WO2010100127A1 - Disubstituted imidazole derivatives as modulators of raf kinase - Google Patents

Abstract

Novel substituted imidazole compounds, compositions containing them, and methods of using them for the inhibition of Raf kinase activity are provided. The new compounds and compositions may be used either alone or in combination with an additional agent for the treatment of a Raf kinase mediated disorder, such as cancer.

Description

DISUBSTITUTED IMIDAZOLE DERIVATIVES AS MODULATORS OF RAF KINASE

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit under 35 U.S.C. §H9(e) to U.S. provisional application serial No. 61/209,31 1, filed on March 4, 2009, which is incorporated herein in its entirety by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to new substituted imidazole compounds and pharmaceutically acceptable salts thereof, compositions of the new compounds together with pharmaceutically acceptable carriers, and us.es 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.

BACKGROUND OF THE INVENTION

{0003} The llaf serine/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- speclfic 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, p21 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 iso forms of Mitogen- Activated Protein Kiivase (called Mekl and Mek2), that are dual specificity threonine/tyrosine kinases. Both Mek isoforms activate Mitogen Activated Kinases 1 and 2 (MAPK, also called Extracellular Ligand Regulated Kinase 1 and 2 oτ 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 cellular functions such as proliferation, differentiation, survival, oncogenic transformation and apoptosis. [0004] 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 Has, indicating that R as functions upstream of Raf. Upon activation, Raf then phøsphorylaies and activates Mek, resulting in the propagation of the signal to downstream effectors, such as MAPK (milogen-activatcd protein kinase) (Crews et al. (1993) Cell 74:215).

[0005] Raf kinase has three distinct isoforms, Raf~l (c-Rat), a-Raf, and b-Raf, distinguished by their ability to interact with Ras, to activate MAPK kinase pathway, tissue distribution and subcellular localization (Marias et. al., Biochem. J. 351: 289-305, 2000; Weber et. al., Oncogene 19:169-176, 2000; Pritchard et. al., MoI Cell. Biol. 15:6430-6442, 1995).

[Θ0Θ6] Activating mutation of one of the Ras genes can be seen in '-20% of all tumors and the Raf/MEK/ERK pathway is activated in -30% of all tumors (Bos et. al., Cancer Res. 49:4682- 4689, 1989) (Hoshino et. 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 melanocyte neoplasia (Pollock et. ah. Nature Genetics 25: 1-2, 2002). Furthermore, most recent studies indicate that activating mutation in the kinase domain of b-Raf occurs 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 Research 62:6997-7000, 2002).

[0007] Inhibitors of Raf/MEK/ERK pathway at the level of Raf kinases can potentially be effective as therapeutic agents against tumors with over-expressed and/or mutated receptor tyrosine kinases, activated intracellular tyrosine kinases, tumors with aberrantly expressed Grb2 (an adapter protein that allows stimulation of Ras by the Sos exchange factor) as wcli as tumors harboring activating mutations of Ras or Raf. In the early clinical trials inhibitors of Raf- 1 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). (0008} Disruption of Raf expression in cell lines through the application of RNA anti sense technology has been shown to suppress both Ras and Raf-mediated tumorigenicity (Kolch ct a)., Natυre 349'A 16-428, 1991 ; Monia et al., Nature Medicine 2(6):668-675, 1996).

[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., VS. Pal. 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 6,91 1 ,446). Recently, WO 2009/016460 discloses certain pyrazole compounds said to inhibit Raf and to be useful for treating cancers. There remains a need in the art for additional Raf inhibitors having novel properties.

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 embraces compounds having the formula I:

or a pharmaceutically acceptable sail thereof, wherein:

R^! represents an optionally substituted heteroaryl;

R² represents an optionally substituted heteroaryl group;

R³ represents an optionally substituted aryl group, or an optionally substituted Cj-Cg branched alkyl group, or an optionally substituted Ci-Ca aJkyl group, an optionally substituted heterocyclic group, or an optionally substituted CyCg cycloalkyl group; and

R⁴ represents II, an optionally substituted CrCg alkyl group, or a C^-Q cycloalkyl group. [0Θ12J A preferred embodiment provides a compound of Formula (I):

or a pharmaceutical Iy acceptable salt thereof, wherein:

R¹ represents an optionally substituted 5 to 10 numbered heteroaryl group, wherein one to four ring members of said heteroaryl group arc heleroatoms selected from N, O, and S, and the remaining ring members are carbon atoms;

R² represents an optionally substituted S to 10 membered heteroaryl group wherein said heteroaryl group contains one to three heteroatoms selected from N, O, and 8 as ring members, and the remaining ring members are carbon atoms;

R³ represents an optionally substituted 6 to 10 membered aryl group, an optionally substituted CrC₆ branched alkyl group, an optionally substituted Cj-C₈ cycloalkyl group, or an optionally substituted Ci-C₁S alkyl group; and

R⁴ represents 11, an optionally substituted Cj-C₆ cycloalkyl group, or an optionally substituted CrCe alkyl group.

[00131 A further preferred embodiment provides a compound of Formula I, wherein, R¹ represents an optionally substituted heteroaryl group, selected from pyra/.olo pyridinyl, pyrimidinyl, pyrazinyi, and pyridinyl; and R² represents an optionally substituted heteroaryl selected from pyridinyl, pyrimidiny], nyridaziny], tetrazinyl, triazinyl, pyrrolyl, or pyra/olyl. Another preferred embodiment provides a compound of Formula I, wherein R³ represents an optionally substituted phenyl group, an optionally substituted C₃-Q cycloalkyl group, an optionally substituted Ci'C_f, branched alkyl group, or an optionally substituted Cj-Ca alkyl group; and R⁴ represents H, or an optionally substituted C1-C4 alkyl group.

[0014} A further preferred embodiment provides a compound of Formula 1 wherein R¹ represents optionally substituted

wherein X, independently at each occurrence, represents N, or CH; R² represents optionally substituted

wherein X, independently at each occurrence, represents N, or CJ I; and

R" represents (CM₂)LjR" , (CHOi-J-CH(OH)-R²³, (CH₂)o.₃C(0)R²³, (CH₂),o-OR", (CH₂) I- ,-NH-C(OHCH₂)LjOR²³, (CH₂)LrNH-C(O)-R²³, (CH₂)M-C(O)- NM-(CH_s)_t.₃θR²³, (CHj)_M- C(O)NH-R²³, or an optionally substituted 5-6 membered heterocyclic group; and where each R²³ is independently H OrCi-C₄ alkyl.

[0015] Preferrably R³ represents an optionally substituted phenyl group, wherein said optional substituents are selected from halogen, CFj, OCF₃, C₁-C₄ alkoxy, helerocycly), helerocyclyloxy, Cs-C₆ heteroar>'l, Cj._? alkyl, and CV₆ branched alkyl, where each alkyl, alkoxy, heterocyclyl, heterocyclyloxy, and heteroaryl is optioπaily substituted; or R³ is an optionally substituted alkyl group selected from methyl, ethyl, propyl, isopropyl, t-butyl, Cy₆ cycloalkyl, and C₃-₆ branched alkyl.

[0016] A particularly preferred embodiment of the present invention provides a compound of Formula I wherein, R^J represents a pyridyU or a pyrazinyl group, wherein each said pyridyl and pyraziinyl is substituted with an amino group and a methoxy group; R² represents a pyridyl, or a pyrimidinyl group, wherein each said pyridyl and pyrimidinyl, is substituted with an amino group of the formula -NHR¹³; R" represents (CH₂) _WR²³, (Cl I₂) _LrCH(OH)-R²³, C(O)R²³, (CH₂)_L3-OR²³, an optionally substituted 5-6 membered heterocyclic group, (CH₂)_I-J-NH-C(OHCH₂)LSOR²³, or (CH₂)u-NH-C(O)-R²\ wherein each R²³ is independently H or Ci-C₄ alkyl; R³ represents a CM alkyl, t-butyl, cyciopropyi, i-propyl, CFj, or a phenyl group optionally substituted with halo; and R⁴ represents H, or methyl.

[0017] Preferred compounds of the present invention are selected from compounds listed below:

armaceutically acceptable salt thereof.

[0018] Another aspect of the present invention provides a compound of Formula ! I :

Or a pharmaceutically acceptable salt thereof, wherein:

Z¹ and /} are each independently N, Cl], or CD;

R³ is optionally substituted phenyl, or a C₁-C₆ hydrocarbyl group;

R* U NHR'*. where R¹⁴ is H or optionally substituted C₁-C₆ alkyU

K¹ is H, D, halo, optionally substituted amino or optionally substituted C₁-Cj alkoxy; and R¹⁰ is NIJR¹⁵, wherein R¹⁵ is selected from the group consisting of optionally substituted Cr C(J alkyi, optionally substituted heterocyclyl, -C(O)R²⁵, optionally substituted C₃-C₆ eycloalkyl, optionally substituted amino, optionally substituted aryl, and optionally substituted heteroaryl; and R²⁵ is H or optionally substituted Ci -O alkyl.

[0019] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of Formula I or Formula II, admixed with at least one pharmaceutically acceptable excipient.

[0020] A preferreed embodiment provides a pharmaceutical composition wherein the excipient is selected from the group consisting of com starch, potato starch, tapioca starch, starch paste, pre-gelalinized starch, sugars, gelatin, natural gums, synthetic gums, sodium alginate, alginic acid, tragacanth, guar gum, cellulose, ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyleellulose, methyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium aluminum silicate, polyvinyl pyrrolidone, talc, calcium carbonate, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, agar-agar, sodium carbonate, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycol ate, clays, sodium stearate, 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, com oil, soybean oil, zinc stearate, sodium oleate, ethyl oleate, ethyl laureate, silica, and combinations thereof. A further preferred embodiment provides a pharmaceutical composition further comprising an additional therapeutic agent.

[0021 J Another preferred embodiment provides a pharmaceutical composition wherein the additional therapeutic agent is selected from an anticancer compound, an analgesic, an antiemetic, an antidepressant, and an anti-inflammatory agent.

[0022] Another aspect of the present invention provides a compound of Formula I for the treatment of cancer. A preferred embodiment of this avspect provides the use of a compound of Formula I, wherein the cancer to be treated is selected from the group consisting of lung carcinoma, pancreatic carcinoma, bladder carcinoma, colon carcinoma, myeloid disorders, prostate cancer, thyroid cancer, melanoma, and adenomas. [0023] Provided in another aspect of the present invention is a method to treat cancer, comprising administering to a subject in need of such treatment an effective amount of a compound of Formula ! or 11, or a pharmaceutical composition of any one of a compound of Formula I or Formula II, A preferred embodiment of this aspect provides a method to treat cancer, wherein the cancer is selected from the group consisting of lung carcinoma, pancreatic carcinoma, bladder carcinoma, colon carcinoma, myeloid disorders, melanomas, and adenomas.

[0024] Another aspect of the present invention provides a method to treat cancer, further comprising administering to the subject an additional therapeutic agent. A further preferred embodiment provides a method wherein the additional therapeutic agent comprises an anticancer drug, a pain medication, an antiemetic, an antidepressant or an anti-inflammatory agent.

[0025] Provided in yet another aspect of the present invention is a method of treating cancer, comprising administering to a subject in need of such treatment an effective amount of a compound of Formula I or H, or a pharmaceutical composition of any one of a compound of Formula I or Formula H and an additional agent, wherein the additional therapeutic agent is a different Raf kinase inhibitor or an inhibitor of MEK, mTOR, 1M3K, CDK9, PAK, Protein Kinase C, a MAP kinase, a MAPK Kinase, or EiRK. A preferred emnbodiment provides a method wherein the additional therapeutic agent is administered to the subject concurrently with the compound of Formula I or II.

[0026] Yet another aspect of the prresent invention provides a method to treat a condition mediated by Raf kinase, comprising administering to a subject in need thereof an effective amount of a compound of Formula I or Formula I, or a pharmaceutical composition according to any one said compounds. A preferred embodirπentprovides a method wherein the Raf kinase is a mutant b-Raf kinase, and particular wherein (he mutant b-Raf kinase is b-Raf.

[0027] In certain embodiments of the present invention are provided formulations comprising an effective amount of a compound of any one of the compounds described herein and a pharmaceutically acceptable carrier.

[0028} 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 analgesic, an antiemetic, an antidepressant, an anti-inflammatory agent, a different Raf kinase inhibitor, an inhibitor of MEK, mTOR, PDK, CDK9_> PAK, Protein Kinase C, & MAP kinase, a MAPK Kinase, ERK, irinøtecan, løpotecan, gemcitabine, 5-fϊuorouraciI, leucovorin, carboplatin, cisplatin, oxalipiatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracycHnes, rituximah, and trasluzumab,

[0029] In certain embodiments of the present invention, the additional therapeutic agent is administered to the subject concurrently with the compound.

[00301 In another aspect of the present invention are provided methods for the treatment or prevention of a condition mediated by Raf kinase, comprising administering to a subject in need thereof an effective amount of any of the compounds or pharmaceutical compositions described herein. In some variations, the Raf kinase is a mutant b-Raf kinase.

[(10311 In another aspect of the present invention is any one of the compounds described herein for use as a medicament, or for the manufacture of a medicament, or use of a compound as described herein as a medicament for treating cancer.

[0032] In another aspect, the present invention includes the use of one or more of any one of the compounds described herein for the manufacture 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

Abbreviations and Definitions

[0033] Where linking groups are specified by their 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 left, e.g., -CH₂O- is intended to include -OCHs- for this purpose only.

[00341 The term "alkyl," by itself or as part of another substhuent, 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 {ie, Ci-Ci₀ means one to ten carbons). Eϋamptes include, but are not limited to, groups such as methyl, ethyl, n-propyl, ispprøpvϊ, n-butyl, t-butyl isofπityl, sec-butyl, bomσløgs and isomers of, for example, a-perrtyl, n- hexyl, n-heptyl, n-octyl, and the like. If no size is designated, the alkyl groups mentioned herein contain 1-10 carbon atoms, typically 1 -8 carbon atoms, and often 1-6 or 1 -4 carbon atoms.

(003S] The phrase refers to C₃.κ alkyl groups, including but not limited to, -CH(CHs)₂, -CH(CH₃XCl I₂CH₃), -CH(CH₂CHj)₂, -C(CH₃)J, -C(CH₂CH₃)* -CH₂CH(CHJ)₂, -CHJCH(CH₃XCH₂CH₃), -CHICH(CH₁CH₃)I, -CH₂C(CHOJ, -CH₂C(CH₂CHJ)₃, -CH(CH₃)- CH(CH₃)(CI I₂CH₃), -CH₂CH₂CH(CHJ)₂, -CH₂CH₂CIl(CIiO(CIl₂CH₃), -CH₂CHJCH(CH₂CHJ)₂, -CH₃CH₂C(CHOJ, -CH₂CH₂C(CH₂CHJ)₃, -CH(CH₃)CH₂CH(CHS)₂, -CH(CHOCH(CH₃)CH(CHS)₂, -CH(CH₂CHJ)CH(CH₃)CH(CH₃)(CH₂CHO, and the like.

[0035] [1⁾012] As used herein, the term "alkoxy" refers to alkyl-O-, wherein alkyl is defined herein above. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, btrtoxy, ter/-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- and the like. Typically, alkoxy groups have about 1-7, more preferably about 1-4 carbons.

[0036] As used herein, the term "cycloalkyl" refers to saturated or unsaturated monocyclic, bicyciic or tricyclic hydrocarbon groups of 3-12 carbon atoms. Unless otherwise provided, cycloalkyl refers to cyclic hydrocarbon groups having between 3 and 9 ring carbon atoms or between 3 and 7 ring carbon atoms, each of which can be optionally substituted by one, or two, or three, or more substituents independently selected from the group consisting of alkyl, halo, oxo, hydroxy, alkoxy, alkyl-C(O)«, acylamino, carbamoyl, alkyl-NH-, (alkyl)₂N-, thiol, alkyl-S-, nitro, cyano, carboxy, alky 1-0-C(O)-, sulfonyl, suifonαmido, sulfamoyl, and heterocyclyl. Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclσpentenyl, cyclohexyl and cyclohexenyl and the like. Exemplary bicyciic hydrocarbon groups include borπyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydrønaphthyl, bicyclo[2.U]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2, 1 ]hcptenyl, 6,6-dhnethylbicycIo[3, 1.1 ]heptyl, 2,6,6- trimethylbicyclo[3.1.1 jheplyl, bicyclol2.2.2]octyl and the like. Exemplary tricyclic hydrocarbon groups include adamantyl and the like.

[0037] The term "aryl" means, unless otherwise stated, an aromatic hydrocarbon group which can be a single ring or multiple rings (e.g., from 1 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 described as a heteroaryl group, and a phenyl ring fused to a heterocyclic ring is described herein as a heterocyclic group. Examples of aryl groups include, but are not limited to, phenyl, 1-naphlhyl, 2- naphthyl, tetrahydronaphthyl and the like.

(0038) The term "heteroaryl" as used herein refers to groups comprising a single ring or two or three fused rings, where at least one of the rings is an aromatic ring that contain from one to four heteroatoms selected from N, O, and S as ring members (i.e., it contains at least one heteroaromatic ring), wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaiernized. A heteroaryl group can be attached to the remainder of the molecule through an annular carbon or annular hetcroatom, and it can be attached through any ring of the heteroaryl moiety, if that moiety is bicycHc or tricyclic. Heteroaryl may contain fused rings, wherein one or more of the ήngs is optionally cycloalkyl or heterocycloalkyl or aryl, provided at least one of the rings is a heteroaromatic ring. Non-limiting examples of heteroaryl groups are l-pyrrolyl, 2-pyrrolyl, 3-pyrroIyl, 3-pyrazoIyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazoJy), 2-phenyl-4- oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazoIyl, 5-isoxazolyl, 2-thiazolyI, 4-thiazolyl, 5-thiazoIyi, 2- furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyI, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5- benzαthiazolyl, purinyl, 2-henzirnidazolyi, 5-indolyl, 1 -lsoquinolyl, 5-isoqu.inolyi, 2-quinoxaHnyl, 5- quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

[0039] Aryl or heteroaryl groups commonly contain up to four substituents per ring (0-4), and sometimes contain 0-3 or 0-2 subslituents. The terms "aryloxy" and "heteroarylnxy" refer to aryl and heteroaryl groups, respectively, attached to the remainder of the molecule via an oxygen linker (-O-),

[0040] 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 monohaloalkyt and perhaloalkyl. For example, the term "halo(Ci- C4)alkyl" is meant to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4- chlorobutyl, 3-bromopropyl, and the like. The prefix "perhalo" refers to the respective group wherein all available valences are replaced by halo groups. For example ^ltperhaloalkyl" includes -CCb, -CF₃, -CCl₂CF₃* aiϊd the like, The terms "perfluøroalkyF mi "perehlotόalkyr'ate a subsets of perhaJoalkyl wherein all available valences arc replaced by fluoro and chloro groups, respectively. Non limiting examples of perfluoroalkyl include -CF₃ and -CF2CF₃. Non limiting examples of perchloroalkyl include -CCl₃ and -CCI₂CCIi.

[(HHi ] [00131 "Amino" refers herein to the group -NH₂ or -NRR', where R and IV are each independently selected from hydrogen or an alkyl (e.g, lower afkyl).

10042) 10014] 'Treat", Seating" and "treatment" refer to a method of alleviating or abating a disease and/or its attendant symptoms.

[0043] [0015] The term "compounds of the present invention" (unless specifically identified otherwise) refer to compounds of Formula (I), prodrugs thereof, pharmaceutically acceptable salts of the compounds, and/or prodrugs, and hydrates or solvates of the compounds, salts, and/or prodrugs, as well as, all stereoisomers (including diastereoisomers and enantiomers), taulorπers and isotopically labeled compounds

[0044] The terms "co-administration" or "combined administration" or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.

[0045] [0016] The term "pharmaceutical combination" or "pharmaceutical composition" as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term 'Tixed combination" means that the active ingredients, e.g. a compound of Formula I or Forrayula H and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination'* means that the active ingredients, e.g. a compound of Formula I or Formula 11, and a co-agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of 3 or more active ingredients. [0046] unless otherwise stated, each radical/moiety described herein (e.g., "alkyi," "cycloalkyl," "heterocycloalkyl," "aryl," "heieroaryl," "alkoxy," etc.) is meantto include both substituted and unsubstituted forms.

[0047] 'Optionally substituted" as used herein indicates thai the particular group or groups being described may have no non-hydrogen substituents (i.e., it can be unsubstituted), or the group or groups may have one or more non-hydrogen substhuents. If not otherwise specified, the total number of such substituents 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 0"O)₁ the group takes up two available valences on the group being substituted, so the total number of subslituents that may be included is reduced according to the number of available valences. Suitable substituent groups include, for example, hydroxy], nitro, amino, imino, cyano, halo, thio, suhbnyl, thioamido, amidino, imidino, oxo, oxamidino, melhoxamidino, imidino, guanidino, sulfonamide, carboxyl, formyl, loweralkyl, loweralkoxy, loweralkoxyalkyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, aralkylcarbonyl, carbonylamino, heteroarylcarbonyl, heteroaralkyl- carbonyl, alkylthio, aminoalkyl, cyanoalkyl, aryl and the like. Deuterium, when introduced into a compound at levels at least 5x above natural abundance, can also be considered a substituent for purposβvS 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 (H) in addition to other substituents and should not be counted in the numerical limitations that apply to other substituents.

[0048} A substituent group can itself be substituted by the same groups described herein for the corresponding type of structure. The group substituted onto the substituted group can be carboxyl, halo, nitro, amino, cyano, hydroxyl, loweralkyl, loweralkenyl, loweralkynyl, loweralkoxy, aminocarbonyl, -SR, thioamido, -SOjH,, -SO₂R or cycloalkyl, where R is typically hydrogen or loweralkyl.

[0049} When the substituted substituent includes a straight chain group, the substituent can occur either within the chain (e.g., 2-hydroxypropyl, 2-aminobutyl, and the tike) or at the chain terminus (e.g., 2«hycfroxyethyl, 3-cyanopropyl, and the like). Substituted substituents can be straight chain, branched or cyclic arrangements of cøvalently bonded carbon or heteroaloms (N, O or S). fO<H50] Alkyi groups are often substituted to the extent that such substitution makes sense chemically. Typical substituents include, but are not limited to, halo, D, ^!!!O, ^!!!N-CN, -N-OR, -NR, OR, NR₂, SR, SO₂R, SO₂NR₂, NRSO₂R, NRCONR₂, NRCOOR, NRCOR, CN, COOR, CONR₂, OOCR, COR, and NO₂, wherein each R is independently H, C1-C8 alky], C2-C8 heteroalkyl, Cl-CS acyl, C2-C8 heteroacyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heleroalkynyl_J C6-C 10 aryl, or C5-C10 heteroaryl, and each R is optionally substituted with halo, ^«O, "N-CN, «N- 0R^!, *NR\ OR', NR'_2J SR', SO₂R', SO₂NR '₂, NR¹SO₂R^*, NR'CONR'j, NR'COOR', NIVCOR', CN, COOR', C0NR'_3s OOCR', COR', and NO₂, wherein each R' is independently H₁ D, C1-C8 alkyl. C2-C8 heteroalkyl, C I-C8 acyl, C2-C8 heteroacyl, C6-C I O aryl or CS-C 10 heteroaryl. Alkyl, alkenyl and alkynyl groups can also be substituted by CI-C8 acyl, C2-C8 heteroacyl, C6-CI0 aryl or C5-C 10 heteroaryl, each of which can be substituted by the substituents that are appropriate for the particular group,

[0051] As used herein, "isomer" includes all stereoisomers of the compounds referred to in the formulas herein, including enantiorners, diastereomers, as well as all conforrners, rotamers, and tautomers, unless otherwise indicated. The invention includes all enantiomβrs of any chiral compound disclosed, in cither substantially pure lεvorotatory or dextrorotatory form, or in a racemic mixture, or in any ratio of enantiomers. For compounds disclosed as an (Λ)-enantiomer, the invention also includes the (,S>enaMio.mer; for compounds disclosed as the (S)-enantiomer, the invention also includes the (/f)-enantiomer. The invention includes any diastereomers of the compounds referred to in the above formulas in diastereomericaliy pure form and in (he form of mixtures in all ratios.

[0052] Unless stereochemistry is explicitly indicated in a chemical structure or chemical name, the chemical structure or chemical name is intended to embrace all possible stereoisomers, conformers, rotamers, and tautømcrs of the compound depicted. For example, a compound containing a chiral carbon atom is intended to embrace both the (Zf) enantiomer and the (S) enantiomer_* as well as mixtures of enantiomers, including racemic mixtures: and a compound containing two chiral carbons is intended to embrace all enantiomers and diastereomers (including (/.,Λ), (S,S), (R£% and (RJ?) isomers).

(0053] In all uses of the compounds of the formulas disclosed herein, the invention aiso includes use of any or all of the stereochemical, enantiomeric, diastereomeric, conformational, rotomeric, tautomeric, solvate, hydrate, polymorphic, crystalline form, non-crystalline form, salt, pharmaceutically acceptable salt, metabolite and prodrug variations of the compounds as described.

[0054J The invention includes ail salts of the compounds described herein, as well as methods of using such salts of the compounds. The invention aiso 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. The desired salt 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, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, hippuric, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, sulfonic acids, and salicylic acid. The desired salt of an acidic functional group of a compound can be prepared by methods known to lhose 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. Examples of organic salts of acid compounds include, but are not limited to, procaine, dibenzylamine, N-ethytpiperidine, N.N'-dibenzylethylenediamine, and triethylamine salts.

[0055] Pharmaceutically acceptable metabolites and prodrugs of the compounds referred to in the formulAs herein are also embraced by the invention. The term "pharmaceutically acceptable prodrugs" as used herein refers to thαse prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment_* suitable for use in contact with, the tissues of commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwhterionic forms, where possible, of the compounds of the invention, The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. Λ thorough discussion is provided in T. Higuchi and V. Stella, PRO-DRtJOS ΛSNOVKL DFXIVER Y SYSTEMS, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., BIOREVBRSIBLE CARRIERS IN DRUG DESIGN, American Pharmaceutical Association and Pergamon Press, 1987.

[0056] The invention further provides dcuterated versions of the above-described compounds. As used herein, "deuterated version" refers to a compound in which at least one hydrogen atom is enriched in the isotope deuterium beyond the natural rate of deuterium occurrence. Typically, the hydrogen atom is enriched to be at least 50% deuterium, frequently at least 75% deuterium, and preferably at least about 90% deuterium. Optionally, more than one hydrogen atom can be replaced by deuterium. For example, a methyl group can be deuterated by replacement of one hydrogen with deuterium (i.e., it can be -CHjD), or it can have all three hydrogen atoms replaced with deuterium (i.e., it can be -CD*). )n each case, D signifies that at least 50% of the corresponding Fi is present as deuterium.

[0057] 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 the condition and/or adverse effect attributable to the condition. Therapeutically effective amounts of the compounds of the invention generally include any amount sufficient to detcctably inhibit Rafactivity by any of the assays described herein, by other Raf kinase activity assays known to those having ordinary skill in the art or by detecting an inhibition or alleviation of symptoms of cancer,

(0058] As used herein, the term ''pharmaceutically acceptable carrier," and cognates thereof, refers to adjuvants, binders, diluents, etc. known to the skilled artisan that are suitable for administration to an individual (e.g., a mammal or non-mammal). Combinations of two or more carriers are also contemplated in the present invention. The pharmaceutically acceptable earrier(s)

I. coi route coadministration (e.g., oral, parenteral) for a particular dosage form. Such suitability will be easily recognized by the skilled artisan, particularly in view of the teaching provided herein. Pharmaceutical compositions described herein include at least one pharmaceutically acceptable carrier or excipient; preferably, such compositions include at least one carrier or excipient other than or in addition to water.

[0059] As used herein, the term "pharmaceutical 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 agent(s) 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 herein (e.g., cancer)) or, the pharmaceutical agent may be intended to treat or prevent a symptom of the underlying condition (e.g., tumor growth, hemorrhage, ulceration, pain, enlarged lymph nodes, cough, jaundice, swelling, weight loss, cachexia, sweatings anemia, paraneoplastic phenomena, thrombosis, etc.) or to further reduce the appearance or severity of side effects of administering a claimed compound,

[0060] 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 kinase can be produced in vitro or in vivo. In some embodiments, the Ilaf inhibitor compound reduces or eliminates the activity of Raf Kinase in a reversible or irreversible manner, f n .some embodiments, the Raf inhibitor compound exhibits an IC50 with respect to Raf Kinase activity of no more than about 100 μM and more typically not more than about 50 μM, as measured in the Raf/Mek Amplified Luminescence Proximity Homogeneous Assay described generally hereinbelow. Preferred isofoπns 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-1), "ICV is that concentration of inhibitor which reduces the activity of an enzyme (e.g. , Raf kinase) to half-maximal level. Representative compounds of the present invention have been shown to exhibit inhibitory activity against Raf. In some embodiments, compounds of the present invention exhibit an lCso with respect to Raf of no more than about H) μM, or no more than about 7.5 μM, or no more than about 5 μM, or no more than about 2.5 μM, or not more than about 1 μM, or not marc than about 750 nM, or not more than about 500 uM, or not more 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 nM, or not more than about 5 nM, or not more than about I nM, as measured in the Raf kinase assays described herein.

[0061 j 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, pancreas, thyroid, bladder or coion), myeloid disorders (e.g., myeloid 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 mutated version of b-Raf.

[0062] As used herein and in the appended claims, the singular forms "a", "an" and "the" include plural forms, unless the context clearly dictates otherwise.

[0065] Unless defined otherwise or clearly indicated by context, ail 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.

Raf kinase Inhibitors

JQ064J 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 comouπds 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 of a Raf kinase enzyme.

[0065} In one aspect of the present invention are provided compounds of Formula 1:

or a pharmaceutically acceptable salt thereof, wherein;

R¹ represents an optionally substituted heteroaryl;

R² represents an optionally substituted heteroaryf group;

R³ represents an optionally substituted aryl group, or an optionally substituted CyCs branched alkyl group, or an optionally substituted CrCe alky) group, an optionally substituted heterocyclic group, or an optionally substituted CVCs cycloalkyl group; ami

R⁴ represents H, an optional Jy substituted Ci-Ce alky) group, or a CrCs cycloalkyl group.

[0066} A preferred embodiment provides a compound of Formula (1):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ represents an optionally substituted 5 to 10 membered heteroaryl group, wherein one to four ring members of said heteroaryl group are heteroatoms selected from N, O, and S, and the remaining ring members are carbon atoms;

R² represents an optionally substituted 5 to 10 membered heteroaryl group wherein said heteroaryl group contains one to three heteroatoms selected from N, O, and S as ring members, and the remaining ring members are carbon atoms;

R³ represents an optionally .substituted 6 to 10 membered aryl group, an optionally substituted Cj-C₆ branched alkyl group, an optionally substituted C₃-C$ cycloalkyl group, or an optionally substituted Ci-C₆ alkyl group; and

II⁴ represents H, an optionally substituted CrCs cycloalkyl group, or an optionally substituted Q-C₆ alkyl group.

[0067} In certain embodiments of the compounds of Formula I of Formula II, R¹ is an optionally substituted group selected from dihydropyridooxazmyl, pyrazoiopyridinyl, pynυlo pyridinyl, dihydropyrrolo pyridinyl,, pyrimidinyl, pyrazinyl, and pyridinyl. In certain embodiments, R¹ is an optionally substituted ring system selected from:

wherein X, independently at each occurrence, represents N, or Cl L

[0068] Suitable sυbstituents for the heteroaryl groups represented by ft' include those described herein as generally suitable for heterocyclic groups. In particular, R¹ can be substituted with one or more halo (especially F or Cl), amino and substituted amino, aminocarbonyl, Cl-C 4 alky I, C 1 -CA alkoxy, ™O (oxo, suitable for heterocyclic groups but not heteroaromatic ones), C 1 -CA haloalkyl (e.g._> CF₃), D, -OH, -CN, MeNH-, Me₂N-, acetyl, acetylamino, aminosulfαnyloxy, C1-C4 alkoxycarbonyl, carboxyl, and combinations of these groups. Specific combinations of these groups of particular note include amino with C 1-C4 alkoxy; amino with halo; C 1 »C4 alkoxy with halo, and the like. In some embodiments the heterocyclic ring is a pyridine or pyrazine and the amino group will be located 'para' to the ring position of the heterocyclic ring that is attached to the central ring (imidazole) in Formulas MV. In such embodiments, the C1-C4 alkoxy substituent on the heterocyclic ring can he adjacent to the amino group.

[0069] In some of these embodiments, R¹ is optionally substituted pyridyl or pyrazinyl, including deuterated versions thereof, In certain embodiments, R¹ is optionally substituted 3- pyridyl. In other certain embodiments, R¹ is optionally substituted 2«pyraz;jnyl. R 1 in these embodiments can be substituted with the substituents described below; in some embodiments it is substituted with an amino group, or an alkoxy group such as methoxy; or both an amino group and a methoxy group. fOO7O| For R¹, sometimes 2-amino-3-methoxypyπdin-5-yl or 2-amino-3-methoxypyraxh>5~ yl is preferred.

[0671] fβO17] hi some of these embodiments, R¹ is selected from:

J0072] [0018} R² is optionally substituted heteroaryi; it can be a 5-10 membered ring system containing from one to three heteroatoms selected from N₁0 and S as ring members, and having at least one R² can be an optionally substituted monocyclic ring such as pyridine, pyrimidine, furan, thiophene, thiazole, isothiaxole, oxajsole, isoxazole, pyrazolyl, imidazolyl, and the like. In some embodiments, R² can be an optionally substituted bicyclic group, comprising a phenyl, pyridyj or pyrimidinyi, for example, fused to an additional ring such as cyclopentyl, cyclohexyl, pyrrole, imidazole, pyrazole. piperidinc, and the like; provided one ring of the bicyclic group contains a heteroatom as a ring member and is aromatic. R² can be attached to the base molecule through either ring of a bicycHc moiety, including through phenyl when R² comprises a phenyl ring fused to a heieroaromatic ring. Typical examples of these heteroaryl groups include optionally substituted indole, benzimidazole, indazole, benzofuran, benzothiophene, quinoline, isoquinoline, quinoxaline, naphthyridine, benzopyrazole. benzoxazole, benzothiazole, ben/isoxazole, and benzoisothiazole, each of which can be linked to the central ring in Formula I through either ring of these bicyclic R² groups. One example of such bicyclic rings is pyrrolopyridine.

[0073] In certain embodiments, the optional suhstituenls for R² are selected from the group consisting of halo, D, 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 11 or optionally substituted alkyl, and wherein each R" is independently hydrogen or optionally substituted alkyl.

[0074] [00Ϊ9] In some embodiments, R² contains at least one substituted amino group having the formula -NHR^l\ wherein R^u is optionally substituted alkyl or optionally substituted aryl. In certain embodiments, the R^u optionally substituted alkyl group is røt'-butyl, - CR₂CR₂NRC(O)CR₂OCRJ, or

-CR₂CR₂NRCXO)OCRJ, wherein each R is independently hydrogen or C 1 -C6 alkyl, such as -CM₃CH₂NHCfO)CH₂OCH₅, CH₂CH(CH-ONHC(O)CMJOCH₃,

-CHaCH(CH₃)NHC(O)CH(CHj)OCH₃, Or-CI I₂CH(CHj)NHC(O)OCHj and any enantiomers or diastereomers thereof.

[00751 In some embodiments, R² is a group of one of the following formulas:

wherein X, independently at each occurrence, represents N, or CH; and

II¹³ represents (Cltøi-jR²³ , (CH₃)J -J-CH(OH)-R²', (CH₂V₃C(O)R²³, (CH₂)i..-OR²\ (CH₂)i- .,-NH-C(O>(CN_?.),.₃OR²\ (CHa)_W-NM-C(O)-R", (CH₂)_L3-C(O)- Ni-I-(CH₂)_L3OR²³, (CH₂)_U3- C(O)NH-R.²³, or an optionally substituted 5-6 membered heterocyclic group; and where each R²³ is independently H or C1-C4 alkyl.

(0Θ76J [OG20J hi some embodiments, R¹³ is a substituted aryl group, which can be for example -C₆H₄-O-OCH₃, -C₆H₄-W-OCF₃, -C_AH₄-M-CF₃, -C₆HrP-CF₃, or -C₆H₃-W-CF₃-P-Cl. In specific embodiments, R² is pyridyl or pyrimidinyl, and this amino group on R² is at a ring position of R² that is meta to the point where R² is attached to the central imidazole ring of Formula (ϊ).

[0077] In some embodiments, the substituted amino on R² can be selected from acetylamino, 2~hydroxyethylamino, hydroxyacetylamino, acelylaminσethytamino, piperidinylamino, substituted piperidinylamino; or amino substituted with C)-C₄ alkyl, C₃-Cs cycloalkyl (e.g., cyclohexyl, cyclopropyl, cyclohexyl). Cs-C* heterocycloalkyl containing one or two heteroatoms selected from N, O and S as ring members, or phenyl optionally substituted with halo, CpC₄ alkyl, Ci-C* alkoxy; and the like. Specific embodiments of the substituted amino group include 2-methox.yethylarnine, 2- hydroκyethylamine, cyclopropylamine, 2-(hydroxyacetylamino)ethyl, 3-piperidinylamino, l-(4- chlorophenylsuHbnyOptperidine-3-ylamino, l-(4-(2-amino-3-methoxypyridin- 5yl)phenyl)piperidiny-3-y1amino, 2-(methoxyacetylamino)ethylamino, 2-(4- chtorophenylsulfonyl)aminoethylaniino, cyelopropytamino, 2-hydroxypropylamino, 2- (cyclopropylsulfonyl>.minoethylamino, 2-(methylsulfonylamino)ethylamino, 1 - (cycIopropylsuIfonyOpiperidine-S-ylamino, 1 ~(methoxyacetyl)piperidinc-3-y lamino, 1 - (cyclopropylsulfonyOpipcπdine^-ylaminoJsobutylamino, 3-methoxyphenyIammo, isopropylamino, 2-methoxyethylamtno, cyclopentylamino, cyclohexylamino, 2- (methoxyacetylamino)propylamino, 3-trifiuoromethylphenyIamino, 3-fluorophenylamino, methoxybenzylamino, 1 -acetylpyiTOlidin-3-ylamino, 2-(methylsυlfoπylamino)propy]amino, 1 ,2- (difluorodioxolanyl)phen-4-yIamino, 4-trifluoromethylamino, 2-(2~ melhoxypropanoylamino)propylamme, 1 -(methy)suIfonyl)-pyrroHdin-3-ylamino, 2- (methoxyacetylamino>l-methylethylamino_> 2-(2-methopropanoylamhio)-1-methylethylanuno, 2- (triΩυoracetylamino)ethylamino, 2,2,2-trifluorethyIamino, 4-triπuoromelhyIphenylamino, 2-

[meihylaminocarbαtiyIamino)propyIamino_s 4-ch1<>ro-3-lτifluoromethyIamino, 2-m«thoxypyridinyl-4- amino, 2-(methoxycarbon>'lamino)propylamino, 2-(isopropoxycarbonylamino)propylamino, 2- (isobutoxycarbonylamim^propylainino, and 2-(neopenlyloxycarbonylamitio)propylamine>

[0ft78| In some of these embodiments, R² is selected from

J0079J |0(>2!] R³ can be an optionally substituted Ci-C₆ alkyl, an optionally substituted Cj- Ci₆ eycloalkyl, optionally substituted aryl. In some embodiments, R³ is optionally substituted Ci-C₆ alkyl, such as methyl, ethyl, propyl, isopropyl, t-butyl. neopentyl, and the like, or a deuterated version of one of these. These alkyl groups can be substituted with one or more groups, typically one to three groups, selected from oxo ( -O), halo, D, R", OR", COOR", NR"₂, CONR'V CN, Cj-C₆ cycloalkyl, optionally substituted phenyl, and the like; whei« R" is H or C1-C4 alkyl individually at each occurrence, and where NR"? can represent pyrrolidine, piperidϊne,, piperøzme, or morpholtne or aii ©XO" or methyl-substiluted version of one of these heterocycles. In some embodiments, this alkyl is unsubstituted, or is substituted with OR" or NR'Y

[0080] In some embodiments, R³ is cycioalkyl, wherein the cycloaϊkyl can be a 3-66 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; where R" is H or C₁-C₄ alkyl or Ci-C₄ halomethyl individually at each occurrence, and where NR"₂ can represent pyrroHdnvs, piperidine, piperazine, or morpholine or an oxo- or methyl-substituted version of one of these heterocycles. In some embodiments, this cycloalkyl is a 3-8 membered ring. In some embodiments it is a 3-6 membered ring. Frequently, it is substituted with up to three substituents, or is unsubstituted. The cycloalkyl can also contain a carbon-carbon double bond. Examples of suitable cycloalkyls include cyclopropyl, l- cyanocyclopropyl, MrifluoromethylcyclopropyJ, l-chlorocyclopropyl, l-methylcyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclobutyi, and the like.

10081 ] In other embodiments, R³ is unsubstituted phenyl or phenyl substituted with one, two or three substituents. In certain embodiments, the optional substituents on the optionally substituted phenyl represented by R^J are selected from the group consisting of halo, hydroxyl, cyano, tbrmyl, optionally substituted pyridyl, optionally substituted C1-C₆ alkyl, optionally substituted CpC₆ alkoxy, -C(O)OR', -S(O)₂R', -S(O)₂NR^₂, and -C(O)NR"₃, and wherein R' is optionally substituted C1-C4 alkyl and each R" is independently hydrogen or optionally substituted C ₁-C₄ alkyl. Alternatively, the substituents on this phenyl ring can be selected from halogen, Cf-'j, OCF₃, C1-C4 alkoxy, heterocyclyl, heterocyclyloxy, C5-C6 heteroaryl, Ci. j alkyl, and C₃.0 branched alkyl, where each alkyl, alkoxy, heterocyclyl, heterocyclyloxy, and heteroaryl is optionally substituted. Suitable substituents include, for example, 4-ρiperidinyI, l-methyl-4-piperidinyl, 2-dimethylamino)ethoxy, Me, OMe, OCFj, CF₃, CN^-methoxyethoxy, F, Cl, Kt, nPr, OEt, OCH₂OMe, pyrrolidinyloxy, N- methylpyiTolidinyloxy, N-methylpyrroIidinylmethoxy, tetrahydrofuranyloxy, tetrahydropyranyloxy, and the like.

[0082] hi some of these embodiments, R³ is selected from:

[0083] R⁴ in the compounds of Formula I can be H or an optionally substituted C1-C6 alkyJ group. In many embodiments, R⁴ is H. In some embodiments, FV¹ is Me, CF₃, or Et.

II; WO 2010/100127 PCT/EP2010/0S2SS9

wherein Z¹ and 7} are each independently N, CH, or CD;

R³ is optionally substituted phenyl, or a Ci-C₆ hydrocarbyl group;

K⁶ is NHR¹⁴, where R^M is H or optionally substituted Cj-C₆ alkyl;

R⁷ is H_» D, halo, optionally substituted amino or optionally substituted Cj-C₄ alkoxy; and

R^l0 isNHR¹⁵, wherein R¹⁵ is selected from the group consisting of optionally substituted Ci- Cft alkyl, optionally substituted heterocyclyl, «C(O)R^2S, optionally substituted Cj-Q, cycloalkyl, optionally substituted amino, optionally substituted aryl, and optionally substituted heteroaryl; R^2S is H or optionally substituted C]-Q alkyl; or a pharmaceutically acceptable salt thereof.

(0085} These compounds include the pharmaceutical Iy acceptable .salts, and isomers, deuterated versions and tautomers, as discussed above for compounds of Formula (1). In these compounds, R² and R³ and R⁴ can be selected from the specified R² and R³ and R⁴ groups described above for Formula (I).

|OΘ86j In certain embodiments of the compounds of Formula (II), R⁷ is -OMe or a deuterated version of -OMe, such as OCDj. In some embodiments, R⁵ is H. In some embodiments, R⁵ is Deuterium.

[OO87J In certain embodiments of the compounds of Formula (H),, 7.} is CH and R⁵ is H. In other embodiments, Z¹ is N. [00881 In certain embodiments, the compounds of the present invention include any one compound of Table I, or a pharmaceutically acceptable salt, isomer, or solvate thereof; or a deuterated version thereof. In some variations, the compounds of the present invention include any one compound of any subset of compounds of Table 1 , or a pharmaceutically acceptable salt, isomer, or solvate thereof. In some variations, the compounds of the present invention include any one of all the compounds of Table 1 , or a pharmaceutically acceptable salt, isomer, or solvate thereof.

[0089] In certain embodiments, the compounds of the invention include, for example, any one of the compounds in Table 1 herein. Each of the compounds in Table 1 and combinations of these compounds are preferred embodiments of the invention,

(0090J The invention also includes isotopically-labeled compounds, that are structurally identical Io 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 incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as ²H, ³H, ¹⁵C, ¹⁴C, ¹⁵N, ¹⁸0, ¹⁷O, ^J11>, ³²P, ³⁵S, ¹⁸F and ³¹⁵Cl, respectively. Compounds of the present invention, tautomcrs thereof, prodrugs thereof, and pharmaceutically acceptable salts of the compounds and of the prodrugs that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as ³IT and ^MC are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ¹H, and earboπ-14, i.e,, ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectabϋity. These radiolabeled isotopically substituted compounds are useful with quite low amounts of the isotope incorporated, e.g., 0.01% isotopic substitution or more may provide a readily-detectable labeled species. Further, substitution with heavier isotopes such as deuterium, i.e. , ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. For deuterated compounds, it is typically desirable to incorporate at least 20% substitution of D for M; often at least 50% substitution of t) for H; and preferably at compounds of this invention and prodrugs thereof can generally be prepared by carrying out known or referenced procedures and by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0091] 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 (east one compound of the invention as herein described, admixed with at least one pharmaceutically acceptable excipient. In certain embodiments, the excipieπt is selected from the group consisting of corn starch, potato starch, tapioca starch, starch paste, pre~gelatinizcd starch, sugars, gelatin, natural gums, synthetic gums, sodium alginate, aiginic acid, lragacanth, guar gum, cellulose, ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carbσxymethylcellulose, methyl cellulose, hydroxypropyl meihylcellulose, microcrystalline cellulose, magnesium aluminum silicate, polyvinyl pyrrolidone, talc, calcium carbonate, powdered cellulose, dextrates, kaolin, maimitol, silicic acid, sorbitol, agar-agar, sodium carbonate, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, clays, sodium stearate, calcium stcarate, 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, com oil, soybean oil, zinc stearate, sodium oJeale, ethyl oleate, ethyl laureate, silica, and combinations thereof

[0092] In some embodiments, the pharmaceutical composition of the invention further comprises an additional therapeutic agent. Examples of suitable additional therapeutic agents include an anticancer compound, an analgesic, an antiemetic, an antidepressant, and an antiinflammatory agent.

[0093} 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 Raf kinase, comprising administering to a subject in need thereof an effective amount of a 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. [0094] In one embodiment, the compounds of the invention are used for treating cancer or for manufacturing a medicament, which can be a medicament for treating cancer. Specific cancers Io be treated by the compounds or methods of the invention include, but are not limited to, lung carcinoma, pancreatic carcinoma, bladder carcinoma, colon carcinoma, myeloid disorders, prostate cancer, thyroid cancer, melanoma, and adenomas.

[0095] 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, myeloid disorders, melanomas, and adenomas. Treatment can further include 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.

[0096] In certain embodiments, the additional therapeutic agent is a different Raf kinase inhibitor or an inhibitor of MEK, mTOR, PJ3K, CDK9, PAK, Protein Kinase C, a MAP kinase, a MAPK Kinase, or BRK. This additional therapeutic agent can be administered to the subject concurrently with the compound of the invention, or the two can be administered separately but limed so that they act concurrently in the subject's body. In certain embodiments, the additional therapeutic agent is an anticancer drug selected from irinotecan, topotecan, gemcitabine, S- Huorouracil, leucovorin carboplatin, cisplatin, oxalipladn, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, tmatinib, anthracyclmes, rituximab and trasfuzumab.

Conditions Mediated by Raf kinase

10097] Compounds and formulations discussed herein are useful for treatment or prevention of a condition mediated or characterized by Raf kinase, such as cancer. As used herein, "treatment or prevention of a condition mediated by Raf kinase" indicates administering 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 one or more symptoms of the condition, or to retard the progression of the disease or of one or more symptoms of the condition, or to reduce the severity of the disease or of one or more symptoms of the condition.

[0098] In one aspect the present invention provides methods of treating 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 treatment comprising administering to the subject a therapeutically effective amount of a compound one or more of the compounds described herein, either alone or in combination with other anticancer agents.

10099J In other aspects, the present invention provides methods for the treatment or prevention of a Raf related disorders in an individual in need of such treatment or prevention, comprising administering to said subject one or more of the compounds of the invention in an amount effective to reduce or prevent tumor growth in the individual

[0100] Antiestrogens, such as tamoxifen, inhibit breast cancer growth through induction of cell cycle arrest, that requires the action of the cell cycle inhibitor p27Kip. Recently, it has been shown that activation of the Ras-Raf-MAP Kinase 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 a), J. Biol. Chem. 27^:40888, 2001 ). As reported by Donovan et al., inhibition of MAPK signaling through treatment with MEK inhibitor changed the phosphorylation status of p27 in hormone refractory breast cancer cell lines and in so doing restored 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.

(0101} In yet other aspects, the present invention provides compounds which are inhibitors of the enzyme Raf kinase. Since the enzyme is a downstream effector of p21 ^RM, the instant inhibitors are useful in pharmaceutical compositions for human or veterinary use where inhibition of the Raf kinase pathway is indicated, e.g., in the treatment of tumors and/or cancerous cell growth mediated by Raf kinase, 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 inhibiting Raf kinase 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, myeloid disorders (e.g., myeloid leukemia) or adenomas (e.g., villous colon adenoma).

[0102] In yet other aspects, the present invention provides methods for treating or preventing Raf kinase-related disorders in an individual in need of such treatment or prevention, comprising administering to said individual an amount of one 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 arc contemplated for use in the methods of the present invention, indeed, the present invention contemplates, but is not limited to, administration of numerous anticancer agents such as: agents that induce apoptosis; polynucleotides (e.g., ribozymes); polypeptides (e.g., enzymes); drugs; biological mϊmetics; alkaloids; alkylating agents; antitumor antibiotics; antimetabolites; hormones; platinum compounds; monoclonal antibodies conjugated with anticancer drugs, toxins, and/or radionuclides; biological response modifiers (e.g., interferons [e.#, IFN-a, etc.] and interleυkins [e.g., IL-2, etc.], etc.); adoptive immunotherapy agents; hematopoietic growth factors; agents that induce tumor cell differentiation (e.g., all-trans-retinoic acid, etc.); gene therapy reagents; antisense therapy reagents and nucleotides; tumor vaccines; inhibitors of angiogenesis, and the like. Numerous other examples of chemotherapeutic compounds and anticancer therapies suitable for coadministration with the disclosed compounds of the invention are known to those skilled in the art.

[0103] 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., Epidermal Growth Factor Receptor [EOFR] kinase inhibitor, Vascular Growth Factor Receptor [VGFR] kinase inhibitor, Fibroblast Growth Factor Receptor IFGFR] kinase inhibitor, Platelet-derived Growth Factor Receptor [PGFR] I kinase inhibitor, and Bcr-Abl kinase inhibitors such as ST1-57I, Gleevec, and Glivec]); antisense molecules; antibodies [e.g., Herceptin and Rituxan]; anti-estrogens [e.g., raloxifene and tamoxifen]; antϊ-androgens [e.g., fiutamide, bicalutamide, finasteride, amtnoglutethamide, ketoconazole, and corticosteroids]; cyclooxygenase 2 (COX-2) inhibitors [e.g., Celecoxib, meloxicam, NS-398, and nøn-sieroid&i antiinflammatory drags (NSAlDs)U and cancer cjiemothempeutie drugs {e,g., irinotecan (Camptosar), CPT-1 1, fJudarabine (Fludara), dacarba/jne (DTIC), dexamethasone, mitoxantrone, Mylotarg, VP- 16, cJsplatinum, 5-FU, Doxorubicin, Taxotere or taxol); cellular signaling molecules; ceramides and cytokines; and staurosporine, and the like.

[0104] In certain embodiments, a Raf inhibitor compound of the invention can be combined with an inhibitor of MEK, ERK, PI3K, mTOR, or a dual PI3K-mTOR inhibitor. In addition, the compounds may be combined with inhibitors of VEGF, EGFR, FGFR, HER-Z FLT-3_»or HDAC to provide compositions for treatment of certain disorders including cancers described herein,

10105] In yet other aspects, the cancer to be treated is characterized by increased Raf kinase 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-Jlaf kinase. Cancers wherein a mutated Raf kinase has been detected include melanoma, colorectal cancer, ovarian cancer, gliomas, anaplastic thyroid carcinoma, papillary thyroid carcinoma, Barrett's esophageal carcinoma, adenocarcinomas, sarcomas, breast cancer, liver cancer, acute myeloid leukemia, head and neck squamous cell carcinoma, lung cancer, gastric carcinoma, non-Hodgkins lymphoma, and cholangiocarcinoma. Mutated b-Raf kinase is especially prevalent in many melanomas. The mutations in b-Raf that have been detected in human cancers are point mutations that occur in the kinase domain and are clustered in exøns 1 1 and 15 of the gene which contains several regulatory phosphorylation sites. The most prevalent mutation results in a V600B mutation in b-Raf. The V600E mutation was formerly designated V599E due to an error in the GenBank nucleotide sequence. Beeram, et al._s Journal pf Clinical Oncology (2005), 23(27):677I-6790 and U.S. Pat. Application Nos. 20080176840, 20060293340, and 20060079494. In some embodiments, the invention thus provides a method to treat a condition mediated by the mutated b-Raf, (V600lr!).

Formulations

|0i 06} The compounds described herein can be in formulations (including pharmaceutical compositions) by formulation with additives such as excipicnts (e.g., one or more excipients), antioxidants (e.g., one or more antioxidants), stabilizers (e.#, one or more stabilizers), preservatives (fcg, one or more preservatives), jβi adjusting and buffering agents fag., one or mm p\i adjustiβg and/or buffering agents), tonicity adjusting agents (e.g., one or more tonicity adjusting agenls), thickening agents (e.g., one or more thickening agents), suspending agents (<?,&, 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 pharmaceutically acceptable for the particular condition to be treated. In some embodiments, the formulation may include combinations of two or more of the additional components as described herein (β.g, 2, 3, 4, 5, 6, 7, 8, or more additional components). In some embodiments, the additives include processing agents and drug delivery modifiers and enhancers, such as, for example, calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl-β-cyclodextrin, 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 PHARMACEUTICAL SCIENCES, Mack Pub. Co., New Jersey (1991), and REMINGTON: THE SOBNCE AND PRACTICE OF PHARMACY, Uppincott Williams & Wilkins, Philadelphia, 20th edition (2003) and 21st edition (20Q5).

[0107] Some exemplary excipients may include corn starch, potato starch, tapioca starch, starch paste, pre-gelatinized starch, sugars, gelatin, natural gums, synthetic gums, sodium alginate, alginic acid, tragacanth, guar gum, cellulose, ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxypropyl methy .cellulose, microcrystalline cellulose, magnesium aluminum silicate, polyvinyl pyrrolidone, talc, calcium carbonate, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, agar- agar, sodium carbonate, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, clays, sodium stearate, 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 stearate, sodium oieate, ethyl oleate, ethyl laureate, silica, and combinations thereof. 10108] 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.

[0109] 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 Co about 7.0, from about 6.0 to about 7.0.

Administration and Dosage

[OHO] 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 agents 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 underlying 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.

[0111] While the compounds of the invention can he administered as the sole active pharmaceutical agent in a formulation, they can also be used in combination with one or more other agents used in the treatment of cancer. Representative agents useful in combination with the compounds of the invention for the treatment of cancer include, for example, irinotecan, topotecan, gemcitabine, 5-tluorouracil, leucovorin carboplatin, cisplatin, oxaliplatin, taxancs, tezacitabine, cyclophosphamide, vinca alkaloids, imatimb (Gleevec), anlhracyclines, rituximab, trastuzumab, as well as other cancer chemolherapeutic agents.

[0112] The above compounds Io be employed in combination with the compounds of the invention wilt be used in therapeutic amounts as indicated in the PHYSICIANS' DKSK REFERENCE (PDR) 47th Iϊdition (1993), or such therapeutically useful amounts as would be known to one of ordinary skill ϊn the art. [0113] 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 he varied so as to obtain a desired therapeutic response depending on the route of administration, severity of the disease and the characteristics and response of the patient. The combination can be administered as separate compositions or as a single dosage form containing both agents. When administered as a combination, the therapeutic agents can be formulated as separate compositions, which are given at the same time or different times, or the therapeutic agents, can be given as a single composition.

[0114] As will be well appreciated by the skilled artisan, for particular conditions, different pharmaceutical agents) and/or additional treatment modality(ies) may be indicated.

[⁽1115J 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 treatments {e.g., adjunctive therapy with additional pharmaceutical agents described herein with reference to pharmaceutical formulations of the claimed compounds or known to the skilled artisan) used to treat or prevent the condition being treated/prevented 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 term "additional treatment modality" refers to treatment/prevention of the conditions described herein without the use of a pharmaceutical agent (e.g., surgery, radiotherapy, etc.). Where combinations of pharmaceutical agent(s) and/or additional treatment modality(ies) are used, they may be, independently, administered prior to, concurrently with, or after administration of one or more of the quinuclidine compound(s) (or formulation(s) thereof) as described herein.

[0116] The optimal combination of one or more additional treatment modalities and/or additional pharmaceutical agents in conjunction with administration of the formulations described herein, can be determined by an attending physician or veterinarian based on the individual and taking into consideration the various factors effecting the particular individual, including those described herein. I© J 17} The formulations described herein will generally be used in an amount effective to achieve the intended result, for example in an amount effective to treat or prevent the particular condition 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 feeling or condition, notwithstanding that the individual may still be afflicted with the underlying condition. Therapeutic benefit also includes halting or slowing the progression of the condition, regardless of whether improvement is realized.

[0118] The amount of the formulation administered in order to administer an effective amount will depend upon a variety of factors, including, for example, the particular 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.

[0119] The compounds of the invention may be administered enterally (e.g., orally or rectally), parenterally (e>g,, subHngually, 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, subcutaneous, transdermal, trammucosal, 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. For delivery to the central nervous system, spinal and epidural administration, or administration to cerebral ventricles, can be used. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrastemal injection, or infusion techniques.

[0120] The compounds may be mixed with pharmaceutically acceptable carriers, adjuvants, and vehicles appropriate lor 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 for use herein can be administered in solid form, in liquid form, in aerosol form, or in the form of tablets, pills, powder mixtures, capsules, granules, mjectables, creams, solutions, suppositories, enemas, colonic irrigations, emulsions, dispersions, food premixes, and in other suitable forms. The route of administration may vary according to the condition to be treated. Additional methods of administration are known tnthe art.

[0121] Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent 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. hi the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.

[0122] [0022] 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,

[Θ.123J The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes arc 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 formulations in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. Suitable lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescort, Ed., METHODS IN CKIX BIOIXXW, Volume XIV, Academic Press, New York, N. W., p. 33 et xeq (1976).

(0124} The compounds 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. Bυndgaard, DESIGN OF PRODRUGS, New York: Elsevier, 1985; in R. Silverman, THE ORGANIC CHEMISTRY OF DRUO DESIGN AND DRUG ACTION, Boston: Eilsevier, 2004; in R.L. Juiiano (ed.), BIOLOGICAL APPROACHES TO THK CONTROLLED DBMVKRY OF DRUOS (Annals of the New York Academy of Sciences, v. 507)_» New York: New York Academy of Sciences, 1987; and in E.B. Roche (ed,),

DKSICiN OF BfOPHARMACHUTICAI.. PROPERTIES THROUGH PRODRUGS AND ANALOGS (Symposium sponsored by Medicinal Chemistry Section, APhA Academy ofPharmaceulical 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.

[0125] The frequency and duration of administration of the foπnulation will depend on the condition being treated, the condition of the individual, and the iike. The formulation may be administered to the individual one or more times, for example, 2, 3, 4, 5, 10, I 5, 20, or more times. The formulation may be administered to the individual, for example, once a day, 2 times a day, 3 times a day, or more than 3 times a day. The formulation may also be administered to the individual, for example, less than once a day, for 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.

[0126] The amount of active ingredient that may 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 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 (BMI), 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 pharmaceutical unit dosage chosen is usually fabricated and administered 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 and judgment of the ordinary clinician.

[0127] Examples of dosages which can be used are a therapeutically effective amount within the dosage range of about 0.1 μg/kg to about 300 mg/kg, or within about 1.0 μg/kg to about 40

1.0 ug/kg to about 20 mg/kg body weight, or within about 1.0 μg/kg to about 10 mg/kg body weight, or within about 10.0 μg/kg to about 10 mg/kg body weight, or within about 100 μg/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 SO mg/kg to about 150 mg/kg body weight, or within about 100 mg/kg to about 200 rηg/kg 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. I mg/kg body weight, about 1 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 may be administered in a single dally dose, or the total daily dosage may be administered in divided dosage of two, three or four times daily.

[0128] [0023] 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. In other embodiments, 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 and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for performing any methods described herein.

[0129] 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,

[0130] In certain embodiments the kits may include a dosage amount of at least one formulation as disclosed herein. Kits may also comprise a means for the delivery of the formulation thereof. Synthetic Methods

[0131] Compounds of the invention may be prepared using a number of methods familiar to one of skill in the art. The discussion below is offered to illustrate certain of the diverse methods available for use in assembling the compounds of the invention. However, the discussion is not intended to define the scope of the reactions or reaction sequences that arc useful in preparing compounds of the invention.

[0132] Preparative separations are carried out using a CombiFlash Rf s'ystem (TeJedyne Isco Inc. Lincoln, NE) in combination with RediSep Normal-Phase Silica Flash Columns (4 g -120 g, 35- 70 micron particle size; Teledyne Isco Inc.), or by flash column chromatography using silica gel (230-400 mesh) packing material, or by HPLC using a Waters 2767 Sample Manager, C- 18 reversed phase column, 30X50 mm, flow 75 mL/min, Typical solvents employed for the CombiFlash system and flash column chromatography are dichloromethane, methanol, ethyl acetate, hexane, acetone, aqueous ammonia (or ammonium hydroxide), and trielhyl amine. Typical solvents employed for the reverse phase HPLC are varying concentrations of acetonitrile and water with 0.1% triftuoroacetic acid. Microwave reactions conducted in a Creator or Initiator microwave system (Biotage, Charlottesville, VA)

Examples

[0333} The present invention will be understood more readily by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention.

Scheme 1

STEP 1

[0134] To solution of 4-phenylimidazole (SMlA, 0,721 g, 5.0 mmol) in anhydrous DMF (5 ml) at 0 °C was added NaM (0.26 g, 60% in mineral oil, 6.5 mmol). The mixture was stirred at such temperature for lOminutes, then at ambient temperature for additional 1 hour, then cooled back to 0 °C followed by addition of 4-chloro-2-(methylthio)pyrϊmidine (SMlB, 0.803 g, 5.0 mmol). The reaction mixture was stirred al 0 °C for 30 minutes and quenched with water (0.2 ml). The quenched mixture was concentrated and residue was partitioned between BtOAcZM₂O (30 ml/20 ml). HtOAc layer was collected, sequentially washed with HaO (20 ml), brine (20 ml), dried over anhydrous Na₂SU4, concentrated and crude residue was purified with flash chromatography on silica gel eluted with gradient EtQAc/hexanes (0400%) to yield compound Il A, as a light yellow solid (1.32 g_* 4.92 tamd, yield 984%), LCMS (wfe): 269.0 (MH-*), K*: Q,?5 min. STEP 2

[0135J Compound II A (0.2932 g, 1.093 nunol) in THF (5 ml) was mixed with N- bromosucemimide (0.43 Ig, 2.42 mmol) at 0° C. The resulting mixture was warmed to ambient temperature and stirred overnight. The stirred reaction mixture was concemrated,and the crude residue was purified with flash chromatography on silica gel eϊuted with gradient EtOAc/hexanes (0- 50%) to yield HB as a light yellow solid (0.123 g_s 0.289 mmol, yield 26.4%). LCMS (m/z): 426.8 (MH⁺), R₁: 1.17 mm.

STEP 3

[0136] A mixture of HB (0.190 g, 0.446 mmol) in methanol (10 ml) and oxone/watcr (0.274 g in 5 ml 1-feO, 0.446 mmol) was stirred at 0⁰C for 90 minutes, and then at ambient temperature for an additional 1 hour, then concentrated and the residue was partitioned between CH₂CVH₂O (15 ml/) 5 ml), CM₂CI2 layer was washed with brine (15 ml), dried over ^SO*, concentrated to yield compound UC as a yellow oil (0.165 g, 0.373 mmol). LCMS {m/z)\ 442.9 (MH^*), R₄: 0.78 min.

STEP 4 f 0137J A mixture of Il C (0.165 g, 0.373 mmol) in NMP (0.5ml) and ethylcnediamine (0.20 ml, 2.99 mmol) was stirred at 0 °C for 30 minutes. The reaction mixture then was diliuted with water (6 ml), the product was separated via centrifugatkm, the residue was rinsed with water (2 ml), dried under high vacuum to yield HD as a yellow solid. LCMS (m/z): 438.9 (MIf*), R,: 0.69 min.

STEP 5

101381 To above compound HD, in CH₂CI₂ was added DMAP (55 mg, 0.45 mmoi) and 2- methoxyacetyl chloride(40 ul» 0.44 mmol) and reaction mixture was stirred at ambient temperature for 10 minutes, then quenched with water (I ml), CH₂CIs layer was separated, and concentrated to yield HE as a waxy solid (OJ l 1 g, 0.218 mmol). i£MS (m/z): 510_*9 (MH'), K₁: 0,86 min. STEP 6

10139] Compound HE (55.5 mg, 0.109 mmol) was dissolevd in DME (1,2 mj) in a vial following addition OfNa₂CO₅ (2.0 M, 0.60 nil) and boronic ester HF (21.6 mg, 0.086 mmol). The resulting mixture was sparged with argon, and added with Pd(PPlIs)₄ (17 rng, 0.015 mmol), and the mixture was sparged again. The mixture then was sealed in a vial and heated to J 10 °C for 20 minutes. The reaction mixture was cooled to ambient temperature, partitioned between UtOAc (2 ml) and saturated aqueous NaαCQ3 (1 ml), the organic layer was collected, washed with brine (1 m!) and concentrated to yield a residue. The residue was purified via preparative HPLC to yield the TFA salt of XlG [28.5 mg, 0.043 mmol) as an off-white powder.

LCMS (m/z); 555.1 (MH"), R₁: 0.72 min.

STEP 7

[01401 A mixture of the TFA salt of HG (24.3 mg, 0.036 mmol), ElOH (5 ml), ammonium formate(56 mg, 0.888 mmol), and Pd/C(10%, 45 mg) was stirred under argon for 5 hours. The Pd/C catalyst was removed via filtering through eel he, the filtrate was concentrated and residue was partitioned between EtOAc/sat. Na₂CO₅(IO ml/5 ml). The EtOAc layer was collected, washed with brine (5 ml), dried over Na₂SO*, and concentrated to yield a residue which was diluted in 14ml \ : 1 acetonitrile/H₂0/U.l% TFA and lyophilized to yield Example 1 as a TFA salt (2.6 mg, 0.0044 mmol).

LCMS (m/z): 4752 (MH '), R₄: 0.57 min.

Scheme 2

STEP l

[Θ141] To solution of4.phenylimidaz.ole (SM2A, 0.280 g, 1.94 mmol) in anhydrous DMI⁷ (8 ml) was added NaH (0.176 g, 60% in mineral oil, 4.35 mmol) at ambient temperature. The resulting mixture was sdrred at ambient temperature for 15minutes, followed by addition of 2-chIαro-4- πitropyridine (SM2B, 0,320 g, 2.0 mmol), and further stirring the mixture at ambient temperature for about 10 minutes. The mixture then was partitioned between BtOAe/I bO (20 ml/40 ml), the EtOAc layer was collected, sequentially washed with I hO (2 x 20 ml), dried over anhydrous Na₂SO^ concentrated and crude residue was triturated with hexanes (20 ml) Io yield I2A as a white solid (0.502 g, 1.96 mmol, yield 101%). LCMS (w/z): 255.9 (MH'), R_t: 0.69 min.

STEP2

[Θ142] Compound 12 A (0.457 g, 1.79 mmol) was mixed with MeOH (40 ml), ammonium formate (LO g, 15.9 mmol), and Pd/C(10%, 100 mg). The resulting reaction mixture was stirred under argon for 45 minutes. The Pd/C catalyst was removed via Alteration through celite, and (20 ml/10 ml). EtOAc layer was collected, washed with brine (10 ml), dried over Na_ZSO₄, concentrated to yield I2B (0.3334 g, 1 ,51 mmol) as a white solid.

JXMS (w/z): 222.0 (MH⁺), R₁: 0.49 min.

STEP 3

[0143} To flame-dried flask was added I2B (166 mg, 0.75 mmol) in TMF <5 nil) and the solution was cooled to -78 ^ftC. To the cooled solution was added BuLt/hexane (2 M, 0.40 ml, 0.8 mmol) and the resulting reaction mixture was stirred at -78° C for 10 minutes, followed by dropwise addition of CBr₄ZFHF (250 mg, 0.75 mmol, in 5ml THF). The resulting mixture was stirred for additional 10 minutes, and quenched with aqueous saturated NH₄Cl at -78 °C. The quenched mixture was partitioned between EtOAc/saturated NaaCOji (20 ml/ 10 ml), the organic layer was washed with brine (10 ml), dried over NSaSO₄, concentrated, and the crude residue was purified with flash chromatography on silica eluted with gradient EtOΛc/hexanes (0- 100%) to yield I2C as a light color solid (133.1 mg, 0.44 mmol).

LCMS (m/zY 302.0 (MH^1-), R,: 0.64 min. STEP 4

(0144] Compound I2C (121 mg. 0.403 mmol) was dissolevd in DME (3 ml) in a vial following addition OfNa₂CO₃ (2,0 M, 1.5 ml) and boronic ester HF (150 mg, 0.60 mmol). The mixture was sparged with argon, and combined with Pd(PPhj)* (51 mg, 0.044 mmol), and the mixture was sparged again with argon. The mixture then was sealed in the vial and heated to 1 15 °C for 20 minutes via microwave reactor, partitioned between EtOAc (5 ml) and saturated aqueous Na₂COa (2.5 ml), the organic layer was collected, washed with brine (2.5 ml), dried over Na₂SO₄. and concentrated. The residue was purified via preparative HPLC to yield Example 2 as a TFA salt (19.0 mg, 0.039 mmol).

LCMS (m/z): 344.2 (MH⁴), R₁: 0.52 min. Scheme 3

I3E

STEP 1

[01441 To solution of 4<4'-flυorophenyl)imidazole (SM3A, 1.627 g, 10.0 mmot) in anhydrous DMF (10 ml) at ambient temperature was added NaIi (0.S27 g, 60% in mineral oil, 13.2 mmol) and the resulting mixture was stirred for 30 minutes. The mixture was then cooled to 0"C followed by addition of 4-chloro-2-(methylthio)pyrimidine (SM2B, 2.21 g, 13.8 mmol). The resulting reaction mixture then was stirred overnight wilh temperature gradually rising from 0 ⁰C to ambient temperature, then quenched by addition of water (1 ml). The quenched mixture was concentrated and residue was partitioned between CH₂Cl₂/] hO (60 ml/30 ml). CH₂CI₂ layer was collected, washed with brine (30 ml), concentrated and the solid residue was mixed with BOAc (10 ml), and filtered to yield a solid, The filter cake was rinsed with M TBE (20 ml) to yield 13A as a solid (2.B g, 7,79 nunol, yield 77.9%). LCMS (wt&): 287.2 <MϊA Rtf 0,83 nun. STEP 2

[»1461 To flame-dried flask was added I3A (1.00 g, 3.49 mniol) in anhydrous THF (20 ml) and the solution was cooled to -78 °C To the cold solution was added BuLi/cyclohexane (2 M, 2 ml, 4.0 mmol) and reaction mixture was stirred at -78°C for about 15 minutes, followed by dropwise addition of CBr₄ZlTlF (1.16 g, 3.5 mmol in 5 ml THF) over 5 minutes, and the resulting mixture was stirred for additional 40 minutes, and quenched with aqueous saturated NHtCl (1 ml) at -78°C, The quenched mixture was concentrated, the residue was redissolved in EtOAc (30ml), dried over anhydrous Na₂SO₄, concentrated, and lhc crude residue was purified with flash chromatography on silica eluted with gradient EtOAc/hexanes (0-40%) to yield 13B as a tan solid (0.402 g, 1.10 mmol). LCMS (m/z): 367.0 (MH'), R₁: 1.08 min.

STEP 3

(G147J To Ϊ3B (0.364 g, 1.00 mmol) in methanol (40 miχ at ambient temperature, was added oxone/water (0.62Θ g in 40 ml H₂O, 1.00 mmol), and then the mixture was stirred for additional 2 hours. The supernant reaction mixture was isolated, concentrated and the residue was partitioned between EtOAc/sat, Na^CO₃ (20 ml/10 ml), KtOAc layer was washed with brine (10 ml), dried over Na₂SO₄, and concentrated Io yield OC as tan solid (0.289 g_» G.7S8 mmol). LCMS (m/z): 382.8 (MH '), R₁: 0.76 min.

STEP 4

[OJ 481 Compound Ϊ3C (0.138 g, 0,363 mmol) in NMP (0,5ml), and ethylenedϊamine (0.20 ml, 2,99 mmol), was stirred at ambient temperature for about 30 minutes. To the reaction mixture then was added water (7.5 ml) and product was separated via centrifugation, rinsed with water (S ml), dried under high vacuum to yield I3D as a yellow waxy solid which was used in next step with wit further purification. LCMS (m/z): 379.0 (Ml -⁺), R,: 0.63 min. STEP S

10149] To above obtained 13» in CH₂Cl₂ (1 ml) was added DMAP (50.3 mg, 0.412 mmol) and 2-methoxyacetyI chloride (30 ul, 0.33 mmol) and reaction mixture was stirred at ambient temperature for 30 minutes, then concentrated to obtain a residue. The residue was washed with adding water (5 ml), sonicated to yield a solid suspension, which was separated by ccntήfugalion. The preceding procedure was repeated to yield a residue which was dried under high vacuum to yiled 13E as a waxy solid (0.1 11 g, 0.218 mmol). LCMS (M/Z): 450.9 (MH⁺), R₁: 0.76 min.

10150] Compound I3E (55.5 mg, 0.109 mmol) was dissolved in DME (4 ml) in a vial followed by addition of Na2CO₃ (2,0 M, 2 ml) and boronic ester HF (120 mg, 0.48 mmol), and the mixture was sparged with argon, combined with Pd(PPhOa (73.5 mg, 0.0636 mmol), and the resulting mixture was sparged again with argon. This mixture then was sealed in the vial and heated to 1 15 X for 20 minutes. The mixture was partitioned between EtOAc (6 ml) and saturated aqueous Na^COj (3 ml); organic layer was collected, washed with brine (3 ml), dried over NaaSCU and concentrated to yield a residue. The residue was purified via preparative HPLC and pure fractions were combined, saturated with Na₂CO₅, extracted with EtOAc (50 ml), EtOAc layer was collected, and washed with saturated Na₂COj (2 x 25 ml), dried over Na₂SO<», concentrated, to yield a free base of the compound of Example 3 (20.2 mg, 0.041 mmol) as a solid. The free base was combined with HCl (0.986 N, 83 ul) and acetomtri.le/H₂O (1 ml/3 ml/), and the resulting solution was frozen, and then lyophilized to yield the compound of Example 3 as its bis IfCl salt.

LCMS {mlty. 493.1 (MH ^■+")\, R₁: 0.60 min

Scheme 4

STEP l

|015J] To a flask was sequentially charged with /vtoluenesulfoπy I methyl isocyanide (SM4A, 3.945 g, 20.21 mmol), Pivalaldehyde (SM4B, 1.775 g, 20.61 mmol), absolute elhanol (60 ml) and sodium cyanide (0.098 g, 2 mmol) and resulting reaction mixture was stirred overnight al ambient [0152] The residue was triturated with water [ 150 ml), and the resulting solid precipitate was collected via filtration. The filtered solid was rinsed with water (100ml), dried under high vacuum to yiled I4Λ as a light colored solid (4.94 g, 17.56 mmol).

1 H NMR (400 MHz, CDCh) 6 ppm 0.946 (s, 9 H), 2,458 (s, 3 H), 4,764 (d, J- 5,6 Hz, 1 H), 4.83* 4.85 (m, 1 H), 7.032 (d, J= .1.2 Hz, 1 H), 7.38.1 (d, J^« 8.0 Hz, 2 H), 7,830 (d, J= 6.4 Hz₅2 H)

STEP 2

[0.153] Λ steel bomb was charged with 14A (0.S66 g, 2.012 mmol) and methanol (7 N, S ml, 35 mmol) and the resulting mixture was sealed, heated in an oil bath to a temperature of about 110 ⁰C for about 24 hours. The reaction mixture was concentrated to yield 14 B as a residue. LCMS (m/z): 125.1 (MH⁺), R₁: 0.38 min

STEP 3

[01541 Compound I4B (2,012 mmol), from step 2 above, was dissolved in DMF, cooled to 0 °C followed by addition of NaH (60% in mineral oil, 0.50 g, 12.52 mmol). The resulting mixture was thereafter stirred at room temperature for 10 minutes, followed by addtlon of 4-chloro«2- (methylthiol)pyrimidine (I4C, 0.483 g, 3.01 mmol) and reaction mixture was stirred at room temperature for 1 hour, followed by quenching with water (0.5 ml). The quenched reaction mixture was concentrated to yield a residue, the residue was partitioned between KtOAcZH₂O (40 ml/20 ml), the ElOAc layer was sequentially washed with brine (20 ml), dried over NazSO^ concentrated to yield a residue. The residue was was purified via chrpmatography on silica gel eluted with gradient EtOAc/hexane (0-50%). Final product I4D was obtained as a colorless solid (198.4 mg, 0.80 mmol). 1 H NMR (400 MHz, CDCl.,) δ ppm 1.333 (s, 9 H), 2.604 (s, 3 H), 6.912 (d,J ^"- 5.6 Hz, 1 H), 7.31 (d, J - 1.2 Hz, 1 H)₁ 8.339 (d. J^« 1.2 Hz, 1 H), 8.522 (d,J- 5.2 Hz, 1 H). LCMS (m/z): 249.2 (MH"), R,: 0.59 min. STEP 4

[01551 To a /TITF solution ofI4D (740 mg, 2.98 mmol in 10 ml TOF) at -78 °C was dropwise added LHMDS (1.0 M THF solution* 2,98 ml, 2.98 mmol), and reaction mixture was stirred at -78 °C for 1.5 hour. A solution OfCBr₄ (988 rog, 2.98 mmol in 3 ml THF) was added dropwised at -78 °C, The resulting mixture was gradually warmed to room temperature over 2 hours, The reaction mixture then was quenched with water (200 ul), concentrated undeer reduced pressure, and resulting residue was partitioned between EtOAc/H_?.O (20 ml/20 ml). The ElOAc layer was separared and dried over Na₂SO₄, and then concnetrated undeer reduced pressure to obtain a residue. The residue was purified by flash chromatography on silica gel eluled with gradient EtOAc/hexane (0-50%) to yield I4B as a light brownn waxy material (415.2 mg, 1.27 mmol) with some unreacted 140 (194.2 mg) recovered. LCMS (w/r): 329.0 (MH⁺), R₁: 1.02 min.

STEP 5

(0156) A sotution of I4E in CH₂Cl₂ (415.2 mg, 1.27 mmol in 10 ml CI f₂Cl₂) was treated with røCPBA (~7Q%, 302 mg, 1,23 mmol) at room temperature for 10 minutes. Reaction mixture was sequentially washed with saturated NaHCO₃ (3 x 20 ml) and brine (20 ml). The CH₂Cl₂ layer was dried over Na2SO₄, concentarted to yield Ϊ5F as a light brown waxy residue (435 mg, 1.267 mmol) and used directly in the next step. LCMS (m/z); 345.1 (MH⁴), R₁: 0.65 min

STEP 6 j€157] Compound ISF (435 mg, 1.267 mmol) was dissolved in NMP (5 ml), treated with (S)- tert-butyl 1 -aminopropan-2-ylcarbamale (265 mg, 1.521 mmol) and DIEA (0.443 ml, 2,53 mmol) at 90 *€ for 5 minutes. Reaction mixture was then cooled down to room temperature, partitioned between EtOAc/H₃O (30 ml/60 ml), EtOAc layer was sequentially washed with H₂O (2 x 60 ml), brine (30 ml), dried over NaaSO^ concentrated to yield 15(3 as a light brown waxy residue(569.5 mg, 1 -256 mmol). LCMS (w/2): 455.2 (MH⁺), R_f: 0.94 min. STEl* 7

|01S8j In a microwavable vial was charged ISG (284 mg, 0.626 mmol), ISH (269 mg, 0.94 mmol), auqeous Na^CO? (2 M, 1.88 ml, 3.76 mmol) and DME (4 ml). The preceding mixture was purged with Argon, followed by addition of Pd(tetrakis), and purged with Argon again. Reaction then was was seated, heated at 1 15 °C for 20 minutes via microwave reactor. DME layer was collected, and concentrated to yield 151 as a residue (244 mg, 0.458 mmol). LCMS {m/z): 533.4 (MlA R_t: 0.77 min

STEP 8

J0159] A methanol solution of 151 (211.5 mg, 0.397 mmol in 4 ml) was treated with concentrated HCl (1 ml, 32,9 mmol) at 60 ⁰C for 1 hour, followed by cooloing down to room temperature, followed by neutralizing with solid NaHCOj (3.5 g, 41.7 mmol). The reaction mixture ^•was then partitioned between saturated NaHCOs (20 ml) and EtOAc (30 ml), EitOAc layer was sequentially washed with saturated NaHCO₃ (30 ml), brine (15 ml), dried over Na₂SO^ then concentrated via rotary evaporator to yield crude I5J (144.6 mg, 0.334 mmol) as a white solid, which was used directly in next step. LCMS (m/s): 433.3 (MH⁺), R<: 0.47 min

STEP 9

[0160] A mixture of BJ (144.6 mg, 0.334 mmol), THF (10 ml), H₂O (10 ml), solid NaHCO₃ (1.00 g, 1 1.9 mmol) was cooled to 0 ⁰C, treated with methyl chloroformate (24.6 mg, 0.26 mmo.) and stirred at 0° C for 30 minutes. The reaction mixture was partitioned between EtO Ac/brine (20 ml/10 ml); ElOAc layer was washed with brine (20 ml), dried over 1^32804, concentrated and a crude residue was obtained. The crude residue was further purified via preparative HPLC, and pure fractions were combined* adjusted pH with solid Na₂COj to -12, extracted with BtOAc; ElOAc extract was sequentially washed with saturated NajCOs twice, brine, dried over Na₂SO₄, concentrated and residue was redissolved in acetonifrile/water (1 :1)_t frozen and iyophilized to yield compound of Example 4 (104.5 mg, 0.213 mmol) as a powder.

¹H NMR (4-⁽H⁾ MHz, Acetic acid) 5 8.34 (d, J = 4.30 Hz, I H), 7.95-8.08 (m, 1 H), 7.63-7.76 (m, 1 H), 7,3&39*?.630κ, I % 6j£<t_r>7£8, . ϊfy, ,&57-6.72 (m, ϊ H), 3.73-4.03 (m, 1 H), Ml & 3- H), 3.29-3.41 (m_τ 1 H), 3.07-3.29 (m, I H), 1.40 (s, 9 H), 1.08-1.22 (m, 3 H); LCMS (m/z): 491.3 (MH⁺), R,: 0.62 min.

Scheme 5

(01611 To a flask was sequentially charged with jp-tolucncsulfonylmethyl isocyanide (SM5A, 10.0 g, 5L2 mmol), cyclopropanccarbaldehyde (SM5B, 3,66 g, 52.2 mmol), absolute elhano! (150 ml) and sodium cyanide (0.251 g, 5.12 mmol) and resulting reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated via rotary evaporator under reduced pressure to yield a residue which was triturated with water (30 ml), and solid precipitate was collected via filtration, the filter cake was rinsed carefully with water (100ml), dried under high vacuum to yield I5Λ as a light color solid. LCMS (m/z): 198.0 (MH'), R₁: 0.49 min,

STEP 2

[01621 To a steel bomb was charged with ESA (6.4 g, 24.12 mmol) in methanol (100 ml) and the mixture was cooled to 0 °C. Jn to this mixture was bubbled with anhydrous NHj (13.15 g, 772 mmol), the resulting mixture was sealed, heated to 1 10 °C in an oil bath for 20 hours. The reaction mixture was concentrated to yield ISB as a residue.

STEP 3

[01631 A mixture of ISB (24.12 mmol) in 40 ml DMF was cooled to 0 °C followed by addition of NaH (60% in mineraJ oil, 0.965 g, 24.12 mmol) and resulting mixture was thereafter stirred at room temperature for 30 minutes, and then cooled down to O°C. To it was added 4-chloro- 2-(methyHhio.)pyrimic[ine (SM5C, 3.87 g, 24.1 mmol) and reaction mixture was stirred at room temperature for 2 hours, followed by quenching with water (3 ml). Quenched reaction mixture was concentrated, residue was partitioned between EtOAc/HjQ (50 ml/50 ml), EtOAc layer was sequentially washed with Fl₂O (50 ml), brine (30 ml), dried over NajSO^ concentrated to yield ISC as a brown oil, which upon purification by flash chromatography on silica gel eluted with gradient KtOAtt/n-heptane(0-100%) yielded purer ISC as a white solid (1.458 g, 6.28 mmol). 1.,CMS (m/z): 233.0 (MH"), R₁: 0.52 min STEP 4

(0164] To a Ϊ5C/THF solution (1.45 g, 6.24 mmoJ in 30 ml THF) at about -78 to -70 °C, was dropwise added 1.,HMDS (1.0 M THF solution, 7.49 ml, 7.49 mmol), and the resulting reaction mixture was stirred at -78 °C for 1 hour. Then CBr₄ (2.173 g, 6.55 mmol in 6 ml THF) was dropwised added with internal temperature controlled below -65 °C. Cold bath was removed after LHMDS addtion and reaction was gradually warmed up to about B °C within 30 minutes, and reaction was complete by [.CMS of reaction mixture aliquot. The preceding reaction mixture was then quenched with water (1 ml), concentrated, and residue was purified by flash chromatography on silica gel ehrted with gradient BtOAc/hexane (0-50%). Compound ISI) was obtained as light brown oil (1.38 g, 4.43 mrnol). LCMS («/*): 312.9 (MH⁴), R_t: 0.86 min.

STEP S

10165] A solution of I5D in CH₂Cl₂ (1.36 g, 4.37 mmol) was cooled to 0 ⁰C, treated with mCPBA (-70%, 1.077g, 4.37 mmol) between 0-10 ⁰C and stirred for 10 minutes at this temperature. Reaction mixture then was washed with saturated NaHCOs (2 x 30 ml), CH2CI2 layer was dried over Na₂SO*, concentarted to yield I5E as a light color foam (1.4489 g, 4.43 mmol). LCMS (mfc): 328.9 (MH⁺), R₁: 0.53 min.

STEP 6

[βl66] Compound ISE (1.4489 g) was dissolved in NMP (10 ml), treated with (S>tert-butyl 1-amiτu>proρan-2~ykarbamate (0.926 g, 5.31 mmol) and DlEA (1.16 ml, 6.64 mmol) at 50 °C for 30 minutes. The reaction mixture was cooled down to room temperature, partitioned between EtOAcZH₂O (30 ml/60 ml), the EtOAc layer was sequentially washed with H₂O (60 ml), brme(2Q ml), dried over Na^SO^ and concentrated to yield ISF as a light color solid (1.8285 g, 4.18 mmol). LCMS On/*): 439.1 (MH⁺), R₁: 0.89 min.

STEP 7

[0167] [0024] A microwavable vial was charged with ISF (220 mg, 0.503 mmol), SM5D (411 røg, ϊ .006 mmol), auqeous Ma^CG₃ Q. M, t .5 i ml, 3,02 mmol} and OME (4,5 mi% Thø resulting mixture was purged with Argon, followed by addition of Pd(tetrakis), and another Λrgon purge. Reaction mixture then was sealed, heated at 1 15 °C for 30 minutes via microwave reactor, DME layer was collected, and concentrated Io yield 1SG_» which was used directly in next step. LCMS (m/s): 502.2 (MH"), R<: 0.71 min.

STEP 8

[0168] Λ solution ofJ5G in methanol (4 mi) was treated with concentrated HCJ (1 ml, 32,9 mmol) at 50 "C for 1 hour, followed by cooloing down to room temperature, and then concentrated via rotary evaporator to yield. ISI as a light brown solid which was used directly in next step. LCMS (m/z): 402,2 (MH⁺), R_s: 0.44 min

STEP 9

[01691 A mixture of 15Ϊ, sat. NaHCO₃ (0.423 g, 5.03 mmol), water (5 ml), and THF (15 ml) was cooled to 0 °C₅ treated with methyl chloroformate (0.077 ml, 1.0 mmol) and stirred at O°C for 50 minutes. The IW layer was collected and concentrated to yield ISJ which was used directly in next step. LCMS (jn/zy. 460.1 (MH"), R,: 0.58 min.

STEP 10

[0170] Compound I5J was dissolved in anhydrous pyridine (1 ml), cooled to 0 ^αC and treated with methanesuifonyl chloride (118 ul, excess), and reaction was quenched with water (200 ul) after LCMS of reaction aliquot did not indicate any further presence of ISJ. The reaction mixture was quenched with water, and then heated to 60 °C via an external oil bath for 30 minutes, concentrated via rotary evaporator and further dried under high vacuum. The dried residue was then diluted with DME (4 ml), treated with saturated Na₃CO₃ (4 ml) at 60 °C for 30 miutes, followed by cooling to room temperature, DME layer was collected, extracted with dilute NaOH (0.10 M, 2 x 2ml). Aqueous layers were combined and adjusted to pH ~5 by adding MCl (1.0 M, 0.4 ml), extracted with EtOAc (3 ml). EtOAc layer was concentrated and residue was redissolved In acetonhrile/HbO (1.5 ml/1.5 ml), frozen and lyophilizcd to yield compound of Example 5 as a white powder ( 1 1.5 nig). tCMS <m&> 53«.! (MH⁺), R₁: 0,63 mm. INTERMEDIATES

2-a mi-io-3-methoxy-5-(4,4,S,5-tt^ltr amethy I- 1,3_»2-dioxaborolan-2-yl)py ridin* (I! F) Scheme 6

2-aitro-3-inetboxy-5-bromopyridme (2)

|Θ171 \ To a cooled flask containing 3-methoxy-5-bromopyridine I (39,8 g, 0.21 mol) was slowly added concentrated H₂SO4 (120 ml) with the reaction mixture temperature maintained below 20 °C. The resulting mixture was stirred unitl homogeneity. The reaction mixture was cooled to 0-5 f^tC and 90% I INO3 (16>5 g, 0.24 moi) was added dropwise while maintaining constant temperature. The resulting reaction mixture was stirred for 24 h, at ambient temperature. The reaction was deemed complete (<5% of 1 by HPLC) and the reaction mixture was poured onto ice (400 g), then partitioned with EtOAc (400 ml). The layers were separated and (he organic phase was sequentially washed with saturated aqueous Na₂CO₃ solution (400 ml), water (400 ml) and brine (400 ml), dried overNa₂SO-i) Tillered, and concentrated under reduced pressure to furnish a pale yellow solid (45.8 g) as crude product. The material was recrystallized from MTBE (175 mL) and the crystals were harvested, washed with cold MTBK (80 mL-), and dried under high vacuum to give 22.7 g of yellow soiM as product. The mother liquor and filtraie were combined, concentrated, and recrystøllized from MTBE (35 mL) gave 6.3 g of pure product, The remaining mother liquor and filtrates were combined and concentrated. The resulting residue was purified by silica gel chromatography, eluting with a slow gradient of hexanes-EtOAc (hexanes, 4:1 hexancs-EtOAc) to give 8.5 g of product, Λ combined total of 37.5 g (0.16 mol, 76% yield) of a yellow crystalline solid was obtained as 2-nitro-3 -methoxy-5 -bromopyridine:

¹H NMR (30Q MHz, CDCl₃) 6 8.16 (d, J™ 1.9 Hz, 1 H), 7.68 (d, J = 1.6 Hz, 1 H), 4.01 (s, 3 H); IXMS m/z (MH') 232.9, /_R ^» 0.73 min.

2-amino-3~methoxy-5-brϋ.n<>μyridιιie (3)

[0172} A 3-neck I -L flask was fitted with a heating mantle, temperature controller, and an overhead stirrer. To the reaction flask was added 2-nitro-3_'«iethoxy-5-bromopyridine 2 (37.5 g» 0.16 mol), acetic acid (600 ml), and iron powder ( 18.9 g, 0.34 mol), and the resulting mixture was stirred and heated at 80 ⁰C for 2.5 h. The reaction was deemed complete by LCMS and allowed to cool to rt. The reaction mixture was filtered through Celite and the filter cake was washed with acetic acid, and the combined filtrate and washings were concentrated. The resulting residue was partitioned between saturated aqueous Na₂CO₃ solution (400 mi) and EtOAc (400 ml) and the layers separated. The organic phase was washed with brine (200 mL), dried (Na≥SC^), filtered, and concentrated to afford 32.5 g (0.16 mol, 99 % yield) of a tan solid as 2-amino-3-methoxy-5- bromopyridine:

¹H NMR (300 MHz, DMSO^fe) δ pom 7.56 (d, ./= 2.1 Hz, 1 H), 7.17 (d, ./ = 2.1 Hz, 1 H), 5.93 (br s, 2 H), 3.79 (s, 3 H); LCMS m/s (MH⁺) 203.0, /_R - 0.34 min.

2~amino-3-methoxy-5-(4,4_J5_»5-tetramethyJ-lβ,2-dioxisborolan-2-_'yl)pyridine (IlF)

[0t73] Λ suspension of 2-amino-3-methoxy-S-bromopyridine 3 (2.04 g, 10 mmol), bis(pinacolato)diboron (5.11 g, 20 mmol), potassium acetate (2.38 g, 24 mmol) in dry dioxane (50 mL) was sparged with argon for 15 min. Pd(dppf)Cl₂-DCM (0.82 g, UO mmol) was added in one portion and the reaction flask was sealed with a greased ground glass stopper. The reaction mixture was heated to 90 °C and maintained for 16 h. The reaction mixture was allowed to cool to rt and an aliquot was assayed fcy LCMS¹ and the reaction was deemed complete. The reaction mixture was filtered through ("elite and the filter cake was washed with dioxane. The combined filtrates were concentrated and the resulting residue was suspended in hexanes (125 ml.) and sonicated for 30 rain, The finely suspended brown mixture was filtered through Celite and filter cake was washed with hexanes. The combined filtrates were concentrated to afford a yellow solid which was triturated with hexanes (20 inL). The solids were collected by filtration and washed with cold hexanes (5 mL). The combined filtrate and washings were allowed to stand at rt to afford another crop of solids which were collected by filtration. The combined solids (1.96 g) were placed in a drying pistol (0.5 torr, 85 °C) for 4 h to effect sublimation of excess bis(ptnacolato)diboron, leaving behind 1.18 g (4.7 mmol, 47% yield) of a light tan solid as 2~amino-3->methoxy-5-(4,4_>5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine.

¹H NMR (300 MHz, CDCI₃) 6 ppm 8.07 (d, J^« 1.2 Hz, .1 H), 7.20 (d, J = 1.2 Hz, 1 H), 4.88 (br s, 2 H), 3.86 (s, 3 H), 1.33 (s, 12 H); LCMS m/z (MH⁴, boronic acid) 169.0, /_R ^» 0.22 min.

2-Amino-3-metbox>-5-bromopyridine (3) Alternate Synthesis

2-Amino-3-m«thoxy pyridine (2A)

10174] To a solution of 2-nii-O-3-methoxypyridine (2, 32 grams, 208 mmol) in EtOAc (150 mL) and MeOH (35 mL)under nitrogen atmosphere was added 10% palladium on carbon (1 ,5 g, 1.4 mmol). This mixture was purged three times with H₂, and the mixture was stirred for 3 h (or until LC-MS shows the starting material was consumed) under a hydrogen atmosphere. The reaction mixture was purged three times with TM₂ , filtered through Celite, and the solid residue was washed with EtOAc (2 X 3SmI), The filtrate was concentrated and. dried over high vacuum to afford 2- ¹H NMR (300 MHz, CDCI j) δ ppm 7.66 (m, 1 H), 6.90 (m, 1H), 6.61 (m, 2H), 4.64 (s, br, 2H), 3.83

(s, 3H)

LC/MS (m/z): 125.0 (MH⁺)

2-Amim»-3-roctUoxy-5-bromopyridine (3)

[0175] A 2000ml Ertenmeyer flask was charged with 10% sulfuric acid (800ml). At ambient temperature, 2-am.no-3-methoxy~pyr.dine (2, 25.80 grams, 206 mmol) was added with stirring. After a clear solution was obtained, the solution was cooled in an ice/water bath until the solution temperature reached about 3 °C. A mixture of bromine (10.8 ml, 210 mmol) in acetic acid < 140ml) was added dropwise while maintaining the reaction mixture internal temperature at 3-5 °C. After the addition was complete (-40 min) the mixture was stirred at this temperature for 2 h (or until the reaction was complete by LC-MS). This mixture was poured onto 800 grams of ice under stirring and to the resultant mixture was slowly diluted with saturated ammonium hydroxide solution (30% w/w) until the pH = 8. A dark solid precipitates and the mixture was stirred for additional half hour at 3-5 ⁰C. The solid was collected 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 BtOAc (500 ml) and the resulting dark mixture was stirred vigorously for 0.5 hour and filtered through CeI he. The black solid was washed with EtOAc (2 X) and the combined filtrates were washed with 10% sodium thiosulfite solυtion(IOO ml), saturated brine and dried (Na^SO*)- Concentration of this mixture afforded 29.0 grams (68,3% yield) of 2-amino-3-methoxl-5-bromopyridine (3) as a yellow solid. ¹H NMR (300 MHz, CDClO S ppm 7.71 (d, J ^» 21.Hx, 1 11), 7.01 (d, J - 21.Hz, 1 H), 4.69 (br s, 2 MX 3.84 (s, 3 H). LCVMS (m/z): 204.9.0 (MH) Scheme 7

3-(difluorotnethoxy)pyridin-2-amine (7)

[0176] A mixture of3-(diflυoroinetho?ty)-2-ιiitropyridine(, 5.428 g, 28.6 mmol) in absolute EtOH (50 ml) solution with catalytic Pd/C (0.55 g, lθwt% Palladium on activated carbon) was stirred under 1 atm Hj at ambient temperature. LCMS aliquot indicated reaction completion after overnight stirring. Catalyst Pd/C was removed by filtration through a celite pad, filtrate was concentrated and desired product 7 (4.41 g, 27.5 mmol, 96% yield, [IVWI] ^:!!! 161.1, /R ^!!! 0.28 min) was obtained as a colorless solid. ¹H NMK (400 MHz, CDCI₃) δ ppxn 7,90-7.97 (m, 1 H), 7.24-7.31 (m, I H), 6.61-6.68 (m, 1 H), 6.49 (t, J^r 64.4 Hz, 1 H), 4.73 (br s, 2 H).

S-broιno-3-(difluor»methoxy)pyrid}ιi-2-aininc (8)

|0I77j A solution of 3-(difluoromethoxy)pyridin-2-amine (7, 4.402 g, 27.5 mmol) in ACN (50 ml) was cooled to O°C₅ followed by treatment of NBS(4,89 g, 27.5 mmol) with internal reaction mixture temperature controlled between 0-1O⁰C during 5 minutes, and the reaction mixture was further stirred at O°C for an additional 10 minutes, LCMS of an aliquot indicated absence of starting material (7) indicating that, the reaction was complete. Reaction mixture was concentrated; residue was partitioned between EtOAc/sat. NaHCOj(30 ml/20 ml); EtOAc layer was sequentially washed with saturated NaHCO₃ (20 ml) and brine (20 ml), dried over Na₂SO,,, concentrated, Crude residue was triturated with EtOAc/hcptane (10 ml/40 ml), suspension was removed via filtration, and filtrate was concentrated to afford 8 (6.212 g, 26.0 mmol, |M+I-ty=24L.O, /R ^« 0.5Smin) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.99 (d, J^« 2.0 Hz, 1 I I), 7.41 (d, J- 2.1 Mz, 1 H), 6,50 (l, J_r. ,/- 72J Hz, III), 4.74 (br s, 2 H).

3-(difluoromethoxy)-5-(4,4,S,5-tdτaπic-hyJ4,3,2-dioxaborolan-2-yl)pyridin-2-am»ije (l4II)

[M 78} A glass reaction vessel (bomb) was charged with a mixture of 5-bromo-3- (difluoromethoxy)pyridin-2-amme(8, 6.212 g, 26,0 mmol), Bis(pinacolato)diboron (6.93 g, 27.3 mmol), Pd₂(dba)₃(0.952 g, 1.040 mraol), tricyclohexylphosph»ne(l .020 g, 3.64 mmol), and KOAc(5.36 g, 56.4 mmol) in anhydrous dioxane(70 ml). The mixture was carefully sparged with argon, the reaction vessel sealed, and heated to about 1 1O°C in an oil bath for 24 hours. LCMS of aliquot indicated complete conversion of 8 to product I4H ([M+H]^« 205.0 as acid, /R - 0.27min), Reaction mixture was diluted with EtOAc(70ml) aftere it cooled down to ambient temperature, filtered through neutral alumina(~30ml, 2.5ml thickness), alumina cake was washed throughly with IUtOAc(IOOmI), and filtrate was combined, concentrated and a light brown solid residue was obtained. The brown residue was triturated in heptane( 100ml) at (PC, desired product precipitated out, was collected via filtration and filter cake was rinsed throughly with heptane, final product 14H was obtained as a yellow solid(7.777g, 74% yield, }M+H]^:!!!205.0, /_κ = 0.27min) after dried under high vacuum. ' H NMR confirmed structure, and an unidentified impurity at ~1.3ppm was found by ¹H NMR. This impurity peak was probable a pinacole t-Bu group, and -1 : 1 tnol ratio to product. 1H NMR (400 MHz, CDCl,) δ ppm 8,27 (d, ./ ^« 1.5 Hz, 1 H), 7.55 (a, 1 H), 6.51 (t, JF-H= 73.6 Hz, 1H), 1.27 (8, 12 VI).

3-bromo-2-chloro-5-Ωttoroan-lin«(12)

|Θ179] A scalable tube was charged with 1,3-dibromo-2-chloro-5-fluoroben;jene(1.0, 12.52 g, 43.4 mmoi), benzophεπone iniine(H.26 g, 45.6 mmoi), sodium tert-Bυtoxide(8.26 g, 65.1 mmoi), and loluene(100 ml). The resulting mixture was thoroughly sparged with Argon, then followed by addition of Pd₂(dba)_Λ(Q398 g, 0.434 mmoi) and (S)«B.NAP(0.81 1 g, 1.3 mmoi) and Argon sparge was repealed. Reaction was sealed and heated overnight to 85°C using an oil bath. Reaction mixture was cooled down to ambient temperature, quenched with water(20ml). Toluene layer was isolated, concentrated and residue was a mixture of mono-coupling product and his-coupUng byproduct with ratio -4:1 by fc:JPLC area at 220 nm. Residue was dissolved in TlIF (70 ml), treated with 3M MCI (20 ml) at room temperature for 1 hour and basified with sat. -Na₂CO₃ (40 ml). THF layer was separated, washed with brine, concentrated and residue was purified by flash chromatography on silica gel and 12 was obtained as a light yellow solid( 6.32 g, 30.4 mmot, yield 70%.

LC/MS: (M+HJ=ncrt ionized, f« - 0.9 \ min);

1H NMR(CDCl₃, 300 MHz) 6 ppm 4.32 (s, 2 H), 6.44(dd, J, <• 9.82 Hz, J₂ *2.78 Hz, 1 H), 6.77<dd, J₁ ^« 7.91 Hz, J₂ -- 2.64 Hz, I H). 2-chloro~5-fluoro-3~(4,4,5,5-tetraniethyM ,3,2-dioxaboroia ιι-2-yl)a niline (SM 5D)

(0180) A microwavable vial was charged with 3-bromo-2-chloro-5-fluoroa-iiline (12, 673.5mg, 3.0 mmol), bts(ρmacolato)diboron (838mg, 3.30 mmol), KOAc(1.767g, 18.0 mmol), and 1,4-dioxane<15ml), and the mixture was thoroughly sparged with Argon, then followed by addition of Pd₂(dba)j(235.5 mg, 0.257 mmol) and tricyclohcxylphosphine(252 mg, 0.899 mmol), and Argon sparge was repeated. Reaction mixture was sealed and heated at 120 °C overnight. Reaction mixture was cooled to ambient temperature, diluted wilh diethyl ether(45 ml) and resulting precipitate was removed by filtering through a neutral alumina pad(d = 1 1/4 inch, h ™ 1 inch) on top of a celite pad. Filter cake was thoroughly washed with diethyl ether( 100ml), and ether filtrate was combined, concentrated and oily residue solidified after mixed with n-heptane. Crude product of SM5D was obtained as a yellow solid after n-heptane removed via evaporation(900 mg, 51 ,7wt% by 1H NMR assay, 1.714 mmol, yield 57%, [MHiJ - 272.0, te = 0.99 min). 1H NMR (CDCl₃, 300 MHz) 6 ppm \ .36 (s, 12 H)₁4. L7 (s, 2 H), 6.53(dd, .7_/ - 9.67 Hz, J₃ - 2.93 Hz, 1 H)₅ 6.77(dd, J₁ - 8.35 Hz, J₂ = 2.78 Hz, 1 H).

|01811 The compounds of the present invention, including those shown in the following Table 1 (Compounds No, 1-6), have been prepared by these methods and modifications of these methods tltat are apparent to the person of orndiary skill. Additional compounds of the invention can be prepared similarly by the teachings of one or more procedures described in the Examples above and/or by general synthetic schemes described herein, and using the appropriate starting materials as readily determined by one of skill in the art.

?

Cell Viability Assay Protocol

J0182J The Cell Ϊiter-Glø® assay (Promega) can be used to measure cell viability, for assessing the effect of the compounds of the invention on tumor cells. Cells are plated into 96-well black wailed tissue culture plates in complete growth media. The plates are then incubated under standard growth conditions of 37°C and 5% COj until die cells attach to the plales (3-6 hows), then compounds are added to the cells. Compounds are serially diluted in DMSO using 3-fold dilutions and then diluted in complete media before being added to the cells (final DMSO concentration on cells was 0.1 - 0.2%). Suitable cell numbers plated per well and compound incubation times for certain cell lines are shown in Table 2.

[0183} After compound incubation, the cell plates are equilibrated to room temperature, culture media is removed, and 200 uL of Cell Titer-Glo® reagent mix is added to each well ( 1 : 1 mixture of ("ell Titer-Gio<8> reagent and complete growth media, equilibrated to room temperature). The plates are shaken for 5-10 minutes, then sealed and luminescence is measured (using Triiux plate reader, Perk in Elmer). [0184] Assay background luminescence values are determined from wells which have been treated with a potent control compound that completely inhibits ceil growth or causes cell death at the highest concentration of 10 uM. Analysis of data is then done by subtracting the background luminescence value from each data point, then determining the percent inhibition of total growth (as determined by the values for DMSO-treated wells).

[0185] To determine the ECM tor each compound, the data can be fit using the Levenburg Marquardt algorithm, represented in the XLfit software as y = A + ((B-A)/(I+((C/x)^ΛD))), the four parameter dose response model 205, where A is the minimum Y value, B is the maximum Y value, C is the Log lCso and D is the slope.

Raf/Mek Amplified Luminescence Proximity Homogeneous Assay (Alpha Screen)

Buffers

Assay buffer: 50 mM Tris, pH 7.5, 15 mM MgCI₂, 0.01% BSA, 1 mM DTT

Stop buffer: 60 mM EDTA, 0.01 % Tween20

Bead buffer: 50 mM Tris, pH 7.5, 0.01% Tween20

Materials b-Raf(V600E), active: Recombinant in-house material biotinylated Mek, kinase dead: Recombinant in-house material

Alpha Screen detection kit PcrkinKlmer, #6760617R

Anti phospho-MEK 1/2 Cell signaling #9121

384 well assay plates: White Greiner plates, #781207

Assay conditions b-RaftVόOOE) approximately 4 pM c-IUf approximately 4 nM biotinylated Mek, Kinase dead approximately 10 nM

ATP lO μM

Pre-incubation time with compounds 60 min at room temperature

Reaction time 1 or 3 hours at room temperature

Assay protocol

[0186] Raf and biotinylated Mek, kinase dead, were combined at 2X final concentrations in assay buffer (SO mM Tris, pH 7.5, 15 mM MgCI₂, 0.01% BSA and 1 mM DTT) and dispensed 10 μl per welt in assay plates (Oreiner white 384 well assay plates #781207) containing 0.5 μl of 4OX of a raf kinase inhibitor test compound diluted in 100% DMSO. The plate was incubated for 60 min at room temperature.

IΘ187] The RaV kinase activity reaction was started by the addition of 10 μi per well of 2X ATP diluted in assay buffer. After 3 hours <bRattV600ϊi)) or 1 hour (c-Raf), the reactions were stopped with the addition of 10 μl of stop reagent (60 mM EDTA). Phosphorylated product was measured using a rabbit anti-p-MEK (Ceil Signaling, #9121) antibody and the Alpha Screen IgG (ProteinA) detection Kit (PerkinElmer #6760617R), by the addition of 30 μL to the well of a mixture of the antibody (1 :2000 dilution) and detection beads ( i :2000 dilution of both beads) in bead buffer (50 mM Tris, pJ 1 7.5, 0.0i% Tween20), The additions were carried out under dark conditions to protect the detection beads from light. A tid 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 (lC₅ø) was calculated by non-linear regression using XL Fit data analysis software.

[0188] The Raf/Mek Amplified Luminescence Proximity Homogeneous Assay described was used to generate the luminescence and mutant b-Raf(V600E) I C₅₀ data for selected Raf Kinase Inhibitors shown in Table 1 above.

Claims

1. A compound of Formula 1,

or a pharmaceutically acceptable salt thereof, wherein:

R¹ represents an optionally substituted heteroaryl;

R² represents art optionally substituted heteroaryl group;

R* represents an optionally substituted aryl group, or an optionally substituted Cj-C* branched alkyi group, or an optionally substituted C₁-Q alkyl group, an optionally substituted heterocyclic group, or an optionally substituted Cj-Cg cycloalkyl group; and

R⁴ represents H, an optionally substituted C₁-Cs alkyl group, or a CVQ cycloalkyl group.

2. A compound of Formula (1):

or a pharmaceutically acceptable sail thereof, wherein:

R¹ represents an optionally substituted S to 10 membεred heteroaryl group, wherein one to four ring members of said heteroaryl and helerocydyl groups are heteroatoms selected from N, O, and S, and the remaining ring members are carbon atoms;

R² represents an optionally substituted 5 Io 10 membercd heteroaryl group wherein said heteroaryl group contains one to three heteroatoms selected from N, C⁾, and S as ring members, and the remaining ring members are carbon atoms; R³ represents an optionally substituted 6 to 10 membered aryl grαup₍ CVCβ branched alkyl group, an optionally substituted CrCs cycloalkyl group, or an optionally substituted CfCe alky I group; and

R⁴ represent H, Cj-Cc, cycloalkyl group, or an optionally substituted C₁-Cg alkyl group.

3. A compound of Claims 1 or 2, wherein:

R¹ represents an optionally substituted heteroaryl group, selected from pyrazolo pyridinyl* pyrUmdtnyL, pyrazinyl, and pyrtdinyi; and

R² represents an optionally substituted heteroaryl selected from pyridinyl, pyrimidinyl, pyridazinyl, tetrazinyl, triazinyl, pyrrolyl, or pyrazolyl.

4. A compound of Claims 1 , 2, or 3, wherein:

R' represents an optionally substituted phenyl group, an optionally substituted Cϊ-C_fi cycloalkyl group, an optionally substituted Cj-Ce branched alkyl group, or an optionally substituted Ci-Cf, alkyl group; and

R⁴ represents M, or an optionally substituted C₁-C₄ alkyl group.

5. A compound of Claims 2 or 4 wherein: R¹ represents optionally substituted

wherein X, independently at each occurrence, represents N, or CH; R³ represents optionally substituted

wherein X, independently at each occurrence, represents N, or CH; and

R'³ represents (CH₂)L₃R²³ , (CH₂)LrCH(OH)-R²', (CH₂V₃C(O)R²³, (CH_a)_M-0R^a, (CH₂J₁. J-NH-C(OHCH₂)MOR²³, (CH₂)_M-NH-C(O)-R²', (CH₂),.₃-C(0)- NH-(CH₂)L₃OR²³, (CH₂), j- C(O)NH-R⁵³, or an optionally substituted 5-6 membered heterocyclic group; and where each R²³ is independently H or C1-C4 alkyl,

6. A compound of Claims 1 , 2, 3, or 5, wherein;

R* represents an optionally substituted phenyl group, wherein said optional substituents are selected from halogen, CF₃, OCFj, C_\-C4 alkoxy, heterocyclyt, heterocyclyloxy, CyC<_> heteroaryl, Ci-j alkyl, and C₃.₆ branched alkyl, where each alkyl, alkoxy, heterocyclyl, heterocyclyloxy, and heteroaryl is optionally substituted; or R³ is an optionally substituted alkyl group selected from methyl, ethyl, propyl, isopropyl, t-butyl, Cj.₆ cycloalkyl, and Cj^ branched alkyl.

7. A compound of Claims 1 , 2, 5, or 6, wherein:

R¹ represents a pyridyl, or a pyrazinyl group, wherein each said pyridyl and pyrazinyl is substituted with an amino group and a methoxy group;

R² represents a pyridyl, or a pyrimidinyl group, wherein each said pyridyl and pyrimidinyl, is substituted wi& an amino group of the formula -NHR¹³; R¹³ represents (CH₂),..,R²\ (CHOM-CH(OHH*²³, C(O)Il", (CH₂) _w-OR^aϊ, an optionally substituted 5-6 membered heterocyclic group, (CH2)j.3-NH.C(OHCll2)i-₃θR²³, or (CHa)i.j-NH- C(O)-R". where each R²³ is independently H or C₁-C₄ alkyl;

R³ represents a Cκi alkyl, t-butyl, cyclopropyl, i-propyl, Ci⁷ _J, or a phenyl group optionally substituted with halo; and

R⁴ represents H, or methyl,

8. A compound of Claims 1 , 2, 3, 4, 5, 6, or 7, selected from:

or a pharmaceutically acceptable salt thereof.

9. A compound of Formula H:

wherein Z¹ and Z² are each independently N, CH, or CD;

R³ is optionally substituted phenyl, or a Ci-C* hydrocarbyl group;

R⁶ is NHR¹*, where R^u is H or optionally substituted Cj-C₆ alkyl;

R⁷ Is H, D, halo, optionally substituted amino or optionally substituted C₁-C₄ alkoxy; and

R¹⁰ is NHR^1S, wherein R^1S is selected from the group consisting of optionally substituted CV Ce alkyl, optionally substituted heterocyclyl, -C(O)R²⁵, optionally substituted Cj-C₆ cycloalkyl, optionally substituted amino, optionally substituted aryl, and optionally substituted heteroaryl; R²⁵ is H or optionally substituted Ci-C₄ alkyl; or a pharmaceutically acceptable salt thereof.

10, A pharmaceutical composition comprising a compound of any one of claims 1 -9, admixed with at least one pharmaceutically acceptable exciptent.

1 1. The pliamiaceutical composition of claim 10, wherein the excipient is selected from Che 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, cellulose, ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium aluminum silicate, polyvinyl pyrrolidone, talc, calcium carbonate, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, agar-agar, sodium carbonate, croscarmeilose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, clays, sodium stearate, calcium stearate, magnesium stearate, stearic acid, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, sodium lauryl sulfate, hydrogenated vegetable

011. peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, soybean oii, zinc stearate, sodium oleate, ethyl olcate, ethyl laureate, silica, and combinations thereof.

12. The pharmaceutical composition of claim 1 1 , further comprising an additional therapeutic agent.

13. The pharmaceutical composition of claim 12, wherein the additional therapeutic agent is selected from an anticancer compound, an analgesic, an antiemetic, an antidepressant, and an antiinflammatory agent.

14. A compound according to any one of claims 1 -9 for treatment of cancer.

15. The compound according to claim 14, wherein the cancer to be treated is selected from the group consisting of lung carcinoma, pancreatic carcinoma, bladder carcinoma, colon carcinoma, myeloid disorders, prostate cancer, thyroid cancer, melanoma, and adenomas.

16. 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 -9 or a pharmaceutical composition of any one of claims 11-13.

17. The method of claim 16, wherein the cancer is selected from the group consisting of lung carcinoma, pancreatic carcinoma, bladder carcinoma, colon carcinoma, myeloid disorders, melanomas, and adenomas.

18. The method of claim 16 or 17, further comprising administering to the subject an additional therapeutic agent.

19. The method of claim 18, wherein the additional therapeutic agent comprises an anticancer drug_* a pain medication, an antiemetic, an antidepressant or an anti-inflammatory agent,

20. The method of claim 19, wherein the additionai therapeutic agent is a different Raf kinase inhibitor or an inhibitor of MEK, mTOR, PI3K, CDK9, PAK, Protein Kinase C, a MAP kinase, a MAPK Kinase, or BRK.

21. The method of claim 20, wherein the additional therapeutic agent is administered to the subject concurrently with the compound.

22. 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 -9, or a pharmaceutical composition according to any one of claims 10-15.

23. The method of claim 22 wherein the Raf kinase is a mutant b-Raf kinase.

24. The method of claim 23, wherein the mutant b-Raf kinase is b-Raf.