” are independently hydrogen, or urmsubstituted C;-Czq allyl. [0 119] In some embodiments, _A' has the formula of Formula (ID) and A? has the fo. mula of

Fomulae (V) or (VI). In some related embodiments, L! and/or 12 isa bond. In othemr related en—ibodiments, x is 1 and y is 0. I'm other related embodiments, FR" is attached at positzion 1.

In other related embodiments, R! is attached at position 2. In o=ther related embodim_ents, x is 2,y1s 0, and R" is attached at positions 1 and 4. In other relzated embodiments, x i_s 2, y is 0, aod R'is attached at positions 1 and 5. In other related embodiments, x is 1, yis ®,R? is att ached at position 3’, and R'? is attached at position 1. In othemr related embodiments, x is 1, yi s2,R¥ is attached at positions 3'and 4, and R'? is attached a-t position 1. In other related enrmbodiments, x is 2, y is 0, and o ne R" is attached at position 2 . [0M 20] In some embodiments, tthe compound of the present inwention has the formu Ja:

PCCT/US2005/026792

H

JEN 2 d EA

R

(rR), VID.

[0121] In Formula (VI), L', 1% R!, RY, R*_ x, and y are as defined above in Formulae om, (I), and (V). In some embodiments, L! and/or L2 is a bond. In some embo=diments, x is 1 and y is 0. Im other embodiments, R!? is attach ed at position 1 and/or positi_on 2. R! may be -C(Z)R® (defined above). In some related emb>odiments, Z is O and R® is -INR“R (defined above). R" amay be -OR® (defined above).

[0122] Ins ome embodiments, the compound of the present invention has the formula: rs

Nar, —)

R!

R1® (vi.

[0123] In Formula (VII), L! L? Rl, R", and R*are as defined above in the Formulae @O, (ID), and (V). In some embodiments, L' and/or ZL” is a bond. R! may be -C(=Z)R® (defined above). In so me related embodiments, Z is O amd R® is -NR “R$ (defined aWbove). R'® may be -OR’ (defimed above). In some embodiments, R? is halogen, -OR?, or -NJIRSR’ (defined above).

[0124] In some embodiments, the compound of the present invention has t he formula: (0

R20 AY

Lt

Rr?

R1® IX).

[0125] In Foermula (IX), L', L% R', RY, and R= are as defined above in the Formulae , (ID), and (V). Jn some embodiments, L' and/or I_"is a bond. R' may be -C(Z=)R® (defined above). In sorme related embodiments, Z is O an dR® is -NR'R'* (defined ab ove). R'® may be -OR’ (defin_ed above).

[0126] In sorme embodiments, the compound ofthe present invention has thee formula:

/015123 PC_X/US2005/026792

H

Na N

J Re

Er ay rR! =19 Xx).

[0127] In Formula (Xe, Li 1 R!, and R" are as defimed above in the Formulae (I), (ID), and (V). R' may be -C(ZZ)R® (defined above). In some related embodiments, =Z is O and R® is

NR“R" (defined abovez). In some embodiments, L! amd/or L? is a bond. R'™ attached at the 1 position may be -OR®_ RY attached at the 4 position may be halogen.

[0128] In some embodiments, the compound of the present invention has thme formula:

R20 Na a

R20 a Pow, 4)

RI

R19 (XD).

[0129] In Formula (<I), L, 1% R, RY, and R* are as defined above in the= Formulae (I), (ID), and (V). In some embodiments, L! and/or L?is a bond. R' may be -C(Z)R® (defined above). In some relate=d embodiments, Z is O and R® Hs -NR'“R" (defined atoove). RY may be -OR® (defined above). R* attached at the 3' position may be -OR”. R? a_ttached at the 4' position may be halogeen or substituted or unsubstitutesd alkyl (such as C,-Cs alkyl).

[0130] Insome emb odiments, the compound of the present invention has —the formula:

H

Fy 2 A\ pov, pr— i» \1 | 2/) (R*) x (x11).

[0131] In Formula &XII), L, 12 RY, RY, R%, x, and y are as defined above in the Formulae (D, (11), and (VD. In some embodiments, L! and/or ¥ }is a bond. In some embodiments, X is _ 1 and yis 0. In other- embodiments, R'® is attached zat position 1 and/or possition 2. R! may be -C(Z)R® (defined abowve). In some related embodimesnts, Z is O and RS is -INRMR" (defined above). R'” may be —OR>.

[0132] In some embodiments, the compound of th_e present invention hass the formula:

®

N of YY = 2 Lt 3 rR! <9) rR? 9 ( ) x (XOI).

[0133] In Formula (XII), L', L2 R!, R!®, R¥, and x are as defined above in the Formulae (0, (I). and (VI). In some embodiments, I' and/or L?is a bond. In sorme embodiments, x is 1. R! may be -C(Z)R® (defined above). R_!’ may be -OR® (defined abov—e). In some related embodi_ments, Z is O and R® is NR“R"*® (defined above). R*® may be hamlogen, or substituted or unsu_bstituted alkyl (such as C,-Cs alkyl). R? may be -OR’,

[0134] In some embodiments, the compound of the present invention “has the formula:

H

De

ALT

R? = u 4

I 2//

R19 ( ) x (XIV).

[0135] In Formula (XIV), L', L? R', R'®, and x are as defined above i 1 the Formulae (J) and (X[)s. In some embodiments, L' and/or L? is a bond. In some embod_iments, x is 1. R! may be -C(Z)R® (defined above). R'® may be -OR> (defined above). In some related embodi_ments, Z is O and R? is NR'*R'® (defined above).

[0136] In some embodiments, the compound of the present invention has the formula:

S ; py AY _

R? = L? 4, \' 2//

R19

[0137] In Formula (XV), L', L% R' R'. and x are as defined above im the Formulae (I) and (I). In some embodiments, L' and/or I.? is a bond. In some embodimerts, x is 1. R! may be -C(Z)R= (defined above). R'® may be -OR_® (defined above). In some re=lated embodiments, Z is O anc R® is NR'“R" (defined above).

[0138] In some embodiments, each substituted group described above in the compounds of

Formulaze (D-(XV) is substituted with at le ast one substituent group. Moore specifically, in some emmbodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituated heterocycloalkyl, substitutesd aryl, substituted heteroaryl, substituted alkylene, and/or substituted heteroalkylene, desc ribed above in the compounds of Formulae (I)-(X\-) are substituted with at least one substitwuent group. In other embodiments, at least one or &all of these groups are substituted with at Reast one size-limited substiteuent group. Alternatively, at least one or all of these groups are si-abstituted with at least one lower substituent group —

[0139] In other embodiments of the compounds of Formulae ([)-(C XV), each substituted or unsubst ituted alkyl is a substituted or unsubstituted C,-Cs alkyl, eamch substituted or unsubst ituted heteroalkyl is a substitutesd or unsubstituted 2 to 20 mmembered heteroalkyl, each substitu ted or unsubstituted cycloalkyl isa substituted or unsubstihmted C4-Cs cycloalkyl, e=ach substitu ted or unsubstituted heterocyclcalkyl is a substituted or unswubstituted 4 to 8 membemced heterocycloalkyl, each substituted or unsubstituted alkyl ene is a substituted or unsubstituted C,-Cy alkylene, and/or e ach substituted or unsubstitimted heteroalkylene is am. substitu_ted or unsubstituted 2 to 20 memmbered heteroalkylene.

[0140] Alternatively, each substitutecd or unsubstituted alkyl is a substituted or unsubstituted Ci-Cs alkyl, each substitiated or unsubstituted heteroa Ikyl is a substituted or unsubstituted 2 to 8 membered heteroaP kyl, each substituted or unsiabstituted cycloalkyl is a substituted or unsubstituted Cs-C; cycloalkyl, each substituted or urasubstituted heterocw/cloalkyl is a substituted or unswibstituted 5 to 7 membered Ieterocycloalkyl, each substitu®ted or unsubstituted alkylene is a substituted or unsubstitute-d C-Cy alkylene, and/eor each substituted or unsubstituted hetero~alkylene is a substituted or tansubstituted 2 to 8 membered heteroalkylene.

[0141] In another embodiment, the coompounds of the present invention include the compounds of any one of Tables 1-39, cor any one of the methods 1—61. In other embodirments, the compounds of the pre=sent invention include the ceompounds of any one of

Tables 22-39, or any one of the methods 2-61.

Exemplz=ary Syntheses

[0142] The compounds of the inventicon are synthesized by an appropriate combination of gencrallsy well known synthetic methods. Techniques useful in synthesizing the compouncs of the invention are both readily apparerat and accessible to those of skill in the relevant art .

The discussion below is offered to illust=rate how, in principle, to gai-n access to the compounds claimed under this invention and to give details on certain of the diverse rmethods available for use in assembling the compounds of the invention. However, the discus=sion is not intended to define or limit the scope of reactions or reaction sequences that are use=ful in preparing the compounds of the present invention. The compourds of this invention may be made by the procedures and techniques disclosed in the Example=s section below, as well as by known organic synthesis techniques. In Schemes 1, 2 and 3, I! and I? are as defimmed above. R'in Schemes 1,2 and 3 correspond to A' as defined above. R? in Schemes 1 ,2 and 3 correspond to A? as defined above.

[0143] The complete synthesis of certain compounds of the pre=sent invention is out®Rined in

Scheme 1. Many of these compounds can be synthesized convermiently from commerc=ially available 2-amino-nicotinic acid. Starting from 2-aminonicotinic= acid, bromination in_ the §- position to 1 (X = Br) can be achieved by various methods well known in the chemical literature, such as, but not limite=d to reactions using elemental bromine or N- bromosuccinimide (step a in Scheme Dn.

Scheme 1

NH, NH, NH; ¢ OMe NH; o

Cy a or bv or EL Sa

X X b 4 1 (X=Br, I) 2 3

OMe

NH, HN 1 HN \

X X rR? 6 4 gn =F ™] 5b [M] = e.g. BRy, SriR3, MgX,ZnX_, Li

[0144] Synthesis of a ketone intermediate of general formula 3 (3X = Br) can be achieved by treating the corresponding WEINR EB-amide 2 or its hydrochloride ss alt with a suitable organometallic species, for example, using an organomagnesium or= organolithium compound [step c in Scheme 1]. (for examples of the use of N-methoxy-N-met=hylamides (WEINREIS

PCT/US2005/026792 amides) in ketomne synthesis, see S.Nam, S M.W einreb — Tetrahedron Lett. 981, 22,3815)

The WEINREB--amide 2 (X = Br) is accessible by condensation of the parent acid 1 (X= Br,

X?= CH) with N,O-dimethylhydroxylamine usang standard methods for amaide-formation, either by prior activation of the acid or in situ oT via a direct condensation. Methods and reagents for booth transformations are described in the chemical literature ard well known to someone skillesd in the art [step b in Scheme 1]. For example, amide formaation is achieved by direct metlmods using suitable coupling reag; ents such as, but not limited _ to, PyBOP, HBTU or HATU.

[0145] The organometallic reagents required for the introduction of a ke=tone residue R'in3 (X = Br) [step ¢ in Scheme 1] can be obtained either commercially or synt=hesized by various methods desc=ribed in the literature, such as, but not limited to the Grignar d-reaction of organic chior=ides, bromides, or iodides, with magnesium (cf. J. March — Sldvanced Organic

Chemistry, 3—xd ed., John Wiley & Sons, 1992), metal-halogen exchange reactions of organic bromides or iodides using suitable organolith ium or organomagnesium compounds such as, but not limit: ed to, n-butyllithium, tert-butylli thinm or iso-propylmagnesi—um chloride or bromide (e.&=. J.Clayden — Organolithiums: Selectivity for Synthesis, Perggamon, 2002;

A. Boudier, IL.O.Bromm, M.Lotz, P.Knochel— Angew. Chem. Int. Ed. (20000) 39, 4414) or deprotonation of sufficiently acidic compourads, such as for example pyrimidines, pyrazines, 2.-chloro- or 2-fluoropyridines using a suitable base, such as for examples lithium N,N- diisopropyl=amide or lithium 2,2,6,6-tetramethylpiperidide (cf 1.Clayden_ - Organolithiums:

Selectivity for Synthesis, Pergamon, 2002; An.Turck, N.Pl¢, F.Mongin, G—.Quéguiner —

Tetrahedro=: (2001) 57,4489; F.Mongin, G.Quéguiner — I ctrahedron (28001) 57,4059). The aforementiconed group R! can be substituted. with one or more functiona~1 groups, in which acidic protons such as, for example, the hydrogen atoms attached to nitr—ogen or oxygen may, as needed, “be protected by a suitable protec ting group by methods well known in the chemical li terature (cf. T.W.Greene, P.G.ML.Wuts — Protective Groups &n Organic Synthesis, 3rd ed., JoThn Wiley & Sons, 1999). Such Functional groups will allow for the elaboration of the producsts obtained in such fashion to various compounds claimed urnder this invention by generally wwell known methods.

[0146] Olefination of the resulting keton_es 3 (X = Br) [step d in Sche=me 1] can be achieved by severall methods known to those skilled in the art but is most convemniently carried out via a

WITTIG-rezaction (cf B.E.Maryanoff, A.B. Reitz — Chem. Rev. (1989) 8~9, 863) using an ylide generated from commercially available methoxymethyltriphenylphospehonium chloride and a

Suitable base, for example, but not limited to, a strong orga—nometallic base such as, but not

Rimited to, 2 non-nucleophilic mmide such as the lithium, sosdium or potassium salt off

Wois(trimethylsilyl)amine. Such. olefinations can also be conveniently carried out withmout

Iourification of the respective kzetone 3 (X = Br), using the c=rude material obtained freom the meaction of the WEINREB amide 2 (X = Br) with an organormetallic reagent as descritwed =above.

WH 0147] Subsequent cyclization of the resulting olefin 4 (3=< = Br), [step e in Schemes 1] which can be utilized in either the E- or Z-form or a mixtur—e of these both forms, cara be achieved under general acid catalysis conditions using stromng inorganic or organic acids, such =, but not limited to sulfuric a cid, perchloric acid, hydrochaloric acid, frifluoromethanesulfonic acid «or triflucroacetic acid in suit=able solvents such as, but not

Mimited to THF, dioxane, diethyl ether, dimethoxyethane, d_iglyme, dichloromethane_, dichloroethane or chloroform, water, methanol, or ethanol, or mixtures thereof. A similar acyclization has been described. by Sakamoto et al., Heteroczycles (19592), 34(12), 2379-84.

There the authors describe the conversion of 2-nitro-3-(2-e thoxyvinyl)pyridine to thee parent

Poyrrolo[2,3-b]pyridine. Formation of the vinyl group is achieved via a STILLE-coup Ming of he 3-bromo analog with tribufyl-2-ethoxyvinylstannane. 0148] Introduction of aromatic, olefin, alkyne, or an aliphatic substituents at the S-position af bromide 5 to afford compouands of the general formula Ge (X = Br) [step fin Scherme 1] can be achieved via standard halogeen cross-coupling methodoleogies (cf F.Diederich, P.J Stang eds.) — Metal-catalyzed Cross -coupling Reactions, Wiley-VCH, 1998; J.Tsuji — Pa®ladium

Reagents and Catalysts, John Wiley & Sons, 1995). Coupmings of the bromide 5 (X = Br) with suitable reagents such as, but not limited to, boronic a=cids and boronates, oorganoboranes, trifluoroborate salts (e.g. G.A. Molander, G-.-8.Yun, M.Ribagorda, B __Biolatto — J.Org.Chem. (2003) 68, 553<1, G.A Molander, B.Biolatto -J Org Chem. (2003) 6&3, 4302.),

Organostannanes, organozinc compounds, organomagnesiu—m compounds, olefins or terminal : alkynes, either purchased or obtained via protocols well kn-own in the chemical literature, are carried out in the presence of a suitable transition metal cat alyst, for example, but nowt limited t=o, suitable palladium compoumds, either in the presence of ligands such as, but not 1-imited to, pohosphines, diphosphines or arsines or without and, as necessary, organic or inorgan_ic bases, ssuch as tertiary or secondary amines, alkaline carbonates, beicarbonates or phosphates and, as r1eeded, other additives that are known in the chemical liter—ature to assist or acceleratte such transformations, such as lithiurn chloride, copper halides or— silver salts. These cross coupling reactions are carried out in suitable sol vents such as, but not limited —to, THF, dioxane, dimethoxyethane, diglyme, dichloromethane, dichloroethane, aceton_itrile, DMF, N- nx ethylpyrrolidone, ethanol, or water, ©r mixtures of these at temperatures ranging from 25 °C to 200 °C using either no heating, conventional heating or microwav~e irradiation.

[0149] This methodology may be extended to the incorporation of non-carbon based nucleophiles such as, but not limited to alcohols, thiols, primary or s econdary amines, heterocyclic rings containing hydrogem attached to a nitrogen atom, —that may or may not contain groups which are known in the chemical literature to be suitzable protecting groups (examples of such groups can be found in T.W.Greene, P.G.M.Wutss — Protective Groups in

Organic Synthesis, 3rd ed., John Wiley & Sons, 1999) of alcohols, thhiols or amines by methods well known in the chemical Literature such as, by way of exzample, those mentioned ira 8.V.Ley, A.W.Thomas — Angew.CFaem. (2003) 115, 5558; J.P.Woolfe, S.Wagaw, J.-

F .Marcoux, S.L.Buchwald — Acc. Chern.Res. (1998) 31, 805 and J.F. Hartwig - Acc. Chem. Res. (1998) 31, 852. The compounds obtained by such methods can be frurther elaborated by methods well known in the chemical Literature to other compounds claimed under this iravention.

[0150] In one embodiment of the in-vention, a halide 5 (X = Br) is treated with a boronic acid in the presence of a suitable palladium catalyst, for example, biat not limited to testrakis(triphenylphosphino)alladium(0), dichlorbis(triphenylphosplino)palladium(it) or dHchloro[1,1’-bis(diphenylphosphino) ferrocene]palladium(ln), and a suitable base (e.g. sodium carbonate, cesium carbonate or cesium fluoride) in aqueous solvent mixtures such as, acetonitrile/water or dimethoxyethane/water at temperatures between 110 °C and 200 °C either using conventional heating or microwave irradiation. [D151] In some cases it may be advantageous to achieve cross-colplings to carbon or non- carbon atoms such as all those mentioned above, by first converting a halide 5 into an organometallic derivative 5b such as & boronic acid or ester, trifluor=oborate salt, oxganomagnesium, 0rganozine, or orgsanotin compound. Such compoounds are accessible by means of substituting the bromide mo iety with an appropriate metal or metalloid in which case any functional group present in derivative 5, most notably the ring nitrogen in position 1 o fthe pyrrolo[2,3-b]pyridine, may be protected by a suitable protecting group (examples of swach groups can be found in T.W.Greene, P.G.M.Wuts — Protective Groups in Organic

Synthesis, 3rd ed., John Wiley & Sons, 1999). Introduction of such metals or metalloids can bre achieved in a number of ways, such as via reductive ruetallation using metz=als such alkaline os alkaline earth metalss or activated forms of such metalss such as lithium, ma_gnesium or 1® thium naphthalide or ~via a metal-halogen exchange reaections using suitable =organolithium oer organomagnesium ceompounds (e.g. n-butyllithium, tert-butyllithium or isco- prropylmagnesium chlo-ride or bromide) and, as needed, ssubsequent transmeta_lation reactions o= {the organometallic intermediate with a suitable solubl e and reactive metal compound (e.g. magnesium chloride, mmagnesium bromide, tri-n-butyltin chloride, trimethyltir chloride, tarimethyl borate, triethyl borate, tri-iso-propyl borate, zirc triflate or zinc chloride).

Imiroduction of a boron _ic acid pinacol ester may be conv—eniently achieved by reacting derivative § directly wi_th bis(pinacolato)diboron in the presence of dichloro i ,1°- beis(diphenylphos-phino)-ferrocene]palladium(ir) and suitable bases (e.g. potasssium or sodium acetate) in solvents such as DMSO, DMF, DMA or N-m ethylpyrrolidone at temperatures ranging from 80-160 °C either using conventional heatimmg or microwave irradlliation (literature precedent for similar transformations can be found in T. Ishiyama, M. Muratam, N. Miyaura -

J< Org. Chem. (1995) 6 0,7508.). Methods for conversior of the boronic acid rpinacol ester o btained by this method into other boronic acid derivativ=es such as boronic acids, boronates, o x trifluoroborate salts =are well described in the chemicad literature. [@©152] Cross-couplin_gs of metallated derivatives 5b with suitable reagents such as aromatic, heteroaromat=ic or olefinic chlorides, bromides, iodides, triflates or =xcyl halides eather purchased or obtaained via protocols well known im the chemical literatumre, are carried out in the presence of a suitable transition metal catalyst (e.g. suitable palladivim compounds, ex ther in the presence o—f ligands such as phosphines, diptnosphines or arsines cr without and, ass necessary, organic or= inorganic bases, such as tertiary or secondary amines. alkaline carbonates, bicarbonate-s or phosphates and, as needed, other additives that are known in the ckemical literature to assist or accelerate such transformamtions, such as copper— halides or si_lver salts). These crosss coupling reactions are carried osut in suitable solvent=s (e.g. THF, dioxane, dimethoxyethamne, diglyme, dichloromethane, di chloroethane, acetonitrile, DMF, N- mu ethylpyrrolidone, or nmixtures of these) at temperatures ranging from 25 °C t=o0 200 °C using either no heating, conve=ntional heating or microwave irradiation. The compor-inds obtained by such methods, partic-ularly those containing suitable fi_inctional groups (e.g.- carboxylic acids or esters, nitriles, samines, aldehydes or olefins) can be further elaborated by methods well known in the chemuical literature to other compoundss claimed under this i-nvention.

[0153] More reactive organic m.ucleophiles such as organometallic compounds 5b containing alkaline, or alkaline ezarth or certain transition metals (e.g. organolithium, ~ organomagnesium or organozinc compounds) can also be couple=d to a range of other electrophilic coupling partners stach as activated olefins (MICHA “EL-acceptors), aldehydes, nitriles, aromatic nitro compounds (see for example I.Sapountziss, P. Knochel - J. Am. Che rm.

Soc. (2002) 124, 9390.), carboxy lic acid derivatives, carbon dio=xide, organic disulfides or organic halides. Such couplings can be achieved using either no catalyst or a suitable transition metal catalyst, such as a suitable copper, cobalt or iro compound in suitable solvents (e.g. ether, THF, dioxame, dimethoxyethane, or diglyme=, or mixtures of these) at temperatures ranging from —100 °C to 100 °C either in the presence of other additives that are known in the chemical literature to assist or accelerate such trarmsformations, such as, for example, lithium halides, amines or diamines or their derivative=s, or without. As will be apparent to someone with skill im the art, the compounds obtain_ed by such methods, particularly such compounds coxtaining suitable functional growmps, such as carboxylic aci ds or esters, nitriles, amines, aldehydes or olefins, can be further eMaborated by methods well known in the chemical literatures to other compounds claimed uznder this invention.

[0154] 3,5-disubstituted pyrro lo[2,3-b]pyridines can also be amccessed via another method outlined in Scheme 2 (see also WVWO 2004/032874). Iodination Of 2-amino-S-bromopyridimne can be achieved by reacting it with iodine and sodium periodate in a suitable solvent such_ as

DMF, DMA or N-methylpyrroli done at elevated temperatures ©f100-200 °C to afford intermediate 31. This intermedi_ate 31 can be acylated under standard conditions, such as reacting it with acetyl chloride im a suitable solvent such as pyrmdine at 25 — 100°C.

Coupling of bromide 32 with ethhynyltrimethylsilane to afford a_lkyne 33 can be achieved ~via standard halogen cross-couplings methodologies (cf. F. Diedericsh, P. J. Stang (eds.), Meta d- catalyzed Cross-coupling Reactzons, Wiley-VCH, 1998; J.Tsuj =, Palladium Reagents ana®

Catalysts, John Wiley & Sons, X995) such as using suitable pal ladium compounds, such &as dichlorobis(triphenylphosphino Jpalladium(n) or dichloro[1,1'- bis(diphenylphosphino)ferroceme] palladium (11) as a catalyst ir the presence of copper(1)— salts, such as cuprous iodide in whe presence of organic bases, s uch as triethyl amine, in suitable solvents, such as dichlosromethane at temperatures of 2 5 °C or above. Cyclization of the resulting alkynylpyridine 33- can be most conveniently achi~eved by exposure to soluble fluorides, such as tetrabutylamncionium fluoride, in suitable sol=vents such as THF or diox=ane at temperatures of 25-110 °C to afford 5-bromo- pyrrolo[2,3-b pyridine (34).

Scheme 2 i I VO WRN 4 P4 — ==

Br Br ~— or 1 3 32 33

HN HN HN

PP Z =z =

Br Br Br Br 33 34 35 36

L

"7 My TL

Rt Re R 37 38 : 6

[0155] Elaboratiomm of halides 34, 35 or 38 can be rea«dily accomplished by gemerally well known methods. Fox example, metal catalyzed cross coupling reactions may bes employed using various known. transition metal compounds (e.g. compounds derived fron palladium, iron or nickel). Exarmples of such transformations can Tbe found in the followings references:

Diederich, F., Stang, P.J.- Metal-catalyzed Cross-coupsling Reactions, Wiley-V= CH, 1998;

Beller, M., Transitioa Metals for Organic Synthesis, Wiley-VCH, 1998; Tsuji, W., Palladium

Reagents and Catalysts, Wiley-VCH, 1%. & 2" ed.s, 15395, 2004; Fuerstner, A., etal,

J Am.Chem.Soc. (2002) 124, 13856; and Bolm, C., et all., Chem.Rev. (2004) 10-4, 6217.

Other useful methods involve the conversion of a bromine or iodine substituent into a metal or metalloid substituent (e.g. organoboron, organolithium, organotin, organosili=con, organozinc, organocopper or organomagnesium compo und) using generally welll known methods (e.g. metal Inalogen exchange and, as appropriate or required, subseque=nt transmetallation usin 2 soluble and reactive compounds of boron, magnesium, zi_nc, tin, silicon or copper; for representative examples of such nmethodology see: Schlosser, M.,

Organometallics in S_ynthesis, 2nd. ed., Wiley-VCH, 20802.). Organometallic de=rivatives obtained in such fashion may itself be of use in transiticon metal catalyzed coupling reactions with aromatic or olef3inic halides or triflates, or, if sufficziently reactive, be reacte=d directly with suitable electrophiless, such as, for example, certain organic halides, MICTHAEL-acceptors, oxiranes, aziridines, aldehydes, acyl halides, or nitriles.

[0156] Selective functiconalization at either the 3- or 5—position may requires different strategies depending on tlie nature of the transformations utilized to introduces functionalities at either position, especially the sequence of functionali=ation at either positieon. Thus, it may be advantageous or necesssary to achieve functionalizaticn at the 3-position prior to functionalization of the 5—position in some cases while tlhe opposite approach may be required in other cases, despending on the nature of the spoecific groups to be introduced, the methods required to accormplish such transformations, omr the inherent selectisvity of the methods utilized. For exammple, some reactants, such as for example some boronic acids or their esters that are electron deficient (i.e. contain one or more electron withdrawing substituents or that repres ent derivatives of certain hetersocyclic systems) and_/or contain one or more substituents orth to the boron-carbon bond ma_y require the use of Imighly active palladium catalysts (such as, for example, those mentiormed in Vilar, R., Chrisstman, U.

Angew. Chem. (2005) 117,370; Littke, A.F., Fu, G. — Arigew. Chem. (2002) 114, 4350.) and more forcing conditions, ssuch as for example higher termperatures and/or longeer reaction times. Such conditions may not be conducive to achieving appreciable selectivities in reactions of 5-bromo-3-icodo-1H- pyrrolo[3,4-b]pyridine. Hence, in such cases, it will be advantageous to avoid sel ectivity issues altogether by se quential substitution of bromine in 5- bromo-1H- pyrrolo[3,4-5 pyridine, iodination at the 3-pcosition and subsequemnt introduction of the second substituent at position 3 utilizing the methods detailed above. CSenerally speaking, whenever substmtution of the halogen atom at either position may require conditions that involve highly reactive catalysts or reagents under c-onditions that generamlly do not favor high levels of selectivity b>etween the two halogen atomss present in 5-bromo- 3-iodo-1H- pyrrolo[3,4-b]pyridine it wvill be advantageous to resort t o this sequential app—roach.

[0157] It will also be ap preciated that protection of reactive groups within ER" and/or R? as well as the pyrrolo[3,4-b]oyridine scaffold, (e.g. the prot on at position 1), with a suitable protecting group may be advantageous or required. For example it was foun to be advantageous in some crosss-coupling reactions to protect the nitrogen at posistion 1 of the 1H-pyrrolo[3,4-b]pyridine= scaffold by introduction of, for example, a 4-toluo—ylsulfonyl, tri- iso-propylsilyl or tetrahyd-ro-1H-pyranyl group at that poesition. Introduction and removal of these protecting groups co~uld be conveniently accomplis hed by methods well. known in the chemical literature. As wi_llbe apparent to someone witl= skill in the art, the ccompounds obtained by any of the aforementioned methods may conta—in functional groups, either free or protected, that can be fur-ther elaborated by generally well Bxnown methods.

[0158] A more detailed description of the utilization of ¢' ross-coupling procedures ira the synthesis of the compoumds claimed under this invention iss illustrated in Scheme 3: X 1 and

X? are selected from, but not limited to, halogen, boronic acid or ester, trifluoroborate salt, organomagnesium, orgamozinc, or organotin. With respect to the introduction of individual residues L'R! or LR? swe.ch transformations, as outlined abeove, can be achieved via standard halogen cross-coupling rmethodologies.

Scheme 3

PG PG, i Do SOR wo SR. U7) a — — UL — 0 R lo x2 2 re 22

HN— HN) HN) PE— V0 a x2 122 122 al,

[0159] Couplings of the corresponding bromide or iodides (X', X? = Br, I) with suitable reagents such as boronic acids and boronates, organoboran es, organostannanes, organcozinc compounds, organomagraesium compounds, olefins or terminal alkynes (either purchas=sed or obtained via generally well known protocols) can be carrie~d out in the presence of a siaitable transition metal catalyst e.g. palladium compounds). The coupling may optionally bes performed in the presence of ligands such as, but not limite=d to, phosphines, diphosphiines,

ARDUENGO-type heterocyclic carbenes (cf. A.J.Arduengo II et al. — Organometallics (1998) 17,3375; AJ. Arduengo Tl et al. — J Am.Chem.Soc. (1994)= 116, 4391) or arsines. Org=anic or inorganic bases (e.g. tertdary or secondary amines, alkaline carbonates, bicarbonates, fluorides or phosphates) and/or other well known additives (e.g. lithium chloride, copper halides or silver salts) may be utilized to effect, assist or ac-celerate such transformations.

[0160] These cross cotipling reactions may be carried oust in suitable solvents such as THF, dioxane, dimethoxyetharue, diglyme, dichloromethane, dicialoroethane, acetonitrile, DWF, N- methylpyrrolidone, water, or mixtures of thereof at temperzatures ranging from 25 °C to 200

°C using. The temperature may optionally be maintained with heatirg, conventional heating or microwave irradiation. In the case ofthe 3-iodo-5-bromo-1H-pyrmrolo(3,4-b]pyridine, thhe selective or preferential substitution of #the iodo substituent over the tromo substituent is possible und. er generally less forcing co-nditions, such as lower temperature and shorter reaction times using a suitable transitiorn metal catalyst. Selective fumnctionalizations of di— or oligohalogera compounds by means of tmransition metal catalyzed tran-sformations are well precedented in the chemical literature: ssee for example Ji, J., et al. - Org Lett (2003) 5, 46711;

Bach, T. et azl. - J.Org.Chem (2002) 67, 5789, Adamczyk, M. et.al. - Tetrahedron (2003) 59, : 8129. [0161} Thi s methodology may be extended to the incorporation of mon-carbon based nucleophiles (e.g. alcohols, thiols, primaary or secondary amines) that may optionally contain suitable protecting groups of alcohols, tHhiols or amines. Examples of= such groups can be found in Greene, T., et al., Protective Ga oups in Organic Synthesis, 3 1d ed., John Wiley &-

Sons, 1999. Exemplary methods of such utilization of non-carbon nucleophiles in related cross-couplirug reactions may be found in Ley, S., et al., Angew. Chena. (2003) 115, 5558;

Wolfe, I., et al, Acc. Chem.Res. (1998) 31, 805; Hartwig, Acc. Chem. _Res. (1998) 31, 852;

Navarro, O., etal.J.Org.Chem. (2004) 9, 3173, Ji, 1., et al, Org. Leta (2003) 35,4611. The skilled artisamr will recognize that the commpounds obtained by such mesthods can be further elaborated by~ generally well known met hods to obtain other compourads of the present inv=en- tion.

[0162] In some cases it may be advant-ageous to achieve cross-coup lings to carbon or nomn- carbon atoms by first converting the respective halogen derivative into the corresponding organometallac derivative (e.g., a boronic acid or ester, trifluoroborate= salt, organomagne: sium, Organozinc or organcotin compound). Such compo=unds are accessible bey means of substituting the halide moiety vith an appropriate metal or nmetalloid. Any functional groups present (e.g. the ring n-itrogen in position 1 of the py~1rolo[3,4-b]pyridine)w, may need to bee protected by a suitable protecting group ("PG", c.f Greene, T., et al.,

Protective Greoups in Organic Synthesis, 31d ed., John Wiley & Sons, 1999).

[0163] Introsduction of such metals or retalloids can be achieved by generally well-know=n methods, suche as metallation using metal_s or a metal-halogen exchangze reaction. Useful metals for me®allation include alkaline or- alkaline earth metals or activated forms of such metals. Suitable reagents for use in meta Il-halogen exchange reactions include organolithiumm

PCT/US20805/026792

Or organomagnesiuim compounds (e.g. n-butyllithium, tert-butyll ithium or iso- propylmagnesium chloride or bromide). Subsequent transmetalantion reactions of the organometallic intermediate may oe performed as needed with a suitable soluble and reactive metal compound such as magnesinam chloride, magnesium brom._ide, tri-n-butyltin chloride, trimethyltin chloride, trimethyl borate, triethyl borate, tri-iso-propyl borate, zinc trifla—te or zinc chloride. Introduction of a boronic acid pinacol ester can bee conveniently achieved by reacting the halogen derivative dixectly with bis(pinacolato)diboron in the presence 0° dichlorof,1"bis(diphenylphosph-ino)ferrocene]palladium(i) an_d suitable bases (e.g. potassium or sodium acetate) in solvents such as DMSO, DMF _, DMA or N- methylpyrrolidone at temperatures ranging from 80-160 °C. Ceonventional heating o=x microwave irradiation may be employed to maintain the appropriate temperature (fox literature precedent of similar transformations, see Ishiyama, T. et al. - J. Org. Chern. (1995) 60, 7508.).

[0164] Methods for conversiom of the boronic acid pinacol e=ster obtained by this ruetbod into other boronic acid derivatives such as boronic acids, boromates, Or trifluoroboramte salts are generally well known. As will be apparent to the skilled a_rtisan, such organome=tallic derivatives may be utilized in cross-coupling reactions similamr to those described atoove in the case of halogen containing deriwatives of pyrrolo[3,4-b]pyridine. Such couplings ¢ an be effected utilizing suitable coupl ing partners, such as aromatic , heteroaromatic halidlles or olefinic reagents under conditions identical or evidently similar and/or related to thme methods described above.

[0165] Other methods may wu tilize the reactivity of organormetallic derivatives gesnerated from halogen containing derivatives of pyrrolo[3,4-bpyridinme by any of the methods described above. For example , derivatives containing alkalimne or alkaline earth meetals (e.g. organolithium, organomagnesi um or Organozine compoundss) may be employed irm direct couplings to a range of other electrophilic coupling partners such as, for example, activated olefins (MICHAEL-acceptors), aldehydes, nitriles, aromatic n_itro compounds, carbaoxylic acid derivatives, oxiranes, aziridines, organic disulfides or organic halides. Such trans= formations are generally well known in the art (for reactions with arom atic nitro compounds, see for example Sapountzis, L, et al., J Am. Chem. Soc. (2002) 124, 9390.).

PCT/US2®005/026792

Protecting Growups

[0166] The term "proflecting group" refers to chemical moieties that block somee or all reactive moieties of a compound and prevent such moiet3es from participating in chemical reactions until the proteective group is removed, for exam ple, those moieties liste] and described in T.W. Greere, P.G.M. Wuts, Protective Groups in Organic Synthesis , 3rd ed.

John Wiley & Sons (19999). It may be advantageous, wheere different protecting £2roups are employed, that each (diferent) protective group be removable by a different means.

Protective groups that ar—e cleaved under totally disparate reaction conditions allo—w differential removal of s—uch protecting groups. For example, protective groups czan be removed by acid, base, amnd hydrogenolysis. Groups sucha as trityl, dimethoxytrityw/], acetal and tert-butyldimethylsilyl a—xe acid labile and may be used to protect carboxy and hyciroxy reactive moieties in the poresence of amino groups protect«ed with Cbz groups, whi=ch are removable by hydrogencolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moietie=s may be blocked with base labil_e groups such as, withot at limitation, methyl, ethyl, and acetyl in the presence of amines blocke=d with acid labile group ssuch as tert-butyl carbamate or with carbamates that are both acid and base stable but hyd rolytically removable.

[0167] Carboxylic acid” and hydroxy reactive moieties may also be blocked witha hydrolytically removable- protective groups such as the bemzyl group, while amine - groups capable of hydrogen boncling with acids may be blocked vwith base labile groups smuch as

Fmoc. Carboxylic acid recactive moieties may be blocked with oxidatively-removaable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups rmay be blocked with fluoride labile silyl carbamates.

[0168] Allyl blocking gzroups are useful in the presence Of acid- and base- protecting groups since the former are stable and can be subsequently removed by metal or pi-acid caatalysts.

For example, an allyl-bloccked carboxylic acid can be deprotected with a palladiums=(0)- catalyzed reaction in the presence of acid labile t-butyl carboamate or base-labile acetate amine protecting groups. Yet an. other form of protecting group is a resin to which a compound or intermediate may be attacked. As long as the residue is attzached to the resin, that foanctionat group is blocked and cann-ot react. Once released from the resin, the functional gro—up is available to react. :

PCT/US200S5 /026792 [V169] Typical blockirmg/protecting groups include, but are not limited to the follo~wing moieties:

Ha H 0] c 2 H

H ~ Cc. PN CwnO gr OT OFS ey ee

Hy o) allyl Bn Cbz alloc Me

H=C, CHj AN / 0 i O (H3C)sC— (H3C)am CSI si ~~ (CHa)C™ I t-butyl TBDMS Teoc Boc=

O

H, oo c— 0 HoC

J A Ge

HaCO ) pMB tratyl acetyl

Frmoc

Methods of Inhibiting Kinases

[0170] In another aspect , the present invention provides methods of modulating pro tein kinase activity using the p=yrrolo-pyridine kinase modulators «of the present invention. The term "modulating kinase activity,” as used herein, means that the activity of the protein kinase is increased or decreased when contacted with a pyrroMo-pyridine kinase modul_ator of the present invention relative to the activity in the absence of the pyrrolo-pyridine kin=ase modulator. Therefore, the present invention provides a method of modulating protein “kinase activity by contacting the p rotein kinase with a pyrrolo-pyridi-ne kinase modulator of the present invention (e.g. the ccompounds of any one of Formulae (I)~(XV)). In some embodiments, the compourmd of Formula (IV) is contacted with the protein kinase.

[0171] In some embodimeents, the pyrrolo-pyridine kinase nmodulator inhibits kinase activity. The term "inhibit,""* as used herein in reference to kinase activity, means that the kinase activity is decreased ‘when contacted with a pyrrolo-pyr-idine kinase modulator reclative to the activity in the absences of the pyrrolo-pyridine kinase modulator. Therefore, the present invention further provides a method of inhibiting protein kinas e activity by contacting the protein kinase with a pyrrolo-pyridine kinase modulator of the present invention.

[0172] In certain embodimemts, the protein kinase is a protein tyrosine Kinase. A pro=tein tyrosine kinase, as used hereim, refers to an enzyme that catalyzess the phosphorylation of tyrosine residues in proteins vevith a phosphate donors (e.g. 2 nucleotide phosphate donor such zs ATP). Protein tyrosine kinaases include, for example, Abelsom tyrosine kinases ("Al") (e.g. c-Abl and v-Abl), Ron re=ceptor tyrosine kinases ("RON"), Met receptor tyrosine “kinases ("MET"), Fms-like tyrosine kinases ("FLT") (e.8. FLT3), src-fammily tyrosine kinases Ce.g. lyn, CSK), and p21-activated kinase-4 ("PAK"), FLT3, aurora A<inases, B-lymphoid ty=rosine kinases ("B1k"), cyclin-deperndent kinases ("CDK") (e.8. CDK 1. and CDKS5), src-family related protein tyrosine kinasses (e.g. Fyn kinase), glycogen symthase kinases ("GSK") (e.g.

GSK3a and GSK3p), lympheocyte protein tyrosine kinases ("Lk"), ribosomal S6 kin=ases (e.g.

Rsk1, Rsk2, and Rsk3), sperm tyrosine kinases (e.g. Yes), and subtypes and homolog=s thereof exhibiting tyrosine k-inase activity. In certain embodinments, the protein tyrosine kinase is Abl, RON, MET, PAK, or FLT3. In other embodimesnts, the protein tyrosirae kinase is a FLT3 or Abl family memmber.

[0173] In another embodi—ment, the kinase is a mutant kinases, such as a mutant Bcr—-Abl kinase, FL.T3 kinase or aurora kinases. Useful mutant Ber-Abol kinases include those having at least one of the following clinically isolated mutations: M2 44V, 1.248V, G250E, aG250A,

Q252H, Q252R, Y253F, Y=253H, E255K, B255V, D276G, F311L, T3151, T315N, T 315A,

F317V, F317L, M343T, M 351T, E355G, F359A, F359V, V3 79L F3 821., L387M, FA396P,

H396R, S417Y, E459K aned F486S. In some embodiments, t he mutant Ab] kinase as a

T3151 mutation. The nunboering system denoting the positio of the amino acid mutation above is the well known wild-type ABL numbering according to ABL exon Ia. See

Deininger, M., et al., Blood 105(7), 2640 (2005). The numbering system is reprodumced in

Figure 1. In some embodi—ments, the mutant Ber-Abl kinase includes at least one off the mutations listed above anc has at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%4, or 100% sequence identity toe the sequence of Figure 1. In some embodiments, the mwutant Ber-

Abl kinase includes at leasstone of the mutations listed abov-e, has a sequence ident=ity to

Figure 1 as discussed above, and includes at least 50, 100, 1 50, 200, 250, 300, 350 , 400, 450. 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 105 0, or 1100 amino acidss.

[0174] Insome embodiments, the kinase is selected from Abelson tyrosine kinase, Ron receptor tyrosine kinase, MMet receptor tyrosine kinase, Fms—like tyrosine kinase-3,. Aurora kinases, p21-activated kirmase-4, and 3-phosphoinositide-degpendent kinase-1. In seome embodiments, the compo und of Formula (I) is contacted wi th the kinase.

[0175] In some embodiments, the kinase is homologous to a known kinase (also referred to herein as a "homologous kinase"). Compourads and compositions usefull for inhibiting the biologic al activity of homologous kinases may be initially screened, for example, in binding assays. Homologous enzymes comprise an zamino acid sequence of the ssame length that is at least 502%, at least 60%, at least 70%, at least: 80%, or at least 90% identical to the amino acid sequence of full length known kinase, or 702%, 80%, or 90% homology t=o the known kinase active domains. Homology may be determimed using, for example, a PSSIBLAST search, such as, but not limited to that described in Asltschul, et al., Nuc. Acids R ec. 25:3389-3402 (1997). In certain embodiments, at least 50%, or at least 70% of the seqmuence is aligned in this analysis. Other tools for performing the alignment include, for exan—ple, DbClustal and

ESPript, which may be used to generate the PostScript version of the aligonment. See

Thompson et al., Nucleic Acids Research, 28 =2919-26, 2000; Gouet, et aZl., Bioinformatics, 15:305-08 (1999). Homologs may, for examaple, have a BLAST E-value of 1 x 10° over at least 100 amino acids (Altschul et al., Nucleic Acids Res., 25:3389-402 (71997) with FLT3,

Abl, or amother known kinase, or any functioxal domain of FLT3, Abl, or another known kinase.

[0176] Homology may also be determined by comparing the active site= binding pocket of the enzyme with the active site binding pocke=ts of a known kinase. For e=xarnple, in homologous enzymes, at least 50%, 60%, 702%, 80%, or 90% of the amins 0 acids of the molecule or homolog have amino acid structural coordinates of a domain _ comparable in size to the kin ase domain that have a root mean square deviation of the alpha ecarbon atoms of up to about L.54, about 1.254, about 1A, about 0.754, about 0.54, and or albout 0.254.

[0177] “The compounds and compositions off the present invention are useful for inhibiting kinase activity and also for inhibiting other enzymes that bind ATP. Theyw are thus useful for the treatrruent of diseases and disorders that may be alleviated by inhibitin_g such ATP-binding enzyme activity. Methods of determining such ATP binding enzymes inc -lude those known to those of skill in the art, those discussed herein relating to selecting homologous enzymes, and by the use of the database PROSITE, where erazymes containing signature=s, sequence patterns, motifs, or profiles of protein families or domains may be identifieed.

[0178] The compounds of the present invention, and their derivatives, ray also be used as kinase-bin ding agents. As binding agents, suck compounds and derivatives may be bound to a stable resin as a tethered substrate for affinity chromatography applicaticons. The compounds of this invention, and their deri vatives, may also be modified (e.g., radiolabelled or affinity labeled, etc.) in order to utilize tBrem in the investigation of e:nzyme or polypeptide characteri=zation, structure, and/or function.

[0179] Iman exemplary embodiment, the pyrrolo-pyridine kinase moadulator of the present

Invention is a kinase inhibitor. In some embodiments, the kinase inhibi_tor has an ICso of inhibition constant (K;) of less than 1 micromolar. In another embodimuent, the kinase inhibitor lmas an ICs or inhibition constant «K)) of less than 500 micronmmolar. In another embodime=nt, the kinase inhibitor has an IC =, or K; of less than 10 micromolar. In another embodiment, the kinase inhibitor has an IC =p or K; of less than 1 micrormolar. In another embodime=nt, the kinase inhibitor has an IC <j or K; of less than 500 nancomolar. In another embodime=nt, the kinase inhibitor has an IC =; or K; of less than 10 nanornolar. In another embodiment, the kinase inhibitor has an IC =; or K; of less than 1 nanomolar.

Methods «of Treatment

[0180] Im another aspect, the present inve=ntion provides methods of treating a disease mediated by kinase activity (kinase-mediated disease or disorder) in a subject (e.g. mammals, such as hu mans) in need of such treatment. By "kinase-mediated" or "k=inase-associated" diseases is: meant diseases in which the disease or symptom can be alleviated by inhibiting kinase acti vity (e.g. where the kinase is involved in signaling, mediatior, modulation, or regulation of the disease process). By "diseases" is meant diseases, or dilisease symptoms.

The method includes administering to the swibject an effective amount o fa pyrrolo-pyridine kinase mocdulator of the present invention (e.g. the compounds of any ore of Formulae D- (XV).

[0181] FExamples of kinase associated diseases include cancer (e.g. lelakemia, tumors, and metastases ), allergy, asthma, obesity, inflanmamation (e.g. inflammatory liseases such as inflammatory airways disease), hematological disorders, obstructive airways disease, asthma, autoimmure diseases, metabolic diseases, irafection (e.g. bacterial, viral,. yeast, fungal), CNS diseases, brain tumors, degenerative neural «diseases, cardiovascular diseases, and diseases associated with angiogenesis, neovasculariz ation, and vasculogenesis. In an exemplary embodimemnt, the compounds are useful for treating cancer, including let akemia, and other diseases or- disorders involving abnormal cel proliferation, such as myeMoproliferative disorders. In some embodiments, the compound of Formula (I) is admiristered to the subject.

006/015123 PCT/US22005/026792

[0182] More specifi ¢ examples of cancers treated with thes compounds of the preseent invention include breaast cancer, lung cancer, melanoma, colorectal cancer, bladder ecancer, ovarian cancer, prostate cancer, renal cancer, squamous cel] cancer, glioblastoma, pwancreatic cancer, Kaposi's sarcoma, multiple myeloma, and leukemias (e.g. myeloid, chronic rmyeloid, acute lymphoblastic, <hronic lymphoblastic, Hodgkins, anc other leukemias and hematological cancer s).

[0183] Other specific examples of diseases Or disorders #or which treatment by thhe compounds or compositions of the invention are useful for- treatment or preventiorm include, but are not limited tos transplant rejection (for example, kiciney, liver, heart, lung, i=slet cells, pancreas, bone marrow, cornea, small bowel, skin allografts or xenografts and othe=er transplants), graft vs . host disease, osteoarthritis, rheumatoid arthritis, multiple scl_erosis, diabetes, diabetic retinopathy, inflammatory bowel diseas ¢ (for example, Crohn's —disease, ulcerative colitis, an_d other bowel diseases), renal disease=, cachexia, septic shock... lupus, myasthenia gravis, [osoriasis, dermatitis, eczema, seborrhea, Alzheimer’s disease, “Parkinson's disease, stem cell protection during chemotherapy, €x vivo selection or ex vivo prarging for autologous or allogeneic bone marrow transplantation, ocular disease, retinopathi_es (for example, macular d_egeneration, diabetic retinopathy, andk other retinopathies), coomeal disease, glaucoma, infections (for example bacterial, viral, or fungal), heart disease, including, but not la mited to, restenosis.

Assays

[0184] The compounds of the present invention may b= e easily assayed to deter—mine their ability to modulate protein kinases, bind protein kinases and/or prevent cell growth or proliferation. Sorme examples of useful assays are prese=nted below.

Kinase Inh bition and Binding Assays

[0185] Inhibition of various kinases is measured by methods known to those Of ordinary skill in the art, such as the various methods presented herein, and those discusse=d in the

Upstate KinaseProfiler Assay Protocols June 2003 publ ication.

[0186] For exarmple, where in vitro assays are performed, the kinase is typically diluted to the appropriate concentration to form a kinase solution A kinase substrate and_ phosphate donor, such as AXP, is added to the kinase solution. Thae kinase is allowed to transfer a phosphate to the kinase substrate to form a phosphorylated substrate. The formation of 2 phosphorylated subsstrate may be detected directly by any appropriate means, su <h as radioactivity (e.g. [-*"P-ATP]), or the use of detecta ble secondary antibodies (e=.g. ELISA).

Alternatively, the fosrmation of a phosphorylated substrate may be detected usingg any appropriate technique, such as the detection of ATP «concentration (e.g. Kinase-CSlo® assay system (Promega)). Kinase inhibitors are identified Wy detecting the formation of a phosphorylated subsstrate in the presence and absences of a test compound (see Ezxarnples section below).

[0187] The ability~ of the compound to inhibit a kirmase in a cell may also be assayed using methods well know in the art. For example, cells containing a kinase may be c-ontacted with an activating agent (Csuch as a growth factor) that acti_vates the kinase. The amount of intracellular phospheorylated substrate formed in the &absence and the presence of the test compound may be d_etermined by lysing the cells andl detecting the presence phoesphorylated substrate by any appropriate method (e.g. ELISA). V*Vhere the amount of phosphorylated substrate produced imn the presence of the test compovand is decreased relative to —the amount produced in the abse=nce of the test compound, kinase= inhibition is indicated. More detailed cellular kinase assays are discussed in the Examples section below.

[0188] To measure the binding of a compound to a kinase, any method known to those of ordinary skill in the zart may be used. For example, a test kit manufactured by Dai scoverx (Fremont, CA), ED-SStaurosporine NSIP™ Enzyme B= inding Assay Kit (see U.S. Patent No. 5,643,734) may be used. Kinase activity may also be= assayed as in U.S. Patent »,589,950, issued July 8, 2003.

[0189] Suitable kirase inhibitors may be selected from the compounds of the imvention through protein crystallographic screening, as discloseed in, for example Antonys=amy, et al.,

PCT Publication No. WOO03087816A1, which is incomporate herein by reference in its entirety for all purposes.

[0190] The compowinds of the present invention ma=y be computationally screeraed to assay and visualize their ability to bind to and/or inhibit varaous kinases. The structure may be computationally screesned with a plurality of compourmds of the present invention to determine their ability to bind to a kinase at various sites. Such compounds can be used as targets or leads in medicinal cheemistry efforts to identify, for ex ample, inhibitors of potenti.al therapeutic importance (Travis, Science, 262:1374, 19 93). The three dimensional structures of such compounds may be superimposed on a three d_imensional representation of kinases or arm active site or binding pockezt thereof to assess whether the c-ompound fits spatially imato the representation and hence the protein. In this screening, the quality of fit of such entities or compounds to the binding pocket may be judged either by shape complementarity or oy estimated interaction energy (Meng, et al., J. Comp. Chem. 128:505-24, 1992). [€191] The screening of comupounds of the present inventiomn that bind to and/or moedulate kinases (e.g. inhibit or activatze kinases) according to this inve=ntion generally involves consideration of two factors. First, the compound must be capable of physically and structurally associating, eithesr covalently or non-covalently with kinases. For example, —ovalent interactions may be important for designing irreverszible or suicide inhibitorss of a protein. Non-covalent molecular interactions important in th_e association of kinases “with the compound include hydrogen bonding, ionic interactions, van_ der Waals, and hydrophobic

FEnteractions. Second, the commpound must be able to assume a conformation and orientation ~in relation to the binding pocket, that allows it to associate with kinases. Although ceertain —portions of the compound will not directly participate in this association with kinases, those portions may still influence -the overall conformation of the rmolecule and may have aa significant impact on potency. Conformational requirement s include the overall three-dimensional structure and orientation of the chemical =group or compound in relation to all or a portion of the bindirag pocket, or the spacing betweemn functional groups of a compound comprising several chemical groups that directly interact with kinases.

[0192] Docking programs described herein, such as, for e—xample, DOCK, or GOLD, are used to identify compoundss that bind to the active site and/or binding pocket. Comppounds may be screened against meore than one binding pocket of tine protein structure, or r-ore than one set of coordinates for tne same protein, taking into account different molecular dynamic conformations of the protein. Consensus scoring may then be used to identify the c=ompounds that are the best fit for the orotein (Charifson, P.S. et al., J. Med. Chem. 42: 5100-9 (1999).

Data obtained from more than one protein molecule structumre may also be scored according to the methods described in Klinger et al, U.S. Utility Application, filed May 3, 2002, entitled "Computer Systems and Miethods for Virtual Screening of Compounds.” Compourds having the best fit are then obtainezd from the producer of the chenanical library, or synthesi=zed, and used in binding assays andl bioassays.

[0193] Computer modeling techniques may be used to asssess the potential modu lating or "binding effect of a chemical compound on kinases. If corraputer modeling indicate=s a strong interaction, the molecule may then be synthesized and tested for its ability to bind to kinases and affect (by inhibiting «or activating) its activity.

[0194] Modulating or other binding compounds of kinasses may be computational ly evaluated by means of a series of steps in which chemical groups or fragments are sscreened and selected for their abi lity to associate with the individumal binding pockets or other areas of kinases. This process may begin by visual inspection of, for example, the active sit eon the computer screen based om the kinases coordinates. Select=ed fragments or chemical groups may then be positioned in a variety of orientations, or docked, within an individual binding pocket of kinases (Blane-y, J.M. and Dixon, J.S., Perspece=ives in Drug Discovery ard Design, 1:301, 1993). Manual decking may be accomplished usirag software such as Insighmt I (Accelrys, San Diego, C_A) MOE (Chemical Computing CGroup, Inc., Montreal, Que=ebec,

Canada); and SYBYL (Xripos, Inc., st. Louis, MO, 19927), followed by energy min imization and/or molecular dynam ics with standard molecular mechanics force fields, such ass

CHARMM (Brooks, et cal., J. Comp. Chem. 4:187-217, 1-983), AMBER (Weiner, e ¢ al, J.

Am. Chem. Soc. 106: 76 5-84, 1984) and C*MMFF (Merck Molecular Force Field; Accelrys,

San Diego, CA). More zutomated docking may be accormplished by using programs such as

DOCK (Kuntz et al., J. .Mol. Biol., 161:269-88, 1982; DCOCK is available from Unmversity of

California, San Francisc 0, CA); AUTODOCK (Goodsell & Olsen, Proteins: Structure,

Function, and Genetics 8:195-202, 1990; AUTODOCK i_s available from Scripps FResearch

Institute, La Jolla, CA); GOLD (Cambridge Crystallogra—phic Data Centre (CCDC)s; Jones et al., J. Mol. Biol. 245:43—53, 1995); and FLEXX (Tripos, St. Louis, MO; Rarey, M. , etal, J

Mol. Biol. 261:470-89, 1996). Other appropriate progran—s are described in, for exeample,

Halperin, et al.

[0195] During selection of compounds by the above m_ethods, the efficiency witla which that compound may bind to kinases may be tested and opotimized by computationali evaluation. For exampl €, a compound that has been designed or selected to function as a kinases inhibitor may occupy a volume not overlapping t=he volume occupied by thme active site residues when the n_ative substrate is bound, howevemr, those of ordinary skill ir the art will recognize that theres is some flexibility, allowing for rearrangement of the maizn chains and the side chains. In =:ddition, one of ordinary skill meaty design compounds that could exploit protein rearrang ement upon binding, such as, for example, resulting in an iznduced fit.

An effective kinase inhi bitor may demonstrate a relative_ly small difference in ener-gy between its bound and free statess (i.e., it must have a small deforrmation energy of binding zand/or low conformational strain upon binding). Thus, the most efficien—t kinase inhibitors should, for example, be designed with a deformation energy of binding c>fnot greater than 10 kcal~mol, not greater than 7 kcal/mol, not greater than 5 kcal/mol, or not greater than 2 kcal/mol.

Kinase inhibitors may interact with the protein in more than one conformation that is smmilar in overall binding energy. In those cases, the deformation en_ergy of binding is taken to be the difference between the «energy of the free compound and the average energy of the conformations observed when the inhibitor binds to the enzymme.

[0196] Specific computer: software is available in the art to evaluate compound defor-mation energy and electrostatic interaction. Examples of programs Aesigned for such uses incMude:

Gaussian 94, revision C (Fxrisch, Gaussian, Inc., Pittsburgh, P* A. ©1995); AMBER, ver sion 7. (Kollman, University of California at San Francisco, ©2002) ; QUANTA/CHARMM (Accelrys, Inc., San Diego, CA, ©1995); Insight Il/Discover (Accelrys, Inc., San Diegeo, CA, ©1995); DelPhi (Accelrys, Inc., San Diego, CA, ©1995); ancl AMSOL (University of

Minnesota) (Quantum Chemmistry Program Exchange, Indiana University). These programs may be implemented, for irastance, using a computer worksta tion, as are well known in the art, for example, a LINUX. SGI or Sun workstation. Other h_ardware systems and software packages will be known to those skilled in the art.

[0197] Those of ordinary~ skill in the art may express kinasee protein using methods lkcrown in the art, and the methods disclosed herein. The native and mmutated kinase polypepticlles described herein may be chnemically synthesized in whole or —part using techniques that are well known in the art (see, e.g., Creighton, Proteins: Structur es and Molecular Principl es,

W.H. Freeman & Co., NY, 1983).

[0198] Gene expression systems may be used for the synth esis of native and mutated polypeptides. Expression \~ectors containing the native or mutated polypeptide coding sequence and appropriate taranscriptional/translational control signals, that are known to those skilled in the art may be co nstructed. These methods includes in vitro recombinant DN_A techniques, synthetic techniques and ir vivo recombination/g enetic recombination. See, for example, the techniques de scribed in Sambrook ef al., Molec=ular Cloning: A Laboratcery

Manual, Cold Spring Harbor Laboratory, NY, 2001, and Aussubel et al., Current Protocols in

Molecular Biology, Greene= Publishing Associates and Wiley— Interscience, NY, 1989.

[0199] Host-expression vector systems may be used to exp xess kinase. These includ e, but are not limited to, microorgzanisms such as bacteria transformmed with recombinant

NO 2006/015123 PCT/US2005/026799? bacteriophage DNA, plasmid DIMA or cosmid DNA expressiora vectors containing the coding sequence; yeast transformed with recombinant yeast expressiomn vectors containing the comding seqmuence; insect cell systems infescted with recombinant virus expression vectors (e.g., baculovirus) containing the coding sequence; plant cell system s infected with recombinamt vinaas expression vectors (e.g., cauliflower mosaic virus, CaMV¥; tobacco mosaic virus, TMV) or transformed with recombinant= plasmid expression vectors (e2.g., Ti plasmid) containing the cod. ing sequence; or animal cell systems. The protein may also be expressed in human ge=ne ther—apy systems, including, for example, expressing the proteir to augment the amount o—f the pro®ein in an individual, or to express an engineered therapeutiec protein. The expression elerments of these systems vary ir their strength and specificities, [02@00] Specifically designed veectors allow the shuttling of D®NA between hosts such ass bacwteria-yeast or bacteria-animal cells. An appropriately const-Tucted expression vector nay contain: an origin of replication for autonomous replication in host cells, one or more sele=ctable markers, a limited nurmber of useful restriction enzyme sites, a potential for high copy number, and active promoters. A promoter is defined as =a DNA sequence that directs

RIN_A polymerase to bind to DNA and initiate RNA synthesis. A strong promoter is one ®hat causses mRNAs to be initiated at Bhigh frequency. [02€@01] The expression vector rmay also comprise various elerments that affect transcript—ion and translation, including, for example, constitutive and induci ble promoters. These elements are =often host and/or vector depemndent. For example, when clowning in bacterial systems, inducible promoters such as the M7 promoter, pL of bacteriophage A, plac, ptrp, ptac (ptrpo-lac hybrid promoter) and the like ma_y be used; when cloning in inssect cell systems, promoters such as the baculovirus polyhedrin promoter may be used; whe=n cloning in plant cell syst.ems, promoters derived from the genome of plant cells (e.g—., heat shock promoters; tie promoter for the small subunit of" RUBISCO; the promoter for ~the chlorophyll a/b binding prot=ein) or from plant viruses (e.., the 35S RNA promoter of CaMV; the coat protein promoter of TMV) may be used; when cloning in mammalian cell systems, mammalian prormoters (e.g., metallothionein toromoter) or mammalian viral promoters, (e.g., adenovirus late promoter; vaccinia virus 7.5} promoter; SV40 promoter; bwovine papilloma virus prormoter; and Epstein-Barr virus promoter) may be used.

[02032] Various methods may b-e used to introduce the vector into host cells, for exampl e, transsformation, transfection, infection, protoplast fusion, and el_ectroporation. The expres-sion vector-containirmg cells are clonally propagated and Andividually analyzed to «letermine whether they praaduce the appropriate polypeptides. Various selection metho ds, including, for example, antibioetic resistance, may be used to identi_fy host cells that have be: en transformed.

Identification of polypeptide expressing host cell clomnes may be done by several means, including but no#t limited to immunological reactivity with anti- kinase antibo dies, and the presence of host cell-associated activity.

[0203] Expression of cDNA may also be performe d using in vitro produced synthetic mRNA. Synthetic mRNA can be efficiently translated in various cell-free systems, including but not limited tos wheat germ extracts and reticulocyte extracts, as well as cffRciently translated in cell- based systems, including, but not lirmited, to microinjection f nto frog oocytes.

[0204] To determine the cDNA sequence(s) that yie=lds optimal levels of activity and/or protein, modified cDNA molecules are constructed. =A non-limiting example Of a modified cDNA is where thme codon usage in the cDNA has bee=n optimized for the host cell in which the cDNA will be expressed. Host cells are transformed with the cDNA molecules and the levels of kinase R"NA and/or protein are measured.

[0205] Levels o=fkinase protein in host cells are quantitated by a variety of methods such as immunoaffinity amd/or ligand affinity techniques, kinzase-specific affinity beads or specific antibodies are usec to isolate **S-methionine labeled omr unlabeled protein. Lab eled or unlabeled protein as analyzed by SDS-PAGE. Unlabeled protein is detected by~ Western blotting, ELISA or RIA employing specific antibodies .

[0206] Following expression of kinase in a recombiraant host cell, polypeptides may be recovered to provicie the protein in active form. Several purification procedures are available and suitable for uses. Recombinant kinase may be purified from cell lysates or rom conditioned cultures media, by various combinations ofS or individual application of, fractionation, or chromatography steps that are known —in the art.

[0207] In additiom, recombinant kinase can be separa~ted from other cellular proteins by use of an immuno-affin ity column made with monoclonal ©r polyclonal antibodies specific for full length nascent protein or polypeptide fragments the=reof. Other affinity base d purification techniques known im the art may also be used.

[0208] Alternatively, the polypeptides may be recovered from a host cell in an unfolded, inactive form, e.g., from inclusion bodies of bacteria. Proteimms recovered in this form many be solubilized using a denaturant, e.g., guanidinium hydrochloricie, and then refolded into ar active form using methods known to those skilled in the art, ssuch as dialysis.

Cell Growth Assays

[0209] A variety of cell growth assays are known in the art and are useful in identifying pyrrolo-pyridine compounds (i.e. "test compounds") capable of inhibiting (e.g. reducing) cell growth and/or proliferation.

[0210] For example, a variety of cells are known to requires specific kinases for growth and/or proliferation. The ability of such a cell to grow in thes presence of a test compourad may be assessed and comp» ared to the growth in the absence =of the test compound therel>y identifying the anti-prolifexative properties of the test compomund. One common method. of this type is to measure the degree of incorporation of label, s-uch as tritiated thymidine, i nto the DNA of dividing cells. Alternatively, inhibition of cell proliferation may be assayed by determining the total meta bolic activity of cells with a surrogate marker that correlates wvith cell number. Cells may be treated with a metabolic indicator in the presence and absence of the test compound. Viable cells metabolize the metabolic indicator thereby forming a detectable metabolic product. Where detectable metabolic product levels are decreased- in the presence of the test compound relative to the absence of the test compound, inhibition of cell growth and/or proliferations indicated. Exemplary metabolic indicators include, for example tetrazolium salts and AlamorBlue® (see Examples section below).

Pharmaceutical Compositions and Administration

[0211] In another aspect, the present invention provides a pharmaceutical compositiosn including a pyrrolo-pyridine kinase modulator in admixture with a pharmaceutically acceptable excipient. One of skill in the art will recognize that the pharmaceutical compositions include the pharmaceutically acceptable salts of the pyrrolo-pyridine kinzse modulators described above.

[0212] In therapeutic ard/or diagnostic applications, the compounds of the invention can be formulated for a variety of modes of administration, including systemic and topical or localized administration. Techniques and formulations gen:erally may be found in

Remington: The Sci~ence and Practice of Pharmacy 20" ed.) Lippincott, VVilliams & Wilkins

[0213] The compomunds according to the invention are effective over a w=ide dosage range.

For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to SO mg per day, and from 5 to 40 rng per day are exampMes of dosages that may be used. A mosst preferable dosage is 10 to 30 mg per day. The exact dosage will depend upon the route of adrministration, the form in which the compound is admimnistered, the subject to be treated, the bod_y weight of the subject to be treated, and the preferenece and experience of the attending phys -ician.

[0214] Pharmaceut-ically acceptable salts are generally well known to those of ordinary skill in the art, and m _ay include, by way of example but not limitation, ace®tate, benzenesulfonate, bessylate, benzoate, bicarbonate, bi#tartrate, bromide, calc ium edetate, : camsylate, carbonate. citrate, edetate, edisylate, estolaate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorc inate, hydrabamine, h—ydrobromide, hydrochloride, hydrom¢ynaphthoate, iodide, isethionate, lactate, lactobionate=, malate, maleate, mandelate, mesylate, Tmucate, napsylate, nitrate, pamosate (embonate), pantothenate, phosphate/diphosphat=e, polygalacturonate, salicylate, stearate, subacetate, szuccinate, sulfate, tannate, tartrate, or tecoclate. Other pharmaceutically acceptable salts may bes found in, for example, Remington: The Science and Practice of Pharmacy (20™ ed.) Lipp~-incott, Williams & Wilkins (2000). Precferred pharmaceutically acceptable salts include, for example, acetate, benzoate, bromide, caxrbonate, citrate, gluconate, hydrobromide, hydrochlormde, maleate, mesylate, napsylate, pamoate (embonate), phosphate, salicylate, succinate, ssulfate, or tartrate.

[0215] Depending oan the specific conditions being tareated, such agents may be formulated into liquid or solid doss age forms and administered systemically or locally. Whe agents may be delivered, for example, in a timed- or sustained- low release form as is krmown to those skilled in the art. Techmniques for formulation and admj. nistration may be foumnd in Remington:

The Science and Practi’ce of Pharmacy (20% ed.) Lippircott, Williams & WilZkins (2000).

Suitable routes may include oral, buccal, by inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, . masal or intestinal administratior; parenteral delivery, including mtramuscular, subcutareous, intramedullary injections, as well as intrathecal’, direct intraventricular, intravesnous, intra-articullar, intra —sternal, intra-synovial, inv¢ra-hepatic,

intralesional, intracranial, intraperitoneal, intranasal, or intraocular injections or- other modes of delivery.

[0216] For injection, the agents of the invention rmay be formulated and dilute=d in aqueous solutions, such as im physiologically compatible buffers such as Hank's solution , Ringer's solution, or physiol .ogical saline buffer. For such tra nsmucosal administration, peenetrants appropriate to the b-arrier to be permeated are used i n the formulation. Such penestrants are generally known in the art.

[0217] Use of pharmaceutically acceptable inert c= arriers to formulate the compounds herein disclosed for the praactice of the invention into dosagzes suitable for systemic adnministration is within the scope of the invention. With proper choi <e of carrier and suitable maenufacturing practice, the compo sitions of the present invention, -in particular, those formulated as : solutions, may be aciministered parenterally, such ass by intravenous injection. The compounds can be #ormulated readily using pharma ceutically acceptable carrier-s well known in the art into dosagzes suitable for oral administration. Such carriers enable the «compounds of the invention to oe formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the= like, for oral ingestion by a subject (e.g. patient) to be treate=d.

[0218] For nasal or inhalation delivery, the agents of the invention may also bee formulated by methods known —to those of skill in the art, and m_ay include, for example, but not limited to, examples of solubilizing, diluting, or dispersing substances such as, saline, pmreservatives, such as benzyl alcool, absorption promoters, and fl uorocarbons.

[0219] Pharmacev tical compositions suitable for tase in the present invention i—nclude compositions where=in the active ingredients are con#ained in an effective amoun_t to achieve its intended purpose=. Determination of the effective= amounts is well within the capability of those skilled in the art, especially in light of the deta_iled disclosure provided hereein.

[0220] In additior=m to the active ingredients, these goharmaceutical compositionss may contain suitable pharmaceutzically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be use=d pharmaceutically. T he preparations formulated for o ral administration may be in_ the form of tablets, dragees, capsules, or solutions.

[0221] Pharmacetatical preparations for oral use camn be obtained by combining the active compounds with sol_id excipients, optionally grinding a resulting mixture, and pr-ocessing the mi=xture of granules, after adding susitable auxiliaries, if desired, to obtain tablets or dliragee cores. Suitable excipients are, in particular, fillers such as sugarss, including lactose, ssucrose, mannitol, or sorbitol; cellulose preparations, for example, maize starch, wheat starchm, rice stamch, potato starch, gelatin, gum tr-agacanth, methyl cellulose, Bhydroxypropylmethsae/l- cel lulose, sodium carboxymethyl-ce=llulose (CMC), and/or polywrinylpyrrolidone (PV=P: po=widone). If desired, disintegrating: agents may be added, such =as the cross- linked poRyvinylpyrrolidone, agar, or algin-ic acid or a salt thereof such as sodium alginate.

[0222] Dragee cores are provided with suitable coatings. For this purpose, concermtrated sugar solutions may be used, which may optionally contain gunm arabic, talc, poRyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG), and/or titanium dioxide, lac=quer solutions, and suitable orgamiic solvents or solvent mixtimres. Dye-stuffs or p igments maemy be added to the tablets or dragee coatings for identification or to characterize dm fferent combinations of active compound doses.

[0223] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, scaled cagosules made of gelatin, and & plasticizer, such as glycerol or sorbitol. The push-fit capsules caan contain the active ingredients in admixture with filler - suech as lactose, binders such as star—ches, and/or lubricants such as talc or magnesiurn stearate an-d, optionally, stabilizers. In soft «capsules, the active compoumnds may be dissolveed or susspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethyleme glycols (PEGs). In addition, stabilizers may be added.

[02224] Depending upon the particular condition, or disease st-ate, to be treated or porevented, ad ditional therapeutic agents, whickn are normally administered to treat or prevent thmat condition, may be administered tog; ether with the inhibitors of this invention. For exxample, ch_emotherapeutic agents or other amnti-proliferative agents may “be combined with thae inkibitors of this invention to treat goroliferative diseases and camcer. Examples of kenown ch_emotherapeutic agents include, b ut are not limited to, adriamycin, dexamethasone=, vimcristine, cyclophosphamide, fluorouracil, topotecan, taxol, iraterferons, and platiraum de=rivatives.

[02225] Other examples of agents the inhibitors of this inventi on may also be com¥bined with include, without limitation, anti-inf-lammatory agents such as corticosteroids, TNF Iolockers,

II_-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; irmmunomodulatory a-nd immmunosuppressive agents such as cyclosporin, tacrolimus, rapeamycin, mycophenawlate mofetil. interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotreophic factors such as acetylcholimesterase inhibitors, MAO inhibitors, interferons, anti-cornvulsants, ion channel blockers, xiluzole, and anti-Parkinsonian zagents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, liuretics, nitrates, calciunm channel blockers, and statins; a gents for treating liver disease s.uch as corticosteroids, cholest®=yramine, interferons, and anti-vixral agents; agents for treating bleood disorders such as corticosteroids, anti-leukemic agents, ard growth factors; agents for tre ating diabetes such as insulin, insulin analogues, alpha glucosi dase inhibitors, biguanides, andl insulin sensitizers; and age=nts for treating immunodeficiency disorders such as gamma glo bulin.

[0226] These additional agents may b e administered separately, as part of a multiple dosage regimern, from the inhibitor-containing composition. Alternatively, thes e agents may be part of a single dosage form, mixed together with the inhibitor in a single ccamposition.

[0227] The present invention is not to be limited in scope by the exermplified embodiments, which amre intended as illustrations of siragle aspects of the invention. Iradeed, various modificzations of the invention in addition to those described herein willl become apparent to those having skill in the art from the for-egoing description. Such modifications are intended to fall v=within the scope of the invention- Moreover, any one or more fe atures of any embodiment of the invention may be co mbined with any one or more other features of any other ermbodiment of the invention, witkout departing from the scope of the invention. For exampl-e€, the pyrrolo-pyridine kinase meodulators described in the Pyrro=lo-pyridine Kinase

Modulamtors section are equally applicable to the methods of treatment amnd methods of inhibitimng kinases described herein. References cited throughout this agoplication are exampl~es of the level of skill in the art &and are hereby incorporated by reference herein in their en_tirety for all purposes, whether previously specifically incorporated or not.

EXAMPLES

[02228] The following examples are offered to illustrate, but rot to limit the claimed invention. The preparation of emb odiments of the present invention is described in th € fol lowing examples. Those of ordinary skill in the art will understand that the chemic -al reactions and synthesis methods provided may be modified to gorepare many of the otlmer commpounds of the present invention. Where compounds of the= present invention have= not beeen exemplified, those of ordinary skill in the art will recogni_ze that these compounds may be prepared by modifying synthesi s methods presented herein, and by using synthesis methods known in the art. The cormpounds with assay results geiven are marked with ~AE.

Svyruthesis of compounds:

M <thod 1: a HN Toon ) ™N ) 0” “x \ if

Ce oa STEP 2 oO STEP 3 0 STEP 4 & 2 I — | — 1 _ EE NP

Step 1: Synthesis of 5-bromo-3-iodo-1H-pyrrolo[2,3-b]} pyridine.

[0229] Into a 500 mL round botEomed flask were added 5-br-omo-1H-pyrrolo[2,3- b] pyridine (10.11 g, 51.3 mmol) and 250 ml acetone. N-iodoswiccinimide (NIS, 12.7 p=, 56.4 mmol) was added, and the reactior mixture was stirred at roorm temperature for 1 houmr. The precipitate was collected and waslaed with cold acetone to afford 12. 2 g (74%) of the= title compound as a tan powder. "H-NMR (500 MHz, dg-DMSO) -5= 12.35 (br.s, 1H), 8.29 (d,

J=2.0 Hz, 1H), 7.84 (d, J=2.0 Hz 1 H), 7.79 (s, 1H); MS: m/z 322.8/324.8 [MH].

Step 2: Synthesis of 5-Brom -0-3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3- b]pyridine. [®230] Into a 250 mL round bottomed flask were added 5-bromo-3-iodo-1H-pyrrol_o[2,3- b Ppyridine (8.00 g, 40.6 mmol) an d 120 mL dry THF. The sol ution was cooled in an ice baath at 0 °C and NaH (2.40 g, 60.0 mmol) was added in three portions. After 20 min, p- tos luenesulfonyl chloride (8.70 g, <45.63 mmol) was added, ancd the reaction mixture was al lowed to warm to rt over 30 mira. The reaction mixture was concentrated and hexanmes was aclded to obtain a precipitate, which was collected and washed with ice cold 2M NaOwH.

T he crude product was recrystallizzed from EtOAc/hexanes to afford 17.8 g (92%) of the title compound as a light tan powcler. "H-NMR (500 MHz, d=-DMSO) § 8.49 (d, J=22.5 Hz,

1H), 8.2 1 (s, 1H), 7.99 (d, J=2.0 Hz , 1 H), 7.98(d, J=8.5 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 2.32(s, 3H); MS: m/z 476.8/478.8 [MH].

Steps 3: Synthesis of S-Bromo-3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)—1H- pyrr-olo[2,3-b]pyridine.

[0231] Into a 500 mL round bottomed flask were added 5-Bromo-3-iodo-1-(toluene-4- sulfonyl )-1H-pyrrolo{2,3-b]pyridine (11.80 g, 20.9 6 mmol), 2-methoxyphenyl boronic acid (3.76 g, 24.74 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.756 g, 1.08 mmol), acetonitxile (100 mL) and 100 mL of 2M Na,CO3 (aq). The flask was fitted with a mreflux condens er and heated at 60° C with rapid stirring under N; for 8 h. The reaction mi—xture was filtered to obtain a grey-tan precipitate, which was dissolved in EtOAc and washed with water forllowed by brine. Concentration of this solution afforded 7.70 g (80%) of time title compound as a tan powder. "H-NMR (500 MHz, d6-DMSO) & 8.50 (d, J=2.0 Hz, BH), 8.14 (d, J=2.5 Hz, 1H), 8.07(s, 1 H), 8.03(d, J=8.0 Hz, 2H), 7.54(dd, J=1.5, 7.5 Hz, 1H) , 7.43(d,

J=8.0 H.z, 2H), 7.39 (m, 1H), 7.15(d, J=7.5 Hz, 1H), 7.05(t, J=7.0 Hz, 1H), 3.80(s. 3H), 2.34(s, 3H); MS: m/z 456.9/458.9 [MH].

Step 4: Synthesis of 3-(2-Methoxy-phenyl)-5-(4,4,5,5-tetramethyl- [1,352]dioxaborolan-2-yl)-1-(toluene-4-sulfonnyl)-1H-pyrrolo[2,3-b] pyridine=.

[0232] Into a5 mL Personal Chemistry microwave reaction vial were added 5-F3romo-3- (2-meth oxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyxrolo[2,3-b]pyridine (0.102 g, 0. 220 mmol), Bis(pinacolato)diboron (0.123 g, 0.483 mmol), 1,1'- bis(diphaenylphosphino)ferrocenepalladium(m)-dichloride dichloromethane adduct «(9.1 mg, 0.01 mrmol) and anhydrous sodium acetate (55 mg, 0.67 mmol) and anhydrous DMF (1 mL). The resulting mixture was irradiated in a Personal Chemistry Optimizer at 1=40 °C for 60 min and then diluted with EtOAc and extracted 4X with water. The organic ph=ase was treated “with brine, dried (Na;SOy), filtered and concentrated. The crude product w=as purified by flash silica gel chromatography using a gradient of ethyl acetate in hex anes to afford 90.9 mg (81%) of the title compound a white powder. "H-NMR (500 MHz, CDCl3) § 8.79 (d, J=1.0 Hz, 1H), 8.32 (d, J=1.0 Hz, 1H), 8.1 1(d, J=5.5 Hz, 2 H), 7.94 (d, }=3.0 Hz, 1H), 7.50(m, 1H), 7.35(t, J=7.5 Hz, 1H), 7.25(d, J=7.5 Hz, 2H), 7.05(t, ]=7.2 Hz, MH), 7.01(d, J=7.2 Hz, 1H), 3.85(s, 3H), 2.35(s, 3H), 1.31(s, 12H); MS: m/z 505.1 [ME].

[0233] Other compounds prepared by Method 1:

Table / RF hn! Ts, ©) X

Ts, (8) N A =N Tse 0 0

NT NT \ \

N™ _ N RS ww I P

B Qo oN oo ——= oo

MS: m/z 506 [MH].

MS: m/z 519 [IVE]. MS: m/z 55 5 [MH].

Ts, F TF F F

Ts, N

N N A\ Ts oF

NT *N N

NT lL

PP NTS

LB. =

JB. Qo oO 0 B +H Tv 77

MS: m/z 511 [MH].

MS: m/z 503 [INH]. 2511 [MH]

MS: m/z 55 9[MH"].

Ts,

N \ Rn To \ Q

Ts,

NX NH NX N \ = = N7X >)

B | _ N oie} 00 + 32 i oie

MS: m/z 514 [NIH] MS: m/z 517 [ME* 7. [A *

MS: m/z 50-5 [MH].

TS Ts, 0p

No N=

PZ [ _ oo oo al +H

MS: m/z 465 [MH]. MS: m/z 519 [MOH]. "See Mettmod 23 on synthesis of 2-(5—(pyridine-3-yl)-1H-pymrolo[2=,3-b]pyridine-3- ylthiazole.

Method 2: :

Ts < a

N \ HN—

NT NT

CR step1 LU

Oo

Step 1: Synthesis of 5-[3-(2-Methoxy-ph enyl)-1H-pyrrolo[2,3-b]pyri.din-5-yI}-N,N- dimethysIl-nicotinamide. :

[0234] Intcoa 5S mL Personal Chemistry microwave reaction vial were add ed 3-(2-

Methoxy-plaenyl)-5-(4,4,5,5-tetramethyl-[1,3,2 Jdioxaborolan-2-yl)-1-(toluerme-4-sulfonyl)- 1H-pyrrolo[_2,3-b]pyridine (0.136 g, 0.270 mmol), 5-Bromo-N,N-dimethyl-n_icotinamide (0.0756 g, 0=.332 mmol; preparation described below), 1,1'- bis(dipheny Iphosphino)ferrocenepalladium(m)- dichloride dichloromethane a=dduct (16.2 mg, 0.01 mmol), acetonitrile (2 mL) and saturated aqueous NaHCO; (2 mL). Th_e vial was sealed, purgzed with Ny, and irradiated in a Pers onal Chemistry Optimizer at ®90 °C for min. Thes= layers were separated, and the aqueous phase was extracted 3X with EtOAc.

The combin_ed organic phase was treated with brine, dried (N2,SOy), filtered and concentrated. The crude product was dissolved in 3:1 MeOH/acetone (4 mI. total) and treated with 500 pL of 50% w/w KOH(aq) for 1h. Glacial Acetic acid was aedded to obtain pH 7, then whe reaction mixture was concentrated. The residue was partitioned between

EtOAc and ~water, then the layers were separated, and the organic phase was washed 2X with water. “The organic phase was treated with. brine, dried (Na,S0,), filtere=d and concentrated. Purification by flash silica gel chromatography ussing a gradient of ethyl sacetate (containing 10% MeOH) and hexanes afforded the title compound as a tan powcier «(57 mg, 57%). "H-NMR (500 MHz, de-DMSO) §= 11.96 (br. s , 1H), 8.95 (d,J=2.5 Hz. 1H), 8.56(d, J=2.0 Hz, 1H), 8.52 (d, J=2.0 Hz, 1H), 8.24(d, J=2-.0 Hz, 1H), 8.13(t, J=2.0O Hz, 1H), 7.72(4, J=3.0 Hz, 1H), 7.59¢dd, ]=2.0, 5.5 Hz, 1H), 7. 25 (dd, J=1,7.5 Hz, 1H), 7.008(d, .J=7.5 Hz, 1H), 6.99(t, J=7.5 Hz, 1H), 3.76(s, 3H), 2.97 (s, 3H), 2.92(s, 3H); MS: m/z 3773.1 [MH]. :

[0235] Preparation of intermecdiate: 5-Bromo-N,N-dimethyl—nicotinamide: Into a 100 mL round bottomed flask were added 5-bromonicotinoyl chloride (C0.531g, 2.41 mmol) and anhydrous pyridine (5 mL). A 2M solution of dimethylamine ix THF (SmL, 10.0 mmol) was added dropwise, and the reaction mixture was stirred at rt wunder N; for 6 h after which it was concentrated under vacuurm. The crude residue was parti. tioned between EtOAc and water. The layers were separated., and the organic phase was w ashed 3X with water, then treated with brine, dried (Na;SO.), filtered and concentrated to afford 5-Bromo-N,N- dimethyl-nicotinamide as a brown oil (0.4951g, 89%). MS: m/= 229/231 [MH].

[0236] Other compounds prepared by Method 2 (Either silica gel chromatography or- mass triggered reverse phase HPLC or both may be used for the puri fication of the following compounds):

Table 2

I cc A cB

J o EO : HN HN) IN \ ii i 2) NTS 7 Z J z

Za i 2 H ) HO Noe NG

MS: m/z 345 [MH] © 0

MSS: m/z 403[MH] AEL7

MSS: m/z 373.1 (M+H)

I cc J cc JEN o vs FC

HN A HN \ HN A

C BY 'S

LZ

= o AE1 OH Nx Ne_—

MS: m/z 359 [MH'] MS: m/z 317[MH'] ©

MS: m/z 453.1 (OM+H") <’ < F2CO

HN NN HN \ HN \

Lo Uo NTS 4

AN = \ N 7 [o]

MM AE2 Ts ~

MS: m/z 320[MH"] 0

MS: m/z 364 [MH']

MS: m/z 427.1 CM+H") = id FiCQ

HN) HN HN 2 » 4 © Na | N

N— N ~ / AE3 $ I : m/z 378 [MH

MS: m/z 378 [MH] MS: m/z 400[MEL']

MS: m/z 413.1 «(M-+H")

Wa 2006/015123 PCT/US2005/026792

I cc o o F3CO,

HN \ HN iN HN \ bo i NTs = ® z | 5

Ss Nao oN Zz (@] = he NN

Cp MS: me=/z 319[MH'] ©

MS : m/z 420 [MH']

MS: mn/z 469.1 (M+H") o rd

HN 2 HN A i. no NT =X = F4 [ os (

Va x N? TNH \ \

De ve CE

N MH

HD MS: mmi/z 337[MH'] \ AE4 MS: m/z 339

MS: m/z 433 [MH] [MEL] o o

HEN HN H

\

Ss oY y — 4 = — fo] 7

SUS oN Cw

[0] OH

MSS: m/z 415[MH'] MS: mn/z 351[MH'] MS = m/z 343 [MH] ie J

HIN HN H

N 3 3 gD i v aD » =

Pe

Nae > Cl NH, CO) NH, [o] OH [+] OM I

MCS: m/z 399[MH"] MS: m/z 360 [MH'] MS-: m/z 358 [MH]

I i

S 7

HN A HN A

NT i = HN ~—

X N A

7 FF s-L Lo Ev “

NS MEH] OH 1% MS: m/z 395

MS: m/z 340 [MH]

MS: m/z 378[MH']

J vg

HN HN

\ N "

C » 9 i a = Ne =

LA e

Nao N NaN

Y “, o NH;

MS: m/z 428[MH] MS: m/z 318 [MH] MS: m/z 3165 [MH] o o

HN \ HN } y \

NT NX AA

P ] P = ~~ NH i gi r = 0 F AEI18

MS: m/z 317 [MH]

MS: m/z 442[MH'] MS: m/z 318 [MH] rd &

HN HN

\ 3 HN = = =

QL e x ~ o 0 HN 4 CH NO, o AEI10 H

MS: m/z 401 [MH fd MS: m/z 398 [MH] MS: m/z 363 [MH']

i Nc ¢ o

HN HN

\ \ HN

NT NT

P » { OJ = STN 7

N i! Q j= xX ~~pa” 4 Na o | AES Na, AE1l 1

MS: m/z 430M H'] MS: m/z 386 [MH] MS: m/z 336 [MH] o o

HN \ HN A "

NT NESS 3

P | P = 8X ns 4 vo A AE19 o ors 5

MS: m/z 429[MIE'] MS: m/z 351 [ME] MS: m/z 291 [MH'] o J

HN iN HN \ iP » i$ » 0

FZ

4g ‘ @ ° I ) HN NH N — NO,

MS: m/z 372[MVIH'] 0 AE12 y

MS: m/z 347 [MH

MS: m/z 399 [MH] 4 /

Q 9

HN 2 HN \ H \ g

NTR () NX & )

L~ lL ) 9

HN

QD BV; 98), §=0 o AE13 H

MS: m/z 398M" MS: m/z 379 [MH'] MS: m/z 356 [MH]

ST I

J J

HN

\ HN \

P Hi

NT XX NEE - = | PP \ Pp, g (YY om RSS d — Mon ur o AE6

MS: m/z 318 [MH] TMS: m/z 305 [MH']

MS: m/z 442[MH] oo

HN HN

\ \ 3

TO SOY AX

LZ pe P (To g [o} ON /

NA So al 0 NH

MS: m/z 414[MH'] MS: m/z 380 [MH] MS: m/z 350 [MH] o rd

HN HN

\ \

VF ) oS TH

LZ > PD

SUS e

NJ Soe Ig [o]

MS: m/z 320 [MH .

MS: m/z 427[MH] BMS: m/z 303 [MH" / / EfO

HN 2 5 HN \ q HN \

N PD () \ > () nS 0) ~~, (he

Swe J 2) © 7 ha CN

MS: m/z 413[MH'] OH

MS: m/z 397 [MH]

MS: m/z 356 [MH].

= o HN EtQ

HN \ HN A y Ly i 2 i 2

Cal @ JENN a 0] ~ 3

J 9 s 0 AR7

MS: m/z 318 [MH] MS: m/z 334 [MEO].

MS: m/z 455[MH"]

HN < 4 HN \ eQ 3 ! 0)

N™ SN 0 > QU) | NS | PD

NT =X =

ALT Sy ~ 0 EN | HN . + MS: m/z 355 [M-TH].

MS: m/z <469[MH"] MS: m/z 318 [ME] [ ] / / EtO 2 q HN

HN iN HN A \

N oY OS C

SO = 21 4g mJ Na N o Hu y/ OH

MS: m/z ~484[MH') MS: m/z 341 [NVI] MS: m/z 332 [MAH].

J J

NTR 4 | [\

Z N = S N ND

Ps U/ 0) ° Nx NH, Ng NH,

[0]

MS: m/z -453[MH'] lo} *

MS: m/z 359 [INAH+].

MS: m/z 321.8 (M+H")

7 FN wy y— J

JAS P NTT S Ha, 0 > _~ NY

N ~N 2) 7

NH nN N=/ -

AES " NE

TMS: m/z 358 {MH} MSS: m/z 318.0 (M+HY) | MSS: m/z 334 [MH], o Et J)

HN IN \ H_ o

TO NTS $

LZ | N NN

V4 1 “7

Ny oo” cal To — i

Nao NJ ~— Neo

TMS: m/z 332[MH"] z

MSS: m/z 332 [MH+].

MSS: m/z 413.1 (M+H"

J N J]

TN HINT) | H_ 0 p ~~ NX NY pz | 2 N <N yz L/

I Naw NA <k

TMS: m/z 318[MH"] o NH,

AE14

MSS: m/z 331 [MHA].

MSS: m/z 424.1 (M+H)

PCT/USS2005/026792

Sowers [Smee 7 Smee 7

HN 3 K o” » og

NT XX HN \ \ 7 NT N EN _ P

Nn

H° AR9 “3 0) o- Nx NH,

MS: m/z 318[MH™] I He

MS: m/z 355 [MH+ _].

MS: m/z 361.1 (M+H") 4 HN N ig ad on

NS NS S \ N lL yp NEN () ve

PP

= (o]

HN NH

! o < ° OH oN

MS: m/z 335[MH"] " OH

MS: m/z 318.0 (M+H") AE20

MS: m/z 351 [MH+] . _— HN = o ) \ HN

Se nese

LZ ] _ 0) XL

SUN ®

OH

MS: m/z 331[MH"] © 502

AE15 bl A E21 : MS: m/z 371.1 (M+H") MS: m/z 380 [MH+).

i 7 N Et HN) \ ay,

NH

FE WS YC

V4 7

HN / Z @

Na IR N

MS: m/z 290MH'] ~ HN~Y AE22 0]

MS: m/z 350 CMH+].

MS: m/z 357.1 QVI+HD) ve EO

HN DN HN \ ip NA = f

ZZ

= < 7 nN NH

Nx Ne

MS: m/z 317MH'] o

AElL6

MS: m/z 387.1 (M+H")

Suzuki c-oupling was carried out at 140 °C in microwave for 30 min. amnd no base treatment was need —for the removal of the Ts group.

Method 3= / 4 Ts d Q

Ts, 0 IN

NR) NY HI

Ng NTS No lL STEP 1 y STEP 2 =

B. Va = oO Rl

KC Nx OEt Nx N Y o oO

Step 1: Synthesis of 5-[3-(2-Methoxy-phenyl)-1 ~(toluene-4-sulf=onyl)-1H- pyrreolo[2,3-b]pyridin-5-yl]-nicotinic acid ethyl ester.

[0237] Intoa20mL Personal Chemistry microwave reaction vial were added 3-(2-

Methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1 »3,2] dioxaborolan-2-yl)- 1-Ctoluene-4-sulfonyl)- 1H-pyrrolo[2,3-blpyridine (0.995 g,2.18 mmol), 5_Bromo-nicotinic acid ethyl ester (0.645 g, 2.33 mmol), 1,1'-bis(diphenylp hosphino)ferrocenepalladium(lr)-dictaloride dichloromethane adduct (95.5 mgz, 0.117 mmol), acetonitrile (10 mL) znd saturated aqueous

NaHCO; (10 mL). The vial was sealed, purged with Nj, and irradiatec} in a Personal

Chemistry Optimizer at 90 °C for 15 min. The layers were separated, zand the aqueous phase was extracted 3X with EtOAc. The combined organic phase was treate=d with brine, dried (Na;SOy), filtered and concentrated. Purification by flash silica gel chromatography using a gradient of ethyl acetate and hexanes afforded 5-[3-(2-Methoxy-pheny-1)-1-(toluene-4- sulfonyl)-1H-pyrrolo[2,3-b]pyrid-in-5-yl}-nicotinic acid ethyl ester as a white powder (0.794 g, 69%). MS: m/z 528.1 [MH].

Step 2: Synthesis of N-Isoparopyl-5-[3-(2-methoxy-phenyl)-1H- pyrrolo[2,3- b]pyridin-5-yl]-nicotinamid ee.

[0238] Into a 5 mL screw-cap v-ial were added 5-[3-(2-Methoxy-phemyl)-1-(toluene-4- sulfonyl)-1H-pyrrolo[2,3-b]pyriddn-5-yl]-nicotinic acid ethyl ester (50-2 mg, 0.095 mmol) and isopropylamine (500 pL). Th e vial was sealed and placed in heatead block at 100 °C for 48 h. The reaction solution was concentrated and the residue was dissolved in 1:1

MeOH/acetone (2 mL total) and treated with 100 pL of 50% w/w KOHE(aq) for 1 h. Glacial

Acetic acid was added to obtain psH 7, then the reaction mixture was c-oncentrated. The residue was partitioned between EEtOAc and water, then the layers werse separated, and the organic phase was washed 2X with water. The organic phase was treat ed with brine, dried (NaSOy), filtered and concentrated. Purification by flash silica gel chromatography using a gradient of ethyl acetate (containimg 10% MeOH) and hexanes afforded the title compound as a white powder (13 mg, 35%). 'H-NMR (500 MHz, ds-DMSO) 5= 11.96 (br. s, 1H), 9.05 (d, J=2.5 Hz, 1H), 8.94(d, J=2.0 Hz, 1H), 8.64 (d, J=2.0 Hz, 1H), 8.51(d, J=8.0 Hz, 1H), 8.46(d, J=2.0 Hz, 1H), 8.30(d, J=2.0 Hz, 1H), 7.76(s, 1H), 7.61(d-, J=5.5 Hz, 1H), 7.29(dd, J=2, 7.5 Hz, 1H), 7.12(d,, ]=7.5 1H), 7.04 (d, J=7.5 Hz, 1H), 4-.11(m, 1H), 3.84 (s, 3H), 1.17(s, 6H); MS: m/z 387.1 [MH'].

[0239] Other compounds prepax-ed by Method 3:

Table 3 . J :

HN J HN

NT La A\ NT i PZ NTS ZZ 2 =z =

Na. Ne = Na | | ’

NS: dg 0 AV fo} 0

MS: m/z 373[MH'] MS: m/z 387[MH']

MS: m/z 385[MH]

J ie

HN iN BN iN

NT NTR i _ lL _ = =

Nx PN N= | NS o o

MS: m/z 401[MH'] NAS: m/z 416]MH]

Method 4:

HN 0” HN o”

Ts, P \ \ 3 HY UO yO

NT STEP 1 \~ STEP 2 & _

Br ) OH J Non 0 © | AEDS

Step 1: Synthesis of 3-[3—(2-methoxy-phenyl)-1H-pyrrolo[2,3-b}pyridin-5-yl}- benzoic acid.

[0240] To a solution of 5-bromo-3-(2-methoxy-phenyl)-1-(t oluene-4-sulfonyl)-1H- pyrrolo[2,3-bIpyridine (1.01 g, 2.21 mmol) in a 1:1 acetonitril e/saturated aqueous NaEICO; solution (20 mL total) was addled (3-tert-butoxycarbonylphen=yl)boronic acid (0.54 g, 22.43 mmol) and [1,1’-bis(diphenylohosphino)ferrocene]dichloropa lladium (ID), complex with dichloromethane (1:1) (0.90 g, 0.11 mmol) in a microwave vial. The vial was capped flushed with N,, evacuated uneder vacuum, and subsequently Ineated in a microwave atc 90 °C for 1800 seconds. The materizal was diluted with ethyl acetate and the organic layer w=as washed with H,O then d_ried over Na;SO4. The solutior was adsorbed onto silic=a gel and purified by flash chromamtography with a gradient of eth_yl acetate and hexanes, eaffording 3- [3-(2-methoxy-phenyl)- 71-(toluene-4-sulfonyl)-1H-pyrreolo [2,3-b]pyridine-5-yl]—benzoic acid tert-butyl ester as a white solid (1.07 g, 87% yield). 'H™ NMR (500 MHz, CDCL 3) 8.68 (s, 1H), 8.17 (br s, 3H), 8.089 (s, 1H), 7.99 (m, 2H), 7.71 (A, J=6.5 Hz, 1H), 7.50 (mx, 2H), 7.34 (t, J=8.0 Hz, 1H), 7.32 (d, J= 6.5 Hz, 2H), 7.06 (m, 27H), 3.88 (s, 3H), 2.39 (s, 3H), 1.60 (s, 9H). MS: m/e 555.1 (M +H").

[0241] To 3-[3-(2-methoxy-phenyl)-1-(toluene-4-sul fonyl)-1H-pyrrolo[2,3-b_]pyridine-5- yl]-benzoic acid tert-butyl ester (1.07 g, 1.82 mmol) in a 1:1 MeOH/acetone so lution (40 mL total) was added 4 ruL of a 50% KOH (aq) solutior. The reaction mixture =was stirred for 20 hours at ambient temperature. Glacial acetic acid was added dropwise umntil the solution had apH = 6. The product was extracted into ethyl acetate and dried over Na,S0s.

The material was adsorbed onto silica gel and purified by flash chromatograph=y in an ethyl acetate and hexane gracient, affording 3.[3-(2-methoxy-phenyl)-1H-pyrrolo[2,=3-b]pyridin- 5-yl]-benzoic acid zerz-Toutyl ester as a colorless oil tha_t started to crystallize info a white solid (1.97 g, quantitati—ve yield). 'H NMR (500 MHz, CDCl) & 11.34 (s, 1H), 8.50, 2H), 8.21 (s, 1H), 8.05 (d, J =8.0 Hz, 1H), 7.75 (m, 2H), 7. 55 (m, 2H), 7.40 (t, J= &.0 Hz, 1H), 7.10 (m, 2H), 3.88 (s, 3-H), 1.25 (s, 9H). MS: m/e 401.1 (M +H.

[0242] To a solution of 3.[3-(2-methoxy-phenyl)-1 F-pyrrolo[2,3-b]pyridin-= -yl]-benzoic acid tert-butyl ester (1.997 g, 4.92 mmol) in acetic acid (4 mL) was added dropvvise a premixed solution of h=ydrogen bromide (33% wt in ac=etic acid) (889 uL, 4.92 —1mmmol) and mercaptoacetic acid (4=44 uL, 6.39 mmol). The sides Of the flask were rinsed wvith additional acetic acid (33 mL) and the reaction solution. was stirred at ambient temperature for 10 minutes whereugpon the product began to precipmitate out of solution. Th_e reaction was stirred for an additzional hour at ambient temperatwure. The precipitate was filtered and rinsed well with acetic acid and diethyl ether, affordina g the title compound as aa bright yellow solid (448 mg, «67% yield). 'H NMR (500 MENMz, ds-DMSO) 8 12.03 (b-1s, 1H), 8.58 (s, 1H), 8.21 (d, 2H), 77.99 (4, 1H), 7.94 (d, 1H), 7.76 «(d, 1H), 7.61 (m, 2H), 7.331 (t, 1H), 7.14 (d, LH), 7.06 (t, 17H), 3.83 (s, 3H). MS: m/e 345 .1(M +H.

Step 2: N-(2-D®imethylamino-ethyl)-3-[3-(2-me=thoxy-phenyl)-1H-pyrrolo2,3- blpyridin-5-yl] -N-methyl-benzamide.

[0243] To a solution of 3-[3-(2-methoxy-phenyl)-1 H-pyrrolo[2,3-b)pyridin-5-=yl]-benzoic acid (21 mg, 0.06 mmol) in anhydrous DMF (1 mL) ~was added HATU (23 mg, O.06 mmol) and N,N,N -trimetimylethylenediamine (7.9 nL, 0.06 rxmol). The reaction solution was stirred 16 hours at mmibient temperature then diluted =with DMSO (1 mL), filterecl through a 0.45 um syringe fil ter, and purified by reverse phase chromatography in a mobil e phase of

H,0 and acetonitrile (with 0.1% formic acid as the modifier). Clean fractions were combined and lyophilized, affording the title compovand as a white powder (14.0 mg, 54% yield). '"H NMR (500 MHz, CD;0D) 68.51 (d, J=22.0 Hz, 1H), 8.29 (d, J= 2.0 Hz, 1H), 7.83 (brs, 1H), 7.8 1 (bs, 1H), 7.69 (s, 1H), 7.60 (m, 2H), 7.49 (m, 1H), 7.32 (t,.J=7.5 Hz, 1H), 7.13 (4, 8.5 H(z, 1H), 7.07 (t, J = 6.5 Hz, 1H), 3 .90 (t, J =6.0 Hz, 2H), 3.86- (s, 3H), 3.33 (s, 3H), 3.17 Cs, 3H), 2.91 (s, 3H), 2.80 (br s, 2FJ). MS: m/e 429.1 (M + HH.

[0244] Other cormpounds prepared by Method 4:

Table 4 cB Ic JO id

HN J HN o HN & av ~ oy

N™ N° lL

P

= Zi \\] AN

OUD qo SUS ~

No~ nN NA © 0 | 3) MS: m/z 51.2 [MH]

MS: m/z 415 [MH] MS: m/z 490 [MET]

J qd HN ]

HN HN Q

~C av oO 2 yz 3 NSA

ON oS NT NJ . ZN NJ 5 © © MS: naa/z 456 [MH']

MS: m/z 504 [MH] AE24

MS: m/z 526 [MH] i" o og 5 \ HN HN-— eR NF o SCR So fo co F ©

MS: m/z 510 [MH"_] MS: m/z 406 [MH" MS: nz /2390 [MH]

HN J HN J J

\ \ HN ees SRNR eS R Ka So

Ll l_ lL

A 9 QW

No NT No 0 © c oO F 0

MS: m/z 402 [MH] MS: m/z 463 [MH 1 MS: mz 447 [MH']

(05/026792

I Hc / (@] .

HN o » 0

HN \ yO L =

YZ

[ON | CT

Cl N__J TONAN g IN N_ J AN

N AN

FO — © 0 ct O .

MS: m/z 502 [MH] MS: m/z 51-4 [MH]

MS: m/z 518 [MH']

RF oX

HN O vy l a g " on oO

MS: m/z 507 [MH" ]

Method 5:

Ts Ts

Ny o” NY o” HN 0”

C 0, JU

L~ sTEP1 Lo STEP 2 ~F -B. 77 a

ERY Ox NN

OH © OH O | AE25

Step 1: Synthesis of 2-Hydroxy-5-[3-(2-methoxy—phenyl)-1-(toluene-4-suMfonyl)- 1H-pyrrolo[2,3—b]pyridin-5-yl}-benzoic acid methyl ester.

[0245] To a soluti on of 3-(2-methoxy-phenyl)-5-(4,4, 5,5-tetramethyl-[1,3,2]dio=xaborolan- 2-yl)-1-(toluene-4-swlfonyl)-1 H-pyrrolof2,3-5]pyridine (502 mg, 1.00 mmol) in 1 .5 mL saturated aqueous NaH COs and 5.0 mL acetonitrile was= added methyl 5-bromosalicylate (253 mg, 1.10 mmol) and [1,1’-bis(diphenylphosphino) sferrocene]dichloropalladivam (II),

E2CT/US2005/026792 complex with dichlor-omethane (1:1) (41 mg, 0.05 mmol) in a microwase vial. The vial was capped, flushed with IN,, evacuated under vacuum _, and subsequently heated in 2a microwave at 90 °C for 300 secornds. The material was diluted with ethyl acetate ard the organic layer was washed with satwmarated NaHCO; (aq) and brine then dried over Na,SS04. The material was filtered then adsoerbed onto silica gel and purified by flash chromatography with a gradient of ethyl acet=ate and hexane, affording the title compound as a haydroscopic white solid (480 mg, 91% y=ield). 'H NMR (500 MHz, CD;0D) 68.55 (d, J= 2.0 Hz, 1H), 8.06 (m, 4H), 7.96 (s, 1H), 7.77(dd,J=2.5, 6.0 Hz, 1H), 7.52 (dd, /=2.0, 6 .0 Hz, 1H), 7.40 (m, 3H), 7.16 (d, J = 8.5 Fz,1H), 7.08 (m, 2H), 3.98 (=, 3H), 3.87 (s, 3H), 2. 39 (s, 3H). MS: m/z 529.1 (M + HY).

Step 2: Synthesiss of N-(2-Dimethylamino-ethhyl)-2-hydroxy-5-[3- (2-methoxy- phenyl)-1H-pyrrole[2,3-5) pyridin-5-yl}-N-meethyl-benzamide.

[0246] To a solutiorm of 2-hydroxy-5-[3-(2-metho- xy-phenyl)-1-(toluene=-4-sulfonyl)-1H- pyrrolo[2,3-b]pyridin-_S-yl]-benzoic acid methyl ester (52 mg, 0.10 mmol) in pyridine (0.5 mL) was added an exc ess of N,N,N’ -trimethylethylenediamine (0.5 mL). The reaction was stirred for 16 hours at 100 °C in a scintillation vial. There appeared to be= ~50% product formation and ~50% h—ydrolysis of the methyl ester to the carboxylic acid”. PS-carbodiimide resin (244 mg, 0.29 mrmol, 1.21 mmol/g load capacZ ty) and DMF (1 mL) were added to the reaction solution and h-eating was continued for 16 Fours at 70 °C. The ressin was filtered off and rinsed well witta THF and MeOH. The filtreate was concentrated own to a yellow oil and then redissolved in a 1:1 MeOH/acetone soli ation (4 mL total). Tine solution was treated with 200 ul of =a 50% KOH (aq) solution anc stirred at ambient te_mperature for 3 hours. Glacial acetic acid was added dropwise until the pH = 7. The procuct was extracted into ethyl acetate, whereeupon the organic layer was wvashed with H,0, drieed over Na,S0,, filtered, and concentrate=d under vacuum. The material was dissolved in MeOH and filtered through a 0.45 um syrirmge filter. The solution was purified by reverse ph=ase chromatography using am gradient of H,O and acetoni_trile (with 0.1% form—ic acid as a modifier). Clean fractiosns were lyophilized, affordirag the title compound as a white powder (5.2 mg, 12% yield). "EH NMR (500 MHz, de-DMSC3) § 11.80 (d, J = 2.5 Fz, 1H), 8.49 (s, 1H), 8.19 (s, 1H), 8.10 ('s, 1H), 7.74 (d,J=2.5 Hz, 17H), 7.63 (dd, J=2.0, 6.0 Hz, 1H), 7.51 (d,J=8.5 Hz, 1H), 7.43- (5, 1H), 7.33 (m, 1H), 7.17 (Cd, /=8.5Hz, 1H), 7.-09 (t, J=6.5 Hz, 1H), 7.01 (d,J=9.0 Hz, 1H), 3.85 (s, 3H), 3.01 (br s,, 3H), 2.90 (brs, 2H), 2.59 (m, 2H), 2.36 (brs, 3H), 2.00 (br =s, 3H). MS: m/z 445.1 (M + H).

PCT/US2005/026792

[0247] Other compounds prepazxed by method 5:

Table 5

Tc. 00 Ec J

J q qo

HN \ HN \ HN \

NSS eS sb e ~ lL

SVS 9; :

NS AN N

OH © AE26 OH O OH O

MS: m/z 443 [MH] MS: m/z 430 [MH] MS: m/z 374 [MH]

HN J ao’ o 0 YO 0 {~ l l~ =¥ oy. 1

N_~ Ny nL

OH © OH © OH © :

MAS: m/z 388 [MH] MS: m/z 402 [MH] } MS: m/z 416 [MH] i. g og oq \ HN \ HN \ av vy TO AY _ [

Ck JD :

OH © OH © OH O

MSS: m/z 400 [MH"] MS: m/z 457 [MH] MS: m/z 431 [MH]

PCT/US200547026792 of J HN ol

HN A HN A N

0 O-0 WO

Ll L lL

Sue SUC U1

N NN N~

OH O OH O OH O

MS: 72/2 428 [MH] MS: m/z 445 [MH] MS: m/z 416 [MH] . J og i" J

OY NOC

Pp | _z I =

CID ous -

OH O oH O OH ©

MS: m/z 414 [MH'] MS: m/z 471 [MH] MS: m/z 485 [ME]

HN q Jd HAT q a ay ® = = ¢

QO

SUS hS oUshe

OH O

NS NA AE27

QO

HO OH © MS: m/z 528 [ME']

MSS: m/z 487 [MH] MS: m/z 473 [MH] 4 HN J HN <

HN ) \ \ 0) SU Oy

Z

Pee) i

ON SAS

«Us a SUBAS

NA OH © OH ©

Oo .

OH AE28 MS: m/z 542 [ME] MS: m/z 5240 [MH']

MS: m/z 506 [MH]

I Nc od J » qd

HN—) HN) \ C

N™ N° {) N= \ 4 = = = 4g rN /

N N_ 3 {=

OH O OH © OH O

MS: m/z 388 [MET] MS: m/z 4772 [MH] MS: ran/z 457 [MH]

HN of HN) of \ NTS () NH i » 3

J “~~ UD- n OH

OH © a OH O \ )

MS: m/z 439 [MH] MS: rmifz 430 [ME]

MS: m/z 458 [MEX]

HN o J o \ HN \ HN \ op 0 eyo

Uf DO | Ch Dw

N \ ™~N \ N 2

OH O OH O OH O

MS: m/z 457 [MHL] MS: m/z 457 [MH] MS: n/z 429 [MH'] o H J o

HN NT HINT

S() NTU STL _ = ==

C > J 0 Ny

N ~N “

OH O N H, OH O o NH, OH O N . —+

MS: miz 443 [MH "] MS: m/z 45 7 [MH'] MS: m/z 457 [MH]

I Wc J Wh g

HN A —

N° \ y

P ~~

We

OH © ~

MS: m/z 511 [ME]

Method 6:

Ts.

HN HN) NY of STEP 1 7 STEP2 _STEP3 _ 7 7 0 0 a s $ A (3 0 o © sy \ F HN | F

Nx

STEP 4 ™ PD ® STEP 5 | P ) (0 (To

CS LL

0 © AE29

Step 1: Synthesis of (3-(1H-pyrrolo[2,3-b]pymridin-5-yl)phenyl)(morph lino) methanone.

[0248] A mixture of 5-bromo-1H-pyrrolo[2,3-b]peyridine (3 g, 15 mmol), 3-(mnorpholine- 4-carbonyl)pheny~lboronic acid (4 g, 18 mmol), sod®urn bicarbonate (4 g, 46 mrol), and tetrakis(triphenylgohosphine)palladium(0) in dioxanes/water (100 mL/20 mL) w=s stirred at 110 °C for 15 houmrs. The mixture was then poured —into ice water and extracted with ethyl acetate (3X). The organic layers were combined, dmried over sodium sulfate, fil—tered and concentrated to dr—yness. Silica gel chromatography~ of the crude product afforded (3-(1H- pyrrolo[2,3-b]pyr=idin-5-yl)phenyl)(morpholino)met-hanone (3.86 g, 84% yield) as yellow solids. MS: m/z 308. 1(M+H").

Step 2 : Synthesis of (3-(3-iodo-1H-pyrrolo[2,3-b]pyridin-S-y=l)phenyl)(morpholino) metha:-none.

[0249] L’o a solution of (3-(1H-pyrrolo[2,3-b]pyridin-5- yDphenyl): (morpholino)methanone (55 0 mg, 1.79 mmol) in acetone (10 mL) was added NIS (604 mg, 2.68 mmol) and the mixture was stirred at room temperatu_re for 20 minutes.

Acetone w~as removed by reduced pres sure and the crude product wzas purified by silica gel chromatog=raphy to afforded (3-(3-iodo-1H-pyrrolo[2,3-b]pyridin-5- yDphenyl) (morpholino)methanone (60 O mg, 77% yield). MS: m/z 4-34.2 (M+H").

Step 3 : Synthesis of (3-(3-iodo-1—tosyl-1H-pyrrolo[2,3-b]pyri&din-5-yl)phenyl) (morp holino)methanone.

[0250] A= mixture of (3~(3-iodo-1H-pyyrrolo[2,3-b]pyridin-5- yl)phenyl)a(morpholino)methanone (600 mg, 1.38 mmol), p-toluenes . ulfonyl chloride (528 mg, 2.77 ramol), potassium hydroxide (50% w/v in water, 0.387 mI-, 3.45 mmol) and tetrabutyla-mmonium hydroxide (40% “w/v in water, 0.448 mL, 0.69 mmmol) in toluene 5 mL) was s&irred at room temperature for 15 hours. Water was added to the mixture and the aqueous mixture was extracted by ethy acetate (3x). The organic la—yers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Silic=a gel chromatography of the crud =e product afforded (3-(3-iodo-1 -tosyl-1H-pyrrolo[2,3-b]p=yridin-5- - yDphenyl)(Cmorpholino)methanone (600 mg, 74% yield) as yellow soplids. MS: m/z 588.1 (M+HY).

Step 4: Synthesis of (3-(3-(2-fluor-ophenyl)-1 -tosyl-1H-pyrrol-o{2,3-b]pyridin-5- yDphemyl)(morpholino)methanon e.

[0251] A mixture of (3-(3-iodo-1-tossy/l-1H-pyrrolo[2,3-b]pyridin-5=- yDphenyl)(=morpholino)methanone (40 amg, 0.068 mmol), 2-fluorophe=nylboronic acid (18 mg, 0.128 r=amol), [1,1 *~Bis(diphenylphosphino)ferrocene]dichloropa_lladium(II) complex with dichlozromethane (3.9 mg, 0.005 mmol) and sodium carbonate (2M aqueous solution, 0.102 mL, O.204 mmol) in acetonitrile ( 1 mL) was heated in a Person-al microwave at 90 °C for 30 min. The resulting mixture was cliluted with water and extracteed with ethyl acetate,

The organics layers were combined, dried over sodium sulfate, filtered and concentrated to dryness to a_fford crude (3-(3-(2-fluoropThenyl)-1-tosyl- 1H-pyrrolo[2,3-blpyridin-5 - yl)phenyl)(rmorpholino)methanone, which was used in step 5 without further purification.

PCT/US200255/026792

Step 5: Synth esis of (3-(3-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5- yl)phenyl)(mo xpholino)methanone.

[0252] Crude (3—(3-(2-fluorophenyl)-1-tosyl-1H-pyrr-olo[2,3-b]pyridin-5- yDphenyl)(morpho lino)methanone from last step was @issolved in methanol (1 mI) and potassium hydroxicie (50% w/v, 0.038 mL, 0.136 mmo 1) was added to the solutiorn. The resulting mixture was stirred at room temperature for 3 © minutes before being dilvated with water and extracted with ethyl acetate. The organic lay=ers were combined, dried over sodium sulfate, filteered and concentrated to dryness. Thhe crude product was then cissolved in DMSO and purified by mass triggered reverse phase HPLC to afford pure (3-(3—(2- fluorophenyl)-1H-peyrrolo([2,3-b]pyridin-5-yl)phenyl)(norpholino)methanone (5.6 mg, 21% yield from (3-(3-i0cdo-1-tosyl-1H-pyrrolo[2,3-b]pyridin —5- yDphenyl)(morphoX ino)methanone) as light brown syrup. "HNMR (500 MHz, DNa1SO-d6) 9 3.60 (m, br, 8H), 7.33 (m, 3H), 7.39 (m, 1H), 7.55 (t, =/=17.5 Hz, 1H), 7.74 (m, 17H), 7.84 (m, 3H), 8.28 (m, 13H), 8.61 (d, J=2.5 Hz, 1H), 12.17 (ss, 1H). MS: m/z 402.1 (M+H").

[0253] Other conn pounds prepared by Method 6:

Table 6

I I

EtO. /

HN NH

J o~L wy” re 'e a, ® W '@

NTS l ci

SUS; g

O . .

N

~ US AS oO N_ o

MS: m/z 428.1 (M+ET). 0

MHD) MS: m/z 448.1 (M+H™).

MS: m/z 427.1 (M+H),

J. J. Jd

H

SS OJP so RENN =e

MNT NT NTS

7 9 0

SUS AS US

© 0 AE30 o AE31

MIS: m/z 444.1 (MAE). MS: m/z 432.1 (M+H). MS: m/z 428.1 (M—HTY.

Et / /

OQ Oo {ON HN ~ iN Foe P \ Ci HN cl 3 ) NT ENT

N Xx | l =z ~ =

LY SUSI IOUS

NA NJ N._ © 0 AE33 o

AE32

MS: m/z 462.1 (M+HD). MS: m/z 448.1 (M+HH,

MIS: m/z 444.1 (M+E), m/z 462.1 (MHI) (MH)

Et

Oo

SE OTN et ot 0-0) 0 =v ® b= i =

Pa

ZC] (To ) 0 0

NA C @ NJ

O AE34 0 0}

AE35

MSS: m/z 442.2 (M+HD. MS: m/z 398.1 (M+TH.

MS: m/z 432.1 (M+H")

Seewre | Sewemwe [Seman]

N

HN = “N \ oy HN \ / ) HN 2 Cp /

N ~~ NN" S NX = l lL _ ©] Oo (0—

MS: m/z 403.1 (M+HY). MS: m/z 404.1 QM+H).

MS: m/z 424.1 (M+H).

CN 0

HN \ —=N HN HN _N

P< =O

N N N = NX \, = > { _ 0 © (0)

NL CS 3 lo) o 3

MS: m/z 3868.1 (M+H"). AE36

MS: m/z 423.1 @uEY), | MS:m/z4 15.1 (M+HD). 8 Cl E “o

N™ NT NT oo oo 0 lo} 0 o)

MS: m/z 423. 1 MHD). MS: m/z 418.1 INAH). MS: m/z 4382.1 (M+),

WO

2006/01s123 PCT/US2005/026792 cl

HN A ) a HN \ C) HN 0 ®

NI N= NT p> | = | P 0) (To $ (To

J (S 4g NS N oO Oo O

MSS: m/z 452.0 (M+HD. MS: m/z 412.1 (M+HD). MS: na/z 398.1 (M+HD). [

HN \ — HIN \ ) HN \ ®

N TX \ KN NT NS

L lL c | = (J ous CAS

O fo) o

NS: m/z 385.1 (MAH).

MSS: m/z 420.0 (M+H). MS: m/z 412.1 (MHH),

HN HN HN =

Mrs a CO) nN SN 3 N Rt N = / o (0 (To 4 S ZC NA NS

MS: m/z 428.1 (M+H"). MAS: m/z 416.1 (MAH). MS : m/z 385.1 (M+).

Method 7:

Too x Ts, x o HN 0” oa ANT OJ lL STEP 1 LL Q __STEP2 = Q gE SUS; Se.

NA NS N

0 0 © AE37

Step 1: Synthesis of (3-(3-(2,6-dimethoxy phenyl)-1-tosyl-1H-pyrrelo[2,3-b]pyridin- 5-y)phenyl)(morpholino)methanone.

[0254] A mmixture of (3-(3-iodo-1-tosyl-1H-psyrrolo[2,3-b]pyridin-5- yl)phenyl)(rmorpholino)methanone (40 mg, 0.068 mmol), 2,6-dimethoxyp=henylboronic acid (18.6 mg, 0. 102 mmol), tetrakis(triphenylphosp=hine)palladium(0) (3.9 mzg, 0.0034 mmol) and sodium carbonate (2M aqueous solution, 0. 102 mL, 0.204 mmol) in a_cetonitrile (1 mL) was heated mn a Personal microwave at 120 °C £or 30 minutes. The result®mng mixture was diluted with. water and extracted with ethyl acet-ate. The organic layers were combined, dried over sodium sulfate, filtered and concentr.ated to dryness to afford cmrude (3-(3-(2,6- dimethoxyp_henyl)-1-tosyl-1H-pyrrolo[2,3-b]py ridin-S-yl)phenyl)(morpholino)methanone, which was cased in step 2 without further purification.

Step 2: Synthesis of (3-(3-(2,6-dimethoxy phenyl)-1H-pyrrolo[2,3-Bb]pyridin-5- yl) phen yl)(morpholino)methanone.

[0255] Methanol (1 ml) was added to crude (3-(3-(2,6-dimethoxyphenyyl)-1-tosyl-1H- pyrrolo[2,3-"blpyridin-5-yl)phenyl)(morpholino Jmethanone from step 1 armd potassium hydroxide (50% w/v, 0.038 mL, 0.34 mmol) wams added to the resulting so- lution. The mixture was stirred for 30 minutes at room temjerature before being dilut-ed with water and extracted wi th ethyl acetate. The organic layerss were combined, dried ovesr sodium sulfate, filtered and «concentrated to dryness. Silica gel «chromatography afforded «(3-(3-(2,6- dimethoxyplhenyl)-1H-pyrrolo[2,3-b]pyridin-5-—yl)phenyl)(morpholino)me=thanone (7) (31% yield from (3~(3-iodo-1-tosyl-1H-pyrrolo[2,3-b_g pyridin-5- yl)phenyl)(raiorpholino)methanone) as light yell_ow solids. "HNMR (500 MHz, CD;0D) 6 3.65 (m, br, 8H), 3.75 (s, 6H), 6.77 (d, J = 8.5 Hz, 2H), 7.31 (t, J = 8.5 H==, 1H), 7.39 (m, 1H), 7.46 (s., 1H), 7.55 (t, J =7.5 Hz, 1H), 7.67 (m, 1H), 7.74 (m, 1H), 7.9*1 (d, J = 2.0 Hz, 1H), 8.45 (d_, J = 2.0 Hz, 1H). MS: m/z 444.1 (\/+H).

PCT/WS2005/026792

[0256] Other compounds prepared by Method 7:

Table 7 sr 7 7 - 0] ®) 0

N™™ NT == Cl Z F ro ro g N.S CO) NA «<< 0)

MS: m/z 448.1 (M+HY). MS: m/z 432.1 (IM+H").

Method =: \

N—

HN HN— HN \ HN Ho

N

N > STEP 1 N > o __STEP2 NS ( STEP 3 Cy

LZ ZZ

Br Br Br Br

Ts, Ti H

Ts, . Ts N AN N HN \ N. N

My NS UY NTS \ _STEP4 Ny \ 4 steps | P STEP 6 oz _ tte. mt

Bo = 0]

Step XA: Synthesis of 1-(5-bromo-1H-pyrrol o[2,3-b]pyridin-3-yl)-ethaneone.

[0257] "To a stirring solution of aluminum chloride (6.77 g, 50.75 mmol) suspended in anhydrouss CHCl; (100 mL) under N;, was added 5-bromo- 1H-pyrrolo[2,3-b]oyridine (2.00 8, 10.15 mmol). The reaction solution was stirred for 1 hour at ambient tempeSrature whereupomn acetyl chloride (3.61 mL, 50.75 mmo 1) was added dropwise and th_e resulting solution w~as stirred for 5 more hours. The reaction was cooled to 0 °C in an ice bath and quenched carefully by addition of MeOH until the solution became clear. The reaction was concentrat-ed under vacuum. HO was added and 1 N NaOH was added dropwise until the

PCT/US2005/026792

PH = A. The product was extracted into ethyl acetate and the organiec layer was washed with a saturated solution of sodium potassium tartrate to remove any remaining aluminum salts.

The or-ganic layer was dried over NaS; and concentrated under va_cuum. The material was re: dissolved in ethyl acetate and filtered through a bed of silica g=el. The filtrate was concerntrated to afford the title compourd as an orange solid (2.25 g, 93% yield). 'H NMR (500 MHz, ds-DMSO) § 12.70 (br s, 1H), 8.56 (d, J=2.5 Hz, 1H), 82.55 (s, 1H), 8.40 (d, J= 2.5 Hz , 1H), 2.46 (s, 3H). MS: m/z 238. 9/240.9 (M + H").

Ste=p 2: Synthesis of 1-(5-bromo-1 H-pyrrolo(2,3-b]pyridin-3-yl)-3-dimethylamino- propencne.

[0258] To 1-(5-bromo-1H-pyrrolo[2,3-b}pyridin-3-yl)-ethanone (2 .25 g, 9.41 mmol) was added £ert-butoxybis(dimethylamino)methane (5.83 mL, 28.23 mmom) (neat) and refluxed in an oil bwath at 100 °C for 6.5 hours. The reaction was cooled and titra ted with diethyl ether.

The sol id was filtered and dried under vacuum to afford the title compound as an orange powder— (1.93 g, 70% yield). 'H NMR (500 MHz, ds-DMSO) 5 8.67 «(d, J=2.5 Hz, 1H), 8.37 (s, 1H), 8.31 (d,J=2.0 Hz, 1H), 7.57 (d,J=12.5 Hz, 1H), 5.78 (d,J=12.0 Hz, 1H), 2.49 (s, 6H).

Step 3: Synthesis of 5-bromo-3-(2 F-pyrazol-3-yl)-1H-pyrrolo A2,3-b]pyridine,

[0259] To a solution of 1-(5-bromo- 1FZ-pyrrolo[2,3-b]pyridin-3-yl)—3-dimethylamino- propeno=ne (1.93 g, 6.54 mmol) in ethano 1 (5 mL) in a microwave vial was added anhydrous hydrazire (247 uL, 7.85 mmol). The reaction mixture was heated in ax microwave at 80 °C for 2.5 hmours. The reaction mixture was Concentrated under vacuum tc afford the title compoumid as a reddish brown powder (1. 50 g, 87% yield). 'H NMR (C500 MHz, ds-DMSO) 6 12.71 Cs, 1H), 11.97 (s, 1H), 8.62 (s, 1H), 8.30 (s, 1H), 7.94 (s, 1H), 7.75 (s, 1H), 6.65 (s, 1H). MS: m/z 263.0 (M +H).

Step 4: Synthesis of S-bromo-1-(tolwene-4-sulfonyl)-3-[2-(tolue. ne-4-sulfonyl)-2H- pyrazzol-3-ylj-1H-pyrrolo[2,3-b] pyridine.

[0260] To a solution of S-bromo-3-(2H-pyrazol-3-yl)- 1H-pyrrolo[2,3-b]pyridine (1.51 g 5.75 mmeol) in toluene (5 mL) was added tetrabutylammonium hydroxide (40% wt in H,0, 285 ul) sand a 50% KOH (aq) solution (5.7 mL). The reaction mixture was stirred for 20 minutes aat ambient temperature and para-toluenesulfonylchloride (2.17% 8, 11.50 mmol) was added. The reaction was stirred at ambien® temperature for 2.5 hours. The product was extracted into ethyl acetate and the organic layer was washed with HO then dried over

Na,SO4. The material wass concentrated under vacuum and =dsorbed onto silica gel—

Purification by flash chrormatography on silica gel with a graxdient of ethyl acetate amd hexane afforded the title c=ompound as a yellow solid (1.73 =, 53% yield). IH NMR=. (500

MHz, de-DMSO) 5 8.68 (=, 1H), 8.57 (d,J=2.5 Hz, 1H), 8-54 (d,J= 2.5 Hz, 1H), 849d,

J=12.5Hz, 1H), 7.96 (4, J =9 Hz, 2H), 7.92 (d,J=8.5 Hz, 2H),7.47(,J= 8.5 H:z, 2H), 7.41 (d, J =8 Hz, 2H), 7.229 (d,J=3 Hz, 1H), 2.36 (s, 3H), 232(s, 3H). MS: m/z 570.9/571.9 (M +H).

Step 5: Synthesis fh) =4 5.(4,4,5,5-tetramethyl-[1,3,21dieoxaborolan-2-yD-1-(toMucne-d- sulfonyl)-3- [2-(tolue=ne-4-sulfony)-2H-pyrazol-3-y1l —1H-pyrrolo[2,3 -b] pyridine.

[0261] To a solution of 5_bromo-1-(toluene-4-sulfonyl)- 3[2-(toluene-4-sulfony1)-21- pyrazol-3-yl]-1H-pyrrole(2,3-b]pyridine (1.73 g, 3.02 mm_ol) in DMF (7 ml)ina microwave vial was add ed bis(pinacolato)diboron (1.54 g.. 6.04 mmol), {1,1°- bis(diphenylphosphino)=ferrocene]dichloropalladium (ID), complex with dichloronmiethane (1:1) (86 mg, 0.11 mmos=1), and sodium acetate (0.74 g, 9.096 mmol). The vial was. capped, flushed with Na, evacuauted under vacuum, and heated in & microwave at 140 °C or 3600 seconds. The product vvas extracted into ethyl acetate, washed with HO, dried omver

Na,S0;, filtered, and aclsorbed onto silica gel. The crude material was purified j-mmediately by flash chromato graphy using a gradient of ethyl acetate and hexane. The purification afforded the title compeound as a white solid (0.72 g, 39% yield). "HNMR (500 MHz,

CDCl) & 8.81 (s, 1H), 8.73 (s, 1H), 8.16 (m, 1H), 8.07 (J = 8.0 Hz, 2H), 8.04 (m, 2H), 7.038 (d, J = 8.0 Hz, 27H), 7.24 (d, J=18.0 Hz, 2H), 6.67 (m, 1H),2.41(d,J= 6.=5 Hz, 3H), 2.36 (d, J = 5.5 Hz, 3FH), 1.39 (s, 12H). MS: m/z 619.1 (M+ HY.

Step 6: Synthesis: of 5 [3-(2H-pyrazol-3-yl)-1H-pwrrolo[2,3-blpyridio-S—yll- nicotinamide.

[0262] Toa solutior of 5.(4,4,5,5-tetramethyl-{1,3,2]ioxaborolan-2-yD)-1-(toluene-4- ulfonyl)-3-[2-(toluenLe-4-sulfonyD)-2H-pyrazol-3-yl-L Fpyrrolo[2,3-blpyricin.© (56 mg, 0.09 mmol) ina 1:1 a~cetonitrile/saturated aqueous NaH COs solution (2 mL total)ina microwave vial was aadded 5_bromonicotinamide (20 m_g, 0.10 mmol) and [1,17 - bis(diphenylphosphirmo)ferrocene]dichloropalladium (IL), complex with dichloromethane (1:1) (3.7 mg, 0.004 1rmmol). The vial was capped, flusthed with Na, evacuated under vacuum, and heated 1. na microwave at 90 °C for 1800 seconds. The product w=2as extracted into ethyl acetate anc the organic layer was dried over Nap;SQ4. The solution wwas filtered and concentrated uncer vacuum. The residue was redissolved in a 1:1 MeOH acetone solution (2 mL total) andl treated with 200 uL of 50% KOH (aq) solution and stimred at ambient temperature for 1 hour. Citric acid (1 M) was audded dropwise untilpH = 7 and the product was extracted into ethyl acetate. The organic la_yer was dried over Na; S04, filtered, and adsorbed onto silica gel. The material was purified by flash chromatograplmy using a gradient of ethyl acetate (containing 10% MeOH) and hmexane then concentrated? under vacuum. The residue w=as titrated with diethyl ether to =afford the title compound as a beige solid (0.8 mg, 3% yield. 'H NMR (500 MHz, ds-DMSS0) 8 12.67 (s, 1H), 11.87 (s, 1H), 8.95 (s, LH), 8.62 (s, LEX), 8.50 (s, 1H), 8.25 (5, 1H), 7.89 (5, 1H), 7.63 (s, 1H), 741(d,J= 7.5 Hz, 1H), 7.05 (d, J="7.5 Hz, 1H). MS: m/z 305.0 (OM +H).

[0263] Other compoumnds prepared by Method 8:

Table 8

H H H

HN \ Ney HN \ Ney HN \ Nyy

NT \_/ NTS \_/ NT \_/

I _ | _g I x N+ o- Ss N on NN AE3 OH AE { MS: m/z 278.1 (MHHD. 3 39

MS: m/z 302.0 MAH). MS: m/z 403.9 (CM+HD).

H

HN Noy, HN H x N

N NI NX < N

Z

YZ

C]

NH xX

N=/ N° "OH

MS: m/z 301.1 (VHT). MS: m/z 278.1 (M+HI).

Method 9: )

NH, NH, OH NH; O NH,

Sa STEP 1 OD STEP 2 0 SSTEP3 Spe = - ZZ — > — =

Br Br Br Br

HN \ HN \

STEF>4 Sas stePs NN — SteErs _

OH

Step 1: Synthesis of (2-amino-5S-bromo-phenyl)-cyclopentyl _-methanol.

[0264] To a solution of 2-Amino-5 -bromo-pyridine-3-carbaldehy-de (632 mg, 3.14 mmol) in anhydrous THF (20 mL) was methylmagnesium bromide 3M in diethyl ether (6.06 mL, 34.8 mmol) is added at -50 °C. The reaction mixture was warmed tc room temperature and stirred o=vernight. Saturated aqueous ammonium chloride was adde=d to the mixture (15 mL), the organic layer separated and the aqueous phase extracted with EtOAc (3x20 mL).

Organic layers were dried over sodium sulfate, filtered and concent=rated. The crude residue was purified by flash silica chromato graphy with a gradient of ethy=1 acetate in hexanes. (2-

Amino-55-bromo-phenyl)-cyclopentyl-methanol (425.9 mg, 50% yiesld) was obtained as a yellow powder. MS: m/z 271/273[MH").

Stepe 2: Synthesis of (2-amino-5-bromo-pyridin-3-yl)-cyclop entyl-methanone.

[0265] A mixture of (2-Amino-5-bromo-phenyl)-cyclopentyl-met=hanol (425.9 mg, 1.57 mmol) a-nd manganese(IV) oxide (2.7 3g, 31.4 mmol) in dichloroetinane (12 mL) was heated at 50°C for 20 hrs. The mixture was filtered over a pad of celite, the= filtrate was then evaporated down to give (2-Amino-5-bromo-pyridin-3-yl)-cycloperntyl-methanone (363.2 mg, 86%S yield) as a yellow powder. IMS: m/z 269/271 [MH].

Step 3: Synthesis of S-bromo-3-(1-cyclopentyl-2-methoxy-vinyl)-pyridin-2- ylanmire.

[0266] To a suspension of methoxymethyltriphenylphosphonium - chloride (2.03 g, 5.92 mmol) ira THF (8 mL) cooled to 0 °C, potassium(bistrimethylsilyl)ammide was added (1.26 g, 6.32 mm_ol). The mixture was stirred ait 0 °C for 30 minutes, and 2-a_mino-5-bromo-pyridin- 3-yD-cyczlopentyl-methanone (363.2 mg, 1.35 mmol) in 5 mL of THF was added. The reaction mixture was stirred at room temperature overnight. The solution waus filtered over a pad of silicam gel, the filirate was then evaporated, and the residue was purifie=d on flash chromatography with a gradient of EtOAc in hex anes to give 5-bromo-3-(1-=cyclopentyl-2- methoxy-vimyl)-pyridin-2-ylamine (116.9 mg, 29 © yield) as a white solid. T™S: m/z 297/299 [IM H'].

Step 4: Synthesis of 5-bromo-3-cyclopenty 1-1H-pyrrolo[2,3-b]pyridiine.

[0267] A mixture of 5-bromo-3-(1-cyclopentyl—2-methoxy-vinyl)-pyridin—2-ylamine (116.9 mg, €.39 mmol) and perchloric acid (0.1 nL) in dioxane (1 mL) was heated at 80 °C for 2 hrs. Solvents were evaporated and the residiie was washed with a solut=ion of 2M sodium cartoonate (5 mL). A precipitate was formed and filtered off. Yt was washed with water and daried to afford the product 5-bromo-3-cyclopentyl-1H-pyrrolo[2,38-b]pyridine (69.8 mg, 677% yield) as a brown solid. MS: m/z 265/266 [MH].

Step 5: Synthesis of 3-(3-cyclopentyl-1H-pwrrolo[2,3-b]pyridin-5-yl) -phenol.

[0268] A mixture of 5-bromo-3-cyclopentyl-1H-pyrrolo[2,3-b]pyridine (3 “1.8 mg, 0.12 mmol), 3-hodroxyphenylboronic acid (33.1 mg, 0.24 mmol) and 4.2 mg (5 n=l %) of : dichlorobis( triphenylphosphino)palladium(l) were placed in a vial and 0.8 nl of acetonitrile and 0.8 ml of a 2M aqueous solution of sodium carbonate were added and thes mixture irradiated in. a Personal Chemistry® microwave reactor to 150 °C for 900 seaconds. The resulting mixture was distributed between 15 mL of a saturated aqueous solumtion of sodium bicarbonate and 30 mL of dichloromethane. The organic phase was dried ov=er sodium sulfate and evaporated. The crude was purified vZa silica gel chromatography using a gradient of ethyl acetate in hexanes to give 3-(3-Cyclopentyl-1H-pyrrolo[2,3 -blpyridin-5- yl)-phenol (<4.5 mg, 14% yield) as off white powd er. 'H NMR (500 MHz, CID30D) 6 8.36 (s, 1H), 8.14 (d, 2H, 1H), 7.29 (t, 8Hz, 1H), 7.19 (s, 1H), 7.10 (d, 7Hz, 1H),_ 7.06 (s, 1H), 6.79 (dd, 2H z, 8Hz, 1H), 2.1 (m, 2H), 1.94 (m, 23), 1.8 (m, 4H), 1.37 (m, 11). MS: m/z 279.1 [MH].

™ethod 10: o~ 0” o—

TSN HN HN

NT NTS P NTS () (50 sep 1, Wo ; # 3p -

HN "Ve

Step 1: Synthesis of 5—[3-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-3-(2-mmethoxy- phenyl)-1H-pyrrolo[23-b]pyridine (723-21-262) and 2-{3-[3-(2-Methoxy—phenyl-

H-pyrrolo[2,3-bjpyrdin-5-yll-phenyl-imidazolidirm-2-ol

[0269] A mixture of the 3. (2-Methoxy-phenyl)-5-(4,4,5,5-tetramethyl- [1,3 ,2]dioxaborolan-2-yl)- 1-(tolucne-4-sulfonyl)-1H-pyrro 1o[2,3-b]pyridine (4 mg, 0.085 mmol), 2-(3-Todo-phenyl)—4,5-dihydro-1 H-imidazole (34.7 mg, 0.128 mmol) ard 1,1'- bis(diphenylphosphino)fer=rocencpalladium(n)-dichloride Gichlormethane adduect (3.1 mg, 4.2 pmol) in 0.8ml acetoritrile/0.8ml 2N sodium carbonate irradiated in a Personal

Chemistry Optimizer at 135 oC for 20 minutes. The crude reaction mixture waas distributed between dichloromethane= and a saturated aqueous solutiom of sodium bicarbornate. The aqueous phase was then e=xiracted with dichloromethane and the combined org=anic phases were dried over sodium s ulfate, filtered and concentrated. The crude product —was then purified by flash silica ge=1 chromatography using a gradient of ethyl acetate inm hexanes to afford 5-[3-(4,5-Dihydro- _{4-imidazol-2-yl)-phenyl]-3-(2-methoxy-phenyl)- 1H-pyrrolo[2,3- b]pyridine (11.2 mg, MS-: MS: m/z 369.1 (MH) and 2-{ 3-[3-(2-Methoxy-pheenyl)-1H- pyrrolo[2,3-b]pyridin-5-y}-phenyl}-imidazolidin-2-ol (1 3.2 mg, m/z 387.1 [N~AH']), both as green solid.

Method 11:

MeO

HN MeO HN) O)

NT

NT () lL \ _STEP1,

J OH

OH (oN oS

Step 1: Syntheesis of 5-[3-(2-Methoxy-phenyl)- 1H-pyrrolo[2,3-b] p>yridin-5-yl]-2- morpholin-4-y=1methyl-phenol.

[0270] A mixtures of 3-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridir-5-yl}-phenol (14.2 mg, 0.045 mmol), morpholine (5.87 pl, 0.067 rxmol) and paraformamldehyde (2.7 mg, 0.09 mmol) in 400 pl of methanol/toluene (3:7) was stirred at 60 °C for 1 hour, then 90 °C for 3 hours. The resulting light brown residue was purified by flash silicam gel chromatography ussing a gradient of ethyl acetate in Inexanes to afford 5-[3-(2-methoxy- phenyl)-1H-pyrrol o[2,3-b]pyridin-5-yl}-2-morpholinm-4-ylmethyl-phenol C 11.7 mg, 63% yield) as white sold. II NMR (500 MHz, CD30D) § 8.44 (d, 1.5Hz, 11"), 8.22 (4, 1.5Hz, 1H), 7.65 (s, 1H), 7.56 (dd, 1.5Hz, 7Hz, 1H), 7.37 («d, 8Hz, 1H), 7.32 (dt 2Hz, 7.8Hz, 1H), 7.19 (dd, 2Hz, 8H=, 1H), 7.17 (4, 1.5Hz, 1H), 7.14 (<, 8Hz, 1H), 7.06 (dt 1Hz, THz, 1H), 4.18 (s, 2H), 3.87 «(s, 3H), 3.85 (br s, 4H), 3.09 (brs, 4H). MS: m/z 416.1 MH".

[0271] Other commpounds prepared by Method 11:

Table 9

Stwnme ] Swews | See

MeO MeO MeO

HN \ HN \ HN \

APC Na AC) & l= '

OH | OH OH

HN SNT N

LL) _ NG HO 1

MS: m/z 431 [MH 7]. MS: m/z 444 [MH].

MS: m/z 457 [MHZ].

HN MeO HN MeO J} \ \ H, o

N° ~~ NN N \ ©

N ~

OH AN 9g OH

N OH N

> MS: m/z 459 [MH']. oH -*

AE40 MS: m/z 458 [MH].

MS: m/z 443 [MF].

J od o

HN \ HN \ HN \

SAY SAY SAY

1 _ [} PP [| P

SUSHNIE ly

A PJ LL

OH OH N OH OLN

\

MS: m/z 416 [ME]. MS: m/z 431 [MH].

MS: m/z 457 [MH] . nd o

HN \ HN \

NTS © NS ©» lb >

N

J “RI

N 0,

OH OH AFA

MS: m/z 444 [MET]. MS: m/z 443 [MH].

Method 12: — 0 MeO 0 Ts

Ts<y 1 N \ HN \

IN x

NT vy © yy © lL STEP1 ~~ STEP2 F 9g QT g OMe N

CN

NH NH

Step 1 : Synthesis of methyl 3-(3-(2—methoxyphenyl)-1-tosyl—1H-pyrrolo[2,3- b]pyridin-5-yl)benzimidate.

[0272] ECI gas was bubbled through a suspension of 3-[3-(2-Me-thoxy-phenyl)-1- (toluene-4~-sulfonyl)-1H-pyrrolo[2,3-blpy~ridin-5-yl]-benzonitrile (287.8 mg, 0.60 mmol in 3.5mL of anhydrous MeOH. The mixture was then stirred for 5 homurs at room temperatmre before ethuer (20 mL) was added. The precipitate was then collecte d by filtration and dri_ed to afford rmethyl 3-(3-(2-methoxyphenyl)y -1-tosyl-1H-pyrrolo[2,3-t> [pyridin-5- ylbenzimmidate without further purification.

Step 2: Synthesis of (1-(imin o(3-(3—(2-methoxyphenyl)-1H-"pyrrolo[2,3-b]pyridi&n-5- yhpheenyl)methyl)piperidin-4-yl)methanol.

[0273] ~The imidate precipitate was them dissolved in MeOH to a_ total volume of 15.0 mL, it was then divided into 15 equal portions (ca. 0.04 mmol each) for= reaction with 15 different mines. To this imidate solution was added the 4-hydrox_ymethylpiperidine (9.9mg, 0-.086mmol, 2eq) and triethylamine (60 ul, 0.43 mmol, 10 eq.), the mixture wass stirred at —room temperature for 2days. A tthe end of 2 days, NaOF (20 mg, 0.5 mmol) mn 100 ul water was added to each reaction mixture to hydrolyze the =sulfonamide. The reaction wvas done 0 °C overnight. After removing the solvents, th_e crude product was purified con reverse phase HPLC to give =5.0mg of [4-(imino- {3-[3—(2-methoxy-phenyl)- 1H- pyrrolo[2 ,3-b]pyridin-5-y1]-phenyl}-methyl)-cyclohexyl}-methanco] as a white solid. 'H—

NMR (5080 MHz, CD30D) 58.54 (d, 2Hiz, 1H), 8.33 (d, 2.5Hz, 1H), 8.00 (dt, 1.5Hz, 9K1z, 1H), 7.91 (brs, 1H), 7.35 (t, 7.8Hz, 1H), 7.70 (s, 1H), 7.58 (m, 2H), 7.32 (dt, 1Hz, 8.3Fz, 1H), 7.12. (dd, 1Hz, 8Hz, 1H), 7.07 (dt, L Hz, 7.3Hz, 1H), 3.86 (s, 3H), 3.48 (d, 6.5Hz, 2-H), 3.38 (m, =4H), 1.78 (m, 1H), 1.42 (m, 4H). MS: m/z 441.1 [MH].

[0274] Other compounds prepared by Method 12:

Table 10

I cc RE

MeO MeO HN MeO

HN \ HN \ \ eS SI Ve 5 NE Ye Ve © 1 — LJ ~~ ! “

OH

OH

SUSEINISUS SIN «UST

NH NH NH OH

MS: m/z 427.1 [MH]. MIS: m/z 441.1 [MH]. MSS: m/z 441.2 [MH].

MeO MeO MeO

HN \ HN \ HEN \

Se CI Sa © T= Ya 1 1_ ® 1 ro H ON >

SYST LAA SY

NH NH NH

MS: m/z 427.1 [MH]. MIS: m/z 456.2 [MH]. MSS: m/z 440.2 [MH].

MeO MeO MeO

HN \ HN \ HEN \

Se VI a CI "= a 1 ~ OEt 1 ~~ 1 7”

J a 9 oN 2) PEN 2) ( e

NA NA J

NH NH NH

MS: m/z 484.2 [MH]. MIS: m/z 454.2 [MH]. MSS: m/z 440.2 [MH].

MeO MeO MeO

HN \ HN \ HN \

ST) nS) YL) ! ~~, n ~ l 7

OH

SUSIE SUL

N N_ NO

NH NH NH

MS: m/z 413.1 [MH]. MS: m/z 371.1 [MH]. IMSS: m/z 399.1 [MH].

I i I

Mel MeO HN ‘MeO

HN \ HN \ \

SAY SAY SEY r 1 r OH

NM J

SON SUN CUS:

New, N Nn

NH NH MH

MS: m/z 399.2 [MH]. MS: m/z 428.2 [MH]. MS: m/z 456.1 [MH'].

HN MeO MeO MeO \ HN \ HN \

AE WO YO

& 1 1 9 QI 0D

N N N

NH AE42 NH BNH

MS: m/z 411.1 [MH]. MS: m/z 413.1 [MH]. MS: m/z 397.2 [MH'].

HN MeO MeO MeO \ HN \ HN \

YY TR) SAY, wy 1) 1 “ ! ~ 1 ~~

S$: QS: QS iv hd “A

NH NH INH

MS: m/z 383.1 [MH]. MS: m/z 385.2 [MH]. MS: m/z~ 399.2 [MH].

Method 13:

MEeO

MesO HN

HN A

XX

NT STEP 1 N > = oo

CN HN" SN

N=N

Step 1: S=ynthesis of 3-(2-Methoxy-phenyl)-5—(1 H-tetrazo}-5-y1)-1H-pyrrolo[2,3- b]pyridin«e.

[0275] A m#xture of -(2-Methoxy-phenyl)-1H-py-rolo[2,3-b]pyridine-5-c=arbonitrile (24.9 mg, 0.10 mmol), sodium azide (78 mg, 1.2 mmol) aand ammonium chloride (64.2 mg, 1.2 mmol) were p-laced in a vial and 2m} of DMF were added. The mixture was irradiated in a

Personal Chermistry® microwave reactor at 150 °C for 900 sec, then 165 °C for 600 sec.

The mixture v=vas concentrated and purified via flash silica gel chromatography using a gradient of etinyl acetate in hexanes to give 3-(2-Methoxy-phenyl)-5-(1H-tetrazol-5-yl)-1H- pyrrolo[2,3-b pyridine (28 mg, 95% yield) as a pale yellow solid. 'H NMR_. (500 MHz,

DMSO-d6) § 11.95 (brs, 1H), 8.92 (d, 2Hz, 1H), 8-59 (d, 2Hz, 1H), 7.99 (b=xs, 1H), 7.74 (s, 1H), 7/59 (dd, 1.5Hz, 7.5Hz, 1H), 7.33 (t, 7.8Hz, 1H), 7.16 (d, 8Hz, 1H), 7. 10 (t, 7.5Hz, 1H), 3.84 (s, 3H). MS: m/z 293.1 [MH].

Method 14:

MeO

MeQ HN) sae SAY i —

HO ® OMe

OMe ’ OMe

Step 1: S.ynthesis of [3-(2-Methoxy-phenyl)- 1H-pyrrolo[2,3-b]pyriditin-5-y1]-(3,4,5- trimethoxxy-phenyl)-methanol.

[0276] A soolution 1.5M n-BuLi in hexanes (160 pL, 0.24 mmol) was add_ed to a solution of the 5-brom_o-3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2 ,3-b]pyridine (91.5 mg, 0.2@0 mmol) in 2ml THF at -78 °C. The mixture was stirred at -7 8 °C for 30 minutes befor-e 3,4,5-trimethoxy-benzaldehyde (94- .2 mg, 0.48 mmol) in 3 rulL of THF was added. The mixture was stirred at -78 °C for 1 howrand then at 0 °C for 30 minutes, quenched witzh MeOH, and then concentrated. The crude residue was purified by silica gel chromatograpwhy using a gradient of ethyl acetate ira hexanes to give [3-(2-Methoxy-phenyl)- 1H-pyrrolo[2,3-blpyridin-5-y1]-(3,4,5-trimethoxy-phenyl)-methanol (32 mg, 38% yield) as a white solid. MS: m/z 420.1 [MH"].

[0277] Other compounds prepared by Method 14: :

Table 11

MeO Me=0

HN \ HN \

NTS 7) NTS 1 '

HO 0) OMe HOT YS

Pp

OMe

OMe MS: m/z 332 [MH].

MS: m/z 421 [MH'].

Method 15:

HN MeO

Ts, MeO \ :

ES l~

N STEP 1 = —— = Na

Ns"cho NY

L_ No

Step 1: Synthesis of [2-(4@-{5-[3-(2-Methoxy-phenyl)-1 E1-pyrrolo[2,3-b]pyridi n-5- yl]-pyridin-3-yl}-piperazin-1-yl)-ethyl]-dimethyl-amine.

[0278] To a solution of 5-[3—(2-Methoxy-phenyl)-1-(toluene=-4-sulfonyl)- 1H-pyrroleo|2,3- b]pyridin-5-yl]-pyridine-3-carbraldehyde (24 mg, 0.050 mmol") and dimethyl-(2-pipereazin-1- yl-ethyl)-amine (10 pL, 0.065 1nmol) in 1.5 ml dichloroethane was added 3 pL of AceOH.

The mixture was stirred at rooxm temperature for 30 minutes before sodium trioxyacetylborohydride (22mgz, 0.10mmol) was added. The reaction mixture was stimred at room temperature for another 2 hours before being concentrat-ed. The resulting residize was then dissolved in 2m! of MeOH], to this was added 100 pL of =SN NaOH, the mixture wvas stirred at 60 °C for 2 hours. Solvents were removed and the ressidue was purified by flash silica gel chromatography usin_g ethyl acetate and then a solve .nt mixture (NH4OH/MeOH/CHCL/EtOAnc=0.05/1/4/4) to afford [2-(4-{=5-[3~(2-Methoxy-pheny-1)-1H- pyrrolo[2,3-blpyridin-5-yl]-pywridin-3-yl}-piperazin- 1-yl)-ethy~1]-dimethyl-amine (4.70 mg, 20% yield ) as a white solid. NAS: m/z 471 [MH"].

[0279] Other compounds prepared by Method 15:

Table 12 aN o’ H, J H, of

N HIE ll) 0 EO KE

Z ' =

ANS ~~ NMe; a C) SUS)

NS N Na NS

F F MS: m/z 471 [MH+].

MS: ra1/z 488 [MH+]. MS : m/z 402 [MH+].

H, J H, d H, of

N \ N \ NE \ 'S "SAY SOY 1 _R 1 1 __

LED SUS LID

3

MS: on/z 385 [MH+]. MS : m/z 470 [MH+]. MS: m/z 384 [MH+].

Methosd 16: / 0]

Ts, o HN - av

N=

NT STEP1 ll 1

Bo =o CT 4 N

HN—{

Stezp 1: Synthesis of 5-[3-(2-MI ethoxy-phenyl)-1H-pyrrolo[2,.3-b]pyridin-5-yl]-2- me=thyl-1H-benzoimidazole. [02801 To a solution of 5-(4,4,5,5 —tetramethyl-[1,3,2]dioxaborola—n-2-yl)-1-(toluene-4- sulfon-yl)-3-[2-(toluene-4-sulfonyl)-2H-pyrazol-3-yl]-1 H-pyrrolo[ 2, 3-b]pyridine (50.4 mg, 0.10 namol) in a 1:1 acetonitrile/satuarated aqueous NaHCO; solutiom (2 mL total) in a microwave vial was added 5-bromo2-methyl-1H-benzoidmidazole (46 mg, 0.22 mmol) and [1,1°-bis(diphenylphosphino)ferrocene]dichloropalladiumm (II), complex with dichloromethane (1:1) (3.7 mg, 0.004 mmol). The vial vas capped, flushed with ID, evacuated under vacuum, and stirred in a microwave at 155 °C for 1800 seconds. “The product was extracted into ethyl acetate and the organic layer was dried over NaS Os. The solution was filtered and concentrated under vacuum. T he residue was purified by reverse- phase HPLC to affor-d 5-[3-(2-Methoxy-phenyl)-1H-pyr—rolo[2,3-b]pyridin-5-yl]-2—methyl- 1H-benzoimidazole zs a beige solid (10.1 mg, 28% yielcd m/e 355 (M + HY.

Intermediate Synth esis:

Synthesis of 5-Bromno-2-isopropyl-1H-benzoimidazoMe

Br

NH2 "he + Yo — QL wl

Br

[0281] A mixture of 4-bromo-benzene-1,2-diamine da-HCl salts (1 g, 3.8 mmol?) and isobutyraldehyde (0-71 mL, 7.7 mmol) in 10 mL of wat=er was stirred at 100 °C for 15 hours.

Solvents were remowed to afford the crude 5-bromo-2-i sopropyl-1H-benzoimidaz ole as a dark brown solid, which was used directly without furtler purification. MS: m/e 239.0/241.0 [MH].

Synthesis of 5-Broxmo-2-methyl-1H-benzoimidazole

NH2 Br

NH2 OH

Cr SE Ql,

Br HNL

[0282] A mixture of 4-bromo-benzene-1,2-diamine d_i-HCl salts (2 g, 3.8 mmol ) and acetic acid (0.87 mL_, 15.2 mmol) in 10 mL of water waas heated at 100 °C for 15hars.

Solvents were removed, the crude 5-bromo-2-methyl-1"H-benzoimidazole was obtained as a dark brown solid, which was used directly without furtlher purification. MS: m/e 239.0/241.0 [MH]. [(0283] Other compounds prepared by Method 16:

15123 PCT/U1S2005/026792

Table 13 7 MeO MeO

HN o HN A HN \ \ ()

NT NT

IY P ® lz { _ 7

Q oN 0

N HN ab SOON " MS: m/z 341 H - =b

S: 41 (M+H). 2341 (MAH) MS: m/z 342 (VIE).

MS: m/z 383 [MH].

MeO

HN oaY

ZZ

F 9 F

OH AE44_,

MS: m/z 353 M+H+)— a) Purification on sili. ca gel with a gradient of metharol/dichloromethane b) Dichlorobis (tripheenylphosphino)palladium (I) as catalyst

Method 17: 0 lo]

NH: Ai An Pls HN" HN

NT STEP 1 NS! _sTEP2 NN STEP 3 NX STEPS NTS = | es | _ | Pr =

Br . Br Br Br Br

Step 1: Synthesis of N-(5-bromo-3-iodo-pyridin-2=-yl)-acetamide.

[0284] Toa solution osf 2-amino-5-bromopyridine (12-7g,73.4 mmol) in DMF (150 ml) was added iodine (14.9g=, 58.7 mmol) and sodium periodate (6.3 & 29.4 mmol). The reaction mixture was sti-yred at 90 °C for 20 hours, then ediluted with water and extracted with ethyl acetate. The —ombined organic extracts were washed twice with za 1 M aqueous solution of sodium thiossulfate, dried over anhydrous magnesium sulfate, amd filtered over a pad of silica gel. Solvert was evaporated to give 16.5 g of abrown solid. T he solid was dissoelved in THF (150 ml) and cooled t-o 0 °C. Pyridine (6.7 ml, 717 mmol) was added, followed by dropwise addition of acetyX chloride (5.1 mi, 71.7 mmol). The reaction mixtures was sstirred at room temperature for 20 Thours then at 60 °C for 4 hours. Solvent was evapworated and the residue was partitiomed between water (200 ml) atnd dichl_oromethane(250 ml). The aqueous layer was extracted three tirmes with dichloromethane and the combined organic layers were dried over &anhydrous magnesium sulfate and filtered off. Purification by —flash chromotography on sil3ca gel with a gradient ©f ethyl. acetate/hexanes afforded the title ecompound as an orange solidi (7.76 g, 41% yield). by =i

NMR (DMSO-dg): § 10.17 (s, 1H), 8.5 5(d, J=2.0 Hz, 1H), 8.54 (&,]J=2.0 Hz, 1H), 2.01 (Cs, 3H); HPLC/MS m/z: 340.8, 342.8 [MH]. Diacetylated material wa_s also isolated as a ligh=t orange solid (7.0g, 33 % yield). '"H NMR (DMSO-ds): & 8.78 (d, J=—2.5 Hz, 1H), 8.74 (d,

J=2. 5 Hz, 1H), 2.17 (s, 6H); HPLC/MS m/z: 402.8, 404.8 [MNa]". [0285S] The diacetylated material (7 g , 18.27 mmol) was dissolved] in dichloromethane (180 ml) and treated with PS-trisamine (26 g, 3.53 mmol/g loading, Argonaut

Tech nologies) for 17 hours. The resin vsvas filtered off, washed with_, dichloromethane and the seolvent was evaporated to give 5.95 g of the title compound, comataminated with 10 % o=f 2-amuino-3-iodo-5-bromopyridine.

Setep 2: Synthesis of N-(5-bromo-3-trimethylsilanylethynyl-gpyridin-2-yl)- a_cetamide.

[02886] To a suspension of N-(5-brom_o-3-iodo-pyridin-2-yl)-acetaamide (6.42 g, 18.83 mmol) in dichloromethane (90 m1) was added triethyl amine &(3.15 ml, 22.6 mmol), then —the mixture was cooled to 0 °C anAdichlorobis(triphenylphosplino)palladium (11) (66 mg, (0.094 mmol) and copper(1) iodide (36 mg, 0.188 mmol) were aadded sequentially.

Final .ly trimethylsilylacetylene (2.93 ml, 20.71 mmol) was added dr—opwise, and the ice bata was removed. After stirring at room temperature for 17 hours, the cmrude mixture was directly adsorbed on silica gel. Purificat-ion by flash chromatography on silica gel with a gradi ent of ethyl acetate/hexane afforde=d the title compound as ligh=t yellow solid (4.75 g, 81 % yield). '"H NMR (DMSO-d): 8 9-.99 (s, 1H), 8.31 (d, J=2.5 Hz, 1H), 7.95 (d, I= 2.5

Hz, 1 H), 1.82 (s, 3H), 0.00 (s, 9H); HPL_C/MS m/z: 311, 313 [MH]™.

Step 3: Synthesis of 5-bromo-1H-pyrramlo[2,3-b]pyridine.

[0287] To» asolution of N-(5-bromo-3-trimesthylsilanylethynyl-pyridin-22-yl)-acetamide (4.75 g, 15.26 mmol) in THF (90 ml) was adced dropwise a 1 M solution of tetra-n-butyl ammonium fluoride in THF (30.5 ml, 30.5 mmol). After stirring at reflux for 15 hours, the reaction mixture was concentrated in vacuo ad water was added. The aqueous layer was extracted tha ree times with dichloromethane with, and the combined extra=cts were directly adsorbed or silica gel. Purification by flash ¢ hromotography on silica gel. with a gradient of ethyl acetat e/hexanes afforded 2.29 g of a bedge solid. Recrystallization f5rom ethyl acetate/hex anes provided the title compound as light beige flakes (1.33g)e. Further purificatiorm of the filtrate on silica gel with a_ gradient of ethyl acetate/he—xanes afforded more of the= title compound as a crystalline peowder (675 mg) for a combi ned yield of 2.01 g; 67 % . "H NMR (DMSO-d¢): 8 11.89 (s, HE), 8.24 (d, J=2.0 Hz, 1H), 8-.17 (d, J=2.5 Hz, 1H), 7.53 (t,J=3.0 Hz, 1H), 6.42 (dd, J= 1.0, 3.0 Hz, 1H); HPLC/MS m~/z: 197 MH].

Step 4= Synthesis of 5-bromo-3-iodo-1 “H-pyrrolo[2,3-b] pyridine.

[0288] T oa solution of 5-bromo-1H-pyrro=1o[2,3-b]pyridine (300 mg, 71.52 mmol) in acetone (10 ml) was added N-iodosuccinimiade (377 mg, 1.67 mmol) in one portion. The reaction m-ixture was stirred at room temper&ature for 45 minutes. The ressulting precipitate was filtere«d off, washed with a minimal amount of acetone, and dried in vacuo to give the title compound as a cream-colored solid (329 mg, 67 % yield). 'H NMR_ (DMSO-d¢): 8 12.36(s, 1H), 8.30 (d, J= 2.0 Hz, 1H), 7.85 «4, /=2.0 Hz, 1H), 7.80 (d, .J= 2.5 Hz, 1H);

HPLC/MS m/z: 323.

Method 18:

HN 7 HN )

NT ® N ~ @

STEP 7

J AT

N

OH OH

Step 1: Synthesis of 4-[3-(2-ethyl-phe=nyl)-1H-pyrrolo[2,3-b]pyr-idin-5-yl]-2-(4- hydro xy-methyl-piperidin-1-ylmethyR)-phenol.

[0289] 59.8 mg(0.19 mmol) of 4-[3-(2-etchyl-phenyl)-1H-pyrrolo[2,3- -b]pyridin-5-yl}- phenol waas dissolved in a mixture of 0.6 mM of methanol and 2.4 ml of t-oluene. 11.4 mg

( 0.38 mmol) of paraformaldelhyde and 32.3 mg (0.28 mmeol) of 4-piperidinemethamol were emdded and the mixture heated. to 90 oC for 20 hours.

J 0290] The mixture was distributed between ethyl acetate and a saturated aqueo -us =solution of ammonium chloride. The aqueous layer was «extracted three times with ethyl _ucetate and the combine organic layers were washed witln brine, dried over sodiurm sulfate and evaporated. The crude wvas purified by mass-triggeresd reverse-phase HPLC to afford 2 mg (4 pmol, 2 % yield) of” 4[3-(2-ethyl-phenyl)- 1 H-psymolo[2,3-blpyridin-5-yL 1-2-4 hydroxymethyl-piperidin-1-~yimethyl)-phenol as a beige solid. IH-NMR (ds-metichanot) &. 8.50 (m, 1H), 8.45 (s, 1H), 7.90 (d, = 2 Hz, 1H), 7.52 Cm, 2H), 7.41 (s, 1H), 7.38 (d,J)~ 7.3 Hz, 1H), 7.32-7.34 (m, 2H), 7.26 (t, J= 7.3 Hz, 1H), 6.96 (d,J=8.8 Hz, 1H), 4.17 (s, 2H), 3.44 (d, J= 5.9 Hz, 2H), 3.38 (4, J= 12.2 Hz, 2H), =.80 (t, J= 11.2 Hz, 2H), 2.68(q,J= 7.3 Hz, 2H), 1.91 (d, /= 13.2 Hz, 2H), 1.46 (m, 2H), 1.088 (t,J="7.8 Hz, 3H). MSs: m/z 442 [MH].

Method 19:

HN ) HN )

NT NE

A STEP 1 = g _

N~ °F N OH

Synthesis of 4-[(2-¢ thyl-phenyl)- 1H-pyrrolo[2..3-b]pyridin-5-yll-pyriditin-2-ol.

[0291] 26 mg (82 pmol» of 3.(2-sthyl-phenyl)-5-(2-loro-pyridin-4-yl)- 1 H-gpyrrolo(2,3- blpyridine was dissolved ina mixture of 3 ml of 1,4-dSoxane, 1.5 Ll of water, z=and 0.5 mL of concentrated aqueous hydrochloric acid. The solution_ was stirred at room temperature for 16 hours and then at 100 =C for 3 hours.

[0292] Upon cooling th_e mixture was distributed be-tween ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The aqueouss layer was extracted twi ce with ethyl acetate and the combined. organic phases were subsequently washed with brines, dried over sodium sulfate and evaporated to afford 25 mg (79 pmol, 96 % yield) of 4-[3 -w(2-cthyl- phenyl)-1H-pyrrolo[2,3-Blpyridin-5-yl]-pyridin-2-ol. "H-NMR (ds-methanol)- & 8.52 (s, 1H), 7.97 (d, J=2 Hz, 11), 7.44 (d, J= 6.3 Hz, 1H), ~7.40 (m, 1H), 7.32 (d, J/= 1.8 Hz, 1H),

7.25-7.28 (m, 2H), 7.18-7.22 (m, 1H), 6.69-6.71 (m , 2H), 2.59-2.63 (m, 2H), 1.02 (m, 3H).

MS: m/z 316 [MH].

Table 14

HO

HN \

NT

~

C

Na

OH AEA4S, *

MS: m/z 304 [MET]. *30% HBr was u_sed instead of conc. HCL

Method 20: - HN

Ts~p Ts N ) \

NT STEP 1 | ster2 oH lL -— Z OTs

OTs 8 NZ _

Br JL —

Step 1: Syn thesis of toluene-4-sulfonic acid. 4-[5-(4,4,5,5-tetramethy®- [1,3,2]dioxa™b orolan-2-yl)-1-(toluene-4-sulfo-nyl)-1 H-pyrrolo[2,3-b]py=ridine-3-yl]- phenyl estex—.

[0293] 2.82 g (9.75 mmol) of 4-(5-bromo-1H-p yrrolo[2,3-b]pyridine-3-yl)-phenol and 3.10 g of para-teoluenesulfonyl chloride were dispwersed in 400 ml of toluene at 45 °C. 45ml of 50 % aqueoums solution of KOH and 1.5 ml of «40 % aqueous solution of Cetra-i- butylammoniun hydroxide were added and the resulting mixture stirred vig-orously at ambient temperature for 6 h. The resulting mixtu re was diluted with 100 m1 of a saturated aqueous solutiomn of sodium bromide, the phases separated and the aqueous “layer extracted three times witha toluene. The combined organic yhases were washed with &2 2 M aqueous solution of sodiwum hydroxide, dried over sodium sulfate and evaporated. T_he crude was crystallized frorm ethanol containing 10 % v/v of toluene to afford 3.22 g (5 .29 mmol, 55%

yield) of toluene-4-sulfonics acid 4-[5-bromo-1-(toluene-4-sull fonyl)-1H-pyrrolo[2,3- blpyridine-3-y1]-phenyl ester as ivory crystalline needles.

[0204] 1.50 g (2.51 mmo»l) of this material, 1.30 mg of bisCpinacolato)diboron, 680 -mg of anhydrous sodium acetate, and 100 mg of [1,1°-bis(diphenylnphosphino)ferrocene]- palladium(1)-dichloride dichloromethane adduct were placec] in Smith® vial and the =vial was flushed with nitrogen. 15 ml of anhydrous DMF was adllded and the mixture irracliated in a Personal Chemistry microwave reactor to 130 °C for 1 bm. The mixture was then evaporated at 65 °C under reduced pressure and the resultinex residue distributed between ether and saturated aqueous sodium bromide solution. The saqueous layer was extract-ed three times with ether, the organic phases combined, dried o ver sodium sulfate and filtered over celite. The filtrate was evaporated and dried in vacuurz.

[0295] The residue was re-dissolved in 150 ml of ether an d the resulting suspensior washed three times with 80 ml of a saturated aqueous sodiumn bromide solution, dried over sodium sulfate and evaporated. The residue was stirred witin 200 ml of hexanes until a beige suspension was obtained. The insoluble residue was Filtered off and dried in vezcuo to afford 1.00 g (1.55 mmol, 62 %) of toluene-4-sulfonic acid —4-[5-(4,4,5,5-tetramethyl— [1,3,2]dioxaborolan-2-yl)—1 -(toluene-4-sulfonyl)-1 H-pyrroleo(2,3-b]pyridine-3 -yl]-ph_enyl ester as a beige powder. ! H-NMR (ds-methanol): 59.19 (d, J=1.4 Hg, 1H), 8.95(d, J 15

Hz, 1H), 8.57 (d, J= 8.3 Hz, 2H), 8.57 (s, 1H), 8.26 (d, /= 8 .3 Hz, 2H), 8.16 (d, /~=8_3 Hz, 2H), 7.96 (d, J= 7.8 Hz, 2H), 7.88 (d, J/= 8.3 Hz, 2H), 7.64 Cd, J=8.7 Hz, 2H), 2.99 ( s,3H), 2.89 (s, 3H), 1.89 (s, 12H). -

Step 2: Synthesis of 4-[5-(1-methyl-1H-imidazol-2-yl)-1H-pyrrolo [2,3-b]pyrddine- 3-yl]-phenol.

[0296] 50 mg (80 pmol) of toluene-4-sulfonic acid 4-[5-( 4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl) ~ 1-(toluene-4-sulfonyl)-1 H-pyrrol. 0[2,3-b]pyridine-3-yl]-ptaenyl ester and 7 mg of [1,1°-bi s(diphenylphosphino) ferrocene]paalladium(tr)-dichloride dichloromethane adduct vavere placed in a Smith® vial. 1 nmlof acetonitrile, 1 mlof 2 M aqueous solution of sodiusm carbonate and 16 pl of 2-bromo-1-methyl-1H-imidazole= were added and the resulting mixture was irradiated in a Persona _1 Chemistry microwave r €actor to 165 °C for 20 min. Th_e resulting mixture was diluted with 2 ml of DMSO and 1 mn] of methanol and subsequent ly filtered over sodium sulfate ancl a 0.45 pm PTFE syringe filter,

The filtrate is directly purified via mass-triggered reverse p hase HPLC to afford 12 rng 41 pmol, 52 % yield) of 4-[5-(1-methyl-1 H-imidazol-2-y~1)-1 H-pyrrolo{2,3-b])pyrid_ine-3-yi]- phenol as a colorless solid. "H-NMR (de-DMSO): 51 1.97 (s, 1H), 9.40 (5, 1H). 8.53 (d, J= 2.0 Hz, 1H), 8.40 (d, /=1.4Hz, 1H), 8.14 (s, 1H), 7.777 (d, J= 2.4 Hz, 1H), 7.54.- d,J=8.3

Hz, 2H), 7.30 (s, 1H), 7.02 (s, 1H), 6.86 (d, J= 8.7 Hz, 2H), 3.78 (s, 3H); MS: n—2/2 291 [MH].

[0297] Other commpounds prepared by Method 20:

Table 15

H H H

) | §

N EN ( oH (J ( ori ) (2) OH pa #

HN vs 9 ge 8

SO,NH, AER46 N Yo, . + «

MS: m/z 366 [MIL] MS: m/z 342 [MH] MS: m/z 333 [ME]

H H H

\ \ ) ® {Don OY Oe i on 7 a ON - n—? ml

MS: m/z 291 [MH '] MS: m/z 277 [MH] MS: m/z 336 [MH]

HN \ ~ OH re # nh

MS: m/z 289 [MH ™]

Method 21:

HN 0”

HN TIPS~ TIPS~ 0” \ ! | N \ N | N Ny

NTS STEP 1 Nol sTEP2 NS steps UL = Lz Ll — i!

Br Br Br ~ 0)

Step 1: S ynthesis of 5_bromo-3-iodo-1-tr-iisopropylsilanyl-1H-pyrmrolof2,3- b]pyridime.

[0298] 2.30 g(11.67 mmol) of 5 -bromo-3-icedo-1H-pyrrolo[2,3-b]pyrid Tine was dissolved in 90 ml of arhydrous THF under nitrogen. AT excess of sodium hydride= was added at room temperzature and subsequently 3 mi of tri -iso-propylsilyl chloride weere added. The reaction mix #ure was allowed to stir at ambierat temperature for 4h.

[0299] Thes mixture was distributed between ethyl acetate and a saturat_ed aqueous solution of a_mmonium chloride. The aqueous phase was extracted three times with ethyl acetate and the organic phases were combinec], washed with brine, dried over sodium sulfate and evapora ted. The crude material was puri fied by flash chromatorgrapohy on silica gel using a gradient of ethyl acetate in hexanes to afford 3.493 g (7.235 mmol, 62 % yield) of — bromo-3-iocdo-1-triisopropylsilanyl- 1 H-pyrrolo[2,3 _b]pyridine as a crystalline solid. 'H-

NMR (ds-D®MSO): 68.34 (d, J= 1.9 Hz, 1H) , 7.88 (d,/=2.0 Hz, 1H), 7.72 (s, 1H), 1.86 (m, 3H), 1.05 (cd, J= 7.8 Hz, 18H).

Step 2: Synthesis of 5.bromo-3-(2-mewhoxy-phenyl)-1-triisoprogpylsilanyl-1H- pyrroloo[2,3-b]pyridine.

[0300] 1-0l1g (2.10 mmol) of 5 _bromo-3-&odo-1-triisopropylsilanyl-1_ H-pyrrolo(2,3- blpyridine, 336 mg of 2-methoxyphenylboronic acid, and 75 mg of (1,1-bis(diphenyl- phosphino ferrocene)palladium(m)-dichloricie dichloromethane adduct ~were placed in a

Smith® vi_al and dissolved in a mixture of 1. 5 mi of acetonitrile, 5 ml of toluene, and 7 ml of a saturatecl aqueous solution of sodium bicarbonate. The mixture was heated to 65 °C for 4 hh and theen cooled to room temperature. The crude was distributed b-etween dichloronmethane and water and the organic phase was dried over sodivum sulfate and evaporate-d. The crude was then purified by flash chromatorgraphy orm silica gel using a gradient of ethyl acetate in hexanes to affoxd 708 mg (1.53 mmol, 73 ©) of 5-bromo-3-(2- methoxy—phenyl)-1-triisopropylsilanyl-1H- —pyrrolo[2,3-b]pyridine as a yellow oil (containimg about 20 % of residual startings, material as an inseparable mixture). "H-NMR (ds-DMS QO): 68.33 (4, J=2.4 Hz, 1H), 8.15 (d, J=2.0 Hz, 1H), 7.76 (Cs, 1H), 7.55 (dd, J=1.3

Hz, 7.3 Fiz, 1H), 7.33 (ddd, J= 1.9 Hz, 7.3 Hz, 1H), 7.15 (dd, J= 1.0 Hz, 8.3 Hz 1H), 7.06 (at, J=1 .0Hz,7.3 Hz, 1H), 3.82 (s, 3H), 1.88 (m, 3H), 1.10 (4, 18H)-.

WYO 2006/015123 PCT/US2005/02 6792

Step 3: Synthesis of [3-(2-me®&thoxy-phenyl)-1H-pyrrolo[ 2,3-b]pyridine-5-yl]— ’ methyl-phenyl-amine. [O301] 30 mg of sodium-tert-buteoxide and 12 mg of bis(tert-utylphosphino)pallaclium(0) were placed in a Smith® vial and the vial flushed with nitrogerm. 100 mg (0.22 mmo 1) of 5- b-romo-3-(2-methoxy-phenyl)-1-tri-isopropylsilanyl-1 H-pyrrolo l2,3-b]pyridine in 1 nl of anhydrous 1,4-dioxane and 35 pl o- f N-methylaniline were added and the resulting mixture ho eated to 130 °C for 15 h. The rea ction mixture was then cooled to ambient temperature and 0.4 ml of a 1 M solution of tetra-n-butylammonium fluorides in THF added. The mixture v=as stirred at room temperature for 2 h. 2 ml of methanol and amberlyst strongly acidic ion e=xchange resin loaded with sodiunm was added. After shaking =at room temperature £or 2 h tThe crude material is directly adsorbed onto silica gel and purifSed by flash chromatomrgraphy

Onsilica gel using a gradient of etlyl acetate in hexanes to affcard 42 mg (0.14 mmol; 64 % yield) of [3-(2-methoxy-phenyl)-1_H-pyrrolo[2,3-b]pyridine-5-=yl]-methyl-phenyl-ammine asa torown residue. "H-NMR (ds-DMS0): 511.88 (s, 1H), 8.11 (d= /=2.5 Hz, 1H), 7.75 a, ~=2.4 Hz, 1H), 7.70 (d, J= 2.5 Hz, 1H), 7.48 (dd, /= 1.5 Hz, 7-3 Hz, 1H), 7.26 (ddd, ~=1.5

Elz, 8.3 Hz, 1H), 7.16 (1, J= 7.9 H=, 2H), 7.08 (d, J= 8.3 Hz, 1K), 7.00 ((d), /= 0.9 Hz, 83

Elz, 1H), 6.72-6.68 (m, 3H), 3.76 Cs, 3H), 3.29 (5, 3H); MS: mr 2330 [MH]. [[0302] Other examples prepared by Method 21:

Table 16

ST

MeO MeQ

HN \ HN \

F A

HN. ) ie 0

IMS: m/z 316 [MH] MS: m/z 298 [MH']

Method 22: , _ _ MEM-~y o” HN) 0”

HN ) o N ) 0 NX N 7X

TC STEP 1 sae STEP 2 sav STEP 3 ae

N N o or CJ CJ

Step 1: Synthesis of 5-bromo-1-(2-meth oxy-ethoxymethyl)-3-(2-met_hoxy-phenyl)- 1H-pyrrolo{2,3-b]pyridine.

[0303] Under nitrogen 755 mg (2.49 mmol) of 5-bromo-3-(2-methoxy-ph=enyl)-1H- pyrrolo[ 2 ,3-b]pyridine was dissolved in 30 mi of anhydrous THF. 200 mg of sodium hydride were added and the resulting mixture vas stirred at ambient temperature for 4 h. 0.5 ml of” (2-methoxy-ethoxy)methyl chloride wvas added and the resulting nmixture stirred at room temperature for 72 h. 0.75 ml of (2-methaoxy-ethoxy)methyl chloride and an excess of sodium hydride were added and the reaction mixture allowed to stir at ambient temperature for am aclditional 4 h. 250 mg of tetra-n-butylaxmmonium iodide were adde=d and the reaction mixture stirred for 2 h at room temper ature. The reaction was then quenched by addition of methanol and distributed between a saturated aqueous solution Of ammonium chloride and dichloromethane. The aqueous plhase was extracted with pyriciinepethane and the combined organic phases dried over sodiurm sulfate and evaporated. Thme crude was then purified by chromatorgraphy on silica gel usin g a gradient of ethyl acetate i_n hexanes to afford 922 mg (2.36 mmol, 95 % yield) of 5-bxromo-1-(2-methoxy-ethoxyn=ethyl)-3-(2- methoxy -phenyl)-1H-pyrrolo[2,3-b]pyridine asa yellow oil. "H-NMR (ds-_ DMSO): 58.40 (d, J= 1.9 Hz, 1H), 8.17 (d, J=1.9 Hz, 1H), 7.97 (s, 1H), 7.52 (dd, J=1.3 H=, 7.3 Hz, 1H), 7.34 (dd , J= 1.4 Hz, 8.7 Hz, 1H), 7.15 (d, J= 8.2 Hz 1H), 7.06 (t, J= 7.3 H=z, 1H), 5.71 (s, 2H), 3.83 (s, 3H), 3,57 (m, 2H), 3.41 (m, 2H), 3.20 (s, 3H); MS: m/z 315, 3=17 [MH"-

MeOC,ELO].

Steps 2: Synthesis of 1-(2-methoxy-ethoncymethyl)-3-(2-methoxy-pheeny)-5- mor pholin-4-yl-1H-pyrrolo[2,3-b]pyridine.

[0304] 180 mg (0.5 mmol) of 5-bromo-1-(2—methoxy-ethoxymethyl)-3-(2-methoxy- phenyl)— 1H-pyrrolo[2,3-b]pyridine, 10 mg of bis(benzonitrile)palladium(r)-chloride, 11 mg of 2,5-bis-(2,6-di-iso-propylphenyl)imidazolitam chloride, and 65 mg of postassium-tert- butoxide were placed in a Smith® vial. The v~ial was flushed with nitrogera and 3 ml of anhydrous 1,4-dioxane amd 70 ul of morpholine were ad_ded. The resulting rnixture was heated to 120 °C for 14 a. The mixture was cooled to room temperature, adssorbed onto silica gel, and purified by flash chromatorgraphy on silieca gel using a gradient of ethyl acetate in hexanes to affcord 65 mg (0.17 mmol, 33 % yi eld) of 1-(2-methox=y- thoxymethyl)-3-(2-methoxy-pheny))-5-morpholin-4-yR-L-pyrrolo[2,3-Plpeyridine asa colorless oil. "H-NMR &CDCL): 68.17 (d, =2.8 Hz, LH), 7 63 (s, 1H), 7.59 (4, J=2.5 Hz, 1H), 7.54 (dd, J= 1.6 H=, 7.4 Hz, 1H), 7.31 (ddd, J~= 1.6 Hz, 7.4 Hz, 9 Hz, mH), 7.07 (ddd,

J= 1.1 Hz, 7.4 Hz, 7.4 Iz, 1H), 7.03 (d(m), J= 8.3 Hz, 1H), 5.71 (s, 2H), 3 .87 (5, 3H), 3.68 (mm, 2H), 3.49 (m, 2H), 3.35 (s, 3H); MS: m/z 398 [MH 1.

Step 3: Synthesis eof 3.(2-methoxy-phenyl)-5-maprpholin-4-yl-1H-pyrrolo[2,3- b]pyridine

[0305] 65 mg (0.17 mmol) of 1-(2-methoxy-ethoxyrmethyl)-3-(2-methox_y-phenyl)-5- morpholin-4-yl-1H-pyr=rolo[2,3-b]pyridine was dissolwed in a mixture of 3 ml of ethanol and 2 ml of water. 500 pl of formic acid was added amd the mixture heate«d to 65 °C for 16 h and then irradiated ir the microwave to 150 °C for 40 min. The resultin=g mixture was neutralized by additior of sodium bicarbonate and wa_ter and the crude dis-tributed between ethyl acetate and brine=. The aqueous phase was extra_cted twice with ethy_1 acetate. The combined organic phazses were dried over sodium sul#fate and evaporated #&o afford 47 mg (0.15 mmol, 94 % yield) of 3-(2-methoxy-phenyl)-5 -mmorpholin-4-yl-1H-poyrrolo[2,3- blpyridine. "H-NMR (ds-DMSO): 511.58 (s, 1H), 8-11 (4, /=2.5 Hz, 11H), 7.59 (d, /~=2.4

Hz, 1H), 7.51 (dd, /= 14 Hz, 7.3 Hz, 1H), 7.46 (s, 1K), 7.27 (ddd, J=1.5 Hz, 8.8 Hz, 1H), 7.11 (d, J= 8.3 Hz, 11), 7.02 (dd(d), J= 1.5 Hz, 7.3 Hz, 15), 3.82 (s, 3H). 3.77 (m, 4H), 3.07 (m, 4H); MS: m/z 310 [MH'].

Method 23:

Too o Ts ; = HN o~ sae STEP 1 sae STEP 2 Sav _ =

Br

Va 0 2006/015123 PCT/US2005/026792

Step 1: Synthesis of 5-iodo-3-(2-methoxy-phenyl)-1-(toluemne-4-sulfonyl)-1H- pyrrolo[2,3-b]pyridine.

[0306] 337.3 mg (0.74 mmol) of S-bromo-3-(2-methoxy-phenyM)-1-(toluene-4-sulfonyl)- 1 =4-pyrrolo[2,3-blpyridine, 11.3 mg: (59 pmol) of copper(l)-iodide, and 185 mg (1.24 mmol) of ~ sodium iodide were placed in a S mith® vial and the vial flushe=d with nitrogen. 6 ml of an_hydrous toluene and 14 ul (0.13 mmol) of N,N -dimethylethyle mediamine were added andl thee resulting suspension was heated to 120 °C for 16 h. [0-307] The mixture was cooled to» room temperature and distribeuted between ethyl acetate anad water. The aqueous layer was extracted three times with ethy~1acetate. The combined or_ganic phases were washed with brine, dried over sodium sulfate and evaporated. The crrude was purified by flash chromatography on silica gel using a gradient of ethyl acetate ina he=xanes to afford 261 mg (0.52 mmol, 70 % yield) of 5-iodo-3-(2 -methoxy-phenyl)-1- (toluene-4-sulfonyl)- 1 H-pyrrolo[2,3-b]pyridine as a colorless solid.

Step 2: Synthesis of 3-(2-metlmoxy-phenyl)-5-pyrrol-1-yl-1_H-pyrrolo[2,3- b]pyridine. :

[0308] 40 mg (79 umol) of 5-iodo-3-(2-methoxy-phenyl)-1-(tol_uene-4-sulfonyl)-1H- py~rrolo[2,3-b]pyridine, 30 mg (0.14- mmol) of anhydrous potassivem phosphate and 1.2 mg (6 pmol) of copper(r)-iodide were p laced in a Smith® vial. The vial was flushed with nistrogen and 1 ml of anhydrous toluene, 6.7 pl (95 pmol) of pyrrole, and 2 pl (10 pmol) of ra c-trans-N,N’-dimethyl-1,2-cyclolmexanediamine were added. Thhe resulting suspension wazas heated to 120 °C for 22 h. 1.2 xng (6 pmol) of copper(1)-iodiede and 2 pl (10 pmol) of ra c-trans-N,N’-dimethyl-1,2-cyclolnexanediamine were added anc3 the reaction mixture he=ated for another 20 h. [0=309] The resulting mixture was distributed between water anc ethyl acetate, the phases sepparated, and the aqueous layer extracted three times with ethyl &acetate. The combined orzganic phases were washed with brine, dried over sodium sulfate= and evaporated. The craude material was purified by flash. chromatography on silica gel using a gradient of ethyl ac-etate in hexanes to afford 27.9 mg (63 mol, 80 % yield) of 3-(22-methoxy-phenyl)- 1- (tooluene-4-sulfonyl)-5-pyrrol-1-yl-1 H-pyrrolo[2,3-b]pyridine as a beige solid.

[0310] The material was dissolved in ethanol and 400 pul of 50 24 aqueous potassium hy~droxide solution added. The solu tion was heated in a Personal «Chemistry Optimizer® microwave reactor to 165 °C for 20 min. The crude vevas distributed between “water and ethyl acetate, thes phases separated, and the aqueous layer extracted three time=s with ethyl acetate. The corubined organic phases were washed with brine, dried over soadium sulfate and evaporated €o afford 20 mg (70 umol, 87 % yield) of 3-(2-methoxy-phenyi)-5-pyrrol-1- yl-1H-pyrrolo[2 ,3-b]pyridine as a beige solid. H-NMR (dg-CDCls): §10.48 (5) [1H], 8.49 (s) [1H], 8.09 (<1) [1H], 7.73 (s) [1H], 7.56 (d) [1H], 7.34 (t) [1H], 7.05-7.10 (m) [4H], 7.40 (d) [2H], 3.81 (ss) [3H]. MS: m/z 290 (88%) [MH].

Method 24:

Ts. Ts, ys

N \ N \ Ss NT wi or" STEP rs y step: 4 l l~ N a

Br Br Na

Step 1: Symathesis of 2-(5-bromo-1-tosyl-1H-py/rrolo [2,3-b]pyridine-3—yl)thiazole.

[0311] A mix ture of 5-bromo-3-iodo-1-tosyl-1H-p yrrolo[2,3-b]pyridine (1 66g, 3.48 mmol), 2-tribut_ylstannanyl-thiozole (1.3 g, 1.21 mL, 3.48 mmol) and tetrakis(triphen-ylphosphine)palladium (0) (116 mg, ©O.1 mmol) in anhydrous dioxane was stirred under reflux conditions under nitrogen atmosyphere for 3 days. The re action mixture was cooled to room temperature, treated with activat-ed carbon and filtered o=ver Celite. The filtrate was con. centrated, purified by silica gel chrormatography and recrystallized in ethyl acetate to afford a mixture of 2-(5-bromo-1-tosyl-1F-pyrrolo[2,3-b]pyridine—3-yl)thiazole (1.11 g, 73% yi eld). MS: m/z 434/436 (M+H").

Step 2: Symthesis of 2-(5-(pyridine-3-yl)-1H-psyrrolo [2,3-b]pyridine-3-yl)thiazole.

[0312] A mixture of 2-(5-bromo-1-tosyl-1H-pyrro- lo[2,3-b]pyridine-3-yDtiniazole (75 mg, 0.17 mmol), py~ridine-3-ylboronic acid (27 mg, 0.22 mmol) 1,1’-bis(dipheny-Iphos- phino)ferrocenespalladium(1)-dichloride dichloromethane adduct (6.9 mg, 0.€009 mmol), acetonitrile (1 rnL) and saturated aqueous NaHCO; «(1 ml) were stirred in a sealed microwave tubee at 140 °C for 30 minutes. The mixture was then cooled to recom temperature, di luted with ethyl acetate, washed with brine and concentrated ~to dryness.

Silica gel chrormatography afforded 2-(5-(pyridine-3- -yl)-1H-pyrrolo[2,3-b]p_yridine-3- yDthiazole (36 mg, 76% yield) as a white solid. "H NMR (500 MHz, DMS(-d6) 6 7.47 (m, 1H), 7.56 (d, J =3.5 Hz, 1H), 7.81 (d, J = 3.5 Hz, 1H), 8.10 (m, 1H), 8.24 (s, 1H), 8.55 (dd,

J1=2.0,5.0 Hz, 1H), 8.61 (d, J =2.5 Hz, 1H), (4, =2.0Hz, 1H), 8.89 (m, 1H), 12.37(s, 1H). MS: m/= 279.0 M+H")

[0313] Otheer compounds prepared by method 24=

Table 17 cu cc J RJ

HN N HN

\ 2] HN 4 \ oT) i = NTS S NTS S = | = ! SZ = = “4

Ne

NTF 3 N” “OH

F

MS: m/z 297.0 M+H"

MS: m/z 295.0 (M+H")

MS: m/z 297.0 (M+H )

Method 25:

HN OMe

HN OMe

NT

N = ster1.

PZ

A

Br \

N-O

Step 1: Synthesis of 5.(3,5-dimethyl-isoxaz ol-4-yl)-3-(2-methoxy-pherayl)-1H- pyrrolo|[2,3-b]pyridine.

[0314] To 5-bromo-3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine (40 ng, 0.087 mmol), 3,5 ~dimethyl-isoxazole-4-boronic acid (1 6 mg, 0.114 mmol) and [1,1 °- bis(diphen=ylphosphino)ferrocene]dichloropalladi um (I), complex with dichleoromethane (1:1) (4 mgz, 0.0044 mmol) in a Smith process vial was added 0.6 mL of a 1:1 mixture of acetonitrile, and a 2 M solution of sodium carbonate in water . The reaction vas Tun ina

Personal C=hemistry® microwave reactor at 165 © for 1200 s. The reaction ronixture was diluted with 1:1 methanol/dichloromethane, filtered, and the filtrate was adscorbed on silica gel. Purifi cation on silica gel with a gradient of MeOH/CH2CI2 afforded 5-(3,5-dimethyl- isoxazol-4 —y1)-3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine as beige cry=stals (20 mg, 71% yield). IH NMR (500 MHz, DMSO-d6) § 2.23 (s, 3H), 2.41 (s, 3H), 3.821 (s, 3H), 7.01

(dt, J= 1.0, 7.0 Hz, 1E3), 7.11 (dd,J= 1.0, 8.0 Hz, 1H), 728 (dt, J=1.5, 7.0 Kz, 1H), 7.51 (dd, J=2.0, 8.0 Hz, 1EY), 7.73 (d, J=3.0Hz, 1H), 7.9-0(d,J=1.5Hz, 1H), 8.22 (4, J=2.0

Hz, 1H), 11.9 (s, 1H). MS: m/z 320 (M+H).

[0315] Other composunds prepared by method 25:

Table 18

MeO HN

HN © N° » iP iP » pz

OMe

Cd OH a a,b-

MS: m/z 331 (MH. MS: m/z 253 (M+H+). a) Dichlorobis (triphenylphosphino)palladium (10) ass catalyst b) Obtained from 1-( 5-bromo-1H-pyrolo[2,3-b]pyri dine-3-yl)-ethanone

Method 26:

Sw HN—

NTS DAS

LL STEP 1 F of

OTs OH AR47

Step 1: Synthesis of 3-(3-furan-3-yl-1H-pyrreolo[2,3-b]pyridine-5-yl)- -phenol.

[0316] To toluene=-4-sulfonic acid 3-[3-iodo-1-(to luene-4-sulfonyl)-1H-py=rrolo[2,3- b]pyridine-5-yl}-phenyl ester (50 mg, 0.077 mmol, —prepared method 6), furamn-3-boronic acid (11 mg, 0.1 mouaol) and dichlorobis (triphenylp. hosphino)palladium (i) «(3 mg, 0.0046 mmol) in a Smith parocess vial was added 0.6 mL off a 1:1 mixture of acetonJtrile, and a 2M solution of sodium ecarbonate in water . The reactiom was run in a Personal Chemistry® microwave reactor zat 165 °C for 1200 s. The mixture was diluted with DME= (ca. 5 mL) and filtered with a syrin_ge filter (0.45 micron). The filtrate was concentrated in —vacuo and redissolved in DMSSO. Purification by reverse phas e chromatography using a gradient of

H,O and acetonitrile (with 0.1% formic acid as a modifier) afforded 3-(3-fumran-3-yl-1H-

pyrrolo[2,3-Bo]pyridine-5-yl)-phenol as an off-white solid (6 mg, 56% yield). '"H NMR (500

MHz, DMSCD-d6) 6 6.70 (dd, J=2.5, 8.0 Hz, 1H), 6.92 (d,J=2.0H 21H), 7.07 (t, J=2.0

Hz, 1H), 7.1 3(d,J=8.0 Hz, 1H), 7.21 (t, J=28.0 Hz, 1H), 7.67 (t,J =1.5Hz, 1H), 7.77 d,

J=2.5Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.27 (s, 1H), 8.41 (d, J=2=.0 Hz, 1H), 9.5 (broad s, 1H), 11.8 (5, 1H). MS: m/z 277 (M+H").

[0317] Ot her compounds prepared by Me€hod 26:

Table 19

HN Ci 7) \ x HN HN

Ss NS NS OMe == LL | _ cl

OH a OH b g OH b

MS: m/z 293 (M+H+). MS: m/z 355 (M+H+). MS: m/z= 347 (M+H+).

Me=0 OtBu MeO

HN \ HN \

HN oY I~

J NT ) J ~~ MeS i Z'M e0

Z

OH b $g . CH pb

OH b

MS: m/z 3653 (M+H+). MS: m/= 347 (M+H+).

MS: m/z 37% M+HH).

HN OM MeO \ = HN = © HN dn

N™ ~~ ~N ES \§ ZZ 7 \ \ N N oS \ 4

TSOH = Z

OH b OH b OH b : —+H+). .

MS: m/z 288 (M—+H+) MS: m/z 318 (M+HT). MS: m/z (MAE).

HN) HN HN =

NI (> NTS () NTS =

PP NH | N " »Z — ¥% @g ~ QO)

OH b,c OH oc OH b.c

MS: m/z 386 (ME+H). MS: m/z 326 (M+HA). MS: m/z 289 (M+H+) .

MeQ HN

HN HN \

Dede 0 OT —nN3 NT | Oo _z P = =

OMe 2) OH

OH b OH b b

MS: m/z 306 (MI+HH). MS: m/z 347 (V+ELS). MS: m/z 379 M+H+D).

HN \ ~ nN HN \ HN \

SA av ST - > N P PP

OH b g OH b g OH b

MS: m/z 291 (IM+H). MS: m/z 287 (M+HT) . IMS: m/z 305 (M+H+-).

HN N HN \ HN \ oe NTO ry TU

Ll

SU |G UR € SH.

MS: m/z 321 (OM+H+). MS: m/z 301 (M+H+D). MS: m/z 301 (MAH).

WVWO 2006/015123 PCT/US2005/02e6792

I

= HN )

TY to O

NTS

= |Y v

NT

J § ~Y

OH b oH ,

MKS: m/z 339 (M+H+). MS: m/z 301 (ME). a on b

IMSS: m/z 363 (M+HH).

FN HN CFa FIN

N= {) COOH | NS P N= » CF3 _ Lo FF g OH b g oH 5 _ OH b

MS: m/z 331 (M+H+). MS: m/z 355 (M+H+). IM aS: m/z 355 (M+H+).

HN— HN o hy F

Co [Bo [Bo lL L~ = g OH b OH b - OH b

MAS: m/z 315 (M+H+). MS: m/z 327 (M+H+). M.S: m/z 305 (M+H+).

HN Cl HN F EtO 3 } I ys vO yO gz | _ [ _ g “OH b g OH b _ OH b

MS: m/z 321 (M+H+). MS: m/z 305 (M+H+). MS: m/z 331 (M+H#).

F HN

HN \ () OH - oe ;

N = | _ HN \ g JO 3 rd

J on . a <

MS: m/z 317 (M+H+). H

MS: m/z 323 (M+H+). 0 b

S: m/z 345 MHA).

F HN F

HN \ HN

NTS {) OMe NT F NTS (2) l~ z l g OH b g OH b 9 OH b

MS: m/z 335 (M+H+). MS: m/z 323 (M+H+). MS: m/z 315 (M+H—).

HN ONle = De 1 =< o— 7 bo &

MS: m/z 331 (M+H+). MS: m/z 345 (M+HH). MS: m/z 347 (M+).

OHC

HN A HN \ HN \

N os () OCF, N ~~ () EN 78

Va ZZ 0 ] P

OH b OH b on . : : +H).

MS: m/z 371 (MH). MS: m/z 329 (M+H+) MS: mlz 321 (MET).

I I I

0 HO MeO

HN s HN HN or oY

NT

= | PZ = cl oH 4g 9 OH b OH b b

MS: /z 3 5 +H+). J . 351 +H). m/z 3 35 (VEE) MS: m/z 317 (NIFH). S: m/z 351 =(MAHY)

N F

HN A CN H N IN \

N™~X LL) > Ls lL on N™S (2) F == | P

S oN $ om b " b OH b

MS: m/z 312 (MH). MS: m/z 312 (IM+HT). IS: m/z 323 (VEEL),

HN OCF; o HN J

N72 {) HN \ N xX: C2) Ss = NT ) Pr 0,

J x 9g

CoH b § OH b

OH b MS: m/z 36S (M+HH)

MS: m/z 371 (MAH). L m/z .

MS: m/z 329 CM+HH).

F F

F HN

HN \ HN N \

SEY, aU

P

4 7” F q OH b J OH b OH b

MS: m/z 323 (M+HH). MS: m/z 323 (M+HH). MS: m/z 315 (MH).

cc cc i ) ) reat > av

I = 2) $ : +H+).

MS: m/z 315 (MAE). MS mis 335 (Mir), [SE 319 QA)

HN) iN F OMe AN \

VY pon a ae ~ N PZ H ¥Z g 0 @ J OH

H b OH b b

MS: m/z 3 +H). IMS: m/z 344 +H+). m/z 3 31 (MAE) MS: m/z 335 (MH). Q-HE)

HN Vie HN \ HN 2 ) NCR ey LY

NX | J | 0] = ZZ = Cn g OH b g OH b

OH b

MS: m/z 359 +H). IMS: m/z 329 +H+).

MS: m/z 331 (MH). (MAH) (MHI)

Et HN ey AP «7

SH CosANl. ® 5 ¥Z NT

Ll $ or or ae

MS: m/z 307 +H+).

MS: m/z 315 (MFHH). n/z 307 (NAHE) OH b

MS: m/z 345 @M+H). a) 10 wt®6 Pd/C as catalyst b) [1,1 »_tois(diphenylphosphino)ferrocene]dic Thloropalladium (II), complex with dichlorommethane (1:1) as catalyst ¢) Purification on silica gel with a gradient of ~methanol/dichloromethane= 1.24

Method 27:

Py | HN = ] ol

Pe STEP 1 Z

OTs g OHs AE48

Swtep 1: Synthesis of 3-[3-(3-flumsro-4-hydroxyphenyl)-3 -yl-1H-pyrrolo[2,3- bTlpyridine-5-yl)-phenol.

[03183] To toluene-4-sulfonic acid 3-[3-iodo-1-(toluene-4-su-lfonyl)-1H-pyrrolo[2,3- b]pyr—idine-5-yl]-phenyl ester (50 mg, 0.077 mmol), 3-fluoro-48-benzyloxyphenyl boronic acid (724 mg, 0.1 mmol) and [1,1’-bisqdiphenylphosphino)ferrcOcene]dichloropalladium (I), compolex with dichloromethane (1:1) (3 mg, 0.0046 mmol) in a Smith process vial was addeci 0.6 mL of a 1:1 mixture of acetonitrile, and a 2 M solut-ion of sodium carbonate in water—. The reaction was run in a Personal Chemistry® microwave reactor at 165 °C for 1200 s. Water was added, followed b-y a saturated aqueous soMution of NH4Cl to pH 6.

Aque=ous layer was extracted with Et©Ac three times. The crumde organics were concentrated and Aissolved in 4 mL of (1:1) EtOH./ aqueous KOH (50% wt"). The mixture was stirred at 100°aC for 21h , then diluted with watzer and acidified to pH 4 ~with aqueous IN HCL The resul—ting precipitate was filtered, washed with water, and drie=d in vacuum. The grey solid was ssuspended in IN aqueous HCI (2 mL) and stirred at reflu=x for 17 h. 1 N Aqueous

NaO-H was added to pH 4, the mixtumre was concentrated in vemcuo and diluted with MeOEL ’ Salts. were filtered, and the filtrate waas adsorbed on silica gel. Purification on silica gel with a gra_dient of methanol/dichlorometh=ane afforded 3-[3-(3-fluomro-4-hydroxyphenyl)-3-yl- 1H- pyrrolo[2,3-blpyridine-5-yl)-phenol zas a yellow solid (5 mg, 20% yield). TH NMR (500

MHz=, DMSO0-d6) 8 6.75 (dd, J=2.5 , 7.5 Hz, 1H), 7.03 (dd, ~=9.0, 10.0 Hz, 1H), 7.09 (t,J =2.0O Hz, 1H), 7.16 (d, J = 8.0 Hz, 13H), 7.27 (t, J = 8.0 Hz, 13H), 7.41(dd,J=1.5,8.5 H=, 1H), 7.51(dd,J=1.5, 13.0 Hz, 1H), 7.82(d,/=2.0Hz, 1H), 8.30 (d, /J=2.0 Hz, 1H), 8 .47 (d, J” =2.0 Hz, 1H), 9.54 (s, 1H), 9.840 (broad s, 1H), 11.9 (s, 1H). MS: m/e 321 M+H.

Method 28 = /

HN 3 HN HO ?

NR () \ \ Zz 0 <g \

OH $

OH

Step 1 : Synthesis of 1-{2-hydroxy-3-[S ~(3-bydroxy-phenyl)-1H-pyrrolo[2,3- b]pyriidine-3-yl}-4-methoxy-phenyl}-et hanone.

[0319] Wo 3.[3-(2,6-dimethoxy-phenyl)- 1 Ed-pyrrolo[2,3-b]pyridine-5- yi]-phenol (12 mg, 0.0346 mxrol) was added 0.5 mL of 33 wit% bromine in AcOH. The mixture was stirred at 70°C for 6h, then it was treated with 1.2 mL 50 wt% of aqueous KOH and it was further stirred at room temperature for 3 days, then at 80 °C for 3 hours. The mixture was acidified to pH4 wath IN aqueous HCl and extracted ~with EtOAc three times. Th: e extracts were combined and adsorbed on silica gel. Purification on silica gel with a gradient of methanol/dichloromethane afforded 1- {2-hy/droxy-3-[5-(3 -hydroxy-phenyl)-1H- pyrrolo[2-,3-b]pyridine-3-yl}-4-methoxy-phenyl}-ctbanone as a white seolid (2.6 mg, 20 % yield). "HI NMR (500 MHz, DMSO-d6) § 2-65 (s, 3H), 3.85 (s, 3H), 6.772(dd,J=25,8.5

Hz, 1H), 6.83(d,J=8.5Hz, 1H), 6.99 (t, J =2.0Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 7.23 (t,

J= 8.0 Hiz, 1H), 7.54 (d, J=2.5 Hz, 1H), 7_73 (d, J=2.0 Hz, 1H), 8.00 (d, J=9.0 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H), 9.49 (5, 11D, 11.9 (5, 11, 13.0 (s, 1H). MS: mniz 375 (M+H).

Method 229: /

HN ] HN HQ ~~ ster1,. LJ yo 4 OH J OH

Stepw 1: Synthesis of 2-[5-(3-hydroxy-phenyl)-1H-pyrrolo[2,3-E5]pyridine-3-yll- ben=zene-1,3-diol.

[0320] Toa suspension of 3-[3-(2,6-dim ethoxy-phenyl)-1H-pyrrolo= [2,3-b]pyridine-5-y1]- phenol (23 mg, 0.066 mmol) in dichloromethane (1 mL) at -78°C wass added 1 M boron tribrom>ide solution in dichloromethane (0-23 mL, 0.23 mmol) dropwise. The reaction mixture was warmed up to room temperature over 4 h, then quenched —with water and neutralized to pH8 with a saturated solution of aqueous sodium bicarbeonate. The mixture was extractec] with EtOAc three times and the extracts were combined_ and adsorbed on silica gel. Purification on silica gel with a gradient of methanol/dichlo—romethane afforded 2- [5-(3-hydrox y-phenyl)-1H-pyrrolo[2,3-b]pyri dine-3-y1]-benzene-1,3-Cliol as a beige solid (17 mg, 81 %=% yield). lH NMR (500 MHz, DMSO-d6) 5 6.43 (d, J = 8 ~0Hz, 1H), 6.73 (dd, J =2.35,7.5 He=, 1H), 6.91 (t,J= 8.0 Hz, 1H), 7 .00 (,J=2.0Hz, 1H), 77.05 d,J= 8.0 Hz, 1H), 7.24 (t, J=28.0 Hz, 1H), 7.46 (d,J= 2.5 Hz, 1H), 7.85 (d, J=2.0O Hz, 1H), 8.42 (d,J= 2.0 Hz, 1H), 9.10 ( broad s, 2H), 9.49 (broad s, 1H), 11.7 (s, 1H). MSS: m/z 319 (M+H).

Method 30:

HN H

HN \ | i yh STEP 1 \~

ZZ 0)

Br

OH AE49 .

Step 1: Synthesis of 3-[3-(2H-pyrazol- 3-yl)-1H-pyrrolo[2,3-b] pyridine-5-yl]- phenol.

To a suspermsion of 1-(5-bromo-1H-pyrrolo[ 2 3-b]pyridine-3-yl)-3-di_methylamino- propenone &30 mg, 0.102 mmol) in EtOH was added hydrazine (5 ul, 0.122 mmol). The reaction mixture was stirred at 80°C for 3 h, then concentrated in vacuo. To the crude was added 3-hysdroxyphenyl boronic acid (18 mg, 0.132 mmol) and dichMorobis (triphenylp hosphino)palladium (ii) (4 mg, 0.006 mmol), and 1 mL o—fa 1:1 mixture of acetonitrile=, and a 2 M solution of sodium carbonate in water . The reaction was run in a

Personal CThemistry® microwave reactor at 150 °C for 600 s. The re action mixture was diluted witTh methanol (ca. 6 mL), filtered, and the filtrate was adsorPbed on silica gel.

Purificatiomn on silica gel with a gradient of TMeOH/CH2C12 affordec a beige solid that was further purified by reverse phase chromatography using a gradient oef H,0 and acetonitrile (with 0.1% formic acid as a modifier) to give 3-[3-(2H-pyrazol-3-yL)-1H-pyrrolo[2,3- b]pyridine—5-yl]-phenol as white solid (9.6 1mg, 34 % yield). TH NMR (500 MHz, DMSO- d6) 66.61 (d, J=2.0 Hz, 1H), 6.71 (dd, J=12.5,8.0 Hz, 1H), 7.03 Gs, 1H), 7.08 (d, J= 8.0

Hz, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.65 (broad s, 1H), 7.84 (d, J = 2.5 Hz, 1H), 843 (d, /= 2.0 Hz, 1), 8.53 (broad s, 1H), 9.51 (broads, 1H), 11.8 (broad s, AH). MS: m/z 277 (M-+HY).

[0322] Other composunds prepared by method 30:

Table 20

I Wi

HN nN HN Neg

N

NY AN NTS NN lL

OH a OH AES50,b

MS: m/z 291 (M+H+)s. MS: m/z 304 (M+R). a) From methylh ydrazine b) From guanidine hydrochloride and sodium car—bonate

Method 31:

Ts,

N \ HN \ { —

NT NT == lL STEP | ()

OTs OH

Step 1: Synthesis of 3~(3-phenylethynyl-1H-pymrrolo[2,3-b]pyridine-=5-yl}-phenol.

[0323] To a solutio-nof toluene-4-sulfonic acid 3-[3 -iodo-1-(toluene-4-sull fonyl)-1H- pyrrolo[2,3-b]pyridimme-5-yl]-phenyl ester (60 mg, 0.0%53 mmol, prepared as exemplified in

Method 6) in dichloromethane (0.5 mL) under nitrogen atmosphere was added successively triethylamine (16 uL,. 0.112 mmol), copper (I) iodide -€0.6 mg, 0.00315 mmol), dichlorobis . (triphenylphosphino)-palladium (ii) (0.9 mg, 0.00128 mrmmol), and phenyl acetylene (11 uL, ’ 0.102 mmol). The rezaction mixture was stirred at roorm temperature for 16 In, then adsorbed directly on silica gel. Purification on silica gel with a gradient of MeOH/CF2C12 afforded 46 mg of an off-white solid that further suspended in _2 ml of EtOH and 2 mmL of aqueous

KOH (50wt%). The reaction mixture was stirred at 80°C for 4 h, then acidified to pH 4 with 1 N aqueous HCL. Tae milky solution was extracted wwith EtOAc three timess, and the extracts were combirmed and adsorbed on silica gel. Purification on silica ge 1with a gradient of MeOH/CH2C]12 afforded 3-(3-phenylethynyl-1H-payrrolo[2,3-b]pyridine—5-yl)-phenol as a beige solid (12 mg, 41 % yield). 'H NMR (500 MEHz, DMSO-d6) 6 6.77 (dd, J =2.5, 7.5

Hz, 1H), 7.10 (t, J==2.0 Hz, 1H), 7.17 (d, J=6.0 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.37- 7.43 (m, 3H), 7.58 Cd, J= 7.0 Hz, 1H), 7.97 (s, 1H) , 8.18 (d,J=2.5Hz, 1H), 854(d,J= 2.5 Hz, 1H), 9.55 ( s, 1H), 12.2 (broad s, 1H). MS= m/e 311 (M+H.

Method 32:

Tso \ 3

NX I NT Yi : STE=P 1 l

OTs CH

Step 1: Synthaeesis of 3-[3-(2-pyridin-2-yl-vinyl)-1H-pyrrolo{2,3-b]pyr=idine-5-yl}- phenol.

[0324] To toluen_e-4-sulfonic acid 3-[3-iodo-1-(t«oluene-4-sulfonyl)-1H-pyr-rolo[2,3- blpyridine-5-yl]-ptoenyl ester (50 mg, 0.077 mmol), tri-ortho-tolylphosphine (10 mg, 0.031 mmol), palladium (I) acetate (2 mg, 0.0077 mmol) was added DMF (0.5 mL), triethylamine (32 wml, 0.232 mmol), and 2-vinylpyxcidine (42 ul, 0.388 mmol"). The vial was flushed with nitrog=en, and the reaction was run in = Personal Chemistry® microwave reactor at 150 °C foor 900 s. Water was added and the mixture was neutralizead to pH 6 with 1 N aqueous HC], sthen extracted with EtOAc three times. The extracts were combined and concentrated in vacuo. The crude was treated with 1 mL of EtOH and 1 mL eof aqueous

KOH (50wt%). Th_e reaction mixture was stirred at 80 °C for 15 h. The mixtware was neutralized to pH 2 with 1 N aqueous HC], and the resulting precipitate was filtered, washed with water, dried ima vacuo, and adsorbed on silica gel. Purification on silica mel with a gradient of MeOH./CH2CI2 afforded 3-[3~(2-pyridLin-2-yl-vinyl)-1H-pyrrolol[2,3-b]pyridine- 5-yl]-phenol as a y~ellow solid (17 mg, 35 % yield. 1H NMR (500 MHz, DM-1SO-d6) 6 6.78 (dd, J =2.0, 8.0 H==z, 1H), 7.13 (s, 1H), 7.15-7.20 (am, 2H), 7.26 (d, J = 16.0 Hz, 1H), 7.29 (4,

J=8.0Hz, 1H), 7..57 (d, J="7.5 Hz, 1H), 7.73 (d€&,J = 2.0, 8.0 Hz, 1H), 7.99 (d, J = 16.0

Hz, 1H), 7.93 (d, A = 2.0 Hz, 1H), 8.50 (d, J=2.0 Hz, 1H), 8.52 (d,J=5.0 Hz, 1H), 8.54 (d,

J=2.5 Hz, 1H), 9_56 (s, 1H), 12.1 (s, 1H). MS: n2/z 314 (M+H").

[0325] Other compounds prepared by method 322:

W” 0 2006/015123 PCT/US2005/02679™2

Table 21

HEN Oo

Ns

NT N— / _

OH

MSS: m/z 308 (M+H+).

Me=thod 33:

N=

N x Y NX \ 7 STEP 1 7

OH : OH

Step 1: Synthesis of 3-[3-(2-pyrid.in-2-yl-ethyl)-1H-pyrrolo[23-b]pyridine-5-yl li - phenol.

[0326] A suspension of 3-[3-(2-pyridin-2-yl-vinyl)-1H-pyrrolo[2,3 -b]pyridine-5-yl}- pheenol (10 mg, 0.032 mmol) and 10wt%% Pd/C (1.7 mg, 0.0016 mmo 1)in 0.9 mlofa (1: 1:1) mixture of MeOH/CH2CI2/DMF was stirred for 2 days under H; atrmosphere. The mixture was adsorbed directly on silica gel. Purification on silica gel with a gradient of

MeOH/CH2C12 afforded 3-[3-(2-pyridin-2-yl-ethyl)-1H-pyrrolo[2,3 —b]pyridine-5-yl]- ph enol as a yellow solid (6 mg, 60 % yield). 'H NMR (500 MHz, D™MSO0-d6) 63.22 (t, J= 7.5 Hz, 2H), 3.37 (t, J ="7.5 Hz, 2H), 6 77 (d, J= 7.5 Hz, 1H), 7.07 Cs, 1H),7.11(d,J=10

Hz=, 1H), 7.27 (m, 2H), 7.82 (m, 1H), 7.93 (d, J= 7.0 Hz, 1H ), 8.21 (s, 1H), 8.43 (m, 2K), 8.779 (d, J= 5.5 Hz, 1H), 9.54 (broad s, 1H), 11.53 (s, 1H). MS: m/z 316 (M+H).

V0 2006/015123 PCT/US2005/0226792

M ethod 34:

Tes, 7)

N \ | 2

NT N™ = _ STEP 1 | __

OTs J OH

Step 1: Synthesis of 3-[3-«(3-fluoro-benzyl)-1H-pyrrolo(2,3-b]pyridine-5-yl]- phenol. [0.327] To a solution of tolueme-4-sulfonic acid 3-[3-iodo—1-(toluene-4-sulfonyl)-1"H- py~rrolo[2,3-b]pyridine-5-yl]-phenyl ester (50 mg, 0.077 mrol, prepared as exemplified in meethod 6) in THF (2 mL) at -9 0°C under nitrogen atmosplaere was added a solution of tBsuLi in pentane (1.7 M, 90 ul_) dropwise. After stirring fo-r 5 min, 3-fluoro-benzald ehyde (4 OuL, 0.38 mmol) was added and the reaction mixture wa_s slowly warmed up to 10°C over 2 h, then quenched with a saturated solution of ammorium chloride and extract-ed with

EtOAc three times. The extracts were combined and adsort>ed on silica gel. Purificat=ion on sillica gel with a gradient of MeeOH/CH2CI12 afforded 26 mg of toluene-4-sulfonic ac-id 3-[3- [(3-fluoro-phenyl)-hydroxy-mesthyl]-1-(toluene-4-sulfonyl) -1H-pyrrolo[2,3-b]pyridimne-5- yl ]-phenyl ester. The material was dissolved in dichloromewthane (0.3 mL) under nitr=ogen atmosphere. Triethylsilane (24 ul, 0.149 mmol) was added, followed by boron triflumoride ethherate (7 pL, 0.149 mmol) dr-opwise. After stirring for 15 h, the reaction was queneched with a saturated solution of socium bicarbonate and extract-ed with dichloromethane three tirmes. The extracts were combined and concentrated under vacuum. The crude was treated with 2 mL of EtOH and 2 mL of aqueous KOH (50wt%). The reaction mixture was sstirred at 70°C for 1 h. The mixture was acidified to pH 4 with 1 NJ aqueous HC], and extracted with EtOAc three times. The extracts were combined and adsorbed on silica gel.

Purification on silica gel with & gradient of MeOH/CH,Cl, afforded 3-[3-(3-fluoro-b enzyl)- 1F-pyrrolo[2,3-b]pyridine-5-y1]-phenol as a beige solid (8 _mg, 66 % yield). "H NMR (500

MHz, DMSO-d6) 6 4.11 (s, 3H), 6.74 (dd, J= 2.5, 8.5 Hz, 1H), 6.97 (dt,J=2.0,8.5 Hz, 1H), 7.00 (s, 1H), 7.05 (d, J= 8.0 Hz, 1H), 7.13 (d,J= 10.55 Hz, 1H), 7.17 (d, J= 8.O Hz, 1K), 7.25 (t,J= 17.5 Hz, 1H), 7.30 (q, J= 8.0 Hz, 1H), 7.40~ (d, J=2.5 Hz, 1H), 8.07 (d,/= 2.€ Hz, 1H), 8.42 (d, J=2.0 H=, 1H), 9.56 (broad s, 1H), 1 1.6 (s, 1H). MS: m/z 319

OHH. [0 328] Other compounds prespared by Method 34:

Table 22

HN A

NT vr @ N-~

OH

MS: m/z 344 (DM+HT).

Method 35:

HN

\ eo FC

N = STEP 1 Lz

Fa : J

OH

Step 1: Synthesis of 3-(3-cyclohex-1-enyl-1H-pyrrolo[2,3-b]pyridine-5—y))-phenol.

[0329] To a solution of 5-bromo-1H-pyrrolo[2,3-bJpyridine (100 mg, 0.507 rmmol) in

MeOH (1 mL") was added cyclohexanone (52 uL, 1.015 mmol). The reaction nmixture was stirred at 80°C for 16 h then concentrated in vacuo. To the residue was added 3-- hydroxyphenzy! boronic acid (91 mg, 0.66 mmol), dichlorobis (triphenylpho- sphino)palladium (II) (18 mg, 0.025 mmol), and 2 mL of a 1:1 mixture of acetonitrile, and a 2 M solution of sodium carbonate in water. The reaction wassrunina

Personal Che nistry® microwave reactor at 150 °C for 600 s. The reaction mixture was diluted with cnethanol, filtered, and the filtrate was adsorbed on silica gel. Purification on silica gel with a gradient of MeOH/CH,C}, afforded 3.(3-cyclohex-1-enyl-1H—pyrrolo[2,3- blpyridine-5—yl)-phenol as an off-white solid (12.6 mg, 12 % yield). 'H NMR. (500 MHz,

DMSO0-d6) & 1.64 (m, 2H), 1.74 (m, 2H), 2.23 (m, 2H), 2.42 (m, 2H), 6.27 (mu, 1H), 6.74 (dd, J=2.0, 80 Hz, 1H), 7.05 (s, 1H), 7.11 (d, J = 7.5 Hz, 1H), 7.26 (t, J= 8.0 Hz, 1H), 7.50 (d, J==2.0 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H), 8.42 (d, J=2.0 Hz, 1H), 9.51 (broad s, 1H), 11.7 (s, 1H). MS: m/z291 (M+HY).

[0330] Otlaer compounds prepared by Method 35:

V0 2006/015123 PCT/US2005/026792

Table 23

A a aN _BOC

HN ) NN . \ 74 N N >

N AS | -

PZ

OH

OH

MS: m/z 392 (M+HH).

MS: m/z 320 (M+H+).

Method 36:

FN HN— "a, i NTS = sept.

OH OH

Step 1: Synthesis of 3-(3-cycloh exyl-1H-pyrrolo[2,3-b]pyricline-5-yl)-phenol.

[331] A suspension of 3-(3-cyclohex-1-enyl-1H-pyrrolo[2,3-b]oyridine-5-yl)-phenol 6.7 mg, 0.023 mmol) and 10wt% Pd/C (3 mg) in methanol (0.9 ml) wa_s stirred for 24 h under

H_, atmosphere. The reaction mixture was filtered through a silica plug, the solvent was ewaporated to give 3-(3-cyclohexyl-1 ¥H-pyrrolo[2,3-b]pyridine-5-yM)-phenol as a white solid (2.5 mg, 37 % yield). 'H NMR (500 MHz, MeOH-d4) 6 1.35 (m, 1H), 1.54 (m, 4H), 1.80 (mm, 1H), 1.88 (m, 2H), 2.10 (m, 2H), 2.87 (m, 1H), 6.79 (dd, J=2. 5, 8.0 Hz, 1H), 7.06 (t, J = 2.0 Hz, 1H), 7.10 (d, J=7.5 Hz, 1H]), 7.16 (s, 1H), 7.29 (t, /= 8. 0 Hz, 1H), 8.14 (d, J= 2_0Hz, 1H), 8.35 (d, J=2.0 Hz, 1H), 9.51 (broad s, 1H), 11.7 (s, 1 H). MS: m/e 293 (NHH). :

[0332] Other compounds prepared by method 36:

Table 24

I

BOC EtO

HN ) HN N HN—) \ N NT

NS ® rs

PP PZ

OH on OH

IMS: m/z 394 (M+H+). .

MS: m/z 322 (MEHEE). (MH) MS: m/z 337 (NAH).

Method 37:

Ts.

NY | HN )

N™™ NT Ss

PP STEP 2 =

OTs

OH AES51

Step 1: Synthesis of 3-(3-phenylsulfanyl-1H-pyrr-olo[2,3-b] pyridine-5--yl)-phenol.

[0333] To toluene-4—sulfonic acid 3-[3-iodo-1-(toluen e-4-sulfonyl)-1H-pyrrolo[2,3- b]pyridine-5-yl1]-pheny~1 ester (50 mg, 0.077 mmol), copper(l) iodide (1.5 mg, 3.004 mmol), and potassium carbona_te (16 mg, 0.155 mmol) under nitrogen atmosphere was= added isopropanol (0.2 mL), ®benzenethiol (8 pL, 0.077 mmol) ,, and ethylene glycol (55 uL, 0.155 mmol). The reaction mixture was stirred at 80 °C for 24 h. A (1:1) mixture of 2 M aqueous

KOH and MeOh (1 mI) was added, and the reaction mi xture was further stirre=d at 50 °C for 3 h. The mixture was acidified to pHS with IN aqueous HCI and extracted wit_h EtOAc twice. Extracts were ¢c ombined and concentrated under vacuum. Purification boy reverse phase chromatography~ using a gradient of H,O and acetonitrile (with 0.1% for-mic acid as a modifier) afforded 3-(3-phenylsulfanyl-1H-pyrrolo[2,3—blpyridine-5-yl)-phencol as a white solid (4.3 mg, 17 % yield). 'H NMR (500 MHz, DMSO--d6) 6 6.74 (dd, J = 2.5, 9.0 Hz, 1H), 6.98 (t, J = 2.0 H=z, 1H), 7.08 (m, 4H), 7.23 (1m, 3H0),7.85 (d, J=2.5Hz, 1H), 7.98¢(s, 1H), 8.56 (d, J = 2.0 Hz, 1H), 9.55 (broad s, 1H), 12.4 ( broad s, 1H). MS: m/==319 (M+H).

[0334] Other examp Jes prepared by Method 37:

Table 25

HN HN

Ds Mg

N™™ NT

P oO P 3

Br

OH OH

MS: m/z 397 (M+H+). MS: m/z 320 (M+H+).

Method 38: a

I HN NX

NTN _stEP1 NY VW _sTep2 PJ 0 = ZZ

Br Br Z]

OH

Step 1: Synthesis of (5-bromo-1H-pyrrolo[2,3-b]joyridine-3-yl)-phenyl-meth=anone.

[0335] To a suspens-ion of AICI; (338 mg, 2.54 mmol) in dichloromethane (10 mL) was added 5-bromo-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.5€7 mmol). After stirring for 4-5 min, benzoyl chloride (0.3 mL, 2.54 mmol) was added and th_e reaction mixture was stirrecl for 3 h, before quenching w ith MeOH at 0 °C. The mixture was concentrated in vacuum, tie pH was changed to 4 by addition of IN aqueous NaOH, andl the aqueous layer was extracted twice with EtOAc. Thee organic layer was dried over Mg=SOs, filtered and adsorbed or silica gel. Purification on sil ica gel with a gradient of EtOAc/Iaexanes afforded (5-bromo-1E1- pyrrolo{2,3-b]pyridines-3-yl)-phenyl-methanone as a white solid (61 mg, 40 % yield).

Step 2: Synthesis of [5-(3-hydroxy-phenyl)-1H-pwyrrolo[2,3-b]pyridine-3-yl]- phenyl-methanome,

[0336] To (5-bromo -1H-pyrrolo[2,3-b]pyridine-3-yl)-phenyl-methanone (50 mg, 0.167 mmol), 3-hydroxyphemyl boronic acid (30 mg, 0.217 mrmol), and dichlorobis (triphenylphosphino)pealladium (II) (6 mg, 0.0083 mmol ) in 2 Smith process vial was added 1 mL of a 1:1 mixture of acetonitrile, and a 2 M solutior of sodium carbonate in wateSr. The reaction was run in a Personal Chemistry® microwave reactor at 150 °C for 1200 s. Whe mixture was di_luted with DMF (ca. 5 mL) and filtered on a silica plug. The filtrate was adsorbed on siBica gel. Purification on silica gel with a gradient of Me(OH/dichloromethane afforded [5-(3—hydroxy-phenyl)-1H-pyrrolo[2,3 -b]pyridine-3-yl}-phen»yl-methanone as a yellow solid (3 7 mg, 71 % yield). 'H NMR (500 MHz, DMSO-d6) 6 6-80 (dd, J=2.0,7.5

Hz, 1H), 7.10 &t,J = 2.0 Hz, 1H), 7.14 (4, J=9_-0Hz, 1H), 7.31 (t, J= "7.5 Hz, 1H), 7.57 (t,J =7.5 Hz, 2H), 7.65 (t,J=7.5Hz, 1H), 7.84 (d, J=7.0 Hz, 2H), 8.14 ( s, 1H), g.61(d,J= 2.0 Hz, 1H), 8_68 (d, J=2.0 Hz, 1H), 9.65 (broad s, 1H). MS: m/z 315 (M+H").

Method 39:

HN RN “ HN) NL,

Cas STEP 1 1 > \ = ==.

Br “zs x N

Step 1: Synthesis of 3-(2H-pyrazol-3-yl)- 5-pyridin-3-yl-1H-pyr—rolo[2,3-b]pyridine.

[0337] To 5—bromo-3-2H-pyrazol-3-yl)-1H-goyrrolo[2,3-b]pyridine &30 mg, 0.114 mmol), 3-pyridyl boro=nic acid pinacol ester (30 mg, 0.1 48 mmol), and dichloreobis (triphenyl- phosphino)pal ladium (0) (4 mg, 0.0057 mmol) in a Smith process vial was added 1 mL of a 1:1 mixture of” acetonitrile, and a 2 M solution of sodium carbonate in —water. The reaction was run in a Peersonal Chemistry® microwave reactor at 150 °C for 90 0's. The mixture was diluted with DMF (ca. 5 mL), filtered on a silic a plug, and solvent wass evaporated.

Purification bye reverse phase chromatography rising a gradient of H2O- and acetonitrile (with 0.1% formic acid as a modifier) afforded the fo Tmate salt of 3-(2H-pyr—azol-3-yl)-5-pyridin- 3-yl-1H-pyrro_10[2,3-b]pyridine as a white solid (4.5 mg, 13 % yield). =H NMR (500 MHz,

DMSO-d6) 5 £5.61 (broad s, 1H), 6.73 (broad s, 1H), 7.53 (dd,J=5.5, 7.0 Hz, 1H), 7.71 (broad s, 1H), 7.94 (d,J=2.5 Hz, 1H), 8.18 (broad s, 1H), 8.60 (m, 2H), 8.68 (broad s, 1H), 8.98 (broad s, 1H), 12.0 (broads, 1H), 12.7 (bread s, 1H). MS: m/z 262 (M+H").

[0338] Othe=x compounds prepared by method 39:

Tables 26

HN N. 7 =

NH AE52

MS: m/z 30€0 (M+H+).

Method 40:

Et

TS HN \ vg h STEP 1 1 PD

LL 21 MLE =

Br = ] > -N

Step 1= Synthesis of 3-(2-ethyl-phenyl)—5-pyridin-3-yl-1H-pyrmrolo [2,3-b]pyridine.

[0339] To 5-bromo-3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-t>]pyridine (15 mg, 0.0314 mmol, prepared as described in method 1), 2-ethylphenyl boronic acid (5.2 mg, 0.034 mmo), and dichlorobis (triphenylphosgphino)pailadium (ID) (1.33 mg, 0.0002 mmol) in a Smith preocess vial was added 0.5 mL of a k :1 mixture of acetonitril_e, and a 2 M solution of sodium carbonate in water. The reaction mixture was stirred for 6 Hh, then 3-pyridyl boronic ac-id pinacol ester (8.4 mg, 0.041 mnmol) and dichlorobis (tripehenyl- phosphinos palladium (10) (1.3 mg, 0.0002 mmol) were added and the= reaction was run in a

Personal (hemistry® microwave reactor at 1.50 °C for 900 s. The mi xture was diluted with

DMF (2 ml), filtered on a silica plug, and sOlvent was evaporated. Purification by reverse phase chromatography using a gradient of H,0 and acetonitrile (witta 0.1% formic acid as a- modifier) afforded 3-(2-ethyl-phenyl)-5-pyridin-3-yl-1H-pyrrolo[2,3 -b]pyridine as a solid (5.8 mg, 61% yield). TH NMR (500 MHz, IOMS0-d6) 1.05 (t, J= 7.5 Hz, 3H), 2.66 (4, J =7.5Hz, 2H),7.27(J=70Hz, 1H), 7.31 (t,J=7.0Hz, 1H), 7.38% (d, J= 7.5 Hz, 2H), 7.45 (dd, .J=5.5,8.5 Hz, 1H), 7.60 (s, 1H), 798(d,J= 2.0 Hz, 1H). 8.10(dd,J=15, 8.0

Hz, 1H), 854(d,J=5.0 Hz, 1H), 8.60 (d, J” =2.0 Hz, 1H), 8.90 (s, JAH), 12.0 (s, 1H). MS: m/z 300 MHHD).

'{0340] Other compounds prepared by Method 40:

Table 27

EtO EtO AN Et

HN HN \

NX NT NT lL lL lL = = = x N xX =

N N

MS: m/z 316 (M+HT). IMS: m/z 316 (MAH). MLS: m/z 300 (M+HH).

Et HN HN

HN— LPEN NEPEN : ) NT NI NT \_o

N7 x

Z 7 _ = 5 @ =N

Hl NH MS: m/z 262 (MAH). ~SO,Me IMS: m/z 300 (M+H).

MS: m/z 392 (M+HH).

HN HN MeO

NEES NPN HN ®

NX \ 4 N™~ \ 0 A =N > | N \ pz

Z

4

N

] HN. \

MS: m/z 262 (M+HT). S0,Me AE53 NH

IMS: m/z 354 (MAH). WMS: m/z 341 (MAH).

MeO HN HN \

HN den \ OCF3 a NE @® NS NH

Zz / <UsIle

NA SN

NN

S MS: m/z 311 [MH+]

MS: m/z 303 (M+H+). MS: m/z 468 [MH+]

MeO F F

F F

HN. heyy HN HN

N° = N°

YW vs | ®

ZZ PZ ZZ

& =

NN SN

HN. some MS: m/z 308 (MH). MS: m/z 308 (M—+H+).

MS: m/z 395 (M+H+-).

EO i" Et MeO \ \ HN =m

AY av NLA z ! ge | i = g 4 C) \ \

NH NH MS: m/z 303 (VI+HH).

MS: m/z 354 (M+H +). MS: m/z 338 (M+ETH).

F E

F = 0

NTS () NS (J NT C2) » L » \ /

NH HN\s0,Me HN a : 4 +E).

MS: m/z 346 (MET) IS: m/z 400 M+-HH), | MS: m/z 352.1 [MEH]. o\ FF FF

HN o» H og H 0G \ °N °N 0G 1 N < N' DN ~~ ~ $ $ aor 23 NTH, / nA NA

HN b . o Cc Oo c

MS: m/z 354.1 [MAH].

MS: m/z 507 [MIE]. MS: m/z 491 [[MH+].

I ccc

F. A a

F H (0) H 0]

H ><, °N 0 °N 0 °N \ \ ~S SAY a®

N ~N 1 Ir ~, 2 To 2 NTCH,

QLD n nS 0 AES54, b 0 b o Cc

MS: m/z 428 [MH]. MS: m/= 455 [MH+].

MSS: m/z 448 [MHE+]. m/z 428 [MH] m/= 455 [MEH]

F.

F H (¢) H (0) a oo A X °N o NR N= ~~ AYIA

N ~N 1 _ 1 ~ 0] Ho

No QA J

N

2 NA A NA 0 a OH 0 a oO c

MS: m/%Z 426 [MH]. m/z +.

MSS: m/z 464 [MH+]. m/z 426 [MEL+] MS: m/= 442 [MH]

HL 0 H, 0 Ng

HN

$ 0

SN) Sa 1 1 2 .CH

SUSE CUS I"

NA NA MS: m/=z315 [MH+] 0 a OH © b

MSS: m/z 439 [MH+]. MS: m/z 444 [MH].

ry $

OH

MS: m/z 315 [MHA] a5¢ 9 3-Dihydree-benzofuran-7-bronic acid, benzo- [1,3]dioxole-4-boronic acid and 2,2- difluoro-benzo[ 1,3]dioxole-4-boronic acid were prepared according to thee procedures described belovv.

Synthesis of 1, 3-Dibromo-2-(2-bromo-ethoxy)—benzene.

Br Br oC — op

Br | Br

[0341] 1,2-IDibromoethane (5 .0ml, 58mmol) was added to a solution of sodium hydroxide (2.5g, 63mmoM) and 2,6-dibromophenol (14.5g, =7.6mmol) in 45 ml of vvater. The mixture was stirred uncer reflux for 20 hours and then extracted with ether. The combined organic layers was driezd over Na,S0y, filtered and conceentrated to give colorles soil. Silica gel chromatography using a gradient of ethyl acetate in hexanes to afforded _ 1,3-dibromo-2-(2- bromo-ethoxy~)-benzene (11.55, 57% yield) as a colorless oil.

Synthesis of ~7-Bromo-2,3-dihydro-benzofuran.

Br Br oo — CO

Br

[0342] A solution of 2.5M n-BuLi (13.0ml, 3.2.5mmo]) was added to a solution of 1,3- dibromo-2-(2--bromo-ethoxy)-benzene (11.5, 322.0mmo}) in 115ml of THF and 28ml of hexane at -7& °C over 30mins. The reaction was continued at -78 °C fox 30 minutes, then warmed to 0 °C. The mixture was poured into water (100ml) and the amqueous phase was extracted witzh ether. The combined organic layers were dried over Na_,S0y, filtered, and concentrated . to give a pale yellow oil. Silica geel chromatography usin_ga gradient of ethyl acetate in he=xanes to give 7-bromo-2,3-dihydreo-benzofuran as colorless needles (5.00g,

78%). '"H NMR (500 MHz, DMSO0-d6) 6 7.27Cdd, 1Hz, 8Hz, 1H), 7.20 (dd, 1Hz, 7.5Hz, 1H), 6.75 (t, 7.8Hz, 1H), 4.59 (t, 9Hz, 2H), 3.22 (t, 8.8Hz, 2H).

Synthesis of 2,3-Dihydro-benzofuran-7-bromic acid.

Br B(OH)2 solu Ov

[0343] A solution of 1.7M t-BuLi (6.5ml, 11 .lmmol) in pentane was adde=d to a solution of 7-bromo—2,3-dihydro-benzofuran (2.00g, 10.1mmol) in 15ml of THF at —78 °C over 15 minutes. Thhe mixture was stirred at -78 °C fox 30 minutes before trimethyl boroate (1.34mi, 12.0mmol) was added. The mixture was slow ly warmed to 0 °C and water (100ml) added.

The organic layer was separated and the aqueOus phase was extracted with ether. The combined organic layers was dried over Na,S«,, filtered and concentrated to give a white sticky residue. The crude product was then w-ashed with water and then 200% EtOAc in hexanes to afford 2,3-dihydro-benzofuran-7-bsronic acid (1.48g, 90% yield)asa white solid.

[0344] Sdimilarly, benzo[1,3]dioxole-4-boro-nic acid and 2,2-difluoro-bermzo[ 1,3]dioxole-4- boronic acid were prepared.

Method 41 :

HN Ng NH

HN Na 0 STESP 1 oat Br_STEP2 CE 3 2

J iJ o TL S

Br Br Br

HN AESS5

Step 1 : Synthesis of 2-bromo-1-(5-brommo-1H-pyrrolo[2,3-b]pyridiin-3-yD- ethaneone.

[0345] Xo a suspension of AICl; (338 mg, 2.54 mmol) in dichloromethzane (10 mL) was added 5-b-romo-1H-pyrrolo[2,3-b]pyridine (1.00 mg, 0.507 mmol). After sstirring for 30 min, bromoace-tyl chloride (0.21 mL, 2.54 mmo]) was added and the reaction nmnixture was stirred for 2 h, before quenching with MeOH at 0°C=. The mixture was concentrarted in vacuo, the pH was clnanged to 7 by addition of a saturated solution of aqueous sodiu-im bicarbonate, and the aqueo-us layer was extracted twice with FEtOAc. The organic layer wass dried over

MgSO, amd filtered through a plug of silica gel. Solvent was evaporated t-o dryness to give

2-bromo-1-(5-bromo- 1H-pyrrolo[2,3-b]pyridin-3-yl)-e-thanone as a light yellow solid (160 mg, quantitative). 'H NMR (500 MHz, DMSO-d6) § 4-70 (s, 2H), 8.44 (d, J= 2.0 Hz, 1H), 8.55 (d, J=2.5 Hz, 1 EJ), 8.68 (d, J=3.5 Hz, 1H), 12.9 (5, 1H). MS: m/z 316 A~M+HY.

Step 2: Synthesis of 4-(5-bromo-1H-pyrrole[2,3—b] pyridin-3-yl)-thiazael-2-ylamine.

[0346] A solution o f2-bromo-1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-e®hanone as a light yellow solid (80 mg, 0.251 mmol) and thiourea (21 mg, 0.276 mmol) in FEtOH (1 mL) was stirred at 80°C for 1.5 h. The resulting precipitate —was filtered, washed wisth MeOH, and dried in vacuo to gives 4-(5-bromo-1H-pyrrolo[2,3-b]p=ridin-3-yl)-thiazol-2-yl amine hydrobromide salt as a beige solid (66 mg, 70 % yield®. 'H NMR (500 MHz, TOMSO-d6) 6 7.11 (s, 1H), 8.00 (d, —J=2.5 Hz, 1H), 8.39 (t, /=2.5 Fz, 1H), 8.52 (d, /= 2.0 Hz, 1H), 12.4 (s, 1H). MS: m/z 295 (M+H").

Step 3: Synthesi sof 4-[5-(1H-indo}-5-y1)-1 H-pymrrolo{2,3-b]pyridin-3-wl]-thiazol-2- ylamine. [0347) To 4-(5-brommo-1H-pyrrolo[2,3-b]pyridin-3-y~l)-thiazol-2-ylamine hy=drobromide salt (20 mg, 0.053 mrmol), 5-indolyl boronic acid (13 rmg, 0.08 mmol), and [1, 1’- bis(diphenylphosphimmo)ferrocene]dichloropalladium (IT), complex with dichlo-romethane (1:1) (2 mg, 0.0026 namol) in a Smith process vial wass added 0.5 mL of a 1:1 mixture of acetonitrile, and a 2 No solution of sodium carbonate ira water . The reaction w asrunina

Personal Chemistry®» microwave reactor at 150 °C for— 1200 s. The mixture was diluted with

DMF (3 mL), filtered on a silica plug, and solvent wass evaporated. Purificatio nby reverse phase chromatograph _y using a gradient of H,O and acetonitrile (with 0.1% fommic acid as a modifier) afforded thee formate salt of 4-[5-(1H-indol-S-yl)-1H-pyrrolo[2,3-blmpyridin-3-yl]- thiazol-2-ylamine as =an off-white solid (8.5 mg, 42 % yield). 'H NMR (500 M-1Hz, DMSO- d6) 8 6.44 (m, 1H), 6 .82 (s, 1H), 6.91 (s, 2H), 7.32 (t, =J = 2.5 Hz, 1H), 7.41 (x2, 2H), 7.67 (d,J=2.5 Hz, 1H), 7 .81 (s, 1H), 8.14 (s, 1H), 8.46 (d, J=2.0Hz, 1H), 8.49 (<i,J=2.0 Hz, 1H), 11.0 (s, 1H), 11. 7(s, 1H). MS: m/z 332 (M+).

Method 42:

NH; O NH, O OMe

NN N-OMe NN y NH,

Cr | _STEP1 or, STEP 2 Ser STEEP 3

Br Br 7 # F

Br

HN

SE VT 10)

CL STEP 4 7 C-

OH

Br ’

OMe

OMe

Step 1: Synthesis ef (2-Amino-5-bromo-pyridin-3-y~1)-(6-fluoro-pyridin-3--yl)- methanone.

[0348] To a solution ef S-bromo-2-fluoropyridine (5.6 mal, 54.2 mmol) in THF (50 ml) at 0 °C under nitrogen wass added dropwise a 2 M solution of iso-propylmagnesium clhloride in

THF (27 ml) over a perdod of 10 minutes. The ice bath wass removed and the reaction mixture was stirred at recom temperature for 2 hours. The r-esulting slurry was adde=d dropwise via cannula tos a solution of 2-amino-5-bromo-N—methoxy-N-methyl-niccotinamide hydrochloride (3.0 g, 1 1.5 mmol) in THF (50 ml) at room —temperature under nitrogzenover a period of 30 minutes. Ax fier stirring for 3 hours, the reactio m was quenched by addi tion of a saturated aqueous solution of ammonium chloride (50 ml) at 0 °C and the mixture was stirred at room temperature for another 20 minutes. Water was added and the mixture was extracted with ethyl acetate (three times). The combined omganic layers were dried over sodium sulfate, then filEered and concentrated. Crystallizat ion from methanol (ca. €0 ml) afforded the title compound as dark yellow crystals (1.48 =, 49 % yield). 'HNMR (DMSO- de): & 8.49 (s, 1H), 8.3<1(d, J= 1.5 Hz, 1H), 8.23 (dt, J= 2.5, 8.0 Hz, 1H), 7.81 (d, J=2.5 Hz, 1H), 7.74 (broad s, 2H) , 7.36 (dd, J=2.0, 8.0 Hz, 1H); MS : m/z 285.9, 297.9 [MH

Step 2: Synthesis @f 5-bromo-3-[1-(6-fluoro-pyridiom-3-yD-2-methoxy-vinyH)- pyridin-2-ylamine_

[0349] To a suspension of (methoxymethyl)triphenylphcsphonium chloride (1.16 g, 3.38 mmol) in THF (4 rl) at 0 °C under nitrogen was addeed dropwise a 1M solution of lithium bis(trimethylsil~yl)amide in THF (3.4 ml, 3.4 mmol ). The resulting dark red mixture was stirred at 0°C for 1€) minutes to generate the ylide reag=ent. To a solution of (2—amino-5-

bromo-pyr-idin-3-yl)-(6-fluoro-pyridin-3-yl)—methanone (400 mg, 1.35 rmmol) in THF (6 ml) was added. dropwise a 1 M solution of tert-buatylmagnesium chloride in THF (1.35 ml) at 0 °C under nitrogen The reaction mixture waas stirred at 0 °C for 5 minut=es, then the ylide reagent was added dropwise in 5 minutes. The reaction mixture was allo—wed to warm up to room temperature in 45 minutes before quermching with a saturated aqueous solution of ammoniurm chloride (50ml) at 0 °C. The mixture was stirred vigorously . for 1.5 hours at room tempperature. Water was added, followed by extracting ethyl acetat—e (three times). The combined. organic layers were washed with “brine, and directly adsorbed on silica gel.

Purification on silica gel with a gradient of ethyl acetate/hexane affordead the title compound (single isomer) as a dark foam (220 mg, 5024 yield). 'H NMR (DMSO—dg): 8 8.15(d,J= 2.5 Hz, 1H), 8.00 (d, J= 2.5 Hz, 1H), 7.78 (at, J=2.5, 8.5 Hz, 1H), 7.48 (d, I= 2.5 Hz, 1H), 7.10 (dd, J=3.0, 8.5 Hz, 1H), 6.61 (s, 1H), 5.73 (broad s, 2H), 3.80 (s, 35H); MS: m/z 324, 326 [MH J".

Step 3: Synthesis of 5-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl) -pyridin-2-ol.

[0350] To a solution of 5-bromo-3-[1-(6~ fluoro-pyridin-3 -y])-2-metheoxy-vinyl}-pyridin-2- ylamine (220 mg, 0.678 mmol) in 1,4-diox ane (3 ml) in a Smith process vial was added 0.3 ml of 70 % aqueous perchloric acid. The reaction was irradiated in a Personal

Chemistcy® microwave to 150 °C for 300 =. The reaction mixture was diluted with water and neutwralized to pH 7 by addition of an a«queous solution of sodium hmydroxide. The resulting precipitate was filtered, washed with water, and dried in vacu~o to yield the title compourd as a beige solid (152 mg, 77 % yield). '"H NMR (DMSO-d): 8 12.1 (broad s, 1H), 11.77 (broad s, 1H), 8.32 (d, = 2.5 Hz, 1H), 8.30 (d, J=2.5 Hz, 1F), 7.83 (dd, J= 2.5, 11.5 Hz, 1H), 7.82 (s, 2H), 7.67 (s, 1H), 6.43 (d, J= 11.5 Hz, 1H); MS: m/z 290 [MH].

Step 4: Synthesis of 5-[5-(3,4-dimettmoxy-phenyl)-1 H-pyrrolo[2-,3-b]pyridin-3-yl}- pyridin-2-ol.

[0351] To 5-(5-bromo-1H-pyrrolo{2,3-b Tpyridin-3-yl)-pyridin-2-ol, _3,4-dimethoxyphenyl boronic acid (1.3 equiv.) and dichlorobis (“triphenylphosphino)palladium (ii) (6 mol %) ina

Smith process vial was added a 3:2:1 mixture of acetonitrile, water, an.d a 2 M solution of sodium «carbonate in water to achieve an overall concentration of the sutarting material of 0.10 M. The reaction was run in a Personal Chemistry® microwave re=actor at 165 °C for 1200 s. “Water was added and the mixture extracted three times with et=hyl acetate.

Purifica-tion on silica gel with a gradient o £ MeOH/CH2CI2 afforded 55-[5-(3,4-dimethoxy- phenyl)—H-pyrrolo[2,3-b]pyridin-3-yl]-pyridin-2-0l as an off-white scolid (34 % yield). 'H

NMIR (DMSO-de): 6 11.86 (broad s, 1 H), 11.67 (broad s, 1H), 8.52 Cd, J=2.0 Hz, 1H), 8.22 (d, J=2.0 Hz, 1H), 7.89 (dd, /=2.5,10 Hz, 1H), 7.75 (s, 1H), 7.773 (s, 1H), 7.29 d, F 2.0 Hz, 1H), 7.23 (dd, J= 2.0, 8.0 Hz, 1H), 7.04 (d, J= 8.5 Hz, 1H), 6 44 (d, /=9.0Hz, 17H), 3.8 5(s, 3H), 3.79 (s, 3H); MS: m/z 348.1 [MH].

[0352] Other compounds prepared by method 42:

Table 28

FAN \ ~=N OMe

N™ \ y lL OMe

OMe

OMe

MCS: m/z 468 (M+H+). a) From 5-bromo-3-(6-chloro-pyidin-3-yl)-1H-pyrrolo[2,3-b]oyridine, which was= prepared by one of the following ways.

Synthesis of 5-bromo-3-(6-chloro-p yridin-3-yl)-1H-pyrrolo [2,3-Wb]pyridine from 5—(5- baromo-1H-pyrrolo[2,3-b]pyridin-3—yl)-pyridin-2-oi.

HIN HN

NET ~N = NT XN

LJ Ph

OH Cl

Br Br [@353] 5-(5-bromo-1H-pyrrolo[2,3 -b]pyridin-3-yl)-pyridin-2-ol ( 152 mg, 0.524 mmc) was heated in 2 ml of phosphorus oxychloride in a capped vial. The reaction mixture vevas stirred at 110 °C for 2 hours, then poured onto ice and neutralized t«o pH 4 witha 1 N a_queous solution of sodium hydroxide. The precipitate was filtered off, washed with water, and dried in vacuo. The resulting solid was heated in methanol for 30 min, then filtered old, washed with methanol, and dried in vacuo to yield the title coompound as a beige solid (_ 117 mg, 72 % yield). IH NMR (DMISO—dg): & 12.4 (broad s, 1H), 8.80 (d, J=2.5Hz, 1H), $3.53 (d, J= 2.0 Hz, 1H), 8.36 (d, J= 1.5 Hz, 1H), 8.23 (dd, J=2.0, 8.0 Hz, 1H), 8.16 (s= 1H), ~7.54 (4, J= 7.5 Hz, 1H); MS: m/z 307.9, 309.9 [MH]".

Synthesis of Ss-bromo-3-(6-chloro-pyridin-3-yR)-1H-pyrrolo[2,3-b]pyrid-ine from 5- bromo-3-[1-(63-fluoro-pyridin-3-yl)-2-methoxy~-vinyl]-pyridin-2-ylamines.

OMe=

NH, | HN

F Cl

Br Br

[0354] 5-bro>mo-3-[1-(6-fluoro-pyridin-3-yl)-2-methoxy-vinyl]-pyridin-2 -ylamine (375 mg, 1.16 mmol) was treated with a 4 M solution of HCl in 1,4-dioxane (5 nml). The reaction mixture was s¥tirred at 110 °C in a sealed tube fox 16 hours, then poured ont=o ice and neutralized to pH 6 with a 1 N aqueous solution of sodium hydroxide. The precipitate was filtered off, w=ashed with water, and dried in vacuo to give 333 mg of a beigge solid. The solid was heat-ed with 2 ml of phosphorus oxychloride in a capped vial. The reaction mixture was stirred at 110 °C for 2 hours, then proured onto ice and neutralized to pH 2-3 with a 1 N aqueous solution of sodium hydroxide. The precipitate was filte red off, washed with water, ard dried in vacuo. Purification on silica gel using a gradient o—f methanol in dichloromethaane afforded the title compound as a beige solid (241 mg, 67 =% yield).

Method 43:

HN—

Ng NHy =F HaN NE 0— [® (=, © N ) OMe

OMe AES6

Step 1: SSynthesis of [2-amino-5-(3,4-dimethoxy-phenyl)-pyridin-3—yl]-(6-amino- pyridin-3s-yI)-methanone.

[0355] A solution of (2-amino-5-bromo-pyridlin-3-yl)-(6-fluoro-pyridin-3-yl)-methanone (120 mg, 0.4005 mmol), ammonium chloride (5 e€quiv.), and triethyl amine (5 eq.) in absolute ethanol (0.2 M4) was sealed in a Smith process val. The reaction was heatecl in a Personal

Chemistry® r-nicrowave reactor to 200 °C for 25 minutes. The mixture wass diluted with water, and the= resulting yellow precipitate was filtered off, washed with water, and dried in vacuo. The crude product was mixed with 3,4-cGimethoxyphenyl boronic aczid (1.3 equiv.), 6 mol % of di chlorbis(triphenylphosphino) palladium (II) and a 3:2:1 mixtwure of acetonitrile, water, and a =2 M aqueous solution of sodium carbonate (0.11 M). The reactzion was run in a

Personal Che-mistry® microwave reactor at 165 °C for 1200 s. Water was zadded and the mixture was esxtracted three times with ethyl acetate. Purification was accomplished by flash chromatograp=hy on silica gel with a gradient of ethyl acetate/hexanes and afforded [2- amino-5-(3,4—dimethoxy-phenyl)-pyridin-3-yl]-(6-amino-pyridin-3-yl )-methanone as a yellow solid (C37 mg, 31 % yield). 'H NMR CDMSO-dq): 5 8.50 (d, J=2.5 Hz, 1H), 8.29 (d,

J=2.0 Hz, 1H), 7.86 (d, /=2.0 Hz, 1H), 7.75 (dd, = 2.0, 8.5 Hz, 1H), 7.15 (d, /=2.0 Hz, 1H), 7.06 (m, 3H), 6.98 (d, J= 8.0 Hz, 1H), 6.92 (broad s, 2H), 6.50 (1, J= 9.0 Hz, 1H), 3.80 (s, 3H), 3.75 (s, 3H). HPLC/MS m/z: 351 [MAH].

Step 2: S=ynthesis of 5-[5-(3,4-dimethoxy-phenyl)-1H-pyrrolo[=2,3-b]pyridin-3-yl]- pyridin-2--ylamine.

[0356] To am suspension of (methoxymethy~1)triphenylphosphonium chloride (166 mg, 0.485 mmol) din THF (1 mi) at 0 °C under nitzogen was added potassitam bis(trimethylssilyl)amide (97 mg, 0.485 mmo 1). The mixture was stirre d at room temperature for 30 min, th_en it was added to [2-amino-5- (3,4-dimethoxy-phenyl)-pyridin-3-yl]-(6- amino-pyridira-3-yl)-methanone (34 mg, 0.097 mmol) in one portion. ~The reaction mixture was stirred fox 2 hours, then quenched with vet methanol and concent=rated in vacuo. The crude was diltated with 2 ml of 1,4-dioxane znd treated with 0.1 ml of ~ aqueous 70 % perchloric acied. The mixture was stirred at 8 °C for 19 hours, diluted with THF/methanol (1:1), and treamted with 2.0 g of PS-trisamine (Argonaut Technologies, 4 equivalents per equivalentof amcid used) for 30 minutes. The resin was filtered off and —washed with

THF/MeOH (_ 1:1). Purification was accomplished by flash chromotogmraphy on silica gel with a gradiemt of methanol/dichloromethanes afforded 5-[5-(3,4-dimet=hoxy-phenyl)-1H- pyrrolo[2,3-b Wpyridin-3-yl]-pyridin-2-ylamirme as a yellow solid (9.7 nag, 29 % yield). 'H

NMR (DMSO-d): 611.8 (s, 1H), 8.51 (d, J=2.0 Hz, 1H), 8.31 (d, /~ 2.0 Hz, 1H), 8.25 (d,

J=2.0 Hz, 1H"), 7.77 (dd, J/~ 2.0, 10.0 Hz, 1¥), 7.70 (4, J= 2.5 Hz, 1H), 7.28 (d, /= 2.0 Hz, 1H), 7.24 (dd, J=2.0,7.5 Hz, 1H), 7.04 (d, J=28.5 Hz, 1H), 6.55 (d, /— 8.5 Hz, 1H), 5.90 (broad s, 2H), 3.86 (s, 3H), 3.79 (s, 3H). HPL_C/MS m/z: 347.1 [MH]" _ 1.48

Method 44: o— or _ Wad os "NT \_¢" IN = J 1 J ~_OMe = _ NH, _STEP1,_ HN = oA aN ( 7 4 N 3 “= OMe

F 9 0 OMe r AEST

Step 1: Synthesis of (2-amino-5-bromo-pyridin-3-y1)-[6-(2-maethoxy-ethylamino)- pyridin-3-yl]-methanone.

[0357] A solution of (2-amino-5 —bromo-pyridin-3-yl)-(6-fluoro-pyridin-3-yl)-methanone, 2-methoxyethylamine (1 equiv.) and triethylamine (1.2 equiv.) in alosolute EtOH (0.17 M) was sealed in a Smith process vial. The reaction was run in a Persoral Chemistry® microwave reactor at 160 °C for 900 s. The mixture was diluted with water, and the resulting precipitate was filtered off, washed with water, and dried —in vacuo to give (2- amino-5-bromo-pyridin-3-yl)-[6-(2-methoxy-ethylamino)-pyridin-3-yl]-metbanone as a yellow solid (86 % yield). 'H NMR (DMSO-d): 8 8.28 (d,J=2.5 Hz, 1H), 8.23 (d,J=2.5

Hz, 1H), 7.75 (d, J= 2.5 Hz, 1H), 7.69 (dd, J=2.0, 9.0 Hz, 1H), 7.6 4 (broad s, 1H), 7.12 (broad s, 2H), 6.59 (d,J=9.5 Hz, 1H), 3.51 (t, J= 4.5 Hz, 2H), 3.47 (1, J= 4.5 Hz, 2H), 3.26 (s, 3H); HPLC/MS m/z: 351, 353 [MH].

Step 2: Synthesis of [2-amimo-5-(3,4-dimethoxy-phenyl)-pyridin-3-yl-[6-(2- methoxy-ethylamino)-pyridiin-3-yl]-methanone.

[0358] To (2-amino-5-bromo-p yridin-3-y1)-[6-(2-methoxy-ethyl amino)-pyridin-3-yl]- methanone, 3,4-dimethoxyphenylboronic acid (1.3 equiv.) and dic hlorobis (triphenylphosphino)palladium (ii) (6 mol %) in a Smith process v=ial was added a 3:2:1 mixture of acetonitrile, water, and a2 m solution of sodium carbomnate in water to achieve an overall concentration of the starting material of 0.10 m. The reacti_on was run in a Personal

Chemistry® microwave reactor at 165 °C for 1200 s. Water was andded and the mixture extracted three times with ethyl acetate. Purification on silica gel with a gradient of

MeOH/CH2CI2 afforded [2-amix10-5-(3 4-dimethoxy-phenyl)-pyr-idin-3-yl}-[6-(2-methoxy- ethylamino)-pyridin-3-yl]-methanone as a yellow solid (74 % yieRd). 'H NMR (DMSO-d): 8.49 (d, /=2.0 Hz, 1H), 8.33 (d, J=2.5 Hz, 1H), 7.85 (d,/=2.0 Hz, 1H), 7.73 (d, =8.5

Hz, 1H), 7.58 (broad s, 1H), 7.14 (s, 1H), 7.05 (m, 3H), 6.98 (d, /*=8.5 Hz, 1H), 6.59 (d, J=

9.0 Hz, 1H), 3.79 (=, 3H), 3.75 (s, 3H), 3.50 (broad t, J™=5.0 Hz, 2H), 3.46 (t, J/=~ 5.0 Hz, 2H), 3.26 (s, 3H); FIPLC/MS m/z: 409.2 [MH]'.

Step3: Synthesis of {5-[5-(3,4-dimethoxy-pheny" 1)-1H-pyrrolo[2,3-b]pymridin-3-yl]- pyridin-2-y1}-(2-methoxy-ethyl)-amine.

[0359] To a suspension of (methoxymethyl)tripheny—Iphosphonium chloride C7-10 equiv.) in THF (0.45 M) at «0 °C under nitrogen was added potassium bis(trimethylsilyl Jamide (1 equivalent to phosp honium chloride). The mixture wass stirred at room temperamture for 30 minutes. The resulting mixture was added to [2-aminO-5 -(3,4-dimethoxy-pherayl)-pyridin- 3-yl]-[6-(2-methox &/-ethylamino)-pyridin-3-yl]-methamnone dissolved in THF (©.1-0.2M) in one portion. The reaction mixture was stirred for 1~16e hours, then diluted witlm methanol and adsorbed on sil dca gel. Purification by flash chromatography on silica gel with a gradient of methanol/dichloromethane afforded the corresponding vinyl ether €hat was used in the next reaction. .

[0360] The vinyl ether was dissolved in 1,4—dioxane= (0.1 M) and treated with 2.6 equivalents of 70 Yo aqueous perchloric acid. The mix ture was stirred at 80-10 0 °C for 19- 24 hours, diluted with THF/MeOH (1:1), and treated wwith PS-trisamine (Argomnaut

Technologies ,10 e«quivalents per equivalent of acid used) for 30 minutes. The resin was filtered off and wasshed with THF/MeOH (1:1). Purifiacation by flash chromatosgraphy on silica gel with a gradient of methanol/dichloromethanee afforded {5-[5-(3,4-dirmethoxy- phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-pyridin-2-y1} —(2-methoxy-ethyl)-amirae as a white solid (65 % yield). 'H NMR (DMSO-ds): using the compound prepared accor ding to example 83 as a starting material. 'H.NMR 611.8 (s, 1H),8.51(d,/=2.0Hz, 1H), 839d,

J=2.5 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H), 7.77 (dd, /= 25, 9.0 Hz, 1H), 7.70 (d , /=2.5 Hz, 1H), 7.29 (d, J= 2.0 Hz, 1H), 7.25 (dd, /= 2.0, 8.5 Hz_, 1H), 7.04 (d, ~9.0 Hz , 1H), 6.62 (d,

J=8.5 Hz, 1H), 6.55 (t, J= 5.5 Hz, 1H), 3.86 (s, 3H), 33.79 (s, 3H), 3.47 (m, 419), 3.28 (s, 3H). HPLC/MS m/z: 405.2 [MH].

[0361] The following one-pot procedure was used in some cases:

NH, O NH, O oC TOUT

Br H

OMe

OMe

[0362] A solution of (2- amino-5-bromo-pyridin-3-yl)-(C6-fluoro-pyridin-3-yl )-methanone, 1.1 equivalents of isobutylamine and 1.2 equivalents (or =2.3 equivalents for amines in salt form) of triethyl amine ares dissolved in absolute ethanol (overall concentratioxn of the starting material: 0.22 M) and sealed in a Smith process wal. The reaction was mnina

Personal Chemistry® microwave reactor at 150 °C for 9€00 s. The solvent was evaporated and the crude mixed with 1.3 equivalents of 3,4-dimetho Xyphenylboronic acicH, 6 mol % of dichlorobis (triphenylphossphinol) palladium (ir) and a 3:22:1 mixture of aceton_itrile, water, and an aqueous 2 M soluti_on of sodium carbonate (overa_1l concentration of stamrting material: 0.18 M). The reaction wass run in a Personal Chemistry® microwave reactor aft 165 °C for 1200 s. Water was added and the mixture extracted threes times with ethyl ace tate

Purification by flash chro matography on silica gel with = gradient of ethyl ace=tate/hexane to afforded [2-Amino-5-(3,4-dimethoxy-phenyl)-pyridin-3 —yl]-(6-isobutylamino -pyridin-3-y1)- methanone as a yellow solid (71 % yield). 'H NMR (DMASO-de): 6 8.49 (d, #=2.0 Hz, 1H), 8.32 (d, J=2.5 Hz, 1H), 7.86 (d, /=3.0Hz, 1H), 7.72 (d ,/~=9.0Hz, 1H), 7.547 (broad s, 1H), 7.14 (d, J=2.0 Hz, 1H), 7.06 (dd, J=2.0, 8.5 Hz, 1H), 703 (broad s, 2H), 6.9 8(d,/~=8.0

Hz, 1H), 6.56 (d, J= 8.5 Fz, 1H), 3.79 (s, 3H), 3.75 (s, 3-H), 3.15 (broad s, 2HE), 1.83 (m, 1H), 0.89 (d, J= 6.5 Hz, GH); HPLC/MS m/z: 407.2 [MH].

[0363] Other compounds prepared by Method 44:

Table 29

HN =~N =N » a

NT \ 8 NTS \ Nh N\__~=N =N

L w_° = H NTS \ AN

H

OMe OMe OM

OMe OMe a OMe © a

MS: m/z 417 (MAH). . (MH) MS: m/z 391 (MAH). MS: m/z 452 (M—H).

WO) 2006/015123 PCT/US2005/026792

HE =N

YY) Ww a

N

OMe

MS-: m/z 332 (M+HH). a) Compounds synthesized by the one-pot procedure.

Me thod 45: i) 7 HN—

HN | ~/ "OH NSS yO STEP 1 STEP 2 # “OH x — AL

Br oO o | OMe

OH

0

Step 1: Synthesis of 5-{5-[3-me=thoxy-4-(4-methoxy-benzyleoxy)-phenyl]-1H- pyrrolo[2,3-b]pyridin-3-yl}-pyx-idin-2-ol.

[03864] To the 5-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyrid-in-2-ol, 4-(4- me=thoxyphenylmethoxy)-3-methoxyphenylboronic acid (1.3 equiw.), and 6 mol % of dic=hlorobis(triiphenylphosphino)pall adium (If) in a Smith process vial was added a 3:2:1 mixture of acetonitrile, water and a 2 M aqueous solution of sodiumm carbonate (0.10 M). The reaction was run in a Personal Chemuistry® microwave reactor at M65 °C for 1200 s. Water was added and the mixture was extracted three times with ethyl acetate Purification on silica gell with a gradient or methanol/dich loromethane by flash chroma®ography afforded 5-{5-[3- mesthoxy-4-(4-methoxy-benzyloxy)-yphenyl]-1H-pyrrolo[2,3-b]pyr=idin-3-yl}-pyridin-2-ol as a tan solid (46 % yield). '"H NMR (DMSO-d): & 11.86 (broad s, 1H), 11.67 (broads, 1H), 8.51(d, J=2.5 Hz, 1H), 8.22 (s, 1H), 7.89 (dd, J=2.5, 9.5 Hz, 1HD), 7.75 (d, J= 2.5 Hz, 1H), 7.72 (s, 1H), 7.38 (d, J=8.5 Hz, 2H) , 7.30 (d, J= 2.0 Hz, 1H), 7.20 (d4, J=2.0, 8.5 Hz, 1H), 7.11 (d, J= 8.0 Hz, 1H), 6.94 (d, J= 8.5 Hz, 2H), 6.44 (d, ]=9.5 H z, 1H), 5.03 (s, 2H), 3.85 (s, 3H),3.75 (s, 3H); HPLC/MS m/z: 454.1 [MH].

VWO0 2006/015123 PCT/US2005/026 7992

Step 2: Synthesis of 5-(5-(4-hyedroxy-3-methoxyphenyl)-1E3-pyrrolo[2,3-b]pyridip- 3-yl)pyridin-2-ol. [03 65] To a suspension of 5-{5-[3 —methoxy-4-(4-methoxy-ben=yloxy)-phenyl]-1H- pyrxolo[2,3-blpyridin-3-yl}-pyridin- 2-01 (25 mg, 0.055 mmol) in 1.5 ml of dichlorometh ane wass added 78 mg of PS-thiophenol resin (Argonaut Technologies, 1.41 mmol-g™*), followved by “TFA (0.3 ml). The clear suspensi on was stirred at room tempe=rature for 1 hour, then the res-in was filtered off, washed with e=thyl acetate, then methanol. “The filtrate was evaporamted anc the residue was taken up in 2 mA of ethyl acetate and saturate- d aqueous solution of soc ium bicarbonate. The resulting p Tecipitate was filtered off, washed with water, then e=thyl acetate and dried in vacuo to afford 5.(5-(4-hydroxy-3-methoxyrshenyl)-1H-pyrrolof2,3— b]pyridin-3-yl)pyridin-2-ol as a ligh t beige solid (15 mg, 80 % y# eld). 'H NMR (DMSO—dg): & 11.83 (broad s, 1H), 11.67 (broad s, 1H), 9.05 (s, 1H), 8.49 (d, J=2.0Hz, 1H), 8.18 (d-,J= 2.0 Hz, 1H), 7.88 (dd, J=3.0, 9.5 Hz, 1H), 7.74 (d, J= 2.5 Hz, 1H), 7.71 (d, J=2.0 Hz, 1 H), 7.26(d, J=2.0 Hz, 1H), 7.12 (dd, J=2.0, 8.5 Hz, 1H), 6.87 (d, J==8.0Hz, 1H), 6.44 (4, J = 9.0 Hz, 1H), 3.86 (s, 38); HPLC/MLS m/z: 334.1 [MH].

M-ethod 46:

F

1 _ ) HN gs r= YC 5

NH, NT l~ NT No_—

NY 0 stEP1 N STEP 2 H =\

Br ° 8 CMe oO <

Step 1: Synthesis of 3-[1-(6-f Tuoro-pyridin-3-yl)-2-meth ©xy-vinyl]-5-[3-methoxy-4- (4-methoxy-benzyloxy)-phenyl]-pyridin-2-ylamine.

[0366] 5-Bromo-3-] 1-(6-fluoro-goyridin-3-yl)-2-methoxy-viny/1]-pyridin-2-ylamine was swibjected to method 20, Step 1 to yield 3-[1-(6-fluoro-pyridin-38-yl)-2-methoxy-vinyl]— 5-[3- rrethoxy-4-(4-methoxy-benzyloxy~)-phenyl]-pyridin-2-ylamine as a yellow solid (70% yield). '"H NMR (DMSO-de): & 8.27 (d, J=2.5 Hz, 1H), 8.20 (ss, 1H), 7.83 (dt, I= 2.5, 85

Hz, 1H), 7.61 (d, J=2.0 Hz, 1H), 7.36 (d, J= 8.5 Hz, 27H), 7.18 (s, 1H), 7.10 (m, 2H), 7.07 (d, J=8.5 Hz, 1H), 6.94 (d, J= 8.5 Hz, 2H), 6.63 (s, 1E), 5.53 (broad s, 2H), 5.008 (s, 2H), 3.82 (s, 3H), 3.81 (s, 3H), 3.75 (s, 3H); HPLC/MS m/=: 488.2 MH].

Step 2: Synthesis of 2-Methoxy-4-{3-[6-(2-morgpholin-4-yl-ethylamino)-poyridin-3- yl}-1H-pyrroloe[2,3-b]pyridin-5-yl}-phenol.

[0367] A solution of 3-[1-(6-fluoro-pyridin-3-yl)-2--methoxy-vinyl]-5 -[3-meth oxy-4-(4- methoxy-benzyloxy)-phenyl]-pyridin-2-ylamine (50 rag, 0.102 mmol) and 2-momrpholin-4- yl-ethylamine (0 -6 ml, 4.59 mmol) in anhydrous N-meethylpyrrolidone (0.5 ml) was sealed in a Smith process vial. The reaction was run in a Perssonal Chemistry® microwave reactor at 250 °C for 1200 s. The mixture was diluted with a saturated aqueous solution of ammonium chloride (20 ml), the resulting precipitate was filtered off, washed w=ith a saturated aqueots solution of ammonium chloride and water, then dried in vacu-o. The solid was transferred ®o a Smith process vial and dissolved in dioxane (1 ml). Aqueois perchloric acid (70 %, 0.1 xl) was added and the reaction was run ina Personal Chemistrys® microwave reactor at 150 °C for 300s. The mixture was diluted with (1:1) THF ~methanol (10 ml) and treated with 2.0 g of PS-trisamine (Argomnaut Technologies, 3.53 mmmol-g™) for 1 hour. The resim was filtered off, washed with (1:1) “THF/methanol, and the filmrate evaporated to gi ve 75 mg of a dark oil. Purification cen mass-triggered preparati ve HPLC provided 2-Methoxy-4- {3-[6-(2-morpholin-4-yl-ethy=lamino})-pyridin-3-yl}-1 H—pyrrolo{2,3- b]pyridin-5-yl1} —phenol as an off-white fluffy solid (1_0.7 mg, 21 % yield, 0.75 equiv. formate salt). "FI NMR (DMSO-dg): 6 11.70 (s, 1H) , 8.98 (s, 1H), 8.42 (d, J=25 Hz, 1H), 8.32 (d, J=2.0 Elz, 1H), 8.16 (d, J= 2.0 Hz, 1H), 8.08 (5, 0.75H, formate), 7.71 (dd, J=2.5, 9.0 Hz, 1H), 7.63 (d, J=2.5 Hz, 1H), 7.19 (d, J= 1.5 Hz, 1H), 7.07 (dd, J= 2.0, 8.0Hz, 1H), 6.80 (d, J= 8.5 Hz, 1H), 6.53 (d, I= 9.5 Hz, 1H), 6.32 (t, J=5.5 Hz, 1H), 3.81 (ss, 3H), 3.52 (t, J=4.5 Hz, 4H), 3.33 (m, 2H), 2.44 (m, 2H), 2.36 «(broad s, 4H); HPLC/MS r/z: 446.2 [MH].

Method 47:

WN \ " (OH HN

BO © ol

STEP 1 ~/"N _SsTEP2_ {2 Ay

Br x H

Br

OMe

OH

Step 1: Synthesis of trans-4-[5-(5-bromo-11H-pyrrole[2,3-b] pyridi_n-3-yl)-pyridin-2- ylamino]-cycloh exanol.

[0368] A solution sof 5-bromo-3-(6-chloro-pyriciin-3-yl)-1H-pyrrolo[2,38-b]pyridine (100 mg, 0.324 mmol), tr=ans 4-aminocyclohexanol (485 mg, 4.21 mmol), and wtriethyl amine hydrochloride(134 nag, 0.974 mmol) in anhydrous N-methylpyrrolidone (1 ml) was sealed in a Smith process vial. The reaction was run in a Personal Chemistry® nmicrowave reactor at 250 °C for 1 hour_ The mixture was diluted with water (40 ml), and the= resulting precipitate was filter—ed off, washed with water, amd dried in vacuo. Purifi cation by flash chromatography on ssilica gel with a gradient of nethanol/dichloromethare afforded trans-4- [5-(5 -bromo5-1H-pywrrolo[2,3-b]pyridin-3-yl)-pymidin-2-ylamino}-cycloh .exanol as a white solid (82 mg, 66 % yield). TH NMR (DMSO-dg)= 12.00 (s, 1H), 8.32 (dl, J=2.5 Hz, 1H), 8.21-8.32 (m, 2H), "7.75 (d, I= 11.5, 1H), 7.67 (d-t,J= 2.5, 9.0 Hz, 1H), 651 {, J=9.0 Hz, 1H), 6.36 (d, J=7.0 Hz, 1H), 4.55 (d, = 5.0 Hz, 1H), 3.64 (m, 1H), 3.42 (m, 1H), 1.95 (m, 2H), 1.82 (m, 2H), 1.22 (m, 4H); HPLC/MS m/z : 387.0, 389.1 [MH].

Step 2: Synthessis of trans-4-{3-[6-(4-hydroxy-cyclohexylamino)-gpyridin-3-yl}-1H- pyrrolof2,3-b]peyridin-5-yl}-2-methoxy-pheenol.

[0369] To trans-4--[5-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyridira-2-ylamino]- cyclohexanol (52 m_g, 0.134 mmol), 4-(4-methoxz yphenylmethoxy)-3- methoxyphenylborcanic acid (65 mg, 0.174 mmol), and (6 mg. 6 mol %) dichlorobis(triphensylphosphino)palladium(ir) in a Smith process vial wa=s added a 3:2:1 mixture of acetonitrile water and a 2 M aqueous =solution of sodium carbOnate 0.9 ml. The reaction was run in a Personal Chemistry® micreowave reactor at 165 °C. for 1200 s.

Methanol was adde. d and the mixture was adsort>ed on silica gel. Purification by flash chromatography on_ silica gel with a gradient of mmethanol/dichloromethamne afforded 57 mg of a dark foam. The= dark foam was dissolved in dichloromethane (3 ml) and PS-thiophenol resin (150 mg, Argonaut Technologies, 1.41 mnrol/g loading) was added, followed by TFA (0.6 ml). The clear suspension was stirred at room temperature for 1 houmr, then the resin was filterecA& off, washed with ethyl acetate, then methanol. The filtrates w ere evaporated and the residues was treated with saturated aqueous solution of sodium bicarb-onate to basic pH and extract-ed with ethyl acetate. Purification by flash chromotography om silica gel with a gradiemt of methanol/dichloromethane afforded trans-4- {3-[6-(4-hydmroxy- cycloh_exylamino)-pyridin-3-yl]-1H-py~rolo[2,3-b]pyridin-5-y1} -2-m_ethoxy-phenol as a white ssolid (18 mg, 41 % yield). TH NMR (DMSO—dg): 611.75 (d, J==2.5 Hz, 1H), 9.03 (s, 1H), 8 .47 (d, J=2.5 Hz, 1H), 8.37 (d, T=2.5 Hz, 1H), 8.22 (d,J=2.0 Hz, 1H), 7.73 (dd, J= 2.5, 9.0, 1H), 7.66 (d, I= 3.0 Hz, 1H), 77.25 (d, J=2.0 Hz, 1H), 7.12 (=dd, }=2.0, 8.0 Hz, 1H), 6.86 (3, J= 7.5 Hz, 1H), 6.53 (d, J= 8.0 Hz, 1H), 6.31 (d, J=7.0 Hz, AH), 4.55 (d, J=4.5Hz, 1H), 3 .86 (s, 3H), 3.65 (m, 1H), 3.43 (am, 1H), 1.95 (m, 2H), 1.82 (m_, 2H), 1.21 (m, 4H);

HPLC=/MS m/z: 431.2 [MH].

Method 48:

TH 2 COOH re COOH 1 i N-oMe NH, 1

CY STEP 1 of STEP 2 og | STEP 3 ae = — \F > ZZ

Br Br Br

OMe T )

NH |] HINT N = ()

STIEP 4 Sa STEPS SAT STEP=6 _ LZ

Br Br JJ oo

Ol

Sskep 1: Synthesis of 2-amine-5-Foromonicotinic acid. [0370W] 25.00 g (0.181 mol) of 2-am inonicotinic acid were dispers ed in 100 ml of glacial acetic= acid. To this suspension was aclded a solution of 12.0 ml (0.23 mol) of bromine in 50 ml of glacial acetic acid. The mixture was stirred at room temperatwure for 20 hours. The precigpitate formed was filtered off ane washed with 100 ml of glaci al acetic acid in several porticons until the filtrate remained colorless. The crude was dried by suction and crystaallized from boiling methanol to afford 38.63 g (0.178 mol, 98 % yield) of 2-amino-5- brom._onicotinic acid as slightly greenish to off-white crystalline nee=dles. "H-NMR (d¢-

DMSS0) & 8.45 [1H] d, 8.34 [IH] d.; MS: m/z217 [MH'].

Step 2: Synthesis of N- methoxy-N-methyl-2-amino-5--bromonicotinamide. a) isolated as the free base

[0371] 2-amino-5-bromonicotinic acid (4.000 g, 18.43 mrmol), N,O- dimethylhydroxylamine hydrochloride (4.550 g , 46.6 mmo_]) and PyBOP (1- benzotriazolyloxy-tris(pyrro lidino)phosphonium hexafluorosphosphate) (15.00 g, 28.882 mmol) were placed in a nitrogen flushed flask. 150 ml of acetonitrile and 25 ml of dJ-iso- propylethylamine were added and the mixture was heated to 95 °C for 20 hours. The= solvent was then evaporated. and the residue distributed betoveen 200 ml of chloroform and 100 ml of a 10 % solution of citric acid in water. The orgaric phase was separated ard washed with 100 ml of 1 M ;aqueous sodium hydroxide and dried over sodium sulfate=. The solvent was evaporated and the crude material purified by c-hromatography on silica geel using a non-linear gradient of ethyl acetate and hexane affording 2.193 g (8.436 mmol, 46 % yield) of N-methoxy-N-nnethyl-2-amino-5-bromonicotin.amide as an off-white sold. 'H-

NMR (ds-DMSO) 8: 8.10 [1H] d, 7.71 [1H] d, 6.35 [2H] s, 3.55[3H]s, 3.24 [3H] s.; MS: m/z 260 [MH]. b) isolated as the hydrochloxide salt

[0372] Ina nitrogen flush ed flask 3.00 g (30.76 mmol) off N,O-dimetylhydroxylan-ine hydrochloride and 3.53 g (1 6.27 mmol) of 2-amino-5-brommonicotinic acid are dissol-ved in a mixture of 350 ml of dichloromethane, and 30 ml of N-met-hylmorpholine. 12.70 g (224.40 mmol) of PyBOP (1-benzotriazolyloxy-tris(pyrrolidino)phcsphonium hexafluorophcsphate) is added and the reaction mixture stirred at room temperature for 5 hours. The mixture is then washed with 150 ml of a 2 M solution of sodium hydroxide in water and then twice with 100 ml of a 10 % aqueous citric acid solution and drie=d over sodium sulfate. The solvent is evaporated and the resulting oil is dissolved in 3C00 ml of ether. The precipitate formed is filtered off and discarded. The clear filtrate is cosncentrated to about half its volume and diluted with 30-60 ml of dichloromethane. The resulting solution is stirr—ed vigorously and a 1 M solution of hydrogen chloride in anhydrous ether is added until formation of the resulting pprecipitate is complete. The precipitate is filtered off, washed with ether and dried by suction to afford 3.15 g (12.04 mm_ol, 74 % yield) of N-metlaoxy-N- methyl-2-amino-5-bromoni cotinamide hydrochloride as arm off-white to beige-browr powder. "H-NMR (ds-DMSO) 8: 8.24 [1H] d, 7.97 [1H] d.., 3.56 [3H] 5, 3.26 [3H] s— MS: m/z 260 [MH]

[0373] The hydrechloride can be conveniently conve=rted into the free base by distributing this product between ethyl acetate and 2 M aqueous sodium hydroxide, washing the aqueous layer three times with ethyl acetate, then drying the cormbined organic phases ower sodium sulfate and evaporation and drying of the residue undemr vacuum.

Step 3: (2-am ino-5-bromo-3-pyridyl)-phenylke®one.

[0374] 1.00 g (3-38 mmol) of N-methoxy-N-methyl—2-amino-5-bromonicotin=amide hydrochloride was suspended in 50 ml of anhydrous T_HF under nitrogen. The ssuspension was cooled to —S0 °C and 13.5 ml of a 1.0 M solution Of phenylmagnesium brormide in ether was added rapidly to afford an orange solution. The n=ixture was stirred, and sl-owly warmed to room temperature. The resulting yellow-or-ange solution was distrib uted between 75 ml of 2210 % aqueous citric acid solution amnd 200 ml of ethyl acetates. The organic phase was separated and washed with 75 ml o=fa 10 % aqueous citric acid solution and 75 ml of saturated aqueous sodium bicarbonate so lution. The organic phas=e was then dried over sodium sulfate and evaporated to afford 985 mg of a yellow crystalline solid. 'H-

NMR (dg-DMSO) 6: 8.34 [1H] d, 7.72 [2H] s, 7.70 [1H] d, 7.65 [1H] t(m), 7.63 [2H] d(m), 7.56 [2H] t(m). MAS: m/z 277 [MH].

Step 4: Synthesis of 5-bromo-3-(2-methoxy-1-p henylvinyl)-2-pyridylammine.

[0375] 2.600 g ((8.77 mmol) of N-methoxy-N-methy=1-2-amino-5-bromonicoti& namide hydrochloride wass suspended in 50 ml of anhydrous T HF under nitrogen. The suspension was cooled to ~50 °C and 32 ml of a 1.0 M solution of ~ phenylmagnesium brommde in ether was added rapidly to afford an orange solution. The nixture was stirred, allowing to slowly warm to room temperature. After 1.5 hours the resultmng solution was distribut ed between 50 ml of 10 % aqueous citric acid solution and 400 ml _ of ethyl acetate. The organic phase was separated and_ washed with 50 ml of saturated aqumeous sodium bromide soMution. The organic phase wass then dried over sodium sulfate and evaporated to afford 2.676 g of (2- amino-5-bromo-p-yridin-3-y1)-phenyl-methanone as a yellow solid. The isolated solid was dissolved in 50 m1 of anhydrous THF under nitrogen and added at room tempemrature to a solution obtained as follows: At 0 °C 3.836 g (19.23 mmol) of potassium bis(trimethylsilyl) amide was dissolved in 100 ml of arahydrous THF under nitrogen. At 0 °C 7.214 g (21.04 mrmol) of methoxymethyltriphenylphossphonium chloride was aided and the resulting mixture stirred at room temperature for 75 minutes.

[0376] Upon addi tion of (2-amino-5-bromo-pyridira-3-yl)-phenyl-methanon._e to the solution, the resulting mixture was stirred at room termperature for 75 minutess. The reaction mixture was then quaenched by addition of a saturated aqueous solution of am-—monium chloride and distrib—uted between 100 ml of water and 250 ml of ethyl acetate The aqueous phase was extractec three times with 100 ml of ethyl acetate, each. The comboined organic phases were dried cover sodium sulfate and evaporate«d. The crude material w as purified by flash chromatography on silica gel using an ethyl acetate/hexane mixture and a non-linear gradient to afford 1 .718 g (5.630 mmol, 64 % yield o-ver 2 steps) of 5-bromo—3-(2-methoxy- 1-phenylvinyl)-2-p—yridylamine. H-NMR (ds-DMSQO) (E)-isomer 8: 8.00 [1H] d, 7.44 [1H] d, 7.34 [2H] d(m), “7.29 [2H] t(m), 7.18 [LH] (m), 6.551 [1H] 5, 5.50 [2H] 5, 3 .78 [3H] s; (Z)-isomer 8: 7.97 [1H] d, 7.28 [1H] d, 7.27 [2H] t(nx), 7.17 [1H] t(m), 7.14 [CTH] d(m), 6.95 [1H] s, 5.60 [2H] s_, 3.73 [3H] s. MS: m/z 305 [MH] .

Step 5: 5-brormo-3-phenylpyrrolo[2,3-b]pyrid ine.

[0377] 1.093 g (33.582 mmol) of 5-bromo-3-(2-methoxy-1-phenylvinyl)-2-goyridylamine was dissolved in 60 ml of anhydrous 1,4-dioxane. 80 pl of 70 % aqueous perchloric acid was added and the mixture heated to 100 °C for 13 hwours. The mixture was shen cooled to room temperature sand 3 ml of triethylamine was addled and the mixture evap-orated to dryness. The resulting crude was crystallized from hot ethanol to afford 763 mg (2.79 mmol, 78 % yield of 5-bromo-3-phenylpyrrolo[2,3—b]pyridine as a beige-br own to brown crystalline solid. ! H-NMR (ds-DMSO) &: 12.19 [1HI] 5, 8.44 [1H] d, 8.34 [17H] 4, 7.97 [1H] d, 7.72 [2H] d(m), 7.45[2H]t, 7.27 [1H] t(m). MS: m/z 273 [MH].

Step 6: Syntim esis of 5-(3,4-dimethoxyphenyl)—3-phenylmethylpyrrol of2,3- b]pyridine.

[0378] A vial waas charged with 50 mg (0.18 mmo»]) of 5-bromo-3-phenylyrrolo[2,3- b]pyridine, 43 mg (0.24 mmol) of 3,4-dimethoxyphenylboronic acid and 6.5 mg (9.3 pmol, mol %) of dichlorobis(triphenylphosphino)palladi-um(m). To this mixture ~was added 1 ml of acetonitrile and. 1 ml of a 2 M aqueous solution of sodium carbonate. The= vial was sealed and irradiated in a_ Personal Chemistry® microwaves reactor with a temperat=ure setting of 165 °C for 20 minuutes. The resulting mixture was Qlistributed between 75 nml of dichloromethane and 20 ml of a saturated aqueous solution of sodium bicartoonate in water.

The organic phases was dried over sodium sulfate arad evaporated. The resid: ue obtained was recrystallized frorm a hot mixture of acetonitrile and. ethanol to afford 20 meg (61 pmol, 34 %

yield) of 5-(3,4-climethoxyphenyl)-3-phenylmethylypyrrolo[2,3-b]pyridine as a colorless crystalline solid. 'EI-NMR (de-DMSO) 8: 11.97 [1H] s, 8.55 [1H] d, 8.38 [1H ]d, 7.90 [1H] d, 7.79 [2H] d, 7.45 [2H] t, 7.30 [1H] d, 7.26 [2H] %(m), 7.06 [1H] d, 3.87 [3H]s, 3.81 [3H] s. MS, m/z: 331 [MH].

[0379] Other compounds prepared by Method 48:

Table 30

HN \ HN J HN \

EE ava _ ] P | _ 9g OMe OMe

MS: m/z 321 [MH] MS: m/z 315 [MH] MS: m/z 329 [MEH]

HN \ HN \ HN \ 0 | iO l~ l ~ ~~ 4 CI J

OMe O

Os

MS: m/z 3 15 [MH'] MS: m/z 361 [MH] MS: m/z 329 [MH]

HN 2 HN \ HN \

Lo | 50 [yo

P | _ | _ 44 Ol, QP cl cl

MS: m/z 3-23 [MH] MS: m/z 339 [ME] | MStm/z314 [MH]

HN \

Z

9 SMe

MS: m/z 317 [MH"]

Method 49:

HN) Ts TS \

NTR \

SATE STEP 1 SATE STEP 2 SAS

ZZ

Br Br Br

HIN)

STEP 3 ry O- STEP 4 yO

PP EN 0) LD

Br CJ OMe

OH

Step 1: Synthesis of 5- bromo-3-[4-(tetrahydro-pyra: n-2-yloxy)-phenyl]-1-(stoluene- 4-sulfonyl)-1H-pyrrolos[2,3-b]pyridine.

[0380] 1.092 g (3.77 mmol) of 5-bromo-3-[4-hydroxyph=enyl]-1H-pyrrolo[2,3-b] pyridine and 200 mg of para-toluene sulfonic acid monohydrate wer dissolved in 180 ml of£ dichloromethane. 10 ml of clihydro-1H-pyran was added ard the mixture was heated to reflux for 4 hours. The mixture was then cooled to room teemperature and an excesss of - triethylamine was added. T he mixture was evaporated ancl 2.50 g (13.11 mmol) off para- toluenesulfonyl chloride wzas added. The mixture was disssolved in 150 ml of THF and the resulting solution was cooled to 0 °C. An excess of sodiurm hydride powder was a_dded until further addition did not resualt in the formation of more hycirogen gas and the mixture was stirred for 16 hours at rooms temperature. The resulting mia xture was cooled to 0 °CC and another 2.5 g (13.11 mmol} of para-toluenesulfonyl chloriede along with more sodi—um hydride was added. The mixture was then quenched by acdition of a saturated aquaeous solution of ammonium chloride and distributed between 5800 mi of ether and water—. The organic phase w~as washed three times with a satwirated aqueous solution omf sodium bicarbonate, driesd over sodium sulfate and evaporated. The crude produc-t was purified by flash chromatog=raphy on silica gel using a gradient of ethyl acetate in hex—anes to afford 1.163 g (2.21 m=mol, 58 % yield) of 5-bromo-3-[«4-(tetrahydro-pyran-2-yloxy)-phenyl]-1- (toluene-4-sulfo-nyl)-1H-pyrrolo[2,3-b]pyridine =as a pale yellow or pink seolid. "H-NMR (ds-DMSO) 6: 8.53 [1H] d, 8.46 [1H] d, 8.20 [1H] s, 8.03 [2H] d(m), 7.7 [2H] d(m), 7.43 [2H] d, 7.14 [2K] d(m), 5.54 [1H] t, 3.78 [1H] mm, 3.57 [1H] m, 2.35 [3H] s, 1.95-1.74 [2H] (m), 1.68-1.52 [-4H] (m). MS, m/z: 527 [MH].

Step 2: Symmthesis of 4-[5-bromo-1-(toluen ee-4-sulfonyl)-1H-pyrroleo [2,3-b]pyridin- 3-yl]-pheno 1.

[0381] 575 g «1.09 mmol) of S-bromo-3-[4-(te-trahydro-pyran-2-yloxy)—phenyl]-1- (toluene-4-sulfomnyl)-1H-pyrrolo[2,3-b]pyridine wvas dissolved in 250 ml of dichloromethanee. To this solution was added 2.50 g (3.53 mmol) of PS-tEaiophenol (Argonaut Tech—nologies) and 1.5 ml of a 2 M sol ution of hydrochloric aci din ether. The mixture was stirred at room temperature for 3 ho=urs before the resin was #filtered off, washing extensi_vely with dichloromethane. The- filtrate was evaporated teo afford 389 mg (877 umol, 81 %%) of 4-[5-bromo-1-(toluene-4-sumlfonyl)-1H-pyrrolo[ 2,3-t= Jpyridin-3-y1]- phenol as a pale= yellow solid. "H-NMR (ds-DM SO) 6: 9.67 [1H] s, 8.52 [1H] d, 8.43 [1H] d, 8.11 [1H] s, &.03 [2H] d, 7.58 [2H] d(m), 7.43 [2H] d, 6.89 [2H] d(m), 2.35 [3H]s. MS, m/z: 443 [MH XK.

Step 3: Syrathesis of 5-bromo-3-[4-(3-pipemidin-1-yl-propoxy)-phe=nyl]-1H- pyrrolo[2,3—b]pyridine hydrochloride.

[0382] 200 mg (0.45 mmol) of 4-[5-bromo-1-( toluene-4-sulfonyl)-1H-poyrrolo[2,3- b]pyridin-3-yl]-—phenol and 1.20 g (2.80 mmol) o=f PS-triphenylphosphine (2.33 mmol-g”,

Argonaut Techraologies) were dissolved in 30 mM of anhydrous toluene. 3-25 mg 2.27 mmol) of 3-(1-poiperidinyl)propanol and 300 pul ( 1.52 mmol) of di-iso- propylazodicartooxylate were added at room temyperature and the mixture stirred for 72 hours,

[0383] The re sin was filtered off and washed r epeatedly with dichloronethane and ether. :

The filtrates we—re combined and evaporated. Th_e residual beige oil was issolved in 20 ml of methanol tog ether with an excess of potassiurm hydroxide. The mixtur~e was stirred for 48 hours at roorn temperature. The resulting sus pension was distributed toetween dichloromethane and a saturated solution. of sodium bicarbonate in wa=ter. The phases were separated and the aqueous layer was extracted twice with dichloromet#hane. The combined organic phases were dried over sodium sulfate and evaporated. The crude was purified by flash chromatography on an amine functi onalized silica gel (ISCO RecliSep® amine column) using a gradient of ethyl acetate in hexanes. The isolated material was dispersed in 75 ml of ether and the insoluble part filtexed off. To the clear filtrate vovas added an excess of a2 WM solution of hydrochloric acid in ether. The precipitate was fil tered off and dried in vacuo to afford 133 mg (0.30 mmol, 66 +4 yield) of 5-bromo-3-[4-(3-piperidin-1-yl- propo=xy)-phenyl}-1H-pyrrolo[2,3-b]pyricline hydrochloride as a yellow solid. "H-NMR (ds-

DMS) 8:12.17 [1H] (d), 10.68 [1H] s,bor, 8.39 [1H] d, 8.33 [1H] d, 7.87 [1H] d, 7.65 [2H] d, 7.03 [2H] 4, 4.10 [2H] t, 8.46 [2H] d, 3.18 [2H] m, 2.89 [2H] m, 2.24 [2H] m, 1.89-1.76 [4H] Cm), 1.71 [1H] m, 1.39 [1H] m. MS, m/z: 414 [MH"].

Step 4: Synthesis of 2-methoxy-4-{3-[4-(3-piperidin-1-yl-propoxy)-phenyl}-1H- pyrrolo[2,3-b]pyridin-5-yl}-phenol. [0384 ] 100 mg (0.24 mmol) of 5-brome-3-[4-(3-piperidin-1-yl-prop oxy)-phenyl]-1H- pyrrolLo[2,3-b]pyridine hydrochloride, 12 Q mg (0.33 mmol) of 2-[3-MKethoxy-4-(4-methoxy- benzy~loxy)-phenyl]-4,4,5,5-tetramethyl-[_ 1,3,2]dioxaborolane and 10 rng (5 mol %) of dichlorobis(triphenylphosphino)palladiurn(lr) were placed in a vial anc 1.5 ml of acetonitrile and 1..5mlof a2 M aqueous solution of sodium carbonate were added . The mixture was irradizated in a Personal Chemistry® microwave reactor to 165 °C for 71200 sec. The result-ing mixture was distributed betweem dichloromethane and a satu rated aqueous solution of sodium bicarbonate. The aqueous layer was extracted three times vith dichloromethane and tle combined organic phases were dx-ied over sodium sulfate and esvaporated. The crude produ_ct was purified by flash chromatography on amine functionalize=d silica gel (ISCO

RediS ep® amine column) using a gradiemt of ethyl acetate in hexanes.. The resulting intern—ediate was dissolved in 30 ml of dichloromethane and 750 mg (C1.06 mmol) of PS- thioplnenol (Argonaut Technologies) was added. To this was added 1..5 ml of trifluoroacetic acid amend the mixture was stirred at room temperature for 2 hours. The= resin was filtered off and washed with dichloromethane, The filtrate was washed with a satzurated aqueous soluti-on of sodium bicarbonate, dried over sodium sulfate and evaporated. The residue was tritureated with 20 ml of dichloromethane and dried by suction to affored 9 mg (20 pmol, 8 % yield)s of 2-methoxy-4-{3-[4-(3-piperidin-1-yl-propoxy)-phenyl}-1H-poyrrolo[2,3-b]pyridin- 5-yl} —phenol as a beige powder. "H-NMR (ds-DMSO) &: 11.83 [1H] «d, 9.06 [1H] s, 8.50

[1H] d, 8.28 [1H] dl, 7.76 [1H], 7.67 [2H] d(m), 7.25 [1 H] d, 7.12 [1H] dd, 7.0L [2H] d(m), 6.88 [1H] d, 4.02 [ 2H] t, 3.87 [3H] s, 2.39 [2H] t, 2.34 4H] (m),br, 1.88 [2H] t , 1.50 [4H] qui, 1.38 [2H] (m) . MS, m/z: 458 [MH].

Method 50:

HN TL \ @

CATE STEP 1 l~ on > —

Br g

OMe

OH AES8

Step 1: Synthesis of 4-{5-[3-methoxy-4-hydroxy~-phenyl}-1H-pyrrolo [2=,3-b] pyrazin-3-yl} -phenol.

[0385] 145 mg «0.44 mmol) of 5-bromo-3-[4-hydro<yphenyl]-1H-pyrrolo[2. ,3-b]pyridine, 240 mg (0.65 momol) of 2-[3-Methoxy-4-(4-methoxy-_benzyloxy)-phenyl]-4,455,5- tetramethyl-[1,3,2]dioxaborolane and 25 mg (8 mol %=) of dichlorobis(triphen—ylphosphino) palladium(1r) wer e placed in a vial and 1.5 ml of acetomnitrile and 1.5 ml of a2 M aqueous solution of sodiurn carbonate were added. The mixtur—e was irradiated in a Pemrsonal

Chemistry® microwave reactor to 165 °C for 1200 sec. The resulting mixture was distributed betwe=en dichloromethane and a saturated =aqueous solution of sodium bicarbonate. The= aqueous layer was extracted twice vavith dichloromethane amd the combined organi < phases were dried over sodium sulfate and evaporated. Th e crude was purified by flash chromatography on silica gel using & gradient of ethyl acetate in hexanes.

The resulting intermediate was dissolved in 70 ml of «dichloromethane and 2.000 g (2.82 mmol) of PS-thiophenol (Argonaut T echnologies) wams added. To this was ac3ded 1 ml of trifluoroacetic ac=id and the mixture stirred at room temmperature for 1 hour. T he resin was filtered off and vwashed with dichloromethane. The faltrate was washed with a saturated aqueous solutiors of sodium bicarbonate. The phases were separated and the aqueous layer extracted twice sovith ethyl acetate. All organic phase s were combined, dried over sodium sulfate and evaporated. The residue was heated up with acetonitrile, cooled clown to room temperature and. the supernatant was removed. The residue was dried in vacwmo to afford 72 mg (0.22 mmol, 50 % yield) of 4-{5-[3-methoxy-4-h_ydroxy-phenyl]- 1H-pyrrolo[2,3- b]pyrazin-3-yl} —phenol as a beige powder. TH-NMR_ (d-DMS0) 8: 11.77 [LH] d, 9.37 [1H]

s,br, 9.06 [LF] s,br, 8.49 [1H] d, 8.27 [1H] 4, 7.69 [AH] d, 7.56 [2H] d(m), 7- 25 [1H] d, 7.12 [1H] dd, 6.8 [1H] d, 6.86 [2H] d(m), 3.87 [3H] s. I™MS, m/z: 333 [MH"].

Method 51: 6

NH, O NH, 0 07 NH ("©

NT N— STEP 1 NTS STEP 2 NTS _STEP3 _ = Ove ZZ =

Br Br J Br

HN \ y F< i

Z

\ 9 ~~ le) Oo

Step 1: Synthesis of 5-bromo-3-(2-methoxy-pphenyl)-1H-pyrrolo[2,3- b]pyridine.

[0386] To aflame-dried 100 ml round bottomed flask were added 2-aminam-5-bromo-N- methoxy-N-muethyl-nicotinamide (661 mg, 2.54 mmol) and anhydrous THF «(15 ml). The solution wass stirred at —55 °C for 5 minutes under n itrogen, then a 0.5 M soliation of 2- methoxyphenyl magnesium bromide in THF (18 ml, 9.0 mmol) was added d—ropwise over 3 minutes. The resulting solution was allowed to waren to room temperature over 2 hours then quenched by~ addition of 1 M citric acid. (25 ml). Ethyl acetate (50 ml) was amdded, and the layers were separated. The aqueous fraction was extracted three times with e=thyl acetate, and the com bined organic fractions were washed wath brine, dried (Na,SO.), filtered and concentrated] to give a sticky yellow solid. Recrysta lization from ethanol provided 619.5 mg (79 %) of (2-amino-5-bromo-pyridin-3-yl)-(2-rmethoxy-phenyl)-methan=one as yellow needles. MSS m/z: 308 [MH]".

Step 2: Synthesis of 5-bromo-3-[2-methoxy-K -(2-methoxy-phenyl)-visinyl]-pyridin-2- ylamine-.

[0387] Intoa 50 ml flame-dried round bottomed flask were added potassitam bis(trimethy~1silyl)amide (832 mg, 39.2 mmol) and anhydrous THF (10 ml). “The slurry was cooled to 0 ©C for 5 minutes under nitrogen, then (rmethoxymethyl)triphenyl—phosphonium chloride (1.53 g, 4.47 mmol) was added. The resulting red-orange solution v=vas stirred at room temperature for 45 min, then a solution of (2-amino-25S-bromo-pyridin-3-yl)-(2=2- methoxy-phenyl)-methanorae (601 mg, 1.95 mmol in 10 mM THF) was added all at nce. The reaction was stirred under maitrogen for 4 hours then quenclned by addition of a satur—ated aqueous solution of ammommium chloride (25 ml). Ethyl acestate (100 ml) was added. and the layers were separated. The =aqueous fraction was extracted three times with ethyl ac=etate, and the combined organic fractions were washed with brin_e, dried (Na;SOs), filtere=d and concentrated to give a brow-n, sticky oil. Purification by flamsh chromatography on silica gel using a gradient of ethyl aceetate in hexanes gave 554 mg (84 %) of 5-bromo-3-[2-nethoxy- 1-(2-methoxy-phenyl)-viny-1]-pyridin-2-ylamine as a mixture of E- and Z-isomers.

Step 3: Synthesis of 5—bromo-3-(2-methoxy-phenyl)n-1H-pyrrolo[2,3-b]pyriidine.

[0388] A 50 ml round bottomed flask was charged with =403 mg of 5-bromo-3-[2— methoxy-1-(4-methoxy-phesnyl)-vinyl]-pyridin-2-ylamine «1.2 mmol; combined E- and Z- isomers), 1,4-dioxane (5 m1), and 70 % aqueous perchloric= acid (250 pl). The flask— was fitted with a reflux condensser and nitrogen inlet adapter anmd heated in an oil bath tc 100°C for 8 hours. The reaction mixture was concentrated, then tr—eated with 15 ml of a saturated . aqueous solution of sodium bicarbonate followed by ethyl acetate (20 ml). The layeers were separated, and the aqueous fraction was extracted twice wiith ethyl acetate. The cormnbined organic fractions were washhed with brine, dried (Na;SOy), filtered, and concentrated. The residue was triturated with ether to afford 300mg (82 %) o=f 5-bromo-3-(2-methoxy~-phenyl)- 1H-pyrrolo[2,3-b]pyridine as a tan powder. "H-NMR (ds-TOMSO) 8 = 12.16 (br. s, 1H), 8.36 (d, 1H), 8.18 (d, 1H), 7.82 (d, 1H), 7.58 (d, 1H), 7.36 (t, 13H), 7.19 (d, 1H), 7.10 (t, 1H), 3.88 (s, 3H); MS m/z: 303 [MH]".

Step 4: Synthesis of 5 -[3-methoxy-4-(4-methoxy-be-nzyloxy)-phenyl]-3-(2-rmethoxy- phenyl)-1H-pyrrolo[2 3-b]pyridine.

[0389] 2-[3-Methoxy-4-C4-methoxy-benzyloxy)-phenyl §-4,4,5,5-tetramethyl- [1,3,2]dioxaborolane was prepared as follows. To a flame=-dried 50 ml round bottomed flask were added 2-methox=y-4-(4,4,5,5-tetramethyl-[ 1,3,2 ]dioxaborolan-2-yl)-pher-ol (1.00 g, 4.00 mmol) and anhydrcous DMF (20 ml). Sodium hydride (251 mg, 6.29 mmol; _ 60 % dispersion in mineral oil) vvas added in three portions, and. the suspension was stirred under nitrogenfor 30 minutes par a-Methoxy benzyl chloride (655 ul, 3.62 mmol) and tetr—abutyl ammonium iodide (10 mg, 0.03 mmol) were added, and tine reaction mixture was stirred for an additional 16 hours. The reaction mixture was concentrated, then cooled in an icze-bath, and 50 ml of 1 M citric acicl was added followed by 100 mul ethyl acetate. The layer—s were separated, and the acyueous phase was extracted three times with ethyl aecetate. The combined organic fr. actions were washed with brine=, dried (Na;S0Os), fil tered and concentrated to give atan powder. Trituration with diethyl ether gave 134g (91 %) of 2-[3-

Methoxy-4-(4-methcoxy-benzyloxy)-phenyl]-4,4,5,5= -tetramethyl-[1,3,2] dioxaborolane as a tan powder. "H-NMR (CDCl;) 8= 7.35 (m, 2 H), 7.29 (s, 1H), 7.26 (5, 1 H), 6.89(m, 3H), 5.11(s, 2H), 3.91 (s, 3H), 3.80 (s, 3H), 1.33 (s, 12H); MS m/z: 393 [M+Na]".

[0390] A Personal Chemistry® microwave vial (2-5 ml size) was cha-rged with 5-bromo- 3-(2-methoxy-phenxyl)-1H-pyrrolof2,3-b]pyridine (98 mg, 0.33 mmol), 2-[3-methoxy-4-(4- methoxy-benzyloxy™)-phenyl]-4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolane (148 mg, 0.400 mmol), 6.5 mg (9.3 pmol, 5 mol %) of dichlorobis(triphenylphosphino)palladium(), 1 ml of acetonitrile and 1 ml of a 2 M aqueous solution o fsodium carbonate. The vial was sealed, evacuated ard purged three times with nitrosgen, then irradiated in a Personal

Chemistry® microvevave reactor with a temperature setting of 150 °C fom 30 minutes. Ethyl acetate (50 ml) was added, and the layers were separated. The aqueous fraction was extracted three time=s with ethyl acetate, and the coxmbined organic frac®ions were washed with brine, dried (N"2,SO4), filtered and concentrated. Purification by fl_ash chromatography on silica gel using am gradient of ethyl acetate in hexxanes gave 75 mg (5-0 %) of 5-[3- methoxy-4-(4-meth_oxy-benzyloxy)-phenyl]-3-(2-niethoxy-phenyl)-1H -pyrrolo[2,3- b]pyridine as a light yellow solid. "H-NMR (d¢-DMASO) § = 12.12 (br.ss, 1H), 8.51 (d, | H), 8.11 (4, 1H), 7.70 (=d, 1H), 7.57 (dd, 1H), 7.38 (d, 2H), 7.27 (t, 1H), 7.25(d, 1H), 7.18 (dd, 1H), 7.11 (m, 2H), “7.02 (t, 1H), 6.95 (d, 2H), 5.03 (5, 2H), 3.85 (s, 3H)-, 3.82 (s, 3H), 3.75 (s, 3H); MS m/z: 4657 [MH]".

[0391] Other conmipounds prepared by Method SM:

Table 31

I IT

/ /

HN \ Q HN \ Q vy OO ome

PZ = N = « OMe

So

Se So ~~ 0 HO © o

MS: m/z 404 [MIH]". MS: m/z 433 [MH] MS: m/z 36 1 [MH]". d d pa

A A AE lL _ [ 4. 9g Cl, 0 ~~ MS: M/Z 3 17 [MH].

MS: m/z 361 [MIH]". 2 AE61

MS: M/Z 394 [MH]. / / /

HN 2 Q HN \ Q HN \ << vy OO oaY oY. > P

CJ Cl, gs

O, N oN MS: M/Z B47 [MH]". \ MS: M/Z 379 [MH]*".

MS: m/z 358 [MH].

W”0 2006/015123 PCT/US2005/026m792 / / /

Q 0] of

HN \ HN \ HN \

CPO SO PC lL

J QW: J

N Ny odd o MS: M/Z 331 [MH].

NH, AE62 MS: M/Z 394 [MH]. [MEH]

MSS: m/z 344 [MH].

J o

EN \ HN \ ely bole

ZZ =

OH

EON HO.

MLS: m/z 331 [MH]. o) AE63 *

MS: M/Z 403 [MH]". *Sbtained from 7-Bromo-4,5-adihydro-3H-benzo[bJoxepin-2-eone (obtained via Bacyer-

Vlliger reaction).

Method 52: / 0 / 1 THN) ° vy OO ip

STEP 1 = o~¢ \ J oo” CJ 0” 0)

OH AE64

Step 1: Synthesis of 2-VMethoxy-4-[3-(2-methoxy-pherayl)-1H-pyrrolof2,3- b]pyridin-5-yl}-phenol. [©392] To a 50 ml round bowttomed flask were added 5-[3-rnethoxy-4-(4-methoxy- beenzyloxy)-phenyl]-3-(2-met¥hoxy-phenyl)-1H-pyrrolo[2,3-to pyridine (48 mg, 0.10 =mmol),

methylene chloride (2.5 ml) and 396 mg (0.28 mmol) PS -thiophenol (1.41 mmole;

Argonaut Technologies) . Trifluoroacetic acid (500 pil) wras added and the suspension was shaken in a orbital shaker for 1 hour. The yellow reactio-n mixture was filtered and the resin was washed three t=imes with dichloromethane and -ether, then twice with dichloromethane. The c=ombined filtrate was concentrate=d to obtain a yellow residue, which was distributed betweena ethyl acetate and saturated aquesous solution of sodium bicarbonate.

The layers were separated, and the aqueous phase was extracted three times wi_th ethyl acetate. The combined organic fractions were washed with brine, dried (Na,S®0,), filtered and concentrated. Purification by flash chromatography on silica gel using a gmradient of ethyl acetate and hexanees gave 31 mg (86 %) of 2-methexy-4-[3 -(2-methoxy-Hohenyl)-1H- pyrrolo[2,3-b]pyridin-5 -yl]-phenol as a light yellow powder. "H-NMR (ds-DM1SO) & = 11.87 (br.s, 1 H), 9.04 Crs, 1H), 8.48 (d, 1H), 8.07 (d, 1H), 7.68 (dd, 1H), 7.587 (dd, 1H), 7.27 (t, 1H), 7.20 (d, 1E3), 7.13 (d, 1H), 7.08 (dd, 1H), 7 .02 (t, 1H), 6.85 (d, 1-1), 3.85 (5, 3H), 3.82 (s, 3H); MS =w/z: 347 [MH]".

[0393] Other compounds prepared by Method 52:

Table 32

HN we oF

NT () oo \ HN ® vy SAY

LL gg 0 ¢ J

Vad

OH oO 0”

OH *

MS: m/z 347 [MHT". OH *

MS: m/z 363 [MH]. MS: m/z: 400 [EMH]. 0” o”

HN \ HN \

Sar yy ©

ZF Z

4 CL,

OH OH

We 2006/015123 PCT/US2005/026792

MSS: m/z 317 [MH]. *(Z -amino-5-bromopyridin-3-yl)(2-(tri fluoromethox y)phenyl)meth=anone and (2-amino-5- brosmopyridin-3-yl)(2-(methylthio)phenyl)methanone needed in thesse cases were prepared by —the method illustrated below.

Symthesis of (2-amino-5-brome-pyridin-3-yl)-(2-triflucrometho—xy-phenyl)-methanone.

Br NH, O OCF,

C—O (=

Br [03 94] To a flame-dried 100 ml rourad bottomed flask was added ~1-bromo-2- (trixfluoromethoxy)benzene ( 2.39 g, 9.9 mmol). The flask was fitted_ with a rubber septum, pur_ged with nitrogenthen charged with anhydrous THF (20 ml). Th_e solution was cooled to -78 °C for 10 min, then a 2.5 M solution of n-butyl lithium in hexanees (3.9 ml, 9.8 mmol) wass added dropwise over 3 minutes. T he resulting solution was stirr—ed at —78 °C for 40 mirautes under nitrogen, then a solutiora of 739 mg (2.84 mmol) of 2—amino-5-bromo-N- methoxy-N-methyl-nicotinamide in 5 xml of THF was added dropwisse over 3 minutes. The resulting red solution was allowed to warm to room temperature ovesr 5 hours, then the reac tion was quenched by addition of 1 0 mi of a saturated aqueous ssolution of ammonium chloride. Ethyl acetate (50 ml) was addled, and the layers were separ-ated. The aqueous fraction was extracted three times with. ethyl acetate, and the combirned organic fractions wer~e washed with brine, dried (Na;SO.), filtered and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hex-anes gave 530 mg (52 %) wof (2-amino-5-bromo-pyridin-3-yl)~(2-triflucromethoxy-phenyl)—methanone as a yellow- orarage solid. "H-NMR (CDCls) & = 8.29 (d, 1 H), 7.60 (m, 2H,), 7.4.5 (t, 1H), 7.42 (m, 3H), 1.79(br. s, 2H); MS m/z: 361 [MH]".

Mesthod 53: /

NT lz Ls STEP 1 Lz o” 9 0”

OH (py —>°

AE6S

Step 1: Synthesis of 3-(2-Methoxy-phenyl)-5-[3-methoxy-4-«(2-pyrrolidin-1-yl- ethoxy)-phenyl]-1H-pyrrolo[2 ,3-b]pyridine. [0 395] To an 8 ml borosilicate reaction vial were added 150 mg (C0.350 mmol) of PS- tra phenylphosphine (2.33 mmol- g~! 5 Argonaut Technologies) and anhydrous methylene chloride (5 ml). The vial was fitted with a rubber septum and the si1aspension was stirred for minutes in an ice-bath (0 °C). Dii sopropyl azodicarboxylate (68 14L, 0.35 mmol) was aclded dropwise, and the mixture was allowed to warm to room temperature over 20 minutes. To the reaction vial was added 2-pyrrolidin-1-yl-ethanol (C54 mg, 0.47 mmol) and 2—methoxy-4-[3-(2-methoxy-pheny1)-1H-pyrrolo[2,3-b]pyridin-5-y~1]phenol (60 mg, 0.17 mmol), and the suspension was stirred at room temperature for 8 heours. The yellow reaction mixture was filtered, and tThe resin was washed three times with DCM and ether, tien twice with DCM. The combin ed filtrate was concentrated to obtain a yellow residue, which was purified by flash chromatography on amine functionali=ed silica gel (ISCO

R_ediSep® amine column) using a gradient of ethyl acetate in hexa—nes to afford 12 mg (8 %a0) of 3-(2-methoxy-phenyl)-5-[3-metlhoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H- p-yrrolo[2,3-b]pyridine as a light yellow powder. "H-NMR (d¢-DM_SO) 8 = 11.87 (brs, 1

FY), 8.51 (d, 1H), 8.18 (s, 1H), 8.11 (d, 1H), 7.70 (4, 1H), 7.57 (dd. 1H), 7.27 (m, 1H), 7.24 (<3, 1H), 7.17 (dd, 1H), 7.12 (dd, 1 Ed), 7.06 (s, 1H), 7.04 (m, 1H), 4-.08 (t, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 2.82 (t, 2H), 2.55 (m, 4H), 1.69 (m, 4H); MS m/z: 44-4 [MH]". [@0396] Other compounds prepared according to Method 53:

Table 33 / /

HN N Q d HN Q

HIN \ ar oar

P NTS () P

PL

, - Ql, 7

OJ WN > 0 HN J . +

MS: m/z 460= [MH]". MS: m/z 473 [MH]. MS: m/z 459 [MH]". / / 7

HN— Q HN Q HN A

SO) SOY vy TO = = Pa

C3 oo” g oo” ¢ 0”

MS: m/z 418 [MH]". MS: m/z 405 [MH]".

MS: m/z 45-8 [MH]. / /

HN— A HN— 2

C0 | PO

QQ oo” 0 g o— fo fo

Or oA

N A

E66 MS: m/z 405 [MET].

MS: m/z 444 [MH].

WNO 2006/015123 PCT/US2005/026792

[0397] The purification of the cormpounds in above table was amccomplished using reverse pha_se HPLC (C18; 5-95 % gradient solvent A: 0.1 % formic acid aq. containing 5 % ~ACN, solwent B: 0.1 % formic acid in ACN, with mass-triggered collection).

Method 54: / d HN <

HN— oo ry 0 STEP 1 lL 2

Br HN TS == AE67

Step 1: Synthesis of 3-(2-Metlnoxy-phenyl)-5-(1H-pyrrol—2-yl-1H-pyrrolo[2, 3 b] pyridine.

[0398] To a Personal Chemistry®> microwave vial (2-5 ml siz=e) were added 5-brono-3- (2—methoxy-phenyl)-1H-pyrrolo[2,3 -b]pyridine (96 mg, 0.32 mmol), 1-N-(BOC)pyrr=ole-2- bomronic acid (103 mg, 0.487 mmol) and 12 mg (5 mol %) of diczhloro[1,1°- bis (diphenylphoshino)ferrocene]pal Jadium(m) dichloromethane adduct, 1 ml of aceto-nitrile aned 1 ml of a 2 M aqueous solution of sodium carbonate. The vial was sealed, evacu=ated an-d purged three times with nitrogen, then irradiated in a Persomal Chemistry® microwave resactor with a temperature setting o £150 °C for 15 minutes. EtThyl acetate (50 ml) was ad_ded, and the layers were separated. The aqueous fraction wass extracted three time=s with etkayl acetate, and the combined orgeanic fractions were washed with brine, dried (Na==S0u), fil tered and concentrated. Purification by flash chromatography on silica gel using a gr adient of ethyl acetate in hexaness gave 28.1 mg (30 %) of 3-(2-methoxy-phenyl)-5-(1H- pywrrol-2-yl)-1H-pyrrolo[2,3-b]pyriddine as a tan solid. '"H-NMR_ (d-DMSO) & = 11.778 (br.s, 1E7), 11.32 (br. 5, 1H), 8.56 (d, 1 HL), 8.20 (d, 1H), 7.66 (d, 1H) 7.59 (dd, 1H), 7.29 dd, 1E9), 7.12 (d, 1H), 7.07 (¢, 1H), 6.83 (m, 1H), 6.49 (m, 1H), 6.1 0(m, 1H), 3.82 (s, 33); MS m_/z: 290 [MH]". : [0®399] Other compounds preparexd according to Method 54:

Table 34 / / /

Q Oo Q

HN \ HN \ HN \ [NIN NT N = lL lL » = a Zz

Na | N NS

NS oo” £

OMe

MS: m/z 332 [MET]. MS: m/z 332 [MH]". MS: m/z 320 [MH]. / / ~

Oo oO e]

HN

\ HN \ HN \

NT () NT NT ~ l~ l~ 4 Dp

Na \ O

HN Y : .

MS: m/z 340 [MET]. MS: mz 302 [ Mu. MST 291 MET

Method 535: qd

B(OH) HT ¥ ry OO 0 ie: Y

STEP 1 ST EP 1

Oo a [@) —_—

ICN N Al ®

Oo 0)

N e) \ ie) 1

OL 5

AE68

Step 1: Synthesis of 3,4-bis(2-methoxyetho—y)phenylboronic acid.

[0400] 6.51 g ((D.0300 mol) of 4-bromoveratrolez is dissolved in 50 ml of dichloromethane.

To this suspensiozrn is added 37.6 g (0.150 mol) of boron tribromide at 0 °C. The mixture was stirred for 3 hmours at room temperature. Solv—ents were removed under reduced pressure. The resumlting brown oil was dissolved ir ethyl acetate and filtered through a pad of silica gel. The filtrate was concentrated to afford 5.45 g of 4-bromo catechol as a light brown oil.

[0401] 1.89 g (10.0 mmol) of this oil is dissolved in 50 ml of anhydrowus DMF and 576 mg (24.0 mmol) of sodium hydride was added. To the resulting solution waas added 5.56 g (40.0 mmol) of bromoethyl methyl ether at O °C over 25 minutes. The rmixture was stirred overnig'ht from 0 °C to room temperature. S ml of water was added to quench the reaction.

After removal of the solvent, the black oily mresidue was adsorbed on cel ite, and the resulting solid washed with ethyl acetate. The filtrate= was then concentrated to gmve 3,4-bis (2- methox yethoxy)bromobenzene as a yellowissh solid.

[0402] The solid was dissolved in anhydrous THF and the resulting solution cooled to —78 °C _ To the solution was added 4.8 ml o=fa 2.5 M solution of n-butyl lithium in hexanes at —78 =C over 10 minutes. The mixture wa_s then stirred for 30 minutes at -78 °C. 2.77 ml (12 mmol) of tri-iso-propyl borate was then added. The reaction was st-irred for another minutes at —78 °C and then warmed to 0 °C over 2 hours. The mixti are was then cooled to —20 <C and 10 ml of aqueous 2 N hydrochloric acid was added to the= mixture. After stirring for 20 minutes, the reaction mixture was transferred to a separating funnel and extracted three times with 100 ml of ethyl aecetate. The combined orgarnic layers were dried over so-dium sulfate and concentrated to affcord 2.85 g of a brown oil. The oil was titurated with ether to afford 625 mg (2.44 mmol; 8%= overall yield) of 3,4-bis (2 - methox yethoxy)phenylboronic acid as a col orless powder. 'H-NMR (d 4-methanol) 8: 7.36 [2H] mx, 7.23 [2H] m, 6.98 [1H] d (7.5 Hz), 694 [1H] d (8.5 Hz), 4.16 [4H] m, 3.75 [4H] m, 3.43 [3H] s, 3.42 [3H] s. MS m/z: 271.1 [MH], 293.1[MNa+].

Ste p 2: Synthesis of 5-[3,4-Bis-(2-met-hoxy-ethoxy)-phenyl]-3-(2- -methoxy-phenyl)- 1H —-pyrrolo[2,3-b] pyridine,

[0403] A vialis charged with 81.0 mg (0. 300 mmol) of 3,4-bis (2- methox yethoxy)phenylboronic acid, 60.6 mug (0.200 mmol) of 5-bromo -3-(2- methox yphenyl)- 1H-pyrrolo [2,3-blpyridines and 8.3 mg (5S mol %) of bis(tripphenylphosphino)palladium(II)-dichlcoride. 1.5 ml of acetonitrile and 1.5mlofa2M aqueous solution of sodium carbonate were added and the mixture irradiated in a Personal

Chemi stry® microwave reactor to 150 °C feor 15 minutes. The mixture was extracted with three times with 15 ml of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated... The dark brown residue (1:87 mg) was purified by flash chromatography on silicon using a gradient of ethyl acetate in he=xane to give 57 mg of 5.3 4-bis-(2-methoxy-ethoxy)-pheny1]-3-(2-methoxy-phenyl)-IH—pyrrolo(2,3- b]pyricline as a colorless powder. JH-NMR (d4-methanol) 3: 8.41 [IH] d (2.0Hz),8.17 [1H] da (2.0 Hz), 7.63 [1H] s, 7.56 [1H] dd (1.5 Hz, 7.5 Hz), 730 [1H] m , 7.26 [1H] d (2.5

Hz), 7 .20 [1H] dd (2.3 Hz, 8.3 Hz), 7.11 [1H] d (8 Hz), 7.08 [1H] d (8.5 Hz), 7.05 [1H] dt (1 Hz. 7.5 Hz) 4.24 [2H] m, 4.19 [2H] m, 3.77 [4H] m, 3.44 [3H] s, 3.43- [3H] s. MS m/z: 449.2 [MH'], 471.1.1[MNat].

Method 56:

Jd

B(OH), Ti

Br NT ()

O STEP 1 ie __STEP2 ov

HO

TEES C

N 1 o»

Ov 0 Lo \ 1

BAe

Step 1: Synthesis of 3,4-bis(2-morpholinoethoxy)phenylboroniec acid. [040m4] 864 mg (36.0 mmol) of sodium hydride was added to a suspe=nsion of 900 mg (5.0 mmol) of 4-bromocatechol and 3.72 (20.0mmol) of 2-chloroeth=ylmorpholine hydwrochloride in 50 ml of anhydrous DMF at 0 °C over 25 minutes. The mixture was stirr-ed for 3 days at room temperature. 5 ml water was added to quench the reaction. After rem_oval of the solvent, the black oily residue was adsorbed onto celite= and the resulting soli-d washed with ethyl acetate. The filtrate was then concentrated to give 0.75 g (1.81 mmmol; 36 % yield) of 3,4-bis (2-morpholinoethoxy)bromobenzene as ahygroscopic yellow soli_d. "H-NMR (CD30D) 8: 842 [1H] d (2.0 Hz), 8.18 [1H] d (1.5 Ea), 7.64 [1H] s, 7.56 [1FX)dd (1.5 Hz, 7.5 Hz), 7.30 [1H] dt (1.5 Hz, 7.5 Hz), 7.25 [1H] d (25 Hz), 7.19 [1H] «dd (2.S Hz, 8.5 Hz), 7.12 [1H] d (8.5 Hz), 7.08 [1H] d (8.5 Hz), 7.05 [114] dt (1 Hz, 7.5 Hz) 42 5[2H]t (5.75 Hz), 4.20 [2H] t (5.5 Hz), 3.72 [8H] m, 2.84 [4H] ma, 2.66 [8H] m. MS : 559.2 [MH].

[04805] 24mlofa2.5M solution of n—buthyl lithium in hexanes wams added at —78 °C oa sol ution of 2.08 g (5.0 mmol) 3,4-bis(2-morpholinoethoxy)bromobermzene in THF over mimautes. The mixture was stirred for 30 minutes at —78 °C before 1.3-9 ml (6.0 mmol) of tri-n-is-opropyl borate was added. The mixture was stirred for another 30D minutes at —78 °C and thesn warmed to 0 °C over 2 hours. The mixture was cooled to —20 >=C and 5 ml of aqueovas 2 N hydrochloric acid was added. After stirring for 20 minutes the reaction mixture was transferred to a separating funnel and extracted three times ~with 100 ml of ethyl =acetate. The combined organic lay ers were dried over sodium sulfate and concemtrated to give a brown oil. The oil was titurated with ether to giv-e 925 mg of a very hygroscopic dark brown oil, which was about 50 9% pure by LC/MS and. used directly withowut further purification.

Step 2: Synthesis of 5-[3,4-bis-(2-rmorpholin-4-yl-ethoxy)-pheny 1)-3-(2-methoxy- pkaenyl)-1H-pyrrolo[2,3-b]pyridine. : [0406s] A vial is charged with 228 mg (approx. 0.3 mmol of pure borcanic acid) of the crude boronic acid, 60.6 mg (0.20 mmoX) of 5-bromo-3-(2-methoxy-phmenyl)-1H- pyrro 10[2,3-b]pyridine and 8.3 mg (5 mol %) of dichlcororbis(triphenylphosphino)palladium(m). 1.5 ml of acetonitrile ard 1.5 mlof a2 M aqueous solution of sodium carbonate were added and the mixture irraciated in a Personal

Chemistry® microwave reactor to 150 <C for 15 minutes. The resultin_g mixture was extrascted three times with 15 ml of ethy/1 acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated. The resulting dark breown residue was purifSied by flash chromatography on silica gel using a gradient of ethyM acetate in hexanes to give 9.4 mg (16 pmol; 8 % yield) of 5-[ 3,4-bis-(2-morpholin-4-yl-etho-xy)-phenyl}-3-(2- meth. oxy-phenyl)-1H-pyrrolo[2,3-b]pyridine as a light yellow solid. 'F4-NMR (ds- methaanol) &: 8.42 [1H] d (2.0 Hz), 8.18 [IH] d (1.5 Hz), 7.64 [1H] 5, 7.56 [1H] dd (1.5 Hz, 7.5 Fz), 7.30 [1H] dt (1.5 Hz, 7.5 Hz), 725 [1H] d (2.5 Hz), 7.19 [1H] dd (2.5 Hz, 8.5 Hz), 7.12 [1H] d (8.5 Hz), 7.08 [1H] d (8.5 Hz), 7.05 [1H] dt (1 Hz, 7.5 HzD 4.25 [2H] t (5.75

Hz), 4.20[2H]t(5.5 Hz), 3.72 [8H] m_, 2.84 [4H] m, 2.66 [8H] m. MS m/z: 559.2 [MH].

VO 2006/015123 PCT/US2005/0267 92

Method 57

J

HIN \

H = NT ()

N.__O lL

Y _step1, | _STEP2,

AI Ch fo) NH, O N._

NE, O

Step 1: Synthesis of 2-Ammino-5-bromo-N,N-dimethyl—benzamide. [ 0407] Into an 15 mL high paessure glass vial (with Teflomn screw cap) were added =S- romoisatoic anhydride (0.401 g, 1.66 mmol), DMAP (20 m_g, 0.16 mmol), and

Aimethylamine (2 M in THF; 5 0 mL, 10.0 mmol). The vial was sealed and placed in zn oil oath at 70 °C for 8 h after which it was concentrated under vacuum. The crude product was dissolved in EtOAc and washed 2x with water followed by torine. The organic phase v=vas ried (Na;S0,), filtered and comcentrated to afford 0.428 g o=f2-Amino-5-bromo-N,N— cdimethyl-benzamide as a pink solid, which was used directly for the next step. "H-NMR (500 MHz, d-DMSO) 6= "7.19 (dd, J=2.0, 8.5 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.63(=d,

W=8.5 Hz, 1H), 5.31(br. s, 2H), 2.89(br. s, 6H). MS: m/z 198~200 [C=0"].

Step 2: Synthesis of 2-Amino-5-[3-(2-methoxy-pheny—1)-1H-pyrrolo[2,3-b]pyr-idin- 5-yl}-N,N-dimethyl-benza mide.

[0408] Into a5 ml Personal Chemistry microwave reacticon vial were added 3-(2- ruethoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolara-2-yl)-1-(toluene-4-sulfonyl)-

MW H-pyrrolo[2,3-b]pyridine (0.1 67 g, 0.331 mmol), 2-amino-=S-bromo-N,N-dimethyl- toenzamide (0.088 g, 0.364 mm ol), 1,1"-bis(diphenylphosphimno)ferrocenepalladium(ir)s- dichloride dichloromethane adcluct (14 mg, 0.017 mmol), acetonitrile (5 mL) and satumrated aaqueous NaHCO; (5S mL). The vial was sealed, purged with_ Nj, and irradiated in a Pesrsonal

Chemistry Optimizer at 90 °C for 5 min. The layers were separated, and the aqueous gohase was extracted 3X with EtOAc. The combined organic phase was treated with brine, dwried (NazS0y), filtered and adsorbed onto silica gel. The crude naterial was purified by si_lica gzel chromatography in an EtOAc (containing 10% MeOH) amnd hexane gradient. The purified material was dissolved in a MeOH/acetone solution_ (5 mL) and 200 uL. of a 50%

WK OH solution was added and the solution was stirred at roor-m temperature for 3 hourss. The

WO» 2006/015123 WPCT/US2005/026792 reacti on was quenched by adding 1 M citric acid dropwise until pH=S5. The quenched reacti_on mixture was partitioned betweem EtOAc and water, the layers vavere separated, and the acyueous phase was extracted 2X with EtOAc. The combined organiec phase was treated with ‘brine, dried (Na,SO,), filtered and adsorbed onto silica gel. The material was purified on armino silica in an EtOAc (containing 10% MeOH) and hexane grad®ent to afford the title comppound as a pale yellow powder (13.5mg, 11% yield). "H-NMR (5900 MHz, d¢-

DMSS0) §=11.80 (br. s, 1H), 8.42 (d, / = 2.0 Hz, 1H), 8.02 (d, /=2.0 Hz, 1H), 7.68 (d,J= 2.5 Fiz, 1H), 7.58 (dd, J = 1.5, 6.0 Hz, 1H), 7.44 (dd, J=2.0, 6.0 Hz, 17¥), 7.31 (d,7=2.0

Hz, 1H),7.27(t,J=7.5Hz, 1H), 7.12 (4, J=175Hz, 1H), 7.04 (J = ~7.0 Hz, 1H), 6.80 (d,

J= 0 Hz, 1H), 5.26 (s, 2H), 3.80 (s, 3H), 2.95 (s, 6H). MS: m/z 387. 1 [MH].

[04039] Other compounds prepared by Method 57:

Table 35 / o J gd

HIN A HN \ HN I 5) ray nea 7 SZ = . .

EN ~N 2 sUsallle san

No ~~ NA NJ

NH, O NH, O NH, O

MSS: m/z 444 [MH].

MS: m/z 456 [MH]. MS: m/z 499 [MH]. /

Oo J od

HAN A HN \ HN aN 0-0 [BO 0 { = = = (Mo

RUA eVsanic Vs ane

N NS NS

NH, O NH, O NH= O

MAS: m/z 456 [MH].

MS = m/z 486 [MH]. MS: mei/z 541 [MH].

a / 0) 0]

HN A HN A

N° Cp NT _ | Pp

SUS AGNICE

No _N N

NH, O NH, O 0) \

MS: m/z 519 [MH'].

MS: m/z 556 [MH].

Method 58: /

Ts, = HN Q

NR) \

Soa

NT [I

PZ

= STEP 1 9 le

SOx=NH %o 2 2

NH, HN Y NH

Step 1: Synthesis of 7-[3-(2-Methoxy-phenyl)-1H-pyrrolo{2,3-be]pyridin-5-yl]-3- methyl—3,4-dihydro-2H-benzo[1,2,4]thiadiazine 1,1-dioxide.

[0410] In—toan 8 mL screw-cap vial were added 2- Amino-5-[3-(2-me=thoxy-phenyl)-1- (toluene-4-ssulfonyl)-1H-pyrrolo[2,3 -b]pyridiin-5-yl}-benzenesulfonamtide (0.0492 g, 0.090 mmol), acevtaldehyde (200 uL, 3.54 mmol), and acetonitrile (700 nL). "The vial was sealed and placed in a heat block at 90 °C for 1 h. The reaction mixture was c=oncentrated under vacuum the=n dissolved in THF (1 mL), and 5500 pL of 50% w/w KOH aq. was added to the resulting solution. After 2 h, the reaction wa s quenched by addition of glacial acetic acid then concemntrated under vacuum to afford a brown residue. Purificatiown by flash chromatogmraphy on SiO; gel, eluting with ethyl acetate and hexanes ((D-100% gradient) afforded thae title compound as a yellow powder (23.3 mg, 61 %). HNMR (500 MHz, ds-

DMSO) 5==11.88 (br.s, 1H), 8.44 (d, J=2.0 Hz, 1H), 8.04(d, I=2.0 Hz=, 1H), 7.71(m, 2H), 7.68(dd, J==2.5, 8.6 Hz, 1H), 7.59(dd, J=2.5, 8.5 Hz, 1H), 7.54(br.d, 13), 7.29 (m, 1H), 7.26(br.s, 1H), 7.12(dd, J=8.5, 1Hz, 1H), 7.€05(t, ]=7.5 Hz, 1H), 6.89 (Cd, J=9.0 Hz, 1H), 4.86 (m, 1H), 3 .81(s, 3H), 1.44(d, }=5.5.0 Hz, 3ED). MS: m/z 421.1 MH] —

[0411] Other compouands prepared by Method 58:

Table 36 os

HN A

NT

\ 4g 20

HN.__NH

MS: m/z 407 [MH].

Method 59:

MeO

TsN \ ¢ HN MeQ \

F L/ N™™ NTS

COzH = = 1. STEPH nN CCH stEP2 STEP 3 =z — —_— FZ —_— 7 Ne J

Br Br «CO,H Na. N_ mY ©

Step 1: Synthesis of 5-bromo-2-diethylamino-nicoti mic acid.

[0412] 880 mg (4.00 mmol) of 5-bromo-2-fluoronicotin-ic acid was dissolved in 3 mlof acetonitrile. 1.0 ml ( 9.7 mmol) of diethylamine was addec] and the resulting mixture heated to 80 °C for 18 h. The mixture was evaporated and the resulting brown oil used without further purification. MS: m/z 273 [MH].

Step 2: Synthesis of 2-diethylamino-5-[3-(2-methox_y-phenyl)-1-(toluene=-4- sulfonyl)-1H-py xrolo[2,3-b]pyridin-5-yl]-nicotinic =cid

[0413] 230 mg (0.45 mmol) of 3-(2-methoxy-phenyl)-5 -(4,4,5,5-tetramethyl- [1 3,2]dioxaborolan—2-yl)-1-(toluene-4-sulfonyl)-1 H-pyrr-olo[2,3-b]pyridine, 137 mg (0.50 mmol) of 5-bromo-2- -diethylamino-nicotinic acid and 16 rug (23 pmol) of 1,1'- bis(diphenylphosphi-no)ferrocenepalladium(m)-dichloride dichloromethane addwuct were dissolved in a mixture of 2.5 ml of acetonitrile and 2 ml of a 2 M aqueous solution. of sodium carbonate. The reaction mixture was heated for 1.5 h to 100 °C.

[0414] The resulting mixture was distributed between brine and ethyl acetate an_d the aqueous phas € extracted three times with ethyl acetate. The combined organic ph ases were washed with brine, dried over sodium sulfate and ewaporated. The crude was ther purified by flash chrommatography on silica gel using a gradient of ethyl acetate and a solveent mixture of ethyl actet=ae, dichloromethane and methanol (4:24:1) containing 1 % v/v of 35 246 w/w aqueous ammonia solution to afford 150 mg of 2-di ethylamino-5-[3-(2-methoxy-gphenyl)-1- (toluene-4-su Ifonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl J-nicotinic acid as a brown soldd. MS: m/z 571 [MHL ).

Step 3: S ynthesis of 2-diethylamino-5-[3-(2-maethoxy-phenyl)-1H-pyrrolo §2,3- b]pyridim-5-yl]-N,N-dimethyl-nicotinamide.

[0415] 40 rng (0.07 mmol) of 2-diethylamino-5-[ 3-(2-methoxy-phenyl)-1-(toluesne-4- sulfonyl)-1H =pyrrolo[2,3-b]pyridin-5-yl]-nicotinic acid was dissolvedin 1.5mlo f dichloromethaane. 40 mg (0.11 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N IN. tetramethyluzronium hexafluorophosphate, 55 pl (0. 11 mmol) of 2 M dimethylami ne in THF, and 1 ml of IDMTF were added and the resulting mixcture was stirred for 1 h.. The solvent was completely evaporated.

[0416] The residue was dissolved in a mixture off methanol and DMSO and 1.1 mlof2M aqueous sodium hydroxide added in three portions over the period of 24 h. After stirring at ambient temperature for 48 h total the mixture was evaporated and the residue acidified by addition of glacial acetic acid and the resulting material purified by mass triggere=d reverse phase HPLC to afford 6.8 mg (14 pmol; 20 % yield) of 2-diethylamino-5-[3-(2-noethoxy- phenyl)-1H-poyrrolo[2,3-b]pyridin-5-yl]-N,N-dimet hyl-nicotinamide as a brown s olid. 'H-

NMR (ds-DIMSO): 511.94 (s, 1H), 8.52 (d, 1H), 8-50 (d, 1H), 8.14 (d, 1H), 7.73 (d, 1H), 7.73 (s, 1H), 7.63 (dd, 1H), 7.29 (ddd, 1H), 7.13 (d.(d), 1H), 7.05 (dd(d), 1H), 3.8 3 (s, 3H), 3.3.46-3.28 Cm, 4H), 3.00 (s, 3H), 2.87 (s, 3H), 1.1 O(t, 6H). MS: m/z 444 [MH].

[0417] Otlaer compounds prepared by Method 59:

Table 37

MeO MeO HN MeCD

HN—) - HN \

NT 0% NT NT lL _ | lL “oH “| ~] H

Nx NN Ns No~n" Nx Le NG NE 0 ™ Oo NH O wl

MS: m/z 487 [MH].

MS: m/z 501 [MH].

MS: m/z 502 [MEH].

MeQ MeO Me=0

HN) HN HN

N™ NT NT

I

= = ~3

ALA SN dw x ~ x ~N x -

J ol Ia ol Jai 0 ™N SN ~N

I

MS: m/z 473 [MH].

MS: m/z 516 [MH]. MS: m/z 459 [NAH].

Method 60:

MeO

HIM)

OH OH NT

N S = 1 CO,H N N Z 2! 54 STEP 1 (J STEP 2 (J o _swer3 NJ \

Br N ns CO;H N A NT NC] 0 > SAREE

NJ

Br Br

OH

Step 1= Synthesis of 5-bromo-2-[4-(2-hydro xy-ethyl)-piperazin-1-yB]-nicotinic acid.

[0418] 540 mg (4.00 mmol) of 5-bromo-2-fluor-onicotinic acid was dissolved in 3 ml of acetonitriles. 620 ul of 1-(2-hydroxyethyl)piperazine was added and the re=sulting mixture heated to 70 °C for 24 h. The mixture was distributed between ethyl aceta-te and water containing 35 % w/w aqueous ammonia solution to adjust the pH to about 12. The aqueous phase is exxtracted twice with ethyl acetate. The aqueous phase was then I=yophyllized to afford a beige residue.

[0419] The residue was dissolved in a mixture of dichloromethane, acet=onitrile and methanol and treated with an excess of MP-isocy~anate resin (Argonaut Te=chnologies®).

The resin was then filtered off and the filtrate evaporated to afford 632 mg= (1.91 mmol; 84 % yield) o»f 5-bromo-2-[4-(2-hydroxy-ethyl)-pip erazin-1-yl]-nicotinic aci- d as a beige, partially crystalline residue. MS: m/z 330 [MH].

Step 2: Synthesis of 5-bromo-2-[4-(2-hydroxy-ethyl)-piperazin-1-y=1]-N,N-dimethyl- nicotimamide.

[0420] 630 mg (1.90 mmol) of 5-bromo-2-[4-( 2-hydroxy-ethyl)-piperaz=in-1-yl]-nicotinic acid was suspended in 50 ml of dichloromethanes. 6 ml of 2 M dimethylarmine in THF and 850 mg (1 .63 mmol) of benzotriazol-1-yl-oxytripsyrrolidinophosphonium hexafluoreophosphate were added and the resultirag mixture was stirred for— 18 h at ambient temperature. The resulting mixture was diluted wwith dichloromethane anc washed with water. Thue aqueous phase was extracted with dichloromethane and the omrganic phases were combined. , dried over sodium sulfate and evaporated to afford crude 5-bromo-2-[4-(2- hydroxy-esthyl)-piperazin-1-yl]-N,N-dimethyl-nicotinamide as a pale brovvn oil containing tris(pyrrodidinyl)phosphoramidate as a contamin ant. MS: m/z 357 [MH'].

Step 3: 2-[4-(2-hydroxy-ethyl)-piperazin-1 -ylj-5-(3-(2-methoxy-plmenyl)-1H- pyrroelo[2,3-b]pyridin-5-yl}-N,N-dimethyl—nicotinamide.

[0421] 50 mg (99 pmol) of 3-(2-methoxy-phemyl)-5-(4,4,5,5-tetrameth—yl- [1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1 H-pyrrolo[2,3-b]pyrid#ine, 215 mg of the crude 5-b romo-2-[4-(2-hydroxy-ethyl)-piperazira-1-y1]-N,N-dimethyl-niceotinamide obtained from step 2 and 5 mg (6 pmol) of 1,1'-bis(diphemylphosphino)ferrocenep- alladium(m)- dichloride dichloromethane adduct were dissolved in a mixture of 3 ml o—f acetonitrile and 2 ml of a saturated aqueous solution of sodium bicarbonate. The reaction rmixture was heated to 120 °C for 4 h.

[0422] The resulting mixture was disstributed between water and ethyl acetate and the aqueous phase extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium ssulfate and evaporated. The residue was dissolved in metharaol and 400 pl of 50 % w/v aquesous potassium hydroxide wems added. The resulting mixture was left at ambient temperatures for 3h. The crude solution was directly purified by mass triggered reverse phase HPLC purification to afford 14.7 mg «(29 umol; 29 % yield) ofS 2-[4-(2Z-hydroxy-ethyl)-piperazin-1-ylJ—35-[3-(2-methoxy-phenyl)-1.H-pyrrolo[2,3-b]pyridin- 5-y1]-MW,N-dimethyl-nicotinamide as a colorless solid. 'H-NMR (des-DMSO): 511.93 (s, 1H), 8.59 (d, 1H), 8.52 (d, 1H), 8.17 (A, 1H), 7.85 (d, 1H), 7.74 (s, 1H), 7.63 (dd, 1H), 7.29 (ddd, LH), 7.12 (d(d), 1H), 7.05 (dd(d)- 1H), 3.83 (s, 3H), 3.55 (m, 2H), 3.4-3.3 (m, 4H), 3.01 (ss, 3H), 2.88 (s, 3H), 2.58 (m, 4H), 2.54-2.46 (m, 2H) MS: m/z 501 [MH].

[0423] Other compounds prepared b—y Method 60:

Table 38

MeO

HN \

N™ XX

P }

Nx No @ C 4

NIEt,

MS: 7 2/2 556 [MH].

WW” 0 2006/015123 PCT/US2005/02«6792

Method 61:

MeO Me=aO

OH NT () NT {)

OH

~~ STEP 1 164 "step? _SSTEP3_ : J QO) ' F CO,Me F HN

OH OH O

Step 1: Synthesis of 5-bromo-3-fluoro-2-hydroxybenzoic acid methyl ester. [©424] 5.00 g (32 mmol) of 3-flucrosalicylci acid was suspencled in 50 ml of glacial acetic acid. 2.2 ml of bromine were added and the mixture was stirred =at ambient temperature for 48h. The resulting suspension was diluted with 500 ml of watemr and the precipitate= filtered off and dried by suction to afford 9.394 g of 5-bromo-3-fluoro-2--hydroxybenzoic acid as an ivory solid.

[0425] 4.08 g (13.9 mmol max.) ofthe crude was dissolved in amixture of 70 ml of toluene and 30 ml of methanol. 9 mal ofa 2 M solution of trimethylsilyl diazomethane was a=dded until the mixture remains yelXow. 200 pl of glacial acetic acid was added until the mixture was colorless and the solvemt was evaporated to afford 33.037 g (12.20 mmol; 88 % o ver both steps) of 5-bromo-3-fluor-o-2-hydroxybenzoic acid methyl ester. "H-NMR (ds-

DMSO): § 10.57 (s, br., 1H), 7.83 dd, 1H), 7.67 (d(d), 1H), 3.230 (s, 3H).

Step 2: Synthesis of 3-fluoro-2 -hydroxy-5-[3-(2-methoxy—phenyl)-1-(toluene-4- sulfonyl)-1H-pyrrolo[2,3-b]py ridin-5-yl]-benzoic acid methyl ester. [#0426] 600 mg (1.19 mmol) of 3- (2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl- [ 1,3,2]dioxaborolan-2-y1)-1-(toluen e-4-sulfonyl)-1H-pyrrolo[2,33-b]pyridine, 509 m_g (2.04 mmol) of 5-bromo-3-fluoro-2-hydroxybenzoic acid methyl ester and 43 mg (60 purmol) of 1 ,1'-bis(diphenylphosphino)ferrocemepalladium(Ii)-dichloride di: chloromethane adduct were dissolved in a mixture of 10 ml of toluene and 10 ml of a saturated aqueous solutiomn of s ©odium bicarbonate. The reaction mixture was heated to 70 °C —for 2.5 h and then tc 90 °C feor an additional 1.5 h.

[0427] The crude was distributed between dichloromethane ard a saturated aqueous s olution of sodium bicarbonate. Thre aqueous phase was extractzed three times with dichloromethane and the combined organic phases were dried o—ver sodium sulfate and evaporated. The crude was purified by flash «<hromatography on silicza gel using a gradient of ethyl ace=tate in hexanes to afford 427 mg (0.79 mmol; 66 % yield) -of 3-fluoro-2- hydroxy-5- [3-(2-methoxy-phenyl)-1-(toluene>-4-sulfonyl)- 1H-pyrrolo[2,3-b]pyridin-5-yi]- benzoic acid methyl ester. MS: m/z 547 (MHL).

Step 3: Symthesis of 3-fluoro-2-hydroxy-5- [ 3-(2-methoxy-phenyl)-"1 H-pyrrolo[2,3- b]pyridin-=5-yl]-N,N-dimethyl-benzamide.

[0428] 222 mg (40 pmol) of 3-fluoro-2-hydroxy-5-[3 -(2-methoxy-phaenyl)-1-(toluene-4- sulfonyl)-1_ H-pyrrolo[2,3-b]pyridin-5-yl]-bermzoic acid methyl ester was dissolved in 2 ml of a 2 M solutZion of dimethylamine in THF. The solution was heated to 100 °C in a closed vial for 24 h aned then concentrated. The residue was dissolved in 2 ml of methanol and 350 pl of 50 % w./v aqueous potassium hydroxide added. The mixture was 1 eft at ambient temperaturee for 1 h and then neutralized by addition of glacial acetic =cid. The crude was directly pumrified by mass triggered reverse phase HPLC purification teo afford 6.0 mg (14 pmol; 337 % yield) of 3-fluoro-2-hydroxy--5-[ 3-(2-methoxy-pheny1)-1H-pyrrolo[2,3- blpyridin-Se -yl]-N, N-dimethyl-benzamide as an ivory solid. H-NMR. (ds-DMSO): 511.91 (s, 1H), 8.551 (d, 1H), 8.14 (d, 1H), 7.73 (d, 1H), 7.64 (d, 1H), 7.62 (dd, 1H), 7.32-7.25 (m, 2H), 7.14 ( d, 1H), 7.05 (m, 1H), 3.82 (s, 3H). 2.99 (s, 3H), 2.87 (s, 3Ed). MS: m/z 406 [MH].

[0429] Other compounds prepared by Metlaod 61:

Talble 39

HN veQ nN M1eO in MeO 0 av av

NT NT NT

Lo | [ . ~No ~~

OH OO OH © OH O

MS: m/z 4032 [MH].

MS: m/z 514 [MH]. MSS: m/z 459 [MH].

WYO 2006/015123 PCT/US2005/0267 92

I cc

MeO MeQ HN MeQ

X L005 | AO

ZZ 4 | = ~__N ~nNn~

USN eV:

OH O OH O OH ©

BMS: m/z 430 [MH].

MS: m/z 542 [MH"). MS: m/z 487 [MH 1.

MeO MeO

HN \ HN N

SAY, oa, lL $ NTN $g | ~NT

F NA F NS

OH O OH O

MS: m/z 518 [MH].

MS: m/z 463 [MH].

Example 2: Bioassays

[0430] Kinase assays know. to those of skill in the art maay be used to assay the inmibitory activities of the compounds an_d compositions of the presen_t invention. Kinase assays include, but are not limited to, the following examples.

[0431] Although the first of these examples uses the kina se domain of a mutant formm of

Abl T3151 (“Abl T3151 KD”), the kinase assays may use v—arious forms of mutant an _d wild type enzymes, including, for example, the entire protein, th_e kinase domain, or a port ion thereof (e.g. Abl Y393F). The kinases used in the assays may also be of varying phosphorylation states. In the c-Abl example, a mutant kine ase at a zero phosphorylat=ion state was used. ¢-Abl Pyruvate Kinase/Lactzate Dehydrogenase Coupled Enzyme Assay

[0432] In the c-Abl Pyruvate Kinase (PK)/Lactate Dehydrogenase (LDH) Coupled Assay the protein kinase dependant phosphorylation of a substrates peptide was coupled to tine oxidation of NADH. The oxiclation of NADH to NAD+ w as detected by monitoring a decrease in absorbance at 340mm.

[0433] Materials: A_bl substrate peptide = EATY AAPF_AKKK-OH (Biopeptide, San

Diego, CA); BNADH (Sigma Cat#N-8129, FW=709.4); 2M MgCl; 1M HEPES bwuffer, pH 7.5; Phosphoenolpyrmvate (PEP) (Sigma Cat#P-7002, FWW=234); Lactate dehydro geenase (LDH) (Worthington Biochemical Cat#2756); Pyruvate Kinase (PK) (Sigma Cat#P-9136);

ATP (Sigma Cat#A-3=377, FW=551); Greiner 384-well TJV star plate; and purified and unphosphorylated T3 15I Abl kinase domain.

[0434] Stock Solutions: 10mM NADH (7.09 mg/ml ira miliQH,0) made fresh daily; 10 mM Ab! substrate pegptide (13.4mg/ml in miliQH,0) stowred at -20°C; 100 mM HEPES buffer, pH 7.5 (5 ml “IM stock + 45 ml miliQH,0); 100rnM MgCl; (5 ml 2M MgCl, +95 ml dH,0); 100mM PEP (23.4mg/ml in dH,0) stored at —20°C; 10mM ATP (5.51ng/ml in dH, 0) stored at -20°CC (diluted 50 pl into total of 10 ml miliQH,O daily =50pM ATP working stock); 1000U/ml PK (U/mg varies with lot) flaash-frozen under liquid N= and stored at -80°C; and "1000U/m! LDH (U/mg varies with lot) flash-frozen under licquid N; and stored at -80°C. {0435] Standard Asssay Setup for 384-well format (50 ul reaction): 300uM NATDOH; 10mM

MgCl; 2 mM PEP; <45U/ml PK; 60U/ml LDH; 200uM Ab] substrate peptide; 2.5 ul test compound (in DMSO); 2ug/ml Abl kinase domain; 10M ATP; 100mM HEPES buffer.

Positive controls con_tained DMSO with no test compound. Negative controls comtained 5 pl of 0.5M EDTA (5 OmM in the assay). The dephospheorylated form of the c-AbT T3151 mutant was used in tlhe biochemical screening assays. Whe kinase reaction was irmitiated at time t=0 by the addit ion of ATP.

[0436] Activity weas measured by following the time-edependent loss of NADH by absorbance spectroscopy at 340nm. The linear portion of the resulting progress curve was then analyzed by line=ar regression to get the activity in -absorbance units/time, reported as the slope of that best_ fit line (moles/unit time can be calculated from using molar extinction coefficient for NADMH at 340nm, 6250M'cm™).

[0437] Data was evaluated using the equation: Z'=1-[ 3*(cs+o.)/|ps-p[] (Zhang, ef al, 1999 J Biomol Screesning 4(2) 67-73), where p denotes the mean and © the stand=ard deviation. The subscript designates positive or negatives controls. The Z' score for a robust screening assay shoumld be > 0.50. The typical threshold = pu-3*G.. Any value that falls below the threshold ~was designated a "hit".

[0438] Dose response was analyzed using th-€ equation: y=min+{(max— min)/(1+1 QFomeoundloglCtyy where y is the obsserved initial slope, max=tine slope in the absence of inhibitor, min=the slope at infinite Mnhibitor, and the ICs is th_e [compound] that corresponds to ¥; the total observed amplitude (Amplitude=max-min).

[0439] Xo measure modulation, activation, cor inhibition of Abl KD, a t-est compound was added to t'he assay at a range of concentrationss. Inhibitors may inhibit AR! KD activity at an_

ICs in the micromolar range, the nanomolar range, or, for example, in tie subnanomolar range.

Additional Kinase Assays

[0440] Xn addition to the c-Abl PK/LDH coupled assay (above), homo ggeneous luminescesnce-based inhibitor screening assayss were developed for c-AbL., MET, AurA, and

PDK kirmases (among others). Each of these —assays made use of an ATE? depletion assay (Kinase-CSlo™, Promega Corporation, Madisoen, WI) to quantitate kinase activity. The

Kinase-G1o™ format uses a thermostable luci—ferase to generate luminescent signal from

ATP remaining in solution following the kinasse reaction. The luminescent signal is inversely correlated with the amount of kinase= activity. cAbl Lurminescence-based Enzyme Assay

[0441] XMaterials: Abl substrate peptide = EAATYAAPFAKKK-OH (BiOpeptide, San

Diego, CA), ATP (Sigma Cat#A-3377, FW=5 51), HEPES buffer, pH 7.5, Bovine serum albumin (BSA) (Roche 92423420), MgCl,, St_aurosporine (Streptomyces sp. Sigma

Cat#8566-0-1MG), white Costar 384-well flat —bottom plate (VWR Cat# 29444-08 8), Abl kinase (see below), Kinase-Glo™ (Promega (CCathV6712).

[0442] Stock Solutions: 10mM Abl substrat € peptide (13.4mg/ml in m_iliQH;O) stored at — 20°C; 100mM HEPES buffer, pH 7.5 (5 ml 1™M stock + 45m! miliQH,0); 10mM ATP (5.51mg/xnl in dH,0) stored at -20°C (diluted 50 pl into total of 10 ml rmiliQH,0 daily =50pM ATP working stock); 1% BSA (1 g BESSA in 100 ml 0.1 M HEPE-S, pH 7.5, stored at -20°C), 100mM MgCl,; 200pM Staurosporine=, 2X Kinase-Glo™ reagent (made fresh or stored at —20°C).

[0443] Standard Assay Setup for 384-well format (20 ul kinase reacticon, 40 pl detection reaction): 10mM MgCl,; 100uM Ab] substrates peptide; 0.1% BSA; 1 pl test compound (in

DMSO); 0.4ug/ml Abl kinase domain; 10uM ATP; 100mM HEPES buffer. Positive controls contained DMSO with no test compound. Negative controls contamned 10pM staurosporine. The kinase reactions were initiated at time t=0 by the additiomn of ATP.

Kinase rezactions were incubated at 21°C for 30 min, then 20 pl of Kinase-Galo™ reagent were add ed to each well to quench the kinase reaction and initiate the lumirmescence reaction. After a 20 min incubation at 21°C, the luminescence was detected in a plate- reading lmiminometer.

MET Lumminescence-based Enzyme Assay

[0444] Materials: Poly Glu-Tyr (4:1) substrate (Sigma Cat# P-0275), ATP (Sigma Cat#A- 3377, F¥W=551), HEPES buffer, pH 7.5, Bovine serum albumin (BSA) (Ro—che 92423420),

MgCl,, Staurosporine (Streptomyces sp. Sigma Cat#85660-1MG), white COstar 384-well flat-bottom plate (VWR Cat#29444-088). MET kinase (see below), Kinase-Glo™ (Promega Cat#fV6712). :

[0445] Stock Solutions: 10mg/ml poly Glu-Tyr in water, stored at -20°C;. 100mM HEPES buffer, p7H 7.5 (5 ml 1M stock + 45 mi miliQH(;0); 10mM ATP (5.51mg/mal in dH,0) stored at -20°C (diluted 50 pl into total of 10 ml mili€QH,O daily =50uM ATP wo rking stock); 1%

BSA (1 s2BSA in 100 ml 0.1M HEPES, pH 7. 5, stored at -20°C), 100mM MgCl; 200uM

Staurospworine, 2X Kinase-Glo™ reagent (madi e fresh or stored at -20°C).

[0446] Standard Assay Setup for 384-well format (20 ul kinase reaction, 40 pl detection reaction’: 10mM MgCl,; 0.3 mg/ml poly Glu-"Tyr; 0.1% BSA; 1 pl test cormapound (in

DMSO)z 0.4ug/ml MET kinase; 10uM ATP; 100mM HEPES buffer. Positive controls containe d DMSO with no test compound. Negative controls contained 101M staurosporine.

The kinzse reactions were initiated at time t=0 by the addition of ATP. Kirnase reactions were inc-ubated at 21°C for 60 min, then 20 ul of Kinase-Glo™ reagent were added to each well to cyuench the kinase reaction and initiate the luminescence reaction. After a 20 min incubatieon at 21°C, the luminescence was detected in a plate-reading lumirmometer.

AurA L-uminescence-based Enzyme Assay

[0447] Materials: Kemptide peptide substrate = LRRASLG (Biopeptide, San Diego, CA),

ATP (Si. gma Cat#A-3377, FW=551), HEPES buffer, pH 7.5, 10% Brij 35 {Calbiochem

Cat#203- 728), MgCl, Staurosporine (Streptonzyces sp. Sigma Cat#85660-1_MG), white

Costar 384-well flzat —bottom plate (VWR Cat#29-444-088), Autophossphorylated AurA kinase (see below) , Kinase-Glo™ (Promega Cat V6712).

[0448] Stock Solutions: 10 mM Kemptide peptide (7.72mg/ml in vevater), stored at -20°C; 100mM HEPES bwaffer + 0.015% Brij 35, pH 7.5 (5 ml 1M HEPES sstock + 75 uL 10% Brij + 45 ml miliQF3,0); 10mM ATP (5.51mg/ml Ln dH,0) stored at - 20°C (diluted 50 pl into total of 10 ml miliQH,O daily =50pM ATP working stock); 1008mM MgCl,; 200puM

Staurosporine, 2X Kinase-Glo™ reagent (made fresh or stored at -20°C).

[0449] AurA Avatophosphorylation Reaction: ATP and MgCl; wemre added to 1-5mg/ml

AurA at final concentrations of 10mM and 100m™M, respectively. THe autophosphorylation reaction was incubated at 21°C for 2-3 h. The rezaction was stopped “by the addition of

EDTA to a final ceoncentration of S0mM, and san—ples were flash fro -zen with liquid N and stored at -80°C.

[0450] Standard Assay Setup for 384-well fornmat (20 pl kinase re=action, 40 pl detection reaction): 10mM I'™MgCl,; 0.2mM Kemptide peptide; 1pl test compot=nd (in DMSO); 0.3ug/ml Autophcsphorylated AurA kinase; 10u=M ATP; 100mM HEPES + 0.015% Brij buffer. Positive ceontrols contained DMSO with mo test compound. Negative controls contained 5 uM s®aurosporine. The kinase reacti ons were initiated amt time t=0 by the addition of ATP. Kinase reactions were incubate=d at 21°C for 45 min, then 20pl of Kinase-

Glo™ reagent we-re added to each well to quencln the kinase reactior- and initiate the luminescence reaction. After a 20 min incubatiora at 21°C, the lumin_escence was detected in a plate-reading lumminometer.

PDKI1 Luminesc-ence-based Enzyme Assay

[0451] Materiakis: PDKtide peptide substrate =

KTFCGTPEYLA _PEVRREPRILSEEEQEMFRIDFDYIADWC (Upsstate Cat#12-401), ATP (Sigma Cat#A-33 77, FW=551), HEPES buffer, poH 7.5, 10% Brij 35 (Calbiochem

Cat#203728), Mg=Cl,, Staurosporine (Streptomyc=es sp. Sigma Cat#8- 5660-1 MG), white

Costar 384-well flat-bottom plate (VWR Cat#299444-088), PDK1 kinase (see below),

Kinase-Glo™ (Pr-omega Cat#V6712).

[0452] Stock Scolutions: ImM PDKtide substramte (1 mg in 2001, = as supplied by Upstate), stored at -20°C; 1. 00mM HEPES buffer, pH 7.5 C5 ml! IM HEPES stock + 45 ml miliQH,0);

10mM ATP (5.51mg/ml in dE3;0) stored at -20°C (diluted 258 pl into total of 10 ml miliQH,0 daily =25uM ATP working stock); 100 mM MgCl; 10% Brij 35 stored at 2-8°C; 200uM Staurosporine, 2X Kimase-Glo™ reagent (made freska or stored at -20°C).

[0453] Standard Assay Setwip for 384-well format (20 pl kinase reaction, 40 ul detesction reaction): 10mM MgCl,; 0.021 mM PDKtide; 1 pl test compowmnd (in DMSO); 0.1pg/mnl

PDK] kinase; 5uM ATP; 10=nM MgCl; 100mM HEPES + «0.01% Brij buffer. Posit ive controls contained DMSO with no test compound. Negatives controls contained 10u™M staurosporine. The kinase re actions were initiated at time t==0 by the addition of ATF.

Kinase reactions were incubated at 21°C for 40 min, then 20= pl of Kinase-Glo™ reagent were added to each well to quench the kinase reaction and iritiate the luminescence reaction. After a 20 min incumbation at 21°C, the luminescence was detected in a plate- reading luminometer.

Preparation of Co-expressiion Plasmid

[0454] A lambda phosphatase co-expression plasmid was constructed as follows.

[0455] An open-reading frame for Aurora kinase was ampolified from a Homo sapZens - (buman) HepG2 cDNA library (ATCC HB-8065) by the polymerase chain reaction PCR) using the following primers:

Forward primer: TCAAAAAAGAGGCAGTGGEGCITTG

Reverse primer: €CTGAATTTGCTGTGATCCA_GG.

[0456] The PCR product (795 base pairs expected) was g=el purified as follows. T he PCR product was purified by electrophoresis on a 1% agarose ge=1in TAE buffer and the appropriate size band was excised from the gel and eluted vmsing a standard gel extranction kit. The eluted DNA was li gated for 5 minutes at room terrperature with topoisomerase into pSB2-TOPO. The vector pSB2-TOPO is a topoisomer—ase-activated, modified ~version of pET26b (Novagen, Madi son, WI) wherein the following sequence has been inserted into the Ndel site: CATAATGG-GCCATCATCATCATCATCACGGT GGTCATATGLCCCTT and the following sequence inserted into the BamHI site:

AAGGGGGATCCTAAACSTGCAGAGATCC. The sequemnce of the resulting plasrmid, from the Shine-Dalgarno se=quence through the "original" Ndel site, the stop site aned the "original" BamHI site is as follows:

AAGGAGGAGATATACATAATGGGCCATCATCATC.ATCATCACGGTGGTCCATATG

TCCCTT [ORE] AAGGGGGATCCTAAACTGCAGAGATCC. The Aurora Mkinase expressed using this vector has 14 amino acids added to the N-terminus (MetGlyHisHissHisHisHisHisGlyGlyHisMetSerLeta) and four amino acids add ed to the C- terminus (GluCSlyGlySer). <

[0457] The prhosphatase co-expression plasmid was then created by inserting the phosphatase ge=ne from lambda bacteriophage into the above plasmid (Matsui 71, et al.,

Biochem. Biopshys. Res. Commun., 2001, 284:798—-807). The phosphatase gerne was amplified usingz PCR from template lambda bacteriophage DNA (HinDIII digest, New

England Biolabos) using the following oligonucleotade primers:

Forvvard primer (PPfor): GCAGAGATCCGAATTCGAGCTC

CGTCGACGGATGGAGTGAAAGAGATGC GC

Rev erse primer (PPrev): GGTGGTGGT GCTCGAGTGCGGCCG(CTAA

GCTTTCATCATGCGCCTTCTCCCTGTAC.

[0458] The PCR product (744 base pairs expecte=d) was gel purified. The prarified DNA and non-co-expression plasmid DNA were then digested with SacI and Xhol e-estriction enzymes. Both the digested plasmid and PCR prociuct were then gel purified and ligated together for 8 Ih at 16°C with T4 DNA ligase and transformed into Top10 cells using standard proce=dures. The presence of the phospha tase gene in the co-expression plasmid was confirmed by sequencing. For standard molecular biology protocols followed here, see also, for examyple, the techniques described in Sama brook ez al., Molecular Closning: A

Laboratory Manual, Cold Spring Harbor Laboratoxry, NY, 2001, and Ausubel et al, Current

Protocols in Molecular Biology, Greene Publishing Associates and Wiley Interscience, NY, 1989.

[0459] This co-expression plasmid contains botla the Aurora kinase and lambda phosphatase geenes under control of the lac promot er, each with its own riboscome binding site. By clonimg the phosphatase into the middle o»f the multiple cloning site, =downstream of the target gene, convenient restriction sites are available for subcloning the plmosphatase into other plasmidss. These sites include Sac, Sall and EcoRI between the kinase =and phosphatase amd HinDIII, NotI and XhoI downstream of the phosphatase.

Protein Kinase Expression [04600 An open-reading frame for c-Abl was amplified from a Mus musculus (mousse) cDNA. library prepared from freshly harvested mouse liver using= a commercially avai lable kit (Invitrogen) by PCR using the following primers:

Forward primer: GACAA GTGGGAAATGGAGC

Reverse primer: CGCCTCGTTTCCCCAGCTC. [0461 7 The PCR product (846 base pairs expected) was purified from the PCR reac=tion mixture using a PCR cleanup kit (Qiagen). The purified DNA was ligated for 5 minutes at room temperature with topoisomerase into pSGX3-TOPO. The vector pSGX3-TOPO isa topoissomerase-activated, modified version of pET26b (Novagerm, Madison, Wisconsi m) wherein the following sequence has been inserted into the Ndel site: CATATGTCCCCTT and the following sequence inserted into the BamHI site:

AAG GGCATCATCACCATCACCACTGATCC. The sequence of the resulting plasmid, from the Shine-Dalgarno sequence through the stop site and the BamHI, site is as fol lows:

AAG-GAGGA GATATACATATGT C CCTT[ORF]JAAGGGCATCAT

CACSCATCACCACTGATCC. The <-Abl expressed using this vector had three amimno acids added to its N-terminus (Met S er Leu) and 8 amino acids added to its C-terminus (GluGlyHisHisHisHisHisHis).

[0462] A c-Abl/phosphatase co expression plasmid was then created by subcloning the phosgphatase from the Aurora co-expression plasmid of Examples 1 into the above plamsmid.

Both the Aurora co-expression plasmid and the Abl non-co-exp-ression plasmid were= digessted 3 hrs with restriction enzymes EcoRI and NotI. The D®NA fragments were ggel purified and the phosphatase gene from the Aurora plasmid wass ligated with the digested c-

Abl plasmid for 8 h at 16°C and transformed into Top10 cells. ~The presence of the phosphatase gene in the resulting comstruct was confirmed by resstriction digestion araalysis.

[04623] This plasmid codes for c-Abl and lambda phosphatase= co expression. It ha_sthe additional advantage of two unique restriction sites, Xbal and Mdel, upstream ofthe target gene that can be used for subcloning; of other target proteins int=o this phosphatase co- expressing plasmid. [046-4] The plasmid for Abl T315T was prepared by modifyin_g the Abl plasmid us-ing the

Quicck Change mutagenesis kit (Stratagene) with the manufactumrer's suggested proce=dure and &the following oligonucleotides:

Mm05582dS4 5'-«CCACCATTCTACATAATCATT(GAGTTCATGACCTATG#GG-3'

Mm05582dA4 5'~CCCATAGGTCATGAACTCAAT GATTATGTAGAATGG”IGG-3".

[0465] Protein —from the phosphatase co-expression plasmids was purified as Follows. The non-co-expressiom plasmid was transformed into chemically competent

BL21(DE3)Codo n+RIL (Stratagene) cells and the co -expression plasmid was transformed into BL21(DE3) gpSA0145 (a strain that expresses the lytic genes of lambda phage and lyses upon freezing anc thawing (Crabtree S, Cronan JE Jr. J Bacteriol 1984 Apr;1582(1):354-6)) and plated onto petri dishes containing LB agar with kanamycin. Isolated singl e colonies were grown to m_id-log phase and stored at -80°C in LB containing 15% glycereol. This glycerol stock weas streaked on LB agar plates with k=anamycin and a single colony was used to inoculate 10 mal cultures of LB with kanamycin armd chloramphenicol, which was incubated at 30°C overnight with shaking. This cultwre was used to inoculate a 2 L flask containing 500 mal of LB with kanamycin and chlora-mphenicol, which was gro—wn to mid- log phase at 37°C and induced by the addition of [PIG to 0.5mM final concentration. After induction flasks =were incubated at 21°C for 18 h witTh shaking,

[0466] The c-Abl T3151 KD (kinase domain) was purified as follows. Cells —were collected by centrifugation, lysed in diluted crackings buffer (50mM Tris HCI, oH 7.5, 500mM KCl, 0.1% Tween 20, 20mM Imidazole, with sonication, and centrifuged to remove cell debris. The soluble fraction was purified over a IMAC column charged v=vith nickel (Pharmacia, Uppsala, Sweden), and eluted under nat-ive conditions with a gradi ent of 20mM to 500mM imida_zole in 50mM Tris, pH7.8, SO0mM NaCl, 10mM methionine, 10% glycerol. The pr otein was then further purified by geel filtration using a Superd ex 75 preparative grade column equilibrated in GFS buffer- (10mM HEPES, pH7.5, 1 mM methionine, 500mnM NaCl, SmM DTT, and 10% gly~cerol). Fractions containirag the purified c-Abl T"3151 KD kinase domain were pooled. The protein obtained w~as 98% pure as judged by electrophoresis on SDS polyacrylamide gels. Mass spectroscopics analysis of the purified proteein showed that it was predominantly singly phosphorylated. ~The protein was then dephos-phorylated with Shrimp Alkaline Plosphatase (MBI Fermenta_s, Burlington,

Canada) under tlae following conditions: 100U Shri_mp Alkaline Phosphatase/rmg of c-Abl

T3151 KD, 100rmaM MgCl,, and 250mM additional INaCl. The reaction was ruzn overnight at 23°C. The protesin was determined to be unphospho rylated by Mass spectroscopic analysis.

Any precipitate ~was spun out and the soluble fractio-n was separated from reac®ants by gel filtration using a Superdex 75 preparative grades column equilibrated ira GF4 buffer (10mM

HEPES, pH7.5, M0mM methionine, 150mM NaCl, 5mM DTT, and 1024 glycerol).

Purification of TMet:

[0467] The ceR1peliets produced from half of a 12 L Sf9 insect cell culture expressing the kinase domain o ¥human Met were resuspendeci in a buffer containing 50mM Tris-HCl pH 77 and 250mM NaCl, in a volume of approxinmately 40 mi per 1 LL of original culture. One tablet of Roche €Complete, EDTA-free proteases inhibitor cocktail (Cat=# 1873580) was added per 1 L of origirmal culture. The suspension wa s stirred for 1 hour at 4=°C. Debris was removed by centrifugation for 30 minutes at 353,800 x g at 4°C. The supernatant was decanted into a =S500 ml beaker and 10 ml of 50% slurry of Qiagen Ni-NTA Agarose (Cat# 30250) that had been pre-equilibrated in 50mM Tris-HCl pH 7.8, 50M NaCl, 10%

Glycerol, 10mM Imidazole, and 10mM Methionine, were added and stirred for 30 minutes at 4°C. The sample was then poured into a dri-p column at 4°C and w=ashed with 10 column volumes of 50nM Tris-HCl pH 7.8, 500mM NaCl, 10% Glycerol, 10mmM Imidazole, and 10mM Methion_ine. The protein was eluted us ing a step gradient witla two column volumes each of the same buffer containing 50mM, 200mM, and 500mM Imicazole, sequentially.

The 6x Histidine tag was cleaved overnight using 40 units of TEV preotease (Invitrogen Cat# 10127017) per “1 mg of protein while dialyzing in 50mM Tris-HCl pH 7.8, 500mM NaCl, 10% Glycerol, “10mM Imidazole, and 10mM Methionine at 4°C. The 6x Histidine tag was removed by passsing the sample over a Pharmacia 5 ml IMAC column (Cat# 17-0409-01) charged with Nickel and equilibrated in 50mM Tris-HCl pH 7.8, 500-mM NaCl, 10%

Glycerol, 10mM/ Imidazole, and 10mM Methi_onine. The cleaved protein bound to the

Nickel column at a low affinity and was eluteed with a step gradient. The step gradient was run with 15% a.nd then 80% of the B-side (A-=side = 50mM Tris-HCl pH 7.8, 500mM NaCl, 10% Glycerol, 10mM Imidazole, and 10mM PMethionine; B-side = S@0mM Tris-HCl pH 7.8, 500mM NaCl, 10% Glycerol, 500mM Imidaz-ole, and 10mM Methionine) for 4 column volumes each. The Met protein eluted in the first step (15%), whereas the non-cleaved Met and the cleavec Histidine tag eluted in the 804 fractions. The 15% #ractions were pooled after SDS-PACSE gel analysis confirmed the presence of cleaved Met; further purification was done by ge=l filtration chromatography orm an Amersham Bioscie—nces HiLoad 16/60

Superdex 200 grep grade (Cat# 17-1069-01) equilibrated in 50mM Tris-HCl pH 8.5, 150mM NaCl, 10% Glycerol and 5 mM DTT". The cleanest fractionss were combined and 1.98

WOOD 2006/015123 PCT/US2005/026792 coracentrated to ~10.4mg/ml by centrifugation in an Amicon Ultra-15 10,000 DaMWCO cermtrifugal filter unit (Cat# UFC901024).

Purification of AurA: [0M68] The SI insect cell pellets (~ 18 g) produced from 6 L of cultured cells expressing humman Aurora-2 were resuspended in 50mM Na Phosphate pH 8.0, S=00mM NaCl, 10% glycerol, 0.2%n-octyl-B-D-glucopyranoside (BOG) and 3mM B-Merczaptoethanol (BME).

Ome tablet of Roche Complete, EDT Av-free protease inhibitor cocktail (Cat# 18735 80) and 85 units Benzonase (Novagen Cat#70 746-3)) were added per 1 L of eoriginal culture. Pellets we=re resuspended in approximately SO ml per 1 L of original culture and were then somnicated on ice with two 30-45 sec bursts (100% duty cycle). Debris was removed by cemirifugation and the supernatant wa s passed through a 0.8 pm syrirmge filter before being lozaded onto a 5 ml NiZ* HiTrap column (Pharmacia). The column was washed with 6 column volumes of 50mM Na Phosphate pH 8.0, 500mM NaCl, 109~% glycerol, 3mM BME.

Thme protein was eluted using a linear gradient of the same buffer corataining S00mM

Irmidazole. The eluant (24 ml) was cl eaved overnight at 4°C in a buf=fer containing 50mM

Nz Phosphate pH 8.0, 500mM NaCl, 10% glycerol, 3mM BME and 10,000 units of TEV (Iravitrogen Catt 10127-017). The protein was passed over a second nickel] affinity column as described above; the flow-through was collected. The cleaved protein fractions were co-mbined and concentrated using spim concentrators. Further purification was done by gel fil tration chromatography on a S75 si zing column in 50mM Na Phossphate (pH 8.0), 250mM

NzaCl, ImM EDTA, 0.1mM AMP-PNIP or ATP buffer, and 5mM DICT. The cleanest fractions were combined and concentrated to approximately 8-11mg=/ml, and were either fl=ash frozen in liquid nitrogen in 120 ul aliquots and stored at -80°C , or stored at 4°C.

Purification of PDK1: [0 469] Cell pellets produced from © L of Sf9 insect cells expressirng human PDK1 were resuspended in a buffer containing SOmM Tris-HCI pH 7.7 and 250=nM NaCl in a volume of approximately 40 mL per 1 L of oxiginal culture. One tablet of R_oche Complete, EDTA- freze protease inhibitor cocktail (Cat# 1873580) and 85 units Benzon_ase (Novagen

C=t#70746-3)) were added per 1 L of original culture. The suspensi_on was stirred for 1 hoour at 4°C. Debris was removed by centrifugation for 30 minutes =at 39,800 x g at 4°C.

The supernatant was decanted into a 500 mL beaker and 10 ml of a 50% slurry of Qiagen

Ni-NTA Agarose (Cat# 30250) that had been pre-equilibrated in 50rmM Tris-HCI pH 7.8,

500 mM NaCl, 10% Glycerol, 10mM Xmidazole, and 10mM Methionine, were added and stirred for 30 minutes at 49°C. The sarmple was then poured into a drigp column at 4°C and wasshed with 10 column volumes of 5€0mM Tris-HCl pH 7.8, 500mMK NaCl, 10% Glycerol, 10rmaM Imidazole, and 10mM Methioxine. The protein was eluted ussing a step gradient with two column volumes each of the same buffer containing 50mM _, and 500mM

Imi_dazole, sequentially. The 6x Histk dine tag was cleaved overnight using 40 units of TEV pro tease (Invitrogen Cat# 10127017) per Img of protein while dialy=ing in 50mM Tris-HCl pH 7.8, 500mM NaCl, 10% Glycerol. 10mM Imidazole, and 10mM Methionine at 4°C.

The 6x Histidine tag was removed by~ passing the sample over a Phammacia 5 ml IMAC column (Cat# 17-0409-01) charged with Nickel and equilibrated in S0mM Tris-HCI] pH 7.8, 500mM NaCl, 10% Glycerol, 10mM Imidazole, and 10mM Methionine. The cleaved prostein eluted in the flow-through, whereas the uncleaved protein an_d the His-tag remained bowand to the Ni-column. The cleaved protein fractions were combirmed and concentrated using spin concentrators. Further purification was done by gel filtration chromatography on an Amersham Biosciences HiLoad 165/60 Superdex 200 prep grade (_Cat# 17-1069-01) equailibrated in 25mM Tris-HCl pH 7 .5, 150mM NaCl, and 5SmM DIT. The cleanest fra~ctions were combined and concentrated to ~15mg/ml by centrifugation in an Amicon

Ulfra-15 10,000 Da MWCO centrifugal filter unit (Cat# UFC901024).

Example 3: Cell Assays [0c#70] MV4-11 and THP cells were maintained in Iscove's Modified Dulbecco's Medium supplemented with 10% fetal bovine serum (FBS) and penicillin/stresptomycin, Ba/F3 cells we=re maintained in RPMI 1640 supp lemented with 10% FBS, penic-illin/streptomycin and 5n_g/ml recombinant mouse IL-3. ’

Ce=ll Survival Assays [0=471] Compounds were tested in the following assays in duplicate. [0=472] 96-well XTT assay: Cells wvere grown in growth media coentaining various concentrations of compounds (duplicates) on a 96-well plate for 72 Thours at 37°C. The starting cell number was 5000-8000 «cells per well and volume was 120 pul. At the end of the 72-hour incubation, 40 pl of XTT labeling mixture (50:1 solution off sodium 3'-[1- (pEnenylamino-carbonyl)-3,4-tetrazol Gum]-bis (4-methoxy-6-nitro) b enzene sulfonic acid hy~drate and Electron-coupling reagemt: PMS (N-methyl dibenzopyr azine methyl sulfate) were added to each well of the plate. After an additional 2-6 hours of incubation at 37°C,

the absorbance reading at 405mm with background correction at @650nm was measured with a spectrophotometer.

[0473] 384-well AlamarBlue assay: 90 pl of cell suspension vevere plated onto each well of a 384-well plate preprinted “with 0.5 pl of compound in DMSC or DMSO only. The starting cell number was 4000 cells per well. After a 72-hour incubation, 10 pl of

AlamarBlue solution (440 uM resazurin in PBS) were then adde=d to each well of the plaate.

After an additional 2-hour incubation at 37°C, fluorescence was measured using a TEC2AN plate reading fluorometer with excitation at 535nm and emissior at 59 1nm.

BCR-ABL Phospho-ELISA _Assay

[0474] The following table shows the reagents that were typically used in the BCR-A_BL phospho-ELISA ("P-ELISA") assay.

Table 40 BCR-ABY _ phospho-ELISA(p-ELISA) Typical Reagent List 10% Fetal Bovime Serum, VWR m6777-014 characterized, ln eat inactivated

Human Plasma, Bioreclamation EIMPLEDTA

Anticoagulant=IEDTA Inc. 3

EC I RE

96well PP 325.1 round bottom Thompson =)32465 plate w/ lid TC Instrument Co 96well Nunc Maaxisorp plate (for Fisher Scientific 12-565-136 colorimetric assay) 96well white flat-bottom plate (for | Matrix —4923 luminescent assay)

DC ER EE

Teee@o

Nwowy

Ee CS EE RR

Sodium pyrophosphate (NaPP; 5mM)

EC I I EE

IE SE ER EE

EC RR I EE ee OFZ I ER

EE ER EE

We 2006/015123 PCT/US2005/026792

Ee To Tr ER

Ee A conjugate (if unconjugated 4G10 is used) 12-.349

Coating Buffer (0.1M N =z-carbonate, pH 9.5)

EL I EE

CT er ER EE [SwopSolufon ON swttuwicacid)

Er ES RE

SuperSignal ELISA Pi«o Pierce 37070

Chemiluminescent Sul»strate (may be used instead of Substrate

Reagents A&B) [0 475] Cells (Ba/F; cells transfected with WT BCR-ABL, othe 1 kinases, or T3151,

Y~253F, or other mutant forms of B CR-ABL) were grown in the &absence of IL-3 at least 2 weeck before the assay. The day be fore assay, the cells were fed with fresh media so that at th c time of assay the cells were in 1 og phase. Ba/F3 cells that hac been grown in the absence of IL-3 for at least ¥ weeks were resuspended in RPMI 1 640 so that each well of a 96 -well plate would contain approximately 200,000 cells. Cells ~were distributed in a 96- well plate containing serially dilutezd concentrations of test comp «ounds. Cells were typically in_cubated with or without test compounds for 60-120 minutes at 5%CO,, 37°C. The in_cubation was performed with or without other additives such a=s 10% FCS or 50% human plasma. After incubation of compounds, lysis buffer was added aand incubated for 10-15 minutes; the lysate was cleared by centrifugation.

[0476] To make the ELISA plates, commercially available Anti -ABL antibodies (e.g. (Ab— 3,. Calbiochem OP20) were prepared at a concentration of 0.125,4g/ml in coating buffer (©3.1M Na-carbonate, pH 9.5), and plated at 10 ml per plate (12.5 pl 100pg/ml Ab/10ml). Im a “high binding multi-well plate, 10 Q ul Ab in coating buffer were added to each well, and e=ach plate was covered with a plates seal and incubated overnight at 4°C.

[477] Excess antibody was rem oved and the ELISA plate wass washed 3-4 times with 200 pul of wash buffer (0.05%Tween in PBS, pH 7.4). 150 pl of “lysate (see above) were tr ansferred to the ELISA plate. Plates were scaled and incubate 2 hours at room temperature. The detection antibody (e.g. HRP conjugated anti-gpTyr or unconjugated o-p-=Y 4aG10, Upstate) was prepared in as say diluent. The antibody wass diluted 1:1000 (sstock=2pg/pl, 200 pg in 100pl; f.c.=2pg/ml) in assay diluent an-d 10 ml of diluted antibody» peer plate were added. The lysate was removed from the ELISA plates, and wells were washed four times with 200 pl of wash buffer per well. 100 pl of detection antibody was added to each well; the plate was covered, and incubated lhr at room temperature (21°C).

Excess detection antibody was removed from the ELISA platess, and the wells were washed four times with 200 pl of wash buffer per well.

[0478] If necessary, (i.e. for unconjugated anti-pTyr antibody) secondary antibody (goat anti-rabbit HRP) was diluted 1:3000 in assay diluent (3.33 pl p=er 10 ml diluent) and added at 10 ml of diluted antibody per plate. Excess secondary antibody was removed from the

ELISA plate, and the plate was washed four times with 200 pl per well of wash buffer.

[0479] Substrate Reagent A and Substrate Reagent B (Pierce= Cat#37070 SuperSignal

ELISA Pico Chemiluminescent Substrate) were added immedi ately before use (10 ml resultant solution per plate). 100 ul substrate were added per vevell, mixed for 1 minute, ani chemiluminescent signal was measured with a luminometer.

Assay results on selected compounds:

Abl_T315 bioassay:

[0480] ICso< 0.05 uM: AE1, AE2, AE3, AE4, AES, AE6, ~AE7, AES, AE9, AE10,

AE11, AE12, AE13, AEl14, AE15, AE16, AE17, AE18, AE19=, AE20, AE21, AE22, AE233,

AE24, AE25, AE27, AE28, AE29, AE30, AE31, AE32, AE33 , AE34, AE35, AE37, AE4O,

AEA41, AE42, AE43, AE44, AE47, AE48, AE49, AE50, AE52_, AESS, AES8, AES9, AE6O,

AE61, AE64, AE62, AE63, AE65, AE66, AE67 and AE68.

[0481] 0.05 uM < ICs <0.2 uM: AE26, AE36, AE38, AE39, AE45, AE46, AE51, AES3 and AES4.

Abl_T315 p-ELISA cellular assay:

[0482] ICs <0.1 uM: AE, AE3, AES, AE6, AE7, AE14, _AE20, AE25, AE26, AE30,

AE31, AE37, AE41, AE42, AE44, AE54, AESS5, AES8 and A_E64.

[0483] 0.1 PM <ICso<1 uM: AE2, AE4, AE9, AE11, AEM 3, AELS, AE16, AEIS,

AE19, AE22, AE29, AE32, AE34, AE35, AE48, AE49, AE52, AE61, AE62 and AE63.

AurA bioassay:

[0484] ICso<0.5 uM: AE6, AE7, AE1S, AE30, AE31, AE332, AE34, AE35, AEA47,

AES1, AES2, AES3, AES4, AESS and AE60.

[04857] 0.5 uM <ICso<5 uM: AE1, AE11, AE13, AE33, AES9, AME62, AE67, AEG68.

Met bioassay: [0486s] ICs, <1 uM: AES, AE14, A F40, AE42, AE43, AE48, AE-53, AES6 and AE66.

[04877] 1puM<ICso<5 uM: AE22, AE26, AE41, AE46, AES2, AAE57, AE38 and AE6S.

PDK bioassay:

[04888] ICso <1 uM: AESO, AESS and AESS.

[04898] 1M <ICso<5 pM: AE2, AE3, AE9, AE10, AE11, AE220, AE21, AE38, AE44,

AE45, AE46, AF48, AB49, AES2, AEES53, AE5S9, AE60, AE61, AEG3 and AE64.

Claims (1)

1. WHAT IS CLAIMED IS:

   1 1. A compound havings the formula: Ne N 2 R! aw, 3 wherein 4 L! and L? are independentl=y a bond, -S(O)n-, -O-, -NH-, unsubstituted C;-Cs alkylene, or unsubstituted 2 to 5 membered heteroalkyle=ne, wherein n is an 6 integer from O to 2; 7 A! is a 6-membered substit-uted or unsubstituted aryl or 6—membered 8 substituted or unsubstituted heteroaryl; 9 A? is substituted or unsubstituted cycloalkyl, substituted Or unsubstituted heterocycloalkyl, substitu ated or unsubstituted aryl, or siabstituted or 11 unsubstituted heteroaryl; 12 R! is halogen, -OR?, -NR°RR’, -C(Z)R®, -S(0)wR’, -CN, -M0;, -CF3, substituted 13 or unsubstituted alkyl, stmbstituted or unsubstituted hetemroalkyi, substituted or . 14 unsubstituted cycloalkyl... substituted or unsubstituted hesterocycloalkyl, substituted or unsubstitusted aryl, or substituted or unsubostituted heteroaryl; 16 X! is -C(RY)=, -CRHRY)- , N=, -NR*)-, -S-, or -O-; 17 R? and R? are independently hydrogen, halogen, -OR’, NR°R, -C(Z)R®, 18 -S(0)wR’, -CN, -NO,, -CF3, substituted or unsubstituted alkyl, substituted or 19 unsubstituted heteroalky 1, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocsycloalkyl, substituted or unsubsstituted aryl, or 21 substituted or unsubstitu_ted heteroaryl; 22 R*is hydrogen, -C(O)R®, —S(O)RY, substituted or unsub=stituted alkyl, 23 substituted or unsubstitu_ted heteroalkyl, substituted or wunsubstituted 24 cycloalkyl, substituted o T unsubstituted heterocycloalksyl, substituted or unsubstituted aryl, or sulbstituted or unsubstituted heter oaryl; 26 Z is N(R®), S, or O, whersein R* is hydrogen, substitutec] or unsubstituted 27 alkyl, or substituted or u_nsubstituted heteroalkyl; 28 w is an integer from 0 to 22;

   29 R’ is independently hydrogen, -CF3, substituted or unsubstituted alky=1, substituted or unsubstituted heteroalkyl, substituted or unsubstituteed 31 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substitute=d or 32 Lansubstituted aryl, or substituted or unsubstituted heteroaryl; 33 R% and R’ are independently hydrogen, -C(O)R", -S(0),R", substitvated or 34 wansubstituted alkyl, substituted or unsubstituted heteroalkyl, substintuted or winsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, 36 substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 37 Rand R"" are independently hydrogen, -NR'’R', substituted or 38 wmsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or 39 wmnsubstituted cycloalkyl, substituted or unsubstituted heterocycloa_lkyl, 40 ssubstituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 41 R™? and R'? are independently hydrogen, substituted or unsubstituted alkyl, 42 substituted or unsubstituted heteroalkyl, substituted or unsubstitute=d 43 «cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or 44 -unsubstituted aryl, or substituted or unsubstituted heteroaryl; 45 RB is independently hydrogen, -NR'“R'’, -OR'®, substituted or unsutostituted 46 alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted 47 «cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituteed or 48 -unsubstituted aryl, or substituted or unsubstituted heteroaryl; 49 R2* R' and R'S are independently hydrogen, substituted or unsubst-ituted 50 alkyl, substituted or unsubstituted hetex-calkyl, substituted or unsutostituted 51 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituteed or 52 -unsubstituted aryl, or substituted or unsubstituted heteroaryl; 53 R= is independently hydrogen, substitute« or unsubstituted alkyl, sutostituted or 54 “unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, =substituted 55 or unsubstituted heterocycloalkyl, substituted or unsubstituted aryll, or 56 substituted or unsubstituted heteroaryl, wherein if w is 2, then R® ray 57 optionally be NR'7R!8; and 58 R 7 and R'® are independently hydrogen, substituted or unsubstitutecd alkyl, 59 substituted or unsubstituted heteroalkyl, substituted or unsubstituted 60 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or 61 unsubstituted aryl, or substituted or unsubstituted heteroaryl,

   62 whesrein R® and R7, R'? and R'?, R'* and R'’, and R' and R'® amre, 63 immdependently, optionally joined wi_th the nitrogen to which t=hey are attached 64 te form substituted or unsubstituted heterocycloalkyl, or substituted or 65 umsubstituted 5-membered heteroaryl.

   1 2. The compound of claim 1, wherein Al is 6-membered ssubstituted aryl 2 or 6-membered substituted heteroaryl.

   1 3. The compound of claim 1, wherein Al is substituted plenyl, 2 substituted pyridiryl, substituted pyrimidinyl, substJtuted benzodioxolyl, substituted 3 benzimidazolyl, ox substituted indolyl.

   1 4. The compound of claim 3, wherein A' is substituted with a halogen.

   1 5. The compound of claim 1, wherein A' is substituted plhenyl.

   1 6. The compound of claim 1, w”herein A! has the formula: = : \1 A 19 2 (=e), (ID, 3 wherein 4 x i_s an integer from 1 to 5; R! ? is independently halogen, -OR®, -NRR’, -C(Z)R®, -S(O)w_R’, -CN, -NO,, 6 —CF3, substituted or unsubstituted =alkyl, substituted or unsulibstituted 7 heteroalkyl, substituted or unsubst tuted cycloalkyl, substitiated or 8 wansubstituted heterocycloalkyl, substituted or unsubstituted aryl, or 9 ssubstituted or unsubstituted hetero- aryl, wherein two R'® groups are optional ly combined to form a su” bstituted or 11 wLinsubstituted ring with the carbon sto which they are attachaed.

   1 7. The compound of claim 6, w=herein an RY" attached at position 1 is 2 combined with ar R'® attached at position 2 to fornm a substituted or unsubst=ituted ring.

   1 8. The compound of claim 6, wherein an R' attached at position 2 is 2 combined with ar R'® attached at position 3 to form a substituted or unsubstituted ring.

   1 9. The compound of claim 6, whereim two R'® groups are option ally 2 combined to form a substituted or unsubstituted ring with the carbons to which they are 3 attached, wherein said substituted or unsubstituted ring i s substituted or unsubstitute=d 4 heterocycloalkyl or substituted or unsubstituted heteroaryl. 1 10. The compound of claim 6, wherei n R! is independently halo_gen, 2 NRR’, OR’, or substituted or unsubstituted alkyl. 1 11. The compound of claim 10, whereein R®, RS, and R” are indep endently 2 hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalky=1, 3 substituted or unsubstituted cycloalkyl, substituted or urasubstituted heterocycloalky~], 4 substituted or unsubstituted aryl, or substituted or unsubmstituted heteroaryl, wherein RS and R’ are optionally joined with nitrogen to which they are att =ched to form substituted or— 6 unsubstituted heterocycloalkyl, or substituted or unsubstituted 5-membered heteroa-ryl. 1 12. The compound of claim 10, wherein R’, RS, and R’ are indepmendently 2 hydrogen, or substituted or unsubstituted alkyl. 1 13. The compound of claim 10, wher-ein RRS, and R’ are independently 2 hydrogen, or substituted or unsubstituted C;-Cs alkyl. 1 14. The compound of claim 6, where=in x is 1 and R'is attached at 2 position 2. 1 15. The compound of claim 6, where=in x is 1 and R!? is attached_ at 2 position 1. 1 16. The compound of claim 6, where=in x is an integer from 2 to Sand at 2 least one R'® is attamched at position 1. 1 17. The compound of claim 6, where=in x is an integer from 2to 5and at 2 least one R* is attamched at position 2. 1 18. The compound of claim 1, wherezin A? is substituted or unsubstituted 2 aryl or substituted eor unsubstituted heteroaryl.

   1 19. The compound of claim 1, where-in A? is substituted or urnsubstituted 2 phenyl, substituted or unsubstituted thiopenyl, substituteed or unsubstituted pyridtinyl, 3 substituted or unsubstituted pyrrolyl, substituted or unsubstituted triazolyl, subs#tituted or 4 unsubstituted pyrimiclinyl, substituted or unsubstituted gpyrazinyl, or substituted or unsubstituted imidazolyl. 1 20. The compound of claim 1, wherein A? has the formula: (re), 2 rR V), 3 wherein 4 y is am integer from 0 to 4; 5 R® is independently halogen, -OR’, -NIR'R’, -C(Z)R”, -S(0)wR=, -CN, -NO,, 6 -CI=3, substituted or unsubstituted alkyl, substituted or unsubstzituted 7 heteroalkyl, substituted or unsubstitut ed cycloalkyl, substitute«d or 8 unsubstituted heterocycloalkyl, substi_tuted or unsubstituted aryl, or 9 sub stituted or unsubstituted heteroary], wherein two R? groups are optionally combined to form a substituted or 11 unsubstituted ring with the carbons tos which they are attached&, or 12 whereein one R? and R! are optionally combined to form a subs#tituted or 13 unssubstituted ring with the carbons toe which they are attached. 1 21. The compound of claim 20, wheerein R% is independent] _y halogen, 2 NR°R’, OR’, or substituted or unsubstituted alkyl. 1 22. The compound of claim 21, wheerein R’ RS and R’ are independently 2 hydrogen, substitutesd or unsubstituted alkyl, substitute=d or unsubstituted hetereoalkyl, 3 substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycl oalkyl, 4 substituted or unsubmstituted aryl, or substituted or unswibstituted heteroaryl, wimerein R® and R’ 5 are optionally joineed with nitrogen to which they are attached to form substituted or 6 unsubstituted heterocycloalkyl, or substituted or unsubstituted S5-membered hesteroaryl. 1 23. The compound of claim 21, wh_erein R® R® and R’ are —independently 2 hydrogen, or substiftuted or unsubstituted alkyl.

   1 24. The compound of claim 21, wherein R=, RS, and R’ are independently 2 hydrogen, or substituted or unsubstituted C;-Cs alkyl. 1 25. The compound of claim 20, wherein y Js 1; and R? is attached a-t 2 position 3". 1 26. The compound of claim 20, wherein y is 2; and Ris attached amt 2 position 3' and position 4'. 1 27. The compound of claim 1, wherein A2 has the formula: (2) N= ZA 2 = R! (VD, 3 wherein a y is an inte ger from 0 to 3; =] R? is indegoendently halogen, -OR®, -NR'R’, -C(Z)R, -S(0)uR’, -CN, -NO,, (&} -CF,, substituted or unsubstituted alkyl, sub=stituted or unsubstituted 7 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or } 8 unsubstit-uted heterocycloalkyl, substituted wor unsubstituted aryl, or oS substitutesd or unsubstituted heteroaryl, wherein orne R? and R! are optionally combitmed to form a substituted =or 13 unsubstituted ring with the carbons to which they are attached. 1 28. The compound of claim 27, wherein 3. is 1; and R% is attached at 2 position 3". 1 29. Thee compound of claim 1, wherein L= is a bond. 1 30. Th e compound of claim 1, wherein L=is abond. 1 31. Th_e compound of claim 1, wherein L 7? and 1? are a bond. 1 32. Th_e compound of claim 1, wherein R_" is -C(Z)R®, Z is O, and TR’ is 2 -NR'RP.

   1 33. The compound of claim 27, wherein R'is -C(Z)R}, Zis 0, and Réis 2 -ENRMRY. 1 34, The compound of claim 42, wherein R' is -C(Z)R%, Z is O, and R®is 2 -INRMRP. 1 35. The compeound of claim 1, wherein 2 R! is -C(Z)R®, 3 Zs O; 4 R® is -NR"“R'’; ard R'* and R? are independently substituted or unsiabstituted alkyl, substituted or 6 unsubstituted heteroalkyl, or are combined witkn the nitrogen to which thes 7 are attached to fForm substituted or unsubstituted piperidinyl, or substituted 8 or unsubstituted piperazinyl, substituted or unsubstituted pyrrolidinyl, or 9 substituted or unsubstituted morpholino. 1 36. The compound of claim 35, wherein y is -C. 1 37. The compwound of claim 32, wherein R'* znd R!® are combined with the 2 maitrogen to which they are attacked to form a piperazinyl substituted with a substituted or 3 wunsubstituted alkyl or substitutec] or unsubstituted heteroalkyl. 1 38. The compwound of claim 37, wherein said piperazinyl is substituted 2 with a substituent having the formula -(CH)-NR*'R?, whereirm 3 t is an integer froom O to 6; 4 R?! and R? are iradependently hydrogen, substituted or unsubstituted alkyl, 5 substituted or unsubstituted heteroalkyl, substi—tuted or unsubstituted 6 cycloalkyl, sub stituted or unsubstituted heterocycloalkyl, substituted or 7 unsubstituted a yl, or substituted or unsubstitu-ted heteroaryl; 8 wherein R*' and TR? are optionally combined with the nitrogen to which thesy 9 are attached to form a substituted or unsubstitiated heterocycloalkyl or substituted or wansubstituted heteroaryl.

   1 39. The compound of claim 38, wherein BR” and R* are combined witch the 2 nitrogen to which they are attached to form a substituted or —unsubstituted piperazinyl, 3 substituted or unsubstituted piperidinyl, or substituted or un substituted morpholino.

   1 40. The compound of claim 38, wherein “R?' and R* are independently

   2 hydrogen, substituted or unsubstituted alkyl, or substituted eor unsubstituted aminoalkyl.

   1 41. The compound of claim 1, wherein Aa is substituted with at least cone

   2 -OR’, wherein R® is immdependently hydrogen, substituted or= unsubstituted alkyl, substituted or 3 unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted 4 heterocycloalkyl, sub stituted or unsubstituted aryl, or substmtuted or unsubstituted hetero aryl. 1 42. The compound of claim 6, wherein =” has the formula:

   ( 7) y 2 _

   2 R (V), 3 wherein

   4 y is arn integer from O to 4; ‘ R¥ is halogen, -OR®, -NR°R’, -C(Z)R?, -S(O)uR’, -CN, -NO,, -CFs,

   6 substituted or unsubstituted alkyl, substitu ted or unsubstituted heteroallikyl,

   7 substituted or unsubstituted cycloalkyl, substituted or unsubstituted

   8 heterocycloalkyl, substituted or unsubstitumted aryl, or substituted or

   9 unsubstituted heteroaryl, where in two R%° groups are optionally combined to form a substituted or- 11 unstabstituted ring with the carbons to whi_ch they are attached, or 12 where in one R?® and R' are optionally combined to form a substituted or 13 unsubstituted ring with the carbons to whi ch they are attached.

   1 43. The compound of claim 42, wherein_ an R? attached at position 3 "is

   2 combined with R' to form a substituted or unsubstituted rirg.

   1 44. The compound of claim 42, whereins an R? attached at position 3-'is

   2 combined with an R=? attached at position 4' to form a substituted or unsubstituted ring.

   1 45. The compound «of claim 42, wherein R'is —C(Z)R®, Z is O, and R%is 2 -NR™R', wherein R'* and R2? are cormbined to form a substitute. d or unsubstituted ring withm

   3 the cacxbon to which R? is attached an«d the nitrogen to which R'> is attached.

   1 46. The compound of claim 42, wherein L' an dL? are a bond.

   1 47. The compound of claim 42, wherein x is 1 andy is 0.

   1 48. The compound of claim 47,wherein R'%is attached at position 1.

   1 49. The compound of claim 47,wherein R'is attached at position 2.

   1 50. The compound of claim 42 wherein

   2 X 18 2;

   3 y is 0; and

   4 RY is attached at posit-ions 1 and 4.

   1 51. The compound of” claim 42, wherein

   2 xis 2;

   3 y is 0; and

   4 RY is attached at positions 1 and 5.

   1 52. The compound of claim 42 wherein

   2 xis 1;

   3 yis 1;

   4 R? is attached at position 3'; and

   R' is attached at position 1.

   1 53. The compouncd of claim 42 wherein

   2 xis 1;

   3 yis 2;

   4 R? is attached at positions 3' and 4"; and

   5 RY is attached at posi tion 1.

   1 54. The compound of claim 42 wherein

   2 x is 2;

   3 y is 0; and

   4 one R* is attached at position 2.

   1 5S.

   The compound of claim 6, wherein A? has the formula :

   (72) Nl 2

   2 R' (VD, 3 wherein

   4 y is ar integer from 0 to 3;

   Ris halogen, -OR®, -NR®R’, -C(Z)R}, -S(O)wR’, -CN, -CF3, -NO,

   6 subsstituted or unsubstituted alkyl, sub stituted or unsubstituted heteroalkyl, 7 substituted or unsubstituted cycloalky—1, substituted or unsubstituted

   8 hetesrocycloalkyl, substituted or unsubmstituted aryl, or substi_tuted or

   9 unswubstituted heteroaryl.

   1 56. The compound of claim 55, wherein y is 1 and R? is mattached at

   2 position 3".

   1 57. A method of modulating the act—ivity of a protein kinasse comprising : 2 contacting said protein kinase with the compound of claim I.

   1 58. A method of modulating the activity of a protein kinasse selected from 2 the group consisting of Abelson tyrosine kinase, Ron receptor tyrosine kinasse, Met receptor 3 tyrosine kinase, Fmss-like tyrosine kinase-3, Aurora kirases, p21-activated k-inase-4, and 3- 4 phosphoinositide-de pendent kinase-1, said method cormprising contacting said kinase with a 5 compound having time formula:

   Na—NH 20

   6 ®,

   7 wherein

   8 L' armd L? are independently a bond, -S «(0),-, -O-, -NH-, subs. tituted or

   9 unssubstituted C;-Cs alkylene, or subsstituted or unsubstitutesd 2 to 5 membered heteroalkylene, wherein nu is an integer from 0 to 2; and

   11 A! and A? are independently submstituted or unsubstituted cycloalkyl, 12 substituted or unsubstituted he terocycloalkyl, substituted or= unsubstituted 13 aryl, or substituted or unsubstituted heteroaryl. 1 59. The method of claim 58, wherein 2 1! and L? are independently a beond, -S(0)y-, -O-, -NH-, unsumbstituted C;-Cs 3 alkylene, or ummsubstituted 2 to 5 membered he-teroalkylene. 1 60. The method of claim 58_, wherein L! and L? are a bomd. 1 61. The method of claim 58 _, wherein A! and A? are indegpendently 2 substituted or unsubstituted aryl, or substitutede or unsubstituted heteroaryl. 1 62. The method of claim 58 , wherein A' and A? are independently 2 substituted or unsubstituted aryl, or 6-membereed substituted or unsubstitute=d heteroaryl. 1 63. The method of claim 58, wherein 2 AZ is substituted with at least omne ~C(Z)R®, wherein 3 Z is N(R®), 8, or O, wherein R_* is hydrogen, substituted or unsubstituted 4 alkyl, or substituted or unsubstituted heteroalkyl; R® is hydrogen, -NR'*R'5, OR. '¢, substituted or unsubstitute=d alkyl, 6 substituted or unsubstituted Im eteroalkyl, substituted or unssubstituted 7 cycloalkyl, substituted or unssubstituted heterocycloalkyl, ssubstituted or 8 unsubstituted aryl, or substitiated or unsubstituted heteroar—yl; and 9 RY R', and R' are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted 11 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or 12 unsubstituted aryl, or substitiated or unsubstituted heteroaryl. 1 64. The method of claim 63, wherein Z is O and R®is I~RYR”. 1 65. The method of claim 5&8, wherein said compound is the compound of 2 claim 1. 1 66. The method of claim 58, wherein said protein kinasee is a Ber-Abl 2 kinase having a mutation selected from the group consisting of M244V, 1.7248V, G250E, 3 G250A, Q25 2H, Q252R, Y253F, Y253H, E2 55K, E255V, D276G, F3111-, T3151, T315N,

   T315A,F317V, F317L, M343T, M351T, E355G, F359A, F 359V, V3791, F382L, L38~M, H396P, H396R, S417Y, E459K and F486S.

   67. "Whe method of claim 66, wherein said protein kinase has a T3151 mutation.

   68. “The compound of claim | for use in the treatment of cancer, alleergy, asthma, inflammation, obstructi—ve airway disease, autoimmune dise=ases, metabolic disease, infection, CNS disease, brain tumor, oloesity, asthma, hematological disord. er, degenerative neural dise=ase, cardiovascular disease, or disease associated with angiogem esis, neovascularization, or vasculogenesis.

   69. “The compound of claim 68, whereir said cancer is leukemia or myeloproliferative diso-rder.

   70. A compound having the formula: 0 3 / NF L \ , wherein L'and WM. are independently a bond, -S(O),,—, -O-, -NH-, substituted or munsubstituted C, -Cs alkylene, or substituted or unsubstituted 2 to 5 membered hetero- alkylene, wherein n is an integer from 0 to 2; and #A' and A” are independently= substituted or unsubstituted cycloalkyl, substituted or tansubstituted heterocycloall=yl, substituted or urmsubstituted aryl, or substituted or ursubstituted heteroaryl for umse in the treatment of cancer.

   71. The compound of claim 70, where®n said cancer is leukemia 0 r myeloproliferative dis-order.

   72. A pharmaceutical composition cormprising a pharmaceutically= acceptable excipient and a compound having the formula: 216 - AMENDED SHEET

   R’ is indepemdently hydrogen, substituted or unsubstituted alkyl, sutostituted or unsubstitwted heteroalkyl, substituted <r unsubstituted cycloalkyl, substituted or unsubstitmuted heterocycloalkyl, substit-uted or unsubstituted aryl, —or substituted or unsubstitwuted heteroaryl, wherein if w is 2, then R® may optionall ybe -NR'R'®; and R'7 and R'® zare independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstitauted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, «or substituted or unsubstiteuted heteroaryl, wherein R® zand R’, R' and R"?, R" and RR", and R'" and R'® are, independently, optionally joined wi th the nitrogen to which they arc attached to form substi tuted or unsubstituted heterocycloalkyl, or substituted or unsubstituted 5-membered hetmeroaryl.

   74. A compound having formula. VII H (R20), | Na N T= PP J > 4 ) ~.)

   ig . R! \ Y (Rx (VID), wherein L' znd L? are bonds; R! 4s -C(O)NR"R"; R"Y isind ependently halogen, -OR>, -NNR°R’, or substituted or unsubstituted alkyl, wherein R'® is -OR® at goosition 1, and wherein x is a_n integer from 1 to 5; R* is ind ependently halogen, -OR®, -NR®R’, -C(O)NR®R’, -S(0)=wR?, -CN, -NO,, -CF;, substituted or unsubstituted alkyl, substituted or unswubstituted heteroalkyl, subsstituted or unsubstituted cycloalky~], substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein w is an integer from 0 tzo 2, and wherein y is an integer from 0 to 4, or two R? groups are optionally combined to form a substituted or unsubstituted ring with the carbons to which they ares attached; 217 AMT OT

   Ris in dependently hydrogen, -CF;, substituted or unsubstituted alkyl; R®and R’ are independently hydrogen, -C(3X*)R'?, -S(0),R"", substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkcyl, substituted or unsubstituted cycloalkyl, substituted or unsubs®tituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroa ryl, wherein X%is 0, S, or NH; R’ is independently hydrogen, -NR'’R'®, su bstituted or unsubstituted alkyl, substituted or unsubstituted heter~calkyl, substituted or unsubstituted «cycloalkyl, substituted or unsubstituted heterocycloalkyl, sub stituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl ; R'% and R' are independently hydrogen, -N R'?R'2, -OR'®, -SR'®, substituted o r unsubstituted alkyl, smbstituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted «or unsubstituted aryl, or substitutecd or unsubstituted heteroaryl, R'?and R*" are independently hydrogen, sulbstituted or unsubstituted alkyl, substituted or unsubstituted heter-oalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, sub stituted or unsubstituted aryl, or subsstituted or unsubstituted heteroaryl 3 R', R'>, and R'® are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Rand R'®are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heter-calkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, subsstituted or unsubstituted aryl, or subsstituted or unsubstituted heteroaryl 5 or wher ein R® and R’, R"? and R", R'* and R", and R" and R"® are independemitly joined with the nitrog en to which they are attached to forrm substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted S-membe=red heteroaryl.

   75. The compound of claim 74, wheres in R' is halogen. 218 BREUNATIOD Spy RT

   76. The compound of claim 74, wherein R® and R” are= independently hydrogen, substituted or unsumbstituted alkyl, substituted or tmnsubstituted heteroalky BR, substituted or unsubstituted cyclcoalkyl, substituted or unsubstitiated heterocycloalkyl, su abstituted or unsubstituted aryl, or substituted- or unsubstituted heteroaryl, or wherein R® and R” are j oined with nitrogen to which they are attamched to form substituted or unsubstituted heterocycloa. lkyl, or substituted or unsubstituted S-me=mbered heteroaryl.

   77. The compound of claim 7-4, wherein R®, R®, and R=” are independently hydrogen, or subst ituted or unsubstituted alkyl.

   78. The compound of claim 7<4, wherein R’, R®, and R= are independently hydrogen, or substituted or unsubstituted C;-Cs aL kyl.

   79. The compound of claim 7<4, wherein x is 1; and R™’ is attached at position 1.

   80. The compound of claim 7=4, wherein x is an intege=r from 2 to 5; and at least one R'is attached . at position 2.

   81. The compound of claim 7<%, wherein R? is indepemndently halogen, -NR°R’, OR’, or substituted or unsubstituted alkyl.

   82. The compound of claim 8 1, wherein the R® and R™ of said R? are independently hydmrogen, substituted or unsubstitue ted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsu._bstituted cycloalkyl, substitutecd or unsubstituted hetercocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or wherein FR® and R are joined with the nitrogen to which they are attached to form substi tuted or unsubstituted hesterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl.

   83. The compound of claim 8 1, wherein the R’, R®, amd R’ of said R* are independently hydmrogen, or substituted or unsubstituted alkyl.

   84. The compound of claim 8 2, wherein the R>, R®, amd R’ of said R?° are independently hydrogen, or substituted or unsubstituted C,-Cs alkyl. 219 SWING BET

   8s. The compound of claim 74, w=herein y is 1; and R?° is attached at position 3’.

   86. The compound of claim 74, w~herein y is 2; and R* is attacthed at position 3 and position 4°.

   87. The compound of claim 74, w=herein R'* and R'® are indepe=ndently substituted or unsubstituted alk yl, substituted or unsubstituted heteroalkyl, or wherein R'* and R'’ are combined with the nitrogen to which they are attached; to form substituted or unsubstituted a_zetidine, substituted or unsutostituted piperidinyl, or substituted or unsubstituted piperazinyl _ substituted or unsubstituted pyrroMidinyl, or substituted or unsubstitwuted morpholino.

   88. The compound of claim 87, w~herein y is 0.

   89. The compound of claim 74, w=herein R" and R'® are combi med with the nitrogen to which they are attached to form piperazin—y! substituted with substitute or unsubstituted alkyl or substituted or unsubstituted heteroalkyl.

   90. The compound of claim 89, w~herein piperazinyl is substitu—ted with -(CH,)- NR?'R*, wherein t is an. integer from 0 to 6; and R*!' ard R* are independently hydroger, substituted or unsubstituted alkyl, substituted or unsubstituted het eroalkyl, substituted or unsubstitumted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or wherein R?' and R?= are combined with the nitrogen t o which they are attached to £orm a substituted or unsubstituted het . erocycloalkyl or substituted or un substituted heteroaryl.

   91. The compound of claim 89, w~herein R?' and R* are combi ned with the nitrogen to which tizzey are attached to form a substitu_ted or unsubstituted piperazirayl, substituted or unsubstituted piperi dinyl, or substituted or unsubstitu ted morpholino.

   92. The compound of claim 89, w-herein R?' and R*? are indepe=ndently hydrogen, substituted or unsubostituted alkyl, or substituted or urasubstituted aminoalkyl. 220 Acie Wd Bl FT

   93. The compound of claim 74, whe=rein an R?? attached at peosition 3” is combined with R! to f~orm a substituted or unsubstituted. ring.

   94. The compound of claim 74, whe=rein an R*’ attached at peosition 3’ is combined with an R? attached at position 4’ to form a ssubstituted or unsubstituted ring.

   9s. The compound of claim 74, whe=rein R'> and R?’ are commbined to form a substituted or unsubstituted ring with the carbon to which R* is attached and thes nitrogen to which R' is attached.

   96. The compound of claim 74, whe=rein the R'* and R'"” of s=aid R' are substituted or unsubstituted (C[-C)) alkyl, or substituted or unsubs tituted 2 to 10 memberec heteroalkyl.

   97. The compound of clam 96, whemein R¥ is -NRR’.

   98. The compound of claim 97, wherein the R® of said R¥ iss hydrogen. 99, The compound of claim 98, wherein the R” of said R% iss hydrogen, - C(XHR'?, unsubstituteed alkyl, or substituted or unsubstm tuted cycloalkyl.

   100. The compound of claim 99, wherein X? is O.

   101. The compound of claim 99, whesrein R? is attached at position 3°.

   102. The compound of claim 99, wherein R' is -OR®.

   103. The compound of claim 102, wlerein said R® of said R'*" is substituted or unsubstituted C,-C,o alkyl.

   104. The compound of claim 103, wherein said R® of said R'= is unsubstituted C,- Cio alkyl.

   10S. The compound of claim 74, wherein x is 1; and y is 0.

   106. The compound of claim 74, wherein an R' is attached a .t position 2.

   107. The compound of claim 74, whesrein x is 2; y is 0; and R_" is attached at positions 1 and 4. 221 ARITA) RY

   108. The= compound of claim 74, wherein xis 2; y is 0; and R'is attached at positions 1 and 5.

   109. The compound of claim 74, wherein xis 1; y is 1; R*’ is attached at position 3’; and R'? is attached at position 1.

   110. The compound of claim 74, wherein xis 1; y is 2; R*® is attached at positions 3’ and 4’; and R'" is attached at position 1.

   111. The compound of claim 74, wherein xis 2; y is 0; and one R'® is =attached at position 2.

   112. The compound of claim 74, wherein xis 2; y is 1; and one R' is =attached at position 1; R¥ is attached a_t positions 3° and 4°.

   113. The compound of claim 74, wherein xis 2; y is 2; and one R'is attached at position 1; R? is attached a t positions 3” and 4°.

   114. A compound of Formula IV: H oe AZ L2 = V/ 1 R av), wherein L' and L? are bonds ; A! is substituted or unsubstituted phenyl; A? is substituted or -unsubstituted pyridinyl; R' is halogen, -OR® , -NR°R’, -C(Z)R?, -S(0)R’, -CIN, -NO,, -CF;, substituted or= unsubstituted alkyl, substittated or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or minsubstituted aryl, or substiti ited or unsubstituted heteroaryl, wherein w is an integer from 0 to 2 ; X' is -C(R%)=, or -NI=; 222 CETERA ve

   R? is independents hydrogen, halogen, -OR®, -NR*R/, -C(Z)R?, SOME, -C2N, -NO;, -CF3, substituted or unsubstituted alkyl, substituted or unsubstitutezd heteroalkyl, substitutec or unsubstituted cycloalkyl, substituted or unsubstituted hetero cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein w is- an integer from 0 to 2;

   Z is N(R%), S, or O, wherein R? is hydrogen, substi tuted or unsubstituted alk=yl, or substituted or unsubstitutecd heteroalkyl;

   R’ is independentlsy hydrogen, -CFj, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, =substituted or unsubstituted cyclo alkyl, substituted or unsubstituted : heterocycloalkyl, substitute=d or unsubstituted aryl, or substimuted or unsubstituted heteeroaryl;

   R® and R” are independently hydrogen, -C(O)R'?, -S2(0),R"!, substituted or urasubstituted alkyl, substituted or unsubsstituted heteroalkyl, substituted om unsubstituted cycloalkyl_, substituted or unsubstituted heterocycloa lkyl, substituted or unsubstituted aryl, or substituted or uns=ubstituted heteroaryl;

   R® is independentlsy hydrogen, -NR'“R'®, -OR'®, sub stituted or unsubstituted amlkyl, substituted or unsubstituted heteroalky|, substituted or unsubstituted cycloalkyl, substituted or urmsubstituted heterocycloalkyl, substituteed or unsubstituted aryl, or substi=®uted or unsubstituted heteroaryl;

   R’ is independently hydrogen, -NR''R'®, substituted. or unsubstituted alkyl, si_1bstituted or unsubstituted heteroalkyl, =substituted or unsubstituted cyclo alkyl, substituted or unsubstituted heterocycloalkyl, substituteed or unsubstituted aryl, or substituted or unsubstituted het-eroaryl

   R'® and R"' are indlependently hydrogen, -NR'?R", substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsulbstituted cycloalkyl, subsaituted or unsubstituted heterocycloa_lkyl, substituted or unsubstituted aryl, or substituted or unssubstituted heteroaryl;

   223 Alain Saag

   R'? and R" are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or uns-ubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R'%, R'®, and R'® are independently hydrogen, substituted or unsubstituted a 1kyl, substituted or unsu bstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or 1 ansubstituted heteroc ycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted he=teroaryl; R'7 and R'® are independently hydrogen, substituted or unsubstituted alkyl, =substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unssubstituted heteroc ycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted hesteroaryl; or wherein R® and R”, R'? and R", R" and R"®, and R'” and R"® are independemtly joined with the nitreogen to which they are attached to form substituted or unsubstituted heterocwycloalkyl, or substitated or unsubstituted 5-membered heteroaryl.

   115. The compound of claim 114, wherein A! is substituted phen_yl.

   116. The compound of claim 115, wherein A' is substituted with a halogen.

   117. The compound of claim 114, wherein A' has formula II: (<9 "m, whereirm x is an integer from 1 to 5; R'? is independently halogen, -OR®, -N RR’, -C(Z)R®, -S(0).,R’, -CN, -NO—,, -CF;, substiti_1ted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substitutzed or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted «or unsubstituted aryl, or- substituted or unsubstituted heteroaryl, or wherein two R'? groups are combined to form a substituted or unsubstituted ring with the carbons to which they are attached. 224 Al NGTID SEH

   118. The commpound of claim 117, wherein an R'® attached at pos-ition 1 is combined with an R' attached. at position 2 to form a substitiated or unsubstituted ring.

   119. The commpound of claim 117, wherein an R'” attached at pos -ition 2 is combined with an R'® attached. at position 3 to form a substifiated or unsubstituted ring.

   120. The commpound of claim 117, wherein two R'® groups are co: mbined to form a substituted or unsubstituted rirmg with the carbons to which theey are attached, where in the substituted Or unsubstituted ring is substituted or unsubstituted heterocyc loalky! or substituted or unsubstituted heteroaryl.

   121. The compound of claim 117, wherein R'® is independently Imalogen, -NR°R, OR, or substituted or unsubsti tuted alkyl.

   122. The commpound of claim 117, wherein R3, R®, and R’ are ind- ependently hydrogen, substituted or unsubmstituted alkyl, substituted or urmsubstituted heteroalky=], substituted or unsubstituted cycloalkyl, substzituted or unsubstituted heteroc—ycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstirtuted heteroaryl, or wherein R® and R’ are joined witkn nitrogen to which they are attached to forrm substituted or unsubstituted Ineterocycloalkyl, or substituted or unsubstituted S-membered heteeroaryl.

   123. The compound of claim 121, wherein R®, R® and R’ are ind ependently Ihydrogen, or substituted or unsubstituted alkyl.

   124. The compound of claim 121, wherein R’, R%, and R” are independently hydrogen, or substituted or unsubstituted C,-Cy alkyl.

   125. The co—mpound of claim 117, wherein xis 1; and R'® is attac=hed at position 2.

   126. The co-mpound of claim 117, wherein xis 1; and R' is attaczhed at position 1.

   127. The co-mpound of claim 117, wherein x is an integer from 2 to §; and at least one R' is attached at position 1. 225 Brat SEY

   128. The compound of clairm 117, wherein x is an integer frcom 2 to 5; and at least one R'® iss attached at position 2.

   129. ‘The compound of clairm 1 14, wherein A? has formula WI. (rR) No! 2 RY VD, wherein y isan integer from O to 3; R'is independently halogen, -OR’®, -NNR®R’, -C(Z)R?, -S(O),R’, -CN, -NO,, -CF, substitute d or unsubstituted alkyl, substituted <r unsubstituted heteroalkyl, sub stituted or unsubstittated cycloalkyl, substituted or unsubstituted heterocycloalkyl, substitmited or unsubstituted aryl, or stabstituted or unsubstituted heteroaryl , or wherein one R% and R! are combined to form a substitute-d or unsubstituted ring with the carbons to which they are attached.

   130. The compound of clairm 129, wherein y is 1; and R** is attached at position 3'.

   131. The compound of clairm 114, wherein R' is -C(O)NR"_R".

   132. The compound of clairn 129, wherein R' is -C(O)NR'*_R".

   133. The compound of clairm 115, wherein R'is -C(O)NRMR",

   134. The compound of clairm 1 14, wherein R'is -C(O)NR"R"’; and R' and R"® are independently suabstituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or wherein R' and R'® are combined with the nitrogzen to which they are attached t-o form substituted or unsubstituted piperidinyl, or substituted or unsuabstituted piperazinyl, substitute=d or unsubstituted purrolidinyl, or substituted or unsubstituted morphmolino.

   135. The compound of clairm 134, wherein y is 0. 226 ARIND RL ERT

   136. The compound ©f claim 131, wherein R'* and R'®> are combined with the nitrogesn to which they are attached to feorm a piperazinyl substituted with a substituted or unsubsstituted alkyl or substituted or unsubstituted heteroalkyl.

   137. The compound «of claim 136, wherein the piperazinyl is substituted with -(CH;DNR*'R?, wherein tis an integer from 0 to 6 5 and R* and R* are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substitutecd or unsubstituted cycloalkyl, substituted or unsubstituted hetero cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or where in R?' and R* arc combined with. the nitrogen to which they are attached to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroary/1L.

   138. The compound «of claim 137, wherein R?' and R?? are combined with the nitrogeen to which they are attached to form a substituted or unsubstituted piperazinyl, substituted or unsubsstituted piperidinyl, or substitute or unsubstituted morpholino.

   139. The compound «of claim 137, wherein R*' and R?? are independently hydro sgen, substituted or unsubstituted =lkyl, or substituted or unsubstituted aminoalkyl.

   140. The compound of claim 137, wherein A' is substituted with at least one -OR’, where in R’ is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heterowalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubs tituted heterocycloalkyl, substituted or unsubstituted aryl, or sul>stituted or unsubstituted heteroary 1.

   141. The compound of claim 117, wherein A? has formula VI: (R29) N= 2 R! (VD, 227 ARIAT ar vy

   WNO 2006/015123 P*CT/US2005/026792 v=vherein y is an integer from 0 to 3; and R? is halogen, -OR’, -NR® R’, -C(Z)R?, -S(0).R’, -CN, -CF;, —NO,, substituted or Lansubstituted alkyl, substituted or unsubstituted heteroalkyl, substitute=d or unsubstituted cycloalky~l, ssubstituted or unsubstituted heterocycloalkyl, substituted or unsubstitumted aryl, or substituted or vansubstituted heteroaryl.

   142. The compo und of claim 141, wherein y is 1; arad R” is attached at position_ 3".

   143. A compound of any one of claims 1, 74 or 114 , substantially as herein described and exemplified.

   144. A method of claim 57 or 58, substantially as herein described and exemplified.

   145. A pharmaceutical composition of claim 73, sultostantially as herein describe=d and exemplified. 228 SRATINISSD yg ny