AU2012203026B2 - Novel heterocyclic compounds and uses thereof - Google Patents

Abstract

C.WRV'otbDCkii ta4S9- II)DC.22A)201 2 Al3STRACT New substituted heterocyclic compounds, compositions containing them, and methods of using them for the inhibition of Raf kinase activity are provided. The new compounds and compositions may he used either alone or in combination with at least one additional agent for the treatment of a Raf kinase mediated disorder, such as cancer.

Description

A ustralian Palnts A ct 1990 - Regulation 3.2A ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT Invention Title "Novel heterocyclic compounds an( LiSeS thereof" The following statement is a full description of this invention, including the best method of performing it known to me/us: C \NR ortbl\IDCC\RBRC'3-156 I DOC CAN~osbl\CC\ilRUMM .. DOC-mu'5lr I1 NOVEL HETEROCYCLIC COMPOUNDS AND USES THEREOF RELATED APPLICATIONS [0001] This application claims benefit of priority to U.S. Provisional Serial Number 61/038723, filed March 21, 2008, and U.S. Provisional Serial Number 61/208458, filed February 24, 2009, the contents of which are incorporated herein by reference in their entirety. This application is a divisional application of Australian Application No. 2009227013 the specification and drawings of which as originally filed are incorporated herein in their entirety by reference. FIELD OF THE INVENTION 100021 The present invention relates to new substituted heterocyclic compounds and pharmaceutically acceptable salts thereof, compositions of the new compounds together with phariimacetitically acceptable carriers, and uses of the new compounds, either alone or in combination with at least one additional therapeutic agent, in the prophylaxis or treatment of cancer and other disorders mediated by Raf kinase. BACKG ROUND OF TIE INVENTION 10003] The Raf scrine/threonine kinases are essential components of the Ras/Mitogen Activated Protein Kinase (MAPK) signaling module that controls a complex transcriptional program in response to external cellular stimuli. Raf genes code for highly conserved serine -threonine-specific protein kinases which are known to bind to the Ras oncogene. They are part of a signal transduction pathway believed to consist of receptor tyrosine kinases, p 2 1 Ras, Raf protein kinases, Mek kinases and ERK (MAPK) kinases, which ultimately phosphorylate transcription factors. In this pathway Raf kinases are activated by Ras and phosphorylate and activate two isoforms of Mitogen-Activated Protein Kinase (called Mekl and Mek2), that are dual specificity threonine/tyrosine kinases. Both Mek isoforms activate Mitogen Activated Kinases I and 2 (MAPK, also called Extracellular Ligand Regulated Kinase I and 2 or Erkl and Erk2). The MAPKs phosphorylate many substrates, including transcription factors, and in so doing set up their transcriptional program. Raf kinase participation in the Ras/MAPK pathway influences and regulates many ccl lular functions such as proliferation, differentiation, survival, oncogenic transformation and apoptosis. 100041 Both the essential role and the position of Raf in many signaling pathways have been demonstrated from studies using deregulated and dominant inhibitory Raf mutants in mammalian cells as well as from studies employing biochemical and genetic techniques to model organisms. In many cases, the activation of Raf by receptors that stimulate cellular tyrosine phosphorylation is dependent on the activity of Ras, indicating that Ras functions upstream of Raf. Upon activation, R afthen phosphorylates and activates Mck, resulting in the propagation of the signal to downstream effectors, such as MAPK (mitogcn-activated protein kinase) (Crews et al. (1993) Cel/ 74:215). 100051 Rafkinase has three distinct isoforms, Raf- I (c-Raf), a-Raf, and b-Raf, distinguished by their ability to interact with Ras, to activate MAPK kinase pathway, tissue distribution and sub-cellular localization (Marias ct. al., Biochem. J 351: 289-305, 2000; Weber et. al., Oncogene 19:169-176, 2000; Pritchard ct. al., Mo/. Cell. Biol. 15:6430-6442, 1995). 100061 Activating mutation of one of the Ras gecs can he seen in -20% ofall tumors and the R af/M EKIERK pathway is activated in ~30% ofall tumors (Bos cf. al., Cancer Re. 49:4682-4689, 1989) (Hoshino ct. al., Oncogene 18:813-822, 1999). Recent studies have shown that b-RaF mutation in the skin nevi is a critical step in the initiation of melanocytic neoplasia (Pollock ct. al., Nature Genetics 25: I -2, 2002). Furthermore, most recent studies indicate that activating mutation in thc kinase domain of b-Rafoccurs in -66% of melanomas, 12% of colon carcinoma and 14% of liver cancer (Davies et. al., Nature 417:949-954, 2002) (Yuen et. al., Cancer Research 62:6451 6455, 2002) (Brose et. al., Cancer Reseurch 62:6997-7000, 2002). [00071 Inhibitors of Raf7MEK/ERK pathway at the level of Rafkinases can potentially be effective as therapeutic agents against tumors with over-expressed an(/or mutated receptor tyrosine kinases. activated intracellular tyrosine kinases, tumors with aberrantly expressed Grb2 (al adapter protein that allows stimulation of Ras by the Sos cxchangc factor) as well as tumors harboring activating mutations of Ras or Raf. In the early clinical trials inhibitors of Ral I kinase that also inhibit b-Raf have shown promise as therapeutic agents in cancer therapy (Crump, Current Pharmaceutical Design 8: 2243-2248, 2002; Sebastien et. al., Current Pharmaceutical Design 8: 2249-2253, 2002). |0008i Disruption of Raf expression in cell lincs through the application of RNA antisense technology has bccn shown to suppress both Ras and Rafmcdiatcd tumorigenicity (Kolch ct al., Nature 349:416-428. 1991; Monia et al., Nature Medicine 2(6):668-675, 1996). 2 H:\rbr\lnienvoven\NRPortbl\DCC\RBR\6326308 LDOC-13/05/2014 [0009] Several Raf kinase inhibitors have been described as exhibiting efficacy in inhibiting tumor cell proliferation in vitro and/or in vivo assays (see, e.g., U.S. Pat. Nos. 6,391,636, 6,358,932, 6,037,136, 5,717,100, 6,458,813, 6,204,467, and 6,268,391). Other patents and patent applications suggest the use of Raf kinase inhibitors for treating leukemia (see, e.g., U.S. Patent Nos. 6,268,391, 6,204,467, 6,756,410, and 6,281,193; and abandoned U.S. Patent Application Nos. 20020137774 and 20010006975), or for treating breast cancer (see, e.g., U.S. Patent Nos. 6,358,932, 5,717,100, 6,458,813, 6,268,391, 6,204,467 and 6,911,446). SUMMARY OF THE INVENTION [0010] The present invention provides novel compounds and methods for their use, including methods of treating cancer and other conditions mediated by Raf kinase. [0011] In one aspect, the present invention provides a compound of Formula I, a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof: Rx R3 R2 Formula I wherein: X N tX R3 R3 R3 represents or X or Y, whichever is present, is selected from the group consisting of 0, and S; R1 is optionally substituted 2-pyrazinyl;

R

2 is optionally substituted heteroaryl, or optionally substituted heterocyclyl;

R

3 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl; and or a stereoisomer or pharmaceutically acceptable salt thereof. 3 These compounds are further described herein. [00121 In another aspect, the invention provides a compound of the following Formula (VI):

R

3 A R'' (VI) or a pharmaceutically acceptable salt thereof, wherein: one of A or 13 is N and the other ofA or 13 is NR 2 ; one of dashed lines ---- represent a single bond and the other represents a double bond, so the central ring is an imlidazol e; R' is sclecled from 1-, C - alkyl, cyclopropyl, phenyl, (4-OH)-phenyl, (4-CH 3 0)-phcnyl, (4-CF 3 0) plienyl, (4 -1)-plienyl, (4-a lkylsu lfonyl)piperazin- I -yl, and -O-(C-l 2 )1.,-N Ri 0 R.;

R

2 is selected from -1 and CI.2 alkyl; R is selected from: H N NN -~ N H C11 / S "'N O 'N NH,

NHCOCH

3 N , N ) H H F NH1 2 N- N N, N, 7- N 7 H I C11:, NH N NH 2 NI-I SN N 2 N 7 NH, NH 2

NHCOCH

3 7 N N N~ FCG N NH, HN F N NH' 2 N /N Ly L H OCH 3 Ci 14 alkyl N Nil 2 N NHI- 2 N OC I e. NN O-C,-, alkyl 01-i 'oNI-1 2 7 N NHF- C,. alIky 1N NH 2 pl 0)-(,., alkyl O-C, alkyl 5 N NH, N NH, N N O- klCF, - CONH, N -z C -L N NHCHj H CA (C:I N W' is SCICCtCd froml: N

OC

3 N H H NH H H N -. N ~CH 3 N N ~ N 0CH H 0 H "~L -N N"2' 0C NO NHR C aklH2 HH N N R1 N sal Ch oalkyl ""N N H IAN, N N R" Iz LN N R4 N (VII) wherein R', R 2 , RZ3, and R" are as defined for F'ormula (VI). [0014] In another aspect of the present invention are provided formulations comprising any of the compounds described heroin andi a pharniaceuticall y acceptable carrier. 100151 In certain embodiments ofthe pr-csent invention arc provided formulations comprising an effective amount of a compound of any one of the compounds described herein and a pharmaceutically acceptable carrier. [0016] In certain embodiments of the prcscnt invention arc provided formulations comprising any one of the compounds described herein admixed with at least one pharmaceutically acceptable excipicni. 7 100 171 In certain embodiments, the excipient is selected from the group consisting of corn starch, potato starch, tapioca starch, starch paste, pre-gelatinized starch, sugars, gelatin, natural gums, synthetic guns, sodium alginate, alginic acid, tragacanth, guar gum, cellulose, ethyl cellulose, cellulose acetate, carboxymcthyl ccllulosc calcium, sodium carboxymcthylccllulosc, methyl cellulose, hydroxypropyl mCthylcellulose, microcrystalline cellulose, magnesium aluminum silicate, polyvinyl pyrrolidone, talc, calcium carbonate, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, agar-agar, sodium carbonate, croscarrmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, clays, sod iumn sicaraIC, calcium stcarate, magncsium stearate, stearic acid, mineral oil, light mineral oil, glycerin. sorbitol, mannitol, polyethylene glycol, other glycols, sodium lriiyl sulfite, hydrogenated vegetable oil, licaILit oil. cotOtatscCd oil, sunflower oil, sesame oil, olive oil, corn oil, soyhcan oil, zinc stcarate, socliuam olcate, cthyl olcatc, ethyl laureate, silica, and combinations thereof. 10018 In certain embodiments of the present invention are provided formulations described herein which further comprise at least one additional agent for the treatment or prevention of cancer. In some variations, the additional therapeutic agent is selected from an anticancer compound, an analgesic, an antiemetic, an antidepressant, an anti-intlammatory agent, a different Rat kinase inhibitor, an inhibitor of MEK, mTOR, Pl3K, CDK9, PAK, Protein Kinasc C, a MAP kinase, a MAPK Kinase, ER.K, irinotccan, topotecan. gemcitabine, 5-fluorouracil, Icucovorin, carboplatin, cisplatin, oxaliplatin, taxanes, tezacitabine, cyclophosphamidce, vinca alkaloids, imatinib, an th racycl ines, rituximab and trastuzumab. |0019] In another aspect ofthe present invention methods are provided to treat cancer, comprising adm inisitring to a subject in need of such ireatimeni an effective amount ofany one of the compounds or pharmaceutical compositions described herein. In certain embodiments of the present invention, the cancer is selected from the group consisting of lung carcinoma, pancreatic carcinoma, bladder carcinoma, colon carcinoma, amyeloid disorders. prositic cancer, thyroid cancer, melainoia, and adenomas. 100201) In certain embodiments of the present invention, the methods described herein further comprise administering to the individual at least one additional agent for the treatment or prevention of cancer. In some variations, the additional agent is selected from an anticancer compound, an 8 analgesic, an antienetic, an antidepressant, an anti-inflammatory agent, a different Raf kinase inhibitor, an inhibitor of MEK, nTOR, P13K, CDK9, PAK, Protein Kinase C, a MAP kinase, a MA PK Kinase, ERK, irinotecan, topotcean, gemcitabine, 5-fluorouracil. leucovorin, carboplatin, cisplatin, oxaliplatin, taxancs, tczacitabinc, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab, and trastuzumab. [0021] In certain embodiments of the present invention, the additional therapeutic agent is administered to the subject concurrently with the compound. 10022| In another aspect ofthe present invention are provided methods flbr the treatment or picve ntion of a condition mediated by Rafkinase, comprising administering to a subject in need thereof an effective amount of any o fthe compounds or pharmaceutical compositions described herein. In some variations, the Raf kinase is a mutant b-Raf kinase. [00231 In another aspect of the present invention is any one of the compounds described herein for usc as a predicament, or for the manufacturc ofa medicament, or use ofa compound as described here in as a medicament for treating cancer. 10024J In another aspect of the present invention is the use of one or more of any one of the compounds described herein for the manIIfiheture of a medicament for the treatment or prevention of a condition characterized by Raf kinase activity. In some variations, the condition is cancer. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS Abbrevialions and De|ini/ions 100251 Where linking groups are specified by thcir conventional chemical formula herein, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to leil, e.g., -CH 2 0- is intended to include -OC-1 2 - for this purpose only. 100261 As used herein, "hydrocarbyl" refers to a rcsiCdue which contains only carbon and hydrogen, unIless otherwise described as 'substituted'. The residue may be aliphatic or aromatic, straight-chain, Cyclic, branched, saturated or unsaturated, or any combination of these. The hydrocarbyl residue, 9 when so described, however, may contain heteroatoms in addition to or instead of the carbon and hydrogen members of the hydrocarbyl group itself. Thus, when specifically noted as containing heteroatois the hydrocarbyl group may contain heteroatoms within the "backbone" of the hydrocarbyl residue, and whcn optionally substituted, the hydrocarbyl rcsiduc may also have one or more carbonyl groups, amino groups, hydroxyl groups and the like in place of one or more hydrogens of the parent hydrocarbyl residue. 100271 The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a fully saturated straight-chain (linear; unbranched) or branched chain, or combination thereof, having the number of carbon atoms specified, if designated (i.e. C-C lo rneans one to ten carbons). Examples include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n octyl, and the like. If no size is designated, the alkyl groups nmCntioned herein contain 1 -10 carbon atoms, typically 1 -8 carbon atoms, and often 1-6 or I - carbon alois. 100281 The term "alkenyl" refers to unsaturated aliphatic groups including straight-chain (linear; unbranchecd), branched-chain groups, and combinations thereof, having the number of carbon atoms speciled, if designated, which contain at least one double bond (-C=C-). All double bonds may be independently either (E) or (Z) geometry, as well as mixtures thereof Examples of alkenyl groups include, but are not limited to, -C-1 2 -CH =Cf--C-13; -CH=CH-CI-l=CH 2 and -C-1C--1=CH;l-CH-I(C-H 3

)-CH-CH

3 . if no size is specified, the ulkenyl groups discussed herein contain 2-6 carbon atoms. 100291 The term "alkynyl" refers to unsaturated aliphatic groups including straight-chain (linear; unbranched), branched-chain groups, and combinations thereof, having the number of carbon atoms specified, if designated, which contain at least one carbon-carbon triple bond (-CEC-). Examples of alkynyl groups include, but arc not limited to, -CH-C C-Ca-11; -C=C-C=l-H and -Clr-CEC-CHl(CH 3 )-ClC-1 3 . If no size is specified, the alkynyl groups discussed herein contain 2-6 carbon atoms. [00301 Alkynyl and alkenyl groups can contain more than oC unsalurated bond, or a mixture of double and triple bonds, and can be otherwise substituted as dcscribcd for alkyl groups. 10 [00311 The tcrms "alkoxy,". "alkenyloxy," and "alkynyloxy" refer to -0-alkyl, -0-alkenyl, and -O-alkynyl, respectively. [00321 The term "cycloalkyl" by itself or in combination with other terms, represents, unless otherwise stated, cyclic versions of alkyl, alkenyl, or alkynyl, or mixtures thereof. Additionally, cycloalkyl may contain fused rings, but excludes fused aryl and heteroaryl groups, and cycloalkyl groups can be substituted unless specifically described as unsubstituted. Examples ofcycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, I -cyclohexentyl, 3 cyclohexenyl, cycloheptyl, norbornyl, and the like. If no ring size is specified, the cycloalkyl groups described herein contain 3-8 ring members, or 3-6 ring members. 100331 As used herein "1oweralkyl" incliudes both substituted or unsubstituted straight or branched chain alkyl groups having from Il to 6 carbon atoms. Representative loweralkyl groups include, for example, iethyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopenrtyl, trifluoromethyl, pentafluorocthyl and the like. Loweralkyl groups may be substituted, such as with halo, hydroxy, amino, nitro and/or cyano groups, and the like. Representative of halo-substituted and hydroxy substituted loweralkyl include chloromethyl, trichloromethyl, ehloroethyl, hydroxyethyl, and the like. Other suitable substituted loweralkyl moieties include, for example, aralkyl, aninoalkyl, arminoaralkyl, carbonylaminoalkyl, alkylearbonylaminoalkyl, arylearbonylaminoalkyl, atraIlkylcarbonylaminoai lkyl, aminoalkoxyalkyl and arylarninoalkyl. 100341 The term "heterocyclic" or "heterocyclyl," by itselfor in combination with other terms, represents a cycloalkyl radical containing at least one annular carbon atom and a! least one annular heteroatom selected from the group consisting ofO, N, P, Si and S, preferably from N. 0 and S, wherein the ring is not aromatic bot can contain unsaturations. The nitrogen and sulfur atoms in a heterocyclic group nay optionally be oxidized and the nitrogen heteroatom may optionally be qIatern iz.ed. In many embod inents, the ainnular heteroiatoms arc selected From N, 0 and S. The heterocyclie groups discussed herein, if not otherwise specified, contain 3-10 ring members, and at least one ring member is a heleroatom selected from N, 0 and S; commonly not more than three of these heteroatoms are included in a heterocyclic group, and generally not more than two of these heteroatoms are present in a single ring olthe heterocyclic group. The heterocyclic group can be fused to an additional carboclic, heterocyclic, or aryl ring. A heterocyclic group can be attached to il the reminder of the molecule at an annular carbon or annular hctcroatom, and the heterocyclic groups can bc substituted as described for alkyl groups. Additionally, heterocyclic may contain fused rings, but excludes fuscd systems containing a heteroaryl group as part of the fused ring system. Examples of heterocyclic groups include, but arc not limited to, 1-(I 2,5,6-tctrahydropyridyl), I piperidinyl. 2-piperidinyl, 3-piperidinyl, 4-inorpholinyl, 3-morpholinyl, tctrahydrofuran-2-yl, 1,2,3,4-tetrahydropyridyl, dihydroindole (indoline), tetrahydrofiuran-3-yl, tetrahydrothien-2-yl, tctrahydrolhicii-3-yl, I -piperazinyl, 2-pipcrazinyl, and the like. [00351 As with other moieties described herein, heterocycloalkyl moietics can he unsubstituted, or substituted with various substituents known in the art, e.g., hydroxy, halo, oxo (C=0), alkylimino (RN=, wherein R is a loweralkyl or loweralkoxy group), amino, alkylamino, dialkylamino, acylarninoalkyl, alkoxy, thioalkoxy, polyalkoxy, loweralkyl, cycloalkyl or haloalkyl. Non-limiting examples of substituted heterocycloalkyl groups include the following, where each moicty may be attached to the parent molecule at any available valence: 0 0 N N ON N O N N NO N ON 0 N 0)N -- 0 -L 0 N 0 o N N NH No N O N <oN.< N N-1 NH L ,0 -- '0 a b OH 0 H N) N N N l <N 0 S and . Also included within heterocyclic arc piperidine, morpholine, thiomorpholine, piperazine, pyrrolidine, tetrahydrofuran, oxetane, oxepane, oxiranc, tetrahydrothiofuran, thiepane, thiiranc, and optionally substituted versions ofeach of these. [00361 The terms "cycloalkyloxy" and "heterocycloalkyloxy" refer to -0-cycloalkyl and -0-heterocycloalkyl groups, respectively (e.g., cyclopropoxy, 2-piperidinyloxy, and the like). 12 100371 The terms "cyclylalkyl" and "heterocyclylalkyl" designate an alkyl-substituted cycloalkyl group and alkyl-substituted heterocycloalkyl, respectively, where the alkyl moiety is attached to the parent structure. Non-limiting examples include cyclopropyl-ethyl, cyclobutyl-propyl, cyclopeltyl hexyl, cyclohexyl-isopropyl, I -cyclohcxenyl-)ropyl, 3-cyc lohcxcnyl-t-butyl, cycloheptyl-heptyl, norbornyl-inethyl, I -piperidinyl-ethyl, 4-morpholinyl-propyl, 3-morpholinyl-t-butyl, tetrahydrofuran-2-yl-hexyl, tetrahydrofbran-3-yl-isopropyl, and the like. Cyclylalkyl and helircyclylalkyl also include substituents in which at least onc carbon atom is present in the alkyl group and wherein another carbon atom of the alkyl group has been replaced by, for example, an oxygen, nitrogen or sulfur atom (e.g., cyclopropoxymethyl, 2-piperidinyloxy-t-butyl, and the like). [00381 The term "aryl" means, unless otherwise stated, an aromatic hydrocarbon group which can be a single ring or rnultiple rings (e.g., from I to 3 rings) which are fused together. Aryl may contain fused rings, wherein one or more of the rings is optionally cycloalkyl, but not including heterocyclic or heleroaromatic rings, a fused system containing at least one heteroaromatic ring is described as a heteroaryl gro up, and a phenyl ring fused to a heterocyclic ring is described herein as a hetcrocycleic group. Exminplcs of aryl groups include, but are not limited to, phenyl, I -naphthyl, 2-naphthyl, tetrahydronaphthyl and the like. [00391 The term "heteroaryl" as used herein refers to groups comprising a single ring or two or three fused rings, where at least one ofthe rings is an aromatic ring that contain from one to four heteroatoms selected from N, 0, and S as ring members (i.e., it contains ut least one heteroaromtuic ring), wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A hctemaryl group can be attached to the remainder of the molecule through an annular carbon or annular heteroatom, and it can be attached through any ring of the heteroaryl moiety, if that moiety is bicyclic or tricyclic. Heteroaryl may contain fused rings, wherein one or more ofthc rings is optionally cycloalkyl or heterocycloalkyl or aryl, provided at Icast one of the I ings is a hucteroaromnatic ring. Non-limiting examples of iet croaryl groups are I -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4 oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2 furyl, 3- furyl, 2-thienyl, 3-thicnyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5 benzothiazolyl, purinyl, 2-benzittidazolyl, 5-indolyl, I -isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5 13 quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aiyl and hcteroaryl ring systems are selected from the group of acceptable substituents described below. 100401 Aryl or hetcroaryl groups commonly contain up to four substituents per ring (0-4), and sometimes contain 0-3 or 0-2 substituents. The terms "aryloxy" and "heteroaryloxy" refer to aryl and heteroaryl groups, respectively, attached to the remainder of the molecule via an oxygen linker (-0-). 1004 11 The term "arylalkyl" or :"aralkyl" designates an alkyl-linked aryl group, where the alkyl portion i is attached to the parent structure and the aryl is attached to the alkyl portion of the arylalkyl noicty. Examples arc benzyl, phonet hyl, and the like. "ecteroarylalkyl" or "hetcroaralkyl" d esignates a heteroaryl moiety antached to the parent stm eture via an alkyl residue. Examples Include fIuranyl methyl, pyridinylnIet hyl, pyrimidinylcthyl, and the like. Aralkyl and heteroaralkyl also include substituents in which at least one carbon atorn of the alkyl group is present in the alk-yl group and wherein another carbon of the alkyl group has been replaced by, for example, an oxygen atom (e.g., phenoxyniethyl, 2-pyridylniethoxy, 3-(I -naphthyloxy)propyl, and the like). 100421 The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl," are meant to include monohaloalkyl and perhaloalkyl. For example, the terrn "halo(Ci CI)alkyl" is meant to include, but not be limited to, trifluorornethyl, 2,2,2-trifluorocthyl, 4 chlorobutyl, 3-bronopropyl, and the like. The prefix "perhalo" refers to the respective group wherein all available valences are replaced by halo groups. For example "perhaloalkyl" includes -CCU, -CF3, -CCI 2

CF

3 , and the like. The terms "perfluoroalkyl" and "perchloroalkyl"are a subsets of perhaloalkyl wherein all available valences are replaced by fluoro and chloro groups, respectively. Non limiting examples of perfluoroalkyl include -CF 3 and -CF 2 CF3. Non limiting examples of perchloroalkyl include -CC 3 and -CC1 2 CCh. 10043) "Amino" refers herein to the group -NI-I 2 or -NRR', where R and R' are cach independently selected from hydrogen or an alkyl (e.g, lower alkyl). The term "arylamnino" refers herein to the group -NR R' where R is aryl and R' is hydrogen, alkyl, or an alyl. The term "aralkylanino" refers herein to the group -NR R' where R is an aralkyl and R' is hydrogen, an alkyl, an aryl, or an aralkyl. 14 "Substituted amino" refers to an amino wherein at least one of R and R' is not H, i.e., the amino has at least one substituent group on it. 100441 The term "alkoxyaLkyl" refers to the group -alk-O-alk 2 where alki is alkyl or alkcnyl, and alk2 is alkyl or alkenyl. The term "lowcralkoxyalkyl" refers to an alkoxyalkyl where alki is loweralkyl or loweralkenyl, and alk 2 is loweralkyl or loweralkenyl. The term "aryloxyalkyl" refers to the group -alkyl-0-aryl. The term "aralkoxyalkyl" refers to the group -alkyl-O-aralkyl. 100451 The term "alkoxyalkylamino" refers herein to the group -NR-(alkoxyalkyl), where R is hydrogen, aralkyl, or alkyl. 100461 The term "aminocarbonyl" refers herein to the group -C(0)-NH2 , i.e., it is attached to the base structure through the caibonyl carbon atom. "Substituted aminocarbonyl" refers herein to the group -C(O)-NRR' where R is alkyl and R' is hydrogen or an alkyl. The term "arylaminocarbonyl" refers herein to the group -C(O)-NRR' where R is an aryl and R' is hydrogen, alkyl or aryl. "Aralkylaminocarbony]" refers herein to the group -C(O)-NRR' where R is aralkyl and R' is hydrogen, alkyl, aryl, or aralkyl. 100471 "Aminosulfonyl" refers herein to the group -S(0) 2 -NHl12. "Substituted arninosulfonyl" refers herein to the group -S(0) 2 -NRR' where R is alkyl and R' is hydrogen or an alkyl. The term "uraIlkyl a miiosuli fonlyaryl" refers herein to the group -aryl-S(O) 2 -N-l-aralkyl. 100481 "Carbonyl" refers to the divalent group -C(O)-. 100491 "Carbonyloxy" refers generally to the group -C(0)-0-. Examples in include, -C(O)-O-R where R is H. alkyl, cycloalkyl, aryl, or aralkyl. The term "carbonyloxycycloalkyl" refers generally herein to both a "carbonyloxycarbocycloalkyl" and a "carbonyloxyheterocycloalkyl", i.e., where R is a carbocycloalkyl or heteroeycloalkyl, respectively. The term "arylcarbonyloxy" refers herein to the group -C(O)-O-aryl, where aryl is a mono- or polycyclic, carbocycloaryl or heterocycloaryl. The term "aralkylcarbonyloxy" refers herein to the group -C(O)-O-aralkyl. 100501 The term "sulfonyl" refers herein to the group-S02-. "Alkylsulfonyl" refers to a substituted sulfonyl ofthe structure -SO 2 R in which R is alkyl. Alkylsulfonyl groups employed in compounds of the present invention are typically loweralkylsulfonyl groups having from I to 6 carbon atoms in R. Thus, exemplary alkylsulfonyl groups employed in compounds of the present invention include, 15 for example, mcihylsul fonyl (i.e., where R is methyl), ethylsul fonyl (i.e., whcrc R is ethyl), propylsul fonyl (i.e., where R is propyl), and the like. The term "arylsulfonyl" refers herein to the group -S0 2 -ary). The nerm "aralkylsul fonyI" refers hCrCin to the group -S0 2 -aralkyl. The term "sul fonarnido" refers herein to -SO2NH 2 , or to -SO 2 NRR' if substituted. l00511 As used herein, the term "carbonylamino" refers to the divalent group -NIH -C(O)- in which the hydrogen atom of the amide nitrogen of the carbonylamino group can be replaced by an alkyl, aryl, or aralkyl group. Such groups include moieties such as carbamate asters (-NH-C(0)-0-R) and amides -NH-C(O)R, where R is a straight or branched chain aLkyl, cycloalkyl, or aryl or loweraralkyl. The term "lowerilkylcarbonylamino" refers to alkylcarbonyl-amino where R is a loweralkyl having from I to about 6 carbon atoms in its backbone stricture. The term "arylcarbonylamino" refers to group -NH-C(O)-R where R is an aryl. Similarly, the terin "aralkylcaibonylimino " refers to carbonylamino where R is an aralkyl. As used herein, the term "aminocarbonyl" refers to the divalent group -C(O)-NHII- in which the hydrogen atom of the amide nitrogen of the carbonylamino group can be replaced by an alkyl, aryl, or aralkyl group, as described above. 100521 As used herein, the term "guanidino" or "guanidyl" refers to moieties derived from guanidine, H2N-C(=NH)-NH-I 2 . Such moietics include those bonded at the nitrogen atom carrying the formal double bond (the '2"-position of the guanidine, e.g., diaminomethyleneani ino, (l1 2

N)

2 C-NlH-) und those bonded it either of the nitrogen atoms carrying a formal single bond (the "I -" and/or "3"-positions of the guanidine, e.g., lH 2 N-C(=Nl)-NH-). The hydrogen atoms at any of the nitrogens can be replaced with a suitable substituent, such as loweralkyl, aryl, or loweraralkyl. 100531 As used herein, the term "amidino" refers to the moieties R-C(=N)-NR'- (the radical being at the "N'" nitrogen) and R(NR')C=N- (the radical being at the "N 2 " nitrogen), where R and R' can be hydrogen, alkyl, aryl, or aralkyl. 100541 Unless otherwise stated, each radical/moiety described herein (e.g., "alkyl," "cycloalkyl," "hctcrocycloal.kyl," "aryl," "heteroaryl," "alkoxy," etc.) is meant to include both substituted and unsubstituted forms. 16 100551 "Optionally substituted" as used herein indicates that the particular group or groups being described may have no non-hydrogen substituenLs (i.e., it can be unsubstituted), or the group or groups may have one or morc non-hydrogen substituents. If not otherwise specified, the total nuinbcr of'such substitucnts that may be present is equal to the number of H atoms present on the unsubstituted form of the group being described. Typically, a group will contain up to three (0-3) substituents. Where an optional substituent is attached via a double bond, such as a carbonyl oxygen (-O), the group takes up two available valences on the group being substituted, so the total number of substituents that may be included is reduced according to the number of available valences. Suitable substituent groups include, for example, hydroxyl. nitro, amino, imino, cyano, halo, thio, sulfolyl, thiomnido, amidinmo, inidino, oxo, oxumidino, methoxamidino, imidino, guanidino, sulfonamido, carboxyl, formyl, loweralkyl, loweralkoxy, loweralkoxyalkyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, aralkylcarbonyl, carbonylamino, hctcroarylcarbonyl, hctcroaralkyl carbonyl, alkylthio, aminoalkyl, cyanoalkyl, aryl and the like. Deutcrium, when introduced into a compound at levels at least 5x above natural abundance, can also be considered a substituent For purposes of describing the compounds herein. Note that because deuterium is an isotope of hydrogen that does not substantially change the shape of the molecule, deuterium is exempt from the typical numerical limitations placed on numbers of'substituents: deuterium (D) can be included in place of hydrogen (-1) in addition to other substituents and should not be counted in the numerical limitations that apply to other substituents. 100561 A substituent group can itself bc substituted by the same groups described herein for the corresponding type ofstructure. The group substituted onto the substituted group can be carboxyl, halo, nitro, amino, cyano, hydroxyl, lowcralkyl, loweralkenyl, lowcralkynyl, loweralkoxy, aminocarbonyl, -SR, thioamido, -SO3-, -SO2R or cycloalkyl, were R is typically hydrogen or loweralkyl. 100571 When the substituted substituent includes a straight chain group, the substituent can occur either within the chain (e.g., 2-hydroxypropyl. 2-amino btyl, and the like) or at the chain terminus (e.g., 2-hydroxycthyl, 3-cyanopropyl, and the like). Substituted substituents can be straight chain, branched or cyclic arrangements of covalently bonded carbon or heteroatoms (N, 0 or S). 17 100581 Alkyl, alkenyl and alkynyl groups are oflen substituted to the extent that such substitution makes sense chemically. Typical substituerits include, but are not limited to, halo, D, =0, =N-CN, =N-OR, =NR, OR, NR 2 , SR, SO2R, S02NR:>, NRSO 2 R, NRCONR 2 , NRCOOR, NRCOR, CN, COOR, CONIZ, OOCR, COR, and NO,,, wherein each R is independently 1-1, Cl-C8 alkyl, C2-C8 heteroalkyl, Cl-C8 acyl, C2-C8 heteroacyl, C2-C8 alkcnyl. C2-C8 hCtcroalkenyl, C2-C8 alkynyl, C2-C8 hcteroalkynyl, C6-CI0 aryl, or C5-Cl0 hetcroaryl. and each R is optionally substituted with halo, =0, =N-CN, =N-OR', =NR', OR', NR'2, SR', SO 2 R', SO 2

NR'

2 , NR'SO 2 R'. NR'CONR' 2 , NR'COOR', NR'COR', CN, COOR', CONR' 2 , OCR', COR', and NO 2 , wherein cach R' is independently H, D, Cl -C8 alkyl, C2-C8 heteroalkyl, Cl -C8 acyl, C2-C8 hiteroacyl, C6-CI10 aryl or C5-CI0 hicroaryl. Alkyl, alkenyl and alkynyl groups can also be substitutCd by Cl-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl or C5-CI0 heteroaryl, each of which can be substituted by the substituents that are appropriate for the particular group. 100591 While "alkyl" as used herein includes cycloalkyl and cycloalkylalkyl groups, the term "cycloalkyl" may be used herein to describe a carbocyclic non-aronatic group that is connected via a ring carbon atom, and "cycloalkylalkyl" may be used to describe a carbocyclic non-aromatic group that is connected to the molecule through an alkyl linker. Similarly, "heterocyclyl" may be used to describe a non-aromatic cyclic group that contains at least one heteroatom as a ring tnember and that is connected to the molecule via a ring atom, which may be C or N; and "hetcrocyclylalkyl" may be used to describe such a group that is connected to another molecule through a linker. The sizes and substi tents that arc suitable for tIhe cycloalkyl, cycloalkylalkyl, tbeteiueyclyl, and icterocyclylalkyl groups are the saic as those described above for alkyl groups. As used herein, these terms also include rings that contain a double bond or two, as long as lhe ring is not aromatic. 100601 "Hletcroalkyl", "heteroalkenyl" and "hctcroalkynyl", like other 'heteroforms' of groups described herein, as used herein, refer to an alkyl, alkenyl or alkynyl group wherein at least one carbon of the alkyl, alkenyl or alkynyl has been replaced by a heteroatom selected from 0, S and N. Typically only one, or 1-2 heteroatoms are incorporated into these groups in place of carbon atoms. [0061] Aryl and heteroaryl moieties may be substituted with a variety of substituents including Cl C8 alkyl. C2-C8 ulkenyl, C2-C8 alkynyl, C5-Cl2 aryl, Cl-C8 acyt, and heteroforms of these, coach of which can itself be further substituted. Other substitruents for aryl and heteroaryl moieties include 18 halo, 1), OR, NR2, SR, SO 2 R, SO 2

NR

2 , NRSO 2 R, NRCONR 2 , NRCOOR, NRCOR, CN, COOR,

CONR

2 , OOCR, COR, and N0 2 , wherein each R is independently H, ), Cl-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C6-CI0 aryl, C5-C10 heteroaryl, C7-Cl2 arylalkyl, or C6-C12 heteroarylalkyl, and cach R is optionally substituted as desciibed above for alkyl groups. The substituent groups on an aryl or hetcroaryl group nay of course be further substituted with the groups described herein as suitable for each type of such substituents or for each component of the substituent. Thus, for example, an arylalkyl substituent may be stibstituted on the aryl portion with substituenits described herein as typical for aryl groups, and it may be further substituted on the alkyl portion with substituents described herein aIs typical or suitable for alkyl groups. 100621 In gencral, any alkyl, alkenyl, alkynyl, acyl, or aryl or arylalkyl group, or any hctcro form thereof, that is contained in a substituent may itself optionally be substituted by additional substituents. The naturc of these substituents is similar to those recited with regard to the primary substituents themselves if the substituents are not otherwise described. Thus, where an embodiment of, for example, R' is alkyl, this alkyl may optionally be substituted by the remaining substituents listed ais embodiments for R' where this makes chemical sense, and where this does not undermine the size limit provided for the alkyl per se; e.g., alkyl substituted by alkyl or by alkenyl would simply extend the upper limit of carbon atoms for these embodiments, and is not included. However, alkyl substituted by aryl, amino, alkoxy, =0, and the like would be included within the scope of the invention, and the atoms of these substituent groups are not counted in the number used to describe the alkyl, alkenyl, etc. group that is being described. Where no number of substituents is specified, each such alkyl, alkenyl, alkynyl, acyl, or aryl group may be substituted with a number of substituents according to its available valences; in particular, any of these groups may be substituted with fluorine atoms at any or all of its available valences, for example. [00631 As used herein, "isomer" includes all sbercoisomers of the compounds referred to in the formulas herein, including enantiomers, diastercomers, as well as all conformers, rotamers. and tautomers, unless otherwise indicated. The invention includes all enantioners of any chiral compound disclosed, in either substantially pure levorotatory or dextrorotatory form, or in a race ic mixture, or in any ratio of enantioners For compounds disclosed as an (R)-enantiorner, the 19 invention also includes the (S)-cnantiomer; for compounds disclosed as the (S)-enantiomer, the invention also includes the (R)-enantiomer. The invention includes any diastercomers of the compounds referred to in the above formulas in diastercomerically pure form and in the form of mixtures in all ratiOs. 100641 Unless stereochcniistry is explicitly indicated in a chemical structure or chemical name, the chemical structure or chemical name is intended to embrace all possible stercoisomers, conformers, rotamers, and tautomers of the compound depicted. For example, a compound containing a chiral carbon atorn is intended to embrace both the (R) enantiomer and the (S) enantiomer, as well as mixtures of enantiomers, including racenic mixtures; and a compound containing two chiral carbons is intendcleid to embrace all enantioniers and diasterconers (including (R,?), (S,S), (R,S), and (R,S) isomers). [00651 In all uses of the compounds ofthe formulas disclosed herein, the invention also includes use of any or all of the stercochemical, cnantiomcric, diastercomcric, conformational, rotomeric, tautomeric, solvatc, hydrate, polymorphic, crystalline form, non-crystalline form, salt, pharmaceutically acceptable salt, metabolite and prodrug variations of the compounds as described. 100661 "Protecting group" refers to a chemical group that exhibits the following characteristics: I) is stable to the projected reactions for which protection is desired; 2) is removable from the )rotected substrate to yield the desired functionality; and 3) is removable by reagents compatible with the other functional groups) present or generated in such projected reactions. Selection of suitable protecting groups for use in the methods described heroin is within the ordinary skill level in the art. F.xamples oF suitable protecting groups can be found in Greene et al. (1991) PROTECTIVE GOoUSt' IN ORGANIC SYNTHESIS, 3rd Ed. (.lohn Wiley &. Sons, Inc., New York). Amino protecting groups include, but arc not limited to, mcsitylenesulfonyl (Mts), benzyloxycarbonyl (CBz or Z), t butyloxycarbonyl (13oc), t-butyldinethylsilyl (TBS or TBDMS), 9-filuorenylhneth yloxycarbonyl (Fnioc), tosyl, benzenesulfonyl, 2-pyridyl sullfonyl, or suitable photolabile protecting groups such as 6-nitroveratryloxy carbonyl (Nvoc), nitropiperony 1, pyrenyl methoxycarbonyl, nitrobenzy, r1,a di methyl-dim ethoxybenzyloxycarbonyl (DDZ), 5-broro-7-ni troindoliinyl, and the like. Hydroxyl proiccting groups include, but are not limited to, Fmoc, TMS, TBS, T31)PS, TES, acetyl, bcnzoyl, photolabile protecting groups (such as nitroveratryl oxymethyl ether (Nvom)), SEM, MOM 20 (methoxy ncthyl ether), and M EM (methoxyethoxymethyl ether), NPEOC (4 nitrophencthyloxycarbonyl) and NPEOM (4-nitrophenethyloxymcthyloxycarbonyl). 100671 As used herein, the term "carboxy-protecting group" refei- to a carbonyl group which has been esterified with one of the commonly used carboxylic acid protecting ester groups employed to block or protect the carboxylic acid function while reactions involving other functional sites of the compound are carried out. In addition, a carboxy protecting group can be attached to a solid support whereby the compound remains connected to the solid support as the caiboxylate until cleaved by hydrolytic methods to release the corresponding free acid. Representative carboxy-protecting groups include, for example, loweralkyl esters, secondary aides and the like. 100681 Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms (i.e., solvates). Compounds of the invention may also include hydrated forms (i.e., hydrates). In general, the solvated and hydrated forms are equivalent to unsolvated forms For purposes of biological utility and are encompassed within the scopc of the present invention. The invention also includes all polymoiphs, including crystalline and non-crystallinc forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within thc scope of the present invention. 100691 The invention includes all salts of the compounds described herein, as well as methods of using such salts of the compounds. The invention also includes all non-salt forms of any salt of a compound named herein, as well as other salts of any salt of a compound named herein. In one embodiment, the salts of the compounds comprise pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" are those salts which retain the biological activity of the free compounds and which can be administered as drugs or pharmaceuticals to humans and/or animals. Thc desired sali of a basic functional group of a compound may be prepared by methods known to those of skill in the art by treating the compound with an acid. Examples of inorganic acids include, but are not limited to, hydrochloric acid, hydmbromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids include, but are not limited to, formic acid, aectic acid, propionic acid, glycolic acid, hippuric, pyruvic acid, oxalic acid, malcic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, rnandelic acid, sulfonic acids, and Naicylice acid. The desired salt of an acidic Functional group of a compoLund ean be prepared by 21 methods known to those of skill in the art by treating the compound with a base. Examples of inorganic salts of acid compounds include, but are not limited to, alkali metal and alkaline earth salts, such as sodium salts, potassium salts, magnesium salts, and calcium salts; ammonium salts; and aluminum salts. ExampIcs of organic salts of acid compounds include, but arc not limited to, procaine, dibcnzylamine, N-ethylpiperidine, N,N'-dibenzylethylenediamnine, and triethylamine salts. 100701 Pharmaceutically acceptable metabolites and prodrugs of the compounds referred to in the formulas herein are also embraced by the invention. The term pharmaceuticallyy acceptable prodrngs" as used herein refers to those prodrugs of the compounds of the present invention which arc, within the scope ofsound medical judgment, suitable for use in contact with the tissues of inmains and lower aniimals without undue toxicity, irritation, allergic response, and the like, commenUcsurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "prodrug" refeus to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for cx ample by hydrolysis in blood. A thorough discussion is provided in T. I-iguchi and V. Stella, PRO-DRuGs As Novrm.i DntVERtY SYsTims, Vol. 14 of thc A.C.S. Symposium Series, and in Edward 13. Roche, ed., B3ORiVORStLt CARRtRS IN DRL(i N, Ainerican Pharmaceticl Association aind Pergamlion Press, 1987 100711 Pharmaceutically acceptable esters of the compounds referred to in the formulas herein are also embraced by the invention. As used herein, the term "phirmaceutically acceptable ester" refers to esters, which hydrolyze in vivo and include those that break down readily in the hinman body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include forrnates, acetates, propionates, butyrates, acrylates and ethylsuccinates. 100721 The invention further provides deuterated versions of the above-dcscribcd compounds. As used hierCin, "mmdeuterated version" refers to a compound in which at least one hydrogen atom is en richcd in the isotope denuteruin beyond the natural rate of deuteriun occurrence. Typically, the hydrogen atom; is enriched to he at lcast 50% deuterium, li-cquently at Icast 75% deuterium, and 22 preferably at least about 90% deuteriu m. Optionally, more than one hydrogen atom can be replaced by deuterium. For example, a methyl group can be dculerated by replacement of one hydrogen with deuterium (i.e., it can be -C1 2 D), or i1 can have all three hydrogen atoms replaced with dcuteri um (i.c., it can bc -- CD 3 ). In cach case, ) signifies that at Icast 50% of the corresponding -1 is present as deuteri ul. [00731 A substantially pure compound means that the compound is present with no more than 15% or no more than 10% or no more than 5% or no morc than 3% or no more than P% of the total amount of compound as impurity and/or in a different form. For instance, substantially purc S,S compound means that no more than 15% or no more than 10% or no more than 5% or no more than 3% or no more than 1% of the total RR; S.R; and RS forms are present. 100741 As used herein, "therapeutically effective amount" indicates an amount that results in a desired pharmacological and/or physiological effect for the condition. The effect may be prophylactic in terms of completely or partially preventing a condition or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for tIre condition and/or adverse effect attributable to the condition. Therapeutically effective arrounts of the compounds of the invention generally inlucle arty am1ounrt sufficient to detectably inhibit Raf activity hy any of the assays described herein, by other Raf kinase activity assays known to those having ordinary skill in the art or by detecting anr inhibition or alleviation of symptoms of cancer. 100751 As used herein, the term "pharmaceutically acceptable carrier," arnd cognates thereof, refers to adjuvants, binders, dilurnts, etc. known to the skilled artisan that arc suitable for administration to an individual (e.g., a mammal or non-marmrrmal). Combinations of two or more carriers are also contemplated in the present invention. The pharmaceutically acceptable carrier(s) and any additional components, as described herein, should be compatible for use in the intcndcd route of administration (e.g., oral, parenteral) for a particular dosage form. Such suitability will be easily recognized by thc skilled artisan, particularly in view of the teaching provided herein. PIrarnaccutical compositions described hrercinr iInclude at least one pharnmaceutically acceptable carrier or excipient; preferably, such cormpositions include at least one carrier or excipient other than or in addition to water. 23 100761 As used herein, the term pharmaceuticall agent" or "additional pharmaceutical agent," and cognates of these terms, are intended to refer to active agents other than the claimed compounds of the invention, for example, drugs, which are administered to elicit a therapeutic effect. The pharmaceutical agents) may be directed to a therapeutic effect related to the condition that a claimed compound is intended to treat or prevent (e.g., conditions mediated by Raf kinase, including, but not limited to those conditions described heroin (e.g., cancer)) or, the pharmaceutical agent may be intended to treat or prevent a symptom of thle underlying condition (e.g., tumor growth, hemorrhage, ulceration, pain, enlarged lymph nodes, cough, jaundice, swelling, weight loss, cachexia, sweating, anemia, paraneoplastic phenomena, thrombosis, etc.) or to further reduce the appeiiriance or severity of side effects of administering a claimed compound. 100771 A "Raf inhibitor compound" is used herein to refer to a compound that reduces or eliminates the activity of Raf Kinase. This inhibition of Raf kinasc can be produced in vitro or in vivo. In some embodiments, the Raf inhibitor compound reduces or eliminates the activity of Raf Kinase in a reversible or irreversible manner. In some embodiments, the Raf inhibitor compound exhibits an ICso with respect to Raf Kinzase activity of no more than about 100 PM and more typically not more than about 50 pM, as measured in the lIaf/Mek Amplified Luminescence Proximity Homogeneous Assay described generally hereinbclow. Preferred isoforms of Raf Kinase in which the compounds of the present invention will be shown to inhibit, include a-Raf, b-Raf, b-Raf (V599E) and c-Raf (Raf- I). "lC5o" is that concentration of inhibitor which reduces the activity of an enzyme (e.g., Raf kinase) to half-maximal level. Representative compounds oftlie preserit invention have been shown to exhibit inhibitory activity against Raf. In some embodiments, compounds of the present invention exhibit an IC5o with respect to Raf of no more than about 10 pM, or no more than about 7.5 pM, or no rnore than about 5 pM, or no more than about 2.5 pM, or not more than about I pM, or not more than about 750 nM, or not more than about 500 nM, or not norc than about 200 nM, or not more than about 100 nM, or not more than about 50 nM, or not more than about 20 nM, or not more than about 10 iM, or not more than about 5 nM, or not more than about I nM, as measured in the Raf kinase assays described here i. 100781 The term "cancer" or "cancer disorder" refers to cancer diseases that can be treated by the inhibition of Raf kinase, including, for example, solid cancers, such as carcinomas (e.g., of the lungs, 24 pancreas, thyroid, bladder or colon), myeloid disorders (e.g., mycloid leukemia) and adenomas (e.g., villous colon adenoma). In some embodiments, the cancer of interest for this invention will be a cancer that expresses a imutated version of b-Raf. 100791 When used with respect to methods of trcatment/prevention and the use of the compounds and fbrmulations thereof described herein, an individual "in need thereof' may be an individual who has been diagnosed with or previously treated for the condition to be treated. With respect to prevention, the individual in need thereof'may also be an individual who is at risk for a condition (e.g., a family history of the condition, life-style factors indicative of risk for the condition, etc.). Typically, when a step of administering a compound of the invention is disclosed herein, the invention firther contemplates a step of identifying an individual or subject in need of the particular treatment to be administered or having the particular condition to bc treated. 100801 In some embodiments, the individual is a mammal, including, but not limited to, bovine, horse, fcl inc, rabbit, canine, rodent, or primate. In some embodiments, the mammal is a primate. In some embodiments, tlic primate is a hum an. In sonic embodiments, the individual is human, including adults, children and premature infants. In some embodiments, the individual is a non manuinal. In some variations, the primate is a non-human primate such as chimpanzees and other apes and monkey species. In some embodiments, the man mmal is a farm animal such as cattle, horses, sheep. goats, and swine; pets such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like. The term "individual" does not denote a particular age or sex. [00811 In sonic variations, the individual has been identified as having one or more of the conditions described herein. Identification of the conditions as described herein by a skilled physician is routine in the art (e.g., via blood tests, X-rays, CT scans, cndoscopy, biopsy, etc.) and may also be suspected by the individual or others, fbir example, due to tumor growth, hemoirrhage, ulceration, pain, enlarged lymph nodes, cough, jaundice, swelling, weight loss, cachexia, sweating, anemia, parancoplastic phenomena, thrombosis, etc. In sonic eimbodinicts, the individual has further been identified as having a cancer that expresses a mutated Raf, such as a mutated b-Raf. 25 100821 In some embodiments, the individual has been identified as susceptible to one or more of the conditions as described herein. The susceptibility of an individual may be based on any one or more of a number of risk factors and/or diagnostic approaches appreciated by the skilled artisan, including. but not limited to, genetic profiling, family history, medical history (e.g., appearance of related conditions), li festyle or habits. 100831 As used herein and in the appended claims, the singular forms "a", "an" and "the" include plural forms, unless the context clearly dictates otherwise. 10084] Unless defined otherwise or clearly indicated by context, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. RafOkinuse Inhibitors [0085) 'The compounds described herein are effective to treat cancers, as further discussed herein. Without being bound by theory, it is believed they are effective due to their inhibitory activity on Raf, and in some embodiments they are believed to be effective by inhibition of b-Raf, particularly certain mutated forms of b-Raf. Accordingly, the invention provides compounds that are inhibitors of Raf kinase and methods to use such conounds for the treatment of disorders associated with Raf activity, including cancers. In one aspect, the present invention provides compounds that inhibit or decrease the catalytic activity ofa Rafkinase enzyme. In one aspect, the compounds have the Formula (1): R1 -X

R

2 (I) wherein: 26 X -- N X R R R3 represents 01 X or Y, whichever is present, is selected from the group consisting of NR", 0, and S; Rl is optionally substituted heteroaryl or optionally substituted heterocyclyl; R2 is optionally substituted het croaryl, or optionally substituted heterocyclyl; R3 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl; and R4 is hydrogen or optionally substituted alkyl, including tautormers of he citral imidazolc ring whei X or Y is Nt-I or a stercoisomer or pharmaceutically acceptable salt thereof. [00861 In these compounds, one of X and Y is present, and can be NR 4, 0 or S. When X or Y is N R' where Rd is 1-1, this provides an imidazole as the central ring in Formula 1, and that ring can exist as either of two lautomers (one where X is NI-I, and one whCre Y is NI-I). In that case it does not matter whether X or Y is NI-, because the two tautomers are readily interconverted; indeed they are in equi liritim when the compound is dissolved in solution and the compound probably exists as a mixture of these tautomers whether in solid form, as an oil, or in soltttion. For other X or Y groups, the compound in which X is present differs from the one in which Y is present. For ccrtuin aspects of the present invention, it is prefcrred to have X present; for other aspects it is preferred to have Y present in the central ring. [0087 R' is an optionally substituted heterocyclic or heteroaryl ring, which can be monocyclic or it can be a fused to a sccond ring to form a bicyclic or even a tricyclic ring system. In sotne embodiments, Rt is an optionally substituted monocyclic heteroaryl containing up to three hetcroatoms selected from N, 0 and S as ring mctnbcrs, exemplified by pyridinc, pyrimidine, triazine, fturan, thiophenc, pyrazinc, pyridazinc, pyrrole, pyrazolc, imidazolc, oxazoic, isox azolc, thiazolc, or isothiazole, or triazole. Pyrazine and Pyridine are sometimes preferred. In some embodiments, R' is an optionally substituted bicyclic heteroaryl ring system, comprising phenyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl, or pyrimidinyl used to a second ring; the second ring Can be a phenyl, pyrrole, pyrazole, triazole, inidazole, piperidine, piperidinonc, pyrrolidinc, 27 pyrrolidinone, or the like; provided at east one of the two rings is a heteroaromatic ring (aromatic ring containing at least one N, 0 or S as a ring member). Typical examples ofthese bicyclic heteroaromatic groups include i inclole, benzimidazole, indazole, benzofuran, benzothiophene, quinolinc, isoquinolinc, quinoxalinc, naphthyridinc, benzopyrazolc, benzoxazolc, bcnzothiazolc, benzisoxazole, and benzoisothiazole, for example. In some embodiments, the optionally substituted heteroaryl ring is a deuterated version ofone of the above described rings. [0088] In othcr embodiments, R' is optionally substituted hetemcyclic group, which can be a heterocyclic ring fbsed to an additional aryl, cycloalkyl, or heterocyclyl ring, which is also opItionilly substituted. In sonic embodiments when R' is an optionally substituted heterocyclic ring fused to an optionally substituted phenyl, so R can be an optionally substinited dihydroindolc, dilhydroindazole, dihydroindole, dihydroisoindolc, tetrahydroquinoline, tctrahydroquinoli none, tetrahydroisoqcui noline, or teitrahydroisoqin noli none, cach of which can be linked to the central ring in Formula I through the heterocyclic ring or tlie phenyl portion of tiesc R groups. [100891 Suitable substitucnts for R' include those descri bed herein as generally suitable for h elerocyclic groups. In particular, R can be substituted with onc or more halo (especially F or CI), amino and substituted amino, aminocarbonyl, Cl -C /I alkyl, Cl -C4 alkoxy, =0 (oxo), Cl -C4 haloalkyl (e.g., CF3), ID, -01-, -CN, MeNI-l-, MC 2 N-, acetyl, acetylamino, aminosulfbnyloxy, Cl -C4 alkoxycarbonyl, carboxyl, and combinations of these groups. Specific combinations ofthese groups of particular note Include amino with Cl -C4 alkoxy, amino with halo, Cl -C4 alkoxy with halo, and the like. [0090] In some embodiments, X or Y, whichever is present, is NR", and R' is IH or Me. [00911 In sonc of these embodiments, R" is hydrogen or an optionally substituted Cl -C6 alkyl. In other embodiments, NR 4 is NI or N Me. [100921 In other embodinienis, X or Y, whichever is present, is 0. In other embodiments, X or Y, whichever is present, is S. 100931 In some of these cm bodcriments, R' is optionally substituted pyridyl or pyrazinyl, including dcutcrated versions thereof. In certain embodimcnts, R' is optionally substituted 3-pyriclyl. In other certain embodiments. R' is optionally substituted 2-pyrazinyl. 28 100941 For R', sometimes 2-anino-3-mcthoxypyrilin-5-yl or 2-amino-3-ncthoxypyrazin-5-yl is preferred. 100951 In some of these embodiments, the optional substituents for R' are selected from the group consisting of halo, ), cyano, hydroxy, -C(O)R', -NR"C(O)R', -C(O)NR-2, -OS(O) 2 NR ' 2 , optionally substituted alkyl, optionally substituted amino, and optionally substiitued Cl -C4 alkoxy including C I -C4-haloalkoxy (e.g., -OCFh, -OCF 2 H, or -OCFI-1 2 ), and wherein R' is optionally substituted alkyl, and wherein each R" is independently hydrogen or optionally substituted Cl -C4 alkyl. In somc embodiments, one such substituent on R' is a deuterated versio of one of thcsc, e.g.,

OCD

1 , for example. 100961 In some of thesc embodiments, R' is scIcected from: 29 N N N N N14 N Nl X N: OH - i N'-. N IN N 11 1 11 N. NNN N'1 N N Nil N H NH N N N N N N NN, N N 7=N N N HH IIN N 11N N 11 1 N I, N ) IIN N0 ~N N 10J0971 R 2 Is optionally substituted hctcroaryI, or optionally substituicd hetcrocyclyl. R' can bc an op)tionally substituted monocyclic ring such as pyridlinc. pyrimidinc, furan, thiophcnc. thiazolc, sothiazole, oxazo Ic, Isoxazoic, ipyrazolyl, Imidazolyl, dlihydropyranyl. tetrahydropyranyl, and the 31 like. In some embodiments, R 2 can be an optionally substituted bicyclic group, comprising a phenyl, pyridyl or pyrimidinyl, for example, fused to an additional ring such as cyclopentyl, cyclohexyl, pyrroic, imidazole, pyrazole, piperidine, and the like; provided one ring of the bicyclic group contains a heteroatom as a ring member. R 2 can be attached to the base molecule through either ring ofa bicyclic noiety, including through phenyl when R 2 comprises a phenyl ring fused to a heterocyclic ring or a heteroaromatic ring. Typical examples ofthesc heteroaryl groups include optionally substituted indole, benzimidazolc, indazole, benzofuran, bcnzothiophcnc, cuinolinc, isoquinolinc, quinoxaline, naphthyridine, benzopyrazole, benzoxazole, benzothiazole, bcnz.isoxaxolc, and henzoisothiazole, each of which can be linked to the central ring in Formula I through either ring of these bicyclic R 2 groups. One example of such bicyclic rings is pyrrolopyridine. In other embodiments, R' can be an optionally substituted heterocyclyl group such as letrahyropyran, Ictrahydrofiran, dihydropyran, piperidhi ne, piperidinone, pyrrolidinc, pyrrolidinone, dihydroindole, dihydroindazole, dihydroindole, dihydroisoindole, tetrahydroquinol ine, tctrahydroquinolinone, tetrahydro isoquinoline, tetrahydroisoquinolinonc, and the like. 100981 In certain cmbodiments, the optional substituents for 1 2 arc selected from the group consisting ofthalo, ), cyano, hydroxy, -C(O)R', -NR"C(O)R', -C(O)NR'2, -OS(O)2NR"2, optionally substituted alkyl, optionally substituted amino, and optionally substituted alkoxy, and wherein R' is i-1 or optionally substituted alkyl, and wherein each R" is independently hydrogen or optionally substituted alkyl. 100991 Some particularly suitable su bstituIens ror R2 include halo (especially F and Cl), ), CI -C4 alkyl, amino, diniethylanino, inethylainino, substituted amino, Ct -Cl alkoxy, CN, -OHl, optionally substituticd pleniyi or pyridyl, or optionally substituted phenylmnethyl or pyridylmclhyl groups. PiCferCd subst ituted amino groups can be of the formula--(CR ')wNH-C(0)-R*, where each R' is independently -I or Me, an1d R* represents 1-, Cl -C4 alkyl, or Cl -C4 alkoxy, where the Cl -C4 alkyl or Cl -C4 alkoxy can be substituted with up to three groups s-uch as Halo, ), CN, NI-2, NMe 2 , N H Mc, OH, OMe, CF3, OCF 3 , =0, and the like. [01001 In some embodiments, R contains at least one substituted amino group having the formula -NR-IR", wherein R " is optionally substituted alkyl or substituted aryl. In certain embodimenis, the 32 R 13 optionally subst ituted alkyl group is sec-butyl, -CR 2

CR

2 N RC(O)CR 2 0CR 3 , or -CiCRbNRC(O)OCR 3 , whcrcin each R is indcpcndently hydrogen or Cl-C6 alkyl, such as

-CIH

2 CH2N HC(O)CI-1 2 0CH, -ClH 2 CI-(CHl 3 )NI-IC(O)CHl20CH 3 , -CH2CI-(CHl,)NH C(O)CH (CHtj)OCH]3, or -- Cf 2

CH(CH

3 )NH C(O)OCHI 3 and any cnantiomers or diasiereomcrs thereof. In some variations, the R C substituted myl group is -C 6 li-o-OCHI, --Cr,Hi m-OCF,, -C 6 1+L-m-CF, -Cj-I.,-p-CF3, or -C6-1 3 -mi-CM-p-Cl. 10 10l In some cmbodiments, the substit uted amino on R2 can be selected from acetyhimino, 2 hydroxyethyl amino, hydroxyacctyl amino, acetylarninocthylanino, piperidinylamino, soubstituted piperidinylamino; or amino substituted with C 1-C4 alkyl, C3-C6 cycloalkyl (e.g., cyclohexyl, cyclopropyl, cyclohexyl), C5-C6 heterocycloalkyl containing one or two heteroatoms selected from N, 0 and S as ring members, or phenyl optionally substituted with halo, Cl -C4 alkyl, Cl -C4 alkoxy; and the like. Specific cmbodiments of the substituted amino group include 2-methoxyethylumine, 2 hydroxyethyla me, cyclopropylaminc, 2-(hydroxyacetylamino)ethyl, 3-piperidinyl amino, I -( chlorophcnylsulfonyl)pipcridinc-3-ylaminri, 1 -(4-(2-amino-3-methoxypyridin 5yl)phcnyl)pipcridiny-3-ylamino, 2-(imethoxyacetylaiiiino)ctliylamnino, 2-(4 chlorophenylsolfonyl)ami noethylani no, cyclopropylamino, 2-hydroxypropylamino, 2 (cyclopropylsulfonyl)amiirioethylamino, 2-(mcthylsul fonylamino)cthylanino, I (Cyclopropylsulfonyl)pipcridine-3-ylamino, 1-(mcthoxyacetyl)piperidine-3-ylamino, I (cyclopropylsul fonyl)piperi di ne-4-yhnni no. isobutylainno, 3-meihoxyphenylamino, isopropylamino, 2-iethoxycthylamino, cyclopentylamino, cyclohexylamino, 2 (imetloxyacctylamino)propyl anino, 3-tri fluorom ethylphcnylaiino, 3-fluorophenylainino, ethylanino, propylamine, 2-butylamino, 3-methoxypropylanino, cyclopropylinethylanino, 2-(2,6 diimethylimorpholin-4-yl)pyricline-5-ylamnino, 3-trifluormClhoxyphenyhuniino, 4 nethoxybenzylamino, I -acetylpyrrolilin-3-ylamino, 2-(methylsulfonylamino)propylarnino, 1,2 (diflLorodioxolanyl)phen -4-ylanino, 4-trifluoronethylamino. 2-(2 met hoxypropanoylaii no)propylainine, I -(imethylsul foriyl)-pyrrolidi n-3-ylami no, 2 (rnethoxyacctylainio)- -ImCthylethylamino, 2-(2-imethopropanoylaiino)-I -methylethylamino, 2 (tri fluoracetylinirio)cthylamino, 2,2,2-triflorethylamino, 4-trifluoromcthylphenylamino, 2 (imcthylIa miniiocarbonaylI ami no) propylIamiiio, 4-clioro -3-ti riflu00roicthlylainin o, 2-meth oxypyridinyl-4 33 mininio, 2-(methoxycarbonylaiino)piopyhuni no, 2-(isopropoxycarbonylamino)propylam ino, 2 (isobutoxycarbonylamiino)propylaminino, and 2-(n copentyloxycarbonylaini no)propylarni ne. [01021 For the substitutCd phCnyl or pyridyl groups in thcsc R 2 substitucnts, the substitutents can be selected from halo, D, CI -C4 alkyl, CI-C4 alkoxy, CN, CF,, amino, hydroxy, and the like. [0103] In soine cinbodiiments, R2 is optionally substituted pyridinyl or optionally substituted pyrimidinyl. In other ciribodiments, R 2 is optionally substituted 4-pyridinyl. II other embodiments,

R

2 is optionally substituted 4-pyrimidinyl. In particular embodiments, R 2 can be 2-(substitutcd amino)-pyridin-4-yl or 2-(substituted amino)-pyrimidin-4-yl. 10 101] In Sone oft hese embodiments, R 2 is selected from 34 N N N N N

N

7 N,) N N N1 HoN ~ N NN 0 N Nr Y N N NN NH( 0 N 7 N NY Nil~ NHN, N N N N N N N 'i N 'N I :35 N-\ NN1 N0 N N 0 0 HI N N-N N 0 N N N I N 111 S HN s OFH H'3FI~lC 0 NN, N N N , N0 N "O0-/ N (N FIN N 7 H 36 NN N 0 OCr C1uInlhiomlcr

CF

3 F NyN ' N'r NyN N N N y NyN N N,, Iq N OIII la d li l l(IIIIO le 73 Nrl IlyN N N Ny HI N HFNFI 00 j i N. Pi<N N N or cantoni ( ny cium i omeir or distec oinic N N 0 N N N--Sor cilaniihhci or ciiaiome N . 11 N N4 ori enahiiOri oranl> ciliioiir kir diillrveoniur 38

N

1 N HN

CF

3 HH NN HN N or el[ n oinr or ena neiIlr el N HN o N NN N N N r e nnni o er or nant er HN C N NyN H Y, H H N H H ) N 0 N Ny N N N HNi NN or enan tei cr or enantiomer j010S R 3 can be an optionally substituted alkyl, optionally substitnted aryl, optionally substituted hcteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl group. In some emhodiments, R is optionally substituted CI -C6 alkyl, such as nethyl, ethyl, propyl, isopropyl, t butyl, neopentyl, and the like, or a deIcterated version of onc of these. Thesc alkyl groups can be subsitoted with one or more groups, typically one to three groups, selected from oxo ( =0), halo, D, R", OR", COOR", NR" 2 , CONR" 2 , CN, C3-C6 cycloalkyl, optionally substituted phcnyl, and the like; where R" is H or C I-C4 alkyl individually at cach occurrence, and where NR" 2 can represent 39 pyrrolidine, pipcridinc, piperazinc, or morpholinc or an oxo- or methyl-substituted version of one of these heterocycles. In some embodiments, this alkyl is unsubstituted, or is substituted with OR" or NR "2. [01061 In other embodincnts, R 3 is cycloalkyl, wherein the cycloalkyl can be a 3-8 membered ring of carbon atoms and can be substituted by up to three groups selected from oxo (=0), halo, D, CN, R", OR", COOR", NR" 2 , CONR" 2 , C3-C6 cycloalkyl, optionally substituted phenyl, and the like; wherc R" is 1- or Cl-C4 alkyl or CI -C4 haloicthyl individually at each occurrence, and where

NR"

2 can represent pyrrolidinc, piperidine, piperazine, or morpholine or an oxo- or methyl substituted version of one of these hctcrocycles. The cycloalkyl can also contain a carbon-carbon double bond. Exapn Ies of su table cycloalkyls include cyelo)ropyl., l-cyanocyclopropyl, I trliuromcthylcyclopropyl, I -chlorocyclopropyl, 1-methylcyclopropyl, cyclopentyl, cyclopentenyl, cyclohcxyl, cyclohexcnyl, cyclobutyl, and the like. [0 107l In other embodiments, R3 is heterocyclyl, wherein the hctcrocyclic ring can be a 3-8 membered ring containing up to three heteroatoms selected from N, 0 and S as ring members, and can bc substituted by up to three groups selected frorn oxo (=0), halo, D, R", OR", COOR", NR" 2 ,

CONR"

2 , SOR", SO 2

NR"

2 , C3-C6 cycloalkyl, optionally substituted phenyl, and the like; where R" is -1 or Cl -C4 alkyl individually at each occurrence, and where NR" 2 can represent pyrrolidine, piperidine, jiperazine, or morpholine or an oxo- or methyl-substituted version of one of these heterocycles. The heterocyclic ring can also contain a carbon-carbon double bond. Examples of suitable heicrocyclic rings include pyrrolidine, piperidine, piperazine, letrahydrofuran, tetrahydropyran, tetrahydropyridine, dihydropyridine, and the like. [0108] In other embodiments, R3 is aryl or heteroaryl, which can be unsubstituted or it can be substituted with up to three groups. Suitable aryl groups include phenyl, naphthyl and substituted versions oF these. Suitable heteroaryl groups include pyrazole, pyrid inyl, indolyl, quinolinyl, isoquinolinyl, benzopyrazolyl, and the like. Substiutents for the aryl or heteroaryl in some embodiments can be selected from Cl -C4 alkyl, Cl-C4 alkoxy, CN, halo, D, CF,, CIHO, aminosulfonyl, aminocarbonyl, methylaminocarbonyl, cinethylaminocarbonyl, carboxyl, methoxycarbonyl, methylsulfonyl, tri fluoromethoxy, substituted Cl -C4 alkoxy (e.g., 2 dimethylaminoethyl), and the like. 40 [0 1091 In some ofthese embodiments, R3 is optionally substituted phcnyl, optionally substituted Cl C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In other embodiments, R 3 is unsubstituted phenyl or phenyl substituted with onc, two or three subst ituents. In other embodimcnts, the optional substituents on the optionally substituted phenyl reuprcsented by R 3 are selected from the group consisting of halo, hydroxyl, cyano, formyl, optionally substituted pyriclyl, optionally substituted Cl -C6 alkyl, optionally substituted C I C6 alkoxy, -C(O)OR ', -S(O) 2 R', -S(O) 2 NR "2, and -C(O)NR "2, and wherein R' is optionally substituted Cl -C4 alkyl and each R" is independently hydrogen or optionally substituted Cl -C4 alkyl. In other embodiments, R3 is substituted or unsubstituted Cl -C6 alkyl. In other embodiments, R3 is optionally substituted C3-C6 cycloalkyl. In other embodinents, R 3 is optionally substituted C3-C8 heterocyclyl. [01101 In some of these embodiments, R 3 is selected from: F 0 0 N XFc 00 F 0 F 42I Ya 00 C)cI CF, C I YYF CI,, C)'a F :al F 43/ H:\rbr~lnienvoven\NKPortbl\DCC\RBR\632630H _.DUC-13105/2014 [0111] In some embodiments, R 3 is preferably not a perfluoralkyl group, or R 3 is not CF 3 . [0112] In certain embodiments of these compounds, X or Y, whichever is present, is NR 4 . [0113] In certain embodiments, R 4 is hydrogen or an optionally substituted Cl-C6 alkyl. In certain embodiments, NR 4 is NH or NMe. [0114] In certain embodiments, X or Y, whichever is present, is 0. In certain embodiments, X or Y, whichever is present, is S. [0115] In certain embodiments, the compound is of Formula II: R 6

--

N R5 RT

R

7 \ / zI x R 3 R2 Y(II) wherein Z' is N; and R', R , R', and R' are independently selected from the group consisting of hydrogen, deuterium, halo, cyano, hydroxy, -C(O)R', -NR"C(O)R' -C(O)NR" 2 , -OS(0)2NR" 2 , optionally substituted Cl-C6 alkyl, optionally substituted amino, and optionally substituted Cl-C6 alkoxy; R' is optionally substituted alkyl and each R" is independently hydrogen or optionally substituted Cl -C4 alkyl;

R

2 , R 3 , X and Y are as defined for Formula (I); and any two of R 6 , R 7 and R 8 that are attached to adjacent atoms of a ring in Formula II can be taken together to form an additional optionally substituted 5-6 membered ring. These compounds include the pharmaceutically acceptable salts, and isomers, deuterated versions and tautomers, as discussed above for compounds of Formula (I). In 44 these compounds, R 2 and R can be selected from the specified R 2 and R' groups described above For Formula (1). 101161 In certain embodiments ofthe compounds of Formula (11), R 6 is NH 2 . 101171 In certain embodiments, R 7 is -OMe or a deuterated version of-OMc, such as -- OCD 3 . In some embodiments, R 5 is -]. In somc embodiments, Rt? is Deuterium. 10 I 181 In certain embodiments, Z is CH and R is 1-1. In other embodiments, Z' is N. 10 191 In certain em bodimennts, R2 is optionally substituted pyrid inyl or optionally substituted pyrinidinyl. In some variations, R 2 is optionally substituted 1-pyridinyl. In some variations, R2 is optionally substituted 41-pyrirmidinyl. Preferably, this ring is substituted by a substituted amino group that is -meta' to the point of attachment of R2 to the central ring of Fornula (It). 10 1201 R 2 can bc an optionally substituted heteroaryl, or optionally substituted helemneyclyl. RZ2 can be a nonocyclic hctemoaromatic or heterocyclic group such as pyridine, pyrimidinc, furan, Ibiophenc, thiazole, isothiazolc, oxazole, isoxazole, pyrazolyl, imidazolyl, dihydropyranyl, letrahydropyranyl, and the like. In some embodiments, R 2 can be a bicyclic group, comprising a phenyl, pyridyl or pyrimidinyl, for example, fised to an additional ring such as cyclopentyl, cyclohexyl, pyrrolc, im idazole, pyrazole, piperidine, and the like. One example of such bicycle rings is pyrrolopyridine. 101 211 The optionally substituted heteroaryl or heterocyclyl groups of R 2 can be substituted with one to three groups such as halo (especially F and Cl), deuteriumn ()), Cl -C4 alkyl, amino, substituted ami no, C1 -C4 alkoxy. CN, -OH[I, optionally substiluted phenyl or pyridyl, or optionally substituted phenyl methyl or pyridylniethyl groups. Substituted amino is sometimes preferred. In some cinbodiments, the substituted a mino is of the formula-NH(CR' 2 wNH-C(=0)R* where each R' is independently 11 or Me, and R* represents -, Cl -C4 alkyl. or Cl -C4 alkoxy, where the C I-CA alkyl or Cl -C4 alkoxy can be substituted with up to three groups such as Halo, D, CN, NI-Ia, NMc 2 , NIMe, 01-, OMe, CF, OCF, =0, and the like. In sonic embodiments, at least one substituent on R2, when R 2 is a six-mnembered ring, is at the position meta to the point where R 2 is attached to the central ring. In some embodiments, the substitucnt at this position is substituted a mino. Thus R 2 can be 2-(substituted ahmmino)-4-1pyridyl or 2-(substitutecl amino)-1-pyrimidinyl. 45 10 1221 In cer-tain embodiments, R' is selected f-rm NH, N N N N~ NN N N4 N N HH NN N N- , ZN N N N HN H' N NH Ny ll-N Ny 0 0 0 or dllanlioil iCi- o1 Criaintiojim N NH 2 NN -N I H N 0 N 46 NNN N I N N N a H 2N Ni N N\ Ny Ny 0 H1 H 0 0 f 0 0ON 11 N N N 0 Nil N I A oro umill j1niner H N N N N 0D () N N H N HN 47 N NN H N N N N N N N N H 0 0~~o ur cia nnomer N N N Nr Nil Cl Nljiir Nrdfslro Nil, N yN ~-48 N 7 N Ny N yN Nr IN HN,, HN IN 0-4 NN 0 0-L " l C)N N or~ ~ ~ ~~o essohinme ormuimitoni o imeco r ae Nr N N N NN 00 or coiiiloilie or sy esioir or dissio leroor 49 I CFJ N N I N rN HN N N N N 0N 0 Nr N N N NN N NN C) N NS N N I 50) |0 1231 In certain embodiments, the compound is of Formula (11l): R 1

RR

3 23 R10 Z R Y N R 12 RM (Ill) wherein Z 2 is CRO or N; and R., R', R", and R 2 are indcpcndcntly selected from the group consisting of hydrogen, halo, ), cyano, hydroxy, -NR''C(O)R', optionally substituted alkyl, optionally substituted amino, optionally substituted hcteroaryl, and optionally substituted alkoxy; R' is optionally substituted Cl -C4 alkyl and R'' is hydrogen or optionally substituicd C 1 -C4 alkyl; and any two of R', R', R', and R1 2 that arc aitachcd to adjacent atoms of a ring in Fonnula Il can be taken together to form an additional opt finally substituted 5-6 membered ring. R, R3, X and Y in these compounds arc as described for Formula (I). These compounds include the pharmaceutically acceptable salts, and isomers and tautomers, as discussed aovc for compounds of Formula (1). In these compounds, R'I and R3 can be chosen from the specified R' and R3 groups described above for Formula (1). 10 1241 In some embodiments of the compounds of Formuln (1ll), one or both of R'' and R 2 is 1H, or one of them is ) and one is -1, or R1" and R.' 2 taken together forin a ring fused to the ring containing z2 RIO can he -1, or 1), or it can be a substituent other than -1 or ). In certain embodiments, R"m is selected From the group consisting of hydrogen, D, optionally substituted alkyl, and optionally substituted amino. In cecrin embodiments, 1 0 is -- NI-IR '. w\.herein1 R 3 is selected from the group consisting ofoptionally substituted alkyl, optionally substituted hcterocyclyl, -C(O)R'. optionally substituted cycloalkyl, optionally substituted amino, optionally substitutel aryl, and optionally 51 substituted heteroaryl. In some embodiments, R " is a group ofthc formula -NH(CR' 2

)

2 .- NI-l C(=0)-R*, where each R' is independently H or Me, and R* represents H, C I-C4 alkyl, or Cl -C4 alkoxy, where the Cl -C4 alkyl or Cl -C alkoxy can be substituted with up to three groups such as Hale, ), CN, NH 2 ., NJMez, NI-IMe, 01-, OMe, CF 1 , OCF 3 , =0, and the like. In selected embodiments, R' is -NH R 3 and R" and R 2 are both hydrogen. 101251 In certain embodiments, R" is optionally substituted alkyl or substituted aryl. In certain embodiments, the R optionally substiruted alkyl group is sec-butyl, -CR 2

CR

2 NRC(0)CR 2

OCR

3 , or

-CR

2 CR2NRC(0)OCR 3 , wherein each R is independently hydrogen or C I -C6 alkyl, such as -C1 ICH2N HC(0)CH 2 0CHi, -C-I 2

C-I(CI-

3 )N I C(0)C-1 2 0C-I,

--

2 C l-l(C-I 3 )N C(0) i(C )OC 1-13, or -CH 2 CI(CHI3)N IC()OC-3 and any enantiorners or diastercomers thereof. In some variations, the R " substituted aryl group is -C61I-11-o-OC-1 3 , -C-'l n-OCF-, -C 6 1-[I-nr-CF 3 , -C 6 p.-CF-,, or -C,11-m-CFrp-CL. 101261 in certain embod i mentis of Form ula (Ii), Z is CH. In otIer emibodiments, Z2 is N. [0 1271 In certain embodiments of Formula (11), R' and R1 are both I-I. 101281 In certain embodiments of Formula (11), X or Y is NR", where R" is I-. 10 1291 In certain embodiments of Formula (11), R' is optionally substituted phenyl, optionally substituted Cl -C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted lheterocyclyl, or opt ionally substitu ed heteroaryl. In some variations, R 3 is unsubstiturted phenyl or phenyl substituted with one, two or three substituents. In some variations, the optional substituents on the optionally substituted phenyl represented by R 3 are selected from the group consisting of halo, hydroxyl, cyano, forimyl, optionally substituted pyidyl, optionally substituted alkyl, optionally substituted alkoxy, -C(O)OR', -S(0) 2 R', -S(0)2NR 2, and -C(0)NR"2, and wherein R' is optionally substit uted alkyl and each R" is independently hydrogen or optionally substituted alkyl. In some variations, R3 is subsuituted or unsubstituted Cl -C6 alkyl. In other erbodirents, R3 is optionally substituted C3-C6 cycloalkyl. In some variations, R 3 is optionally substituted heterocyclyl. [01301 in certain embodinents of Form ula (II), R 3 is selected From: 52 F, HO 7 00 00 F5F 0 0 N11 0 C)F y F CI , F F 7 7 7F and 7 7 -o F 754 H:\rbr\lnaterwoven\NK'Orll\UUU\ KX\632630B_lUUC- 13/05/2014 [01311 In certain embodiments of the compounds of Formulas (I)-(III), X is present, and X is NMe. [0132] In certain embodiments of the compounds of Formulas (I)-(III), Y is present, and Y is NMe. [0133] In certain embodiments of the compounds of Formulas (I)-(III), X is present, and X is 0. [0134] In certain embodiments of the compounds of Formulas (I)-(III), Y is present, and Y is 0. [0135] In certain embodiments of the compounds of Formulas (I)-(III), X is present, and X is S. [0136] In certain embodiments of the compounds of Formulas (I)-(III), Y is present, and Y is S. [0137] In another aspect, a compound of Formula IV is provided: N R 7 z x 1 2 3R3 N (IV) herein Z' and Z2 are each independently N or CH; X NX R3 R3 R3 represents or where X or Y, whichever is present, is selected from the group consisting of 0, and S;

R

3 is optionally substituted phenyl, or a Cl -C6 hydrocarbyl group; R is NHR 14, where R' 4 is H or optionally substituted Cl-C6 alkyl;

R

7 is H, D, halo, optionally substituted amino or optionally substituted Cl-C4 55 alkoxy; and

R

10 is NHR", wherein R' is selected from the group consisting of optionally substituted Cl-C6 alkyl, optionally substituted heterocyclyl, -C(O)R', optionally substituted C3-C6 cycloalkyl, optionally substituted amino, optionally substituted aryl, and optionally substituted heteroaryl; R' is H or optionally substituted Cl-C4 alkyl; or a pharmaceutically acceptable salt thereof, a deuterated version thereof, or a tautomer or stereoisomer thereof. [01381 In certain embodiments of the compound of Formula (IV), X or Y, whichever is present, is NH or NMe. In alternative embodiments, X or Y is 0. In other embodiments, X or Y is S. [0139] In certain embodiments of the compound of Formula (IV), R 6 is NH 2 . [0140] In certain embodiments of the compound of Formula (IV), R 7 is -OCH 3 or a deuterated version of -OCH 3 (e.g., -OCH 2 D, -OCHD 2 , -OCD 3 ). [0141] In some embodiments of the compound of Formula (IV), R 6 is NH 2 and R 7 is

-OCH

3 . [0142] In some embodiments of the compound of Formula (IV), R 3 is an unsubstituted alkyl such as Me, Et, nPr, iPr, or t-Bu, or cyclopropyl, 1 -methylcyclopropyl, cyclopentyl, cyclopentenyl, or cyclohexyl; or R is phenyl, which can be unsubstituted or it can be phenyl substituted with halo or CF3 or C1 -C4 alkyl or Cl -C4 alkoxy. [01431 In certain embodiments of the compound of Formula (IV), R'" is NHR' 5 , where R1 5 is optionally substituted alkyl or substituted aryl. R1 0 can be a group of the formula -NH(CR'2)2-4NH-C(=0)-R*, where each R' is independently H or Me, and R* represents H, Cl-C4 alkyl, or Cl-C4 alkoxy, where the Cl -C4 alkyl or Cl -C4 alkoxy can be substituted with up to three groups such as Halo, D, CN, NH2, NMe2, NHMe, OH, OMe, CF3, OCF3, =0, and the like. [01441 Optionally, Z' and Z 2 are each CH, or CD. In other embodiments Z is N and Z 2 is CH. In other embodiments, Z' is CH and Z 2 is N. 56 101451 In certain embodiments of the compound of Formula (IV), the R 5 optionally substituted alkyl group is sec-butyl, -CR 2 CRN RC(O)CR 2 0CR-, or -CR 2

CR

2

NRC(O)OCR

3 , wherein R is independently at each occurrence hydrogen or Cl-C6 alkyl, such as -CH 2

CH

2

NHC(O)CH

2 0CH3,- Cl-I 2 CH (C -1 ),)N 1-1 C(O)CI-20C-13, -C H 2

CI-T(CH

3 )N-C(O)C-I(Cl-1 3 )OC H 3 ,or- CI-1 2

(-(CH

3 ()NC(O)OCH3 and any cnantiomers or diastercomers thereof. In some variations, the R ' substituted aryI group is -C 6 1-1 4 -o-OCHl 3 , -C 6 1-i-1m-OCF 3 , --CcfH-m-CF 3 , -C 6 He-1p-CF 3 , or 10.1461 In certain embodiments, the compounds of the prcscnt invention include any one compound ofTable I , or a pharmaceutically acceptable salt, isomer, or solvatc thereof; or a deuterated version thereof In some variations, the con pounds of the present invention inc lude any one compound of any subset of compounds of Table ), or a pharmaceutically acceptable salt, isomer, or solvate thereof. In some variations, the compounds ofthe present invention include any one of all the Compounds of Table 1, or a pharmaceutically acceptable salt, isomer, or solvate thereof 10 1471 In certain em bodiments, the compouanIs of 1he invention include, for example: N-(2-(4-(5-(6-amino-5-mcthoxypyridin-3-yl)-2-(4-flK)Iophenyl)-l H-imidazol-4 yl)pyriinin - 2 -ylam i no)ct hyl)-2-inetho xyacetam i(IC; N-(2-(4-(4-(6-aino-5-methoxypyridin-3-yl)-2-(4-(tifluoromethy1liheyl)-I H-imidazol 5-yl)pyrimidin-2-ylamino)cthyl)-2-mthoxy actamide; (S)-N-(l -(4-(4-(6-amino-5-methoxy pyridin-3-yl)-2-(4-niorophenyl)-I H-imidazol-5 yl)pyri mid in -2-ylari no) propan- 2-yl)- 2 -metho xyacctarnide 4 -(4 -(6-ami no-5-methoxypyridin-3-yl)-2-tert-butyl-HI Il-imidazol-5-yl)-N-(3 (tri 1uuor-omethoxy)phenyl)pyrimidin -2-am iine; 4-(4 -(6-ai no-5-met hoxypyrid in-3-yl)-2-tert-hut yl-1 I-I-inidazol-5-yl)-N-(3 (t ri fhtoro methyl )phen yl) pyri mid in-2-am i ie: (S)-N-(I-(4-(4 -(5-amiiio-6-mnethoxypyrazin-2-yl)-2-(4-(tri flumoromethyl)phenyl)-iH ii dazol-5-yl)pyrimindin-2-ylami no)propa n-2-yl)-2-me tlioxyacetanmidc: 57 (S)-N-( I -(4-(4-(5-nii no -6-rniethoxy)'riazin-2 -yI)- 2

-(

4 -flhio-o phe nylI) -I 1--imiclazo 1-5 yl)pyri mid in-2 -ylami no) propan- 2-yI)-2 -inetho xyaicta m ide; (S)-N-( I -(-4(-iiio5ii-ioyp l Ii-- )--,~rIfuriityI phnl- I i dazo 1-5-yI)pyri mid in-2-y Iitm I no)piopn-2-yl).

2 -mct hoxyacet am Idc; (S)-N-( 1 -(4-(,1-(6- amin o-5-mcth axypyidii-3-yI)-2-tcrt--bLtyl-) f 1-imidazol-5 yl )pyri mid in-2.ylaimino)proain-2-yl)-2-cthoxyucctairil; (S)- N-( I -(-4-6ain--ehxprdn3-I--? l )r-(Iri fiuorornethyl)phcnyl) I H-Imidazol-5-yl)pyrirn IdlI n-2-y IanI ioflO)rofafl2Yl)-2-rctloxyacclamide; (S)-N-( I -(4-(4-(5-ainio-6-nicthoxypyiain-2-y)- 2 -trei-t-l)U)'- I H1- Imidazol-5 yl)pyri midi n-2-yi ami no) propan-2-yI)- 2 -inctlioxyacciam Idc 4 -(4 -(6-aiino-5-rncthoxypyricdiin-3-yl)- 2 -tert-bu I),I- 11- -1 Ii I cazolI-5-yD)-N-(4 (t rifnluoromct iyl)phcnyI) pyri-mildi n-2 -ami nc; 4-(4-(6 -intio---nthoxy yid I -3-yl)-2- Icrt-)utyI I 1- 1midlazol-5-yI)-N-(4-ch Ioro-3 (liloro met hylI) phcnyI) pyri mid in-2-anii nc; 4-(4-(6-arnilino-5-.cthoxypyiiii-3-y1)--t-t-titlY I -mecthyl-i I--imidazol-5-yl)-N isobut-ylpyrimidin-2-ami ne; 4 -(4 -(6-,ii nio- 5-iihox)Iyyid I n-3-yI)-2-tert-hiityl- I 1-1-i in I dazo 1-5 -yI)-N-(2 inetho xypylid din-4 -yl )pyri mn id ii -2-aiic; (S)-mecthyl I -(4-(4l-(5-amiino-6-nothioxypyi-zin-2-yI)-2-tcit-btitlY- I I-imiiiazol-5 yI )pyi in i in-2- yIai niio) pr-opai i-2 -yIcairbaiuiaicI I S(4N(((S)--,-15imlino-6-mTclhox)ypyr17-in-2-y)-2-ici-l-biiYI-Il1-l-irniclnlzol-5 yI )p)y-rii ci in -2 -,I amino) pr-opant-2-y I)-? -iiletlioxyprioI)arilinlid c; 4-(4-(6-ainio-5-mcithioxypyi(in-3-y)--Cthyl- 11-l-iiidazol-5-yI)-N-(2-micthoxypyridifl 4 -vI)pyri midin-2-aniine; 4-(4-(5-aminio-6-inethoxypyr-ziln-2-YIl)-2-teirt-btityt-11--imidaozol-5-yI)-N-(2 mnetlho Xyyri i n-4 -yI)pyi'i mi ci ii-2-amiine; 58 4-(4-(6--arinno -5-rnetlioxypyiidi-3-y)-2-imctlhy- I -I-imid azolI-5-yI)-N-(2 inethoxypyri d in-4 -y!)pyrim idin-2- amine; (S)-N-( I -(4-(4 -(5-ai no-6-mictlhoxypyr-azin-2 -yi)-2-cyclopi-opyl-1 Imnida7.oI-5 yI)p)yri midin-2-ylami o) propan-2-yI)- 2 - incthoxyucctarnl idc; (S)-mcthyl 1 -(4 -(4-(5-ami no-6-inethoxypya7A n-2.yI)-2-( I -11 eth ylcyclopropyl)- 1 indaizc) -5 -yi)pyimid iii -2-yli am no)lpropai-2 -yI carba matte; 4-(4-(6-amiino-5-methoxypyridil-3-yi)-2-(4ihliorophflyl)- i i--imidazol-5-yl)pyi-imidin) 2-amninc; (S)-N-(l -(4-(2-tcrti-butyl-4-(3-c;htoro- I 1--pyiolo[2,3-hllpyiiin-5-yl)-I 1-l-imidazol-5 yI)pyriid in-2- ylamnino)propan-2 -yl)-2-mciethoxyacctarn dc; (S)-incthyl ]I (44(6-amiino-5-nmethoxylyridil-3-yl)- 2

-(

4 ,-(ti fluioromicthyl)phcnyl)-lI -l imid azo I-5-yI)pyri i idi n-2-yI am in o)propan -2 -yI carbarn ate; .3-metlioxv-5-(2-phcnyl-4-(pyf-idin- 4 -yi)- I I 1-im-idazol-5.yI)pyridin-2-amiiie-I 5-(2-(4-tluiorophcnyl)-5-(pyridln-4-yI)- I 1-1-iid~azoI--'I)-3-meithoxypyridifl-2-aimine; 3-miethioxy-5-(1 -(pyidin-4-yD)-2-('i-(tri fluoiomethyl)pliciyl)- I l-imidazol-5-yI)pyridin 2-amine; 5-(2-(2,4-iifluor-opheniyl)-4-(pyridiri-1-yl)- I [--Iiimnilazol-5-yI)-3-miethnox yyidin-2-amlile; 3-met ,Iliox y-5 -(2 -phlcnyl-5-(p)i-i i ii-4 -y l)oxaizol -4 -yl )yid Ii-2-amiine; (S)-N-(] I (4-(4 -(6-amlio-5-mcthoxypyridi~n-3 -yI)- 2 -(4-[lii orophcnyl)oxazol-5 yI)pyiid~in-2-ylamiino)propan-2-yI)-2-mcthoxyaicetarnide; and (S)-N-(l I -4(-rio6iehxyy-ili2)I--4floolclloac15 yl)pyi-iniidin-2-ylaiiino)propaEn-2-I)-2-ii:lxietho ;Ct~iiiildc 10 ,81 In yet another aspect, the Invention provides a compound ofthe following Formula (VI): 59 R3 A R1 B (VI1) or a pharmaceutically acceptable salt thrcof, wherein: onc of A or 13 is N and the other of A or 3 is NR 2 ; one of dashed lines represent a single bond and the other represents a double bond, so the central ring is an inidazole; RI is selected from H, C-.- alkyl, cyclopropyl, phenyl, (4-OH)-phenyl, (4-CH 3 0)-phenyl, (4-CF 3

O)

phenyl, (4-F)-phenyl, (4-alkylsulfonyl)pipcrazin-I -yI, ancd -O-(C-l 2

)

1 -eNR iORi;

R

2 is selected from -1 and CI 2 alkyl; R- is selected from: -H N N N F N H /N N N N, H NI6 2 H N IN N N , N 60 N HN H N NH 2

NH

2 N N N 4 - 7N N N NH2 NH, N N. NRHCOCH, N N N H ~2.F,C 4 H N F N NH2 N N N N O~C .alkyl N O N NH, N L .

N I N 0-Cl u alkyl OHF ~N. KOH NH N N 11 N 2( N N Y ' N.i--, 4 a k N NH2> N ~ l2 N N. lN N k6

N

R' "is SCleC~CId Fromi:

OI

3 N NC N- 902 - \ Nf 2 NI 1*1 1/12 N N N Cil N H 0 A, Nil 2 'Na NN N N 0N NI10 11

C

11 ilkyl 0 N N ,N and N R1 1 > N and Rlo an d 10' in dcp~cndcnt Iy are c Ielected Fro i 1-1 and Ci..

1 alIkyl. 10 1491 1 n ano Ile cri b od Irncnt provided is a compound Of' Fo IMLIa (V II) Of- a pha-maCCtIOCalI ly acee 1 ,ibl e salIt thec f: 62

R-

2 R1 N R (VI) where in R', R23, and R" are as dcefincd flb Formula (VI). [01501 Various features relating to Formula (VI)-(VII) are given below. These features when referring to different substituents or variables can be combined with each other or with any other embodiments described in this application. In somlnc aspects, provided are compounds o f Formula (\I)-(VIl) having one or more of thc following features below. 101511 In onc embodiment: R ' is selected from HI, C 2 alkyl, phenyl, and -O-(CH 2

)

1

..

2 NR oR ni; I2 is selected from HI and C1.2 alkyl; R3 is selccted from: Ni 2

NHCOCH

3 N N N N 3 N N NNH2 "N /N N\ NNi N Oq N~~~ 1-N' "N ,N NN , N -~N /, N~ F1 /2~~ NNl N N 63 N F aNNH, N N 2I N NH 2

NI-I

2 N~ Cl-I 3 ' N 0-C 1 alkyl N OH-I N N 2 NH, CI N H 2 N N ~N NH-C, alkyl 'iNN OCHA 3 -L 0-Cl 4 aikyl c H3 N?[ N N3 2N. N - N 2 .. N 2 Ni '7cc N. N-0 N <I N H \ / cl H , NS'- N N YN O H 02 0 64 N NNO I I CI,., alkyl N N ~LN ~ N NN N / N N NI 12 N N NH, N NH 2 NUC1 N

OCI]

3 N N)I.CIii N N N NM-I, N N NH 2 . 65 N/ N NHCH 3 ' L N NH.CH 2 -CHC-O 11L NO

NH

2 ~ N and N N N2 H 10 1531 In another cmbodiment RA is selected from:

N?-

2 N Ni NOC11 3 N NH-CH-I N H O-CH1 NHC NHCHrC 9 L N NH22 N N N NH2 N NNil, 3 L-ZL A NHNC112To H -~0 N

NH

2 [0 1541 The in vcntion a so iNcludes isotopical ly-labcled compounds, that are structurally identical to those disclosed above, except that one or more atom is/are replaced by an isotope, i.e., an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature for the particular atom. Examples of isotopes that can be incurporated into compounds of thc invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, luinnc and chlorinc, such as 2H1, 3 H, 13C, T, 15N, 0, 40, P P, P, 'S, "F- and 'C1, respectively. Compounds of the pIesent invention. tautomers thereof, prodrugs thereof, and pharmaceutically acceptable salts of he compounds and ofthc prodrugs that contain the 66 a aforementioned isotopes and/or other isotopes of other atoms arc within the scope of this invention. Certain isotopicaly-labeled compounds of the present invention, for example those into which radioactive isotopes such as .3H- and IC are incorporated, arc useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., IH, and carbon- 14, i.e., C, isotopes are particularly preferred for their ease of preparation and delectability. These radiolabeled isoto p ically substiluted compounds are useful with quite low amounts ofthe isotope incorporated, e.g., 0.01 % isotopic substilution or More may provide a readily-detectable labeled species. Further, substitution with heavier isotopes such as deuterium, i.e. , 21-1, may afford certain therapeutic advantages resulting from greater metabolic stability. for example increased in vivo halfl'i fe or reduced dosage requirements and, hence, may be preferred in somic circumstances. For deuterated comnpouiids, it is typically desirable to incorporate at least 20% substitution of ) for 1-1; ollen at least 50% substitution ofl) for H; and preferably at least about 75% or at least about 90% replacement of D with 1-1 is provided. Isotopically labeled compounds of this invention and prodwgs thereof can generally be prepared by carrying out known or re ferenced procedures and by substituting a readily available isotopically labeled rcagcnt for a non-isotopically labeled reagent. I01551 The invention also provides pharmaceutical compositions comprising any of the compounds described above. In one aspect, the invention provides a pharmaceutical composition comprising a at least one compound of the invention as herein described, admixed with at least one pharimicctically acceptable excipient. In certain embodiments, the excipient is selected from the group consisting of corn starch, potato starch, tapioca starch, starch paste, pre-gelatinized starch, sugars, gelatin, natural gums, synthetic gums, sodium alginate, alginic acid, tragacanth, guar gum, cell Il ose, ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxypropyl methyleellulose, microcrystalline cellulose, magnesium aluminum silicate, polyvinyl pyrrolidone, tale, calcium carbonate, powdered cellulose, dextrates. kaolin. mannitol, silicic acid. sorbitol. agar-agar. sodium carbonate. croscarmcllose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, delays, sodium stcarate, calcium sicarate, magnesium stearate, Stearic acid, mineral oil, light mineral oil, glycerin, sorbitol, inannitol, polycthylciie glycol. other glycols, sodium lauryl sulfate, hydrogenated vegetable oil, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, soybean oil, zinc stearate, sodium olcate, ethyl olcate, ethyl laureate, silica, and combinations thereof. 67 10156] In some embodiments, the pharmaceuticals composition ofthe invention further comprises an addiltonalI therapeu tic agent. Examples of suitable additional therapeutic agents include an anticancer compound, ain analgesic, an antiemnetic, an antidepressant, and an anti-inflammatory agent. 101571 The invention also provides methods to use the compounds described herein as pharmaceutical agents. These agents are typically used to treat a condition mediated by Raf kinase. The invention thus provides a method to treat a condition mediated by Rafkinase, comprising administering to a subject in need thereof an effective amount ofa compound of the invention as described herein, or a pharmaceutical composition containing at least one such compound. In some embodiments, the Raf kinase is a mutant b-Raf kinase. |0 1581 In one embodiment, the compounds of the invention are used for treating cancer or for manufIcturing a medicament, which can be a muedicament for treating cancer. Specific cancers to be treated by the compounds or methods of the invention include, but are not limit ted to, lung carcinoma, pancreatic carcinoma, bladder carcinoma, colon carcinoma, inyeloid disorders, prostate cancer, thyroid cancer, melanoma, -and adenomIias. [0 1591 In one embodiment, the invention provides a method to treat cancer, comprising administering to a subject in need of such treatment an effective amount of a compound as described herein, or of a pharmaceutical composition containing at least one compound described herein. Cancers to be treated by these compounds and pharmaceutical compositions include lung carcinoma, pancreatic carcinoma, bladder carcinoma, colon carcinoma, mycloid disorders, melanomas, and adlenomras. Treatment carn fu riher inluaode administering to the subject an additional therapeutic agent, which can be an anticancer drug, a pain medication, an antiemetic, an antidepressant or an anti-inflammatory agent. 10 1601 In certain embodiments, the additional therapeutic agent is a different Raf kinase inhibitor or an inhibitor of MEK, m'lOR, 113K, CDK9, PAK, Protein Kinrase C, a MAP kinase, a MAPK Kinmsc, or ER K. This additional therapeutic agent can be administered to the subject concurrently with the compound of the invention, or the Iwo can be administered separately but timed so that they act concurrent ly in the subject's body. In certain emnbodimnents, the additional therapeutic agent is an arnicancer drug selected from irinotecan, topotecan, gemcitabine, 5-fluorouracil, leucovorin 68 carboplatin, cisplatin, oxaliplatin, taxancs, tezacitabine, cyclophosphainide, vinca alkaloids, imatinib, anthracyclines, rituximab and trastuzurmab. Comdilions Mediated by R af kinase 101611 Compounds and formulations discussed heroin arc useful for trcatmcnt or prevention ofa condition mediated or characterized by Rafkinasc, such as cancer. As used herein, "treatment or prevention of a condition mediated by Rafkinasc" indicates admin istering one or more of the compounds discussed herein, with or without additional pharmaceutical agents, in order to reduce, eliminate, and/or prevent either the condition or or one or moe Symptoms oF the condition, or to retard the progression of thc disease or of'onc or more symptoms ofthc condition, or to reduce the severity of the disease or ofone or more symptoms of the condition. 10 1621 In one aspect, the present invention provides methods oftreating individuals suffering from a condition mediated or characterized by Raf kinase (AKA, a Raf related disorder), such as cancer. Thus, the present invention provides methods of treating an individual in need of such Ireatment comprising administering to the subject a thcrapeutically cffcctivc amount of a compound one or more of the compounds described herein, either alone or in combination with other anticancer agents. 101631 In other aspects, the present invention provides methods for the tirc;itment or prevention of a Raf related disorders in an individual in need ofsuch treatment or prevention, comprising administering to said subject one or more of the compounds of the in vention in an amount efIctive to reduce or prevent tumor growth in the individual. 101641 Antiestrogens, such as tamoxifern, inhibit breast cancer growth through induction of ecll cycle arrest, that requires the action of the cell cycle inhibitor p27Kip. Recently, it has been shown that activation of the Ras-Raf-MAP Kinasc pathway alters the phosphorylation status of'p27Kip such that its inhibitory activity in arresting the cell cycle is attenuated, thereby contributing to antiestrogen resistance (Donovan et al, J. Biol. Chem. 276:40888, 2001). As reported by Donovan ct al., inhibition ofM APIK signaling through treatment with MEK inhibitor changed the phosphorylation status of p27 in hormone refractory breast cancer cell lines and in so doing restored 69 hormone sensitivity. Accordingly, in one aspect, the compounds of the invention may be used in the treatment of hormone dependent cancers, such as breast and prostate cancers, to reverse hormone resistance commonly seen in these cancers with conventional anticancer agents. 101651 In yet other aspects, the present invention provides coMpounds which are inhibitors of the enzyme Ra fkinase. Since the enzyme is a downstream effector of p21 RIs, the instant inhibitors are useful in pharmaceutical compositions for human or veterinary use wherC inhibition oftlie Raf kinase pathway is indicated, e.g., in the treatment of tumors and/or cancerous cell growth red iated by Rafkinase. In particular, the compounds are useful in the treatment of an individual with, e.g., a solid tumor, since the progression of these cancers is dependent upon the Ras protein signal transduction cascade and therefore is susceptible to treatment by interruption of the cascade by inhibiting Rafkinase activity. Accordingly, the compounds of the invention are useful in treating cancers, such as, for example, carcinomas (e.g., of the lungs, pancreas, thyroid, bladder or colon, mycloid disorders (e.g.. mycloid leukemia) or adenomas (e.g., villous colon adenorna). [0 1661 In yet other aspects, the present invention provides methods for treating or preventing Raf kinasc-related disorders in an individual in need of such trcatmcnt or )revcntion, comprising admTlinistcring to said individual an amount of onc or more compounds of the invention effective to reduce or prevent tumor growth in the subject, in combination with at least one additional agent for the treatment of cancer. A number of suitable anticancer agents to be used as combination therapeutics are con teniplated for use in the methods of the present invention. Indeed, the present invention contemplates, but is not limited to, administration ofnumcrous anticancer agents such as: agents that induce apoptosis; polynucleotides (e.g., ribozymes); polypeptides (e.g.. enzymes); drugs: biological mimetics; alkaloids; alkylating agents; antitumor antibiotics; antimetabolites; hormones; platinuin compounds; monoclonal antibodies conjugated with anticancer drugs, toxins, and/or mdion uclieIcs; biological response modifiiers (e.g., interferons [e.g., IFN-a., etc.] and interleukins 1e.g., IL-2, etc.], etc.); adoptive inmmunotherapy agents; hematopoictic growth factors; agents that iriduce tumor cell differentiation (e.g., all-truns-rctinoic acid, ctc.); gene therapy reagents; antisense therapy reagents and nucleotides; tumor vaccines; inhibitors of angiogenesis, and the like. Numerous other examples ofchcrnotherapeutic compounds and anticancer therapies suitable for coadministration with the disclosed compounds of the invention are known to those skilled in the art. 70 101671 In yet other aspects, anticancer agents to be used in combination with compounds of the present invention comprise agents that induce or stimulate apoptosis. Agents that induce apoptosis include, but are not limited to, kinase inhibitors (e.g.. Epidcrmal Growth Factor Receptor [EGFR] kinasc inhibitor, Vascular Growth Factor Rcceptor [VGFR] k inasc inhibitor, Fibroblast Growth Factor Receptor [FGFRj kinase inhibitor, Platelet-derived Growth Factor Rcceptor [PGFR] I kinase inhibitor, and 13cr-AbI kinase inhibitors such as ST]-571, Glcevec, and Glivec]); antiscnsc molecules; antibodies [e.g., -Icreeptin and Rituxan]; anti-estrogens [e.g., raloxifenc and tamoxifen]; anti-androgcns [e.g., flutamide, bicalutamide, finasteride, aminoglutcthamide, ketoconazole, and corticosteroids]; cyclooxygenase 2 (COX-2) inhibitors [eg. Ceccoxib, meloxicam, NS-398, and non-steroidal antiinIi flammatory drugs (NSAIDs)]; and cancer chemotherapeutic drugs [e.g., i rilotecan (Camptosar), CPT-1 I , Iiudarabine (Fludara), dacarbazine (DTIC), dexarmethasone, nitoxantronc, Mylotarg, VP-16, cisplatinum, 5-FU, Doxorubicin, Taxotere or taxoll; cellular signaling molecules; ceramides and cytokines; and staurosporine, and the like. [01681 In certain embodiments, a Raf inhibitor compound of the invention can be combined with an inhibitor of MEK, ERK, P3K. motor, or a dual P t3K-mTOR inhibitor. In addition, the compounds may be combined with inhibitors of VEGF, EGFR, FGFR, HER-2, FLT-3, or HIDAC to provide compositions for treatment of certain disorders including cancers described herein. 10 1691 In hernatological cancers, such as chronic myelogenous leukemia (CM I), chromosomal translocat ion is responsible for the constitutively activated 13cr-Abl tyrosine kinusc. The afflicted patients are responsive to Gleevec, a small molecule lyrosine kinase inhibitor, as a -esult of inhibition of AbI kinase activity. However, many patients with advanced stage disease respond to Gleevec initially, but then relapse later due to resistance-conferring mutations in the Abi kinase domain. In viro- studies have demonstrated that Bcr-Ahl employs the R af kinase pathway to elicit its effects. In addition, inhibiting more than one kinase in the sane pathway provides additional protection against resistance-conferring notations. Accordingly, in another aspect of the invention, the compotinds of the invention are used in combination with at least one additional agent, such as Gleevcc, in the treatment ofhematological cancers, such as chronic myelogenous leukemia (CML), to reverse or prevent resistance to the at least one additional agent. 71 [0 1701 In yet other aspects, the cancer to be treated is characterized by increased Rafkinasc activity, for example, one which overexpresses wild-type b- or c-Raf kinase or that expresses an activating mutant Raf kinase, for example a mutant b-Raf kinase. Cancers wherein a mutated Rafkinasc has been detected include melanoma, colorectal cancer, ovarian cancer, gliomas, anaplastic thyroid carcinoma, papillary thyroid carcinoma, Barrett's esophagcal carcinoma, adenocarcinomas, sarcomas, breast cancer, livci cancer, acute myeloid leukemia, head and neck squamous cell carcinoma, lung cancer, gastric carcinoma, non--lodgkins lyimphoarn, and cholangiocarcinoma. Mulated b-Raf kinase is especially prevalent in many melanomas. The mutations in b-Raf that have been detected iII human cancers are point mutations that occur in the kinase domain and are clustered in exons I I and 15 of the gene which contains several regulatory phosphorylation sites. The most prevalent mutlation results in a V600E mutation in b-Raf. The V600E, mutation was formerly designated V599E due to an error in the Genl3ank nucleotide sequence. Bccram, et al., Journal of Clinical Oncology (2005). 23(27):6771-6790 and U.S. Pat. Application Nos. 20080 1768,40, 20060293340, and 20060079194. In some embodiments, the invention thus provides a method to treat a condition mediated by the mutated b-Raf, (V600E). 101711 In yet other aspects, a sample of diseased tissue may be taken from the patient, for example, as a result ofa biopsy or resection, and tested to detcrminc whether the tissue produces a mutant raf kinase, such as a mutant b-Raf kinase or overexpresses a wild-type Rafkinase, such as wild-type b or c-Rafkinase. If the test indicates that mutant Rafkinase is produced or that a Raf kinasc is overproduced in the diseased tissue, the patient is treated by administration of an effective Raf inhibiting amount ofa Raf inhibitor compound described herein. 101721 Tissue samples are tested by methods generally known in the art. For example, b-Raf mutations are detected by allele specific PCR, DIHIPLC, mass spectropscopy and overexpression of wild-type b- or e-Raf detected by immunohistochemistry, immunofluorcscensc, or Western blot analysis. Frmlat)ions 101731 The compounds described herein can be in formulations (including pharmaceutical compositions) by formulation with additives such as excipicnts (e.g., one or more excipients), an tioxidants (e.g., one or more antioxidants), stabilizers (e.g., one or morc stabi lizers), preservatives 72 (e.g., one or more preservatives), pH adjusting and buffering agents (e.g., one or more pH adjusting and/or buffering agents), tonicity adjusting agents (e.g., one or more tonicity adjusting agents), thickening agents (e.g., one or more thickening agents), suspending agents (e.g., one or more suspending agents), binding agents (e.g., one or more binding agents, viscosity-increasing agents (e.g., one or more viscosity-increasing agents), and the like, either alone or together with other anticancer agents, provided that the additional components are pharmacecutically acceptable for the particular condition to be treated. In some embodiments, the fornulation may include combinations of two or more of the additional components as described herein (e.g., 2, 3, 4, 5, 6, 7, 8, or more additional components). In some embodiments, the additives include processing agents and drug dcliveiy inodifiers and enhancers, such as, for example, calciurn phosphate, magnesium stearatc, tale, monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropy:-i-cyclodcxtrin, polyvinylpyrrolidinone, low melting waxes, ion exchange resins, and the like, as well as combinations of any two or more thereof. Other suitable pharmaceutically acceptable excipients are described in REMINGTON'S PItARMACEUTICAL SCIENCt.s, Mack Pub. Co., New Jersey (1991), and REMINGTON: TEt SCtENCE AND PRACTIC. OF PHARMACY, Lippincott Williams & Wilkins, Philadelphia, 20th edition (2003) and 2 tst edition (2005). 101741 Some exemplary excipients may include corn starch, potato starch, tapioca starch, starch paste, pre-gelatinized starch, sugars, gelatin, natural gimis, synthetic gums, sodium alginate, alginic acid, tragacanth, guar gum, cellulose, ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodi un carboxymnethylcellulose, met hyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium aluninmn silicate, polyvinyl pyrrolidone, talc, calcium carbonate, powdered cellulose, dextrates, kaolin, manitiol, silicic acid, sorbitol, agar-agar, sodiuii carbonatc, croscarinellose sodiumin, eros povi done, polacrilin potassium, sodium starch glycolatc, chlys, sodium sicarate, calcium stearate, magnesium stearate, stearic acid, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, sodium lauryl sulfate, hydrogenated vegetable oil, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, soybean oil, zinc slearate, sodium oleatc, ethyl olcate, ethyl lauiieale, silica, and combinations thereof 73 [01751 The formulations may vary according to the condition to be treated, the amount of compound to be administered, the condition of the individual, and other variables that will readily be apparent to one of ordinary skill in the art in view of the teachings provided herein. [01761 In some embodiments, the pH of the formulations may be from about 3.5 to about 9.5, or from about 4.5 to about 7.5, or from about 5.0 to about 7.0, from about 5.5 to about 7.0, from about 6.0 to about 7.0. Administralion and Dosage 101771 The formulations comprising one or more compounds described herein may be administered in conjunction with one or more of the pharmaceutical agents as described herein and as known in the art. including one or more additional pharmaceutical agetis to further reduce the occurrence and/or severity of symptoms and/or clinical manifestations thereof, as well as pharmaceutical agents that treat or prevent the undcrlying conditions, or in conjunction with (e.g., prior to, concurrently with, or after) additional treatment modalities. The formulations as described herein may be administered before, concurrently with, or after the administration of one or more of the pharmaceutical agents described herein. The compounds described herein may also be administered in conjunction with (e.g., prior to, concurrently with, or after) agents to alleviate the symptoms associated with either the condition or the treatment regimen. [01781 While the compounds of the invention can be administered as the sole active pharmaceutical agent i a. formwi nation, they can also be used in combination with one or more other agents used in the treatmen of cancer. Representative agents useful in combination with the compounds of the invention for the treatment of cancer include, for example, irinotecan, lopotecan, gemcitabine, 5 fluorouracil, leucovorin carboplatin, cisplatin, oxaliplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib (Gleevec), anthracyclines, rituximab, trastuzutnab, as well as other cancer chemotherapeutic agents. 101791 The above compounds to be employed in combination with the compounds of the invention will be used in therapeutic amounts as indicated in the PHYSCIANS' DESK REFERENCE (PDR) 47th Edition (1993), or such therapeutically useful amounts as would be known to one of ordinary skill in the art. 74 101801 The compounds of the invention and the other anticancer agents can be administered at the recommended maximum clinical dosage or at lower doses. Dosage levels of the active compounds in the compositions of the invention may be varied so as to obtain a desired therapeutic response dcpcnding on the route of administration, scvcrity of the discasc and the characteristics and rcsponsc of the patient. The combination can be administered as separate compositions or as a single dosage form containing both agents. Whcn administered as a combination, the therapeutic agents can be lormuhkitcd as sCparate compositions, which are given at the same timc or different times, or the therapeutic agents, can be given as a single composition. 10181 As will be well appreciated by the skilled artisan, for particular conditions, different pharmaceutical agent(s) and/or additional treatment modality(ies) may be indicated. 101821 The formulations and methods described herein may be used alone or in conjunction with (e.g., prior to, concurrently with, or after) other modes of ticatmenis (e.g., adjunctive therapy with additional pharmaceutical agents dcscribed herein with reldrcnce to pharmaceutical formulations of the claimed compounds or known to the skilled artisan) used to treat or prevent the condition being treated/prcvented and/or administration of an additional treatment modality, or combinations of the foregone). For example, in combination with one or more additional pharmaceutical agents as described herein and known to those of skill in the art and/or currently available treatment modalities, including, for example, surgery or radiotherapy. As used herein, the tenn "additional treatment modality" rcfbrs to treatinent/prevention of the conditions described herein without the use of a pharmaceutical agent (e.g., surgery, radiotherapy, etc.). Where combinations of pharmaceutical agent(s) andVor additional treatment modality(ics) are used, they may be, independently, admin istercd prior to, concurrently with, or afler administration of one or more of the quinuclidine compound(s) (or foriulation(s) thereof) as described herein. 101831 The optimal combination of one or more additional treatment modalities and/or additional pharmaceutical agents ini conjunction with administration of the formulations described herein, can be determined by an attending physician or veterinarian based oi the individual and taking into coiisidcration the various factors effecting the particular individual, including those described herein. 101841 The formulations described hcrcin will generally be used in an amount cffectivc to achicc the inicnded result, for example in an amount cfTective to treat or prevent the particular condition 75 being treated or prevented. The formulations may be administered therapeutically to achieve therapeutic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying condition being treated and/or eradication or amelioration of one or more of the symptoms associated with the underlying condition such that the individual reports an improvement in lecli ng or condition, notwithstanding that the individual may still be aMicted with the underlying condition. Therapeutic benefit also includes halting or slowing the progress ion of the condition, regardless of whether improvement is realized. 101851 The amount of the formulation administered in order to administer an effective amount will depend upon a variety of factors, including, for example, the particuhir condition being treated, the frequency of administration, the particular formulation being administered, the severity of the condition being treated and the age, weight and general health of the individual, the adverse effects experienced by the individual being treated, etc. Determination of an effective dosage is within the capabilities of those skilled in the art, particularly in view of the teachings provided herein. Dosages may also be estimated using in vivo animal models. 101861 The compounds of the invention may he adininistered generally (e.g., orally or rectally), parenterally (e.g.. sublingually, by injection, or by inhalation (e.g.. as mists or sprays)), or topically, in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. For example, suitable modes of administration include oral, subcutancous, trunsdermal, transmucosal, iontophoretic, intravenous, intraarterial, intramuscular, intraperitoneal, intranasal (e.g., via nasal mucosa), subdural, rectal, gastrointestinal, and the like, and directly to a specific or affected organ or tissue. Foi delvciy to the central nervous system, spinal and cpiduiral adin i nistration, or administration to cerebral ventricles, can be used. Topical administration may also involve the use of transdermal administration such as transderinal patches or iontophorcsis devices. The term parenteral as used herein includes subcutaneous injections, intravenlous, iiinti scular. intrastcrnal injection. or infusion techniques. [01871 The compounds may be mixed with pharmaceutically acceptable carriers, adjuvants, and vehicles appropriate for the desired route of administration. In some embodiments, the route of administration is orally. In other embodiments, formulations are suitable for oral administration. The compounds described fbr use herein can be administered in solid form, in liquid form, in aerosol 76 form, or in the form of tablets, pills, powder mixtures, capsules, granules, injectables, creams, solutions, suppositories, enemas, colonic irrigations, emulsions, dispersions, food premnixes, and in other suitable forms. The routc of administration may vary according to the condition to be treated. Additional methods of administration arc known in the ail. 101881 Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or .suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in propylene glycol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may bc employed including synthetic mono- or diglycerides. In addition, fatty acids such as olcic acid find use in the preparation of injectables. 101891 Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols that are solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum and release the d r g. 101901 Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and grani les. In such solid dosage fiormis, the active compound may be admixed with at least one inert dilucnt such as sucrose, lactose, or starch. Such dosage forms may also comprise additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enterie coatings. 101911 Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such formulations may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, cyclodextrins, and sweetening, flavoring, and perfuming agents. 77 10 1921 The compounds of the present invention can also be administered in the form of liposomes. As is known in the arl, liposomcs are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present formulitions in liposorne form can contain, in addition to a compound of the present inveniion, stabilizers, preservatives, excipients, and the like. Suitable lipids are the phospholipids and phosphatidyl cholines (lceithins), both natural and synthetic. Methods to lbrm liposomes are known in the art. See, for example, Prescott, Ed., MtiETHOD)S IN CELL l3IOLOGY, Volume XIV, Academic Prcss, New York, N.W., p. 33 el seq (1976). [0 1931 The componIds can be administered in prodrug form. Suitable prodrug formulations include, but are not limited to, peptide conjugates of the compounds of the invention and esters of compounds of the inventions. Further discussion of suitable prodrugs is provided in H. Bundgaard, )ESGN of PRODRUGS, New York: Elsevier, 1985; in R. Silverman, THE ORGANIC CHEMISTRY OF DRUG DESIGN AND DRuC, ACTION, Boston: Elsevier, 2004; in R.L. Juliano (cd.), BiOLOGilCAL APPROACtt.HS TO THE CONTROLL..H) DJ.:tUVtERY OF DRUGS (Annals of the New York Academy of Sciences, v. 507), New York: New York Academy of Sciences, 1987; and in E B. Roche (ed.), DEtSIGN 0tF B3tOPHARMACEUTICAL PROPERTtES THROUGH PRODRUGS AND ANALOGS (Symposium sponsored by Medicinal Chemistry Section, APhA Academy of Pharmaceutical Sciences, November 1976 national meeting, Orlando, Florida), Washington: The Academy, 1977. In some variations, the compounds are administered in a form of pharmaceutically acceptable esters. 101941 The frequency and duration of administration of the formulation will depend on the condition bcing treated, the condition of the individual, and the like. The formulation may be administered to the individual one or more times, for example, 2, 3, 4, 5, 10, 15, 20, or more times. The formulation may be administered to the individual, flor example, once a day, 2 times a day, 3 times a day, or more than 3 times a day. The formultion may also be administered to the individual, for example, less than once a day, fbr example, every other day, every third day, every week, or less frequently. The formulation may be administered over a period of days, weeks, or months. 101951 The amount of active ingredient that nay be combined with the carrier materials to produce a single dosage form will vary depending upon the host to which the active ingredient is administered 78 and the particular mode of administration. It will be understood, however, that the specific dose level for any particular individual will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, body area, body mass index (13MI), general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the type, progression, and severity of the particular disease undergoing therapy. The pharnmaceuti cal unit dosage chosen is usually fabricated and admirnistcrcd to provide a defined final concentration of drug in the blood, tissues, organs, or other targeted region of the body. The therapeutically effective amount for a given situation can be readily determined by routine experimentation and is within the skill andjudgment of the ordinary clinician. 101961 Examples of dosages which can be used are a therapeutically effective amount within the dosage range of about 0.1 pg/kg to about 300 mg/kg, or within about 1.0 pg/kg to about 40 mg/kg body weight, or within about 1.0 pg/kg to about 20 mg/kg body weight, or within about 1.0 pg/kg to about 10 mg/kg body weight, or within about 10.0 pg/kg to about 10 mg/kg body weight, or within about 100 pg/kg to about 10 mg/kg body weight, or within about 1.0 mg/kg to about 10 mg/kg body weight, or within about 10 mg/kg to about 100 mg/kg body weight, or within about 50 mg/kg to about 150 mg/kg body weight, or within about 100 mg/kg to about 200 mgikg body weight, or within about 150 mg/kg to about 250 mg/kg body weight, or within about 200 mg/kg to about 300 mg/kg body weight, or within about 250 mg/kg to about 300 mg/kg body weight. Other dosages which can be used are about 0.01 mg/kg body weight, about 0.1 mg/kg body weight, about I mg/kg body weight, about 10 mg/kg body weight, about 20 mg/kg body weight, about 30 mg/kg body weight, about 40 mg/kg body weight, about 50 mg/kg body weight, about 75 mg/kg body weight, about 100 mg/kg body weight, about 125 mg/kg body weight, about 150 mg/kg body weight, about 175 mg/kg body weight, about 200 mg/kg body weight, about 225 mg/kg body weight, about 250 mg/kg body weight. about 275 mg/kg body weight, or about 300 mg/kg body weight. Compounds of the present invention rnay be administered iii a single daily dose, or the total daily dosage may be administered in divided dosage of two, three or four times daily. 101971 For topical application, the formulation may be administered, For example transdermally at about 5 mg to about 100 nig over 24 hours. For IV administration, the formulation may be administcrcd at a dosage of, for example, from about 0.1 mg per day to about 500 mg per day, 79 typically firom about I to about 200 mg/day. For oral administration, the formulation may be administered at a dosage of, for example, from about I mg per day to about 1500 mg per day, often from about 5 to about 250 mg/day. 101981 When additional active agents Ure used in combination with the compounds of the present invention, the additional active agents may generally be employed in therapeutic amounts as indicated in the PHYSICIANS' DESK REFERFNCE (PDR) 53rd Edition (1999), or such therapeutically useful amounts as would be known to one of ordinary skill in the art 101991 The compounds of the invention and the other therapeutically active agents can be administered at the recommended maximum clinical dosage or at lower doses. Dosage levels of the active compounds in the formulations of the invention may be varied so as to obtain a desired therapeutic response depending on the route of administration, severity of the disease and the response of the individual. When adminisiered in combination with other pharmaceutical agents, the phannaceutical agents can be formulated as separate formulations that are given at the same time or di fferent times, oi the pharmaceutical agents can be given as a single formulation. Kis 102001 The invention also provides articles of manufaciluire and kits containing materials useful for the treatment Or prevention of a condition mediated by Raf kinase. T'he article of manufacture nay comprise a contailner with ii label. Suitable containers include, for example, bottles, vials, and Lest tubes. The containers may be formed from a variety of materials such as glass or plastic. The container may hold a formulation having an active agent which is effective in treating or preventing conditions mediated by Raf kinase. The active agent in the formulation is one or more of the compounds of the invention. The label on the container may indicate that the formulation is used for treating or suppressing conditions mediated by Raf kinase, and may also indicate directions for either in vivo or in viiro use, such as those described above. (02011 The invention also provides kits comprising any one or more of the compounds of the invention. In some embodiments, the kit of the invention comprises the container described above. fn other embodinents, the kit of the invention comprises the container described above and a second container comprising a buffer. It may further include other materials desirable from a commercial 80 and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for performing any methods described herein. 102021 In other aspects, the kits may be used for any of the methods described herein, including, for example, to treat an individual with one or more conditions mediated by or characterized by Raf kinase, or to suppress one or more such conditions. 102031 In certain embodiments the kits may include a dosage amoutnt of at least one formulation as disclosed herein. Kits may also comprise a means for the delivery of the formulation thereof. 102041 The kits may include other pharmaceuticals agents for use in conjunction with the formulation described herein. In some variations, the pharmaceutical agent(s) may be one or more anti-cancer drugss. These agents may be provided in a separate form, or mixed with the compounds of the present invention, provided such mixing does not reduce the effectiveness of either the pharmaceutical agent or forinnulation described herein and is compatible with the route of administration. Similarly the kits may include additional agents for adjunctive therapy or other agents known to the skilled artisan as effective in the treatment or prevention of the conditions described herein. 102051 Thc kits may optionally include appropriate instructions for preparation and administration of' the formulation, side effects of the formulation, and any othcr relevant information. The instructions may be in any suitable format, including, but not limited to, printed matter. videotape, computer readable disk, optical disc or directions to internet-based instructions. 102061 In another aspect of the invention, kits for treating an individual who suffers from or is susceptible to the conditions described herein are provided, comprising a first container comprising a dosage arnount of a composition as disclosed herein, and instructions for use. The container may be any of those known in the art and appropriate for storage and delivery ofintravenous formulation. In certain embodiments the kit further comprises a second container comprising a pharmaceutically acceptable carrier, dilient, adjuvant, etc. for preparation of the formulation to be administered to the individual. 102071 Kits may also be provided that contain sufficient dosages of the compounds described herein (including formulat ions thereof) to provide effective treatment for an individual for an extended 81 period, such as 1-3 days, 1-5 days, a week, 2 weeks, 3, weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 6 months, 7/ month hs, 8 months, 9 months or more. 102081 Kits may also include multiple doses of the formulation and instructions for use and packaged in quantities sufficient for storage and use in pharmacies, for example, hospital pharmacies and compounding pharmacies. 10209] The kits may include the composition as described herein packaged in either a unit dosage form or in a multi-use form. The kits may also include intiltple units of the unit dose forni. [02101 In certain embodiients, are provided a formulation described herein in a unit dose fonn. In other cm bodimnierits a formulation may be provided in a mnulti-dose form (e.g., a blister pack, etc.). |02111 The present invention also relates to the processes for preparing the compounds of the invention and to the synthetic intermediates useful in such processes, as described in detail below. Synthetic Methods 102121 Compounds of the invention may be prepared using a number of methods familiar to one of skill in the art. [he discussion below is offered to illustrate certain of the diverse methods available for Ise in assembling the compounds of the invention. However, the discussion is not intended to define the scope ofthe reactions or reaction sequences that are useful in preparing compounds ofthe invention. 102131 For compounds with the general structure as depicted by 4, the following synthetic approach may be employed 82 Method A Br NH N >Ri + H 2 N _ MF H2N N 1. NaH, SEMCI Br N 0 1 1. Pd(O). baso R X N 2.3r?, DCM N N IN N N SEM -o N ra x r 2 3 4 2. aq. HCI X =N or C 102141 Condensation between a bromoketonc and a substituted bcnzarnidinc furnishes the disubstituted inidazole 1. Prosaic SEM protection and bromination affords brornoimidazolc 2 as a miXtliC regioiSOmers. Suzuki cross coupling with a substituted aminopyridine or pyrimidine boronate ester 3 and final deprotection results in the trisubstituted imidazole 4. Protection of the i midazole ni itrogen is not restricted to the SEM group; other protecting group may be used (see Grcenc and Wuts, PlntFv(ii. GROUPS IN OR;ANIC SYNnTlsis, 2'" Edition, John Wiley & Sons). 102151 An alternative approach to access analogs as represented by 4 is described in Method B. 83 Method B Br NaH, SEMCI Br31 N Pd(0), base Br N Br -Br Br Br N (0)B- Br N H SEM SEM 5 6 7 HN -N HN N Pd(O), base McO R, Pd(O), base R2 117N N Mr N1 H HS N r EM (HO), B- N N 08 2. aq. HCI 3 X=NoC 102161 SEM protected 2,4,5-tribromoimidazole 6 can be selectively C-2 arylated using the Suzuki cross-coupling reaction (Revesz, L.; Bonne, F.; Makavou, P. Tetrahedron Leuers, 1998, 39, 5171.) to provide the substituted dibrornoinidazole 7. A second Suzuki cross-coupling with boronate ester 3 gives the monobromninatcd imidazolc 8 as a mixture of regioisomcrs. Final cross-coupling with 4 pyridyl bOrOnic acid and SEM deprotection furnishes the trisubstituted imidazole 4. The Suzuki cross couplings described in this route may be generally substituted with the corresponding Stille reactions where by the boronatc esler or boronic acid is replaced with the corresponding stannanc. 102171 A variation of Method B that involves a more circuitous route from dibromoimidazole 7 to mnonebrominated imidazole 8 is ccscribed below. 84 Br N R, 1. n-BuLi Br N R Pd(o), basic Rr N 2.120 H SEM H 2 N Ni SEM N 2 IM 7 9 3 x Nor C NN HNN N MoO X N _ 9 McO X SEM SEM 10 8 102181 Dirccted lithiation by the SEM protecting group yields the corresponding monobromoimidazolc 9. Cross-coupling followed by bromination of the remaining unsubstituted C 5 position of 10 gives the common intermediate 8. 102191 Mcthod 13 is not rcstrictcd to C-2 aryl imidazoIcs. For example for C-2 alkyl imidazoIcs, the following reaction sequence may be employed to access the kcy internediate It which then follows the rest of Method 13. O O 1. NH Br N H H HiR3 2. Hr 2 Br N 3. SEMCI H R 3 = alkyl11 [02201 A geicral approach to functionalized C-5 pyrimidinyl imidazoles such as 12 can be realized using Method C (Bursavich, M.G.; Lombardi, S.; Gilbcr, A.M. Oiganic Leiters, 2005, 4113.). M'tethol C N M R1 1. n-BuLi N r N NH SE .4,-N N SN Hr N /M -. SNP N.EN 2,N N NN N 7 3. 0DO or MnO- CI 12 R2,N.gR 13 85 [022 11 Monolithiation of dibromoirnidazole 7 by one equivalent of n-BuLi followed by treatment with 2-chloropyrimidinc results in the dihydrochliorpyrimidinc adduct which is oxidized by DDQ or MnO 2 to furnish the 4-broro-5-(2-chloropyrimidin-3-yl)inida7zole 12. Displacement of the chloro group by simple primary and secondary amines afford am ino substituted pyrimidines as depicted by 13. 2-Methylthiopyrirnidine may be used instead (Itami, K.; Yarnazaki, D.; Yoshida, J. JACS, 2004, 126. 15396.) The thiorethyl group can be readily oxidized to the sulfonc or sulfoxide in preparation for amine displaccncnt. Further elaboration of 13 may be completed in accordance with Miethod A. [02221 Conversely, in Method 1), chloropyrimidinc 12 may be coupled to anilines and aminoheterocycles under Buchwald conditions to provide substituted pyrinidines with the general structure 14. Subsequent cross-coupling and deprotection can he effected as per Method A. Method 1) Pd(O), base

-

K SEM rI SEM N N N N N ci 12 HN ~ 1 x = N or C x 4 1(02231 For oxazolcs with the general structure as illustrated by 19, the synthetic approach depicted by Method E may be used. 86 Method E, - NH 2 oxaly) chloride N. TMSCHN 2 0 N R 1 15 16 H2 N IN (CISO2)2() TfD N - 1. Pd(O). base XN N 2,6-uidino 03 N1N N - X R 17 R2 X o' 18 3 2. Br 2 X= N or C HN N Fd(O), base --- - -- R2 X t'91~ 0 0 t -\N NO N 19 [02241 Treatment of a benzamidinc with oxalyl chloride generates an acyl isocyanate 15 (McGrcw, L.A.; Sweeny, W.: Campbell, T.W.; Foldi, V.S../. Org. Chen. 1964, 29, 3002) which followed by reaction with TMSCHN 2 fihrnishes the oxazolonc 16 (Iari, Y.; Iguchi, T.; Aoyama, T. Synthesis 2004, 1359). Exposure to trinflic anhydridc furnishes the coupling partner 17. The subsequent Suzuki reaction (Flegeaui, .F.; Popkin, M.E.; Greancy, M.F. Org. Left. 2006, 8, 2495) and bromination of the remaining unsubstituted C-5 position afTords 18. Final elaboration to 19 is accomplished by Suzuki cross-coupling with 4-pyridyl boronic acid. The converse oxazolc regioisomer may be accessed by simply reversing the order of the cross-coupling reactions. [0225 For access to (-5 pyrimidinyl oxazoles, as depicted by intermediate 20, the reaction sequence illustrated in Method F may he employed. 87 Method F, n + N BCi NEt: NR N 3S, A BN Br N3B + R1 -- C 0 20 .. R i 1.LDA / Br 0 2. C-c 21 NN 22 3. DDOQ or MnO 2 CI 102261 The precursor oxazoline 20 can be prepared by to:atncnt of an aryl acid chloride with 2 bromocthylamine hydrobrornide (Kajima, C.; Arao, f. Synthesis 1989, 873). Concomitant oxidation and bromination can be achieved by using NBS in the presence of AII3N to yield 21. Deprotonation using LDA results in a halogen migration (Stanetty, P.,; Spina, M.; Mihovilovic, M.D. Synihesis 2005, 1433), which followed by addition into 2-chloropyrimidine and oxidation furnishes the C-5 pyriinidinyl oxazolc 22. Further elaboration may be achicvc(d using Method A. 102271 Preparative separations arc carried out using a CornbiFlash Rf system (Teledync Isco Inc. Lincoln, NE) in combination with RediSep Nonnal-Phasc Silica Flash Columns (4 g -120 g, 35-70 micron particle size; Teledync Isco Ine.), or by lash coluini chromatography using silica gel (230-400 mesh) packing material, or by HL-C using a Watcrs 2767 Sample Manager, C-18 reversed phase column, 30X50 min, flow 75 mnL/min. Typical solvents employed for the Combillash systcni and flash colurnn chromatography are dichloroietliane, methanol, ethyl acetate, hexane, acetone, aq ucous imm onin (or ammonium hydroxide), and timethyl arninc. Typical solvents employed for the reverse phase -P111LC are varying concentrations of aceioni rile and water with 0.1% trifluoroacetic acid. M icrowavc reactions conducted in a Creator or Initiator microwave system (Biotage, Charlottesville. VA) 88 Examples [02281 The present invention will be understood more readily by reference to the following examples, which arc provided by way of illustration and are not intended to bc limiting ofthe present inveitiOn. Example 1 3-Methoxy-5-(2-plheny1-5-(pyridinc-4-yl)- I H-iidIclazol-4-yl)pyridline-2-amine N N I H N/ 10229] Step I. Preparation of 4-(2-phnciyl-IH-imidazol1-4-yl)pyridine: 2-Bromo-l-(pyrindin-4 yl)ethanonc hydrobiomide (6.4 g, 23 mmol) was added portionwise to a solution of benzarnidilie (11.2 g, 93 nimol) in dry DMF (50 mL) at 0 "C, maintaining an internal temperature of <5 'C. The stirred reaction was allowed to warm to rt over 2 h and then heated to 40 C for 16 h. The crude reaction was poured into saturated a(lucous NaRCO3 solution (600 mnL), and partition and extracted with EtOAe (3 X 300 mL). The combined organic layers were dried (Na 2 SOr) and evaporated. The resulting crude residue was purified by flash chromatography (SiO 2 , 100 : 0 - 90 : 10 DCM-MeOH) to give 3.68 g (72%) of4-(2-phenryl-H-imidazol-4-yl)pyridinc: 1-1 NMR (C)Cb) 6 9.73 (broad s, I H1), 8.61 (d1,./ = 6.0, 1.2 Hz, 2 -1), 7.91 (d,.J = 8.0, 1.6 Hz, 2 H-), 7.77 (d, / = 6.0, 1.2 Hz, 2 H), 7.57 (s, I -1), 7.48 (rn, 311). 102301 Step 2. Preparation of 4-(2-phenyl- I -((2-(trimcthylsilyl)cthoxy)methyl)- I Hl-imidazol-4 yl)pyridine: 60% Sodium hydride (200 mg , 5.0 mmol) was added slowly into a solution of 4-(2 phenyl- 1 -Uidazol-4 -yI)pyridine (1.0 g. 4.5 Mmol; Example 1, Step 1) in dry DMF (5 ml..) at 0*C. The reaction mixture was stirred at it for I h and re-cooled to 0 "C and 2 (trimethylsilyl)ctloxymethyl chloride (SEM chloride; 0.88 ml., 0.83g, 5.0 mmol) was added. The reaction was stirred at 10 "C for 2 h and quenched with water (40 niL). The mixture was partitioned anud extracted with EtOAc (3 X 60 mL) and the organic layers were combined, dried (Na 2

SO

4 ), and coicenirited. The resLilting residue was purified by flash chromatography (SiO 2 , 100 : 0 - 90 : 10 89 DCM-McOH) to give 1.2 g (75%) of 4-(2-phenyl-1-((2-(trimethylsilyl)cthoxy)rmethyl)-IH Imidazol-4-yl)p yridine: 'H NM R (CDC 1 ) 8 8.61 (d, J= 6.0, 1.2 H z, 2 H), 7.8 1 (d, J= 8.0, 1.6 H z, 2 H). 7.74 (d, J= 6.0, 1.2 H z, 2 -1), 7.58 (s, I -1), 7.49 (i, 3 H), 5.30 (s, 2 H), 3.60 (t, .= 8.0 Hz, 2 IJ), 0.94 (,. .I-- 8.0 Hz, 2 H), 0.00 (s, 9 H). [10 23 11 Step 3. Preparation of 4-(5-bromo-2-phenyl-I -((2-(trimethylsilyl)cthoxy)methyl)-l H imidazol-4-yl)pyridine: Bromine (0.2 nL, 3.8 mniol) was added slowly to a solution of4-(2-phenyl I-((2-(trimcthylsilyl)cthoxy)methyl)- I H-imii idazol-4-yl)pyridine (1.2 g, 3.41 mmol; Example I, Step 2) in dry DCM at 0 "C, followed by saturated aqueous Na 2

CO

3 solution (40 mnL). The reaction rmixture was then stirred at rt for 16 h.. The reaction was then allowed to partition and the layers separated. The aqueous phase was extracted with EtOAc (2 X 20 ml.,) and the combined organic phases were dried (Na 2 SO). The resulting residue was purified by lash chromatography (SiO 2 , 100 0 - 90 : 10 DCM-MeOH) to furnish 1.06 g (72%) of 4-(5-bromo-2-phenyl-I-((2 (trimethylsilyl)etlhoxy)iethyl)-Il H-imidazol-4-yl)pyridine: '11 NM R (400 MlHz, CDC1 3 ) 6 8.62-8.70 (m, 2 -1), 7.78-8.05 (in, 2 1-1), 7.77-7.86 (rn, 2 H), 7.45-7.54 (m, 3 -1), 5.37 (s, 2 1-), 3.60-3.70 (m. 2 11), 0.92-1.02 (in, 2 H), 0.003(s, 9 1-). 102321 Step 4. Preparation of 3-methoxy-5-(2-phenyl-5-(pyridine-4-yl)- I H-imidazol-4 -yI)pyridine 2-amine: A mixture of 4-(5-bromo-2-phenyl-1-((2-(triinethylsilyl)ethoxy)niethyl)- I-iridazol-4 yI)pyridine (620 ig, 1.4 iniol; Example I, Step 3), 3-imethoxy-5-(4,4,5,5-tetraimethyl-1,3,2 dioxoborolan-2-yl)pyridi ne-2-aininc (570 mg, 2.3 mrnol, Example 17, Step 3), and aqueous 2.0 M Na:CO 3 solution (2mL, 4 mmiol) in DM E (8 mL) was pLurge(d with Ar for 3 min. Pd(dppf) C 2 -DCM (34 mg, 0.04 inmol) was added and the reaction rnixture was purged with Ar For another 5 min. The reaction rnixture was then heated to and maintained at 90 "C for 18 h under Ar. The reaction was allowed to cool to rt and was concentrated. The resulting residue was suspended in EtOAc (15 rnL) and passed through a syringe filter. The filtrate was concentrated, treated with aqueous 3 M HCI solution (6 iL), and heated at 60 'C for 2 hi.. The reaction was allowed to cool to it and was evaporated in vacuo. The resulting residue was purified by reverse-phase FIPLC and lyopholized to afford 160 tmg (33%) of 3-mtethoxy-5-(2-phenyl-5-(pyridi ne-4-yl)-I/-/-imidazol-4-yl)pyridinc-2 amine as the TF'A salt: LCMS (m/z): 344.2 (MH+); la = 0.46 nun; IH NMR (CD 2 OD) 8 3.88 (s, 3 90 H), 6.22 (br s, 2 -1), 7.16 (m, I -I), 7.38 (1, J = 7.2 H z, I I-), 7.47 (t, J= 7.2 Hz, 2 H), 7.61 (m, 2 -1), 7.67 (m, I H), 8.05 (d, J = 6.0 lz, 2 H), 8.48 (d, J = 6.0 Hz, 2 H-). Exaniple 2 3-rncthoxy-5-(5-(pyrid iinc-I-yl)-2-(4-(tri fluorormethyl)phcnyl)-I H-imicazol-4-ylt)pyridin-2-amine

H

2 N N N/ N 102331 Step 1. Preparation of 2,4,5-tribromo-I-((2-(trimethylsilyl)cthoxy)mcthyl)- I-H-imidazole: A dried 500 mL round bottom flask was charged with 2,4,5-tribromcirnidazolc (20.0 g, 65.62 mmol) and anhydrous DMvIF (100 mL), the resulting solution was cooled to 0 C. To this cold solution was added Na-l (60% in mineral oil, 2.80 g, 70.0 mimol) portionwise with gas evolution under control and an internal temperature maintained helow 10 'C. A fter addition, the cold bath was removed and the resulting mixture was stirred at ambient temperature fior 30 minutes. The reaction mixture was cooled back to 0 "C, and SEM chloride (12.2 mL, 69.5 mmol) was added to the reaction via syringe pump ovcr 30 minutes. Te reaction was stirred at 0 "C fbi an additional 30 minutes and at arbicni temperature for another 30 minutes. The reaction was deemed complete by LCMS and the mixture was partitioned between EIOAc (150 rmL) and water (300mL-,), and the layers separated. The organic phase was sequentially washed with dilute aqueous NaC (5% w/w, 2 X), then brinc(] 00 mL), dried (Na 2 SO.), concentrated and a light yellow solid was obt ained. The crude material was recrystallized from hot petroleum ether (30 ml.,) and the solids were harvested from the mother liquor at 0 "C. The product was washed with cold petroleum cther (30 mL) and dried under vacuum to afford 2,4,5 trihromo- I -((2-(trimetchylsilyl)cthoxy)imet hyl)-I H-irnidazole (26.3 g, 92% yield): 'H NM R (400 Ml lz, CDC].) 6 5.3 1 (s, 2 1-t), 3.59 (t,./ = 7.2 Hz, 2 H), 0.92 (t, J= 7.2 Hz, 2 -1), -0.01 (s, 9 1I, Si(CHl-)). 10234] Step 2. Preparation of 4,5-dibiomo-2-(4-(trifluoromcthyl)phcnyl)-l-((2 trimcthylsilyl)cthoxy)methyl- I H-imidazo Ic: A mixture of 2,4.5-tribromo-l -((2 (trimethylsilyl)cthoxy)mcthyl)-l I--imidazole (10.2 g, 23.5 imol), 4-(trifluoromcthyl)phenylboronic acid (5.4 g, 28.4 mmol), and 2.0 M aqueous sodium carbonate solution (20 mL, 40 mnol) in DMVIE 91 (70 mL). was sparged with Ar. Pd(PPh 3 )4 (746 mg, 0.65 mmol) was added in one portion, and the reaction mixture was sparged again with Ar, then heated to 95 C for 16 h. LCMS indicated only 70% convcrsion. Another charge of 4 -(trifluoromethyl)phcnylboronie acid (2.0 g, 10.5 nimol) was added and the reaction was maintained at 95 C for 24 h. The reaction was allowed to cool to rt and was Ohen partitioned between water and EtOAc. The aqueous layer was separated and extracted with EtOAc (2 X). The combined organic phases were then dried (Na 2

SO

4 ), concentrated, and adsorbed onto silica gel. Purification by flash chromatography (Si02; 100 : 0 - 50 : 50 hexancs-EtOAc) afforded 9.9 g (19.3 mmol, 82%) of 4,5-dibrono-2-(4-(tri fluoromethyl)phenyl)-] -((2 trimcthylsilyl)cthoxy)methyl-l -- inidazole: LCMS (n/z): 500.9 (MHI'); (R = 1.33 min; 'H NMR (400 MfH z, CDCI 3 ) 6 7.98 (d,. J= 9.0 Hz, 2 H), 7.72 (d, .1 = 9.0 Hz, 2 H), 5.32 (s, 2 H), 3.74 (t,. J= 7.2 H z, 2 H), 0.99 (t, .= 7.2 H z, 2 1-), 0.03 (s, 9 1-1). 102351 Step 3. Preparation of 5-(5- brom o-2 -(4-trifluoronethyl) phenyl)-l -((2 (trimetiylsilyl)ethoxy)methyl)- I Il-imidazol-4-yl)-3-ielhoxypyridin-2-anine: A mixture 1,5 dibromo-2-(4-(tri lfIuoromethyl)phncryl)-I-((2-trimcthylsilyl)ethoxy)nethyl-l/-I-imidazole (730 mg, 1.5 miol) and 3-me lhoxy-5 -(4,4,5,5 -tetranethyl- 1,3,2 -di ox aborolan-2-y I)pyridin-2-amine (400 mg, 1.6 mmol; Example 17, Step 3), and 2.0 M aqueoIs Na 2

CO

3 solution (3 ml, 6.0 nmmol) in DME (10 mL) was purged with Ar for 3 min. Pd(PPh3)4 (65 Ing, 0.055 mmol) was added the reaction was heated to 100 )C by for 20 h. The reaction was allowed to cool to rt and phases partitioned. The organic portion was separated and ccenct ratcd. The resulting residue crude was purificd by flash chiromatography (SiO%; 80 : 20 - 0 :I 00 hexanes-EtOAc) to ftmish 640 mg (l.2 mmol, 80%) of 5 (5-brono-2-(4-trifluoronietlyl) phenyl)-l -((2-(trimethylsilyl)ethoxy)methyl)-I H-imidazol-4-yl)-3 methoxypyridin-2-amine: LCMS (m/z): 545.0(M H+), la = 1.02 min. 102361 Step 4. Preparation of 3-rncthoxy-5-(5-(pyridinc-4-yl)-2-(4-(tri fluoromethyl)phenyl)-l IH Iridazol-4-yl)pyridin-2-amine: A mixture of 5-(5-brorno-2-(4-trifluorornethyl) phenyl)-I-((2 (trimethylsilyl)ethoxy)Iethyl)-lI-I-i miciazol-4-yl)-3-methoxypyridiii-2-amine (420 mg, 0.77 immol), pyridin-4-ylboronic acid (186 tng, 1.54 mmol), and 2.0 M aqueous Na 2 CO, solution (2 mL, 4.0 mmol) in DME (8 ml) was sparged with Ar for 3 min. Pd(PPh 3

)

4 (78 mg, 0.067 mmol) was added and the reaction was irradiated at 110 C for 20 min in a microwave reactor. The reaction was allowed to cool to rt and phases partitioned. The organic portion was separated, concentrated, and 92 the resulting residuC was treated with 4 M HICI uqucous solution at 60 "C for 2 h. The reaction was allowed to cool to rt and was directly purified by reverse phase HPLC, which after freez dying, provide 96 ig of the title compound as the TFA salt: LCMS (m/z): 412.0 (MH ), ti = 0.61min. 'H NMR (400 MHz, CD 1 O)): 8.67 (d, J= 6.8 Hz, 2 H); 8.29 (d, J= 6.8 Hz, 2 I); 8.26 (d, J= 8.0 Hz, 2 H); 7.84 (d,.J = 8.0 Hz, 2 H); 7.78 (s, I H); 7.60 (s, I i-I); 4.02 (s, 3 11). Exai1ple 3 2-(4-(4-(6-ainino-5-nicthoxypyridin-3-yl)-2-phenyl- I H--imida7.ol-5-yl)pyrimidin-2-ylamino)ethanol

H

2 N N N N N NN ONil 102371 Step I. Preparation of /1-(4-hoio-2-phenyl-I-((2-(trimethylsilyl)ethnxy)methyl-l/ irnitizol-5-yl)-2-chloropyriimidine: n-BuLi (2.2 M in hexane, 3.1 nL, 6.8 mmnol) was added dropwise to a stirring solution of 4,5-dibrono-2-phenyl-l-((2-(trimethylsilyl)ethoxy)methyl)-l H imidazole (2.9 g, 6.8 mmol; prepared similarly as per Example 2, Steps 2-3) at -78 "C. The reaction was maintained at -78 oC For 45 min, after which 2-chloropyrimidine (0.884 g, 7.72 mmol) was added in one portion, and the reaction was then allowed to warm to -40 "C over 20 min. The reaction was quenched at -40 C by the addition ofTHF/H 2 0 (3 ml /0.2ml) and the resulting mixture was allowed to warm to 5 "C over 20 min. The mixture was cooled to -40 "C and a solution ofDDQ (1.86 g, 8. 19 mmol) in THFI (5 mL) was added and the resulting reaction was allowed to warm to 10 "C ovcr 50 min. 3.0 M NaOl- (20 mnL, 60 minmol) was added followed by water (60 mL) and the resulting mixture was stirred for 10 min at rt. The layers were allowed to partition and then separated. The organic portion was washed with brine (30 mL.), dried (Na 2 SO4), and concentrated. The resulting residue was purified by flash chromatography (SiO2, 100 : 0 - 70 : 30 hexanes-EtOAc) to provide 2.70 g (85%) of 4-(4-bromo-2-phenyl-I-((2-(t rimethylsilyl)cthoxy)methyl-HI l--imidazol 5-yl)-2-chloropyriiidine: LCMS (m/z): 466.8 (M I), l = 1.33 min;. 'H NMR (400MHz, CDCb) 8 8.66 (Al),.J = 5.2 Hz, 2 1-1), 7.98 (AB,.J = 5.2 Hz, 2 t-1), 7.70-7.80 (ni, 2 1-), 7.42-7.56 (m, 3 H), 5.77 (s, 2 -1), 3.34-3.40 (m, 2 11), 0.72-0.77 (in, 2 H), -0.12 (s, 9 1-1). 93 [0238] Step 2. Preparation of 2-(4-(4-bromo-2-phenyl-I -((2-trimethylsilyl)cthoxy)methyI)- 1-1 irmidazol-5-yl)pyrimidin-2-ylamino)cthanol. A solution of 4-(4-bromo-2-phenyl- l -((2 (trimethylsilyl)ethoxy)iethyl- I /-I-imidazol-5-yl)-2-chloropyrinidine (145 mg, 0.31 rmol Example 3, Stcp 1) and cthanolamine (0.30 ml, 4.97 mmol) in dry NMP (I nil) was heated at 120 C for I h. The reaction was allowed to cool to rt and water (5 mL) was added. The resulting suspension was centrifhiged and the remaining solid was washed with water and dried under vacuum to furnish 150 ig (98%) of 2-(44-4-brormo-2-phenyl- l -((2-tr imethylsilyl)etlhoxy)methyl)- I H-imidazol-5 yl)pyri midin-2-ylamino)ethanol: LCMS (n/z): 492.0 (M *l),I =0.96 min. 102391 Step 3. Preparation of 2-(4-(4-(6-anino-5-rmethoxypyridin-3-yl)-2-phenyl-1 H-imidazol-5 yl)pyrimidi n-2-ylami no)eth anol: A mixture of 2-(4-(4-bromo-2-phenyl- l-((2 tiiricthylsilyl)ethoxy)methyl)-IH-imidazol-5-yl)pyrimidin-2-ylamino)ethanol (38 ig, 0.08 mmol; Example 3, Step 2), 3-nethoxy-5-(4,4,5,5-tetrumethyl- 1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.39 M in I 1,4-dioxane, 0.51 mL, 0.2 immol), and aqueous 2.0 M Na 2

CO

3 solution (I riL, I mmrnol) in DME (1.2 ml..) was sparged with Ar. Pd(Pllh) (27 ig, 0.023 niol) was added in one portion and the reaction mixture was sparged again and scaled. The reaction was irradiated at 115 'C for 20 min in a microwave reactor. The reaction was allowed to cool to rt and partitioned between EtOAc (2 mL.,) and saturated aqueous Na 2

CO

3 solution (I im1L). The layers were separated arid the organic phase was washed with brine (I ml), dried (Na 2

SO

4 ), and concentrated. The resulting residue was treated with ethanol (I ml) and conc. ICI (0.2 ml) and heated to 60 "C for I h. After allowing to cool to rt, the reaction was concentrated in vacuo and the resulting residue was purified by reverse phase H Pt.C, arid after lyopholization, afforded 19 mg of 2-(4-(4-(6-amino-5-methoxypyridin-3-yl) 2-phenyl-IH-inidazol-5-yl)pyrimidin-2-ylamino)ctihanol as the TFA salt: LCMS (m/z): 404.1 (Mt-I'), -a = 0.54 in. Example 4 (S)-N-( I -(4-(4-(5-amino-6-imethoxypyrazin-2-yl)-2-(4-(triluoiomethyl)phcnyl)- I H-imidazol-5 yl)pyrimidin-2-ylanino)propan-2-yl)-2-inethoxyacetamide 94 H;,N N M N N N -U | H HN N OMo H 102401 Step 1. Preparation of 4-(4-bromo-2-(4-(tri flu oromethyl)phenyl)- 1 -((2 (trimethylsilyl)ethoxy)nethyl)-IlH-imidazol-5-yl)-2-chloropyrimidine: A solution of4,5-dibromo-2 (4- (trifluoromcthyl)phcnyl)- -((2-(trinethylsilyl)ethoxy)methyl)-l1--imnidazole (1.0 g, 2.0 mmol, Example 2, Step 2) in dry THF (10 rnL) was cooled to -78 "C under Ar. n-BuLi (1.0 rmL, 2.5 NI in hexane, 2.5 mmol) was added dropwise, afterwards the reaction was maintained below -70 "C for an additional 45 min. A solution of 2-chloropyrimidine (0.29 g, 2.5 mmol) in dry THF (2 mnL) was added dropwisc at -78 "C. After addition, the reaction was allowed to warm to -40 "C over 25 min and maintained at -40 "C for 20 min. The reaction was then warmed to -5 "C in a brine-ice bath, quenched with water (30 mL), and stirred at rt for 30 min. The reaction mixture was concentrated and partitioned between EtOAc and water. The organic phase was separated, dricd (Na 2

SO

4 ), and concentrated. The resulting residue was further purified by flash chromatography (SiO 2 , 100 : 0 - 20 80, hexancs-EtOAc) to afford 1.1 g (2.05 mmol, 82%) of 6-(4-bromo-2-(4 (trifluoromctlyl)phenyl)-I -((2-trirnclhylsilyl)cthoxy)methyl)-l H-irnidazol-5-yl)-2-chloro-1,6 dihydropyr ii dine. A solution of 6-(4 -bromo-2-(4-(tri fluoromncthyl)phenyl)- 1 -((2 trimcthylsilyl)thoxy)methyl)- I lH-imidazol-5-yl)-2-chloro-1,6-dihydropyrimnidinc (4 10 mg, 0.8 mniol) in EtOAc (20 mL) was treated with MnO 2 (920 mg, 10.6 mmol) and the resulting reaction mixture was heated to and maintained at reflux for 18 h. The reaction was allowed to cool to rt and was then filtered through Celite. The filer cake was washed with EtOAc (2 X 20 moL) and the combined filtrates were concentrated to give 400 mg (0.75 mmol, 98 %) of 4-(4-bromo-2-(4 (trifluoromcthyl)phenyl)- I -((2-(trimcthylsilyl)ethoxy)methyl)-I H--imidazol-5-yl)-2 chloropyrimidine: 1-1 NMR (400 MHz, CDC) 6 8.71 (d, .J 5.4 Hz, I H), 8.02 (d,. = 5.4 Hz, I H), 7.96 (d, .1 = 8.1 Hz, 2 -1), 7.77 (d./ = 8.1 Hz, 2 H), 5.77 (s, 2 H), 3.49 (t,.J = 7.5 Hz, 2 H), 0.83 (t, J =7.5 -lz, 2 1-), 0.01 (s, 9 H). 95 102411 Step 2. Preparation of (S)-teri-butyl-l-(4-(4-bromo-2-(4-triflIuoromCthyl)phcnyl)-I-((2 (trimethylsilyl)cthoxy)methyl)-IH-I-imidazol-5-yl)pyrinidin-2-ylamino)propan-2-ylcarbanate: A solution of 4-(4-bromo-2-(4-tri fluoromethyl)phenyl)- I -((2-(tiiniethylsilyl)cthoxy)nethyl)-l H midazol-5-yl)-2-chloropyrimidine (4.1 g, 7.7 mmol) in dry NMP (10 mL) was trcatecd with (S)-teri butyl-l I-aminopropan-2-ylcarhamate (I.9 g, I1.0 nnol; Example 23, Step 2), followed by Na 2

CO

3 (0.82 , 7.7 mmol). The resulting mixture was heated to 80 "C for 4 h whereupon the reaction was decrned complete by LCMS, and allowed to cool to rt. Water was added and the resulting suspension was compacted by centrifugation. The filtrate was decanted, the the remaining solids were washed with water, and dried under vacuum to provide 41.6 g (6.9 mmol, 90%) as (S)-leri-butyl I -(4-(4-bromo-2-(4-trifluoromnethyl)phenyl)-l -((2-(trimcthylsily)cthoxy)methyl)-I H-imidazol-5 yl )pyrii din-2-yliam ino)piopan-2-ylcarbaiate, which was carried forward without fiirther I fi cation. [02421 Step 3. Preparation of (S)-N-(1-(4-(4-biomo-2-(4-(trifluoromethyl)phenyl)-IH-imidazol-5 yl)pyrinidin-2-ylanino)propan-2-yl)-2-methoxyacctamii(le: A solution of (S)-ter-butyl-I-(4-(4 brono-2-(4-trifluoromnethyl)plhenyl)-I-((2-(trirnethylsilyl)ctho xy)rmcthyl)-l H-inidazol-5 yl)pyrimidin-2-ylaniino)propan-2-ylcarbam ate (4.7 g, 6.9 mmol) in dry ethanol (8 miL) was treated witl aCucous '4 N HCI solution (4 mL, 16 mmol) and the resulting reaction mixture was heated to 60 "C for 4 h. After the reaction was judged complete. the mixture was allowed to cool to rt and evaporated to dryness. The resulting residue was carried forward without further purification. The preceding residue (2.0 g, 4.6 mmol) was dissolved in dry DCM (60 mL) und treated with diisopropylethylamine (DIPIEA, 1.0 mL, 5.7 mmol). The resulting mixture was stirred at rt for 5 min until the reaction became homogenous. A solution of 2-methoyxacetyl chloride (0.46 ml, 4.6 rnmol) in dry DCM (5 ml.) was added dropwise and the resulting reaction was maintained at rt for 4 i. An additional charge of 2-methoyxacetyl chloride (0.03 ml. 0.3 mmol) was added to complete the reaction. Afterwards. the reaction was partitioned between DCMvI and water, and the layers were separated. The aqLIcous phase was extracted with DCM (2 X 30 mL) and the combined organic layers were dried (Na 2 SO.), and concentrated to fiirnish (S)-N-(I -(4(4-brorno-2-(4 (trifluoromethyl)phenyl)- I H-imidzol-5-yl)pyrimidin-2-ylimino)propan-2-yl)-2-methoxyacetaride: I.CMS (m/z): 513.1 (M'] IHC), l t = 0.88 muin. 96 102431 Step 4. Preparation of (S)-N-(1 -(4 -(4-(5-airni ro-6-methoxypyrazin-2-yl)-2-(4 (trifluoromethyl)phcnyl)- -l-i midazol-5 -yl)pyrimidin-2-ylamino)propan- 2 -yl)- 2 -methoxyacelanide: A 20 nL microwave vial containing (S)-N-( I -(4-(4-bromo-2-(4-(tri fluoronethyl)phcnyl)-IH midazo l-5-yl)pyrimidin-2-ylarnino)propan-2-yl)-2-rnethoxyacetamide (0.8 g, 1.6 Im101), 3 methoxy-5-(4,4,5,5-tetrarnethyl- 1,3,2-dioxaborolan-2-yI)pyrazin-2-aminue (0.52 g, 3.1 mmol, Example 18, Step 2), and 2.0 M Na 2

CO

3 aqucous solution (5.0 nL, 10.0 ninol) in DME (l7 mlL) was spargcd with Ar for 15 min. Pd(PPh 3

)

4 (0.16 g, 0. 14 nimol) was added in one portion and the reaction via] scaled, and irradiated at 120 "C for 30 min in a microwave reactor. The reaction was allowed to cool to rt and the organic and aqueous phases palit(ied upon standing. The layers were separated and the aqueous phasc was back extracted with EtOAc (2 X). The combined organic phases were concentrated, and the resulting residue was suspended in DIMSO (20 iL) and filtered through a plastic mcnbranc. Thc filtratc was purified by preparative revcrsc-phasc HPLC and the combined isolated factions were partitioned with EitOAe and saliurated aqueotus Na 2

CO

3 solution. The layers were separated and the organic phase was washed with saturated aqueous Na 2 CO3 solution (2 X), brine, dried (Na2SOm), and concentrated. The resulting free base was suspended in a ceton itrilc-vater (I : 4), acidified with one equivalent of ].0 NI aqueous ICI solution, and lyophilized to give the title compound as the HCI salt: LCMS (rn/z): 558.2 (MIH'), ft = 0.72 min; '1H NMR (400 MHz, CD 3 COOD, 45 C) 6 8.43 (d, .J= 8.1 Hz, 2 H), 8.26 - 8.36 (in, 2 H), 7.82 (d,.I J 8.1 Hz, 2 -), 7.67*(d, J = 5.7 Hz, I 1), 4.31 (m, 1 1-I), 4.13 (s, 3 I-), 3.95 (i, 2 1-1), 3.79 (dd, J= 13, 5.0 Hz, I H), 3.68 (dd,.1 = 13, 6.5 Hz, I H), 3.35 (s, 3 H), 1.30 (d, . = 6.6 Hz, 3 H). Examiniple 5 (5)-N-(1-(4-(4-(5-:imin-6-methoxylpyrazin-2-yl)-2-(4-flnorophenyl)-) IH-imidazol-5-yl)pyrimidin-2 yl am ino) propan -2 -yl )-2 -mnet hox yacctiam ideI

H

2 N N I- I MeO N - - N IH N N : O HN N O, 97 102441 Step I. Preparation of 4,5-clibromo-2-(4- fluorophenyl)- I -((2-(tri methylsilyl)cthoxy)methyl) I -1-imiidazole: A microwave vial was charged with 2,4,5-tribromo-I -((2 (trimcthylsilyl)ctboxy)methyl)- I --imidazole (881 mg, 2.0 mmol, Example 2, Step 2), 4 fluorophonyl boronic acid (308 mg, 2.2 mmol), aqueous NaACO 3 solution (6 ml, 2.0 M, 12.0 mmol) and DME (12 il) The mixture was sparged with argon for 15 min, followed by addition of P1d(P1Ph 3 ), (120 m1g, 0.1 mmol). The react ion vial was scaled and heated at I 10 *C for 20 minutes in a microwave reactor; the reaction was deemed complete by LCMS. The reaction mixture was partitioned between saturated Na 2

CO

3 solution and EIOAc (10 ml/30 ml), the organic layer was separated, washed with brine (10 ml), dried (Na 2 SOd), and concentrated. The resulting residue was puiflied by flash column chroimiatography (SiO2; 100 : 0 - 80 : 20 hexanes-EtOAc) to furnish 4,5 dibromo-2-(4- fluorophenyl)-1-((2-(trimet hylsilyl)ethoxy)methyl)- /-[-iiidazole (780 mng, 1.73 mmnol, 87%) as a solid: '1-1 NMIR (400 MFIz, DMSO-d) 6 7.80-7.70 (im, 2 H), 7.37 (app t, .= 9.0 Hz, 2 -1), 5.33 (s, 2 1-1), 3.52 (t, .J= 8.2 H z, 2 HI), 0.83 (t,.1 = 8.2 lz, 2 1-1), -0.06 (s, 9 H). 102451 Step 2. Preparation of (.S)-N-(I -(4-(4-(5-amino-6-methoxylpyrazin-2-yl)-2-(4-fluorophenyl) I H-i m idazol-5-yl)pyrimidi n-2-ylamino)propan-2-yl)-2-methoxyacctam ide: 4,5-dibromo-2-(4 fluorophenyl)- I -((2-(trimethylsilyl)cthoxy)mcthyl)-l H-imidazole was elaborated' to the title compl)oLnd following Example 4, Steps 1-4: 'I-I NMR (400 MHz, CD 3 COOD): S 8.20-8.32 (in, 3 H-), 8.16 (s. 1 I-), 7.50 (dI,.J 6.7 H z, I 11), 7.25 (t, . = 8.6 Hz, 2 1-), 4.24 - 4.35 (in, I H), 4.04 (s, 3 II), 3.93 (s, 2 -1), 3.75 (dd,.! 13 3, 1.5 I-Iz, I H), 3.59 (dd, 1 = 13.3, 7.0 11/, 1 H), 3.33 (s, 3 1-), 1.25 (dJ= 7.0 Hz, 3 11). Example 6 (S)- I -(4-(4-6-ain o-5-imellioxypyrdin-3-yl)-2-tcrt-butyl-I -1H-irnidazol-5-yl)pyri midin-2 ylanino)piopan-2-ol

H

2 N N MoO N N. N HN N N Onl 98 102461 Step 1. Preparation of 2-t-butylimidazole: A solution of glyoxal (40% in water, 16.4 g, 113.4 mmol) in water (180 ml) was added to trimnethylacetaldehyde (12.4 ml, 112.6 mmol) and the resultant solution was cooled to 10 "C in an ice/water bath. To this solution was added ammonium hydroxide solution (28% in water, 56 rmL) with stirring. The reaction mixture was stirred overnight and the resulting precipitate was filtered and dried to afford 12.1 grams of the title compound as a white crystalline solid. LCMS (m/z): 125.10 (MI-I), il. = 0.26 mini; 'H NMR (300 MHz, CD30D) 6 6.86 (21-, s), 1.32 (91-, s). [02471 Step 2. Preparation of 4,5-dibi-omo-2-tert-butyl-I H-imidazole: Bromine (8.4 grams, 52.42 mmol) was added dropwise to a mixture of 2--butylimidazole (2.6 grams, 20.97 mmol) and potassium bicarbonate (5.4 grams, 52.42 mmol) in dry DMF (25 ml). The reaction mixture was then stirred at 70 'C for 4 h. The reaction was allowed to cool to rt and was then filtered through a sintered funicl. The collected filtrate was cooled in an ice bath and diluted with cold water (100 i[,) with stirring. 102481 The resultant precipitate was collected by Filtration, washed with cold water (3 X) and dried under vacuum to furnish 2.79 g of 4,5-dibromo-2-tert-butyl- I l--imidazolc as a light yellow solid: LCMS (m/z): 28310 (MI-I'), IR = 0.63 min; 'H NMR (300 MHz, DMSO- d 6 ) 8 1.23 (91-, s). [10249] Step 3. Preparation of 4,5-Dibi-omo-2-tert-butyl-I-((2-(trimethylsilyl)ethoxy)methyl)-IH imidazole: To a cooled solution of 2-i-hutyl-4,5-dihromoimidazole (1.4 grams, 5.0 mmol; Example 5, Step 2) in dry THF (10 ml) at 0 "C was added sodium hydride (95%, 0.15 grams, 6.0 nimol) portion wise. The reaction mixture was stirred for 10 min at 0 "C, at rt for 40 min. The reaction was rc-cooled to 0 "C and SEM-chloride (0.97 ml, 5.5 mmol) was added in dropwise. The reaction mixture \was stirred overnight allowing the ice bath to expire and poured into a mixture of water (30 mL) and EiOAc (50 mi). The resulting layers were partitioned and separated. The organic portion was washed with brine, Ihen water, dried (Na 2 SOi), and concentrated. The remaining residue was purilied by lash chromtography (SiO 2 , 100 : 0 - 90 : 10 hexanes-EtOAc) to provide 2.1 g of 4,5 di bromo-2-er-butyl-I -((2-( ri methylsi lyl)et hoxy)metlhyl)- liH-imidazole: LCMS (m/z): 447. 10 (MI'), li = I.30 min; - NMR (400 MI-z, CDCh) 5 8.75 (dd, I H,). 7.92 (dd, I -,), 5.90 (s, 2 11), 3.5 1(m, 2 1-), 1.55 (s, 9 -,), 0 82 (m, 2 H), 0.08 (s, 9 1-). [02501 Step 4. Preparation of 4-(4-bromo-2-tert-butyl-I H-iinidazol-5-yl)-2-chloropyrimidine: n 99 BuLi (1 .5 M in hexane, 40 mL, 60 mmol) was added dropwisc to a cooled solution of 4,5-dibromo 2-/eri-butyl-l-((2-(trimethylsilyl)ethoxy)methyl)-III-imidazole (23.6 g, 57.2 nmmol) in anhydrous TI-IF (250 mL) at -78 "C. Afler 30 min at -78 "C, a solution of 2-chloropyrimidine (7.21 g, 63.0 mmol) in anhydrous TIF (2 mL) was added dropwisc and the reaction was stirred at -78 "C for I h. The reaction was quenched by the addition of samrated aqueous NI-1C solution and allowed to warm to rt. The mixture was partitioned with EtOAc and the layers separated. The aqueous portion was extracted with EtOAc (3 X) and the combine organic layers were washed with water, brine, dried (MgSO4), and concentrated. The resulting residue was dissolved in dry EtOAc, treated with MnO2 (5.2 g, 60 mmol), and heated to reflux for 3 h. The reaction was allowed to cool to rt and filtered through Celiwe. The filter cake was washed thoroughly with EtOAc and the combine filtrates were concentrated. The remaining residue was purified by flash chromatography (Si0 2 , I00 : 0 - 90 : 10 hexancs- EtOAc) to give 10 g (37%) of 4-(4-bromo-2-ieri-butyl-l H-inidazol-5-yl)-2 chloropyrimidine: I..CMS(n/z): 447.0 (M-I),/ 1 l.30 min.' I- NMR (400 M l-z, CDCN) 8 8.64 (d,. = 5.3 Hz, I H), 7.83 (d, -= 5.3 Hz, I H-), 5.85 (s, 2 11), 3.45 (i, 2 1-1), 0.76 (i, 2 1I), -0.08 (s, 9 -1). 10251| Step 5. Preparation of (S)- -(4-(4-broio-2-tIert-butyl- 1-((2-(triiethylsil Iyl)cthoxy)methyl) I H-iinidazol-5-yl)pyriniidin-2-ylamino)propan-2-ol: The subtitled compound was prepared similarly to Example 3, Step 2 using (S)-1-aininopropanol-2-ol instead of ethanolamine: LCMS (m/z): 486. 1 (MH. ),l = 0.96 mn [02521 Step 6. Preparation of (S)- -(4-(4-6-ami no-5-methoxypyrdin-3-yl)-2-tcrt-butyl-I H-mi dazol 5-yl)pyrirnidin-2-ylurino)propan-2-ol: The title compound was prepared from (S)-1 -(4-(4-broio-2 tert-butyl- 1 -((2-(trimethylsilyl)cthoxy)methyl)- I H-imidazol-5-yl)pyrimidin-2-ylamiino)propan-2-ol, utilizing the procedure fron Example 3, Step 3: LCMS (m/z): 398.1 (MI'), /t = 0.40 min. Example 7 (S)-N-(I -(4.-(4--(5-amino-6-imetoxypyrazin-2-yl)..2-ier-bt..utyl- I H-iimidazol-5-yl)pyrinidin-2 ylamino)propan-2-yl)-2-mcthoxyacetaiide 100

H

2 N N N N H'N N (M H NYN [02531 Step 1. Preparation of (S)-eIt-butyl 1-(4-(4-bromo-2-iert-butyl- I H-imidazol-5-yl)pyrIniIdin 2-ylarm ino)propan-2-ylcarbamatc: A mixture of 4-(4-bromno-2-ter/-butyl-lH-1-imidazol-5-yl)-2 chloropyrimidinc (2.0g, 4.5 mmol; Example 6, Stcp 4), (S)-ier;-butyl-I-am inopropan-2-ylc arbamtaic (1 .0 g, 5.8 mmol; Examplc 23, Step 2). and diisopropylcthyl amine (2.4 mL, 13.5 mmol) in dry acetonitrilC waS heated at 85 "C for 16 h. An additional charge of (S)-ter,-butyl-I-am inopropran-2 ylcarhamniatc (145 rng, 0.8 Mmol) was added and the reaction was maintained at 85 'C for 5 h. Aller allowing to cool to rt, the reaction was diluted with FtOAc (40 mL), washed with water (2 X 15 mL,), diced (Na2SO.,), and concentrated to provide 2.6 g of (S)..seri-hutyl 1-(4-(4-bromno-2-/ert-butyl I/-/--imidazol-5-yl)pyrimidi n-2-ylamino)propan-2-ylcarbamate which was carried forward without Further purification: LCMS (m/z): 585.0 (MH), lR= 1.07 min. [02541 Step 2. Preparation of (S)-N-(I-(4-(4-biomo-2-tert-butyl-IH[-iiriidazol-5-yl)pyrimidin-2 ylimino)propan-2-yl)-2-mcthoxyacctimide: A solitiOn of (S)-Ieri-hIutyl I-(4-(4-brorno-2-IerI-hutyl 1HI-iidzol-5y)pyrimidin-2-ylamino)propan- 2 -ylcarhamate (2.6 g, 4.4 mmol) in, methanol was trcatcd with aqueous 12 N HCI (1 .4 ml... 16.8 mmol). The reaction was hcatcd at 60 "C for I h, and allowed to cool to rt. The reaction was then concentrated and dried in vacuo to give 1.6 g ofa crude residue which was carried forward without further puriication. The residue was treated with diisopropylcthyl amine (4.6 mL, 26.3 mol) in dry DCM (18 mL.), followed by the dropwisc addition of methoxyacetyl chloride (0.44 mL, 4.8 mmol). The reaction mixture was stirred at it for I h, then concentrated, in vacuo. to dryness. The remaining residue was dissolved in EtOAc (40 mL) was washed with water (2 X), dried (Na)S0 4 ), and concentrated. The crude residue was purified by fhash clIromatogIaplIy (SiO 2 , 90 : 10 - 50 : 50 hexanes-EtOAc) to afford 1.3 g of (S)-N-(l-(4-(4 biroio-2-ieii-hutyl-IH-mi dazol-5-yl)pyrimidin-2-ylaii no)propan -2-yl)-2-IeIhoxyacctamidc: LCMS (ni/z): 427.0 (MI-'), IR = 0.61 min. 102551 Step 3. Preparation of (S)-N]-I-(4-(4-(5-amino-6-mcthoxypyraziri-2-yl)-2-ter-butyl-

H

101 i midIazo l-5-yI) pyrim idi n-2-yl a rnino)prolan-2-yl)-2-methoxyacetam idc: A 20 miL microwave vial containing (S)-N-(I -(4-(4 -bromo-2-/CrI-butyl- I1H-i ni dazol-5-yl)pyri mid in -2-ylami no)propan-2-yl) 2-methoxyacetamide (1.17 g, 2.75 mmol), 3-methoxy-5-(4 ,4,5.5-tetramethyl- 1,3,2-dioxaborolan-2 yl)pyrazin-2-arninc (0.97 g, 3.9 mmol, Example 18, Stcp 2), 2.0 M Na 2

CO

3 aqueouS solution (14 mll, 28 minol), and Pd(PPh 3

),

1 (0.16 g, 0.14 m mol) in DME (20 ml.) was sparged wiih Ar for. The reaction vial was scaled, and irradiated at 115 "C for 10 min in a microwave reactor. The reaction was allowed to cool to rt and the organic and aqueous phasCs partitioned upon standing. The layers were separated and the aqueous phase was extracted with EtOAc (2 X). The combined organic phases were concentrated, and the rCsuiltinig residue was suspended in DMSO (10 mL), sonicated, and filtered through a plastic Membrane. The 1iltrate was purified by preparative reversc-phase HPLC and the combined isolated fractions were partitioned with EtOAc and saturated aqueous Na 2

CO

3 solution. The layers were separated and the organic phase was washed with saturated aqueous NaIC0 3 solution (2 X), brine, dried (Na 2 SO.i), and concentrated. The resulting free base was suspended in acetonitrile-water (I : 4), acidified with one equivalent of 1.0 M aqueous HCI solution, andI lyophilized to give the title compound as the HCI salt: LCMS (m/z): 470.2 (MH) la 0.50 min; 'H NMR (400 MHz, CfY-COOD): 5 8.29 (br d,.J = 5.6 -lz, I -I), 8.07 ( br s, I H), 7.30 (d,.J = 6.0 Hz, I -1), 4.26 (m, I H), 4.02 (s, 3 H), 3.93 (s, 2 I-), 3.75 (II, 1 1-1), 3.61 (dd,.J = 14.0, 7.2 Hz, 1 H-), 3.34 (s, 3 H1), 1.61 (s, 9 11), 1.26 (d. .= 6.8 Hz, 3 11). Example 8 (S)-mcthyl I -(4-(4-(5-ainino-6-mnethoxypyraz.in-2-yl)-2-tert-butlyl- I -i-inidazol-5-yl)pyrimidin-2 ylamino)propan-2-ylcairbanatc HN N MoO N N N IH N N N OME H [102561 Step I. Preparation of (S)-methyl I-(4-(4-hroimo-2-iert-hutyl-I1-imidazol-5-yl)pyrimidin-2 y lam irno)propan-2-ylcarba mate: To a solution of (S)-terI-bntyl I-(4-(4-bromo-2-teirt-butyl-I-((2 102 (trimethylsilyl)cthoxy)nethyl)- 1--imiizol-5-yl)pyrimidin-2-ylam ino)propan-2-ylcarbamate (2.66 g, 3.94 ininol, Example 7, Step I) in MeOH (17 ml) was added aqueous concentrated HCI (1 .97 ml, 23.65 mnnol) and the resulting reaction was stirred at 60 C fbr I It. The reaction was allowed to cool to ri and concentrated in vacuo to give 2.28 g of crudec residue. This material was then suspended in I : - THF-water (100 mL) followed by the addition of'Nal]C0 3 (1 .66 g, 19.70 mmol). The mixture was cooled to 5 oC and methyl chloroformate (1.0 M in THF, 4.33 ml, 4.33 mmol) was added dropwise. After 50 mint, ait additional charge oft ethyl chloroformate (1.0 M in THF', 4.33 ml, 4.33 ininol) was added and the reaction maintained for 45 min at 0 oC. The reaction was quenched with water (300 mL) and the resulting layers were separated. The aqueous phase was extracted with EtOA c (2 x 200 nL) and the combined orgaItic portions were washed with brine (2 x 400 mL). dried (Na2SOn), and concentrated. The resulting residue was triturated with I : 4 EtOAc hexancs (10 ml-) and washed with ether to provide 958 mrtg of (S)-mihyl I-(4-(4-bromo-2-ierit bit iyl-ll -imiidazol-5-yl)pyrinidint-2-ylami no)propant -2-ylcarbamtuate: LCMS (n/z): 411 .0 (MHI-), lR = 0.65 min. [02571 Step 2. Synthesis of (S)-methyl I -(4-(4-(5-arnino-6-methoxypyrazin-2-yl)-2-tert-buttyl-

H

imidazo l-5-yl)pyri midi n-2-ylIamino)piopan-2-ylcarbam ate: (S)-methyl 1-(4-(4-bromo-2-ier-butyl I H-iimidazol-5-yl)pyrimidi n-2-ylamino)propan-2-ylcarbanate was elaborated as per Example 7, Step 3 to give (S)-methyl 1-(4-(4-(5-amino-6-methoxypyrazin-2-y)-2-tert-butyl- H-imnidazol-5 yl)pyri mid in-2-ylami no) propan-2-yl carbamate as the HCl salt: LCMS (n/z): 456.2 (MH'), Ic = 0.52 min; '-I NMR (300 MIH, CD3COOD): 8 8.30 (d,./ = 6.6 -1z, I 1-1), 8.08 (br s, I 1-1), 7.33 (di,.J= 6.6, I H-), 4.05 (s, 3 1), 4.00 (m, I H), 3.87 (m, I H), 3.67 (s, 3 11), 3.41 (m, I H), 1.65 (s, 9 I-), 1.23 (d. J = 6.9 Hz. 3 1-). Example 9 4-(4-(5-amiino-6-methoxypyraziii-2-yl)-2-ter/-bityl- I H-imidazol-5-yl)-N-(2-methoxypyilin-4 yl)pyrimidin-2-amine 103 H2NX N MoO N N N N~ HN OMC N [02581 Stcp I. Synthesis of 4-(4-bromo-2-ter-butyl-l-((2-(trimethylsilyl)cthoxy)mcthyl)-IH imidazol-5-yl)-N-(2-mctho xypyridin-4-yl)pyri mid in-2-amine: 102591 A m ixI ure l 4-(4-bomo-2-terti-butyl- I-((2-(1ii methylsilyl)cthnoxy)methyl)-IlH-i midazol-5 yl)-2-chloropyrimidinc (500 mg, 1.1 imol; lxatmple 6, Step 4), 2-mtethoxypyrid in-4-aninc (153 mg, 1.2 mmol), Pd(OAC) 2 (30 mg. 0. 14 mmol), XANTPHOS (117 mng. 0.20 rnmol), cesium carbonate ('731 ng, 2.2 mmol) in dry dioxane (9 ml) was sparged with N 2 for 5 min. The reaction was scaled and heated at 100 'C for 2 hr. The reaction was allowed to cool to i and partitioned between EtOAc and water. The layers were separated and the aqueous portion was extracted with EtOAc. The combined organic portions were dried (MgSOi) and concentrated to an orange residue which as purified by column chromatography (SiO2, 100 : 0 - 0 : 100, hexanes-EtOAc) to provide 386 mg of 4-(4-bromo-2-terI-butyl-I-((2-(trinethylsilyl)ethoxy)mcthyl)- IH-imidazol-5-yl)-N-(2 mcthoxypyrilin-4-yl)pyinidin-2-amine: LCMS (m/z): 533.2 (M-1), fi = 0.92 min. 102601 Step 2. Preparation of 4-(4-(5-amino-6-methoxypyrazin-2-yl)-2-ierr-butyl- H-imidazol-5 yI)-N-(2-methoxypyridin-1 -yl)pyrimidin-2-amine: A mixture of 4-(4-bromo-2-teritbutyl-I-((2 (trimcthylsilyl)ethoxy)mcthyl)- I H-imilazol-5-yl)-N-(2-rmethoxypyridin-4-yl)pyrimidin-2-amine (100 rmg, 0.19 nimol), 3-m-rethoxy-5-(4,4,5,5-tetramtclhyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-amine ( 118 rg, 0.47 mmol, Example 18, Step 2), aqueous 2.0 M Na1 2 CO3 solution (I ml, 2.0 mmol), and Pd(PPh 3 )t (22 rug, 0.019 nimol) in DME (2 mL) was sparged with N 2 for 5 min. The reaction was sealed and heated to 10D "C r 2 Ih. The reaction was allowed to cool to rI, poured into EtOAc and partitioned with water. The layers were separated and the organic portion was washed with water, dried (MgSOi), and concentrated. The resulting residue was purified by flash chromatography (SiO2, 100: 0- 0 : 100, hexanes-25% Me-OH in EtOAc) to afford 102 mg (69% purity) of 4-(4-(6 aiiirio-S -methoxypyridin-3-yl)-2-teri-butyl-I-((2-(tri methylsilyl)ethoxy)rnethyl)-lI H-imidazol-5-yl) 104 N-(2-mcthoxypyridin-4-yl)pyrimidin-2-amine: LCMS (ni/z): 578.5 (MH'), t =0.74 min. 102611 Step 3. Synthesis of 4-(4-(5-amino-6-mcthoxypyrazin-2-yl)-2-ter-butyl- I H-imidazol-5-yl) N-(2-methoxypyridin-4-yl)pyrimidin-2-amine: A solution of 4 -(4-(6-amino-5-methoxypyridin-3 yl)-2-ieri-hutyl- I -((2-(trimethylsilyl)ethoxy)mcthyl)-I H-imidazol-5-yl)-N-(2-methoxypyridin-4 yl)pyriildin-2-amine ( 12 mg, 0.021 mmol) in dry McOl-l (I mil) was treated with aqueous 4 N HC1 (0.26 iL, 1.04 mmnol) and the resulting reaction was maintained at rt for 2 h. The reaction was then concentrated and the resulting residue was triturated with ether to give 8.2 mg of the title compound as the HIC! salt: LCMS (n/z): 147.1 (MI-), IR = 0.39 min. Example 10 5-(2-(4 -nuorophenyl)-5-(tctrahydio-21H-pyian-4-yl)-I H-imidazol-4-yl)-3-mcthoxypyridin-2-amine -1 2 N N Me 0 N H 0 102621 Step I. Preparation of 3,6-dihydru-2H-pyian-4-yl trifluoromethanesulfoiiate: A solution of LiHMDS (1 .0 M in TH11F, I irL, I I mmiol) was added dropwise to a cooled solution of 4 tetrahydropyranone (1g, 10 nmmol) in dry TIF (5 ml ,) at -78 "C and the resulting reaction was mainlained at -78 "C. for I I. A sol ution of 2-[N, N-bis(tri fluoronethanesul fontyl) aninol-5 chloropyridine (3.93 g, 10 mmol) in dry TIF (6 nil-) was added dropwise and the reaction maintained overnight, allowing lhe cooling bath to expire. The reaction was quenched with water (10 mL) and partitioned with DCM. The layers were separated and the aqlueous portion was extracted with DCM (2 X). The combined organic portions were dried (Na 2

SO

4 ) and evaporated. The crude residue was purified by flash chromlntography (neutral alumina, 80 : 20 DCM-hexanes) to provide 800 mg of3,6-dihydro-21-pyran-4-yI trifluoromethanesulfonate as a colorless oil: 'H NMR (400 Mliz, CDCl 3 ) 6 5.82-5.81 (i. 1 I-), 4.27-4.25 (m, 2 -I), 3.91-3.88 (in, 2 I-I), 2.48-2.45 (i, 2 1H). 102631 Step 2. Preparation of 2-(3,6-dihydro-2H1--pyran-4-y1)-4,4,5.5-tetramethyI- 1,3,2 dioxaboroline: A mixture of 3,6-dihydro-21--pyran-4-yI trifluromethancsuilfonate (250 mg, 1.1 minol), bis(pinacoliato)diboron (410 ig, 1.6 mol), and KOAc(323 mg, 3.3 imol) dioxane (3 mL) 105 was sparged with Ar for 5 min. Then PdCl 2 dppf-DCM (45 mg, 0.05 mmol) was added and reaction was sparged again with Ar for 5 min. The reaction was sealed and heated to and maintained at 80 "C for overnight. The reaction mixture was allowed to cool rt and was filtered through Celite, washing the filter cake with EtOAc. The combined filtrate was concentrated and the resulting residue was purified purified by flash chromatography (SiO 2 , 100 : 0 - 80 : 20 hexanes-EtOAc) to furnish 150 ing of 2-(3,6-dihydro-2H1-pyraii-4-yl)-4,4,5,5-tetramcthyl-1,3,2-dioxaborolanc:. LCMS (n/z): 211 .0 (M-l), , = 0.89 min; 'H NMR (400 MHz, CDCl3) 8 6.48 (br s, 1 H); 4.15-4.14 (app dd, J= 2.8, 5.6 1-z, 2 -1); 3.72-3.69 (app t, 5.2, 2 11); 2.19-2.17 (m, 2 H); 1.22 (s, 12 H-). [02641 Step 3. Preparation of 5-(2-(4-iuorophenyl)-5-(tetrahydro-2H-pyran-4-yl)- lH-imidazol yl)-3-mcthoxypyiidin-2-amine: A mixture of 2-(3,6-dihydro-21-pyran.-4-yl)-4,4,5,5-tetramethyl 1,3,2-dioxaiborolanc (53 rag, 0.25 minol), 5-(5-bromo-2-(4-luorophenyl)-l H-imidazol-4-yl)-3 methoxypyridin-2-aminc (123 ing, 0.25 inmol; prepared similarly as per Example 2, Steps 2-3), and aqueous 2.0 M Na 2 CO3 solution (0.5 rL, 1.0 mmol) in DME (3 ml,) was sparged with Ar for 5 min.. A catalytic amount of Pd(PPh 3

)

1 was added and the mixture was purged with Ar again. Then the reaction was healed to and maintained at 90 'C for 16 h. The reaction mixture was allowed cool to rt arid partitioned between EtOAc and water. The layers were separated and the aqueous phase was extracted with EtOAc (2 X). The combined organic layers were dried (Na 2 SOI) and concentrated. Thc resultirng residue was dissolved in dry MecOH (5 mL,) and treated with Pd/C (10% w/w, 5.7 mg, 0.005 nmol). The reaction mixture was placed and maintained under a 1-12 atmosphere for 2 d. The reaction was then filtered through Celite, the filter cake was washed thoroughly with EtOAc. The combined filtrate was concentrated and the resulting residue was purified by flash chromatography (Si0 2 , 50 : 50 - 0 : 100 hexanes-EtOAc). The isolated material was treated with 3 N HCI at 60 oC for I h. The reaction was allowed to cool to rt and was directly purified on reverse phase HPLC, as afier freeze drying, provided 6.0 ig of 5-(2-(4-fluorophenyl)-5-(tetrahydro-2H pyran-4 -yl)- lI--i midatzol-4-yl)-3-mnethoxypyridin-2-armine as the TFA salt: LCMS (m/z): 369.0 (MH'1), ij = 0.44 in 5-(2-(4-fluorophenyl)-5-(thiizol-5-yl)- I IH-imidazol-4-yl)-3-nethoxypyridin-2-umine 106 H2N N MeO I S N N [02651 Step I Preparation of 5-(2-(4-fliuorophenyl)-5-(thiazol-5-yl)-l H-iinidazol-4-yl)-3 methoxypyridin-2-amine: A mixture of 5-(5-biomo-2-(4-fluorophenyl)-1-((2 (trimethyIlsilyl)ethoxy)rmethyl)-il--imidazol-4-yl)-3-imethoxypyridin-2-amine (0.10 g, 0.20 nmol: prepared similarly as per Example 2, Steps 2-3), 5-(tributyl)stannyl)thiazole (0. 10 g, 0.27 mmol) and tricthylamine (0.14 inL, 1.0 mmol) in DMF (I mL) was purged with N 2 for 10 rnin. Pd(dppi)Cl 2

CH

2 Cl 2 (17 ng, 0.02 mmol) was added in one potion und the reaction vial was sealed, heated to and maintained at 100 "C overnight. LCMS indicated slow conversion, additional stannanc (excess) and catalyst (excess) were then added, and the reaction was heated again to 100 "C overnight. The reaction was allowed to cool to rt and was triturated with hexancs (2 X). The hexane layers were discarded and the DMF layer was directly purified by reverse phase HPLC, and upon lyopholization, provided 5-(2-(4-fluorophenyl)-5-(thiazcl-2-yl)- 1 -((2-(triniethylsilyl)ethoxy)m ethyl) 1-l-imidlazol-4-yl)-3-methoxypyridin-2-amine as the TFA salt, which was dissolved in ethanol (3 mL) and treated with aqueous 12 N HICI solution (0.5 mL). The reaction mixture was heated to 60 "C for 40 min and was then allowed to coot to rt. The reaction mixture was concentrated and the resulting residue was purilied by reverse-phasc HPLC to furnish the title compound as the TFA aler freeze drying: LCMS (mn/z)= 368.0 (MI), tv = 0.52 min. Example 12 3-clolnro-5-(2-(4-lhuorophenyl)-4-(pyridine-4-yl)-I l-inmidazol-5-yl)-1II-pyrrolo[2,3-bhpyridine N c F 102661 To a solution of 5-(2-(4-fluor-ophen~yl)-4-(p~yridini-4-yl)-I-((2-(timethylsilyl)cthoxy)methiyl) I -|Himdazol-5-yl)-l1H1-pyrriolo(2,.3-bjpyr-idinec (18 mg, 0.04 mmnol) in A CN (0.6 mL) was added NCS (5 mg, 0.04 mnmo)). A fter stirring for l8 h, the reaction mixture was partitioned between E1OAc (20 107 mL) and aqueous saturated Na-CO:, (10 ml..). The layers were separated and the organic phase was washed with aqueousO. M HCI solution (10 mL) , brine (10 ml..), and dried (Na 2

SO

4 ). After Coil cent rating in vacuo, tIe resulting crude product was dissolved in ethanol (1.5 m L) and conc. H Cl (0.25 ml., 3 nmol) was added and the reaction was heated at 60 "C for 20 min and then concentrated in vucuo. The crude material was dissolved in DMSO (1.3 mL) and purified by reverse phase HPLC, which after lyopholization, yielded 7 mg (38 %) of the title compound as the TFA salt: .C/MS (m/z): 390.1 (MI'), t R = 0.67 min. Example 13 5-(2-(4- fluoiophenyl)-5-(pyridin-4-yI)oxazol-4-yl)-3-methoxypyridin-2-aminc

H

2 N N MeN

--

N /F N C 102671 Step 1. Synthesis of 4-luorobenzoyl isocyanate: To a solution of 4-fluorobenzamide (I g, 7.2 mmol) in DCM (25 In) was added slowly oxalylchloride (0.76 mL, 8.62 mmol). The mixture was heated to 50 "C for ~18 hr. The mixture was allowed to cool to room temperature and concentrated in vacuo to afford crude 4-fluorobenzoyl isocyanate (1 .2 g). The crude material was used in the next step without further purification. 102681 Step 2. Synthesis of 2-(4 -luorophlenyl)oxazol- 4 (5H/)-onte: To a solution of 4-fluorobenzoyl isocyanate (1.2 g, 7.2 minol) in DCM (25 nL) was added (trimcthylsilyl)diazomcthane (2.0 M in hexane, 4.3 mL., 8.6 mmol) at 0 C. The reaction mixture was stirred for 45 min at rt. The mixture was diluted with water and the scparatcd aqueous phase was extracted with DCM (3 X). The combined organic layers were dried over (Na 2

SO

4 ), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO 2 , 100 : 0 - 80 : 20 DCM-rnethanol) to afford 870 Ing of'2-(4-fluorophcnyl)oxazol-4(5Hf)-one: LCMS (nm/z): 180.0 (Ml-1'), l, = 0.39 min [0269] Step 3. Synthesis of 2-(4-fluorophenyl)oxazol-4l-yl trifliuoroicthanesulfonate: To a solution of 2-(4-fluorophcny)oxazol-4(5H)-oine (870 mg, 4.9 nimol) in DCM (25 mL) was added 2,6-lutidine (0.91 mL, 7.8 mmol) and trill uoromethaniiesulforie anhydride (1.8 mL., 7.3 mmol) at 0 'C. The 108 reaction mixturC Vas allowed to warm up to rt ovcr - 18 hr. The mixture was concentrated in vacuo and the residue was purified by lash chromatography (SiO 2 , 100% DCM) to give 1.40 g of 2-(4 fiuorophenyl)oxazol- 4 -yl trill uoro mcthaiesul fonate. 102701 Step 4. Synthesis of 5-(2-(4-fliuorophenyl)oxazol-4-yl)-3-rnethoxypyridin-2-amine: A mixture of 3-imethoxy-5-(4,4,5,5-tetramethyl-,3,2-dioxaborolan-2-yl)pyridin-2-amine (200 mg, 0.8 mmol) and 2-(4- fluorophenyl)oxazol-4-yl trilitioromethanesulfonate (250 mg, 0.8 mmol), and 2.0 M aqueous Na2COI (1.2 mL, 2.4 mmol) in DME (2.0 mL) was sparged with Ar. Dichlorobis(triphcnylphosphinc)palladinm(0) (281 mg, 0.4 nmol) was added and the reaction mixtum was irradiated at 150 'C for 15 min in a microwave reactor. Afler cooling to rt, the reaction mixture was diluted with water and extracted with EtOAc (3 X). 'The combined organic layers were (ried OVCF sodium sIulfaute, 1iltered and concentrated in vacuo. The residue was purified by flash chromatography over (SiO 2 , 100 : 0 - 0 : 100 hexanes-EtOAc) to provide 145 mg of 5-(2-(4 fluorophcnyl)oxazol-4-yl)-3-methoxypyridin-2-aminc: LCMS (m/z): 286.1 (MI-I), R = 0.68 min. 10271 I Step 5. Synthesis of 5-(5-bromo-2-(4-fluorophcnyl)oxazol-4-yl)-3-methoxypyridin-2-aminc: To a solution of 5-(2-(4-fluorophenyl)oxazol-4-yl)-3-methoxypyridin-2-amine (145 mg, 0.5 mmol) in chloroform (20 ml.) al 0 C was added a prc-cooled solution of bromine (40 pL, 0.7 mmol) in CHClH (5 nil..). The reaction mixture was stirred for <5 min, concentrated in vaiuo, and the resulting residue was azeotroped with CHCl 3 (2 X). Purification by flash chromatography (SiO 2 , 100 : 0 - 95 5 DCM-MeO-l) provided 135 mg of 5-(5-brormo-2-(4-fluorophenyl)oxazol- 4 -yl)-3 ncthoxypyridin-2-amnine as a yellow solid: LCMS (mn/z): 365.8 (M1Hl'), IR = 0.83 min. 102721 Step 6. 5-(2-(4-fluorophenyl)-5-(pyridin-4-yl)oxazol-4-yl)-3-methoxypyridin-2-amine: A mixture of4-pyridineboronic acid (113 mg, 0.9 tnnol) and 5-(5-broino-2-(4-fluorophenyl)oxazol-4 yl)-3-mcthoxypyr'idin-2-amine (135 mg, 0.4 mrmol), and in DME (1.0 mL) and 2.0 M aqueous Na2CO (1.0 nL, 2.0 mmol) was spdrged with Ar. 'I'etrakis(triphenylphosphine)palladium(0) (21 ung, 0.018 mmol) was added and the mixture was again sparged with Ar. The reaction was irradiated at 120 'C for 15 min in a microwave reactor. The reaction mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were dried over sodium sulfate, filtered and coneritratcd in vacuo. The residue was purified by flash chromatography over (SiC 2 , 100 : 0 0 : 100 bicxancs-EtOAc). Enriched fractions were concentrated in vacicuo and further purified by 109 column chromatography (SiO 2 , 100 : 0 -- 80 : 20 DCM-MeOH) to afford 82 mg of the title compound: LC/MS (mi7/z): 362.9 (MH), 1 =- 0.54 mill. Example 14 (S)-N-(l -(4-(4-(6-ainno-5-imetlioxypyridin-3-yl)-2-(4-(tritlnuoroncthyl)phenyl)oxazol-5 yl)pyrimidin-2-ylamino)propan-2-yl)-2-methoxyacctamidinc H1,N N N -cF MOO \ -CF 3 N N HN ONMo H [02731 Step I . Preparation of 2-(4-(trifluoromcthyl)pheryl)-4 ,5-dihydrooxazolc: 4 (trifluoromcthyl)benzoyl chloride (4.6 mL, 31 mmol) was slowly added to a solution of 2 bromoethanamine hydrobromide (6.27 g, 30.6 mmol) and triethylamine (23 mL, 165 mmol) in dry DCM (150 mL) at 0 oC. The reaction was stirred for 18 h, allowing the cooling bath to expire. The resulting mixture was filtered through a Bucchner funnel and the filter cake was washed thoroughly with DCM. The collected filtrate was washed with water (100 mL), brine (75 mL), and dried (Na 2 SOI). The volume was reduced in vacuo to 5 ml, and the resulting crystals were harvested. The remaining filtrate was again reduced in volume to provide a second crop of crystals to give a total of 4.8 g of 2-(4-(trifluoromethyl)plhenlyl)-4,5-d ihydrooxazole. The combined crop of crystals were dissolved in CCI 4 (200 mL) and the resulting solution was decanted away from a dark oily residue and was carried forward without further purification: LC/MS (m?/z): 2 16.1 (Ml-*), , = 0.60 min. 102741 Step 2. Preparation of 5-bromo-2-(I-(trifluoromethyl)phenyl)oxazole: The above solution of 2-(4-(trifluoromethyl)phcnyl)-4,5-dihydrooxazole (4.8 g, 22 minol), N13S (11.9 g, 66.9 mmol), and A113N (0.18 g, 1.12 niniol) in CCLI (200 mL) was refluxed for 16 h. The resulting solution was filtered and the filtrate was washed with aqueous 10% Na 2

S

2 0 3 (3 x 150 mL), brine (100 ml..), dried (Na 2 SO4), and coIcentrated. The resulting residue was recrystallized from hexanes (350 mL) to provide 3.2 g of 5-broro-2-(4-(trifluororrethyl)phenyl)oxazole as a crystalline solid. The filtrate 110 and inothcr liquor was concentrated and purified by flash chromatography over (SiC 2 , 100 : 0 - 90 10 hexanes-EtOAc). to furnish an additional 1.8 g : LCMS (m/z): 294.0 (MH'), /I = 1.14 min. 102751 Step 3. Synthesis of 4-bromo-5-(2-chloropyrimidin-4-yl)-2-( 4 (trifluoromethyl)phcnyl)oxazolc: A solution of lithium diisopropylamidc (1.8 M in THF-heptanc ethylbcnzenc, 1 .4 mL, 2.6 timol) was added dropwisc into a cooled solution of 5-bromo-2-(4 (trifluorometliyl)phenyl)oxazole (620 mg, 2.1 mmol) in dry THF (20 mL) at -78 "C. After 2.5 h, 2 chloropyrimidine (292 Img, 2.6 mmol) was added. After 10 inin, the reaction llask was raised half way out of the acetone-dry ice bath and maintained for 30 min, ailer which the reaction was warmed to 10 C in an ice-water bath and Maintained for I h). The reaction was quenched with water (I mL) and concentrated. The resulting mixture was partitioned between EtOAc (70 mL) and water (40 ImL), and the layers were separated. The organic phase was washed with water, brine, dried (Na 2

SO

4 ), and concentrated to give 859 rg of a residue as 4-bromo-5-(2-chloro-4,5 dlihydropyrimidin-4-yl)-2-(4-(trifluoromethyl)phcnyl)oxazole which was used in the next step without further purification: LCMS (m/z): 407.9 (MIH*), ti = 0.83 min. A suspension of 4-bromo-5 (2-chloro-4,5-dihydropyiidin-4-yl)-2-(4-(tiluoromethyl)penyl)oxazole (859 mg, 2.12 rmol) and MnO 2 (1.8 g, 2 1.2 mmol) in EtOAc (10 mL) was irradiated at I 10 'C for 10 min in a microwave reactor. The reaction was allowed to cool to rt and was filtered through a plastic membrane. The filtrate was concentrated and resulting residue was triturated with EtOAc to afford 234 ing of 4-bromo-5-(2-chloropyrimidii-4-yl)-2-( 4 -(triltuoromethyl)phenyl)oxazole: LCMS (ni/z): 406.0 ( ') a= 1. 19 mnin. 102761 Step 4. Synthesis of (S)-N-(I-(4-(4-(6-amino-5-iriethoxypyrid in-3-yl)-2-(4 (triOuoromethy l)p hcnyl)ox azol-5-yl)pyrimidin-2-ylin iio)propan-2-yl)-2-m ethoxyacetamidine: The elaboration of 4-bromo-5-(2-chloropyrimuidin-4-yl)-2-(4-(tri-luoromethyl)pheny)oxazole follows that of Example 4, Steps 2-4. Etxianple 15 3-inethoxy-5-(2-phenyl-4-(pyridi ne-4-yl)thiazol-5-yl)pyridire-2-nmi ne I ll

H

2 N N MoO N N N / [0277] Step 1. Synthesis of 2-phcnyl-4-(pyridin-4-yl)thiazole: To the solution of 4 (broinoacetyl)pyridinc hydrobromide (500 mg, 1.8 mmol) in dry DMF (5mL) was added thiobenzamide (242mg, 1.8 mmol,) and the resulting reaction was stirred at rt for 12 h. Thereafter, the reaction quenched with saturated aqueous Nal-IC0 3 solution (25mL) and the mixture extracted with EtOAc (3 X 25 mL). The combined organic extracts were washed with water (25 mL), dried (NaySO), and concentrated. The resulting residue was purified by flash chromatography (SiO 2 , 100 0 - 0 100 hexanes-EtOAc) furnished 2-phcnyl-4-(pyridin-4-yl)thiazole: LCMS (n/z): 239.0 (MI-), ti 0.64 min. 102781 Step 2. Synthesis of5-bromo-2-phenyl-4-(pyridin-4-yl)tliiazole. To the solution of2-phenyl 4 -(pyrid il byl)th iazole (70mg, 0.3 minol) in CHCh was added Na 2

CO

3 (31 1 mg, 2.9 ninol) and Br 2 (75 pl., I 470 mmol) at rt. Aller I h, additional charges of Na 2 CO3 (I g, 9.4 mmol) and Br2 (0.5 mL, I innol) were added and the reaction maintained for another hour. The reaction was diluted with CI-1C3 and filtered through a pad of Celite, washing the filter cake thoroughly with CI-1C 3 . The combined filtrates were concentrated of provide .5-bromo-2-plienyl-4-(pyridin-4-yl)thiazole which was carried Forward without further purification: LCMS (m/z): 318.9 (MI),R = 0.75 min. [02791 Stcp 3. Synthesis of 3-methoxy-5-(2-phenyl-4-(pyridlin-4-yl)thiazol-5-yl)pyridin-2-amine: A mixture of 5-bromo-2-phenyl-4-(pyrilin-4-yl)thiazole (20 mg, 0.062 mmol), 3-methoxy-5-(4,4,5.5 tetramethyl-1,3,2-dlioxaborolan-2-yl)pyrid iii-2-aiiiiiie (39mg, 0.157 minol), and aqueous 2.0 M

K

2

CO

1 solution (0.5 ml, I mmol) in dioxane (0.5 ml.) was sparged with Ar. Pd(PPh) (181 Ing, 0 157 minol) was added, the reaction was sealed and irradiated at 120 C for 15 min. While allowing to cool to rt, the reaction partitioned and the resulting layers were separated. The aqueous phase was extracted with EtOAc (3 X) and the combined organic phases were washed with brine, dried (Na2SO4), and concentrated. The resulting residue was purified by reverse phase HIPLC to give, after Frecz drying, 3-mcthoxy-5-(2-phenyl-4-(pyridin-4-yl)tliiazol-5-yl)pyridin-2-amine as the TFA salt: LICMS (m/z): 36 1.0 (MH ') it = 0.58 nin. 1 12 Example 16 5-(2-(4-flu orophenyl)-5-(pyridin-4 -yl)th i azol -4-vl)-3-methoxypyridi n-2-ami nc H21 N N moo N MoO N / 102801 Step I. Preparation of 4-bromuo-2-(4-fluorophcnyl)thia7ole: Following a modified procedure (Bach, T.; H-Icuser, S. Tetrahedron Leu. 2000, 41, 1707), a mixture of 2,4-dibromothiazole (486 rmg, 2.0 inmol),4-luorophenyl boronic acid (266 mng, 1.9 inniol), and aqueous 2.0 NI Na 2 CO3 solution (23 m L, 4.6 mmnl) in DME (6.8 mnL) was spargcd with Ar for 3 min. Tetrakis(triphenylphosphiiie)paladirum(O) (150 mug) was added and the reaction mixture was sparged with Ar for I min. The reaction was scaled and irradiated at )05 0 C for 12 ruin in a microwave reactor. The reaction mixture was partitioned with EtUAc (50 il.,) and saturated aqueous NaIC0 solution (10 niL). The layers were separated and the organic layer was washed with saturated aqueous NaHCO03 solution (10 muL), brine (20 rnL), dried (Na 2

SO

4 ), and concentrated in vacuo. The crude material was purified by column chromatography over silica gel to provide 450 mg of 4 bromo-2-(4-fluorophenyl)Ihiazole which was directly used in the next step without further purification: LCMS (m/z): 259.9 (MHI '), I = 1.08 min. 102811 Step 2: A ruixture of 4-bromo-2-(4-fluorophenyl)thiazole (450 mg, 1.7 rmnol), 3-inethoxy 5-(4,4,5,5-tctramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (400 mg, 1.6 mmol ), and aqueous 2.0 M Na2CO 3 solution (2.3 miL, 4.6 mrnol) in DME (6.8 mL) was sparged with Ar for 3 min. Tetrakis(iriphcnylphosphinc)pal ladiumu(0) (120 mug, 0.1 minol) was added and the reaction mixture was spargcd with Ar for I mlin. The reaction was scaled and irradiated at 115 'C for 25 min in a microwave reactor. The reaction mixture was partitioned with EtOAc (50 mL) and saturated aqucous NaHCO3 solution (100 muL). The separated organic layer was washed with saturated aqueous Nal-C0 3 solution (50 mnL). The organic layer was extracted with aqueous 0.5 N HCI solution (2 X 25 mL). The combined acidic aqueous portions were washed with EtOAc (30 mL), neutralized with saturated aqueous NaI-CO3 solution and extracted with EtOAc (3 X 50 muL). The 113 Orgnic layer was dried (Na2SO 4 ), filtered, and concentrated in vaeuo. The crude niaterial was purified by column chromatography over silica gel (SiO2, 100% ItOAc) to furnish 145 mg (88% purity) of 5-(2-(4-lluorophcnyl)thiazol-4-yl)-3-iethoxypyridin-2-amine which was directly used in the next stcp: LCM S (ni/z): 302.1 (MI '), Ix = 0.75 min. 102821 Step 3. Preparation of 5-(5-bromo-2-(4-fluorophenyl)thiazol-4-yl)-3-methoxypyridin-2 amine: To a solution of 5-(2-(4-Iluoroplicnyl)thiazol-4-yl)-3-methoxypyridin-2-anine (68 mg, 0.23 mmol) in chloroform (3.6 mL) at 0 "C was added a solution of bromine (2.0 M in CHCb, 0.17 mL, 0.34 mmol). The reaction was stirred at rt for 6-10 min and concentrated in vacun. The resulting residue was azeotroped with 5% methanol in DCM solution (5 mL) and purified by prep TLC (SiO2, 1.0 mm, 95 : 5 DCM-methanol) to give 67 mg of5-(5-bomo-2-(4-fluoiophenyl)thiazol-4-y)-3 methoxypyridin-2-amine was isolated as a tan solid: LCMS (ni/z): 380.0 (MH-'), R 0.85 min. 10283! Stcp 4: A mixturc of 5-(5-broio-2-(4-fluorophenyl)thiazol-4-yl)-3-melhoxy pyridin-2-amine (40 mng, 0. II mmol), 4-pyridincboonic acid (39 mg, 0.32 mmol), and , and aqueous 2.0 M Na 2

CO

3 solution (0.6 mL) in DMF (1.8 ml.,) was sparged with Ar for 3 mii. Tetrtkis(triphenylphosphine)palladium(0) (20 ing, 0.02 minol) was added and the reaction mixture was sparged with Ar for 1 min. The reaction was scaled and irradiated at 115 'C for 15 min in a microwave reactor. The reaction mixture was partitioned with EtOAc (25 mL) and saturated aqueous NaHCO 3 solution (25 niL). The separated organic layer was washed with saturated aqueous Nal-IC03 solution (25 ml..), brine (25 mL), dried (NU 2

SO

4 ), Filtered and concentrated in vacuo. The resulting residue was purl ied by reverse phase HPLC, which after lyopholization, provided 23 mg of the titled compound as the TFA salt: LCMS (ni/z): 378.9 (MH'), I, = 0.57 minl. Example 17 2-ami no-3-methoxy-5-(4l,4,5,5-tct ratmlethyl-1,3,2-dioxaborolan-2-yl)pyridiie H,N N MuO 102841 Step 1. Preparation of 2-amino-3-mcihoxypyridinc: To a solution of 2-nitro-3 methoxypyridinc (32 g, 208 miiol) in EtOAc (150 mL) and McOH (35 mL) under a nitrogen S14 atmosphere was added 10% palladium on carbon (1 .5 g, 1.4 mnol). This mixture was purged with t12 three times and the mixture was stirred for 3 h under a hydrogen atmosphere. The reaction mixture was purged with N 2 thrcc times, filtered through Cclitc, and the Filter cake was washed with E'tOAc (2 X 35ml). The combined filtrate were concentrated and dried over high vacuum to afford 25.8 grams (100%) of 2-amino-3-methoxypyridine: LCMS (m/z): 125.0 (MH*); 'H NMR (300 MI-lz, CDC1 3 ): 7.66 (m, I 1-1), 6.90 (m, I 1), 6.61 (i. 2H), 4.64 (s, br, 2H), 3.83 (s, 311). [0285) Step 2. Preparation of 2-anino-3-methoxy-5-bromopyridine: A 2 L Erlenmcycr flask was charged with 10% sulfuric acid (800m]). At ambient temperature, 2-amino-3-methoxy-pyridine (25.8 grams, 206 nimol) was added portionwisc with stirring. Afler a clear solution was obtained, the solution was cooled in an icc/water bath until the solution temperature reached 3 C. A solution of bromine (10.8 ml, 210 mmol) in acetic acid (140ml) was added dropwise while maintaining the internal temperature at 3-5 "C. After the addition was complete, the mixture was stirred at 5 C for 2 h. This mixture was poured into 800 grams of ice with stirring and saturated ammonium hydroxide solution (30% w/kw) was added slowly to the resultant mixture until the pH = 8 was reached. A dark solid precipitates and the mixture was stirred for additional 30 min at 3-5 C. The solid was obtained by Filtration and was washed with cold water (2 X 30 ml) and dried to afford 39.0 grams of crude product. The crude was suspended in EtOAc (500 ml) and the resulting dark mixture was stirred vigorously for 30 min and filtered through Celite. The filter cake was washed with EtOAc (2 X) and the combined Filtrates were washed with 10%/., sodium thiosulfite solution (100 ml), brine and dried (Na 2 SO,). Concentration of this mixture afforded 29.0 grams (68%) of 2-amino-3-methoxi-5 bromopyridinc: LCMS (m/z): 204.9.0 (MI-I); 'H NMR (300 MHz, CDCl 3 ): 7.71 (d, J = 2.1 Hz, I H-), 7.01 (d, J = 2.1 Hz, 1 H-), 4.69 (br s, 2 11), 3.84 (s, 3 1-). 102861 Step 3. Preparation of 2-amino-3-niethoxy-5-(4,4,5,5-tetraniethyl-l,3,2-dioxaborolan-2 yl)pyridinc: A mixture of 2-amino-3-mcthoxy-5-bromopyridine (8.5 g, 41.6 niol), bis(pinacolato)diboron (11 .1 g, 43.7 minol), potassium acetate (8.2 g, 83.6 minol), Pd 2 (dba)3 (774 mg, 0.8 mmol), and PCyi (827 ing, 2.9 mnol) in dry dioxanc (60 mL) was sparged with argon for 20 in. The reaction lask was scaled and the reaction was heated to I10 "C and maintained for 6 h. The reaction was allowed to cool to rt and diluted with EtOAc. The mixture was filtered through neutral alumina, washing the 115 filter cake thoroughly with EtOAc (3 X). The combined filtrates were thcn filtcrcd through Cclite. The resulting hoinogenous filtrate was concentrated. The resulting residue was triturated with hexancs to provide 7.39 g (71%) of the title compound: LCMS (m/z): 169.0 (MIT', boronic acid), /i = 0.22 miiI; '-1 NMR (300 MI-Iz, CDCh) 6 8.07 (d, .1 = 1.2 Hz, I H), 7.20 (d, .1 = 1.2 Hz, I H), 4.88 (br s, 2 H), 3.86 (s, 3 H), 1.33 (s, 12 H). Example 18 3 -mcthoxy-5-(4,4A,5,5-tetramethyl-I 3,2 -dioxaborolan-2-yl)pyrazin-2-amine H12N IN MeO N -0 0 102871 Step 1. Preparation of 5-bromo-3-nethoxypyrazin-2-anine: A 30% w/w solution of NaOMc in MeOH (8.4 mL, 41.8 nmol) was added to a stirring suspension of 3,5-dibromo-2 aminopyrazine (10 g, 39.5 mmol) in dry MeOH (40 mL). The reaction mixture was heated to reflux and maintained for 3 h. The reaction was allowed to cool to rt and concentrate to 1/3 volume. The reaction was then partitioned between DCM and samrated aqueous Na-ICO solution. The layers were separated and the organic phase was washed with saturated aqueous NaHCO, solution (3 X). The combined iqueous portions were back extracted with DCM (3 X). The combined organic portions \vere washed with brine, dried (Na 2 SOi), and concentratcd to provide 8.1 g of 5-brono-3 methoxypyrazin-2-amine: 'H NMR (300 MI-Iz, CDCbi): 7.64 (s, I H), 4.79 (br s, 2 H), 4.01 (s, 3 1-1). 102881 Step 2. Preparation of 3-methoxy-5-(4,4,5,5-tetrametlyl- I ,3,2-dioxaborolan-2-yl)pyrazin-2 amine: 5-bromo-3-methoxypyrazin-2-amni ne was elaborated to the title compound in an identical manner as described in Example 17, Step 3: LCMS (m/z): 169.9 (MI-I', boronic acid), IR = 0.18 min; 'IH NMR (300 M H z, DMSO-d 6 ) 6 7.78 (s, 1 11), 6.69 (br s, I 1-), 3.86 (s, 3 1-), I .25 (s, 12 -1). 116 Example 19 3 -d-rethoxy-5-(4 ,4,5,5-tct ramethyl-I 3,2-dioxaborolan-2-yl)pyrazin-2-amine

H

2 N N D3CO N 102891 Stcp 1. Preparation of 5-bromo-3-d 3 -methoxypyrazin-2-amine: Sodium (0.55 g, 23.7 mmol) was added to dry nethaiiol-di (20 ml) the reaction was stirred until homogeneity. 2-Amino-3,5 dibromo-aminopyrazinc (5 g, 19.8 rnmol) was added and the resulting reaction mixture was heated to reflux for I hr. The reaction was allowed cool to rt and concentrated to-1/3 volume. The reaction was then partitioned between DCM (100 rnL) and brine (100 mL). The layers were separated and the aqueous portion was extracted with DCM (50 mL). The combined organic portions were washed with brine (100 rnL), dried (MgSO 4 ), and concentrated in vacuo to give 4.1 g of 5-bromo-3-d nethoxypyrazin-2-amine: LCMS (n/z): 207.0 (MH-1), 1, = 0.55 min; '1 NMR (400 MI-lz, CDCb3) 3 7.65 (s, I -1), 4.69 (hr s, I F). 102901 Step 2. Preparation of 3-d-methoxy-5-(4,4,5,5-tetiamelhyl-1,3,2-dioxaborolan-2-yl)pyrazin 2-aiminc: 5-biono-3-d 1 -mctlioxypvrazin-2-ami ne was elaborated to the title compound as per Example 17 Step 3: LCMS (nz): 1 73.) (MIH', boronic acid), j = 0.19 min; 'I NMR (300 MHz, CDC ): 8.03 (s, I H-), 5.05 (br s, 2 H1), 1.36 (s, 12 H-1). Example 20 3-mtlioxy-6-methyl-5-(4,4l,5,5-tetramethyl-,I 3,2-dioxaborolan-2-yl)pyrazin-2-am inc I i EN I MoO N 3 102911 Step 1. Preparation of 6-Mcthylpyrazin-2-arninc: Following a literature procedure (Walters, I.A.S. Tetrahedron Leti. 2006, 47, 341), a solution of dimethylzinc (2.0 M in toluene, 75.0 mL, 150.0 mmol) was carefully added in 25 mL portions to a solution of2-anino-6-chloropyrazinc (10.0 g, 77.0 mmol) and 1,3 -bis(diplicnylIphospliino)piopanc- nickel (I) chloride (4.2 g, 7.8 ilmmol) were 117 dry in dioxanc (400 mL) undcr a nitrogen atmosphere. The reaction was stirred at rt for 2 h1 and then heated to 50 C for I h and 95 C overnight. The reaction was allowed to cool to rt and an additional charge of dimethylzinc was added (22 niL, 44 mmol) and the reaction was then maintained at 95 "C overnight. The reaction was cooled to rt, quenched over 15 min with McOH and then concentrated to a brown solid. Water and EtOAc were added to the solid, and the mixture was sonicated. The solid was removed by filtration and brine was added to the EtOAc-water mixture. The layers were separated, aid the organic hiyer was dried (Na 2 SO.), and concentrated to give 9.72 g (-70 purity) of 6-methyl pyrazi n-2-ami ne, which was carried forward without further purification: LCMS (/z): 10.0 (MH '), ik = 0.21 nin. 102921 Step 2. Synthesis of 3,5-d ibromo-6-netlylpyiazin-2-ami ne: Following a literature Iroceduire (WO 20071035154, p 29), bromine (12 m.,, 231.0 mm1ol) was added portion-wise over 5 minutes into a cooled solution of 6-methylpyrazin-2-amine (9.72 g, 89.0 mmol) and lutidine (31.0 il, 266.0 minol) in dry acetonitrile at 10 'C. The reaction was maintained overnight, allowing the cooling bath to expirc. The reaction was queched with aqueous 2.0 M sodium sul fite solution and the p1 was adjusted to 8 with the addition of 6 M NaO-l. The mixture was concentrated in vacuo and the remaining aqueous portion was cooled to 5 C overnight. The resulting brown solid was isolated by ilItration and triturated with a 9 : I EtOAc-hextincs soluti on to furnish 1 1.9 g of 3,5 (itioio-6-mctlhylpyrazin-2-ami ne. The collected filtrate was concenmrated and the resulting solid triturated again to provide an additional 2.2 g of product: LCMS (m/z): 267.9 (MH' + 2), Ilk = 0.80 102931 Step 3. Preparation of 5-bromo-3-methoxy-6-methylpyrazin-2-amine: A solution of NaOMc (--4.4 M in McOHl-, 14,0 mL, 61.6 mmol) was added to solution of 3,5-sibromo-6-methylpyrazin-2 amine (14.1 g, 52.7 inmol) in dry McOH. The reaction was heated to 70 "C for 18 h and then cooled to rt and stirred for 48 hi. Water then added to rcac.ion. and mixture cooled at 5 "C for 3 h. The resul tiig solid was isolated by filtration to give 10.1 g of 5-bromo-3-micthoxy-6-metlhylpyrazin-2 aminc: LCMS (m/z): 218.0 (MI-), /, = 0.59 min; '- NM R (300 MHz, CDCl,) 6 6.42 (bs, 2 -1), 3.83 (s, 3 1-), 2.24 (s, 3 1-). 102941 Step 4. Synthesis of 3-methoxy-6-ncthyl-5-(4,4,5,5-tctranethyl-1,3,2-dioxaborolan-2 yI)pyrazin-2-armine: 5-3romo-3-mcthoxy-6-mcthylpyrazin-2-amu inc was converted to the title 118 compound in a manner identical to Example 17, Step 3: LCMS (m/z): 184.0 (MH H, boronic acid), tl = 0.23 min. Example 21 3-ethyl-5-(4,l,5,5-tctramcthyl-1,3,2-dioxaborolan-2-yl)pyriline-2-amine 11,N N, 0 [02951 Step l. Synthesis ofier-butyl 3-methylpyridin-2-ylcarbiumate. 13C anhydride (9.6 g, 44 mml) was added slowly to a solution of 3-methylpyridin-2-arnine (4 g, 37 mniol) and ccsiurn carbonate (7.2 g) dry in DMF (20 mL) and the reaction was maintained at rt for 2 d. The reaction mixture was poured into water (300 nL) with stirring. The resulting white precipitate was collected by filtration and dried under vacuum to give 4.45 g of Iert-butyl 3-nethylpyridin-2-ylcarbamnatc: 'H NMR (300 MHz, CDC1 3 ) 6 8.26 (i, I H-); 7.52 (in, 1 11); 7.02 (m, I H); 6.88 (br s, 1 H-); 2.29 (s, 3 11); 1.52(s, 9 H). 102961 Step 2. Preparation of trt-butyl 3-etliylpyridin-2-ylcarbamate: Following a literature procedure (Synthesis 1996, 877), n-Buti (2.2 M in hexane, 9.1 mL, 20 inmol) was added dropwise to solui on of tert-butyl 3-netliyilpyridin-2-ylcarbamate (1.98 g, 9.5 minol) in dry TIF (2 1 mL) at -5 'C. The reaction was maintained at -5 "C for I h, then cooled to -7N "C in a diy icc-acetone bath. A solution of Mel (0.62 mL, 10 mmol) in dry lTIF (3 ml.) was added over 20 min. Thc reaction was maintained at -78 "C for I I and lien raised slowly to -55 C. The reaction was quenched with water (20 ml..) and the resulting mixture was parlitioned and the layers separated. The aqueous phase was extracted vl Ih EtOAe (2 X 20 mL..) and the combined organic portions were washed with brinc, dried (Na2CO3), and conceItrated to furnish 1.8 g of ier-butyl 3-ethylpyridin-2-ylcarbamate: LCMS (m/z): 223.1 (MI-'), Ip = 0.54 min 119 [02971 Step 3. Preparation of 5-bromo-3-cth ylpyridin-2-amine: Following a literature procedure (Journal of Molecular Catalysis A:Chemical 2007, 267, 30) ieri-butyl 3-ethylpyridin-2-ylcarbamale (820 mg, 3.68 mmol) was treated with 4.0 M HCI in dioxane (4 niL, 4 mmol) and the reaction was maintained at ri for 2 h. Water (2 mL) was addCd and K 2 CO. was addcd until pH >I 0. The resulting suspension was filtered and the isolated solid was washed with EtOAc (2 mL). The organic filtrates werc concentrated and the resulting residue was dissolvCd in acctonitrile (4 m L). A portion (2 niL) was treated with NHFIOAc (100 mg), followed by NBS (280 mg, 1.57 inmol). The reaction was maintained at rt for 15 min. The reaction was then partitioned between EtOAc and water and the resulting layers scparatcd. The aqueouS portion was extract with EtOAc (2 X 5 mL) and the combined organic layers were concentratecd. The resulting residue was purified by reverse phase HPLC. The collected Fractions were basifhed to pH >10 by the addition of saturated aqueous Na2CO3 solution. Extraction with EtOAc (2 X 20 mL) followed by concentration provided 240 mg of 5-bromo-3-ethylpyridin-2-amine: ' 1 NMR (400 MI-lz, CDCl 1 ) 6 7.99 (d, J= 2.4 H z, I 1-1); 7.39 (c,J = 2.4 Hz, I H); 4.41 (br s, 2 1-1); 2.42 (q,J = 7.2 Hz, 2 Fl); 1.26(t, .J= 7.2 Hz, 3 H). 102981 Step 4. Preparation of 3-ethyl-5-(4,4,5,5-tetramcthyl- ,3,2-dioxaborolan-2-yl)pyridiiie-2 amine: 5-3romo-3-cthylpyridin-2-arine (230 mg, 1.5 rmol). bis(pinacolato)diboron (500 mg, 1.97 nmol) and KOAc (210 mng, 2.1 mmol) were suspended in dry dioxane (15 mL). The mixture was spargcd with Ar for 3 min followed by the addition of PC(PP1h (42mg, 0.036 mmol. The reaction mixtiirc was sparged again with Ar. The reaction was scaled and heat to and maintained at 100 'C for 18 hr under Ar. The reaction was allowed to cool to rt and to settle. The supernatant was decanted and used in the next step without further puii.nication: LCMS (m/z): 166.9 (MH', boronic acid), /I = 0.32 min. Example 22 3-met liyl-5-(4,4,5,5-tetanmethyl-I 3,2-dioxaborolan-2-yl) 1-4-((2-(trimethylsilyl)ethoxy)methyl)-I H pyrrolo[ 2,3,-bjpyrid ine 120 SEM 0 [02991 Step 1. Preparation off5-bromo-3-iodo- 1 -((2-(trimethylsilyl)cthoxy)ncthyl)- H Fl-pyrrolo[2.3, h]pyridine: 60% Nal- in oil (150 mg, 3.74 mmol) was added to a solution of 5-bromo-3-iodo-l I pyrrolo[2,3-b]pyridinc (1.0 g, 3.12 mmol) in dry DMF (6 mL) at 0 'C. The reaction mixture was allowed to warm to rt over I h and cooled again to 0 "C. 2-(chloromethoxy)cthyl)trimethylsilane (661 uL, 3.74 mmol) was then added and the reaction was maintained for 1.5 h. The reaction was then quenched with water and the mixture was concentrated in vacuo. The resulting crude solid was dissolved in EtOAc (75 mL) and washed sequentially with water (2 X 25 mL), aqueous 2.0 M HCI (50 mL), water (25 ml.,), and then brine (50 mL). The solution was dried (Na2SOt) and concentrated to yield 1.48 g of 5-bromo-3-iodo-I -((2-(triiethylsilyl)cthoxy)niethyl)-l H--pyrrolo[2,3,-b]pyridinc: LCMS (n/z): 455.0 (M Il), i,= 1.47 min . 103001) Step 2. Preparation of 5-bromo-3 -methyl-I-((2-(trimethylsilyl)cthoxy)methyl)- lH pyrrolo12,3 b]pyridine: A mixture of 5-bromo-3-odo-l-((2-(tritnethylIsi lyl)cthoxy)nethyl)- Ifpyrrolo[2,3-b1pyridine (1.05 g, 2.33 mmol), 2,4,6-trieinthyl-I,3,5,2,4,6-trioxatriborinane (2.6 nL, 18.6 mnol), and potassium carbonate (0.97 g, 7.0 mmol) in 10 % aqueous dioxane (19 mL) was sparged vith A r. Pd(PPh 3 ). (134 mng, 0. 12 nimol) was added and the reaction was scaled and heated to 90'C for 6.5 h. The reaction was allowed to cool to rt and concentrated in vacuo. The remaining residue was dissolved in EtOAc (250 mL), washed sequentially with water (100 mL), aqueous 0.1 M 1lI solution (150 mL), and brine (100 mL). The resulting solution was dried (Na 2 SO4) and concentrated. Purification by reverse phase HPLC yielded 23 mg of 5-bromo-3-methyl-1-((2 (trimCthylsilyl)ethoxy)methyl)- I l-pyrrolo[2,3-b pyridine as the TFA salt: LCMS (n/): 342.9 (MI'), t, = 0.74 min Step 3. Preparation of 3-metlyl-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-l -((2 (trimetliyls l yl)cthoxy)mcthyl)-1I l--pyrrolo[2,3 -)pyI-i(iic: A mixturC of 5-bromo-3-niethyl-l -((2 (trimethylsilyl)cthoxy)methyl)- I I--pyrrolo[2,3-b]pyridine (33 mg, 0.097 minol) and bis(pinacolato)diboron (27 mg, 0.107 mmol) in 0.5 mL dioxane sparged with nitrogen was added KOAc (29 mg, 0.291 mmol) and Pd(dppf) Cl-DCM (8 mg, 0.0110 mmol). This mixture was heated 121 in an oil bath at I 10 "C for 3 h. After cooling to rt the reaction mixture was centrifuged and the supernatant decanted, and used in the next step without further purification. LCMS (n/z): 307.0 (MI', baronic acid), it= 0.80 min. Example 23 (S)-tert-3utyl-1 i-aminopropiin-2-ylcairbaimate 1-1 H Boc-N NH2 103(0 11 Step I. Preparation of (S)-er-buty] I -(l ,3-dioxx isoindol in-2-yl)p ro pan -2-ycarbanate: To a stirred solution of (S)-'ert-butyit 1-ydroxypropan-2-ylcarhanate (7.4g, 42.2mmol) in dry THF (4I20ml11) were added phthalimide (6.83g, 46.4inmol) and PPth (12.18g, 46.4mmol). DEAD (7.3ml, 46 mnol) was then added diopwise to the stirred solution at rt, and inaintaincd for 3 h. The reaction mixture was then concenitrated and the residue was purified by flash chromatography (SiOC 70 : 30 - 50 : 50 hexanes-EtOAc) to provide 12.5 g of (S)t-erit-buyl l-(1,3-dioxxisoindolin-2 yl)propan-2-ylcarbamate: LCMS (mI/z, M+H-Roc): 205.1, li = 0.86min; 'H NMR(CDCb, 400 MHz) 6 7.82-7.87 (m, 2 1-1), 7.67-7.75 (in, 2 H), 4.60-4.76(br d, I H), 4.03-4.20 (br s, 1 H), 3.62-3.72 (m, 2 -1), 1.25 (s, 9 H), 1.21 (d, .= 6.64 Hz, 3 1-). [03021 Step 2. Synthesis of (S)-fer/-13utyl- -aininopropan-2-ylcarbamatc: Hydrazine monohydrate (20ml, 642.7minol) was added to i suspension of(S)-lert-butyl 1-(1,3-dioxxisoindolin-2-yl)propan 2 -ylcarbamate (12.50g, 41.1mmol) in 1ry MeOH (15 nl), and the resulting mixture was heated to 50 "C for I b. After cooling to ri, the reaction mixture was fliltrcd through a sintered funnel, and the litrate concentrated. The resulting residue was suspended in Et20 (300 nL) and filtered, washing the filter cake thoroughly with Et 2 0. The combine filtrates were. Filtered and concentrated to furnish 6.3 g of (S)-leri-tl-Butyl--arninopropan-2-ylcarbainate: '-1 NMR(CDC 3 , 400 MHz) 8 4.44-4.7 1 (br s, I -1), 3.53-3.74 (br m, 1 I-), 2.75 (dd, J= 4.9, 12.9 Hz, I H), 2.64 (dd, J = 6.6, 12.9 Hz, I -1), 1.45 (s, 9 H-), 1.21 (d, J= 6.6 Hz, 3 1-), 1.15-1.34 (br s, 2 1-1), 1.12 (d, J = 6.7 Hz, 3 H). I 22 Example 24 Synthesisof 5-(2-(4-(ethylsulfonyl)piperazin-l -yl)-5-(pyridin-4-yl)-lH1-1-imidazol-4-yl)-3 methoxypyridin-2-arni ne HN N MoO N /---\ M>-N N-SO 2 lE N H N/ 103031 Step I. Preparation of 1 -(4 ,5-dibrono-l -((2-(t rimrethylsilyl)ethoxy)mcthyl)-II-imidazo1-2 yl)piperazinc: A mixture of 2,4,5-tribromo- I -((2-(trimethylsilyl)ethoxy)mcethyl)-I H1-iridazole (653 mg, 1.5 mmol) and piperazinc (1.03 g, I 2.0 mmol) under Ar wasiradiated at 130 'C for 15 min in a microwave reactior. The reaction mixture was partitioned between DCM and water (100 m L, lt). The layers were separated and the aqueous layer was extracted with DCM (2x 50 mL). Thc combined organic layers were dried (Na 2 SO.), Filtcred and concentrated in vacuo. The rcslting was purified by flash chromatography (SiO 2 , 100 . 0 - 90 : 10 DCM-McOH) to provide 186 mg of I (4,5-dib romo- i -((2-(r ri met hylsi lyl)ethoxy)ncthyl )-I 1-1-imrridazol-2-yl)piperazine as a colorless oil: LCMS (m17): 44 1.0 (MHt ), it= 0.86 min 103041 Step 2. Preparation of 5-(5-bromo-2-(pipcrazin-l-yl)-I -((2-(trimethylsilyl)cthoxy)methyl) I/-i -iiazol-4 -yl)-3-methoxypyridi n-2-anine : A mixture of 3-mrethoxy-5-(4 ,4, 5,5-tetramoet hyl 1,3,2-dioxaborolan-2-yl )pyridi n-2-aminc (66.5 mg, 0.27 mol) and I (4,5-dibromo-l -((2 (trimcthylsilyl)cthoxy)methyl)- I --imidazol-2-yl)piperazine (90 mg, 0.20 mmol) in DME (2.4 ml) and 2.0 M aqueous Na 2

CO

3 (0.8 ml) was sparged with A r for 2 mn. P1dt(PhP) 1 (47.2 mg, 0.0411 mmol) was added. The mixture was sparged with Ar for an additional 2 min and was irradiated in a scaled tube in a microwave reactor at 115 'C for 20 min. The reaction rnixture was extracted with EtOAc (3x IS mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO 4 ), filtered and concentrated in vacuo. 103051 A mixture of 3-niethoxy-5-(4,,5,5-tetram ethyl-I ,3,2-dioxaborolan-2-yl)pyridiin-2-aminc (56.2 mg, 0.225 rnmol) and 1-(4,5-d ibromo-I -((2-(trimetl ylsilyl)ctloxy)nethyl)- I H-imidazol-2 123 yl)pipcrazinc (90 mg, 0.204 mmol) in DME (2.1 i ml) and 2M aqueous Na 2 CO3 (0.7 ml) was sparged with Ar for 2 min. Pd(Ph-P)I (23.6 mg, 0.02 mmol) was added. The mixture was sparged with Argon for anadditional 2 min and was heated in a sealed tubc in a microwave reactor at 115 'C for 15 min. The reaction mixture was cxtractcd with EtOAc (3x 15 mL). Thc combined organic laycrs were washed with brine (50 mL), dried (Na 2

SO

4 ), filtered and concentrated in vacuo. The crude materials of both reactions were combined and purified by preparative TLC (SiO2, 1.0 mm, 90 : 10 )CM-MeO-l) to fumish 5-(5-bromo-2-(pipcrazin- I-yl)- -((2-(trirnethylsilyl)ethoxy)methyl)- I H imidazol-4-yl)-3-mcthoxypyridin-2-arminc was isolated as a white solid which was directly used in the next step: LCMS (n/z): 485.2 (M lH'), t= 0.56 min. 103061 Step 3. Preparation of 5-(5-bromo-2-(4-(ethylsulfonyl)piperazin-l-yl)-l -((2 (trimethylsilyl)ethoxy)methyl)-] H-imidazol-4-yl)-3-methoxypyrilin-2-amine: In a 10 mL round bottomed flask was 5-(5-bromo-2-(piperazin- I -yl)- I -((2-(trimethylsilyl)cthoxy)mcthyl)- IH iniidazol-4-yl)-3-methoxypyridlin-2-amine (22 mng, 0.046 mmol) in TI-F (1.2 ml) and DMF (0.2 mL) under Ar at 0 'C to give a colorless solution. Ethanesulfonyl chloride (8.62 pl, 0.091 mmol) and triethylamine (0.014 m1, 0.100 mmol) were added. The ice bath was removed and the mixture was stirred at ambient temperature fbr 30 min. The mixture was quenched with water (3 mL) and diluted with E1Ac (10 ml..). The aq layer was extracted with EtOAc (2x 10 mL). The combined org layers were washed with sat aq NaI CO 3 solution (tx 30 mL), brine (I x 30 nL), dried over Na 2 SO,i, filtered and conc in vacuo. The crude material was directly used in the next step without puri fication: LCMS (ni/z): 577.2 (MII), il = 0.82 min. 103071 Step 4. Preparation of 5-(2-(4-(ethylsul fonyl)piperazin-l-yl)-5-(pyridine-4-yl)-1 -((2 (trimethylsilyl)cthoxy)methyl)-1/--imidazol-4-yl)-3-methoxypyridin-2-amine: A mixture of pyridin 4-yI boronic acid (I 7.0 mg, 0.14 mmol) and 5-(5-bromo-2-(4-(ethylsul fonyl)piperazin- I -yl)-l -((2 (trimcthylsilyl)ctlhoxy)rnethyl)- I -1-imidazol-4-yl)-3-mcthoxypyridin-2-amine (26.5 mg, 0.05 mmol) in DME (1.5 iiL) and 2.0 M aqueous Na:tCO3 (0.5 mL) was sparged with Ar for 2 min. Tetrakis(triphcnylphosphine)palladium(0) (10.6 mg, 9.2 pmol) was added. The mixture was sparged with Ar for an additional 2 min and was irradiated in a sealed tube in a microwave reactor at I 15 C for 15 min. The reaction mixture was extracted with EtOAc (3x 10 mL). The combined organic layers were washed with sat aqueous NalHC0 3 (30 mL), brine (30 mL), dried over Na 2

SO

1 , filtered 124 and concentrated in vacuo. The material purified by preparative TLC (Si0 2 , 0.25 mm, 95 : 5 DCM MeOH) to afford 5-(2-(4-(ethylsulfonyl)pipeiazin-I-yl)-5-(pyridin-4A-yl)-1 -((2 (t ri ethylsil yl)ethoxy)Iethyl)- I H-i m idazol-4-yl)-3 -methoxypyridin-2-ani ine was isolated as colorless solid: LCMS (ni/z): 574.3 (M-i'), il= 0.68 min. [03081 Step 5. Synthesis of 5-(2-(4-(ethylsulfonyl)piperazin- I -yl)-5-(pyridin-4-yl)- I H--imidazol-4 yl)-3-inethoxypyridin-2-arinc: 5-(2-(4-(thylsulfonyl)pipcrazin-I-yl)-5-(pyridin-4-yl)-I-((2 (t riniethylsilyl)cthoxy)-m eth yl)-I H -imidazol-4 -yl)-3-methoxypyridin-2-armine (6.1 mg. 10.63 pimol) in McOH (1.6 ml) and conc hydrochloric acid (OA ml) was heated at 60 "C for 50 min. The reaction mixture VWas concentrated in vacuo and purified by reverse phase II PLC, which after freeze drying, gave the title compound as thc TFA salt: LCMS (m/z): 144.2 (MH'), ita = 0.37 min . Example 25 3-(difluoromcthoxy)-5-(4,4,5,5-tetramethyl- ,3,2-dioxaborolan-2yl)pyridine-2 -amine

H

2 N N 0 F F 1 103091 Step I. Preparation of 2-bromo-3-(diluoroncthoxy)pyridine: A mixture of 2 bromopyridin-3-ol (3.55 g, 20.4 mmol), sodium chlorodifluoroacetate (6.22 g, 40.8 mmol), and NaOH (0.90 g, 22.A mmol) in DMF (20ml) was heated al 55"C for I I h. The reaction was allowed to cool to rt and concentrated, and resulting residue was partitioned between EtOAc/sat. Na 2

CO

3 (80ml/40inl). The organic phase was collected and washed with brine(40ml), dried (Na 1 SO), concentratcd and the resulting residue was purified by flash chromatography (Si02, 100 : 0 - 0 : 100 hexancs-EtOAc) to provide 1.95 g (43%) of 2-bromo-3-(difluoromethoxy)pyridine: LCMS (ni/z, M H'): 225.9, il = 0.74 min; IH NMR(CDC1 3 , 100 MlH z) 8.23-8.33 (in, I -), 7.52-7.60 (m. I 1-), 7.27-7.35 (im, I H), 6.60 (t,./= 72.4 Hz, I -1). 103101 Step 2. Preparation of 3-(difluoroiethoxy)pyrilin-2-amine: To a steel bomb were charged with 2-iethoxyeihanot (20mnl), 2-biomo-3-(difluoromethoxy)pyridine (1.95g, 8.7 mmol), conc. 125 aqueous NH101-H (28-30%, 5 ml, 79 mmol) and Cu2O (0.25 g,, 1.7 inmol). Thc reaction mixture was heated at 100 "C for 23 h, then cooled to 0 "C, and partitioned between mixture of EtOAc/aq. 3 N NaOH/11 2 0 (40m1/1 Ornl/30ml). The organic phase layer was collected, washed with saturated aqueous NaHCO- solution (30ml), brine (40ml), dried (Na 2

SO

4 ), and concentrated to produce 1.12 g of 3-(di fltioronethoxy)pyridin-2-amine which was carried forward without further purification: L.,CMS (Im/z, M H): i 6 .0, /= 0.31 miin. [03111 Step 3. Preparation of 5-broino-3 -(diluoromethoxy)pyridine-2-ainijoe:

N

Bromosuccinamide (1.00g, 5.62 mmol) was added portionwise over 10 min to a cooled solution of 3-(d ifluocromethoxy) pyri din-2-aninc (1.12 g) in dry aectonitrile (20ml) at 0 "C. The reaction m ixtuic was fiorther stirred at 0 "C for 1i0min. The mixture was concentrated, and residue was partitioned between EtOAc/sat. Na 2

CO

3

/H

2 0(30m11/1 5ml/ 15ml). The organic phase was sequentially washed with sat. aqueous Na 2

CO

3

/H

2 0(I5mol/I5ml) and brinc(30ml), dried (Na 2 SOm), and conicent rated. TheC resulting residue was extracted with EtOAc/hexanes(6ml/30ml), and the resulting suspension was filtered through Cclitc, and the resulting filtrate was concentrated to provide 1.32 g (80%) of 5-bromo-3-(difluoronethoxy)pyridinc-2-anine. LCMS (m/z, MIH): 238.9, / = 0.52min; 11 NMR (CDC 3 . 400 MI'lz) 8 7.99 (d, .1 = 2.0 Hz, I 11), 7.41 (in, I 1-), 6.50 (t, J = 72.8 Hz, I 1-), 4.75 (br s, 2 H). 103121 Step 1I. Preparation of 3-(difliuor oiethoxy)-5-(4!,4,5,5-tetramcthyl-1,3,2-dioxaborolan 2yl)pyridinc-2-ainine: A mixture of 5-bromo-3-(difluoromethoxy)pyridinc-2-aminc (88ing, 0.37 inmol), his(pinacolato)diboron (102mg, 0.4t0 mrol), potassium acetate (0.215mg, 2.2 minol), and Pd(dpf)-C-1 2 C2 (30mg, 0.037mnnol) in dy dioxane (2.0 inL) was spargcd with argon, and heated at 120"C for 30 min. A fer cooling to rt, the reaction mixture was centrifuged and the supernatant decalited, and used in the next step without Further purification: LCMS (rn/z, MI-I', boronic acid): 205.0, i= 0.27minH. Examples 26-290 103131 The compounds of' he piescit invention, including those shown in the following Table I (Conpounds No. 1-265), have been prepared by these methods il modiICaiions of these methods that are apparent to the person of orndiary skill. Compounds P1I -P 19 can be prepared similarly by the teachings of one or imore procccluires described in the Examples above and/or by general 126 synthetic schemes described h1crcin, and using the appropriate starting materials as rcadily detuirmined by one of skill in the art. TABLE I mut-b- retenti o.pll SmTRUTURE RAF Oil Ilal Method Compound Name o.pu (tC5t) in time (Mt-W) 11,M) (mll) H N .N '1C H 3 -m c tho xy 5 -(2 -plcny1- 4 I> 1 0.0010) 0.46 344.2 A (pidn-y)lI N -imidaz-ol-5-yl)pyrIdIn-2 H2 N 3-nmethoxy-5-(4-(pyridIn NF I H-imidazol-5-yl)pyridin N- 2-amine N 2 - (4 -(4 -(6 -a mii no -5 / I NAmcitioxypyridin-3 -yI)-2 3 -01 0.0013 0.52 404.1 C ph en y I-] I- im idtEzol1-5 yi)pyrimid in-2 NI 1 2 ylamino)etlianol ,(:I)iN- I- -(4-(4-(5-arni no 6-mctlioxypyrazin.2-yi) N i 'N -2-(0 H- ' 001 06 (tri fluoromcthyl)phenyl) 4 N (r 0.01 06 0 1 CI 1--Iimidazol-5 N N F - 1 2 yl)pyri mid in N ylau aeI)pr-opan-2 -yl)-2 ________ ____________________ _______ _____ __________ metloxyacciamide 127 miil-b- reicnti copun STRIJCTURFB RAF Oil I I S9Mcitod Compounld Namec oon (IC50 in timlc (Mi-r) tIM) (mmi) (S)-N-(1 -(4-(4-(5-umtnO c- 6- mcthox ypyrazi n-2 -y I) 5 I000d07 5. C -(4-fluoropheny)- I Fi { 0 CY0 iniidazol-5-y1)pyrirnidin N 141, o.,2-ylam Ino)prcipan-2-yI)- 2 mcthoxyticctamide N 0- / ~(S)-I -(4-(4-(6-ammno-5 I -'c rnct h o xy p yr Id 13 -y 1 -2 6 1 I1 ~' ,Ij 0.0003 0.40 398.1 C e i--b utIy I- I I- i ni d, in -5 N N I I' y, vpriid in-2 0H N (S)-N-(I -(4.(4-(5-wmno 1-N CH, .03 04 7. 5-yI)pyrimid 112 HN 0 yI anino )propaii-2 -yI)-2 A_ mflthoxy-acetaide(I (S)-niothy! ]I4(-S .,0 N=ami no-6- mcthoxypyn-azin B 0I' 0001 0.52 456 2 C 2-y])-2-ierl-buty i I-1 (' Iil,'-ykuino)proptin-2) \11_ 1 curbamatc N O-CH, N 4-(4-(S-antIn-6 N- Nf1- .meNnthoixypyrazrm-2 -yI)-2 9 N -N M 0 ii 0.0001 0.45 448 1 D ler/-butyl- I Fkidazol-5 N:= y1)-.N-(2-methoxypyridin Nit, 4-yl )pvri midin -2- Utilifl 128 munt-h- !rctcoti ool' TU R. RAF MI11.SNeiod Compound Name N ijo. I JCL (IC5() in imc MI liM) (ll) I 1,N N l "C 5 -(2-(4 -flu orophcnyl) 11) (let rahycdro-21-J-pyran -4 N .03 gi 6. yI)- I I--imidazol-5-yi)-3 m etliox ypyr i -2 -am11* ic 0 N i?. N - 5 -(2-(4 -fluorophcnyl)-4 0 N,- 0 fV 0? 39 B (thiazol-5-yi)-I li N ,>nji- jimdazo -5 -yI)- 3 K~~I mehoxypyrid in-2-am inc N N I N3-chloro-5-(2-(4 12 C N 0,020 0.67 39.1 B fl uorophcny I-4-(pyr IdIII NN HN N N 5-(2-(4 -fluorophenyI)-5 0 (pyridin-4-yI)oxazoI-1 13 I>-C~ 0.0005 0.54 3629 E y)-mehyprd-2 amnine Ii , N (S)-N-( I -(4-(4-(6-amino 1,10 5- mct hoxypyri dln- 3-y l)-2 (4 14 0.0030 0.77 558.3 F (ri n u o ro methyl) 1)hcen y1) o xI a zo I- 5-y I)p yr im id in -2 I ~~~y I am i n o) prop a n -2 -y1) -2 mmc methoxyacetam ide 129 Compo' ici SJ*R iJcILJRb ICO ho NI RAF: Oil lMss 1vie! hod Compomnd Name 11I) (ini) '-'2N -N H c;. 0 3-methoxy-5 -(2-phcnyi-4 15 I/ / 0.0019 0.57 361.0 A (pyrid in-4.y1)thiazo.1 5 N yI)pyrid 1n-2-a rn inc NA H 2N ~N 5 -(2-(4- flu oro ph cnyl)- 5 16 0 ' N = .13 05 7. B (pyrid in-4.-yfth iazol1-4 161 .13 .7 31. Ex.1 6 yI)-3 -mcthoxypyrid in-2 N am lnc N- H 6-(2-phciiy)-4-(pyr"d in -4 240.0580 1.76 353.1 A yI)- I 1--imnidazol-5-yI)- I I/ 1/ \/indazol-3-amninc HN N N I5-(2.phcnyl.4-(pyrd in-4 25 .N0.4890 1.74 3151 A yl)-IH-inidhzo)-5 N N yI)pyrim id in-2 -amine N . H N SH 5.(2-phcny1.4-(pyrid in-4 26 H,N 0.1730 1.76 353.1 A yl)-I H--imidazol-5-yI)- I H .~ N indazol-3-amninu 1 30 )kI I -b - retel I i Copud.TUH E RAF Onl Ib18S M thod Compound Namec CNifjIi)IS u~J (IC50 it) liml-o (M II' I IM) (mil) - 4(2 -ph cn y I- 4 -(1)yr id in -4 27 ~ N /. 0.4170 0.43 314.1 A l)-!1- H- iinid azo 1-5 HN CH3 N-(6-(2 )-phcnyi -4 28 N N I - 0.4490 1.04 395.2 A mirdzl-5-yI)- IH H N I in~dazo! -3-y!)a(ctanido NN~ N-1 11 N N 5-(2-phcnyl-4-(Jyrid in-4 29 (1) ~/ 02600 1.63 314.2 A yI)- I -imidzlS

H

2 N N I (lpyridi n--n)-in-I N inclazol-3-ami 10 N, N N 6-(2-phcnvl-4-Oinvid in-4 32 I/ / 0.017D 0.57 338.1 A yI)-I 1-IrnIdazol-5-yI)- 11-1 N indazole NZ 131 11111t-b- rc I I ti colivotiil STRUCTURE: RAF oil lWass Method Compound Nanic No. (IC50 io ili (M 1-I" ImNI) (mill1) N -6-(2-phcnyl-4-(pyid in -4 33 ~>\) 0.0540 0.61 337.1 A yl)-Ill-imiclizol.5.yi)-ifH '~~~ N - ndo Ic NZ 0 N 6-(2-phcnyl-4-(pyridin-4 34 I -K/ 0.00501 0.59 330.1 A yI)-I 11-imidumzol-5 N yI)bcnzof ci]isoxazolc NZ H I N 3 -incth yl-5-(2-phcnyl-4 35 HC 0.0990 0.55 352.0 A(prdn4y)I "3( N> imidazol-5-yZ)- I N indazoic N 7, 0-yJ 3-niclhoxy-5-(2-phcnlyl-4 363/ 0.0130 0.4/ 329.1 A (pyridin-4-yI)- 11-1 37 N 0 8 0 0.9 3 21 A iIII icl azo-5 -y I)pyriIi n -2 N amin NH 0\/ N3 Compolund SIRUCIU RI R AF Oli 11~ mcihod Compownd Name No.(I'50 iii lime (lv I C 11 2 N 'N i.

3 c~jI3 - ~3incthoxy-5 -(2 -phcnyl1-4 0 N .060 .4 '~R~(pyri din- 4-yI1) - 11 1> N i irn id zo1.5 -y1) py razi n-2 I amine H? 4- inct ho xy-S5-(2-pIcn yl1-4 40 H-N- 0.5020 0.4 344.2 A (yiidino--yl)y-1 i

H

3 C-O ) amid i ne.i~yiir 2 N o N 2 -icthoxy-5 -(2 -phjcnyl-4 42 H N 0.3490 0.49 344.2 A (prdn4y)I I *> Ii ini1dv oF- 5 -y1) py rid in -3 N amine N ,7 HN N 3 -inci h o xy- N- inc ihyl -5 1H; H .25 5 (2- phenyl -4 -(pyidiin -4 43 N 0 0), 0.44 382 A I> -( )/ yI)- I Hi-ii-nidlazol-5 N yI)pyriclin-2-aminc ii0 N H S-(2-plienyl-4 -Opyridin-4 44 I > , 0.4650 0.4, 314.9 A yI. -1iii zol-5 N yI )pyrii -2-0 N ~ 133 inut-b. retciiti Comtpund STRUCTURE,15 n tiC (1 RAFI Oil II)HS Mciliod Comnpound Name 11m) (mmi) H N H 5-(2-phcny1-4 -(p yrid In -4 45 -N0.0046 051 3382 A yl)- I H-imidazol-5-Y)-I 11 N N \pyrrolo[2,3-b]pyridintc 9~N N 3-chloro-5-(2-phcny1-4 46G N/ N 00207 0.51 343 1 A .(pyridin.4-yI)- 11 />- iiidazol-5-y1)pyridIn-2 ain ice

N

0 ~N 6-(2-phcny!-4-(pyi-idin -4 47 084 0.0380 A yl)- I H-imidazol-5-yl) 0.085 0.0 360 A3,4-dihydiro-I ,8 N naphthyi-idin-2(I 1-)-onc

CH

3 N NI 3 -methoxy- 5-(5-(2 48 N 0.1201 0.48 358.1 B ctlyidn-4l)2 phonyl-!I H-imidazol-4 NH2 N N _ N5 -(2-phcilyl-4-(pyrid I n-4 49 1~ O.0222 0.50 339.0 A yi)-l H-irnidazol-5-yI)- I FH I NpTyrtizclic[3,4-bjpyridinc NV 134 I ull-b- rtl Compund<A il ti'S~~ mehod Compound N amec N o (]C50 in IjO (Mi ) 01rv) (mil) 2 ~3-nicthoxy-5 -(2 -rncthyl-4 50 ''C' 0 IN \* 1

~C

3 0.2591 0.27 2830) A (yii--D1I -- N irn idvzo 1-5-y I) pyrazin -2 N" 11,N N ijC. 3-rnctlioxy-5 -(2 -nic thyl-4 0 N (pyridin-4-yI)-] H 51 ~>-CHi 0.0196. 0.2?2 2832.2 A imiduzol-5 -yI)ipyri din -2 N j N~ 5-(2--phenyl-4-Upyridin-4 52 -N002 .3302 A y)-l 1-1-irnidazol-5-ylD r - 0 2 4 2.3-dihydro-l

H

N- pyrrloi ol2,3-b]pyridi e N N I~ I 6 -(2 -ph etiy I- 4-(p)yr id i -4 53 ,j0.2901 0.43 339. A yI)-l I H-imid,1zol-5-y)-3- __ imidazo[4.5-b Ipyiridi oc N-" N 5 5-(5-(2 -ain inopyri d)n N) Nil 2 0.08 04 50 ByI)-2-phicnyl-~ I H 0.09 0.44\ 35.0midazoI -4-yl)-3 C CH3 mcthoxypyrid in-2-arnii ne Nil 2 CompoundI STRflC]U)RI RA 011 1118." McI hod Compound Nam utv1) (mm1i) N 4-(4-(6-arin o-5 N' N NHmethoxypyridinl-3 -yI)-2 56 0.0029 0.48 374.1 B phcnyl- I H-imidazol-5 -. CH, yI)-N-mcthyl pyrintidin-2 NH 2 S N 4 -(2 -phcnyl-5-(th iophen 57 I>i ~_ 0.6200) 0.55 304.0 A 3-yI)-I I-iidzl4 yJ)pyrIdjIne N_7 11 2 N N (R)-4-(5-(6-am ino-S 1 1 methoxypyi-idin-3-yl)-2 '> phicnyl- I H-irnjdazol-4 58 N 0.0002 0.74 6171 C l-( (4 N o cheliorophenylsul fonyl)pipe 2-(2-phcnyl-4-(pyrIdin-4 N yl)- I H--iidazol-5-yi) 5 -0.6803 0.45 341.0 A6,7-dihydro-5 F Mal pvirolo[3,2 -b]pyraziric N N IH,N NN 2 -(4 -(4- (6-am ino-5 0 N methoxypyridin-3-yI)-2 60 '-1 0.0001 0.53 4.61.1 C pheny-IHiidazol-5 NN 0~ ALyr (ni]i2 -IU0 I I N NI 1011 I i hydr ox yc t h y1)acc t arn i d c ilii-b - c lii Compouind STRU1CTU~RE- RAF oil IflSs kMcihod Compound Name No. (ICSO it) linlic (MI I' \0 HN / 3 -mctho xy-5 -(2 -phcn y-5 61 N- (pyrimidinA4-yI)-) 1-1 610.0049 0.54 345.0 B irnIMdazo I-4-yL)pyridi n-2 N- cH-, amnine

NH

2 11 2 N(S)-4 -(5 -(6-arni no -5 () - N, methoxypyridin-3 y) C~lJ I/~Jpheny!- I FH-imiciazol-4 62 N 1 00003 0.77 6171l B yI)-Af-(i-(4 chilorophemiylsul fonyl)p ipc -N-s ~ri d in- 3 -ylpy ri m id i n-2 )a ct aminle H NN 4-(4-(6-ainino-5 N / methoxypyvidimi-3-yI)-2 / NA N-C N NCH 3 phciyl- I !-1-imiclazol-5 63 H,(, 0,6407 0.55 388.0 B yl)-NN N - CH 3 diehlpi Ilhfin (l?)-4 -(5-(6-a nmino-5 rnctho ypyridin-3 -yI)-2 6t )IN"I phlenyl- I I--i lliciazol-4 64 N .N 00.0003 0.61 705.2 C yl)-A'-(I -(4-(6-amino-5 HN '-Nmnithoxypyricdi n-3 ,-,) ~yl)ph~cnylsil fony!)pipcricli 'N "Nil, n-3-yl)pyrirnidin-2-anlinc 14-, N N p (/)-4-(5-(6-amimo-5 Cli4, I <mcthoxypymidin-3 -yl)- 2 65 11 0.0599 0.43 443.1 B pheimyl- I H-irnidazol-4 N y NyI)-N-(pi peridfi -3 yI)pyrinidin-2-amne 1 '37 Comoun IflIOFULI ,lR(A MS S 'l Ilod1 .omflpound Name No.J[R . (1C50 il filie (MIT ) No. 1 5 -(2-(4-fluorophcnyl)-S 0.0006 0.47 362.1 B iridzl--.)3 N- CH 3 im-cthoxyp~yid(in-2-ainie NH7 H N-(2-(4-(5-(6-ai-i no-5 0000 N.~ 440 methoxypyridin-3-yI)-2 67 N ,0001 0.47 450 c pheilyl- I 1-1-iliidazoi-4 IN N 0yl)pyrirnidin-2 HN-". yl a fun o)ethyl )ace tamni dc 0 methoxypyridin-3-yI)-2 CH1 3 I '1> 475.1 phenyl- I I-imidjazol-4 IN N0001 04 yI)pyrirnidin-2 Y f 0 yI am ino)ethyl)-2 [IN ' N JtK. 0,C mc th x yac amid c 14,N N .3-mcthoxy-5-(2 -(4. 000 0.3 34. neth XYphlell yI)- 4 (14 I0 (yrdin-4-yI)-I 11 N CAi micdazo 1-5 -yI)pyricdin -2 N ~ ami nc IAN N4 N-(2-(4-(5-(6-amino-5 I IA mcthoxypyridin-3-yI)-2 64, 1 >phcnyl- I I-Iinidazol-4 70 11 N 0.0004 0.64 577 10 C yl)pyrimidin-2 11 yl arnino)cthyl)-4 N1- n"chlorobcnzenesulfonamid C. 13R iu-- rcten ~i Compinund STRUCTUROE R A F Oil InaS Meilhod Compound Naiinu No. (1C50 in fimuic (M I I 1 2 NN - -~m 0000 0.4 300 '~-(5-(6-ainarI o-S o methoxypyridin -3 -yI)At 11 0.000 0.3 360/ (pyridin-4-yI)- 1-1 N ~ inidzol-2-yI)phcnol )-( , NA metlioxypyrid in-3 -yI)-2 N N4 phenyl-MI-imidazol-5 72 H 0,0016 0.49 400.1 B !-V N Gil 3 cyclopropyipyiirn-ilii-2 NFI, aminc N N '~ ~ N-A 4-(4-(6-amino-5 73INN 2 0.001 1 0.441 360.0 B mcthoxypyricl1 in-3 -yI)-2 plicnyl- I 1--imidazol-5 N- ciIu1 yI)pyrirnidin-?-amnine NHi 2 N 'N Od(S)- I -(4-(4-(6-ani no-5 /rN mcthoxypyridin-3-yl)-2 N74Y1 0.0006 0.46 418.1 C phcnyl- I H- midazol-5 N 'c HI, yI )pyrimidin-2 Nil, yfarnino)propan-2-ol __ rncthcoxypyridin-3-yI)-2 75 - fom 0.0011 0.47 418.1 C phcnyl- I-imidazol-fi N c1,yl)pyrinlidin-2. NI1 y~ la m i n o) propa n-2 -o I ]39 in i-h- rott-ni Comiponiid R AF oil liUIls No~ SiRUCIRAC (i(C5O inl Lilie (No 1 Mciliod Compound Name I 1 2 N N 113C 5-(2-c yclopropyl-4 7b C - N (pyridin-4.yl)- I H i %~~J 0.0015 0.29 307 9 B iiz 15-l N' mictiox ypyri dI n-2 -am ni I)c [I2N _N l N s A 3-rn ethoxy-5 -(2 -ph cny 1-4 77 1 0.0890 0.70 362.0 (pyrid In -4 -yI)th i izo 1-5 ~~- yI)pyrazi n-2 -am inc NA F HN N 5-(2 -(3,5 -d IfAuori phenyl) 78 F N-0.000 04 380 B 5-(pyridin-L1-yl)- 11-1 78 1 N- .001 0.5 3800 Bimidazol-4-yl)-3 N ~CI mcthoxypyridi n-2-ami lie

NH

2 HN N 3-mcthoxy-5-(5-(pyridin /I> / 4 -yI)- 2

-(

4 N 79 -0.0020 0.64 428.0 B (Iritluoromcthoxy)phcnyl) \/ C) -1 H-imiclazol-4 N-/ H CHI yI)pyid i n-2 -amino H,N N I.. 5-(4-(3,6-d ihydro-2 I- 00 0.N0 0 44 490 pyran-4-yI)-2-plicnyl- 11 N ndir/.oid Z-5-yI) -3 C) methoxypyricimn-2-aminc 140 Compnpiid STRC*URIi RAF onl Mcthod Compounld Name No. ~(IC5O in tine-t (MJ. clo 11m) (mmn) N- (2 (4-(5 -(6-urn ino -5 mctlioxypyridiin-3 -yI)-2 k,C i- (4-florophen-Iyl)-i H1 r N, rJ .0001 0.54 493.0 C inidazol-4-yI)pymmi 2 )-yI ani uo)cthyI)-2 met hoxyacc Iarni ide N-(4-(4-(6-amino-5 B2N 0.02 N.1 0 m ct I10x ypy r id in -3- y1) -2 82 / I -0.020 048 01 3 plicinylI H-Imldazol-5 / I y)1) y r idIini- 2- yI ) ac ct armid c N- Cu 3 , H N __ /V Nm ct Iiy I- 5 -(2 -p Iicn y1 5 83 N-0.1970 0.40 329.0 A (pyridin-4..yI).I H- ~ N imil -4-yI)pyrimidin N -( 2-aminc N N1 4,4'- (2 -(4 N (t r i tl u ~o ro m etIiy 1) p Iic nyl1) 84 I '4 _ -X 0.2290 0.61 367.0 13 (riHmdaoc, N I -mdzoc45 dyi) di pyri dine IIN mcthoxypyridin-3 -yI)- 2 o (4 85N 0.000 0.68r 543.1 Gcnl) 85 '4 I H--imiclazol-5 0 ~YI)pyr-imidinl-2 II~N y lamino)cthmyl)-2 Imc h oxyn cci am ide 141 mtit-b- rtit Co opoind STRUCTUR RA F onl aISmilo opun a No. SU JJ(1C50 in timei (M I I') ii .nrtntidNm uNl) (In iii) I2 H 3 -rncthoxy-5 -(2 -pheny 1-4 0 N\/ (I H1-pyi-azol-5-yi)-i 11 CH, N - 57 .2 330 B imicla7zol-5-yi)pyridin-2 amnine N-NH 2 -a i Ino- 5 -(2 -ph cn yI-4 7 N N -. 7 0910 0.51 3391 A (pyifidin-4-yI)-I 11 H7031 .5 3. itn idazo 1-5 '. N Nyi )n i c o t i inonii ti I e N IINNN- (2 -(4 -(5 .(6-ano5 /> phct'yl- I I--inidazol-4 NI yI)pyrim idin-2 S 0 ylamino)ethyl)cyclopropa N nesul fonarnidc

H

2 N N Fi 3 c. 0 3-imetloxy-5-(2-phcnyi-4 89 0\-~/ 0.01 37 0.57 344.9 E (pyridin-1-yl)oxazol-5 N yl1)pytlin-2-'trnnc N ~ HN N t0c ji.~I3-vmethoxy-5-(2--plicnyl-4 90 I __ 0.11283 0.58 345.9 E (pytidin-4-yI)oxuzo)-5 I/ yI )pyrazi n-2-amiinc N" 142 mut-b- ent Cotipol md sTRU~CTURI RAF M)ilima' RMethod Compound Name No. (IC50 i hollc (M 1.) uNI) (mmil) lAN N (R)-4 -(5 -(6 -a in i tio- 5 I H rnethoxypyri(Ii n-3 -yI)- 2 61 H ",- phenyl- I H-imidazol-4 91 N 1fN 0.0044 0.59 547.2 C yl)-N -(I 0 (cyclopropylsul fonlyIpi PiC NH mid i i-3-yI)pyrir d in-2 'EiJQ'Vamin H2N ,N

H

3 0 -. N -- 3-mc thoxy-5-(2-phcnyl-5 92 H3C 0 0.000:3 0.550 345.1 E (pyr-idin -4-yI)oxzizoI-4 0 yI)pyridin-2-aminc '2N N H 5 -(2-(4 - fluoirophenyl)-4 4-~ () I -N003 .5 7. (3-nfuoropyridi n-4-yl)- I H N inm dazo 1-5 >'l) N- F mctho xypyridin -2 -amie H-N N H3C 0 5 .(4-(3-chloropyridin-4 94 _ F 0.0606 0.56 395.9 B N- Cci nithoxypyridin-2-animc N '1 N -(5 -(6 -am i no-5 N Nm- i cthoxypyrid n 3 y ) 2 /!~ N (4-fluorophcnlyl)-I

H-

95 , N 0.0025 0.63 565.1 C imidmizoI-4-yI)-N-(l 0 N GH: (CYCDPr-OPYISU Ifonyl)pjpC ridin-4-yI)pyrimidin-2 F .1minec 143 nut-h- retellil Copun TitiFUF A F~~ Off 119', Method Compounud Namec No (TC5in (iii)M ~r f-12N N i 3 C. _ 5 -(2 -(4 - flu oiophenyl)-4 0 (1 I-pyrazo 1-el -yi)- I H1 I I>~ -: 4 30 iinidazol-5-yl)-3 IIN N methoxypyridin-2-ami ne N II N (I?)- I -(3-(4-(5-(6-ariiflo p I I - i 5-incthoxypyr~ic]n-3-yI)-2 I _ _p ( 97 / I 0.0310 0.67 58. C (trifluorornethyl)phenyl) N (N 1I H-irnidazoi-4 CH.,ylarnino)piperidin- I -yI)-2 __________________I I____ ___ __ niethoxyethanone

H

2 N N N-(2-(4-(5-(6-aimino-5. 0 1 jnethoxypyridin-3-yI)-2

CH

3 I-K -- (4-fluorophenyi)- I Ii 9I1 0001 0.58 525.1 C ii IazoI- 4- y1) py i in 4 ( in N _fN 2 IIN ~~y I a nin o) e iy I)cyc I o 1)ropa n esulIfo nain ide ,N N N-(2-(4-(5-(6-ainino-5 o - n cthoxypyridin - 3 -yI)- 2 99 N- I / 011 ph enyl- Il1-I-i midazol-4 N9 -N0.01 05 41. yI)pyrimidin-2 y ylami no)ethyl)methanestil IIN N c113fon amid e 1-0 112N IN (R)I -(3-(4.(5-(6-arniio 0 5-mcthoxypynId ~in-3-yI)-2 00 0.0259 0.57 533.2 C (11-fluoropbienyl)-) H

NH

1 1 jrTti dizol-4 -yI)pyri ifldin HNO A_.CI(,2-ylamino)piperidin-I -yI) 2- meth oxyeth an one 144 mut-b- rcicuti Compimind STUT :RA F Oil naRS. Men11d Compound Namec No. (ICSO in tiluic (M I) 11m) (]mml) (~ I N 0 6GIimethyl 3.(5-(6-amino-5 Nmeth xypyid1 -3-yl)-4 101 1 0.0013 0.49 402.1 B prdn--OlH N ~'i n-idazol-2-yl)bcnzoatt NC I 3-(5-(6-amino5 12c) N 0,01 04-6. mcthoxypyridin-3-yI)-4 102 '> / 0001 0.1 3692 B (pyridin-4-yI)-] - N I,N _N methyl 4-(5-(6-arnino-5 B mcthclxypyridin-3-yI)-4 103~'o~i 0 0007 0.48 402.1 Bprdn4y) lI im daze l-2-yI)bcnzoatc IZ N 4-(5-(6-ariino-5 0 > 0.014 047 39.2 ncthoxypyridin-3 -yl)- 4 10 I'X :N 0 .0\/.7 6. (pyridin-4-yI)-l IH N imizoI-2-y!)benzonhi~ ie H2N N I \_, 0.2145 0.53 360.0 A 4-yi)- I 1--imdol N yI)pyidin-2-aininc N.. 45 111b- rdetcni Compound STRUCTURE [RAF onMis vcldiol Compound Name No. (1C50 in li ne (MIT) 11M) (ll) H 2N ~N H 3C, H 5-(2-(2,4-difluoropheny)) 10 1 0.00*10 09 379,9 B (yrdn4y)il N~inidazol-5-yi)-3 N-'rncthioxypyridin-2-anl In 'N ic NC 1 G d inicthoxyphcnyO-4 107 I/ /- 0.0007 0.40 404.0 0 (pyridin-4-y)-1 I i ilzol-5 -yI)-3 N ~mchoxypyridin-2-am ine 0 ~1 N I rcthloxyphcny1) 108 D.0007 0.5-7 392.0 a (pyridin-4-yI)- I - :1 N iidayzoi-5-yI)-3 N7 methoxypyrid in-2-am inc H 2 N -N o~c ~ 05-(2-(3,4-dinfuorophonyl) 109 0 F~(- 0.0012 0.53 380.1 8 4-(pyridinA-y1) I H - N C/- imida7.ol-5-y1)-3 N-' rncthoxypyricin-2-ali ntc HIN N CH, 3-rncthoxy-5-(4-(pyrlill 110 N,- .05 05 5. 4-yl)-2-m-tolyI H 110 >- .005 055 56. B mi dazo1-5 -yI)pyri di i-2 146 inut-b- rclenti (;lo i)nd( Rnu~ oA F Oiln I. Method Com pounid N anic uN']) (mmii) H2N N N ~5 -(2 -(4 -fluomiophenyl)-5 (2- tluoropyridin-4-yl)- 1 111N C) 0.0292 0 57 380 1 B imiclazolI-4~-y I)-3 N - m etho xypyr id i n-2 -am i ne F -N -5 -(2 -(4 -flu o rophc ny!1) -5 112 ,N0.737(0 0.62 3922 [3 (mchxyrdn4y) / ') / I L--irnidazolA4-yI)-3 N , / F1 ii e th ox ypy r i I n - 2 -a mn n N irnidazoi-4-yI)-3 /ni c th ox y pyi d i n -2 -a ni i n c N~/ N IN N IC5 -(2-(4-(2 11 ~ L ~-&~-o' .064 0.1 312 3 (d i m ct hyIa m i n o) c th ox y) 1 a- 0y -4-(pyridin-4-yi) C-I I H-imnidazol-5-yI)-3 N-1. ~~~m cth ix ypy r idin -2-am in c 0t~ N 4 -2-p3-idopnpy4 cyi) 115 I 0.0030 0.65 3861 B3 '1(yIdny-I- N S i~flidaLOI10-5-yI)-3 mctliox ypyridi i-2-imi lie 147 Mii-b- ecl Confiounid STiR1CTURU RAF Oil ialS~ mulbod Compownd Name No. (1C50 i iic (MHO ii, ,N N 5-(2-(2-fluoro-3 il rnctho xyphicn yI)- 4 116 I 0.0017 0.47 3q2.0 B (pyridin-4-yI)- 1- H (I i in idwzol -5 -yl)-3 N,~ in ctlioxypyrid in-2 -atr i r

H

1 N ~N 5 -(2 -(3 -flu om -4 ii~flin ethyl phcnyl)-4 -(pyri diin 117 Q, -c-. 0.0007 0.56 450 1 4 -yi)- I I-inidazol-5-yl) F ~3-inethoxypyridiii-2 N' amine 1 -1 2 N N5 -( 2 -c ~y c l c h x y -5 '118 - 0.0020 0.55 350 1 8 ( pyridin-4-yD- I H -N nnidazol-4-yl)-3 N m_ iethoxypyridi n-2-aminc 1 -1 2 N N3 - r c h o x y -5 -( 2 -( litp Nnicthyl-I H--pyazol-3-yl) 11/ 0.0019 0.33 375.9 B 5-(pyridin-4-yI)- I H / N "I iiidazoI-4-yi)pyridIn-2 0 H N-N.ane i-tN ,N 03-incthoxy-5-(2-(3 120 0/-\ 0088 0.44 421.9 B 4-(pyrIdin-4 -yl)- I H ln idazo .5 -yi )pyri dIn-2 YL amine 118 mut-b Con nnh S Cod 1 0 in cRAF(*) Mel hod Compound Name No. (ICM min I IN ,N 4-(5-(6-amino-5 HII.() N - g mcthoxypyridin-3-yI)-4 121 > 9. 0.0017 0.39 422.9 B (pyridin-4-yl)-1 H N NI timidazol-2 yl)bcnzencsulfontm dc I N N ) Sc --NH, 3-(5-(6-amino-5 0N i Ti Ih o xy py r d i -3 -y )- 4 122 | k 0.0021 0.313 380.9 B pyridin-3-yl)- N mi dazol-2-yl)bcnzami dc N-(2-(4-(2-(4 Sfluorophenyl)-5-(l H o .3.1 4I pyrrolo[2,3-b]pyridin-5 123 - 0.0013 0.61 487.1 C yl)-I1-1-imidazol-4 c yl)pyrimidin-2 ylamino)cthyl)-2 nethoxyacclamide IZN N 3-(5-(6-amino-5 RC N methoxypyridin-3 -yl)-4 124 I - 0.0166 0.43 433.0 B (pyridin-4-yl)-1 H- I N c i imidazol-2-yl)-4-fluoro N / C143 N,N-dimethylbenzamide N-(2-(4-(5-(5-amino-6 methoxypyrazin-2 -yl)-2 125 o o c 7- 0.0005 0.60 494.0 C (4-fhliorophcnyl)-I H 2-ylamino)cthyl)-2 me thoxyacet amide 149 (;~nouudSTRUCTURE ~ RAF rV C hod Compound Namec No. (IC.50 in tilme (NI I (Iih) (minl) I I N N4-(5-(6-amino-5 0 05 03 8 mcthoxypyridmi-3 -yl-4 imidazol -2-yI)benzami dc N034. 5 -(2-cycl opentcnyl- 5 127 IC 0.00103 0.44 83. ( .pyridin-4-yI)- 11-1 N i midazol-4-yI)-3 N methoxypyridlin-2-ami ne N5-(2 -tcit-buty I-5-(pyri d i n 1260.010 0.3 34.2 B -yl)-IH I inidazol-4-yI) 128 13(' 0.010 0.8 32.2 B 3 -incthoxypyrid in-2 /~~CH~aminc HN N -JCci 5-(2 -(4 -flu oro phcnyl1)-4 3N ,-~-r 008 (I H--pyrrolor2 .3 129 N008 0.55 401 0 B b]pyricfin-4-yI)- I FH in idazo 1-5 -yI-3 N_ mchoxypyridin-2-ainine /z: N N N 6 -(2-(4 -fluoropheny 1)-4 I H (pyridin-4-yI)- 11 130 N -0.4160 0.54 357.2 A itnidazoi-5-yi) I > -F /il 1,5 N 1 I,2,A trtaolt ajpyricI ine NZ 150 ntt-h- dcLni Colipollil (STRUCTUR(EN RA F Ciii t"IS WOd Coinpoli ii Nanme iI) (((iii) H?N N I H 3 -flu oro -S -(2 -(4 131-FN F 70 .2 35, ucliophe ny 1)-4 -(pyri i 131~I Q 14 05 5 4 -yI)-I H-imnidnzol-5 z N N- yl)pyiid In-2 -am I i H N ~N 3 -(5 -(6 -am ino-5 I -in ci1hoxypyrid i n-3 -y l)- 4 132 I~\/ 0,0010 0.39 423.1 B (pyridin-4-yI)-i 11 C;.._ / NH, iniil/-O-2 N0" yl)bcnzcn)CSuL fon am I Ee HN N 5-(2-(5-chloro-2

H

3

C.

0 m ncthoxyphcnyl)-4 130.0005 0.0 481 0(pyridin-4-yi)- 1-1 N imidazol -5 -yI)- 3 N,~ rn ethbox ypyri ciin- 2-am inc N - 5-(2-(4-fluorop)hcnyD-4 N (fui-an-3 -yI)- I-Il-i midazol 134~ I _ o~ 5 ~2 B 5-yI)-3-mncthoxypyridin-2 H2 N nin H3C N H 5 -(2-(2-ch Iorophcny I)-4 150N0.0004 0.45 378.0 B (pyridin-4-yI)- 11 135I/ / iri a/ol-5 -yl)-iI cI methoxypyriclin-2-am i nc 151 miut-b- rectd o.ul TUIR RAF M)I Ma1s I'ielliod Compound Name CNmo.n IU R (1C50 ill imei (NMH' 1m') (inimm)

H

2 N ~N 3 -m cthoxy-5 -(4 -(pyri di n 13 I_ 0.0028 0.48 412.0 B (tifl toro mcthylI)phcny I 13 l--inidazol-5-yl)pyrid in NFr: 2 -ain ne I~. 12 NI_ 5 -(2 -(2 -fl u oro p hc ny) 13 o I N (ydi-4 -yD- I 171>XX 0.0017 0.44 362.2 B mprniIz-5y)3 N F m cth oxypy r Id Iii- 2-a ni in e H-1N N iic I H 3- m cth ox y-5 -(4 -(py rldin1 0N -1)2otly-I1f 13B /> 0.0012 0.'15 358.0 B I)OOy N ' imicda7zo-5.y1)pyridin-2

H

3 C amiife I IN ~N 5 -(2-(2 -fl Ho o-5 I13C. 0 i-: me thIyl1)1 plmy1) - 4 - (p y ri d in 139 /> / 0.0012 0.50 3-16(0 B 4-yl)-I H-l-midazo1-5-yI) N F3 -methoxypyridin-2 -N 5-(2-isopropyl.5-(pyridin 4-y)- I f--imidazol-4-yi) 140 3 N0.0016 0 33 310.2 B 43-metlioxypyridi-2 N\/ N~ amine 152 iui t-b- tcl Compound TR TRCRAF 1 111 naSStid CopudNm No. Si J~R(1C50 inho Compoun Name4 11 M) (loin) N ' N 6-(2 -(4 -flu orophenly 0-4 141 N N 05180 0.49 356.2 B (yii--l-III I 1> -F irnidazol-5 N yl)iidazof I ,2-u]pyridinc; N-. (N N 7 -( 2-(4 -flu rnphe ny )-4 0 NH ~ 032 05 7. (pyridin- 4 -yI)- I I 142 I X .80 05 3M. 6 / iidazol-5-yI)-3, 4 ,' N difiydro-2H-pyrido[3,2 N-. b][ I ,4]oxazine H NN it 10N 2,amilo-5-(2-phcnyl-4 143 / >\ 0.2151 0.42 :330.0 a (Pyridin-4-yI)- I II N .. N imidazol-5-yl)pyridim-3-cI N" H 5-(2-(4-fluorophcnyl)-4 '~-' N - (pyridin-4-yI)- I HI 144 >_ 0.00:30 0.56 356.1 13 im Idao--I- l N-.pyrrolo[2,3-bjpyridinlc I , 5-(2-(2-fluoro-4 me y hnlN (yidin 145 >4 a/-H 0.0009* 0.49 .376.0 B 4-yI)-1 Il-1.midvzol1-5-yI) N 3-rncthoxypyridin-2 N-" amine 1 53 ui-b - reclli Comlpounid smucrOil ilAa'Ott Method Compound Name No. SRCUE(1C50 ill timei (M I I' iiM) (ii

H-

7 N N 5-(2-(4-chloro)-2 I-i.C H F -- p rdn N = fluorophenyl)-4(yi n 146 I t -/ci 0.0023 0.54 39 6. 1 B 4-)yI)-I l-I-imidazol-5-yi) N 3 -methoxypyrid in-2 N aminc i-i~N N5-(2-(4-fluoro-2 H mncihylphcnyl)-4 -(pyridi n 147 I ~_ : 0.0016 0.49 376.0 B 4.yi)-l 1--imnidazol-5-yI)

SH

3 0 3-rncthoxy *pyridin-2 N" amino H N N 5 -(5 -(6--amino-5 HGC. n I Hcthoxypyriclin-3 -yI)- 4 14B ~ 0.0015 0.46 390.0 B (pyridin-4.yI)- 11 N1 m17idazol-2-yi)-2 N n-'fuorobetiza Idehyde I174N N 5-(2-(4-fluoro-3 HN - meihylplienyl)-4 -(p~yridil [I 149 / > /F 0.0006 0.54 375.0 B 4-yI)-I 1--iiidazol-5-yI) N 3-rncthoxypyi-idin-2 Nc amine H N N 4 -(2-(4 -fhoroplicnyl)-4 I (pyiidi*n-4-yi)-I 11-1 150 /N - 0.7751 0.53 355,9 B "iao-I' )I H N pyrr olo[ 2,3 -bjpyrid'i fie

N

I 54 I IIII-b- te i N' Ilo I T CFJR RA F OilIn ma s rViedlod Compound Name No.I iiJrR (1(50 in 6i 11C (M H LIM) (Onin) N N 3-bromo-S-(2)-(4 15 N. 0.07 07 461 B ALJOI-Ophe fy 1)a--(p yr IdIn Hr ~ 1 0\/~- 007 01 3 4-yI)-J H1-imidazol-5-yI) I H--pyriolo[2,3-bjpyidic ' N 152~ ~~~~~ ) ~ 060 5 41 B(yridi n-4-yIj-l 11 N - iidazol-5-yI)-3 ITIethlyl pyrid in- 2-ami ic

N

'1-(4-(6-amino-5 r. methoxypyrid in-3 -yI)- 2 , N- / '\(4-fluorophenyl)- I H 153 N/ 'o O .0002 0.63 484.1 B3 ini dazol1-5-yI)-N-(3 N, ( _0l N1n14 ethoxyphenyl)pyrimidin -2-amine fiN -N 5-(2-(3,6-d 1hydro-2 H 154 13C .003 0.3 350 13 pyran-4-yi )-5-(pyrid in-I 15 0003 0.6 50N yl)-I 1-1i midazol-4 -yI)-3 N 0mcthoxypyridin-2 -ainc 11 2 N N3-mcthclxy-5-(5-(pyridin p- L -yl)-2-(1I 2,3.6 155 13"N0.0162 0.23 349.2 B tc trah ydropyr id In -4 -yI - ~ NI 1A-imidazcl-4-y1)pyridjn N, N 2-am inc 155 IfLItI-b- cct Comp~ol il STRUTUR IZu A17 Oill 1lliaSS Me thod Comp~ound1( Namle No. (IC50 ini time (MIC 11Mi) (mil) 11 2 N N4-(4-(6-ainino-5 nicth ox ypyr idi n-3-yI) -5 156s N- 1 0.0093 0.24 381.2 B (pyridin-4-yI)- 11 imidazol-2-yl)-i N~ I N N- ICtIhyl )ipcridifl-4-0 I HIN. 5-(2.(4- fluorophcnyl)-4 157 rN\ / 0.0170 0. 52 360.1 B13 (pyridin.4-yI)- I H N '>'--imidazo 1-5-yI)-N,N N, d irnethylpyri din-3 -aminec I C4 N:, 4-(4-(6-ainino-5 A m ~~~rc tho x ypyridIIn -3 -y1) -2 158 N 1 0.0051 0.58 420.0 C (4.-nuorphcy1)-11 /> m zol5-yI)-N. 0 N -isopropylpyrirnidin-2 N\ amine Nil 4-(4-(6-amino-5 N 41 ~metho xy pyrid n -3 -yi)-2 / N - H(4-fluorophicnyl)-i Hi ___ 0.0015 0.62 434. c mdzl5y)N .0 isobutyl pyrirnidin-2 I LN -, amine N,__ N N-(2-(4-(S-(3-chloro- I H I' pyrrolo[2,3-b]pyrIdirI-S ci -jF yI )-2-(4- fluorophcny I) 160 No. 0003 0.70 521.1 C I H--imrnduzol-4 N ,N 0yI)pyimIdIn2 0 y~ami no)clhyl)-2 II~JJ0C:113 mc ho xyac ciamidc 156 o.ll T " RI- RAF i 01) as Methlod Comnpoundit Name o.udSRtCU (1C50 in timc (M If') (IM) (ll)

H

2 N N 4 -(5 -(6-u mi no- 5 0 mrethoxypyrid in-3 -yl)- 2 161' IH I> - _ 0.00-F (4-fliuorophenyl)- I H 16 002 0.55 '136.1 C irnidazo1-4-yD)-N-(2 N y N rncthoxyethylpyrinlidin 0113 2-amine IIN 3-mcthoxy-5-(S-(p yridinl 162 0.00155 0.32 3522 03 4 -y'D-2-(tetrahydro 2! N pyran-4-yl)- I F-1imidazol 4 4-yI)pyii in-2 -arn i n 'N (S)-1'-(I -(4-(4-(6-amino 5.rncthoxypyridir-3-yI)-2 ~ (4-fluorophenyl)-1 163 1 N 0.0001 0.56 507.1 C imidazol-5-yI)pyrimnidin NI 2-ylainio)pi-opaii-2-yI)-2 methioxyac et aid c HNN 4-(5-(6-ainino-5 0 mcthoxypyrlidin-3-yV)-2 1> _>-F (4-fluorophunyl)- I H 164 N0,0163 0.63 146 1 C inlidazo1-4-y)-V N N cyclopentylpyriroidin-2 I i aminc I 1N N 14 4-(5-(6-uMii 1-5 0 , N mcthoxypyridin-3-yI)-2 165 CH03/ N - 0.0483 0.69 460.1 G (4 .- fluorophenyl)-!H N 1imidazol-4 -yI)-N N cyclohexylpyrimidin-2 H -0 HIT1iIOc 157 Comupoulnd t C"UIUiR L R15 An F ine1 MIS NoqA n ms Method Compound Name H N-(2-(4-(5-(3-bronIo- I - N. H pyrrolo[2,3-b]pyridin-5 yI)-2-(4-fluorophenyl) 166 rr- , 0.0001 0.71 567.0 C I i--imidazoi-11 N 0yI )pyimidin -2 A,(.CH 3 mctho xy acc amid c H2N N 5-(2-( I H-indazol-5-yI)-4 IC C) ~ -~(pyridin-4-yl)- 11-1 167 />5 :N 0.0007 0.37 304.0 B N.' rncthoxypyridin-2 -anlinc H N N 1 3 C. 3-rnthoxy-5-(4-(pyridin 168 I'- 0.0009 0.41 395 1 B8 -l--qioln8y) ~~ N / -imiclazol-5-yI)pyridin INq 2-amnine Ii N N - 3me th ox y.- -(4 -(1)y ri (Iin 169 '~~~-~~ / 00016 V3 3950 -)-(qiot--I N _ I--iidazoi-5-yI)pyridinl N 2-amine N7\ 117N N 3-mcthoxy-5 -(4-(pyri din 170 0 ()0002 0.:33 421.1 B 4 -y 1 )-2 -(3-OpyriIn-4 I /> yI)phlenyl)-l HI-inidazol N 5 -yI )pyri dill-2-a mi me NZ 1 59 Intii-b- ccl C-.ompllotund STRUM'URi R A F n (vl)Moihod Comipound Name No. ~(1C50 in tinl-c (I 4-(4-(6-unlino-5 4 c N ch o x ypyr id 1n -3-y1) -2 N7 0.01 0.1652. (4-fluorophcniyl)-I H 171~~ -C 11,3 .5 52. imidazoI-5-yI)-N-(3 N-l, (t ri n uo ro mcIt hy1) ph cnIiyl1) y -Iri I di1n -2 - amine) 4-(4-(6amIno-5 / m c th ox ypy r 1di n -3 -y1) -2 N N-. (4 -f u oro 1)hcon yl)I 172 -F 0.0014 0.67 472.1 0 imIdaz L)I- 5-y 1) -N -(3 14 N'I , fl u o ro 1h1ecnylI ) pyr in i d i n -2 am ine A N N 4-(4-(6-amniio-5

IA

3 c mtIi ox y pyr i dIi- 3 -y1) - 2 173 N 0.1070 0.63 381.0 B (4-fluorophenyl)-! 1-1 ~ UF nid azol -5 yl)picolinon itric II?2N N mm 4-(5-(6-aminio-5 0 N in etho xypyrid in - 3 -yl)- 2 174 cO- >-N 0.0023 0.53 406.0 C (4-nfLuOrophcnyl) 11 NY. NmmIdazol-4-yI)-N IFIN, CI 1,thylpyriimdin-2-anincIL H2N N I '~ In4-(5-(6-amiino-S Ntoyy -id in-3 -yl)-2 175 Ch N - 0.0012 0.55 420.0 C (4 -fluoirophenyl)-1 H N-. N irndazol-4-yI)-N propylpyriinidin-2-aminc '59 to-b- tl~t CopudSRCUI RAI' NIt (iT') Method Compound Name No tCill (imc m) HN N - ~ (S)-4-(5-(6-amino-5 y 1 />-O\-17 mctho xypyridi n-3 -yJ)- 2 176 0.0046 0.58 434.0 C (4-fluorophcnyl)-1 11 Ny N j i idazol -4 -yi)-N-sec: HN, e, - i, butylpyrirnid in -2-arn inc Ci' 3 I iN N 1 -(2 -ain irmo-5-(2 -( 4 o fuoophenlyl) 177 Hu > -F 0.0030 0.51 '374.1 B -4-(pyridin-4-y)- I H- N imidazol1-5 -yI)pyidin-3 N- yl)ethanonec H2N N Hi ~ ~000095-(2-(lI H-indol-5-yl)-4 178 1> L 0.09 0.40 383.2 E (pyidi- N -l T--inidazol-5-yI)-3 N met hoxypyrid in-2 -amine H2N N4-(5 -(6 -amiiro-5 0 Ni methoxypyridin-3-yI) 61 I'-* 2-(4-fluorophenyl)- 11-1 179 -N 0.0010 0.56 450.1 B iiao--~--3 N y N mn ict h oxyp ro 1)y1 ) y r im idin HN,-N HC -2-unmine 11 2 N H 4-(5-(6-ami no-S o mct h ox yp y rd in -3 -yI1) 1830 \1 / .81 0.48 3P8.9 8 -2-(4- flu orophcriyl)-I 1-1 N~ y 2-ol 0O.l 1 60 nuilt-b- rclclfi CnfliTpRiUncl srUicti RA Fi (I. vci Compound Name No. (IC50 in linei ( I.)t lo u11m) (mmil) (J?)-4-(5-(6-arnino-5 I />5 wmcth oxypyridi n-3-yl) 181 N. N.09 05 434,2 C -2-(4-fluorophemyl)-I 1 N i uicazol-4-yI)-N-scc HNy - ll bUtylpyrimidin-2-mintc N N 5 -(2 -(4 -flu o ro pheny I )- 1 1 , (pyridinl-4-yI) 182 cc 0.0002 0.59 370.0 B -I 1-1-ilidazo-5.yl).3 m ct hyl- 1 1-1 -pyrrol o [2,3 N bjpyrid inc N 4 4-(5 -(6-ain ino -5 1C N H riet hoxypyri d In-3-y) 183 N 0.0007 0.56 432.0 C -2-( 4-fluorophcnyl)-I 1 N imidazol-4-yi)-N N (cyclopropylnicthyl)pyrini 4-(4-(6-ainino-5 rnethoxypyridi n-3-yI) 184 "N cI 0.0003 0.46 530.2 0 -2 -t;i-t-butyl-1I1-1-inidazol I I -y I)-N -(6 -((2 R, 6S) -2,6 (Ii icthy io p oIi n o) pyri d 31 CC..,I(/)-I -(3-(4-(4-(6-amino "-K 5-methoxypyrid in-3-yi) N 3 .c( -2 -tert-butyl- I H--iridazo! 18561 0.0032 0.41 451.1 D .~yindn2 ) yluruino)pyirolidIn-) yI)cthanonc 161 iniit-b- rcciti Coin1polud S*TRlUCTjUREl] RAF i is NIIIIXI i Copuind Naine No (IC50 i ilme (MI IC 5-(4-(4-(6-aino-5 rncthoxypyrid In-3-y I) 13G N C1, 0.0299 0.41 447.1 D -2-tcrt-butyl- II]-iiniditzol N5 -y')i yriin idin-2-yl)-3 N) r.H n cthox ypyr Icl in-2 -am i nc IIZN IN H 4-(5-(6-ainino-5 II, rncthoxypyridin-3-yl) -2-(4 -fluorophenyl)- I 1 E37 N,-r 0.0005 0.513 568.2 0 i midazol-4-yi)-N-(6 CII, ((2 S, R)-2 .6 dim ethylrnorphol ino)pyrid 'l-(4-ainino-fi HG rnchoxypyridl n-3-yI) 189 I .0.0003 0.62 496.1 D trbilI-1icaz 5-yl)-N-(2,2 di fluorobenzo[d][ 1,3]diu ol-5-yl)pyriinidin-2-uniine '1-(4-(6-uiriino-5 1q: me~\ nthoxypyrid in-3 -yl) NH CI, 0000 0.6 5002 0 -2-tert-butyl- I 1--imidazul 190 IN5-yI)-N-(3 (tri fluorornethoxy)phieryl) yimiifl-amiine 4-(4-(6-irino-5 m c th o xyp y rid in- 3 -y1) 191 N N -2-tcrt-buty( I H-imidazol 11N Mt 0.0004 0.63 484.1 1)-y)N-3 (ti fluuoomethyl) rhonyI) p yrimidin-2-amine (62 ilut-h- rotent c~onpo ii s-UGIA) IV[ on liIMc11d C(JOInd~~f~ Namne Noa (1C:5() iii tili c (NIH) (IM) (min) 4-Q1 -(6-,aminno-5 methoxypyridin-3-y]) 192 N0.0002 05S4 4602 D 2ti-uy-1--mdz 5- 5yl) N-(4 mncthox ybeizy1) py ri in id *1 -am ine H N N CN ;.. I I) I -(3 -(4.-(5 -(6-ain o 5 -: 5metho xypy ri d In-3- yl) 193 N 000 0.51 189.1 D - 2-( -filuorophecnyl)- 11-1 0J80N irnidazol-4-yI)pyrimidin1 HN 02-ylam ino)pyrrolidin- I Z N 11,yI )ethanonL; I N N HC -r (S-1 -(3.(4.(5-(6-Ramino-5 0- N nethoxypyridin-3-yi) 194 N 008 .143 -2-(4-fluorophenyl)- 11I-1 N N imidazol-4-yIpyrirnidin N 02-ylamino)pyrroiidin-I I I ~y1)cthanoiic 195 , r*N 000 0.52 5131 C (4-fhiorophcnyl)- 11-1 .... CH 2-ylarnino)propaii-2 yl)tnethanesul flonamide ami~no-5 -1metho xypyri d i n 0.002 0.7 52.9 C 3-yI)- 2 -(4-fluoroplienyl) u yI)pyrimidin-2 y~alarno)propan-2 -yI)-2 me-thoxypropanam ide 163 Com ponid STUTII RAF OHII liaSs Mcihod Compound NRame No. (1C50 ill Ii inc (MI I) 1 S-N-(S)-(4( c~arn 1 no -5-iniethoxypyrid in 3 -y1) -2-(4 - f]lu o op h cn y 197 __ 0.0001 0.57 521.2 C I 1--imidazol-5 0yI )pyimi cini-2 y Iarnino)propan- 2 -yI)-2 nicthoxypropanamide I iN~f~5-nicthoxypyridin-3-yI)-2 c 1 (4 1 9 8 N 3 r 1 11 C- i n i d a z o l- 5 0 yI )pyrirnd in-2 -N ylamino)propan-2-yI)- 2 _____ _____ methoxyalciamildc iiN "I(?-1-(5-(6-ami no-5 0 .. i mcthoxypyr-idin-3 -yI)-2 199 0,0150 0.55 525.1 C (.4noohnl-1 NIN Imcao--l -( iIN (mnethylsuIfonyl)pyrroI idI I~S ., n-3-yl)pyiidini-2 -am ie ii~$ N(,S)-4-(5-(6-amino-5 0N m cth o xypyr Id in -3 -y 1) -2 20N 00( .5 21 G 4-fuorophenyl)- 11 20 004 .5 55 imidiizol-4-yI)-N-(I IIN ____ (mnethylstlfbnyI)pyrrolidi 3( N N ci-i3 4-(4-(6-ainino-5 201 j> > c 3 'i, .000 0.36 341 c r meth oxy pyri1d in -3 -yI1) - 2 .. N ("1 t~uJ eri -b utylI 1-1 -ini d zo 1-5 N N yI)pyrirnidin-2-ami lie N "2 164 11111-b- reteitti Copun STRUCTURE RA F cm ll~ Method Compound Name o.un (1C50 in lilc(M-' ciNI) (uclin) N-2(-(-4 N, fluorophcnyl)-5-(8 .HI3j methyl 202 C/ 0.0250 0.62 502.1 C [I ]iao , a]pyridin-6-yl)- 11I-1 NN 0 irnidazol-4-yl)pyrimldin HN,,N O (111:, 2-yI ari no)ethyl)-2 ______________________ __ methoxyacetamide H N cI'-I 0-' (l?)-4 -(4 -(6 -amin o-5 fi' mc tho xypy ri d in-3 -y1) -2 203 N c,0.0035 0.44 487 1 c ctuy -- mdzl5 (cncthylscil Ibnyl)pyrrol i s n-3-yI)pyrimidin-2-arninc f J"4 Cfl' ~5 -mcth o xypy riding -3 -y 1-2 204 rN 0.0008 0.46 4692 c tc rt-h utylI 1-1 -ImId ol1-4 cli, yl)pyrimidin-2 N- ylamino)propyl)- 2 0 c lI mcth oxya cettim ide 5-rncthoxypyridiln-3-yl).2 205N Y 004 45 463H tcrt-butyl- I 1--imidazol-5 I I ;11,yl)pyrimidin-2 14N\ C ylamino)propdn-2-yl)-2 11methoxyacetamd I 1,N H13C 5-methoxypyrid in-3-yi)-2 206 N / N 0.0003 0.53 4931 C e-ht-!Hindzl5 H CyI)pyrimidin-2 0 ylaminu)prupan-2-yl) 2.2,2-trifluoroacetam]idc F 165 Ct)iltlJOti(I STIRUJCTUR[E1 RAF ott Imas. Method (CtllpoLtfd Naine No. (1C50 ill 11111 (Mi1 1 ) uM) (linl) N- iI (S -N (( )2-4-5 J JNarrttno-5-incthoxypyrid in I 1,c3-yl)-2-ieri-buiyi- I H 207 N- ,N (1,0.0158 0.50) 483.2 C i mizol-4-y))pyriimid in Ni I\. P,2-ylamnino)profpy1)-2 0 -o-CI, meiboxypropartiar idc N- ,-... itp _H,~-~CO am[rto-5-rnetlioxypyri in 208 ! 0.0011 0.50 4B03.0 C 3-yI)-2-ert-buiyl- I H (:H, i mldazol1-1)pyrirn idin1 N ~~j ~~ 2-ylamioo)poy)- 0 0- roiho xypropanarn1 ide -N ~j N CO 3 4-(4-(6-umino-5 F1C)< N N C1 mcthoxypyridin-3 -yI)-2 I0~ Hc N N 2-, 0.0001 0.50 300.3 C tert-hutyl-I H-imidazol-5 NH yI)-N-isqobutylpyri mid Dn 0, 2-aminc N 4-(4-(6-amno-5 31 N N 11nithoxypyridin-3-yl)-2 210) HC N -~N 0.0001 0.410 354.2 C t er - b t itylI-I H -i ni dazo 1-5 Ml i yI)-N-mcihylpyimdo amine 0,CH -N N 4-(4-(6-amino-5 FFJC N Nmethoxypyridin1-3 -y)-2 211 113C-)-3-1,1N 0.0001 0.43 368. c teri-butyl- I H-i-imidazol-5 11yD-N-ethyipy'rinidin-2 NH, l amine 166 toni-b- rltl Coipoliid STRrUCTUiR RAF oil Ilia' .S Method Comnpounid Name No. (iC50 in imei (M IT) N 13 N Nnithoxypyimidin-3 -yI)-2 212 113C_-,N ('C1 3 0. 0001 OAl 382.3 C Icrt-h~utyl- I H--iriduzol-5 N ,yl)-N-propypyrni mdi 11-2 N12 aine 4-(4-(6-mminci-5 I 1,C N N \ F niethoxypyridin-3-yi)-2 I c F lert-hutyl- I fl-imidazoi-5 21 HC X*N F 0.0001 0,49 4222 C )(G N H 2 ~tin 1uoroiethyl)pyri midin 0. CH, 2-amine (S)-N-(] -(4-(4-(6-arninci 0 ~ _N 5-mcthoxypyrid in-3-y1)-2 214 00.0010 067 502 F (4-furpey~xzI5 N ,N 1yI)pyrimidin-2 N ylamInu)prcipari-2-yI)-2 N rile thoxyacctmm i de II N 4-(4-(6-arnino-5 H3(. nethoxypyid in-3-yI)-2 215 CH.,' 0.00 0,63 498.1 C eri-hutyl- I H--i ni dazol-5 N U.U~ .yl)-N-(4 r. ~~i n u oiro nrI ctIi y 1)11c rt zy 1) IN /\ ('yriniidi n-2 -urn Iic (S)-N-(I -(4-(4-(6-nmnO *~ ~ '...5-riicthoxypyrid in-3-yl)-2 0.. N -~(2-fluoro-4 (tv fl tuoiorncthyi)phcny I) 216 0.02 050/ 1"c .00 6 7 C i--iidazol-5 yljpyrinmid in-2 yI am inu)p ropan-2 -y I)-2 ______________ ____ ______ ethoxyzicelarnic 167 nut-b- rotonti Gulinpoiund suuj RA]" ODf Mas'sCopon Nm N) Slzjclul- (1Q50 in tinlic (MI-1 i ilmC pon ac tiN') (mil) )-IN N

(S)-A

t -( I -(4-( 4 -(5-imi no 6 -mncithox ypy ra7Ln -2 -yl) 217 0,Q 0020 0.67 509 3 F 2 -(4 -fl uorophcnyi)oxazo I N~y 5-yl)pyrimidin-2 HN 3,-:ylarnino)propan-2 -yI)- 2 I N rneihoxyacciamidc -(6-, nnIn n 5 -met hoxyp yri d in-3 -y 1)-2 218 ,0.00((0: 0.43 4392 C eri -bu tyI -11-1 -i i d zo 1-5 N -1CH yflpyrimnid in-2 FIN,_P ylarnino)propati-2 N l1 yI)acctamidc I-1N N ( 1 -( -(4 -(6-1ami no-5 CI: - , m cthox ypyr id in -3 .l)-2 219 r- 't~003 0.1 442 C serl-butyl- I H--imidazol-5 ti H cli, yl)pyrirnidin-2 "0 yl am i no)propan-2 -yI)-3 N1 N-cil, methyfurea I I I,N N 1,C.OX IN -04-(4-(6-annino-5 0 m>~

-

methoxypyrid in-3 -yI)-2 220 10.0020 0.69 435.1 F (4 -fluoroplienlyl)ox azol-5 I N yI)-N-isobutylpyri mlidi n 2-aminc 4-(4.(6-ai-ni nD-S. "C c mth o xypyri d 1n -3- y1) -2 221 N tJl 0.0002 0.70 4084. 1 D leri-butyl- I H-imidazol-5 I N ylncNhy4) yrimidt n-2-ariiti 1 68 mut-h- recnhi CopudRAF (M I mIas Mcq o CompSTUCTUR si C(CS) n H 10Ndl' Compound Name No. C5in 1W 1MmI) (mmn) tiN - N 4 -(4-(6-omino-5 I ic " incthoxypyridi n-3-yI).2 22 /M0 .- 6 S1.1 D ,Ie-bu tyl - 11-]-iin idazo 1-5 222 Nj N 000 0.16 1.1 0YI-N-(4-c h loo-3 IN , (tri flu o ro niethly 1) phjeny )p C- yrmidin-2-arninc II( N N 4-(4-(5-amino-6 NN 1 mcthoxypyrazin -2 -yI)- 2 S0 (4 223 10.0110 0.09 '186.2 F (WIr fuoromncthyi)phcnyl)o N IN xazol-5-yI)-N isobutylpyrimidin-2 Ftc amine N N 0 N~ F rncthoxypyrid in-3 -y1)- 2 2 2 4( 4 24I0.0140 0.81 485.2 F (trri flu orom ct h y 1) h cny 1) o N-.N xazol-5-yO)-N isobutylpyrimidin-2 H iC Cu 3 am inc "C ~jCi, 3-yI)-2-ierl-butyl-I H 225 'A~~Tg0.: 0.0013 0.45 483.2 C; iiao.-Iprmdn till,2-ylmimino)propur-2-yI)-2 melhoxypropunami de (S)-N-(] -(4-(4-(6-aniino ~ ~ 5-rnct11oxypyridin-3-yI)-2 IJI i 226 .000 0.4 4552 c Isopr-Opyl-l 1-1-iniidazol-5 o 0~. .03 04 5. yl)pyiinidin-2 ylIamrni n o)1)ro 1)an -2 -y 1) -2 nicthoxyacctamidc 169 Compond FRCT RAF (On uiia' MethI(X Coinpow id Name No. (]C50 in 61ime (MU r) (S)-N-(l -(4-(4-(S-tmino ~ 6-rncthoxypyraziri-2-yl) 227 0.0003 0.45 455.2 C -spip-IHrndo -61',c5-yl)pyriinidin-2 y lain i no)propan - 2 -yl)-2 mnethoxyacelai-nidc c c H, 4-(4-(6-ainino-5. 11C, NI N enchoxypyridin-3-yI)-2 /- iert-butyl- I-methyl-I11 22 N-- N. OH 6 0.535 410.4 C -/ H13C iinidazol-5-yl)-N N- cfA4 isohuty) pyri i idi jn-2 N14, amine HI~N N '(S-- (-I(-nno x 6-inctlioxypyrazin-2-y]) 229 1 0.0030 0. 82 559.2 F (tri fl ioroint h yl)phc n y )o N, N HN ~~~x azolI- 5-yl)p yiin id in-2 ~ )~,-ci~,y laini Ino) propan -2 -y ])-2 I(C i mcthoxyacctainidce '43C C'*4 3 N4 -(4-(6 -a iino-5 N ,-mcthoxypyidin-3)-yI)-2 230 N 0.0001 0.40 1117.2 D ieri-butyl- I H-ImIdazol-5 NY CH, N~' ~ 0yl)-N-(2-rncthoxypyiin HN C N -yl)pyrimnidin-2-arninc 231H N N 000 .7 431 0 iorpl!Hindzl5 C H, 3 0 ~yl)-N-(2-nmcthoxypyiii C 4 4y )pyii inidin-2 -ain inc H2N 170 11ut1-b- rie i Gui npllid STUT 1R A F onl I a Micl hod Compound Namne No. (1C50 in li mic (mlt 1) IuM) (mliii) I'lit" N4-(4-(6-umlno-5 ni c t h oxy py rIimn- 3-y 1) -2 2:32 1 0.0084 0.75 184.3 F ( NZ (trifluoromcthyl)phcnyl)o IN xazol-5 -yi)-N ICH, isobutylpyr-idin-2-aminc C, - 4-(2-/eri-bulyl-4-(3 '/ chlo ro - 11- -py rrol o [2.3.

233 D I 00 05 7. b~pyridin-5-yl)- 11-1 'I imidaz.ol-5-yb-N-(2 nicthoxypyridin-4 IyI) py rimnI d In -2-a m in c I iN .1 Ch- (S)-rncthyl ]-4(-5 1 0 i 51 acetyl-6-aminopyridin-3 23 N 3 46Hf: ~ -2-tert-butyl- IF l13 N CH~ iridazol-4-yI)pyrirniidin 0 df 2 -ylarniino)propun-2 N____ N__ ylcarbarnute IIt, 4>' , (5)-ethyl I1-(4-(4-(5 1I, N arnino-6-inctlhoxypyrazinl 2 3( F 0.0001 0.55 470.2 C 2-yI)-2-tert-butyl-I HI N I I C I, irniciazol-5-yI)pyrirniidiin IN o1 2 -ylarnino)propan-2 H 0--\ylcarbainutc 0- / N ~(SD-isopropyl ]I4(-S 3. N arnino-6-rnethoxypyrazi n 237 0.0001 0.60 48,12 C 2-yl)-2-ierl-butyl- 11 N , I ir-nidazr/ol-5-yI)pyriimiditn HN ',y 2-ylamino)propaii-2 NA arurn1t H yIubmt 171 1TItI-b - rI~ N~ioi ST IzUCURI:RAF 01 Method Compound Nanic No.1I~tI( Jl~f*I* (ICQ50 iii 1111C (MIT -N (S)-neopentyl 1 .(4-(4-(5 N'- ami no-6-methoxypyi-azi n 23t12-yI)-2-teri-butyl- I H CI , 0.0001 0.70 512.2 D ind, o1-5-y1)pyj-Imidin I N jk 2-ylamino)propail-2 II i, ylcarbamate (S)-isobuityl 1I4(-5 - N amino-6-mcthoxypyirazin 23 ~Ci, 0.0001 0.66 498.2 c 2.yI)-2-terl-btityl- I H 23 N I Cl irniditzol-5-yI)pyrimidiin 4iN,> 0~ 2-ylarnino)pi-opaii-2 14 ylcarbamate II1 3 ,N (S-inethyl I -(4-(2-(crt N ~ butyl-5.(I I-1-indol-5-yi) 240 ~ - N CI, I 018 06i48 -imidazol-4- 24I ; . 03 ~34 yl ~pyrimid in-2 N . N ca )ylam liao)propan-2 I N K0'l ,ylcarbamate (S-N (() -( (4-( 44. N '4N 2N _(l,,0007 04 8. 3-y!)-2-1crt-biuty1- I I-I 2411 6 0.07 .9 48. imila7zo!-5-yI)pyrimidin N < NH 4 2 -yI am ino)propan-2-yI).2 rnethoxypi-opun urn id c (S )-N-((S)- 1 -(4 -(4 -(5 4 cNN am ino -6 -nethox ypyrazi i .2/2 N 000 .5 8. 2-y]).2-tert-butyl- I H N~ \~ , 000 .408 imi dazol-5-yi)pyrimidin NIN, 2--ylam-i no)pr-opan-2-yI)-2 mcthoxypropanami dc 172 Com11poniii sTR UCTUR ER F 01) iis McIlud Coinpouild Naine No.(IC5O il ii hue (MItf' 11Mi) (mmfi) v ~4-(4-(6-ai-nino-5 / il m ctho xy p yr Id jn-3 -y1) -2 243 ot, o-CH5 0.0004 0.34 419.1 D cthyl-lI l-1-irnidazol-5-yl) I/ ~- 0- N-(2-nicthoxypyridin-4 ill, yI)pyrirnidin-2 -arni nc it sN--, 4-(4-(6-aini-5 N( '- UN tcthcixypyridin-3 -yI)- 2 244 (46, 0-c1,: 0.0030 0.32 405.1 D incthyl- I l--inidazol-5 a yI)-N-(2- methoxypyriiii NitNH 4-yI)pyrlirid f-2-aminc N N 4-(4-(5-umino)-6 I~c~~< N)S \in utho xypyrazi i -2 -yl1)- 2 24 m -11 .10 038 405.1 D met h yI- 1-1 -Irnidazo 1-5 y I)-N-(2 -in ct Iox ypy rI d 111 NNil, 4 -yl) py rim id in -2-am i nc I.1 3 G c e N CH1 4-(4-(6-amnio-5 I \>--C- rothoxypyridi -3-yl)- 2 24 C 1-13 0.0001 0. 62 395.2 E lert-hLty lox azo -5 -yI) -N% N CH isobuly Ipyr idin-2-ami nc 6-rncthoxypyrazin-2-yI) F (tri2-(2-fluoro-4 247 ~ ~ ~ ~ ' o 00001 0.73 575.3 ~ f~l nty)pel) 24 IN I-IC l-imidazol-5 yI)pyri-idIn-2 y lani i no)propaii -2-yI)- 2 ________ ____________________ ______ _____ ____ _____ methoxyacclamide 173 milit-b- ICLCnlti Com fpound 'S.R tIMMURE RAP Oil I1i I MNCtOdC Compound Nainc N.(IC50 in ime (M11) 11M) (mlln) (,S)-N-(i .(4-(4-(5-amino 6-mcthoxypyrazin-2-yI) (:FF,2-(2-fluoro-4 248 1.'7~ o 0.0001 0.73 576.3 C I loomchlpcy) F ' r4N F I I--imnidazol-5 IN Nit, yl)pyrimidin-2 ylami no)propan-2-y1)- 2 _____ mcth oxyac clam id c (R)-N-(] -(4.(1 -(5-amino ~ F:,6 -mcthoxypyrazin -2 -yl) F..(~2 *j' ,2-(4 -fl torop henyl)- I H 249 N-=/ Nt.. "o 0.0120 0.59 508.3 C imidazol-5.yl)pyrim id III N NFF.2-ylamino)propan-2-yI)- 2 meilloxyacctamide -. - F(S)-N-(I -(4-(4-(5-amnino CF I~ K6 -mcthoxypyrai n-2 -yl) 250 N.N 0.001 0.45 4541 C 2-cyclopropyl- 11 H 250N IN000 .5441 c imidazol-5-yl)pyrimidin

HNI

2 -y lam ino)propan.2 -y l)-2 HN mcrhoxyaccinmide I.,N. IN> N (S)-zrmethy1 1-4(-5 O N'j Wile & amino-6-mnclhox ypyrazin Ci) 2-yI)-2-(lI 251 ~~ ~~N 0.00004 0.57 4541 C ehlyopol)ti, Nirnidaol-5-yl)pyrimjidin I CN C 2-yl ami~Ino)propan -2 1. CI) ylcarbamate NY N 6-methox y-3 IN 4 mcihyipyraziln-2-yI)- i-(' 252 0.0024 0.59 5223 C flOr-Ophellyl)- I H I I mid azo 1-5 -y I)pyri mid in 2-ylamino)propan-2-y1)-2 0mc h oxyacct aii de 171 mm -b- rIft NoRICIIJI RAF oi 1 SMelhod Comnpouiid Namec No. IC5in (iii) Nl-' 11 N X N N C11 4-(4 -(5-iAmi no-6- mcihoxy N CH, 3-nethylpyrazin - 2 -yI)- 2 253 1N 00062 0.44 462.3 C, N wri-butyl- I--imidazol-5 NN yI)-N-(2- mothoxypyridin 4-y I)py rimidin -2-amine 254 N N 0.003 0.2 40.t mino-6-methoxy-3 < - C.4 methylpyrazi n-2.yl )-2 25 .033 0524B zelr-buityl- I I--itmdzizoi-5 I) ylarnino)piopan_2-y)-2 IN .. N (S)-N-(I -(4-(4-(5-arnino N 6-methoxy-3 25 .N0.0039 0.45 468.3 C c;yclopropy-IH-imidazol NH 5-yI)pyrninidin-2 IlC- ylIa m ino) pro pa n-2-y 1) -2 0 mctho xyacciarmid c IIN>NI4(S)-ethyl 1-4(,-5 I ~amirio-6-mcethoxy-3 II3C.~N N ClImethylpyrazin-2-y )-2 256 '~ N CH, 0.0011 0.55 484.4 c t eri-butyl-IHI-imidazol-5 N -N i 0yI)pyri rnidin-2 HN"' N ()O (cml ylamino) propan-2 H yl carb amnale IIN N C hI(S)-isopropyl 1I4(-5 ~ N ~amino-6-mcthoxy-3 I N> - c 14, rnethylpyrazin-yI) 257 Clij 0,0012 0.56 498.4 C i er -b u iy I- I H -I i 1 (1 io 1-5 N yN C0 CH3yl)pyrimidin-2 C) CR y la in i io) pro pa n-2 yI carbamate 175 No. RA I ] Mciilo Comrpouind Namec o.oic srucuu C5 in Liij(; (MI-I 11M) (mill) iiyq cN (S)-isobutyl 1 -(4-(4-(5 0 N N Gl amino-6-methoxy-3 I l>--cilmcthylpyrazi n-2 -yl)-2 25B 0.0011 0.54 512.4 C teri-butyl-lI H-irniidazol-5 N .~N i,0ypymndii2 Y y~II.i. idcun 3 2 N" . NH 0-Y 'N 1 ylaim iio)propa n-2 CHyI carb amatc I Il a-ni no-6-mcthoxy-3 N I ni-ci c;thylI pyrazi n -2-yl )-2 259 0.00)15 0.70 525.65 C tia-butyl-IH-idzl N .- yl)pyrimidin-2 c(I O-Y'cliylaminco)propan-2 C~t3 ylcarhamatc I .,N (I, O. ~(S)-rnthyl I~4(.5 C' .N' N amino-6-rnethoxy-3 *" 1, IN IsCH mcthylpyrazin-2.yI)-2 260 N 0.001 0.49 470.3 C ier - b u ty I- I--i ni dazo 1- 5 IN-,yl )pyrimid in-2 ylami no)propan-2 0 c Fl ylcarbamatc H N N C.(S)-l-ncthyl 1-4(-5 1) 0 CIAami no-6-(D 3 0A\>( C 11 ni-c c Ih o xy) py razi n-2 -yI1) -2 261 D 0 N cii1 0.01)1 0.52 4 59.1 C teii-butyl- I H-imiduzol-5 N Y N H,0yl)pyirimidin-2 iN -"A' N 0 cn,3 ylamino)pi-opan-2 N ylcarbamatc (S)-mcthyl I .(4 -(2-'erl Ni butyl-5-( I H-I)yri0I0I2 3 262 ~ N 0.)))N.5 4. blpyridin-5-yl)- I H 26 2 'I -/ ~r Ni jcl0002 o5 4. imidiaol-4-yI)pyiimidin _;'m i c 2 -yI amin no)propaii-2 ylcaibamatc 176 Compound STRU UR1. RAFj Ol ila q1AS Pyici hod COMPOLnd Namec N.(1C50 ill lindi (MH ). utvl) (ll) (S)-mcthyl 1 -(4 -(2-tert. F -'*butyl-5-(3 NI (trifluoromcthyl)-l I I H f pyrrolo[2,3-b]pyridln-5 263 N - . - 0.065 068 517.2 C yl -I-rid l4 yl )pyi-imid in-2 ylarniiio)propan-2 ylcarbarnate ------ (cthylsulfony)pipcriazmn 254 ___~ \ ~ 0.040 1.32 4114.2 C I -yI)-4-Gpyridln-4-yI)- I Hl _____ N *-~Ml dazo -5 -yi)-3 N. <rikulhoxypyridin-2-am ic 1- 2 N ~N (S)-rnothyl]- -( (6 H -N arino-5 N N (difluoroinethoxy)pyridin 265 1 1- 0.00001 0.55 491.0 C 3-yl)-2.tcrt-butyl- I Hi N -N ~ ~u ~ d '( 0 Il idazo1 , ,1pyro n HI N 1kOMc 2 -yl amino)propan -2 a-i ylcarbamatc

FI

2 N Nl (S)-rnethyl ]I4(-5 M(,O " N N, aiino-6-anietlhoxypyi-azi n Mu() N\>(Iii 2-yl)-2-(l N CF (trfluoroinethyl)cyclopro H N C 3 yl)- I H-imidazol-5 o yI)pyrirnidin-2 H N.. -N ) 1 K y Ia m ino) propa n-2 NH M ylcarbaniatc 1-11 nul-b- cCfLCLi Compound STR u CfIU R AF Oil Mass McIIIod C01Iompond Namec No (ICSO it)n inc (M If) LIM) (mil) 1-1 2 N N I(S)-rncihyl I-4(4(S Mo N N A amino-6-methoxypyi azin MOO N2-yl)-2-(I P2 N N CI chlorocyclopropyl)- I I N I ' 0i midazvol-5-yI)pyrimicdin 2?-ylarnino)propan -2 HN N O 0M L ylcarbamate HN N(S)-metlyi 1-(4-(4-(5 N amino-6-rnethoxypyrizin Meo N yI--I P3I N Ncyanocycl opropyl)- 1- H N I N H 1 .midv/ol-5-yl)pyrmIrndII ttN~-'-~2-ylamIno)propan-2 N OMo )'icarbamatc H2N(S)-mothyl 1 -(4-(4-(5-amio Moo N N\\ 6-methoxy-3 I deuteriopyrazin-2-YI2-eml N N butyl-1 H-irniidazoI-5J P I, 1-1 yI)pyrirnidirm-2 y~ ylarnino)propan-2 l-1 2 N N (S)-rrncthyi ]I4(-5

I:

2 1.IO N mino-6 N (d ifluoroamethoxy)pyaz o P5 N IN H -2-yI)-2-tcrt-butyl- I H N 0N*~ iiayo 1-5 -y)pyrimid III HNN~7N )~-.2-ylarnino)propan-2 O~o ylcarbnatc 178 ColpldSTRucTUIU: R A tI 2 Ol II Y Method Compound Namec 1m~) (mill)

H

2 N ,N (S)-nicthyl I .(4-(4-(6 FHCC) Nami no -5 N 1> N(di fluoronicthoxy)pyriclin Ij it 3-yL)-2-tert-butyl- I I N xN OMc 2-ylamino)propan-2 ii ylcarbamate 1 2 N TN N /(S)-mcthyl -4((6

MI

2 C() \-arnino-5 S N (fluoromthoxy)pyi-id in-3 N 11 N Hyl)-2-1crt-butyl- I Ff- ~~T'< ~ i iraol -5 -yl)pymi ii in I iN W 2-ylaitmno)propun-2 IA y ca rbam atc I iN N X IN~ (S)-nicihyl 1-(4-(4-(5 nic I 2 () N I '> __arnino-6 -. N (fluoioinethoxy)pyrazi n 'A2 2-yl)-2-tert-butyl- 11I-1 PRn Ny 7dazo I-S-yl)pyri f iii N OMe 2yiarrino)propari-2 II ylcarbamate HN N (S)-mcthyl I-(4-(4-(5 F-:3CC N (trifluoromcthoxy)pyrazin jig N .2_-yl)-2-tcrt-bmtyI- 1l-1 NNirn idazol-5 -y l)py nt cli n 2-ylami no)propmin-2 1-1N N NOo ylcarbaniate 179 Comnpolid STR UCTURF, RAFM I In (MiS Method Compound Name 1Mdv) (Oil) N'0 a IntIno -5 P10 N -3-yl)-2-tcrt-butyl-I 1-I N Nim idazol .5 yI)pyri midi n :.:2 -ylamI no)propan-2 HN N xOMa ylcarbam atc H H N ~N (S)-rnethyl 1-4(-6 N N\/acctyi-5-anninopyrazi n-2 P11 0 I N~ yI)-2-tcii-hutyl- I H N 1 11 mI dazol -5- yI)pyri inid in T 7 02-ylam inc)propan -2 11N N 'kOMo ylcarbarnatc H2 N H (S)-methyl 1-4(-5 N aiccty1-6-aminopyrdrm-3 Piz 0 N yl)-2-tcmi-butyl- I fi I N H irni dazo1-5.y1)pyrirnidin 0 2-yarn ino)proplan-2 HN .N ik. ylcarbarnatc N OMLC H HN N (S)-ITCthyl I -(4-(4-(6

F

2 HI1C 0 amino-S \>. Nd (I flu oro rn c th oxy) p yrI iin NN 0 ~In i dazol-5 -yI )pyri nid in I-I ) N We 2 -ylam i no)prupan -2 H y abmt mi11t-b- ret cilti Cmnd TRCF..3 RAF oil Thi;NS MC1ihod Compound Namne o,~nnc SIC5 inI 6111Cn (NIH' ttlv) (mil) HNNI(S)-methyli-4((5 F'11CO N Nam'no-6 ~~( N(i flu ormethoxy)pyraziln 1114 11 Hi -2.yl)-2-cyclopropyl- 11-1 N,,rN imi idazol -5 -yI)pyri rn idc in 1N N OMe 2-yiarni no)propan-2 HA yicarhamnatc HN ~N (S)-methyl I -(4-(4-(6 tim ino-5 F'CO N(tri fi uoromcthoxy)pyrid in P15 (K N -3 -yI)-2-cycloprptiyIl- H N yN _itt idazol -5 -yI)pyi Ind III ttN,,- . )L.Om 2-ylami no)propan-2 OH y Icarh amate t1N N(S)-mcthyl I-4(-5

F

3 c'() N (I i (1Unrolittiox y) pyrozVi Ii PIGI_6N -2-yi)-2-cyciopropyl- 11-1 N x-N i midtzoi-5-yi)pyrirnidin ~~K9 2-ylani ino)propan -2 H .N NOMe )'icarbamnatc -~ N amino-5 Ftt 2 X) ~ -K1(fluoromcthoxy)pyridin-3 N1 N yI)-2-cyciopropyi- 11-l N - N _ 11 iazo I-5-y I)pyri nidin 0 1.yiannino)propan-2 i-NN*-- OMe yi carbhamnatc i 1 2 N N> (S)-irncthyl 1 .(4-(,1-(5 ar aI no -( Ftt 2 GO N (fluo meth ox y) pyrazill. 'li '- N 2-vI)-2-cyclopropyl. iN N N i midazo1-5 -yl)pyri mid in N k Ome2-yiamino)propan-2 tl. HN~ ~ ylcarbannate 181 Noj'RlAcPlIll - NICIllod Compound Namne opon (IC5() in fimui (MI{ ). HN N (S)-rncthyl 1I4(-6 ainino-5- -ehx~yi '~~' -N ~~(tridcuteriolntoyprc P19 .~ Nin-3-yl)-2-tcrt-butyl- I H I H iunidazoI-5-yI)pyrimidin N yN C)2-ylami no)propan.2 iN N ) OMO ylcarbainatc 1 82 Example 291 Cell Viability Assay Protocol 10314] The Cell Titer-Glo@ assay (PromCga) was used to measure cell viability. Cells were plated into 96-well black walled tissue culture plates in complete growth media. The plates were then incubated under standard growth conditions of37"C and 5% CO 2 until the cells had attached to the plates (3-6 hours), then compounds were added to the cells. Compounds were serially diluted in DMSO using 3-fold dilutions and then diltited in complete media before being added to the cells (final DMSO concentration on cells was 0.1 - 0.2%). The cell number plated per well and the compound incubation time for each cell line arc shown in Table 2. TALE 2 A375 G361 Malnie3M CapanI SU86.86 PC3MM KI Ii Cells/Well 1000 1000 1000 2000 1000 1500 1500 Plated / lDays Compound 3 4 5 5 5 5 4 Incubation 031 SI A fler compound incubation, the cell plates were equilibrated to room temperature, culture mcdia was removed, and 200 uL.. of Cell Titcr-G Il reagent mix was added to each well (1: 1 mixture of Ccl Titer-Glo@ reagent and complete growth media, equilibrated to room temperature). The plates were shake for 5- 10 minutes, then sealed and liiiiuesecie was measured (using Trilux plate reader, Perkin Elnier). 103 161 Assay background luminescence values were determined from wells which were treated with a potent control compouinld that completely inhibited cell growth or caused] cell death at the highest concent ration of' 10 iM. Analysis of data was done by subtracting the background luminescence valie from each data poin1, then determining the percent inhibition of total growth (as determined by the values for DMSO-treatcd wells). 1 83 [(13171 To determine the ECso for each compound, the data were fit using the Levenburg Marquardt algorithm, represented in the XLfit software as y = A + ((3-A)/(1-I+((C/x)AD))), the four parameter (lose response model 205, where A is the minimum Y value, B is the maximum Y value, C is the Log IC 5 0 and D is the slope. Results for selected compounds are shown in Table 3. TABLE 3 T Papillary Compound No. Melanoma Pancreatic Prostate Thyroid _A375 G36l | Malme3M Capant SU86.86 PC3MM K I

EC

50 (uI\M) I0.376 0.070 0.429 0.570 0.116 66 0.623 1.016 0.816 81 0.547 0.305 0.194 0.319 85 0.163 0.111 I16 0.674 0.118 163 0.535 0.028 0.083 5 0.354 0.892 198 0.787 9 0.250 Example 292 Rat/M'ek Amplified Luiminesence Proximily llomogeneons Assay (AlphIIa Screenl) lht|Jers Assay buffer: 50 mM Tris, pH 7.5, 15 mM MgClk, 0.01% BSA, I mM DTT Stop buffer. 60 rnM EDTA, 0.01% Tween20 1 84 Bead buffer: 50 mM Tris, pH 7.5, 0.01 Tween20 Mater ials b-Ral(V600l), active: Recombinant in-house material biot inylated Mck, kinase dead: Recombinant in-house material Alpha Screen detection kit PerkinElmer. 1/67606 1 7R Anti phospho-M EKI/2 Cell signaling /19 12l 384 well assay plates: White Greinci plates, //781207 .Assay conditions b-Raf(V600.,) approximately 4 pM c-Raf approximately 4 nM biotinylated Mek, Kinase dead approx imaicly 10 nM ATP lo pM Pre-incubation time with compounds 60 miln at room temperature Reaction time I or 3 hours at room temperature Assay) protocol 10318l Raf and biot inylatcd Mek, kinase dead, werc combined at 2X final concentrations in assay buffer (50 mM Tris, .H 7.5, 15 mM MgC1,, 0.01% BSA and i mM DTT) and dispensed 10 l per well in assay plates (Greiner white 384 well assay plates 1/78 1207) containing 0.5 pl of 40X of'a raf kinase inhibitor test compound diluted in 100% DMSO. The plate was incubated for 60 min at room tcimperature. 10319) The Raf kinase activity reaction was started by the addition of 10 pl per well of 2X ATIP diluted inl assay u ffer. A fter 3 hours (bRaf(V600E3)) or I hour (c-Raf) the reactions were stopped with the addition of 10 pl of stop reagent (60 mM EDTA). Phosphorylated product was measured using a rabbit anti-p-M EK (Cell Signaling, #9121) antibody and the Alpha Screen IgG (ProteinA) detection Kit (Perkin Elmer //676061 7R), by the addition of 30 pL to the well of a mixture of the 185 C:\NRPonbW CC\RBR\4428X4I IDOC-256/2012 antibody (1:2000 dilution) and detection beads (1:2000 dilution of both beads) in bead buffer (50 mM Tris, pH 7.5, 0.01% Tween20). The additions were carried out under dark conditions to protect the detection beads from light. A lid was placed on top of the plate and incubated for 1 hour at room temperature, then the luminescence was read on a PerkinElmer Envision instrument. The concentration of each compound for 50% inhibition

(IC

50 ) was calculated by non-linear regression using XL Fit data analysis software. 103201 The Raf/Mek Amplified Luminescence Proximity Homogeneous Assay described was used to generate the luminescence and mutant b-Raf(V600E) IC 50 data for selected Raf Kinase Inhibitors shown in Table 1 above. 103211 The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates. (03221 Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. 186

Claims (28)

1. A compound of Formula I, a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof: R1 x R 3 R2 Y Formula I wherein: X N X R3 R3 R3 / R R R represents or I-N X or Y, whichever is present, is selected from the group consisting of 0, and S; R' is optionally substituted 2-pyrazinyl; R 2 is optionally substituted heteroaryl, or optionally substituted heterocyclyl; R 3 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl; and or a stereoisomer or pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein X or Y, whichever is present, is 0.

3. The compound of claim 1, wherein X or Y, whichever is present, is S.

4. The compound of any one of claims 1-3, which is a compound of Formula II: 187 R N R 5 ZR x R3 2 R (II) wherein Z' is N; and R', R', R , and R' are independently selected from the group consisting of hydrogen, deuterium, halo, cyano, hydroxy, -C(O)R', -NR"C(O)R', -C(O)NR' '2, -OS(O) 2 NR"2, optionally substituted C1-C6 alkyl, optionally substituted amino, and optionally substituted C1-C6 alkoxy; R' is optionally substituted alkyl and each R" is independently hydrogen or optionally substituted Cl-C4 alkyl; R2, R3, X and Y are as defined for Formula (I) in claim 1; any two of R 6 , R 7 and R 8 that are attached to adjacent atoms of a ring in Formula II can be taken together to form an additional optionally substituted 5-6 membered ring; and the pharmaceutically acceptable salts, and isomers, deuterated versions and tautomers thereof.

5. The compound of any one of claims 1-4, wherein R 2 is optionally substituted pyridinyl or optionally substituted pyrimidinyl.

6. The compound of any one of claims 1-4, wherein R 2 is selected from: 188 H:\rbrlillitenvVCI1\NKF0nDI\UU\KWK\0303U-I.U 'l/a4 NH, N N N H N N H N N N N 0 N' N N HN NH N or enantioeoer N yN NysN INI I I or enantiomer or enantiomer N NH 2 N N -N HN) H I0 H N -Sl 189 H:\br\lienvovcn\NRPotbl\DCC\RBR\6326308_ .DOC-1 3/05/2014 N H 2 N N N N H H or enantiomer HN N N N N N N N H HN HN F Ni l FY H 0 N H 0 yNNy N N NA N N N N N 7 NO C I H N N SH N NH N 0 nSrm// or enantiomer or enantiomner 0 F O0 O0 N N N N N H H HN O 190 H:\rurflitCerwOVeCINKroflDI\ULLUUKOJ2OJ3n I.UUC.3/05/2014 N NN N Ny NCH H N ' HN ,, Oor enantiomer CF 3 F N N H H H N rI N yN N s-N NyN HN HN N'N H N or enantiomer N N N N N N N HN "" HN O OH HN N N or any enantiomer or diastereomer NO NH 2 191 NyN N N NyN N N HN HN HN HN 0 "/N 0 O F 10 or enantiomer F 3 C F S N 0 N IIY H H F 0 or enantiorner or any enantiomer or diastereomer F 3 C N O N N N -N ' NN HHN,, 0 H or e io or enantiorer or enantioer H N F 3 CyN N Nl 'N YH N N N or enantiomer or any enantiomer or diastereomer 192 H:\mrr\iRI-rwOy~NT- KI M1DI\UUU\KW$~630_ 1.UUC-13/03/M014 CFN CF3 HN N FN HN yN I H H o N 0 N or enantiomer or enantiomer or enantiomer or enantiomer H2 H NHR12 NN N N R H H" N" N y H w r Z2 i or Nander N N YN N N N 0H 0H or enantiomner or enantiomner

7. The compound of claim 5, which a compound of Formula III: 101 RR 3 wherein Z 2 iSCR 9 or N; and 193 H:\rbr\lnenvovn\NRMOWbl\DC\BR\6326308 1.DOC.3/05/2014 R 9 , R' 0 , R", and R1 2 are independently selected from the group consisting of hydrogen, halo, D, cyano, hydroxy, -NR"C(O)R', optionally substituted alkyl, optionally substituted amino, optionally substituted heteroaryl, and optionally substituted alkoxy; R' is optionally substituted Cl -C4 alkyl and R" is hydrogen or optionally substituted Cl C4 alkyl; R', R 3 , X and Y are as defined for Formula (I); and any two of R 9 , R1 0 , R", and R 2 that are attached to adjacent atoms of a ring in Formula III can be taken together to form an additional optionally substituted 5-6 membered ring.

8. The compound of claim 7, wherein R' 0 is -NHR , wherein R' is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, -C(O)R', optionally substituted cycloalkyl, optionally substituted amino, optionally substituted aryl, and optionally substituted heteroaryl.

9. The compound of claim 7 or 8, wherein Z 2 is CH or CD.

10. The compound of claim 7 or 9, wherein Z2 is N.

11. The compound of any one of claims 1-10, wherein R3 is optionally substituted phenyl, optionally substituted Cl-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.

12. The compound of claim 11, wherein R 3 is selected from 194 F3 F 3 C0 F HO F 3 F" 0 0 0F F 0 0 F 0~~~ 0 ' NH 2 NI 195 H I\tbr\lfflcnvovci\NRPoflbI\DCC'RBR\6326308_ lDOC-13O5/2014 0 H 2 N F H 2 N 0 0 0\\ "INH 2 0 I X CF, F F ',aF CI , F 0~~ F~ F-0 F 0 / N HNa Na H H N~ 'NN / 3 C F N NN 0

13. A compound of Formula IV: 196 H:\rbrnrienvoven\NRPorlbl\DCC\RBR\6326308_l.DOC-]13/05/2014 R 6 7/ Nx 3 N (IV) wherein Z' and Z 2 are each independently N or CH; RR YZ -- X N 6 21' whri ZrneZ reacs npnen tly N orH where X or Y, whichever is present, is selected from the group consisting of 0, and S; R 3 is optionally substituted phenyl, or a ClI-C6 hydrocarbyl group; R6 is NHR' 4 , where R14 is H or optionally substituted Cl-C6 alkyl; R 7 is H, D, halo, optionally substituted amino or optionally substituted Cl -C4 alkoxy; and R1 0 is NHR 15 , wherein R1 5 is selected from the group consisting of optionally substituted Cl-C6 alkyl, optionally substituted heterocyclyl, -C(0)R', optionally substituted C3-C6 cycloalkyl, optionally substituted amino, optionally substituted aryl, and optionally substituted heteroaryl; R' is H or optionally substituted Cl -C4 alkyl; or a pharmaceutically acceptable salt thereof, a deuterated version thereof, or a tautomer or stereoisomer thereof.

14. The compound of claim 13, wherein X or Y, whichever is present, is 0.

15. The compound of claim 13 or claim 14, wherein R 6 is NH 2 .

16. The compound of any of claims 13-15, wherein R 5 is substituted alkyl or substituted aryl. 197 H:\rbr\jntenvoven\NRPorIbi\DCC\RBR\6326308_1.DOC-]3/5/2014

17. The compound of claim 1, which is selected from the group consisting of the compounds in Table 1.

18. The compound selected from the group consisting of H 2 N N H3CO N F 0 N 5-(2-(4-fluorophenyl)-5-(pyridin-4-yl)oxazol-4-yl)-3-methoxypyridin-2-amine; H 2 N N chiral H 3 C. IuN F O" F N ,N HN 0 O CH N O H 3 C H (S)-N-(1 -(4-(4-(6-amino-5-methoxypyridin-3-yl)-2-(4-(trifluoromethyl)phenyl)oxazol-5 yl)pyrimidin-2-ylamino)propan-2-yl)-2-methoxyacetamide; H 2 N N OS N N/ 198 H:\rbr\linlormvoven\N Pofl bIMJCC\RB R\6326308_ 1.DOC- 13/05/2014 3 -methoxy-5 -(2-phenyl-4-(pyridin-4-yl)thiazol-5-yl)pyridin-2-amine; H 2 N N HO 3c N N F 5-(2-(4-fluorophenyl)-5 -(pyridin-4-yl)thiazol-4-yl)-3-methoxypyridin-2-amine; H 2 N ~N o>3CtCH3 N CHCH HN O) CH 3 4-(4-(6-amino-5 -methoxypyridin-3 -yl)-2-tert-butyloxazol-5-yl)-N-isobutylpyridin-2 amine; H 2 N ~N o c 0 -~ N N 3 -methoxy-5 -(2-phenyl-4-(pyridin-4-yl)oxazol-5-yl)pyridin-2-amine; H 2 N NN 199 H:r\ tcmovcn\N RPorlbDC B BR\63 263 08 1.IDOC-] 3/05/2014 3 -methoxy-5 -(2-phenyl-4-(pyridin-4-yl)oxazol-5-yl)pyrazin-2-amine; H 2 N N 0 3 -methoxy-5-(2-phenyl-5 -(pyridin-4-yl)oxazol-4-yl)pyridin-2-amine; H 2 N N Chiral H 3 C, IN N F ~-- 0 N 14 N 0 IN H 3 C H (S)-N-( 1 -(4-(4-(6-amino-5 -methoxypyridin-3 -yl)-2-(4-fluorophenyl)oxazol-5-yI)pyrimidin 2-ylamino)propan-2-yl)-2-methoxyacetamide; H N N Chiral HC 0 N N N ,N NN H 3 C H (S)-N-( 1 -(4-(4-(5 -amino-6-methoxypyrazin-2-yl)-2-(4-fluorophenyl)oxazol-5 yl)pyrimidin-2-ylamino)propan-2-yl)-2-methoxyacetamide; 200 H:\ibrl nrmovcnN RPol bI\DtLRBR\63 26308_ 1. UC.j13105/2014 H 2 N N H 3 0. 0 F N ~ HN H 3 0 H 4-(4-(6-amino-5 -methoxypyridin-3 -yl)-2-(4-fluorophenyl)oxazol-5 -yl)-N isobutylpyrimidin-2-amine; HN N 0 N N - F N FN N HO O H 3 4-(4-(5 -amino-6-methoxypyrazin-2-yl)-2-(4-(trifluoromethyl)phenyl)oxazol-5 -yl)-N isobutylpyrimidin-2-amine; H 2 N ~N H~l0 N - F - FF S 0>F N N N H HOC O H 3 4-(4-(6-amino-5-methoxypyridin-3 -yl)-2-(4-(trifluoromethyl)phenyl)oxazol-5 -yl)-N isobutylpyrimidin-2-amine; 201 H:\ ~itnociN~rbD a R6231-.DOC- I 3A)5/2014 H 2 N N Chiral H 3 C. 0 N N - F F d-. 0 F N ,N HN 0 H 3 C H (S)-N-( 1 -(4-(4-(5-amino-6-methoxypyrazin-2-yl)-2-(4-(trifluoromethyl)phenyl)oxazol-5 yl)pyrimidin-2-ylamino)propan-2-yl)-2-methoxyacetamide; H N N 03C N - F 0 F N H 3 C CH 4-(4-(6-amino-5 -methoxypyridin-3 -yl)-2-(4-(trifluoromethyl)phenyl)oxazol-5-yl)-N isobutylpyridin-2-amine; and H 2 N N H, 3 ,0 N 3 -methoxy-5 -(2-phenyl-4-(pyridin-4-yl)thiazol-5-yl)pyrazin-2-amine. 202

19. A pharmaceutical composition comprising a compound of any one of claims 1-18, admixed with at least one pharmaceutically acceptable excipient.

20. A method to treat cancer, comprising administering to a subject in need of such treatment an effective amount of a compound of any of claims 1-18 or a pharmaceutical composition of claim 19.

21. The method of claim 20, wherein the cancer is selected from the group consisting of lung carcinoma, pancreatic carcinoma, bladder carcinoma, colon carcinoma, myeloid disorders, melanomas, and adenomas.

22. The method of claim 20 or 21, further comprising administering to the subject an additional therapeutic agent.

23. The method of claim 22, wherein the additional therapeutic agent comprises an anticancer drug, a pain medication, an antiemetic, an antidepressant or an anti inflammatory agent.

24. The method of claim 23, wherein the anticancer drug is selected from irinotecan, topotecan, gemcitabine, 5-fluorouracil, leucovorin carboplatin, cisplatin, oxaliplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab and trastuzumab.

25. A method to treat a condition mediated by Raf kinase, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1-18, or a pharmaceutical composition according to claim 20.

26. Use of a compound according to any one of claims 1-18 or a composition according to claim 19 in the manufacture of a medicament for treating cancer.

27. Use of a compound according to any one of claims 1-18 or a composition according to claim 19 in the manufacture of a medicament for treating a condition mediated by Raf kinase. 203 H:rbrNtenyovcn\NRPorbI\IJLCRBUR\6326308 1.DOC-I3/A5/2014

28. A compound according to claim 1 or 13; or a pharmaceutical composition according to claim 19; or a method according to claim 20 or 25; or a use according to claim 26 or 27 substantially as hereinbefore described with reference to the Examples. 204